Arjun Pennathur

Exome and whole-genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity

The incidence of esophageal adenocarcinoma (EAC) has risen 600% over the last 30 years. With a 5-year survival rate of ∼15%, the identification of new therapeutic targets for EAC is greatly important. We analyze the mutation spectra from whole-exome sequencing of 149 EAC tumor-normal pairs, 15 of which have also been subjected to whole-genome sequencing. We identify a mutational signature defined by a high prevalence of A>C transversions at AA dinucleotides. Statistical analysis of exome data identified 26 significantly mutated genes. Of these genes, five (TP53, CDKN2A, SMAD4, ARID1A and PIK3CA) have previously been implicated in EAC. The new significantly mutated genes include chromatin-modifying factors and candidate contributors SPG20, TLR4, ELMO1 and DOCK2. Functional analyses of EAC-derived mutations in ELMO1 identifies increased cellular invasion. Therefore, we suggest the potential activation of the RAC1 pathway as a contributor to EAC tumorigenesis.

Outcomes After Minimally Invasive Esophagectomy Review of Over 1000 Patients

Background: Esophagectomy is a complex operation and is associated with significant morbidity and mortality. In an attempt to lower morbidity, we have adopted a minimally invasive approach to esophagectomy. Objectives: Our primary objective was to evaluate the outcomes of minimally invasive esophagectomy (MIE) in a large group of patients. Our secondary objective was to compare the modified McKeown minimally invasive approach (videothoracoscopic surgery, laparoscopy, neck anastomosis [MIE-neck]) with our current approach, a modified Ivor Lewis approach (laparoscopy, videothoracoscopic surgery, chest anastomosis [MIE-chest]). Methods: We reviewed 1033 consecutive patients undergoing MIE. Elective operation was performed on 1011 patients; 22 patients with nonelective operations were excluded. Patients were stratified by surgical approach and perioperative outcomes analyzed. The primary endpoint studied was 30-day mortality. Results: The MIE-neck was performed in 481 (48%) and MIE-Ivor Lewis in 530 (52%). Patients undergoing MIE-Ivor Lewis were operated in the current era. The median number of lymph nodes resected was 21. The operative mortality was 1.68%. Median length of stay (8 days) and ICU stay (2 days) were similar between the 2 approaches. Mortality rate was 0.9%, and recurrent nerve injury was less frequent in the Ivor Lewis MIE group (P < 0.001). Conclusions: MIE in our center resulted in acceptable lymph node resection, postoperative outcomes, and low mortality using either an MIE-neck or an MIE-chest approach. The MIE Ivor Lewis approach was associated with reduced recurrent laryngeal nerve injury and mortality of 0.9% and is now our preferred approach. Minimally invasive esophagectomy can be performed safely, with good results in an experienced center.

MicroRNA expression profiles of esophageal cancer

OBJECTIVE Expression of microRNAs by array analysis provides unique profiles for classifying tissues and tumors. The purpose of our study was to examine microRNA expression in Barrett esophagus and esophageal cancer to identify potential markers for disease progression. METHODS MicroRNA was isolated from 35 frozen specimens (10 adenocarcinoma, 10 squamous cell carcinoma, 9 normal epithelium, 5 Barrett esophagus, and 1 high-grade dysplasia). MicroRNA expression was analyzed with Ambion bioarrays (Ambion, Austin, Tex) containing 328 human microRNA probes. RESULTS Unsupervised hierarchic clustering resulted in four major branches corresponding with four histologic groups. One branch consisted of 7 normal epithelium samples and 1 squamous cell carcinoma sample. The second branch consisted of 7 squamous cell carcinoma samples and 1 normal epithelium sample. The third branch contained 4 Barrett esophagus samples and 1 squamous cell carcinoma sample. The fourth contained all the adenocarcinoma samples and 1 sample each of Barrett esophagus, normal epithelium, squamous cell carcinoma, and high-grade dysplasia. Supervised classification with principal component analysis determined that the normal epithelium samples were more similar to the squamous cell carcinoma tumors, whereas the Barrett esophagus samples were more similar to adenocarcinoma. Pairwise comparisons between sample types revealed microRNAs that may be markers of tumor progression. Both mir_203 and mir_205 were expressed 2- to 10-fold lower in squamous cell carcinoma and adenocarcinomas than in normal epithelium. The mir_21 expression was 3- to 5-fold higher in both tumors than in normal epithelium. Prediction analysis of microarray classified 3 Barrett esophagus samples as Barrett esophagus, 1 as adenocarcinoma, and 1 as normal epithelium. CONCLUSION Expression profiles of miRNA distinguish esophageal tumor histology and can discriminate normal tissue from tumor. MicroRNA expression may prove useful for identifying patients with Barrett esophagus at high risk for progression to adenocarcinoma.

Gastrointestinal Adenocarcinomas of the Esophagus, Stomach, and Colon Exhibit Distinct Patterns of Genome Instability and Oncogenesis

A more detailed understanding of the somatic genetic events that drive gastrointestinal adenocarcinomas is necessary to improve diagnosis and therapy. Using data from high-density genomic profiling arrays, we conducted an analysis of somatic copy-number aberrations in 486 gastrointestinal adenocarcinomas including 296 esophageal and gastric cancers. Focal amplifications were substantially more prevalent in gastric/esophageal adenocarcinomas than colorectal tumors. We identified 64 regions of significant recurrent amplification and deletion, some shared and others unique to the adenocarcinoma types examined. Amplified genes were noted in 37% of gastric/esophageal tumors, including in therapeutically targetable kinases such as ERBB2, FGFR1, FGFR2, EGFR, and MET, suggesting the potential use of genomic amplifications as biomarkers to guide therapy of gastric and esophageal cancers where targeted therapeutics have been less developed compared with colorectal cancers. Amplified loci implicated genes with known involvement in carcinogenesis but also pointed to regions harboring potentially novel cancer genes, including a recurrent deletion found in 15% of esophageal tumors where the Runt transcription factor subunit RUNX1 was implicated, including by functional experiments in tissue culture. Together, our results defined genomic features that were common and distinct to various gut-derived adenocarcinomas, potentially informing novel opportunities for targeted therapeutic interventions.

Outcomes after a Decade of Laparoscopic Giant Paraesophageal Hernia Repair

OBJECTIVE Laparoscopic repair of giant paraesophageal hernia is a complex operation requiring significant laparoscopic expertise. Our objective was to compare our current approach and outcomes for laparoscopic repair of giant paraesophageal hernia with our previous experience. METHODS A retrospective review of patients undergoing nonemergency laparoscopic repair of giant paraesophageal hernia, stratified by early versus current era (January 1997-June 2003 and July 2003-June 2008), was performed. We evaluated clinical outcomes, barium esophagogram, and quality of life. RESULTS Laparoscopic repair of giant paraesophageal hernia was performed in 662 patients (median age 70 years, range 19-92 years) with a median percentage of herniated stomach of 70% (range 30%-100%). With time, use of Collis gastroplasty decreased (86% to 53%), as did crural mesh reinforcement (17% to 12%). Current era patients were 50% more likely to have a Charlson comorbidity index score greater than 3. Thirty-day mortality was 1.7% (11/662). Mortality and complication rates were stable with time, despite increasing comorbid disease in current era. Postoperative gastroesophageal reflux disease health-related quality of life scores were available for 489 patients (30-month median follow-up), with good to excellent results in 90% (438/489). Radiographic recurrence (15.7%) was not associated with symptom recurrence. Reoperation occurred in 3.2% (21/662). CONCLUSIONS With time, we have obtained significant minimally invasive experience and refined our approach to laparoscopic repair of giant paraesophageal hernia. Perioperative morbidity and mortality remain low, despite increased comorbid disease in the current era. Laparoscopic repair provided excellent patient satisfaction and symptom improvement, even with small radiographic recurrences. Reoperation rates were comparable to the best open series.

Esophagectomy for T1 Esophageal Cancer: Outcomes in 100 Patients and Implications for Endoscopic Therapy

OBJECTIVES Esophagectomy is the standard treatment for T1 esophageal cancer (EC). Interest in endoscopic therapies, particularly for T1 EC, is increasing. We evaluated the long-term outcomes after esophagectomy and examined the pathologic features of T1 cancer to determine the suitability for potential endoscopic therapy. METHODS We reviewed the outcomes of esophagectomy in 100 consecutive patients with T1 EC. The primary end points studied were overall survival (OS) and disease-free survival (DFS). In addition to detailed pathology review, we evaluated prognostic variables associated with survival. RESULTS Esophagectomy was performed in 100 patients (79 men, 21 women; median age, 68 years) for T1 EC, comprising adenocarcinoma, 91; squamous, 9; intramucosal (T1a), 29; and submucosal (T1b), 71. The 30-day mortality was 0%. Resection margins were microscopically negative in 99 patients (99%). N1 disease was present in 21 (T1a, 2 of 29 [7%]; T1b, 19 of 71 [27%]), associated high-grade dysplasia in 64 (64%), and angiolymphatic invasion in 19 (19%). At a median follow-up of 66 months, estimated 5-year OS was 62% and 3-year DFS was 80% for all patients (including N1). Nodal status and tumor size were significantly associated with OS and DFS, respectively. CONCLUSIONS Esophagectomy can be performed safely in patients with T1 EC with good long-term results. Many patients with T1 EC have several risk factors that may preclude adequate treatment with endoscopic therapy. Further prospective studies are required to evaluate endoscopic therapies. Esophagectomy should continue to remain the standard treatment in patients with T1 EC.

American College of Chest Physicians and Society of Thoracic Surgeons Consensus Statement for Evaluation and Management for High-Risk Patients with Stage I Non-small Cell Lung Cancer

BACKGROUND The standard treatment of stage I non-small cell lung cancer (NSCLC) is lobectomy with systematic mediastinal lymph node evaluation. Unfortunately, up to 25% of patients with stage I NSCLC are not candidates for lobectomy because of severe medical comorbidity. METHODS A panel of experts was convened through the Thoracic Oncology Network of the American College of Chest Physicians and the Workforce on Evidence-Based Surgery of the Society of Thoracic Surgeons. Following a literature review, the panel developed 13 suggestions for evaluation and treatment through iterative discussion and debate until unanimous agreement was achieved. RESULTS Pretreatment evaluation should focus primarily on measures of cardiopulmonary physiology, as respiratory failure represents the greatest interventional risk. Alternative treatment options to lobectomy for high-risk patients include sublobar resection with or without brachytherapy, stereotactic body radiation therapy, and radiofrequency ablation. Each is associated with decreased procedural morbidity and mortality but increased risk for involved lobe and regional recurrence compared with lobectomy, but direct comparisons between modalities are lacking. CONCLUSIONS Therapeutic options for the treatment of high-risk patients are evolving quickly. Improved radiographic staging and the diagnosis of smaller and more indolent tumors push the risk-benefit decision toward parenchymal-sparing or nonoperative therapies in high-risk patients. Unbiased assessment of treatment options requires uniform reporting of treatment populations and outcomes in clinical series, which has been lacking to date.

Contemporaneous management of esophageal perforation

BACKGROUND Esophageal perforation is an important therapeutic challenge. We hypothesized that patients with minimal mediastinal contamination at the time of diagnosis could be managed successfully with nonoperative treatment modalities. METHODS We performed a retrospective review of 119 consecutive patients with esophageal perforation from 1998 to 2008. Demographics, cause of perforation, clinical presentation, diagnostic methods, and management results were evaluated. The decision to operate was based on the extent of mediastinal contamination and systemic sepsis rather than cause of perforation. RESULTS Median time to diagnosis among all patients was 12 hours (range, 1-120). Spontaneous (Boerhaaves) perforation occurred in 44 (37%) patients. Iatrogenic perforations constituted the remaining patients (n = 75). After instrumental perforation, 9 patients (13%) required esophagectomy, 48 patients were managed with repair and drainage, and the remaining 18 were managed nonoperatively. All 34 patients undergoing operative therapy for spontaneous perforations were treated with esophageal repair. Overall mortality was 14%, with intrathoracic perforations having 18% mortality, cervical 8%, and gastroesophageal junction 3%. Patients undergoing nonoperative therapy had a shorter hospitalizations (13 vs 24 days), fewer complications (36% vs 62%), and less mortality (4% vs 15%) compared with those undergoing operative intervention. CONCLUSION An approach to esophageal perforation based on injury severity and the degree of mediastinal and pleural contamination is of paramount importance. Although operative management remains the standard in the majority of patients with esophageal perforation, nonoperative management may be successfully implemented in selected patients with a low morbidity and mortality if favorable radiographic and clinical characteristics are present.

Anatomic Segmentectomy for Stage I Non-Small Cell Lung Cancer in the Elderly

BACKGROUND Anatomic segmentectomy for stage I non-small cell lung cancer (NSCLC) offers the potential of surgical cure with preservation of lung function. This may be of particular importance in elderly NSCLC patients with declining cardiopulmonary status and a limited life expectancy. METHODS The study compared outcomes of 78 elderly patients (aged > 75 years) with stage I NSCLC undergoing segmentectomy and 106 undergoing lobectomy for stage I NSCLC from 2002 to 2007. Primary outcome variables included perioperative morbidity and mortality, hospital course, recurrence patterns, and survival. RESULTS Age, gender, tumor histology, and surgical approach were similar between groups. Comorbidities were similar except for a higher incidence of chronic obstructive pulmonary disease and diabetes in segmentectomy patients. The tumors in the lobectomy group were significantly larger (3.5 vs 2.5 cm, p = 0.0001). Operative mortality was 1.3% for segmentectomy and 4.7% for lobectomy. Segmentectomy patients had fewer major complications (11.5% vs 25.5%, p = 0.02). There were no differences in median hospitalization (7 vs 6 days). The estimated overall survival at 2, 3, and 5 years was 76%, 69%, and 46% for segmentectomy patients and 68%, 59%, and 47% for lobectomy patients (p = 0.28). The 5-year disease-free survival was equivalent (segmentectomy, 49.8%; lobectomy, 45.5%; p = 0.80). CONCLUSIONS Anatomic segmentectomy can be performed safely in elderly patients with early-stage NSCLC. This approach is associated with reduced perioperative complications and comparable oncologic efficacy compared with lobectomy in older patients with a limited life expectancy.

Antireflux Surgery Preserves Lung Function in Patients With Gastroesophageal Reflux Disease and End-stage Lung Disease Before and After Lung Transplantation

BACKGROUND Gastroesophageal reflux disease (GERD) is common in patients with end-stage lung disease (ESLD). GERD may cause obliterative bronchiolitis after lung transplantation (LTx), represented by a decline in forced expiratory volume in 1 second (FEV(1)). OBJECTIVES To identify the patterns of reflux in patients with ESLD and to determine whether antireflux surgery (ARS) positively impacts lung function. DESIGN Retrospective review of prospectively collected data. SETTING Tertiary care university hospital. PATIENTS Forty-three patients with ESLD and documented GERD (pre-LTx, 19; post-LTx, 24). INTERVENTIONS Antireflux surgery. MAIN OUTCOME MEASURES Reflux patterns including laryngopharyngeal reflux as measured by esophageal impedance, and FEV(1), and episodes of pneumonia and acute rejection before and after ARS. RESULTS Before ARS, 19 of 43 patients (44%) were minimally symptomatic or asymptomatic. Laryngopharyngeal reflux events, which occurred primarily in the upright position, were common in post-LTx (56%) and pre-LTx (31%) patients. At 1 year after ARS, FEV(1) significantly improved in 91% of the post-LTx patients (P < .01) and 85% of the pre-LTx patients (P = .02). Of patients with pre-ARS declining FEV(1), 92% of post-LTx and 88% of pre-LTx patients had a reversal of this trend. Episodes of pneumonia and acute rejection were significantly reduced in post-LTx patients (P = .03) or stablilized in pre-LTx patients (P = .09). CONCLUSIONS There should be a low threshold for performing objective esophageal testing including esophageal impedance because GERD may be occult and ARS may improve or prolong allograft and native lung function.