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BackgroundAs progress continues in oncology drug development, this study aimed to examine whether the previously established association between drug dose and efficacy in the era of cytotoxic therapies remains true in today's phase I dose-escalation oncology trials.MethodsA systematic review of early-phase dose-finding trials of single-agent oncology drugs from 2015 to 2018 was conducted to examine the relationship between drug dose and objective responses. Cancer-specific trials were included if they determined maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D). Data related to the study drug, study design, treatment response, cancer type, dose levels, MTD, and RP2D were all collected. Dose level was categorized into 4 categories (≤40%, 41%-80%, 81%-120%, and >120% of the RP2D) and was further analyzed by class of drug.ResultsA total of 175 phase I studies were identified, with a total of 7,330 patients showing a median response rate of 5% (range, 0%-83%) across trials. A total of 93 trials with 2,506 participants had response data corresponding to drug dose level. In this subset, the median response rate was 5% (range, 0%-83%) across trials. Across all participants in this subset, the response rate was 12% (57 of 491) among those in the dose range of ≤40% of RP2D, 17% (95 of 562) among those in 41% to 80% of RP2D, 23% (272 of 1,206) among those in 81% to 120% of RP2D, and 29% (71 of 247) among those in >120% of RP2D (P

Keywords: Erdheim-Chester disease; genotypic; phenotype; radiographic EN Erdheim-Chester disease genotypic phenotype radiographic 454 457 4 10/25/22 20221101 NES 221101 Erdheim-Chester disease (ECD) is a rare neoplasm characterised by multiorgan infiltration of clonal histiocytes bearing activating mutations, predominantly in the I MAPK-ERK i pathway. The major highlight of our finding is the higher burden of organ involvement among patients with C-ECD compared with NC-ECD. GLO:1XW/01nov22:bjh18422-fig-0001.jpg PHOTO (COLOR): 1 Sites of involvement of classical Erdheim-Chester disease (C-ECD) versus non-classical ECD (NC-ECD). gl GLO:1XW/01nov22:bjh18422-fig-0002.jpg PHOTO (COLOR): 2 Heat map of sites of involvement of classical Erdheim-Chester disease (C-ECD) versus non-classical ECD (NC-ECD). [Extracted from the article]

Introduction: An algorithmic approach, termed the prolonged clot time profile (PROCT), consisting of initial screening with prothrombin time (PT) and activated partial thromboplastin time (aPTT), reflexive mixing studies if indicated, and follow‐up assays depending on initial testing results, offers an efficient approach to delineate the etiology of a prolonged PT/aPTT. Herein, we present the outcomes of the PROCT in the outpatient setting. Methods: In this retrospective study, we reviewed medical records of consecutive outpatients who had prolonged PT and/or aPTT noted in the routine coagulation laboratory and who had PROCT ordered in our institutional Special Coagulation Laboratory between 2010 and 2017. Results: One hundred and six patients, median age 55 years (IQR 30‐67), met our study criteria. Twenty‐nine patients had normal PT/aPTT, while 77 had persistent abnormalities and underwent reflexive testing. A prolonged PT, aPTT, or PT and aPTT was noted in 27 (35%), 27 (35%), and 23 (30%) respectively. Forty‐nine (64%) had an acquired condition, 17 (22%) had a congenital condition, 7 (9%) had unclear etiology, and 4 (5%) were the result of laboratory artifact. The most common known cause of an isolated prolonged PT in our study was vitamin K deficiency in 8 (10%), the most common cause of an isolated prolonged aPTT was lupus anticoagulant in 4 (5%), and the most common cause of prolonged PT and aPTT was liver disease in 11 (14%). Conclusion: Prolonged PT/aPTT have a wide range of causes, including artifactual prolongation or abnormalities in secondary hemostasis due to both inherited and acquired conditions. [ABSTRACT FROM AUTHOR]

Langerhans cell histiocytosis (LCH) is a rare histiocytic neoplasm. To date, there is a lack of U.S. Food and Drug Administration–approved treatments in adult LCH to establish optimal first‐line therapy. We conducted a retrospective, single‐center case series evaluating the use of BRAF inhibitors in adult patients with BRAFV600E‐ LCH proven by biopsy. Our case series is the first to report the use of BRAF inhibitors as first‐line therapy in adults with LCH. We also report the efficacy with single‐agent dabrafenib in adult LCH. All but one of our patients had favorable response to targeted therapy. Optimal first‐line treatment for Langerhans cell histiocytosis (LCH) has not been established. This case series evaluates the use of BRAF inhibitors in adult patients with LCH. [ABSTRACT FROM AUTHOR]

Erdheim-Chester disease (ECD) is a rare histiocytic neoplasm derived from the macrophage/dendritic cell lineage and harbors the I BRAF SP V600E sp i mutation in 50-60% of patients [[1]]. The U.S. Food and Drug Administration (FDA) approved vemurafenib 960 mg twice daily for the treatment of adult patients with I BRAF SP V600E sp i -mutated ECD based on a phase II trial that showed high efficacy with an overall response rate of 54.5% [[2]]. 15 patients (65%) experienced grade I toxicities, 12 patients (52%) had grade II toxicities, and 2 patients had grade III toxicities. While none of our ECD patients treated with vemurafenib at 50% of the FDA-approved dose had PD, 50% of these patients still required further dose reductions and 29% discontinued the medication due to intolerable AEs. [Extracted from the article]

Nocardiosis is caused by various species of Nocardia and typically occurs as an opportunistic infection. It frequently disseminates, most often involving the lungs, subcutaneous tissues and central nervous system. It has rarely been reported to affect native heart valves. We report the case of a 64-year-old man with disseminated nocardiosis involving the brain, lungs, muscle and tricuspid valve of a transplanted heart. Following antimicrobial therapy, the patient improved clinically and there was no evidence of residual infection on follow-up imaging. This case highlights the presentation of nocardiosis, current therapeutic guidelines and the question of prophylaxis against Nocardia in immunocompromised patients. [ABSTRACT FROM AUTHOR]

Small-cell lung cancer (SCLC) is an aggressive form of lung cancer that displays rapid proliferation and early metastatic potential. It accounts for approximately 15% of lung cancers and is strongly associated with tobacco carcinogens. Despite patients' initial response to systemic therapy, the majority develop early resistance and relapse. The outcomes of patients with metastatic SCLC are poor, prompting the need for new therapies. Over the past decade, the treatment landscape for NSCLC (non-small cell lung cancer) has significantly changed with the immergence of novel targeted therapies and immunotherapies. However, inroads of these therapies into SCLC have posed significant challenges due to its molecular and genomic heterogeneity. Despite the challenges of this disease, promising new first-in-class immunomodulatory agents have emerged and are currently undergoing extensive research. Herein, we review the current treatment paradigm of immunotherapy in SCLC and discuss future directions of this evolving field.