bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.
Multicenter phase II trial of RRx-001 in previously treated SCLC.
Authors: Morgensztern Daniel , Rose Michal G. , Morris John Charles , Ma Patrick C. , Brzezniak Christina E. , Zeman Karen Grace , Padmanabhan Arvinda , Hirth JoAnn , Spira Alexander I. , Wong Ellice Yuen-Ming , Padda Sukhmani Kaur , Waqar Saiama Naheed 
Published: March 2020

e20104 Background: This exploratory single arm phase II study evaluated the efficacy and safety of RRx-001 followed by reintroduction of platinum plus etoposide in patients with previously treated small cell lung cancer (SCLC). Methods: Patients with SCLC that was platinum-resistant or received at least 2 prior lines were treated with RRx-001 4 mg IV on day 1 of each week of a 21-day cycle followed at progression by re-challenge with etoposide and cisplatin or carboplatin. The primary endpoints were overall survival (OS) and overall response rate to platinum therapy. Results: Between December 2016 and March 2018, 26 patients were enrolled and received at least one dose of RRx-001. The median number of prior lines of therapy was 2 (range 1-9) and 19 (73.1%) patients had platinum-resistant disease. In the intention-to-treat population, 1 (3.8%) achieved partial response (PR) and 7 (26.9%) had stable disease (SD) during treatment with RRx-001, whereas 1 patient (3.8%) had complete response and 6 (23.1%) had partial response on platinum plus etoposide. The estimated median and 12-month OS from enrollment were 8.6 months and 44.1%, respectively. The most common treatment-emergent adverse events from RRx-001 was mild discomfort at the infusion site (23%) and decreased appetite (15.3%). Conclusions: RRx-001 followed by re-challenge with platinum plus etoposide chemotherapy is feasible and associated with promising results. Clinical trial information: NCT02489903.