Portosinusoidal Vascular Disorder: A Heretofore Unrecognized Manifestation of Sickle Cell Disease?

Portosinusoidal vascular disorder (PSVD) is a recently proposed histopathologic entity that encompasses a spectrum of often subtle hepatic microvascular lesions and related microarchitectural abnormalities. Clinical manifestations may arise years after histologic diagnosis and include extrahepatic portal vein thrombosis and portal hypertension. While the histopathologic features of PSVD have been associated with numerous clinical conditions, most notably prothrombotic/vasculopathic disorders, PSVD has not yet been described in sickle cell disease. This gap is striking given the central role of microvascular dysfunction in sickle cell disease and well-described patterns of hepatic injury and dysfunction in this population. This case series is the first to explore the prevalence and pathogenesis of PSVD in sickle cell disease. Forty-one diagnostically adequate liver biopsies from patients with sickle cell disease were identified across the archives of 5 tertiary medical centers. All biopsies exhibited at least 1 histopathologic feature associated with PSVD (mean 3.8 features/case). Overall, 90.2% of patients met the criteria for a diagnosis of PSVD based on the presence of specific histopathologic and/or clinical findings. Immunohistochemical stains for von Willebrand factor, CD34, and glutamine synthetase were performed on 36 cases (87.8%). Aberrant (centrilobular sinusoidal) CD34 and von Willebrand factor staining was present in 97.2% and 86.1% of cases, respectively. Glutamine synthetase reactivity was at least mildly decreased in zone 3 hepatocytes in 52.8% of cases. We posit that chronic erythrocyte sickling results in dysfunction and remodeling of the portal microvasculature, culminating in regression of zone 3 hepatocytes. The presence of PSVD may explain, at least in part, the hepatic dysfunction observed in this patient population. These patients may also benefit from extended clinical surveillance for portal hypertension and other complications. While subtle and prone to overdiagnosis, the features of PSVD should be carefully considered when interpreting liver biopsies from patients with sickle cell disease.

A Case Report and Literature Review of a Rare Jejunal Solitary Peutz-Jeghers-Type Polyp Resected Endoscopically in an Elderly Patient Presenting with Subacute Gastrointestinal Bleeding.

Solitary Peutz-Jeghers-type polyp (SPJP) is a rare hamartomatous lesion. It is considered a different entity from Peutz-Jeghers syndrome despite similar histopathological findings. It can be found in the GI tract but rarely in the jejunum. Jejunal SPJP is susceptible to necrosis, ulceration, and intussusception, resulting in GI bleeding or small bowel obstruction. We describe a case of subacute gastrointestinal bleeding secondary to jejunal SPJP to share our approach to this challenging case using therapeutic endoscopy. An 81-year-old male patient with a history of atrial fibrillation on warfarin with stable therapeutic INR levels presented with a 1-week history of melena, generalized fatigue, and shortness of breath on exertion and was found to have profound iron deficiency anemia. Esophageal gastroduodenoscopy and colonoscopy failed to identify the source of bleeding; however, single-balloon enteroscopy detected a 4 cm polyp with a stalk in the proximal jejunum. Endoscopic polypectomy was performed, and the whole polyp was removed. Histopathological examination was consistent with Peutz-Jeghers polyp. The genetic analysis was negative for STK11 mutation. Follow-up magnetic resonance enterography and video capsule endoscopy did not reveal any other polypoid lesion in the GI tract. The patient's symptoms resolved gradually, and his hemoglobin level returned back to normal levels within 6 months. To our knowledge, this is the first case of endoscopic polypectomy during balloon-assisted enteroscopy for jejunal SPJP.

A Deep Learning-Based Approach to Estimate Paneth Cell Granule Area in Celiac Disease.

CONTEXT.­: Changes in Paneth cell numbers can be associated with chronic inflammatory diseases of the gastrointestinal tract. So far, no consensus has been achieved on the number of Paneth cells and their relevance to celiac disease (CD). OBJECTIVES.­: To compare crypt and Paneth cell granule areas between patients with CD and without CD (non-CD) using an artificial intelligence-based solution. DESIGN.­: Hematoxylin-eosin-stained sections of duodenal biopsies from 349 patients at the McGill University Health Centre were analyzed. Of these, 185 had a history of CD and 164 were controls. Slides were digitized and NoCodeSeg, a code-free workflow using open-source software (QuPath, DeepMIB), was implemented to train deep learning models to segment crypts and Paneth cell granules. The total area of the entire analyzed tissue, epithelium, crypts, and Paneth cell granules was documented for all slides, and comparisons were performed. RESULTS.­: A mean intersection-over-union score of 88.76% and 91.30% was achieved for crypt areas and Paneth cell granule segmentations, respectively. On normalization to total tissue area, the crypt to total tissue area in CD was increased and Paneth cell granule area to total tissue area decreased when compared to non-CD controls. CONCLUSIONS.­: Crypt hyperplasia was confirmed in CD compared to non-CD controls. The area of Paneth cell granules, an indirect measure of Paneth cell function, decreased with increasing severity of CD. More importantly, our study analyzed complete hematoxylin-eosin slide sections using an efficient and easy to use coding-free artificial intelligence workflow.

Establishment of persistent enteric mycobacterial infection following streptomycin pre-treatment.

Mycobacterium avium subsp. paratuberculosis (MAP) is the causative agent of paratuberculosis, a chronic gastrointestinal disease affecting ruminants. This disease remains widespread in part due to the limitations of available diagnostics and vaccines. A representative small animal model of disease could act as a valuable tool for studying its pathogenesis and to develop new methods for paratuberculosis control, but current models are lacking. Streptomycin pre-treatment can reduce colonization resistance and has previously been shown to improve enteric infection in a Salmonella model. Here, we investigated whether streptomycin pre-treatment of mice followed by MAP gavage could act as a model of paratuberculosis which mimics the natural route of infection and disease development in ruminants. The infection outcomes of MAP were compared to M. avium subsp. hominissuis (MAH), an environmental mycobacterium, and M. bovis and M. orygis, two tuberculous mycobacteria. Streptomycin pre-treatment was shown to consistently improve bacterial infection post-oral inoculation. This model led to chronic MAP infection of the intestines and mesenteric lymph nodes (MLNs) up to 24-weeks post-gavage, however there was no evidence of inflammation or disease. These infection outcomes were found to be specific to MAP. When the model was applied to a bacterium of lesser virulence MAH, the infection was comparatively transient. Mice infected with bacteria of greater virulence, M. bovis or M. orygis, developed chronic intestinal and MLN infection with pulmonary disease similar to zoonotic TB. Our findings suggest that a streptomycin pre-treatment mouse model could be applied to future studies to improve enteric infection with MAP and to investigate other modifications underlying MAP enteritis.

Crohn's Disease Features in Anastomotic Biopsies from Patients With and Without Crohn's Disease: Diagnostic and Prognostic Value.

Endoscopic evidence of disease activity is a critical predictor of clinical relapse in patients with Crohn's disease (CD), and histologic disease activity is evolving as a similarly important end point for patient management. However, classical morphologic features of CD may overlap with postoperative inflammatory changes, confounding the evaluation of anastomotic biopsies. There is a clear unmet need for better characterization of diagnostic and clinically significant histologic features of CD in these surgically altered sites. We evaluated ileocolonic and colocolonic/rectal anastomotic biopsies performed at 3 academic institutions in patients with and without CD. The biopsies were blindly assessed for CD histologic features and correlated to clinical and endoscopic characteristics. In CD patients, the presence of each feature was correlated with the subsequent clinical exacerbation or relapse. We obtained anastomotic biopsies from 208 patients, of which 109 were operated on for CD and 99 for another indication (neoplasia [80%], diverticular disease (11%), and other [9%]). Mean time since surgery was 10 years (0-59; 14 years for CD [1-59], 6 years for non-CD [0-33]). Endoscopic inflammation was noted in 52% of cases (68% for CD and 35% for non-CD). Microscopic inflammation was present in 74% of cases (82% for CD and 67% for non-CD). Only discontinuous lymphoplasmacytosis (P < .001) and pyloric gland metaplasia (P = .04) occurred significantly more often in CD patients. However, none of the histologic features predicted clinical disease progression. In subset analysis, the presence of histologic features of CD in nonanastomotic biopsies obtained concurrently in CD patients was significantly associated with relapse (P = .03). Due to extensive morphologic overlap between CD and postoperative changes and the lack of specific histologic features of relapse, biopsies from anastomotic sites are of no value in predicting clinical CD progression. Instead, CD activity in biopsies obtained away from anastomotic sites should be used for guiding endoscopic sampling and clinical management.

Relation between mismatch repair status, chemoresponse, survival and anatomic location in gastroesophageal adenocarcinoma.

BACKGROUND: It has recently been reported that mismatch repair (MMR) status and microsatellite instability (MSI) status in gastroesophageal carcinomas predict surgical, chemotherapeutic and immunotherapeutic outcomes; however, there is extensive variability in the reported incidence and clinical implications of MMR/MSI status in gastroesophaegal adenocarcinomas. We characterized a Canadian surgical patient cohort with respect to MMR status, clinicopathologic correlates and anatomic tumour location. METHODS: We investigated MMR and BRAF V600E status of gastroesophaegal adenocarcinomas in patients who underwent gastrectomy or esophagectomy with extended (D2) lymphadenectomy at a single centre between 2011 and 2019. We correlated patterns of MMR expression in the overall cohort and in anatomic location-defined subgroups with treatment response and overall survival using multivariate analysis. RESULTS: In all, 226 cases of gastroesophaegal adenocarcinoma (63 esophageal, 98 gastroesophageal junctional and 65 gastric) were included. The MMR-deficient (dMMR) immunophenotype was found in 28 tumours (12.3%) (15 junctional [15.3%], 13 gastric [20.0%] and none of the esophageal). The majority (25 [89%]) of dMMR cases showed MLH1/PMS2 loss without concurrent BRAF V600E mutation. Two MSH2/ MSH6-deficient gastric tumours and 1 MSH6-deficient junctional tumour were detected. The pathologic response to preoperative chemotherapy was comparable in the dMMR and MMR-proficient (pMMR) cohorts. However, dMMR status was associated with significantly longer median overall survival than pMMR status (5.8 yr v. 2.4 yr, hazard ratio [HR] 1.91, 95% confidence interval [CI] 1.06-3.46), particularly in junctional tumours (4.6 yr v. 1.9 yr, HR 2.97, 95% CI 1.27-6.94). CONCLUSION: Our study shows that MMR status has at least prognostic value, which supports the need for biomarker testing in gastroesophageal adenocarcinomas, including junctional adenocarcinomas. This highlights the clinical significance of determining the MMR status in all adenocarcinomas of the upper gastrointestinal tract. Response to induction chemotherapy, however, was not influenced by MMR status.

Vedolizumab-Associated Hypereosinophilia and Hepatoxicity.

Vedolizumab, which is approved for the treatment of ulcerative colitis, has been associated with drug-induced liver injury because of an unclear mechanism. We describe the case of a 29-year-old man who presented with abnormal liver enzymes and peripheral hypereosinophilia after vedolizumab initiation. A complete workup for causes of hepatitis and hypereosinophilia was negative, and liver biopsy showed signs compatible with drug-induced liver injury. After the withdrawal of vedolizumab, the patient's eosinophil count and liver enzymes normalized. As vedolizumab becomes more prominent, it is important to understand the potential side-effect profile of vedolizumab.

Impact of Endoscopic and Histologic Activity on Disease Relapse in Ulcerative Colitis.

INTRODUCTION: Endoscopic healing is currently considered the main target in the management of ulcerative colitis (UC). There are conflicting data about the role of histology as a stricter treatment objective. We aim at evaluating the additional benefit of histologic remission over endoscopic remission. METHODS: We performed a prospective observational study at the McGill University Health Center. We enrolled adult patients with UC in clinical remission for at least 3 months undergoing a colonoscopy. Endoscopic disease activity was based on the Mayo endoscopic score. Rectal biopsies were obtained, and the histologic activity was evaluated using the Geboes score (active disease defined as Geboes score ≥ 3.1) with the addition of assessing the presence of basal plasmacytosis. Patients were followed up for 12 months for disease relapse defined as a partial Mayo score of > 2. At the time of relapse or end of follow-up, all patients underwent repeat endoscopic evaluation. The primary end point was clinical relapse. RESULTS: Two hundred fifty-three patients were included. The presence of basal plasmacytosis was associated with relapse (adjusted odd ratio = 2.07, 95% confidence interval [CI] 1.06-4.18, P = 0.042). Time to clinical relapse was significantly higher for patients with Mayo endoscopic score > 0 with adjusted hazard ratio = 2.65, 95% CI 1.31-5.39, and P = 0.007. Time to clinical relapse was not significantly higher for Geboes score ≥ 3.1 with adjusted hazard ratio = 1.29, 95% CI 0.67-2.49, and P = 0.45. DISCUSSION: Active histologic disease did not affect time to clinical relapse in patients with UC who achieved endoscopic remission while the presence of basal plasmacytosis is associated with relapse.

A novel mouse model of PMS2 founder mutation that causes mismatch repair defect due to aberrant splicing.

Hereditary non-polyposis colorectal cancer, now known as Lynch syndrome (LS) is one of the most common cancer predisposition syndromes and is caused by germline pathogenic variants (GPVs) in DNA mismatch repair (MMR) genes. A common founder GPV in PMS2 in the Canadian Inuit population, NM_000535.5: c.2002A>G, leads to a benign missense (p.I668V) but also acts as a de novo splice site that creates a 5 bp deletion resulting in a truncated protein (p.I668*). Individuals homozygous for this GPV are predisposed to atypical constitutional MMR deficiency with a delayed onset of first primary malignancy. We have generated mice with an equivalent germline mutation (Pms2c.1993A>G) and demonstrate that it results in a splicing defect similar to those observed in humans. Homozygous mutant mice are viable like the Pms2 null mice. However, unlike the Pms2 null mice, these mutant mice are fertile, like humans homozygous for this variant. Furthermore, these mice exhibit a significant increase in microsatellite instability and intestinal adenomas on an Apc mutant background. Rectification of the splicing defect in human and murine fibroblasts using antisense morpholinos suggests that this novel mouse model can be valuable in evaluating the efficacy aimed at targeting the splicing defect in PMS2 that is highly prevalent among the Canadian Inuits.

Pancreatic Cancer Progression in a Patient With Lynch Syndrome Receiving Immunotherapy: A Cautionary Tale.

Pancreatic ductal adenocarcinomas (PDACs) with DNA mismatch repair deficiency (MMRd) respond preferentially to immune checkpoint inhibitors (ICIs). However, a subset of MMRd PDACs does not respond to these agents. This report describes a patient with PDAC who experienced rapid disease progression suggestive of hyperprogressive disease. The case involved a 63-year-old man carrying a pathogenic germline PMS2 mutation who developed metastatic PDAC. His tumor showed isolated loss of PMS2 expression by immunohistochemistry (IHC). He was treated with pembrolizumab, but his disease rapidly progressed. Whole-genome and transcriptome sequencing of a liver metastasis biopsy, acquired at disease progression, showed a retained wild-type PMS2 allele and hallmarks of microsatellite stability, including low tumor mutational burden and low MSIsensor score. PCR-based microsatellite instability (MSI) testing of the treatment-naïve tumor showed microsatellite stability. The ICI-treated tumor had a lower density of CD8+ T-cell infiltration than the treatment-naïve tumor, which is contrary to the expected evolution with ICI responsiveness. Through this case and a review of the literature, we highlight the low penetrance of PMS2 germline mutations in PDAC and discuss pitfalls in ascertaining MMRd and MSI based on IHC testing alone. An orthogonal confirmatory assay is warranted in the presence of uncommon immunophenotypes, such as isolated PMS2 loss, to optimize selection of patients with PDAC for immunotherapy.

Faecal Calprotectin Predicts Endoscopic and Histological Activity in Clinically Quiescent Ulcerative Colitis.

INTRODUCTION: Faecal calprotectin [FC] is a reliable surrogate marker for disease activity in ulcerative colitis [UC]; however, there are no consensus cut-off values for remission. The study aim was to correlate FC with Mayo Endoscopic Score [MES] and histological disease activity of UC patients in clinical remission. METHODS: Our study recruited adult UC patients at the McGill IBD Center between 2013 and 2017. Patients in clinical remission [partial Mayo score ≤2], undergoing endoscopy for disease activity or dysplasia surveillance, were enrolled. Before bowel preparation, FC was collected. MES was documented during colonoscopy. Biopsies were taken; histological activity was assessed using Geboes score and the presence of basal plasmacytosis. RESULTS: A total of 185 patients were recruited. The area under the curve [AUC] in receiver operating characteristic [ROC] analysis to predict MES 1-3 [from 0] was 0.743 [95% CI 0.67-0.82; p <0.001] with an FC cut-off value 170 µg/g [64% sensitivity, 74% specificity], and to predict MES 2-3 [from 0-1] was 0.722 [95% CI 0.61-0.83; p <0.001] with an FC cut-off value 170 µg/g [69% sensitivity, 65% specificity]. To differentiate MES 0 from MES 1, an FC value 130 µg/g yields a 70% sensitivity and 68% specificity. The AUC in ROC analysis to predict Geboes <3.1 was 0.627 [95% CI 0.55-0.71; p = 0.003], with an FC value 135 µg/g [54% sensitivity, 69% specificity]. CONCLUSIONS: In this large study, FC ≥170 µg/g predicts endoscopic activity and FC ≥135 µg/g predicts histological activity. Therefore in clinical practice, lower faecal calprotectin thresholds can be chosen to optimise identification of patients with ongoing endoscopic and histological disease activity.

Safety and Feasibility of Using Magnetic Resonance Imaging Criteria to Identify Patients With "Good Prognosis" Rectal Cancer Eligible for Primary Surgery: The Phase 2 Nonrandomized QuickSilver Clinical Trial.

IMPORTANCE: Chemoradiotherapy (CRT), followed by surgery, is the recommended approach for stage II and III rectal cancer. While CRT decreases the risk of local recurrence, it does not improve survival and leads to poorer functional outcomes than surgery alone. Therefore, new approaches to better select patients for CRT are important. OBJECTIVE: To conduct a phase 2 study to evaluate the safety and feasibility of using magnetic resonance imaging (MRI) criteria to select patients with "good prognosis" rectal tumors for primary surgery. DESIGN, SETTING, AND PARTICIPANTS: Prospective nonrandomized phase 2 study at 12 high-volume colorectal surgery centers across Canada. From September 30, 2014, to October 21, 2016, a total of 82 patients were recruited for the study. Participants were patients newly diagnosed as having rectal cancer with MRI-predicted good prognosis rectal cancer. The MRI criteria for good prognosis tumors included distance to the mesorectal fascia greater than 1 mm; definite T2, T2/early T3, or definite T3 with less than 5 mm of extramural depth of invasion; and absent or equivocal extramural venous invasion. INTERVENTIONS: Patients with rectal cancer with MRI-predicted good prognosis tumors underwent primary surgery. MAIN OUTCOMES AND MEASURES: The primary outcome was the proportion of patients with a positive circumferential resection margin (CRM) rate. Assuming a 10% baseline probability of a positive CRM, a sample size of 75 was estimated to yield a 95% CI of ±6.7%. RESULTS: Eighty-two patients (74% male) participated in the study. The median age at the time of surgery was 66 years (range, 37-89 years). Based on MRI, most tumors were midrectal (65% [n = 53]), T2/early T3 (60% [n = 49]), with no suspicious lymph nodes (63% [n = 52]). On final pathology, 91% (n = 75) of tumors were T2 or greater, 29% (n = 24) were node positive, and 59% (n = 48) were stage II or III. The positive CRM rate was 4 of 82 (4.9%; 95% CI, 0.2%-9.6%). CONCLUSIONS AND RELEVANCE: The use of MRI criteria to select patients with good prognosis rectal cancer for primary surgery results in a low rate of positive CRM and suggests that CRT may not be necessary for all patients with stage II and III rectal cancer. TRIAL REGISTRATION: ISRCTN.com identifier: ISRCTN05107772.

Pathology of Gastrointestinal and Liver Complications of Hematopoietic Stem Cell Transplantation.

CONTEXT.­: Despite advances in therapeutic and preventive measures, hematopoietic stem cell transplant recipients remain at risk for a variety of gastrointestinal and liver complications. OBJECTIVE.­: To detail the pathologic features of the various gastrointestinal and liver complications occurring after hematopoietic stem cell transplantation in relation to their clinical context. The specific complications covered include graft-versus-host disease, mycophenolate mofetil-induced injury, timeline of infections, neutropenic enterocolitis, gastrointestinal thrombotic microangiopathy, sinusoidal obstruction syndrome, hepatic iron overload, and the controversy around cord colitis syndrome. DATA SOURCES.­: The content of this article is based on pertinent peer-reviewed articles in PubMed, relevant textbooks, and on the authors' personal experiences. CONCLUSIONS.­: The final histopathologic diagnosis requires the integration of clinical and histologic findings and the exclusion of other competing causes of injury. Review of the clinical data, including the original disease pretransplant, the type of transplant, the timing of the gastrointestinal and/or liver manifestations, the timing of the biopsy after transplant, the presence of graft-versus-host disease in other organs and sites, the list of drug regimens, and the clinical and laboratory evidence of infection, is the key to reaching the proper histologic diagnosis.

Reflex Testing for Germline BRCA1, BRCA2, PALB2, and ATM Mutations in Pancreatic Cancer: Mutation Prevalence and Clinical Outcomes From Two Canadian Research Registries.

PURPOSE: We investigated the translational value of reflex testing for germline mutations in four homology-directed DNA repair predisposition genes (BRCA1, BRCA2, PALB2, and ATM) in consecutive patients with pancreatic adenocarcinoma. METHODS: One hundred fifty patients with French-Canadian (FC) ancestry were evaluated for founder mutations, and 114 patients were subsequently assessed by full gene sequencing and multiplex ligation-dependent probe amplification for nonfounder mutations. Two hundred thirty-six patients unselected for ancestry were also assessed for mutations by full gene sequencing. RESULTS: The FC founder mutation prevalence among the 150 patients was 5.3% (95% CI, 2.6% to 10.3%), and the nonfounder mutation prevalence across the four genes among the 114 patients tested was 2.6% (95% CI, 0.6% to 7.8%). In the case series unselected for ancestry, 10.0% (95% CI, 2.7% to 26.4%) of patients reporting Ashkenazi Jewish (AJ) ancestry carried an AJ founder mutation, with no nonfounder mutations identified. The mutation prevalence among patients without FC/AJ ancestry was 4.9% (95% CI, 2.6% to 8.8%). Mutations were more frequent in patients diagnosed at ≤ 50 years of age (P = .03) and in patients with either two or more first- or second-degree relatives with pancreas, breast, ovarian or prostate cancer, or one such relative and a second primary of one of these cancer types (P < .001). BRCA1, BRCA2, and PALB2 carriers with late-stage (III or IV) disease had an overall survival advantage (P = .049), particularly if treated with platinum-based chemotherapies (P = .030). CONCLUSION: Considering these results, we recommend reflex founder mutation testing of patients with FC/AJ ancestry and full gene sequencing of patients who are ≤ 50 years or meet the identified family history criteria. Reflex testing of all incident patients for these four genes may become justified as full gene sequencing costs decline.

A multidimensional integration analysis reveals potential bridging targets in the process of colorectal cancer liver metastasis.

Approximately 9% of cancer-related deaths are caused by colorectal cancer. Liver metastasis is a major factor for the high colorectal cancer mortality rate. However, the molecular mechanism underlying colorectal cancer liver metastasis remains unclear. Using a global and multidimensional integration approach, we studied sequencing data, protein-protein interactions, and regulation of transcription factor and non-coding RNAs in primary tumor samples and liver metastasis samples to unveil the potential bridging molecules and the regulators that functionally link different stages of colorectal cancer liver metastasis. Primary tumor samples and liver metastasis samples had modules with significant overlap and crosstalk from which we identified several bridging genes (e.g. KNG1 and COX5B), transcription factors (e.g. E2F4 and CDX2), microRNAs (e.g. miR-590-3p and miR-203) and lncRNAs (e.g. lincIRX5 and lincFOXF1) that may play an important role in the process of colorectal cancer liver metastasis. This study enhances our understanding of the genetic alterations and transcriptional regulation that drive the metastatic process, but also provides the methodology to guide the studies on other metastatic cancers.

Sinusoidal endotheliitis as a histological parameter for diagnosing acute liver allograft rejection.

AIM: To investigated the feasibility of using sinusoidal endotheliitis (SE) as a histological marker for liver allograft rejection. METHODS: We compared the histological features of 88 liver allograft biopsies with acute cellular rejection (ACR) and 59 cases with no evidence of ACR. SE was scored as: (1) focal linear lifting up of the endothelial cells by lymphocytes with no obvious damage to adjacent hepatocytes; (2) focal disruption of the endothelial lining by a cluster of subendothelial lymphocytes (a group of > 3 lymphocytes); and (3) severe confluent endotheliitis with hemorrhage and adjacent hepatocyte loss. RESULTS: The sensitivity and specificity of SE was 81% and 85%, respectively. Using SE as the only parameter, the positive predictive value for ACR (PPV) was 0.89, whereas the negative predictive value for ACR (NPV) was 0.75. The correlation between RAI and SE was moderate (R = 0.44, P < 0.001) (Figure 3A), whereas it became strong (R = 0.65, P < 0.001) when correlating SE with the venous endotheliitis activity index only. CONCLUSION: Our data suggest that SE scoring could be a reliable and reproducible supplemental parameter to the existing Banff schema for diagnosing acute liver allograft rejection.

[Corrigendum] Weighted gene co-expression network analysis of colorectal cancer liver metastasis genome sequencing data and screening of anti-metastasis drugs.

After the publication of the article, the authors noted that the affiliation for Dr Hani Choudhry is wrong. The correct affiliation should be as follows: Bo Gao1, Qin Shao2, Hani Choudhry3, Victoria Marcus2, Kung Dong5, Jiannis Ragoussis4 and Zu-Hua Gao2, 1Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China; 2Department of Pathology, The Research Institute of McGill University Health Center, Montreal, Québec H4A 3J1, Canada; 3Department of Biochemistry, Faculty of Science, Cancer and Mutagenesis Unit, King Fahd Center for Medical Research, Center of Innovation in Personalized Medicine, King Abdulaziz University, Jeddah, Saudi Arabia; 4McGill University and Genome Quebec Innovation Centre, Montreal, Québec H3B 1S6, Canada; 5Department of Pathology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, P.R. China. [the original article was published in the International Journal of Oncology 49: 1108-1118, 2016; DOI: 10.3892/ijo.2016.3591].

Weighted gene co-expression network analysis of colorectal cancer liver metastasis genome sequencing data and screening of anti-metastasis drugs.

Approximately 9% of cancer-related deaths are caused by colorectal cancer (CRC). CRC patients are prone to liver metastasis, which is the most important cause for the high CRC mortality rate. Understanding the molecular mechanism of CRC liver metastasis could help us to find novel targets for the effective treatment of this deadly disease. Using weighted gene co-expression network analysis on the sequencing data of CRC with and with metastasis, we identified 5 colorectal cancer liver metastasis related modules which were labeled as brown, blue, grey, yellow and turquoise. In the brown module, which represents the metastatic tumor in the liver, gene ontology (GO) analysis revealed functions including the G-protein coupled receptor protein signaling pathway, epithelial cell differentiation and cell surface receptor linked signal transduction. In the blue module, which represents the primary CRC that has metastasized, GO analysis showed that the genes were mainly enriched in GO terms including G-protein coupled receptor protein signaling pathway, cell surface receptor linked signal transduction, and negative regulation of cell differentiation. In the yellow and turquoise modules, which represent the primary non-metastatic CRC, 13 downregulated CRC liver metastasis-related candidate miRNAs were identified (e.g. hsa-miR-204, hsa-miR-455, etc.). Furthermore, analyzing the DrugBank database and mining the literature identified 25 and 12 candidate drugs that could potentially block the metastatic processes of the primary tumor and inhibit the progression of metastatic tumors in the liver, respectively. Data generated from this study not only furthers our understanding of the genetic alterations that drive the metastatic process, but also guides the development of molecular-targeted therapy of colorectal cancer liver metastasis.

Decreased PCSK9 expression in human hepatocellular carcinoma.

BACKGROUND: The management of hepatocellular carcinoma (HCC) is limited by the lack of adequate screening biomarkers and chemotherapy. In response, there has been much interest in tumor metabolism as a therapeutic target. PCSK9 stimulates internalization of the LDL-receptor, decreases cholesterol uptake into hepatocytes and affects liver regeneration. Thus, we investigated whether PCSK9 expression is altered in HCC, influencing its ability to harness cholesterol metabolism. METHODS: Thirty-nine patients undergoing partial hepatectomy or liver transplantation for HCC were consented for use of HCC tissue to construct a tissue microarray (TMA). The TMA was immunostained for PCSK9. Imagescope software was used to objectively determine staining, and assess for pathological and clinical correlations. PCSK9 and LDL receptor mRNA levels in flash-frozen HCC and adjacent liver tissue were determined by quantitative RT-PCR. Serum PCSK9 levels were determined by ELISA. RESULTS: By immunohistochemistry, there was significantly lower expression of PCSK9 in HCC as compared to adjacent cirrhosis (p-value < 0.0001, wilcoxon signed-rank test). Significantly greater staining of PCSK9 was present in cirrhosis compared to HCC (p value <0.0001), and positivity (percentage of positive cells) was significantly greater in cirrhosis compared to HCC (p-value < 0.0001). Conversely, significantly higher expression of LDL-R was present in HCC as compared to the adjacent cirrhosis (p-value < 0.0001). There was no significant correlation of PCSK9 staining with grade of tumor, but there were significant correlations between PCSK9 staining and stage of fibrosis, according to spearman correlation test. PCSK9 mRNA levels were relatively less abundant within HCC compared to adjacent liver tissue (p-value =0.08) and normal control tissue (p-value =0.02). In contrast, serum PCSK9 levels were significantly increased among patients with HCC compared to those with chronic liver disease without HCC (p-value =0.029). LDL receptor mRNA was consistantly greater in HCC when compared to normal control tissue (p-value = 0.06) and, in general, was significantly greater in HCC when compared to adjacent liver (p-value = 0.04). CONCLUSIONS: The decreased expression of PCSK9 and conversely increased LDL-R expression in HCC suggests that HCC modulates its local microenvironment to enable a constant energy supply. Larger-scale studies should be conducted to determine whether PCSK9 could be a therapeutic target for HCC.