tbuckley/cabot-search huggingface dataset:
Patients' preferences for adjuvant sorafenib after resection of intermediate or high-risk renal cell carcinoma in the SORCE trial: What makes it worthwhile?
Authors: Prunella Louise Blinman, Ian D. Davis, Andrew Martin, Simon Troon, Shomik Sengupta, Elizabeth J. Hovey, Xanthi Coskinas, Richard S. Kaplan, Alastair W. S. Ritchie, Angela M. Meade, Tim Eisen, Martin R. Stockler
Journal: Journal of Clinical Oncology (2015)

415 Background: SORCE is an international, double-blind, placebo-controlled, phase 3 trial comparing adjuvant sorafenib for 1 year, for 3 years, or observation after resection of intermediate or high risk (as per the Leibovich score), localised renal cell carcinoma (RCC). We determined the survival benefits that SORCE participants judged necessary to make adjuvant sorafenib worthwhile 3 months after starting study treatment. Methods: Participants recruited to SORCE from Australia and selected UK sites completed a validated, self-administered questionnaire 3 months after starting study treatment to determine the minimum survival benefits they judged necessary to make adjuvant sorafenib worthwhile. Scenarios used baseline survival times (without adjuvant sorafenib) of 5 and 15 years; and baseline survival rates (without adjuvant sorafenib) of 65% and 85% at 5 years. Preferences were determined for 1 year of adjuvant sorafenib (versus none) and for 3 years of adjuvant sorafenib (versus 1 year). All tests were 2-sided and non-parametric. This substudy of SORCE was conducted by the Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP). Results: The 179 participants were mostly male (72%) with a median age of 57 years (range 29 to 78). Participants allocated sorafenib judged larger benefits necessary to make 1 year of adjuvant sorafenib worthwhile than those allocated placebo: median benefit of an extra 1 year versus an extra 1 month for baselines of 5 years (p=0.004) and 15 years (p=0.02); median benefit of an extra 5% versus an extra 1% for baseline of 65% (p=0.03), and an extra 3% versus an extra 1% for a baseline of 85% (p=0.07). Larger survival benefits were judged necessary to make 3 years of adjuvant sorafenib worthwhile (versus 1 year) regardless of treatment allocation: median benefit of an extra 2 months to 1 year for baselines of 5 years (p=0.02) and 15 years (0.02). Conclusions: Experienced toxicity and duration of treatment are important determinants of patients’ preferences for adjuvant sorafenib in RCC.
Investigating a holobiont: Microbiota perturbations and transkingdom networks
Authors: Renee Greer, Xiaoxi Dong, Andrey Morgun, Natalia Shulzhenko
Journal: Gut Microbes (2016)

The scientific community has recently come to appreciate that, rather than existing as independent organisms, multicellular hosts and their microbiota comprise a complex evolving superorganism or metaorganism, termed a holobiont. This point of view leads to a re-evaluation of our understanding of different physiological processes and diseases. In this paper we focus on experimental and computational approaches which, when combined in one study, allowed us to dissect mechanisms (traditionally named host-microbiota interactions) regulating holobiont physiology. Specifically, we discuss several approaches for microbiota perturbation, such as use of antibiotics and germ-free animals, including advantages and potential caveats of their usage. We briefly review computational approaches to characterize the microbiota and, more importantly, methods to infer specific components of microbiota (such as microbes or their genes) affecting host functions. One such approach called transkingdom network analysis has been recently developed and applied in our study.Citation1 Finally, we also discuss common methods used to validate the computational predictions of host-microbiota interactions using in vitro and in vivo experimental systems.
Schizophrenia: affect and outcome
Authors: T E Gift, J S Strauss, R F Kokes, D W Harder, B A Ritzler
Journal: American Journal of Psychiatry (1980)

Considerable data suggest that schizophrenic patients with affective symptoms have a more favorable outcome than other schizophrenic patients. This may indicate that such patients are more validly regarded as having either an affective disorder or a schizoaffective psychosis. Studies of this issue have suffered from significant methodologic problems, including inappropriate sampling, unsystematic collection of symptom data, unreliable diagnostic procedures, and restricted outcome assessment. The present study, designed to surmount these methodologic difficulties, indicates that while levels of psychotic symptoms in schizophrenic patients correlate with poor outcome, affective symptoms have little prognostic power.
Prediction of 5-year survival of non-small cell lung cancer patients with stage IIIA and IIIB after complete resections
Authors: O. Kshivets
Journal: Journal of Clinical Oncology (2004)

7235 Background: The influence of clinicomorphological data on 5-year (5Y)survival (5YS) and life span (LS) of non-small lung cancer (LC) patients (LCP) with stage III after radical resections (R0) was investigated. Methods: In trial (1985–2003) the data of consecutive 139 LCP (age=57.8±0.6 years; m=129, f=10; LC diameter=5.6±0.2 cm; pneumonectomy=75, lobectomy=64, combined procedures with resection of pericardium, left atrium, aorta, v. cava superior, carina, diaphragm, ribs=67; only surgery=54, adjuvant chemoimmunoradiotherapy - AT=40: CAV/gemzar + thymalin/taktivin + radiotherapy 45–50 Gy, postoperative radiotherapy 45–50 Gy - PR=45) with stage III (squamous cell=94, adenocarcinoma=34, large cell=11; stage IIIA=109, stage IIIB=30; T1=11, T2=48, T3=50, T4=30; N0=13, N1=32, N2=94; G1=24, G2=31, G3=84) was reviewed. Variables selected for 5YS study were input levels of blood factors, sex, age, TNMG. Survival curves were estimated by Kaplan-Meier method. Differences in curves were evaluated using a log-rank test. Neural networks, Cox regression, clustering, discriminant analysis, structural equation modeling and Monte Carlo simulation were used to determine any significant regularity. Results: General LS was 1019.3±82.9 days (median=519). 49 LCP (35.3%) were alive, 44 from them lived more than 5Y (31.7%) without any features of LC. 87 LCP (62.6%) died because of generalization during the first 5Y after surgery. Cox modeling displayed that 5YS of LCP (n=139) after complete resections significantly depended on: N0–2 (P=0.027), histology (P=0.002), G1–3 (P=0.036), character of operation (P=0.010), AT (P=0.0003), 20 blood factors (P=0.001–0.044). Neural networks computing and genetic algorithm selection revealed relationships between 5YS of LCP and AT (rank=1), G1–3 (2), PR (3), N0–2 (4), tumor growth (5), histology (6), procedure type (7), stage IIIA/IIIB (8), monocytes (9), ESS (10). Conclusions: Correct prediction of LCP 5YS after radical procedures was 75.6% by logistic regression (odds ratio=7.57), 85.5% by discriminant analysis and 100% by neural networks computing (area under ROC curve=1.0; error=0.0027). No significant financial relationships to disclose.
Phase II open-label study to investigate efficacy and safety of PTK787/ZK 222584 (PTK/ZK) orally administered once daily or twice daily at 1,250 mg as second-line monotherapy in patients (pts) with stage IIIB/IV non-small cell lung cancer (NSCLC)
Authors: T. C. Gauler, B. Besse, J. B. Meric, V. Gounant, B. Fischer, T. Overbeck, H. Krissel, D. Laurent, J. C. Soria, W. E. Eberhardt
Journal: Journal of Clinical Oncology (2007)

7541 Background: Overexpression of vascular endothelial growth factor receptor (VEGF-R) in NSCLC-tumors is linked to poor prognosis and shorter overall survival (OS). PTK/ZK is a novel, oral, anti-angiogenic compound blocking all currently known VEGF receptors (VEGF-R 1–3). Methods: A prospective, single-arm, multi-center, proof-of-principle phase II study to investigate efficacy and safety of PTK/ZK in pretreated pts with stage IIIB/IV NSCLC. Only one platinum-based chemotherapy regimen was allowed as first-line treatment. 55 pts each were planned to receive a fixed dose of 1,250 mg PTK/ZK once daily (qd) or twice daily (500 mg a.m. + 750 mg p.m.) (bid) for continuous treatment until disease progression or unacceptable toxicities. Response evaluation was based on RECIST. A disease stabilization of at least 12 weeks was defined as clinically relevant drug activity. Additional biomarker evaluation included DCE-MRI and serum proteomics. Results: Enrolment is completed with 54 pts starting qd and 58 pts starting bid treatment. Most frequent adverse events in both cohorts were nausea (44%), vomiting (40%), and dizziness (34%). Three possibly related deaths were observed, 2 due to pulmonary hemorrhage and 1 due to pulmonary embolism. Best response by RECIST for the qd cohort (n=54) include 1 pt with a confirmed partial response (cPR) (2%), 32 pts (59%) with stable disease (SD) at week 4, hereof 18 pts (33%) for at least 12 weeks, and 21 pts (39%) with progressive disease (PD); for the bid cohort (n=57) 4 pts with cPR (7%), 18 pts (32%) with SD (=12 weeks), 19 pts (33%) not yet evaluated, and 16 pts (28%) with PD. Progression free survival (PFS)/OS were 2.4/7.0 months (mo) for the qd vs. 3.7/6.8 mo for the bid cohort. Conclusions: These results suggest that both qd and bid second-line treatment with single-agent PTK/ZK is generally safe and well tolerated. In this unfavorable pt population a considerably high rate of disease control could be achieved. Four pts with PR out of 38 evaluated pts in the bid cohort might indicate additional benefit of bid dosing. Final data of the primary endpoint (efficacy) for both cohorts will be presented at the meeting. [Table: see text]
New Developments in the Treatment of Castration-Resistant Prostate Cancer
Authors: Celestia S. Higano
Journal: Journal of the National Comprehensive Cancer Network (2014)

During the past 4 years, a host of new agents have been approved for the treatment of patients with advanced prostate cancer. As a result, selecting the right agent for the right patient at the right time is a clinical challenge. At the NCCN 19th Annual Conference, Dr. Celestia Higano explored the rationale behind such therapeutic decisions and the supporting clinical trial data. She reviewed the different classes of therapeutic agents, from immunotherapy and hormonal therapies to chemotherapy and radioisotopes, and offered suggestions for the clinical scenarios in which they may be used most successfully.
Endoscopic ultrasound-guided fine needle aspiration of a pericardial mass
Authors: Piyush Somani, Malay Sharma, Amol Patil, Avinash Kumar
Journal: Endoscopy (2016)

The prevalence of primary pericardial neoplasms ranges from about 0.001 % – 0.007 %. Primary malignant pericardial mesothelioma is extremely rare, with a reported prevalence of 0.0022 % in autopsy series [1]. Although malignant mesothelioma is the most common primary malignancy of the pericardium, only approximately 350 cases of pericardial mesothelioma have been reported in the literature.
T cell development runs marrow deep
Authors: Juan Carlos Zúñiga-Pflücker
Journal: The Journal of Experimental Medicine (2015)

The Journal of Experimental Medicine Communication between cells is vital for maintenance of immune homeostasis and is also required for rapid and effective immune responses.Nowhere is this balance of activity more important than at mucosal surfaces such as the respiratory tract, where resident cells must ignore potentially antigenic inhaled material while responding swiftly to clear viruses and bacteria.In this issue, Bourdonnay et al. describe a novel form of intercellular communication that helps to explain how alveolar macrophages and epithelial cells maintain pulmonary homeostasis.The function of SOCS proteins is to constrain JAK-STAT signaling and repress inflammatory reactions.We do not usually expect to find these intracellular signaling molecules in extracellular compartments, but Bourdonnay et al. showed that lung-resident alveolar macrophages (AMs) were able to secrete SOCS1 within exosomes and SOCS3 within extracellular microparticles.Uptake of these extracellular vesicles by alveolar epithelial cells (AECs) allowed SOCS1 and -3 to suppress STAT signaling following activation by cytokines.The authors demonstrated that this novel extracellular transfer system was promoted by IL-10 and PGE 2 and inhibited by LPS.The phenomenon was demonstrated in a number of model systems including both rats and mice and also, importantly, in human AMs.Moreover, secretion was not simply dependent on expression of SOCS3, because fibroblasts expressed high levels of SOCS3 but did not secrete it.Any in vitro finding needs to be robustly tested in vivo to demonstrate a physiologic effect.The authors showed that SOCS3 was abundant in bronchiolar lavage (BAL) even in naive mice; SOCS3 levels increased after administration of PGE 2 to the lungs and decreased after pulmonary delivery of LPS.Moreover, SOCS3 was retrieved from BAL from healthy human volunteers.Interestingly, exposure to cigarette smoke reduced levels of both SOCS1 and -3 in both mice and humans; so, smoking could lead to unchecked JAK-STAT activation, thereby contributing to inflammatory responses.Although it remains to be seen whether this particular form of epithelial-macrophage communication operates during respiratory infection, these data are important because they shed some light on the complex interactions that maintain homeostasis within the lung.It may be possible to exploit this system in order to down-regulate inflammation following infection and ultimately facilitate the restoration of immune homeostasis.
Etoposide and cytosine arabinoside combination chemotherapy for refractory acute lymphocytic leukemia in childhood.
Authors: N Esumi, S Todo, S Arakawa, S Imashuku
Journal: Journal of Clinical Oncology (1986)

Eighteen children with refractory acute lymphocytic leukemia (ALL) who had been heavily pretreated, were treated with combination etoposide and cytosine arabinoside (ara-C) chemotherapy. Seventeen of these 18 patients were in their first to third relapses; the remaining patient had never responded to induction therapy. The drug combination of etoposide followed by ara-C was administered as an intravenous (IV) infusion twice a week for two consecutive weeks, a total of four doses. The dosage was 150 mg/m2/dose for each drug. Seven (39%) of the 18 patients attained a complete remission (CR) and three (17%) attained a partial remission (PR). Complete response was obtained in two of eight patients in first marrow relapse, and in five of nine patients in second and third relapse. Five patients achieved a CR after one course of therapy and two achieved a CR after two courses of therapy. Of three patients who had previously received teniposide, two attained a CR with this combination. The duration of these responses was brief with a median of 1 month, ranging from 0.5 to 3 months, with the exception of one case, which has been in remission for 2.5 + months. Although myelosuppression was observed, none of the patients died from infection or bleeding. Allergic reaction with fever and rash was observed in two patients. The efficacy of the etoposide and ara-C combination for refractory childhood ALL is encouraging in several current reinduction regimens.
P70 Can antiviral therapy for hepatitis C reduce the prevalence of HCV among injecting drug user populations? A modelling analysis of its prevention utility
Authors: M Hickman, N Martin, P Vickerman, S Hutchinson, D Goldberg, G Foster
Journal: Gut (2010)

Introduction  HCV antiviral treatment (peginterferon and ribavirin) is effective for individual patients, but few active injecting drug users (IDUs) are treated.  Aim  We considered the utility of antiviral treatment for reducing HCV transmission amongst active IDUs.  Method  An HCV transmission model amongst IDUs was developed, incorporating HCV antiviral treatment. We projected the chronic prevalence reductions resulting from different treatment rates over 5–40 years. Treatment efficacy was varied for three genotype scenarios (mixed, genotype 1, and genotype 2/3) and assumed to result in IDUs becoming susceptible (75%) or resistant/immune (25%). Two models were considered with treatment non-responders either allowed (unrestricted model) or not allowed (restricted model) to be retreated with the same success rates.  Results  In the unrestricted model with mixed genotype, annually treating 10 infections per 1000 IDUs results in a relative decrease in HCV prevalence over 10 years of 31%, 14% or 7% for baseline (untreated endemic chronic infection) prevalences of 20%, 40% or 60%, respectively. Prevalence reductions are lower (by ∼25% at this treatment level) for populations with all genotype 1 and similarly higher for genotype 2/3 populations. Reduction of prevalence to negligible levels within 20 years could be achieved by treating 21 infections per 1000 IDUs annually with 20% baseline prevalence, increasing to 53 or 99 in the 40% and 60% prevalence situation. Restricting retreatment does not alter the short-term ( 55%). Lastly, the HCV free life years gained from treating active IDUs are projected to be higher than from treating non-IDUs for prevalences below 60%.  Conclusion  Despite the possibility of re-infection, modest rates of HCV treatment amongst active IDUs could effectively reduce transmission. Evaluating and extending strategies to treat HCV among active injectors is warranted.
Early versus Late Parenteral Nutrition in Critically Ill Children
Authors: Tom Fivez, Dorian Kerklaan, Dieter Mesotten, Sascha Verbruggen, Pieter J. Wouters, Ilse Vanhorebeek, Yves Debaveye, Dirk Vlasselaers, Lars Desmet, Michael P. Casaer, Gonzalo Garcia Guerra, Jan Hanot, Ari Joffe, Dick Tibboel, Koen Joosten, Greet Van den Berghe
Journal: New England Journal of Medicine (2016)

Recent trials have questioned the benefit of early parenteral nutrition in adults. The effect of early parenteral nutrition on clinical outcomes in critically ill children is unclear.We conducted a multicenter, randomized, controlled trial involving 1440 critically ill children to investigate whether withholding parenteral nutrition for 1 week (i.e., providing late parenteral nutrition) in the pediatric intensive care unit (ICU) is clinically superior to providing early parenteral nutrition. Fluid loading was similar in the two groups. The two primary end points were new infection acquired during the ICU stay and the adjusted duration of ICU dependency, as assessed by the number of days in the ICU and as time to discharge alive from ICU. For the 723 patients receiving early parenteral nutrition, parenteral nutrition was initiated within 24 hours after ICU admission, whereas for the 717 patients receiving late parenteral nutrition, parenteral nutrition was not provided until the morning of the 8th day in the ICU. In both groups, enteral nutrition was attempted early and intravenous micronutrients were provided.Although mortality was similar in the two groups, the percentage of patients with a new infection was 10.7% in the group receiving late parenteral nutrition, as compared with 18.5% in the group receiving early parenteral nutrition (adjusted odds ratio, 0.48; 95% confidence interval [CI], 0.35 to 0.66). The mean (±SE) duration of ICU stay was 6.5±0.4 days in the group receiving late parenteral nutrition, as compared with 9.2±0.8 days in the group receiving early parenteral nutrition; there was also a higher likelihood of an earlier live discharge from the ICU at any time in the late-parenteral-nutrition group (adjusted hazard ratio, 1.23; 95% CI, 1.11 to 1.37). Late parenteral nutrition was associated with a shorter duration of mechanical ventilatory support than was early parenteral nutrition (P=0.001), as well as a smaller proportion of patients receiving renal-replacement therapy (P=0.04) and a shorter duration of hospital stay (P=0.001). Late parenteral nutrition was also associated with lower plasma levels of γ-glutamyltransferase and alkaline phosphatase than was early parenteral nutrition (P=0.001 and P=0.04, respectively), as well as higher levels of bilirubin (P=0.004) and C-reactive protein (P=0.006).In critically ill children, withholding parenteral nutrition for 1 week in the ICU was clinically superior to providing early parenteral nutrition. (Funded by the Flemish Agency for Innovation through Science and Technology and others; ClinicalTrials.gov number, NCT01536275.).
Influence of Renal Insufficiency on Levels of Serum Ribonuclease in Patients With Multiple Myeloma 2
Authors: Timothy P. Karpetsky, Richard L. Humphrey, Carl C. Levy
Journal: JNCI Journal of the National Cancer Institute (1977)

Journal Article Influence of Renal Insufficiency on Levels of Serum Ribonuclease in Patients With Multiple Myeloma Get access Timothy P. Karpetsky, Timothy P. Karpetsky Search for other works by this author on: Oxford Academic PubMed Google Scholar Richard L. Humphrey, Richard L. Humphrey Search for other works by this author on: Oxford Academic PubMed Google Scholar Carl C. Levy Carl C. Levy Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 58, Issue 4, April 1977, Pages 875–880, https://doi.org/10.1093/jnci/58.4.875 Published: 01 April 1977 Article history Received: 26 May 1976 Accepted: 27 September 1976 Published: 01 April 1977
Population pharmacokinetic (PK)/pharmacodynamic (PD) modeling and simulations for exposure‐;tumor response relationships: Motesanib in a phase II thyroid cancer (TC) trial
Authors: J. Lu, L. Claret, L. Sutjandra, M. Kuchimanchi, D. Stepan, R. Bruno, R. Melara, Y. Sun
Journal: Journal of Clinical Oncology (2009)

e14528 Background: Motesanib is a highly selective, oral inhibitor of VEGF receptors 1, 2, and 3; PDGFR; and Kit that is being investigated for its antitumor activity. In a phase 2 monotherapy study, a response rate of 14% (per RECIST) was observed in patients (pts) with differentiated thyroid cancer (DTC; NEJM 359:31–42, 2008) compared with 1% in pts with medullary TC (MTC; Endocr Soc Ann Meeting 2007, abstract OR39–3). We evaluated the relationship between motesanib PK and tumor response, investigated whether differences in PK between MTC and DTC pts contributed to the observed difference in response, and simulated tumor response with different dose regimens in pts with TC. Methods: Data from the phase 2 TC trial were used for PK/PD modeling. The study enrolled 93 DTC and 91 MTC pts who received motesanib 125 mg once daily (QD). Motesanib concentrations were fitted to a 2- compartment population PK model. Estimates of pts’ PK parameters were used to calculate concentration and steady-state area under the curve values for motesanib, which were used as the exposure measures in population PK/PD modeling (ie, longitudinal exposure-tumor response modeling of drug effect on tumor growth dynamics). Monte Carlo simulations were used to evaluate the potential effect of doses other than 125 mg QD (75 mg and 100 mg QD) on tumor response in TC pts. Results: Clearance in MTC pts was 40% faster than in DTC pts (74 vs 44 L/h). The fit was significantly improved (P&lt;0.001) when exposure instead of dose was used in the model. The exposure-tumor response model that incorporated the difference in exposure described change in tumor size well in both MTC and DTC populations. Clinical trial simulations using the preliminary model based on week 24 data predicted that DTC pts would achieve 19.7%, 15.7%, and 11.3% reductions in tumor size at week 24 following doses of 125 mg QD, 100 mg QD, and 75 mg QD, respectively. The actual change in median tumor size at week 24 following 125-mg QD dosing in DTC pts included in the PK/PD analysis was 17.9%. Conclusions: The use of 125 mg QD motesanib in DTC pts was supported by PK/PD modeling and Monte Carlo simulations. Differences in PK may explain the difference in tumor response observed in MTC and DTC patient populations. [Table: see text]