bluuebunny/crossref_metadata_2025_split huggingface dataset:
Uncontrolled diabetes mellitus and the progression of monoclonal gammopathy of undetermined significance to multiple myeloma in US veterans.
Authors: Liu Lawrence , Sigel Byron , Wang Mei , Grandhi Nikhil , Schoen Martin W. , Sanfilippo Kristen Marie , Janakiram Murali , Thomas Theodore Seth , Chang Su-Hsin 
Published: June 2024

7551 Background: Studies have shown that, independent of obesity, the metabolic effects of diabetes mellitus (DM) promote the progression of monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM). However, it is unclear whether glycemic control is associated with MGUS progression in DM patients. We aimed to evaluate the association between poor glycemic control, measured by HbA1c >6.5%, and progression. Methods: Patients diagnosed with MGUS from 1999-2021 in the Veterans Health Administration (VHA) were identified using a published natural language processing (NLP)-based algorithm. We focused on patients whose MGUS subtype was IgG, IgA, or light chain. We excluded patients lacking body weight measurements from the time of MGUS diagnosis to the end of follow-up to ensure receiving care in the VHA. We further excluded patients with extended gaps >1 year between HbA1c measurements. Time-varying HbA1c measurements during the follow-up, evaluated at 1-day intervals and categorized into uncontrolled (HbA1c >6.5%) or controlled (≤6.5%) DM was the exposure variable. Progression of MGUS to MM was also confirmed by a published NLP algorithm. The association between the time-varying controlled/uncontrolled DM and progression was estimated by multivariable-adjusted hazard ratio (aHR) with death as a competing event. The covariates included sex, race, MGUS subtype as well as age, body mass index, monoclonal protein level, Charlson Comorbidity Index, DM medication, and DM type (type 1, type 2 with insulin-dependency status, type 2 without insulin-dependency status), all at MGUS diagnosis. Same analysis was conducted in a subgroup of patients with non-insulin dependent DM type 2 (NIDDMT2) without insulin use between MGUS diagnosis and the end of follow-up. Results: After applying inclusion and exclusion criteria, we identified 9,682 patients with both DM and MGUS. The multivariable analysis revealed a positive association between poor glycemic control and MM progression (see Table): (aHR 1.27, 95% CI 1.13-1.42). In NIDDMT2 without insulin use (n=3,498), poor glycemic control was associated with MM progression (aHR 1.81; 95% CI 1.57-2.10). Conclusions: For patients with DM and MGUS, the risk of MGUS progression to MM was 27% higher in uncontrolled DM and 81% higher in patients with NIDDMT2. This finding highlights a modifiable risk factor for MM progression in MGUS patients. Future studies should examine if interventions to enhance glycemic control could potentially reduce MGUS progression.
Effect of dose-adjusted melphalan on MRD-negativity to full dose melphalan in patients with multiple myeloma post-autologous stem cell transplant.
Authors: Kort Jeries , Ignatz-Hoover James John , Naleid Nikolas , Oley Frank , Cooper Brenda W. 
Published: June 2024

7557 Background: Despite significant therapeutic advancements, Multiple Myeloma (MM) remains an incurable disease. Autologous stem cell transplantation (ASCT) is a standard treatment for eligible patients, with high-dose melphalan (MEL200) as the preferred conditioning regimen. Reduced-dose melphalan (MEL140) is used for older or less fit patients. However, this was not prospectively studied and there has been ongoing debate about the efficacy of reduced dosing. This study aimed to investigate the impact of melphalan dose on minimal residual disease (MRD) negativity rates in MM patients undergoing upfront ASCT. Methods: We conducted a retrospective, single-center study involving 74 MM patients who underwent ASCT between 2018 and 2022 at UHCMC, Cleveland, OH and had MRD testing done after transplant. MRD testing was performed using the ClonoSEQ next generation sequencing platform. Results: Median age was higher in the MEL140 group compared to MEL200 (70.3 vs 59.8 years), both groups were similar in terms of sex and race distribution, BMI and KPS scores. Both groups have comparable ISS staging and high-risk cytogenetics. Similar numbers of lines of treatment prior to transplant were seen, with approximately 64% having only one line. First-line induction therapy included triplet therapy (Lenalidomide, Bortezomib, and Dexamethasone) in 73% of patients. Depth of remission at transplant was comparable between groups. MRD negativity rates at 10-5 and 10-6 were comparable between MEL140 and MEL200 groups (64% and 39% in MEL140; 61% and 41% in MEL200; p=0.8 and 0.7 respectively). Sustained MRD negativity at 10-5 over at least 12 months was also comparable (43% in MEL140; 50% in MEL200, p=0.8). After a median follow-up of 37 months, PFS was not reached for either group (p=0.69). Patients achieving MRD negativity at levels of 10-5 had a not reached median PFS, while those not achieving MRD negativity had a median PFS of 41 months (95%CI 23-NR; p=0.024). There was no significant difference in hospital stay duration, time to neutrophil engraftment, readmission rate, or infections within 100 days post-transplant between the MEL140 and MEL200 groups. Conclusions: Our real-world analysis demonstrates that MEL140 yields similar deep post-transplant remissions as MEL200, translating to improved PFS for patients achieving MRD negativity, regardless of the dose used. This is the first report to our knowledge of MRD negativity rate in patients receiving MEL140. [Table: see text]
Indirect comparison of linvoseltamab versus teclistamab for triple-class exposed (TCE) relapsed/refractory multiple myeloma (RRMM).
Authors: Jagannath Sundar , Lee Hans C. , Richter Joshua Ryan , Zonder Jeffrey A. , Hoffman James E. , Zhou Zheng-Yi , Horton Viviana Garcia , Fillbrunn Mirko , Wang Hongjue , Mattera Matthew , Ma Qiufei , Inocencio Timothy J , Xu Yingxin , Bergrath Evelien , Harnett James , Roccia Tito , Kroog Glenn Scott , Rodriguez-Lorenc Karen , Houvras Yariv , Bumma Naresh 
Published: June 2024

7560 Background: No head-to-head clinical trials have compared effectiveness of anti-BCMA×CD3 bispecific antibodies for TCE RRMM. This analysis compared efficacy of linvoseltamab vs teclistamab via an unanchored matching-adjusted indirect comparison (MAIC). Methods: A MAIC was deemed feasible after excluding 10 patients (pts) with prior BCMA antibody–drug conjugate exposure from LINKER-MM1 (linvoseltamab) to match MajesTEC-1 (teclistamab) criteria. Pt-level data from LINKER-MM1 (107 pts receiving 200 mg in Phase 1/2, data cut-off [DCO] 9/2023, median follow-up 11.1 months [mos]) and published data from MajesTEC-1’s efficacy population (150 pts, DCO 11/2021, median follow-up 9.8 mos) were analyzed. LINKER-MM1 pts were weighted to match key baseline characteristics in MajesTEC-1 (cytogenetic risk, age, refractory status, ISS stage, ECOG score, extramedullary disease/plasmacytoma status) selected via a prespecified algorithm (Kumar et al., 2023). Objective response rate (ORR), very good partial response or better (≥VGPR), complete response or better (≥CR), and minimal residual disease (MRD) negativity (- [at 10-5 threshold]) rates, duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were compared. Odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (CIs) were reported before and after matching; a sensitivity analysis included all LINKER-MM1 200 mg pts (n=117). Results: Effective sample size for linvoseltamab was 82 after matching and baseline characteristics were balanced with MajesTEC-1. Before and after matching, linvoseltamab exhibited higher ORR, ≥VGPR, ≥CR, and MRD(-) rates, with significant differences in ≥CR. Linvoseltamab had significantly longer PFS and a trend toward longer OS and DOR (Table). Sensitivity analysis results were similar. Conclusions: The results suggest potentially greater efficacy for linvoseltamab vs teclistamab for all outcomes, highlighting its potential as a highly effective treatment option for TCE RRMM. [Table: see text]
Effect of maintenance therapy (MT) on real-world outcomes (RWO) of patients (pts) with newly diagnosed multiple myeloma (NDMM) post stem cell transplant (SCT).
Authors: Parmar Harsh , Barcellos Anna , Biran Noa , Phull Pooja , Vesole David H. , Belli Andrew J. , Fernandes Laura L. , Hansen Eric , Zettler Christina , Wang Ching-Kun , Goran Stefanie , Anderson Courtney , Doucette Kimberley , Gunning Thomas S , Ip Andrew , Siegel David Samuel DiCapua 
Published: June 2024

7562 Background: SCT followed by MT is the standard of care for pts with transplant-eligible (TE) NDMM. Five randomized clinical trials (RCTs) comparing lenalidomide MT versus no MT showed improved progression free survival (PFS), but no overall survival (OS) benefit except for one by McCarthy et al. that allowed pt crossover between treatment arms. Use of MT has also been associated with an increased risk of second primary malignancies and an inferior quality of life. We report RWO post SCT with and without MT in TE NDMM. Methods: We performed a multi-center, retrospective, observational study using the de-identified COTA real-world database derived from the EMRs of US centers. Pts with NDMM from 1/1/2012 to 1/1/23 were included in the study. Kaplan-Meier method was used to evaluate time to next treatment (TTNT), OS, follow-up time (reverse OS endpoint), and report log-rank test p-values. TTNT was defined in two ways: time from SCT to the earliest of initiation of next line of therapy (LOT) or death (TTNT1) and the time from 2nd LOT post-SCT to the earliest of initiation of next LOT or death (TTNT2). A propensity score (PS) matched analysis was used to compare study cohorts and report hazard ratios (HRs) using the Cox proportional hazards method. High risk cytogenetic abnormalities (HRCA) were defined as pts with 17p(-), t(4;14), t(14;16), t(14;20) and 1q+. Results: 1928 ptsmet the study criteria: 957 pts received SCT with MT (M) and 971 pts received no MT (NM). Median age at Dx was 61 y, 57% were male, 70% were White, and 31.2% had HRCA with a median follow-up of 64 months (mos) (95% CI: 61.6, 66.7). In the M vs NM arms, 29.6% and 32.7% pts had HRCA, respectively. Median TTNT1 for M vs NM was 51 vs 36 months (mos), (p<0.001), respectively. Median TTNT2 for M vs NM was 11.7 vs 21.6 mos, (p<0.001), respectively. Median OS for M vs NM was 108.8 mos vs 126.3 mos, (p=0.08), respectively. In the PS model, the NM group had significantly lower hazard of TTNT2 and OS events (HRs 0.65 and 0.85, p<0.001 and p=0.08, respectively). Conclusions: Our study demonstrates improved TTNT2 outcomes with the NM approach. M therapy did not have an impact on OS in this cohort. Both results indicate an absence of long-term benefit with the use of M therapy. OS is a difficult primary outcome to achieve in MM RCTs where survival may have to be collected for decades. Thus, our large study of RWO with long-term follow-up is valuable. [Table: see text]
Genome-wide 5-hydroxymethylation mapping and epigenetic pathways in multiple myeloma.
Authors: Zhang Zhou , Wang Bei , Kowitwanich Krissana , Cui Xiaolong , Bhatti Parveen , He Chuan , Chiu Brian , Zhang Wei 
Published: June 2024

7566 Background: Multiple myeloma (MM), a B-cell neoplasm characterized by bone marrow infiltration of malignant plasma cells, is the second most common blood malignancy, with an estimated number of ~35,000 new patients annually in the United States. The molecular pathogenesis of MM is complex and involves various genetic and epigenetic alterations. Key molecular mechanisms, including chromosomal abnormalities such as translocations involving the immunoglobulin heavy chain locus and various oncogenes (e.g., MMSET, FGFR3, CCND1, MAF), alterations in epigenetic regulators (e.g., EZH2, DNMT3A), dysregulation of cell cycle control, and aberrant activation of signaling pathways (e.g., NF-kB, PI3K/AKT, and JAK/STAT), play critical roles in MM pathogenesis. However, epigenetic pathways implicated in MM has not been comprehensively investigated, partly due to technical limitations that cannot distinguish major cytosine modification types. Methods: Using the 5hmC-Seal, a highly sensitive chemical labeling technique, we profiled genome-wide 5-hydroxymethylcytosines (5hmC) in circulating cell-free DNA (cfDNA) from a population-based case-control study of MM (cases, n = 313; controls, n = 317) conducted in Canada. Results: The 5hmC modification levels were summarized for various genomic features, showing an enrichment in gene bodies and enhancer markers, consistent with the putative role of gene regulation for 5hmC modification. A genome-wide scan of gene bodies identified 771 differential features between cases and controls, adjusting for age, sex, smoking status, education, and first two principal components, at a permutation-based empirical p-value cutoff of 10-4. For instance, IL1RAP, a component of the interleukin-1 signaling cascade, may impact tumor progression and immune system evasion. Furthermore, functional analysis indicated canonical pathways associated with MM pathology and treatment, such as calcium signaling, and synthesis and secretion of cortisol/aldosterone, were enriched in the differential 5hmC features between cases and controls. Notably, the calcium signaling pathway, integral to Ca2+ transport and involved in various physiological and pathological processes, plays a critical role in MM pathogenesis. Within this pathway, the CAMK1D gene, which has been identified as a crucial regulator of tumor-intrinsic immune resistance, showed differential 5hmC level between cases and controls, highlighting a vital connection between epigenetic modifications and immune evasion mechanisms in MM. Conclusions: Leveraging a state-of-the-art technique, we identified novel epigenetic modifications and pathways in the risk of MM. This approach establishes a solid foundation for further investigating etiology of MM, deepening our understanding of the disease, and advancing the discovery of biomarkers, which could potentially guide preventive strategies.
Artificial intelligence-based prediction model of malignant lung nodules for preoperative planning.
Authors: Lu Di , Cai Yupeng , Chen Liuyin , Yuan Xing , Chen Zhiming , Wang Zhizhi , Tong Yu , Cai Kaican 
Published: June 2024

8034 Background: The histopathological prediction of malignant lung nodules is crucial for preoperative planning, but it always remains not precise until the detailed pathological evaluation is performed after the surgery. Thus, to define the histology types (in situ adenocarcinoma (AIS), microinvasive adenocarcinoma (MIA), and invasive adenocarcinoma (IA)) of pulmonary adenocarcinoma appearing as lung nodules before the operation and reduce unnecessary invasive diagnosis and treatment operations, we developed a classification model of based on CT images. Methods: Patients who were diagnosed with pulmonary adenocarcinoma (tumor diameter ≤ 3cm) at Nanfang Hospital, Southern Medical University, China, were retrospectively enrolled, including detailed pathology results, computed tomography (CT) images, and basic information. Through training the model proposed in our previous study, we proposed a new model for defining histopathological types. Then, we used this data to train and compare the diagnostic efficacy of our model with another previously reported deep learning (DL) model (that was a segmentation - classification model with the 3D Unet++ - ResNet-50 combined model) and machine learning (ML) model (that was a traditional model Grey Level Co-occurrence Matrices (GLCM) as the feature extractor and the support vector machine (SVM) as the classifier) in the same method. Results: A total of 2061 patients (with 395 of AIS, 334 of MIA and 1332 of IA) were retrospectively enrolled from January 2019 to April 2022. The data from 2/3 of the patients were randomly selected for training and another 1/3 for verifying. Through training and verifying, our model shows much better diagnostic efficacy, with areas under receiver operating characteristic (ROC) curves with 95% confidence interval (CI) of 0.97(0.96, 0.98), comparing with those of the ML model of 0.77(0.73, 0.81) and the DL model of (0.90(0.88, 0.92). The heatmap visualization of the proposed model shows the classification ability with prediction probabilities of our model clearly and understandably. Conclusions: In this study, we developed a novel artificial intelligence multi-task learning model to precisely predict the pathology type of malignant lung nodules with satisfying diagnostic efficacy, which might provide a new and reliable way for preoperative planning of lung nodules. Further external verifying should be done in the future. In addition, prediction of the growth patterns of pulmonary adenocarcinoma could be more helpful in addition to predicting histopathological types.
Clinicopathologic and molecular landscape of invasive mucinous adenocarcinoma of the lung.
Authors: Kim Hye Sung , Dugan Adam Joseph , Godden Jen , Chao Calvin Y. , Chae Young Kwang 
Published: June 2024

8037 Background: Invasive mucinous adenocarcinoma (IMA), accounting for 2–10% of lung adenocarcinomas, often mimics pneumonia with multicentric opacities in multiple lobes and both lungs. Notable for its microscopic skip lesions leading to tumor spread through air spaces (STAS), IMA is still under-researched in terms of its comprehensive clinical and genetic characteristics in large, multicenter studies. Methods: Primary lung cancer cases were obtained from the Tempus database, categorized into either IMA or non-IMA, and compared by patient, clinical, biopsy, and molecular characteristics. The normalization of RNA-seq data involved computing transcripts per million (TPM), performing log2 transformations, and adjusting for assay and batch effects. Significantly up- and down-regulated genes were defined as false discovery rate q-values < 0.05 and |log2(fold change)| > 0.5. Results: The study analyzed 18,857 cases, with 655 (3.5%) in the IMA group and 18,202 (96.5%) in the non-IMA group. The IMA group predominantly consisted of older individuals (median age 70 vs. 68; p<0.001), had fewer smokers (63% vs. 73%; p<0.001), and included more individuals of Hispanic or Latino ethnicity (4.3% vs. 2.7%; p=0.007). This group was more likely to be diagnosed with early-stage cancer and less likely to have stage 4 cancer at diagnosis (stage 1: 23% vs. 14%, stage 2: 18% vs. 7.3%, stage 3: 23% vs. 17%, stage 4: 36% vs. 62%; p<0.001). They exhibited significantly lower tumor mutational and neoantigen burdens (median 3.1 vs. 4.6 mutations/Mb and 6 vs. 9 neoantigens/Mb, respectively; both p<0.001), fewer positive PD-L1 statuses (27% vs. 58%; p<0.001), and different immune cell infiltration patterns (Table). Gene expression analysis revealed 416 upregulated and 258 downregulated genes in the IMA group compared to the non-IMA group. Conclusions: This analysis underscores the unique clinicopathologic and molecular characteristics of IMAs. An improved understanding of IMA’s biological behavior could lead to the development of more effective, personalized treatment strategies. [Table: see text]
Induction therapy with PD-1 antibody combined with platinum-based doublet chemotherapy for locally-advanced non-small cell lung cancer: A randomised controlled, open-label, phase 2 trial.
Authors: Wang Suyu , Zhang Peng 
Published: June 2024

8044 Background: Chemoradiotherpay plus immunotherapy is recommended for unresectable locally-advanced non-small cell lung cancer (NSCLC) based on PACIFIC trial. However, it is unclear whether surgery can provide survival benefit for patients with tumors initially unresectable transformed into resectable ones after chemoimmunotherapy. This trial aims to investigate the efficacy and safety of the therapeutic regimen of chemoimmunotherapy plus surgery or radiotherapy. Methods: Patients with unresectable stage IIIB-IIIC NSCLC were enrolled to receive 4 cycles (q21d) of PD-1 antibody (Serplulimab, 4.5mg/kg) and platinum-based doublet chemotherapy. After the induction therapy, those with disease downstaged to IIIA or lower stage and resectable were randomized to receive radical surgery or radiotherapy with a ratio of 1:1, and those with stage IIIB or higher stage or unresectable disease after induction therapy were then treated by oncologists. Primary endpoint was event-free survival (EFS). Secondary endpoints included objective response rate (ORR), major pathologic response (MPR), pathologic complete response (pCR), progression-free survival (PFS), disease-free survival (DFS), overall survival (OS), R0 rate of resection, severe adverse event (SAE) rate, and health related quality of life (HRQol). Preliminary short-term results were collected. Results: One hundred patients will be enrolled as planned, and a total of 82 patients were enrolled by the data cutoff date (January 6, 2024). Fifty-four and 28 patients were diagnosed with stage IIIB and IIIC disease, respectively. The percentage of squamous carcinomas, adenocarcinomas, and NSCLCs not otherwise specified were 68.3% (56/82), 15.9% (13/82), and 15.9% (13/82), respectively. ORR in 73 evaluable patients was 74.0% (54/73). Twenty-six of them are still in induction therapy phase, and the other 47 and 9 patients received 4 cycles and 1-3 cycles of induction therapy, respectively. Thirty-one patients had downstaged and resectable disease after 4 cycles of induction therapy, and 26 of them were randomized to arm A (n = 13) and arm B (n = 13), and 5 refused randomization (3 received surgery). One patient received surgery after 2 cycles of induction therapy. In 56 patients finished 1-4 cycles of induction therapy, the rate of conversion to resectability was 57.1% (32/56). In total, 17 patients received surgery, and the MPR and pCR rate in 16 evaluable patients were 62.5% (10/16) and 31.3% (5/16), respectively. The grade 3-5 adverse event rate in 56 patients finished induction therapy was 50.0% (28/56). One patient died of immune-related pneumonia. Conclusions: Induction therapy with PD-1 antibody (Serplulimab) and chemotherapy could transform half of unresectable stage IIIB-IIIC NSCLC into resectable, and the efficacy and safety were satisfactory. Clinical trial information: NCT05766800 .