Nivolumab in patients with metastatic castration-resistant prostate cancer with and without DNA repair defects.

PURPOSE: Despite the success of immune checkpoint inhibitors (ICIs) across various cancers, their efficacy in metastatic castration-resistant prostate cancer (mCRPC) is modest, except for a subset of patients who experience significant, yet unpredictable, benefits. DNA repair defects (DRD) are associated with higher neoantigen load, which may predict response. Our study explored the potential of DRD for enhanced responsiveness to the ICI nivolumab. METHODS: We conducted a phase II, multi-center, single-arm trial evaluating nivolumab in post-docetaxel mCRPC patients. DRD was assessed using circulating tumor DNA (ctDNA). The primary endpoint was PSA50 response. Secondary endpoints included objective response rate (ORR), radiographic progression-free survival (rPFS), and overall survival (OS). Also, exploratory comprehensive genomic profiling was performed via whole-exome sequencing (WES) of tumor samples and matched normal tissue, alongside PD-L1 expression evaluation. RESULTS: Among the 38 enrolled patients, DRD was identifiable in 30.5% (11/36) through ctDNA and/or WES analysis. The overall PSA50 response rate was 10.5% (4/38). PSA50 response and ORR did not significantly differ between patients with and without DRD (18.2% vs. 8%; p = 0.57 and 50% vs. 17.6%, p= 0.27, respectively). Median PSA-PFS (1.9 vs. 2.8 months, p=0.52) and rPFS (3.4 vs. 5.5 months, p=0.7) were not statistically different between patients with and without DRD. Grade ≥ 3 adverse events were reported in 47.3% of participants. CONCLUSION: Nivolumab has clinical activity in a subset of mCRPC patients, however, DRD do not predicted response.These results highlight the necessity of identifying new biomarkers to more accurately determine mCRPC patients who might respond to ICIs.

Dose dense versus 3 weekly AC during neoadjuvant chemoimmunotherapy for triple negative breast cancer.

Neoadjuvant pembrolizumab plus chemotherapy (P + CT) has emerged as a standard of care for stage II-III triple-negative breast cancer (TNBC). However, the best anthracycline-cyclophosphamide (AC) schedule remains to be determined. While the KEYNOTE-522 regimen employs AC every 3 weeks (q3w AC), previous studies have shown overall survival benefits of dose-dense regimens for early-stage breast cancer. The Neo-Real study (GBECAM-0123) is a real-world data effort evaluating patients with TNBC treated with neoadjuvant P + CT in ten cancer centers since July 2020. The objective of this analysis was to evaluate the effectiveness and safety of dose-dense AC (ddAC) versus q3w AC. Among 333 patients included until November 2023, 311 completed neoadjuvant therapy and 279 underwent surgery with pathology reports available; ddAC was used in 58.2% and q3w AC in 41.8% of the cases. Most patients (69.1%) had stage II TNBC. A pCR was observed in 65.4% with ddAC and 58.7% with q3w AC (P = 0.260), while RCB 0-1 occurred in 82.4% and 73.5%, respectively (P = 0.115). Patients with stage III disease had a numerically higher pCR with ddAC (59% vs 40%, P = 0.155), while pCR rates were similar regardless of AC regimen in stage II disease (66.6% vs 64.5%; P = 0.760). While no significant disparities in drug discontinuation was noted, ddAC showed a trend towards higher rates of grade ≥3 AE (40.5% vs. 30.7%, P = 0.092). The Neo-Real study could not rule out a difference between ddAC and q3w AC during neoadjuvant P + CT. The observation of a potentially higher pCR with ddAC in stage III disease warrants further investigation.

Long-lasting recognition memory impairment and alterations in brain levels of cytokines and BDNF induced by maternal deprivation: effects of valproic acid and topiramate.

Exposure to stressful events early in life may have permanent deleterious consequences on nervous system function and increase the susceptibility to psychiatric conditions later in life. Maternal deprivation, commonly used as a source of neonatal stress, impairs memory in adult rats and reduces hippocampal brain-derived neurotrophic factor (BDNF) levels. Inflammatory cytokines, such as interleukins (IL) and tumor necrosis factor-α (TNF-α) have been shown to be increased in the peripheral blood of patients with psychiatric disorders. The aim of the present study was to investigate the effects of maternal separation on the levels of IL-10 and TNF-α, and BDNF in the hippocampus and prefrontal cortex of adult rats. We also evaluated the potential ameliorating properties of topiramate and valproic acid on memory deficits and cytokine and BDNF changes associated with maternal deprivation. The results indicated that, in addition to inducing memory deficits, maternal deprivation increased the levels of IL-10 in the hippocampus, and TNF-α in the hippocampus and in the cortex, and decreased hippocampal levels of BDNF, in adult life. Neither valproic acid nor topiramate were able to ameliorate memory deficits or the reduction in BDNF induced by maternal separation. The highest dose of topiramate was able to reduce IL-10 in the hippocampus and TNF-α in the prefrontal cortex, while valproate only reduced IL-10 levels in the hippocampus. These findings may have implications for a better understanding of the mechanisms associated with alterations observed in adult life induced by early stressful events, and for the proposal of novel therapeutic strategies.

Cannabidiol normalizes caspase 3, synaptophysin, and mitochondrial fission protein DNM1L expression levels in rats with brain iron overload: implications for neuroprotection.

We have recently shown that chronic treatment with cannabidiol (CBD) was able to recover memory deficits induced by brain iron loading in a dose-dependent manner in rats. Brain iron accumulation is implicated in the pathogenesis of neurodegenerative diseases, including Parkinson's and Alzheimer's, and has been related to cognitive deficits in animals and human subjects. Deficits in synaptic energy supply have been linked to neurodegenerative diseases, evidencing the key role played by mitochondria in maintaining viable neural cells and functional circuits. It has also been shown that brains of patients suffering from neurodegenerative diseases have increased expression of apoptosisrelated proteins and specific DNA fragmentation. Here, we have analyzed the expression level of brain proteins involved with mitochondrial fusion and fission mechanisms (DNM1L and OPA1), the main integral transmembrane protein of synaptic vesicles (synaptophysin), and caspase 3, an apoptosis-related protein, to gain a better understanding of the potential of CBD in restoring the damage caused by iron loading in rats. We found that CBD rescued iron-induced effects, bringing hippocampal DNM1L, caspase 3, and synaptophysin levels back to values comparable to the control group. Our results suggest that iron affects mitochondrial dynamics, possibly trigging synaptic loss and apoptotic cell death and indicate that CBD should be considered as a potential molecule with memory-rescuing and neuroprotective properties to be used in the treatment of cognitive deficits observed in neurodegenerative disorders.

O uso dos novos anticoagulantes no tratamento do tromboembolismo pulmonar / The use of new anticoagulants in the treatment of pulmonary thromboembolism

O tromboembolismo pulmonar é uma doença potencialmente grave, de difícil diagnóstico devido a apresentações diversas, exigindo diagnóstico rápido e a implementação de tratamento adequado. Torna-se importante a discussão sobre as novas alternativas no manejo medicamentoso contemporâneo desta patologia.

Pulmonary thromboembolism is a potentially serious disease, difficult to diagnose due to various presentations, requiring rapid diagnosis and implementation of appropriate treatment. It is important to discuss about new alternatives in contemporary medical management of this condition.

Síndrome da veia cava superior / Superior vena cava syndrome

A Síndrome da Veia Cava Superior (SVCS) trata-se de uma manifestação clínica resultante da obstrução do fluxo sanguíneo ao nível da veia cava superior, podendo se manifestar em pacientes sem diagnóstico de base conhecido. O objetivo deste trabalho é revisar o manejo diagnóstico e terapêutico desses pacientes em atendimento de emergência.

Superior Vena Cava Syndrome is a clinical manifestation resulting from the obstruction of blood flow at the level of the Superior Vena Cava, which could manifest in patients without an etiologic diagnosis known. The objective of this work is to review the diagnosis and therapeutic management of these patients in emergency rooms.