bluuebunny/crossref_metadata_2025_split huggingface dataset:
Malignant hemangiopericytoma: Treatment patterns and survival.
Authors: Barjas Rolando , Piccioni David Eric 
Published: September 2018

e13520 Background: Hemangiopericytoma (HPC), or solitary fibrous tumor of the central nervous system (CNS), is a rare mesenchymal tumor that arises from the pericytes of the meningeal capillaries. These tumors account for less than 1% of all CNS tumors and are categorized into low-grade (WHO grade I and II) or high-grade (WHO grade III, anaplastic) neoplasms. The optimal treatment for grade III HPC is unclear. The aim of this study was to evaluate treatment patterns and survival for grade III HPC using the California Cancer Registry (CCR). Methods: Treatment and demographic data were extracted from the CCR for patients with grade III HPC of the CNS, from 1988-2010. Overall Survival (OS) was evaluated as a function of treatment (surgery, radiation or both), as well as extent of resection. Kaplan Meier survival analyses were performed for OS. Bivariate and multivariable analyses were done via cox proportional hazard regression models for all demographic and treatment variables. Results: A total of 94 patients with grade III HPC were identified from the registry. The most prevalent demographics were age > 50 years (59%), female (61%), non-Hispanic White (60%), and married (54%). 54% received radiation, and subtotal resection (STR) (63%) was the most common surgical outcome. However, survival was greatest in patients that received gross total resection (GTR) with radiation (median OS not reached). GTR/radiation (median OS not reached) demonstrated improved OS compared to STR/radiation (median OS 10.3 years; HR = 0.389, 95%CI 0.157-0.960) or GTR alone (median OS 6.6 years; HR = 0.254, 95%CI 0.073-0.880). Age < 50 (median OS 15.7 years), Asian/PI (median OS not reached) and married (median OS 9.9 years) were significant predictors of OS. In the multivariable cox model worse overall survival remained for older age (HR = 3.079, 95%CI 1.428-6.636) and divorced/widowed/separated (HR = 2.027, 95%CI 1.054-3.897) when compared to their younger and married counterparts. Conclusions: Patients that received GTR and radiation demonstrated the best long-term prognosis. Demographic analyses identified additional independent predictors of survival.
Use of immunotherapy in recurrent glioblastoma.
Authors: Sumrall Ashley Love , Jennings David Lowell , Haggstrom Daniel Ernest , Symanowski James Thomas 
Published: September 2018

e13523 Background: With the recent explosion of interest in immunotherapy to treat cancer, it has moved into management of glioblastoma (GBM). Several trials are ongoing, investigating use of checkpoint inhibition for newly diagnosed and recurrent GBM. Methods: We reviewed the records of patients with recurrent glioblastoma (including gliosarcoma). Six of the eight patients demonstrated PD-1 positivity via immunohistochemical (IHC) staining. Two patients demonstrated PD-L1 positivity as 2+ staining intensity via IHC. Patients were managed with checkpoint inhibitors for at least four weeks. When feasible, patients had tumor profiling of initial tumor and recurrent tumor. Patients were followed for response, progression, and survival. Results: Eight patients were identified with recurrent GBM who received immunotherapy with checkpoint inhibitors. They ranged from first through fifth recurrence following radiation and temozolomide. Three patients received pembrolizumab. Of those, two were PD-L1 positive. Five patients received nivolumab, and all were PD-1 positive. There were no partial or complete responses. Five of the eight subjects died, and the median survival time among the 8 subjects was 3.6 months. Six of eight subjects progressed on treatment, and the median PFS was 2.2 months. Bevacizumab was given to two patients for suspected “tumor flare” while on nivolumab. Four of the eight patients had tumor profiling completed at initial diagnosis and recurrence. Treatment was well-tolerated with only minimal toxicity observed. Conclusions: Despite increasing interest in utilizing these medications for recurrent glioblastoma, overall survival in our cohort was consistent with historical control (3 to 5 months). Additionally, we did not witness any responses.
Prospective evaluation of stress in patients with newly diagnosed glioblastoma and in a close partner (TOGETHER-study).
Authors: Conen Katrin Lisa , Schüpbach Regula , Handschin Barbara , Zwahlen Diana , Voss Martin , Eisele Günter , Rentsch Katharina , Beyrau Ralf , Vogt Deborah R , Katan Mira , Weller Michael , Steinbach Joachim Peter , Hess Viviane 
Published: September 2018

e13524 Background: Diagnosis and treatment of glioblastoma (GBM), the most common and aggressive malignant brain tumor in adults, impose profound chronic distress on patients and their partners. In order to assess how distress in patients and partners affects GBM outcome, we describe in a first step the level of distress – both biological and psychological – in patients and partners before and during standard radiochemotherapy -as measured by different assessment tools. Methods: Stress, measured by salivary cortisol levels (diurnal cortisol slope (DCS), cortisol awakening response (CAR)), copeptin serum level and distress thermometer (DT), perceived stress scale (PSS), anxiety/depression (HADS) and quality of life (FACT-G) was assessed prospectively in all patients with newly diagnosed GBM and their partners at 3 participating centers. The baseline measurements (T1), reported here, were taken immediately before start of standard first-line radiochemotherapy. Further follow-up is ongoing. The TOGETHER-Study with the primary aim to describe the impact of distress and exercise behavior on progression-free survival in GBM in patients and in a close partner was closed prematurely due to poor recruitment. Results: 12 patients and 11 partners were included. Pts were newly diagnosed with histologically confirmed GBM and immediately prior to starting radiochemotherapy with temozolomide. Age of pts in years (median = 62.5, range = 34-70), partners (median = 58, range = 47-79); sex (pts = all male/ partners = all female). Conclusions: Results from our small cohort lead to the hypothesis, that shortly after diagnosis and before start of radiochemotherapy partners of GBM patients seem to be more distressed than patients themselves -as assessed by DT and CAR. Clinical trial information: NCT02129335. [Table: see text]
Galectin-1 (Gal-1) expression as a prognostic factor in patients with newly diagnosed glioblastoma (GB) treated with Stupp regimen (GLIOCAT study).
Authors: Vilarino Noelia , Martinez-Bosch Neus , Balana Carmen , Alameda Francesc , Estival Anna , Pineda Estela , del Barco Sonia , Gil Gil Miguel J. , Mesia Carlos , Gallego Oscar , Carrato Cristina , Ribalta Teresa , Vidal Sarro Noemi , Balana Natalia , Velarde Jose Maria , Navarro Pilar , Martinez-Garcia Maria 
Published: September 2018

e13526 Background: Gal-1 is a β-galactoside binding protein that plays an important role in cancer, promoting cell invasion, proliferation, migration, angiogenesis and evasion of the immune response. Gal-1 is involved in glioma progression and is related to tumor grade and poor clinical outcome. Gal-1 has been implicated in resistance to chemotherapy and as a potential mediator of resistance to anti-VEGF therapy. The aim of our study was to evaluate the prognostic significance of Gal-1 in a homogenous cohort of GB patients and to analyze its potential predictive value of response to bevacizumab at recurrence. Methods: A substudy of GLIOCAT, a multicenter study of newly diagnosed GB patients treated with standard Stupp regimen (previously reported). GLIOCAT enrolled 432 patients between 2005-2014. Tissue was available from 243 cases, from which a tissue microarray (TMA) was constructed. Gal-1 expression in tissue from initial surgery was analyzed by immunohistochemistry. Results were evaluated by three reviewers and quantified by H-score. Expression levels were correlated with clinical outcome, known GB prognostic factors and response to bevacizumab. Results: We defined a cut off for Gal-1 H-Score of >60 (cytoplasm) and >25 (nucleus). HighcytoplasmicGal-1 expression significantly correlated with worse OS and with a trend for shorter PFS. In the multivariate analysis KPS, age, MGMT methylation status and, extent of resection but not Gal-1 expression were independent prognostic factors for survival. Of 92 patients who received bevacizumab at recurrence, only 54 were included in the TMA, and only 1 had low Gal-1 expression. We couldn’t find any relationship with OS or PFS in this population. Conclusions: Gal-1 expression may represent a prognostic factor for GB patients treated with standard therapy. [Table: see text]
Relative thrombocytosis following chemoradiation of patients with glioblastoma to predict survival.
Authors: Boonyawan Keeratikarn , Yang Jie , Long Lihong , Wang Qianghu , Ezhilarasan Ravesanker , Alessandra Audia , Hess Kenneth R. , Alfaro Kristin , De Groot John Frederick , Bhat Krishna , Sulman Erik P. 
Published: September 2018

e13527 Background: Thrombocytosis is associated with poor survival in several malignancies and is both triggered by and promoting of tumor growth. We hypothesized that an increase in circulating platelets following standard temozolamide (TMZ) CRT and/or adjuvant TMZ would predict for decreased survival in patients with glioblastoma (GBM). Methods: We reviewed data of 122 patients with newly diagnosed, pathological-proven GBM from 2007 to 2016 with documented complete blood counts before the start of CRT, after CRT, before adjuvant TMZ, and after a minimum 2 cycles of adjuvant TMZ. The association between changes in blood count levels and patient survival was analyzed by log-rank test. Multivariate analysis was performed using known prognostic co-variates, including MGMT methylation, patient age, and performance status (PS). Results: The mean change in platelets before and after CRT was -46 k/µl (range -387 to 179 k/µl) and before and after adjuvant TMZ was -25 k/µl (range -408 to 143 k/µl). As a reference, the mean change in lymphocytes was -5.7 k/µl (range -0.7 to 1.3 k/µl) and -0.0 k/µl (range -1.6 to 0.9 k/µl) for CRT and adjuvant TMZ, respectively. Patients were dichotomized based on the relative change in platelets and lymphocytes from baseline (≤30% increase, “low”, n = 101 vs > 30% increase, “high”, n = 12). The median survival of low patients vs. high patients was 30 vs 13 months (p = 0.006). Potential confounders, such as infection or thrombosis, were not associated with the high group. However, no significant survival difference was observed between groups based on platelet changes during adjuvant TMZ. Similarly, changes in lymphocyte counts were not significantly prognostic. In multivariate analysis, extent of resection, MGMT status, PS and the increase in platelets after CRT were significantly associated with survival (HR for platelets 4.0, 95% CI 1.6-10.1). Conclusions: Increased platelet counts after CRT predict for poor survival in patients with GBM. The effect is platelet specific and does not reflect general bone marrow changes, as lymphocyte changes were not significantly prognostic. These results suggest a potential interaction between platelets and tumor aggressiveness.
Phase 1 single-center, dose escalation study of D2C7-IT administered intratumorally via convection-enhanced delivery for adult patients with recurrent malignant glioma.
Authors: Randazzo Dina , Desjardins Annick , Chandramohan Vidyalakshmi , Sampson John H. , Peters Katherine B. , Vlahovic Gordana , Threatt Stevie , Herndon James Emmett , Boulton Susan , Lally-Goss Denise , Healy Patrick , Lipp Eric S , Friedman Allan H. , Bigner Darell D. 
Published: September 2018

e13532 Background: D2C7 immunotoxin (D2C7-IT) is a dual-specific recombinant immunotoxin consisting of EGFR-wt and EGFRvIII monoclonal antibodies with a genetically engineered Pseudomonas exotoxin, PE-38KDEL. The primary objective is to determine the maximum tolerated dose of D2C7-IT when delivered intratumorally by convection enhanced delivery (CED). Methods: Inclusion criteria includes subjects with a single, recurrent supratentorial WHO grade III or IV glioma, KPS ≥ 70 and a washout of chemotherapy, bevacizumab or study drug of ≥ 4 weeks. Prior to administration of D2C7-IT, recurrent tumor must be confirmed by histopathology. A minimum of 2 subjects are accrued by dose level. Results: Currently, 23 subjects have been treated (16 male, 7 female) with a median age of 54 years. Out of 9 dose levels, 2 subjects have been treated at every dose except for 4 at dose level 3 (120 ng/ml) and 5 at dose 6 (405ng/ml). Adverse events possibly, probably or definitely related to D2C7-IT are mostly grade 1 or 2 events consisting of, but not limited to: intracranial hemorrhage (n = 1), stroke (n = 2), headache (n = 15), seizure (n = 5), confusion (n = 4), paresthesia (n = 4), dysarthria (n = 1), dysphasia (n = 4), visual disturbances (n = 7), fatigue (n = 4), gait disturbance (n = 2), elevated transaminases (n = 5), decreased platelets (n = 3), decreased neutrophil count (n = 1), nausea (n = 3), vomiting (n = 1), and thromboembolic event (n = 1). There was 1 dose limiting toxicity (grade 4 seizure at dose level 3), 2 grade 3 headaches and 1 grade 3 elevated ALT. 14 subjects are still alive with 6 remaining on study. So far, the longest survival time from infusion is 18.2+ months. Conclusions: D2C7-IT infusion via CED is safe with encouraging results. This dose escalation Phase I study is ongoing and will set the stage for the Phase II trial. Clinical trial information: NCT02303678.
In situ expression of hypoxia inducible factor 2-alpha in gliomas.
Authors: Renfrow Jaclyn , Mott Ryan , Huang Yue , Wong Tai , Lesser Glenn Jay , Debinski Waldemar , Strowd Roy E. 
Published: September 2018

e13534 Background: Hypoxia, a driver of malignancy, is fundamental to glioblastoma (GBM). Of the hypoxia inducible transcription factors (HIFs), HIF-2a is expressed in GBM tumor cells, responds to prolonged hypoxia, and is a prime candidate for HIF therapeutic targeting. PT2385 is a novel, orally available, first-in-class, HIF-2a inhibitor with a brain:plasma ratio of 0.9 in rats. To establish HIF-2a as a therapeutic target in GBM, in situ expression needs to be described. Methods: Twenty-two paraffin-embedded gliomas (grade II-IV) underwent immunohistochemistry for HIF-2a. After rehydration, a hot Tris EDTA pH 9.0 solution retrieved epitopes, non-specific sites were blocked, and HIF-2a antibody (Santa Cruz, sc-13596) was added. A horseradish peroxidase detection system identified staining. Representative samples were digitally scanned. Localization and quantification of HIF-2a was independently verified by a neuropathologist. Patient survival and molecular genetics were retrospectively collected with Institutional Review Board approval. Results: HIF-2a expression was not detected in the 4 Grade II and 2 Grade III gliomas.Of the 16 GBMs, HIF-2a was expressed in 13 specimens (81%) - highly in 7 ( > 10% cells positive), intermediate in 6 ( < 10% cells positive), and minimally in 3. Recurrent disease stained highly for HIF-2a. Staining was specific to tumor cells and occasionally monocytic cells, clustering in perivascular and perinecrotic regions. Amongst the 16 GBMs, median patient age and survival was 58 and 13.9 months. The two longest survivors harbored positive prognostic genetics (six-year survival with a 1p/19q co-deletion and ten-year survival with MGMT gene methylation). Twelve of 16 patients received chemoradiation. Survival was not correlated with HIF-2a. Conclusions: This first in situ description of HIF-2a demonstrates expression is absent in low-grade gliomas, present in the majority of GBMs, and high in recurrent GBMs. HIF-2a abundance varies with clustering in perivascular and perinecrotic niches. Survival did not appear to be correlated with HIF-2a in this small cohort though well-known prognostic genetic mutations and treatment heterogeneity limit firm conclusions. Preclinical studies with PT2385 are in progress.
Effects of cranial irradiation on dendritic spine complexity in the rat hippocampus and to induce memory decline.
Authors: Ji Shengjun 
Published: September 2018

e13545 Background: Cognitive deficit was the most serious complication of cranial irradiation in brain metastatic carcinoma. However, the underlying mechanisms remain obscure. Dendrites are the anatomic bases of synaptic contact and action potential propagation. Alterations of dendritic architecture may contribute to radiation-induced memory dysfunction. Methods: 21-day-old Sprague-Dawley rats received 10Gy cranial irradiation. 1 and 3 months later, Morris Water Maze, Fear Conditioning test and novel object recognition were used to test the memory function. Golgi staining was used to assess changes in dendritic spine density and morphology. Moreover, cytoskeletal proteins PSD-95 were analyzed with Western blot. Results: Our data showed that 10Gy cranial irradiation induced significant decline in the spatial memory and memory retention of rats and accompanied the morphological changes in dendritic spines. The result revealed significant reductions in spine density at 1 month (40.58%) and 3 months (28.92%) in the DG. In CA1 basal dendrites, irradiation resulted in a significant reduction (33.29%) in spine density only at 1month postirradiation. Compared to control, mushroom spines reduced at 1 month (7.17%, 10.01%) and 3 months (9.29%, 11.94%) post irradiation in DG and CA1 basal dendrites, respectively. Also, we found PSD-95 depletion coincided in time with alteration in dendritic spines. Conclusions: These data suggest that cranial irradiation decreased the dendritic spine density and mushroom spines, which may be associated with radiation-induced memory dysfunction. Acknowledgment: This study was supported by the National Natural Science Foundation of China 81402517 and the Suzhou Science and Technology Project SYS201651.
Spectrochemical analysis highlights similarities in adenocarcinomas irrespective of primary tissue origins.
Authors: Bury Danielle , Faust Guy , Paraskevaidi Maria , Dawson Timothy P , Martin Francis L. 
Published: September 2018

e13551 Background: Identification of primary tissue origin of brain metastases can be histopathologically challenging. Initial diagnosis of malignancy can be provided on intraoperative tissue smears; however, it requires formal histopathological examination along with immunohistochemistry to reach a final diagnosis. On occasion this will still fail to determine primary origin. This study aims to demonstrate if Raman spectroscopy is able to determine primary tissue origin of brain metastasis of three common primary tumours. Methods: Formalin fixed paraffin embedded tissue from twenty brain metastasis comprising colorectal adenocarcinomas ( n= 7), lung adenocarcinomas ( n= 7) and melanomas ( n= 6) were obtained from the Brain Tumour NorthWest tissue bank. Sections (10-μm thick) were placed onto glass slides covered in aluminium foil and de-waxed prior to spectral acquisition. 25 spectra per section were collected at random, using a 785 nm laser at 1200 g mm-1grating with an acquisition time of 30 sec. Computational analysis within a MatLab environment was then conducted. Results: Following PCA-LDC analysis, classification accuracy of the three groups was; colorectal adenocarcinoma 71.3%, lung adenocarcinoma 71% and melanoma 70%. A one-way ANOVA showed statistically significant differences between the three groups, p = 0.0014. On combining adenocarcinoma groups accuracy increased to 87.8%, whilst melanoma fell to 68.9%. A student’s t-test confirmed statistical significance between the two groups, p < 0.0001. Conclusions: Raman spectroscopy can classify different tumours by type, though sensitivity and specificity is diminished if used to classify primary tissue origin of adenocarcinomas. Therefore for clinical use, such new tools may aid the clinician to determine tumour type intra-operatively but classic histopathology is still required for tissue origin confirmation. Such technologies may provide a useful adjunct to more conventional approaches; for instance, decreasing the number of immunohistochemical stains required to determine tissue origin. These results also suggest strong similarities between adenocarcinomas of different primary origins.
Computational exploration of mechanistic determinants of antibody drug-conjugate pharmacokinetics using quantitative systems pharmacology modeling strategies.
Authors: Burke John M , Wilkins Anna Katharina , Matteson Andrew , Gruenbaum Lore , Apgar Josh F 
Published: September 2018

e14000 Background: The pharmacokinetics of antibody drug conjugate (ADC) therapeutics typically show a discrepancy between the PK of total antibody (conjugated and unconjugated antibody) and that of conjugated antibody, carrying one or more payload molecules This discrepancy is often attributed to deconjugation (Kamath, 2014), however recent evidence suggests that the underlying mechanisms may be more complex. Methods: This work employs a computational quantitative systems pharmacology (QSP) approach to understand the impact of drug antibody ratio (DAR) and the resulting changes in molecular properties on overall PK and relative payload disposition as observed in preclinical and clinical studies. Results: Using QSP approaches, the model (1) describes the kinetics of individual DAR species and agrees well with typical ADC PK, individual DAR PK, and average DAR measurements in vivo; (2), quantitatively describes the trade-off between higher DAR and lower exposure; consequently, we predict that ADC2 is half as potent as ADC4 and ADC8, which are equipotent; (3) longer mAb half-life reduces payload delivery after multiple doses; and (4) ADC half-life affects the percent of payload delivered through different mechanisms. Conclusions: A QSP model describing mechanism is a useful tool to translate and understand PK from preclinical species to human, by acting as a central repository of data, knowledge, and hypotheses. It provided a rational basis to generate testable hypotheses and provide early insights into complex ADC PK data and established the benefit of using computational models to design novel ADCs and to optimize the discovery and development of existing ADCs.