tbuckley/cabot-search huggingface dataset:
QOL-58. IMPROVEMENT IN VISUAL ACUITY OF PEDIATRIC PATIENTS WITH BRAIN TUMORS WITH BEVACIZUMAB
Authors: Matthew McEvoy, Molly Hemenway, Jennifer Raybin, Adam Green, Anandani Nellan, Jean Mulcahy Levy, Rajeev Vibhakar, Nicholas Foreman, Emily McCourt, Kathleen Dorris
Journal: Neuro-Oncology (2018)
ATRT-11. MOLECULAR SUBGROUPS OF ATYPICAL TERATOID/RHABDOID TUMOR (ATRT): TOWARDS A CONSENSUS
Authors: Martin Hasselblatt, Pascal D Johann, Ben Ho, Yura Grabovska, Fupan Yao, Franck Bourdeaut, Michael C Frühwald, Dan Williamson, Marcel Kool, Annie Huang
Journal: Neuro-Oncology (2018)

Atypical teratoid/rhabdoid tumor (ATRT) is a highly malignant brain tumor arising in young children. Inactivation of chromatin remodeling complex members SMARCB1 (INI1/hSNF5) or (rarely) SMARCA4 (Brg1) are the sole recurrent genetic alterations. Despite this apparent genetic homogeneity, several studies have independently shown that ATRT represents an epigenetically heterogeneous disease and can be divided into molecular subgroups based on gene expression and DNA methylation profiles. In an international cooperative effort, published and unpublished methylation and transcriptome data of 304 and 133 ATRTs, respectively, were compiled in order to develop a consensus on the number of molecular subgroups and their characteristics. Clustering analyses independently performed in Toronto, Heidelberg, Newcastle and Paris identified three major molecular subgroups, previously annotated as Group1/SHH/hIC2, Group2A/TYR/hIC1 and Group2B/MYC/hIC3. Concordance was high and the vast majority of ATRT was allocated to the same main molecular subgroup across different clustering approaches. Additional heterogeneity was noted within the neurogenic Group1/SHH/hIC2 subgroup, characterized by NOTCH/SHH signaling. The other two subgroups, Group2A/TYR/hIC1 and Group2B/MYC/hIC3 share activation of BMP and PDGFRB pathways, but also show subgroup-specific differences (e.g. MYC/HOX more highly expressed in Group2B/MYC/hIC3 tumors) and different anatomical associations. The majority of Group1/SHH/hIC2 and Group2B/MYC/hIC3 tumors were supratentorial, while 77% of Group2A/TYR/hIC1 tumors were located infratentorially. Of note, 7/8 spinal tumors of the dataset were allocated to Group2B/MYC/hIC3. These results represent an important step towards reaching a consensus on molecular subgrouping in ATRT, which will be pivotal for the development of subgroup-specific therapies and stratification in future clinical trials.
ATRT-37. TARGETING ATYPICAL TERATOID/RHABDOID TUMOR USING MATURE LET-7 LEADS TO INCREASED APOPTOSIS
Authors: Shubin Shahab, Jeffrey Rubens, Charles Eberhart, Eric Raabe
Journal: Neuro-Oncology (2018)

Atypical teratoid rhabdoid tumors (AT/RT) are one of the most malignant brain tumors of childhood with very limited treatment options available. AT/RT tumors are characterized by INI1 (SMARCB1/BAF47/SNF5) loss. Deletions or mutations in INI1 is associated with upregulation of LIN28 which is a regulator of developmental timing and self-renewal. LIN28 is also a known regulator of let-7 family of miRNAs. Previously we have demonstrated that downregulation of LIN28 inhibits AT/RT growth and proliferation. Transfection of mature miRNA mimetic into CHLA-06 and BT37 AT/RT cells can achieve greater than ~50% efficient transduction. We find increased apoptosis as measured by cleaved caspase 3 immunofluorescence using mature let-7g in BT37 and CHLA06 ATRT cells (14.5% and 5.3% increase; p value = 0.045 and 0.03 respectively). We are optimizing in vivo delivery strategies using nanoparticles to deliver mature let-7g to AT/RT tumor cells in the brain. Such a strategy could be helpful to limit local recurrence of tumor and reduce the need for local radiation therapy in very young AT/RT patients.
RADI-01. DIAGNOSTIC ACCURACY AND ADDED VALUE OF QUALITATIVE RADIOLOGICAL REVIEW OF 1H-MRS IN EVALUATION OF CHILDHOOD BRAIN TUMORS
Authors: Karen Manias, Simrandeep Gill, Lesley MacPherson, Adam Oates, Benjamin Pinkey, Paul Davies, Niloufar Zarinabad, Nigel Davies, Ben Babourina-Brooks, Martin Wilson, Andrew Peet
Journal: Neuro-Oncology (2018)

1H-Magnetic Resonance Spectroscopy (MRS) facilitates non-invasive diagnosis of pediatric brain tumors through providing metabolite profiles. Prospective studies of diagnostic accuracy and comparisons with conventional Magnetic Resonance Imaging (MRI) are lacking. AIM: To evaluate diagnostic accuracy of qualitative radiological review of MRS for childhood brain tumors, and determine added clinical value compared with conventional MRI. Children presenting to a Tertiary Pediatric Centre with brain lesions from December 2015-17 were eligible for inclusion. MRI and single-voxel MRS were acquired on 52 tumors and sequentially interpreted by three radiologists, blind to histopathology. Proportions of correct diagnoses and inter-rater agreement at each stage were compared. Cases were reviewed to determine added value through increased certainty of correct diagnosis, reduced number of differentials, or diagnosis following spectroscopist evaluation. Final diagnosis was agreed by the Tumor Board (TB) at study end. Radiologists’ principal MRI diagnosis was correct in 69%, increasing to 77% with MRS. MRI+MRS resulted in significantly more additional correct diagnoses than MRI alone (p=0.035). There was significant increase in inter-rater agreement when correct with MRS (p=0.046). Added value following radiologist interpretation of MRS occurred in 73% of cases, increasing to 83% with additional spectroscopist review. First histopathological diagnosis was available a median 9.5 days following imaging, with 25% of all patients managed without conclusive histopathology. MRS can improve accuracy of non-invasive diagnosis of pediatric brain tumors and add value in the diagnostic pathway. Incorporation into practice has potential to facilitate early diagnosis, guide treatment planning and improve patient care.
CRAN-26. COMPARING SURGERY ALONE OR SURGERY PLUS RADIATION THERAPY IN CRANIOPHARYNGIOMA MANAGEMENT
Authors: Godfrey Chi-Fung Chan, Dennis Tak-Noi Ku, Chun Wing Luk, Alvin Siu-Cheung Ling, Matthew Ming-Kong Shing, Anthony Pak-Yin Liu
Journal: Neuro-Oncology (2018)

The management approach for craniopharyngioma has not reach a consensus between neurosurgeons and radiation oncologists for the past decades. We reviewed our experience and assessed the outcome of these 2 approaches. This is a retrospective review and children with oncological conditions were admitted to 5 public hospitals. Their data were collected prospectively by 2 full time data managers. Patients’ progress was updated annually and the data were crossed checked by the principle investigators. Survival data was analyzed by the Kaplan-Meier Analysis. From Jan 1994 to Dec 2016 (13-yrs), 21 children (<18yrs) with craniopharyngioma was identified. The estimated incidence was 1.47/million children<15yrs/yr. M:F=10:9 and median age was 9.7yrs (range 2mons to 16.5yrs). 12/21 (57%) children were treated with surgery alone as primary approach. Even statistically insignificant, the 6yrs relapse-free-survival was 80% vs 50.3% between surgery+radiation therapy (RT) vs surgery alone. 8/13(61.5%) children in one hospital (HospA) were treated with surgery+RT as primary approach if there was residual lesion post-operatively, but other hospitals (Others) mainly adopted surgery alone as primary approach. The relapsed rate was only 1/13 (7.7%) from HospA. However, 6/8 (75%) patients in Others relapsed and 3 patients eventually died (2 disease progression; 1 sepsis). The overall incidence of hypopituitarism was lower in the HospA (72% vs 87.5%). No other radiation induced complication was noted. If with residue, surgery alone approach for craniopharyngioma is associated with a high risk of relapse. Despite being a benign tumor, patients with multiple relapses can have fatal outcome.
Adjuvant chemotherapy for colorectal cancer using oxaliplatin induced irreversible sinusoidal obstruction syndrome
Authors: K. Hara, T. Yamada, M. Koizumi, S. Shinji, Y. Yokoyama, G. Takahashi, M. Hotta, T. Iwai, K. Takeda, H. Yoshida
Journal: Annals of Oncology (2018)

Introduction: Oxaliplatin reduces the recurrence rate after curative surgery in high risk stage II and stage III colorectal cancer. However, it can cause hepatic sinusoidal obstruction syndrome (SOS). SOS can cause an adverse effect associated with chemotherapy or morbidity after liver resection at the time of recurrence. Conventionally, SOS is diagnosed using liver biopsy which is invasive. We have reported that the 10% increase in splenic volume (SV) indicate SOS (Journal of Surgical Oncology 2017). In this retrospective study, we evaluated SOS caused by adjuvant chemotherapy by measuring SV. Methods: High-risk stage II and stage III patients with colorectal cancer who received complete resection at our hospital between January 2011 and December 2016 were retrospectively analyzed in the current study. All patients received mFOLFOX6, CapeOX or UFT/UZEL as adjuvant chemotherapy. We excluded patients with recurrence within 1-year after finishing adjuvant chemotherapy, and patients whose age were over 80. Patients treated with oxaliplatin (mFOLFOX6 or CapeOX) belong to group 1 and patients treated with UFT/LV belong to group 2. We measured SV three times; before surgical treatment, after finishing adjuvant chemotherapy, and 1-year after finishing adjuvant chemotherapy. SV was calculated by using a volume calculator SYNAPSE VINCENT v3.0® (Fujifilm, Japan) base on Computed tomography images taken in 5-mm slices. We defined that the cut off volume increasing is 10%. Results: This study included 148 patients (High risk stage II: n = 25, stage III: n = 123). All patients received adjuvant chemotherapy after curative surgery. Group 1 included 53 patients (FOLFOX: n = 42, CapeOX: n = 11), and group 2 included 95 patients (UFT/LV: n = 95). 83% of the patients in group 1 and 92% of the patients in group 2 completed chemotherapy. In group 1, SV after chemotherapy was significantly higher than that before surgery (P < 0.001), and SV 1-year after finishing chemotherapy returned to the same level with before surgery. In 84% of the patients, SV increased after chemotherapy and did not recover in 47% 1-year after finishing chemotherapy. Conversely, there was no significant difference in SV between before and after or 1 year after chemotherapy in group 2. In 13% of the patients, SV increased after chemotherapy and did not recover in 12% 1-year after finishing chemotherapy. No patients treated with FOLFOX less than 8 course experienced SV increasing. Conclusion: In 80% of patients treated with oxaliplatin, SV increased after adjuvant chemotherapy. SV did not recover in half of these patients within 1 year after finishing chemotherapy.
A Comparison of Response Patterns for Progression-Free Survival and Overall Survival Following Treatment for Cancer With PD-1 Inhibitors
Authors: Bishal Gyawali, Spencer Phillips Hey, Aaron S. Kesselheim
Journal: JAMA Network Open (2018)

<h3>Importance</h3> Based on efficacy results from pivotal randomized clinical trials, PD-1 (programmed cell death 1) inhibitors, such as nivolumab and pembrolizumab, have been approved to treat various cancers. Response patterns with varying effects on progression-free survival (PFS) and overall survival (OS) have been reported for these drugs. <h3>Objective</h3> To compare 2 outcomes for PD-1 inhibitors: the correlation between PFS and OS and the differences in treatment effect size between PFS and OS. <h3>Data Sources</h3> A systematic search of PubMed, Google Scholar, the Cochrane Library, Web of Science, and conference abstracts for randomized clinical trials of nivolumab and pembrolizumab published in English. <h3>Study Selection</h3> Randomized clinical trials of nivolumab or pembrolizumab in adults with solid-tissue cancers with a nonimmunotherapy control. <h3>Data Extraction and Synthesis</h3> Two reviewers screened the studies for selection and extracted data on medians and hazard ratios (HRs) for PFS and OS. A pooled meta-analysis was conducted. <h3>Main Outcomes and Measures</h3> Across all trials, correlation coefficients between median PFS and median OS and between PFS benefit and OS benefit as well as the HRs of PFS and OS were assessed. The difference in treatment effect sizes between PFS and OS was assessed using a ratio of HRs (rHR). Subgroup analyses were conducted to observe differences based on drug, tumor type, and timing of therapy. <h3>Results</h3> Ten randomized clinical trials that included 4653 patients and met inclusion criteria were identified, as were 2 others (comprising 764 patients) in which nivolumab or pembrolizumab was used following treatment with ipilimumab. The correlations between median PFS and median OS (<i>r</i> = 0.676;<i>R2</i> = 0.457;<i>P</i> = .09) and the correlations between the change in PFS and the change in OS (<i>r</i> = 0.474;<i>R2</i> = 0.225;<i>P</i> = .28) were not significant. However, the correlation between HRs of PFS and OS was significant (<i>r</i> = 0.637;<i>R2</i> = 0.406;<i>P</i> = .048). Using random-effects meta-analysis, the protective effects of treatment were greater for OS than for PFS (pooled rHR, 1.18; 95% CI, 1.06-1.31;<i>P</i> = .002). There was no statistical evidence for heterogeneity across the studies (<i>Q</i> = 6.24;<i>P</i> = .72;<i>I2</i> = 0%). Subgroup analyses showed some differences in the treatment effect sizes based on drug type, tumor type, and line of therapy. <h3>Conclusions and Relevance</h3> There was no significant correlation between OS and PFS in terms of medians and gains in medians, but their HRs were significantly correlated. The protective effects of treatment were greater for OS than for PFS. Traditional Response Evaluation Criteria in Solid Tumors–based PFS cannot capture the benefit of PD-1 inhibitors in patients with solid tumors, and OS should remain the gold standard.
Re: Keen et al.: Treatment of acute conjunctivitis in the United States and evidence of antibiotic overuse: isolated issue or a systematic problem? ( Ophthalmology . 2017;124:1096-1098)
Authors: Shachar Tauber, William Trattler, Christopher Starr, Marguerite McDonald, Jodi Luchs, Thomas Boland
Journal: Ophthalmology (2018)
Trial-level analysis of early tumor shrinkage and disease control rate as intermediate end points of first-line medical treatment in randomized studies of metastatic colorectal cancer
Authors: G. Colloca, A. Venturino, D. Guarneri
Journal: Annals of Oncology (2018)

Introduction: Early tumor shrinkage (ETS) is a response-related end point (EP), defined as a radiologic dimensional reduction of at least 20% after 8 weeks of chemotherapy, and it has been shown to be predictive of overall survival (OS) in studies of metastatic colorectal cancer (mCRC). From the available studies and a patient-level meta-analysis it appears that ETS correlates better than overall response rate (ORR) with OS [Sommereir 2014, J Clin Oncol 32:3538]. However, a trial-level pooled analysis concluded that ETS predicted progression-free survival (PFS) but not OS. Disease control rate (DCR) by RECIST appeared as a good intermediate end point of OS from a previous analysis of 11 randomized trials of patients with mCRC who underwent first-line treatment with chemotherapy plus bevacizumab vs. chemotherapy alone, reporting a better performance than PFS [Colloca 2016, Clin Oncol 28:e155-64]. The aim of the present study is to perform a trial level analysis to verify if DCR and ETS after a first-line chemotherapy are related to OS in patients with mCRC receiving various regimens. Methods: After a systematic search of randomized trials reporting ETS, randomized clinical trials (RCTs) were selected whenever they evaluated PFS, ETS, ORR and DCR in relation to OS. Two arms per trial were selected, and the differences in the results of these two arms for every EP (Δ, delta) were calculated. The nonparametric Spearman ρ (r) was used as a measure of correlation between the difference in each end point and the difference in OS. The analysis evaluated the treatment effects on ΔPFS, ΔETS, ΔORR or ΔDCR and on ΔOS, by separate linear regressions for every EP, and the proportions of variability explained (R2trial) on OS for the four EPs (PFS, ETS, ORR and DCR) have been calculated. Results: The systematic review of the literature led to the selection of 12 RCTs (7 phase-3, 5 phase-2). Despite the limitations and possible bias related to the limited number of patients with an ETS report for each study (in total 3117/4327 patients; 72%), ETS have a different performance in the whole sample vs. phase-3 trials (R2trial = 0.172 vs. 0.842), similarly to ORR (R2trial = 0.349 vs. 0.740). Of the response-related EPs DCR is the most closely related to OS (R2trial = 0.541 vs. 0.816). PFS was significantly related to OS when all trials are included but not when phase-3 trials only are considered (R2trial = 0.586 vs. 0.466). Conclusion: In phase-3 trials response-related end points are more accurate in OS prediction and performs better than PFS. However ETS needs a prospective validation, considering its retrospective determination in all available trials. DCR is a very interesting intermediate EP also in studies with chemotherapy plus EGFR-inhibitors or chemotherapy alone and should be explored at pre-established time points.
IMMU-11. BRAINCHILD PIPELINE: LOCOREGIONAL IMMUNOTHERAPY WITH CHIMERIC ANTIGEN RECEPTOR (CAR) T-CELLS FOR RECURRENT/REFRACTORY CENTRAL NERVOUS SYSTEM TUMORS
Authors: Nicholas Vitanza, Juliane Gust, Sarah Leary, Navin Pinto, Amy Lee, Jason Hauptman, Jeff Ojemann, Leslie Elliott, Olivia Finney, Catherine Lindgren, Zahid Hossain, Robert Pierce, Nicole Lieberman, Courtney Crane, Adam Johnson, Rebecca Gardner, Laura Finn, Julie Park, Michael Jensen
Journal: Neuro-Oncology (2018)

Chimeric antigen receptor (CAR) T-cell therapy carries the promise of a broadly applicable, targeted, yet molecular pathway-independent, intervention for pediatric central nervous system (CNS) tumors. The BrainChild pipeline at Seattle Children’s utilizes engineered CAR T-cells directed against the surface epitopes HER2, EGFR, B7-H3 and IL13Ralpha2, which are commonly expressed in pediatric CNS tumors including high-grade glioma, diffuse intrinsic pontine glioma, medulloblastoma, and ependymoma. Using in vitro and in vivo preclinical modeling, we have optimized the efficacy and specificity of the CAR constructs. The extracellular target-specific scFv domain for the HER2-specific and EGFR-specific CARs are derived from trastuzumab and an EGFR806 antibody, respectively. Third-generation CAR T-cells with medium-length (HER2-CAR) and short (EGFR806-CAR) spacers coupled to an intracellular 4-1BBζ domain result in complete and durable tumor eradication in mouse xenograft CNS tumor models. We now are poised to begin enrolling Phase 1 clinical trials for children and young adults with recurrent or refractory CNS tumors expressing the respective target epitopes. We will deliver locoregional adoptive therapy with autologous CD4 and CD8 T cells lentivirally transduced with the optimized CAR constructs. Using a dose-escalation regimen, CAR T-cells will be injected on a weekly schedule via indwelling catheters into the tumor resection cavity or the ventricular system. The primary objectives are safety and feasibility, along with secondary and exploratory objectives to define the CAR T-cell distribution in the CSF and peripheral circulation, target epitope expression across tumor populations, progression free and overall survival, and biomarkers of anti-tumor CAR T-cell activity.
Comparison between the toxicity profile of fluorouracil versus capecitabine concomitant with radiotherapy in patients with non-metastatic rectal cancer
Authors: A. Lotfy, M. Yassin, G. Rashwan, A. Nagy
Journal: Annals of Oncology (2018)

Introduction: The incidence of colorectal cancer varies considerably around the world. About 944,717 cases were identified worldwide in the year 2000. High incidences of colon and rectal cancer cases are identified in the developed countries. Concurrent preoperative radiotherapy with chemotherapy (5-Flurouracil based) followed by total mesorectal excision (TME) surgery and further systemic therapy is the recommended standard first-line treatment. Fluorouracil (5-FU) remains the most widely used agent for colorectal cancer. Capecitabine is a rationally designed 5-FU pro-drug developed to mimic the continuous infusion of 5-FU while avoiding complications and inconvenience of intravenous administration. Methods: This is a retrospective study aiming at evaluating the toxicity profile (Hematological and non-hematological) in rectal cancer patients who received fluorouracil with radiotherapy versus those who received capecitabine with radiotherapy as neoadjuvant treatment in period from 1-1-2012 till 1-1-2015 in Ain shams university Department of Clinical Oncology and Nasser institute in Cairo-Egypt. Data collected from files of patients included 196 patients (male 101 patients and female 95 patients), the patients were arranged into two groups: group I included 96 patients received 5-FU concomitant with radiotherapy and group II included 103 patients received capecitabine concomitant with radiotherapy. The evaluated side effects were: anemia, neutropenia, thrombocytopenia, hepatotoxicity, renal impairment, cardiotoxicity, neurotoxicity, diarrhea, emesis, mucositis, alterations in taste, xerostomia, gingival bleeding, hypersensitivity reactions, pigmentary changes, alopecia, nail disorders, acral erythema. The collected data was revised, coded, tabulated and introduced to PC using statistical package for social science (SPSS 20.0 for windows; SPSS Inc, Chicago, IL, 2001). Suitable analysis was done according to the type of data obtained for each parameter. Results: The evaluated toxicities showed that there was a statistical significant difference with increase in number of patients who suffered from hypersensitivity reactions (p < 0.009) and alopecia (p < 0.005) in the group who received 5-Fu compared to Capecitabine group, while acral erythema was higher in the Capecitabine group (p < 0.001). The remaining toxicities were not statistical significantly higher in either groups. Conclusion: Capecitabine and 5-flurouracil have comparable toxicity profile but capecitabine offers the feasibility of being oral drug.
RONC-18. CNS TOXICITY AFTER PROTON RADIOTHERAPY IN PEDIATRIC PATIENTS TREATED IN PTC PRAGUE
Authors: Barbora Ondrová, Jiří Kubeš, David Sumerauer, Vladimír Vondráček, Martin Kynčl, Stepan Vinakurau
Journal: Neuro-Oncology (2018)

Between April 2013 and December 2017 135 pediatric patients were irradiated in PTC Prague. 99 patients were identified to be in risk of CNS toxicity (received more than 50 GyE to the CNS structures and were followed-up for more than 3 months). 89 of them were treated for CNS tumors, 10 of them were treated for different diagnoses, but CNS was a part of the treatment volume. Intensity modulated proton therapy (IMPT) was used for treatment in all cases. Patients were not screened for CNS toxicity, all imaging was schedulled according to the protocol or in case of clinical indication. Radiological signs of CNS toxicity were found in 17 patients (17,2%). Median of age was 6 years (range 2-15), median follow-up was 24 months (range 8-48), median time to development was 6 months (range 4-22). In those with CNS toxicity, craniospinal axis was irradiated in 5 cases, 12 patients were irradiated locally, 8 patients had tumors in the posterior fossa and 9 tumors were localized supratentorially. Toxicity was scored according to the NCI CTCAE v.4.02. No intervention was necessary in 12 patients (G1 toxicity), 5 patients were treated (dexamethasone only, dexamethasone with hyperbaric oxygenotherapy, dexamethason with bevacizumab). One patient died from brainstem and cervical spine necrosis, all other are alive. Grade 2 and higher toxicity was found in 5 patients in risk - incidence of the clinically manifested toxicity in our patient cohort is 5,05% with median of follow-up 24 months.