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Image-guided video-assisted thoracoscopic surgery (VATS) excision of small peripheral pulmonary nodules… Almousa, Omamah H, 2015

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IMAGE-GUIDED VIDEO-ASSISTED THORACOSCOPIC SURGERY (VATS) EXCISION OF SMALL PERIPHERAL PULMONARY NODULES (SPPN) IN PATIENTS WITH PREVIOUS EXTRA-THORACIC MALIGNANCIES by Omamah H. Almousa MBBS, King Saud University, 2012  A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF  THE REQUIREMENTS FOR THE DEGREE OF   MASTER OF SCIENCE  in  THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES  (SURGERY)   THE UNIVERSITY OF BRITISH COLUMBIA  (Vancouver)  November 2015    © Omamah H. Almousa, 2015   ii Abstract Objective: The purpose of this study is to determine the utility of preoperative CT-guided microcoil localization (CTML) followed by fluoroscopy guided VATS resection in the diagnosis and management of SPPN in patients with extra-thoracic malignancies.  Methods: This study was a retrospective analysis of prospectively collected data between August 2003 and September 2013. Fifty patients underwent preoperative localization of undiagnosed SPPN using percutaneously placed CT-guided platinum microcoils (CTML). Coils were placed with the distal end deep to the nodule and the superficial end coiled on the visceral pleural surface. Nodules were removed by VATS wedge excision using endostapler with visualization by intraoperative fluoroscopy and VATS.  Results: A total of 50 patients with a cumulative history of 14 different extra-thoracic cancers (57% female, mean age 62 years) had 55 nodules resected (mean size = 12.11mm, depth from visceral pleura = 22.07 mm) using CTML and fluoroscopic guided VATS wedge excision. The previously treated extra-thoracic tumor sites were colorectal (16), breast (9), urogenital (9), sarcoma (5), melanoma (3), lymphoma (3), thyroid (3), gastro esophageal (2), others (3). Nodule histology showed metastasis (25/50 patients), benign (11/50) and (15/50) early stage primary lung cancer. On logistic regression analysis, lung nodules in smokers were found 6 times more likely to represent primary lung cancer than metastasis (p 0.009). CTML procedure was successful in all patients with a mean time of 31.5 minutes and allowed successful diagnostic VATS wedge resection in all cases with no major complications. The mean time of VATS and   iii fluoroscopy were 26.68 minutes and 1.35 minutes, respectively. After a follow up period of 35 months, all patients were alive and none of the patients had local recurrence of disease.  Conclusions: Pre-operative localization of small peripheral pulmonary nodules using percutaneous CT-guided microcoil localization followed by fluoroscopic guided VATS resection was effective in achieving early definitive diagnosis, and changed the management and improved the prognosis in 50% of patients with presumed metastasis with minimal morbidity. The 20% of patients with benign disease required no further therapy while the 30% of patients with early stage primary lung cancer underwent curative surgical resection.               iv Preface  This dissertation is original and unpublished. All of the work presented in this paper was conducted at Vancouver General Hospital, Division of Thoracic Surgery, Department of Surgery, the University of British Columbia (UBC). The study was approved by the Vancouver Coastal Health and University of British Columbia Institutional Review Board (CREB) (certificate #H02-70562 C02-0562).                v Table of Contents Abstract……………………………………………………………………………………………ii Preface……………………………………………………………………………………………iv Table of Contents………………………………………………………………………………….v List of Tables……………………………………………………………………………………viii List of Figures…………………………………………………………………………………….xi Acknowledgments…………………………..…………………………………………………..xiii 1. Chapter One: Introduction……………………………………………………………………...1 2. Chapter Two: Background……………………………………………………………………..5 2.1 Management of Pulmonary Nodules in Patients with Extra-thoracic Malignancy………………………………………………………………………….5 2.2 Open Thoracotomy versus Video Assisted Thoracoscopic Surgery in  Management of Pulmonary Nodules………………………………………………..8 2.3 Video-Assisted Thoracoscopic Wedge Resection of Pulmonary Nodules:  Advantages and Limitations……………………………………………………….13 2.4 Localization Techniques of Indeterminate Pulmonary Nodules…………………..15 3.  Chapter Three: Study Protocol………………………………………….…………………18 3.1  Study Design and Objective………………………………………………………18 3.1.1 Study Design …………………………………………………………….18 3.1.2 Problem Statement…………...…………………………………………..18 3.1.3 Hypothesis ……………………………………………………………….19   vi 3.1.4 Objective …………..………………………………….………………….19 3.1.5 Aims………………...…………………………………………………....19 3.1.6    Research Questions………………………………………………………20 3.2 Materials and Methods………………………………………………………….....20 3.2.1  Patients’ Selection…………………………………………………...…..20 3.2.2 Eligibility Criteria…………………………………….…………………..21 3.2.3 Data Collection…………………………………………………………...22 3.2.4 Percutaneous CT-guided Micro-Coil Localization Procedure…………...23 3.2.5 Video-Assisted Thoracoscopic Wedge Resection………………………..25 3.2.6 Statistical Analysis……………………………………………….............26 4.  Chapter Four: Results………………………………………………………………………...27 4.1 Descriptive Analysis……………………………………………………...….….....27 4.2 Inferential Analysis……………………………………………………………...…30 5.  Chapter Five: Discussion…………………………………………………………………….33 5.1 Incidence of Malignant Pulmonary Nodules in Patients with Extra-thoracic              Cancer……………………………………………………………………………35 5.2  Prevalence of Metastasis, Primary Lung Cancer and Benign Lesions Stratified         by Patients’ Predictive Variables………………………………………………..36 5.3 Prognosis and Overall Survival after Surgical Resection…………..…………..44 5.4 Summary………………………………………………………………………..51 5.5 Limitations……………………………………………………………………...52 5.6 Future Directions…………………………………………………………..…...53   vii 6.   Chapter Six: Conclusion……………………………………………………………….….....54 Bibliography……………………………………………………………………………….…….92                   viii List of Tables Table 1: Demographic data of the patients………………………………………………………56 Table 2: Primary extra-thoracic cancer data (14 different extra-thoracic cancer in 50 patients).........................................................................................................................57 Table 3: Characteristics of Resected Pulmonary Nodules (n=55)………………………………58 Table 4: Microcoil Localization Procedure and Operative Details……………………………...59 Table 5: Details of coiling procedure and VATS operation……………………………………..60 Table 6: Pathology of 55 resected nodules in 50 patients……………………………………….64 Table 7: Details of patients with multiple nodules resected……………………………………..65 Table 8: Histology of previous extra-thoracic primary cancer and its relation to pathology of                                                                                    resected nodules………………………………………………………………………...66 Table 9: Pathology of resected nodules and its relation to location of nodules…………………67 Table 10: Pathology of resected nodules and its relation to patients’ smoking history…………67 Table 11: Follow up status for patients who had metastatic nodules “therapeutic resection”                   and patients with primary lung cancer “Diagnostic + Therapeutic Resection”………….....................................................................................................68 Table 12: Univariate analysis of patients and nodules characteristics in relation to final pathology of resected nodules “Metastasis” Total number of patients: 50; Yes ML=25………………………………………………………………………………...69   ix Table 13: Risk factors for Metastatic Lesions (n=25), as identified by multivariate logistic regression……………………………………………………………………….……..70 Table 14: Univariate analysis of patients and nodules characteristics in relation to final pathology of resected nodules “Primary Lung Cancer” Total number of patients: 50; Yes Primary Lung Cancer =15..………………………………………………………71 Table 15: Risk Factors for Primary Lung Cancer (n=15), as Identified by Multivariate Logistic Regression……………………………………………………………………….……72 Table 16: Risk Factors for Pathology- Benign (n=11), as Identified by Multivariate Logistic Regression……………………………………………………………………….........73 Table 17: Compare Distributions: METASTASIS vs. PRIMARY LUNG CANCER + BENIGN........................................................................................................................74 Table 18: Compare Distributions: Metastasis vs Primary Lung Cancer vs Benign Lesions…….75 Table 19: Univariate Logistic Regression Analysis of Primary Extra-thoracic Tumor and Metastasis…………………………………………………………………………......76 Table 20: Compare Distributions METASTASIS vs. PRIMARY LUNG CANCER……………………………………………………………………………...76 Table 21: Compare Distributions METASTASIS vs. BENIGN………………………………...77 Table 22: Compare Distributions: METASTASIS + PRIMARY LUNG CANCER vs. BENIGN………………………………………………………………………………78 Table 23: Frequency of Solitary and Multiple Nodules Stratified by Pathology of Resected Specimen……………………………………………………………………………...79   x Table 24: Frequency of Solitary and Multiple Nodules Stratified by Histology of Extra-thoracic                       Malignancy………………………………………………………………………………………80 Table 25: Comparative Analysis of the Final Diagnosis……….……………………………….81                   xi List of Figures Figure 1: Drawing illustrates 30 mm of the mic85rocoil (arrow) ejected from the tip of the Chiba needle and assumes a tight coiled configuration (arrow head) approximately 5 mm deep to the nodule………...…………………………………...…………………….82 Figure 2: Drawing illustrates Chiba needle withdrawn to the pleural surface (arrow head) and remaining part of the microcoil ejected out of the needle (arrow). The microcoil forms a loop on the visceral pleural of the lung overlying the nodule………………83 Figure 3: Non-enhanced transverse chest CT scan shows complete ejection of the microcoil from the Chiba needle and successful localization of a nodule at the left lung apex (black arrow). The deep end of the microcoil is coiled into a ball adjacent to the nodule (white arrow) and the superficial end is coiled on the visceral pleural surface. No hemorrhage is noted in the normal lung tissue adjacent to the wire (arrow head)…………………………….………………………………….............84 Figure 4: Coronal view CT image shows a microcoil placed through a 10-mm-diameter solid nodule (straight arrow) in the left lower lobe of the lung. This 3-dimensional image assisted in placing a port for VATS resection based on the relation between the proximal end of the microcoil (curved arrow) and the overlying ribs…………......85 Figure 5: Intra-operative thoracoscopic view showing superficial end of the microcoil lying on the visceral pleura of the lung……………………………………………………...86 Figure 6: Intraoperative fluoroscopic view showing both the superficial end of the microcoil on the lung surface and the deep end of the microcoil (attached to the nodule) in the lung parenchyma…………………………………………………………………..87   xii Figure 7: Intra-operative fluoroscopy image showing the microcoil within the lung parenchyma that was being excised by a GIA stapler. A grasper was applied to the lung adjacent to the superficial end of the microcoil on the visceral pleura…………………...…88 Figure 8: Drawing illustrates VATS wedge resection of the microcoil and the nodule using an endostapler.........................................................................................................…...89 Figure 9: The resected wedge specimen shows the microcoil (arrow head) coiled on the pleural surface (P) and extending through the nodule (arrows). No parenchymal hemorrhage is noted in the specimen due to the thrombogenic fuzz on the microcoil………………...…………………………………………………..……..89              xiii Acknowledgements          A special feeling of gratitude to my loving mother, Najat Altheeb, who is my hero, for her endless love and support throughout my life. She has never failed to guide me and motivate me. She has shown me the value of faith and dedication by being the greatest example of that. I attribute all my success in life to the moral, intellectual and physical education I received from her. Thank you for giving me the strength to reach for the stars and chase my dreams. My sisters, Arwa and Jumana, and my brothers, Albara and Musaab deserve my whole hearted thanks as well. My one-year old nephew, Yazan, your smile has the power to light up my days, even in my moments of crisis.           I wish to thank my committee members who were more than generous with their expertise and precious time. A special thanks to Prof. Richard Finley, my primary supervisor for his countless hours of reflecting, reading, encouraging, and most of all patience throughout the entire process. I truly appreciate and value everything I have learned from you. It will forever remain a major contributor behind my success and achievements.          I wish to express my sincere thanks to Prof. Karim Qayumi, my co-supervisor. The knowledge and wisdom you have imparted upon me has been a great help and support. Your continued support and willingness to provide feedback made the completion of my master’s project an enjoyable experience. I am extremely indebted to you for your valuable guidance and sincere encouragement extended to me. Thank you for being my life mentor and father.         I would like to thank my sponsoring institution, King Saud University, and the government of Saudi Arabia for giving me this opportunity by financially supporting my education over the course of the program.  1  1. CHAPTER ONE: INTRODUCTION  New or growing lung nodules in patients with extra-thoracic malignancies are highly suspicious for metastasis (Hanamiya M, 2012 Jan) (Esposito L, 2010 Nov) (Mery CM, 2004 Jun). Lungs are the second most common site for metastasis in patients with a known history or recently discovered extra-thoracic malignancy. Moreover, 20%-54% of extra-thoracic malignancies metastasize to the lungs during the course of the disease (Mohammed TL, 2011 Feb). Therefore, early definitive diagnosis is crucial in decision making and planning therapy in patients with extra-thoracic malignancies who might be cured by surgical resection (Pfannschmidt J D. H., 2007 Jul). Although advances in radiological techniques and the widespread use of multi-detectors CT scans have facilitated early detection of suspicious lung nodules in high risk patients, this has been complicated by an increasing number of small indeterminate pulmonary nodules which are very challenging to manage (Xiao F, 2013 Oct). Computed tomographic (CT) scanning is an integral and fundamental tool for surgeons and oncologists in patients with malignant neoplasms in determining the clinical stage on initial CT staging and in monitoring for disease recurrence (Hanamiya M, 2012 Jan). However, lung lesions in this subset of patients represent significant clinical problem, due to lack of benign/malignant characteristics in initial CT images (Rena O P. E., 2007) (Hanamiya M, 2012 Jan) (S Khokhar, 2006 Apr) (S Khokhar, 2006 Apr).  When the case of a patient with a known cancer history is considered, the possible etiologies of lung lesions are numerous. Pulmonary nodules in these patients may represent a   2 metastasis from the previous cancer, a primary lung cancer, or a benign lesion (Rena O P. E., 2007). Lung lesions found in the course of a neoplastic disease or during initial staging are usually considered to be metastasis of the primary cancer. These presumed metastases are very often diagnosed later as benign lesions or new primary lung neoplasms, which affects treatment options and long-term prognoses (Prisadov GC, 2010). Sortini et al reviewed the final histology results of lung nodules resected in 45 patients with extra-thoracic malignant neoplasms. Although they found 41% of the resected lesions to be metastasis, 32% turned out to be a second new primary lung cancer, and 27% of the lesions were actually benign (Sortini A, 2001 Dec). Therefore, suspicion of primary lung cancer and other etiologies should always remain even among patients thought to be at high risk for metastasis. The frequency of metastasis versus primary lung cancer varied widely in the literature and was greatly influenced by the histology of the primary tumor (Hanamiya M, 2012 Jan). Further, tobacco smoking history raises the concern for primary lung cancer and lower the threshold for diagnostic measures (Hanamiya M, 2012 Jan) (McWilliams A, 2013 Sep) (Aberle DR, 2011 Aug). On the other hand, benign etiologies such as infections, hamartomas and granulomas must remain part of the differential and should be excluded only with a definitive histologic diagnosis (Hanamiya M, 2012 Jan) (S Khokhar, 2006 Apr). Reliable and early diagnosis is therefore essential to avoid delay or inaccurate management (Rena O., 2013).  Overall survival rates are enhanced with early detection and management of new primary lung cancer and local control of disease in metastatic tumors (Rena O., 2013). The chance of cure is high, especially in the case of an early stage lung cancer (stage 1A). In fact, if managed early, the long term survival of patients with lung cancer as a second or third tumor is similar to those with no history of previous tumor (Rena O., 2013). On the other hand, pulmonary   3 metastasectomies have proven to improve patients’ overall prognoses and therefore the technique is accepted as an important therapeutic endeavor (Deo SS, 2014 Jul-Sep) (Pfannschmidt J E. G., 2012). In benign lesions, the diagnostic value eliminates the psychological stress and avoids the application of unnecessary interventions or serial radiation exposure (Xu DM, 2009 Jan). Even though patients presenting with lung lesions after a previous history of extra-thoracic malignancy have a relevant risk of either primary lung cancer or metastatic disease, which may reach 79%-91% (Rena O., 2013) (Mery CM, 2004 Jun) (Peuchot M, 1987 Sep), there exists no universally accepted approach to management due to diagnostic challenges (S Khokhar, 2006 Apr).   Initial management options are usually limited by lesion size. Small nodules cannot be reliably classified as benign or malignant using CT criteria or PET/CT scan analysis (McWilliams A, 2013 Sep). Failure to characterize these nodules by means of positron emission tomography (PET) and difficult accessibility by percutaneous or CT-guided biopsy with substantially low accuracy have resulted in the utilization of serial imaging as a commonly employed alternative technique in the evaluation of non-specific pulmonary nodules (Xu DM, 2009 Jan). In patients with extra-thoracic cancer the possibility of delayed cancer diagnosis and treatment, with consequently uncertain effects on prognosis is the main disadvantage of the serial imaging approach (Lohrmann C, 2014 Feb). Histopathology is the gold standard for definitive and reliable diagnosis in all cases (Johannes Czernin, 2013 May).  Positron Emission Tomography (PET) has proved to be of limited value in small lung lesions, with low diagnostic accuracy and unreliable results that may lead to inappropriate management (Rena O., 2013) (Nair VS, 2010 May) (Murphy F, 2012 March). Unfortunately, percutaneous CT-guided biopsy have been shown to have several   4 limitations including difficult accessibility, sampling error, and inadequate tissue sample, which often results in no diagnosis (Francis J. Podbielski, 2004 Jul-Sep).  Pathologic diagnosis with excisional biopsy using VATS (Video-assisted thoracic surgery) is more appealing to physicians and patients due to several advantages (Finley RJ, 2015 Jan). The minimally invasive thoracoscopic surgery removes the entire nodule and eliminates the sampling error associated with needle biopsy. Further, it facilitates the diagnostic evaluation of potentially malignant lesions with minimal morbidity (Finley RJ, 2015 Jan). However, due to a failure to visualize or palpate these early small (< 15 mm) nodules, particularly if they are sub-pleural with VATS have resulted in conversion to open thoracotomy. Several localization techniques have been developed to overcome these challenges and facilitate precise resection (Khereba M, 2012) (Finley RJ, 2015 Jan). Unfortunately these techniques had several limitations that prevented their wide adaptation (Finley RJ, 2015 Jan).   The purpose of this study was to determine the utility and clinical significance of preoperative CT-guided microcoil localization (CTML) of SPPN followed by fluoroscopically guided VATS resection in the management of these nodules in patients already diagnosed with solid malignant neoplasms other than lung cancer.        5 2. CHAPTER TWO: BACKGROUND  2.1 MANAGEMENT OF PULMONARY NODULES IN PATIENTS WITH EXTRA-THORACIC MALIGNANCY  Major issues in clinical decision making include the definition of a positive result of lung nodules detected on a scan (Finley RJ, 2015 Jan). The 2013 American College of Chest Physicians (ACCP) guidelines for management of indeterminate lung nodules are based on nodules’ size and risk factors for lung cancer. Risk factors include older age, smoking, and history of malignancy. Growth assessment by serial CT scans for small nodules (less than 8 mm) at 3-6-12 month’s interval for 24 months is recommended by the American College of Chest Physicians (ACCP) in patients with risk factors for malignancy (Gould MK D. J., 2013 May). Patients with nodules 8 mm or larger are managed by a different algorithm based on their pretest probability of malignancy. The pretest probability of malignancy can be calculated either qualitatively using clinical judgement and/or quantitatively using a validated model. The majority of patients will fall in the intermediate range (5-60 percent), requiring functional imaging, preferably PET, and/or CT-guided biopsy (Gould MK D. J., 2013 May). The main disadvantage of this approach is delayed cancer diagnoses (Lohrmann C, 2014 Feb).  Moreover, the diagnostic accuracy of the growth criterion at 3–month intervals is relatively low and may add more confusion as benign lesions can also increase in size. A study that analyzed the growth and baseline assessments of solid indeterminate nodules detected at CT scans illustrated that 85% of the nodules with significant growth at 3 months were actually benign (Xu DM, 2009 Jan).    6 Other limitations of serial CT imaging are the side effects of the substantial exposure to radiation and its potential harms to the patients. It is estimated that radiation from current use of CT studies may attribute to 1.5-2% of all cancers, which may create a public health issue in the future (Brenner DJ, 2007 Nov). The dilemma of other incidental findings (Veeramachaneni NK, 2009 Jan), such as over-diagnoses of pseudo-diseases (JM, 2008 Apr), and the financial burden of serial CT scans on the health care system and patients have shown that this modality of management is neither optimal nor cost effective (Heber MacMahon, 2005 Nov).  Combined CT/PET scanners have become a valuable noninvasive functional imaging test for detecting and staging cancer and metastatic disease (Lohrmann C, 2014 Feb). Cells with neoplastic activity have higher rates of glucose uptake and metabolism, which are detected and demonstrated by PET scans. The addition of CT component offers a precise localization and an aligned functional and anatomical image (Lohrmann C, 2014 Feb). Therefore, a large number of clinical studies have explored the usefulness of CT/PET scans in tumor diagnosis, disease staging, and evaluation of treatment response and prognosis (Lohrmann C, 2014 Feb). Although this noninvasive imaging test has become very popular and is gaining wide acceptance in both clinical and oncological practice, its diagnostic accuracy has shown to be limited by lesion size (Chandarana H, 2013 Sep). A meta-analysis of 13 studies conducted by Gould et al for the diagnostic accuracy of FDG-PET for malignant pulmonary nodules reported that the true negative value cannot be determined for small nodules (Gould MK M. C., 2001 Feb). More recent studies are also in agreement, reporting lower accuracy of 18F-FDG PET for small lung lesions and significant underestimation of the true concentration of FDG in these nodules (Nair VS, 2010 May) (Berghmans T, 2008 Jan) (Soret M, 2007 Jun). The most recent guidelines by the American College of Chest Physicians identified nodule size an important factor for the use of   7 FDG PET/CT, because small malignant lung nodules are more frequently false negative (Gould MK D. J., 2013 May). Due to low sensitivity of PET in small lesions, a negative result can’t reliably exclude malignancy and indicates further investigations (Berghmans T, 2008 Jan) (Nair VS, 2010 May) (Soret M, 2007 Jun). Observation in low risk patients is probably safe when FDG-PET shows no uptake, however the same principle cannot be applied in high risk patients, as the negative predictive value of PET depends on the pretest probability of malignancy (Gould MK M. C., 2001 Feb).  Histopathology is believed to serve as the gold standard for accurate diagnosis (Johannes Czernin, 2013 May). A tissue sample can be obtained by percutaneous needle biopsy or surgical excision. Percutaneous fine needle biopsy (FNB) can be performed with CT guidance, which allows better localization and feasibility (HT, 2006 Apr). However, nodule size is a determining factor in diagnostic accuracy of CT-guided needle biopsy. A retrospective study of 612 consecutive CT-guided needle biopsies analyzed factors affecting diagnostic accuracy and reported that lung lesions less than 1.5 cm in diameter were associated with low diagnostic yield (Priola AM, 2007 Dec). Other limitations of this technique include difficult accessibility and inadequate tissue samples, which often result in no diagnosis (Francis J. Podbielski, 2004 Jul-Sep).  Surgical resection of suspicious nodules eliminates sampling error by complete resection via VATS or open thoracotomy. Moreover, complete resection can be diagnostic and therapeutic, and facilitate immediate histopathological diagnosis of the growing nodule, followed by staging and lobectomy if necessary (Finley RJ, 2015 Jan).    8 2.2 OPEN THORACOTOMY VERSUS VIDEO ASSISTED THORACOSCOPIC SURGERY IN PULMONARY NODULES MANAGEMENT   Advances in minimally invasive techniques and the development of better instrumentation have revolutionized surgical approaches to lung nodules. Video-assisted thoracoscopic surgery (VATS) is a minimally invasive diagnostic and therapeutic modality that proved safe and with several advantages over open thoracotomy for pulmonary resections (Reddy, 2005 March). The operative applications of VATS in lung diseases are rapidly expanding and its indications continue to evolve.  The diagnostic utility of VATS was first studied in the early 1990s with more than 40 participating institutions and 1820 cases included. The study successfully demonstrated the safety of this new technique in its early years of adaptation (Hazelrigg SR, 1993 Nov). Over the last 15-20 years video-assisted thoracoscopic surgery have become widely adopted from basic thoracic procedures to major pulmonary resections and is currently an essential part of thoracic surgeon practice (Rachit D. Shah, 2014 Oct). VATS procedures allow precise wedge resections and anatomic pulmonary resections with minimal morbidity (Marilee Carballo, 2009). A systematic review by Sedrakyan et al of randomized controlled trials was conducted to determine the clinical outcomes and advantages of VATS procedure in comparison to open thoracotomy for three common procedures, including minor lung resections and lobectomies (Sedrakyan A, 2004 Oct). Overall, VATS demonstrated substantial advantages over thoracotomy, both intra- and post- operatively. As a minimally invasive procedure, video-assisted thoracoscopic surgery offers less morbidity to the patients with less surgical trauma and better quality of life. VATS is better tolerated and associated with reduced length of hospital stay, reduced post-operative pain   9 or use of pain medications, early patient mobilization, faster recovery, and less operative time (Reddy, 2005 March) (Sedrakyan A, 2004 Oct). Moreover, VATS was associated with cost savings due to shorter hospital stays and fewer complications (Sedrakyan A, 2004 Oct). Resection of pulmonary nodules by VATS was reported as the approach of choice as a diagnostic and therapeutic procedure (Cardillo G, 2003 May). Cardillo et al successfully managed 429 patients with solitary pulmonary nodules with and without history of malignancy by VATS resection as the treatment of choice. Minithoracotomy was necessary in 21.67% of the cases due to failure to locate some of the small nodules (Cardillo G, 2003 May). In terms of diagnostic accuracy, VATS has 100% specificity rate in the diagnosis of pulmonary nodules (MF, 2001 May). Definitive diagnosis has become one of the main reasons for performing VATS (Landreneau RJ M. M., 1992 Oct). A Spanish prospective study of 209 patients who had one or more lung nodules were operated on by VATS to avoid any delay in the diagnosis and management of malignant nodules showed a definitive diagnosis in 100% of the cases, with a  malignancy rate of almost half of these patients (MF, 2001 May). The diagnostic accuracy and low morbidity of VATS are the main reason for its popularized use (Hau T, 1996 Jan). Video-assisted thoracoscopic wedge resection of small indeterminate lung nodules was carried out as a standard treatment in another prospective study by Pericelli et al, with a 95% success rate, low morbidity, no mortality, and definitive diagnosis in 100% of the cases. The study illustrates the implications for early diagnosis and management of lung cancer, and emphasizes the importance of VATS resection of indeterminate nodules to establish definitive diagnosis and commence prompt management (Pericelli A, 2004).  In patients with previous history of cancer who developed new pulmonary nodules suspicious of metastasis, the use of VATS for wedge resection was initially controversial and its   10 safety was questionable. Unlike the conventional thoracotomy approach, VATS was criticized for its inability to perform thorough palpation of the entire lung to detect nodules possibly missed on CT, the probability of incomplete resection of malignant nodules, and the insecurity of port site and pleural cavity seeding (Marilee Carballo, 2009). However, recently technological advancements in radiological imaging allow detection of very small nodules that may not be amenable even to palpation. Furthermore, a comparison of long term clinical outcomes in metastasectomies between VATS and the conventional open thoracotomy revealed an equivalent 5-year overall survival between the two techniques. Video-assisted thoracoscopic wedge resections of pulmonary metastasis was reported to be safe, efficacious, and was associated with longer recurrence free survival (Marilee Carballo, 2009). In fact, VATS showed improved overall 5-year survival rates, 70% following resection of pulmonary metastasis, while conventional thoracotomy demonstrated 5-year survival rates ranging from 30% to 50% (Marilee Carballo, 2009). Long-term outcomes were further studied by systematic review and meta-analysis that included nine studies with 2 limbs for direct comparison of the two techniques for pulmonary metastasectomies in 796 patients. The conclusion by Herle et al confirmed the equivalence of long term oncological outcomes between VATS and open thoracotomy in both overall survival and recurrence free survival (P Herle, 2013). Therefore, video-assisted thoracoscopic wedge resection of pulmonary metastases with curative intent is now performed routinely throughout the world. (Marilee Carballo, 2009) (Nakajima J, 2008 Apr) (Mutsaerts EL, 2002 Dec).  In major anatomic lung resections, VATS lobectomy is clearly gaining momentum and has also proved its safety, efficacy, and reproducibility (Rachit D. Shah, 2014 Oct). Low morbidity and mortality in VATS lobectomy have been reported by previous studies, and intra-  11 operative bleeding or cancer recurrence in an incision was found to be minimal (McKenna RJ Jr, 2005 Jul). McKenna et al reported their successful 12 years’ experience in 1,100 VATS lobectomies performed in 505 men and 595 women, with only 2.5% requiring conversion to thoracotomy. The study showed an 0.8% mortality rate with no intraoperative mortality rate due to bleeding, an 0.57% local recurrence rate, and a mean hospital stay of 4.78 days (McKenna RJ Jr, 2005 Jul). Five hundred VATS lobectomies by Onaitis and colleagues showed a 1.6% conversion rate, and 1% mortality with no operative mortality. The study also demonstrated 2-year survival of 85% for Stage 1, and 77% for Stage 2 non-small cell lung cancer (NSCLC) (Onaitis MW, 2006 Sep). Overall, survival rates of lobectomy with VATS were found comparable to thoracotomy (Onaitis MW, 2006 Sep) (Walker WS, 2003 March).  Video-assisted thoracoscopic lobectomy is a safe procedure, associated with low conversion rates to thoracotomy, encouraging long term survival rates, and believed to serve as the operation of choice for early stage NSCLC (Walker WS, 2003 March) (Nakanishi R1, 2012 Feb). The outcomes of this technique were further examined in 110 patients with clinical stage 1 NSCLC and one or more comorbidities cited in the modified Kaplan-Feinstein Index. Nakanishi et al found VATS lobectomies to be a safe and feasible procedure even in those with comorbidities (Nakanishi R1, 2012 Feb). A Korean study demonstrated an excellent survival rate for early stage lung cancer, 92.7% at 1 year and 87.6% at 3 years in 704 patients who underwent VATS lobectomies (Kim K, 2010 Jun). Other series showed a much higher survival rate of 63% to 97% at 4 and 5 years in those who underwent VATS lobectomy for stage 1 lung cancer in comparison to the traditionally reported rate of 46% to 65% with the open approach (Whitson BA, 2007 Jun). Moreover, VATS lobectomy demonstrated significantly less respiratory complications compared to open thoracotomy in patients with poor pulmonary function (Ceppa   12 DP, 2012 Sep). Therefore, the adaptation and utility of thoracoscopic lobectomy is increasing across the world (Rachit D. Shah, 2014 Oct).  The incidence of post-operative major complications such as atrial fibrillation, pneumonia, renal failure, prolonged air leak, sepsis, and even death were reported to be lower with thoracoscopic lobectomies compared to thoracotomies in a prospective database evaluation of a 10 year period that included 1,079 patients (Villamizar NR, 2009 Aug). The increasing benefit of VATS approach in the management of patients with lung cancer was also demonstrated in its ability to facilitate more effective administration of adjuvant regimen without delay or reduced doses compared to patients who had open lobectomies (Petersen RP1, 2007 Apr). In addition to less morbidity, thoracoscopic lobectomy was associated with shorter hospital stays and chest tube duration (Villamizar NR, 2009 Aug) (Surg, 2010 Feb) (Swanson SJ, 2012 Apr). A multi-institutional database analysis reviewed total costs of almost 4,000 patients who underwent a lobectomy for a cancer by a thoracic surgeon and showed that hospital costs were higher for open compared to VATS (21,016 vs $20,316 , P=0.027) (Swanson SJ, 2012 Apr). All this is believed to further increase worldwide adaption of the minimally invasive lobectomy approach in patients with early stage lung cancer. Analysis of the Society of Thoracic Surgery (STS) database in 2012, which included 12,970 patients, showed that 45% of lobectomies were performed with VATS techniques (Ceppa DP, 2012 Sep).      13 2.3 VIDEO-ASSISTED THORACOSCOPIC WEDGE RESECTION OF PULMONARY NODULES: ADVANTAGES AND LIMITATIONS   Thoracoscopic procedures, named video-assisted thoracoscopic surgery (VATS), was first described in 1910 by Jacobaeus (HC, 1921; ), however, the technique was restricted to a limited number of minor procedures such as biopsy, management of pneumothorax, and empyema irrigation (H, 1999). The great technological developments of video imaging and instrumentation originally designed for laparoscopic use have led to dramatic improvement of VATS techniques. Since 1990 the role and clinical indications of VATS have expanded widely and replaced many of the surgical operations that would otherwise have been performed by open thoracotomy (Landreneau RJ M. M., 1992 Oct) (H, 1999). Owing to the minimally invasive nature of the procedure and its low morbidity, VATS has already become a standard treatment of choice in several thoracic diseases (H, 1999). The significant reduction in both acute and chronic post-operative pain, shorter operation time, reduced hospital stay and overall cost savings are major potential benefits associated with VATS, and therefore contributed to its worldwide adaptation (H, 1999) (Landreneau RJ M. M., 1994). As the application of video-assisted thoracoscopic surgery is globally increasing, its limitations are also becoming clearer (H, 1999). Diagnostic approaches to indeterminate pulmonary nodules are several, however VATS is the only modality that provides definitive diagnoses with virtually 100% sensitivity, 100% specificity, no mortality, and minimal morbidity (Mack MJ, 1993). Thoracoscopic biopsy by wedge resection plays a significant role as a diagnostic and therapeutic tool with the least invasiveness to the patients (H, 1999) (Saito H, 2002). However, advances in CT scanners with their ability to reconstruct thinner sections have increased detection rates of lung nodules that are   14 smaller in size and difficult to localize by VATS. Visibility and localization of these small nodules are the major limitations of thoracoscopic wedge resection and the main reasons for conversion to thoracotomy (Suzuki K, 1999) (Finley RJ, 2015 Jan). Suzuki and coworkers studied 92 consecutive patients underwent an attempted VATS excision of small peripheral lung nodules. They reported more than half of these cases (54%) required conversion to thoracotomy. On analysis, failure to localize nodules was found to be the commonest reason causing the conversion. Further analysis have shown that the probability of failure to detect a nodule by VATS was 63% when the distance from nearest pleural surface is more than 5 mm , and the nodule size is less than 10 mm in the widest diameter. The study also demonstrated a significant rate of malignancy (40%) of the resected nodules that required conversion to thoracotomy (Suzuki K, 1999). An interesting study have been conducted to evaluate the histopathological results of small pulmonary nodules measuring 1 cm or smaller (sub-centimeter nodules) detected at CT and removed by VATS. The study included 64 patients, of whom 42% had a previous malignancy. Authors reported 58% overall malignancy rate of these sub-centimeter nodules. In fact, among patients with previous history of cancer, the rate of malignant nodules was much higher at 81%. A substantial number of the malignant lesions were second primary lung cancer. The study reinforced the importance of early diagnosis of indeterminate lung nodules with an acceptable surgical technique. In patients with a previous malignancy and high suspicion of metastasis, early definitive diagnosis can substantially alter management (Munden RF, 1997).  Technological developments of helical CT scanners have increased the clinical load of small lung nodules, on the other hand, improvements in video optics and surgical instrumentation have broadened the capabilities of VATS in the diagnosis and treatment of these nodules. The benefits of VATS however, might be offset by inability to visualize or localize such   15 nodules. Challenges faced during thoracoscopic resection of nodules that are too small or located too deep necessitated conversion to open thoracotomy in a considerable number of cases (Finley RJ, 2015 Jan) (Suzuki K, 1999). Therefore, there has been extensive research and surgical innovations into localization techniques to assist in thoracoscopic resection of small nodules.  2.4 LOCALIZATION TECHNIQUES OF INDETERMINATE PULMONARY NODULES  Thoracoscopic precise localization of small peripheral lung nodules is fundamental for planning a successful VATS wedge resection (Finley RJ, 2015 Jan). Localization techniques for challenging pulmonary nodules can be divided into three main categories. The first category is pre-operative percutaneous localization with hook wire placement. The second category is intra-operative utilization of imaging such as ultrasound, fluoroscopy, and gamma-detection probes. The third category is pre-operative localization with percutaneous injection of dyes, contrast media, radionuclides, or colored adhesive agents (Powell TI, 2004).  One of the oldest and most common localization techniques is the use of hook wires. Unfortunately in comparison to other techniques, the percutaneous mammographic needle and hook wire system has been associated with complications and problems during and after the insertion (Dendo S, 2002). A high incidence of wire dislodgement pre-operatively has been reported with this technique, which is also associated with pneumothorax, intrapulmonary hemorrhage, and pleural pain. The hook wire is considered more invasive than other targeting techniques as it may cause tearing and damage if dislodged (Dendo S, 2002) (Powell TI, 2004). Also, it may lead to massive air embolism. Thaete and colleagues reported dislodgement of the   16 hook wire in the time interval between the CT placement procedure and the surgical operation in almost 25% of the cases (Thaete FL, 1999). Wire dislodgement might generally happen at one of three times as described by Mullan et al; during transportation of the patient to the surgical floor, during surgical deflation of the lung, or during the operative wedge resection when wire retraction is often caused by the surgeon (Mullan BF, 1999). Displacement of the wire can also happen with patients’ motion, clothing, and draping. Moreover, the rigidity and stiffness of the hook wire prevents the physiological sliding of the visceral pleura on the parietal pleura, which predisposes the underlying lung to torsional stress and damage. This may also prevent the lung from collapsing in case of pneumothorax, which potentially leads to tearing of the lung parenchyma with intrapulmonary hemorrhage and hemothorax (Thaete FL, 1999). All these limitations have hindered the widespread use of hook wires for nodule localization.    Although localization of pulmonary nodules with intra-operative ultrasound is safe and non-invasive (Khereba M, 2012), the technique is highly operator dependent and proven to have several limitations (E., 1998) (Mahvash Zaman, 2012). The use of ultrasound requires the lungs to be fully deflated in order to visualize the nodules, and that requires additional 30-150 minutes, significantly lengthening surgery time (Jangra D, 2002). Furthermore, the complete collapse of the lung is difficult to achieve and often impossible in patients with obstructive pulmonary disease such as emphysema (Dendo S, 2002) (Jangra D, 2002). The failure rate of this technique even when pre-operative localization was used was reported to be as high as 24% (E., 1998). On the other hand, literature and experience with real-time CT fluoroscopy is limited. Artifacts from surgical instruments and the limited space within the scanner have been shown to add more difficulty to the surgery and degrade the CT image (Jangra D, 2002). Localization of nodules using gamma probe after injection of radioactive tracer has been associated with some   17 drawbacks (Sortini A, 2001 Dec). The lung is a highly vascularized organ, which causes fast diffusion of the injected contrast medium into the surrounding parenchyma, resulting in the loss of nodule localization. Other limitations of this technique are difficulty and failure of localizing deep and posterior nodules due to the size and the structure of the surgical probe that cannot move freely in the thorax. Unfortunately, pneumothorax is another problem that has been reported with the radio-guided technique (Thaete FL, 1999) (Dendo S, 2002) (Sortini D, 2005).  Percutaneous localization with injection of liquid markers such as dyes, contrast media, radionuclide, or colored adhesive agents have been limited by a major factor: unknown retention time. In fact, the longer the time elapsed between the localization procedure and the surgical operation, the greater the diffusion of the injected marker into the lung parenchyma surrounding the nodules (Sortini D, 2005) (Dendo S, 2002). Therefore, these techniques impose restrictions on the allowable time between CT-guided localization procedures and VATS resection (Powell TI, 2004). Other limitations include risk of shock from dye injections and difficulty of visualization in patients with extensive anthracotic pigmentation, like smokers (Dendo S, 2002). Injection of iodinated contrast material or diluted barium is limited by its potential to distort or damage the frozen-section histologic specimens, especially with ground glass opacity nodules or those with semisolid consistency at CT. Injection with radionuclides has been shown to be limited by additional factors such as radiation exposure and equipment and training requirements. Finally, risk of systemic embolization was reported as a potential complication with injection of all liquid markers if they were injected into the pulmonary venous system (Mayo JR, 2009 Feb). All these limitations have restricted the wide adaptation of these localization techniques and mandated the innovation of new techniques that will offer more precision, higher success rates, and less complications and invasiveness.   18   3. CHAPTER THREE: STUDY PROTOCOL 3.1 STUDY DESIGN AND OBJECTIVES 3.1.1 STUDY DESIGN  This was a retrospective analysis of prospectively collected data from a clinical study conducted between August 2003 and September 2013, of patients diagnosed with extra-thoracic cancers who underwent preoperative localization of indeterminate new small peripheral pulmonary nodules (SPPN) using percutaneously placed CT-guided platinum microcoils (CTML) and followed by fluoroscopy guided VATS resection. The study was approved by the VCH and UBC Institutional Review Board (CREB).  3.1.2 PROBLEM STATEMENT   Due to diagnostic challenges of growing or thickening SPPN in patients with previous extra-thoracic malignancies, these nodules are usually presumed to be metastasis, which may lead to misdiagnosis and subsequently inaccurate management.      19 3.1.3 HYPOTHESIS  In patients with previous extra thoracic malignancies, I hypothesize that pre-operative localization of small, peripheral pulmonary nodules, using percutaneous CT guided microcoil localization followed by fluoroscopy guided VATS resection, is a safe and effective technique for histopathology diagnosis and accurate management of these lesions.  3.1.4 OBEJECTIVE  The purpose of this study is to determine the utility of preoperative CT guided microcoil localization (CTML) followed by fluoroscopy guided VATS resection in the diagnosis and management of SPPN in patients with extra thoracic malignancies.  3.1.5 AIMS  1. To assess the safety, accuracy and precision of the preoperative CTML followed by fluoroscopically guided VATS on the resection of these nodules. 2. To evaluate the pathological diagnosis of these nodules. 3. To determine the subsequent effect of accurate diagnosis on treatment strategies. 4. To determine the effect of accurate diagnosis related treatment strategies on prognosis and overall survival.   20 5. Study the relationship between the final pathological diagnosis and patients’ independent variables.  3.1.6 RESEARCH QUESTIONS  1. Dose the pre-operative localization of small peripheral pulmonary nodules using percutaneous CT guided microcoil localization followed by fluoroscopy guided VATS resection enable definitive diagnosis in a safe and effective manner? 2. Does this diagnostic technique change the management of small lung nodules in patients with previous extra thoracic malignancies? 3. Is there a cause effect relationship between the independent variables such as age , gender, smoking, nodules type, location in the lung lobes, time from previous extra-thoracic cancer to VATS and outcome (dependent variables) namely - metastases, primary lung cancer and benign lesions in patients with small lung modules and extra thoracic cancer?  3.2 MATERIALS AND METHODS 3.2.1 PATIENT SELECTION  Adult patients referred to thoracic surgery service at Vancouver General Hospital for evaluation of new indeterminate pulmonary nodules, located in peripheral lung tissue, and deemed   21 amenable to thoracoscopic wedge excision were examined between August 1 2003 and September 30 2013 for inclusion in this study. Patients referred for thoracic surgical evaluation of small growing peripheral lung nodules that manifested during initial staging or follow up after treatment of an extra-thoracic malignancy were also included in the study. Patients who did not meet the inclusion criteria and those known to have primary malignant tumors of the lung or within the thorax were excluded. In all cases, chest CT scan images were reviewed to determine the feasibility and accessibility of microcoil nodule localization and VATS excision. Fifty patients agreed to participate after being informed of the risks and benefits of the procedure as well as all alternatives for treatment. Once eligibility was established, a written consent was obtained from all patients if he/she agreed to participate in the study.   3.2.2 ELIGIBILITY CRITERIA  3.2.2.1 INCLUSION CRITERIA  1- Adult patients > 18 years of age. 2- Previous history of extra-thoracic malignancy. 3- Newly developed < 1.5 cm nodules or nodules growing or thickening. 4- Patients are physically fit for surgery.    22 3.2.2.2 EXCLUSION CRITERIA  1- Patients < 18 years of age. 2- Patient’s diagnosed with lung, esophageal, mediastinal or pleural malignancies. 3- Centrally located lung nodules < 2cm. of the main pulmonary vessels. 5- Patients are not physically fit for the surgery. 6- Patients’ refusal.  3.2.3 DATA COLLECTION  The following data was collected between August 1 2003 and September 30 2013 from both patient charts and patient care information system (Table 1): • Patients’ name and medical record number. • Age, gender, and smoking history. • Primary cancer type(s), date of diagnosis of the primary cancer(s), and all subsequent treatment (chemotherapy, radiation, or surgery). • Clinical and radiological information regarding the nodule(s) including date of identification on CT, number of nodules present, maximum diameter, and distance from pleural surface.   23 • Nodule biopsy information, and PET scan results, if applicable. • Elapsed time between the date of diagnosis of the primary cancer and the identification of the new pulmonary nodule.  • Follow up clinical status of the patients post VATS procedure.  3.2.4 PERCUTANOUS CT-GUIDED MICROCOIL LOCALIZATION PROCEDURE  First CT scanning was performed to identify the suspicious nodule and plan the access route. Radiological characteristics of the nodule identified for localization were entered into the study database including size, number, lobar location, and depth from the nearest pleural surface.  All CT scans were obtained using a 16-detector scanner (Siemens Sensation; Siemens Medical Systems, Erlangen, Germany) and the following technical parameters: 16-section helical acquisition mode, 0.75-mm detector aperture, 0.5-second rotation time, table speed of 3.6 cm/sec, beam pitch of 1.5, 120 kVp, and 130 mAs (effective). One-millimeter-thick images were reconstructed at 1-mm intervals by using a 180 linear-interpolation algorithm and both low (B45) and high (B60) spatial frequency reconstruction algorithms. The suspicious nodule was evaluated by using electronic calipers and region-of-interest tools on the picture archiving and communication system workstation (Agfa PACS, Toronto, Ontario, Canada). All microcoil localization procedures were performed or closely supervised by one chest interventional radiologist. Under CT guidance the skin area over the chest at the site most accessible to the target nodule was sterilized, marked, and shaved. After the proper   24 measurements were taken, a 100- or 150-mm long spinal Chiba Sugai needle (Cook Canada, Stouffville, Ontario, Canada) was loaded with an 80-mm-long, 0.018 inch diameter fiber coated platinum microcoil (Vortx-18, Diamond Shape; Boston Scientific, Cork, Ireland) using the stiff end of a 40-cm-long, 0.018-inch-diamter guidewire from a micropuncture catheter introducer set (Mini-Stick Kit; Boston Scientific, Waterton, Mass). The Chiba needle has stenciled marks spaced 10-mm apart on the outside of the needle shaft. After loading the microcoil a hemostat was used to mark the pusher wire at two points: the length necessary to eject 30 mm of the microcoil and the length necessary to eject the entire 80-mm-long microcoil from the Chiba needle. The loaded Chiba needle is then inserted percutaneously and pushed through and 5 mm deep to the suspicious nodule. At this point, the premeasured guide wire is advanced through the Chiba needle up to the first mark placed by the hemostat, and subsequently 30-mm of the 80-mm-long microcoil was deployed into the lung parenchyma and assumed a tight coiled configuration just beyond the tip of the needle (distal end) (Figure 1).  In order to avoid self-extraction of the deployed end of the microcoil to the pleural surface, at least 20-mm has to be ejected to firmly anchor the distal end in the lung parenchyma. 30 mm deployment was routinely used to ensure sufficient and safe anchoring. To confirm microcoil deployment and measure the distance required to withdraw the Chiba needle tip back to the pleural surface, a localizer CT scan was obtained. After that, the needle tip was pulled back to the pleural surface and another CT scan was obtained to confirm its location. The guidewire was then advanced to the second mark on the needle shaft causing full ejection of the remaining part of the platinum microcoil into the lung pleural surface. At the visceral pleural surface, the microcoil changed to a flattened spiral coil (proximal end) (Figure 2). Finally, the empty needle and guidewire were withdrawn.    25 A post-procedural CT scan was obtained to assess the following: the final position of the microcoil relative to the nodule and the pleural surface, and presence of post procedural hemorrhage or pneumothorax (Figure 3). At an imaging workstation (Leonardo; Siemens Medical Systems), the data was reformatted into a 3D image to illustrate the relationship between the microcoil and the ribs to facilitate port placement during VATS resection (Figure 4). The patients were then transferred to the pre-operative area were they waited for 1-6 hours before undergoing VATS resection. Minimal discomfort reported after microcoil placement and seldom required oral pain medication.   3.2.5 VIDEO ASSISTED THORACOSCOPIC SURGERY RESECTION   Under general anesthesia the patient was ventilated with a double lumen endotracheal tube and placed in the lateral decubitus position with the involved lung superior and collapsed. The first 5 mm thoracoscopic port was inserted through the appropriate rib interspace with the guidance of the previously constructed 3D CT image. The proximal end of the microcoil was visualized on the visceral pleural surface, serving as a guide to the precise location of the nodule (Figure 5). Based on the location of the microcoil proximal end two other ports were inserted: a 5 mm port for a grasping instrument and a 12 mm port for a linear stapler (Endo GIA II, United States Surgical, Norwalk, Conn; Echelon Endostapler, Ethicon Endo-Surgery, Cincinnati, Ohio). Following this, the lung next to the visualized microcoil proximal end was elevated using a grasping instrument and an endostapler device was then placed deep to the nodule ready to cut. For precise and complete resections, intra-operative fluoroscopy guidance was used to guide the   26 placement of the stapler bellow the deep end of the microcoil attached to the nodule (figure 6 and 7). The stapler then made the first cut. Under fluoroscopy guidance and after confirmation that the full coil was implanted in the resected segment, the lesion was fully excised by multiple staplings (Figure 8). Using an endoscopic retrieval bag the resected wedge of lung tissue was withdrawn through the 12 mm chest incision and sent for histopathologic examination (figure 9).   3.2.6 STATISTICAL ANALYSIS  Statistical analyses were performed with the SPSS ver. 22.0 software package (SPSS Inc. Chicago, Illinois). P-Value of <0.05 was considered statistically significant, with a 95% confidence interval.  Univariate and multivariate logistic regression analysis were carried out between the selected 7 Independent Variables (Risk Factors) and the 3 Dependent Variables (Outcome Variables). The seven dichotomous categorical independent variables, namely- Age [<60 / =>60], Gender [M/F], Smoking [No/Yes], Nodules Type [Single/Multiple], Lobes [Other/Upper], Lobes [Other/Lower], Time from Previous extra-thoracic Cancer to VATS [<2yrs/>=2yrs] as Counts (Percent).  Comparative p-values are reported throughout. Independent sample t-tests were used to compare the differences between mean values. The three outcome results, metastatic lesions, primary lung cancer and pulmonary benign lesions, were compared for prevalence using Z-tests.     27 4. CHAPTER FOUR: RESULTS 4.1 DESCRIPTIVE ANALYSIS  Between August 2003 and September 2013, fifty patients with extra-thoracic malignancy underwent fluoroscopy guided VATS resection for pulmonary nodules after CT-guided platinum microcoil localization “CTML”. Patients’ demographic data are shown in table 1. The majority of the patients were women (57.14%), with an average age of 62.56 for all patients. A total of 14 different extra-thoracic cancers were identified in the 50 patients, with 3 patients having more than one extra-thoracic cancer (Table 2). The median time interval between the diagnosis of the primary tumor and the finding of pulmonary nodule(s) on CT scans was 36 months (range 4–588) with a mean of 76.7 +/- 110.33. Primary cancer diagnosis date was not available for one patient, and 8 patients had synchronous finding of lung nodules at the time of primary extra-thoracic cancer diagnosis.  Table 2 shows the histological types of primary malignancies found in the study population. Colorectal adenocarcinoma was the most prevalent primary extra-thoracic cancer. The previously treated extra-thoracic malignancies were colorectal (16), breast (9), renal (4), sarcoma (5), melanoma (3), lymphoma (3), thyroid (3), prostate (2), gastro esophageal (2), cervix (2), bladder (1), others (3). Table 3 shows lung nodules characteristics. Fifty five nodules were resected with a mean size of 12.11 +/- 4.55, and a mean depth from visceral pleura of 22.07 +/- 10.86. The resected nodules locations were RUL (n=17), RLL (n=20), LLL (n=7), RML (n=5), LUL (n=5), and Lingula (n=1).    28 Operative details are summarized in table 4 and 5. Nodules were successfully resected in all patients, with a mean operative time of 27.72 minutes +/- 12.4, and fluoroscopy time of 3.17 minutes +/- 5.93. Video-assisted thoracoscopic surgery wedge resection after CT-guided microcoil localization was successfully diagnostic in all patients. Eighty percent of patients underwent VATS wedge resection only, which was therapeutic in 54% of patients. In the remaining 20% of patients, 14% underwent VATS therapeutic lobectomies following their diagnostic wedge resection. One patient (2%) underwent open wedge resection due to extensive metastatic disease (chordoma) and adhesions which prevented a thoracoscopic approach. Another patient (2%) had two lesions in the same lobe which necessitated diagnostic VATS lobectomy to ensure a clear margin resection.  The mean time for CT-guided microcoil placement procedure was 31.5 +/- 10.7. CT-guided microcoil localization techniques allowed surgeons to intraoperatively determine the adequate deep margin required for safe resection of lung nodules. No major complications developed during and/or following the coiling procedure or the surgical resection of lung nodules (Table 5).  Fifty five nodules were resected in 50 patients. Pathology of the resected nodules are shown in table 6. Of 50 patients studied, 40 (80 %) had malignant lung nodules (one patient had both malignant and benign lesions) and 10 (20%) had benign lesions only. Fifteen patients (30%) had primary lung cancer and twenty five patients (50%) had metastatic lesions. Out of the 15 patients with primary lung cancer, 12 (80 %) were adenocarcinoma, and 3 (20 %) were squamous lung cancer. All the resected primary lung cancer nodules were early stage non-squamous lung cancer (T1aN0 in 14 patients, T2N0 in one patient) (Table 4).   29 Among the 10 (20 %) patients in the study who had only benign lung lesions, the pathology of their resected nodules were granuloma (4), hamartoma (2) hyperplasia (4).  Five patients had two lung nodules resected. Among those, three had metastatic lesions, one had benign lesions, and one had both benign lesion and primary lung cancer. Details of these patients are presented in table 7. In relation to the histology of primary extra-thoracic tumors, metastasis was noted as developing more commonly in patients with urogenital carcinoma (85.7%), sarcoma (80%), melanoma (66.66%), and colorectal carcinoma (62.5%). On the other hand, primary lung cancer noted to develop more commonly in patients with lymphoma (100%) and breast cancer (62.5%) (Table 8). In regards to the location of the resected lung nodules, the majority of metastatic lesions were found in the lower lobes (57.14%). While the majority of primary lung cancer lesions were in the upper lobes (56.25%). Benign lesions were distributed almost equally between different lobes (Table 9). History of tobacco smoking was found in 73.33%, 36%, and 20%, in patients with primary lung cancer, metastatic lesions, and benign lesions, respectively (Table 10). Classification of lung cancer recurrence has varied widely in the literature with no standard definition. The optimal method of reporting patterns of failure is not yet clear (David Fedor, 2013) (Lopez Guerra JL, 2012). In our study, local recurrence was defined as disease recurrence at the stable/suture line, bronchial stump, or same lobe. Regional recurrence was defined as disease recurrence within the operated hemithorax including the ipsilateral lymph nodes, the pleura, and the chest wall. Other   30 sites of recurrence including the contralateral hemithorax, and lymph nodes in the neck or axilla were considered distant metastasis.   The mean follow up period for patients who had malignant nodules and underwent therapeutic resections was 35 months +/-25. The mean follow up period for patients who had metastasis was 34 months +/-24.5 and primary lung cancer was 36 months +/-27. Among patients who developed primary lung cancer, 69% had no recurrence of disease. Furthermore, those who underwent therapeutic lobectomies and diagnostic wedge resections had no local or regional recurrences during the follow up period. Among patients who developed metastasis and underwent therapeutic resections, 61% had no recurrence of disease. In addition, there were no local recurrences, and only one patient developed regional recurrences. (Table 11).  Comparison of the three outcome results (metastasis, primary lung cancer and benign lesions) for prevalence revealed that metastatic lesions are not significant (p=NS) when compared with the combination of primary lung cancer and benign lesions.   4.2 INFERENTIAL STATISTICS Metastasis  Univariate logistic regression analysis demonstrated a significant inverse relationship of age and metastatic lesions (p 0.045). Patients aged 60 and above were found less likely to develop metastatic lesions in comparison to those bellow age of 60. In addition, lung nodules located in   31 the upper lobes were significantly less likely to be metastatic compared to nodules located in other lobes (p 0.006). (Table 12) Multivariate logistic regression analysis confirmed the significant inverse relationship between age and metastatic lesions (p 0.014). Patients younger than 60 years of age were 11 times more likely to develop metastasis than patients aged 60 and older. Further, lung nodules not located in upper lobes were found 19 times more likely to represent metastasis in comparison to upper lobe nodules (p 0.011). (Table 13) Multivariate analysis showed that the relationship between multiple nodules and risk of metastasis is borderline, however, not significant (p 0.07). (Table 13)  Primary Lung Cancer  Univariate logistic regression analysis has shown significant (p 0.009) associations between smoking and primary lung cancer. Lung nodules in smokers were found 6 times more likely to represent primary lung cancer than metastasis in comparison to non-smokers (Table 14). This association was also significant in multivariate logistic regression analysis (p 0.03) (Table 15).   Benign Lesions  Multivariate logistic regression analysis have shown a significant (p 0.029) proportional relationship between age and benign lesions. Patients aged 60 and older were found 29 times   32 more likely to have benign lesions than younger patients. Moreover, a significant (p 0.02) association has been demonstrated between benign lesions and non-smokers. Non-smokers were found 15 times more likely to present with benign lesions compared to smokers. In addition, lung nodules in upper lobes had a significant (p 0.02) association with benign lesions. Upper lobe nodules were 24 times more likely to represent benign lesions compared to nodules in other lobes (middle/lower lobes). (Table 16)                33 5. CHAPTER FIVE: DISCUSSION  In contrast to the general assumption of metastasis in patients with previous history of extra-thoracic cancer, lung nodules in 50% of our patients turned out to be non-metastasis, which significantly affects the management plan. Our study proved that patients with extra-thoracic malignancies and pulmonary nodules have an equal chance of having metastatic versus non-metastatic lesions, which lowers the threshold for diagnostic and therapeutic measures. The prevalence of metastasis was not significant statistically when compared to non-metastatic lesions and this proves that the generally perceived notion of metastatic lesions being prevalent in this category of patients is false. This also proves our hypothesis that the proposed surgical technique for removal of small lung nodules provides 100% accuracy for final diagnosis that will subsequently change the course of therapy. Therefore, in shaping the management plan for these patients the equivalent chance and importance of etiologies other than metastasis should be taken into consideration.  Detection of non-calcified pulmonary nodules in patients already diagnosed with extra-thoracic malignancy are worrisome, however, surgeons are challenged to balance the benefits of obtaining an early diagnosis with the potential risks of unnecessary intervention (S Khokhar, 2006 Apr). A German study that performed VATS wedge resection of solitary pulmonary nodules in patients with a history of malignant tumors found 27% benign lesions and an equal number of metastasis and primary lung cancer of 36.4%. The study concluded that in order to define the nature of these nodules more precisely they should be resected by VATS (Prisadov GC, 2010). Another study that applied the same approach during follow up or staging of cancer patients found 35% of these lesions benign (Laisaar T, 2008). Both studies concluded that not all   34 pulmonary nodules in patients diagnosed with malignancy are metastasis. In addition, thoracoscopic removal of these lesions can be curative in many patients (Prisadov GC, 2010) (Laisaar T, 2008). If detected early, the chance of cure is high, particularly in the case of an early stage lung cancer (Hanamiya M, 2012 Jan). Although diagnostic accuracy has been ameliorated by imaging and pre-operative diagnostic procedures, surgical excision biopsy is often the standard procedure for establishing definite diagnosis (Laisaar T, 2008). Because of the curative role of resection in primary lung cancer, the high control of disease in single/limited metastasis, and the diagnostic value in benign lesions, demand for surgical excision biopsy by VATS is increasing and considered by many thoracic surgery centers to be the standard procedure for clarifying the histological substrate of these nodules (Laisaar T, 2008). Successful VATS excision of these nodules with low morbidity can be achieved by preoperative CT-guided microcoil localization and fluoroscopy-guided VATS. This technique has proved to be safe, effective, and provided pathological diagnosis by precise and complete excision of the target nodule at 1 setting without conversion to open thoracotomy or VATS anatomic resection (segmentectomy or lobectomy) (Finley RJ, 2015 Jan). In our study, pre-operative localization of suspicious small peripheral pulmonary nodules using percutaneous CT-guided microcoil localization followed by fluoroscopy-guided VATS resection changed management in half of the patients with presumed metastasis, with minimal morbidity. Microcoil localization procedure was successful in all our cases, with no complications. Few patients developed mild pneumothorax, which was managed conservatively with no chest tube insertion required in any patients. Successful VATS wedge resection of target nodules was accomplished in all our patients. Specimens including nodules were examined   35 pathologically to ensure safe resection margins free of malignancy. No complications were encountered during or after the VATS surgery. None of the patients in our study were taken back to surgery because of inadequate resection margins or any other reason. Definite diagnosis was achieved in all our cases, with no conversion to open thoracotomy. One patient had anatomic resection (diagnostic lobectomy) to ensure safe resection of two nodules in one lobe with adequate margins. The minimally invasive procedure provided the patients with short hospital stay, minimal post-operative pain, and early mobilization.  5.1 INCIDENCE OF MALIGNANT PULMONARY NODULES IN PATIENTS WITH EXTRA-THORACIC CANCER   Malignant pulmonary nodules were reported significantly high, ranging from 79-91% in patients with extra-thoracic malignancies (Mery CM, 2004 Jun) (Peuchot M, 1987 Sep). Our results were in agreement showing 80% of the resected lung lesions to be malignant. Further our analysis showed that patients with extra-thoracic cancer are 2.3 times more likely to develop malignant nodules (p 0.028) (Table 22). Although uniformed diagnostic algorithms and optimal management plans are still lacking (Xiao F, 2013 Oct), cancer must be ruled out in high risk patients with new or expanding lung lesions. Malignant etiologies of these nodules may represent metastasis, new primary lung cancer or carcinoid tumors (Gould MK F. J., 2007 Sep) (Wahidi MM, 2007 Sep).     36 5.2 PREVALENCE OF METASTASIS, PRIMARY LUNG CANCER AN BENIGN LESIONS STRATIFIED BY PATIENTS’ PREDICTIVE VARIABLES   Overall, our analysis showed that patients with extra-thoracic malignancy are twice more likely to have metastasis compared to primary lung cancer (p 0.02) (Table 25), and 3.5 times more likely to have metastasis compared to benign lesions (p 0.001) (Table 25).  Age  Our analysis showed that lung metastasis was more prevalent in patients younger than 60 years. On univariate analysis, the risk of lung metastasis in patients younger than 60 years was 3.4 times greater than older patients (p 0.04) (Table 12), while on multivariate analysis the risk was significantly greater for these patients with 11 times more likelihood of metastasis compared to older patients (p 0.01) (Table 13). Although primary lung cancer reported was more prevalent in older patients in the general population (Meoni G, 2013), our multivariate analysis for benign lesions demonstrated 28 times more likelihood of benign lesions in patients of 60 years of age and older compared to younger patients, in patients with a previous history of extra-thoracic cancer (p 0.02) (Table 16).       37 Smoking  The analysis of Mayo Clinic and Veterans Affairs clinical models showed that patients with current or past history of tobacco smoking and previous history of extra-thoracic malignancies are at highest risk for developing malignant nodules (Gould MK A. L., 2007) (Swensen SJ, 1997). Tobacco smoking is a causative factor of primary lung cancer (McWilliams A, 2013 Sep). In patients with no history of cancer, the reported relative risk of primary lung cancer among cigarette smokers is 10 times that of non-smokers, and 15-30 times greater in heavy smokers (Ali Nawaz Khan, 2011) (MacMahon H & Society., 2005). Furthermore, in patients with extra-pulmonary cancers, the finding of primary lung cancer was reported higher than metastasis among smokers (S Khokhar, 2006 Apr). Therefore, lung nodules identified in former or current smokers are more suspicious of early stage lung cancer rather than metastasis (S Khokhar, 2006 Apr). Our results were in agreement showing 6-fold increase in the likelihood of primary lung cancer in smokers. This result was confirmed by both univariate (p 0.009), and multivariate (p 0.03) analysis (Table 14, 15). In addition, non-smokers were 15.7 times more likely to have benign lesions (p 0.02) (Table 16).   Histological Type of the Underlying Extra-thoracic Cancer  Univariate logistic regression analysis showed a significant (p 0.001) association between certain types of extra-thoracic tumors and metastasis. Patients with colorectal, urogenital, sarcoma and   38 melanoma tumors were 11 times more likely to develop metastasis compared to patients with other types of neoplasms. (Table 19).   Breast Cancer  Nodules in patients with breast cancer were found to have a higher probability of being primary lung cancer rather than metastasis. Tanaka et al studied 30 consecutive patients with history of breast cancer who underwent surgical resection for solitary pulmonary nodules. The pathological diagnosis of the resected nodules were primary lung cancer in 67% and metastasis in 23% (AZUMI TANAKA, 2013). Similarly, results by Rena et al reported a higher rate of primary lung cancer in patients who underwent surgery for breast cancer, 48% compared to metastasis at 34%, and benign lesions at 18% (Rena O P. E., 2007). Our study results were in agreement, showing higher incidence of primary lung cancer 62.5% in comparison to metastasis 0% and benign lesions 37.5% in those diagnosed with breast cancer. (Table 8)  Colorectal cancer  Higher rates of lung metastasis were reported in patients diagnosed with colorectal cancer. Colorectal cancer is an extremely prevalent disease with more than 1 million cases diagnosed annually worldwide. Of these cases, 19% present with stage IV disease and the lungs are the second most common site of metastasis (Villeneuve PJ, 2009). A retrospective study of 123   39 patients with history of colorectal cancer that underwent surgical resection of solitary lung nodules showed metastasis in 69 patients (56.1%), primary lung cancer in 45 patients (35.8%), and benign lesions in 10 (8.1%) (Cheuk-Kin Lo, 2008). Our study results were similar demonstrating metastasis in 62.5%, and equal number of primary lung cancer and benign lesions 18.75% in patients diagnosed with colorectal cancer. (Table 8)  Melanoma  Melanoma is a neoplasm known to frequently metastasize to the lungs (E. C. Smyth, 2012) (Murphy F, 2012 March). A study that was conducted at the Memorial Sloan-Kettering Cancer Center in New York showed a high incidence of metastasis found in patients diagnosed with melanoma. Two hundred and twenty nine patients with melanoma and suspicious lung lesions were included in the study. Pathological results showed metastatic melanoma in more than two thirds (69%) of the patients, and non-melanoma lesions in one third (31%) of the patients. Fourteen percent of the non-melanoma lesions were new potentially curable primary lung cancer, and 12% were benign lesions (E. C. Smyth, 2012). The study emphasized the importance of tissue diagnosis before decision making in situations in which one would expect a diagnosis of melanoma metastasis. Our patients had similar results: two thirds (66.66%) had metastatic melanoma, and one third (33.33%) had primary lung cancer, but with no benign lesions detected.      40 Sarcoma  Sarcoma is a malignant neoplasm that represents less than 1% of all new malignancies (Zachary Burningham, 2012), which limits the number of clinical trials. Although it’s relatively rare, lungs are the most common site of distant metastasis. Newly developed lung nodules in patients diagnosed with sarcomas are most likely to be metastatic (Cormier JN, 2004). Meyerson et al studied 14 patients diagnosed with sarcoma and newly developed lung nodules. Tissue diagnosis showed that 92% of these lesions were metastatic, and 8% were benign. Primary lung cancer was not detected in sarcoma patients (Meyerson SL, 2009). Similarly, in our study 80% of sarcoma patients had metastatic lung lesions, and 20% had benign etiologies. However, no primary lung cancer was diagnosed in patients with sarcomas.  Head and Neck Cancer  Lungs are the most common site of distant metastasis in patients with head and neck tumors. The incidence of pulmonary metastasis from head and neck cancers is reported to range from 6% to 9.1% (Shiono S, 2009). However, these patients also have a far higher risk of developing a second primary lung cancer, the incidence of which is approximately 0.6-1% per year (Quint LE1, 2000 Oct) (W G Cahan, 1978 March). The incidence of metastasis versus primary lung cancer in head and neck cancer patients varied widely in the literature (Laura Evangelista, 2014) (S Khokhar, 2006 Apr) (Quint LE1, 2000 Oct). Several studies have reported higher incidences of primary lung cancer than metastasis in patients diagnosed with head and neck neoplasms.   41 Other studies reported higher rates of metastasis in head and neck cancer patients (Sortini A, 2001 Dec). The reported ratio of primary lung cancer to metastatic disease was 6:2 by Khokhar et al and 25:2 by Quint et al (S Khokhar, 2006 Apr) (Quint LE1, 2000 Oct) . In contrast, in our series the incidence of metastasis was double (40%) the incidence of primary lung cancer (20%). However, these discrepancies can be explained by other factors including differences in the number of nodules at presentation (single vs. multiple). Quint et al included patients with single nodules only. On the other hand, Ginsberg et al reported 73% metastatic lesions in head and neck cancer patients presenting with multiple nodules (Ginsberg MS, 1999). In our study the majority of head and neck cancer patients presented with multiple nodules. Moreover, thyroid cancers reported to metastasize more frequently to the lungs (S Khokhar, 2006 Apr), which constituted 60% of our head and neck cancer patients.  Renal Cell Carcinoma  Twenty to thirty percent of patients with renal cell carcinoma have distant metastasis at time of initial presentation (Mano R, 2014). Lungs are the most common site of metastasis occurring in 50-60% of patients. Furthermore, lungs are the most frequent site of distant relapse after radical nephrectomy (Jung DC1, 2009). Despite the high rate of lung metastasis in renal cell carcinoma, a solitary pulmonary nodule that is detected at a longer interval (48-51 months) after radical nephrectomy is more worrisome for primary lung cancer (Nakamoto T1, 1995). Therefore, the finding of lung nodules in patients diagnosed with renal cell carcinoma should be reliably   42 diagnosed before initiating therapy for metastasis. In our series, all pulmonary lesions in patients with renal cell carcinomas were metastatic.  Lymphoma  Of the 4 patients with lymphoma in our study, 3 developed primary lung cancer and one patient had benign lung lesion. In contrast, another study had 4 lymphoma patients with new lung nodules, of whom 3 patients had metastatic lung lesions (Meyerson SL, 2009). Studies investigating the probability of lung cancer versus metastasis versus benign lesions in patients diagnosed with lymphoma are very few and limited by small sample size which may generate bias.  Solitary versus Multiple Nodules Multiple Nodules   Of 50 patients enrolled in our study, 32 (64%) presented with multiple nodules. Of these 32 patients, 81.25% had malignant lesions, 50% had metastasis and 31.25% had primary lung cancer. On the other hand 18.75% of patients with multiple nodules had benign lesions. (Table 23) Multiple lung lesions in patients with malignant disease were reported more likely to be metastasis compared to solitary nodules (S Khokhar, 2006 Apr) (Rena O D. F., 2013), which   43 matches our results. Further, multivariate analysis of our data showed that multiple nodules are 4.6 times more likely to be metastatic compared to single lesions (p 0.073) (Table 13).   Solitary Nodules  Of 50 patients enrolled, 18 (36%) presented with solitary nodules. Of these 18 patients, 77.7% had malignant lesions: 50% metastasis and 27.7% primary lung cancer. On the other hand, 22.3% of patients with solitary nodules had benign lesions. (Table 23) Some studies have shown that patients with extra-thoracic malignancies and solitary pulmonary nodules are more likely to have primary lung cancer rather than a metastasis or a benign lesion (S Khokhar, 2006 Apr) (Quint LE1, 2000 Oct). The probability of solitary nodules to be a single metastasis is very low, however influenced by other factors such as histology of the underlying extra-thoracic cancer (Rena O D. F., 2013). In our series the incidence of metastasis was more than primary lung cancer in patients with solitary nodules. This can be explained by discrepancies of the underlying histology of the extra-thoracic neoplasms. The majority of our patients with solitary nodules had colorectal cancer which is known to metastasize more frequently (Table 24). Our results were more similar to Rena et al, who studied 131 patients with solitary lung lesions and history of cancer, with colorectal cancer being the most prevalent. Their results showed 50% metastasis, 43% primary lung cancer and 7% benign lesions (Rena O D. F., 2013). Furthermore, patients presenting with solitary nodules were found 6.8 times more likely to have benign lesions compared to those presenting with multiple nodules in multivariate   44 analysis (p 0.086) (Table 16). On the other hand, no association was demonstrated in our analysis between primary lung cancer and solitary nodules (Table 15).   Location of Lung Nodules  Literature showed that the majority of primary lung cancer nodules are located in the upper lobes, while two thirds of metastatic nodules are located in the lower lobes (Ali Nawaz Khan, 2011). Our study results were in agreement, showing most of the primary lung cancer lesions (56.25%) were located in the upper lobes, while most of the metastatic lesions (57.15%) were in the lower lobes (Table 9). Further, univariate analysis demonstrated that lung nodules which are not located in upper lobes are 5 times more likely to be metastasis (p 0.006) (Table 12). This result was confirmed by multivariate analysis showing 19 times risk of metastasis for lung nodules that are not located in upper lobes (p 0.01) (Table 13). Multivariate analysis of benign lesions showed that nodules located in upper lobes were 24 times more likely to be benign than nodules located in other lobes (p 0.02) (Table 16).   5.3 PROGNOSIS AND OVERALL SURVIVAL AFTER SURGICAL RESECTION  Metastatic Lesions  Lung metastasectomy can be diagnostic as well as therapeutic in selected cases (Reddy, 2005 March). An International Registry of Lung Metastases was established in 1991 to assess the   45 long-term results of pulmonary metastasectomy in patients with both thoracic and extra-thoracic malignancies. The registry has accrued 5206 cases from 18 departments of thoracic surgery in US, Canada, and Europe confirmed that lung metastasectomy is a potentially curative procedure and improves the patients’ prognosis and the overall 5-year survival rate (Pastorino U, 1997 Jan). The impact of pulmonary metastasectomy on overall survival was further established by several clinical trials. After video-assisted thoracoscopic wedge resection with curative intent, the expected 5-year survival rates can reach 30%-50%, depending on the underlying primary cancer (Siyuan Dong, 2014).   Colorectal Cancer Metastasis  In colorectal cancer, a systematic review of surgical resection of pulmonary metastases incorporating 1684 patients have demonstrated a high overall survival rate at 60% after pulmonary metastectomy (Pfannschmidt J D. H., 2007 Jul). Further, early surgical resection of these metastatic nodules have shown to improve the 5-year survival rate up to 40% in stage IV colorectal cancer patients, compared to only 11.3% if untreated (Villeneuve PJ, 2009).   Melanoma Metastasis  In melanoma, survival in patients with distant metastasis is generally poor, however, improved by complete surgical resection. The analysis of 1720 patients with pulmonary metastasis by   46 Petersen et al found the 5 year survival rate for patients who underwent complete resection of lung metastasis range between 21-22% (Petersen RP, 2007 Jan), which is more than double the survival rate observed in those receiving non-surgical therapy (Falkson CI, 1998 May). Other studies showed that survival rates after complete pulmonary metastasectomy range from 22% to as high as 39% in those with a solitary pulmonary metastasis, and to less than 10% in those treated non-surgically (E. C. Smyth, 2012) (Murphy F, 2012 March).  Soft Tissue Sarcoma Metastasis  In soft tissue sarcoma, a clinical study of 716 patients with isolated pulmonary metastasis reported a 3-year survival rate of 23% in those who underwent metastectomy compared with only 2% in patients treated non-surgically. The authors concluded that complete surgical resection of metastatic sarcomatous lung lesions presents the only option for cure (Gadd MA, 1993 Dec). In addition, literature on bone and soft tissue sarcomas has shown that lung metastectomy is indicated whenever complete resection is technically feasible aiming for permanent cure. Lungs are almost always the only site of distant metastasis (Pastorino, 1998 Jan) and in 50-80% of patients with stage IV sarcoma, lung metastasis was found to be the major reason of treatment failure.      47 Breast, Head and Neck Metastasis  Although breast and head and neck cancer patients are more likely to present with new primary lung cancer, metastasis to lungs in these patients have also been reported (Shiono S, 2009) (Meimarakis G, 2013 Apr). In head and neck cancer, Shiono and colleagues reported a 5-year survival rate of 59% in pulmonary metastasectomy group compared to only 4% in non-metastasectomy group (Shiono S, 2009). In metastatic breast cancer, resection of isolated lung metastasis has proven to yield improved 5- and 10-year survival rates at 59.6% and 43.0%, respectively (Meimarakis G, 2013 Apr).  Survival after Metastasectomy in Our Series   Results of our study confirmed metastasis in 50% of the patients. Our analysis showed that patients with extra-thoracic cancer are 2.8 times more likely to develop metastasis in comparison to other etiologies (p 0.003) (Table 17). VATS wedge resection after microcoil localization was diagnostic and therapeutic in 72% of these patients, who benefited from early control of disease. After a median follow up period of 24.5 months (range 6-99), all patients were alive. No evidence of disease recurrence was noted in 61% of these patients. Moreover, none of these patients developed local recurrence after their therapeutic resection during the same follow up period. (Table 11)    48 Primary Lung Cancer  Primary lung cancer is an aggressive and heterogeneous disease and the leading cause of cancer related deaths worldwide, among men and women (Aberle DR, 2011 Aug). The main reason is believed to be that lung cancer is often well advanced at the time of diagnosis, which limits treatment options (Valentina Ambrosini, 2012). The lack of early prompt diagnosis results in poor prognosis and low 5-year survival rates of 14%, and more than 1 million deaths annually (Gould MK F. J., 2007 Sep) (Esposito L, 2010 Nov). Nevertheless, the curable form of lung cancer (Stage 1A), can manifest as solitary lung nodule less than 3 cm in diameter, and early detection and management can significantly improve the 5-year survival rates to 70-80% (Gould MK F. J., 2007 Sep) (Esposito L, 2010 Nov). According to the American Cancer Society approximately 20% to 30% of lung cancers will be diagnosed as solitary pulmonary nodules, which have the most favorable prognosis (American Cancer Society, 2006). Therefore, serious attempts and focus are aimed towards early detection and safe resection of primary lung cancer in its early stage and curable form in order to improve overall survival.  As mentioned previously, patients with pulmonary nodules and breast cancer, head and neck squamous cell cancer, prostate cancer or lymphoma are at a greater risk for having a new primary lung cancer, therefore these patients will benefit the most from early management.  In patients with breast cancer and solitary pulmonary nodule, lung resection is believed to be the treatment of choice because it is likely to be a second primary cancer originating in the lung rather than a metastasis (Casey JJ, 1984 Oct). Following early surgical resection of primary   49 lung cancer in patients with history of breast cancer, Tanaka et al observed an excellent 5-year survival of 100% (AZUMI TANAKA, 2013).  The five-year survival in patients with head and neck cancer after resection of metachronous lung lesions was reported to range from 19% to 43%, demonstrating the significance of early surgical intervention (Geurts TW, 2010). Primary lung cancer in patients with head and neck malignancy is considered to be a very bad prognosis, often diagnosed at an advanced stage. Survival of those patients is related to the primary lung cancer grade at the time of diagnosis (D. Dequantera, 2011), ranging from 46% for grade I, 13% for grade II and 0% for grade III and IV (E. De Mones, 1999). Modern treatment of Hodgkin’s lymphoma has significantly improved the survival and the curability of the disease. Unfortunately the achieved excellent life expectancy can be offset by the late effects of treatment, including second malignancies (Milano MT, 2012). Cumulative mortality rates due to second primary malignancies developed in treated lymphoma patients was found higher than deaths caused directly by lymphoma. In patients with Hodgkin’s lymphoma, who developed non-small cell lung cancer, 85% of deaths was due to NSCLC compared to only 4% due to the lymphoma. Lung cancer has the largest absolute risk of second primary cancer and it is the greatest contributor of overall mortality from second cancers in Hodgkin’s lymphoma patients (Milano MT, 2012). Few studies have been published about lung cancer after non-Hodgkin lymphoma. Nevertheless, elevated risks for lung cancer after indolent lymphomas, chronic lymphocytic leukemia/small cell leukemia and follicular lymphoma were noted, which might be due to an inherent predisposition, systemic therapy or immunosuppression (Morton LM, 2010). Early diagnosis and complete resection are crucial and improved the overall survival in these patients.   50 The reported 2, 3 and 5-year survival rates after surgical resection of lung cancer were 52.7%, 26.3% and 13% respectively. Conversely, the reported median survival of non-surgical patients was 9 months only (Morton LM, 2010).  Survival after Primary Lung Cancer Resection in Our Series  Early stage lung cancer was diagnosed in 30% of our patients, which allowed early management. The median follow up period of patients who underwent VATS lobectomies (7/15) and/or VATS wedge resection alone (8/15), was 29 months (range 5-97). During the follow up period, all the patients were alive. Furthermore, no evidence of disease recurrence (local, regional, or distant) was noted in all patients (100%). Follow up data was missing for two patients. (Table 11)  Benign Lesions  Distant spread of malignant tumors to the lungs (stage IV cancer) has a major negative impact on the overall survival rate and might involve debilitating therapeutic measures such as chemotherapy, radiotherapy, or even ablative therapy. Therefore, reliable histopathological clarification by VATS provides peace of mind and cessation of further management in benign lesions, with minimal morbidity (Ceppa DP, 2012 Sep). This was accomplished in 20% of our patients, in whom lung nodules proved to be benign.      51 5.4 SUMMARY  Fluoroscopy guided VATS after CT-guided microcoil localization was an effective procedure to make a definitive diagnosis and decide upon a therapeutic strategy. It provided the evidence that primary lung cancer and benign pulmonary lesions constitute 50% of possible etiologies in lung nodules detected in patients with extra-thoracic cancer. The achieved definitive pathological diagnosis changed the management in 50% of our patients with presumed metastasis and improved their overall prognosis.  Preoperative prediction of the etiology of pulmonary nodules detected in patients diagnosed with extra thoracic malignancy is difficult. Imaging modalities and guided biopsy can be useful to estimate the relative probability of cancer, but could not replace surgical resection due to diagnostic limitations. Furthermore, removal of the entire nodule is indicated for the following reasons: to obtain local control or perform chemotherapy in metastatic disease, for curative surgery in early stage lung cancer, and to avoid chemotherapy or radiotherapy in case of benign pulmonary lesions. In fact, metastasectomy had a life prolonging effect in selected patients, while on the other hand, prognosis of primary lung cancer proved to be no worse than for the general population if treated appropriately. In our series, 30% were diagnosed with a new primary lung cancer. Early intervention allowed the detection of Primary Lung Cancer in its early stage in all patients and therefore facilitated curative resection. Moreover, 20% of the patients were found to have benign disease and avoided potentially harmful and unnecessary management.    52 Histology of the primary extra-thoracic cancer found to play a role in predicting the pathology of lung lesions. Metastatic lung lesions were more common in patients diagnosed with colorectal cancer, melanoma, or sarcoma. On the other hand, those diagnosed with breast or head and neck cancer were found more likely to develop new Primary Lung Cancer.  Smoking history proved to increase the likelihood of Primary Lung Cancer significantly, even in patients with extra-thoracic malignancy, and therefore should lower the threshold for early definitive intervention. Location of nodules in the lung can add valuable information. Upper lobe nodules found were more likely to represent Primary Lung Cancer, whereas nodules in the lower lobes were more likely to be metastasis.  The optimal approach to the management of pulmonary nodules in patients diagnosed with extra-thoracic cancer is evolving as technologies develop. In our study, the utilization of CT-guided microcoil localization followed by fluoroscopy guided VATS was safe, feasible, and successful in all cases. In addition, it allowed early definitive management with minimal morbidity and no complications. Most importantly, our management approach improved the prognosis and overall survival, demonstrated by absence of local recurrence and 100% survival rate during the follow up period.  5.5 LIMITATIONS   Larger sample size is required for better generalization of results.  Longer follow up period (5-10 year), for better evaluation of survival and comparison with literature.    53 5.6 FUTURE DIRECTIONS   Evidence-based algorithms for the management of new small pulmonary nodules in patients with extra-thoracic malignancies.  Evidence-based algorithms for the management of new small pulmonary nodules in patients with extra-thoracic malignancies.  Longer follow up period (5-10 year) after early resection of these nodules by CTML and VATS, for precise survival evaluation and comparison with other techniques.               54 6. CHAPTER SIX: CONCLUSIONS  1. In patients with previous extra thoracic malignancies, pre-operative localization of small, peripheral pulmonary nodules, using percutaneous CT guided microcoil localization followed by fluoroscopy guided VATS diagnostic wedge resection was:  A safe procedure with minimal morbidity and no mortality. The average localization time was 28 minutes and OR time was 30 minutes.  An effective procedure with 100% histopathology diagnosis (94% by VATS wedge only).  2. In patients with previous extra thoracic malignancies, pre-operative localization of small, peripheral pulmonary nodules, using percutaneous CT guided microcoil localization followed by fluoroscopy guided VATS diagnostic wedge resection showed the following histopathology:  Metastasis from the original extra-thoracic malignancy in 50% of patients  Early primary lung cancer in 30% of patients.  Benign disease in 20% of patients. 3. In patients with previous extra thoracic malignancies, pre-operative localization of small, peripheral pulmonary nodules, using percutaneous CT guided microcoil localization   55 followed by fluoroscopy guided VATS diagnostic wedge resection changed management in 50% of patients. This technique allowed:   A curative resection of early primary lung cancer in 30% of patients.  A precise removal of the entire nodule and adequate negative margins resulting in no local recurrences of cancers with wedge excision alone.   Avoidance of unnecessary further therapy in 20% of patients with benign disease. 4. The achieved early definitive diagnosis changed the management in 50% of our patients with presumed metastasis and improved their overall prognosis. 5. The likelihood of metastasis was found higher in patients with colorectal cancer, melanoma, or sarcoma. On the other hand, the likelihood of primary lung cancer was found higher in patients with breast and head and neck cancer.  6. Smoking history proved to increase the likelihood of primary lung cancer significantly (p<0.009), even in patients with extra-thoracic malignancy, and therefore should lower the threshold for early definitive intervention.          56 TABLES  Table 1: Demographic data of the patients Patient Characteristics N=50 Age (years) Median 65, range (20-81) Mean 62.58 / SD 13.22 Gender (%Male) 21 (42%) Gender (%Female) 29 (58%) Smokers % 22 (44%) Non-Smokers % 28 (56%)           57 Table 2: Primary extra-thoracic cancer data (14 different extra-thoracic cancer in 50 patients) Type of primary cancer N=13 N=53 Colorectal 16 (32%) Breast 9 (16%) Urogenital (renal, bladder, prostate, cervical) 9 (14%) Sarcoma 5 (10%) Lymphoma 3 (6%) Thyroid 3 (6%) Melanoma 3 (6%) Gastroesophageal carcinoma 2 (4%) Tongue squamous cell carcinoma 1 (2%) Leukemia 1 (2%) Chordoma 1 (2%) Time from Management of Primary diagnosis to VATS (months) Median 36, range (4-588) Mean 76.7 / SD 110.33      58 Table 3: Resected pulmonary nodules characteristics n=55 Nodule Size/ mm Median 11 , range (4-23) Mean 12.11 / SD 4.55 Depth of Nodules/ mm Median 20, range (5-63) Mean 22.07 / SD 10.86 Location RUL  RML  RLL  LUL  LLL  Lingula  17 (30.90%) 5 (9.09%) 20 (36.36%) 5 (9.09%) 7 (12.72%) 1 (1.81) Total Number of Nodules Resected 55 Patients presenting with Single nodules 19/50 (38%) Patients presenting with Multiple nodules 31/50 (62%)         59 Table 4: Microcoil localization procedure and operative details  Surgery Details Mean, Median, Range, SD Microcoil localization procedure time/ seconds (n=40) “Time was not recorded for the last 10 patients" Mean 31.5 / SD 10.7 Median 28.5 / range (18-60) Operation time/ minutes (n=50) Mean 27.72 / SD 12.4 Median 25, range (13-64) Fluoroscopy time/ minutes (n=50) Mean 3.17 / SD 5.93 Median 1.03 , range (0.01-5) Successful resection  50 (100%) VATS wedge        Diagnostic wedge        Therapeutic wedge 40 (80%) 14 (28%) 26 (52%) Open wedge 1 (2%) VATS Diagnostic Lobectomy 1 (2%) VATS wedge + Therapeutic Lobectomy  7 (14%) VATS lingulectomy  1 (2%)         60 Table 5: Details of coiling procedure and VATS operation Patient Coiling procedure time Coiling procedure successful Hemo- thorax Pneumo- thorax Tube insertion OR time (min) Fluoroscopy time (min) Resection Technique 1 40 Yes No no No 64 2 VATS therapeutic wedge  2 45 Yes No no No 35 2.9 VATS therapeutic wedge 3 40 Yes No mild No 30 0.32 VATS therapeutic wedge 4 60 Yes No mild No 20 5 VATS wedge + Therapeutic lobectomy + nodal clean out 5 50 yes No mild No   VATS therapeutic wedge 6 40 yes No mild No 25 0.17 VATS therapeutic wedge 7 32 yes No mild No 20 1.5 VATS therapeutic wedge 8 30 yes No mild No 30 1.2 VATS therapeutic wedge 9 30 yes No no No 20 0.93 VATS therapeutic wedge 10 20 yes No mild No 18 0.15 VATS wedge and Therapeutic Lobectomy + nodal clean out   61 Patient Coiling procedure time Coiling procedure successful Hemo- thorax Pneumo- thorax Tube insertion OR time (min) Fluoroscopy time (min) Resection Technique 11 23 yes No no No   VATS diagnostic wedge 12 25 yes No mild No 20 0.53 VATS diagnostic wedge 13 50 yes No mild No 20 0.10 VATS diagnostic wedge 14 25 Yes No no No 15 0.75 VATS wedge and therapeutic Lobectomy+ nodal clean out 15 30 Yes No mild No 42 1.20 VATS wedge and therapeutic lobectomy “one month after” 16 30 yes No mild No 17 0.20 VATS wedge + therapeutic Lobectomy + nodal clean out 17 25 yes No mild No 13 0.50 VATS wedge + therapeutic Lobectomy +nodal clean out 18 20 yes No no No 15 0.28 VATS diagnostic wedge 19 30 yes No mild No 25 1.20 VATS diagnostic wedge   62 Patient Coiling procedure time Coiling procedure successful Hemo- thorax Pneumo- thorax Tube insertion OR time (min) Fluoroscopy time (min) Resection Technique 20 20 yes No mild No 26 0.10 VATS therapeutic wedge 21 25 yes No mild No 18 0.23 VATS wedge + therapeutic Lobectomy + nodal clean out 22 35 yes No no no 35 1.5 Open thoracotomy diagnostic wedge 23 47 yes No no no 41 4.24 VATS therapeutic wedge 24 34 yes No no no 28 4.09 VATS therapeutic wedge 25 20 yes No mild no   VATS therapeutic wedge  26 24 yes No mild no   VATS therapeutic wedge 27 30 yes No mild no 25 1 VATS therapeutic wedge 28 40 yes No mild no 21 6 VATS therapeutic wedge 29 25 yes No no no 45 3 VATS diagnostic wedge   63 Patient Coiling procedure time Coiling procedure successful Hemo- thorax Pneumo- thorax Tube insertion OR time (min) Fluoroscopy time (min) Resection Technique 30 25 yes no no no 35 3 VATS therapeutic wedge 31 60 yes No mild no 30 1.4 0 VATS diagnostic Lobectomy “2 lesions same lobe” 32 24 yes No mild no 23 1.03 VATS therapeutic wedge 33 25 yes No mild no 32 0.60 VATS diagnostic wedge  34 25 yes No mild no 20 0.42 VATS therapeutic wedge 35 40 yes No mild no 20 0.75 VATS therapeutic wedge 36 25 yes No no no 40 1.01 VATS diagnostic wedge 37 24 yes No mild no 61 2.33 VATS diagnostic wedge 38 18 yes No mild no   VATS therapeutic wedge 39 27 yes No mild no 18 0.45 VATS therapeutic wedge 40 25 yes No mild no 10 0.09 VATS therapeutic wedge   64 Patient Coiling procedure time Coiling procedure successful Hemo- thorax Pneumo- thorax Tube insertion OR time (min) Fluoroscopy time (min) Resection Technique 41  yes No mild no 55 41RLL/21RML VATS therapeutic Wedge 42  yes No mild no  0.6 VATS diagnostic wedge 43  yes No mild no   VATS diagnostic wedge 44  yes No no no 20 13 VATS therapeutic wedge 45  yes No no no 27 14 VATS diagnostic wedge 46  yes No no no   VATS Lingulectomy 47  yes No no no  1.26 VATS therapeutic wedge 48  yes No mild no 33 21 VATS therapeutic wedge 49  yes No no no 17 30 VATS diagnostic wedge 50  yes No no no   VATS diagnostic wedge      65 Table 6: Pathology of 55 resected nodules in 50 patients Pathology of resected nodules Number  N=55 Primary Lung Cancer   Histology Adenocarcinoma Squamous cell cancer   Stage T1aN0 T1aN1 T1bN0 T2aN0 T3N0   15  12 3    14 0 0 1 0 Metastasis  Colorectal  Breast  Urogenital   Sarcoma  Melanoma  Lymphoma  Thyroid  Gastroesophegeal  Leukemia  Chordoma  Tongue squamous cell carcinoma   28 10 0 6 5 3 0 2 1 0 1 0 Benign  Granuloma  Hamartoma  Hyperplasia  12 5 2 5      66 Table 7: Details of patients with multiple nodules resected Patient Primary extra-thoracic tumor Number of resected nodules Location of resected nodules Pathology of resected nodules 1 Breast cancer 2 1-RUL  2-RLL 1-Benign 2-Primary lung adenocarcinoma 2 Leiomyo-sarcoma 2 1-RUL 2-RLL Metastasis (both) 3 Melanoma 2 1-RLL 2-RLL Metastasis (both) 4 Thyroid follicular cell cancer 2 1-RUL 2-RLL Metastasis (both) 5 Tongue invasive squemous cell carcinoma 2 1-RML 2-RLL Benign Hyperplasia (both)            67 Table 8: Histology of previous extra-thoracic primary cancer and its relation to pathology of resected nodules  Primary Cancer Histology Number  of Patients Metastasis Primary Lung Cancer Benign Colorectal  16 10 (62.5%) 3 (18.75%) 3 (18.75%) Breast 8 0 (0%) 5 (62.5%) 3 (37.5%) Melanoma 3 2 (66.66%) 1 (33.33%) 0 (0%) Sarcoma 5 4 (80%) 0 (0%) 1 (20%) Lymphoma 3 0 (0%) 3 (100%) 0 (0%) Urogenital (Renal, Prostate, Cervical, Bladder) 7 6 (85.71%) 1 (14.28%) 0 (0%) Gastroesophageal carcinoma 2 1 (50%) 1 (50%) 0 (0%) Thyroid 3 1 (33.33%) 1 (33.33%) 1 (33.33%) Chordoma 1 1 (100%) 0 (0%) 0 (0%) Leukemia 1 0 (0%) 0 (0%) 1 (100%) Tongue invasive squemous cell carcinoma 1 0 (0%) 0 (0%) 1 (100%)    68 Table 9: Pathology of resected nodules and its relation to location of nodules Pathology of Resected Nodules  Total Number of Nodules RUL/LUL RML/Lingula RLL/LLL Primary lung cancer 16 9 (56.25%) 0 (0%) 7 (43.75%) Metastasis 28 9 (32.14%) 3 (10.71%) 16 (57.14%) Benign lesions 12 4 (33.33%) 3 (25%) 5 (41.66%)   Table 10: Pathology of resected nodules and its relation to patients’ smoking history Pathology of Resected Nodules Total number of Patients Smokers Non-smokers Primary Lung Cancer 15  11 (73.33%) 4 (26.66%) Metastasis 25  9 (36%) 16 (64%) Benign lesion 10  2 (20%) 8 (80%)       69 Table 11: Follow up status for patients who had metastatic nodules “therapeutic resection” and patients with primary lung cancer “Diagnostic + Therapeutic Resection”   Follow up Status Post Resection Primary Lung Cancer N=15 Metastasis N=18 Follow up time (months) Mean 35.9 / SD 27 Median 29, range (5-97) Mean 34.1 / SD 25.6 Median 24.5, range (6-99) Alive during follow up period All All No Evidence of Disease 9/13 11/18 Recurrence at staple Line 0/13 0/18 Recurrence same lobe not at staple line 0/13 0/18 Recurrence different lobe/same side 0/13 1/18 Recurrence different lobe/opposite side 0/13 1/18 Distant Metastasis 1/13 ( from primary extra-thoracic cancer “melanoma”) 3/18 New Bilateral Lung Nodules Recurrence and Distant Recurrence 0 2/18 New primary lung cancer  1/13 0/18 New primary extra-thoracic 1/13 0/18 New primary lung cancer and new extra-thoracic cancer 1/13 0/18 No follow up 2/15 0/18   70 Table 12: Univariate analysis of patients and nodules characteristics in relation to final pathology of resected nodules “Metastasis” Total number of patients: 50; Yes ML=25                    Independent Variables  Odds Ratio  95% CI   P-value  AGE  **   <60       >=60   0.29  0.09-0.97  0.045 GENDER  **     Male           Female  0.61  0.19-1.89  0.39 SMOKING **       No            Yes  0.51  0.17-1.61  0.25 NODULE TYPE **        Single            Multiple   1.18   0.37-3.71   0.77 NODULES LOCATION **    Other Lobes        Upper Lobes      0.183   0.05-0.62  0.006 NODULES LOCATION **   Other Lobes       Lower Lobes       2.30   0.73-7.27   0.15 TIME Years  **    < 2yrs          >=2yrs  0.52  0.16-1.71  0.28   71 Table 13: Risk factors for Metastatic Lesions (n=25), as identified by multivariate logistic regression  Total number of patients in the analysis = 49                OR: odds ratio CI: confidence interval **: baseline Constant = -4.249 p=0.021   Independent Variables  Odds Ratio  95% CI   p-values AGE             <60  **      >=60   10.98   1.62 - 74.58   0.014 GENDER                Male  **         Female  2.50.  0.46 -  13.48   0.285 SMOKING   **            No                  Yes  1.36   0.28 - 6.64   0.704 NODULE TYPE   **         Single               Multiple   4.67    0.87 - 25.12    0.073 NODULE LOCATION         Other Lobes **    Upper Lobes       19.14     1.98 - 184.97   0.011 NODULE LOCATION         Other Lobes **    Lower Lobes       1.55     0.17 - 14.12   0.699 TIME Years                   < 2yrs   **            >=2yrs     1.75     0.40 - 7.65   0.459   72 Table 14: Univariate analysis of patients and nodules characteristics in relation to final pathology of resected nodules “Primary Lung Cancer” Total number of patients: 50; Yes Primary Lung Cancer =15   Independent Variables  Odds Ratio  95% CI   P-value AGE  **   <60       >=60   3.36  0.81-14.07  0.096 GENDER  **        Male           Female  1.125  0.33-3.85  0.85 SMOKING **       No          Yes  6.00  1.56-23.11  0.009 NODULES TYPE **          Single            Multiple   1.33   0.37-4.74   0.66 NODULES LOCATION **    Other Lobes        Upper Lobes      3.00   0.84-10.67  0.09 NODULES LOCATION **   Other Lobes       Lower Lobes       0.59   0.17-2.09   0.42 TIME Years  **    < 2yrs          >=2yrs  1.67  0.43-6.38  0.46 For all Chi square tests the Yates Corrected (Continuity Correction) statistic is reported  – Since Minimum   Expected Counts are < 10 and >= 5     73 Table 15: Risk factors for primary lung cancer (n=15), as identified by multivariate logistic regression  Total number of patients in the analysis = 49                OR: odds ratio      CI: confidence interval **: baseline          Constant = -3.758 p=0.011     Independent Variables  OR   95% CI  p-values AGE **     <60       >=60   2.01    0.29 - 13.93  0.482 GENDER     **   Male           Female  1.00    0.20 - 5.13  0.998 SMOKING    **    No          Yes  6.16    1.19 - 31.84  0.030 NODULE TYPE            Single     **   Multiple   1.56     0.28 - 8.63   0.608 NODULE LOCATION  **  Other Lobes        Upper Lobes       3.82     0.33 - 44.87   0.286 NODULE LOCATION        Other Lobes  **   Lower Lobes       1.09     0.09 - 13.65   0.947  TIME Years   **   < 2yrs          >=2yrs  1.74   0.34 - 8.95   0.507   74 Table 16: Risk factors for pathology {benign (n=11)}, as identified by multivariate logistic regression  Total number of patients in the analysis = 49                 OR: odds ratio CI: Confidence Interval  **: baseline Constant = -9.776 p=0.004   Independent Variables  Odds Ratio  95% CI   p-values AGE **     <60       >=60   28.94    1.40 - 598.61  0.029 GENDER     **   Male           Female  9.96     0.75 - 131.55  0.081 SMOKING               No     **      Yes  15.77    1.56 – 159.73  0.020  NODULE TYPE            Single     **   Multiple   6.83     0.76 - 61.031   0.086  NODULE LOCATION  **  Other Lobes        Upper Lobes       24.11     1.61 - 360.82   0.021 NODULE LOCATION  ** Other Lobes       Lower Lobes      2.14   0.19 - 23.79   0.535   TIME Years   **   < 2yrs          >=2yrs  1.22    0.21 - 7.10  0.822    75 Table 17: Compare distributions: Metastasis vs. primary lung cancer + benign pathology  Diagnosis * Outcome Crosstabulation    Outcome YES NO Diagnosis Metastatic Lesions Count % within Diagnosis % within Outcome 25 50.0% 49.0% 25 50.0% 25.3%  Primary Lung  Cancer+Path.Benign Count % within Diagnosis % within Outcome 26 26.0% 51.0% 74 74.0% 74.7%  Risk Estimate  Odds Ratio  P-Value 95% Confidence Interval Lower Upper 2.846 .003  1.396  5.801         76 Table 18: Compare distributions: metastasis vs primary lung cancer vs benign lesions Diagnosis * Outcome Crosstabulation    Outcome YES NO Diagnosis Metastatic Lesions Count % within Diagnosis % within Outcome 25 50.0% 49.0% 25 50.0% 25.3% Primary Lung Cancer Count % within Diagnosis % within Outcome 15 30.0% 29.4% 35 70.0% 35.4% Pathology: Benign Count % within Diagnosis % within Outcome 11 22.0% 21.6% 39 78.0% 39.4%   Chi-Square Tests (P-Value)  Value df Asymp. Sig. (2sided) Pearson Chi-Square Likelihood Ratio 9.269a 9.219 2 2 .010 .010 a. 0 cells (.0%) have expected count less than 5. The minimum expected count is 17.00.   77 Table 19: Univariate logistic regression analysis of primary extra-thoracic tumor and metastasis   Variable Odds Ratio P-Value 95% CI Primary Extra-thoracic Tumors (Urogenital cancer* + Colorectal cancer + Sarcoma + Melanoma)  11  0.001  2.58-46.78 *Urogenital tumors = renal cancer, bladder cancer, prostate cancer and cervical cancer.   Table 20: Compare distributions metastasis vs. primary lung cancer Diagnosis * Outcome Crosstabulation    Outcome YES NO Diagnosis Metastatic Lesions Count % within Diagnosis % within Outcome 25 50.0% 62.5% 25 50.0% 41.7% Primary Lung Cancer Count % within Diagnosis % within Outcome 15 30.0% 37.5% 35 70.0% 58.3%      78 Risk Estimate Odds Ratio P-Value 95% Confidence Interval Lower Upper 2.33 0.041  1.027  5.300    Table 21: Compare distributions metastasis vs. pathology: benign Diagnosis * Outcome Crosstabulation    Outcome YES NO Diagnosis Metastatic Lesions Count % within Diagnosis % within Outcome 25 50.0% 69.4% 25 50.0% 39.1% Pathology: Benign Count % within Diagnosis % within Outcome 11 22.0% 30.6% 39 78.0% 60.9%      79 Risk Estimate Odds Ratio P-Value 95% Confidence Interval Lower Upper 3.545 .004 1.487 8.454   Table 22: Compare distributions: metastasis + primary lung cancer vs. pathology: benign  Diagnosis * Outcome  Crosstabulation   Outcome YES NO Diagnosis Metastatic Lesions+Primary  Lung Cancer Count % within Diagnosis % within Outcome 40 40.0% 78.4% 60 60.0% 60.6% Pathology: Benign Count % within Diagnosis % within Outcome 11 22.0% 21.6% 39 78.0% 39.4%       80 Risk Estimate  Odds Ratio  P-Value 95% Confidence Interval Lower Upper 2.364 .028 1.084 5.154   Table 23: Frequency of solitary and multiple nodules stratified by pathology of resected specimen  Pathology of Resected Nodules Total number of Patients (n=50) Solitary Nodules (n=18) Multiple Nodules (n=32) Primary Lung Cancer 15 (30%) 5 (27.7%) 10 (31.25) Metastasis 25 (50%) 9 (50%) 16 (50%) Benign lesion 10 (20%) 4 (22.3%) 6 (18.75%)         81 Table 24: Frequency of solitary and multiple nodules stratified by histology of extra-thoracic malignancy   Histology of Primary Cancer Solitary Multiple Colorectal (n=16) 8 8 Breast (n=9) 3 6 Urogenital (n=9) 3 6 Sarcoma (n=5) 2 3 Lymphoma (n=3) 2 1 Melanoma (n=3) 0 3  Thyroid (n=3) 1 2 Gastro esophageal  (n=2)  0 2 Tongue squamous cell (n=1) 0 1 Chordoma (n=1) 0 1 Leukemia (n=1) 0 1           82 Table 25: Comparative analysis of the final diagnosis              Description Z P 2 P 1 Metastatic Lesions vs Primary Lung Cancer 2.309 .02 * .02 * Metastatic Lesions vs. Benign 3.582 .001 ** .001 ** Primary Lung Cancers vs Benign 1.123 NS NS Metastatic Lesions vs. Primary Lung Cancers + Benign .198 NS NS   83 FIGURES  FIGURE 1: Drawing illustrates 30 mm of the microcoil (arrow) ejected from the tip of the Chiba needle and assumes a tight coiled configuration (arrow head) approximately 5 mm deep to the nodule.         84 FIGURE 2: Drawing illustrates Chiba needle withdrawn to the pleural surface (arrow head) and remaining part of the microcoil ejected out of the needle (arrow). The microcoil forms a loop on the visceral pleural of the lung overlying the nodule.           85 FIGURE 3: Non-enhanced transverse chest CT scan shows complete ejection of the microcoil from the Chiba needle and successful localization of a nodule at the left lung apex (black arrow). The deep end of the microcoil is coiled into a ball adjacent to the nodule (white arrow) and the superficial end is coiled on the visceral pleural surface. No hemorrhage is noted in the normal lung tissue adjacent to the wire (arrow head).            86 FIGURE 4: Coronal view CT image shows a microcoil placed through a 10-mm-diameter solid nodule (straight arrow) in the left lower lobe of the lung. This 3-dimensional image assisted in placing a port for VATS resection based on the relation between the proximal end of the microcoil (curved arrow) and the overlying ribs.            87 FIGURE 5: Intra-operative thoracoscopic view showing superficial end of the microcoil lying on the visceral pleura of the lung.            88 FIGURE 6: Intraoperative fluoroscopic view showing both the superficial end of the microcoil on the lung surface and the deep end of the microcoil (attached to the nodule) in the lung parenchyma.         89 FIGURE 7: Intra-operative fluoroscopy image showing the microcoil within the lung parenchyma that was being excised by a GIA stapler. 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