Highlights d SIRT1 expression is frequently decreased in aggressive breast cancers d Reducing SIRT1 levels in breast cancer cells impairs lysosomal acidification d Loss of SIRT1 gives rise to a secretome that promotes cell invasion and survival d SIRT1 mediates these effects by regulating V-ATPase expression

Background: First-line (1L) immunotherapy (I-O) has improved outcomes in patients with advanced non-small cell lung cancer (NSCLC) in clinical trials and is now routinely used alone or combined with chemotherapy. Although efficacy and safety of I-O therapies have been established in clinical trials, little is known about their performance and long-term efficacy in the real-world setting. We aimed to characterize real-world outcomes for patients with advanced NSCLC treated with 1L I-O therapy in the United States. Methods: Patients aged ≥18 years with confirmed advanced (stage III-IV) NSCLC who received either 1L I-O monotherapy or single-agent I-O combined with chemotherapy on or after January 1, 2016 were identified from the Flatiron Health database. Primary objectives were to examine overall survival (OS) and real-world progression-free survival. Index date was defined as date of 1L treatment initiation; data cut-off date was June 30, 2020. Results: Among 4271 patients receiving I-O plus chemotherapy, median OS was 10.6 (95 % confidence interval [CI], 9.3-11.8) months in patients with squamous NSCLC (n=814) and 12.0 (95 % CI, 11.3-12.8) months in those with non-squamous disease (n=3457). Regardless of histology, patients with high (≥50 %) tumor programmed death ligand 1 (PD-L1) expression demonstrated longer median OS vs those with low expression. Among 3041 patients receiving I-O monotherapy, median OS was 11.3 (95 % CI, 9.8-12.8) months in patients with squamous NSCLC (n=875) and 14.1 (95 % CI, 12.4-15.8) months in those with non-squamous disease (n=2166). OS benefit appeared to be greatest in the ≥50 % tumor PD-L1 expression group of the non-squamous cohort. Conclusion: Survival estimates were generally lower than those reported in pivotal clinical trials. These findings indicate that there remains room for improvement of real-world survival outcomes in patients with advanced NSCLC who receive 1L I-O-based regimens and for identification of subgroups of patients not benefitting from treatment with current I-O regimens.

Totally implantable catheters (TICs) have recently been employed for long-term central venous access in patients with sickle cell disease (SCD). We have reviewed our experience with 10 TICs inserted in patients with SCD. These were compared to 33 TICs inserted in patients without SCD (controls). The primary diagnosis was malignancy in most of the controls. The SCD patients experienced a marked increase in total complications (70 vs. 24%), as well as in complications requiring catheter removal (50 vs. 3%). No variable explained these differences except the presence of SCD. The complications requiring catheter removal from SCD patients were infections, catheter thrombosis, and venous thrombosis. The increased risk of these complications must be considered before a catheter is inserted; however, the average useful life of these catheters exceeded 12 months. They remained useful in the care of patients with poor venous access and multiple complications of SCD.

Intrathecal fentanyl induces rapid and satisfying dose-dependent analgesia in early labor; however, it also produces dose-related decreases in ventilation in the absence of overt somnolence.

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