tbuckley/cabot-search huggingface dataset:
P14.108 Bevacizumab versus alkylating chemotherapy in recurrent glioblastoma
Authors: K Seystahl, B Hentschel, S Loew, D Gramatzki, J Felsberg, U Herrlinger, M Westphal, G Schackert, N Thon, U Schlegel, M Tatagiba, T Pietsch, G Reifenberger, M Löffler, W Wick, M Weller
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND The use of alkylating chemotherapy versus bevacizumab for recurrent glioblastoma remains controversial. Here we tested the hypothesis that the activity of alkylators, but not that of bevacizumab, would be associated with the O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status PATIENTS AND METHODS We analyzed a cohort of patients treated at centers of the German Glioma Network or the University Hospital Zurich with alkylating agent-based chemotherapy (n=260) or bevacizumab without or with irinotecan (n=84) for first recurrence of glioblastoma. Outcome was stratified for MGMT status and cross-over to bevacizumab or alkylators at further tumor progression. RESULTS Median post-recurrence survival-1 (PRS-1) for patients receiving alkylating agent chemotherapy at first recurrence was longer than for patients receiving bevacizumab (11.1 versus 7.4 months, p&lt;0.001). The use of alkylating agents was associated with longer PRS-1 for patients with a methylated versus an unmethylated MGMT promoter (p=0.017). For patients receiving bevacizumab, PRS-1 was not different with or without MGMT promoter methylation. PRS-1 was longer in the group receiving alkylating chemotherapy compared to bevacizumab for patients with a methylated (p&lt;0.001) or unmethylated MGMT promoter (p=0.034). For patients with alkylators at first recurrence receiving bevacizumab at any further recurrence, PRS-1 was longer than in patients receiving bevacizumab first and alkylators thereafter (p=0.002). CONCLUSION This study confirms limited value of bevacizumab in recurrent glioblastoma independent of MGMT status. Alkylating agents have activity in recurrent glioblastoma, especially in the context of a methylated MGMT promoter.
Do Not Learn a Technique, Learn the Biology Underlying the Disease: Techniques Evolve, Biology Prevails
Authors: Marco Moschini, Shahrokh F. Shariat, Peter Black, Ashish M. Kamat, Armando Stabile, Xavier Cathelineau, Wassim Kassouf, Bernard H. Bochner, Evanguelos Xylinas, Morgan Roupret, Stephen A. Boorjian, James W. Catto, Rafael Sanchez-Salas
Journal: European Urology (2019)
OS6.3 The complex role of lactate dehydrogenases in glioblastoma development
Authors: T Daubon, J Guyon, T Chouleur, H Espedal, C Leon, R Bjerkvig, A Bikfalvi
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Glioblastomas are among the most malignant primary brain tumors. GBMs are highly angiogenic, exhibit invasive growth, and elevated glycolysis. Under glycolytic conditions, glucose from the blood is metabolized in astrocytes into lactate by LDHA, and exported by MCT4 into the extracellular compartment, inducing a concomitant acidification of the microenvironment. LDHB, generally expressed in oligodendrocytes or neurons, metabolizes lactate into pyruvate for generating ATP in mitochondria. LDH expression was reported to be linked to phenotypic modifications in vitro in GBMs but the mechanisms and the precise role in vivo have not yet been investigated. MATERIAL AND METHODS We designed LDHA and LDHB Crispr-Cas9 constructs for infecting glioblastoma stem-like cells. Results: In vitro tumor cell invasion was not significantly impaired in sgLDHA glioblastoma cells, even under extreme hypoxic conditions. Tumor development was moderately impacted in terms of invasion or vascular density. We then explored the role of LDHB in these processes. LDHB knock-out cells had decreased invasive properties in vitro but surprisingly tumors were highly hemorrhagic and angiogenic, supporting a role of tumor-derived LDHB in blood vessel development. We furthermore evaluated the consequences of a double LDHA and LDHB knock-out in the glioma cells. Under hypoxic conditions, sgLDHA/B cell invasion was dramatically decreased in comparison to control cells, and apoptosis was also increased. Tumor development was dramatically impaired for LDHA/LDHB knockout tumors. CONCLUSION These results indicate the complex role of LDH enzymes in glioblastoma development. It constitutes the basis for further mechanistical studies linking lactate metabolism to brain tumor development and perturbation of the neuro-vascular microenvironment.
OS12.6 Intracranial GBM PDX Mutations Induced by Temozolomide Treatment
Authors: C James, C Horbinski, E Bartom, K Burdett, D Scholtens, A Ahmed
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Temozolomide (TMZ) is routinely used in the post-surgical treatment of patients with newly diagnosed glioblastoma (GBM). Nearly all GBM recur following TMZ treatment, and there is an increasing body of data that detail TMZ-associated mutations in recurrent GBM. In vivo models of recurrent GBM are scarce in comparison to models of treatment-naïve GBM. MATERIAL AND METHODS Mice with intracranial treatment naïve GBM patient derived xenograft (PDX) were treated with radiotherapy (RT) only, TMZ only, or RT + TMZ. Tumors were monitored for recovery from treatment by bioluminescence imaging (BLI), and upon animal subject decline due to growing tumor, subjects were euthanized, with viable intracranial tumor dissected and used to establish subcutaneous tumor in new animal hosts that received no treatment. Subcutaneous tumors were sequentially passaged through two additional animal hosts. DNA was extracted from third passage subcutaneous tumors and subjected to full exome sequencing. PDX exome sequence data were examined for genes with nonsynonymous frameshift and nonsense variants (mutations). RESULTS Exome sequence analysis showed striking differences between PDX receiving RT only vs. TMZ with or without RT. Most notable is the substantially greater incidence of G-C to A-T transition mutations in TMZ-treated PDX, which are a signature of TMZ treatment. All TMZ-treated PDX also showed substantially more genes being mutated than PDX receiving RT only: one cycle RT only = 88; one cycle TMZ only = 339; one cycle of concurrent RT + TMZ = 531; one cycle of concurrent RT + TMZ followed by two additional cycles of TMZ only = 1502. The PDX subjected to multiple cycles of TMZ treatment prior to establishment as a subcutaneous tumor has shown stable resistance to TMZ treatment in subsequent experiments. Importantly, TMZ-treated PDX had mutations in LTBP4, MSH6, and PREX1 genes that are enriched in patient GBM following recurrence after initial TMZ treatment (Nat Genet 2016;48:768–76); these genes were not mutated in PDX receiving RT only. CONCLUSION Our study results support the following: 1) Intracranial GBM PDX treated with TMZ develop a global genomic treatment signature, as well as specific mutations that are observed in recurrent patient GBMs; 2) Mutations detected in TMZ-treated intracranial tumors are stable, persisting after repeated subcutaneous passages without further treatment; 3) Paired naïve and TMZ-treated GBM PDX will facilitate studies aimed at increasing our understanding of TMZ resistance, and help identify new therapies for more effective treatment of recurrent GBM.
JS1.2 Increased frequency of paraneoplastic encephalitis with anti-Ma2 antibodies in the cancer immunotherapy era
Authors: A Vogrig, M Fouret, B Joubert, G Picard, V Rogemond, A Pinto, S Muñiz Castrillo, M Roger, J Raimbourg, C Dayen, L Grignou, M Pallix-Guyot, J Lannoy, F Ducray, V Desestret, D Psimaras, J Honnorat
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Given the mechanism of action of immune checkpoint inhibitors (ICIs), a possible association with the development of paraneoplastic neurological syndromes (PNS) has been hypothesized. We sought to determine if ICI treatment might trigger anti-Ma2 antibody-associated paraneoplastic neurological syndromes (Ma2-PNS). MATERIAL AND METHODS We performed a retrospective nationwide study of all patients with Ma2-PNS developed during ICI treatment between 2017–2018. The frequency of neuronal-antibody detection before and after ICI implementation was also analyzed. RESULTS Our series of patients included 5 men and 1 woman (median age, 63 years). The patients were receiving either nivolumab (n = 3), pembrolizumab (n = 2) or a combination of nivolumab and ipilimumab (n=1), for treatment of neoplasms that included lung (n=4) and kidney (n=1) cancers, and pleural mesothelioma (n=1). Median delay between ICI introduction and onset of the neurological syndrome was 4 months. Clinical syndromes included a combination of limbic encephalitis and diencephalitis (n=3), isolated limbic encephalitis (n=2) and a syndrome characterized by opthalmoplegia and head-drop (n=1). Patients with diencephalitis manifested hyperphagia, weight gain and somnolence. Post-ICI Ma2-PNS accounted for 35% of the total 17 Ma2-PNS diagnosed in our center over the 2017–2018 biennium. Eight cases had been detected in the preceding biennium 2015–2016, corresponding to a 112% increase of Ma2-PNS frequency since the implementation of ICIs in France. No other neuronal-antibody demonstrated a similar increment. CONCLUSION We show a clear association between ICI use and increased frequency of Ma2-PNS. Physicians need to be aware that ICIs can trigger Ma2-PNS since clinical presentation can be challenging.
Clinical Validation of <i>PBRM1</i> Alterations as a Marker of Immune Checkpoint Inhibitor Response in Renal Cell Carcinoma
Authors: David A. Braun, Yuko Ishii, Alice M. Walsh, Eliezer M. Van Allen, Catherine J. Wu, Sachet A. Shukla, Toni K. Choueiri
Journal: JAMA Oncology (2019)

Clinical Validation of
P14.71 Tumor Treating Fields combined with radiotherapy and temozolomide for newly diagnosed glioblastoma: final safety and efficacy results from a pilot study
Authors: R Grossman, F Bokstein, D Blumenthal, C Ben Harush, D Limon, Z Ram
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Tumor Treating Fields (TTFields) are a non-invasive, loco-regional, anti-mitotic treatment consisting of low intensity alternating electric fields. The combination of TTFields with maintenance temozolomide significantly improved survival versus temozolomide alone in the phase 3 EF-14 study in newly diagnosed glioblastoma (ndGBM). In preclinical studies, TTFields increased the number of glioma cells undergoing cellular death following radiotherapy (RT) by inhibiting DNA damage repair, suggesting a radio-sensitizing effect of TTFields. This pilot study is the first to evaluate the safety and feasibility of administering TTFields concomitant to RT and TMZ in ndGBM patients. MATERIAL AND METHODS Patients diagnosed with ndGBM were treated with TTFields/RT/TMZ followed by maintenance TMZ and TTFields for up to 24 months. TTFields (200kHz) were delivered for &gt;18 hours/day while the transducer arrays were removed during delivery of RT. TMZ was administered at a dose of 75 mg/m2/daily for 6 weeks and RT at a total dose of 60 Gy. The primary endpoint was safety of the combined TTFields/RT/TMZ; secondary endpoints included progression-free survival (PFS), overall survival (OS) and toxicity. Adverse events (AEs) were graded according to CTCAE V4.0. RESULTS 10 ndGBM patients that recovered from maximal debulking surgery or biopsy were enrolled at a single center in Israel between April and December 2017. Five patients (50%) had undergone gross total resection while the rest had biopsy only. Eight of the patients were male, median age was 59, median KPS was 80 and median dose of RT was 60 Gy. Six patients (60%) reported at least one AE. The most common AE was TTFields-related skin toxicity, reported in four patients (40%), all of which were grade 1–2 in severity. Two patients reported serious AEs (seizures and general deterioration) that were considered unrelated to TTFields. Median PFS with RT/TMZ/TTFields was 10.5 months. Median OS has not yet been reached. CONCLUSION The proportion of patients with TTFields-related skin toxicity was similar to that reported in ndGBM patients in the randomized Phase III study (52%), where patients started TTFields at least 4 weeks after RT. No other TTFields-related toxicities were reported and there were no increase in RT- or TMZ-related toxicities as a result of combining TTFields with RT in addition to TMZ. Based on the safety and preliminary efficacy results of this pilot study, a phase II randomized study has been initiated to investigate the efficacy of concomitant RT/TMZ/TTFields in 60 ndGBM patients.
A phase III trial of adjuvant chemotherapy following chemoradiation as primary treatment for locally advanced cervical cancer compared to chemoradiation alone: The OUTBACK TRIAL.
Authors: Linda R. Mileshkin, Kailash Narayan, Kathleen N. Moore, Danny Rischin, Edward Lloyd Trimble, Martin R. Stockler, Madeleine King, Ilka Kolodziej, Julie Martyn, Michael Friedlander, Michael Quinn, Shyam K Shrivastava, William Small, Gillian Thomas, Peter S Craighead, Val Gebski
Journal: Journal of Clinical Oncology (2012)

TPS5116 Background: Cervical cancer is a global health problem and the most common cause of cancer-related death among women in developing nations. Despite the recently developed cervical cancer vaccine, many women will continue to die from cervical cancer for many decades unless existing treatments can be improved. Unscreened women often present with locally-advanced disease that has a 5 year overall survival (OS) rate of 60% or less following standard chemo-radiation. Although some evidence suggests that adjuvant chemotherapy following chemo-radiation may be of value, its role remains controversial. Methods: OUTBACK is a randomized phase III Gynecologic Cancer InterGroup (GCIG) trial designed and led by the Australia New Zealand Gynaecological Oncology Group (ANZGOG) in collaboration with the NHMRC Clinical Trials Centre. Participating countries (groups) include Australia and New Zealand (ANZGOG), India, the USA and Canada (GOG, RTOG). OUTBACK is suitable for women with locally advanced cervical cancer (FIGO stage IB 1 and node positive, IB 2 , II, IIIB or IVA). The primary objective is to determine if the addition of adjuvant chemotherapy to standard cisplatin-based chemo-radiation improves OS. Women are randomized to either A) standard cisplatin-based chemo-radiation or B) standard cisplatin-based chemo-radiation followed by 4 cycles of carboplatin and paclitaxel chemotherapy. Secondary objectives are to compare progression-free survival, treatment-related toxicity, patterns of disease recurrence, quality of life and psycho-sexual health, and the association between radiation protocol compliance and outcomes. Blood and tumour samples are collected from consenting patients for future translational studies. 780 women will be enrolled to determine if the addition of adjuvant chemotherapy can improve the 5-year OS rate by ≥ 10%. OUTBACK opened in Australia and New Zealand in 2011. In early 2012 the trial opened in the USA and activation of GOG sites is ongoing. 15 patients have been randomized. It is expected that RTOG and India will open the trial later this year with recruitment increasing substantially once all sites are activated.
P14.61 Tumor Treating Fields (TTFields) combined with lomustine (CCNU) and temozolomide (TMZ) in newly diagnosed glioblastoma (GBM) patients - a bi-centric analysis
Authors: L Lazaridis, N Schäfer, T Schmidt, A Stoppek, J Weller, T Tzaridis, B Scheffler, D Pierscianek, C Kleinschnitz, M Stuschke, U Sure, U Herrlinger, S Kebir, M Glas
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND TTFields combined with TMZ demonstrated significantly improved PFS, OS and long-term survival in newly diagnosed glioblastoma (ndGBM) patients, compared to TMZ monotherapy in the EF-14 trial; independent of MGMT-promotor methylation-status, age, grade of resection and performance status. Recently, improved efficacy of lomustine (CCNU)/TMZ compared to TMZ monotherapy in ndGBM patients with MGMT-promotor methylation was reported in the CeTeG trial (NOA-09). Taken into account that TTFields showed a strong safety profile as well as a high potential being combined with other modalities and the very encouraging results for methylated MGMT-promotor GBM patients in the CeTeG trial, there is a strong rationale in combining these treatment regimens. Here, we present a case series of patients receiving a combination of both modalities, TTFields and CCNU/TMZ. METHODS Patients with ndGBM and MGMT-promotor methylation underwent a combined therapy of TTFields plus CCNU/TMZ after surgery and radiochemotherapy. Safety, feasibility as well as first efficacy results of this combined therapy are reported at data cut-off (31.12.2018). Most recent data, including compliance to TTFields therapy, will be presented at the EANO annual meeting. RESULTS Twelve patients with MGMT-promotor methylated ndGBM (median, range: age 49.5, 26–69; KPS 90, 60–100) have been treated with a combination of TTFields plus CCNU/TMZ. The analysis included patients with complete resection (n=6), partial resection (n=5) as well as biopsy (n=1). CTCAE grade 3 hematotoxicities were observed in six patients, but were not considered to be related to the addition of TTFields to lomustine/TMZ. Medical device site reactions (low-grade skin reactions) were detected in five patients. At data cut-off, the analyzed patient population demonstrated a median PFS of 18.7 months, whereas the median OS was not yet reached. CONCLUSION The results of this analysis provide first indication that the combination of TTFields/lomustine/TMZ is safe and feasible. Moreover, the observed survival outcomes point to preliminary beneficial effects of the triple combination. Additional follow-up and a higher sample size is required and planned for further toxicity analysis and efficacy assessment of this combination.
Association of diabetes and kidney function according to age and systolic function with the incidence of sudden cardiac death and non‐sudden cardiac death in myocardial infarction survivors with heart failure
Authors: Stefano Coiro, Nicolas Girerd, Abhinav Sharma, Patrick Rossignol, Isabella Tritto, Bertram Pitt, Marc A. Pfeffer, John J.V. McMurray, Giuseppe Ambrosio, Kenneth Dickstein, Arthur Moss, Faiez Zannad
Journal: European Journal of Heart Failure (2019)
Placental growth factor contributes to bronchial neutrophilic inflammation and edema in allergic asthma
Authors: Sonja Bobic, Sven Seys, Vanessa De Vooght, Ina Callebaut, Valérie Hox, Christophe Dooms, Jean-Marie Saint-Remy, Dominique Bullens, Jan Ceuppens, Peter Hellings
Journal: Allergy (2012)
OS3.2 Relevant topics for brain tumor patients in the Distress Thermometer, first results of the HEAT study
Authors: M Renovanz, J Coburger, G Tabatabai, F Ringel, C Wirtz, M Mehdorn, S Goebel
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Patient-centered assessments and disease-adjusted patient-reported outcome measures (PROMs) are crucial in neuro-oncology. The Distress Thermometer (DT) is a well-accepted screening tool for cancer patients including a numerical rating scale (1–10, cut-offs indicating relevant distress ≥4–6) and 40 items describing possible problem categories (emotional, social, physical, practical and spiritual). The aims of the first part of the “Adaption of the Distress Thermometer in patients with intracranial tumors” (HEAT) study were to evaluate the importance and relevance of items for brain tumor patients (BTP). MATERIAL AND METHODS The multicenter study included three University hospitals. After given informed consent patients were prospectively evaluated either during their hospital stay or in the outpatient setting using DT as well as the 40 item problem list. Clinical and demographic data were recorded. We performed an analysis regarding frequency of indicated topics and evaluated their relevance for patients’ psychosocial well-beings via Pearson correlations with the DT score. RESULTS Data of n = 670 patients were analyzed. Mean age was 52 years (SD = 14, range 18–81), most of the patients harbored WHO°I tumors (37%) and WHO°IV tumors (28%). Male to female ratio was 1:1, 17% were assessed preoperatively, 40% postoperatively and 43% during adjuvant therapy or follow-up. 14% of the patients faced a tumor recurrence at assessment. Mean score of DT was 5.23 (SD = 2.9, range 0–10). Applying a cut-off score ≥ 4, 61% reported distress (≥ 5: 46% and ≥ 6: 37%). Regarding the relevance of the problem list for BTP, emotional problems (e. g., anxiety, depression) were most frequently reported. A total of 14/40 (35 %) of items were endorsed by less than 10% of patients. With exception of emotional problems all areas were reflected: practical problems (e. g., problems with child care or insurance), social problems (e. g., problems with children), spiritual concerns (e. g., loss of faith), and physical problems (e. g., breathing, fever). However, some of these rarely reported problems were of relevance for patients’ psychosocial well-being as indicated by significant correlations between the respective item and the DT score. This was, for example, the case for problems with childcare (r = .106; p &lt; .01) or breathing (r = .125; p = .001). CONCLUSION Tools developed for cancer patients do not yet perfectly reflect all needs of BTP. Based on our data, we suggest further adjustments of available tools. Yet, it should be taken into account that subgroups of BTP may require different problem lists in the DT, as we observed some topics (e.g. breathing) probably be related to BTP under chemotherapy or steroids only. Moreover, our data require cross-cultural validation as especially results regarding practical problems and insurance might differ in cultures with different social security systems.
Antimicrobial Treatment for Viral and Related Infections
Authors: Maxwell Finland
Journal: New England Journal of Medicine (1952)

THE introduction of the broad-spectrum antibiotics and the demonstration that their effectiveness extends beyond the infections due to gram-positive and gram-negative bacteria to encompass those caused by the rickettsias and the viruses of the psittacosis-lymphogranuloma-trachoma group has raised hopes that these or other antibiotics might prove beneficial against a host of other infections known or assumed to be caused by viruses. Among many practitioners, however, the impression actually prevails, and has been expressed in many medical papers, that these antibiotics are effective against many or all viral infections. Numerous clinical case reports of favorable effects ascribed to these antibiotics in . . .