Citations

Cachexia is a debilitating skeletal muscle wasting condition for which we currently lack effective treatments. In the context of cancer, certain chemotherapeutics cause DNA damage and cellular senescence. Senescent cells exhibit chronic activation of the transcription factor NF-κB, a known mediator of the proinflammatory senescence-associated secretory phenotype (SASP) and skeletal muscle atrophy. Thus, targeting NF-κB represents a logical therapeutic strategy to alleviate unintended consequences of genotoxic drugs. Herein, we show that treatment with the IKK/NF-κB inhibitor SR12343 during a course of chemotherapy reduces markers of cellular senescence and the SASP in liver, skeletal muscle, and circulation and, correspondingly, attenuates features of skeletal muscle pathology. Lastly, we demonstrate that SR12343 mitigates chemotherapy-induced reductions in body weight, lean mass, fat mass, and muscle strength. These findings support senescent cells as a promising druggable target to counteract the SASP and skeletal muscle wasting in the context of chemotherapy.

Introduction Frontline therapy for pts with follicular lymphoma (FL) is not based on the molecular profile of the tumor. The PI3K pathway is central to FL biology, but the molecular profile of tumors most sensitive to PI3K inhibition (PI3Ki) is unknown. Copanlisib inhibits both PI3Kα and δ isoforms, and we hypothesized that most pts with treatment naïve FL will have PI3Ki-sensitive tumors and durable complete responses (CRs) may be achievable with short durations of targeted therapy. A gene expression profiling (GEP) predictor utilizes a combination of the expression of 45 selected informative genes and an additional 19 housekeeping genes to identify FL pts at high-risk for early progression within 24 months (Wright et al. ASH Annual Meeting2022). We also hypothesized that copanlisib would induce durable CRs in high-risk pts by the GEP assay. Here, we report a preliminary analysis of an ongoing “window of opportunity” study of copanlisib followed by response-adapted copanlisib and rituximab in treatment-naïve pts with FL (NCT03789240). Methods Pts with untreated grade 1-2, 3A FL, ≥stage 2 are eligible if systemic therapy is indicated: symptoms, progressive lymphadenopathy, or organ compromise. Prior radiation is permitted. Eligibility includes age ≥18 and adequate organ function unless due to lymphoma. HIV, CMV, Hep B or C, and autoimmune conditions are excluded. Pts first receive copanlisib 60mg on days 1, 8, and 15 of a 28-day “window of opportunity” to explore the activity of copanlisib. Following the window, pts receive 6 cycles of copanlisib 60mg on days 1, 8, and 15 of a 28-day cycle along with rituximab 375mg weekly x 4 then on day 1 of each cycle and response is assessed with FDG-PET and CT scans. Pts without response after C6 are taken off study and those with a partial response (PR) can continue for an additional 6 cycles and then stop therapy. Pts who achieve a CR after 6 cycles stop therapy. No maintenance is given. Supportive care includesPCP prophylaxis. The primary endpoint is the CR rate with secondary endpoints of safety, duration of CR, and PFS. Exploratory objectives include identification of a predictive signature of PI3Ki response and the response rate in high-risk pts identified by the GEP assay. Results Twenty-eight pts have enrolled. Median age was 56y (range, 24-80). Seventeen (61%) and 12 (43%) pts had high-risk FLIPI and FLIPI-2 scores ≥3, respectively; 6 (21%) pts had Grade 3A FL, and 17 (61%) pts met two or more GELF criteria. After copanlisib monotherapy in the window, 27 (96%) pts had tumor reductions by CT with a median change of -38% (-62% to +16%) (Figure 1). Among 22 pts who completed 6 cycles, 21 (96%) responded, including 9 (41%) pts with PR and 12 (55%) pts with CR. Of 9 pts with PR who received an additional 6 cycles of therapy, only 1 (11%) converted to a CR bringing the overall CR rate to 59% (13/22 pts). After a median follow-up of 25.8 months, the 2-year PFS was 43.2% (95% CI, 20.7-64.0%). The median duration of CR was 29.7 months (95% CI, 6.3 months - not estimable) with 8 (62%) CRs ongoing (Figure 2). Toxicity was evaluated in 28 pts across 220 cycles. Most common were rash (64%), mucositis (50%), and nausea/vomiting (50%), all G1-2 except 1 (4%) pt with G3 mucositis. The most common ≥G3 toxicities were neutropenia and infections in 5 (18%) pts each. ≥G3 neutropenia occurred in 10 (5%) cycles, responded to therapy interruption and/or growth factors, and did not require dose reduction. Two (8%) pts had copanlisib dose reduced, 1 (4%) each due to rash and mucositis. Therapy was prematurely discontinued in 5 pts: 3 due to COVID-19, 1 for hepatotoxicity that resolved, and 1 due to infusion reaction to rituximab. Nine of 24 (38%) pts were poor risk by the GEP assay. Complete responses were observed in 71%, 67%, and 57% of pts categorized as high-risk by FLIPI, FLIPI-2, and GEP assay, respectively. The CR rate was not affected by bulky disease (any LN >7cm; p=1.00), high-risk FLIPI (p=0.19), high-risk FLIPI-2 (p=0.67), poor-risk GEP (p=1.00), or metabolic tumor volume (p=0.33). Conclusion Nearly all pts with treatment naïve FL have PI3Ki-responsive tumors, and the combination of copanlisib with rituximab achieved a CR rate of 59% at the end of induction therapy. The median duration of CR is nearly 30 months, including ongoing remissions without maintenance. CRs were observed in pts deemed high-risk by the GEP assay and FLIPI score. The safety profile is excellent, with mostly G1-2 toxicities manageable with supportive care.

Background: Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of pathologic immune activation and uncontrolled inflammation. Neonatal HLH (nHLH), defined as HLH that presents in the first month of life, is clinically devastating. nHLH is estimated to comprise 10% of familial HLH (fHLH) diagnoses. There have been few, large descriptive studies of nHLH. Objectives: The primary objective of this study was to perform a scoping review and descriptive analysis of published cases of nHLH. The secondary objective of this study was to assess the reporting quality of published nHLH cases. Methods: A comprehensive literature database search was performed. Cases of HLH were eligible for inclusion if clinical analysis was performed at age < 30 days. As many as 70 variables were extracted from each case. Frequencies and percentages of variables reported per case in the articles included were provided. Qualitative variables were summarized by frequency and percentage. Quantitative variables which were not approximately normally distributed were summarized with median and interquartile range (IQR). Results: 544 studies were assessed for eligibility. Studies were excluded if they did not discuss nHLH (n=280), aggregated nHLH patient data with all ages (n=83), provided insufficient detail and/or data describing nHLH (n=28), and for other reasons (n=8).205 cases of nHLH from 142 articles were included. Cases were published from 31 countries from 1985-2023. Primary presenting features included fever (38.1%, n=67/176), organomegaly (11.9%, n=21/176) respiratory distress (11.4%, n=20/176), jaundice (4.5%, n=8/176), and signs of bleeding (3.4%, n-6/176). Symptoms began in utero in 20 patients (n=20/161). The median age of symptom onset was day of life (DOL) 3 (IQR: 0-14) (n=141). Median age at diagnosis was DOL 15 (IQR: 6-27) (n=87). The median time from initial evaluation to initiation of HLH therapy was 8 days (IQR: 3-14) (n=53). The frequency of HLH criteria and criteria median values are summarized in Table 1. The median number of diagnostic criteria met by patients were 5/8 (IQR: 4, 6). CNS manifestations were reported in 62.7% of cases (n=64/102). Skin manifestations were reported in 75.4% of cases (n=52/69). Liver injury (67.9%, n=91/134) and/or liver failure (23.9%, n=32/134) were common. Infections were reported in 46.7% of patients (n=70/150). Causes of nHLH included familial/inherited disease (46.8%, n=96/205), infection (26%, n=53), macrophage activation syndrome (2.9%, n=6), primary immunodeficiency (2.9%, n=6), inborn error of metabolism (2.4%, n=5), and malignancy (2%, n=4). Diagnosis was made using clinical and laboratory features (82.4%, n=169/205), gene panel (16.1%, n=33/205), sanger sequencing (1.0%, n=2/205), and ultra-rapid whole genome sequencing (0.5%, n=1/205). Genetic causes of fHLH included mutations in PRF1, STX11, STXBP2, UNC13D, NOCAR-H, and XIAP. The majority of patients (62.7%, n=121/193) died within the period of reporting. The estimated median survival time from nHLH onset of symptoms was 83 days. Only 4.4% (n=9/205) of studies reported complete data to calculate an H-score. Studies reported discernable values for HLH diagnostic variables at the following frequencies: temperature (71.7%), organomegaly (82.9%), hemoglobin (69.3%), thrombocytopenia (82.4%), neutrophils (55.1%), fibrinogen (64.4%), triglycerides (5.5%), hemophagocytosis (73.2%), ferritin (71.2%), low/absent NK cell activity (33.2%), and sIL2R (29.3%). Other clinically relevant variables such as the presence or absence of skin manifestations (33.7%), and CNS manifestations (49.8%) frequently went unreported. There were many cases that made a categorical description of a lab value (e.g., thrombocytopenia) without providing an absolute value (e.g., platelets level). Conclusions: This is the largest aggregated study of nHLH presentations, diagnostic criteria, clinical trajectory, and etiologic diagnoses. Neurologic, dermatologic, and hepatic manifestations occur in the neonatal population. Current reports of nHLH suggest a grim prognosis. Future publications containing data on nHLH should report all clinically relevant variables. Studies looking at multiple patients in aggregate should provide supplemental information with detailed nHLH cases.

Abstract Background: The National Comprehensive Cancer Network (NCCN) recommends the use of tissue-based genetic tests, such as Decipher, Prolaris, and Confirm mdx for localized prostate cancer, to help patients and caregivers make more informed treatment decisions at the time of diagnosis. However, while much enthusiasm currently exists for the burgeoning field of genomic medicine, prostate cancer disparities continue to persist in underserved communities despite the existence of evidence-based treatment guidelines. Methods: A diverse 15-member Community Advisory Board (CAB) representing rural and urban communities in Duval County, Florida were recruited from May to June 2023, to build a community-academic partnership, for the development and implementation of a genetic literacy patient-caregiver educational intervention for localized prostate cancer. The 15-member CAB was divided into groups of 5 for focus group discussions. Qualitative and quantitative data from CAB members were integrated to gain better understanding of the facilitators and barriers for prostate cancer genetic literacy in underserved communities. Results: The thematic analysis reveals several key themes related to prostate cancer, screening, treatment, and genetics. These themes reflect the diverse perspectives and experiences of the CAB members regarding prostate cancer, ranging from personal anecdotes to broader societal issues. Participants expressed thoughts related to fear, lack of knowledge, cultural beliefs, and access to healthcare. The discussion on prostate cancer and tissue based genetic testing highlighted the complexities surrounding prostate cancer and the need for further education, awareness, and access to affordable healthcare for all individuals at risk. Conclusion: CAB members emphasized the importance of improving access to information, promoting education, and addressing cultural barriers to ensure that individuals are informed about available options for prostate cancer diagnosis and treatment. Citation Format: Ewan K. Cobran, Jocelyn Turner, Folakemi Odedina, Alan H. Bryce, Christopher Williams, Jose Rodriguez, Roger Williams, Woodrow Nathan, Thomas Bryant III, LoveVonia Nathan, Laureen Husband. Community advisory board members’ perspectives on genetic literacy and patient-caregiver communication of prognostic genomics for localized prostate cancer [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr A042.

Background Innovative restructuring of cardiac rehabilitation (CR) delivery remains critical to reduce barriers and improve access to diverse populations. Destination Cardiac Rehab is a novel virtual world technology‐based CR program delivered through the virtual world platform, Second Life, which previously demonstrated high acceptability as an extension of traditional center‐based CR. This study aims to evaluate efficacy and adherence of the virtual world–based CR program compared with center‐based CR within a community‐informed, implementation science framework. Methods Using a noninferiority, hybrid type 1 effectiveness‐implementation, randomized controlled trial, 150 patients with an eligible cardiovascular event will be recruited from 6 geographically diverse CR centers across the United States. Participants will be randomized 1:1 to either the 12‐week Destination Cardiac Rehab or the center‐based CR control groups. The primary efficacy outcome is a composite cardiovascular health score based on the American Heart Association Life's Essential 8 at 3 and 6 months. Adherence outcomes include CR session attendance and participation in exercise sessions. A diverse patient/caregiver/stakeholder advisory board was assembled to guide recruitment, implementation, and dissemination plans and to contextualize study findings. The institutional review board–approved randomized controlled trial will enroll and randomize patients to the intervention (or control group) in 3 consecutive waves/year over 3 years. The results will be published at data collection and analyses completion. Conclusions The Destination Cardiac Rehab randomized controlled trial tests an innovative and potentially scalable model to enhance CR participation and advance health equity. Our findings will inform the use of effective virtual CR programs to expand equitable access to diverse patient populations. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT05897710.

Ultrasound has been used more frequently in the anatomical sciences to reinforce core anatomy concepts in the classroom and introduce commonly applied imaging technologies encountered in a clinical setting. Interprofessional Education (IPE) is being incorporated into health sciences training as a learning model for real world interactions. The primary objective of the current study was to determine the impact of an IPE ultrasound curriculum on students' anatomy and ultrasound knowledge, as well as attitudes towards interprofessional collaboration. We hypothesized that students who participated in an IPE experience would have improved recall of anatomical and ultrasound concepts as well as improved attitudes and perceptions towards IPE when compared to students who did not participate in an IPE session. First year medical students (MD, n = 40) and first year physical therapy students (PT, n = 25) were randomly assigned to PT‐only, MD‐only, or mixed PT‐MD ultrasound instruction groups studying the shoulder. Students were assessed using an anatomy and ultrasound knowledge test and University of the West of England Interprofessional Questionnaire (UWEIPQ) prior to and following the session. The results of this study suggest that while ultrasound instruction significantly improves ultrasound post‐test scores when compared to pre‐test scores regardless of group assignment (PT‐only: p < 0.001; MD‐only: p = 0.007; PT‐MD: p < 0.001), learning in an interprofessional PT‐MD group did not significantly impact knowledge recall of ultrasound concepts when compared to non‐IPE groups. Interestingly, students in PT‐MD groups had significantly higher anatomy post‐test scores when compared to the MD‐only groups (PT‐MD post‐test = 93.2%; MD‐only post‐test = 84.1%; p = 0.041), but not when compared to the PT‐only groups. Additionally, the results of the UWEIPQ are consistent with the impression that students who participate in an IPE experience are more likely to be cognizant of inherent biases in the interactions between different health professionals as well as demonstrate increased confidence in their interprofessional relationships. In conclusion, our study reinforces that IPE programs should quantify knowledge recall in order to assess the effectiveness of a specific program. Furthermore, such endeavors should assess important competencies including communication, teamwork, and interdisciplinary respect that are necessary to succeed in a multidisciplinary health care team. Support or Funding Information Department of Anatomy, Mayo Clinic College of Medicine and Science, Mayo Clinic, Rochester, MN; Social Science and Humanities Research Council, Government of Canada

Abstract Calorie restriction (CR) with adequate nutrient intake is a potential geroprotective intervention. To advance this concept in humans, we tested the hypothesis that moderate CR in healthy young‐to‐middle‐aged individuals would reduce circulating biomarkers of cellular senescence, a fundamental mechanism of aging and aging‐related conditions. Using plasma specimens from the Comprehensive Assessment of Long‐term Effects of Reducing Intake of Energy (CALERIE™) phase 2 study, we found that CR significantly reduced the concentrations of several senescence biomarkers at 12 and 24 months compared to an ad libitum diet. Using machine learning, changes in biomarker concentrations emerged as important predictors of the change in HOMA‐IR and insulin sensitivity index at 12 and 24 months, and the change in resting metabolic rate residual at 12 months. Finally, using adipose tissue RNA‐sequencing data from a subset of participants, we observed a significant reduction in a senescence‐focused gene set in response to CR at both 12 and 24 months compared to baseline. Our results advance the understanding of the effects of CR in humans and further support a link between cellular senescence and metabolic health.

BACKGROUND Hemispherectomy is a surgical procedure reserved for hemispheric intractable epilepsy. Sagittal craniosynostosis is a congenital disorder treated with open or endoscope-assisted approaches for synostosis correction. These procedures are not commonly performed in the same setting. OBSERVATIONS In this report, the authors present a 6-month-old female with sagittal craniosynostosis, hemimegalencephaly, and intractable epilepsy who underwent a left hemispherotomy with open sagittal synostosis correction followed by cranial molding orthosis therapy. LESSONS The report highlights the technical nuances of the procedure, but also discusses the possible genetic disorder responsible for both conditions, megalencephaly-capillary malformation syndrome.

As the population in many industrial countries is aging, the risk, incidence, and prevalence of CKD increases. In the kidney, advancing age results in a progressive decrease in nephron number and an increase in glomerulosclerosis. In this review, we focus on the effect of aging on glomerular podocytes, the post-mitotic epithelial cells critical for the normal integrity and function of the glomerular filtration barrier. The podocytes undergo senescence and transition to a senescence-associated secretory phenotype typified by the production and secretion of inflammatory cytokines that can influence neighboring glomerular cells by paracrine signaling. In addition to senescence, the aging podocyte phenotype is characterized by ultrastructural and functional changes; hypertrophy; cellular, oxidative, and endoplasmic reticulum stress; reduced autophagy; and increased expression of aging genes. This results in a reduced podocyte health span and a shortened life span. Importantly, these changes in the pathways/processes characteristic of healthy podocyte aging are also often similar to pathways in the disease-induced injured podocyte. Finally, the better understanding of podocyte aging and senescence opens therapeutic options to slow the rate of podocyte aging and promote kidney health.