Faculty Bibliography

PURPOSE/UNASSIGNED:In QUILT-3.032, the efficacy of IL-15 receptor agonist, nogapendekin alfa inbakicept (NAI) in combination with BCG for BCG-unresponsive high-grade papillary-only non-muscle invasive bladder cancer (NMIBC) was assessed. Herein we report the 36-month follow-up among participants with BCG-unresponsive papillary disease (Cohort B). MATERIALS AND METHODS/UNASSIGNED:NCT03022825 is an open-label, multi-center study with BCG-unresponsive high-grade Ta/T1 papillary NMIBC who received 400μg NAI plus 50mg BCG intravesically weekly for six consecutive weeks. The primary endpoint is disease-free survival (DFS) at 12-months. Progression-free survival (PFS), disease-specific survival (DSS), and cystectomy avoidance were assessed. Treatment-related adverse events (TRAEs) were assessed. RESULTS/UNASSIGNED:At July 15, 2024 data cutoff, the DFS rates at 12-, 24-, and 36-months were 58.2% (95% CI 46.6, 68.2), 52.1% (95% CI 40.3, 62.7), and 38.2% (95% CI 25.6, 50.6), respectively. The PFS rates at 12- and 36-months were 94.9% (95% CI 86.9, 98.0) and 83.1% (95% CI 69.5, 91.0). The DSS rates at 12- and 36-months were 98.7% (95% CI 91.4, 99.8) and 96.0% (95% CI 88.2, 98.7). The median DSS has not been reached. Cystectomy avoidance rates at 12- and 36-months were 92.2% (95% CI 83.4, 96.4) and 81.8% (95% CI 68.1, 90.1), with median time to cystectomy not reached. Most TRAEs were grade 1-2 (61%) with 3% grade 3, and no grade 4-5. CONCLUSIONS/UNASSIGNED:The 12- and 36-month DFS, PFS, DSS, and cystectomy avoidance rates demonstrate the effectiveness and safety of NAI plus BCG in the management of BCG-unresponsive papillary disease.

INTRODUCTION/BACKGROUND:Neurologic complications, including seizures, are common in pediatric patients undergoing heart surgery, especially those requiring postoperative extracorporeal membrane oxygenation (ECMO), requiring prompt, vigilant postoperative monitoring. Prolonged EEG monitoring in critically ill children presents a risk of scalp/pressure injuries. The skin's sensitivity to microcirculatory changes can also provide valuable insights into the patient's overall tissue perfusion, making it a critical component in the management of these vulnerable patients. METHODS:We initiated a quality improvement (QI) project to assess and reduce scalp injuries related to prolonged EEG monitoring in critically ill neonates and infants. The project involved reviewing baseline data, which included 2336 inpatient video EEGs performed from January 2022 to December 2024, and implementing interventions to improve skin safety during electrode placement, while incorporating best practices from ACNS and ASET guidelines. RESULTS:Five critically ill infants developed deep tissue injuries (DTIs) related to EEG electrodes, with most injuries occurring over the occipital region. The frequency of scalp injuries decreased from 0.30% in 2022 to 0% in 2024 after implementing the QI protocol, and was observed in conditions with known hypoperfusion. DISCUSSION/CONCLUSIONS:Electrode-related skin injuries are a common complication of prolonged EEG monitoring, particularly in critically ill pediatric patients. Our findings suggest that adherence to expert guidelines and tailored skin care protocols focused on skin preparation, electrode application, and monitoring parameters can reduce the risk of electrode-related skin injuries. Further research is needed to refine safety protocols and address the unique skin care challenges faced by this high-risk population.

We carried out a single-cell (sc) multiomic analysis on a series of MYD88 mutated Waldenström macroglobulinemia (WM) cases and identified two distinct subtypes of disease, memory B-cell-like (MBC-like) and plasma cell-like (PC-like), based on their expression of key lineage defining genes. Biologically, the subtypes are characterized by their variable capacity to differentiate fully towards a plasma cell (PC) and exhibit unique transcriptomic, chromatin accessibility, and genomic profiles. The MBC-like subtype is unable to differentiate beyond the memory B-cell (MBC) stage, upregulates key MBC genes, and is characterized by upregulated BCR and AKT/mTOR signaling. In contrast, the PC-like subtype can partially differentiate towards a PC, upregulates key PC genes, has enhanced NF-kB signaling, and has an upregulated unfolded protein response. Pseudotime trajectory analysis of combined scRNA-sequencing and scATAC-sequencing supports the variable differentiation capacity of each subtype and implicate key transcription factors SPI1, SPIB, BCL11A, and XBP1 in these features. The existence and generalizability of the two disease subtypes were validated further using hierarchical clustering of bulk RNA-seq data from a secondary set of cases. The biological significance of the subtypes was further established using whole genome sequencing, where it was shown that CXCR4, NIK, and ARID1A mutations occur predominantly in the MBC-like subtype and 6q deletions in the PC-like subtype. We conclude that the variable differentiation blockade seen in WM manifests itself clinically as two disease subtypes with distinct epigenetic, mutational, transcriptional, and clinical features with potential implications for WM treatment strategies.

BACKGROUND:Bruton's tyrosine kinase inhibitors (BTKis) are central to the medical management of chronic lymphocytic leukemia (CLL). However, accumulating data suggest an important association with cardiovascular (CV) adverse events (AEs), including arrhythmias, hypertension, and bleeding, in patients with CLL and other hematological malignancies treated with this therapeutic class. Data from comparative trials with BTKis suggest second-generation agents, eg, acalabrutinib and zanubrutinib, may be associated with fewer CV AEs than first-in-class BTKi ibrutinib. METHODS:PubMed and the proceedings of key hematology congresses were searched for relevant information using broad search terms including CLL, BTKi, and toxicity. RESULTS:When managing patients with CLL, screening before and during treatment to assess CV risk is suggested to guide decision-making. Due to the increased toxicity with ibrutinib, the second-generation BTKis are now preferred (per the NCCN Clinical Practice Guidelines in Oncology [NCCN Guidelines®]). For patients with a high CV-risk, the decision between second-generation BTKi or a time-limited alternative, like venetoclax plus an anti-CD20 monoclonal antibody, should be made on an individual basis after patient consultation and consideration of the presenting characteristics of CLL in any given patient. The management of anticoagulant/antiplatelet medication during BTKi treatment requires specific attention, with coexistent medications being carefully assessed before starting a BTKi to reduce the risk of bleeding. For patients with a new-onset or worsening CV events during BTKi therapy, management may involve temporarily stopping the BTKi or switching to another class of therapy. To ensure the best outcomes, a collaborative care approach is essential, and some patients may need to be referred to a cardiologist/cardio-oncologist for specialist management. CONCLUSION/CONCLUSIONS:Baseline and ongoing CV risk assessment, careful monitoring, management, and a multidisciplinary team approach are all critical to ensure optimal oncologic and CV outcomes for patients with CLL receiving BTKis.

BACKGROUND AND PURPOSE/UNASSIGNED:To evaluate the dosimetric and toxicity profiles of stereotactic body radiotherapy (SBRT) for prostate cancer, comparing cohorts with and without intraprostatic boost (IPB) to assess feasibility and safety of IPB, with particular attention to urethral and bladder dose and toxicity. MATERIALS AND METHODS/UNASSIGNED:This retrospective cohort study analyzed 349 patients with localized prostate cancer treated between 2018 and 2023. Of these, 266 received SBRT with IPB, and 83 received SBRT without IPB. Patients were treated using a robotic SBRT platform with fiducial tracking. Dosimetric parameters for the urethra, including D0.03cc, D0.3cc, and V40Gy, and for the bladder, including D0.03cc, D5cc, D10cc, and V37Gy, were evaluated. Acute and late toxicities were assessed using CTCAE criteria. RESULTS/UNASSIGNED:For the urethra, median values for D0.03cc, D0.3cc, and V40Gy, and for the bladder, median values D0.03cc, D5cc, D10cc, and V37Gy were compared and no statistically significant differences were observed between the two cohorts. Late urinary toxicity of grade 3 or higher occurred in 2.25 % of patients in the IPB group and 2.47 % in the no IPB group, with no grade 3 acute toxicities reported. DISCUSSION/UNASSIGNED:These findings support the use of SBRT using an IPB as a feasible and safe approach to achieve focal dose escalation to dominant intra-prostatic lesions (DILs) without significantly increasing urethra or bladder dose or toxicity. Future research should focus on standardizing DIL contouring, exploring adaptive planning techniques to increase accuracy, and prospectively studying toxicity and quality of life in patients treated with IPB with SBRT.

BACKGROUND:Studies of type 1 diabetes in sub-Saharan Africa have suggested that the clinical phenotype might differ from phenotypes reported elsewhere. We aimed to establish whether type 1 diabetes diagnosed in children and young adults in three countries across sub-Saharan Africa is of autoimmune origin. METHODS:In this observational, cross-sectional study, we identified participants without obesity from outpatient clinics in government and private hospitals in Cameroon, Uganda, and South Africa who were of self-reported Black African ethnicity with young-onset (age <30 years), insulin-treated, clinically diagnosed type 1 diabetes. We measured islet autoantibodies to GADA, IA-2A, and ZnT8A, and calculated a genetic risk score (GRS) for type 1 diabetes, which we compared with control populations without diabetes derived from the Uganda Genome Resource databank and other studies. Endogenous insulin secretion was assessed using plasma C-peptide. We compared findings with those for participants with self-reported Black (n=429) and White (n=2602) ancestry with type 1 diabetes from the SEARCH for Diabetes in Youth (SEARCH) study in the USA. FINDINGS/RESULTS:(19·5-24·1). Only 312 (34·9%) of 894 participants were positive for islet autoantibodies; these participants had classic features of type 1 diabetes, including 225 (82·7%) of 272 with plasma C-peptide <200 pmol/L, and high type 1 diabetes GRS. Those without islet autoantibodies (582 [65·1%] of 894) had significantly lower median type 1 diabetes GRS than those with autoantibodies (9·66 [IQR 7·77-11·33] vs 11·76 [10·49-12·91]; p<0·0001), suggesting a subgroup with a non-autoimmune diabetes subtype, with clinical features and C-peptide concentrations not consistent with type 2 diabetes. Among participants diagnosed younger than 20 years, autoantibody-negative diabetes was also observed in 65 (15·1%) of 429 participants with Black ancestry in SEARCH (although less frequently than in sub-Saharan Africa [59 (55·1%) of 107]), and these participants also had a low type 1 diabetes GRS (median 10·41 [IQR 8·65-12·22] in autoantibody-negative subgroup). No such pattern was observed in White participants in SEARCH: 241 (9·3%) of 2602 were autoantibody negative and median GRS for type 1 diabetes was similar in autoantibody-negative and autoantibody-positive participants (median 13·42 [IQR 11·80-14·61] vs 13·49 [12·29-14·58]). INTERPRETATION/CONCLUSIONS:In sub-Saharan Africa, clinically diagnosed type 1 diabetes is heterogeneous, comprising classic autoimmune type 1 diabetes and a novel, non-autoimmune, insulin-deficient diabetes subtype. There is evidence of this subtype in Black but not White individuals in the USA. Therefore, alternative causes must be considered in this group of individuals, and understanding the drivers of this subtype might offer new insights into prevention and treatment. FUNDING/BACKGROUND:UK National Institute of Health and Care Research. TRANSLATION/UNASSIGNED:For the French translation of the abstract see Supplementary Materials section.