Zebra-like bodies in COVID-19: is phospholipidosis evidence of hydroxychloroquine induced acute kidney injury?

COVID-19 (from SARS-CoV-2) is the cause of an ongoing pandemic, with an increasing number of cases and significant mortality worldwide. Clinical trials and extensive studies are being conducted on a large scale for a better understanding of the pathophysiology of this disease and its effect on different organs. Several experimental treatment protocols have been introduced, in which hydroxychloroquine (HCQ) was one of the first drugs used. While patients can develop many side effects of HCQ, studies have documented a rare association of long-term HCQ treatment with zebra-like bodies in the ultrastructural examination of kidney biopsies, a finding typically seen in Fabry's disease, as well as in association with chronic HCQ use, among other drugs. We present a similar finding in the postmortem examination of a male in his early seventies with COVID-19 infection, who received five days of HCQ treatment before stopping the medication due to cardiac and renal toxicity.

Superoxide Dismutase Mimetic Avasopasem Manganese Enhances Radiation Therapy Effectiveness in Soft Tissue Sarcomas and Accelerates Wound Healing.

Soft tissue sarcomas (STSs) are mesenchymal malignant lesions that develop in soft tissues. Despite current treatments, including radiation therapy (RT) and surgery, STSs can be associated with poor patient outcomes and metastatic recurrences. Neoadjuvant radiation therapy (nRT), while effective, is often accompanied by severe postoperative wound healing complications due to damage to the surrounding normal tissues. Thus, there is a need to develop therapeutic approaches to reduce nRT toxicities. Avasopasem manganese (AVA) is a selective superoxide dismutase mimetic that protects against IR-induced oral mucositis and lung fibrosis. We tested the efficacy of AVA in enhancing RT in STSs and in promoting wound healing. Using colony formation assays and alkaline comet assays, we report that AVA selectively enhanced the STS (liposarcoma, fibrosarcoma, leiomyosarcoma, and MPNST) cellular response to radiation compared to normal dermal fibroblasts (NDFs). AVA is believed to selectively enhance radiation therapy by targeting differential hydrogen peroxide clearance in tumor cells compared to non-malignant cells. STS cells demonstrated increased catalase protein levels and activity compared to normal fibroblasts. Additionally, NDFs showed significantly higher levels of GPx1 activity compared to STSs. The depletion of glutathione using buthionine sulfoximine (BSO) sensitized the NDF cells to AVA, suggesting that GPx1 may, in part, facilitate the selective toxicity of AVA. Finally, AVA significantly accelerated wound closure in a murine model of wound healing post RT. Our data suggest that AVA may be a promising combination strategy for nRT therapy in STSs.

Genomic Profiling of Metastatic Uveal Melanoma Shows Frequent Coexisting BAP1 or SF3B1 and GNAQ/GNA11 Mutations and Correlation With Prognosis.

OBJECTIVES: To identify therapeutic targets and correlate with clinical outcomes from mutation profiling of metastatic uveal melanoma (UM) using next-generation sequencing (NGS). METHODS: Melanoma cases that were tested using DNA-based NGS panels of 25 and/or 214 genes were evaluated retrospectively (263 cases) and identified 27 UM cases. BAP1 expression was examined by immunohistochemistry. RESULTS: Mutations in GNA11 (14) and GNAQ (12) were found in 96% (n = 27) of cases of UM, and most had coexisting BAP1 (17) or SF3B1 (4) mutations. Coexisting GNAQ/11-SF3B1 mutations correlated with a longer average time to first metastasis compared with GNAQ/11-BAP1 mutations (99.7 vs 38.5 months, P = .047). Three patients with BAP1 mutations received trametinib; two are still alive (15 months; 23 months), and one died (32 months). In non-UMs, only 4.2% (n = 236) had BAP1 and 3.8% had SF3B1 mutations; none had coexisting GNAQ/11 mutations. CONCLUSIONS: Coexisting BAP1/SF3B1 and GNAQ/11 mutations were unique to UM. SF3B1 mutations were reported to be UM-specific in melanoma and associated with rare/no metastasis. The finding of mutated SF3B1 in 14.8% (n = 27) of UMs suggests its role should be further evaluated. The correlation of BAP1/SF3B1 mutation with survival also warrants investigation.

PRC2 loss drives MPNST metastasis and matrix remodeling.

The histone methyltransferase PRC2 plays a complex role in cancer. Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas with frequent loss-of-function mutations in PRC2 that are associated with poor outcome. Here, we identify a critical role for PRC2 loss in driving MPNST metastasis. PRC2-dependent metastatic phenotypes included increased collagen-dependent invasion, upregulation of matrix-remodeling enzymes, and elevated lung metastasis in orthotopic mouse models. Furthermore, clinical sample analysis determined that PRC2 loss correlated with metastatic disease, increased fibrosis, and decreased survival in patients with MPNSTs. These results may have broad implications for PRC2 function across multiple cancers and provide a strong rationale for investigating potential therapies targeting ECM-remodeling enzymes and tumor fibrosis to improve outcomes in patients with MPNSTs.

The Postmortem Features of Mucormycosis.

Mucormycosis is a rare and severe invasive fungal infection caused by ubiquitous fungi of the order Mucorales. Infection often occurs in immunocompromised hosts and includes cutaneous, pulmonary, gastrointestinal, rhinocerebral, and disseminated forms of disease. Although the clinical characteristics of mucormycosis are well established, infection can be difficult to diagnose antemortem, resulting in frequent postmortem diagnoses. Despite this, the gross appearance of mucormycosis at autopsy has not been well described. In the present report we illustrate the gross and histologic findings in four autopsy cases of mucormycosis, including one case of pulmonary disease and three cases of disseminated mucormycosis with cerebral, pulmonary, hepatic, renal, and gastrointestinal involvement. In all cases autopsy examination demonstrated characteristic hemorrhagic infarcts with a targetoid appearance in the affected organs. These findings are secondary to fungal angioinvasion with subsequent thrombosis and tissue necrosis. Mucormycosis should be suspected at autopsy when these characteristic infarcts are identified within the proper clinical context, and a high suspicion for atypical infections should be maintained postmortem in immunosuppressed patients.

Creating Pathologists From a Post-Sophomore Pathology Fellowship: 21 Years and 126 Fellows at an Academic Pathology Department.

Medical student exposure to pathology is a continued concern for departments across the country as traditional pathology content is trimmed from medical school curricula. In a longstanding effort to recruit and expose more medical students to the practice of pathology, our institution has supported a year-long post-sophomore fellowship in pathology since the 1930s. The program employs 6 full-time medical students per year to function as junior residents, taking an active role in delivering surgical pathology and autopsy services, with additional opportunities for teaching, research, and electives. We evaluated residency specialty choices and current practice locations for our department's former post-sophomore fellows (PSFs) who participated in the program from 1995 to 2016. We surveyed them about their reasons for pursuing the post-sophomore fellowship and the program's effect on their clinical practice. From 1995 to 2016, our department employed 126 PSFs, 54 (43%) of whom pursued careers in pathology after completion of the post-sophomore fellowship. This represented 63% of our medical school's graduates who matched into pathology during this time frame (1997-2018; 86 total). Thirteen former PSFs (32.5%) have held academic faculty positions in pathology. PSFs who chose another specialty affirmed the positive influence of the fellowship on their current practice. Our post-sophomore fellowship program is exceptional in the number of students participating each year, and our institution shows a higher percentage of former PSFs pursuing careers in pathology compared to similar studies. The post-sophomore fellowship is an effective tool for recruiting medical students to a career in pathology.

Urothelial carcinoma with an NRF1-BRAF rearrangement and response to targeted therapy.

Although BRAF mutations are commonly identified in many solid tumors and the response of BRAF p.V600E-positive tumors to targeted therapy is well documented, BRAF rearrangements are less frequent and are predominantly found in low-grade glioma, melanoma, lung, colorectal, and thyroid carcinoma. Preclinical and clinical studies have demonstrated effectiveness of multiple therapies (RAF-targeted, ERK-targeted, or MEK-targeted) targeting BRAF-fusion harboring tumors. We report a rare NRF1-BRAF fusion with novel breakpoints, identified by next-generation sequencing-based assay, from a 69-year-old man with metastatic urothelial carcinoma (UC) of the renal pelvis and his initial clinical response to a second-generation MEK inhibitor, trametinib, before stopping the medication because of adverse side effects. The NRF1-BRAF fusion has only been reported in a single case of anaplastic pleomorphic xanthoastrocytoma, and BRAF rearrangement has never been reported in UC.