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Circulating miR-371a-3p has excellent performance in the detection of viable (non-teratoma) germ cell tumor (GCT) pre-orchiectomy; however, its ability to detect occult disease is understudied. To refine the serum miR-371a-3p assay in the minimal residual disease setting we compared performance of raw (Cq) and normalized (∆Cq, RQ) values from prior assays, and validated interlaboratory concordance by aliquot swapping. Revised assay performance was determined in a cohort of 32 patients suspected of occult retroperitoneal disease. Assay superiority was determined by comparing resulting receiver-operator characteristic (ROC) curves using the Delong method. Pairwise t-tests were used to test for interlaboratory concordance. Performance was comparable when thresholding based on raw Cq vs. normalized values. Interlaboratory concordance of miR-371a-3p was high, but reference genes miR-30b-5p and cel-miR-39-3p were discordant. Introduction of an indeterminate range of Cq 28-35 with a repeat run for any indeterminate improved assay accuracy from 0.84 to 0.92 in a group of patients suspected of occult GCT. We recommend that serum miR-371a-3p test protocols are updated to (a) utilize threshold-based approaches using raw Cq values, (b) continue to include an endogenous (e.g., miR-30b-5p) and exogenous non-human spike-in (e.g., cel-miR-39-3p) microRNA for quality control, and (c) to re-run any sample with an indeterminate result.

N6-Methyladenosine (m6A) is the most abundant posttranscriptional modification, and its contribution to cancer evolution has recently been appreciated. Renal cancer is the most common adult genitourinary cancer, approximately 85% of which is accounted for by the clear cell renal cell carcinoma (ccRCC) subtype characterized by VHL loss. However, it is unclear whether VHL loss in ccRCC affects m6A patterns. In this study, we demonstrate that VHL binds and promotes METTL3/METTL14 complex formation while VHL depletion suppresses m6A modification, which is distinctive from its canonical E3 ligase role. m6A RNA immunoprecipitation sequencing (RIP-Seq) coupled with RNA-Seq allows us to identify a selection of genes whose expression may be regulated by VHL-m6A signaling. Specifically, PIK3R3 is identified to be a critical gene whose mRNA stability is regulated by VHL in a m6A-dependent but HIF-independent manner. Functionally, PIK3R3 depletion promotes renal cancer cell growth and orthotopic tumor growth while its overexpression leads to decreased tumorigenesis. Mechanistically, the VHL-m6A-regulated PIK3R3 suppresses tumor growth by restraining PI3K/AKT activity. Taken together, we propose a mechanism by which VHL regulates m6A through modulation of METTL3/METTL14 complex formation, thereby promoting PIK3R3 mRNA stability and protein levels that are critical for regulating ccRCC tumorigenesis., Introduction Estimated new cases and deaths from renal cancer in the US for 2020 were 73,750 and 14,830 respectively (1). Kidney cancer incidence has been steadily increasing over the past [...]

Responses of tropical cyclones (TCs) to CO2 doubling are explored using coupled global climate models (GCMs) with increasingly refined atmospheric/land horizontal grids (~ 200 km, ~ 50 km and ~ 25 km). The three models exhibit similar changes in background climate fields thought to regulate TC activity, such as relative sea surface temperature (SST), potential intensity, and wind shear. However, global TC frequency decreases substantially in the 50 km model, while the 25 km model shows no significant change. The ~ 25 km model also has a substantial and spatially-ubiquitous increase of Category 3–4–5 hurricanes. Idealized perturbation experiments are performed to understand the TC response. Each model’s transient fully-coupled 2 × CO2 TC activity response is largely recovered by “time-slice” experiments using time-invariant SST perturbations added to each model’s own SST climatology. The TC response to SST forcing depends on each model’s background climatological SST biases: removing these biases leads to a global TC intensity increase in the ~ 50 km model, and a global TC frequency increase in the ~ 25 km model, in response to CO2-induced warming patterns and CO2 doubling. Isolated CO2 doubling leads to a significant TC frequency decrease, while isolated uniform SST warming leads to a significant global TC frequency increase; the ~ 25 km model has a greater tendency for frequency increase. Global TC frequency responds to both (1) changes in TC “seeds”, which increase due to warming (more so in the ~ 25 km model) and decrease due to higher CO2 concentrations, and (2) less efficient development of these“seeds” into TCs, largely due to the nonlinear relation between temperature and saturation specific humidity.

Well-differentiated neuroendocrine tumor rarely occurs as a testicular primary tumor, accounting for less than 1% of all testicular cancers, and is rarely reported with sufficient molecular profiles. After searching our departmental database (2003-2023), two testicular primary well-differentiated neuroendocrine tumors were identified in a 35-year-old man and a 23-year-old man, respectively, both of whom had normal serum level of tumor markers. Both tumors grossly exhibited solid, yellow-tan, and homogeneous appearance and histologically displayed a mixture of growth patterns, including organoid, tubular, cribriform, nests, cords, and single cells, were composed of eosinophilic tumor cells with salt-and-pepper chromatin and indistinct cell borders. Immunoreactivity for chromogranin and synaptophysin were detected, with Ki-67 labeling 9% and 2% of tumor cells on counting of 500 tumor cells, respectively. There was no germ cell neoplasia in situ in the background testicular parenchyma. Furthermore, fluorescence in situ hybridization failed to identify the presence of isochromosome 12p in both tumors. A panel-based next-generation sequencing was done in one of tumors and showed no reportable pathogenic variants with a mutation burden of 0.5 mutations per megabase. Although elevated mitotic figures (up to 6 per 10 high power fields), lymphovascular invasion and marked nuclear pleomorphism were present in this tumor, there was no evidence of disease detected in this patient via Dotatate positron emission tomography/computed tomography scan after the surgery. This report expands the spectrum of testicular primary well-differentiated neuroendocrine tumor. Considering its rarity, it may pose a diagnostic challenge or pitfall in certain clinical circumstances. In addition, the literature pertaining to this entity is herein reviewed. [ABSTRACT FROM AUTHOR]

Sarcomatoid yolk sac tumor is a very rare histologic type of testicular germ cell tumor and is mainly reported in testicular germ cell tumor patients who receive chemotherapy. Herein, we report an extremely rare concurrent retroperitoneal sarcomatoid yolk sac tumor in a man with a testicular postpuberal teratoma before he received chemotherapy. A 37-year-old man initially presented with a persistent abdominal pain. Subsequent imaging studies revealed a 9.6-cm retroperitoneal mass, and 2 testicular masses (3.1 cm and 0.9 cm in greatest dimension, respectively). His serum tumor markers were within normal ranges. His radical orchiectomy demonstrated a postpubertal type teratoma with an adjacent scarring nodule. Later, his retroperitoneal tumor showed spindle tumor cells embedded in predominantly myxoid and focally fibrous stroma with diffuse and strong immunoreactivity for keratin AE1/AE3, SALL4 and glypican 3. No tumor necrosis or brisk mitotic figures were observed. A diagnosis of sarcomatoid yolk sac tumor was rendered. Fluorescence in situ hybridization analysis of his retroperitoneal sarcomatoid yolk sac tumor revealed polysomy 12 and MYC amplification, whereas no evidence of isochromosome 12p [i(12p)], and DNA sequencing showed 6 mutations per megabase (muts/Mb), and the somatic alterations included ARAF amplification and ATR I774Yfs*5. Considering its rarity, sarcomatoid yolk sac tumor may pose diagnostic challenges. Therefore, relevant clinicoradiologic information and ancillary work up, including immunohistochemistry and molecular studies, may be helpful for the accurate classification. Our tumor further raises awareness of this rare event, expands the spectrum of its clinical presentation, and explores the molecular features. [ABSTRACT FROM AUTHOR]

Coastal upwelling plays a vital role in the support and maintenance of productive marine ecosystems throughout the California Current System (CCS). Here, we evaluate upwelling forecast skill using ∼30 years of seasonal reforecasts from four global climate models contributing to the North American Mulitmodel Ensemble (NMME). The models skillfully predict upwelling intensity throughout much of the CCS in boreal winter, and in the South‐Central CCS in spring/summer. The models also skillfully predict various aspects of upwelling phenology, including the timing of the spring transition, as well as the total vertical transport integrated over the course of the upwelling season. Climatic sources of forecast skill vary with season, with contributions from the El Niño‐Southern Oscillation in winter‐spring, and the North Pacific Oscillation and the North Pacific Meridional Mode in the winter‐summer. Our results highlight the potential of seasonal climate forecasts to inform management of upwelling‐sensitive marine resources. Plain Language Summary: Upwelling—the process of drawing cold, nutrient rich ocean waters toward the surface—plays a vital role in supporting vibrant and diverse biological populations throughout the California Current System (CCS). Here, we assess whether four global climate models can forecast seasonal upwelling 1–12 months in advance. We show that for much of the year (winter through summer), models can predict anomalous upwelling intensity several months in advance. We also show that the models can predict the timing of the "spring transition" (i.e., the start of the upwelling season) for much of the CCS. The model skill is related to large‐scale climate modes, including the El Niño‐Southern Oscillation, the North Pacific Oscillation, and the Pacific Meridional Mode. These climate modes alter the strength of the surface winds along the U.S. west coast from winter‐summer, giving rise to predictable patterns of upwelling. Our results highlight the potential of seasonal climate forecasts to inform management of upwelling‐sensitive marine resources. Key Points: Global climate models skillfully predict upwelling in the California Current System in winter‐summerModels also skillfully predict timing of spring transitionWinter skill is linked to the El Niño‐Southern Oscillation and North Pacific Oscillation, summer skill with the Pacific Meridional Mode [ABSTRACT FROM AUTHOR]

Context.--Lesions in the genitourinary (GU) organs, both benign and malignant, can demonstrate overlapping morphology, and practicing surgical pathologists should be aware of these potential pitfalls and consider a broad differential diagnosis for each specific type of lesion involving the GU organs. The following summary of the contents presented at the 6th Annual Chinese American Pathologists Association (CAPA) Diagnostic Course (October 10-11, 2020), supplemented with relevant literature review, exemplifies the common diagnostic challenges and pitfalls for mass lesions of the GU system of adults, including adrenal gland, with emphasis on immunohistochemical and molecular updates when relevant. Objective.--To describe the common mass lesions in the GU system of adults, including adrenal gland, with emphasis on the diagnostic challenges and pitfalls that may arise in the pathologic assessment, and to highlight immunohistochemical workups and emerging molecular findings when relevant. Data Sources.--The contents presented at the course and literature search comprise our data sources. Conclusions.--The diagnostic challenges and pitfalls that arise in the pathologic assessment of the mass lesions in the GU system of adults, including adrenal gland, are common. We summarize the contents presented at the course, supplemented with relevant literature review, and hope to provide a diagnostic framework to evaluate these lesions in routine clinical practice. (Arch Pathol Lab Med. 2021;145:1387-1404; doi: 10.5858/arpa.2021-0107-RA), Lesions in the genitourinary (GU) organs, both benign and malignant, can demonstrate overlapping morphology, and practicing surgical pathologists should be aware of these potential pitfalls and consider a broad differential [...]

Fibrin-associated large B-cell lymphoma (FA-LBCL) is a rare subtype of Epstein-Barr virus (EBV)-associated lymphoma, recognized as an independent entity per the 5th edition of the WHO classification of hematolymphoid neoplasms. It is usually associated with longstanding chronic inflammation and arises within fibrinous material in confined anatomic spaces. We report the clinicopathologic manifestations of two patients of FA-LBCL involving the adrenal gland and kidney. Both tumors were diagnosed after presenting as cystic masses on imaging studies. These lymphomas were non-invasive, with microscopic aggregates of large B-lymphoma cells along/within cystic wall and admixed with fibrinous material and without prominent inflammation. By immunohistochemistry and in-situ hybridization, lymphoma cells were positive for CD45, PAX5, CD79a, MUM1, BCL2, PD-L1, and EBV/EBER (Epstein-Barr virus encoded small RNA) with a high proliferation index. Both patients remain in remission after management with complete surgical resection and additional chemo-immunotherapy in one patient. Considering its rarity, scant tumor cells, and varied clinical presentations, FA-LBCL may pose diagnostic challenges, especially when presenting as extensively necrotic cystic lesions, needing multidisciplinary collaboration in formulating management. [ABSTRACT FROM AUTHOR]