Thymostimulin versus placebo for palliative treatment of locally advanced or metastasised hepatocellular carcinoma: a phase III clinical trial.

BACKGROUND: Thymostimulin is a thymic peptide fraction with immune-mediated cytotoxicity against hepatocellular carcinoma (HCC) in vitro and palliative efficacy in advanced HCC in two independent phase II trials. The aim of this study was to assess the efficacy of thymostimulin in a phase III trial. METHODS: The study was designed as a prospective randomised, placebo-controlled, double-blind, multicenter clinical phase III trial. Between 10/2002 and 03/2005, 135 patients with locally advanced or metastasised HCC (Karnofsky >or=60%/Child-Pugh <or= 12) were randomised to receive thymostimulin 75 mg s.c. 5x/week or placebo stratified according to liver function. Primary endpoint was twelve-month survival, secondary endpoints overall survival (OS), time to progression (TTP), tumor response, safety and quality of life. A subgroup analysis according to liver function, KPS and tumor stage (Okuda, CLIP and BCLC) formed part of the protocol. RESULTS: Twelve-month survival was 28% [95%CI 17-41; treatment] and 32% [95%CI 19-44; control] with no significant differences in median OS (5.0 [95% CI 3.7-6.3] vs. 5.2 [95% CI 3.5-6.9] months; p = 0.87, HR = 1.04 [95% CI 0.7-1.6]) or TTP (5.3 [95%CI 2.0-8.6] vs. 2.9 [95%CI 2.6-3.1] months; p = 0.60, HR = 1.13 [95% CI 0.7-1.8]). Adjustment for liver function, Karnofsky status or tumor stage did not affect results. While quality of life was similar in both groups, fewer patients on thymostimulin suffered from accumulating ascites and renal failure. CONCLUSIONS: In our phase III trial, we found no evidence of any benefit to thymostimulin in the treatment of advanced HCC and there is therefore no justification for its use as single-agent treatment. The effect of thymostimulin on hepato-renal function requires further confirmation. TRIAL REGISTRATION: Current Controlled Trials ISRCTN64487365

Inhibition of T-Cell Acute Lymphoblastic Leukemia Proliferation In Vivo by Re-expression of the p16(INK4a) Tumor Suppressor Gene

T-cell acute lymphoblastic leukemia (T-ALL) is characterized by the presence of differentiation-inhibited pro- and pre-T-cell blasts. The p16(INK4a) tumor suppressor gene has been shown to be frequently deleted in human T-ALL cases. Deletion of p16(INK4a) may be associated with poor prognosis and relapse of the disease. Radiation-induced murine T-ALL in C57B1/6 mice shares pathogenetic and molecular characteristics with the human disease. We used the murine disease as a model to study the status of the INK4/ARF gene locus and to examine the effect of p16(INK4a)-re-expression in T-ALL cells on their leukemic potential in vivo. In 9 of 17 radiation-induced murine T-ALL cell lines, the p16(INK4a) protein was not expressed as determined by immunoblotting. Southern blot analysis revealed homozygous deletions of the p16(INK4a) gene locus in three of the nine lines, along with the genes encoding p15(INK4b) and p19(ARF). Transduction of p16(INK4a)-negative T-ALL lines with retrovirus encoding p16(INK4a) significantly inhibited their in vitro proliferation by inducing G(1)-arrest. Importantly, re-expression of p16(INK4a) in p16(INK4a)-negative T-ALL cells obliterated the induction of lethal disseminated leukemia in syngeneic mice. This is the first demonstration that re-establishment of p16(INK4a) expression is critical for in vivo growth regulation of T-ALL cells

Pitfall alveolar echinococcosis in non-endemic areas Alveolar echinococcosis migrating northward

Alveolar echinococcosis of the liver can be mistaken as a liver tumor. The occurrence of the fox tapeworm echinococcus multilocularis is increasing in formerly unaffected European regions. As a consequence, alveolar echinococcosis is becoming an important differential diagnosis in Eastern and Northern Europe

Surgical and Palliative Management and Outcome in 184 Patients With Hilar Cholangiocarcinoma: Palliative Photodynamic Therapy Plus Stenting Is Comparable to R1/R2 Resection

OBJECTIVE: First, to analyze the strategy for 184 patients with hilar cholangiocarcinoma seen and treated at a single interdisciplinary hepatobiliary center during a 10-year period. Second, to compare long-term outcome in patients undergoing surgical or palliative treatment, and third to evaluate the role of photodynamic therapy in this concept. SUMMARY BACKGROUND DATA: Tumor resection is attainable in a minority of patients (<30%). When resection is not possible, radiotherapy and/or chemotherapy have been found to be an ineffective palliative option. Recently, photodynamic therapy (PDT) has been evaluated as a palliative and neoadjuvant modality. METHODS: Treatment and outcome data of 184 patients with hilar cholangiocarcinoma were analyzed prospectively between 1994 and 2004. Sixty patients underwent resection (8 after neoadjuvant PDT); 68 had PDT in addition to stenting and 56 had stenting alone. RESULTS: The 30-day death rate after resection was 8.3%. Major complications occurred in 52%. The overall 1-, 3-, and 5-year survival rates were 69%, 30%, and 22%, respectively. R0, R1, and R2 resection resulted in 5-year survival rates of 27%, 10%, and 0%, respectively. Multivariate analysis identified R0 resection (P < 0.01), grading (P < 0.05), and on the limit to significance venous invasion (P = 0.06) as independent prognostic factors for survival. PDT and stenting resulted in longer median survival (12 vs. 6.4 months, P < 0.01), lower serum bilirubin levels (P < 0.05), and higher Karnofsky performance status (P < 0.01) as compared with stenting alone. Median survival after PDT and stenting, but not after stenting alone, did not differ from that after both R1 and R2 resection. CONCLUSION: Only complete tumor resection, including hepatic resection, enables long-term survival for patients with hilar cholangiocarcinoma. Palliative PDT and subsequent stenting resulted in longer survival than stenting alone and has a similar survival time compared with incomplete R1 and R2 resection. However, these improvements in palliative treatment by PDT will not change the concept of an aggressive resectional approach