Efficacy and safety of combination therapy with everolimus and sorafenib for recurrence of hepatocellular carcinoma after liver transplantation.

BACKGROUND: Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) is still associated with a dismal outcome. Combination therapy with everolimus (EVL) and vascular endothelial growth factor inhibitor sorafenib (SORA) is based on the role of both b-Raf and mammalian target of rapamycin/protein kinase B pathways in the pathogenesis of HCC and is being investigated in clinical practice. METHODS: This was a single-center retrospective analysis on LT recipients with unresectable HCC recurrence and undergoing combination therapy with EVL and SORA. Patients were included if they were switched to EVL+SORA at any time after surgery. Primary endpoint was overall survival (OS) after both LT and recurrence, and response to treatment based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST) in the intention-to-treat (ITT) population. Secondary analysis was safety of combination therapy with EVL and SORA in the population of patients who received ≥1 dose of the study drug. RESULTS: Seven patients (100% male; median age 53 years [interquartile range (IQR) 9 years]) were considered for analysis. HCC recurrence was diagnosed at a median (IQR) interval since LT of 9 (126) months, and patients were administered EVL+SORA at a median interval since LT of 11 (126) months. Baseline immunosuppression was with tacrolimus (TAC) in 2 patients (28.6%), cyclosporine (CsA) in 2 (28.6%), and EVL monotherapy in 3 (42.8%). At a median (IQR) follow-up of 6.5 (14) months, 5 patients (71.4%) were alive, 4 of them (57.1%) with tumor progression according to the mRECIST criteria. Median (IQR) time to progression was 3.5 (12) months. Two patients died at a median (IQR) follow-up of 5 (1) months owing to tumor progression in 1 patient (14.3%) and sepsis in the other (14.3%). EVL monotherapy was achieved in 6 patients (85.7%), whereas 1patient (14.3%) could not withdraw from calcineurin inhibitor owing to acute rejection. Treatment complications were: hand-foot syndrome in 5 patients (71.4%), hypertension in 1 (14.3%), alopecia in 1 (14.3%), hypothyroidism in 1 (14.3%), diarrhea in 2 (28.6%), pruritus in 1 (14.3%), abdominal pain in 1 (14.3%), rash in 1 (14.3%), asthenia in 3 (42.8%), anorexia in 3 (42.8%), and hoarseness in 2 (28.6%). Adverse events led to temporary SORA discontinuation in 2 patients (28.6%) and to SORA dose reduction in 3 (42.8%). CONCLUSIONS: Treatment of HCC recurrence after LT with a combination regimen of EVL+ SORA is challenging because of SORA-related complications. Longer follow-up periods and larger series are needed to better capture the impact of such combination treatment on tumor progression and patient survival.

GIDEON (Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib): second interim analysis.

BACKGROUND: GIDEON (Global Investigation of therapeutic DEcisions in hepatocellular carcinoma [HCC] and Of its treatment with sorafeNib) is a global, prospective, non-interventional study undertaken to evaluate the safety of sorafenib in patients with unresectable HCC in real-life practice, including Child-Pugh B patients who were excluded from clinical trials. METHODS: Patients with unresectable HCC, for whom the decision to treat with sorafenib, based on the approved label and prescribing guidelines, had been taken by their physician, were eligible for inclusion. Demographic data and disease/medical history were recorded at entry. Sorafenib dosing and adverse events (AEs) were collected at follow-up visits. The second interim analysis was undertaken when ~1500 treated patients were followed up for ≥ 4 months. RESULTS: Of the 1571 patients evaluable for safety, 61% had Child-Pugh A status and 23% Child-Pugh B. The majority of patients (74%) received the approved 800 mg initial sorafenib dose, regardless of Child-Pugh status; however, median duration of therapy was shorter in Child-Pugh B patients. The majority of drug-related AEs were grade 1 or 2, and the most commonly reported were consistent with previous reports. The incidence and nature of drug-related AEs were broadly similar across Child-Pugh, Barcelona Clinic Liver Cancer (BCLC) and initial dosing subgroups, and consistent with the overall population. CONCLUSIONS: Consistent with the first interim analysis, overall safety profile and dosing strategy are similar across Child-Pugh subgroups. Safety findings also appear comparable irrespective of initial sorafenib dose or BCLC stage. Final analyses in > 3000 patients are ongoing.

First interim analysis of the GIDEON (Global Investigation of therapeutic decisions in hepatocellular carcinoma and of its treatment with sorafeNib) non-interventional study.

AIMS: Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib (GIDEON), a global, non-interventional, surveillance study, aims to evaluate the safety of sorafenib in all patients with unresectable hepatocellular carcinoma (uHCC) under real-life practice conditions, particularly Child-Pugh B patients, who were not well represented in clinical trials. METHODS: Treatment decisions are determined by each physician according to local prescribing guidelines and clinical practice. Patients with uHCC who are candidates for systemic therapy, and for whom a decision has been made to treat with sorafenib, are eligible for inclusion. Demographic data and medical and disease history are recorded at entry. Sorafenib dosing and adverse events (AEs) are collected throughout the study. RESULTS: From January 2009 to April 2011, >3000 patients from 39 countries were enrolled. The prespecified first interim analysis was conducted when the initial approximately 500 treated patients had been followed up for ≥4 months; 479 were valid for safety evaluation. Preplanned subgroup analyses indicate differences in patient characteristics, disease aetiology and previous treatments by region. Variation in sorafenib dosing by specialty are also observed; Child-Pugh status did not appear to influence the starting dose of sorafenib. The type and incidence of AEs was consistent with findings from previous clinical studies. AE profiles were comparable between Child-Pugh subgroups. DISCUSSION: The GIDEON study is generating a large, robust database from a broad population of patients with uHCC. First interim analyses have shown global and regional differences in patient characteristics, disease aetiology and practice patterns. Subsequent planned analyses will allow further evaluation of early trends.

Design and rationale for the non-interventional Global Investigation of Therapeutic DEcisions in Hepatocellular Carcinoma and Of its Treatment with Sorafenib (GIDEON) study.

BACKGROUND: Hepatocellular carcinoma (HCC) is a complicated condition influenced by multiple confounding factors, making optimum patient management extremely challenging. Ethnicity, stage at diagnosis, comorbidities and tumour morphology affect outcomes and vary from region to region, and there is no common language to assess patient prognosis and make treatment recommendations. Despite recent efforts to reduce the incidence of HCC, most patients present with unresectable disease. Non-surgical treatments include ablation, transarterial chemoembolisation and the multikinase inhibitor, sorafenib, but their effects in all patient subgroups are not known and further information is needed to optimise the use of these treatments. AIMS: The Global Investigation of Therapeutic DEcisions in Hepatocellular Carcinoma and Of its Treatment with SorafeNib (GIDEON) study (ClinicalTrials.gov identifier NCT00812175; http://clinicaltrials.gov/) is an ongoing global, prospective, non-interventional study of patients with unresectable HCC who are eligible for systemic therapy and for whom the decision has been taken to treat with sorafenib under real-life practice conditions. The aim of this study is to evaluate the safety and efficacy of sorafenib in different subgroups, especially Child-Pugh B where data are limited. DISCUSSION: This study will recruit 3000 patients from > 40 countries and follow them for approximately 5 years to compile a large and robust database of information that will be used to analyse local, regional and global differences in baseline characteristics, disease aetiology, treatment practice patterns and treatment outcomes, with a view to improve the knowledge base used to guide physician treatment decisions and to improve patient outcomes.

MnDPDP-enhanced MRI vs dual-phase spiral CT in the detection of hepatocellular carcinoma in cirrhosis.

The objectives of this study were twofold: (a) to assess safety and tolerability of the hepatobiliary MR contrast agent MnDPDP; and (b) to investigate the sensitivity of MnDPDP-enhanced MRI, in comparison with dual-phase spiral CT, in the detection of hepatocellular carcinoma (HCC) in cirrhosis. Fifty patients with liver cirrhosis and histologically proven HCC were enrolled in a prospective phase-IIIB clinical trial. All patients underwent evaluation with dual-phase spiral CT and pre-contrast and post-contrast MRI at 1.5 T. The MR examination protocol included spin-echo (SE) and gradient-recalled-echo (GRE) T1-weighted images acquired before and 60-120 min after administration of 0.5 micromol/kg (0.5 ml/kg) MnDPDP (Teslascan, Nycomed Amersham, Oslo, Norway); and fast T2-weighted SE images obtained solely before contrast injection. Gold standard was provided by findings at Lipiodol CT in combination with follow-up spiral CT studies, which were repeated at 4-month intervals over a 10- to 27-month (mean +/- SD 20.1 +/- 5.1 months) follow-up period. No serious adverse event occurred. Eighty tumors ranging 0.8-9.1 cm in diameter (mean +/- SD 3.2 +/- 2.4 cm) were detected by Lipiodol CT or confirmed as cancerous foci by follow-up CT studies. Pre-contrast MRI detected 38 of 80 lesions (48%); MnDPDP-enhanced MRI, 65 of 80 lesions (81%); pre-contrast plus post-contrast MRI, 69 of 80 lesions (86%); and dual-phase spiral CT, 64 of 80 lesions (80%). The difference between unenhanced and MnDPDP-enhanced MRI was statistically significant (p < 0.001). The difference between MRI (pre-contrast plus post-contrast) and dual-phase spiral CT was not statistically significant (p = 0.33). The confidence in the final diagnosis, however, was significantly higher for MRI as compared with spiral CT (p<0.001). MnDPDP is a safe and well-tolerated hepatobiliary MR contrast agent. Magnetic resonance imaging with use of MnDPDP is significantly more sensitive than unenhanced MRI and as good as dual-phase spiral CT for detection of HCC in cirrhosis.

[Diagnostic imaging and interventional therapy in hepatocarcinoma. Multicenter study of 290 cases]. / La diagnostica mediante immagini e la terapia interventistica dell'epatocarcinoma. Studio multicentrico su 290 casi.

We report the results of a multicenter study on the diagnosis and interventional therapy of hepatocellular carcinoma (HCC). The first aim--diagnosis--was to evaluate the sensitivity of 4 imaging techniques, namely ultrasonography (US), Computed Tomography (CT), digital arteriography (DSA) and Lipiodol CT (LCT), in HCC detection. The accuracy of these techniques was also investigated in tumor staging, which is important for treatment planning. Two hundred ninety patients underwent this imaging protocol. The patients were classified by tumor spread into three groups, namely group 1 (single HCCs < 5 cm), group 2 (multifocal HCCs with max. 3 nodules or tumor volume < 80 cc), group 3 (multifocal HCCs with more than 3 nodules and/or tumor volume > 80 cc). US and CT diagnosed more cases as group 1 and fewer cases as group 3 than DSA and LCT; the latter two techniques gave a similar classification. With LCT as the gold standard, US and CT understaged 27.9% and 26.5% of cases, respectively. Even though LCT is known to have 53% sensitivity, it is currently the most sensitive preoperative investigation and therefore the best tool for treatment planning. In surgical patients, however, intraoperative US, with its nearly 100% sensitivity, is suggested. The second aim--treatment--consisted in assessing the therapeutic efficacy of intraarterial chemoembolization (CEAT) versus percutaneous ethanol injection (PEI) in non advanced HCC and of CEAT versus no treatment (NT) in advanced HCC. Treatment efficacy was evaluated with the following randomized protocols: PEI versus CEAT in group 1, PEI versus CEAT in group 2 and CEAT versus NT in group 3. The data were analyzed relative to 215 patients for 6 to 30 months. The Kaplan-Meier method was used to calculate survival rates, which were, at 24 and 30 months, 72% and 72% for PEI and 72% and 52% for CEAT in group 1, 52% and 28% for PEI and 70% and 50% for CEAT in group 2 and finally 30% and 20% for NT and 45% and 30% for CEAT in group 3. In group 1, PEI appeared markedly superior to CEAT. In group 2, the difference between PEI and CEAT was not statistically significant; the results in this group indicate that CEAT should be considered when three nodules are present because of PEI invasiveness in these cases. In group 3, CEAT results were definitely better in the first two years, but there was no difference with NT patients at the end of the third year. Therefore, CEAT is indicated in advanced HCC because it improves the survival rate in the first 24 months. After this period, the survival time is not modified by treatment.

Intrahepatic metastatic nodules of hepatocellular carcinoma detected at lipiodol-CT: imaging-pathologic correlation.

BACKGROUND: The purpose of this study was to determine whether tiny (< 2 cm) areas of iodized-oil retention diagnosed as intrahepatic metastatic nodules of hepatocellular carcinoma (HCC) at computed tomography (CT) following intraarterial injection of Lipiodol (Lipiodol-CT) correlate with truly cancerous foci on the corresponding sectioned pathologic specimens. METHODS: Thirty-two consecutive patients with biopsy-proven HCC (26 men and six women, aged 41-72 years) underwent prospective evaluation with Lipiodol-CT before undergoing surgery (hepatic resection, 30 patients; liver transplantation, two patients). Imaging findings were correlated with intraoperative and pathologic findings. RESULTS: Twenty-one areas of retained Lipiodol (0.5-1.6 cm in diameter, mean +/- SD: 0.9 +/- 0.3 cm) had features consistent with intrahepatic metastatic nodules of HCC on Lipiodol-CT scans. Nineteen of the 21 areas correlated with tumor deposits at pathologic examination of the surgical specimens, whereas two of 21 were due to abnormal retention of iodized oil within noncancerous liver parenchyma. The positive predictive value of findings at Lipiodol-CT for the diagnosis of intrahepatic metastatic nodule of HCC was 90.5%. CONCLUSIONS: Findings at Lipiodol-CT enable a reliable diagnosis of intrahepatic metastatic nodules of HCC.

Small hepatocellular carcinoma. Detection with US, CT, MR imaging, DSA, and Lipiodol-CT.

Twenty-two patients with 37 small (3 cm or less) nodular lesions of hepatocellular carcinoma (HCC) were examined with ultrasonography (US), CT, MR imaging, digital subtraction angiography (DSA), and CT following intraarterial injection of Lipiodol (Lipiodol-CT). All patients subsequently underwent surgery, and the gold standard was provided by intraoperative US. The detection rate was 70% for US, 65% for CT, 62% for MR imaging, 73% for DSA, and 86% for Lipiodol-CT. A significant difference (p < 0.05) was observed between the detection rate of Lipiodol-CT and the detection rates of all the other imaging modalities. The difference was even more manifest (p < 0.02) when only lesions smaller than or equal to 1 cm were considered. It is concluded that Lipiodol-CT is the single most sensitive examination to detect small nodules of HCC. It should therefore be considered a mandatory step in the preoperative evaluation of patients with HCC considered to be surgical candidates after noninvasive imaging studies.

[Diagnostic imaging of intestinal invaginations in the adult. Report of 9 cases]. / Diagnostica per immagini delle invaginazioni intestinali dell'adulto. Descrizione di 9 casi.

Adult intestinal intussusception affects the distal portions of the small bowel and the colon in 90% of cases. As a rule, its nature is neoplastic, its clinical presentation aspecific and its diagnosis is frequently an occasional finding during routine imaging examinations. We report on 9 adult patients with intestinal intussusception. All patients were examined with more than one of the following imaging modalities: radiologic study of the small bowel, barium enema, ultrasonography (US), and Computed Tomography (CT). The first diagnostic suspicion of intussusception was correctly made at US in 5 patients and at CT in 4 patients. At surgery, intussusception sites were the following: jejunum in one case, ileum in two cases, ileocolon in two cases and colon in four cases. CT correctly detected lesion site in all the patients who underwent it as the first diagnostic step, while US missed lesion site in one case. Pathology diagnosed a hamartomatous jejunal polyp, a lymphomatous ileal polyp, a lymphomatous polyp of the ileocecal valve, four cecocolonic adenocarcinomas and a left colic lipoma. Lesion nature was suspected at US in one case of ileal lymphoma, while CT suggested the presence of lipoma in one case of ileoileal intussusception. Our experience shows that intussusception can be diagnosed not only with conventional radiologic modalities, but also with US and CT, which are useful to depict both the lesion and its site and extent.

[Staging of hepatocellular carcinoma. Comparison of ultrasonography, computerized tomography, magnetic resonance, digital angiography, and computerized tomography with lipiodol]. / Stadiazione del carcinoma epatocellulare. Confronto tra ecografia, tomografia computerizzata, risonanza magnetica, angiografia digitale e tomografia computerizzata con Lipiodol.

Accurate staging is necessary in hepatocellular carcinoma (HCC) patients to choose the most appropriate therapeutic approach. In the present study, 50 patients with one or more HCC lesions were prospectively examined with ultrasonography (US), Computed Tomography (CT), Magnetic Resonance Imaging (MRI), digital subtraction angiography (DSA) and CT after intraarterial injection of Lipiodol (Lipiodol CT). The study was aimed at suggesting the most appropriate diagnostic work-up for HCC staging. A hundred and twenty-one HCC lesions were detected in the 50 examined patients by means of the above imaging techniques: namely, 21 patients had single lesions, 15 had two lesions, 4 had three lesions and 10 patients had more than three lesions (range: 4-12). US detected 98/121 lesions (81%), CT 92/121 (76%), MRI 90/121 (74%), DSA 102/121 (84%) and Lipiodol CT 115/121 lesions (95%). The sensitivity of Lipiodol CT was significantly higher than that of all the other imaging techniques (p < 0.05). The detection rate of each technique was correlated with the size of the tumors, which were divided into three groups: lesions < or = 1 cm (no. 28), lesions ranging 1.1 to 3 cm (no. 43) and lesions > 3 cm (no. 50). In the lesions < or = 1 cm, detection rates ranged 29-93%; in this group a statistically significant difference (p < 0.01) was observed between Lipiodol CT and all the other imaging modalities. In the lesions 1.1-3 cm, detection rates ranged 77-93%; in this group a statistically significant difference (p < 0.05) was observed between Lipiodol CT and MRI. In the lesions > 3 cm, sensitivity was very high for all imaging modalities--i.e., 94% or higher; in this group no statistically significant difference was observed among the various imaging modalities. Combined US and CT detected 104/121 lesions (86%), US and MRI 101/121 (83%) and CT and MRI 98/121 (81%). The combination of US, CT and MRI allowed the detection of 107/121 lesions (88%), which markedly improved the results of US alone (the statistical index was just above the one usually considered to be significant). In conclusion, our data suggest the following staging work-up for HCC: (a) US as the first step diagnostic tool; (b) CT and possibly MRI, in the cases with a single lesion at US and in the patients eligible for surgery; (c) Lipiodol CT in the cases which CT and MRI confirmed to be single lesions.

Lipiodol-CT in the detection of tumor persistence in hepatocellular carcinoma treated with percutaneous ethanol injection.

Our purpose was to investigate the usefulness of Lipiodol-CT for detection of residual viable neoplastic tissue in hepatocellular carcinoma (HCC) lesions treated by means of percutaneous ethanol injection (PEI). An emulsion of 5 to 20 ml iodized oil and 50 to 70 mg doxorubicin hydrochloride was intraarterially injected in 18 patients with 25 HCC lesions treated by means of PEI one to 24 months before. At CT performed 3 to 5 weeks after injection, retention of Lipiodol was observed in 9 of 13 tumors that still contained viable neoplastic tissue and in 2 of 12 tumors proven to have undergone complete necrosis after PEI. The sensitivity and specificity of Lipiodol-CT were 69.2% and 83.3%, respectively. Thus, Lipiodol-CT seems to have limited diagnostic value after PEI, probably as a consequence of the alcohol-induced vascular damage, accounting for both false-negative and false-positive results.

[The echo-guided percutaneous injection of ethanol: a therapeutic alternative in the "autonomous thyroid nodule". Our experience]. / Iniezione percutanea ecoguidata di etanolo: alternativa terapeutica del "nodulo tiroideo autonomo". Nostra esperienza.

The authors report their experience on the therapeutic value, in terms of efficacy and tolerance, of percutaneous ethanol injection (PEI) in the treatment of autonomous thyroid nodules (ATN). A group of 15 patients, 13 in clinical pretoxicity and 2 in initial thyrotoxicosis, were submitted to fine-needle ethanol injection (95%) performed under US guidance. The amount of injected alcohol was measured on the basis of the volume and diffusion of alcohol itself within the nodule, in the whole of 79 injections given. Follow-up lasted 3-15 months. Thyroid scanning demonstrated a complete or partial recovery of extranodular parenchymal function in 80% and 20% of cases, respectively. In all cases a volume reduction greater than 50% was obtained, with an initial sharp fall, already after the first month, thanks to early alcohol cytotoxicity. In the 2 patients with toxic ATN serum, normal values of free hormones have been observed ever since the third weekly injection. Good tolerance to treatment was observed, and no permanent complications. In agreement with other authors, we believe our experience to show that PEI represents a new therapeutic approach in patients with ATN. PEI will certainly play a preferential role, relative to other conventional therapies, in the management of clinical pretoxic ATN, regarding which no uniform treatment protocol exists yet.

Thiamphenicol in the treatment of chancroid in men.

Fifty-five men were treated for culture-positive chancroid with two 2.5-g doses of thiamphenicol given on each of two consecutive days. Forty-nine patients (89.1%) were cured on this regimen. No adverse effects were noted. Cultured strains of Haemophilus ducreyi were found to be sensitive to thiamphenicol.