Smyrk, Thomas C.

Multinucleated epithelial giant cells mimicking viropathic effect or dysplasia have been documented in the gastrointestinal tract, specifically in the esophagus and colorectal polyps. This finding has been associated with either inflammation or hyperplasia in prior case series. The authors report the first occurrence in the small intestine involving a 30-year-old woman without a coexisting inflammatory or hyperplastic process. The multinucleated epithelial giant cells featured numerous homogenous nulei (mean 9 nuclei, range 5-18) limited to duodenal villi. Immunohistochemistry revealed strong positivity for cytokeratin AE1/AE3 and negativity for herpes simplex virus 1 and 2, varicella simplex virus, and cytomegalovirus. In situ hybridizations for adenovirus and Epstein–Barr virus were also negative. Despite a lack of a specific etiologic agent, evidence suggests multinucleated epithelial giant cells are the consequence of inflammation, chronic injury, or cellular degeneration.

Abstract Background and Aims: In patients with Barrett's esophagus (BE), reflux-induced injury promotes esophageal adenocarcinoma, presumably through cyclooxygenase 2 (COX-2) related pathways. Proton pump inhibitors (PPIs) and nonsteroidal anti-inflammatory drugs (NSAIDs) may interrupt reflux-associated carcinogenesis by reducing acid exposure and subsequent inflammation. However, clinical trial data regarding the chemopreventive efficacy of a PPI + NSAID combination are limited. The aim of this multi-center, randomized, phase II trial was to assess the effects of a 28-day intervention with esomeprazole 40 mg bid and aspirin 81 mg qd, 325 mg qd, or placebo qd on tissue prostaglandin E2 (PGE2) concentrations in BE patients. Methods: Using the infrastructure of the Cancer Prevention Network, participants (> 18 years) with histologically confirmed non dysplastic BE were randomly assigned to receive one of three interventions for 28 days: (arm A) esomeprazole 40 mg bid+ aspirin 81 mg placebo qd + aspirin 325 mg placebo qd (n=42); (arm B) esomeprazole 40 mg bid+ aspirin 81 mg qd + aspirin placebo 325 qd (n=63); (arm C) esomeprazole 40 mg bid + aspirin 81 mg qd placebo + aspirin 325 mg qd (n=63). Esophageal biopsies were obtained pre- and post-intervention to assess change in PGE2 concentration as the primary endpoint. Results: In total, 122 participants were randomized, 121 (99%) completed the trial per protocol, and 115 (94%) were evaluated for the primary endpoint. Baseline characteristics were similar across intervention arms. The absolute change (mean + SD) in tissue PGE2 concentration was −67.6 (229.68) in Arm A, −120.9 (281.28) in Arm B (p = 0.10 vs Arm A) and −174.9 (263.62) in Arm C (p = 0.02 vs Arm A). Conclusions: In combination with esomeprazole 40 mg twice per day, aspirin 325 mg per day significantly reduced tissue PGE2 concentration in BE patients after a 28-day intervention, as compared to aspirin placebo. Given the relevance of PGE2 pathways in BE-associated carcinogenesis, further evaluation of this chemoprevention strategy in larger, more definitive phase III trials is warranted. Citation Information: Cancer Prev Res 2011;4(10 Suppl):CN06-03.

Fibrosing mediastinitis (FM) and IgG4-related disease (IgG4-RD) are two fibroinflammatory disorders with potentially overlapping clinical and radiological features. In this paper, we looked for histopathologic features of IgG4-RD and enumerated infiltrating IgG4-positive plasma cells within mediastinal tissue biopsies from FM patients. We identified 15 consecutive FM surgical mediastinal tissue biopsies between 1985 and 2006. All patients satisfied the clinical and radiological diagnostic criteria for FM. All patients had either serological or radiological evidence of prior histoplasmosis or granulomatous disease, respectively. Formalin-fixed paraffin-embedded tissue sections of all patients were stained for H&E, IgG, and IgG4. Three samples met the predefined diagnostic criteria for IgG4-RD. In addition, characteristic histopathologic changes of IgG4-RD in the absence of diagnostic numbers of tissue infiltrating IgG4-positive plasma cells were seen in a number of additional cases (storiform cell-rich fibrosis in 11 cases, lymphoplasmacytic infiltrate in 7 cases, and obliterative phlebitis/arteritis in 2 cases). We conclude that up to one-third of histoplasmosis or granulomatous-disease-associated FM cases demonstrate histopathological features of IgG4-RD spectrum. Whether these changes occur as the host immune response against Histoplasma or represent a manifestation of IgG4-RD remains to be determined. Studies to prospectively identify these cases and evaluate their therapeutic responses to glucocorticoids and/or other immunosuppressive agents such as rituximab are warranted.

Abstract Background: Colorectal cancer (CRC) is the third most common incident cancer among women in the United States. Alcohol use has been proposed as a CRC risk factor, but existing observational data remain inconsistent. To date, relatively few studies have examined associations between alcohol use and CRC risk based on molecularly-defined subtypes. Aim: To evaluate associations between alcohol use and incident CRC overall, as well as by molecularly-defined subtypes including microsatellite instability (MSI), CpG island methylator phenotype (CIMP) and BRAF mutation status in the prospective, population-based, Iowa Women's Health Study (IWHS). Methods: The IWHS recruited 41,836 randomly selected Iowa women, ages 55–69 years at enrollment, in 1986. Women with prevalent cancers or no follow-up were excluded, leaving 38,001 eligible for this study. Alcohol use was obtained from a self-administered food frequency questionnaire at study baseline. Incident CRCs were identified through annual linkage with the State Health Registry of Iowa. Archived, paraffin-embedded tissue specimens were recently requested for incident CRC cases diagnosed through December 31, 2002. In the present study, useable tissue specimens were obtained and molecularly characterized for 563/1,255 cases (45%), whose baseline age, body mass index, physical activity level, total energy intake and alcohol use were similar to non-retrieved cases (p > 0.05 for each comparison). Alcohol use was categorized as never (n=21,464), < 3.4 g/day (n=8,313) and > 3.4 g/day (n=8,224), based on the median split among users. Molecularly-defined CRC subtypes were categorized as MSI-high (MSIH; n=148), MSI-low or microsatellite stable (MSI-L/MSS; n=400); CIMP-positive (n=167) or CIMP-negative (n=368); and BRAF-mutation (n=154) or BRAF-wildtype (n=391). Relative risks (RRs) and 95% confidence intervals (95% CIs) were estimated for alcohol use compared to never drinkers, using multivariable Cox regression models adjusted for body mass index, waist-to-hip ratio, smoking status, physical activity level, exogenous estrogen use, and daily intakes of total energy, total fat, red meat, sucrose, calcium, folate, methionine and vitamin E. Results: There was no statistically significant association between alcohol use and overall CRC risk (RR=1.00; 95% CI = 0.86–1.15 for < 3.4 g/day versus none; RR=1.06; 95% CI=0.91–1.24 for >3.4 g/day versus none). Further, there were no associations with alcohol use for specific, molecularly-defined CRC subtypes (RRs shown for > 3.4 g/day versus none): MSI-H (RR=1.07; 95% CI=0.70–1.64); MSI-L or MSS (RR=1.12; 95% CI=0.85–1.47); CIMP-positive (RR=0.97; 95% CI=0.64–1.47); CIMP-negative (RR=1.13; 95% CI=0.85–1.50); BRAF-mutation (RR=0.94; 95% CI=0.61–1.45); and BRAF-wildtype (RR=1.20; 95% CI=0.91–1.57). Conclusion: In this cohort of older women, alcohol use did not appear to be a risk factor for incident CRC, overall or by the defined molecular subtypes. Citation Information: Cancer Prev Res 2010;3(1 Suppl):A115.

Abstract Background: Postmenopausal hormone (PMH) therapy represents a controversial colorectal cancer (CRC) preventive intervention. Because colorectal carcinogenesis is a heterogeneous process, we evaluated associations between PMH therapy and incident CRC in relation to KRAS mutation status in a population-based cohort of older women [Iowa Women's Health Study (IWHS)]. Methods: The IWHS enrolled 41,836 randomly selected women, ages 55 to 69 years, in 1986. PMH therapy and other exposure data were recorded at baseline. Tissue samples from prospectively identified CRC cases (n = 507) were analyzed for somatic KRAS mutations (exon 2, codons 12 and 13). Multivariable Cox regression models were fit to estimate relative risks (RR) and 95% confidence intervals (CI). Results: PMH therapy (ever vs. never) was inversely associated with KRAS mutation–negative (RR = 0.83; 95% CI, 0.66–1.06; P = 0.14) and KRAS mutation–positive (RR = 0.82; 95% CI, 0.58–1.16; P = 0.27) tumors, although the observed risk estimates were not statistically significant. When anatomic subsite was additionally considered, the strongest association was found for KRAS mutation–negative, distal colorectal tumors (RR = 0.64; 95% CI, 0.43–0.96; P = 0.03). Conclusions: To our knowledge, we provide the first report of KRAS-defined CRC risks associated with PMH therapy. These data suggest that PMH therapy may reduce CRC risk through mechanisms beyond KRAS mutation status but might provide greater benefits for KRAS mutation–negative than mutation-positive tumors (at least in the distal colorectum). Impact: Findings from this prospective cohort study provide novel insights about the molecular biology of PMH therapy–related CRC risk reduction. Cancer Epidemiol Biomarkers Prev; 21(4); 681–4. ©2012 AACR.

AbstractBackgroundThis study evaluated the impact of tumor regression grading (TRG) and other pathologic variates in a cohort of rectal carcinoma patients treated with neoadjuvant chemoradiotherapy (CRT). The value of a grading less than pCR for predicting survival is unknown. Tumor budding has not been systematically studied in rectal cancer after neoadjuvant therapy.MethodsPathologic risk factors for survival were evaluated on surgical specimens of 237 patients with stages I, II, and III rectal cancer treated between 1996 and 2006. All patients underwent preoperative CRT followed by surgical resection 6–8 weeks later. TRG, tumor grade, budding, venous invasion, radial margin, and nodal status were evaluated. The prognostic value of TRG categories was calculated with Cox regression models and validated with resampling methods.ResultsTRG of <25% occurred in 61 (25.7%) and a complete response in 39 (16.4%) of the resected specimens. TRG of <25% was shown to be a statistically significant predictor for cancer‐specific survival (CSS) and recurrence‐free survival (RFS) compared to TRG ≥25% (P = 0.013). Tumor budding was present in 24 (10.1%) of the patients and was negatively associated with CSS (P = 0.013). Lymph node involvement was observed in 83 (35.0%) patients. TRG and nodal status (P < 0.001) were the most significant predictors associated with outcome.ConclusionPartial pathologic response ≥25% was a superior predictor compared to pCR for improved survival after preoperative CRT. CSS and RFS were adversely affected by the presence of lymph node metastases.

PurposeAlthough the importance of obesity in colon cancer risk and outcome is recognized, the association of body mass index (BMI) with DNA mismatch repair (MMR) status is unknown.Patients and MethodsBMI (kg/m2) was determined in patients with TNM stage II or III colon carcinomas (n = 2,693) who participated in randomized trials of adjuvant chemotherapy. The association of BMI with MMR status and survival was analyzed by logistic regression and Cox models, respectively.ResultsOverall, 427 (16%) tumors showed deficient MMR (dMMR), and 630 patients (23%) were obese (BMI ≥ 30 kg/m2). Obesity was significantly associated with younger age (P = .021), distal tumor site (P = .012), and a lower rate of dMMR tumors (10% v 17%; P < .001) compared with normal weight. Obesity remained associated with lower rates of dMMR (odds ratio, 0.57; 95% CI, 0.41 to 0.79; P < .001) after adjusting for tumor site, stage, sex, and age. Among obese patients, rates of dMMR were lower in men compared with women (8% v 13%; P = .041). Obesity was associated with higher recurrence rates (P = .0034) and independently predicted worse disease-free survival (DFS; hazard ratio [HR], 1.37; 95% CI, 1.14 to 1.64; P = .0010) and overall survival (OS), whereas dMMR predicted better DFS (HR, 0.59; 95% CI, 0.47 to 0.74; P < .001) and OS. The favorable prognosis of dMMR was maintained in obese patients.ConclusionColon cancers from obese patients are less likely to show dMMR, suggesting obesity-related differences in the pathogenesis of colon cancer. Although obesity was independently associated with adverse outcome, the favorable prognostic impact of dMMR was maintained among obese patients.

Background Postmenopausal hormone (PMH) therapy may reduce colorectal cancer (CRC) risk, but existing data are inconclusive. Objectives To evaluate associations between PMH therapy and incident CRC, overall and by molecularly defined subtypes, in the population-based Iowa Women's Health Study of older women. Methods Exposure data were collected from Iowa Women's Health Study participants (55–69 years) at baseline (1986). Archived, paraffin-embedded tissue specimens for 553 CRC cases were collected and analysed to determine microsatellite instability (MSI-L/MSS or MSI-H), CpG island methylator phenotype (CIMP-negative or CIMP-positive) and BRAF mutation ( BRAF -wildtype or BRAF -mutated) status. Multivariable Cox regression models were fit to estimate RRs and 95% CIs. Results PMH therapy (ever vs never use) was inversely associated with incident CRC overall (RR=0.82; 95% CI 0.72 to 0.93), with a significantly lower risk for MSI-L/MSS tumours (RR=0.75; 95% CI 0.60 to 0.94), and borderline significantly lower risks for CIMP-negative (RR=0.79; 95% CI 0.63 to 1.01) and BRAF -wildtype (RR=0.83; 95% CI 0.66 to 1.04) tumours. For PMH therapy >5 years, the subtype-specific risk estimates for MSI-L/MSS, CIMP-negative and BRAF -wildtype tumours were: RR=0.60, 95% CI 0.40 to 0.91; RR=0.68, 95% CI 0.45 to 1.03; and RR=0.70, 95% CI 0.47 to 1.05, respectively. PMH therapy was not significantly associated with the MSI-H, CIMP-positive or BRAF -mutated CRC subtypes. Conclusions In this prospective cohort study, PMH therapy was inversely associated with distinct molecularly defined CRC subtypes, which may be related to differential effects from oestrogen and/or progestin on heterogeneous pathways of colorectal carcinogenesis.

Abstract Increased alcohol consumption is a putative colorectal cancer (CRC) risk factor. However, existing data are less conclusive for women than men. Also, to date, relatively few studies have reported alcohol-related CRC risks based on molecularly defined tumor subtypes. We evaluated associations between alcohol intake and incident CRC, overall and by microsatellite instability [MSI high (MSI-H) or MSI low/microsatellite stable (MSI-L/MSS)], CpG island methylator phenotype (CIMP positive or CIMP negative), and BRAF mutation (mutated or wild-type) status in the prospective, population-based Iowa Women's Health Study (IWHS; n = 41,836). Subjects were 55 to 69 years at baseline (1986), and exposure data were obtained by self-report. Incident CRCs were prospectively identified and archived, paraffin-embedded tissue specimens were collected from 732 representative cases, diagnosed through December 31, 2002. Multivariate Cox regression models were fit to estimate relative risks (RR) and 95% confidence intervals (CI). Among alcohol consumers, the median intake (range) was 3.4 (0.9–292.8) g/d. Compared with nonconsumers, alcohol intake levels of 3.4 g/d or less (RR = 1.00; 95% CI, 0.86–1.15) and more than 3.4 g/d (RR = 1.06; 95% CI, 0.91–1.24) were not significantly associated with overall CRC risk. Analyses based on alcohol intake levels of 30 g/d or less and more than 30 g/d or quartile distributions yielded similar risk estimates. Null associations were also observed between each alcohol intake level and the MSI-, CIMP- or, BRAF-defined CRC subtypes (P &gt; 0.05 for each comparison). These data do not support an adverse effect from alcohol intake on CRC risk, overall or by specific molecularly defined subtypes, among older women. Cancer Prev Res; 4(12); 2035–43. ©2011 AACR.

Abstract Background Serrated polyps are an inhomogeneous group of lesions that harbour precursors of colorectal cancer. Current research has been directed at further defining the histopathological characteristics of these lesions, but definitive treatment recommendations are unclear. The aim was to review the current literature regarding classification, molecular genetics and natural history of these lesions in order to propose a treatment algorithm for surgeons to consider. Methods The PubMed database was searched using the following search terms: serrated polyp, serrated adenoma, hyperplastic polyp, hyperplastic polyposis, adenoma, endoscopy, surgery, guidelines. Papers published between 1980 and 2010 were selected. Results Sixty papers met the selection criteria. Most authors agree that recommendations regarding endoscopic or surgical management should be based on the polyp's neoplastic potential. Polyps greater than 5 mm should be biopsied to determine their histology so that intervention can be directed accurately. Narrow-band imaging or chromoendoscopy may facilitate the detection and assessment of extent of lesions. Complete endoscopic removal of sessile serrated adenomas in the left or right colon is recommended. Follow-up colonoscopy is recommended in 2–6 months if endoscopic removal is incomplete. If the lesion cannot be entirely removed endoscopically, segmental colectomy is strongly recommended owing to the malignant potential of these polyps. Left-sided lesions are more likely to be pedunculated, making them more amenable to successful endoscopic removal. Conclusion Even though the neoplastic potential of certain subtypes of serrated polyp is heavily supported, further studies are needed to make definitive endoscopic and surgical recommendations.