RESUMEN

PURPOSE: Effective treatments are needed for melanoma that progresses on inhibitors of programmed cell death protein-1 (PD-1) or its ligand (PD-L1). We conducted the phase II LEAP-004 study to evaluate the combination of the multikinase inhibitor lenvatinib and the PD-1 inhibitor pembrolizumab in this population (ClinicalTrials.gov identifier: NCT03776136). METHODS: Eligible patients with unresectable stage III-IV melanoma with confirmed progressive disease (PD) within 12 weeks of the last dose of a PD-1/L1 inhibitor given alone or with other therapies, including cytotoxic T-cell lymphocyte-associated antigen 4 (CTLA-4) inhibitors, received lenvatinib 20 mg orally once daily plus ≤ 35 doses of pembrolizumab 200 mg intravenously once every 3 weeks until PD or unacceptable toxicity. The primary end point was objective response rate (ORR) per RECIST, version 1.1, by independent central review. RESULTS: A total of 103 patients were enrolled and treated. The median study follow-up was 15.3 months. ORR in the total population was 21.4% (95% CI, 13.9 to 30.5), with three (2.9%) complete responses and 19 (18.4%) partial responses. The median duration of response was 8.3 months (range, 3.2-15.9+). ORR was 33.3% in the 30 patients with PD on prior anti-PD-1 plus anti-CTLA-4 therapy. The median progression-free survival and overall survival in the total population were 4.2 months (95% CI, 3.8 to 7.1) and 14.0 months (95% CI, 10.8 to not reached), respectively. Grade 3-5 treatment-related adverse events occurred in 47 (45.6%) patients, most commonly hypertension (21.4%); one patient died from a treatment-related event (decreased platelet count). CONCLUSION: Lenvatinib plus pembrolizumab provides clinically meaningful, durable responses in patients with advanced melanoma with confirmed PD on prior PD-1/L1 inhibitor-based therapy, including those with PD on anti-PD-1 plus anti-CTLA-4 therapy. The safety profile was as expected. These data support lenvatinib plus pembrolizumab as a potential regimen for this population of high unmet need.

Asunto(s)

Inhibidores de Puntos de Control Inmunológico , Melanoma , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Antígeno B7-H1 , Melanoma/tratamiento farmacológico , Proteínas Reguladoras de la Apoptosis/uso terapéutico , Melanoma Cutáneo Maligno

RESUMEN

INTRODUCTION: Lenvatinib is an oral multitargeted tyrosine kinase inhibitor that has shown efficacy and manageable safety across multiple cancer types. The recommended starting doses for lenvatinib differ across cancer types and indications based on whether it is used as monotherapy or as combination therapy. AREAS COVERED: This review covers clinical trials that established the dosing paradigm and efficacy of lenvatinib and defined its adverse-event profile as a monotherapy; or in combination with the mTOR inhibitor, everolimus; or the anti-PD-1 antibody, pembrolizumab; and/or chemotherapy. EXPERT OPINION: Lenvatinib has been established as standard-of-care either as a monotherapy or in combination with other anticancer agents for the treatment of radioiodine-refractory differentiated thyroid carcinoma, hepatocellular carcinoma, renal cell carcinoma, and endometrial carcinoma, and is being investigated further across several other tumor types. The dosing and adverse-event management strategies for lenvatinib have been developed through extensive clinical trial experience. Collectively, the data provide the rationale to start lenvatinib at the recommended doses and then interrupt or dose reduce as necessary to achieve required dose intensity for maximized patient benefit. The adverse-event profile of lenvatinib is consistent with that of other tyrosine kinase inhibitors, and clinicians are encouraged to review and adopt relevant symptom-management strategies.

Asunto(s)

Antineoplásicos , Carcinoma de Células Renales , Neoplasias Renales , Neoplasias Hepáticas , Quinolinas , Neoplasias de la Tiroides , Antineoplásicos/efectos adversos , Carcinoma de Células Renales/patología , Humanos , Radioisótopos de Yodo , Neoplasias Renales/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Compuestos de Fenilurea/efectos adversos , Inhibidores de Proteínas Quinasas/efectos adversos , Quinolinas/efectos adversos , Neoplasias de la Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/patología

RESUMEN

BACKGROUND: Lenvatinib (18 mg) plus everolimus (5 mg) is approved for patients with advanced renal cell carcinoma (RCC) after one or more prior antiangiogenic therapies. OBJECTIVE: To assess whether a lower starting dose of lenvatinib has comparable efficacy with improved tolerability for patients with advanced RCC treated with lenvatinib plus everolimus. DESIGN, SETTING, AND PARTICIPANTS: A randomized, open-label, phase 2 global trial was conducted in patients with advanced clear cell RCC and disease progression after one prior vascular endothelial growth factor-targeted therapy (prior anti-programmed death-1/programmed death ligand-1 therapy permitted). INTERVENTION: Patients were randomly assigned 1:1 to the 14- or 18-mg lenvatinib starting dose, both in combination with everolimus 5 mg/d. Patients in the 14-mg arm were to be uptitrated to lenvatinib 18 mg at cycle 2, day 1, barring intolerable grade 2 or any grade ≥3 treatment-emergent adverse events (TEAEs) requiring dose reduction occurring in the first 28-d cycle. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary efficacy endpoint was investigator-assessed objective response rate (ORR) as of week 24 (ORRwk24); the noninferiority threshold of the 14- versus 18-mg arm was p ≤ 0.045. The primary safety endpoint was the proportion of patients with intolerable grade 2 or any grade ≥3 TEAEs within 24 wk of randomization. RESULTS AND LIMITATIONS: The ORRwk24 for the 14-mg arm (32% [95% confidence interval {CI} 25-39]) was not noninferior to the ORRwk24 in the 18-mg arm (35% [95% CI 27-42]; odds ratio: 0.88; 90% CI 0.59-1.32; p = 0.3). The proportion of intolerable grade 2 or any grade ≥3 TEAEs was similar between the two arms (14 mg, 83% vs 18 mg, 80%; p = 0.5). The secondary endpoints of overall ORR, progression-free survival, and overall survival numerically favored the 18-mg arm. A limitation of this study was that the study design did not allow for a full comparison of progression-free survival between treatment arms. CONCLUSIONS: The study findings support the approved dosing regimen of lenvatinib 18 mg plus everolimus 5 mg daily for patients with advanced RCC. PATIENT SUMMARY: In this report, we examined two doses of lenvatinib (the approved 18-mg dose and a lower dose of 14 mg) in people with advanced renal cell carcinoma to determine whether the lower dose (which was increased to the approved 18-mg dose after the first treatment cycle) could improve safety without affecting efficacy. The results showed that the efficacy of the lower lenvatinib dose (14 mg) was not the same as that of the approved (18 mg) dose, although safety results were similar, so the approved lenvatinib 18-mg dose should still be used.

Asunto(s)

Carcinoma de Células Renales , Neoplasias Renales , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Células Renales/patología , Everolimus/efectos adversos , Humanos , Neoplasias Renales/patología , Compuestos de Fenilurea , Quinolinas , Factor A de Crecimiento Endotelial Vascular

RESUMEN

BACKGROUND: Standard therapy for advanced endometrial cancer after failure of platinum-based chemotherapy remains unclear. METHODS: In this phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with advanced endometrial cancer who had previously received at least one platinum-based chemotherapy regimen to receive either lenvatinib (20 mg, administered orally once daily) plus pembrolizumab (200 mg, administered intravenously every 3 weeks) or chemotherapy of the treating physician's choice (doxorubicin at 60 mg per square meter of body-surface area, administered intravenously every 3 weeks, or paclitaxel at 80 mg per square meter, administered intravenously weekly [with a cycle of 3 weeks on and 1 week off]). The two primary end points were progression-free survival as assessed on blinded independent central review according to the Response Evaluation Criteria in Solid Tumors, version 1.1, and overall survival. The end points were evaluated in patients with mismatch repair-proficient (pMMR) disease and in all patients. Safety was also assessed. RESULTS: A total of 827 patients (697 with pMMR disease and 130 with mismatch repair-deficient disease) were randomly assigned to receive lenvatinib plus pembrolizumab (411 patients) or chemotherapy (416 patients). The median progression-free survival was longer with lenvatinib plus pembrolizumab than with chemotherapy (pMMR population: 6.6 vs. 3.8 months; hazard ratio for progression or death, 0.60; 95% confidence interval [CI], 0.50 to 0.72; P<0.001; overall: 7.2 vs. 3.8 months; hazard ratio, 0.56; 95% CI, 0.47 to 0.66; P<0.001). The median overall survival was longer with lenvatinib plus pembrolizumab than with chemotherapy (pMMR population: 17.4 vs. 12.0 months; hazard ratio for death, 0.68; 95% CI, 0.56 to 0.84; P<0.001; overall: 18.3 vs. 11.4 months; hazard ratio, 0.62; 95% CI, 0.51 to 0.75; P<0.001). Adverse events of grade 3 or higher occurred in 88.9% of the patients who received lenvatinib plus pembrolizumab and in 72.7% of those who received chemotherapy. CONCLUSIONS: Lenvatinib plus pembrolizumab led to significantly longer progression-free survival and overall survival than chemotherapy among patients with advanced endometrial cancer. (Funded by Eisai and Merck Sharp and Dohme [a subsidiary of Merck]; Study 309-KEYNOTE-775 ClinicalTrials.gov number, NCT03517449.).

Asunto(s)

Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Endometriales/tratamiento farmacológico , Compuestos de Fenilurea/administración & dosificación , Quinolinas/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Endometriales/mortalidad , Femenino , Humanos , Persona de Mediana Edad , Compuestos de Fenilurea/efectos adversos , Quinolinas/efectos adversos , Análisis de Supervivencia

RESUMEN

National ID cards have been debated for some time, especially with the recent Covid-19 global pandemic and increases in technological capabilities, coupled with the need for higher national security. This paper is an empirical extension of Smith's work but in light of the current economic and political turmoil. These differences were inspected from a gender perspective, but the distrust was generally universal. As the beneficial reasons why National ID cards should be implemented (e.g., enhanced security, convenience, and enhancing CRM concepts), still many professionals exhibit numerous fears and are concerned with the risks involved.

Asunto(s)

COVID-19 , Pandemias , Humanos , Pandemias/prevención & control , SARS-CoV-2

RESUMEN

BACKGROUND: Despite advances in the first-line treatment of metastatic renal cell carcinoma (RCC), there is an unmet need for options to address disease progression during or after treatment with immune checkpoint inhibitors (ICIs). Pembrolizumab and lenvatinib are active as monotherapies in RCC; thus, we aimed to evaluate the combination of lenvatinib plus pembrolizumab in these patients. METHODS: We report results of the metastatic RCC cohort from an open-label phase 1b/2 study of lenvatinib plus pembrolizumab in patients aged at least 18 years with selected solid tumours and an Eastern Cooperative Oncology Group performance status of 0-1. Oral lenvatinib at 20 mg was given once daily along with intravenous pembrolizumab at 200 mg once every 3 weeks. Patients remained on study drug treatment until disease progression, development of unacceptable toxicity, or withdrawal of consent. Efficacy was analysed in patients with clear cell metastatic RCC receiving study drug by previous therapy grouping: treatment naive, previously treated ICI naive (previously treated with at least one line of therapy but not with an anti-PD-1 or anti-PD-L1 ICI), and ICI pretreated (ie, anti-PD-1 or anti-PD-L1) patients. Safety was analysed in all enrolled and treated patients. The primary endpoint was the objective response rate at week 24 per immune-related Response Evaluation Criteria In Solid Tumors (irRECIST) by investigator assessment. This trial is registered with ClinicalTrials.gov (NCT02501096) and with the EU Clinical Trials Register (EudraCT2017-000300-26), and is closed to new participants. FINDINGS: Between July 21, 2015, and Oct 16, 2019, 145 patients were enrolled in the study. Two patients had non-clear cell RCC and were excluded from the efficacy analysis (one in the treatment-naive group and one in the ICI-pretreated group); thus, the population evaluated for efficacy comprised 143 patients (n=22 in the treatment-naive group, n=17 in the previously treated ICI-naive group, and n=104 in the ICI-pretreated group). All 145 enrolled patients were included in the safety analysis. The median follow-up was 19·8 months (IQR 14·3-28·4). The number of patients with an objective response at week 24 by irRECIST was 16 (72·7%, 95% CI 49·8-89·3) of 22 treatment-naive patients, seven (41·2%, 18·4-67·1) of 17 previously treated ICI-naive patients, and 58 (55·8%, 45·7-65·5) of 104 ICI-pretreated patients. Of 145 patients, 82 (57%) had grade 3 treatment-related adverse events and ten (7%) had grade 4 treatment-related adverse events. The most common grade 3 treatment-related adverse event was hypertension (30 [21%] of 145 patients). Treatment-related serious adverse events occurred in 36 (25%) patients, and there were three treatment-related deaths (upper gastrointestinal haemorrhage, sudden death, and pneumonia). INTERPRETATION: Lenvatinib plus pembrolizumab showed encouraging antitumour activity and a manageable safety profile and might be an option for post-ICI treatment of metastatic RCC. FUNDING: Eisai and Merck Sharp & Dohme.

Asunto(s)

Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Compuestos de Fenilurea/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinolinas/uso terapéutico , Anciano , Anticuerpos Monoclonales Humanizados/efectos adversos , Antineoplásicos Inmunológicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Células Renales/inmunología , Carcinoma de Células Renales/secundario , Europa (Continente) , Femenino , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Neoplasias Renales/inmunología , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Compuestos de Fenilurea/efectos adversos , Inhibidores de Proteínas Quinasas/efectos adversos , Quinolinas/efectos adversos , Factores de Tiempo , Resultado del Tratamiento , Estados Unidos

RESUMEN

BACKGROUND: Lenvatinib in combination with pembrolizumab or everolimus has activity against advanced renal cell carcinoma. The efficacy of these regimens as compared with that of sunitinib is unclear. METHODS: In this phase 3 trial, we randomly assigned (in a 1:1:1 ratio) patients with advanced renal cell carcinoma and no previous systemic therapy to receive lenvatinib (20 mg orally once daily) plus pembrolizumab (200 mg intravenously once every 3 weeks), lenvatinib (18 mg orally once daily) plus everolimus (5 mg orally once daily), or sunitinib (50 mg orally once daily, alternating 4 weeks receiving treatment and 2 weeks without treatment). The primary end point was progression-free survival, as assessed by an independent review committee in accordance with Response Evaluation Criteria in Solid Tumors, version 1.1. Overall survival and safety were also evaluated. RESULTS: A total of 1069 patients were randomly assigned to receive lenvatinib plus pembrolizumab (355 patients), lenvatinib plus everolimus (357), or sunitinib (357). Progression-free survival was longer with lenvatinib plus pembrolizumab than with sunitinib (median, 23.9 vs. 9.2 months; hazard ratio for disease progression or death, 0.39; 95% confidence interval [CI], 0.32 to 0.49; P<0.001) and was longer with lenvatinib plus everolimus than with sunitinib (median, 14.7 vs. 9.2 months; hazard ratio, 0.65; 95% CI, 0.53 to 0.80; P<0.001). Overall survival was longer with lenvatinib plus pembrolizumab than with sunitinib (hazard ratio for death, 0.66; 95% CI, 0.49 to 0.88; P = 0.005) but was not longer with lenvatinib plus everolimus than with sunitinib (hazard ratio, 1.15; 95% CI, 0.88 to 1.50; P = 0.30). Grade 3 or higher adverse events emerged or worsened during treatment in 82.4% of the patients who received lenvatinib plus pembrolizumab, 83.1% of those who received lenvatinib plus everolimus, and 71.8% of those who received sunitinib. Grade 3 or higher adverse events occurring in at least 10% of the patients in any group included hypertension, diarrhea, and elevated lipase levels. CONCLUSIONS: Lenvatinib plus pembrolizumab was associated with significantly longer progression-free survival and overall survival than sunitinib. (Funded by Eisai and Merck Sharp and Dohme; CLEAR ClinicalTrials.gov number, NCT02811861.).

Asunto(s)

Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Everolimus/administración & dosificación , Neoplasias Renales/tratamiento farmacológico , Compuestos de Fenilurea/administración & dosificación , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Quinolinas/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/efectos adversos , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Células Renales/mortalidad , Everolimus/efectos adversos , Femenino , Humanos , Neoplasias Renales/mortalidad , Masculino , Persona de Mediana Edad , Compuestos de Fenilurea/efectos adversos , Supervivencia sin Progresión , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinolinas/efectos adversos , Sunitinib/efectos adversos , Sunitinib/uso terapéutico , Análisis de Supervivencia

RESUMEN

Cabazitaxel is used to treat patients with metastatic castration-resistant prostate cancer progressing after docetaxel. It is prepackaged in 60 mg single-dose vials, a quantity much higher than the average prescribed dose, which leads to, substantial drug wastage (DW) and associated costs. To minimize DW we implemented a cost-saving, cohorting strategy where multiple patients scheduled to receive cabazitaxel (at a dose of 20mg/m2 every 3 wks) were cohorted and treated on a single weekday whenever possible. Excess drug from each vial was then saved and used for subsequent patients treated on the same day. The drug cost with cohorting was calculated from the actual number of vials used, and the drug cost without cohorting was estimated by assumingthat one vial was used per treatment. The cost of DW was determined based on the amount of drug that was discarded. All cost calculations also accounted for the discount incentives offered by Sanofi-Aventis. Over a 3-yr period, 74 patients received 402 treatments of cabazitaxel. Multiple patients were treated on 67.4% of the treatment days, and grouping of three patients on one day saved one vial. The estimated total drug cost saved was $394 536 CAD (21.1%). Pending further studies on safety and efficacy, this strategy could potentially be adopted to mitigate DW for cabazitaxel and similarly for other oncology drugs. This would significantly decrease the overall financial burden on patients, institutions, and stakeholders. PATIENT SUMMARY: Cabazitaxel chemotherapy is associated with substantial drug wastage and associated costs. By cohorting patients scheduled to receive cabazitaxel on a single weekday, the total drug cost was decreased by $394 536 CAD (21.1%) over a 3-yr period. Similar strategies could be considered to overcome the prohibitory costs associated with drug wastage for cabazitaxel and other cancer drugs.

Asunto(s)

Ahorro de Costo , Costos de los Medicamentos , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Taxoides/economía , Taxoides/uso terapéutico , Humanos , Masculino , Metástasis de la Neoplasia , Neoplasias de la Próstata Resistentes a la Castración/patología

RESUMEN

BACKGROUND/AIM: Carbonic anhydrase IX (CA9) catalyses the interconversion of carbon dioxide to carbonic acid and bicarbonate and is considered a putative biomarker of tumour hypoxia. We set out to evaluate the prognostic significance of CA9 in prostate cancer. PATIENTS AND METHODS: Plasma samples were assessed from 68 men with high-risk localised prostate cancer treated with radical prostatectomy (RP) or radiotherapy (RT), and 20 men with castration-resistant prostate cancer (CRPC) treated with docetaxel chemotherapy between 2010 and 2012 at the Princess Margaret Cancer Centre, Canada. RESULTS: Of the 68 patients with high-risk localised prostate cancer, 57 underwent RP and 11 underwent RT. Baseline CA9 was not associated with recurrence or prostate-specific antigen in either group (p=0.98 and 0.20, respectively). CA9 levels before chemotherapy correlated with overall survival (r=-0.37; two-sided p=0.11). CONCLUSION: Baseline CA9 in men with CRPC may portend a more aggressive prostate cancer phenotype with poorer survival.

Asunto(s)

Antígenos de Neoplasias/sangre , Anhidrasa Carbónica IX/sangre , Recurrencia Local de Neoplasia/sangre , Recurrencia Local de Neoplasia/diagnóstico , Neoplasias de la Próstata Resistentes a la Castración/sangre , Neoplasias de la Próstata Resistentes a la Castración/diagnóstico , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/diagnóstico , Anciano , Antineoplásicos/uso terapéutico , Biomarcadores de Tumor , Docetaxel , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Fenotipo , Pronóstico , Antígeno Prostático Específico/sangre , Prostatectomía , Neoplasias de la Próstata/mortalidad , Neoplasias de la Próstata Resistentes a la Castración/mortalidad , Taxoides/uso terapéutico , Resultado del Tratamiento

RESUMEN

Castration-resistant prostate cancer (CRPC) is associated with a poor prognosis and poses considerable therapeutic challenges. Recent genetic and technological advances have provided insights into prostate cancer biology and have enabled the identification of novel drug targets and potent molecularly targeted therapeutics for this disease. In this article, we review recent advances in prostate cancer target identification for drug discovery and discuss their promise and associated challenges. We review the evolving therapeutic landscape of CRPC and discuss issues associated with precision medicine as well as challenges encountered with immunotherapy for this disease. Finally, we envision the future management of CRPC, highlighting the use of circulating biomarkers and modern clinical trial designs.

Asunto(s)

Antineoplásicos/administración & dosificación , Descubrimiento de Drogas/métodos , Terapia Genética/métodos , Terapia Molecular Dirigida/métodos , Neoplasias de la Próstata Resistentes a la Castración/terapia , Investigación Biomédica Traslacional/métodos , Animales , Antineoplásicos/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Descubrimiento de Drogas/tendencias , Terapia Genética/tendencias , Humanos , Masculino , Terapia Molecular Dirigida/tendencias , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Investigación Biomédica Traslacional/tendencias

RESUMEN

BACKGROUND: The availability of multiple new treatments for metastatic castration-resistant prostate cancer (mCRPC) mandates earlier treatment switches in the absence of a response. A decline in prostate-specific antigen (PSA) is widely used to monitor treatment response, but is not validated as an intermediate endpoint for overall survival (OS). OBJECTIVE: To evaluate the association between early PSA decline and OS following abiraterone acetate (AA) treatment. DESIGN, SETTING, AND PARTICIPANTS: We identified mCRPC patients treated with AA before or after docetaxel at the Royal Marsden NHS Foundation Trust between 2006 and 2014. Early PSA decline was defined as a 30% decrease in PSA at 4 wk relative to baseline, and early PSA rise as a 25% increase. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Association with OS was analyzed using multivariate Cox regression and log-rank analyses. Spearman's rho correlation coefficient (r) was calculated to evaluate the association between PSA changes at 4 wk and 12 wk. RESULTS AND LIMITATIONS: There were 274 patients eligible for this analysis. A 30% PSA decline at 4 wk was associated with longer OS (25.8 vs 15.1 mo; hazard ratio [HR] 0.47, p<0.001), and a 25% PSA rise at 4 wk with shorter OS (15.1 vs 23.8 mo; HR 1.7, p=0.001) in both univariate and multivariable models. The percentage PSA decline at 4 wk was significantly correlated with the percentage PSA change at 12 wk (r=0.82; p<0.001). Patients achieving a 30% PSA decline at 4 wk were 11.7 times more likely to achieve a 50% PSA decrease at 12 wk (sensitivity 90.9%, specificity 79.4%). Limitations include the retrospective design of this analysis. CONCLUSIONS: Patients not achieving 30% PSA decline after 4 wk of AA have a lower likelihood of achieving PSA response at 12 wk and significantly inferior OS. Prospective multicentre validation studies are needed to confirm these findings. PATIENT SUMMARY: Prostate-specific antigen (PSA) is commonly used to evaluate response to treatment in metastatic castration-resistant prostate cancer. Expert recommendations discourage reliance on PSA changes earlier than 12 wk after treatment initiation. Our data suggest that early PSA changes are associated with survival in patients receiving abiraterone acetate.

Asunto(s)

Acetato de Abiraterona/administración & dosificación , Monitoreo de Drogas , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata Resistentes a la Castración , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Docetaxel , Monitoreo de Drogas/métodos , Monitoreo de Drogas/estadística & datos numéricos , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Evaluación de Resultado en la Atención de Salud/métodos , Evaluación de Resultado en la Atención de Salud/estadística & datos numéricos , Neoplasias de la Próstata Resistentes a la Castración/sangre , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/mortalidad , Neoplasias de la Próstata Resistentes a la Castración/patología , Sistema de Registros , Estadística como Asunto , Análisis de Supervivencia , Taxoides/uso terapéutico , Reino Unido/epidemiología

RESUMEN

The antiandrogen withdrawal syndrome (AAWS) is characterized by tumour regression and a decline in serum PSA on discontinuation of antiandrogen therapy in patients with prostate cancer. This phenomenon has been best described with the withdrawal of the nonsteroidal antiandrogens, bicalutamide and flutamide, but has also been reported with a wide range of hormonal agents. Mutations that occur in advanced prostate cancer and induce partial activation of the androgen receptor (AR) by hormonal agents have been suggested as the main causal mechanism of the AAWS. Corticosteroids, used singly or in conjunction with abiraterone, docetaxel and cabazitaxel might also be associated with the AAWS. The discovery of the Phe876Leu mutation in the AR, which is activated by enzalutamide, raises the possibility of withdrawal responses to novel hormonal agents. This Review focusses on the molecular mechanisms responsible for withdrawal responses, the role of AR mutations in the development of treatment resistance, and the evidence for the sequential use of antiandrogens in prostate cancer therapy. The implications of AR mutations for the development of novel drugs that target the AR are discussed, as are the challenges associated with redefining the utility of older treatments in the current therapeutic landscape.

Asunto(s)

Antagonistas de Andrógenos/administración & dosificación , Antineoplásicos Hormonales/administración & dosificación , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Privación de Tratamiento , Antagonistas de Andrógenos/uso terapéutico , Antineoplásicos Hormonales/uso terapéutico , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Esquema de Medicación , Humanos , Masculino , Mutación , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Resultado del Tratamiento

RESUMEN

Technological advancements in the molecular characterization of cancers have enabled researchers to identify an increasing number of key molecular drivers of cancer progression. These discoveries have led to multiple novel anticancer therapeutics, and clinical benefit in selected patient populations. Despite this, the identification of clinically relevant predictive biomarkers of response continues to lag behind. In this review, we discuss strategies for the molecular characterization of cancers and the importance of biomarkers for the development of novel antitumor therapeutics. We also review critical successes and failures in oncology, and detail the lessons learnt, which may aid in the acceleration of anticancer drug development and biomarker discovery.

Asunto(s)

Antineoplásicos/farmacología , Biomarcadores de Tumor/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Animales , Descubrimiento de Drogas , Humanos

RESUMEN

Trapline foraging (repeated sequential visits to a series of feeding locations) is a taxonomically widespread but poorly understood behavior. Investigating these routing strategies in the field is particularly difficult, as it requires extensive tracking of animal movements to retrace their complete foraging history. In a recent study, we used harmonic radar and motion-triggered video cameras to track bumblebees foraging between artificial flowers in a large open field. We describe how all bees gradually developed a near optimal trapline to link all flowers and have identified a simple learning heuristic capable of replicating this optimisation behavior. Our results provide new perspectives to clarify the sequence of decisions made by pollinating insects during trapline foraging, and explore how spatial memory is organized in their small brains.   "I have always regretted that I did not mark the bees by attaching bits of cotton wool or eiderdown to them with rubber, because this would have made it much easier to follow their paths." Charles Darwin(1.)

RESUMEN

Central place foragers, such as pollinating bees, typically develop circuits (traplines) to visit multiple foraging sites in a manner that minimizes overall travel distance. Despite being taxonomically widespread, these routing behaviours remain poorly understood due to the difficulty of tracking the foraging history of animals in the wild. Here we examine how bumblebees (Bombus terrestris) develop and optimise traplines over large spatial scales by setting up an array of five artificial flowers arranged in a regular pentagon (50 m side length) and fitted with motion-sensitive video cameras to determine the sequence of visitation. Stable traplines that linked together all the flowers in an optimal sequence were typically established after a bee made 26 foraging bouts, during which time only about 20 of the 120 possible routes were tried. Radar tracking of selected flights revealed a dramatic decrease by 80% (ca. 1500 m) of the total travel distance between the first and the last foraging bout. When a flower was removed and replaced by a more distant one, bees engaged in localised search flights, a strategy that can facilitate the discovery of a new flower and its integration into a novel optimal trapline. Based on these observations, we developed and tested an iterative improvement heuristic to capture how bees could learn and refine their routes each time a shorter route is found. Our findings suggest that complex dynamic routing problems can be solved by small-brained animals using simple learning heuristics, without the need for a cognitive map.

Asunto(s)

Abejas/fisiología , Vuelo Animal/fisiología , Flores/fisiología , Movimiento (Física) , Fotograbar/instrumentación , Polinización/fisiología , Radar , Animales , Grabación en Video

RESUMEN

A general overview of various blood products operational effectiveness and related strategies that can be utilised by service providers (in particular, healthcare providers) is presented in the present study. In terms of the massive volumes of blood products, the North American blood centres collect more than eight million units of whole blood, which represents appropriately 50% of the US and Quebec, Canada?s volunteer donor blood supply. A case study of the quality inspection and inventory control concerns of the Central Blood Bank, located in the metropolitan area of Pittsburgh, PA, is presented. Initially, brief introduction to its general operating environment is followed by sections describing its general situation, quality-service initiatives, and followed by a fairly detailed discussion of the practical applications of lessons learned from the case study.

Asunto(s)

Bancos de Sangre/organización & administración , Necesidades y Demandas de Servicios de Salud/organización & administración , Estudios de Casos Organizacionales , Garantía de la Calidad de Atención de Salud/organización & administración , Bancos de Sangre/economía , Bancos de Sangre/normas , Costos y Análisis de Costo , Recesión Económica , Eficiencia Organizacional , Necesidades y Demandas de Servicios de Salud/economía , Necesidades y Demandas de Servicios de Salud/normas , Humanos , Auditoría Administrativa , América del Norte , Organizaciones sin Fines de Lucro/organización & administración , Pennsylvania , Garantía de la Calidad de Atención de Salud/economía , Garantía de la Calidad de Atención de Salud/normas , Manejo de Especímenes/economía , Manejo de Especímenes/métodos , Procesos Estocásticos

RESUMEN

Vast numbers of insects and passerines achieve long-distance migrations between summer and winter locations by undertaking high-altitude nocturnal flights. Insects such as noctuid moths fly relatively slowly in relation to the surrounding air, with airspeeds approximately one-third of that of passerines. Thus, it has been widely assumed that windborne insect migrants will have comparatively little control over their migration speed and direction compared with migrant birds. We used radar to carry out the first comparative analyses of the flight behaviour and migratory strategies of insects and birds under nearly equivalent natural conditions. Contrary to expectations, noctuid moths attained almost identical ground speeds and travel directions compared with passerines, despite their very different flight powers and sensory capacities. Moths achieved fast travel speeds in seasonally appropriate migration directions by exploiting favourably directed winds and selecting flight altitudes that coincided with the fastest air streams. By contrast, passerines were less selective of wind conditions, relying on self-powered flight in their seasonally preferred direction, often with little or no tailwind assistance. Our results demonstrate that noctuid moths and passerines show contrasting risk-prone and risk-averse migratory strategies in relation to wind. Comparative studies of the flight behaviours of distantly related taxa are critically important for understanding the evolution of animal migration strategies.

Asunto(s)

Migración Animal , Vuelo Animal , Mariposas Nocturnas/fisiología , Pájaros Cantores/fisiología , Movimientos del Aire , Altitud , Animales , Inglaterra , Orientación , Radar , Estaciones del Año

RESUMEN

There are many studies that have tried to evaluate some of the determining factors in smoking cessation, but with limited success. In particular, the present study deals with these concerns within the context of the current global recession and the roles of technology and social networking as moderating variables in the examination of smoking working professionals' relationships between people's background experiences with smoking, their self-reported perceptions about health, economic, and social aspects of smoking, and their perspectives on quitting. The empirical section examines current opinions of smoking analogues as alternatives to cessation and identify whether these opinions were influenced by negative perspectives of smoking in general. Several hypotheses and factor analyses related to smoking cessation statistically evaluated assumptions that economic and social considerations had more effects on quitting than health concerns; personal experience with smoking leads to less confidence in cold turkey quitting; and that technology-based solutions and virtual communities can gain wide acceptance despite the chemical addictiveness of tobacco-related products.

Asunto(s)

Internet , Motivación , Cese del Hábito de Fumar/métodos , Cese del Hábito de Fumar/psicología , Apoyo Social , Adulto , Recesión Económica , Femenino , Salud Global , Humanos , Masculino , Factores de Riesgo , Factores Sexuales , Estadística como Asunto

RESUMEN

Many insects undertake long-range seasonal migrations to exploit temporary breeding sites hundreds or thousands of kilometers apart, but the behavioral adaptations that facilitate these movements remain largely unknown. Using entomological radar, we showed that the ability to select seasonally favorable, high-altitude winds is widespread in large day- and night-flying migrants and that insects adopt optimal flight headings that partially correct for crosswind drift, thus maximizing distances traveled. Trajectory analyses show that these behaviors increase migration distances by 40% and decrease the degree of drift from seasonally optimal directions. These flight behaviors match the sophistication of those seen in migrant birds and help explain how high-flying insects migrate successfully between seasonal habitats.

Asunto(s)

Migración Animal , Mariposas Diurnas/fisiología , Vuelo Animal , Mariposas Nocturnas/fisiología , Viento , Altitud , Animales , Simulación por Computador , Orientación , Radar , Estaciones del Año

RESUMEN

Studies made with both entomological and meteorological radars over the last 40 years have frequently reported the occurrence of insect layers, and that the individuals forming these layers often show a considerable degree of uniformity in their headings--behaviour known as 'common orientation'. The environmental cues used by nocturnal migrants to select and maintain common headings, while flying in low illumination levels at great heights above the ground, and the adaptive benefits of this behaviour have long remained a mystery. Here we show how a wind-mediated mechanism accounts for the common orientation patterns of 'medium-sized' nocturnal insects. Our theory posits a mechanism by which migrants are able to align themselves with the direction of the flow using a turbulence cue, thus adding their air speed to the wind speed and significantly increasing their migration distance. Our mechanism also predicts that insects flying in the Northern Hemisphere will typically be offset to the right of the mean wind line when the atmosphere is stably stratified, with the Ekman spiral in full effect. We report on the first evidence for such offsets, and show that they have significant implications for the accurate prediction of the flight trajectories of migrating nocturnal insects.

Asunto(s)

Altitud , Migración Animal , Oscuridad , Vuelo Animal/fisiología , Insectos/fisiología , Viento , Animales , Mariposas Nocturnas/fisiología , Orientación