Advanced HCC: emerging molecular therapies.

Hepatocellular carcinoma (HCC) is a common complication of chronic liver disease and represents the third-leading cause of death world-wide. While the majority of cases occur in Asia, the incidence has been rising in the West for some time. This is driven not only by the Hepatitis C epidemic but also the rising incidence of non-alcoholic steatohepatitis and resulting liver disease. Despite its frequency, treatments for HCC have generally been limited. Curative treatments are limited to surgical resection or liver transplant for a subset of patients and locally ablative techniques such as radiofrequency ablation (RFA) and trans-arterial chemoembolization (TACE) have been shown to extend survival for patients with unresectable and intermediate stage liver cancer. For patients with advanced HCC, sorafenib, a small molecule multitargeted kinase inhibitor is the only agent that has been shown to improve survival. At this time there is an abundance of research activity in HCC with an emphasis on developing new agents that target specific molecular alterations in HCC. In this review, we will focus on those agents currently in Phase III studies for front-line, second-line and other indications.

Apparent remission of a solitary metastatic pulmonary lesion in a liver transplant recipient treated with sorafenib.

Hepatocellular carcinoma (HCC) remains a significant disease worldwide and its incidence is expected to increase. In selected patients, liver transplantation offers a 5-year patient survival between 48% and 75%. However, HCC recurrence occurs in approximately 20% of transplant recipients. No therapy has proven efficacious in decreasing the risk of recurrence after transplantation. Sorafenib, a multitargeted tyrosine kinase inhibitor, has been shown to improve survival in patients with advanced HCC that have no history of liver transplantation. We report complete remission of HCC in a 54-year-old man who developed biopsy-proven lung metastasis after liver transplantation treated with sorafenib.

N7: a novel multi-modality therapy of high risk neuroblastoma (NB) in children diagnosed over 1 year of age.

BACKGROUND: The N7 protocol for poor-risk neuroblastoma uses dose-intensive chemotherapy (as in N6 protocol [Kushner et al.: J Clin Oncol 12:2607-2613, 1994] but with lower dosing of vincristine) for induction, surgical resection and 2100 cGy hyperfractionated radiotherapy for local control, and for consolidation, targeted radioimmunotherapy with 131I-labeled anti-GD2 3F8 monoclonal antibody and immunotherapy with unlabeled/unmodified 3F8 (400 mg/m2). PROCEDURE: The chemotherapy consists of: cyclophosphamide 70 mg/kg/d x 2 and a 72-hr infusion of doxorubicin 75 mg/m2 plus vincristine 2 mg/m2, for courses 1, 2, 4, and 6; and cisplatin 50 mg/m2/d x 4 and etoposide 200 mg/m2/d x 3, for courses 3, 5, and 7. 131I-3F8 is dosed at 20 mCi/kg, which is myeloablative and therefore necessitates stem-cell support. RESULTS: Of the first 24 consecutive previously untreated patients more than 1 year old at diagnosis, 22 were stage 4 and two were unresectable stage 3 with MYCN amplification. Chemotherapy achieved CR/VGPR in 21 of 24 patients. Twenty patients to date have completed treatment with 131I-3F8, and 15 patients have completed all treatment. With a median follow-up of 19 months, 18 of 24 patients remain progression-free. CONCLUSIONS: Major toxicities were grade 4 myelosuppression and mucositis during chemotherapy, and self-limited pain and urticaria during antibody treatment. Late effects include hearing deficits and hypothyroidism.

Positron emission tomography imaging for herpes virus infection: Implications for oncolytic viral treatments of cancer.

Molecular therapy using viruses would benefit greatly from a non-invasive modality for assessing dissemination of viruses. Here we investigated whether positron emission tomography (PET) scanning using [(124)I]-5-iodo-2'-fluoro-1-beta-d-arabinofuranosyl-uracil (FIAU) could image cells infected with herpes simplex viruses (HSV). Using replication-competent HSV-1 oncolytic viruses with thymidine kinase (TK) under control of different promoters, we demonstrate that viral infection, proliferation and promoter characteristics all interact to influence FIAU accumulation and imaging. In vivo, as few as 1 x 107 viral particles injected into a 0.5-cm human colorectal tumor can be detected by [(124)I]FIAU PET imaging. PET signal intensity is significantly greater at 48 hours compared with that at 8 hours after viral injection, demonstrating that PET scanning can detect changes in TK activity resulting from local viral proliferation. We also show the ability of FIAU-PET scanning to detect differences in viral infectivity at 0.5 log increments. Non-invasive imaging might be useful in assessing biologically relevant distribution of virus in therapies using replication-competent HSV.

Factors that affect the uptake of ammonia by the brain: the blood-brain pH gradient.

The brain uptake index (BUI) for [13N]ammonia was measured in 7 areas of the rat brain at 8 different pH values ranging from 6.58 to 7.73. When the regional BUI was plotted as a function of the pH of the test bolus, a significant linear correlation was found for each region (P less than 0.001). The highest slope was observed in the thalamus-basal ganglia complex (0.392 +/- 0.018) (S.D.), and the lowest in the ventral pons (0.143 +/- 0.011). These studies indicate that the brain-blood pH gradient plays a major role in determining the forward flux of ammonia from the blood into the brain in the physiological pH range. Regional differences in the slope may be due to metabolic factors. This pH effect may be important in clinical conditions characterized by hyperammonemia such as hepatic encephalopathy, and in the interpretation of [13N]ammonia emission tomographic images of the brain.

"Food allergy": Fact or Fiction?

Six patients with longstanding physical and mental symptoms who had not been helped by many years of conventional medical investigation and treatment experienced immediate relief of symptoms when they avoided certain foodstuffs. This clinical study supports the view that some foods may cause widespread and disabling symptoms in people who are sensitive to them.

Possible role of laxatives in analgesic nephropathy.

Eight out of ten of patients with analgesic nephropathy were regular and usually heavy laxative takers compared with 12 out of 200 controls from the general population and four out of 70 patients attending a renal clinic. The finding that regular laxative taking was greatly increased in patients with analgesic nephropathy suggests that this condition may often be due to the combined abuse of both laxatives and analgesics. In a series of 40 patients with rheumatoid arthritis all were found to have normal renal function and no patient took laxatives regularly. This finding would explain why analgesic nephropathy is so uncommon in patients with rheumatoid arthritis despite the fact that they are regular and heavy analgesic takers.