Citations

Summary Functional high‐risk (FHR) multiple myeloma (FHRMM) is often defined as progression within 12–24 months of front‐line autologous hematopoietic stem cell transplantation (AHSCT). For patients with early progression after suboptimal front‐line therapies, it is challenging to assign the disease progression to a true FHR phenotype versus less effective front‐line therapy. In this study, we combined data from three Center for International Blood and Marrow Transplant Research studies (MM18‐02, MM19‐01 and MM20‐03). We included patients who received front‐line AHSCT between 2008 and 2018 and had progression <12 (FHR12, n = 465), <18 (FHR18, n = 672) or <24 months (FHR24, n = 853) after AHSCT. We classified induction therapy as standard lenalidomide‐containing triplets (bortezomib, lenalidomide, dexamethasone [VRD]/carfilzomib, lenalidomide, dexamethasone [KRD]) versus other (bortezomib, thalidomide, dexamethasone [VTD]/bortezomib, cyclophosphamide, dexamethasone [VCD]/bortezomib, dexamethasone [VD]/lenalidomide, dexamethasone [RD]) and studied the impact of front‐line therapy on post‐FHR overall survival (OS). In the FHR12 cohort (follow‐up 48 months), the OS after VRD/KRD ( n = 238) was 21 versus 17 months with other regimens ( n = 227, hazard ratio [HR] = 1.2, 95% confidence interval [CI]: 0.6–1.06). In a multivariable model, the HR for OS was 0.94 (95% CI: 0.7–1.3, p = 0.69) for VRD/KRD versus other regimens. There was no significant interaction between type of first‐line (1L) therapy and time from 1L AHSCT to first relapse in predicting OS. Similar results were seen for FHR18 and FHR24. FHRMM remains a negative prognostic factor irrespective of front‐line therapy and warrants consideration of T‐cell engagers' second‐line therapy.

ABSTRACT Background Retrospective evaluations of multidisciplinary team (MDT) review of pancreatic cystic lesions (PCL) demonstrate improved PCL management. Endoscopic ultrasound (EUS) evaluates PCL for worrisome features; however, its influence on MDT is unclear and may be attenuated by anchoring/confirmation bias. We aimed to evaluate the impact of EUS and the overall performance of MDT evaluation of PCL. Methods Four mock MDT sessions at two institutions were presented imaging from 40 consecutive PCL cases (20 “high‐risk” with advanced neoplasia, 20 “low‐risk” with pathologic low‐grade dysplasia or ≥ 3 years of non‐progression on surveillance), with and without upfront EUS/FNA (cytology, CEA, Amylase), in a randomized, crossover design. Group 1 adjudicated without EUS, Group 2 adjudicated with EUS, and Group 3 adjudicated with EUS after initially adjudicating without it. Results The cohort included branch‐duct ( n = 20), mixed type ( n = 6), and main duct ( n = 4) IPMN, MCN ( n = 5), and non‐mucinous PCL ( n = 5). Group 2 (EUS) correctly identified mucinous PCL with 97% sensitivity and 70% specificity, significantly higher than Group 1 (No EUS) (Sensitivity 91%, Specificity 20%; p = 0.04). Group 3 (Unblinded to EUS) performed significantly worse in mucinous PCL identification compared with Group 2, indicating cognitive bias (Sensitivity 97%, Specificity 10% ( p = 0.0003)). Group 2 correctly identified high‐risk PCL that required surgical intervention with 85% sensitivity and 85% specificity, significantly higher than Group 1 (Sensitivity 60%, Specificity 75%; p = 0.0016) and Group 3 (Sensitivity 73%, Specificity 80%, p = 0.0485). Conclusion While susceptible to cognitive bias, EUS significantly improves MDT assessment of PCL. MDT establishes a high bar for iterative additions of biomarkers to PCL analysis.

ABSTRACT IDH-mutant astrocytomas maintain telomeres through the alternative lengthening of telomeres (ALT) pathway, producing extreme inter-arm telomere length heterogeneity, yet how this heterogeneity shapes structural genome evolution remains unknown. Using Oxford Nanopore long-read sequencing of 20 IDH-mutant astrocytomas, we profiled structural variants (SVs), copy number variants, extrachromosomal DNA (ecDNA) and measured allele-specific telomere lengths from individual long reads. We identified pervasive complex rearrangements, including chromothripsis and foldback events consistent with breakage-fusion-bridge cycles, and widespread ecDNAs. SV breakpoints were enriched at telomeric and centromeric regions regardless of local telomere length, revealing constitutive structural fragility. Arm-level telomere length analysis uncovered a dual-mode model: arms with short telomeres preferentially harbored breakage-associated events, while arms with long ALT-maintained telomeres were enriched for ecDNA and amplification-associated events. These findings identify chromosome-arm-specific telomere length as a determinant of structural genome evolution in ALT-driven tumors.

Abstract Purpose: Neurocognitive and endocrine dysfunction are potential complications of cranial irradiation. However, risk factors are poorly understood, impeding accurate prognostication and exploration of potential preventive interventions. The objective of this study was to evaluate the prognostic value of various vascular and genotypic risk factors for the development of radiation-related toxicities. Methods: This single-institution retrospective cohort study included patients with metastatic and malignant primary brain tumors who received cranial irradiation as part of their initial tumor-directed therapy. Demographic and treatment characteristics were collected, as well as putative vascular and genotypic risk factors. Univariate, multivariate, and machine-learning analyses were performed using five pre-specified measures of radiation-related toxicity. The primary outcome was change in mini-mental status exam (MMSE). Results: Eighty patients (53% male, mean age 55.7, 53% primary and 44% metastatic brain tumors) were included. Elevated homocysteine and ApOE4genotype were the strongest predictors of MMSE decline in the multivariate model (OR 3.96 [6.5-200, p<0.001 and 2.85 [1.92-27.6], p=0.004). Elevated homocysteine was associated white matter change on MRI and both physician and patient assessment. ApoE4allele was associated with new endocrine deficiency, and physician assessment. An online nomogram provides risk predictions for each of the five late toxicity outcomes: (https://afranklin22.shinyapps.io/PRMMSERadiationRiskFactors/) Conclusion: Two pre-treatment laboratory values (elevated homocysteine and ApOE genotype) were strongly associated with post-radiation neurocognitive and endocrine dysfunction using a variety of simple but clinically meaningful definitions of dysfunction. Our predictive algorithm can aid clinicians in stratifying baseline risk and should be validated in prospective trials.

Abstract Pancreatic cancer disproportionately affects Black individuals in the United States, but they have limited representation in genetic studies of pancreatic ductal adenocarcinoma (PDAC). To address this gap, we performed admixture mapping and genome-wide association analysis (GWAS) in genetically inferred African ancestry individuals (1,030 cases and 889 controls). Admixture mapping identified three regions with a significantly higher proportion of African ancestry in cases compared to controls (5q33.3, 10p1, 22q12.3). GWAS identified a genome-wide significant association at 5p15.33 ( CLPTM1L , rs383009:T>C, T Allele Frequency=0.51, OR:1.45, P value=1.24×10 -8 ), a locus previously associated with PDAC. Known loci at 5p15.33, 7q32.3, 8q24.21 and 7q25.1 also replicated (P value <0.01). Multi-ancestral fine-mapping identified two potential causal SNPs (rs3830069 and rs2735940) at 5p15.33. Collectively these findings identified novel PDAC risk loci and expanded our understanding of this deadly cancer in underrepresented populations, emphasizing the multifactorial nature of PDAC risk including inherited genetic and non-genetic factors. Statement of Significance To understand how genetic variation contributes to PDAC risk in Black people in North American, we studied individuals of genetically-inferred African ancestry. We identified novel risk loci and differences in the contribution of known loci. This demonstrates that ancestry-informed genetic analyses improve our understanding of PDAC risk and enhances discovery.

ABSTRACT Polyglucosan body myopathy type 2 (PGBM2; OMIM #616199) is an autosomal recessive myopathy caused by biallelic variants in GYG1 , which encodes glycogenin‐1. It is characterized by progressive muscle weakness and PAS‐positive, diastase‐resistant polyglucosan inclusions on muscle biopsy. We report a 64‐year‐old woman who developed progressive proximal weakness beginning in her early 50s, with polyglucosan bodies identified on muscle histopathology. Genome sequencing (GS) detected a single heterozygous pathogenic splice‐site variant, NM_004130.4( GYG1 ):c.143+3G>C. Given strong histopathologic evidence of PGBM2, GS data were reanalyzed, revealing an additional rare deep intronic variant, NM_004130.4( GYG1 ):c.7+992T>G, predicted to activate a cryptic exon. RNA sequencing (RNA‐seq) confirmed aberrant splicing from both variants, demonstrating exon 2 skipping associated with c.143+3G>C and cryptic exon inclusion caused by c.7+992T>G. Variant phasing posed a diagnostic challenge due to unavailable parental DNA, and long‐range PCR results were inconclusive. Long‐read GS definitively demonstrated that the two variants were in trans , establishing compound heterozygosity and confirming the molecular diagnosis. These findings enabled reclassification of the deep intronic variant as likely pathogenic. This case highlights the diagnostic limitations of conventional phasing approaches in adult‐onset recessive disorders and demonstrates the clinical utility of integrating genome reanalysis, RNA‐seq, and long‐read GS for resolving complex phasing challenges.

Introduction Approximately 50% of patients with uveal melanoma develop metastatic disease, most commonly involving the liver, and prognosis remains poor. Immunoembolization (IE) is an established liver-directed therapy for patients with liver-dominant metastatic uveal melanoma (mUM), though comparative data with other regional therapies remain limited. We present a single-center retrospective analysis of IE in hepatic mUM and compare outcomes with those reported in the Phase 3 FOCUS trial evaluating melphalan via percutaneous hepatic perfusion. Methods All patients with liver-dominant mUM treated with IE between 2010 and 2023 at our institution were included. Clinical records were reviewed for demographics, tumor characteristics, treatment details, and outcomes. The primary endpoint was disease control rate (DCR), defined as complete response (CR), partial response (PR), or stable disease (SD). Secondary endpoints included progression-free survival (PFS) and overall survival (OS), with subgroup analyses based on prior systemic therapy exposure. Descriptive statistics were used for analysis. Results Forty-three patients (62.8% female; median age 62 years; all Caucasian) underwent 249 IE procedures (mean 5.8 procedures per patient) over a median treatment duration of 9.1 months. Choroidal primaries accounted for 95.3% of cases, and 90.7% had liver-only metastases. The overall DCR was 27.9% (CR 4.7%, PR 20.9%, SD 2.3%), while 62.8% experienced disease progression. Median PFS was 0.85 months, and median OS was 32.7 months. One- and two-year OS rates were 69.8% and 55.8%, respectively. In subgroup analysis, patients who had received prior systemic therapy (n=12) demonstrated improved outcomes compared with treatment-naïve patients, with longer median PFS (29.9 vs. 7.2 months) and higher 2-year OS (60.0% vs. 47.0%). Compared with outcomes reported in the FOCUS trial, IE demonstrated shorter median PFS (0.85 vs. 9.0 months) and lower DCR (27.9% vs. 73.6%), but longer median OS (32.7 vs. 20.5 months). Discussion IE produced overall survival outcomes comparable to hepatic melphalan delivery despite lower radiographic response rates. Notably, patients previously treated with systemic therapy experienced improved outcomes, suggesting a potential sequencing effect. These findings support IE as a viable liver-directed therapy for liver-dominant mUM. Prospective, multicenter trials are warranted to clarify optimal sequencing strategies and enhance therapeutic outcomes.

OBJECTIVE Overuse of broad-spectrum empiric antimicrobials remains common in children hospitalized with respiratory tract infections (RTI). A negative methicillin-resistant Staphylococcus aureus (MRSA) nasal swab (MNS) polymerase chain reaction (PCR) result has been shown to have a high negative predictive value for MRSA in RTI. In this quality improvement (QI) initiative, we developed a pharmacist-driven approach to reduce the duration of empiric vancomycin for RTI in children. The primary aim was the time to de-escalation of vancomycin, and the secondary aim was the reduction in vancomycin monitoring in patients hospitalized with RTI. METHODS Baseline duration of vancomycin therapy was assessed by conducting a retrospective chart review. After root cause analysis and engaging key stakeholders, an electronic health record OurPractice Advisory (OPA) was implemented, prompting pharmacists to order an MNS PCR during order verification for vancomycin with an RTI indication. RESULTS Preimplementation (01/01/2021 to 08/31/2023) included 89 patients, and 25 postimplementation (09/21/2023 to 05/31/2024). We found a 36% decrease in mean vancomycin duration from 53 to 34 hours after implementation of the pharmacist-driven OPA. Postimplementation, 24% of patients had a vancomycin concentration obtained, compared with 37% preimplementation. No patients were readmitted within 30 days postimplementation, compared with 1 patient preimplementation. CONCLUSIONS This QI initiative provides preliminary data that empiric vancomycin duration in pediatric patients with RTI may be impacted by pharmacist-facing OPA implementation, prompting ordering of MNS PCR at the time of vancomycin verification. This initiative could be replicated at other institutions seeking to reduce empiric vancomycin usage.

Abstract Cerebral blood flow is stabilized through dynamic adjustments across both macro‐ and microvascular compartments. While dynamic cerebral autoregulation (dCA) quantifies upstream pressure–flow coupling, downstream microvascular responses are less well characterized and may represent a distinct but functionally linked process. This study tested whether a two‐component cascade model, treating dCA and an empirically derived index of microvascular function (MF) as sequential stages can represent the integrated regulation of cortical oxygenation. Data from 41 healthy adults (20–45 years) were analysed. Beat‐to‐beat mean arterial pressure (MAP), middle cerebral artery flow velocity (CBFV) and cortical oxyhaemoglobin (O 2 Hb) were recorded during supine spontaneous oscillations and forced oscillations at 0.05 Hz using repeated sit–stand manoeuvres. Transfer function analysis quantified frequency‐domain gain, phase and coherence for MAP→CBFV (dCA), CBFV→O 2 Hb (MF) and MAP→O 2 Hb (total pathway). The cascade model was computed as the product of dCA and MF transfer functions. The cascade model derived indices showed strong correlations with total pathway gain, phase and coherence measures during both spontaneous and forced oscillations, with improved linear coupling under forced oscillations. These results support the applicability of a two‐component cascade model for integrated cerebrovascular regulation and suggest that serial interactions between macrovascular and microvascular regulatory mechanisms jointly shape the frequency‐dependent propagation of arterial pressure to brain‐tissue oxygenation dynamics. image Key points Cerebral blood flow is stabilized by coordinated regulation across large arteries and microvessels, but their dynamic interaction has not been experimentally modelled. We examined whether a two‐component cascade model linking upstream dynamic cerebral autoregulation and downstream microvascular function can explain how blood pressure oscillations influence cortical oxygenation. In 41 healthy adults, we recorded beat‐to‐beat blood pressure, middle cerebral artery blood flow velocity and near‐infrared spectroscopy‐derived oxygenation during rest and sit–stand manoeuvres, and analysed them using transfer function analysis. Gains, phases and coherences derived from the cascade model closely matched those from the direct blood pressure–O 2 Hb relationship, particularly under forced oscillations during sit–stand, demonstrating the model's physiological relevance. The cascade model provides a mechanistic framework to separate and quantify large‐ and small‐vessel contributions to cerebral blood flow regulation, with potential application in future studies of ageing and cerebrovascular disease.