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Gastric cancer (GC) has a good prognosis, if detected at an early stage. The intestinal subtype of GC follows a stepwise progression to carcinoma, which is treatable with early detection and intervention using high-quality endoscopy. Premalignant lesions and gastric epithelial polyps are commonly encountered in clinical practice. Surveillance of patients with premalignant gastric lesions may aid in early diagnosis of GC, and thus improve chances of survival. An expert professional workgroup was formed to summarise the current evidence and provide recommendations on the management of patients with gastric premalignant lesions in Singapore. Twenty-five recommendations were made to address screening and surveillance, strategies for detection and management of gastric premalignant lesions, management of gastric epithelial polyps, and pathological reporting of gastric premalignant lesions. Keywords: Early gastric neoplasia, endoscopic surveillance, gastric cancer, intestinal metaplasia, polyp

Drug-induced autoimmune hepatitis (DIAIH) is a specific phenotype of drug-induced liver injury that may lead to the devastating outcome of acute liver failure requiring liver transplantation. Drugs implicated in DIAIH include antimicrobials such as nitrofurantoin and minocycline, non-steroidal anti-inflammatory drugs, statins as well as anti-tumor necrosis agents. The clinical features of drug-induced liver injury are indistinguishable from idiopathic autoimmune hepatitis (AIH) as both may have positive AIH-related autoantibodies, elevated immunoglobulin G, as well as similar histopathological findings. In patients who show no clinical improvement, or there is progressive liver injury despite cessation of the suspected drug, a liver biopsy should be considered, whereby the presence of advance fibrosis on histology favors the diagnosis of idiopathic AIH. Empirical treatment with corticosteroids may be required in patients with non-resolving liver injury. A typical clinical scenario supportive of DIAIH includes a history of drug exposure with spontaneous resolution of liver injury after drug withdrawal and the absence of relapse after rapid steroid taper. In this article we report two cases of DIAIH secondary to Sorafenib and Atorvastatin along with a review of currently available literature. Early identification and treatment often lead to a favorable outcome in DIAIH.

Purpose: Nelfinavir, a PI3K pathway inhibitor, is a radiosensitizer that increases tumor blood flow in preclinical models. We conducted an early-phase study to demonstrate the safety of nelfinavir combined with hypofractionated radiotherapy (RT) and to develop biomarkers of tumor perfusion and radiosensitization for this combinatorial approach.Experimental Design: Ten patients with T3-4 N0-2 M1 rectal cancer received 7 days of oral nelfinavir (1,250 mg b.i.d.) and a further 7 days of nelfinavir during pelvic RT (25 Gy/5 fractions/7 days). Perfusion CT (p-CT) and DCE-MRI scans were performed pretreatment, after 7 days of nelfinavir and prior to the last fraction of RT. Biopsies taken pretreatment and 7 days after the last fraction of RT were analyzed for tumor cell density (TCD).Results: There were 3 drug-related grade 3 adverse events: diarrhea, rash, and lymphopenia. On DCE-MRI, there was a mean 42% increase in median Ktrans, and a corresponding median 30% increase in mean blood flow on p-CT during RT in combination with nelfinavir. Median TCD decreased from 24.3% at baseline to 9.2% in biopsies taken 7 days after RT (P = 0.01). Overall, 5 of 9 evaluable patients exhibited good tumor regression on MRI assessed by tumor regression grade (mrTRG).Conclusions: This is the first study to evaluate nelfinavir in combination with RT without concurrent chemotherapy. It has shown that nelfinavir-RT is well tolerated and is associated with increased blood flow to rectal tumors. The efficacy of nelfinavir-RT versus RT alone merits clinical evaluation, including measurement of tumor blood flow. Clin Cancer Res; 22(8); 1922–31. ©2016 AACR.See related commentary by Meyn et al., p. 1834

Supplementary Table 1: Laboratory values (Liver Function Tests) Supplementary Table 2: Overview of mean pCT parameters for tumour VOI on sequential scans Supplementary Table 3: Overview of median DCE-MRI parameters, Ktrans, Ve and Kep for tumour VOI on sequential scans. Mean across all patients of the median per patient values is shown. Supplementary Table 4: Correlations of baseline characteristics, mutation status & overall mrTRG score with TCD. Supplementary Table 5 Correlations of baseline characteristics, mutation status & overall mrTRG score with median Ktrans. Supplementary Table 6: Correlations of baseline characteristics, mutation status & overall mrTRG score with mean Blood Flow. Supplementary Figure 1: Axial and sagittal images from T2W MRI scans at baseline and 8 weeks after completion of therapy. Supplementary Figure 2: Perfusion parameter maps illustrating an increase in Blood Flow and reduction in MTT between Scans 2 and 3. Supplementary Figure 3: Examples of (a) positive immunohistochemistry staining in pre-treatment rectal tumour biopsies and (b) absent staining in negative control.

Colonoscopy with endoscopic resection of detected colonic adenomas interrupts the adenoma-carcinoma sequence and reduces the incidence of colorectal cancer and cancer-related mortality. In the past decade, there have been significant developments in instruments and techniques for endoscopic polypectomy. Guidelines have been formulated by various professional bodies in Europe, Japan and the United States, but some of the recommendations differ between the various bodies. An expert professional workgroup under the auspices of the Academy of Medicine, Singapore, was set up to provide guidance on the endoscopic management of colonic polyps in Singapore. A total of 23 recommendations addressed the following issues: accurate description and diagnostic evaluation of detected polyps; techniques to reduce the risk of post-polypectomy bleeding and delayed perforation; the role of specific endoscopic resection techniques; the histopathological criteria for defining endoscopic cure; and the role of surveillance colonoscopy following curative resection.

BACKGROUND AND AIM Gastrointestinal (GI) lesions may have subtle morphological changes. Linked color imaging (LCI) combines narrow-band wavelength light and white light imaging (WLI) in appropriate balance to enhance lesion detection. We compared the detection rates of upper GI lesions using LCI and WLI. METHOD Patients were randomized in a 1:1 ratio to receive tandem gastroscopy with WLI inspection followed by LCI, or vice versa. Endoscopic examination was performed using the EG-L590ZW gastroscope and the LASEREO endoscope system (Fujifilm Co., Tokyo, Japan). Histology was reported by a specialist GI pathologist blinded to the technique of lesion detection and was used as the gold standard for diagnosis. RESULTS Ninety patients (mean age 66.8 years, 51.5% male patients) were randomized to either LCI examination first followed by WLI (LCI-WLI), or vice versa (WLI-LCI). An 18.9% of gastroscopies in the study were for surveillance of previously known gastric cancer precursors. Ten patients (11.1%) had a history of Helicobacter pylori infection. There was no significant difference in the time taken for examination under LCI (311 ± 96 s) and WLI (342 ± 86 s) (P = 0.700). LCI detection rates were higher than WLI detection rates for gastric cancer precursors such as atrophic gastritis (2.19% vs 0.55%) (P

BackgroundColorectal cancer (CRC) is associated with patient demographics, lifestyle exposures and molecular alterations. However, it is not possible to determine which adenomas will progress to CRC, as ethically it is unacceptable to leave and follow adenomas. We hypothesised that certain lifestyle exposures at high levels could precondition exposed bowel tissue by changing and aging it, increasing the risks of deleterious DNA methylation and genetic alterations. We used a novel study design comparing adenomas with concurrent CRC (thus more likely exposed to deleterious lifestyle effects) to single adenomas in bowels with no history of CRC; we called these high (HR) and low-risk (LR) adenomas respectively.MethodsWe carried out a discovery and replication epigenome-wide association study (EWAS) on 106 HR and 111 LR adenomas, profiled with MethylationEPIC BeadChips. In order, to identify differentially methylated positions (DMP), regions (DMR), and DNAm (DNAmethylation) lifestyle exposures and risks, with adjustment for confounders, and gene ontology (GO) and pathway enrichment. Then, two open-source gene expression omnibus (GEO) validation datasets (52, 57 and 49, 48 HR and LR normal bowel tissues respectively) were analysed for these DNAm lifestyle exposures and risks, with adjustment for confounders.ResultsOur EWAS found 5 Bonferroni significant DMPs with absolute delta betas ≥ 5%, and 14 significant DMRs with absolute mean DMR delta betas ≥ 5%, replicated in the GPX7, RGS3 and TMEM135 cancer-associated genes. DNAm high alcohol exposures were strongly associated with increased risk of HR adenomas (odds ratio (OR) per standard deviation (SD) = 2.16 (95% confidence interval (CI) 1.55 - 3.09, p-value = 9.7 × 10-6)). In the validation datasets, DNAm high alcohol (ORperSD = 2.12 (95% CI 1.35 - 3.55, p-value = 2.0 × 10-3) and ORperSD = 1.79 (95% CI 1.14 - 2.96, p-value = 1.7 × 10-2)), and high body mass index (BMI) exposures (ORperSD = 1.72 (95% CI 1.13 - 2.73, p-value = 1.5 × 10-2)) were associated with increased risk of HR normal bowel tissues.ConclusionsHigh alcohol and BMI exposures may precondition normal bowel tissues and adenomas for increased risk of DNA methylation alterations associated with CRC progression. The DNAm exposure signatures and our newly identified genes may be useful epigenetic biomarkers for CRC prevention.

Funder: Oxford Experimental Cancer Centre, Background: This Phase 2a dose expansion study was performed to assess the safety, tolerability and preliminary efficacy of the maximum tolerated dose of the oral histone de-acetylase (HDAC) inhibitor CXD101 in patients with relapsed / refractory lymphoma or advanced solid organ cancers and to assess HR23B protein expression by immunohistochemistry as a biomarker of HDAC inhibitor sensitivity. Methods: Patients with advanced solid-organ cancers with high HR23B expression or lymphomas received CXD101 at the recommended phase 2 dose (RP2D). Key exclusions: corrected QT > 450 ms, neutrophils < 1.5 × 109/L, platelets < 75 × 109/L, ECOG > 1. Baseline HR23B expression was assessed by immunohistochemistry. Results: Fifty-one patients enrolled between March 2014 and September 2019, 47 received CXD101 (19 solid-organ cancer, 28 lymphoma). Thirty-four patients received ≥80% RP2D. Baseline characteristics: median age 57.4 years, median prior lines 3, male sex 57%. The most common grade 3–4 adverse events were neutropenia (32%), thrombocytopenia (17%), anaemia (13%), and fatigue (9%) with no deaths on CXD101. No responses were seen in solid-organ cancers, with disease stabilisation in 36% or patients; the overall response rate in lymphoma was 17% with disease stabilisation in 52% of patients. Median progression-free survival was 1.2 months (95% confidence interval (CI) 1.2–5.4) in solid-organ cancers and 2.6 months (95%CI 1.2–5.6) in lymphomas. HR23B status did not predict response. Conclusions: CXD101 showed acceptable tolerability with efficacy seen in Hodgkin lymphoma, T-cell lymphoma and follicular lymphoma. Further studies assessing combination approaches are warranted. Trial registration: ClinicalTrials.gov identifier NCT01977638. Registered 07 November 2013.

Brunner’s gland hamartoma (BGH) is a rare sub-epithelial tumour of the duodenum, which may cause haemorrhagic or obstructive gastrointestinal symptoms. Their accurate histological diagnosis often remains elusive before resection. Although endoscopic ultrasonography (EUS) is considered an excellent modality to study lesions within the gastrointestinal wall, only a few reports have described endosonographic characteristics of BGHs. A reliable pre-resection diagnosis with EUS may not only allay fear of malignancy but may as well avert a major surgery for the patients. In this report, we present a rare case of a large BGH in a young female who presented with acute gastrointestinal bleeding. Here, the endosonographic features assuaged the concern for malignancy while aiding in complete and uneventful surgical resection of the tumour via a submucosal plane.

Background and Objective: EUS-guided fine-needle biopsy (EUS-FNB) with acquisition of tissue core is possible with the use of 19G fine-needle aspiration (FNA) and dedicated biopsy needles. Published data of direct comparisons between biopsy needles are more limited compared to the abundant data comparing EUS-FNA with EUS-FNB. We performed a retrospective study to determine the difference in histologic yield between 19G FNA needle and EUS-FNB needles in patients with solid masses. Materials and Methods: Consecutive patients who underwent EUS-FNB of solid masses from January 2014 to July 2018 were identified from a database. The difference in histologic yield between needles was analyzed. Results: A total of 159 patients underwent 179 EUS-FNB procedures (median of 2 needle passes [range: 1–4]). The use of 19G FNA, 19G, 20G, and 22G FNB needles allowed acquisition of a histologic core in 67.4% (29/43), 72.5% (29/40), 82.1% (46/56), and 75.9% (22/29), respectively (P = 0.368). A significant difference in the yield of histologic core was detected when 19G FNA needle was compared with 22G Acquire™ FNB needle (67.4% [29/43] vs. 94.1% [16/17], P = 0.032). The presence of histologic core was significantly associated with a positive diagnosis (95.6% vs. 30.2%, P < 0.0001). Conclusion: EUS-FNB with acquisition of histologic core improved the diagnostic yield. Dedicated FNB needles appeared to achieve a higher yield of histologic core compared to 19G FNA needles.

The introduction of endoscopic ultrasound-guided fine-needle aspiration into clinical practice was a pivotal moment for diagnostic gastrointestinal endoscopy. It facilitates the ease of tissue acquisition from previously inaccessible sites. The performance characteristics of cytological diagnosis are excellent. However, there remain areas of inadequacies. These include procedural inefficiencies such as the need for rapid on-site cytological evaluation or macroscopic on-site evaluation, the crucial role of histology for diagnosis in specific conditions, the issue of sampling errors and the need for repeat procedures, and the shift towards personalized medicine, which requires histology, immunohistochemical studies, and molecular analysis. The original Trucut biopsy needle had been cumbersome to use, but the recent introduction of newer-generation biopsy needles has transformed the landscape, such that there is now a greater focus on tissue acquisition for histological assessment. Concomitant technological advances of endoscopic ultrasound processors enabled higher-resolution imaging, and facilitated image enhancement using contrast harmonic endoscopic ultrasound and endoscopic ultrasound elastography. These techniques can be used as an adjunct to guide tissue acquisition in challenging situations. There is ongoing research on the use of artificial intelligence to complement diagnostic endoscopic ultrasound and the early data are promising. Artificial intelligence may be especially important to guide clinical decision-making if biopsy results are nondiagnostic.

In the intestine, the homeostatic effect of Bone Morphogenetic Protein (BMP) on cell fate has predominantly been inferred through pathway inactivation. Here, we assessed the impact of autocrine Bmp4 expression on secretory cell fate. Ligand exposure reduced proliferation, expedited terminal differentiation, abrogated long-term secretory cell survival and prevented dedifferentiation. As stem cell plasticity is required for regenerative adaptive reprogramming, we spatiotemporally mapped and functionally explored BMP’s role in epithelial restitution. Following ulceration, physiological attenuation of BMP signalling arose through upregulation of the secreted antagonist, Grem1, from topographically distinct populations of stromal cells. Concomitant expression supported functional compensation, following Grem1 deletion from tissue-resident fibroblasts. BMP pathway manipulation showed that antagonist-mediated BMP attenuation was obligatory, but functionally sub-maximal, as regeneration was impaired or enhanced by epithelial overexpression of Bmp4 or Grem1 respectively. Mechanistically, Bmp4 abrogated regenerative stem cell reprogramming, despite a convergent impact of YAP/TAZ on cell fate in remodelled wounds.

Purpose To use a novel segmentation methodology based on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to define tumour subregions of liver metastases from colorectal cancer (CRC), to compare these with histology, and to use these to compare extracted pharmacokinetic (PK) parameters between tumour subregions. Materials and Methods This ethically-approved prospective study recruited patients with CRC and ≥1 hepatic metastases scheduled for hepatic resection. Patients underwent DCE-MRI pre-metastasectomy. Histological sections of resection specimens were spatially matched to DCE-MRI acquisitions and used to define histological subregions of viable and non-viable tumour. A semi-automated voxel-wise image segmentation algorithm based on the DCE-MRI contrast-uptake curves was used to define imaging subregions of viable and non-viable tumour. Overlap of histologically-defined and imaging subregions was compared using the Dice similarity coefficient (DSC). DCE-MRI PK parameters were compared for the whole tumour and histology-defined and imaging-derived subregions. Results Fourteen patients were included in the analysis. Direct histological comparison with imaging was possible in nine patients. Mean DSC for viable tumour subregions defined by imaging and histology was 0.738 (range 0.540-0.930). There were significant differences between K trans and k ep for viable and non-viable subregions (p < 0.001) and between whole lesions and viable subregions (p < 0.001). Conclusion We demonstrate good concordance of viable tumour segmentation based on pre-operative DCE-MRI with a post-operative histological gold-standard. This can be used to extract viable tumour-specific values from quantitative image analysis, and could improve treatment response assessment in clinical practice.

Aneuploidy, defined as the loss and gain of whole and part chromosomes, is a near-ubiquitous feature of cancer genomes, is prognostic, and likely an important determinant of cancer cell biology. In colorectal cancer (CRC), aneuploidy is found in virtually all tumours, including precursor adenomas. However, the temporal evolutionary dynamics that select for aneuploidy remain broadly uncharacterised. Here we perform genomic analysis of 755 samples from a total of 167 patients with colorectal-derived neoplastic lesions that cross-sectionally represent the distinct stages of tumour evolution, and longitudinally track individual tumours through metastasis and treatment. Precancer lesions (adenomas) exhibited low levels of aneuploidy but high intra-tumour heterogeneity, whereas cancers had high aneuploidy but low heterogeneity, indicating that progression is through a genetic bottleneck that suppresses diversity. Individual CRC glands from the same tumour have similar karyotypes, despite prior evidence of ongoing instability at the cell level. Pseudo-stable aneuploid genomes were observed in metastatic lesions sampled from liver and other organs, after chemo- or targeted therapies, and late recurrences detected many years after the diagnosis of a primary tumour. Modelling indicates that these data are consistent with the action of stabilising selection that ‘traps’ cancer cell genomes on a fitness peak defined by the specific pattern of aneuploidy. These data show that the initial progression of CRC requires the traversal of a rugged fitness landscape and subsequent genomic evolution, including metastatic dissemination and therapeutic resistance, is constrained by stabilising selection.

Background and Aims Lymphocyte activation gene [LAG]-3 is an immune checkpoint and its expression identifies recently activated lymphocytes that may contribute to inflammation. We investigated the role of LAG-3 by analysing its expression and function in immune cells from blood and tissue of patients with ulcerative colitis [UC]. Methods The phenotypic properties of LAG-3+ T cells were determined by flow cytometry, qRT-PCR and single-cell RNA-sequencing. LAG-3+ cells were quantified and correlated with disease activity. The functional effects of LAG-3+ cells were tested using a depleting anti-LAG-3 monoclonal antibody [mAb] in a mixed lymphocyte reaction [MLR]. Results LAG-3+ cells in the blood were negligible. LAG-3+ lymphocytes were markedly increased in inflamed mucosal tissue and both frequencies of LAG-3+ T cells and transcript levels of LAG3 correlated with endoscopic severity. LAG-3 expression was predominantly on effector memory T cells, and single-cell RNA-sequencing revealed LAG3 expression in activated and cytokine-producing T cell subsets. Foxp3+CD25hi Tregs also expressed LAG-3, although most mucosal Tregs were LAG-3−. Mucosal LAG-3+ cells produced mainly interferon γ [IFNγ] and interleukin-17A. LAG-3+ cell numbers decreased in patients who responded to biologics, and remained elevated in non-responders. Treatment with a depleting anti-LAG-3 mAb led to a reduction in proliferation and IFNγ production in an MLR. Conclusions LAG-3+ cells are increased in the inflamed mucosa, predominantly on effector memory T cells with an activated phenotype and their cell numbers positively correlate with disease activity. Depleting LAG-3 eliminates activated proliferating T cells, and hence LAG-3 could be a therapeutic target in UC.

Background In the current study, the authors sought to determine the maximum tolerated dose (MTD) of the novel class 1 selective histone deacetylase inhibitor CXD101 in a dose escalation study in patients with advanced solid tumors or recurrent/refractory lymphoma. Methods The authors escalated the dose of CXD101 from 1 mg twice daily orally for 5 days in a 21-day cycle (3+3 design). Results A total of 39 patients were enrolled, 36 of whom received CXD101. Of the 30 patients in the escalation cohort, 29 were evaluable for determination of the dose-limiting toxicity (DLT). DLTs were noted at doses of 16 mg twice daily (1 of 6 patients), 20 mg twice daily (1 of 6 patients), and 24/25 mg twice daily (2 of 5 patients, both of whom developed neutropenic fever). The MTD was 20 mg twice daily, which achieved maximal plasma concentrations (±standard deviation) of 231±76 nM to 342±126 nM, which was within the biologically active range. Six patients received 20 mg twice daily in an expansion cohort. The most frequent adverse events were fatigue, nausea, and reversible cytopenia. Key grade 3 to 4 adverse events (according to Common Terminology Criteria for Adverse Events criteria [version 4.03]) included thrombocytopenia (11%), neutropenia (17%), and neutropenic fever (2%) across the 133 CXD101 cycles given. The toxicity profile was similar to that of licensing studies with other histone deacetylase inhibitors. In 22 evaluable patients receiving a dose of ≥16 mg twice daily (17 of whom had lymphoma and 5 of whom had solid tumors), 3 partial responses (2 in patients with classic Hodgkin lymphoma after allogenic stem cell transplantation and 1 in a patient with angioimmunoblastic T-cell lymphoma) and 1 complete response (in a patient with follicular lymphoma) were noted (overall response rate of 18%) in addition to 9 patients who achieved durable stable disease. Responses were noted predominantly among patients with lymphoma (tumor reduction noted in 63% of patients on standard computed tomography). Conclusions The MTD in the current study was found to be 20 mg twice daily. Encouraging and durable activity was observed in patients with Hodgkin lymphoma, T-cell lymphoma, and follicular lymphoma.

Endoscopic ultrasound (EUS) is now well established as an important tool in clinical practice. From purely diagnostic imaging, it has progressed to include tissue acquisition, which provided the basis for therapeutic procedures. Even as interventional EUS developed, there has been ongoing progress in EUS diagnostic capabilities due to improved imaging systems, better needles for tissue acquisition and development of enhanced imaging functions such as contrast harmonic EUS (CHEUS) and EUS elastography. EUS is well established for differentiation of subepithelial lesions, for T-staging of luminal gastrointestinal and pancreaticobiliary malignancies, for differentiation of benign pancreaticobiliary disorders and for diagnostic tissue acquisition, which can be achieved by EUS-guided fine needle aspiration or by EUS-guided fine needle biopsy using dedicated biopsy needles. This review briefly describes the technique of performing EUS and then discusses its clinical utility in terms of gastrointestinal cancer staging, the evaluation of pancreaticobiliary disorders and tissue acquisition. Enhanced imaging techniques such as CHEUS and EUS elastography are briefly reviewed.

Cholangiocarcinoma is the second most common hepatobiliary cancer following hepatocellular carcinoma, and 20% to 25% are intrahepatic. We describe 2 cases of intrahepatic cholangiocarcinoma arising within unusual and rare hepatic lesions, fibropolycystic liver disease form of ductal plate malformation and biliary adenofibroma, whose association with malignancy is rarely reported in the literature.

Introduction Patients with inflammatory bowel disease (IBD) undergoing polypectomy are recommended by current guidelines to have biopsies taken from adjacent mucosa to determine whether there is dysplasia present. With improvements in endoscopic imaging, it is now possible to characterize colonic lesions with higher levels of confidence than previously. We have reviewed the diagnostic yield of polyp-adjacent biopsies in IBD. Materials and methods A systematic search of our histopathology database revealed cases in which polyps had been endoscopically resected or biopsied in patients with IBD. Endoscopy reports and medical records were reviewed, and patient demographic and disease-specific details were recorded, along with details of polyp characteristics and histopathology outcomes. Results Three hundred and two polyps were biopsied or resected in 131 patients undergoing 178 colonoscopies. The median polyp size was 4 mm (range 1-45), and the predominant morphology was Paris 0-Is (n = 98, 32%). The histology was tubular adenoma in 76 (25%), tubulovillous adenoma in 14 (5%), hyperplastic in 112 (37%), post-inflammatory in 32 (11%), sessile serrated polyp in 31 (10%), traditional serrated adenoma in 2 (0.7%), flat high-grade dysplasia or cancer in 2 (0.7%) and other in 33 (11%). Dysplasia in adjacent biopsies was detected in 2 patients (0.7%), and was endoscopically visible in both cases. The proportion of endoscopically unsuspected dysplasia was 0/300 (0%, 95% CI 0-1.6%). Conclusion The diagnostic yield for polyp-adjacent biopsies in patients with IBD is negligible. With high-definition technology and chromoendoscopy, it may no longer be necessary to biopsy endoscopically normal adjacent tissue to detect invisible dysplasia.

BACKGROUND & AIMS: In homeostasis, intestinal cell fate is controlled by balanced gradients of morphogen signaling. The bone morphogenetic protein (BMP) pathway has a physiological, prodifferentiation role, predominantly inferred through previous experimental pathway inactivation. Intestinal regeneration is underpinned by dedifferentiation and cell plasticity, but the signaling pathways that regulate this adaptive reprogramming are not well understood. We assessed the BMP signaling landscape and investigated the impact and therapeutic potential of pathway manipulation in homeostasis and regeneration. [Figure: see text] METHODS: A novel mouse model was generated to assess the effect of the autocrine Bmp4 ligand on individual secretory cell fate. We spatio-temporally mapped BMP signaling in mouse and human regenerating intestine. Transgenic models were used to explore the functional impact of pathway manipulation on stem cell fate and intestinal regeneration. RESULTS: In homeostasis, ligand exposure reduced proliferation, expedited terminal differentiation, abrogated secretory cell survival, and prevented dedifferentiation. After ulceration, physiological attenuation of BMP signaling arose through upregulation of the secreted antagonist Grem1 from topographically distinct populations of fibroblasts. Concomitant expression supported functional compensation after Grem1 deletion from tissue-resident cells. BMP pathway manipulation showed that antagonist-mediated BMP attenuation was obligatory but functionally submaximal, because regeneration was impaired or enhanced by epithelial overexpression of Bmp4 or Grem1, respectively. Mechanistically, Bmp4 abrogated regenerative stem cell reprogramming despite a convergent impact of YAP/TAZ on cell fate in remodeled wounds. CONCLUSIONS: BMP signaling prevents epithelial dedifferentiation, and pathway attenuation through stromal Grem1 upregulation was required for adaptive reprogramming in intestinal regeneration. This intercompartmental antagonism was functionally submaximal, raising the possibility of therapeutic pathway manipulation in inflammatory bowel disease.

Background Standard surgical practice for colorectal cancer involves resection of the primary lesion and all draining lymph nodes. Accurate intraoperative assessment of nodal status could allow stratified resectional extent. One-step nucleic acid (OSNA) can provide a rapid method of interrogating nodal tissue, whilst near-infrared (NIR) laparoscopy together with indocyanine green (ICG) can identify relevant nodal tissue intraoperatively. Methods ICG was administered around the tumour endoscopically prior to the operation. Fluorescent nodes identified by NIR were marked and submitted for whole-node OSNA analysis. Further fresh lymph nodes dissected from the standard resection specimen were examined and analysed by both conventional histology and OSNA. In addition, the status of the fluorescent nodes was compared to that of non-ICG nodes to assess their predictive value. Results Sixteen patients were recruited with a total final lymph node count of 287. 78 fresh lymph nodes were identified on fresh dissection for both histological and OSNA assessment with an analytical concordance rate of 98.7% (77/78). OSNA sensitivity was 1 (0.81–1, 95% CI) and specificity 0.98 (0.91–1, 95% CI). Six patients had a total of nine nodes identified intraoperatively by ICG fluorescence. Of these nine nodes, one was positive for metastasis on OSNA. OSNA analysis of the ICG-labelled node matched the final histological nodal stage in 3/6 patients (two being N0 and one N1). The final pathological nodal stage of the other three was N1 or N2, while the ICG nodes were negative. Conclusion OSNA is highly concordant with standard histology, although only a minority of nodes identifiable by full pathological analysis were found for OSNA on fresh dissection. OSNA can be combined with NIR and ICG lymphatic mapping to provide intraoperative assessment of nodal tissue in patients with colorectal cancer.

This study aimed to ascertain views, incidence of reporting and diagnostic criteria for gastric foveolar dysplasia. A questionnaire, a post-questionnaire discussion and microscopic assessment of selected cases was conducted by gastrointestinal pathologists to explore the above-stated aims. Fifty-four percent of respondents never or rarely diagnosed gastric foveolar-type dysplasia. The general consensus was that round nuclei, lack of nuclear stratification, presence of inflammation/damage and surface maturation favoured reactive change; while architectural abnormalities/complexity and nuclear enlargement mainly were used to separate low-grade from high-grade foveolar dysplasia. Immunohistochemistry was rarely used to make the diagnosis of dysplasia and was thought not to be of help in routine practice. Inter-observer agreement in grading of dysplasia versus reactive, and the type of dysplasia (foveolar versus adenomatous), was substantial/almost perfect amongst 35.7% and 21.4% of participants, respectively. This reflects low reproducibility in making these diagnoses. In conclusion, foveolar dysplasia was a rarely made diagnosis among 14 gastrointestinal pathologists, there are no uniform criteria for diagnosis and there is poor inter-observer agreement in separating low-grade foveolar dysplasia from reactive gastric mucosa and low-grade adenomatous dysplasia. Greater awareness and agreed criteria will prevent misdiagnosis of low-grade foveolar dysplasia as reactive, and vice versa.

The carcinoid syndrome is rare but it is associated with carcinoid heart disease in more than a half of the cases. Carcinoid heart disease is typically characterised by morphological and functional modifications of right-sided valves. Its aetiology is probable multifactorial but serotonin appears to play a key role in the development of this valvular disease. Unlike gastrointestinal neuroendocrine tumours, ovarian neuroendocrine tumours can present with carcinoid syndrome and carcinoid heart disease in the absence of liver metastases; such ovarian neuroendocrine tumours are a unique clinical entity. The additional burden of cardiac impairment in these patients represents a significant reduction in survival. Early recognition and surgical valve replacement before advanced heart failure is established may improve the clinical outcome. We report the case of a woman with an ovarian neuroendocrine tumour and highly symptomatic carcinoid heart disease who was submitted to tumour resection followed by valvuloplasty. She demonstrated an outstanding clinical improvement and has remained free of tumour and symptomatology.A síndrome carcinoide é rara mas encontra-se associada, em cerca de metade dos casos, a doença carcinoide cardíaca. Esta patologia cardíaca caracteriza-se tipicamente por alterações morfo-funcionais das válvulas direitas. A sua etiologia é provavelmente multifatorial mas, aparentemente, a serotonina parece exercer um papel preponderante no desenvolvimento desta doença valvular. Ao contrário dos tumores neuroendócrinos gastrointestinais, os tumores neuroendócrinos do ovário podem apresentar síndrome carcinoide e doença carcinoide cardíaca na ausência de metastização hepática, tornando os tumores neuroendócrinos do ovário uma entidade clínica única. Estas alterações cardíacas acarretam uma diminuição adicional da sobrevivência destes doentes. Portanto, o reconhecimento precoce desta entidade e a substituição valvular prévia ao estabelecimento da insuficiência cardíaca avançada podem melhorar a evolução clínica destes doentes. Os autores apresentam o caso de uma mulher com tumor neuroendócrino do ovário e doença carcinoide cardíaca muito sintomática que foi submetida a resseção tumoral seguida de valvuloplastia. A doente demonstrou uma marcada melhoria clínica e tem permanecido livre de doença e assintomática.