PARP inhibitors and metastatic castration-resistant prostate cancer: uture directions and pitfalls.

PARP inhibitors (PARPi) gained major interest among prostate cancer researchers in the last few years, thanks to the outstanding results coming from the PROfound an TRITON2 studies. Following that, PARPi gained approval also in metastatic, castration-resistant prostate cancer (mCRPC) with mutations in homologous repair (HR) - related genes. Nevertheless, some questions still remain unanswered concerning the management of drug resistance and PARPi-sensitivity in patients harboring alterations in various DNA damage response (DDR) related genes, not only BRCA1 and BRCA2. In this perspective article we focus on the key issues concerning PARPi in mCRPC, specifically those related to drug sensitivity and resistance mechanisms, exploring the possible role of combination therapeutic approaches and trying to depict potential future addresses in translational oncology research.

Treatment of mild chronic hepatitis C with interferon alpha-2b: results of a multi-centre randomized study in 80 patients.

OBJECTIVE: The natural history of mild chronic hepatitis C is not well-known and the benefit of treating this form of the disease is not well-defined. We conducted a pilot study to answer this question. DESIGN: Mild chronic hepatitis C was defined by positivity for anti-HCV antibodies, detectable serum HCV RNA by PCR, and a Knodell score < or = 5 on a liver biopsy performed within the previous 6 months. Eighty patients from six centres were randomized into two groups receiving interferon alpha-2b, 3 MU three times a week for 6 months (group 1, n = 39) or no treatment (group 2, n = 41). Sustained response was defined by the loss of detectable serum HCV RNA at 6 months after therapy. RESULTS: The two groups were not different at entry with respect to age, sex ratio, source of infection, disease duration, genotype, viral load and Knodell score. One patient (group 1) was excluded from the study, while two patients in group 1 (5%) and seven in group 2 (17.1 %) did not complete the trial. A sustained response was observed in seven patients (18%) in group 1 versus none in group 2 (P < 0.01). The difference in mean Knodell score remained non-statistically significant between the two groups at the end of the study. Reduction or interruption of interferon was necessary in eight patients (24.2%). CONCLUSIONS: This first randomized controlled study in mild chronic hepatitis C shows a proportion of sustained responders to interferon alpha-2b similar to that observed in active chronic hepatitis C.

European collaborative study on factors influencing outcome after liver transplantation for hepatitis C. European Concerted Action on Viral Hepatitis (EUROHEP) Group.

BACKGROUND & AIMS: Liver transplantation for hepatitis C virus (HCV)-related liver disease is characterized by frequent graft infection by HCV. The prognosis and risk factors for morbidity and mortality in this condition were determined. METHODS: A retrospective study of 652 consecutive anti-HCV-positive patients undergoing liver transplantation between 1984 and 1995 in 15 European centers was conducted; 102 patients coinfected with hepatitis B virus (HBV) received immunoglobulin prophylaxis for antibody to hepatitis B surface antigen. RESULTS: Overall, 5-year survival was 72%. Five-year actuarial rates of hepatitis and cirrhosis were 80% and 10%. Genotypes 1b, 1a, and 2 were detected in 214 (80%), 24 (9%), and 24 (9%) of 268 patients analyzed. The only discriminant factor for patient or graft survival was hepatocellular carcinoma as primary indication. Independent risk factors for recurrent hepatitis included the absence of HBV coinfection before transplantation (relative risk [RR], 1.7; 95% confidence interval [CI], 1.2-2.6; P = 0.005), genotype 1b (RR, 2; 95% CI, 1.3-2.9; P = 0.01), and age > 49 years (RR, 1.4; 95% CI, 1.1-1.8; P = 0.01). CONCLUSIONS: The results of transplantation for HCV-related disease are compromised by a significant risk of cirrhosis, although 5-year survival is satisfactory. Genotype 1b, age, and absence of pretransplantation coinfection by HBV are risk factors for recurrent HCV.

Ciprofloxacin and long-term prevention of spontaneous bacterial peritonitis: results of a prospective controlled trial.

The aim of this prospective double-blind study was to evaluate the value of long-term antibiotic prophylaxis using ciprofloxacin for the prevention of spontaneous bacterial peritonitis (SBP) in 60 cirrhotic patients with low ascitic fluid protein levels (< 15 g/L). The patients were assigned to two groups: group I (n = 28) ciprofloxacin 750 mg per os once a week for 6 months, group II (n = 32) placebo. The two groups were similar for clinical and laboratory characteristics. Twelve patients developed an intercurrent disorder, and 10 patients died during the trial. There were no adverse effects in the treated group. There was a significant decrease in the incidence of SBP (3.6 vs. 22%) (P < .05) and duration of hospitalization (9.3 +/- 4.5 vs. 17.6 +/- 6.2 days) (P < .05) in the treated group as compared with the placebo group. The bacteriological study showed no acquired resistance to ciprofloxacin after 6 months' treatment. These results suggest that long-term preventive antibiotic prophylaxis based on the weekly administration of 750 mg of ciprofloxacin is effective in the prevention of SBP in cirrhotic patients.

[Indications and results of liver transplantation for hepatocellular carcinoma. Retrospective study in 17 patients]. / Indications et résultats de la transplantation hépatique au cours du carcinome hépatocellulaire. Etude rétrospective de 17 malades.

Orthotopic liver transplantation has been considered as one of the therapeutic tools in certain patients with hepatocellular carcinoma. In our liver Unit in Besançon, 17 patients with hepatocellular carcinoma were treated by orthotopic liver transplantation between March 1986 and December 1991. This series included 14 men and 3 women. The mean age was 51 years (range: 36-62). In 11 cases, hepatocellular carcinoma was multifocal and larger than 5 cm, in 6 cases, the tumor was encapsulated, and was well differentiated in 11 cases. Lymph node invasion was observed in 2 cases and the portal vein was invaded in 5 cases. Before orthotopic liver transplantation, alpha foetoprotein was increased in 10 cases. Kaplan-Meier actuarial survival was 76%, 53%, 40%, at one, two and three years, respectively, and remained unchanged at four years. There were 9 recurrences of hepatocellular carcinoma. There were 8 deaths, 4 due to a tumor recurrence. A tumor larger than 5 cm was the only parameter statistically associated with recurrence in this study.

Orthotopic liver transplantation for incurable alveolar echinococcosis of the liver: report of 17 cases.

Between 1986 and 1989, orthotopic liver transplantations were performed in our unit for 17 patients with incurable alveolar echinococcosis. Ten patients had hilar involvement (group I), and seven patients had posterior localization (five of them had chronic Budd-Chiari syndrome) (group II). The delay between diagnosis and the orthotopic liver transplantation was more than 48 mo in group Ia (six patients), less than 24 mo in group Ib (four patients) and less than 48 mo in group II. Previous operations were more common in group Ia than in group Ib and II. Five patients have died-four in group I and one in group II. The actuarial survival rate at 15 mo was 75%. Early reoperations were frequent (69%), mainly caused by rebleeding. Bacterial and fungal infections occurred only in group Ia (four cases) and group II (three cases). In eight patients (palliative group), residual foci of infected nonhepatic tissue occurred after surgery. The titer of specific antibodies decreased during the first 3 mo in all the patients but one. In patients with radical liver transplantation, the complete disappearance of specific antibodies occurred within 2 yr in four cases. In the remaining five patients, specific antibodies remained detectable, but no evidence of recurrence has been obtained up to now. In the palliative group, a peak of specific IgM occurred at 3 mo; an increase of specific IgG was observed later. The growth of residual parasitic foci was relatively slow, and all these patients remained asymptomatic with a mean follow-up of 19 mo. We conclude that orthotopic liver transplantation is feasible in incurable alveolar echinococcosis and could be proposed without delay to patients with parasitic Budd-Chiari syndrome or complicated secondary biliary cirrhosis. In the other cases, the best time to perform an orthotopic liver transplantation is more difficult to determine. Nevertheless, in the perspective of an orthotopic liver transplantation, the management of these patients has to change, and repetitive laparotomies for palliative surgical procedures have to be replaced by interventional radiology.

[Prevalence of and changes in hepatitis C virus antibodies in 64 patients with liver transplant]. / Prévalence et évolution des anticorps dirigés contre le virus de l'hépatite C chez soixante-quatre transplantés hépatiques.

The aim of this retrospective study was to assess the prevalence of hepatitis C virus antibodies and their follow-up in a series of 64 orthotopic liver transplantation patients. Indications for transplantation were cirrhosis in 28 cases, primary biliary cirrhosis in 6 cases, liver cancer in 11 cases, fulminant hepatitis in 2 cases, and alveolar echinococcosis in 17 cases. The prevalence of serum antibodies to hepatitis C virus was assessed by an ELISA test (Ortho-Diagnostic-Systems). Sera were tested before liver transplantation and every two months after. Twenty-nine patients seronegative before transplantation remained negative. Four patients seropositive before liver transplantation remained seropositive. Twenty-eight patients seropositive before transplantation, became seronegative after, and 3 patients seronegative before transplantation became seropositive after. The prevalence of seroconversion was 9.3 percent. The prevalence of seropositive patients after transplantation was 11 percent. The high number of seropositive patients before transplantation (50 percent) could be explained by false positive results. Seropositivity before transplantation appeared to be related to hypergammaglobulinemia (p less than 0.001). This hypothesis was confirmed a posteriori by a concomitant disappearance of both seropositivity and hypergammaglobulinemia after transplantation in 62 percent of patients.

Transient global amnesia: a clinical and EEG study.

33 cases of transient global amnesia are reported. An interaction between organic and functional factors in determining the syndrome is supposed.