tbuckley/cabot-search huggingface dataset:
Thresholds in Linear Dose-Response Models for Carcinogenesis
Authors: Nathan Mantel, W. E. Heston, Joan M. Gurian
Journal: JNCI Journal of the National Cancer Institute (1961)

This report shows how a curvilinear dose-response curve relating the number of tumors induced to the level of carcinogen employed can be reconciled with a single-stage model (insofar as the carcinogen is concerned) for carcinogenesis. This is an extension of the results of Heston and Schneiderman who showed that the number of pulmonary tumors induced in mice by dibenz[a,h]anthracene was proportional to the amount by which the dosage exceeded some “threshold” level. In the present investigation, each animal is postulated to have its own characteristic “threshold” for the carcinogen and its own characteristic “sensitivity” (increase in number of tumors per unit-dose increase). Under rather broad conditions it is demonstrated, and some hypothetical instances are given, that at sufficiently high doses there will be a linear relationship between the number of tumors per animal and the dosage used. At the lower levels curvilinearity results from the variation between individual “thresholds.” How the curvilinear and the linear portions of the response curve are related to the patterns of individual variation in “threshold” and “sensitivity” and the intercorrelation of these two are described. Data on pulmonary-tumor induction in mice by dibenz[a,h]anthracene (2 experiments) and urethan are presented. At the higher levels these show characteristic linear dose-response patterns. On the two occasions of testing, the carcinogenic activity of dibenz[a,h]anthracene differed by about a factor of 3, which may have been related to differences in particle-size distribution for the two preparations used. There was no significant difference in “thresholds” on these occasions when adjustment was made for the differences in activity. The activity of urethan was about 1 percent of that for dibenz[a,h] anthracene, and the activity-adjusted “threshold” was about the same as for dibenz[a,h]anthracene.
Evaluation of pharmacokinetic interaction between everolimus and erlotinib in patients with advanced cancer
Authors: William Petros, Karen Bullock, Hope Uronis, Dorris Lockamy, Leigh Howard, Islam Younis, Gloria Broadwater, Herbert Hurwitz, Johanna Bendell
Journal: Clinical Cancer Research (2008)

AACR Centennial Conference: Translational Cancer Medicine-- July 20-23, 2008; Monterey, CA

B3 

Background: Combined VEGF, EGFR, and mTOR inhibition with bevacizumab, erlotinib, and everolimus, respectively, may provide complimentary targeting of both tumor and stromal compartments. Everolimus and erlotinib are metabolized by, and potential inhibitors of, CYP450 3A4. Potential pharmacokinetic interactions between these agents were evaluated in a phase I /pharmacokinetic study of bevacizumab, erlotinib, and everolimus (aka BEE study).    Methods: Patients were enrolled onto this phase I/pharmacokinetic study who had confirmed malignancy which was metastatic or unresectable and for which standard curative or palliative measures did not exist or were no longer effective. Bevacizumab was administered by IV infusion (10 mg/kg) every two weeks, while everolimus (5 mg), and erlotinib (75 mg) were given as daily oral doses. Patients were enrolled onto one of two administration schedules so that within-patient pharmacokinetic comparisons could be made for both everolimus and erlotinib. Patients in treatment group A had initiation of erlotinib delayed for 1 week from initiation of erlotinib and bevacizumab (n = 9) while those in treatment group B delayed everolimus for 1 week (n = 9) on the first cycle. The systemic pharmacokinetics of everolimus, erlotinib, and its principle metabolite (OSI-420), were analyzed by LC-MS-MS methods from serial blood samples collected on days 8 and 22. Pharmacokinetic parameters of everolimus, erlotinib and OSI-420 were determined on each day and compared using standard, two stage, non-compartmental approaches. Signed rank test p-values are presented for comparing the central tendencies of day 8 to day 22 PK measures.    Results: The oral clearance of everolimus was 14.3 ± 4.8 and 11.7 ± 4.1 L/h on days 8 and 22, respectively (p = 0.039). Similarly, systemic exposure of everolimus was significantly higher on day 22 (476 ± 161 ng*hr/mL) compared to day 8 (393 ± 156 ng*hr/mL; p = 0.020). Erlotinib oral clearance was 4.6 ± 2.3 L/h on day 8, and 4.4 ± 2.7 L/h on day 22 (p = 0.65). There was also no significant difference in systemic exposure to erlotinib or OSI-420 between days 8 and 22. Erlotinib systemic exposure was lowest among those who smoked tobacco, as was systemic exposure to OSI-420.    Conclusions: The systemic exposure of erlotinib was not affected by everolimus. However everolimus exposure is increased when administered concomitantly with erlotinib. These data are consistent with previous reports demonstrating reduced clearance of another CYP450 3A4 substrate (midazolam) by erlotinib.
French drug journal is sued for criticising Protopic’s licence extension
Authors: Paul Benkimoun
Journal: BMJ (2011)

<h3>Objectives</h3> We aim to quantify the cost difference between patients with incisional cerebrospinal fluid (iCSF) leakage and those without after intradural cranial surgery. Second, the potential cost savings per patient when a decrease in iCSF leakage rate would be achieved with and without added costs for preventative measures of various price and efficacy are modelled. <h3>Design</h3> Health economic assessment from a hospital perspective based on a retrospective cohort study. <h3>Setting</h3> Dutch tertiary referral centre. <h3>Participants</h3> We included 616 consecutive patients who underwent intradural cranial surgery between 1 September 2017 and 1 September 2018. Patients undergoing burr hole surgery or transsphenoidal surgery, or who died within 1 month after surgery or were lost to follow-up were excluded. <h3>Primary and secondary outcome measures</h3> Outcomes of the cost analysis include a detailed breakdown of mean costs per patient for patients with postoperative iCSF leakage and patients without, and the mean cost difference. For the scenario analyses the outcomes are the potential cost savings per 1000 patients when a decrease in iCSF leakage would be achieved. <h3>Results</h3> Mean cost difference between patients with and without iCSF leakage was €9665 (95%CI, €5125 to €14 205). The main cost driver was hospital stay with a difference of 8.5 days. A 25% incidence reduction would result in a mean cost saving of −€94 039 (95% CI, −€218 258 to −€7077) per 1000 patients. A maximum cost reduction of −€653 025 (95% CI, −€1 204 243 to −€169 120) per 1000 patients could be achieved if iCSF leakage would be reduced with 75% in all patients, with 72 cases of iCSF leakage avoided. <h3>Conclusions</h3> Postoperative iCSF leakage after intradural cranial surgery increases healthcare costs significantly and substantially. From a health economic perspective preventative measures to avoid iCSF leakage should be pursued.
TRANSITORY PULMONARY INFILTRATIONS MISTAKEN FOR TUBERCULOSIS, WITH A REPORT OF FIVE CASES
Authors: A. A. Karan, Emanuel Singer
Journal: Annals of Internal Medicine (1942)

ExcerptFor some time the chest roentgenogram has been the most valuable diagnostic measure in the recognition of pulmonary tuberculosis. It has been shown repeatedly that physical examination of the chest as the only procedure in the diagnosis of pulmonary diseases is entirely inadequate. Spellman1 gives an illuminating exposition of this fact in a recent article relating the experience of attempting, by physical examination, to detect pulmonary tuberculosis in army recruits in 1917-1918. It is not the purpose of the present authors, therefore, to minimize the efficacy of the roentgenogram in the diagnosis of pulmonary tuberculosis.Five patients are presented, whose...
Intravenous Fibrinolytic Therapy in Central Retinal Artery Occlusion
Authors: Matthew Schrag, Teddy Youn, Joseph Schindler, Howard Kirshner, David Greer
Journal: JAMA Neurology (2015)

Central retinal artery occlusion (CRAO) is an ophthalmologic emergency that can result in blindness. At present, no proven therapy for CRAO exists. Treatment with fibrinolytic agents has shown promise but remains of unproven benefit.To assess the efficacy of systemic fibrinolytic therapy for patients with CRAO and to define a time window of efficacy.We systematically queried PubMed, Web of Science, and Scopus using the following index terms: "retinal artery occlusion" OR "retinal ischemia" AND "thrombolysis" OR "fibrinolysis" OR "tissue plasminogen activator" OR "streptokinase" OR "urokinase." Search was not limited by year of publication or language and was conducted in August 2014. In addition, we evaluated the references from relevant review articles.We assembled observational studies reporting on visual acuity outcomes after CRAO. Inclusion criteria were complete reporting of visual outcomes after CRAO (with or without fibrinolytic therapy) and a series of more than 5 patients for fibrinolysis treatment or more than 20 cases when untreated or treated with conservative modalities.Patient-level data were sought for studies reporting outcomes of treatment with fibrinolysis. Summary statistics were obtained for conservative treatment and natural history studies. The studies were weighted by the inverse of variance and merged in a random-effects model.Rate of visual recovery (defined as improvement of visual acuity from 20/200 or worse at presentation to 20/100 or better) was calculated for patients treated with fibrinolytic and conservative therapies and those who received no treatment.We obtained summary statistics from 7 studies that included 396 patients who received no treatment after CRAO and from 8 studies that included 419 patients treated with ocular massage, anterior chamber paracentesis, and/or hemodilution (conservative treatment). Patient-level data were obtained for 147 patients treated with systemic fibrinolysis. We found that fibrinolysis was beneficial at 4.5 hours or earlier after symptom onset compared with the natural history group (17 of 34 [50.0%] vs 70 of 396 [17.7%]; odds ratio, 4.7 [95% CI, 2.3-9.6]; P < .001). Absolute risk reduction was 32.3%, with a number needed to treat of 4.0 (95% CI, 2.6-6.6). We also found that conservative treatment significantly worsened visual acuity outcomes and recovery rates after CRAO compared with the natural history group (31 of 419 [7.4%; 95% CI, 3.7%-11.1%] vs 70 of 396 [17.7%; 95% CI, 13.9%-21.4%]; P < .001; number needed to harm, 10.0 [95% CI, 6.8-17.4]).Our analysis suggests that a clinical trial of early systemic fibrinolytic therapy for CRAO is warranted and that conservative treatments are futile and may be harmful.
Abstract 1913: C/EBPdelta links hypoxia and inflammation to the promotion of tumor cell stemness through inhibition of FBXW7: A molecular target for HDAC inhibitor action
Authors: Kuppusamy Balamurugan, Glenn H. Summers, Shikha Sharan, Esta Sterneck
Journal: Cancer Research (2014)

Abstract Hypoxia and inflammation are linked to progression of epithelial cancers by promoting epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs). A better understanding of the mechanisms by which these conditions augment tumor progression is necessary to combat metastases and treatment resistance. The transcription factor C/EBPδ promotes hypoxia adaptation and inflammatory signaling by inhibiting expression of FBXW7, which targets many oncoproteins (e.g. Notch, c-myc) and also C/EBPδ for degradation (Balamurugan et al., EMBO J, 2010; Nature Commun 2013). FBXW7 is also known to regulate self-renewal, differentiation and quiescence of neural and hematopoietic stem cells. Therefore, we hypothesized that C/EBPδ supports the development of CSCs through inhibition of FBXW7 and that this pathway has potential as therapeutic target. We investigated the roles of C/EBPδ and FBXW7 through overexpression and silencing approaches in human breast tumor cell lines and primary mouse mammary tumors; followed by gene expression analyses and assays for stem cell-like functions under hypoxia and in response to interleukin 6 (IL-6). We found that C/EBPδ augments _ while FBXW7 inhibits _ hypoxia- and IL-6-induced formation of mammospheres, a surrogate assay for stem cell function, and expression of markers for EMT and CSCs. Furthermore, C/EBPδ was necessary for hypoxia-induced expression of IL-6, providing a link between these pathways. Indeed, silencing of C/EBPδ delayed the outgrowth of MCF-7 xenograft tumors, indicating that C/EBPδ supports CSC development. Because C/EBPδ can interact with histone deacetylases (HDACs), we tested the effect of HDAC inhibitors (HDACi) that are in clinical trials for breast cancer (e.g. SAHA). HDACi inhibited C/EBPδ expression and induced FBXW7 expression. Furthermore, HDACi reduced mammosphere formation specifically under hypoxia, and this effect could be partially reversed by FBXW7 knockdown. These results suggest a therapeutic benefit of HDACi for breast cancer through activation of FBXW7 and inhibition of C/EBPδ followed by reduction in CSCs. Future investigations will explore drug combinations with HDACi to maximize the effectiveness of the FBXW7 tumor suppressor pathway under hypoxia and inflammatory conditions. Citation Format: Kuppusamy Balamurugan, Glenn H. Summers, Shikha Sharan, Esta Sterneck. C/EBPdelta links hypoxia and inflammation to the promotion of tumor cell stemness through inhibition of FBXW7: A molecular target for HDAC inhibitor action. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1913. doi:10.1158/1538-7445.AM2014-1913
Issues in Prostate Cancer Screening
Authors: M J Friedrich
Journal: JAMA (1999)

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Specialist registrar training
Authors: G. Catto
Journal: BMJ (2000)

Papers p 832 

The headline news from the NHS has made grim reading this year: funding crises, shortages of beds, and crimes. The public is increasingly aware of our unenviable record of morbidity and mortality from cardiovascular diseases and cancer, and constructive criticism has been replaced by the destructive soundbite. The perception is of an NHS that has gone downhill since the halcyon days of the 1950s—overwhelmed by bureaucracy and initiatives that impede advances in clinical practice.1

Yet there is another tale to tell. Over the past decade a quiet revolution has occurred in medical education. After the publication of the General Medical Council's recommendations in Tomorrow's Doctors in 19932 all UK medical schools have revised their undergraduate curriculums. Alongside a strong science base, 3 Tomorrow's Doctors emphasised the importance of communication skills, learning through curiosity, understanding public health medicine, and adapting to changing patterns of health care. The burden of factual information really was reduced, and a core curriculum defined. The implementation of …
Mandatory and recommended vaccination in the EU, Iceland and Norway: results of the VENICE 2010 survey on the ways of implementing national vaccination programmes
Authors: M Haverkate, F D’Ancona, C Giambi, K Johansen, P L Lopalco, V Cozza, E Appelgren, collective on behalf of the VENICE project gat
Journal: Eurosurveillance (2012)

This report provides an updated overview of recommended and mandatory vaccinations in the European Union (EU), Iceland and Norway, considering the differences in vaccine programme implementation between countries. In 2010, the Vaccine European New Integrated Collaboration Effort (VENICE) network, conducted a survey among the VENICE project gatekeepers to learn more about how national vaccination programmes are implemented, whether recommended or mandatory. Information was collected from all 27 EU Member States, Iceland and Norway. In total 15 countries do not have any mandatory vaccinations; the remaining 14 have at least one mandatory vaccination included in their programme. Vaccination against polio is mandatory for both children and adults in 12 countries; diphtheria and tetanus vaccination in 11 countries and hepatitis B vaccination in 10 countries. For eight of the 15 vaccines considered, some countries have a mixed strategy of recommended and mandatory vaccinations. Mandatory vaccination may be considered as a way of improving compliance to vaccination programmes. However, compliance with many programmes in Europe is high, using only recommendations. More information about the diversity in vaccine offer at European level may help countries to adapt vaccination strategies based on the experience of other countries. However, any proposal on vaccine strategies should be developed taking into consideration the local context habits.
Effects of the P-Selectin Antagonist Inclacumab on Myocardial Damage After Percutaneous Coronary Intervention for Non–ST-Segment Elevation Myocardial Infarction
Authors: Jean-Claude Tardif, Jean-François Tanguay, Scott R. Wright, Valérie Duchatelle, Thibaut Petroni, Jean C. Grégoire, Reda Ibrahim, Therese M. Heinonen, Stephen Robb, Olivier F. Bertrand, Daniel Cournoyer, Dominique Johnson, Jessica Mann, Marie-Claude Guertin, Philippe L. L'Allier
Journal: Journal of the American College of Cardiology (2013)

The study aimed to evaluate inclacumab for the reduction of myocardial damage during a percutaneous coronary intervention (PCI) in patients with non–ST-segment elevation myocardial infarction. P-selectin is an adhesion molecule involved in interactions between endothelial cells, platelets, and leukocytes. Inclacumab is a recombinant monoclonal antibody against P-selectin, with potential anti-inflammatory, antithrombotic, and antiatherogenic properties. Patients (N = 544) with non–ST-segment elevation myocardial infarction scheduled for coronary angiography and possible ad hoc PCI were randomized to receive 1 pre-procedural infusion of inclacumab 5 or 20 mg/kg or placebo. The primary endpoint, evaluated in patients who underwent PCI, received study medication, and had available efficacy data (n = 322), was the change in troponin I from baseline at 16 and 24 h after PCI. There was no effect of inclacumab 5 mg/kg. Placebo-adjusted geometric mean percent changes in troponin I with inclacumab 20 mg/kg were −24.4% at 24 h (p = 0.05) and −22.4% at 16 h (p = 0.07). Peak troponin I was reduced by 23.8% (p = 0.05) and area under the curve over 24 h by 33.9% (p = 0.08). Creatine kinase-myocardial band yielded similar results, with changes of −17.4% at 24 h (p = 0.06) and −16.3% at 16 h (p = 0.09). The incidence of creatine kinase-myocardial band increases >3 times the upper limit of normal within 24 h was 18.3% and 8.9% in the placebo and inclacumab 20-mg/kg groups, respectively (p = 0.05). Placebo-adjusted changes in soluble P-selectin level were −9.5% (p = 0.25) and −22.0% (p < 0.01) with inclacumab 5 and 20 mg/kg. There was no significant difference in adverse events between groups. Inclacumab appears to reduce myocardial damage after PCI in patients with non–ST-segment elevation myocardial infarction. (A Study of RO4905417 in Patients With Non ST-Elevation Myocardial Infarction [Non-STEMI] Undergoing Percutaneous Coronary Intervention; NCT01327183)
Strategies and endpoints of antifibrotic drug trials: Summary and recommendations from the AASLD Emerging Trends Conference, Chicago, June 2014
Authors: Natalie J. Torok, Jonathan A. Dranoff, Detlef Schuppan, Scott L. Friedman
Journal: Hepatology (2015)

There is an urgent need to develop antifibrotic therapies for chronic liver disease, and clarify which endpoints in antifibrotic trials will be acceptable to regulatory agencies. The American Association for the Study of Liver Diseases sponsored an endpoints conference to help accelerate the efficient testing of antifibrotic agents and develop recommendations on clinical trial design for liver fibrosis. In this review, we summarize the salient and novel elements of this conference and provide directions for future clinical trial design. The article follows the structure of the conference and is organized into five areas: (1) antifibrotic trial design; (2) preclinical proof‐of‐concept studies; (3) pharmacological targets, including rationale and lessons to learn; (4) rational drug design and development; and (5) consensus and recommendations on design of clinical trials in liver fibrosis. Expert overviews and collaborative discussions helped to summarize the key unmet needs and directions for the future, including: (1) greater clarification of at‐risk populations and study groups; (2) standardization of all elements of drug discovery and testing; (3) standardization of clinical trial approaches; (4) accelerated development of improved noninvasive markers; and (5) need for exploration of potential off‐target toxicities of future antifibrotic drugs. (H epatology 2015;62:627–634