Citations

PURPOSE Most oncology trials define superiority according to dichotomized P value thresholds, which are frequently misinterpreted. Posterior probability, however, directly estimates the probability of the hypothesis at hand. Here, we reanalyze a large collection of modern phase III trials and benchmark posterior probability versus the standard trial interpretation based on statistical significance. METHODS Outcomes from 194,129 patients were manually reconstructed from the primary end points of 230 phase III, superiority-design oncology trials. Posterior probabilities of treatment effect were then calculated across multiple priors and several effect sizes of clinical relevance, including minimum clinically important difference (MCID) defined as hazard ratio (HR) < 0.8 per ASCO criteria or HR < 0.64 per European Society of Medical Oncology (ESMO) criteria. RESULTS All trials interpreted as superior using P value thresholds had probabilities >90% for achieving at least marginal benefits (HR < 1). However, only 62% of positive trials (74/120) had >90% probabilities of achieving the ASCO MCID (HR < 0.8), even under an enthusiastic prior, including 70% of trials (57/82) leading to regulatory approval. Only 30% of positive trials (36/120) had >90% probability of achieving the ESMO MCID (HR < 0.64). Conversely, 24% of trials (26/110) interpreted as not superior had >90% probability of achieving marginal benefits (HR < 1), even under a skeptical prior. CONCLUSION Bayesian models, although often in agreement with statistical significance thresholds, add considerable unique interpretative value for a subset of phase III oncology trials. Posterior probability may provide a solution for overcoming the discrepancies between refuting the null hypothesis and detecting clinically relevant effects.

Background: The timing of coronary artery bypass grafting (CABG) in patients with non-ST-elevation myocardial infarction (NSTEMI) may critically impact clinical outcomes, yet the ideal surgical window remains unclear. We aimed to evaluate the association between time-to-CABG and in-hospital outcomes among NSTEMI admissions undergoing CABG. Methods: This retrospective cohort study utilized the US National Inpatient Sample database from 2017 to 2021 to evaluate the association between time-to-CABG and key in-hospital outcomes, including mortality, cardiac arrest, cardiogenic shock, ischemic stroke, acute kidney injury, and blood transfusion rates, while assessing length of stay (LOS) and hospital charges exclusively among survivors. Adult admissions with principal diagnosis of NSTEMI who underwent CABG without prior interhospital transfer were grouped by the calendar day of CABG from admission (0, 1, 2, 3, 4, 5, 6, and ≥7). Multivariate regression models were used to assess the outcomes across these eight groups. Results: Of 142,200 included admissions, same-day CABG (hospital day 0) was associated with the highest rates of in-hospital mortality, cardiac arrest, cardiogenic shock, and ischemic stroke. The adjusted odds of mortality, cardiac arrest, and cardiogenic shock were lower among admissions undergoing CABG between days 2 and 5. Likewise, the adjusted odds of ischemic stroke were lowest when CABG occurred on days 2 to 4. The odds of AKI increased when CABG was delayed beyond day 6, whereas blood transfusion rates showed no statistically significant association with time-to-CABG. Among survivors, LOS and hospital charges progressively increased with delayed CABGs. Conclusions: Among NSTEMI admissions undergoing CABG, CABG performed on hospital days 2 to 4 was associated with lower adjusted odds of several adverse in-hospital outcomes compared with same-day CABG. Further prospective studies are needed to validate these results and guide clinical decision-making.

Combined histopathological and metabolomic analysis of the same tissue specimen can reduce biological variability compared to independent analyses of similar samples. However, conventional workflows are incompatible: tissue fixation leads to metabolite loss through dilution and chemical reactions with fixative, while metabolomic extraction typically destroys the specimen. We propose a method that reconciles these conflicting requirements by enabling metabolite recovery from fixative while preserving tissue for histopathology. In this approach, tissue is initially fixed in a small volume of fixative; an aliquot of the fixative is then collected for nuclear magnetic resonance-based metabolomic analysis before additional fixative is added for standard processing. As a proof-of-concept, mouse kidneys from the same subject were analyzed using two protocols: standard perchloric acid extraction (ensuring complete metabolite recovery but destroying tissue) and metabolite extraction from fixative. Several metabolites were fully recoverable from the fixative, others partially, while some were lost due to chemical reactions. Despite some limitations, this strategy may be useful for analyzing precious specimens, such as human biopsies, that must remain intact for further studies. Moreover, using the same specimen for dual analyses reduces the number of animals required and enhances statistical robustness.

RELA-related disease is a rare, autosomal-dominant condition presenting with immune dysregulation and immunodeficiency. RELA encodes the p65 subunit, a component of the canonical NFκB pathway. The underlying pathogenesis, at least in part, involves impaired NFκB activation, increased susceptibility to TNFα-induced apoptosis, and hyperinflammation. To date, only a modest number of cases have been documented worldwide, and the full clinical and functional spectrum of disease remains incompletely defined. This study represents a large global cohort identified with RELA variants, comprising 40 patients from 30 institutions, expanding our previous report of a single large kindred (1). The clinical spectrum includes arthritis, mucocutaneous ulcers, uveitis, dermatitis, irritable bowel disease, recurrent infections, lymphopenia, hypogammaglobulinemia, recurrent fevers, and susceptibility to neoplasia. The patients represent 36 kindreds with 28 unique RELA variants, of which 15 are missense, 7 nonsense, and 6 frameshift variants. Fifteen are in the Rel homology domain, 7 in the transcriptional activation domain, and 6 in the C-terminal region proximal to TAD (Fig. 1). Functional studies assessed the canonical NFκB pathway in 27% of the cohort (n = 11; healthy controls = 40). Patient peripheral blood mononuclear cells (PBMCs) were used to quantify total and phosphorylated p65 (ph-p65, Ser529) by flow cytometry after stimulation with PMA (100 ng/ml) and ionomycin (1 uM). In 8 patients, we assessed the kinetics of IκBα degradation, required for p65 phosphorylation and nuclear translocation of p65/p50. All patients tested had decreased total p65, while 64% had decreased ph-p65 with altered phosphorylation kinetics. Nearly 45% had impaired IκBα degradation. One patient (P4) demonstrated increased IκBα degradation and ph-p65, while a related proband (P1) had decreased ph-p65. Additionally, P4 did not have the same mucocutaneous clinical phenotype as P1 despite sharing the same RELA variant. This could reflect the effect of other genetic modifiers, epigenetic, environmental, or stochastic variations, which could lead to variable expressivity and/or incomplete penetrance. All patients appeared to have haploinsufficiency, as none had normal levels of p65. This study expands the clinical and genetic spectrum of RELA-related disease and provides mechanistic insights into the impact of these variants on p65 phosphorylation and downstream function, resulting in variable expressivity. Figure 1. RelA protein structure. Represents unique variant locations and categories, key domains, and phosphorylation sites. Source: UniProt. Adapted from (2). BioRender.

Background Granulomatous-lymphocytic interstitial lung disease (GLILD) is a major cause of morbidity and mortality in common variable immunodeficiency (CVID), yet its pathophysiology remains incompletely understood, and no Food and Drug Administration (FDA)-approved therapies exist. Cellular senescence, a state associated with inflammation and fibrosis, has been implicated in chronic lung diseases, including idiopathic pulmonary fibrosis, where senolytic therapies have shown benefit. Cellular senescence has also been described in some cases of GLILD. Objective To evaluate the efficacy of fisetin, a senolytic flavonoid, compared with placebo in adults with CVID-associated GLILD. Methods We conducted a randomized, double-blind, placebo-controlled pilot trial in 10 adults with GLILD (Figure 1). Participants received fisetin 20 mg/kg or placebo on days 0–1 and 28–29, with follow-up over 180 days. Assessments included pulmonary function testing (PFT) and Short Form Health Survey (SF-36). Results Fisetin was well tolerated, with no adverse events. SF-36 Mental Health scores were numerically higher in fisetin participants (day 28: −0.28; day 180: 0.00) than placebo (day 28: −0.56; day 180: −0.28). Mental Component Summary scores remained stable in the fisetin group (−0.65 to −0.70) but declined in the placebo group (−1.09 to −1.94). All other SF-36 domains were comparable between groups. Mean spirometry measures were stable in both groups. With fisetin, lung volumes increased over time, with increases in mean total lung capacity (5.46 to 5.76 L), residual volume (1.69 to 2.09 L), and residual volume (RV)/total lung capacity (TLC) (0.31 to 0.37). In contrast, the placebo group demonstrated decreases in total lung capacity (4.72 to 4.62 L), residual volume (1.89 to 1.72 L), and RV/TLC (0.41 to 0.38). Diffusion capacity corrected increased from baseline to day 90 in the fisetin group (13.9 to 15.9) and remained stable at day 180, whereas it declined in the placebo group by day 180 (19.1 to 17.6). Discussion In this randomized pilot study, fisetin was well tolerated and showed benefit in diffusion capacity, lung volumes, and mental health–related outcomes compared to placebo in GLILD. The temporal pattern of changes suggests that alternative dosing strategies may warrant further evaluation, in addition to potentially larger future studies. Figure 1. CONSORT flow diagram.

Introduction Individuals with inborn errors of immunity (IEI) are increasingly reaching reproductive age, yet guidance on fertility preservation, genetic counseling, medication adjustments in pregnancy and breastfeeding, monitoring for complications, and multidisciplinary coordination is lacking. This joint effort between two committees of the Clinical Immunology Society (CIS), the Women of the Clinical Immunology Society (WCIS) and the Adult Immune Deficiency Committee (AID) survey aimed to characterize current reproductive care practices for IEI patients. Methods A survey was disseminated to 809 CIS members. The response rate was 6.43% (52 respondents). The 24-item questionnaire addressed management of pregnancy in IEI, medications adjustment, participation in hematopoietic stem cell transplant (HSCT) care and fertility preservation, and maternal/neonatal outcomes. Results Because survey items were optional, the number of respondents varies by question. Forty-two participants completed core items: 64% (27/42) allergists/immunologists, 71% (30/42) practicing at academic centers, and 48% (20/42) with &gt;50% immunology-focused practices. Most respondents (78%, 41/52) currently or previously cared for pregnant/planning IEI patients. Preconception counseling was common (90%, 37/41), yet only 2% (1/41) have access to a formal reproductive multidisciplinary team. Among clinicians involved in HSCT care, 45% (13/29) referred patients for fertility preservation. More than half, 52% (22/42), observed reduced fertility in IEI patients, and 56% (20/36) observed adverse maternal outcomes. Medication management varied: 61% (24/39) discontinued known teratogenic medications, and 64% (25/39) adjusted dosing during pregnancy. Regarding immunoglobulin replacement therapy, 79% adjusted dosing based on IgG levels and 42% increased dosing by trimester. Conclusions This CIS survey reveals practice variability and notable gaps in reproductive health support for individuals with IEIs. Due to the relatively low response rate, generalizability across providers and practice settings is challenging. However, the results of this survey suggest that although most clinicians provide preconception counseling and manage IgG and immunomodulatory therapy during pregnancy, formal multidisciplinary structures are rare. High rates of reported fertility concerns and maternal complications underscore the need for enhanced collaboration with obstetrics/gynecology and the development of structured, evidence-based, multidisciplinary guidelines for reproductive care in IEI. Tabular data are included as downloadable supplement files.

Background T cell–mediated hepatitis is an uncommon cause of acute pediatric liver injury. Most patients respond to steroids, but management of refractory disease remains challenging. We describe four patients with non-monogenic CD8+ T cell–mediated hepatitis with close temporal presentation and variable response to therapies. All four patients had severe elevations in liver enzymes, synthetic dysfunction, hyperbilirubinemia, cytopenias, elevations in cytokines (supplemental table), and CD8+ T cell predominance on biopsy, without meeting criteria for autoimmune hepatitis. All underwent next-generation or whole-exome sequencing; no monogenic causes were elucidated. Broad infectious workup was unrevealing. Case 1 A 17-year-old male with epilepsy presented with abdominal pain and jaundice, with labs and biopsy consistent with portal and lobular hepatitis with CD8+ T cell predominance. Bone marrow aspirate (BMA) was reassuring. Hepatitis was refractory despite corticosteroids, tacrolimus, sirolimus, anakinra, intravenous immune globulin (IVIG), and anti-thymocyte globulin (ATG). Infliximab led to dramatic but incomplete improvement. He remains on steroids, tacrolimus, and infliximab, with planned hematopoietic stem cell transplantation (HSCT). Case 2 A 7-year-old female with type 1 diabetes presented with jaundice and abdominal pain, with labs and biopsy consistent with CD8+ T cell hepatitis. Steroids induced a partial response, while infliximab led to marked improvement. She transitioned to azathioprine and maintains normal liver enzymes. Case 3 A 5-year-old male with autism presented with fevers and abdominal distention, with labs and biopsy consistent with portal and lobular hepatitis with CD8+ T cell predominance. IVIG/steroids provided only a transient improvement. Tacrolimus normalized labs and enabled steroid discontinuation. Case 4 An 11-month-old healthy female presented with jaundice. Labs and biopsy were consistent with giant cell hepatitis with CD8+ T cell predominance, and no evidence of autoimmune hemolytic anemia. She was listed for liver transplantation. Partial steroid response prompted tacrolimus initiation, leading to normalization of labs and removal from transplant listing. Conclusion CD8+ T cell–mediated hepatitis may progress rapidly and be steroid refractory. Early initiation of infliximab or tacrolimus may prevent progression to liver failure. Case one represents a severe presentation with limited response; however, most avoided liver or hematopoietic stem cell transplantation. All cases presented within a three-month window, suggesting a possible infectious trigger. Tabular data are included as downloadable supplement files.

Introduction Hyperuricemia, pulmonary hypertension, renal failure, alkalosis (HUPRA) syndrome is a mitochondrial disease caused by mutations in SARS2 (seryl-tRNA synthetase 2), which plays a role in protein synthesis. Limited case reports describe an association of HUPRA with immunodeficiency; however, no in-depth immune phenotyping has been described. We present a case of HUPRA with recurrent infections and lymphopenia, with clinical improvement on immunoglobulin replacement therapy (IgRT). Case Description An 11-month-old male born at 29 weeks’ gestational age with pulmonary hypertension (PH) and tracheostomy dependence was admitted with recurrent fevers and worsening PH. History revealed prior Enterococcus faecalis bacteremia as well as Staphylococcus aureus and Pseudomonas aeruginosa tracheitis. Laboratory evaluation revealed mildly low IgG with normal IgM and IgA. Lymphocyte subsets revealed T cell, B cell, and natural killer cell lymphopenias, with CD4+ T cell compartment skewing to a memory phenotype, normal total switched memory B cells, and normal T follicular helper cells. Vaccine titers were not obtained, given receipt of only one set of vaccines. T cell proliferations were reassuring. Genetic testing revealed compound heterozygous mutations in SARS2, confirming a diagnosis of HUPRA. He is being treated with IgRT with significant clinical improvement. Discussion In case series, up to half of patients with HUPRA can present with increased infections, often with leukopenia. Multiple studies have shown that aminoacyl-tRNA synthetases can play a role in immune cell development, regulation, and autoimmunity through interactions with innate and adaptive immune responses. Additionally, hyperuricemia is known to induce innate and adaptive immune responses. It is difficult to know how these findings relate to the function of SARS2 or patients with HUPRA. Our patient was found to have multilineage lymphopenia with mildly low IgG, with significant clinical improvement on IgRT. More in-depth evaluations are needed to better understand the pathophysiology of immune dysfunction with SARS2 deficiency. This case provides in-depth immune phenotyping and a potential treatment option for others with HUPRA. Tabular data are included as downloadable supplement files.

Introduction BACH2-related immunodeficiency and autoimmunity (BRIDA) increases the risk of developing B cell lymphoma. We present a case of a patient with a known history of common variable immunodeficiency (CVID) and BACH2 variant of uncertain significance, presenting with hypercalcemia and acute kidney injury (AKI), found to have T cell histiocyte-rich large B cell lymphoma of the spleen. Case Description 46-year-old male with CVID-like clinical picture with variant of uncertain significance in BACH2 (Combined Annotation Dependent Depletion [CADD] 25.2, allele frequency 2) and granulomatous-lymphocytic interstitial lung disease (GL-ILD), admitted for acute kidney injury with hypercalcemia. He is pancytopenic, hypercalcemic, with marked splenomegaly on CT. PET-CT showed retroperitoneal and iliac chain lymphadenopathy along with mixed changes of osseous/marrow lesions with new lesions in the thoracic spine and left mid femur. There is a notable improvement in GL-ILD on CT chest while the patient is on prednisone. Renal biopsy showed acute tubular injury with increased deposition of calcium phosphate, along with moderate interstitial fibrosis and tubular atrophy with mild fibrointimal thickening of arteries. No monoclonal protein detected in the serum, negative JC virus, BK virus, EBV, CMV, and HIV. Splenic biopsy showed B cell lymphoma with features of micronodular T cell/histiocyte-rich large B cell lymphoma of the spleen. Patient initiated on rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone treatment protocol. Discussion BACH2 is a regulator of T and B cell differentiation and maturation. The effect of BACH2 on T cells involves limiting the differentiation of regulatory T (Treg) cells, which aid in preventing autoimmunity. BACH2 mutations have been described in the literature in patients with CVID and autoimmunity, such as ulcerative colitis. Lymphoma can cause hypercalcemia, which can lead to acute kidney injury. This patient has a variant of uncertain significance in BACH2 with CADD 25.2, allele frequency 2. His clinical picture of CVID, acute kidney injury in the setting of hypercalcemia, and newfound B cell lymphoma of the spleen may be due to this variant of uncertain significance. Further studies need to be conducted to better understand this gene and its role in CVID and B cell lymphoma. Tabular data are included as downloadable supplement files.