bluuebunny/crossref_metadata_2025 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.
Efficacy and safety of radiotherapy (RT) plus temozolomide (TMZ) in elderly patients (EP) with glioblastoma (GBM).
Authors: Lombardi Giuseppe , Bellu Luisa , Berti Franco , Farina Patrizia , Galuppo Sara , Zustovich Fable , Della Puppa Alessandro , Carollo Carla , Bertorelle Roberta , D'Avella Domenico , Zagonel Vittorina
Published: March 2020

2043

Background: the optimal management of EP with GBM remains controversial. The role of RT with TMZ for EP is unclear, and EP are often treated with RT alone, TMZ alone or palliative approaches. We describe our experience of combining RT with concurrent TMZ for treatment of EP with GBM Methods: medical records of patients ≥65 years old with newly GBM, histologically confirmed at Veneto Institute of Oncology – Padua, and treated with RT plus TMZ, were reviewed. Concomitant TMZ was 75mg/m2/die. The adjuvant treatment consisted of TMZ 150-200mg/m2/die for six cycles. Median progression-free survival(PFS) and overall survival(OS) were estimated with Kaplan-Meier method. Toxicity was scored according to CTCAE 4.0 Results: we analyzed 60 patients(PTS), 34 males and 26 females; the average age was 70 (range 65-82); ECOG PS was 0-1 in 35 PTS and 2 in 25 PTS; complete surgery was performed in 35 PTS, partial surgery in 25 PTS. 40 and 20 PTS received RT within 6 or more weeks (range 7-9) from surgery. MGMT and IDH1 were analyzed in 43 PTS: MGMT methylated in 20 PTS (46%), all PTS had wild-type IDH1. 34 PTS were treated with RT 40Gy in 15 fractions, 26 PTS with RT 60Gy in 30 fractions with no significant difference in ECOG PS, MGMT and type of surgery between the two subgroups. For all PTS, PFS and OS were 9.5 and 12.7 ms, respectively. OS was 13.7 and 12.4 ms (p=0.9) in PTS receiving RT within 6 or more weeks from surgery, respectively. 13% of PTS showed grade 3-4 haematological toxicity, 12% grade 3-4 asthenia, 3% nausea/vomiting. MGMT methylated and complete surgery was associated with a longer survival. PFS was 9 vs 10 months (p=0.4) and OS was 11.7 vs 13.7 ms (p=0.1), for PTS treated with 40Gy and 60Gy, respectively. Regarding toxicity: grade 3-4 haematological toxicity was 9% vs 23%, severe asthenia was 9% vs 15%, nausea/vomiting was 3% vs 4% of PTS receiving RT 40Gy and 60Gy, respectively. Conclusions: RT plus TMZ is effective and safe in EP with GBM and good ECOG PS. PFS and OS was not statistically different between PTS receiving RT 40Gy or 60Gy, although we showed a trend for longer OS with RT 60Gy; in contrast, severe toxicity was higher in PTS with RT 60Gy. OS was similar between PTS receiving RT within 6 or more weeks (7-9ws) from surgery.
Quality of life (QOL) and cognitive status among irradiated brain tumor survivors treated with donepezil or placebo.
Authors: Case Doug , Naughton Michelle Joy , Stieber Volker W. , Bayer Gerald K. , Bilodeau Paul A. , Moore Dennis Frederic , Falchuk Steven Charles , Needles Burton M. , Piephoff James , Edenfield William Jeffery , Giguere Jeffrey K. , Erickson Nicholette , Loghin Monica Elena , Shaw Edward G. , Rapp Stephen R.
Published: March 2020

2051

Background: Cognitive problems after cancer therapy can decrease QOL. This phase III randomized trial tested the effect of donepezil (5-10 mg daily for 24 weeks) on cognition and QOL in brain cancer patients. Methods: Between 2/2008-12/2011, 198 (99 placebo; 99 donepezil) adult primary and metastatic brain tumor survivors > 6 months post radiation (> 30 Gy) were recruited at 24 sites affiliated with the Wake Forest CCOP Research Base, 3 CTSU sites, and M.D. Anderson. Outcomes were assessed at baseline, 12 and 24 weeks. Regression analyses examined the association of demographics, fatigue (FACIT-Fatigue), and a cognitive performance composite score (CC) (comprised of the Controlled Oral Word Association Test, Hopkins Verbal Learning Test-Revised, Digit Span Test, Trail Making Test A&B, Rey-Osterreith Complex Figure-modified, Grooved Pegboard) on QOL, measured by the FACT-Brain (FACT-Br) total score. Results: Participants had a median age of 55, were predominantly female (54%) and non-Hispanic White (91%), with a median time from diagnosis of 38 months. Study completion was 74%. At 12 and 24 weeks, treatment had no significant effect on QOL, unadjusted and adjusted for race/ethnicity, age, sex, fatigue, baseline FACT-Br, and baseline CC. However, for those below the median on the baseline FACT-Br subscale (i.e., greater cognitive symptoms), donepezil was associated with higher (better) post-tx FACT-Br total scores (p =0.004), unadjusted for covariates. After adjustment for covariates, donepezil was borderline significantly associated with higher post-tx QOL (p=0.052). Improvement in QOL was associated with being female (p=0.017) and less baseline fatigue (p=0.005). For participants with baseline FACT-Br subscale scores above the median, only lower baseline FACT-Br total scores (p=0.015) were significantly related to greater improvements in FACT-Br. Donepezil treatment was not significant (p=0.48). Conclusions: The impact of donepezil on QOL was greater in survivors with more cognitive symptoms at baseline, although the results were borderline significant. Fatigue continued to be a major factor in lower QOL. Other interventions to better manage survivors’ symptoms are needed. Clinical trial information: NCT00369785.
Patterns of relapse after concurrent temozolomide and dose-escalated intensity-modulated radiation therapy (IMRT) in newly diagnosed glioblastoma (GBM).
Authors: Speers Corey , Junck Larry , Heth Jason , Cao Yue , Lawrence Theodore Steven , Tsien Christina
Published: March 2020

2052

Background: We hypothesized that IMRT would permit us to safely escalate the dose of radiation with concurrent temozolomide substantially above the current standard of 60 Gy and that this increased dose would more adequately control local disease leading to an alteration in the patterns of relapse in patients with GBM. Methods: Between 2003 and 2012 a total of 69 patients were treated with dose-escalated IMRT with concurrent temozolomide. 39 patients were initially treated in a combined phase I/II trial with IMRT doses of 66 to 81 Gy over 6 weeks with concurrent daily temozolomide (75 mg/m2) followed by adjuvant cyclic temozolomide (200 mg/m2 d1-5 q28d for 6 or more cycles). Subsequently, 30 additional patients were treated to 66-72 Gy based on the reported efficacy and safety of the initial phase I/II study. Results: All 69 patients were assessed to evaluate the effect of dose escalation on late toxicity and patterns of progression. Median RT dose was 72 Gy and median overall survival was 19.0 months. Late CNS grade III toxicity was observed at 78 (2 of 7 patients) and 81 Gy (1 of 9 patients). 0 of 53 patients receiving 75 or less Gy developed necrosis. 64% (44/69) of patients had progression of their disease after dose-escalated chemoradiotherapy. The patterns of progression differ, however, from previous studies which identify in-field relapse of 72-80% with standard dose radiation (Brandes AA, Tosoni A, Franceschi E, et al: J Clin Oncol. 27:1275-9, 2009). In this cohort, 41% (18/44) of patients developed marginal or distant relapse compared to 59% (26/44) who developed local, in-field relapse. Conclusions: Patients with GBM can safely receive standard temozolomide with up to 75 Gy in 30 fractions, delivered using IMRT. Dose-escalated chemoradiotherapy improves local control and leads to an increased percentage of patients progressing distally, highlighting the need for improved tumor targeting with newer imaging modalities to identify the initial extent of tumor involvement as well as the need for more effective systemic treatment. I/II study.
Phase I adult brain tumor consortium (ABTC) trial of ABT-888 (veliparib), temozolomide (TMZ), and radiotherapy (RT) for newly diagnosed glioblastoma multiforme (GBM) including pharmacokinetic (PK) data.
Authors: Kleinberg Lawrence , Supko Jeffrey G. , Mikkelsen Tom , Blakeley Jaishri O'Neill , Stevens Glen , Ye Xiaobu , Desideri Serena , Ryu Samuel , Desai Bhardwaj , Giranda Vincent L. , Grossman Stuart A.
Published: March 2020

2065

Background: ABTC conducted a dose finding trial of ABT-888, an orally administered Poly(ADP-ribose) polymerase [PARP] inhibitor, during daily TMZ with post-operative RT for GBM. PARP is important in repair pathways for RT induced DNA injury and TMZ induced alkylation at N7-methylguanine and N3-methyldenine. Methods: An initial safety group (no concurrent RT), received ABT-888 10 mg BID po during 42 days of daily TMZ 75 mg/m2. After this, the planned dosing steps included ABT-888 BID concurrent with standard RT and TMZ, with planned ABT-888 dose escalation or de-escalation based on observed toxicity. Dose limiting toxicity (DLT) is ≥ grade 3 non-hematologic or neurologic not responding to steroids, and hematologic ANC<500/mm3 and platelets (PLT) < 25K/mm3. The pharmacokinetics (PK) of ABT-888 were characterized for dose 1 and at steady-state. Results: Without concurrent RT, DLT (thrombocytopenia) occurred in 1/6 patients. With concurrent RT/TMZ and ABT-888 10 mg BID, 4/12 patients had DLT (thrombocytopenia). As per the planned dose de-escalation, ABT-888 10 mg BID was then given every other week during TMZ/RT. This resulted in 3/6 patients with DLT (2 thrombocytopenia, 1 neutropenia). The hematologic toxicity with this regimen was judged high enough that accrual was discontinued. In the setting of continuous dosing for 6 weeks, the total body clearance of ABT-888 for the first dose (27.5±9.5 L/h, n = 15) and at steady-state after BID dosing (23.5±10.4 L/h, n = 18) were similar. Accumulation for BID dosing was 56±33%. Steady-state peak and trough concentrations of the drug in plasma were 66±29 ng/mL and 18±10 ng/mL, respectively. Additional PK data will be presented. Conclusions: Administering ABT-888 BID po in combination with standard RT/TMZ was not tolerable in GBM patients as a result of hematologic toxicity. ABT-888 PK in GBM patients were very similar to findings reported for solid tumor patients. There is strong scientific rationale for continued development of an appropriate dosing regimen for this agent in the initial therapy of GBM. Clinical trial information: NCT00770471.
Retrospective multicentric study on adult intramedullary spinal cord gliomas from a cohort of 319 patients.
Authors: Campello Chantal , Parker fABRICE , Slimani Sonia , Le Floch Anne , Aghakhani Nozar
Published: March 2020

2068

Background: Intramedullary spinal cord tumors (IMST) are among the rarest types of tumors, account for 2 to 4% of all central nervous system tumors. This study was conducted to describe clinical features, radiological imaging, anatomopathological characteristics, management and outcome of neuroepithelial IMST. Methods: in this retrospective review, a total of 319 patients were included from 7 French neurosurgical University Hospital Centers, between 1984 and 2011. The patient’s pre and postoperative neurological state were classified according to the Mac Cormick scale. Only patients with a preoperative MRI and confirmed histological were included. Results: Mean age at diagnostic was 42.4 for ependymomas, 39.6 for astrocytomas, (included 20 patients older than 65 years old). The male/female ratio was 1.6 for ependymomas, and 1.1 for astrocytomas. Ependymomas were associated with neurofibromatosis in four patients. Pain was the most common presenting symptom (74%), followed by motor (72%), and sensory (66%) complaints. Pre and post operative neurological states were more severe in astrocytomas than ependymomas. The most frequently involved localization was the cervical region for ependymomas, and the thoracic region for astrocytomas. Partial and total resection was achieved in 80% of ependymomas, and 20% of astrocytomas, (diagnostic of other tumors was performed by biopsy). Histological types, according to WHO classification were ependymomas in 72% patients, (94% were low grades), astrocytomas in 24% patiens, (29% were high grades), oligoastrocytomas in 2.4% , and oligodendrogliomas in 1.7%. Postoperative radiotherapy was used especially in high-grade tumors, (67% of ependymomas, 71% of astrocytomas), in absence of severe toxicity. 18% of low-grade astrocytomas received radiotherapy. Chemotherapy was used only in 33% of ependymomas and 24% of astrocytomas. The five-year overall survival rate was 76.8% for astrocytomas, and 94.5% for ependymomas. Conclusions: Histology, preoperative functional score, and grades tumors are confirmed as prognostic factors in this study. Questions about adjuvant therapy for astrocytomas, like intracranial tumors, are answered.
An EGFRvIII-specific IHC IUO test for patient selection in AMG 595 phase I trial.
Authors: Damore Michael A. , Coberly Suzanne K. , Wakamiya Karen , Webster Scott , Tanna Vaishali , Xu Xiaolei , Klement Ivan , Welcher Rosanne , Kiaei Panteha , Liu Yi , Samayoa Kimberly , Wong Susan , Shamon-Taylor Lisa , Friberg Gregory R. , Hill John S. , Patterson Scott D.
Published: March 2020

2071

Background: EGFRvIII is a mutant version of EGF receptor resulting from the genomic deletion of exons 2 through 7 and is expressed only in certain tumors. AMG 595 is an experimental therapeutic specifically targeting EGFRvIII and consists of an EGFRvIII-specific antibody conjugated to the maytansinoid antimicrotubule agent DM-1. Due to its specificity, mechanism of action, and pre-clinical activity, AMG 595 is expected to have clinical effect only in tumors expressing EGFRvIII. Since the reported prevalence of EGFRvIII in glioblastoma multiforme (GBM) is ~30%, prospective selection of patients with EGFRvIII positive tumors was desired for clinical development. An immunohistochemical (IHC) assay developed with Dako using a novel EGFRvIII antibody is currently being employed for patient selection for the AMG 595 phase I study in recurrent GBM (NCT01475006). Methods: An appropriate IHC reagent for human tissue was created using the variable region of a novel EGFRvIII-specific antibody developed using Xenomouse technology. Staining conditions were optimized using Dako pharmDx reagents, the Dako Link 48 Autostainer, and FFPE tissue sections. Confirmatory transcript analyses of adjacent sections were conducted using the NanoString platform. Results: Robust and reproducible staining for EGFRvIII was observed using archived GBM resections. Percentage of stained cells correlated with levels of EGFRvIII transcripts, and tumors without staining did not express EGFRvIII transcripts. Although some tumors exhibited homogenous staining, most were heterogeneous with varying distribution and percentages of stained tumor cells similar to literature reports of IHC analysis utilizing other EGFRvIII-specific antibodies. Tumor samples from patients entering into the AMG 595 Phase 1 study analyzed with this IHC test have displayed the predicted staining prevalence. Conclusions: The developed EGFRvIII IHC assay, approved under an Investigational Device Exemption, is currently being successfully employed to prospectively select patients in an ongoing phase I trial. Use of this well characterized IHC test will enable correlation of clinical outcome and staining characteristics to inform subsequent studies.
Genotypes of human glioma xenografts compared with glioma stem cell-derived tumors.
Authors: Chen Selby , Peterson Timothy , Anderson S. Keith , Eckel-Passow Jeanette , Decker Paul A. , Sarkaria Jann Nagina , Parney Ian F
Published: March 2020

2072

Background: Human glioma stem cells and xenograft lines are common translational models in neuro-oncology but it has not been established if they are genetically and phenotypically comparable. This study aimed to determine if human glioma xenografts and stem cell-derived tumors had similar genotypes. Methods: Matched glioma stem cell cultures and subcutaneous xenograft lines were generated from four human glioblastoma specimens (BT114, BT116, BT120, BT132). Comparison was made between subcutaneous stem cell-derived tumors (flank) and xenografts established in nude mice. Copy number variation (CNV) and gene expression microarray studies were performed. Results: Various differences in copy number and gene expression were seen. Observed CNVs included regions within EGFR, myc, and p16 (INK). For example, EGFR copy number was two fold higher in xenografts vs. stem cell-derived tumor in one line (BT114). This difference was corroborated by western blot. Other differences included a heat shock protein homolog (DNAJA4), tetraspanin 13, and a p53 family target gene (ISG20L1). Two lines (BT114, BT116) had a greater than two fold increase in DNAJA4 expression in xenografts vs. stem cell-derived tumors (p = 0.04, 0.01). Two cell lines (BT116, BT120) had a two to eight fold increase in tetraspanin 13 expression in xenografts (p = 0.02, 0.05). However, neither copy number nor gene expression variations were consistent across all cell lines. Conclusions: Xenografts and glioma stem cell-derived tumors established from the same patient specimens have distinct genotypes. Further work is needed to establish if these differences are random or represent characteristic changes selected by different in vitro or in vivo pressures. However, these variations raise questions regarding which model is ideal for studying glioma biology, and which ones best replicate glioma characteristics in human patients.
Effect of RTVP-1 on the mesenchymal transformation of glioma stem cells (GSCs) and their self-renewal and migration.
Authors: Brodie Chaya , Giladi Nissim , Ziv-Av Amotz , Lee Hae Kyung , Finniss Susan , Cazacu Simona , Xiang Cunli , Poisson Laila , Slavin Shimon , Mikkelsen Tom
Published: March 2020

2073

Background: Glioblastoma (GBM), the most aggressive primary brain tumors, exhibit increased invasiveness and resistance to anti-tumor treatments. GBM are categorized into proneural, neural, classical and mesenchymal subgroups, the latter being characterized by increased invasion and poor prognosis. We recently reported that RTVP-1 is highly expressed in GBM and its expression is correlated with astrocytic tumor grade. Methods: We employed promoter and Chip analyses, analysis of tumor specimens submitted to TCGA , GSC self-renewal and migration assays, mesenchymal and neural differentiation, gene array analysis and pull-down assay followed by FRET. Results: The RTVP-1 promoter binds STAT3 and C/EBPb, the transcription factors that regulate mesenchymal transformation of GBM. The expression of RTVP-1 is higher in mesenchymal GBM and is inversely correlated with patient survival in the proneural group. We examined the expression and functions of RTVP-1 in GSCs, a small population of cancer stem cells that are implicated in the increased migration, radio- and chemo-resistance of GSCs and tumor recurrence. RTVP-1 was expressed in the different GSCs but not in the normal human neural stem cells (NSCs). Overexpression of RTVP-1 in NSCs induced their mesenchymal transformation, whereas silencing of RTVP-1 in GSCs decreased their mesenchymal and increased their neural phenotypes. Moreover, RTVP-1 promoted the self-renewal and migration of GSCs. Using gene array analysis of RTVP-1 silenced cells we identified IL-6 and CXCR4 as major mediators of RTVP-1 effects on the mesenchymal transformation and self-renewal of GSCs. In addition, using a pull down assay with His-tagged RTVP-1 we identified N-WASP and hnRNPK as novel interacting proteins of RTVP-1 that mediate its effects on glioma cell migration. Conclusions: RTVP-1 expression is associated with mesenchymal transformation of GSCs. RTVP-1 promotes self-renewal and migration of GSCs and these effects are mediated by the increased expression of IL-6 and CXCR4 and via interaction with N-WASP and hnRNPK. Collectively, these results suggest that RTVP-1 may represent a novel diagnostic marker and a therapeutic target in GBM.
Final results of a single-arm phase II study of bevacizumab and temozolomide following radiochemotherapy in newly dignosed adult glioblastoma patients.
Authors: Nicholas Martin Kelly , Lukas Rimas Vincas , Amidei Christine , Vick Nicholas , Paleologos Nina , Malkin Mark Gordon , Krouwer Hendrikus , Junck Larry , Arzbaecher Jean , Lai Albert , Merrell Ryan
Published: March 2020

2076

Background: This study evaluated efficacy and safety of bevacizumab (BEV) added to the post-radiation treatment phase for patients with newly diagnosed glioblastoma (GBM). Methods: Sixty-two participants with newly diagnosed GBM were enrolled between May 2007 and June 2010. Participants received standard radiation therapy (RT) within 6 weeks of surgery, and concomitant administration of temozolomide (TMZ). Four weeks after radiation, treatment with TMZ (Days 1-5 of a 28 day cycle) with BEV, (days 1 and 15 of a 28 day cycle) was started, and continued until disease progressed or adverse effects indicated need to stop treatment. Analyses were completed for all participants by intention to treat (ITT), with progression-free survival (PFS) and overall survival (OS) serving as primary and secondary endpoints respectively. Results: Subbjects completed a mean of 7.7 (range 0-29) cycles of post-RT with BEV and TMZ. Twenty participants (32%) were unable to proceed to the post-RT phase. The forty-two participants who did proceed to the post-RT phase completed a mean of 11.5 cycles of treatment. Thirty-eight participants (61%) stopped the study due to disease progression; 6 participants (14%) voluntarily discontinued treatment after 24 cycles with at least stable disease. At a median follow-up time of 24 months, median progression-free survival (PFS) for all participants was 8.8 months while median overall survival (OS) was 16.5 months for all participants. Ly with These results also compare favorably with recently reported results from the AVAglio study (PFS = 10.6 mo.). The toxicity profile was consistent with that reported in similar studies. MGMT promoter methtion.ylation status is under investiga Conclusions: Participants in this study demonstrated a median 1.9 month PFS benefit as compared to the 6.9 median OS reported by Stupp, et al. (2005) and a median 1.9 month OS benefit as compared to the 14.6 month median OS reported by Stupp, et al. (2005). Results suggest that the addition of bevacizumab to the post-RT phase of treatment improves both PFS and OS for persons with GBM despite the high percentage of participants being unable to progress to post-radiation treatment. Clinical trial information: NCT005906.
Chemopredictive assay for patients with primary brain tumors.
Authors: Claudio Pier Paolo , Valluri Jagan , Mathis Sarah E , Alberico Anthony , Alberico Thomas , Denvir James , Kimmey Gerrit A. , Mogul Mark Jeffrey , Sehgal Rajesh , Chowdhary Aneel A. , Mozayen Mohammad , Tirona Maria R. B. Tria , Matt Laurie Beth , Oakley Gerald , Denning Krista L , Dougherty Thomas
Published: March 2020

2089

Background: Cancer stem-like cells (CSLCs) in primary brain tumors can resist certain chemotherapies, thereby causing relapse of the disease. Thus, development of a test that identifies the most effective chemotherapy management offers great promise for personalized anticancer treatments. Methods: We have developed an ex vivo ChemoID assay designed to predict the sensitivity and resistance of CSLCs and bulk of tumor cells of a given patient's solid tumor to a variety of chemotherapy agents by measuring the percentage of cell death. In a retrospective study of five patients with malignancies of the central nervous system, we assessed the correlation between the results of the ChemoID assay and clinical response. Two anaplastic WHO grade-III ependymomas, two IDH-1 negative WHO grade 4 glioblastomas, and one medulloblastoma were tested. Tumors were classified as responsive (50-100% cell kill), intermediately responsive (30-50% cell kill), and nonresponsive (0-30% cell kill) to chemotherapy. Treatment selection was blinded to assay results. MRI and CT scan determined response to therapy. Results: The ChemoID assay performed on the tumor bulk produced a correct prediction in 4 out of 5 cases (p = 0.4, Fisher's Exact Test; PPV = 75%, NPV = 100%) when compared to the drugs received. The same assay performed on the CSLCs produced a correct prediction in all 5 cases (p = 0.1, Fisher's Exact Test; PPV=NPV=100%). Conclusions: An assay such as ChemoID that measures cell death of CSLCs and bulk of tumor cells appears to be beneficial in selecting specific standard chemotherapy agents ex vivo for patients with malignancies of the central nervous system.