tbuckley/cabot-search huggingface dataset:
PARP1 expression drives the synergistic antitumor activity of trabectedin and PARP1 inhibitors in sarcoma preclinical models
Authors: Ymera Pignochino, Federica Capozzi, Lorenzo D’Ambrosio, Carmine Dell’Aglio, Marco Basiricò, Marta Canta, Annalisa Lorenzato, Francesca Vignolo Lutati, Sandra Aliberti, Erica Palesandro, Paola Boccone, Danilo Galizia, Sara Miano, Giulia Chiabotto, Lucia Napione, Loretta Gammaitoni, Dario Sangiolo, Maria Serena Benassi, Barbara Pasini, Giovanna Chiorino, Massimo Aglietta, Giovanni Grignani
Journal: Molecular Cancer (2017)

Enhancing the antitumor activity of the DNA-damaging drugs is an attractive strategy to improve current treatment options. Trabectedin is an isoquinoline alkylating agent with a peculiar mechanism of action. It binds to minor groove of DNA inducing single- and double-strand-breaks. These kinds of damage lead to the activation of PARP1, a first-line enzyme in DNA-damage response pathways. We hypothesized that PARP1 targeting could perpetuate trabectedin-induced DNA damage in tumor cells leading finally to cell death.We investigated trabectedin and PARP1 inhibitor synergism in several tumor histotypes both in vitro and in vivo (subcutaneous and orthotopic tumor xenografts in mice). We searched for key determinants of drug synergism by comparative genomic hybridization (aCGH) and gene expression profiling (GEP) and validated their functional role.Trabectedin activated PARP1 enzyme and the combination with PARP1 inhibitors potentiated DNA damage, cell cycle arrest at G2/M checkpoint and apoptosis, if compared to single agents. Olaparib was the most active PARP1 inhibitor to combine with trabectedin and we confirmed the antitumor and antimetastatic activity of trabectedin/olaparib combination in mice models. However, we observed different degree of trabectedin/olaparib synergism among different cell lines. Namely, in DMR leiomyosarcoma models the combination was significantly more active than single agents, while in SJSA-1 osteosarcoma models no further advantage was obtained if compared to trabectedin alone. aCGH and GEP revealed that key components of DNA-repair pathways were involved in trabectedin/olaparib synergism. In particular, PARP1 expression dictated the degree of the synergism. Indeed, trabectedin/olaparib synergism was increased after PARP1 overexpression and reduced after PARP1 silencing.PARP1 inhibition potentiated trabectedin activity in a PARP1-dependent manner and PARP1 expression in tumor cells might be a useful predictive biomarker that deserves clinical evaluation.
Continuous treatment (CT) versus fixed duration of therapy (FDT) in newly diagnosed myeloma patients: PFS1, PFS2, OS endpoints.
Authors: Antonio Palumbo, Francesca Gay, Pellegrino Musto, Tommaso Caravita, Alessandra Larocca, Davide Rossi, Dina Ben Yehuda, Massimo Offidani, Francesca Donato, Paola Finsinger, Paola Omedè, Concetta Conticello, Arnon Nagler, Roberto Ria, Maide Cavalli, Roberto Mina, Maria Teresa Petrucci, Izhar Hardan, Federica Cavallo, Mario Boccadoro
Journal: Journal of Clinical Oncology (2014)

8515 Background: Continuous therapy significantly prolongs remission duration, resistant relapse may reduce the duration of subsequent remission which can negatively impact on OS. PFS1 defines the time from start of therapy to the occurrence of 1st relapse. PFS2 is defined as per EMA as the time from start of therapy to the occurrence of 2nd relapse, incorporating the duration of both 1st and 2nd remission. We evaluated PFS1, PFS2 and OS in newly diagnosed multiple myeloma (NDMM) patients who received CT or FDT. Methods: Patients were enrolled in 2 phase III randomized trials, comparing CT vs FDT (RVMM209: lenalidomide-based induction, consolidation, followed by maintenance [CT] vs lenalidomide-based induction, consolidation, no maintenance [FDT]; GIMEMA0305: bortezomib-based induction followed by maintenance (CT) vs bortezomib-based induction, no maintenance [FDT]). At diagnosis, in all randomized patients, we evaluated PFS1 (time: diagnosis followed by 1st relapse), PFS2 (time: diagnosis followed by 2nd relapse), and OS (time: diagnosis followed by death). In patients who experienced 1st relapse we tested 2nd PFS (time: 1st relapse followed by 2nd relapse) and survival from relapse (time: 1st relapse followed by death). Results: In the pooled analysis, 452 patients received CT and 461 patients received FDT. Median follow-up was 52 months [mo]. CT significantly prolonged PFS1 (median 35 vs 24 mo, HR 0.58; P<0.0001), PFS2 (median 63 vs 47 mo, HR 0.69, p=0.0001) and OS (median not reached [NR] vs 70 mo, HR 0.70, P=0.0019) in comparison with FDT. 2nd PFS and OS from relapse were similar among patients who received CT or FDT upfront. Results were similar in the single studies (Table). Conclusions: In NDMM patients, CT significantly improved PFS1, PFS2, and OS. Prolongation of PFS2 suggests that the clinical benefit observed during 1st remission is not cancelled by a shorter 2nd remission. PFS2 should be included in all CT vs FDT studies to evaluate the risk of tumor-resistance induced by CT. Clinical trial information: NCT01063179 and NCT00551928. GIMEMA MM0305 RVMM209 CT FDT HR P CT FDT HR P (Median, mo) (Median, mo) From diagnosis PFS1 35 24 0.58 <0.001 38 25 0.58 <0.001 PFS2 59 42 0.69 0.003 63 49 0.69 0.015 OS NR 60 0.70 0.01 NR NR 0.68 0.047 From 1st relapse PFS 14 12 1.1 0.61 17 19 1.09 0.61 OS 26 28 0.99 0.94 47 42 1.0 0.99
Mast cell–derived prostaglandin D 2 attenuates anaphylactic reactions in mice
Authors: Tatsuro Nakamura, Yuki Fujiwara, Ryota Yamada, Wataru Fujii, Taiki Hamabata, Monica Yunkyung Lee, Shingo Maeda, Kosuke Aritake, Axel Roers, William C. Sessa, Masataka Nakamura, Yoshihiro Urade, Takahisa Murata
Journal: Journal of Allergy and Clinical Immunology (2017)
P01.14 MicroRNA signatures and molecular subtypes of glioblastoma - MicroRNA signatures and molecular subtypes of glioblastoma - the role of extracellular transfer
Authors: A. Bronisz
Journal: Neuro-Oncology (2017)

Despite the importance of molecular subtype classification of glioblastoma multiforme (GBM), the extent of extracellular vesicle (EV) - driven molecular and phenotypic re-programming remains poorly understood. To reveal complex subpopulation dynamics within the heterogeneous intra-tumoral ecosystem, we characterized microRNA expression and secretion in phenotypically diverse subpopulations of patient-derived GBM stem-like cells (GSC). As EVs and microRNAs convey information that drives phenotype and re-arrange the molecular landscape in a cell type-specific manner, we argue that intra-tumoral exchange of microRNA augments the heterogeneity of GSC that is reflected in highly heterogeneous profiles of microRNA expression in GBM subtypes.
P17.05 Can re-irradiation for recurrent malignant gliomas be a good option?
Authors: W. Yoon
Journal: Neuro-Oncology (2017)

Introduction: In patients with recurrent gliomas, multimodal treatments were performed including surgery and chemotherapy. Re-irradiation therapy also have been used as one of options, but brought up the concern about the toxicity. We analyzed the survival benefit and treatment outcomes in patients with recurrent gliomas after the re-irradiation. METHODS: From January 2009 to May 2016, 24 patients with recurrent or progressive gliomas received re-irradiation. Re-irradiation was performed with intensity-modulated radiation therapy. Results: The median time interval between initial radiation therapy and re-irradiation was 11 months. Median Kanofsky performance status (KPS) on prior re-irradiation was 70 and median dose of re-irradiation was 49.2 Gy with 20 fractions. Median overall survival (OS) time and the 12-month OS rate after re-irradiation were 13.3 months and 56.6%, respectively. Median KPS status was decreased on follow-up period. The median difference between initial KPS and follow-up period on 3 months, 6 months, and 12 months were 10, 20, and 40, respectively. CONCLUSION: Re-irradiation could be a ponderable treatment in selected patients with recurrent malignant gliomas. The toxicity influencing performance status was occurred in long follow-up period after re-irradiation.
Psychosocial Stress and Brain Function in Adolescent Psychopathology
Authors: Erin Burke Quinlan, Anna Cattrell, Tianye Jia, Eric Artiges, Tobias Banaschewski, Gareth Barker, Arun L.W. Bokde, Uli Bromberg, Christian Büchel, Rüdiger Brühl, Patricia J. Conrod, Sylvane Desrivieres, Herta Flor, Vincent Frouin, Jürgen Gallinat, Hugh Garavan, Penny Gowland, Andreas Heinz, Jean-Luc Martinot, Marie-Laure Paillère Martinot, Frauke Nees, Dimitri Papadopoulos-Orfanos, Tomáš Paus, Luise Poustka, Michael N. Smolka, Nora C. Vetter, Henrik Walter, Robert Whelan, Jeffrey C. Glennon, Jan K. Buitelaar, Francesca Happé, Eva Loth, Edward D. Barker, Gunter Schumann
Journal: American Journal of Psychiatry (2017)

The authors sought to explore how conduct, hyperactivity/inattention, and emotional symptoms are associated with neural reactivity to social-emotional stimuli, and the extent to which psychosocial stress modulates these relationships.Participants were community adolescents recruited as part of the European IMAGEN study. Bilateral amygdala regions of interest were used to assess the relationship between the three symptom domains and functional MRI neural reactivity during passive viewing of dynamic angry and neutral facial expressions. Exploratory functional connectivity and whole brain multiple regression approaches were used to analyze how the symptoms and psychosocial stress relate to other brain regions.In response to the social-emotional stimuli, adolescents with high levels of conduct or hyperactivity/inattention symptoms who had also experienced a greater number of stressful life events showed hyperactivity of the amygdala and several regions across the brain. This effect was not observed with emotional symptoms. A cluster in the midcingulate was found to be common to both conduct problems and hyperactivity symptoms. Exploratory functional connectivity analyses suggested that amygdala-precuneus connectivity is associated with hyperactivity/inattention symptoms.The results link hyperactive amygdala responses and regions critical for top-down emotional processing with high levels of psychosocial stress in individuals with greater conduct and hyperactivity/inattention symptoms. This work highlights the importance of studying how psychosocial stress affects functional brain responses to social-emotional stimuli, particularly in adolescents with externalizing symptoms.
P16.06 Management and long term outcome of intracranial subependymoma
Authors: D. Giraldi, A. Varma, A. R. Brodbelt, M. D. Jenkinson
Journal: Neuro-Oncology (2017)

Introduction: Intracranial subependymoma (WHO grade 1) account for 0.2-0.7% of all central nervous system (CNS) tumours. They are intraventricular tumours and present as incidental findings or cause hydrocephalus. The study aim was to evaluate the management and ­outcome following surgical resection of subependymoma. Materials and Methods: Retrospective, single centre case note review in adults with WHO grade 1 subependymoma diagnosed between 1990-2015. Ependymomas and subependymal giant cell astrocytomas were excluded. Tumour location, extent of resection (defined as gross total resection (GTR), sub-total resection (STR) or biopsy) and the WHO performance status (PS) were recorded at time of presentation and at follow- up. Results: 13 patients (7 male; 6 female) with a mean age of 47.6 years (range 33-58 years) were included. Mean follow-up was 62.7 months (range 24-216). 5 patients had incidental findings; 8 patients had symptomatic tumours (headache, cerebellar ataxia, cranial nerves deficits). PS at diagnosis was 0 (n=8) and 1 (n=5). Tumours were located in the 4th (n=9), lateral (n=2 left, n=2 right) and 3rd ventricle (n=1). 12 patients underwent craniotomy for excision (GTR n=11; STR n=1) and 1 craniectomy for co-existing Chiari Malformation (biopsy n=1). Early post- operative PS was 0 (n=3) and 1 (n=10). At last follow-up PS was 0 (n=11) and 1 (n=2). 2 patients developed symptomatic post-operative hydrocephalus (13.3%) and required ventriculoperitoneal shunt. There was no recurrence following GTR, and no growth following STR or biopsy. Only 2 patients, remains in PS 1 at last follow- up, while 84.6% are symptom free and PS 0. Conclusions: Typical neuroradiology appearance is diagnostic of subependymoma. When diagnosis is secure subependymoma are known to be indolent tumours. Whilst modern neurosurgery is safer, surgical resection should be restricted to those with symptomatic tumours given the risk of post-operative hydrocephalus. Incidental subependymoma could be followed with surveillance MRI without the need for surgery.
Phase 3 trial results for rolapitant, a novel NK-1 receptor antagonist, in the prevention of chemotherapy-induced nausea and vomiting (CINV) in subjects receiving moderately emetogenic chemotherapy (MEC).
Authors: Ian D. Schnadig, Manuel R. Modiano, Allen Poma, Mary Lynne Hedley, Robert E. Martell, Lee Steven Schwartzberg
Journal: Journal of Clinical Oncology (2014)

9633 Background: Rolapitant is a highly selective competitive long acting NK-1 receptor antagonist that demonstrated efficacy in a large randomized phase 2 dose-finding study. This study evaluated the 200 mg dose for efficacy and safety in the prevention of CINV in subjects receiving MEC. Methods: Randomized phase 3 double-blind active-control study. 1,369 chemo-naïve patients treated with MEC (cyclophosphamide, doxorubicin, epirubicin, carboplatin, irinotecan, daunorubicin or cytarabine) were randomized 1:1 to either (1) rolapitant + granisetron + dexamethasone or (2) placebo + granisetron + dexamethasone. The primary endpoint was complete response (CR=no emesis and no rescue medication) in delayed phase (>24-120 hrs) post-chemo. Secondary endpoints included CR in acute (0-24 hrs) and overall (0-120 hrs) phases. Treatment comparisons were performed using Mantel-Haenszel chi-square test; to control for type 1 error testing for key secondary endpoints was conducted in a stepwise fashion. Subjects recorded episodes of emesis, nausea and rescue medication using a diary during 0-120 hrs post-chemo. Results: There were 1,344 evaluable patients (>50% received anthracycline-cyclophosphamide therapy). Subjects in rolapitant group had a significantly higher CR rate for the primary study endpoint during delayed phase compared to control (71.3% vs 61.6%, p<0.001, respectively). CR rates were also higher in rolapitant group for acute and overall phases (83.5% vs 80.3%, p=0.143; 68.6% vs 57.8%, p<0.001, respectively). The rolapitant group achieved higher rates of complete protection (no emesis, no rescue medication and maximum nausea VAS <25mm) in both delayed and overall phases compared to control (64.3% vs 56.9%, p=0.006; 62.0% vs 53.2%, p=0.001, respectively). AE rates were similar across both groups. Conclusions: Rolapitant in combination with a 5-HT3 receptor antagonist and dexamethasone was well-tolerated and demonstrated superior efficacy over control in the primary endpoint of the prevention of delayed CINV in subjects receiving MEC in a global phase 3 study. Clinical trial information: NCT01500226.
P08.52 Metformin as adjuvant therapy for glioma
Authors: C. Seliger, K. Renner
Journal: Neuro-Oncology (2017)

Introduction: To this day, glioblastoma (GBM) remains an incurable brain tumor. Metformin is one of the most frequently prescribed oral antidiabetic drugs. In addition to its known hypoglycemic effects, metformin was found to reduce the incidence of several human cancers and to prolong survival of tumor patients. Previous research has shown that metformin may decrease GBM cell proliferation and migration especially in brain tumor initiating cells (BTICs). Pharmaco-epidemiologic studies stimulated a large number of laboratory models, which often showed impressive antineoplastic effects of metformin, mostly by inhibition of oxidative phosphorylation. However, exact metabolic mechanisms underlying metformin’s inhibitory effects on BTICs and predictors of metformin susceptibility are poorly elucidated. Materials and Methods: We investigated glioma incidence and survival among patients with or without metformin use in large and validated databases. We also examined the effects of metformin on a number of BTICs from fresh tumor resections of GBMs using several different functional and metabolic assays in vitro and initiated corresponding in vivo models. Results: In our epidemiological studies, long-term use of metformin was not significantly associated with decreased risk of glioma, but preliminary results show a survival benefit of patients with high-grade glioma using metformin. In laboratory assays, we observed that high-dose metformin (10 mM) inhibited BTIC function in the majority of investigated cells, whereas low-dose metformin (0.01mM) affected only a subset of cells. Preliminary analyses showed that the level of response to metformin correlated with dependence on oxidative energy production. CONCLUSION: Metformin represents a promising treatment strategy for GBM, but may affect only a subset of patients, when applied in clinically relevant doses. Specific populations of patients may be more responsive to metformin treatment, even at low doses. Careful patient selection, rational combinatory approaches, and novel biguanides may enhance drug sensitivity. In addition, indirect effects of biguanides, leading to changes in the host endocrine environment, may also account for enhanced patient response and survival. This work was funded by the German Research Foundation (KFO 262-P10).
The impact of rare and low-frequency genetic variants in common disease
Authors: Lorenzo Bomba, Klaudia Walter, Nicole Soranzo
Journal: Genome biology (2017)

Despite thousands of genetic loci identified to date, a large proportion of genetic variation predisposing to complex disease and traits remains unaccounted for. Advances in sequencing technology enable focused explorations on the contribution of low-frequency and rare variants to human traits. Here we review experimental approaches and current knowledge on the contribution of these genetic variants in complex disease and discuss challenges and opportunities for personalised medicine.
Do patient access schemes for high-cost cancer drugs deliver value to society?—lessons from the NHS Cancer Drugs Fund
Authors: A. Aggarwal, T. Fojo, C. Chamberlain, C. Davis, R. Sullivan
Journal: Annals of Oncology (2017)

The NHS Cancer Drugs Fund (CDF) was established in 2010 to reduce delays and improve access to cancer drugs, including those that had been previously appraised but not approved by NICE (National Institute for Health and Care Excellence). After 1.3 billion GBP expenditure, a UK parliamentary review in 2016 rationalized the CDF back into NICE.
Hemostatic Alterations in Patients Undergoing Hematopoietic Stem Cell Transplantation.
Authors: Stefanie Buchholz, Alexander Woywodt, Johanna Scheer, Lothar Hambach, Haytham Kamal, Hermann Haller, Marion Haubitz, Arnold Ganser, Bernd Hertenstein, Mario von Depka
Journal: Blood (2004)
Early mortality and overall survival of acute myeloid leukemia based on facility type
Authors: Vijaya R. Bhatt, Valerie Shostrom, Smith Giri, Krishna Gundabolu, K. M. Monirul Islam, Frederick R. Appelbaum, Lori J. Maness
Journal: American Journal of Hematology (2017)

Cancer health disparities may exist based on the facility type. We aimed to determine the association between the academic status of centers and outcomes of patients with acute myeloid leukemia (AML). Using the National Cancer Data Base, we compared 1-month mortality and long-term overall survival (OS) of 60 738 patients with AML, who received first course treatment between 2003 and 2011 at academic or nonacademic centers (community cancer program, comprehensive community cancer program, and others). Multivariate analysis was done using logistic regression for one-month mortality and Cox regression with backward elimination approach for OS. Patients treated at academic centers differed from those at nonacademic centers in that they were younger with a median age of 62 versus 70 years (P < .0001), more often an ethnic minority (P < .0001), had lower education level (P = .005), lower co-morbidity score (P < .0001), a different income (P < .0001), and insurance profile (P < .0001), and more often received chemotherapy (P < .0001) and transplant (P < .0001). Receipt of care at nonacademic centers was associated with worse 1-month mortality (29% vs. 16%, P < .0001) and 5-year OS (15% vs. 25%; P < .0001). After adjusting for prognostic covariates, the 1-month mortality (odds ratio, 1.52; 95% confidence interval, CI 1.46-1.59; P < .0001) and OS were significantly worse in nonacademic centers, compared to academic centers. Our large database study suggests that the receipt of initial therapy at academic centers is associated with lower 1-month mortality and higher long-term OS. Investigation of the underlying reasons may allow reducing this disparity.
P09.39 WNT signaling antagonist CXXC4 is a potential tumor suppressor in GBM and adjunct biomarker for grading and prognosis in gliomas
Authors: P. Pankaj, A. Kumar
Journal: Neuro-Oncology (2017)

Introduction: Aberrant expression of WNT signaling is associated with glioblastoma (GBM) and shown to be an important pathway in gliomagenesis and growth of stem-like glioma cells and drug resistance. Despite combined chemo-radiotherapy, WNT signaling upregulation promotes tumor recurrence. Thus inhibition of the WNT pathway holds promise as another treatment measure in gliomas. The CXXC domain protein 4 (CXXC4) functions as an antagonist of WNT signaling. Additionally epigenetic factor EZH2 (enhancer of zeste homolog 2) have also been reported to play key role in aberrant activation of WNT signaling by downregulating CXXC4 expression in some non CNS tumors. Materials and Methods: Gene expression of CXXC4, WNT3, EZH2 was assessed in different grades of gliomas including 33 glioblastomas (GBM), 7 diffuse astrocytomas (DA), 8 anaplastic astrocytomas (AA) and 8 oligodendrogliomas (ODG) and 6 non-neoplastic brain tissues using qRT-PCR. EZH2 protein expression was determined by immunohistochemistry. An association between these markers in addition to TCGA and REMBRANDT dataset was analyzed to validate our findings and determine clinical outcome. Results: qRT-PCR analysis showed that CXXC4 is significantly downregulated in GBMs (p=0.01) than in non-neoplastic brain tissues. A significant upregulation of CXXC4 mRNA in ODGs (p=0.01) and borderline significant upregulation in AA and DA (p=0.06 each) was also found. Importantly, a significant downregulation of CXXC4 mRNA was observed in GBMs as compared to AA (p=0.009), DA (p=0.04) and ODGs (p=0.03) respectively. A nearly significant difference (p=0.05) was also found between CXXC4 mRNA expression in ODGs vs AAs. Notably, a correlation of low expression of CXXC4 and high expression of WNT3 mRNA (p=0.05) and EZH2 mRNA/protein immunoexpression (p=0.0001 each) was found in GBMs which was in concordance with REMBRANDT and TCGA dataset of gliomas. Kaplan-Meier analysis of TCGA dataset of GBMs indicated that patients with high expression of EZH2 and low expression of CXXC4 are significantly related to poorer OS (P<0.001). Taken together GBM, ODGs and astrocytomas, Kaplan-Meier analysis in RAMBRANDT and TCGA dataset showed that low expression of CXXC4 are significantly related to poorer OS (p=0.00 and p=0.005 respectively). Conclusions: These data suggest that CXXC4 plays a critical role in tumor progression of gliomas through Wnt signaling. CXXC4 is a novel potential tumor suppressor which may be regulated by EZH2, and its expression may be considered a new significant diagnostic and prognostic factor for both high and low grade gliomas. EZH2 overexpression is suggested to promote the activation of WNT pathway in GBMs through the downregulation of CXXC4. Accumulating further in-vivo data to support the crucial roles of CXXC4-EZH2-WNT axis in GBM may increase the feasibility of WNT inhibition as a therapeutic approach in gliomas.