Citations

Abstract During aging, muscle gradually undergoes sarcopenia, the loss of function associated with loss of mass, strength, endurance, and oxidative capacity. However, the 3D structural alterations of mitochondria associated with aging in skeletal muscle and cardiac tissues are not well described. Although mitochondrial aging is associated with decreased mitochondrial capacity, the genes responsible for the morphological changes in mitochondria during aging are poorly characterized. We measured changes in mitochondrial morphology in aged murine gastrocnemius, soleus, and cardiac tissues using serial block‐face scanning electron microscopy and 3D reconstructions. We also used reverse transcriptase‐quantitative PCR, transmission electron microscopy quantification, Seahorse analysis, and metabolomics and lipidomics to measure changes in mitochondrial morphology and function after loss of mitochondria contact site and cristae organizing system (MICOS) complex genes, Chchd3 , Chchd6 , and Mitofilin . We identified significant changes in mitochondrial size in aged murine gastrocnemius, soleus, and cardiac tissues. We found that both age‐related loss of the MICOS complex and knockouts of MICOS genes in mice altered mitochondrial morphology. Given the critical role of mitochondria in maintaining cellular metabolism, we characterized the metabolomes and lipidomes of young and aged mouse tissues, which showed profound alterations consistent with changes in membrane integrity, supporting our observations of age‐related changes in muscle tissues. We found a relationship between changes in the MICOS complex and aging. Thus, it is important to understand the mechanisms that underlie the tissue‐dependent 3D mitochondrial phenotypic changes that occur in aging and the evolutionary conservation of these mechanisms between Drosophila and mammals.

Abstract WSD0922-Fu is an oral, CNS-penetrant, small molecule EGFR inhibitor which potently inhibits EGFR aberrations specific to non-small cell lung cancer (NSCLC) and high-grade astrocytoma (HGA). MC1914 (NCT04197934) is a first-in-human phase 1 trial in patients with EGFR aberrant recurrent HGA and NSCLC. Adult patients with either recurrent EGFR mutant NSCLC with CNS metastases or recurrent EGFR aberrant HGA were enrolled and treated across six cohorts (40 mg once daily to 320 mg twice daily, 28-day cycles) to determine the maximum tolerated dose (MTD). 25 patients (17 HGA, 8 NSCLC) were enrolled (median age = 57 years; 24% female; 36% ECOG 0). All patients with HGA received prior radiation and temozolomide. All patients with NSCLC had previous disease progression on EGFR inhibitor therapy (prior osimertinib 88%). The median duration of WSD0922-Fu exposure among all patients was 55 days (range 3 to >279 days) [NSCLC median = 131 days; HGA median = 51 days]. Common treatment-related adverse events are comparable to other EGFR inhibitors (fatigue, acneiform rash, diarrhea, nausea, pruritis). At Cycle 1 Day 15 for patients treated at MTD (160 mg twice daily), the mean terminal elimination half-life (%CV) in the plasma was 31.6 h (102%) (median 14.5 h). The mean Cmax, Tmax, oral clearance at steady state, and AUC (0-12 h) (%CV) were 4513 ng/mL (50%), 2.0 hr (69%), 6.9 L/hr/m2 (42%), and 28084 h*ng/mL (52%), respectively. Among patients with NSCLC treated at MTD or higher dose levels and with available response data, 100% (5/5) of patients demonstrated clinical benefit (SD + PR) while 60% of patients had partial responses. Intracranial and extracranial efficacy was concordant. Furthermore, prolonged stable disease (9 cycles) was observed in a patient with EGFRvIII mutant GBM. Expansion cohorts are in progress to optimize WSD0922-Fu dose and schedule for future phase 2 development.

Abstract H3 K27-altered diffuse midline gliomas (DMG) are uniformly lethal tumors for which no therapy has been found to be effective. The blood-brain barrier (BBB) restricts uptake and accumulation of systemically administered drugs in the brain. Convection-enhanced delivery (CED) circumvents the BBB by directly infusing therapeutics into the tumor, facilitating homogenous distribution of drugs at high local concentrations with minimal systemic toxicity. However, most drugs given by CED are rapidly cleared from the brain, severely limiting its therapeutic potential. Here, we determine the impact of drug characteristics rather than mechanism of action on compatibility with CED. Various medicinal chemistry prediction models were interrogated to define drug categories predicated on inherent physicochemical properties of the drugs. A panel of FDA-approved drugs with biologically validated activity in DMG were selected for each group: panobinostat/ponatinib, everolimus/topotecan, tolnaftate/tretinoin, and carmofur/eltrombopag. In vivo pharmacokinetic studies of these drugs delivered by CED into the pons of tumor-naïve mice showed that drugs expected to be less likely to undergo active efflux persisted at the site of infusion over prolonged periods of time. Conversely, efflux transporter (ET) substrate drugs were quickly excreted from the brain and readily detectable in the plasma following CED. Based on the observed brain and plasma concentration-time profiles, the brain exit rate constant and clearance out of the brain were much higher for ET substrate drugs compared with ET non-substrates, resulting in a significant increase in the residence time (the time spent by drugs in the brain) in the absence of ET-mediated clearance. These properties were further validated in efficacy studies in DMG animal models. The proclivity of many drugs to be rapidly effluxed from the brain after CED generates a vulnerability that can be exploited for the development of novel therapeutic regimens, such as with pharmacokinetics-informed drug selection or concomitant dosing of ET-inhibiting drugs.

Abstract Background Vasoactive medications and Mechanical Circulatory Support (MCS) are both central to the contemporary management of cardiogenic shock (CS). There are limited data on the interaction between vasoactive medication dosing and MCS in patients with CS. Purpose We investigated the association between in-hospital mortality and vasoactive medication dosing among patients with CS who did and did not receive MCS during hospitalization. Methods We included patients with CS admitted to our cardiac intensive care unit (CICU) between 2007 and 2015. The peak combined vasoactive medication dose during the first 24 hours of CICU admission was recorded and converted to norepinephrine equivalents (NEE)(references 1 & 2). The primary outcome was in-hospital mortality. Multivariable logistic regression was used to adjust for relevant variables and calculate adjusted odds ratios (OR). Results Of 1078 patients with CS (median age 69.0 years [Interquartile Range 59.1-77.3], 36.8% female, 59% with acute myocardial infarction), 721 (66.9%) received vasoactive medications in the first 24 hours and 510 (47.3%) received MCS (87% intra-aortic balloon pump). Among those receiving vasoactive medications during the first 24 hours, the median NEE was 0.16 (Interquartile Range 0.06-0.40) mcg/kg/min. In hospital mortality was 34.4% overall, and was lower among those who received MCS (26.1% versus 41.9%, p<0.001; adjusted OR 0.71 95% CI 0.50-0.99) and higher among those who received vasoactive medications (38.1% versus 26.9%, p<0.001). A gradient of mortality was observed according to the use of vasoactive medications and MCS (Fig. 1). We found a strong incremental association between in-hospital mortality and NEE (adjusted OR 1.11 per 0.1 mcg/kg/min, 95% CI 1.06–1.16, P<0.001; Fig. 2). Mortality was lower across the spectrum of NEE for patients who received MCS (Fig. 2). There was no statistically significant difference in the slope of the relationship between in-hospital mortality and NEE in patients who did and did not receive MCS (p = 0.86). Conclusion Increasing vasoactive medication requirement during the first 24 hours of CICU admission is incrementally associated with in-hospital mortality in CS, representing a simplified marker of shock severity. Patients who received MCS were at lower risk of mortality across the spectrum of vasopressor requirements, emphasizing the potential synergy between these two complementary approaches to hemodynamic support.Figure 1Figure 2

Early integrated palliative care (EIPC) significantly improves clinical outcomes for patients with advanced cancer. Telehealth may be a useful tool to deliver EIPC sustainably and equitably. Palliative care clinicians completed a survey regarding their perceptions of the barriers, facilitators, and benefits of using telehealth video visits for delivering EIPC for patients with advanced lung cancer. Forty-eight clinicians across 22 cancer centers completed the survey between May and July 2022. Most (91.7%) agreed that telehealth increases access to EIPC and simplifies the process for patients to receive EIPC (79.2%). Clinicians noted that the elderly, those in rural areas, and those with less-resourced backgrounds have greater difficulty using telehealth. Perceived barriers were largely patient-based factors, including technological literacy, internet and device availability, and patient preferences. Clinicians agreed that several organizational factors facilitated telehealth EIPC delivery, including technological infrastructure (85.4%), training (83.3%), and support from study coordinators (81.3%). Other barriers included systems-based factors, such as insurance reimbursement and out-of-state coverage restrictions. Patient-, organization-, and systems-based factors are all important to providing and improving access to telehealth EIPC services. Further research is needed to investigate the efficacy of telehealth EIPC and how policies and interventions may improve access to and dissemination of this care modality.

Background: Immune checkpoint inhibitors (ICIs) are a first-line and perioperative treatment for lung cancer. Pneumonitis is a potentially life-threatening complication of ICI treatment in 2% to 5% of patients; however, risk factors for developing ICI pneumonitis (ICI-p) remain undefined. Methods: We conducted a retrospective cohort study of consecutive patients with lung cancer who received at least one dose of ICI from 2015 through 2020 at The Ohio State University. Pneumonitis cases were documented by the treating oncologist and retrospectively evaluated for agreement between an oncologist and a pulmonologist. Patient demographic and clinical characteristics were recorded and summarized between those with and without pneumonitis for the overall cohort. Univariate and multivariable survival analyses using the Fine-Gray competing risk model were used to examine the associations. Results: A total of 471 patients with lung cancer were included, of which 402 had non–small cell lung cancer and 69 had small cell lung cancer; 39 (8%) patients in the overall cohort developed ICI-p. Preexisting interstitial abnormalities and prior chest radiation were both significantly associated with ICI-p on univariate analysis (hazard ratio [HR], 8.91; 95% CI, 4.69–16.92; P<.001; and HR, 2.81; 95% CI, 1.50–5.28; P=.001). On multivariable analyses, interstitial abnormalities remained a strong independent risk factor for ICI-p when controlling for chest radiation and type of immunotherapy (HR, 9.77; 95% CI, 5.17–18.46; P<.001). Among patients with ICI-p (n=39), those with severe (grade 3–5) pneumonitis had worse overall survival compared with those with mild (grade 1 or 2) pneumonitis (P=.001). Abnormal pulmonary function test results at both 12 and 18 months prior to ICI initiation were not significantly associated with ICI-p. Conclusions: Preexisting interstitial abnormalities on chest CT and prior chest radiation are independent risk factors that are strongly associated with ICI-p in patients with lung cancer. These findings highlight a potential need for closer observation for ICI-p among patients with these risk factors.

Background One‐time assessment of the Society for Cardiovascular Angiography and Interventions (SCAI) shock classification robustly predicts mortality in the cardiac intensive care unit (CICU). We sought to determine whether serial SCAI shock classification could improve risk stratification. Methods and Results Unique admissions to a single academic level 1 CICU from 2015 to 2018 were included in this retrospective cohort study. Electronic health record data were used to assign the SCAI shock stage during 4‐hour blocks of the first 24 hours of CICU admission. Shock was defined as hypoperfusion (SCAI shock stage C, D, or E). In‐hospital death was evaluated using logistic regression. Among 2918 unique CICU patients, 1537 (52.7%) met criteria for shock during ≥1 block, and 266 (9.1%) died in the hospital. The SCAI shock stage on admission was: A, 37.6%; B, 31.5%; C, 25.9%; D, 1.8%; and E, 3.3%. Patients who met SCAI criteria for shock on admission (first 4 hours) and those with worsening SCAI shock stage after admission were at higher risk for in‐hospital death. Each higher admission (adjusted odds ratio, 1.36 [95% CI, 1.18–1.56]; area under the receiver operating characteristic curve, 0.70), maximum (adjusted odds ratio, 1.59 [95% CI, 1.37–1.85]; area under the receiver operating characteristic curve, 0.73) and mean (adjusted odds ratio, 2.42 [95% CI, 1.99–2.95]; area under the receiver operating characteristic curve, 0.78) SCAI shock stage was incrementally associated with a higher in‐hospital mortality rate. Discrimination was highest for the mean SCAI shock stage ( P <0.05). Each additional 4‐hour block meeting SCAI criteria for shock predicted a higher mortality rate (adjusted odds ratio, 1.15 [95% CI, 1.07–1.24]). Conclusions Dynamic assessment of shock using serial SCAI shock classification assignment can improve mortality risk stratification in CICU patients by quantifying the magnitude and duration of shock.

Introduction: Venoarterial extracorporeal membrane oxygenation (VA ECMO) provides full hemodynamic support for cardiogenic shock (CS), but optimal timing of ECMO initiation remains uncertain. Hypothesis: We hypothesized that earlier initiation of ECMO would be associated with improved survival in CS patients. Methods: We analyzed adult patients with CS who received VA ECMO from the Extracorporeal Life Support Organization (ELSO) Registry from 2009 - 2019, excluding those cannulated following an operation. Multivariable logistic regression evaluated the association between time from admission to ECMO initiation and in-hospital mortality. Results: Among 8619 patients (median 56.7 years; 33.5% females), the duration from admission to ECMO initiation was 14 (5, 32) hours. Patients who had ECMO initiated within 24 hours (n = 5882 [68.2%]) differed from those who had ECMO initiated after 24 hours, with younger age, more preceding cardiac arrest, and worse acidosis. After adjustment, patients with ECMO initiated more than 24 hours after admission had higher risk of adjusted in-hospital mortality (adjusted OR 1.20, 95% CI 1.06-1.36, p = 0.004) (Figure 1). Each 12-hour increase in the time from admission to ECMO initiation was incrementally associated with higher adjusted in-hospital mortality (adjusted OR 1.06, 95% CI 1.03-1.10, p < 0.001). The association between longer time to ECMO and worse outcomes appeared stronger in patients with lower shock severity. Among patients who were cannulated within 24 hours, those cannulated during the same day shift had lower mortality than those who were admitted at night and cannulated the following day (adjusted OR adjusted OR 0.81, 95% CI 0.66-0.99, p = 0.04). Conclusions: Longer delays from admission to ECMO initiation were associated with higher mortality in a large-scale, international registry. Our analysis supports optimization of door-to-support time and the avoidance of inappropriately delayed ECMO initiation.