Metastatic renal cell carcinoma with fibromyomatous stroma associated with tuberous sclerosis or MTOR, TSC1/TSC2-Mutations: A Series of 4 cases and a review of the literature.

Renal cell carcinoma with fibromyomatous stroma (RCCfms) are characterized by a constellation of morphologic findings that include elongated tubules lined by cells with clear to pale eosinophilic cytoplasm and intersecting bands of smooth muscle stroma. Consistent immunohistochemistry findings in RCCfms include diffuse positivity for carbonic anhydrase 9 and variable expression of keratin 7. Molecular profiling of such tumors show either pathogenic alterations of the ELOC (TCEB1) gene, or alterations of MTOR, TSC1, and TSC2.

GATA3 Expression in Solid Vimentin-Negative Eosinophilic Renal Epithelial Tumors-A Comprehensive Study of 48 Tumors.

Vimentin-negative solid eosinophilic renal tumors, such as renal oncocytoma, chromophobe renal cell carcinoma (chromophobe RCC), low-grade oncocytic tumor (LOT) of the kidney, and eosinophilic vacuolated tumor (EVT), often present diagnostic challenge to pathologists as they can have significant morphologic overlap. Recent studies have shown that the LOT is consistently positive for GATA3. To test the utility of GATA3 in this potentially challenging diagnostic setting, we investigated GATA3 expression in 48 vimentin-negative solid eosinophilic renal tumors with unequivocal diagnosis, which included 19 LOTs, 3 EVTs, 12 chromophobe RCCs, 11 renal oncocytomas (ROs), and 3 -mutated renal tumors.

Real world predictors of response and 24-month survival in high-grade TP53-mutated myeloid neoplasms.

Current therapies for high-grade TP53-mutated myeloid neoplasms (≥10% blasts) do not offer a meaningful survival benefit except allogeneic stem cell transplantation in the minority who achieve a complete response to first line therapy (CR1). To identify reliable pre-therapy predictors of complete response to first-line therapy (CR1) and outcomes, we assembled a cohort of 242 individuals with TP53-mutated myeloid neoplasms and ≥10% blasts with well-annotated clinical, molecular and pathology data. Key outcomes examined were CR1 & 24-month survival (OS24).

Germline Variants Incidentally Detected via Tumor-Only Genomic Profiling of Patients With Mesothelioma.

Importance: Patients with mesothelioma often have next-generation sequencing (NGS) of their tumor performed; tumor-only NGS may incidentally identify germline pathogenic or likely pathogenic (P/LP) variants despite not being designed for this purpose. It is unknown how frequently patients with mesothelioma have germline P/LP variants incidentally detected via tumor-only NGS.

Objective: To determine the prevalence of incidental germline P/LP variants detected via tumor-only NGS of mesothelioma.

Characterizing the distribution of alterations in mesothelioma and their correlation to morphology.

Objectives: Mesothelioma is a lethal disease that arises from the serosal lining of organ cavities. Several recurrent alterations have been observed in pleural and peritoneal -mesotheliomas, including in BAP1, NF2, and CDKN2A. Although specific histopathologic parameters have been correlated with prognosis, it is not as well known whether genetic alterations correlate with histologic findings.

Endometrial Carcinomas With Subclonal Loss of Mismatch Repair Proteins: A Clinicopathologic and Genomic Study.

Subclonal loss of mismatch repair (MMR) proteins has been described in a small subset of endometrial carcinomas (ECs), but the genomic basis for this phenomenon has received limited attention. Herein, we retrospectively evaluated all ECs with MMR immunohistochemistry (n=285) for subclonal loss, and in those (n=6), performed a detailed clinicopathologic and genomic comparison of the MMR-deficient and MMR-proficient components. Three tumors were FIGO stage IA, and one each stage IB, II, and IIIC2.

TSC/MTOR mutated renal cell carcinoma with leiomyomatous stroma is a distinct entity: a comprehensive study of 12 cases.

The 2016 World Health Organization (WHO) Classification of Tumors of the Urinary System includes renal cell carcinoma (RCC) with leiomyomatous stroma (RCC-LS) as a provisional category. Recent studies have shown that this category includes at least 4 subtypes: clear cell (CCRCC), clear cell papillary renal cell tumor (CCPRCT), ELOC (TCEB1) mutated, and a subtype of RCC with TSC/MTOR mutations. The most recent 2022 World Health Organization (WHO) Classification of Tumors of the Urinary System includes ELOC mutated RCC-LS as a distinct entity but does not address any other renal tumors with smooth muscle stroma.

Use of a Vanadate Oxidation Conjugated Bilirubin Assay to Reduce Test Cancellations Resulting from Hemolyzed Specimens in Pediatric Patients.

Objectives: We sought to replace the highly hemolysis-susceptible diazo conjugated bilirubin (Bc) assay with the more robust vanadate oxidation method and determine its impact on test cancellation in the pediatric population.

Methods: Analytical validation of the Randox vanadate assay and comparison with the Roche diazo method were performed. The frequency of pediatric sample cancellation because of hemolysis was compared between the diazo and vanadate methods by retrospective analysis of clinical test data.

NF2-mutated Renal Carcinomas Have Common Morphologic Features Which Overlap With Biphasic Hyalinizing Psammomatous Renal Cell Carcinoma: A Comprehensive Study of 14 Cases.

Genetic alterations involving NF2 occur at low frequencies in renal cell carcinoma across all of the major histologic subtypes and have been associated with adverse outcomes. To better characterize tumors harboring these alterations, we identified 14 cases with NF2 mutations that had been previously diagnosed as papillary renal cell carcinoma; renal cell carcinoma, unclassified; or translocation associated renal cell carcinoma. These tumors were characterized by a tubulopapillary architecture, sclerotic stroma, microscopic coagulative necrosis, and psammomatous calcifications.

EZR-ROS1 fusion renal cell carcinoma mimicking urothelial carcinoma: report of a previously undescribed gene fusion in renal cell carcinoma.

A subset of renal cell carcinomas harbor gene fusions, and we report the first case of an EZR-ROS1 fusion in renal cell carcinoma. A 47-year-old female presented with hematuria and a mass involving the renal pelvis. Renal biopsy revealed a tumor with solid and tubular architecture that was diffusely positive for PAX8, CK7, and vimentin; retained expression of INI1; focally positive for P504S; and negative for GATA3 and TFE3.

Functional Assessment of Platelet Dense Granule ATP Release.

Objectives: This study was undertaken to explore the feasibility of assessing platelet dense granule release in response to platelet stimuli, using less than 1 mL of whole blood (WB).

Methods: Optimization of the luciferin-luciferase (LL) assay for ATP release, together with additional modifications, was applied to 1:10 diluted WB.

Results: LL assay optimization using nonstirred 1:10 diluted WB resulted in dense granule ATP release in response to thrombin receptor-activating peptide (TRAP) of similar magnitude to that observed using stirred platelet-rich plasma.

TSC/MTOR-mutated eosinophilic renal tumors are a distinct entity that is CK7+/CK20-/vimentin-: a validation study.

Unclassified renal cell carcinoma (RCC) accounts for ∼10% of renal tumors, and the most common histologic finding in these cases is eosinophilic cytoplasm. We previously demonstrated that a subset of eosinophilic renal tumors with heterogeneous morphology and immunohistochemical (IHC) staining harbored pathogenic mutations in tuberous sclerosis complex (TSC) or mammalian target of rapamycin (MTOR) as the primary defining mutation. We identified an additional 8 cases of eosinophilic tumors with unusual morphology that were originally diagnosed as chromophobe RCC (CHRCC) or CHRCC, eosinophilic variant.

Educational Case: Pilocytic Astrocytoma With Atypical Features.

http://journals.sagepub.com/doi/10.

A case of dual-mechanism immune-related anaemia in a patient with metastatic melanoma treated with nivolumab and ipilimumab.

Background: The combination of the immune checkpoint inhibitors (ICIs) ipilimumab and nivolumab is a mainstay of treatment for selected patients with metastatic melanoma. This combination also results in more frequent immune-related adverse events (irAEs) than either ICI alone. These irAEs can be severe and their pathogenesis is poorly understood.

IL-33 Drives Monocyte Recruitment to Lung Interstitium through Chemokine Upregulation.

Tissue infiltration by circulating monocytes is a critical step in the initiation and augmentation of type 2 inflammatory responses in the lungs. Our studies demonstrate that IL-33 mice have a defect in monocyte extravasation from the vasculature to the lung interstitium during induction of type 2 inflammatory responses. This result suggests that monocyte migration to the lungs is IL-33 dependent, and we found that administration of exogenous recombinant IL-33 is sufficient to restore monocyte localization to the lung interstitium.

Nuclear grade and necrosis predict prognosis in malignant epithelioid pleural mesothelioma: a multi-institutional study.

A recently described nuclear grading system predicted survival in patients with epithelioid malignant pleural mesothelioma. The current study was undertaken to validate the grading system and to identify additional prognostic factors. We analyzed cases of epithelioid malignant pleural mesothelioma from 17 institutions across the globe from 1998 to 2014.

The role of dendritic cells and monocytes in the maintenance and loss of respiratory tolerance.

Promoting tolerance to inhaled antigens is an active area of study with the potential to benefit the millions of Americans currently suffering from respiratory allergies and asthma. Interestingly, not all individuals with atopy are symptomatic, arguing that sensitization alone does not lead to an allergic clinical phenotype. Respiratory dendritic cells (rDCs), classically associated with inducing inflammatory responses, can actively promote tolerance.

Distinct dendritic cell subsets actively induce Th2 polarization.

The mechanisms by which dendritic cells induce Th2 polarization (DC(Th2) cells) have been controversial. Many have argued that DC(Th2) cells are not a distinct functional DC subset, but rather, DC-induced polarization of Th2 cells is a default pathway that occurs in the absence of inflammatory signals leading to DC-induced polarization of Th1/Th17 cells. However, recent studies demonstrate that distinct subsets of tissue DCs actively polarize Th2 cells after stimulation with type-2 inducing stimuli.

Commensal bacteria protect against food allergen sensitization.

Environmentally induced alterations in the commensal microbiota have been implicated in the increasing prevalence of food allergy. We show here that sensitization to a food allergen is increased in mice that have been treated with antibiotics or are devoid of a commensal microbiota. By selectively colonizing gnotobiotic mice, we demonstrate that the allergy-protective capacity is conferred by a Clostridia-containing microbiota.

Signaling through FcRγ-associated receptors on dendritic cells drives IL-33-dependent TH2-type responses.

Background: Although allergic sensitization can be generated against various allergens, it is unknown how such a diversity of antigens is able to promote TH2-mediated inflammation leading to atopy. Our previous studies demonstrated that allergen-specific IgG immune complexes (ICs) and house dust mite (HDM) extract both induced dendritic cells (DCs) to drive TH2-mediated inflammation, but the mechanism by which these diverse stimuli produce similar responses is unknown.

Objective: We sought to identify the DC signaling pathways used by TH2 stimuli to promote TH2-mediated inflammation.

Transcription factor IRF4 drives dendritic cells to promote Th2 differentiation.

Atopic asthma is an inflammatory pulmonary disease associated with Th2 adaptive immune responses triggered by innocuous antigens. While dendritic cells (DCs) are known to shape the adaptive immune response, the mechanisms by which DCs promote Th2 differentiation remain elusive. Herein we demonstrate that Th2-promoting stimuli induce DC expression of IRF4.

IL-33-dependent induction of allergic lung inflammation by FcγRIII signaling.

Atopic asthma is a chronic inflammatory disease of the lungs generally marked by excessive Th2 inflammation. The role of allergen-specific IgG in asthma is still controversial; however, a receptor of IgG-immune complexes (IgG-ICs), FcγRIII, has been shown to promote Th2 responses through an unknown mechanism. Herein, we demonstrate that allergen-specific IgG-ICs, formed upon reexposure to allergen, promoted Th2 responses in two different models of IC-mediated inflammation that were independent of a preformed T cell memory response.

The contribution of allergen-specific IgG to the development of th2-mediated airway inflammation.

In both human asthmatics and animal models of allergy, allergen-specific IgG can contribute to Th2-mediated allergic inflammation. Mouse models have elucidated an important role for IgG and Fc-gamma receptor (FcγR) signaling on antigen presenting cells (APC) for the induction of airway inflammation. These studies suggest a positive feedback loop between IgG produced by the adaptive B cell response and FcγR signaling on innate immune cells.