Citations

Background/Objectives: Adult hearing-impaired patients qualifying for cochlear implants typically exhibit less than 60% sentence recognition under the best hearing aid conditions, either in quiet or noisy environments, with speech and noise presented through a single speaker. This study examines the influence of deep neural network-based (DNN-based) noise reduction on cochlear implant evaluation. Methods: Speech perception was assessed using AzBio sentences in both quiet and noisy conditions (multi-talker babble) at 5 and 10 dB signal-to-noise ratios (SNRs) through one loudspeaker. Sentence recognition scores were measured for 10 hearing-impaired patients using three hearing aid programs: calm situation, speech in noise, and spheric speech in loud noise (DNN-based noise reduction). Speech perception results were compared to bench analyses comprising the phase inversion technique, employed to predict SNR improvement, and the Hearing-Aid Speech Perception Index (HASPI v2), utilized to predict speech intelligibility. Results: The spheric speech in loud noise program improved speech perception by 20 to 32% points as compared to the calm situation program. Thus, DNN-based noise reduction can improve speech perception in noisy environments, potentially reducing the need for cochlear implants in some cases. The phase inversion method showed a 4–5 dB SNR improvement for the DNN-based noise reduction program compared to the other two programs. HASPI v2 predicted slightly better speech intelligibility than was measured in this study. Conclusions: DNN-based noise reduction might make it difficult for some patients with significant residual hearing to qualify for cochlear implantation, potentially delaying its adoption or eliminating the need for it entirely.

Objectives To reassess the role of primary retroperitoneal lymph node dissection (RPLND) in patients with marker‐negative non‐seminomatous germ cell tumour (NSGCT) clinical stage (CS) 2a, to explore results in patients with CS 2b and to evaluate surgical methods, recurrence, and adjuvant chemotherapy indications. Materials and Methods Data from 17 institutions were collected, comprising 305 men who underwent primary RPLND for CS 2 NSGCT. Regression analyses were conducted to predict histology in the RPLND specimen and disease‐free survival (DFS). Results A larger retroperitoneal lymph node diameter was associated with pure teratoma in the RPLND specimen (odds ratio [OR] 1.02, 95% confidence interval [CI] 1.01–1.07; P = 0.03), but no association was observed with DFS. The 5‐year DFS rates in marker negative CS 2a and 2b were 79% and 76%. In men with non‐teratomatous viable cancer in the RPLND specimen, the 5‐year DFS rates for CS 2a and 2b were 95% and 87% with adjuvant chemotherapy, and 67% and 74% without adjuvant chemotherapy. We did not identify an association between the number of adjuvant chemotherapy cycles and DFS. Conclusions Our study suggests considering primary RPLND not only in marker‐negative CS 2a but also in CS 2b. Further research should determine the efficacy of primary RPLND in men with CS 2c and marker‐positive CS 2, as well as which patients may benefit from adjuvant chemotherapy and the optimal cycle number.

Abstract Background The National Clinical Trials Network (NCTN) is the largest government-sponsored organization in the United States; it is tasked with funding randomized controlled trials in oncology. It is unknown whether there are differences in study design by treatment modality. We evaluated differences in methodology between trials testing radiation therapy (RT) vs systemic therapy. Methods The Clinical Trials Support Unit website was used to identify active randomized controlled trials of systemic therapy or RT across NCTN cooperative groups through December 31, 2023. Studies in disease sites with more than 5 RT trials were included. Each trial’s protocol was reviewed to obtain key design information that was descriptively compared: primary endpoint, hypothesis testing type (superiority vs noninferiority), noninferiority margin, hypothesized effect size, power, and statistical significance level. Results A total of 186 randomized controlled trials (142 systemic therapy, 44 RT) were examined. Comparing primary endpoints, 59.1% vs 26.8% of RT vs systemic therapy trials, respectively, had a primary endpoint of overall survival. Nearly one-third (31.2%) of RT trials were noninferiority vs 6.3% of systemic therapy trials. Among breast cancer trials, 75% of RT studies were noninferiority vs 11.1% systemic therapy. Target effect size, power, and statistical significance level were similar by treatment modality within tumor types and disease settings. Conclusion Among NCTN cooperative group randomized controlled trials, there were marked differences in study design between RT vs systemic therapy trials. A higher benchmark for defining success for RT interventions was observed, with greater emphasis on overall survival as the primary endpoint. This finding may reflect differences in therapeutic mechanism by modality and types of study questions posed.

Introduction: Primary diffuse large B-cell lymphoma (DLBCL) of the central nervous system (CNS), traditionally referred to as primary CNS lymphoma (PCNSL), is a rare type of primary large B-cell lymphoma of immune-privileged sites with significantly poorer prognosis than systemic DLBCL. Genetic profiles of PCNSL were widely studied, whereas the tumor microenvironment has not been well characterized. Patients and Methods: A series of molecular analyses were performed using DLBCL FFPE tissues collected by the International Lymphoma Consortium. First, multiplex fluorescent immunohistochemistry (mfIHC) using antibodies for CD20, PAX5, CD3, CD4, CD8, FOXP3, CD45RO, CD68, CD56, PD-1, PD-L1, PD-L2, and CTLA-4 was performed on PCNSL tissues from 121 immunocompetent patients and de novo systemic DLBCL tissues from 405 patients. Digital quantification results for 405 patients with EBV-negative systemic DLBCL or primary testicular (PT) DLBCL have been reported previously. The preliminary mfIHC results of PCNSL will be presented. Second, mfIHC for multiple B cell biomarkers, CD3, CD4, CD8, CD68, CD163, CD11c, and CD31 were performed for 10 PCNSL validation cases, 24 PT-DLBCL and 451 systemic DLBCL tissues (unpublished). Third, RNA samples were extracted and sequenced for the targeted 1408 cancer-associated genes, successfully in 142 PCNSL cases, including 102 cases evaluated by either of these two mfIHC panels and additional 40 PCNSL cases, Results: First, in the first large mfIHC cohort, PCNSLs compared with de novo systemic nodal or extranodal DLBCL had significantly higher mean/median CD56+ cell densities whereas lower T cell densities (consistent with the immune privilege), as well as lower CD45RO+, PD-1+, and FOXP3+ percentages in T cells whereas higher CD4¯CD8¯ double-negative percentages in T cells. Prognostic analysis in the PCNSL cohort showed that high CD56+ cell densities and high CD45RO+CD8+ T cell densities were associated with significantly poorer and better patient survival, respectively, which are opposite to their prognostic effects in systemic DLBCL as previously reported. Twelve patients had very high PD-L1 expression in B cells and significantly poorer survival in the PCNSL cohort. Second, as validation, the 10 PCNSL cases in the second mfIHC study showed significantly less T cells than systemic DLBCL and PT-DLBCL cases, and low CD8 T cell densities and having low percentage of CD8 T cells adjacent to tumor cells were associated with significantly poorer survival. Immunofluorescence landscapeand spatial analysisrevealed significant differences in immune privilege between PCNSL and PT-DLBCL. Third, gene expression profiling analysis by targeted RNA-seq identified 282 significantly differentially expressed genes between PCNSL and systemic DLBCL, referred to as the PCNSL signature. Unsupervised clustering analysis divided the PCNSL cohort into two clusters, which had no significant difference in MYD88 mutation frequencies analyzed at the mRNA level. Importantly, the cluster with higher expression of many neural glial genes in the PCNSL signature had significantly poorer survival, which remained significant in multivariate analysis adjusting for clinical factors and/or treatments, two PCNSL subcohorts (as training and validation cohorts), and methotrexate-treated patients. NCAM1 (Neural Cell Adhesion Molecule 1, encoding CD56) was among the upregulated PCNSL signature genes, explaining the poorer prognosis associated with higher CD56+ cell densities in PCNSL by the mfIHC analysis. Summary: Our studies represent the largest immunophenotypic and gene expression profiling studies currently in PCNSL, a rare type of primary DLBCL of immune-privileged sites. Multiplex immunofluorescence revealed the immune landscape in PCNSL in comparison with systemic and testicular DLBCL, and identified prognostic immune biomarkers. Targeted RNA-seq identified a PCNSL gene signature enriched with neuronal-glial genes and showing significant prognostic effect in PCNSL. These novel findings in the PCNSL microenvironment warrant further studies.

Multiple myeloma (MM), an incurable hematologic malignancy, presents significant challenges in managing its recurrence. The bone marrow tumor microenvironment (BM-TME) is critical to MM progression. However, classical immune checkpoint blockade (ICB) therapies, like anti-PD1, have shown limited efficacy in MM. Therefore, elucidating the compositional features and regulatory mechanisms of the TIME in MM is crucial for developing novel immunotherapeutic targets. Tissue-resident memory CD8+ T cells (CD8+ TRMs) reside indefinitely at multiple anatomical locations like the skin, intestine, and bone marrow, functioning as frontline responders against reencountered pathogens and tumors. Whether CD8+ TRMs within BM-TME are involved in the MM cell immune escape and pathogenesis has not been systematically elucidated. Firstly, we leverage single-cell RNA sequencing (scRNA-seq) to dissect the BM CD8+ T cells across patients at different stages of MM, and identify that CD69+CD8+ T subsets were BM residents, and the proportion of BM CD8+ TRMs between health donors and MM patients was comparable. Moreover, our findings indicated that BM CD8+ TRMs exhibit exhausted features and enrichment of NK genes with MM progresses. Importantly, we observed a considerable elevation of the NK gene KLRB1 and its encoded protein CD161 in BM CD8+ TRMs in MM patients. Immunofluorescence labeling of BM biopsy samples from MM patients confirmed the infiltration of the BM-TME with CD3+CD8+CD69+CD161+ cells. Then, we found that KLRB1 expression in BM CD8+ TRMs was higher than that of other classical inhibitory receptor genes (e.g., PDCD1, CTLA4, LAG3), and CLEC2D (encodes the ligand of CD161) was also markedly expressed in patients' MM cells, exhibiting considerably higher than classical immunosuppressive receptor ligand genes (e.g., PDL1, CD80, CD86). Moreover, patients with higher CLEC2D expression had unfavorable overall survival. We further found that the CD161 expression was higher in CD69+CD8+ TRMs compared to circulating CD69-CD8+ T cells, and the percentage of BM CD161+CD8+ TRMs in MM patients was significantly higher than in healthy donors, while there was no difference for PD-1, LAG3, and TIM3 expression. Notably, only a small fraction of BM CD8+ TRMs have mucosal-associated invariant T cell phenotypes (identified by CD161+TCR-Vα7.2+). Additionally, the CLEC2D expression of BM cells was analyzed, and the highest level of CLEC2D expression was observed in B cells from MM patients, followed by plasma cells. Importantly, CLEC2D expression in MM patients was significantly higher than in plasma cells from healthy donors. Next, to investigate whether the blockade of CD161 could restore the function of CD8+ TRMs, the primary BM cells from MM patients were isolated and stimulated ex vivo. Compared to the anti-PD-1 and isotype group, CD161 blocking presents enhanced CD8+ TRMs proliferation and cytokine secretion levels (TNF-α, IFN-γ, IL2), increasing MM cells apoptosis. Chimeric antigen receptor T (CAR-T) cell therapy has achieved impressive success in treating relapsed/refractory MM. How to prevent CAR-T cell exhaustion and enhance function remains a significant challenge. Therefore, we next set out to investigate the impact of CD161 on CAR-T cells. Our results demonstrated that CD161 was highly expressed in early peripheral blood (PB) CAR-T cells after infusion in MM patients but decreased with time. Moreover, the CD161 expression of CAR-T cells was considerably higher than endogenous T cells. Notably, BM-derived CAR-T cells have higher CD161 expression than PB counterparts for the same patient, suggesting CD161 may have BM-specific expression enrichment. After co-culturing MM and CAR-T cells in vitro for 24 hours, we found that blocking CD161 led to an augmented proportion of CAR-T cells, increased IFN-γ secretion, and a notable elevation in tumor cell apoptosis compared to the anti-PD-1 and isotype groups. Taken together, we demonstrated that CD8+ TRMs constitute a vital anti-tumor cell subset in the MM BM-TME, which exhibits a high expression of the inhibitory CD161 receptor, binding to the CLEC2D expressed by MM cells, thereby mediating the dysfunction of CD8+ TRMs. Blocking the CD161-CLEC2D pathway is expected to become a novel target for MM immunotherapy. The combination of CD161 inhibitors and CAR-T cell therapy can potentially enhance the anti-myeloma function of CAR-T cells.

Background : Rituximab is a monoclonal antibody that targets CD20 and can significantly improve the prognosis of patients with CD20-positive B-cell non-Hodgkin lymphoma (B-NHL). Nonetheless, a significant number of patients experience disease progression or relapse post-rituximab therapy. CD19-chimeric antigen receptor (CAR) T cells have demonstrated remarkable efficacy in B-NHL treatment. However, few studies have focused on the efficacy and safety of CD20 CAR-T cells in rituximab-refractory/relapsed (R/R) B-NHL patients, particularly those treated with rituximab for a short time. Here, we conducted a prospective study, aimed to assess the long-term remission and survival in patients with rituximab-R/R B-NHL after treatment with U16 (CD20 CAR-T cells). Methods : This first-in-human study is an open-label, single center investigator-initiated trial (IIT) to determine the safety and efficacy of CD20 CAR-T in R/R B-NHL after previous rituximab treatment failure (no. ChiCTR2000036350). CD20 CAR-T was administered at a target dose of 1.0×107 CAR-T cells/kg after a 3-day conditioning chemotherapy with fludarabine and cyclophosphamide. The primary objective was to assess the safety and tolerability of CD20 CAR-T. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded according to ASTCT 2019 criteria. The secondary objectives were to evaluate efficacy and pharmacokinetics (PK). Response was assessed per Lugano 2014 criteria. Results:A total of 16 patients with R/R B-NHL were enrolled.The median age was 49 years (range, 28-66). Median number of prior lines of therapy was 3 (range, 2-5). All patients had received rituximab therapy; of these, 9 had done so within the 3 months before CAR-T infusion. CRS occurred in all patients, with 11 patients (68.75%) experiencing grade 1 or 2 CRS and 5 patients (31.25%) experiencing grade 3 CRS. No patient developed grade 4 CRS , and only one patient had ICANS.The most common grade 3 or higher adverse events observed after infusion included leukopenia (93.3%), anemia (40%) and thrombocytopenia (60%). An overall response rate of 100% was observed among enrolled patients, with 11 patients (68.75%) achieving complete remission(CR) and 5 patients (32.25%) achieving partial remission(PR) within 3 months. The median follow-up time was 11.7 months(range 0.69-47.47). The median overall survival was not reached, and the median progression-free survival was 14.5 months. 9 patients remained CR or PR for 12 months, with 7 of them continuing in CR for up to 24 months. The pharmacokinetics of CD20 CAR-T cells were assessed using quantitative PCR to determine the expansion and persistence ability. Peak CAR amplification were detected 7-14 days after infusin. Patients 1, 2 and 4 achieved long-term remission, and persistent positive CAR-T cell copy numbers were detected for 15 months, 30 months and 26 months, respectively. However, patients 7, 8 and 12 relapsed within 3 months, and the CAR-T cell copies of all three patients were reduced to fewer than 1×103 copies/μg of DNA within 3 months. The qPCR results indicated that the maintenance of efficacy was closely related to the persistence of CAR-T cells. Notably, patients who received rituximab less than 3 months before CAR-T infusion had a poorer prognosis, with higher relapse rates (77.8% vs. 28.6%) and shorter progression-free survival, regardless of the degree of response. Conclusion : Long-term follow-up demonstrated that CD20 CAR-T therapy can produce a deep and durable response with a favorable safety profile in patients with rituximab-refractory/relapsed B-NHL. Notably, patients who had received rituximab within 3 months had a poorer prognosis.

Introduction: Advances in AI have enabled the generation of synthetic individual patient data (SynthIPD) that mimics the statistical properties of the real IPD, which can help generate subgroup-specific insights in the absence of subgroup-specific IPD. We apply this technology in evaluating Daratumumab treatment benefit in high-risk cytogenetic multiple myeloma subgroup. The addition of daratumumab to standard multiple myeloma (MM) regimens has been associated with improved response rates and clinical outcomes. A systematic review (meta-analysis) enables further evaluation of the effectiveness of daratumumab for MM patients with high-risk cytogenetic factors. However, concerns have been raised about meta-analyses due to the statistical model assumptions they impose. This study aims to address these limitations by employing SynthIPD to provide a more robust analysis. Methods: This study focuses on newly diagnosed multiple myeloma (NDMM) and relapsed or refractory multiple myeloma (RRMM) patients with high-risk cytogenetic profiles. We included six published studies: ALCYONE, CASSIOPEIA, and MAIA for NDMM, and CANDOR, CASTOR, and POLLUX for RRMM. Large language models were used to extract up-to-date clinical evidence from the literature. SynthIPD including cytogenetic risk profile were generated via digitization and an innovative optimization algorithm. Meta-analyses based on random effects models were then conducted, and the results were compared with those from pooled analyses using synthetic data. Results: SynthIPD for cytogenetic high-risk patients were generated for three studies for NDMM: ALCYONE (treatment vs control: n=53 vs n=45), CASSIOPEIA (n=82 vs n=86), MAIA (n=48 vs n=44); and three studies for RRMM: CANDOR(n=48 vs n=26), CASTOR (n=40 vs n=35), POLLUX (n=35 vs n=35). The generated hazard ratios (HRs) for each study closely aligned with the reported HRs for high-risk patients, with a maximum relative error of less than 2%. By pooling these datasets, we obtained SynthIPD datasets for NDMM and RRMM patients. Stratified Cox regression analyses yielded HRs of 0.764 (95% CI 0.529-1.104) for NDMM and 0.431 (95% CI 0.294-0.613) for RRMM. Random-effects meta-analyses showed HRs of 0.764 (95% CI 0.529-1.104) for NDMM and 0.425 (95% CI 0.287-0.621) for RRMM. Compared with traditional meta-analysis techniques, the synthetic data approach provides additional clinical insights that were not available in the original publications. For instance, the clinical results for the six studies within high-risk group (e.g., KM curves in high-risk subgroup) can be reproduced, which were not reported in the original studies. Conclusion: AI-generated synthetic data enhances the robustness of conventional meta-analysis outcomes. The identification of HRs and corresponding confidence intervals through SynthIPD enhances the credibility of our proposed method, offering a reliable approach to evaluating the efficacy of daratumumab in high-risk patients. Since SynthIPD includes individual covariate information, any statistical results derived from the original IPD can be effectively approximated using SynthIPD. Using the SynthIPD, we show that the addition of daratumumab to standard regimens improves PFS for RRMM patients with high-risk cytogenetic factors, although its benefit for NDMM patients is not statistically significant. This analysis can be extended to other multiple myeloma high risk subgroups.

Abstract Background Hypergammaglobulinemia poses a challenge for identifying and quantitating monoclonal proteins (M-protein). The Increased polyclonal immunoglobulin background can lead to imprecise estimation of the M-protein when quantitated by serum protein electrophoresis (SPEP). This is especially true using the perpendicular drop method of peak integration. Hypergammaglobulinemia also makes it difficult to detect small M-proteins on immunofixation electrophoresis. Overestimation of M-protein concentration can lead to unnecessary follow-ups while missing small M-proteins can mask the underlying diagnosis for patients. In this study, we retrospectively evaluated the prevalence and concentration of M-protein within polyclonal hypergamma backgrounds using immunocapture matrix-assisted laser desorption ionization time-of-flight mass-spectrometry (MASS-FIX). Methods We retrospectively analyzed 47061 unique patients tested for SPEP and MASS-FIX in 2022 at Mayo Clinic. If a patient underwent multiple tests during this period, only the first result was included in the analysis. Polyclonal hypergammaglobulinemia was defined as a gamma fraction >1.7g/dL by SPEP. MASS-FIX was used to identify and isotype M-proteins. MASS-FIX was then combined with total immunoglobin quantitation (IgG, IgA or IgM) using nephelometry to quantify concentration of the M- protein using mathematical modeling (method currently under validation). Results Of the 47,061 unique patients, 24,796 were normal by SPEP (53%). M-spikes were present in 5,808 cases (12%). Hypogammaglobulinemia (gamma fraction < 0.5g/dL) in 2897 cases (6%). Small non-quantifiable M-proteins by SPEP were present in 8363 cases (18%). [JC2] There were 4222 hypergamma cases in the cohort (9%), without a quantitative M-spike on SPEP. Of these, 16.1% (680/4222) patients had an M-protein by MASS-FIX. When polyclonal hypergamma was the sole SPEP abnormality, 5.5% were MASS-FIX positive. However, when a small abnormality pattern was observed within the polyclonal hypergamma background on SPEP, 50% of patients were MASS-FIX positive. The most common isotype was IgG (27.2%), followed by IgM (10.2%), IgA (8.1%), and biclonal (3.7%), which is similar to overall isotype distribution in other backgrounds. Using quantitative MASS-FIX, we identified that 95% MASS-FIX positive small monoclonal proteins in polyclonal hypergamma are < 1 g/dL, which is the recommended limited of quantitation for M-protein using SPEP in setting of hypergammaglobulinemia. Conclusion Majority of polyclonal hypergammaglobulinemia cases (83.9%) do not have a monoclonal protein. MASS-FIX allows quantitation of small monoclonal proteins below the SPEP limit of quantitation, which can enhance our understanding of conditions which present with small M-proteins in a polyclonal hypergammaglobulinemia background. Small visual abnormalities within polyclonal hypergamma background on SPEP should be followed-up with immunofixation or MASS-FIX to confirm the presence or absence of M- proteins.

Background: Value is defined as the ratio of patient outcomes to the cost of care. One method to assess value is through patient-level value analysis (PLVA). To our knowledge, this tool has not previously been implemented in the setting of total hip arthroplasty (THA). The purposes of this study were to perform PLVA for a 1-year episode of care among patients undergoing primary THA and to identify characteristics that affect value in a metropolitan health-care system. Methods: The patient-reported outcome (PRO) measure database of the institution was queried for all primary THAs from 2018 to 2019. The PRO measure that was utilized was the Hip disability and Osteoarthritis Outcome Score, Joint Replacement (HOOS-JR). Cost was evaluated with use of time-driven activity-based costing (TDABC) for a 1-year episode of care (consisting of the day of surgery, inpatient stay, discharge facility, postoperative appointments, and physical therapy). The primary outcome was the 1-year value quotient, or the ratio of the 1-year change in HOOS-JR to the cost of the episode of care (V HOOS ). The value quotient was compared among all included patients and evaluated for variables that may affect the overall value of the episode of care. Results: In total, 480 patients were included in the analysis. The mean improvement in the HOOS-JR was +34.9 ± 16.1 (95% confidence interval [CI]: 33.5, 36.3). The mean cost was $13,835 ± $3,471 (95% CI: $13,524, $14,146). The largest contributor to cost was implants (39.0%), followed by post-recovery care (i.e., inpatient stay and specialized nursing facilities; 24.1%). Change in the HOOS-JR was poorly correlated with the cost of care (r = −0.06; p = 0.19). THAs performed at an ambulatory surgery center (ASC) with discharge to home demonstrated higher value (V HOOS = 0.42) than THAs performed at a hospital with discharge to a rehabilitation facility (V HOOS = 0.15; analysis of variance F-test, p < 0.01). Conclusions: Our study found that PROs did not correlate with costs in the setting of primary THA. Implants were the largest cost driver. Surgical setting (an ASC versus a hospital) and discharge destination influenced value as well. PLVA is a value measurement tool that can be utilized to optimize components of the care delivery pathway. Level of Evidence: Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence.