Clinical Pathological Analysis of Surgically Resected Superficial Esophageal Carcinoma to Determine Criteria for Deciding on Treatment Strategy

We performed a clinical pathological study of conventionally resected superficial esophageal carcinomas since this type of lesion has been increasing, in order to develop criteria of determination for therapeutic strategies. Pathological studies were performed on specimens obtained by radical surgical resection in 133 cases of superficial esophageal cancer. Evaluation was performed in terms of the gross classification of the lesion type, depth of invasion, lymph node metastasis, vascular invasion, size of the lesion, outcome, etc. In 0-I, 0-IIc+0-IIa, and 0-III type submucosal cancer lesions the rate of metastasis to lymph nodes was more than 40%, but in 0-IIa and 0-IIb mucosal cancer cases no lymph node metastasis was observed. 0-IIc type lesions showed a wide range of invasiveness, ranging from m1 to sm3. In cases with m1 or m2 invasion, no lymph node or lymph-vessel invasion was recognized, but in m3, sm1, sm2, and sm3 cases lymph node metastasis was recognized in 12.5%, 22.2%, 44.0% and 47.4%, respectively. In 47% of lesions with a greatest dimension of less than 30 mm invasion was limited to the mucosa. Seventy-two percent of m1 and m2 cases were 30 mm in size or less. Lymph node metastasis was recognized in only 16.7% of cases less than 30 mm in size, but in cases of lesions 30 mm or more the rate of lymph node metastasis was 35.8%. 0-IIb and 0-IIa type lesions are indications for endoscopic esophageal mucosal resection (EEMR), while 0-I, 0-IIc+0-IIa, and 0-III lesions should be candidates for radical surgical resection. In the 0-IIc category, lesions in which the depression is relatively flat and with a finely granular surface are indications for EEMR, but those cases in which the surface of depression shows granules of varying sizes should be treated with radical surgical resection. Cases of 0-IIa type 30 mm or larger in greatest dimension which have a gently sloping protruding margin shoulder or reddening should be treated with caution, but EEMR can be performed first and subsequent therapeutic strategy decided on, based on the pathological findings of the specimen

Autoimmune enteropathy with a CD8+ CD7- T-cell small bowel intraepithelial lymphocytosis: case report and literature review

<p>Abstract</p> <p>Background</p> <p>Adult onset autoimmune enteropathy (AIE) is a rare condition characterized by diarrhea refractory to dietary therapy diagnosed in patients with evidence of autoimmune conditions. Auto-antibodies to gut epithelial cells and other tissues are commonly demonstrated. Despite increasing awareness, the pathogenesis, histologic, immunologic and clinical features of AIE remain uncertain. There remains controversy regarding the diagnostic criteria, the frequency and types of auto-antibodies and associated autoimmune conditions, and the extent and types of histologic and immunologic abnormalities. CD4+ T-cells are thought to at least responsible for this condition; whether other cell types, including B- and other T-cell subsets are involved, are uncertain. We present a unique case of AIE associated with a CD8+CD7- lymphocytosis and review the literature to characterize the histologic and immunologic abnormalities, and the autoantibodies and autoimmune conditions associated with AIE.</p> <p>Case Presentation</p> <p>We present a case of immune mediated enteropathy distinguished by the CD8+CD7- intra-epithelial and lamina propria lymphocytosis. Twenty-nine cases of AIE have been reported. The majority of patients had auto-antibodies (typically anti-enterocyte), preferential small bowel involvement, and predominately CD3+ CD4+ infiltrates. Common therapies included steroids or immuno-suppressive agents and clinical response with associated with histologic improvement.</p> <p>Conclusions</p> <p>AIE is most often characterized (1) IgG subclass anti-epithelial cell antibodies, (2) preferential small bowel involvement, and (3) CD3+ alphabeta TCR+ infiltrates; there is insufficient evidence to conclude CD4+ T-cells are solely responsible in all cases of AIE.</p

Expression of p21WAF1 in Astler–Coller stage B2 colorectal cancer is associated with survival benefit from 5FU-based adjuvant chemotherapy

In several, but not all, previous studies, positive p21WAF1 expression has been suggested as an indicator of a good prognosis in patients with stage III/IV colorectal cancer. However, it is not known whether the same is true for stage B2 patients. The purpose of this study is to assess the influence of p21WAF1 expression in tumor cells on disease-free survival (DFS) and overall survival (OS) of Astler–Coller stage B2 and C patients with colorectal cancer who underwent 5-fluorouracil-based adjuvant chemotherapy. Nuclear p21WAF1 was detected by immunohistochemistry in tissue microarrays from 275 colorectal cancers. The expression of p21WAF1 was associated with DFS (p = 0.025) and OS (p = 0.008) in the subgroup of stage B2 patients that was treated with adjuvant chemotherapy. In multivariate analysis, it remained the only independent prognostic parameter in relation to DFS and OS (p = 0.035 and p = 0.02, respectively). In the subgroup of 72 stage B2 patients with positive p21WAF1 expression but not in the subgroup of 61 stage B2 patients with negative p21WAF1 expression, adjuvant chemotherapy was associated with better DFS (85% 5-year survival versus 65% without chemotherapy, p = 0.03) and OS (96% versus 82%, p = 0.014). In the combined stage B2 and C group of patients treated with adjuvant chemotherapy, positive p21WAF1 expression was also associated with better DFS and OS (p = 0.03, p = 0.002, respectively). Expression of p21WAF1 in colorectal tumor cells identifies a subgroup of Astler–Coller stage B2 patients who could benefit significantly from 5FU-based chemotherapy and may improve the selection of patients for adjuvant chemotherapy

Cyclooxygenase-2 overexpression is common in serrated and non-serrated colorectal adenoma, but uncommon in hyperplastic polyp and sessile serrated polyp/adenoma

<p>Abstract</p> <p>Background</p> <p>Cyclooxygenase-2 (COX-2, <it>PTGS2</it>) plays an important role in colorectal carcinogenesis. COX-2 overexpression in colorectal cancer is inversely associated with microsatellite instability (MSI) and the CpG island methylator phenotype (CIMP). Evidence suggests that MSI/CIMP+ colorectal cancer may arise through the serrated tumorigenic pathway through various forms of serrated neoplasias. Therefore, we hypothesized that COX-2 may play a less important role in the serrated pathway.</p> <p>Methods</p> <p>By immunohistochemistry, we assessed COX-2 expression in 24 hyperplastic polyps, 7 sessile serrated polyp/adenomas (SSA), 5 mixed polyps with SSA and adenoma, 27 traditional serrated adenomas, 515 non-serrated adenomas (tubular adenoma, tubulovillous adenoma and villous adenoma), 33 adenomas with intramucosal carcinomas, 96 adenocarcinomas with serration (corkscrew gland) and 111 adenocarcinomas without serration.</p> <p>Results</p> <p>Strong (2+) COX-2 overexpression was more common in non-serrated adenomas (28% = 143/515) than in hyperplastic polyps (4.2% = 1/24, p = 0.008) and serrated polyps (7 SSAs and 5 mixed polyps) (0% = 0/12, p = 0.04). Furthermore, any (1+/2+) COX-2 overexpression was more frequent in non-serrated adenomas (60% = 307/515) than in hyperplastic polyps (13% = 3/24, p < 0.0001) and serrated polyps (SSAs and mixed polyps) (25% = 3/12, p = 0.03). Traditional serrated adenomas and non-serrated adenomas showed similar frequencies of COX-2 overexpression. Regardless of serration, COX-2 overexpression was frequent (~85%) in colorectal adenocarcinomas. Tumor location was not significantly correlated with COX-2 overexpression, although there was a trend towards higher frequencies of COX-2 overexpression in distal tumors (than proximal tumors) among hyperplastic polyps, SSAs, mixed polyps, traditional serrated adenomas and adenocarcinomas.</p> <p>Conclusion</p> <p>COX-2 overexpression is infrequent in hyperplastic polyp, SSA and mixed polyp with SSA and adenoma, compared to non-serrated and serrated adenoma. COX-2 overexpression becomes more frequent as tumors progress to higher grade neoplasias. Our observations suggest that COX-2 may play a less significant role in the serrated pathway of tumorigenesis; however, COX-2 may still play a role in later stage of the serrated pathway.</p

Targeted Deletion of Kcne2 Causes Gastritis Cystica Profunda and Gastric Neoplasia

Gastric cancer is the second leading cause of cancer death worldwide. Predisposing factors include achlorhydria, Helicobacter pylori infection, oxyntic atrophy and TFF2-expressing metaplasia. In parietal cells, apical potassium channels comprising the KCNQ1 α subunit and the KCNE2 β subunit provide a K+ efflux current to facilitate gastric acid secretion by the apical H+K+ATPase. Accordingly, genetic deletion of murine Kcnq1 or Kcne2 impairs gastric acid secretion. Other evidence has suggested a role for KCNE2 in human gastric cancer cell proliferation, independent of its role in gastric acidification. Here, we demonstrate that 1-year-old Kcne2−/− mice in a pathogen-free environment all exhibit a severe gastric preneoplastic phenotype comprising gastritis cystica profunda, 6-fold increased stomach mass, increased Ki67 and nuclear Cyclin D1 expression, and TFF2- and cytokeratin 7-expressing metaplasia. Some Kcne2−/−mice also exhibited pyloric polypoid adenomas extending into the duodenum, and neoplastic invasion of thin walled vessels in the sub-mucosa. Finally, analysis of human gastric cancer tissue indicated reduced parietal cell KCNE2 expression. Together with previous findings, the results suggest KCNE2 disruption as a possible risk factor for gastric neoplasia

Prognostic DNA methylation markers for sporadic colorectal cancer: a systematic review

Background Biomarkers that can predict the prognosis of colorectal cancer (CRC) patients and that can stratify high-risk early stage patients from low-risk early stage patients are urgently needed for better management of CRC. During the last decades, a large variety of prognostic DNA methylation markers has been published in the literature. However, to date, none of these markers are used in clinical practice. Methods To obtain an overview of the number of published prognostic methylation markers for CRC, the number of markers that was validated independently, and the current level of evidence (LoE), we conducted a systematic review of PubMed, EMBASE, and MEDLINE. In addition, we scored studies based on the REMARK guidelines that were established in order to attain more transparency and complete reporting of prognostic biomarker studies. Eighty-three studies reporting on 123 methylation markers fulfilled the study entry criteria and were scored according to REMARK. Results Sixty-three studies investigated single methylation markers, whereas 20 studies reported combinations of methylation markers. We observed substantial variation regarding the reporting of sample sizes and patient characteristics, statistical analyses, and methodology. The median (range) REMARK score for the studies was 10.7 points (4.5 to 17.5) out of a maximum of 20 possible points. The median REMARK score was lower in studies, which reported a p value below 0.05 versus those, which did not (p = 0.005). A borderline statistically significant association was observed between the reported p value of the survival analysis and the size of the study population (p = 0.051). Only 23 out of 123 markers (17%) were investigated in two or more study series. For 12 markers, and two multimarker panels, consistent results were reported in two or more study series. For four markers, the current LoE is level II, for all other markers, the LoE is lower. Conclusion This systematic review reflects that adequate reporting according to REMARK and validation of prognostic methylation markers is absent in the majority of CRC methylation marker studies. However, this systematic review provides a comprehensive overview of published prognostic methylation markers for CRC and highlights the most promising markers that have been published in the last two decades