tbuckley/cabot-search huggingface dataset:
Efficacy of tailored treatment for high- and low-risk medulloblastoma in adults: A large prospective phase II trial.
Authors: A. A. Brandes, E. Franceschi, A. Tosoni, G. Frezza, R. Agati, A. Maestri, C. Ghimenton, V. Mazzocchi, L. Scopece, M. Ermani
Journal: Journal of Clinical Oncology (2010)

2003 Background: To assess the efficacy of treatment of medulloblastoma (MB) in adults (> 18 years). Methods: Ninety-five MB patients (pts) were enrolled a prospective phase II trial conducted between 1/1989 and 2/2009; 30 low-risk (LR) pts (T1, T2, T3a, M0, without postoperative residual disease) underwent radiotherapy (36 Gy) to the craniospinal axis, supplemented by a local tumor dose (18.8 Gy; total, 54.8 Gy), and 65 high-risk (HR) pts (T3b–T4, or postoperative residual tumor) received 2 cycles of “up-front chemotherapy” (cisplatin 25 mg/m2/daily for 4 days, etoposide 40 mg/m2/daily for 4 days, and cyclophosphamide 1,000 mg/m2 on day 4; every 4 weeks) before the same radiation therapy, followed by maintenance chemotherapy if M1, M2 or M3 disease was present. Results: Progression-free survival at 5 and 10 years (PFS-5 y and PFS-10 y) were 78% (62-93) and 46% (23-70) in LR vs. 50% (37- 62) and 36% (23-49) in HR (p = 0.009 and p = 0.03, respectively) patients. Survival at 5 and 10 years (OS-5 y and OS-10 y) was 92% (81-100) and 65% (43-7) in LR vs. 58% (46-71) and 45% (31-8) in HR (p = 0.002 and p = 0.02, respectively). Five-year and 10-year PFS was 68% (50-85) and 54% (34-74) in M0 pts vs. 35% (18-51) and 19% (2-35) in M1-2-3 pts (p = 0.007 and p = 0.006). OS- at 5 years and 10 years were 71% (54-88) and 62% (43-81) in M0 vs. 47% (29- 65) and 29% (11-47) in M1-2-3 pts (p = 0.09 and p = 0.04); residual disease had no significant impact on 10-year PFS or 10-year OS. There were no deaths from toxicity, which was mainly hematological and successfully managed with dose reductions and supportive care. Conclusions: Since the incidence of MB in adults is extremely rare, data appearing in literature on this condition have been reported in small retrospective series. The findings made in the present prospective study on a large series of patients, the first of its type to appear in literature, clearly indicate the standard of care in MB in adults, and should constitute a benchmark for further studies. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb, OncoMethylome Sciences, Roche, Schering-Plough GlaxoSmithKline, Merck Sharp & Dohme, Pfizer, Roche, Schering-Plough
Hematopoietic stem cell transplantation for T-cell large granular lymphocyte leukemia: a retrospective study of the European Society for Blood and Marrow Transplantation
Authors: T Marchand, T Lamy, H Finel, W Arcese, S Choquet, J Finke, A Huynh, G Irrera, D Karakasis, J Konopacki, J Lambert, M Michieli, H C Schouten, W Schroyens, G Sucak, J Tischer, E Vandenberghe, P Dreger
Journal: Leukemia (2015)
Randomized multicenter phase III trial comparing two neoadjuvant chemoradiotherapy (CT-RT) regimens (RT45-Cap versus RT50-Capox) in patients (pts) with locally advanced rectal cancer (LARC): Results of the ACCORD 12/0405 PRODIGE 2
Authors: J. Gerard, D. Azria, S. Gourgou-Bourgade, I. Martel-Laffay, C. Hennequin, P. Etienne, V. Vendrely, T. Conroy, E. Francois, C. Montoto-Grillot
Journal: Journal of Clinical Oncology (2009)

LBA4007 The full, final text of this abstract will be available in Part II of the 2009 ASCO Annual Meeting Proceedings, distributed onsite at the Meeting on May 30, 2009, and as a supplement to the June 20, 2009, issue of the Journal of Clinical Oncology. No significant financial relationships to disclose.
Abstract #5507: Targeting apoptosis in renal cell carcinoma (RCC): In vitro synergy between ABT-737 and inhibition of PI3-Kinase in RCC cell lines
Authors: Daniel Cho, Matthew Cohen, Michael Atkins, James Mier
Journal: Cancer Research (2009)

Introduction : Most currently available therapies in RCC primarily target the tumor endothelium and have little intrinsic toxicity to RCC tumor cells. ABT-737 is a small molecule inhibitor of several anti-apoptotic Bcl-2 family members (e.g. Bcl-2, Bcl-X L , Bcl-w) which has been shown to induce apoptosis as a single agent and enhance that induced by death-receptor agonists (e.g. TRAIL)in many different cancer cell lines. PI3-Kinase, through FOXO, regulates the expression of numerous proteins relevant to the extrinsic apoptosis pathway including TRAIL and Fas ligand as well as BH3-only Bcl-2 family members such as Bim and BNIP. Given the limitations of current RCC therapies, we sought to explore the efficacy of ABT-737 in RCC and whether this efficacy may be enhanced through the concurrent inhibition of PI3-Kinase.  Methods : 786-0, 769-P, and Caki-1 RCC cell lines were treated  in vitro  with varying concentrations of ABT-737 ranging from 0-10µM in the presence and absence of LY294002 at 50µM and analyzed for viability by propidium iodide staining. Cell lysates were analysed by western blot for PARP cleavage. The dependency of observed cytotoxicity on caspase activation was assessed by concurrent treatment with Z-VAD (pan-caspase inhibitor), Z-IETD (caspase 8 inhibitor), or Z-LEHD (caspase 9 inhibitor).  Results : Treatment with ABT-737 resulted in variable lethality in the RCC cell lines which in all cases was synergistically enhanced by the concurrent treatment with LY294002. The combination of ABT-737 and LY294002 resulted in significantly increased cleavage of PARP, caspase 8, and caspase 3 compared with ABT-737 alone. Cells treated with LY294002 showed downmodulation of Mcl-1 and upregulation of Bim expression. BNIP and Noxa levels were unaffected. The lethality of both single-agent ABT-737 and the combination of ABT-737 with LY294002 was completely abrogated by treatment with ZVAD, significantly reduced by Z-IETD, but only modestly protected by Z-LEHD.  Conclusions : ABT-737 induces apoptosis in RCC cell lines which is synergistically enhanced through concurrent inhibition of PI3-Kinase. The complete dependence of this lethality on caspase activation, along with the greater protection of cells with inhibition of caspase 8 as compared with caspase 9, strongly argues for involvement of death-receptor pathways, a notion which will be confirmed in studies in which signaling through DR4/5 and fas is disrupted. Numerous PI3-Kinase inhibitors are currently undergoing development for RCC therapy. Our data suggest that they may be particularly effective in combination BH3 mimetics such as ABT-737.   Citation Information:  In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5507.
No evidence that £1bn Cancer Drugs Fund has helped patients, says watchdog
Authors: Zosia Kmietowicz
Journal: BMJ (2015)

There is no way of knowing whether the Cancer Drugs Fund, which has cost the NHS £1bn (€1.37bn; $1.55bn) over five years, has improved the survival or quality of life of patients who accessed new treatments, a National Audit Office report has said.1

The fund, which has provided cancer patients with drugs that are not approved by the National Institute for Health and Care Excellence (NICE), is likely to cease to exist from next April, said the report from the government spending watchdog. Decisions about which cancer drugs are available on the NHS would revert to NICE, the organisation set up in 1999 to determine the affordability of new drugs.

Meg Hillier, MP and chair of the Public Accounts Committee, said, “At a time …
In vitro characterization of a novel inhaled PI3Kd inhibitor LAS194223
Authors: Marta Calbet, Martin Lehner, Monica Bravo, Judit Cabedo, Stephane Paris, Salome Soria, Montse Erra, Montserrat Miralpeix
Journal: European Respiratory Journal (2014)

Rationale : PI3Kd is a lipid kinase involved in the activation, proliferation and differentiation of leukocytes and thus is an anti-inflammatory target for the treatment of asthma and COPD.

Aim : to characterize the enzymatic and cellular potency and selectivity of LAS194223.

Methods : PI3Ka, PI3Kb, PI3Kd, PI3Kg enzymatic activities were assessed by HTRF kinase assays. Cellular potency was assessed in different relevant cell types: inhibition of phospho- AKT induced by M-CSF in THP-1 cells, inhibition of fMLP induced ROS production in PMN, and inhibition of CD3 induced IFNg in PBMC. PI3Kb cellular potency was determined in HUVEC cells through inhibition of S1P induced phosphoAKT. The selectivity profile was assessed at 1 mM in a Millipore KinaseProfiler panel (Millipore), CEREP Express profile panel (CEREP) and in a lipid kinase panel (ProQinase) comprising a total of 114 target proteins.

Results : LAS194223 potently inhibits PI3Kd kinase activity (IC500.1 nM) and shows a fold ratio of 137, 10 and 4 for PI3Ka, PI3Kb and PI3Kg respectively. LAS194223 was also potent in cellular assays including M-CSF induced pAKT in THP-1 (IC50 1.6 nM), fMLP induced ROS production in PMN (IC50 18nM) and CD3 induced IFNg in PBMC (IC50 4 nM). No relevant off-target activities were identified. Cellular potency for PI3Kb isoform in HUVEC cells shows a 260 fold vs PI3Kd in THP-1 assay.

Conclusions : LAS194223 is a potent, non-cytotoxic compound, with good selectivity vs PI3Ka and PI3Kb isoforms that shows activity also in PI3Kg. These promising in vitro results prompted us to further characterize its ADME profile and in vivo efficacy by inhaled route.
Pharmacokinetic analysis of an all intraperitoneal carboplatin and paclitaxel regimen in ovarian cancer patients demonstrates favorable systemic bioavailability of both agents
Authors: C. N. Krasner, M. V. Seiden, A. F. Fuller, M. Roche, C. L. Verrill, F. D’Amato, O. Tretyakov, K. Tyburski, U. A. Matulonis, J. G. Supko
Journal: Journal of Clinical Oncology (2006)

5008 Background: A phase III trial (GOG172) demonstrated improved survival for patients with newly diagnosed and optimally debulked ovarian cancer treated with intraperitoneal (ip) cisplatin and paclitaxel (P), given both as a 24 h iv infusion and ip, as compared with standard iv dosing. Studies to further enhance efficacy and minimize toxicity of ip taxane/platinum regimens are needed. Because adequate systemic drug exposure is thought to be essential for maximum therapeutic benefit of ip chemotherapy, the pharmacokinetics (PK) and bioavailability of ip P and carboplatin (C) were determined in this pt population in a phase II trial to evaluate dosing by the ip route alone. Methods: P 60 mg/m 2 once a week and C at an AUC 6 every weeks were infused over 1 h, iv in cycle 1 and ip in the 5 subsequent 21-day cycles. Plasma samples were collected during week 1 of cycles 1, 2 and 6. P was measured by LC/MS and free platinum (fPt) was determined by flameless atomic absorption. Results: PK data is available for 14 pts receiving at least 1 cycle of ip therapy and for 7 pts who received all 5 cycles. When given ip, P achieved a peak conc. in plasma (C max ) of 0.086 ± 0.034 μM (mean ± SD) at 6.4 ± 2.2 h, 22-times lower than C max for iv infusion (1.92 ± 0.80 μM). Thereafter, P plasma levels were comparable for both routes and decayed at similar rates with a half-life of 13.9 ± 4.1 h for iv and 13.7 ± 2.2 h for ip dosing. The systemic bioavailability of ip P was 53 ± 19% for the initial dose and 46 ± 10% in cycle 6. P plasma levels exceeded 0.05 μM, the pharmacologic threshold conc., for &gt;20 h upon ip dosing in 67% (10/15) and 71% (5/7) of pts in cycles 2 and 6, respectively. C was rapidly absorbed into systemic circulation when given ip with a C max of 83 ± 11 μM for fPt at 1.6 ± 0.2 h in cycle 2. Consistent with prior reports, systemic availability of fPt exceeded 100% (133 ± 22% in cycle 2; 142 ± 47% in cycle 6). Conclusions: Weekly ip P 60 mg/m 2 with ip C (AUC 6) every 3 weeks achieved a potentially effective pattern of systemic exposure to both agents in a majority of pts. The cumulative time that P plasma levels are &gt;0.05 μM per cycle of therapy is likely to be longer than provided by the iv/ip dosing regimen for P (135 mg/m 2 24 h iv infusion day 1; 60 mg/m 2 ip day 8) used in GOG172. No significant financial relationships to disclose.
Polymorphisms within the Tumor Necrosis Factor–α Promoter Region in Patients with HLA-B27–Associated Uveitis
Authors: Yosuf El-Shabrawi, Beate J. Wegscheider, Martin Weger, Wilfried Renner, Ursula Posch, Silvia Ulrich, Navid Ardjomand, Josef Hermann
Journal: Ophthalmology (2006)
Abstract 17927: Transcatheter Implantation of Autologous in vivo Tissue-Engineered, Valved Stents (BIOVALVED STENTs) in the Pulmonary Position in a Beagle Model
Authors: Masami Uechi, Marina Funayama, Yuichi Matsui, Takeshi Mizuno, Megumi Fujiwara, Tsutomu Tajikawa, Kenkichi Ohba, Masashi Yamanami, Taiji Watanabe, Keiichi Kanda, Hitoshi Yaku, Yasuhide Nakayama
Journal: Circulation (2011)

Objectives We developed completely autologous valved conduits (BIOVALVEs) using simple, safe and economical in vivo tissue engineering, which is a practical concept of regenerative medicine. In this study, self-expandable BIOVALVEs impregnating stents (BIOVALVED STENTs) were successfully replaced to pulmonary valves by transcatheter method in a beagle model. The use of BIOVALVED STENTs might solve the problem of degeneration and limited durability of biological heart valves. Methods and Results As a mold for BIOVALVED STENTs preparation, a pair of the custom-designed acrylate rods (diameter, 14 mm; length, 40 mm), assembled with a small aperture in a trileaflet shape, were covered with NiTi stents, and then capped with another pair of acrylate covers at their both terminals. The molds were placed in the dorsal subcutaneous spaces of beagle dogs. After 4 weeks of implantation, autologous connective tissues, impregnating stents, completely covered the surface of the molds and migrated into the apertures for the leaflets. BIOVALVED STENTs with autologous three leaflets, strongly connected with stent strut, were obtained after removing the molds. They had appropriate compliance and robustness (&gt; 3000 mmHg) as the conduit-valves for aortic full root replacement. They were subsequently deployed into the main pulmonary arteries through catheters after technical establishment using allogenic implantation. Postoperative UCG demonstrated smooth movement of the leaflets with little regurgitation for at least up to 3 months. Conclusion Good functioning as the pulmonary valve was observed after implantation of firstly developed BIOVALVED STENTs with completely autologous tissues, which will become a valid future option in adolescents.
My most fortunate mistake
Authors: Andrew Riordan
Journal: BMJ (2015)

It was my first day on call as a paediatric registrar and nearly my last—I missed a case of meningococcal disease. A concerned looking doctor in the emergency department came to find me, and being new to the hospital I didn’t know she was the department’s consultant. She took me to see a toddler, saying, “This is the rash we see with meningococcal disease.” Emily, who was sitting on her mother’s lap, smiled at me. She had a fever of …
Autosomal-Recessive Mutations in SLC34A1 Encoding Sodium-Phosphate Cotransporter 2A Cause Idiopathic Infantile Hypercalcemia
Authors: Karl P Schlingmann, Justyna Ruminska, Martin Kaufmann, Ismail Dursun, Monica Patti, Birgitta Kranz, Ewa Pronicka, Elzbieta Ciara, Teoman Akcay, Derya Bulus, Elisabeth A M Cornelissen, Aneta Gawlik, Przemysław Sikora, Ludwig Patzer, Matthias Galiano, Veselin Boyadzhiev, Miroslav Dumic, Asaf Vivante, Robert Kleta, Benjamin Dekel, Elena Levtchenko, René J Bindels, Stephan Rust, Ian C Forster, Nati Hernando, Glenville Jones, Carsten A Wagner, Martin Konrad
Journal: Journal of the American Society of Nephrology (2015)

Idiopathic infantile hypercalcemia (IIH) is characterized by severe hypercalcemia with failure to thrive, vomiting, dehydration, and nephrocalcinosis. Recently, mutations in the vitamin D catabolizing enzyme 25-hydroxyvitamin D3-24-hydroxylase (CYP24A1) were described that lead to increased sensitivity to vitamin D due to accumulation of the active metabolite 1,25-(OH)2D3. In a subgroup of patients who presented in early infancy with renal phosphate wasting and symptomatic hypercalcemia, mutations in CYP24A1 were excluded. Four patients from families with parental consanguinity were subjected to homozygosity mapping that identified a second IIH gene locus on chromosome 5q35 with a maximum logarithm of odds (LOD) score of 6.79. The sequence analysis of the most promising candidate gene, SLC34A1 encoding renal sodium-phosphate cotransporter 2A (NaPi-IIa), revealed autosomal-recessive mutations in the four index cases and in 12 patients with sporadic IIH. Functional studies of mutant NaPi-IIa in Xenopus oocytes and opossum kidney (OK) cells demonstrated disturbed trafficking to the plasma membrane and loss of phosphate transport activity. Analysis of calcium and phosphate metabolism in Slc34a1-knockout mice highlighted the effect of phosphate depletion and fibroblast growth factor-23 suppression on the development of the IIH phenotype. The human and mice data together demonstrate that primary renal phosphate wasting caused by defective NaPi-IIa function induces inappropriate production of 1,25-(OH)2D3 with subsequent symptomatic hypercalcemia. Clinical and laboratory findings persist despite cessation of vitamin D prophylaxis but rapidly respond to phosphate supplementation. Therefore, early differentiation between SLC34A1 (NaPi-IIa) and CYP24A1 (24-hydroxylase) defects appears critical for targeted therapy in patients with IIH.
Estimation of cardiorespiratory fitness in the clinical setting.
Authors: Ana Ruiz-Casado, Lidia Brea, Javier Ramos, Itziar Pagola, Maria Jesus Ortega, Ana Soria, Rocio Navarro, Guillermo Fernandez, Tania Duarte, Hector Cebolla, Alejandro Lucia
Journal: Journal of Clinical Oncology (2015)

e20631 Background: Cardiorespiratory fitness (CRF) is a powerful predictor of mortality in general population and in cancer survivors. There is emerging evidence that treatments for cancer negatively impact CRF. VO2max is impaired in cancer survivors compared with healthy controls. Maximal oxygen uptakes of 15 ml/kg/min are required for functional independence and lower figures were associated with an increase in perioperative complications. Cardiopulmonary exercise tests cannot be routinely done in the clinical setting. There are some validated submaximal tests such as the one- mile and six- minutes test. Methods: CRF evaluation results from three independent studies were analyzed and compared: 1) 93 patients (pts) had G-I metastatic disease (MD); 2) 272 pts had a history of cancer with no current evidence of disease (NED); 3) 46 controls (CTR). All pts were evaluated by their physician as ECOG-Performance Status (PS) < 3. Individuals should be able of walking a mile. Treatment with beta blockers was not allowed.Cardiorespiratory fitness was evaluated at the hospital through the one-mile-test. VO2max was calculated through a formula 132.853 - (0.0769 × Weight) - (0.3877 × Age) + (6.315 × Gender) - (3.2649 × Time) - (0.1565 × Heart rate) described by Kilne. Results: Pts with MD (Age 61; M/F: 56/37) had an estimated VO2max 22.66 ml/kg/min; Pts NED (Age 57; M/F: 80/192) VO2max 26,38 ml/kg/min; CTR (Age 51; M/F: 12:34). There were significant differences among the three different status (p = 0.00) and also MD vs NED (p = 0.04) and NED vs CTR (p = 0.00). 27 (29%) patients with metastatic disease had more than 30 ml/kg/min. Conclusions: Cardiorespiratory fitness can be estimated in the clinical setting. People with a history of cancer had a worse objective functional capacity than their healthy counterparts. 1/3 of patients with metastatic disease kept a very good physical condition. An objective evaluation of PS could be useful (1) for recommending physical exercise, (2) stratifying patients with PS 0-2 and (3) selecting patients for some new therapies or clinical trials on an objective basis.
Outbreak of 2009 pandemic influenza A(H1N1), Los Lagos, Chile, April-June 2009
Authors: Collective Chilean Task Force for study of Pandemic Influenza A (H1N1), E Pedroni, M García, V Espínola, A Guerrero, C González, A Olea, M Calvo, B Martorell, M Winkler, M V Carrasco, J A Vergara, J Ulloa, A M Carrazana, O Mujica, J E Villarroel, M Labraña, M Vargas, P González, L Cáceres, C G Zamorano, R Momberg, G Muñoz, J Rocco, V Bosque, A Gallardo, J Elgueta, J Vega
Journal: Eurosurveillance (2010)

Binary file ES_Abstracts_Final_ECDC.txt matches
Authors' response: antibodies to GP2, the major zymogen granule membrane glycoprotein, are specific for Crohn's disease and may reflect treatment response
Authors: Dirk Roggenbuck, Dirk Reinhold, Thomas Wex, Ulrike von Arnim, Peter Malfertheiner, Andreas Sturm, Lael Werner, Dimitrios P Bogdanos, Martin W Laass, Karsten Conrad
Journal: Gut (2011)

We would like to thank Op De Beeck et al 1 for their interest in the evaluation of antibodies to the zymogen granule membrane glycoprotein 2 (GP2) in patients with inflammatory bowel disease (IBD). Their meticulous investigation of a large, well-characterised cohort of patients and controls revealed good reproducibility, linearity and robustness of the anti-GP2 assays, confirming the assay performance reported in a recent study by our group.2 Both studies found a comparable, high specificity of anti-GP2 for Crohn's disease (CD). On testing 100 patients with ulcerative colitis (UC) and 162 blood donors (BDs) as controls in our study, the specificity reached a value of 94.3% (95% CI 90.7% to 96.8%). This value is similar to the specificity of 93.9% reported by Op De Beeck et al , including 118 UC patients, 75 …
ICAM-1–Related Noncoding RNA in Cancer Stem Cells Maintains ICAM-1 Expression in Hepatocellular Carcinoma
Authors: Weixing Guo, Shupeng Liu, Yuqiang Cheng, Lei Lu, Jie Shi, Guixia Xu, Nan Li, Kai Cheng, Mengchao Wu, Shuqun Cheng, Shanrong Liu
Journal: Clinical Cancer Research (2015)

Abstract Purpose: Portal vein tumor thrombus (PVTT) is a major complication of hepatocellular carcinoma (HCC) and is associated with poor survival. Long noncoding RNAs (lncRNA) contribute to HCC metastasis, but whether and how lncRNAs affect PVTT development remains unclear. In the present study, a novel highly expressed lncRNA (ICAM-1–related, ICR) was identified in ICAM-1+ cancer stem cells (CSC) in HCC. This lncRNA regulated CSC properties and contributed to PVTT development. Experimental Design: We used microarray and bioinformatics analyses to identify differentially expressed lncRNAs. Real-time PCR and Western blotting were used to assess gene expression in cell lines and tumors. Sphere formation assays were performed to investigate stem cell properties of tumor cells in vitro. Retrospective and prospective studies were used to investigate the relationship between ICR expression and clinical outcomes. Results: Compared with the corresponding primary tumors, PVTT expressed different lncRNAs and mRNAs, including the upregulated lncRNA ICR and ICAM-1. ICR regulated ICAM-1 expression by increasing the stability of its mRNA through RNA duplex formation, which modulated the CSC properties of ICAM-1+ HCC cells. ICR transcription in ICAM-1+ HCC cells was regulated by Nanog, and inhibition of ICR in situ significantly reduced ICAM-1 expression and ICAM-1+ HCC cells in tumors in vivo. Moreover, elevated ICR and ICAM-1 expression in tumors was correlated with PVTT development and poor clinical outcomes. Conclusions: Our study demonstrates that ICR specifically regulates CSC properties of ICAM-1+ HCC cells and that ICR contributes to PVTT development. Therefore, ICR may be a promising target for HCC therapy. Clin Cancer Res; 22(8); 2041–50. ©2015 AACR.