Inderpal S. Sarkaria

Use of Cigarette-Smoking History to Estimate the Likelihood of Mutations in Epidermal Growth Factor Receptor Gene Exons 19 and 21 in Lung Adenocarcinomas

PURPOSE Lung adenocarcinomas with mutations in exons 19 and 21 of the epidermal growth factor receptor gene (EGFR) demonstrate sensitivity to gefitinib or erlotinib. Investigators have reported an association between EGFR mutations and the amount and duration of cigarette smoking, with the highest incidence of mutations seen in never smokers. METHODS EGFR exon 19 and 21 mutation status was determined in 265 tumor samples using direct sequencing, polymerase chain reaction (PCR), or PCR-based restriction fragment length polymorphism analysis. A detailed smoking history was obtained. Patients were categorized as never smokers (< 100 lifetime cigarettes), former smokers (quit > or = 1 year ago), or current smokers (quit < 1 year ago). RESULTS We detected EGFR mutations in 34 (51%) of 67 never smokers (95% CI, 38% to 64%), 29 (19%) of 151 former smokers (95% CI, 13% to 27%), and two (4%) of 47 current smokers (95% CI, 1% to 16%). Significantly fewer EGFR mutations were found in people who smoked for more than 15 pack-years (P < .001) or stopped smoking less than 25 years ago (P < .02) compared with individuals who never smoked. The number of smoking pack-years and smoke-free years predicted the prevalence of EGFR mutations (areas under receiver operating characteristic curve = 0.78 and 0.77, respectively). CONCLUSION The likelihood of EGFR mutations in exons 19 and 21 decreases as the number of pack-years increases. Mutations were less common in people who smoked for more than 15 pack-years or who stopped smoking cigarettes less than 25 years ago. These data can assist clinicians in assessing the likelihood of exon 19 and 21 EGFR mutations in patients with lung adenocarcinoma when mutational analysis is not feasible.

Casein Kinase II Alpha Subunit and C1-Inhibitor Are Independent Predictors of Outcome in Patients with Squamous Cell Carcinoma of the Lung

Purpose: Gene expression profiling has been shown to be a valuable tool for prognostication and identification of cancer-associated genes in human malignancies. We aimed to identify potential prognostic marker(s) in non-small cell lung cancers using global gene expression profiles. Experimental Design: Twenty-one previously untreated patients with non-small cell lung cancer were analyzed using the Affymetrix GeneChip high-density oligonucleotide array and comparative genomic hybridization. Identified candidate genes were validated in an independent cohort of 45 patients using quantitative real-time reverse transcription-PCR and Western blot analyses. Follow-up data for these patients was collected and used to assess outcome correlations. Results: Hierarchical clustering analysis yielded three distinct subgroups based on gene expression profiling. Cluster I consisted of 4 patients with adenocarcinoma and 1 with squamous cell carcinoma (squamous cell carcinoma); clusters II and III consisted of 6 and 10 patients with squamous cell carcinoma, respectively. Outcome analysis was performed on the cluster groups containing solely squamous cell carcinoma, revealing significant differences in disease-specific survival rates. Moreover, patients having a combination of advanced Tumor-Node-Metastasis stage and assigned to the poor prognosis cluster group (cluster II) had significantly poorer outcomes. Comparative genomic hybridization analysis showed recurrent chromosomal losses at 1p, 3p, 17, 19, and 22 and gains/amplifications at 3q, 5p, and 8q, which did not vary significantly between the cluster groups. We internally and externally validated a subset of 11 cluster II (poor prognosis)-specific genes having corresponding chromosomal aberrations identified by comparative genomic hybridization as prognostic markers in an independent cohort of patients with lung squamous cell carcinoma identifying CSNK2A1 and C1-Inh as independent predictors of outcome. Conclusion: CSNK2A1 and C1-Inh are independent predictors of survival in lung squamous cell carcinoma patients and may be useful as prognostic markers.

Post-treatment endoscopic biopsy is a poor-predictor of pathologic response in patients undergoing chemoradiation therapy for esophageal cancer

Purpose:Endoscopic biopsy after chemoradiation therapy (CRT) for esophageal cancer has been used to determine response to treatment. We wanted to determine if endoscopic biopsy can accurately establish evidence of local pathologic complete response (pCR) in patients undergoing CRT. Methods:We queried a prospectively maintained database for patients seen at Memorial Sloan-Kettering Cancer Center from 1996 to the present who underwent, (1) CRT for local-regionally advanced esophageal cancer, (2) post-CRT endoscopic biopsy, and (3) esophagectomy. Data points included pathology of post-CRT endoscopy and surgical specimens, tumor histology, and survival. Correlations were analyzed by the &khgr;2 test and one-way analysis of variance. Survival comparisons were assessed using the Kaplan-Meier method and log-rank analysis. Results:One hundred fifty-six patients were identified. Over 80% of patients received cisplatin-based chemotherapy and 5040 cGy of radiation. One hundred eighteen patients had no tumor identified on endoscopic biopsy. A negative biopsy at endoscopy was a poor predictor of pCR (negative predictive value: 31%), with 69% having local disease at esophagectomy. A positive biopsy was predictive of residual disease (positive predictive value: 95%). Negative endoscopic biopsy better predicted a pCR for squamous cell carcinomas versus adenocarcinomas (P[r] < 0.001). Nodal status of surgical specimens was not correlated with post-treatment endoscopic findings. Survival was equivalent after surgery in patients with a negative endoscopic biopsy versus patients with positive pathology. Conclusion:A negative endoscopic biopsy is not a useful predictor of a pCR after CRT, final nodal status, or overall survival.

Mutational Analysis of EGFR and Related Signaling Pathway Genes in Lung Adenocarcinomas Identifies a Novel Somatic Kinase Domain Mutation in FGFR4

Background Fifty percent of lung adenocarcinomas harbor somatic mutations in six genes that encode proteins in the EGFR signaling pathway, i.e., EGFR, HER2/ERBB2, HER4/ERBB4, PIK3CA, BRAF, and KRAS. We performed mutational profiling of a large cohort of lung adenocarcinomas to uncover other potential somatic mutations in genes of this signaling pathway that could contribute to lung tumorigenesis. Methodology/Principal Findings We analyzed genomic DNA from a total of 261 resected, clinically annotated non-small cell lung cancer (NSCLC) specimens. The coding sequences of 39 genes were screened for somatic mutations via high-throughput dideoxynucleotide sequencing of PCR-amplified gene products. Mutations were considered to be somatic only if they were found in an independent tumor-derived PCR product but not in matched normal tissue. Sequencing of 9MB of tumor sequence identified 239 putative genetic variants. We further examined 22 variants found in RAS family genes and 135 variants localized to exons encoding the kinase domain of respective proteins. We identified a total of 37 non-synonymous somatic mutations; 36 were found collectively in EGFR, KRAS, BRAF, and PIK3CA. One somatic mutation was a previously unreported mutation in the kinase domain (exon 16) of FGFR4 (Glu681Lys), identified in 1 of 158 tumors. The FGFR4 mutation is analogous to a reported tumor-specific somatic mutation in ERBB2 and is located in the same exon as a previously reported kinase domain mutation in FGFR4 (Pro712Thr) in a lung adenocarcinoma cell line. Conclusions/Significance This study is one of the first comprehensive mutational analyses of major genes in a specific signaling pathway in a sizeable cohort of lung adenocarcinomas. Our results suggest the majority of gain-of-function mutations within kinase genes in the EGFR signaling pathway have already been identified. Our findings also implicate FGFR4 in the pathogenesis of a subset of lung adenocarcinomas.

Video-assisted thoracoscopic surgery (VATS) lobectomy: catastrophic intraoperative complications.

OBJECTIVE Large case series have demonstrated that video-assisted thoracoscopic surgery (VATS) lobectomy is feasible and safe. However, catastrophic intraoperative complications during VATS lobectomy requiring thoracotomy can be overlooked and are not reported in the current literature. We reviewed our experience to determine the frequency, management, and outcome of these complications. METHODS A systematic review of a prospective database was performed after institutional review board approval. All patients who underwent VATS lobectomy or a combination of any VATS procedure plus a thoracotomy were identified. A catastrophic complication was defined as an event that resulted in an additional unplanned major surgical procedure other than the planned lobectomy. RESULTS From 2002 to 2010, a total of 633 VATS lobectomies were performed and 610 patients had any VATS procedure plus a thoracotomy. Thirteen catastrophic complications were identified in 12 (1%) patients. We included all cases in which a VATS was performed as well as a thoractomy since this would include conversions as well. These cases included 3 main pulmonary arterial and 1 main pulmonary venous transection requiring reanastomosis, 3 unplanned pneumonectomies, 1 unplanned bilobectomy, 1 tracheoesophageal fistula, 1 membranous airway injury to the bronchus intermedius, 1 complete staple line disruption of the inferior pulmonary vein injury to the azygos/superior vena cava junction, and 1 splenectomy. There were no intraoperative deaths. CONCLUSIONS Catastrophic intraoperative complications of VATS lobectomy are uncommon. However, awareness of the possibility of such injuries is critical to avoid them, and development of specific management strategies is necessary to limit morbidity should they occur.

Squamous Cell Carcinoma Related Oncogene/DCUN1D1 Is Highly Conserved and Activated by Amplification in Squamous Cell Carcinomas

Chromosomal amplification at 3q is common to multiple human cancers, but has a specific predilection for squamous cell carcinomas (SCC) of mucosal origin. We identified and characterized a novel oncogene, SCC-related oncogene (SCCRO), which is amplified along the 3q26.3 region in human SCC. Amplification and overexpression of SCCRO in these tumors correlate with poor clinical outcome. The importance of SCCRO amplification in malignant transformation is established by the apoptotic response to short hairpin RNA against SCCRO, exclusively in cancer cell lines carrying SCCRO amplification. The oncogenic potential of SCCRO is underscored by its ability to transform fibroblasts (NIH-3T3 cells) in vitro and in vivo. We show that SCCRO regulates Gli1--a key regulator of the hedgehog (HH) pathway. Collectively, these data suggest that SCCRO is a novel component of the HH signaling pathway involved in the malignant transformation of squamous cell lineage.

Combined thoracoscopic and laparoscopic robotic-assisted minimally invasive esophagectomy using a four-arm platform: experience, technique and cautions during early procedure development

OBJECTIVES This study reports an early, single-institution experience of combined thoracoscopic and laparoscopic robotic-assisted minimally invasive esophagectomy (RAMIE) using a four-arm robotic platform, with special attention given to the pitfalls and complications during procedure development. METHODS We conducted a prospective, single-cohort, observational study of patients undergoing RAMIE at a single institution. RESULTS A total of 21 patients (median age, 62 years [range, 37-83 years]) underwent RAMIE with a four-arm robotic platform (17 by Ivor Lewis and 4 by McKeown). Of the patients, 17 (81%) had a complete (R0) resection, and 16 (76%) received induction treatment, the majority (14/21 [67%]) with combined chemoradiation. The median operative time was 556 min (range, 395-807 min), which decreased to 414 min (range, 405-543 min) for the last 5 cases in the series. The median estimated blood loss was 307 cm(3) (range, 200-500 cm(3)), and the median length of hospital stay was 10 days (range, 7-70 days). The median number of lymph nodes resected was 20 (range, 10-49). Five (24%) patients were converted to open procedures. Five patients (24%) had major complications. One (5%) died of complications on postoperative Day 70, and 3 (14%) had clinically significant anastomotic leaks (Grade II or greater, by Common Terminology Criteria for Adverse Events version 3.0). Three patients (14%) in this early experience developed airway fistulas. CONCLUSIONS While four-arm RAMIE may offer advantages over standard minimally invasive esophagectomy approaches, its adoption in a structured program, with critical evaluation of adverse events and subsequent adjustment of technique, is paramount to maximize patient safety, minimize complications and improve the conduct of operation early in the learning curve. Particular technical consideration should be given to prevention of airway complications.

Neoadjuvant and Adjuvant Chemotherapy in Resected Pulmonary Large Cell Neuroendocrine Carcinomas: A Single Institution Experience

BACKGROUND Pulmonary large cell neuroendocrine carcinomas (LCNEC) are aggressive neoplasms with poor prognosis. The role of neoadjuvant and adjuvant therapies in these tumors remains uncertain. METHODS We performed a retrospective review of a prospective database. Kaplan-Meier estimates of overall survival (OS) were determined and compared across prognostic factors using log-rank analysis and the Cox proportional hazards model. RESULTS One hundred patients with resected LCNEC were identified from 1992 to 2008. Of these, 54% were male and 98% current or former smokers (mean 60.3 pack-years). Twenty-two patients received neoadjuvant platinum chemotherapy with a response rate of 68% (15 of 22). Eighty percent (80 of 100) underwent lobectomy and 11% (11 of 100) pneumonectomy with a 90% (90 of 100) complete resection (R0) rate. Seventy-one percent (71 of 100) were stage I-II, and 20 of 71 received platinum adjuvant chemotherapy. Mean OS was 40 months. Univariate factors associated with decreased OS included male gender (p = 0.007), increasing tumor (T) stage (p = 0.004), and stage III-IV disease (p = 0.04). Stage IB patients fared significantly worse than IA (p = 0.006). Multivariate analyses identified male gender (hazard ratio [HR] 2.3, p = 0.007), comorbid pulmonary disease (HR 2.3, p = 0.012), and pathologic stage (HR = 2.2, p = 0.011) as associated with risk of death. Univariate analysis in stage IB-IIIA completely resected (R0) patients receiving combination platinum-based induction and (or) adjuvant chemotherapy showed a trend toward improved OS (median survival 7.4 vs 2 years, p = 0.052). CONCLUSIONS The LCNEC has a high response rate to platinum-based neoadjuvant chemotherapy. Resected advanced-stage patients receiving combination neoadjuvant and (or) adjuvant chemotherapy may have a survival advantage. These therapies should be considered in resectable patients with LCNEC.

Esophageal Cancer Recurrence Patterns and Implications for Surveillance

Introduction: After definitive treatment of esophageal cancer, patients are at high risk for recurrence. Consistent follow-up is important for detection and treatment of recurrence. The optimal surveillance regimen remains undefined. We investigated posttreatment recurrence patterns and methods of detection in survivors of esophageal cancer. Methods: We retrospectively studied a cohort of patients who had undergone surgical resection for esophageal cancer at our institution between 1996 and 2010. Routine computed tomography scan and upper endoscopy were performed for surveillance. Results: In total, 1147 patients with resected esophageal adenocarcinoma or squamous cell carcinoma were included (median follow-up, 46 months). Of these, 723 patients (63%) had received neoadjuvant therapy before surgery. During follow-up, there were 595 deaths (52%) and 435 recurrences (38%) (distant [55%], locoregional [28%], or both [17%]). Half of recurrences were detected as a result of symptoms (n = 217), 45% by routine chest and abdominal computed tomography scan (n = 194), and 1% by surveillance upper endoscopy (n = 6). The recurrence rate decreased from 27 per 100 person-years in posttreatment year 1 to 4 per 100 person-years in year 6. In the first 2 years, the rate of recurrence was higher among patients who had received neoadjuvant therapy (35 per 100 person-years) than among those who had not (14 per 100 person-years) (p < 0.001). Conclusions: The incidence of recurrence is high after esophagectomy for cancer. Surveillance endoscopy has limited value for detection of asymptomatic local recurrence. The yield from follow-up scans diminishes significantly after the sixth year; surveillance scans after that point are likely unnecessary.

Thyroid Transcription Factor–1 Expression Is an Independent Predictor of Recurrence and Correlates with the IASLC/ATS/ERS Histologic Classification in Patients with Stage I Lung Adenocarcinoma

In the current study, the authors investigated whether thyroid transcription factor‐1 (TTF‐1) expression is correlated with the International Association for the Study of Lung Cancer (IASLC)/American Thoracic Society (ATS)/European Respiratory Society (ERS) classification and whether it stratifies patients with stage I lung adenocarcinoma with respect to disease recurrence.