tbuckley/cabot-search huggingface dataset:
Idiopathic Retroperitoneal Fibrosis
Authors: Augusto Vaglio, Federica Maritati
Journal: Journal of the American Society of Nephrology (2016)

Idiopathic retroperitoneal fibrosis (RPF), reviewed herein, is a rare fibro-inflammatory disease that develops around the abdominal aorta and the iliac arteries, and spreads into the adjacent retroperitoneum, where it frequently causes ureteral obstruction and renal failure. The clinical phenotype of RPF is complex, because it can be associated with fibro-inflammatory disorders involving other organs, is considered part of the spectrum of IgG4-related disease, and often arises in patients with other autoimmune conditions. Obstructive uropathy is the most common complication, although other types of renal involvement may occur, including stenosis of the renal arteries and veins, renal atrophy, and different types of associated GN. Environmental and genetic factors contribute to disease susceptibility, whereas the immunopathogenesis of RPF is mediated by different immune cell types that eventually promote fibroblast activation. The diagnosis is made on the basis of computed tomography or magnetic resonance imaging, and positron emission tomography is a useful tool in disease staging and follow-up. Treatment of idiopathic RPF aims at relieving ureteral obstruction and inducing disease regression, and includes the use of glucocorticoids, combined or not with other traditional immunosuppressants. However, biologic therapies such as the B cell–depleting agent rituximab are emerging as potentially efficacious agents in difficult-to-treat cases.
Community Care: The First Year: Community care in Bassetlaw
Authors: T Groves
Journal: BMJ (1994)

Last April the United Kingdom's system for providing community care--practical and social care for ill and disabled people who need help with daily life--was changed in an effort to make it better and more efficient. The BMJ ran a series of articles about the changes that included descriptions of community care in four places: Gwent in Wales, Bassetlaw in Nottinghamshire, Northern Ireland, and Newcastle in north east England. In this and the next three articles we look at what has happened to community care over the past year in these places.
P-127 Efficacy of Y-Shaped Bilateral Self-Expandable Metallic Stent Placement in Patients with Unresectable Hilar Cholangiocarcinoma
Authors: J.J. Hyun, H.S. Lee, J.M. Lee, I.K. Yoo, S.H. Kim, S.J. Nam, H.S. Choi, E.S. Kim, B. Keum, Y.T. Jeen, H.J. Chun, C.D. Kim
Journal: Annals of Oncology (2015)
A Randomized Phase II/III Study of Naptumomab Estafenatox + IFNα versus IFNα in Renal Cell Carcinoma: Final Analysis with Baseline Biomarker Subgroup and Trend Analysis
Authors: Robert E. Hawkins, Martin Gore, Yaroslav Shparyk, Vladimir Bondar, Oleg Gladkov, Tosho Ganev, Mihai Harza, Serhii Polenkov, Igor Bondarenko, Petr Karlov, Oleg Karyakin, Rustem Khasanov, Gunnar Hedlund, Goran Forsberg, Örjan Nordle, Timothy Eisen
Journal: Clinical Cancer Research (2016)

Abstract Purpose: To prospectively determine the efficacy of naptumomab estafenatox (Nap) + IFNα versus IFN in metastatic renal cell carcinoma (RCC). Experimental Design: In a randomized, open-label, multicenter, phase II/III study, 513 patients with RCC received Nap (15 μg/kg i. v. in three cycles of four once-daily injections) + IFN (9 MU s.c. three times weekly), or the same regimen of IFN monotherapy. The primary endpoint was overall survival (OS). Results: This phase II/III study did not meet its primary endpoint. Median OS/PFS for Nap + IFN patients was 17.1/5.8 months versus 17.5/5.8 months for the patients receiving IFN alone (P = 0.56; HR, 1.08/P = 0.41; HR, 0.92). Post hoc exploratory subgroup and trend analysis revealed that the baseline plasma concentrations of anti-SEA/E-120 (anti-Nap antibodies) for drug exposure and IL6 for immune status could be used as predictive biomarkers. A subgroup of patients (SG; n = 130) having concentrations below median of anti-SEA/E-120 and IL6 benefitted greatly from the addition of Nap. In SG, median OS/PFS for the patients treated with Nap + IFN was 63.3/13.7 months versus 31.1/5.8 months for the patients receiving IFN alone (P = 0.02; HR, 0.59/P = 0.02; HR, 0.62). Addition of Nap to IFN showed predicted and transient immune related AEs and the treatment had an acceptable safety profile. Conclusions: The study did not meet its primary endpoint. Nap + IFN has an acceptable safety profile, and results from post hoc subgroup analyses showed that the treatment might improve OS/PFS in a baseline biomarker-defined RCC patient subgroup. The results warrant further studies with Nap in this subgroup. Clin Cancer Res; 22(13); 3172–81. ©2016 AACR.
Intrapatient consistency of imatinib pharmacokinetics (PK) in patients (pts) with advanced cancers
Authors: P. L. Abrams, M. J. Egorin, R. K. Ramanathan, R. A. Parise, T. F. Lagattuta, M. Hayes, B. Peng, S. P. Ivy, A. Murgo, S. Remick
Journal: Journal of Clinical Oncology (2004)

2081 Background: Imatinib (STI-571), approved for treatment of CML & GIST, is administered as daily PO therapy and is primarily metabolized by CYP3A. By analyzing PK data from pts receiving daily imatinib, we examined whether chronic dosing is associated with induction or impairment of imatinib clearance. Methods: 46 pts receiving daily imatinib (100–800 mg) for advanced cancers underwent intensive PK sampling on days 1 & 15. 20 pts had acceptable (NL) renal function (CLCr ≥60 mL/min). 26 pts had renal impairment (RI). Imatinib concentrations were quantitated by LC/MS. Plasma imatinib C x t data were modeled using non-compartmental methods. The elimination rate constant (k) was calculated using the plasma t1/2 (k=0.693/t1/2) & used to determine the accumulation index (1/1-e-kτ), where τ is the dosing interval. Accumulation (d15 AUC/d1 AUC) was calculated for each pt & compared to the predicted accumulation index ratio. Results: There was large inter-pt variability in imatinib t1/2 & AUC on days 1 & 15 (table below). Except in 2 pts with severe RI, intra-pt variability in imatinib PK was small, as indicated by each pt's day 15 AUC agreeing well with that predicted by the accumulation index. Conclusions: Over 2 weeks of daily dosing, intra-pt imatinib PK was consistent. These data suggest sustained dosing is not associated with induction or impairment of imatinib clearance. Support: NCI No. N01-CO-12400, 2P30 CA47904, Novartis Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Pharmaceuticals Corp. Novartis Pharmaceuticals Corp. Novartis Pharmaceuticals Corporation
Progression-free survival in a phase II study of perioperative bevacizumab plus XELOX in patients with potentially curable metastatic colorectal cancer
Authors: T. Gruenberger, K. Kaczirek, M. Bergmann, C. C. Zielinski, B. Gruenberger
Journal: Journal of Clinical Oncology (2008)

4073 Background: Patients (pts) with colorectal cancer (CRC) and liver metastases have a poor prognosis and may benefit from perioperative chemotherapy and disease resection. The impact of bevacizumab (BEV) on the prolongation of progression-free survival (PFS) in the perioperative setting has not been evaluated. Methods: Metastatic CRC patients with liver metastases potentially curable by resection were eligible for this single-centre phase II trial. Eligibility criteria define pts at high risk of early recurrence: synchronous, multiple or large liver metastases. Pts received BEV 5mg/kg q2 weeks plus XELOX (capecitabine 3,500mg/m2/day days 1–7 plus oxaliplatin 85mg/m2 day 1 of a 2-week cycle) for 6 cycles prior to liver surgery and 6 cycles thereafter. Feasibility has already been shown and the aim of this analysis is the long term benefit of the perioperative approach. Results: 56 patients have been enrolled and 52 curative resected pts are evaluable for PFS having received a median of 6 cycles of BEV plus XELOX in the neoadjuvant setting. Overall response rate was 73% (CR 9%, PR 64%), SD was achieved in 21%. After a median follow-up of 20 months the actual mean PFS of all patients is 27 months (95% CI 23.6–30.5). A significant PFS difference was noticed dependent upon response to neoadjuvant treatment (CR 100% recurrence-free, PR 75%, SD 36%; p < 0.001). A Cox regression model revealed response to neoadjuvant chemotherapy significantly correlated to a prolonged progression-free survival (p < 0.001). Additionally completion of adjuvant chemotherapy had an independent influence on PFS (p = 0.04). Synchronous disease, large metastases, multiple tumors and bilobar metastases were of no influence on PFS. Overall survival was also significantly influenced by response to treatment (p < 0.01), with no death in the CR group, 2 PR pts died, one without tumor recurrence and 4 tumor related deaths in the SD group. Conclusions: These data suggest that the perioperative combination of Bevacizumab with XELOX can sufficiently increase progression-free survival in resected mCRC patients. Our data highlight the importance to identify responding patients, who seem to benefit most from the combination of bevacizumab, chemotherapy, and surgery. No significant financial relationships to disclose.
A multicentric phase II trial of gemcitabine (Gem), oxaliplatin (Oxa) and vinorelbine (VNB) in untreated stage IIIB and IV non-small cell lung cancer (NSCLC) patients (pts): Preliminary results of GON triplet regimen
Authors: J. Tredaniel, C. Becht, M. Bekradda, S. Culine, H. De Cremoux, J. Misset, A. Alexandre, F. Goldwasser, F. Chomy, E. Ecstein-Fraisse, E. Cvitkovic
Journal: Journal of Clinical Oncology (2006)

17104 Background: Oxa, Gem and VNB are active agents against NSCLC and have shown synergy in combination. VNB plus Gem showed efficacy comparable to platinum combinations with a more favorable toxicity profile, while Oxa/VNB and Oxa/Gem combinations have established recommended doses. Platinum given on day 2 after Gem appears safer and more active. A fixed Gem infusion rate of 10 mg/m 2 /min is a pharmacologically optimized dosing intended to provide plasma concentrations (≈20 μmol/L) sufficient to maximize the rate of Gem triphosphate accumulation. The aim of the trial was to assess the efficacy (response rate) and safety of GON regimen. Methods: Chemo naive pts with stage IIIB and IV NSCLC received VNB 25 mg/m 2 , 20-min IV followed by Gem 700 mg/m 2 in 10 mg/m 2 /min IV on day 1, and Oxa 85 mg/m 2 , 2h IV, on day 2, cycles repeated every 2 weeks. 88 pts are planned in a two-stage design. Results: From February 2004 to November 2005, 39 pts were eligible and treated: 26M/13F; median age: 58 (36–75) years; PS 0/1: 17/22; stage IIIB/IV: 6/33; 21 adenocarcinoma, 9 squamous, 9 large cell carcinoma. Metastatic sites were 67% lung, 21% liver, 36% bone. 229 cycles (cyc) were administered; median cycles/pt 8. Relative dose intensity: Oxa 89%, VNB 94%, Gem 100%. Thirty-four pts were assessable for response (RECIST, external radiological panel review), 5 pts too early: 1 CR, 14 PR (44% ORR, 95% CI 27–62%) with a median OR duration of 12.5 months (range: 3.1–19+), 9 SD, 10 PD. Median follow-up of 6 months (1–21) with median TTP of 4.6 months (95% CI: 1.0–8.3, range: 1–19+); estimated 6-month survival: 80%. Safety is assessable in 38 pts with grade 3–4 toxicities (pts/cyc): neutropenia 6/18, febrile neutropenia 1/1, anemia 1/2, neurotoxicity 3/4, diarrhea 2/3, vomiting 1/1, transaminitis 2/3. Conclusions: The GON triplet is a safe and active outpatient regimen in advanced NSCLC. If these promising results are confirmed in the full cohort, the regimen warrants comparison with standard doublet regimens. [Table: see text]
Safety of bevacizumab (BV) among patients (pts) receiving first-line chemotherapy (CT) for metastatic colorectal cancer (mCRC): Preliminary results from a larger registry in the U.S
Authors: M. Kozloff, A. Cohn, N. Christiansen, P. Flynn, F. Kabbinavar, R. Robles, M. Ulcickas Yood, S. Sarkar, J. Hambleton, A. Grothey
Journal: Journal of Clinical Oncology (2005)

3566 Background: In a phase III pivotal trial in pts with mCRC, BV (Avastin) increased overall survival when added to first-line irinotecan, fluorouracil, and leucovorin. Safety data from that trial have been described, and indicate that certain serious adverse events (SAEs, primarily gastrointestinal perforations [GI perfs]) occurred more often in pts who received CT with BV than those who received CT alone. Methods: To evaluate targeted safety events of BV in unselected pts, a surveillance registry was opened to enroll 2000 mCRC pts in the US receiving BV with first-line CT (choice of CT was at physician’s discretion). Eligibility criteria have been minimized to facilitate enrollment of a broad mCRC population. Data collected at baseline include history of hypertension, stroke or myocardial infarction, diabetes, hypercholesterolemia, atrial fibrillation, chronic anticoagulant or aspirin use, peptic ulcer disease, diverticulosis, and recent surgery or endoscopy. Pts are followed for up to 3 years, and clinical data (including survival, disease progression, changes in CT or BV regimen, interim surgery or endoscopy, and SAE occurrence) are collected every 3 months. Results: Through 11/10/04, 932 pts (male 54%; median age 63 [range 26–92]; PS 0–1 87%; primary colon 80%) have been enrolled from 267 sites in 49 states. The most common first-line CT regimens used with BV are FOLFOX (47.7%), FOLFIRI (15.3%), IFL (13.9%), and bolus 5FU/LV (8.2%). Four hundred fifty-two pts have had a 3-month follow-up assessment; 167 pts have had a 6-month assessment. From these 932 pts, 71 BV-related SAEs have been reported from 59 pts (6.3% of enrolled pts), including 16 GI perfs (1.7%) and 3 post-operative hemorrhage or wound-healing complications (0.3%); other reported SAEs include GI symptoms, infection, thromboembolic events, and non-surgical bleeding. Conclusions: In this large ongoing registry, the safety profile of BV in a broad population of mCRC pts receiving a variety of CT regimens appears consistent with that observed in the pivotal trial. Updated safety data (including additional SAEs) will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Genentech, Sanofi-Synthelabo Genentech Genentech, Sanofi-Synthelabo Genentech Genentech
Biomarkers in the Diagnosis of ST-Segment Elevation Myocardial Infarction
Authors: Guillaume Leurent
Journal: JAMA Internal Medicine (2016)

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Phase I Pharmacotoxicology Study of Human Fibroblast Interferon in Human Cancers&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;
Authors: T A McPherson, Y H Tan
Journal: JNCI Journal of the National Cancer Institute (1980)

Twelve patients with advanced cancer were treated with human fibroblast interferon. Interferon administered im in doses up to 10x106 ⋃ three times weekly for 2 weeks was associated with highly variable, but detectable, plasma levels. Bolus interferon given iv was associated with a reproducible, immediate peak of activity followed by a rapid loss of detectable activity. Continuous infusion of interferon over 2 hours resulted in a slowly increasing dose-related level to a maximum near the end of the infusion followed by a loss of detectable activity for about 1 hour following infusion. Interferon administered both im and iv caused a mild, easily tolerated pyrexia as the only regularly occurring side effect. In 1 patient interferon treatment suppressed a malignant clone of circulating blasts trisomic for chromosomes #8 and 21 from 59 to 0%.
Response to Letters Regarding Article, “Early Detection of Anthracycline Cardiotoxicity and Improvement With Heart Failure Therapy”
Authors: Daniela Cardinale, Alessandro Colombo, Giulia Bacchiani, Ines Tedeschi, Carlo A. Meroni, Maurizio Civelli, Giuseppina Lamantia, Nicola Colombo, Carlo M. Cipolla, Fabrizio Veglia, Cesare Fiorentini, Giuseppe Curigliano
Journal: Circulation (2016)
Pharmacological Inhibition of the Histone Lysine Demethylase KDM1A Suppresses the Growth of Multiple Acute Myeloid Leukemia Subtypes
Authors: John P. McGrath, Kaylyn E. Williamson, Srividya Balasubramanian, Shobu Odate, Shilpi Arora, Charlie Hatton, Thomas M. Edwards, Thomas O'Brien, Steven Magnuson, David Stokoe, Danette L. Daniels, Barbara M. Bryant, Patrick Trojer
Journal: Cancer Research (2016)

Lysine-specific demethylase 1 (KDM1A) is a transcriptional coregulator that can function in both the activation and repression of gene expression, depending upon context. KDM1A plays an important role in hematopoiesis and was identified as a dependency factor in leukemia stem cell populations. Therefore, we investigated the consequences of inhibiting KDM1A in a panel of cell lines representing all acute myelogenous leukemia (AML) subtypes using selective, reversible and irreversible KDM1A small-molecule inhibitors. Cell models of AML, CML, and T-ALL were potently affected by KDM1A inhibition, and cells bearing RUNX1-RUNX1T1 (AML1-ETO) translocations were especially among the most sensitive. RNAi-mediated silencing of KDM1A also effectively suppressed growth of RUNX1-RUNX1T1-containing cell lines. Furthermore, pharmacologic inhibition of KDM1A resulted in complete abrogation of tumor growth in an AML xenograft model harboring RUNX1-RUNX1T1 translocations. We unexpectedly found that KDM1A-targeting compounds not only inhibited the catalytic activity of the enzyme, but evicted KDM1A from target genes. Accordingly, compound-mediated KDM1A eviction was associated with elevated levels of local histone H3 lysine 4 dimethylation, and increased target gene expression, which was further accompanied by cellular differentiation and induction of cell death. Finally, our finding that KDM1A inhibitors effectively synergize with multiple conventional as well as candidate anti-AML agents affords a framework for potential future clinical application. Cancer Res; 76(7); 1975-88. ©2016 AACR.
COX-2 status is a significant factor to predict a postoperative survival as well as an efficacy of postoperative adjuvant therapy in non-small cell lung cancer
Authors: F. Tanaka, K. Takenaka, K. Yanagihara, M. Fukushima, H. Wada
Journal: Journal of Clinical Oncology (2004)

9556 Background: Clinical significance of biomarkers in non-small cell lung cancer (NSCLC) remains unclear, and an exact and quantitative evaluation of biomarkers may be required to clarify the clinical significance. Methods: A total of 110 patients (pts) with completely resected p-stage I NSCLC were reviewed. RNAs were isolated from laser-captured tumor cells, and gene expression of VEGF, COX-2, MMP-2, MMP-9, EGFR, p27, TS, DPD, TP, and OPRT was quantitatively evaluated by a real-time RT-PCR assay. Results: COX-2 gene expression status was the only significant prognostic factor (Table), and a multivariate analysis confirmed that high COX-2 gene expression was an independent factor to predict a poor prognosis (p=0.005, RR=3.848 [95% CI, 1.500–9.874]). COX-2 gene expression status also predicted the efficacy of postoperative adjuvant chemotherapy using UFT (an oral 5-FU derivative); UFT administration was effective for low COX-2 gene-expression tumor (5-year survival rate, 93% for UFT-treated pts and 67% for surgery-alone pts; p=0.045), and was not effective for high COX-2 gene-expression tumor (5-year survival rate, 64% for UFT-treated pts and 62% for surgery-alone pts; p=0.677). COX-2 protein-expression status determined immunohistochemically was well correlated with COX-2 gene-expression status (p=0.001). However, COX-2 protein-expression status was not a significant prognostic factor nor a significant predictive factor of UFT administration. Conclusions: High COX-2 gene-expression in tumor cells was a significant factor to predict not only a poor prognosis but also an inefficacy of postoperative adjuvant chemotherapy for resected NSCLC. No significant financial relationships to disclose.
End TB with precision treatment!
Authors: Evelien P.M. van der Burgt, Marieke G.G. Sturkenboom, Mathieu S. Bolhuis, Onno W. Akkerman, Jos G.W. Kosterink, Wiel C.M. de Lange, Frank G.J. Cobelens, Tjip S. van der Werf, Jan-Willem C. Alffenaar
Journal: European Respiratory Journal (2016)

We read with interest the recent Perspective paper by Lönnroth et al. [1] describing a framework for tuberculosis (TB) elimination. In our opinion, monitoring drug exposure by measuring blood concentrations over time (therapeutic drug monitoring (TDM)) may be helpful in contributing to TB elimination in low- and medium-burden setting. TB precision treatment, including optimised drug exposure in relation to drug susceptibility testing, may help end TB <http://ow.ly/Utu2u>