bluuebunny/crossref_metadata_2025_split huggingface dataset:
Therapeutic targeting of polyamines in malignant pleural mesothelioma xenograft models.
Authors: Ho James C. M. , Yan Sheng , Lam Sze Kwan 
Published: March 2020

e20060 Background: Although the use of asbestos has been restricted, the incidence of malignant pleural mesothelioma (MPM) is still rising. The US FDA approved a combination of pemetrexed with cisplatin for treatment of unresectable MPM. And development of novel adjuvant therapeutic options for resected early-stage disease is also urgently needed. From our preliminary data, ornithine decarboxylase (ODC) is highly expressed in MPM xenografts and clinical tumor samples. Upregulation of ODC increases polyamines production and enhances tumor growth. a-difluoromethylornithine (DFMO) is a specific ODC inhibitor. This study aims to disclose the adjuvant (minimal residual disease setting) and therapeutic (metastatic setting) effects of DFMO in MPM xenografts. Methods: In adjuvant therapy setting, nude mice were fed with DFMO in drinking water 7 days before subcutaneous inoculation of 200,000 tumor cells. In therapeutic setting, 107 corresponding cells were injected subcutaneously into nude mice which were randomized for treatment after established tumor growth. Mice with tumor size > 600mm3 were considered reaching humane endpoint. Spermidine levels, protein expression, cytokines concentration, and apoptosis were investigated by Dot plot, Western blot, ELISA, and TUNEL assay respectively. Results: In adjuvant therapy setting, DFMO suppressed tumor growth and increased median survival in both 211H and H226 xenografts. In H226 xenografts, 43% of treated mice have not yet reached humane endpoint, mimicking long-term survival. Upon DFMO treatment, decrease in spermidine level, increase in nitrotyrosine content, and activation of apoptosis were observed in both xenografts. In addition, increase in nitrosocysteine level, intratumoral IL-6, keratinocyte chemoattractant and TNFα, DNA lesions and inhibition of Akt/mTOR pathway were induced by DFMO in H226 xenografts, which may explain higher potency of DFMO in these xenografts. In therapeutic setting, DFMO also suppressed tumor growth in both xenografts with similar mechanisms. Conclusions: DFMO may have a potential role as adjuvant therapy in MPM especially epithelioid mesothelioma.
Survival meta-analysis from fifteen years of a standard systemic therapy in malignant pleural mesothelioma.
Authors: Friedberg Joseph S. , Culligan Melissa 
Published: March 2020

e20066 Background: Malignant pleural mesothelioma is a rare malignancy with an annual incidence of 3,000 cases in the US and is still considered incurable. The standard of care for this cancer, a combination of pemetrexed and a platinum drug, was established in 2003 as the result of a landmark study that reported a median overall survival of 12.1 months for this combination in patients not eligible for surgery. The aim of the current analysis was to determine if there has been a change in the outcome for this population in the past 15 years. Methods: A PubMed search was performed and 9 prospective, randomized or single arm (minimum n = 50), trials were selected. All studies included patients treated using pemetrexed in combination with platimun as front line therapy in unresectable mesothelioma patients. Average and weighted average OS were calculated and also corrected per the reported odds ratio for survival between the epithelioid and non-epithelioid histologies. Results: The average OS was 12.9 months and the weighted average OS was 13.3 months (range: 8.5 – 16.1 months). The two studies showing the highest median OS (MAPS and LUME-meso) had a higher percentage of tumors with epithelioid histology, which could explain their favorable outcome. Adjusting the average OS using the reported odds ratios for survival between epithelioid and non-epithelioid histologies eliminated the superior outcome in these studies. Furthermore, correcting average survival per the original ratio between tumor histologies for all studies included in the meta-analysis showed an average and weighted average OS lower than 13 months. Conclusions: This analysis strongly supports the contention that survival results for nonoperative patients with mesothelioma should be stratified by histology, epithelioid versus nonepithelioid, similar to the trend in the surgical mesothelioma literature. When factoring in histology, it appears that overall advances in patient care and additional treatments have not significantly changed the overall survival for nonoperative mesothelioma patients in the last 15 years. This meta-analysis underscores the desperate need for new and innovative treatments for this cancer.
Predictors associated with development of pleural and pericardial effusions in patients with small cell lung cancer treated with third-line therapy.
Authors: Jiang Rui , Koch Martina , Gulbranson Scott , Komarnitsky Philip B. , Papademetriou Eros , Tyczynski Jerzy Edward 
Published: March 2020

e20088 Background: Pleural (Pl) and pericardial (Pc) effusions are often encountered clinical problems in patients with lung cancer, contributing to a poor quality of life. Population-based data on predictors for Pl and Pc effusions in small cell lung cancer (SCLC) are scarce, particularly, in later lines. Methods: We estimated the predictors for treatment-emergent Pl and Pc effusions in SCLC patients treated with third-line of therapy (LOT) using Optum’s electronic health records (EHR) de-identified database. Of 8,291 patients with newly diagnosed SCLC between 01/01/2008 and 09/30/2016, 428 patients received 3rd LOT. Pc/Pl effusions were identified by a combination of ICD-9/ICD-10 codes, procedures, or natural language processing (NLP) SDS term and sentiment. Each patient contributed to follow-up time from start of 3rd LOT to the day prior to start of next LOT or earlier of (loss to follow-up date or 365 days from end of 3rd LOT) if there was no subsequent LOT, or first occurrence for those with an outcome event. Stepwise Cox regression with sle = 0.25 and sls = 0.10 was applied for variable selection. Results: At start of 3rd LOT, median age was 65, 46% were male, 97% had extensive disease (excluding n = 53 with missing staging). Cardiac history, pulmonary history, renal impairment (eGFR < 60 mL/min/1.73m2), prior Pl and Pc effusion, albumin levels below 3.5 g/dl, sodium levels below < 136 mmol/l, treatment regimens (others except platin-containing vs. topotecan mono) was each associated with increased risk of Pl effusions. Cardiac history, prior Pl and Pc effusion, and region (South vs. Midwest/West) was each associated with increased risk of Pc effusions. When the stepwise Cox regression was applied, cardiac history, prior Pl effusion, and treatment regimens were selected as significant predictors of Pl effusions (p < 0.05). Prior Pc effusion and cardiac history were selected as significant predictors of Pc effusion (p < 0.05). Conclusions: Awareness of the determinants associated with development of Pl and Pc effusions in SCLC patients treated in third-line therapy may aid in earlier recognition of patients at risk and lower the risk of developing Pl/Pc effusions in this group of patients.
A novel mutation panel for predicting etoposide in small cell lung cancer.
Authors: Luo Peng , Qiu Zhengang , Lin Anqi , Li Kun , Lin Weiyin , Wang Qiongyao , Wei Ting , Zhu Weiliang , Zhang Jian 
Published: March 2020

e20090 Background: Platinum-based chemotherapy, consisting of etoposide and cisplatin (EP), has been the cornerstone of therapy for extensive-stage small cell lung cancer (ES-SCLC) for decades. Despite the marked initial sensitivity of SCLC to chemotherapy, EP regimens cannot avoid the emergence of drug resistance in clinical practice. With the rise of new chemotherapy regimens in recent years and the primary resistance or insensitivity of ES-SCLC to EP regimens, it is desirable to be able to identify patients with resistant or insensitive ES-SCLC. Methods: The sequencing and drug sensitivity data of SCLC cell lines were provided by The Genomics of Drug Sensitivity in Cancer Project (GDSC); the data regarding of sensitivity to etoposide of 54 SCLC cell lines were analyzed, and etoposide-sensitive cell lines and etoposide-resistant cell lines were differentiated according to the IC50 values defined by the GDSC. ROC curve analysis was performed on all mutations and combinations of mutations to select the optimal panel to predict resistance to etoposide. Results: Receiver Operating Characteristic(ROC) analysis of etoposide resistance revealed that the most significant single gene mutation indicating resistance to etoposide was CSMD3, and the accuracy of predicting resistance to etoposide proved to be the highest when there was any mutation in CSMD3/PCLO/RYR1/EPB41L3, area under the curve (AUC) = 0.804 (95% confidence interval (CI): 0.679-0.930, p < 0.001). Conclusions: This study found that a panel with four genes (CSMD3, EPB41L3, PCLO, and RYR1) can accurately predict sensitivity to etoposide. These findings provide new insights into the overall treatment for patients with ES-SCLC that is resistant or insensitive to etoposide.
Thoracic radiotherapy in a cohort study of patients with metastatic small-cell lung neoplasms.
Authors: Mañes Anabel , Jove Josep , Antelo Gabriela , Esteve Anna , Arellano Antonio , Caro Monica , Luguera Ernest , Ballester Rosa , Tuset Victoria , Planas Isabel , Rosales Hugo , Baena Eduardo , Villà Salvador 
Published: March 2020

e20093 Background: Thoracic radiotherapy (TRT) for extensive stage small-cell lung cancer (ES-SCLC) patients is controversial. Slotman et al. (2015) demonstrated a 2-year overall survival (OS) benefit for patients who received TRT after chemotherapy (CT) and prophylactic cranial irradiation (PCI), but obtaining a median OS of 8 months (m). We wanted to confirm results of Slotman’s work in a real-world setting with higher doses of TRT. Methods: We retrospectively reviewed 67 patients with ES-SCLC treated between 1995 and 2015, after completing CT administration. Patients with initial brain metastasis and those who rejected PCI were excluded. All of them received PCI. All patients were followed until death. Disease-specific survival (DSS), disease-free survival (DFS) and OS were analyzed and computed with Kaplan-Meier method, groups were compared with log-rank test. Adjusted hazard risk (HR) of death for TRT was estimated through multivariate Cox model. Results: Patients (59 male, 8 female) with median age 64 years (42-79) had a median Karnofsky performance status (KPS) of 80. Twenty-three patients received high doses TRT (mean dose: 45.4 Gy). No significant differences between groups were found in age, gender, KPS, number of metastatic sites, residual thoracic disease or smoke activity. Non-TRT patients had more metastatic lesions. Median OS for TRT-patients was 19.9 m and 11.2 m for non-TRT patients (p = 0.01). DSS was 23.4 m for TRT-patients and 13.5 m for non-TRT patients (p = 0.007). For TRT-patients and non-TRT patients, median DFS were 15.5 and 8.3 m (p = 0.001), respectively. In the multivariate analysis, TRT (p = 0.003, HR 0.35), KPS (p = 0.012, HR 0.95) and residual thoracic disease (p = 0.02, HR 3.30) were independent prognostic factors for survival. The best benefit was obtained for those patients with consolidative TRT (CTRT): OS of 24.7, DSS of 27.4 and DFS of 15.9 m, compared with 13.4 (p = 0.003), 13.9 (p = 0.003) and 8.5 m (p = 0.007), respectively, for patients not treated with CTRT. Conclusions: TRT impacts positively in OS, DSS and PFS and should be administered to ES-SCLC patients who complete CT and PCI. High TRT doses could achieve better results than those described for low TRT doses.
Defining the role of RUNX1T1 in "combined" small cell lung cancer.
Authors: He Tian , Wildey Gary , McColl Karen , Kresak Adam , Tan Aik-Choon , Dowlati Afshin 
Published: March 2020

e20101 Background: The RUNX1T1 gene, also known as ETO, was first identified in the fusion transcript AML1/ETO, generated by the translocation between chromosome 8 and 21, which occurs in 12%-15% of AML. We recently discovered that RUNX1T1 was specifically amplified only in the small cell lung cancer (SCLC) but not the non-small cell lung cancer (NSCLC) component of combined SCLC tumors. Here, we investigated if RUNX1T1 expression plays a role in transforming NSCLC to SCLC in combined SCLC tumor formation. Methods: We examined tumors from 92 of our SCLC patients by targeted exome and CNV analyses. RUNX1T1 mRNA expression was determined in various cancers by analysis of the CCLE and TCGA databases. RUNX1T1 mRNA expression was detected by RNAscope analysis of another 22 patient SCLC tumors. Stable overexpression of RUNX1T1 in NSCLC and SCLC cell lines used commercial RUNX1T1 lentiviral constructs. The resulting stable cell lines were analyzed by RT-qPCR, western blotting, Affymetrix gene array, and E2F-luciferase assays. Results: We found that 2 of 2 patients with combined SCLC demonstrated RUNX1T1 amplification in the SCLC component. Notably, only 2 of the remaining 90 patients with pure SCLC demonstrated RUNX1T1 amplification. RUNX1T1 mRNA is highly expressed in SCLC compared to the majority of other cancers, including NSCLC, using either CCLE or TCGA databases. Western blots confirmed higher RUNX1T1 protein expression in SCLC vs NSCLC cell lines, and RNAscope analysis confirmed greater RUNX1T1 mRNA expression in SCLC vs NSCLC patient tumors. When we stably overexpressed RUNX1T1 in NSCLC cell lines, there was no increase in neuroendocrine protein expression, however we did find an increased sensitivity to etoposide. Bioinformatic analysis of microarray data demonstrated significantly altered E2F pathway activity, and we could show a significant increase in E2F-luciferase activity after RUNX1T1 overexpression. Interestingly, this was associated with decreased p21 expression, which is a putative suppressor of E2F activity. Conclusions: RUNX1T1 expression is specifically upregulated in SCLC compared to NSCLC. E2F pathway activity is elevated after RUNX1T1 overexpression, consistent with an increased SCLC phenotype.
Immunotherapy plus chemotherapy versus chemotherapy alone in metastatic non–small-cell lung cancer: A systematic review with meta-analysis.
Authors: Sasse Andre Deeke , Ferreira Fernanda Proa , Scherr Adolfo Jose de Oliveira , Cunha David Pinheiro , Vasconcelos Vivian Castro Antunes , Ramalho Susana Oliveira Botelho , Conceicao Vinicius Correa , do Carmo Rafael Luis Moura Lima 
Published: March 2020

e20700 Background: Palliative systemic therapy is the primary approach for stage IV non-small cell lung cancer(NSCLC). For patients with NSCLC that lacks targetable mutations, immunotherapy alone or in combination with chemotherapy has become a promising alternative, focusing survival and quality of life. Our objectives were to review, summarize and compare the evidence of immunotherapy plus chemotherapy in first-line treatment in comparison with chemotherapy alone in patients with metastatic NSCLC in terms of effectiveness. Methods: A systematic review of randomized controlled trials (RCTs) was planned. PubMed, Embase and Lilacs were searched for trials evaluating metastatic NSCLC patients, comparing chemotherapy alone versus chemotherapy plus anti-PD1, anti-PDL1 or anti-CTLA-4 agents. Four investigators independently extracted characteristics and results of identified studies and performed standardized quality ratings. Meta-analyses for overall survival (OS), progression-free-survival (PFS), overall response rates (ORR) and toxicities were performed. Results: Six RCTs met the inclusion criteria. One trial with anti-PD-L1 (Atezolizumab), three trials with anti-PD-1 (Pembrolizumab) and two trials with anti-CTLA-4 (Ipilimumab) were included. Three trials included non-squamous carcinomas, two trials included squamous cell carcinoma and one trial included all NSCLC. The combination of anti-PD-1 or anti-PDL1 to chemotherapy improved OS (Hazard Ratio [HR] for death, 0.62; 95% confidence interval [CI], 0.49 to 0.79; p < 0.0001). This combination also improved PFS (HR for progression or death, 0.57; 95% CI, 0.51 to 0.63; p < 0.00001) and ORR (Odds Ratio [OR], 2.55; 95% CI, 1.80 to 3.61; p < 0.00001). The combination of anti-CTLA-4 to chemotherapy slightly increased the PFS (HR 0.84; 95% CI, 0.73 to 0.96; p = 0.01), but not OS (HR 0.92; 95% CI, 0.80 to 1.05; p = 0.21) or ORR (OR 0.92; 95% CI, 0.71 to 1.19; p = 0.52). General and immune mediated adverse events were higher in all combination groups. Conclusions: In patients with previously untreated metastatic squamous and non-squamous NSCLC without EGFR or ALK mutations, the addition of anti-PD-1 or anti-PD-L1 to standard chemotherapy resulted in significantly longer overall survival and progression-free survival than chemotherapy alone.
Decreasing BMI/weight immediately prior to starting anti-PD-1/PDL-1 monoclonal antibodies for treatment for stage IV non-small cell lung cancer is associated with shorter progression-free survival.
Authors: Kollipara Revathi , Fughhi Ibtihaj , Batus Marta , Basu Sanjib , Borgia Jeffrey Allen , Bonomi Philip D. , Fidler Mary J. 
Published: March 2020

e20710 Background: Currently, prognostic markers associated with immunotherapy treatment outcomes in patients with metastatic NSCLC include PDL-1 expression, tumor mutational burden (TBM), and neutrophil to lymphocyte ratio (NLR). In this study we examine the influence of pretreatment changes in weight, BMI, and NLR in 237 patients treated with anti-PD-1/PDL-1 therapy (ICI) at our institution. Methods: This was a retrospective analysis of previously-treated stage IV NSCLC patients who received ICI. Pretreatment (≥ 6 weeks before starting therapy) values of weight, BMI, and NLR were compared to baseline values and NLR was analyzed as continuum and according to standard cutoffs of 3.5 and 5. The same variables were correlated with progression-free survival (PFS) and overall survival (OS) using the Log-Rank test. Results: 237 patients were analyzed: 45% were male, 73% were Caucasian, 72% were former smokers, and 25% were age ≥ 75 years. 148 patients had pretreatment NLR values. Of these, 32% had a ratio < 3.5 and 54% had ratio < 5. 34% had increased NLR at baseline, the majority of which (48/77) had a > 5% increase. 187 patients had pretreatment weight and BMI. Of these, 14% had a pretreatment BMI < 20. 71% had a negative change in BMI and 29% had a > 5% decrease in BMI. 65% had a negative change in weight and 26% had a > 5% decrease in weight. BMI decrease greater than 5% (p = 0.0039), negative weight change (p = 0.0371), and pretreatment NLR > 5 (p = 0.0136) were associated with shorter PFS. Change in NLR trended towards decreased PFS but was not statistically significant (p = 0.07) though only 77 of 237 patients had both values available. There was no statistical PFS difference between patients less than or ≥ 75 years old. Conclusions: The results suggest that decrease in pretreatment BMI and weight along with high baseline NLR are associated with significantly shorter PFS in NSCLC treated with anti-PD-1/PDL-1 therapy. If confirmed, these observations raise the possibility that specific treatment which reverses cancer associated weight loss might enhance effectiveness of immunotherapy.
Precision medicine for lung cancer decision-making: Evaluation of an -omics based FFT approach to personalized medicine.
Authors: Mambetsariev Isa , Djulbegovic Benjamin , Pharaon Rebecca , Hewelt Blake , Massarelli Erminia , Koczywas Marianna , Reckamp Karen L. , Salgia Ravi 
Published: March 2020

e20713 Background: The prevalence of next-generation sequencing and the availability of a large number of targeted therapies in the clinics, has complicated treatment decision-making in lung cancer. While national guidelines and commercial pathways offer a method to improve the oncologists’ adherence to appropriate testing and treatment modalities available, more effort is required to solidify this as a standard of care model at academic and community sites. A better understanding of the improved durable survival of targeted therapy assignment compared with non-targeted therapy outside of the clinical trial setting is needed to understand the efficacy and accuracy of precision medicine. Methods: We perform an in-depth analysis of a series of lung AD patients (n = 798) with genomic and clinical data in a recently created thoracic patient registry, who were treated at COH between 2009-2018 period. Results: 798 individuals with lung AD were identified in the Thoracic Oncology Registry who were treated or were intended to be treated at COH; 662 (83%) of the patients had genomic testing performed at the request of their treating oncologist and 460 (58%) of whom received a 1st-line targeted therapy decision (including clinical trial assignment based on bio-marker). Oncogenic alterations were detected in 653 (82%) patients with the majority presenting with EGFR (47%), who were mostly treated with erlotinib (78%). 462/653 (70%) patients had an alteration detected with an available FDA approved therapy and 90% (416/462) of the patients were appropriately matched to a targeted therapy based on the oncologist’s decision. Several decision-making algorithms were tested and fast-and-frugal trees (FFTs) proved superior with a positive predictive value (PPV) of 90% and only required two important cues in informing the decision of the type of treatment to give to the patient. Furthermore, a targeted therapy treatment decision showed a significant benefit with a median OS of 38 months as compared to 22 months in the non-targeted therapy decision-making group (p < 0.00001). This was also evident in the PFS analysis where targeted therapy decision-making had a median survival of 9 months as compared with 5 months in the other groups (p < 0.00001). Conclusions: FFTs are a novel tool to test the efficacy of precision medicine in a real-world setting and can provide a more streamlined method for clinical guidance and decision-making. FFTs were able to predict with 90% PPV a precision medicine decision that was correlated with improved PFS (9 vs 5 months) and OS (38 vs 22 months).