Citations

Abstract Objective To determine COVID-19 vaccine-related adverse events (AEs) in the seven-day post-vaccination period in patients with SLE vs autoimmune rheumatic diseases (AIRDs), non-rheumatic autoimmune diseases (nrAIDs), and healthy controls (HC). Methods Data were captured through the COVID-19 Vaccination in Autoimmune Diseases (COVAD) questionnaire (March–December 2021). Multivariable regression models accounted for age, gender, ethnicity, vaccine type and background treatment. Results Among 9462 complete respondents, 583 (6.2%) were SLE patients (mean age: 40.1 years; 94.5% females; 40.5% Asian; 42.9% Pfizer-recipients). Minor AEs were reported by 83.0% of SLE patients, major by 2.6%, hospitalization by 0.2%. AE and hospitalization frequencies were similar between patients with active and inactive SLE. Rashes were more frequent in SLE patients vs HC (OR; 95% CI: 1.2; 1.0, 1.5), chills less frequent in SLE vs AIRDs (0.6; 0.4, 0.8) and nrAIDs (0.5; 0.3, 0.8), and fatigue less frequent in SLE vs nrAIDs (0.6; 0.4, 0.9). Pfizer-recipients reported higher overall AE (2.2; 1.1, 4.2) and injection site pain (2.9; 1.6, 5.0) frequencies than recipients of other vaccines, Oxford/AstraZeneca-recipients more body ache, fever, chills (OR: 2.5, 3.0), Moderna-recipients more body ache, fever, chills, rashes (OR: 2.6, 4.3). Hospitalization frequencies were similar across vaccine types. AE frequencies were similar across treatment groups, although chills were less frequent in antimalarial users vs non-users (0.5; 0.3, 0.9). Conclusion While COVID-19 vaccination-related AEs were reported by four-fifths of SLE patients, those were mostly minor and comparable to AEs reported by healthy individuals, providing reassurance regarding COVID-19 vaccination safety in SLE.

A hexanucleotide repeat expansion in intron 1 of the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia, or c9ALS/FTD. The RNA transcribed from the expansion, r(G 4 C 2 ) exp , causes various pathologies, including intron retention, aberrant translation that produces toxic dipeptide repeat proteins (DPRs), and sequestration of RNA-binding proteins (RBPs) in RNA foci. Here, we describe a small molecule that potently and selectively interacts with r(G 4 C 2 ) exp and mitigates disease pathologies in spinal neurons differentiated from c9ALS patient-derived induced pluripotent stem cells (iPSCs) and in two c9ALS/FTD mouse models. These studies reveal a mode of action whereby a small molecule diminishes intron retention caused by the r(G 4 C 2 ) exp and allows the liberated intron to be eliminated by the nuclear RNA exosome, a multi-subunit degradation complex. Our findings highlight the complexity of mechanisms available to RNA-binding small molecules to alleviate disease pathologies and establishes a pipeline for the design of brain penetrant small molecules targeting RNA with novel modes of action in vivo.

The standard method for cardiac allograft preservation for the past 50 years has been static storage using crushed ice. A heart transplant transportation system designed to improve preservation quality with temperature monitoring, the Paragonix SherpaPak Cardiac Transport System (SCTS), was evaluated for its impact on postoperative costs relative to conventional ice storage. Observational US multicenter registry data collected during the August 2015 to November 2021 timeframe from 12 transplant hospitals were analyzed using logistic regression analysis and propensity matching to balance measured baseline covariates and to reduce selection bias. Hospital cost and outcome data post-transplant were then evaluated using various statistical methods. One hundred seventy-four (174) patients were identified resulting in 87 matches. Baseline characteristics were similar between groups. The SCTS group had a significantly lower proportion of ICU days on post-transplant mechanical circulatory support ( p < 0.0001); significantly fewer patients on extracorporeal membrane oxygenation ( p = 0.017); and significantly fewer patients experiencing severe primary graft dysfunction (PGD) ( p = 0.03). Overall hospital plus mechanical circulatory support post-transplant costs were significantly lower by $26.7K in the CTS cohort ( p = 0.03). Use of the SCTS is associated with improved clinical outcomes resulting in significantly lower overall hospital care costs.

Abstract Increased pancreatic cancer (PC) risk in first-degree relatives (FDRs) of PC patients with germline pathogenic/likely pathogenic variants (PLPV) is a motivator for cascade genetic testing. To date, unbiased FDR risk estimates for gene-specific risks of genetic cancer syndrome-associated cancers are unknown. These estimates would enhance genetic counseling of at-risk FDRs in families where the PC proband has been found to carry a PLPV. Study Aim: To objectively quantify gene-specific risks of six relevant cancers among FDRs of PC patients with germline PLPV in ATM, BRCA1, BRCA2, CDKN2A, MLH1, MSH2, MSH6, PALB2, and PMS2. Methods: In the prospective, clinic-based Mayo Clinic Biospecimen Resource for Pancreas Research registry, 4,562 PC patients had previously undergone germline genetic testing for pancreatic cancer-associated genes through either research studies or clinical testing. Of these, 234 PC probands were found to carry PLPV among 9 genes of interest and had provided detailed demographic and cancer data on their FDRs by questionnaire. We focused on six cancer types (ovary, breast, uterus, pancreas, colon, and malignant melanoma) in FDRs as reported by the probands. Standardized incidence ratios estimated risk by gene of six cancers among FDRs of PC patients carrying PLPV. Results: 1,670 FDRs (mean age 58.1+17.8SD; 48.9% female) were included in the study. We found significantly increased risk of ovarian cancer in female FDRs of PC probands who carry PLPV in BRCA1 (SIR 9.49, 95%CI:3.06-22.14) or BRCA2 (3.72, 95%CI:1.36-8.11), and breast cancer risks were higher with BRCA2 (2.62, 95%CI:1.89-3.54). Uterine cancer risk was increased in FDRs of PC probands who carry PLPV for Lynch Syndrome mismatch repair (MMR) (6.53, 95%CI:2.81-12.86). PC risk was also increased (ATM 4.53, 95% CI:2.69-7.16; BRCA2 3.45, 95%CI:1.72-6.17; CDKN2A 7.38, 95%CI:3.18-14.54; PALB2 5.39, 95%CI:1.45-13.79). Increased colon cancer risk was observed in FDRs of probands who carried MMR PLPV (5.83, 95%CI:3.70-8.75), while melanoma risk was elevated for FDRs of probands with CDKN2A PLPV (7.47, 95%CI:3.97-12.77). Conclusion: PLPV in nine syndrome-associated genes in PC probands are associated with increased risk of six cancers in FDRs in PC families. The findings underscore the importance of risk estimation of various other cancers in PC families for screening, early detection, and intervention. The gene-specific quantified cancer risks for FDRs of PC patients with syndrome-associated germline PLPV can inform counseling regarding extra-PC risks when considering cascade genetic testing. Citation Format: Xuan Chen, Kari Rabe, Margaret Meyer, Jennnifer Kemppainen, Masayasu Horibe, Shruti Chandra, Shounak Majumder, Gloria Petersen. Gene-specific risk of syndrome-associated cancers in first-degree relatives of pancreatic cancer patients with pathogenic/likely pathogenic variants [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A033.

Abstract INTRODUCTION In patients with newly-diagnosed glioblastoma, rapid early progression (REP) refers to tumour regrowth between surgery and postoperative chemoradiotherapy. This systematic review and meta-analysis appraised published data on REP to better characterise and understand it. METHODS Systematic searches of MEDLINE, EMBASE and the Cochrane database from inception to 21/10/21. Studies describing the incidence of REP – tumour growth between the postoperative MRI scan and pre-radiotherapy MRI scan in newly-diagnosed glioblastoma, were included. The primary outcome was REP incidence. RESULTS From 1590 search results, 9 studies were included with 716 patients. The median age was 56.9 years (IQR 54.0-58.8 years). There was a male predominance with a median male-to-female ratio of 1.4 (IQR 1.1-1.5). The median number of days between MRI scans was 34 days (IQR 18-45 days). The mean incidence rate of REP was 45.9% (range 19.3%-72.0%) and significantly lower in studies employing functional imaging to define REP (p&lt; 0.001). REP/non-REP groups were comparable with respect to age (p=0.99), gender (p=0.33) and time between scans (p=0.81). REP was associated with shortened overall survival (HR 1.78, 95% CI 1.30-2.43, p&lt; 0.001), shortened progression-free survival (HR 1.78, 95% CI 1.30-2.43, p&lt; 0.001), subtotal resection (OR 6.96, 95% CI 4-51-10.73, p&lt; 0.001) and IDH wildtype versus mutant tumours (OR 0.20, 95% CI 0.02-0.38, p=0.03). MGMT promoter methylation was not associated with REP (OR 1.29, 95% CI 0.72-2.28, p=0.39). CONCLUSIONS REP occurs in almost half of patients with newly-diagnosed glioblastoma and has a strongly negative prognostic effect. Future studies should investigate its biology and effective treatment strategies.

Abstract While the allure of targeted therapies in oncology has been their high degree of specificity and potency for key tumor drivers, they have been disappointing in glioblastoma (GBM), even for drugs that are blood brain barrier permeable and CNS retained. This point is highlighted by the experience with mitotic spindle inhibitors, drugs which block the G2M transition and induce mitotic catastrophe—a phenotype characterized by cell enlargement and polyploidy that leads to apoptotic cell death. We have shown that one of these, a potent inhibitor of the mitotic kinesin Kif11 (ispinesib), is highly active against GBM tumor initiating cells and prolongs survival in murine models of this disease. However, tumors eventually progress, reflecting the development of drug resistance. Although ispinesib resistant GBM cells develop mitotic catastrophe, they become highly resistant to the apoptosis that typically follows and continue to proliferate. We find that this apoptosis resistance requires phosphorylation of the transcription factor STAT3 at two residues—Y705 and S727. Phosphorylation of Y705, mediated by SRC kinase, translocates STAT3 to the nucleus where it induces transcription of anti-apoptotic proteins. Phosphorylation at S727, mediated by EGFR, translocates STAT3 to the mitochondria where it blocks release of cytochrome c—the penultimate effector in apoptosis. Simultaneously inhibiting both SRC and EGFR with FDA-approved, CNS permeant inhibitors reverses this resistance and significantly prolongs survival in ispinesib-treated GBM-bearing mice. Furthermore, we find that resistance to several other mitotic inhibitors also utilizes this STAT3-driven mechanism and can likewise be reversed with combined EGFR and SRC inhibition. Thus, our work demonstrates how a promising therapeutic approach, which has been disappointing in GBM, can in fact be rendered effective by anticipating and prospectively treating ab initio the mechanism that drives treatment resistance.

Gastrointestinal stromal tumors (GIST) are the most common type of soft tissue sarcoma that occur throughout the gastrointestinal tract. Most of these tumors are caused by oncogenic activating mutations in the KIT or PDGFRA genes. The NCCN Guidelines for GIST provide recommendations for the diagnosis, evaluation, treatment, and follow-up of patients with these tumors. These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines, including revised systemic therapy options for unresectable, progressive, or metastatic GIST based on mutational status, and updated recommendations for the management of GIST that develop resistance to specific tyrosine kinase inhibitors.

Abstract Objectives The COVID-19 vaccination in autoimmune diseases (COVAD) study aimed to assess short-term COVID-19 vaccination-related adverse events (AEs) in RA patients. Methods An online self-reported questionnaire (March–December 2021) was used to capture data related to COVID-19 vaccination-related AEs in RA, other autoimmune rheumatic diseases (AIRDs) (excluding RA and inflammatory myositis), non-rheumatic autoimmune diseases (nrAIDs) and healthy controls (HCs). Descriptive and multivariable regression analyses were performed. Results Of the 9462 complete respondents, 14.2% (n = 1347) had been diagnosed with RA; they had a mean (s.d.) age of 50.7 (13.7) years, 74.2% were women and 49.3% were Caucasian. In total, 76.9% and 4.2% of patients with RA reported minor and major AEs, respectively. Patients with active and inactive RA had similar AE and hospitalization frequencies. Overall, AEs were reported more frequently by BNT162b2 and mRNA-1273 recipients and less frequently by BBV152 recipients compared with the rest. Major AE and hospitalization frequencies were similar across recipients of different vaccines. Patients receiving methotrexate and hydroxychloroquine reported fewer minor AEs than those patients not on them. Compared with HCs and patients with other AIRDs, patients with RA reported similar total AEs, overall minor AEs, and hospitalizations. Compared with nrAIDs, patients with RA reported lower frequencies of overall AEs, minor AEs (both odds ratio [OR] = 0.7; 95% CI: 0.5, 0.9), and injection site pain (OR = 0.6; 95% CI: 0.5, 0.8) with similar major AE and hospitalization frequencies. Conclusion Despite the differences in AE frequency across different COVID-19 vaccines, all were well tolerated in patients with RA and were comparable to HCs, providing reassurance as to the safety of COVID-19 vaccination.