tbuckley/cabot-search huggingface dataset:
Limited sampling models for doxorubicin pharmacokinetics.
Authors: M J Ratain, J Robert, W J van der Vijgh
Journal: Journal of Clinical Oncology (1991)

Although doxorubicin is one of the most commonly used antineoplastics, no studies to date have clearly related the area under the concentration-time curve (AUC) to toxicity or response. The limited sampling model has recently been shown to be a feasible method for estimating the AUC to facilitate pharmacodynamic studies. Data from two previous studies of doxorubicin pharmacokinetics were used, including 26 patients with sarcoma and five patients with breast cancer or unknown primary. The former were divided into a training data set of 15 patients and a test datum set of 11 patients, and the latter patients formed a second test data set. The model was developed by stepwise multiple regression on the training data set: AUC (nanogram hour per milliliter) = 17.39 C2 + 163 C48-111.0 [dose/(50 mg/m2)], where C2 and C48 are the concentrations at 2 and 48 hours after bolus dose. The model was subsequently validated on both test data sets: first test data set--mean predictive error (MPE), 4.7%; root mean square error (RMSE), 12.4%; second test data set--MPE, 4.5%, RMSE, 9.2%. An additional model was also generated using a simulated time point to estimate the total AUC for a daily x 3-day schedule: AUC (nanogram hour per milliliter) = 44.79 C2 + 175.65 C48 + 47.25 [dose/(25 mg/m2/d)], where the C48 is obtained just prior to the third dose. We conclude that the AUC of doxorubicin after bolus administration can be adequately estimated from two timed plasma concentrations.
Impact of Concurrent PIK3CA Mutations on Response to EGFR Tyrosine Kinase Inhibition in EGFR-Mutant Lung Cancers and on Prognosis in Oncogene-Driven Lung Adenocarcinomas
Authors: Juliana Eng, Kaitlin M. Woo, Camelia S. Sima, Andrew Plodkowski, Matthew D. Hellmann, Jamie E. Chaft, Mark G. Kris, Maria E. Arcila, Marc Ladanyi, Alexander Drilon
Journal: Journal of Thoracic Oncology (2015)
Tumor-suppressor p53: implications for tumor development and prognosis.
Authors: D G Kirsch, M B Kastan
Journal: Journal of Clinical Oncology (1998)

The p53 protein plays a central role in modulating cellular responses to cytotoxic stresses by contributing to both cell-cycle arrest and programmed cell death. Loss of p53 function during tumorigenesis can lead to inappropriate cell growth, increased cell survival, and genetic instability. p53 gene mutations occur in approximately half of all malignancies from a wide range of human tumors. In some tumor types, these p53 mutations are associated with poor prognosis and treatment failure. Based on these insights, new approaches are being developed to prevent, diagnose, and treat cancer.
Meta-analysis of adjuvant chemotherapy in gastric cancer: a critical reappraisal.
Authors: J P Pignon, M Ducreux, P Rougier
Journal: Journal of Clinical Oncology (1994)

Article Tools Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.1994.12.4.877 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 8151332 Meta-analysis of adjuvant chemotherapy in gastric cancer: a critical reappraisal. J P PignonxJ P PignonSearch for articles by this author , M DucreuxxM DucreuxSearch for articles by this author , P RougierxP RougierSearch for articles by this author https://doi.org/10.1200/JCO.1994.12.4.877 PDF "Meta-analysis of adjuvant chemotherapy in gastric cancer: a critical reappraisal.." Journal of Clinical Oncology, 12(4), pp. 877–878© 1994 by American Society of Clinical Oncology
Effect of FGFR1 on epithelial-mesenchymal transition and EGFR resistance in HNC: A systems biology approach.
Authors: Damian Rieke, Zhixiang Zuo, Apoorva Chawla, Michaela K. Keck, Katharina Endhardt, Petra Fang, Arun Khattri, Johannes Braegelmann, Mark W. Lingen, Everett E. Vokes, Tanguy Y. Seiwert
Journal: Journal of Clinical Oncology (2014)

6091 Background: Fibroblast Growth Factor Receptor 1 (FGFR1) plays an important role in cancer and is an emerging treatment target for squamous lung cancer and other tumor types. We determined the functional implicatiosn of FGFR1 signaling using a systems biology approach. Methods: 120 HNSCC tumor samples from patients treated at Univ. of Chicago were analyzed. We determined copy number alterations (Nanostring, +qPCR validation), gene expression (Agilent) as well as mutations (Illumina)and employed in-silico modeling/published gene expression signatures (GSEA) to investigate receptor kinases as well as mechanisms correlated with FGFR1 signaling. HNC TCGA data was used for validation. Secondly we performed in-vitro validation in a panel of 12 HNSCC cell lines. Viability testing was performed with PD173074, ponatinib, gefitinib, as well as combinations of these drugs. Immunoblotting was performed for MAPK and AKT pathways, Vimentin and E-Cadherin total protein. Results: FGFR1 copy number gain occurred in 3% or our cohort and 8% of TCGA samples and was most prominent in laryngeal tumors. Interestingly high FGFR1 expression were identified in 20% of HNSCC and highly correlated with Epithelial-to-Mesenchymal Transition (EMT) (p<0.001). Several additional receptor Tyrosine Kinases (RTKs) strongly correlated with EMT including PDGFRA, PDGFRB, AXL, and ACVRL1 (TGF-beta pathway). By contrast EGFR and MET expression strongly correlated with an epithelial phenotype. We identified 6 mesenchymal-like and 6 non-mesenchymal-like cell lines out of a panel of 40 cell lines. Mesenchymal cell lines were resistant to Epidermal Growth Factor Receptor-inhibition with gefitinib, but combined FGFR and EGFR inhibition showed strong synergy in these resistant cell lines. Ponatinib showed the highest level of activity, due to evidence of co-inhibition of other EMT associated kinases. Conclusions: FGFR1 drives the EMT phenotype in HNC, and is a valid treatment target that may help overcome EGFR resistance when used in combination.
Abstract 12635: Surgical Treatment of Atrial Fibrillation: Effects of Different Techniques on Atrial Mechanical Function
Authors: Seth H Sheldon, John P Bois, John M Stulak, Naser M Ammash, Peter A Brady, Grace Lin
Journal: Circulation (2013)

Introduction: Multiple techniques exist for surgical treatment of atrial fibrillation (AF) including cut and sew (C&S), cryo and radiofrequency (RF) ablation. Restoration and maintenance of sinus rhythm, however, does not guarantee improved left atrial mechanical function (LAMF). We sought to determine the effect of surgical AF treatment technique on LAMF. Methods: Echocardiograms were retrospectively reviewed for adult patients that underwent a left atrial surgical AF treatment between 2004 and 2010. Eligible patients had an echocardiogram in sinus rhythm or atrial paced rhythm preceding and > three months following surgery. Clinical, surgical, and echocardiographic variables were compared. LAMF was defined as: present (presence of A wave on mitral inflow and A’ on medial mitral annular tissue Doppler imaging), partial (either A or A’ present), or absent (neither A or A’ present). Active left atrial emptying fraction (LAEF) was determined by percent reduction in left atrial area from the onset of the P w...
The prognostic significance of early molecular and cytogenetic response for long-term progression-free and overall survival in imatinib-treated chronic myeloid leukemia (CML).
Authors: Rudiger Hehlmann, Benjamin Hanfstein, Martin C Müller, Philipp Erben, Michael Lauseker, Alice Fabarius, Susanne Schnittger, Claudia Haferlach, Gudrun Goehring, Stefan W. Krause, Jolanta Dengler, Christiane Falge, Andreas Neubauer, Frank Stegelmann, Michael Pfreundschuh, Karsten Spiekermann, Gabriela M Baerlocher, Joerg Hasford, Susanne Saussele, Andreas Hochhaus
Journal: Journal of Clinical Oncology (2012)

6510 Background: In the face of competing first line treatment options for CML early prediction of prognosis on imatinib is desirable to assure favorable survival or otherwise consider the use of an alternative therapy. We sought to evaluate the prognostic impact of early response landmarks. Methods: A total of 1,303 newly diagnosed imatinib-treated patients (pts) from the randomized CML Study IV were investigated to correlate molecular and cytogenetic response at 3 and 6 months with progression-free and overall survival (PFS, OS). Median follow-up was 4.7 years (range 0-9). The BCR-ABL expression was determined by quantitative RT-PCR and standardized according to the international scale (BCR-ABL IS ). The proportion of Philadelphia-chromosome positive metaphases (Ph+) was determined by conventional metaphase analysis. To confirm the prognostic significance of early molecular response, an independent validation sample of 174 pts treated with imatinib within the IRIS trial was analyzed. Results: The persistence of &gt;10% BCR-ABL IS at 3 months separated a high-risk group (28% of pts; 5-year OS: 87%) from a group with 1-10% BCR-ABL IS (41% of pts; 5-year OS: 94%; p=0.012), and from a group with &lt;1% BCR-ABL IS (31% of pts; 5-year OS: 97%; p=0.004). By cytogenetics high-risk patients could be identified by the persistence of &gt;35% Ph+ (27% of pts; 5-year OS: 87%) as compared to ≤35% Ph+ (73% of pts; 5-year OS: 95%; p=0.036). At 6 months the &gt;1% BCR-ABL IS group (37% of pts; 5-year OS: 89%) showed inferior survival compared to ≤1% (63% of pts; 5-year OS: 97%; p&lt;0.001); survival of the &gt;0% Ph+ group (34% of pts; 5-year OS: 91%) was inferior to 0% Ph+ (66% of pts; 5-year OS: 97%; p=0.015). Regarding the IRIS pts 3 month BCR-ABL IS &gt;10% (25% of pts; 8-year OS: 81%) was associated with inferior survival compared to ≤10% (75% of pts; 8-year OS: 93%; p=0.011). Conclusions: Failure to achieve the response landmarks of 10% BCR-ABL IS or 35% Ph+ at 3 months of imatinib treatment and 1% BCR-ABL IS or 0% Ph+ at 6 months identifies high-risk patients which might benefit from an early change of therapy.
Policy Solutions for Better Hearing
Authors: Christine Cassel, Ed Penhoet, Robert Saunders
Journal: JAMA (2016)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Low chronic workload and the acute:chronic workload ratio are more predictive of injury than between-match recovery time: a two-season prospective cohort study in elite rugby league players
Authors: Billy T Hulin, Tim J Gabbett, Peter Caputi, Daniel W Lawson, John A Sampson
Journal: British Journal of Sports Medicine (2016)

Background Between-match recovery time, and acute and chronic workloads likely affect subsequent match-injury risk in elite rugby league players. Methods Workloads of 28 players throughout two seasons were calculated during short (&lt;7 days), and long (≥7 days) between-match recovery times. ‘Acute’ workloads (1 week) greater than ‘chronic’ workloads (4-week rolling average acute workload) resulted in acute:chronic workload ratios above 1. Results No difference was found between the match-injury risk of short and long between-match recovery periods (7.5±2.5% vs 6.8±2.5%). When players had a short recovery between matches, high chronic workloads (18.9–22.0 km) were associated with a smaller risk of match injury than chronic workloads &lt;18.9 km (relative risk (RR) range 0.27–0.32 (CI 0.08 to 0.92); likelihood range 90–95%, likely). Players who had shorter recovery and acute:chronic workload ratios ≥1.6, were 3.4–5.8 times likely to sustain a match injury than players with lower acute:chronic workload ratios (RR range 3.41–5.80 (CI 1.17 to 19.2); likelihood range 96–99%, very likely). Acute:chronic workload ratios between 1.2 and 1.6 during short between-match recovery times demonstrated a greater risk of match injury than ratios between 1.0 and 1.2 (RR=2.88 (CI 0.97 to 8.55); likelihood=92%, likely). Conclusions Contrary to the philosophy that high workloads and shorter recovery equate to increased injury risk, our data suggest that high and very-high chronic workloads may protect against match injury following shorter between-match recovery periods. Acute:chronic workload ratios ∼1.5 are associated with a greater risk of match injury than lower acute:chonic workload ratios. Importantly, workloads can be manipulated to decrease the match-injury risk associated with shorter recovery time between matches.
PARP inhibition reverses radiation resistance conferred by ETS fusions in prostate cancer.
Authors: F. Y. Feng, S. Han, C. Brenner, A. Sabolch, D. A. Hamstra, T. S. Lawrence, A. Chinnaiyan
Journal: Journal of Clinical Oncology (2011)

4545 Background: ETS gene fusions are considered to be driving mutations in approximately half of all prostate cancers. They result in overexpression of an ETS transcription factor, of which ERG is the prototype. We previously discovered that ERG interacts with the DNA damage response protein poly(ADP-ribose)polymerase 1 (PARP1) in human prostate cancer specimens. Therefore, we hypothesized that the ERG-PARP1 interaction may confer radiation resistance by increasing DNA repair efficiency, and this radioresistance can be reversed with PARP1 inhibition. Methods: We used lentiviral approaches to establish isogenic models of ERG overexpression in PC3 and DU145 prostate cancer cell lines. We then assessed the role of ERG overexpression on 1) clonogenic survival, 2) PARP1 activity (via immunoblots for poly ADP-ribose (PAR) formation), and 3) DNA repair (via COMET assays and immunofluorescent microscopy for gamma-H2aX foci), following radiation in the absence and presence of the PARP inhibitor olaparib. Results: In both PC3 and DU145 cells, ERG overexpression resulted in a 1.3 fold increase in clonogenic survival following radiation. ERG overexpression also resulted in increased PARP1 activity. PARP1 inhibition with olaparib preferentially radiosensitized ERG-positive cells, by a factor of 1.5 relative to ERG-negative cells (p<0.05). Neutral and alkaline COMET assays demonstrated that ERG overexpression results in statistically smaller mean tail moments at 15 minutes following radiation, consistent with increased efficiency of short-term DNA repair. Immunofluoresence microscopy showed significantly quicker resolution of gamma-H2aX foci in ERG-positive cells at 6 and 24 hours after radiation, consistent with improved long-term DNA repair. Olaparib treatment eliminated the increased DNA repair efficiency conferred by ERG overexpression. Conclusions: In these prostate cancer cell models, ERG overexpression confers radiation resistance via increased efficiency of DNA repair following radiation. This radioresistance can be reversed via inhibition of PARP1. These novel findings motivate the use of PARP1 inhibitors as radiosensitizers in patients with localized ETS fusion-positive prostate cancers.
US pediatricians call for tougher rule enforcement to reduce football injuries
Authors: Michael McCarthy
Journal: BMJ (2015)

US football coaches and game officials should improve the teaching of proper tackling techniques and enforce existing rules to reduce the incidence and severity of football injuries, the American Academy of Pediatrics has said in a policy statement released this week.1

In the statement, released on 25 October at the academy’s national conference in Washington, DC, the academy said that eliminating tackling from football would likely lead to a reduction in numbers of injuries but would also lead to a fundamental change in the way the game was played. “Participants in football must decide whether the potential health risks of sustaining these injuries are outweighed by the recreational benefits associated with proper tackling,” the academy said.

American football is an enormously popular sport, with more than 1.1 million high …
High-dose metoclopramide + lorazepam versus low-dose metoclopramide + lorazepam + dehydrobenzperidol in the treatment of cisplatin-induced nausea and vomiting
Authors: J. Herrstedt, J. Hannibal, J. Hallas, E. Andersen, L.C. Laursen, M. Hansen
Journal: Annals of Oncology (1991)
Tirapazamine Plus Cisplatin Versus Cisplatin in Advanced Non–Small-Cell Lung Cancer: A Report of the International CATAPULT I Study Group
Authors: Joachim von Pawel, Reinhard von Roemeling, Ulrich Gatzemeier, Michael Boyer, Lars Ove Elisson, Peter Clark, Denis Talbot, Augustin Rey, Thomas W. Butler, Vera Hirsh, Ian Olver, Bengt Bergman, Joseph Ayoub, Gary Richardson, David Dunlop, Anthony Arcenas, Robert Vescio, Jean Viallet, Joseph Treat
Journal: Journal of Clinical Oncology (2000)

PURPOSE: A phase III trial, Cisplatin and Tirapazamine in Subjects with Advanced Previously Untreated Non–Small-Cell Lung Tumors (CATAPULT I), was designed to determine the efficacy and safety of tirapazamine plus cisplatin for the treatment of non–small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with previously untreated NSCLC were randomized to receive either tirapazamine (390 mg/m 2 infused over 2 hours) followed 1 hour later by cisplatin (75 mg/m 2 over 1 hour) or 75 mg/m 2 of cisplatin alone, every 3 weeks for a maximum of eight cycles. RESULTS: A total of 446 patients with NSCLC (17% with stage IIIB disease and pleural effusions; 83% with stage IV disease) were entered onto the study. Karnofsky performance status (KPS) was ≥ 60 for all patients (for 10%, KPS = 60; for 90%, KPS = 70 to 100). Sixty patients (14%) had clinically stable brain metastases. The median survival was significantly longer (34.6 v 27.7 weeks; P = .0078) and the response rate was significantly greater (27.5% v 13.7%; P &lt; .001) for patients who received tirapazamine plus cisplatin (n = 218) than for those who received cisplatin alone (n = 219). The tirapazamine-plus-cisplatin regimen was associated with mild to moderate adverse events, including acute, reversible hearing loss, reversible, intermittent muscle cramping, diarrhea, skin rash, nausea, and vomiting. There were no incremental increases in myelosuppression, peripheral neuropathy, or renal, hepatic, or cardiac toxicity and no deaths related to tirapazamine. CONCLUSION: The CATAPULT I study shows that tirapazamine enhances the activity of cisplatin in patients with advanced NSCLC and confirms that hypoxia is an exploitable therapeutic target in human malignancies.
Abdominal regional hyperthermia with an annular phased array.
Authors: M D Sapozink, F A Gibbs, M J Egger, J R Stewart
Journal: Journal of Clinical Oncology (1986)

Twenty-eight patients with advanced upper-abdominal malignancy were treated at the University of Utah on a pilot protocol involving regional hyperthermia (HT) produced by the BSD-1000 HT system and the annular phased array applicator (AA), usually driven at 60 MHz. Eighty-two percent of the patients had widespread metastatic disease, and the mean tumor burden was 2,900 cc. Seventy-nine percent of the patients received concurrent radiotherapy. Acute toxicity consisted primarily of pain within the AA aperture (43%), systemic stress (43%), and nausea or vomiting (29%). Systemic stress was the most frequent power-limiting factor (46%). There were two treatment-related complications: sciatic neuritis from intramuscular injection (one) and pleural effusion from thermometry probe placement (one). Detailed thermal mapping and thermal dosimetry were performed on 26 patients. The mean thermal dosimetry parameters were quite low. Concurrent radiation doses were also quite low (mean, 1,500 rad) to avoid toxicity of sensitive organ systems within the abdomen. The objective response rate was only 18%, all partial, but 43% of the patients achieved effective symptomatic palliation. The five objective responders did survive significantly (P = .02) longer than the 23 nonresponders.
Persistence of immunotherapy survival effects of sipuleucel-T and relationship to postrandomization docetaxel use in phase III studies.
Authors: D. P. Petrylak, N. A. Dawson, T. Gardner, L. Klotz, B. D. Curti, R. C. Flanigan, M. N. Fishman, Y. Xu, J. B. Whitmore, M. W. Frohlich
Journal: Journal of Clinical Oncology (2010)

4551 Background: Sipuleucel-T is an investigational autologous active cellular immunotherapy for the treatment of metastatic castration resistant prostate cancer (CRPC). Reported here is an integrated analysis of the effect of post-randomization docetaxel use on overall survival (OS) and the observed sipuleucel-T survival effect. Methods: OS for 3 randomized, double blind, placebo controlled trials in metastatic CRPC was analyzed using a Cox regression model with treatment, adjusted for baseline PSA and LDH, and stratified by study. Docetaxel use was examined as a dichotomous and a time dependent covariate. Results: The integrated analysis included 737 randomized patients (488 sipuleucel-T: 249 placebo) with median follow-up of 36 months. Sipuleucel-T treatment was associated with a 26.5% reduction in risk of death (HR=0.735, 95% CI:0.613, 0.882, P<0.001). Post-randomization docetaxel use was reported in 363 patients (49%); observed median time to use was 8.4 months. A sipuleucel-T effect was observed in patients with subsequent docetaxel use (HR=0.825, 95% CI:0.619, 1.101) and in patients without (HR=0.693, 95% CI:0.545, 0.880). The sipuleucel-T effect was also significant in an analysis in which patients were censored at the time of docetaxel use (HR=0.714, 95% CI:0.562, 0.908, P=0.006). At baseline, patients who subsequently received docetaxel tended to be younger with greater predicted survival (Halabi 2003), and had lower alkaline phosphatase, fewer bone metastases, greater use of bisphosphonates, and less prior docetaxel use. Patients with subsequent docetaxel use had better OS compared to those without, but when entered as a time-dependent covariate, docetaxel use was not a significant predictor of OS (HR=0.941, P=0.54), and the sipuleucel- T effect remained significant (HR=0.736, 95% CI:0.613, 0.883, P<0.001). Conclusions: A sipuleucel-T treatment effect was observed both in patients who did and did not receive subsequent docetaxel. The overall sipuleucel-T treatment effect remained robust when adjusting for docetaxel use. There was no evidence to suggest that subsequent docetaxel use explains the observed sipuleucel-T effect. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Dendreon Dendreon Dendreon Dendreon
Concomitant mobilization of plasma cells and hematopoietic progenitors into peripheral blood of multiple myeloma patients: positive selection and transplantation of enriched CD34+ cells to remove circulating tumor cells
Authors: RM Lemoli, A Fortuna, MR Motta, S Rizzi, V Giudice, A Nannetti, G Martinelli, M Cavo, M Amabile, S Mangianti, M Fogli, R Conte, S Tura
Journal: Blood (1996)