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1.  Outcomes After Minimally Invasive Esophagectomy 
Annals of surgery  2012;256(1):95-103.
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.
doi:10.1097/SLA.0b013e3182590603
PMCID: PMC4103614  PMID: 22668811
2.  Three-Gene Immunohistochemical Panel Adds to Clinical Staging Algorithms to Predict Prognosis for Patients With Esophageal Adenocarcinoma 
Journal of Clinical Oncology  2013;31(12):1576-1582.
Purpose
Esophageal adenocarcinoma (EAC) is a highly aggressive disease with poor long-term survival. Despite growing knowledge of its biology, no molecular biomarkers are currently used in routine clinical practice to determine prognosis or aid clinical decision making. Hence, this study set out to identify and validate a small, clinically applicable immunohistochemistry (IHC) panel for prognostication in patients with EAC.
Patients and Methods
We recently identified eight molecular prognostic biomarkers using two different genomic platforms. IHC scores of these biomarkers from a UK multicenter cohort (N = 374) were used in univariate Cox regression analysis to determine the smallest biomarker panel with the greatest prognostic power with potential therapeutic relevance. This new panel was validated in two independent cohorts of patients with EAC who had undergone curative esophagectomy from the United States and Europe (N = 666).
Results
Three of the eight previously identified prognostic molecular biomarkers (epidermal growth factor receptor [EGFR], tripartite motif-containing 44 [TRIM44], and sirtuin 2 [SIRT2]) had the strongest correlation with long-term survival in patients with EAC. Applying these three biomarkers as an IHC panel to the validation cohort segregated patients into two different prognostic groups (P < .01). Adjusting for known survival covariates, including clinical staging criteria, the IHC panel remained an independent predictor, with incremental adverse overall survival (OS) for each positive biomarker (hazard ratio, 1.20; 95% CI, 1.03 to 1.40 per biomarker; P = .02).
Conclusion
We identified and validated a clinically applicable IHC biomarker panel, consisting of EGFR, TRIM44, and SIRT2, that is independently associated with OS and provides additional prognostic information to current survival predictors such as stage.
doi:10.1200/JCO.2012.45.9636
PMCID: PMC3625712  PMID: 23509313
3.  Feasibility, Safety, Acceptability and Yield of Office-based, Screening Transnasal Esophagoscopy 
Gastrointestinal endoscopy  2012;75(5):945-953.e2.
Background
Endoscopic screening for esophageal neoplasia can identify patients eligible for early intervention for pre-cancerous lesions. Unsedated transnasal esophagoscopy may provide an efficient and accurate endoscopic assessment with fewer risks and less cost compared to conventional upper endoscopy.
Objective
To assess the feasibility, safety, acceptability and yield of unsedated transnasal esophagoscopy in a primary care population.
Design
Multi-center, prospective, cross-sectional study.
Setting
Two outpatient tertiary centers.
Patients
General medical clinic population between the ages of 40 and 85.
Interventions
Unsedated, office-based transnasal esophagoscopy.
Main outcomes measurements
1) Procedure yield, 2) Completeness of examination, 3) Procedure length, 4) Adverse events and complications, 5) Choking, gagging, pain or anxiety during the examination, and 6) Overall tolerability
Results
Four hundred and twenty-six participants (mean age 55.8 ± 9.5, 43% male) enrolled in the study, and 422 (99%) completed the examination. Mean examination time was 3.7 ± 1.8 minutes. There were no serious adverse events and 12 participants (2.8%) reported minor complications. Participants reported minimal choking, gagging, pain or anxiety. The examination was well tolerated by most participants. Overall, 38% of subjects had an esophageal finding that changed management (34% erosive esophagitis, 4% Barrett’s esophagus).
Limitations
Nonrandomized study; tertiary centers only; self-selected population with a large proportion reporting esophageal symptoms.
Conclusions
Unsedated transnasal esophagoscopy is a feasible, safe, and well-tolerated method to screen for esophageal disease in a primary care population. Endoscopic findings are common in this patient population.
doi:10.1016/j.gie.2012.01.021
PMCID: PMC4154478  PMID: 22425272
Barrett’s esophagus; endoscopy; screening; transnasal; esophageal cancer
4.  The Laparoscopic Approach to Paraesophageal Hernia Repair 
Laparoscopic paraesophageal hernia repair continues to be one of the most challenging procedures facing the minimally invasive surgeon. A thorough understanding of the tenets of the operation and advanced skills in minimally invasive laparoscopy are needed for long-term freedom from symptomatic and anatomic recurrence. These include complete reduction of the hernia sac from the mediastinum back into the abdomen with careful preservation of the integrity of muscle and peritoneal lining of the crura, aggressive and complete mobilization of the esophagus to the level of the inferior pulmonary vein, clear identification of the gastroesophageal junction to allow accurate assessment of the intraabdominal esophageal length and use of Collis gastroplasty when esophageal lengthening is required for a tension-free intraabdominal repair. Liberal mobilization of the phrenosplenic and phrenogastric attachments substantially increases the mobility of the left limb of the crura, allowing for a tension-free primary closure in a large percentage of patients. The following describes our current approach to laparoscopic paraesophageal hernia repair following a decade of refinement in a high-volume center.
doi:10.1007/s11605-011-1690-8
PMCID: PMC4114521  PMID: 22160778
Hernia; hiatal; Laparoscopy; Gastroesophageal Reflux; Mesh; surgical; Gastroplasty
5.  How Much Pharyngeal Exposure Is “Normal”? Normative Data for Laryngopharyngeal Reflux Events Using Hypopharyngeal Multichannel Intraluminal Impedance (HMII) 
Background
Laryngopharyngeal reflux (LPR) can cause atypical symptoms, asthma, and pulmonary fibrosis. The aim of this study was to establish the normative data for LPR using hypopharyngeal multichannel intraluminal impedancepH (HMII).
Methods
Asymptomatic subjects underwent endoscopy followed by 24-h HMII using a specialized impedance catheter configured to detect LPR before and after a 2-week course of proton pump inhibitors (PPI). Subjects were excluded if they had esophageal pathology or a positive DeMeester score. A cohort of 24 LPR patients who had a complete response to treatment was used for comparison with the normative data.
Results
Forty subjects were enrolled. Thirty-four subjects completed one, and 25 completed both HMII testing periods off and on PPI. There was no difference in the total number of reflux events between off and on PPI [22 (8–32) and 24 (10–28), respectively, p=0.89]. The 95th percentiles of LPR off and on PPI were 0 and 1, respectively. All patients with treatment responsive LPR had pre-treatment HMII values of LPR greater than the 95th percentile.
Conclusion
LPR events are rare in an asymptomatic population. One or more LPR events should be considered abnormal in patients with LPR symptoms regardless of whether there is a positive DeMeester score.
doi:10.1007/s11605-011-1741-1
PMCID: PMC4091908  PMID: 22033702
Laryngopharyngeal reflux; Hypopharyngeal multichannel intraluminal impedance-pH; Normative data; Full column reflux
6.  Gastroesophageal Reflux Disease Symptom Severity, Proton Pump Inhibitor Use, and Esophageal Carcinogenesis 
Hypothesis
Screening for esophageal adenocarcinoma has focused on identifying Barrett esophagus (BE) in patients with severe, long-standing symptoms of gastroesophageal reflux disease(GERD). Unfortunately, 95%of patients who develop esophageal adenocarcinoma are unaware of the presence of BE before their cancer diagnosis, which means they never had been selected for screening. One possible explanation is that no correlation exists between the severity of GERD symptoms and cancer risk. We hypothesize that severe GERD symptoms are not associated with an increase in the prevalence of BE, dysplasia, or cancer in patients undergoing primary endoscopic screening.
Design
Cross-sectional study.
Setting
University hospital.
Patients
A total of 769 patients with GERD.
Interventions
Primary screening endoscopy performed from November 1, 2004, through June 7, 2007.
Main Outcomes Measures
Symptom severity, proton pump inhibitor therapy, and esophageal adenocarcinogenesis (ie, BE, dysplasia, or cancer).
Results
Endoscopy revealed adenocarcinogenesis in 122 patients. An increasing number of severe GERD symptoms correlated positively with endoscopic findings of esophagitis (odds ratio, 1.05; 95% confidence interval, 1.01-1.09). Conversely, an increasing number of severe GERD symptoms were associated with decreased odds of adenocarcinogenesis (odds ratio, 0.94; 95% confidence interval, 0.89-0.98). Patients taking proton pump inhibitors were 61.3% and 81.5% more likely to have adenocarcinogenesis if they reported no severe typical or atypical GERD symptoms, respectively, compared with patients taking proton pump inhibitors, who reported that all symptoms were severe.
Conclusions
Medically treated patients with mild or absent GERD symptoms have significantly higher odds of adenocarcinogenesis compared with medically treated patients with severe GERD symptoms. This finding may explain the failure of the current screening paradigm in which the threshold for primary endoscopic examination is based on symptom severity.
doi:10.1001/archsurg.2011.174
PMCID: PMC4086744  PMID: 21768433
7.  Quality of Life After Collis Gastroplasty for Short Esophagus in Patients With Paraesophageal Hernia 
The Annals of thoracic surgery  2011;92(5):1854-1861.
Background
Collis gastroplasty is an important component of laparoscopic giant paraesophageal hernia (GPEH) repair in patients with persistent shortened esophagus after aggressive laparoscopic mobilization. Concerns remain, however, regarding symptomatic outcomes compared with fundoplication alone. This study assessed the impact of Collis gastroplasty on quality of life after laparoscopic GPEH repair.
Methods
We performed 795 nonemergent laparoscopic GPEH repairs with fundoplication (with Collis, n = 454; fundoplication alone, n = 341). Radiographic follow-up and symptom assessment were obtained a median 22 months and 20 months, respectively, after fundoplication alone and 36 and 33 months, respectively, after Collis (p < 0.001). Radiographic recurrence, reoperation for recurrent hernia or intolerable symptoms, overall symptom improvement, and quality of life were examined.
Results
Compared with fundoplication alone, Collis patients had significantly larger GPEH (p = 0.027) and fewer comorbidities (p = 0.002). Radiographic recurrences were similar (p = 0.353). Symptom improvement was significant for both (p < 0.001), although Collis was associated with better pain resolution (p < 0.001) and less gas bloat (p = 0.003). Quality of life was good to excellent in 88% (90% Collis versus 86% fundoplication alone, p = 0.17).
Conclusions
Symptomatic outcomes after laparoscopic fundoplication with Collis gastroplasty are excellent and comparable with those of fundoplication alone. These results confirm that utilization of Collis gastroplasty, based on intraoperative assessment for shortened esophagus, is not detrimental to the overall outcome or quality of life associated with the laparoscopic approach to GPEH. Collis gastroplasty is recommended as an important procedure in the surgeon's armamentarium for laparoscopic repair of GPEH.
doi:10.1016/j.athoracsur.2011.06.030
PMCID: PMC4067000  PMID: 21944737
8.  The “Best Operation” for Esophageal Cancer? 
The Annals of thoracic surgery  2010;89(6):S2163-S2167.
There are several controversies in the surgical management of esophageal cancer including the surgical approach, extent of resection, optimal fields of lymph node dissection, and the ideal location of anastomosis. Optimal surgical treatment strategies must include accurate staging and the selection of an appropriate surgical approach. In addition, other considerations include complete resection, lymph node dissection and evaluation of oncologic and functional outcomes. The objective of this article is to review the literature and discuss our surgical approach to esophageal cancer.
doi:10.1016/j.athoracsur.2010.03.068
PMCID: PMC3769958  PMID: 20494003
9.  Cyclin E involved in early stage carcinogenesis of esophageal adenocarcinoma by SNP DNA microarray and immunohistochemical studies 
BMC Gastroenterology  2014;14:78.
Background
Cyclin E is a cell cycle regulator which is critical for driving G1/S transition. Abnormal levels of cyclin E have been found in many cancers. However, the level changes of cyclin E in esophageal adenocarcinoma and its precancerous lesion have not been well studied. Here, we focus on the gene amplification and expression of cyclin E in these lesions, and aim to ascertain the relationship with clinicopathological characteristics.
Methods
Genomic DNA was analyzed from 116 esophageal adenocarcinoma and 26 precancerous lesion patients using Affymetrix SNP 6.0 arrays. The protein overexpression of cyclin E was also detected using immunohistochemistry from tissue microarrays containing esophageal adenocarcinoma and precancerous lesions. Patient survival and other clinical data were collected and analyzed. The intensity and percentage of the cyclin E expressing cells in tissue microarrays were scored by two pathologists. Fisher exact tests and Kaplan-Meier methods were used to analyze data.
Results
By genomic analysis, cyclin E was amplified in 19.0% of the EAC samples. By immunohistochemistry, high expression of cyclin E was observed in 2.3% of squamous mucosa tissues, 3.7% in columnar cell metaplasia, 5.8% in Barrett’s esophagus, 19.0% in low grade dysplasia, 35.7% in high grade dysplasia, and 16.7% in esophageal adenocarcinoma. The differences in cyclin E high expression between neoplastic groups and non-dysplasia groups are statistically significant (p < 0.05). The prognosis for patients with high cyclin E expression appeared slightly better than for those with low cyclin E expression although this was not statistically significant (p = 0.13).
Conclusions
The expression of cyclin E significantly increases from non-dysplasia esophageal lesion to low and high grade dysplasia, suggesting that cyclin E plays an important role in the early stage of carcinogenesis. Importantly, cyclin E is also amplified and highly expressed in a subset of esophageal adenocarcinoma patients, but this increase is not associated with worse prognosis.
doi:10.1186/1471-230X-14-78
PMCID: PMC3998234  PMID: 24742107
Esophageal adenocarcinoma; Cyclin E; Amplification; High expression; Barrett’s esophagus; SNP DNA microarray; Biomarker; Overall survival
10.  A clinical prediction rule for perioperative mortality and major morbidity after laparoscopic giant paraesophageal hernia repair 
Objective
In the current era, giant paraesophageal hernia repair by experienced minimally-invasive surgeons has excellent perioperative outcomes when performed electively. Nonelective repair, however, is associated with significantly greater morbidity and mortality, even when performed laparoscopically. We hypothesized that clinical prediction tools using pretreatment variables could be developed that would predict patient-specific risk of postoperative morbidity and mortality.
Methods
We assessed 980 patients who underwent giant paraesophageal hernia repair (1997-2010; 80% elective; 97% laparoscopic). The association between clinical predictor covariates, including demographics, comorbidity and urgency of operation, and risk for in-hospital or 30-day mortality and major morbidity was assessed. Using forward, stepwise logistic regression, clinical prediction models for mortality and major morbidity were developed.
Results
Urgency of operation was a significant predictor of mortality (elective 1.1% [9/778] versus nonelective 8% [16/199]; p<0.001) and major morbidity (elective 18% [143/781] versus nonelective 41% [81/199]; p<0.001). The most common adverse outcomes were pulmonary complications (n=199; 20%). A 4-covariate prediction model consisting of age 80 or greater, urgency of operation and two Charlson comorbidity index variables (congestive heart failure and pulmonary disease) provided discriminatory accuracy for postoperative mortality of 88% while a 5-covariate model (sex, age by decade, urgency of operation, congestive heart failure and pulmonary disease) for major postoperative morbidity was 68% predictive.
Conclusions
Predictive models using pretreatment patient characteristics can accurately predict mortality and major morbidity after giant paraesophageal hernia repair. After prospective validation, these models could provide patient-specific risk prediction, tailored for individual patient characteristics, and contribute to decision-making regarding surgical intervention.
doi:10.1016/j.jtcvs.2012.12.026
PMCID: PMC3971917  PMID: 23312974
11.  F-box protein complex FBXL19 regulates TGFβ1-induced E-cadherin down-regulation by mediating Rac3 ubiquitination and degradation 
Molecular Cancer  2014;13:76.
Background
Rac3 is a small GTPase multifunctional protein that regulates cell adhesion, migration, and differentiation. It has been considered as an oncogene in breast cancer; however, its role in esophageal cancer and the regulation of its stability have not been studied. F-box proteins are major subunits within the Skp1-Cullin-1-F-box (SCF) E3 ubiquitin ligases that recognize particular substrates for ubiquitination and proteasomal degradation. Recently, we have shown that SCFFBXL19 targets Rac1 and RhoA, thus regulating Rac1 and RhoA ubiquitination and degradation. Here, we demonstrate the role of FBXL19 in the regulation of Rac3 site-specific ubiquitination and stability. Expression of TGFβ1 is associated with poor prognosis of esophageal cancer. TGFβ1 reduces tumor suppressor, E-cadherin, expression in various epithelial-derived cancers. Here we investigate the role of FBXL19-mediated Rac3 degradation in TGFβ1-induced E-cadherin down-regulation in esophageal cancer cells.
Methods
FBXL19-regulated endogenous and over-expressed Rac3 stability were determined by immunoblotting and co-immunoprecipitation. Esophageal cancer cells (OE19 and OE33) were used to investigate TGFβ1-induced E-cadherin down-regulation by Immunoblotting and Immunostaining.
Results
Overexpression of FBXL19 decreased endogenous and over-expressed Rac3 expression by interacting and polyubiquitinating Rac3, while down-regulation of FBXL19 suppressed Rac3 degradation. Lysine166 within Rac3 was identified as an ubiquitination acceptor site. The FBXL19 variant with truncation at the N-terminus resulted in an increase in Rac3 degradation; however, the FBXL19 variant with truncation at the C-terminus lost its ability to interact with Rac3 and ubiquitinate Rac3 protein. Further, we found that Rac3 plays a critical role in TGFβ1-induced E-cadherin down-regulation in esophageal cancer cells. Over-expression of FBXL19 attenuated TGFβ1-induced E-cadherin down-regulation and esophageal cancer cells elongation phenotype.
Conclusions
Collectively these data unveil that FBXL19 functions as an antagonist of Rac3 by regulating its stability and regulates the TGFβ1-induced E-cadherin down-regulation. This study will provide a new potential therapeutic strategy to regulate TGFβ1 signaling, thus suppressing esophageal tumorigenesis.
doi:10.1186/1476-4598-13-76
PMCID: PMC3994216  PMID: 24684802
Small GTPase protein; Protein stability; E3 ligase; Ubiquitin-proteasome system; TGFβ1; E-cadherin
12.  Pretreatment SUVmax predicts progression-free survival in early-stage non-small cell lung cancer treated with stereotactic body radiation therapy 
Background
This retrospective study aims to assess the usefulness of SUVmax from FDG-PET imaging as a prognosticator for primary biopsy-proven stage I NSCLC treated with SBRT.
Methods
This study includes 95 patients of median age 77 years, with primary, biopsy-confirmed peripheral stage IA/IB NSCLC. All patients were treated with 60Gy in 3 fractions with a median treatment time of six days. Local, regional, and distant failures were evaluated independently according to the terms of RTOG1021. Local, regional, and distant control, overall- and progression-free survival were estimated by the Kaplan-Meier method. Cox proportional hazards regression was performed to determine whether SUVmax, age, KPS, gender, tumor size/T stage, or smoking history influenced outcomes. SUVmax was evaluated as both a continuous and as a dichotomous variable using a cutoff of <5 and ≥5.
Results
Median follow-up for the cohort was 16 months. Median OS and PFS were 25.3 and 40.3 months, respectively. SUV with a cutoff value of 5 predicted for OS and PFS (p = .024 for each) but did not achieve significance for LC (p = .256). On Cox univariate regression analysis, SUV as a dichotomous variable predicted for both OS and PFS (p = .027 and p = .030, respectively). Defined as a continuous variable, SUVmax continued to predict for OS and PFS (p = .032 and p = .003), but also predicted LC (p = .045) and trended toward significance for DC (p = .059).
SUVmax did not predict for OS as a dichotomous or continuous variable. It did, however, predict for PFS as a continuous variable (p = .008), neared significance for local control (p = .057) and trended towards, significance for distant control (p = .092).
Conclusions
SUVmax appears to be a statistically and clinically significant independent prognostic marker for progression-free survival in patients with stage I NSCLC treated with SBRT. Prospective studies to more accurately define the role of tumor FDG uptake in the prognosis of NSCLC are warranted.
doi:10.1186/1748-717X-9-41
PMCID: PMC3922961  PMID: 24479954
13.  The Degree of Segmental Aneuploidy Measured by Total Copy Number Abnormalities Predicts Survival and Recurrence in Superficial Gastroesophageal Adenocarcinoma 
PLoS ONE  2014;9(1):e79079.
Background
Prognostic biomarkers are needed for superficial gastroesophageal adenocarcinoma (EAC) to predict clinical outcomes and select therapy. Although recurrent mutations have been characterized in EAC, little is known about their clinical and prognostic significance. Aneuploidy is predictive of clinical outcome in many malignancies but has not been evaluated in superficial EAC.
Methods
We quantified copy number changes in 41 superficial EAC using Affymetrix SNP 6.0 arrays. We identified recurrent chromosomal gains and losses and calculated the total copy number abnormality (CNA) count for each tumor as a measure of aneuploidy. We correlated CNA count with overall survival and time to first recurrence in univariate and multivariate analyses.
Results
Recurrent segmental gains and losses involved multiple genes, including: HER2, EGFR, MET, CDK6, KRAS (recurrent gains); and FHIT, WWOX, CDKN2A/B, SMAD4, RUNX1 (recurrent losses). There was a 40-fold variation in CNA count across all cases. Tumors with the lowest and highest quartile CNA count had significantly better overall survival (p = 0.032) and time to first recurrence (p = 0.010) compared to those with intermediate CNA counts. These associations persisted when controlling for other prognostic variables.
Significance
SNP arrays facilitate the assessment of recurrent chromosomal gain and loss and allow high resolution, quantitative assessment of segmental aneuploidy (total CNA count). The non-monotonic association of segmental aneuploidy with survival has been described in other tumors. The degree of aneuploidy is a promising prognostic biomarker in a potentially curable form of EAC.
doi:10.1371/journal.pone.0079079
PMCID: PMC3894223  PMID: 24454681
14.  Exome and whole genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity 
Nature genetics  2013;45(5):10.1038/ng.2591.
The incidence of esophageal adenocarcinoma (EAC) has risen 600% over the last 30 years. With a five-year survival rate of 15%, identification of new therapeutic targets for EAC is greatly important. We analyze the mutation spectra from whole exome sequencing of 149 EAC tumors/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 to C transversions at AA dinucleotides. Statistical analysis of exome data identified significantly mutated 26 genes. Of these genes, four (TP53, CDKN2A, SMAD4, and PIK3CA) have been previously implicated in EAC. The novel significantly mutated genes include chromatin modifying factors and candidate contributors: SPG20, TLR4, ELMO1, and DOCK2. Functional analyses of EAC-derived mutations in ELMO1 reveal increased cellular invasion. Therefore, we suggest a new hypothesis about the potential activation of the RAC1 pathway to be a contributor to EAC tumorigenesis.
doi:10.1038/ng.2591
PMCID: PMC3678719  PMID: 23525077
16.  Image-Guided Radiofrequency Ablation of Lung Neoplasm in 100 Consecutive Patients by a Thoracic Surgical Service 
The Annals of thoracic surgery  2009;88(5):1601-1608.
Background
Surgical resection is the standard of care for patients with resectable non-small cell lung cancer or selected patients with pulmonary metastases. However, for high-risk patients radiofrequency ablation (RFA) may offer an alternative option. The objective of this study was to evaluate computed tomography guided (CT-guided) RFA for high-risk patients and report our initial experience in 100 consecutive patients by a thoracic surgical service.
Methods
Medically inoperable patients were offered RFA. Thoracic surgeons evaluated and performed RFA under CT guidance. Patients were followed in the thoracic surgery clinic. The primary endpoint evaluated was overall survival.
Results
One hundred patients underwent image-guided RFA for lung neoplasm (40 men, 60 women; median age 73.5 years; range 26-95). Forty-six (46%) patients with primary lung neoplasm, 25 (25%) with recurrent cancer and 29 (29%) with pulmonary metastases underwent RFA. The mean follow-up for alive patients was 17 months. The median overall survival for entire group of patients was 23 months. The probabilities of 2-year survival for the entire group, primary lung cancer patients, recurrent cancer patients and metastatic cancer patients were 49 % (CI 37- 60), 50 %(CI 33-65), 55% (CI 25- 77) and 41% (CI 19-62), respectively.
Conclusion
Our experience indicates that image-guided RFA done by the thoracic surgeons is feasible and safe in high-risk patients with lung neoplasm with reasonable results in patients who are not fit for surgery. Thoracic surgeons can perform RFA safely, and should continue to investigate this new image-guided modality which may offer an alternative option in medically inoperable patients.
doi:10.1016/j.athoracsur.2009.05.012
PMCID: PMC2921840  PMID: 19853119
17.  Postesophagectomy chylothorax: Incidence, risk factors and outcomes 
The Annals of thoracic surgery  2012;93(3):897-904.
Background
Chylothorax is a rare but potentially lethal complication of esophagectomy. The study aims were to evaluate the rate of postesophagectomy chylothorax, identify associated risk factors and compare postoperative outcomes with patients who do not develop chylothorax.
Methods
We reviewed 892 consecutive patients undergoing esophagectomy (1997-2008). Preoperative, operative and postoperative details, including adverse outcomes and mortality, were analyzed.
Results
We identified postesophagectomy chylothorax in 34 patients (3.8%). Chylothorax was significantly associated with adverse outcomes, including 30-day major complications (85% vs. 46%; p<0.001) and mortality (17.7 vs. 3.9%, p<0.001). Patients with chylothorax were significantly more likely to develop sepsis (p=0.001), pneumonia (p=0.009), need reintubation (p=0.002) or require reoperation (p<0.001). Median length of stay was significantly longer (17 vs. 8 days; p=0.005). Median time to chylothorax diagnosis was 5 days. Thoracic duct ligation was performed in 62% (n=21; median 13 days after esophagectomy). Repeat duct ligation for persistent chylothorax was required in 2 patients. Squamous cell cancer histology (9/34; 26%) was an independent predictor of postoperative chylothorax (OR 4.18; 95% CI 1.39, 12.6). Odds of chylothorax were 36 times greater with average daily chest tube output >400 ml in the first 6 postoperative days (OR 35.9; 95% CI 8.2, 157.8).
Conclusions
Postoperative chylothorax is associated with significant postoperative morbidity and mortality. Patients with squamous cell cancer may be at increased risk. In addition, >400 ml average daily chest tube output in the early postoperative period should prompt fluid analysis for chylothorax to facilitate early diagnosis and consideration of thoracic duct ligation.
doi:10.1016/j.athoracsur.2011.10.060
PMCID: PMC3430511  PMID: 22245587
Chyle; Esophageal surgery; Outcomes; Postoperative care; Thoracic duct; Surgery; complications
18.  Radiofrequency Ablation for the Treatment of Pulmonary Metastases 
The Annals of thoracic surgery  2009;87(4):1030-1039.
Objectives
Surgical resection is the preferred treatment in selected patients with pulmonary metastases. In high-risk patients, radiofrequency ablation (RFA) may offer an alternative option. RFA may be used either alone or in combination with surgical resection as a lung parenchymal-sparing approach. Our objectives were to evaluate the intermediate term outcomes after RFA and to determine the prognostic variables associated with outcome in patients with pulmonary metastases
Methods
Thoracic surgeons evaluated and performed RFA under computed-tomography (CT) guidance or in combination with surgical resection as a lung parenchymal-sparing modality. Patients were monitored in the thoracic surgery clinic for recurrence and survival.
Results
Twenty-two patients {10 men, 12 women; median age 63 years (37-88)} underwent RFA. The primary cancer was colorectal in 9 (41%), renal in 2 (9%), sarcoma in 4 (18%) and other in 7 (32%) patients. CT-guided RFA was performed as a sole modality of treatment in 17 patients (77%), and in combination with surgical resection in 5 (23%) patients. There were no procedure-related mortalities. At a mean follow-up of 27 months (13.3-53.6 months), 9 patients are alive. The median survival was 29 months (CI 9.1-33.8). Size of the lesion was an important prognostic variable associated with overall and disease-free survival (P<0.05).
Conclusions
Our experience indicates that RFA is safe in this group of pulmonary metastases patients with reasonable results. Surgery remains the standard for resectable patients, but RFA offers an alternative option in selected patients or may be used as a parenchymal-sparing approach in combination with surgical resection in selected patients.
doi:10.1016/j.athoracsur.2008.12.061
PMCID: PMC2921841  PMID: 19324124
19.  Esophagectomy for T1 esophageal cancer: Outcomes in 100 patients and Implications for Endoscopic therapy 
The Annals of thoracic surgery  2009;87(4):1048-1055.
Objectives
Esophagectomy is the standard treatment for T1 esophageal cancer (EC). With an increasing interest in endoscopic therapies particularly for T1 EC, our objectives were to evaluate the long term outcomes following esophagectomy and to examine the pathological features of T1 cancer in detail to determine the suitability for potential endoscopic therapy.
Methods
We reviewed the outcomes of esophagectomy in 100 consecutive patients with T1 EC. The primary endpoints 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 (adenocarcinoma 91, squamous 9; intramucosal (T1a):29, submucosal (T1b):71). The 30 day mortality was 0%. Resection margins were microscopically negative in 99% (99/100) of patients. N1 disease was present in 21 patients (T1a:2/29(7%); T1b:19/71(27%)), associated high-grade dysplasia in 64/100 (64%) and angiolymphatic invasion in 19/100 (19%) of patients. At a median follow-up of 66 months, estimated 5-year OS and 3-year DFS were 62% and 80%, respectively, for all patients (including N1). Nodal status and tumor size were significantly associated with overall survival and disease-free survival, respectively.
Conclusions
Esophagectomy can be performed safely in patients with T1 cancer with good long term results. Many patients with T1 EC have several risk factors which 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.
doi:10.1016/j.athoracsur.2008.12.060
PMCID: PMC2912110  PMID: 19324126
20.  KIT (CD117) Expression in a Subset of Non-Small Cell Lung Carcinoma (NSCLC) Patients 
PLoS ONE  2012;7(12):e52885.
We have previously described the expression of CD44, CD90, CD117 and CD133 in NSCLC tumors, adjacent normal lung, and malignant pleural effusions (MPE). Here we describe the unique subset of tumors expressing CD117 (KIT), a potential therapeutic target. Tumor and adjacent tissue were collected from 58 patients. Six MPE were obtained before therapy. Tissue was paraffin embedded for immunofluorescent microscopy, disaggregated and stained for flow cytometry or cryopreserved for later culture. The effect of imatinib on CD117high/KIT+ tumors was determined on first passage cells; absolute cell counts and flow cytometry were readouts for drug sensitivity of cell subsets. Primary tumors divided into KITneg and KIT+ by immunofluorescence. By more sensitive flow cytometric analysis, CD117+ cytokeratin+ cells were detected in all tissues (1.1% of cytokeratin+ cells in normal lung, 1.29% in KIT “negative” tumors, 40.7% in KIT+ tumors, and 0.4% in MPE). In KIT+/CD117high, but not KIT+/CD117low tumors, CD117 was overexpressed 3.1-fold compared to normal lung. Primary cultures of CD117high tumors were sensitive to imatinib (5 µM) in short term culture. We conclude that NSCLC tumors divide into CD117low and CD117high. Overexpression of CD117 in CD117high NSCLC supports exploring KIT as a therapeutic target in this subset of patients.
doi:10.1371/journal.pone.0052885
PMCID: PMC3527622  PMID: 23285214
21.  Clinicopathologic characteristics of high expression of Bmi-1 in esophageal adenocarcinoma and squamous cell carcinoma 
BMC Gastroenterology  2012;12:146.
Background
High expression of Bmi-1, a key regulatory component of the polycomb repressive complex-1, has been associated with many solid and hematologic malignancies including esophageal squamous cell carcinoma. However, little is known about the role of Bmi-1 in esophageal adenocarcinoma. The aim of this study is to investigate the amplification and high expression of Bmi-1 and the associated clinicopathologic characteristics in esophageal adenocarcinoma and squamous cell carcinoma.
Methods
The protein expression level of Bmi-1 was detected by immunohistochemistry (IHC) from tissue microarrays (TMA) constructed at the University of Rochester from using tissues accrued between 1997 and 2005. Types of tissues included adenocarcinoma, squamous cell carcinoma and precancerous lesions. Patients’ survival data, demographics, histologic diagnoses and tumor staging data were collected. The intensity (0–3) and percentage of Bmi-1 expression on TMA slides were scored by two pathologists. Genomic DNA from 116 esophageal adenocarcinoma was analyzed for copy number aberrations using Affymetrix SNP 6.0 arrays. Fisher exact tests and Kaplan-Meier methods were used to analyze data.
Results
By IHC, Bmi-1 was focally expressed in the basal layers of almost all esophageal squamous mucosa, which was similar to previous reports in other organs related to stem cells. High Bmi-1 expression significantly increased from squamous epithelium (7%), columnar cell metaplasia (22%), Barrett’s esophagus (22%), to low- (45%) and high-grade dysplasia (43%) and adenocarcinoma (37%). The expression level of Bmi-1 was significantly associated with esophageal adenocarcinoma differentiation. In esophageal adenocarcinoma, Bmi-1 amplification was detected by DNA microarray in a low percentage (3%). However, high Bmi-1 expression did not show an association with overall survival in both esophageal adenocarcinoma and squamous cell carcinoma.
Conclusions
This study demonstrates that high expression Bmi-1 is associated with esophageal adenocarcinoma and precancerous lesions, which implies that Bmi-1 plays an important role in early carcinogenesis in esophageal adenocarcinoma.
doi:10.1186/1471-230X-12-146
PMCID: PMC3544684  PMID: 23078618
Esophageal adenocarcinoma; Bmi-1; Squamous cell carcinoma; Barrett’s esophagus; Dysplasia; High expression; Biomarker; Overall survival
23.  Comparative Genomics of Esophageal Adenocarcinoma and Squamous Cell Carcinoma 
The Annals of Thoracic Surgery  2012;93(4):1101-1106.
Background
Esophageal cancer consists of two major histologic types: esophageal squamous cell carcinoma (ESCC) predominant globally and esophageal adenocarcinoma (EAC) with a higher incidence in westernized countries. Five-year overall survival is 15%. Clinical trials frequently combine histologies although they are different diseases with distinct origins. In the evolving era of personalized medicine and targeted therapies, we hypothesized that ESCC and EAC have genomic differences important for developing new therapeutic strategies for esophageal cancer.
Methods
We explored DNA copy number abnormalities (CNAs) in 70 ESCCs with publicly available array data and 189 EAC from our group. All data was from Affymetrix single nucleotide polymorphism (SNP) arrays. Analysis was performed with Nexus 5.0 Copy number software using a SNPRank segmentation algorithm. Log ratio thresholds for copy number gain and loss were set at +/− 0.2 (approximately 2.3 and 1.7 copies respectively).
Results
ESCC and EAC genomes showed some CNAs with similar frequencies (e.g., CDKN2A, EGFR, KRAS, MYC, CDK6, MET) but also many CNAs with different frequencies between histologies, most of which were amplification events. Some of these regions harbor genes to which targeted therapies are currently available (VEGFA, ERBB2) or where agents are in clinical trials (PIK3CA, FGFR1). Other regions contain putative oncogenes that may be targeted in the future.
Conclusions
Using SNP arrays we compared genomic abnormalities in a large cohort of EAC and ESCC. We report here the similar and different frequencies of CNAs in ESCC and EAC. These results may allow development of histology-specific therapeutic agents for esophageal cancer.
doi:10.1016/j.athoracsur.2012.01.064
PMCID: PMC3401935  PMID: 22450065
Esophageal cancer; genetics; genomics
24.  MicroRNA Prognostic Signature for Nodal Metastases and Survival in Esophageal Adenocarcinoma 
The Annals of Thoracic Surgery  2011;91(5):1523-1530.
Background
The incidence of esophageal adenocarcinoma is rapidly increasing and is now one of the leading causes of cancer death in the western world. MicroRNAs (miRNAs) are small non-coding RNAs which regulate the expression of protein-encoding genes and are involved in the development, progression and prognosis of other malignancies. We hypothesized that global miRNA expression would predict survival and lymph node involvement in a cohort of surgically resected esophagus cancer patients.
Methods
miRNA analysis was performed using a custom Affymetrix microarray with probes for 462 known human, 2102 predicted human, 357 mouse and 238 rat miRNAs. miRNA expression was evaluated in 45 primary tumors, and the association of miRNA expression with patient survival and lymph node metastasis was assessed. The prognostic impact of identified unique miRNAs was verified with quantitative RT-PCR.
Results
Our data indicate that the expression of individual human miRNA species is significantly associated with post-resection patient survival. Using data from five unique miRNAs, we were further able to generate a combined miRNA expression signature that is associated with patient survival (p=0.005; HR = 3.6) independent of node involvement and overall stage. The expression of three miRNAs (miR-99b, miR-199a_3p and _5p) was also associated with the presence of lymph node metastasis.
Conclusions
These results suggest miRNA expression profiling could provide prognostic utility in staging esophagus cancer patients and treatment planning with endoscopic and neoadjuvant therapies. The alterations of specific miRNAs may further elucidate steps in the metastatic pathway and allow for development of targeted therapy.
doi:10.1016/j.athoracsur.2011.01.056
PMCID: PMC3399250  PMID: 21420070
Esophageal cancer; Genetics; genomics; Statistics; survival analysis
25.  Early G1 cyclin-dependent kinases as prognostic markers and potential therapeutic targets in esophageal adenocarcinoma 
Clinical Cancer Research  2011;17(13):4513-4522.
Purpose
Chromosomal gain at 7q21 is a frequent event in esophageal adenocarcinoma (EAC). However, this event has not been mapped with fine resolution in a large EAC cohort and its association with clinical endpoints and functional relevance are unclear.
Experimental design
We used a cohort of 116 patients to fine map the 7q21 amplification using SNP microarrays. Prognostic significance and functional role of 7q21 amplification and its gene expression were explored.
Results
Amplification of the 7q21 region was observed in 35% of tumors with a focal, minimal amplicon containing 6 genes. 7q21 amplification was associated with poor survival and analysis of gene expression identified CDK6 as the only gene in the minimal amplicon whose expression was also associated with poor survival. A low level amplification (10%) was observed at the 12q13 region containing the CDK6 homolog, CDK4. Both amplification and expression of CDK4 correlated with poor survival. A combined model of both CDK6 and CDK4 expression is a superior predictor of survival than either alone. Specific knockdown of CDK4 and/or CDK6 by siRNAs shows that they are required for proliferation of EAC cells and that their function is additive. PD-0332991 targets the kinase activity of both molecules and suppresses proliferation and anchorage-independence of EAC cells through activation of the pRB pathway.
Conclusions
We suggest that CDK6 is the driver of 7q21 amplification and that both CDK4 and CDK6 are prognostic markers and bona fide oncogenes in EAC. Targeting these molecules may constitute a viable new therapy for this disease.
doi:10.1158/1078-0432.CCR-11-0244
PMCID: PMC3390776  PMID: 21593195
Esophageal adenocarcinoma; CDK6; CDK4; PD-0332991

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