bluuebunny/crossref_metadata_2025_split huggingface dataset:
Anti-GD2 immunotherapy in adults with high-risk neuroblastoma (HR-NB): The Memorial Sloan Kettering Cancer Center (MSKCC) experience.
Authors: Suzuki Maya , Kushner Brian H. , Kramer Kim , Basu Ellen M. , Roberts Stephen S. , LaQuaglia Michael P , Cheung Nai-Kong V. , Modak Shakeel 
Published: September 2018

10550 Background: The diagnosis of NB in adulthood is rare and little is known about its biology and clinical course. There is no established therapy for adult NB. Anti-GD2 immunotherapy is now standard in children with HR-NB but its use has not been reported in adults. Methods: After obtaining IRB waiver, records of all patients with adult-onset (≥18 years) NB seen at MSKCC between 1983 and 2015 were reviewed. Overall survival (OS) was tested by log-rank test. Cox-regression was used for multivariate analysis. Results: The subjects were 42 adults (median: 25; range18-71 years); 23 male and 19 female. Five, 1, 1 and 35 patients had INSS stage 1, 2, 3 and 4 disease, respectively. Genetic abnormalities included somatic ATRX (59%) and ALK mutations (43%) but not MYCN-amplification. 16 patients remain alive at a median follow-up of 5.3 years. OS for non-stage 4 patients was superior to stage 4 (median survival 14.6 vs 5.3 years; p < 0.05). However 5/7 patients with < stage 4 NB progressed to stage 4. Among 35 stage 4 patients, 4 achieved complete remission (CR) after induction chemotherapy and surgery, 11 underwent autologous stem cell transplant (ASCT) and 15 received multiple cycles of anti-GD2 antibodies 3F8 or hu3F8 without complications. In univariate analysis, patients ≤ 29 years old (n = 24) at diagnosis, those achieving CR, and those receiving anti-GD2 antibodies had superior OS (p < 0.05 for each). ASCT was not beneficial (p = 0.3 for ASCT vs no ASCT). For stage 4 patients, anti-GD2 immunotherapy was associated with favorable OS in multivariate analysis (95% CI of anti-GD2 antibody: 1.270 to 7.990). Conclusions: Adult-onset stage 4 NB demonstrates a high incidence of somatic mutations and is only partially chemosensitive. However, 3F8/hu3F8-based anti-GD2 immunotherapy appears to improve long-term survival and is well tolerated.
Neuroblastoma metastatic to the central nervous system: Survival analyses from the German Childhood Cancer Registry and the literature.
Authors: Berthold Frank , Hömberg Marc , Baadsgaard Ole 
Published: September 2018

10555 Background: Therapeutic innovation has resulted in an overall decline in childhood neuroblastoma (NB) mortality; however, metastatic NB to the central nervous system (CNS NB), which has emerged as a sanctuary site for NB metastases, remains difficult to treat and is typically fatal. The objective of this study was to describe the natural course of CNS NB. Methods: Data were sourced from a custom query of the German Childhood Cancer Registry (GCCR) and from the literature. Survival statistics were prepared from a diverse, thus generalizable, pool of CNS NB patients. Data are presented as secondary event-free and overall survival (EFS and OS) after diagnosis of first CNS recurrence from initial high-risk NB. Results: The GCCR query identified 85 patients with CNS NB diagnosed from 1990–2010, including 57 with isolated CNS disease. The median (95% confidence) EFS and OS times were 2.6 (1.5–3.8) and 4.7 (2.1–7.2) months, respectively, for all CNS NB patients, and 2.8 (1.4–4.1) and 6.8 (2.1–11.5) months, respectively, for isolated CNS NB patients. Secondary OS at 12, 18, and 36 months was 29.4%, 18.8%, and 8.2%, respectively, for all CNS NB patients, and 35.1%, 22.8%, and 12.3%, respectively, for isolated CNS NB patients. Thirteen publications were selected with 83 patients treated from 1979–2013. In addition to an inclusive analysis, a restricted analysis was performed, excluding patients who did not receive therapy with curative intent, to assess survival after therapeutic intervention. Median OS (95% confidence) was 5.6 (3.0–8.0) and 8.7 (5.8–11.0) months in the inclusive and restricted analyses, respectively. The proportion of patients surviving 12, 18, and 36 months at reporting were 24%, 12%, and 3.6%, respectively, for the inclusive population, and 33%, 17%, and 5%, respectively, for the restricted population. Conclusions: An assessment of the natural course of CNS NB from two sources arrived at similar conclusions with respect to overall and long-term survival. In general, median secondary OS is < 6 months and < 10% of patients survive 36 months. The findings were consistent across geographic regions and have not changed appreciably in 4 decades.
Apatinib for patients with unresectable high-grade osteosarcoma progressing after standard chemotherapy: A multi-center retrospective study.
Authors: Yu Wenxi , Yu Xiuchun , Wu Sujia , Tang Lina , Zheng Shui'er , Zhou Yan , Huang Yujing , Qian Guowei , Li Hongtao , Zhang Jianjun , He Aina , Wang Yonggang , Hu Haiyan , Lin Feng , Shen Zan , Yao Yang 
Published: September 2018

11031 Background: Prognosis for patients with relapsed/metastatic osteosarcoma is dismal and the optimal treatment strategy remains to be refined. Sorafenib and sorafenib plus everolimus are the only two second-line targeted therapies recommend by FDA. The median progression-free survival (PFS) was 4–5 months. In this study, the efficacy and safety of apatinib, another oral tyrosine kinase inhibitor targeting VEGFR-2, were evaluated in patients (pts) with inoperable high-grade osteosarcoma progressing after standard multidisciplinary treatment. Methods: This retrospective study reviewed the medical records of 26 pts with metastatic osteosarcoma who received apatinib at a dose of 500 mg qd or 250 mg bid after failure of standard treatment including doxorubicin, cisplatin, ifosfamide and high-dose methotrexate from Jul 2015 to Nov 2016. Results: Among all pts, 25 (96.2%) had pulmonary metastases and 4 (15.4%) had metastases in the bone (Table). Eleven pts achieved partial response, 10 stable disease and 5 progressive disease, yielding an objective response rate of 42.3% and a clinical benefit rate of 80.8%. Followed up to Dec 31 2016, the median PFS was 8 months (95%CI, 3.2–12.8 months), and the median overall survival (OS) was not reached. The 12-month PFS and OS rates were 22.5% (95%CI, 1.6%–58.1%) and 68.7% (95%CI, 37.5%–86.5%), respectively. Noteworthy, the 12-month PFS rate for patients treated with apatinib in the second-line setting was 51.3% (95%CI, 9.1%–83.1%). The most frequent treatment-related adverse events (AEs) were hand-foot skin reaction (HFSR) (84.6%), hypertension (46.2%), and diarrhea (23.1%). Severe AEs included grade 3 HFSR (7.7%) and hypertension (3.8%). No unexpected AE was found. Conclusions: Apatinib was well tolerated and demonstrated activity as a second- or later-line treatment in patients with metastatic osteosarcoma, which deserves further investigations. [Table: see text]
Novel germline risk loci in familial melanoma (FM).
Authors: Kazlow Esther , Ferguson Robert , Simpson Danny , Martinez Carlos N. , Vogelsang Matjaz , Moran Una , Lee Yesung , Osman Iman , Polsky David , Kirchhoff Tomas 
Published: September 2018

1535 Background: While about 10% of cutaneous melanoma (CM) clusters in families, known high-risk loci explain not more than 40% of expected inherited risk. Besides the most frequently mutated genes in FM (e.g. CDKN2A), it is estimated that the remaining 60% of FM susceptibility is due to the interaction of environment with specific pools of rare known loci and yet unknown high-risk genes. In our study, we report the discoveries of novel germline genetic risk factors in FM in a recently developed FM cohort at New York University Langone Medical Center (NYULMC) consisting of CM and multiple primary melanomas (MPM) of Ashkenazi Jewish (AJ) and non-AJ European ancestries. Methods: As part of an ongoing ascertainment of FM at NYULMC, we assessed the status of CDKN2A mutations using Sanger sequencing, examining the coding regions of 47 AJ FM families and 81 non-AJ FM kindreds. In high-risk mutation-negative families, we applied whole-exome sequencing (WXS) and an innovative hot-spot mutational analysis of non-coding regions to identify novel high-risk loci associated with FM susceptibility. Results: We found that frequencies of CDKN2A deleterious mutations in our FM cohort (13%) are comparable with observations from previous studies. We have also identified a specific CDKN2A coding mutation in FM kindreds of AJ ancestry, which is particularly interesting as CDKN2A mutations in AJ cohorts have been sparsely reported in prior studies. The WXS/targeted non-coding sequencing of mutation-negative families identified putatively deleterious mutations in regulatory regions in the vicinity of several novel loci, including SMAD4 and PAX8, co-segregating in FM kindreds. Conclusions: Our unique FM ascertainment, including > 50% AJ kindreds, provides an excellent platform for mapping high-risk genetic susceptibility in FM. Novel deleterious mutations identified in non-coding regulatory regions of SMAD4 and PAX8 genes, some with increased frequency in AJ families, suggest a need for a more thorough investigation of the non-coding genome using a founder FM population, as we propose here. As our ongoing ascertainment expands, we are pursuing validation of our observations through comprehensive sequencing efforts.
Effects of physical condition and body composition on cancer risk in a nationwide cohort of 31,158 men from Finland.
Authors: Sormunen Jorma Tauno Juhani , Arnold Melina , Soerjomataram Isabelle , Pukkala Eero 
Published: September 2018

1565 Background: Regular physical activity seems to protect men from colorectal cancer and possibly also from prostate cancer. In the case of other cancers the evidence is adding up, and physical activity seems to have a small protective effect to its incidence. The aim of this study was to analyse the effects of physical condition (PC) in early adulthood on cancer incidence later in life. Methods: We collected data on general health, anthropometry and PC for 31,158 Finnish men born in 1958 from the time of their military service between the ages of 17 and 30 years. Using linkage with the Finnish Cancer Registry, all men were followed-up for cancer incidence up to 2014. Results: Overweight and obesity (body mass index (BMI) ≥ 25 kg/m2) were associated with an increased overall cancer risk [hazard ratio (HR): 1.08, 95% confidence interval (CI): 0.89-1.30] when compared to those with BMI < 25 kg/m2. Those with normal weight but bad PC had an increased risk of all cancers combined as compared to those with normal weight and good PC (HR 1.18, 95% CI: 1.01-1.38), which further increased in those who were also overweight (HR 1.30, 95% CI: 1.01-1.69). We noticed an increased overall cancer risk in men in who entered service with minor health problems (HR 1.46, 95% CI 1.19-1.80), when compared to those that were completely healthy. This was especially observed for advanced prostate cancer (HR: 3.35, 95% CI: 1.14-9.90). Increased HRs, yet statistically insignificant, were also seen for colorectal and other obesity-related cancers. Conclusions: Good PC at young age seems to protect men from cancer later in life. Early adulthood obesity, when combined with bad PC, seems to further increase cancer risk.
Anti-cancer effect among patients with familial Mediterranean fever: Outcome of 258,803 person-years analysis.
Authors: Brenner Ronen Mordechay 
Published: September 2018

1566 Background: Familial Mediterranean fever (FMF) is an autoinflammatory disease that causes recurrent serosal inflammation. The association between FMF and malignancy has not been previously described. We estimated cancer risk in a large single-institution cohort of FMF patients. Methods: The study cohort consisted of 8,534 FMF patients registered in the Israel National FMF Center at Tel Hashomer, Israel. We linked the study cohort to the database of the Israel National Cancer Registry using the national identity number. Cancer incidence in FMF patients was determined and stratified by age and gender. Standardized incidence ratios (SIR) for cancers were calculated. Results: Among 8,534 FMF patients (4,400 men, 4,134 women), 350 developed cancer during the years 1970-2011. Overall cancer risk among patients with FMF was significantly lower than that expected in the following gender and population groups, based on cancer incidence rates in those groups in the Israeli population: males of Jewish ethnicity SIR 0.66, CI 95% [0.55-0.77], p< 0.001; females of Jewish ethnicity SIR 0.75 CI 95% [0.64-0.86], p< 0.001; males of Arabic ethnicity SIR 0.34, CI 95% [0.07-0.99], p= 0.024. Conclusions: FMF patients have a significantly lower incidence of cancer than the general population. This pattern was demonstrated in two different ethnic populations, Jewish and Arabic. We speculate that the lower cancer incidence could be attributed to the direct physiological effect of FMF or to the anti-FMF treatment.
RNA-Seq analysis of glioma tumors to reveal targetable gene fusions.
Authors: Subramaniam Deepa Suresh , Xiu Joanne , Mehta Shwetal , Gatalica Zoran , Swensen Jeffrey , Sanai Nader , Heimberger Amy B. 
Published: September 2018

2019 Background: Fusions involving oncogenes have been reported in gliomas and may serve as novel therapeutic targets. We aim to use RNA-sequencing to interrogate a large cohort of gliomas for targetable genetic fusions. Methods: Gliomas were profiled using the ArcherDx FusionPlex Assay at a CLIA-certified lab (Caris Life Sciences) and 52 gene targets were analyzed. Fusions with preserved kinase domains were investigated. Results: Among 404 gliomas tested, 39 (9.7%) presented potentially targetable fusions, of which 24/226 (11%) of glioblastoma (GBM), 5/42 (12%) of anaplastic astrocytoma (AA), 2/25 (8%) of grade II astrocytoma and 3 of 7 (43%) of pilocytic astrocytoma (PA) harbored targetable fusions. In GBMs, 1 of 15 (6.7%) IDH-mutated tumors had a fusion while 22 of 175 (12.6%) IDH-wild type tumors had fusions. 46 oligodendroglial tumors were profiled and no fusions were seen, which was lower than frequency of fusions in astrocytic tumors (34/300, p = 0.0236). The most frequent fusions seen involved FGFR3 (N = 12), including 10 FGFR3-TACC3 (1 AA, 6 GBM and 3 glioma NOS); 1 FGFR3-NBR1 (AA) and 1 FGFR3-BRAP (GBM). 11 fusions involving MET were seen, 10 in GBM and 1 in AA. The most common MET fusion was PTPRZ1-MET (1 in AA and 4 in GBM), followed by ST7-MET (N = 3, GBM), CAPZA2-Met (N = 2, GBM) and TPR-MET (N = 1, GBM). 8 NTRK fusions were seen; 1 involving NTRK1 (BCAN-NTRK1, PA), 6 NTRK2 (1 NOS1AP-NTRK2 in AA; GKAP1-NTRK2, KCTD8-NTRK2, TBC1D2-NTRK2 and SOSTM1-NTRK2, 1 each in GBM and 1 VCAN-NTRK2 in grade II astrocytoma) and 1 NTRK3 (EML4-NTRK3 in GBM). EGFR fusions (2 EGFR-SEPT14 and 1 EGFR-VWC2) were seen in 3 GBMs, BRAF in 3 (1 KIAA1549-BRAF, 1 LOC100093631-BRAF in PA and 1 ZSCAN23-BRAF in glioma NOS) and PDGFRA (RAB3IP-PDGFRA, in GBM) in 1. C11orf95-RELA fusions were seen in 2 of 3 grade III ependymomas but not in the 2 grade II ependymomas. Conclusions: We report targetable fusion genes involving NTRK, MET, EGFR, FGFR3, BRAF and PDGFRA including novel fusions that haven’t been previously described in gliomas (e.g., EGFR-VWC2; FGFR3-NBR1). Fusions were seen in over 10% of astrocytic tumors, while none was seen oligodendrogliomas. Identification of such kinase-associated fusion transcripts may allow us to exploit therapeutic opportunities with targeted therapies in gliomas.
Epidemiologic study of risk factors for meningioma in the Mayo Clinic Study of Aging.
Authors: Butts Alissa , Syrjanen Jeremy A. , Aakre Jeremiah , Brown Paul D. , Jack Clifford R. , Petersen Ronald C. , Roberts Rosebud O. , Cerhan Jane H 
Published: September 2018

2067 Background: An estimated 2% of the general population has a meningioma (Vernooij et al. 2007), which accounts for about 36% of all primary intracranial tumors (Ostrom et al. 2015). The most established risk factors are older age and female gender. One small study identified gender but no other risk factors with meningioma (Krampla et al 2004). A larger study using the Iowa Women’s Health study data found lower levels of physical activity, greater body mass index (BMI), greater height and uterine fibroids were associated with meningioma (Johnson et al. 2011). We sought to replicate these findings and to identify additional risk factors related to meningioma in a large population-based sample. Methods: Study participants were enrolled in the Mayo Clinic Study of Aging (MCSA), a population-based sample of Olmsted County, Minnesota residents used to study prevalence, incidence, and risk-factors for Mild Cognitive Impairment and dementia and includes a variety of medical factors. Using a text search of radiologists’ notes of 2,402 MCSA individuals, mean age 77±8 years and scanned between 2004-2014.We identified 52 subjects who had at least one meningioma. We estimated the association of selected potential risk factors with presence of meningioma using odds ratios and 95% confidence intervals from logistic regression models adjusted for age and gender, which informed the multivariable models. Results: In the initial models, significant risk factors identified included BMI (as a continuous variable) (OR = 1.06 95%CI 1.01 to 1.12), taking NSAIDS (OR = 2.11, 95%CI 1.13 to 3.95), aspirin (OR = 1.90, 95%CI 1.04 to 3.46), and blood pressure lowering medication (OR = 2.06, 95%CI 1.07 to 3.99). Protective factors included male gender (OR = 0.51, 95%CI 0.29 to 0.90), coronary artery disease (CAD; OR = 0.46, 95%CI 0.22 to 0.97) and higher Beck Anxiety Inventory (BAI) total score (OR = 0.88, 95%CI 0.78 to 0.98). Simultaneous adjustment for these factors in a multivariable model did not attenuate these associations. Conclusions: Findings reveal gender and BMI as risk factors for meningioma. Additionally, certain medications such as NSAIDS and BP lowering medications warrant follow up as potential factors related to development of meningioma.
A phase I trial of TRC102 (methoxyamine HCl) with temozolomide (TMZ) in patients with solid tumors and lymphomas.
Authors: Meehan Robert S. , O'Sullivan Coyne Geraldine Helen , Kummar Shivaani , Collins Jerry M. , Anderson Larry , Zlott Jennifer , Juwara Lamin , Takebe Naoko , Piekarz Richard , Streicher Howard , Sharon Elad , Conley Barbara A. , Rubinstein Larry , Wilsker Deborah , Dull Angie B , Ferry-Galow Katherine V. , Kinders Robert J. , Parchment Ralph E. , Doroshow James H. , Chen Alice P. 
Published: September 2018

2518 Background: TRC102 inhibits BER by binding to abasic sites and acting as a topo II poison to cause DNA strand breaks; it potentiates the activity of alkylating agents including TMZ in murine models. In xenograft studies, TRC102 efficiently enhanced the antitumor effect of TMZ regardless of cell line genetic characteristics, e.g., O6-methylguanine DNA-methyltransferase, mismatch repair (MMR), or p53 status. This is the first report for the expansion phase (the escalation phase was reported previously (ASCO2016)). Methods: We conducted a phase 1 trial of TRC102with TMZ in patients (pts) with refractory solid tumors. Eligibility criteria included adults that had progressed on standard therapy, ECOG PS of 0-2, and adequate organ function. TRC102 and TMZ were given orally days 1-5, in 28-day cycles. The pharmacokinetic and pharmacodynamic profile of TRC102 with TMZ was evaluated. Antitumor responses were determined using RECIST 1.1 criteria. The DNA damage response (DDR) markers γH2Ax, pNbs1, and Rad51 were evaluated in the expansion cohort at DL6, tested by previously described methods on paired tumor biopsies prior to and after the first course of therapy. Results: After the recommended Phase 2 Dose was defined as DL6 (TRC102 125mg, TMZ 150mg/m2 D1-5), 15 pts were accrued to the expansion cohort between 9/2015 to 11/2016. A total of 52 pts were enrolled (37 escalation, 15 expansion). Grade 3/4 adverse events included neutropenia (13%), anemia (the DLT;10%), thrombocytopenia (7%), hemolysis (5%) or hypophosphatemia (3%). 4 pts had a partial response (PR) (NSCLC, ovarian (2), and colon); 13 pts had stable disease (SD), 29 progressive disease (PD), and 6 were not evaluable; three pts remain on study. 11/14 paired biopsies were suitable for analysis. Rad51 signal was induced in 6/11pts. One patient showed γH2Ax and 2 showed pNbs1 induction. 4/5 colon cancer specimens had evidence of DDR marker induction. Conclusions: The combination of TRC 102/TMZ is active with 4 PRs and 13 SDs, and the side effect profile is manageable. DDR markers were induced in 4 of 5 paired colon biopsies indicating DNA damage following treatment. A phase 2 trial of patients with colon cancer, NSCLC, and granulosa cell ovarian cancer is accruing. Clinical trial information: NCT01851369.
Deflexifol (a novel formulation of 5FU): Pharmacokinetics in a phase 1 trial in comparison to 5FU.
Authors: Ackland Stephen P. , Garg Madhu Bala , Ranson Marie , Jokela Rebecca , Brungs Daniel , Aghmesheh Morteza , Tafreshi Ali , Ranson Richard David , Parker Suzanne , De Souza Paul L. , Clingan Philip R. 
Published: September 2018

2530 Background: Simultaneous administration of 5-fluorouracil (5FU) and leucovorin (LV) is generally not feasible as 5FU and LV are chemically incompatible (CaPO4 crystals), so the maximum possible interaction for benefit is not achieved. Deflexifol, an all in one formulation of 5FU/LV with cyclodextrin (HP-β-CD 100mg/ml, 5-FU 15mg/ml & LV 1mg/ml) at pH 7, was developed to overcome this problem. Methods: Limited sampling PK was done with dose 1 and 6 in a standard 3+3 phase I trial of Deflexifol given in two schedules (46-h infusion Q2W or bolus weekly x6) with no intrapatient dose escalation, at doses shown in Table. Sample times were infusion: 0, 2, 46h; bolus: 0, 0.2, 0.4, 1, 24h. 5FU and dihydroFU were measured as per Ackland et al, Anal Biochem 1997. 5FU AUC, clearance (CLR) and t1/2 were estimated for each patient to assess PK variability and adequacy of dosing compared to previous reports. Results: 40 patients were treated (21 infusion, 19 bolus, median age 67, 19 M, 21 F). The MTD(bolus) was 575 mg/m2, with no DLT in infusion schedule to 3600 mg/m2. PK showed substantial inter-patient variability – CLR(bolus) 21-900 L/h, t1/2 0.11-0.52 h, with intra-patient dose 6 CLR = 54-117% of dose 1, and a trend to increased AUC (mg/L.h) with dose (Table). Infusion CLR and AUC estimates were highly variable (CLR range 2-1200), with many cases with insufficient data. Compared to historical data with 5FU alone, AUC was likely subtherapeutic until 475mg/m2 bolus and for many patients with infusion <3000mg/m2. Conclusions: 5FU PK with Deflexifol is similar to 5FU alone. No evidence of saturation of kinetics over this dose range was seen, or induction of metabolism with repeated dosing. In each schedule AUC data supports the clinical impression of reduced toxicity at the same dose of 5FU. Accurate estimation of infusion PK requires more than 2 timepoints. PK in a phase II study is planned. Clinical trial information: 044867. [Table: see text]