tbuckley/cabot-search huggingface dataset:
The ImmunoTOX multidisciplinary board: A descriptive study of collaborative management of immune-related adverse events
Authors: J.-M. Michot, A. Lappara, A. Simonaggio, F.-X. Danlos, R. Belkhir, M. Collins, A. Berdelou, C. Cauquil, S. Edhery, J. Le Pavec, D.M. Eleonora, C. Mateus, A. Hollebecque, A. Varga, J.-C. Soria, C. Massard, A.-L. Voisin, A. Marabelle, S. Champiat, O. Lambotte
Journal: Annals of Oncology (2019)
RhoC and Rac1 GTPases in prostate cancer cell motility, invasion, and metastasis
Authors: Min Lin, Cynthia Van Golen, Kenneth L. Van Golen
Journal: Cancer Research (2005)

1027  Prostate cancer (CaP) bone metastasis is a major clinical concern, as it is associated with intractable pain, bone fracture and paralysis. Therefore, an understanding of the mechanisms involved in CaP cell bone metastasis is key to development of novel treatments. The Rho GTPases are molecular switches involved in cell survival, motility and invasion. Increased expression of RhoC GTPase is linked to enhanced metastatic potential in several cancers; however, it has never been studied in CaP. In the current study we demonstrate that RhoC GTPase is expressed and active in human PC-3 CaP cells which are derived from a bone metastasis. Inhibition of RhoC with C3 exotransferase (a potent inhibitor of Rho but not Rac1 or Cdc42 proteins) or by expression of a dominant negative RhoC leads to increased IGF-I stimulated random motility on collagen I, but decreased in vitro invasion and in vivo metastases. The changes seen in the motile and invasive phenotype is due to increased and prolonged expression and activation of Rac1 GTPase. In addition, RhoC inhibition leads to a change in cellular morphology and expression of E- and N-cadherin, ZO-1 and vimentin, molecular markers of the epithelial to mesenchymal transition. Expression, activation and distribution of the focal adhesion proteins; focal adhesion kinase, paxillin, paxillin kinase linker are altered significantly upon RhoC inhibition but are not affected by Rac1 activation. These data suggest that expression of active RhoC is required for the invasive phenotype of PC-3 cells which may have significant implications for CaP bone metastasis.
Prognostic models for outcome prediction in patients with chronic obstructive pulmonary disease: systematic review and critical appraisal
Authors: Vanesa Bellou, Lazaros Belbasis, Athanasios K Konstantinidis, Ioanna Tzoulaki, Evangelos Evangelou
Journal: BMJ (2019)

Abstract Objective To map and assess prognostic models for outcome prediction in patients with chronic obstructive pulmonary disease (COPD). Design Systematic review. Data sources PubMed until November 2018 and hand searched references from eligible articles. Eligibility criteria for study selection Studies developing, validating, or updating a prediction model in COPD patients and focusing on any potential clinical outcome. Results The systematic search yielded 228 eligible articles, describing the development of 408 prognostic models, the external validation of 38 models, and the validation of 20 prognostic models derived for diseases other than COPD. The 408 prognostic models were developed in three clinical settings: outpatients (n=239; 59%), patients admitted to hospital (n=155; 38%), and patients attending the emergency department (n=14; 3%). Among the 408 prognostic models, the most prevalent endpoints were mortality (n=209; 51%), risk for acute exacerbation of COPD (n=42; 10%), and risk for readmission after the index hospital admission (n=36; 9%). Overall, the most commonly used predictors were age (n=166; 41%), forced expiratory volume in one second (n=85; 21%), sex (n=74; 18%), body mass index (n=66; 16%), and smoking (n=65; 16%). Of the 408 prognostic models, 100 (25%) were internally validated and 91 (23%) examined the calibration of the developed model. For 286 (70%) models a model presentation was not available, and only 56 (14%) models were presented through the full equation. Model discrimination using the C statistic was available for 311 (76%) models. 38 models were externally validated, but in only 12 of these was the validation performed by a fully independent team. Only seven prognostic models with an overall low risk of bias according to PROBAST were identified. These models were ADO, B-AE-D, B-AE-D-C, extended ADO, updated ADO, updated BODE, and a model developed by Bertens et al. A meta-analysis of C statistics was performed for 12 prognostic models, and the summary estimates ranged from 0.611 to 0.769. Conclusions This study constitutes a detailed mapping and assessment of the prognostic models for outcome prediction in COPD patients. The findings indicate several methodological pitfalls in their development and a low rate of external validation. Future research should focus on the improvement of existing models through update and external validation, as well as the assessment of the safety, clinical effectiveness, and cost effectiveness of the application of these prognostic models in clinical practice through impact studies. Systematic review registration PROSPERO CRD42017069247
Secondary ROS1 mutations and lorlatinib sensitivity in crizotinib-refractory ROS1 positive NSCLC: Results of the prospective PFROST trial
Authors: L. Landi, M. Tiseo, L.C. Heukamp, R. Menon, G. Spitaleri, D.L. Cortinovis, A. Delmonte, D. Galetta, M. D’Arcangelo, F. D’Incà, M. Bertrand, B. Jóri, A. Zacher, C. Gridelli, S. Novello, R. Chiari, C. Verusio, L. Crinò, F. Cappuzzo
Journal: Annals of Oncology (2019)
Penicillin V four times daily for five days versus three times daily for 10 days in patients with pharyngotonsillitis caused by group A streptococci: randomised controlled, open label, non-inferiority study
Authors: Gunilla Skoog Ståhlgren, Mia Tyrstrup, Charlotta Edlund, Christian G Giske, Sigvard Mölstad, Christer Norman, Karin Rystedt, Pär-Daniel Sundvall, Katarina Hedin
Journal: BMJ (2019)

To determine whether total exposure to penicillin V can be reduced while maintaining adequate clinical efficacy when treating pharyngotonsillitis caused by group A streptococci.Open label, randomised controlled non-inferiority study.17 primary healthcare centres in Sweden between September 2015 and February 2018.Patients aged 6 years and over with pharyngotonsillitis caused by group A streptococci and three or four Centor criteria (fever ≥38.5°C, tender lymph nodes, coatings of the tonsils, and absence of cough).Penicillin V 800 mg four times daily for five days (total 16 g) compared with the current recommended dose of 1000 mg three times daily for 10 days (total 30 g).Primary outcome was clinical cure five to seven days after the end of antibiotic treatment. The non-inferiority margin was prespecified to 10 percentage points. Secondary outcomes were bacteriological eradication, time to relief of symptoms, frequency of relapses, complications and new tonsillitis, and patterns of adverse events.Patients (n=433) were randomly allocated to the five day (n=215) or 10 day (n=218) regimen. Clinical cure in the per protocol population was 89.6% (n=181/202) in the five day group and 93.3% (n=182/195) in the 10 day group (95% confidence interval -9.7 to 2.2). Bacteriological eradication was 80.4% (n=156/194) in the five day group and 90.7% (n=165/182) in the 10 day group. Eight and seven patients had relapses, no patients and four patients had complications, and six and 13 patients had new tonsillitis in the five day and 10 day groups, respectively. Time to relief of symptoms was shorter in the five day group. Adverse events were mainly diarrhoea, nausea, and vulvovaginal disorders; the 10 day group had higher incidence and longer duration of adverse events.Penicillin V four times daily for five days was non-inferior in clinical outcome to penicillin V three times daily for 10 days in patients with pharyngotonsillitis caused by group A streptococci. The number of relapses and complications did not differ between the two intervention groups. Five day treatment with penicillin V four times daily might be an alternative to the currently recommended 10 day regimen.EudraCT 2015-001752-30; ClinicalTrials.gov NCT02712307.
Abstract 4880: The Common Variant Rs9939609 In The FTO Gene Is Associated With Early-onset Myocardial Infarction
Authors: Piera A Merlini, Carlo Berzuini, Pier M Mannucci, Flora Peyvandi, Marco Tubaro, Daniela Lina, Maria F Notarangelo, Luisa Foco, Luisa Bernardinelli, Diego Ardissino
Journal: Circulation (2008)

Background and objective Type 2 diabetes and increase in body mass index (BMI) are major risk factors for myocardial infarction. Recently the common variant rs9939609 in the fat mass and obesity-associated (FTO) gene was reported to associate with type 2 diabetes only through an effect on body mass index (BMI). In the present study we investigated whether rs9939609 variant in the FTO gene is directly associated with early-onset myocardial infarction. Method The Italian genetic study of early-onset myocardial infarction is a nationwide prospective case-control study involving 1842 patients hospitalised for a first myocardial infarction before the age of 45 years, and 1842 healthy subjects matched for age, gender and geographical origin. The following baseline data were collected for each case and control: age, gender, family history, body mass index, smoking habits, hypertension, hypercholesterolemia, diabetes, cocaine use, physical activity and alcohol consumption. Genotyping was performed using a Sequenome MassARRAY platform. Results The rs9939609 variant in FTO gene was significantly associated with early-onset myocardial infarction (odds ratio 1,25, 95% confidence interval 1.08 to 1.45; p=0.000015) with a multiplicative model of the effect. After adjusting for diabetes, BMI, hypercholesterolemia and smoking the rs9939609 risk allele was still significantly associated with early-onset myocardial infarction (odds ratio 1.20, 95% confidence interval 1.05–1.38; p=0.006), thus indicating that this variant has a direct effect on myocardial infarction, not mediated by BMI. As previously reported FTO genotype was also associated with an increase in BMI, more specifically the p-value of no association in the control group is equal to 0,01. Conclusions The rs9939609 variant in the FTO gene was significantly associated with the risk of early-onset myocardial infarction and with the increase in BMI. The rs9939609 variant in the FTO gene directly influences the risk of early-onset myocardial infarction.
Abortion: Northern Ireland law breaches European human rights, rules Belfast court
Authors: Clare Dyer
Journal: BMJ (2019)

Northern Ireland’s abortion law, in denying terminations to women whose babies have fatal fetal abnormalities, is incompatible with the European Convention on Human Rights, a judge in Belfast’s High Court has ruled.1

Mrs Justice Keegan ruled that the Northern Ireland law violated Sarah Ewart’s right to protection for her private and family life, as guaranteed by the convention. Ewart learnt from a scan at 20 weeks that her unborn baby would not survive but was told she would have to continue with the pregnancy. Unable to face …
Clinical Significance of AR-V567es in Prostate Cancer—Letter
Authors: Takuma Uo, Stephen R. Plymate
Journal: Clinical Cancer Research (2019)

There are conflicting results regarding incidence of ARv567es detected by PCR in prostate cancer, displaying frequencies ranging from 3% in metastatic to more than 70% in circulating tumor cells (CTC; refs. [1, 2][1]). To resolve this issue, Bernemann and colleagues performed a comprehensive
Sarcopenia and pretreatment anemia as prognostic factors for patients with localized muscle invasive bladder cancer treated by neoadjuvant chemotherapy and radical cystectomy
Authors: E. Billon, P. Regnier, V. De Luca, S. Brunelle, J. Walz, S. Dermeche, M. Guerin, C. Vicier, T. Maubon, S. Rybikowski, N. Branger, S. Fakhfakh, G. Pignot, G. Gravis
Journal: Annals of Oncology (2019)
OS05.6 Final risk model for Temozolomide (TMZ)-Myelotoxicity in patients with Glioblastoma treated on NRG Oncology’s RTOG 0825
Authors: T. S. Armstrong, M. R. Gilbert, M. Bondy, E. Sulman, Y. Yuan, R. Zhou, E. Vera, M. Wendland, S. Pugh, M. Scheurer
Journal: Neuro-Oncology (2017)

BACKGROUND: Myelotoxicity is a rare but serious side effect of TMZ. In RTOG0825, 16% and 23% of patients experienced grade 3 or higher myelotoxicity during chemoradiation or adjuvant phase, respectively. Our goal was to evaluate risk and validate prediction of myelotoxicity in patients treated with TMZ +/- bevacizumab (BEV). METHODS: Clinical characteristics (including age, height, weight, gender, race/ethnicity, concurrent medications, baseline laboratory studies, performance status, and tumor characteristics) as well as severe TMZ-related myelotoxicity (CTCAE version 3.0 for grade 3 and higher leukopenia, neutropenia and/or thrombocytopenia) were extracted from the RTOG 0825 database. First, a risk prediction model of myelotoxicity was built including only clinical factors; second, that model was extended using the single nucleotide polymorphisms (SNPs) identified by a genome-wide association study (GWAS). We also conducted a joint effects analysis to test the hypothesized dose-response relationship between genotype and myelotoxicity, by summing the number of at-risk alleles of the top SNPs identified from the main effect analysis. Results: There were 134 cases and 457 controls. Receiving BEV with TMZ increased myelotoxicity risk 80% (odds ratio OR=1.82; 95% confidence interval [CI], 1.02–3.27; adjusted p= 0.04). Females were approximately 4.5 times more likely to develop toxicity (OR=4.45; 95% CI, 2.45–8.08; adjusted p <0.0001). Taking anticonvulsants trended toward increased risk but was not statistically significant (OR=1.64; 95%CI 0.85–3.18; adjusted p=0.14). The SNP association study (367 patients tested) revealed 15 SNPs significant at 10–7 genome-wide level; the five top SNPs remained after removing those in LD (D’ ≥ 0.99). Four SNPs were in the MGMT gene on chromosome 10 and the fifth in gene ANKS1B on chromosome 12. Carrying one risk (minor) allele of the top 5 SNPs was associated with 64% increased risk of myelotoxicity (OR=1.64; 95% CI, 1.43–1.89; adjusted p <0.0001). The AUC of the final model increased to 0.827 after including the genetic variants. After thirty-fold cross-validation the area under the ROC curve for the model was 0.807. Conclusions: Germline risk alleles in the MGMT and ANKS1B genes, among others, improve prediction of TMZ myelotoxicity when combined with clinical-pathologic factors. TMZ myelotoxicity is a significant clinical issue, and being able to predict risk should allow treatment optimization. NIH grant-1R01NR013707-01A1, U10CA21661, U10CA180868, U10CA180822, U10 CA37422, U24CA180803 (NCI), NIH grant- 1R01NR013707-01A1 and Genentech.
Waste in the US Health Care System
Authors: William H. Shrank, Teresa L. Rogstad, Natasha Parekh
Journal: JAMA (2019)

The United States spends more on health care than any other country, with costs approaching 18% of the gross domestic product (GDP). Prior studies estimated that approximately 30% of health care spending may be considered waste. Despite efforts to reduce overtreatment, improve care, and address overpayment, it is likely that substantial waste in US health care spending remains.To estimate current levels of waste in the US health care system in 6 previously developed domains and to report estimates of potential savings for each domain.A search of peer-reviewed and "gray" literature from January 2012 to May 2019 focused on the 6 waste domains previously identified by the Institute of Medicine and Berwick and Hackbarth: failure of care delivery, failure of care coordination, overtreatment or low-value care, pricing failure, fraud and abuse, and administrative complexity. For each domain, available estimates of waste-related costs and data from interventions shown to reduce waste-related costs were recorded, converted to annual estimates in 2019 dollars for national populations when necessary, and combined into ranges or summed as appropriate.The review yielded 71 estimates from 54 unique peer-reviewed publications, government-based reports, and reports from the gray literature. Computations yielded the following estimated ranges of total annual cost of waste: failure of care delivery, $102.4 billion to $165.7 billion; failure of care coordination, $27.2 billion to $78.2 billion; overtreatment or low-value care, $75.7 billion to $101.2 billion; pricing failure, $230.7 billion to $240.5 billion; fraud and abuse, $58.5 billion to $83.9 billion; and administrative complexity, $265.6 billion. The estimated annual savings from measures to eliminate waste were as follows: failure of care delivery, $44.4 billion to $97.3 billion; failure of care coordination, $29.6 billion to $38.2 billion; overtreatment or low-value care, $12.8 billion to $28.6 billion; pricing failure, $81.4 billion to $91.2 billion; and fraud and abuse, $22.8 billion to $30.8 billion. No studies were identified that focused on interventions targeting administrative complexity. The estimated total annual costs of waste were $760 billion to $935 billion and savings from interventions that address waste were $191 billion to $286 billion.In this review based on 6 previously identified domains of health care waste, the estimated cost of waste in the US health care system ranged from $760 billion to $935 billion, accounting for approximately 25% of total health care spending, and the projected potential savings from interventions that reduce waste, excluding savings from administrative complexity, ranged from $191 billion to $286 billion, representing a potential 25% reduction in the total cost of waste. Implementation of effective measures to eliminate waste represents an opportunity reduce the continued increases in US health care expenditures.
PAM50 and CGH-array genomic characterization of HER2-equivocal breast cancers defined by the 2018 ASCO/CAP recommendations
Authors: C. Ngo, E. Borcoman, A. Rapinat, F. Simaga, N. Mouterfi, O. Mariani, L. Fuhrmann, E. Jeannot, M. Lae, J.-Y. Pierga, D. Gentien, G. Pierron, P. Morel, H.A. Brauer, A. Vincent-Salomon
Journal: Annals of Oncology (2019)
Long-term outcomes from the randomized phase II study of nivolumab (nivo) or nivo+ipilimumab (ipi) in patients (pts) with melanoma brain metastases (mets): Anti-PD1 brain collaboration (ABC)
Authors: G.V. Long, V.G. Atkinson, S. Lo, S.K. Sandhu, M. Brown, M. Gonzalez, A. Guminski, R.A. Scolyer, L. Emmett, A.M. Menzies, G.A. McArthur
Journal: Annals of Oncology (2019)
Impact of prior pegylated liposomal doxorubicin (PLD) treatment in recurrent ovarian cancer (ROC): Sub-group analysis from a randomized, open-label study comparing trabectedin (T) and PLD versus PLD alone in ROC (ET743-OVC-3006)
Authors: B.J. Monk, T.J. Herzog, S. Triantos, S. Maul, G. Wang, M J Pontes Valero, T. McGowan, W.S. Shalaby, R.L. Coleman
Journal: Annals of Oncology (2019)
Data‐driven step doses for drug provocation tests to nonsteroidal anti‐inflammatory drugs
Authors: Dunya Nohra, Nicolas Molinari, Pascal Demoly, Anca‐Mirela Chiriac
Journal: Allergy (2019)

Abstract Introduction Hypersensitivity to nonsteroidal anti‐inflammatory drugs (NSAIDs) is of great concern because they are frequently encountered in daily clinical practice. Drug provocation tests (DPTs) are particularly needed for NSAIDs. Methods The aim of this retrospective study was to detect eliciting dose thresholds during NSAIDs DPT in order to suggest optimal step doses, using the survival analysis method. Our secondary objective was to describe subgroups at higher risk during DPT and evaluate the safety of our 30 minutes incremental 1‐day protocol. The study comprised all the patients attended the Allergy of the University Hospital of Montpellier (France), between 1997 and 2017 for a suspicion of drug hypersensitivity reaction to NSAIDs. Results Throughout the study period, 311 positive DPT were analyzed (accounting for 285 hypersensitive patients). We identified eliciting thresholds (dose and time), and we suggest the following steps for future DPT: for the rapid absorption group (acetylsalicylic acid, ibuprofen, ketoprofen, and tiaprofenic acid), every 30 minutes: 20%‐30%‐50% of daily therapeutic dose, for the moderate absorption group, every 30 minutes: for diclofenac 5%‐15%‐30%‐50%, and for celecoxib, 20%‐80%. For the slow absorption group, piroxicam, 25%‐75%, was separated by a 3‐hours interval. A surveillance period of 3 hours after the last dose is mandatory for patients. Conclusion Drug provocation test protocols for NSAID are empirical, driven by the knowledge on patterns of DHR, cross‐reactivity between NSAID and pharmacological effects of these all drugs. This is the second experience in improving DPT protocols, after BL (B‐lactam) antibiotics.
Safety, efficacy, PK and PD biomarker results of the first-in-human study of mutant isocitrate dehydrogenase 1 (mIDH1) inhibitor BAY 1436032 in patients (pts) with mIDH1 advanced solid tumours
Authors: W. Wick, G. Tabatabai, M. Schuler, K. Rorhberg, S.P. Chawla, F. Janku, D. Schiff, V. Heinemann, Y. Narita, Y. Ando, H.J. Lenz, M. Ikeda, I. Genvresse, C. Rentzsch, S. Reschke, C. Cyris, C. Cai, M. Jeffers, C. Peña, O. Bähr
Journal: Annals of Oncology (2019)
Phased avelumab combined with chemotherapy as first-line treatment for patients with advanced small cell lung cancer (SCLC): The PAVE study, a Hellenic Cooperative Oncology Group Study
Authors: H. Linardou, G. Mountzios, A. Psyrri, A. Christopoulou, K. Sakellariou, H. Vaja, A. Grivas, T. Makatsoris, G. Aravantinos, E. Samantas
Journal: Annals of Oncology (2019)
Relationship of baseline PSA and degree of PSA decline to radiographic progression-free survival (rPFS) in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC): Results from COU-AA-302.
Authors: Charles J. Ryan, Anil Londhe, Arturo Molina, Matthew R. Smith, Johann Sebastian De Bono, Peter Mulders, Dana E. Rathkopf, Fred Saad, Christopher Logothetis, Karim Fizazi, Howard I. Scher, Eric Jay Small, Shannon Matheny, Thian San Kheoh, Thomas W. Griffin
Journal: Journal of Clinical Oncology (2013)

5010 Background: Abiraterone acetate (AA), an androgen biosynthesis inhibitor, prolongs overall survival (OS) in mCRPC patients and is approved for use in this population. The relationship of PSA kinetics to rPFS was evaluated in an exploratory analysis of patients from COU-AA-302, a randomized phase III study of AA in chemotherapy-naive mCRPC patients. Methods: 1,088 patients were randomized 1:1 to AA (1 g) + prednisone (P) (5 mg BID) or P alone. rPFS and OS were co-primary endpoints. rPFS was defined as time to first occurrence of bone scan progression by PCWG2 criteria, progression by CT/MRI by modified RECIST 1.0 criteria, or death from any cause; PSA changes were not a factor in determining rPFS. Quartiles of baseline PSA and % PSA decrease from baseline to nadir were analyzed. Stratified Cox regression models were used with factors for treatment, PSA outcomes, and baseline covariates performed at 55% of OS events. Results: 54/546 patients (10%) in AA + P arm achieved undetectable PSA vs 14/542 patients (3%) in the P arm; at median follow-up of 27.1 mos, radiographic progression was observed in 28% (AA + P) vs 50% of patients (P). There was a consistent trend of decreasing hazard of progression with decreasing baseline PSA and increasing % PSA decline (Table). Treatment effect of AA + P vs P with decreasing baseline PSA or % PSA decline remained significant (p=0.001) after adjusting for other factors (PSA, LDH, alk phos, hemoglobin, bone metastasis) in the model. Conclusions: rPFS was positively associated with the magnitude of PSA decline and inversely associated with baseline PSA. These effects remained after correcting for covariates. In all analyses, treatment with AA led to rPFS outcomes superior to P. Clinical trial information: NCT00887198. [Table: see text]