Evaluation of the serotonin pathway as a biomarker in cholangiocarcinoma.

Background: Cholangiocarcinomas (CCAs) are rare and aggressive malignant tumors of the biliary tract. Serotonin (5HT) has tumor-promoting effects in CCA while inhibition of 5HT synthesis can decrease tumor growth. Methods: In this retrospective study, we evaluated the expression of 5HT and tryptophane hydroxylase-1 (TPH-1) in tumor specimens from patients treated with cisplatin plus gemcitabine (CisGem). We included consecutive patients ≥18 years, with locally advanced unresectable, recurrent, or metastatic CCA who were treated with CisGem and had available archival tumor tissue for immunohistochemistry. Formalin-fixed paraffin (FFPE) sections were stained for 5HT and TPH-1. Specimens were evaluated for neuroendocrine features and tumor-infiltrating lymphocytes (TILs). Serum 5HT was measured. Results: We identified 23 patients fulfilling the inclusion criteria. 5HT expression was absent in almost all tumors examined. TPH-1 expression was neither associated with stage or primary tumor location nor predictive of response to CisGem. There was a trend for improved overall survival (OS) in patients whose tumors had high TPH-1 expression. The examined tumor specimens had no neuroendocrine features. Most sections had no TILs. There was a trend for worse OS in patients with high serum 5HT concentration. Conclusions: Tumor TPH-1 expression was not predictive of response to treatment. There was a trend for improved long-term outcomes in patients with high tumor TPH expression and lower serum 5HT concentration.

Case Report: Immune Checkpoint Inhibitor-Induced Exuberant Tumor Inflammation With Accelerated Clinical Deterioration in Metastatic Renal Cell Carcinoma.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy. Nivolumab, an anti-PD-1 monoclonal antibody, markedly improved overall survival in advanced renal cell carcinoma (RCC). However, ICIs can rarely trigger massive inflammation, a phenomenon characterized by rapid acceleration in radiographic tumor growth, the mechanisms underlying which are largely unknown. We report three patients with metastatic RCC who experienced rapid radiographic progression and clinical deterioration following treatment with nivolumab. However, histological analysis revealed no viable cancer despite the evidence of radiological progression. Instead, extensive necrosis and lymphohistiocytic infiltration were noted, as described previously in patients with ICI-induced pseudoprogression. Based on these observations, we postulate that exuberant antitumor inflammatory responses may contribute to adverse clinical outcomes in some patients with ICI-induced radiographic progression. Prospective studies incorporating tumor biopsies may shed more light on this rare phenomenon.

Case reports on a gastric mass presenting with regional lymphadenopathy: A differential diagnosis is gastric schwannoma.

BACKGROUND: Gastric schwannomas are uncommon among a broad range of possible diagnoses in the work up of a gastric mass. Regional lymphadenopathy associated with gastric schwannoma is an even less common occurrence and one would otherwise suspect a malignant neoplasm. CASE PRESENTATION: We present two non-consecutive cases from a signle academic center depicting Caucasian females in their 5th and 6th decades of life with gastric schwannoma and adjacent lymphadenopathy. Multiple lymph node excisions were performed without evidence of neoplasia. DISCUSSION: Lymphadanopathy in the presence of a gastric mass typically represents malignant neoplasm. A less than likely presentation of gastric schwannoma with reactive regional lymph nodes poses a challenge to adequate preoperative diagnosis and increases risk for a more aggressive than necessary surgical approach with lymphadenectomy. CONCLUSION: While the correlation between gastric schwannoma and lymphadenopathy is uncertain, this ought to be considered. If diagnosis can be confirmed preoperatively, omission of lymphadenectomy is appropriate.

Treatment recommendations to cancer patients in the context of FDA guidance for next generation sequencing.

BACKGROUND: Regulatory approval of next generation sequencing (NGS) by the FDA is advancing the use of genomic-based precision medicine for the therapeutic management of cancer as standard care. Recent FDA guidance for the classification of genomic variants based on clinical evidence to aid clinicians in understanding the actionability of identified variants provided by comprehensive NGS panels has also been set forth. In this retrospective analysis, we interpreted and applied the FDA variant classification guidance to comprehensive NGS testing performed for advanced cancer patients and assessed oncologist agreement with NGS test treatment recommendations. METHODS: NGS comprehensive genomic profiling was performed in a CLIA certified lab (657 completed tests for 646 patients treated at Roswell Park Comprehensive Cancer Center) between June 2016 and June 2017. Physician treatment recommendations made within 120 days post-test were gathered from tested patients' medical records and classified as targeted therapy, precision medicine clinical trial, immunotherapy, hormonal therapy, chemotherapy/radiation, surgery, transplant, or non-therapeutic (hospice, surveillance, or palliative care). Agreement between NGS test report targeted therapy recommendations based on the FDA variant classification and physician targeted therapy treatment recommendations were evaluated. RESULTS: Excluding variants contraindicating targeted therapy (i.e., KRAS or NRAS mutations), at least one variant with FDA level 1 companion diagnostic supporting evidence as the most actionable was identified in 14% of tests, with physicians most frequently recommending targeted therapy (48%) for patients with these results. This stands in contrast to physicians recommending targeted therapy based on test results with FDA level 2 (practice guideline) or FDA level 3 (clinical trial or off label) evidence as the most actionable result (11 and 4%, respectively). CONCLUSIONS: We found an appropriate "dose-response" relationship between the strength of clinical evidence supporting biomarker-directed targeted therapy based on application of FDA guidance for NGS test variant classification, and subsequent treatment recommendations made by treating physicians. In view of recent changes at FDA, it is paramount to define regulatory grounds and medical policy coverage for NGS testing based on this guidance.

A Phase Ib Study of the FGFR/VEGFR Inhibitor Dovitinib With Gemcitabine and Capecitabine in Advanced Solid Tumor and Pancreatic Cancer Patients.

OBJECTIVES: Preclinical studies demonstrated antitumor activity of dovitinib in pancreatic cancer models. This phase Ib study aimed to determine the maximum tolerated dose (MTD) of dovitinib in combination with gemcitabine and capecitabine and to characterize the safety and pharmacokinetic profile in patients with advanced pancreatic and biliary tract cancers and solid malignancies. MATERIALS AND METHODS: Patients received gemcitabine 1000 mg/m² intravenously on days 1 and 8, capecitabine 1300 mg/m² oral daily from day 1 to 14, and dovitinib oral daily 5 days on and 2 days off, every 21-day cycle. The standard 3+3 dose escalation design was utilized and the study expanded to treat an additional 20 advanced pancreatic and biliary tract cancers patients at MTD. RESULTS: A total of 29 patients were enrolled. One patient experienced dose-limiting grade 3 colitis. Two patients developed clinically significant neuropathy after the first cycle requiring dose reduction. The MTD was not reached and dovitinib 300 mg was declared the recommended dose for expansion. The most frequent grade 2 or worse adverse events were fatigue (45%), neutropenia (41%), thrombocytopenia (34%), anemia (24%), nausea (24%), and palmer-plantar erythrodysaesthesia syndrome (21%). Partial responses were observed in 5 patients. Pharmacokinetic studies showed no drug-drug interaction between dovitinib, capecitabine and gemcitabine. Fibroblast growth factor 23 plasma level increased in 4 of 5 patients during the first cycle of treatment. CONCLUSIONS: Dovitinib 300 mg daily is the recommended dose when combined with gemcitabine and capecitabine, achieving clinically relevant plasma concentrations. The study combination demonstrated encouraging efficacy signals in advanced pancreatic cancer.

Clinicopathological characteristics and outcomes of rare histologic subtypes of gallbladder cancer over two decades: A population-based study.

BACKGROUND: There is limited literature about the clinicopathological characteristics and outcomes of rare histologic variants of gallbladder cancer (GBC). METHODS: Using SEER database, surgically managed GBC patients with microscopically confirmed adenocarcinoma, adenosquamous/squamous cell carcinoma and papillary carcinoma were identified from 1988 to 2009. Patients with second primary cancer and distant metastasis at presentation were excluded. The effect of clinicopathological variables on overall survival (OS) and disease specific survival (DSS) were analyzed using univariate and multivariate proportional hazards modeling. All associations were considered statistically significant at an alpha error of 0.01. RESULTS: Out of 4738 cases, 217 adenosquamous/squamous (4.6%), 367 papillary (7.7%), and 4154 adenocarcinomas (87.7%) were identified. Median age was 72 years. Higher tumor grade (grade 2, 3, 4 versus grade 1), higher T stage (T2, T3, T4 versus T1), lymph node positivity (N1 versus N0) and adenosquamous/squamous histology (versus adenocarcinoma) had worse OS and DSS (p < .001). Papillary GBC had better OS and DSS than adenocarcinoma (HR = 0.7; p < .001). Radical surgery (versus simple cholecystectomy) had better OS (HR = 0.83, p = 0.002) in multivariate analysis. OS rates at 3 and 5 years were 0.56 and 0.44 for papillary, 0.3 and 0.22 for adenocarcinoma, and 0.14 and 0.12 for adenosquamous/squamous histology, while DSS rates at 3 and 5 years were 0.67 and 0.61 for papillary, 0.38 and 0.31 for adenocarcinoma, and 0.17 and 0.16 for adenosquamous/squamous subtypes respectively. CONCLUSION: Papillary GBC had better survival outcomes while adenosquamous/squamous GBC had worse survival outcomes compared to gallbladder adenocarcinoma.

Depth of Muscularis Propria Invasion Does Not Prognosticate Survival in T2 Esophageal Adenocarcinoma.

AIM: Although tumor depth of invasion is strongly associated with risk of lymph node metastasis and long-term survival in patients with esophageal adenocarcinoma, the significance of differential T2 invasion (inner circular layer versus outer longitudinal layer) is unknown. The current study was undertaken to explore the hypothesis that greater T2-specific depth of invasion is associated with inferior long-term outcomes in patients with esophageal adenocarcinoma treated with esophagectomy. PATIENTS AND METHODS: Demographic, treatment, and outcome data were collected for patients with resected pT2N0-3M0 esophageal adenocarcinoma treated between 2005 and 2015 pooled from four U.S. academic medical centers. Two blinded pathologists evaluated depth of muscularis propria tumor invasion. Univariate and Cox proportional hazard regression analyses were performed to identify prognostic factors for overall (OS) and disease-free (DFS) survival, and Kaplan-Meier analysis to compare survival differences specific to prognostic factors. RESULTS: A total of 84 patients were identified for analysis (53 with circular invasion; 31 with longitudinal invasion), with a median age of 66 years. Sixty percent of patients (50/84) received induction therapy prior to esophagectomy. The median OS and DFS was 58 months (95% confidence interval(CI)=42 months-not reached) and 27 months (95% CI=13.7-66 months) respectively. Depth of muscularis propria invasion did not correlate with OS or DFS on univariate (p=0.42; and p=0.34, respectively) or multivariate (p=0.15 and p=0.21, respectively) analysis after adjustment for age, nodal status, perineural invasion, and tumor grade. These findings did not vary by induction therapy status. CONCLUSION: Depth of muscularis propria invasion does not appear to correlate with survival in patients with esophageal adenocarcinoma.

A phase II trial of erlotinib monotherapy in advanced pancreatic cancer as a first- or second-line agent.

INTRODUCTION: Pancreatic adenocarcinoma carries a grim prognosis. In 2007, gemcitabine with erlotinib emerged as an appropriate treatment option for patients with advanced inoperable or metastatic disease (APC). In this phase II trial we sought to evaluate the efficacy of erlotinib monotherapy in patients with APC who had disease refractory to or ineligibility for gemcitabine-based therapy. METHODS: Eligible patients who had received 0 or 1 non-EGFR inhibitor containing gemcitabine-based chemotherapy for APC were recruited prospectively and treated with erlotinib 150 mg orally daily until unacceptable toxicity or disease progression. Primary endpoint was progression-free survival (PFS). Correlations of clinical response with smoking, rash, steady-state concentration of erlotinib and its metabolite (OSI-420) as well as the nicotine metabolite cotinine were performed. RESULTS: The trial was terminated early for futility. Eighteen of the 34 planned subjects were recruited. Median PFS and OS were 42 and 95 days, respectively. Best response was stable disease (21%). There was a trend for improved PFS and OS in never smokers compared to current and past smokers (128.5, 39, 42 days and 173, 100, 88 days, respectively). Past/current smokers had lower steady-state concentrations of erlotinib and OSI-420 compared to never smokers. There was evidence of recent smoking exposure in 30% of patients self-identified as past smokers. Rash was infrequent, with no cases of grade III/IV rash and it was not related to treatment outcomes. CONCLUSIONS: Overall, erlotinib monotherapy failed to improve outcomes compared to historical controls in patients with APC after 0-1 prior systemic therapies. There was a trend for improved PFS and OS in never smokers.

Lymphovascular and perineural invasion are associated with poor prognostic features and outcomes in colorectal cancer: A retrospective cohort study.

BACKGROUND: Lymphovascular and perineural invasion (LVI and PNI) are associated with poor outcomes in several cancers. We sought to identify clinical variables associated with LVI and PNI in colorectal cancer (CRC) and to determine their impact on survival. METHODS: A retrospective review was performed of the National Cancer Data Base (NCDB), 2004-2011. Patients with CRC and a documented LVI or PNI status were included. Multivariate analysis was conducted to examine the associations between clinical variables and LVI/PNI, PNI and survival, and LVI/PNI and lymph node (LN) status in patients with T1 and T2 tumors. RESULTS: In total, 158,777 patients were included. LVI status was documented for 139,026 patients, 26.3% of whom were positive. PNI status was documented in 142,034 patients, 11.1% of whom were positive. The multivariable model identified a number of pathologic and clinical characteristics associated with the presence of LVI and PNI, including a number of features of advanced CRC. PNI was independently associated with reduced survival (HR 3.55, 95%CI 1.78-7.09). In T1 or T2 tumors, LVI and PNI were significantly associated with LN involvement. CONCLUSIONS: LVI and PNI are associated with advanced CRC. PNI is an independent poor prognostic marker for survival in CRC. LVI and PNI are associated with LN involvement in T1 and T2 tumors. Documentation of LVI and PNI status on biopsy specimens may help in prognostication and decision-making in the management of these early tumors.

Key gaps in pathologic reporting for appendiceal mucinous neoplasms: time for universal synoptic reporting?

INTRODUCTION: The prognosis of appendiceal mucinous neoplasms (AMN) is directly related to their histopathology. Existing classification schemes encompass tumors with widely divergent clinical behaviors within a single diagnosis, making it difficult for clinicians to interpret pathology reports to counsel patients on optimal management. We sought to examine pathology reports generated for AMN for inclusion of essential histologic features. METHODS: Pathology reports of appendectomy specimens with a diagnosis of AMN (2002-2015) at our center ("internal") and from referring institutions ("external") were retrospectively reviewed for inclusion of the following 5 essential items: layer of invasion, mucin dissection (low grade neoplasms only), perforation, margins, and serosal implants. RESULTS: Sixty-nine patients were included, 54 with external reports available. Benign/low grade tumors comprised 29.0% and 27.8% of internal and external reports, respectively. Thirty-seven internal reports (53.6%) were signed out by specialist gastrointestinal pathologists. External reports were 66.7% complete for layer of invasion, 26.7% for mucin dissection, 64.8% for perforation, 68.5% for margins, 53.7% for serosal implants, and 18.5% for all items. Internal reports were 75.4% complete for layer of invasion, 40.0% for mucin dissection, 40.6% for perforation, 82.6% for margins, 69.6% for serosal implants, and 17.4% for all items. Eight external (14.8%) and 24 internal (34.8%) reports were synoptic. Synoptic reports were more likely to be complete for all key items both external and internal. CONCLUSION: Most pathology reports are incomplete for essential features needed for management and discussion of AMN with patients. Synoptic reports improve completeness of reporting for these tumors.

Ki67 score as a potential predictor in the selection of liver-directed therapies for metastatic neuroendocrine tumors: a single institutional experience.

BACKGROUND: Neuroendocrine tumors (NETs) metastatic to the liver are treated with transarterial radioembolization (TARE) using yttrium-90 (Y-90) microspheres or transarterial chemoembolization (TACE). However the criteria for patient selection are not well defined. We sought to determine if Ki67 score could help select patients for one therapy over the other in the management of hepatic neuroendocrine metastases. METHODS: Single institution analysis of patients treated with Y-90 or TACE between 2001 and 2014. Pathologists blinded to clinical information performed Ki67 staining. Data were analyzed using multivariate association for survival outcomes. RESULTS: Amongst 72 patients (male: 39, female: 33, median age: 57 years) with metastatic NET, the most common site of origin was small bowel (n=35, 49%), while pancreas constituted 32% (n=23). Forty-four patients were treated with Y-90 (61%) and 28 patients received TACE (39%). Ki67 score was available in 28 patients (64%) treated with Y-90 and 16 patients (57%) with TACE. Within Y-90 group, there was greater use of Sandostatin (95% vs. 75%, P=0.02) and less number of total treatments completed (89% vs. 46%, P<0.001). There was no significant difference in overall survival (OS) between Y-90 and TACE when used without selection (median, 69 vs. 82 months, P=0.47). When adjusted for Ki67, patients with Ki67 score ≥3% had better OS with Y-90 compared to TACE (HR, 0.1; CI, 0.01-0.9), however for Ki67 <3%, OS was better when treated with TACE compared to Y-90 (HR, 13.5; CI, 1.22-148.87). CONCLUSIONS: There is significant interaction between Ki-67 score and liver-directed treatment benefit in patients with hepatic neuroendocrine metastases. Ki-67 score ≥3% predicts greater benefit with Y-90 and a Ki-67 score <3% predicts greater benefit with TACE.

Reappraisal of Serosal Invasion in Patients With T3 Colorectal Cancer by Elastic Stain: Clinicopathologic Study of 139 Surgical Cases With Special Reference to Peritoneal Elastic Lamina Invasion.

CONTEXT: Peritoneal elastic lamina invasion (PELI) has been reported to be an important adverse prognostic factor in pT3 colorectal cancer (CRC). However, the data supporting this contention are limited. OBJECTIVE: To clarify the associations between PELI of pT3 CRC and prognostic significance, 139 consecutive surgical cases of pT3 CRC were examined. DESIGN: One hundred thirty-nine consecutive in-house surgical cases of pT3 CRC between 1993 and 2011 were examined. Thirty consecutive surgical cases of pT4a CRC resected during the same period were examined for comparison. Case selections were restricted to pT3 CRCs with the sections containing the deepest adenocarcinoma invasion partially or entirely covered with the peritoneum. Elastic staining was performed on one section containing the deepest tumor invasion partially or entirely covered with the peritoneum. The associations between the presence of PELI and clinicopathologic factors including prognosis of the patients were examined. RESULTS: Peritoneal elastic lamina invasion was identified in 23.0% (32 of 139) of the pT3 CRCs. PELI was associated with primary site (P = .006), lymph node metastasis (P < .001), lymphovascular invasion (P < .001), recurrence (P = .007), and patient's age (P = .002). The proportions of patients with a 4-year recurrence-free period in those with negative PELI, positive PELI, and pT4a tumor were 90.3%, 66.7%, and 28.9%, respectively (P < .001). CONCLUSIONS: Elastic staining is useful to evaluate the serosal invasion of CRC. Positive PELI is a significant predictive factor for lymph node metastasis and recurrence-free survival in patients with pT3 CRC. This indicates that pT3 tumors with PELI should be treated like pT4a tumors.

Modulating gut immunity and neoplasia with oral cytokine adjuvants.

Oral administration of particulate IL-10 suppressed polyposis, ameliorated systemic pathology and extended lifespan in APCmin/+ mice. Therapeutic effect was associated with selective activity of IL-10 on intestinal CD4+Foxp3+RORγt+IL-17+ pathogenic T-regulatory cells. Studies were recently extended to a bacterially-driven murine colon adenocarcinoma model with similar results. Clinical implications of these findings are discussed.

Oral interleukin-10 alleviates polyposis via neutralization of pathogenic T-regulatory cells.

Immune dysregulation drives the pathogenesis of chronic inflammatory, autoimmune, and dysplastic disorders. While often intended to address localized pathology, most immune modulatory therapies are administered systemically and carry inherent risk of multiorgan toxicities. Here, we demonstrate, in a murine model of spontaneous gastrointestinal polyposis, that site-specific uptake of orally administered IL10 microparticles ameliorates local and systemic disease to enhance survival. Mechanistic investigations showed that the therapeutic benefit of this treatment derived from neutralization of disease-promoting FoxP3(+)RoRγt(+)IL17(+) pathogenic T-regulatory cells (pgTreg), with a concomitant restoration of FoxP3(+)RoRγt(-)IL17(-) conventional T-regulatory cells (Treg). These findings provide a proof-of-principle for the ability of an oral biologic to restore immune homeostasis at the intestinal surface. Furthermore, they implicate local manipulation of IL10 as a tractable therapeutic strategy to address the inflammatory sequelae associated with mucosal premalignancy.

Breast cancer resistance protein (BCRP) and excision repair cross complement-1 (ERCC1) expression in esophageal cancers and response to cisplatin and irinotecan based chemotherapy.

BACKGROUND: Esophageal cancer patients face a dismal outcome despite tri-modality management and median survival remains 15-18 months. Breast cancer resistance protein (BCRP) is an ATP-dependent efflux protein associated with chemotherapy resistance. The role of BCRP expression in esophageal cancer and normal esophageal cells is not known. Excision repair cross complement-1 (ERCC1) overexpression has been correlated with poorer response to cisplatin based chemotherapy. We examined the expression of BCRP and ERCC1 in patients with esophageal cancer and correlated it with survival in patients receiving irinotecan and cisplatin based chemotherapy. METHODS: With IRB approval, 40 cases of esophageal cancer diagnosed from 2004-2008, were stained for BCRP and ERCC1 expression by immunohistochemistry and scored by a pathologist blinded to clinical data. Baseline demographics, therapy given and survival data were collected and correlated with BCRP and ERCC1 expression. Fisher's exact test was used to determine association between BCRP and ERCC1 expression and demographics. Cox proportional hazards model was used for association of BCRP and ERCC1 with survival. RESULTS: On immunohistochemistry, 30/40 cancers (75%) expressed BCRP. Interestingly, down-regulation of BCRP expression in tumor compared with normal cells was seen in 40% of patients. ERCC1 positivity was seen in 15/30 cases (50%). Median overall survival (OS) was 19 months with no difference in survival between BCRP positive and negative patients (P=0.13) or ERCC1 positive and negative patients (P=0.85). Estimated hazard ratio (HR) of death for BRCP positive patients was 2.29 (95% CI: 0.79-6.64) and for ERCC1 positive patients was 1.09 (95% CI: 0.46-2.56). There was no association of BCRP and ERCC1 expression with disease stage, age, gender or histology. For patients who received cisplatin and irinotecan as first line chemotherapy, there was no difference in survival based on BCRP or ERCC1 status. CONCLUSIONS: BCRP expression is seen in a majority of esophageal cancers and normal esophageal mucosa. ERCC1 expression is seen in about half of the patients with esophageal cancer. Irinotecan based studies with esophageal and gastric cancer suggest response rates of 14-65%. Whether the 40% of tumors in our study found with down regulation of BCRP expression, constitute a majority of these responders needs to be prospectively validated in a larger data set. It should include markers such as ERCC1 predicting response to 5-fluorouracil and platinum based chemotherapy, to enable individualizing therapy for this cancer.

Oral floor and gingival metastasis of cholangiocarcinoma: a case report and review of the literature.

The oral cavity is very unusual site of metastases even though wide spread metastatic disease may be present. The most common primary sites that metastasize to the oral cavity are lung, kidney, breast, and hepatocellular carcinoma. We present a rare case of a 77-year-old Caucasian female with metastasis from a cholangiocarcinoma to the oral floor contiguous with lingual gingival mucosa. The patient presented with left sided rib pain. A CT scan of the chest, abdomen, and pelvis showed multiple pulmonary nodules and a single dominant mass in the right lobe of the liver. This tumor was 6.5 cm with multiple satellite lesions surrounding it. The liver biopsy was diagnostic of a moderately to poorly differentiated adenocarcinoma, consistent with a primary cholangiocarcinoma. After undergoing one cycle of gemcitabine chemotherapy, the patient noticed an extremely rapidly growing mass involving her right lower gingiva and the entire right floor of her mouth. The biopsy of that mass also showed a moderately to poorly differentiated adenocarcinoma. The gingival tumor had a similar cytomorphology and immunophenotype as her cholangiocarcinoma. Therefore, an unusual site for metastatic cholangiocarcinoma was confirmed.

Sexual dimorphism, weight gain and glucose intolerance in a B- and T-cell deficient mouse model.

BACKGROUND: Estrogen is thought to aid maintenance of insulin sensitivity potentially through modulation of a counter-regulatory mechanism that interferes with the contribution of adaptive and innate immune systems to visceral fat deposition. We evaluated the impact of estrogen on long-term high fat diet (HFD) intake in B- and T-cell deficient and immunocompetent animals comparatively. METHODS: A total of 16 BALB and 16 SCID mice, 8 of each sex and strain, were randomized to receive low fat diet, 4.1% fat or HFD, 35% fat, such that there was a group of both each sex and each strain receiving each diet. Biweekly levels of adiponectin, leptin and insulin levels were assessed and a glucose tolerance test (GTT) was performed after 13 weeks. RESULTS: Unlike their male counterparts, HFD-fed SCID females neither gained weight, nor became insulin resistant. Meanwhile, in the HFD-fed BALB groups both males and females gained weight similarly, but remarkable sexual dimorphism was nonetheless observed. The females had notable higher adiponectin levels as compared to males (10-60 µg/mL vs. 6-10 µg/mL respectively) causing the adiponectin-to-leptin (A/L) ratio to reach 80 one week after HFD initiation. The A/L dropped to 10, still higher than males, by week 13, but dropped to 2 by the end of the study in agreement with inverse insulin trends. None of the HFD-fed female groups developed insulin resistance (IR) by week 13, while all male counterparts had. Similar results were observed in the HFD-fed SCID groups whereby the females did not develop IR and had a higher A/L; however, adiponectin levels were comparable between groups (5-11 µg/mL). CONCLUSIONS: The present study provides lacking evidence indicating that estrogen may be sufficient to prevent weight gain and development of glucose intolerance in high-fat fed B- and T-cell deficient mice.

Outcomes of endoscopic resection for high-grade dysplasia and esophageal cancer.

BACKGROUND: Endoscopic resection (ER) is an important advance in the management of esophageal tumors. It has been used successfully for superficial esophageal cancer and high-grade dysplasia (HGD) arising out of Barrett epithelium. METHODS: From a single institution within the Department of Surgery, patients who underwent ER for esophageal tumors between December 2001 and January 2012 were evaluated. Demographic, clinical, and pathologic variables were collected and reviewed. RESULTS: We identified 81 patients who underwent ER for esophageal lesions. Median patient age was 69 years, and the median follow-up was 3.25 years. In patients with HGD, at the time of last endoscopy, the complete eradication rate of HGD was 84 % and cancer-specific survival was 100 %. During surveillance, one patient developed an invasive carcinoma that required endoscopic therapy. Patients with T1a and negative deep margins on ER had a recurrence-free and cancer-specific survival of 100 %. There were seven patients with T1b and negative margins on ER. Three patients underwent esophagectomy; final pathology revealed no residual malignancy or lymph node metastasis. Two patients had definitive chemoradiation, and two patients were observed. To date, there has been no cancer recurrence. In all patients who underwent ER, there was one episode of bleeding that required endoscopic treatment and admission for observation. CONCLUSIONS: ER can be performed safely and can adequately stage and often treat patients with HGD and superficial cancers. Patients with HGD and T1a disease with negative margins are cured with ER alone. Observation and surveillance may be an option for select patients with low-risk, early submucosal disease (T1b) and negative margins.