Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study

BACKGROUND: Isocitrate dehydrogenase 1 (IDH1) mutations occur in approximately 13% of patients with intrahepatic cholangiocarcinoma, a relatively uncommon cancer with a poor clinical outcome. The aim of this international phase 3 study was to assess the efficacy and safety of ivosidenib (AG-120)-a small-molecule targeted inhibitor of mutated IDH1-in patients with previously treated IDH1-mutant cholangiocarcinoma. METHODS: This multicentre, randomised, double-blind, placebo-controlled, phase 3 study included patients from 49 hospitals in six countries aged at least 18 years with histologically confirmed, advanced, IDH1-mutant cholangiocarcinoma who had progressed on previous therapy, and had up to two previous treatment regimens for advanced disease, an Eastern Cooperative Oncology Group performance status score of 0 or 1, and a measurable lesion as defined by Response Evaluation Criteria in Solid Tumors version 1.1. Patients were randomly assigned (2:1) with a block size of 6 and stratified by number of previous systemic treatment regimens for advanced disease to oral ivosidenib 500 mg or matched placebo once daily in continuous 28-day cycles, by means of an interactive web-based response system. Placebo to ivosidenib crossover was permitted on radiological progression per investigator assessment. The primary endpoint was progression-free survival by independent central review. The intention-to-treat population was used for the primary efficacy analyses. Safety was assessed in all patients who had received at least one dose of ivosidenib or placebo. Enrolment is complete; this study is registered with ClinicalTrials.gov, NCT02989857. FINDINGS: Between Feb 20, 2017, and Jan 31, 2019, 230 patients were assessed for eligibility, and as of the Jan 31, 2019 data cutoff date, 185 patients were randomly assigned to ivosidenib (n=124) or placebo (n=61). Median follow-up for progression-free survival was 6·9 months (IQR 2·8-10·9). Progression-free survival was significantly improved with ivosidenib compared with placebo (median 2·7 months [95% CI 1·6-4·2] vs 1·4 months [1·4-1·6]; hazard ratio 0·37; 95% CI 0·25-0·54; one-sided p<0·0001). The most common grade 3 or worse adverse event in both treatment groups was ascites (four [7%] of 59 patients receiving placebo and nine [7%] of 121 patients receiving ivosidenib). Serious adverse events were reported in 36 (30%) of 121 patients receiving ivosidenib and 13 (22%) of 59 patients receiving placebo. There were no treatment-related deaths. INTERPRETATION: Progression-free survival was significantly improved with ivosidenib compared with placebo, and ivosidenib was well tolerated. This study shows the clinical benefit of targeting IDH1 mutations in advanced, IDH1-mutant cholangiocarcinoma. FUNDING: Agios Pharmaceuticals

Final Overall Survival Efficacy Results of Ivosidenib for Patients With Advanced Cholangiocarcinoma With IDH1 Mutation: The Phase 3 Randomized Clinical ClarIDHy Trial

IMPORTANCE: Isocitrate dehydrogenase 1 (IDH1) variations occur in up to approximately 20% of patients with intrahepatic cholangiocarcinoma. In the ClarIDHy trial, progression-free survival as determined by central review was significantly improved with ivosidenib vs placebo. OBJECTIVE: To report the final overall survival (OS) results from the ClarIDHy trial, which aimed to demonstrate the efficacy of ivosidenib (AG-120)—a first-in-class, oral, small-molecule inhibitor of mutant IDH1—vs placebo for patients with unresectable or metastatic cholangiocarcinoma with IDH1 mutation. DESIGN, SETTING, AND PARTICIPANTS: This multicenter, randomized, double-blind, placebo-controlled, clinical phase 3 trial was conducted from February 20, 2017, to May 31, 2020, at 49 hospitals across 6 countries among patients aged 18 years or older with cholangiocarcinoma with IDH1 mutation whose disease progressed with prior therapy. INTERVENTIONS: Patients were randomized 2:1 to receive ivosidenib, 500 mg, once daily or matched placebo. Crossover from placebo to ivosidenib was permitted if patients had disease progression as determined by radiographic findings. MAIN OUTCOMES AND MEASURES: The primary end point was progression-free survival as determined by blinded independent radiology center (reported previously). Overall survival was a key secondary end point. The primary analysis of OS followed the intent-to-treat principle. Other secondary end points included objective response rate, safety and tolerability, and quality of life. RESULTS: Overall, 187 patients (median age, 62 years [range, 33-83 years]) were randomly assigned to receive ivosidenib (n = 126; 82 women [65%]; median age, 61 years [range, 33-80 years]) or placebo (n = 61; 37 women [61%]; median age, 63 years [range, 40-83 years]); 43 patients crossed over from placebo to ivosidenib. The primary end point of progression-free survival was reported elsewhere. Median OS was 10.3 months (95% CI, 7.8-12.4 months) with ivosidenib vs 7.5 months (95% CI, 4.8-11.1 months) with placebo (hazard ratio, 0.79 [95% CI, 0.56-1.12]; 1-sided P = .09). When adjusted for crossover, median OS with placebo was 5.1 months (95% CI, 3.8-7.6 months; hazard ratio, 0.49 [95% CI, 0.34-0.70]; 1-sided P < .001). The most common grade 3 or higher treatment-emergent adverse event (≥5%) reported in both groups was ascites (11 patients [9%] receiving ivosidenib and 4 patients [7%] receiving placebo). Serious treatment-emergent adverse events considered ivosidenib related were reported in 3 patients (2%). There were no treatment-related deaths. Patients receiving ivosidenib reported no apparent decline in quality of life compared with placebo. CONCLUSIONS AND RELEVANCE: This randomized clinical trial found that ivosidenib was well tolerated and resulted in a favorable OS benefit vs placebo, despite a high rate of crossover. These data, coupled with supportive quality of life data and a tolerable safety profile, demonstrate the clinical benefit of ivosidenib for patients with advanced cholangiocarcinoma with IDH1 mutation. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT0298985

Scholarship on Gender and Sport in Sex Roles and Beyond

In this paper we critically review how research on girls or women and sport has developed over the last 35 years. We use a post-positivist lens to explore the content of the papers published in Sex Roles in the area of women, gender and sport and examine the shifts in how gender and sport have been conceptualized in these accounts. In order to initiate a broader dialogue about the scholarly analysis of gender and sport, we subsequently explore ideas inspired by feminist theorizing that have dominated/guided related research in other outlets over this time period but have received relatively little attention in papers published in Sex Roles. We conclude by briefly making suggestions for further research in this area

Validação da equação de Brzycki para a estimativa de 1-RM no exercício supino em banco horizontal Validez de la ecuación de Brzycki para la estimativa de 1-RM en ejercicio press de banco Validation of the Brzycki equation for the estimation of 1-RM in the bench press

O objetivo deste estudo foi analisar a validade da equação proposta por Brzycki para a predição de uma repetição máxima (1-RM) no exercício supino em banco horizontal. Para tanto, 50 homens (22,2 &plusmn; 3,5 anos; 64,7 &plusmn; 8,6kg), sedentários ou moderadamente ativos, foram inicialmente submetidos a seis sessões de testes de 1-RM no exercício supino em banco horizontal, com 48 horas de intervalo entre cada sessão, para a determinação da carga máxima. Posteriormente, um protocolo de resistência de força foi executado para a determinação de 7 a 10-RM. Os critérios utilizados para a validação incluíram: teste t de Student para amostras dependentes, para comparação entre os valores médios obtidos pela equação preditiva e pelo teste de 1-RM; coeficiente de correlação de Pearson, para análise do grau de associação entre as medidas; erro padrão de estimativa (EPE), para avaliação do grau de desvio dos dados individuais ao longo da reta produzida; erro total (ET), para a verificação do desvio médio dos valores individuais da reta de identidade; erro constante (EC), para análise da diferença entre os valores médios obtidos no teste de 1-RM e preditos pela equação proposta. Nenhuma diferença estatisticamente significante foi verificada entre os valores produzidos pelo teste de 1-RM e a equação de Brzycki (P > 0,05). Tanto o EPE quanto o ET foram relativamente baixos (2,42kg ou 3,4% e 1,55kg ou 2,2%, respectivamente), bem como o EC (0,22kg ou 0,3%). Além disso, o valor do coeficiente de correlação encontrado foi extremamente elevado (r = 0,99; P < 0,05), demonstrando, assim, forte associação entre os valores encontrados pelo teste de 1-RM e a equação de Brzycki. Portanto, a equação analisada por este estudo atendeu satisfatoriamente aos critérios de validação estabelecidos pela literatura. Os resultados sugerem que a equação de Brzycki parece ser uma alternativa bastante atraente para a estimativa dos valores de 1-RM no exercício supino em banco horizontal, a partir da execução de testes submáximos de 7 a 10-RM, em homens adultos sedentários ou moderadamente ativos.<br>El objetivo de este estudio ha sido analizar la validez de la ecuación propuesta por Brzycki para la predicción de una repetición máxima (1-RM) en el ejercicio press de banco. Para esto, 50 hombres (22,2 &plusmn; 3,5 años; 64,7 &plusmn; 8,6 kg), sedentarios o moderadamente activos, fueron inicialmente sometidos a seis sesiones de tests de 1-RM en ejercicio press de banco, con 48 horas de intervalo entre cada sesión, para determinar la carga máxima. Posteriormente, un protocolo de resistencia de fuerza fue ejecutado para determinar de 7-10-RM. Los criterios utilizados para la validación incluyeron: test "t" de Student para muestras dependientes, para comparar los valores medios obtenidos por la ecuación predictiva y por el test de 1-RM; coeficiente de correlación de Pearson, para analizar el grado de asociación entre las medidas; error padrón de estimativa (EPE), para la evaluación del grado del desvío de los datos individuales a lo largo de la recta producida; error total (ET), para verificar el desvío medio de los valores individuales de la recta de identidad; error constante (EC), para el análisis de la diferencia entre los valores medios obtenidos en el test de 1-RM y proveídos por la ecuación propuesta. Ninguna diferencia estadística significante fue verificada entre los valores producidos por el test de 1-RM y la ecuación de Brzycki (P > 0,05). Tanto el EPE como el ET fueron relativamente bajos (2,42 kg o 3,4% y 1,55 kg o 2,2%, respectivamente), así como el EC (0,22 kg o 0,3%). Además de esto, el valor del coeficiente de correlación encontrado fue extremamente elevado (r = 0,99; P < 0,05), mostrando así una fuerte asociación entre los valores encontrados por el test de 1-RM y la ecuación de Brzycki. Por tanto, la ecuación analizada por este estudio atendió satisfactoriamente a los criterios de validez establecidos por la literatura. Los resultados sugieren que la ecuación de Brzycki parece ser una alternativa bastante atrayente para estimar los valores de 1-RM en el ejercicio press de banco, a partir de la ejecución de tests submáximos de 7-10-RM, en hombres adultos sedentarios o moderadamente activos.<br>The aim of the present study was to analyze the validation of the equation proposed by Brzycki for the prediction of a maximum repetition (1-RM) in the bench press. Fifty sedentary or moderately active male subjects (22.2 &plusmn; 3.5 years; 64.7 &plusmn; 8.6 kg), were initially submitted to six test sessions of 1-RM in the bench press, with 48 hours of interval between each session, in order to determine the maximum workload. A protocol of force resistance was then performed for the determination of 7-10-RM. The used criteria for the validation included: t-Student test for dependent samples, for comparison among the mean values obtained by the predictive equation and by the 1-RM test; Pearson correlation coefficient for analysis of the association degree among the measurements; standard error of estimate (SEE) for evaluation of the mean deviation degree of the individual data along the produced line; total error (TE) for the verification of the mean deviation of the individual values of the identity line; constant error (CE) for analysis of the difference among the mean values obtained in the 1-RM test and predicted by the proposed equation. None statistically significant difference was verified among the values produced by the 1-RM test and the Brzycki equation (P > 0.05). Both the SEE and the TE were relatively low (2.42 kg or 3.4% and 1.55 kg or 2.2%, respectively), as well as the CE found (0.22 kg or 0.3%). Moreover, the correlation coefficient value found was extremely high (r = 0.99; P < 0.05), thus showing a strong association between the values found by the 1-RM test and the Brzycki equation. Therefore, the equation analyzed by this study satisfied the validation criteria established by the literature. The results suggest that the Brzycki equation seems to be a fairly attractive alternative for the estimation of 1-RM values in the bench press from the performance of submaximal tests of 7-10-RM, in sedentary or moderately active male adults

An antibiotic produced by an insect-pathogenic bacterium suppresses host defenses through phenoloxidase inhibition

Photorhabdus is a virulent pathogen that kills its insect host by overcoming immune responses. The bacterium also secretes a range of antibiotics to suppress the growth of other invading microorganisms. Here we show that Photorhabdus produces a small-molecule antibiotic (E)-1,3-dihydroxy-2-(isopropyl)-5-(2-phenylethenyl)benzene (ST) that also acts as an inhibitor of phenoloxidase (PO) in the insect host Manduca sexta. The Photorhabdus gene stlA encodes an enzyme that produces cinnamic acid, a key precursor for production of ST, and a mutation in stlA results in loss of ST production and PO inhibitory activity, which are both restored by genetic complementation of the mutant and also by supplying cinnamic acid. ST is produced both in vitro and in vivo in sufficient quantities to account for PO inhibition and is the only detectable solvent-extractable inhibitor. A Photorhabdus stlA− mutant is significantly less virulent, proliferates slower within the host, and provokes the formation of significantly more melanotic nodules than wild-type bacteria. Virulence of the stlA− mutant is also rescued by supplying cinnamic acid. The proximate cause of the virulence effect, however, is the inhibition of PO, because the effect of the stlA− mutation on virulence is abolished in insects in which PO has been knocked down by RNA interference (RNAi). Thus, ST has a dual function both as a PO inhibitor to counter host immune reactions and also as an antibiotic to exclude microbial competitors from the insect cadaver

A definitive prognostication system for patients with thoracic malignancies diagnosed with COVID-19: an update from the TERAVOLT registry.

BackgroundPatients with thoracic malignancies are at increased risk for mortality from Coronavirus disease 2019 (COVID-19) and large number of intertwined prognostic variables have been identified so far.MethodsCapitalizing data from the TERAVOLT registry, a global study created with the aim of describing the impact of COVID-19 in patients with thoracic malignancies, we used a clustering approach, a fast-backward step-down selection procedure and a tree-based model to screen and optimize a broad panel of demographics, clinical COVID-19 and cancer characteristics.ResultsAs of April 15, 2021, 1491 consecutive evaluable patients from 18 countries were included in the analysis. With a mean observation period of 42 days, 361 events were reported with an all-cause case fatality rate of 24.2%. The clustering procedure screened approximately 73 covariates in 13 clusters. A further multivariable logistic regression for the association between clusters and death was performed, resulting in five clusters significantly associated with the outcome. The fast-backward step-down selection then identified seven major determinants of death ECOG-PS (OR 2.47 1.87-3.26), neutrophil count (OR 2.46 1.76-3.44), serum procalcitonin (OR 2.37 1.64-3.43), development of pneumonia (OR 1.95 1.48-2.58), c-reactive protein (CRP) (OR 1.90 1.43-2.51), tumor stage at COVID-19 diagnosis (OR 1.97 1.46-2.66) and age (OR 1.71 1.29-2.26). The ROC analysis for death of the selected model confirmed its diagnostic ability (AUC 0.78; 95%CI: 0.75 - 0.81). The nomogram was able to classify the COVID-19 mortality in an interval ranging from 8% to 90% and the tree-based model recognized ECOG-PS, neutrophil count and CRP as the major determinants of prognosis.ConclusionFrom 73 variables analyzed, seven major determinants of death have been identified. Poor ECOG-PS demonstrated the strongest association with poor outcome from COVID-19. With our analysis we provide clinicians with a definitive prognostication system to help determine the risk of mortality for patients with thoracic malignancies and COVID-19