bluuebunny/crossref_metadata_2025_split huggingface dataset:
Correlation of gefitinib and its metabolites with gefitinib induced rash in patients with non-small cell lung cancer (NSCLC).
Authors: Guan Shaoxing , Chen Xi , Huang Min , Zhang Li , Wang Xueding 
Published: May 2020

e21712 Background: Gefitinib induced rash is the most common adverse reaction and severe rash of gefitinib often leads to discontinuation or termination of treatment. The concentrations of drug and its metabolites may affect drug induced toxicities, however, the association of gefitinib/metabolites with gefitinib-induced rash are poorly investigated. Therefore, we explored the association between concentrations of gefitinib and its four metabolites with gefitinib-induced rash in non-small cell lung cancer (NSCLC) patients. Methods: A total of 180 advanced NSCLC patients carrying EGFR sensitive mutations receiving gefitinib were enrolled. The concentrations of gefitinib, and its four metabolites including M537194, M387783, M523595 and M605211 were determined by liquid chromatography–tandem mass spectrometry (LC–MS/MS). The associations between concentration of gefitinib/its metabolites and gefitinib-induced rash were analyzed by Mann-Whiney U test. Operating characteristic curves(ROC) were used to determine gefitinib/metabolites cutoff values for gefitinib-induced rash. Results: M605211 was first detected in plasma in NSCLC patients. The concentrations of gefitinib and M605211, M537194 were found to be correlated with the incidence of gefitinib-induced rash ( P= 0.0002, 0.027 and 0.0097, respectively), moreover, the concentration of gefitinib was correlated with severe rash (Grade 0,1 vs. 2+, P= 0.017). Multivariate Logistic regression analysis showed that only gefitinib concentration was independent risk factor for gefitinib-induced rash (grade 0 vs grade1+, OR = 1.006, 95%CI (1.002-1.009), P = 0.00078; grade0,1 vs grade2+, OR = 1.003, 95%CI (1.001-1.005), P = 0.015, respectively). The cutoff values of gefitinib were 160.2 ng/ml (grade 0 vs grade1+, sensitivity = 78.7%, specificity = 47.7%, area under the curve (AUC) = 0.686, P = 0.0002, 95% CI (0.592-0.779)) and 201.7ng/ml (grade0,1 vs grade2+, sensitivity = 69.3%, specificity = 47.6%, AUC = 0.605, P = 0.0168, 95%CI (0.521-0.689)). Conclusions: This research demonstrated that the concentration of gefitinib and its metabolites were associated with gefitinib induced rash in NSCLC patients. Therapeutic drug monitoring of gefitinib concentration may have potential improvement for optimization of treatment with gefitinib. Clinical trial information: NCT01994057.
Sequential serum let-7a to predict accelerated reproliferation of lung cancer cells during chemotherapy and long-term survival.
Authors: Xie Peng , Li Xiaolin , Guan Yan , Tang Wenjie , Xie Xueqi , Wang Chungang , Sun Xindong , Yu Jinming 
Published: May 2020

e21721 Background: Accelerated reproliferation during radiation is a classic theory in radiobiology. The long intervals between cycles of chemotherapy provides a better micro-circumstance to reproliferate of cancer cells. Few studies explored the accelerated reproliferation among cycles of chemotherapy. Methods: Patients with inoperable stage III and stage IV lung cancer from Shandong Cancer Hospital and Institute were enrolled prospectively. Tumor tissue and sequential peripheral blood were obtained before treatment and among cycles of chemotherapy to detect Ki-67 and let-7a expression. All patients were followed up to observe the occurrence and survival. Results: Fifty-two consecutive consenting patients were enrolled prospectively. The median follow-up was 13 months (range, 2–62 months). A strong correlation was found between serum let-7a and tissue Ki-67 before treatment (r = − 0.667, P < 0.001). The serum let-7a expression level was significantly upregulated at the time point after 2 and 4 cycles of chemotherapy, respectively, compared with the original. Then, at the time point after 6 cycles of chemotherapy, the expression levels of let-7a returned to relatively low level (F = 7.994, P < 0.001). Patients with high level of baseline serum let-7a had significantly better OS and PFS than patients with relatively low level of baseline serum let-7a (The 1-year OS and PFS rates were 80.6% VS 33.3%, X2 = 12.81, P < 0.001, and 54.2% VS 20%, X2 = 8.001, P = 0.005, respectively). Conclusions: The study showed that serum let-7a could reflect the proliferation of tumor tissue reliably in lung cancer, with high prognostic value. Furthermore, the study showed that accelerated reproliferation exists during treatment of cancer, not only in radiotherapy, but also in chemotherapy, which can give us a new perspective to overcome drug resistance of lung cancer, and would help in determining individual treatment strategy. This project was supported by National Natural Science Foundation of China (Grant No. 81502667) and Key Research and Development Plan of Shandong, China (Grant No. 2016GSF201167).
The role of radiation dose-dependent enhancement of fatty acid oxidation in radiation surviving/resistant lung cancer cells.
Authors: Li Shangbiao , Zhu Xiaoxia , Wang Lijuan , Zheng Zhihao 
Published: May 2020

e21724 Background: Radiotherapy plays a critical role in the integrated management of lung cancer. However, radioresistance limits the long-term control. Exploring the dynamic changes of metabolic reprogramming in radiation surviving/resistant (S/R) lung cancer cells is helpful to clarify the metabolic mechanism of radiation resistance and to develop new targets for intervention and early detection. Methods: Cell lines were irradiated with different doses (2Gy × 20F, 2Gy × 30F, 2Gy × 40F) in conventional dose fractionation. The cellular radiosensitivity was verified by colony formation assay and neutral comet assay. Cell proliferation ability was determined by EdU assay. Metabonomic analysis was used to identify the differentially expressed metabolites between high-dose radiation-resistant cells and their parent cells. Lipid droplet content was detected by Oil Red O (ORO) staining. Cell oxygen consumption rate (OCR) was measured by Seahorse XF24e analyzer. Western blot was used to detect the expression of metabolic enzymes. The growth of xenograft tumors from these cell lines in BALB/c nude mice were measured after the treatment of radiation (2Gy×5F), Etomoxir, or radiation combined with Etomoxir. Results: Compared with parent cells, the radioresitance of S/R lung cancer cells after different doses of radiationwas significantly increased with the increase of radiation exposure. ORO staining showed that fatty deposition of radiation S/R cells was obviously higher than their parent cells, and more fatty deposition in cells received higher dose of radiation. The ketone body metabolism-related substances, including acetoacetic acid, a metabolite of FAO, were significantly enriched in high-dose radiation-resistant cells. The expression of carnitine palmitoyltransferase1 (CPT1) and the OCR in radiation S/R cells were also radiation-dose dependently increased. Etomoxir, an inhibitor of fatty acid oxidation, significantly enhanced the radiosensitivity and decreased the OCR and DNA repair ability of various S/R cells exposed to radiation. We further confirmed that Etomoxir could significantly inhibit proliferation of radiation S/R cells in vivo, which also presented with radiation-dose dependent model. Conclusions: The enhancement of radiation dose-dependent FAO promotes radiation surviving/resistance of lung cancer cells. CPT1A, a key metabolic enzyme mediating FAO, may be a potential target for treatment of radiation resistant lung cancer. Funding: 81972853, 81572279, 2016J004, LC2019ZD009, 2018CR033.
Efficacy and safety of bevacizumab biosimilar FKB238 versus originator bevacizumab: Results from a phase III trial in patients with non-squamous non-small cell lung cancer (NS-NSCLC).
Authors: Syrigos Konstantinos N. , Fu Dongyue , Jones Stephanie , Bashir Zahid ,   on behalf of the FKB238-002 Investigators
Published: May 2020

e21728 Background: Bevacizumab (bev) is a recombinant humanized monoclonal antibody that binds selectively to VEGF-A and prevents it from interacting with its receptors, thereby inhibiting formation of new tumor vasculature to block tumor growth. FKB238, a bev biosimilar, has similar pharmacokinetic and safety profiles to originator bev (o-bev). This phase 3 trial (NCT02810457) compared the efficacy and safety of FKB238 with o-bev in patients with advanced/recurrent non-squamous non-small cell lung cancer (NS-NSCLC). Methods: This global, multicenter, double-blind, parallel, randomized, comparative clinical trial enrolled and randomized 731 patients with advanced/recurrent NS-NSCLC to receive 15 mg/kg intravenous (IV) infusion of either FKB238 (N = 364) or o-bev (N = 367). All patients received IV infusions of paclitaxel (200 mg/m2) and carboplatin (AUC 6.0) immediately prior to investigational drugs for 4-6 cycles. FKB238 and o-bev were administered on day 1 of each 21-day cycle until objective progressive disease or other discontinuation criteria were met. Results: The objective response rate (ORR) based on blinded independent central review assessment for the intent-to-treat population was 51.6% and 53.7% for patients in the FKB238 and o-bev arms, respectively. The FKB238/o-bev ORR ratio was 0.96 (90% CI: 0.86 to 1.08) and the 90% CI fell within the pre-specified equivalence margin. The estimated proportion of patients alive and progression free at 12 months was 25.0% in the FKB238 arm vs 25.3% in the o-bev arm (HR of 0.97, 95% CI 0.82-1.16). The estimated median progression-free survival was 7.72 months in the FKB238 arm and 7.62 months in the o-bev arm. TEAEs were reported for 94.2% (FKB238) and 95.1% (o-bev) of patients. TEAEs ≥ grade 3 were reported for 53.6% (FKB238) and 55.5% (o-bev) of patients. SAEs were reported for 25.1% and 26.0% of patients treated with FKB238 and o-bev, respectively. Conclusions: There were no meaningful differences in efficacy and safety between FKB238 or o-bev in patients with NS-NSCLC. ORR efficacy equivalence was demonstrated, and the safety profiles of both drugs were similar. Clinical trial information: NCT02810457.
Comparative effectiveness of immune-checkpoint inhibitors as first-line treatment for advanced nonsquamous non-small cell lung cancer patients: A network meta-analysis and a systematic review.
Authors: Bitton Roberto Jorge , Jacob Natalia , Carrera Juan Manuel , Perez Ezequiel Cayetano 
Published: May 2020

e21731 Background: Over the last decade six different immune-checkpoint inhibitors (ICI) have obtained approval in 42 tumor types, several of them are indeed competing for the same indication and there is a lack of direct comparative data to guide the medical oncologist. Network meta-analysis (NMA) is a technique developed as an extension of pairwise meta-analysis to allow comparisons of multiple treatments, using both direct and indirect evidence. This NMA evaluates the effectiveness of several ICIs, either in combination or as single agents, as frontline therapy for patients with advanced non-squamous non-small cell lung cancer (NSCLC). Methods: We conducted a systematic review of randomized controlled trials (RCT) through Pubmed, Embase, Cochrane Central register of Controlled trial databases, Clinicaltrial.gov database and ASCO abstracts (up to June 2019), to identify phase III RCTs on advanced non-squamous NSCLC in the first-line setting. Both the search and study screening were performed for two independent reviewers. NMA of survival outcomes in different subsets of PD-L1 expression groups was performed and ICIs indirect comparisons were performed. Results: 6 RCTs with 5860 patients were included for the NMA. ICIs were evaluated in combination with several chemotherapy regimens and in the case of Nivolumab in combination with ipilimumab. Atezolizumab was evaluated in one of the RCTs in combination with chemotherapy and bevacizumab. Both Pembrolizumab and Nivolumab were evaluated as monotherapy, either in a separate treatment arms within a trial or in a separate trial. Overall ICI in combination improved survival across PD-L1 expression level subgroups compared with chemotherapy (platinum doublets +/- bevacizumab). Indirect comparisons of ICIs in combination therapy for first-line treatment in advanced non-squamous NSCLC showed little evidence of differences between pembrolizumab or atezolizumab in combination with chemotherapy and nivolumab/ipilimumab. Evaluated as monotherapy pembrolizumab seems to have more evidence of effectiveness than nivolumab. Conclusions: ICIs in combination therapy improve survival in previously untreated advanced NSCLC across PD-L1 expression levels compared with standard first line chemotherapy regimens. There is little evidence of survival difference between pembrolizumab and atezolizumab in combination, and nivolumab requires a combination with ipilimumab to reach similar levels of effectiveness.
ROS1 immunohistochemistry as a screening tool for detection of ROS1 rearrangement in non-small cell lung cancer: Comparison between SP384 and D4D6 clones.
Authors: Chang Yi-wen , Liang Yun-hsin , Liao Li-rung , Yeh Yi-chen , Chou Teh-Ying 
Published: May 2020

e21733 Background: ROS1 rearrangement occurs in approximately 1%-2% of non-small cell lung cancer, and it is predictive of treatment response to tyrosine kinase inhibitor. The gold standard method to detect ROS1 rearrangement is break-apart fluorescence in situ hybridization (FISH). ROS1 immunohistochemistry has been proposed as a cost-effective screening test for detection of ROS1 rearrangement. Most studies about the correlation between ROS1 FISH and immunohistochemistry derived from the D4D6 clone anti-ROS1 antibody. Recently, a novel anti-ROS1 antibody (SP384 clone) is available. However, data regarding the performance of this new anti-ROS1 antibody is still limited. In this study, we evaluated the performance of these two anti-ROS1 antibody as a screening tool to detect ROS1 rearrangement. Methods: Two hundred non-small cell lung cancers, including 18 ROS1 FISH-positive and 182 ROS1 FISH-negative samples, were studied. All specimens were stained with D4D6 clone and SP384 clone anti-ROS1 antibodies. The stained slides were scored by a pathologist using the H-score method, which was defined as the sum of products of multiplying intensity (0, 1, 2, and 3) by extent of each staining intensity (%). Receiver Operating Characteristics (ROC) curves were used to determine the optimal cut-off value that discriminates between ROS1-rearranged and non-rearranged tumors. Results: There was high correlation between the H-score of D4D6 clone and SP384 clone (Spearman's rho correlation coefficient = 0.862, P-value < 0.001). The SP384 clone showed a higher H-score than D4D6 clone (Wilcoxon signed rank test, P-value < 0.001). ROC analysis showed H-score of ≥ 150 was the optimal cut-off value for both D4D6 clone and SP384 clone to discriminate between ROS1-rearranged and non-rearranged tumors. Using this cut-off value, the D4D6 clone showed 100% sensitivity and 96.7% specificity; the SP384 clone showed 100% sensitivity and 95.1% specificity. The areas under ROC curve for D4D6 clone and SP384 clone were 0.992 and 0.990, respectively. Conclusions: The performance of D4D6 clone or SP384 clone is comparable. ROS1 IHC with either D4D6 clone or SP384 clone is a cost-effective screening tool for the presence of ROS1 rearrangements. [Table: see text]
The effect of under and uninsured status on survival in lung cancer while adjusting for other mortality risk factors.
Authors: Mohamed Mohamed K. , Herndon Dana , Schmidt Monica , Manning Matthew A. 
Published: May 2020

e21734 Background: Lung cancer is the leading cause of cancer death in the US. Significant improvements in survival have occurred with improved treatments. Payer status has been recognized as a barrier to treatment access across multiple cancer types including lung. This study aims to evaluate the impact of payer on 2-year survival rates for patients presenting in one health system with newly diagnosed lung or bronchus cancer. Methods: This is a retrospective survival analysis. There were 1,681 patients with lung cancer (small and non-small) under observation from time of first diagnosis. The first diagnosis date in the Cone health system defined study entry. Failure was defined as death during the 2-year observation period with right censoring after 2-years. Patients were categorized as underinsured if they had no insurance or Medicaid while those with commercial and Medicare were considered having full coverage. Cox proportional hazard models were used reporting hazard ratios. Results: Mortality rates per 10 patients diagnosed with lung or bronchus cancers were 3.5 for those with commercial insurance, 3.8 for Medicare, 3.3 for Medicaid and 5.4 for uninsured patients. Of those patients considered underinsured, 56.7% presented with stage IV cancer compared to those with full coverage (41.4%)*. 40.7% of those without insurance or underinsured were current tobacco product users compared to 25.1% of those with full coverage. Cox proportional hazard models revealed the risk of death is 1.34* times (95% CI 1.07-1.68) greater for underinsured patients compared to those with full coverage. The model adjusted for age, race, gender, marital status, language, Gini coefficient, Elixhauser comorbidity index, illicit drug use, cigarette smoker, smokeless tobacco user, alcohol use, PCP on record, and religion. However, when we add the AJCC stage to this model, the underinsured estimate is no longer statistically significant (1.23; 95% CI 0.92-1.65). Conclusions: Patients without insurance are diagnosed at later stages of disease. This late diagnosis is the primary driver of poor survival. Although being underinsured or uninsured is associated with a greater risk of death after diagnosis, adjusting for stage mitigates this effect. These findings support the need for equal access to early screening and diagnosis regardless of payer. *statistically significant at p < 0.05.
Single-institution outcomes with less than two-year anti-PD-1 antibody therapy in metastatic melanoma.
Authors: Lama Tamang Tsering G. , Fruehauf John P. , Ejadi Samuel 
Published: May 2020

e22001 Background: Optimal duration of anti-PD-1 antibody therapy remains undefined. Currently, treatment is given up to two years in metastatic melanoma based on clinical trials. However, recent observations suggest that anti-PD-1 antibodies may work as well if given for shorter time periods. To better understand duration of anti-PD-1 antibody treatment, we reviewed outcomes for patients who discontinued immunotherapy earlier than 2 years in our Cancer Center. Methods: This is a retrospective, single-institution review of metastatic melanoma patients who received anti-PD-1 antibodies from January 2010 to December 2019. We further identified the patients discontinuing treatment before completion of 2 years for reasons other than disease progression. Duration was categorized into three groups: < 6 months (A), 6-12 months (B) and > 12 months (C) and outcomes were analyzed. Progression free survival (PFS) was defined as the time from the initiation of anti-PD1-therapy to the date of progression as determined by treating physician based on radiological, biochemical and/or clinical criteria. Results: 25 patients with mean age 69 years (49-91; N = 19 > 60yo) were identified. Number of patients who received anti-PD-1 antibodies were N = 8, N = 9 and N = 8 in in groups A, B and C respectively. 44% of patients discontinued treatment after achieving either partial or near complete remission, whereas the remaining 66% of patients discontinued treatment due to adverse events. Majority of patients who stopped treatment due to adverse events were older than 60 (71.4%). In 29 months of median follow up (range 11-54), none of patients who received treatment in group B progressed, whereas in groups A and C, 25% percentage progressed in each group with 80% PFS at 12.8 months and 88% PFS at 26 months respectively. 12.5% of patients in group A had progression at 12 months follow up, where no progression was noticed in groups B and C during the same time period. Conclusions: Retrospective analysis of our experience supports other retrospective findings that treatment with anti-PD-1 antibodies more than 12 months might not add further benefit in responding or non-progressing older patients though further study with longer follow up is required.
Real-world experience of talimogene laherparepvec in patients receiving immunotherapy in metastatic melanoma.
Authors: Behera Tapas Ranjan , Song Jung Min , Ko Jennifer S. , McNamara Michael J. , Funchain Pauline , Gastman Brian 
Published: May 2020

e22003 Background: Talimogene laherparepvec (TVEC) is an oncolytic herpes virus approved by the FDA for intralesional therapy in unresectable metastatic melanoma. However, little is known regarding the effectiveness of TVEC+checkpoint inhibition (CPI) outside of clinical trials. We present outcomes of the largest single institution experience with TVEC in the context of different immune checkpoint inhibitors. Methods: All patients with stage III-IV unresectable melanoma having received TVEC were evaluated. Patient demographics, clinicopathological characteristics, TVEC treatment response and outcomes were assessed. Final analysis included those who received TVEC adjacent to CPI with a minimum 6-month follow-up, excluding patients on clinical trials. Response was estimated by sequential measurement of injectable on-target lesions. Results: A total of 62 patients received TVEC from 2016 to 2019, of which 43 remained excluding Merkel cell carcinoma, patients on trials, and TVEC monotherapy. Of 30 patients with available treatment response data and at least 6-months follow-up, median age was 68.5 years (30-99 years), 40% were female, 16 (53.3%) stage IV. Median follow-up was 17.5 months (6-43 months). At 6 months, 20 (67.7%) patients were alive; at 1 year, 17 (56.7%) patients were alive. Eighteen patients received pembrolizumab, 7 nivolumab and 5 ipilimumab/nivolumab. Median number of TVEC doses received was 8 (3-31 doses). Median time on TVEC therapy was 4 months (1-26 months). Overall response rate for on-target lesions was 24 (80%), with complete local response (CR) in 15 (50%), partial response (PR) in 9 (30%), and progressive disease (PD) in 6 (20%). Median time to response was 6 weeks (2-17 weeks); 5 in CR, 6.5 in PR and 5.5 in PD groups. Adverse events were mostly mild and limited to constitutional symptoms. Conclusions: To our knowledge this is the largest real-world experience assessing TVEC in patients receiving CPI. Local overall response rate appears higher in comparison to historic numbers for TVEC monotherapy. The findings demonstrate that TVEC is an effective and safe treatment for metastatic melanoma and has robust outcomes in real-life clinical settings.