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1.  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
2.  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
4.  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
5.  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
6.  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
7.  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
8.  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
9.  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
10.  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
11.  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
12.  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.  A Phase I Study of Concurrent Chemotherapy (Paclitaxel and Carboplatin) and Thoracic Radiotherapy with Swallowed Manganese Superoxide Dismutase Plasmid Liposome Protection in Patients with Locally Advanced Stage III Non-Small-Cell Lung Cancer 
Human Gene Therapy  2010;22(3):336-342.
Abstract
Manganese superoxide dismutase (MnSOD) is a genetically engineered therapeutic DNA/liposome containing the human MnSOD transgene. Preclinical studies in mouse models have demonstrated that the expression of the human MnSOD transgene confers protection of normal tissues from ionizing irradiation damage. This is a phase I study of MnSOD plasmid liposome (PL) in combination with standard chemoradiation in surgically unresectable stage III non-small-cell lung cancer. Chemotherapy (carboplatin and paclitaxel) was given weekly (for 7 weeks), concurrently with radiation. MnSOD PL was swallowed twice a week (total 14 doses), at three dose levels: 0.3, 3, and 30 mg. Dose escalation followed a standard phase I design. Esophagoscopy was done at baseline, day 4, and 6 weeks after radiation with biopsies of the squamous lining cells. DNA was extracted and analyzed by PCR for the detection of the MnSOD transgene DNA. Ten patients with AJCC stage IIIA (three) and IIIB (seven) completed the course of therapy. Five had squamous histology, two adenocarcinoma, one large cell, and two not specified. Patients were treated in three cohorts at three dose levels of MnSOD PL: 0.3 (three patients), 3 (three patients), and 30 mg (four patients). The median dose of radiation was 77.7 Gy (range 63–79.10 Gy). Overall response rate for the standard chemoradiation regimen was 70% (n = 10). There were no dose-limiting toxicities reported in all three dosing tiers. It is concluded that the oral administration of MnSOD PL is feasible and safe. The phase II recommended dose is 30 mg.
Esophageal toxicity is a side effect of some chemoradiotherapy treatments for lung cancer. Preclinical gene therapy studies have demonstrated that expression of the human manganese peroxide dismutase gene (MnSOD) confers protection of normal tissues from ionizing irradiation damage. Here, Tarhini and colleagues follow up on previous preclinical results and conduct a phase I dose escalation study examining the safety of an ingestible genetically engineered DNA/liposome containing the human MnSOD transgene in research subjects undergoing chemotherapy.
doi:10.1089/hum.2010.078
PMCID: PMC3057216  PMID: 20873987
15.  Gastrin-releasing peptide receptor expression in non-cancerous bronchial epithelia is associated with lung cancer: a case-control study 
Respiratory Research  2012;13(1):9.
Background
Normal bronchial tissue expression of GRPR, which encodes the gastrin-releasing peptide receptor, has been previously reported by us to be associated with lung cancer risk in 78 subjects, especially in females. We sought to define the contribution of GRPR expression in bronchial epithelia to lung cancer risk in a larger case-control study where adjustments could be made for tobacco exposure and sex.
Methods
We evaluated GRPR mRNA levels in histologically normal bronchial epithelial cells from 224 lung cancer patients and 107 surgical cancer-free controls. Associations with lung cancer were tested using logistic regression models.
Results
Bronchial GRPR expression was significantly associated with lung cancer (OR = 4.76; 95% CI = 2.32-9.77) in a multivariable logistic regression (MLR) model adjusted for age, sex, smoking status and pulmonary function. MLR analysis stratified by smoking status indicated that ORs were higher in never and former smokers (OR = 7.74; 95% CI = 2.96-20.25) compared to active smokers (OR = 1.69; 95% CI = 0.46-6.33). GRPR expression did not differ by subject sex, and lung cancer risk associated with GRPR expression was not modified by sex.
Conclusions
GRPR expression in non-cancerous bronchial epithelium was significantly associated with the presence of lung cancer in never and former smokers. The association in never and former smokers was found in males and females. Association with lung cancer did not differ by sex in any smoking group.
doi:10.1186/1465-9921-13-9
PMCID: PMC3305653  PMID: 22296774
Gastrin-releasing peptide receptor; lung cancer risk; case-control study; surrogate tissue
16.  Laparoscopic Roux-en-Y Gastric Bypass for Recalcitrant Gastroesophageal Reflux Disease in Morbidly Obese Patients 
Background and Objectives:
Gastroesophageal reflux disease (GERD) is commonly associated with morbid obesity (MO). Antireflux surgery has a higher failure rate in MO and addresses only one of the comorbidities present. This paper reviews the results of laparoscopic Rouxen-Y gastric bypass (LRYGBP) performed for recalcitrant GERD in MO.
Methods:
Patients with recalcitrant GERD and a body mass index (BMI)>35 undergoing LRYGBP were included. LRYGB included crural repair, creation of a small gastric pouch (30 mL), and intestinal bypass (150 to 180 cm). All patients were followed in clinic and by telephone.
Results:
From February 1999 to April 2001, 57 patients (51 F, 6 M) with a mean age of 43 (range, 22 to 67) and a median BMI of 43 underwent LRYGBP. Hiatal hernia or esophagitis, or both, were present in 48, Barrett's in 2. LRYGBP was possible in 52 patients; 5 required open conversion. The median hospital stay was 3 days. Complications included 1 leak, 1 pulmonary emboli, 2 reoperations for internal roux limb hernia, and 7 gastrojejunal strictures. At a mean follow-up of 18 months (range, 3 to 30), all patients report improvement or no symptoms of GERD and a mean weight loss of 40 kg (range, 16 to 70). Quality of life scores (SF-36) were above national norms for physical and mental components (median 55, norms=50). GERD-health related quality of life median score was <1 (scale, 0 to 45, 0=asymptomatic, 45=worse).
Conclusion:
LRYGBP was effective for recalcitrant GERD in MO. LRYGBP also led to weight loss and improvement in other comorbidites. Surgeons with minimally invasive expertise should consider LRYGBP for treatment of GERD in the morbidly obese.
PMCID: PMC3015506  PMID: 14974657
Gastric bypass; Gastroesophagel reflux disease; Morbid obesity
17.  HER2 amplification, overexpression and score criteria in esophageal adenocarcinoma 
The HER2 oncogene was recently reported to be amplified and overexpressed in esophageal adenocarcinoma. However, the relationship of HER2 amplification in esophageal adenocarcinoma with prognosis has not been well defined. The scoring systems for clinically evaluating HER2 in esophageal adenocarcinoma are not established. The aims of the study were to establish a HER2 scoring system and comprehensively investigate HER2 amplification and overexpression in esophageal adenocarcinoma and its precursor lesion. Using a tissue microarray, containing 116 cases of esophageal adenocarcinoma, 34 cases of BE, 18 cases of low grade dysplasia and 15 cases of high grade dysplasia, HER2 amplification and overexpression were analyzed by HercepTest and CISH methods. The amplification frequency in an independent series of 116 esophageal adenocarcinoma samples was also analyzed using Affymetrix SNP 6.0 microarrays. In our studies, we have found that HER2 amplification does not associate with poor prognosis in total 232 esophageal adenocarcinoma patients by CISH and high density microarrays. We further confirm the similar frequency of HER2 amplification by CISH (18.10%; 21/116) and SNP 6.0 microarrays (16.4%, 19/116) in esophageal adenocarcinoma. HER2 protein overexpression was observed in 12.1 % (14/116) of esophageal adenocarcinoma and 6.67% (1/15) of HGD. No HER2 amplification or overexpression was identified in BE or LGD. All HER2 protein overexpression cases showed HER2 gene amplification. Gene amplification was found to be more frequent by CISH than protein overexpression in esophageal adenocarcinoma (18.10% vs 12.9%). A modified two-step model for esophageal adenocarcinoma HER-2 testing is recommend for clinical esophageal adenocarcinoma HER-2 trial.
doi:10.1038/modpathol.2011.47
PMCID: PMC3138485  PMID: 21460800
Barrett’s esophagus; dysplasia; adenocarcinoma; HER2; immunohistochemistry; DNA microarray; tissue microarray; CISH; overexpression; amplification; prognosis
18.  Minimally Invasive Esophagectomy in the Elderly 
Objectives:
In recent years, older patients are being referred for esophagectomy, and the associated morbidity and mortality is not well defined. Advances in minimally invasive techniques now allow minimally invasive esophagectomy (MIE) to be performed that may minimize the morbidity of this procedure. The objective of this report was to summarize our experience with MIE in the elderly.
Methods:
From February 1997 through February 2001, 41 patients (14 women, 27 men) 75 years of age or older (mean age 78, range 75 to 89) underwent esophagectomy (28 for adenocarcinoma, 7 squamous, 6 Barrett's with high-grade dysplasia).
Results:
Esophagectomy was performed in a minimally invasive fashion in 41 patients. No open conversions were necessary. The median ICU stay was 1 day (range 1 to 34). The median hospital stay was 7 days (range 5 to 50). Major morbidity occurred in 19% of the cases and included 1 persistent air leak, 1 case of pneumonia with acute respiratory failure, 1 tracheal tear, 1 chylothorax, and 1 myocardial infarction. Three anastomotic leaks and 1 small bowel perforation occurred. All were recognized early and treated surgically. No perioperative mortalities took place.
Conclusion:
In our center, MIE was performed in elderly patients with an acceptable morbidity, low mortality, and reduced length of hospital stay compared with that in previous reports.
PMCID: PMC3043449  PMID: 12500826
Minimally invasive esophagectomy; Elderly; Esophageal cancer
19.  The Pigtail Catheter for Pleural Drainage: A Less Invasive Alternative to Tube Thoracostomy 
Background:
Tube thoracostomy remains the standard of care for the treatment of pneumothoraces and simple effusions. This report describes a favorable experience with the 8.3 French pigtail catheter as a less invasive alternative to traditional chest tube insertion.
Methods:
We retrospectively reviewed 109 consecutive pigtail catheter placements. Catheters were inserted under local anesthesia at the bedside without radiographie guidance. Pre- and post-insertion chest radiographs were reviewed to determine efficacy of drainage.
Results:
Fifty-one of 109 patients (47%) were mechanically ventilated and 26 patients (24%) had a coagulopathy. There were no complications related to pigtail catheter insertion. Seventy-seven pigtail catheters were placed for pleural effusion and 32 for pneumothorax. Mean effusion volume decreased from 43 to 9 percent, and drainage averaged 2899 ml over 97 hours. Mean pneumothorax size diminished from 38 to 1 percent during an average 71-hour placement. Clinical success rates in the effusion and pneumothorax groups were 86 and 81 percent, respectively.
Conclusion:
The pigtail catheter offers reliable treatment of pneumothoraces and simple effusions and is a safe and less invasive alternative to tube thoracostomy.
PMCID: PMC3015347  PMID: 10323171
Pneumothorax; Pleural effusion; Catheter; Drainage
20.  Detection of Occult Lymph Node Metastases in Esophageal Cancer by Minimally Invasive Staging Combined with Molecular Diagnostic Techniques 
Background and Objectives:
Lymph node metastases are the most important prognostic factor in patients with esophageal cancer. Histologic examination misses micrometastases in up to 20% of lymph nodes evaluated. In addition, non-invasive imaging modalities are not sensitive enough to detect small lymph nodes metastases. The objective of this study was to investigate the use of reverse transcriptase-polymerase chain reaction (RT-PCR) of messenger RNA (mRNA) for carcinoembryonic antigen (CEA) to increase the detection of micrometastases in lymph nodes from patients with esophageal cancer.
Methods:
RT-PCR of CEA mRNA was performed in lymph nodes from patients with malignant and benign esophageal disease. Each specimen was examined histopathologically and by RT-PCR and the results were compared.
Results:
Metastases were present in 29 of 60 (48%) lymph nodes sample by minimally invasive staging from 13 patients with esophageal cancer when examined histopathologically. RT-PCR identified nodal metastases in 46 of these 60 (77%) samples. RT-PCR detected CEA mRNA in all 29 histologically positive samples and in 17 histologically negative lymph nodes. All lymph nodes from patients with benign disease (n=15) were negative both histopathologically and by RT-PCR. The stage of two patients was reclassified based on the RT-PCR results, which identified lymph node spread undetected histopathologically. Both of these patients developed recurrent disease after resection of the primary tumor.
Conclusions:
RT-PCR is more sensitive than histologic examination in the detection of lymph node metastases in esophageal cancer and can lead to diagnosis of a more advanced stage in some patients. The combination of minimally invasive surgical techniques in combination with new molecular diagnostic techniques may improve our ability to stage cancer patients.
PMCID: PMC3015245  PMID: 10036123
Laparoscopy; Esophageal cancer; Lymph node metastasis
21.  Minimally Invasive Approach to Esophagectomy 
Background:
Recent advances in laparoscopic and thoracoscopic surgery have made it possible to perform esophagectomy using minimally invasive techniques. The aim of this report was to present our preliminary experience with minimally invasive esophagectomy.
Methods:
We reviewed our experience on eight patients who underwent minimally invasive esophagectomy using either laparoscopic and/or thoracoscopic techniques from June 1996 to May 1997. Indications for esophagectomy included stage I carcinoma (5), palliative resection (1), Barrett's with high grade dysplasia (1) and end stage achalasia (1).
Results:
The average age was 68 years (54-82). The surgical approach to esophagectomy included laparoscopic transhiatal esophagectomy with cervical anastomosis (n=4), thoracoscopic and laparoscopic esophagectomy with cervical anastomosis (n=1), and laparoscopic mobilization with right mini-thoracotomy and intra-thoracic anastomosis (n=3). Conversion to mini-laparotomy was required in two patients (25%) to complete esophageal dissection and facilitate gastric pull-up. The mean operative time was 460 minutes. The mean intensive care stay was 1.9 days (range of 0-7 days) with a mean hospital stay of 13-8 days. Minor complications included atrial fibrillation (n=1), pleural effusion (n=2) and persistent air leak (n=1). Major complications included cervical anastomotic leak (n=1), and delayed gastric emptying requiring pyloroplasty (n=1). There was no perioperative mortality.
Conclusions:
This preliminary experience suggests that minimally invasive esophagectomy is safe and feasible in centers with experience in advanced minimally invasive surgical procedures. Further studies are necessary to determine advantages over open esophagectomy.
PMCID: PMC3015302  PMID: 9876747
Esophagectomy; Minimally invasive surgery; Laparoscopic surgery; Video-assisted thoracoscopic surgery
22.  Laparoscopic Transhiatal Esophagectomy for Barrett's Esophagus with High Grade Dysplasia 
Background:
A number of case reports have described the application of minimally invasive surgical techniques to accomplish esophagectomy. However, most reports have employed thoracoscopic or laparoscopic techniques to perform esophagectomy in addition to an “access” incision which often approaches a standard laparotomy or thoracotomy.
Case Report:
This report describes a total laparoscopic transhiatal esophagectomy in a 55 year old female with Barrett's esophagus and high grade dysplasia.
Conclusions:
The patient had an uneventful recovery and was discharged home on the fourth day after a total laparoscopic esophagectomy. This report demonstrates the technical feasibility of this complex procedure by a minimally invasive approach.
PMCID: PMC3015264  PMID: 9876716
Esophagectomy; Minimally invasive surgery; Laparoscopic surgery
23.  Outcomes after a Decade of Laparoscopic Giant Paraesophageal Hernia Repair 
OBJECTIVE
Laparoscopic repair of giant paraesophageal hernia (GPEH) is a complex operation requiring significant laparoscopic expertise. Our objective was to compare our current approach and outcomes with LRGPEH to our previous experience.
METHODS
A retrospective review of patients undergoing non-emergent LRGPEH, stratified by early and current era (1/1997–6/2003 and 7/2003–6/2008) was performed. Surgeon credentialing required a minimally invasive surgical fellowship and/or careful proctoring prior to independent LRGPEH. We evaluated clinical outcomes, barium esophagram and quality-of-life (QoL).
RESULTS
LRGPEH was performed in 662 patients (median age 70, range 19–92); median percent of herniated stomach 70% (range 30–100%). Over 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 >3. Common complications included pleural effusion (56/652; 9%) and pneumonia (29/653; 4%). Thirty-day mortality was 1.7% (11/662). Mortality and complication rates were stable over time, despite increasing comorbid disease in the current patient cohort. Post-operative GERD-health-related QoL 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
Over time, we have obtained significant minimally invasive experience and refined our approach to LRGPEH. Perioperative morbidity and mortality remain low, despite increased comorbid disease in the current patient cohort. LRGPEH provided excellent patient satisfaction and symptom improvement, even with small radiographic recurrences. Reoperation rates were comparable to the best open series.
doi:10.1016/j.jtcvs.2009.10.005
PMCID: PMC2813424  PMID: 20004917
Laparoscopy; hernia; hiatal; outcome assessment (health care); recurrence; gastroesophageal reflux; mesh; surgical
24.  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
25.  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

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