Combined CTLA-4 and PD-L1 blockade in patients with chemotherapy-naïve metastatic castration-resistant prostate cancer is associated with increased myeloid and neutrophil immune subsets in the bone microenvironment.

BACKGROUND: Immune checkpoint therapy (ICT) has low response rates in patients with metastatic castration-resistant prostate cancer (mCRPC), in part due to few T cells in the tumor microenvironment (TME). Anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) promotes intratumoral T cell infiltration but induces upregulation of PD-1 and programmed death ligand-1 (PD-L1) within the prostate TME. Combined anti-CTLA-4 plus anti-PD-1 can partly overcome this adaptive resistance and was recently shown to augment responses in patients with mCRPC with measurable disease. Although bone is the most common site of metastasis in prostate cancer, patients with bone-predominant disease are frequently excluded from trials because they lack measurable disease, which limits assessment of disease progression and tissue sampling. We therefore designed this study to investigate combined ICT in mCRPC to bone. HYPOTHESIS: Combined anti-CTLA-4 (tremelimumab) plus anti-PD-L1 (durvalumab) is safe and well tolerated in patients with chemotherapy-naïve mCRPC to bone. PATIENTS AND METHODS: In this single-arm pilot study, men with chemotherapy-naïve mCRPC to bone received tremelimumab (75 mg intravenous) plus durvalumab (1500 mg intravenous) every 4 weeks (up to four doses), followed by durvalumab (1500 mg intravenous) maintenance every 4 weeks (up to nine doses). The primary endpoint was incidence of adverse events. Secondary endpoints included serum prostate-specific antigen (PSA), progression-free survival (PFS), radiographic PFS (rPFS), and maximal PSA decline. RESULTS: Twenty-six patients were treated between August 8, 2017 and March 28, 2019. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 11 patients (42%), with no grade 4 or 5 events. TRAEs leading to discontinuation occurred in three patients (12%). PSA decline ≥50% occurred in three patients (12%). Six patients (24%) achieved stable disease for >6 months. At a median follow-up of 43.6 months, median rPFS was 3.7 months (95% CI: 1.9 to 5.7), and median overall survival was 28.1 months (95% CI: 14.5 to 37.3). Post-treatment evaluation of the bone microenvironment revealed transcriptional upregulation in myeloid and neutrophil immune subset signatures and increased expression of inhibitory immune checkpoints. CONCLUSIONS: Tremelimumab plus durvalumab was safe and well tolerated in patients with chemotherapy-naïve mCRPC to bone, with potential activity in a small number of patients as measured by rPFS. Combination of CTLA-4 and PD-L1 blockade with therapies targeting the myeloid compartment or other inhibitory immune receptors may be necessary to overcome mechanisms of resistance within prostate bone microenvironment. TRIAL REGISTRATION NUMBER: NCT03204812.

Acute postcesarean pain is associated with in-hospital exclusive breastfeeding, length of stay and post-partum depression.

STUDY OBJECTIVE: The primary aim of the proposed study was to determine the association between postoperative pain and breastfeeding after cesarean delivery during hospital stay. DESIGN: Retrospective cohort study. SETTING: Postoperative recovery area and operating room. PATIENTS: Data was obtained on singleton pregnancies undergoing scheduled cesarean deliveries under spinal anesthesia between 2013 and 2016. INTERVENTIONS: Determine the association between postoperative pain and breastfeeding after cesarean delivery. MEASUREMENTS: Postoperative pain score, breastfeeding, LATCH score post-partum depression and length of stay values collected. MAIN RESULTS: The dataset consisted of electronic medical records from 5350 patients. We found that the pain score is negatively associated with the LATCH score; higher pain was associated with lower LATCH scores, -0.01 [-0.01,-0.00], p < .0402. Every one-point increase in average pain score was associated with a 21% reduction in the odds of in-hospital exclusive breast-feeding relative to exclusive formula-feeding, OR = 0.79 [0.70-0.90], p < .0002. We observed that the post-partum depression status was associated with the average postoperative pain score, F (1, 5347) = 41.51, p < .0001. We also found a significant positive association between the average pain score and the duration of hospital stay (p < .0001); every one-point increase in the average pain-score was associated with a 7.98 [6.28, 9.68] hour increase in length of stay. CONCLUSIONS: Our results demonstrate significant association between the increase in post-cesarean pain scores and deterioration of breastfeeding initiation while also exposing slight reductions in the quality of breastfeeding. Additionally, we found that increases in post-cesarean pain scores also positively associate with postpartum depression and duration of stay, with each increase in pain score resulted in an almost one-day increase in the length of stay.