tbuckley/cabot-search huggingface dataset:
Why methotrexate suboptimal dosing is a potential source of bias in biologic drugs clinical trials
Authors: Josefina Durán, David T Felson
Journal: Annals of the Rheumatic Diseases (2016)

Why methotrexate suboptimal dosing is a potential source of bias in biologic drugs clinical trialsWe appreciate the editorial Dr Kremer 1 wrote regarding our article 2 and we want to clarify some of the issues he raises.Dr Kremer states that there is no evidence of benefit from increasing the methotrexate dose from 20 to 25 mg 'given the appropriate parenteral route of administration'.What he states is accurate; it is a bit misleading, as evidence does exist of the benefit of switching from oral to subcutaneous methotrexate, which was a focus of our paper.In a crossover trial by Schiff et al 3 that we cite in our article, subjects achieved a higher effective therapeutic level with no increase in adverse events when switching from oral to subcutaneous methotrexate.It is precisely the lack of use of parenteral methotrexate, which we believe is the most important potential source of bias, and this is stated in our discussion.He questions the adverse event profile of methotrexate in a dose >20 mg, but in a comparative effectiveness trial in early rheumatoid arthritis published in 2015 by Hazlewood et al, 4 only 3 out of 112 subjects who received parenteral methotrexate in a dose >20 mg failed treatment due to toxicity.In his editorial, Dr Kremer cites a study associating genetic polymorphisms with toxicity, which actually found that 'In the overall population, the prevalence of adverse events among patients taking 25 mg/week MTX was not significantly different from that among patients taking 15 mg/week study'. 5n addition, he argues that the methotrexate consensus paper that recommends a higher methotrexate dose cited in our discussion was based on expert opinion, but the recommendations made in this paper considered a literature review that included a randomised controlled trial comparing oral versus subcutaneous methotrexate that showed the superiority of the latter and also studies comparing different dosing regimens of methotrexate, one of which compared 15 vs 25 mg of methotrexate as a starting dose and found no difference in withdrawals and dose reductions between groups. 6In addition to the two randomised controlled trials which showed a greater efficacy with subcutaneous methotrexate, 7 8 multiple observational studies have reinforced this evidence. 9 10We acknowledge that the use of methotrexate in its recommended dose is not widespread, at least in the USA, but this does not justify the suboptimal dosing of methotrexate when used as a comparator in trials.Finally, our study is not meant to be applicable to Asians, as they use methotrexate in much lower doses (<15 mg/week).
Abstract PR15: Predicting the essentialities of protein-protein interactions in cancer
Authors: Lee AD Cooper, Josue D. Moran, Zenggang Li, Yuhong Du, Sahar Harati, Andrey A. Ivanov, Phillip Webber, Jonathan J. Havel, Margaret A. Johns, Haian Fu, Carlos S. Moreno
Journal: Cancer Research (2015)

Abstract Many protein-protein interactions (PPIs) are essential to cellular proliferation and survival, and thus represent potential targets for novel compounds with high specificity and therapeutic potential in the treatment of cancer. Despite their therapeutic significance, there are currently no high-throughput experimental platforms to interrogate the essentiality of individual protein-protein interactions. The ability to computationally predict or infer PPI essentiality would help prioritize the development of therapeutic targets and advance understanding of cancer biology, and remains a significant barrier. We have developed a computational method to predict PPI essentiality by combining shRNA studies with network models of protein interaction pathways in an analytic framework. High-throughput single-gene shRNA silencing is a well-established experimental approach to study protein essentiality in genome-wide screens. The silencing of a single gene in an shRNA screen effectively disrupts multiple PPIs, masking their individual contributions to the observed protein essentiality. Our method uses a network model to infer cliques of PPIs that are disrupted as each gene is silenced, then uses these sets to formulate an additive model of how the unknown PPI essentialities combine to form the observed protein essentialities. This process is then deconvoluted to recover the unknown essentialities of each PPI using a regularized solver. We performed this analysis in 108 cell lines characterized for protein essentiality in Project Achilles [1, 2]. A superpathway of 2186 proteins and 11488 protein interactions was constructed from prior knowledge databases [3] and protein interaction screenings. We demonstrate the validity of our approach via prediction of essential PPIs such as TP53-MDM4 in cell lines sensitive to nutlin and CDK4-RB1 interactions in cell lines sensitive to CDK4 inhibitors. [1] Cowley, Weir &amp; Vazquez, et al. Nature Scientific Data 1, Article number: 140035. September 30, 2014 [2] Cheung HW, Cowley GS, Weir BA, et al. Proc Natl Acad Sci. 2011 Jul 26; 108(30):12372-7. [3] Schaefer CF, Anthony K, Krupa S, et al. Nucleic Acids Research. Jan 2009. 37:674-9 Citation Format: Lee AD Cooper, Josue D. Moran, Zenggang Li, Yuhong Du, Sahar Harati, Andrey A. Ivanov, Phillip Webber, Jonathan J. Havel, Margaret A. Johns, Haian Fu, Carlos S. Moreno. Predicting the essentialities of protein-protein interactions in cancer. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr PR15.
Phase II study of front-line dovitinib (TKI258) versus sorafenib in patients (Pts) with advanced hepatocellular carcinoma (HCC).
Authors: Ann-Lii Cheng, Sumitra Thongprasert, Ho Yeong Lim, Wattana Sukeepaisarnjaroen, Tsai-Sheng Yang, Cheng-Chung Wu, Yee Chao, Stephen Lam Chan, Masatoshi Kudo, Masafumi Ikeda, Yoon-Koo Kang, Hongming Pan, Kazushi Numata, Guohong Han, Binaifer Balsara, Yong Zhang, Ana-Maria Rodriguez, Yi Zhang, Yongyu Wang, Ronnie Tung-Ping Poon
Journal: Journal of Clinical Oncology (2015)

237 Background: HCC is a highly vascularized tumor, and inhibition of angiogenesis by sorafenib (Sor)—a VEGFR and PDGFR inhibitor—delays tumor progression. However, angiogenic escape from Sor may result from activation of the FGFR pathway, which also plays an important role in angiogenesis. Dovitinib (Dov) inhibits FGFR as well as VEGFR and PDGFR. Here, we study frontline Dov vs Sor in pts with advanced HCC. Methods: Eligible pts in this open-label study had ≥ 1 measurable lesion at baseline. All pts were ineligible for or had disease progression after surgical and/or locoregional therapies. Prior systemic HCC therapy was not allowed. Pts were randomized to receive Dov (500 mg/day, 5 days on/2 days off) or Sor (400 mg twice daily) until disease progression, unacceptable toxicity, or death. No treatment crossover was allowed. The primary endpoint was overall survival (OS). The key secondary endpoint was time to tumor progression (TTP) by local investigator’s assessment (per RECIST v1.1). Results: Pts received Dov (n = 82) or Sor (n = 83). Most pts—43 (52.4%) in the Dov arm and 60 (72.3%) in the Sor arm—discontinued treatment due to progressive disease. Median OS (95% CI) was 34.6 wk (28.6-39.4 wk) for Dov and 36.7 wk (23.3-49.3 wk) for Sor; Kaplan-Meier HR, 1.27; 95% CI, 0.89-1.80. Median TTP (95% CI) was 17.6 wk (12.3-18.4 wk) and 17.9 wk (12.3-18.9 wk), respectively. In pts who received ≥ 1 dose of study drug, median duration of exposure was 2.5 mo for Dov (n = 79) and 3.2 mo for Sor (n = 83). The most common adverse events, regardless of cause, were diarrhea (62.0%), decreased appetite (43.0%), nausea and vomiting (40.5% each), fatigue (35.4%), rash (34.2%), and pyrexia (30.4%) in the Dov arm and palmar-plantar erythrodysesthesia syndrome (66.3%), diarrhea (42.2%), and decreased appetite (31.3%) in the Sor arm. VEGFR1 and HGF baseline plasma levels appear to be associated with OS only in the Dov arm. Median OS in the lower biomarker group for both VEGFR1 and HGF was 11 mo while it was 5.6 and 5.9 mo for VEGFR1 and HGF, respectively, in the higher biomarker group. Conclusions: Activity of Dov was not greater than that of Sor in frontline HCC. The safety profile was similar to that observed in other single-agent Dov trials. Clinical trial information: NCT01232296.
Basal Cell Carcinoma
Authors: Roger H. Brodkin
Journal: JAMA (1974)

<h3>To the Editor.—</h3> We have recently observed a case in which a physician advised a patient against removal of a basal cell carcinoma because it was "not a serious tumor." A related episode of severe hemorrhage almost required transfusion. A brief description of the case might persuade such advisors to change attitudes. <h3>Report of a Case.—</h3> A 74-year-old retired physician had been incapacitated by a cerebrovascular accident for several years. Although numerous subspecialists attended his many medical problems, his overall care was supervised by a devoted brother, an internist of surpassing stature in the area where he practices. The brother had repeatedly advised the patient's family to disregard the ulcerated tumor on the patient's left temple as medically insignificant and cosmetically unimportant. After repeated episodes of bleeding, the family finally prevailed upon him to have the lesion removed. The tumor was a 2.5×3-cm fungating mass that was removed by currettage
Recent Developments in the Management of Brain Abscess
Authors: W. Lewin
Journal: BMJ (1955)

<h3>Abstract</h3> We present a comprehensive statistical framework to analyze data from genome-wide association studies of polygenic traits, producing distinct and interpretable discoveries while controlling the false discovery rate. This approach leverages sophisticated multivariate models, correcting for linkage disequilibrium, and accounts for population structure and relatedness, adapting to the characteristics of the samples at hand. A key element is the recognition that the observed genotypes can be considered as a random sample from an appropriate model, encapsulating our knowledge of genetic inheritance and human populations. This allows us to generate imperfect copies (knockoffs) of these variables which serve as ideal negative controls; knockoffs are indistinguishable from the original genotypes in distribution, and independent from the phenotype. In sharp contrast with state-of-the-art methods, the validity of our inference in no way depends on assumptions about the unknown relation between genotypes and phenotype. We develop and leverage a model for the genotypes that accounts for arbitrary and unknown population structure, which may be due to diverse ancestries or familial relatedness. We build a pipeline that is robust to the most prominent possible confounders, facilitating the discovery of causal variants. Validity and effectiveness are demonstrated by extensive simulations with real data, as well as by the analysis of several phenotypes in the UK Biobank. Finally, fast software is made available for researchers to apply the proposed methodology to Biobank-scale data sets.
Bulimia nervosa
Authors: R. Z Lilly
Journal: BMJ (2003)

Bulimia nervosa is an eating disorder that affects women 9-10 times more often than men.It has three key features:x Intense preoccupation with body weight and shape x Repetitive episodes of binge eating (uncontrollably eating a large quantity of food in a defined period-usually less than two hours)x Routinely taking extreme measures to prevent weight gain, including self induced vomiting, fasting, excessive exercise, and misuse of laxatives and diuretics.The condition is characterised by the patient's inability to control the urge to indulge in binge eating.Medical complications are caused by the weight reducing behaviours, particularly vomiting and laxative misuse.The frequency of these behaviours is, on average, at least twice a week for three months.Episodes may be spontaneous or planned and can be triggered by stress, intense hunger, or dysphoria.Patients are usually in the normal weight range. TreatmentDespite the availability of effective treatments, few people with bulimia nervosa seek help.One study found that only 1 in 10 people with the condition are in treatment. 1 Treatments that are likely to workAntidepressants Antidepressants can reduce binge eating and purging, and improve depressive symptoms and attitude towards food.There is not enough evidence on how long the benefits last or for comparing the effects of different classes of antidepressants.Antidepressants and cognitive behaviour therapy are equally effective for bulimia nervosa, though dropout rates are higher with antidepressants, probably due to their side effects.For information on drug doses, see www.besttreatments.org/bulimianervosa. Cognitive behaviour therapyAs with antidepressants, cognitive behaviour therapy can reduce binge eating and purging, and improve depressive symptoms and attitude towards food.It may be preferable to medication in patients who are sensitive to, or wish to avoid, side effects of medication.Cognitive behaviour therapy and other psychological treatments seem to be equally good at treating binge eating, although cognitive behaviour therapy is better at improving depression scores.There is some evidence that cognitive behaviour therapy has long term benefits in treating bulimia, but there is insufficient evidence about patients' characteristics that predict response.
Sex therapy and psychophysiological research
Authors: R C Schiavi
Journal: American Journal of Psychiatry (1976)

The author discusses two areas of psychophysiological research that may be relevant to the diagnosis and treatment of sexual dysfunction: investigations of sexual arousal in men and studies of nocturnal penile tumescence. There has been no convincing evidence to date of a predictable, generalizable autonomic response pattern to sexual arousal, but neuroendocrine research in this area has shown promise. A close temporal relationship has been found between REM sleep and penile tumescence in normal men-deviations from this pattern may be related to sexual dysfunction. The author suggests that further research is necessary in these areas of potential diagnostic and prognostic significance.
Neurofibromatosis
Authors: Janet M. Torpy
Journal: JAMA (2009)

NeurofibromatosisN eurofibromatosis (NF) is a genetic disorder causing skin abnormalities and tumors that form on nerve tissues.These tumors can be small or large and can occur anywhere in the body, including the brain, spinal cord, large nerves, or smaller nerves.NF affects persons of both sexes and all racial groups.There are 2 types of neurofibromatosis, called NF1 and NF2.These are 2 distinct disorders that are caused by mutations (changes) in different genes.NF1 is also referred to as von Recklinghausen disease and is a rather common genetic disease, affecting approximately 1 in 3000 individuals.Some patients who have NF1 only display characteristic skin abnormalities such as café au lait spots, which are flat, hyperpigmented (darker than surrounding skin) areas.Other patients can have severe physical complications such as malignant (cancerous) tumors or have mental retardation.NF2 is much more rare than NF1, affecting less than 1 in 30 000 individuals, usually becoming apparent in the late teens, and typically causing hearing loss and problems with balance due to tumors on nerves to the ears.The November 18, 2009, issue of JAMA includes an article about a recently described condition called Legius syndrome in which patients have skin pigment abnormalities indistinguishable from NF1.This Patient Page is based on one published in the July 16, 2008, issue of JAMA.
Immunologic profiling and clinical outcome in HER2+ breast cancer patients treated in a neoadjuvant phase II study: A step forward to understand trastuzumab activity.
Authors: R. Dolcetti, D. Crivellari, E. Muraro, D. Martorelli, G. Miolo, D. Lombardi, S. Massarut, T. Perin, R. Talamini, E. Turchet, E. Comaro, A. Carbone, A. Veronesi
Journal: Journal of Clinical Oncology (2011)

e11083 Background: A phase II study was performed to assess the role of patients’ immune profile in the activity of a trastuzumab (T) based, non anthracycline containing neoadjuvant chemotherapy (NC) regimen in breast cancer (BC) patients (pts). Methods: Newly diagnosed T2-3 HER2+ BC pts received a 12 week NC with weekly paclitaxel (P) and T, which was continued for further 12 weeks before surgery in the absence of progression (PRO). Further 12 weeks of the same therapy was planned after surgery and then T alone to 1 year of treatment ± hormonal therapy and radiotherapy. In case of PRO, T was discontinued and anthracyclines were planned. Blood samples were collected at diagnosis and every 3 months for 1 year then yearly. The % of NK cells, T cells and Treg cells was evaluated by flow cytometry, and serum levels of 9 cytokines were assessed by SearchLight multiplex array technology. In vitro T-mediated, antibody-dependent cell cytotoxicity (ADCC) was also assessed using patients’ PBMCs. Results: From July 2006 32 pts were enrolled, 31 were evaluable (1 ongoing). Pathological complete response (pCR) was reported in 15 pts (48%, 95% CI: 31-66%), objective overall clinical response was observed in 30 pts (97%, 95% CI: 91-100%). No cardiotoxicity occurred. In 3 cases (9.7%) PRO occurred at 26.3 months median follow-up. At diagnosis, pts showed an immune profile similar to that of healthy women, whereas higher numbers of Treg cells (p=0.02), NK cells (p=0.03), lower T cell numbers (p<0.01) and lower amounts of serum IL-2, IL-6, and IL-8 were found in a concomitant control group of untreated HER2- pts. Notably, study pts achieving pCR presented higher efficiency of basal T-mediated ADCC compared to pts with partial responses (p=0.05). The treatment induced a progressive increase in the number of NK cells and in the efficiency of T-mediated ADCC. Conclusions: NC with P and T induces high rates of pCR with no cardiotoxicity. This clinical efficacy is favored by the retained immunological proficiency of HER2+ pts, who may benefit from the immunomodulating properties of T started early. Whether T-mediated ADCC is significant also for event-free survival is under evaluation.
Pooled patient level data are better suited than study level data to investigate the link between dipeptidyl peptidase-4 inhibitors and the risk of heart failure in type 2 diabetes
Authors: Tejas Patel, Bereket Tesfaldet, Charu Gandotra
Journal: BMJ (2016)

Li and colleagues’ systematic review and meta-analysis included a large number of studies and diverse populations of patients with diabetes.1 However, certain limitations make it difficult to interpret the results. Firstly, durations of exposure and length of follow-up varied between trials, making it difficult to assess the effect of treatment duration on the occurrence of heart failure. Secondly, dipeptidyl peptidase-4 (DPP-4) inhibitors were used both as monotherapy and in combination with other antihyperglycaemic agents, making it difficult to determine a direct causal association between DPP-4 inhibition and heart failure. Thirdly, heart failure events were not always prespecified, well defined, or adjudicated across trials. Finally, study level meta-analyses and systematic reviews lack the ability to identify or …
Infrared Spectroscopy of Crystalline Albumin in Human Neoplasia&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: C T FONG, S W LIPPINCOTT, N ERIKSEN
Journal: JNCI Journal of the National Cancer Institute (1957)

Infrared Spectroscopy of Crystalline Albumin in Human Neoplasia Conrad T. O. Fong, Conrad T. O. Fong Field Investigations and Demonstrations Branch, National Cancer Institute,5 and Department of Pathology, School of Medicine, University of Washington, Seattle, Washington Search for other works by this author on: Oxford Academic PubMed Google Scholar Stuart W. Lippincott, Stuart W. Lippincott Field Investigations and Demonstrations Branch, National Cancer Institute,5 and Department of Pathology, School of Medicine, University of Washington, Seattle, Washington Search for other works by this author on: Oxford Academic PubMed Google Scholar Nils Eriksen Nils Eriksen Field Investigations and Demonstrations Branch, National Cancer Institute,5 and Department of Pathology, School of Medicine, University of Washington, Seattle, Washington Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 18, Issue 2, February 1957, Pages 271–275, https://doi.org/10.1093/jnci/18.2.271 Published: 01 February 1957 Article history Received: 13 July 1956 Published: 01 February 1957
Abstract P5-07-05: Development of individual adjuvant chemotherapy benefit estimating program for breast cancer patients management
Authors: R Rouzier, D Stevens, C Bonneau, M-C Falcou, D Hequet, J-Y Pierga, F Lerebours
Journal: Cancer Research (2016)

Abstract Background To predict the individual benefit of adjuvant chemotherapy (CT) is challenging especially in estrogen receptor tumors HER2 negative tumors. Existing tools are based on data from randomized trials or on genomic tests with benefit calculated for outmoded CT. The aim of this study was to develop an exportable model to predict from real life data the invidual benefit of adjuvant anthracyclines/taxanes based CT. Patients and methods Women with estrogen receptor-positive HER2-negative tumors without metastasis at the time of the diagnosis treated at the Institut Curie - Centre René Huguenin (St Cloud, France) between 2000 and 2008 were included. Clinical characteristics, pathological data and information concerning the treatments and outcomes had been prospectively registered. We divided the study population into 2 groups: patients who did not receive adjuvant CT and patients who did. Multivariate survival analysis and prediction were performed according to the Cox model (proportional hazard model). Non-informative variables in the Cox model were excluded from the final model. The individual benefit of CT was calculated by comparing predicted distant disease-free survival without chemotherapy (using a model constructed in patients treated without adjuvant CT) and modeled distant disease-free survival with CT. Benefit of chemotherapy was validated by cross validation and compared to Adjuvant online predictions. Results Data from 3385 women were available: 2137 treated without adjuvant chemotherapy and 1248 with. The models to predict survival without and with CT were based on tumor size, number of metastatic nodes, grade and KI67 (all patients had ER-positive-HER2 negative tumors). The discrimination and the calibration of the models were excellent: C-index were 0.81 and 0.76 for patients treated without and with CT. In this population, the mean 10-year benefit provided by CT was 6.2% (median: 1.5%, min: -4%, max: 35%). The accuracy of the model was internally validated and over-performed predictions of adjuvant online because Ki67 and HER2 status are included in our model (p&amp;lt;.05). A web-based interface is available. Conclusion We constructed a tool to evaluate the benefit of adjuvant anthracycline / taxane at an individual level. This tool is based on a model that outperform currently availble methods. Citation Format: Rouzier R, Stevens D, Bonneau C, Falcou M-C, Hequet D, Pierga J-Y, Lerebours F. Development of individual adjuvant chemotherapy benefit estimating program for breast cancer patients management. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-07-05.