Isolated nonspecific terminal ileitis: prevalence, clinical evolution and correlation with metachronous diagnosis of Crohn's disease: a retrospective study and review of the literature.

Background: The existing literature does not provide adequate guidance on the diagnosis and management of patients with nonspecific terminal ileitis, while data regarding the percentage of patients who ultimately develop Crohn's disease (CD) are scarce. We evaluated the prevalence and natural course of nonspecific terminal ileitis in patients who underwent colonoscopy during a 11-year period. Methods: All patients with endoscopic findings of terminal ileitis and nonspecific histological findings were included. Exclusion criteria were a clinical history of CD or any other disease that can cause terminal ileitis, or a recent history of using drugs implicated in lesions of the terminal ileum. Results: From 5353 colonoscopies, 92 patients with nonspecific terminal ileitis were identified (prevalence: 1.7%). Among these patients, 56 (61%) had available follow up for ≥6 months after the initial endoscopy. Main indications for endoscopy were chronic diarrhea (37.5%), screening endoscopy (23%), and abdominal pain (20%). Sixteen (29%) patients received medical treatment, while recession of symptoms was recorded in 19 of 43 symptomatic patients (44.1%). Twenty-three (41%) of the 56 patients underwent a second endoscopy and 15 (65.2%) cases had persistent endoscopic findings. Eleven (19.6%) of the 56 patients were eventually diagnosed with CD. The probability of CD diagnosis was significantly higher in patients with persistent symptoms (P=0.002) and endoscopic findings at follow up (P=0.038). Conclusions: Nonspecific terminal ileitis generally has a benign clinical course. However, patients with persistent symptoms and endoscopic lesions are at increased risk for subsequent development of CD.

Colonic mucosa barrier defects in collagenous and ischemic colitis.

AIMS: The subepithelial myofibroblasts (SEMFs) and the subepithelial band of macrophages (SEBM) are major components of the colonic mucosa barrier. Although their role in homeostasis is widely recognized, their contribution to disease states is largely unknown. Our aim was to explore histological characteristics of SEMFs and SEBM in collagenous and ischemic colitis in order to identify specific changes in distinct mucosa backgrounds lacking significant inflammation. METHODS: SEMFs, SEBM and lamina propria (LP) macrophages were identified immunohistochemically by alpha smooth muscle Actin and Cluster of Differentiation 68 respectively in 38 colonic biopsies [14 collagenous colitis (CC), 14 ischemic colitis (IC), 10 normal mucosa]. RESULTS: In CC, SEMFs were rarely detectable in the collagenous band while aSMA-negative pericryptal fibroblast-like cells appeared. In lower LP interconnecting SEMFs processes were formed. SEBM was preserved in areas with a collagenous layer up to 20 µm. In thicker layers, it was fragmented and gradually disappeared in parallel with engulfment of enlarged macrophages. LP macrophages were usually increased. In IC, slight SEMFs changes preceded discernible epithelial alterations. Rounding, disintegration and extinction of SEMFs constituted successive alterations coinciding with crypt shrinkage and denudation. SEBM displayed total or almost total abolishment in areas with crypt damage but also in sites with minimal changes and in adjacent normal mucosa. CONCLUSION: Our findings provide evidence of impairment of both mucosa barrier constituents in CC and IC. In CC, histological alterations are closely related to the collagenous layer which seems to affect SEMFs differentiation and migration as well as SEBM integrity. The early extinction of SEBM in IC is indicative of its high sensitivity to hypoxia and hypoperfusion.

MFGE-8 identified in fetal mesenchymal-stromal-cell-derived exosomes ameliorates acute hepatic failure pathology.

Liver transplantation is the gold-standard therapy for acute hepatic failure (AHF) with limitations related to organ shortage and life-long immunosuppressive therapy. Cell therapy emerges as a promising alternative to transplantation. We have previously shown that IL-10 and Annexin-A1 released by amniotic fluid human mesenchymal stromal cells (AF-MSCs) and their hepatocyte progenitor-like (HPL) or hepatocyte-like (HPL) cells induce liver repair and downregulate systemic inflammation in a CCl4-AHF mouse model. Herein, we demonstrate that exosomes (EXO) derived from these cells improve liver phenotype in CCl4-induced mice and promote oval cell proliferation. LC-MS/MS proteomic analysis identified MEFG-8 in EXO cargo that facilitates rescue of AHF by suppressing PI3K signaling. Administration of recombinant MFGE-8 protein also reduced liver damage in CCl4-induced mice. Clinically, MEFG-8 expression was decreased in liver biopsies from AHF patients. Collectively, our study provides proof-of-concept for an innovative, cell-free, less immunogenic, and non-toxic alternative strategy for AHF.

Liver Biopsy: To Do or Not to Do - A Single-Center Study.

INTRODUCTION: A variety of liver disorders are associated with characteristic histopathological findings that help in their diagnosis and treatment. However, percutaneous liver biopsy (PLB) is prone to limitations and complications. We evaluated all PLBs done in our hospital in a 13-year period, aiming to assess PLB's utility and complications. METHODS: All PLBs conducted in an internal medicine department of a tertiary university hospital in Athens, Greece, during a 13-year period were reviewed. Recorded data included demographic characteristics, laboratory results acquired on biopsy day, indication for liver biopsy, and occurrence of side effects. All patients were followed for 1 month post-hospital discharge for possible PLB-related complications. RESULTS: A total of 261 patients underwent PLB during the study period. The commonest indication of PLB was investigation of liver mass, followed by transaminasemia. PLB assisted in setting a diagnosis in 218 patients and was unhelpful in only 43, in 14 of them due to inadequate or inappropriate biopsy specimen. Complications attributable to PLB were rare, with 10 patients exhibiting pain, either at biopsy site or in the right shoulder, and 3 having bleeding episodes; no deaths were noted. CONCLUSIONS: Our study shows that PLB is still a powerful diagnostic tool in everyday practice, provided it is used when indicated.

Analysis of glucocorticoid receptor and microRNAs expression in pathological renal tissues.

Glucocorticoid receptor (GR) is expressed in normal renal podocytes; however, its expression differs among renal diseases. The expression of GR as well as its epigenetic regulators microRNA (miR)30a, miR24 and miR370 was studied in the renal tissues of patients with systemic lupus nephritis (LN), minimal changes disease (MCD) and pauci-immune glumeronephritis (PIN). A total of 51 patients undergoing renal biopsy and 22 nephrectomised controls with no history of parenchymal renal disease were recruited from the Clinic of Nephrology and Renal Transplantation of General Laikon hospital between November 2016 and March 2019. All patients were newly-diagnosed and they were naïve of any treatment. The mRNA and protein expression were analyzed through reverse transcription-quantitative PCR and immunohistochemistry respectively. Written consent was obtained from all participants. GR mRNA expression was significantly reduced in all pathological samples compared with the 'normal' renal tissues used as controls (P=0.023 for LN, P=0.05 for MCD and P=0.004 for PIN). Similarly, GR protein expression was lower in all pathological samples (>6 GR positive podocytes/glomerulus in 50% of patients with LN and MCD and 18% with PIN) compared with controls (>6 positive podocytes/glomerulus in all the controls). PIN samples presented significantly lower GR mRNA and protein expression compared with LN and MCD samples. No significant differences were observed in the miR30a expression when comparing pathological with 'normal' renal samples. miR24 and miR370 expression demonstrated statistically significant difference in all pathological compared with 'normal' tissues. Moreover, GR expression was not significantly associated with either LN disease activity score or the response to the treatment. GR and miR24 expression was significantly reduced whereas miR370 significantly increased in all pathological compared with 'normal' renal tissues implying their protentional role in nephritis pathogenesis and treatment. Analysis of larger samples are required for more robust statistical analysis.

Clinical and Oncological Impact of the Toll-like Receptor-3 and -4 in Esophageal and Gastro-esophageal Junction Adenocarcinoma.

BACKGROUND/AIM: Esophageal and gastro-esophageal junction cancer is a major cause of cancer-related mortality, with poor prognosis. Toll-like receptors (TLRs) play a significant role in the innate immune system; their increased expression has been associated with esophageal adenocarcinoma. This study aimed to determine the association between TLR-3 and TLR-4 expression with clinical and oncological outcomes of patients that underwent esophagectomy for cancer. PATIENTS AND METHODS: This is a retrospective analysis of prospectively collected data from consecutive patients within a 2-year period. Primary endpoints of the study were the assessment of the expression of TLR-3 and TLR-4 in primary tumors as well as in metastatic lymph nodes. Secondary endpoints were the correlation of TLR-3 and TLR-4 values with the clinical, pathological, and oncological outcomes. RESULTS: A significantly higher expression of TLR-3 and TLR-4 in primary tumors and metastatic-lymph nodes was observed. There was a significant association between TLR-3 expression and T-stage, as well as TLR-4 expression and grade of differentiation in the primary site. Additionally, metastatic-lymph node TLR-4 expression was significantly correlated with N-stage. A strong correlation between TLR-4 expression and overall or progression-free survival rates was detected. CONCLUSION: This study found a significantly increased TLR expression in malignant tissue/metastatic lymph nodes, as well as a significant positive correlation between TLRs and worse clinical outcomes. TLRs have a pivotal role in the inflammation pathway in the esophagus and during esophageal carcinogenesis. This study highlights the need for further investigation into TLR-mediated signaling pathways and their potential role as diagnostic and therapeutic targets.

Impact of Minimally Invasive Intrathoracic Hand-sewn Esophago-gastric Anastomosis in Esophagectomy for Cancer.

BACKGROUND/AIM: Ivor Lewis esophagectomy is considered the gold standard approach for the treatment of distal esophageal and gastro-esophageal junction Siewert I-II tumors. Minimally invasive esophagectomy has provided improved outcomes compared to the open approach, offering reduced morbidity, and improved clinical and oncological outcomes. This is the largest study so far reporting the impact of hand-sewn esophago-gastric anastomosis in the prone position, during the 2-stage totally minimally invasive esophagectomy. PATIENTS AND METHODS: A retrospective analysis of prospectively collected data regarding consecutive patients with distal-esophageal and gastroesophageal junction Siewert I-II tumors was conducted. All patients underwent 2-stage totally minimally invasive esophagectomy with thoracoscopic manual esophago-gastric anastomosis in the prone position. Clinical and oncological outcomes were examined and presented. RESULTS: One hundred and fifty consecutive patients were included in the study during a period of five years. Median operative time was 320 minutes, while median time for the construction of anastomosis was 45 minutes. We had no conversions to open esophagectomy. Anastomotic leakage was observed in 2% of the patients; anastomotic stricture rate reached up to 7.33%. Respiratory complications were seen in 18% and cardiac complications in 6.66% of the patients, respectively. Thirty-day mortality and 90-day mortality rates were 1.33% and 2.66%, accordingly. CONCLUSION: Intrathoracic hand-sewn esophago-gastric anastomosis in the prone position during totally minimally invasive esophagectomy has provided favorable outcomes in our cohort of patients, offering significantly reduced anastomotic-related complications, compared to other standardized techniques. Further prospective comparative studies are needed, to better interpret and amplify our results, that may lead to a paradigm shift regarding the preferred method of reconstruction from esophageal surgeons.

The effect of hepatocyte growth factor on intestinal adaption in an experimental model of short bowel syndrome.

PURPOSE: Nowadays, the standard therapy for patients with short bowel syndrome is parenteral nutrition (PN). Various growth factors have been tested to achieve weaning from prolonged PN administration. We evaluated the effect of hepatocyte growth factor (HGF) on structural intestinal adaptation and cell proliferation in a rat model of SBS. METHODS: Thirty Sprague-Dawley rats were divided into three groups; group A rats (sham) underwent bowel transection, group B rats underwent a 75% bowel resection, and group C rats underwent the same procedure but were treated postoperatively with HGF. Histopathologic parameters of intestinal adaptation were determined, while microarray and rt-PCR analyses of ileal RNA were also performed. RESULTS: Treatment with HGF resulted in significant increase in body weight, while the jejunal and ileal villus height and crypt depth were increased in HGF rats (36%, p < 0.05 and 27%, p < 0.05 respectively). Enterocyte proliferation was also significantly increased in HGF rats (21% p < 0.05). Microarray and quantitative rt-PCR analyses showed that the genes hgfac, rac 1, cdc42, and akt 1 were more than twofold up-regulated after HGF treatment. CONCLUSION: HGF emerges as a growth factor that enhances intestinal adaptation. The future use of HGF may potentially reduce the requirement for PN in SBS patients.

Digging into the NGS Information from a Large-Scale South European Population with Metastatic/Unresectable Pancreatic Ductal Adenocarcinoma: A Real-World Genomic Depiction.

Despite ongoing oncological advances, pancreatic ductal adenocarcinoma (PDAC) continues to have an extremely poor prognosis with limited targeted and immunotherapeutic options. Its genomic background has not been fully characterized yet in large-scale populations all over the world. Methods: Replicating a recent study from China, we collected tissue samples from consecutive Greek patients with pathologically-confirmed metastatic/unresectable PDAC and retrospectively investigated their genomic landscape using next generation sequencing (NGS). Findings: From a cohort of 409 patients, NGS analysis was successfully achieved in 400 cases (56.50% males, median age: 61.8 years). Consistent with a previous study, KRAS was the most frequently mutated gene in 81.50% of tested samples, followed by TP53 (50.75%), CDKN2 (8%), and SMAD4 (7.50%). BRCA1/2 variants with on-label indications were detected in 2%, and 87.50% carried a variant associated with off-label treatment (KRAS, ERBB2, STK11, or HRR-genes), while 3.5% of the alterations had unknown/preliminary-studied actionability (TP53/CDKN2A). Most of HRR-alterations were in intermediate- and low-risk genes (CHEK2, RAD50, RAD51, ATM, FANCA, FANCL, FANCC, BAP1), with controversial actionability: 8% harbored a somatic non-BRCA1/2 alteration, 6 cases had a high-risk alteration (PALB2, RAD51C), and one co-presented a PALB2/BRCA2 alteration. Elevated LOH was associated with HRR-mutated status and TP53 mutations while lowered LOH was associated with KRAS alterations. Including TMB/MSI data, the potential benefit from an NGS-oriented treatment was increased from 1.91% to 13.74% (high-MSI: 0.3%, TMB > 10 muts/MB: 12.78%). TMB was slightly increased in females (4.75 vs. 4.46 muts/MB) and in individuals with age > 60 (4.77 vs. 4.40 muts/MB). About 28.41% showed PD-L1 > 1% either in tumor or immune cells, 15.75% expressed PD-L1 ≥ 10%, and only 1.18% had PD-L1 ≥ 50%. This is the largest depiction of real-world genomic characteristics of European patients with PDAC, which offers some useful clinical and research insights.

The Expression Patterns and Implications of MALAT1, MANCR, PSMA3-AS1 and miR-101 in Esophageal Adenocarcinoma.

Esophageal adenocarcinoma (EAC) is a malignant tumor with poorly understood molecular mechanisms. This study endeavors to elucidate how the long non-coding RNAs (lncRNAs) MALAT1, MANCR and PSMA3-AS1, as well as the microRNA miR-101, exhibit specific expression patterns in the pathogenesis and prognosis of EAC. A total of 50 EAC tissue samples (tumors and lymph nodes) and a control group comprising 26 healthy individuals were recruited. The samples underwent quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analyses. The relative expression levels of MALAT1, MANCR, PSMA3-AS1, and miR-101 were ascertained and correlated with various clinicopathological parameters including TNM staging, tumor characteristics (size and grade of the tumor) lymphatic invasion, disease-free (DFS) and overall survival (OS) of EAC patients. Quantitative analyses revealed that MALAT1 and MANCR were significantly upregulated in EAC tumors and positive lymph nodes when compared to control tissues (p < 0.05). Such dysregulations correlated positively with advanced lymphatic metastases and a higher N stage. DFS in the subgroup of patients with negative lymph nodes was higher in the setting of low-MANCR-expression patients compared to patients with high MANCR expression (p = 0.02). Conversely, miR-101 displayed a significant downregulation in EAC tumors and positive lymph nodes (p < 0.05), and correlated negatively with advanced tumor stage, lymphatic invasion and the grade of the tumor (p = 0.006). Also, patients with low miR-101 expression showed a tendency towards inferior overall survival. PSMA3-AS1 did not demonstrate statistically significant alterations (p > 0.05). This study reveals MALAT1, MANCR, and miR-101 as putative molecular markers for prognostic evaluation in EAC and suggests their involvement in EAC progression.

Hereditary Diffuse Gastric Cancer: A 2022 Update.

Gastric cancer is ranked fifth among the most commonly diagnosed cancers, and is the fourth leading cause of cancer-related deaths worldwide. The majority of gastric cancers are sporadic, while only a small percentage, less than 1%, are hereditary. Hereditary diffuse gastric cancer (HDGC) is a rare malignancy, characterized by early-onset, highly-penetrant autosomal dominant inheritance mainly of the germline alterations in the E-cadherin gene (CDH1) and ß-catenin (CTNNA1). In the present study, we provide an overview on the molecular basis of HDGC and outline the essential elements of genetic counseling and surveillance. We further provide a practical summary of current guidelines on clinical management and treatment of individuals at risk and patients with early disease.

Inflammatory fibroid polyp of the anus in a 12-month-old girl: Case report and review of the literature.

Inflammatory fibroid polyp (IFP) is a rare, usually solitary and intraluminal polypoid benign tumour that can affect any part of the gastrointestinal (GI) tract. Its aetiology is unknown and clinical presentation depends on the site of involvement. We present the case of a 12-month-old girl with IFP and review all reported cases of IFP in children and adolescents <18 years. A 12-month-old girl presented with rectal bleeding. The patient underwent colonoscopy which revealed an anus polyp. Surgical resection was performed and histopathological examination of the specimen showed features of IFP. A literature review of 20 cases (including ours) between 1966 and January 2022 is also presented. To our knowledge, this is the youngest reported patient with IFP and the first in the anal area.

The Role of Toll-like Receptors in Esophageal Cancer.

Esophageal adenocarcinoma (AC) develops through Barrett's esophagus (BE) and columnar dysplasia, preceded by gastro-esophageal reflux disease (GERD). Incidence of esophageal squamous cell carcinoma (SCC) is increased with tobacco smoking and alcohol abuse. Toll-like receptors (TLRs) can act as prognostic factors and potential therapeutic targets of esophageal cancer. TLRs, an important family of pattern recognition receptors, allow immune cells to recognize pathogens triggering inflammation. TLR-signaling pathway activates signaling-elements, regulating inflammatory response, possibly correlating to carcinogenesis. In the normal esophagus, TLRs recognize molecular patterns on microorganisms and inflammatory response produced by tissue-damage. TLR3, TLR4, TLR5, and TLR9 are expressed at increasing levels from GERD to AC. TLR4 is a mediator of proliferation in AC, while TRL1 and TLR4 over-expression in AC is related to poor prognosis and metastasis. Additionally, TLR3, TLR4, and TLR9 expression in SCC has been associated with lymphatic metastasis, whereas increased expression of TLR7 and TLR9 has been also associated with advanced disease. It seems that TLR expression can indicate esophageal metaplasia, dysplasia, and cancer. Herein, we aimed to present all available data regarding the relation of TLRs and esophageal cancer. They may represent significant and valuable diagnostic or prognostic factors for esophageal cancer.

Histological diversity of anti-PD1-induced colitis.

AIM: Histological data on anti-PD1-associated colitis are limited, while the colitis subtypes are still not clearly defined and different terms are being used. The aim of the study was to explore the histopathology of anti-PD1-induced colitis. METHODS AND RESULTS: Colonic biopsies from 9 patients under anti-PD1 agents presenting diarrhea were examined. Histological evaluation revealed colitis of mild to moderate severity in almost all cases. Four distinct dominant histological patterns were identified with nearly the same incidence: Ulcerative colitis (UC)-like (n=2), GVHD-like (n=2), collagenous-like (n=3) and a mixed colitis pattern combining features of microscopic and UC-like colitis (n=2). The latter was additionally characterized by high crypt epithelium apoptosis and cryptitis with mixed inflammatory infiltrate. Thickening of the subepithelial band of collagen, detachment of the surface epithelium and increased apoptosis of the crypt epithelium were commonly encountered features, irrespective of colitis subtype. CD4/CD8 ratio was lower in the "combined" and higher in the GVHD-like subtype. CONCLUSIONS: Anti-PD1-induced colitis is expressed by different patterns of injury which share distinct histological hallmarks harboring diagnostic value, while a "combined" colitis subtype is being established. The histological alterations are indicative of mucosa barrier damage after antΙ-PD1 treatment and its participation in the pathogenetic process.

Laying the groundwork for the Biobank of Rare Malignant Neoplasms at the service of the Hellenic Network of Precision Medicine on Cancer.

Biobanks constitute an integral part of precision medicine. They provide a repository of biospecimens that may be used to elucidate the pathophysiology, support diagnoses, and guide the treatment of diseases. The pilot biobank of rare malignant neoplasms has been established in the context of the Hellenic Network of Precision Medicine on Cancer and aims to enhance future clinical and/or research studies in Greece by collecting, processing, and storing rare malignant neoplasm samples with associated data. The biobank currently comprises 553 samples; 384 samples of hematopoietic and lymphoid tissue malignancies, 72 samples of pediatric brain tumors and 97 samples of malignant skin neoplasms. In this article, sample collections and their individual significance in clinical research are described in detail along with computational methods developed specifically for this project. A concise review of the Greek biobanking landscape is also delineated, in addition to recommended technologies, methodologies and protocols that were integrated during the creation of the biobank. This project is expected to re­enforce current clinical and research studies, introduce advances in clinical and genetic research and potentially aid in future targeted drug discovery. It is our belief that the future of medical research is entwined with accessible, effective, and ethical biobanking and that our project will facilitate research planning in the '­omic' era by contributing high­quality samples along with their associated data.

Methotrexate-Related Liver Cirrhosis in Psoriatic Arthritis: A Case Report and Review of the Literature.

Methotrexate is an anchor-drug for the treatment of inflammatory arthritides affecting peripheral joints, such as rheumatoid and psoriatic arthritis (PsA), but also for other immune-mediated diseases like psoriasis. Although it is generally a well-tolerated drug, adverse effects often occur. Reversible derangement of liver function test is the most common laboratory adverse event. However, in some cases, liver cirrhosis and/or fibrosis can occur. Besides, many of these diseases like PsA and psoriasis are closely linked with clinical conditions and risk factors that also contribute to liver damage/cirrhosis, such as increased body mass index, dyslipidaemia and diabetes mellitus (DM). It has been hypothesised that the aforementioned risk factors along with methotrexate usage can act synergistically, causing liver damage in these patients. Herein, we describe a PsA patient with DM who developed fatal liver cirrhosis after 10 years of treatment with MTX. We also review the literature about the liver toxicity of MTX in the context of PsA and psoriasis, describing concurring risk factors and histopathological findings. PubMed and Scopus were searched, without date limits. The keywords "methotrexate" AND "psoriatic arthritis" OR "psoriasis" AND "Liver damage" OR "liver fibrosis" OR "cirrhosis" were used. We found that although fibrosis/cirrhosis is present in about 10-25% of the patients, MTX can rarely cause liver damage itself. However, it can exert its effect when other factors, like increased alcohol consumption and obesity coexist. Prospective studies are needed, specifically examining the hepatotoxicity of MTX in individuals with immune-mediated diseases.