Citations

Abstract In this systematic review, we aimed to assess the sensitivity of serum immunofixation (SIFE), urine immunofixation (UIFE), and serum free light chain (sFLC) in detecting plasma cell dyscrasia associated with light chain (AL) amyloidosis. We searched the literature using PubMed, Embase, and CENTRAL databases since inception through March 2024. We included studies reporting the diagnostic accuracy of immunofixation and/or sFLC in patients with AL amyloidosis. We used the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach to assess the certainty of the evidence and QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies-2) to assess the risk of bias. After deduplication, 29 237 records were screened, and 44 studies (n = 18 071) were included. For the meta-analysis, 28 studies reported sensitivity for SIFE (n = 3390), 24 studies for UIFE (n = 2830), 19 studies for SIFE and UIFE (n = 2819), 21 studies for sFLC ratio (n = 3678), 6 studies for SIFE and sFLC ratio (n = 372), 3 studies for UIFE and sFLC ratio (n = 242), and 10 studies for all 3 tests (n = 1430). Pooled sensitivities were as follows: SIFE, 0.68 (95% confidence interval [CI], 0.62-0.73); UIFE, 0.77 (95% CI, 0.72-0.81); SIFE and UIFE, 0.89 (95% CI, 0.84-0.93); and sFLC ratio, 0.82 (95% CI, 0.78-0.86). When SIFE, UIFE, and sFLC ratio were combined, the sensitivity reached 0.99 (95% CI, 0.96-1.00). The high sensitivity of combining SIFE, UIFE, and sFLC ratio supports their use as a reliable initial testing strategy to raise suspicion for AL amyloidosis and guide decisions regarding future diagnostic modalities.

Abstract We evaluated outcomes by management type for patients with stage IA nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) in the Global NLPHL One Working Group retrospective database of 2243 patients with stages I to IV disease diagnosed from 1992 to 2021 at 38 international institutions. A total of 779 patients had stage IA disease with median age of 35 years (range, 3-89) and median follow-up of 6.1 years. The 6-year progression-free survival (PFS) and overall survival were 86.3% and 97.7%, respectively. Outcomes were analyzed for the 2 groups: complete resection and unresected disease. Patients with a complete resection and observation alone (n = 99) had a 6-year PFS of 65.5% vs 90.5% for those who received radiotherapy (RT) (n = 53). Patients with unresected disease (n = 627; 80.5%) had a 6-year PFS of 62.0% for rituximab alone (n = 31), 89.6% for RT alone (n = 325), 76.8% for ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) alone (n = 40), and 94.3% for ABVD plus RT (n = 130). A total of 127 patients relapsed (16.3%), of which 25 (19.7%) had transformation. Our analysis suggests the following: (1) RT improves the PFS in patients with completely resected disease; (2) rituximab or ABVD alone does not appear to achieve a durable response; and (3) chemotherapy was not observed to add additional PFS benefit when used in combination with RT. Thus, for stage IA NLPHL, RT alone is likely sufficient for definitive treatment.

OBJECTIVE This study investigated the relationship between diabetes and the incidence of postoperative dysphagia following cervical spine surgery (CSS). METHODS A prospectively collected multi-institutional quality registry was retrospectively reviewed. Patients who underwent CSS were categorized on the basis of diabetes status, and correlations with preoperative and postoperative Eating Assessment Tool-10 (EAT-10) dysphagia questionnaire scores were assessed. Mixed-effects logistic regressions were performed to examine the impact of preoperative diabetes on postoperative dysphagia. RESULTS Of the 2001 patients who met the inclusion criteria, 400 (20%) had diabetes. Baseline dysphagia rates were not significantly different between groups (18% vs 14%, p = 0.08). Patients with diabetes had a significantly higher incidence of dysphagia at 1 month (66% vs 54%, p = 0.002), 3 months (39% vs 26%, p < 0.001), and 12 months (33% vs 24%, p = 0.004) after surgery compared to patients without diabetes. Including baseline dysphagia as a fixed effect, multivariable analysis indicated that diabetes was a significant predictor of postoperative dysphagia at 1 month (OR 1.46, p = 0.041) and 3 months (OR 1.63, p = 0.001) but not at 12 months (OR 1.21, p = 0.3). In patients with no baseline dysphagia, those with diabetes (329 of 400 [82.3%]) had a significantly higher incidence of new dysphagia than nondiabetics at 1 month (62% vs 50%, p = 0.003), 3 months (34% vs 21%, p < 0.001), and 12 months (27% vs 18%, p = 0.001). The mean change in EAT-10 scores between baseline and 12 months was significantly worse in patients with preoperative diabetes (2.440 ± 5.013 vs 1.688 ± 4.139, p = 0.025). Multivariable analysis indicated that diabetes was a significant predictor of new postoperative dysphagia at 1 month (OR 1.49, p = 0.040) and 3 months (OR 1.81, p < 0.001) but not at 12 months (OR 1.31, p = 0.2). CONCLUSIONS Diabetes is a significant risk factor for experiencing postoperative dysphagia following CSS. Diabetes correlated with higher incidence of dysphagia at all postoperative time points and was a strong independent predictor of postoperative dysphagia at 1 and 3 months.

Abstract Gastrointestinal (GI) involvement is a clinically relevant but undercharacterized manifestation of systemic light chain amyloidosis (AL). We aimed to define the clinical spectrum, histologic patterns, and outcomes of symptomatic GI involvement in AL. We retrospectively analyzed 4396 patients with AL from 2010 to 2024, of whom 521 (11.9%) had provider-attributed symptomatic GI involvement; 66% had biopsy-proven GI AL. Symptoms most commonly included early satiety (61%), bowel irregularities (58%), nausea (35%), abdominal pain (28%), and dysphagia (23%). Autonomic neuropathy was frequent (43% clinician attributed; 23% via autonomic reflex testing) and contributed to dysmotility-related symptoms, often without GI biopsy positivity. Among 747 GI biopsies, mucosal infiltration predominated (71%) and was associated with bleeding (22% vs 9%), cachexia, and inferior survival, whereas vascular involvement was associated with lower bleeding risk. Combined involvement of mucosa, submucosa, and vessels conferred the worst prognosis (median overall survival [mOS], 2.4 vs 5.1 vs 7.8 years for 3 vs 2 vs 1 layer); mOS was 6.8 years and was primarily driven by cardiac stage and hematologic response (very good partial response [VGPR] or better: hazard ratio, 0.20; 95% CI 0.13-0.32), with more favorable outcomes in patients with isolated GI involvement. Cachexia and persistent diarrhea were the main drivers of morbidity, need for nutritional support, and GI-related mortality (odds ratio, 2.7 for the combined end point). GI bleeding rarely recurred after achieving VGPR or better. Overall, mucosal involvement, cachexia, and dysmotility define clinically meaningful GI AL and support systematic assessment of autonomic dysfunction as well as evaluation of the need for nutritional support as a GI-specific end point for AL trials.

Hawai‘i and other island communities around the globe are experiencing high exposures to micro- and nanoplastics (MNPs). Widespread use of various types of plastics and the action of wave physics coupled with abundant silica creates a constant production of MNPs. The community health effects of exposure to MNPs are not yet fully understood. The aquatic vertebrate model zebrafish, Danio rerio , was utilized to evaluate the developmental and behavioral effects of nanoplastic (NP) exposure as well as visual confirmation of plastic accumulation after embryonic and larval exposure. Eye and yolk size, heart rate, angle of development, and early larval locomotion behavior were quantified after early NP exposure lasting 3 or 5 days. In this work, a digital laboratory environment is used as the context for research trainees spanning high school to graduate and medical school in Hawai‘i to explore health outcomes of developmental NP exposures. Presence of MNPs in the early developmental environment led to changes in growth and behavior of exposed fish. Data analysis showed significant effects of exposures on changes in the rate of development and yolk consumption on day 2 and reduced body length and increased locomotion on day 6. Nanoplastic exposure also affected overall body length, but this effect was not significant. These data support the potential dangers of MNP exposure and demonstrate their persistent detrimental effects on development and behavior in young zebrafish. Accordingly, our work contributes toward shifting focus toward understanding longer impacts on health, growth, and behaviors and potentially the reduction of harm in developing vertebrates.

Abstract Systemic light chain amyloidosis (AL) arises from monoclonal immunoglobulin light chains, but determinants of progression from precursor states remain poorly defined. In a cross-sectional cohort comprising 1950 systemic AL patients diagnosed 2010-2024, 258 (13.2%) patients with a previously diagnosed plasma cell disorder (PCD) were compared to patients with no prior PCD diagnosis. Patients with monoclonal gammopathy of undetermined signficance (MGUS) and smoldering multiple myeloma (SMM) in the former group had lower difference between involved and uninvolved FLCs (dFLC), higher M-protein, and lower rates of t(11;14) at AL diagnosis. Patients developing AL from SMM had a shorter time to AL (median 34.2 versus 61.3 months) and higher dFLC (median 28.9 versus 11.0 mg/dl) compared to those from MGUS. Patients developing AL after known multiple myeloma (MM) or lymphoplasmacytic lymphoma (LPL) commonly lacked deep hematologic response before AL (≤ very good partial response in 78% of MM, 100% of LPL patients). We additionally studied longitudinally followed cohorts of 3,966 MGUS and 426 (SMM) patients with longitudinal FLC measurements and matched follow-up, in which 1.8% of MGUS and 7.2% of SMM patients developed AL. Those patients who developed AL showed markedly higher dFLC at MGUS/SMM diagnosis and more frequent λ restriction and rates of t(11;14). Higher dFLC was associated with progressively earlier AL development; a 10% cumulative risk occurred at 20 months for patients with a dFLC >80 mg/dL but was not reached if dFLC <10 mg/dL at an estimated median follow-up of 86 months. In multivariable analysis, dFLC >6.4 mg/dL (HR 11.3) and λ isotype (HR 3.6) independently predicted AL, whereas heavy chain secretion was associated with lower risk (HR 0.2 for IgG). These findings indicate that AL risk is primarily driven by cumulative light chain exposure, refining our knowledge of AL pathophysiology and providing guidance for follow-up of patients with elevated dFLC.

Abstract Purpose: In RET-rearranged non–small cell lung cancer (NSCLC), treatment options after first-generation selective RET inhibitors (SRI) are limited, and the value of SRI retreatment remains unclear. This study evaluates outcomes of SRI retreatment. Experimental Design: This multicenter retrospective study included patients with advanced RET-rearranged NSCLC who received ≥2 SRI-based therapy lines. Of 411 SRI-treated patients, 41 (10%) underwent SRI retreatment. Outcomes included objective response rate (ORR), progression-free survival (PFS), 6-month PFS, time to treatment failure, adverse events (AE). Results: Among 41 patients, 14 (34%) discontinued the initial SRI because of toxicity and 27 (66%) because of progression. After discontinuation for toxicity, all switched to an alternate SRI, achieving an ORR of 67%, median PFS of 9.9 months, and 6-month PFS of 80.3%. AEs reoccurred in nine patients (64%), with grade ≥3 AEs in 3 (21%) who switched at full dose. Among patients who discontinued because of progression, SRI monotherapy (n = 13) achieved an ORR of 23%, median PFS of 7 months, and 6-month PFS of 61.5%. Benefit was observed in patients with brain-only or oligoprogressive disease or dose reduction on first SRI. Combination therapy (n = 14; targeted agents, n = 11; chemotherapy, n = 3) achieved an ORR of 39%, median PFS of 4 months, and 6-month PFS of 27.3%. Conclusions: Same-class SRI switch after toxicity is feasible and clinically active but warrants cautious, dose-adjusted switching to mitigate toxicities. The efficacy of SRI rechallenge after progression seems limited overall. However, selected patients, such as those with brain-only or oligoprogressive disease, may derive benefit.

Abstract Background. Genome-wide association studies (GWAS) have identified 35 genetic susceptibility single-nucleotide polymorphisms (SNPs) for multiple myeloma (MM) in individuals of European ancestry (EA) and shown strong genetic correlation between MM and its precursor, monoclonal gammopathy of undetermined significance (MGUS). We evaluate the contribution of the 35 MM variants to MGUS susceptibility overall and by prognostic subgroups. Methods. The study included 20,756 participants (14,486 controls, 1,883 with MGUS, and 2,163 with MM) from the Mayo Clinic. Logistic regression assuming an additive model estimated odds ratios (ORs) and 95% confidence intervals (CIs) for individual SNPs and for the MM-PRS, adjusted for age, sex, study, and principal components. The PRS was a weighted sum of 35 SNPs with effect estimates from the largest MM GWAS and was modeled continuously (per SD) and by quintiles (Q1-Q5). SNPnexus annotated variants that replicated in MGUS (P &lt; 0.05 and OR &gt; 1.01) versus those that did not (P &gt; 0.05 and OR &lt; 1.01). Results. The 35-SNP MM-PRS was strongly associated with MM risk and modestly with MGUS. Compared with the middle quintile (Q3), MM odds rose from OR=0.55 (CI=0.46-0.65, P=2.2e-11) in Q1 to OR = 1.82 (CI=1.59-2.09, P=6.2e-18) in Q5. MGUS showed a similar, attenuated pattern (Q1 OR = 0.74, CI=0.64-0.84, P=6.4e-6 / Q5 OR=1.36, CI=1.21-1.53, P=3.4e-7). Each SD increase in PRS corresponded to OR=1.52 (CI=1.45-1.59, P=1.3e-66) for MM and OR = 1.22 (CI=1.18-1.27, P=1.0e-23) for MGUS. Higher PRS values were linked to larger M-protein ((0.1-1.5 g/dL: OR=1.40, CI=1.18-1.65, P=5.8e-12) vs &lt;0.1 g/dL: OR = 1.19, CI=1.13-1.24, P=5.8e-12)) and abnormal free light chain (FLC) ratio ((OR = 1.33, CI=1.21-1.46, P=1.0e-9) vs normal ratio (OR=1.19, CI=1.14-1.25, P=1.4e-13)). Ten risk loci replicated in MGUS, mapping to genes involved in plasma-cell function, immune regulation, and DNA repair and enriched for Rho GTPase signaling, NF-κB-mediated apoptosis, and RNA polymerase II transcription, implicating early plasma-cell activation and transcriptional control. The 12 non-replicating loci, including PHC3, ATG5, and NFIC, mapped to genes involved in chromatin remodeling, autophagy, and SUMOylation, suggesting roles in stress response and genomic maintenance. Conclusions. The MM-PRS captures shared heritability between MM and MGUS and correlates with MGUS subtype and severity. Replicating variants highlight immune and cell-cycle pathways relevant to MGUS onset, whereas non-replicating loci cluster in DNA-repair and stress-response processes, underscoring their potential role in progression. Citation Format: Alyssa Ione Clay-Gilmour, Angelica Macauda, Cristine Allmer, Danelle Moonen, Aaron D. Norman, Nicholas Boddicker, Janet E. Olson, Elizabeth E. Brown, Vincent S. Rajkumar, Esteban Braggio, David Murray, Susan Slager, Shaji Kunnathu Kumar, Celine Vachon. Implications of multiple myeloma polygenic risk scores (PRS) for MGUS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3603.

Abstract Background: Combination immune checkpoint inhibitor (ICI) therapy represents a standard-of-care for patients with metastatic melanoma. However, &gt;40% of patients do not respond to treatment and severe immune-related toxicity affects up to 60% of patients. Accordingly, we need more precise ways to select patients for combination ICIs. To address this, we developed LiquidTME, a liquid biopsy method based on Spatial EcoTyper (Cancer Res (2025) 85 (8_Supplement_1): 153) that leverages a deep learning approach to noninvasively assess the tumor microenvironment from cell-free DNA (cfDNA) methylation data. LiquidTME was previously trained to predict ICI response using 78 patients with advanced melanoma treated at Yale University. Here we performed a blinded validation of LiquidTME in coordination with clinicians at Washington University (WashU). Methods: The WashU cohort consisted of pre-ICI plasma from 34 patients with advanced melanoma, each treated with ipilimumab and nivolumab (n=27) or relatlimab and nivolumab (n=7). ICI response was classified as durable clinical benefit (DCB) or no durable benefit (NDB) by a board-certified oncologist. Tumor mutational burden (TMB) was determined for 27 patients using commercial CLIA assays and analyzed as nonsynonymous mutations (mt) per megabase (Mb), using the FDA-approved 10 mt/Mb cutpoint for TMB-high and -low groups. The WashU cohort was sent to a scientific team that was blinded to all clinical and TMB data. Cell-free DNA was extracted from 2 mL plasma per patient and subjected to enzymatic methyl-seq (EM-seq) at a median depth of 15x. LiquidTME was performed on the resulting profiles, yielding a binary response prediction and a continuous response score for each sample. Test results were locked down and returned. Both assays were compared by AUC and two-sided Wilcoxon rank-sum tests for response classification, and Kaplan-Meier analysis for progression-free survival (PFS). Results: Median follow-up time of the cohort was 21.6 months. LiquidTME performed on cycle 1 day 1 pre-ICI plasma significantly stratified PFS with a hazard ratio (HR) of 0.27 (P = 0.005), with LiquidTME(+) patients achieving a median PFS of 1.7 years longer than LiquidTME(-) patients. LiquidTME distinguished DCB from NDB with an AUC of 0.77 (P = 0.007). Similar performance was seen across distinct combination ICI regimens. In patients with TMB data, LiquidTME maintained whole-cohort performance with a PFS HR of 0.30 (P &lt; 0.03; AUC = 0.77). In contrast, TMB high vs. low subsets failed to stratify PFS (HR = 0.49; P = 0.17) or response (AUC = 0.53; P = 0.8). Conclusion: LiquidTME identified durable responders to combination ICI from pretreatment plasma in this blinded validation cohort of melanoma patients. Given its favorable performance, LiquidTME shows promise as a clinical tool to guide personalized immunotherapy decision-making. Citation Format: Aadel A. Chaudhuri, David Y. Chen, Tucker Hansen, Mirna Jarosz, Vincent A. Miller, Aaron M. Newman. Blinded clinical validation of LiquidTME, a cell-free DNA assay for predicting response to immunotherapy by noninvasively profiling the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1040.