Citations

e15708 Background: AFTT is characterized by physical, nutritional, and psychosocial decline. In GIC, AFTT arises from malnutrition, disease progression, or treatment-related toxicity resulting in poor quality of life. We evaluated the association between AFTT and IM, length of stay (LOS), and hospital charges (HC) in hospitalized GIC patients. Methods: The National Inpatient Sample (2016-21) was used to identify adult hospitalizations with GIC using ICD-10 codes, which were stratified as primary or secondary diagnoses by AFTT. Clinical characteristics and primary outcomes including IM, LOS, and HC were extracted. Multivariable regression models adjusting for demographics, insurance, comorbidity burden, census tract income, and hospital teaching status were evaluated. Results: Among 2,732,505 GIC hospitalizations, colorectal (46.9%) and pancreatic (20.4%) cancer predominated; 121,035 (4.4%) had AFTT. Patients with AFTT vs non-AFTT, were older (mean = 69.3 vs 66.5 yrs), more often male (58.1% vs 57%), and from the lowest income quartile (27.7% vs 26%). AFTT cohort had higher comorbidity burden (mean CCI = 7.24 vs 6.26), more Black patients (19.1% vs 12.8%), higher Medicare use (62.7% vs 56.0%), increased palliative care consultation (37.4% vs 13.6%), risk of malnutrition, AKI, and dementia (all p< 0.001). AFTT was associated with higher IM, longer LOS, and lower HC. Higher age, males, and self-pay were associated with increased IM and HC, but shorter LOS. Lower CCI was associated with reduced IM, LOS, HC, whereas urban hospitals showed lower IM but higher LOS and HC. Black patients had higher IM and LOS but lower HC, contrary to Hispanic patients. Conclusions: The grave impact of AFTT and variability in survival and practice patterns is driven multifactorially, raising concerns about inequitable care access and differences in healthcare utilization. Standardized guidelines and multidisciplinary interventions are urgently needed to combat AFTT in GIC. Predictor IM aOR (95% CI) LOS Adj. Ratio (95% CI) HC Adj. Ratio (95% CI) AFTT Status (vs. Non-AFTT) 1.96 (1.93-2.00) 1.13 (1.12-1.14) 0.86 (0.85-0.86) Age (/year increase) 1.02 (1.02-1.02) 1.00 (1.00-1.00) 1.00 (1.00-1.00) Sex (vs. Female) Male 1.18 (1.17-1.19) 0.99 (0.98-0.99) 1.05 (1.05-1.06) CCI Score (vs. High, ≥5) Low (≤2) Mid (3-4) 0.33 (0.32-0.33) 0.48 (0.47 - 0.48) 0.87 (0.87 - 0.88) 0.93 (0.93 - 0.94) 0.93 (0.93 - 0.94) 1.02 (1.02 - 1.02) Insurance (vs. Medicare) Private Medicaid Self-Pay 1.03 (1.01 - 1.05) Ref in model 1.29 (1.24 - 1.33) 0.92 (0.91 - 0.92) 0.96 (0.95 - 0.97) 0.98 (0.97 - 1.00) 1.03 (1.02 - 1.03) 1.06 (1.05 - 1.06) 0.96 (0.95 - 0.97) Race (vs. White) Black 1.03 (1.00 - 1.06) 1.07 (1.06 - 1.08) 0.95 (0.94 - 0.96) Facility Status (vs. Rural) Urban Non-Teaching Urban Teaching 0.87 (0.85 - 0.89) 0.78 (0.77 - 0.80) 1.10 (1.09 - 1.11) 1.18 (1.17 - 1.19) 1.64 (1.63 - 1.65) 1.86 (1.84 - 1.87)

Summary Cancer genome sequencing is essential for understanding tumor evolution and advancing precision medicine. 1 However, reference gaps and germline variants obscure detection of small and large somatic variants and methylation in repetitive regions. 1–3 It is common for tumor cells to gain or lose chromosome arms due to somatic structural changes that occur inside highly repetitive satellite DNA sequences in the centromeres. 4 To identify the full spectrum of somatic variants, including complex rearrangements, we construct and curate near-complete, haplotype-resolved assemblies of the most recent common ancestor of an early-passage broadly-consented hypodiploid pancreatic cancer cell line and matched normal tissues. The tumor assembly completely recapitulates all 35 tumor chromosomes observed with karyotyping, with multiple translocation-induced hybrid chromosomes. The hybrid chromosomes contain putative functional dicentric and fused centromeres, nested foldback inversions causing 14 breakpoints with a haplotype switch in a single event, and centromeric satellite tandem duplications up to 136 kbp. Direct comparison of tumor and normal assembly haplotypes uncovers >7,000 variants altering >1 Mbp of sequence in repetitive regions that have been hidden by reference gaps and germline variants. 44 % of somatic small variants change representation because they alter germline variants on GRCh38, impacting mutational signatures and kataegis/omikli clusters. Most somatic LINE insertions originate from two hypomethylated non-reference germline LINE insertions, highlighting their impact on insertion mutation burden. These assemblies demonstrate that centromeric, acrocentric, and telomeric regions conventionally excluded from analysis harbor extensive somatic and epigenetic changes. Resolving complete tumor genomes enables a deeper understanding of cancer structural plasticity and the endpoints of breakage-fusion-bridge cycles. These assembled, curated paired normal-tumor benchmarks will serve as a critical foundation for developing future algorithms to characterize the most intractable regions of cancer genomes.

Bruton tyrosine kinase inhibitors (BTKis) and BCL2 inhibitor (BCL2i)–containing regimens significantly improve survival outcomes in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Results from randomized clinical trials have demonstrated that time-limited treatment with BCL2i-containing regimens resulted in higher rates of undetectable measurable residual disease (uMRD) than BTKi monotherapy or chemoimmunotherapy (CIT). Pirtobrutinib (a noncovalent BTKi) and lisocabtagene maraleucel (CD19-directed CAR T-cell therapy) are newer options for relapsed or refractory disease after prior therapy with BTKi and BCL2i-contining regimens. Histologic transformation of CLL/SLL to diffuse large B-cell lymphoma (Richter transformation) is associated with a poor prognosis. Molecular analysis to determine whether there is clonal relationship between CLL/SLL and transformed diffuse large B-cell lymphoma is useful to select an appropriate treatment option. These NCCN Guideline Insights highlight significant updates to the NCCN Guidelines for the treatment of CLL/SLL and Richter transformation.

Abstract Introduction Mature T-cell lymphomas, including aggressive nodal PTCL, advanced stage CTCL, and extranodal cytotoxic lymphomas, are associated with poor outcomes. While karyotype (KT) abnormalities are frequently detected in these diseases, limited data exist on their prognostic significance. We evaluated the impact of KT abnormalities, including complex KT and specific chromosomal lesions, along with clinical and demographic factors, on overall survival (OS) in a single-center cohort. Methods We retrospectively reviewed 189 patients (pts) diagnosed with T-cell lymphoma who had successful metaphase KT at diagnosis from peripheral blood (PB), bone marrow (BM), or tumor tissue. T-cell lymphomas were classified according to WHO 2022 into nodal, extranodal/cytotoxic, and cutaneous subtypes. CTCLs were stratified into indolent (Early-stage CTCL, IA–IB) and aggressive (Sézary syndrome, transformed mycosis fungoides). KTs classified as normal, abnormal, and complex (≥3 abnormalities), and recurrent abnormalities were recorded. Baseline clinical and lab data were collected. OS was estimated using the Kaplan-Meier (KM) method with 95% confidence intervals (CI). Univariate Cox proportional hazards (CPH) model identified factors associated with OS, and significant variables were entered into multivariate CPH models. Results The median age was 66 years (IQR 55-74); 65% were male and 35% were female. Overall, 58% of pts were alive at analysis. Nodal PTCL was the most common subtype (113 pts, 60%), followed by early CTCL (30, 16%), aggressive CTCL (24, 13%), and extranodal lymphomas (22, 12%). KT was obtained from 166 BM (86%), 26 PB (13%), and 2 tissue (1%) specimens. Among abnormal KTs, 63% were from BM, 35% from PB, and 2% from tissue. Specific abnormalities included gain of chr1 (5%), gain of chr3 (5%), gain of chr7 (5%), gain of chr8 (5%), monosomy 5 or del(5q) (4%), monosomy 9 or del(9q13q22) (4%), Monosomy 10 (4%), loss of chrY (5%), and presence of marker chromosomes (5%).Of the 189 pts, 48 (25%) had an abnormal KT, while 141 (75%) had a normal KT. Complex KT was observed in 31 (16%) pts. Abnormal non-complex and complex KTs were seen respectively in: aggressive CTCL (8%, 42%), nodal PTCL (4%, 13%), extranodal (9%, 14%), and early CTCL (27%, 10%). KM survival analysis showed a median OS for the entire cohort of 95 months (95% CI: 65-245). Pts with a normal KT had a median OS of 143 months (95% CI: 81-inf) compared with 34 months (95% CI: 18-83) for those with an abnormal KT. Pts without a complex KT had a median OS of 144 months (95% CI: 85-inf), whereas those with a complex KT had 14 months (95% CI: 4-25). For specific abnormalities, pts with gain of chr7 had OS of 3 months, gain of chr8 had 19 months, monosomy 5 or del(5q) had 4 months, loss of chrY had 30 months, gain of chr1 had 4.5 months, gain of chr3 had 7.5 months, monosomy 9 or del(9q13q22) had 2 months, monosomy 10 had 17 months, and marker chromosome presence had 5.5 months. Univariate CPH identified complex KT (HR = 3.9, p &lt; 0.001), gain of chr1 (HR = 5.7, p &lt; 0.001), gain of chr3 (HR = 4.6, p &lt; 0.001), monosomy 5 or del(5q) (HR = 4.6, p &lt; 0.001), gain of chr7 (HR = 4.2, p &lt; 0.001), gain of chr8 (HR = 3.3, p &lt; 0.001), monosomy 9 or del(9q13q22) (HR = 4.9, p &lt; 0.001), monosomy 10 (HR = 2.8, p = 0.008), and marker chromosomes (HR = 4.6, p &lt; 0.001) as adverse factors. Higher platelet count was protective (HR = 0.9, p &lt; 0.001), while greater number of abnormalities increased hazard (HR = 1.1, p &lt; 0.001). In multivariate CPH model, complex KT (HR = 3.1, 95% CI: 1.2-8.2, p = 0.019), monosomy 9 or del(9q13q22) (HR = 4.4, 95% CI: 1.2-15.4, p = 0.022), gain of chr1 (HR = 3.5, 95% CI: 1.1-11.8, p = 0.042), and low platelet count (HR = 0.98, 95% CI: 0.97-0.99, p = 0.006) remained independent predictors of poor OS. Conclusion: We demonstrate that cytogenetic abnormalities detected in PB or BM, most notably complex KTs, confer a markedly poor prognosis in aggressive T-cell lymphomas. The integration of KT data with clinical parameters, such as platelet count, offers a powerful approach to refine risk stratification, identify biologically high-risk subgroups, and potentially guide personalized therapeutic strategies in this challenging disease spectrum. To our knowledge, this is one of the largest single-center studies assessing the prognostic significance of KT in mature T-cell lymphomas, providing novel insights into the role of specific chromosomal lesions in patient outcomes.

Background: In recent years, there has been an increased push for diversity in orthopaedics at the residency level. There has also been a noticeable shift away from foot and ankle fellowship, with many fellowship positions open throughout the country annually. With the increase in osteopathic and female orthopaedic applications to orthopaedic surgery residency, we hypothesized that this would be reflected in the foot and ankle fellowship applications in the last decade. Methods: The San Franscisco Match data from 2012 to 2023 were analyzed for degree type and from 2013 to 2023 for gender. There were 1082 applicants for adult foot and ankle fellowships from 2012 to 2023, 74 osteopathic applicants (11.4%), and 573 allopathic applicants (88.6%). There were 126 female applicants (21.3%) and 465 male applicants (78.7%). The 435 international graduates were excluded from this analysis. The degree type, gender, number of applicants, and number of applicants matched into orthopaedic foot and ankle fellowship was reviewed. Results: The number of osteopathic applicants and female applications did not change significantly over the study period. There was a statistically significant decrease in the number of allopathic applicants ( P = .003) and a significant decrease in the number of male applicants to foot and ankle fellowship ( P = .00004). The match rate for allopathic, osteopathic, and male applicants all statistically increased over the study periods, whereas the female applicant match rate remained stable. Programs tended to rank their matched allopathic residents higher, whereas osteopathic applicants’ position in the fellowship program rank list remained steady. Female and male applicants matched at programs higher on their rank lists, whereas programs match applicants lower on theirs. Conclusion: More orthopaedic foot and ankle surgeons are needed nationwide. Understanding recent trends in applicant demographics and match outcomes may help inform strategies to increase interest and participation in this subspecialty. Level of Evidence: IV, cross-sectional study.

Abstract Background Migraine patients show choroid plexus (CP) changes, impairing the blood-CSF barrier. The CP regulates circadian rhythms, but links between CP circadian genes and migraine are unexplored. Objective This study examined CP circadian gene transcriptome changes in a chronic migraine rat model versus controls to identify migraine-related pathways. Design Chronic migraine model: Sprague Dawley rats (3 females, 3 males) received nitroglycerine (NTG) every other day for 9 days; controls (3 females, 3 males) got saline. CP from the 4th ventricle was collected 2 hours post-final injection for RNAseq. Methods Migraine Behavior: Von Frey hair tests on days 1, 5, and 9, pre- and 2 hours post-NTG/saline injection, assessed basal and NTG-induced pain thresholds. RNAseq & Analysis: Differentially expressed genes (p < 0.05, fold change > 1) were identified. GO, KEGG, and Reactome enrichment analyses evaluated circadian gene expression changes. Results NTG group showed reduced basal and NTG-induced pain thresholds on days 1, 5, and 9. Females had more upregulated genes ( MT2A , SLC7A11 ), males upregulated ZBTB16 , S100A8 . SLC7A11 , SCG2 , GRIA1 showed inverse regulation (up in females, down in males). Circadian gene expression altered: 10 genes upregulated (e.g., SERPINE1, MAPK9, ATF4 ), 13 downregulated (e.g., PER2, DBP, EZH2 ). Sex-specific differences: females ( FBXL12, GPR157 ), males ( NKX2-1, ATF4, CLOCK ). GO/KEGG analyses revealed significant enrichment of circadian rhythm-related pathways, insulin resistance, and inflammatory response processes, with sex-specific differences: females showed HIF-1 signaling and hemoglobin-related pathways, while males exhibited arachidonic acid and leukotriene production. Conclusion CP transcriptomics in the rat migraine model revealed sex-specific gene regulation, with females upregulating antioxidant genes (MT2A, SLC7A11) and males upregulating inflammatory factors (ZBTB16, S100A8), alongside circadian disruption (e.g., SERPINE1 upregulated, PER2 downregulated). Pathway analyses indicate enriched circadian rhythms, HIF-1 signaling (females), inflammatory processes (males), lipid metabolism (PPARα), and heme signaling, highlighting sex-specific and circadian targets for migraine therapy.

Importance Completion of the Human Genome Project prompted predictions that genomics would transform medicine, including through genomic screening that identifies potentially medically actionable findings that could prevent disease, detect it earlier, or treat it better. However, genomic screening remains anchored in research and largely unavailable as part of routine care. Objective To summarize 11 years of experience with genomic screening and explore the landscape of genomic screening efforts. Design, Setting, and Participants This cohort study was based in Geisinger’s MyCode Community Health Initiative, a genomic screening program in a rural Pennsylvania health care system in which patient-participants exomes are analyzed. Main Outcomes and Measures Genomic screen-positive rates were evaluated and stratified by condition type (cancer, cardiovascular, other) and US Centers for Disease Control and Prevention (CDC) Tier 1 designation. The proportion of participants previously unaware of their genomic result was assessed. Other large-scale population-based genomic screening efforts with genomic results disclosure were compiled from public resources. Results A total of 354 957 patients participated in Geisinger’s genomic screening program (median [IQR] age, 54 [36-69] years; 194 037 [59.7%] assigned female sex at birth). As of June 2024, 175 500 participants had exome sequencing available for analysis, and 5934 participants (3.4%) had a pathogenic variant in 81 genes known to increase risk for disease. Between 2013 and July 2024, 5119 results were disclosed to 5052 eligible participants, with 2267 (44.2%) associated with risk for cardiovascular disease, 2031 (39.7%) with risk for cancer, and 821 (16.0%) with risk for other conditions. Most results (3040 [59.4%]) were in genes outside of those with a CDC Tier 1 designation. Nearly 90% of participants (4425 [87.6%]) were unaware of their genomic risk prior to disclosure. In a survey of large-scale biobanks with genomic and electronic health record (EHR) data, only 25.0% (6 of 24) disclosed potentially actionable genomic results. Conclusions and Relevance In this large, genomics-informed cohort study from a single health system, 1 in 30 participants had a potentially actionable genomic finding. However, nearly 90% were unaware of their risk prior to screening, demonstrating the utility of genomic screening in identifying at-risk individuals. Most large-scale biobanks with genomic and EHR data did not return genomic results with potential medical relevance, missing opportunities to significantly improve genomic risk ascertainment for these individuals and to perform longitudinal studies of clinical and implementation outcomes in diverse settings.

Background: Physical function (PF) is an important outcome that can inform cancer treatment tolerability from a clinical and regulatory perspective. PF can be assessed through different modalities: patient-reported (PRO), clinician-reported (ClinRo), performance tests (PerfO), and digital sensors (wearables). No standard approach for PF measurement has been defined, and each modality bears unique implementation challenges. The Integrating 4 Measures to Assess Physical Function study (In4M, NCT05214144) characterized the performance of these PF modalities in patients receiving cytotoxic chemotherapy, with a goal of guiding an assessment strategy in future cancer trials. Here we present feasibility results of the In4M study in patients with lymphoma. Methods: In4M is a prospective observational study with longitudinal PF assessment of PROs, ClinRo, PerfO, and wearable sensor data for over 9 months in patients initiating chemotherapy for lymphoma or breast cancer at Mayo Clinic and Yale University. Patient-reported PF was assessed using several validated ePRO instruments, ClinRo utilized clinician-reported Eastern Cooperative Oncology Group (ECOG) performance status, PerfO was measured via 6-minute walk test (6MWT), and digital sensor data was obtained from a wearable (Fitbit) provided to all participants. We evaluated the feasibility of implementing these PF modalities through compliance outcomes and a study-specific exit survey. Descriptive statistics included medians and interquartile ranges (IQR) for continuous variables and frequencies for categorical variables. We used a mixed model to estimate mean number of Fitbit compliant days per week. Results: Among 66 patients with lymphoma in the study (median age was 57 years; 52% were male), 90% self-reported as White, 4.9% as Black, 1.6% as Asian, 1.6% as American Indian or Alaska Native, and 1.6% as multiple races. Ethnicity was reported as non-Hispanic/Latino by 93% of patients. Education status was reported as more than high school by 92% of patients, and 49% reported full-time employment at time of enrollment. The overall ePROs completion rate was 80.7% for the entire study period. Baseline ePRO completion rate was 93.9%. Completion rate while undergoing chemotherapy was 91.3% and 75.4% in the post-treatment follow-up. The median time to complete ePROs was 4.1 minutes (IQR 2.8-5.9), ranging from 3.1 minutes for surveys with 37 questions to 5.6 minutes for surveys with 55 questions (survey length varied by timepoint). The baseline 6MWT was completed by 91% of patients. The most common reasons for not completing the baseline 6MWT were: patient refusal (50%, 3/6), patient not physically present (33%, 2/6), and unable to complete due to fatigue (17%, 1/6). The 3-month 6MWT was completed by 66% (40/61) of patients, with the most common reasons for missingness being: patient not physically present (38%, 8/21) and unable to complete due to fatigue (14%, 3/21). When considering the days when Fitbit was used, the median wear time was 21.3 hours (IQR 18.9-22.5) per day. The proportion of compliant days (&gt;10 hours of wear time during waking hours) was 53% (IQR 20-84). The median of participants' average compliant days per week was 5.4 (IQR 4.3-6.1) days/week after enrollment, with a slight downward trend over time (-0.017 compliant days per week [95% CI: -0.021, -0.012, p &lt;0.001] over each consecutive week in the study). The exit survey was completed by 39 (59%) patients. Most participants (85%) indicated they did not find the ePRO surveys burdensome to complete. Using the Fitbit (charging and syncing) was found to be manageable by most patients (87% and 84%, respectively). 60.8% of patients did not find the wearable bothersome to use, while the main themes reported by the remaining patients were related to the operation of the wearable itself (functions, small text size, forgetting login information) or discomfort (band material, wearing at night). Conclusion: Multi-modal assessment of PF with PRO, ClinRo, PerfO and wearable sensor data in patients with lymphoma undergoing treatment is feasible. Designing lymphoma therapeutic trials that incorporate at least one PF assessment modality, or assessment with a parsimonious combination of modalities, is achievable and may yield valuable insights into treatment tolerability for clinical and regulatory purposes.