Citations

Aging is a major risk factor for osteoarthritis (OA), but the specific mechanisms connecting aging and OA remain unclear. Although chondrocytes rarely divide in adult articular cartilage, they undergo replicative senescence in vitro, offering a model to study aging-related changes under controlled conditions. OA cartilage was obtained from an 80-year-old male and a 72-year-old female, while normal cartilage was sourced from a 26-year-old male. Chondrocyte cultures were established and sub-cultured to their Hayflick limit. Bulk RNA sequencing on early- and late-passage human articular chondrocytes identified transcriptomic changes associated with cellular aging. Early-passage OA chondrocytes already showed senescent phenotypes, unlike normal chondrocytes. All three cultures underwent 30 population doublings before replicative exhaustion, at which point all cells displayed senescence. During this process, cells lost their ability to form cartilaginous pellets. Differential gene expression analysis revealed distinct transcriptomic profiles between early- and late-passage chondrocytes and between normal and OA-derived cells. Genes related to matrix synthesis, degradation, inflammation, and the senescence-associated secretory phenotype (SASP) showed significant expression changes. Despite being a small pilot study, these findings suggest that further research into the molecular and metabolic changes during chondrocyte senescence could provide valuable insights into OA pathobiology.

Abstract Standard of care (SOC) for ndGBM begins with maximal safe resection followed by adjuvant radiotherapy and temozolomide, and maintenance temozolomide. IGV-001 is an autologous biologic-device combination immunotherapy for the treatment of ndGBM that consists of autologous GBM tumor cells and an antisense oligonucleotide against IGF-1R mRNA, irradiated and administered via biodiffusion chambers implanted in the abdomen. In a phase 1b study, IGV-001 was well tolerated without unexpected adverse events in subjects with ndGBM. Multiple efficacy signals were observed, including significant improvements in progression-free survival (PFS), overall survival (OS), radiographic evidence of tumor response, and changes in immune response biomarkers. Here, we present early safety data from the phase 2b randomized, multicenter, double-blind, placebo-controlled study (NCT04485949) designed to assess efficacy and safety of IGV-001 in subjects with ndGBM across 20 sites in the United States. After surgical resection, subjects were randomized 2:1 and treated with IGV-001 or placebo followed by SOC. The primary outcome is PFS, defined as the time from randomization to first progression, as determined by blinded central radiology review, or death. Secondary outcomes include OS, defined as the time from randomization to death due to any cause, and safety. As of May 22, 2024, 99 subjects were randomized and 95 implanted with IGV-001 or placebo plus SOC. A total of 39/45 (86.7%) subjects had sufficient follow-up time after initiated treatment with concurrent radiation and temozolomide. Nine of 72 randomized (12.5%) discontinued treatment, including 7 who stopped during the SOC treatment period. None ceased treatment for adverse events, protocol deviations, or death. A total of 11/72 (15.3%) randomized subjects discontinued the study after randomization. A review of blinded safety data did not show any emerging risk and supports no change to the benefit-risk profile of IGV-001 versus placebo. Updated data will be presented.

Abstract BACKGROUND Glioblastoma (GBM) is the most common primary brain malignancy in adults. Standard of care (SOC) for suspected GBM begins with maximal safe resection followed by adjuvant radiotherapy and temozolomide, and maintenance temozolomide. Imvax has utilized its Goldspire™ platform to create IGV-001, an autologous biologic-device combination product for the treatment of newly diagnosed GBM (ndGBM). IGV-001 consists of autologous GBM tumor cells and an antisense oligonucleotide against IGF-1R mRNA (IMV-001), irradiated and administered via biodiffusion chambers implanted in the abdomen. Together, these components stimulate immunogenic cell death and antigen release. In a phase 1b study in patients with ndGBM, IGV-001 was well tolerated without unexpected adverse events. Multiple efficacy signals were also observed, including significant improvements in progression-free survival, overall survival, radiographic evidence of tumor response, and changes in immune response biomarkers. A phase 2b randomized, multicenter, double-blind, placebo-controlled study to assess the safety and efficacy of IGV-001 in patients with ndGBM (ClinicalTrials.gov identifier: NCT04485949) is ongoing. Here, we present the first safety data from the study. MATERIAL AND METHODS After surgical resection, patients are treated with IGV-001 or placebo followed by SOC. The study will enroll approximately 93 patients at 20 sites in the United States, with a 2:1 randomization favoring IGV-001. The primary outcome is progression-free survival, defined as the time from randomization to first progression, as determined by blinded central radiology review, or death. Secondary outcomes include overall survival, defined as the time from randomization to death due to any cause, and safety. RESULTS As of February 2, 2024, a total of 72 patients have been randomized and 69 have been implanted with IGV-001 or placebo plus SOC. The median age was 60.0 years (range, 24-70 years). Most randomized patients (76.4%) were 51-70 years of age, and the male:female ratio was 2.27. A total of 39/45 (86.7%) patients with enough follow-up time, initiated treatment with concurrent radiation and temozolomide. A total of 9/72 (12.5%) randomized patients discontinued treatment, including 7 patients who discontinued during the SOC treatment period. No patients discontinued treatment for adverse events, protocol deviations, or death. A total of 11/72 (15.3%) randomized patients discontinued the study after randomization. CONCLUSION To date, the review of blinded safety data did not show any emerging risk and supports that there is no change to the benefit-risk profile of treatment with IGV-001 versus placebo. The data will be updated before presentation.

Abstract Objective Aging is a major risk factor for OA, but the specific mechanisms underlying this connection remain unclear. Although chondrocytes rarely divide in adult articular cartilage, they undergo replicative senescence in vitro which provides an opportunity to study changes related to aging under controlled laboratory conditions. Methods Cartilage was recovered from two knees with OA and one normal knee. Chondrocyte cultures were established and sub-cultured until their Hayflick limit. Bulk RNA sequencing on early- and late-passage human articular chondrocytes allowed identification of transcriptomic changes associated with cellular aging. Results One male (80 years old) and one female (72 years old) patient provided OA cartilage. The donor of normal chondrocytes was a 26-year old male. Early passage chondrocytes from the two OA samples already had the phenotype of senescing cells, unlike normal chondrocytes. Nevertheless, all three chondrocyte cultures underwent 30 population doublings before replicative exhaustion, by which point all cells displayed a senescent phenotype. During this process, the cells lost their ability to form cartilaginous pellets. Differentially expressed genes (DEGs) analysis confirmed distinct transcriptomic profiles between early- and late-passage chondrocytes, as well as between cells isolated from normal and OA cartilage. Various changes in expression of genes related to cartilage matrix synthesis, degradation, inflammation and the senescence-associated secretory phenotype (SASP) were noted. Conclusions Although only a small pilot study, its data suggest that a larger and deeper study of the molecular and metabolic events accompanying the senescence of chondrocytes could provide important insights into the pathobiology of OA.

Since 1988 the demand for the pancreas transplantation has continued to increase. This has been accompanied by a growth in the number of centers offering the procedure, and an increase in the number of transplants performed. The National Cooperative Transplantation Study was undertaken to document the costs of all transplants, including pancreas transplantation. Data on transplantation procedure charges, from date of transplant to discharge, were obtained from 66.7% of all pancreas transplantation programs active in 1988. These programs accounted for 72% of all transplants performed that year. Valid sample survey data (no more than 25 transplants per center) were obtained for 133 randomly selected patients. This constituted 54% of all procedures done in the United States in 1988. Detailed data were also collected on sources of payment and amount reimbursed. Due to outlier data, we report statistical medians, rather than means, as our measure of central tendency. The median charge for a pancreas transplant with or without a kidney was $66 917, with a hospital length of stay of 21 days, compared with a kidney transplant alone at $39 625 and a hospital length of stay of 14 days. Total pancreas transplant charges fell between $45 260 and $105 375 for 50% of the cases studied. Half of the patients had a hospital length of stay between 16 and 33 days. Due to the small number of cases available for analysis, it was not meaningful to cross‐classify the data according to various prognostic variables. Fifty percent of the transplants studied were paid for by private insurers, and reimbursement exceeded 80% of billed charges for 50.6% of the cases analyzed. Insurance reimbursement for pancreas transplantation is not uniform, but is favorable for those covered. While the number of procedures performed annually has increased since 1980, with the largest increases occurring since 1988, sustained growth may well be a function of insurance coverage. Many transplant centers are unable to bear the expense of pancreas transplants insurers fail to cover. As a result, access will be a problem for some patients.

Abstract Background The CDC reported a 35% increase in hospital-onset (HO) carbapenem-resistant Enterobacterales (CRE) infections during the COVID-19 pandemic. We evaluated patient outcomes following HO and community-onset (CO) CRE bloodstream infections (BSI). Methods Patients prospectively enrolled in CRACKLE-2 from 56 hospitals in 10 countries between 30 April 2016 and 30 November 2019 with a CRE BSI were eligible. Infections were defined as CO or HO by CDC guidelines, and clinical characteristics and outcomes were compared. The primary outcome was desirability of outcome ranking (DOOR) 30 days after index culture. Difference in 30-day mortality was calculated with 95% CI. Results Among 891 patients with CRE BSI, 65% were HO (582/891). Compared to those with CO CRE, patients with HO CRE were younger [median 60 (Q1 42, Q3 70) years versus 65 (52, 74); P < 0.001], had fewer comorbidities [median Charlson comorbidity index 2 (1, 4) versus 3 (1, 5); P = 0.002] and were more acutely ill (Pitt bacteraemia score ≥4: 47% versus 32%; P < 0.001). The probability of a better DOOR outcome in a randomly selected patient with CO BSI compared to a patient with HO BSI was 60.6% (95% CI: 56.8%–64.3%). Mortality at 30-days was 12% higher in HO BSI (192/582; 33%) than CO BSI [66/309 (21%); P < 0.001]. Conclusion We found a disproportionately greater impact on patient outcomes with HO compared to CO CRE BSIs; thus, the recently reported increases in HO CRE infections by CDC requires rigorous surveillance and infection prevention methods to prevent added mortality.

PURPOSE Acute lymphoblastic leukemia (ALL) can occur across all age groups, with a strikingly higher cure rate in children compared with adults. However, the pharmacological basis of age-related differences in ALL treatment response remains unclear. METHODS Studying 767 children and 309 adults with newly diagnosed B-cell ALL enrolled on frontline trials at St Jude Children's Research Hospital, MD Anderson Cancer Center, the Alliance for Clinical Trials in Oncology, and the ECOG-ACRIN Cancer Research Group, we determined the ex vivo sensitivity of leukemia cells to 21 drugs. Twenty-three ALL molecular subtypes were identified using RNA sequencing. We systematically characterized the associations between drug response and ALL genomics in children, adolescents and young adults, and elderly adults. We evaluated the effect of age-related gene expression signature on ALL treatment outcomes. RESULTS Seven ALL drugs (asparaginase, prednisolone, mercaptopurine, dasatinib, nelarabine, daunorubicin, and inotuzumab ozogamicin) showed differential activity between children and adults, of which six were explained by age-related differences in leukemia molecular subtypes. Adolescents and young adults showed similar patterns of drug resistance as older adults, relative to young children. Mercaptopurine exhibited subtype-independent greater sensitivity in children. Transcriptomic profiling uncovered subclusters within CRLF2 -, DUX4 -, and KMT2A -rearranged ALL that were linked to age and cytotoxic drug resistance. In particular, a subset of children had adult-like ALL on the basis of leukemia gene expression patterns across subtypes, despite their chronological age. Resistant to cytotoxic drugs, children with adult-like ALL exhibited poor prognosis in pediatric ALL trials, even after adjusting for age and minimal residual diseases. CONCLUSION Our results provide pharmacogenomic insights into age-related disparities in ALL cure rates and identify leukemia prognostic features for treatment individualization across age groups.

AbstractBackgroundImmune thrombocytopenia (ITP) and Evans syndrome (ES) are manifestations of immune dysregulation. Genetic variants in immune‐related genes have been identified in patients with ITP and especially ES. We aimed to explore familial autoimmunity in patients with ITP and ES to understand possible contributions to chronicity.ProcedureWe assessed family history in two ways: via patient report for ITP and ES and by population‐based analysis using the Utah Population Database (UPDB) for ITP. A total of 266 patients with ITP and 21 patients with ES were identified via chart review, and 252 of the 266 patients with ITP were also identified in the UPDB.ResultsChart review showed familial autoimmunity in 29/182 (15.9%) and 25/84 (29.8%) of patients with newly diagnosed+persistent (nd+p) ITP and chronic ITP (cITP), respectively, (p = .009). The UPDB analysis revealed that autoimmunity in relatives of patients with nd+pITP was higher than in relatives of controls (odds ratio [OR]: 1.69 [1.19–2.41], p = .004), but was not significantly increased in relatives of patients with cITP (OR 1.10 [0.63–1.92], p = .734). Incomplete family history in medical records likely contributed to the observed discrepancy.ConclusionsThe findings suggest that familial autoimmunity may have a stronger association with the development of ITP rather than its duration. Twelve (57.1%) patients with ES reported autoimmunity in their relatives. UPDB analysis was omitted due to the small number of patients with ES. The use of population databases offers a unique opportunity to assess familial health and may provide clues about contributors to immune dysregulation features within families.