Citations

Background: Bimiralisib is a pan-PI3K/mTOR inhibitor demonstrating antitumor efficacy in preclinical models. The objectives of this study were to identify a maximum tolerated dose (MTD), pharmacokinetics (PK), a dosing schedule, and adverse events (AEs) in patients with advanced solid tumors. Patients and Methods: Patients received oral bimiralisib to determine the MTD of one continuous (once daily) and two intermittent schedules (A: Days 1, 2 weekly; B: Days 1, 4 weekly) until progression or unacceptable AEs occurred. Results: The MTD for the continuous schedule was 80 mg, with grade three fatigue as the dose-limiting toxicity (DLT). No MTD was reached with intermittent schedules, with only one DLT in schedule B. PK analysis suggested that 140 mg (schedule A) was within the biologically active dose range and was selected for further exploration. The most frequent treatment-emergent AEs were hyperglycemia (76.2%) in the continuous schedule, and nausea (56–62.5%) in schedules A and B. The most frequent treatment-emergent > grade three AE for all schedules combined was hyperglycemia (28.6%, continuous schedule; 12.0%, schedule A; 12.5%, schedule B). There was one partial response in a head and neck squamous cancer patient with a NOTCH1T1997M mutation. Conclusions: Bimiralisib demonstrated a manageable AE profile consistent with this compound class. Intermittent schedules had fewer > grade three AEs, while also maintaining favorable PK profiles. Intermittent schedule A is proposed for further development in biomarker-selected patient populations.

Abstract Lack of robust activation of Stimulator of Interferon Genes (STING) pathway and subsequent induction of type I IFN responses is considered a barrier to antitumor immunity in acute myeloid leukemia (AML). Using common human AML cell lines as in vitro tools to evaluate the efficacy of novel STING agonists, we found most AML lines to be poor producers of IFNs upon exposure to extremely potent agonists, suggesting cell-intrinsic suppression of STING signaling may occur. We observed unexpected patterns of response that did not correlate with levels of STING pathway components or of known enzymes associated with resistance. To identify a genetic basis for these observations, we cloned and sequenced STING from the cDNA of human AML cell lines and found both frequent mutations and deviations from normal RNA splicing. We identified two novel spliced isoforms of STING in these lines and validated their expression in primary human AML samples. When transduced into reporter cells, these novel STING isoforms exhibited complete insensitivity to agonist stimulation. These observations identify alternative splicing as a mechanism of STING pathway suppression and suggest that most AML silences the STING pathway through direct modification rather than through engagement of external inhibitory factors. Significance: We find that AML acquires resistance to innate immune activation via the STING pathway through aberrant splicing of the STING transcript including two novel forms described herein that act as dominant negatives. These data broaden understanding of how cancers evolve STING resistance, and suggest that the AML tumor microenvironment, not the cancer cell, should be the target of therapeutic interventions to activate STING.

Abstract Introduction Patients living in rural areas have worse cancer‐specific outcomes. This study examines the effect of family‐based social capital on genitourinary cancer survival. We hypothesized that rural patients with urban relatives have improved survival relative to rural patients without urban family. Methods We examined rural and urban based Utah individuals diagnosed with genitourinary cancers between 1968 and 2018. Familial networks were determined using the Utah Population Database. Patients and relatives were classified as rural or urban based on 2010 rural–urban commuting area codes. Overall survival was analyzed using Cox proportional hazards models. Results We identified 24,746 patients with genitourinary cancer with a median follow‐up of 8.72 years. Rural cancer patients without an urban relative had the worst outcomes with cancer‐specific survival hazard ratios (HRs) at 5 and 10 years of 1.33 (95% CI 1.10–1.62) and 1.46 (95% CI 1.24–1.73), respectively relative to urban patients. Rural patients with urban first‐degree relatives had improved survival with 5‐ and 10‐year survival HRs of 1.21 (95% CI 1.06–1.40) and 1.16 (95% CI 1.03–1.31), respectively. Conclusions Our findings suggest rural patients who have been diagnosed with a genitourinary cancer have improved survival when having relatives in urban centers relative to rural patients without urban relatives. Further research is needed to better understand the mechanisms through which having an urban family member contributes to improved cancer outcomes for rural patients. Better characterization of this affect may help inform policies to reduce urban–rural cancer disparities.

AbstractBackgroundDiffusion‐weighted magnetic resonance imaging (dMRI) examines tissue microstructure integrity in vivo. Prior dementia with Lewy bodies (DLB) diffusion tensor imaging studies yielded mixed results.ObjectiveWe employed free‐water (FW) imaging to assess DLB progression and correlate with clinical decline in DLB.MethodsBaseline and follow‐up MRIs were obtained at 12 and/or 24 months for 27 individuals with DLB or mild cognitive impairment with Lewy bodies (MCI‐LB). FW was analyzed using the Mayo Clinic Adult Lifespan Template. Primary outcomes were FW differences between baseline and 12 or 24 months. To compare FW change longitudinally, we included 20 cognitively unimpaired individuals from the Alzheimer's Disease Neuroimaging Initiative.ResultsWe followed 23 participants to 12 months and 16 participants to 24 months. Both groups had worsening in Montreal Cognitive Assessment (MoCA) and Movement Disorder Society‐Unified Parkinson's Disease Rating Scale (MDS‐UPDRS) scores. We found significant FW increases at both time points compared to baseline in the insula, amygdala, posterior cingulum, parahippocampal, entorhinal, supramarginal, fusiform, retrosplenial, and Rolandic operculum regions. At 24 months, we found more widespread microstructural changes in regions implicated in visuospatial processing, motor, and cholinergic functions. Between‐group analyses (DLB vs. controls) confirmed significant FW changes over 24 months in most of these regions. FW changes were associated with longitudinal worsening of MDS‐UPDRS and MoCA scores.ConclusionsFW increased in gray and white matter regions in DLB, likely due to neurodegenerative pathology associated with disease progression. FW change was associated with clinical decline. The findings support dMRI as a promising tool to track disease progression in DLB. © 2024 International Parkinson and Movement Disorder Society.

AbstractThe fibrotic tumor microenvironment is a pivotal therapeutic target. Nintedanib, a clinically approved multikinase antifibrotic inhibitor, is effective against lung adenocarcinoma (ADC) but not squamous cell carcinoma (SCC). Previous studies have implicated the secretome of tumor‐associated fibroblasts (TAFs) in the selective effects of nintedanib in ADC, but the driving factor(s) remained unidentified. Here we examined the role of tissue inhibitor of metalloproteinase‐1 (TIMP‐1), a tumor‐promoting cytokine overproduced in ADC‐TAFs. To this aim, we combined genetic approaches with in vitro and in vivo preclinical models based on patient‐derived TAFs. Nintedanib reduced TIMP‐1 production more efficiently in ADC‐TAFs than SCC‐TAFs through a SMAD3‐dependent mechanism. Cell culture experiments indicated that silencing TIMP1 in ADC‐TAFs abolished the therapeutic effects of nintedanib on cancer cell growth and invasion, which were otherwise enhanced by the TAF secretome. Consistently, co‐injecting ADC cells with TIMP1‐knockdown ADC‐TAFs into immunocompromised mice elicited a less effective reduction of tumor growth and invasion under nintedanib treatment compared to tumors bearing unmodified fibroblasts. Our results unveil a key mechanism underlying the selective mode of action of nintedanib in ADC based on the excessive production of TIMP‐1 in ADC‐TAFs. We further pinpoint reduced SMAD3 expression and consequent limited TIMP‐1 production in SCC‐TAFs as key for the resistance of SCC to nintedanib. These observations strongly support the emerging role of TIMP‐1 as a critical regulator of therapy response in solid tumors.

Background Women show increased prevalence and severity of migraine compared to men. Whether small molecule calcitonin gene-related peptide receptor (CGRP-R) antagonists (i.e., gepants) and monoclonal antibodies targeting either the CGRP-R or the CGRP peptide might show sexually dimorphic outcomes for acute and preventive therapy has not been established. Methods We conducted a subpopulation analysis of available published data from FDA reviews to evaluate potential sex differences in the response rates of ubrogepant, rimegepant and zavegepant for acute migraine therapy. Available data from FDA reviews of erenumab, fremanezumab, galcanezumab and eptinezumab, approved CGRP-R and CGRP monoclonal antibodies and of atogepant were examined for prevention outcomes based on patient sex. Preventive outcomes were analyzed separately for patients with episodic migraine and chronic migraine. Results In women, the three approved gepants produced statistically significant drug effects regardless of dose tested on the FDA mandated co-primary endpoints, the proportion of patients achieving two-hour pain-freedom and the proportion of patients free of their most bothersome symptom at two hours post-dose. In women, the average placebo-subtracted two-hour pain-freedom proportion was 9.5% (CI: 7.4 to 11.6) and the average numbers needed to treat was 11. The free from most bothersome symptom at two hours outcomes were also significant in women. The gepant drugs did not reach statistically significant effects on the two-hour pain-freedom endpoint in the men, with an average drug effect of 2.8% (CI: −2.5 to 8.2) and an average number needed to treat of 36. For freedom from most bothersome symptom at two hours post-dose endpoint, differences were not significant in male patients. The treatment effect in each of the gepant studies was always numerically greater in women than in men. In evaluation of prevention outcomes with the antibodies or atogepant using the change from the specified primary endpoint (e.g., monthly migraine days), the observed treatment effect for episodic migraine patients almost always favored drug over placebo in both women and men. For chronic migraine patients the treatment effects of antibodies were similar in men and women and always favored the drug treated group. Conclusion/Interpretation: Small molecule CGRP-R antagonists are effective in acute migraine therapy in women but available data do not demonstrate effectiveness in men. CGRP-targeting therapies are effective for migraine prevention in both male and female episodic migraine patients but possible sex differences remain uncertain. In male and female chronic migraine patients, CGRP/CGRP-R antibodies were similarly effective. The data highlight possible differential effects of CGRP targeted therapies in different patient populations and the need for increased understanding of CGRP neurobiology in men and women.

Primary Care Physicians (PCPs) are the first point of contact in healthcare. Because PCPs face the challenge of managing diverse patient populations while maintaining up-to-date medical knowledge and updated health records, this study explores the current outcomes and effectiveness of implementing Artificial Intelligence-based Clinical Decision Support Systems (AI-CDSSs) in Primary Healthcare (PHC). Following the PRISMA-ScR guidelines, we systematically searched five databases, PubMed, Scopus, CINAHL, IEEE, and Google Scholar, and manually searched related articles. Only CDSSs powered by AI targeted to physicians and tested in real clinical PHC settings were included. From a total of 421 articles, 6 met our criteria. We found AI-CDSSs from the US, Netherlands, Spain, and China whose primary tasks included diagnosis support, management and treatment recommendations, and complication prediction. Secondary objectives included lessening physician work burden and reducing healthcare costs. While promising, the outcomes were hindered by physicians’ perceptions and cultural settings. This study underscores the potential of AI-CDSSs in improving clinical management, patient satisfaction, and safety while reducing physician workload. However, further work is needed to explore the broad spectrum of applications that the new AI-CDSSs have in several PHC real clinical settings and measure their clinical outcomes.

Background: There is limited evidence related to the effects of autograft type on functional performance after anterior cruciate ligament reconstruction (ACLR). Purpose/Hypothesis: This study aimed to compare biomechanical outcomes during a drop vertical jump (DVJ) between patients with a hamstring tendon (HT) autograft, quadriceps tendon (QT) autograft with bone block, QT autograft without bone block, and bone–patellar tendon–bone autograft at 6 months postoperatively in an adolescent population. The authors’ hypothesized there would be differences in DVJ biomechanics between athletes depending on the type of autograft used. Study Design: Controlled laboratory study. Methods: Patients aged 8 to 18 years who underwent primary ACLR were included for analysis. Kinematic and kinetic data collected during a DVJ using a 3-dimensional computerized marker system were assessed at 6 months after ACLR and compared with the uninjured contralateral limb. Results: A total of 155 participants were included. There were no significant differences in terms of age, sex, or affected leg ( P≥ .1973) between groups. The HT group was significantly associated with a larger knee valgus moment at initial contact compared with the QT group (28 × 10 –2 vs −35 × 10 –2 N·m/kg, respectively; P = .0254) and a significantly larger maximum hip adduction moment compared with the QT with bone block group (30 × 10 –2 vs −4 × 10 –2 N·m/kg, respectively; P = .0426). Both the QT with bone block (–12 × 10 –2 vs −3 × 10 –2 N·m/kg, respectively; P = .0265) and QT (–13 × 10 –2 vs −3 × 10 –2 N·m/kg, respectively; P = .0459) groups demonstrated significantly decreased mean knee extension moments compared with the HT group. Conclusion: The findings of this study suggest that utilizing an HT autograft resulted in a significantly increased knee valgus moment at initial contact compared with a QT autograft without bone block at 6 months after ACLR in adolescent patients performing a DVJ. A QT autograft was found to be associated with significantly decreased extensor mechanism function compared with an HT autograft. Clinical Relevance: This study adds unique kinematic and kinetic information regarding various ACLR autograft options and highlights the biomechanical deficits that should be taken into consideration in rehabilitation.