Identification and validation of fusidic acid and flufenamic acid as inhibitors of SARS-CoV-2 replication using DrugSolver CavitomiX.

In this work, we present DrugSolver CavitomiX, a novel computational pipeline for drug repurposing and identifying ligands and inhibitors of target enzymes. The pipeline is based on cavity point clouds representing physico-chemical properties of the cavity induced solely by the protein. To test the pipeline's ability to identify inhibitors, we chose enzymes essential for SARS-CoV-2 replication as a test system. The active-site cavities of the viral enzymes main protease (Mpro) and papain-like protease (Plpro), as well as of the human transmembrane serine protease 2 (TMPRSS2), were selected as target cavities. Using active-site point-cloud comparisons, it was possible to identify two compounds-flufenamic acid and fusidic acid-which show strong inhibition of viral replication. The complexes from which fusidic acid and flufenamic acid were derived would not have been identified using classical sequence- and structure-based methods as they show very little structural (TM-score: 0.1 and 0.09, respectively) and very low sequence (~ 5%) identity to Mpro and TMPRSS2, respectively. Furthermore, a cavity-based off-target screening was performed using acetylcholinesterase (AChE) as an example. Using cavity comparisons, the human carboxylesterase was successfully identified, which is a described off-target for AChE inhibitors.

Carditis: a relevant marker of gastroesophageal reflux disease. Data from a prospective central European multicenter study on histological and endoscopic diagnosis of esophagitis (histoGERD trial).

The columnar-lined mucosa at the gastroesophageal junction may contain an inflammatory infiltrate, commonly referred to as carditis (or cardia gastritis). The etiology of carditis is not entirely clear since published data are conflicting. Some authors believe it to be secondary to gastroesophageal reflux disease (GERD) and others to Helicobacter pylori gastritis. This prospective study aims at clarifying the relationship between carditis and the histological, clinical, and endoscopic findings of GERD, in a large cohort of individuals negative for H. pylori infection. Eight hundred and seventy-three individuals (477 females and 396 males, median age 53 years) participated in this study. Biopsy material was systematically sampled from above and below the gastroesophageal junction. Reflux-associated changes of the esophageal squamous epithelium were assessed according to the Esohisto consensus guidelines. Grading of carditis was performed according to the Updated Sydney System, known from the histological evaluation of gastritis. In total, 590 individuals (67.5%) had chronic carditis. Of these, 468 (53.6%) had mild chronic inflammation, with 321 individuals (68.6%) showing no or minimal changes on endoscopic examination (Los Angeles Categories N and M). The presence of chronic carditis was associated with several GERD-related parameters of the esophageal squamous epithelium (P < 0.0001), and data retained statistical significance even when analysis was restricted to individuals with mild chronic carditis and/or endoscopically normal mucosa. Chronic carditis was also associated with the presence of intestinal metaplasia (P < 0.0001). In addition, chronic carditis had a statistically significant association with patients' symptoms of GERD (P = 0.0107). This observation remained valid for mild chronic carditis in all patients (P = 0.0038) and in those with mild chronic carditis and normal endoscopic mucosa (P = 0.0217). In conclusion, chronic carditis appears to be the immediate consequence of GERD, correlating with patients' symptoms and endoscopic diagnosis. These results are valid in individuals with nonerosive reflux disease, which indicates a higher sensitivity of histological diagnosis. Our findings may impact the routine assessment of reflux patients.

[Heterotopic tissue in the gastrointestinal tract]. / Ektopes Gewebe des Gastrointestinaltraktes.

Heterotopia of the gastrointestinal tract is a common finding. This is due to the complex embryogenesis and the relative ease to detect heterotopic tissue during endoscopy. The reason for biopsy is mostly to rule out neoplasms or to define specific causes of inflammation. Heterotopic tissue can occur in any location of the gastrointestinal tract. The most frequent are gastric heterotopia, pancreatic heterotopia, and heterotopia of Brunner's gland. On rare occasions, heterotopic tissue of salivary gland type as well as heterotopias of apocrine glands, thyroid, and prostatic tissue have been described. The most frequently involved organs are the small intestine, in particular the duodenum, the esophagus, and the stomach. Heterotopia of the large bowel occurs exclusively in the rectum. Most heterotopias do not cause symptoms and are easily diagnosed by biopsy and histology. However, depending on location, size, and the kind of underlying heterotopic tissue, they may cause significant complications, such as inflammation, ulceration and perforation, obstruction, intussusception, and severe life-threatening bleeding. Another rare but significant complication is neoplasia. Gastric heterotopias may give rise to pyloric gland adenomas within the bowel or rarely adenocarcinomas of the esophagus. Pancreatic heterotopia can be complicated by ductal type pancreatic adenocarcinomas, by acinus cell carcinomas, by intraductal papillary mucinous neoplasias, and also by endocrine tumors. The present paper summarizes our current knowledge about heterotopias in a topographic clinico-pathological manner.

Recommendations for reporting tumor budding in colorectal cancer based on the International Tumor Budding Consensus Conference (ITBCC) 2016

Tumor budding is a well-established independent prognostic factor in colorectal cancer but a standardized method for its assessment has been lacking. The primary aim of the International Tumor Budding Consensus Conference (ITBCC) was to reach agreement on an international, evidence-based standardized scoring system for tumor budding in colorectal cancer. The ITBCC included nine sessions with presentations, a pre-meeting survey and an e-book covering the key publications on tumor budding in colorectal cancer. The 'Grading of Recommendation Assessment, Development and Evaluation' method was used to determine the strength of recommendations and quality of evidence. The following 10 statements achieved consensus: tumor budding is defined as a single tumor cell or a cell cluster consisting of four tumor cells or less (22/22, 100%). Tumor budding is an independent predictor of lymph node metastases in pT1 colorectal cancer (23/23, 100%). Tumor budding is an independent predictor of survival in stage II colorectal cancer (23/23, 100%). Tumor budding should be taken into account along with other clinicopathological features in a multidisciplinary setting (23/23, 100%). Tumor budding is counted on H&E (19/22, 86%). Intratumoral budding exists in colorectal cancer and has been shown to be related to lymph node metastasis (22/22, 100%). Tumor budding is assessed in one hotspot (in a field measuring 0.785 mm2) at the invasive front (22/22, 100%). A three-tier system should be used along with the budding count in order to facilitate risk stratification in colorectal cancer (23/23, 100%). Tumor budding and tumor grade are not the same (23/23, 100%). Tumor budding should be included in guidelines/protocols for colorectal cancer reporting (23/23, 100%). Members of the ITBCC were able to reach strong consensus on a single international, evidence-based method for tumor budding assessment and reporting. It is proposed that this method be incorporated into colorectal cancer guidelines/protocols and staging systems.

Regulation of apoptosis is impaired in atrophic gastritis associated with gastric cancer.

BACKGROUND: Gastric premalignant conditions, atrophic gastritis (AG) and intestinal metaplasia (IM) are characterized by an increase of proliferation and a reduction of apoptosis in epithelial cells. The epithelial cell kinetics in AG and IM in gastric mucosa adjacent to gastric cancer is still unclear. The aim of this study was to evaluate the epithelial cell turnover and expression of proliferation and apoptosis-related genes in gastric cancer (GC) and adjacent mucosa with atrophic gastritis or intestinal metaplasia (AG/IM GC+), as well as in atrophic gastritis or intestinal metaplasia mucosa of patients without GC (AG/IM GC-) and in control biopsy samples of non-transformed gastric mucosa (Control). METHODS: We selected 58 patients (M: F = 34:24; age range 20-84 years, median 61.06 years) with 4 well defined histological conditions: 20 controls with histological finding of non-transformed gastric mucosa, 20 patients with AG or IM (AG/IM GC-), and 18 patients with intestinal type gastric adenocarcinoma (GC) and AG or IM in the adjacent mucosa (3 cm from the macroscopic tumour margin, AG/IM GC+). We performed an immunohistochemical staining of Ki67 and TUNEL and quantitative RT-PCR to determine the expression of PCNA and Bax/Bcl-2. RESULTS: The immunohistochemical expression of Ki67 and TUNEL in AG/IM GC- was significantly increased compared to not transformed gastric mucosa (p < 0.0001) but not compared to AG/IM in gastric mucosa adjacent to GC. Levels of Bcl-2 were reduced in GC and AG/IM GC- compared to controls as well as in AG/IM GC- compared to AG/IM in mucosa adjacent to GC+ (p < 0.05). Proliferation and apoptosis markers did not correlate with H.pylori status in our study population. CONCLUSIONS: In AG/IM associated with GC, no significant changes in the epithelial cell turnover were detected. Decreased Bcl-2 gene expression signified atrophic gastritis and IM in presence of cancer, as well as intestinal type gastric adenocarcinoma.

[Pathology of the R1 classification in visceral cancer surgery]. / Pathologie der R1-Klassifikation in der viszeralonkologischen Chirurgie.

The completeness of tumor removal is described in the residual tumor classification (R classification). The R category of a surgical specimen reflects the effects of treatment, influences further treatment decisions and is associated with patient survival. Thorough pathological examination of all resection planes, including the circumferential margin, is necessary for accurate classification.

[Hereditary gastric and pancreatic cancer]. / Hereditäres Magen- und Pankreaskarzinom.

Most cases of gastric and pancreatic cancer are sporadic, but familial clustering can be observed in approximately 10% of cases. Hereditary gastric cancer accounts for a very low percentage of cases (1-3%) and two syndromes have been characterized: hereditary diffuse gastric cancer (HDGC) and gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS). Gastric and pancreatic cancer can develop in the setting of other hereditary cancer syndromes, such as hereditary breast and ovarian cancer syndrome (HBOC), Li-Fraumeni syndrome, Lynch syndrome, familial adenomatous polyposis (FAP), or various hamartomatous polyposis syndromes, including juvenile polyposis and Peutz-Jeghers syndrome. Patients with hereditary pancreatitis carry an increased risk of cancer (40-55%).

[Precursors of gastric cancer : Dysplasia and adenoma]. / Vorstufen des Magenkarzinoms : Dysplasie und Adenom.

Gastric cancer develops from preneoplastic and early neoplastic precursor lesions. In particular, the intestinal type according to the Lauren classification is driven by chronic inflammation and progresses via a chronic gastritis - atrophy/metaplasia - dysplasia - carcinoma sequence. Staging of the extent of atrophy (OLGA) or intestinal metaplasia (OLGIM) enables risk stratification and determines follow-up investigations according to the management of precancerous conditions and lesions in the stomach (MAPS) international guidelines. True adenomatous lesions are relatively rare in the stomach. Three major types need to be considered: the intestinal type (tubular, tubulovillous and villous), the foveolar type (with superficial gastric differentiation) and the pyloric gland adenoma (with deep gastric differentiation). The intestinal type is the most common and needs to be differentiated from nonneoplastic polypoid regenerative hyperplasia, but also from well-differentiated tubular adenocarcinoma.

Impact of the angulus biopsy for the detection of gastric preneoplastic conditions and gastric cancer risk assessment.

BACKGROUND: Gastric atrophy and intestinal metaplasia (IM) are preneoplastic conditions in the development of gastric cancer. Histopathological assessment is based on the updated Sydney system and superordinate staging systems, operative link on gastritis assessment (OLGA) and operative link on gastritis assessment using IM (OLGIM), all requiring a biopsy from the incisura angularis (angulus). AIM: To determine the value of the angulus biopsy for the detection of preneoplastic conditions and cancer risk evaluation using OLGA and OLGIM prospectively. METHODS: Biopsies from antrum (2), angulus (1) and corpus (2) were obtained from 213 patients (age 19-94 years, median 54 years, female to male ratio 138:75) undergoing upper endoscopy. Histological assessment according to the updated Sydney system, OLGA and OLGIM staging was performed by gastrointestinal pathologists. Statistical analysis used exact confidence limits for dichotomous variables and repeated measurement analysis of variance. RESULTS: 8% of the cases with atrophic gastritis and 3% with IM (17 vs 6/213) would have been missed without the angulus biopsy. More patients were diagnosed with a preneoplastic condition when the angulus biopsy was considered (13.1%, CI 8.9% to 18.4%), but the grade of atrophy, if present at both sides, did not vary significantly in angulus and antrum. OLGA and OLGIM scores dropped significantly when recalculated without the angulus (difference in means±SD 0.131±0.402 and 0.075±0.313, respectively). The impact on the identification of high-risk stages is limited. CONCLUSIONS: The angulus biopsy adds to the detection of mild gastric atrophy in particular. It allows identifying a small additional number of patients with high-risk gastritis.

Endoscopic submucosal dissection: European Society of Gastrointestinal Endoscopy (ESGE) Guideline

This Guideline is an official statement of the European Society of Gastrointestinal Endoscopy (ESGE). The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system 1 2 was adopted to define the strength of recommendations and the quality of evidence. Main Recommendations: 1 ESGE recommends endoscopic en bloc resection for superficial esophageal squamous cell cancers (SCCs), excluding those with obvious submucosal involvement (strong recommendation, moderate quality evidence). Endoscopic mucosal resection (EMR) may be considered in such lesions when they are smaller than 10 mm if en bloc resection can be assured. However, ESGE recommends endoscopic submucosal dissection (ESD) as the first option, mainly to provide an en bloc resection with accurate pathology staging and to avoid missing important histological features (strong recommendation, moderate quality evidence). 2 ESGE recommends endoscopic resection with a curative intent for visible lesions in Barrett's esophagus (strong recommendation, moderate quality evidence). ESD has not been shown to be superior to EMR for excision of mucosal cancer, and for that reason EMR should be preferred. ESD may be considered in selected cases, such as lesions larger than 15 mm, poorly lifting tumors, and lesions at risk for submucosal invasion (strong recommendation, moderate quality evidence). 3 ESGE recommends endoscopic resection for the treatment of gastric superficial neoplastic lesions that possess a very low risk of lymph node metastasis (strong recommendation, high quality evidence). EMR is an acceptable option for lesions smaller than 10 - 15 mm with a very low probability of advanced histology (Paris 0-IIa). However, ESGE recommends ESD as treatment of choice for most gastric superficial neoplastic lesions (strong recommendation, moderate quality evidence). 4 ESGE states that the majority of colonic and rectal superficial lesions can be effectively removed in a curative way by standard polypectomy and/or by EMR (strong recommendation, moderate quality evidence). ESD can be considered for removal of colonic and rectal lesions with high suspicion of limited submucosal invasion that is based on two main criteria of depressed morphology and irregular or nongranular surface pattern, particularly if the lesions are larger than 20 mm; or ESD can be considered for colorectal lesions that otherwise cannot be optimally and radically removed by snare-based techniques (strong recommendation, moderate quality evidence).(AU)

European consensus on the histopathology of inflammatory bowel disease.

The histologic examination of endoscopic biopsies or resection specimens remains a key step in the work-up of affected inflammatory bowel disease (IBD) patients and can be used for diagnosis and differential diagnosis, particularly in the differentiation of UC from CD and other non-IBD related colitides. The introduction of new treatment strategies in inflammatory bowel disease (IBD) interfering with the patients' immune system may result in mucosal healing, making the pathologists aware of the impact of treatment upon diagnostic features. The European Crohn's and Colitis Organisation (ECCO) and the European Society of Pathology (ESP) jointly elaborated a consensus to establish standards for histopathology diagnosis in IBD. The consensus endeavors to address: (i) procedures required for a proper diagnosis, (ii) features which can be used for the analysis of endoscopic biopsies, (iii) features which can be used for the analysis of surgical samples, (iv) criteria for diagnosis and differential diagnosis, and (v) special situations including those inherent to therapy. Questions that were addressed include: how many features should be present for a firm diagnosis? What is the role of histology in patient management, including search for dysplasia? Which features if any, can be used for assessment of disease activity? The statements and general recommendations of this consensus are based on the highest level of evidence available, but significant gaps remain in certain areas.

[Congenital esophageal duplication cysts: progressive dysphagia in adulthood]. / Kongenitale zystische Duplikatur des Ösophagus: Progrediente Dysphagie im Erwachsenenalter.

Esophageal duplications are congenital abnormalities of the foregut. We present the case of a 33-year-old woman suffering from progressive dysphagia who had surgery for esophageal duplication. The following three criteria define the cystic lesion: an intimate attachment to the esophageal wall, the presence of a smooth muscle coat and a mucosal lining consisting of squamous and/or ciliated respiratory epithelium. Diverticula, bronchogenic cysts and cystic neoplasms have to be considered in the differential diagnosis. Congenital cystic esophageal duplication is a rare cause of dysphagia in adulthood.

[Inflammatory esophageal polyp with bizarre stromal cells: possible diagnostic pitfall]. / Bizarre Stromazellen in einem inflammatorischen Ösophaguspolypen: Ein möglicher diagnostischer Fallstrick.

In the gastrointestinal tract an accurate diagnosis of tumor-like lesions can be challenging. In patients with reflux disease regenerative hyperplasia of esophageal squamous epithelium may show marked pleomorphism and atypia thereby simulating malignancy. Bizarre stromal cells are another diagnostic pitfall. We present the case of a 46-year-old patient with symptoms of reflux disease who was diagnosed with a benign inflammatory polyp at the distal end of the esophagus. Histology revealed bizarre cells within the stroma of the polyp characterized by nuclear hyperchromatism and enlargement. Mitoses were not observed. The atypical cells were positive for vimentin. The Ki67/MIB-1 proliferation rate was low. The morphology and etiology of bizarre stromal cells, including helpful features for differential diagnosis are thoroughly discussed.

[Gastric ulcer suspected of being a carcinoma part 2]. / Karzinomverdächtiges Magenulkus Teil 2.

Differentiation between pseudoneoplastic regenerative epithelium and gastric carcinoma can be challenging. In cases with pseudoneoplastic regeneration, so-called lateral expansion of tubules and changing of nuclear rows within one gland should not be present. The gastritis status is of particular significance as gastric cancer is a rare occurrence without Helicobacter pylori infections.

[Secondary tumors of the gastrointestinal tract]. / Sekundäre Tumoren im Gastrointestinaltrakt.

Metastatic involvement of the gastrointestinal tract is rare and may cause considerable difficulties with respect to differential diagnosis. The gastrointestinal tract may either be affected by direct invasion, intraperitoneal dissemination or hematogenous cancer spread, the latter most often originating from malignant melanoma, breast and lung carcinomas. Metastatic deposits primarily develop within the submucosa. Secondary involvement of the mucosa typically leads to centrally depressed and/or ulcerated (volcano-like) nodular lesions. In histology, lack of a mucosal in situ component favors diagnosis of metastasis, whereas presence of an adenomatous precursor lesion is regarded to be characteristic of primary tumors. This concept, however, has recently been challenged by demonstrating metastatic cancer growth along intact basement membranes within the mucosal layer, i.e. mucosal colonization. The histopathological, immunohistochemical and clinical features of secondary gastrointestinal tumors are discussed in detail, focusing on criteria for differential diagnosis. The prognosis of affected patients is generally poor.

[Granular cell tumor of the stomach]. / Granularzelltumor des Magens.

Granular cell tumors are peripheral neuroectodermal tumors. Within the gastrointestinal tract, they have to be differentiated from gastrointestinal stromal tumors (GIST). We present the case of a 61-year-old patient who was diagnosed with a granular cell tumor of the stomach. The tumor cells showed transmural infiltration form the mucosa into the adipose tissue of the lesser curvature. The tumor cells were diffusely positive for S100-protein and negative for KIT, CD34 und SMA. The MIB1-proliferation index was below 2%. Granular cell tumors rarely occur within the gastrointestinal tract. Oesophagus and colon are most commonly affected. Diagnostic criteria and differential diagnosis of this peculiar lesion are thoroughly discussed.