Citations

Abstract Background: The goal of this study is to evaluate the immunomodulatory effects of daratumumab-(anti-CD38)-based therapy on fHRMM patients enrolled in the MMRF sponsored MyDRUG umbrella clinical trial (NCT03732703) over the duration of therapy and to correlate immune changes with patient response. Methods: fHRMM who had received 1-3 prior therapies (exposed to at least one proteasome inhibitor and an IMiD) were given a combination of daratumumab (D), ixazomib (I), pomalidomide (P) and dexamethasone (d) (D-IPd) quadruplet therapy. Bone marrow (BM) aspirates were then collected from patients prior to therapy (BL), after 2 cycles (EOC2), after 4 cycles (EOC4) of the quadruplet therapy and at the end of treatment or disease progression (EOT). Immune and tumor fractions were enriched by CD138 selection. Here, CD138- bone marrow mononuclear cells were isolated and transcriptionally profiled by scRNAseq and scTCRseq. Results: Single-cell RNA and TCR profiles were generated from ∼90,000 cells across 41 samples from 16 subjects. scRNAseq identified CD3+ T cells, NK cells, classical and non-classical monocytes and B cells. CD8+ T cells were further resolved into their subsets including precursor (TPEX) and terminally exhausted T cells (TEX) within the bone marrow microenvironment. Within the CD8+ T cell compartment, an expansion of the effector memory (TEM) cell population was observed following 2-cycles of therapy (EOC2). However, this TEM expansion was not sustained at timepoint EOC4. Towards the end of therapy, enrichment of precursors to exhausted and terminal dysfunctional effector memory cells (TEMRA) was observed. Subjects with partial (PR), very good partial (VGPR) and complete (CR) best overall responses showed an initial increase in TEM cells followed by a slow expansion of TEX and TEMRA cells over time. Longitudinal tracking of T cell clonality showed preferential progressive expansion of TEMRA cells after the therapy. We mapped hyperexpanded (more than 16 copies) clonotypes, presumed to be tumor-reactive, to various CD8+ T cell subsets. These hyperexpanded clonotypes mapped to the TEMRA, TEX and TEM CD8+ T cells. Analysis of TCR repertoires clonality and diversity also demonstrated a reduced richness and increased clonality of CD8+ TCRs in responders. Conclusions: Paired single cell RNA and TCR sequencing of BM T cells from RRMM patients receiving D-IPd quadruplet therapy revealed a selective expansion of clonotypic CD8+ T cells with a clonal replacement of BM exhausted clonotypes by dysfunctional circulating CD8+ T cells in responders over time. Citation Format: Chaitanya R. Acharya, Darwin D'souza, Reyka Jayasinghe, Mark Hamilton, Zhihong Zhihong, Seunghee Kim-Schulze, Hearn J. Cho, Shaji Kumar, George Mulligan. The immunomodulatory effects of daratumumab-based therapy on functional high-risk relapse/refractory multiple myeloma (fHRMM) patients enrolled in the MyDRUG trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5258.

ImportanceSpecialized ophthalmology terminology limits comprehension for nonophthalmology clinicians and professionals, hindering interdisciplinary communication and patient care. The clinical implementation of large language models (LLMs) into practice has to date been relatively unexplored.ObjectiveTo evaluate LLM–generated plain language summaries (PLSs) integrated into standard ophthalmology notes (SONs) in improving diagnostic understanding, satisfaction, and clarity.Design, Setting, and ParticipantsRandomized quality improvement study conducted from February 1, 2024, to May 31, 2024, including data from inpatient and outpatient encounters in a single tertiary academic center. Participants were nonophthalmology clinicians and professionals and ophthalmologists. The single inclusion criterion was any encounter note generated by an ophthalmologist during the study dates. Exclusion criteria were (1) lack of established nonophthalmology clinicians and professionals for outpatient encounters and (2) procedure-only patient encounters.InterventionAddition of LLM-generated plain language summaries to ophthalmology notes.Main Outcomes and MeasuresThe primary outcome was survey responses from nonophthalmology clinicians and professionals assessing understanding, satisfaction, and clarity of ophthalmology notes. Secondary outcomes were survey responses from ophthalmologists evaluating PLS in terms of clinical workflow and accuracy, objective measures of semantic quality, and safety analysis.ResultsA total of 362 (85%) nonophthalmology clinicians and professionals (33.0% response rate) preferred the PLS to SON. Demographic data on age, race and ethnicity, and sex were not collected. Nonophthalmology clinicians and professionals reported enhanced diagnostic understanding (percentage point increase, 9.0; 95% CI, 0.3-18.2; P = .01), increased note detail satisfaction (percentage point increase, 21.5; 95% CI, 11.4-31.5; P < .001), and improved explanation clarity (percentage point increase, 23.0; 95% CI, 12.0-33.1; P < .001) for notes containing a PLS. The addition of a PLS was associated with reduced comprehension gaps between clinicians who were comfortable and uncomfortable with ophthalmology terminology (from 26.1% [95% CI, 13.7%-38.6%; P < .001] to 14.4% [95% CI, 4.3%-24.6%; P > .06]). PLS semantic analysis found high meaning preservation (bidirectional encoder representations from transformers score mean F1 score: 0.85) with greater readability than SONs (Flesch Reading Ease: 51.8 vs 43.6; Flesch-Kincaid Grade Level: 10.7 vs 11.9). Ophthalmologists (n = 489; 84% response rate) reported high PLS accuracy (90% [320 of 355] a great deal) with minimal review time burden (94.9% [464 of 489] ≤1 minute). PLS error rate on ophthalmologist review was 26% (126 of 489). A total of 83.9% (104 of 126) of errors were deemed low risk for harm and none had a risk of severe harm or death.Conclusions and RelevanceIn this study, use of LLM-generated PLSs was associated with enhanced comprehension and satisfaction among nonophthalmology clinicians and professionals, which might aid interdisciplinary communication. Careful implementation and safety monitoring are recommended for clinical integration given the persistence of errors despite physician review.

BACKGROUND Malignant peripheral nerve sheath tumors (MPNSTs) are rare and highly malignant tumors of neural crest origin. No matter their anatomical location, they are difficult to treat and carry a poor prognosis. OBSERVATIONS This report highlights the complexities of the diagnosis and management of a patient with MPNST of the cauda equina. The tumor retained the expression of H3K27me3, which is expected in spinal MPNSTs but uncommon in most sporadic and neurofibromatosis type 1–driven MPNSTs. LESSONS The described diagnostic nuance should be taken into consideration in patients with suspected MPNST of the cauda equina, as these tumors require swift neurosurgical intervention in order to maintain neurological function. Additional treatment modalities include neoadjuvant and adjuvant chemotherapy and radiotherapy. Although improvements in local control and progression-free survival have been reported, the role of radiation therapy and chemotherapy has been underinvestigated due to the rarity of MPNSTs presenting in this region. https://thejns.org/doi/10.3171/CASE24723

The trial-to-implant ratio for spinal cord stimulation (SCS) has long served as a cornerstone metric for optimizing patient selection and cost containment. Historically, screening trials played a pivotal role in identifying non-responders, thereby minimizing unnecessary permanent implantations. The utility of the trial paradigm is supported by Medicare data from 2009, which reported a trial-to-implant ratio of 42.5%. However, advancements in SCS technology have significantly transformed the neuromodulation landscape and have been associated with higher rates of trial success. By 2018, the Medicare data showed trial-to-implant ratios exceeding 63%, with randomized clinical trials from 2020 to 2021 reporting ratios exceeding 80%–90%. These significant increases in trial-to-implant ratios suggest that only a minority of SCS candidates do not undergo a subsequent permanent device implantation. As such, re-evaluation of the trial-to-implant paradigm, from the perspective of practicing pain physicians in the USA, in light of evolving clinical practices and economic pressures, is warranted. This discourse explores the benefits and limitations of the trial-to-implant ratio, emphasizing its role as a safeguard against overutilization and a tool for standardizing clinical practices but weighed against its shortcomings including a lack of alignment with long-term outcomes, underscore the need for alternative metrics that include per capita trial utilization and explant-to-implant ratios. European responses to similar questions have resulted in utilizing validated symptom screening tools and direct-to-implant pathways in lieu of a screening trial altogether as potential strategies to optimize SCS utilization while maintaining cost-effectiveness. As healthcare systems adapt to advancements in neuromodulation, a balanced perspective on trial-to-implant ratios and complementary metrics is essential to ensure equitable access, sustainable outcomes and evidence-based care for the future of SCS therapy.

Background: Both perineural and intravenous dexamethasone have been proposed as effective adjuncts that prolong the duration of peripheral nerve blocks. The authors sought to explore whether combining systemic with perineural dexamethasone yields any additive or synergistic effect on the characteristics and analgesic effects of peripheral nerve blocks. Methods: Adult patients having distal radius open reduction and internal fixation and/or carpometacarpal arthroplasty under supraclavicular block were randomized to intravenous dexamethasone, a combination of perineural plus intravenous dexamethasone, or no dexamethasone (control). Sensory block duration was set as the primary outcome. Secondary outcomes included motor block duration; postoperative rebound pain scores as well as worst pain at 8, 16, 24, 32, 40, and 48 h; opioid consumption at 0 to 24 and 25 to 48 h; incidence of nausea/vomiting; and presence of burning sensation in the blocked limb at 24 and 48 h. The null hypothesis was lack of difference in sensory block duration between the three groups. Results: A total of 104 patients were included in the analysis (intravenous dexamethasone, 37; intravenous plus perineural dexamethasone, 34; control, 33). Compared to intravenous dexamethasone alone, adding perineural dexamethasone did not yield any incremental benefits in any of the outcomes examined. The mean ± SD of sensory block duration was 21.3 ± 7.3 h in the intravenous dexamethasone group, 20.6 ± 6.1 h in the perineural plus intravenous group, and 16.8 ± 6.8 h in the control group. The mean difference (95% CI) of sensory block duration was significantly prolonged by 4.5 h (95% CI, 1.3 to 7.7; P = 0.006) in the intravenous dexamethasone group and 3.8 h (95% CI, 0.8 to 6.8; P = 0.015) in the perineural plus intravenous dexamethasone group compared to control; however, no difference was observed when the two dexamethasone groups were compared to each other (0.7 h [95% CI, –2.5 to 3.9]; P = 0.670). Compared to control, both intravenous and intravenous plus perineural dexamethasone similarly reduced 24-h pain scores and opioid consumption and decreased incidence of rebound pain. Conclusions: The authors’ findings suggest that intravenous dexamethasone alone is sufficient to improve analgesic outcomes for patients receiving supraclavicular block for upper extremity surgery. Combining the intravenous and perineural dexamethasone routes does not yield an additive or synergistic effect on the characteristics and analgesic effects of supraclavicular block.