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The eighth Paediatric Strategy Forum focused on multi-targeted kinase inhibitors (mTKIs) in osteosarcoma and Ewing sarcoma. The development of curative, innovative products in these tumours is a high priority and addresses unmet needs in children, adolescents and adults. Despite clinical and investigational use of mTKIs, efficacy in patients with bone tumours has not been definitively demonstrated. Randomised studies, currently being planned or in progress, in front-line and relapse settings will inform the further development of this class of product. It is crucial that these are rapidly initiated to generate robust data to support international collaborative efforts. The experience to date has generally indicated that the safety profile of mTKIs as monotherapy, and in combination with chemotherapy or other targeted therapy, is consistent with that of adults and that toxicity is manageable. Increasing understanding of relevant predictive biomarkers and tumour biology is absolutely critical to further develop this class of products. Biospecimen samples for correlative studies and biomarker development should be shared, and a joint academic-industry consortium created. This would result in an integrated collection of serial tumour tissues and a systematic retrospective and prospective analyses of these samples to ensure robust assessment of biologic effect of mTKIs. To support access for children to benefit from these novel therapies, clinical trials should be designed with sufficient scientific rationale to support regulatory and payer requirements. To achieve this, early dialogue between academia, industry, regulators, and patient advocates is essential. Evaluating feasibility of combination strategies and then undertaking a randomised trial in the same protocol accelerates drug development. Where possible, clinical trials and development should include children, adolescents, and adults less than 40 years. To respond to emerging science, in approximately 12 months, a multi-stakeholder group will meet and review available data to determine future directions and priorities.
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Neoplasias Óseas , Osteosarcoma , Adolescente , Adulto , Neoplasias Óseas/tratamiento farmacológico , Niño , Humanos , Recurrencia Local de Neoplasia , Osteosarcoma/tratamiento farmacológico , Estudios Prospectivos , Estudios Retrospectivos , Estados Unidos , United States Food and Drug AdministrationRESUMEN
Novel agents are needed to improve chemoradiotherapy for locally advanced rectal cancer. In this study, we assessed the ability of CRLX101, an investigational nanoparticle-drug conjugate containing the payload camptothecin (CPT), to improve therapeutic responses as compared with standard chemotherapy. CRLX101 was evaluated as a radiosensitizer in colorectal cancer cell lines and murine xenograft models. CRLX101 was as potent as CPT in vitro in its ability to radiosensitize cancer cells. Evaluations in vivo demonstrated that the addition of CRLX101 to standard chemoradiotherapy significantly increased therapeutic efficacy by inhibiting DNA repair and HIF1α pathway activation in tumor cells. Notably, CRLX101 was more effective than oxaliplatin at enhancing the efficacy of chemoradiotherapy, with CRLX101 and 5-fluorouracil producing the highest therapeutic efficacy. Gastrointestinal toxicity was also significantly lower for CRLX101 compared with CPT when combined with radiotherapy. Our results offer a preclinical proof of concept for CRLX101 as a modality to improve the outcome of neoadjuvant chemoradiotherapy for rectal cancer treatment, in support of ongoing clinical evaluation of this agent (LCC1315 NCT02010567). Cancer Res; 77(1); 112-22. ©2016 AACR.
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Camptotecina/farmacología , Ciclodextrinas/farmacología , Reparación del ADN/efectos de los fármacos , Subunidad alfa del Factor 1 Inducible por Hipoxia/biosíntesis , Fármacos Sensibilizantes a Radiaciones/farmacología , Neoplasias del Recto/patología , Animales , Western Blotting , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Quimioradioterapia/métodos , Técnica del Anticuerpo Fluorescente , Humanos , Inmunohistoquímica , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Nanoconjugados , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: CRLX101 is an investigational nanoparticle-drug conjugate with a camptothecin payload. Preclinical evidence indicated preferential uptake in tumors, and tumor xenograft models demonstrate superiority of CRLX101 over irinotecan. A pilot trial was conducted at recommended phase 2 dosing (RP2D) using the bimonthly schedule to assess preferential uptake of CRLX101 in tumor vs. adjacent normal tissue in endoscopically accessible tumors in chemotherapy-refractory gastroesophageal cancer. Results from the biopsies were previously reported and herein we present the clinical outcomes. METHODS: Patients initiated CRLX101 dosed at RP2D (15 mg/m2) on days 1 and 15 of a 28-day cycle. Detection of preferential CRLX101 tumor uptake was the primary endpoint and objective response rate (ORR) was a secondary endpoint. With a sample size of ten patients, the study had 90% power to detect ≥1 responder if the true response rate is ≥21%. RESULTS: Between Dec. 2012 and Dec. 2014, ten patients with chemotherapy-refractory (median 2 prior lines of therapy, range 1-4) gastric adenocarcinoma were enrolled. The median time-to-progression was 1.7 months. Best response was seen in one patient with stable disease (SD) for 8 cycles. Only ≥ grade 3 drug-related toxicity occurred in one patient with grade 3 cardiac chest pain who was able to resume therapy after CRLX101 was reduced to 12 mg/m2. CONCLUSIONS: Bimonthly CRLX101 demonstrated minimal activity with SD as best response in this heavily pretreated population. Future efforts with CRLX101 in gastric cancer should focus on combination and more dose-intensive strategies given its favorable toxicity profile and evidence of preferential tumor uptake.
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PURPOSE: Increased tumor hypoxia and hence elevated hypoxia-inducible factor-1α (HIF1α) is thought to limit the efficacy of vascular endothelial growth factor (VEGF) pathway-targeting drugs by upregulating adaptive resistance genes. One strategy to counteract this is to combine antiangiogenic drugs with agents able to suppress HIF1α. One such possibility is the investigational drug CRLX101, a nanoparticle-drug conjugate (NDC) containing the payload camptothecin, a known topoisomerase-I poison. EXPERIMENTAL DESIGN: CRLX101 was evaluated both as a monotherapy and combination with bevacizumab in a preclinical mouse model of advanced metastatic ovarian cancer. These preclinical studies contributed to the rationale for undertaking a phase II clinical study to evaluate CRLX101 monotherapy in patients with advanced platinum-resistant ovarian cancer. RESULTS: Preclinically, CRLX101 is highly efficacious as a monotherapy when administered at maximum-tolerated doses. Furthermore, chronic low-dose CRLX101 with bevacizumab reduced bevacizumab-induced HIF1α upregulation and resulted in synergistic efficacy, with minimal toxicity in mice. In parallel, initial data reported here from an ongoing phase II clinical study of CRLX101 monotherapy shows measurable tumor reductions in 74% of patients and a 16% RECIST response rate to date. CONCLUSIONS: Given these preclinical and initial clinical results, further clinical studies are currently evaluating CRLX101 in combination with bevacizumab in ovarian cancer and warrant the evaluation of this therapy combination in other cancer types where HIF1α is implicated in pathogenesis, as it may potentially be able to improve the efficacy of antiangiogenic drugs.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bevacizumab/administración & dosificación , Camptotecina/administración & dosificación , Ciclodextrinas/administración & dosificación , Nanopartículas/administración & dosificación , Neoplasias Ováricas/patología , Animales , Bevacizumab/efectos adversos , Camptotecina/efectos adversos , Ciclodextrinas/efectos adversos , Sinergismo Farmacológico , Femenino , Humanos , Ratones , Ratones SCID , Nanopartículas/efectos adversos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Patients with advanced solid malignancies were enrolled to an open-label, single-arm, dose-escalation study, in which CRLX101 was administered intravenously over 60 min among two dosing schedules, initially weekly at 6, 12, and 18 mg/m(2) and later bi-weekly at 12, 15, and 18 mg/m(2). The maximum tolerated dose (MTD) was determined at 15 mg/m(2) bi-weekly, and an expansion phase 2a study was completed. Patient samples were obtained for pharmacokinetic (PK) and pharmacodynamic (PD) assessments. Response was evaluated per RECIST criteria v1.0 every 8 weeks. Sixty-two patients (31 male; median age 63 years, range 39-79) received treatment. Bi-weekly dosing was generally well tolerated with myelosuppression being the dose-limiting toxicity. Among all phase 1/2a patients receiving the MTD (n = 44), most common grade 3/4 adverse events were neutropenia and fatigue. Evidence of systemic plasma exposure to both the polymer-conjugated and unconjugated CPT was observed in all treated patients. Mean elimination unconjugated CPT Tmax values ranged from 17.7 to 24.5 h, and maximum plasma concentrations and areas under the curve were generally proportional to dose for both polymer-conjugated and unconjugated CPT. Best overall response was stable disease in 28 patients (64 %) treated at the MTD and 16 (73 %) of a subset of NSCLC patients. Median progression-free survival (PFS) for patients treated at the MTD was 3.7 months and for the subset of NSCLC patients was 4.4 months. These combined phase 1/2a data demonstrate encouraging safety, pharmacokinetic, and efficacy results. Multinational phase 2 clinical development of CRLX101 across multiple tumor types is ongoing.
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Camptotecina/uso terapéutico , Celulosa/uso terapéutico , Ciclodextrinas/uso terapéutico , Nanopartículas/uso terapéutico , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Adulto , Anciano , Área Bajo la Curva , Biopsia , Camptotecina/efectos adversos , Camptotecina/sangre , Camptotecina/farmacocinética , Celulosa/efectos adversos , Celulosa/sangre , Celulosa/farmacocinética , Ciclodextrinas/efectos adversos , Ciclodextrinas/sangre , Ciclodextrinas/farmacocinética , Demografía , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Inmunohistoquímica , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Nanopartículas/efectos adversos , Estadificación de Neoplasias , Neoplasias/diagnóstico por imagen , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
BACKGROUND: Amplification of the mesenchymal-epithelial transition factor (MET) gene can promote tumor resistance to epidermal growth factor receptor (EGFR) inhibition. Dual EGFR-MET inhibition may overcome this resistance. Tivantinib (ARQ 197) is a selective, oral, non-ATP-competitive, small-molecule inhibitor of the MET receptor tyrosine kinase. This phase 1 trial assessed the safety, pharmacokinetics, and preliminary antitumor activity of tivantinib combined with the EGFR inhibitor erlotinib. METHODS: Patients with advanced solid malignancies were administered oral tivantinib at escalating doses of 120, 240, 360, and 480 mg twice daily (BID) plus 150 mg erlotinib once daily (QD). Single or multiple intrapatient dose escalation was planned in the absence of dose-limiting toxicity in the first cycle of therapy (21 days). RESULTS: Thirty-two patients received combination treatment. Tivantinib serum concentrations were not dose-proportional. The most common (≥ 20%) adverse events (AEs) regardless of causality included rash (n = 17), fatigue (n = 12), nausea (n = 10), abdominal pain (n = 10), diarrhea (n = 9), bradycardia (n = 9), and anemia (n = 7). AEs considered related to study treatment occurred in 28 patients (87.5%), and 5 patients (15.6%) had treatment-related serious AEs, including neutropenia, leukopenia, syncope, sinus bradycardia, and sick sinus syndrome. Fifteen of 32 patients (46.8%) had a partial response (n = 1) or stable disease (n = 14) as assessed by Response Evaluation Criteria in Solid Tumors. Six of 8 patients with nonsmall cell lung cancer achieved stable disease. The recommended phase 2 dose is tivantinib 360 mg BID plus erlotinib 150 mg QD. CONCLUSIONS: Tivantinib plus erlotinib was well tolerated with encouraging clinical activity, especially in patients with nonsmall cell lung cancer.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Receptores ErbB/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Pirrolidinonas/administración & dosificación , Quinazolinas/administración & dosificación , Quinolinas/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Clorhidrato de Erlotinib , Femenino , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Pirrolidinonas/efectos adversos , Pirrolidinonas/farmacocinética , Quinolinas/efectos adversos , Quinolinas/farmacocinéticaRESUMEN
PURPOSE: c-MET (MET) receptor activation is associated with poor prognosis and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance in non-small-cell lung cancer (NSCLC). This global, randomized phase II trial examined erlotinib plus tivantinib (ARQ 197; ArQule, Woburn, MA), a novel MET inhibitor. METHODS: Previously treated patients with EGFR TKI-naive advanced NSCLC were randomly assigned to receive oral erlotinib (150 mg daily) plus oral tivantinib (360 mg twice daily) or erlotinib plus placebo (EP). The primary end point was progression-free survival (PFS). At the time of progression, cross-over from EP to erlotinib plus tivantinib (ET) was permitted. Archival tumor tissue specimens were required. RESULTS: One hundred sixty-seven patients were randomly assigned to ET (n = 84) and to EP (n = 83). Median PFS was 3.8 months for ET and 2.3 months for EP (hazard ratio [HR], 0.81; 95% CI, 0.57 to 1.16; P = .24). Exploratory analysis revealed that the small cohort with KRAS mutations achieved a PFS HR of 0.18 (95% CI, 0.05 to 0.70; interaction P = .006). Objective responses were seen in 10% of patients on ET, 7% of patients on EP, and in two patients who crossed over from EP to ET, including one with EGFR mutation and MET gene copy number greater than 5. There were no significant differences in adverse events between study arms. CONCLUSION: The combination of the MET inhibitor tivantinib and erlotinib is well-tolerated. Although the study did not meet its primary end point, evidence of activity was demonstrated, especially among patients with KRAS mutations. Additional study of tivantinib and erlotinib in patients with NSCLC is planned.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Pirrolidinonas/administración & dosificación , Quinazolinas/administración & dosificación , Quinolinas/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Supervivencia sin Enfermedad , Clorhidrato de Erlotinib , Femenino , Humanos , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Placebos/administración & dosificación , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Receptores de Factores de Crecimiento/antagonistas & inhibidores , Análisis de SupervivenciaRESUMEN
Expression of the receptor tyrosine kinase c-MET (MET, mesenchymal-epithelial transition factor) in many cancers, and its participation in multiple signal transduction pathways involved in malignant tumor growth, suggest a wide therapeutic potential for MET inhibition in human cancer. Here we describe the discovery and early clinical development of ARQ 197, a novel, selective, non-ATP-competitive inhibitor of MET. Phase I studies demonstrate that ARQ 197 has a predictable pharmacokinetics and favorable safety profile, making it a potentially ideal partner for combination with cytotoxic chemotherapies and targeted anticancer agents. Results from phase I and phase II trials demonstrate preliminary evidence of anticancer activity. New data from a global phase II randomized trial comparing a combination of ARQ 197 plus erlotinib with erlotinib/placebo, in endothelial growth factor receptor inhibitor-naïve patients with locally advanced/metastatic non-small cell lung cancer, demonstrate improvement in progression-free and overall survival with combined therapy. Results were especially pronounced for patients with non-squamous lung cancer histologies, and in particular molecularly defined subgroups including KRAS mutations. These and other data from ARQ 197 clinical trials in hepatocellular, germ-cell, pancreatic (in combination with gemcitabine), and colorectal (in combination with cetuximab and irinotecan) cancers further highlight the potential role of ARQ 197 in existing and emerging anticancer therapeutic regimens.
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Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Pirrolidinonas/uso terapéutico , Quinolinas/uso terapéutico , Receptores de Factores de Crecimiento/antagonistas & inhibidores , Animales , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Antineoplásicos/administración & dosificación , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Camptotecina/uso terapéutico , Cetuximab , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/administración & dosificación , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Clorhidrato de Erlotinib , Factor de Crecimiento de Hepatocito/metabolismo , Humanos , Irinotecán , Ratones , Neoplasias/tratamiento farmacológico , Pirrolidinonas/administración & dosificación , Quinazolinas/administración & dosificación , Quinazolinas/uso terapéutico , Quinolinas/administración & dosificación , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
PURPOSE: The hepatocyte growth factor/c-MET axis is implicated in tumor cell proliferation, survival, and angiogenesis. ARQ 197 is an oral, selective, non-adenosine triphosphate competitive c-MET inhibitor. A phase I trial of ARQ 197 was conducted to assess safety, tolerability, and target inhibition, including intratumoral c-MET signaling, apoptosis, and angiogenesis. PATIENTS AND METHODS: Patients with solid tumors amenable to pharmacokinetic and pharmacodynamic studies using serial biopsies, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and circulating endothelial cell (CEC) and circulating tumor cell (CTC) enumeration were enrolled. RESULTS: Fifty-one patients received ARQ 197 at 100 to 400 mg twice per day. ARQ 197 was well tolerated, with the most common toxicities being grade 1 to 2 fatigue, nausea, and vomiting. Dose-limiting toxicities included grade 3 fatigue (200 mg twice per day; n = 1); grade 3 mucositis, palmar-plantar erythrodysesthesia, and hypokalemia (400 mg twice per day; n = 1); and grade 3 to 4 febrile neutropenia (400 mg twice per day, n = 2; 360 mg twice per day, n = 1). The recommended phase II dose was 360 mg twice per day. ARQ 197 systemic exposure was dose dependent and supported twice per day oral dosing. ARQ 197 decreased phosphorylated c-MET, total c-MET, and phosphorylated focal adhesion kinase and increased terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labeling (TUNEL) staining in tumor biopsies (n = 15). CECs decreased in 25 (58.1%) of 43 patients, but no significant changes in DCE-MRI parameters were observed after ARQ 197 treatment. Of 15 patients with detectable CTCs, eight (53.3%) had ≥ 30% decline in CTCs after treatment. Stable disease, as defined by Response Evaluation Criteria in Solid Tumors (RECIST), ≥ 4 months was observed in 14 patients, with minor regressions in gastric and Merkel cell cancers. CONCLUSION: ARQ 197 safely inhibited intratumoral c-MET signaling. Further clinical evaluation focusing on combination approaches, including an erlotinib combination in non-small-cell lung cancer, is ongoing.
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Inhibidores de la Angiogénesis/uso terapéutico , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Pirrolidinonas/uso terapéutico , Quinolinas/uso terapéutico , Receptores de Factores de Crecimiento/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Adolescente , Adulto , Anciano , Inhibidores de la Angiogénesis/efectos adversos , Inhibidores de la Angiogénesis/farmacocinética , Apoptosis/efectos de los fármacos , Hidrocarburo de Aril Hidroxilasas/genética , Hidrocarburo de Aril Hidroxilasas/metabolismo , Biopsia , Citocromo P-450 CYP2C19 , Células Endoteliales/efectos de los fármacos , Células Endoteliales/patología , Inglaterra , Femenino , Quinasa 1 de Adhesión Focal/metabolismo , Humanos , Etiquetado Corte-Fin in Situ , Imagen por Resonancia Magnética , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neoplasias/irrigación sanguínea , Neoplasias/enzimología , Neoplasias/patología , Células Neoplásicas Circulantes/efectos de los fármacos , Células Neoplásicas Circulantes/patología , Neovascularización Patológica/prevención & control , Fosforilación , Polimorfismo de Nucleótido Simple , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacocinética , Proteínas Proto-Oncogénicas c-met/metabolismo , Pirrolidinonas/efectos adversos , Pirrolidinonas/farmacocinética , Quinolinas/efectos adversos , Quinolinas/farmacocinética , Receptores de Factores de Crecimiento/metabolismo , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Catheter-related bloodstream infections remain costly with no simple prevention. We report preliminary results of a phase I trial of ethanol-lock administration to prevent mediport catheter-related bloodstream infections in children. METHODS: Twelve patients receiving intravenous antibody treatments for neuroblastoma were enrolled. On 4 days of each 5-day antibody cycle, 70% ethanol was administered instead of heparin to dwell in each patient's mediport overnight. We used clinical monitoring/questionnaires to assess symptoms and measured blood ethanol levels and liver functions. Patients were tracked for positive blood cultures. Time to infection for ethanol-lock-treated patients was compared with historical controls. RESULTS: We administered 123 ethanol-locks. No adverse symptoms attributable to ethanol occurred; one patient's urticaria worsened. Blood ethanol levels averaged 11 mg/dL. The study was voluntarily suspended after 3 patients' catheters became occluded, 1 of which fractured. A positive blood culture occurred in 1 (8%) of 12 patients, but suspension of the study precluded statistical power to detect impact on time to infection. CONCLUSIONS: Although children with mediport catheters exhibited nontoxic blood ethanol levels and a low rate of bloodstream infections following prophylactic ethanol-lock use, there was a high incidence of catheter occlusion. Adjustments are necessary before adopting ethanol-locks for routine prophylaxis against catheter infections in children.
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Antiinfecciosos/administración & dosificación , Bacteriemia/prevención & control , Infecciones Relacionadas con Catéteres/prevención & control , Cateterismo Venoso Central/efectos adversos , Catéteres de Permanencia/efectos adversos , Infección Hospitalaria/etiología , Infección Hospitalaria/prevención & control , Contaminación de Equipos/prevención & control , Etanol/administración & dosificación , Antiinfecciosos/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales de Origen Murino , Bacteriemia/etiología , Bacteriemia/microbiología , Infecciones Relacionadas con Catéteres/etiología , Infecciones Relacionadas con Catéteres/microbiología , Cateterismo Venoso Central/métodos , Catéteres de Permanencia/microbiología , Etanol/sangre , Etanol/uso terapéutico , Humanos , Inmunoglobulina G/uso terapéutico , Neuroblastoma/inmunología , Neuroblastoma/terapia , Estudios Prospectivos , Resultado del TratamientoRESUMEN
PURPOSE: We examined the rate of increase in the body mass index (BMI; kg/m(2)) after final height attainment in survivors of acute lymphoblastic leukemia (ALL) and a noncancer comparison group. METHODS: Childhood Cancer Survivor Study (CCSS) is a retrospectively ascertained cohort study that prospectively tracks the health status of adults who were diagnosed with childhood cancer between 1970 and 1986 and a comparison group of siblings. Changes in BMI from baseline enrollment to time of completion of follow-up (mean interval, 7.8 years) were calculated for 1,451 ALL survivors (mean age, 32.3 years at follow-up) and 2,167 siblings of childhood cancer survivors (mean age, 35.9 years). RESULTS: The mean BMI of the CCSS sibling comparison group increased with age (women, 0.25 units/yr, 95% CI, 0.22 to 0.28 units; men, 0.23 units/yr, 95% CI, 0.20 to 0.25 units). Compared with CCSS siblings, ALL survivors who were treated with cranial radiation therapy (CRT) had a significantly greater increase in BMI (women, 0.41 units/yr, 95% CI, 0.37 to 0.45 units; men, 0.29 units/yr; 95% CI, 0.26 to 0.32 units). The rate of BMI increase was not significantly increased for ALL survivors who were treated with chemotherapy alone. Younger age at CRT exposure significantly modified risk. CONCLUSION: CRT used in the treatment of childhood ALL is associated with a greater rate of increasing BMI, particularly among women treated with CRT during the first decade of life. Health care professionals should be aware of this risk and interventions to reduce or manage weight gain are essential in this high-risk population.
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Índice de Masa Corporal , Obesidad/epidemiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Adolescente , Adulto , Estatura , Niño , Femenino , Estado de Salud , Humanos , Modelos Lineales , Estudios Longitudinales , Masculino , Estudios Retrospectivos , Encuestas y Cuestionarios , SobrevivientesRESUMEN
Prostate cancer is the most common cancer occurring among men in the United States. In spite of the disease's favorable prognosis, approximately 30,000 U.S. men develop incurable metastatic disease each year, making prostate cancer the second-leading cause of cancer-related deaths among men in the United States. Although hormone-based therapies generally result in rapid responses, virtually all patients ultimately develop androgen-independent progressive disease. It is among these men with hormone-refractory prostate cancer (HRPC) that the role of chemotherapy continues to be investigated. To date, three drugs (estramustine, mitoxantrone, and docetaxel) have been approved by the US Food and Drug Administration (FDA) for first-line chemotherapy in HRPC, with other agents and combinations now under evaluation in ongoing clinical trials. Patients whose tumors progress through first-line chemotherapy have limited treatment options available to them and less than half of all men with HRPC will receive any second-line chemotherapy. To date, only one phase III randomized clinical trial has been completed in this setting and no therapies are FDA-approved. We review here the entirety of phase II and III data evaluating chemotherapy agents in second-line HRPC.
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Antineoplásicos Hormonales/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Neoplasias de la Próstata/tratamiento farmacológico , Terapia Recuperativa/métodos , Antagonistas de Andrógenos/uso terapéutico , Antineoplásicos Alquilantes , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Humanos , Masculino , Cuidados Paliativos , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
OBJECTIVE: To determine uptake and socio-demographics predictors of acceptance of voluntary counseling and testing (VCT) among post-partum women in Botswana. METHODS: Women attending maternal and child health clinics for their first post-partum or well baby visit in three sites in Botswana were offered VCT after a written informed consent. A standardized questionnaire was used to collect socio-demographic characteristics and reasons for declining VCT. RESULTS: From March 1999 to November 2000, we approached 1735 post-partum women. Only 937 (54%) of those approached accepted VCT. In multiple logistic regression analysis, younger maternal age, not being married, and less formal education were significant predictors of acceptance of VCT. Thirty percent of women who accepted VCT were HIV-positive. CONCLUSION: Our results indicated that in Botswana prior to the initiation of a government Mother to Child Transmission (MTCT) prevention program, younger, unmarried, and less educated post-partum women were more likely to undergo VCT. PRACTICE IMPLICATIONS: Our results have shown that interventions to improve VCT among post-partum women and more generally among women of reproductive age are warranted in Botswana. These interventions should account for differences such age, marital status, education, and partner involvement to maximize VCT uptake.