Markedly increased duodenal villous surface apoptosis in patients taking pre-exposure prophylaxis (PrEP) against human immunodeficiency virus.

AIMS: Pre-exposure prophylaxis (PrEP) consists of combination antiretroviral therapy and is increasingly utilized to prevent human immunodeficiency virus (HIV) in high-risk populations. Two index cases noted during routine care showed markedly increased duodenal villous surface apoptosis in patients on PrEP. We sought to examine the prevalence of this finding and identify any clinicopathologic correlations. METHODS: Gastrointestinal biopsy specimens from 23 male patients aged 18-40 years taking PrEP and 23 control patients were reviewed. Patients with HIV, inflammatory gastrointestinal diseases, and celiac disease were excluded. Apoptoses were counted on surface epithelium and deep crypts. The highest apoptotic body count per tissue fragment was recorded. Clusters were defined as groups of ≥5 apoptoses. Apoptotic counts between patients taking PrEP and controls were compared using t-tests. RESULTS: In PrEP patients, the median age was 35 years (range 25-40) and 83% (19/23) were white. The control patients were demographically similar (median age: 32 years [range 23-40]; 70% [16/23] white). Duodenal apoptosis in villous surface epithelium was increased in PrEP patients, with 14/23 (60.9%) patients having ≥10 surface apoptoses compared to 2/23 (8.7%) controls (P = 2.1 × 10-3 ) and 14/23 (61%) having clusters compared to 3/23 (13%) controls (P = 2.0 × 10-3 ). There was no significant association between increased surface apoptosis or clusters and clinical symptoms or duration of PrEP use. CONCLUSION: Markedly increased villous surface apoptosis, particularly in clusters, is often seen in the duodenum of patients taking PrEP. Although the mechanism and significance are unknown, knowledge of this peculiar finding may prevent unnecessary additional testing.

Capecitabine-induced Gastrointestinal Injury Shows a Graft-Versus-Host Disease (GVHD)-like Pattern.

Capecitabine is a commonly used oral chemotherapeutic agent. Gastrointestinal (GI) side effects are clinically well-known, however, the histopathologic changes have not been comprehensively studied. This study describes the largest case series (8 patients) characterizing the histopathology of capecitabine-induced GI injury. All patients were adults (median age: 64.5 y, range: 61 to 76 y) and there was gender parity. Patients were receiving treatment for malignancies of the colorectum (n=5), breast (n=1), pancreas (n=1), and appendix (n=1). All had GI symptoms, including 7 with diarrhea and abdominal pain and 1 with melena. Five of 8 (63%) showed graft-versus-host disease (GVHD)-like histologic changes in small intestinal and/or colonic biopsies characterized by crypt disarray and dropout, crypt atrophy, dilated crypts lined by attenuated epithelium, and increased crypt apoptosis. Neuroendocrine cell aggregates were present in 4 of 5 cases. Four of 5 showed patchy prominence in lamina propria eosinophils. One patient receiving concomitant radiation therapy had a small intestinal biopsy showing regenerative changes. Two patients had histologically unremarkable biopsies. On follow-up, capecitabine was discontinued or dose-reduced in all patients. Three of 5 patients with a GVHD-like pattern had clinical improvement, whereas 2 died shortly after biopsy. One with regenerative changes also had radiation dose reduction and improved clinically. Two with unremarkable biopsies improved symptomatically. In summary, capecitabine-related GI injury shows a GVHD-like pattern. Knowledge of this is important to confirm the diagnosis as patients typically improve with dose reduction or discontinuation of the drug.

Glycogenic hepatopathy is associated with type 1 diabetes mellitus in only a minority of cases in a contemporary adult population.

OBJECTIVES: This study examines the clinical-pathological profiles of patients with glycogenic hepatopathy in a contemporary cohort of patients at an adult acute care hospital. METHODS: Liver biopsies with glycogenic hepatopathy were retrieved from the departmental surgical pathology database, the histological findings were studied, and the clinical findings were reviewed. RESULTS: Five cases of glycogenic hepatopathy were found, including cases associated with type 1 diabetes mellitus (n = 1), type 2 diabetes mellitus (n = 1), corticosteroids (n = 2), and anorexia (n = 2, including the patient with type 1 diabetes). AST and ALT were normal to mildly elevated (13-115 U/L and 7-126 U/L, respectively). Trace ascites was present in two patients. Hepatomegaly was only present in the patient with type 1 diabetes at the time of diagnosis. CONCLUSIONS: Four of five cases were associated with etiologies other than type 1 diabetes, which is widely reported as the most common etiology of glycogenic hepatopathy. This study suggests that etiologies currently only rarely recognized may actually be more common causes of glycogenic hepatopathy than type 1 diabetes in a contemporary adult population. It is important not only to recognize that these rarely reported causes of glycogenic hepatopathy may be underrecognized, but that the clinical presentation may also be mild.

Aberrant p53 Expression in Gastric Biopsies and Resection Specimens Following Neoadjuvant Chemoradiation: A Diagnostic Pitfall.

Gastric mucosal biopsies and resections from patients treated with neoadjuvant radiation and/or chemotherapy are frequently encountered. These samples may show histologic features related to therapy including inflammation, ulceration, and epithelial atypia. In some cases, epithelial atypia may be marked, prompting the use of adjunct p53 immunohistochemistry. We examined p53 expression by immunohistochemistry in gastric mucosa following therapy.We evaluated the histology and p53 immunohistochemical expression in gastric mucosa from 57 resections and 3 mucosal biopsies, from 60 patients treated with radiation and/or chemotherapy for gastroesophageal carcinoma (n = 33) or pancreatic carcinoma (n = 27).We identified histomorphologic features of therapy-related epithelial changes in 50 of 60 cases (83%). Abnormal p53 expression was present at least focally in nearly half the cases (27 of 60 cases; 45%), all of which showed morphologic evidence of therapy-related epithelial changes. Neuroendocrine cell micronests were present in 37 of 60 cases (62%). Next-generation sequencing (NGS) of foci with therapy-related epithelial changes showing abnormal p53 expression and carcinoma from the same patient was attempted and yielded results in 1 patient. Interestingly, differing TP53 alterations in the patient's adenocarcinoma and in a histologically benign esophageal submucosal gland with therapy-related epithelial changes and abnormal p53 expression were identified.Our results demonstrate that abnormal p53 expression is relatively common in gastric mucosal samples following radiation and/or chemotherapy and suggest that p53 expression should be avoided when distinguishing therapy-related changes from dysplasia or carcinoma. Furthermore, our NGS results raise interesting biological questions, which may warrant further investigation.

Exploring the spectrum of serrated epithelium encountered in inflammatory bowel disease.

Patients with inflammatory bowel disease (IBD) are at an increased risk for colorectal cancer. Currently, dysplasia is the best marker of CRC risk. Assessing dysplasia is a challenging task for pathologists as the longstanding inflammation causes marked reactive cytologic changes and architectural distortion. Recent descriptions of nonconventional types of dysplasia in IBD have added to the complexity. In this review, we focus on the clinical, endoscopic, histologic, and molecular findings in lesions with serrated epithelium. Serrated epithelial change (SEC), sessile serrated lesion (SSL)-like, serrated lesion-not otherwise specified (SL-NOS), and traditional serrated adenoma (TSA)-like lesions all typically occur in patients with longstanding IBD with mean ages in the fifth-sixth decade. SEC is often encountered in nontargeted biopsies while the others form visible polyps. While serrated lesions have significant histologic overlap, subtle differences can help pathologists separate them. SEC has markedly distorted architecture with crypts losing perpendicular orientation to the muscularis mucosae. The crypts are goblet cell-rich and have irregular serrations that involve the full length of the crypt. SSL-like lesions are goblet cell poor and have microvesicular cytoplasm. Like their sporadic counterpart in non-IBD patients, these lesions have lateral growth at the crypt bases. TSA-like lesions are characterized by their villous architecture, ectopic crypts, pink cytoplasm, and hyperchromatic elongated nuclei. We also explore molecular findings that help in distinguishing these lesions, current knowledge on the association of each of these lesions with dysplasia and CRC, and future research needed to better characterize these entities.

Claudin-18.

CONTEXT.­: Claudin-18 is expressed in some gastric cancers. Clinical trials are evaluating it as a therapeutic target. OBJECTIVES.­: To evaluate claudin-18 expression in intestinal metaplasia, dysplasia, and adenocarcinoma of the distal esophagus/gastroesophageal junction and stomach and to evaluate claudin-18 expression in gastric and nongastric neuroendocrine tumors as a marker of gastric origin. DESIGN.­: Samples included gastroesophageal junction with intestinal metaplasia (n = 40), dysplasia (n = 54), and adenocarcinoma (n = 20) and stomach with intestinal metaplasia (n = 79), dysplasia (n = 43), and adenocarcinoma (n = 25). Additionally, gastric (n = 40) and nongastric (n = 322) neuroendocrine tumors were included. Claudin-18 expression was evaluated for any staining as positive and by meeting clinical trial inclusion criteria (≥2+ intensity in ≥50% of tumor). RESULTS.­: Claudin-18 staining was not significantly different across dysplasia categories in the gastroesophageal junction (P = .11) or stomach (P = .12). The rate of positive staining was higher in gastroesophageal junction than stomach for intestinal metaplasia (37 of 40 [92.5%] versus 37 of 79 [46.8%]; P < .001) and high-grade dysplasia (33 of 38 [86.8%] versus 9 of 16 [56.3%]; P = .03). Intestinal metaplasia showed staining in 7 of 37 autoimmune gastritis samples (18.9%) compared with 30 of 42 samples without autoimmune gastritis (71.4%) (P < .001). Adenocarcinoma showed similar staining in gastroesophageal junction (15 of 20; 75.0%) and stomach (17 of 25; 68.0%) (P = .85). Eighty percent (32 of 40) of gastric neuroendocrine tumors were positive for claudin-18 expression, with 57.5% (23 of 40) meeting clinical trial inclusion criteria. Comparatively, 0.62% (2 of 322) of nongastric neuroendocrine tumors showed staining (P < .001). CONCLUSIONS.­: Claudin-18 staining was similar in intestinal metaplasia, dysplasia, and adenocarcinoma. Claudin-18 was negative in most cases of intestinal metaplasia in autoimmune gastritis, indicating that intestinal metaplasia in this setting may differ from other forms. Claudin-18 was sensitive and specific for gastric origin in neuroendocrine tumors.

The Histopathology of Anorectal Neisseria gonorrhoeae Infection.

OBJECTIVES: Neisseria gonorrhoeae infection of the anorectal tract is often asymptomatic and infrequently biopsied, but pathologists can be tasked with identifying the histologic features of possible infection. The study was undertaken to better characterize clinical and morphologic features of confirmed anorectal gonococcal infection. METHODS: From 2011 to 2020, 201 positive gonococcal nucleic acid amplification testing samples from 174 patients collected from the distal colorectum and/or anus were matched to eight patients with concurrent biopsy specimens of the distal anorectum. Complete demographic, clinical, and infectious information was collected for each biopsied patient. The histomorphologic features of each biopsy were systematically tabulated. RESULTS: All eight gonococcal cases were obtained from men who have sex with men. Each case showed at least mild acute inflammation with moderate activity identified in one case with concurrent cytomegalovirus infection. Intense lymphoplasmacytic infiltration was not commonly seen (two of eight). Half of the cases showed mucosal ulceration, and seven of eight cases demonstrated lymphoid aggregates. CONCLUSIONS: The microscopic features are mild compared with other well-described types of infectious proctitis, with most cases displaying mild acute inflammation and scattered lymphoid aggregates. These findings highlight the importance of obtaining a complete patient history and recommending additional infectious workup even when only subtle changes are present.

Some Morphology Frontiers of Dysplasia in the Tubular Gastrointestinal Tract: The Rodger C. Haggitt Memorial Lecture.

This review, based on the content of the 2020 US Gastrointestinal Pathology Society's Rodger Haggitt Lecture, concerns an array of tubular gastrointestinal tract dysplastic or possible "predysplastic lesions" with an almost purely morphologic focus based on our collaborative efforts over the past few years. These processes include esophageal epidermoid metaplasia, Barrett esophagus-associated dysplasia, polypoid gastric dysplastic lesions, small intestinal dysplasia, and the ability of metastases to mimic it, the controversial "serrated epithelial change" encountered in the setting of long-standing ulcerative and Crohn colitis, and recently described anal columnar human papilloma virus-associated neoplasms.

The path(ology) from reflux oesophagitis to Barrett oesophagus to oesophageal adenocarcinoma.

This review seeks to summarise the steps in the path from reflux oesophagitis to Barrett oesophagus to oesophageal adenocarcinoma. The epidemiology, clinical presentation, definitions, pathological features, diagnostic pitfalls, and emerging concepts are reviewed for each entity. The histological features of reflux oesophagitis can be variable and are not specific. Cases of reflux oesophagitis with numerous eosinophils are difficult to distinguish from eosinophilic oesophagitis and other oesophagitides with eosinophils (Crohn's disease, medication effect, and connective tissue disorders). In reflux oesophagitis, the findings are often most pronounced in the distal oesophagus, the eosinophils are randomly distributed throughout the epithelium, and eosinophilic abscesses and degranulated eosinophils are rare. For reflux oesophagitis with prominent lymphocytes, clinical history and ancillary clinical studies are paramount to distinguish reflux oesophagitis from other causes of lymphocytic oesophagitis pattern. For Barrett oesophagus, the definition remains a hotly debated topic for which the requirement for intestinal metaplasia to make the diagnosis is not applied unanimously across the globe. Assessing for dysplasia is a challenging aspect of the histological interpretation that guides clinical management. We describe the histological features that we find useful in making this evaluation. Oesophageal adenocarcinoma has been steadily increasing in incidence and has a poor prognosis. The extent of invasion can be overdiagnosed due to a duplicated muscularis mucosae. We also describe the technical factors that can lead to challenges in distinguishing the mucosal and deep margins of endoscopic resections. Lastly, we give an overview of targeted therapies with emerging importance and the ancillary tests that can identify the cases best suited for each therapy.

Evaluation of tumor mutational burden in small early hepatocellular carcinoma and progressed hepatocellular carcinoma.

While researchers know that tumor mutational burden (TMB) is low in hepatocellular carcinoma (HCC), prior studies have not investigated TMB in cirrhosis, small early HCC and progressed HCC. HCC (n = 18) and cirrhosis (n = 6) cases were identified. TMB was determined by a 1.7 megabase, 409-gene next-generation sequencing panel. TMB values were defined as the number of nonsynonymous variants per megabase of sequence. There was no significant difference between cirrhosis versus small early HCC or between cohorts when stratified by size, early versus progressed, differentiation or morphology. There was a significant difference between cirrhosis and small early HCC versus progressed HCC (p = 0.045), suggesting TMB may be related to HCC progression. TMB similarities in small early HCC and background cirrhosis suggest TMB is not a useful tool for diagnosing small early HCC. Additional study is needed to address TMB in histological and molecular subsets of HCC.

Complete response to neoadjuvant pembrolizumab and capecitabine in microsatellite stable, Epstein-Barr virus-positive, locally advanced gastric adenocarcinoma: case report.

Immunotherapy has been established as a standard in select molecular subgroups of treatment-refractory advanced gastric cancer. However, its role in resectable gastric cancer where perioperative systemic therapy is the standard remains unclear. We present a case of a man who was diagnosed with resectable gastric cancer that was microsatellite stable but programmed death-ligand 1 (PD-L1) and Epstein-Barr Virus (EBV)-positive. Given extenuating circumstances of the SARS-CoV-2 pandemic, preferences to limit exposure to the healthcare setting, and the unique tumor molecular features, neoadjuvant pembrolizumab and capecitabine was pursued after multidisciplinary discussion. He was able to achieve a complete response to this neoadjuvant regimen with no further signs of radiographic or pathologic disease on follow-up. We highlight a dramatic response to this novel approach that represents among the first cases to support a potentially viable neoadjuvant chemoimmunotherapy strategy to resectable gastric cancer. In select patients, perioperative immunotherapy-based therapy may constitute a promising strategy in resectable gastric cancer and warrants further investigation.

Targeted next-generation sequencing supports serrated epithelial change as an early precursor to inflammatory bowel disease-associated colorectal neoplasia.

Serrated epithelial change (SEC) manifests in patients with long-standing inflammatory bowel disease (IBD) and is characterized by disorganized crypt architecture, irregular serrations, and goblet cell-rich epithelium. The serrated nature of SEC is reminiscent of serrated colorectal polyps, which frequently harbor KRAS/BRAF mutations. SEC is, however, not only histologically distinct from sporadic serrated polyps but also associated with colorectal neoplasia. Whether SEC is a precursor to IBD-associated neoplasia remains unclear. To further define the relationship of SEC with serrated colorectal polyps and IBD-associated neoplasia, we performed targeted next-generation sequencing on colorectal specimens to include the following: SEC without dysplasia/neoplasia (n = 10), SEC with separate foci of associated dysplasia/adenocarcinoma from the same patients (n = 17), and uninvolved mucosa (n = 10) from 14 patients. In addition, we molecularly profiled sessile serrated lesion (SSL)-like or serrated lesion, not otherwise specified (SL-NOS), specimens, from 11 patients who also had IBD. This control cohort included SSL-like/SL-NOS without dysplasia/neoplasia (n = 11), SSL-like/SL-NOS with associated low-grade dysplasia (n = 2), and uninvolved mucosa (n = 8). By next-generation sequencing, the most frequently mutated gene in SEC without neoplasia and associated dysplasia/adenocarcinoma from separate foci in the same patients was TP53. Recurrent TP53 mutations were present in 50% of SEC specimens without dysplasia/neoplasia. In addition, alterations in TP53 were detected at a prevalence of 71% in low-grade dysplasia, 83% in high-grade dysplasia, and 100% in adenocarcinoma. Paired sequencing of SEC and associated neoplasia revealed identical TP53 missense mutations for 3 patients. In contrast, 91% of SSL-like/SL-NOS specimens without dysplasia/neoplasia harbored KRAS/BRAF mutations, which were conserved in associated low-grade dysplasia. No genomic alterations were found in uninvolved mucosa from either patients with SEC or patients with SSL-like/SL-NOS. Based on our findings, we conclude SEC is distinct from SSL-like serrated colorectal lesions in patients with IBD and an early precursor to IBD-associated neoplasia that warrants colonoscopic surveillance.

Lymphogranuloma venereum (LGV) of the anorectum: evaluation of clinicopathological associations and the utility of a novel RNA in-situ hybridisation stain.

AIMS: Recent studies from multiple global regions have reported a resurgence of lymphogranuloma venereum (LGV) proctitis, which is caused by Chlamydia trachomatis (CT). LGV proctitis is histologically indistinguishable from other forms of sexually transmitted proctitis and is difficult to differentiate from inflammatory bowel disease. While immunohistochemical stains are available for syphilis, there is no commonly available stain for the tissue identification of CT. MATERIALS AND METHODS: From 200 positive CT nucleic acid tests (NAT) from anorectal swabs, we identified 12 patients with biopsies collected from the distal colorectum or anus within 90 days of the positive NAT. We collected basic demographic information and tabulated clinical and histological findings. We examined the performance of a novel RNA in-situ hybridisation (ISH) stain targeting CT 23s rRNA on these 12 cases and 10 controls from the anorectum. RESULTS: All 12 patients were male; nine were HIV+, two had concurrent gonococcal infection, one had concurrent syphilis and one had cytomegalovirus co-infection. The majority of biopsies (11 of 12) showed mild or moderate acute inflammation, had a prominent lymphoplasmacytic infiltrate (eight of 11) and lacked marked crypt distortion (10 of 10). The RNA ISH stain was positive in 10 of 12 cases (sensitivity 83%). One case showed equivocal staining. No controls showed definitive positive staining (specificity 100%). One had equivocal staining. CONCLUSION: Our series showed that anorectal LGV had similar histological findings to those of prior STI proctitis series predominantly comprised of syphilis. The novel RNA ISH stain was sensitive and specific and may show utility in differentiating types of STI proctitis.

Cell polarity (the 'four lines') distinguishes gastric dysplasia from epithelial changes in reactive gastropathy.

AIMS: Gastric dysplasia is a risk factor for synchronous and subsequent gastric carcinoma. Distinguishing gastric dysplasia from reactive changes is subject to interobserver disagreement and is a frequent reason for expert consultation. We previously used assessment of surface cell polarity (the 'four lines') as a key feature to decrease equivocal diagnoses in Barrett oesophagus. In the current study, we examined for the presence or absence of the four lines in gastric dysplasia and reactive gastropathy. MATERIALS AND METHODS: The study includes all (n = 91) in-house biopsies with at least gastric dysplasia from the surgical pathology archives of two academic institutions during a 5-year period from 2008 to 2012. A reactive gastropathy group (n = 60) was created for comparison. RESULTS: The dysplasia/neoplasia group was comprised of 14 biopsies of gastric foveolar-type dysplasia, 59 of intestinal-type dysplasia, 14 with dysplasia in fundic gland polyps, three pyloric gland adenomas and one oxyntic gland adenoma. Loss of surface cell polarity was seen in all 88 dysplasia cases with evaluable surface epithelium. All 57 reactive gastropathy cases with evaluable surface epithelium showed intact surface cell polarity except in focal areas directly adjacent to erosions in 17 cases, where the thin wisp of residual surface mucin could not be appreciated on haematoxylin and eosin. CONCLUSION: Surface cell polarity (the four lines) was lost in all gastric dysplasia biopsies with evaluable surface epithelium and maintained in all biopsies of reactive gastropathy. Caution should be taken in using this feature adjacent to erosions in reactive gastropathy.

New Names for Old Tumors.

OBJECTIVES: Previous studies described "clear cell" hepatocellular carcinoma (HCC), although definitions have varied. New clear cell subtypes of HCC have been proposed, including chromophobe (C-HCC), steatohepatitic (SH-HCC), and steatotic (S-HCC), and this study assessed the utility and clinical-pathologic profile of these subtypes. METHODS: Current histologic definitions, including 3 separate proposed definitions for SH-HCC, were applied to tumors previously characterized as clear cell HCC. Histologic and clinical variables were analyzed. RESULTS: Of 66 HCCs, 51 (77%) were classified using modern definitions, including 34 SH-HCCs, 15 S-HCCs, and 2 C-HCCs. Compared with the most permissive SH-HCC definition, the other 2 definitions designated 30 and 25 SH-HCCs (-12% and -26% cases, respectively). Unsurprisingly, S-HCC and SH-HCC were associated with steatotic clear cells (P < .0001). S-HCC was also more typically early type and low grade (P = .0017). The remaining unclassified clear cell HCCs were associated with flocculent (rather than steatotic or optically clear) cytoplasm (P < .0001) but otherwise demonstrated no discrete clinical-pathologic profile. CONCLUSIONS: Current definitions could be used to reclassify the majority of "clear cell" HCCs. The subtypes are significantly correlated with a few variables, suggesting valid differences of the subtypes, although additional study is warranted, particularly to standardize the definition of SH-HCC.

Endoscopic History and Provider Characteristics Influence Gastric Cancer Survival in Asian Americans.

Gastric carcinoma (GC) disproportionately affects Asian Americans. We examined whether history of upper gastrointestinal (GI) endoscopy was associated with lower stage at GC diagnosis among Asian Americans and whether origin of providers influenced referral for endoscopy. We employed Surveillance Epidemiology and End Results-Medicare data on Asian Americans diagnosed with GC in 2004-2013 (n = 1,554). Stage distribution, GI conditions at diagnosis, and history of endoscopy were compared between Asian ethnic groups. Multivariate logistic regression adjusting for age, sex, poverty level, tumor location, and histology was used to examine the association of ethnicity and endoscopic history with stage I disease at diagnosis of GC. Koreans were more likely to be diagnosed with stage I, T1a GC and have prior history of endoscopy, compared with other Asian ethnicities (24% vs. 8% for stage I, T1a; 40% vs. 15% for endoscopy). Patients with primary care providers of concordant ethnic origin were more likely to have history of endoscopy. Asian American patients with GC with history of endoscopy were more likely to be diagnosed with GC at stage I disease (adjusted OR, 3.07; 95% confidence interval, 2.34-4.02). Compared with other Asian Americans, Koreans were diagnosed with GC at earlier stages owing to common history of endoscopy, which was more often undergone by patients with primary care providers of concordant ethnic origin. Overall, upper GI endoscopy was associated with early detection of GC in Asian Americans. Novelty and Impact. It is well-established that Asian Americans in the United States are disproportionately affected by gastric cancer. In our study we found that Asian American patients treated by physicians of similar ethnic background are more likely to undergo upper GI endoscopy in the United States, leading to early detection of gastric cancer and longer survival. Given this, targeted endoscopic screening in Asian Americans should be considered for early detection of GC.

Master transcription factors form interconnected circuitry and orchestrate transcriptional networks in oesophageal adenocarcinoma.

OBJECTIVE: While oesophageal squamous cell carcinoma remains infrequent in Western populations, the incidence of oesophageal adenocarcinoma (EAC) has increased sixfold to eightfold over the past four decades. We aimed to characterise oesophageal cancer-specific and subtypes-specific gene regulation patterns and their upstream transcription factors (TFs). DESIGN: To identify regulatory elements, we profiled fresh-frozen oesophageal normal samples, tumours and cell lines with chromatin immunoprecipitation sequencing (ChIP-Seq). Mathematical modelling was performed to establish (super)-enhancers landscapes and interconnected transcriptional circuitry formed by master TFs. Coregulation and cooperation between master TFs were investigated by ChIP-Seq, circularised chromosome conformation capture sequencing and luciferase assay. Biological functions of candidate factors were evaluated both in vitro and in vivo. RESULTS: We found widespread and pervasive alterations of the (super)-enhancer reservoir in both subtypes of oesophageal cancer, leading to transcriptional activation of a myriad of novel oncogenes and signalling pathways, some of which may be exploited pharmacologically (eg, leukemia inhibitory factor (LIF) pathway). Focusing on EAC, we bioinformatically reconstructed and functionally validated an interconnected circuitry formed by four master TFs-ELF3, KLF5, GATA6 and EHF-which promoted each other's expression by interacting with each super-enhancer. Downstream, these master TFs occupied almost all EAC super-enhancers and cooperatively orchestrated EAC transcriptome. Each TF within the transcriptional circuitry was highly and specifically expressed in EAC and functionally promoted EAC cell proliferation and survival. CONCLUSIONS: By establishing cancer-specific and subtype-specific features of the EAC epigenome, our findings promise to transform understanding of the transcriptional dysregulation and addiction of EAC, while providing molecular clues to develop novel therapeutic modalities against this malignancy.

Solvent detergent treated pooled plasma and reduction of allergic transfusion reactions.

BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) patients have increased risk for allergic transfusion reactions (ATR) due to the number of plasma products they require. This study evaluated the efficacy of solvent detergent treated plasma (S/D treated plasma) to reduce ATRs. STUDY DESIGN AND METHODS: All TTP patients who presented from April 2014 to February 2015 and experienced a moderate-severe ATR to untreated plasma with TPE were switched to S/D treated plasma (Octaplas) for their remaining procedures and included in the study. Patient records were retrospectively reviewed. RESULTS: The overall ATR rate per procedure decreased from 35.0% (95% CI = 15.4%-59.2%) with untreated plasma to 1.4% ([1/73] 95% CI = 0.0%-7.4%) with S/D treated plasma. The moderate-severe ATR rate decreased from 20.0% ([4/20] 95% CI = 5.7%-43.7%) with untreated plasma to 0.0% ([0/73] 95% CI = 0.0%-4.9%) with S/D treated plasma. The overall ATR rate per plasma unit decreased from 2.6% (95%CI = 1.0%-5.1%) with untreated plasma to 0.1% (95% CI = 0.0%-0.4%) with S/D treated plasma. No patients experienced VTE while receiving untreated plasma. Four patients experienced VTE events while receiving S/D treated plasma. All patients who experienced a VTE had additional risk factors for VTE. CONCLUSION: S/D plasma has promise as an effective product to reduce the risk of ATRs in TTP patients. Given the high risk of ATR in TTP patients, consideration of S/D plasma instead of untreated plasma for TPE in these patients may be warranted, especially for patients with a history of moderate to severe ATR. More extensive studies are needed to confirm these findings.

Evaluation of Peritumoral Fibrosis in Metastatic Colorectal Adenocarcinoma to the Liver Using Digital Image Analysis.

Objectives: It is challenging to separate peritumoral fibrosis from fibrosis due to chronic liver disease in mass-directed liver biopsies. We evaluated the distance that peritumoral fibrosis extends from metastatic colorectal adenocarcinoma in liver. Methods: Peritumoral and distant uninvolved liver trichrome stains from 25 cases were analyzed using digital image analysis. Fibrosis was quantitated at concentric intervals from each tumor and in uninvolved liver. Results: There was a 3.9 fold (range 0.9-18.6) median increase in fibrosis in the first 0.5 mm of peritumoral liver compared to distant liver. Fibrosis levels returned to baseline at median 2.5 mm (interquartile range 1.5-5.0 mm) from tumor. Conclusions: Fibrosis is markedly increased in peritumoral liver. Fibrosis levels returned to baseline by 5 mm from tumor in approximately 75% of cases. Pathologists should be cautious of fibrosis in mass-directed liver biopsies without at least 5 mm of liver tissue distal to the mass.