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A letter to the editor is presented, in response to the article, "The Significance of 'Indefinite for Dysplasia' Grading in Barrett Metaplasia" by Mamoun Younes and colleagues, in the April 2011 issue; a response to the letter is also presented.

We report the use of neodymium:yttrium-aluminum-garnet (Nd:YAG) laser ablation to treat high-grade dysplasia and intramucosal esophageal adenocarcinoma associated with Barrett's esophagus in a patient who refused surgery. Throughout laser therapy, the patient received omeprazole 40 mg/day. After 1 1/2 yr, five laser treatments totaling 22,055 J given over a period of 13 months achieved squamous reepithelialization and absence of malignant transformation in the first area in which carcinoma was diagnosed. Squamous reepithelialization was maintained 1 yr later, confirming recent reports that photoablation plus omeprazole can achieve regression of Barrett's esophagus. During the last year of follow-up, a second contiguous area discovered to contain carcinoma was treated three times by photoablation, with a total of 13,164 J; biopsy showed only low-grade dysplasia in this area after two laser treatments totaling 8,108 J. No complications were seen during or after any of the laser sessions, and the patient remained asymptomatic 2 1/2 yr after the first photoablation and 3 yr after presentation. [ABSTRACT FROM AUTHOR]

An introduction is presented in which the authors discuss various reports within the issue on topics including the histologic concepts of esophagitis, the assessment of serrated polyps and the neuroendocrine tumors of the luminal gastrointestinal tract.

The article reports on the special section consists of articles derived from the talks at the 2007 HSCP Spring Symposium devoted to an Update in Gastrointestinal Pathology. It discusses that the purpose of this special section on "Molecular Signatures of Lung and Pleural Tumors," is to depict new methodologic growths in molecular pathology to the general pathologist as well as to the specialist.

This article discusses a rare case of bleeding gastric polyps as a presentation of metastasis from renal cell carcinoma (RCC). The patient, a 76-year-old man with a history of RCC metastases, presented with melena and abdominal pain. Esophagogastroduodenoscopy revealed multiple gastric polyps that were friable and oozed with simple water irrigation. Pathology confirmed metastatic RCC. This case highlights the importance of considering gastric metastases as a possible diagnosis in patients with known RCC or other malignancies presenting with upper gastrointestinal bleeding. [Extracted from the article]

Hepatocellular carcinoma (HCC) is a leading cause of cancer deaths, and the most common primary liver malignancy to present in the clinic. With the exception of liver transplant, treatment options for advanced HCC are limited, but improved tumor stratification could open the door to new treatment options. Previously, we demonstrated that the circadian regulator Aryl Hydrocarbon‐Like Receptor Like 1 (ARNTL, or Bmal1) and the liver‐enriched nuclear factor 4 alpha (HNF4α) are robustly co‐expressed in healthy liver but incompatible in the context of HCC. Faulty circadian expression of HNF4α– either by isoform switching, or loss of expression‐ results in an increased risk for HCC, while BMAL1 gain‐of‐function in HNF4α‐positive HCC results in apoptosis and tumor regression. We hypothesize that the transcriptional programs of HNF4α and BMAL1 are antagonistic in liver disease and HCC. Here, we study this antagonism by generating a mouse model with inducible loss of hepatic HNF4α and BMAL1 expression. The results reveal that simultaneous loss of HNF4α and BMAL1 is protective against fatty liver and HCC in carcinogen‐induced liver injury and in the "STAM" model of liver disease. Furthermore, our results suggest that targeting Bmal1 expression in the absence of HNF4α inhibits HCC growth and progression. Specifically, pharmacological suppression of Bmal1 in HNF4α‐deficient, BMAL1‐positive HCC with REV‐ERB agonist SR9009 impairs tumor cell proliferation and migration in a REV‐ERB‐dependent manner, while having no effect on healthy hepatocytes. Collectively, our results suggest that stratification of HCC based on HNF4α and BMAL1 expression may provide a new perspective on HCC properties and potential targeted therapeutics. [ABSTRACT FROM AUTHOR]

Background: Increased esophageal cyclooxygenase-2 (COX-2) expression has been associated with Barrett's esophagus (BE); however, it is unknown whether COX-2 expression varies among patient groups with different clinical or socio-demographic factors. Methods: We conducted a case-control study among eligible patients scheduled for elective esophagogastroduodenoscopy and patients eligible for screening colonoscopy recruited from primary clinics. We compared 39 BE tissue samples and 47 squamous tissue samples from BE cases and 240 squamous tissue samples from controls. Clinical and socio-demographic data were prospectively collected. Immunohistochemical staining for esophageal COX-2 was performed and scored. Results: The median COX-2 score was significantly higher in BE tissue than squamous tissue from cases or controls ( p < 0.001). Median COX-2 expression levels were higher in tissue samples from participants with a waist-to-hip ratio (WHR) in the 2nd tertile [unadjusted odds ratio (OR) 2.04; 95 % confidence interval (95 % CI) 1.17-3.57] and 3rd tertile (unadjusted OR 2.24; 95 % CI 1.20-4.16) compared with the 1st tertile and from current smokers compared with former or non-smokers (unadjusted OR 1.68; 95 % CI 1.03-2.75). In the multivariate analysis, WHRs in the 2nd tertile (OR 1.92; 95 % CI 1.07-3.45) and the 3rd tertile (OR 2.14; 95 % CI 1.10-4.16) were associated with high COX-2 compared with the 1st tertile, as was current smoking (OR 1.78; 95 % CI 1.06-2.97) compared with former and non-smoking. Conclusion: We found a significant association between elevated esophageal mucosa COX-2 levels and the presence of BE tissue, as well as between elevated COX-2 levels and high WHR and current tobacco smoking. This information may assist in identifying patients likely to benefit from chemoprevention with COX-2 inhibitors. [ABSTRACT FROM AUTHOR]

We have previously demonstrated that the pancreas can recover from chronic pancreatitis (CP) lesions in the cerulein-induced mouse model. To explore how pancreatic recovery is achieved at the molecular level, we used RNA-sequencing (seq) and profiled transcriptomes during CP transition to recovery. CP was induced by intraperitoneally injecting cerulein in C57BL/6 mice. Time-matched controls (CON) were given normal saline. Pancreata were harvested from mice 4 days after the final injections (designated as CP and CON) or 4 weeks after the final injections (designated as CP recovery (CPR) and control recovery (CONR)). Pancreatic RNAs were extracted for RNA-seq and quantitative (q) PCR validation. Using RNA-seq, we identified a total of 3,600 differentially expressed genes (DEGs) in CP versus CON and 166 DEGs in CPR versus CONR. There are 132 DEGs overlapped between CP and CPR and 34 DEGs unique to CPR. A number of selected pancreatic fibrosis-relevant DEGs were validated by qPCR. The top 20 gene sets enriched from DEGs shared between CP and CPR are relevant to extracellular matrix and cancer biology, whereas the top 10 gene sets enriched from DEGs specific to CPR are pertinent to DNA methylation and specific signaling pathways. In conclusion, we identified a distinct set of DEGs in association with extracellular matrix and cancer cell activities to contrast CP and CPR. Once during ongoing CP recovery, DEGs relevant to DNA methylation and specific signaling pathways were induced to express. The DEGs shared between CP and CPR and the DEGs specific to CPR may serve as the unique transcriptomic signatures and biomarkers for determining CP recovery and monitoring potential therapeutic responses at the molecular level to reflect pancreatic histological resolution. [ABSTRACT FROM AUTHOR]

Background: A systemic evaluation of immune cell infiltration patterns in experimental acute pancreatitis (AP) is lacking. Using multi-dimensional flow cytometry, this study profiled infiltrating immune cell types in multiple AP mouse models. Methods: Three AP models were generated in C57BL/6 mice via cerulein (CAE) injection, alcohol and palmitoleic acid (EtOH + POA) injection, and alcohol diet feeding and cerulein (EtOH + CAE) injection. Primary pancreatic cells and splenocytes were prepared, and multi-dimensional flow cytometry was performed and analyzed by manual gating and computerized PhenoGraph, followed by visualization with t-distributed stochastic neighbor embedding (t-SNE). Results: CAE treatment induced a time-dependent increase of major innate immune cells and a decrease of follicular B cells, and TCD4+ cells and the subtypes in the pancreas, whereas elicited a reversed pattern in the spleen. EtOH + POA treatment resulted in weaker effects than CAE treatment. EtOH feeding enhanced CAE-induced amylase secretion, but unexpectedly attenuated CAE-induced immune cell regulation. In comparison with manual gating analysis, computerized analysis demonstrated a remarkable time efficiency and reproducibility on the innate immune cells and B cells. Conclusions: The reverse pattern of increased innate and decreased adaptive immune cells was consistent in the pancreas in CAE and EtOH + POA treatments. Alcohol feeding opposed the CAE effect on immune cell regulation. Together, the immune profiling approach utilized in this study provides a better understanding of overall immune responses in AP, which may facilitate the identification of intervention windows and new therapeutic strategies. Computerized analysis is superior to manual gating by dramatically reducing analysis time. [ABSTRACT FROM AUTHOR]

* Context.--Recent studies examining immunohistochemical staining of colorectal biopsies for cytomegalovirus (CMV) reported that some cases showed only occasional small positive nuclei that were called equivocal for CMV. Objectives.--To determine the extent and clinical significance of equivocal CMV staining in colorectal biopsies. Design.--Two-hundred twenty-one consecutive cases of colon and rectal biopsies that were stained for CMV by immunohistochemistry were retrieved from our files and reviewed. Staining results were recorded as negative, unequivocal, or equivocal. Results were correlated with clinicopathologic data, results of polymerase chain reaction studies for CMV, and treatment history. Results.--Fifty-two cases (24% of all tested, 63% of positive cases) showed equivocal staining for CMV, and of these, 41 had follow-up information. Polymerase chain reaction for CMV was performed largely on blood samples and was not found to be sensitive for the detections of CMV proctocolitis. Of 25 patients who received antiviral treatment, 21 (84%) had complete resolution of symptoms, compared with 8 of 16 (50%) who did not receive antivirals (P = .02). There was no statistically significant difference in response to antiviral drugs in patients with equivocal and unequivocal CMV staining (P = .17). Conclusions.--Equivocal CMV staining likely represents true CMV proctocolitis. Prospective studies are needed to confirm these findings. [ABSTRACT FROM AUTHOR]

Abstract Pancreatic cancer remains a highly lethal malignancy. We have recently shown that simultaneous expression of Kras and mutant Tp53 R175H promotes invasive ductal adenocarcinoma from pancreatic ductal cells. We hypothesized specific mutations in TP53 have divergent mechanisms of transforming ductal cells. In order to understand the role of mutant TP53 in transforming pancreatic ductal cells, we used a lentiviral system to express mutant TP53 R175H and TP53 R273H , two of the most frequently mutated TP53 alleles in pancreatic cancer patients, in immortalized, but not transformed, pancreatic ductal epithelial cells carrying a KRAS mutation (HPNE: KRAS G12D ). Mutant TP53 expression enhanced colony formation and an RPPA assay results revealed TP53 R175H uniquely induced HSP70 expression in HPNE: KRAS G12D cells. In the context of TP53 R175H expression; we observed nuclear localization of HSP70. We performed immunoprecipitation experiments to show mutant p53R175H binds to HSP70. We also provide evidence mutant p53R175H is important for HSP70 stability and, more importantly, HSP70 is required for mutant p53 stability. These data are critical in the context of events leading to cellular transformation in the pancreas. Highlights • Expression of mutant p53R175H increases colony forming capacity in immortalized pancreatic epithelial cells. • A proteomics screen reveals HSP70 is highly expressed in mutant p53R175H expressing cells. • Mutant p53R175H immunoprecipitates with HSP70 and promotes HSP70 stability. [ABSTRACT FROM AUTHOR]

Context.--The cause of pancreatic acinar metaplasia (PAM) at the distal esophagus/esophagogastric junction is still controversial. Whereas some authors believe it is congenital, others believe it is acquired because of inflammation of the gastric cardia, and more recently it was proposed to be due to chronic proton pump inhibitor use based on a study in rats. Objective.--To determine whether there is correlation between chronic proton pump inhibitor use and PAM in humans. We also investigated the correlation between several clinical and pathologic factors and PAM. Design.--Four hundred forty-four consecutive biopsies from the distal esophagus/esophagogastric junction were reviewed for the presence of PAM, which was then correlated with several clinical and pathologic findings. Results.--Pancreatic acinar metaplasia was found in 71 patients (16%). Pancreatic acinar metaplasia was significantly associated with patient age younger than 51 years (P, .001), chronic carditis (P ¼ .01), and chronic proton pump inhibitor use (P ¼ .008). Surprisingly, we also found significant association between PAM and chronic nonsteroidal anti-inflammatory drug use (P, .001). These associations, including that with chronic nonsteroidal anti-inflammatory drug use, remained significant in multivariate analysis. Conclusions.--Our findings confirm the previous reports of significant association between PAM and chronic carditis and the findings from animal studies of association with chronic proton pump inhibitor use. The strong association with chronic nonsteroidal anti-inflammatory drug use has not been previously reported and warrants further studies. [ABSTRACT FROM AUTHOR]

Aberrant regulation of cellular extrusion can promote invasion and metastasis. Here, we identify molecular requirements for early cellular invasion using a premalignant mouse model of pancreatic cancer with conditional knockout of p120 catenin (Ctnnd1). Mice with biallelic loss of p120 catenin progressively develop high-grade pancreatic intraepithelial neoplasia (PanIN) lesions and neoplasia accompanied by prominent acute and chronic inflammatory processes, which is mediated, in part, throughNF-kB signaling. Loss of p120 catenin in the context of oncogenic Kras also promotes remarkable apical and basal epithelial cell extrusion. Abundant single epithelial cells exit PanINepitheliumbasally, retainepithelial morphology, survive, and display features of malignancy. Similar extrusion defects are observed following p120 catenin knockdown in vitro, and these effects are completely abrogated by the activation of S1P/S1pr2 signaling. In the context of oncogenic Kras, p120 catenin loss significantly reduces expression of genes mediating S1P/S1pr2 signaling in vivo and in vitro, and this effect ismediated at least, in part, through activation of NF-kB. These results provide insight into mechanisms controlling early events in the metastatic process and suggest that p120 catenin and S1P/S1pr2 signaling enhance cancer progression by regulating epithelial cell invasion. [ABSTRACT FROM AUTHOR]

Background and Aims: It has been reported that the incidence of intrahepatic cholangiocarcinoma (ICC) has increased in the USA, while extrahepatic cholangiocarcinoma (ECC) has decreased or remained stable. However, neither the recent trends nor the effects of the misclassification of Klatskin tumors are known. Methods: Using the Surveillance, Epidemiology, and End Results program databases, we calculated the average annual age-adjusted incidence rates (AA-IRs) of ICC and ECC in 4-year time periods (1992-1995, 1996-1999, 2000-2003, 2004-2007). These AA-IRs were calculated with misclassified as well as correctly classified Klatskin tumors. AA-IRs were also calculated based on age, sex, and race. Multivariable Poisson regression models were used to evaluate the secular trends of ICC and ECC. Results: The AA-IR of ICC was 0.92 in 1992-1995 and 0.93 in 2004-2007, while the AA-IR of ECC increased from 0.70 in 1992-1995 to 0.95 in 2004-2007. There was no significant trend in AA-IR of ICC ( p = 0.07), while there was a significant increase in ECC across the 4-year time periods ( p < 0.001). Klatskin tumors comprised 6.7 % of CCs with approximately 90 and 45 % misclassified as ICC during 1992-2000 and 2001-2007, respectively. Adjusted Poisson models showed no significant differences in the temporal trend of ICC or ECC due to misclassification of Klatskin tumors. Conclusions: The incidence of ICC has remained stable between 1992 and 2007 with only slight fluctuations, while the incidence of ECC has been increasing. Misclassification of Klatskin tumors does not appear to play a significant role in the trends of CCs. [ABSTRACT FROM AUTHOR]

The following on histology and immunohistology of Barrett's esophagus (BE) includes commentaries on the various difficulties remaining in reaching a consensus on the definition of BE; the difficulties in the characterization of intestinal and cardiac mucosa, and in the role of submucosal glands in the development of BE; the importance of a new monoclonal antibody to recognize esophageal intestinal mucosa; the importance of pseudo goblet cells; the best techniques for the endoscopic detection of Barrett's epithelium; and the biomarkers for identification of patients predisposed to the development of BE. [ABSTRACT FROM AUTHOR]

Honma N, Arai T, Takubo K, Younes M, Tanaka N, Mieno M N, Tamura K, Ikeda S, Sawabe M & Muramatsu M (2011) Histopathology 59, 216-224 Oestrogen receptor-β CA repeat polymorphism is associated with incidence of colorectal cancer among females Aims: Increasing evidence suggests an association between oestrogens and colorectal cancer. Oestrogen receptor beta, ER-β, putatively plays a pathobiological role in colorectal cancer as colorectal epithelial cells frequently express ER-β. The aim was to elucidate the association of the dinucleotide (CA) repeat polymorphism of the ER-β gene ( ESR2) with colorectal cancer. Methods and results: Deoxyribonucleic acids extracted from the renal cortex of 1488 Japanese autopsies with complete clinical/pathological data were studied. CA repeat polymorphism was determined by polymerase chain reaction using fluorescein-labelled primers. Patients were divided into three genotype groups according to the number of CA repeats of each allele (S < 22, L ≥ 22); SS (with two S alleles), SL (with one each S and L allele) and LL (with two L alleles). The presence/absence of colorectal cancers was determined by examining the clinical records and autopsy material. The incidence of colorectal cancer was significantly different according to the ESR2 CA repeat genotype only among females (SS, 37/202 = 18.3%; SL, 19/332 = 5.7%; LL, 5/155 = 3.2%, P < 0.0001). Immunohistochemically, cancers in females with the SS genotype, but not the SL genotype, frequently expressed the C-terminus portion of ER-β1 (wild-type ER-β). Conclusions: A role for ESR2 CA repeat polymorphism in the pathogenesis of colorectal cancer among females is suggested. [ABSTRACT FROM AUTHOR]

Apocrine carcinoma of the breast, which frequently expresses oestrogen receptor-β (ER-β) in the absence of ER-α and only infrequently is treated endocrinologically, gives an opportunity to investigate the clinicopathological role of ER-β in breast cancer independent of ER-α expression or tamoxifen treatment. Several isotypes of ER-β, ER-β1–5 etc., have been identified thus far; however, the clinicopathological importance of each ER-β isotype in breast cancer is still uncertain. Here we aimed to clarify the clinicopathological importance of ER-β1 and ER-βcx (ER-β2) in apocrine carcinomas, immunohistochemically examining expressions of ER-β1 and ER-βcx in 47 apocrine carcinomas. Positivity for ER-β1 and ER-βcx was observed in 41 (87%) and 18 (38%) of 47 cases, respectively. ER-β1 positivity was related to smaller tumor size ( P=0.0359), lower histological grade ( P=0.0322), and higher disease-free survival ( P<0.0001), whereas ER-βcx status was related to none of these parameters. ER-β1 positivity was also associated with favorable clinical outcome in 24 so-called triple-negative (ER-α-negative/PR-negative/HER2-negative) apocrine carcinomas. ER-β1 itself, independent of ER-α expression and tamoxifen treatment, seems to have a tumor-suppressive effect, at least in apocrine carcinomas. Further study of ER-β1 is desired to optimize breast cancer treatment. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate estrogen receptors as a therapeutic target for human bladder cancer. Methods: The ability of the selective estrogen receptor modulators (SERMs) tamoxifen and raloxifene to inhibit 5637 human transitional cell carcinoma cell proliferation was determined in vitro and in xenograft studies using 5637 cells in female athymic BALB/c nu/nu mice. Results: Treatment with tamoxifen, raloxifene, or the pure antiestrogen ICI 182,780 inhibited proliferation of 5637 cells in vitro. In the first xenograft study, raloxifene (10, 100, or 1000 μg/day) administered by oral gavage inhibited the growth of tumors compared with placebo or untreated controls (P <0.05). In a second experiment, tamoxifen (8.3, 125, or 1250 μg/day) delivered by time-release pellet inhibited tumor growth compared with placebo-treated controls (P <0.01). A comparison study in which tamoxifen (8.3 or 125 μg/day) or raloxifene (100 μg/day) was administered by slow-release pellet demonstrated that both SERMs reduced growth compared to placebo-treated controls (P <0.05), with comparable effectiveness. There was no detectable tumor in 17 of 30 treated mice. In all studies, average tumor volumes in SERM-treated animals declined over the course of treatment. Conclusions: Selective estrogen receptor modulators inhibit the growth of 5637 transitional cell carcinoma cell xenografts, supporting the rationale to evaluate these agents as targeted therapeutics for patients with urothelial carcinoma. [Copyright &y& Elsevier]

Context.—Carcinoid tumors are classified according to their site of origin into foregut, midgut, or hindgut carcinoids, which have different presentations and prognosis. The intestinal transcription factor CDX2 has been found to be expressed in most intestinal adenocarcinomas but in less than one half of the gastrointestinal carcinoids according to 1 study. Objective.—To determine whether CDX2 expression in carcinoid tumors varies by the site of origin and whether CDX2 expression is retained in metastatic disease. Design.—Sections of formalin-fixed and paraffin-embedded tissue from 36 primary carcinoid tumors and 5 cases of metastatic carcinoid to the liver were immunohistochemically stained for CDX2. The percent of cells with nuclear immunoreactivity and the intensity of staining were assessed. Results.—All 18 foregut carcinoids (10 pulmonary and 8 gastric) were negative (0%) for CDX2. All 11 midgut carcinoids (100%) were positive for CDX2 with moderate to strong staining in more than 50% of the cells. Only 2 (29%) of 7 of hindgut carcinoids were CDX2-positive with the 2 positive cases showing weak to moderate staining intensity in less than 10% of the cells. Expression of CDX2 in more than 50% of tumor cells was seen only in midgut carcinoids (P < .001). CDX2 expression in metastatic tumors was consistent with the site of origin. Conclusions.—Midgut carcinoid tumors and their metastases are distinct from foregut and hindgut carcinoids in that they express high levels of CDX2. Additional studies are needed to determine whether CDX2 immunostaining may be helpful in determining the primary site of metastatic carcinoid tumors of unknown origin. [ABSTRACT FROM AUTHOR]

Gross cystic disease fluid protein-15 (GCDFP-15) is a commonly used apocrine marker; however, its expression was recently found to decrease in infiltrating, larger, or metastasizing apocrine carcinomas of the breast. In the breast, monoclonal antibody (MAb) B72.3 has been reported to be useful as an apocrine marker although it is used for that purpose much less frequently than GCDFP-15. In the search for a more consistent apocrine marker, immunoreactivity for MAb B72.3 was examined in apocrine carcinomas at different stages and compared with GCDFP-15. 47 of 51 apocrine carcinomas (92%) and 9 of 62 ordinary carcinomas (15%) were MAb B72.3 positive, while 39 of 51 apocrine carcinomas (76%) and 13 of 62 ordinary carcinomas (21%) were GCDFP-15 positive. Thus, both sensitivity and specificity were higher for MAb B72.3. Furthermore, unlike GCDFP-15, MAb B72.3 exhibited positivity irrespective of infiltrating status, tumor size, or metastatic status. There was no correlation between MAb B72.3-immunoreactivity and GCDFP-15-expression. The combined usage of MAb B72.3 with GCDFP-15 was useful to confirm the diagnosis of apocrine carcinoma, especially for advanced tumors, with only two cases being negative for both MAb B72.3 and GCDFP-15. Whether these two cases should be differentiated from ordinary apocrine carcinomas remains to be investigated. [ABSTRACT FROM AUTHOR]

Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L) is a death protein that preferentially kills tumour cells while sparing normal cells. TRAIL has four exclusive receptors, two of which (TRAIL-R1, TRAIL-R2) are death receptors. Both TRAIL/Apo2L and agonistic antibodies to the TRAIL death receptors are currently being explored for cancer therapy. Although the activity of TRAIL/Apo2L in a variety of haematological malignancies has been examined, the activity of anti-TRAIL receptor agonistic antibodies in primary and cultured lymphoma cells has not. Using two fully human selective agonistic monoclonal antibodies to the TRAIL death receptors TRAIL-R1 (HGS-ETR1) and TRAIL-R2 (HGS-ETR2) this study demonstrated that both monoclonal antibodies activated caspase-8 and induced cell death in five of nine human lymphoma cell lines, and induced >10% cell death in 67% and 70%, respectively, of 27 primary lymphoma cells, and >20% cell death in at least one-thirds of the samples. HGS-ETR1 and HGS-ETR2 demonstrated comparable activity in the fresh tumour samples, which was independent of TRAIL receptor surface expression, Bax, cFLIP, or procaspase-8 expression, or exposure to prior therapy. Furthermore, both antibodies enhanced the killing effect of doxorubicin and bortezomib. Our data demonstrate that HGS-ETR1 and HGS-ETR2 monoclonal antibodies can induce cell death in a variety of cultured and primary lymphoma cells, and may have therapeutic value in lymphoma. [ABSTRACT FROM AUTHOR]

Abstract: A number of variants of the wild-type (wt) estrogen receptor beta (ERβ-1) coexist in a wide range of tissues. In the human these include, together with others, the expression of several isoforms (ERβ-2–ERβ-5) due to alternative splicing of exons encoding the carboxy terminus. In this study, we determined whether virally transformed cell cultures of human lens epithelial cells (HLE-B3) express both full length (or wt) and variant isoforms of ERβ in comparison to normal secondary cultures of human lens epithelial cells (nHLE) and furthermore, identify the subcellular localization of the wtERβ-1 and ERβ isoform variants in HLE-B3 and nHLE cells, as well as from human breast adenocarcinoma cells (MCF-7) which provided a positive control. ERβ isoform mRNA expression was evaluated by coupled RT-PCR. Subcellular localization of ERβ isoforms was determined on formaldehyde-fixed, Saponin-permeabilized cells using conventional immunofluorescence techniques and affinity purified polyclonal antibodies specific for ERβ-1 as well as to two of the truncated carboxy terminus isoforms (β-2 and β-5). Total RNA was extracted from HLE-B3 and nHLE cells and lens tissue, as well as from human breast adenocarcinoma cells (MCF-7) and subjected to RT-PCR using specific estrogen receptor primers intended to distinguish ERβ-1–ERβ-5 mRNA. The PCR products corresponded to wtERβ-1 as well as to the isoform variants β-2 and β-5. The proportional distribution of wtERβ-1, β-2 and β-5 PCR products differed between the normal lens epithelial cells and the SV-40 transformed lens epithelial cell line; the nHLE being similar to lens tissue with respect to relative expression of ERβ isoform cDNAs. Confocal microscopy and immunofluorescence revealed ERβ-2 was distributed throughout the cytosol and was associated with the nucleus of all cells examined, although sporadic immunostaining was observed with the nuclei of MCF-7. Prominent immunostaining of ERβ-1 appeared in the mitochondria (along with weaker staining in the nucleus) of all cell types as authenticated by co-localization with Mitotrack-633. ERβ-5 immunostaining was diffuse in the cytosol and also associated with the nuclei of all cell types. The differential subcellular partitioning of ERβ-1 to the mitochondria and ERβ-2 to the nucleus suggests a new aspect of regulation and function of the estrogen signalling system. [Copyright &y& Elsevier]

OBJECTIVES:Several previous studies have shown that malignant progression in Barrett’s metaplasia (BM) occurs even in patients treated with fundoplication or acid suppression therapy (AST). The aim of this study was to test the hypothesis that AST may not alter malignant progression in BM if key genes involved in DNA repair and cell cycle control, particularly p53, are defective.METHODS:Initial and follow-up biopsies from 21 patients with BM treated with AST and observed for 1–13 yr were entered in the study. All biopsies were graded for dysplasia and evaluated for p53 protein accumulation and oxidative DNA damage by immunohiostochemistry, using antibodies to p53 and to 8-hydroxydeoxyguanosine, respectively. DNA ploidy was determined using image analysis. Statistical analysis was performed using Kaplan-Meier curves, log rank test, and multivariate regression.RESULTS:Patients with p53 positive initial biopsies were more likely to have progression in dysplasia grade (p = 0.022) and DNA ploidy status (p = 0.023) than those with p53 negative biopsies. In eight patients AST resulted in significant reduction in oxidative DNA damage in the five patients with p53-negative initial biopsies, but not the three with p53 positive ones (p = 0.0007).CONCLUSIONS:We conclude that failure of AST to alter malignant progression in BM may be due, at least in part, to defects in DNA repair and cell cycle control resulting from p53 gene mutation, present before AST treatment. Although AST may be effective in preventing further DNA damage, it is unlikely to alter progression in genetically unstable cells. [Copyright &y& Elsevier]

We report a case of mucinous cystadenocarcinoma (MCA) of the breast in a 96-year-old woman. This is an extremely rare variant of primary breast carcinoma that bears a striking resemblance to MCAs of the ovary and pancreas. The macroscopic appearance and secretion pattern (cytologic findings) resembled cystic hypersecretory carcinoma. However, microscopically, the epithelial cells were quite different from those of cystic hypersecretory carcinoma. In the present study as well as in the literature, MCAs tend to occur more frequently in elderly women. Immunohistochemical findings suggest that they may develop independently of estrogenic stimulation. Although MCAs show high proliferative activity, the prognosis was favorable in the present case as well as in the reported cases. Because MCAs appear to have a distinct pathogenesis and biologic behavior, they should be distinguished from ordinary mucinous carcinomas, cystic hypersecretory carcinomas, and carcinomas of other histologic subtypes. [ABSTRACT FROM AUTHOR]

Pancreatic cancer remains a highly lethal malignancy. We have recently shown that simultaneous expression of Kras and mutant Tp53R175H promotes invasive ductal adenocarcinoma from pancreatic ductal cells. We hypothesized specific mutations in TP53 have divergent mechanisms of transforming ductal cells. In order to understand the role of mutant TP53 in transforming pancreatic ductal cells, we used a lentiviral system to express mutant TP53R175H and TP53R273H, two of the most frequently mutated TP53 alleles in pancreatic cancer patients, in immortalized, but not transformed, pancreatic ductal epithelial cells carrying a KRAS mutation (HPNE:KRASG12D). Mutant TP53 expression enhanced colony formation and an RPPA assay results revealed TP53R175H uniquely induced HSP70 expression in HPNE:KRASG12D cells. In the context of TP53R175H expression; we observed nuclear localization of HSP70. We performed immunoprecipitation experiments to show mutant p53R175H binds to HSP70. We also provide evidence mutant p53R175H is important for HSP70 stability and, more importantly, HSP70 is required for mutant p53 stability. These data are critical in the context of events leading to cellular transformation in the pancreas. [ABSTRACT FROM AUTHOR]

The rapidly aging population is consuming more alcohol, leading to increased alcohol-associated acute pancreatitis (AAP) with high mortality. However, the mechanisms remain undefined, and currently there are no effective therapies available. This study aims to elucidate aging- and alcohol-associated spatial transcriptomic signature by establishing an aging AAP mouse model and applying Visium spatial transcriptomics for understanding of the mechanisms in the context of the pancreatic tissue. Upon alcohol diet feeding and caerulein treatment, aging mice (18 months) developed significantly more severe AAP with 5.0-fold increase of injury score and 2.4-fold increase of amylase compared to young mice (3 months). Via Visium spatial transcriptomics, eight distinct tissue clusters were revealed from aggregated transcriptomes of aging and young AAP mice: five acinar, two stromal, and one islet, which were then merged into three clusters: acinar, stromal, and islet for the comparative analysis. Compared to young AAP mice, > 1300 differentially expressed genes (DEGs) and approximately 3000 differentially regulated pathways were identified in aging AAP mice. The top five DEGs upregulated in aging AAP mice include Mmp8, Ppbp, Serpina3m, Cxcl13, and Hamp with heterogeneous distributions among the clusters. Taken together, this study demonstrates spatial heterogeneity of inflammatory processes in aging AAP mice, offering novel insights into the mechanisms and potential drivers for AAP development. KEY MESSAGES: Mechanisms regarding high mortality of AAP in aging remain undefined. An aging AAP mouse model was developed recapturing clinical exhibition in humans. Spatial transcriptomics identified contrasted DEGs in aging vs. young AAP mice. Top five DEGs were Mmp8, Ppbp, Serpina3m, Cxcl13, and Hamp in aging vs. young AAP mice. Our findings shed insights for identification of molecular drivers in aging AAP., (© 2024. The Author(s).)

Patients with Lynch syndrome, most commonly associated with colorectal cancer, have an increased risk of developing other tumors including pancreatic ductal adenocarcinoma and precursor lesions, such as intraductal papillary mucinous neoplasms. Here, we present a case of a man in his early 20s who presented with a retroperitoneal mass involving the head of the pancreas. Following a pancreaticoduodenectomy combined with para-aortic lymphadenectomy, a pathologic diagnosis of colloid carcinoma, also known as mucinous noncystic carcinoma, of the pancreas was reported. Further testing established the diagnosis of Lynch syndrome. This case is unique because colloid carcinoma of the pancreas is rare and has never been reported as an initial presentation of Lynch syndrome., (© 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Objective: The pancreatic ductal adenocarcinoma (PDAC) microenvironment is primarily composed of cancer-associated fibroblasts (CAFs) and immune cells. Gremlin1 (Grem1) is a profibrogenic factor that promotes tumorigenesis in several cancers. However, the role of Grem1 in the PDAC microenvironment is not adequately defined., Methods: We correlated Grem1 levels with activated stroma and immune cells in human PDAC using The Cancer Genome Atlas (TCGA) RNA-sequencing data and characterized the expression of Grem1 transcripts and isoforms in pancreatic cell lines and PDAC tissues. We assessed the role of Grem1 in the microenvironment by in vitro studies., Results: Grem1 expression is associated with an activated stroma and increased M1 and M2 macrophages. Only full length Grem1 variant 1 and isoform 1 were detectable in human pancreatic cells, and remarkably high levels of Grem1 were observed in pancreatic fibroblasts (P < 0.05). Immunohistochemistry detected Grem1 protein in PDAC tumor cells and stromal cells, which correlated with infiltrating macrophages in PDAC tumors. Grem1 knockdown in CAFs suppressed transforming growth factor (TGF)-β-induced extracellular matrix proteins (P < 0.05). Grem1 recombinant protein treatment in vitro increased M1 and M2 macrophages (P < 0.05)., Conclusions: Grem1 acts as a profibrogenic factor in the PDAC microenvironment via modulation of fibroblasts and macrophages. Grem1 may have the potential to be developed as a therapeutic target for PDAC., Competing Interests: The authors declare no conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: There has been no significant improvement in remission rate in inflammatory bowel disease (IBD) despite several new drugs being introduced in the past two decades. Post-treatment biopsies sometimes show histologic healing in some areas of the intestine while other areas within the same intestine continue to show active inflammation. The aim of this short descriptive study was to determine whether heterogeneous treatment response in IBD may be caused by heterogeneous expression of treatment targets within the same intestine., Methods: Six cases of Crohn's disease and five cases of ulcerative colitis in which moderate to severe active inflammation was present in at least two biopsies from the same intestine obtained during the same endoscopy procedure were entered in the study. Sections were stained for TNFα and phospho-JAK1 (p-JAK1) using immunohistochemistry. Expression of TNFα and p-JAK1 was recorded as high when the staining intensity was moderate or high, or low when there was no or week staining. The number of eosinophils per high power field was counted in the area of peak density., Results: Different sites within the same intestine from IBD patients with moderate to severe active inflammation may express different levels of TNFα and p-JAK1. For example, in one patient with Crohn's disease with histologically moderate to severe activity in biopsies from the ileum (site 1) and cecum (site 2), there was high expression of p-JAK1 and low TNFα in the ileum biopsy with the exact opposite in the cecum biopsy (low p-JAK1 and high TNFα expression). In this example neither small molecule drug targeting JAK1 nor anti-TNFα biologic given as single agent therapy would be expected to induce histologic remission in both actively inflamed sites in this patient., Conclusions: The heterogeneous expression of treatment targets within the same intestine may explain why some patients with IBD may not have complete remission on single drug. Studies are needed to determine whether assay for target expression in mucosal biopsies from IBD patients can help to optimize treatment selection., (© 2024 by the Association of Clinical Scientists, Inc.)

Objective: Incomplete intestinal metaplasia (IIM) of the stomach is associated with higher risk of progression to dysplasia and gastric cancer than complete intestinal metaplasia (CIM). Whether the causative factors underlying IIM are different from those underlying CIM is currently unknown. In a recent study, bile acids were found to induce gastric intestinal metaplasia (IM) in mice by activating STAT3 signaling and accelerated the development of dysplasia. The aim of this study was to determine whether there are differences in associations between IIM and CIM and clinicopathologic features known to be associated with intestinal metaplasia, bile reflux, and activated STAT3., Methods: Fifty-two consecutive gastric biopsies with IM were examined for the type of metaplasia, presence of inflammation, and Helicobacter pylori ( H. pylori ) status. Immunohistochemical staining was performed for phospho-STAT3 (p-STAT3) and evaluated by image analysis. The type of IM was then correlated with relevant clinicopathologic variables and p-STAT3 expression., Results: Seven cases had IIM only, 31 had CIM only, and 14 had both CIM and IIM (CIIM). Significantly fewer cases with IIM had chronic gastritis than either CIM or CIIM (43%, 93%, 79%, respectively, p =0.005). H. pylori was not detected in any of the IIM cases but was positive in 29% of CIM and 29% of CIIM. Fifty-seven percent of patients with IIM had a history of cholecystectomy compared to 25% of those with CIM and 23% of those with CIIM. The mean BMI was 32.3 kg/m 2 for patients with IIM compared to 28 kg/m 2 for those with CIM and 31.2 kg/m 2 for those with CIIM. Median p-STAT3 for biopsies with was IIM was 6.36 compared to 3.54 for CIM and 6.27 for CIIM. Reactive gastropathy was present in 57% of biopsies with IIM, 39% of CIM and 50% of CIIM., Conclusion: In contrast to CIM, IIM is significantly less likely to be associated with chronic gastritis. CIIM also tended to be less associated with H. pylori infection and more associated with reactive gastropathy, history of cholecystectomy, higher BMI, and higher median p-STAT3. These results tend to suggest that IIM is probably more likely to be associated with bile reflux than H. pylori -associated gastritis. Larger studies are needed to confirm these findings.Presented in part at Digestive Disease Week 2023, Chicago, IL, May 6, 2023., (© 2023 by the Association of Clinical Scientists, Inc.)

Objective: One of the most serious complications of Crohn's disease is intestinal strictures that may lead to bowel obstruction. Understanding the underlying mechanisms of stricture formation is essential in order to develop more effective nonsurgical prevention and treatment modalities. The aim of this pilot study was to determine whether Gremlin1, a protein implicated in fibrogenesis and smooth muscle proliferation, is overexpressed in Crohn's-associated bowel strictures., Methods: Paired sections from three strictured and non-strictured surgically resected bowel from patients with Crohn's disease were evaluated for Gremlin1 expression by immunohistochemistry., Results: Strictured areas from all three specimens showed strong Gremlin1 staining in the hypertrophic muscularis mucosae area compared to no staining in the mucosa or muscularis propria in the same sections and in contrast to sections from non-strictured areas which were negative., Conclusions: This short report is the first to describe the overexpression of Gremlin1 in the hypertrophied muscularis mucosae of strictured small intestine from patients with Crohn's disease. Additional studies are needed to elucidate the potential role of Gremlin1 in the etiopathogenesis of Crohn's disease strictures, and to investigate whether targeting Gremlin1 may be an option for preventing or treating strictures in patients with Crohn's disease., (© 2023 by the Association of Clinical Scientists, Inc.)

Objective: This study evaluated differences in eosinophil (Eos) count in the right colon (RC) and left colon (LC) relative to known clinical and pathologic features., Methods: H&E slides from 276 subjects with biopsies taken from both RC and LC were reviewed. Eos/mm2 were counted in the area with highest concentration then correlated with clinical and pathologic findings for RC and LC., Results: There were higher numbers of Eos/mm 2 in RC than in LC (mean 177 vs 122, respectively p <0.0001), and there was significant positive correlation between Eos numbers in the two locations (r=0.57, p <0.001). In RC, the mean Eos/mm 2 was 242 with active chronic colitis, 195 with inactive chronic colitis, 160 in microscopic colitis, 144 in quiescent IBD, and 142 with normal histology ( p <0.001), and was higher in males (204 vs 164, p =0.022). In LC, mean Eos/mm 2 was 186 with active chronic colitis, 168 with inactive chronic colitis, 154 in microscopic colitis, 82 in quiescent IBD, and 84 with normal histology ( p <0.001), and was higher in males (154 vs 107, p <0.001). In biopsies with normal histology, RC showed higher mean Eos/mm 2 in Asian patients (228 vs 139, p =0.019), and patients with history of UC (205 vs 136, p =0.004), but was not significantly different in patients with or without irritable bowel syndrome with diarrhea (IBS-D) or history of Crohn's disease (CD). In LC the mean Eos/mm 2 was higher in males (102 vs 77, p =0.036), and history of CD (117 vs 78, p =0.007), but was not significantly different in patients with or without IBS-D or history of UC. The number of Eos/mm 2 was greater in biopsies performed in the summer than during other seasons of the year., Conclusion: The mean number of Eos/mm 2 in colorectal biopsies varies significantly by location, histopathologic changes, clinical diagnosis, season, gender and ethnicity. Of particular interest is the association between high Eos/mm 2 in RC biopsies with otherwise normal histology and clinical history of UC, and in LC biopsies with clinical history of CD. Additional larger and prospective studies that include normal healthy volunteers are needed to establish a reliable cutoff for the histopathologic diagnosis of eosinophilic colitis, taking into consideration the biopsy site within the colon and rectum, as well as patient gender and ethnicity.Presented in part at the annual American College of Gastroenterology meeting, San Antonio, TX October 2019., (© 2023 by the Association of Clinical Scientists, Inc.)

We studied the expression of two hepatocyte nuclear factor 4 alpha (HNF4α) isoforms, p-STAT3. and c-Myc in 49 consecutive liver biopsies with nonalcoholic fatty liver disease (NAFLD) using immunohistochemistry. All 49 biopsies (100%) were positive for nuclear expression of P1-HNF4α. Twenty-eight (57%) cases were positive for P2-HNF4α, 6 (12%) were positive for p-STAT3 and 5 (10%) were positive for c-Myc. All 6 (100%) p-STAT3-positive cases were also positive for P2-HNF4α ( p = 0.03). p-STAT3-positive cases were more likely to be positive for c-Myc (67% vs. 2%, p = 0.0003). Four cases were positive for P2-HNF4α, p-STAT3 and c-Myc. p-STAT3 expression was associated with hypertension ( p = 0.037). All c-Myc positive biopsies were from patients with obesity, diabetes and hypertension. Only c-Myc expression was associated with advanced fibrosis; three (60%) of the c-Myc positive cases were associated with advanced fibrosis in contrast to 7 (10%) of the 44 c-Myc negative cases ( p = 0.011). Based on these results, we hypothesize with the following sequence of events with progression of NAFLD: P2-HNF4α expression is followed by expression of p-STAT3 which in turn is followed by the expression of c-Myc. Additional larger studies are needed to confirm these findings.

Objective: To elucidate the reasons for the decreased effectiveness of Vedolizumab (VDZ) treatment in patients with Crohn's disease (CD) previously treated (CD-T) with anti-TNF-α biologics., Methods: Immunohistochemical staining was performed on sections of formalin-fixed paraffin-embedded ileocolonic biopsies using antibodies for the mucosal addressin molecule (MAdCAM-1) and Etrolizumab., Results: The mean number of MAdCAM-1 positive capillaries (MAdCAM-1-C) was 3 in controls, 8.5 in CD, 5.37 in CD-T, 5.7 in ulcerative colitis (UC), and 3.1 in lymphocytic colitis (LC) ( p =0.0032). When all biopsies with inflammatory bowel disease (IBD) in this series were considered together, the number of MAdCAM-1-C increased with an increased histologic activity score (HAS) ( p <0.001). The mean MAd-CAM-1-C was lower in CD-T than CD (5.37 vs. 8.5, p =0.0362), even in cases with high HAS (6.46 vs. 9.5, p =0.073). Two of 6 (33%) controls, 4 of 6 (67%) CD, 9 of 16 (56%) CD-T, 6 of 7 (86%) UC, and 0 of 8 (0%) LC showed Etrolizumab-positive lymphocytes (E-Ly, p =0.0106). IBD biopsies positive for E-Ly were associated with higher HAS ( p =0.0546). MAdCAM-1-C was heterogenous in some IBD cases., Conclusions: Our results suggest that treatment with anti-TNF-α reduces the number of MAdCAM-1-C in CD, even in biopsies with high HAS. This suggests that high inflammation in such cases obviously failed to respond to anti-TNF-α, may be less dependent on the migration of a4b7-lymphocytes to the inflamed mucosa, and therefore may not optimally respond to VDZ treatment.Presented in part at the Digestive Diseases Week meeting, San Diego, CA, May 2019. Supported by Takeda Pharmaceuticals., (© 2021 by the Association of Clinical Scientists, Inc.)

Objective: Unlike eosinophilic esophagitis (EoE), there is no consensus on the minimum number of intraepithelial lymphocytes (IEL) that is diagnostic of lymphocytic esophagitis (LyE). The aim of this study was to determine whether significant correlations exist between the numbers of intraepithelial lymphocytes (IEL) in esophageal biopsies and clinical and endoscopic manifestations usually associated with EoE., Methods: H&E slides from esophageal biopsies from 330 patients were reviewed. The number of IEL and intraepithelial eosinophils (IEE) per mm 2 was counted in the area with the highest concentration in each biopsy. The numbers were then correlated with clinical and endoscopic findings., Results: As expected, a higher number of IEE was significantly associated with food impaction ( p =0.001), dysphagia ( p =0.021), esophageal stricture ( p =0.017), rings ( P <0.0001), and furrows ( p <0.0001). By contrast, there was no significant association between increased IEL and any of the aforementioned clinical and endoscopic features in the original 330 patients or in a subset of 233 patients with no IEE. Interestingly, the number of both IEE and IEL varied significantly by the season when the biopsy was obtained, being lowest in the fall and highest in the spring ( p =0002 for IEE and p <0.0001 for IEL)., Conclusion: In esophageal biopsies, increased IEL has no significant correlation with food impaction or dysphagia or with esophageal stricture, rings, or furrows. There is significant variation in the number of IEL depending on the season when the biopsy is obtained, which has not been previously reported., (© 2021 by the Association of Clinical Scientists, Inc.)

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death in the United States. Despite the high prevalence of Kras mutations in pancreatic cancer patients, murine models expressing the oncogenic mutant Kras (Kras mut ) in mature pancreatic cells develop PDAC at a low frequency. Independent of cell of origin, a second genetic hit (loss of tumor suppressor TP53 or PTEN) is important for development of PDAC in mice. We hypothesized ectopic expression and elevated levels of oncogenic mutant Kras would promote PanIN arising in pancreatic ducts. To test our hypothesis, the significance of elevating levels of K-Ras and Ras activity has been explored by expression of a CAG driven LGSL-Kras G12V allele (cKras) in pancreatic ducts, which promotes ectopic Kras expression. We predicted expression of cKras in pancreatic ducts would generate neoplasia and PDAC. To test our hypothesis, we employed tamoxifen dependent CreER T2 mediated recombination. Hnf1b:CreER T2 ;Kras G12V (cKras Hnf1b/+ ) mice received 1 (Low), 5 (Mod) or 10 (High) mg per 20 g body weight to recombine cKras in low (cKras Low ), moderate (cKras Mod ), and high (cKras High ) percentages of pancreatic ducts. Our histologic analysis revealed poorly differentiated aggressive tumors in cKras High mice. cKras Mod mice had grades of Pancreatic Intraepithelial Neoplasia (PanIN), recapitulating early and advanced PanIN observed in human PDAC. Proteomics analysis revealed significant differences in PTEN/AKT and MAPK pathways between wild type, cKras Low , cKras Mod , and cKras High mice. In conclusion, in this study, we provide evidence that ectopic expression of oncogenic mutant K-Ras in pancreatic ducts generates early and late PanIN as well as PDAC. This Ras rheostat model provides evidence that AKT signaling is an important early driver of invasive ductal derived PDAC.

Introduction: Inflammatory bowel disease (IBD) patients in apparent clinical remission who present with irritable bowel syndrome (IBS)-like symptoms pose a diagnostic and therapeutic dilemma that is called post-IBD IBS. When associated with a diarrheal IBS presentation, this clinical syndrome is known as post-IBD IBS-D., Areas Covered: We review and describe the literature regarding the clinical overlap of IBD and IBS. We discuss prevalent theories regarding the pathophysiology of post-IBD IBS-D and whether this presentation represents coincident inherent IBS-D, IBS-D triggered by IBD, or an even more subtle level of IBD activity that is unrecognized by available laboratory modalities. We also discuss observations that post-IBD IBS-D patients harbor significantly increased colon mucosal eosinophils and appear to respond to a GI-hypoallergenic diet and budesonide therapy., Expert Opinion: The symptoms overlap between IBD and IBS complicates diagnosis and subsequent management of patients with post-IBD IBS-D. In addition to current theories regarding the pathophysiology of this condition such as alterations in mucosal inflammation, the microbiota, mucosal permeability, and gut-brain interactions. This new avenue of eosinophilic colopathy and therapy directed toward food-derived immune response in patients with post-IBD IBS-D deserves additional investigation.

Germline telomere maintenance defects are associated with an increased incidence of inflammatory diseases in humans, yet whether and how telomere dysfunction causes inflammation are not known. Here, we show that telomere dysfunction drives pATM/c-ABL-mediated activation of the YAP1 transcription factor, up-regulating the major pro-inflammatory factor, pro-IL-18. The colonic microbiome stimulates cytosolic receptors activating caspase-1 which cleaves pro-IL-18 into mature IL-18, leading to recruitment of interferon (IFN)-γ-secreting T cells and intestinal inflammation. Correspondingly, patients with germline telomere maintenance defects exhibit DNA damage (γH2AX) signaling together with elevated YAP1 and IL-18 expression. In mice with telomere dysfunction, telomerase reactivation in the intestinal epithelium or pharmacological inhibition of ATM, YAP1, or caspase-1 as well as antibiotic treatment, dramatically reduces IL-18 and intestinal inflammation. Thus, telomere dysfunction-induced activation of the ATM-YAP1-pro-IL-18 pathway in epithelium is a key instigator of tissue inflammation.

Chronic pancreatitis (CP) is a major risk factor of pancreatic ductal adenocarcinoma (PDAC). How CP promotes pancreatic oncogenesis remains unclear. A characteristic feature of PDAC is its prominent desmoplasia in the tumor microenvironment, composed of activated fibroblasts and macrophages. Macrophages can be characterized as M1 or M2, with tumor-inhibiting or -promoting functions, respectively. We reported that Gremlin 1 (GREM1), a key pro-fibrogenic factor, is upregulated in the stroma of CP. The current study aimed to investigate the expression of GREM1 and correlation between GREM1 and macrophages within the pancreas during chronic inflammation and the development of PDAC. By mRNA in situ hybridization, we detected GREM1 mRNA expression within α-smooth muscle actin (SMA)-positive fibroblasts of the pancreatic stroma. These designated Fibroblasts Grem1+ marginally increased from CP to pancreatic intraepithelial neoplasia (PanIN) and PDAC. Within PDAC, Fibroblasts Grem1+ increased with higher pathological tumor stages and in a majority of PDAC subtypes screened. Additionally, Fibroblasts Grem1+ positively correlated with total macrophages (Mac CD68+ ) and M2 macrophages (M2 CD163+ ) in PDAC. To begin exploring potential molecular links between Fibroblasts Grem1+ and macrophages in PDAC, we examined the expression of macrophage migration inhibitory factor (MIF), an endogenous counteracting molecule of GREM1 and an M1 macrophage promoting factor. By IHC staining of MIF, we found MIF to be expressed by tumor cells, positively correlated with GREM1; by IHC co-staining, we found MIF to be negatively correlated with M2 CD163+ expression. Our findings suggest that GREM1 expression by activated fibroblasts may promote PDAC development, and GREM1/MIF may play an important role in macrophage phenotype., Competing Interests: The authors have no conflict of interests to declare.

Objective: This study aims to present the clinical, endoscopic, and histopathologic characteristics associated with intestinal spirochetosis (IS). It also serves to heighten awareness among pathologists, since the histologic appearance of spirochetosis could be subtle and easily overlooked., Methods: Hematoxylin & eosin (H&E) slides and special stains of intestinal biopsies from six patients with a diagnosis of IS at our institution were reviewed. Clinical history, endoscopic, and histopathologic findings were obtained from electronic medical records., Results: The patients presented with diverse clinical symptoms, and only one patient was asymptomatic. The most consistent symptoms were watery diarrhea and abdominal cramps. Two out of five treated patients reported symptomatic improvement after antibiotics therapy. The colonoscopy findings were not specific, ranging from normal mucosa to polyps, to mucosal ulcerations in one patient. On histologic examination, the typical "brush-like" organisms lying perpendicular to the surface epithelium are seen both on H&E stain and special stains., Conclusions: IS is usually an incidental histologic finding, and the association with symptoms is still unclear. The clinical presentation could be very diverse, hence, a long list of differential diagnosis should be ruled out. Additional clinical testing should be pursued if patients are unresponsive to antibiotic treatment., (© 2020 by the Association of Clinical Scientists, Inc.)