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Bronchopleural fistula (BPF) remains a significant source of morbidity and mortality after right pneumonectomy (RPN). Postoperative mechanical ventilation represents a primary risk factor for BPF. We undertook an experiment to determine the influence of airway diameter on suture line tension during mechanical ventilation after RPN. RPN was performed in 6 fresh human adult cadavers. After initial standard bronchial stump closure (BSC), the airway suture lines were subjected to 5 cm H 2 O incremental increases in airway pressures beginning at 5-40 cm H 2 O. To minimize airway diameter, a carinal resection was then performed with trachea to left main bronchial anastomosis and the airway suture lines subjected to similar incremental airway pressures. Wall tension (N/m) at the suture lines was measured using piezoresistive sensors at each pressure point. As delivered airway pressure increased, there was a concomitant increase in wall tension after BSC and carinal resection. At every point of incremental positive pressure, wall tension was however significantly lower after carinal resection when compared to BSC (P < 0.05). Additionally the differences in airway tension became even more significant with higher delivered airway pressure (P < 0.001). Airway diverticulum after BSC leads to significantly increased tension on the bronchial closure with positive airway pressure as compared to a closure which minimize airway diameter after RPN. This supports the role of Laplacian Law where small increases in airway diameter result in significant increases on closure site tension. Techniques which reduce airway diameter at the airway closure will more reliably reduce the incidence of BPF following RPN., (Published by Elsevier Inc.)

Background: Esophagectomy is the mainstay treatment for early stage and locoregionally advanced esophageal cancer. Anastomotic leaks following esophagectomy are associated with numerous detrimental sequelae. The management of anastomotic leaks has evolved over time. The present study is a single-institution experience of esophageal leak management over an 11-year period, in order to identify when these can be managed nonoperatively., Methods: All patients undergoing esophagectomy with gastric reconstruction at our institution between 2004 and 2014 were identified. Preoperative patient characteristics and perioperative factors were reviewed. Failure of initial leak treatment was defined as need for escalation of therapy. Length of stay (LOS) and postoperative mortality were the primary outcomes. Follow-up was obtained through institutional medical records and the Social Security Death Index., Results: Sixty-one of 692 (8.8%) patients developed an anastomotic leak. Forty-six patients (75.4%) first underwent observation, which was successful in 35 patients. Predictors of successful observation included higher preoperative albumin (P=0.02), leak diagnosed by esophagram (P=0.004), and contained leaks (P=0.01). Successful observation was associated with shorter LOS (P=0.001). Predictors of mortality included lower preoperative serum albumin (P=0.01) and induction therapy (P=0.03). Thirty and 90-day mortality among patients who developed an anastomotic leak were 9.8% and 16.7%, respectively., Conclusions: Over half of anastomotic leaks were managed successfully with observation alone and did not require additional interventions. We have identified factors that may predict successful therapy with observation in these patients. Further research is warranted to determine more timely interventions for patients likely to fail conservative management., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Objectives: Anastomotic complications represent a significant source of morbidity and occasionally mortality after esophagectomy. Since 2009, we have used a novel "side-to-side: staple line-on-staple line" (STS) technique for intrathoracic esophagogastric anastomoses, designed to create a wide-diameter esophagogastric anastomosis while preserving stomach conduit blood supply. In this study, we describe the technique and review outcomes of our institution's initial 6-year experience., Methods: An institutional database query identified 278 consecutive patients who underwent Ivor Lewis esophagogastrectomy using an STS esophagogastric anastomotic technique from 2009 through 2015. A retrospective review was conducted to assess outcomes with a focus on anastomotic complications., Results: There were a total of 8 (2.9%) anastomotic leaks in patients who underwent STS esophagogastric anastomosis, 3 of which were grade I/II leaks and required no intervention. There was a leak rate of 6.3% (2 of 32) after esophagectomy for benign conditions (both leaks occurring in 8 total patients (25%) who received surgery for end-stage achalasia) compared with a 2.4% leak rate (6 of 246) in whom esophagectomy was performed for malignancy (P = .22). Fourteen patients (5.0%) required a median of 2 dilatations for anastomotic stricture after STS anastomosis. Supplemental jejunostomy feedings were required in only 11.1% of these patients after hospital discharge., Conclusions: We believe this novel STS technique provides excellent results with respect to the incidence of intrathoracic esophagogastric anastomotic leak and stricture after esophagectomy. Additionally this technique has significantly reduced the need for enteral feeding after hospital discharge., (Copyright © 2018 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Background and aims  The impact of the advent of an institutional endoscopic eradication therapy (EET) program on surgical practice for Barrett's esophagus (BE)-associated high grade dysplasia (HGD) or suspected T1a esophageal adenocarcinoma (EAC) is unknown. The aims of this study are to evaluate the different endoscopic modalities used during development of our EET program and factors associated with the use of EET or surgery for these patients after its development. Methods  Patients who underwent primary endoscopic or surgical treatment for BE-HGD or early EAC at our hospital between January 1992 and December 2014 were retrospectively identified. They were categorized by their initial modality of treatment during the first year, and the impact over time for choice of therapy was assessed by multivariable logistic regression. Results  We identified 386 patients and 80 patients who underwent EET and surgery, respectively. EET included single modality therapy in 254 (66 %) patients and multimodal therapy in 132 (34 %) patients. Multivariable logistic regression showed that, for each subsequent study year, EET was more likely to be performed in patients who were older ( P  = 0.0009), with shorter BE lengths ( P  < 0.0001), and with a pretreatment diagnosis of HGD ( P  = 0.0054) compared to surgical patients. The diagnosis of EAC did not increase the utilization of EET compared to surgery as time progressed ( P  = 0.8165). Conclusion  The introduction of an EET program at our hospital increased the odds of utilizing EET versus surgery over time for initial treatment of patients who were older, had shorter BE lengths or the diagnosis of BE-HGD, but not in patients with EAC.

Background: The posterior mediastinum is the preferred location for reconstruction following esophagectomy. Occasionally alternative routes are required. We examined patient outcomes of esophageal reconstruction in order to determine whether substernal reconstruction (SR) is an equivalent alternative to orthotopic placement., Methods: Following IRB approval, we performed a retrospective review of all patients who underwent an esophagectomy from 1988-2014. Only patients reconstructed with a gastric conduit and cervical anastomosis by either substernal or posterior mediastinal (PM) routes were included in the study. Endpoints assessed included anastomotic leak rate, post-operative complications, reoperation, hospital length of stay, and 30- and 90-day mortality., Results: Thirty-three patients underwent SR and 182 had a PM gastric conduit with cervical anastomosis. The SR pathology was predominantly benign while PM was mostly malignant. Sixteen SR patients had a delayed reconstruction after prior diversion. Mean hospital LOS was longer in the SR group (P<0.001). There was no significant difference in 30- and 90-day mortality. PM patients had significantly fewer respiratory complications (P<0.04), reoperations (P<0.04), and transfusions (P<0.0001) and a trend towards fewer anastomotic leaks (17.1% vs. 30.3%; P<0.09)., Conclusions: This single institution experience demonstrated no significant difference in mortality between substernal and PM reconstruction following esophagectomy. However, SR was associated with significantly increased LOS and morbidity, including a trend toward increased anastomotic leaks. SR reconstruction should probably be considered an option of last resort., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Background: Level 1 programs have improved outcomes by expediting the multidisciplinary care of critically ill patients. We established a novel level 1 program for the management of esophageal emergencies., Methods: After institutional review board approval, we performed a retrospective analysis of patients referred to our level 1 esophageal emergency program from April 2013 through November 2015. A historical comparison group of patients treated for the same diagnosis in the previous 2 years was used., Results: Eighty patients were referred and transported an average distance of 56 miles (range, 1-163 miles). Median time from referral to arrival was 2.4 hours (range, 0.4-12.9 hours). Referrals included 6 (7%) patients with esophageal obstruction and 71 (89%) patients with suspected esophageal perforation. Of the patients with suspected esophageal perforation, causes included iatrogenic (n = 26), Boerhaave's syndrome (n = 32), and other (n = 13). Forty-six percent (n = 33) of patients were referred because of pneumomediastinum, but perforation could not be subsequently demonstrated. Initial management of patients with documented esophageal perforation included operative treatment (n = 25), endoscopic intervention (n = 8), and supportive care (n = 5). Retrospective analysis demonstrated a statistically significant difference in mean Pittsburgh severity index score (PSS) between esophageal perforation treatment groups (p < 0.01). In patients with confirmed perforations, there were 3 (8%) mortalities within 30 days. More patients in the esophageal level 1 program were transferred to our institution in less than 24 hours after diagnosis than in the historical comparison group (p < 0.01)., Conclusions: Development of an esophageal emergency referral program has facilitated multidisciplinary care at a high-volume institution, and early outcomes appear favorable., (Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Management of clinical T2N0M0 (cT2N0M0) esophageal cancer remains controversial. We reviewed our institutional experience over 21 years (1990-2011) to determine clinical staging accuracy, optimal treatment approaches, and factors predictive of survival in this patient population., Methods: Patients with cT2N0M0 esophageal cancer determined by endoscopic ultrasound (EUS) were identified through a prospectively collected database. Demographics, perioperative data, and outcomes were examined. Cox regression model and Kaplan-Meier plots were used for statistical survival analysis., Results: A total of 731 patients underwent esophagectomy, of whom 68 cT2N0M0 patients (9 %) were identified. Fifty-seven patients (84 %) had adenocarcinoma. Thirty-three patients (48.5 %) were treated with neoadjuvant chemoradiation followed by surgery, and 35 underwent surgical resection alone. All resections except one included a transthoracic approach with two-field lymph node dissection. Thirty-day operative mortality was 2.9 %. Only 3 patients (8.5 %) who underwent surgery alone had T2N0M0 disease identified by pathology: the disease of 15 (42.8 %) was found to be overstaged and 17 (48.5 %) understaged after surgery. Understaging was more common in poorly differentiated tumors (p = 0.03). Nine patients (27.2 %) had complete pathologic response after chemoradiotherapy. Absence of lymph node metastases (pN0) was significantly more frequent in the neoadjuvant group (29 of 33 vs. 21 of 35, p = 0.01). Median follow-up was 44.2 months. Overall 5-year survival was 50.8 %. On multivariate analysis, adenocarcinoma (p = 0.001) and pN0 after resection (p = 0.01) were significant predictors of survival., Conclusions: EUS was inaccurate in staging cT2N0M0 esophageal cancer in this study. Poorly differentiated tumors were more frequently understaged. Adenocarcinoma and absence of lymph node metastases (pN0) were independently predictive of long-term survival. pN0 status was significantly more common in patients undergoing neoadjuvant therapy, but long-term survival was not affected by neoadjuvant therapy. A strategy of neoadjuvant therapy followed by resection may be optimal in this group, especially in patients with disease likely to be understaged.

Background: Since 2001 we have utilized a novel surgical approach for Pancoast tumors in which lobectomy and mediastinal lymph node dissection are performed directly though the chest wall defect. The defect is then patched at the completion of the procedure ("cut-in patch-out") thereby avoiding a separate thoracotomy with rib spreading. We undertook a study to compare outcomes of this novel "cut-in patch-out" technique with traditional thoracotomy for patients with Pancoast tumors., Methods: We retrospectively identified 41 patients undergoing surgical resection of Pancoast tumors requiring en-bloc removal of at least 3 ribs at our institution from 1999 to 2012. Surgery was accomplished by either a "cut-in patch-out" technique (n = 25) or traditional posterolateral thoracotomy and separate chest wall resection (n = 16). Multiple variables including patient demographics, neoadjuvant therapy, extent of resection, and pathology were analyzed with respect to outcomes from morbidity, narcotic use, and oncologic perspectives., Results: Baseline demographics, neoadjuvant therapy, and perioperative factors including extent of surgery, complete resections (R0), nodal status and lymph node number, morbidity, and mortality were similar between the two groups. The mean duration of out-patient narcotic use was significantly lower in the "cut-in patch-out" group compared to the thoracotomy group (80.6 days ± 62.4 vs. 158.2 days ± 119.2, p < 0.01). Using multivariate regression analysis, the traditional thoracotomy technique (OR 7.72; p = 0.01) was independently associated with prolonged oral narcotic requirements (>100 days). Additionally, five year survival for the "cut-in patch-out" group was 48% versus the traditional group at 12.5% (p = 0.04)., Conclusions: Compared with a traditional thoracotomy and separate chest wall resection approach for P-NSCLC, a "cut-in patch-out" technique offers an alternative approach that appears to have at least oncologic equivalence while decreasing pain. We have more recently adapted this technique to select patients with pulmonary neoplasms involving chest wall invasion and believe further investigation is warranted.

Background: When the stomach is not available, long-segment esophageal reconstruction remains a surgical challenge. Since 2005, we have used a "supercharged" isoperistaltic colon interposition conduit for long-segment esophageal reconstruction that reestablishes a dual blood supply., Methods: An institutional database search of 449 patients who underwent esophagectomy from 2005 to 2012 identified 11 consecutive patients who underwent long-segment esophageal reconstruction using an isoperistaltic supercharged right (n=9) or left (n=2) colon conduit. All conduits were routed through the anterior mediastinum, maintaining the middle colic (right) or ascending left colic vessels (left) in situ, with reimplantation of the ileocolic vessels (right) or middle colic vessels (left) into the left internal thoracic artery and brachiocephalic vein to improve distal conduit blood flow., Results: Patients were a mean age of 64 years (range, 47 to 76 years). Seven patients had a history of malignancy and 4 had a benign process. The stomach was unavailable for reconstruction due to prior gastric operations (n=9) or neoplastic involvement (n=2). All reimplanted vessels demonstrated excellent flow by Doppler evaluation. Esophagocolonic healing was successful in all patients; however, 1 patient required a temporary stent., Conclusions: Supercharged isoperistaltic colon interposition appears to be an excellent option for the challenging situation where long-segment esophageal reconstruction is needed and the stomach is not available. The additional effort required to reestablish a dual blood supply appears justified to minimize ischemic-related morbidity. Unlike long-segment small bowel "supercharged" techniques, adequate blood supply to the distal conduit may still be present in case thrombosis of the reimplanted vessels occurs., (Copyright © 2013 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objective: Criteria for the growing teratoma syndrome in patients with primary mediastinal nonseminomatous germ cell tumors have not been well established according to current practice., Methods: An institutional database identified 188 patients who underwent postchemotherapy surgery for primary mediastinal nonseminomatous germ cell tumors from 1981 to 2009. We reviewed the subset of patients who underwent urgent surgery for tumor growth resulting in cardiopulmonary deterioration secondary to mediastinal compression precluding safe completion of 4 cisplatin-based chemotherapy cycles with rapidly declining serum tumor markers., Results: Five men (2.6%) with an average age of 25.8 years were identified. All patients initially presented with a large symptomatic anterior mediastinal mass and elevated serum tumor markers. Patients received an average of 2.4 chemotherapy cycles of a scheduled 4 courses before cardiopulmonary deterioration. Pathology of the resected specimens demonstrated mature teratoma in all patients; however, it was admixed in 4 patients with foci of immaturity (n=1), malignant transformation of teratoma to sarcoma (n=2), and nonseminomatous germ cell tumor (n=2). There was 1 operative death. Three of the 4 operative survivors subsequently completed a total of 4 cycles of chemotherapy after recovery. Two patients are alive and well after an average of 14 years. Two patients died of metastatic disease., Conclusions: The growing teratoma syndrome should be defined not only as a growing mediastinal mass but also with secondary cardiopulmonary deterioration precluding safe completion of planned chemotherapy in the presence of declining serum tumor markers. Prompt recognition of this syndrome, discontinuation of chemotherapy, and surgical intervention can result in cure., (Copyright © 2012 The American Association for Thoracic Surgery. All rights reserved.)

Background: Thymic carcinoma is a rare malignancy with little information regarding outcomes after therapy with curative intent. We undertook a retrospective analysis of all patients who underwent resection of thymic carcinoma at 2 hospitals., Methods: From 1990 to 2011, 16 patients (9 men, 7 women) underwent surgical resection of thymic carcinoma at a mean age of 52 years. Patient demographics, extent of surgical resection, and outcomes were compiled., Results: The distribution of Masaoka stages at presentation was I in 3 (19%), II in 4 (25%), III in 8 (50%), and IV in 1 (6%). Neoadjuvant chemotherapy was administered to 6 patients (38%) whose tumors were deemed to be more locally invasive. Surgical resection included en bloc extrapleural pneumonectomy in 1, lobectomy in 2, and superior vena cava resection and reconstruction in 4. There were no perioperative deaths. Complete resection was achieved in 14 (88%), and of these patients, only 1 experienced local recurrence. At last follow-up, 10 patients were alive and well, 1 patient was alive with disease, and 5 patients had died. Mean survival was 4.2 years., Conclusions: Although considered to have greater malignant potential, long-term survival can be achieved in patients with thymic carcinoma who are amenable to surgical therapy. With increased use of computed tomography imaging, patients with early-stage disease are being identified more frequently, and complete surgical resection appears to have favorable cure rates in these patients. Select patients with locally advanced disease can experience long-term survival with a multimodality approach., (Copyright © 2012 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Purpose: Bronchopleural fistula (BPF) remains an important source of morbidity and mortality after right pneumonectomy. We reviewed our 18-year institutional experience with right pneumonectomy to identify risks factors for BPF., Methods: From 1992 to 2010, a total of 145 patients who underwent right pneumonectomy were identified from an institutional database. Median age was 56 years. Most patients (66.2%) underwent surgery for non-small cell lung cancer. Sixty-seven patients (46.2%) received either chemotherapy or radiotherapy before surgery. Medical records were reviewed for 14 variables potentially predictive for BPF, including two airway closure techniques (standard bronchial closure and carinal closure). Variables predictive of BPF by univariate analysis were entered into a logistic regression model., Results: The overall mortality rate was 13.1% (n=19), with 15.9 and 10.5% mortality in the bronchial closure and carinal closure groups, respectively (P=0.33). The overall BPF rate was 7.6% (n=11), with a 3.9% (3 of 76) rate in the carinal closure group compared to 11.6% (8 of 69) in the bronchial closure group (P=0.08). Seven of eight bronchial closure patients who developed BPF required operative repair. Only one of three patients who developed BPF after carinal closure did not spontaneously heal after open drainage. Multivariate analysis identified preoperative radiation dose (P=0.042) and bronchial closure (P=0.041) as independent risk factors for BPF, while the length of postoperative ventilation before development of BPF approached significance (P=0.057)., Conclusions: In our experience, higher preoperative radiation doses are a risk factor for BPF after right pneumonectomy, while carinal closure exerts a protective effect.

Purpose: This study was performed to discover prognostic genomic markers associated with postoperative outcome of stage I to III non-small cell lung cancer (NSCLC) that are reproducible between geographically distant and demographically distinct patient populations., Experimental Design: American patients (n = 27) were stratified on the basis of recurrence and microarray profiling of their tumors was performed to derive a training set of 44 genes. A larger Korean patient validation cohort (n = 138) was also stratified by recurrence and screened for these genes. Four reproducible genes were identified and used to construct genomic and clinicogenomic Cox models for both cohorts., Results: Four genomic markers, DBN1 (drebrin 1), CACNB3 (calcium channel beta 3), FLAD1 (PP591; flavin adenine dinucleotide synthetase), and CCND2 (cyclin D2), exhibited highly significant differential expression in recurrent tumors in the training set (P < 0.001). In the validation set, DBN1, FLAD1 (PP591), and CACNB3 were significant by Cox univariate analysis (P ≤ 0.035), whereas only DBN1 was significant by multivariate analysis. Genomic and clinicogenomic models for recurrence-free survival (RFS) were equally effective for risk stratification of stage I to II or I to III patients (all models P < 0.0001). For stage I to II or I to III patients, 5-year RFS of the low- and high-risk patients was approximately 70% versus 30% for both models. The genomic model for overall survival of stage I to III patients was improved by addition of pT and pN stage (P < 0.0013 vs. 0.010)., Conclusion: A 4-gene prognostic model incorporating the multivariate marker DBN1 exhibits potential clinical utility for risk stratification of stage I to III NSCLC patients., (©2011 AACR.)

Background: Since the advent of cisplatin-based chemotherapy, nonseminomatous germ cell tumors (NSGCT) have been considered one of the most curable solid neoplasms and a model for multimodality cancer therapy. We undertook an institutional review of testicular NSGCT patients who underwent operations to remove lung or mediastinal metastases after chemotherapy in the cisplatin era to determine outcomes., Methods: From 1980 to 2006, 431 patients underwent 640 postchemotherapy surgical procedures to remove lung (n = 159, 36.8%), mediastinal (n = 136, 31.6%), or both lung and mediastinal (n = 136, 31.6%) metastases within 2 years of chemotherapy. Multiple variables potentially predictive of survival were analyzed., Results: The overall median survival was 23.4 years, with 295 (68%) patients alive and well after an average follow-up of 5.6 years. There was no survival difference in patients who underwent removal of lung or mediastinal metastases. Pathologic categories of resected residual disease were necrosis (21.5%), teratoma (52.7%), persistent NSGCT (15.0%), and degenerative non-germ cell cancer (10.1%). Multivariable analysis identified older age at time of diagnosis (p = 0.001), non-germ cell cancer in testes specimen (p = 0.004), and pathology of residual disease (p < 0.001) as significantly predictive of survival., Conclusions: Patients who undergo resection of residual lung or mediastinal disease for metastatic testicular NSGCT as a planned approach after cisplatin-based chemotherapy have overall excellent long-term survival. Survival is equivalent comparing hematogenous and lymphatic routes of metastases but depends on the pathology of the resected disease. These results justify an aggressive surgical approach, particularly to remove residual teratoma in the lung or mediastinum after chemotherapy, including multiple surgical procedures if necessary., (Copyright © 2011 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Resection and reconstruction of the superior vena cava (SVC) is occasionally required in the surgical treatment of intrathoracic neoplasms or symptomatic occlusion secondary to benign causes. We reviewed our institutional experience with SVC reconstruction using externally stented-polytetrafluoroethylene vascular prostheses., Methods: From 1991 to 2009, medical records of 38 patients who underwent SVC resection and reconstruction with externally stented-polytetrafluoroethylene vascular prostheses were reviewed. Indications for surgery were malignancy in 34 (89%) patients (germ cell, 13; thymoma, 10; lung cancer, 9; sarcoma, 2) and benign symptomatic occlusion in 4 (11%) patients., Results: Eighteen patients (47%) underwent right innominate vein to SVC interposition graft reconstruction, which became the favored approach during the study interval when resection of the innominate confluence was necessary. Eight patients (21%) had left innominate vein to SVC interposition grafts, earlier in the series or when the right innominate vein was unavailable. Nine patients (24%) received graft interposition of the proximal to distal SVC. The remaining 3 patients had a Y reconstruction. There were 2 perioperative mortalities. Follow-up averaged 15 months (range, 1 to 113 months), including 11 (29%) patients who died of disease. All patients demonstrated minimal to no brachiocephalic swelling at last follow-up. Twenty (53%) patients underwent imaging after an average of 24 months (range, 1 to 113 months) with only two grafts demonstrating complete occlusion., Conclusions: Although several SVC reconstructive techniques have been described, externally stented-polytetrafluoroethylene vascular prostheses are readily available for off-the-shelf use. In our experience, patency rates are high, and patients who do demonstrate graft thrombosis have minimal to no symptoms., (Copyright 2010 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objective: Atrial fibrillation is common after esophagectomy. The objective of this study was to determine the efficacy and safety of amiodarone for prevention of atrial fibrillation after transthoracic esophagectomy., Methods: Eighty patients undergoing transthoracic esophagectomy were randomly, prospectively assigned to receive amiodarone (n = 40) or no prophylaxis (control group, n = 40). Amiodarone-treated patients received the drug by continuous infusion, initiated at the time of induction of anesthesia, at a rate of 0.73 mg/min (43.75 mg/h), and continued for 96 hours (total dose 4200 mg). The primary end point was atrial fibrillation requiring treatment. Secondary end points included any atrial fibrillation lasting longer than 30 seconds and postoperative hospital and intensive care unit stays., Results: There were no significant differences between the amiodarone and control groups in demographic characteristics, comorbid conditions, or preoperative or postoperative use of beta-blockers or calcium-channel blockers. The incidence of atrial fibrillation requiring treatment was lower in the amiodarone group than in the control group (15% vs 40%, P = .02, relative risk reduction 62.5%). There were no significant differences between the amiodarone and control groups in median hospital stay (11 days vs 12 days, P = .31) or median intensive care unit stay (68 hours vs 77 hours, p = .097). There were no significant difference between the groups in the incidences of adverse effects., Conclusions: Amiodarone prophylaxis significantly reduced the incidence of atrial fibrillation after transthoracic esophagectomy., (2010 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Background: We undertook a 20-year retrospective institutional study to investigate prognostic indicators after surgery for thymoma., Methods: From 1989 to 2009, 83 patients underwent surgical resection of thymoma or thymic carcinoma at our institution. Twelve of these patients were determined to have either World Health Organization type C disease or Masaoka stage IV-B disease and were excluded from analysis. The remaining 71 patients were reviewed., Results: The majority of patients in this series were female 64.7% (n=46) with an overall average age of 51.0 years. The distribution of Masaoka stages I, II, III, and IV-A was 40.8% (n=29), 19.7% (n=14), 18.3% (n=13), and 21.1% (n=15), respectively. Thirteen of the 28 (46.2%) patients who presented with stage III or IV-A disease received preoperative chemotherapy. After a mean follow-up of 66 months (range, 6 to 241 months), 54 (75.3%) patients are alive and well while six are alive with disease. Eleven (16.0%) patients have died, but only 3 (4.3%) of these patients died of thymoma. The overall disease-specific survival was 97% and 89% at 5 and 10 years. Of the variables analyzed, only age was predictive of overall survival (p=0.03). Masaoka stages I to III as compared with stage IV-A was significantly predictive of disease-free survival (p<0.01)., Conclusions: Long-term disease-specific survival can be expected not only after surgery for early stage thymoma but also after surgery for advanced disease, including patients with pleural metastases. However, patients who undergo surgery for stage IV-A disease have reduced disease-free survival. Late mortality due to secondary cancers and associated immunologic disorders was more frequent than mortality from thymoma in this series., (Copyright (c) 2010 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Atrial fibrillation (AF) occurs commonly after anatomic pulmonary resection. In this study, the efficacy of amiodarone for prevention of post-pulmonary resection AF was investigated., Methods: One hundred thirty patients undergoing lobectomy, bilobectomy, or pneumonectomy were randomly assigned prospectively to receive amiodarone (n = 65) or no prophylaxis (control group, n = 65). The amiodarone group received 1,050 mg by continuous intravenous infusion over 24 hours, initiated at the time of anesthesia induction, followed by 400 mg orally twice daily until hospital discharge or for a maximum of 6 days. The primary endpoint was AF requiring treatment during hospitalization. Secondary endpoints included postoperative length of hospital and intensive care unit stays., Results: There were no significant differences between the amiodarone and control groups in demographics, comorbid conditions, extent of pulmonary resection, or preoperative or postoperative use of beta-blockers or calcium-channel blockers. The incidence of AF was lower in the amiodarone group than in the control group (13.8% versus 32.3%, p = 0.02; relative risk reduction = 57%). There was no difference between the amiodarone and control groups in median length of hospital stay (7 versus 8 days, p = 0.79), but median length of intensive care unit stay was shorter in the amiodarone group (46 versus 84 hours, p = 0.03). There was no significant difference between the amiodarone and control groups in the incidence of pulmonary complications or other adverse effects., Conclusions: Amiodarone prophylaxis significantly reduces the incidence of AF after anatomic pulmonary resection, and is associated with a significant reduction in length of intensive care unit stay.

Background: Differential gene expression offers an attractive means by which to study genes that may be involved in disease development and/or progression. We performed quantitative gene expression in various stages of esophageal adenocarcinoma, treated exclusively by surgery with complete 2-field lymphadenectomy, in an attempt to discern genes involved in disease progression as well as genes that may predict survival., Methods: Gene expression profiling was accomplished by cDNA-mediated annealing, selection, extension, and ligation (DASL) assay. RNA was extracted from 89 archived formalin-fixed, paraffin-embedded esophageal adenocarcinoma tissues. DASL assay was performed with the Sentrix Universal Array (Illumina Corp, San Diego, Calif) of 502 known cancer-related genes. Bioinformatics tools were used to determine significant differential gene expression in T1-2 versus T3-4 tumors and tumors without lymph node involvement (N0) versus tumors with lymph node involvement (N+). Gene expression was also correlated with overall survival., Results: Twenty-one genes were overexpressed in T1-2 compared with T3-4 tumors (false discovery rate of 0). Underexpression of 1 gene was seen in N+ compared with N0 tumors (false discovery rate of 0). For overall survival, underexpression of 9 genes correlated with long survival., Conclusions: Using differential gene expression of 502 known cancer genes, we identified genes that may be involved at various stages in the progression of esophageal adenocarcinoma. We also identified genes that may correlate with prolonged survival and, thus, may serve as prognostic markers. These findings may provide further insight into the mechanisms of development and/or progression of esophageal adenocarcinoma. Prospective studies are needed to verify the prognostic value of these genes.

Background: Bronchopleural fistula remains a significant source of morbidity and mortality after right pneumonectomy. We reviewed our initial experience with a novel "carinaplasty" airway closure technique aimed at reducing the risks of bronchopleural fistula., Methods: Since 2003, 51 consecutive patients who required right pneumonectomy at our institution underwent carinaplasty airway closure. Malignancy was the indication for pneumonectomy in all but 2 patients. Eighteen patients received preoperative radiation therapy, including 5 patients who received 6000 cGy or more. Postoperatively, 17 patients required mechanical ventilation for an average of 13 days (range, 3 to 42 days)., Results: Six operative deaths occurred, four (8.6%) of which were in the 46 patients who did not receive preoperative bleomycin. All deaths were secondary to respiratory failure. None of these patients demonstrated bronchopleural fistula despite mechanical ventilation for up to 30 days. In 2 patients, a small (< or = 2 mm) bronchopleural fistula developed at 3 and 4 months after operation, respectively. Both patients presented with minor symptoms and spontaneously healed within 1 month after open drainage., Conclusions: These data suggest that the carinaplasty airway closure may reduce the morbidity and mortality of bronchopleural fistula after right pneumonectomy. We speculate mechanisms include elimination of the bronchial stump diverticulum in combination with more submucosal blood supply at the suture line compared with the standard bronchial closures. We currently consider carinaplasty airway closure the technique of choice at our institution and plan continued evaluation.

Background: The treatment of primary mediastinal nonseminomatous germ cell tumors (PMNSGCT) with cisplatin-based chemotherapy, followed by surgical resection of residual disease, has been established. We reviewed our institution's 25-year experience in the cisplatin era to determine surgical risks and predictors of survival after surgery for PMNSGCT., Methods: A total of 158 patients (mean age, 29 +/- 8 years) who underwent postchemotherapy operations for PMNSGCT were reviewed and multiple variables analyzed., Results: Ten (6%) operative deaths occurred, nine of which were attributed to respiratory failure, and 26 (18%) patients experienced postoperative complications, including 9 with respiratory failure. None of 17 recent patients who received chemotherapy regimens that did not contain bleomycin experienced pulmonary complications (p = 0.12 vs patients who received bleomycin). Operative survivors were followed up a median of 34 months (range, 1 to 194 months). Multivariable analysis demonstrated that the postchemotherapy pathologic category of complete necrosis vs teratoma), persistent germ cell or nongerm cell cancer, and elevated serum tumor markers after operation were independently predictive of survival., Conclusions: Operative risks for PMNSGCT appear to be improved with the use of chemotherapy regimens that do not contain bleomycin. Patients pathologically demonstrating complete tumor necrosis in the residual mass after chemotherapy have excellent long-term survival, with decreasing survival after resection of teratoma and persistent germ cell or nongerm cell cancer. Patients pathologically demonstrating persistent germ cell or nongerm cell cancer have poor but possible long-term survival, which justifies an aggressive surgical approach in patients who are deemed operable.

Background: Atrial fibrillation occurs in up to 46% of patients following esophagectomy; amiodarone may be used for prophylaxis or treatment in these patients. There are few data regarding drug absorption following esophagectomy., Objective: The aim of this study was to determine serum amiodarone concentrations when the drug is administered into the stomach conduit following esophagectomy., Methods: Patients who underwent noncardiac thoracic surgery were enrolled in this prospective, controlled study. One group of patients underwent esophagectomy, and a second group of patients comprised a control group who underwent pulmonary resection (PR). A continuous IV amiodarone infusion (0.73 mg/min) was initiated at anesthesia induction and continued for 24 hours (total IV dose 1050 mg), followed by 400 mg via a nasogastric tube (in the esophagectomy group) or orally (in the PR group) every 12 hours for 6 days. Blood samples for determination of serum amiodarone concentrations were obtained at completion of the infusion (postoperative day [POD] 1), and before the third (POD 2) and seventh (POD 4) enteral doses., Results: A total of 27 patients were enrolled (esophagectomy group, 13 patients; PR group, 14 patients). Patients in the 2 groups had statistically similar ages (mean [SD], 60 [10] vs 53 [10] years; P = 0.07) and proportions of men (12/13 [92%] vs 8/14 [57%]; P = 0.08). Patients in the 2 groups were statistically similar with respect to race (white, 13/13 [100%] vs 13/14 [93%]) and preoperative weight (mean [SD], 83.3 [11.5] vs 77.7 [18.6] kg). On POD 1, age-adjusted and sex-adjusted serum amiodarone concentrations were not significantly different in the esophagectomy group versus the PR group (mean [SD] 0.65 [0.22] vs 0.84 [0.20] microg/mL). Mean (SD) serum amiodarone concentrations were significantly lower in the esophagectomy group on POD 2 (0.35 [0.27] vs 0.60 [0.18] microg/mL; P = 0.02) and on POD 4 (0.30 [0.34] vs 0.87 [0.16] microg/mL; P < 0.001). Serum amiodarone concentrations were undetectable in 33% and 50% of patients in the esophagectomy group on PODs 2 and 4, respectively, compared with 0% in the PR group (both, P = 0.03)., Conclusions: Serum amiodarone concentrations were significantly lower (and in some cases undetectable) when the drug was administered via a nasogastric tube into the stomach conduit in patients after esophagectomy compared with those concentrations after oral administration in a PR population. Nasogastric administration of amiodarone should probably be avoided for prophylaxis or treatment of postesophagectomy tachyarrhythmias.

Purpose: Prolonged air or fluid chest tube drainage may delay chest tube removal in thoracic surgery patients otherwise ready for discharge. We reviewed 20 months of experience at our institution with postoperative, outpatient chest tube management using a new portable chest tube device., Description: From May 2003 to December 2004, 457 major thoracic procedures were performed at our institution. Besides excessive chest tube output or air leak, 50 patients met the criteria for discharge. There were 36 patients who were discharged with a new portable chest tube system (Express Mini 500; Atrium Medical Corp, Hudson, NH). Patients received written instructions and demonstrated competence on system use. Patients returned for chest tube removal after satisfactory resolution of air leak or fluid drainage., Evaluation: Postoperative outpatient chest tube management accounted for 404 days. There were no major complications. Four patients experienced minor complications. Thirty-two patients (89%) experienced uneventful and successful outpatient chest tube management., Conclusions: These data suggest that successful postoperative outpatient chest tube management can be accomplished in select patients. This program resulted in substantial hospital cost reduction and enhanced patient satisfaction by allowing earlier discharge.

Background: Treatment of nonseminomatous germ cell tumors frequently requires bleomycin-combination chemotherapy followed by resection of residual disease. Bleomycin administration however raises concerns with respect to postoperative respiratory complications, particularly for patients undergoing large pulmonary resections. We undertook an institutional review to determine the outcome of large pulmonary resections after bleomycin-combination chemotherapy., Methods: Between 1981 and 2001, 530 patients presented to our institution for resection of residual intrathoracic disease for either metastatic testicular or primary mediastinal nonseminomatous germ cell tumors. We subsequently reviewed 32 of these patients who required pneumonectomy (n = 19; RIGHT = 9, LEFT = 10) or bilobectomy (n = 13) after bleomycin-combination chemotherapy., Results: There were four operative deaths (13%). All postoperative deaths occurred in patients undergoing right-sided resections (pneumonectomy, n = 2; bilobectomy, n = 2) as a consequence of pulmonary complications. Operative survivors had a pulmonary morbidity of 18%. Fourteen of 20 long-term survivors were found to have a satisfactory performance status at follow-up., Conclusions: Otherwise young and healthy male nonseminomatous germ cell tumors patients requiring large pulmonary resections after bleomycin-combination chemotherapy appear to be at higher than anticipated risk for pulmonary-related morbidity and mortality. However long-term survivors report an acceptable functional status.

Background: Several surgical methods have been described to treat achalasia with a recent trend toward utilizing minimally invasive techniques to perform a myotomy. Since 1998 our institution has utilized a minimally invasive thoracoscopy-assisted technique (ThAM) that allows a myotomy to be performed under direct visualization., Methods: From 1992 to 2002, 57 patients underwent transthoracic Heller myotomy at our institution. Thirty-eight patients (67%) who underwent ThAM were reviewed and compared with 19 (33%) who previously underwent myotomy through a standard open left thoracotomy (OM)., Results: There were no operative deaths in the ThAM group (n = 38) and 4 patients (11%) experienced minor morbidity. Four ThAM patients required conversion to open thoracotomy and 2 were lost to follow-up. Of the remaining 32 patients, 29 have improved postoperative dysphagia scores after a mean follow-up of 17 months. Only 4 patients have required further endoscopic or surgical intervention. Compared with the OM group, ThAM patients experienced significantly shorter average surgery time (97 versus 139 minutes), less blood loss (80 versus 155 mL), less postoperative narcotic requirement (8 versus 20 days), and shorter recovery to normal activity (20 versus 73 days)., Conclusions: Thoracoscopy-assisted myotomy results in excellent relief of dysphagia in the short term and would be expected to have long-term results similar to OM. Shorter operating and recovery times as compared with OM without the need for an antireflux procedure makes ThAM an attractive minimally invasive technique.

Objectives: The purpose of this study was to determine the pattern of mediastinal dissemination of nonseminomatous germ cell tumors of testicular origin and evaluate variables that may influence survival with mediastinal dissection in patients with metastatic nonseminomatous germ cell tumors., Methods: From 1981 to 2000, a total of 421 patients were seen at our institution for extirpation of residual lung or mediastinal disease after cisplatin-based chemotherapy for metastatic testicular nonseminomatous germ cell tumors. We reviewed 268 of these patients, with a mean age of 26.8 years, who required at least one surgical procedure to remove residual mediastinal disease. Pathologic types of resected residual mediastinal disease were necrosis (15%), teratoma (59%), persistent nonseminomatous germ cell cancer (15%), and non-germ cell carcinomatous degeneration (11%). Twelve variables were evaluated by univariate analyses, and four variables potentially statistically significant at P <.10 were subsequently entered into a Cox regression model., Results: All patients demonstrated metastases to the visceral mediastinum. Fewer patients also demonstrated metastases to the paravertebral sulcus or anterior compartments (16% and 7%, respectively). Overall 5- and 10-year survivals were 86% +/- 2% and 74% +/- 4%, respectively. According to multivariate analysis, disease-related survival was negatively influenced by an elevated preoperative beta-human chorionic gonadotropin level (P =.028) and adverse pathologic characteristics of residual mediastinal disease (P =.006)., Conclusions: Testicular nonseminomatous germ cell tumors follow a predictable pattern of mediastinal dissemination, primarily following the course of the thoracic duct and its major tributaries. Patients who require surgery to remove residual mediastinal disease after cisplatin-based chemotherapy for metastatic nonseminomatous germ cell tumors have good to excellent long-term survivals. These results justify an aggressive surgical approach, including multiple surgical procedures if clinically indicated.

Objectives: To compare the effects of norepinephrine (NOR) and the nonselective nitric oxide synthase inhibitor, N(G)-monomethyl-L-arginine (L-NMMA), on intestinal blood flow, oxygen exchange, and energy metabolism over 24 hrs of hyperdynamic, normotensive porcine endotoxic shock., Design: Prospective, randomized, experimental study with repeated measures., Setting: Investigational animal laboratory., Subjects: Twenty-seven pigs were divided into three groups: seven animals received no vasopressor therapy (ETX) during endotoxic shock; ten animals were treated with NOR; and ten animals were treated with L-NMMA., Interventions: Pigs were anesthetized, mechanically ventilated, and instrumented. Eight hours later, endotoxic shock was initiated by an infusion of Escherichia coli lipopolysaccharide. Animals were resuscitated by hetastarch directed to maintain the intrathoracic blood volume and a mean arterial pressure (MAP) of >60 mm Hg. Twelve hours after the start of the endotoxin infusion, NOR or L-NMMA was administered for 12 hrs in the treatment groups to maintain a MAP at preshock levels., Measurements and Main Results: ETX caused a continuous fall in MAP, despite a sustained increase in the cardiac output achieved by fluid resuscitation. NOR maintained MAP at preshock levels because of a further rise in cardiac output, whereas hemodynamic stabilization during L-NMMA resulted from systemic vasoconstriction. NOR increased portal venous blood flow concomitant with decreased intestinal oxygen extraction, whereas L-NMMA influenced neither portal venous blood flow nor intestinal oxygen extraction. Mean capillary hemoglobin oxygen saturation of the ileal mucosa as well as the frequency distributions reflecting microcirculatory oxygen availability remained unchanged as well. Nevertheless, portal venous pH similarly decreased and portal venous lactate/pyruvate ratios increased in all three groups. The arterial-ileal mucosal PCO2 gap progressively increased in the ETX and L-NMMA groups, whereas NOR blunted this response., Conclusions: Neither treatment could reverse the ETX-induced derangements of cellular energy metabolism as reflected by the increased portal venous lactate/pyruvate ratios. The NOR-induced attenuation of ileal mucosal acidosis was possibly caused by a different pattern of blood flow redistribution compared with L-NMMA.

Background: The aim of this study was to determine the effects of independent prognostic variables, such as prechemotherapy tumor markers, the extent of disease at diagnosis, the tumor markers postchemotherapy (PC), and the pathology of the PC residual mass on the overall survival of patients with primary mediastinal nonseminomatous germ cell tumors (PMNSGCT)., Methods: The authors undertook a retrospective review of 39 patients with PMNSGCT between 1983 and 1997 who received their initial chemotherapy at Indiana University and 36 additional patients referred for PC resection. All patients received chemotherapy based on the combination of cisplatin and etoposide. The median follow-up was 22 months (range, 12-144 months)., Results: The prechemotherapy tumor markers did not affect overall survival. Extent of disease (mediastinal only vs. visceral metastases) was an important prognostic factor for survival in univariate analysis (P = 0.042). Sixty-two of 75 patients underwent PC resection of residual disease. Fifteen of the 62 patients achieved a CR with chemotherapy alone, as the PC resection revealed only necrosis. Fourteen of these 15 patients continuously had no evidence of disease (NED). Forty-seven of the 62 patients had NED with chemotherapy and PC resection, including 31 with teratoma and 16 with carcinoma. However, 11 of 31 with teratoma and 11 of 16 with carcinoma subsequently relapsed. Although 18 patients had elevated tumor markers at the time of PC resection, 6 of 18 had only necrosis and 4 had teratoma. The PC tumor markers did not affect survival. The pathology of the resected specimen was the most significant predictor of survival in multivariate analysis (P < 0.001)., Conclusions: Twenty-eight of 39 patients (71.8%) with PMNSGCT treated at Indiana University achieved NED status, but only 16 (41%) continuously had NED. Twenty of 36 (55.5%) referred for resection continuously had NED. Disease confined to the mediastinum and necrosis in the PC specimen were important prognostic factors for survival., (Copyright 2000 American Cancer Society.)

Objectives: The treatment of nonseminomatous germ cell tumors with cisplatin-based chemotherapy followed by aggressive surgical resection of residual disease is one of the most successful models for multimodality cancer therapy. We reviewed the case histories of 91 patients treated at our institution from 1981 to 1998 with primary mediastinal nonseminomatous germ cell tumors to evaluate variables that may influence survival after surgery., Methods: Twelve of the 91 patients did not undergo postchemotherapy resection because of progressive disease. Seventy-nine of them underwent 82 thoracic surgical procedures and are the basis of this review. The majority (71/75) had elevated serum tumor markers, 75% (n = 50) of which returned to normal levels after first- or second-line chemotherapy., Results: There were 3 operative deaths and 1 late death, attributed to pulmonary complications. Twenty-four patients died of recurrent disease and 3 of leukemia, for an overall survival of 61% after an average follow-up of 48 months. The pathologic findings of complete tumor necrosis (n = 19) and benign teratoma (n = 28) in the surgical specimen predicted excellent and good long-term survival, respectively, which was statistically better than that of patients having persistent nonseminomatous germ cell tumors (n = 24) or carcinomatous/sarcomatous degeneration (n = 8)., Conclusions: Primary nonseminomatous germ cell tumors of the mediastinum can be cured with a multimodality therapy, particularly in the subset of patients with postchemotherapy pathologic findings of tumor necrosis and teratoma. Survival is poor but possible in patients with unfavorable pathologic findings after chemotherapy, currently justifying an aggressive surgical approach in patients with otherwise operable disease.

We compared the effects of norepinephrine (NOR; n = 11) and the nonselective nitric oxide synthase inhibitor Nomega-monomethyl-L-arginine (L-NMMA; n = 11) on hepatic blood flow (Q liv), O2 exchange, and energy metabolism over 24 h of hyperdynamic, normotensive porcine endotoxic shock. Endotoxin (ETX; n = 8) caused a continuous fall in mean arterial pressure (MAP) despite a sustained 50% increase in cardiac output (Q) achieved by adequate fluid resuscitation. NOR maintained MAP at preshock levels owing to a further rise in Q, while the comparable hemodynamic stabilization during L-NMMA infusion resulted from systemic vasoconstriction, increasing the systemic vascular resistance (SVR) about 30% from shock level after 6 h of treatment concomitant with a reduction in Q to preshock values. Whereas NOR also increased Q liv and, hence, hepatic O2 delivery (hDO2), but did not affect hepatic O2 uptake (hVO2), L-NMMA influenced neither Q liv nor hDO2 and hVO2. Mean capillary hemoglobin O2 saturation (HbScO2) on the liver surface as well as HbScO2 frequency distributions, which mirror microcirculatory O2 availability, remained unchanged as well. Neither treatment influenced the ETX-induced derangements of cellular energy metabolism reflected by the progressive decrease in hepatic lactate uptake rate and increased hepatic venous lactate/pyruvate ratios. ETX nearly doubled the endogenous glucose production (EGP) rate, which was further increased with NOR, whereas L-NMMA nearly restored EGP to preshock levels. Nevertheless, despite the different mechanisms in maintaining blood pressure neither treatment influenced ETX-induced liver dysfunction.

We investigated hepatic blood flow, O2 exchange and metabolism in porcine endotoxic shock (Control, n = 8; Endotoxin, n = 10) with administration of hydroxyethylstarch to maintain arterial pressure (MAP)>60 mmHg. Before and 12, 18 and 24 h after starting continuous i.v. endotoxin we measured portal venous and hepatic arterial blood flow, intracapillary haemoglobin O2 saturation (Hb-O2%) of the liver surface and arterial, portal and hepatic venous lactate, pyruvate, glycerol and alanine concentrations. Glucose production rate was derived from the plasma isotope enrichment during infusion of [6,6-2H2]-glucose. Despite a sustained 50% increase in cardiac output endotoxin caused a progressive, significant fall in MAP. Liver blood flow significantly increased, but endotoxin affected neither hepatic O2 delivery and uptake nor mean intracapillary Hb-O2% and Hb-O2% frequency distributions. Endotoxin nearly doubled endogenous glucose production rate while hepatic lactate, alanine and glycerol uptake rates progressively decreased significantly. The lactate uptake rate even became negative (P<0.05 vs Control). Endotoxin caused portal and hepatic venous pH to fall significantly concomitant with significantly increased arterial, portal and hepatic venous lactate/pyruvate ratios. During endotoxic shock increased cardiac output achieved by colloid infusion maintained elevated liver blood flow and thereby macro- and microcirculatory O2 supply. Glucose production rate nearly doubled with complete dissociation of hepatic uptake of glucogenic precursors and glucose release. Despite well-preserved capillary oxygenation increased lactate/pyruvate ratios reflecting impaired cytosolic redox state suggested deranged liver energy balance, possibly due to the O2 requirements of gluconeogenesis.

Within a panel of 15 colon carcinoma cell lines we have characterized the p53 gene status using immunocytochemistry (ICC), SSCP and direct sequence analysis. Extension of this analysis to the use of ICC on 104 colonic lesions, representative of different stages of colonic neoplastic progression, showed an absence of detectable p53 nuclear staining in preneoplastic polyp lesions (20 cases) with staining of 52% (25/48) of primary colon carcinomas and 81% (29/36) of hepatic metastases, suggestive of an increased incidence of p53 mutations in late stage lesions of colonic cancer. To address this issue more directly, we analysed 18 primary colon carcinomas and hepatic metastases excised coincidentally from the same patients. In ICC, p53 nuclear staining was recorded in matching lesions from eight individuals where direct sequencing revealed identical mutations in each case. In four individuals no ICC staining was detected in either lesion and molecular analysis revealed wild type sequence in exons 4-9. In six individuals p53 nuclear staining was observed in the hepatic metastases of patients but not the primary lesion. Molecular analysis revealed point mutation events in hepatic metastases from these patients which were not detected in the primary tumor. The point mutations identified in colon carcinomas were predominantly transition events (83%) located in previously characterized colon hotspot regions. These results demonstrate an increased incidence of p53 mutations associated with secondary lesions of colorectal tumors suggestive of a role for p53 in the establishment of colorectal hepatic metastases.