Repeat Next-Generation Sequencing Testing on Progression in Men With Metastatic Prostate Cancer Can Identify New Actionable Alterations.

PURPOSE: There are limited data available on the real-world patterns of molecular testing in men with advanced prostate cancer. We thus sought to evaluate next-generation sequencing (NGS) testing in the United States, focused on single versus serial NGS testing, the different disease states of testing (hormone-sensitive v castration-resistant, metastatic vs nonmetastatic), tissue versus plasma circulating tumor DNA (ctDNA) assays, and how often actionable data were found on each NGS test. METHODS: The Prostate Cancer Precision Medicine Multi-Institutional Collaborative Effort clinical-genomic database was used for this retrospective analysis, including 1,597 patients across 15 institutions. Actionable NGS data were defined as including somatic alterations in homologous recombination repair genes, mismatch repair deficiency, microsatellite instability (MSI-high), or a high tumor mutational burden ≥10 mut/MB. RESULTS: Serial NGS testing (two or more NGS tests with specimens collected more than 60 days apart) was performed in 9% (n = 144) of patients with a median of 182 days in between test results. For the second NGS test and beyond, 82.1% (225 of 274) of tests were from ctDNA assays and 76.1% (217 of 285) were collected in the metastatic castration-resistant setting. New actionable data were found on 11.1% (16 of 144) of second NGS tests, with 3.5% (5 of 144) of tests detecting a new BRCA2 alteration or MSI-high. A targeted therapy (poly (ADP-ribose) polymerase inhibitor or immunotherapy) was given after an actionable result on the second NGS test in 31.3% (5 of 16) of patients. CONCLUSION: Repeat somatic NGS testing in men with prostate cancer is infrequently performed in practice and can identify new actionable alterations not present with initial testing, suggesting the utility of repeat molecular profiling with tissue or blood of men with metastatic castration-resistant prostate cancer to guide therapy choices.

Prospective Approach to Deciphering the Impact of Intercellular Mitochondrial Transfer from Human Neural Stem Cells and Brain Tumor-Initiating Cells to Neighboring Astrocytes.

The communication between neural stem cells (NSCs) and surrounding astrocytes is essential for the homeostasis of the NSC niche. Intercellular mitochondrial transfer, a unique communication system that utilizes the formation of tunneling nanotubes for targeted mitochondrial transfer between donor and recipient cells, has recently been identified in a wide range of cell types. Intercellular mitochondrial transfer has also been observed between different types of cancer stem cells (CSCs) and their neighboring cells, including brain CSCs and astrocytes. CSC mitochondrial transfer significantly enhances overall tumor progression by reprogramming neighboring cells. Despite the urgent need to investigate this newly identified phenomenon, mitochondrial transfer in the central nervous system remains largely uncharacterized. In this study, we found evidence of intercellular mitochondrial transfer from human NSCs and from brain CSCs, also known as brain tumor-initiating cells (BTICs), to astrocytes in co-culture experiments. Both NSC and BTIC mitochondria triggered similar transcriptome changes upon transplantation into the recipient astrocytes. In contrast to NSCs, the transplanted mitochondria from BTICs had a significant proliferative effect on the recipient astrocytes. This study forms the basis for mechanistically deciphering the impact of intercellular mitochondrial transfer on recipient astrocytes, which will potentially provide us with new insights into the mechanisms of mitochondrial retrograde signaling.

Venetoclax-based therapy in treatment-naïve and relapsed/refractory acute myeloid leukemia.

Combining venetoclax with the hypomethylating agents azacitidine or decitabine has shown high complete response rates (60-70 %) in newly diagnosed (ND) acute myeloid leukemia (AML). However, studies addressing the efficacy of this approach in relapsed/refractory (R/R) AML remain limited. We conducted a retrospective analysis on patients treated with venetoclax-based therapy at a single institution. Objective response rates (ORR) and overall survival (OS) were assessed using logistic regression and Cox regression models, respectively. The total study population exhibited an ORR of 64 % with a complete remission at 34 %, complete remission with incomplete count recovery at 19%, and morphologic leukemia free state at 11 %. Patients with ND AML had a better ORR (71 %) compared to R/R AML (55 %), but the difference was not statistically significant. Median OS for the overall population was 14.4 months (range: 2-26 months). In the ND group, patients had a longer 6-month OS (82 % vs. 55 % in R/R AML), while both cohorts showed similar 12- and 24-month OS. Factors such as the hypomethylating agent chosen, adverse cytogenetics, TP53 mutations, prior hypomethylating agent use, and stem cell transplant status did not significantly affect ORR or OS. These findings support the effectiveness of venetoclax-based treatments in ND and R/R AML.

Biomarker-Directed Therapy in Black and White Men With Metastatic Castration-Resistant Prostate Cancer.

Importance: Black men have higher incidence and mortality from prostate cancer. Whether precision oncology disparities affect Black men with metastatic castration-resistant prostate cancer (mCRPC) is unknown. Objective: To compare precision medicine data and outcomes between Black and White men with mCRPC. Design, Setting, and Participants: This retrospective cohort study used data collected by the Prostate Cancer Precision Medicine Multi-Institutional Collaborative Effort (PROMISE) consortium, a multi-institutional registry with linked clinicogenomic data, from April 2020 to December 2021. Participants included Black and White patients with mCRPC with molecular data. Data were analyzed from December 2021 to May 2023. Exposures: Database-reported race and ethnicity. Main Outcomes and Measures: The primary outcome was the frequency of actionable molecular data, defined as the presence of mismatch repair deficiency (MMRD) or high microsatellite instability (MSI-H), homologous recombination repair deficiency, or tumor mutational burden of 10 mutations per megabase or greater. Secondary outcomes included the frequency of other alterations, the type and timing of genomic testing performed, and use of targeted therapy. Efficacy outcomes were prostate-specific antigen response rate, site-reported radiographic response, and overall survival. Results: A total of 962 eligible patients with mCRPC were identified, including 204 Black patients (21.2%; median [IQR] age at diagnosis, 61 [55-67] years; 131 patients [64.2%] with Gleason scores 8-10; 92 patients [45.1%] with de novo metastatic disease) and 758 White patients (78.8%; median [IQR] age, 63 [57-69] years; 445 patients [58.7%] with Gleason scores 8-10; 310 patients [40.9%] with de novo metastatic disease). Median (IQR) follow-up from mCRPC was 26.6 (14.2-44.7) months. Blood-based molecular testing was more common in Black men (111 men [48.7%]) than White men (317 men [36.4%]; P < .001). Rates of actionable alterations were similar between groups (65 Black men [32.8%]; 215 White men [29.1%]; P = .35), but MMRD or MSI-H was more common in Black men (18 men [9.1]) than White men (36 men [4.9%]; P = .04). PTEN alterations were less frequent in Black men than White men (31 men [15.7%] vs 194 men [26.3%]; P = .003), as were TMPRSS alterations (14 men [7.1%] vs 155 men [21.0%]; P < .001). No other differences were seen in the 15 most frequently altered genes, including TP53, AR, CDK12, RB1, and PIK3CA. Matched targeted therapy was given less frequently in Black men than White men (22 men [33.5%] vs 115 men [53.5%]; P = .008). There were no differences in response to targeted therapy or survival between the two cohorts. Conclusions and Relevance: This cohort study of men with mCRPC found higher frequency of MMRD or MSI-H and lower frequency of PTEN and TMPRSS alterations in Black men compared with White men. Although Black men received targeted therapy less frequently than White men, no differences were observed in clinical outcomes.

Neutropenic Enterocolitis: A Rare Complication of Sacituzumab Govitecan.

Neutropenic enterocolitis (NE) is a rare form of inflammatory colitis seen in severely neutropenic patients. Patients with NE typically have severe neutropenia (absolute neutrophil count [ANC] <500/mm3) in the setting of exposure to cytotoxic chemotherapy. Taxanes have traditionally been associated with NE, but there has been a growing amount of literature, linking a variety of other chemotherapeutic agents. Sacituzumab govitecan (SG) is a novel antibody-drug conjugate comprising a topoisomerase I inhibitor component conjugated to an antibody targeting human trophoblast cell-surface antigen 2 (Trop-2). SG is approved for the treatment of unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC) and urothelial cancer. We report a case of NE in a patient with mTNBC receiving SG and its successful management. Prompt diagnosis and management of NE in such patients can be potentially lifesaving.

Manuscript Review at the Journal of Pediatric Gastroenterology and Nutrition: The Impact of Reviewers on Editor Decisions.

OBJECTIVE: Given the importance of scholarly work in academic medicine, better understanding of the manuscript review process (MRP) is useful for authors, reviewers, and editorial boards. We aim to describe the MRP at the Journal of Pediatric Gastroenterology and Nutrition (JPGN), assess the correlation between editor decisions and reviewer recommendations, and provide transparency to this process. METHODS: All manuscripts submitted in 2018 to JPGN were included in this analysis. Data included reviewers' manuscript scores and recommendations, time spent on each review by reviewers, the editor's rating of the reviewers' reviews, the editor's first decision, and final outcome. Data were collated using the JPGN manuscript submission website, Editorial Manager. RESULTS: 1023 manuscripts were submitted to JPGN in 2018 and included in this analysis. Of these, 486 manuscripts had at least two peer reviewers. The recommendations of the two reviewers were in agreement 43% of the time. Intra-class correlation (ICC) between the two reviewers suggests moderate agreement (ICC = 0.40). When both reviewers agreed to Not Reject (289/486), the editor agreed in 93% of cases (269/289). When both reviewers agreed to Reject (55/486), the editor agreed 100% of the time (55/55). The reviewers disagreed in about one-third of submissions (142/486), and the editor recommended to Reject in two-thirds of these cases (95/142). Overall, inter-reviewer agreement strongly correlated with the editor's initial decision (P < 0.001). CONCLUSIONS: The editor most often agreed with reviewers' assessments when there was concordance between the two reviewers' recommendations. About a third of peer reviews result in discordant recommendations between the two reviewers.

Beyond glucose: alternative sources of energy in glioblastoma.

Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults. With a designation of WHO Grade IV, it is also the most lethal primary brain tumor with a median survival of just 15 months. This is often despite aggressive treatment that includes surgical resection, radiation therapy, and chemotherapy. Based on the poor outcomes and prevalence of the tumor, the demand for innovative therapies continues to represent a pressing issue for clinicians and researchers. In terms of therapies targeting metabolism, the prevalence of the Warburg effect has led to a focus on targeting glucose metabolism to halt tumor progression. While glucose is the dominant source of growth substrate in GBM, a number of unique metabolic pathways are exploited in GBM to meet the increased demand for replication and progression. In this review we aim to explore how metabolites from fatty acid oxidation, the urea cycle, the glutamate-glutamine cycle, and one-carbon metabolism are shunted toward energy producing pathways to meet the high energy demand in GBM. We will also explore how the process of autophagy provides a reservoir of nutrients to support viable tumor cells. By so doing, we aim to establish a foundation of implicated metabolic mechanisms supporting growth and tumorigenesis of GBM within the literature. With the sparse number of therapeutic interventions specifically targeting metabolic pathways in GBM, we hope that this review expands further insight into the development of novel treatment modalities.

Herpes Simplex Virus 1 Infection Promotes the Growth of a Subpopulation of Tumor Cells in Three-Dimensional Uveal Melanoma Cultures.

Herpes simplex virus 1 (HSV-1)-mediated oncolytic therapy is an emerging cancer treatment modality with potential effectiveness against a variety of malignancies. To better understand the interaction of HSV-1 with neoplastic cells, we inoculated three-dimensional (3D) cultures of human uveal melanoma cells with HSV-1. 3D melanoma cultures were established by placing tumor cells on the surface of a Matrigel matrix, which was followed by the growth of tumor cells on the matrix surface and invasion of the Matrigel matrix by some tumor cells to form multicellular tumor spheroids within the matrix. When established 3D melanoma cultures were inoculated with HSV-1 by placing virus on the surface of cultures, virus infection caused extensive death of melanoma cells growing on the surface of the 3D matrix and significantly decreased the number of tumor cell spheroids within the matrix. However, HSV-1 infection did not lead to a complete destruction of tumor cells in the 3D cultures during a 17-day observation period and, surprisingly, HSV-1 infection promoted the growth of some melanoma cells within the matrix as determined by the significantly increased size of residual viable multicellular tumor spheroids in virus-inoculated 3D cultures at 17 days after virus inoculation. Acyclovir treatment inhibited HSV-1-induced tumor cell killing but did not block the virus infection-induced increase in spheroid size. These findings suggest that although HSV-1 oncolytic virotherapy may cause extensive tumor cell killing, it may also be associated with the unintended promotion of the growth of some tumor cells.IMPORTANCE Cancer cells are exposed to HSV-1 during oncolytic virotherapy with the intention of killing tumor cells. Our observations reported here suggest that potential dangers of HSV-1 oncolytic therapy include promotion of growth of some tumor cells. Furthermore, our findings raise the possibility that HSV-1 infection of neoplastic cells during natural infections or vaccinations may promote the growth of tumors. Our study indicates that HSV-1 infection of 3D tumor cell cultures provides an experimental platform in which mechanisms of HSV-1-mediated promotion of tumor cell growth can be effectively studied.

The impact of aging, hearing loss, and body weight on mouse hippocampal redox state, measured in brain slices using fluorescence imaging.

The relationships between oxidative stress in the hippocampus and other aging-related changes such as hearing loss, cortical thinning, or changes in body weight are not yet known. We measured the redox ratio in a number of neural structures in brain slices taken from young and aged mice. Hearing thresholds, body weight, and cortical thickness were also measured. We found striking aging-related increases in the redox ratio that were isolated to the stratum pyramidale, while such changes were not observed in thalamus or cortex. These changes were driven primarily by changes in flavin adenine dinucleotide, not nicotinamide adenine dinucleotide hydride. Multiple regression analysis suggested that neither hearing threshold nor cortical thickness independently contributed to this change in hippocampal redox ratio. However, body weight did independently contribute to predicted changes in hippocampal redox ratio. These data suggest that aging-related changes in hippocampal redox ratio are not a general reflection of overall brain oxidative state but are highly localized, while still being related to at least one marker of late aging, weight loss at the end of life.