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Objective Gastric cancer (GC) is a leading cause of cancer death, occurs predominantly in older age, with increasing incidence in young patients. The Cancer Genome Atlas indicates four subtypes for GC among which Epstein-Barr virus (EBV) subtype is estimated at 8.7%. We aim to determine the prevalence of EBV subtype in young GC patients (≤45 years) compared with an average-onset cohort (≥55 years) and characterize the clinicopathologic pattern of young-onset GC. Methods Gastric cancer samples of patients of both cohorts were screened for EBV by qPCR. Additional staining was done for Human epidermal growth factor receptor 2 (HER2), microsatellite instability (MSI) status and Programmed death-ligand 1 (PD-L1). Demographics and clinical data were retrieved from the medical records. Results Thirty-nine young-onset and 35 average-onset GC patients were reviewed. There was no apparent difference in tumor location, family history, histology and HER2 status between the cohorts. More young-onset patients were diagnosed with metastatic disease (27% vs 9%, p = 0.0498). EBV was significantly more prevalent in the young-onset cohort (33% vs 11%, p = 0.025). 15/17 EBV positive patients were under the median age of diagnosis for GC in the US (68 years). MSI-H was found only in the average-onset cohort [0% vs 27%, p = 0.001). PD-L1 positivity was higher in the young-onset cohort (31% vs 3%, p = 0.002). Conclusion Our study indicates that EBV subtype is more prevalent in young-onset GC and may play a key role in the pathogenesis. Higher rate of PD-L1 positivity in young-onset GC could change treatment strategies. We are currently evaluating these findings in a prospective trial.

Intestinal metaplasia (IM) is an intermediate step in the progression from premalignant to malignant stages of gastric cancer (GC). The Popeye domain containing (POPDC) gene family encodes three transmembrane proteins, POPDC1, POPDC2, and POPDC3, initially described in muscles and later in epithelial and other cells, where they function in cell–cell interaction, and cell migration. POPDC1 and POPDC3 downregulation was described in several tumors, including colon and gastric cancers. We questioned whether IM-to-GC transition involves POPDC gene dysregulation. Gastric endoscopic biopsies of normal, IM, and GC patients were examined for expression levels of POPDC1-3 and several suggested IM biomarkers, using immunohistochemistry and qPCR. Immunostaining indicated lower POPDC1 and POPDC3 labeling in IM compared with normal tissues. Significantly lower POPDC1 and POPDC3 mRNA levels were measured in IM and GC biopsies and in GC-derived cell lines. The reduction in focal IM was smaller than in extensive IM that resembled GC tissues. POPDC1 and POPDC3 transcript levels were highly correlated with each other and inversely correlated with LGR5, OLFM4, CDX2, and several mucin transcripts. The association of POPDC1 and POPDC3 downregulation with IM-to-GC transition implicates a role in tumor suppression and highlights them as potential biomarkers for GC progression and prospective treatment targets.

Intestinal metaplasia (IM) is an intermediate step in the progression from premalignant to malignant stages of gastric cancer (GC). The Popeye domain containing (POPDC) gene family encodes three transmembrane proteins, POPDC1, POPDC2, and POPDC3, initially described in muscles and later in epithelial and other cells, where they function in cell–cell interaction, and cell migration. POPDC1 and POPDC3 downregulation was described in several tumors, including colon and gastric cancers. We questioned whether IM-to-GC transition involves POPDC gene dysregulation. Gastric endoscopic biopsies of normal, IM, and GC patients were examined for expression levels of POPDC1-3 and several suggested IM biomarkers, using immunohistochemistry and qPCR. Immunostaining indicated lower POPDC1 and POPDC3 labeling in IM compared with normal tissues. Significantly lower POPDC1 and POPDC3 mRNA levels were measured in IM and GC biopsies and in GC-derived cell lines. The reduction in focal IM was smaller than in extensive IM that resembled GC tissues. POPDC1 and POPDC3 transcript levels were highly correlated with each other and inversely correlated with LGR5, OLFM4, CDX2, and several mucin transcripts. The association of POPDC1 and POPDC3 downregulation with IM-to-GC transition implicates a role in tumor suppression and highlights them as potential biomarkers for GC progression and prospective treatment targets.

Background Anatomic location of primary tumors across the colon correlate with survival in the metastatic setting, whereas left-sided tumors may exhibit superior survival compared with right-sided tumors. The Oncotype Recurrence Score (RS) assay is a clinically validated predictor of recurrence risk in patients with stage II colorectal cancer (CRC). Previous studies had indicated that without adjuvant chemotherapy, CDX2-negative stage II CRC tumors are associated with a lower rate of disease-free survival than CDX2-positive stage II CRC tumors. We aimed to evaluate whether these two validated prognostic biomarkers may correlate with primary tumor location, and whether tumor location may reflect differential prognosis in stage II CRC. Materials and Methods We retrospectively analyzed patients with T3 mismatch repair-proficient (MMR-P) stage II CRC for whom RS assay was performed. Pathological report was reviewed for exact primary tumor location and CDX2 immunostaining. RS and CDX2 expression were correlated with primary tumor location. Results The analysis included 1,147 patients with MMR-P stage II CRC (median age 69 years [range 29–93]). Tumor distribution across the colon was as follows: 46% (n = 551) were right-sided and 54% (n = 596) were left-sided. RS was higher in right-sided tumors (p = .01). The RS results gradually decreased across the colon (cecum, highest score; sigmoid, lowest score; p = .04). Right-sided tumors exhibited more CDX2-negative tumors (p = .07). Conclusion Our study indicates that right-sided colorectal tumors may display worse prognosis compared with left-sided tumors in MMR-P stage II CRC. Primary tumor location may serve as a prognostic factor that should be taken into account for recurrence risk assessment and consideration of adjuvant treatment.

Aims The distinction between benign and malignant thyroid nodules has important therapeutic implications. Our objective was to develop an assay that could classify indeterminate thyroid nodules as benign or suspicious, using routinely prepared fine needle aspirate (FNA) cytology smears. Methods A training set of 375 FNA smears was used to develop the microRNA-based assay, which was validated using a blinded, multicentre, retrospective cohort of 201 smears. Final diagnosis of the validation samples was determined based on corresponding surgical specimens, reviewed by the contributing institute pathologist and two independent pathologists. Validation samples were from adult patients (≥18 years) with nodule size >0.5 cm, and a final diagnosis confirmed by at least one of the two blinded, independent pathologists. The developed assay, RosettaGX Reveal, differentiates benign from malignant thyroid nodules, using quantitative RT-PCR. Results Test performance on the 189 samples that passed quality control: negative predictive value: 91% (95% CI 84% to 96%); sensitivity: 85% (CI 74% to 93%); specificity: 72% (CI 63% to 79%). Performance for cases in which all three reviewing pathologists were in agreement regarding the final diagnosis (n=150): negative predictive value: 99% (CI 94% to 100%); sensitivity: 98% (CI 87% to 100%); specificity: 78% (CI 69% to 85%). Conclusions A novel assay utilising microRNA expression in cytology smears was developed. The assay distinguishes benign from malignant thyroid nodules using a single FNA stained smear, and does not require fresh tissue or special collection and shipment conditions. This assay offers a valuable tool for the preoperative classification of thyroid samples with indeterminate cytology.

Background: The aim of this study was to characterize the signs of invasive lobular carcinoma of the breast on digital breast tomosynthesis (DBT) imaging. Patients and Methods: The study group included 23 women with pathologically proven invasive lobular carcinoma of the breast for whom both digital mammography (DM) and DBT images were available. The images were read jointly by 2 experienced breast radiologists. Findings were recorded according to the descriptors in the Breast Imaging and Reporting Data System lexicon and correlated with the detailed pathology results. Results: In 21 of the 23 patients, the combination of DM and DBT yielded pathologic findings (91%). Architectural distortions or spiculations were demonstrated in 87% of cases. The addition of DBT to DM improved lesion detection by more clearly depicting both the lesion margins and architectural distortions. Only 2 lesions were occult by both DM and DBT, including 1 lesion in a peripheral location that was not incorporated in the standard mediolateral oblique and craniocaudal views. Conclusion: DBT improves the detection of invasive lobular carcinoma lesions by more clearly depicting architectural distortions and spiculations.

Background & Aims The guidelines of the European Society of Pediatric Gastroenterology, Hepatology, and Nutrition allow for diagnosis of celiac disease without biopsies in children with symptoms and levels of immunoglobulin A against tissue-transglutaminase (TGA-IgA) 10-fold or more the upper limit of normal (ULN), confirmed by detection of endomysium antibodies (EMA) and positivity for HLA-DQ2/DQ8. We performed a large, international prospective study to validate this approach. Methods We collected data from consecutive pediatric patients (18 years or younger) on a gluten-containing diet who tested positive for TGA-IgA from November 2011 through May 2014, seen at 33 pediatric gastroenterology units in 21 countries. Local centers recorded symptoms; measurements of total IgA, TGA, and EMA; and histopathology findings from duodenal biopsies. Children were considered to have malabsorption if they had chronic diarrhea, weight loss (or insufficient gain), growth failure, or anemia. We directly compared central findings from 16 antibody tests (8 for TGA-IgA, 1 for TGA-IgG, 6 for IgG against deamidated gliadin peptides, and 1 for EMA, from 5 different manufacturers), 2 HLA-DQ2/DQ8 tests from 2 manufacturers, and histopathology findings from the reference pathologist. Final diagnoses were based on local and central results. If all local and central results were concordant for celiac disease, cases were classified as proven celiac disease. Patients with only a low level of TGA-IgA (threefold or less the ULN) but no other results indicating celiac disease were classified as no celiac disease. Central histo-morphometry analyses were performed on all other biopsies and cases were carefully reviewed in a blinded manner. Inconclusive cases were regarded as not having celiac disease for calculation of diagnostic accuracy. The primary aim was to determine whether the nonbiopsy approach identifies children with celiac disease with a positive predictive value (PPV) above 99% in clinical practice. Secondary aims included comparing performance of different serological tests and to determine whether the suggested criteria can be simplified. Results Of 803 children recruited for the study, 96 were excluded due to incomplete data, low level of IgA, or poor-quality biopsies. In the remaining 707 children (65.1% girls; median age, 6.2 years), 645 were diagnosed with celiac disease, 46 were found not to have celiac disease, and 16 had inconclusive results. Findings from local laboratories of TGA-IgA 10-fold or more the ULN, a positive result from the test for EMA, and any symptom identified children with celiac disease (n = 399) with a PPV of 99.75 (95% confidence interval [CI], 98.61–99.99); the PPV was 100.00 (95% CI, 98.68–100.00) when only malabsorption symptoms were used instead of any symptom (n = 278). Inclusion of HLA analyses did not increase accuracy. Findings from central laboratories differed greatly for patients with lower levels of antibodies, but when levels of TGA-IgA were 10-fold or more the ULN, PPVs ranged from 99.63 (95% CI, 98.67–99.96) to 100.00 (95% CI, 99.23–100.00). Conclusions Children can be accurately diagnosed with celiac disease without biopsy analysis. Diagnosis based on level of TGA-IgA 10-fold or more the ULN, a positive result from the EMA tests in a second blood sample, and the presence of at least 1 symptom could avoid risks and costs of endoscopy for more than half the children with celiac disease worldwide. HLA analysis is not required for accurate diagnosis. Clinical Trial Registration no: DRKS00003555.

Summary Background Increased numbers of duodenal intraepithelial lymphocytes (IELs) characterise coeliac disease (CD) but have also been described in noncoeliacs. Controversy exists regarding an association between increased IELs and infection with Helicobacter pylori, which is commonly found in children. Aim To assess the relationship between H. pylori infection and duodenal IELs in a large cohort of children, with and without CD. Methods We reviewed gastric and duodenal biopsies of children who underwent esophagogastroduodenoscopy between January 2006 and February 2013 because of either recurrent abdominal pain (RAP) or suspected CD at Schneider Children's Medical Center of Israel, a referral centre for Israel's largest Health Maintenance Organization. The duodenal IEL count and H. pylori presence in antral biopsies were determined for each specimen. Results Children with RAP (n = 693) or CD (n = 306) were included. Among children with RAP, H. pylori was present in 33.8%. The mean IEL count in the H. pylori positive RAP group was 17.8(±8.8)/100 enterocytes, vs. 15.8(±8.3) in the H. pylori negative patients (P = 0.004). Increased IEL counts (≥25 IELs/100 enterocytes) were found in 15.7% of H. pylori negative, noncoeliac children. Among children with CD, there was no significant difference in IEL counts according to H. pylori status: 73.1(±26.1) vs. 72.6 (±26.5) in H. pylori positive and negative patients respectively. Conclusions Our study suggests that slightly elevated duodenal intraepithelial lymphocyte counts are common in the paediatric population. Helicobacter pylori infection has no major influence on the intraepithelial lymphocyte counts in children with recurrent abdominal pain or children with coeliac disease.

The type of pathological response to neoadjuvant chemoradiation in patients with locally advanced esophageal cancer predicts overall survival (OS). We aimed to assess early 18F-FDG positron emission tomography/computed tomography parameters in predicting the pathological response to neoadjuvant treatment. The cohort included consecutive patients with locally advanced esophageal cancer who underwent baseline 18F-FDG positron emission tomography/computed tomography between September 2006 and February 2015. Positron emission tomography variables of maximum and average standardized uptake values (SUVmax, SUVaverage), metabolic tumor volume (MTV), and total lesion glycolysis were recorded in addition to computed tomography volume. MTV was calculated using cut-off values of 42%, 50% and 60% (MTV 0.42, 0.5, and 0.6) of the tumoral SUVmax. Receiver operating characteristic (ROC) analysis was used to determine sensitivity and specificity. Sixty-one patients (44 male, 17 female) fulfilled the inclusion criteria. Only MTV values of 13.6 mL (MTV 0.42) and 7.4 mL (MTV 0.5) remained significant on ROC analysis, with an area under the curve of 0.690 (confidence interval 0.557–0.823, p = .02] and 0.664 (confidence interval 0.527–0.802, P = .048), respectively in differentiating patients with a complete (n = 44) or incomplete (n = 17) pathological response. MTV at presentation is associated with the pathological response to neoadjuvant chemoradiation in patients with locally advanced esophageal cancer.

The definitive identification of malignant pleural mesothelioma (MPM) has significant clinical implications, yet other malignancies often involve the lung pleura, confounding the diagnosis of MPM. In the absence of accurate markers, MPM can be difficult to distinguish from peripheral lung adenocarcinoma and metastatic epithelial cancers. MicroRNA expression is tissue-specific and highly informative for identifying tumor origin. We identified microRNA biomarkers for the differential diagnosis of MPM and developed a standardized microRNA-based assay. Formalin-fixed, paraffin-embedded samples of 33 MPM and 210 carcinomas were used for assay development. Using microarrays, we identified microRNAs differentially expressed between MPM and various carcinomas. Hsa-miR-193–3p was overexpressed in MPM, while hsa-miR-200c and hsa-miR-192 were overexpressed in peripheral lung adenocarcinoma and carcinomas that frequently metastasize to lung pleura. We developed a standardized diagnostic assay based on the expression of these microRNAs. The assay reached a sensitivity of 100% and a specificity of 94% in a blinded validation set of 68 samples from the lung and pleura. This diagnostic assay can provide a useful tool in the differential diagnosis of MPM from other malignancies in the pleura.

To determine the expression of membrane-bound mucins and glycan side chain sialic acids in Helicobacter pylori (H. pylori)-associated, non-steroidal inflammatory drug (NSAID)-associated and idiopathic-gastric ulcers.We studied a cohort of randomly selected patients with H. pylori (group 1, n = 30), NSAID (group 2, n = 18), combined H. pylori and NSAID associated gastric ulcers (group 3, n = 24), and patients with idiopathic gastric ulcers (group 4, n = 20). Immunohistochemistry for MUC1, MUC4, MUC17, and staining for Erythrina cristagalli agglutinin and Sambucus nigra agglutinin (SNA) lectins was performed on sections from the ulcer margins.Staining intensity of MUC17 was higher in H. pylori ulcers (group 1) than in idiopathic ulcers (group 4), 11.05 ± 3.67 vs 6.93 ± 4.00 for foveola cells, and 10.29 ± 4.67 vs 8.00 ± 3.48 for gland cells, respectively (P0.0001). In contrast, MUC1 expression was higher in group 4 compared group 1, 9.89 ± 4.17 vs 2.93 ± 5.13 in foveola cells and 7.63 ± 4.60 vs 2.57± 4.50 for glands, respectively (P0.0001). SNA lectin staining was increased in group 4, in parallel to elevated MUC1 expression, indicating more abundant α2-6 sialylation in that group.Cytoplasmic MUC17 staining was significantly decreased in the cases with idiopathic ulcer. The opposite was observed for both MUC1 and SNA lectin. This observation may reflect important pathogenic mechanisms, since different mucins with altered sialylation patterns may differ in their protection efficiency against acid and pepsin.

There is emerging evidence for the prognostic role of various microRNA (miRNA) molecules in colon cancer. The aim of this study was therefore to compare the miRNA profiles in the primary tumor of patients with recurrent and non-recurrent colon cancer. The study population included 110 patients, 51 (46%) with stage I and 59 (54%) with stage II disease, who underwent curative colectomies between 1995 and 2005 without adjuvant therapy and for whom reliable miRNA expression data were available. RNA was extracted from formalin-fixed paraffin-embedded (FFPE) tumor samples. Initial profiling, using microarrays, was done in order to identify potential biomarkers of recurrence. The miRNA expression was later verified by quantitative real-time polymerase chain reaction (qRT-PCR). Findings were compared between patients who had a recurrence within 36 months of surgery (bad prognosis group, n=23, 21%) and those who did not (good prognosis group, n=87, 79%) in the entire group and within each stage. The results showed that in stage I, none of the 903 miRNAs tested showed differential expression between patients with good prognosis compared with those with poor prognosis. In contrast, in stage II, one miRNA, miR-29a, showed a clear differential expression between the groups (p=0.028). High expression of miR-29a was associated with a longer disease-free survival (DFS), on both univariate and multivariate analyses. Using miR-29a, the positive predictive value for non-recurrence was 94% (2 recurrences among 31 patients). The differential expression of miR-29a was verified by qRT-PCR, showing a similar impact of this miR on DFS. In conclusion, this study demonstrated a significant impact of miR-29a on the risk of recurrence in patients with stage II but not in patients with stage I colon cancer. Based on these results, a validation study is planned.

Colorectal cancer (CRC) is a common malignancy in both genders with a high death rate, accounting for about 56,000 each year in the USA only. In this study we examined the differences in CRC between the genders. We also looked for differences in the staining of the tumors and adjacent colonic mucosa to estrogen receptor β1 and its possible prognostic value. Fifty-five specimens from patients who underwent resection of colon cancer in our institute were sectioned and stained for estrogen receptor β1. The histopathological slides were evaluated for positive staining in the tumor and the normal colonic mucosa as well. The results were statistically analyzed. Positive estrogen receptor β1 stain was found in the nuclei of the tumor cells. We noted positive stain also in the cytoplasm of the tumor cells. Similar findings were observed in the normal colonic mucosa. Statistically significant differences were found regarding the positivity of the staining between the deceased and surviving patients, men/women and those who had metastases vs. the non-metastatic ones. Our data suggest that there is an estrogen influence on the development and progression of colon cancer. Furthermore, it was found to be higher in the more severe cases.

UC (ulcerative colitis) patients have an increased risk of developing colorectal cancer compared with the normal population. The cause underlying this higher risk is not fully defined but includes nutritional and environmental factors concomitant with genetic alterations. We aimed to evaluate genetic stability in the colonic tissue of UC patients in clinical remission compared with the healthy population, and to establish a possible correlation between nutritional habits and these molecular assessments. UC patients (n 42) and healthy controls (n 37) participated in the study. All participants were histopathologically and medically diagnosed. Participants completed five separate 7d dietary records, food-frequency questionnaires and validated 24h recalls for nutritional assessment. The extent of chromosome 17 loss and the calculated chromosome index was determined in colon tissue biopsies by fluorescence in situ hybridisation. Correlations between the molecular and nutritional assessments were performed using Pearson's correlation coefficients. Significant differences in the nutritional intake of total fat (65 (SD 15) v. 89 (SD 25) g), cholesterol (330 (SD 168) v. 464 (SD 177) mg), dietary fibre (32 (SD 4·7) v. 9 (SD 4) g), vitamin A (1009 (SD 209) v. 506 (SD 204) μg), vitamin C (308 (SD 108) v. 72 (SD 53) mg) and folic acid (412 (SD 89 μg) v. 187 (SD 107)) were recorded for UC patients compared with controls. Significant correlations were found for the consumption of different food groups and the chromosome index for chromosome 17. The results of our study suggest that the nutritional habits adopted by UC patients during clinical remission may affect key cellular components of the colonic tissue, inducing a high degree of aneuploidy and genetic instability, and probably affecting the development of colon cancer.

Aims—To examine the expression of HLA-DR and s2 microglobulin in medullary carcinoma and atypical medullary carcinoma of the breast to determine if the effective presentation of tumour antigens to the immune system can differentiate between these two histopathologically similar entities. Methods—Expression of HLA-DR and s2 microglobulin was examined by immunohistochemical methods in five samples of medullary carcinoma of the breast, which has a relatively favourable prognosis, six samples of atypical medullary carcinoma of the breast, which has a prognosis closer to that of regular invasive duct carcinoma, and 20 samples of invasive duct carcinomas, 10 with an accompanying lymphocytic infiltrate. Results—A positive and significant correlation was found between tumour type and both HLA-DR and s2 microglobulin expression. Expression was most prominent in medullary carcinoma, followed by atypical medullary carcinoma and invasive duct carcinoma with and without lymphocytic infiltrates. The mean intensity and percentage of HLA-DR tumour immunostaining were significantly higher in medullary carcinoma than in the other three tumour groups, as was the mean intensity of s2 microglobulin immunostaining. Mean percentage of s2 microglobulin immunostaining was significantly higher in medullary carcinoma than in invasive duct carcinoma without lymphocytic infiltrates, and showed a trend to increase from invasive duct carcinoma with lymphocytic infiltrates to atypical medullary carcinoma and medullary carcinoma. Conclusions—Medullary carcinoma and atypical medullary carcinoma of the breast differ in their expression of HLA-DR and s2 microglobulin. The relatively favourable prognosis of medullary carcinoma of the breast may be related to effective tumour antigen presentation to the immune system through MHC-I and MHC-II expression. Immunotherapy aimed at MHC-I and MHC-II induction might have a beneficial effect in breast cancer. Key Words: medullary carcinoma of the breast • HLA-DR expression • s2 microglobulin expression

Objective To create monoclonal anti–endothelial cell antibodies (mAECA) from a patient with Takayasu arteritis to evaluate their ability to activate human umbilical vein endothelial cells (HUVEC), and to characterize the mechanism of EC activation. Methods A panel of mAECA was generated from peripheral blood lymphocytes of a patient with Takayasu arteritis, using Epstein-Barr virus transformation. Activity against macrovascular EC (HUVEC) and microvascular EC (human bone marrow EC immortalized by SV40) antigens was detected by enzyme-linked immunosorbent assay. Inhibition studies were used to select the monoclonal antibodies (mAECA) which share the same EC epitope binding specificity as the total IgG-AECA from the Takayasu arteritis patient. The binding of the mAECA to human aortic EC was studied by immunohistochemistry. The secretion levels of interleukin-6 (IL-6) and von Willebrand factor (vWF) were determined, to serve as markers for EC activation. The activated EC were examined for the adherence of a monocytic cell line (U937), as well as for expression of vascular cell adhesion molecule 1, intercellular adhesion molecule 1, and E-selectin. In addition, nuclear extracts of the mAECA-treated EC were analyzed for the induction of translocation of nuclear factor κB (NF-κB), using a specific NF-κB oligoprobe in an electrophoretic mobility shift assay. Results Six mAECA were selected, the mixture of which produced 100% inhibition of binding of the original IgG (from the patient with Takayasu arteritis) to HUVEC. All mAECA possessed high activity against macrovascular EC, but none had significant anti–microvascular EC activity. The mAECA, but not normal human IgG, had anti–human aortic EC activity. Four of the 6 mAECA activated EC, manifested by increased IL-6 and vWF secretion. The 4 mAECA induced EC expression of adhesion molecules and increased adhesion of U937 monocytic cells to EC. In addition, these mAECA stimulated the nuclear translocation of the NF-κB transcription factor. Conclusion Our findings suggest that AECA may directly stimulate EC in Takayasu arteritis through elevation of adhesion molecule expression associated with NF-κB activation and adhesion of monocytes, and may therefore play a pathogenic role in the development of the vasculopathy in Takayasu arteritis.

Background Preoperative radiochemotherapy (RCT) is standard in locally advanced rectal cancer (LARC). Initial data suggest that the tumor’s metabolic response, i.e. reduction of its 18 F-FDG uptake compared with the baseline, observed after two weeks of RCT, may correlate with histopathological response. This prospective study evaluated the ability of a very early metabolic response, seen after only one week of RCT, to predict the histopathological response to treatment. Methods Twenty patients with LARC who received standard RCT regimen followed by radical surgery participated in this study. Maximum standardized uptake value (SUV-MAX), measured by PET-CT imaging at baseline and on day 8 of RCT, and the changes in FDG uptake (ΔSUV-MAX), were compared with the histopathological response at surgery. Response was classified by tumor regression grade (TRG) and by achievement of pathological complete response (pCR). Results Absolute SUV-MAX values at both time points did not correlate with histopathological response. However, patients with pCR had a larger drop in SUV-MAX after one week of RCT (median: -35.31% vs −18.42%, p = 0.046). In contrast, TRG did not correlate with ΔSUV-MAX. The changes in FGD-uptake predicted accurately the achievement of pCR: only patients with a decrease of more than 32% in SUV-MAX had pCR while none of those whose tumors did not show any decrease in SUV-MAX had pCR. Conclusions A decrease in ΔSUV-MAX after only one week of RCT for LARC may be able to predict the achievement of pCR in the post-RCT surgical specimen. Validation in a larger independent cohort is planned.

sion in the esophagus at three critical stages, specification, metaplasia and maturation. The esophagi were isolated from wild-type, Nrf2-/-, Keap1-/-, or Nrf2-/-;Keap1-/embryos or young adults. Array data were statistically analyzed for differentially expressed genes and pathways. Histochemical and immunohistochemical staining were used to verify potential involvement of the Wnt pathway, PPARβ/δ and the PI3K/Akt pathway in the development of esophageal epithelium. Results Dynamic gene expression pattern accompanied the morphological changes of the developing esophagus at the critical stages. Particularly, the Nrf2/ Keap1 pathway had a baseline activity in the metaplasia phase and was further activated in the maturation phase. The Wnt pathway was active early and became inactive later in the metaplasia stage. In addition, global transcript profiling of the esophagus isolated from Keap1-/mice showed increased expression of Nrf2 downstream targets and genes involved in keratinization. Microarray data also suggested that esophageal hyperkeratosis in the Keap1-/mice was due to activation of PPARβ/δ and the PI3K/Akt pathway. Conclusions Morphological changes of the esophageal epithelium are associated with dynamic changes in gene expression. The activity of Nrf2/Keap1 pathway is required for the maturation of the esophagus.

To determine the pattern of secreted mucin expression in Helicobacter pylori (H. pylori)-related, nonsteroidal anti-inflammatory drug (NSAID)-related and idiopathic gastric ulcers.We randomly selected 92 patients with H. pylori-associated (n = 30), NSAID-associated (n = 18), combined H. pylori and NSAID-associated gastric ulcers (n = 24), and patients with idiopathic gastric ulcers (n = 20). Immunohistochemistry for T-cell CD4/CD8, and for mucin 5AC (MUC5AC) and mucin 6 (MUC6), was performed on sections of the mucosa from the ulcer margin. Inflammation score was assessed according to the Sydney system.MUC5AC was expressed on the surface epithelium (98.9%) and neck glands (98.9%) with minimal expression in the deep glands (6.5%). MUC6 was strongly expressed in the deep glands (97.8%), variable in the neck glands (19.6%) and absent in the surface epithelium (0%). The pattern of mucin expression in idiopathic ulcer margins was not different from the expression in ulcers associated with H. pylori, NSAIDs, or combined H. pylori and NSAIDs. CD4/CD8 ratio was higher in H. pylori-positive patients (P = 0.009). Idiopathic ulcers are associated with hospitalized patients and have higher bleeding and mortality rates.Idiopathic ulcers have a unique clinical profile. Gastric mucin expression in idiopathic gastric ulcers is unchanged compared with H. pylori and/or NSAID-associated ulcers.

OBJECTIVES: Cowden syndrome (CS), associated with germline PTEN mutations, is an autosomal-dominant disorder with increased frequencies of thyroid and breast cancers. Recent reports document the occurrence of gastrointestinal (GI) polyps and increased risk of colon cancer in PTEN mutation carriers. Studies to date, however, have not been based on mutation carriers undergoing active, systematic, routine-interval GI surveillance. Our objective is to document the upper and lower GI findings in CS patients undergoing such an active GI surveillance program. METHODS: In a 5-year period, 3,000 consecutive patients were referred to our high-risk GI cancer clinic for various reasons. Of these 3,000, 10 met full-blown clinical criteria for the diagnosis of CS. Individuals with identified PTEN mutations underwent annual upper and lower endoscopy surveillance programs using dual white light and narrow-band imaging. All biopsies including archived materials were reviewed by a single dedicated GI pathologist. RESULTS: Ten PTEN mutation carriers from different ethnic backgrounds were invited and all participated in the active GI surveillance program. Eight patients had colonic polyps, mostly hyperplastic (eight patients) and hamartomatous (five patients), but also adenomatous (three patients), ganglioneuromatous (three patients), and juvenile polyps (two patients). One patient (10%) had an early-onset rectal cancer (aged 44 years), which was null for PTEN expression on immunohistochemistry. All patients had gastric polyps and nine (90%) had duodenal polyps, mostly hyperplastic and hamartomatous. Additional three patients (30%) had adenomatous duodenal polyps. CONCLUSIONS: PTEN mutation–positive CS patients have a higher frequency of upper GI polyps than previously believed. They appear prone to develop adenomatous upper and lower tract dysplastic polyps and cancer. Thus, the polyps encountered during upper or lower endoscopy in these patients should not be automatically considered innocent hamartomas without malignant potential. Active surveillance programs in specialized centers should be considered in these patients.

AIM: To compare the microRNA (miR) profiles in the primary tumor of patients with recurrent and non-recurrent gastric cancer. METHODS: The study group included 45 patients who underwent curative gastrectomies from 1995 to 2005 without adjuvant or neoadjuvant therapy and for whom adequate tumor content was available. Total RNA was extracted from formalin-fixed paraffin-embedded tumor samples, preserving the small RNA fraction. Initial profiling using miR microarrays was performed to identify potential biomarkers of recurrence after resection. The expression of the differential miRs was later verified by quantitative real-time polymerase chain reaction (qRT-PCR). Findings were compared between patients who had a recurrence within 36 mo of surgery (bad-prognosis group, n = 14, 31%) and those who did not (good-prognosis group, n = 31, 69%). RESULTS: Three miRs, miR-451, miR-199a-3p and miR-195 were found to be differentially expressed in tumors from patients with good prognosis vs patients with bad prognosis (P < 0.0002, 0.0027 and 0.0046 respectively). High expression of each miR was associated with poorer prognosis for both recurrence and survival. Using miR-451, the positive predictive value for non-recurrence was 100% (13/13). The expression of the differential miRs was verified by qRT-PCR, showing high correlation to the microarray data and similar separation into prognosis groups. CONCLUSION: This study identified three miRs, miR-451, miR-199a-3p and miR-195 to be predictive of recurrence of gastric cancer. Of these, miR-451 had the strongest prognostic impact.

Background: Our ability to determine the prognosis of an individual patient with gastric cancer and thereby to select patients for adjuvant therapy is still limited. Preliminary data suggest that microRNAs may have a prognostic role in this disease. We hence decided to compare the microRNA profiles in the primary tumor of patients with recurrent and non-recurrent gastric cancer and to evaluate the prognostic impact of these molecules. Patients and Methods: Eligible patients, who underwent curative gastrectomies between 1995 and 2005 and did not receive any pre- or postoperative adjuvant therapy, were identified from the database of the participating institutions. Total RNA was extracted from tumor formalin-fixed paraffin embedded (FFPE) samples using proprietary protocols that preserve the small RNA fraction. Initial profiling using microRNA microarrays identified potential microRNA biomarkers that can be used to predict recurrence of gastric cancer after resection. The expression of differential microRNAs, was verified by qRT-PCR. Results: Forty-five eligible patients had adequate tumor content and microRNA expression data and were included in the analysis. Of these, 14 (31%) experienced recurrence of disease within three years from surgery (“bad prognosis” group) and 31 (69%) did not (“good prognosis” group). Advanced pathological stage and extensive surgical procedure correlated with bad prognosis. Signal levels of three microRNAs were found to be significantly differentially expressed in tumors from patients with good prognosis vs. patients with bad prognosis. High expression of each of these microRNAs was associated with significantly poorer prognosis for both recurrence and survival. Proprietary microRNA qRT-PCR showed a high correlation to microarrays and similar separation into prognosis groups based on microRNA expression. Conclusion: We identified a set of microRNAs whose high expression was predictive of tumor recurrence and poor prognosis in patients with gastric cancer. This finding provides a basis for a novel tool for risk stratification in this disease and allows further insight into its pathogenesis. Based on these results, a validation study, on a larger and independent cohort of patients, is planned. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3017.

A principios de los años 60, las disciplinas relacionadas con la educación cobraron una importancia hasta entonces desconocida. Además de adquirir un status de respetabilidad académica, se les reconoció importancia en el campo de la planificación económica-social. Los nuevos aires provenían de una nueva ideología, encarnada en la Alianza para el Progreso patrocinada por la Administración Kennedy, cuyo punto de partida era la convicción de que el atraso y la miseria eran superables dentro del marco capitalista. En tanto las reformas debían plantearse de forma planificada y gradual, la educación se presentaba como un instrumento clave en el diseño y puesta en práctica del proyecto. El clima internacional, expresado en la "coexistencia pacífica" ofrecía un marco adecuado para imaginar un mundo donde la beligerancia estaba controlada y las sociedades nacionales se pensaban como comunidades homogéneas. La planificación permitía en este contexto prevenir los conflictos potenciales y también asegurar en un futuro el bienestar individual y social. Como es lógico, la ciencia social prevalente en estos años no parecía preocupada demasiado por las tensiones sociales; en última instancia el análisis de la conflictividad sólo distorsionaría la óptica de asepsia y objetividad que se requiere para los expertos en planificación. No es de extrañar entonces que la comunidad científica, al menos en los países centrales compartiera extensamente el paradigma neo-positivista. En este mundo encantado, la Sociología y la Economía de la Educación invadieron la escena académica como disciplinas serias, que sustituían con un ethos modernizante a las especulaciones de los filósofos y pedagogos de viejo cuño. En España este ethos llegó tardíamente, casi con una década de retraso de la mano del Opus Dei y en una peculiar combinación de espiritualismo y materialismo tecnocrático que poco tenía que ver con las críticas que el proyecto desarrollista suscitaba ya para entonces. La nueva ideología presentaba a la educación de forma omnipotente. Para decirlo de forma gráfica y apelando a la metáfora psicoanalítica, imperaba entre los teóricos de la educación una imagen narcisista de su propia práctica, por otra parte, desentendida de los contextos históricos reales donde se aplicaba. La eficacia de la educación estaba garantizada de antemano, eficacia tanto para socializar en la perpetuación del orden social, como para seleccionar a los más aptos para desempeñar los distintos roles que la sociedad adjudicaba en virtud de las necesi dades del desarrollo económico. Así, el funcionalismo sociológico se unía a la Economía Marginalista de la educación en un matrimonio muy bien avenido, comple mentario en la división de tareas: mientras el primero informaba teóricamente de las bondades y posibilidades de la educación, la segunda se ocupaba de las cuestiones prácticas que llevarían a la planificación de los recursos humanos.