tbuckley/cabot-search huggingface dataset:
P10.12 Prognostic impact of 2016 WHO classification in anaplastic gliomas
Authors: J. Hong, H. Park, J. Moon, T. Roh, E. Kim, S. Kang, S. Kim, J. Chang
Journal: Neuro-Oncology (2017)

OBJECTIVE: 2016 World Health Organization (WHO) classification of Tumors of the Central Nervous System (CNS) added molecular information to histology to redefine CNS tumors. We investigated whether the updated 2016 WHO classification in anaplastic gliomas has more prognostic impact for disease progression and mortality than 2007 WHO classification. METHODS: A total of 113 consecutive patients with newly diagnosed anaplastic gliomas by 2007 WHO classification at our hospital from Jan. 2001 to Dec. 2013 were enrolled in this study. We integrated the molecular profiles in each patient and reclassified the diagnosis according to 2016 WHO classification. The Kaplan-Meier methods and a stepwise multivariate Cox proportional regression analysis were performed to evaluate the survival and prognostic factors. To further evaluate the predictability of 2016 WHO classification across the entire follow-up period, we applied a time-dependent receiver operating characteristic (ROC) analysis for censored survival data. We then compared the global concordance probability (integrated area under the curve, iAUC) of the 2016 model with 2007 model. RESULTS: A total of 57 anaplastic astrocytoma (AA) patients in the 2007 classification were classified by the new 2016 classification as 51 patients of AA, IDH-wildtype (AAw); 3 patients of AA, IDH-mutant (AAm); 2 patients of Anaplastic oligodendroglioma, NOS (AOnos); 1 patient of AO, IDH-mutant and 1p/19q-codeleted (AOmc). A total of 27 anaplastic oligoastrocytoma (AOA) patients were newly classified as 7 patients of AAw; 10 patients of AAm; 2 patients of AOnos; 8 patients of AOmc. And 29 AO patients were newly classified as 4 patients of AAw; 2 patients of AAm; 6 patients of AOnos; 17 patients of AOmc. The overall survival of total group of anaplastic gliomas was 42.7 months, of which the AAw group was 21.0 months. The progression free survival of total group was 31.7 months, of which the AAw group was 16.8 months. After a multivariate Cox regression analysis, age, preoperative Karnofsky Performance Scale (KPS) score, postoperative enhanced tumor volume in contrast enhanced T1-weighted magnetic resonance imaging (MRI), postoperative tumor volume in T2-weighted MRI, extent of resection measured in T2-weighted MRI, deep location of tumor were associated with the overall survival. Time-dependent ROC curve demonstrated that concordance probability increased from 2007 WHO classification model to 2016 WHO classification model. On visual inspection, the 2016 WHO classification model had a higher iAUC throughout the entire follow-up period than the 2007 WHO classification model. These findings suggest that the 2016 WHO classification to the survival increases the predictive accuracy for mortality. CONCLUSION: We showed that 2016 WHO classification of Tumors of the CNS may be more predictable of survival in patients with anaplastic gliomas.
P09.63 Postmortem evaluation of end-organ toxicity in patients with glioblastoma treated with temozolomide, bevacizumab and irinotecan
Authors: G. Lu, M. Rao, P. Zhu, X. Tian, N. Linendoll, M. Pilichowska, W. F. Glass, R. Hunter, J. Zhu
Journal: Neuro-Oncology (2017)

Chemotherapies [temozolomide (TMZ), bevacizumab (BEV), irinotecan (IRI)] are commonly used drugs treating glioblastoma multiforme (GBM). The side effects from individual drug are well-known clinically and are manageable. Most of side effects are reversible after discounting the suspected drug(s). Combination chemotherapies either concurrently or in sequence are common in oncology practice. Most GBM patients received TMZ first followed by BEV with or without IRI. However, the side effects or permanent end-organs injuries of cumulative toxicity profiles are not well established. Whether these chemotherapies will lead to permanent end-organ damage by post-mortem pathological examination after long term use of either single drug or combination of two or three of the above listed chemotherapy drugs has never been studied in detail. In this study, 45 post-mortem pathological examination and some with electronic microscopic examinations are performed to study possible end-organ toxicity attributed to chemotherapies. Consent for autopsy were obtained from next of kin from each of the subjects. Postmortem organ specific studies including gross exam, H&E, immunohistochemistry study, electron microscopy (EM) (n=8) and immunofluorescence (IF). Autopsy cases include 35 GBMs, 6 brain metastatic cancers, 1 grade II and 2 grade III gliomas, 1 spinal glioma from UTHealth and Tufts medical center since 2007 to 2016. Twenty eight male and 17 female subjects were included with ages ranging from 20 to 79 years old (median 62 years old). Clinical toxicities and laboratory abnormalities were collected and correlated with autopsy results. At autopsy, there was no significant morphologic evidence of TMZ/BEV or TMZ/BEV/IRI-related injury in heart, lung, liver, adrenal glands, thyroid, pancreas, spleen, bladder or bone marrow which we did not know clinically. The cause of death in most patients was bronchopneumonia. Pulmonary embolism was confirmed in 4 cases with 2 case showing additional alveolar hemorrhage. One case had peritonitis with diverticular perforation diagnosed pre-mortem during BEV therapy. EM evaluation of renal glomerular ultrastructure reveal extensive postmortem autolytic change; however there was sufficient preservation to determine that podocyte foot processes were mostly preserved, but glomeruli had segmental to global subendothelial expansion by edematous, flocculent, matrix indicative of endothelial injury. IF examination showed no immune complex deposition. With exception of kidney, there is no significant end-organ damage found by standard postmortem pathological examinations including subjects with long term use of combination of TMZ, BEV and IRI therapies. In the kidney, the toxicity is mild to moderate endothelial injury which is consistent with thrombotic microangiopathy which may be the cause of proteinuria and hypertension seen clinically.
ARE THE MUSCLE ACTIVATIONS DIFFERENT IN VARIOUS TYPE OF PUSH-UP EXERCISE?
Authors: Kam-Ming Mok, Christianne On Nor Anna Ho, Patrick Shu-Hang Yung, Kai-Ming Chan
Journal: British Journal of Sports Medicine (2017)

Background Push-up exercises are widely used to build strength and endurance in muscles primarily across the upper body, and it is a recommended home-based strengthening exercise. Few biomechanics investigations of push-ups had been done focusing on the activation of upper limb major muscles in different hand positions. However, their results cannot fully explain the workload done by Triceps Brachial (TB), Pectoral Major (PM) and Anterior Deltoid (AD) with substantial quantifiable evidence. Objective The aim of this study is to measure the EMG signals of TB, PM and AD while performing push-ups in five different hand positions. Design and Particpants Twelve subjects performing push-ups using EMG to collect data to compare. The 5 different hand positions are neutral, narrow base, wide base, anterior and posterior positions. The mean of peak EMG signals of three repetitions were extracted for comparison. A non-parametric Kruskal-Wallis H test was applied and followed by Wilcoxon Signed-Rank test as the post hoc paired difference test. A Bonferroni correction of p=0.01 was applied which was derived from p=0.05/5. Results TB were activated significant more in anterior, neutral and narrow base when compared to wide base and posterior position. No significant differences found in PM and AD from different hand positions. Conclusions Higher muscle activation of TB in anterior, neutral and narrow base positions implies that the training effect of TB may be higher in the above-mentioned hand positions. Further study on the increase in muscle strength is needed to ensure the findings.
P14.02 Proton radiation therapy combined with immunomodulatory drugs for central nervous system invasive multiple myeloma: case report and review of the literature
Authors: R. A. Buerki, G. Kauffmann, V. Gondi, J. M. Collins, T. M. Zimmerman, S. J. Chmura, R. V. Lukas
Journal: Neuro-Oncology (2017)

Central nervous system invasion of multiple myeloma is a rare extra-medullary form of the disease, presenting as intraparenchymal lesions, leptomeningeal disease, or via direct dural invasion. Survival of leptomeningeal myelomatosis in historical series is considered to be extremely poor, but seems to be improving in the era of novel therapy, namely proteosome inhibitors and immunomodulatory class drugs. Here we present the case of a 48 year-old male with isolated central nervous system relapse of multiple myeloma who had multiple rapidly progressive intraparenchymal myeloma lesions, cauda equina lesions, as well as leptomeningeal myelomatosis that developed years after complete response to autologous stem cell transplant. This patient’s central nervous system disease progressed following systemic high-dose methotrexate, but demonstrated a durable partial response to proton beam craniospinal irradiation combined with immunomodulatory chemotherapy using pomalidomide plus dexamethasone. Little is known about the use of proton radiation therapy in the treatment of plasma cell neoplasms as compared to other hematologic malignancies (such as leukemia), nor about its efficacy, with no published reports to our knowledge. Finally, we review the current literature regarding treatment of both intraparenchymal and leptomeningeal myelomatosis.
Rb Loss and <i>KRAS</i> Mutation Are Predictors of the Response to Platinum-Based Chemotherapy in Pancreatic Neuroendocrine Neoplasm with Grade 3: A Japanese Multicenter Pancreatic NEN-G3 Study
Authors: Susumu Hijioka, Waki Hosoda, Keitaro Matsuo, Makoto Ueno, Masayuki Furukawa, Hideyuki Yoshitomi, Noritoshi Kobayashi, Masafumi Ikeda, Tetsuhide Ito, Shoji Nakamori, Hiroshi Ishii, Yuzo Kodama, Chigusa Morizane, Takuji Okusaka, Hiroaki Yanagimoto, Kenji Notohara, Hiroki Taguchi, Masayuki Kitano, Kei Yane, Hiroyuki Maguchi, Yoshiaki Tsuchiya, Izumi Komoto, Hiroki Tanaka, Akihito Tsuji, Syunpei Hashigo, Yoshiaki Kawaguchi, Tetsuya Mine, Atsushi Kanno, Go Murohisa, Katsuyuki Miyabe, Tadayuki Takagi, Nobutaka Matayoshi, Tsukasa Yoshida, Kazuo Hara, Masayuki Imamura, Junji Furuse, Yasushi Yatabe, Nobumasa Mizuno
Journal: Clinical Cancer Research (2017)

Purpose: Patients with pancreatic neuroendocrine neoplasm grade-3 (PanNEN-G3) show variable responses to platinum-based chemotherapy. Recent studies indicated that PanNEN-G3 includes well-differentiated neuroendocrine tumor with G3 (NET-G3). Here, we examined the clinicopathologic and molecular features of PanNEN-G3 and assessed the responsiveness to chemotherapy and survival.Experimental Design: A total of 100 patients with PanNEN-G3 were collected from 31 institutions, and after central review characteristics of each histologic subtype [NET-G3 vs. pancreatic neuroendocrine carcinoma (NEC-G3)] were analyzed, including clinical, radiological, and molecular features. Factors that correlate with response to chemotherapy and survival were assessed.Results: Seventy patients analyzed included 21 NETs-G3 (30%) and 49 NECs-G3 (70%). NET-G3 showed lower Ki67-labeling index (LI; median 28.5%), no abnormal Rb expression (0%), and no mutated KRAS (0%), whereas NEC-G3 showed higher Ki67-LI (median 80.0%), Rb loss (54.5%), and KRAS mutations (48.7%). Chemotherapy response rate (RR), platinum-based chemotherapy RR, and prognosis differed significantly between NET-G3 and NEC-G3. Chemotherapeutic outcomes were worse in NET-G3 (P < 0.001). When we stratified PanNEN-G3 with Rb and KRAS, PanNENs-G3 with Rb loss and those with mutated KRAS showed significantly higher RRs to platinum-based chemotherapy than those without (Rb loss, 80% vs. normal Rb, 24%, P = 0.006; mutated KRAS, 77% versus wild type, 23%, P = 0.023). Rb was a predictive marker of response to platinum-based chemotherapy even in NEC-G3 (P = 0.035).Conclusions: NET-G3 and NEC-G3 showed distinct clinicopathologic characteristics. Notably, NET-G3 does not respond to platinum-based chemotherapy. Rb and KRAS are promising predictors of response to platinum-based chemotherapy for PanNEN-G3, and Rb for NEC-G3. Clin Cancer Res; 23(16); 4625-32. ©2017 AACR.
P09.29 Anaplastic Astrocytoma (AA) and Glioblastoma (GBM): a real-life experience in Padua Neuro-Oncology Center
Authors: G. Lombardi, L. Bellu, A. Pambuku, P. Fiduccia, A. Della Puppa, M. Gardiman, F. Berti, D. D’Avella, V. Zagonel
Journal: Neuro-Oncology (2017)

Background: various prospective clinical trials on high-grade gliomas were performed in the last years but patient (PTS) characteristics and outcome may be different in real clinical practice. We performed a retrospective analysis to evaluate the real-life experience in Padua Neuro-Oncology center. Matherials and Methods: retrospectively, we reviewed the medical records of PTS admitted to our observation from June 2010 to June 2015 with a diagnosis of AA or GBM. We analyzed clinical outcome with prognostic factors. Results: we analyzed 592 PTS with a diagnosis of CNS primary tumor. Among these, we enrolled 395 PTS: 33 (8.4%) with a histological diagnosis of AA, 293 (74%) with a histological diagnosis of GBM and 69 (17.4%) with a radiological diagnosis of GBM. At diagnosis, median age was 63.2 (range 24-88), 61.8% were male; 80% of PTS had an ECOG PS 0-2. Among PTS who underwent surgery, 48% had a radical surgery; 279 PTS (70.6%) performed RT in association to chemotherapy. 17% of PTS performed a second surgery at relapse and 45% a second-line treatment. MGMT was analyzed in all PTS who underwent surgery: it was methylated in 38.7% of PTS, IDH1 was mutated in 6%. GBM PTS with ECOG PS 0-2 and >2 had a median OS of 21.1 and 7.2 ms, respectively. GBM PTS with met and unmet MGMT had a mOS of 22.7 and 13.7 ms (p=0.005). AA PTS with met and unmet MGMT had a mOS of 29.5 and 16.6 ms (p=0.03). Considering all high-grade gliomas, PTS with met MGMT + mutIDH1 reported a mOS of 23.1ms, PTS with metMGMT + wtIDH1 had a mOS of 20.9 ms and PTS with unmetMGMT + wtIDH1 showed a mOS of 12.6ms (p<0.001). On multivariate analysis, ECOG PS 0-2 (HR=0.6), radical surgery (HR=0.7), methylated MGMT (HR=0.5) and PTS receiving a second-line chemoterapy (HR=0.7) were positive prognostic factors in terms of OS. Conclusions: in our real-life experience most PTS underwent surgery, performed a radiation therapy in association to chemotherapy and nearly half of PTS performed a second-line chemotherapy, although a subset of PTS had a poor performance status. However, we reported a good clinical outcome demonstrating the importance of molecular characterization in these PTS. Type of surgery, ECOG PS, MGMT methylation and lines of chemotherapy were independent prognostic factors.
WEAK LOWER EXTREMITY MUSCLE STRENGTH IS A RISK FACTOR FOR TRAUMATIC KNEE INJURY IN YOUTH FEMALE ATHLETES
Authors: Sofia Ryman Augustsson, Eva Ageberg
Journal: British Journal of Sports Medicine (2017)

Background The role of muscle strength for the risk of knee injury is not well investigated. Objective To examine the potential relationship between lower extremity (LE) muscle strength and the risk of traumatic knee injury in young female and male athletes. Design Case-control study. Setting Athletes at senior high school sport programs in Sweden. Patients (or Participants) 226 athletes (43% females) aged 15–19 years participating in ice-hockey, alpine skiing, handball, soccer, basketball or floorball were included. Those with any previous injury were excluded. Interventions (or Assessment of Risk Factors) A 1-repetition maximum (1-RM) barbell squat test, adjusted for body weight, was assessed by a well-trained instructor at each school, according to “Fysprofilen™”. The strength variable was dichotomized, according to the median, to analyse “weak” vs “strong” athletes. Main Outcome Measurements Any traumatic knee injury (ACL or other ligament injury, meniscal, cartilage damage, fracture) (yes/no) sustained during the high school years was reported by the athletes on a web-based questionnaire. Results 115 traumatic knee injuries were reported. The majority (83%) of injuries were in the weak group in females (p=0.0001), while there were no differences between weak and strong groups in males (p=0.589). Females with weak LE strength had 13 times higher risk of sustaining a knee injury compared with strong females (OR, 13.07; 95% CI, 3.53–48.44; p=0.0001). 36 ACL injuries were reported, with a higher prevalence among females (18%) compared with males (5%) (p=0.002). Females in the weak group had 7 times higher risk of sustaining an ACL injury compared with the strong group (OR, 7.64; 95% CI, 1.60–36.52; P=0.011). There were no differences between the weak and strong groups in the male athletes (p=0.348). Conclusions Weak LE muscle strength appears to be a risk factor for sustaining a traumatic knee injury in youth female athletes but not in males.
P08.20 The significance of Tissue Factor suppression in mediating the less aggressive, and less thrombogenic, phenotype of IDH1 mutant gliomas
Authors: D. Unruh
Journal: Neuro-Oncology (2017)

Isocitrate dehydrogenase 1 mutation (IDH1mut) occurs in 20-30% of gliomas and induces DNA hypermethylation. IDH1mut is associated with a much better prognosis than IDH1 wild-type (IDH1wt) gliomas, yet the basis for this remains unclear. We recently discovered that IDH1mut gliomas are much less likely than IDH1wt gliomas to cause venous thromboembolism (VTE), which is a serious complication in glioma patients. Our data strongly suggest that suppression of Tissue Factor (TF), the primary initiator of coagulation, is a key reason for this. The TF gene, F3, was hypermethylated in patient-derived IDH1mut cells (TB09, BT142, GBM164) but not in IDH1wt cells (GBM6, GBM12, GBM43), with correspondingly lower TF protein expression and TF procoagulant activity (PCA) in the IDH1mut cells. Treatment with decitabine, a demethylating agent, increased TF mRNA in IDH1mut cells, but not in IDH1wt cells. Exogenous treatment with the metabolic product of IDH1mut enzyme, D-2-hydroxyglutarate, also directly suppressed TF PCA, as did forced expression of IDH1mut in IDH1wt cells. In an in vivo model of thrombosis, wherein the inferior vena cava (IVC) was surgically stenosed to slow blood flow and increase risk of thrombus formation, mice engrafted with IDH1mut gliomas produced fewer and smaller IVC thrombi than mice with IDH1wt gliomas (0.86 ± 0.86 mg vs 10.3 ± 3.6 mg, P=0.02). Furthermore, patients with IDH1mut gliomas had lower preoperative circulating TF PCA compared to patients with IDH1wt gliomas (0.49 ± 0.19 vs 1.2 ± 0.21 pg/mL, P=0.036), and elevated TF PCA correlated with an increased risk of subsequent VTE (P=0.025). In addition to coagulation, TF is known to directly enhance the malignancy of many cancers via activation of protease-activated receptor 2 (PAR2). In our IDH1wt glioma cells, TF knockdown greatly reduced in vitro cell proliferation, invasion, and colony formation. TF knockdown also reduced the in vivo growth of IDH1wt gliomas, and increased the median survival of engrafted mice by 86% (41.5 vs 77 days, P=0.001). Likewise, the potent and selective PAR2 antagonist, GB83, inhibited IDH1wt cell proliferation by 54% (P<0.0001) and reduced cell invasion by 25% (P<0.05). Our data therefore suggest that suppressing TF expression and PCA is a critical component of the less thrombogenic, and less malignant, IDH1mut phenotype. Targeting TF, and its activation of PAR2, may therefore represent a novel strategy to make IDH1wt gliomas behave more like IDH1mut gliomas.
Comparison of Visual Outcomes in Coats' Disease
Authors: Sally S. Ong, Edward G. Buckley, Brooks W. McCuen, Glenn J. Jaffe, Eric A. Postel, Tamer H. Mahmoud, Sandra S. Stinnett, Cynthia A. Toth, Lejla Vajzovic, Prithvi Mruthyunjaya
Journal: Ophthalmology (2017)
E-selectin ligands recognised by HECA452 induce drug resistance in myeloma, which is overcome by the E-selectin antagonist, GMI-1271
Authors: A Natoni, T A G Smith, N Keane, C McEllistrim, C Connolly, A Jha, M Andrulis, E Ellert, M S Raab, S V Glavey, L Kirkham-McCarthy, S K Kumar, S C Locatelli-Hoops, I Oliva, W E Fogler, J L Magnani, M E O'Dwyer
Journal: Leukemia (2017)
OS09.6 Long-term follow-up data from 126 patients with recurrent high grade glioma from three Phase 1 trials of Toca 511 and Toca FC: Update and justification for a Phase 2/3 trial
Authors: M. Aghi, M. A. Vogelbaum, S. N. Kalkanis, D. Bota, D. Piccioni, B. Elder, J. Engh, G. J. Kaptain, J. Landolfi, T. F. Cloughesy
Journal: Neuro-Oncology (2017)

Toca 511 (vocimagene amiretrorepvec) is an investigational, conditionally lytic, retroviral replicating vector. The vector infects human cells with selectivity for cancer cells because genome integration is dependent on cell division and viral replication is inhibited by innate and adaptive immune responses, defective in malignant tissues. Toca 511 spreads through cancer cells and stably delivers the gene for an optimized yeast cytosine deaminase that converts courses of the prodrug Toca FC (an investigational, extended-release version of 5-fluorocytosine) into 5-fluorouracil (5-FU). The combined treatment is designed to generate 5-FU in the tumor micro-environment, directly killing cancer cells, leading to activation of antigen presenting cells. 5-FU can also diffuse into nearby immunosuppressive myeloid cells and kill them, leading to further activation of the immune system against the tumor by removing important brakes on the lymphocytes. The safety, viral kinetics, immune response, and preliminary efficacy of Toca 511 and Toca FC have been investigated clinically since 2010 in three, open-label, ascending dose, Phase 1 studies of 126 treated patients with recurrent high grade glioma (rHGG), each evaluating different methods of Toca 511 administration (intratumoral injection, injection into the cavity wall following resection, and intravenous injection followed by resection and injection into the cavity wall). Repeated courses of oral Toca FC follow Toca 511 administration. Results to date include good tolerability; no persistent viremia; successful gene transduction within resected tumors: no evidence for clonality by vector insertion site analysis; and increased median overall survival compared to historical controls with all three methods of vector administration. Partial responses and complete responses with a median duration of initial response of > 26 months start approximately 6–19 months after Toca 511 administration, and are associated with a long term survival. Based on 18Nov2016 data, patients in the resection trial with Toca 5 enrollment criteria and dosing had a clinical benefit rate of 42 % (3CRs, 2PRs, 5 SDs of 24 patients). Examination of IDH1 mutation status shows patients with a response are either wildtype or mutant. Preliminary data from these studies supported initiation of a randomized, Phase 2/3 study in patients with rHGG (NCT02414165) in 2015. Updated pooled safety data, immune response findings, and efficacy data for the Phase 1 studies will be presented.
Water, dams, and prawns: novel ecological solutions for the control and elimination of schistosomiasis
Authors: Susanne H Sokolow, Isabel J Jones, Merlijn Jocque, Diana La, Olivia Cords, Anika Knight, Andrea Lund, Chelsea L Wood, Kevin D Lafferty, Christopher M Hoover, Phillip A Collender, Justin Remais, David Lopez-Carr, Jonathan Fisk, Armand M Kuris, Giulio A De Leo
Journal: The Lancet (2017)