tbuckley/cabot-search huggingface dataset:
2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity
Authors: Parker L. Sulkowski, Christopher D. Corso, Nathaniel D. Robinson, Susan E. Scanlon, Karin R. Purshouse, Hanwen Bai, Yanfeng Liu, Ranjini K. Sundaram, Denise C. Hegan, Nathan R. Fons, Gregory A. Breuer, Yuanbin Song, Ketu Mishra-Gorur, Henk M. De Feyter, Robin A. de Graaf, Yulia V. Surovtseva, Maureen Kachman, Stephanie Halene, Murat Günel, Peter M. Glazer, Ranjit S. Bindra
Journal: Science Translational Medicine (2017)

2-Hydroxyglutarate (2HG) exists as two enantiomers, (R)-2HG and (S)-2HG, and both are implicated in tumor progression via their inhibitory effects on α-ketoglutarate (αKG)-dependent dioxygenases. The former is an oncometabolite that is induced by the neomorphic activity conferred by isocitrate dehydrogenase 1 (IDH1) and IDH2 mutations, whereas the latter is produced under pathologic processes such as hypoxia. We report that IDH1/2 mutations induce a homologous recombination (HR) defect that renders tumor cells exquisitely sensitive to poly(adenosine 5'-diphosphate-ribose) polymerase (PARP) inhibitors. This "BRCAness" phenotype of IDH mutant cells can be completely reversed by treatment with small-molecule inhibitors of the mutant IDH1 enzyme, and conversely, it can be entirely recapitulated by treatment with either of the 2HG enantiomers in cells with intact IDH1/2 proteins. We demonstrate mutant IDH1-dependent PARP inhibitor sensitivity in a range of clinically relevant models, including primary patient-derived glioma cells in culture and genetically matched tumor xenografts in vivo. These findings provide the basis for a possible therapeutic strategy exploiting the biological consequences of mutant IDH, rather than attempting to block 2HG production, by targeting the 2HG-dependent HR deficiency with PARP inhibition. Furthermore, our results uncover an unexpected link between oncometabolites, altered DNA repair, and genetic instability.
HCP-02EXPERIENCE WITH MANAGEMENT OF GERM CELL TUMOURS IN TERTIARY CARE CENTRE IN EASTERN INDIA
Authors: Gopal Achari, Rimpa Basu Achari, Uttara Chatterji, Sandip Chatterji
Journal: Neuro-Oncology (2015)

AIM OF THE STUDY: To analyze paediatric patients who were diagnosed with intracranial germ cell tumours, to assess their presentation, management details and to understand their overall prognoses in terms of survival. MATERIAL AND METHODS: Of the 22 patients, there were 12 patients with germinoma, 4 patients with immature teratoma and 1 patient with mature teratoma, 1 with embryonal cell carcinoma, and 4 mixed germ cell tumours. The age of presentation ranged from 3 months to 15 years and there was a clear female preponderance. The most common presentation was with raised intracranial pressure and 11of our patients had papilledema at presentation, 1 presented with seizure, 1 with diabetes insipidus and 1 had precocious puberty at the time of presentation. With the exception of 4 infants who were admitted with poor levels of consciousness and who had presumptive diagnoses of teatimes, and where squash preparation provided definite diagnoses at the time of endoscopic third ventriculostomy, serum markers were obtained in all patients, while CSF tumour markers were obtained in only 14 patients (not done in 4 for technical reasons), Alpha-fetoprotein and beta HCG were measured in all cases. Placental alkaline phosphatase (PLAP) was again not available to us. In 12 patients endoscopic third ventriculostomy and biopsy procedures were done. Those with positive tumour markers (3 patients) no histological diagnoses were obtained and underwent direct radiotherapy. RESULTS: Median survival in the teratoma group was 11.6 months. The germinoma and mixed germ cell tumours had better outcome(stable and asymtomatic at 2 years). The child with embryonal carcinoma did not even survive till adjuvant therapy could be started. CONCLUSION: In our scenario we faced some special problems. 1) tumour markers in CSF could not be measured in 4 cases and we had to depend on serum markers in those cases. 2) almost all our patients with severely raised intracranial pressure required immediate CSF diversion procedures and so we could histological samples for squash examination. Limited resources and limited access to high end laboratory facilities provided a challenge for management of these patients.
Total direct and segmented medical cost-of-care for stage IV (adv) non-small cell lung cancer (NSCLC) in a private insurance population.
Authors: J. M. Koeller, A. Bell, M. Corral, Y. Zhang, J. R. Penrod
Journal: Journal of Clinical Oncology (2011)

e16540 Background: New treatments for stage IV (adv) NSCLC have emerged this past decade. The direct medical cost-of-care for adv NSCLC has not recently been studied. Our primary objective was to characterize the direct cost of adv NSCLC from 2000-9. We also want to determine cost segmented by time in the disease course (diagnosis, active treatment, end-of-life), cost impact of new therapies, and cost trend from 2000-9. Methods: This PharMetrics claims database study uses a retrospective cohort study design. Diagnosed NSCLC patients ≥ 20 yo were included. Small cell lung cancer was excluded. Sub analyses include division into disease segments and time periods representative of changes in therapy available throughout the study period. The study period was divided into the “pre” (2000-2), “transition” (2003-5), and “current” (2006-9) periods to account for the change from standard chemotherapy to the introduction of pemetrexed, TKIs, and the biologics. Results: The study sample contains 5,847 eligible patients. Over the study period the mean total cost of care was $162,134 per patient (patients receiving ≥ 5 months of therapy; n=432), while the mean per patient per month (pppm) cost was $10,284 (med [median] $7,696; SD $12,295). Diagnosis mean cost was $9,162 pppm (med $6,978; SD $8,328). Active mean treatment cost was $10,141 pppm (med $7,807; SD $10,435) and end-of-life mean cost was $18,033 pppm (med $12,301; SD $19,370). Pemetrexed (5%), TKIs (6%), and biologic agents (5%) accounted for 16% of the active treatment segment. In total, they accounted for 4% of overall cost. Cost of “pre” was $8,662 pppm (med $6,747; SD $8,747), “transition” was $10,578 pppm (med $7,722; SD $13,716), and “current” was $10,141 pppm (med $7,731; SD $11,186). Conclusions: The mean total direct cost of care for advanced NSCLC was over $160,000 per patient or $10,284 pppm. The most costly segment was end-of-life at $18,033 pppm. The newer agents (pemetrexed, TKIs, and biologics) represent only a modest portion of the active treatment cost, which was a mean of $10,141 pppm, but represented only a very small portion of total cost. The “current” time period retained similar costs as the “transition” period.
Customised and Noncustomised Birth Weight Centiles and Prediction of Stillbirth and Infant Mortality and Morbidity: A Cohort Study of 979,912 Term Singleton Pregnancies in Scotland
Authors: Stamatina Iliodromiti, Daniel F. Mackay, Gordon C. S. Smith, Jill P. Pell, Naveed Sattar, Debbie A. Lawlor, Scott M. Nelson
Journal: PLoS Medicine (2017)

Background There is limited evidence to support the use of customised centile charts to identify those at risk of stillbirth and infant death at term. We sought to determine birth weight thresholds at which mortality and morbidity increased and the predictive ability of noncustomised (accounting for gestational age and sex) and partially customised centiles (additionally accounting for maternal height and parity) to identify fetuses at risk. Methods This is a population-based linkage study of 979,912 term singleton pregnancies in Scotland, United Kingdom, between 1992 and 2010. The main exposures were noncustomised and partially customised birth weight centiles. The primary outcomes were infant death, stillbirth, overall mortality (infant and stillbirth), Apgar score <7 at 5 min, and admission to the neonatal unit. Optimal thresholds that predicted outcomes for both non- and partially customised birth weight centiles were calculated. Prediction of mortality between non- and partially customised birth weight centiles was compared using area under the receiver operator characteristic curve (AUROC) and net reclassification index (NRI). Findings Birth weight ≤25th centile was associated with higher risk for all mortality and morbidity outcomes. For stillbirth, low Apgar score, and neonatal unit admission, risk also increased from the 85th centile. Similar patterns and magnitude of associations were observed for both non- and partially customised birth weight centiles. Partially customised birth weight centiles did not improve the discrimination of mortality (AUROC 0.61 [95%CI 0.60, 0.62]) compared with noncustomised birth weight centiles (AUROC 0.62 [95%CI 0.60, 0.63]) and slightly underperformed in reclassifying pregnancies to different risk categories for both fatal and non-fatal adverse outcomes (NRI -0.027 [95% CI -0.039, -0.016], p < 0.001). We were unable to fully customise centile charts because we lacked data on maternal weight and ethnicity. Additional analyses in an independent UK cohort (n = 10,515) suggested that lack of data on ethnicity in this population (in which national statistics show 98% are white British) and maternal weight would have misclassified ~15% of the large-for-gestation fetuses. Conclusions At term, birth weight remains strongly associated with the risk of stillbirth and infant death and neonatal morbidity. Partial customisation does not improve prediction performance. Consideration of early term delivery or closer surveillance for those with a predicted birth weight ≤25th or ≥85th centile may reduce adverse outcomes. Replication of the analysis with fully customised centiles accounting for ethnicity is warranted.
Combined PET Imaging of the Inflammatory Tumor Microenvironment Identifies Margins of Unique Radiotracer Uptake
Authors: Bastian Zinnhardt, Hayet Pigeon, Benoit Thézé, Thomas Viel, Lydia Wachsmuth, Inga B. Fricke, Sonja Schelhaas, Lisa Honold, Katrin Schwegmann, Stefan Wagner, Andreas Faust, Cornelius Faber, Michael T. Kuhlmann, Sven Hermann, Michael Schäfers, Alexandra Winkeler, Andreas H. Jacobs
Journal: Cancer Research (2017)

The tumor microenvironment is highly heterogeneous. For gliomas, the tumor-associated inflammatory response is pivotal to support growth and invasion. Factors of glioma growth, inflammation, and invasion, such as the translocator protein (TSPO) and matrix metalloproteinases (MMP), may serve as specific imaging biomarkers of the glioma microenvironment. In this study, noninvasive imaging by PET with [18F]DPA-714 (TSPO) and [18F]BR-351 (MMP) was used for the assessment of localization and quantification of the expression of TSPO and MMP. Imaging was performed in addition to established clinical imaging biomarker of active tumor volume ([18F]FET) in conjunction with MRI. We hypothesized that each imaging biomarker revealed distinct areas of the heterogeneous glioma tissue in a mouse model of human glioma. Tracers were found to be increased 1.4- to 1.7-fold, with [18F]FET showing the biggest volume as depicted by a thresholding-based, volumes of interest analysis. Tumor areas, which could not be detected by a single tracer and/or MRI parameter alone, were measured. Specific compartments of [18F]DPA-714 (14%) and [18F]BR-351 (11%) volumes along the tumor rim could be identified. [18F]DPA-714 (TSPO) and [18F]BR-351 (MMP) matched with histology. Glioma-associated microglia/macrophages (GAM) were identified as TSPO and MMP sources. Multitracer and multimodal molecular imaging approaches may allow us to gain important insights into glioma-associated inflammation (GAM, MMP). Moreover, this noninvasive technique enables characterization of the glioma microenvironment with respect to the disease-driving cellular compartments at the various disease stages. Cancer Res; 77(8); 1831-41. ©2017 AACR.
Mononuclear cell-derived interleukin 1 beta increases chemo-resistance in pancreatic cancer cells by stimulating COX-2 expression
Authors: Guido Eibl, Howard A. Reber, Oscar J. Hines
Journal: Cancer Research (2005)

790  The tumor microenvironment is increasingly recognized as a pivotal modulator of the cancer phenotype. Tumor-host interactions may thereby render cancer cells resistant to common chemotherapeutic agents. Cyclooxygenase-2 (COX-2) may be a critical regulatory molecule in this process as it causes resistance to cell death in various cell models and its expression can be induced by inflammatory stimuli. In the present study we sought to determine whether mononuclear inflammatory cells enhance the resistance of human pancreatic cancer cells to apoptotic cell death and to evaluate the possible involvement of COX-2 in this process. The human histiocytic lymphoma cell line U937 terminally differentiated with phorbol ester and stimulated with lipopolysaccharide (U937diff) served as a human monocyte/macrophage model. Human pancreatic cancer cells (Capan-2) were incubated with U937diff-conditioned culture medium (CM) for 24 hours and the effect on camptothecin (DNA topoisomerase I inhibitor)-induced DNA fragmentation, a hallmark of apoptosis, was measured by ELISA. U937diff-CM significantly reduced camptothecin-induced DNA fragmentation (30±5% reduction). This effect was largely abrogated by pre-incubation with an interleukin-1 receptor antagonist (IL1-RA, 500ng/ml). The presence of interleukin-1 beta (IL-1β) in U937diff-CM was confirmed by ELISA. U937diff-CM and recombinant IL-1β dose (0-10ng/ml)- and time (0-24 hours)-dependently increased COX-2 expression in Capan-2 cells. This effect was mediated by activation of the p44/42 MAPK signaling cascade, as IL-1β dose- and time-dependently stimulates p44/42 MAPK phosphorylation and the MEK-1 inhibitor PD98059 dose-dependently inhibited the IL-1β-induced increase in COX-2 expression. To study whether COX-2 expression is sufficient for conferring chemo-resistance, MIA PaCa-2 cells (COX-2 negative) were transiently transfected with COX-2. Successful transfection was confirmed by immunoblotting. COX-2 transfected MIA PaCa-2 cells showed enhanced resistance to camptothecin-induced DNA fragmentation, which was reversed by the selective COX-2 inhibitor nimesulide. The selective COX-2 inhibitor nimesulide also reversed the U937diff-CM-mediated resistance to camptothecin-induced apoptotic cell death in Capan-2 cells. Taken together we found that mononuclear inflammatory cells increase the resistance of pancreatic cancer cells to apoptotic cell death. This effect is mediated by binding of mononuclear cell-secreted IL-1β to the IL-1 receptor on pancreatic cancer cells and subsequent up-regulation of COX-2 protein levels by activation of the p44/42 MAPK signaling cascade. Targeting the IL-1β-induced COX-2 expression may provide a useful tool to sensitize pancreatic cancer to common chemotherapeutic agents.
Outcome of Second Allogeneic Transplants Using Reduced Intensity Conditioning Following Relapse after an Initial Allogeneic Transplant.
Authors: B.E. Shaw, G.J. Mufti, S. Mackinnon, J. Cavenagh, K. Towlson, R. Pearce, A. Pagliuca, J. Apperley, C. Craddock, M. Kazmi, T. Littlewood, D. Milligan, D. Marks, Nigel H. Russell
Journal: Blood (2006)
Identification of New Megakaryocytic Subpopulations in Mouse Bone Marrow.
Authors: Shinji Sogo, Kuniko Matsumura-Takeda, Yoshimasa Isakari, Yasuo Harada, Kinue Nishioka, Takuma Kawakami, Toshihide Ono, Takao Taki
Journal: Blood (2005)
Rapid Response to Treatment of Multiple Myeloma Detected with FDG PET Scanning in Multiple Myeloma - Early Results from Total Therapy III.
Authors: Ronald Walker, L. Jones-Jackson, Eric Rasmussen, M. Miceli, Elias Anaissie, Joshua Epstein, Guido Tricot, John Shaughnessy, Bart Barlogie
Journal: Blood (2004)
NHS budget per person will fall in real terms in 2018, government admits
Authors: Gareth Iacobucci
Journal: BMJ (2017)

The government has confirmed for the first time that the NHS budget per person in England will fall in real terms in 2018-19 and has revealed by how much.

Figures released by the health minister Philip Dunne in response to a written parliamentary question from Labour MP Luciana Berger1 show that NHS England’s budget per capita will fall by 0.6% in real terms in 2018-19.

The response confirms the recent claim by NHS England’s chief executive, Simon Stevens,2 that …
BMET-17REPEAT RADIOSURGERY FOR LOCALLY-RECURRENT BRAIN METASTASES WITH EXTENSIVE PERI-LESIONAL EDEMA: INCREASED RISK OF RADIATION-RELATED TOXICITY?
Authors: Douglas Holt, Beant Gill, John Flickinger, David Clump, Steven Burton, Johnathan Engh, Dwight Heron
Journal: Neuro-Oncology (2015)

BACKGROUND: Extensive peri-lesional edema of brain metastases following stereotactic radiosurgery (SRS) is highly associated with radiation injury confirmed by surgical resection.We hypothesized that repeat SRS (rSRS) to the same lesion would have a higher risk of symptomatic radiationrelated toxicity when extensive peri-lesional edema (ExPLE) is present.METHODS: We analyzed the records of 87 patients (105 brain metastases) who were initially treated with SRS followed by rSRS to the same lesion for suspected local-recurrence between 2004-2014.We defined ExPLE as a ratio of edema-volume/tumor-volume of .10.For 98 lesions (93%), MR imaging was available for review, including T1 post-contrast, T2, Fluid-attenuated inversion recovery (FLAIR), and thin-slice contrast-enhanced spoiled gradient recalled acquisition in steady state sequences.Lesion volumes and FLAIR edema volumes were manually contoured and measured by an investigator blinded to the clinical outcome.Alpha/Beta of 10 was used for biological effective dose (BED).Toxicities and local recurrences were captured from clinical charts; the latter defined by increase in size or re-emergence on serial imaging.Student's t-test and Cox proportional hazards regression were used in assessing statistical significance at p , 0.05.RESULTS: The median follow-up from time of rSRS was 12.7 months .Median time between SRS and rSRS was 10.1 months (IQR 7.1-16.0).Thirty-seven (38%) of the lesions had ExPLE.Median tumor volumes and doses were 2.5/2.9cc(p ¼ 0.520) and 57.4/59.1 BED (p ¼ 0.444) for the tumors with/ without ExPLE, respectively.There were 10 (9.5%) grade 3 radiation-toxicity events following rSRS for local-recurrence with no grade 4 or 5 toxicities.Using univariate analysis, ExPLE was not statistically associated to a higher risk of radiation-related toxicity (p ¼ 0.651) or to a higher risk of local failure (p ¼ 0.932) following rSRS.CONCLUSIONS: Repeat radiosurgery to locally-recurrent brain metastases with ExPLE did not increase the risk of radiation injury compared to lesions with low peri-lesional edema.Overall survival
Myeloid Derived Suppressor Cells in Acute Leukemia and Its Association with Conventional Cytogenetic and Molecular Risk Factors
Authors: Ansu Abu Alex, Eric Tartour, Alain Gey, Poonkuzhali Balasubramanian, Vivi Srivastava, Rayaz Ahmed, Aby Abraham, Auro Viswabandya, Biju George, Alok Srivastava, Vikram Mathews
Journal: Blood (2012)
Listeriolysin S: A bacteriocin from epidemic<i>Listeria monocytogenes</i>strains that targets the gut microbiota
Authors: Juan J. Quereda, Jazmín Meza-Torres, Pascale Cossart, Javier Pizarro-Cerdá
Journal: Gut Microbes (2017)

Listeria monocytogenes is a Gram-positive food-borne pathogen that in humans may traverse the intestinal, placental and blood/brain barriers, causing gastroenteritis, abortions and meningitis. Crossing of these barriers is dependent on the bacterial ability to enter host cells, and several L. monocytogenes surface and secreted virulence factors are known to facilitate entry and the intracellular lifecycle. The study of L. monocytogenes strains associated to human listeriosis epidemics has revealed the presence of novel virulence factors. One such factor is Listeriolysin S, a thiazole/oxazole modified microcin that displays bactericidal activity and modifies the host microbiota during infection. Our recent results therefore highlight the interaction of L. monocytogenes with gut microbes as a crucial step in epidemic listeriosis. In this article, we will discuss novel implications for this family of toxins in the pathogenesis of diverse medically relevant microorganisms.
Ethnic Difference in Genomic Profiles of Chronic Lymphocytic Leukemia in Korea: Targeted Exome Sequencing and Molecular Cytogenetics
Authors: Jung-Ah Kim, Byungjin Hwang, Si Nae Park, Sunghoon Huh, Kyongok Im, Seon Young Kim, Joo Ryung Huh, Eul-Ju Seo, Je-Hwan Lee, Sunghoon Kwon, Sung-Soo Yoon, Duhee Bang, Dong Soon Lee
Journal: Blood (2015)
The virtuous circle, a knowledge sharing cooperative for community medical oncology
Authors: L. J. Heifetz, W. M. Jordan, T. R. Barr
Journal: Journal of Clinical Oncology (2005)

6122 Background: In October 2002, a group of high performing medical oncology practices began an experiment in open communication. The business term for this endeavor is a virtuous circle, a knowledge-sharing cooperative. This cooperative was designed to provide insight into heretofore profoundly sensitive areas of practice functionality and design. Methods: Data shared included procedure & productivity reports, partnership buy-in and buy-out designs, practice consolidation experiences, practice diversification experiences, and the effective utilization of mid-level providers. The potentials for anti-trust violations were identified in advance, with all safe harbors adhered to: only one practice from a given Metropolitan Service Area (MSA), a disinterested 3rd party managing the data (Oncology Metrics), and each practice’s data identified by a blinded key. Results: The initial meeting included 4 practices, all at least 750 miles from each other with an average of 9 physicians per group. Initially designed to be an annual event, the participants insisted on meeting every 3–4 months. The clinical, operational and financial benefits of participation have been significant for all of the participants. There are now 8 practices in this group, with growth continuing steadily. Conclusions: It is anticipated that such knowledge-based cooperatives among successful community medical groups will evolve into a new definition of partnership for those groups, one with all of the positive effects of knowledge sharing, but without the negative effects of loss of regional practice control. No significant financial relationships to disclose.
Reversion of the Experimental Hemodilutional Coagulopathy Induced by Crystalloids and Colloids Using Different Coagulation Factor Concentrates
Authors: Carolina Caballo, Ana M Galan, Maribel Diaz-Ricart, Irene Lopez-Vilchez, Miguel Lozano, Joan Cid, Marcos Pino, Joan Beltran, Misericordia Basora, Arturo Pereira, Gines Escolar
Journal: Blood (2011)