bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dynamic 18F-FDG Total body PET Imaging as a predictive marker of induction chemo-immunotherapy response in locally advanced non-small cell lung cancer.
Authors: Liu Hui , Qiu Bo , Wang DaQuan , Zhang Xu , Liu Hui , Zhou Yin , Li QiWen , Chu Chu , Liu FangJie , Chen NaiBin , Hu Nan , Ai XinLei , Guo JinYu , Fan Wei 
Published: June 2021

e20551 Background: The purpose of this study was to evaluate the efficacy of dynamic 18F-FDG total body PET imaging as a predictive maker of induction chemo-immunotherapy response in locally advanced non-small cell lung cancer(NSCLC) by a prospective study. Methods: Stage IIIA-IIIC NSCLC patients were prospectively enrolled in a prospective total body PETCT study ( NCT04654234, GASTO-1067) and a randomized phase II clinical trial ( NCT04085250) between September 2020 and December 2020. All patients underwent a dynamic total-body 18F-FDG PET/CT scan before any treatment and after 2 cycles of induction chemo-immunotherapy (docetaxel+cisplatin+nivolumab). The primary lung tumor, metastatic regional lymph node and inflammatory lymph node before and after treatment were manually delineated by a nuclear medicine physician and a radiation oncologist. Total Body PET was acquired between 0 – 60 mins after the injection of FDG from the subject’s feet. Patients was separated into high dynamic FDG metabolic (H-DFM) group and low DFM(L-DFM) group by the scatter plot of SUV-mean and Ki-mean of primary lung tumor. We compared lesion heterogeneity and different image-derived PET metrics including the metabolic tumor volume(MTV), SUV total lesion glycolysis(SUV-TLG), Patlak-derived influx rate constant (Ki) TLG (Ki-TLG). Results: Fifteen patients were analyzed, 8 patients was in H-DFM group and 7 in L-DFM group. Patients in H-DFM group had significant decreased levels of MTV(p < 0.001), SUV-TLG(p < 0.001) and Ki-TLG(p < 0.001) both in primary lung tumor and metastatic lymph node by the induction chemo-immuotherapy. However, patients in L-DFM group only had a significant reduction of MTV in primary lung tumor(p < 0.05). There was no significant difference in the MTV of metastatic lymph node(p > 0.5), the SUV-TLG(p > 0.5) and Ki-TLG(p > 0.5) of primary lung tumor and metastatic lymph node, before and after induction chemo-radiotherapy. Conclusions: Patients in H-DFM group had the better treatment response of induction chemo-immunotherapy with significant decreased levels of MTV, SUV-TLG and Ki-TLG. Dynamic 18F-FDG Total body PET Imaging could be regard as a potential predictive marker of induction chemo-immunotherapy response in the setting of LA-NSCLC.
Cause of death among patients with non-small cell lung cancer treated with postoperative radiation therapy (PORT).
Authors: Singareddy Aashray , Waqar Saiama Naheed , Devarakonda Siddhartha , Ward Jeffrey P. , Govindan Ramaswamy , Robinson Clifford , Morgensztern Daniel , Samson Pamela Parker 
Published: June 2021

e20555 Background: The indications for post-operative radiation therapy (PORT) in locally advanced non-small cell lung cancer (NSCLC) remain undefined and a major concern is the perceived risk of increased mortality from cardiopulmonary causes. The purpose of this study was to quantify the rate of cardiopulmonary death in patients with resected NSCLC receiving PORT using a large national database. Methods: Using the Surveillance, Epidemiology, and End Results (SEER) database for lung cancer, patients with Stage IIIA or Stage IIIB NSCLC according to the 6th AJCC edition treated with surgery followed by PORT, who also received chemotherapy were identified. Cause of death was categorized as due to lung cancer, other cancer, cardiac, pulmonary, or other and reported as a percentage of total deaths at one and 2 years. Kaplan-Meier survival analysis was done to compare overall survival between Stage IIIA and IIIB patients. Results: From 2004 to 2015, 4387 patients with stage IIIA and IIIB meeting the eligibility criteria were identified. The median age at diagnosis was 65 years old, most patients were male (53%), Caucasian (83%), had adenocarcinoma (54.8%), stage IIIA disease (69%), and N2 disease (78%). The median overall survival for Stage IIIA and IIIB patients was 39 months and 27 months respectively (p < 0.001). Among the 2586 patients that died during the study period, the most common COD was lung cancer (81.3%). Cardiac and pulmonary COD occurred in 86 patients (3.3% of deaths) and 84 patients (3.2% of deaths) respectively, whereas 158 patients (6.1%) died from other cancers and 154 (5.9%) from other causes. There were 77 deaths from cardiopulmonary cause at 2 years (1.7% of patients and 2.9% of deaths). Cardiopulmonary COD was more common in patients with stage IIIB compared to IIIA disease (4.9% vs 3.3% of deaths, p < 0.001). Lung cancer was the most common COD both at 1 and 2 years (85%) whereas cardiopulmonary was the COD in 5.2% of patients at 1 year and 5.1% at 2 years. Conclusions: This analysis showed a low cardiopulmonary mortality from PORT in the first 2 years. The role for adjuvant radiotherapy remains undefined and treatment decisions for patients with resected stage III NSCLC should be guided by co-morbidities and the competing risk for death from lung cancer.
Differential role of residual metabolic tumor volume in patients with inoperable stage III NSCLC after chemoradiotherapy ± immune checkpoint inhibition.
Authors: Unterrainer Marcus , Taugner Julian , Käsmann Lukas , Eze Chukwuka , Kunz Wolfgang G. , Tufman Amanda , Reinmuth Niels , Belka Claus , Manapov Farkhad 
Published: June 2021

e20558 Background: PET-derived metabolic-tumor-volume (MTV) has shown to be an independent prognosticator in non-small cell lung cancer (NSCLC) patients treated with chemoradiotherapy (CRT). We analysed the prognostic value of residual MTV after completion of thoracic irradiation (TRT) in inoperable stage III NSCLC patients treated with CRT with and without immune check-point inhibition (ICI). Methods: Fifty-six inoperable stage III NSCLC patients (16 female, median age: 65 years) underwent 18F-FDG PET/CT at the same institution before and after completion of CRT. MTV was delineated on 18F-FDG PET/CT using a standard threshold (hepatic SUVmean + 2 x standard-deviation). Patients were divided in volumetric subgroups using median split dichotomization (residual MTV ≤4.0 ml & > 4.0 ml). Residual MTV, clinical features and ICI maintenance (RCT-IO; 21/56 (37.5%) patients) were correlated with clinical outcome (progression-free survival (PFS), local PFS (LPFS), metastasis-free survival (MFS), and overall survival (OS). Results: Median follow-up was 52.0 months. 52 (93%) patients were treated with CRT, 12 (21%) patients with CRT followed by durvalumab, and 9 (16%) patients treated with CRT plus nivolumab (concurrent and sequential). In the entire cohort, smaller residual MTV was associated with longer PFS (median 29.3 vs. 10.5 months, p = 0.015); PFS in patients treated with CRT and ICI was also significantly longer compared to the CRT-only subgroup (median 29.3 vs. 11.2 months, p = 0.010). However, residual MTV was predictive for longer PFS in CRT-only (median 33.5 vs. 8.6 months, p = 0.001), but not in the CRT-ICI patients (p = 0.909). Analogously, patients with smaller MTV had a longer LPFS (median 49.9 vs. 16.3 months, p = 0.002); CRT-ICI patients showed a significantly longer LPFS compared to CRT-only patients (median not reached vs. 16.9 months, p = 0.016). Residual MTV remained a significant prognosticator for LPFS in the CRT-only (median 49.9 vs. 10.1 months, p = 0.01), but not in CRT-ICI patients (p = 0.291). Again, smaller residual MTV remained a significant prognosticator for OS in the CRT-only subgroup (median 63.0 vs. 16.3 months, p = 0.004), but not in CRT-ICI patients (p = 0.720). Even in patients with larger residual MTV, the application of ICI significantly improved OS compared to CRT-only subgroup (median not reached vs. 22.9 months, p = 0.004). Conclusions: Smaller residual MTV is associated with superior clinical outcome in inoperable stage III NSCLC, especially in patients undergoing CRT-only. In contrast, in patients undergoing concurrent or sequential consolidation clinical outcome was independent of residual MTV. Hence, even patients with extensive residual MTV might significantly profit from ICI consolidation.
Efficacy and safety of PD-1/PD-L1 antibody combined with chemotherapy as second-line or third-line treatment for metastatic small cell lung cancer.
Authors: Wang Jun , Yin Beibei , Guan Yaping , Feng Dongfeng 
Published: June 2021

e20574 Background: For a small subset of patients, immune checkpoint blockade heralds a promising strategy for achieving disease control in small cell lung cancer (SCLC). Nivolumab or pembrolizumab monotherapy has been granted accelerated approval for treatment of patients with extensive-stage SCLC with disease progression after platinum-based chemotherapy and at least one other line of therapy. Moreover, Based on IMpower133 and CASPIAN data, addition of PD-L1 antibody such as atezolizumab or durvalumab to first-line platinum-based chemotherapy prolongs overall survival over chemotherapy alone. However, it remains exclusive that whether PD-1/PD-L1 antibody combined with chemotherapy is effective against extensive-stage SCLC when progressed on previous chemotherapy. Methods: We reviewed patients with extensive-stage SCLC who have failed in first-line or beyond chemotherapy and received PD-1/PD-L1 antibodies with chemotherapy in a single institute. The efficacy and safety were evaluated. The primary end point was the objective response rate according to Response Evaluation Criteria in Solid Tumors, version 1.1. Results: A total of 11 patients were included in this retrospective cohort study. The median age was 46 years (range from 29 to 62). Seven patients were male. Four were current or former smokers. Six received two prior therapies. Nine had previously received radiation therapy. PD-1 and PD-L1 inhibitors were administrated in 5 and 6 patients, respectively. No patient had a complete response. 2 patients had a partial response, and the objective response rate was 18.2%. 5 patients were evaluated as stable disease with a disease control rate of 63.6%. The median overall survival and progression-free survival was 3.0 months and 2.3 months, respectively. A patient with partial response had a long duration of response of 5.2 months. The most common grade 3 or 4 treatment-related were neutropenia, anemia, and decreased neutrophil count. Most immune-related adverse events were grade 1 or 2, with rash, pruritus and hypothyroidism being the most common, and 1 patient had grade 3 pneumonia. Conclusions: Immunotherapy plus chemotherapy could be beneficial for a subgroup of extensive-stage SCLC patients who have progressed after previous chemotherapy. Further prospective, randomized studies are warranted.
Small cell lung cancer: Real-world data from two institutions in Lebanon for patients receiving carboplatin etoposide or atezolizumab in first line of treatment.
Authors: Nasr Fadi , El Khoury Reem , Yehia Intissar , Diab Saada , Al Ghoche Ahmad , Nasr Lewis 
Published: June 2021

e20578 Background: Small-cell lung cancer (SCLC), accounts for approximately 15% to 17% of all diagnosed lung cancers. It is an aggressive high-grade neuroendocrine carcinoma, diagnosed during advanced stages in the majority of patients. Despite the fact that first line treatment provides response rates of up to 80%, the majority of patients relapse within 6 months after completion of initial treatment. Few advances have been made in the management of recurrent disease and treatments patterns are poor and limited in each line of the disease. The aim of this study is to present real world data regards survival outcomes such as progression free survival and overall survival in SCLC patients receiving carboplatine etoposide or tecentriq carboplatin etoposide regimens as first line of treatment. Methods: This is a retrospective (descriptive) study on 56 patients aged ≥ 18 years and with confirmed histological SCLC. Patients with extensive stage of SCLC were enrolled in this cohort study from 2 health institutions in Lebanon from July 2007 to December 2019 and followed up until progression or death. Primary end points were overall survival (time from randomization to death from any cause) and progression free survival at 6 and 12 months (time from randomization to disease progression). Secondary endpoints included objective response rate and the duration of response. Exploratory analyses included the assessment of survival outcomes of each type of treatment according to liver and brain metastasis. Results: Overall, 56 SCLC patients, diagnosed between 2003 and 2019, were observed (age <65: (27.0%, 10 patients); ≥65 (73.0%, 41 patients)). Most often prescribed treatment were etoposide-carboplatyl (80.8%, 42 patients) and atezolizumab (19.2%10 patients). Regarding metastasis at diagnosis, liver and brain metastasis were respectively (26.8%, 11 patients) and (17.1%, 7 patients). 27patients (71.1%) were alive at 6 months without progressive disease and 13 patients (34.21 %) alive at 12 months without PD. Median progression free survival incidence since diagnosis was 8.8 months. Overall survival was 10.86 months. Objective response rate after first line was 84.2%. In a cox regression analysis, liver metastasis, brain metastasis, survival at 6 or 12 months without progressive disease did not decrease significantly PFS or OS since diagnosis. Conclusions: To our knowledge, this is the first real world clinical data on SCLC in Lebanon. This study showed limited treatment options and short survival outcomes with PFS= 8.8months and OS= 10.86 months respectively for carboplatin etoposide regimen and tecentriq carboplatin etoposide regimen. There is an essential needs for clinical comparative studies in real world practicing between treatments at each line, specially for novel treatment like atezolizumab that may present new hope and directions for SCLC.
Clinical and genetic characteristics of EGFR-mutant lung adenocarcinoma transformed SCLC.
Authors: Gu Linping , Zhang Bei , Zhang Ding , Jian Hong 
Published: June 2021

e20588 Background: Transformation from non-small cell lung cancer (NSCLC) to small cell lung cancer (SCLC) is one of the resistance mechanism of EGFR tyrosine kinase inhibitors. However, the clinical course of transformed SCLC and the difference of genomic profiling between de novo SCLC patients and transformed SCLC patients are still poorly characterized. Methods: Patients from our hospital diagnosed with SCLC were enrolled retrospectively in this study, including de novo SCLC patients and SCLC patients transformed from EGFR-mutant lung adenocarcinomas. Genomic profiling was performed on formalin-fixed paraffin-embedded tumor samples by next generation sequencing (NGS). In statistical analysis, fisher ‘exact test was used. All tests were bilateral, with P<0.05 indicating significant statistical difference. Results: In total, 16 patients with SCLC transformed from EGFR-mutant lung adenocarcinomas and 230 de novo SCLC patients were included in our study. Transformed SCLC patients were more in younger (p=0.007), female (p<0.001) and non-smokers (p<0.001) than de novo SCLC patients. In transformed SCLC patients, 12 patients (75%) occurred SCLC transformation within 2 years after the lung adenocarcinomas diagnosis. Median transformation time was 20 months. During the treatment of adenocarcinomas, the overall response rate (ORR) was 75% and the median progression-free survival was 12 months. After the initiation of SCLC therapy, the ORR of 1st line chemotherapy was 40%. For the genomic profiling, EGFR mutations, including exon 19 deletion (56%), L858R (38%), and others (6%), were detected. 11 patients with acquired resistance were received EGFR T790M test, 82% of patients had acquired EGFR T790M mutation. 11 patients after transformation to SCLC had NGS test, 100% maintained their founder EGFR mutation, and other recurrent mutations included TP53, RB1 and EGFR amplification. Compared with the genetic alterations in de novo SCLC patients, TP53 mutations were significantly decreased (p=0.006) while EGFR mutations were significantly elevated (p<0.001) in transformed SCLC patients. However, no significant difference on RB1, ALK and ROS1 mutations were observed. Interestingly, a 60-year-old woman in our transformed SCLC cohort harbored EGFR 19 del mutant at allele frequency of 50.39%，she received osimertinib plus epirubicin/cyclophosphamide as 1st line treatment and reached partial response, with survival of 4 years to date. Conclusions: We demonstrated the clinical and genetic characteristics of EGFR-mutant lung adenocarcinoma transformed SCLC and found one patient still benefited from EGFR-TKI. Our study suggested that SCLC patients with EGFR mutation who transformed from lung adenocarcinoma may be potential benefit population using EGFR inhibitors.
Omics guided small molecule inhibitor screen for the identification of therapeutic vulnerabilities in metastatic lung adenocarcinoma.
Authors: Morris Benjamin B. , Gray Lisa G. , Gentzler Ryan D. , Jones David Randolph , Mayo Marty W. 
Published: June 2021

e21015 Background: Recent studies from our lab and others have demonstrated that double-strand DNA break accumulation, error-prone repair, and genomic instability are strongly linked to increased metastasis to distant organs. Our lab has shown that lung adenocarcinomas overexpressing the transcription factor MYBL2 display chronic replication stress, elevated error-prone repair, and widespread genomic instability. Importantly, this MYBL2-driven phenotype accounts for ̃21% of all lung adenocarcinomas and identifies aggressive disease enriched for metastases to brain, liver, and kidney. This study was performed to identify clinically actionable therapeutic vulnerabilities in MYBL2-driven metastatic lung adenocarcinoma. Methods: RNA-sequencing and proteomic data from the TCGA and ORIEN consortiums were mined to identify highly expressed druggable targets in MYBL2-driven lung adenocarcinomas. Identified targets were used to assemble a custom inhibitor library of 50 small molecules targeting DNA repair effectors, epigenetic factors, protein translation, kinase-signaling, autophagy, and post-translational modifications. Omics data from the Cancer Cell Line Encyclopedia was used to identify human cell line models (H1650 (pleura), H1568 (lymph node), H1299 (lymph node)) of MYBL2-driven metastatic disease. Inhibitors were tested at two doses, 5 uM and 500 nM, in triplicate, across replicate experiments. The PrestoBlue HS viability reagent was used to quantify cell viability in a 96 well plate format. The primary endpoint of this study was statistically significant cancer cell death, compared to vehicle controls. Results: Screen results demonstrated that, at nanomolar doses, inhibitors of protein translation have strong anti-tumor effects in MYBL2-driven disease. Interestingly, small molecules targeting EIF4G1 (SBI-0640756), ribosome biogenesis/RNA export (YM155), and rRNA synthesis (CX5461) were effective in inducing cell death while inhibitors blocking mTOR signaling, EIF2A phosphorylation, and EIF4F complex assembly were not. Bioinformatic analysis revealed that ̃60% of MYBL2-driven transcripts are dependent on EIF4G1 for translation. Importantly, effected transcripts include effectors controlling DNA repair, cell cycle coordination, and cell survival. Conclusions: Our data demonstrates that MYBL2-driven metastatic disease is uniquely sensitive to inhibitors of the protein translation machinery. Importantly, these inhibitors significantly outperform current standard-of-care agents cisplatin and pemetrexed. To our knowledge, our study is the first to demonstrate that blocking EIF4G1 effectively induces widespread cell death in metastatic lung adenocarcinoma models. Collectively, our work supports initiation of clinical trials testing the efficacy of SBI-0640756 in MYBL2-driven metastatic lung adenocarcinoma.
Costs of the immune check point inhibitors versus survival ratio in first-line non-small lung cancer, cost bundling proposal.
Authors: Guirgis Helmy M. 
Published: June 2021

e21034 Background: Pembrolizumab (Pembro) demonstrated marked prolongation of 5-year overall survival (OS) in 1st-line advanced/metastatic (a/m)-non-small lung cancer (nsLC). Adjuvant Durvalumab (Durv), Atezolizumab/Bevacizumab (Atezo/Bev), Ipilimumab/Nivolumab (Ipi/Nivo) and Pembro-combination have since improved the outcome. Progress, however, came at high costs of the immune check point inhibitors (ICI). There is unmet need for cost-constraining policies. We purposed 1- Weigh costs of ICI vs outcome 2- Propose cost bundling at negotiable $450,000 - $550,000 thresholds, depending on the number of companies and drugs involved. Methods: OS, hazard ratio (HR) and survival ratio (SR), defined as (1.0-HR) were used. Chemo-drugs excluded, costs of ICI doses were calculated in US$. Results: Durv one-year costs in unresectable stage III were $130,956, OS gain 363 days and SR 0.47. Pembro one-year costs were $134,778, OS 474 and SR 0.37 in PD-L1 > 50%. At 5 years, costs were $673,890. Bundling negotiated at $450,000-$550,000 would save $123,112-$223,890. Costs of 35 cycles of Pembro-combination were $336,945, OS 339 and SR 0.51. Costs of Atezo/Biosimilar-Bev-comnination supplied by > one company, were $429,744, OS 135 and SR 0.22. Ipi/Nivo costs were $544,696, OS 141 and SR 0.34. Costs of Atezo/Bev and Nivo/Ipi used beyond 2 years exceeded $550,000 and multiplied by one more of use. Costs of Pembro-combination were 0.78 lower than Atezo/Bev and 0.62 than Ipi/Nivo. Pembro SR were 2.32 higher than Atezo/Bev and 1.65 than Ipi/Nivo. Lack of direct comparison undermined Pembro SR advantage. Conclusions: Costs of one-year adjuvant Durv, 3-year Pembro and 35-cycle Pembro-combination seemed equitable with their corresponding SR and below the $450,000 threshold. Pembro-combination costs were cheaper than Atezo/Bev and Nivo/Ipi. ICI costs of extended use tend to support the bundling proposal.
STAT6 polymorphism was correlated with gefitinib-induced diarrhea in patients with non-small cell lung cancer.
Authors: Guan Shaoxing , Chen Xi , Chen Youhao , Huang Min , Zhang Li , Wang Xueding 
Published: June 2021

e21046 Background: Gefitinib-induced diarrhea can be severe, if not properly handled, and can result in severe dose reductions and treatment interruptions or discontinuation. However, the mechanism of gefitinib-induced diarrhea remains unclear. STAT6 promotes disruption of epithelial tight junction integrity, intestinal inflammation and allergic disorders in intestine. Therefore, we explored the correlation between variations in STAT6 and gefitinib-induced diarrhea in advanced non-small cell lung cancer (NSCLC) patients. Methods: A total of 160 advanced NSCLC patients carrying EGFR mutations were enrolled. 8 tag single nucleotide polymorphisms (SNP) in STAT6, including rs10876963, rs167769, rs3122929, rs3024975, rs841718, rs324013, rs324015 and rs703817, were selected by Heploview 4.2 and sequenced by Agena MassARRAY System. The associations between tag SNPs of STAT6 and diarrhea were analyzed by Chi square test and multivariate logistic regression. This study was approved by the ethical committee of Sun Yat-Sen University Cancer Center. Results: 71 patients (44.4%) suffered at least grade 1 gefitinib-induced diarrhea. We found rs167769 was associated with gefitinib- induced diarrhea in NSCLC patients. STAT6 rs167769 TT carriers were all suffering from gefitinib-induced diarrhea (OR = 2.4*1010, p = 0.999). Patients with STAT6 rs167769 TT have higher risk of developing severe (grade ≥ 2) diarrhea than those with STAT6 rs167769 CC/CT. Conclusions: STAT6 rs167769 is a predictive biomarker for gefitinib-induced diarrhea and the analysis of polymorphisms of STAT6 rs167769 might be beneficial to optimize gefitinib treatment. Further studies are needed to clarify the underlying mechanisms. Clinical trial information: NCT01994057.