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Hereditary diffuse gastric cancer : cancer risk and the personal cost of preventive surgery Kaurah, Pardeep Kaur 2017

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HEREDITARY DIFFUSE GASTRIC CANCER: CANCER RISK AND THE PERSONAL COST OF PREVENTIVE SURGERY byPardeep Kaur KaurahMSc. McGill UniversityA THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OFDOCTOR OF PHILOSOPHY inTHE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES(Medical Genetics) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver)  December, 2016 © Pardeep Kaur Kaurah, 2016 iiAbstract Germline CDH1 mutation carriers are at risk for early-onset diffuse gastric cancer and female carriers have an additional risk of lobular breast cancer.  Reliable estimates of cancer risk are essential for genetic counselling and clinical management of mutation carriers. Prophylactic total gastrectomy (PTG) to eliminate the gastric cancer risk is an option for mutation carriers. Current information on post-surgical outcomes and quality of life is limited. The objectives of this research were 1) To improve the evidentiary basis of genetic counselling by deriving reliable estimates of cancer risk in CDH1 mutation carriers; 2) To catalogue a comprehensive list of all novel and previously reported germline mutations to date; and 3) To provide data on post-surgical clinical outcomes and to describe the impact of the surgery on participants’ quality of life. Methods: Penetrance was derived from 67 mutation-positive families comprising 4031individuals (350 affected with gastric cancer and 99 with breast cancer). Participants were recruited through multiple sources for clinical outcomes and quality of life study.  Hospital records provided information on clinical outcomes. All participants were asked to complete validated questionnaires measuring generic and condition specific QOL (PROMIS, EORTC and SF 36v.II) at a single point.  Results: By age 75 years, the cumulative incidence of gastric cancer was 70% (95% confidence interval [CI], 40%-94%) for males and 56% (95% CI, 27%-90%) for females.  The risk of breast cancer for females was 42% (95% CI, 23%-68%) by 75 years. The mutational landscape of CDH1 did not reveal mutational hotspots but several shared mutations are seen in unrelated families. The 53 participants who had undergone PTG reported frequent symptoms of fatigue (59%), abdominal pain (55%), and diarrhea (45%).  Cognitive, role and social function plus the symptoms anxiety, pain, taste, dyspnea and diarrhea were significant predictor variables for quality of life (p<0.05). Conclusions: Our more precise and robust iiipenetrance figures will improve genetic counselling of unaffected carriers. Although this study reveals good overall QOL for individuals after PTG, attention should be given to managing symptoms as part of long term care to further enhance quality of life.  ivPreface The results for Objectives 1 and 2 (Chapter 5) of this thesis were published as a manuscript in June 2014.  Hansford S*, Kaurah P*, Li-Chang H*, Woo M, Senz,J,, Pinheiro H, Schrader KA, Schaeffer DF, Shumansky K, Zogopoulos G, Santos TA, Claro I, Carvalho J, Nielsen C, Padilla S, Lum A, Talhouk A, Baker-Lange K, Richardson S, Lewis I, Lindor NM,  Pennell E, MacMillan A, Fernandez B, Keller G, Lynch H, Shah S, Guilford P, Gallinger S, Corso G, Roviello F, Caldas C, Oliveira C, Pharoah, P, Huntsman DG. “Hereditary Diffuse Gastric Cancer Syndrome: CDH1 Mutations and Beyond”. JAMA Oncol. 2015; 1(1):23-32. S.Hansford, H. Li-Chang and I co-wrote the manuscript and coordinated the edits with the co-authors. I collected all families (except the familial gastric cancer families) and pertinent documentation.  I performed all literature reviews for the mutation catalogue.  I collected and assembled the data for the penetrance study.  The penetrance analysis was performed by Dr. P. Pharaoh.   DG Huntsman conceived the study.2EMHFWLYHRIWKLVGLVVHUWDWLRQLVthe RULJLQDOUHVHDUFKRIWKHDXWKRU3DUGHHS.DXUDKApproval to study the families with clinically defined Hereditary Diffuse Gastric Cancer was sought through the 8QLYHUVLW\RI%ULWLVK&ROXPELD%ULWLVK&ROXPELD&DQFHU$JHQF\5HVHDUFK (WKLFV%RDUG8%&%&&$5(%>&HUWLILFDWHnumber: +@vTable of Contents Abstract ..........................................................................................................................................iiPreface ........................................................................................................................................... ivTable of Contents ........................................................................................................................vList of Tables .............................................................................................................................YLLiList of Figures...............................................................................................................................LxList of Abbreviations .................................................................................................................. x Chapter 1: Introduction ................................................................................................................1 1.1 Hereditary Diffuse Gastric Cancer: An Overview of the Syndrome and its Implications…………………………………………………………………………………………..1 1.2 Gastric Cancer................................................................................................................. 5  Incidence and Mortality Rates .................................................................................... 5 Incidence ....................................................................................................... 5 Mortality and Survival .................................................................................. 7  Histological Classification of Gastric Cancer............................................................. 9 Intestinal-type Gastric Cancer ..................................................................... 10 Diffuse Gastric Cancer ................................................................................ 11  Risk Factors for Gastric Cancer ................................................................................ 13 1.2.3 Genetics of Gastric Cancer ....................................................................................... 14 1.2.4 Quality of Life and Gastric Cancer ........................................................................... 15 Study Objectives ........................................................................................................... 16 Specific Aims of Objective 3. ............................................................................................... 17 1.4 Hypotheses.................................................................................................................... 17 1.5 Rationale for Study ....................................................................................................... 18 1.6 Definitions..................................................................................................................... 19 1.7 Assumptions Made in This Study................................................................................. 21 Chapter 2: Literature Review of Hereditary Diffuse Gastric Cancer ....................................22 2.1 Clinical Description of HDGC...................................................................................... 23 2.2 Genetics of HDGC........................................................................................................ 26  CDH1 ........................................................................................................................ 26 2.2.1 Other Genes Implicated in the HDGC Syndrome..................................................... 28 Penetrance ..................................................................................................................... 29 2.4 Genetic Counseling and Genetic Testing...................................................................... 30 2.5 Clinical Management Options for Diffuse Gastric Cancer Risk in Mutation Carriers. 32  Surveillance............................................................................................................... 33 2.5.1 Prophylactic Total Gastrectomy ............................................................................... 34 2.5.2 Post-surgical Complications and Symptoms .................................................... 37 Pregnancy after Prophylactic Total Gastrectomy ......................................................... 42YLChapter 3: Literature Review for Quality Of Life after Gastrectomy ...................................44 3.1 Overview....................................................................................................................... 44 3.2 Current Concepts of Quality of Life ............................................................................. 44 3.3 Wilson-Cleary Conceptual Framework ........................................................................ 53  Biological Functions ................................................................................................. 54 3.3.1 Symptoms ................................................................................................................. 56 3.3.2 Functional Status....................................................................................................... 58 3.3.3 General Health Perceptions....................................................................................... 61 3.3.4 Characteristics of the Individual ............................................................................... 62 3.3.5 Characteristics of the Environment........................................................................... 63 Instruments for Measuring Quality of Life................................................................... 65 3.5 Definition of QOL in This Study.................................................................................. 68 Chapter 4: Methodology..............................................................................................................70 4.1 Objective 1: Penetrance Analysis ................................................................................. 70 4.2 Objective 2: Catalogue of CDH1 Mutations in the Literature. ..................................... 73 4.3 Objective 3: To Describe the Post-operative Complications, Major Symptomatology and Quality of Life in CDH1 Mutation Carriers After PTG..................................................... 74  Study Design............................................................................................................. 74 4.3.1 Study Sample ............................................................................................................ 75 4.3.2 Subject Selection Criteria for Participants ........................................................ 75 Accrual of Subjects ........................................................................................... 75 Participant Contact............................................................................................ 76 Newfoundland Cohort....................................................................................... 77 Instruments/Data Collection Tools (Independent variables) .................................... 78 4.3.3 Characteristics of the Individual ....................................................................... 78 Characteristics of the Environment................................................................... 78 Biological Factors ............................................................................................. 78 Post-gastrectomy Symptom Status - Instruments ............................................. 79 Functional Status/Condition Specific QOL ...................................................... 83 Human Subjects Protection........................................................................................... 85 4.5 Data Analyses for Objective 3 ...................................................................................... 86  Data Analyses for the Specific Aims: ....................................................................... 87 4.5.1Chapter 5: Results........................................................................................................................96 5.1 To Derive Reliable Estimates of Cancer Risk for CDH1 Mutation Carriers................ 96 5.2 CDH1 Germline Mutation Landscape in HDGC.......................................................... 98 5.3 Objective 3: Post-operative Complications, Major Symptomatology and Quality of    Life after PTG. ........................................................................................................................ 112  Sample Summary.................................................................................................... 112 5.3.1 Participants from British Columbia ................................................................ 112 Participants from Other Canadian Provinces .................................................. 112 Participants from Centers outside Canada ...................................................... 113 Patient Demographics (Characteristics of the Individual and Environment). ........ 113 5.3.2 Post-surgical Clinical Outcomes and Complications after PTG............................. 116 5.3.3 Immediate Post-operative Clinical Outcomes ................................................ 116 Complications ................................................................................................. 116 Weight Loss and Body Mass Index (BMI). .................................................... 118 Patient Reported Symptoms, Frequency and Intensity in Individuals after PTG. .. 119 Early Dumping Syndrome Symptoms (Clinical Questionnaire) ............... ......119 Late Dumping Syndrome Symptoms ........................................................ 122 Function scales and symptoms (EORTC C30 and STO22) ........................124 5.3.4. Anxiety............................................................................................................ 128 Depression....................................................................................................... 128 5.3.4.  Patient Satisfaction with Surgery and Involvement with Decision-Making........... 129 5.3.5 Satisfaction with Prophylactic Total Gastrectomy ......................................... 129 Involvement in the Decision to Have Prophylactic Total Gastrectomy ......... 130 Advice to Get the Surgery............................................................................... 131 Support after the Surgery ................................................................................ 131 Cancer Worry.................................................................................................. 132 Quality of Life in Individuals after PTG..................................................................... 133 Predictors of QOL after PTG.......................................................................... 133 5.4.1. Chapter 6: Discussion and Conclusions...................................................................................138 6.1 Penetrance in CDH1 Mutation Carriers ...................................................................... 138 6.2 CDH1 Mutation Spectrum. ......................................................................................... 140 6.3 Quality of Life............................................................................................................. 141 6.4 Contribution of this Research to Clinical Practice...................................................... 153 6.5 Limitations and Opportunities of the Study................................................................ 156 6.6 Conclusions................................................................................................................. 158 6.7 Future Directions ........................................................................................................ 159 Bibliography ...............................................................................................................................163 Appendices ..................................................................................................................................187 YLLiList of Tables Table 2.1 A literature summary of cases/families and their post-surgical outcomes after PTG. . 40 Table 2.2 :  Incidence of known common micronutrient deficiencies occurring after total gastrectomy and the conditions caused........................................................................................ 41Table 4.1 Dummy coding for nominal variables gender and marital status……………………..94 Table 5.1 Cumulative risks of GC and BC in CDH1 mutation carriers of both sexes .................97 Table 5.2 CDH1 mutations described in this study and  in the literature. .................................. 102 Table 5.3 Demographic Characteristics of Study Participants (N=53)....................................... 115 Table 5.4 A summary of the postsurgical complications within the first year ........................... 117 Table 5.5 A summary of BMI before surgery and at the time of surgery ................................... 119 Table 5.6 Summary of early dumping syndrome symptoms, frequency and severity……… ...  121 Table 5.7 Summary of late dumping symptoms, frequency and patient-reported severity. ....... 123Table 5.8 Summary of functional scales and symptoms from EORTC instruments…………. .124Table 5.9 Satisfaction measured in participants ......................................................................... 130 Table 5.10a Summary of analysis results of full model.............................................................. 134 Table 5.10b Summary of analysis of results of reduced model.................................................. 136Table 6.1  Group means of this study population, Worster study cohort and general population reference values………………………………………………………………………………...149LxList of Figures Figure 1.1. A bar chart showing the estimated worldwide age-standardized rates of gastric cancer per 100,000 for both sexes.   ................................................................................................ 6Figure 1.2. Photomicrograph of diffuse gastric cancer ................................................................. 12Figure 2.1 Two representative HDGC families with germline CDH1 mutation………………....23 Figure 2.3 Total gastrectomy with Roux-enY reconstruction…………………………………....36Figure 3.1 The Wilson Cleary model ............................................................................................ 49Figure 3.2 The Wilson Cleary model with study variables inserted into each level. ................... 69Figure 5.1 Cumulative risk of gastric and breast cancer for CDH1 mutation carriers by sex…………………………………………………………………………………………...…....98 Figure 5.2 Mapping of germline CDH1 mutations described to date by mutation-type and location on CDH1-transcript ………………………..………………………………..................100Figure 5.3 Bar chart comparing the means of functional scales from the EORTC C30 in the  3 time elapsed groups……………………………………………………………………….......125 Figure 5. 4 Bar chart comparing EORTC C30 symptoms between the 3 time elapsed grou.…..126 Figure 5. 5 Bar chart comparing means of STO 22 symptoms between the 3 time elapsed groups……………………………………………………………………………………….…...127xList of Abbreviations APC Adenomatosis polyposis coliATM Ataxia Telangiectasia-MutatedBC Breast cancerBCCA British Columbia Cancer Agency BMI Body mass index (weight (kg) / (length (m) *length (m)) BRCA2 Breast cancer 2, early onset CDH1 cadherin 1, type 1, E-cadherin c-HDGC clinically defined hereditary diffuse gastric cancer CTNNA1 Catennin, Alpha-1CI Confidence IntervalDGC Diffuse gastric cancer EMBASE Excerpta Medica EORTC European Organisation for Research and Treatment of Cancer FAP Familial adenomatous polyposis GI Gastrointestinal tract H pylori Helicobacter pylori HDGC Hereditary diffuse gastric cancer  GC Gastric cancer IGC Intestinal gastric cancer IGCLC International Gastric Cancer Linkage Consortium LBC Lobular breast cancer MAP3K6 Mitogen Activated Protein Kinase 6 NIH National Institute of Health OMIM Online Mendelian Inheritance in Man PALB2 partner and localizer of BRCA2 PROMIS Patient Records and Outcome Management Information System PTG Prophylactic total gastrectomy QOL Quality of life SD Standard deviation SF-36 Medical Outcomes Study 36-Item Short-Form Health Survey TG Total gastrectomy xiv Acknowledgements I would like to express my gratitude to my supervisor, Dr. David Huntsman whose immense knowledge in so many areas contributed to my research.  His motivation, guidance, encouragement and patience benefited my overall experience as a graduate student.  I could not have hoped for a better advisor and mentor for my PhD. I would also like to thank my advisory committee members, Dr. Jan Friedman, Dr. Barbara McGillivray, Dr. Joan Bottorff and Dr. Rick Sawatzky for all the encouragement and insightful comments they provided at all levels of this research.  Many thanks also go out to Dr. Aline Talhouk who provided me with expert statistical advice at times of critical need. A special thank you to all the participants who volunteered for this study as without them this research would not be possible.  xvDedication To my family without whose unwavering love, support and encouragement, I wouldnot have completed this research and who carried me through until the end of P\thesis.1Chapter 1: Introduction 1.1 Hereditary Diffuse Gastric Cancer: An Overview of the Syndrome and its Implications The first documented case of gastric cancer was found in the Ebers papyrus, written in 1600 BC [1].  Since that time, reports by Hippocrates and Galen have emerged that document the gross pathology of gastric cancer.  However, it was not until the late 1800s that the French surgeon Jules Emile Pean started the modern history of gastric cancer by performing the first gastric cancer surgery [2].  Approximately 10% of all gastric cancers arise in individuals who have a significant family history of the disease [3, 4] due to commonly shared environmental factors such as diet and Helicobacter pylori (H. pylori) infection. About 1-3% of cases are attributable to germline mutations in highly penetrant cancer susceptibility genes [5]. This thesis will focus on the Hereditary Diffuse Gastric Cancer syndrome.  Clinically defined hereditary diffuse gastric cancer (c-HDGC) [OMIM #137215] is characterized by early-onset, multi-generational diffuse gastric cancer (DGC) and lobular breast cancer (LBC). Approximately 40% of HDGC families have germline mutations in the CDH1 gene (E-cadherin) [ENSG00000039068; OMIM *192090].  Since its implication in HDGC, there have been over 100 different pathogenic germline mutations reported across multiple ethnicities [6]. Currently used cumulative lifetime GC risks in CDH1 mutation carriers are derived from a small number of families: eleven families were included in one study and four families sharing a founder mutation in another, with predicted DGC risks ranging from 40-67% and 63-83% in male and 2female carriers, respectively [7, 8]. Female carriers also have an increased risk of breast cancer (BC) ranging between 39-52% [7, 8], lobular breast cancer (LBC) being most characteristic.  Once the specific genetic basis for a cancer predisposition syndrome is identified, genetic testing becomes available to family members who are at risk.  Identifying individuals who have an increased risk of developing gastric cancer allows for cancer prevention strategies to be put into place.  These may include prophylactic total gastrectomy, a surgery that prevents invasive gastric cancer by surgical removal of the at-risk tissue.   Diffuse gastric cancer is difficult to detect by current screening modalities.  Total gastrectomy (TG) is considered the treatment of choice for patients with a germline mutation of the CDH1gene.  This surgery is effective in preventing DGC but is associated with long-term complications, making functional status and quality of life important factors in describing patient outcomes. There have been several studies on the short and long-term functional outcomes after PTG in asymptomatic carriers [9, 10, 11, 12, 13, 14].  Apart from the 23 patients reported by Hebbard and colleagues [13], the rest of these studies are based either on single cases or a small number of case reports, generally on individuals within one or two families.  There is currently only one study reporting health-related quality of life in CDH1 germline mutation carriers after PTG [15] . Although several reports in the literature support PTG for CDH1 germline mutation carriers as an acceptable treatment recommendation for HDGC, there are no large studies documenting the inherent risks that may be associated with the surgery. Not much is known about the best surgery 3type (open versus laparoscopy), reconstruction methods (pouch formation versus no pouch), post-surgical clinical outcomes and especially the psychosocial burdens in this group of individuals. Currently, information provided to germline mutation carriers considering PTG onpost-surgical complications is derived either from data collected on this small number of studies, or on anecdotal evidence from individuals who have undergone prophylactic total gastrectomy (PTG) or total gastrectomy for gastric cancer (GC).  The problem with extrapolating outcomes from patients diagnosed with GC is that the health of this group is already compromised at the time of surgery due to the cancer.  In contrast, most of the individuals undergoing PTG are younger and healthier.  Both the available case reports and anecdotal evidence suggests that individuals undergoing PTG tend to have less severe clinical complications than individuals undergoing TG for GC.   Prior to the start of this study, we were aware of over 120 individuals who had had PTG in North America, but we did not have information on how these individuals were faring post-surgically. In speaking with some of the individuals who had undergone PTG, as a genetic counsellor Iheard that their biggest concerns were the length and intensity of the clinical post -surgical complications that they were experiencing, challenges in changes in their diet and their functional status including their physical, social and psychological well-being.  Interestingly, these were also concerns often raised by those who were contemplating the surgery.  These sentiments were frequently echoed in counseling sessions as well as in an online chat group for CDH1 germline mutation carriers (nostomachforcancer.org). 4Therefore, there was a need for a more comprehensive study to describe the type and frequency of post-surgical complications, and the physical, social and psychological well-being inindividuals who have undergone PTG.  The lack of knowledge regarding these issues was impeding the development of evidence-based clinical management of these individuals’ post- surgery.  This study has endeavored to rectify these deficits observed in clinical counselling, and in so doing contribute to the evidence base used to guide decision-making for PTG patients and their clinical management after surgery.  Understanding the characteristics or conditions that predict subsequent quality of life may help clinicians identify patients who may be at increased risk of adverse psychosocial problems. The need for more information is probably best summarized by a direct quote from a patient: I’m recalling the time before my TG, when I was still in the investigation stage. What should I expect? How will my life change following TG? Will I still be able to…(fill in the blank). Hike? Play racquetball? Enjoy my wine? Lattes? Forget about that – what will happen to my quality of life? Will I be tethered to the nearest bathroom?  Will I feel good, like I do now?  Or will I become sickly and fragile?  Will I regret having surgery?  Will I regret not having surgery?  Will I still have a life? I was scared. Seriously scared. Frankly, the things I was reading were not very encouraging. I got lucky though. I found, or in some instances was found by, some very special people who had been down this road before me. They had words of support and encouragement to share. “I’m doing really well…don’t worry, you’ll adjust too…it’ll be ok…you’ll find a “new normal…51.2 Gastric Cancer 1.2.1 Incidence and Mortality Rates IncidenceThe worldwide incidence of gastric cancer has been falling steadily since the 1970s with the phenomenon being most noticeable in developed countries. [16, 17, 18].  Despite this downward trend, gastric cancer still ranks as the fifth most common type of cancer worldwide behind lung, breast, colorectal and prostate cancers [19].  It is the third leading cause of cancer death in both men and women [19]. The incidence of GC varies considerably according to age, gender, socio-economic conditions and geographical location [19, 20]. In North America, and Northern and Western Europe it hasbecome a relatively rare cancer [21].  It is ranked as the 14th most frequent cancer in Canada withan incidence of 7.5 per 100,000 men and women per year (3300 new cases in 2013). The numberof deaths was 3.5 per 100,000 for both sexes per year. These rates are age-adjusted and based on 2007-2011 cases and deaths.  About half of all GC cases in the world occur in East Asian countries, particularly in Japan, Korea and China. The incidence is also high in Eastern Europe and parts of Central and South America. It is low in Southern Asia, North and East Africa, Western and Northern Europe, North America and Australia (Figure 1) [22]. Figure 1 shows the worldwide incidence of gastric cancer in both males and females. The incidence is twice as high in men as in women [23]. 6Figure 1.1.  A bar chart showing the estimated worldwide age-standardized rates of gastric cancer per 100,000 for both sexes.  Image taken from GLOBOCAN 2012 (IARC), Section of Cancer Surveillance.  (http://globocan.iarc.fr/old/FactSheets/cancers/stomach-new.asp) [24].The x-axis denotes the numbers of individuals in thousands. This wide geographical variation may be related to a variety of reasons that include global differences in life-style factors such as smoking [25, 26] and diet [26, 27] and socio-economic 7conditions [28].  Although nearly two thirds of the cases of this cancer occur in developing countries, it cannot readily be categorized as a disease of less developed economies as some of the highest risk populations are in developed Asian countries such as Japan and Korea. The biggest contributor is believed to be the prevalence of Helicobacter pylori in developing countries; H. pylori infection alone accounts for more than 60% of gastric cancer worldwide [17, 29].The overall incidence for gastric cancer has undergone a steady general decline during the past decades [18, 30].  This downward trend is observed in both the sexes and in both high- and low-risk areas, although it is more pronounced in developed countries [21, 30]. The fall in the incidence is particularly associated with non-cardia gastric carcinoma [30, 31], in contrast, cardia cancer that seems to be experiencing a slight increase [32, 33]. Similarly, epidemiological studies have shown that the general decrease in the incidence of gastric cancer is mainly attributable to the fall in the incidence of the intestinal subtype of gastric cancer, while the diffuse subtype shows little change [34]. The general decline in its incidence may be explained by refrigeration, better food preservation, lifestyle changes and an improvement in environmental conditions, primarily in the eradication of the bacteria Helicobacter pylori. Mortality and Survival A recent updated analysis of the mortality patterns and trends of gastric cancer confirm thesteady decline in gastric cancer mortality [35].  Despite this trend, gastric cancer is still the third leading cause of cancer death worldwide, accounting for almost 9% of total cancer deaths in 82012.  As with its incidence, there is a wide geographical variation in the mortality rate, with the highest rates being in the developing world.  The highest estimated mortality rates are in Eastern Asia (24 per 100,000 in men and 9.8 per 100,000 for women) and the lowest are in North America (2.8 per 100,000 for men and 1.5 per 100,000 in women) (http://globocan.iarc.fr/). A study of gastric cancer mortality in major European countries between the years 1980 to 2011 demonstrated an annual percent change in mortality rate of -3.7% in men and -3.4% in women[20]. The annual percent change rates were larger for Japan (-15%) and Korea (-26%).  The rates in North America were similar to previous years. In Latin America, the decline was less marked, but constant.Although the mortality for GC is still high at 8.8% of the total number of cancer cases (approximately 723,000 cases in 2012), the relative survival is improving worldwide, especially in areas where the prevalence is high [36].  This could be ascribed to earlier diagnosis of the disease through screening protocols in high prevalence countries (especially Japan and South Korea), and improvement in diagnostic methods as well as in improvement in treatment. Prognosis is dependent on tumour extent [37, 38] and tumour grade at the time of diagnosis [38][39].The percentage of patients who are alive five years after their diagnosis (the five-year survival rate) of GC is less than 30% in most countries although there is a large geographical variation,[36].  In Japan, the five-year survival rates of GC have improved since the implementation of a mass screening program using photofluorography in 1960 [40] .  This practice was implemented due to the high incidence of the intestinal gastric cancer (IGC) type disease in the population.  9The success of this screening in detection of early, asymptomatic disease has led to a reduction of the mortality rate by more than 50% since the 1970s [41]. The five-year survival rate in Japan is about 60% for all stages of the disease [42].In contrast, in Western countries, gastric cancer is often diagnosed at an advanced stage and prognosis remains poor.  This is primarily due to the case-finding approach in these countries because of the low incidence of the disease.  The five-year survival for all GC patients in Western Europe is 24.1% [43] and 26.5% in North America [44]. Prognosis depends on the stage at which it is detected (ranging from 71% at Stage 1a to 4% at stage 4) (National Cancer Institute’s SEER database, accessed February 2013), and complete removal of the cancer is the only curative option.  The importance of detecting GC at early stages (stage 1) is underlined by the five-year survival rate of 70- 90% in Western countries and Japan respectively [45]. While earlier diagnosis would help to improve outcomes for patients with GC, a better understanding of the biology of the disease is also needed, along with advances in therapy.Histological Classification of Gastric Cancer 1.2.2The pathology of gastric cancer is heterogeneous with respect to both its anatomical location and its histological subtypes. The majority (90%) of gastric cancers are adenocarcinomas or malignant epithelial neoplasms.   There are several classification systems that are used to aid in the description of GC on the basis of either the macroscopic or histological features.  The common ones cited in the literature include the Borrmann classification [46], Ming [47] and 10  Lauren [48], World Health Organization (WHO) [49], and the Japanese system [50].  Of these, the Lauren and WHO systems are the most utilized by pathologists.  The World Health Organization (WHO) classification of gastric cancer consists of four major types: papillary adenocarcinoma, tubular adenocarcinoma, mucinous adenocarcinoma poorly cohesive carcinoma (with or without signet ring cells) and mixed or uncommon histologic variants [51].  However, the most commonly used classification system for gastric adenocarcinomas is by Lauren [48] who divided them into two major (90%) histological variants: 1) gland-forming or intestinal-type gastric cancer (IGC) and 2) diffuse gastric cancer (DGC).  These variants have distinct morphologic appearances, molecular pathogenesis and genetic profiles.  They also tend to occur in distinctive epidemiological settings [52]. The remaining 10% are classified as mixed type, that is, they have components of both the diffuse and intestinal-types of gastric cancer [48]. Intestinal-type Gastric Cancer Intestinal-type gastric carcinoma (IGC) is the more common of the two types described by Lauren [48]. Intestinal-type adenocarcinomas are well-differentiated, that is, the cohesive carcinoma cells are arranged in tubular or glandular structures with an expanding or infiltrative growth pattern [53]. Intestinal-type gastric carcinomas are associated with a premalignant gastric change like Helicobacter pylori-associated atrophic chronic gastritis.  This is followed by intestinal metaplasia, which is thought to be a precursor of the dysplastic changes that evolve 11  into carcinoma [54]. IGC forms the typical exophytic tumour ulcerating the stomach lining making it amenable to endoscopic screening.     The intestinal-type of gastric carcinoma tends to occur more frequently in high-risk countries, is more common in men, and increases significantly in incidence with age [55]. IGC tends to be sporadic and is related to environmental factors that include the presence of Helicobacter pylori, diet (for example salted meat and fish), alcohol use and cigarette smoking. Diffuse Gastric Cancer Diffuse gastric cancers are poorly differentiated tumours composed of cells that infiltrate the wall of the stomach as single cells or in small groups (Figure 1.2).  In DGC, loss of the E-cadherin protein causes the individual tumour cells to grow and invade neighbouring structures. A malignant infiltrate containing cells with a large globule of intracellular mucin and an eccentric nucleus permeates the wall of the stomach, often spreading under histologically normal mucosa leading to the widespread thickening and rigidity of the gastric wall, known as linitis plastica [56] or “leather bottle appearance”.  Unlike the intestinal-type, the DGC tumour very rarely forms a solid mass but even when there is one, the cells appear to have little cohesiveness and do not form epithelial cords [48].  Unlike the IGC type, DGC usually arises in the absence of atrophic gastritis [55], especially when there is a germline mutation in the CDH1 gene [57].  Unlike IGC, the diffuse type GC does not show marked geographic variation. It also has a worse prognosis than the intestinal-type, with its early invasion into the muscularis propria and the lymphatic vessels with frequent metastases to the lymph nodes. DGC also often occurs in 12  younger patients with a positive family history. This latter cohort of patients tends to have a primary genetic etiology, a subset of which has a genetic syndrome known as Hereditary Diffuse Gastric Cancer (HDGC) [58].  In addition to the distinct morphologic, clinical, and epidemiologic features, IGC and DGC each have a different molecular mechanism of tumor development and progression [59].  Figure 1.2. Photomicrograph of diffuse gastric cancer showing the characteristic signet ring cells in diffuse gastric cancer. The neoplastic cells have a distinctive signet ring appearance (red arrows) caused by an accumulation of intracellular mucin that pushes the nucleus to one side. Slide from D Huntsman laboratory stained with hematoxylin and eosin.      13   Risk Factors for Gastric Cancer 1.2.3Environmental factors are believed to be more important than genetics in the development of the intestinal-type of gastric cancer than genetics.  The most important environmental factors implicated in gastric carcinogenesis are diet and Helicobacter pylori (H. pylori) infection [60]. H. pylori is a spiral-shaped bacterium that grows in the mucus layer coating the inside of the human stomach.  It is estimated that approximately two-thirds of the world's population is infected with this bacterium with the highest rates being in the developing countries [61].   The infection is generally acquired during childhood and persists unless eradicated by antibiotic use [62]. Although most individuals infected with H. pylori are asymptomatic, it is a major risk factor for peptic ulceration, distal gastric adenocarcinoma and gastric mucosa-associated lymphoid tissue (MALT) lymphoma [63].  Only 1-5% of individuals with the bacteria actually develop GC and the pathogenesis is dependent on bacterial strain virulence, host genetic susceptibility and environmental factors [64]. In 1994 the International Agency for Research on Cancer classified H. pylori as a human carcinogen due to its association with GC [65].   Dietary factors show a consistent association with the development of GC, especially in the intestinal-type [36].  There are several studies showing that there is a positive association between an excessive intake of salt and salted foods such as smoked and cured meat and fish and pickled vegetables [66, 67]. The decline of intestinal-type GC in certain countries where consumption of this food was high may be explained by the replacement of salting by refrigerators for food preservation [68].   14  High consumption of meat [69], refined carbohydrates, saturated fats and cholesterol has also been associated with a significant increase in intestinal-type GC [70].  Fruit and vegetable consumption appears to have an inverse relationship with GC risk [71, 72].  It is thought that the inverse correlation between GC risk and intake of fresh fruit and vegetables is due to the consequence of the anti-oxidant properties of micronutrients present in these foods.  This hypothesis is supported by a study demonstrating regression of cancer precursor lesions with dietary supplementation with anti-oxidant micronutrients in a GC high-risk population. [73].   The large influence of environmental factors is reflected in the decrease risk of GC in second-generation populations that move from a higher incidence to lower incidence area [74]    Genetics of Gastric Cancer  1.2.4Most gastric cancer cases tend to be sporadic and occur as a result of a complex relationship between environmental and/or life-style factors and low susceptibility genes [75].   Gastric adenocarcinoma has been classified into four tumour subtypes based on 25 frequently mutated genes by The Cancer Genome Atlas: 1) tumours positive for Epstein Barr virus 2) microsatellite stable; 3) genomically stable tumours (diffuse subtype make up the majority); and 4) chromosomally unstable tumours as an adjunct to histopathology [76].  Gastric cancer is a molecularly heterogeneous disease with a diverse array of genetic influences that include functional single nucleotide variants [77, 78], chromosomal instability [79], microsatellite instability [80], promoter methylation [81], and abnormal microRNA expression [82].    15  There is familial clustering of gastric cancer but this happens in less than 15% of all cases and most of these do not have a cancer gene germline mutation [4].  Familial clustering can be due to non-hereditary factors but also due to the environment/gene interaction.  It is believed that only 1-3% of GC cases are associated with high penetrance inherited genetic factors [5] .     There is an increased risk of both IGC and DGC in several well-known  cancer predisposition syndromes including Lynch syndrome [83], familial adenomatous polyposis [84], [85], juvenile polyposis syndrome [86] [87], Peutz-Jeghers syndrome [88], Li-Fraumeni syndrome [89], Cowden syndrome [90] and hereditary breast and ovarian cancer syndrome [91].  The life-time risk of GC varies in each of these syndromes but is generally low.     The most frequently observed gastric cancer syndrome is hereditary diffuse gastric cancer syndrome (HDGC).   Families with this syndrome have an increased risk of developing both diffuse gastric cancer and lobular breast cancer [92].   Hereditary diffuse gastric cancer is an autosomal dominant cancer predisposition syndrome and is caused by germline mutations in the CDH1 gene [58].  There is further discussion of HDGC and CDH1 in Chapter 2.    Quality of Life and Gastric Cancer 1.2.5As more CDH1 mutation carriers opt to have PTG world-wide, it is important for patients and physicians to understand the long-term psychosocial consequences that patients may experience so as to aid in decision making.  In addition to these outcomes, overall patient satisfaction with surgery is an important outcome to measure because it may give some measure of reassurance to those individuals seeking PTG.   16   Removing the stomach completely, as is done in TG, means that there will be problems related not only to a complete loss of a food reservoir but also vitamin and mineral deficiency that could lead to deterioration in QOL [92] .     1.3 Study Objectives There were 3 main objectives for this study.  The first objective of this study was to derive reliable estimates of cancer risk for CDH1 mutation carriers based on a collated analysis of cohorts, including previously published families [93, 94, 7, 8, 95, 96], mutation positive families from our most recent study [6], and previously unpublished families. The findings from this study provided a reliable assessment of risk and represent the largest series of CDH1-mutation carriers studied to date.   The second objective was to catalog a comprehensive list of all reported germline mutations in the literature to date.  These included the mutations recently found in our laboratory.  The third objective of this study was to describe the post-operative complications, major symptomatology, quality of life in CDH1 mutation carriers and to examine the variables which may affect the overall quality of life after PTG. A retrospective study was conducted with a group of individuals who had already undergone PTG. The ideal study design would have included a prospective cohort.  However, due to the small number of individuals undergoing PTG, difficulty recruiting participants and no central registry that collects the data on these 17  individuals in most countries, including Canada or the United States, a prospective study was not possible.    Specific Aims of Objective 3   The third objective was broken down into the following aims:  1. Document and describe, through survey instruments, the current satisfaction with decision to have surgery, anxiety and depression in individuals after PTG.  2. Document and describe, through a medical chart review, the post-surgical clinical outcomes in individuals during the first 12 months after PTG.  3. To document and describe, through survey instruments, post-gastrectomy symptoms, their frequency and their intensity in individuals after PTG.   4. Document and describe the quality of life in individuals after PTG. 4.2 Question 1: Do characteristics of the individual and environment and symptoms affect the quality of life in persons after PTG?   4.3 Question 2: Do characteristics of the individual and environment, symptoms and functional status affect the quality of life in individuals after PTG?  1.4 Hypotheses Objectives 1 and 2:  Ascertainment of more families with CDH1 germline mutations will improve the penetrance figures for cancer risks in carriers. Objective 3: The quality of life in individuals who have undergone PTG improve over time and the symptoms decrease in frequency and intensity over time.   18  1.5 Rationale for Study I first began working on the study of HDGC in January 2002 when the study was still in its infancy.  We began collecting families that fit the criteria for clinically defined HDGC [92] (discussed in section 2.1).  The study essentially began as a research endeavour to study the genetic factors involved in hereditary gastric cancer and began with looking for CDH1 germline mutations in families that had clinically defined HDGC.  Apart from genetic counselling of these families, my role also included the ascertainment of families that fulfilled the criteria for HDGC.  I coordinated the collection of pedigrees, medical information, blood and tissue samples on all affected individuals in the family.  I was also involved in varying degrees with analysis of genetic and penetrance results in these families.   Over the years, I have been involved, in varying capacity, in the care of the many germline mutation carriers from these families.  Experiences with working with families with clinically defined HDGC underscores the need to gain accurate estimates of the gastric and breast cancer risks in CDH1-mutation carriers.  These more reliable estimates of cancer risk and spectrum in germline mutation carriers are essential for clinical management of mutation carriers.  In addition, with the number of reports describing mutations in individual or small numbers of families in the literature increasing, it is important to catalog these for better understanding of the types of mutations, presence of possible hotspots in the gene and possible genotype-phenotype correlations.  I have had many discussions with individuals from families where there has been no history of gastric cancer but a CDH1 mutation is found in an individual who had lobular breast cancer.  The main concern for these individuals and the family members at risk was whether they are at the same risk of developing diffuse gastric cancer as carriers in clinically 19  defined HDGC families.  In speaking to these families, I know that the emotional impact of the diagnosis of HDGC cannot be underestimated and it can a huge (sometimes very negative) impact on family members, forcing them to make difficult decisions about their future.   Furthermore, not enough is known about the post-operative complications and major symptomatology and their relationship to the individuals’ quality of life following prophylactic gastrectomy.  We do not know which postoperative symptoms are transient or persistent.  We are also unaware to what extent any clinical features influence a patient’s QOL after the surgery. If health professionals are going to recommend the surgery, then we need to be able to provide evidence-based information about surgical outcomes and potential QOL to patients.  Most carriers I have spoken to regarding PTG have concerns about their lives after PTG and how they will be affected.    1.6 Definitions The following terms are defined for the purpose of this study: 1. CDH1 mutation carrier:  an individual who carries a germline mutation in the CDH1 gene and has been diagnosed through a genetic test 2. Prophylactic total gastrectomy: A complex surgical procedure performed to remove the entire stomach, all the gastric epithelia, the perigastric lymph nodes and those along the feeding vessels (also known as a D-2 node dissection).  The removal is followed by a reconstruction of the digestive transit using the Roux-en-y esophagojejunostomy.  3. Overall quality of life or quality of life: A composite assessment of an individual’s physical and emotional health that stems from satisfaction or dissatisfaction with the other areas of life 20  that are important to him/ her [97]. In this study, overall quality of life was operationalized as the scores on the general European Organisation for Research and Treatment of Cancer (EORTC-C30) questionnaire for cancer patients [98] and the site-specific stomach module (STO22) [99].   4. Biological function:  the molecular, cellular, and organ processes that support life [100].  In this study, biological function was measured by post-surgical complications and body mass index of the participant.  5. Symptoms: A person’s perception of an abnormal physical, emotional, or cognitive state [97, 100].  For this study, symptoms were measured in 2 separate ways: (a) the patient-reported outcomes on the demographic questionnaire and (b) the scores on the Patient Reported Outcome Measurement System (PROMIS) [101] depression and anxiety scales and the EORTC STO22 questionnaire. 6. Functional status: The ability to perform tasks of daily living, within the 4 major domains of physical, role, psychological and social.  In this study, functional status was measured using 2 instruments, the Medical Outcomes Study (MOS) Short-Form Health Survey (SF-36) version2 [102]and the EORTC C-30. 7. General Health Perceptions: An overall perception of wellness that is individualized and subjective. For this study, general health perceptions was operationalized as the score Medical Outcomes Study Short Form-36 (MOS SF-36). 8. Characteristics of the individual: The demographic, biological, developmental, and psychological, factors that influence health outcomes [97].  In this study characteristics of the individual included (a) age of the participant in years (b) sex (male or female), (c) ethnicity and (d) education level (high school, some college, associate degree, Bachelor’s degree, Masters, Doctoral, Professional Degree) 21  9. Characteristics of the environment: The physical or social factors in a person’s life which can influence their health. For this study, characteristics of the environment included (a) self-reported marital status (now married (including common-law), widowed, divorced/separated, never married), (b) self-reported employment status (working outside the home, homemaker, retired, student, unable to work) and (c) time-lapsed between surgery and survey in months.  1.7 Assumptions Made in This Study The first assumption for this study is that all data obtained from medical records was accurate.  The second assumption is that symptom burden and health status can actually be quantified through existing instruments and can be statistically analyzed.  Third assumption is that the participants answer the questions honestly.  Finally, an important assumption is that quality of life is a multi-dimensional construct.   22  Chapter 2: Literature Review of Hereditary Diffuse Gastric Cancer In 1964, Jones [103] reported a 98 member Maori kindred in which 28 individuals were affected with GC at young ages and over three generations.  These red flags indicated that the cancer was being inherited in an autosomal dominant manner.  Thirty- five years later, the molecular basis underlying the familial clustering of DGC was identified by Guilford and colleagues [58]. The group analyzed the family reported by Jones as well as 2 other Maori families using linkage and candidate gene analysis.  They reported the association of an increased risk of diffuse gastric cancer in individuals who had germline mutations in the CDH1 gene, located on chromosome 16q22.1.  This new cancer predisposition syndrome was termed Hereditary Diffuse Gastric Cancer (HDGC) [OMIM #137215].  Hereditary diffuse gastric cancer syndrome is characterized by multigenerational DGC and LBC.  Over 100 CDH1 germline pathogenic mutations have now been reported across multiple ethnicities, with segregation analyses providing further proof that these abnormalities play a direct role in DGC susceptibility [6].  Clinical and basic research on HDGC has been carried out since 1998 by an ever-growing group of multidisciplinary clinicians and researchers worldwide [92].  This group, named the International Gastric Cancer Linkage Consortium (IGCLC), has been playing a crucial role in clinical and basic research of HDGC and at periodic intervals provides the consensus guidelines for defining the syndrome, genetic testing criteria and clinical management as more information becomes clearer about the syndrome [92, 104]    23  2.1 Clinical Description of HDGC The average age of onset of HDGC is 38 years, with a wide range between 14 to 82 years [58] [7].  The age of onset is also variable both between and within families [7, 58, 105].  Figure 2.1 shows two representative families with HDGC.  Figure 2.1 Two representative HDGC families with germline CDH1 mutation. Squares are males and circles are females. Icons with a strike through them represent a deceased individual. Yellow quarter circle represents GC diagnosis; blue quarter circle represents breast cancer diagnosis. Teal quarter circle represents those who have had a PTG.  Numbers below each icon represent the age at death.  Numbers after gastric/breast represent age at diagnosis of the cancer.     24     As with sporadic DGC, symptoms are nonspecific in the early stages of the disease, mimicking those of mild indigestion [106].  By the time symptoms such as excessive weight loss and melena appear, most affected individuals are in an advanced stage of the disease. Mortality rate in Stage I or 2, is approximately 10-20%, increasing to 90% in Stage 3 and 4.  Lymph node metastasis, depth of invasion, and tumour invasion to adjacent organs are all believed to be independent prognostic factors for gastric carcinoma [107]. In tumours that have not gone beyond the mucosa (early GC), the rates of lymph node invasion are low, ranging from 0 to 20.3% (mean 3.2%).  However, if the cancer is found in the submucosa, the rate of lymph invasion is higher, ranging between10.2% to 33.3% (mean 19.2%) [108]. Diagnosing diffuse 25  gastric carcinoma by endoscopy is very difficult because the cancer cells do not form a visible mass, but rather spread under the surface of the stomach as single cells or clustered islands of cells.   In addition to DGC, lobular breast cancer is also seen in families with clinically defined HDGC [7, 109, 110].  The average age of onset for breast cancer in the mutation positive women in these families is 53 years [92].  Recent reports have shown that lobular breast cancer may be the first cancer presentation in a family with a CDH1 mutation [111, 112].  There are an increasing number of these families being identified as more individuals are being tested using next generation cancer gene panels (anecdotal evidence).  Further studies to elucidate any genotype-phenotype correlations will have to be done to explain this phenomenon.   Although there is currently no direct evidence of an increased risk of colorectal cancer in the HDGC clinical spectrum, a smattering of reports in the literature have found familial CDH1 mutations in patients with colorectal cancer [93, 113, 114]  The criteria for the clinical diagnosis of HDGC have been revised several times [92, 93, 96, 104].  The latest revisions in 2015 [115] are similar to the 2010 guidelines [116] except that the first 2 criteria have been merged.  The current criteria for the clinical diagnosis of HDGC and subsequently CDH1 genetic testing are as follows [115]:  1. Two or more GC cases in a family, regardless of age, with at least one case with pathologically confirmed DGC OR 26  2. An individual with DGC diagnosed at less than 40 years old if there is no other family history of GC or BC (that is, an isolated case in a family) OR 3. Personal or family history of DGC and LBC, with one of the affected persons diagnosed at less than 50 years of age.  In addition, the current guidelines to offer CDH1 genetic testing also include considerations for families that fulfil the following criteria:   4. Bilateral LBC in an individual < 50 years old OR multiple first or second degree with LBC, with at least 2 affected individuals less than 50 years old OR   5. Personal or family history of cleft lip/palate OR 6. Detection of in situ signet ring cells and/or pagetoid spread of signet ring cells in the stomach.   2.2 Genetics of HDGC  CDH1  2.2.1Epithelial (E)-cadherin is encoded by the CDH1 gene [OMIM 192090] which is located on the long arm of chromosome 16 (16q22.1).  The gene is comprised of 16 exons that are transcribed into a 4.5-kb mRNA and then translated to the mature 120 kDalton E-cadherin protein.  The mature E-cadherin protein has three major domains: the extracellular domain (exons 4-13), the transmembrane domain (part of exons 13 and 14) and the highly conserved cytoplasmic domain (rest of exon 14 – 16). [59]  27  E-cadherin is an integral part of the large superfamily of transmembrane glycoproteins that mediate calcium-dependent cell-cell adhesion [117].  E-cadherin plays a key role in the structural components of the adherens junctions between epithelial cells and also has major roles in epithelial architecture, cell adhesion, and cell invasion [117, 118]. In fact, so key is its role in the transcellular network that loss of e-cadherin causes the loss of the adherens junctions leading to an impairment of the cell adhesiveness and cell-proliferation signaling pathways [119]  In addition, E-cadherin has been documented as a tumour suppressor in several different epithelial cancers [120, 121].  Its role in the development and progression of cancer can occur through several molecular mechanisms which include germline mutations, large genomic rearrangements [95], direct inhibition by transcriptional repressors, CDH1 promoter hyper-methylation, and microRNA [122].  It is believed that cells deficient in E-cadherin lose the ability to adhere to each other thus becoming invasive and metastasizing [123].  CDH1 is the primary gene in which pathogenic variants are associated with clinically defined HDGC. Germline pathogenic CDH1 mutations have been reported in 30-50% of families that meet clinical criteria for HDGC [116] [124].  Screening for mutations in this gene is vital for management of cancer risk.      Corso et.al ( [125] took an in-depth look at the geographical variability of the incidence of CDH1 germline mutations and found that in regions where the incidence of GC is low, the frequency of CDH1 germline mutations is high and vice versa.  It is possible that most of the gastric cancer cases in the high incidence populations are explained primarily by environmental risk factors 28  such as H. pylori and diet [126]. Notably, germline CDH1 mutations are being increasingly reported in high-incidence GC populations over the last 2 years, whereas this phenomenon had been rare previously. This could be a result of more prevalent genetic testing in these populations in recent years.    Other Genes Implicated in the HDGC Syndrome 2.2.2Heterozygous germline mutations in CDH1 have been described in 30-40% of families with c-HDGC [116, 124]. It is possible that the other 60-70% of these clinically defined HDGC families may harbour germline mutations in other cancer susceptibility genes.   Due to the recent advances in sequencing technologies, we and others have been able to identify additional cancer susceptibility genes [6, 127] in a small number of these families.   Apart from CDH1, the only other gene that has been implicated in the HDGC syndrome is CTNNA1 gene [127].  CTNNA1 encodes the protein, alpha-catenin, which binds actin binding proteins and filaments. Alpha-catenin, like E-cadherin, is involved in intercellular adhesion, the adherens junction is linked to the actin cytoskeleton by α-catenin [128]. CTNNA1 is also a suspected of acting as a tumor suppressor gene in GC [127].  Our group recently identified two CDH1-negative clinically defined HDGC families with novel CTNNA1 germline truncating mutations [6].    As with families that harbor CDH1 germline mutation, penetrance in families CTNNA1 germline truncating mutations was also incomplete.  Age of onset occurred late in two families (after 50 years) and in the other family, there was one individual affected before 50 years.  Further 29  families will need to be ascertained in order to provide a better understanding of the clinical implications of this gene in clinically defined HDGC families.  Gaston and colleagues [129] recently described a large HDGC family from the Maritimes in which a germline variant was identified in the mitogen-activated protein kinase 6 (MAP3K6) gene in four of six affected individuals who were tested.  Penetrance was incomplete and age of onset of gastric cancer occurred in their seventies and eighties.   Further germline and tumour studies suggest that MAP3K6 may be a strong candidate as a cancer predisposition gene.  More investigations are required to confirm the role of this gene in HDGC.   In addition, our group has also shown the existence of a rare germline mutation in the BRCA2 gene in a family that was clinically defined as HDGC [6].   Furthermore, more frequent, but less penetrant, mutations have been identified in families with gastric cancer clustering, in moderate or low penetrant genes such as ATM and PALB2 [6].  2.3 Penetrance The penetrance in HDGC is incomplete as demonstrated by obligate carriers who are known to survive cancer-free into their 8th and 9th decades.  In a study of 11 families the GC risks were calculated as 67% in mutation positive men and 83% in mutation positive women to age 80 years.  There was an increased risk of LBC in women mutation carriers of 39% [8].  Our group has also previously shown a cumulative risk of GC in 4 families with the 2398delC founder mutation to be 40% for mutation positive men and 63% for mutation positive women by the age 30  of 75 years [7].  Within these four families the cumulative risk for breast cancer for mutation positive women by the age of 75 years was found to be 52% [7].    With these high risks to develop a cancer as deadly as DGC, it is imperative that DGC is either diagnosed at an early stage or prevented by total gastrectomy in mutation carriers.  With genetic testing for CDH1 mutations becoming more widespread, there are greater opportunities for risk stratification, elimination of DGC risk through prophylactic gastrectomy, and increased surveillance for LBC [9, 94, 130].      2.4 Genetic Counseling and Genetic Testing Genetic counselling is an important part of assessing and managing families with HDGC as there are several issues surrounding genetic testing. These include potential medical and psychological aspects as well as issues surrounding insurance and other economic factors.  The process includes obtaining a three-generation family history or pedigree and histopathological reports on all family members affected with cancer, especially on those with GC and LBC.  Once an individual is identified as having a family history of diffuse gastric cancer, genetic counselling is indicated for the family members [92, 116].    The first session includes an overview of GC and the specifics of HDGC which include the pickup rate of CDH1 germline mutations, penetrance and management options. With the penetrance of 80%, there is the 20% chance that a CDH1 carrier will not develop gastric cancer.  With so much different information involved in the sessions, the whole counselling process must be performed within a multidisciplinary setting including a geneticist/genetic counselor, surgeon 31  with expertise with major abdominal surgery, gastroenterologist and dietician - in which cancer risk assessment, and the pros and cons of the surgery need to be discussed with the patient. Quality of life issues are also pertinent to these discussions as functional outcomes related to gastrectomy may have a major impact on functional status, mood, general health and overall quality of life.   The first person to have genetic testing in a family that has been diagnosed with clinically defined HDGC is usually an individual affected with DGC and/or LBC.  Testing an unaffected individual from an HDGC family can be often be uninformative because a negative result does not rule out the presence of a cancer susceptibility gene in the family or the person being tested. Fully informed consent is always required before testing is initiated. If a germline mutation is identified, then at-risk family members can be offered genetic testing to ascertain their CDH1 carrier status.  As in other adult onset cancer predisposition syndromes, the age at which testing is offered to at-risk family members is not set in stone.  The IGCLC recommends that genetic testing can be considered and offered at the age of 16-18 years, depending on the age of onset in the family.  This has to be accompanied by psychosocial counselling of both the young consultand and his/her family. Carrier testing for unaffected individuals is important because it allows the health-care professionals to stratify an individual’s risk and then to proceed with appropriate clinical care.  In a family in which a pathogenic CDH1 germline mutation has been identified, individuals who have been tested and found not to carry the mutation have DGC and LBC risks equivalent to those of the general population. They no longer require intensive screening and instead can 32  follow screening recommended for the general population. For those asymptomatic carriers of a familial CDH1 germline mutation, recommendations include intensive and regular screening with endoscopy or prophylactic total gastrectomy.  Female CDH1 mutation carriers also have a high risk of developing breast cancer.  It is therefore recommended that these women are referred to a high-risk breast clinic [116].  Screening is similar to other high-risk breast cancer familial syndromes and should include monthly breast self-examinations and biannual clinical breast examination. Annual mammogram and breast MRI beginning at 35 years is advised by the current censuses guidelines [116]. Although the age of 35 years is more of a pragmatic choice, screening should begin 5-10 years earlier depending on the earliest onset of breast cancer in the family.  Although prophylactic mastectomy is not uniformly recommended, it may be a good option for some women and especially in families where there is a predominance of breast cancer.   Also, chemoprevention with tamoxifen may be of benefit to these women although there are currently no universal recommendations owing to insufficient data, [116].   2.5 Clinical Management Options for Diffuse Gastric Cancer Risk in Mutation Carriers Early GC is defined as gastric carcinoma that is generally confined to the mucosa or sub-mucosa irrespective of the presence or absence of lymph node metastases. The survival rate is 90% if the cancer is detected at an early stage. Therefore, early detection of GC is of prime importance for asymptomatic germ-line mutation carriers.   33  The optimal management of individuals at risk for DGC is controversial because of the unproven value of current surveillance regimes.  Surveillance by white-light endoscopy, PET scan, and chromoendoscopy have all been unsuccessful at reliably detecting DGC as noted by the findings of multiple small cancer foci (less than 1 mm in diameter) in gastrectomy specimens from CDH1 carriers undergoing gastrectomy within weeks of screening [10, 94, 130, 131].  As a result, individuals who have a CDH1 germ line mutation are often encouraged to consider the option of PTG. This represents a difficult choice between the two current options: screening has repeatedly been shown to miss early DGC and prophylactic total gastrectomy carries certain morbidity and perhaps mortality associated with the surgery [13, 14].   Surveillance  2.5.1Endoscopy allows for direct inspection and subsequent biopsy of any suspicious areas of the gastric mucosa.  High-resolution endoscopy can potentially detect slight changes in the colour and architecture of the gastric mucosa.  However, since DGC cells tend to spread in the submucosa as opposed to forming exophytic masses, this cancer is difficult to detect at an early, treatable stage. Most of the signet ring cell clusters found in resected stomachs after PTG are less than 1 mm in diameter and occur in apparently normal appearing gastric mucosa [94, 130, 131].  This makes them very difficult to diagnose on routine endoscopy thus delaying the diagnosis of a potentially fatal disease.    As difficult as these submucosal lesions are to identify, an additional challenge is the possibility of biopsy sampling bias in a macroscopically normal-appearing gastric mucosa [116, 130, 131].  Mutation carriers are advised to undergo the “Cambridge protocol”, which is a detailed 30-34  minute white light high definition endoscopic examination of the gastric mucosa on a yearly basis [131].  The recommendation is for the GI specialist to take at least 30 biopsies, six from each of the five anatomical regions of the stomach during the endoscopy.  The high number of biopsies is needed so as to maximize the likelihood of finding any of the very tiny microscopic foci of signet ring cells [131].  Due to its inefficiency at detecting such tiny foci, endoscopy is usually only recommended to individuals who do not wish to have PTG for one of several reasons, including poor physical health, psychosocial factors or advanced age (or younger than 20 years old though this is independent of age of onset in the family).  Sometimes, mutation carriers are not ready to have PTG for varying reasons (family planning, career trajectory, or fear of the post-surgical outcomes) and defer the surgery.  This cohort needs to have regular endoscopy and biopsy.      Prophylactic Total Gastrectomy  2.5.2Given that the prognosis for GC, especially in the late stages, is poor, CDH1 mutation carriers are also provided with the choice of having a prophylactic total gastrectomy.  The surgery is performed either as an open surgery or by laparoscopy.   PTG is a complex surgery that involves two stages.  The first is the surgical removal of the complete stomach and all gastric epithelia plus resection of the perigastric lymph nodes and those along the feeding vessels (also known as a D-2 node dissection).  It is then followed by a reconstruction of the digestive transit using the Roux-en-y esophagojejunostomy [132]. Figure 1.5 is a schematic representation of this surgery.  The recommendation is for the jejuno-jejunal 35  anastomosis to be at least 50 cm distal to the esophago-gastric anastomosis as this reduces the risk of biliary reflux [132]. The complete removal of the gastric cardia mucosa should be confirmed by examination of the resected specimen or by frozen section [14].    Laparoscopic gastrectomy has become more popular over the last 20 years with surgeons because of its advantages in terms of decrease in pain and quicker recovery time for the patient. A short-term study following patients over a year also indicated decreased mortality and morbidity [133].  There are 4 reports in the literature that discuss laparoscopic TG in a total of 12 CDH1 mutation carriers [134, 135, 136, 137].  In these patients, the hospital stay ranged from 3 – 23 days; compared to 10 to 18-day range for open gastrectomy.  Both reports indicated that the patients also had earlier return of bowel function and earlier oral intake after laparoscopic surgery.  There are no long-term outcomes reported yet.    36  Figure 2.3.  Total Gastrectomy with Roux-en-Y reconstruction. The blue and red arrows show where the surgical cuts are made and the remaining digestive tract rejoined.  Figure obtained from Dr. Samuel Yoon at Massachusetts General Hospital (Boston, USA) and used with his permission.      37   Post-surgical Complications and Symptoms primary functions of the stomach are to act as a reservoir and to initiate the digestive process.  Contents from the stomach are released gradually into the duodenum allowing optimal digestion.  A total gastrectomy and subsequent reconstruction of the gastrointestinal (GI) tract results in a variety of physiological disorders which are collectively known as post-gastrectomy syndrome [138].    Mortality rates in individuals undergoing TG for cancer ranges between 2% - 6%. [139, 140, 141] . These patients also tend to be much older (60 – 70 years) and are already comprised by the cancer when compared to the cohort of individuals who have had PTG.    In a young, healthy individual the risk of mortality with PTG when done by an experienced surgeon (one who has either performed PTG or several major abdominal surgeries) is estimated to be less than 1% [142].  There is also a high risk of long-term complications.  These complications are well-described in patients who have had the surgery as treatment for cancer or other serious gastrointestinal disease.  Morbidity rates vary with the type of complication and include oesophageal anastomic leakage rates ranging in 8-12%, esophageal anastomic strictures from 10-15%, wound and intra-abdominal septic complications range in 5-10% [116, 143]  The changes in both the anatomy and physiology of the stomach after the surgery result in a group of gastrointestinal and vasomotor symptoms [138].  The primary cause of dumping syndrome is believed to be the rapid emptying of the gastric content into the small bowel.  However, severe dumping can also be caused by severe malnutrition leading to a poor quality of life.   38  Dumping syndrome is divided into early and late dumping depending on the time elapsed after a meal and the symptoms.  Symptoms of early dumping occur within 10 – 30 minutes after a meal and are due to the rapid emptying of a large hyperosmolar load into the small intestine.  This causes a shift in fluids from the intravascular compartment to the intestinal lumen leading to small bowel distension and increased intestine contractility which are the cause of the GI symptoms such as abdominal cramps, diarrhea, nausea and bloating [138].  Most patients suffer from early dumping syndrome symptoms which include both the GI and vasomotor symptoms.  Late dumping occurs 1–3 hours after a meal, and the symptoms are the result of reactive hypoglycemia due to increased release of insulin.  Late dumping is characterized by systemic vascular symptoms including flushing, dizziness, palpitations, and an intense desire to lie down. Almost 25% of patients experience late dumping syndrome. Most patients with dumping syndrome can be treated conservatively with dietary modifications.  Most of the reports discussing post-surgical outcomes tend to concentrate on clinical complications and pathology findings in the PTG specimens. Since the first report describing these findings in 2001 [94], there have been several papers that have reported post-surgical complications during hospitalization period of individuals who have undergone PTG [9, 10, 11, 12, 13, 14, 134, 135, 136, 144].  There were no deaths reported in any of these reported cases.  Few post-surgical complications were observed (Table 1.1) and most occurred in the first month after surgery.   The largest of these studies is a cohort of 23 patients from a single centre in Newfoundland, Canada [13].  The surgeries spanned a 2.5-year period.  The authors reported that 11 of the 23 patients had complications during their hospitalization after surgery. There was no 39  long-term follow-up to look at outcomes such as dumping syndrome, diarrhea or other symptoms.    Loss of body weight, primarily fat loss, is a common outcome in patients with gastric cancer who have undergone total gastrectomy.  Loss of body weight generally occurs in the first 3 months post-gastrectomy [145] but this loss continues for the first 6 months after surgery [142, 146]  Studies have shown that the weight loss over the first 6 months is approximately 10-20% of the pre-operative weight [142, 147].  Loss in body weight, to a similar extent has also been documented in individuals who have undergone PTG [130, 135, 144].  There is 100% long-term morbidity after total gastrectomy related to alteration of eating habits, dumping syndrome, and weight loss [141, 143].  However, there are only three papers that actually report that the patients they followed experienced variable degrees of dumping syndrome. All had to adjust their eating habits and diet accordingly and with these changes symptoms decreased in severity over time and were more tolerable in daily life.  Norton and his colleagues [130] noted the same issues with their cohort of patients.  Table 2.1 summarizes the studies in the literature that describe post-gastrectomy clinical complications in CDH1 mutation carriers.   40  Table 2.1 A literature summary of cases/families and their post-surgical outcomes after PTG. Report (year) No. of cases (# of kindred) Age at surgery (years) Sex Major complications (#. affected)  Minor complications (# affected)   # PTG specimens with signet ring cells Follow-up (months) Chun et. al. (2001) [10] 5 (1) 37 – 47  3 females 2 males  None None 5/5 (100%) Not provided Huntsman et.al. (2001) [94] 5 (2) 22-40 4 females  2 males  None  None 5/5 (100%) Not provided Lewis et.al. (2001) [9] 6 (2) 22-40 4 females 2 males Anastomic stricture (1) Septic phlebitis (1)  None Not provided 18 Norton et.al. (2007) [130] 6 (1) 51-57 4 females 2 males  none None 6/6 (100%) 12 Hebbard et.al. (2009) [13] 23 (3) 26-63 14 females 9 males  Venous thromboembolism (3);  Wound infection (4) Intra-abdominal abscess (1) Subclinical leak (4) Anastomotic leak with abscess (2)  Wound infection (4) Urinary tract infection (2) Pneumonia (2) Small bowel obstruction (1) Ileus (1) Not provided Retrospective medical chart review (surgeries done approx. 12-36 months prior) Hackenson et.al. (2010) [135] 6 (1) 21 - 51 3 females 3 males    None  Small bowel obstruction (1) Esophageal stricture (1).    100% Not provided Pandalai et.al. (2011) [14] 10 (6) 27-51 4 females 6 males Pulmonary embolism (1); SBO (2); anastomotic stricture (1); Intussusception after 2 years (1)    None 9/10 (90%) > 12  Chen et.al. (2011) [148] 13 (6) 18-70 9 females 4 males None  None 12/13 (92%) 1-55 Li et.al. (2013) [136] 2 (1) 32,38 2 females Tachycardia (1) None  0/2  35 Badram (2014) [144] 6 (2) 26-45 3 females 3 males  None None 6/6 (100%) 5-10 41   Even with the improvement in surgical reconstructive procedures over the last few decades to allow for correct oral intake, postoperative malnutrition still occurs in patients, possibly due primarily to malabsorption. These nutritional complications prompted Lewis et. al. [9] to comment that PTG " represents a new level of risk for patients with a genetically defined disease.”   These problems can occur months or even years after gastric surgery.  Although it is known that nutritional deficiencies do occur after TG (see Table 2.2) specific details about these deficiencies in the patients undergoing PTG were discussed in only one paper [14].    Table 2.2 :  Incidence of known common micronutrient deficiencies occurring after total gastrectomy and the conditions caused.  Micronutrient % affected Condition caused by deficiency Iron 40–70% Microcytic anaemia Vitamin B12 36–80% Megaloblastic anaemia Folate 33–41% Megaloblastic anaemia/Pernicious anaemia Vitamin D 0–50% Decreased absorption of both causes bone disease  (osteoporosis, osteopenia, osteomalacia) Calcium 0–30%    42  2.6 Pregnancy after Prophylactic Total Gastrectomy As more and more young women from families with HDGC find out that they are carriers of a CDH1 mutation, the issue of family planning must also be addressed in the counselling sessions.  Understandably, there are concerns amongst both the women and their health-care providers with regard to the potential complications in both the mother and the foetus that may arise during pregnancy following PTG.  One of the more significant risks facing women contemplating pregnancy is malabsorption of nutrients such as vitamins B12 and D, folate, calcium and iron [9].  The deficiencies in these vitamins and minerals have the potential to cause maternal complications such as severe anaemia and foetal complications such as neural tube defects and intrauterine growth restriction [149].   Most of the studies investigating the effects of pregnancy after gastric surgery are concentrated on women who have undergone bariatric surgery for obesity.  Mild anemia has been found in 15-60% of the women after bariatric surgery [150, 151, 152, 153, 154].  One study [154] found that even with supplementation of vitamin B12, there was a decrease of these levels in pregnancy.  Although the women did not show any clinical symptomatology, it prompts the query of whether the amount of B12 supplementation should be increased during pregnancy.  This same study also noted low birth weight and small for gestational age babies born to mothers who had bariatric surgery.    With only a handful of case reports in the literature of women having children after gastrectomy [155, 156] we explored the outcomes of pregnancy following PTG in three women as well as in a 43  woman who had three successful pregnancies after TG following diagnosis of early DGC [157].   Information on weight gain was available on four of the women and ranged between 10-16 kilograms.  Four of the women had serial ultrasound examinations in their second and third trimesters to monitor normal foetal growth. All the women were closely monitored by a dietician. In total, there were seven normal pregnancies among the four women.    However, until there is long-term follow-up data for both the women who are post-gastrectomy and their children who were conceived post-gastrectomy, continued caution regarding planned post-operative conception is necessary.  It is important that women of childbearing age who are undergoing PTG be counselled that pregnancies occurring post-gastrectomy will have specific nutritional requirements. These women will need to be monitored by both an obstetrician and a dietician throughout the pregnancy. Young women of childbearing age are especially encouraged to continue taking vitamins so that a deficiency early in pregnancy can be avoided.         44  Chapter 3: Literature Review for Quality Of Life after Gastrectomy The ultimate measure by which to judge the quality of a medical effort is whether  it helps patients (and their families) as they see it. Anything done in health-care  that does not help a patient or family is, by definition, waste, whether or not the professions and their associations traditionally hallow it (p.1564) [158].  3.1 Overview Survival of patients with gastric cancer has improved in recent times [21].   Much of this improvement is the result of earlier detection of the disease and the development of better surgical procedures.  However, when surgery is employed as a means of either preventing or curing GC, the patients tend to suffer from various functional and psychological symptoms.  Although different variants of reconstruction have been developed to relieve these symptoms, they remain a problem.   As a consequence, health-care professionals have become interested in how these symptoms and other aspects of the patients affect not only their quantity of life (survival in years) but also their quality of life (QOL).   The need to measure quality of life objectively is now widely recognized as being an important outcome in health care. The term “quality of life” has quickly become a catch-all term not only in the medical literature but also in the layman’s language.  It appeared as if QOL was a multidimensional concept without a clear definition [159].     3.2 Current Concepts of Quality of Life The term, quality of life, is a broad-ranging concept that has been defined inconsistently and with various connotations by investigators over time. This lack of consensus is in part related to the 45  fact that the term QOL is used within diverse multidisciplinary fields ranging from health-care to politics ( [160]. The term QOL has been associated with the concept of well-being [161], happiness [162] and life satisfaction [163].  Whilst some of these terms, like happiness, imply a fleeting emotion, others such as life satisfaction imply a more permanent state that stem from core values.   Gasper [164] recommended that quality of life be understood as an “umbrella term” (p. 359) that covers several different meanings.  He stated “The concept of quality of life refers to an evaluation (an evaluative judgement) about major aspects, or the entirety, of a life or a society” (p. 351) [164].  Gasper divided QOL into 2 dimensions, objective and subjective. The former refers to a set of collectively agreed upon values such as mobility and the latter refers to an individual’s personal evaluation of her/his own life. He defined six dimensions that affect one’s evaluations of these major aspects of life: 1) scope and focus (which aspects of life are being considered?), 2) values that reinforce the use of the term well-being or QOL, 3) research instrument(s) used (that is, the methods of observation, measurement and interpretation), 4) purposes of evaluation of QOL, 5) standpoint adopted (individualistic or societal) and 6) theoretical framework employed.  Gasper suggests that QOL be understood as having different roles under different circumstances and that these need to be understood within the six dimensions he outlines.  Although most researchers agree that quality of life has several domains or dimensions, there is still no consensus on which of these dimensions are essential in its definition.  QOL dimensions have included life satisfaction, socioeconomic status, physical health, affect, perceived stress, 46  friendship, family, marriage, life goals, housing and neighborhood, city and nation, self-esteem, depression, psychological defense mechanisms and coping [165].  QOL is thought to be determined not only by these dimensions, but also by the individual’s perception of the importance of these dimensions [166].   Despite the lack of consensus in its definition, five essential dimensions have been proposed: disease or treatment-related symptoms, physical functioning or well-being, emotional and psychological well-being, social role well-being, and spiritual well-being [167].    QOL has become an important concept for health-care providers because health has a large impact on a person’s perceived quality of life. Despite this increasing importance though, the confusion with respect to the definition of QOL has also been seen in the biomedical field.   1n 1995, the WHO defined health as “a state of complete physical, mental and social well-being and not merely absence of disease or infirmity” (p.1403) [168].  Soon after this definition of health by the WHO, the term quality of life began to encompass even more dimensions such as physical functioning, symptoms, health status and psychosocial status [97].    The term,” health-related quality of life” (HRQOL) was developed to describe the influence of illness and treatment on an individual’s overall quality of life [97] or the impact of an illness or disease on areas considered to be important in a person’s life. These latter are based on an individual's subjective experiences. These experiences relate both directly and indirectly to her or his health, disease, disability, and impairment [168].  However, if health- related quality of life is to be based on only these constructs, it will not include the several other potential influences such as culture [169], spirituality [170], societal influences or even political leanings [171] that 47  may potentially influence an individual’s perception of QOL. Therefore, it may be that health-related quality of life should extend not only to the impact of the treatment and the subsequent side effects but also to the recognition that each patient is an individual and needs to be looked at as a whole person- body, mind and spirit [172].  A very comprehensive definition of QOL is provided by the World Health Organization: An individual’s perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards and concerns.  It is a broad ranging concept affected in a complex way by the person's physical health, psychological state, level of independence, social relationships, personal beliefs and their relationship to salient features of their environment (p.1579) [173].    In the medical literature, the terms health-related quality of life, quality of life and health status are generally not defined and are sometimes even used in the same paper interchangeably [174, 175].  Usually though, health researchers do tend to follow either a disease-based, deficit framework or a holistic, global framework when reporting their studies, even if they do not refer to any specific theoretical framework in their papers.  Although there are several conceptual models, the three most commonly used QOL models in the literature are the Wilson and Cleary’s health-related quality of life conceptual model, Ferrans and colleagues revised Wilson and Cleary model and the WHO model [176] .   The Wilson-Cleary model focuses primarily on the physical dimensions of QOL because the authors theorized that there is a need for a physiologically-based framework to capture the 48  impact of health and disease on quality of life.  The authors stated that this physiological-based approach was taken because previous models had “foundations in sociology, psychology, and economics and use concepts and methodologies often foreign to physicians and clinical researchers” (p. 59) [100].    The most common domains found in the literature on studies involving individuals after TG tend to include the physiological, psychological, general health perceptions, functional status and social components.  However, despite identifying and using these domains to understand the causal and significant relationships, it does not necessarily define the term QOL.  Interestingly Wilson and Cleary themselves (1995) did not define the term quality of life. Instead, they stated, “Health status and health-related quality of life can refer to different concepts, but in this article we use the terms interchangeably” (p. 60).   Ferrans and Powers [159] did define QOL as “a person’s sense of well-being that stems from satisfaction or dissatisfaction with the areas of life that are important to him or her” (p.29).  This definition includes the satisfaction factor which represents an individual’s different values that impact their own perception of QOL (Figure 3.1 - box 5 in the model).  Another definition of QOL by Gotay [177] which emphasizes both boxes 3 and 5 in Figure 3.1 is:   “Quality of life is a state of well-being that is a composite if two components: 1) the ability to perform everyday activities that reflect physical, psychological, and social well-being and (2) patient satisfaction with levels of functioning and the control of disease and/or treatment-related symptoms.” (p.58).  49  Figure 3.1 Wilson Cleary Model of Health-Related Quality of Life.  Conceptual model of the relationship between various health outcomes and overall quality of life.  The arrows represent the causal relationships between the various levels of health outcome with an overall impact on quality of life. Individual and environmental factors may alter health outcomes along the causal pathway. From “Linking Clinical Variables with Health-related quality of life: A conceptual model of patient outcomes” by I.B. Wilson and P.D. Cleary, 1995, JAMA, 273, p. 60. Used with permission.     In the field of oncology, QOL is becoming an important issue because there are more patients being treated successfully and hence living longer than before.  This means that as health-care researchers we need to go beyond the concept of “quantity of life” and start looking at making our patients feel their best, that is, enhance their quality of life.    The discoveries of several genes that predispose individuals to cancer have sparked the implementation of clinical mutation testing [178, 179, 180] aimed at identifying individuals who are at a much higher risk of developing specific cancers. This has led to increasing numbers of 50  high-risk individuals facing decisions regarding cancer risk management options. These high-risk individuals are presented with options which may include screening and prophylactic surgery. These options have varying degrees of effectiveness, with prophylactic surgery providing more reduction in cancer risk compared to screening procedures [181, 182, 183, 184, 185, 186, 179].   With the realization that QOL is an increasingly important outcome criterion for patients with hereditary cancer syndromes, there have been several papers in the literature discussing these issues. There is a body of literature examining the effects of prophylactic mastectomy (PM), oophorectomy (PO) and colectomy (PC) on quality of life. All of these surgeries carry post-surgical complications and affect several aspects of overall quality of life.    The largest body of literature on prophylactic surgeries due to cancer predisposition is on women with BRCA1 or BRCA2 germline mutations.  These women have an estimated lifetime risk of ovarian and fallopian tube cancer from 15% - 45% plus breast cancer risks of 40% - 80% [187, 188, 189, 190].  Studies have shown that earlier and more frequent cancer surveillance and surgical risk-reducing options which include prophylactic mastectomy and bilateral salpingo-oophorectomy reduce cancer incidence and mortality [191, 192, 193].  The major advantage of prophylactic surgery when compared to surveillance in carriers is an up to 90% risk reduction in breast cancer and up to 96% reduction for ovarian cancer [187].   Several domains of QOL, including cancer worry, satisfaction with the decision to have the surgery, menopausal symptoms, sexual functioning, body image, pain, psychosocial aspects, and 51  general health have been evaluated in women who have had surgery to reduce their risk of breast cancer [194, 195, 196, 197, 198, 199].  Despite the complication rates, women generally report minimal negative change in their overall quality of life after these surgeries [195, 200, 201, 202].  In individuals with a hereditary syndrome of colorectal cancer predisposition, prophylactic colectomy is considered an option for clinical management [203, 204]. This involves major surgery, which is associated with major implications for lifestyle that have to do with the changes in the gastrointestinal tract function. Despite the clinical and functional complications following surgery, several studies have shown that patient satisfaction with surgery, general health, functional outcomes and QOL after surgery are equivalent to before surgery [205, 206, 207, 208].  Patients have indicated that they favour QOL over quantity of life [209].  So, in addition to studying the medically-related outcomes in cancer treatment, QOL has becoming increasingly accepted as an important endpoint.  However, despite the fact that prophylactic gastrectomy causes several gastrointestinal problems, there is only one study [15] that has explored the issues surrounding QOL and health following this procedure.   Without a definition, or even a conceptual framework, the instruments that are used to measure QOL may to some extent help in understanding the concept.  The subscales of the instrument can be the conceptual domains, which may allow some theoretical comprehension.  Most investigators tend to omit the conceptual model that guides their use of an instrument – for example, if a researcher thinks that a particular domain (such as culture) is important after cancer diagnosis, s/he will use that instrument in her/his study [210].  In the early literature, the most 52  common domains to be studied after TG tended to focus on the gastrointestinal function score and were measured by instruments developed by Troidl and Kusche [211].  As cancer health-care researchers became more aware of the multidimensional character of QOL, some researchers began to incorporate the Medical Outcomes Study 36-item Short Form Health Survey (SF-36) [175, 212, 213].  The SF-36 is a general health questionnaire and is referred to as a measure of QOL, HRQOL, physical and mental functioning, general health and health outcomes in various studies.  The SF-36 has 36 items/questions that are arranged into eight scales that include physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional and mental health. There are also two summary scores- the physical component and mental component summaries.    The European Organization for Research and Treatment of Cancer (EORTC) developed a general QOL questionnaire (QLQ-C30) [98] for cancer patients and a gastric site-specific module to assess QOL. EORTC QLQ-STO22 [99].  The latter instrument is focuses on issues that are important to patients with gastric cancer at every stage of treatment.  Using both the cancer-specific questionnaire and the more specific stomach cancer module can provide valuable information about the long-term effects of surgery.  The majority of gastrectomy studies now use these two questionnaires to define QOL.  The use of these multidimensional instruments allows researchers to compare results across studies.    While there have been many studies that measure QOL in patients undergoing TG after cancer, there are few that look at those having PTG.  Research on these individuals is needed to understand their QOL in a holistic way, that is, through research that underlines their satisfaction 53  with current well-being.  While health is a dominant component of this concept, one must also be cognizant of other influences that impact an individual’s subjective perception of wellbeing.    A holistic model that potentially provides theoretical strength to this QOL research is the Wilson-Cleary model [100].  Inclusion of the characteristics of the individual and the environment expands the model from a HRQOL model to a QOL model – the influence of interpersonal, intrapersonal, community and overall QOL is affected by more than just the individual’s health status (Figure 3.1)   3.3 Wilson-Cleary Conceptual Framework  A conceptual framework is used in building a set of coherent ideas or thoughts in research. It is usually depicted as a map or a diagram that connects the different parts of the research study. In order to meet the goals of this study, different conceptual frameworks were considered. A broad conceptual framework is needed to ensure the adequate description of both symptom experience, and subsequent QOL. The framework must include all dimensions of the symptom experience, as well as the physical, psychological, social factors that potentially impact or influence the symptoms.    The Wilson-Cleary (WC) [100] model was selected as a suitable way of exploring the relationships between QOL and clinically relevant factors (Figure 3.1) in this study.  It provides the most comprehensive view of pathways that link the traditional clinical variables to overall QOL.  The model is comprised of five conceptually distinct health outcomes (biological variables, symptom status, functional status, general health perception and overall quality of life) 54  that are linked in a series of causal relationships on a continuum.  Each level of outcome is increasingly more complex and integrates multiple influences.  Characteristics of the individual and characteristics of the environment influence all these outcomes.  Although Wilson and Cleary do not define individual characteristics or environmental factors, both concepts are included in the schematic representation of the model (Figure 3.1).  Given that QOL is a multidimensional construct, each of the components of the WC model can be thought of in terms of multiple domains; for example, functional status can refer to psychological, social and role functioning.  The Wilson-Cleary model has been shown to provide valuable information symptom management and outcomes in cancer patient trials that would not have been captured if a narrower focused approach had been used [214].  The 5 domains in the Wilson-Cleary model have been addressed in QOL studies of patients after gastrectomy.     Biological Functions 3.3.1Biological function includes the physiological processes that support life and is the most fundamental determinant of QOL [100].  Biological function focuses on the performance of cells and organ systems and can often be measured through laboratory tests, physical assessment and medical diagnosis.  Medical interventions are focused on improving outcomes within this domain.  Changes in biological function can affect all the subsequent determinants of QOL in the WC model, including symptoms, functional status and general health perceptions.   Biological factors that have been shown to impact QOL in individuals with gastric cancer after gastrectomy in individuals include extent of the surgery, that is, subtotal versus total gastrectomy [215], surgery type (open versus laparoscopic) [216], type of reconstruction after gastrectomy 55  [217], tumour location [218], and post-operative complications including malnutrition , respiratory failure, pneumonia, anastomic leaks and sepsis [219].   In individuals undergoing PTG, the extent of surgery is not relevant as all these individuals undergo TG.  However, the type of surgery (laparoscopic versus open TG) may be an important factor given that studies with small cohorts of GC patients who have undergone laparoscopic surgery have been shown to have less blood loss, less postoperative pain, quicker bowel function recovery, shorter hospital stays and lower postoperative morbidity compared to patients who have undergone open gastrectomy [220, 221].  Similar results occur in CDH1 carriers who have undergone PTG by laparoscopy [134, 135, 136, 137].    There are currently over 60 types of digestive reconstruction that can be performed after TG and selection of an appropriate reconstruction approach can have important clinical significance in reducing the incidence of postoperative complications, maintaining nutritional status and improving quality of life for patients [222].  Studies that provide operative details on on carriers having PTG have all indicated standard Roux-en-y esophagojejunostomy for TG where the jejuno-jejunal anastomosis between 50-60 cm distal to the esophago-gastric anastomosis [9, 13, 130, 14, 144].  Optimal management of complications post-gastrectomy in those with gastric cancer has been found to lead to a longer life expectancy and better quality of life [175].  The potential major complications include anastomotic leakage, intra-abdominal bleeding, intra-abdominal abscess, intestinal obstruction, pancreatitis, and wound dehiscence.  These complications lead to overall 56  reoperative rates of 2.8% to 10% [223, 224].  In addition, post-operative complications tend to be higher in older patients (>75 years) due to the higher incidence of comorbidities and decreased functional reserve [225].    Causes for malnutrition in individuals who have undergone TG include malabsorption, early satiety/poor appetite and postprandial symptoms [141, 226, 227].  Loss of the stomach results in a loss of intrinsic factor secretion by parietal cells in the gastric mucosa, which in turn then leads to problems with vitamin B12 absorption [226] and iron malabsorption and deficiency [226]. Consequently, patients receive monthly intramuscular injections of Vitamin B12 and a daily oral multivitamin containing ferrous sulphate [228]. Vitamin D and calcium absorption can also be a problem after TG, potentially causing decreased bone mass and thus increased risk of osteoporosis, osteopenia or osteomalacia [229].  In addition, the decreased intestinal transit time after TG can cause fat malabsorption, which in turn leads to deficiencies in vitamins A, D, E and K [141].  My study looked at whether the patients had open or laparoscopic surgery, and assessed post-operative complications including anaemia, vitamin B12, calcium, and/or protein deficiencies.     Symptoms 3.3.2Symptoms are “a patient’s perception of an abnormal physical, emotional, or cognitive state” (p.61) [100].  This means that symptoms are unique to each individual experiencing them and may differ from symptoms of other people who are experiencing the same disease process.  The Wilson-Cleary model [100] suggests that symptoms are influenced by not only the biological and 57  physiological factors, but also characteristics of the individual and environment [100].  Patients who have undergone gastrectomy suffer from a variety of symptoms that can affect their QOL [230, 231]  Long-term sequelae after total gastrectomy in GC patients are well-documented in the literature [147, 232]. The post-gastrectomy symptoms are a result of loss of the stomach’s reservoir function and disruption of the pyloric mechanism.   Symptoms of the dumping syndrome and diarrhea are well-documented issues after gastrectomy [233, 234] and have also been documented in prophylactic gastrectomy patients [9, 15, 130, 135, 144].  In general, patients who experienced a higher frequency of symptoms and greater severity were more likely to report a lower QOL [235, 236].  Patients who underwent TG have significant worse digestive symptom scores for diarrhea, eating restrictions, dysphagia, nausea and vomiting, appetite loss, and chest and abdominal pains than those who had partial gastrectomy [230, 237, 238, 239].  Studies have demonstrated that fatigue is a severe problem in individuals who have undergone TG with a strong impact on overall QOL [239, 240, 241].  Fatigue, reflux and eating restrictions persisted beyond 5 years after surgery in one study [242].  In CDH1 mutation carriers undergoing PTG, symptom scores, including loss of appetite, nausea, vomiting and fatigue got worse in the first 3 months post-surgery and then became better after this time [9, 15].  Generally, diarrhea was noted to be worse at 6 months and did not improve until after 12 months.   Studies that demonstrate an improvement of dumping syndrome 58  symptoms and diarrhea in PTG patients over time tend to be short-term (less than 2 years).   The largest study to date of individuals undergoing PTG included 32 CDH1 mutation carriers followed over 24 months, and found significant persistence in fatigue (63%), abdominal pain (81%), diarrhea (70%), eating restrictions (45%), body image (41%) and reflux (63%) [15].   Studies have shown that establishing new eating habits may help patients to control postsurgical symptoms after gastrectomy [141, 243].  Even with alteration of eating habits and sometimes with taking either prescribed or over-the-counter drugs, there are individual differences in postsurgical symptoms, both between patients and also in the same patient over time.  Very little is known about the factors that affect these differences.    In addition, since depression and anxiety have been noted in individuals who have undergone TG for GC, it was important to assess these symptoms in our study population.  In individuals who have had gastrectomy due to cancer, some studies have revealed that depression is closely associated with the postsurgical symptoms such as dumping, abdominal pain and nausea, leading to a negative effect on overall QOL [244, 245, 246].  This is not surprising as these symptoms can be frequent and very bothersome.     Functional Status 3.3.3This level in the Wilson-Cleary model assesses the ability to perform certain tasks and can often be influenced by both the biological function and symptoms [100].   While symptom status is a vital factor of functioning, other aspects of an individual's personal and social environment may also have important effects on functioning.  Personal and environmental factors such as family 59  relationships and access to health care or medical treatment can impact the individual’s functioning status.  This domain must be measured separately as it may be influenced by biological function and symptoms. Five domains of functioning that are usually measured are physical, social, role-related, cognitive and emotional [171].    The majority of studies compare patients who have undergone partial gastrectomy against those who have had total gastrectomy for GC.  In patients with GC undergoing TG, physical functioning declines rapidly in the first month after gastrectomy but then start to recover through to 6 months [247, 248, 249, 250, 239].   Most studies comparing QOL in GC patients who underwent partial versus total gastrectomy reported better scores for the former group [249, 230, 251, 213].  However, the scores do not tend to return to baseline levels in any of the studies.    In patients undergoing laparoscopic gastrectomy, physical functioning did improve over time when compared to patients who had open gastrectomy [221, 252, 253].   Worster and colleagues [15] reported lower scores in physical functioning in the first month after surgery with a steady increase over 11 months.  The overall physical functioning for these patients did reveal a slight but non-significant decrease at the 24-month mark.   The emotional scores in most studies utilizing the EORTC instruments reveal an initial decline within the first month of surgery but show a continuous improvement after that [249, 250, 230].  When scores between the partial gastrectomy group and total gastrectomy group are compared, the former again tends to perform better on their scores [250, 251, 213].  When comparing the laparoscopy group to the open gastrectomy group, the findings were generally showed the pattern of initial decline for both groups and then a steady rise over time [236, 249, 253].  CDH1 60  mutation carriers who underwent PTG also reported a decline in their emotional scores in the first month after surgery but these increased steadily over until 12 months and stayed very similar at 24 months [15].  Social functioning scores also showed a decline in the first months but then recovered by 6 months to almost the same or the same levels prior to surgery [221, 248, 250, 249, 251, 253]. Although the scores for the TG group compared to the partial gastrectomy GC group were slightly higher in 2 of the studies, these were not statistically significant [238, 254]. The scores between the laparoscopy groups and the open gastrectomy groups did not show any statistically significant differences [221, 249, 253].    In Worster’s study [15], the CDH1 mutation carriers who had PTG showed a decrease of 35 points (p<0.01) between their baseline and 1-month post-surgery score.  There was an increase in scores at the 3 and 12-month time points, but the scores at 24 months declined slightly and were about 15 points below the overall baseline.    The majority of the studies did not reveal a statistically significant difference in the pre-and post-surgical scores for cognitive functioning [221, 248, 230, 250, 242].  Kobayashi et.al. [249] did report consistently lower scores in the open TG group compared to the laparoscopy group.  The PTG group in the Worster [15] study found no significant differences in cognitive functioning scores one, three, 12 or 24 months post-surgery.   61  Role functioning is a measure of an individual’s participation in defined roles within their community. The majority of studies reported the role-functioning scores as either similar to their pre-surgical cores or even better by 12 months [248, 250, 254] .  As expected, patients with GC who underwent partial gastrectomy had higher scores than the TG patients [221, 230, 251].  Kobayashi [249] reported better scores in the laparoscopy group compared to the open TG group but only until 3 months post-surgery for GC; after this the scores were similar.  In the PTG cohort study, the patients reported a steep decline in scores 1-month post-surgery but there was a steady recovery until 24 months; however, the scores did not recover to baseline [15].    General Health Perceptions 3.3.4The general health perceptions level is a representation of all the health concepts plus any others that may not be depicted by the model.  In the Wilson-Cleary model, general health perceptions are directly related to functional status and indirectly related to symptom status and biological and physiological factors [100].  General health perceptions are completely subjective.   They are usually measured as a single global question, indicating an overall health rating on a Likert-type scale from poor to excellent.  Although several of the QOL instruments (including the EORTC QLQ-C-30 and SF-36) include a question on general health perception, most of the studies on QOL after gastrectomy do not report this variable.   Wu and colleagues [231] measured this using the Spitzer index (a general Quality of Life index that covers five dimensions of quality of life including activity, daily living, health, support of family and friends, and outlook) [255] and noted an increase in general health perception over a 12-month period after gastrectomy in GC patients.  The authors did not 62  state what this improvement was due to but one can speculate that is probably because of the removal of the cancer itself and consequently in the belief that they have been cured   Characteristics of the Individual  3.3.5Characteristics of the individual (such as patient preferences and values) are demographic (including age, sex, ethnicity, religious and political affiliations), biological, developmental, psychological factors that can influence health outcomes [171]. According to the Wilson-Cleary model, characteristics of the individual can influence all the levels in the model prior to overall QOL.  In this study, the characteristics of the individual included age, sex and years since surgery as these may impact quality of life in persons after PTG.  Age is generally used as a demographic variable to describe a study sample and is sometimes used as a variable in studies of QOL of GC patients after gastrectomy.   Some of these studies that have used age as a variable have shown that older patients report lower physical functioning and more dyspnea symptoms than those of younger patients [237, 256]. However, younger patients are more likely to experience late dumping syndromes [233] possibly because of their tendency to eat larger meals and more rapidly than older individuals.  Some other studies have noted a statistically significant correlation between younger age and depression [244, 245, 246] in which the younger patients tend to have worse QOL than older patients.   It is believed that younger individuals diagnosed with cancer may have more intrusive thoughts about the disease and its impact on their future whereas older persons do not have these same thoughts as they have fulfilled most of their life tasks [245].   In contrast, other studies reported that younger patients had better QOL than the older patients [231, 237, 257]. 63  A few studies have looked at the influence of sex on symptoms and QOL after gastrectomy for GC.  Two studies [233, 258] reported that women appear to have a higher incidence of dumping syndrome symptoms; however, the reason for why this might be the case is unclear.  Two studies have reported better physical and role functioning for men after gastrectomy [174, 259] and this may explain why that the male patients had a more positive outlook after gastrectomy than the female patients in other studies [231, 257].    Although race/ethnicity as a characteristic of the individual may be important when examining quality of life in individuals after gastrectomy, there are no reported studies that have explored this variable.  This might be because most of the published studies have been done in countries that are predominantly of one race/ethnicity.    Characteristics of the Environment 3.3.6Characteristics of the environment include both physical surroundings and social interactions (such as social and psychosocial support and socioeconomic status) and can influence an individual’s view of their QOL [171].  I chose to include marital status and social support as characteristics of the environment that can influence a person’s QOL.   As with individual characteristics, most studies looking at GC patients who have had gastrectomy use marital status as a demographic variable. Marital status is believed by sociologists to be a defining feature of the social environment [260].  The emotional and practical everyday living support aspects provided by a partner can have implications on an individual’s quality of life.  There are only a handful of studies that have looked at the 64  relationship between marital status and QOL after gastrectomy in GC patients and these provide conflicting results.  An Iranian study did not find a relationship between marital status and QOL in individuals who had undergone gastrectomy for GC [261].  In a Japanese study, lower depression rates seen in the married individuals suggesting that perceived spousal availability and support were important. [246].   Most of the studies use time lapse between surgery/discharge from hospital to describe how QOL is affected over time.  Three studies did look at this time lapse to show that it is inversely correlated (statistically significant) with depression [246, 262, 263].  No explanations were given for this finding but it probably relates to a number of possibilities including decreased symptoms, better functioning.  More research will need to be done to see what other factors may be involved in this path.  In one study, almost 44% of patients diagnosed with GC had depression even one year after achieving disease-free status [264].  These were patients who had lower household incomes as a result of either loss of employment after their diagnosis or associated with the cost of medical treatment.  Figure 3.2 shows the variables being investigated in my study within the different levels of the WC model.  65  3.4 Instruments for Measuring Quality of Life The goal of most health-care providers is to improve their patients’ health.  In recent years, health-care providers have slowly come to acknowledge the fact that the patient’s perspective is important in improving the effectiveness and quality of health-care.  This has resulted in the advent of several series of generic and disease-specific questionnaires that measure patient-reported outcomes.  Patient-reported outcomes (PROs) are defined as “any report of the status of a patient’s health condition that comes directly from the patient, without interpretation of the patient’s response by a clinician or anyone else.” (p.79) [265]. The measurement of PROs plays an increasingly important role in healthcare as these instruments allow patients to provide information that is used to assess the outcomes and quality of care from their own perspective.  PROs include information about an individual’s QOL, symptoms, functional status, and satisfaction.  Data from the PROs can potentially be used to improve clinical decision making and patient-centred care (health status of patients).  PROs are also useful for research (such as effectiveness of a particular intervention) as they allow a systematic approach to patient assessment and problem identification that can easily be overlooked during routine check-ups.  Direct patient reporting of symptoms and QOL has become an important aspect not only of clinical research but also in clinical practice; this has led both the Food and Drug Administration and the European Medicines Agency to emphasize the importance of PROs in measuring QOL and have recommended that they be used in clinical trials [266].  66A PRO questionnaire or instrument should not only collect data in a valid and reliable way but also contribute toward better clinical care [266]. Chen and colleagues performed a systematic review of 27 studies and showed that the use of PROs by clinicians in a cancer setting improved patient-provider communication and increased patient satisfaction.  The authors suggest that this increased patient satisfaction may be attributable in part to the clinicians’ willingness to discuss their patient’s feelings and health status, leading to a sharing of treatment goals between provider and patient. [267]There are 2 main types of PROs – generic and disease-specific.  Thousands of different questionnaires or surveys have been developed in each category.  Both types are based on a series of questions on health and QOL that are answered by the patients themselves.  Generic PROs are general in that the same questions are used with all subjects – either those who are normal or who have very different conditions or diseases.  These results can then be compared across different patient and population groups. The focus of these generic questionnaires is how an individual’s state of health impacts his/her overall life.  The disease-specific or condition-specific PROs are questionnaires that measure the severity of a particular disease or condition by focusing on particular symptoms and limitations that individuals experience as a result of the condition. These questionnaires are not usually used in studying general health of normal populations.  Most studies of specific patient groups tend to use both generic and disease-specific instruments.  The SF-36 is a generic PRO that measures QOL and is widely employed [268].  Condition-specific QOL instruments that have been commonly used in GC patients included the 67  Gastroenterology Quality of Life Index (GQLI) [269], Life after Gastric Surgery (LAGS) [238], Gastrointestinal Symptoms Rating Scale (GSRS) [270], and the Functional Assessment of Cancer Therapy-General (FACT-G) [166].   The European Organization for Research and Treatment of Cancer Core (EORTC QOLQ-C30) [98] was developed to assess QOL of oncology patients in various diagnostic cancer categories.  The gastric cancer-specific EORTC-QOLQ-STO22 [99] module is an important instrument that has been developed specifically to measure QOL of gastric cancer patients. Both the EORTC-C30 and STO22 measure the impact of the disease together with the impact of the therapeutic interventions, expectations and personal satisfaction. Most studies of gastrectomy in GC patients have used the EORTC-C30 and STO22.  Worster and colleagues [15] also used the EORTC-C30, STO22 and SF-36 instruments in their cohort of patients who had PTG.   There are certain issues that need to be considered before a particular instrument is selected for any study - the validity and reliability of the instrument being used is very important.  Validity in research has long been known to refer to how well the instrument measures what it claims to measure and performs as it is designed to perform [167].   However, it is not the measurements, samples or methods/design of the study that have validity, it is the inferences or conclusions reached that have validation [271].  Therefore, the instrument or a sample enables valid inferences.  The instrument being utilised must include content, construct and criterion validity so as to be comparable with other accepted instruments. Furthermore, validation of the inference and in order to ensure that the instrument’s validation has to be a continuous process whereby Reliability refers to the consistency of the data being collected, including for example, whether the results are reproducible in repeated trials.   68  As highlighted in the literature of patients with mutations in other cancer predisposition genes, an accurate assessment of QOL in germline mutation carriers is essential to inform clinical decisions [194].  QOL provides insights into patients' experiences of the impact of the disease and its treatments on physical, social and emotional health. Prior to receiving a PTG, individuals are generally asymptomatic and healthy. They are also usually young, working or at school, and have families. Preserving the health and lifestyle of these patients is crucial in order for this surgery to be considered an alternative to endoscopic surveillance in CDH1 gene carriers.    3.5 Definition of QOL in This Study As reviewed above, most studies on quality of life research in individuals who had a gastrectomy were done in individuals diagnosed with GC.  These studies have focused on the health outcomes or health status of the individual.  This is also true for the one study [15] that looked at CDH1 mutation carriers who underwent PTG.  None of these studies have used a conceptual model.   In order to guide multidimensional QOL research, it is important to use one of the several QOL conceptual frameworks. Without a framework, the focus of the study may be narrowed, leaving out important factors on QOL such as the characteristics of the individual and environment.  In my study, I opted for the Wilson-Cleary model as it provides a framework for understanding the interrelationships between the different patient clinical outcomes and the potential influence of the sociodemographic and psychological influences.   It also provided a theoretical basis for choosing the variables to be studied.  This holistic look on quality of life may provide a better understanding of this multi-dimensional construct in individuals after PTG.   69 Figure 3.2 The Wilson Cleary model with study variables inserted into each level.  70  Chapter 4: Methodology 4.1 Objective 1: Penetrance Analysis  This analysis is part of a study on risk assessment in clinically-defined HDGC families that has been ongoing in our laboratory since January 2002.  I have been ascertaining these families since then on an ongoing basis through genetics clinics or oncology specialists, primarily in North America. All patients or next-of-kin from deceased individuals provided written, informed consent to participate in the study.  Clinical data, including pathology reports and pedigrees, were collected by the genetic specialist at each site. The pedigrees and all available medical records were centrally reviewed (Kaurah and Huntsman) for verification and eligibility into the study.  In families where a germline mutation was identified, the proband or next-of-kin was given the test results by the referring site’s genetic specialist. Family members were contacted by the proband and then referred to their local genetic specialist for counseling and carrier testing.   Families in the current analysis were recruited between February 2006 and June 2013 [6].  A total of 183 new index cases meeting IGCLC 2010 clinical criteria were tested during this time period.  Thirty different pathogenic germline mutations plus 4 variants of unknown significance were found within 37 families (20.2% of 183 tested) [6]  A total of ninety-two families, both published and from our database, in which a familial CDH1 pathogenic germline mutation had been identified, were available for estimating the penetrance of CDH1 mutations.  Families which had germline missense variants of CDH1 that were not confirmed to be pathogenic either by expression of the protein (E-cadherin) in cell populations by immunofluorescence or family segregation studies were excluded from the analysis.  We also 71  excluded families in which the only known member with a CDH1 mutation was the index case, that is, no information on carrier tests results (including on obligate carriers) was available on individuals who had not developed cancer. Penetrance data were therefore derived from a total of 67 families – a summary table of the families is provided in Appendix A.   I ascertained all of these families internationally and then collected data on each family.  If the families were from our study database, I went back to each genetic counsellor/geneticist who had referred the family into our study to obtain further information on the family. For example any newly diagnosed individuals and carrier tests in the family since last contact with me.  I entered all data required into a pre-designed data sheet in excel as requested by colleagues at the University of Cambridge.  The actual penetrance analysis was all performed by Dr. Paul Pharaoh (Professor of Cancer Epidemiology, University of Cambridge).  Pedigree information to estimate the penetrance of CDH1 was performed using the MENDEL program [272].  Mendel is a comprehensive software package that is available through the University of California Los Angeles for statistical analysis of both qualitative and quantitative genetic traits.  Family ascertainment was made on the basis of the availability of multiple affected members with an index case who tested positive for a pathogenic CDH1 mutation.  A pedigree file was created for each family using the default pedigree format of the program.  Each line in the pedigree file contained data on each individual in the pedigree.  Each individual record contained the following data (in order): 1. Pedigree ID code 2. Individual’s ID code 72  3. ID code of parent #1, if in the pedigree 4. ID code of parent #2, if in the pedigree 5. Individual’s sex 6. Identical twin status 7. Age of individual 8. Phenotype, that is whether affected with cancer or not 9. Age at diagnosis of cancer 10. Genotype at the CDH1 locus  In the Mendel program, missing values are allowed for all fields except for the pedigree name, individual’s name, and sex.   For other fields with missing data, specific commands can be input to allow the program to read in data sets.  Since each pedigree contained a number of affected individuals when it was first ascertained, each of these initial affected individuals was labelled as a proband in the pedigree file.  When more than one proband exists in a file, MENDEL undertakes an ascertainment correction.  This correction which relies on likelihood evaluation, is done by conditioning on proband phenotypes.  Mendel takes into account all the probands and creates a proband pedigree that has enough connecting people to allow for the correct relationships between all the probands.  Then, likehood correction takes place whereby the log likelihood of the proband pedigree is subtracted from the log likelihood of the original pedigree.   L(Pedigree|Ascertained Pedigree) = L(pedigree) / L(Ascertained pedigree). Thus the conditional likelihood of the pedigree was maximized given the phenotype of all the available family members and genotype of the index case at ascertainment.   73  The model was parameterized in terms of log relative risk for GC and BC in mutation carriers compared with population risks. This assumes that cancer incidences in mutation carriers is the same for all families, whatever their ethnic origin. The number of families from different countries was too small to enable country specific penetrance estimates.  Non-carriers of the deleterious mutation in each family were assumed to have a probability of developing this disease as reported in the United Kingdom thus assuming that the cancer incidence is the same for all families regardless of ethnicity.  The GC RR were estimated separately for men and women and allowed to vary with age using 6 age groups between 10-75 years.  The RR of BC for women was modeled to be constant with age. The population frequency of CDH1 alleles is not known in the general population but is assumed to be rare.  Given this the population frequency was assumed to be 0.001.  4.2 Objective 2: Catalogue of CDH1 Mutations in the Literature.    There is currently no publicly maintained database that has a comprehensive list of CDH1 mutations. To obtain a comprehensive list of reported germline CDH1 mutations, a MEDLINE and EMBASE search for articles from 1998 (when the first CDH1 mutation was reported) to March 2015 was conducted using the following search terms:  CDH1, E-cadherin, germline mutation, gastric cancer, and hereditary diffuse gastric cancer, familial gastric cancer and diffuse gastric cancer.  The articles included both original reports and literature reviews in the English language.  Information from English abstracts of articles where the main text was in another language, was included if there was sufficient information in the abstract.  Information for CDH1 mutations was generated by: 74  1. Mutation type 2. Year of report 3. Patient ethnicity or country where the mutation was identified 4. Frequency of mutation reported  5. If the mutation was reported to be recurrent or in a review paper, the original paper was checked.   The mutations were catalogued according to exon location and type (missense-pathogenic, missense-unclassified variant, nonsense, insertion, deletion, or splicing).  The missense variants classified as pathogenic included those that led to a truncated protein through splicing defects or where the nucleotide change disrupted the start codon.  I excluded all silent polymorphisms and somatic mutations and all variants of uncertain significance.  4.3  Objective 3: To Describe the Post-operative Complications, Major Symptomatology and Quality of Life in CDH1 Mutation Carriers After PTG.  Study Design 4.3.1This non-experimental research study employed a cross-sectional, design to determine factors affecting quality of life in carriers of a CDH1 mutation who underwent prophylactic total gastrectomy.  A cross-sectional study examines data at one point and is best used to describe the relationship between a health-related state and other variables of interest as they exist in a defined population.  This design was appropriate because I did not look at changes in quality of life over time. Data were collected on one occasion from participants to describe their current level of quality of life, as well as factors potentially affecting their quality of life.  75Study Sample 4.3.2Subject Selection Criteria for Participants criteria for selecting subjects for this study were: 1) At least 18 years of age (adult).2) Tested positive for a CDH1 gene mutation, regardless of when this occurred.3) Never been diagnosed with gastric cancer4) Undergone PTG (time span does not matter).6) Able to read, write and understand English. I could not translate the demographic and clinicaloutcome form into other languages. (Appendix G) Accrual of Subjects order to minimize the potential for breach of confidentiality or invasion of privacy, subjects who were enrolled into the study outside of British Columbia (BC) were invited into the study through their own cancer genetic professional across North America. A summary of the proposed research study was sent to cancer genetic professionals together with a reply form asking for written permission to contact the patient (Appendix B). Surgeons who were known to our group as having performed several prophylactic gastrectomies were also sent this initial package. A study summary was sent to the National Association of Genetic Counsellors listserve in the US.  In addition, the study summary was sent to the website, "Nostomachforcancer.org".  Potential participants in Newfoundland were approached through the genetics clinic in St. John’s through a separate process that is detailed below.  76   Participant Contact permission was obtained from the health professional, the participants were sent an introductory package inviting them to take part in the study. Those who were enrolled through the Hereditary Cancer Program in BC were sent the introductory packages directly. The package included an introduction letter (Appendix C), an authority to divulge medical records form (Appendix D) and a consent form (Appendix E) indicating whether they wanted to be included in the study.  All participants were provided with a stamped, self-addressed envelope.   Once the signed consent form was returned to us, each participant was assigned an anonymized study number.  All study instruments were then mailed to the participants for completion at home (Appendices F-K).  Each questionnaire was labelled with the participant’s study number before it was mailed out.  A stamped, self-addressed envelope was also included and was also labelled with the study number.    Each time a participant was sent either the first mailing (introductory package) or the second mailing (study instruments), this information was entered into a computerized file that tracked the scheduled and completed consents and/or instruments.  The survey method of Salant and Dillman [273] was followed.  This survey method recommends 4 separate mailings and was followed thus: if no reply to the initial letter was obtained within 2-3 weeks of mailing, the potential participant was sent another letter.  A third mailing, if necessary, was posted to participants three weeks after the second mailing. The fourth and final mailing (including a second copy of the questionnaires) was sent to those individuals whose responses had not been received. A stamped return envelope and cover letter were included each time. The deadline to 77  respond was set up for four weeks after this last mailing.  In some cases, participants contacted the researchers via electronic mail and indicated that this was their preferred form of communication.  In this case, all “mailings” and contact was done using e-mail communication but the same time frames were used.     Newfoundland Cohort genetics research in Newfoundland and Labrador is governed by the Health Research Ethics Authority Act (The Act) which came into force on July 1, 2011.  According to this Act, all health research done in the province has to be reviewed and approved by a local research ethics board.  The Health Research Ethics Authority (HREA) oversees all health research ethics review by the Health Research Ethics Board (HREB) or an approved health research ethics review body. Any researchers outside of Newfoundland cannot contact the potential participants directly even with the permission of the local genetics professional involved.    The individuals recruited from Newfoundland (NF) were sent the introductory package and study instruments (Appendices F-K) from the genetics clinic in St John's as per the NF HREA and HREB guidelines.  To allow the NF genetic counsellor to track the documents and avoid unnecessary future mailings, each of the questionnaires included a serial number on the back page. The Salant and Dilman [273] method was not followed in NF despite repeated requests from me. This meant that no reminder notices were sent to any potential participant 2-3 weeks after the introductory package was mailed.  If a participant did not return the study instruments, no reminders were sent.    78   Instruments/Data Collection Tools (Independent variables) 4.3.3In gathering the data for this study, the survey method (also known as the questionnaire method) was used.  Seven instruments were sent to the participants (Appendices F - K). The Wilson-Cleary model (see section 3.2 above) provided the basis for the selection of the variables being studied.  Due to the scarcity of research that has been done in the area of prophylactic gastrectomy, the variables studied were based on previous research done on individuals who had TG for gastric cancer and from discussions with some individuals who have previously undergone PTG.   The questionnaire items and scales were chosen to reflect the variables of interest within each domain in this study.   Characteristics of the Individual demographic data were collected to allow description of the sample (see figure 3.2). Patient data included age (both at time of surgery and survey), sex, education level, and ethnicity. This information was collected using the demographic questionnaire (Appendix F).    Characteristics of the Environment (see figure 3.2) including marital status, employment status, and time elapsed between surgery and survey were collected using the demographics form (Appendix F).   Biological Factors records were obtained from the hospital in which surgery was performed.  The authority to divulge medical information form (Appendix D) specifically asked for pre- and post-clinical laboratory investigations, operative report, and discharge summary.  Any follow-up outpatient 79visits and re-admissions to hospital were also recorded. Post-surgical complications in this study were defined as any difference from the normal postsurgical course and that occurred as a result of the surgery [274].When complications were associated with the surgical technique near the operative field (for example, intra-abdominal abscess), they were considered as local complications.   When the complication was not associated with the operation field, they were considered systemic (for example, pulmonary effusion. Postsurgical complications were divided into three groups: acute or immediate complications (14 to 30 days post-surgery); early postoperative complications (within first 6 months of surgery) and late complications (6 months post-surgery) [275].   Body mass index (BMI) is a measure of body fat based on height and weight that applies to adult men and women.  It is calculated using a simple formula BMI = kg/m2.  Kg is a person’s weightin kilograms and m2 is the square of the height in metres [276]. BMI is used by health-careprofessionals to determine whether an adult individual is underweight (<18.5), a healthy weight (18.5 to <25), overweight (25 to <30) or clinically obese (>30).   Height and weight were collected on the demographics and symptom form (Appendix G).  These were then used to calculate the BMI. Post-gastrectomy Symptom Status - Instruments Symptoms/Clinical Form (Appendix G)A list of pre-selected major post-surgical complications and major symptomatology that are experienced by individuals after PTG was created (Appendix G).  This questionnaire was 80developed with input from a specialized surgeon (Dr. Debrah Wirtzfeld) who is experienced in performing TG and PTG.  Items were included to obtain information on the participants’ experience of common symptoms such as nausea, diarrhoea, and other early and late dumping syndrome symptoms.  This patient-reported outcomes form also allowed me to collect the frequency of the symptoms as well as how bothersome each symptom experience was for the participants.  Each participant was asked to report on symptoms experienced in the seven days prior to the questionnaire being completed.   In addition, there were questions on participant satisfaction with having the surgery (How satisfied are you with your decision to have prophylactic gastrectomy?), their involvement in making the decision to have surgery (How involved were you with your decision to have prophylactic gastrectomy?) and any cancer worry they may have had after their surgery (Do you still worry about developing gastric (stomach) cancer?).  Satisfaction was rated on a five point Likert-type scale from one (extremely dissatisfied) to five (extremely satisfied).  Degree of involvement in the decision-making for PTG was rated on a Likert-type scale from one (completely involved) to five (not involved at all).  The questions were formulated based on discussions with individuals who had undergone the surgery.This questionnaire was piloted with a small group of unaffected individuals outside of the study itself.  Upon receiving the questionnaires back from these individuals, I contacted them to ask them the following questions: 1. Were any of the questions difficult to answer?2. Were any of the questions confusing or not understandable?81 3. Were any of the questions too sensitive or embarrassing to answer?4. Were there any questions that should have been asked but were absent from the form?5. Was the formatting of the response categories easy to follow?6. Was the questionnaire too long?ii. Patient-Reported Outcomes Measurement Information System (PROMIS)Measures of Anxiety and Depression. (Appendix G and H)The anxiety and depression instruments that were used in the study were from the Patient Reported Outcomes Measurement Information System (PROMIS) bank.   This is an initiative spearheaded by the National Institute of Health to develop, evaluate and standardize item banks for measuring patient-reported outcomes in physical, mental and social health well-being across several medical conditions, including cancer.   The item response theory (IRT) statistical model used by PROMIS utilizes a psychometric measurement model for scoring, not just the sum of individual responses. The PROMIS instruments are scored using item-level calibrations; these are achieved using the scoring tools within the NIH PROMIS Assessment Center software.   This model-based scoring is more accurate than using the raw score/scale score look up tables that are also provided by the Assessment centre.  The final score is represented by the T-score, a standardized score with a mean of 50 and a standard deviation (SD) of 10.  This is true for most PROMIS instruments as the calibration testing was performed on a large sample of the general population.  Higher scores indicate better health.  The average score is 50 with a standard deviation of 10 for the United 82  States general population [277].  A final standardized T-score was returned for each participant in the study.  The score is approximated if a participant skips a question.   Anxiety: Adult (PROMIS Emotional Distress – Anxiety) v.1 (Appendix G) has 29 items and measures pure anxiety symptoms: self-reported fear, anxious misery, hyperarousal and somatic symptoms related to arousal.  There are 5 Likert response categories for each question (1= never, 2= rarely, 3 = sometimes, 4 = often, 5= always). Respondents are asked to recall how they felt over the past seven days.  Internal reliability has been reported to be 0.90 and the instrument is highly correlated with the Mood and Anxiety Symptoms Questionnaire [278]. This instrument is generic and not disease-specific and assesses anxiety over the past seven days.   Depression - Adult (PROMIS Emotional Distress—Depression) v.1 (Appendix H) The PROMIS Depression instrument is a 28 item instrument that measures pure depressive symptoms and focuses on assessing self-reported negative mood, views of self, social cognition, and a decrease in the positive affect and engagement.  Unlike most depression measures, the PROMIS-Depression item bank does not measure behavioural and somatic symptoms such as changes in appetite or sleeping patterns which can have confounding effects when assessing patients with comorbid physical conditions [278].  There are five Likert response categories for each question (1= never, 2= rarely, 3 = sometimes, 4 = often, 5= always). Respondents are asked to recall how they felt over the past seven days. The Depression form is universal and not disease-specific. The depression instrument is an established depression screening tool with researched reliability and validity.  The PROMIS-Depression has an internal consistency reliability score of 0.95 [278] 83   Functional Status/Condition Specific QOL The European Organization for Research and Treatment of Cancer (EORTC) Quality of life (QOLQ-C30) questionnaire version 3 (Appendix I)  The European Organization for Research and Treatment of Cancer (EORTC) Quality of life (QOLQ-C30) questionnaire [98] has been translated and validated in 81 languages and has been used in more than 3,000 studies worldwide [279].  This is a 30-item cancer-specific questionnaire to assess the HRQOL of cancer patients within four domains; these include functional scales, symptom scales, global quality of life and single items. There are five functional scales (physical, role, cognitive, emotional and social), three symptom scales (pain, fatigue, nausea/ vomiting), a global health and QOL scale and single items for the evaluation of symptoms commonly reported by patients with cancer.  These symptoms include dyspnea, appetite loss, constipation, diarrhea and sleep disturbance.  No item in the instrument occurs more than once so that each of the scales with multi-items has a different set.    The response categories range from “not at all”, “a little”, “quite a bit”, to “very much” and are scored 1 to 4, respectively. The global health/QOL scale has 7 response options that range from very poor to excellent.  The questionnaire’s psychometric properties have been tested and were found to have the required standards of validity and reliability [280, 281].   The EORTC questionnaire was developed in a European (that is, multicultural) context and so underwent psychometric testing in several alternate languages [98]. Reliability values for the nine scales appear to be similar across cultural and language cohorts [98].  The results of these studies all point to good reliability (that is, alpha coefficient above 0.70) of the scales.   84  ii. European Organization for Research and Treatment QOL Questionnaire-GC Module: QOLQ-STO22 (Appendix J)  The disease-specific module for gastric cancer (QOLQ-STO22) questionnaire is a 22-item form used together with the EORTC QLQ-C30 to assess quality of life in individuals with gastric cancer.  There are five multi-scale items that include dysphagia, pain, reflux, eating and anxiety.  There are also four single items (dry mouth, tasting, body image and hair loss).  These items cover disease and treatment related symptoms and emotional consequences of GC [99].  Many of these symptoms are part of the dumping syndrome spectrum. The EORTC QLQ-STO 22 has been shown to demonstrate clinical validity and reliability in gastric cancer patients [99] [282] supporting its use to supplement the EORTC QLQ C-30 to assess the quality of life in patients with gastric cancer.     iii. The Short Form (36) Health Survey version 2 (SF-36v.2 (Appendix K) The SF-36 v.2 is a multi-purpose, short-form health survey and consists of 36 questions.  It is a generic measure, rather than one that targets a specific age, disease, or treatment group. It has proven useful in surveys of general and specific populations, comparing the relative burden of diseases, and in differentiating the health benefits produced by a wide range of different treatments or procedures.  The instrument consists of an 8-subscale health-related profile: limitations in physical functioning due to health problems (10 items), limitations in usual role activities because of physical health problems (role-physical) (4 items), bodily pain (2 items), vitality (4 items), limitations in social activities because of physical or emotional problems (social functioning) (2 items), limitations in usual role activities because of emotional problems 85  (role-emotional) (3 items), general health perceptions (5 items) and mental health (psychological distress and well-being) (5 items).  Two summary scores are provided, the physical health component summary and the mental health component summary.  These two scores are obtained by weighting and scoring the eight scales. The MCS and PCS scores are standardized so that scores > 50 reflect better physical and emotional functioning that when compared to the general population. Although the SF-36 has been widely validated for use across a range of health care professions, settings and patients, there are only 3 reports that have used this instrument in patients with GC after gastrectomy [175, 283, 284]   In this study, the SF-36 v.2 was used because the cohort is made up of individuals who are asymptomatic with respect to cancer.  The SF-36v.2 was used to see if the results from both this and the QLQ30 corresponded.    4.4 Human Subjects Protection The study was approved by the Behavioural Research Ethics Board of the University of British Columbia (Certificate number H11-00956).  In addition, permission to conduct the study in Newfoundland was obtained from the HREB and HREA.  Participants were fully informed regarding the purpose of the study and expectations of participation. A written consent form was reviewed and signed by each participant prior to collecting data and each participant received a copy of the consent form.   86  Confidentiality was maintained on all data collection forms by using codes to identify participants instead of names, or any other personal identifiers. A master list of participant names was kept separate from the data collection forms. This master list was used during the data collection period to ensure that persons were not recruited more than once. All data collection forms are kept in a locked file in the investigator’s office separate from the master list. In all subsequent analyses, data was only available to the research team and were kept in a secure area where only authorized access is available.     4.5 Data Analyses for Objective 3 All the surveys were examined for completeness and were then coded in a standardized format and entered into IBM SPSS version 22.  Five instruments (PROMIS instruments Anxiety and Depression, EORTC QOLQ-C30, QOLQ-STO22 and SF-36) required calculation of scores.  The computations for the PROMIS instruments were done within the NIH PROMIS Assessment Center (http://www.assessmentcenter.net/).  The EORTC QOLQ-C30 and QOLQ-STO22 computations were performed by creating new variables in SPSS using formulas to determine scale totals.  The SF-36 was scored using the online SF Certified Scoring program.  Descriptive statistics were calculated to describe the sample characteristics.  Mean, median, standard deviation, range, skewness and kurtosis were determined for continuous variables.    Time elapsed between surgery and my survey was divided into 3 groups: Group 1 was short-term (≤12 months), Group 2 mid-range (13-60 months) and Group 3 long-term (> 60 months) to see if symptoms and functional status improve with time after surgery. Each question in the aim was analyzed separately. All analyses, apart from the heatmaps and stepwise regression, were 87  performed using SPSS.  Heatmaps and stepwise regression were performed in R. The two-sided significance level for all statistical tests was p < 0.05.  As this was an exploratory study, no adjustment was made for multiple comparisons (and supported by my advisory committee).  A power analysis was conducted using nQuery Advisor software to determine the required sample size to answer the research questions.  The calculation was for multiple linear regression and the following parameters were entered: a significance level of 0.05, 80% power, 15 predictor variables, and an estimated moderate effect size (R2 = 0.35).  The minimum sample size required was 50 participants. Using an effect size of 0.25, my actual sample size of 53 participants would only allow for 9 predictor variables to achieve 80% power.   Data Analyses for the Specific Aims: 4.5.11. To document and describe, through a medical chart review, post-surgical complications in individuals during the first 12 months after PTG.  Descriptive statistics, including mean and median, standard deviation, range, and frequencies were used to summarize the data.   2. To document, describe and analyze through survey instruments:  A. Symptoms, their frequency and intensity in individuals after PTG.  Symptoms were taken from the clinical demographic form and both the EORTC-QLQ 30 AND EORTC-STO22 instruments. The post-gastrectomy symptoms in the clinical and demographic questionnaire were assessed and summarized by categorizing the participants into those who had their surgery less than or equal to 12 months, between 13 88– 60 months and over 60 months prior to the survey.  This allowed me to see if those whohad their surgeries more than a year prior to their surgery were doing better or worse than those who had it less than a year before the survey. Body mass index was calculated using the formula: BMI = kg/m2 where kg is the participant’s weight in kilograms and m2 is the square ofthe height in metres.  BMI was calculated for both pre-and post-surgery and the mean change in BMI was calculated.   Scoring of both EORTC instruments was done as per the instructions in the EORTC manual [285].  Responses from each instrument were linearly transformed to the 0 to 100 scale.  This was done in SPSS by using syntax provided in the EORTC scoring manual.  The EORTC scoring manual indicates that the principle of scoring both single and multi-scales is the same.  Scoring is done first by estimating the average of the items in the scale to provide a raw score (RS).  The raw score is first calculated by estimating the average of the items for each scale using the following formula: RS= (Item1+ Item2+…+Itemn)/n Where n= number of questions per scale. This raw score is then standardized to the score (S) between 0 – 100 by linear transformation as follows:  89  For Functional scales:      S= (1- ((RS-1)/range) x 100 For global quality of life and symptom scales/items:  S= ((RS -1)/range) x 100  The range is the difference between the maximum and minimum possible values of the RS.  All questions, except for global health status/QOL, have a range of 3.  Global health status/QOL has a range of 6 since there are 7-point items in this scale.    The total scores range from 0 to 100.  For the functional scales of the EORTC-QLQ-C30 and EORTC-QLQ-STO22, a higher score indicates a better QOL, with 100 being a perfect score. For the symptom scores, a lower score indicates a better QOL, with 0 being a perfect score indicating no reported symptoms. The scores can be compared against data that has been published for QOL of gastric cancer patients who had therapeutic gastrectomy [285].  In this case, this study’s data were compared to large random samples of the general population data based in Norway and Sweden as those are the only published data for individuals without prior gastric cancer [286].   Missing values for both EORTC QOLQ-C30 and QOLQ-STO22 were handled according to the recommendations in the European Organization for Research and Treatment of Cancer QOQ-C30 scoring manual [285].  A score is generated if the participant answered at least half of the corresponding items.  Missing items can be ignored when making the calculations if simple imputation by the personal mean is retained.   For example, if a participant did not respond to a question about abdominal pain, then s/he was excluded 90  from analysis of abdominal pain but included in all other analyses of functions and symptoms.    The mean, standard deviation, minimum and maximum for the totals were calculated.  In addition, subscale scores for each instrument were also calculated.  Scores from both EORTC instruments were presented in groups that were categorized according to time elapsed between the surgery and survey (≤12 months; 13-60 months or >60 months).  The one-way ANOVA test was done to compare the 3 groups.    The 5-level response options in the SF-36v2 range from “all of the time” to “none of the time.  Norm-based scoring (NBS) algorithms are used for all 8 scales [212]. Each item response is scored and summed according to a standardized scoring protocol [212].  This is then expressed as a score on a 0–100 scale for each of the eight health concepts, assuming equal weight for each question.  Reference values are a mean of 50 and standard deviation of 10 in the general US population.  The higher the score, the less the disability, that is a higher score indicates a better self-perceived health.  SF-36v2 scoring software also yields less biased estimates of missing responses and makes it possible to estimate scores for more respondents with incomplete data.  B. Anxiety and Depression symptoms after PTG Anxiety and Depression: these were individually scored and descriptive statistics (frequencies, means and standard deviations) were generated.  Each item on the Anxiety and Depression instruments is rated on a 5-point Likert-type scale (1=never; 2=rarely; 91  3=sometimes; 4=often; and 5=always) with a range in total score from 8 to 40; higher scores indicate greater severity of the emotional distress (anxiety and depression).  The PROMIS IRT was used to calculate the scores as described above. A score was approximated if a participant skipped a question. The final score was represented by the T-score, a standardized score with a mean of 50 and a standard deviation (SD) of 10.   A score of 50 (SD = 50) is the average for the United States general population.  The T-scores are interpreted with respect to anxiety and depression as follows [280]: Less than 55 = None to slight 55.0—59.9 = Mild 60.0—69.9 = Moderate 70 and over = Severe  A series of Mann-Whitney tests were done to see if there was any difference in depression between sex, age at surgery, time elapsed since surgery and survey, education, employment and marital status.    A heatmap was constructed in R to allow the simultaneous visualization of symptoms from the EORTC C30 and STO22 instruments to so that I was able to visualize how symptoms were associated with each other and in order to pick out trends in participants’ symptom experience.  A heatmap, which is essentially a colour image with a dendogram added to the left and top columns of the image, involved the reordering of the rows and columns of the data with the restrictions imposed by the dendogram.  The heat map 92  allowed me to identify and group patients according to whether they had symptoms or no symptoms.  Patient IDs and all symptoms from the EORTC instruments were first prepared and pre-processed in an excel sheet and then loaded onto R software for analysis and construction of the map.  The heatmaps are linked to hierarchal clustering in R to clearly show the data in a visual manner.  The clustering allowed me to see if there were participants who shared symptoms or not.    3. To assess patient satisfaction after PTG Analysis of satisfaction with having had PTG was done using descriptive statistics (mode).  The distribution of the responses is displayed using a bar chart.    4. To document and describe the quality of life in individuals after PTG. The scoring algorithms for EORTC instruments have been described in detail above.  The EORTC QLQ-C30 has one global health status/quality of life question with the responses ranging from 1) Very poor to 7) Excellent on a categorical scale.   The mean, standard deviation, minimum and maximum for the total for the global health status/quality of life scale was calculated.  In addition, the scores for each of the five function scales (physical, role, emotional, cognitive and social) were calculated.  Scores were presented in groups that were categorized according to time elapsed between the surgery and survey (≤12 months; 13-60 months or >60 months).  The one-way ANOVA test was done to compare the 3 groups.    93  4.1 In order to examine if any of the characteristics of the environment and individual and symptoms affected the overall QOL of the participants, a linear multiple regression model was fit with QOL as a response variable and variables from Figure 3.2 were entered as predictor variables into R.  Since the characteristics of the individual and environment were nominal/categorical variables with more than two levels, the additional step of recoding (dummy coding) these categorical variables into separate, dichotomous variables was done to reduce the number of parameters. The variables were coded according to the most frequent response in that category. These dummy variables were then directly entered into the regression model as predictor variables. The dummy variables are shown in Table 4.1    94  Table 4.1 Dummy coding for nominal variables gender and marital status  Variable Reference value = 1 Non- reference value = 0 Sex Female Male Marital Status Married (including common-law) Widowed Divorced Separated Never Married  Working status Working (employed for wages/self-employed) Student Homemaker Retired Out of work (looking and not looking for work) Education University (including 4 year degree, Masters, PhD, Professional degree) No high school Some high school High school completed          Prior to examining the regression statistics, the assumptions associated with regression solutions were addressed [287]. Multivariate normality, linearity and homoscedasticity for each variable were checked by examining the standardized residual scatterplots.  The residuals should be centered or distributed equally along the range of fitted values.  The assumptions of normality, linearity and homoscedasticity were satisfied by examining a scatterplot of residuals and predicted values. No distinct patterns were noticed of high or low points were discerned; most of the points were along the midpoint [287].  In addition I checked for multicollinearity of independent variables. The tolerance level and variance 95  inflation factor (VIR) were calculated for all the independent variables to ensure multicollinearity assumption was met.  A tolerance value of less than 0.10 and a VIF greater than 10 was used to recognize multicollinearity in case any variables needed to be removed.  The collinearity statistics of Tolerance and VIF were all within accepted limits, thus the assumption of multicollinearity was considered to be met. Multivariate outliers were checked using the standardized residual values between -3.0 and 3.0. [287].   A full linear model was first ran involving all predictor variables and quality of life as the response variable.  The fitting model was as follows: QL2 ~ PF2 + EF + CF + RF2 + SF + Depression + Anxiety + STOBI + STODYS + STOPAIN + STORFX + STOEAT + STOANX + STODM + STOTA + Sex + PA + DY + NV + CO + SL + FA + DI + FI + AP + EmploymentStatus2 + Education + Age.survey + MonthsSinceSx + MaritalS   A reduced model was also performed by using a stepwise procedure with the AIC criterion.  A restriction was placed on the parameters within the reduced model (QL2 ~ CF + RF2 + SF + Anxiety + STOBI + STODYS + STOPAIN + STOEAT + STOTA + DY + DI + EmploymentStatus2   96  Chapter 5: Results  This chapter describes results of the penetrance data, estimation the mutational landscape of CDH1 in HDGC, and analyses of the surveys of patient-reported outcomes in CDH1 germline mutations carriers who had undergone PTG. In addition to the planned tests, an additional model was explored based on initial findings.  5.1 To Derive Reliable Estimates of Cancer Risk for CDH1 Mutation Carriers.   Pathogenic germline CDH1 mutation data and family histories were available from a total of 92 families.  However, 25 of these families were excluded from the penetrance analysis because there were no genetic testing reports of family members other than the index case.  The remaining 67 families (Appendix A) that were entered into the MENDEL program comprised 4031 individuals, including 350 affected with gastric cancer and 99 affected with breast cancer.    The estimated cumulative risk of gastric cancer by age 75 years in carriers of pathogenic CDH1 germline mutations was 70% (95% confidence interval [CI], 40%-94%) for males and 56% (95% CI, 27%-90%) for females.  The risk of breast cancer for females was 42% (95% CI, 23%-68%) by 75 years. The age categories of 10-20 years were collapsed within the 10-29 category as the cumulative risks for male and female gastric cancer and female breast cancer was 0% until the 20-29 years.  These results are shown by age and sex in Table 5.1.  The cumulative risks are shown graphically in Figure 5.1     97  Table 5.1 Cumulative risks (95% confidence interval) of GC and BC in CDH1 mutation carriers of both sexes     Gastric Breast Age (yrs)  Male Female Female  10-29  4 (0-13) 2 (0-9) 0 (0-1) 30-39   10 (3-26) 17 (9-32) 3 (1-6) 40-49    25 (12-50)  25 (13-47) 11 (9-14) 50-59  32 (14-64)  33 (16-63)    21 (16-26) 60-69  48 (24-80)  41 (19-74)    32 (26-39) 70-75+  70 (40-94)  56 (27-90)    42 (23-68)                          98   Figure 5.1 Cumulative risks of gastric and breast cancer for CDH1 mutation carriers by sex.    5.2 CDH1 Germline Mutation Landscape in HDGC.    As part of the ongoing study to define the mutations in HDGC families, 183 index cases from clinically defined HGDC families were tested in our laboratory.  Most of these families were from Canada and the United States.  Thirty different pathogenic germline mutations plus 4 99  variants of unknown significance were found within 37 families (20.2%) [95]. The mutations in this study, like previously reported mutations, were distributed throughout the CDH1 gene (Figure 5.2), including within the adjacent splice site sequences.  Truncating mutations made up the majority of these changes.  Missense variants made up approximately two-fifths of the mutations and included missense variants leading to truncated protein through splicing defects, mutations impacting the start codon and unclassified variants.    The largest proportion of germline mutations were found in families fulfilling IGCLC criterion 1 (≥ 2 GC cases in a family with at least one with pathologically confirmed DGC <50), followed by families fulfilling criterion 4 (personal or family history of DGC and LBC, with one of the affected persons diagnosed at less than 50 years of age).    Fourteen of the mutations have been previously described in other seemingly unrelated families [7, 93, 105, 109, 288, 112, 111, 289, 290, 291].  Cleft lip and scalp aplasia cutis appeared to co-segregate with the HDGC phenotype in a previously described family with the c.1137G>A mutation [289], but neither has been seen in any of our families with the same mutation.  Another family in our study has a mutation at the same site but with a different nucleotide substitution (c.1137G>T).   Whereas mutation hotspots could account for recurrent single base pair substitutions, recurrent large-scale deletions with identical breakpoints are more likely to be due to shared ancestry.  We have seen these large deletions in our series of patients (Table 5.2) [95]   100 Figure 5.2  Mapping of germline CDH1 mutations described to date by mutation-type and location on CDH1-transcript. Colored circles represent pathogenic mutations; open circles represent unclassified variants and starred circles represent mutations identified in the current study. (B) Genomic breakpoints of CDH1-large deletions. S= signal peptide, Cyto=cytoplasmic, and TM=transmembrane domain. Adapted from S.Hansford et.al. (2015) A) Mapping of germline CDH1 mutations described to date by mutation-type and location on theCDH1-transcriptB. The genomic breakpoints of large deletions within the gene. i – v indicate the large deletions of known breakpoints 101  The literature search yielded a total of 146 articles of which 69 were excluded.  The excluded articles were on reports of somatic mutations in the CDH1 gene, germline mutations in genes other than CDH1 in gastric cancer patients/families, review articles with no germline mutation information, or guidelines for management, genetic counselling and testing of HDGC patients and their families.  The majority of studies (78%) reviewed for the cataloguing of reported CDH1 mutations were original reports.  I also utilized 2 manuscripts where reported mutations were already catalogued as cross-references [124, 125].  In addition, these 2 manuscripts also had new mutations listed by the authors that were not reported elsewhere.  I identified 155 mutations (126 pathogenic and 29 variant of uncertain significance (VUS)) and stratified these according to mutation type and also by ethnicity when this was available (Table 5.2).    These germline mutations are distributed throughout the CDH1 protein coding segments and adjacent splice site sequences (Figure 5.2A).  Truncating mutations make up the majority of these changes, while missense variants make up approximately two-fifths of the mutations. Missense variants include those that lead to truncated protein through splicing defects, mutations that impact the start codon and others.   Approximately 25% (32 of 126) of reported CDH1 pathogenic mutations have been reported in multiple seemingly unrelated families, sometimes in different ethnicities (Table 5.2).   The finding of recurrent mutations suggests that germline mutations can either arise from a common ancestor [7, 96] or be the result of novel events at mutational hotspots.    102  Table 5.2 CDH1 mutations described in this study and in the literature.   CDH1 Mutation Location Mutation Type *Ethnicity or (Country of origin if ethnicity is unknown) Reference  5'UTR(-117)G>A Promoter 5'UTR-Unclassified Variant (Canada) [292]  5'UTR(-71)C > G Promoter 5'UTR-Unclassified Variant (Canada) [292] [293]  -63C>A Promoter 5'UTR-Unclassified Variant Italian [125]  chr16:del 67328695-67328      844 (150bp) 5'UTR and Exon 1 Large Deletion Hispanic [95]  chr16:del 67324886-      67330557 (5671bp) Exon 1 and 2 Large Deletion Lithuanian [95]  chr16:del 67193822- 67387415 (193 593bp) Exon 1 and 2 Large Deletion German-Hungarian; Caucasian [95]   1-?_163+?del Exons 1 and 2 Large Deletion Eastern European [6]  2T>C (M1T) Exon 1 Missense-Pathogenic Unknown [124]    103  CDH1 Mutation Location Mutation Type *Ethnicity or (Country of origin if ethnicity is unknown) Reference  3G>A (start site) (M1I) Exon 1 Missense-Pathogenic Scottish-Irish [6]  3G>C (start site) (M1I) Exon1 Missense-Pathogenic Scottish-Irish [96]    Missense-Unclassified    8C>G (P3R) [7] Exon 1 Variant Unknown [294]  41delT Exon 1 Deletion (Canada) [292]  44_46delTGC Exon 1 Deletion Chinese [148]  45_46insT Exon 1 Insertion European [295]  46_48insTGC Exon 1 Insertion Unknown [124]  48+1G>A Intron 1 Splice Site (United Kingdom); French-Canadian [6] [112]  49-2A>G Intron 1 Splice Site Caucasian; Irish [113] [296]  53delC Exon 2 Deletion Caucasian [290] 55_74del20 Exon 2 Deletion Unknown [297] 59G>A Exon 2 Nonsense British-Irish [113]  104  CDH1 Mutation Location Mutation Type Ethnicity or (Country of origin if ethnicity is unknown) Reference 67C>T Exon 2 Nonsense Unknown Personal communication (Caldas) 70G>T Exon 2 Nonsense European [109] 79C>T (P27S) Exon 2 Missense – Unclassified Variant Italian [6] 88C>A (P30T) Exon 2 Missense – Unclassified CV Unknown [294] 185G>T (G62V) Exon 3 Variant Japanese [298] 187C>T Exon 3 Nonsense Caucasian; Unknown [96] [297] [105] 190C>T [109] Exon 3 Nonsense Maori [58] 283C>T Exon 3 Nonsense Unknown; (France); (France)  [7] [111] [299] [300] 105 CDH1 Mutation Location Mutation Type Ethnicity or (Country of origin if ethnicity is unknown) Reference 1018A>G (T340A) Exon 8 Missense-Pathogenic European; Korean [295] [301] [302]1023T>G Exon 8 Nonsense Unknown [135] 1063delT Exon 8 Deletion Caucasian [96] 1064_1065insT Exon 8 Insertion Caucasian [93] 1107delC Exon 8 Deletion Hispanic [288] 1118C>T (P373L) Exon 8 Missense-Pathogenic Italian [303] 1134del8,ins5 Exon 8 Splice Site European; Caucasian; Dutch [93] [304] [297]1137G>A Exon 8 Splice Site Unknown; Swedish-Norwegian; Jordanian; European; German; Arabic [7] [6] [288];personalcommunication-Caldas1137G>T Exon 8 Splice Site Native American [6]106  CDH1 Mutation Location Mutation Type Ethnicity or (Country of origin if ethnicity is unknown) Reference  1137+1G>A Intron 8 Splice Site African-American; Unknown [109]   1189A>T Exon 9 Nonsense Caucasian [13]  1212delC Exon 9 Deletion English-Japanese; Japanese; Japanese [93] [6] [305]  1223C>T (A408V) Exon 9 Missense – Unclassified Variant Unknown [294]  1226T>C (W409R) Exon 9 Missense-Pathogenic European [111]  1243A>C (I415L) Exon 9 Missense – Unclassified Variant Japanese [306]  1285C>T (P429S) Exon 9 Missense-Pathogenic Caucasian [96]  1297G>A (D433N) Exon 9 Missense-Unclassified Variant Unknown [294]  1306_1307delTT Exon 9 Insertion-Deletion Austrian [137]  1397_1398delTC Exon 10 Deletion English; European  [7] [288]b  1404delC Exon 10 Deletion Dutch [297]  1460T>C (V487A) Exon 10 Missense-Unclassified Variant Korean [307]  1466_1467insC Exon 10 Insertion Caucasian; (United Kingdom) [131] [112]c  1470_1483del14 Exon 10 Deletion (France) [111]  107  CDH1 Mutation Location Mutation Type Ethnicity or (Country of origin if ethnicity is unknown) Reference  1472_1473insA Exon 10 Insertion European [295]  1476_1477delAG Exon 10 Deletion Caucasian; Unknown [111] [297]  1488_1494delCGAGGAC Exon 10 Deletion Unknown [109]  1507C>T Exon 10 Nonsense Chinese [308]  1565+1G>A Intron 10 Splice Site Scottish-Dutch-Swedish-English [6] [291]  1565+1G>C Intron 10 Splice Site Caucasian [6]  1565+1G>T Intron 10 Splice Site Caucasian; Arabic [6] [290] 1565+2dupT Intron 10 Insertion/Splice Site Caucasian; French; Unknown [6] [297] 1566-?_1711+?del Exon 11 Large Deletion (France) [111] 1566-?_1711+?del Exon 11 Large Deletion Japanese [309] 1582delG Exon 11 Deletion Caucasian [300] 1588_1589insC Exon 11 Insertion European [109] 1595G>A Exon 11 Nonsense (France) [111] 1610delC Exon 11 Deletion Spanish [310] 108  CDH1 mutation Location Mutation Type Ethnicity or (Country of origin if ethnicity is unknown) Reference 1619_1620insG Exon 11 Insertion German [114] 1679C>G Exon 11 Missense-Splice Site (France); Caucasian [6] [111]1682_1683insA Exon 11 Insertion Irish [7] 1710delT Exon 11 Deletion African-American [290] 1711_1712insG Exon 11 Insertion European [105] 1711+5G>A Exon 11 Splice Site European [93] 1734delC Exon 11 Deletion Personal communication Carlos Caldas 1748T>G (L583R) Exon 12 Missense-Pathogenic Creole [297] 1774G>A (A592T) Exon 12 Missense – Unclassified Variant (Sweden) [294] [114] [311]1779_1780insC Exon 12 Insertion Caucasian [93] 1792C>T Exon 12 Nonsense Caucasian; Caucasian; Irish-English; Unknown [6] [96] [105] [290][312]1795A>T (T599S) Exon 12 Missense - Unclassified Variant Korean [313] 1813A>G (R605G) Exon 12 Missense – Unclassified variant Unknown [294]109   CDH1 mutation Location Mutation Type Ethnicity or (Country of origin if ethnicity is unknown) Reference 1849G>A (A617T) Exon 12 Missense – unclassified Variant Caucasian [314] 1876T>A (F626V) Exon 12 Missense – unclassified Variant Unknown [315]  1895_1896delAC Exon 12 Deletion Northern European [316]  1901C>T Exon 12 Missense-Splice Site English; Unknown; Maori [7] [304] [317] [288]  1913G>A Exon 12 Nonsense Spanish [7]  1942G>T Exon 13 Nonsense (United Kingdom) [112]  2058_2059delTG Exon 13 Deletion Brazilian [6]  2064_2065delTG Exon 13 Deletion (USA) [93]  2095C>T Exon 13 Nonsense Maori; Chinese [109] [288]  2100delT Exon 13 Deletion English-Scottish [6]  2161C>G Exon 13 Splice Site Hispanic [317]  2164+2T>A Exon 13 Splice Site (France) [111]  2164+5G>A Exon 13 Splice Site Unknown [7]  2195G>A Exon 14 Missense-Splice Site Caucasian; European [7] [93] [297]  110 CDH1 Mutation Location Mutation Type Ethnicity or (Country of origin if ethnicity is unknown) Reference 2245C>T (R749W) Exon 14 Missense-Pathogenic Columbian [7]  2248G>A Exon 14 Variant Unknown Personal communication (Caldas, C) 2265T>A Exon 14 Nonsense Unknown [6] 2269G>A (E757K) Exon 14 Missense-Pathogenic Portuguese [95] 2275G>T Exon 14 Nonsense Iranian [318] 2276delG Exon 14 Deletion Unknown [96] chr16:del 67416845- 67424923 (8078bp) Exon 14-16 Large Deletion European [95] 2287G>T Exon 14 Nonsense Unknown [319] 2295+5G>A Intron 14 Splice Site European [290] 2329G>A (D777N) Exon 15 Missense – unclassified Variant Unknown  [311] 2343A>T (E781D) Exon 15 Missense-Pathogenic English; (France) [7] [111]111 CDH1 Mutation Location Mutation Type Ethnicity or (Country of origin if ethnicity is unknown) Reference 2381_2382insC Exon 15 Insertion Maori [58] 2386delC Exon 15 Deletion (France) [111] 2396C>G (P799R) Exon 15 Missense-Pathogenic German [110] 2398delC Exon 15 Deletion Irish/English/Scottish [7] [111] [112][320]d2399delG Exon 15 Deletion (France) [321] 2400delG Exon 15 Deletion (United Kingdom) Personal communication (Caldas, C) 2413G>A (D805N) Exon 15 Missense- Unclassified Variant Jewish [6] 2430delT Exon 15 Deletion English [6] 2440-6C>G Intron 15 Splice Site [288] 2494G>A (V832M) Exon 16 Missense-Pathogenic Japanese; Unknown [294] [322]chr16:del 67424298- 67425126 (828 bp) Exon 16 Large Deletion Central European [95] aDenoted as 372delC  bDenoted as 1391_1392delTC cDenoted as 1465insC 112  5.3 Objective 3: Post-operative Complications, Major Symptomatology and Quality of                         Life after PTG.    Sample Summary 5.3.1 Participants from British Columbia the six eligible participants from BC, three responded and completed the study.  One was lost to follow-up and there were two non-responders.   Participants from Other Canadian Provinces the other 11 genetics clinics in Canada that were approached, participants were recruited through two clinics (St. Johns, NF and Calgary, AB).  One clinic in Toronto, ON was recruiting their patients for a separate study, seven clinics did not respond and one clinic responded to say they had potential participants; however, they did not refer potential participants despite several prompts from me.  Two participants were referred from the clinic in Calgary.  Both participants had been sent the initial letter by their genetic counsellor. Thirty-four participants from five separate pedigrees in NF were identified as having undergone PTG in the last eight years. The high number of individuals undergoing PTG in Newfoundland stems from the presence of a founder mutation discovered in four families who originate within a 100-mile radius in the south-east coast [7].  All participants were sent the initial letters by their genetic counsellor.  There were ten (19.6%) responses, all of whom completed the study.   Two participants from Canada decided to enrol in the study after they found out from a family member.   113   Participants from Centers outside Canada data are displayed in Table 5.3. In addition, all available clinical information on each participant is provided in a table in Appendix O.  Twenty-two (43%) participants responded after reading about the study on the No stomach for cancer website.  This was the largest response group.  Dr. Samuel Yoon at the Massachusetts General Hospital referred nine (17.6%) of the patients on whom he had performed surgery.  All nine individuals completed the study. Three other surgeons who were personally known to the investigators as having done PTG on several individuals responded favourably to the study but did not refer any participants.   Patient Demographics (Characteristics of the Individual and Environment). 5.3.2Demographic data are displayed in Table 5.3. In addition, all available clinical information on each participant is provided in a table in Appendix O. The combined sample consisted of 53 individuals who had undergone PTG between 2004 and 2013.  The median age at the time of surgery was 41 years (mean = 43, S.D. = 10; range from 22-63 years).  The median age at time of questionnaire completion was 41 years (mean= 43; S.D. = 11; range of 23-69 years).  A median of 52 months (mean=57; SD=30; range of 2 to 104 months) had elapsed between the time of prophylactic gastrectomy and the time the questionnaires were completed.  114  The majority of the patients (n= 31 or 58%) who underwent prophylactic gastrectomy were below 50 years old at the time of their surgery.  Stratifying the participants further by age at surgery, there were, eight (15%) who were less 30 years old, 16 (30 %) who were 31 - 40 years old, 14 (26%) were between 41-50 years old, 14 (26%) between 51-60 years old and one (2%) who was more than 60 years old at the time of their surgery.   The participants were primarily female (74%), white (99%) and married (including common-law) (76.5%).  Thirty-six individuals (68%) had surgery more than three years prior to the time of the survey.      115  Table 5.3 Demographic Characteristics of Study Participants (N=53)  a. Demographics Variable Frequency  Sex   Male  Female  14  (26%) 39  (74%) Age at time of surgery  <50 years  >50 years  34 (64%) 19 (36%) Age at time of survey  <50 years  >50 years  31 (58%) 22 (42%) Ethnicity  White  African American  Hispanic  Asian  Other   52  (98%) 0 0 1     (2%) 0 Marital status  Now Married (including common-law)  Widowed  Divorced/Separated  Never Married  41   (77%) 0     (0%) 5     (10%) 7     (13%) Education  Less than a university bachelor’s degree  Bachelor’s Degree and above     21    (40%) 32    (60%)  Employment  Working   Homemaker  Retired  Student  Unable to work     35   (66%)   6   (11%)   7   (13%)   2    (4%)   3   (6%)  Surgical Type  Open surgery  Laparoscopic surgery  47   (89%)   6   (11%) Time between surgery and survey (months)  ≤ 12  13 – 60 >60    8   (15%) 24 (45%) 21 (40%)  116   Post-surgical Clinical Outcomes and Complications after PTG 5.3.3 Immediate Post-operative Clinical Outcomes records were received and reviewed for 52 participants.  I could not obtain records on one participant despite two repeated attempts to ask the participant to provide signed consent. At least eight kindred were involved, but kindred relationships were not available for most participants.    All participants undergoing PTG were asymptomatic at the time of surgery.  The surgeries were performed in 11 different hospitals (by 14 surgeons).   All the participants had a total gastrectomy with stapled esophagojejunal anastomosis (50 – 60cm) and Roux-en-Y reconstruction.  Six (12%) of participants underwent laparoscopic total gastrectomy.  The mean length of hospital stay for the surgery for all participants was 8.9 days with a median of 7 days (range 4 – 18 days).  Length of stay for three of the individuals undergoing laparoscopic TG was 4 – 7 days.    Complications participants experienced post-surgical complications either during the hospital stay or within the first six months of the surgery. One participant experienced seven oesophageal strictures, of which four were managed with dilation within the first 12 months.  117  Another participant experienced pleural effusion eight days after surgery and required pleurocentesis.  This same individual then developed a clot in the right lung on day 10 and a small wound infection (on day 18).  At 12 months post-surgery, this individual needed post-esophageal dilation for distal and proximal dysphagia.    The patient with bile reflux and two of the patients with strictures between 1 -12 months after surgery had laparocopic procedure.  Table 5.4 summarizes the data on post-surgical complications.   Table 5.4 A summary of the postsurgical complications within the first year following prophylactic gastrectomy among the study participants (N=52).  Numbers in parentheses indicate the number of participants who suffered the complication.            The medical records included pathology reports on only 41 of the participants despite this information being specifically requested on the Authority to Divulge form.   Of these, 32 (78%) had signet ring cells, indicative of diffuse gastric cancer, in their post-gastrectomy specimens.  The number of signet ring foci ranged from 1 to 52 per stomach.  These foci were distributed Complications experienced in hospital/within 1 month of surgery Complications experienced between 1-12 months post- surgery Anastomic leak (2) Urinary tract infection (1) Wound infection (3) Pulmonary embolism (1) Pulmonary effusion (1) Shortness of breath (1) Small bowel obstruction (1) Anastomic strictures (12) a Bile reflux (1)b Duodenal obstruction (1) Partial obstruction at jejunal anastomosis site (1)   Moderate iron deficiency (1) Ileus obstruction (1) 118 throughout the entire stomach.  All the patients who had the signet-ring cell foci had their cancer staged at T1N0M0.     Weight Loss and Body Mass Index (BMI). participants completed the information on their weight prior to the surgery and at the time of the survey. Regardless of how long it had been since the surgery, all but one participant reported lower weight at the time of survey than pre-surgery.   The median weight of participants before surgery was 73 kilograms (range 46 – 140 kg).  The median of the current (post-surgical) weight was 60 kilograms (range 40 – 104 kg).  The median loss of weight overall was 11 kilograms (mean was 15kg) and ranged between 0 – 46 kilograms. Men and women lost about the same amount of weight on average (14 kg versus 15 kg respectively). The one participant who did not lose weight was 80 months post-surgery.  Prior to surgery, 6% of the participants were considered underweight, 36% of participants were in the healthy range of weight, and 34% were overweight whilst 24% were obese. At the time of their survey, the majority (69%) of participants were maintaining a healthy weight.  Sixteen percent were underweight at the time of survey and 14% were obese.  Of the eight participants who were underweight at the time of the survey, three had already been underweight pre-surgery. Table 5.5 shows the BMI of the 53 participants at the time of surgery and at the time of the survey.  119Table 5.5 A summary of BMI before surgery and at the time of surgery among study participants (N=53) BMI range classification Number Preoperative BMI (%)Number Postoperative BMI(%)Underweight (<18.5) 3 (6) 8 (15)Healthy Weight (Normal) Range (18.5 to <25)19 (36) 37 (69)Overweight (25 to <30) 18 (34) 4 (8)Obese class I (30-35) 7 (13) 3 (6)Obese class II (>35) 6 (11) 1 (2)BMI = Body Mass Index (kg/m2)5.3.4 Patient Reported Symptoms, Frequency and Intensity in Individuals after PTG. Early Dumping Syndrome Symptoms (Clinical Questionnaire) These symptoms occur 10 – 30 minutes after a meal.  Table 5.6 summarizes the early dumping syndrome symptoms, their frequency over seven days during the survey and how affected the participants were by the experience of these symptoms. All 53 participants completed this section of the questionnaire.  Only two (4%) of the participants indicated that they did not suffer any of the early dumping syndrome symptoms. One of these had PTG five months prior tocompleting the survey and the other was 57 months post-surgery.  The majority (22%) reported at least two symptoms. The mean number of months between their PTG and the survey was 66 months (range was 8 – 101 months). Four (8%) participants reported that they experienced all seven symptoms associated with early dumping.  They were 21-104 months post-surgery.   120Fatigue was the most common symptom that was reported (59%).  The incidence of this symptom was highest, at 62%, in the group that had their surgery 13-60 months prior to the time of the survey. This group also had the oldest age at the time of survey (mean 51.3 years).  Abdominal cramping (55%), nausea (53%) and bloating/belching (51%) were the next most commonly reported symptoms overall.  On average, most symptoms (apart from vomiting) appeared to still be present in 33% of individuals who were 5 years or more post-surgery.   121Table 5.6 Summary of early dumping syndrome symptoms, frequency and severity in study participants. Symptom Time-lapse between surgery and survey (n= total number of participants per group)≤ 12 months (n=8)12-60months(n=24)> 60 months(n=21)Total (N=53)Nausea 5 (63%) 10 (42%) 13 (62%) 28 (53%)Frequency * 1-10 1-7 1 -7Severity A little (4) Quite a bit (1)Not at all (3) A little (6) Quite a bit (1)Not at all (3) A little (8) Quite a bit (2)Vomiting 0 3 (13%) 3 (14%) 5 (9%)Frequency 1 2-3Severity Quite a bit (1) A little (1)Quite a bit (2)Abdominal Cramps3 (38%) 13 (54%) 13 (62%) 29 (55%)Frequency 1 - 3 2-7 2-7Severity Quite a bit (2)    No response (1)Not at all (1) A little (8) Quite a bit (4)Not at all (1)A little (3) Quite a bit (6)A Lot (2)Diarrhea 1 (13%) 13 (54%) 9 (43%) 23 (43%)Frequency No response 1 1-10Severity No response A little bit (2) Not at all (3) A little (1) Quite a bit (3) Dizziness 3 (13%) 12 (50%) 7 (33%) 22 (43%)Frequency 1 1 – 4 1-10Severity A little bit (3) A little bit (9) Quite a bit (3) A little bit (4) A lot (3) Bloating/belching 4 (50%) 16 (67%) 6 (29%) 26 (51%)Frequency 3-7 2-7 1-severalSeverity A little Bit (3) Quite a bit (1)A little bit (12) Quite a bit (2)A lot (2)A little bit (4) Quite a bit (1) A lot (1) Fatigue 4 (50%) 13 (54%) 13 (62%) 30 (59%)Frequency 2-7 2-7 1-5Severity A little (4) A little bit (4) Quite a bit (2) A little bit (4) Quite a bit (3) * Frequency was measured as the number of times the participant experienced the symptoms over the last week.** Severity of the symptom was measured as “Not at all”, “a little bit”, “quite a bit” and “a lot”.1225.3.4.2 Late Dumping Syndrome SymptomsThese symptoms occur approximately one to three hours after a meal.  All but one person answered all questions in this section.  Of the 53 responses, nine individuals (17%) did not have any late dumping symptoms. Of these nine participants, six avoid particular foods that cause worsening of symptoms after consumption.  Two of these six reported that sugary foods were avoided, two indicated dairy only, one indicated sugary foods and milk, one indicated “any carbohydrates and sugar” and one indicated fatty foods only.  The time between surgery andsurvey for these nine participants ranged from 12 to 81 months (median=60 months).   Weakness/fatigue was the most common symptom (48%) and most participants stated that it bothered them “a lot”.  Shakiness and diarrhea (40% and 42% respectively) were most often said to bother the participants “a little”.  Table 5.7 summarizes the data on late dumping symptoms in the study cohort. 123Table 5.7 Summary of late dumping symptoms, frequency and patient-reported severity.Symptoms Time between surgery and survey (months) Total (N=52)≤12 (n=8) 13-6 0 (n=24) > 60 (n=21)Weakness/Fatigue 3 (38%) 13 (54%) 8 (38%) 24 (48%)Frequency 1 2-3 1 – alwaysSeverity A little (3) Not at all (10)  A little (2) Quite a bit (1)Not at all (3)  A little (2) Quite a bit (3)Shakiness 4 (50%) 10 (42%) 7 (33%) 21 (40%)Frequency 1 1-4 1-8How much did it bother you? (n)Severity A little bit (4) A little bit (8)Quite a bit (2)A little bit (5) Quite a bit (2)  Diarrhea 3 (38%) 9 (38%) 10 (48%) 22 (42%)Frequency 1-several times 1 1-2Severity Not at all (1)  A little (1) A lot (1)Not at all (3) A little (4)Quite a bit (1)A lot (1)  Not at all (2)  A little (4) Quite a bit (1)  A lot (2)Anxiety 2 (25%) 5 (21%) 5 (24%) 12 (24%)Frequency 1-2 1-7 No responsesSeverity A little (2) A little bit (1) Quite a bit (2)A lot (2)A little (1) Quite a bit (2)  A lot (2)  Heart Palpitations 2 (25%) 9 (38%) 6 (29%) 17 (34%)Frequency 1 1 1-8Severity A little bit (2) A little bit (6)    Quite a a bit (1)A lot (1)No response (1) A little (4) Quite a bit (1)  A lot (1)  Fainting 0 0 1 (5%) 1 (2%)Frequency 1Severity A lot (1)Mental Confusion 0 5 (21%) 3 (14%) 8 (16%)Frequency 1 1Severity A little bit (3) Quite a bit (1)A lot (1) A little bit (2) A lot (1)* Frequency was measured as the number of times the participant experienced the symptoms over the last week.** Severity of the symptom was measured as “Not at all”, “a little bit”, “quite a bit” and “a lot”.1245.3.4. Functional scales and symptoms (EORTC C30 and STO22)The means and standard deviation of the function scales from the EORTC C30 and STO 22 instruments are shown in table 5.8 Table 5.8 Summary of functional scales and symptoms of EORTC instruments Variable MeanStd. DeviationPhysical Function 90.4 15.5Role Function 80.8 25.6Emotional Function 76.6 24.4Cognitive Function 79.6 26.5Social Function 77.9 26.3Fatigue 30.2 24.2Nausea / vomiting 16.7 23.8Pain 15.7 23.0Dyspnoea 11.9 23.7Insomnia 30.2 29.4Appetite loss 24.5 31.5Constipation 9.4 23.0Diarrhoea 27.0 26.2Financial problems 20.8 29.4STO Body image 18.9 30.0STO Dysphagia 11.1 17.2STO Pain 27.5 23.2STO Reflux symptoms 13.3 18.3STO Eating Restrictions 21.4 19.7STO Anxiety 25.7 23.8STO Dry mouth 18.3 26.9STO Taste 7.8 19.5STO Hair loss 30.2 27.7125When group comparisons between the 3 groups according to time elapsed between surgery and survey were done, there was no significant difference for any of the scales. These are shown in figures 5.3 To 5.5  Figure 5. 3 Bar chart comparing the means of functional scales from the EORTC C30 in the 3 time elapsed groups p=.6p=.4p=.4 p=.6 p=1.0126Symptoms (EORTC C30 scale) Figure 5.4 is a bar chart summarizing the means of the symptoms from the EORTC C30 instrument in the 3 groups (time elapsed since surgery and survey).  There is no difference between any of the 3 groups and the symptom.  Figure 5. 4 Bar chart comparing EORTC C30 symptoms between the 3 time elapsed groups. p=.2p=.9p=.3p=.6p=.3p=.8 p=.9p=.7p=1.0127Symptoms (STO 22) Figure 5.5 is a bar chart summarizing the means of the symptoms from the STO 22 instrument and the p-values between the 3 groups of time elapsed since surgery.  There is no difference between the groups for any of the symptoms. Figure 5. 5 Bar chart comparing means of STO 22 symptoms between the 3 time-elapsed groups. p=.01p=.4p=.4p=.3p=.4p=.1.1p=.6p=1128Anxiety 5.3.4.Fifty participants completed this instrument.  The mean score for the anxiety instrument was 48 (SD 11) with a range of 31.6 to 72.2.  Twenty-seven (54%) of the study participants scored less than 50, which is below the average score of the normal population (Table 5-9).  Thirty-seven (74%) of the study participants scored at the “none to slight” anxiety level. A series of non-parametric tests were done to see if there was a statistically significant difference between participants’ age at surgery, time elapsed between surgery and survey, gender, marital status, educational level and employment. The results suggested that there was no difference between married or unmarried participants and anxiety (z = -1.4, p = 0.2); sex of participant (z = -0.8, p = 0.); between those who had a university education and higher versus those who did not (z = -0.5, p = 0.6); between those who were working or not working (z = -0.9, p = 0.4)  there was also no difference between participants who were 50 years old or less at the time of surgery versus those who were over 50 (z = - 1.0, p = 0.3).  Depression 5.3.4.Fifty-two participants completed the questionnaire.  The mean score for the depression instrument was 46 (SD=12) with a range between 33.5 and 81.6.  Thirty-five (67%) participants scored below 50 points.  Three participants (6%) scored in the severe depression range. 129There was no difference between the sexes (z = -0.2, p = 0.9) or marital status (z = -0.1, p = 0.9).Those who had a university degree and higher did not show a difference from those who had less than a university degree (z = -0.4, p = 0.7).  Participants who were working were not any more depressed than those who were working (z = -2, p = 0.1).  Those who were over 50 years of age at the time of their surgery did not show any difference from those who were less than 50 years at surgery (z = -.4, p =.7).Depression and anxiety were strongly correlated (p<0.01, rs=0.7) Patient Satisfaction with Surgery and Involvement with Decision-Making 5.3.5Satisfaction with Prophylactic Total Gastrectomy fifty-three participants who completed the questionnaires were asked about their satisfaction with their decision to have the surgery.  Satisfaction was rated on a Likert-type scale from one (extremely dissatisfied) to five (extremely satisfied).   Forty-seven (88%) of the participants were either very satisfied (79%) or satisfied (9%) with their decision to have surgery.  Two (4%) participants were neither satisfied nor dissatisfied. Three (6%) participants were not satisfied with the decision to have surgery.  One (2%) participant indicated that s/he was not satisfied with the surgery because of the symptoms being experienced but on the other hand also indicated extreme satisfaction with the surgery because s/he was still alive. This individual with 2 answers was left out of all the analyses involving 130satisfaction.  Table 5.9 summarizes the information when further broken down by age (<50 years and ≥ 50 years) and time elapsed since surgery. Table 5.9 Satisfaction measured in participants according to age categories and time elapsed since surgery (N=52). Age of Participants Time since surgery and survey (months)< 50 years(n = 23)≥ 50 years(n=29)≤ 12 (n = 8)13 -60(n = 24)≥ 60 (n = 20)Very dissatisfied 0 0 0 0 0Dissatisfied 1 (4%) 0 0 1 (4%) 2 (10%)Neither 1 (4%) 2 (7%) 0 0 3 (15%)Satisfied 2 (9%) 3 (10%) 3 (37%) 3 (13%) 0Very satisfied 19 (83%) 24 (83%) 5 (63%) 20 83%) 17 (85%)When used as a continuous variable, age at time of survey was not correlated with satisfaction (rs= 0.1, p= 0.3).  Involvement in the Decision to Have Prophylactic Total Gastrectomy5.3.5.2All participants were asked about their level of involvement in their decision to have the surgery.  Involvement was rated on a Likert-type scale from one (completely involved) to five (not involved at all).  Fifty-one (96 %) of the participants indicated complete involvement in their 131decision to have surgery.  One (2%) participant indicated involvement as “somewhat involved” and one (2%) participant indicated no involvement at all.  Advice to Get the Surgery fifty-three individuals answered the question about whether they were advised to have the surgery.  Forty-two (79%) participants stated yes. Eleven (22%) participants reported that no one advised them to have the surgery.  The participants were given a choice of who had advised them.  The choices included family physician, oncologist, surgeon, genetics professional, family member (with a choice to include who) and other. Twenty-five of the participants who answered “yes”, selected three or more of these choices.  Of the forty individuals who answered yes to this question, the majority reported that their surgeon (68%) and genetics professional (64%) advised them to have the surgery.  45% chose their family physician and 48% said their oncologist advised them.  44% said that a family member was also involved in advising them to have the surgery. Support after the Surgery participants were also asked about support within the month following surgery.  Fifty-two(98%) of the participants said they had support after the surgery.  Forty-six (88%) chose two or more individuals from a list that was provided who supported them.  132Cancer Worry fifty-three participants answered the question about whether they were still worried about developing gastric cancer.  Forty-six (87%) said "never", and five (9.8%) said "sometimes".  Two (4%) participants chose "other".  One of these indicated that the worry was related to developing esophageal cancer due to the severe gastroesophageal reflux experienced since the surgery.  The other participant wrote about the worry of developing other cancers; no further comment was made.   1335.4 Quality of Life in Individuals after PTG The overall quality of life score was 70.6 (SD = 25.6) out of a possible score of 100 on the EORTC-QLQ C30.5.4.1. Predictors of QOL after PTGAll model checking plots indicate that the residuals follow a normal distribution, and that there does not seem to be evidence of heteroscedacity or dependence among residuals. Table 5.10a shows the analysis results from the full model (Fitting linear model: QL2 ~ PF2 + EF + CF + RF2 + SF +Depression + Anxiety + STOBI + STODYS + STOPAIN + STORFX + STOEAT +STOANX + STODM + STOTA + Sex + PA + DY + NV + CO + SL + FA + DI + FI + AP + EmploymentStatus2 + Education + Age.surgery + MonthsSinceSx + MaritalS).   As can be seen in Table 5.10a, none of the predictor variables are significant. 134Table 5.10a. The full model analysis results Residuals:Min      1Q  Median      3Q     Max -14.5 -2.9 1.0 3.5 17.3Coefficients:Estimate Std. Error  t value Pr(>|t|)  (Intercept)   5.4e+01   3.9e+01 1.4 0.2PF2 5.1e-02 2.2e-01 0.2 0.8EF - 3.3e-02 1.8e-01 -0.2 0.9CF 1.6e-01 1.8e-01 0.9 0.4RF2 2.6e-01 2.3e-01 1.2 0.3SF 3.4e-01 2.1e-01 1.6 0.1Depression 1.6e-01 3.2e-01 0.4 0.6Anxiety          -7.2e-01 3.6e-01 -1.9 0.1STOBI 6.5e-02 8.9e-02 0.8 0.5STODYS -1.9e-01 3.9e-01 -0.5 0.6STOPAIN -1.8e-01 1.80e-01 -0.9 0.3STORFX 2.0e-02 1.4e-01 0.1 0.9STOEAT          2.6e-01 3.9e-01 0.7 0.5STOANX   -2.3e-02 2.3e-01 -0.1 0.9STODM    1.9e-02 1.1-01 0.2 0.9STOTA          2.7e-01 1.5e-01 1.7 0.1Sex (Female)         1.7e+00 7.3e+00 0.2 0.8PA 5.1e-03 1.5e-01 0.03 0.9DY -1.4e-01 1.2e-01 -1.2 0.3NV -2.3e-02 1.4e-01 -0.1 0.9CO 6.5e-02 1.4e-01 0.4 0.6SL 3.6e-02 1.0e-01 0.3 0.7FA -2.6e-02 1.6e-01 -0.1 0.9DI -1.7e-01 1.0e-01 -1.6 0.1FI 3.3e-03 1.1e-01 0.03 0.9AP -2.5e-02 7.3e-02 -0.3 0.7EmploymentStatus 3.0e+00 5.5e+00 0.5 0.6(Not Employed)Education (University)   -1.5e+01 1.1e+01 -1.4 0.1Age (at surgery) -8.5e-04 2.8e-01 -0.003 1.0Months Since Sx      -4.2e-02 1.0e-01 -0.4 0.6Marital (Single) 9.9e-01 5.6e+00 0.2 0.8Abbreviations: STODYS = dysphagiaSTOPAIN = painSTORFX = refluxSTOEAT= eatingSTOANX = anxietySTODM = dry mouthSTOBI= body imageSTOHAIR= hair lossSTOTA = tasteAP = Appetite loss135In the full model, the coefficient of variation R2 is 0.94 and adjusted R2 is 0.84. The full model topredict QOL would statistically predict QOL:  R² = .84, F (17,32) = 9, p < .001.Given the large number of variables, there is likely over-fitting in this full model and hence a reduced model analysis was performed. The reduced model The reduced model was obtained using a stepwise procedure with the AIC criterion. Analysis results of the reduced model ((Fitting linear model: QL2 ~ CF + RF2 + Anxiety + STOBI + STODYS + STOPAIN + STOEAT + STOTA + DY + DI + EmploymentStatus2) are shown in Table 5. 10b.  Model checking plots indicated that the residuals follow a normal distribution, and that there did not appear to be evidence of heteroscedacity or dependence among the residuals. All the predictor variables in this model, except for the symptoms depression, body image and eating restrictions are significant.  136Table 5. 10b The reduced model analysis results Residuals: Min         1Q      Median       3Q      Max -15.1 -4.1       0.8        3.5  18.7 Coefficients: Estimate Std. Error t value Pr(>|t|)    (Intercept) 54.3   12.2   4.4 8.5e-05 CF 0.1    0.06   2.2 0.03 *  RF 0.3    0.08   3.6 0.001 ** SF 0.3    0.1   3.2 0.004 ** Depression 0.2    0.1 1.3 0.2    Anxiety -0.7 0.1  -3.9 0.0004 ***STOBI 0.07 0.04   1.6 0.1    STOPAIN -0.2 0.07  -2.8 0.008 ** STOEAT   0.1 0.08   1.4 0.1    STOTA 0.2 0.07   3.3 0.001 ** DY -0.1 0.06  -2.6 0.013 *  DI -0.1 0.05  -2.7 0.01 *  Abbreviations:CF = Cognitive functionRF = Role functionSF = Social functionSTOBI= body imageSTOPAIN = painSTOEAT= eatingSTOTA = tasteDY = DyspneaDI = DiarrheaIn the reduced model, the coefficient of variation ܴଶ is 0.94 and adjusted ܴଶ is 0.92.  Thesepredictor variables explain 92% of the variability of the data which is a significant improvement over the full model.  137The reduced model to predict QOL, with nine significant variables, statistically predicted QOL  R² = .92, F(14,35) = 40, p < .001.  As can be seen in Table 5.10b, these predictors had significant positive regression weights, indicating participants with worse scores on these scales were expected to have lower quality of life after controlling for the other variables in the model.  138Chapter 6:  Discussion and Conclusions The data in this study provides robust penetrance estimates from 67 families with CDH1germline mutations, the largest reported series to-date of.  In addition, it provides a comprehensive survey of the mutational landscape of germline CDH1 mutations found in HDGCfamilies from both our database and the literature.  The data also sheds further light on post-surgical complications, frequently experienced symptoms and their impact on the patient.  I also described associations between symptoms, functional status and overall QOL. 6.1 Penetrance in CDH1 Mutation Carriers Although causal CDH1 mutations in HDGC families were first described in 1998 [58], large-scale penetrance studies were lacking due to the rarity of this disease.  The clinical value of finding CDH1 mutations in HDGC families depends on using family-specific mutations to determine which unaffected relatives are at increased risk of developing DGC or LBC and which are not.  Individuals with a germline CDH1 mutation have a high risk of developing DGC over their lifetime.  Currently, the only recommended options to reduce this risk in unaffected germline carriers are gastroscopy with multiple random biopsies every 12 months or undergoing PTG [115, 116].  Although both choices aim at reducing or eliminating the risk of DGC, they represent a conundrum for unaffected germline carriers as screening has repeatedly been shown to miss early DGC [94, 130, 131] and prophylactic total gastrectomy carries certain morbidity [9, 13, 14].  The purpose of this highly invasive surgery is to prevent the development of diffuse gastric cancer which if not caught in the early stages can lead to death.  139Since there are no validated biomarkers to assist in the choice of or timing of gastrectomy inHDGC, accurate risk assessment is essential.  Previous studies have provided rough estimates of the risk of GC in germline mutation carriers.  In a study of 11 families the GC risks were calculated as 67% in men and 83% in women, and there was an increased risk of LBC in women mutation carriers of 39% [8].  Our group has also previously shown a cumulative risk of GC in 4 families with the 2398delC founder mutation to be 40% (95% confidence interval [CI], 12%-91%) for males and 63% (95% CI, 19%-99%) for females. In addition, the cumulative risk for breast cancer for females by the age of 75 years was found to be 52% (95% CI, 29%-94%). [7].The small sample size in both of these studies meant that the risk figures were imprecise (as they had very large confidence intervals) and so had to be interpreted with caution. In this study, the cumulative incidence of gastric cancer was 70% (95% confidence interval [CI], 40%-94%) for males and 56% (95% CI, 27%-90%) for females.  In addition, this study confirms the increased risk of breast cancer in female mutation carriers which was 42% (95% CI, 23%-68%) by 75 years. The comprehensive analysis presented here provided penetrance estimates that are broadly similar to the two previous studies [7, 8]; however, these estimates are much more precise, and cumulative risk in women is somewhat lower than previously reported.  It is important to note that both men and women show a similar increase in GC risk between the ages of 30 and 60 years (Table 5.1 and Figures 5A and 5B).  There is a fairly large increase in risk for gastric cancer between the age categories of 60-69 years (48% and 41% respectively for males and females) and 70-75+ years (70% and 56% in males and females respectively).  Given that the model utilized an individual’s age till 99 years, the last age category has an additional 29 140years, with more mutation carriers in their 80s and 90s thus perhaps explaining this greater increase in the gastric cancer risks. Penetrance of HDGC is incomplete, as demonstrated by obligate carriers who survive cancer-free into the 9th and 10th decades. Penetrance estimates were adjusted for ascertainment biasthrough a conditional analysis.  This provides a valid estimate of risk in this type of family and so these risks are appropriate for use in genetic counselling of individuals from such families.  However, it is likely that there are modifiers of risk such as environmental and lifestyle factors or other inherited genetic factors.   These unknown modifiers are likely to cluster in multi-case families and so the penetrance estimates presented here, while clinically appropriate, are likely to be higher than the average penetrance in a series of truly unselected carriers of deleterious CDH1variants. This is now coming to light as personal communications with geneticists is revealing that there are individuals with no personal or family history of either gastric cancer or lobular breast cancer who have been found to have pathogenic CDH1 variants. 6.2 CDH1 Mutation Spectrum. These germline mutations are distributed throughout the CDH1 protein coding segments (Figure 5.2) and adjacent splice site sequences.  Approximately 25% (32 of 126) of reported CDH1pathogenic mutations have been reported in multiple seemingly unrelated families, sometimes in different ethnicities (Table 5.2).   Fourteen of the mutations found in our new cohort of 183 cases have been previously described in other seemingly unrelated families [7, 93, 105, 109, 288, 112, 111, 289, 290, 291] . This finding suggests that germline mutations can either arise from a common ancestor [7, 95] or be the result of novel events at mutational hotspots.  Whereas 141  mutation hotspots could account for recurrent single base pair substitutions, recurrent large-scale deletions with identical breakpoints are more likely to be due to shared ancestry.  We have seen these large deletions in our series of patients [6]  6.3 Quality of Life In this cohort of participants, the mean global health status/QOL was 70.6 (SD = 25.6).  The overall global health status/QOL score for this cohort of participants is no different that the reference values from the general population in Norway and Sweden (71.2 ± 22.4), (p=0. 51) [286].  As expected, the mean score for global health status/QOL for this cohort is much higher than the reference values for gastric cancer patients (53.1±26.5) [286].  The findings suggest that this cohort of CDH1 carriers overall appear to enjoy a satisfactory quality of life after PTG despite their symptom burden.  Ferrans and Powers (1993), after studying a group of haemodialysis patients, suggested that individuals tend to re-define or amend their life goals to conserve their well-being despite adverse changes in their lives [323]. It is possible that a redefinition of life goals may also explain relatively favourable self-reported quality of life in this study sample.  In addition, these individuals may have developed various coping strategies that enabled them to manage their symptoms in the time since PTG.  This result is good news for participants who are looking to undergo this surgery as it provides them with the knowledge that despite the inevitable symptom burden, their overall QOL may still be good.      142 Biological Functions Surgery type (open versus laparoscopy), frequency of post-operative complications and BMI were selected as the biological variables.  None of these variables showed a significant association with global health status/QOL.  However, given the very small numbers in each group, and especially the laparoscopy group (N = 6), these biological factors may have substantial effects that could not be demonstrated in this study. The only other study [15] looking at individuals who had undergone PTG did not examine any of these relationships.   Mortality for PTG has been estimated to be less than 1% [92] given that these patients are younger and healthier than those who undergo TG for gastric cancer.  It is not known what the long term mortality may be for these individuals; n this cohort of participants, we have not heard of anyone dying due to complications from the surgery itself.  However, there is still morbidity, both physical and mental, in this cohort of patients.   Twenty-six post-surgical complications including major complications (anastomic leak, pulmonary embolism and effusion) were seen in 23 participants (46%) in this study.    These complications were not as common as in previously reported smaller series studies [9, 13, 14].  This difference in complication findings can reflect improvements in both surgical techniques and post-operative management.  In this study cohort, there was no difference in any of the functional or symptom scales between those participants who had post-operative complications and those who did not.  Two other studies have shown this lack of influence of post-operative complications on QOL [324, 325] individuals who had undergone gastrectomy.    143  Only six participants in this cohort had undergone laparoscopic total gastrectomy.  This surgery has been gaining popularity with surgeons performing total gastrectomies for gastric cancer because laparoscopic TG is associated with less painful recovery, faster recovery time, minimal scarring, improved short-term symptoms and consequently better QOL when compared to open surgery [217, 252, 236, 326] .  It is not known if these benefits of laparoscopic surgery apply to PTG in CDH1 mutation carriers and the low number of laparoscopic PTG included in this series did not allow me to answer this question.  The small number of laparoscopic procedures in this series of participants may reflect the concern that all the gastric epithelium may not be removed during this procedure.   It is also possible that even though there are advantages that have been summarized, there are other surgical complications (such as anastomic strictures that were seen in 3/6 of the participants) are not reduced in those undergoing laparoscopic surgery. It is possible that the increased technical difficulty of TG through an endoscope is a problem in this regard. It is also possible that few of the surgeons (or hospitals) who took care of the patients in this series can do laparoscopic TG.  Participants in this study had an average of 19% weight loss after the surgery.  This was not surprising as individuals undergoing total gastrectomy for gastric cancer experience an average 20% weight loss within the first 2 weeks of surgery [130, 327].  The decrease in body weight after gastrectomy is largely due to a decrease in body fat but sometimes lean body mass is also reduced. The weight loss results from reduced caloric intake and malabsorption. [226].   Worster and colleagues [15] saw a similar weight loss (18% of pre-surgical weight) in their cohort of 32 CDH1 mutations carriers who underwent PTG and followed over 2 years.  It was not possible to have an accurate estimate of how long it took for weight to stabilize in this 144  cohort.  Anecdotal evidence (personal communication with several of my patients) have shown that most individuals do struggle to maintain their weight after the surgery.  Not all participants reported the involvement of a dietician/nutritionist in their follow-up care after surgery.  Given that micronutrient deficiencies, which can lead to severe clinical complications, can occur even years after a TG, a dietician or nutritionist should be involved during the multi-disciplinary sessions prior to undergoing the surgery.  The patient also needs to be followed by a dietician or nutritionist after surgery so that continuing assessment and management can prevent clinical complications due to potential micronutrient deficiencies.    Individuals who were overweight or obese before the surgery, may consider this weight loss to be a “good thing” (personal communications).  Some of them were actually excited to lose weight; one individual stated that she was excited to wear a bathing suit since it had been a long time since she felt comfortable doing so!     One or more foci of signet ring cell adenocarcinoma were observed on pathological examination of the gastrectomy specimens in previously reported cases of CDH1 carriers undergoing PTG (Table 1.1).  Of the 41 pathology reports in this study, only 32 (78%) were shown to have foci of signet ring cells.  This cohort has a much smaller percentage of gastrectomy specimens with signet ring cell foci than the > 90% seen in previously reported series [13, 57, 14, 130].  The reason for this may be that many of the specimens from this cohort of participants were not examined according to the extensive investigations that are recommended by the IGCLC [116] whereas the other series were.    145 The fact that there are so many mutation carriers in whom signet ring cell foci are seen may lead one to believe that these surgeries are curative rather than prophylactic.  Many patients feel a sense of relief when told that their gastrectomy specimen did indeed have these foci – they feel that they did “the right thing” (personal communication with several individuals after PTG).  Many mutation carriers who are not decided on whether to have PTG are swayed into having the surgery when they find out that over 90% of PTG specimens have signet ring cells.    Symptoms Symptom factors assessed included dumping syndrome symptoms, depression and anxiety.    Of the 53 participants, 51 (96%) stated that they experienced early dumping syndromes.  This is generally caused by the rapid movement and emptying of gastrointestinal contents into the intestines too quickly.  Early dumping syndrome occurs in 20-30% of gastric cancer patients undergoing gastric surgery and this is usually severe in the first 3 months but gradually improves over the next 9 months [328].  In this study, there was no significant difference seen in any of the individual symptoms in either the EORTC QLQ-C30 or the STO22 instruments when looking at time since surgery and survey. It may be that the numbers of participants in each group was too small to pick up any potential difference.  This needs to be repeated with a larger number of patients.   Fatigue (59%), abdominal pain (57%), and diarrhea (45%), as measured on the clinical form, were the most frequently reported in all groups.  However, this symptom was not significant in 146 the regression model (Table 5.10b).  Fatigue is one of the consequences of major surgery and may be present in patients for the first several months while they recuperate.  It is also part of the dumping syndrome but as time goes on and the individual is able to establish healthier eating habits (smaller, healthier meals with higher frequency), symptoms may improve.  Worster and colleagues [15] noted fatigue was present at the 2-year follow-up in 63% of their patients who underwent PTG.   Among the symptoms that were significant in the regression model, some of the “meal-related” symptoms from the STO22 questionnaire proved to be significant.  Abdominal pain was noted in 57% of participants on the clinical form and revealed high (56.2±16.3) overall scores on the EORTC-QLQ-C30 symptom scale.  This pain occurs when eating or after eating and 12/25 participants (48%) stated that they were bothered by it “quite a bit” or “a lot“.  The overall scores for pain on both the EORTC QLQ-C30 and STO22 were high (56.2±16.3 and 49.1±23.7).  These were much higher than the scores reported by Worster’s study [15] where individuals at 2 years after their surgery had mean score of 1.99 (SD = 0.74).  The scores for this study are also higher than those reported for gastric cancer patients (31.4±31.7).   Stopain (STO22 symptom) was a significant predictor variable in the overall regression model revealing the clinical influence of this symptom in an individual’s overall QOL.  Diarrhea was also a common symptom with 45% of participants stating that they experienced it (median frequency was 5 times in the previous week for the group that was > 5 years after surgery).  It is generally thought that establishing healthier eating habits (smaller, healthier meals with higher frequency), helps reduce this symptom with time after surgery.  In as much as my 147  study was cross-sectional and not longitudinal, I have no information regarding whether diarrhea has improved since their surgery.  This symptom was a very significant predictor in the reduced model indicating its clinical influence on QOL.     Dyspnea and taste were also significant predictor variables in the regression model.  Previous studies have reported that patients who have undergone gastric surgery have reported changes in their taste of food and drink after surgery, including aversions to certain foods [329] [330, 331].  In one study [330], 45% of patients also reported loss of taste and/or smell after gastrectomy; this was transient in most cases but in some patients the changes were long term.  Although there is no known mechanism for why this occurs, it has been speculated that vagal influences might be responsible [330], that is, after the surgery, there could be an initial disruption in the homeostasis in olfaction and gestation followed by vacillating hypersensity and hyposensitivity before a static level of sensation is finally achieved.  It would be important to discover how and to what extent, these symptoms affect QOL and the longetivity of these effects in individuals after PTG.  I measured anxiety and depression, which are prevalent in patients with cancer or other chronic conditions [246] [332] with the PROMIS instruments in this study. The majority of participants scored in the “none to slight” range for both anxiety and depression (71% and 76% respectively).    All four of the individuals who scored in the severe range for anxiety and depression had been diagnosed with anxiety disorder, depression or associative identity disorder prior to the PTG.   The risk of depression in patients with cancer is approximately three times higher than in the general population [333] thus potentially contributing to the lower quality of life in these patients [334].  As seen in this study, anxiety and depression are highly comorbid.  However, anxiety has 148  been shown to be independently associated with a poorer overall quality of life in cancer patients [335].   Anxiety was a significant predictor in reduced models in this study.  Given that anxiety is a common response in cancer patients [336] and that anecdotal evidence (personal communications) has indicated that several individuals suffer from anxiety after PTG, this result is not a surprise.  Anxiety is a common response to threats of mortality and suffering and anxiety is believed to help patients to cope with the fluctuating situations in their lives. Anxiety is dynamic and for the majority of cancer patients, it peaks at different times during the course of their disease [337].  Therefore, it would be important for healthcare professionals to elicit the specific concerns of individuals after PTG and provide appropriate intervention if needed.   Functional Status Function was measured with two instruments – the SF-36v.2 and the EORTC QLQ-C30v.3.  The SF-36v.2 that has not been utilized widely in the literature on QOL after gastrectomy [175, 213].  The participants in the study scored very similar to the general population reference in the physical, role and emotional functioning scales of the EORTC QLQ-C30 [286].   A comparison of the five functioning scales in the EORTC QLQ-C30 between this study sample, the Worster [15] PTG study cohort and the general population reference values [286] is shown in Table 6.1. The participants in this cohort did not appear to fare as well as the Worster study participants in the cognitive scales (p=0.003). They also did much worse than the general population reference population in the cognitive functioning scale (p<0.001).   Further investigations are needed to understand why this difference in the cognitive scales exists.    149  Table 6.1 Group means of this study population, Worster study cohort and general population reference values.    This Study Worster et. al (2014) [15] EORTC reference values for general population [286]  Variable Mean (SD) Mean (SD) Mean (SD)  p-value* Physical  89.5 (15.9) 86.7 (1.6) 89.8 (16.2) 0.29 Role  79.3 (25.6) 77.1 (24.3) 84.7 (25.4) 0.40 Emotional  74.9 (24.6) 84.4 (16.9) 76.3 (22.8) 0.01 Cognitive   78.2 (27.1) 91.7 (16.1)  86.1 (20)  0.003** Social   76.6  (26.5) 76.0 (25.8) 87.5 (22.9) 0.44 SD = Standard deviation p-value is for comparison between the means of this study sample and the Worster study cohort.    Cognitive functioning was significant in the reduced model in this study.  Worster’s [15] cohort revealed a significant decrease in cognitive scores within the first month after surgery, but scores recovered to baseline within two years.  In several studies of patients with GC who have undergone gastrectomy, cognitive functioning is largely unaffected by surgery and tends to stay near baseline levels throughout follow-up [239] [249] or are actually back to baseline after three months [132, 338].  This study measured patient outcomes at one time frame; given that approximately half of the participants in this cohort were within three years of their surgery when completing this survey, it is possible that group may have skewed the scores on this variable.  Further work on larger numbers of participants will help tease this effect out. In the meantime, in those with impaired cognitive functioning, a complete medical checkup and consult 150  with a neurologist or a psychiatrist should be provided. In addition, the patient ought to be informed of the positive impact of maintaining their social activity.    The importance of the role functioning scale is reflected in its significant contribution to the regression model.  This scale did not return to baseline in the Worster study [15] and has also been shown to recover either in the short (one year) term or long term (five years or more) [239, 250, 338].  Poor role functioning may be a result of weakness and fatigue, diarrhea and even with age [239].    Social function was significant in the regression model.  The finding of social function as an important predictor variable of QOL in this study corroborates those of Maeda [246]  which revealed a significant negative correlation between social support and depression in gastric cancer patients who had undergone gastrectomy.   Social support is an important predictor of coping with difficult life issues and predicts the well-being of everyone from young children to the elderly in many contexts [339].  Studies have shown that social support can improve the several different aspects of QOL in cancer patients [246, 340].   Assessing an individual’s social support after PTG could help identify those whose QOL might benefit from improved social support such as seeking out peer support, being a part of different networks and participating socially.  Characteristics of the Individual The characteristics of the individual selected as part of this study included age, gender, ethnicity and education level. None of these correlated with any of the independent variables.   151   Age: The age range is this cohort of participants was very wide (22-63 years).  Age was not correlated with global health status/QOL or any of the other scales or symptoms measured.  Age was also not a significant predictor of QOL in the regression model but the majority of the individuals in this cohort were younger than 50 years and the overall sample size may have been too small to reveal any differences that may exist.  Studies of  QOL in individuals after gastric cancer surgery have shown mixed results with respect to age and QOL – some have shown that older patients have a better QOL than younger ones [254] [324], whilst others have shown the opposite trend [237].  It is difficult to compare these findings to our study as the patients in these other studies were much older (> 65 years).   Sex:  Men were under-represented in this study, making up only 26% of the participant cohort.  It is impossible to say why males were under-represented in this study but women are generally are more proactive when it comes to health-related matters such as making the decision to undergo the PTG or being involved in research studies [341].  It would be important to know if this underrepresentation is in part due to the fact that perhaps male carriers are not having PTG in the first place.  Sex was not a significant predictor of QOL in the regression model. In studies of patients who have had gastrectomy for gastric cancer, the results are again mixed – some show that women have poorer QOL [254, 324] and others show the opposite trend [246, 231].  152  Characteristics of the Environment The characteristics of the environment included in the study were marital status, time elapsed between surgery and survey and employment status.    Marital Status:  The majority of participants was married or in common-law relationships (77%). Marital status was not a significant predictor in the model.  In other studies, married individuals reported more symptoms than unmarried ones overall [338], a finding first seen by Maeda and her colleagues [246].  It was postulated that perceived social support influences a person’s psychological well-being.  Therefore, the authors suggested that having a spouse/partner may be an important source of a person’s support. Han et.al. [264] found a significant relationship between marital status and QOL in Korean cancer patients – unmarried patients had a statistically significant decline in QOL compared to their married counterparts.     Time-elapsed Between Surgery and Survey:  This variable was categorized as ≤ 12 months (16%), 13- 60 months (39%) and over 60 months (45%) to determine whether the time differential had an impact on the dependent variables being studied. The average time elapsed between surgery and survey in this study was 50 months. In this study, there were no significant associations between any of the variables and time elapsed between surgery and survey.  This might mean that over time people start to develop a “new normal” in their everyday living.  153  Employment Status:  Sixty-three percent reported that they were working at the time of the surgery.  This is not surprising considering the age range of the study cohort.  Employment was not significantly associated with any of the dependent variables in this study.  The Conceptual Framework I used the Wilson and Cleary [100] model of health-related quality of life as the conceptual framework to guide the third objective of this study.  Apart from the main aspects of health factors, this framework also includes characteristics of the individual and the environment thus lending itself to a more holistic view of QOL.  I used the framework for guidance in selecting variables that may impact overall quality of life in this cohort.  The significant predictor variables in the regression model explained 91% of the variance in quality of life for individuals who had undergone PTG.  This is an important finding as this is the first study reporting this.  Although the use of this theoretical framework to guide the study was a strength, it is possible that the results from this small cohort cannot be generalized to all mutation carriers who have undergone PTG.  It is possible that this cohort of participants was generally healthier and less symptomatic than those who did not participate.  It would be important for future studies to use a conceptual model of health-related quality of life, such as the Wilson and Cleary model, to provide a more integrated approach to both the clinical and psychosocial aspects of PTG.    6.4 Contribution of this Research to Clinical Practice Prior to the current penetrance estimates, genetics professionals were utilizing risk figures from two very small studies in order to counsel CDH1 carriers on their choices regarding surveillance or PTG.  Although the estimated risks of DGC and LBC are fairly similar in this study, the 154  current estimates have much narrower confidence limits and are therefore more precise and reliable.  In addition, I found that the risks for GC are high and rise steeply between the third and fourth decades for both men and women.  These improved estimates may make decisions easier for patients when making a choice between surveillance and surgery.    Ongoing research into clinical outcomes and quality of life is important because of the 100% morbidity of PTG, the limited effectiveness of available surveillance methods for DGC and the poor survival rate of symptomatic patients with DGC and consequent related issues of quality of life.    Clearly there is a need to understand factors that influence these issues to improve the clinical management of HDGC families.    This research provides further information on clinical outcomes, post-surgical symptoms and quality of life in individuals after prophylactic total gastrectomy.  These individuals are usually asymptomatic prior to their surgery and generally in good health.  Although the worry of gastric cancer is generally eliminated for those undergoing PTG, the surgery comes with a price – inevitable post-surgical symptoms that may include symptoms such as anxiety, fatigue, and diarrhea. This re-enforces the recommendation of having a multidisciplinary team involved in the pre- and post-surgical care of these individuals.  Ameliorating dumping syndrome symptoms may require dietary and life-style changes to be made and maintained.    Although symptoms of pain and fatigue were prevalent after PTG in this study cohort, neither symptom was a significant predictor of QOL in this cohort in the full or reduced regression model.  A major surgery like gastrectomy can cause intra-abdominal adhesions that cause 155  intermittent or chronic pain.  Sometimes these adhesions may cause pain without intestinal obstruction and so it is imperative that the individual be assessed by a surgeon [342].  Pain may be due to microbial overgrowth in the gastrointestinal tract or pancreatic enzyme insufficiency and these can be dealt with therapeutically thus improving the symptoms and consequently quality of life [14].  Anxiety was a significant predictor variable that can affect one’s ability to cope and thus one’s QOL.  In individuals who are not able to adjust and make changes to their lifestyle after PTG, it would be important to provide interventions based on the level of anxiety.  Intervention is important in individuals who have moderate to severe anxiety as it may manifest itself in one’s role functioning, as well as presenting physical symptoms such as fatigue, nausea/vomiting and even pain.   Psychosocial issues in patients who have had PTG are also important to assess.  This study has shown that social function is an important predictor of QOL in this cohort.  This is not surprising as the social environment of an individual has strong impact on one’s well-being and also provides protection from the harmful effects of potentially stressful life events that include major surgery [339].  It would be unreasonable to suggest such a drastic surgery if quality of life were seriously impaired, and it is reassuring that we found that QOL scores were high in this study sample.  This study suggests that prophylactic total gastrectomy does not usually have long-term negative implications for a person’s quality of life.  Most of the individuals in this study did not exhibit anxiety or depression either on the PROMIS or EORTC instruments but were functioning 156  at psychosocial levels that are comparable to the general population.  It is hoped that these study outcomes will reassure individuals who are contemplating having the surgery.  Routine measurement of QOL before and after PTG might afford a number of benefits, including identification and prioritization of patients’ problems, screening for hidden concerns and improving the efficacy of the outpatient consultation.  Recognition of the potential negative side effects of PTG may also spur the development of more efficient screening of DGC to avert the need for this surgery in the first place.   6.5 Limitations and Opportunities of the Study  Objective 1:  Cancer risk in CDH1 mutation carriers may be influenced by several factors including type of mutation, location of mutation, lifestyle and environmental factors.  Even though this was the largest set of CDH1 germline mutation carriers ever assembled, we did not have sufficient data to evaluate the effects of these factors on penetrance.  We continue to collect more data on individuals and families so that we may answer these questions in the future.  Objective 2:  Despite a thorough search of the literature and public databases, it is possible that not all articles or reports were located to provide a complete list.  With the advent of clinical testing for CDH1 in commercial laboratories, many novel mutations may not be published or entered into online gene mutation databases.  In 2015, an international working group of gastric cancer experts formed a working group through ClinGen that will actively focus on CDH1 gene curation, variant interpretation and creating consistent curation guidelines.   157  Objective 3:   Although I anticipated a good response rate to this study, the sample size achieved was small (N=53) and may not be completely representative of all patients who have undergone PTG because of their increased risk of developing DGC.  The small sample size also may have limited ability to detect effects of some factors or differences between groups.  There are a limited number of individuals in North America (and world-wide) who have had or will be having a prophylactic gastrectomy because they carry a CDH1 mutation, and performing larger studies in the future, although necessary, will be difficult.    The results from the cross-sectional design assessed complications, symptoms and measurements in QOL after a period of adjustment but at only one time point.  A prospective design would have allowed me to measure changes that occur over time and to distinguish transient and long-term effects. I attempted to enroll PTG patients into a prospective cohort study but was unable to recruit any.  However, the cross-sectional design was relatively inexpensive and did not take long (two years) to obtain the largest cohort of participants who have undergone PTG to date and to collect a lot of data.  Clinical data quality in the cross-sectional study may have been compromised in that some of hospital charts did not have all the information that was requested thus leaving some gaps in data.  Another possible source of medical data would have been through the family doctors who see these patients on a more regular basis.  Limiting the study to English-speaking participants did not allow me to document if there is any variability between language groups.  For example, I am aware of French-speaking PTG patients in Quebec who could not participate.  Some Spanish speakers in the US were also not able to participate.   Future studies should include non-English speaking participants.  158 6.6 Conclusions This study’s penetrance estimates for diffuse gastric cancer and lobular breast cancer were obtained from largest set of CDH1 mutation carriers assembled to date.  These more precise and robust penetrance figures will improve genetic counseling of asymptomatic carriers.  This study also provides an update of the spectrum of germline mutations in the CDH1 gene – these are present throughout the gene with no apparent hot spots. There were 26 post-operative complications noted in 23 participants and were in line with other studies in the literature on post-PTG patients.  Weight loss pre- and post-surgery was similar to other studies at 19%.   Participants in this study reported a good quality of life although some symptoms of dumping syndrome persisted in most patients to varying degrees for years after the surgery.  Gastrectomy has been previously shown to have a negative outcome in individuals, especially over the short term (less than five years) and then typically recovers over time.  Since the ultimate goal of QOL assessment in patients is to restore them as close to or back to their baseline health, any persistent symptoms must be appropriately managed on an individual level by the patient’s healthcare team.  This study has revealed that functional scales of cognitive, role and social and symptoms of anxiety, pain, loss/alteration of taste, dyspnea and diarrhea may significantly reduce QOL after PTG.   Therefore, it would be imperative to continue to find ways to remedy these concerns. 159  Although many of the functional scales deteriorate with associated physical symptoms and also with age, it is suggested that proper nutritional care (which includes monitoring and correcting patients’ daily dietary habits) will improve these [239].  I have noted that this has been the case with several individuals I have spoken to over the last few years.   If anxiety is identified in an individual after PTG, further assessment is needed to rule out first whether it is a result of post-surgical symptoms, and treated accordingly.  The extent to which anxiety is functionally impairing is also important to provide the proper intervention; anxiety as a symptom may be managed via brief intervention, whereas anxiety disorders would require treatments with more lasting effects. Social functioning and role both had significant effects.  Poor role functioning may be the result of several factors so it would be important to tease out the causes. Given that social support is a strong predictor of one’s mental and physical health, individuals planning on (or have had) PTG, have a strong social support.      6.7 Future Directions Given that there is a high lifetime risk of diffuse gastric cancer in males and females and the additional risk of lobular breast cancer in females, the identification of pathogenic germline CDH1 mutations allows carriers to make important clinical management decisions to reduce these risks.  Reliable estimates of penetrance are crucial for counseling and decision making for these individuals.  Penetrance estimates for CDH1 mutation carriers have been derived from studies that ascertain clinically defined HDGC families.    160  It is likely that these penetrance figures can be refined will change over time by studying more families with CDH1 mutations in greater detail.  In some families with CDH1 germline mutations,  lobular breast cancer appears to be unexpectedly frequent and diffuse gastric cancer less frequent than expected [111, 291].  In addition, as a result of the increasing use of next-generation multi-gene panels in the clinical setting pathogenic germline CDH1 mutations are now being found in families that do not have clinically defined HDGC (personal communications).  It would not be surprising if the penetrance estimates for pathogenic CDH1 germline mutations detected in the highly ascertained HDGC families included in this study were found to be higher than the estimates obtained in families with CDH1 germline mutations identified in other ways.    Other families have been reported in which in which elderly members proven to be carriers of pathogenic germline mutation or have not developed DGC while other members have had early onset DGC [7, 93].   This could be the result of additional genomic events and/or environmental factors that are associated with early-onset DGC.  Further studies are needed to elucidate these factors.   Many families with HDGC have been found to have CDH1 missense mutations where the pathogenicity of the mutation is unknown.  There needs to be continued effort to assess the pathogenicity and penetrance of these CDH1 missense mutations using a multidisciplinary approach.    161  Given that no more than 40% of families with clinically defined HDGC harbor a germline CDH1 mutation, there needs to be a continued search to look at both the non-coding regions of the CDH1 gene and for other HDGC susceptibility genes.    Improvement of surveillance for DGC is needed for clinical management of CDH1-mutation carriers so that there would no longer be a need for prophylactic gastrectomy.  Surveillance will also be important in families where HDGC is diagnosed clinically but no CDH1 germline mutation has been found.  We have a database of participants who have all provided permission for re-contact for long-term follow up studies.    This could allow for the assessment of changes in medical outcomes as well as psychosocial functioning over time.  The opportunity to include prospective participants is also available. Future studies may include qualitative assessments that could provide more depth and detail regarding my findings in this study.   The small numbers in this study as well as in series in the literature may not be providing a complete picture of life after PTG.  There are other small (< 15 participants) studies using the EORTC instruments currently underway in other centres that may benefit from combined analyses to achieve larger sample sizes (personal communications).   In this study, we were unable to assess participants prior to their surgery.  We do not clearly understand all of the factors that influence decision-making processes regarding surgery to eliminate the risk of gastric cancer.  It is important to understand this decision-making process to enhance the counselling process.  162By utilizing data from this and other studies, evidence-based knowledge transfer tools can be developed for both patients with CDH1 mutations and their health care providers regarding prophylactic total gastrectomy.   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Multivariate Data Analysis (6thed.).Upper Saddle River, NJ: Pearson Prentice Hall. 187Appendices18Appendix A: Summary of families with CDH1 mutations in this studyFamily Criteriaa Proband (Age at Diagnosis, y)No. of GC Cases; DGC Casesb (Age Range at Diagnosis, y)No. of BC Cases; LBC Casesb (Age Range at Diagnosis, y)Ethnicity CDH1 MutationLocation Mutationc Type ReferenceF1 1 DGC (38 & 43)2;2 (30,35) 0 Hungarian/GermanExons 1 and 2chr16:del 67 193 822 - 67 387 415 (193 593bp)Large deletion Oliveria 2009eF2 4 LBC (61) 3;2 (28-40) 0 Caucasian Exons 1 and 2chr16:del 67 193 822 - 67 387 415 (193 593bp)Large deletionOliveria 2009eF3 1 DGC (34) 1;0 (?) 0 Lithuanian Exons 1 and 2chr16:del 67 324 886 - 67 330 557 (5671bp)Large deletionOliveria 2009eF4 1 DGC (40) 2;2 (24, 39) 0 Mexican Exon 1 chr16:del 67 328 695 - 67 328 844 (150bp)Large deletionOliveria 2009eF5 1 DGC (48) 1 (45) 0 Eastern EuropeanExons 1 and 21-?_163+?del Large DeletionNovelF6 1 DGC & LCIS (32); DGC (49)2;1 (32-54) 2;1 (32-50) Scottish/IrishExon 1 3G>A (M1I) Missense-PathogenicdNovelF7 1 DGC (74) 5;2 (52-72) 0 French-CanadianIntron 1 48 +1G>A Splice Site Petridis 2013F8 3 Unaffected – obligatecarrier1 (30) 0 Italian Exon 2 79C>T  (P27S) Missense-Unclassified VariantNovelF9 3 DGC (29) 0 0 Hispanic Exon 3 286A>G (I96V) Missense-Unclassified Novel18Family Criteriaa Proband (Age at Diagnosis, y)No. of GC Cases; DGC Casesb (Age Range at Diagnosis, y)No. of BC Cases; LBC Casesb (Age Range at Diagnosis, y)EthnicityCDH1 MutationLocation Mutationc Type ReferenceF10 1 DGC (30) 1;0 (75) 0 Lebanese Exon 3 382delC Deletion Brooks-Wilson 2004F11 1 DGC (42) 5;1 (39-88) 1;1 (45) Irish/EnglishExon 4 447_453del CAGAAGA Deletion NovelF12 3 DGC (30) 1;1 (30) 0 Algerian Intron 5 687+1G>T Splice Site NovelF13 3 DGC (31) Not known Exon 6 715G>A (G239R) Missense-Splice SiteKaurah 2007;More 2007F14 1 DGC (46) 3;1 (46-64) 1;0 (70) Swedish/GermanExon 6 832+1G>T Splice Site Benusiglio 2012F15 1 DGC (41) 12;2 (29-75) 0 Not known Intron 6 833-2A>G Splice Site NovelF16 3 DGC (37) 0 0 Not known Exon 7 892G>A (A298T) Missense-Unclassified VariantBrooks-Wilson 2004F17 1 DGC (39) 4;1 (39-49) 3;0 (?-64) Mexican/EuropeanExon 7 940A>T Nonsense NovelF18 1 Unaffected 5;2 (39-52) 1;0(35) Caucasian Exon 8 1009-2A>G Splice Site NovelF19 4 LBC (46) 1; 1 (69) 2;2 (29-46) German Exon 8 1137G>A Splice Site Kaurah 2007;More 2007;Frebourg 20061Family Criteriaa Proband (Age at Diagnosis, y)No. of GC Cases; DGC Casesb (Age Range at Diagnosis, y)No. of BC Cases; LBC Casesb (AgeRange at Diagnosis, y)Ethnicity CDH1 MutationLocation Mutationc Type ReferenceF20 1 Unaffected 7;2 (26-63) 1;0 (?) Arabic Exon 8 1137G>A Splice Site Kaurah 2007;More 2007;Frebourg 2006F21 1 Unaffected 4;3 (35-40) 1;0 (59) Native AmericanExon 8 1137G>T Splice Site NovelF22 1 DGC (36) 4;1 (32-42) 0 Not known Intron 8 1137+1G>A Splice Site Guilford 1999F23 4 LBC (47) 0 2;1 (32-47) Not known Exon 9 1189A>T Nonsense Hebbard 2009eF24 4 LBC (51) 4;0 (31-68) 5;1 (51-87) Japanese Exon 9 1212delC Deletion Brooks-wilson 2003;Yamada 2011F25 4 LBC (53) 1;0 (40) 6;1 (30-60) Northern EuropeanIntron 10 1565+1G>A Splice site Schrader 2008eF26 1 DGC (55) 2;1 (55,76) 2;1 (67,74) Caucasian Intron 10 1565+1G>C Splice Site NovelF27 1 Unaffected 2;1 (30-57) 0 Arabic Intron 10 1565+1G>T Splice Site Humar 2002F28 1 DGC (39) 3;1 (39-58) 0 Not known Intron 10 1565+2dupT Splice Site Rogers 20081Family Criteriaa Proband (Age at Diagnosis, y)No. of GC Cases; DGC Casesb (Age Range at Diagnosis, y)No. of BC Cases; LBC Casesb (Age Range at Diagnosis, y)Ethnicity CDH1 MutationLocation Mutationc Type ReferenceF29 1 DGC (47) 3;1 (47-64) 1;0 (61) Caucasian Exon 11 1679C>G (T560R) Missense-Splice SiteBenusiglio 2012F30 1 Unaffected 6;4 (40-61) 1;1 (58) Not known Exon 12 1792C>T Nonsense Gayther 1998;Suriano 2005F31 1 DGC (59) 5;1 (41-59) 3;0 (36-67) Irish/EnglishExon 12 1792C>T Nonsense Gayther 1998;Suriano 2005F32 1 DGC (46) 2;1 (46-71) 0 Brazilian Exon 13 2058_2059delTG Deletion NovelF33 1 DGC (20) 2;2 (29-?) 0 English/ScottishExon 13 2100delT Deletion NovelF34 1 Unaffected 2;1 (33-38) 0 Not known Exon 14 2265T>A Nonsense NovelF35 1 DGC (42) 3;2 (32-70) 1;1 (52) Not known Exon 15 2310delC Deletion Brooks-Wilson 2004F36 1 Unaffected 4;0 (33-65) 0 Jewish Exon 15 2413G>A(D805N)Missense-Unclassified VariantNovelF37 1 DGC (45) 3;1 (45-66) 0 English Exon 15 2430delT Deletion Novel19Abbreviations:  GC, gastric cancer; DGC, diffuse gastric cancer; LCIS, lobular carcinoma in situ; BC, breast cancer; LBC, lobular breast cancer. aCriteria 1-4 as per 2010 International Gastric Cancer Linkage Consortium guidelines (Fitzgerald et al.) and described in Table 1. bRefers to number of confirmed cases. cNumbering is based on CDH1 cDNA sequence (GenBank NM_) with A in start ATG (methionine) corresponding to position 1.  Amino acid changes for missense mutations denoted in parentheses. dNucleotide change disrupts the start codon. eNovel mutations identified in families ascertained and tested during the time period of this study that were published separately by collaborators. 19APPENDIX B: Letter and reply form (Cancer genetics professional) 19Date Address of physician/GC Dear ___________, We are writing to request your assistance in our study entitled, “Clinical Outcomes and Quality of Life in CDH1 mutation carriers after Prophylactic Total Gastrectomy”,which is being conducted throughout North America.  This study involves collaboration between the University of British Columbia and the British Columbia Cancer Centre inVancouver, BC. We have received ethics approval from the BCCA Research Ethics Board. In order to conduct the study, all individuals who carry a CDH1 germline mutation and who have undergone a prophylactic total gastrectomy are being identified through genetics clinics throughout North America.  If you identify an individual in your practice as having undergone PTG or is planning on undergoing PTG, we ask that you obtain your patient’s consent for us to contact her/him.  We will then send your patient a study package that will include consents for the release of their medical records pertaining tothe gastrectomy as well as questionnaires about their current clinical symptoms and their quality of life after the surgery.  All information will be strictly confidential. We request your assistance in obtaining the consent of your patient, to contact and seek his/her participation.  The consent attached implies that you have contacted your patient who has in turn agreed to be contacted by the research team.Please complete the consent form and return it either by mail or fax to us at SKRQHQXPEHU.  If you have any questions or concerns, please do not hesitate to contact Pardeep Kaurah at SKRQHQXPEHU.19Thank you very much for your cooperation. Sincerely, David Huntsman, MD, FRCPC, FCCMG Pardeep Kaurah, MSc, CCGC Professor, Department of Pathology   Study Coordinator  and Lab Medicine, UBC Medical Director, CTAG, BC Cancer Agency 19PLEASE COMPLETE AND RETURN RE:___________________________________________________  This patient may be contacted at the following address and phone number:Address: ______________________________________________________________ _______________________________________________________________ Phone number:  ________________________________________________________  This patient is deceased.  You may contact the next of kin:Name: _______________________________________________________________________ Address: ______________________________________________________________ _______________________________________________________________ Phone number:  ________________________________________________________  I am not involved with any individual who has undergone a prophylacticgastrectomy. Contact another genetic counselor/physician:Name: _______________________________________________________________________ Address: ______________________________________________________________ _______________________________________________________________ Phone number:  ________________________________________________________ YOUR SIGNATURE:  __________________________________________ DATE:  ______________________________________________________ 19Appendix C: Letter of Invitation to Participant 19Name of Participant Address Dear (Name of Participant):This letter is an invitation for you to participate in a research study of titled “Clinical Outcomes and Quality of Life after Prophylactic Total Gastrectomy in CDH1 mutation carriers”.  The study is being conducted by the Hereditary Cancer Program at the BC Cancer Agency, in collaboration with the University of British Columbia.  We had initially contacted your physician/genetic counselor (insert name) to inform them of this study.  (Name of healthcare provider) then obtained permission from you so that we couldcontact you about this study which you are eligible to participate in. Your rights to privacy are legally protected by federal and provincial laws that require safeguards to insure that your privacy is respected. The purpose of this study is to obtain more information on what happens to an individual after s/he has had prophylactic gastrectomy.  The study examines the medical complications that may occur shortly after the surgery, any clinical symptoms and quality of life of individuals who have had prophylactic surgery in the first year after surgery.  Please find enclosed an information sheet giving more details about the study.  Your participation in this research is voluntary.  Your identity will be protected and any information you choose to share will be confidential and will not affect your medical care. If you agree to participate in this study, we will send you a package containing the first set of the surveyforms. We anticipate that the results of this study will serve to improve the knowledge and care ofservices to individuals such as you in the future. The results of the study may be published or presented at professional meetings, but your identity will not be revealed. If you would like to participate in this research, please sign the enclosed form and return it to me as soon as you can.   If you do not want to be contacted, you may leave a messageDWSKRQHQXPEHU.19You may contact me or Pardeep Kaurah if you have study related questions or problems.If you have any questions about your rights as a research participant, you may contact the Officeof Research Services at the University of British Columbia at 604-822-8581 or toll free at1-877-822-8598, or by email to: RSIL@ORS.ubc.ca.We hope that the results of this study will serve to improve the knowledge and care of services to individuals such as yourself in the future.Sincerely,David Huntsman, MD, FRCPC, FCCMG Professor, Department of Pathology and Lab Medicine, UBC Medical Director, Centre for Translational and Applied Genomics, BC Cancer Agency APPENDIX D:   AUTHORIZATION FOR RELEASE OF MEDICAL INFORMATION20AUTHORIZATION FOR RELEASE OF MEDICAL INFORMATION I hereby authorize_________________________________________________________ (Medical Facility where surgery took place) ________________________________________________________________________(Address)to divulge information regarding: ____________________________________   _____________________________ Last Name, First Name, Middle Initial Date of Birth: Specific Information requested: ______________________________________________ … Operative Report regarding ________________________________________ … Medical Records regarding ________________________________________ … Pathology report _________________________________________________ … Other _________________________________________________________ ___________________________________ ___________________________________ (Name – Printed)  (Relationship to patient)  _____________________________ ___________________________________(Signature) (Date signed) Please send the above information to: Dr David Huntsman, MD 20APPENDIX E: Study Participation Consent Form20 Subject Information and Consent Form CLINICAL OUTCOMES AND QUALITY OF LIFE IN CDH1 MUTATION CARRIERS AFTER PROPHYLACTIC TOTAL GASTRECTOMY  Principle Investigator: Dr David Huntsman,  BC Cancer Agency Vancouver, BC  Canada Background You are being invited to participate in this study because you have had a prophylactic total gastrectomy (PTG).  You underwent this surgery because you were found to carry a mutation in the CDH1 gene.   We are aware that there is a nearly 100% risk of short and long term complications associated with having a PTG.   These include chronic diarrhea, dumping syndrome and weight loss. There is also a 1-2% risk of death related to the procedure itself.  Individuals having PTG are normally asymptomatic and healthy before the surgery. They are also usually young, working or at school, and have families. Therefore, PTG needs to maintain the health and lifestyle of these individuals for it to be considered a reasonable alternative to endoscopic surveillance in carriers.  The decision to have PTG raises many significant issues which include the quality of life after the surgery. There are few studies to date looking at long term clinical outcomes in persons who have had PTG.  There are no studies looking at the quality of life after PTG.  Participation in this study is voluntary, and if you agree to participate you may withdraw your consent at any time and stop your participation at any time.  Your medical care will not be affected if you decide to leave the study. Purpose of research:You have been asked to participate in a research project on the clinical outcomes and quality of life after prophylactic total gastrectomy in North America.  The purpose of this study is to obtain more information on any short term and long term complications of the surgery you may have experienced your personal satisfaction with the decision to have the preventive surgery and how the various aspects of your life may have been affected after the surgery.  This information may provide evidence based management that is essential to inform clinical decisions of those who are contemplating PTG. 20Who Can Participate In This Study? You may participate in this study if: x You fully understand the study and give your informed consent to participate asdemonstrated by signing this consent form.x You are at least 18 years of age, regardless of gender and ethnicity.x You have tested positive for a CDH1 gene mutation, regardless of when this occurred.x You were not been diagnosed with gastric cancer prior to the PTG.x You have already undergone PTG or are thinking of having a PTG.x You are able to read, write and understand English.Study procedures:If you agree to participate in the study, you will be asked about your medical history and your family history of cancer.  You will be asked to sign a consent form for the release of your medical records pertaining to the surgery.  You will also be asked to complete questionnaires thatinclude information about yourself (demographics), your satisfaction with the surgery, any clinical symptoms that you may be currently experiencing and any medical conditions that you may have.  There will also be questionnaires that ask about how you are feeling, the emotional and physical support you feel you are receiving as well as how different aspects of your life may have been affected by the surgery.  The questionnaires will take less than an hour to complete.  You will be asked to complete all questionnaires at only one time. Risks:There are no known risks associated with participating in this study. Possible Benefits:Knowledge gained from this study might not benefit you directly. However, the information that is obtained from this research study will be used scientifically and possibly may be helpful to others who are thinking about having prophylactic total gastrectomy in the future.  Knowledge gained from this study may help the future development of understanding the risks that are associated with the surgery and may help improve counseling to those who seek the surgery.   Confidentiality: Your confidentiality will be to the extent permitted by applicable laws and regulations and your medical and study records will not be publicly available. No information that discloses your identity will be released or published without your specific consent. Your identity will not be used in any reports about the study. In records that leave this centre you will be identified by a study code only. Your birth date will also be provided if requested by the sponsor or responsible regulatory agency. Studies involving humans now routinely collect information on race and ethnic origin as well as other characteristics of individuals because these characteristics may influence how people respond to different treatments. Providing information on your race or ethnic origin is voluntary. All information associated with this study will be kept behind locked doors or in secure computer files. 20Research records and medical records identifying you may be inspected by representatives of Health Canada, the U.S. Food and Drug Administration and the UBC BCCA Research Ethics Board for the purpose of monitoring the research. However, no records that identify you will beallowed to leave the centre. These organizations have policies of strict confidentiality and the individuals inspecting your records must sign a BC Cancer Agency confidentiality form (the form is not applicable to Health Canada or U.S. Food and Drug Administration officials, who have the legal right to inspect health records and are bound to confidentiality by specific laws.) Any study related data, sent outside of Canadian borders or received from outside of Canada may increase the risk of disclosure of information because the laws in those countries dealing withprotection of information may not be as strict as in Canada.  However all study data, that might transferred outside of Canada will be coded (this means it will not contain your name or personal identifying information).  Any information sent outside of Canada by the research team will betransferred in compliance with all relevant Canadian privacy laws.  Your rights to privacy are legally protected by federal and provincial laws that require safeguards to insure that your privacy is respected and also give you the right of access to the informationabout you that has been provided to the sponsor and, if need be, an opportunity to correct any errors in this information.  Further details about these laws are available on request to your study doctor or the UBC BCCA Research Ethics Board.  Reimbursement: You will not be paid for participating in this study. Remuneration: The sponsors of this study may reimburse the BC Cancer Agency for all or part of the costs ofconducting this study or they may provide the BC Cancer Agency some or all of the standard or experimental medications being used in this study. However, the investigators conducting thisstudy will not receive any personal payments for conducting this study. In addition, neither theBC Cancer Agency nor any of the investigators or staff conducting this study will receive any direct financial benefit from conducting this study Contact You understand that if you have any questions or desire further information with respect to this study, you may contact the principal investigator of the study, Dr David Huntsman  <ou may also contact, Pardeep Kaurah (Genetic Counsellor) . If you have any concerns about your treatment or rights as a research subject you may contact the Research Subject Information Line at the UBC Office of Research Services at the Universityof British Columbia at (604)-822-8598 or toll free at 1-877-822-8598, or by email to: RSIL@ORS.ubc.ca.20SUBJECT CONSENT FORM I understand that participation in this study is entirely voluntary. I authorize access to my medical record as described in this consent form. I may choose not to participate or I may withdraw from the study at any time and I will continue to be offered the best available medical care.  I understand that I may ask questions about this study in the future. I will receive a signed copy of this consent form for my own records. I consent to participate in this study. ____ Subject’s Signature Printed name Date ____ ____ Signature of  Printed name Study Role Date Person Obtaining Consent Was the subject assisted during the consent process in one of ways listed below? … Yes … No If yes, please check the relevant box and complete the signature space below: … The consent form was read to the subject, and the person signing below attests that the study was accurately explained to, and apparently understood by, the subject (please check if subject is unable to read ).  … The person signing below acted as an interpreter/translator for the subject, during the consent process (please check if an interpreter/translator assisted during the consent process).____________________________   _______________  _____________ Signature of Person Assisting Printed Name Date in the Consent Discussion ____________________   ______________  _____________ Investigator Signature   Printed name  Date My signature above signifies that the study has been reviewed with the study participant by me and/or by my delegated staff.  My signature may have been added at a later date, as I may not have been present at the time the participant’s signature was obtained. 20APPENDIX F:  Demographic and Symptoms Questionnaire 20STUDY CODE:_______________________ Demographic and Symptoms Questionnaire Thank you for helping us with this questionnaire. The information that you are providing is very valuable to us. Please call PardeepKaurahif you have any questions.Some of the questions may not apply to you. If that is the case, please check the answers, “no” or “never” and move on to the next one. Most of the questions require checking the appropriate box.  If you do not know the answer exactly, please write down your best guess.  You do not have to answer any question if you do not wish to do so. 20PART I:  DEMOGRAPHIC INFORMATIONThis part of the survey asks questions about you. 1. Are you male or female? Male Female2. In what month and year were you born? _________________________________3. Where were you born? _____________________________ 4. Where did you live during your childhood and teen years? _____________________ 5. What is your postal/zip code? ______________________________ 6. What is your marital status? Now married Widowed Divorced Separated Never married7. What is the highest level of education you have completed? If currently enrolled, mark the previous grade orhighest degree received. No schooling completed  Master’s Degree Less than high school  Doctoral Degree High School/GED  Professional Degree (MD, DDS, DVM, LLB, JD) Some college 2-4 year college degree (Associate) 4 year college degree (Bachelors)28. Employment StatusAre you currently...?  Employed for wages  Self-employed  Out of work and looking for work  Out of work but not currently looking for work  A homemaker  A student  Retired  Unable to work 9. EthnicityTo which of these ethnic groups do you consider you belong?  White Please specify (for example, English/French/Spanish)    ______________________________________  First Nations/American Indian  Pakistani  Bangladeshi Chinese  Japanese  Punjabi  Black, Caribbean  Black, African  Korean  Other Asian  Please specify ____________________________ Hispanic/Latino  Other Please specify ________________________ 2Your Height and Weight:1. What is your height? ________ feet _______ inchesOR _________ cm 2. What is your current weight? ________kilograms OR __________ pounds      What was your pre-gastrectomy weight? _________ kilograms OR  ________  pounds 3. What date did you have your surgery?  _________/_________/__________Month      / day           /year 21PART II:  SATISFACTION WITH THE SURGERY The following questions ask how satisfied you are with your decision to have the prophylactic gastrectomy.  Please check the appropriate box.  Please answer the questions as best as you can.  For the following questions, circle the answer you feel is closest 1. How satisfied are you with your decision to have prophylactic gastrectomy?__________________________________________________________________________________________________________ 1 2 3 4 5(very (neither satisfied nor satisfied) (Very satisfied) dissatisfied) 2. How involved were you with your decision to have prophylactic gastrectomy?____________________________________________________________________________________________________________ 1 2 3 4 5(Not involved at all) (Very involved) 217. Were you advised by someone else to have prophylactic surgery? NO YES by whom (check all that apply)  Family doctor  Oncologist  Surgeon  Genetic counsellor  Family member  ____________________  Other  _____________________________ 3. Did you feel you had enough support immediately after your surgery (within the first month?) NO YES From whom: (Check as many as apply)  Spouse  doctor Parent  nurse Sister  psychologist Brother  therapist  Daughter  friend  Son  neighbor 4. Do you still worry about developing gastric (stomach) cancer? Never  Sometimes  Always  Other _________________________________________________________________ 21PART III:  SYMPTOMS AFTER THE SURGERY The following section asks about any serious medical issues that are currently experiencing. We would like to know if you have suffered from any of the following signs and symptoms within the past week. For each symptom listed below, please check "YES" or "NO" to indicate whether you had the symptom in the past week. If you check "YES" for a symptom, let us know how often you had it and how much the symptom bothered you. Please answer all questions to the best of your ability. Early dumping symptoms (within 15 to 30 minutes following a meal) in the past week:How many times in the past weekdid you have this symptom?If you had this symptom in the past week, how much did it bother you when it happened?NOT A LITTLE  QUITE  A AT ALL BIT A BIT  LOTSYMPTOMS 0 1        2           3Nausea        No  Yes    Vomiting      No  Yes        Abdominal pain,    No  YesCramps   Diarrhea     No  Yes    Dizziness, Lightheadedness    No  Yes    Bloating, Belching No  Yes   Fatigue     No  Yes                       21Late dumping symptoms (usually 1-3 hours after a meal) in the past week:How many times in the past weekdid you have this symptom?If you had this symptom in the past week, how much did it bother you when it happened?NOT  A LITTLE  QUITE  A AT ALL BIT  A BIT  LOTSYMPTOMS 0 1 2         3Sweating No  Yes           Weakness,   No  Yes  Fatigue               Shakiness   No  Yes            Diarrhea     No  Yes            Feelings of  anxiety   No  Yes            Heart palpitations No  Yes(rapid heart rate)           Fainting      No  Yes           Mental confusion  No  Yes           213. Have you noticed if the symptoms occur more often or are worse after a particular type of food is eaten?_____ No_____YesIf yes, please explain:________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________21Changes in medical conditions following the surgery: This section looks at any changes in health conditions that you may have had after surgery. We would like to know if you have suffered from any of the following medical conditions. For condition listed below, please check "YES" or "NO" to indicate whether you have or had the condition. If you check "YES" for a condition, let us know how you controlled it and if the condition improved, worsened or showed no change after your surgery. Please answer all questions to the best of your ability. Medical Condition If you had/have the condition, how was it controlled?After surgery, did the condition If the condition improved or worsened after surgery, how long was it before you noticed the change?Diabetes … No… Yes … diet and exercise… pills… insulin injections… Improve… Became worse… No changeHyperlipidemia (high levels of fat in the blood)… No… Yes… diet and exercise… pills… other (please specify) ______________________… Improve… Became worse… No changeGastroesophageal reflux(heartburn)… No… Yes… diet and exercise… pills… other (please specify) ______________________… Improve… Became worse… No change21NUTRITIONAL DEFICIENCIES We would like to know if you have experienced a lack of any of the following important vitamins and/or minerals. If yes, please tell us what medications you are taking to make up for the deficiency. Nutritional Deficiency If yes, what type of supplement are you taking? How often are you taking the supplement? Iron deficiency …No…Yes … Ferrous sulphate… Ferrous fumarate… Parenteral iron (injection)… Other _____________________________________________________Vitamin B-12 …No…Yes … sub-lingual B-12… B-12 injections… Other  ___________________________________________________Thiamine (Vitamin B1) deficiency…No…Yes… Oral (by mouth) thiamine… Through nutritional supplementation (specific   types of food)… other (please specify) ___________________________________________Calcium deficiency …No…Yes   … Oral calcium supplements plus Vitamin D… 10% IV calcium gluconate… Other ___________________________________________________Zinc deficiency …No…Yes … Zinc sulphate… Orazinc… Anuzinc… Zincate… Rivasol… Other _________________________________________________Protein malnutrition …No…Yes   … Protein powder … Protein bars… L- Glutamine… Other ___________________________________________________21MEDICATIONS/SUPPLEMENTS: 1. Please list all medications that you are currently taking. Please fill in the names of the medications on pill bottles or containers andinclude both your prescription and non-prescription types (these include any vitamins and minerals you have not listed above that you may be taking). Name of medication/Supplement Dosage Length of time you have been taking this medicationWhat alternative medicines, herbs and treatments (i.e. acupuncture) do you use (please indicate with a star * medicines, herbs and treatments started after the total gastrectomy): REGULAR MEDICINES(for example, insulin/asthma)HOW OFTEN? ‘AS NEEDED MEDS’(for example, Tylenol)HOW OFEN?Do medicines that you took on a regular basis still have the same effect as they had before your surgery? For example, is Tylenol still an effective pain relief medicine for you? ________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________ Thank you for completing this survey.2APPENDIX G: PROMIS - Emotional Distress – Anxiety PROMIS  Item Bank v. 1.0 – Emotional Distress - Anxiety © 2008 PROMIS Health Organization and PROMIS Cooperative Group Emotional Distress - Anxiety – Calibrated Items  Please respond to each item by marking one box per row.  In the past 7 days... Never Rarely Sometimes Often Always ('$1; I felt fearful .................................................  …1 …2 …3 …4 …5 ('$1; I felt frightened ...........................................  …1 …2 …3 …4 …5 ('$1; It scared me when I felt nervous.................  …1 …2 …3 …4 …5 ('$1; I felt anxious ...............................................  …1 …2 …3 …4 …5 ('$1; I felt like I needed help for my anxiety ......  …1 …2 …3 …4 …5 ('$1; I was concerned about my mental health....  …1 …2 …3 …4 …5 ('$1;I felt upset ...................................................  …1 …2 …3 …4 …5 ('$1;I had a racing or pounding heart .................  …1 …2 …3 …4 …5 ('$1; I was anxious if my normal routine was disturbed .....................................................  …1 …2 …3 …4 …5 PROMIS  Item Bank v. 1.0 – Emotional Distress - Anxiety © 2008 PROMIS Health Organization and PROMIS Cooperative Group   In the past 7 days… Never Rarely Sometimes Often Always ('$1;I had sudden feelings of panic....................  …1 …2 …3 …4 …5 ('$1; I was easily startled ....................................  …1 …2 …3 …4 …5 ('$1; I had trouble paying attention.....................  …1 …2 …3 …4 …5 ('$1; I avoided public places or activities ...........  …1 …2 …3 …4 …5 ('$1; I felt fidgety ................................................  …1 …2 …3 …4 …5 ('$1; I felt something awful would happen .........  …1 …2 …3 …4 …5 ('$1; I felt worried...............................................  …1 …2 …3 …4 …5 ('$1; I felt terrified ..............................................  …1 …2 …3 …4 …5 ('$1; I worried about other people's reactions to me ...............................................................  …1 …2 …3 …4 …5 ('$1; I found it hard to focus on anything other than my anxiety ..........................................  …1 …2 …3 …4 …5 PROMIS  Item Bank v. 1.0 – Emotional Distress - Anxiety © 2008 PROMIS Health Organization and PROMIS Cooperative Group In the past 7 days… Never Rarely Sometimes Often Always ('$1; My worries overwhelmed me ..................... …1 …2 …3 …4 …5 ('$1; I had twitching or trembling muscles ....... …1 …2 …3 …4 …5 ('$1; I felt nervous ............................................... …1 …2 …3 …4 …5 ('$1; I felt indecisive............................................ …1 …2 …3 …4 …5 ('$1; Many situations made me worry................. …1 …2 …3 …4 …5 ('$1; I had difficulty sleeping .............................. …1 …2 …3 …4 …5 ('$1; I had trouble relaxing.................................. …1 …2 …3 …4 …5 ('$1; I felt uneasy................................................. …1 …2 …3 …4 …5 ('$1; I felt tense.................................................... …1 …2 …3 …4 …5 ('$1; I had difficulty calming down..................... …1 …2 …3 …4 …5 22APPENDIX H: PROMIS - Emotional Distress – Depression PROMIS  Item Bank v. 1.0 –  Emotional Distress - Depression © 2008 PROMIS Health Organization and PROMIS Cooperative Group      Emotional Distress - Depression – Calibrated Items Please respond to each item by marking one box per row.  In the past 7 days... Never Rarely Sometimes Often Always (''(3 I felt worthless……………………….. …1 …2 …3 …4 …5 (''(3 I felt that I had nothing to look forward to ............................................................. …1 …2 …3 …4 …5 (''(3 I felt helpless…………………………… …1 …2 …3 …4 …5 (''(3 I withdrew from other people………….. …1 …2 …3 …4 …5 (''(3I felt that nothing could cheer me up… …1 …2 …3 …4 …5 (''(3 I felt that I was not as good as other people……………………………….. …1 …2 …3 …4 …5 (''(3I felt sad……………………………… …1 …2 …3 …4 …5 (''(3I felt that I wanted to give up on everything……………………………. …1 …2 …3 …4 …5 (''(3I felt that I was to blame for things…….. …1 …2 …3 …4 …5 PROMIS  Item Bank v. 1.0 –  Emotional Distress - Depression © 2008 PROMIS Health Organization and PROMIS Cooperative Group     In the past 7 days… Never Rarely Sometimes Often Always (''(3 I felt like a failure……………………. …1 …2 …3 …4 …5 (''(3 I had trouble feeling close to people…… …1 …2 …3 …4 …5 (''(3 I felt disappointed in myself…………. …1 …2 …3 …4 …5 (''(3 I felt that I was not needed…………... …1 …2 …3 …4 …5 (''(3 I felt lonely…………………………... …1 …2 …3 …4 …5 (''(3 I felt depressed…………………………. …1 …2 …3 …4 …5 (''(3 I had trouble making decisions………. …1 …2 …3 …4 …5 (''(3 I felt discouraged about the future…… …1 …2 …3 …4 …5 (''(3 I found that things in my life were overwhelming………………………... …1 …2 …3 …4 …5 (''(3 I felt unhappy…………………………... …1 …2 …3 …4 …5 (''(3 I felt I had no reason for living………. …1 …2 …3 …4 …5 PROMIS  Item Bank v. 1.0 –  Emotional Distress - Depression © 2008 PROMIS Health Organization and PROMIS Cooperative Group  In the past 7 days… Never Rarely Sometimes Often Always (''(3 I felt hopeless…………………………. …1 …2 …3 …4 …5 (''(3 I felt ignored by people……………….. …1 …2 …3 …4 …5 (''(3 I felt upset for no reason……………… …1 …2 …3 …4 …5 (''(3 I felt that nothing was interesting…….. …1 …2 …3 …4 …5 (''(3 I felt pessimistic………………………. …1 …2 …3 …4 …5 (''(3 I felt that my life was empty………….. …1 …2 …3 …4 …5 (''(3 I felt guilty……………………………. …1 …2 …3 …4 …5 (''(3 I felt emotionally exhausted………….. …1 …2 …3 …4 …5 22APPENDIX I: European Organisation for Research and Treatment of Cancer QLQ-C30 ENGLISH EORTC QLQ-C30 (version 3)We are interested in some things about you and your health. Please answer all of the questions yourself by circling the number that best applies to you. There are no "right" or "wrong" answers. The information that you provide will remain strictly confidential. Please fill in your initials: bbbbYour birthdate (Day, Month, Year): cececddeToday's date (Day, Month, Year): 31 cececdde__________________________________________________________________________________________ Not at A Quite Very All Little a Bit Much 1. Do you have any trouble doing strenuous activities,like carrying a heavy shopping bag or a suitcase? 1 2 3 4 2. Do you have any trouble taking a long walk? 1 2 3 4 3. Do you have any trouble taking a short walk outside of the house? 1 2 3 4 4. Do you need to stay in bed or a chair during the day? 1 2 3 4  5. Do you need help with eating, dressing, washingyourself or using the toilet? 1 2 3 4 During the past week: Not at A Quite VeryAll Little a Bit Much 6. Were you limited in doing either your work or other daily activities? 1 2 3 4 7. Were you limited in pursuing your hobbies or otherleisure time activities? 1 2 3 4 8. Were you short of breath? 1 2 3 4 9. Have you had pain? 1 2 3 4 10. Did you need to rest? 1 2 3 4 11. Have you had trouble sleeping? 1 2 3 4 12. Have you felt weak? 1 2 3 4 13. Have you lacked appetite? 1 2 3 4 14. Have you felt nauseated? 1 2 3 4 15. Have you vomited? 1 2 3 4 16. Have you been constipated? 1 2 3 4 Please go on to the next pageENGLISH During the past week: Not at A Quite Very All Little a Bit Much 17. Have you had diarrhea? 1 2 3 4 18. Were you tired? 1 2 3 4 19. Did pain interfere with your daily activities? 1 2 3 4 20. Have you had difficulty in concentrating on things,like reading a newspaper or watching television? 1 2 3 4 21. Did you feel tense? 1 2 3 4 22. Did you worry? 1 2 3 4 23. Did you feel irritable? 1 2 3 4 24. Did you feel depressed? 1 2 3 4 25. Have you had difficulty remembering things? 1 2 3 4 26. Has your physical condition or medical treatmentinterfered with your family life? 1 2 3 4 27. Has your physical condition or medical treatmentinterfered with your social activities? 1 2 3 4 28. Has your physical condition or medical treatmentcaused you financial difficulties? 1 2 3 4 For the following questions please circle the number between 1 and 7 that best applies to you 29. How would you rate your overall health during the past week?  1 2 3 4 5 6 7 Very poor Excellent 30. How would you rate your overall quality of life during the past week?  1 2 3 4 5 6 7 Very poor Excellent © Copyright 1995 EORTC Quality of Life Group. All rights reserved. Version 3.0 23APPENDIX J: EORTC QLQ STO-22 Questionnaire EORTC  QLQ – STO22 Patients sometimes report that they have the following symptoms or problems. Please indicate the extent to which you have experienced these symptoms or problems during the past week. Please answer by circling the number that best applies to you. __________________________________________________________________________________________________________________________ During the past week: Not at A Quite Very All Little a Bit Much 31. Have you had problems eating solid foods? 1 2 3 4 32. Have you had problems eating liquidised or soft foods? 1 2 3 4 33. Have you had problems drinking liquids? 1 2 3 4 34. Have you had discomfort when eating? 1 2 3 4 35. Have you had pain in your stomach area? 1 2 3 4 36. Have you had discomfort in your stomach area? 1 2 3 4 37. Did you have a bloated feeling in your abdomen? 1 2 3 4 38. Have you had trouble with acid or bile coming into your mouth? 1 2 3 4 39. Have you had acid indigestion or heartburn? 1 2 3 4 40. Have you had trouble with belching? 1 2 3 4 41. Have you felt full up too quickly after beginning to eat? 1 2 3 4 42. Have you had trouble enjoying your meals? 1 2 3 4 43. Has it taken you a long time to complete your meals? 1 2 3 4 44. Have you had a dry mouth? 1 2 3 4 45. Did food and drink taste different from usual? 1 2 3 4 46. Have you had trouble with eating in front of other people? 1 2 3 4 47. Have you been thinking about your illness? 1 2 3 4 48. Have you worried about your weight being too low? 1 2 3 4 49. Have you felt physically less attractive as a resultof your disease or treatment? 1 2 3 4 50. Have you worried about your health in the future? 1 2 3 4 51. Have you lost any hair? 1 2 3 4 52. Answer this question only if you lost any hair:If so, were you upset by the loss of your hair? 1 2 3 4 ¤ QLQ-STO22 Copyright 1999 EORTC Group on Quality of life. All rights reserved.23APPENDIX K: Short Form (36) Health Survey version 2 Questionnaire


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