Stereotactic body radiotherapy for castration-sensitive prostate cancer bone oligometastases

To evaluate outcome in patients treated with stereotactic body radiotherapy (SBRT) on bone oligometastases from castration-sensitive prostate cancer after primary treatment. We retrospectively collected data of patients with less than five lesions at time of SBRT and hormone-naïve disease at the first extra-regional localization, treated between 03/2012 and 11/2016. Prostate-specific antigen (PSA) was measured every 3 months after SBRT. Imaging was performed in case of progression. Survival analysis was performed with Kaplan–Meier (log-rank test) approach. Fifty-five patients were treated on 77 bone oligometastases. Median age, initial PSA and pre-SBRT PSA were 72 years, 9.12 and 3.5 ng/mL, respectively. Twenty-five patients (45%) received SBRT alone while the remaining 30 patients (55%) received concomitant ADT. Median follow-up was 24.6 months (range 3.0–67.2 months). No acute or late toxicity of grade?>?1 was reported. Clinical progression was observed in 38 (69%) patients. 1-year biochemical progression-free survival (b-PFS), clinical progression-free survival (c-PFS), prostate-specific survival (PCSS) and local control (LC) rates were 51, 56, 100 and 83%, respectively. Comparing patients treated with SBRT alone and with concomitant ADT, no significant differences were found for those outcomes. SBRT is safe and allows high 1-year LC rate (83%) with low toxicity profile. No significant improvement in outcomes was registered with the addition of ADT to SBRT.     

Mutational landscape of patients with acute promyelocytic leukemia at diagnosis and relapse

Despite the high probability of cure of patients with acute promyelocytic leukemia (APL), mechanisms of relapse are still largely unclear. Mutational profiling at diagnosis and/or relapse may help to identify APL patients needing frequent molecular monitoring and early treatment intervention. Using an NGS approach including a 31 myeloid gene-panel, we tested BM samples of 44 APLs at the time of diagnosis, and of 31 at relapse. Mutations in PML and RARA genes were studied using a customized-NGS-RNA panel. Patients relapsing after ATRA-chemotherapy rarely had additional mutations (P = .009). In patients relapsing after ATRA/ATO, the PML gene was a preferential mutation target. We then evaluated the predictive value of mutations at APL diagnosis. A median of two mutations was detectable in 9/11 patients who later relapsed, vs one mutation in 21/33 patients who remained in CCR (P = .0032). This corresponded to a significantly lower risk of relapse in patients with one or less mutations (HR 0.046; 95% CI 0.011-0.197; P < .0001). NGS-analysis at the time of APL diagnosis may inform treatment decisions, including alternative treatments for cases with an unfavorable mutation profile.     

Rapid modulation of the silent information regulator 1 by melatonin after hypoxia‐ischemia in the neonatal rat brain

Increasing evidence indicates that melatonin possesses protective effects toward different kinds of damage in various organs, including the brain. In a neonatal model of hypoxia‐ischemia (HI), melatonin was neuroprotective and preserved the expression of the silent information regulator 1 (SIRT1) 24 hours after the insult. This study aimed to gain more insight into the role of SIRT1 in the protective effect of melatonin after HI by studying the early (1 hour) modulation of SIRT1 and its downstream targets, and the consequences on necrosis, apoptosis, autophagy, and glial cell activation. We found that melatonin administered 5 minutes after the ischemic insult significantly reduced necrotic cell death assessed 1 hour after its administration. In parallel, we found a reduced activation of the early phases of intrinsic apoptosis, detected by reduced BAX translocation to the mitochondria and preservation of the mitochondrial expression of cytochrome C, indicating a reduced outer mitochondrial membrane permeabilization in the melatonin‐treated ischemic animals. These effects were concomitant to increased expression and activity of SIRT1, reduced expression and acetylation of p53, and increased autophagy activation. Melatonin also reduced HI‐induced glial cells activation. SIRT1 was expressed in neurons after HI and melatonin but not in reactive glial cells expressing GFAP. Colocalization between SIRT1 and GFAP was found in some cells in control conditions. In summary, our results provide more insight into the connection between SIRT1 and melatonin in neuroprotection. The possibility that melatonin‐induced SIRT1 activity might contribute to differentiate neuronal progenitor cells during the neurodegenerative process needs to be further investigated.