tbuckley/cabot-search huggingface dataset:
LV5FU2-cisplatin followed by gemcitabine or the reverse sequence in metastatic pancreatic cancer: Preliminary results of a randomized phase III trial (FFCD 0301)
Authors: E. Mitry, L. Dahan, M. Ychou, J. Arthaud, M. Gasmi, J. Raoul, C. Mariette, J. M. Phelip, L. Bedenne, J. Seitz
Journal: Journal of Clinical Oncology (2008)

4513 Background: Pts with metastatic pancreatic adenocarcinoma (MPA) have a poor prognosis with no major survival improvement since the introduction of gemcitabine (Burris 1997). The LV5FU2-P regimen was reported as safe and active with a 9 months median overall survival (OS) in a phase II trial (Taïeb 2002). This randomized multicenter phase III trial compared LV5FU2-P followed by gemcitabine in arm A versus gemcitabine followed by LV5FU2-P in arm B to evaluate the best sequence. Methods: Pts with measurable MPA, PS 0–2, non prior CT, were randomly assigned to receive either LV5FU2-P (2-hour infusion of LV 200 mg/m2 followed by a FU bolus 400 mg/m2 and 46-hour infusion 2,400 mg/m2 every 2 weeks, with cisplatin 50 mg/m2 as a 2-hour infusion on D1 or 2, followed by gemcitabine (1,000 mg/m2 for 7 weeks out of 8 and then 3 weeks out of 4) at progression or toxicity (arm A) or the opposite sequence (arm B). Randomization was done using minimization with stratification according to center, PS tumoral localization and infusion duration. Primary endpoint was OS. It was required to include 202 pts and observe 170 deaths to detect an expected improvement in median OS from 6.5 to 10 months in arm A (bilateral α = 5% and β = 20%). Secondary endpoints included progression free-survival (PFS) after first and second line, toxicity, quality of life (QLQ-C30) and percentage of second line in each arm. Results: From 08/2003 to 05/2006, 202 pts were included in 33 centers, 102 in arm A and 100 in arm B. Median age (62 [40 - 84] vs 64 [39 - 81] years), male/female ratio (1.7 vs 1.7), PS 0–1 (76.5% vs 83%), previous surgery (22.5% vs 27%). After a median follow-up of 33,6 months [min 17; max 48], 185 pts had died. Median OS for arm A was 6.6 months [95% CI- 5.2 to 8.4] versus 8.2 months [95% CI- 6.1 to 9.7] for arm B (HR B vs A 0.95 [95% CI 0.71 - 1.27], Log Rank p = 0.72). 1- year and 2-year survival rates were 29.5% and 8% for arm A versus 34.5% and 3.5% for arm B, respectively. Conclusions: This trial failed to reach its primary endpoint and both sequences achieved a similar efficacy with no significant differences between the two arms in median OS. Updated results (including response, PFS and toxicity analyses) will be presented at the meeting. No significant financial relationships to disclose.
Ridding NHS of “unwarranted variation” could save £5bn a year, says report
Authors: Gareth Iacobucci
Journal: BMJ (2016)

The NHS in England could achieve £5bn of efficiency savings each year by 2020-21 through a combination of better staff management, improved procurement, driving down drug spending, and better estates management, an independent report has said.

The final report1 by Patrick Carter, a Labour peer, said that eradicating the “unwarranted variation” in spending and productivity between NHS hospitals across England could achieve substantial efficiency gains each year.

The review was commissioned by England’s health secretary, Jeremy Hunt, and its final recommendations follow an interim report by Carter published in June 2015. …
Factors affecting time to adjuvant chemotherapy in stage III colon cancer patients.
Authors: A. Holt, R. A. Nelson, S. Shibata, L. L. Lai
Journal: Journal of Clinical Oncology (2010)

e14097 Background: A survival benefit has been shown when chemotherapy is administered within a two month period following surgery for colon cancer. Whether chemotherapy administered sooner after definitive surgery for colorectal cancer (CRC) affects survival continues to be controversial. We compared time to chemotherapy and determined if cancer outcomes are affected by time to chemotherapy. In addition, we evaluated clinical factors that may be predictive of time to chemotherapy. Methods: Data was abstracted from 156 consecutive Stage III colon cancer patients treated with surgery followed by adjuvant chemotherapy from 2001-2008. Results: The median time to chemotherapy was 44 days. 105/156 (67.3%) patients received chemotherapy within 56 days. Clinical factors including age, gender, location of cancer and type of surgery (open v. laparoscopic) were not predictive of time to chemotherapy on multivariate analysis. However, time period when the patient was treated (2001–2004 [Time 1] v. 2005–2008 [Time 2]) did significantly affect time to chemotherapy (p = 0.0078). Days to chemotherapy during Time 1 were fewer than during Time 2 (median 38 days v. 43 days, p = 0.0003). Also the percentage of patients who received chemotherapy within 56 days for time period 1 vs 2 was 75 vs. 58.3, respectively, (p = 0.0268). When analyzed by time periods, overall survival was better in patients treated in Time 1 than in patients treated in Time 2 on univariate and confirmed on multivariate analysis, (p = 0.0202). Conclusions: Although most patients received chemotherapy within the recommended time period, patients still benefited from decreasing time to chemotherapy. In this study, we did not identify clinical factors predictive of time to chemotherapy. Based on these results, we recommend that time to chemotherapy in CRC patients be minimized in order to improve patient survival. No significant financial relationships to disclose.
Synergism between the mTOR inhibitor rapamycin and FAK down-regulation in the treatment of acute lymphoblastic leukemia
Authors: Pei-Jie Shi, Lu-Hong Xu, Kang-Yu Lin, Wen-jun Weng, Jian-Pei Fang
Journal: Journal of Hematology & Oncology (2016)

Acute lymphoblastic leukemia (ALL) is an aggressive malignant disorder of lymphoid progenitor cells in both children and adults. Although improvements in contemporary therapy and development of new treatment strategies have led to dramatic increases in the cure rate in children with ALL, the relapse rate remains high and the prognosis of relapsed childhood ALL is poor. Molecularly targeted therapies have emerged as the leading treatments in cancer therapy. Multi-cytotoxic drug regimens have achieved success, yet many studies addressing targeted therapies have focused on only one single agent. In this study, we attempted to investigate whether the effect of the mammalian target of rapamycin (mTOR) inhibitor rapamycin is synergistic with the effect of focal adhesion kinase (FAK) down-regulation in the treatment of ALL. The effect of rapamycin combined with FAK down-regulation on cell proliferation, the cell cycle, and apoptosis was investigated in the human precursor B acute lymphoblastic leukemia cells REH and on survival time and leukemia progression in a non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mouse model. When combined with FAK down-regulation, rapamycin-induced suppression of cell proliferation, G0/G1 cell cycle arrest, and apoptosis were significantly enhanced. In addition, REH cell-injected NOD/SCID mice treated with rapamycin and a short-hairpin RNA (shRNA) to down-regulate FAK had significantly longer survival times and slower leukemia progression compared with mice injected with REH-empty vector cells and treated with rapamycin. Moreover, the B-cell CLL/lymphoma-2 (BCL-2) gene family was shown to be involved in the enhancement, by combined treatment, of REH cell apoptosis. FAK down-regulation enhanced the in vitro and in vivo inhibitory effects of rapamycin on REH cell growth, indicating that the simultaneous targeting of mTOR- and FAK-related pathways might offer a novel and powerful strategy for treating ALL.
The effect of margin status and molecular subtype on women with invasive breast cancer treated with breast-conservation therapy.
Authors: Jared Forrester, Adam D. Currey, Bonifride Tuyishimire, Jonathan Lin, Amanda L. Kong
Journal: Journal of Clinical Oncology (2014)

83 Background: A consensus statement was recently published by SSO/ASTRO on margins for stage I and II invasive breast cancer treated with breast conserving surgery (BCS). We examined patients with invasive breast cancer who underwent BCS to determine if margin status and molecular subtype influence outcomes. Methods: We the reviewed charts of 754 Stage I-III breast cancer patients treated with BCS from 2003-2010. Margin status was defined as negative ≥ 2mm, close &lt; 2mm and positive as tumor on ink. Conventional receptor analyses were used as markers for molecular subtype classification (luminal A, luminal B, Her2 positive, and basal). Clinicopathologic variables were tested using the Fisher’s exact, Chi-square, ANOVA F-test, and Kruskal-Wallis tests. A Cox proportional - Hazards model was used to measure the impact of these variables on locoregional recurrence (LRR), breast cancer-specific (BCSS) and overall survival (OS). Results: The median age of the cohort was 58 (range 27-89 years). Most were white (88%), had T1 tumors (76%), luminal A tumors (66%), invasive ductal histology (80%), and were node negative (76%). Of the 754 patients, 26% had close margins, 2% positive margins, and 9% unknown margins. With a median follow-up of 5.2 years, OS was 92%. Twenty eight patients had a LRR with a median time to recurrence of 5.1 years. On multivariate analysis, molecular subtype, pathologic grade (p=0.01), and use of radiation (p&lt;0.0001) were the only significant predictors of LRR. Unknown subtype, compared to Luminal A, was less likely to have a LRR (p=0.04). Basal (p=0.0002), Her2+ (p=0.03), Luminal B (p=0.002) and unknown subtype (p=0.04) had worse BCSS compared to Luminal A tumors. Margins had no impact on LRR or BCSS but those with close margins and unknown margins had worse OS compared to negative margins (p=0.01, p=0.007). Variables predictive of OS were margins, age, race, node status, chemotherapy, anti-endocrine therapy, and radiation. Conclusions: In this cohort treated with BCS, molecular subtype was a predictor of LRR and BCSS but not OS. Margin status did not impact LRR and BCSS. Although margin status was a predictor of OS, tumor biology remains the significant determinant of outcome.
Autofluorescence (safe) bronchoscopy and p21/ki67immunostaining utilizing to distinguish areas of particularattention related to carcinogenesis.Preliminary report.
Authors: Teodor Horváth, Marie MUDr. Horváthová, Jindřich Vomela, Rostislav Vyzula, Číhalová, Ebihara Y, Okada S, FurukawaK, Kakihana, Ikeda N, Aleš Rejthar, J Klusáková, Bohdan Šmajer, Špelda, Tsuboi M, Shaffi-Sahely A, Václav Vagunda, F. Wurst, H. Kato
Journal: European Respiratory Journal (2002)

Autofluorescence (safe) bronchoscopy and p21/ki67
immunostaining utilizing to distinguish areas of particular
attention related to carcinogenesis.Preliminary report.
Abstract 1184: Hdl Protects Macrophages From Oxidized Ldl-induced Apoptosis By Promoting Efflux Of 7-ketocholesterol Via Abcg1
Authors: NAOKI TERASAKA, Nan Wang, Laurent Yvan-Charvet, Alan R Tall
Journal: Circulation (2007)

Oxidized sterols consumed in the diet or formed on low-density lipoprotein (LDL) are toxic to endothelial cells and macrophages and are thought to have a central role in promoting atherogenesis. The ATP-binding cassette transporter ABCG1 was recently shown to promote efflux of cholesterol from macrophages to HDL. We show that HDL protects macrophages from apoptosis induced by loading with free cholesterol or oxidized LDL (oxLDL). The protective effect of HDL was reduced in Abcg1 −/− macrophages, especially after loading with oxidized LDL. Similarly, HDL exerted a protective effect against apoptosis induced by 7-ketocholesterol, the major oxysterol present in oxLDL and atherosclerotic lesions, in Abcg1 +/+ but not in Abcg1 −/− macrophages. In transfected 293 cells, efflux of 7-ketocholesterol was completely dependent on expression of ABCG1 and presence of HDL in media. In contrast, ABCA1 and apoA-1 did not stimulate efflux of 7-ketocholesterol into media. HDL stimulated efflux of 7-ketocholesterol from Abcg1 +/+ but not from Abcg1 −/− macrophages, and Abcg1 −/− macrophages accumulated 7-ketocholesterol in mice fed the Western diet. The findings indicate a specific role of ABCG1 in promoting efflux of 7-ketocholesterol from macrophages onto HDL, and in protecting these cells from oxysterol-induced toxicity.
ETE 3: Reconstruction, Analysis, and Visualization of Phylogenomic Data
Authors: Jaime Huerta-Cepas, François Serra, Peer Bork
Journal: Molecular Biology and Evolution (2016)

The Environment for Tree Exploration (ETE) is a computational framework that simplifies the reconstruction, analysis, and visualization of phylogenetic trees and multiple sequence alignments. Here, we present ETE v3, featuring numerous improvements in the underlying library of methods, and providing a novel set of standalone tools to perform common tasks in comparative genomics and phylogenetics. The new features include (i) building gene-based and supermatrix-based phylogenies using a single command, (ii) testing and visualizing evolutionary models, (iii) calculating distances between trees of different size or including duplications, and (iv) providing seamless integration with the NCBI taxonomy database. ETE is freely available at http://etetoolkit.org.
GEP analysis validates high risk MDS and acute myeloid leukemia post MDS mice models and highlights novel dysregulated pathways
Authors: Laura Guerenne, Stéphanie Beurlet, Mohamed Said, Petra Gorombei, Carole Le Pogam, Fabien Guidez, Pierre de la Grange, Nader Omidvar, Valérie Vanneaux, Ken Mills, Ghulam J Mufti, Laure Sarda-Mantel, Maria Elena Noguera, Marika Pla, Pierre Fenaux, Rose Ann Padua, Christine Chomienne, Patricia Krief
Journal: Journal of Hematology & Oncology (2016)

In spite of the recent discovery of genetic mutations in most myelodysplasic (MDS) patients, the pathophysiology of these disorders still remains poorly understood, and only few in vivo models are available to help unravel the disease. We performed global specific gene expression profiling and functional pathway analysis in purified Sca1+ cells of two MDS transgenic mouse models that mimic human high-risk MDS (HR-MDS) and acute myeloid leukemia (AML) post MDS, with NRASD12 and BCL2 transgenes under the control of different promoters MRP8NRASD12/tethBCL-2 or MRP8[NRASD12/hBCL-2], respectively. Analysis of dysregulated genes that were unique to the diseased HR-MDS and AML post MDS mice and not their founder mice pointed first to pathways that had previously been reported in MDS patients, including DNA replication/damage/repair, cell cycle, apoptosis, immune responses, and canonical Wnt pathways, further validating these models at the gene expression level. Interestingly, pathways not previously reported in MDS were discovered. These included dysregulated genes of noncanonical Wnt pathways and energy and lipid metabolisms. These dysregulated genes were not only confirmed in a different independent set of BM and spleen Sca1+ cells from the MDS mice but also in MDS CD34+ BM patient samples. These two MDS models may thus provide useful preclinical models to target pathways previously identified in MDS patients and to unravel novel pathways highlighted by this study.
Outbreak of Foodborne Botulism Associated with Improperly Jarred Pesto — Ohio and California, 2014
Authors: Patrick Burke, Michael Needham, Brendan R. Jackson, Rick Bokanyi, Eric St. Germain, Steven J. Englender
Journal: MMWR Morbidity and Mortality Weekly Report (2016)

On July 28, 2014, the Cincinnati Health Department was notified of suspected cases of foodborne botulism in two women admitted to the same hospital 12 days apart. Patient A had been treated for 12 days for suspected autoimmune disease. When patient B, the roommate of patient A, was evaluated at the same medical center for similar symptoms, it was learned that on July 13, patient A and patient B had shared a meal that included prepackaged pesto from a jar; clinicians suspected botulism and notified the local health department. The pesto had been purchased from company A's farm stand in San Clemente, California. Laboratory testing detected botulinum toxin type B by enzyme-linked immunosorbent assay (ELISA) in leftovers of pasta with pesto. A culture of these food samples yielded Clostridium spp. that produced botulinum toxin type B; polymerase chain reaction (PCR) testing also was positive for type B toxin gene. Environmental assessment of company A identified improper acidification and pressurization practices and lack of licensure to sell canned products commercially, including products in hermetically-sealed jars. On July 30, the vendor voluntarily recalled all jarred products, and the California Department of Public Health (CDPH) warned the public not to consume company A's jarred foods. This report describes the two cases and the public health investigation that traced the source of the outbreak.
Validity of the modified stoke ankylosing spondylitis spine score (M-SASSS) and of the bath ankylosing spondylitis radiology index (BASRI) for the radiological assessment of axial involvement in psoriatic arthritis. multicentre validation study. Part one.
Authors: E Lubrano, A Marchesoni, I Olivieri, S D'Angelo, A Spadaro, Wj Parsons, A Cauli, C Salvarani, E Zaccara, R Scrivo, M Catanoso, Alessandro Mathieu, G Porru, N Pappone, P. Helliwell
Journal: Annals of the Rheumatic Diseases (2007)
A comparative study on capecitabine (Cape) pharmacokinetics (PK) in elderly or younger patients with metastatic breast (MBC) or colo-rectal cancer (CRC)
Authors: C. Longobardi, E. Strocchi, F. Di Fabio, C. M. Camaggi, N. Zoli, A. A. Martoni
Journal: Journal of Clinical Oncology (2006)

12003 Background: Cape is an efficient oral prodrug of 5FU in MBC and CRC. Unexpected severe toxicity in older patients (pts) was reported after standard dose of 2500mg/sm/day. About 70% of drug and metabolites are excreted with the urine and a 25% reduction of the dose is recommended if the pt has a creatinine clearance (CrCl) &lt;50ml/min. However no prospective study has been done on Cape PK in the elderly pts. Methods: Between Oct 2004 and Nov 2005, 21 pts with MBC or CRC and age ≥70yrs or ≤60yrs who received Cape (1000 mg/sm bid for 14 days every 21 days) entered the study after giving signed informed consent. CrCl was calculated according to the Cockcroft-Gault method. Patient characteristics: 15 elderly pts (median 78 range71–84yrs), 6 younger pts (median 50.5 range 43–57yrs); 9 (42.9%) males and 12 (57.1%) females; median KPS 90 (range 70–100); 8 MBC pts (38%), 13 CRC pts (62%). Blood samples were taken on the first day of treatment at time 0 and at 0.25,0.5,1,2,3,4,5,6,8 hrs after the first drug administration and on 4 th , 8 th , 12 th and 14 th days in the morning. Plasma levels of Cape, 5DFUR, 5DFCR and 5FU were determined by a validated HPLC method and UV detection. Results: At present PK data after the first administration of Cape are available for 13 pts (9 elderly; 4 younger). The mean Cape and 5DFCR AUC 0–8hr are higher in older patients (Cape 6653±2564.8 vs. 4427±2714.5; P=0.09; 5DFCR 8635±5197.1 vs. 6292±3813.6; P=0.26), while no evident differences are present for 5DFUR and 5FU. The same results are obtained both in pts with CrCl &lt; and ≥ 50 ml/min. The ratios of DFUR_AUC to Cape_AUC and 5FU_AUC to Cape_AUC are conversely higher in younger than in older pts (mean: 2.2 vs 1.62). A large interindividual variability in the concentration/time curves is present for Cape and metabolites. Cape dose reduction because of G3 toxicity (2 hand-foot syndrome, 1 stomatitis) was performed in 3 elderly pts. Drug systemic exposure was higher in 2 of these pts independently of CrCl. Conclusions: The preliminary results of this PK study suggest that elderly patients treated with Cape at 1000 mg/sm/bid are more drug-exposed than younger patients, independently of renal function. PK analysis is ongoing for the remaining patients. No significant financial relationships to disclose.
Angiotensin II as a renal growth factor.
Authors: G Wolf, E G Neilson
Journal: Journal of the American Society of Nephrology (1993)

Angiotensin II (ANG II) can have multiple effects on the kidney, including influences on the regulation of glomerular hemodynamics and tubular transport as well as consequences for the glomerular processing of macromolecules. The recognized suppressive effects of angiotensin-converting enzyme inhibitors on compensatory renal growth, even in the absence of hemodynamic effects, and the well-documented proliferative effect of ANG II on vascular smooth muscle cells have provided the background for the recent intensive interest in this peptide as a renal cytokine. Diverse cell types along the nephron express a variety of ANG II receptors. These receptors and their putative signal transduction pathways have been best characterized in mesangial and proximal tubular cells. Culture experiments provide convincing evidence that ANG II can be a phenotypic influence on these cell types. The growth responses and the associated signal transduction pathways, however, are different in mesangial and proximal tubular cells. These ANG II-mediated responses are also associated with an increase in the synthesis of distinct collagen subtypes, potentially linking the growth stimulatory effects of ANG II to the irreversible changes of glomerulosclerosis and tubulointerstitial fibrosis observed in chronic renal failure. Preventing the intrarenal actions of ANG II with angiotensin-converting enzyme inhibitors or with the new, orally active, selective ANG II receptor antagonists may provide a rational therapeutic approach to attenuate the progression of a variety of kidney diseases.
Clinical Responses to EGFr-TKI’s characterized by drug-induced cell death in human NSCLC primary cultures
Authors: R. A. Nagourney, M. Paulsen, D. Mc Connell, R. Shuman
Journal: Journal of Clinical Oncology (2007)

18184 Background: Small molecule inhibitors of the EGFr have proven effective in advanced NSCLC but response rates in unselected populations remain low. Certain subsets of patients appear favored including females, non-smokers and Asians. Molecular profiles suggest that gene amplification or EGFr mutations (codons 19–21) may underlie responses. Our prior observations (Proc. AACR 2002, Abs.3902) indicated that gefitinib and erlotinib induced cell-death in human tumor microspheroids isolated from surgical specimens of some NSCLC patients, suggesting programmed cell death to be an important mechanism of action for these molecules. As part of an IRB-approved clinical trial, patients whose tumors were found sensitive to the EGFr-TKI’s by laboratory analysis, received 1 st line single agent oral erlotinib at 150 mg/day. Methods: Following informed consent, NSCLC patients participating in the trial provided tissue for analysis as previously described (J Clin Oncol, 2000 18: 2245–2249). Dose response curves provided LC50 values by interpolation. Modified Z-score analysis identified patients sensitive to the EGFr-TKI’s by comparison with a database of over 900 EGFr-TKI analyses. Results: Three female caucasian patients were found more sensitive to EGFr-TKI’s than cytotoxic chemotherapy (2 non- &amp; 1 former smoker). All 3 responded to erlotinib, 2 near-CR by PET, 1 lasting 19 months, the 2 nd continuing at 10 months, with a 3 rd patient in continuous PR at month 6. Toxicities have been moderate. One near-CR had virtually no skin rash. The molecular profile of 1 near-CR revealed no known gain of function mutation but instead a novel mutation in the EGFr domain. Conclusions: Exposure of human NSCLC microspheroids to EGFr-TKI’s in short term culture results in cell death events associated with clinical response, suggesting that programmed cell death is an important determinant of clinical response to these agents. This is consistent with the concept of oncogene addiction, in tumors driven by EGFr upregulation. Accrual to this trial continues. Supported by the Memorial Medical Center Foundation. [Table: see text]