Ziad Hassoun

Tivantinib for second-line treatment of advanced hepatocellular carcinoma: a randomised, placebo-controlled phase 2 study

BACKGROUND Tivantinib (ARQ 197), a selective oral inhibitor of MET, has shown promising antitumour activity in hepatocellular carcinoma as monotherapy and in combination with sorafenib. We aimed to assess efficacy and safety of tivantinib for second-line treatment of advanced hepatocellular carcinoma. METHODS In this completed, multicentre, randomised, placebo-controlled, double-blind, phase 2 study, we enrolled patients with advanced hepatocellular carcinoma and Child-Pugh A cirrhosis who had progressed on or were unable to tolerate first-line systemic therapy. We randomly allocated patients 2:1 to receive tivantinib (360 mg twice-daily) or placebo until disease progression. The tivantinib dose was amended to 240 mg twice-daily because of high incidence of treatment-emergent grade 3 or worse neutropenia. Randomisation was done centrally by an interactive voice-response system, stratified by Eastern Cooperative Oncology Group performance status and vascular invasion. The primary endpoint was time to progression, according to independent radiological review in the intention-to-treat population. We assessed tumour samples for MET expression with immunohistochemistry (high expression was regarded as ≥2+ in ≥50% of tumour cells). This study is registered with ClinicalTrials.gov, number NCT00988741. FINDINGS 71 patients were randomly assigned to receive tivantinib (38 at 360 mg twice-daily and 33 at 240 mg twice-daily); 36 patients were randomly assigned to receive placebo. At the time of analysis, 46 (65%) patients in the tivantinib group and 26 (72%) of those in the placebo group had progressive disease. Time to progression was longer for patients treated with tivantinib (1·6 months [95% CI 1·4-2·8]) than placebo (1·4 months [1·4-1·5]; hazard ratio [HR] 0·64, 90% CI 0·43-0·94; p=0·04). For patients with MET-high tumours, median time to progression was longer with tivantinib than for those on placebo (2·7 months [95% CI 1·4-8·5] for 22 MET-high patients on tivantinib vs 1·4 months [1·4-1·6] for 15 MET-high patients on placebo; HR 0·43, 95% CI 0·19-0·97; p=0·03). The most common grade 3 or worse adverse events in the tivantinib group were neutropenia (ten patients [14%] vs none in the placebo group) and anaemia (eight [11%] vs none in the placebo group). Eight patients (21%) in the tivantinib 360 mg group had grade 3 or worse neutropenia compared with two (6%) patients in the 240 mg group. Four deaths related to tivantinib occurred from severe neutropenia. 24 (34%) patients in the tivantinib group and 14 (39%) patients in the placebo group had serious adverse events. INTERPRETATION Tivantinib could provide an option for second-line treatment of patients with advanced hepatocellular carcinoma and well-compensated liver cirrhosis, particularly for patients with MET-high tumours. Confirmation in a phase 3 trial is needed, with a starting dose of tivantinib 240 mg twice-daily. FUNDING ArQule, Daiichi Sankyo (Daiichi Sankyo Group).

Liver transplantation and neuroendocrine tumors: lessons from a single centre experience and from the literature review.

Neuroendocrine tumor (NET) metastases represent at this moment the only accepted indication of liver transplantation (LT) for liver secondaries. Between 1984–2007, nine (1.1%) of 824 adult LTs were performed because of NET. There were five well differentiated functioning NETs (four carcinoids and one gastrinoma), three well differentiated non functioning NETs and one poorly differentiated NET. Indications for LT were an invalidating unresectable tumor (4×), and/or a diffuse tumor localization (3×) and/or a refractory hormonal syndrome (5×). Median post‐LT patient survival is 60.9 months (range 4.8–119). One‐, 3‐ and 5‐year actuarial survival rates are 88%, 77% and 33%; 1, 3 and 5 years disease free survival rates are 67%, 33% and 11%. Due to a more rigorous selection procedure, results improved since 2000; three out of five patients are alive disease‐free at 78, 84 and 96 months. Review of these series together with a review of the literature reveals that results of LT for this oncological condition can be improved using better selection criteria, adapted immunosuppression and neo‐ and adjuvant surgical as well as medical tretament. LT should be considered earlier in the therapeutic algorithm of selected NET patients as it is the only therapy that can offer a cure.

Diagnosis of cyst infection in patients with autosomal dominant polycystic kidney disease: attributes and limitations of the current modalities

Cyst infection is a diagnostic challenge in patients with autosomal dominant polycystic kidney disease (ADPKD) because of the lack of specific manifestations and limitations of conventional imaging procedures. Still, recent clinical observations and series have highlighted common criteria for this condition. Cyst infection is diagnosed if confirmed by cyst fluid analysis showing bacteria and neutrophils, and as a probable diagnosis if all four of the following criteria are concomitantly met: temperature of >38°C for >3 days, loin or liver tenderness, C-reactive protein plasma level of >5 mg/dL and no evidence for intracystic bleeding on computed tomography (CT). In addition, the elevation of serum carbohydrate antigen 19-9 (CA19-9) has been proposed as a biomarker for hepatic cyst infection. Positron-emission tomography after intravenous injection of 18-fluorodeoxyglucose, combined with CT, proved superior to radiological imaging techniques for the identification and localization of kidney and liver pyocyst. This review summarizes the attributes and limitations of these recent clinical, biological and imaging advances in the diagnosis of cyst infection in patients with ADPKD.

Carbohydrate antigen 19-9 as a diagnostic marker for hepatic cyst infection in autosomal dominant polycystic kidney disease

The diagnosis of hepatic cyst infection is difficult in patients with autosomal dominant polycystic kidney disease (ADPKD). We hypothesized that carbohydrate antigen 19-9 (CA 19-9), secreted by the biliary epithelium lining the cysts, is overproduced in the case of cyst infection. In this report, we describe 3 patients with ADPKD with hepatic cyst infection, all with functioning kidney transplants, who had markedly increased serum CA 19-9 levels. Furthermore, CA 19-9 level was extremely increased in cystic fluid obtained in 2 of these individuals. Corresponding with clinical improvement, there was a marked decrease in serum CA 19-9 level in all 3 patients. To assess the potential applicability of these findings, serum CA 19-9 was measured in asymptomatic patients with ADPKD with known liver cysts and in controls without ADPKD. Although serum CA 19-9 levels were significantly higher in asymptomatic patients with ADPKD than in controls, they were markedly increased in patients with cyst infection compared with either asymptomatic ADPKD patients or controls. Immunostaining for CA 19-9 showed strong positivity in biliary tree epithelia and cysts of polycystic livers from patients with ADPKD that appeared more intense than in normal livers. Although further study is necessary, these data suggest that serum CA 19-9 level is markedly increased during liver cyst infection in kidney transplant recipients with ADPKD and has potential utility as a diagnostic marker.

Significant rate of hepatitis B reactivation following kidney transplantation in patients with resolved infection.

BACKGROUND Limited data is available on the risk of hepatitis B virus (HBV) reactivation in patients with resolved infection undergoing kidney transplantation. It is generally thought that this risk is negligible. OBJECTIVES To evaluate the incidence of HBV reactivation in such patients, and the potential risk factors for reactivation. STUDY DESIGN Retrospective cohort study including 93 patients transplanted with a kidney between 1995 and 2007 who had evidence of resolved HBV infection (HBsAg negative, anti-HBc positive, anti-HBs positive or negative, and normal liver enzymes). HBV reactivation was defined as HBsAg reversion with HBV DNA>2000 IU/mL. RESULTS Six patients experienced HBsAg reversion followed by HBV reactivation, 3 within the first post-transplant year. Immunosuppression regimen was similar in patients with and without reactivation. Among patients with reactivation only one was positive for anti-HBs antibodies at time of transplantation; these were progressively lost before reactivation. The odds ratio for reactivation in patients without anti-HBs antibodies at transplantation compared to those with anti-HBs antibodies was 26 (95% CI [2.8-240.5], p=0.0012). In patients with anti-HBs antibody titer above 100 IU/L, no reactivation was observed. CONCLUSIONS Reactivation rate of resolved hepatitis B is not negligible in patients without anti-HBs antibodies at transplantation. We suggest monitoring of liver tests and HBV serology including HBsAg and anti-HBs antibodies after transplantation as well as vaccination pre- and post-transplantation in all patients, including those with resolved hepatitis B, aiming at maintaining anti-HBs antibody level above 100 IU/L.

Hepatitis E virus: an underdiagnosed cause of chronic hepatitis in renal transplant recipients

Hepatitis E virus (HEV) infection can evolve to chronic hepatitis in immunocompromised patients leading to rapidly progressive cirrhosis. Proper diagnosis is therefore important, as reducing immunosuppressive therapy can allow clearance of the virus. We report a case of chronic HEV infection in a renal transplant recipient that went undiagnosed for many years, discuss the therapeutic options, and review the current available literature.

Outcome of hepatitis B and C virus‐associated hepatocellular carcinoma occurring after renal transplantation

Kidney transplant recipients (KTR) are subjected to immunosuppressive therapy that can enhance hepatitis B and C virus replication, leading to cirrhosis and hepatocellular carcinoma (HCC). The aim of this study was to assess the prevalence and outcome of HCC in KTR. Case‐control study. Patients with chronic HBV and/or HCV infection who underwent kidney transplantation between 1976 and 2011 and subsequently developed HCC were compared to a control group of patients with chronic HBV and/or HCV infection, matched for gender and age at HCC diagnosis, who did not receive kidney transplantation. Among 2944 KTR, 330 had hepatitis B and/or C. Fourteen developed HCC, a period prevalence of 4.2%. Age at HCC diagnosis was 52.6 ± 6.5 years (53.5 ± 5.7 in controls, P=.76). Time between transplantation and HCC diagnosis was 16.7 ± 2.7 years. Six HCCs were related to HBV, six to HCV and two to co‐infection with HBV and HCV. Immunosuppressive therapy was comparable in HBV, HCV and HBV+HCV patients. At diagnosis, 71% of patients met Milan criteria (65% in the control group, P=.4). Alpha‐fetoprotein levels, tumour characteristics and treatment modalities were comparable between both groups. Patient survival 2 years after HCC diagnosis was 28% in KTR, compared to 68% in controls (P=.024). Survival after HCC diagnosis is significantly worse in KTR compared to nontransplanted patients with HBV and/or HCV. Prevention is crucial and should be based on viral eradication/suppression before or after transplantation.

Secondary syphilis after renal transplantation

Potent immunosuppressive agents make renal transplant recipients at increased risk of infections. Syphilis is a sexually transmitted disease caused by the bacterium Treponema pallidum with varied and often subtle clinical manifestations. If unrecognized, it can have devastating consequences [1]. The incidence of syphilis decreased significantly in the 1940s with the advent of penicillin, with later outbreaks being related to HIV infections, sexual practices and the use of drugs [2]. With the declining prevalence of syphilis, many physicians have become unfamiliar with its clinical presentation. We report a case of secondary syphilis in a renal transplant recipient who presented with systemic signs of illness and a mild hepatitis, in whom diagnosis was delayed until he developed a characteristic cutaneous rash.