Vergleich der Effektivität von CT-gesteuerter Brachytherapie gegenüber transarterieller Chemoembolisation bei Patienten mit inoperablem HCC : Interimsanalyse zur entgültigen Fallzahlplanung einer randomisierten Phase-III-Studie

Magdeburg, Univ., Med. Fak., Diss., 2011

Methodological assessment of HCC literature.

Despite the fact that the hepatocellular carcinoma (HCC) represents a major health problem, very few interventions are available for this disease, and only sorafenib is approved for the treatment of advanced disease. Of note, only very few interventions have been thoroughly evaluated over time for HCC patients compared with several hundreds in other, equally highly lethal, tumours. Additionally, clinical trials in HCC have often been questioned for poor design and methodological issues. As a consequence, a gap between what is measured in clinical trials and what clinicians have to face in daily practice often occurs. As a result of this scenario, even the most recent guidelines for treatment of HCC patients use low strength evidence to make recommendations. In this review, we will discuss some of the potential methodological issues hindering a rational development of new treatments for HCC patients.

PRECISION V: Randomisierte Phase II-Studie mit Drug Eluting Beads (DEB) zur Behandlung des hepatozelluläre Karzinoms (HCC) mittels transarterieller Chemoemblisation [PRECISION V: Randomized Phase II-Study with Drug Eluting Beads (DEB) for the Treatment of Hepatocellular cancer (HCC) using transarterial Chemoemblisation.]

Zielsetzung: Vergleich von Drug Eluting Bead (DEB)-TACE mit konventioneller TACE bei der Behandlung von ,,intermediate stage-HCC bei Patienten mit Zirrhose. Material und Methodik: 212 Patienten (185 ♂, 27 ♀; mittleres Alter, 67 Jahre) mit Child-Pugh A oder B Leberzirrhose und großem und/oder multinodulärem, irresektablen HCC wurden randomisiert, um das Therapieansprechen nach der Behandlung mit DEB (DC Bead; Biocompatibles, UK) beladen mit Doxorubicin oder konventioneller TACE mit Doxorubicin zu vergleichen. Die Randomisierung wurde nach Child-Pugh Status (A oder B), Performance Status (ECOG 0 oder 1), bilobärer Erkrankung (ja/nein) und frühere kurative Behandlung (ja/nein) stratifiziert. Der primäre Studienendpunkt war das 6-Monats-Tumoransprechen. Eine unabhängige verblindete MRT-Studie wurde durchgeführt, um das Tumoransprechen nach den RECIST Kriterien zu beurteilen. Ergebnisse: DEB-TACE mit Doxorubicin zeigte eine höhere Rate an komplettem Tumoransprechen, objektivem Ansprechen und Tumorkontrolle im Vergleich zur konventionellen TACE (27% vs 22%; 52% vs 44%; and 63% vs 52%; P>0.05). Patienten mit Child-Pugh B Zirrhose, ECOG 1 Performance Status, bilobärer Erkrankung und Rezidiven nach kurativer Behandlung zeigte einen signifikanten Anstieg des objektiven Ansprechens (p = 0.038) im Vergleich zur Kontrollgruppe. Bei Patienten, die mit DEB-TACE behandelt wurden, konnte eine deutliche Reduktion der gravierenden Lebertoxizität erreicht werden. Die Doxorubicin-Nebenwirkungsrate war in der DEB-TACE Gruppe deutlich geringer (p = 0.0001) als in der konventionellen TACEGruppe. Schlussfolgerung: DEB-TACE mit Doxorubicin ist sicher und effektiv in der Behandlung von ,,intermediate-stage HCC und bietet einen signifikanten Vorteil bei Patienten mit fortgeschrittener Erkrankung.

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).

Refluxo Vesicoureteral primário na infância: tratamento conservador versus intervenção cirúrgica

Introdução: A associação entre refluxo vesicoureteral primário e infecções do trato urinário pode acarretar em dano renal permanente. Há, na literatura, a tendência de cura espontânea deste refluxo em crianças e marcante declínio na indicação do tratamento cirúrgico. Objetivo: Estudar a evolução dos refluxos vesicoureterais primários associados a quadros de infecções urinárias de repetição, em pacientes do serviço de Nefrologia Pediátrica da nossa instituição, avaliando os casos nos quais houve cura mediante tratamento conservador apenas, e aqueles nos quais foi necessária a intervenção cirúrgica. Métodos: Analisamos os prontuários dos pacientes com infecções urinárias de repetição associadas ao diagnóstico de refluxo vesicoureteral primário. Os dados coletados diziam respeito aos parâmetros: sexo, idade do diagnóstico da primeira infecção urinária, idade do diagnóstico de RVU, número de infecções urinárias, grau de refluxo, resultado da urocultura, função renal, cicatrizes renais, outras malformações do trato urinário e intervenção cirúrgica ou conservadora. A Análise estatística foi descritiva e realizada com o programa SPSS. Resultados: Dentro do subgrupo de pacientes com graus IV e V, notou-se 63,6% dos casos evoluindo para intervenção cirúrgica e 36,4%, para resolução por intervenção conservadora. Naqueles com graus I, II e III, 38,5% evoluíram para tratamento cirúrgico, contra 61,5%, para resolução por conduta conservadora. Dentre os pacientes com presença de refluxo vesicoureteral bilateralmente,72,7% tiveram evolução cirúrgica. Não se observou relação entre o grau de refluxo e a presença de cicatrizes renais. Conclusão: Pacientes com refluxo vesicoureteral de baixo grau e infecções urinárias de repetição tendem à resolução espontânea do refluxo, com boa evolução renal a longo prazo, de forma que a indicação cirúrgica fica reservada aos refluxos de alto grau ou com outras complicações clínicas.

Clones sous-maximaux inf-réductibles

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal

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