bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cardiometabolic risk factors and survival after cancer in the women’s health initiative.
Authors: Simon Michael S. , Hastert Theresa , Luo Juhua , Chlebowski Rowan T. , Ruterbusch Julie J. , Beebe-Dimmer Jennifer Lynn 
Published: May 2019

1556 Background: Features associated with metabolic syndrome have been connected to both risk and poorer outcomes for certain cancers. Methods: We used data on 12,107 women enrolled in the Women’s Health Initiative diagnosed prospectively with either local or regional stage cancer to evaluate the association between cardiometabolic risk factors identified at study entry, (elevated waist circumference (WC), hypertension, high cholesterol, and presence of type 2 diabetes), with death from either cancer, cardiovascular disease (CVD), or other causes. Cancer sites included those previously linked in the published literature to metabolic syndrome and cancer risk: breast, colorectal, endometrial, non-Hodgkin’s lymphoma, kidney, pancreatic, ovarian, stomach and liver. Multiple imputation methods were used to account for missing data (6.9%). Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI), adjusted for other significant predictors of survival. Results: After a median follow-up of 10.0 years, there were 3,612 total deaths with 1,547 (43 %) due to cancer. Most participants (60.3%) had at least 2 cardiometabolic risk factors, and 5.8% had 3 or 4. Having 3-4 risk factors, was associated with significantly higher mortality due to cancer (HR: 1.39, 95% CI: 1.12, 1.71), CVD (HR: 2.62, 95% CI: 1.91, 3.59), and other causes (HR: 1.97, 95% CI: 1.57-2.47) compared with no risk factors. High WC was associated with higher mortality due to cancer and other causes, and history of diabetes, and hypertension were associated with higher mortality due to CVD, and other causes. Conclusions: Among women diagnosed with early or regional stage cancer, the presence of 3-4 cardiometabolic risk factors which is consistent with a diagnosis of metabolic syndrome, are significantly associated with death due to cancer, CVD, and other causes. Attention to primary prevention focused on weight control, physical activity and diet after cancer diagnosis and treatment, can have an important positive influence on survivorship after cancer.
“Early impact” of the lung cancer screening in United States population in the SEER Registries.
Authors: Emmerick Isabel M , Varlotto John M. , Powers Maggie M , Lou Feiran , Lin Poliana , Maxfield Mark , Uy Karl 
Published: May 2019

1569 Background: The Lung Cancer Screening Trial (NLST) demonstrated improved overall survival (OS) and lung cancer specific survival (LCSS), likely due to finding early-stage NSCLC. Our study investigates the impact of the NLST publication in 2011 on the lung cancer outcomes in the general US Population by assessing the incidence rates, ratio of early/late stage, and lung cancer mortality in the years immediately prior to and following this publication. Methods: Rate sessions from the SEER18 database were accessed during the years 2008-2015. We analyzed overall lung cancer incidence and mortality rates. The ratio of early/late stage was obtained by dividing the number of stage I and II cases by the number of stage III and IV diagnosed by year. We investigate changes in level and trend using interrupted time series in STATA12, considering 2011 as the intervention. In addition, we performed a T-test for averages ratios comparing the years 2007-2010 to the years 2012-2015 for the entire lung cancer population and for subgroups by median family, ethnicity, Sex, Age and SEER Registry. Results: Although the overall lung cancer rates remained stable during the study period, a significant increase in the ratio of early/late stage was observed following the release of NLST for the overall lung cancer population (p=0.006) and for the screening age group (p= 0.014). The effects of ratio of early/late stage as noted in the overall group persisted for all patient subgroups, except for patients associated with a median income <$40,000, for those there were white, and for the following regions Detroit Metro, Iowa, Greater and Rural Georgia and Louisiana where no association was found between the release of the NLST changes in the ratios of early detection even more, in some cases there was a decrease in late stage detection. There was no impact on lung cancer mortality in the general lung cancer population or in any patient subgroups. Conclusions: Since the publication of the NLST in 2011, there has been no impact on lung cancer mortality or incidence of lung cancer in the general US population. However, favorable increase in the proportion of early stage lung cancers, depending upon median family income, race and location. We expected a greater impact of lung cancer screening after 2015 since CT-screening for lung cancer was adopted by CMS and other insurances during that year.
A pan-cancer analysis of microsatellite instability as a predictor of Lynch syndrome in Chinese population.
Authors: Huang Pinzhu , Deng Yanhong , Zhang Jianwei , Huang Meijin , Huang Jun , Liang Jinglin , Huang Mengli , Zhao Jing , Gao Chan , Xie Wenzhuan , Cai Shangli 
Published: May 2019

1574 Background: Microsatellite instability (MSI) and mismatch repair deficiency (dMMR) are primarily tested in colorectal (CRC) and endometrial cancer (EC) to aid Lynch Syndrome (LS) diagnosis. A pan-cancer study presented at 2018 ASCO, however, revealed that up to 50% of LS patients had tumors not typically associated with LS, suggesting that patients with an MSI-high (MSI-H) phenotype should proceed to germline testing regardless of tumor type or family history. We thus set out to examine this potentially practice changing notion in Chinese population. Methods: MSI status and germline mutations in MLH1, MSH2, MSH6 and PMS2 genes were determined using a targeted next generation sequencing panel covering 100 MSI loci as well as MMR genes. Tumor mutation burden (TMB) levels were calculated for LS patients with MSI-H and MSS tumors, and intergroup differences were assessed using Mann Whitney U test or Fisher’s exact test. Results: Of 6,288 advanced tumors spanning > 27 cancers, 0.8% (48/6,288) were EC, 21.6% (1,362/6,288) were CRC, and 77.6% (4,878/6,288) were other malignancies. 3.6% (224/6,288) of the samples were found to be MSI-H and 3.5% (217/6,288) harbored MMR mutations (somatic and germline). Germline mutations indicative of LS were identified in 0.1% (8/6,064) of the MSS group and 17% (38/224) of the MSI-H group (p < 0.001). In contrast with the 2018 ASCO report, up to 63.8% of the 224 MSI-H tumors were CRC/EC, and only 8.9% (3/38) of the LS patients had MSI-H non-CRC/EC tumors (1 ovarian clear cell, 1 small bowel, and 1 gastric cancer). LS patients with non-CRC/EC tumors were more likely to be MSS compared to those with CRC/EC (70.0% vs 2.7%, p < 0.001). Alterations in MLH1/ MSH2 were present in 78.3% (36/46) of the LS patients, and they demonstrated significantly better correlation with a MSI-H phenotype than MSH6/PMS2 alterations (94.4% vs. 40.0%, p = 0.0005). Additionally, in line with previous reports showing co-ocurrence of MSI-H and high TMB in gastrointestinal cancers, the LS patients with MSS tumors had a significantly lower median TMB compared with the MSI-H population (4.6 muts/Mb vs. 91.8 muts/Mb, p < 0.001). Conclusions: Our study showed that in Chinese population, CRC/EC still predominated among LS-associated cancers, while non-CRC/EC LS patients were more likely to present with an MSS phenotype. The value of MSI-H/dMMR as a predictor of LS across different tumor types warrant further investigation.
Blood-based genomic profiling of circulating tumor DNA from patients with advanced biliary tract cancer.
Authors: Wang Junying , Song Jia , Zhao Jing , Zhang Yuzi , Cai Shangli , Chen Chen 
Published: May 2019

1576 Background: Biliary tract cancer (BTC) is a highly lethal malignancy as diagnosis occurring at late stages and marginally sensitive to chemotherapy. Increasing evidence indicates targeted therapeutics may provide new hope for improving clinical response in BTC, hence better comprehending the genomic profile is particularly important. However, tissue of BTC is highly wide tumor heterogeneity and often inadequate for molecular characterization, a proper method is urgently needed. Circulating tumor DNA (ctDNA) is an emerging technology for detecting actionable alterations, and may be regarded as a reliable tool to reveal genomic signature. Methods: Next-generation sequencing (NGS) targeted 150 cancer-related genes was used to detect blood-based ctDNA from 154 Chinese patients with BTC. The mean sequencing depth was more than 3000×. Somatic genomic alternations (GA) including single nucleotide variation (SNV), copy number variation (CNV) and fusion were analyzed and compared with an internal tissue genomic database (545 Chinese patients with BTC) tested by NGS and TCGA database (n = 227) tested by the whole exome sequencing (WES). Allele frequency (AF) represented the percentage of mutant allele reads relative to total allele reads (mutant plus wild type). Maximum somatic allele frequency (MSAF) was defined as the maximum AF (0.1% < AF < 35%) of all the somatic alterations identified per sample. Results: Among ctDNA database, at least one GA was found in 95% (147/154) of samples (a median of 4 GA per patient). The median MSAF across all cases was 6.47% (range, 0%-34.8%). Pathologic type (P < 0.001) and sex (P < 0.001) were significantly related with MSAF, respectively. Frequencies of SNV in commonly mutated genes from ctDNA were similar to those observed among tissue samples, like TP53 (35.1% vs 40.4%) and KRAS (20.1% vs 22.6%), however, a little lower in TCGA database (TP53 24.2%; KRAS 10.1%). Besides, the consistency of CNV detected from ctDNA and tissue was relatively poor, and tumor heterogeneity might be in charge of this phenomenon. Among the highly frequent mutations (AF > 5%) in ctDNA, 45% of genes was considered as druggable targets, such as EGFR/RAS/RAF pathway and AKT/mTOR/PI3K pathway. Conclusions: These findings demonstrated that ctDNA tested by NGS was feasible in revealing genomic profiles and identifying potential therapeutic targets. Noninvasive ctDNA could be used as a complementary approach to tissue testing in patients with metastatic BTC.
Implications of incidental germline findings identified in the context of clinical whole exome sequencing (WES) for guiding cancer therapy.
Authors: Schneider Bryan P. , Stout Leigh Anne , Philips Santosh , Hunter Cynthia , Kiel Patrick , Radovich Milan 
Published: May 2019

1581 Background: The identification of incidental germline mutations in the context of next-generation sequencing to guide therapy for cancer patients has become an unintended consequence of advancing technologies. While not the primary goal, additional information buried within the genomic data generated could be important for family members to better understand inherited disease risks and take action. While targeted gene panels are predominantly used in practice, comprehensive WES is becoming increasingly more common. The broader use of WES increases the complexity and scope of potential cancer and non-cancer pathogenic germline variation. Methods: 582 adult metastatic cancer patients from the Indiana University Health Precision Genomics Program were sequenced with tumor and germline CLIA-based WES. The primary intent was for guiding cancer therapy. Germline variant call files were mined for pathogenic/likely pathogenic (P/LP) variants using the ClinVar database. Clinvar classifications were narrowed only to high quality submitters. Results: We identified 1,454 P/LP variants in 209 genes. 92% of patients harbored at least one variant. 72 P/LP variants were identified in 19 cancer predisposition genes with BRCA2 being the most common. 63 patients (10.8%) carried a P/LP variant in a gene that would be recommended by the ACMG to be reported due to clinical actionability with the most common being ATP7B (N = 17), BRCA2 (n = 13), MUTYH (n = 8), and BRCA1 (n = 5). We observed a preponderance of patients who carried autosomal recessive non-cancer pathogenic mutations of varying penetrance. Notable mutated genes included CFTR (cystic fibrosis, n = 16), BTD (biotinidase deficiency, n = 43), and CBS (homocystinuria, n = 90). Of 209 mutated genes, 173 genes had mutations present in less than 1% of our population, demonstrating significant genetic heterogeneity. Conclusions: The majority of patients undergoing clinical cancer WES harbor pathogenic germline variation. Identification of clinically actionable germline findings will create additional burden on oncology clinics as broader WES becomes commonplace.
Genomic testing and treatment landscape in patients with advanced non-small cell lung cancer (aNSCLC) using real-world data from community oncology practices.
Authors: Gierman Hinco Jasper , Goldfarb Seth , Labrador Monica , Weipert Caroline M. , Getty Bill , Skrzypczak Stan M , Catasus Casey , Carbral Steve , Singaraju Mallika , Singleton Nick , Pai Nikhil , Sanchez Jose , Webster Jennifer , Raymond Victoria M. , Lanman Richard B. , Malik Ash , Scott Jeffrey A. 
Published: May 2019

1585 Background: While aNSCLC is a leading cause of US cancer deaths, targeted therapies and immune checkpoint inhibitors (ICPi) have emerged as important new treatment options for these pts NCCN guidelines recommend testing of eight genes in aNSCLC patients at diagnosis. Targetable alterations (TA) in four genes, EGFR, ALK, ROS1, and BRAF, are associated with FDA-approved therapies. The labels for ICPis indicate that pts with TAs in EGFR and ALK are not candidates for first line treatment with ICPi. Methods: The Integra Connect database, which includes electronic medical record (EMR) and claims data on approximately 600,000 cancer patients, was queried across five community oncology practices (289 oncologists) to identify aNSCLC patients (stage 3B or 4) treated since January 2017. Manual review of charts was done to abstract tumor type/stage, drug regimens, and evidence of somatic genetic testing. A Wilcoxon rank sum test was used to test difference in time to results (TTR) for blood- vs tissue-based tests. Results: A total of 1,203 aNSCLC patients were identified. Testing rates varied from 54% for EGFR to 22% for all 4 genes (table). 163 patients had a TA in EGFR, ALK, ROS1 or BRAF, and 55% of these pts did not receive targeted therapy. 84 pts with TA’s in EGFR or ALK had no evidence of progression on targeted therapy, yet 31 (37%) received an ICPi; 24% had the TA test result prior to ICPi use and 13% received the TA result after starting ICPi. Median TTR for blood-based somatic tests was shorter than tissue-based tests (4 vs 14 days, p-value= 3.5-e07). Conclusions: Our analysis in the community oncology setting for aNSCLC pts finds evidence of underutilization of genomic testing, underutilization of targeted therapies, and ICPi use outside of label. Further research is needed to identify strategies to increase testing in aNSCLC pts to provide physicians with the information needed to make optimal treatment decisions. [Table: see text]
NRG Oncology CC001: A phase III trial of hippocampal avoidance (HA) in addition to whole-brain radiotherapy (WBRT) plus memantine to preserve neurocognitive function (NCF) in patients with brain metastases (BM).
Authors: Gondi Vinai , Deshmukh Snehal , Brown Paul D. , Wefel Jeffrey Scott , Tome Wolfgang , Armstrong Terri , Bruner Deborah , Bovi Joseph A , Robinson Cliff Grant , Khuntia Deepak , Grosshans David R , Konski Andre A. , Roberge David , Kundapur Vijayananda , Devisetty Kiran , Shah Sunjay A , Usuki Kenneth , Anderson Bethany Marie , Mehta Minesh P. , Kachnic Lisa A. 
Published: May 2019

2009 Background: NRG CC001, a phase III trial of WBRT plus memantine (WBRT+M) with or without HA, sought to evaluate the neuro-protective effects of lowering the hippocampal radiation dose. Methods: Patients (pts) with BM were stratified by RPA class and prior radiosurgery/surgery and randomized to WBRT+M or HA-WBRT+M (30Gy/10 fractions). Standardized NCF tests were performed at baseline, 2, 4, 6, and 12 months (mos). The primary endpoint was NCF failure, defined as decline using the reliable change index on Hopkins Verbal Learning Test-Revised, Trail Making Test, or Controlled Oral Word Association. Cumulative incidence estimated NCF failure (death without NCF failure was competing risk); between-arms differences tested using Gray’s test. Deterioration at each collection time point was tested using a chi-square test. Patient-reported symptoms were assessed using the MD Anderson Symptom Inventory Brain Tumor module and analyzed using mixed effects models and t-tests. Results: From 7/2016 to 3/2018, 518 pts were randomized. Median follow-up was 7.9 mos. HA-WBRT+M was associated with lower NCF failure risk (adjusted hazard ratio (HR) = 0.74, p = 0.02) due to lower risk of deterioration in executive function at 4 mos (p = 0.01) and encoding (p = 0.049) and consolidation (p = 0.02) at 6 mos. Age≤61 predicted lower NCF failure risk (HR = 0.60, p = 0.0002); non-significant test for interaction indicated independent effects of HA and age. Patient-reported fatigue (p = 0.036), difficulty speaking (p = 0.049) and problems remembering things (p = 0.013) at 6 mos favored the HA-WBRT+M arm. Imputation models accounting for missing data also favored the HA-WBRT+M arm for patient-reported cognition (p = 0.011) and symptom interference (p = 0.008) at 6 mos. Treatment arms did not differ in toxicity, overall survival, or intracranial progression. Conclusions: HA during WBRT+M for BM better preserves NCF and patient-reported symptoms, while achieving similar intracranial control and survival. Supported by grants UG1CA189867 (NCORP), U10CA180868 (NRG Oncology Operations), DCP from the National Cancer Institute. Clinical trial information: NCT02360215.
SurVaxM with standard therapy in newly diagnosed glioblastoma: Phase II trial update.
Authors: Ahluwalia Manmeet Singh , Reardon David A. , Abad Ajay P , Curry William T. , Wong Eric T. , Belal Ahmed , Qiu Jingxin , Mogensen Kathleen , Schilero Cathy , Hutson Alan , Casucci Danielle , Mechtler Laszlo , Uhlmann Erik J , Ciesielski Michael J , Fenstermaker Robert 
Published: May 2019

2016 Background: SVN53-67/M57-KLH (SurVaxM) is a novel cancer vaccine designed to stimulate an immune response targeting the tumor-specific antigen survivin. A multi-center, single-arm phase 2 clinical trial of SurVaxM in survivin-positive newly diagnosed glioblastoma (nGBM, NCT02455557) is now fully enrolled and data updated. Methods: Patients (n = 63) with nGBM were enrolled at 5 US cancer centers and followed for safety, 6-month progression-free survival (PFS6), 12-month overall survival (OS12) and immunologic response. All patients underwent craniotomy with near-total resection ( < 1 cm3 residual contrast enhancement), TMZ chemoradiation, adjuvant TMZ and SurVaxM. Patients received 4 doses of SurVaxM (500 mcg) in Montanide with sargramostim (100 mcg) biweekly, followed by maintenance SurVaxM with adjuvants every 12 weeks until tumor progression. Immunogenicity of SurVaxM was assessed by detection of survivin-specific antibody (IgG) and CD8+ T-cell levels. Results: Median age was 60 yrs (range, 20-82), 53% methylated MGMT, 46% unmethylated MGMT (1 N/A) and 60% were male. Survivin expression ranged from 1-40% (median 12%) by immunohistochemistry. Median time to first immunization was 3.0 mo (1.9-4.0 mo) from diagnosis. There have been no RLT or grade ≥ 3 SAE attributable to SurVaxM. The most common AE was grade 1-2 injection site reactions. OS12 was 86% from first immunization and 93.4% from diagnosis. OS12 for meMGMT was 93.1% and unMGMT was 78% from first immunization. Median time to tumor progression (mPFS) was 13.9 months from diagnosis. Median OS has not yet been reached. SurVaxM produced an increase in survivin-specific IgG titre from pre-vaccine baseline to ≥ 1:10,000 in 67% of pts and ≥ 1:100,000 in 27%. CD8+ T cell responses were observed. Anti-survivin IgG and OS were correlated. Conclusions: SurVaxM immunotherapy generated encouraging efficacy and immunogenicity in nGBM and has minimal toxicity. A randomized, prospective trial of SurVaxM in nGBM is planned. Clinical trial information: NCT024455557.
Updated phase I trial of anti-LAG-3 or anti-CD137 alone and in combination with anti-PD-1 in patients with recurrent GBM.
Authors: Lim Michael , Ye Xiaobu , Piotrowski Anna F. , Desai Arati Suvas , Ahluwalia Manmeet Singh , Walbert Tobias , Fisher Joy D. , Desideri Serena , Belcaid Zineb , Jackson Christina , Nabors Louis B. , Wen Patrick Y. , Grossman Stuart A. 
Published: May 2019

2017 Background: Preclinical GBM data targeting the checkpoint molecules Lag-3 and CD137 have shown promising anti-tumor immune response with resultant improved survival when combined with anti-PD-1. Here we report our experience from a multi-arm safety study in patients with recurrent GBM treated with anti-Lag-3 and anti-CD137. Methods: The Adult Brain Tumor Consortium (ABTC) 1501 trial is a phase I, open label, multicenter, multi-arm dose-finding/safety study of anti-LAG-3 (BMS-986016) or anti-CD137 (BMS-663513) alone and in combination with anti-PD-1 in patients at first recurrence of GBM. The primary objective is to define MTD for the mono and combinational treatment. The major secondary objective is to explore for a signal in efficacy. The key inclusion criteria are adults, first recurrence of GBM following RT+TMZ, TLC≥1000/ul, KPS≥ 60%, stable corticosteroid regimen, measurable disease, and written informed consent. Sequential allocation was used for the treatment assignment at starting dose of 80mg for anti-LAG-3 and 8mg for anti-CD137. Anti-PD-1was given at a flat dose of 240 mg in the combination treatment arms. The 3+3 design is used for the dose finding with a target DLT rate < 33%. Results: to date 44 patients were enrolled into the trial with median age at 57, median KPS at 90. Median treatment cycle was 3 and 39% tumors were MGMT methylated. The highest safe dose for Anti-LAG-3 alone is 800 mg without a DLT. The safe dose for anti-CD137 alone arm is 8mg with 1 DLT, and 2 grade 3 elevated serum ALT at end of cycle 2. Combination arms of Anti-LAG-3 +anti-PD-1 (160 mg/240mg as the highest dose combination) had one DLT (hypertension) and no toxicities were seen in the combination arm of Anti-CD137+Anti-PD-1 (3 mg/240 mg). mOS was 14 months for anti-CD137 alone, 8 months for Anti-Lag-3, and 7 months for Anti-Lag-3 + Anti-PD-1. Correlative data will be discussed. Conclusions: The trial is ongoing. The RP2D is 800mg for anti-LAG-3 as a monotherapy and 8mg for anti-CD137. For the combination arms, 160 mg of Anti-LAG-3 and 240 mg of anti-PD-1 and 3 mg of anti-CD137 and 240 mg antiPD-1 were the RP2D. Clinical trial information: NCT02658981.