tbuckley/cabot-search huggingface dataset:
RONC-14. REPLICATING CLINICAL RADIATION THERAPY PROTOCOLS IN PRECLINICAL BRAIN TUMOUR MODELS
Authors: Raelene Endersby, Hilary Hii, Brooke Strowger, Mathew Ancliffe, Tracy Seymour, Nicholas Gottardo
Journal: Neuro-Oncology (2018)

Surgical resection and radiotherapy, often followed by chemotherapy, have been the mainstay of paediatric brain cancer treatment for decades. For brain cancers with a predilection to spread throughout the brain and spinal cord, such as medulloblastoma, craniospinal irradiation represents the standard-of-care. An unavoidable consequence of this is collateral damage of healthy tissue, resulting in potentially devastating long-term sequelae, including suboptimal cognitive development. Animal models that accurately recapitulate the genotypes and phenotypes of paediatric brain cancers are essential to evaluate potential new approaches to therapy ahead of clinical trial. The XRAD image-guided small animal radiotherapy (SmART) system combines CT imaging with precision irradiation using x-rays. Our aim was to optimise preclinical radiotherapy protocols in mouse models of medulloblastoma, ependymoma and glioblastoma. To evaluate the accuracy and efficacy of the device, radiation was administered to mice with orthotopically-implanted brain tumours. Tissue was harvested, and markers of DNA damage and apoptosis used to evaluate tumour targeting. A transgenic model of SHH-subtype medulloblastoma (NeuroD2::SmoA1) demonstrated exquisite sensitivity to irradiation with significant DNA damage and apoptosis two hours post-treatment. Moreover, reduced tumour size was evident by MRI after five days of radiotherapy. Multiple patient-derived xenograft (PDX) models of Group 3 medulloblastoma also demonstrated radiation sensitivity, whereas minimal anti-tumour effects were observed in ependymoma and glioblastoma xenografts. These data serve as baseline information for future experimental protocols that will evaluate combinatorial regimens of radiotherapy, conventional chemotherapy, and novel anti-cancer agents. These experiments enable rigorous evaluation and selection of viable agents to consider for future clinical evaluation.
Dietary Insulin Load and Cancer Recurrence and Survival in Patients With Stage III Colon Cancer: Findings From CALGB 89803 (Alliance)
Authors: Vicente Morales-Oyarvide, Chen Yuan, Ana Babic, Sui Zhang, Donna Niedzwiecki, Jennie C Brand-Miller, Laura Sampson-Kent, Xing Ye, Yanping Li, Leonard B Saltz, Robert J Mayer, Rex B Mowat, Renaud Whittom, Alexander Hantel, Al Benson, Daniel Atienza, Michael Messino, Hedy Kindler, Alan Venook, Shuji Ogino, Kana Wu, Walter C Willett, Edward L Giovannucci, Brian M Wolpin, Jeffrey A Meyerhardt, Charles S Fuchs, Kimmie Ng
Journal: JNCI Journal of the National Cancer Institute (2018)

Evidence suggests that diets inducing postprandial hyperinsulinemia may be associated with increased cancer-related mortality. The goal of this study was to assess the influence of postdiagnosis dietary insulin load and dietary insulin index on outcomes of stage III colon cancer patients.We conducted a prospective observational study of 1023 patients with resected stage III colon cancer enrolled in an adjuvant chemotherapy trial who reported dietary intake halfway through and six months after chemotherapy. We evaluated the association of dietary insulin load and dietary insulin index with cancer recurrence and survival using Cox proportional hazards regression adjusted for potential confounders; statistical tests were two-sided.High dietary insulin load had a statistically significant association with worse disease-free survival (DFS), comparing the highest vs lowest quintile (adjusted hazard ratio [HR] = 2.77, 95% confidence interval [CI] = 1.90 to 4.02, Ptrend < .001). High dietary insulin index was also associated with worse DFS (highest vs lowest quintile, HR = 1.75, 95% CI = 1.22 to 2.51, Ptrend= .01). The association between higher dietary insulin load and worse DFS differed by body mass index and was strongest among patients with obesity (HR = 3.66, 95% CI = 1.88 to 7.12, Pinteraction = .04). The influence of dietary insulin load on cancer outcomes did not differ by mutation status of KRAS, BRAF, PIK3CA, TP53, or microsatellite instability.Patients with resected stage III colon cancer who consumed a high-insulinogenic diet were at increased risk of recurrence and mortality. These findings support the importance of dietary management following resection of colon cancer, and future research into underlying mechanisms of action is warranted.
SWRK-03. BARRIERS TO ENROLLMENT ON CNS LATE EFFECTS STUDIES, A SINGLE-CENTER EXPERIENCE
Authors: Emily Owens Pickle, Amie Deak, Michelle Pelletier, Ana Aguilar-Bonilla, Amy Smith
Journal: Neuro-Oncology (2018)

Evaluation, follow-up, and research on neurologic sequelae are essential components of providing comprehensive pediatric neuro-oncology care. One indicator of our needs is low participation in the Children’s Oncology Group study, ALTE07C1. Opened in 2008, this study aims to establish procedures to ensure a consistent, streamlined, and efficient administration of the neuropsychological/behavioral tests conducted at 3 standardized time-points. We chose ALTE07C1 as the COG Behavorial Science Committee has worked hard to maximize participation and remove barriers at group and site levels, and yet we have still struggled. To identify barriers, we examined eligible patients to determine whether participation was offered, as we suspected it was not patient refusal. Between 2010 and 2017, we offered ALTE07C1 enrollment to 17% of eligible patients. Barriers identified were concerns over reimbursement, lack of ongoing neuropsychology availability, lack of knowledge/awareness about the study leading to avoidance or discouragement of enrollment, and prioritization of therapeutic study enrollment. There are many practical strategies to improve our performance. Neuro-oncology social workers have been identified as key study champions on both the medical team and for engaging our patients. Investigators, research personnel, and social work are reviewing late effects literature to develop knowledge and increase staff comfort level in discussing the importance of CNS late effects monitoring and research participation. With the support and guidance of neuropsychology, improvements have been made in the referral process and coding; testing is now more commonly covered by private and state-sponsored insurance which was identified as a major participation barrier.
MBRS-37. IN VITRO MODELLING OF TUMOUR EVOLUTION AND RADIOTHERAPY RESISTANCE IN MEDULLOBLASTOMA
Authors: Stacey Richardson, Rebecca Hill, Matthew Selby, Janet Lindsey, Gholamreza Rafiee, Simon Bailey, Daniel Williamson, Steve Clifford
Journal: Neuro-Oncology (2018)

Medulloblastoma relapse occurs in 30-40% of patients, is almost universally fatal and accounts for ~10% of childhood cancer deaths. Acquisition of combined MYC/MYCN and TP53 defects occurs in 30% of recurrences following standard-upfront-treatment. Therapy-related selection pressure plays a role in the emergence of treatment resistant clones. We hypothesised that in medulloblastoma, radiotherapy provides this pressure, resulting in the converging evolution witnessed at relapse. Modelling this process of selection, provides the opportunity to identify mechanisms of treatment resistance. To investigate this hypothesis, we developed novel in vitro models of radiotherapy resistance. Using two SHH subgroup medulloblastoma cell lines (UW228-2/ONS76) we delivered a radiotherapy regimen in vitro which mimicked that delivered to patients (54Gy administered 5 days/week in 1.8Gy daily fractions). Radiation treatment induced massive cell death, however in all replicates (n=4) a small population of senescent cells remained after treatment. This phenotype persisted for 4-10 weeks, before colonies of surviving cells exited senescence and entered proliferation, mimicking what we hypothesise occurs in the relapsed human disease. Importantly, whole-exome-sequencing of both cell lines revealed an emergence of predicted deleterious variants post-therapy, compared with untreated counterparts. Cross-refencing to human disease identified 22 gene defects (e.g. NOTCH4 and GLI1) emerging in our models which were also detected in biopsies of relapsed human tumours. Our novel in vitro model faithfully recapitulates human disease behaviour and implicates candidate genes in common with human recurrent tumours. This approach provides significant opportunities to understand the biological mechanisms of radiotherapy-related resistance and identify novel therapeutic targets in relapsed medulloblastoma.
NFM-09. PRELIMINARY REPORT OF A MULTICENTER, PHASE 2 STUDY OF BEVACIZUMAB IN CHILDREN AND ADULTS WITH NEUROFIBROMATOSIS 2 AND PROGRESSIVE VESTIBULAR SCHWANNOMAS: AN NF CLINICAL TRIALS CONSORTIUM STUDY
Authors: James Tonsgard, Nicole Ullrich, Jaishri Blakeley, Tena Rosser, Roger Packer, Bruce Korf, Michael Fisher, Gary Cutter, Scott Plotkin, Matthias Karajannis, Jeffrey Allen, D Wade Clapp, Coretta Thomas, Jian Campian
Journal: Neuro-Oncology (2018)

Profound hearing loss is common in patients with neurofibromatosis 2 (NF2) and vestibular schwannomas (VS). Bevacizumab treatment at 7.5 mg/kg every 3 weeks has been associated with hearing improvement and tumor shrinkage in 36% and 43% of patients, respectively. However, the optimal treatment dose and schedule are unknown. This multicenter, phase II, open-label study evaluated subjects (≥6 years old) with NF2 and progressive VS. Subjects received bevacizumab 10 mg/kg every 2 weeks during induction therapy (6 months), and 5 mg/kg every 3 weeks during maintenance therapy (18 months). Hearing response was defined as a significant increase in word recognition score above baseline. Radiographic response was defined as ≥20% decrease in tumor volume from baseline. The primary endpoint was hearing response rate in the target ear at 6 months. We enrolled 22 subjects (median age=23 years). The overall hearing and radiographic response rates were 41% (9/22) and 23% (5/22), respectively. In an unplanned post-hoc analysis, the hearing and radiographic response rates were 14% (1/7) and 0% in pediatric subjects ≤21 years, as compared with 53% (8/15) and 33% (5/15) in adult subjects. Bevacizumab was well tolerated. Adverse events included hypertension, proteinuria, arthralgias, AST/bilirubin elevation, delayed wound healing, fatigue, and irregular menstruation. 11/13 women with elevated FSH underwent evaluation for premature ovarian insufficiency. All continued treatment with bevacizumab. Bevacizumab treatment at 10 mg/kg every 2 weeks is associated with hearing and radiographic response rates comparable to previous studies using lower doses. Pediatric subjects appear to benefit less than adults during bevacizumab treatment.
TBIO-12. NON-TARGETED MUTATION AND FUSION ANALYSES CAN AID IN CLASSIFICATION AND TREATMENT OF PEDIATRIC GLIOMAS
Authors: Ahmed Gilani, Jean Mulcahy Levy, Bette Kleinschmidt-DeMasters
Journal: Neuro-Oncology (2018)

Many tertiary care centers currently utilize a broad panel-based approach for assessment of potentially-actionable fusions or mutations in tumors. Large 300-500 gene panels or those specifically-formulated for mutation common in glial tumors are costly and/or access remains an issue for many institutions. Here, we present recent experience (9/ 2017-1/2018) in acquiring diagnostic, prognostic and predictive information for pediatric brain tumors, using Archer fusion and a limited 26-gene solid tumor mutational panel, not tailored specifically to glial neoplasms. A supratentorial low-grade glioma in a 7-year-old male with non-specific histology revealed a MYB-QKI fusion - a molecular signature for angiocentric glioma, solidifying diagnosis of angiocentric glioma. Conversely, a 14-year-old male with tumor histology classic for angiocentric glioma showed absence of MYB-QK1 fusion; additional genomic alterations of PDGFRA, BCOR, CDKN2A, p14, CDKN2C, SMARCA4, and TERT promotor on a commercially-available larger panel, indicated high-grade glioma and affecting upfront therapy. Another difficult-to- classify low-grade glioma in a 6-year-old male showed GOPC-ROS1 fusion transcript. This alteration, which has been seen in lung cancers but rarely been reported in glial tumors (and unlikely to be included on specifically-formulated glial panels), predicts response to inhibitors, potentially contributing the adjunctive therapy options. In a third case, an ETV6-NTRK3 fusion transcript was identified in a BRAF-V600E- negative epithelioid-glioblastoma, qualifying the patient for potential entrectinib inhibition of NTRK. These examples demonstrate the utility of using even smaller, broad solid tumor panels agnostic to histological diagnosis in successfully revealing interesting/actionable findings in pediatric brain tumor patients.
Assuming the Worst
Authors: Ann-Marie Rosland
Journal: JAMA (2008)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
QOL-41. FATIGUE AND QUALITY OF LIFE IN CHILDHOOD BRAIN TUMOR AFTER THE END OF TREATMENT
Authors: Sonia Di Profio, Marco Crocco, Antonio Verrico, Claudia Milanaccio, Natascia Di Iorgi, Flavia Napoli, Mattia Pacetti, Maria Luisa Garrè
Journal: Neuro-Oncology (2018)

The improvement in survival rates of pediatric patients with brain tumors (BT) has raised questions on the endocrinological, neurocognitive and psychological late effects of long-term survivors. MATERIALS AND We retrospectively collected data from 53 children treated at our Institution for BT between 2005-2015 who received psychological and quality of life (QoL) evaluation at a median age of 12.5 years (range,4.7-18) after a median time of 34 months (range,1-152) from diagnosis. Data regarding treatment and Neuro-Endocrinological Sequelae (NES): hypothyroidism, hypoadrenalism, hypogonadism, growth hormone deficiency and diabetes insipidus were analyzed. Fatigue was assessed by Facit-F-Peds-Revised (FACIT). QoL was assessed by Pediatric-Quality-of-Life-Inventory. Psychological assessment was carried out using the Child-Behavior-CheckList. Twenty-one patients received neurosurgery,3 5 patients chemotherapy, 36 patients radiotherapy. Thirty-five patients were NES-free. Four patients developed 1 NES, 12 patients at least 2 NES, 2 patients all 5 NES;t here were no significant differences in terms of FACIT score among these three groups. However the increasing of the number of NES corresponded with worsening of QoL. Fatigue was reported in 25 patients, 7 of them also showed low level of psychosocial and school QoL. The psychological assessment showed clinical levels of emotional distress in 10 children due to increase in anxiety, depression and social problems. Our preliminary data regarding late effects in childhood BT survivors show that fatigue affects 47% of them. This symptom, not always can be predicted by NES status. QoL was overall good although it worsens with the increase of NES. Further studies will be performed in order to better comprehend the relationship among risk factors and psychosocial outcome.
IMMU-25. RADIO-IMMUNOTHERAPY USING THE IDO PATHWAY INHIBITOR INDOXIMOD FOR CHILDREN WITH NEWLY-DIAGNOSED DIPG
Authors: Theodore S Johnson, Dolly Aguilera, Ahmad Al-Basheer, Craig Castellino, Bree R Eaton, Natia Esiashvili, Nicholas Foreman, Ian M Heger, Eugene P Kennedy, Charles J Link, William Martin, Eric Ring, Ramses F Sadek, Amy Smith, Nicholas N Vahanian, Tobey J MacDonald, David H Munn
Journal: Neuro-Oncology (2018)

Indoximod is an IDO pathway inhibitor with a differentiated mechanism of action directly targeting immune cells to reverse the immune suppression generated by tumors. An ongoing phase-1b/2a study (NCT02502708) using indoximod in combination with temozolomide and/or re-irradiation for children with relapsed/refractory pediatric brain tumors has established the recommended phase-2 dose (RP2D) of indoximod for this regimen and has shown this approach to be well-tolerated and feasible in these highly complex and fragile patients. Diffuse Intrinsic Pontine Glioma (DIPG) is an FDA-designated orphan disease, with no curative treatment options and dismal prognosis. The primary hypothesis is that addition of indoximod-based immunotherapy to standard-of-care radiation, followed by immuno-chemotherapy with indoximod plus temozolomide will improve objective response rates, 12-month event-free survival, and median overall survival. Newly-diagnosed DIPG patients age 3 to 21 years are treated with indoximod (RP2D) in combination with conformal radiation therapy (54 Gy), followed by cyclic immune-chemotherapy using indoximod (RP2D=38.4 mg/kg/day divided BID throughout each cycle) combined with temozolomide (200 mg/m2/day, days 1-5 of each 28-day cycle). Up to 30 patients may be enrolled. The trial is ongoing. At this time, we have enrolled the first 6 newly-diagnosed DIPG patients. At the end of the indoximod plus radiation block, the first two patients had objective tumor response without any significant adverse events to date. Interim outcome and safety data for the first 8 months of accrual will be presented.
Clinical relevance of genetic variants of gonadotrophins and their receptors in controlled ovarian stimulation: a systematic review and meta-analysis
Authors: Carlo Alviggi, Alessandro Conforti, Daniele Santi, Sandro C Esteves, Claus Yding Andersen, Peter Humaidan, Paolo Chiodini, Giuseppe De Placido, Manuela Simoni
Journal: Human Reproduction Update (2018)

Genotype has been implicated in the outcome of ovarian stimulation. The analysis of patient-specific genotypes might lead to an individualized pharmacogenomic approach to controlled ovarian stimulation (COS). However, the validity of such an approach remains to be established.To define the impact of specific genotype profiles of follicle-stimulating hormone, luteinizing hormone and their receptors (FSHR, LHR and LHCGR) on ovarian stimulation outcome. Specifically, our aim was to identify polymorphisms that could be useful in clinical practice, and those that need further clinical investigation.A systematic review followed by a meta-analysis was performed according to the Cochrane Collaboration and Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines without time restriction. We searched the PubMed/MEDLINE, Cochrane Library, SCOPUS and EMBASE databases to identify all relevant studies published before January 2017. Only clinical trials published as full-text articles in peer-reviewed journals were included. The primary outcome was the number of oocytes retrieved.Fifty-seven studies were assessed for eligibility, 33 of which were included in the qualitative and quantitative analyses. Data were independently extracted using quality indicators. COS outcomes related to seven polymorphisms (FSHR [rs6165], FSHR [rs6166], FSHR [rs1394205], LHB [rs1800447], LHB [rs1056917], LHCGR [rs2293275] and LHCGR [rs13405728]) were evaluated. More oocytes were retrieved from FSHR (rs6165) AA homozygotes (five studies, 677 patients, weighted mean difference [WMD]: 1.85, 95% CI: 0.85-2.85, P < 0.001; I2 = 0%) than from GG homozygotes and AG heterozygotes (four studies, 630 patients, WMD: 1.62, 95% CI: 0.28-2.95, P = 0.020; I2 = 56%). Moreover, stimulation duration was shorter in FSHR (rs6165) AA homozygotes than in AG carriers (three studies, 588 patients, WMD -0.48, 95% CI: -0.87 to -0.10, P = 0.010, I2 = 44%). A higher number of oocytes (21 studies, 2632 patients WMD: 0.84, 95% CI: 0.19 to 1.49, P = 0.01, I2 = 76%) and metaphase II oocytes (five studies, 608 patients, WMD: 1.03, 95% CI: 0.01-2.05, P = 0.050, I2 = 0%) was observed in AA than in GG homozygote carriers. FSH consumption was significantly lower in FSHR (rs1394205) GG homozygotes (three studies, 411 patients, WMD: -1294.61 IU, 95% CI: -593.08 to -1996.14 IU, P = 0.0003, I2 = 99%) and AG heterozygotes (three studies, 367 patients, WMD: -1014.36 IU, 95% CI: -364.11 to -1664.61 IU, P = 0.002, I2 = 99%) than in AA homozygotes.These results support the clinical relevance of specific genotype profiles on reproductive outcome. Further studies are required to determine their application in a pharmacogenomic approach to ovarian stimulation.
A multicenter phase II study of TAS-114 in combination with S-1 in patients with pre-treated advanced gastric cancer (EPOC1604): Interim analysis in the first stage
Authors: A. Kawazoe, D. Takahari, Y. Nakamura, M. Suzuki, H. Tamura, M. Fukutani, H. Hasegawa, M. Yano, M. Wakabayashi, S. Nomura, A. Sato, K. Shitara
Journal: Annals of Oncology (2018)

Introduction: High deoxyuridine triphosphatase (dUTPase) in tumor tissue, as a gatekeeper enzyme for 5-fluorouracil (5-FU), is associated with its resistance. TAS-114 is an oral dUTPase inhibitor which enhances antitumor activity with 5-FU or fluoropyrimidines. Phase I study of TAS-114 in combination with S-1 showed its tolerability and preliminary antitumor signals for patients (pts) with non-small cell lung cancer and advanced gastric cancer (AGC). This phase II study has been conducted to evaluate efficacy and safety of TAS-114 and S-1 combination in pts with AGC. Here, we present the results of the first stage in the study. Methods: The main eligibility criteria is pts with AGC after two or more previous chemotherapy regimens containing fluoropyrimidines, platinum agents, and taxanes or irinotecan. The primary endpoint is objective response rate (ORR) by investigators' judgement. Using Simon's optimal two-stage design with a one-sided alpha of 5% and power of 80%, 29 pts are required based on a null hypothesis of 5% and alternative hypothesis of 20%. In the first stage, 10 pts are evaluated and additional 19 pts are enrolled in the second stage if at least one objective response would be confirmed. Results: From October 2017 to December 2017, 10 pts were enrolled in the first stage and assessed for anti-tumor response. All patients had been previously treated with fluoropyrimidines, platinum agents, and taxanes. Among them, one patient achieved confirmed partial response, and five pts showed stable disease. The most common treatment-related adverse events (≥20% of pts) were rash (60%), anemia (30%), neutropenia (30%), thrombocytopenia (20%), and decreased appetite (20%). The second stage is ongoing. Conclusion: TAS-114 with S-1 showed a preliminary efficacy signal with acceptable safety profiles for heavily pretreated pts with AGC, which would be further confirmed in the ongoing study.