Tsung Teh Wu

Endoscopic and Surgical Treatment of Mucosal (T1a) Esophageal Adenocarcinoma in Barrett's Esophagus

BACKGROUND & AIMSnEndoscopic therapy is emerging as an alternative to surgical therapy in patients with mucosal (T1a) esophageal adenocarcinoma (EAC) given the low likelihood of lymph node metastases. Long-term outcomes of patients treated endoscopically and surgically for mucosal EAC are unknown. We compared long-term outcomes of patients with mucosal EAC treated endoscopically and surgically.nnnMETHODSnPatients treated for mucosal EAC between 1998 and 2007 were included. Patients were divided into an endoscopically treated group (ENDO group) and a surgically treated group (SURG group). Vital status information was queried using an institutionally approved internet research and location service. Statistical analysis was performed using Kaplan-Meier curves and Cox proportional hazard ratios.nnnRESULTSnA total of 178 patients were included, of whom 132 (74%) were in the ENDO group and 46 (26%) were in the SURG group. The mean follow-up period was 64 months (standard error of the mean, 4.8 mo) in the SURG group and 43 months (standard error of the mean, 2.8 mo) in the ENDO group. Cumulative mortality in the ENDO group (17%) was comparable with the SURG group (20%) (P = .75). Overall survival also was comparable using the Kaplan-Meier method. Treatment modality was not a significant predictor of survival on multivariable analysis. Recurrent carcinoma was detected in 12% of patients in the ENDO group, all successfully re-treated without impact on overall survival.nnnCONCLUSIONSnOverall survival in patients with mucosal EAC when treated endoscopically appears to be comparable with that of patients treated surgically. Recurrent carcinoma occurs in a limited proportion of patients, but can be managed endoscopically.

Mucosal Recovery and Mortality in Adults With Celiac Disease After Treatment With a Gluten-Free Diet

OBJECTIVES:Clinical response is typically observed in most adults with celiac disease (CD) after treatment with a gluten-free diet (GFD). The rate of mucosal recovery is less certain. The aims of this study were (1) to estimate the rate of mucosal recovery after GFD in a cohort of adults with CD, and (2) to assess the clinical implications of persistent mucosal damage after GFD.METHODS:The study group included adults with biopsy-proven CD evaluated at the Mayo Clinic who had duodenal biopsies at diagnosis and at least one follow-up intestinal biopsy to assess mucosal recovery after starting a GFD. The primary outcomes of interest were mucosal recovery and all-cause mortality.RESULTS:Of 381 adults with biopsy-proven CD, 241 (73% women) had both a diagnostic and follow-up biopsy available for re-review. Among these 241, the Kaplan–Meier rate of confirmed mucosal recovery at 2 years following diagnosis was 34% (95% confidence interval (CI): 27–40%), and at 5 years was 66% (95% CI: 58–74%). Most patients (82%) had some clinical response to GFD, but it was not a reliable marker of mucosal recovery (P=0.7). Serological response was associated with confirmed mucosal recovery (P=0.01). Poor compliance to GFD (P<0.01), severe CD defined by diarrhea and weight loss (P<0.001), and total villous atrophy at diagnosis (P<0.001) were strongly associated with persistent mucosal damage. There was a trend toward an association between achievement of mucosal recovery and a reduced rate of all-cause mortality (hazard ratio=0.13, 95% CI: 0.02–1.06, P=0.06), adjusted for gender and age.CONCLUSIONS:Mucosal recovery was absent in a substantial portion of adults with CD after treatment with a GFD. There was a borderline significant association between confirmed mucosal recovery (vs. persistent damage) and reduced mortality independent of age and gender. Systematic follow-up with intestinal biopsies may be advisable in patients diagnosed with CD as adults.

Severe Spruelike Enteropathy Associated With Olmesartan

OBJECTIVEnTo report the response to discontinuation of olmesartan, an angiotensin II receptor antagonist commonly prescribed for treatment of hypertension, in patients with unexplained severe spruelike enteropathy.nnnPATIENTS AND METHODSnAll 22 patients included in this report were seen at Mayo Clinic in Rochester, Minnesota, between August 1, 2008, and August 1, 2011, for evaluation of unexplained chronic diarrhea and enteropathy while taking olmesartan. Celiac disease was ruled out in all cases. To be included in the study, the patients also had to have clinical improvement after suspension of olmesartan.nnnRESULTSnThe 22 patients (13 women) had a median age of 69.5 years (range, 47-81 years). Most patients were taking 40 mg/d of olmesartan (range, 10-40 mg/d). The clinical presentation was of chronic diarrhea and weight loss (median, 18 kg; range, 2.5-57 kg), which required hospitalization in 14 patients (64%). Intestinal biopsies showed both villous atrophy and variable degrees of mucosal inflammation in 15 patients, and marked subepithelial collagen deposition (collagenous sprue) in 7. Tissue transglutaminase antibodies were not detected. A gluten-free diet was not helpful. Collagenous or lymphocytic gastritis was documented in 7 patients, and microscopic colitis was documented in 5 patients. Clinical response, with a mean weight gain of 12.2 kg, was demonstrated in all cases. Histologic recovery or improvement of the duodenum after discontinuation of olmesartan was confirmed in all 18 patients who underwent follow-up biopsies.nnnCONCLUSIONnOlmesartan may be associated with a severe form of spruelike enteropathy. Clinical response and histologic recovery are expected after suspension of the drug.

The Crosstalk of mTOR/S6K1 and Hedgehog Pathways

Esophageal adenocarcinoma (EAC) is the most prevalent esophageal cancer type in the United States. The TNF-α/mTOR pathway is known to mediate the development of EAC. Additionally, aberrant activation of Gli1, downstream effector of the Hedgehog (HH) pathway, has been observed in EAC. In this study, we found that an activated mTOR/S6K1 pathway promotes Gli1 transcriptional activity and oncogenic function through S6K1-mediated Gli1 phosphorylation at Ser84, which releases Gli1 from its endogenous inhibitor, SuFu. Moreover, elimination of S6K1 activation by an mTOR pathway inhibitor enhances the killing effects of the HH pathway inhibitor. Together, our results established a crosstalk between the mTOR/S6K1 and HH pathways, which provides a mechanism for SMO-independent Gli1 activation and also a rationale for combination therapy for EAC.

CLINICAL STAGING AND SURVIVAL IN REFRACTORY CELIAC DISEASE: A SINGLE CENTER EXPERIENCE

BACKGROUND & AIMSnRefractory celiac disease (RCD) occurs when both symptoms and intestinal damage persist or recur despite strict adherence to a gluten-free diet. In RCD, the immunophenotype of intraepithelial lymphocytes may be normal and polyclonal (RCD I) or abnormal and monoclonal (RCD II). The aim is to describe the clinical characteristics, treatment, and long-term outcome in a large single-center cohort of patients with RCD.nnnMETHODSnWe compared the clinical characteristics and outcome in 57 patients with RCD: 42 with RCD I and 15 with RCD II.nnnRESULTSnFifteen of 57 patients died during follow-up (n=8 with RCD I and n=7 with RCD II), each within the first 2 years after RCD diagnosis. The overall 5-year cumulative survival is 70%, 80%, and 45% for the entire cohort, RCD I, and RCD II, respectively. The refractory state itself and enteropathy-associated T-cell lymphoma (EATL) were the most common causes of death, respectively. A new staging system is proposed based on the cumulative effect of 5 prognostic factors investigated at the time of the refractory state diagnosis: for patients in stages I, II, and III, the 5-year cumulative survival rate was 96%, 71%, and 19%, respectively (P< .0001).nnnCONCLUSIONSnRCD is associated with high mortality with RCD II having an especially poor prognosis because of the development of EATL. A new staging model is proposed that may improve the precision of prognosis in patients with RCD.

Prognostic significance of differentially expressed miRNAs in esophageal cancer

Altered microRNA (miRNA) expression has been found to promote carcinogenesis, but little is known about the role of miRNAs in esophageal cancer. In this study, we selected 10 miRNAs and analyzed their expression in 10 esophageal cancer cell lines and 158 tissue specimens using Northern blotting and in situ hybridization, respectively. We found that Let‐7g, miR‐21 and miR‐195p were expressed in all 10 cell lines, miR‐9 and miR‐20a were not expressed in any of the cell lines, and miR‐16‐2, miR‐30e, miR‐34a, miR‐126 and miR‐200a were expressed in some of the cell lines but not others. In addition, transient transfection of miR‐34a inhibited c‐Met and cyclin D1 expression and esophageal cancer cell proliferation, whereas miR‐16‐2 suppressed RAR‐β2 expression and increased tumor cell proliferation. Furthermore, we found that miR‐126 expression was associated with tumor cell dedifferentiation and lymph node metastasis, miR‐16‐2 was associated with lymph node metastasis, and miR‐195p was associated with higher pathologic disease stages in patients with esophageal adenocarcinoma. Kaplan‐Meier analysis showed that miR‐16‐2 expression and miR‐30e expression were associated with shorter overall and disease‐free survival in all esophageal cancer patients. In addition, miR‐16‐2, miR‐30e and miR‐200a expression were associated with shorter overall and disease‐free survival in patients with esophageal adenocarcinoma; however, miR‐16‐2, miR‐30e and miR‐200a expression were not associated with overall or disease‐free survival in squamous cell carcinoma patients. Our data indicate that further evaluation of miR‐30e and miR‐16‐2 as prognostic biomarkers is warranted in patients with esophageal adenocarcinoma. In addition, the role of miR‐34a in esophageal cancer also warrants further study.

Epidemiology and Natural History of Intestinal Metaplasia of the Gastroesophageal Junction and Barrett's Esophagus: A Population-Based Study

OBJECTIVES:Population-based data on the epidemiology and outcomes of subjects with intestinal metaplasia of the gastroesophageal junction (IMGEJ) and Barretts esophagus (BE) are limited. The objectives of this study were to (i) estimate the incidence of IMGEJ and BE diagnosed from clinically indicated endoscopy in Olmsted County, MN, over three decades (1976–2006) and prevalence as of 1 January 2007, (ii) compare baseline characteristics of subjects with IMGEJ and BE, and (iii) study the natural history and survival of both cohorts.METHODS:This was a population-based cohort study. The study setting was Olmsted County, MN. Patients with BE (columnar segment >1u2009cm with intestinal metaplasia) and IMGEJ (intestinal metaplasia in biopsies from the gastroesophageal junction) from 1976 to 2006 in Olmsted County, MN, were identified using Rochester Epidemiology Project resources. Demographic and clinical data were abstracted from medical records and pathology confirmed by gastrointestinal pathologists. The association of baseline characteristics with overall and progression-free survival was assessed using proportional hazards regression models. Outcome measures were baseline characteristics and overall survival of subjects with IMGEJ compared to those with BE.RESULTS:In all, 487 patients (401 with BE and 86 with IMGEJ) were identified and followed for a median interval of 7 (BE subjects) to 8 (IMGEJ subjects) years. Subjects with BE were older, heavier, reported reflux symptoms more often, and had higher prevalence of advanced neoplasia than those with IMGEJ. No patient with IMGEJ progressed to esophageal adenocarcinoma (EAC) in contrast to BE subjects who had a cumulative risk of progression of 7% at 10 years and increased risk of death from EAC (standardized mortality ratio 9.62). The overall survival of subjects with BE and IMGEJ did not differ from that expected in similar age- and sex-distributed white Minnesota populations.CONCLUSIONS:Subjects with IMGEJ appear to have distinct clinical characteristics and substantially lower cancer progression risk compared to those with BE.

IgG4+ plasma cell infiltrates in liver explants with primary sclerosing cholangitis.

Sclerosing cholangitis can be primary (PSC) or secondary. One unusual cause of secondary sclerosing cholangitis is the newly recognized entity of IgG4-associated cholangitis. The prevalence and significance of IgG4+ plasma cells in patients, who are clinically and radiologically classified as PSC, however, are unknown. Clinical information and histology of liver explants of 98 consecutive liver transplants performed for PSC were reviewed. IgG4 immunohistochemical stain was performed on sections from hilar areas that contained large bile ducts and corresponding cholecystectomy specimens (available in 74 cases). Serum IgG4 levels were measured in stored serum from 81 cases. Tissue IgG4 positivity (≥10 IgG4+ plasma cells/high power field) was correlated with clinical features (age, sex, presence of inflammatory bowel disease and cholangiocarcinoma, pancreatogram, PSC duration, PSC recurrence after transplant, and number of acute rejection episodes) and histologic findings (periductal lymphoplasmacytic infiltrate, storiform fibrosis, and obliterative phlebitis) in the liver explants. Twenty-three (23%) liver explants showed periductal infiltration with IgG4+ plasma cells. Eighteen cases (22%) had elevated serum IgG4 levels, including 8 without tissue IgG4 positivity. All cases showed dense periductal fibrosis; none had storiform fibrosis or obliterative phlebitis. IgG4 positivity in the liver strongly correlated with moderate-to-marked periductal lymphoplasmacytic inflammation (P=0.002). Clinically, IgG4 positivity in tissue, but not in serum, was correlated with shorter PSC duration before transplant and higher risk of recurrence after transplant. Nearly one quarter of explanted livers that carry a clinical diagnosis of PSC contain increased IgG4+ periductal plasma cell infiltrates and positive serum IgG4 levels. However, none of the explants show histologic features diagnostic of IgG4-associated cholangitis. PSC with tissue IgG4 positivity has a more aggressive clinical course manifested by shorter time to transplant and a higher likelihood of recurrence than IgG4 negative PSC.

Association of HER2/ErbB2 Expression and Gene Amplification with Pathologic Features and Prognosis in Esophageal Adenocarcinomas

Purpose: We examined the frequency, tumor characteristics, and prognostic impact of HER2 protein expression and gene amplification in patients with curatively resected esophageal adenocarcinoma (EAC). Experimental Design: HER2 expression was analyzed by immunohistochemistry (IHC) in surgical EAC specimens (n = 713). Gene amplification was examined by FISH in a large subset (n = 344). Most tumors were T3–4 (66%) or node positive (72%); 95% were located in the esophagus or gastroesophageal junction. No patient received neoadjuvant therapy. Cox models were used. Results: Overall, 17% of EACs were HER2 positive (i.e., IHC3+ or IHC2+ with amplification), with strong agreement between HER2 amplification (HER2/CEP17 ratio ≥2) and expression (κ = 0.83). HER2 positivity was significantly associated with lower tumor grade, less invasiveness, fewer malignant nodes, and the presence of adjacent Barretts esophagus (BE). EACs with BE had higher odds of HER2 positivity than EACs without BE, independent of pathologic features [OR = 1.8 (95% CI: 1.1–2.8), P = 0.014]. Among all cases, HER2 positivity was significantly associated with disease-specific survival (DSS) in a manner that differed by the presence or absence of BE (Pinteraction = 0.0047). In EACs with BE, HER2 positivity was significantly associated with improved DSS [HR = 0.54 (95% CI: 0.35–0.84), P = 0.0065] and overall survival (P = 0.0022) independent of pathologic features, but was not prognostic among EACs without BE. Conclusions: HER2 positivity was shown in 17% of resected EACs and associated with reduced tumor aggressiveness. EACs with BE had nearly twice the odds of being HER2 positive and, within this subgroup, HER2 positivity was independently associated with improved survival. Clin Cancer Res; 18(2); 546–54. ©2012 AACR.

Duplication of the muscularis mucosae in barrett esophagus: An underrecognized feature and its implication for staging of adenocarcinoma

Depth of invasion is one of the most important prognostic indicators in esophageal adenocarcinoma. Unlike other regions of the gastrointestinal tract, the esophagus in Barrett metaplasia frequently develops duplication of the muscularis mucosae (MM), but this feature is underrecognized, and its effect on appropriate staging of superficially invasive adenocarcinoma is unclear. We first randomly selected 50 esophageal resections for high-grade dysplasia or T1 adenocarcinoma in Barrett esophagus (BE) to evaluate the sensitivity and specificity of MM duplication for BE and its histologic characteristics, including percentage of the Barrett segment involved by MM duplication, origin of the duplicated muscle layer, and appearance of the tissue between duplicated MM. Twenty esophageal resections for squamous cell carcinoma served as controls. Next, to study the clinical significance of MM duplication, we evaluated 30 resections for BE that had superficial adenocarcinoma confined to regions of duplicated MM. Each case was classified as: depth of invasion (inner MM, space between duplicated MM, or outer MM), angiolymphatic invasion, and rate of lymph node metastasis. We observed MM duplication in 46 of 50 (92%) BE resections, involving 5% to >90% of the Barrett segment, in contrast to none in 20 (0%) resected squamous cell carcinoma, P<0.0001. In 5 (10%) cases, the MM was focally triplicated. The outer MM was continuous with the single MM beneath squamous epithelium, suggesting that outer MM represents the “original” muscle layer. The space between duplicated MM predominantly consisted of loose fibrovascular tissue similar to submucosa; in 15 (30%) cases, there were also areas of fibrosis or thin muscle strands joining the 2 MM layers. Of 30 adenocarcinomas invading duplicated MM, 10 (33%) invaded only inner MM, 12 (40%) invaded the space between MM, and 8 (27%) invaded the outer MM. Angiolymphatic invasion was present in 5 (17%) cases, and nodal metastases in 3 (10%, 1 case each of invasion into inner MM, between MM, and outer MM). These data show that MM duplication is a characteristic finding in BE, but it can pose difficulty in proper staging of superficial adenocarcinomas. The 17% rate of angiolymphatic invasion and 10% rate of lymph node metastases in our patients with invasion into duplicated MM suggest that these tumors can behave aggressively despite their technically intramucosal location.