Interventional Radiological Treatment of Hepatocellular Carcinoma: An Update

Hepatocellular carcinoma is the commonest primary liver tumor and its incidence is on an increase.Transplantation and surgical resection are the gold standard curative treatment options but less than 20%patients are surgical candidates because of advanced liver disease and/or co-morbidities.Various interventional radiological procedures have been developed and intensively investigated for treatment of inoperable HCC.This review summarizes the various interventional radiological treatments in HCC including patient selection, procedural considerations and response evaluation. Transarterial chemoembolization, radioembolization and radiofrequency ablation are mainly discussed.     

Was RA Fisher Right?

Randomized controlled trials have become the most respected scientific tool to measure the effectiveness of a medical therapy. The design, conduct and analysis of randomized controlled trials were developed by Sir Ronald A. Fisher, a mathematician in Great Britain. Fisher propounded that the process of randomization would equally distribute all the known and even unknown covariates in the two or more comparison groups, so that any difference observed could be ascribed to treatment effect. Today, we observe that in many situations, this prediction of Fisher does not stand true; hence, adaptive randomization schedules have been designed to adjust for major imbalance in important covariates. Present essay unravels some weaknesses inherent in Fisherian concept of randomized controlled trial.     

Systematic survey of discrepancy rates in an international teleradiology service

International teleradiology services (ITS) to the United States are based on the principle of deploying American board-certified radiologists across global time zones to optimally distribute the workload. While errors may be reduced by circumventing the traditional night call, there is limited evidence on the actual error rates of teleradiology groups. We have a comprehensive quality assurance (QA) process in our practice, which includes a review of discrepancies between preliminary reports and the final reports by the on-site radiologists. We analyzed the discrepancy QA data to determine the error rates. Archived QA data for 126,449 cases over a period of 1?year (2008) were analyzed for the discrepancy rate, nature of errors, and possible contributory factors. The scores ranged from 0 (no error) to 5 (clinically significant in the acute setting) based on the level of clinical significance. A novel modified Lorenz plot was used to estimate the degree of underreporting and to estimate the true error rate. An internal review of 200 cases was performed to validate the findings. Of the total, there was a total of 227 confirmed errors (0.18%, 95% CI, 0.16 to 0.20). Of these, the majority were levels 2 and 3 (minor error and error of long-term significance but not in the acute setting). Even after correction for underreporting, error rates were less than 1% for clinically significant errors. ITS is associated with very low rates of clinically significant errors. Due to limited feedback, particularly for minor errors, an internal review is important.     

Increased enzyme binding to substrate is not necessary for more efficient cellulose hydrolysis

Substrate binding is typically one of the rate-limiting steps preceding enzyme catalytic action during homogeneous reactions. However, interfacial-based enzyme catalysis on insoluble crystalline substrates, like cellulose, has additional bottlenecks of individual biopolymer chain decrystallization from the substrate interface followed by its processive depolymerization to soluble sugars. This additional decrystallization step has ramifications on the role of enzyme–substrate binding and its relationship to overall catalytic efficiency. We found that altering the crystalline structure of cellulose from its native allomorph I_β to III_I results in 40–50% lower binding partition coefficient for fungal cellulases, but surprisingly, it enhanced hydrolytic activity on the latter allomorph. We developed a comprehensive kinetic model for processive cellulases acting on insoluble substrates to explain this anomalous finding. Our model predicts that a reduction in the effective binding affinity to the substrate coupled with an increase in the decrystallization procession rate of individual cellulose chains from the substrate surface into the enzyme active site can reproduce our anomalous experimental findings.     

Intratumoral coinjection of two adenoviral vectors expressing functional interleukin-18 and inducible protein-10, respectively,synergizes to facilitate regression of established tumors

We have constructed two recombinant adenoviral vectors AdVIP-10 and AdVIL-18 expressing the functional chemokine IFN-gamma inducible protein (IP)-10 and cytokine interleukin (IL)-18, respectively. Injection of either AdVIP-10 or AdVIL-18 subcutaneously into tumor nodules derived from the J558 murine myeloma cell line delayed some tumor growth but it was not curative in all cases. Coinjection of these two vectors at the same tumor nodule not only significantly suppressed the tumor growth, but also cured established tumors in 8 of 10 (80% tumor free) mice. The latter treatment stimulated T-cell infiltration into tumors in association with tumor necrosis formation, induced a type 1 immune response and induced the activation of J558 tumor-specific cytotoxic T lymphocytes. Moreover, the antitumor activity of IP-10 and IL-18 combined gene therapy was significantly diminished in mice with depletion of either CD4(+) (50% tumor free) or CD8(+) (40% tumor free) T cells, and completely lost (0% tumor free) in T cell-deficient nude and IFN-gamma knockout mice, indicating the critical roles of T cells and IFN-gamma in this therapeutical model. Taken together, the findings of this study demonstrate that the combined use of two adenoviral vectors expressing IP-10 and IL-18, respectively, synergize to facilitate regression of established tumors. These observations also suggest the potential use of double-recombinant adenoviral vectors expressing chemokines and immunomodulatory cytokines in cancer gene therapy.     

Enhanced HER-2/neu-specific antitumor immunity by cotransduction of mouse dendritic cells with two genes encoding HER-2/neu and alpha tumor necrosis factor

The present study uses an in vivo murine tumor model expressing the human HER-2/neu antigen to evaluate the potential vaccine using dendritic cells (DCs) infected with adenovirus AdVHER-2. We first investigated whether infected DCs (DC(HER-2)) engineered to express HER-2/neu could induce HER-2/neu-specific immune responses. Our data showed that (i) AdVHER2-infected DC(HER-2) expressed HER-2/neu by Western blot and flow cytometric analysis, and (ii) vaccination of mice with DC(HER-2) induced HER-2/neu-specific cytotoxic T-lymphocyte (CTL) responses, but protected only 25% of vaccinated mice from challenge of 3 x 10(5) MCA26/HER-2 tumor cells. Further, to enhance the efficacy of DC(HER-2) vaccine, we coinfected DCs with both AdVHER-2 and AdVTNF-alpha. The infected DCs (DC(HER-2/TNF-alpha)) displayed the expression of both HER-2/neu and TNF-alpha by flow cytometric and ELISA analysis. We next investigated whether DC(HER-2/TNF-alpha) could induce stronger HER-2/neu-specific immune responses. We found that DC(HER-2/TNF-alpha) displayed up-regulation of immunologically important CD40, CD86, and ICAM-I molecules compared with DC(HER-2), indicating that the former ones are more mature forms of DCs. Vaccination of DC(HER-2/TNF-alpha) induced stronger allogeneic T-cell proliferation and 36% enhanced HER-2/neu-specific T-cell responses in vitro than DC(HER-2) cells. More importantly, it stimulated the significant anti-HER-2/neu immunity in vivo, which protected 8/8 mice from challenge of 3 x 10(5) MCA26/HER-2 tumor cells. Therefore, DCs genetically engineered to express both the tumor antigen and cytokines such as TNF-alpha as an immunoadjuvant are likely to represent a new direction in DC vaccine of cancer.     

Benign cervical thymoma masquerading as a malignant thyroid nodule

A thymoma in the neck region is a rare diagnosis involving a solitary neck nodule that moves with deglutition and is contiguous with the thyroid gland. The authors report an unusual case of a thymoma that accumulated both Tc-99m pertechnetate and Tc-99m MIBI. This is probably the first reported case of a benign neck thymoma concentrating these two radiopharmaceuticals. Thymoma should be added to the gamut of false-positive findings in the neck for thyroidal (with Tc-99m pertechnetate) and malignant (with Tc-99m MIBI) tissue.