New concepts in embolotherapy of HCC.

Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related deaths worldwide with rapidly growing incidence rates in the USA and Europe. Despite improving surveillance programs, most patients are diagnosed at intermediate to advanced stages and are no longer amenable to curative therapies, such as ablation, surgical resection and liver transplantation. For such patients, catheter-based image-guided embolotherapies such as transarterial chemoembolization (TACE) represent the standard of care and mainstay therapy, as recommended and endorsed by a variety of national guidelines and staging systems. The main benefit of these therapies is explained by the preferentially arterial blood supply of liver tumors, which allows to deliver the anticancer therapy directly to the tumor-feeding artery while sparing the healthy hepatic tissue mainly supplied by the portal vein. The tool box of an interventional oncologist contains several different variants of transarterial treatment modalities. Ever since the first TACE more than 30 years ago, these techniques have been progressively refined, both with respect to drug delivery materials and with respect to angiographic micro-catheter and image-guidance technology, thus substantially improving therapeutic outcomes of HCC. This review will summarize the fundamental principles, technical and clinical data on the application of different embolotherapies, such as bland transarterial embolization, Lipiodol-based conventional transarterial chemoembolization as well as TACE with drug-eluting beads (DEB-TACE). Clinical data on 90Yttrium radioembolization as an emerging alternative, mostly applied for niche indications such as HCC with portal vein invasion, will be discussed. Furthermore, we will summarize the principle of HCC staging, patient allocation and response assessment in the setting of HCC embolotherapy. In addition, we will evaluate the role of cone-beam computed tomography as a novel intra-procedural image-guidance technology. Finally, this review will touch on new technical developments such as radiopaque, imageable DEBs and the rationale and role of combined systemic and locoregional therapies, mostly in combination with Sorafenib.

3D quantitative assessment of response to fractionated stereotactic radiotherapy and single-session stereotactic radiosurgery of vestibular schwannoma.

OBJECTIVES: To determine clinical outcome of patients with vestibular schwannoma (VS) after treatment with fractionated stereotactic radiotherapy (FSRT) and single-session stereotactic radiosurgery (SRS) by using 3D quantitative response assessment on MRI. MATERIALS: This retrospective analysis included 162 patients who underwent radiation therapy for sporadic VS. Measurements on T1-weighted contrast-enhanced MRI (in 2-year post-therapy intervals: 0-2, 2-4, 4-6, 6-8, 8-10, 10-12 years) were taken for total tumour volume (TTV) and enhancing tumour volume (ETV) based on a semi-automated technique. Patients were considered non-responders (NRs) if they required subsequent microsurgical resection or developed radiological progression and tumour-related symptoms. RESULTS: Median follow-up was 4.1 years (range: 0.4-12.0). TTV and ETV decreased for both the FSRT and SRS groups. However, only the FSRT group achieved significant tumour shrinkage (p < 0.015 for TTV, p < 0.005 for ETV over time). The 11 NRs showed proportionally greater TTV (median TTV pre-treatment: 0.61 cm(3), 8-10 years after: 1.77 cm(3)) and ETV despite radiation therapy compared to responders (median TTV pre-treatment: 1.06 cm(3); 10-12 years after: 0.81 cm(3); p = 0.001). CONCLUSION: 3D quantification of VS showed a significant decrease in TTV and ETV on FSRT-treated patients only. NR had significantly greater TTV and ETV over time. KEY POINTS: Only FSRT not GK-treated patients showed significant tumour shrinkage over time. Clinical non-responders showed significantly less tumour shrinkage when compared to responders. 3D volumetric assessment of vestibular schwannoma shows advantages over unidimensional techniques.

Systematic review of catheter-based intra-arterial therapies in hepatocellular carcinoma: state of the art and future directions.

Intra-arterial therapies (IATs) play a pivotal role in the management of patients with primary and secondary liver malignancies. The unique advantages of these treatments are their ability to selectively deliver a high dose of anticancer treatment while preserving healthy liver tissue. The proven efficacy of these catheter-based locoregional therapies in a highly systemic chemoresistant cancer such as hepatocellular carcinoma (HCC), along with the minimally invasive nature of these treatments, quickly yielded wide acceptance in the medical community and revolutionized the field of Interventional Oncology. In this article, we describe the clinical rationale and background of catheter-based IATs. We provide an overview of clinical achievements of these treatments alone and in combination with sorafenib in patients with HCC.

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.

Impact of a single-day multidisciplinary clinic on the management of patients with liver tumours.

PURPOSE: Multidisciplinary cancer clinics may improve patient care. We examined how a single-day multidisciplinary liver clinic (mdlc) affected care recommendations for patients compared with the recommendations provided before presentation to the mdlc. METHODS: We analyzed the demographic and clinicopathologic data of 343 patients assessed in the Johns Hopkins Liver Tumor Center from 2009 to 2012, comparing imaging and pathology interpretation, diagnosis, and management plan between the outside provider (osp) and the mdlc. RESULTS: Most patients were white (n = 259, 76%); median age was 60 years; and 146 were women (43%). Outside providers referred 182 patients (53%); the rest were self-referred. Patients travelled median of 83.4 miles (interquartile range: 42.7-247 miles). Most had already undergone imaging (n = 338, 99%) and biopsy (n = 194, 57%) at the osp, and a formal management plan had been formulated for about half (n = 168, 49%). Alterations in the interpretation of imaging occurred for 49 patients (18%) and of biopsy for 14 patients (10%). Referral to the mdlc resulted in a change of diagnosis in 26 patients (8%), of management plan in 70 patients (42%), and of tumour resectability in 7 patients (5%). Roughly half the patients (n = 174, 51%) returned for a follow-up, and 154 of the returnees (89%) received treatment, primarily intraarterial therapy (n = 88, 57%), systemic chemotherapy (n = 60, 39%), or liver resection (n = 32, 21%). Enrollment in a clinical trial was proposed to 34 patients (10%), and 21 of the 34 (62%) were accrued. CONCLUSIONS: Patient assessment by our multidisciplinary liver clinic had a significant impact on management, resulting in alterations to imaging and pathology interpretation, diagnosis, and management plan. The mdlc is an effective and convenient means of delivering expert opinion about the diagnosis and management of liver tumours.

Phase II study of chemoembolization with drug-eluting beads in patients with hepatic neuroendocrine metastases: high incidence of biliary injury.

PURPOSE: To evaluate safety in an interim analysis of transarterial chemoembolization (TACE) with doxorubicin-eluting beads (DEB) in 13 patients with hepatic metastases from neuroendocrine tumors (NETs) as part of a phase II trial. METHODS: Institutional Review Board approval and informed consent were obtained. Thirteen patients completed preliminary safety analysis. Their mean age was 65 years, Eastern Cooperative Oncology Group status was 0/1, tumor burden range was 4-75 %, and mean targeted tumor size was 5.9 cm. Up to four DEB-TACE sessions (100-300 µm beads loaded with ≤100 mg doxorubicin) within 6 months were allowed. Tumor response was assessed by magnetic resonance imaging 1 month after treatment using contrast-enhancement [European Association for the Study of the Liver (EASL) and size Response Evaluation Criteria in Solid Tumors (RECIST)] criteria. Safety was assessed by National Cancer Institute Common Terminology Criteria. RESULTS: DEB-TACE was successfully performed in all 13 patients. At 1 month follow-up, there was a mean 12 % decrease in tumor size (p < 0.0003) and a 56 % decrease in tumor enhancement (p < 0.0001). By EASL criteria, the targeted lesion objective response rate was 78 %. Grade 3 to 4 toxicities were fatigue (23 %), increased alanine amino transferase (15 %), hyperglycemia (15 %), and abdominal pain (8 %). Seven patients developed bilomas (54 %); all of these patients had multiple small (<4 cm) lesions. Subsequently, four underwent percutaneous drainage, three for abscess formation and one for symptoms related to mass effect. CONCLUSIONS: Although biloma and liver abscess are known risks after TACE, the high incidence in our study population was unexpected and forced interruption of the trial. Although this occurred in a small group of patients, we have changed our technique and patient selection as a result of these findings, thus allowing resumption of the trial.

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.

[Intra-arterial treatment of liver metastases from colorectal carcinoma]. / Traitement intra-artériel des métastases hépatiques de cancer colorectal.

Colorectal carcinoma is a major public health concern with its yearly mondial incidence of about one million cases and yearly mortality of 500,000 cases. The liver is the organ most frequently affected by metastases with a frequency of 40 to 60% (contemporaneous in 25% of cases). While surgical resection is the only curative therapy, many patients are not such candidates due to the infiltrative nature of the liver metastases. Systemic chemotherapy and biotherapy regimens are the conventional treatment options for patients with multiple liver metastases. Under such circumstances, intra-arterial therapy may play a major role. We will review the main types of endovascular therapies for liver metastases from colorectal carcinoma including indications, results and potential complications.

Packing technique for endovascular coil embolisation of peripheral arterial pseudo-aneurysms with preservation of the parent artery: safety, efficacy and outcomes.

OBJECTIVES: To evaluate the endovascular treatment of pseudo-aneurysms (PAs) with super-selective coil embolisation using the 3D packing technique. DESIGN: Retrospective study of consecutive patients in one academic centre. MATERIALS: From 2002 to 2009, 16 patients (mean age 51.6 years, range 24-82) underwent PA sac packing with coils. Four patients were asymptomatic, nine had PA rupture, and three had other symptoms. Lesion location was as follows: splenic artery (8), carotid artery (2), hepatic artery (2), superior mesenteric artery (1), cystic artery (1), uterine artery (1), and hypogastric artery (1). METHODS: The sac was packed with 0.018-inch controlled-detachable microcoils, preserving the parent artery. Magnetic resonance angiography was done within 6 months, at 12 months then yearly. RESULTS: Technical success rate was 100%. Complete definitive PA exclusion was achieved with a single procedure in 15 (93.8%) patients. One patient with a secondary bleeding arterio-digestive fistula underwent successful surgery. No major complications or late recanalisations occurred during follow-up (mean, 24.7 months; range 6-49). CONCLUSIONS: Coil PA embolisation by 3D sac packing is safe and effective and may induce less morbidity than complete parent vessel occlusion, stent placement, or open surgery. This procedure should be used whenever possible, as it preserves parent artery patency.

3-bromopyruvate: a new targeted antiglycolytic agent and a promise for cancer therapy.

The pyruvate analog, 3-bromopyruvate, is an alkylating agent and a potent inhibitor of glycolysis. This antiglycolytic property of 3-bromopyruvate has recently been exploited to target cancer cells, as most tumors depend on glycolysis for their energy requirements. The anticancer effect of 3-bromopyruvate is achieved by depleting intracellular energy (ATP) resulting in tumor cell death. In this review, we will discuss the principal mechanism of action and primary targets of 3-bromopyruvate, and report the impressive antitumor effects of 3-bromopyruvate in multiple animal tumor models. We describe that the primary mechanism of 3-bromopyruvate is via preferential alkylation of GAPDH and that 3-bromopyruvate mediated cell death is linked to generation of free radicals. Research in our laboratory also revealed that 3-bromopyruvate induces endoplasmic reticulum stress, inhibits global protein synthesis further contributing to cancer cell death. Therefore, these and other studies reveal the tremendous potential of 3-bromopyruvate as an anticancer agent.

Percutaneous management of bile duct strictures and injuries associated with laparoscopic cholecystectomy: a decade of experience.

BACKGROUND: The 1990s were associated with a dramatic increase in bile duct injuries with the widespread use of laparoscopic cholecystectomy (LC). Interventional radiology has an integral role in diagnosing and managing these injuries. Definitive percutaneous management with balloon dilatation might be possible in select patients with intact biliary-enteric continuity, but longterm data are limited. STUDY DESIGN: Data were collected prospectively on 51 consecutive patients with major bile duct stricture or injury associated with LC, treated with percutaneous management, January 1, 1990, to December 31, 1999. Percutaneous transhepatic cholangiography and biliary catheter placement were followed by balloon dilatation and stenting. Outcomes were assessed with direct patient contact or hospital records. RESULTS: All patients completed treatment, and 50 (98%) were stent free at mean followup of 76 months. The success rate of percutaneous management was 58.8%, without need for subsequent intervention. Presenting symptoms, level of injury, and number of stents or dilatations did not predict outcomes. Percutaneous treatment was more likely to fail in patients stented for less than 4 months (p < 0.001). Operative repair at Hopkins before percutaneous management was predictive of a successful outcome (p < 0.05). Including subsequent operations or percutaneous management, successful outcomes were achieved in 98% of patients. CONCLUSIONS: Major bile duct injuries after LC remain a clinical challenge. Although surgical reconstruction is the treatment cornerstone, selected patients with biliary-enteric continuity can achieve successful long-term results with definitive percutaneous management. The combination of percutaneous management and surgical reconstruction results in successful outcomes in virtually all patients.

Perineal application of cosmetic talc and risk of invasive epithelial ovarian cancer: a meta-analysis of 11,933 subjects from sixteen observational studies.

OBJECTIVE: Prior epidemiological studies suggest an association between perineal cosmetic talc use and increased risk of epithelial ovarian cancer. A meta-analysis was performed to evaluate this suspected association. MATERIALS AND METHODS: Using previously described methods, a protocol was developed for a meta-analysis examining the association between perineal talc use versus non-use and the development of invasive epithelial ovarian cancer. Literature search techniques, study inclusion criteria and statistical procedures were prospectively defined. Data from observational studies were pooled using a general variance based meta-analytic method employing confidence intervals previously described by Greenland. The outcome of interest was a summary relative risk (RRs) reflecting the risk of ovarian cancer development associated with perineal talc use versus non-use. Sensitivity analyses were performed when necessary to explain any observed statistical heterogeneity. RESULTS: Sixteen observational studies meeting protocol specified inclusion criteria were located via a comprehensive literature search. These studies enrolled a total of 11,933 subjects. Analysis for heterogeneity demonstrated that the data were homogenous (p = 0.17) and could be combined in a meta-analysis. Pooling all sixteen studies yielded a RRs of 1.33 (CI = 1.16-1.45), a statistically significant result suggesting a 33% increased risk of ovarian cancer with perineal talc use. Despite this finding, the data showed a lack of a clear dose-response relationship making the RRs of questionable validity. Further sensitivity analyses showed that hospital-based studies showed no relationship between talc use and ovarian cancer risk, i.e. RRs 1.19 (0.99-1.41) versus population-based studies (RRs = 1.38, CI = 1.25-1.52). This suggests that selection bias and/or uncontrolled confouding may result in a spurious positive association between talc use and ovarian cancer risk in population-based studies. CONCLUSION: The available observational data do not support the existence of a causal relationship between perineal talc exposure and an increased risk of epithelial ovarian cancer. Selection bias and uncontrolled confouding may account for the positive associations seen in prior epidemiological studies.

Mitochondrial bound type II hexokinase: a key player in the growth and survival of many cancers and an ideal prospect for therapeutic intervention.

Despite more than 75 years of research by some of the greatest scientists in the world to conquer cancer, the clear winner is still cancer. This is reflected particularly by liver cancer that worldwide ranks fourth in terms of mortality with survival rates of no more than 3-5%. Significantly, one of the earliest discovered hallmarks of cancer had its roots in Bioenergetics as many tumors were found in the 1920s to exhibit a high glycolytic phenotype. Although research directed at unraveling the underlying basis and significance of this phenotype comprised the focus of cancer research for almost 50 years, these efforts declined greatly from 1970 to 1990 as research into the molecular and cell biology of this disease gained center stage. Certainly, this change was necessary as the new knowledge obtained about oncogenes, gene regulation, and programmed cell death once again placed Bioenergetics in the limelight of cancer research. Thus, we now have a much better molecular understanding of the high glycolytic phenotype of many cancers, the pivotal roles that Type II hexokinase-mitochondrial interactions play in this process to promote tumor cell growth and survival, and how this new knowledge can lead to improved therapies that may ultimately turn the tide on our losing war on cancer.

Weight-based rt-PA thrombolysis protocol for acute native arterial and bypass graft occlusions.

PURPOSE: To determine technical success and complications with weight-adjusted dosing of recombinant tissue plasminogen activator (rt-PA) for arterial and bypass graft occlusions. MATERIALS AND METHODS: During an 8-month period, prospective data were collected on patients undergoing catheter-directed thrombolysis. Retrospective review of all medical charts and blood bank data were performed for confirmation. All patients underwent a standard weight-adjusted protocol for catheter-directed thrombolysis. Thrombolytic therapy with rt-PA (0.2 mg/mL) was defined as low-dose when 0.02 mg/kg/h rt-PA was used and high-dose when 0.04 mg/kg/h of rt-PA was used. Low-dose heparin therapy was used. Total infusion time, total dose, and hourly rate of dose were calculated. Technical success, defined as complete removal of all clot without surgical intervention, complications, and frequency of transfusions were tabulated. RESULTS: A total of 35 patients underwent catheter-directed thrombolysis with rt-PA, including a total of 21 bypass grafts (60%) and 14 native arteries (40%). Mean age was 57 years (+/- 22.5; range, 3 mo to 83 y). Average rate of heparin infusion was 472.8 U/h (+/- 227). Success rates for graft thrombolysis were 90% (18 of 21). Success rates for native vessels were 79% (11 of 14). In patients who underwent only a low-dose protocol, the transfusion rate was 15% and major complications were 10%. In patients with a combined low-dose/high-dose administration, the transfusion rate was 46% and major complications were 13%. Overall success rate and major complication rates were 86% (30 of 35) and 11% (four of 35), respectively. Frequency of transfusions was 37% (13 of 35; mean, 2.8 U). CONCLUSION: Although weight-adjusted dosing for rt-PA provides a high efficacy of relieving ischemia, the rate of complications, especially bleeding, seems excessive in comparison to historical experience with urokinase. Administration of short-term high doses of rt-PA did not appear to have any beneficial effect. Further investigation with lower dosing and concentration should be considered.

New nonsurgical therapies in the treatment of hepatocellular carcinoma.

The last decade has seen a rapid increase in the incidence of hepatocellular carcinoma in the United States, mostly because of the increased incidence of hepatitis C. Surgical therapy remains limited to the few patients who are surgical candidates at presentation. In addition, surgery has been plagued by high recurrence rates, which can reach 80% at 3 years. Systemic chemotherapy has been found to be ineffective, with response rates approaching 10% to 20%. Nonsurgical percutaneous therapies, including percutaneous locoregional ablative procedures (ethanol or acetic acid injection, radiofrequency ablation, microwave coagulation therapy, chemotherapy infusion, laser photocoagulation, and high-intensity ultrasound) and intra-arterial procedures (radioembolization with yttrium-90 microspheres or transcatheter intra-arterial chemoembolization) are gaining popularity because they are less invasive than surgery and can be nearly as effective in prolonging survival. Multiple studies have shown good response rates with high technical success rates, as well as significant survival advantages for nonresectable disease. Furthermore, they can be performed repeatedly without compromising liver function and at a considerably lower morbidity and cost than surgery.

Glucose catabolism in the rabbit VX2 tumor model for liver cancer: characterization and targeting hexokinase.

The rabbit VX2 tumor when implanted in the liver has proven convenient as a model for studying hepatocellular carcinomas. However, its metabolic properties have not been well studied. Significantly, studies described here show that the VX2 tumor exhibits a high glycolytic/high hexokinase phenotype that is retained following implantation and growth in rabbit liver. In addition, results of a limited screen show that the glycolytic rate is inhibited best by 2-deoxyglucose (2DOG) and 3-bromopyruvate (3BrPA), the former compound of which is phosphorylated by hexokinase but not further metabolized, while the latter directly inhibits hexokinase. Finally, when tested on hepatoma cells in culture both inhibitors facilitated cell death. These studies underscore the usefulness of the VX2 tumor model for the study of advanced liver cancer and for selecting anti-hepatoma agents.