bluuebunny/crossref_metadata_2025_split huggingface dataset:
ALK resistance mutations and co-occurring genetic alterations to the ALK tyrosine kinase inhibitors in lung cancer.
Authors: Yang Jin-Ji , Zhang Chi , Zhao Jun , Dai Pingping , Lin Gen , Han Liankui , Chen Chen , Guan Yan-Fang , Yang Ling , Yi Xin , Xia Xuefeng 
Published: May 2019

e20675 Background: Acquired ALK mutations pose a challenge in multiple ALK tyrosine kinase inhibitors (TKIs) for lung cancer. In our study, we examined the profiles of ALK resistance mutations and co-occurring genetic alterations after targeted therapy. Methods: Using targeted gene capture and next-generation sequencing technologies, we analyzed the somatic mutations from174 patients (pts) with post-TKI samples. Among them, 123 pts received first-generation TKI crizotinib only, 51 pts (34 with second-generation TKI, 17 with third-generation TKI) treated with multiple ALK-TKIs. Results: After the treatment of ALK-TKIs, 29% (50/174) patients developed ALK resistance point mutations, including G1202R (22 pts), G1269A (13 pts), L1196M (8 pts), D1203N (5 pts), F1174L (4 pts), I1171T (4 pts), E1210K (4 pts), G1128A (3 pts), F1174C (3 pts), C1156Y (1 pts), G1123S (1 pts), I1171S (1 pts), L1152R (1 pts), and 10 of them had multi-clone. Specifically, G1269A was found a higher proportion in crizotinib group contrast to multi-TKIs cohort (10/24 vs 3/26, p = 0.024). The recalcitrant G1202R was another common resistance mutation, but there was no significant difference between the two groups (p = 0.052). Other concurrent genetic alterations related to clinical response were usually observed in TP53 mutations (46%), furthermore it seemed to be more frequently detected in post-crizotinb compared with multi-TKIs (P = 0.023). Activated bypass signaling may promote tumor progression. In non-ALK resistance point mutations samples (n = 124), co-occurring genomic alterations in EGFR (32/124, p = 0.004) were significantly more enriched in crizotinib group (n = 99). The driver gene mutation may limit crizotinib response. However, EP300 (24%), CDKN2A (12%), TRIM58 (12%), STK11 (12%) or KRAS (8%) mutations were common in the multiple ALK-TKIs group (n = 25). Conclusions: In lung cancer patients, ALK resistance point mutations G1269A was significantly enriched in post-crizotinib, while patients with multiple ALK-TKIs may frequently found G1202R or L1196M. The co-occurring genetic alterations in TP53 or EGFR after the TKIs therapeutic may offer directions for further research and therapy in lung cancer.
Nomogram based on multivariable regression model estimates the overall survival of patients with nivolumab who were previously treated for advanced non-small cell lung cancer.
Authors: Tamiya Motohiro , Tamiya Akihiro , Go Hirofumi , Inoue Takako , Kimura Madoka , Kunimasa Kei , Nakahama Kenji , Taniguchi Yoshihiko , Shiroyama Takayuki , Isa Shun-Ichi , Nishino Kazumi , Kumagai Toru , Suzuki Hidekazu , Hirashima Tomonori , Atagi Shinji , Shintani Ayumi , Imamura Fumio 
Published: May 2019

e20683 Background: Nivolumab (Nivo) has demonstrated with its efficacy against metastatic non-small cell lung cancer (NSCLC). However, it has been also reported that Nivo does not show beneficial effects in approximately 80% of patients. The predictive ability of biomarkers still is yet unclear; thus identifying biomarkers which better predict overall survival (OS) of such patients treated with Nivo is crucial. In this study, we conducted multivariable cox regression analysis including biomarkers and clinical factors measured at the time of initiating treatment with Nivo to assess predictive ability of OS of patients. Results of the multivariable analysis were elucidated with a nomogram which estimates the OS of Nivo in previously treated patients with advanced NSCLC. Methods: In this study, data for 201 patients treated with nivolumab during 17 December 2015 to 31 July 2016 at three respiratory medical centers in Japan were retrospectively reviewed. We collected clinical data at the time of nivolumab treatment commencement, and we evaluated two programmed cell death ligand 1 (PD-L1) immunohistochemistry (IHC) assay systems (22C3 and 28-8). Results: The median age at the time of administration nivolumab was 68 years, 135 patients were male, 157 patients had a smoking history, and 152 patients had a performance status (PS) score of 0–1. 39 patients had EGFR (37) or ALK (2) mutation positive. For 22C3 and 28-8, 36.3% and 36.8% of patients were negative, 17.4% and 14.4% had PD-L1 status of 1-49%, and 11.9% and 14.9% had PD-L1 status of ≥50%, 34.3% and 33.8% had PD-L1 status of missing, respectively. Kendall’s rank correlation coefficient between 22C3 and 28-8 was 0.8414. The median OS of all patients was 333 (95% confidence interval (CI): 116-520) days. In the multivariate analysis, PS score ≥2 (hazard ratio (HR): 2.23; 95%CI: 1.36-3.66 p < 0.001), high LDH level at baseline (HR: 1.13 95%CI: 1.03-1.24; p = 0.008, and progression disease (PD) of pre-treatment response (HR: 3.64 95%CI: 2.29-5.79 p < 0.001) were significantly associated with poor OS. There was not significant distance between PD-L1 status and OS of Nivo. Based on these analyses, we created the nomogram to estimate the OS of Nivo in previously treated patients with advanced NSCLC. Conclusions: PS score ≥2, high LDH levels at baseline, and PD of pre-treatment response were predictive of poor OS of Nivo, moreover the nomogram might be useful to estimate the OS of Nivo in previously treated patients with advanced NSCLC.
Cost-effectiveness of PD-L1 testing and tumor mutational burden testing of immune checkpoint inhibitors for non-small cell lung cancer.
Authors: Li Wenqian , Li Lingyu , Chen Naifei , Cui Jiuwei 
Published: May 2019

e20689 Background: Immunotherapy that targeted programmed death ligand 1 (PD-L1)–programmed death 1 (PD-1) pathway showed great benefit on survival compared with other therapies, especially with certain assessments before. However, the high costs limit its use. This cost-effectiveness analysis aimed to measure the significance of various assessments in immunotherapy. Methods: A decision-tree model was established based on the data of OAK study, we compared the economic benefit between immunotherapy and chemotherapy in no test group, PD-L1 test group and tumor mutational burden(TMB) test group respectively with a willingness-to-pay threshold of 3× the per capita gross domestic product ($29307/quality-adjusted life year [QALY]). Besides, we also balanced the benefit of immunotherapy among different groups. Furthermore, we also considered different costs of TMB tests due to the various methods of detection. Sensitivity analyses were conducted to evaluate the stability. Results: Immunotherapy was cost-effective compared with chemotherapy in all groups. Immunotherapy with PD-L1 test achieved economic benefit when comparing with both TMB test group and no test group. However, TMB test group was not cost-effective compared with no test group. The results from average CE and net benefit were consistent. Tissue-based TMB test was the most cost-effective TMB detection methods. One-way sensitivity analyses reflected the impact of utilities. Conclusions: Immunotherapy was cost-effective compared with chemotherapy. PD-L1 test was the most cost-effective immunotherapy test. [Table: see text]
The use of liquid and tissue biopsy genomic testing in lung cancer: A single-institution experience.
Authors: Marina Natalia , Do Tien Phuc , Namireddy Praveen , Sharma Nitika , Cherry Cynthia R. , Parent Teresa , Bowling Mark , Walker Paul R. 
Published: May 2019

e20692 Background: Liquid biopsy is an evolving minimally invasive technique to detect cell-free DNA (cfDNA) and cfRNA mutations by next generation sequencing (NGS) in plasma. In our Thoracic Oncology Program, we compared plasma liquid biopsy and tissue-based NGS assay results. Methods: Circulogene Theranostics Personalized Gene Profile (CGP), a 50-gene plasma NGS panel with proprietary direct-on-specimen enrichment technology, and tissue Caris Molecular Intelligence (CMI) NGS cfDNA and cfRNA including microsatellite instability (MSI)/microsatellite stability (MSS) and total mutational burden (TMB) results were retrospectively compiled and compared upon diagnosis. Results: 106 non-surgical lung cancer patients (median age 65 years, range 27-88; 66 men, 40 women) underwent CGP testing. 49 patients had sufficient tissue for comparative CMI. MSI detected in 20.4% (10/49) by CGP; no tissue MSI was found by CMI (0/44). 3 out of 4 (75%) MSI detected by CGP had high TMB ≥ 10 mut/Mb by CMI. 75% MSS patients by CGP had low TMB (12/16). Comparative plasma versus tissue mutations findings: TP53 mutations 60.3% (64/106) CGP and 69.3% (34/49) CMI. CGP TP53 mutated patients, high TMB 70.5 % (20/34) by CMI; EGFR mutations 13.2% (14/106) CGP and 14.2% (7/49) CMI; KRAS mutations 2.8 % (3/106) by CGP versus 28.5% (19/49); one ROS1 by CGP missed by CMI and one ALK by CGP insufficient tissue CMI. A higher frequency of BRAF 16.9% (18/106), PIK3CA 28.3% (30/106), PTEN 22.6% (24/106), and MET 7.5% (8/106) alterations was identified by plasma/CGP than comparative tissue/CMI 6.1% (3/49), 2% (1/49), 6.1% (3/49), and 0% (0/49) respectively. Conclusions: Our findings indicate that Circulogene liquid biopsy NGS detected common mutations, including actionable variants in lung cancer, providing expanded and complementary tumor molecular biology and therapeutic information to tissue NGS.
Clinical benefit of EGFR-TKIs plus radiotherapy for treating EGFR-mutated metastatic non-small cell lung cancer.
Authors: Wang Ran Lin , Li Tao , Lv Jiahua , Sun Chang , Shi Qiuling 
Published: May 2019

e20694 Background: Despite the high response rate and prolonged OS of patients with EGFR mutations treated with gefitinib or erlotinib, there are still major clinical obstacles. The local control rate is still low, only 19.4%–58%, with first-line treatment using EGFR-targeted therapy. The aim of this study is to provide scientific evidence to support the clinical benefits of EGFR-TKI combined with radiotherapy compared to EGFR-TKI alone. Methods: From February 2015 to May 2017, a total of 103 patients with stage IV EGFR-mutated NSCLC treated at Sichuan Cancer Hospital & Institute were analysed retrospectively. 50 patients were treated with EGFR-TKIs (gefitinib or erlotinib) plus radiotherapy (Group TKI-RT) and 53 patients received EGFR-TKIs alone (Group TKI). Tumour response, survival and toxicities were compared between the two groups. Results: Median follow up time was 11.7 months (range: 2.8–36.3 months). The overall response rate (ORR) and disease control rate (DCR) in Group TKI-RT vs. Group TKI were 62% vs. 37.7% (P = 0.014) and 88% vs. 75.5% (P = 0.101), respectively. The median progression-free survival (PFS) and median overall survival (OS) in Group TKI-RT were superior to those of Group TKI (18.87 months vs. 12.80 months, P = 0.035 and 23.10 months vs. 18.30 months, P = 0.011). OS rates in Group TKI-RT and Group TKI were 56.0% vs. 35.8% at 1-year (P = 0.04) and 16.0% vs. 3.8% at 2-year (P = 0.036). Multivariate Cox model found that TKI-RT related to significantly better OS (hazard ratio = 0.209; 95% CI, 0.066 to 0.661; P = 0.008) than TKI alone. Adverse events did not differ significantly between the two groups. Conclusions: Compared with EGFR-TKIs alone, EGFR-TKIs combined with radiotherapy was well tolerated and showed benefit in tumour response and survival for EGFR mutation-positive metastatic NSCLC patients.
Improvement of lung cancer risk prediction adding SNPs to the HUNT Lung Cancer Model: A HUNT Study.
Authors: Røe Oluf D. , Nguyen Olav Toai Duc , Lakiotaki Klio , Tsamardinos Ioannis , Lagani Vincenzo , Markaki Maria 
Published: May 2019

e20696 Background: A novel validated model for risk prediction of lung cancer, the HUNT Lung Cancer Model predicts 6- and 16-year risk of lung cancer with a C-index = 0.879 and 6-year AUC = 0.87. The model is valid for smokers and ex-smokers of any intensity and quit time and includes seven variables; age, BMI, pack-years, smoking intensity (cigarettes per day), quit time, daily cough in periods of the year and hours of daily indoors smoke exposure. Genome-wide association studies (GWAS) have consistently identified specific lung cancer susceptibility regions. We aimed to improve performance of the HUNT model by integrating the most significant Single Nucleotide Polymorphisms (SNPs). Methods: Lung cancer cases (n = 484) and controls without other cancer (n = 50337) were genotyped for 22 SNPs located in GWAS-identified lung cancer susceptibility regions. Variable selection and model development used backwards feature selection with Akaike Information Criterion in multivariable Cox regression models. Internal validation used bootstrap to assess the change in area under the receiver operator characteristic curve (AUC) in order to compare nested models with and without genetic variables in the ever-smokers´ population (n = 456 cases, n = 28633 controls). We also used likelihood based methods for significance testing. Results: Variable selection and model development in the general population yielded six SNPs, rs1051730, rs11571833, rs13314271, rs2131877, rs2736100 and rs4488809. The added genetic information from these SNPs to the HUNT model, resulted in an improvement according to F test of the nested models (ANOVA p-value 0.000002425). The AUC of the augmented model was 0.881 (95% CI [0.869 0.892]) vs 0.869 without SNPs. Conclusions: In a highly predictive clinical risk prediction model, the integration of SNPs could further improve model performance according to likelihood based methods. Further refinement and validation of this integrated model is needed for clinical use.
A joint model of tumor size dynamics and survival with new lesions in EGFR mutation-positive non-small cell lung cancer patients with treatment of gefitinib or carboplatin and paclitaxel.
Authors: Dunyak James , Yan Hong , Al-Huniti Nidal 
Published: May 2019

e20697 Background: Tumor dynamics have been serving as significant predictors in diagnosis, staging, prognosis and treatment of patients with non-small cell lung cancer (NSCLC). The purpose of this study is to propose a joint model that links the longitudinal tumor burden to progression free survival (PFS) with the appearance of new lesion in a population of NSCLC patients with gefitinib treatment or Carboplatin/Paclitaxel. Methods: The model was extended to the estimation of new lesion based on a previously developed tumor size and survival joint model. The derivative of the tumor loads and the probability of new lesions served as biomarkers in the survival submodel. Parameters were estimated from the posterior distribution in a Bayesian framework and numerical study was realized with R and STAN. A total of 434 NSCLC patients with EGFR mutation positive treated with gefitinib or chemotherapy (carboplatin+paclitaxel) from IPASS (‘NCT00322452’) were used to construct the model. Predictions were performed on the IFUM study (‘NCT01203917’) with 102 EGFR mutation positive NSCLC patients. Results: The model performed well in PFS prediction in both within-sample and out-of-sample estimations. Further improvement of model specifications is necessary since the tumor load developing rate and appearance of new-lesion negatively impacted survival predictions. About 90% accuracy was realized by the joint model when recapitulating the outcomes from the response evaluation criteria in solid tumors (RECIST). The appearance of new lesion contributed less than tumor size in accommodating drug effect when comparing progression-specific hazards. Conclusions: This Bayesian joint model well recapitulated the outcomes from the RECIST with sequentially updated tumor size that linked to survival predictions. New insights of relative predictive values were provided by the joint model regarding the components of RESICT.
Advance care planning and terminal intensive care unit admissions for cancer patients: We can do better.
Authors: Heng Joseph , Sedhom Ramy , Smith Thomas J. 
Published: May 2019

e23000 Background: Terminal oncology intensive care unit (ICU) admissions are associated with high healthcare costs and decreased quality of life. Chemotherapy can be given in non-curative settings to optimize symptom control, but use of it at the end of life does not improve longevity. In addition, goals of care are too often not addressed for patients at high risk of death. Methods: We carried out a retrospective review identifying patients of a large academic cancer center who were admitted to and expired in an ICU between January 1, 2017 to December 31, 2018. Results: 120 patients met inclusion criteria. Median age was 58 years. Only 15.0% (n = 18) of all patients had advance directives. The majority of patients (94.1%, n = 113) were FULL CODE on admission. Median duration of admission was 10 days. Median time to death from ICU admission was 7.5 days. 65.0% (n = 78) of all patients were intubated, while 15.0% (n = 15) received CPR. 58.3% (n = 70) of the study population had solid malignancies; of note, 97.1% (n = 68) of these patients were metastatic at presentation and had a median ECOG performance status of 2. Patients with metastatic solid tumors typically have a more indolent course of progression compared to patients with hematologic malignancies. However, only 23.5% (n = 16) had discussed goals of care or code status with their outpatient oncologists, despite many seeing them within the last month prior to admission (83.8%, n = 57). Similarly, only 4.0% (n = 2) of patients with hematologic malignancies had advance care planning discussions with their oncologists prior to their terminal ICU admission. 27.5% (n = 33) of all patients had an inpatient palliative care consult. The inpatient pulmonary/critical care team had a high rate of inpatient code status transitions, with 85.6% (n = 97) of FULL CODE admissions transitioning to DNR/DNI. Conclusions: These findings reflect contemporary practice at a major academic cancer center. Despite most patients having regular contact with their outpatient oncologists, the intensity of health care utilization noted highlights a need to optimize recognition of patients at high risk of death and to engage patients in advance care planning discussions to avoid terminal ICU admissions.
Place of death and chemotherapy use at the end of life in colorectal cancer.
Authors: Schütte Katharina , Kroggel Tobias , Rentsch Anke , Schuler Ulrich S. , Heuchel Conrad , Folprecht Gunnar 
Published: May 2019

e23006 Background: Over the last decades, new drugs and multidisciplinary treatment increased the therapeutic options for palliative treatment of colorectal cancer (CRC). It is unclear, whether these options led to a more aggressive therapy at the end of life. Methods: For this retrospective cohort trial, we identified all stage IV CRC patients who received their complete therapy at an university hospital in Germany and investigated the use of palliative chemotherapy at the end of life (EOL) and the place of death (POD). Results: Between 01/2002 and 12/2012, 245 patients were treated with palliative chemotherapy for stage IV CRC and were evaluable for duration of palliative chemotherapy and place of death. 21% of the patients received chemotherapy within the last 30 days and 9% within 14 days before death. Overall survival of patients with chemotherapy use within the last 30 days of life was significantly shorter compared to patients without chemotherapy in the last month of life (12 vs. 20 months, p = 0.02), duration of palliative chemotherapy was non-significantly shorter (11 vs. 15 months, p = 0.29). Chemotherapy use was significantly more frequent used within 30 days before death from 2009-2012 (24%) compared to 2002-2005 (17%), p = 0.001. 58% of patients died in their residence (at home or in a nursing home), 27% on a general hospital ward (GHW)/ intensive care unit (ICU) and 15% on a palliative care unit (PCU) or hospice. Patients ≥70 years died significantly more often in their residence (70% vs. 53%; p = 0.013). From 2002-2005 to 2010-2012, less patients died in a GHW or ICU of acute care hospitals (39% vs. 16%; p = 0.007). Patients with a distance of ≤45 minutes to our institution more often died at home and in a PCU, Patients with a short therapy-free interval before death more often died in a hospital, (with chemotherapy in the last 30 days: 38%, with chemotherapy in the last 14 days: 45%). Conclusions: Although chemotherapy use at the EOL increased over the decade, more patients were able to die at home. Older patients and patients living in an urban centre more often died at home indicating that conditions for home care have improved independent of the duration of chemotherapy. However, patients with chemotherapy use at the EOL more often die in hospital.
A community oncology end-of-life care program: Results for hospice length of stay analysis.
Authors: Akhtar Adil Jamal , Margolis Jeffrey H. , Scott-Barney Tammy , Zekman Richard Philip , Muskovitz Andrew A. , Qamruzzaman Yusuf , Ballouz Samer , Ibrahim Mohammed , Maxwell Karma , Stortz Lexi , Fabbiano Maria , Sheth Karna 
Published: May 2019

e23008 Background: Michigan Health Professionals (MHP) is a large multispecialty physician group. MHP Oncology Division participates in quality improvement projects. Palliative and End of Life (EOL) care has been identified as one of the quality improvement areas. A comprehensive community oncology program for early and timely involvement of palliative and EOL care was launched in October 2017. Methods: MHP Palliative and End of life care committee was created of mostly oncologists who are board certified in Palliative care and Hospice. The program, which included pre-program training, user-friendly referral process, and live physician engagement for early involvement of palliative care (PC) and EOL care was developed and implemented. A partnership was created with Premier Hospice to integrate EOL care services with the oncology offices and to collect data. Historical data for average hospice length of stay (LOS) in hospice service for MHP oncology patients was analyzed by Integra Connect. Results: From 1/1/2018 to 12/31/2018 a total of 133 patients (MHP-T) were referred and admitted to Hospice service. Sixty-one patients were on PC service (PC group) and 72 patients (NonPC group) were referred directly to hospice. Total of 527 patients from 2012 to 2017 were analyzed for historical comparison group (HC) and 124 patients were analyzed for MHP-T group. Average LOS was 16.8 days in the HC group. Average LOS for the MHP-T, PC group and NonPC group improved to 34, 35 and 33 days respectively. HC group had 82.2% of patients with average LOS < 30 days. After program implementation average LOS < 30 days improved to 63.7% MHP-T group, 60.0% PC group and 66.7% NonPC group. In HC group, 92 out of 527 patients had average LOS of 2 days or less. Only 2 patients out of 124 patients had average LOS of 2 days or less since the launch of MHP community oncology program. Conclusions: Early and timely patient referral to the EOL care services resulted in average hospice LOS which is more than double as compared to historical comparison group. Fewer number of patients had average LOS of < 30 days and LOS of 2 days or less as compared to the historical comparison group. There was a trend towards higher LOS observed for patients who were under palliative care (PC) before hospice admission.