tbuckley/cabot-search huggingface dataset:
Bedaquiline: how better to use it
Authors: Jose A. Caminero, Alberto Piubello, Anna Scardigli, Giovanni Battista Migliori
Journal: European Respiratory Journal (2017)

We read with interest the correspondence by J. Furin and co-workers and we wish to thank them for their useful comments on our editorial proposing a rationale for a standardised regimen to manage difficult-to-treat cases affected by extensively drug-resistant tuberculosis (XDR-TB) or by so-called pre-extensively drug-resistant tuberculosis (pre-XDR; multidrug-resistant tuberculosis (MDR-TB) cases with additional resistance to fluoroquinolones or second-line injectable drugs) [1]. We agree with the comments by Furin and co-workers and the arguments discussing the possible use of the new drugs (bedaquiline and/or delamanid) for more than 6 months. Clinicians know very well how difficult it is to manage the treatment of these cases in view of their clinical complexity (with frequent adverse events), long duration and high cost [2–4]. Considering the new perspectives for treating MDR-TB and XDR-TB we fully agree that we are presently facing exciting times. We finally have a couple of new and repurposed drugs and we are slowly discovering how best to use them, as well as how effective and safe they are [4–7]. The necessary body of knowledge to support evidence-based recommendations will need time to be raised and this is reflected by the increase in new proposals and recommendations being issued [8, 9]. Among the different ingredients for a potential, future standardised regimen for MDR/XDR-TB cases, the biological plausibility of the core drugs to be used (bactericidal and sterilising) is particularly important (table 1) [1]. As both bedaquiline and delamanid have excellent characteristics, both their prolonged and/or combined use will be challenges that will need to be faced in the future. Slowly but surely new evidence is becoming available [2, 3] and we are confident that, given the high morbidity and mortality caused by MDR/XDR-TB, as well as the collaborative spirit animating clinicians, public health officers, policy makers, donors and members of the affected communities, better evidence will be raised to always ensure that the patient is adequately protected. Finally, the "off-label" use of drugs is sometimes necessary to manage patients for whom no other alternatives exist. Their use requires adequate capacity in terms of clinical expertise, laboratory support and infection control measures. We therefore hope that our proposal will soon be supported by the necessary evidence so as to be useful, safe and effective. Reflections on the best possible use of bedaquiline <http://ow.ly/JiFL30fBZaQ>
Focus on metastatic right-sided colon cancer: the best overall response to the first-line non-EGFR treatment correlates with better overall survival
Authors: F. Abbati, M. Massucci, V. Mollica, A. Palloni, M.A. Barbera, G. Frega, M. Ferracin, E. Porcellini, G. Brandi, G. Biasco, I. Garajová
Journal: Annals of Oncology (2017)
P2.09-003 Dissecting the Immune Environment in Malignant Pleural Mesothelioma: Results from a Prospective Assessment
Authors: C. Riganti, M. Pradotto, L. Righi, C. Marchiò, E. Capelletto, C. Buttigliero, L. Costardi, J. Kopecka, P. Bironzo, E. Ruffini, S. Novello, G. Scagliotti
Journal: Journal of Thoracic Oncology (2017)
Activités de surveillance de la sensibilité de la grippe aux antiviraux au regard des stocks d’antiviraux des États membres en Europe au cours de l’hiver 2006/2007
Authors: A Meijer, A Lackenby, A Hay, M Zambon
Journal: Eurosurveillance (2007)

En raison de la menace d’une pandemie grippale, de nombreux pays constituent des stocks d’antiviraux dans l’espoir de limiter l’impact d’un eventuel virus pandemique. Si l’on considere qu’une resistance aux medicaments antiviraux affecterait probablement leur efficacite, on comprend que les programmes de surveillance destines a surveiller l’emergence d’une telle resistance sont de la premiere importance.
Severity of Neuropathy Is Associated With Long-term Spinal Cord Stimulation Outcome in Painful Diabetic Peripheral Neuropathy: Five-Year Follow-up of a Prospective Two-Center Clinical Trial
Authors: Maarten van Beek, José W. Geurts, Rachel Slangen, Nicolaas C. Schaper, Catharina G. Faber, Elbert A. Joosten, Carmen D. Dirksen, Robert T. van Dongen, Sander M.J. van Kuijk, Maarten van Kleef
Journal: Diabetes Care (2017)

OBJECTIVE Evidence from prospective studies for long-term treatment efficacy of spinal cord stimulation (SCS) in painful diabetic peripheral neuropathy (PDPN) is not available. We report prospective data on the effect of SCS on pain ratings, treatment success and failure, and complications during a 5-year follow-up in patients with PDPN. RESEARCH DESIGN AND METHODS Patients with PDPN (n = 48) were included in this prospective multicenter study. The Michigan Diabetic Neuropathy Score (MDNS) was used to assess the severity of neuropathy. Numerical rating scale (NRS) score for pain, Patient’s Global Impression of Change (PGIC), and treatment success (50% reduction of NRS score or significant PGIC) during 5 years of follow-up were evaluated. Complications of SCS were reported, and associations between baseline characteristics and SCS trial success or failure during a 5-year follow-up were investigated by using survival analyses. RESULTS Treatment success was observed in 55% of patients after 5 years. Median duration of SCS treatment was 60 months (minimum 1 month, maximum 60 months), and 80% of patients with a permanent implant still used their SCS device after 5 years. Higher MDNS was associated with treatment failure during the 5-year follow-up (hazard ratio 3.9 [95% CI 1.3–11.6]; P = 0.014). CONCLUSIONS SCS is successful in reducing chronic pain symptoms in the lower extremities of patients with PDPN up to 5 years after initiation of treatment. Furthermore, 80% of patients with PDPN still use their SCS device after 5 years. Moreover, the severity of neuropathy is associated with a higher chance of long-term treatment failure during a 5-year follow-up.
EXTH-42. H3 K27M MUTANT GLIOMAS ARE SELECTIVELY KILLED BY ONC201, A SMALL MOLECULE INHIBITOR OF DOPAMINE RECEPTOR D2
Authors: Andrew S Chi, James M Stafford, Namita Sen, Richard Possemato, Dimitris Placantonakis, Eveline Teresa Hidalgo, David Harter, Jeffrey Wisoff, John Golfinos, Isabel Arrillaga-Romany, Tracy Batchelor, Patrick Wen, Hiroaki Wakimoto, Daniel Cahill, Joshua E Allen, Wolfgang Oster, Matija Snuderl
Journal: Neuro-Oncology (2017)

Histone H3 K27M mutations distinguish a subgroup of midline gliomas in children and young adults with devastating prognosis for which there are no effective medical therapies. In a recent phase 2 trial in adult recurrent glioblastoma with ONC201, a small molecule selective antagonist of the dopamine receptor D2 (DRD2) and D3 (DRD3), a 22 year old female with recurrent H3 K27M mutant glioblastoma had tumor regression of 92% that has persisted >15 months. Furthermore, antiseizure medication was discontinued and no ONC201 side effects were observed. Based on this exceptional response, we tested whether H3 K27M mutant gliomas were selectively sensitive to ONC201-induced apoptosis. We tested the effect of ONC201 on the cell viability of a panel of patient-derived glioma tumorsphere lines, including four H3 K27M mutant diffuse intrinsic pontine gliomas (two HIST1H3B and two H3F3A mutant), two H3F3A G34R mutant glioblastomas, and five H3 K27M/G34R wildtype (2 pediatric, 3 adult) glioblastomas. We analyzed expression of DRD2, the target of ONC201, in adult glioblastoma (n=24), pediatric H3 K27M wildtype glioblastoma (n=3) and H3 K27M mutant glioblastoma (n=8) archival tumor tissue using RNASeq. ONC201 was most potently cytotoxic to H3 K27M mutant lines (median IC50 ~0.4 uM) and had modest activity against H3 K27M/G34R wildtype lines (median IC50 ~1.2 uM), while H3 G34R lines were relatively resistant (median IC50 > 10 uM). DRD2 expression was significantly increased in H3 K27M mutant glioblastoma archival tumors relative to H3 K27M wildtype adult/pediatric gliomas. H3 K27M mutant patient-derived glioma tumorspheres appear selectively sensitive to ONC201 in vitro. Expression of DRD2 is comparatively increased in H3 K27M mutant versus wildtype gliomas. Studies to further characterize the impact of DRD2 inhibition in H3 K27M mutant glioma are ongoing, however these preliminary data indicate ONC201 may have clinical utility in H3 K27M mutant gliomas.
SURG-27. PREDICTORS OF LOCAL CONTROL OF POST SRS BRAIN METASTASIS TREATED WITH LITT
Authors: Dhiego Chaves De Almeida Bastos, Ganesh Rao, Jeffrey S Weinberg, David Thomas Alfonso Fuentes, Jason Stafford, Sujit S Prabhu
Journal: Neuro-Oncology (2017)

Laser Interstitial Thermal Therapy has been used to treat both recurrent brain metastases after SRS and radiation necrosis, with a good success rate. to evaluate the predictive factors associated with local recurrence after LITT in patients with brain metastasis after use of SRS with signs of progressive disease. METHODOLOGY: Single institution retrospective study with consecutive patients presenting with progressive disease after SRS for brain metastasis. Clinical, demographic and volumetric data were acquired. The primary end point was local recurrence. 56 patients were included, comprising 76 lesions previously treated with SRS. Patients were radiologically classified as presenting with radiation necrosis (35.5%), recurrence (47.4%) or unspecific progression (17.1%). Breast (30.3%), melanoma (21.1%) and NSCLC (25%) were the most common tumor primary histology. Dural based lesions were present in 26.3%, complete ablation was achieved in 65.8%, local recurrence happened in 31.6%, with a mean PFS of 19.5 months (SD 1.7). NSCLC had the worst PFS time with 10.1 months (p=0.33). Patients presenting with radiologically suggestive recurrence disease had the shortest PFS (13 months, p=0.076). Lesions with less than 6cc had the longest PFS (17.2) when compared with lesions with volumes larger than 6cc (11.6 months) (p=0.42). Dural based lesions had shorter PFS when compared to non-dural based lesions (23.4 x 9.2 months, respectively) (p=0.01). Lesions that were completely ablated had a PFS of 24.7 months, in comparison with incomplete ablated lesions (8.7 months) (p<0.01). Multivariate proportional hazard regression analysis showed a HR of 2.4 for breast or NSCLC histology (p=0.09), 2.2 for dural based lesions (0.093) and 0.3 for completed ablated lesions (p=0.023). There is evidence that the primary tumor histology, brain metastasis relation with the dura-mater and the extension of the ablation (complete x incomplete) are the major factors impacting the local recurrence rate.
ANGI-11. DIRECT GLIOMA BLOOD VESSEL DISRUPTION IMPROVES IMMUNE THERAPY BUT WORSENS ANTI-VEGF THERAPY
Authors: Viveka Nand Yadav, Padma Kadiyala, Dan Zamler, Andrew Gutierrez, Carl Koschmann, Maria G Castro, Pedro R Lowenstein
Journal: Neuro-Oncology (2017)

Glioblastoma is the most vascularized and aggressive glioma with a median survival of less than 2 years. Despite promising clinical trials inhibiting vascular endothelial growth factor (VEGF) failed to improve patient survival. We used Tie2p/e LV [Tie2-TK-IRIS-GFP] mice which express the conditionally cytotoxic gene thymidine kinase (TK) under the control of endothelial-specific Tie2 promoter. Administration of gancylovir (GCV) for 7 days disrupts reactive, proliferating blood vessels within the tumor. We implanted mice with NRAS/shp53 (NP) GBM neurospheres. Three days later mice were treated with GCV to kill reactive tumor vessels. GCV prolonged survival by delaying tumor proliferation and increasing tumor necrosis. GCV administration decreased blood vessel density in the center but not in the tumor peripheral. GCV mediated blood vessel disruption resulted in tumor cell death. To further increase tumor cell death and develop anti-tumor immune responses, we used TK+Flt3L adenoviruses mediated immune therapy to increase mouse survival. We found that combination of tumor blood vessel disruption by GCV, and TK/Flt3L immune therapy, significantly extended the survival of mice compared to GCV therapy alone. Furthermore, adding radiation therapy to the GCV/TK+Flt3L immune therapy further enhanced mouse survival. We assumed that if anti-VEGF therapy effectively induces tumor blood vessel normalization then this could further increase the efficacy of TK+Flt3L therapy by increasing immune cells infiltration into the tumor. However, combining anti-VEGF therapy with TK+Flt3L did not improve survival compared to each therapy alone suggesting that blood vessel disruption may actually decrease the efficacy of anti-VEGF therapy. Our results provide evidence that combining direct tumor blood vessel disruption, and TK/Flt3L immune therapy, represents a novel therapeutic approach for the treatment of GBM. We also demonstrate that blood vessel disruption limits the anti-tumor effect of anti-VEGF therapy. This could explain the recently described failure of anti-VEGF therapy in human GBM patients.
Abstract 21383: Associations of Childhood Traits to Adult Aortic Stiffness and Left Ventricular Hypertrophy Vary by Race: The Bogalusa Heart Study
Authors: Justin P Zachariah, Camilo Fernandez, Rupert Barshop, Emily Harville, Wei Chen, Lydia Bazzano
Journal: Circulation (2017)

Background: Aortic stiffness and left ventricular (LV) remodeling increases with age and accumulated CVD risk factors, which vary by race. We hypothesized that childhood risk factors are longitudinally associated with adult aortic stiffness and LV remodeling and that these associations vary by race in the biracial (black vs. white) Bogalusa Heart Study cohort. Methods: Participants sampled had at least three Study visits over the life course, ultrasound as young adults for aorta-femoral pulse wave velocity (afPWV), and echocardiographic LV mass (n=1081, 24-44 years old, 31% black, 57% female, and mean follow-up 27 years). Demographic, anthropometric, blood pressure, lipid, glucose and tobacco exposure data were extracted from each visit. Given variable visit intervals and number, separate growth mixed models were used to compute total area under the curve for risk factor traits on the primary outcomes of interest, a) afPWV or b) LV mass indexed to height 2.7 (LVMI). Childhood trait to adult afPWV and LVMI associations, adjusted for cumulative trait levels, were examined with multivariable-adjusted linear regression. Significant race by trait interaction terms (p&lt;0.001) led to race-specific reporting. Results: Adult afPWV and LVMI were higher in black (5.4±1.2 m/s and 36.3±11.4 g/m 2.7 ) than white (5.2±1.1 and 33.8±9.2) participants (p=0.01). Higher adult afPWV was associated with childhood low density lipoprotein cholesterol (LDL-C, β 0.13;p&lt;0.001) and mean arterial pressure (MAP, 0.1;p=0.02). By race, higher afPWV was associated with childhood LDL-C in blacks (0.17;p&lt;0.01) and whites (0.1;p&lt;0.01) while MAP was associated only in whites (0.08;p=0.04). Adult LVMI was associated with childhood BMI (0.3; p&lt;0.001), triglycerides (TG, -0.08; p=0.04), and afPWV (0.10, p&lt;0.01). By race, higher LVMI was associated with childhood BMI in blacks (0.27; p&lt;0.001) and whites (0.34;p&lt;0.001), while LDL-C (0.1; p=0.02), TG (-0.14; p&lt;0.01), Glucose (0.12; p&lt;0.01), and afPWV(0.11,p&lt;0.01) were associated only in whites. Conclusions: Adult aortic stiffness and LV remodeling were associated with childhood traits, even after adjustment for cumulative trait levels. These associations appear to vary by race.
P1.03-020 Detection of Hypoxia Using EF5 PET/CT in 10 Patients with Advanced NSCLC Receiving Chemotherapy with and without Bevacizumab
Authors: F. Lacroix-Poisson, F. Benard, D. Wilson, M. Adam, D. Yapp, C. Ho, J. Laskin
Journal: Journal of Thoracic Oncology (2017)
P2.15-016 Clinical Significance of Topoisomerase-II Expression in Patients with Relapsed HGNEC of the Lung Treated with Amrubicin
Authors: Y. Miura, K. Kaira, R. Sakurai, Y. Tomizawa, Y. Tsukagoshi, T. Masuda, N. Kasahara, N. Sunaga, R. Saito, T. Hisada
Journal: Journal of Thoracic Oncology (2017)
P3.13-038 The RoaDmaP Study: Feasibility of Implementing a Primary Care Intervention for Referral of Potential Lung Cancer Cases to Specialist Care
Authors: N. Rankin, S. York, L. Trevena, J. Emery, P. Sundaresan, P. Beale, R. Zielinski, S. Vinod, T. Shaw
Journal: Journal of Thoracic Oncology (2017)
IMMU-12. THE HISTONE DEACETYLASE INHIBITOR VALPROIC ACID AUGMENTS THE SUSCEPTIBILITY OF ONCOLYTIC VIRUS-INFECTED GLIOBLASTOMA CELLS TO PD-1 BLOCKADE THERAPY
Authors: Quazim Alayo, Carmela Passaro, John McNulty, Nakashima Hiroshi, E Antonio Chiocca
Journal: Neuro-Oncology (2017)

Oncolytic Herpes Simplex Virus-1(oHSV1) is currently being tested in clinical trials for the treatment of recurrent glioblastoma. Our group has previously shown that valproic acid (VPA), a pan Histone Deacetylase inhibitor (panHDACi) increases the cytotoxic effect of oHSV within tumor cells. VPA has also been shown to significantly increase the survival of oHSV1-treated mice in orthotopic xenograft glioma model. With the increasing interest in combining oncolytic virotherapy with immune checkpoint blockade, the effect of VPA and oncolytic virotherapy on the expression of immune-stimulatory and immunoinhibitory molecules within the tumor micro-environment, and its impact on this combinatorial therapy is not known. Here, we show that VPA augments the expression of PD-L1 on oHSV1–infected mouse glioblastoma cell lines, rendering them particularly susceptible to PD-1 blockade therapy. We also found that VPA treatment prior to oncolytic virotherapy led to significant downregulation of MHC-I on infected tumour cells, therefore making the cells particularly more susceptible to NK cell killing. Indeed, our preliminary in-vivo studies show that VPA treatment augments the rescue of exhausted antigen-specific CD8 T cells in a model of chronic LCMV infection, further suggesting that VPA might enhance the response of tumor to oncolytic virotherapy and immune checkpoint blockade. Our data therefore provide a rationale for exploring the synergistic effect of HDACi on the efficacy of oncolytic HSV and immune checkpoint blockade in the treatment of glioblastoma.
EXTH-81. ACNU AS THE BEST NITROSOUREA FOR LOCAL CONVECTION-ENHANCED DELIVERY: REPORT ON PHARMACOKINETICS
Authors: Ryuta Saito, Jia Wenting, Aya Sato, Saori Okuno, Taigen Nakamura, Masashi Chonan, Rong Zhang, Masayuki Kanamori, Teiji Tominaga
Journal: Neuro-Oncology (2017)

Nitrosourea represents one of the effective chemotherapeutic agents against gliomas. Among clinically available Nitrosoureas; ACNU/BCNU/CCNU/MCNU, ACNU is the most hydrophilic agent. We have demonstrated that hydrophilic agents achieve robust tissue distribution when delivered locally with convection-enhanced delivery (CED). In this study, we studied the pharmacokinetics of the ACNU with local CED. After CED of ACNU mixed with evans-blue dye into rodent brain, distribution of ACNU was visualized using mass spectroscopy. Subsequently, radiolabeled ACNU was delivered locally with CED into rodent brain to determine the clearance of ACNU. Safety profile as well as effects on blood-brain barrier (BBB) with local delivery was studied in rodents. After CED into rodent brain, distribution of ACNU was almost identical to that of evans-blue. After local CED into rodent brain, radioactive ACNU was detected at the infusion site as long as 24 hrs. Local toxicity was defined by the concentration of infusates rather than dose. ACNU transiently opened the BBB. Efficacy of Nitrosoureas is reported to be maximum concentration dependent rather than time of exposure. Our study demonstrated that ACNU can be distributed almost as better as hydrophilic dye, evans-blue. Because of this enhanced distribution, drug concentration becomes the important factor defining local toxicity. This characteristic as well as delayed clearance after CED makes ACNU one of the ideal agents for CED.
PALL-08. HOSPICE USE AMONG PATIENTS WITH HIGH GRADE GLIOMAS
Authors: Deborah Forst, Eric Adams, Ryan Nipp, Allison Martin, Ayal Aizer, Justin Jordan
Journal: Neuro-Oncology (2017)

High-grade gliomas (HGG) are incurable brain tumors with an unfavorable prognosis, yet little information is known about end-of-life practices in this population. Hospice enrollment prior to death is considered a component of high-quality cancer care by the American Society for Clinical Oncology (ASCO), which has begun tracking 3-day and 7-day hospice length of stay (LOS) prior to death as minimum standards. Here, we evaluated hospice utilization patterns for patients with HGG. Using the SEER-Medicare linked database, we identified adult patients with fee-for-service Medicare insurance who received a diagnosis of grade 3 or 4 glioma from January 1, 2002 to December 31, 2011 and who were deceased before December 31, 2012. We extracted hospice use data, as well as clinical and socioeconomic variables. We identified 12,437 patients (46% female) who met entry criteria, of whom 7,849 (63%) were enrolled in hospice before death. On multivariable regression analysis, older age, female sex, higher level of education, white race, and higher median household income by zip code predicted hospice enrollment. Of those enrolled on hospice, 6,996 (89%) were enrolled for >3 days, and 6,047 (77%) were enrolled for >7 days. Older age, female sex, and urban area of residence were predictors of longer LOS (3- or 7-day minimum) on multivariable analysis. Median LOS on hospice for all enrolled patients was 21 days (IQR 8-45 days). Hospice use for HGG is similar to other malignancies, although longer hospice LOS is more common with HGG than other malignancies, which may reflect fewer salvage therapies or more rapidly worsening performance status among HGG patients. Predictors of hospice utilization are in line with other malignancies. To our knowledge, this is the first evaluation of end-of-life practices for patients with HGG, and warrants both further study and redoubled efforts to optimize HGG end-of-life care.