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Simple Summary: In this study, scientists investigated how pathologists test for a protein called HER2 in a type of cancer called endometrial cancer (EC). They checked samples from 180 patients tested over the first two years following approval of the test in the clinic. They found that 28% of the samples had HER2 overexpression, which makes them eligible for HER2-targeted therapies. They also noticed that in some cases, the test results were different depending on the method used. This study shows that there are challenges in testing for HER2 in endometrial cancer and suggests that we need standardized guidelines to help doctors make better decisions about endometrial cancer treatment. HER2-targeted therapies have transformed the management of advanced or recurrent serous endometrial cancer (EC), leading to an increased clinical demand for HER2 testing. Despite its adoption in select academic centers, the global extent of such tumor testing is unclear. In this study, we report on the initial two-year experience of HER2 testing at a major academic center with a reference gynecologic oncology service and biomarker reference laboratory. All patients who underwent HER2 testing based on physician discretion, reflex HER2 testing, and reference laboratory requests were included. From February 2021 to October 2023, HER2 testing was performed on 192 tumor tissue samples from 180 EC patients. Serous carcinoma constituted 52% of samples, reflecting diagnostic challenges and limited therapeutic options for advanced EC. HER2 positivity was found in 28% of all cases and 30% of p53-aberrant cases. An immunohistochemistry (IHC) score of 3+ was found in 15% of samples, while IHC 2+ was found in 45% (13% IHC 2+/ISH+ and 32% IHC 2+/ISH−). The newly identified 'HER2-low' category comprised 46% of the samples. Heterogeneity was noted in 42% of HER2-positive cases, with complex patterns in 3%. NGS and HER2 IHC-FISH showed a 24% discordance, attributed to intratumoral heterogeneity, tumor cellularity, a small number of amplified cells, and the HER2/CEP17 ratio near the cut-off. This study offers real-world insights into HER2 testing in EC, highlighting the challenges and underscoring the need for standardized guidelines in specimen handling, proficiency testing, and scoring criteria to enhance patient management and therapeutic decision-making. [ABSTRACT FROM AUTHOR]

Congenital urinary tract obstruction (UTO) is a commonly noted disorder with the potential to cause permanent loss of renal function. Due to the possibility of spontaneous resolution, postnatal management strategies require lengthy and invasive surveillance methods to monitor the status of renal function and severity of obstruction. Here, a quantitative proteome analysis of urinary exosomes from weanling rats with surgically introduced UTO identifies a number of candidate biomarkers with the potential to improve diagnostic and prognostic methods for this disease. Using gel-assisted digestion coupled to liquid chromatography/tandem mass spectrometry (LC-MS/MS), 318 proteins were identified. Relative protein quantitation by spectral counting showed 190 proteins with significant changes in abundance due to either partial or complete obstruction. Numerous proteins identified here have been shown to be similarly altered in abundance in other renal diseases that cause tubule apoptosis and interstitial fibrosis. Extrapolating the role of the proteins showing quantifiable changes in abundance here from other forms of renal disease suggests they have potential for clinical applicability as biomarkers of congenital UTO. Included in the list of identified proteins are markers of apoptosis, oxidative stress, fibrosis, inflammation, and tubular cell damage, which are commonly associated with UTO. This study therefore provides a number of candidate biomarkers that, following validation in children experiencing UTO, have the potential to improve postnatal management of this disease. Key words: exosomes, proteomics, biomarkers, urinary tract obstruction. L'obstruction congenitale des voies urinaires est un trouble frequemment observe qui peut entrainer la perte de la fonction renale. Etant donne la possibilite de resolution spontanee, les strategies de prise en charge postnatale requierent des methodes de surveillance longues et invasives pour que l'etat de la fonction renale et la gravite de l'obstruction puissent etre suivis. Dans le present article, une analyse quantitative du proteome des exosomes urinaires de ratons sevres sur lesquels une obstruction des voies urinaire a ete pratiquee par chirurgie a permis de relever un certain nombre de biomarqueurs potentiels qui pourraient permettre d'ameliorer les methodes de diagnostic et de pronostic de cette maladie. A l'aide de la digestion sur gel couplee a la Chromatographie liquide et la spectrometrie de masse en tandem (LC-MS/MS), nous avons repere 318 proteines. La quantification relative des proteines par comptage spectral a permis d'en relever 190 dont le changement en abondance etait attribuable a une obstruction soit partielle ou complete. Des modifications similaires de l'abondance de nombreuses proteines parmi celles que nous avons trouvees ont ete observees dans le contexte d'autres maladies renales qui causent l'apoptose tabulaire et la fibrose interstitielle. En extrapolant le rôle des proteines qui ont montre dans les presents travaux des modifications quantifiables de leur abondance a partir de celui qu'elles jouent dans d'autres formes de maladie renale, on peut supposer que ces proteines pourraient trouver des applications cliniques comme biomarqueurs de l'obstruction congenitale des voies urinaires. Parmi les proteines repertoriees, on compte des marqueurs de l'apoptose, du stress oxydant, de la fibrose, de l'inflammation et des lesions des cellules tubulaires, qui sont communement associes a l'obstruction des voies urinaires. Cette etude propose donc un certain nombre de biomarqueurs potentiels qui, apres validation chez des enfants presentant une obstruction des voies urinaires, pourraient ameliorer la prise en charge postnatale de cette maladie. [Traduit par la Redaction] Mots-cles : exosomes, proteomique, biomarqueurs, obstruction des voies urinaires., Introduction Congenital urinary tract obstruction (UTO) is a common cause of prenatally diagnosed hydronephrosis, (1-3) and remains a leading cause of renal functional loss in children. (3,4) Hydronephrosis often resolves [...]

* Context.--Pathologists routinely assess Ki67 immunohistochemistry to grade gastrointestinal and pancreatic neuroendocrine tumors. Unfortunately, manual counts of the Ki67 index are very time consuming and eyeball estimation has been criticized as unreliable. Manual Ki67 counts performed by cytotechnologists could potentially save pathologist time and improve accuracy.Objective.--To assess the concordance between manual Ki67 index counts performed by cytotechnologists versus eyeball estimates and manual Ki67 counts by pathologists.Design.--One Ki67 immunohistochemical stain was retrieved from each of 18 archived gastrointestinal or pancreatic neuroendocrine tumor resections. We compared pathologists' Ki67 eyeball estimates on glass slides and printed color images with manual counts performed by 3 cytotechnologists and gold standard manual Ki67 index counts by 3 pathologists.Results.--Tumor grade agreement between pathologist image eyeball estimate and gold standard pathologist manual count was fair ([kappa] = 0.31; 95% CI, 0.030-0.60). In 9 of 20 cases (45%), the mean pathologist eyeball estimate was 1 grade higher than the mean pathologist manual count. There was almost perfect agreement in classifying tumor grade between the mean cytotechnologist manual count and the mean pathologist manual count ([kappa] = 0.910; 95% CI, 0.697-1.00). In 20 cases, there was only 1 grade disagreement between the 2 methods. Eyeball estimation by pathologists required less than 1 minute, whereas manual counts by pathologists required a mean of 17 minutes per case.Conclusions.--Eyeball estimation of the Ki67 index has a high rate of tumor grade misclassification compared with manual counting. Cytotechnologist manual counts are accurate and save pathologist time.(Arch Pathol Lab Med. 2018;142:402-407; doi: 10.5858/arpa.2017-0203-OA), Neuroendocrine tumors (NETs) of the gastrointestinal tract and pancreas are uncommon neoplasms with marked heterogeneity in clinical behavior. (1,2) Ki67 immunohistochemistry has emerged as an important prognostic indicator and is [...]

* Context.--Two recent studies have identified a high rate of microsatellite instability (MSI) in pancreatic neuroendocrine tumors (pNETs). Microsatellite instability is rare in small intestinal neuroendocrine tumors (NETs). It is unclear why there is discordance in the frequency of MSI in the 2 studies of pNETs and why this mechanism is comparatively rare in small intestinal tumors. Loss of expression of DNA mismatch repair (MMR) proteins, which is known to correlate strongly with MSI, is not well studied in pancreatic or small intestinal NETs. Objective.--To determine if there is loss of expression of MMR protein expression in pancreatic or small intestinal NETs. Design.--Sixty-nine patients (31 male, 38 female; mean age, 59.2 years) were identified who had a resection for a primary pancreatic (n = 35) or primary small intestinal (n = 34) NET during an 18-year period. Immunohistochemical stains for MLH1, MSH2, MSH6, and PMS2 were applied to archived tissue from all cases. All pNETs with adequate tissue (n = 32) were also assessed by MSI analysis. Results.--There was preserved expression of MLH1, MSH2, MSH6, and PMS2 in all 35 pNETs. Of 32 pNETs tested by polymerase chain reaction, 28 were microsatellite stable and DNA did not amplify in 4. In 34 small intestinal NETs, 2 cases had indeterminate MLH1 and 1 case had indeterminate PMS2 expression. The remainder had intact MMR protein expression. Conclusion.--Defects in DNA MMR proteins are rare in pancreatic and small intestinal NETs, raising doubt that MSI plays a significant role in the pathogenesis of these tumors. (Arch Pathol Lab Med. 2011; 135:1539-1544; doi: 10.5858/arpa.2010-0560-OA), Pancreatic and small intestinal neuroendocrine tumors (NETs) are rare, with an incidence of less than 1 in 100000 persons per year. (1) Prognostic information is limited for this group of [...]

Author(s): Weei-Yuarn Huang [1]; Jose Aramburu [2]; Pamela S. Douglas [1]; Seigo Izumo (corresponding author) [1] To the editor A common approach for determining the molecular mechanisms of cardiac hypertrophy [...]

The Canadian NTRK (CANTRK) study is an interlaboratory comparison ring study to optimize testing for neurotrophic receptor tyrosine kinase (NTRK) fusions in Canadian laboratories. Sixteen diagnostic laboratories used next-generation sequencing (NGS) for NTRK1, NTRK2, or NTRK3 fusions. Each laboratory received 12 formalin-fixed, paraffin-embedded tumor samples with unique NTRK fusions and two control non-NTRK fusion samples (one ALK and one ROS1). Laboratories used validated protocols for NGS fusion detection. Panels included Oncomine Comprehensive Assay v3, Oncomine Focus Assay, Oncomine Precision Assay, AmpliSeq for Illumina Focus, TruSight RNA Pan-Cancer Panel, FusionPlex Lung, and QIAseq Multimodal Lung. One sample was withdrawn from analysis because of sample quality issues. Of the remaining 13 samples, 6 of 11 NTRK fusions and both control fusions were detected by all laboratories. Two fusions, WNK2::NTRK2 and STRN3::NTRK2, were not detected by 10 laboratories using the Oncomine Comprehensive or Focus panels, due to absence of WNK2 and STRN3 in panel designs. Two fusions, TPM3::NTRK1 and LMNA::NTRK1, were challenging to detect on the AmpliSeq for Illumina Focus panel because of bioinformatics issues. One ETV6::NTRK3 fusion at low levels was not detected by two laboratories using the TruSight Pan-Cancer Panel. Panels detecting all fusions included FusionPlex Lung, Oncomine Precision, and QIAseq Multimodal Lung. The CANTRK study showed competency in detection of NTRK fusions by NGS across different panels in 16 Canadian laboratories and identified key test issues as targets for improvements., (Copyright © 2023 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)