Advanced prostate cancer (PCa) patients with bone metastases are treated with androgen pathway directed therapy (APDT). However, this treatment invariably fails and the cancer becomes castration resistant. To elucidate resistance mechanisms and to provide a more predictive pre-clinical research platform reflecting tumor heterogeneity, we established organoids from a patient-derived xenograft (PDX) model of bone metastatic prostate cancer, PCSD1. APDT-resistant PDX-derived organoids (PDOs) emerged when cultured without androgen or with the anti-androgen, enzalutamide. Transcriptomics revealed up-regulation of neurogenic and steroidogenic genes and down-regulation of DNA repair, cell cycle, circadian pathways and the severe acute respiratory syndrome (SARS)-CoV-2 host viral entry factors, ACE2 and TMPRSS2. Time course analysis of the cell cycle in live cells revealed that enzalutamide induced a gradual transition into a reversible dormant state as shown here for the first time at the single cell level in the context of multi-cellular, 3D living organoids using the Fucci2BL fluorescent live cell cycle tracker system. We show here a new mechanism of castration resistance in which enzalutamide induced dormancy and novel basal-luminal-like cells in bone metastatic prostate cancer organoids. These PDX organoids can be used to develop therapies targeting dormant APDT-resistant cells and host factors required for SARS-CoV-2 viral entry.

Purpose: Glycogen storage disease type IV (GSD IV) has historically been divided into discrete hepatic (classic hepatic, non-progressive hepatic) and neuromuscular (perinatal-congenital neuromuscular, juvenile neuromuscular) subtypes. However, the extent to which this subtype-based classification system accurately captures the landscape of phenotypic variation among GSD IV patients has not been systematically assessed.Methods: This study synthesized clinical data from all eligible cases of GSD IV in the published literature to evaluate whether this disorder is better conceptualized as discrete subtypes or a clinical continuum. A novel phenotypic scoring approach was applied to characterize the extent of hepatic, neuromuscular, and cardiac involvement in each eligible patient.Results: 146 patients met all inclusion criteria. The majority (61%) of those with sufficient data to be scored exhibited phenotypes that were not fully consistent with any of the established subtypes. These included patients who exhibited combined hepatic-neuromuscular involvement; patients whose phenotypes were intermediate between the established hepatic or neuromuscular subtypes; and patients who presented with predominantly cardiac disease.Conclusion: The application of this novel phenotypic scoring approach showed that–in contrast to the traditional subtype-based view–GSD IV may be better conceptualized as a multidimensional clinical continuum, whereby hepatic, neuromuscular, and cardiac involvement occur to varying degrees in different patients.

Optimal treatment of retroperitoneal sarcoma (RPS) remains undefined. Here, we report the feasibility of using high-dose boost radiation (3-4 Gy) to the central part of the tumor in patients with unresectable RPS. Five patients with unresectable RPS were treated with radiation therapy using a central boost technique with intensity modulated radiation therapy. On average, doses of 25 Gy to 45 Gy were delivered to the outer part of the tumor (planning target volume 1), while the central part of the tumor (planning target volume 2) received a 56 Gy to 75 Gy physical dose, which translates to a 62.67 Gy to 87.5 Gy equivalent dose in 2 Gy fractions (EQD2). To minimize radiation toxicity to the adjacent bowel and other organs, we used sequential, interdigitated, or simultaneous integrated boost (SIB) techniques. In this case series of variable RPS histology, the median survival postradiation therapy was 30 months. Three of the 5 patients had clinically stable local disease on follow-up scans, and none of the patients experienced clinically significant toxicity. In summary, in this small case series of 5 patients, treatment was tolerated well, and excellent local responses were observed regardless of the timing of the central boost. Given the high rates of metastatic disease that developed in responding patients, effective systemic therapy will likely be needed for unresectable RPS treated with aggressive radiation therapy to the central part of the tumor.

Advanced prostate cancer (PCa) patients with bone metastases are treated standardly with Androgen Pathway Directed Therapy (APDT), however, they invariably become APDT-resistant. To elucidate resistance mechanisms and to provide more predictive pre-clinical research platforms reflecting tumor heterogeneity, w e established organoids from patient-derived xenograft (PDX) models of bone metastatic prostate cancer. APDT-resistant PDX-derived organoids (PDOs) emerged when cultured without androgen or with the anti-androgen, enzalutamide. Transcriptomics revealed up-regulation of neurogenic and steroidogenic genes and down-regulation of DNA repair, cell cycle, circadian pathways and the severe acute respiratory syndrome (SARS)-CoV-2 host viral entry factors, ACE2 and TMPRSS2. These experiments demonstrated that PDOs can be used to develop therapies targeting dormant APDT-resistant cells and host factors required for SARS-CoV-2 viral entry. Enzalutamide treatment decreased androgen receptor (AR) protein and induced dormant, hybrid basal-luminal cells as shown here for the first time in live organoids using the Fucci2BL fluorescent cell cycle tracker system.

Epstein–Barr virus (EBV)-positive primary central nervous system lymphoma (PCNSL) is a rare entity typically associated with profound immunosuppression, most commonly in transplant recipients or individuals with HIV. We report a case of EBV-positive PCNSL arising in a 75-year-old male with myasthenia gravis receiving chronic mycophenolate mofetil (MMF) therapy outside the transplant setting. The patient presented with progressive neurological deficits, and brain magnetic resonance imaging demonstrated multiple enhancing lesions. Stereotactic biopsy revealed diffuse large B-cell lymphoma of non–germinal center subtype with immunoblastic features and EBV-encoded RNA (EBER) positivity, confirming EBV-positive PCNSL. MMF was discontinued, and the patient was treated with rituximab and high-dose methotrexate, resulting in stable disease. This case highlights that prolonged MMF therapy may confer sufficient immunosuppression to permit EBV-driven lymphoproliferative disease even in non-transplant patients. Early recognition, withdrawal of immunosuppression, and initiation of methotrexate-based chemotherapy can lead to favorable outcomes.