bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bortezomib-induced cardiotoxicity: Real-world data from a single-center.
Authors: Chennapragada Suma Sri , Ananthaneni Anil , Sharma Shivani , Devarashetty Sindhu Priya , Shi Runhua , Ramadas Poornima 
Published: June 2023

e20008 Background: Bortezomib (Velcade) has emerged as the leading component of first-line therapies in both standard and high-risk multiple myeloma since the SWOGS0777 results were published in 2016. Although the incidence of cardiac side effects is reported to be lower with bortezomib compared to carfilzomib, standardized protocols for cardiac toxicity monitoring are unavailable. Currently, reported rates of cardiomyopathy with Velcade use range between 1-5%. We aim to examine bortezomib related cardiac adverse events and their association with demographics and traditional risk factors, especially in the setting of an ethnically diverse population that our hospital serves. Methods: Our institutional retrospective study extended between 01/2015 - 12/2020 and included patients aged > 18 years who received Velcade for myeloma and excluded prisoners, pregnant women. Our primary objective was to investigate the incidence of Velcade-induced cardiomyopathy, arrythmias and coronary artery disease (CAD) as dependent variables. Independent variables included demographics, prior personal/family history of heart disease, comorbid conditions such as hypertension/diabetes/obesity/hyperlipidemia/smoking/atrial fibrillation/chronic kidney disease, myeloma subtype and RISS staging. Descriptive statistics were used to report frequencies and percentages. Fisher’s exact tests were used to report associations between dependent and independent variables. Results: This study included a total of 64 patients. Majority were males (58%), African Americans (79%), and had a mean age of 62 years. Free light chain and IgG kappa were the most common types of myeloma (73%). Mean dose of velcade and dexamethasone received was 52.4 mg/m2 and 834 mg respectively, over a mean duration of 26.14 weeks. Personal and family history of cardiovascular disease was reported in 39% and 23% patients respectively. A new diagnosis of cardiomyopathy was made in 14% of the patients. No new arrythmias or CAD were seen after Velcade use. In the unadjusted model, incidence of new cardiomyopathy was statistically significant in patients with personal (p = 0.043) and family history (p = 0.022) of cardiovascular disease. No other statistically significant associations were found with other independent variables, including dose or duration of velcade/steroid use. Multi-variate analysis is not reported due to low sample size. Conclusions: Our institution treats a diverse population with a higher multi-morbidity burden as opposed to physically and medically fit population recruited into clinical trials. This gives us an opportunity to bring forward some real world data. Given the higher incidence of cardiac toxicity in our study as opposed to current available data, we propose that high-risk patients with personal or family history of cardiovascular disease could benefit from closer monitoring during the course of their treatment with Velcade.
Outcomes of patients with multiple myeloma refractory to different administration schedules of bortezomib.
Authors: Goel Utkarsh , Charalampous Charalampos , Kapoor Prashant , Binder Moritz , Buadi Francis , Dingli David , Dispenzieri Angela , Fonder Amie L. , Gertz Morie A. , Gonsalves Wilson I. , Hayman Suzanne R. , Hobbs Miriam A. , Hwa Yi Lisa , Kourelis Taxiarchis , Lacy Martha , Leung Nelson , Lin Yi , Warsame Rahma M. , Rajkumar S. Vincent , Kumar Shaji 
Published: June 2023

e20011 Background: Drug refractoriness is an important factor determining choice of next therapy and prognosis in multiple myeloma (MM). It is debatable whether refractoriness to a drug varies among patients (pts) with MM progressing on different administration schedules of the drug. Outcomes of MM pts refractory to different doses of lenalidomide have been previously described, but similar data about proteasome inhibitors (PIs) are limited. In this study, we assessed the impact of refractoriness to different schedules of bortezomib (V) on outcomes with subsequent therapies in MM pts. Methods: We retrospectively reviewed MM pts at our center diagnosed between January 2004 and December 2018, who progressed on/ after receiving first line therapy with V containing regimens. At first relapse, we divided pts into 3 groups- MM progressing on or within 60 days of receiving (1) 1-1.3 mg/m2 V once weekly or more frequently (Standard Dose Refractory), (2) 1-1.3 mg/m2 V once every 2 weeks or less frequently (Low Dose Refractory), and (3) MM progressing at least 60 days after stopping V (Not Refractory). In addition to V, we classified pts as being refractory to cyclophosphamide and immunomodulatory drugs (IMiDs) at first relapse. We classified salvage regimens into daratumumab (Dara), PI, IMiD, PI+IMiD, and VDTPACE like regimens. We then assessed progression free survival (PFS) and overall survival (OS) for next line therapy, and for next V containing therapy using Kaplan Meier and Cox models. Results: A total of 302 pts were included. Median age at diagnosis was 62 years and 60% pts were male. Overall, 23%, 31%, and 27% were International Staging System (ISS) stage I, II, and III respectively; 40% had high risk FISH as per mSMART. Of the 302 pts, 134 (44%) pts received another V containing regimen after the first line therapy at any time during the disease course. Using a multivariable Cox model to adjust for ISS, high risk FISH, refractoriness to other drugs, duration of first line therapy, and treatment received at relapse, the Not Refractory Group had a better PFS for both 2nd line therapy and the next V containing line of therapy, while no significant differences were seen between the Standard Dose Refractory and Low Dose Refractory groups. OS differences followed the same trend but were not statistically significant (Table). Conclusions: On multivariable analysis, the PFS did not differ among standard dose vs low dose refractory pts, and both were significantly inferior to pts not refractory to V. These data suggest that refractoriness to V might not be a dose dependent phenomenon. [Table: see text]
Longitudinal changes in echocardiographic variables and endothelial function to predict cardiovascular toxicities in patients with multiple myeloma receiving carfilzomib.
Authors: Johnston Hannah , Prabhu Nicole , Cunningham Claire , Cooperrider Jennifer H. , Andreatos Evangelia , Gorski Martha , Major Sarah , Wolfe Brittany , Kruse Eric , Derman Benjamin Avi , Lang Roberto , Jakubowiak Andrzej , Major Ajay , DeCara Jeanne 
Published: June 2023

e20012 Background: Carfilzomib (CFZ) is a second-generation proteasome inhibitor with activity in multiple myeloma (MM) that is associated with cardiotoxicity and dyspnea. The pathophysiology and risk factors for developing these toxicities are not well described. We are conducting a prospective observational study (NCT04827563) of longitudinal changes in cardiovascular and endothelial function among MM patients receiving CFZ. We hypothesize that baseline and longitudinal variations in cardiovascular and endothelial function correlate with development of cardiotoxicity and dyspnea in MM patients receiving CFZ. Methods: Patients with MM receiving first-time CFZ therapy are prospectively enrolled and undergo the following study procedures prior to CFZ initiation and then every 2 weeks for the first 6 weeks of CFZ therapy (C1D1, C1D15, C2D1, C2D15): 24-hour ambulatory blood pressure monitoring, echocardiography, pulse wave velocity, and EndoPAT endothelial function assessment. Patient-reported outcomes are also collected. Cardiovascular adverse events (CVAEs) and dyspnea are assessed at all timepoints, as well as at 3 and 6 months after enrollment, by CTCAE v5.0 and are adjudicated by a cardio-oncologist. Patients with endothelial dysfunction will be defined as reactive hyperemia index (RHI) <1.67 via EndoPAT. Baseline variables were analyzed with unpaired t-tests and longitudinal variables were analyzed by one-way repeated measures ANOVA. Results: Ten patients have completed 6 months of follow-up. Demographic data is summarized in the table. Four patients (40%) developed dyspnea, 2 with grade 1 and 2 with grade 3 at maximum, with most patients developing dyspnea by C1D15. Two patients had ongoing grade 1 dyspnea at follow-up. Four patients (40%) developed grade 3 or higher CVAEs, most of which were grade 3 hypertension and/or grade 3 HFpEF. Baseline left ventricular mass was significantly higher in patients who developed dyspnea compared to those who did not (p=0.040). EndoPAT values were significantly different between C1D1 and C1D15 in those with CVAEs (2.28 vs 1.74, p=0.0223). NTproBNP values were also significantly different between C1D1 and C1D15 in those with dyspnea (74.5 vs 129.3, p=0.006). Conclusions: MM patients that developed dyspnea during treatment with CFZ had a higher baseline LV mass and were more likely to develop increases in NTproBNP despite preserved ejection fraction, consistent with HFpEF. This group also had a greater change in EndoPAT values suggesting that short-term alterations in endothelial function may have a role in the development of dyspnea in those who may have the anatomic substrate for HFpEF. Clinical trial information: NCT04827563 . [Table: see text]
Management and outcomes of advanced stage cardiac AL amyloidosis in the daratumumab era.
Authors: Feuvrier-Rivera Ariana , Kumar Anupama Deepa , Urey Marcus Anthony , Costello Caitlin 
Published: June 2023

e20058 Background: AL amyloidosis is plasma cell disorder involving irreversible deposition of amyloid fibrils, leading to end-organ damage. Treatment strategies include systemic therapy, autologous stem cell transplant (ASCT), and organ transplant. The ANDROMEDA trial established daratumumab (Dara) in combination with cyclophosphamide, bortezomib (Bor), and dexamethasone (CyBorD) as a new standard of care in newly diagnosed AL amyloidosis. Notably, only 2% of the trial population had stage IIIB cardiac disease by Mayo 2004 criteria. We present real world data of orthotopic heart transplantation (OHT) recipients with AL amyloidosis at our institution to understand the safety and outcomes of Dara use in the setting of advanced cardiac involvement. Methods: We performed a retrospective review of 9 patients at our institution who had received OHT since 2019 for AL amyloidosis. Demographics, disease details, treatment selection, response, and outcomes data were collected and described. Results: The cohort included 22% Black and 22% Hispanic patients, and the median age at diagnosis was 56. All patients had Revised Mayo stage 3 or 4 disease with advanced cardiac involvement requiring OHT. Patients had a median of 3 (2-4) suspected organs involved; none had symptomatic myeloma. Four patients received induction CyBorD; 2 achieved complete response (CR), 1 very good partial response (VGPR), and 1 partial response (PR) prior to OHT. Three of 4 received bridging therapy (Dara-Bor triplet or Bor alone) prior to ASCT, 2 due to inadequate response and 1 to maintain CR, and all achieved CR post-ASCT. Median time from OHT to ASCT was 13.5 months (range: 8-17), with bridging therapy starting at a median of 6 months post-OHT if received, with concomitant reduction in OHT immunosuppression. Five patients received DaraCyBorD induction: 2 achieved CR, 2 achieved VGPR, and 1 achieved PR prior to OHT. No patient who received DaraCyBorD received ASCT. Those not in CR received further therapy post-OHT. At the time of this analysis, 89% of patients remain in CR with 2 receiving ongoing therapy. All patients are alive with a median follow-up of 22 months (range: 11-35) since OHT without evidence for organ rejection. Conclusions: We demonstrate that the use of subcutaneous Dara is tolerable and effective in advanced stage cardiac AL amyloidosis, an underrepresented group in the literature. Patients who received DaraCyBorD followed by OHT without ASCT achieved similar outcomes to those who received CyBorD, OHT, and ASCT. The routine use of Dara may therefore negate the need for ASCT in this setting, given its favorable toxicity profile and reduced cost. [Table: see text]
Risk of MGUS, a multiple myeloma precursor, in relation to food and beverage intake in the National Health and Nutrition Examination Survey (NHANES).
Authors: Joseph Janine , Tang Li , Hillengass Jens , Landgren Ola , Usmani Saad Zafar , Lesokhin Alexander M. , Moysich Kirsten B. , Shah Urvi A 
Published: June 2023

e20062 Background: Monoclonal gammopathy of undetermined significance (MGUS) is a plasma cell disorder (PCD) with a prevalence of 3% in adults over age 50. The annual risk of progression to multiple myeloma (MM) is 1%. Although one cohort study in Caucasians reported that diets low in certain plant-based foods were associated with MGUS (Thordardottir et al. 2018), research on diet and MGUS in a more diverse population is scarce. Given that diet can vary greatly across ethnic/racial groups, we conducted a population-based study with multiple races and ethnicities. Methods: Using the National Health and Nutrition Examination Survey (NHANES), we conducted a case-control study in 373 individuals with MGUS and 1,406 controls frequency matched on age, body mass index, NHANES cycle, sex, and race. Diet was characterized by one 24-hour dietary recall, with gram intake of individual foods and beverages aggregated into groups. MGUS status was determined by blood screening. Unconditional multivariable logistic regressions were used to model associations between MGUS and intake, with odds ratios and 95% confidence intervals reported for the highest quantile of intake. Results: Daily intake of several food and beverage groups were significantly associated with MGUS, low-risk MGUS (LRMGUS) or intermediate/high-risk MGUS (IHRMGUS). Whole-grain bread, oats, and rice; fruits and vegetables; tomatoes; and cruciferous vegetables were associated with significantly lower risk (28-78%). Sugar- and artificially sweetened beverages were associated with significantly higher risk (34-113%). Interestingly, there were more significant findings for LRMGUS than IHRMGUS, suggesting potential contributing etiologic differences for LRMGUS and IHRMGUS. Conclusions: Our study shows that low intake of whole grains, fruits and vegetables and high intake of sweetened beverages are associated with MGUS. The identification of dietary risk factors for MGUS in a diverse population is of direct public health relevance. These findings also provide rationale for exploration of mechanistic links between diet and PCDs, such as the ongoing studies NCT04920084, NCT05640843, and NCT05312255. [Table: see text]
FGR methylation in blood as a potential marker for the pre-clinical detection of early lung cancer: A case-control study.
Authors: Yang Rongxi , Zhang Wenjing , Zhu Qiang , Song Yakang , Song Huapeng , Zhou Xiajie 
Published: June 2023

e20500 Background: Lung cancer (LC) is the leading cause of cancer-related death. Although low-dose computed tomography (LDCT) is a routine clinical test for early detection of LC, it can introduce excessive false positives. DNA specific methylation identification in peripheral blood can be used for noninvasive diagnosis and monitoring. Therefore, We applied a candidate approach and assess the association between blood-based FGR methylation and the risk of lung cancer in a case–control cohort. Methods: A total of 426 patients with LC and 428 age-and sex-matched healthy controls were recruited from two hospitals to collect peripheral blood and clinical information. The methylation levels of four CPG sites in FGR gene were determined by quantitative mass spectrometry. Linear regression models were used to estimate the association between DNA methylation site levels and lung cancer. And stratified analysis of age and sex. Results: It was found that the hypermethylation of FGR_CPG1 and FGR_CPG2 was associated with early LC (OR = 1.60 (95%CI: 1.35, 1.89, p = 5.35E-08) and 1.08 (95%CI: 1.01, 1.16, p = 3.58E-02), respectively). These associations persist in patients with very early LC (stage I). Stratified analysis showed that the association between hypermethylation of FGR_CPG2 and LC was only found in men and subjects younger than 55 years of age. Conclusions: This work reveals a novel association between aberrant FGR gene methylation in blood and early LC. These results suggest that FGR gene methylation may be used to predict early lung cancer and provide guidance for the prevention and control of lung cancer.
Computational recognition of lncRNA signature of tumor-infiltrating activated CD4+ memory T cells with potential implications in prognosis and immunotherapy of lung adenocarcinoma.
Authors: Liu Shengbo , Li Qiaxuan , You Peimeng , Qiu Hongrui , Zhou HaiYu 
Published: June 2023

e20519 Background: CD4 memory T cells are an important components of the tumour microenvironment and influence tumourigenesis and progression. However, it has not been determined whether lncRNAs in lung adenocarcinoma (LUAD) play a role in activated CD4+ memory T cells (CD4amT). Methods: The LUAD dataset acquired by The Cancer Genome Atlas was used as a training cohort (TCGA-LUAD). For the validation cohort, we used the combination of lung adenocarcinoma datasets from GENE EXPRESSION OMNIBUS database acquired 2 LUAD datasets, and set as the validation cohort (GEO-LUAD). Lung cancer immunotherapy cohorts have been published to test immune responses. The CIBERSORT algorithm was used to assess immune cell infiltration of tumours. Univariate Cox analysis was used to screen for prognostic CD4amT-related lncRNAs (CD4amTRL). LASSO analysis and multivariate Cox analysis were then performed to construct model for prognostic lncRNAs, the effects of which were assessed by Kaplan-Meier curves and subject operating characteristics (ROC). Patients were divided into high and low risk groups based on CD4amTRL signature. We have analyzed differences in enrichment pathways between the two groups and subsequently we investigated genes associated with the cancer-immune process, the immune microenvironment, immunotherapy responses and multiple anti-cancer drug sensitivity correlations. Results: In the two LUAD cohorts, compared with the high infiltration of CD4amT, those in the low infiltration group had better OS benefits (TCGA-LUAD: HR = 0.678; P = 0.028; GEO-LUAD: HR = 0.435; P < 0.0001). We identified 6 prognostic CD4amTRL and constructed prediction models. cd4 CD4amTRL signature distinguished significantly different OS between the high-risk and low-risk groups of TCGA-LUAD (HR = 4.26). The AUCs predicting 1-, 3- and 5-year survival were 0.737, 0.715 and 0.722, respectively. In the GEO-LUAD dataset, the HR was 2.03, while the AUCs predicting 1-, 3- and 5-year survival were 0.719, 0.681 and 0.630, respectively. The risk score model independently predicted OS in LUAD patients and was associated with immune checkpoints. Numerous genes related to the cancer-immune process were highly correlated. In addition, the risk model was significantly associated with multiple immune microenvironment features (p < 0.001). OS was significantly different between the two immunotherapy cohorts in the high- and low-risk groups for CD4amTRL signature (P < 0.001). Conclusions: Our novel risk model developed based on CD4amTRL signatures can aid in predicting clinical prognosis and guiding treatment in patients with LUAD.
Effects of concomitant chronic obstructive pulmonary disease on immune microenvironment in non-small cell lung cancer patients.
Authors: Lin Lin , Chen Rui , Lin Xiaoling , Zhuan Sunyongxun , Li Jianguo , Hu Xue 
Published: June 2023

e20522 Background: Chronic obstructive pulmonary disease (COPD) as a progressive deterioration of lung function, has caused significant morbidity and mortality, especially in developing countries. Persistent lung inflammation and potential lung stroma remodeling in COPD may be important causes of lung cancer. Previous studies have shown that non-small cell lung cancer (NSCLC) patients with COPD have a worse prognosis than those without, but the reasons have not been determined. Due to the increasing application of ICIs in the NSCLC, the characteristics of the immune microenvironment in the NSCLC patients concomitant COPD are worth exploring. Methods: Immune microenvironment and the next generation sequencing (NGS) data of twenty NSCLC patients from Sun Yat-sen Memorial Hospital were analyzed. Formalin-fixed paraffin-embedded biopsy tissue before first-line treatment to prepare tumor tissue slides. Samples were stained using an Opal automation mIF Detection Kit (Akoya) for immune cells. The immune cell infiltration were reported as percentages and density from each individual cell subpopulation in the tumor or stromal area. The landscape of gene mutantions was obtained by NGS detection of 733-gene panel, sequencing depth was 35000x. Results: There were 8 (40%) patients concomitant COPD, and the median age was 65.5-year-old. Analysis the immune cell infiltration in all patients, including T cells, B cells, macrophages and NK cells through 13 markers, showed no difference between COPD and non-COPD groups. However, comparing the differences between tumor and stromal immune microenvironment, it was found that there was a significant difference in the percentages of M1 macrophages between tumor and stromal in COPD group (P = 0.031), but no difference in non-COPD group (P = 0.47). Further analysis of the difference in cell density between tumor and stroma showed that the stromal M1 macrophages in the COPD group was significantly higher than that in the non-COPD group (P = 0.017), as well as PD-1+CD8+ T cells (P = 0.05). Additionally, a preliminary analysis of the gene mutation characteristics had done. In COPD patients with somatic mutations, the most frequently mutated gene was EGFR (60%), followed by TP53 (50%) and GLI2 (50%), which were similar as non-COPD patients. The most common variant of COPD patients are the missense mutation of EGFR L858R, but it was EGFR 19del in non-COPD. Conclusions: The results showed that the COPD was correlated with the infiltration status of M1 macrophages and PD-1+CD8+ T cell, and poor immune cell infiltration in tumor of COPD patients may be the potential influencing factors for the worse prognosis. The characteristics of immune microenvironment suggest that promoting the entry of immune cells from stroma into tumor may be a potential mechanism for the benefit of immunotherapy in NSCLC patients with COPD.