bluuebunny/crossref_metadata_2025_split huggingface dataset:
Proteasome inhibitor associated cardiovascular adverse events: A real-world claims based study.
Authors: Waxman Adam Justin , Clasen Suparna , Garfall Alfred L. , Carver Joseph R. , Vogl Dan T. , O'quinn Rupal , Cohen Adam D. , Stadtmauer Edward Allen , Hennessy Sean , Ky Bonnie 
Published: March 2020

e19534 Background: Cardiovascular adverse events (CVAE) are common in patients with multiple myeloma (MM). Recent evidence suggests higher rates of CVAE occur among patients receiving carfilzomib (CFZ) compared to other MM therapies. We sought to determine the real-world relative incidence of CVAE in patients receiving CFZ and bortezomib (BTZ). Methods: We conducted a retrospective cohort study using the Optum Clinformatics Datamart. Patients with MM were included if they received BTZ or CFZ from 2012 to 2016. Exposure periods were defined as 90 days following infusion of either drug. Cardiac hospitalizations were identified using validated ICD-9 or ICD-10 code algorithms for heart failure, arrhythmia, myocardial infarction, and hypertensive urgency. Incidence rate ratios (IRR) were calculated using Poisson regression. Results: We identified 922 patients receiving CFZ and 4092 patients receiving BTZ (median age 70 and 72; median treatment duration 99 and 107 days; concurrent immunomodulatory drugs received in 28% and 25%, respectively). Unadjusted CVAE rates are summarized below. A multivariable regression model showed age (IRR 1.43, 95% CI 1.33-1.55) and male gender (IRR 1.22, 95% CI 1.07-1.40) were independent risk factors for CVAE while concurrent IMiD prescription was associated with lower risk (IRR 0.70, 95% CI 0.58-0.85). Adjusted CVAE rates were similar for patients treated with CFZ and BTZ (IRR 1.06, 95% CI 0.89-1.27). Conclusions: We found higher rates of CVAE hospitalizations than described in clinical trials. This may reflect differences in real-world treatment, patient selection patterns, or later identification of CVAE. Further study is need to identify patients at high-risk of CVAE and to develop risk reduction strategies. [Table: see text]
Contemporary therapy efficacy for high-risk multiple myeloma: A systematic review.
Authors: Ashraf Afia , Grewal Udhayvir Singh , Thirunagari Prem , Wahab Ahsan , Majeed Ammara , Hassan Hamza , Lakhani Midhat , Russ Atlantis Dawn , Nunes Cavalcante Parr Nadia C , Anwer Faiz 
Published: March 2020

e19536 Background: Multiple Myeloma (MM) is a heterogeneous disease. High Risk (HR) MM is defined as the presence of abnormal cytogenetics i.e. t(4:14), t(14:16), t(14:20), del(17/17p), non hyperdiploidy and gain (1q). HR MM is a treatment challenge. We aim to explore efficacy of anti-myeloma therapy for newly diagnosed (ND) and relapsed/refractory (RR) HR MM. Methods: We used Pubmed, Ebsco and MBASE to select 18 trials with outcome data on ND (n = 598) and RR(n = 726) HR MM (n = 1321), after extensive review, treatment efficacy (CR, VGPR, ORR) and survival (mPFS, OS) data was extracted. Results: In HR MM the range of overall response rate (ORR) was 31%-100% (Standard Risk (SR): 56%-94.7%), complete response (CR) was 10%-58.3% (SR: 7%-38.1%) and very good partial response (VGPR) was 15%-88.3% (SR: 25%-63%). In ND HR patients, range of ORR was 71.2% - 86.2% (SR: 71.2% - 91.7%) and CR was 35% - 58.3% (SR: 22%-35%) and median progression free survival (mPFS) was 18 months (m) - 31.3m (SR: 31.3m – Not Reached). In RR HR patients, range of ORR was 31% – 85.2% (SR: 56%-94.7%) and CR was 10%-29.2% (SR: 7%-38.1%) and mPFS was 3.3m - 23.1m (SR: 4m - Not Reached). In RR HR MM, Daratumumab ( Dara) , lenalidomide (R) and dexamethasone (d) combination resulted in highest minimal residual disease (MRD) negativity 21.4%. In RR HR, Carfilzomib (Car)- R-d resulted in the longest mPFS of 23.1m (SR: 29.6m) followed by (Dara)-R-d of 22.6m (SR:NR) and Ixazomib (I)- R-d of 21.4m (SR:20.6). In ND HR, Bortezomib (V) with thalidomide (T)- d resulted in longest mPFS of 23.5m (SR: NR) and OS of 56.6m followed by Cyclophosphamide (Cy)-T-d of 20m (SR:34m) and (Dara)-V- Melphalan(M) and Prednisone of 18m (SR:NR). Quadruplet therapy in ND with Cy- V – d with pegylated liposomal doxorubicin resulted in the highest CR 58.3% and mPFS of 31.3m (~8m longer). Conclusions: Cytogenetically HR MM achieved high ORR, CR and VGPR similar to SR MM yet, the PFS and OS in HR (mPFS: 11.2m - 31.3m) was significantly shorter than SR (mPFS: 19m - Not Reached) representing poor prognosis. Promising strategies and targeted therapies that are currently evolving include antibody based combination therapy (3 or 4 drugs), various CAR-T cells constructs, targeted inhibitors, and antibody-drug conjugates.
Association of PD-L1 protein expression and TMB in non-small cell lung cancer.
Authors: Chen Yaru , Zhou Yanqing , Xu Yun , Zhang Xiaoni , Xu Mingyan , Melançon Charles E. , Chen Shifu 
Published: March 2020

e20009 Background: Programmed death-ligand 1 (PD-L1) protein expression and tumor mutation burden (TMB) are considered to be two of the most promising biomarkers for predicting response to PD-1/PD-L1 blockade therapy. To evaluate the association of PD-L1 expression and TMB in non-small cell lung cancer (NSCLC), we designed a study to compare PD-L1 expression levels and TMB values from the same FFPE samples. Methods: 153 NSCLC patients were enrolled between August 2018 and January 2019. An FFPE sample with at least 10 sections was taken from each patient. DNA was extracted from half of the FFPE sections, and was sequenced using a 605 gene panel to 5,000× depth. In silico analysis was conducted to compare the TMB value obtained using this 605-gene panel with that determined using whole exome sequencing (WES). The Pearson rank correlation of TMBs determined using the 605 gene panel versus those using WES was 0.9379, indicating results of the two methods are highly consistent. The other halves of the FFPE sections were used to evaluate PD-L1 expression using immunohistochemical (IHC) techniques. Because WES is considered the gold standard for determining TMB, we re-analyzed WES sequencing data obtained from all 1049 NSCLC patient samples in the TCGA database, and demonstrated that the TMB determined using the 605 gene panel was highly consistent with that obtained using WES. Results: We determined that 22.22% (34/153) of samples had high PD-L1 expression (defined as > 50% of cells being PD-L1 positive), but their TMB values varied from 0.76 to 19.84. The correlation between PD-L1 expression and TMB was only 0.154, indicating that PD-L1 expression had no significant association with TMB. Conclusions: PD-L1 expression and TMB are both important biomarkers for PD-L1 therapy. Many patients were only tested for either PD-L1 expression or TMB due to cost and sample limitations. The results of our study suggest that both PD-L1 and TMB should be examined in NSCLC patients.
Preoperative lymph node assessment in surgically resected pathologic T1 lung cancer patients: Real world clinical practice in China.
Authors: Jinming Xu , Han Xingpeng , Liu Lunxu , Fu Xiangning , Li Yin , Li Xiaofei , Xu Lin , Liu Yang , Zhao Heng , Liu Deruo , Wu Yihe , Cao Jinlin , Yang Haiying , HU Jian 
Published: March 2020

e20016 Background: Accurate lymph node assessment is crucial for clinical patient management and prognostic prediction. However, the procedures may not always be performed preoperatively due to time, cost or risk of procedure itself. Present study aimed to investigate the real world clinical practice of preoperative N staging in surgically resected pathologic T1 lung cancer patients in China. Methods: This is a multicenter retrospective study. Real world data on clinical and pathologic N staging was retrieved from electronic medical records in 10 thoracic surgery centers (LinkDoc Database). Kappa index was calculated to determine the agreement between clinical and pathologic N stage. Results: A total of 11360 patients who underwent surgical resection for pT1 lung cancer were identified during January 2014 to September 2017. Clinical N staging was available for 6057 (53.3%) patients. Of which, 959 (15.8%) patients were achieved by invasive procedures. Considering the 5795 patients with clinical and pathologic N staging data, the overall agreement was 89.0% with a kappa index of 0.4220 (95%CI: 0.3842-0.4598). This was 96.4% for N0, 22.1% for N1 and 39.8% for N2 when considering pathologic N stage as gold standard (Table). In general, upstaging (7.3%) was more common in our population. Conclusions: Over 50% of pathologic T1 patients had preoperative N staging in our clinical practice. Clinical N staging showed low accuracy for predicting lymph node status. The findings of our study highlight the increasing attention on clinical N staging and procedure optimization in China. [Table: see text]
Can steroid imbalance in intracrine synthesis of sex hormones in the lung be a pathognomonic factor of lung cancer?
Authors: Bandovkina Valeria A. , Kit Oleg I. , Frantsiyants Elena M. , Ayrapetova Tamara G. , Legostaev Vladislav M. , Babenkov Oleg M. , Chubaryan Anna V. , Ilchenko Maria G. , Agarkova Elena I. 
Published: March 2020

e20020 Background: Local imbalance of the main sex hormones can be detected in various malignancies. Recent studies confirm possible intracrine synthesis of steroid hormones by different tissues of the body, including the skin and lungs. The purpose of the study was to reveal changes in steroid balance in lung cancer (LC) patients of both genders. Methods: Estradiol (E2), testosterone (T) and progesterone (P4) were measured in 10% homogenates of tumors, perifocal tissues (p/t) and intact tissues of the lung by radioimmunoassay using Immunotech kits (Czech). The Е2/Т and Е2/Р4 coefficients were calculated. The study included 33 men and 22 women diagnosed with central and peripheral LC (adenocarcinoma, Т2-3N0-1M0), mean age 62±3.4 years, all women were menopausal. The comparison group included non-cancer patients (13 men and 12 women) operated on for chronic inflammatory lung diseases. Results: Levels of E2 and T were increased in all studied samples in patients of both genders with central and peripheral LC, while P4 decreased in men and increased in women. It caused an imbalance of the main steroid groups: the E2T ratio in tumors, p/t and in distant tissues of men with central and peripheral LC on average more than 16 times exceeded that in the comparison group, and E2/P4 by 45, 61 and 38 times, respectively. E2/T in tissues of women with central LC was on average 6 times higher, and Е2/Р4 – 9 times higher than in the comparison group. In women with peripheral LC, steroidal imbalance was detected only in tumor samples, and E2/T and E2/P4 were 14 times higher than in the comparison group; samples of p/t and distant lung tissues did not show statistically significant differences. According to statistical data, peripheral adenocarcinomas are more common in women and are clinically characterized by a less aggressive course, compared to central LC. Conclusions: Patients with lung cancer demonstrated a local steroid imbalance with a marked prevalence of estrogens over androgens and progestins.
Ectopic prolactin production by lung cancer cells as an indicator of aggressive nature of tumors.
Authors: Legostaev Vladislav M. , Ayrapetova Tamara G. , Kit Oleg I. , Frantsiyants Elena M. , Bandovkina Valeria A. , Babenkov Oleg M. , Chubaryan Anna V. , Ezhova Maria , Duritskiy Maksim N. 
Published: March 2020

e20021 Background: Cancer cells use many unexpected molecular mechanisms to ensure their malignancy, and a comprehensive understanding of cancer cannot be achieved without a global consideration of all oncogenic events. Ectopic activation of tissue-specific hormones accompanies malignant transformation in many cancers. The aim of the study was to determine prolactin (PRL) levels in the blood, tumor and surrounding lung tissues in lung cancer patients of both sexes. Methods: Levels of PRL were measured in the blood and 10% homogenates of the tumor, perifocal tissues and intact lung tissues by radioimmune method using Immunotech kits (Czech Republic). The study included 33 men and 22 women with central and peripheral lung adenocarcinomas (T2-3N0-1M0), mean age 62±3.4 years, all women were menopausal. The comparison group included non-cancer patients (13 men and 12 women) operated on for chronic inflammatory lung diseases. Results: PRL levels in peripheral blood in 74% of men were increased by 3.7 times, and in 85% of women by 5.7 times. Peripheral cancer in men and women had no significant differences in prolactin levels; the hormone distribution was similar in the tumor, perifocal and intact tissues and was on average 1.5 times higher than in lung tissues in patients with inflammatory processes. Women with central cancer were characterized by higher tumor levels of PRL compared to men. In general, both in men and women, PRL levels in perifocal tissues and in intact lung tissue distant from the tumor focus were similar to tumor levels, which could indicate a general change in the organ metabolism, and not a local hormone synthesis by tumor tissues. Conclusions: The detected increase in the PRL content in lung tissues and in the blood may indicate the dysfunction of central regulatory mechanisms and a change in lung metabolism, being one of the links in the causal mechanisms of tumor development.
Genetic profiling of synchronous multiple primary lung carcinomas presenting as ground-glass opacities.
Authors: Yu Fenglei , Tang Jingqun , Liu Wenliang , Wang Xiang , Chen Chen , Peng Muyun , Yuan Mingming , Zhang Min , Chen Rongrong , Xia Xuefeng 
Published: March 2020

e20034 Background: An increased incidence of synchronous multifocal pulmonary ground-glass opacities (GGOs) has been found in recent decades as a result of the advances in lung cancer screening techniques. However, little was known about the molecular mechanisms of their carcinogenesis, which may have important diagnostic, prognostic and therapeutic implications. Methods: 10 patients (pts) with clinically designated synchronous multiple primary lung cancers (sMPLC) who underwent surgical resection at our hospital were included in this study (Table). The imaging findings of all lesions were GGOs. Mutation profiles were analyzed using hybridization capture based next-generation sequencing (NGS), enabling the simultaneous detection of mutations in 1021 cancer-associated genes. Tumor mutation burden (TMB) was calculated as the number of non-synonymous SNVs and Indels per Mb in the coding region. Results: The genetic profiles of 21 tumor lesions were analyzed. No common mutations were detected between different tumors from 70% of pts (7/10). These pts had different actionable mutations, which indicate disparate even contradictory therapeutic implications. 20% of pts (2/10) shared one driver mutation of EGFR or KRAS. Only one patient had a highly consistent mutation profiles between different GGOs. Two nodules of the patient shared 55% (6/11) of mutations, including EGFR L858R, supporting the possibility of aerogenic metastasis. The median TMB difference between nodules from one individual was 2 muts/Mb. The highest TMB difference was 16 muts/Mb, which might influence the decision of immunotherapy. Conclusions: NGS reveals independent clonality of multiple GGO lesions in most sMPLC pts, which may have contradictory therapeutic implications. In addition, it could be an auxiliary tool to differentiate intrapulmonary metastasis from multiple primary lung cancers. Therefore, broader molecular profiling is strongly advised for sMPLC pts. [Table: see text]
Oncogenic activation of the HRR pathway drives RAD54L expression in early stage lung adenocarcinoma.
Authors: Zheng Shaopeng , Xia Jin , Yu Yunfang , Zeng Fanjun , Huang Luyu , Li Fasheng , Liao Guoqing , Lin Zenan , Zhu Hongyuan , Lanuti Michael , Zhou HaiYu 
Published: March 2020

e20037 Background: In recent years, there has been a better understanding of ways to use DNA damage and repair (DDR) mechanisms to improve overall sensitivity and/or overcome resistance to traditional DNA damage treatments. The DDR network is quite complex and highly dynamic with as many as 450 proteins integral to the DNA repair. The current study is to identify the key dysregulated genes and its related pathways especially DDR pathways in early progression of lung adenocarcinoma. Methods: TCGA dataset of lung adenocarcinoma (LUAD) including 59 healthy lung tissues and 517 tumor tissues was utilized to detect the differentially expressed mRNAs and lncRNAs. Gene ontology (GO) analysis was conducted with DAVID, while Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of differentially expressed genes was performed using gene set enrichment analysis (GSEA) methods. Results: 41 lncRNAs and 2,047 mRNAs were screened out to be differentially expressed in LUAD. Besides, 38 lncRNAs and 1,801 mRNAs were found to be differentially expressed in T1 stage LUAD. The homologous recombination repair (HRR) pathway was found to be significantly up-regulated in LUAD, with four genes in this pathway up-regulated. In these genes of HRR pathway, PPP4R4 and RAD54L were recognized to be significantly differential expressed in T1 stage, compared with T2 stage and T3 stage, which were putative biomarkers of early stage LUAD. The survival analysis revealed that the expression of RAD54L was significantly related to the survival rate of patients with tumor of T1 stage. Conclusions: HRR pathway was up-regulated in lung adenocarcinoma, in which the expression of PPP4R4 and RAD54L were found to be tumor stage specific and RAD54L was related with survival rate of T1 stage patients. This study provided a further insight into the mechanism of the progression in early stage lung adenocarcinoma.
Outcomes following lobectomy and pneumonectomy in stage IIIA non-small cell lung cancer (NSCLC) after neoadjuvant chemoradiation.
Authors: Kommalapati Anuhya , Tella Sri Harsha , Ganti Apar Kishor 
Published: March 2020

e20042 Background: INT 0139 study showed that patients who received surgery after neoadjuvant chemoradiation did not have an overall survival (OS) benefit as compared to chemoradiation alone. Moreover, patients who underwent right sided pneumonectomy had non-significantly worse overall survival than chemoradiation alone. Methods: We sought to compare the survival outcomes in patients who received surgery after neoadjuvant chemoradiation based on the surgery type and the laterality of the disease using National Cancer Data Base (2004-15). Kaplan-Meier estimates were used to compare OS between the groups. Results: A total of 2881 and 499 patients had lobectomy and pneumonectomy after neoadjuvant chemoradiation, respectively. We found no difference in median OS in the patients who had left vs right lobectomy (Table). However, 30-, 90-day morality was higher in right lobectomy patients (p = 0.03). Similar trend was seen in the 30-, 90-day mortality and median OS in right and left pneumonectomies (Table). Total number of patients that got right pneumonectomy after neo-adjuvant chemoradiation before and after INT 0139 study (2009) did not change (49% vs 45%, p = 0.33). Conclusions: The short-term mortality was higher in right sided stage IIIA NSCLC patients in our cohort who received surgery irrespective of type of surgery. Interestingly, we did not notice any decrease in pneumonectomy rates since 2009. [Table: see text]
Evaluating the prognostic significance of significant weight loss in patients with stage III non-small cell lung cancer (NSCLC) undergoing definitive chemoradiation (CRT) after FDG-PET staging.
Authors: Senko Clare , Moore Julie , Hay Karen , Lwin Zarnie , Pratt Gary , Fong Kwun , Hughes Brett Gordon Maxwell 
Published: March 2020

e20045 Background: In the pre-PET era, weight loss is a harbinger of occult metastatic disease in patients with stage III NSCLC. Identifying the relationship between weight loss and pattern of relapse (POR), may enable stratification of patients into prognostic groups associated with increased risk of relapse. We sought to identify if weight loss remains a negative independent prognostic factor after FDG-PET staging. Methods: A retrospective audit (using web-based and electronic databases) was conducted in all patients with stage III NSCLC treated with definitive CRT between 01/07/2013 and 30/06/2018 at the Royal Brisbane and Women’s Hospital and The Prince Charles Hospital, Queensland, Australia. A descriptive analysis was applied to describe the primary end-point of PFS and secondary end-points of OS and POR, in relation to the percentage of pre-treatment weight loss (0-10% vs > 10-20% vs > 20%). A subset analysis looked at other prognostic factors identified in NSCLC to account for potential confounders. Results: Of the 127 patients (mean age 65 years, mean weight 76kg, 57% male, 42% current smokers) who commenced treatment during the study period, 24% lost > 10% and 3% lost > 20% weight. Median TTP for the entire cohort was 9 months. Based on multivariable modelling, risk of PD or death was 45% higher with > 10% loss of body weight (p = 0.004), and risk of death was 36% higher with > 10% of body weight (p = 0.05). Of the 54% that died during follow-up, 31 had distant PD, 18 had locoregional PD, 6 had local PD, and 10 had no PD. Males were at increased risk of PD. Conclusions: A prognostic link continues to be identified between significant (> 10%) weight loss and risk of progressive disease or death in stage III NSCLC treated with definitive CRT despite pre-treatment FDG-PET. These findings identify a sub-group of patients where weight loss could still be a surrogate for micro-metastases not detected on PET, or other adverse prognostic markers. Other treatment strategies or improved diagnostic strategies are warranted.
The combined treatment of 150 kHz tumor treating fields (TTFields) and cisplatin or pemetrexed inhibits mesothelioma cells in vitro and in vivo.
Authors: Weinberg Uri , Munster Mijal , Gotlib Karnit , Schneiderman Rosa S. , Porat Yaara , Voloshin Tali , Davidi Shiri , Shteingauz Anna , Kaynan Noa , Zeevi Einav , Giladi Moshe , Kirson Eilon David , Kinzel Adrian , Palti Yoram 
Published: March 2020

e20069 Background: Malignant pleural mesothelioma (MPM) is an aggressive thoracic cancer mostly linked to asbestos exposure. The standard of care (SOC) therapy for unresectable MPM is cisplatin plus pemetrexed. Treating Fields (TTFields) therapy is an effective anti-neoplastic treatment modality delivered via noninvasive application of low intensity, intermediate frequency, alternating electric fields. We explored the potential use of TTFields alone and in combination with SOC as a treatment for MPM. Methods: NCI-H2052 and MSTO-211H cells were treated at various TTFields frequencies for 72 hours using the inovitro system. The combined treatment of TTFields and cisplatin or pemetrexed was tested by applying TTFields at the optimal frequency together with various drug concentrations. Cell counts, clonogenic potential and induction of apoptosis were determined. TTFields (1.2 V/cm) were applied for 8 days to rats injected to the intrapleural cavity with IL-45 cells, and overall survival was tested. Results: TTFields optimal frequency was 150 kHz for both human cell lines. TTFields application (1.1 V/cm, 72 hours) at 150 kHz led to 45%-51% reduction in cell counts and 46-64%% additional reduction in clonogenic potential. The combined treatment of TTFields and cisplatin or pemetrexed led to a significant reduction in cell count, induction of apoptosis and reduced clonogenic potential as compared to each modality alone (p < 0.0001(. TTFields significantly prolonged the survival of rats compared to control group. Safety studies did not reveal any adverse events associated with 150 kHz TTFields application to the rat torso. Conclusions: These results demonstrate that TTFields can be an effective treatment against mesothelioma and the combination with cisplatin or pemetrexed may further enhance treatment efficacy. These results are in consistency with the recent phase 2 study (EF-23 trial) that showed improved overall survival for combined treatment as compared to historical control with no increase in systemic toxicity.