bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effectiveness of ovarian cancer screening in high-risk population and BRCA 1/2 carriers: A systematic review and meta-analysis.
Authors: Fawunmi David , Gojon Helene , Valachis Antonis 
Published: March 2020

1568 Background: The purpose of this study is to assess the effectiveness of different screening modalities in detecting ovarian cancer in high-risk women and BRCA 1/2 carriers. Methods: We searched through MEDLINE and ISI Web of Science, with no language or year restriction, to identify studies that used various screening modalities (Ca125, transvaginal ultrasound (TVUS) or combination) to detect ovarian cancer in high-risk women and BRCA 1/2 carriers. We summarized the sensitivity, specificity, and likelihood ratios of each screening modality. Results: Seven studies including BRCA 1/2 carriers and 12 studies including high-risk women were eligible for analysis. The pooled sensitivity of combined Ca125 and TVUS for BRCA 1/2 carriers was 47.6% (95% Confidence Interval (CI): 36.6%-58.8%). The pooled sensitivity of combined screening modality for high-risk population was 54% (95% CI: 43%-64-8%). The summary negative likelihood ratio for BRCA 1/2 carriers was 0.6 (95% CI: 0.48 – 0.75). In high-risk population (N = 12398) the rate of advanced stage incident screen-detected cancer was 56% (9 of 16 cancer) which is comparable to the rate of advanced stage in prevalent screening-detected cancer (18 of 32, 56%). In BRCA 1/2 carriers (N = 2356) no difference in stage distribution between incident screen-detected and interval cancer was found (26 of 31 cancer (84%) versus 24 of 27 (89%)). Conclusions: Despite annual combined screening with TVUS and Ca125, a high proportion of ovarian cancer in both BRCA 1/2 carriers and high-risk women are diagnosed in advanced stage. In addition, all screening modalities have an unacceptably low sensitivity. Therefore, it is unlikely that these screening modalities will reduce mortality from ovarian cancer. Further studies are needed to evaluate if more frequently screening more frequently than annually would offer a better chance of early-stage detection.
Late effects among testicular cancer survivors (1994-2011).
Authors: Al-Temimi Mohammed Hassan Hussain , Fraser Alison M , Lee Yuan-Chin Amy , Rowe Kerry G. , Rowley Braden D. , Daurelle Micky , Smith Ken R , VanDerslice James , Richiardi Lorenzo , Hashibe Mia 
Published: March 2020

1582 Background: More than 95% of testicular cancer (TC) patients survive at 10 years; however, they develop many complications following diagnosis. Our study is toassess the risk of developing morbidities among TC survivors. Methods: We used the Utah Population Database to identify TC patients (age>13) who 1) were diagnosed between 1994 and 2008, 2) had medical records at the University of Utah and Intermountain Health Care hospitals and 3) survived at least 3 years. Cases were matched to five TC-free patients (controls) from the same hospitals on birth year, birth region and date of residence in Utah. Individuals (cases and controls) with morbidities of interest before the date of TC diagnosis were excluded. Adjusted Cox regression analysis was used to identify the risk of developing ischemic heart disease, renal failure, infertility, hearing loss, peripheral neuropathy, osteoporosis and restrictive lung disease among TC patients relative to controls. The models were adjusted for age, race and other confounders. We also compared the risk of these morbidities among patients with regional/advanced tumor relative to patients with in situ/localized tumor. The latter was adjusted for age and tumor histology. Results: We identified 955 TC patients and 4775 controls. TC stage was: 73.7 % in situ/localized and 26.3% regional/advanced. The hazard rate (HR) of developing any of the target morbidities was 2.57, 95% confidence interval (CI), 2.2-2.9 for patients with localized cancer, 3.85 (95% CI: 2.9-5.1) for patients with regional cancer and 3.3 (95% CI: 2.3-4.8) for patients with advanced cancer relative to controls. Risk of developing renal failure, infertility, peripheral neuropathy, hearing loss and restrictive lung disease was significantly higher among TC survivors (P<0.05). We also identified a significant association (HR 5.2; 95% CI 1.8-15.5) of cancer stage and the risk of developing hearing loss and non-significant positive association of TC stage with the other morbidities. Conclusions: TC survivors were more than twice as likely to develop morbidities following diagnosis when compared to controls. The risk increases when the comparison is stratified by stage, which might be related to the differences in the treatment used for different stages of TC.
A survey of clinical prediction tools in colorectal and lung cancers and melanoma.
Authors: Mahar Alyson L. , Halabi Susan , McShane Lisa M. , Groome Patricia A. , Compton Carolyn C. ,   Molecular Modellers Working Group of the American Joint Committee on Cancer
Published: March 2020

1592 Background: Clinical prediction in cancer depends on a myriad of prognostic factors, and relies on sound methodology for model building and validation. Increased understanding of complex tumour biology allows for simultaneous consideration of biological markers and standard clinical and pathological factors for prediction. We evaluated published studies supporting existing prediction tools in three cancers. Methods: Scientific literature and online resources were searched for clinical prediction tools for survival in three cancers: colorectal, lung, and melanoma. A priori criteria determined by the Molecular Modellers Working Group of the AJCC were evaluated and included: defined patient population, consideration of standard prognostic variables, model development approaches, validation strategies, performance metrics, presentation form of prediction tool, and intended clinical use. Results: Seventy-eight tools intended for prediction of survival were identified for the three cancers: 41 in colorectal, 23 in lung, and 14 in melanoma. Clinical presentations varied within each: 23 of the colorectal cancer tools focused on advanced disease with liver metastases and the remaining varied by stage; 16 lung cancer tools focused on NSCLC and 7 on SCLC. Even in narrowly defined situations, there was no consensus on key variables; for example, no variables were common to all 8 prediction tools for metastatic lung cancer. Variable definitions were missing or vague and the form of the model was often not provided, hampering independent validation and usability. Only 32/78 tools were supported by appropriate internal validity statistics and 21/78 with external validation. Often the development of risk scores did not create groups for whom treatment decisions would be similar. Conclusions: The quality of the literature supporting clinical prediction tools is variable, and the accuracy and utility of many existing tools is undetermined. Methodological guidelines for prediction tool development and validation should be adopted and adhered to. Studies developing and validating clinical prediction tools in cancer must be reported in complete and transparent fashion to facilitate proper interpretation and judgment of utility.
Second primary tumors in cancer patients: A retrospective analysis based on institutional tumor registry.
Authors: Fumagalli Luca , Botteri Edoardo , Locatelli Marzia Adelia , Gelao Lucia , Criscitiello Carmen , Manunta Silvia , Rotmensz Nicole , Goldhirsch Aron , Curigliano Giuseppe 
Published: March 2020

1595 Background: The relative risk of developing a second tumor by site of primary tumor or gender is still unclear. Methods: We retrospectively analyzed data of 24,224 consecutive patients admitted to the European Institute of Oncology between 2000 and 2006 for a first primary invasive tumor. All the data were extracted from the institutional Tumor Registry. All tumors were registered and indexed within the same patient’s record. We limited the analysis to the patients who were diagnosed and received at least one treatment in IEO for their first primary tumor. Follow-up was based on the last registered patient’s control visit. Cumulative incidence was compared across different subgroups by means of the Gray test. The observed cases of second metachronous primary tumors was compared with the number of cancers we expected from the general Italian population. We used the standardized incidence ratio (SIR), defined as the ratio of the number of second cancers observed to the number of second cancers expected, to estimate the relative risk of second cancers, and we calculated 95% confidence intervals (95% CIs) by applying the Wilson and Hilferty approximation for chi-square percentiles. Results: In this population the 5-year cumulative incidence of a second tumor on the average population was 5.0%, SIR (CI 95%) was 1.3 (1.2-1.4). The Table reports details on observed versus expected second metachronous primary tumors by first tumor site. Conclusions: Cancer patients have a higher risk of a second primary tumor than general population. [Table: see text]
Night work and cancer: A systematic review and meta-analysis.
Authors: Tang Lanhua , Zhong Meizuo , Huang Jin , Zhao Shushan 
Published: March 2020

1604 Background: The association between night work (or shift work) and cancers has been studied for decades. However, researches investigating the association have yielded inconsistent results. Methods: A systematic review and meta-analysis was performed to investigate whether night work is a risk factor for different kinds of cancer. PubMed and Cochrane library search were independently conducted by two authors from January 1960 to January 2013 using keywords related to night work and cancer. According to between-studies heterogeneity, pooled risk ratios (RR) were estimated with fixed or random effects models by STATA 12.0 software. Sensitivity analysis and publication bias were also analyzed. Results: A total of 33 studies were identified according to the inclusion criteria. The aggregate estimate for all cancers combined was [1.35, (1.24-1.47)] with a similar signiﬁcant elevation of breast cancer [1.36, (1.21-1.52)], ovary cancer [1.24, (1.08-1.43)] risk among female, and malignant melanoma [1.58, (1.03-2.44)]. No significant risks were observed as regard to patients with prostate cancer, colorectal cancer, cervix cancer and non-Hodgkin lymphoma. Sensitivity analyses indicated no change in all results but malignant melanoma and colorectal cancer. The RRs became significant differences after removing one study from the colorectal cancer [1.60, (1.70-2.18)]. No publication bias was observed in this meta-analysis. Conclusions: The current meta-analysis suggested that night work played an important role in breast cancer, ovary cancer, and malignant melanoma. However, it might be premature to consider night work as a risk factor for prostate cancer, colorectal cancer, cervix cancer and non-Hodgkin lymphoma. [Table: see text]
Progression-free survival (PFS) and health-related quality of life (HRQoL) in AVAglio, a phase III study of bevacizumab (Bv), temozolomide (T), and radiotherapy (RT) in newly diagnosed glioblastoma (GBM).
Authors: Henriksson Roger , Bottomley Andrew , Mason Warren , Saran Frank , Wick Wolfgang , Nishikawa Ryo , Cloughesy Timothy Francis , Carpentier Antoine F , Hoang-Xuan Khe , Kavan Petr , Cernea Dana , Brandes Alba Ariela , Hilton Magalie , Abajo Guijarro Ana Maria , Ravelo Arliene , Chinot Oliver L. 
Published: March 2020

2005^ Background: GBM has a high disease burden and poor prognosis, and impacts negatively on HRQoL. Symptomatic therapies for GBM, such as corticosteroids (CS), may impact patient status negatively Methods: AVAglio, a randomized, double-blind, placebo (P)-controlled trial in patients (pts) ≥18 yrs with newly diagnosed GBM, evaluated the addition of Bv or P (10mg/kg, q2w) to 6 wks of T (75mg/m2/d) + RT (2Gy, 5d/wk) followed by 28 treatment-free days, then 6 cycles of T (150–200 mg/m2/d, 5d q4w) with Bv or P (10 mg/kg, q2w), and then single-agent Bv or P (15 mg/kg, q3w) until disease progression (PD)/unacceptable toxicity. Co-primary endpoints were investigator-assessed PFS and overall survival. Secondary endpoints included HRQoL (EORTC QLQ-C30 and BN20, with 5 prespecified domains based on relevance in GBM). HRQoL time to definitive deterioration (TDD) was defined as time from randomization to ≥10 point deterioration from baseline with no subsequent improvement, PD, or death. Exploratory endpoints included KPS and CS use. Results: Baseline characteristics were well balanced. Bv significantly prolonged PFS (HR 0.64, 95% CI 0.55–0.74, p<0.0001; median 10.6 vs 6.2 mo) and delayed TDD in HRQoL compared with P (p<0.0001; Table). Functional independence (KPS ≥ 70%) was maintained during PFS in both arms (median Bv vs P: 9 vs 6 mo). Among pts on CS (≥ 2mg) at baseline, discontinuation (≥ 5 consecutive days) was more frequent with Bv than P (66% vs 47%). In pts off CS at baseline (< 2mg), time to CS initiation was significantly longer with Bv than P (HR 0.71, 95% CI 0.57–0.88; median 12.3 vs 3.7 mo). Conclusions: Addition of Bv to RT/T provided a clinically meaningful and statistically significant PFS improvement associated with stable/improved HRQoL and KPS, and reduced CS requirement. Clinical trial information: NCT00943826. [Table: see text]
A randomized phase II study of carboplatin and bevacizumab in recurrent glioblastoma multiforme (CABARET).
Authors: Field Kathryn Maree , Simes John , Wheeler Helen , Hovey Elizabeth J. , Nowak Anna K. , Cher Lawrence , Brown Chris , Livingstone Ann , Sawkins Kate , Rosenthal Mark ,   CABARET/COGNO Investigators
Published: March 2020

2017 Background: The optimal use of bevacizumab (bev) in recurrent glioblastoma (GBM) remains uncertain including the choice between monotherapy or combination therapy as well as the role of continuing bev beyond disease progression. Methods: This was a sequential stratified two part randomized phase II study. Eligibility criteria included: recurrent GBM after radiotherapy and temozolomide, no other chemotherapy for GBM, ECOG PS 0-2. The primary objective (Part 1) was to determine the effect of bev plus carboplatin versus bev alone on 6 month progression-free survival (6PFS) using modified RANO criteria. Bev was given 2-weekly 10mg/kg, carboplatin 4-weekly AUC5. On progression, patients (pts) able to continue treatment were randomized to continue or cease bev (Part 2). Secondary endpoints included response rate (RR); cognitive function; quality of life; toxicity and overall survival (OS). Results: 122 pts (median age 55) were enrolled from 18 Australian sites. 87 (71.3%) were PS 0-1. The current median follow up is 14.7 months with median on-treatment time 3.7 months. 6PFS was 26% (combination) versus 24% (monotherapy) (HR 0.96, 95%CI (0.66, 1.39), p = 0.82). RR (CR+PR) was 15% versus 13%. Median OS was 6.9 versus 6.4 months (HR 1.08, 95%CI (0.74, 1.59), p = 0.68). There were 2 treatment (bev) related deaths in the combination arm (one GI perforation, one CNS hemorrhage). To date, overall incidence of bev-related AEs is similar to prior literature with 10 (8.3%) venous thromboembolic events and 5 (4.2%) hemorrhages (all grades) reported. There were 3 episodes of G3-4 neutropenia, all in the combination arm (5%) and 9 episodes of G3-4 thrombocytopenia. As of January 14, 2013, 47 pts have continued on to Part 2. Data for bev beyond progression is not yet available. Conclusions: In this study of patients with recurrent GBM, the addition of carboplatin to bev did not result in additional clinical benefit compared to bev monotherapy. This large multicentre population-based study demonstrated that clinical outcomes in patients with recurrent GBM treated with bev were inferior to previously reported studies. Ongoing follow-up of patients on bev beyond progression, and novel secondary and exploratory endpoints continues. Clinical trial information: ACTRN12610000915055.
Association of matrix metalloproteinase 2 (MMP2) baseline plasma level to objective response (OR), progression free survival (PFS), and overall survival (OS) and changes under treatment in patients treated with bevacizumab (Bev) for recurrent high-grade glioma (HGG).
Authors: Tabouret Emeline , Boudouresque Francoise , Callego Perez-Larraya Jaime , Barrie Maryline , Lombardi Giuseppe , Matta Mona , Di Stefano Anna Luisa , Labussiere Marianne , Boucard Celine , Loundou Anderson , Romain Sylvie , Carpentier Antoine F , Sanson Marc , Ouafik L'houcine , Chinot Oliver L. 
Published: March 2020

2024 Background: Predictive marker of Bev activity is an unmet medical need. We evaluated predictive value of selected circulating prebiomarkers involved in neoangiogenesis and invasion on patient outcome in recurrent HGG treated with Bev. Methods: A set of eleven prebiomakers of interest (VEGF, VEGF-R2, bFGF, SDF1, PlGF, uPA, PAI1, MMP2, MMP7, MMP9, and adrenomedulline) were analyzed in plasma, using ELISA, at baseline from Bev initiation in a prospective cohort of 26 patients (Cohort1). Correlations were validated in a separate retrospective Bev treated cohort (Cohort2; n = 50) and then tested in a cohort of patients treated with cytotoxic agents without Bev (Cohort3; n = 34). Dosages were correlated to OR, PFS, and OS. MMP2 and MMP9 were then analyzed at multiple time points up to progression. Results: In cohort1, high MMP2 baseline level was associated with an OR rate of 83.3% for high levels versus 15.4% for low MMP2 levels (p = 0.001). In multivariate analysis, MMP2 baseline level was correlated with PFS (hazard-ratio (HR), 3.92; 95% confidence-interval (CI):1.46-10.52; p = 0.007) and OS (HR, 4.62; 95%CI 1.58-13.53; p = 0.005), as MMP9 (p = 0.016 for PFS and p = 0.025 for OS). Similar results were found in cohort2 for MMP2, (MMP2: p<0.001 for OR; p = 0.009 for PFS; p = 0.009 for OS) but not for MMP9. In cohort3, no association was found between MMP2, MMP9 and outcome. Significant changes in MMP2 and MMP9 plasma levels were observed during treatment. MMP2 increased after Bev initiation (p = 0.002), and decreased at progression (p = 0.002) while MMP9 initially decreased (p = 0.007) then increased at progression (p = 0.031). Conclusions: In patients with recurrent HGG treated with bevacizumab, but not with cytotoxic agents, high MMP2 plasma levels are associated with prolonged tumor control and survival while changes over time may reflect tumor control. MMP2 should be tested in randomized clinical trials that evaluate bevacizumab efficacy, and its biological role should be reassessed.
Combined whole genome copy number genotyping and multiplex somatic mutation profiling of FFPE brain tumor specimens for clinical diagnosis and trial selection.
Authors: Alexander Brian Michael , Ramkissoon Shakti , Wen Patrick Y. , Reardon David A. , Lee Eudocia Quant , Rinne Mikael , Norden Andrew David , Nayak Lakshmi , Ruland Sandra , Doherty Lisa M. , LaFrankie Debra C. , Brown Loreal E , Arvold Nils D. , Dunn Ian F. , Santagata Sandro , Rollins Barrett J , Lindeman Neal Ian , Beroukhim Rameen , Ligon Azra , Ligon Keith L. 
Published: March 2020

2030 Background: Multi-dimensional cancer genotyping is increasingly needed for clinical diagnostics and trial selection. Whole genome copy number is relevant for glioblastoma and other brain tumors but routine prospective FFPE-based multiplex copy number and somatic mutation genotyping for clinical trials has not been achieved. Methods: Using novel DNA extraction protocols we implemented whole genome copy number (Agilent aCGH stock 1M feature arrays) and somatic mutation profiling (Oncomap v4.4 Sequenom) assays into a CLIA-certified laboratory setting. Twenty-three copy number aberrations (CNAs) relevant to brain tumors were reported from whole genome data and Oncomap results were reported for 471 cancer-related mutations in 41 genes. Results: During the initial eight months of our combined copy number and mutation-testing program, aCGH and Oncomap were performed prospectively on 239 and 157 brain tumor patients respectively. Copy number was reported in 90% of patients (214/239) and failures were due to insufficient DNA from small biopsies. GBMs (n = 94) harbored gains and losses at expected rates and included amplifications of common drug targets (EGFR, EGFRv3, MET, MDM2, MDM4, PDGFRA, CDK4, CDK6). Emerging candidate drug targets were identified including variant EGFR deletions (e.g. EGFRv2) and FGFR3-TACC3 gains for which other clinical tests are not available. Oncomap results for 78 GBMs revealed mutations in TP53, PTEN and IDH1. Less frequent mutations occurred in BRAF, RB1, PIK3CA, PIK3R1 and KRAS. We integrated copy number and mutation data for 27 GBMs, allowing for improved evaluation of tumor suppressor inactivation status (e.g. PTEN mutation with monosomy 10). In combination, our assays reported data on 10 clinically actionable drug targets relevant for 15 clinical trials open at the time of patient testing. Conclusions: We implemented complementary assays for efficiently detecting genome-wide CNAs and mutations on FFPE brain tumor samples in a CLIA-certified environment. Systematic integration of these results broadens the range of diagnostic and actionable data available to identify patients for trials of targeted therapeutics.
Phase Ib study evaluating safety and pharmacokinetics (PK) of the oral transforming growth factor-beta (TGF-ß) receptor I kinase inhibitor LY2157299 monohydrate (LY) when combined with chemoradiotherapy in newly diagnosed malignant gliomas.
Authors: Suarez Cristina , Rodon Jordi , Desjardins Annick , Forsyth Peter A. J. , Gueorguieva Ivelina , Cleverly Ann , Burkholder Tiana , Desaiah Durisala , Lahn Michael M. F. , Wick Wolfgang 
Published: March 2020

2039 Background: Based on preclinical data suggesting an additive antitumor effect of combining TGF-ß inhibitors with temozolomide based chemoradiation (TMZ/RT), a Phase 1b study was initiated to evaluate the safety and PK of LY combined with TMZ/RT in patients with newly diagnosed glioma. Methods: LY was evaluated sequentially in 2 doses (160 mg/day and 300 mg/day) combined with TMZ/RT. TMZ/RT was administered as approved and LY given as intermittent dosing (14 days on/14 days off=1 cycle). Toxicity was assessed using the CTCAE, version 4. The PK profile of LY in combination with TMZ/RT was determined. Results: 19 patients with glioma (16 World Health Organization Grade 4; 3 Grade 3 were treated with LY (160 mg/day, n=10; 300 mg/day, n=9) and TMZ. The median number of cycles was 5 (range 1-13). Regardless of relatedness to study treatment, the following treatment-emergent adverse events (TEAEs) were observed in ≥25% of patients: nausea (n=11), fatigue (n=11), thrombocytopenia (n=11), headache (n=9), vomiting (n=8), lymphopenia (n=6), anorexia (n=6), constipation (n=5), radiation skin injury (n=5), and alopecia (n=5). The following TEAEs were related specifically to at least LY: thrombocytopenia (n=3, 2 Gr 3 and 1 Gr 4), fatigue (n=2), maculopapular rash (n=2, Gr 3), dermatitis acne form (n=3, 1 Gr 3) and in 1 patient each: nausea, vomiting, hypertension, hypersensitivity and leucopenia (Gr 4). No change in the PK profile of LY was shown when LY was combined with TMZ/RT. In the combination therapy, area under the curve (0-∞) at steady state was observed geomean (%CV) to be 5.5 (48%) mg*h/L following 300 mg/day (n=9). Following monotherapy with LY, these exposures were similar with a median (20th-80thpercentiles) of 4.7 (2.5-8.8) mg*h/L (n=37). Conclusions: No dose-limiting toxicities and no clinically meaningful cardiotoxicities were observed; hence, the treatment of LY at 300 mg/day in combination with standard chemoradiation has a manageable toxicity profile. A Phase 2a trial has been initiated to relate the pharmacodynamic effects with overall survival. Clinical trial information: NCT01220271.