Continuous sunitinib treatment in patients with unresectable hepatocellular carcinoma (HCC): A multicenter phase II trial (SAKK 77/06 and SASL 23)

Background: Sunitinib (SU) is a multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenetic activity. Evidence for clinical activity in HCC was reported in 2 phase II trials [Zhu et al and Faivre et al, ASCO 2007] using either a 37.5 or a 50 mg daily dose in a 4 weeks on, 2 weeks off regimen. The objective of this trial was to demonstrate antitumor activity of continuous SU treatment in patients (pts) with HCC. Methods: Key eligibility criteria included unresectable or metastatic HCC, no prior systemic anticancer treatment, measurable disease and Child- Pugh A or B liver dysfunction. Pts received 37.5 mg SU daily until progression or unacceptable toxicity. The primary endpoint was progression free survival at 12 weeks (PFS12) defined as 'success' if the patient was alive and without tumor progression assessed by 12 weeks (±7 days) after registration. A PFS12 of _20% was considered uninteresting and promising if _40%. Using the Simon-two minimax stage design with 90% power and 5% significance the sample size was 45 pts. Secondary endpoints included safety assessments, measurement of serum cobalamin levels and tumor density. Results: From September 2007 to August 2008 45 pts, mostly male (87%), were enrolled in 10 centers. Median age was 63 years, 89% had Child-Pugh A and 47% had distant metastases. Median largest lesion diameter was 84mm (range: 18-280) and 18% had prior TACE. Reasons for stopping therapy were: PD 60%, symptomatic deterioration 16%, toxicity 11%, death 2% (due to tumor), and other reasons 4%; 7% remain on therapy. PFS12 was rated as success in 15 pts (33%) (95% CI: 20%, 49%) and failure in 27 (60%); 3 were not evaluable (due to refusal). Over the whole trial period 1 CR and 40% SD as best response were achieved. Median PFS, duration of disease stabilization, TTP and OS were 2.8, 3.2, 2.8 and 9.3 months, respectively. Grade 3 and 4 adverse events were infrequent and all deaths due to the tumor. Conclusions: Continuous SU treatment with 37.5 mg/d daily is feasible and demonstrates moderate activity in pts with advanced HCC and mild to moderately impaired liver dysfunction. Under this trial design the therapy is considered promising (>13 PFS12 successes).

Partial cricotracheal resection for pediatric subglottic stenosis: a single institution's experience in 60 cases.

In our study, 60 infants and children, each with a severe subglottic stenosis (SGS), underwent partial cricotracheal resection (PCTR) with primary thyrotracheal anastomosis. According to the Myer-Cotton classification, two were grade II, 41 were grade III and 17 were grade IV stenoses. Of the 60 patients, 57 (95%) are presently decannulated, and one patient sustained a complete restenosis. Two patients with better than 80% subglottic airways still are waiting for decannulation: one because of bilateral cricoarytenoid joint fixation and the second because of temporary stenting of the subglottis with a Montgomery T-tube. The rate of decannulation is 97% (36 of 37 cases) in primary PCTRs, 100% (13 of 13 cases) in salvage PCTRs for failed laryngotracheal reconstructions (LTR) and 70% (7 of 10 cases) in extended PCTRs (i.e., PCTR associated with an additional open-airway procedure).

Bolus injections of synthetic atrial natriuretic peptide in patients with chronic renal failure or nephrotic syndrome.

The diuretic and natriuretic responses to exogenous synthetic atrial natriuretic peptide (ANP) were evaluated in patients with chronic renal failure (CRF) or nephrotic syndrome (NS). Patients were studied after an oral water load (8 ml/kg in CRF and 20 ml/kg in NS patients). A short intravenous bolus of either a placebo or ANP was administered when urine output was stable. In each group of patients, three doses of ANP were injected at 24 h intervals, i.e., 1.0, 1.5, and 2.0 micrograms/kg in the CRF and 1.0, 1.5, and 3.0 micrograms/kg in the NS group. Blood pressure and heart rate were monitored throughout the study and urinary volume and electrolyte excretion were measured every 20 min up to 3 h after the bolus. An acute and transient fall in blood pressure was observed immediately after the ANP injection. It was more pronounced in CRF than in NS patients. In CRF patients, ANP caused only a slight increase in urinary volume (13.5-44% over baseline) but a significant increase in urinary sodium excretion (45-114% over baseline). In NS patients, significant increases in both urine volume (60-105%) and sodium excretion (149-248%) were also found. In these latter patients, the renal response to ANP appeared to be better preserved. The hemodynamic and renal changes induced by ANP occurred mainly during the first 20 min following the ANP administration, when the peak plasma ANP levels were obtained. However, no clear dose-response effect could be evidenced in either group with the three doses of ANP chosen in this study.

Regime económico e financeiro para a GESTÃO DA ÁGUA no Directiva Quadro da Água (Directiva 2000/60/CE). Questões de transposição ITS no sistema jurídico espanhol

Se analiza la transposición de la Directiva Marco de Aguas 2000/60/CE al ordenamiento jurídico español, acotando la materia al régimen económico financiero de la obra pública hidráulica y en general del Dominio Público Hidráulico. A tal fin se estudian los principios rectores del régimen económico financiero comunitario del Dominio Público Hidráulico y su transposición al Ordenamiento Jurídico Español: a) Principio de recuperación de costes de los servicios relacionados con el agua y excepciones. El régimen tarifario del DPH (valor versus precio del agua). B) Principio de utilización eficiente de los recursos híbridos a través de una política de precios del agua que proporciona los incentivos adecuados a tal fin. c) Principio de contribución adecuada de los usos del agua desglosados, al menos, en industria, hogares y agricultura, basado en el análisis económico y en el principio del que contamina paga. d) Principio ambiental (creado por la OCDE): quien contamina paga (user-pays-principle). Finalmente también se analizan los costes de los servicios relacionados con el dominio público hidráulico