Treatment-emergent neuroendocrine prostate cancer with a germline BRCA2 mutation: identification of a candidate reversion mutation associated with platinum/PARP-inhibitor resistance.

Neuroendocrine prostate cancer (NEPC) is a highly aggressive histologic subtype of prostate cancer associated with a poor prognosis. Its incidence is expected to increase as castration-resistant disease emerges from the widespread use of potent androgen receptor-targeting therapies, such as abiraterone and enzalutamide. Defects in homologous recombination repair genes, such as BRCA1/2, are also being increasingly detected in individuals with advanced prostate cancer. We present the case of a 65-yr-old man with a germline BRCA2 mutation who developed explosive treatment-emergent, small-cell neuroendocrine prostate cancer. He achieved a complete response to platinum-containing chemotherapy, but a limited remission duration with the use of olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, as maintenance therapy. Upon relapse, tumor genomic profiling revealed a novel 228-bp deletion in exon 11 of the BRCA2 gene. The addition of the anti-PD1 drug pembrolizumab to olaparib was ineffective. This case highlights the ongoing challenges in treating neuroendocrine prostate cancer, even in the setting of homologous recombination repair deficiency.

Fungal rhinosinusitis and imaging modalities.

This report provides an overview of fungal rhinosinusitis with a particular focus on acute fulminant invasive fungal sinusitis (AFIFS). Imaging modalities and findings that aid in diagnosis and surgical planning are reviewed with a pathophysiologic focus. In addition, the differential diagnosis based on imaging suggestive of AFIFS is considered.

Extreme intraoperative hyperkalemia in a non dialysis patient undergoing kidney transplantation.

The majority of patients who present for kidney transplantation have end stage renal disease and are on dialysis. Those patients are known to be at risk for the development of hyperkalemia. A patient who has not required dialysis, and with stable potassium levels would not be expected to acutely develop intraoperative hyperkalemia. Presented here is an unusual case in which a 61-year-old man with chronic renal disease but no history of dialysis developed severe intraoperative hyperkalemia during a renal transplant.

Determination of Kaposi's sarcoma-associated herpesvirus C-terminal latency-associated nuclear antigen residues mediating chromosome association and DNA binding.

Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen (LANA) tethers viral terminal repeat (TR) DNA to mitotic chromosomes to mediate episome persistence. The 1,162-amino-acid LANA protein contains both N- and C-terminal chromosome attachment regions. The LANA C-terminal domain self-associates to specifically bind TR DNA and mitotic chromosomes. Here, we used alanine scanning substitutions spanning residues 1023 to 1145 to investigate LANA self-association, DNA binding, and C-terminal chromosome association. No residues were essential for LANA oligomerization, as assayed by coimmunoprecipitation experiments, consistent with redundant roles for amino acids in self-association. Different subsets of amino acids were important for DNA binding, as assayed by electrophoretic mobility shift assay, and mitotic chromosome association, indicating that distinct C-terminal LANA subdomains effect DNA and chromosome binding. The DNA binding domains of LANA and EBNA1 are predicted to be structurally homologous; certain LANA residues important for DNA binding correspond to those with roles in EBNA1 DNA binding, providing genetic support for at least partial structural homology. In contrast to the essential role of N-terminal LANA chromosome targeting residues in DNA replication, deficient C-terminal chromosome association did not reduce LANA-mediated DNA replication.