bluuebunny/crossref_metadata_2025 huggingface dataset:
Pretransplant hemoglobin and serum creatinine levels correlate with progression free survival in myeloma patients undergoing autologous stem cell transplantation.
Authors: Demirer Taner , Cengiz Seval Guldane , Toprak Selami Kocak , Civriz Bozdag Sinem , Yuksel Meltem Kurt , Topcuoglu Pervin , Arslan Onder , Ozcan Muhit , Akan Hamdi , Ilhan Osman , Beksac Meral , Gurman Gunhan
Published: March 2020

e19532

Background: High dose melphalan and autologous stem cell transplantation (ASCT) significantly prolong survival for patients with multiple myeloma (MM). The purpose of this study is to assess the effects of hemoglobin (Hgb) and serum creatinine (Crea) values at the time of transplantation on the overall outcome of patients with multiple myeloma treated at our transplant center. Material & Methods: This analysis included 247 consecutive patients who underwent ASCT for MM between 2010-2016. Hemoglobin was grouped as low or high relative to their sample median. Patients were also stratified according to serum Crea value at the time of transplantation ( < 2 or ³2 mg/dl). Results: The median age was 57 (29-75) years and most patients were male (n = 151, 61.1%), IgG subtype (n = 124, 50.2%), and ISS stage 3 (n = 122, 49.4%). The interval from the time of diagnosis to ASCT was median 7 months and median follow-up from ASCT was 49 months (range, 3-198 months). The most commonly induction regimens included VAD (vincristine, doxorubicin and dexamethasone) and VCD (bortezomib, cyclophosphamide, dexamethasone), respectively. Since maintenance was not an approved treatment in myeloma most patients did not receive any. For the entire cohort, the median Hgb and Crea were 11.5 g/dL and 0.9 mg/dL respectively. No difference in progression free survival (PFS) was observed between a lower and higher Hgb (82 vs. 81 months, p = 0.96). However, the median PFS was significantly longer in patients with a lower Crea compared to those with a higher Crea (83 vs. 48 months, p = 0.01). Patients with both a lower hemoglobin and higher Crea experienced shorter PFS compared to those with a higher hemoglobin and lower Crea (45 vs. 82 months, p < 0.001). We failed to demonstrate the impact of creatinin levels on time to neutrophil and platelet engraftment. There were no differences in OS according to lower vs. higher Hgb (58 vs. 52 months; p = 0.29, respectively) but in higher crea cohort worse OS was observed (41 months vs. 57 months; p = 0.02, respectively). Conclusions: We demonstrate that hemoglobin and creatinine represent important determinants of clinical outcomes after ASCT. A lower hemoglobin and higher creatinine, individually and when combined, were associated with shorter PFS. Therefore, further studies of larger randomized cohorts are required to clarify the impact of pre-transplant Hgb and Crea levels on ASCT outcomes.
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.
Immune gene signatures and integrative spatially-resolved digital profiling of prognostic biomarkers for mesothelioma.
Authors: Church Sarah Elizabeth , Ballesteros-Merino Carmen , Sullivan Amy H , White Andrew M , Bailey Michael D , Jensen Shawn M , Handy John R , Sanborn Rachel E. , Bifulco Carlo Bruno , Warren Sarah , Beechem Joseph M , Fox Bernard A.
Published: March 2020

e20071

Background: Malignant mesothelioma has been an incurable disease with few effective therapies. While PD-1 targeted therapies have elicited some patient responses, the overall response rate for mesothelioma is low. Since mesothelioma is derived from the mesothelium of the lung, we hypothesize that immune cells in the tumor microenvironment (TME) may behave differently than other solid tumors that are responsive to immunotherapy. Here we characterize prognostic immune gene signatures and spatial protein expression in the mesothelioma TME. Methods: 50 FFPE mesothelioma samples were analyzed using the NanoString PanCancer IO360 assay which measures expression of 770 genes, including the abundance of 14 immune cell types and of 32 IO signatures. All genes and signatures were correlated with overall survival (OS). GeoMx digital spatial profiling (DSP) was performed on 40 samples assessing the protein expression along 12 geometric circular regions-of-interest (ROI). Tissue slides were stained with a combination of fluorescent-labeled antibodies (pan-cytokeratin, CD3, CD68) and a panel of 38-antibodies each conjugated to a unique UV-photocleavable DNA barcode. UV light was applied to the defined ROI, which releases the DNA barcodes for quantitation on the nCounter platform. Results: Unsupervised clustering of samples based on gene signatures showed two distinct groups; one, with low expression of lymphocyte activation/exhaustion signatures and the second, with moderate expression of immune signatures. Two samples had high expression of all immune gene signatures, also confirmed by DSP had increased expression of T cell markers. Tumor proliferation (p < 0.001), hypoxia (p = 0.04), glycolysis (p < 0.001), B7-H3 (p = 0.007) and TGF-β (p = 0.001) signatures were significantly associated with shorter OS. Additional DSP profiling of these mesothelioma samples showed both T cell excluded and desert TMEs. Conclusions: We show that the mesothelioma TME has distinct immune biology associated with OS. Tumors from patients with poor survival had expression profiles previously described to be associated with immune excluded and desert phenotypes. We show that gene expression and DSP identifies unique targets for immunotherapy and we hypothesize that these findings may guide the development of combination trials that will be effective against mesothelioma.
Oral vinorelbine as a second-line chemotherapy option in advanced malignant pleural mesothelioma.
Authors: Trejo Rosales Raul Rogelio , Nuñez Cerrillo Jose Gustavo , Silva Godinez Juan Carlos , Riera Sala Rodrigo Fernando , Peña Campos Maritza
Published: March 2020

e20073

Background: Malignant pleural mesothelioma (MPM) is an infrequent entity with a poor prognosis. Standard first line chemotherapy therapy is based on pemetrexed and cisplatin, however, there is no established standard second-line therapy. We report our experience with patients treated at a third-level referral center in Mexico, making emphasis in the use of oral vinorelbine. Methods: We conducted a retrospective cohort study of MPM patients treated between 2012 and 2018 at the Centro Médico Nacional Siglo XXI, a third-level referral center in Mexico City. Our objective was to evaluate the effectiveness of different second-line chemotherapy schemes in MPM patients. Results: A total of 143 patients were included. There were 47 women (32.8%) and 96 men (67.1%). Median age was 64 (range 39 - 86). The histological subtypes comprised of 73.4 % epitheloid, 9 % with a sarcomatoid component and 17.4% not otherwise specified. The majority of patients presented with advanced disease 32.1 stage III and 63.6 stage IV. 72% of patients had performance status 0-1, however 9.7% of patients had performance status 3-4 at diagnosis, and received only palliative care as treatment. A total of 125 patients received first-line chemotherapy, and 40 patients underwent second-line therapy. Usual schemes were based on pemetrexed, paclitaxel, gemcitabine and oral vinolrebine. Overall, partial response rate was 5% and stable disease was 35%. There were no statistical differences in response rates between schemes (p = 0.75). The most usual second-line scheme was oral vinolrebine. Progression-free survival was 4 months in vinolrebine-treated patients vs 2 months (HR 1.04, 95% CI 0.86 – 1.25, p = 0.63) as compared with patients treated with other schemes. Conclusions: Our results are comparable with similar series in the second-line scenario. Oral-vinolrebine treatment progression-free survival was similar to other, more toxic drugs. However, we included few patients. More work is needed to identify the characteristics of benefitting patients.
Timing of chemotherapy in small cell lung cancer: A National Cancer Database analysis.
Authors: Bhandari Shruti , Pham Danh , Kumar Rohit , Gaskins Jeremy T , Kloecker Goetz H.
Published: March 2020

e20076

Background: Small cell lung cancer (SCLC) is an aggressive disease currently treated as soon as possible given its rapid doubling time. Evidence for appropriate timing of chemotherapy from diagnosis (TCD) for SCLC is lacking. This study evaluates TCD in SCLC on a national level. Methods: National Cancer Database identified SCLC patients treated with chemotherapy from 2010 - 2014. Factors associated with TCD were identified with multiple linear regression analyses. TCD was categorized into four groups using cutoff points of 7, 14, and 28 days. Using these categories, median overall survival (MOS) and log-rank test was used for univariate analysis of the survival outcome and the Cox model for multivariate analysis. Results: Among the 64491 SCLC, 42% received chemotherapy alone, 38% chemotherapy followed by radiation and 20% radiation followed by chemotherapy. Median TCD is 14 days with 21% treated within 7d, 21% 8-14d, 30% 15-28d and 28% > 28d from diagnosis. Age, race, insurance, comorbidities and stage were associated with TCD (Table). Significant difference in survival was found by TCD categories (P < .001). MOS for TCD within 7d was 8.2m, 8-14d was 9.2m, 15-28d was 10.3m, and > 28d was 10.8m. In the multivariate analysis, increased TCD was associated with better survival across all stages. Among stage IV patients, compared to those treated within 1 week, the HR is 0.92 (P < .001) for 1-2 weeks, HR 0.82 (P < .001) for 2-4 weeks, and HR 0.77 (P < .001) for > 4 weeks. Results are similar for Stage III and for Stage I/II. Conclusions: These results show a trend towards poor survival with early treatment. While we do not suggest delaying treatment for SCLC patients, our results provide new evidence to inform a discussion about appropriate treatment timing and individualizing treatment. Optimization of patients' clinical baseline before hasty cytotoxic treatment may lead to better outcomes. [Table: see text]
Preliminary study of S-1 maintenance therapy in extensive stage small-cell lung cancer.
Authors: Nie Keke , Zhang Chunling , Lan Ketao , Ji Youxin
Published: March 2020

e20080

Background: 4-6 cycles platinum and etoposide (EP) or platinum and irinotecan (IP) chemotherapy is the mainstay treatment for the extensive-stage small-cell lung cancer (SCLC); but the role of maintenance treatment is not fully understood. This study compared the efficacy and toxicities of 4-6 cycles EP or IP chemotherapy treatment followed by S-1 maintenance treatment or placebo control. Methods: In this phase 2, open-label, three-center preliminary study, patients who reached complete response (CR), partial response (PR) or stable disease (SD) after 4-6 cycles of EP or IP therapy were randomly assigned (1:1) with a minimization procedure. One group received oral S-1 25mg/mg2 twice a day as maintenance treatment until disease progression or unacceptable toxic effects. The other group was received placebo and routine follow-up. The primary end point of this study was progression-free survival (PFS) and the secondary end points were response rates, toxicities and overall survival (OS). This trial was registered with ClinicalTrials.gov, number NCT03769935. Results: A total of 89 patients were enrolled, of whom 45 received S-1 maintenance therapy and 44 received placebo. The median PFS was 6.35 months in the S-1 group, as compared with 5.98 months in the placebo group (hazard ratio for progression in the S-1 group, 1.057; 95% confidence interval [CI], 0.656-1.707; P = 0.820). The median OS was 10.82 months in the S-1 group, as compared with 10.09 months in the placebo group (hazard ratio for death in the S-1 group, 0.860; 95% CI, 0.374-1.617; P = 0.905). Tumor regression rate influenced patients’ survival. The PFS was 7.2 months and 5.3 months (p = 0.015), and OS was 12.9 months and 10.9 months (p = 0.042) in patients with CR or PR compared to in patients with SD after induction chemotherapy respectively. The adverse events were mild to moderate skin rash and acne, diarrhea, alopecia, dry skin and fatigue; which were mainly induced by induction chemotherapy and S-1 administration. Conclusions: S-1 maintenance treatment for extensive-stage SCLC had acceptable toxicities; however, there was no significant difference in PFS or OS statistically. Further research with novel agents in the maintenance setting is warranted. Clinical trial information: NCT03769935.
Clinical observation of low-dose apatinib in the treatment of small cell lung cancer with antidiuretic hormone secretion.
Authors: Jia Yuming , Ye Wenjing
Published: March 2020

e20087

Background: The treatment of extensive small cell lung cancer (ED-SCLC) is still based on radiotherapy and chemotherapy, but the overall survival is short and the prognosis is poor. The prognosis of ED-SCLC with hyponatremia is worse. At present, the anti-angiogenic small molecule targeted drug apatinib has achieved satisfactory clinical efficacy in advanced non-squamous non-small cell lung cancer. Although there are reports of a small number of apatinib in the treatment of small cell lung cancer, there is still a lack of low integration. In the study of sodiumemia, in this study, we evaluated the efficacy and safety of low-dose abatatinib in the treatment of ED-SCLC with hyponatremia. Methods: Retrospective analysis of 8 patients with hyponatremia at least twice during hospitalization between January 2016 and September 1818, after low-dose apafitini (125 mg or 250 mg, QD, orally; 28 days for one observation period) Case data for patients with SCLC who progressed after first-line or second-line treatment. Efficacy was assessed using the RECIST criteria and adverse reactions (AEs) were graded using the NCI CTC criteria. Results: The efficacy was evaluated as 4 PR, 2 SD, and 2 PD. ORR and DCR are 50% (4/8) and 100% (75%), respectively. The median progression-free survival (PFS) was 91 days (95% CI, 30-167) and the median overall survival (OS) was 150 days (95% CI, 110-197). Up to the follow-up date, 3 patients survived and 5 died; 1 grade 3/4 hypertension, 1 case of neutropenia, and grade 3/4 toxicity were relieved by symptomatic treatment. Did not affect the use of apatinib. Conclusions: The efficacy and tolerability of patients with LD-SCLC with hyponatremia after low-dose atentinil treatment for first- and second-line treatment were good. However, the conclusion still requires a large sample of prospective studies to further evaluate. [Table: see text]
Quantifying EpCAM heterogeneity of circulating-tumor-cells (CTCs) from small cell lung cancer (SCLC) patients.
Authors: Sorotsky Hadas , Aparanthi Mansi , Wang Daniel Zongjie , McFadden Francesca , Popescu Sandra N , Mohamadi Reza M , Pereira Mark , Weiss Jessica , Patel Devalben , Majeed Safa , Cabanero Michael , Sacher Adrian G. , Bradbury Penelope Ann , Leighl Natasha B. , Shepherd Frances A. , Tsao Ming Sound , Liu Geoffrey , Kelley Shana O , Lok Benjamin H.
Published: March 2020

e20091

Background: Tumor heterogeneity and evolution of SCLC is poorly defined. Serial longitudinal interrogation of tumor heterogeneity from CTCs detected in peripheral blood patient (pt) samples is a potential strategy to address this gap in knowledge. However, existing technology is generally limited to the capture and enumeration of CTCs, without a high-throughput method to quantify phenotypic properties. Here, we evaluated a novel nanotechnology platform – nanoparticle-mediated magnetic ranking cytometry (MagRC) to profile SCLC CTCs by EpCAM protein expression. Methods: Blood samples from 20 SCLC pts were processed through the MagRC platform. Magnetic nanoparticles conjugated with anti-EpCAM antibodies were incubated with whole blood samples then introduced into the MagRC device where CTCs are sorted by differently sized nickel micromagnets within microfluidic channels. Captured CTCs are ranked into 8 zones that correlate with EpCAM expression levels (zone 1 = highest to 8 = lowest). For 8 pts, all samples were processed at a 1mL/hr flow rate (fr), and for 12 pts, a 0.5mL/hr fr was also studied; 66% of all chips were processed at a 1ml/hr fr and 34% at a 0.5ml/hr fr. The average zone for each chip was compared to the flow rate, age, and stage (extensive-stage (ES) vs limited-stage (LS)). The differences were tested using the Wald test within the linear mixed effects model. Results: Among 20 pts, 11 were ES; 9 were LS. Median age at diagnosis was 69 years old (yo); 65% were male. We detected CTCs in 12 of 20 pts (60%), similar to other studies. When comparing the MagRC-ranked EpCAM zone, the 0.5mL/hr fr demonstrated a lower median zone (4.3 vs 6.5; p < 0.001) as compared to the 1mL/hr rate. Interestingly, pts > 65 yo had a higher median zone (6.2 vs. 3.5; p = 0.019) compared to those ≤65 yo. The effect remained significant after controlling for flow rate (p = 0.002). No EpCAM zone difference was detected between ES and LS. Conclusions: We demonstrate the ability of MagRC to quantify EpCAM expression levels of CTCs from SCLC pts. We observed a higher MagRC zone (i.e. lower EpCAM expression) from pts > 65 yo. This observation requires validation in larger datasets along with continued investigation into the biology of SCLC CTCs.
Single agent immunotherapy for relapsed or refractory small cell lung cancer (rrSCLC).
Authors: Singh Ankur , Ahmed Tamjeed , Dothard Andy , Grant Stefan C. , Ruiz Jimmy , Farris Michael , Petty William J. , Lycan Thomas
Published: March 2020

e20094

Background: There are limited effective treatment options for rrSCLC. Based on results from CheckMate 032 (n = 98) and KEYNOTE-158 (n = 107), both of which were limited to performance status (PS) 0-1, guidelines recommend consideration of single agent PD-1 immunotherapy (IO) for patients (pts) with PS 0-2. Methods: All rrSCLC pts receiving single agent IO at our institution from May 2016 – April 2018 were retrospectively analyzed with IRB approval. Primary endpoints were overall survival (OS) and end-of-life outcomes. Results: 48 rrSCLC pts who were predominantly PS 2-3 (56%), female (63%), and Caucasian (90%) received single agent IO with either nivolumab (94%) or pembrolizumab (6%) for either relapsed (81%) or refractory (19%; defined as initial diagnosis < 180 days) SCLC. They received median 3 cycles (IQR 2-5). 32 deaths occurred during the analysis period. 6 and 12 month (mo) OS were 31% and 18%, as compared to 45% and 33% reported in CheckMate, respectively. Adverse events (AEs) leading to treatment discontinuation occurred in 5 (10%) and serious AEs (pneumonitis and posterior reversible encephalopathy syndrome) occurred in 2 (4%). For end-of-life outcomes, 18 (38%) were referred to hospice at any point, 8 (17%) began IO within 30 days of death, and 7 (15%) received a dose of IO within 14 days of death. The subgroup of pts who received ≥2 prior lines of therapy appear to have had greater benefit. Conclusions: Although tolerable, salvage single agent IO for rrSCLC in these unselected pts had poor efficacy and may have led to under-utilization of end-of-life resources. It may still be beneficial among pts with more indolent, treatment-responsive disease, as indicated by multiple lines of prior therapy. But overall, these results support the combination of IO with chemotherapy or novel agent as part of a clinical trial. Further investigation is warranted to better define its use in this setting. [Table: see text]
Gene expression profiling of T-cell inflammation in small cell lung cancer.
Authors: Rivalland Gareth , Schmitz Ulf , Molania Ramyar , Bailey Chuck , Wright Gavin Michael , Dobrovic Alexander , Rasko John , John Thomas
Published: March 2020

e20097

Background: Recent success with the use of checkpoint inhibition in SCLC has increased the importance of understanding the immunological tumour microenvironment. In many tumours gene expression profiling (GEP) of T-cell inflammation and IFN-gamma is correlated with response to checkpoint inhibitors. We present GEP results in a SCLC cohort and correlation of gene expression with IHC analysis of common checkpoints. Methods: SCLC tissue microarrays from 105 histologically confirmed SCLC specimens were scored for IHC staining of immune checkpoints on tumour and tumour infiltrating lymphocytes (TILs). A subgroup of 30 patients had sufficient tissue for GEP. Nanostring nCounter Pan-cancer immune panel, using the previously described RUVIII normalisation method, was used to examine GEP. A 28-gene IFN-G related signature was examined. Results: Median age 67y (range 53 – 86); male: 16/30 (53%); stage: limited 22/30 (73%), 5/30 (17%) extensive, 3/30 (10%) stage unknown. Significant heterogeneity was observed in gene expression. Pearson correlation co-efficients between IHC analysis and corresponding mRNA of PD-L1, PD-L2, LAG3 and TIM3, on both tumour and TILs, were not statistically significant. Significant positive correlation was found for mRNA levels of HAVCR2 (TIM3) with LAG3 and with PDCD1LG2 (PD-L2). As in the larger cohort, TIL co-expression of PD-L1, PD-L2, TIM3 and LAG3 were all associated with improved survival; med OS 89.3 v 15.7 mo; p < 0.01. The cohort clustered into 4 groups with respect to the IFN-G GEP. The group with the highest level of gene expression (5/30 pts, 16.7%) had numerically improved OS; 89.3 v 21.3 mo, p = 0.23. Conclusions: In this limited cohort, gene expression did not consistently correlate with IHC. Co-ordinated expression of T-cell inflamed/IFN-G immune checkpoints occurred in 16.7% SCLC and was associated with improved survival.
Nationwide shift in patterns of prophylactic cranial irradiation utilization for extensive-stage small cell lung cancer patients.
Authors: Gjyshi Olsi , Ludmir Ethan B. , Pezzi Todd A. , Boyce-Fappiano David , Mitin Timur , Lin Steven H.
Published: March 2020

e20099

Background: A recent phase III trial (Takahashi et al., 2017) showed no overall survival (OS) benefit in patients with extensive-stage small cell lung cancer (ES-SCLC) treated with prophylactic cranial irradiation (PCI), casting doubt on the practice of PCI as established in a prior phase III trial (Slotman et al., 2007). We undertook a nationwide survey of radiation oncologists to ascertain the impact of the Takahashi trial on the utilization of PCI for ES-SCLC patients. Methods: A total of 3,646 ASTRO-registered radiation oncologists in the United States were invited to answer an anonymous survey on their use of PCI in ES-SCLC, and the impact of the recent Takahashi et al. trial on their practice. The survey consisted of 35 questions created using a branching logic system via RedCAP. Results: A total of 438 (12%) radiation oncologists completed the survey. Responders were well-distributed across geographic regions, practice environment, age, gender, practice size and lung cancer volume. Most respondents (92%) were aware of the Takahashi trial. While 71% routinely offered PCI to ES-SCLC patients prior to the publication of this trial, only 43% continue to do so after its publication (p < 0.001). Most respondents (66%) had altered their practice in response to the study. There was no difference in post-publication practice patterns between academic and private practice radiation oncologists (43% vs. 44%, p = 0.81). While 43% of participants who were aware of the Takahashi trial still offered PCI after its publication, 82% of those unaware of the trial still continued to offer PCI (p < 0.001). Additionally, 25% of participants noted that they have experienced a decrease in medical oncology referrals for PCI for ES-SCLC patients. Twenty-two percent of participants stated that the Takahashi trial impacted their practice with regards to limited-stage SCLC patients as well. Looking toward the future, 47% of respondents reported that they would be willing to enroll both LS- and ES-SCLC patients on a randomized trial comparing active MRI-surveillance to PCI; 15% stated that they would enroll only LS-SCLC patients on such a trial, and 20% would enroll only ES-SCLC patients. Conclusions: The phase III data from Takahashi et al. (2017) has markedly impacted the current practice patterns in the US by reducing PCI utilization for ES-SCLC patients across all practice settings and measured demographic variables. Most respondents expressed openness to a randomized trial comparing active MRI surveillance to PCI for SCLC patients.