Duodenal intraepithelial lymphocytosis in Helicobacter pylori gastritis: comparison before and after treatment.

Our aims were to assess performance of duodenal intraepithelial lymphocyte counting for diagnosis of Helicobacter pylori (H. pylori) gastritis, and effects of eradication therapy on intraepithelial lymphocytosis. Paired duodenal and gastric biopsies from subjects with a pathologic diagnosis of H. pylori gastritis were reviewed. Higher duodenal intraepithelial lymphocyte counts were observed in 40 subjects with H. pylori gastritis (26 ± 5 per villus) than 52 subjects negative for H. pylori (12 ± 2 per villus). After successful eradication therapy, duodenal lymphocytes were indistinguishable from H. pylori-negative subjects, whereas they remained elevated after failed eradication therapy. This study confirms previous reports of increased duodenal intraepithelial lymphocytes in patients with concurrent Helicobacter pylori gastritis. Intraepithelial lymphocyte counts of > 15 per villus or > 10 per 100 enterocytes were predictive of infection. Duodenal lymphocytosis decreases significantly after successful eradication therapy but remains elevated when treatment fails.

Associations between molecular characteristics of colorectal serrated polyps and subsequent advanced colorectal neoplasia.

PURPOSE: BRAF mutation and DNA hypermethylation have linked sessile serrated adenomas/polyps (SSA/Ps) to serrated colorectal cancer (CRC) in cross-sectional studies, but they have not been evaluated in a longitudinal study. We aimed to evaluate the associations between molecular markers of serrated polyps and subsequent advanced colorectal neoplasia. METHODS: Study subjects included Kaiser Permanente Washington members aged 20-75 years who received an index colonoscopy between 1/1/1998 and 12/31/2007 and had hyperplastic polyps (HPs) or SSA/Ps according to study pathology review. Polyps from index colonoscopies were removed and assayed for BRAF mutation, CpG island methylator phenotype (CIMP), and MLH1 methylation. Pathology reports and biopsies from the subsequent lower gastrointestinal endoscopy through 1/1/2013 were reviewed for advanced colorectal neoplasia. We identified additional incident CRC cases through linkage to the Seattle-Puget Sound Surveillance Epidemiology and End Results registry. We used generalized estimating equations to calculate adjusted odds ratios (OR) and 95% confidence intervals (CI) for subsequent advanced colorectal neoplasia, comparing index serrated polyps with different molecular markers. RESULTS: We included 553 individuals with index serrated polyps (420 HPs and 133 SSA/Ps) and 795 subsequent endoscopies. The prevalence of BRAF-mutant, CIMP-high, and MLH1-methylated serrated polyps were 51%, 4%, and 2%, respectively. BRAF and CIMP were not associated with subsequent advanced colorectal neoplasia. MLH1-methylated SSP/As were significantly more likely to have subsequent advanced neoplasia (OR = 4.66, 95% CI 1.06-20.51). CONCLUSION: Our results suggest that BRAF-mutant and CIMP-high serrated polyps are not associated with subsequent advanced colorectal neoplasia. Among SSA/Ps, MLH1 methylation may be an important marker to identify high-risk CRC precursors.

Prediction of survival of HPV16-negative, p16-negative oral cavity cancer patients using a 13-gene signature: A multicenter study using FFPE samples.

OBJECTIVES: To test the performance of an oral cancer prognostic 13-gene signature for the prediction of survival of patients diagnosed with HPV-negative and p16-negative oral cavity cancer. MATERIALS AND METHODS: Diagnostic formalin-fixed paraffin-embedded oral cavity cancer tumor samples were obtained from the Fred Hutchinson Cancer Research Center/University of Washington, University of Calgary, University of Michigan, University of Utah, and seven ARCAGE study centers coordinated by the International Agency of Research on Cancer. RNA from 638 Human Papillomavirus (HPV)-negative and p16-negative samples was analyzed for the 13 genes using a NanoString assay. Ridge-penalized Cox regressions were applied to samples randomly split into discovery and validation sets to build models and evaluate the performance of the 13-gene signature in predicting 2-year oral cavity cancer-specific survival overall and separately for patients with early and late stage disease. RESULTS: Among AJCC stage I/II patients, including the 13-gene signature in the model resulted in substantial improvement in the prediction of 2-year oral cavity cancer-specific survival. For models containing age and sex with and without the 13-gene signature score, the areas under the Receiver Operating Characteristic Curve (AUC) and partial AUC were 0.700 vs. 0.537 (p < 0.001), and 0.046 vs. 0.018 (p < 0.001), respectively. Improvement in predicting prognosis for AJCC stage III/IV disease also was observed, but to a lesser extent. CONCLUSIONS: If confirmed using tumor samples from a larger number of early stage oral cavity cancer patients, the 13-gene signature may inform personalized treatment of early stage HPV-negative and p16-negative oral cavity cancer patients.

The association between colorectal sessile serrated adenomas/polyps and subsequent advanced colorectal neoplasia.

PURPOSE: Colorectal cancer (CRC) screening guidelines recommend increased surveillance of individuals with sessile serrated adenomas/polyps (SSA/Ps), but there is uncertainty about the risk associated with SSA/Ps. We aimed to determine the association between SSA/Ps and subsequent advanced colorectal neoplasia. METHODS: This case-control study included Kaiser Permanente Washington (KPWA) members who received an index colonoscopy between 1/1/1998 and 12/31/2007, and had hyperplastic polyps (HPs) or SSA/Ps but no conventional adenomas according to study pathologist histologic review. Subsequent pathology reports and biopsies through 1/1/2013 were reviewed for advanced colorectal neoplasia. We linked to the Seattle-Puget Sound Surveillance Epidemiology and End Results (SEER) registry to identify additional CRC cases. We used generalized estimating equations with a logit link to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for advanced colorectal neoplasia, comparing those with SSA/Ps to those with HPs. RESULTS: There were 161 individuals with index SSA/Ps, 548 with HPs, and 918 subsequent endoscopies included in analyses. Of those with index SSA/Ps, 19 had subsequent advanced colorectal neoplasia; 39 with HPs had subsequent advanced colorectal neoplasia. Compared to those with HPs, those with SSA/Ps were not statistically significantly more likely to have subsequent advanced colorectal neoplasia (adjusted OR 1.79; CI 0.98-3.28). Polyp size ≥ 10 mm, right colon location, and the presence of multiple serrated polyps were also not associated with advanced colorectal neoplasia. CONCLUSIONS: Our results suggest that there is not a strong association between SSA/Ps and subsequent advanced colorectal neoplasia during the 5 years following SSA/P removal.

Telomere length differences between colorectal polyp subtypes: a colonoscopy-based case-control study.

BACKGROUND: Short telomeres have been associated with increased risk of many cancers, particularly cancers of the gastrointestinal tract including esophagus and stomach. However, the association between telomere length (TL) and colorectal cancer and its precursors, colorectal polyps, is not clear. METHODS: We investigated the relationship between TL and risk of colorectal polyp subtypes in a colonoscopy-based study in western Washington. Participants were 35-79 year-old enrollees at an integrated health care system, who underwent a colonoscopy between 1998 and 2007 (n = 190), completed a self-administered questionnaire, provided blood samples, and were distinguished as having adenomas, serrated polyps, or as polyp-free controls through a standardized pathology review. Telomere length (T) relative to a single copy gene (S) was measured in circulating leukocytes from stored buffy coat samples using quantitative polymerase chain reaction. Multivariable polytomous logistic regression was used to compare case groups with polyp-free controls and other case groups; adjusted odds ratios (OR) and 95% confidence intervals (CI) were estimated. RESULTS: TL in the shortest tertile (T/S ratio < 0.58) was associated with increased risk of adenomas and serrated polyps [OR (95%CI) were 1.77(0.81-3.88) and 2.98(1.15-7.77), respectively). When evaluated by lesion severity within each pathway, short TL was more strongly associated with advanced adenomas and sessile serrated polyps [OR (95% CI) = 1.90(0.76-4.73) and 3.82(0.86-16.86), respectively], although the associations were not statistically significant. CONCLUSIONS: Our results suggest that short TL may be associated with an increased risk of colorectal polyps in both the adenoma-carcinoma and serrated pathways. The risk was particularly notable for sessile serrated polyps, although the association was not statistically significant and sample size was limited.

Impact of tumoral carbonic anhydrase IX and Ki-67 expression on survival in oral squamous cell carcinoma patients.

Oral squamous cell carcinoma (OSCC) is the most commonly diagnosed type of head and neck cancer, accounting for ~300,000 new cases worldwide annually. Carbonic anhydrase IX (CAIX) and Ki-67 have been associated with reduced disease-specific survival (DSS) in patients with OSCC. We previously proposed a combined CAIX and Ki-67 signature of 'functional hypoxia' and sought to replicate this association in a larger independent cohort of patients with OSCC at the Fred Hutchinson Cancer Research Center (FHCRC) in Seattle. The study population included patients with incident primary OSCC treated at the University of Washington Medical Center and the Harborview Medical Center in Seattle between December 2003 and February 2012. Archived tumor blocks were obtained with tissue samples from 189 patients, and triplicate 0.6 mm cores were assembled into tissue microarrays (TMAs). Fluorescence immunohistochemistry and AQUAnalysis® were used to quantify the expression of tumoral CAIX (tCAIX) and stromal CAIX (sCAIX) and tumoral Ki-67 for each TMA core. Hazard ratios for DSS were calculated using Cox proportional hazards analysis. High tCAIX and sCAIX expression levels were associated with reduced DSS (aHR=1.003, 95% CI:1.00-1.01 and aHR=1.010, 95% CI:1.001-1.019, per AQUA score unit, respectively). Ki-67 expression was not associated with survival (aHR=1.01, 95% CI:0.99-1.02) in the FHCRC cohort. DSS for patients with high sCAIX and low Ki-67 did not differ from that of other patient groups. Elevated tCAIX was associated with reduced DSS as a continuous and as a dichotomized (75%) variable. sCAIX was associated with DSS as a continuous variable but not when dichotomized (75%). However, the previously proposed 'functional hypoxia' signature was not replicated in the current FHCRC study. The failure to replicate our prior observation of poorer survival in patients with combined high sCAIX and low tumoral Ki-67 was likely due to the absence of an association between tumoral Ki-67 and DSS in this cohort. However, the association between DSS and tCAIX and sCAIX supports a role for CAIX in OSCC clinical outcomes.

Grade Assignment by Ki-67 Proliferative Index, Mitotic Count, and Phosphohistone H3 Count in Surgically Resected Gastrointestinal and Pancreatic Neuroendocrine Tumors.

OBJECTIVES: The aim of this study was to evaluate the concordance in grade assignment for gastroenteropancreatic neuroendocrine tumors using mitotic count (MC), Ki-67 proliferative index (KPI), and phosphohistone H3 count (PHH3C). METHODS: Resected gastroenteropancreatic neuroendocrine tumors were graded based on MC, KPI, and PHH3C. Concordance was determined using a weighted κ statistic. Median survival across each grade category was determined using Kaplan-Meier methods. RESULTS: Of the 110 patients, the majority had gastrointestinal primaries and grade 1 or 2 tumors. Rates of discordance in grade assignment were 29% of cases for KPI versus MC (κW = 0.26), 32% for PHH3C versus MC (κW = 0.34), and 32% for PHH3C versus KPI (κW = 0.37). There was fair agreement between grading by KPI and MC. Relative to grade by KPI and MC, PHH3C tended to upgrade tumors. The proportion alive at 3 and 5 years was not significantly different for patients with grade 1 versus grade 2 tumors. CONCLUSIONS: The concordance between KPI and MC was fair. Phosphohistone H3 count tended to upgrade tumors using the cutoffs established by MC. Grade 1 and grade 2 tumors were associated with similar survival regardless of grading method. The overall relevance of the current cutoff values used in grading neuroendocrine tumors may need to be revisited.

Radiologically Undetected Hepatocellular Carcinoma in Patients Undergoing Liver Transplantation: An Immunohistochemical Correlation With LI-RADS Score.

Orthotopic liver transplantation is the best option for patients with carefully selected unresectable disease because of underlying liver dysfunction. The 5-year survival rate after orthotopic liver transplantation for early detected hepatocellular carcinoma (HCC) is high, and a similar or even higher rate is reported in those with radiologically undetected HCC. This study evaluated and compared the histologic features of pretransplant radiologically undetected (14 patients, 25 tumors) versus detected (36 patients, 45 tumors) HCCs. Tumor size, tumor differentiation, number of unpaired arteries, mitotic count per 10 high-power fields, CD34 immunostain to assess microvessel density, and Ki67 immunostain were compared with the Liver Imaging Reporting and Data System score, which was retrospectively assigned to each tumor in both groups. The Liver Imaging Reporting and Data System score was significantly higher in the HCC detected group (P<0.001). The vast majority of the undetected HCCs (88%) was <2 cm in size. Only 12% of the undetected HCCs were ≥2 cm, whereas 51% of the detected HCCs were ≥2 cm in size. Higher rate of moderate to poor tumor differentiation was noted in the detected HCCs compared with the undetected group (89% vs. 60%; P=0.004). No statistically significant difference in the number and distribution of unpaired arteries, or mitotic count was observed in 2 groups (although fewer unpaired arteries were identified in the undetected group). The detected HCCs had a higher rate of 2+ CD34 staining compared with the undetected HCCs (68% vs. 27%; P=0.002), whereas the opposite was observed for 1+ CD34 staining (59% undetected HCCs vs. 17% detected HCCs; P=0.002). Ki67 proliferative index was not statistically different between the 2 groups (120.8/1000 cells detected HCCs vs. 81.8/1000 cells undetected HCCs; P=0.36). The factors associated with failing to detect HCCs pretransplant by radiologic studies include small tumor size (<2 cm), low-grade histologic differentiation, and low microvessel density (low CD34 staining). A significant association between the number and distribution of unpaired arteries and HCC detection has not been established by our study.

An International Collaborative Standardizing a Comprehensive Patient-Centered Outcomes Measurement Set for Colorectal Cancer.

IMPORTANCE: Global health systems are shifting toward value-based care in an effort to drive better outcomes in the setting of rising health care costs. This shift requires a common definition of value, starting with the outcomes that matter most to patients. OBJECTIVE: The International Consortium for Health Outcomes Measurement (ICHOM), a nonprofit initiative, was formed to define standard sets of outcomes by medical condition. In this article, we report the efforts of ICHOM's working group in colorectal cancer. EVIDENCE REVIEW: The working group was composed of multidisciplinary oncology specialists in medicine, surgery, radiation therapy, palliative care, nursing, and pathology, along with patient representatives. Through a modified Delphi process during 8 months (July 8, 2015 to February 29, 2016), ICHOM led the working group to a consensus on a final recommended standard set. The process was supported by a systematic PubMed literature review (1042 randomized clinical trials and guidelines from June 3, 2005, to June 3, 2015), a patient focus group (11 patients with early and metastatic colorectal cancer convened during a teleconference in August 2015), and a patient validation survey (among 276 patients with and survivors of colorectal cancer between October 15, 2015, and November 4, 2015). FINDINGS: After consolidating findings of the literature review and focus group meeting, a list of 40 outcomes was presented to the WG and underwent voting. The final recommendation includes outcomes in the following categories: survival and disease control, disutility of care, degree of health, and quality of death. Selected case-mix factors were recommended to be collected at baseline to facilitate comparison of results across treatments and health care professionals. CONCLUSIONS: A standardized set of patient-centered outcome measures to inform value-based health care in colorectal cancer was developed. Pilot efforts are under way to measure the standard set among members of the working group.

Massive Gastric Juvenile Polyposis: A Clinicopathologic Study Using SMAD4 Immunohistochemistry.

OBJECTIVES: Juvenile polyps involving the stomach are uncommon. Massive gastric juvenile polyposis is even rarer. METHODS: We describe the clinicopathologic features of nine cases of massive gastric juvenile polyposis. RESULTS: All patients had anemia; four had hypoalbuminemia. The polyps were composed predominantly of dilated crypts lined by columnar epithelium and abundant edematous stroma with mixed inflammatory infiltrates. One patient had a poorly differentiated adenocarcinoma, arising in juvenile polyp-associated intraepithelial neoplasia. A second patient had a well-differentiated intramucosal adenocarcinoma arising in a juvenile polyp with high-grade dysplasia. Three of our cases had polyposis restricted to the stomach. Six (66.6%) had loss of SMAD4 immunoreactivity, making them subject to severe bleeding and hypoproteinemia, as well as developing severe dysplasia or adenocarcinoma. CONCLUSIONS: SMAD4 immunohistochemstry is a helpful ancillary diagnostic test in cases of suspected juvenile polyposis syndrome involving the stomach.

Reproductive factors and risk of colorectal polyps in a colonoscopy-based study in western Washington State.

BACKGROUND: Oral contraceptives (OC) are associated with a decreased risk of colorectal cancers; however, a recent study reported an increased risk of small colorectal adenomas associated with OC use. To determine if these results were replicable in a different study population, we investigated the relationship between OC use and other reproductive factors and risk of colorectal polyps in a case-control study in western Washington. METHODS: Study participants were 24-79-year-old female enrollees at an integrated health care system in western Washington who were diagnosed as having adenomas (n = 299), serrated polyps (n = 337), both types of polyps (n = 105) or as polyp-free controls (n = 615) through an index colonoscopy and completed a structured interview to collect reproductive history information. Multivariable polytomous logistic regression was used to compare case groups to controls and to each other; odds ratios (OR) and 95% confidence intervals were estimated. RESULTS: There was no association between OC use, duration of use, or recency of use and the risk of either adenomas or serrated polyps [adjusted OR for OC ever use (95% CI) 0.85 (0.58-1.23) and 0.96 (0.66-1.40), respectively], and associations did not differ by lesion severity within the adenoma or serrated pathways. Further, no associations were observed between other reproductive factors and risk of colorectal polyp subtypes. CONCLUSIONS: Our results suggest that reproductive factors, including OC use, are not associated with early colorectal cancer precursor lesions.

Cytomegalovirus (CMV) in gastrointestinal mucosal biopsies: should a pathologist perform CMV immunohistochemistry if the clinician requests it?

Cytomegalovirus (CMV) causes clinically significant gastrointestinal (GI) injury. CMV inclusions can be identified on routine hematoxylin and eosin (H&E) stain, but immunohistochemistry (IHC) is also available for identifying CMV in tissue. The advent of accountable care organization models of care bring into question whether it is cost-effective for immunohistochemistry to be performed upfront at the request of clinicians and whether the quality of viral detection is compromised when the diagnosis of CMV is predicated on histologic review. In this study, a retrospective review of GI biopsies with CMV evaluations was performed. There were 449 cases with clinical requests to rule out CMV and 238 CMV analyses initiated by the pathologist without a clinical request. Among the cases that included a clinician's request, 37 had CMV detected. Immunostaining was performed on 26 cases, while a diagnosis based on readily identifiable viral inclusions on H&E-stained slides was made in 11. Among pathologist-initiated work-ups, 15 were CMV+, 3 of which had inclusions identified by H&E only. Among 38 CMV cases for which IHC had been performed, 27 had overt viral inclusions obvious on H&E. Seventy-two cases revealed uninflamed GI mucosa, and although a clinical concern about CMV infection was present, a CMV IHC work-up was not initially performed; all were negative for CMV by IHC and H&E. Clinical suspicion for CMV has a high yield for CMV detection, but "upfront" testing is likely unnecessary. Careful histopathologic review by a pathologist remains critical in the efficient and cost-effective detection of CMV.

Glutamine Synthetase Immunoreactivity in Peritumoral Hyperplasia in Liver: Case Report of a Metastatic Paraganglioma With Focal Nodular Hyperplasia-Like Changes and Review of an Additional 54 Liver Masses.

OBJECTIVES: Focal nodular hyperplasia (FNH) and peritumoral hyperplasia in the liver exhibit increased immunoreactivity for glutamine synthetase (GS). We observed FNH-like changes with map-like GS staining surrounding a metastatic paraganglioma and sought to determine how often such changes occur around primary and metastatic liver lesions. METHODS: We performed GS immunohistochemistry in liver cases of 20 metastatic neuroendocrine carcinomas (NECs), 21 metastatic colon carcinomas (CCs), seven hepatocellular carcinomas (HCCs), and six FNHs and assessed lesions for size, degree of fibrosis (scored 1-3), and peritumoral hyperplasia. RESULTS: Most NEC or CC cases had few peritumoral hyperplastic features. Three NECs, two CCs, and one HCC (13%) had patchy GS staining at the periphery of the lesions. One CC case had both histologic and immunohistochemical peritumoral hyperplasia. CONCLUSIONS: Peritumoral hyperplasia or FNH-like changes are uncommon findings around primary or metastatic lesions in the liver. GS immunohistochemistry assists in distinguishing true peritumoral hyperplasia from mass effect.

Initiation of universal tumor screening for Lynch syndrome in colorectal cancer patients as a model for the implementation of genetic information into clinical oncology practice.

BACKGROUND: Lynch syndrome confers a hereditary predisposition to colorectal and other cancers. Universal tumor screening (UTS) for Lynch syndrome is recommended by several professional societies, but the implementation can be complex. This article describes the evaluation, process development, and initiation of Lynch syndrome UTS at a tertiary referral cancer center. METHODS: A multidisciplinary team developed the new process design. Issues in 5 themes were noted: timing, funding, second-opinion patients, result processing, and the role of genetics providers. A committee approach was used to examine each issue for process-improvement development. RESULTS: The issues related to testing were addressed individually for the successful implementation of UTS at the institutional level. In the conventional-care period, 9 of 30 cases (30%) received Lynch syndrome screening, and 4 cases were referred to medical genetics. During the 6 months following the implementation of UTS, 32 of 44 patients (73%) received Lynch syndrome screening. The 13 unscreened patients all had identified reasons for nonscreening (eg, financial limitations). Ten patients were referred to medical genetics, which identified no new cases of Lynch syndrome, but a low-risk adenomatous polyposis coli (APC) variant was detected in 1 individual. CONCLUSIONS: The implementation of effective Lynch syndrome UTS can feasibly alter practice at the institutional level. This experience with the assessment and management of issues relevant to the successful implementation of a new clinical care paradigm based on emerging technology has implications for the uptake of advances across molecular oncology into clinical practice, and this is highly relevant in the current era of rapidly evolving genomic technology.

Lymphangiomatous Lesions of the Gastrointestinal Tract: A Clinicopathologic Study and Comparison Between Adults and Children.

OBJECTIVES: Lymphangiomatous lesions involving the gastrointestinal (GI) tract remain incompletely characterized, and their clinical and histopathologic features have not been systematically evaluated. The distinction between a primary lymphatic malformation (lymphangioma) and a dilation of existing lymphatics (lymphangiectasia) is of clinical significance, since lymphangiectasia may occur in the setting of lymphatic obstruction due to an unsampled malignancy. We describe clinical and morphologic features of lymphangiomas of the GI tract in adult and pediatric populations and contrast them with lymphangiectasia. METHODS: We performed a retrospective review of adult and pediatric lymphangiomas and lymphangiectasia involving the GI tract. RESULTS: Thirty-six cases of lymphangioma and lymphangiectasia were retrieved, and clinical presentation and histologic features were compared. Lymphangiomas had distinct clinical presentations in adults and children, with adult lesions being more frequently asymptomatic and more frequently involving the superficial mucosal layers of the GI tract. Microscopically, lymphangiomas mostly consisted of confluent dilated spaces with a smooth muscle component. This appearance differed from lymphangiectasia, which lacked a complete distinct endothelial or smooth muscle lining and diffusely involved the mucosa and submucosa. CONCLUSIONS: Morphologic features of GI tract lymphangiomas can be reliably distinguished from lymphangiectasia by clinical and pathologic characteristics.

Genome-Wide Loss of Heterozygosity and DNA Copy Number Aberration in HPV-Negative Oral Squamous Cell Carcinoma and Their Associations with Disease-Specific Survival.

Oral squamous cell cancer of the oral cavity and oropharynx (OSCC) is associated with high case-fatality. For reasons that are largely unknown, patients with the same clinical and pathologic staging have heterogeneous response to treatment and different probability of recurrence and survival, with patients with Human Papillomavirus (HPV)-positive oropharyngeal tumors having the most favorable survival. To gain insight into the complexity of OSCC and to identify potential chromosomal changes that may be associated with OSCC mortality, we used Affymtrix 6.0 SNP arrays to examine paired DNA from peripheral blood and tumor cell populations isolated by laser capture microdissection to assess genome-wide loss of heterozygosity (LOH) and DNA copy number aberration (CNA) and their associations with risk factors, tumor characteristics, and oral cancer-specific mortality among 75 patients with HPV-negative OSCC. We found a highly heterogeneous and complex genomic landscape of HPV-negative tumors, and identified regions in 4q, 8p, 9p and 11q that seem to play an important role in oral cancer biology and survival from this disease. If confirmed, these findings could assist in designing personalized treatment or in the creation of models to predict survival in patients with HPV-negative OSCC.

"Indefinite for Dysplasia" in Barrett's Esophagus: Inflammation and DNA Content Abnormality are Significant Predictors of Early Detection of Neoplasia.

BACKGROUND: Dysplasia arising from Barrett's esophagus precedes esophageal adenocarcinoma (EAC). Cases that are difficult to diagnose as dysplastic, especially in the setting of inflammation, may be designated "indefinite for dysplasia (IND)." Although flow cytometric analysis of DNA content has shown some promise in detecting EAC, there are few reports that have specifically evaluated the outcome of IND. AIMS AND METHODS: We analyzed a series of 96 IND patients seen at the University of Washington between 2005 and 2013 to determine the outcome of IND and to identify factors (including histologic features and DNA flow cytometric data) associated with subsequent detection of neoplasia. RESULTS: Twenty-five percent of IND cases were found to have low-grade dysplasia, high-grade dysplasia (HGD), or EAC within 1 year, with 37% and 47% detected within 2 and 3 years, respectively. The 1-, 2-, and 3-year detection rates of HGD or EAC were 10%, 13%, and 20%, respectively. Active inflammation (hazard ratio (HR)=3.4, P=0.0005) and abnormal DNA content (HR=5.7, P=0.003) were significant risk factors of neoplasia. When active inflammation and DNA flow cytometric results were considered together, the HR for the combined markers was 18.8 (P<0.0001). The sensitivity and specificity of the combined markers for predicting detection of subsequent neoplasia within 3 years were 100% and 60%, respectively, with 100% negative and 89% positive predictive values. CONCLUSIONS: Histology with the support of DNA flow cytometry can identify a subset of IND patients who may have a higher risk for subsequent detection of neoplasia.

Blood lipids and colorectal polyps: testing an etiologic hypothesis using phenotypic measurements and Mendelian randomization.

PURPOSE: Studies linking cholesterol levels to the development of colorectal neoplasia are inconsistent, and Mendelian randomization has been suggested as a way to help avoid problems with confounding and reverse causation. METHODS: We genotyped individuals who received a colonoscopy at Group Health (1998-2007) for 96 of 102 single-nucleotide polymorphisms identified by the Global Lipids Genetics Consortium. Participants included 139 advanced adenoma cases, 518 non-advanced adenoma cases, 380 non-adenomatous polyp cases, and 754 polyp-free controls. All had at least one available pre-colonoscopy lipid measurement from electronic records maintained by Group Health. RESULTS: Advanced adenoma cases were more likely than controls to have higher pre-colonoscopy zenith low-density lipoprotein (LDL), triglycerides (TG), and total cholesterol (TC) (odds ratio, OR per 20 mg/dL LDL increase: 1.16, 95 % confidence interval, CI 1.03-1.30; per 40 mg/dL TG increase: 1.09, 1.03-1.16; and per 20 mg/dL TC increase: 1.09, 1.02-1.18). For these traits, genotype-polyp ORs using weighted allele scores were not statistically significant (OR per increase in score scaled to a 20 mg/dL LDL increase: 1.17, 0.78-1.75; a 40 mg/dL TG increase: 1.12, 0.91-1.38; a 20 mg/dL TC increase: 0.99, 0.71-1.38). CONCLUSIONS: Cholesterol levels may be associated with advanced adenomas, but larger studies are warranted to determine whether this association can be attributed to genetics.

Rare circulating microRNAs as biomarkers of colorectal neoplasia.

BACKGROUND: MicroRNAs (miRNAs) are regulatory RNAs, stable in circulation, and implicated in colorectal cancer (CRC) etiology and progression. Therefore they are promising as early detection biomarkers of colorectal neoplasia. However, many circulating miRNAs are highly expressed in blood cells, and therefore may not be specific to colorectal neoplasia. METHODS: We selected 7 miRNA candidates with previously reported elevated expression in adenoma tissue but low expression in blood cells ("rare" miRNAs), 2 previously proposed as adenoma biomarkers, and 3 implicated in CRC. We conducted a colonoscopy-based case-control study including 48 polyp-free controls, 43 advanced adenomas, 73 non-advanced adenomas, and 8 CRC cases. miRNAs from plasma were quantified by qRT-PCR. Correlations between miRNA expression levels, adjusted for age and sex, were assessed. We used polytomous logistic regression to estimate odds ratios (ORs) and 95% confidence intervals quantifying the association between expression levels of miRNAs and case groups. We also conducted nonparametric receiver operating characteristic (ROC) analyses and estimated area under the curve (AUC). RESULTS: miRNAs with high expression levels were statistically significantly correlated with one another. No miRNAs were significantly associated with non-advanced or advanced adenomas. Strong (ORs >5) and significant associations with CRC were observed for 6 miRNA candidates, with corresponding AUCs significantly >0.5. CONCLUSIONS: These candidate miRNAs, assayed by qRT-PCR, are probably unsuitable as blood-based adenoma biomarkers. Strong associations between miRNAs and CRC were observed, but primarily with miRNAs highly expressed in blood cells. These results suggest that rare miRNAs will require new detection methods to serve as circulating biomarkers of adenomas.

Translational research on Barrett's esophagus.

The following, from the 12th OESO World Conference: Cancers of the Esophagus, includes commentaries on translational research on Barrett's esophagus that address evidence for genetic instability in esophageal cancer; the role of microsatellite instability; the use of histologic and serum Doublecortin-like kinase 1 expression for progression of Barrett's esophagus to adenocarcinoma; the oxidative stress in Barrett's tumorigenesis; the genomic alterations in esophageal cancer; in vivo modeling in Barrett's esophagus; epigenetic and transcriptional regulation in Barrett's esophagus and esophageal adenocarcinoma; and normal and disordered regeneration in Barrett's esophagus.