Efficacy of trifluridine and tipiracil (TAS-102) versus placebo, with supportive care, in a randomized, controlled trial of patients with metastatic colorectal cancer from Spain: results of a subgroup analysis of the phase 3 RECOURSE trial.

PURPOSE: TAS-102 is a combination of the thymidine-based nucleoside analog trifluridine and the thymidine phosphorylase inhibitor tipiracil. Efficacy and safety of TAS-102 in patients with metastatic colorectal cancer (mCRC) refractory or intolerant to standard therapies were evaluated in the phase 3 RECOURSE trial. Results of RECOURSE demonstrated significant improvement in overall survival (OS) and progression-free survival (PFS) with TAS-102 versus placebo [hazard ratio (HR) = 0.68 and 0.48 for OS and PFS, respectively; both P < 0.001]. The current analysis evaluates efficacy and safety of TAS-102 in the RECOURSE Spanish subgroup. METHODS: Primary and key secondary endpoints were evaluated in a post hoc analysis of the RECOURSE Spanish subgroup, using univariate and multivariate analyses. Safety and tolerability were reported with descriptive statistics. RESULTS: The RECOURSE Spanish subgroup included 112 patients (mean age 61 years, 62 % male). Median OS was 6.8 months in the TAS-102 group (n = 80) versus 4.6 months in the placebo group (n = 32) [HR = 0.47; 95 % confidence interval (CI): 0.28-0.78; P = 0.0032). Median PFS was 2.0 months in the TAS-102 group and 1.7 months in the placebo group (HR = 0.47; 95 % CI: 0.30-0.74; P = 0.001). Eighty (100 %) TAS-102 versus 31 (96.9 %) placebo patients had adverse events (AEs). The most common drug-related ≥Grade 3 AE was neutropenia (40 % TAS-102 versus 0 % placebo). There was 1 (1.3 %) case of febrile neutropenia in the TAS-102 group versus none in the placebo group. CONCLUSIONS: In the RECOURSE Spanish subgroup, TAS-102 was associated with significantly improved OS and PFS versus placebo, consistent with the overall RECOURSE population. No new safety signals were identified. CLINICALTRIALS. GOV STUDY NUMBER: NCT01607957.

Manifestaciones neurológicas en pacientes pediátricos con fenilcetonuria. Revisión bibliográfica / Neurological manifestations in pediatric patients with. phenylketonuria: bibliographic review

La fenilcetonuria (PKU) es una enfermedad congénita de herencia autosómica recesiva, en la que existe el déficit de la enzima fenilalanina hidroxilasa, que produce lesión del sistema nervioso central (SNC). La incidencia mundial es de 1:20.000 recién nacidos vivos. (1,2) El tratamiento es a base de dieta con restricción de fenilalanina que debe mantenerse para toda la vida para prevenir el deterioro intelectual. (3,4) OBJETIVO: Identificar manifestaciones neurológicas de pacientes pediátricos con PKU. METODOLOGIA: Revisión bibliográfica de la literatura acerca de las manifestaciones neurológicas para PKU mediante la búsqueda electrónica en varias bases de datos (MEDLINE, EMBASE, COCHRANE, LILACS, PubMed) con límites en inglés y español de enero de 1970 a 2012. RESULTADOS: Se identifica un estudio transversal, un caso clínico, tres revisiones narrativas en poblaciones pediátricas y un caso clínico combinado niños y adultos. La discapacidad intelectual es la principal manifestación neurológica, el criterio diagnóstico primordial fue el valor sérico de fenilalanina. Existen 29 clasificaciones distintas sobre el punto de corte para hiperfenilalaninemia y 23 para fenilcetonuria.

Phenylketonuria (PKU) is a congenital autosomal recessive disease in which there is a shortage of the enzyme phenylalanine hydroxylase, which produces an injury to the central nervous system (CNS). The global incidence is about 1:20,000 live newborns. (1.2) The treatment is based on phenylalanine restricted diet which should be maintained for lifelong to prevent intellectual impairment. OBJECTIVE: To identify neurological manifestations of pediatric patients with PKU. METHODOLOGY: A review of the literature on the neurological manifestations for PKU by searching several electronic databases (MEDLINE , EMBASE, Cochrane , LILACS , PubMed) with English and Spanish limits from January 1970-2012. RESULTS: One cross-sectional study, one clinical case, three narrative reviews in pediatric populations and one clinical case combine children and adults. Intellectual disability is the main neurological manifestation; the primary diagnostic criterion was the serum level of phenylalanine. There are 29 different classifications on the cutoff to hyperphenylalaninemia and 23 for phenylketonuria

Cisplatin plus continuous infusion vinorelbine for the treatment of advanced non-small cell lung cancer: a phase I-II study.

BACKGROUND: In this Phase I/II trial, the maximumtolerated dose (MTD) and activity of cisplatin plus vinorelbine (VRL) administered in continuous infusion as first-line treatment of advanced non small cell lung cancer (NSCLC) was determined in 12 consecutive chemotherapy-naive patients with advanced NSCLC. PATIENTS AND METHODS: The dose of cisplatin was 100 mg/m(2) in all patients, and vinorelbine was administered as an initial intravenous (iv) bolus of 8 mg/m(2) on day 1 followed by a 4-day continuous iv infusion at 4 different 24 h dose levels (DLs) to be repeated every 21 days. All 12 patients (47 cycles) were evaluable for response and toxicity. RESULTS: The MTD was 8 mg/m(2) bolus followed by a continuous iv infusion of 8 mg/m(2) per day over 4 days. The dose limiting toxicities (DLT) were febrile neutropenia in 4 patients and grade 3 mucositis in 1 patient. There was less neuro-toxicity and compared to the weekly bolus scheme. There was no significant cumulative toxicity after 3 cycles. Partial responses were observed in 6 patients; an overall response rate of 50% (95% CI: 30-65%). Median time to progression was 5,5 months (95% CI: 1,5-11 months) and median survival was 11 months (95% CI: 5-20 months). CONCLUSIONS: The results demonstrate that, in this setting of first-line treatment of NSCLC, cisplatin plus vinorelbine at 8 mg/m(2) bolus followed by a continuous infusion of 8 mg/m(2) per day over 4 days is the recommended schedule. Further trials would be useful to establish activity of this combination.

Hematologic reconstitution following high-dose and supralethal chemoradiotherapy using stored, noncryopreserved autologous hematopoietic stem cells.

Although cryopreservation is the standard for autotransplantation, it has logistic and financial disadvantages in undeveloped countries such as Colombia. In 47 patients, peripheral blood was refrigerated at 4 degrees C up to 144 h before autotransplantation. For mobilization, 27 men and 20 women of median age 37 years affected with hematologic malignancies received G-CSF. The 17 patients in Group 1 showed pre-refrigeration CFU-GM of 2.62 x 10(5)/kg (range 0.36 to 16.6 x 10(5)/kg) and at re-infusion, 1.36 x 10(5)/kg (range 0 to 6.32 x 10(5)/kg) of 83% viability (range, 78% to 96%). These patients showed >0.5 x 10(9)/L granulocytes on day +11 (range, 9 to 15) and >20 x 10(9)/L platelets on day +16 (range, 11 to 44). The 25 patients in Group 2 showed CD34 of 3.9 x 10(6)/kg (range, 0.16 to 9 x 10(6)/kg) and mononuclear cell count (MNC) of 8.7 x 10(8)/kg, reaching >0.5 x 10(9)/L granulocytes at day +13 (range, 10 to 17) and >20 x 10(9)/L on day +15 (range, 14 to 20). Among the 5 patients in Group 3, the average of MNC of 12.7 x 10(8)/kg was reached and >0.5 x 10(9)/L granulocytes on day 11 (range, 10 to 16) and >20 x 10(9)/L on day 14 (range, 10 to 18). No differences were observed between the groups. Refrigeration of stem cells appears to be a simple, effective, and inexpensive method that should be considered for autotransplants within a few days of harvesting when resources are limited for long-term storage.