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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]

Background: Molecular testing is critical to guiding treatment approaches in patients with metastatic non‐small cell lung cancer (mNSCLC), with testing delays adversely impacting the timeliness of treatment decisions. Here, we aimed to evaluate the time from initial mNSCLC diagnosis to treatment decision (TTD) following implementation of in‐house EGFR, ALK, and PD‐L1 testing at our institution. Methods: We conducted a retrospective chart review of 165 patients (send‐out testing, n = 92; in‐house testing, n = 73) with newly diagnosed mNSCLC treated at our institution. Data were compared during the send‐out (March 2017–May 2019) and in‐house (July 2019–March 2021) testing periods. We performed a detailed workflow analysis to provide insight on the pre‐analytic, analytic, and post‐analytic intervals that constituted the total TTD. Results: TTD was significantly shorter with in‐house testing (10 days vs. 18 days, p < 0.0001), driven largely by decreased internal handling and specimen transit times (2 days vs. 3 days, p < 0.0001) and laboratory turnaround times (TAT, 3 days vs. 8 days, p < 0.0001), with 96% of in‐house cases meeting the international guideline of a ≤ 10‐day intra‐laboratory TAT (vs. 74% send‐out, p < 0.001). Eighty‐eight percent of patients with in‐house testing had results available at their first oncology consultation (vs. 52% send‐out, p < 0.0001), and all patients with in‐house testing had results available at the time of treatment decision (vs. 86% send‐out, p = 0.57). Conclusion: Our results demonstrate the advantages of in‐house biomarker testing for mNSCLC at a tertiary oncology center. Incorporation of in‐house testing may reduce barriers to offering personalized medicine by improving the time to optimal systemic therapy decision. [ABSTRACT FROM AUTHOR]

Obstructive nephropathy is a major cause of acute renal failure and end-stage renal disease. We discuss the new findings of Girshovich et al., who show that transformation of intrarenal urothelium into a bladder-like urothelium depends on the activation of the FGF7-FGFR2 signaling pathway following acute ureteral obstruction. A possible link between hypoxia-inducible factor 1α and the FGF-FGFR signaling pathway is suggested. [ABSTRACT FROM AUTHOR]

Presents a comment on the transgenic experiments published in an article of Volume 6 of 'Nature Medicine.' Determination of the molecular mechanisms of cardiac hypertrophy; Examination of the surviving mice by echocardiography; Differentiation between specific and nonspecific effects of expression of the transgene.

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. [ABSTRACT FROM AUTHOR]

The detection of gene fusions by RNA-based next-generation sequencing (NGS) is an emerging method in clinical genetic laboratories for oncology biomarker testing to direct targeted therapy selections. A recent Canadian study (CANTRK study) comparing the detection of NTRK gene fusions on different NGS assays to determine subjects' eligibility for tyrosine kinase TRK inhibitor therapy identified the need for recommendations for best practices for laboratory testing to optimize RNA-based NGS gene fusion detection. To develop consensus recommendations, representatives from 17 Canadian genetic laboratories participated in working group discussions and the completion of survey questions about RNA-based NGS. Consensus recommendations are presented for pre-analytic, analytic and reporting aspects of gene fusion detection by RNA-based NGS. [ABSTRACT FROM AUTHOR]

Genomic profiling of pancreatic cancer using small core biopsies has taken an increasingly prominent role in precision medicine. However, if not appropriately preserved, nucleic acids (NA) from pancreatic tissues are known to be susceptible to degradation due to high intrinsic levels of nucleases. PAXgene fixation (PreAnalytix, Switzerland) represents a novel formalin-free tissue preservation method. We sought to compare the NA and histomorphological preservation of pancreatic cancer tissues preserved with PAXgene-fixed paraffin-embedding (PFPE) and formalin-fixed paraffin-embedding (FFPE). Tissues from 19 patients were obtained prospectively from pancreaticoduodenectomy specimens and evaluated by four gastrointestinal pathologists. The extracted NA were quantified by Nanodrop and Qubit and assessed for quality by qPCR, targeted next-generation sequencing (NGS) assay, and RNA-sequencing. Our results demonstrated that, when assessed blindly for morphological quality, the four pathologists deemed the PFPE slides adequate for diagnostic purposes. PFPE tissues enable greater yields of less fragmented and more amplifiable DNA. PFPE tissues demonstrated significantly improved quality control (QC) metrics in a targeted NGS assay including Median Absolute Pair-wise Difference (MAPD) scores. Our results support the use of PAXgene fixative for the processing of specimens from pancreatic cancers with the potential benefits of improved yields for more amplifiable DNA in low-yield biopsy specimens and its ideal use for amplicon-based NGS assays. [ABSTRACT FROM AUTHOR]

A 61-year-old man presents with sequential painful bilateral proptosis within 36 h and orbital compartment syndrome resulting in complete loss of vision bilaterally. Sequential urgent lateral canthotomy and cantholysis were performed to reverse the compartment syndrome. Orbital imaging showed non-specific orbital inflammation. Biopsies showed necrotizing inflammation and bloodwork was positive for c-ANCA. The patient was therefore treated with prednisone and cyclophosphomide and showed good recovery of vision in one eye, and had no recurrence of orbital inflammation. ANCA-associated orbital vasculitides are rare, but must be kept in mind in the differential diagnosis of acute orbital inflammatory syndromes. [ABSTRACT FROM AUTHOR]

Gastric cancer is among the leading causes of cancer-related deaths worldwide. While heritable forms of gastric cancer are relatively rare, identifying the genes responsible for such cases can inform diagnosis and treatment for both hereditary and sporadic cases of gastric cancer. Mutations in the E-cadherin gene, CDH1, account for 40% of the most common form of familial gastric cancer (FGC), hereditary diffuse gastric cancer (HDGC). The genes responsible for the remaining forms of FGC are currently unknown. Here we examined a large family from Maritime Canada with FGC without CDH1 mutations, and identified a germline coding variant (p.P946L) in mitogen-activated protein kinase kinase kinase 6 (MAP3K6). Based on conservation, predicted pathogenicity and a known role of the gene in cancer predisposition, MAP3K6 was considered a strong candidate and was investigated further. Screening of an additional 115 unrelated individuals with non-CDH1 FGC identified the p.P946L MAP3K6 variant, as well as four additional coding variants in MAP3K6 (p.F849Sfs*142, p.P958T, p.D200Y and p.V207G). A somatic second-hit variant (p.H506Y) was present in DNA obtained from one of the tumor specimens, and evidence of DNA hypermethylation within the MAP3K6 gene was observed in DNA from the tumor of another affected individual. These findings, together with previous evidence from mouse models that MAP3K6 acts as a tumor suppressor, and studies showing the presence of somatic mutations in MAP3K6 in non-hereditary gastric cancers and gastric cancer cell lines, point towards MAP3K6 variants as a predisposing factor for FGC. [ABSTRACT FROM AUTHOR]

Benign epithelial inclusions are rarely found in peripancreatic lymph nodes and have not been studied by up-to-date immunohistochemistry. Here, we describe 2 cases of benign epithelial inclusions in the peripancreatic lymph nodes with discussion of differential diagnosis. The first case was a 2.2 cm lymph node from a 61-year-old woman with pancreatic ductal adenocarcinoma. The second case was a 4.3 cm lymph node from a 28-year-old man with distal common bile duct cholangiocarcioma. The epithelial inclusions in the first case consisted of several small squamous cell nests with central duct-like lumina. The lymph node from the second case showed convoluted cystic inclusions lined by a single layer of bland cuboidal epithelium with scattered mucin-producing cells. We also conducted literature review on similar lesions and found that some lesions were associated with pancreatic hetertopia. It is imperative in clinical practice to distinguish these epithelial inclusions in the lymph nodes from tumor metastasis. A hypothetic connection of these benign epithelial inclusions in the peripancreatic lymph nodes to the enigmatic pancreatic lymphoepithelial cysts is suggested. [ABSTRACT FROM AUTHOR]