bluuebunny/crossref_metadata_2025_split huggingface dataset:
Does ethnicity affect the relationship between body mass index (BMI) and overall survival (OS) in non-small cell lung cancer (NSCLC)? A pooled analysis of 17,326 International Lung Cancer Consortium (ILCCO) patients (pts).
Authors: Fares Aline Fusco , Shepshelovich Daniel , Lu Lin , Brown M. Catherine , Yang Ping , Zhang Jie , Ryan Brid M , Christiani David C. , Schwartz Ann , Chen Chu , Adonina Garcia , Schabath Matthew B. , Shiraishi Kouya , Down Teare , Le Marchand Loic , Zuo-Feng Zhang , Brenner Hermann , Xu Wei , Hung Rayjean J , Liu Geoffrey 
Published: May 2019

1562 Background: In Caucasian-predominant populations, overweight or obese NSCLC pts (BMI≥25-kg/m2) have better prognosis while underweight (BMI≤18.5-kg/m2) pts have a worse prognosis. A large pooled sample allowed us to evaluate the role of ethnicity in this BMI-NSCLC OS relationship. Methods: Using individual data, survival analysis was performed on 15 ILCCO studies, assessing the interactions between ethnicity and BMI on overall survival (OS). Adjusted Hazard Ratios (aHR) from Cox models and adjusted penalized smoothing spline plots were generated. Results: Among 13416 (77%) Caucasian, 2975 (17%) Asian, and 935 (5%) Black NSCLC pts analyzed, we confirmed that for all pts, being underweight at NSCLC diagnosis was associated with worse OS (aHR=1.68, CI 1.5-1.8, p<0.001), while overweight/obese pts had improved survival (aHR 0.89, CI 0.8-0.9, p<0.001), when compared to pts with normal BMI. In general, Black pts had poorer OS than Caucasian pts (aHR 1.26 CI 1.1-1.4, p<0.001). However, the BMI-OS relationship differed according to ethnicity (BMI-ethnicity interaction, p=0.009): Caucasian underweight pts had poorer OS (aHR 1.67, CI 1.5-1.8, P<0.001) while overweight/obese pts had improved OS (aHR 0.89, CI 0.8-0.9, P<0.001). In Asian pts, these two associations were aHR 1.15, CI 0.8-1.5, P=0.33, and aHR 0.91, CI 0.7-1.1, P=0.32, respectively. In Black pts, these two associations were aHR 1.06, CI 0.7-1.5, p=0.73 and 0.75, CI 0.6-0.8 p<0.001, respectively. For overweight/obese patients, as BMI rises from 25-kg/m2 through 45-kg/m2, the prognosis worsens for Caucasian pts, remains stable for Asian pts, but improves for Black pts. Conclusions: InCaucasian pts, being underweight had a greater negative impact on OS than for Asian or Black pts, while being obese had a greater beneficial impact in Blacks than in other ethnic groups. These ethnic differences likely reflect genetically-informed muscle/adipose tissue distributions, where Black pts may have less sarcopenic obesity than other ethnicities. In future prognostic studies, BMI relationships must account for ethnic differences.
Outcomes associated with rapid genetic testing for BRCA1 and BRCA2 at time of breast cancer diagnosis.
Authors: Metcalfe Kelly A. , Poll Aletta , Eisen Andrea , Lerner-Ellis Jordan , Narod Steven 
Published: May 2019

1577 Background: Bilateral mastectomy improves survival for women with BRCA-associated breast cancer. Most women do not know their BRCA status at the time of BC diagnosis when making surgical decisions. Rapid genetic testing (RGT) allows a woman to have genetic test results prior to treatment decision making, but it is unclear if RGT has an impact on treatment choices. It is also unclear if there are psychosocial implications associated with genetic testing at the time of breast cancer diagnosis. The objective of the current study was to assess the impact of RGT at the time of BC diagnosis on surgical decision-making and psychosocial functioning. Methods: Eligible women were referred from participating surgeons at BC diagnosis. Women completed baseline questionnaires assessing treatment preferences, cancer related distress, anxiety, and depression. All participants received in-person pre-test genetic counselling and genetic test results were given within 10 days. Participants completed surveys at 1 week and 1 year post-genetic testing to assess treatments and psychosocial functioning. Results: 1010 women consented to participate and 60 (5.9%) were identified with a BRCA mutation. 15% of those identified with a BRCA mutation did not meet provincial eligibility criteria for genetic testing, and 20% were eligible prior to a breast cancer diagnosis but had not received testing. Mean levels of cancer-related distress, anxiety and depression declined significantly from baseline to 1 year for all women (all p < .05), and there were no differences at any time point between those with and without a BRCA mutation. Of those identified with a BRCA mutation, 67.3% reported that their surgery choice changed. 73.7% of BRCA carriers had a bilateral mastectomy, compared to 20.2% of BRCA negative (p < 0.001). Most women used genetic testing results for surgical decision making (96.1% of BRCA positive and 86.4% for negative). Conclusions: Rapid genetic testing for BRCA1 and BRCA2 at the time of BC diagnosis does not have a negative impact on psychosocial functioning. There are no differences in cancer-related distress, anxiety or depression between women who receive a positive result compare to a negative genetic test result. Furthermore, surgical choice changed for many women identified with a BRCA mutation, with the majority electing for bilateral mastectomy.
Early results from the BRCA Founder Outreach (BFOR) Study: Population genetic screening using a medical model.
Authors: Morgan Kelly , Gabriel Camila , Symecko Heather , Lester Jenny , Levin Jeffrey , Kamara Daniella , Spielman Kelsey , Jenkins Colby , Hamilton Jada G. , Fesko Yuri Anthony , Heitler Jacob , Block Jeremy , Pace Lydia , Robson Mark E. , Nathanson Katherine , Tung Nadine M. , Domchek Susan , Karlan Beth , Garber Judy Ellen , Offit Kenneth 
Published: May 2019

1578 Background: Barriers to population screening for BRCA mutations include access, availability of counseling, and readiness of care providers to participate in this process. The BRCA Founder OutReach (BFOR) study evaluates a digital approach to genetic testing of a defined population using a medical model and risk-adapted follow-up. Methods: The BFOR study (Bforstudy.com) includes web-based enrollment open to individuals in four US cities who are age 25 or older and have at least one grandparent of Ashkenazi Jewish (AJ) ancestry. Participants receive web-based education, provide consent, complete questionnaires, and note their preference for receiving results either from their primary care provider (PCP) or BFOR staff. BRCA AJ founder mutation results are disclosed by (e)mail or phone, depending on need for additional counseling/genetic testing. Participants will be surveyed by email for up to 5 years; a subset of PCPs is also being surveyed. Results: From March 2018 to January 2019, 2562 participants enrolled: 78% female; < 30 years old, 8%; 30-50 years, 39%; > 50 years, 53%. At enrollment, 33% requested disclosure of results by PCP. Among 847 PCPs invited to disclose results, 45% accepted, 50% declined and 5% have yet to respond. 69 (3.2%) participants tested positive for a BRCA founder mutation, of whom 8 (12%) had no significant family history. 2087 participants tested negative, of whom 6% reported a known family mutation, 38% reported a family history of breast/ovarian cancer, and 56% no such history. The most common reason for study participation was referral by a friend. One individual with a distant history of breast cancer tested positive for a BRCA2 mutation and underwent risk reducing surgery that identified an early stage fallopian tube carcinoma. Her daughter then tested positive and underwent prophylactic surgeries. Conclusions: Population screening of individuals at higher risk for cancer-predisposing mutations is feasible and identifies individuals who would not have been tested using clinical criteria. Preliminary findings reveal challenges for engaging PCPs and at-risk individuals, particularly men. Ongoing follow-up and a second phase of the study will address these barriers to testing. Clinical trial information: NCT03351803.
Disparities in pretest genetic counseling among a population-based sample of young breast cancer patients.
Authors: Reid-Lawrence Sonya , Pal Tuya , Mayer Ingrid A. , Shu Xiao-Ou , Tezak Ann , Weidner Anne , Cragun Deborah , Vadaparampil Susan Thomas , Ye Fei , Fan Run 
Published: May 2019

1579 Background: Per national practice guidelines, pre-test genetic counseling (GC) through a board-certified or credentialed genetics health professional (GHP) is recommended when testing for hereditary cancer. We sought to compare differences in rates of pre-test GC among young breast cancer (BC) patients tested with or without GHP involvement across three racial groups (Black, Hispanic and non-Hispanic white (NHW)). Methods: A population-based sample of Black, Hispanic and NHW women diagnosed with invasive BC ≤ age 50 from 2009 to 2012 were recruited through the Florida State Cancer Registry. Participants were asked to complete a baseline questionnaire and release medical records for verification of clinical information and genetic testing. We compared the rates of pre-test GC across racial groups in women tested with or without GHP involvement using Analysis of Variance. Multivariate logistic regression analysis was also conducted to adjust for potential confounders. Results: Of 1618 participants, 828 had genetic testing based on medical records and/or self-reported on their questionnaire. There were 170 (20.5%) with GHP involvement (either through consultation and/or test ordering) and the remaining 658 women (79.5%) had no documentation of GHP involvement. Among patients tested without GHP involvement, rates of pre-test GC were significantly lower among Black women (34.8%) compared to Hispanics (80%) and NHW (78.7%) (p < 0.001). In contrast, among those with GHP involvement, rates of pre-test GC were similar among Black (89.7%), Hispanic (81.1%) and NHW (84.6%) (p = 0.89). Conclusions: Our results suggest that among young breast cancer patients tested for hereditary cancer without GHP involvement, Blacks were significantly less likely to receive pre-test GC, compared to the other two groups. In contrast, rates of pre-test GC among those with GHP involvement were similar across all groups. These results suggest a disparity in receipt of pre-test GC (which is standard of care per national guidelines) among Blacks tested without GHP involvement. These findings are concerning given the need to offer guideline-adherent care to all patients receiving hereditary cancer testing.
Incidence of second primary neoplasms among cancer survivors in the United States, 2000 through 2015.
Authors: Adjei Boakye Eric , Jenkins Wiley D , Osazuwa-Peters Nosayaba , Wang Maggie , Lee Min Jee , Chen Betty , Agamah Edem S. , Sharma Arun 
Published: May 2019

1586 Background: The number of cancer survivors in the United States is projected to exceed 20 million by 2024. Survivors are at risk of developing a second primary neoplasm (SPN) – a leading cause of survivor death. We described the risk of developing a SPN among survivors of common cancers (smoking-related vs non-smoking-related) in the United States. Methods: We identified patients aged ≥18 years who were diagnosed with a primary cancer from the 10 sites with highest survival rates and stratified as smoking-related (urinary bladder, kidney & renal pelvis, uterine cervix, oral cavity & pharynx, and colon & rectum) and non-smoking related (prostate, thyroid, breast, corpus & uterus, and non-Hodgkin lymphoma) from Surveillance, Epidemiology, and End Results (2000-2015). SPN was defined as the first subsequent primary cancer occurring ≥2 months after first cancer diagnosis. Excess SPN risk was quantified using standardized incidence ratios (SIRs) stratified by sex. Results: A cohort of 2,908,349 patients (50.1% female) was identified and 260,267 (9.0%) developed SPN (7.6% of females and 10.3% of males). All index cancer sites were associated with a significant increase in SPN risk for females and males (except prostate cancer). Index smoking-related cancers (SIR range 1.20 – 2.17 for females and 1.12 – 1.91 for males) had higher increased risk of SPN than non-smoking-related cancers (SIR range 1.08 – 1.39 for females and 0.55 – 1.38 for males) relative to the general population. Conclusions: Nearly 10% of cancer survivors developed an SPN, and those with smoking-related cancers had higher risk. Given the increasing number of cancer survivors and importance of SPN as a cause of cancer death, these findings can improve secondary prevention and surveillance guidelines. [Table: see text]
Phase I study of a brain penetrant mutant IDH1 inhibitor DS-1001b in patients with recurrent or progressive IDH1 mutant gliomas.
Authors: Natsume Atsushi , Wakabayashi Toshihiko , Miyakita Yasuji , Narita Yoshitaka , Mineharu Yohei , Arakawa Yoshiki , Yamasaki Fumiyuki , Sugiyama Kazuhiko , Hata Nobuhiro , Muragaki Yoshihiro , Nishikawa Ryo , Shinojima Naoki , Kumabe Toshihiro , Saito Ryuta , Ito Kazumi , Tachibana Masaya , Kakurai Yasuyuki , Nishijima Soichiro , Tsubouchi Hiroshi 
Published: May 2019

2004 Background: WHO grade II/III gliomas frequently harbor isocitrate dehydrogenase 1 ( IDH1) mutations, resulting in intratumoral accumulation of oncometabolite 2-hydroxyglutarate (2-HG) and subsequent clonal expansion. DS-1001b is an oral selective inhibitor of mutant IDH1 R132X that was designed to penetrate the blood-brain barrier. Methods: In this first-in-human, multicenter, phase I study (NCT03030066), eligible patients (pts) with recurrent/progressive IDH1 mutant glioma received DS-1001b twice daily (bid), continuous. A modified continual reassessment method was used for dose escalation. RANO and RANO-LGG criteria were used to assess tumor response. Pts who planned to undergo salvage surgery after developing progressive disease (PD) and who provided informed consent received DS-1001b treatment until surgery. Tumor samples were also obtained from those pts to measure the free form of DS-1001b and 2-HG levels. Results: Between Jan 2017 and Oct 2018, DS-1001b (125-1400 mg bid) had administered for 45 pts (median age 44 yrs, prior radiation therapy 100%, prior chemotherapy 82%), and 17 pts were continuing treatment. Maximum tolerated dose (MTD) was not reached. Most AEs were Gr 1-2. Gr 3 AEs were observed in 42.2% of pts. No Gr 4 or 5 AEs or serious drug-related AEs were reported. One dose limiting toxicity was Gr 3 white blood cell count decreased (1000 mg bid). Common AEs ( > 20%) were skin hyperpigmentation, diarrhea, pruritus, nausea, rash, and headache. Of 29 evaluable pts with contrast enhancing gliomas, one, three and 10 achieved complete response, partial response and stable disease (SD), respectively. Of evaluable nine pts with contrast non-enhancing gliomas, two achieved minor response and seven achieved SD. Peak plasma concentration (Cmax) and area under the curve (AUC) increased dose-dependently. The brain/plasma ratio of free form of DS-1001b ranged 0.19‒0.77 in 3 pts. Conclusions: DS-1001b was well tolerated up to 1400 mg bid with favorable brain distribution, and MTD was not reached. Recurrent/progressive IDH1 mutant glioma pts responded to treatment. Investigation is ongoing to determine the recommended Phase II dose. Clinical trial information: NCT03030066.
Trabectedin for recurrent WHO grade II or III meningioma: A randomized phase II study of the EORTC Brain Tumor Group (EORTC-1320-BTG).
Authors: Preusser Matthias , Silvani Antonio , Le Rhun Emilie , Soffietti Riccardo , Lombardi Giuseppe , Sepúlveda Juan M. , Brandal Petter , Beaney Ronald Philip , Bonneville-Levard Alice , Lorgis Veronique , Vauleon Elodie , Bromberg Jacqueline , Erridge Sara , Cameron Alison , Marosi Christine , Golfinopoulos Vassilis , Gorlia Thierry , Weller Michael , Wick Wolfgang 
Published: May 2019

2007 Background: EORTC-1320-BTG investigated the activity, safety and quality of life of therapy with the tetrahydroisoquinoline alkaloid trabectedin (Yondelis) in patients with recurrent higher-grade meningiomas. Trabectedin was originally derived from the Caribbean sea squirt, Ecteinascidia turbinata, and currently is manufactured by total synthesis. Methods: Adult patients with histological diagnosis of WHO grade II or III meningioma and radiologically documented progression after maximal feasible surgery and radiotherapy were randomly assigned in a 2:1 ratio to receive intravenous trabectedin (1.5 mg/m2every three weeks) or local standard of care (LOC). The primary endpoint was progression-free survival (PFS). Results: Within 22.1 months, we randomized a total of 90 patients (n=29 in LOC arm, n=61 in trabectedin arm) in 35 institutions and nine countries. In the LOC arm, the following treatments were administered: hydroxyurea (n=11), bevacizumab (n=9), none (n=4), chemotherapy (n=3), somatostatin analogue (n=1), combined chemotherapy and somatostatin analogue (n=1). With 71 PFS events, median PFS was 4.17 months in the LOC and 2.43 months in the trabectedin arm (hazard ratio [HR] for progression, 1.42; 80% CI, 1.00-2.03; p=0.204) with a PFS-6 rate of 29.1% (95% CI, 11.9%-48.8%) in the LOC and 21.1% (95% CI, 11.3%-32.9%) in the trabectedin arm. Median OS was 10.61 months in the LOC and 11.37 months in the trabectedin arm (HR for death, 0.98; 95% CI, 0.54-1.76; p=0.94).Grade 3 to 5 adverse events occurred in 44.4% (18.5% related, 4 serious adverse events, 0 lethal events) of the patients in the LOC and 59% (32.8% related, 57 serious adverse events and 2 toxic deaths) of patient in the trabectedin arm. Conclusions: In this first prospective randomized trial performed in recurrent grade II or III meningioma, trabectedin did not improve PFS and OS and was associated with significantly higher toxicity as compared to LOC treatment. The data collected in this study may serve as benchmark for future clinical trials in this setting. Clinical trial information: NCT02234050.
A randomized phase II trial of veliparib (V), radiotherapy (RT) and temozolomide (TMZ) in patients (pts) with unmethylated MGMT (uMGMT) glioblastoma (GBM).
Authors: Khasraw Mustafa , McDonald Kerrie Leanne , Rosenthal Mark , Lwin Zarnie , Ashley David M. , Wheeler Helen , Barnes Elizabeth , Foote Matthew C. , Koh Eng-Siew , Sulman Erik P. , Back Michael , Buckland Michael , Sim Hao-Wen , Fisher Lauren , Leonard Robyn , Hall Merryn , Yip Sonia , Simes John 
Published: May 2019

2011 Background: TMZ offers minimal benefit in uMGMT GBM pts. V is synergistic with both RT and TMZ in preclinical models, safe when combined with either RT or TMZ clinically, but the triplet (V+RT+TMZ) is poorly tolerated. This study examined a novel approach to patients with uMGMT GBM. Methods: VERTU is a randomized Phase 2 trial comparing Arm A (Standard of care) = RT (60Gy/30 fractions) + TMZ (75mg/m2 daily) followed by TMZ (150–200mg/m2D 1–5) every 28 days for 6 cycles vs Arm B (experimental arm) = RT (60Gy/30 fractions) + V (200mg PO BID) followed by TMZ (150–200mg/m2D 1–5) + V (40mg bid, D 1–7) every 28 days for 6 cycles in pts with newly diagnosed centrally determined uMGMT GBM. The study aims to randomize 120 pts (2:1 to the experimental arm). The primary endpoint was 6 months progression free survival (6mPFS) with multiple secondary and tertiary endpoints. Evaluation of feasibility and safety was planned after completion of RT in the first 60 pts (Stage 1). (ANZCTR #ACTRN12615000407594). Tumor tissue and serial bloods were collected for translational research. Results: 125 pts were randomized (41 Arm A, 84 Arm B). Mean (range) age 58 (22–78) years, 70% male, 61% ECOG 0, 86% macroscopic resection, 14% biopsy. At the time of analysis (cut-off date: 04/Feb/2019), median follow up was 16.5 months, 76 pts had died. 6mPFS (95% CI, Kaplan-Meier estimate) was 37% (22–52) in Arm A and 53% (41–63) in Arm B, and median PFS was 4.4m (95% CI 4.0–6.0) for Arm A and 6.2m (95% CI 4.9–7.1) for Arm B (HR = 0.81, 95%CI 0.54–1.21). 50% of pts in Arm A and 53% in Arm B experienced ≥ G3 adverse events (AEs). The most common G 3/4 AEs were decreased platelets, seizures, hyperglycemia and diarrhea (each 5%) in Arm A and decreased platelets (13%) and seizures (11%) in Arm B. Conclusions: In this multicenter, randomized study, the experimental therapy was feasible and well tolerated. The observed 6mPFS appeared longer in Arm B, but at the time of submitting the abstract, this result did not meet the prespecified primary endpoint. More mature results will be presented at the annual meeting. QoL in VERTU is reported separately. Central MR review, biomarker analyses, including DNA repair and methylation signature analyses are ongoing. Clinical trial information: ACTRN12615000407594.
Glioblastoma evolution pattern under surgery and radio(chemo)therapy (RCHT) to identify novel methylome based glioma subtypes.
Authors: Knoll Maximilian , Debus Juergen , Furkel Jennifer , Warta Rolf , Bougatf Nina , Rapp Carmen , Brors Benedikt , Wick Wolfgang , Unterberg Andreas , Herold-Mende Christel , Abdollahi Amir 
Published: May 2019

2012 Background: Identification of isocitrate dehydrogenase mutations (IDHm) and glioma CpG island methylator phenotype (G-CIMP) as well as methylation of O6-methylguanine DNA methyltransferase (MGMT) promotor has substantially improved stratification of glioma patients into prognostic subgroups. In extension of static pre-therapy diagnostic, we sought to investigate the impact of glioblastoma evolution under selection pressure of standard therapy on methylome level. Methods: For the training cohort (T), methylome (450k Illumina) data of paired samples from 50 patients with glioblastoma (GBM, 11 G-CIMP+) were analyzed, i.e., primary (P) and at the time point of recurrence (R, re-surgery) after standard therapy at NCT. For 39 pairs matching RNASeq data was analyzed. Validation cohorts consisted of Heidelberg (V1) total n = 650, GBM (n:585, 8 G-CIMP+), grade III (n:65, CIMP+ 65), Austrian GBM (V2, n = 499, 36 IDHm, pyrosequencing data) and the TCGA (V3) Lower-grade-glioma cohort (LGG, n = 477, grade III n: 247, 178 G-CIMP+, grade II n: 228, 206 G-CIMP+). Results: Limited number of consensus differentially methylated probes (DMP) were found across all P vs. R samples (nCpG = 411 CpGs, FDR < 0.05). In contrast, heterogeneity in GBM evolution was found by similarity analysis of delta-methylome data of 50 PR pairs resulting in two distinct clinical subgroups and one “intermediate” group. Intriguingly, n = 114.652 DMP (FDR < 0.05) was found by comparing the evolutionary “poor” (n = 15) vs. “good” (n = 13) GBM phenotypes. A random forest classifier was built to identify the evolutionary subgroups in P samples. The performance of “good” prognosis classifier was in T cohort HR: 0.54 [0.30-0.97], p = 0.04; V1: 0.57 [0.43-0.76], p < 0.001, V2: 0.62 [0.47-0.82], p < 0.001, LGG: 0.16 [0.08-0.32], p < 0.001. In “good” prognosis group (T), neither G-CIMP+ (n = 3) nor MGMT-STP27 (oddsratio, OR: 0.56, p = 0.47) was enriched. MGMT-STP27 OR was 0.47 (V1, p = 0.47) or 1.28 (V2, p = 0.45), respectively. The evolutionary subgroups remain prognostic independent of GCIMP status in LGG (V3). “Poor” glioma are enriched for RTKI/II methylome subtypes, and contain less frequently the mesenchymal subtype. Bevacizumab treatment showed a survival benefits only in “poor” subtype (V1+2). Conclusions: Discovery of a methylome based classifier of glioma evolution informs on “good” and “poor” prognosis subtypes and may have ramification for stratifying patients for therapy such as e.g., antiangiogenesis.