Kelvin Hong

New Intra-arterial Drug Delivery System for the Treatment of Liver Cancer: Preclinical Assessment in a Rabbit Model of Liver Cancer

Background: In the fight against cancer, new drug delivery systems are attractive to improve drug targeting of tumors, maximize drug potency, and minimize systemic toxicity. We studied a new drug delivery system comprising microspheres, with unique properties allowing delivery of large amounts of drugs to tumors for a prolonged time, thereby decreasing plasma levels. Liver tumors, unlike nontumorous liver, draw most of their blood supply from the hepatic artery. Exploiting this property, we delivered drug-eluting microspheres/beads (DEB) loaded with doxorubicin, intra-arterially, in an animal model of liver cancer (Vx-2). Purpose: The purpose of our study was to determine the pharmacokinetics and tumor-killing efficacy of DEB. Results: Our results show that plasma concentration of doxorubicin was minimal in the animals treated with DEB at all time points (0.009-0.05 μmol/L), suggesting high tumor retention of doxorubicin. This was significantly lower (70-85% decrease in plasma concentration) than control animals treated with doxorubicin intra-arterially. Within the tumor, doxorubicin concentration peaked at 3 days (413.5 nmol/g), remaining high to 7 days (116.7 nmol/g) before declining at 14 days (41.76 nmol/g), indicating continuous doxorubicin elution from beads. In control animals, peak tumor concentration of doxorubicin was 0.09 nmol/g. Tumor necrosis (approaching 100%) was greatest at 7 days, with minimal adverse local side effects reflected in liver function tests results. The plasma concentration of doxorubicinol (doxorubicin main metabolite) was minimal. Conclusions: Our results support the concept of DEBs as an effective way to deliver drugs to tumor. This new technology may prove to be a useful weapon against liver cancer.

Safety and efficacy of transarterial chemoembolization in patients with unresectable hepatocellular carcinoma and portal vein thrombosis.

PURPOSE Despite the absence of conclusive data, portal vein (PV) thrombosis is considered a contraindication to transarterial chemoembolization (TACE) in patients with unresectable hepatocellular carcinoma (HCC). The purpose of our study was to establish the safety of TACE in such patients and identify key prognostic factors and survival. MATERIALS AND METHODS Data were prospectively collected from 32 consecutive patients with unresectable HCC and PV thrombosis who underwent treatment with TACE. History and physical examination, relevant laboratory values, and contrast material-enhanced magnetic resonance (MR) images were obtained before each TACE procedure. Repeated TACE was performed every 6 weeks unless patients developed a contraindication or MR imaging showed complete response. RESULTS Median overall survival was 9.5 months (range, 3-50 months). Child-Pugh numerical disease stage was the prognostic factor most strongly related to survival. The 30-day mortality rate was zero and there was no evidence of TACE-related hepatic infarction or acute liver failure. The 6-, 9-, 12-, and 18-month survival rates were 60%, 47%, 25%, and 12.5%, respectively. CONCLUSIONS PV thrombosis should not be considered a contraindication to TACE. Compared with historical control subjects who received traditional forms of treatment, the patients in the present study had extended survival. However, prospective randomized trials are necessary to show this conclusively and to show which subgroups benefit.

Transcatheter Arterial Chemoembolization in Unresectable Cholangiocarcinoma: Initial Experience in a Single Institution

PURPOSE Unresectable cholangiocarcinoma carries a dismal prognosis, with median survival times ranging from 6 to 12 months from the time of diagnosis. Palliative therapies have been disappointing and have not been shown to significantly prolong survival. Conversely, transcatheter arterial chemoembolization (TACE) has been effective in prolonging the lives of patients with hepatocellular carcinoma but has not been used against cholangiocarcinoma. Therefore, the purpose of the present study was to assess the safety and efficacy (ie, survival) of TACE in patients with unresectable intrahepatic cholangiocarcinoma. MATERIALS AND METHODS Seventeen patients with unresectable cholangiocarcinoma were treated with one or more cycles of TACE between 1995 and 2004 at our institution. Follow-up imaging was performed on all patients 4-6 weeks after each TACE procedure to determine tumor response and need for further treatment. Survival was calculated with use of the Kaplan-Meier survival curve. RESULTS The median survival for 17 patients treated with TACE was 23 months. Two patients with previously unresectable disease underwent successful resection after TACE. The procedure was well tolerated by 82% of the patients, who experienced no side effects or mild side effects that quickly resolved with conservative therapy alone. Two patients had minor complications (12%), which were managed successfully, and one had a major complication that resulted in a fatal outcome. This patient had a rapidly declining course from the time of diagnosis and died shortly after TACE. CONCLUSIONS The results suggest that TACE was effective at prolonging survival of patients with unresectable cholangiocarcinoma. Therefore, for these patients, TACE may be an appropriate palliative therapy.

Human bile contains MicroRNA‐laden extracellular vesicles that can be used for cholangiocarcinoma diagnosis

Cholangiocarcinoma (CCA) presents significant diagnostic challenges, resulting in late patient diagnosis and poor survival rates. Primary sclerosing cholangitis (PSC) patients pose a particularly difficult clinical dilemma because they harbor chronic biliary strictures that are difficult to distinguish from CCA. MicroRNAs (miRs) have recently emerged as a valuable class of diagnostic markers; however, thus far, neither extracellular vesicles (EVs) nor miRs within EVs have been investigated in human bile. We aimed to comprehensively characterize human biliary EVs, including their miR content. We have established the presence of extracellular vesicles in human bile. In addition, we have demonstrated that human biliary EVs contain abundant miR species, which are stable and therefore amenable to the development of disease marker panels. Furthermore, we have characterized the protein content, size, numbers, and size distribution of human biliary EVs. Utilizing multivariate organization of combinatorial alterations (MOCA), we defined a novel biliary vesicle miR‐based panel for CCA diagnosis that demonstrated a sensitivity of 67% and specificity of 96%. Importantly, our control group contained 13 PSC patients, 16 with biliary obstruction of varying etiologies (including benign biliary stricture, papillary stenosis, choledocholithiasis, extrinsic compression from pancreatic cysts, and cholangitis), and 3 with bile leak syndromes. Clinically, these types of patients present with a biliary obstructive clinical picture that could be confused with CCA. Conclusion: These findings establish the importance of using extracellular vesicles, rather than whole bile, for developing miR‐based disease markers in bile. Finally, we report on the development of a novel bile‐based CCA diagnostic panel that is stable, reproducible, and has potential clinical utility. (Hepatology 2014;60:896–907)

Distribution of Iron Oxide–containing Embosphere Particles after Transcatheter Arterial Embolization in an Animal Model of Liver Cancer: Evaluation with MR Imaging and Implication for Therapy

PURPOSE To test whether different-sized iron oxide-containing Embosphere (IOE) particles can be detected by dedicated magnetic resonance (MR) imaging when injected intraarterially in an animal model of liver cancer and whether their distribution could be accurately predicted by MR imaging before confirmation with histopathologic analysis. MATERIALS AND METHODS Twenty New Zealand White rabbits implanted with VX2 liver tumor were randomly assigned to undergo embolization with 100-300-microm particles (group S; n = 10) or 300-500-microm particles (group L; n = 10). Embolization was performed with the catheter placed in the proper hepatic artery. T2*-weighted multiplanar MR imaging was performed within 24 hours after the procedure to detect paramagnetic IOE susceptibility artifact. MR imaging interpretation parameters included presence of artifact in the artery and/or at the tumor bed. Hematoxylin and eosin- and Prussian blue-stained pathologic slides were also obtained and the presence of IOE was evaluated similarly. RESULTS The MR detectability rates for IOEs were 100% in both groups. Paramagnetic susceptibility IOE artifact inside the tumor was detected in 30% of group S animals. On pathologic analysis, IOE particles were detected inside the tumor in 70% of this group. IOEs in group L were found outside the tumor within the hepatic artery on MR imaging and histopathologic study (P < .05). CONCLUSIONS MR imaging readily detected IOE particles in an animal model of liver cancer regardless of the particle size. The smaller particles (100-300 microm) were delivered inside the tumor or in close proximity to the tumor margin, justifying their use for drug delivery or precise embolization.

A Comparison of Clinical Outcomes with Retrievable and Permanent Inferior Vena Cava Filters

PURPOSE To compare the clinical effectiveness of retrievable and permanent inferior vena cava (IVC) filters. MATERIALS AND METHODS A retrospective cohort study of consecutive patients who received retrievable or permanent IVC filters from January 2002 through December 2006 was conducted. Patient characteristics and clinical outcomes were compared with nonparametric and parametric statistics. RESULTS IVC filters were placed in 702 patients: 427 (60.8%) received a retrievable filter (RF) and 275 (39.2%) received a permanent filter (PF). Overall, the mean duration of follow-up was 11.5 months: 10.4 months for RF recipients and 13.1 months for PF recipients (P = .025). PF recipients were older (60.6 y +/- 17.0 vs 55.4 y +/- 17.2; P < .0001) and more likely to have underlying cancer (45.8% vs 29.3%; P < .0001). Symptomatic pulmonary embolism (PE) occurred in 11 PF recipients and 20 RF recipients who were receiving ongoing filtration (4.0% vs 4.7%; P = .67). Patients with PFs and RFs with ongoing filtration experienced symptomatic deep vein thrombosis (11.3% vs 12.6%; P = .59) and symptomatic IVC thrombosis (1.1% vs 0.5%; P = .39) at a comparable frequency. Sixty-six RF recipients (15.5%) underwent attempted retrieval, which was successful in 46 (69.7%). No RF recipients experienced a new PE after retrieval during a mean follow-up of 12.0 months. CONCLUSIONS In this retrospective cohort study, RFs and PFs provided similar protection from PE with comparable complication rates. Clinicians should select an IVC filter based on the projected duration of filtration needed at the time of placement rather than filter type.

Radiofrequency Ablation: Mechanism of Action and Devices

Since the first radiofrequency (RF) ablation description in early 1990s for percutaneous tumor ablation, there has been considerable published data on the subject worldwide. An understanding of RF ablation equipment, mechanism of action and its interactions with tissue is critical to avoid complications and improve patient outcomes. There is considerable variability in the way that RF ablation may be performed, and there is a variety of equipment choices. Despite the accumulated data, the desire to more quickly obtain larger zones of ablation has quickly spurred the introduction of several new ablation modalities. However, RF ablation remains the prototypical thermal ablation technique.

Salvage Therapy for Liver-dominant Colorectal Metastatic Adenocarcinoma: Comparison between Transcatheter Arterial Chemoembolization versus Yttrium-90 Radioembolization

PURPOSE To compare transarterial chemoembolization (CE) versus yttrium-90 ((90)Y) radioembolization (RE) for liver-dominant metastatic colorectal adenocarcinoma as salvage therapy. MATERIALS AND METHODS Of 36 patients, 21 underwent CE (37 procedures; 11 men; mean age, 67 years; 16 with Child-Pugh class A disease) and 15 underwent (90)Y RE (19 procedures; 11 men; mean age, 64 years; 13 with Child-Pugh class A disease) for liver-dominant colorectal adenocarcinoma. Mean index dominant lesion sizes were 9.3 cm and 8.2 cm in the CE and RE groups, respectively. Multilobar disease was seen in 67% and 87% of the respective groups, and extrahepatic metastases were seen in 43% and 33%, respectively. Mean times from diagnosis of liver metastasis to CE or RE were 17.6 months and 22.6 months, respectively. RESULTS A total of 37 CE procedures with cisplatin, doxorubicin, and mitomycin were performed, and 19 RE procedures with (90)Y were performed; 43% of patients in the CE group and 20% in the RE group received multiple treatment sessions, and 100% of procedures were technically successful. Median survival times were 7.7 months for the CE group and 6.9 months for the RE group (P = .27). The 1-, 2-, and 5-year survival rates were 43%, 10%, and 0%, respectively, in the CE group; and 34%, 18%, and 0%, respectively, in the RE group. There was one major complication (2.7%) in the CE group (pulmonary embolism), with a 30-day mortality rate of 5.4% (n = 2). There were no major complications in the RE group, with a 30-day mortality rate of 5.2% (n = 1). CONCLUSIONS Patients with unresectable liver colorectal metastases that progress despite systemic chemotherapy can undergo palliative treatment with CE or RE with similar survival benefit.

Safety and Efficacy of CT-guided Percutaneous Cryoablation for Renal Cell Carcinoma

PURPOSE Image-guided percutaneous cryoablation is a treatment alternative for selected patients with renal cell carcinoma (RCC). The objective of the present study was to present the safety and efficacy of percutaneous cryoablation. MATERIALS AND METHODS The study included 51 lesions in 46 consecutive patients treated with computed tomography (CT)-guided percutaneous cryoablation. Results were based on 40 RCCs with follow-up. Patients had baseline history and physical and laboratory examinations and renal CT or magnetic resonance (MR) imaging and were followed every 3 months. Biopsy of all lesions was performed before or at the time of the procedure. Efficacy was defined as a complete lack of enhancement on follow-up contrast agent-enhanced CT or MR imaging. Lesion size was also followed and correlated with lack of enhancement. Short- and long-term complications were tabulated. RESULTS The technical success rate was 100%, with 20% of cases requiring some form of thermal protection of an adjacent organ. During follow-up (median, 28 weeks; range, 4-81 weeks), the efficacy rate was 100% for lesions smaller than 7 cm. The incidence of significant complications was 18% (8% CTAE), mostly (10%) intercostal or genitofemoral nerve injury. All patients with complications recovered fully, and there were no mortalities. There was no change in creatinine levels, and no patient developed renal failure as a result of cryoablation. CONCLUSIONS CT-guided percutaneous cryoablation resulted in complete response for lesions as large as 4 cm. It may also be a viable alternative for nonsurgical candidates with lesions as large as 7 cm. It has a high efficacy rate, and its modest complications are not only comparable to those of other treatment modalities, but also appear to be reversible.

Lower energy endovenous laser ablation of the great saphenous vein with 980 nm diode laser in continuous mode

PurposeTo assess clinical outcomes, complication rates, and unit energy applied using 980 nm diode endovenous laser treatment at 11 watts for symptomatic great saphenous vein (GSV) incompetence and reflux disease.MethodsThirty-four consecutive ablation therapies with a 980 nm diode endovenous laser at 11 watts were studied. The diagnosis of GSV incompetence with reflux was made by clinical evaluation and duplex Doppler examinations. The treated GSVs had a mean diameter of 1.19 cm (range 0.5–2.2 cm). The patients were followed with clinical evaluation and color flow duplex studies up to 18.5 months (mean 12.19 months ± 4.18).ResultsUsing 980 nm diode endovenous laser ablation in continuous mode, 100% technical success was noted. The mean length of GSVs treated was 33.82 cm (range 15–45 cm). The mean energy applied during the treatment was 1,155.81 joules (J) ± 239.50 (range 545.40–1620 J) for a mean treatment duration of 90.77 sec ± 21.77. The average laser fiber withdrawal speed was 0.35 cm/sec ± 0.054. The mean energy applied per length of GSV was 35.16 J/cm ± 8.43. Energy fluence, calculated separately for each patient, averaged 9.82 J/cm2 ± 4.97. At up to 18.5 months follow-up (mean 12.19 months), 0% recanalization was noted; 92% clinical improvement was achieved. There was no major complication. Minor complications included 1 patient with hematoma at the percutaneous venotomy site, 1 patient with thrombophlebitis on superficial tributary varices of the treated GSV, 24% ecchymoses, and 32% self-limiting hypersensitivity/tenderness/“pulling” sensation along the treatment area. One patient developed temporary paresthesia. Four endovenous laser ablation treatments (12%) were followed by adjunctive sclerotherapies for improved cosmetic results.ConclusionEndovenous laser ablation treatment of GSV using a 980 nm diode laser at 11 watts in continuous mode appears safe and effective. Mean energy applied per treated GSV length of 35.16 J/cm or mean laser fluence of 9.82 J/cm2 appears adequate, resulting in 0% recanalization and low minor complication rates.