Bipolar androgen therapy for treatment of metastatic castration-resistant prostate cancer: A case series.

INTRODUCTION: Advanced prostate cancer treatment has improved with androgen receptor signaling inhibitors (ARPI), yet many patients develop metastatic castration-resistant prostate cancer (mCRPC), characterized by sustained androgen receptor (AR) signaling. Bipolar androgen therapy (BAT) introduces supraphysiologic testosterone levels to inhibit tumor growth, offering novel treatment for mCRPC by exploiting AR-dependent mechanisms. CASE PRESENTATIONS: Case 1: A 53-year-old man with mCRPC, post multiple systemic therapies, initiated BAT and pembrolizumab, achieving PSA reduction and improved quality of life before progression. The patient exhibited AR amplification, which may have contributed to favorable response to BAT. Case 2: A 73-year-old man with recurrent prostate cancer, stable on ADT and abiraterone, experienced PSA decline with BAT to an undetectable level, maintaining stability post-therapy discontinuation. Case 3: A 73-year-old man with metastatic prostate cancer, initially resistant to enzalutamide, achieved clinical benefit and disease control with BAT, although he did not meet PSA response criteria, patient had remarkable response upon enzalutamide rechallenge. Case 4: A 90-year-old man with localized prostate cancer, refractory to multiple treatments, experienced symptom relief and PSA reduction with BAT before progression. CONCLUSION: BAT represents a promising treatment strategy for mCRPC. This case series underscores BAT's potential to induce significant clinical and biochemical responses, resensitize tumors to ARPIs, and improve patients' quality of life. Despite eventual progression in some cases, BAT offers a period of disease control. Further research is needed to optimize patient selection and understand the molecular determinants of BAT responsiveness.

Subthalamic nucleus deep brain stimulation programming settings do not correlate with Parkinson's disease severity.

BACKGROUND: Deep brain stimulation (DBS) is a well-established treatment for Parkinson's disease (PD). While the success of DBS is dependent on careful patient selection and accurate lead placement, programming parameters play a pivotal role in tailoring therapy on the individual level. Various algorithms have been developed to streamline the initial programming process, but the relationship between pre-operative patient characteristics and post-operative device settings is unclear. In this study, we investigated how PD severity correlates with DBS settings. METHODS: We conducted a retrospective review of PD patients who underwent DBS of the subthalamic nucleus at one US tertiary care center between 2014 and 2018. Pre-operative patient characteristics and post-operative programming data at various intervals were collected. Disease severity was measured using the Unified Parkinson's Disease Rating Scale score (UPDRS) as well as levodopa equivalent dose (LED). Correlation analyses were conducted looking for associations between pre-operative disease severity and post-operative programming parameters. RESULTS: Fifty-six patients were analyzed. There was no correlation between disease severity and any of the corresponding programming parameters. Pre-operative UPDRS scores on medication were similar to post-operative scores with DBS. Settings of amplitude, frequency, and pulse width increased significantly from 1 to 6 months post-operatively. Stimulation volume, inferred by the distance between contacts used, also increased significantly over time. CONCLUSIONS: Interestingly, we found that patients with more advanced disease responded to electrical stimulation similarly to patients with less advanced disease. These data provide foundational knowledge of DBS programming parameters used in a single cohort of PD patients over time.

Superior accuracy and precision of SEEG electrode insertion with frame-based vs. frameless stereotaxy methods.

BACKGROUND: Stereotactic electroencephalography (SEEG) has largely become the preferred method for intracranial seizure localization in epileptic patients due to its low morbidity and minimally invasive approach. While robotic placement is gaining popularity, many centers continue to use manual frame-based and frameless methods for electrode insertion. However, it is unclear how these methods compare in regard to accuracy, precision, and safety. Here, we aim to compare frame-based insertion using a CRW frame (Integra®) and frameless insertion using the StealthStation™ S7 (Medtronic®) navigation system for common temporal SEEG targets. METHODS: We retrospectively examined electrode targets in SEEG patients that were implanted with either frame-based or frameless methods at a level 4 epilepsy center. We focused on two commonly used targets: amygdala and hippocampal head. Stealth station software was used to merge pre-operative MR with post-operative CT images for each patient, and coordinates for each electrode tip were calculated in relation to the midcommissural point. These were compared to predetermined ideal coordinates in regard to error and directional bias. RESULTS: A total of 81 SEEG electrodes were identified in 23 patients (40 amygdala and 41 hippocampal head). Eight of 45 electrodes (18%) placed with the frameless technique and 0 of 36 electrodes (0%) placed with the frame-based technique missed their target and were not clinically useful. The average Euclidean distance comparing actual to ideal electrode tip coordinates for frameless vs. frame-based techniques was 11.0 mm vs. 7.1 mm (p < 0.001) for the amygdala and 12.4 mm vs. 8.5 mm (p < 0.001) for the hippocampal head, respectively. There were no hemorrhages or clinical complications in either group. CONCLUSIONS: Based on this series, frame-based SEEG insertion is significantly more accurate and precise and results in more clinically useful electrode contacts, compared to frameless insertion using a navigation guidance system. This has important implications for centers not currently using robotic insertion.

Characterization of FOLH1 Expression in Renal Cell Carcinoma.

PURPOSE: Given the emergence of PSMA-targeted diagnostic agents and therapeutics, we sought to investigate patterns of FOLH1 expression in RCC and their impacts on RCC outcomes. METHODS: We conducted a pooled multi-institutional analysis of patients with RCC having undergone DNA and RNA next-generation sequencing. FOLH1-high/low expression was defined as the ≥75th/<25th percentile of RNA transcripts per million (TPM). Angiogenic, T-effector, and myeloid expression signatures were calculated using previously defined gene sets. Kaplan-Meier estimates were calculated from the time of tissue collection or therapy start. RESULTS: We included 1,724 patients in the analysis. FOLH1 expression was significantly higher in clear cell (71%) compared to non-clear cell RCC tumors (19.0 versus 3.3 TPM, p < 0.001) and varied by specimen site (45% primary kidney/55% metastasis, 13.6 versus 9.9 TPM, p < 0.001). FOLH1 expression was correlated with angiogenic gene expression (Spearman = 0.76, p < 0.001) and endothelial cell abundance (Spearman = 0.76, p < 0.001). While OS was similar in patients with FOLH1-high versus -low ccRCC, patients with FOLH1-high clear cell tumors experienced a longer time on cabozantinib treatment (9.7 versus 4.6 months, respectively, HR 0.57, 95% CI 0.35-0.93, p < 0.05). CONCLUSIONS: We observed differential patterns of FOLH1 expression based on histology and tumor site in RCC. FOLH1 was correlated with angiogenic gene expression, increased OS, and a longer duration of cabozantinib treatment.

Rhesus macaque versus rat divergence in the corticospinal projectome.

We used viral intersectional tools to map the entire projectome of corticospinal neurons associated with fine distal forelimb control in Fischer 344 rats and rhesus macaques. In rats, we found an extraordinarily diverse set of collateral projections from corticospinal neurons to 23 different brain and spinal regions. Remarkably, the vast weighting of this "motor" projection was to sensory systems in both the brain and spinal cord, confirmed by optogenetic and transsynaptic viral intersectional tools. In contrast, rhesus macaques exhibited far heavier and narrower weighting of corticospinal outputs toward spinal and brainstem motor systems. Thus, corticospinal systems in macaques primarily constitute a final output system for fine motor control, whereas this projection in rats exerts a multi-modal integrative role that accesses far broader CNS regions. Unique structural-functional correlations can be achieved by mapping and quantifying a single neuronal system's total axonal output and its relative weighting across CNS targets.