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Background and aimsClinicopathological characteristics of gastric cancer (GC) are changing, especially in the West with a decreasing incidence of distal, intestinal-type tumours and the corresponding increasing proportion of tumours with Laurén diffuse or WHO poorly cohesive (PC) including signet ring cell (SRC) histology. To accurately assess the behaviour and the prognosis of these GC subtypes, the standardization of pathological definitions is needed.MethodsA multidisciplinary expert team belonging to the European Chapter of International Gastric Cancer Association (IGCA) identified 11 topics on pathological classifications used for PC and SRC GC. The topics were debated during a dedicated Workshop held in Verona in March 2017. Then, through a Delphi method, consensus statements for each topic were elaborated.ResultsA consensus was reached on the need to classify gastric carcinoma according to the most recent edition of the WHO classification which is currently WHO 2010. Moreover, to standardize the definition of SRC carcinomas, the proposal that only WHO PC carcinomas with more than 90% poorly cohesive cells having signet ring cell morphology have to be classified as SRC carcinomas was made. All other PC non-SRC types have to be further subdivided into PC carcinomas with SRC component (< 90% but > 10% SRCs) and PC carcinomas not otherwise specified (< 10% SRCs).ConclusionThe reported statements clarify some debated topics on pathological classifications used for PC and SRC GC. As such, this consensus classification would allow the generation of evidence on biological and prognostic differences between these GC subtypes.

BackgroundColorectal, endometrial and upper urinary tract tumours are characteristic for Lynch syndrome (hereditary non-polyposis colon carcinoma, HNPCC). The aim of the present study was to establish whether carriers of mutations in mismatch repair genes MLH1, MSH2 or MSH6 are at increased risk of urinary bladder cancer.MethodsCarriers and first degree relatives of 95 families with a germline mutation in the MLH1 (n=26), MSH2 (n=43), or MSH6 (n=26) gene were systematically questioned about the occurrence of carcinoma. The cumulative risk of cancer occurring before the age of 70 years (CR70) was compared to the CR70 of the general Dutch population. Microsatellite instability (MSI) testing and/or immunohistochemistry (IHC) for mismatch repair proteins was performed on bladder tumour tissue.ResultsBladder cancer was diagnosed in 21 patients (90% men) from 19 Lynch syndrome families (2 MLH1, 15 MSH2, and 4 MSH6). CR70 for bladder cancer was 7.5% (95% CI 3.1% to 11.9%) for men and 1.0% (95% CI 0% to 2.4%) for women, resulting in relative risks for mutation carriers and first degree relatives of 4.2 (95% CI 2.2 to 7.2) for men and 2.2 (95% CI 0.3 to 8.0) for women. Men carrying an MSH2 mutation and their first degree relatives were at highest risks: CR70 for bladder and upper urinary tract cancer being 12.3% (95% CI 4.3% to 20.3%) and 5.9% (95% CI 0.7% to 11.1%). Bladder cancer tissue was MSI positive in 6/7 tumours and loss of IHC staining was found in 14/17 tumours, indicating Lynch syndrome aetiology.ConclusionPatients with Lynch syndrome carrying an MSH2 mutation are at increased risk of urinary tract cancer including bladder cancer. In these cases surveillance should be considered.

To prevent duodenal and ampullary cancer in familial adenomatous polyposis (FAP) patients, a diagnosis of high grade dysplasia (HGD) plays an important role in the clinical management. Previous research showed that FAP patients are both over- and undertreated after a misdiagnosis of HGD, indicating unwarranted variation. We aimed to investigate the laboratory variation in dysplasia grading of duodenal adenomas and explore possible explanations for this variation. We included data from all Dutch pathology laboratories between 1991 and 2020 by retrieving histology reports from upper endoscopy specimens of FAP patients from the Dutch nationwide pathology databank (PALGA). Laboratory variation was investigated by comparing standardized proportions of HGD. To describe the degree of variation between the laboratories a factor score was calculated. A funnel plot was used to identify outliers. A total of 3050 specimens from 25 laboratories were included in the final analyses. The mean observed HGD proportion was 9.4%. The top three HGD-diagnosing laboratories diagnosed HGD 3.9 times more often than the lowest three laboratories, even after correcting for case-mix. No outliers were identified. Moderate laboratory variation was found in HGD diagnoses of duodenal tissue of FAP patients after adjusting for case-mix. Despite the fact that no outliers were observed, there may well be room for quality improvement. Concentration of these patients in expertise centers may decrease variation. To further reduce unwarranted variation, we recommend (inter)national guidelines to become more uniform in their recommendations regarding duodenal tissue sampling and consequences of HGD diagnoses.

The distinction between primary gastric adenocarcinoma and gastric metastatic breast carcinoma can be difficult. Expression of hepatocyte nuclear factor 4A (HNF4A) has been described as being specific to distinguish between neoplastic gastric and breast epithelial cells. The aim of this study was to validate the use of HNF4A with immunohistochemistry in discriminating gastric from breast carcinomas. Immunohistochemical expressions of HNF4A, estrogen receptor (ER), progesterone receptor (PR), and BRST-2 were determined in primary sporadic gastric adenocarcinomas ( n  = 107) and breast carcinomas ( n  = 105). The same markers and clinicopathological features were studied in 1 patient with breast metastasis of gastric cancer, 6 patients with gastric metastases of breast cancer, and 13 patients with both primary gastric and breast carcinomas. HNF4A expression was seen in 106 of 107 primary gastric adenocarcinomas and was absent in all 105 primary breast carcinomas (sensitivity 99 %, specificity 100 %). ER, PR, and BRST-2 were 100 % specific for breast carcinomas with sensitivities of 77, 58, and 38 %, respectively. The metastasis of gastric carcinoma to the breast showed strong expression of HNF4A. None of the metastases of breast carcinomas to the stomach showed expression of HNF4A. Tissues of patients with two primary carcinomas showed strong expression of HNF4A in all gastric carcinomas and no expression in breast carcinomas. Our results indicate that HNF4A is a very good marker to discriminate between primary and metastatic gastric and breast carcinomas.

The authors would like to correct the error in the publication of the original article. The surname and given names of the authors were swapped in the “Acknowledgements”. The corrected detail is given below.

Somatostatin is a tetradecapeptide that is widely distributed in the body. It acts on multiple organs including brain, pituitary, gut, exocrine and endocrine pancreas, adrenals, thyroid, and kidneys to inhibit release of many hormones and other secretory proteins. In addition, it functions as a neuropeptide affecting the electrical activity of neurons. Somatostatin exerts its biological effects by binding to specific high-affinity receptors, which appear in many cases to be coupled to GTP-binding proteins. Here we report the cloning, functional expression, and tissue distribution of two different somatostatin receptors (SSTRs). SSTR1 and SSTR2 contain 391 and 369 amino acids, respectively, and are members of the superfamily of receptors having seven transmembrane segments. There is 46% identity and 70% similarity between the amino acid sequences of SSTR1 and SSTR2. Stably transfected Chinese hamster ovary cells expressing SSTR1 or SSTR2 exhibit specific somatostatin binding, with an apparently higher affinity for somatostatin-14 than somatostatin-28, an NH2-terminally extended form of somatostatin-14. RNA blotting studies show that SSTR1 and SSTR2 are expressed at highest levels in jejunum and stomach and in cerebrum and kidney, respectively. A SSTR1 probe hybridized to multiple DNA fragments in EcoRI digests of human and mouse DNA, indicating that SSTR1 and SSTR2 are members of a larger family of somatostatin receptors. Thus, the biological effects of somatostatin are mediated by a family of receptors that are expressed in a tissue-specific manner.

More than 25 years ago, CDH1 pathogenic variants (PVs) were identified as the primary cause of hereditary diffuse gastric cancer (HDGC), an inherited cancer syndrome that increases the lifetime risk of developing diffuse gastric cancer (DGC) and lobular breast cancer (LBC). Since DGC is associated with a poor prognosis, a prophylactic total gastrectomy (PTG) is currently the gold standard for reducing the risk of DGC in CDH1 PV carriers. However, as germline genetic testing becomes more widespread, many CDH1 PV carriers have been identified, including in families with lower penetrance levels or without a history of gastric cancer (GC). When including these families, recent findings suggest that the cumulative lifetime risk of developing advanced DGC is much lower than previously thought and is now estimated to be 13–19%. This lower risk, combined with the fact that around one third of the CDH1 PV carriers decline PTG due to potential lifelong physical and psychological consequences, raises critical questions about the current uniformity in recommending PTG to all CDH1 PV carriers. As a result, there is a growing need to consider alternative strategies, such as endoscopic surveillance. However, despite the currently lower estimated risk of infiltrative (advanced) DGC, almost every PTG specimen shows the presence of small low-stage (pT1a) signet ring cell (SRC) lesions of which the behaviour is unpredictable but often are considered indolent or premalignant stages of DGC. Therefore, the primary goal of surveillance should be to identify atypical, deeper infiltrating lesions rather than every SRC lesion. Understanding the progression from indolent to more infiltrative lesions, and recognizing their endoscopic and histological features, is crucial in deciding the most suitable management option for each individual.

Introduction Tumor-targeted imaging is a promising technique for the detection of lymph node metastases (LNM) and primary tumors. It remains unclear which biomarker is the most suitable target to distinguish malignant from healthy tissue in esophageal adenocarcinoma (EAC). Objective We performed an immunohistochemistry study to identify viable tumor markers for tumor-targeted imaging of EAC. Methods We used samples from 72 patients with EAC to determine the immunohistochemical expression of ten potential tumor biomarkers for EAC (carbonic anhydrase IX [CA-IX], carcinoembryonic antigen [CEA], hepatic growth factor receptor, epidermal growth factor receptor, epithelial membrane antigen [EMA], epithelial cell adhesion molecule [EpCAM], human epidermal growth factor receptor 2 [HER-2], urokinase plasminogen activator receptor, vascular endothelial growth factor-A [VEGF-A], and VEGF receptor 2). Immunohistochemistry was performed on tissue microarrays of LNM ( n  = 48), primary EACs ( n  = 62), fibrotic tissues ( n  = 11), nonmalignant lymph nodes ( n  = 24), and normal esophageal and gastric tissues ( n  = 40). Tumor marker staining was scored on intensity and percentage of positive cells. Results EMA and EpCAM showed strong expression in LNM (> 95%) and primary EACs (> 95%). Significant expression was also observed for LNM and EAC using VEGF-A (85 and 92%), CEA (68 and 54%), and CA-IX (4 and 34%). The other tumor biomarkers showed expression of 0–15% for LNM and primary EAC. Except for VEGF-A, nonmalignant lymph node staining was scored as slight or absent. Conclusions High expression rates and correlation between LNM in EAC combined with low expression rates in healthy lymph nodes and esophagus tissues were observed for EpCAM and CEA, meaning these are promising targets for tumor-targeted imaging approaches for lymph nodes in patients with EAC.

The early evolution of a supernova (SN) can reveal information about the environment and the progenitor star. When a star explodes in vacuum, the first photons to escape from its surface appear as a brief, hours-long shock-breakout flare 1 , 2 , followed by a cooling phase of emission. However, for stars exploding within a distribution of dense, optically thick circumstellar material (CSM), the first photons escape from the material beyond the stellar edge and the duration of the initial flare can extend to several days, during which the escaping emission indicates photospheric heating 3 . Early serendipitous observations 2 , 4 that lacked ultraviolet (UV) data were unable to determine whether the early emission is heating or cooling and hence the nature of the early explosion event. Here we report UV spectra of the nearby SN 2023ixf in the galaxy Messier 101 (M101). Using the UV data as well as a comprehensive set of further multiwavelength observations, we temporally resolve the emergence of the explosion shock from a thick medium heated by the SN emission. We derive a reliable bolometric light curve that indicates that the shock breaks out from a dense layer with a radius substantially larger than typical supergiants. Using ultraviolet data as well as a comprehensive set of further multiwavelength observations of the supernova 2023ixf, a reliable bolometric light curve is derived that indicates the heating nature of the early emission.

▪ Abstract  Cardiac β-adrenergic receptors, which respond to neuronally released and circulating catecholamines, are important regulators of cardiac function. Congestive heart failure, a common clinical condition, is associated with a number of alterations in the activation and deactivation of β-adrenergic receptor pathways. Studies with failing hearts from humans and animals indicate that such alterations include changes in the expression or function of β-adrenergic receptors, G-proteins, adenylyl cyclases, and G-protein receptor kinases. The net effect of these alterations is the substantial blunting of β-adrenergic receptor-mediated cardiac response. An important unanswered question is whether the loss of cardiac β-adrenergic receptor responsiveness is a contributing cause, or a result, of ventricular dysfunction. Even though this question remains unanswered, the concept of targeting the β-adrenergic pathway in the failing heart is becoming increasingly popular and several new therapeutic strategies are in development.