tbuckley/cabot-search huggingface dataset:
PATH-16. MOLECULAR PATHOLOGY AND CLINICAL CHARACTERISTICS OF MMR DEFICIENCY (MMRd) IN DIFFUSE GLIOMAS
Authors: Mehdi Touat, Sandro Santagata, Erell Guillerm, Wenya Bi, Frédéric Beuvon, Karima Mokhtari, Marine Giry, Justine Guegan, Shannon Block, Alexandre Carpentier, Jean-Yves Delattre, Marc Sanson, Alex Duval, Rameen Beroukhim, Pratiti Bandopadhayay, David Reardon, Patrick Wen, Ahmed Idbaih, Florence Coulet, Keith Ligon, Franck Bielle
Journal: Neuro-Oncology (2018)

MMR deficiency (MMRd) is found in a subset of gliomas. Emerging evidence indicates that MMRd could serve as predictive biomarker for both response to immunotherapy and resistance to alkylating agents. However, the molecular epidemiology, outcome, and the optimal diagnostic method of MMRd are poorly defined in gliomas. A cohort of 350 adult gliomas was characterized as to WHO 2016 diagnosis, IDH1/2 sequencing, MGMT promoter methylation, prior treatment and outcome. Immunohistochemistry of MMR proteins (MSH2, MSH6, MLH1, PMS2) was performed in 260 tumors with available tissue. 100 tumors were analyzed with next generation targeted exome sequencing (NGS, Oncopanel) of 447 cancer genes, including full exon coverage of MMR genes. Comparisons between results from IHC, NGS and microsatellite instability (MSI) testing using pentaplex PCR amplification testing were incorporated to inform best practices. 53/260 tumors showed immunohistochemical (ie MMR protein staining loss) and/or molecular (ie presence of MMR pathogenic mutation with hypermutation) evidence of MMRd. No MSI was found by pentaplex PCR. 38/260 tumors harbored loss of protein expression of one or two MMR proteins: 15 showed loss of MSH6 protein (with/without concomitant MSH2 loss) and 23 had loss of PMS2 (with/without MLH1 loss). Analysis of 201 consecutive recurrent tumors from alkylator pre-treated patients showed significant association between MMRd and the presence of IDH1/2 mutation: MMRd in 20/90 (22.2%) of IDH1/2-mutant tumors vs 2/111 (1.8%) of IDH1/2-wild-type tumors (p<4.10–6). In addition, MMRd was found in 6/17 (35%) of patients with de novo gliomas and clinical features indicating possible inherited MMRd. Outcomes and updated results of molecular biomarker analyses will be presented at the conference. CONCLUSIONS: Loss of MMR protein expression by IHC is significantly associated with IDH-mutant relapses and a clinico-histo-molecular presentation suggestive of germline MMRd. NGS and IHC of MMR proteins are highly concordant in gliomas, while MSI testing lacks sensitivity.
IMMU-55. IMMUNOMODULATORY IL-7 AND IL-12-EXPRESSING MSCs INDUCE LONG-TERM SURVIVAL AND IMMUNITY IN SYNGENEIC INTRACEREBRAL GLIOBLASTOMA MODELS
Authors: Malte Mohme, Cecile Maire, Ulf Geumann, Lasse Dührsen, Simon Schliffke, Krystian Fita, Mascha Binder, Katrin Lamszus, Christine Guenther, Manfred Westphal, Felix Hermann, Nils Ole Schmidt
Journal: Neuro-Oncology (2018)

Mesenchymal stem cells (MSCs) show an inherent brain tumor cell tropism that can be exploited for targeted delivery of therapeutic genes to invasive glioma. We assessed whether a motile MSC-based local immunomodulation is able to overcome the immunosuppressive glioblastoma microenvironment and to induce an antitumor immune response. Apceth-301 is a cell-based immunotherapy consisting of MSCs which are genetically modified to co-express high levels of IL-12 and IL-7. In vitro characterization demonstrated increased T-cell activation, as measured by increased secretion of IFNg and TNFa, and promoted NK cell mediated killing of GBM cell lines in co-culture assays. Therapeutic efficacy was assessed in two immunocompetent orthotopic C57BL/6 glioma models using GL261 and CT2A. Intratumoral administration of MSCIL7/12 induced a significant tumor growth inhibition and displayed tumor necrosis MR imaging. Notably, up to 50% of treated mice survived long-term. Re-challenging of survivors confirmed long-lasting tumor immunity. Immunomodulatory effects were assessed by immunehistology and multicolor flow-cytometry to comprehensively profile immune activation of tumor-infiltrating lymphocytes (TIL). Local treatment with MSC-IL12/7 was well tolerated and led to a significant inversion of CD4+/CD8+ T-cell ratio with an intricate predominantly CD8+ T-cell mediated anti-tumor response. T-cell receptor sequencing demonstrated increased diversity of TILs in MSCIL7/12-treated mice, indicating a broader tumor-specific immune response with subsequent oligoclonal specification during generation of long-term immunity. Local MSC-based immunomodulation is able to efficiently alter the immunosuppressive microenvironment in glioblastoma. The long lasting therapeutic effects warrant a rapid clinical translation of this concept and have led to planning of a phase I/II study.
Targeting the crosstalk between cytokine-induced killer cells and myeloid-derived suppressor cells in hepatocellular carcinoma
Authors: Su Jong Yu, Chi Ma, Bernd Heinrich, Zachary J. Brown, Milan Sandhu, Qianfei Zhang, Qiong Fu, David Agdashian, Umberto Rosato, Firouzeh Korangy, Tim F. Greten
Journal: Journal of Hepatology (2018)
NHS outpatient model is no longer fit for purpose, says RCP
Authors: Gareth Iacobucci
Journal: BMJ (2018)

The current model of outpatient care in the NHS requires wholesale redesign to meet growing demand and patient need, the Royal College of Physicians has argued.

A new report1 from the college says the traditional model of outpatient care, based on specialty opinion, diagnosis, and disease monitoring is “no longer fit for purpose,” and places “unnecessary financial and time costs on patients, clinicians, the NHS, and the public purse.”

The college calls for a new approach that takes into account all the costs related to an intervention, including loss of income for patients attending …
PATH-01. DEVELOPMENT OF A SENSITIVE MULTIPLEX ASSAY FOR DETECTION OF MUTATIONS IN IDH1 AND IDH2
Authors: Anjen Chenn, Scott Parker, Sarah Perrey DeGeare, Lauren Kam-Morgan, Li Cai
Journal: Neuro-Oncology (2018)

Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are the most frequently mutated metabolic genes in human cancer. They encode cytosolic and mitochondrial enzymes that catalyze the conversion of isocitrate to a-ketoglutarate (αKG), a key component in metabolic and cellular pathways including the Krebs cycle. All located within exon 4, IDH1 and IDH2 mutations are found in multiple types of human cancer including, but not limited to, acute myeloid leukemia and gliomas. IDH mutations occur in the vast majority of WHO grade II/III gliomas and secondary GBMs. Here we describe a sensitive and robust single base extension assay to detect mutations affecting amino acids 100, 105, and 132 of IDH1, and amino acids 140 and 172 of IDH2 in human clinical specimens. Accuracy studies using FFPE, blood, bone marrow, and synthetic controls showed 100% concordance in mutant identification, confirmed using orthogonal methods. Repeatability (intra-assay precision) and reproducibility (inter-assay precision) were 100%. The assay can detect reliably the presence of 5% mutation in a wild-type background with input as low as 0.25 ng DNA (FFPE). Glioma FFPE stored at 15–30°C were found to be stable for 90 days. The IDH1/IDH2 assay has been offered as a clinical test based on its performance characteristics. In a set of 289 clinical specimens including glioma and AML, results were obtained in >98%. Consistent with other published findings, the majority of mutations in glioma affected R132 of IDH1, with other mutations less frequently identified. This IDH assay has high sensitivity, can reliably detect mutations in FFPE samples, and can be implemented as part of routine clinical practice.
NCMP-14. TREATMENT RESPONSE OF LEPTOMENINGEAL CARCINOMATOSIS IN CLL: A CASE REPORT AND REVIEW OF THE LITERATURE
Authors: Alipi Naydenov, Lynne Taylor
Journal: Neuro-Oncology (2018)

Leptomeningeal carcinomatosis is a rarely-reported complication of chronic lymphocytic leukemia (CLL), and its significance is debated. We report a case of leptomeningeal CLL presenting with lower extremity weakness with excellent clinical response to ibrutinib and later to intrathecal rituximab. A comprehensive review was performed encompassing 103 published cases of leptomeningeal disease in CLL since 1976. Emphasis was placed on treatment strategy and response, and the clinical significance of CSF clearance. When presenting symptoms were grouped by effect of leptomeningeal carcinomatosis on three anatomic sites (1) cerebral or cerebellar parenchyma, 2) nerve roots, and 3) intracranial pressure due to impaired CSF absorption by arachnoid granulations, 99% of patients had symptoms from at least one category and 40% had symptoms from multiple categories. OS was >14.3 months after diagnosis of leptomeningeal carcinomatosis, and this was unaffected by Rai stage at presentation. All patients treated with ibrutinib (N=7) achieved complete remission (CR), whereas other chemotherapies had failure rates ranging from 7% (intrathecal methotrexate, N=55) to 50% (vincristine, N=10). When best overall response to treatment was scored, 76 patients achieved CR, 7 patients achieved PR, 10 patients were not treated, and 10 patients had no response. CSF clearance was observed in 64 cases with median OS 12 months, failure of clearance was reported in 21 cases with median OS 2 months, and 14 cases did not report CSF response. We confirm that symptoms of leptomeningeal carcinomatosis in CLL are reversible and leptomeningeal disease is associated with a more favorable OS in CLL compared to other cancers. Presenting symptoms follow a clear and predictable pattern. Clearance of CSF with therapy is not required for symptomatic improvement but is associated with increased OS. Finally, ibrutinib and rituximab were the chemotherapies most frequently associated with complete response.
Abstract 15924: Major Depression and Atherosclerotic Burden in Individuals With High Cardiovascular Health Scores. The ELSA-Brasil Baseline Assessment
Authors: Itamar S Santos, Paulo A Lotufo, Alexandre C Pereira, Maria-Carmen Viana, Enirtes C Melo, Marcio S Bittencourt, Alessandra C Goulart, Isabela M Bensenor
Journal: Circulation (2017)

Introduction: Some individuals with optimum cardiovascular health (CVH) scores present unexpectedly high atherosclerotic burden. Major depression is associated with cardiovascular disease (CVD), bu...
CSIG-43. THE TYROSINE PHOSPHATASE PTPN12/PTP-PEST REGULATES PHOSPHORYLATION-DEPENDENT UBIQUITINATION AND STABILITY OF FOCAL ADHESION SUBSTRATES IN INVASIVE GLIOBLASTOMA CELLS
Authors: Joseph McCarty, John Morales, Paola Guerrero, Zhihua Chen
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) is an invasive brain cancer with tumor cells that disperse from the primary mass escaping surgical resection, displaying resistance to chemotherapy and radiation, and invariably giving rise to lethal recurrent lesions. Targeted therapies such as the anti-vascular endothelial growth factor (VEGF) blocking antibody bevacizumab have yielded disappointing results in GBM clinical trials, with no improvements in overall patient survival. Many patients treated with bevacizumab develop acquired resistance leading to lethal recurrent lesions associated with robust tumor cell invasion. While a great deal is known about genes and pathways that promote GBM proliferation and neovascularization, relatively little is understood about mechanisms that drive GBM cell invasion during progression or following anti-angiogenic therapy. Here, we report that PTP-PEST, a cytoplasmic protein tyrosine phosphatase encoded by the PTPN12 gene, controls GBM cell invasion by physically bridging the focal adhesion protein Crk-associated substrate (Cas) to valosin containing protein (Vcp), an ATP-dependent protein segregase that selectively extracts ubiquitinated proteins from multiprotein complexes and targets them for degradation via the ubiquitin proteasome system. Both Cas and Vcp are substrates for PTP-PEST, with the phosphorylation status of tyrosine 805 (Y805) in Vcp impacting affinity for Cas in focal adhesions and controlling ubiquitination levels and protein stability. Perturbing PTP-PEST-mediated phosphorylation of Cas and Vcp led to alterations in GBM cell invasive growth in vitro and in pre-clinical mouse models generated with GBM stem cells. Furthermore, acquired resistance to bevacizumab correlates with reduced expression of PTP-PEST in invasive GBM cells. Collectively, these data reveal a novel regulatory mechanism involving PTP-PEST, Vcp, and Cas that dynamically balances phosphorylation-dependent ubiquitination of key focal proteins involved in GBM cell invasion.
NIMG-79. EARLY TREATMENT RESPONSE ASSESSMENT USING O-(2-18F-FLUOROETHYL)-L-TYROSINE (FET) PET COMPARED TO MRI IN MALIGNANT GLIOMAS TREATED WITH ADJUVANT TEMOZOLOMIDE CHEMOTHERAPY
Authors: Garry Ceccon, Philipp Lohmann, Caroline Tscherpel, Veronika Dunkl, Marion Rapp, Gabriele Stoffels, Ulrich Herrlinger, Jurij Rosen, Michael Wollring, Nadim J Shah, Gereon R Fink, Karl-Josef Langen, Norbert Galldiks
Journal: Neuro-Oncology (2018)

The goal of this prospective study was to compare the value of conventional MRI and O-(2-18F-fluoroethyl)-L-tyrosine (FET) PET for response assessment in patients with malignant glioma treated with first-line adjuvant temozolomide chemotherapy (TMZ). After biopsy/resection and completion of radiotherapy with concomitant temozolomide, 34 malignant glioma patients (glioblastoma, n=31; IDH-wildtype anaplastic astrocytoma, n=2; H3K27-mutated midline glioma, n=1) (age range, 20–66 years) were subsequently treated with adjuvant TMZ (5/28). FET-PET scans were performed at baseline and after 10–12 weeks. The first follow-up MRI after radiotherapy (9 ± 3 weeks) was compared with the early postoperative MRI. We obtained FET metabolic tumor volumes (MTV) and tumor/brain ratios (TBR). Threshold values of FET-PET parameters for treatment response were established by ROC analyses using the progression-free survival (PFS) ≤/>9 months as reference. MRI response assessment was based on RANO criteria. The predictive ability of FET-PET thresholds and MRI changes on early response assessment was evaluated subsequently concerning PFS using univariate survival estimates. Relative TBR changes were not predictive for a PFS>9 months (P>0.05), whereas the absolute MTV at follow-up significantly predicted a PFS>9 months (P=0.016; threshold, 14.5 ml). The relative MTV change enabled the most significant PFS prediction. Responders defined by relative MTV changes (threshold, ≤0%) had a significantly 2-fold longer PFS than non-responders (16 vs. 8 months, P=0.003). RANO criteria at the first follow-up MRI after radiotherapy were not predictive for a PFS>9 months (P=0.260). CONCLUSIONS: FET-PET appears to be useful for identifying responders to adjuvant TMZ early after treatment initiation.
RTHP-37. IMPACT OF 11C-METHIONINE/FDG DURAL TRACER PET-BASED, COMPARED WITH MRI-BASED TARGET DELINEATION OF MALIGNANT GLIOMAS FOR RADIATION PLANNING
Authors: Takero Hirata, Manabu Kinoshita, Keisuke Tamari, Yuji Seo, Osamu Suzuki, Nobuhide Wakai, Takamune Achiha, Toru Umehara, Hideyuki Arita, Naoki Kagawa, Yonehiro Kanemura, Eku Shimosegawa, Naoya Hashimoto, Jun Hatazawa, Haruhiko Kishima, Teruki Teshima, Kazuhiko Ogawa
Journal: Neuro-Oncology (2018)

Precise delineation of target volume for radiotherapy of malignant glioma is one of the crucial processes in glioma treatment. Although MRI is the modality often chosen for this procedure, the authors’ previous research showed that combined use of 11C-methionine (MET) and 18F-fluorodeoxyglucose (FDG) PET was more accurate for glioma visualization (J Nucl Med, 2012). The aim of this study was to analyze volumetric and geometrical properties of RT-target-delineation based on MET/FDG PET and to compared them with those based on MRI. The impact of geometrical properties on progression free survival was further investigated. Twenty-five patients with a diagnosis of malignant glioma were included in our study. Three target volumes were compared, which included contrast-enhancing core lesions identified by contrast-enhanced T1 weighted images (T1Gd), high intensity lesions on T2 weighted images, and lesions showing high DS, a cell density score calculated from MET/FDG PET (> 3; hDS). T1Gd with 2.0 cm margin was able to cover the entire hDS only in 6 (24%) patients, indicating microscopic invasion of glioma cells beyond 2cm from gadolinium-enhanced core. Insufficient coverage of high DS region with RT target volume was suggested to be a risk for out-field recurrence. Higher coverage of hDS (T1Gd + 2/hDS) by T1Gd with 2 cm margin tended to positively impact overall and progression free survival. Cox regression analysis demonstrated that low coverage of hDS by T1Gd with 2 cm margin was predictive of tumor recurrence outside gadolinium-enhanced core, indicative of out-field reoccurrence. Present findings indicate that MRI is inadequate for target delineation for radiation therapy in malignant glioma treatment. Expanding additional margins to MRI based target volume often reduces this uncertainty while unnecessarily irradiated regions increase and MET/FDG PET seemed to provide more accurate information for target delineation than MRI.
Multiple Arterial Grafting Is Associated With Better Outcomes for Coronary Artery Bypass Grafting Patients
Authors: Rodolfo V. Rocha, Derrick Y. Tam, Reena Karkhanis, Rashmi Nedadur, Jiming Fang, Jack V. Tu, Mario Gaudino, Alistair Royse, Stephen E. Fremes
Journal: Circulation (2018)

Background: Observational studies have shown better survival in patients undergoing coronary artery bypass grafting (CABG) with 2 arterial grafts compared with 1. However, whether a third arterial graft is associated with incremental benefit remains uncertain. We sought to analyze the outcomes of 3 versus 2 arterial grafts during CABG. As a secondary objective, we compared CABG with 2 or 3 arterial grafts (multiple arterial grafts [MAG]) with CABG using a single arterial graft (SAG). Methods: Retrospective cohort analyses of all patients undergoing primary isolated CABG in Ontario, Canada, from October 2008 to March 2016. Propensity score matching was performed between patients with 3 arterial grafts (3Art group) versus 2 (2Art group). The primary outcome was time to first event of a composite of death, myocardial infarction, stroke, and repeat revascularization (major adverse cardiac and cerebrovascular events). Additional analyses were performed to evaluate the association between MAG versus SAG and long-term outcomes using propensity score matching. Results: Fifty thousand, two hundred thirty patients underwent isolated CABG during our study period; 3044 (6.1%) and 8253 (16.4%) patients had 3 and 2 arterial grafts, respectively, resulting in 2789 propensity score matching pairs for the primary analyses. Mean and maximum follow-up was 4.2 and 8.5 years, respectively. Radial artery grafting was more common in the 3Art versus 2Art group (79.3% versus 65.6%, P &lt;0.01). In-hospital outcomes were not significantly different, including death (3Art 0.8% versus 2Art 0.5%, P =0.26). Up to 8 years, there were no differences in major adverse cardiac and cerebrovascular events (3Art 27%, 95% confidence interval [CI], 24% to 30% versus 2Art 25%, 95% CI, 22% to 28%; hazard ratio [HR], 1.08, 95% CI, 0.94–1.25), death (HR, 1.08; 95% CI, 0.90–1.29), myocardial infarction (HR, 1.15; 95% CI, 0.87–1.51), stroke (HR, 1.39; 95% CI, 0.95–2.06), or repeat revascularization (HR, 1.04; 95% CI, 0.82–1.32). When evaluating MAG versus SAG, 8629 patient pairs were formed using propensity score matching. At 8 years, cumulative incidences of major adverse cardiac and cerebrovascular events (HR, 0.82, 95% CI, 0.77–0.88), survival (HR, 0.80; 95% CI, 0.73–0.88), repeat revascularization (HR, 0.79; 95% CI, 0.69–0.90), and myocardial infarction (HR, 0.83; 95% CI, 0.72–0.97) were superior in the MAG group. Conclusions: CABG with 3 arterial grafts was not associated with increased in-hospital death nor with better clinical outcomes at 8-year follow-up, compared with CABG with 2 arterial grafts. MAG was associated with superior outcomes compared with SAG.
IMMU-36. IMMUNE RESPONSES IN CANINE GLIOMAS ARE ENRICHED AT THE INFILTRATING EDGE OF ASTROCYTOMAS
Authors: Cynthia Kassab, Jonathan Levine, Beth Boudreau, Xiaoyang Ling, Jared K Burks, Shouhao Zhou, Roel Verhaak, Amy Heimberger
Journal: Neuro-Oncology (2018)

Immune competent spontaneously-arising gliomas in canines could be used to robustly vet immune therapeutic strategies, yet the immune composition in these CNS tumors has not been well characterized. Furthermore, few studies have examined the differences in immune reactivity between different areas of the tumor microenvironment such as the hypoxic core or the infiltrating edge. Immunohistochemistry was used to analyze the distribution of CD3+, CD4+, and CD49a (tissue-resident memory) T cells, CD14+ monocytes, and IBA-1+ macrophages/microglia (incorporating their skew to M2 macrophages based on CD163 expression) in various tumor compartments including at the invasive edge and within the tumor or necrotic center. Tissue segmentation of canine oligodendrogliomas (n=4) and astrocytomas (n=7) was performed at 20x (0.75 NA) magnification using Perkin Elmer Vectra 3 and InForm software (Ver 2.2). Bayesian multilevel logistic regression was used to assess the immune reactivity in the various tumor compartments. Among the various immune populations, canine gliomas were most populated with macrophages, which constituted between 20%-30% of the total cellular population—similar to human gliomas. The macrophages were enriched at the invasive edge (OR, 1.63; 95% CI, 1.61 to 1.65). Monocytes were the next most frequent immune cell population followed by CD3, CD4, and CD49a, with all the T-cell types being rare in all tumor compartments. CD3 (OR, 1.86; 95% CI, 1.01 to 3.87), CD4 (OR, 6.2; 95% CI, 1.22 to 200), and CD163 (OR, 2.75; 95% CI, 1.12 to 37.17) at the invasive edge and CD49a (OR, 1.99; 95% CI, 1.09 to 5.19) within the tumor were more common in astrocytomas than oligodendrogliomas. The necrotic core was almost exclusively infiltrated with macrophages and monocytes. Astrocytic tumors are more immunogenic than oligodendrogliomas in canine models and are highly enriched with macrophages that predominate at the infiltrating edge.