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Background: Stereotactic body radiotherapy (SBRT) has the potential to ablate localised pancreatic ductal adenocarcinoma. Selective dismutase mimetics sensitise tumours while reducing normal tissue toxicity. This trial was designed to establish the efficacy and toxicity afforded by the selective dismutase mimetic avasopasem manganese when combined with ablative SBRT for localised pancreatic ductal adenocarcinoma., Methods: In this adaptive, randomised, double-blind, placebo-controlled, phase 1b/2 trial, patients aged 18 years or older with borderline resectable or locally advanced pancreatic cancer who had received at least 3 months of chemotherapy and had an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled at six academic sites in the USA. Eligible patients were randomly assigned (1:1), with block randomisation (block sizes of 6-12) with a maximum of 24 patients per group, to receive daily avasopasem (90 mg) or placebo intravenously directly before (ie, within 180 min) SBRT (50, 55, or 60 Gy in five fractions, adaptively assigned in real time by Bayesian estimates of 90-day safety and efficacy). Patients and physicians were masked to treatment group allocation, but not to SBRT dose. The primary objective was to find the optimal dose of SBRT with avasopasem or placebo as determined by the late onset EffTox method. All analyses were done on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, NCT03340974, and is complete., Findings: Between Jan 25, 2018, and April 29, 2020, 47 patients were screened, of whom 42 were enrolled (median age was 71 years [IQR 63-75], 23 [55%] were male, 19 [45%] were female, 37 [88%] were White, three [7%] were Black, and one [2%] each were unknown or other races) and randomly assigned to avasopasem (n=24) or placebo (n=18); the placebo group was terminated early after failing to meet prespecified efficacy parameters. At data cutoff (June 28, 2021), the avasopasem group satisfied boundaries for both efficacy and toxicity. Late onset EffTox efficacy response was observed in 16 (89%) of 18 patients at 50 Gy and six (100%) of six patients at 55 Gy in the avasopasem group, and was observed in three (50%) of six patients at 50 Gy and nine (75%) of 12 patients at 55 Gy in the placebo group, and the Bayesian model recommended 50 Gy or 55 Gy in five fractions with avasopasem for further study. Serious adverse events of any cause were reported in three (17%) of 18 patients in the placebo group and six (25%) of 24 in the avasopasem group. In the placebo group, grade 3 adverse events within 90 days of SBRT were abdominal pain, acute cholangitis, pyrexia, increased blood lactic acid, and increased lipase (one [6%] each); no grade 4 events occurred. In the avasopasem group, grade 3-4 adverse events within 90 days of SBRT were acute kidney injury, increased blood alkaline phosphatase, haematoma, colitis, gastric obstruction, lung infection, abdominal abscess, post-surgical atrial fibrillation, and pneumonia leading to respiratory failure (one [4%] each).There were no treatment-related deaths but one late death in the avasopasem group due to sepsis in the setting of duodenal obstruction after off-study treatment was reported as potentially related to SBRT., Interpretation: SBRT that uses 50 or 55 Gy in five fractions can be considered for patients with localised pancreatic ductal adenocarcinoma. The addition of avasopasem might further enhance disease outcomes. A larger phase 2 trial (GRECO-2, NCT04698915) is underway to validate these results., Funding: Galera Therapeutics., Competing Interests: Declaration of interests CMT reports grant or contracts with US National Institutes of Health (NIH and CPRIT), licenses with Xerient Pharmaceuticals for licensed or individual patent for radioprotection of the upper gastrointestinal tract, and consulting fees with Phebry. JMF reports consultant and advisory board roles for Viewray, and payment for presentations for Boston Scientific. TAA reports an unfunded study steering committee role for Galera Therapeutics (Galera). MP reports research support to their institution from Merck and Varian, royalties to serve as section editor for cholangiocarcinoma, consulting fees from Voxelmetric and Syntactx, a speakers honorarium for Oakstone CME, advisory board participation for Varian, and an unpaid ASTRO Education Committee role. BC reports royalties from Springer, honoraria for Varian-Educational and Oakstone, and a leadership or fiduciary role with the National Comprehensive Cancer Network. MSB reports funding from Galera, institution grants or contracts from Nanobiotix, Silenseed, Trisalis, Artidis, SUC2, CPRIT, AstraZeneca, Merck, Siemens Medical, and Boston Scientific (Augmenix) and consulting fees from Oncosil and Strapax. SP reports consulting or advisory roles for Zymeworks, Ipsen, Novartis, Janssen, Boehringer Ingelheim, and AskGene Pharma, and institutional research funding from Mirati Therapeutics, Lilly, Xencor, Novartis, Rgenix, Bristol-Myers Squibb, Astellas Pharma, Framewave, 4D Pharma, Boehringer Ingelheim, NGM Biopharmaceuticals, Janssen, Arcus Biosciences, Elicio Therapeutics, Bionte, Ipsen, Zymeworks, Pfizer, ImmunoMET, Immuneering, and Amal Therapeutics. C-WDT reports an institution-sponsored research agreement with Sirtex, and individual and institutional honoraria from PanTher. DWK reports grants or contracts from Bold Therapeutics, and payment or honoraria from AstraZeneca. JC reports travel expense money from Galera. EJK reports research grants and contracts from NIH, US Department of Defense, Cancer Prevention and Research Institute of Texas, and Artidis, royalties or licenses from Taylor and Francis, and Kallisio, consulting fees from Kallisio, AstraZeneca, RenovoRx, MD Anderson Physician Network, MJH Life Sciences, and Quantum Aurea Capital, honoraria from Northwestern University and Amplity, a patent pending for 3D oral stents, scientific and medical advisory board roles for Cholangiocarcinoma Foundation, and stock or stock options with Quantum Aurea Capital. PD reports consulting fees from the American Society for Radiation Oncology, payment or honoraria from American Society for Clinical Oncology, Conveners, Physicians Education Resource, Imedex, and Bayer. RAW reports royalties from McGraw-Hill. GOS reports a research agreement with Artios Pharma. RSST reports institutional funding from Galera and NIH National Cancer Institute (NCI). YY reports personal fees from AbbVie, Amgen, Bexion Pharmaceuticals, BeyondSpring Pharmaceuticals, Boehringer Ingelheim Pharmaceuticals, Bristol Myers Squibb, Century Therapeutics, Enliven Therapeutics, Repare Therapeutics, Servier Pharmaceuticals, Starpax Pharmaceuticals, and Vertex Pharmaceuticals during the conduct of the study. PFT reports research funding from NIH NCI. RAB is an employee and officer of, reports receiving compensation from, and holds equity in the sponsor, Galera, residual royalties resulting from the acquisition of Confluence from Aclaris Therapeutics, stock or stock options with Galera, Euclises, Aclaris Therapeutics, and Novocure, and patents for methods for treatment of diseases, (US Pat 10,493,081, 2019 issued to Galera); a patent methods for treatment of diseases (US Pat 9,149,483, 2015 issued to Galera). JH was an employee and officer of, reports receiving compensation from, and holds equity in the sponsor, Galera. JMH reports research funding to their institution and support for attending a meeting from Canopy Cancer Collective, royalties or licenses from Springer, stock or stock options with Histosonics, and consulting fees from Histosonics and Boston Scientific. SEH is an employee of MyCareGorithm and has her own limited liability company, Beyond the White Coat. She has received travel assistance from ViewRay, stock options from Rittenhouse, and her institution received research funding from ViewRay and Galera. LEC, JAJ, VB, MM, GM, NR, EBL, MHGK, SB, and SM declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: The tumor microbiome (TM) has been linked to pancreatic cancer prognosis. Specific microbes can confer tumor resistance to therapies. Early knowledge of the TM at time of diagnosis would be clinically relevant for precision therapy based on microbial composition. However, it is difficult to define the TM prior to surgical resection., Methods: In this pilot feasibility study, patients underwent Endoscopic Ultrasound-Fine Needle Aspiration (EUS-FNA) biopsy of pancreatic adenocarcinoma. These samples were analyzed using 16S rRNA and internal transcribed spacer (ITS) sequencing for characterization of the tumor bacteria and fungi., Result: After in silico decontamination and comparison to non-matched tumor, we were able to characterize the TM in biopsies, which was comparable to the TM from surgical specimens., Discussion: EUS-FNA biopsy may represent a feasible modality to characterize the pancreatic TM prior to surgical resection with proper decontamination strategies and improvements in matched controls., Competing Interests: Author JW is founder and owner of Resphera Biosciences LLC. Author FM has a pending patent in microbiome profiling and is part of the SAB for Neologics Bio. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wright, Bartelli, Baydogan, White, Kim, Bhutani and McAllister.)

Introduction: Gastroesophageal adenocarcinoma is relatively common in elderly patients as the incidence increases with age. However, the optimal treatment approach is not well established in this group of patients. The aim of this study is to review our experience for localized gastroesophageal adenocarcinoma in patients aged ≥80 years and to assess association between patient characteristics, clinical factors, and overall survival (OS) in order to optimize the therapeutic approaches for this population., Methods: Patients ≥80 years old treated for localized gastroesophageal adenocarcinoma were retrospectively analyzed. Survival curves were estimated using the Kaplan-Meier method. Univariate and multivariate Cox proportional hazards regression models were applied to assess the association between patient characteristics and OS. Factors that were significant in the multivariate model were included in the final reduced model., Results: 127 patients ≥80 years old, were included in this study with median age of 83 years. The median follow-up time was 3.2 years, and median OS was 2.5 years (95% CI: 2.0-3.1 years). Independent prognostic factors for OS were Eastern Cooperative Oncology Group (ECOG) performance status (PS) (p = 0.003), baseline clinical stage (p = 0.01), and surgery (p = 0.001). ECOG PS, tumor location, baseline stage, tumor grade, and surgery were included in the final reduced model., Conclusion: Surgical treatment can improve survival in elderly patients. Therapeutic decisions should be based on the patients' general condition rather that age alone., (© 2022 S. Karger AG, Basel.)

Background: Endoscopic ultrasound-guided tissue acquisition (EUS-TA), especially endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA), is the mainstay of tissue acquisition for the diagnosis of pancreatic ductal adenocarcinoma (PDAC). Recently, endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) using flexible biopsy needles has been used for patients with PDAC in an effort to increase diagnostic yields and biomarker testing. However, the role of EUS-TA in biomarker testing for personalized therapy or precise chemotherapy for PDAC is not well established., Methods: PDAC cases with specimens acquired through concurrent EUS-FNA and EUS-FNB were identified retrospectively. Smears were prepared from EUS-FNA sampling, and cell blocks (CBs) were prepared from EUS-FNB sampling. Rapid onsite evaluation was conducted for all cases for diagnostic adequacy. The adequacy for biomarker testing, including next-generation sequencing (NGS) and immunohistochemistry (IHC) assays, was evaluated, and cases with smears and CBs adequate for NGS were processed for targeted NGS., Results: There were 26 PDAC cases concurrently sampled by EUS-FNA and EUS-FNB. EUS-FNA smears for all 26 cases and EUS-FNB CBs for 20 cases (77%) were diagnostic for PDAC. Twenty-one smears (81%) and 11 CBs (42%) were adequate for NGS. Nine cases with both smears and CBs adequate for NGS underwent NGS, which identified clinically significant gene mutation variants, including KRAS, TP53, and SMAD4 mutations., Conclusions: Both EUS-FNA and EUS-FNB can provide optimal material for targeted NGS for PDACs. In PDAC cases subjected to concurrent EUS-FNA and EUS-FNB, EUS-FNA specimens had greater diagnostic yields and more adequate material for NGS than EUS-FNB specimens, whereas EUS-FNB was more suitable for IHC-based biomarker testing., (© 2021 American Cancer Society.)

Objective: We aimed to evaluate the frequency of paratracheal lymph nodes (LN) metastases and their prognostic influence., Summary Background Data: Paratracheal LNs are considered regional nodes in the esophageal cancer classification, but their metastatic rate and influence on survival remain unclear., Methods: One thousand one hundred ninety-nine patients with resectable esophageal or gastroesophageal junction adenocarcinoma (EAC) (January 2002 and December 2016) in our Gastrointestinal Medical Oncology Database were analyzed. Paratracheal LNs were defined as1R, 1L, 2R, 2L, 4R, and 4L, according to the 8th American Joint Committee on Cancer classification., Results: Of 1199 patients, 73 (6.1%) had positive paratracheal LNs at diagnosis. The median overall survival (OS) of 73 patients with initial paratracheal LN involvement was 2.10 years (range 0.01-10.1, 5-yrs OS 24.2%). Of 1071 patients who were eligible for recurrence evaluation, 70 patients (6.5%) developed paratracheal LN metastases as the first recurrence. The median time to recurrence was 1.28 years (range 0.28-5.96 yrs) and the median OS following recurrence was only 0.95 year (range 0.03-7.88). OS in 35 patients who had only paratracheal LN recurrence was significantly longer than in patients who had other recurrences (median OS 2.26 vs 0.51 yrs, 5-yrs OS; 26.8% vs 0%, P < 0.0001). Higher T stage (T3/T4) was an independently risk factor for paratracheal LN recurrence (odds ratio 5.10, 95% confidence interval 1.46-17.89). We segregated patients in 3 groups based on the distance of tumor's proximal edge to esophagogastric junction (low; ≤2 cm, medium; 2.0-7.0 cm, and high; >7.0 cm). Paratracheal LN metastases were more frequent with the proximal tumors (low, 4.2%; medium, 12.0%; high, 30.3%; Cochran-Armitage Trend test, P < 0.001)., Conclusion: Paratracheal LN metastases were associated with a shorter survival in resectable EAC patients. Alternate approaches to prolong survival of this group of patients are warranted., Competing Interests: The authors report no conflicts of interest., (Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.)

Purposes: Preoperative chemoradiation is a potential treatment option for localized gastric adenocarcinoma (GAC). Currently, the response to chemoradiation cannot be predicted. We analyzed the pretreatment maximum standardized uptake value (SUV max ) and total lesion glycolysis (TLG) on positron emission tomography/computed tomography as potential predictors of the response to chemoradiation., Methods: We analyzed the SUV max and TLG data from 59 GAC patients who received preoperative chemoradiation. We used logistic regression models to predict a pathologic complete response (pCR) and Kaplan-Meier curves to determine overall survival among patients with high and low SUV max or TLG., Results: Twenty-nine patients (49%) had Siewert type III adenocarcinoma and 30 (51%) had tumors located in the lower stomach. Forty-one patients had poorly differentiated GAC, and 26 had signet ring cells. The median SUV max was 7.3 (0-28.2) and the median TLG was 56.6 (0-1881.5). Patients with signet ring cells had a low pCR rate, as well as a low SUV max and TLG. In the multivariable logistic regression model, high SUV max was a predictor of pCR (odds ratio = 11.1, 95% confidence interval = 2.12-50.0, p = 0.004). Overall survival was not associated with the SUV max (log-rank p = 0.69) or TLG (log-rank p = 0.85) CONCLUSION: A high SUV max was associated with sensitivity to chemoradiation and pCR in GAC, and signet ring cells seemed to confer resistance.

Background: As cancer patients are surviving longer, more patients manifest brain metastases (BRMs). However, the rate of BRMs from upper gastrointestinal cancer is unclear. We therefore evaluated the frequency and prognostic effect of BRMs in this setting., Methods: We analyzed records of 2348 patients who were treated between January 2002 and December 2016 for upper gastrointestinal cancer, including esophageal and gastroesophageal junction adenocarcinoma (EAC; proximal EAC, Siewert types I and II), esophageal squamous cell carcinoma (ESCC), and gastric adenocarcinoma (GAC; Siewert type III and stomach cancer) in our Gastrointestinal Medical Oncology Database. Frequency, risk factors, and survival after BRMs were evaluated., Results: Of 2348 patients, 68 (2.9%) had BRMs upon follow-up. The BRM rates were as follows: proximal EAC, 4.8%; Siewert type I, 5.9%; Siewert type II, 2.2%; Siewert type III, 0.7%; ESCC: 1.2%; and stomach cancer, 0%. Among EAC patients, Siewert type I and lymph node metastases were independent the risk factors for BRMs in the multivariable analysis. The median overall survival (OS) in the 68 patients with BRMs was only 1.16 years (95% CI 0.78-1.61). However, OS for patients who had a solitary BRM, who had BRM but no other distant metastasis, or who underwent surgery or stereotactic radiosurgery favorable., Conclusion: Patients with proximally located adenocarcinoma, or with lymph node metastases are at a higher risk for BRMs and patients fare better after treatment of isolated BRM.

Objective: We aimed to determine whether tumor metabolism could be prognostic of cure in L-EAC patients who receive definitive chemoradiation., Summary Background Data: Patients with inoperable localized esophageal adenocarcinoma (L-EAC) often receive definitive chemoradiation; however, biomarkers and/or imaging variables to prognosticate cure are missing., Methods: Two hundred sixty-six patients with L-EAC who had chemoradiation but not surgery were analyzed from the prospectively maintained EAC databases in the Department of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center (Texas, USA) between March 2002 and April 2015. Maximum standardized uptake value (SUVmax) and total lesion glycolysis (TLG) from the positron emission tomography data were evaluated., Results: Of 266 patients, 253 (95%) were men; the median age was 67 years (range 20-91 yrs) and 153 had poorly differentiated L-EAC. The median SUVmax was 10.3 (range 0-87) and the median TLG was 85.7 (range 0-3227). Both SUVmax and TLG were higher among those with: tumors >5 cm in length, high clinical stage, and high tumor and node categories by TNM staging (all P < 0.0001). Of 234 patients evaluable for cure, 60 (25.6%) achieved cure. In the multivariable logistic regression model, low TLG (but not low SUVmax) was associated with cure (continuous TLG value: odds ratio 0.70, 95% confidence interval (CI) 0.54-0.92). TLG was quantified into 4 quartile categorical variables; first quartile (Q1; <32), second quartile (Q2; 32.0-85.6), third quartile (Q3; 85.6-228.4), and fourth quartile (Q4; >228.4); the cure rate was only 10.3% in Q4 and 5.1% in Q3 but increased to 28.8% in Q2, and 58.6% in Q1. The cross-validation resulted in an average accuracy of prediction score of 0.81 (95% CI, 0.75-0.86)., Conclusions: In this cross-validated model, 59% of patients in the 1st quartile were cured following definitive chemoradiation. Baseline TLG could be pursued as one of the tools for esophageal preservation.

Hippo/YAP1 signaling is a major regulator of organ size, cancer stemness, and aggressive phenotype. Thus, targeting YAP1 may provide a novel therapeutic strategy for tumors with high YAP1 expression in esophageal cancer (EC). Chromatin immunoprecipitation (ChiP) and quantitative ChiP-PCR were used to determine the regulation of the chromatin remodeling protein bromodomain-containing protein 4 (BRD4) on YAP1. The role of the bromodomain and extraterminal motif (BET) inhibitor JQ1, an established BRD4 inhibitor, on inhibition of YAP1 in EC cells was dissected using western blot, immunofluorescence, qPCR, and transient transfection. The antitumor activities of BET inhibitor were further examined by variety of functional assays, cell proliferation (MTS), tumorsphere, and ALDH1+ labeling in vitro and in vivo. Here, we show that BRD4 regulates YAP1 expression and transcription. ChiP assays revealed that BRD4 directly occupies YAP1 promoter and that JQ1 robustly blocks BRD4 binding to the YAP1 promoter. Consequently, JQ1 strongly suppresses constitutive or induced YAP1 expression and transcription in EC cells and YAP1/Tead downstream transcriptional activity. Intriguingly, radiation-resistant cells that acquire strong cancer stem cell traits and an aggressive phenotype can be effectively suppressed by JQ1 as assessed by cell proliferation, tumorsphere formation, and reduction in the ALDH1+ cells. Moreover, effects of JQ1 are synergistically amplified by the addition of docetaxel in vitro and in vivo. Our results demonstrate that BRD4 is a critical regulator of Hippo/YAP1 signaling and that BRD4 inhibitor JQ1 represents a new class of inhibitor of Hippo/YAP1 signaling, primarily targeting YAP1 high and therapy-resistant cancer cells enriched with cancer stem cell properties., (© 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

Background: Preoperative induction chemotherapy followed by chemoradiation yields better R0 resection rates, pathologic complete response (pCR) rates and improved survival for localized gastric adenocarcinoma (GAC). We report the effect of three-drug induction chemotherapy on a large cohort of localized GAC patients., Methods: We identified 97 patients with localized GAC who received three-drug induction chemotherapy followed by preoperative chemoradiation therapy. We assessed various endpoints (overall survival [OS], recurrence-free survival [RFS], R0 resection and pCR rate)., Results: The median follow-up time was 3.5 years (range; 0.4-16.7). The induction chemotherapy regimen was a fluoropyrimidine and a platinum compound (cisplatin or oxaliplatin) with a taxane (docetaxel or paclitaxel) for 95% of patients. Seventy-three (75.3%) out of 97 patients underwent planned surgery. R0 resection and pCR rae were 93.2 and 20.6%, respectively. Pathologic partial response (<50% residual carcinoma) rate was 50.7%. The median OS was 6.4 years (95% Cl 3.3-12.4) for the entire cohort and 11.1 years (95% Cl 7.1-not estimable) for patients that underwent surgery. The estimated 2- and 5-year OS rates were 72.4% (95% CI 62.1-80.3) and 54.3% (95% CI 43.2-64.1) for the entire cohort and 83.2% (95% CI 72.3--90.1) and 66% (95% CI 52.3-75.8) for patients that underwent surgery. Pathologic lesser stage (stage I/II vs. stage III/IV) (p = 0.001) and R0 resection (p = 0.02) were independently associated with longer RFS in the multivariate analysis., Conclusion: Our data shows that three-drug combination is feasible without providing substantial advantage compared with two-drug combination in this setting of preoperative induction chemotherapy followed by chemoradiation and surgery., (© 2020 S. Karger AG, Basel.)

Background: PVT1 has emerged as an oncogene in many tumor types. However, its role in Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) is unknown. The aim of this study was to assess the role of PVT1 in BE/EAC progression and uncover its therapeutic value against EAC., Methods: PVT1 expression was assessed by qPCR in normal, BE, and EAC tissues and statistical analysis was performed to determine the association of PVT1 expression and EAC (stage, metastases, and survival). PVT1 antisense oligonucleotides (ASOs) were tested for their antitumor activity in vitro and in vivo., Results: PVT1 expression was up-regulated in EACs compared with paired BEs, and normal esophageal tissues. High expression of PVT1 was associated with poor differentiation, lymph node metastases, and shorter survival. Effective knockdown of PVT1 in EAC cells using PVT1 ASOs resulted in decreased cell proliferation, invasion, colony formation, tumor sphere formation, and reduced proportion of ALDH1A1 + cells. Mechanistically, we discovered mutual regulation of PVT1 and YAP1 in EAC cells. Inhibition of PVT1 by PVT1 ASOs suppressed YAP1 expression through increased phosphor-LATS1and phosphor-YAP1 while knockout of YAP1 in EAC cells significantly suppressed PVT1 levels indicating a positive regulation of PVT1 by YAP1. Most importantly, we found that targeting both PVT1 and YAP1 using their specific ASOs led to better antitumor activity in vitro and in vivo., Conclusions: Our results provide strong evidence that PVT1 confers an aggressive phenotype to EAC and is a poor prognosticator. Combined targeting of PVT1 and YAP1 provided the highest therapeutic index and represents a novel therapeutic strategy.

Background and Aims: Most patients diagnosed with esophageal adenocarcinoma do not carry a known diagnosis of Barrett's esophagus (BE), suggesting that an improved approach to screening may potentially be of benefit. The use of dysplasia as a biomarker and random biopsy protocols for its detection has limitations. In addition, detecting and appropriately classifying dysplasia in patients with known BE can be difficult., Methods: This document reviews several technologies with a recently established or potential role in the diagnosis and/or surveillance of BE as well as risk stratification for progression to esophageal adenocarcinoma., Results: Two technologies were reviewed for imaging or tissue sampling: (1) wide-area transepithelial sampling and (2) volumetric laser endomicroscopy. Four technologies were reviewed for molecular and biomarker technologies for diagnosis and risk stratification: (1) Cytosponge, (2) mutational load, (3) fluorescence in situ hybridization, and (4) immunohistochemistry., Conclusion: Several technologies discussed in this document may improve dysplasia detection in BE in a wide-field manner. Moreover, the addition of different biomarkers may aid in enhanced risk stratification to optimize approaches to surveillance or treatment for patients with BE., (Copyright © 2019. Published by Elsevier Inc.)

Malignant transformation of ectopic pancreas tissue is a diagnostic challenge as clinical symptoms and radiographic features of these tumors are non-specific. Given the rarity of these lesions, it is usually neither suspected nor included in the diagnostic workup of different tumors. We conducted a comprehensive literature review regarding malignancy arising from ectopic pancreas for a better understanding of its frequency, clinicopathological features, and prognosis. A literature search was performed in three major databases: PubMed, Cochrane, and Web of Science. Fifty-four well-documented cases of malignant ectopic pancreas were identified in the published literature. Our analysis provided the following observations: (1) there was a slight predominance of males over females; (2) most patients with malignant transformation of ectopic pancreas were middle-aged; (3) most commonly, the tumor was located in the stomach; (4) most tumors were adenocarcinomas; (5) most frequently, the malignancy arose within a type I heterotopia according to Heinrich classification; (6) macroscopically, a subepithelial-like appearance was most frequently observed; and (7) improved prognosis for ectopic pancreatic malignancies in comparison with reported survival data for orthotopic pancreatic cancer. Even if the majority of cases of ectopic pancreas are incidental findings and malignant transformation is a rare event, pancreatic heterotopy should be considered as a source of potentially malignant lesions.

Objective: To discern recurrence risk stratification and investigate its influence on postoperative surveillance in patients with esophageal adenocarcinoma (EAC) after neoadjuvant chemoradiotherapy (CRT)., Background: Reports documenting recurrence risk stratification in EAC after neoadjuvant CRT are scarce., Methods: Between 1998 and 2014, 601 patients with EAC who underwent neoadjuvant CRT followed by esophagectomy were included for analysis. The pattern, site, timing, and frequency of the first recurrence and potential prognostic factors for developing recurrences were analyzed. This cohort was used as the training set to propose a recurrence risk stratification system, and the stratification was further validated in another cohort of 172 patients., Results: A total of 150 patients (25.0%) achieved pathologic complete response (pCR) after neoadjuvant CRT and the rest were defined as the non-pCR group (n = 451) in the training cohort. After a median follow-up of 63.6 months, the pCR group demonstrated a significantly lower locoregional (4.7% vs 19.1%) and distant recurrence rate (22.0% vs.44.6%) than the non-pCR group (P < 0.001). Based on independent prognostic factors, patients were stratified into 4 recurrence risk categories: pCR with clinical stage I/II, pCR with clinical stage III, non-pCR with pN0, and non-pCR with pN+, with corresponding 5-year recurrence-free survival rates of 88.7%, 65.8%, 55.3%, and 33.0%, respectively (P < 0.001). The risk stratification was reproducible in the validation cohort., Conclusions: We proposed a recurrence risk stratification system for EAC patients based on pathologic response and pretreatment clinical stage. Risk-based postoperative surveillance strategies could be developed for different risk categories.

Background: Surgery is the best option for cure of localised gastric adenocarcinoma (GAC). When surgery is not possible due to comorbidities or patient choice, definitive chemoradiation is an option. We report on one of the largest cohorts of localised GAC patients who did not have surgery., Methods: We identified 71 patients with localised GAC who received chemo/chemoradiation therapy but did not have surgery. We assessed various end-points: overall survival (OS), relapse-free survival (RFS), and clinical complete response (cCR; negative post therapy biopsy and no evidence of cancer by imaging)., Results: The median follow-up time was 1.8 years (range; 0.4-10.6). Most of the patients were men (64.8%), and the median age was 73 years (range; 30-96). Reason for not having surgery included comorbidities in 34 (47.9%), poor performance status 14 (19.7%), and patient refusal 23 (32.4%). Of all 71 patients, a complete restaging evaluation with endoscopy and imaging could be performed for 50, and 32 (45.1%) achieved a cCR. For the entire cohort, the median OS was 2.1 years (95% confidence interval [CI] 1.78-2.55). The estimated OS rates at 2 and 5 years were 54% and 18%, respectively. Female gender (HR 0.39, 95% CI 0.16-0.98, p = 0.045) and chemoradiation (HR 0.25, 95% CI 0.06-1.01; p = 0.05) were independently associated with longer OS in the multivariate analysis., Conclusion: Our data show that patients with localised GAC treated with chemotherapy and/or chemoradiation, who do not undergo surgery, have a 5-year OS rate of 18%., (Copyright © 2018. Published by Elsevier Ltd.)

Background: Positive peritoneal cytology (+PCyt) or gross carcinomatosis (GPC) carries a poor prognosis. Laparoscopic staging to detect +PCyt/GPC is recommended for all ≥T1b gastric adenocarcinoma (GAC). The natural history of patients with GAC who have baseline -PCyt and then undergo multimodality therapy is not well documented, particularly for the risk of subsequent GPC., Methods: We identified 238 GAC patients with baseline -PCyt who were followed for the development of peritoneal carcinomatosis (PC). Standard statistical methods were employed., Results: Of 238 patients, 192 had attempted surgery after preoperative therapy. Of these, 13 patients (6.8%) had GPC and one had liver metastases, thus surgery was aborted. We followed 164 patients who had an R0 resection. The median follow-up duration was 3.4 (range, 0.6-18) years. The rate of PC was 13.4%, (22/164 patients) and the median time to PC was 15.6 months. Female gender was associated with PC on multivariate analysis. The 5-year OS rate for patients without subsequent PC was 75%. Conclusion Even with baseline -Cyt, ∼25% of patients develop PC following multimodality therapy. Patients who do not develop PC have an excellent OS rate. Further research is warranted to detect PC at baseline by the use of biomarkers., (© 2017 Wiley Periodicals, Inc.)

Introduction: Barrett's esophagus (BE) may be present in patients with esophageal adenocarcinoma (EAC) after bimodality therapy (BMT). There is no specific guidance for follow-up of these patients with regard to the presence of BE or dysplasia. In this study, we assessed the outcomes of patients who, after BMT, had BE and those who did not., Method: Patients with EAC who had BMT were identified and analyzed retrospectively in two groups, with and without BE. We compared patient characteristics and outcome variables (local, distant, and no recurrence)., Results: Of 228 patients with EAC, 68 (29.8%) had BE before BMT. Ninety-eight (42.9%) had BE after BMT, and endoscopic intervention was done in 11 (11.2%). With a median follow-up of 37 months, the presence of post-BMT BE was not significantly associated with overall survival (OS) and local recurrence-free survival (LRFS). Similarly, endoscopic intervention was not significantly associated with OS and LRFS. Fifty (73.5%) patients with BE before BMT had BE after BMT (p < 0.0001)., Conclusion: The presence of BE after BMT was not associated with increased risk of local recurrence. The local recurrence rate was not influenced by endoscopic intervention. Prospective studies are warranted to generate guidance for intervention, if necessary, for this group of EAC patients., (© 2018 S. Karger AG, Basel.)

Objective: The goal of surveillance after therapy of localized esophageal cancer (LEC) is to identify actionable relapses amenable to salvage; however, the current surveillance algorithms are not optimized. We report on a large cohort of LEC patients with actionable locoregional relapses (LRRs)., Methods: Between 2000 and 2013, 127 (denominator = 752) patients with actionable LRR were identified. Histologic/cytologic confirmation was the gold standard. All surveillance tools (imaging, endoscopy, fine needle aspiration) were assessed., Results: Most patients were men (89%), had adenocarcinoma (79%), and had no new symptoms (72%) when diagnosed with LRR. In trimodality patients, endoscopic confirmation of positron emission tomography-computed tomography-suspected LRR occurred in only 44%, and 56% required additional tools (e.g., fine needle aspiration). Alternatively, in bimodality patients, endoscopy confirmed LRRs in 81%. Trimodality patients had a higher risk of subsequent LRR/distant metastases after the first LRR than the bimodality patients (p = 0.03). In all patients, 78% of the subsequent relapses were distant. For patients who were salvaged, survival was significantly prolonged (50.6 vs. 25.1 months, p < 0.01)., Conclusions: Patients live longer after successful salvage of the LRR than if salvage is not possible. After LRR, patients have a high risk of subsequent distant metastasis and whether the second relapse is local or distant, survival is uniformly poor., (© 2018 S. Karger AG, Basel.)

Background: Reports are limited regarding clinical and pretreatment features that might predict a pathological complete response (pathCR) after treatment in patients with esophageal cancer (EC). This might allow patient selection for different strategies. This study examines the association of a pathCR with pretreatment variables, overall survival (OS), recurrence-free survival (RFS), and patterns of recurrence in a large cohort from a single institution., Methods: The baseline clinical features of 911 consecutive patients with EC who were treated with trimodality therapy from January 2000 to November 2013 were analyzed. A pathCR was defined as a surgical specimen with no residual carcinoma (primary or nodes). Logistic regressions were used to identify independent baseline features associated with a pathCR. We applied log-rank testing and Cox models to determine the association between a pathCR and the time-to-event outcomes (OS and RFS)., Results: Of 911 patients, 218 (23.9%) achieved a pathCR. The pathCR rate was 23.1% for adenocarcinoma and 32.2% for squamous cell carcinoma. A lower pathCR rate was observed for 1) older patients (>60 years), 2) patients with poorly differentiated tumors, 3) patients with signet ring cells (SRCs), and 4) patients with a higher T stage. Patients with a pathCR had longer OS and RFS than those without a pathCR (P = .0021 and P = .0011, respectively). Recurrences occurred more in non-pathCR patients. Distant metastases were the most common type of recurrence. PathCR patients developed brain metastases at a marginally higher rate than non-pathCR patients (P = .051)., Conclusions: In this large cohort study, a pathCR is confirmed to be associated with better OS and RFS. The presence of a poorly differentiated tumor or SRCs reduces the likelihood of a pathCR. Future research should focus on molecular classifiers. Cancer 2017;123:4106-4113. © 2017 American Cancer Society., (© 2017 American Cancer Society.)

Background: Predictive biomarkers or signature(s) for oesophageal cancer (OC) patients undergoing preoperative therapy could help administration of effective therapy, avoidance of ineffective ones, and establishment new strategies. Since the hedgehog pathway is often upregulated in OC, we examined its transcriptional factor, Gli-1, which confers therapy resistance, we wanted to assess Gli-1 as a predictive biomarker for chemoradiation response and validate it., Methods: Untreated OC tissues from patients who underwent chemoradiation and surgery were assessed for nuclear Gli-1 by immunohistochemistry and labelling indices (LIs) were correlated with pathologic complete response (pathCR) or

Background: To assess the impact of histology on recurrence patterns and survival outcomes in patients with esophageal cancer (EC) treated with definitive chemoradiotherapy (CRT)., Methods: We analyzed 590 consecutive EC patients who received definitive CRT from 1998 to 2014, including 182 patients (30.8%) with squamous cell carcinoma (SCC) and 408 (69.2%) with adenocarcinoma. Recurrence pattern and timing, survival, and potential prognostic factors were compared., Results: After a median follow-up time of 58.0months, the SCC group demonstrated a comparable locoregional recurrence rate (42.9% vs. 38.0%, P=0.264) but a significantly lower distant failure rate (27.5% vs. 48.0%, P<0.001) than adenocarcinoma group. No significant difference was found in overall survival or locoregional failure-free survival between groups, whereas the SCC group was associated with significantly more favorable recurrence-free survival (P=0.009) and distant metastasis-free survival (P<0.001). The adenocarcinoma group had higher hematogenous metastasis rates of bone, brain, and liver, whereas the SCC group had a marginally higher regional recurrence rate. Among patients who received salvage surgery after locoregional recurrence, no significant difference in survival was found between groups (P=0.12)., Conclusions: The patterns and sites of recurrence, survival outcomes, and prognostic factors were significantly different between esophageal SCC and adenocarcinoma., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Resectable esophageal adenocarcinoma (EAC) patients often receive chemoradiation followed by surgery. However, most patients experience recurrences. Overexpression of MTDH, an oncoprotein with multiple functions, has been found to be associated with poor prognosis in breast cancer, glioblastoma, melanoma and various gastrointestinal malignancies, but not in EAC. We sought to establish its role in resistant EAC (post-treatment residual EAC). MTDH was assessed by immunohistochemistry in resected EAC, and results were correlated with clinical outcomes. MTDH expression was detectable in 72.5% (50/69) of patients, while expression levels were high (positive) in 50.7% (35/69). Of 69 patients analyzed, 25 had no relapse and 44 patients had a relapse (8 with local-regional and 36 with distant). The median follow-up duration was 3 years (0.4-11.6). The median overall survival was not associated with MTDH status (2.79 years for MTDH-negative and 3.60 years for MTDH-positive patients, p = 0.121). In addition, MTDH was not associated with either the type of relapse (local or distant), baseline clinical stage, tumor grade, presence of signet ring cells, surgical (yp) stage, percentage of residual EAC or presence of lymphovascular invasion. Our data reveal that MTDH is not a prognostic biomarker in resistant EAC after trimodality therapy.

Background: Older patients with localized gastric adenocarcinoma (LGAC) have substantial postoperative morbidity and mortality; however, postoperative outcomes of the patients who receive preoperative chemotherapy and/or chemoradiation have not been reported. We examined the impact of age at baseline on potential predictors of postoperative outcomes., Methods: Patients with LGAC who were treated with chemotherapy and/or chemoradiation followed by surgery (n = 203) formed two groups: (1) ≥65 years old (n = 70) and (2) <65 years old (n = 133). We assessed postoperative morbidity and mortality as well as overall survival (OS) and progression-free survival (PFS). Potential predictors of 90-day postoperative outcomes were identified i) by age groups and ii) other clinical covariates. Descriptive statistics and survival analyses were utilized., Results: 90-day postoperative morbidity was similar in older and younger patients (61 % vs 58 %; P = 0.655). 90-day mortality was similar (3 % vs 0 %; P = 0.118). Major Clavien grade III/IV complications were similar (17 % vs 12 %; P = 0.392). OS and PFS were also similar for both groups (P = 0.863 and P = 0.558, respectively). Other factors, such as Charlson comorbidity index (P < 0.001) and median operative time (P = 0.002) were strongly associated with postoperative complications., Conclusion: Our data show that older patients with LGAC generally have similar outcomes as do younger patients after preoperative therapy but comorbidity indices have significant impact on complications and the long-term outcomes rather than age.

Background: Patients with localized gastric adenocarcinoma (LGAC), who get pre-operative therapy, have heterogeneous/unpredictable outcomes. Predictive clinical variables/biomarkers are not established., Methods: We analyzed 107 LGAC patients who had chemoradiation and surgery. LGACs were grouped for (1) presence/absence of signet ring cell histology (SRC) and (2) histologic grade: G2 or G3. %SRC was assessed (0, 1-10, 11-49, and 50-100%) and correlated with pathologic complete response (pathCR) or

Background: Peritoneal metastases (PM) in patients with gastric adenocarcinoma (GAC) may be identified by diagnostic laparoscopy (DL) or imaging (I). Although prognosis is poor, some patients have excellent outcome. We compared the overall survival (OS) of patients in 3 groups: those with positive cytology (CY+) by DL (DL-CY+), those with gross PM (GPM) by DL (DL-GPM+) and with GPM obvious on I (I-GPM+)., Methods: 146 GAC patients were identified. The Kaplan-Meier analysis, univariate, and multivariate Cox proportional hazards regression models were employed., Results: Patients were primarily men (67%), with good ECOG scores (0-1; 89%), had DL (84%), had poorly differentiated GAC (92%), and had received chemotherapy (89%). The median OS for all patients was 15 months (5% CI, 12.9-18.2 months). The DL-CY+ group had median OS of 22.5 months (95% CI, 15-29.3 months). Patients with I-GPM+ had four times the risk of death than those with DL-CY+ (P < 0.001) and patients with DL-GPM+ had two times the risk of death than those with DL-CY+ (P = 0.001). At 36 months, all DL-GPM+ and I-GPM+ had died but 8 patients with DL-CY+ remained alive., Conclusions: Some GAC patients with DL-CY+ have long OS; therefore, novel strategies to further prolong their OS are needed., (© 2015 Wiley Periodicals, Inc.)

Background: Endoscopic resection is increasingly utilized for treating early stage esophageal cancer, and endoscopic ultrasound (EUS) frequently guides treatment selection. Studies report greater than 80% sensitivity and 90% specificity, but our experience suggests less accuracy at the gastroesophageal (GE) junction. The objective of this study is to determine the accuracy of EUS for depth of GE junction cancer and the potential treatment implications., Methods: A retrospective review of a prospective database was performed for patients from 1995 to 2014 with GE junction esophageal cancer that underwent EUS staging and resection (surgical or endoscopic) without neo-adjuvant therapy. Patient, tumor, EUS, and pathologic characteristics were examined., Results: For the 181 patients that met criteria, the median age was 66 years, 17% were female, 91% white, and 98% had adenocarcinoma. Concordance between EUS (u) T and pathologic (p) T was 48%, with 23% under-staged and 29% over-staged. The EUS was accurate in the following: uT0 6% (1 of 18); uT1a 56% (23 of 41); uT1b 58% (41 of 71); uT2 10% (2 of 21); and uT3 70% (21 of 30). Inaccurate EUS depth had potential to lead to over-treatment in 38% (27 of 71) of uT1b and 76% (16 of 21) of uT2. In 50% of pT1a tumors, EUS depth was T1b or greater. Logistic regression revealed tumor length (continuous variable) to be associated with inaccurate uT (p = 0.016). Accurately staged tumors were significantly longer than inaccurately staged tumors (2.7 vs 1.7 cm, p = 0.011)., Conclusions: Early to intermediate GE junction tumors are frequently over-staged. This highlights the importance of diagnostic endoscopic resection for determining accurate tumor depth and selecting correct therapy., (Copyright © 2015 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Pancreatic ductal adenocarcinoma (PDAC), pancreatic neuroendocrine tumors (pNET), and metastatic lesions (pMET) are the most common neoplastic solid pancreatic lesions (SPLs). Early diagnosis enables prompt treatment., Objective: To identify factors differentiating PDAC from non-PDAC lesions and assess the accuracy of EUS-guided FNA., Design and Setting: Retrospective tertiary center., Patients and Intervention: Consecutive patients referred for EUS evaluation of SPLs from 2004 to 2011., Main Outcome Measurements: Pretest (preceding EUS-guided FNA [EUS-FNA]) predictors of PDAC among neoplastic SPLs and accuracy of EUS-FNA., Results: A total of 1333 EUS scans with 1108 EUS-FNAs were performed for pancreatic lesions. Of the 672 patients with neoplastic SPLs, 528 had PDAC and 144 non-PDAC. The sensitivity, specificity, positive predictive value, and accuracy of EUS-FNA for the diagnosis of PDAC were 97.3%, 99.3%, 99.8%, and 97.8%, respectively. Years of EUS experience significantly correlated with fewer needle passes (Rs = -0.18, P < .001). Controlling for all potential confounders, multivariable regression analysis demonstrated that patients with PDAC compared with pNETs and pMETs were older (odds ratio [OR] 4.42; 95% confidence interval [CI], 2.1-9.5; P < .001), had weight loss (OR 3.0; 95% CI, 1.6-5.4; P < .001), hyperbilirubinemia (OR 3.7; 95% CI, 1.8-7.5; P < .001), elevated CA19-9 (OR 6.9; 95% CI, 2.4-20.3; P < .01), evidence of arterial invasion (OR 6.5; 95% CI, 2.7-15.4; P < .001), and PD dilation (OR 3.3; 95% CI, 1.8-5.9; P < .001)., Limitations: Retrospective design, single center., Conclusions: When evaluating neoplastic SPLs, demographic, clinical, laboratory, and imaging characteristics can reliably discern and suggest PDAC. In addition, EUS-FNA is exceedingly sensitive and specific for PDAC., (Copyright © 2015 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Background: We have limited knowledge of the geographic distribution of resistant esophageal adenocarcinoma (EAC) in resected specimens, but its clinical importance can be enormous., Method: We selected patients with baseline stage III EAC who had had chemoradiation followed by surgery and had residual EAC (resistant cases only). Outcomes were correlated with various endpoints (percentage of resistant EAC and anatomic distribution)., Results: A total of 100 clinical stage III patients were studied; 90% had an R0 resection, and 99% had either moderate or poorly differentiated EAC. Twelve percent had >50% residual cancer, 31% had 11-50% residual cancer, 53% had 1-10% residual cancer, and 3% had positive nodes only. Each compartment was frequently involved: mucosa/submucosa (66%), muscularis propria (76%), and serosa (62%); all compartments were involved in 35% of the cases. Lack of EAC (meaning response) was observed in the mucosa/submucosa (34%), muscularis propria (24%), serosa (38%), and nodes (42%). Although the endoscopic biopsies prior to surgery showed no EAC in 79% of the patients, in the surgical specimens, resistant EAC was frequently occurring in the mucosa/submucosa (66%)., Conclusion: Contrary to our hypothesis that resistant EAC would be frequent in the nodes, our data show that its distribution is heterogeneous and unpredictable. Most importantly, the postchemoradiation biopsies are misleading, and a decision to delay/avoid surgery based on negative biopsies can be detrimental for the patients., (© 2015 S. Karger AG, Basel.)

Background/aim: Malignant nodes in patients with localized esophageal adenocarcinoma (L-EAC) portend a poor prognosis. We assessed the correlation of the distribution of nodes with the outcome of patients undergoing chemoradiation/surgery (trimodality therapy)., Methods: We studied 209 L-EAC patients who had confirmed or suspicious nodes at baseline staging. All patients received trimodality therapy and were grouped according to the nodal geography: above the diaphragm (AD), below the diaphragm (BD), or above and below the diaphragm (ABD). Survival estimates were calculated using the Kaplan-Meier method, and the outcomes of the groups were assessed by the log-rank test., Results: Patients were primarily Caucasian (91%) and male (93%), with a baseline stage III L-EAC (89%). The median follow-up was 2.8 years (range, 0.4-11.7). Of the 209 patients, 35% (n = 73) had AD nodes, 20% (n = 41) had BD nodes, and 45% (n = 95) had ABD nodes. ABD patients had a 5-year overall survival rate of 33%, whereas this rate was 55% in AD patients and 60% in BD patients (p = 0.02). Patients with a higher histology grade were also at a higher risk of relapse and had a poor survival (p < 0.01 for both)., Conclusions: L-EAC patients in the ABD group had the worst outcome after trimodality treatment compared to those in the AD or BD group. Novel strategies are needed for ABD patients., (© 2015 S. Karger AG, Basel.)

Background: In patients with localized gastric adenocarcinoma (LGAC) who receive preoperative therapy, tools to predict response or prognosticate outcome before therapy are lacking. We used initial standardized uptake value (iSUV) of positron emission tomography (PET) to evaluate its association with overall survival (OS)., Methods: We identified 60 patients with confirmed LGAC who were treated with preoperative chemoradiation and had a baseline PET in addition to other routine staging. Fisher's exact test and Wilcoxon's rank sum test were used to determine the association between iSUV and other variables, and the log-rank test and Cox proportional hazards model were used for survival analysis., Results: The median iSUV was 6 (range, 0-28). The presence of signet ring cells in pretreatment biopsies correlated highly with low iSUV (≤ 6; p = 0.0017). Patients with a high iSUV (> 6) had a longer OS compared to those with a low iSUV (≤ 6; p = 0.0344). iSUV was not an independent predictor (p = 0.12); however, the risk of death was reduced for patients with an iSUV > 6 (hazard ratio = 0.26)., Conclusion: Our novel findings show that among LGAC patients treated with preoperative chemoradiation and surgery, those with a high iSUV have longer OS than patients with a low iSUV. iSUV appears to have a predictive role in patients with LGAC when treated with preoperative chemoradiation., (© 2015 S. Karger AG, Basel.)

Background: In the current study we present a validated miRNA signature to predict pathologic complete response (pCR) to neoadjuvant chemoradiation in esophageal adenocarcinoma., Methods: Three patient cohorts (discovery, n = 10; model, n = 43; and validation, n = 65) with locally advanced esophageal adenocarcinoma were analyzed. In the discovery cohort 754 miRNAs were examined in pretreatment tumor biopsy specimens using a TaqMan array. Of these, the 44 most significantly altered between tumors with pCR and non-pCR were examined in an additional 43 tumors using a Fluidigm 48.48 array. The 4 miRNAs (mir-505*, mir-99b, mir-451, and mir-145*) significantly predicting pCR in both cohorts were examined in an additional validation cohort (n = 65) using an Illumina array. These 4 miRNAs were used to generate an miRNA expression profile (MEP) score., Results: The 4 miRNAs profiled are highly significantly associated with pCR in the model cohort (Ptrend  = .008), the validation cohort (Ptrend  = .025), and the combined cohort (Ptrend  = 4.6 × 10(-4) ). The receiver-operator characteristic areas under the curves (AUCs) for the MEP score were 0.78 for the model cohort, 0.71 for the validation cohort, and 0.72 for the combined cohort. When combined with clinical variables, the MEP score AUCs increased to 0.89, 0.77, and 0.81, respectively Estimates from logistic regression based on the MEP were determined and used to generate a probability of pCR plot, which identifies a group of patients with very high (≥80%) and very low (≤10%) probability of pCR., Conclusions: The MEP score provides a validated means of predicting pCR to neoadjuvant chemoradiotherapy in esophageal adenocarcinoma that is robust across several analysis platforms., (© 2014 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.)

Background: The purpose of this study was to examine the significance of signet ring cell histology to predict response to preoperative chemoradiotherapy in patients with esophageal adenocarcinoma., Methods: Two groups of patients with locoregional esophageal adenocarcinoma treated with neoadjuvant chemoradiation and surgery were studied: those with signet ring cell adenocarcinoma (n = 85) and a reference group (n = 638) with usual and other types of adenocarcinoma. Surgical specimens were reviewed for degree of pathologic response and pathologic stage. Cox regression models were used to assess the effects of clinicopathologic variables on survival., Results: Tumors from patients in the signet ring cell group had a lower rate of complete pathologic response (9% versus 26%, p < 0.001) and more frequent positive margins (24% versus 10%, p < 0.001) compared with tumors from the reference group. Median overall survival (22 versus 48 months, p = 0.003) and disease-free survival (16 versus 35 months, p = 0.007) were shorter in the signet ring cell group than in the reference group. Signet ring cell histology and high pathologic stage were significant predictors of decreased overall survival and disease-free survival. Survival durations for patients whose resected specimens showed downstaging after neoadjuvant chemoradiation did not significantly differ from survival durations of patients whose specimens did not show downstaging in the signet ring cell group, unlike the reference group., Conclusions: Signet ring cell histology on pretreatment biopsy predicts a decreased likelihood of complete pathologic response and survival for patients with esophageal adenocarcinoma treated with preoperative chemoradiation and surgery., (Copyright © 2014 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Current algorithms for surveillance of patients with esophageal adenocarcinoma (EAC) after chemoradiation and surgery (trimodality therapy [TMT]) remain empiric. The authors hypothesized that the frequency, type, and timing of relapses after TMT would be highly associated with surgical pathology stage (SPS), and therefore SPS could be used to individualize the surveillance strategy. Between 2000 and 2010, 518 patients with EAC were identified who underwent TMT at The University of Texas MD Anderson Cancer Center and were frequently surveyed. Frequency, type, and timing of the first relapse (locoregional and/or distant) were tabulated according to SPS. Standard statistical approaches were used. The median follow-up time after esophageal surgery was 55.4 months (range, 1.0-149.2 months). Disease relapse occurred in 215 patients (41.5%). Higher SPS was associated with a higher rate of relapse (0/I vs II/III, P≤.001; 0/I vs II, P=.002; SPS 0/I vs III, P≤.001; and SPS II vs III, P=.005) and with shorter time to relapse (P<.001). Irrespective of the SPS, approximately 95% of all relapses occurred within 36 months of surgery. The 3- and 5-year overall survival rates were shorter for patients with a higher SPS than those with a lower SPS (0/I vs II/III, P≤.001; 0/I vs II, P≤.001; 0/I vs III, P≤.001; and II vs III, P=.014). The compelling data show an excellent association between SPS and frequency/type/timing of relapses after TMT in patients with EAC. Thus, the surveillance strategy can potentially be customized based on SPS. These data can inform a future evidence-based surveillance strategy that can be efficient and cost-effective., (Copyright © 2014 by the National Comprehensive Cancer Network.)

Purpose: Operable thoracic esophageal/gastroesophageal junction carcinoma (EC) is often treated with chemoradiation and surgery but tumor responses are unpredictable and heterogeneous. We hypothesized that aldehyde dehydrogenase-1 (ALDH-1) could be associated with response., Methods: The labeling indices (LIs) of ALDH-1 by immunohistochemistry in untreated tumor specimens were established in EC patients who had chemoradiation and surgery. Univariate logistic regression and 3-fold cross validation were carried out for the training (67% of patients) and validation (33%) sets. Non-clinical experiments in EC cells were performed to generate complimentary data., Results: Of 167 EC patients analyzed, 40 (24%) had a pathologic complete response (pathCR) and 27 (16%) had an extremely resistant (exCRTR) cancer. The median ALDH-1 LI was 0.2 (range, 0.01-0.85). There was a significant association between pathCR and low ALDH-1 LI (p ≤ 0.001; odds-ratio [OR] = 0.432). The 3-fold cross validation led to a concordance index (C-index) of 0.798 for the fitted model. There was a significant association between exCRTR and high ALDH-1 LI (p ≤ 0.001; OR = 3.782). The 3-fold cross validation led to the C-index of 0.960 for the fitted model. In several cell lines, higher ALDH-1 LIs correlated with resistant/aggressive phenotype. Cells with induced chemotherapy resistance upregulated ALDH-1 and resistance conferring genes (SOX9 and YAP1). Sorted ALDH-1+ cells were more resistant and had an aggressive phenotype in tumor spheres than ALDH-1- cells., Conclusions: Our clinical and non-clinical data demonstrate that ALDH-1 LIs are predictive of response to therapy and further research could lead to individualized therapeutic strategies and novel therapeutic targets for EC patients., (Copyright © 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)

Background: Patients with localized esophageal and esophagogastric junction cancer (EAC) receive chemoradiation and then surgery (trimodality, TMT) or definitive chemoradiation (bimodality, BMT). Distant metastases (DMs) are common but the details of their distribution and timing in a large cohort have not been described., Methods: 629 patients with localized EAC who had TMT or BMT were analyzed. Standard statistical methods were used to define the end points., Results: The median follow-up time was 37.2 months (interquartile range 17.8-65.0). Of 356 TMT patients, 33% (119) developed DM as their first relapse and of 273 BMT patients, 40% (109) developed DM; 91% (TMT) and 96% (BMT) of the DMs were diagnosed within 2 years of local therapy. The most common sites of DM were: lung, distant nodes, liver, peritoneal cavity, bone, brain and pleura in order of frequency. The median overall survival of TMT patients with DM was 10.2 months (95% CI 7.8-12.7) and that for BMT patients with DM was 7.8 months (95% CI 5.7-9.9)., Conclusions: Following TMT or BMT, ≥33% of patients developed DMs and most of these occurred within 2 years (>90%) of local therapy. A clinical model is desirable that associates clinical parameters with a high risk for DM in TMT-eligible patients prior to surgery., (© 2014 S. Karger AG, Basel.)

Background: Locally advanced esophageal cancer is often treated with a trimodality approach. While a substantial proportion of such patients initially achieve a clinical complete response (cCR) after chemoradiation, only a small proportion achieve durable control. We analyzed patients who reached cCR after definitive chemoradiation for esophageal cancer to identify clinical predictors of local disease recurrence., Methods: We identified 141 patients who obtained initial cCR after definitive chemoradiation without surgery for esophageal cancer from 2002 through 2009. The initial response to treatment was assessed by endoscopic evaluation and biopsy results, with cCR defined as having no evidence of disease present. Patterns of failure were categorized as in-field (within the planned treatment volume [PTV]), outside the radiation treatment field, or both., Results: At a median follow-up of 22 months (range, 6-87 months), 77 patients (55 %) had experienced disease recurrence (local or both). Of first failures, 32 (23 %) were outside the radiation field, followed by 30 (21 %) within the field, and 15 (11 %) were both. By multivariate analysis, in-field failure after cCR was associated with a pretreatment standardized uptake value on positron emission tomography of >10 (subhazard ratio [SHR] 3.31, p = 0.023) and poorly differentiated tumors (SHR 3.69, p = 0.031). All failures, in-field and out-of-field, correlated with non-Caucasian ethnicity (SHR 2.55, p = 0.001), N1 disease (SHR 2.05, p = 0.034), T3/T4 disease (SHR 3.56, p = 0.011), and older age (SHR 0.96, p = 0.008)., Conclusions: Our data suggest that selected clinical characteristics can be used to predict failure patterns after definitive chemoradiation. Such risk-assessment strategies can help individualize therapy.

Purpose: The primary purpose of surveillance of patients with esophageal adenocarcinoma (EAC) and/or esophagogastric junction adenocarcinoma after local therapy (eg, chemoradiotherapy followed by surgery or trimodality therapy [TMT]) is to implement a potentially beneficial salvage therapy to overcome possible morbidity/mortality caused by locoregional failure (LRF). However, the benefits of surveillance are not well understood. We report on LRFs and salvage strategies in a large cohort., Patients and Methods: Between 2000 and 2010, 518 patients with EAC who completed TMT were analyzed for the frequency of LRF over time and salvage therapy outcomes. Standard statistical techniques were used., Results: For 518 patients, the median follow-up time was 29.3 months (range, 1 to 149 months). Distant metastases (with or without LRF) occurred in 188 patients (36%), and LRF only occurred in 27 patients (5%). Eleven of 27 patients had lumen-only LRF. Most LRFs (89%) occurred within 36 months of surgery. Twelve patients had salvage chemoradiotherapy, but only five survived more than 2 years. Four patients needed salvage surgery, and three who survived more than 2 years developed distant metastases. The median overall survival of 27 patients with LRF was 17 months, and 10 patients (37%) survived more than 2 years. Thus, only 2% of all 518 patients benefited from surveillance/salvage strategies., Conclusion: Our surveillance strategy, which is representative of many others currently being used, raises doubts about its effectiveness and benefits (along with concerns regarding types and times of studies and costs implications) to patients with EAC who have LRF only after TMT. Fortunately, LRFs are rare after TMT, but the salvage strategies are not highly beneficial. Our data can help develop an evidence-based surveillance strategy.

Background: Patients with localized esophageal adenocarcinoma (EAC) who achieve a clinical complete response (clinCR) after preoperative chemoradiation (trimodality therapy; TMT) or definitive chemoradiation (bimodality therapy; BMT) live longer than those who achieve a

Background: Diagnosis of pancreatic neoplasm is challenging in patients with inconclusive findings on pancreatic multidetector row CT (MDCT)., Objective: To determine the diagnostic accuracy and to identify predictors of pancreatic neoplasm by EUS with FNA in this setting., Design: Retrospective chart review during the study period of January 2002 to December 2010., Setting: Tertiary referral center., Patients: Of the 1046 patients who underwent pancreatic EUS, 116 patients were selected because their clinical presentation was suspicious for pancreatic malignancy, but their MDCT findings were inconclusive., Intervention: EUS with FNA., Main Outcome Measurements: Diagnostic yield of malignancy and significance of clinical variables., Results: When surgical pathology or subsequent clinical course was used as the criterion standard, EUS with FNA had a sensitivity, specificity, positive predictive value, and accuracy of 87.3%, 98.3%, 98.5%, and 92.1%, respectively, in diagnosing a pancreatic neoplasm that was indeterminate on MDCT. Factors significantly associated with EUS detection of pancreatic ductal adenocarcinoma were total bilirubin level greater than 2 mg/dL (P < .001), CT finding of pancreatic duct dilation (P < .001), bile duct stricture (P < .001), and tumor size 1.5 cm or larger detected by EUS (P = .004). Among them, pancreatic duct dilation on CT (odds ratio 4.10; 95% confidence interval, 1.52-11.05), and tumor size 1.5 cm or larger detected by EUS (odds ratio 8.46; 95% confidence interval, 2.02-35.45) were independent risk factors., Limitations: Retrospective design and patient referral bias., Conclusions: When MDCT is indeterminate, EUS is a highly sensitive and accurate modality for the detection of pancreatic neoplasm, especially when the tumor is smaller than 2.0 cm., (Copyright © 2013 American Society for Gastrointestinal Endoscopy. Published by Mosby, Inc. All rights reserved.)

Background: Trimodality therapy (TMT; chemoradiation plus surgery) has level-1 evidence for survival advantage for TMT-eligible esophagogastric cancer patients. Some patients, however, decline surgery after preoperative chemoradiation. The question of which patient should have esophagectomy and which one should not is unlikely to be answered by a prospective comparison; therefore, we matched the clinical covariates of several patients who had surgery with those who declined surgery (DS)., Methods: Between 2002 and 2011, we identified 623 patients in our databases. Of 623 patients, 244 patients had TMT and 61 TMT-eligible patients were in the DS group. Using the propensity-score method, we matched 16 covariates between 36 DS patients and 36 TMT patients., Results: Baseline characteristics between the two groups were balanced (p = NS). The median overall survival times were: 57.9 months (95% CI: 27.7 to not applicable, NA) for the DS group and 50.8 months (95% CI: 30.7 to NA) for the TMT group (p = 0.28). The median relapse-free survival times were: 18.5 (95% CI: 11.5-30.4) for the DS group and 26.5 months (95% CI: 15.5-NA) for the TMT group (p = 0.45). Eleven (31%) of 36 patients in the DS group had salvage surgery., Conclusions: Our results are intriguing but skewed by the patients who had salvage surgery in the DS group. Until highly reliable predictive models are developed for esophageal preservation, TMT must be encouraged for all TMT-eligible gastroesophageal cancer patients., (Copyright © 2013 S. Karger AG, Basel.)

Background: It is unclear whether patients undergoing trimodality therapy (TMT) should be screened or surveyed for brain metastases., Methods: We retrospectively analyzed esophageal cancer (EC) patients who underwent TMT between the years 2000 and 2010. All were systematically staged and surveyed but none had screening or surveillance brain imaging., Results: The median follow-up time for 518 patients was 29.3 months (range 1-149.2); all patients had adenocarcinoma of the esophagus. Of 188 (36.3%) patients who developed distant metastases, 20 (10.6% of 188 patients or 3.9% of 518 patients) had brain metastases. A higher baseline clinical stage (stage III or IVa) was associated with brain metastases. Most (90%) patients with brain metastases were diagnosed within 24 months of surgery. Sixteen patients had central nervous system symptoms at diagnosis. Twelve (60%) patients had solitary metastasis and 8 (40%) patients had multiple metastases. Although 17 patients received therapy for brain metastases, the median overall survival time of 20 patients was only 10.5 months (95% CI 6.6-14.0)., Conclusion: After TMT, 3.9% of EC patients developed brain metastases and their prognosis was poor. Our data suggest that screening and/or surveillance for brain metastases in the EC population undergoing TMT is not warranted., (Copyright © 2013 S. Karger AG, Basel.)

Background: The presence of malignant lymph nodes (+ypNodes) in the surgical specimen after preoperative chemoradiation (trimodality) in patients with oesophageal cancer (EC) portends a poor prognosis for overall survival (OS) and disease-free survival (DFS). Currently, none of the clinical variables highly correlates with +ypNodes. We hypothesised that a combination of clinical variables could generate a model that associates with high likelihood of +ypNodes after trimodality in EC patients., Methods: We report on 293 consecutive EC patients who received trimodality therapy. A multivariate logistic regression analysis that included pretreatment and post-chemoradiation variables identified independent variables that were used to construct a nomogram for +ypNodes after trimodality in EC patients., Results: Of 293 patients, 91 (31.1%) had +ypNodes. OS (p=0.0002) and DFS (p<0.0001) were shorter in patients with +ypNodes compared to those with -ypNodes. In multivariable analysis, the significant variables for +ypNodes were: baseline T-stage (odds ratio [OR], 7.145; 95% confidence interval [CI], 1.381-36.969; p=0.019), baseline N-stage (OR, 2.246; 95% CI, 1.024-4.926; p=0.044), tumour length (OR, 1.178; 95% CI, 1.024-1.357; p=0.022), induction chemotherapy (OR, 0.471; 95% CI, 0.242-0.915; p=0.026), nodal uptake on post-chemoradiation positron emission tomography (OR, 2.923; 95% CI, 1.007-8.485; p=0.049) and enlarged node(s) on post-chemoradiation computerised tomography (OR, 3.465; 95% CI, 1.549-7.753; p=0.002). The nomogram after internal validation using the bootstrap method (200 runs) yielded a high concordance index of 0.756., Conclusion: Our nomogram highly correlates with the presence of +ypNodes after chemoradiation, however, considerably more refinement is needed before it can be implemented in the clinic., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

High body mass index (H-BMI; ≥25 kg/m(2) ) is common in US adults. In a small cohort of esophageal cancer (EC) patients treated with surgery, H-BMI and diagnosis of early stage EC appeared associated. We evaluated a much larger cohort of EC patients. From a prospectively maintained database, we analyzed 925 EC patients who had surgery with or without adjunctive therapy. Various statistical methods were used. Among 925 patients, 69% had H-BMI, and 31% had normal body mass index (<25 kg/m(2) ; N-BMI). H-BMI was associated with men (P<0.001), Caucasians (P=0.064; trend), lower esophageal localization (P<0.001), adenocarcinoma histology (P<0.001), low baseline cT-stage (P=0.003), low baseline overall clinical stage (P=0.003), coronary artery disease (P=0.036), and diabetes (P<0.001). N-BMI was associated with weight loss (P<0.001), alcohol abuse (P=0.056; trend), ever/current smoking (P=0.014), and baseline cN+ (P=0.018). H-BMI patients with cT1 tumors (n=110) had significantly higher rates of gastresophageal reflux disease symptoms (P<0.001), gastresophageal reflux disease history (P<0.001), and Barrett's esophagus history (P<0.001) compared with H-BMI patients with cT2 tumors (n=114). Median survival of N-BMI patients was 36.66 months compared with 53.20 months for H-BMI patients (P=0.005). In multivariate analysis, older age (P<0.001), squamous histology (P=0.002), smoking (P=0.040), weight loss (P=0.002), high baseline stage (P<0.001), high number of ypN+ (P=0.005), high surgical stage (P<0.001), and American Society of Anesthesia scores, three out of four (P<0.001) were independent prognosticators for poor overall survival. We were able to perform propensity-based analysis of surgical complications between H-BMI and N-BMI patients. A comparison of fully matched 376 patients (188 with H-BMI and 188 with N-BMI) found no significant differences in the rate of complications between the two groups. This larger data set confirms that a fraction of H-BMI patients with antecedent history is diagnosed with early baseline EC. Upon validation of our data in an independent cohort, refinements in surveillance of symptomatic H-BMI patients are warranted and could be implemented. Our data also suggest that H-BMI patients do not experience higher rate of surgical complications compared with N-BMI patients., (© 2011 Copyright the Authors. Journal compilation © 2011, Wiley Periodicals, Inc. and the International Society for Diseases of the Esophagus.)

Background: The prognosis of esophageal cancer (EC) depends on the depth of tumor invasion and lymph node metastasis. EC limited to the mucosa (T1a) can be treated effectively with minimally invasive endoscopic therapy, whereas submucosal (T1b) EC carries relatively high risk of lymph node metastasis and requires surgical resection., Objective: To determine the diagnostic accuracy of EUS in differentiating T1a EC from T1b EC., Design: We performed a comprehensive search of MEDLINE, SCOPUS, Cochrane, and CINAHL Plus databases to identify studies in which results of EUS-based staging of EC were compared with the results of histopathology of EMR or surgically resected esophageal lesions. DerSimonian-Laird random-effects model was used to estimate the pooled sensitivity, specificity, and likelihood ratio, and a summary receiver operating characteristic (SROC) curve was created., Setting: Meta-analysis of 19 international studies., Patients: Total of 1019 patients with superficial EC (SEC)., Interventions: EUS and EMR or surgical resection of SEC., Main Outcome Measurements: Sensitivity and specificity of EUS in accurately staging SEC., Results: The pooled sensitivity, specificity, and positive and negative likelihood ratio of EUS for T1a staging were 0.85 (95% CI, 0.82-0.88), 0.87 (95% CI, 0.84-0.90), 6.62 (95% CI, 3.61-12.12), and 0.20 (95% CI, 0.14-0.30), respectively. For T1b staging, these results were 0.86 (95% CI, 0.82-0.89), 0.86 (95% CI, 0.83-0.89), 5.13 (95% CI, 3.36-7.82), and 0.17 (95% CI, 0.09-0.30), respectively. The area under the curve was at least 0.93 for both mucosal and submucosal lesions., Limitations: Heterogeneity was present among the studies., Conclusion: Overall EUS has good accuracy (area under the curve ≥0.93) in staging SECs. Heterogeneity among the included studies suggests that multiple factors including the location and type of lesion, method and frequency of EUS probe, and the experience of the endosonographer can affect the diagnostic accuracy of EUS., (Copyright © 2012 American Society for Gastrointestinal Endoscopy. Published by Mosby, Inc. All rights reserved.)

Objectives: The incidence and consequence of an isolated involved circumferential radial margin (CRM) after resection for esophageal adenocarcinoma in the setting of neoadjuvant chemoradiotherapy (CRT) has not been reported. We aimed to determine the frequency and significance of a close (<1 mm) or involved CRM in patients undergoing esophagectomy after CRT., Methods: We retrospectively analyzed the data from patients undergoing resection from 1997 to 2008 for esophageal adenocarcinoma after neoadjuvant CRT. A positive CRM was defined as microscopic tumor at or less than 1 mm of the radial margin. An R1 resection was tumor at the radial margin. Only patients with ypT3 or greater tumors were included. R2 resections were excluded. Statistical comparisons were performed using Cox regression and Kaplan-Meier analyses., Results: A total of 160 patients met the inclusion criteria, 42 (26%) had a positive CRM. The median survival did not significantly differ between the CRM-negative and -positive groups (28 vs 50 months, P = .84). A propensity score matching analysis also failed to find a significant difference in outcomes. When analyzed by tumor present at the margin (R1), R0 patients had a longer median survival compared with R1 patients (28 vs 8 months, P = .01). This difference, however, was not seen on propensity score matching., Conclusions: Resections of locally advanced esophageal adenocarcinoma with residual transmural viable tumor after CRT frequently showed involvement of the radial margin with tumor either close to or at the margin. Tumor close (<1 mm) to the radial margin did not result in a significant decrease in overall or disease-free survival or increase in local recurrence., (Copyright © 2012 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

The availability of confocal endomicroscopy motivates the development of optical contrast agents that can delineate the morphologic and metabolic features of gastrointestinal neoplasia. This study evaluates 2-NBDG, a fluorescent deoxyglucose, the uptake of which is associated with increased metabolic activity, in the identification of Barrett's-associated neoplasia. Surveillance biopsies from patients with varying pathologic grades of Barrett's esophagus were incubated ex vivo at 37°C with 2-NBDG and imaged with a fluorescence confocal microscope. Images were categorized as neoplastic (high grade dysplasia, esophageal adenocarcinoma) or metaplastic (intestinal metaplasia, low grade dysplasia) based on the degree of glandular 2-NBDG uptake. Classification accuracy was assessed using histopathology as the gold standard. Forty-four biopsies were obtained from twenty-six patients; 206 sites were imaged. The glandular mean fluorescence intensity of neoplastic sites was significantly higher than that of metaplastic sites (p<0.001). Chronic inflammation was associated with increased 2-NBDG uptake in the lamina propria but not in glandular epithelium. Sites could be classified as neoplastic or not with 96% sensitivity and 90% specificity based on glandular mean fluorescence intensity. Classification accuracy was not affected by the presence of inflammation. By delineating the metabolic and morphologic features of neoplasia, 2-NBDG shows promise as a topical contrast agent for confocal imaging. Further in vivo testing is needed to determine its performance in identifying neoplasia during confocal endomicroscopic imaging.

Duplicated muscularis mucosae (MM) in early esophageal adenocarcinoma (EAC) can cause overstaging of the disease on endoscopic ultrasound and pathology specimens. No study has determined the correlation between lymph node metastasis and invasion in the space between duplicated MM in pathologic tumor stage (pT) 1 EAC. Hematoxylin and eosin-stained slides from surgically resected pT1 EAC (n=99) were reviewed for tumor configuration, grade, level of invasion (lamina propria/inner MM, space between duplicated MM, and submucosa), quantitative depth of invasion in millimeter, and lymphovascular invasion (LVI). These pathologic characteristics were correlated with lymph node status and recurrence-free survival (RFS). All specimens had duplicated MM with thick-walled blood vessels. Tumor differentiation was well in 37, moderate in 47, and poor in 15 specimens. EAC invaded the lamina propria/inner MM in 28 cases, duplicated MM space in 41 cases, and submucosa in 30 cases. LVI was identified in 23 tumors. Eleven patients had lymph node metastasis. Quantitative depth of invasion as a continuous variable (P=0.002), poorly differentiated histology (P=0.028), presence of LVI (P=0.001), and submucosal invasion versus duplicated MM/lamina propria invasion (P=0.02) were associated with increased risk of lymph node metastasis and shorter RFS by univariate analysis. By multivariate analysis, LVI was an independent predictor of lymph node status and RFS. EAC invasion into the space between duplicated MM confers a similar risk of lymph node metastasis and recurrence as those of intramucosal EAC, and LVI is the best predictor of lymph node status and RFS in pT1 EAC.

Background: Treatment strategy for patients with adequately staged cT2N0M0 carcinoma of the thoracic esophagus is currently a subject of debate. This study analyzed the largest series of consecutive cT2N0M0 esophageal cancer patients treated with preoperative chemoradiotherapy., Methods: Data from all patients with cT2N0M0 (assessment included endoscopic ultrasonography and computed tomography of the chest and abdomen) thoracic esophageal cancer who were treated with preoperative chemoradiation between 1997 and 2009 were analyzed. The Cox regression model and Kaplan-Meier plots were used to analyze the data., Results: Data from 49 patients were analyzed. The median follow-up was 28.46 months. Male sex and adenocarcinoma histology predominated. Pathologic complete response was observed 19 (39%) patients. The 10-year actuarial overall survival (OS) for adenocarcinoma patients was >60%. In the univariate analysis for OS, squamous histology (P = .006), smoking (P = .015), and alcohol consumption (P = .032) were found to be associated with poor OS. In the univariate analysis for disease-free survival (DFS), squamous histology (P = .009) and smoking (P = .014) were associated with poor DFS. In the multivariate analysis for OS, smoking was an independent prognosticator (P = .02). In the multivariate analysis for DFS, advanced pathologic stage (P = .05) and lymph node metastases (P = .006) were independent prognosticators. Patients with adenocarcinoma (P = .002) and those with pathologic N0 disease had better OS and DFS. Upward stage migration occurred in only 10% of patients., Conclusions: These data suggest that smoking and alcohol influence the long-term outcome of patients with cT2N0M0 disease. Adenocarcinoma patients treated with trimodality therapy had an excellent actuarial 10-year OS and a high rate of pathologic complete response. Trimodality therapy should be prospectively compared with primary surgery in these patients., (Copyright © 2010 American Cancer Society.)

Background: High body mass index (BMI), a prevalent condition in the United States, is associated with esophageal adenocarcinoma (EAC). Its influence on a patient's outcome remains unclear. In the current study, the authors examined the impact of BMI on survival and complications in patients with esophageal cancer (EC) who underwent surgery as their primary therapy., Methods: The authors retrospectively reviewed 301 consecutive EC patients who underwent surgery but received no adjunctive therapy. Patients were segregated into 2 subgroups based on their baseline BMI: normal/low (<25 kg/m(2) ) and high (≥25 kg/m(2) )., Results: Seventy-six (25%) patients had a BMI <25 kg/m(2) and 225 (75%) patients had a BMI ≥25 kg/m(2) . In the high BMI group, there were more men (P < .001), fewer upper ECs (P = .021), a lower baseline clinical stage (P = .006), and frequent EAC (P < .001). Postoperative morbidity was similar in both groups, with the exception of gastrointestinal complications (P = .016). The 5-year overall survival (OS) rates were 44% in the normal/low BMI group and 60% in the high BMI group (P = .017). The 5-year disease-free survival (DFS) rates were 41% in the normal/low BMI group and 60% in the high BMI group (P = .005). On multivariable analysis, age, weight loss, peripheral vascular disease (PVD), and both clinical and pathological stage of disease were found to be independent prognosticators for OS. Older age (hazard ratio [HR], 1.029; 95% confidence interval [95% CI], 1.009-1.049 [P = .004]), weight loss (HR, 1.525; 95% CI, 1.034-2.248 [P = .033]), and PVD (HR, 2.325; 95% CI, 1.039-5.204 [P = .040]) were found to be associated with poor OS., Conclusions: High BMI is common in EC patients and the better OS/DFS noted in patients with a high BMI is because of the diagnosis of a low baseline clinical stage. Confirmation of these findings is warranted., (Copyright © 2010 American Cancer Society.)