Immunization for hepatocellular carcinoma

The importance of duodenogastro-oesophageal reflux (DGOR) in gastro-oesophageal reflux disease (GORD) is controversial. Most evidence points to a possible synergistic effect between refluxed acid and bile, which may be more frequent in patients with Barrett's oesophagus, particularly those with complications. Techniques for long-term measurement of DGOR include continuous aspiration, which is cumbersome and laborious, ambulatory spectrophotometric bilirubin measurement as a proxy for bile acids and sodium ion measurement using a sodium electrode. The two latter are the most promising techniques which are improving understanding of DGOR in clinical situations. Both have advantages and drawbacks. The Bilitec system for measuring bilirubin has been most studied and has been well validated. The sodium electrode has so far only been used for short-term monitoring but may be capable of development into a practical tool for longer-term monitoring of DGOR.     

Erythropoietin in hepatocellular carcinoma

Hemopoietic alterations may occur during tumoral diseases, determining anemia. In most cases, serum EPO levels were lower than normal values. Hepatocellular carcinoma (HCC), one of the most frequent malignancies world-wide, is often characterized by mild anemia and increased serum EPO levels. We studied 30 HCC patients and 20 healthy subjects. We found that HCC patients presented higher serum EPO levels than healthy controls. In HCC patients, there was a significant inverse correlation between serum EPO levels and red blood cell count or hemoglobin levels. We postulated that the elevated serum EPO levels observed in these patients may be due to reduced hepatic clearance of EPO, and to the influence of cytokine-mediated inflammatory factors.     

Non-surgical treatment of hepatocellular carcinoma

A decade ago, surgery was the only satisfactory treatment modality for hepatocellular carcinoma (HCC), but it was limited only to selected cases. For the majority of cases of HCC, systemic chemotherapy was one of the few treatment alternatives, but provided only marginal benefit. In the past 20 years, diagnostic methods have improved to an extent that small HCC less than 1 cm can be detected. Moreover, non-surgical treatment is available, of which regional therapy has been shown to prolong patients' survival, and may even replace surgical resection in some cases. Regional therapy is indicated for the treatment of HCC when there is no extrahepatic metastasis and the patient has adequate liver function reserve, thus permitting repeated therapy. Transcatheter hepatic arterial embolization (TAE) using various embolizers has been well documented to include controlled studies. However, it is not indicated for patients with thrombosed main portal veins. Its therapeutic effect is also doubtful when the tumour is infiltrative in nature or is hypovascular, too large or too small. Additional chemotherapeutic agents mixed into the embolizer with lipiodol and degraded starch microspheres or styrene-maleic acid-neocarzinostatin in which chemotherapeutic agents are embedded, are used with a better response, but the survival rate has not shown significant improvement. Ultrasound-guided local injection therapy is another new method of treatment of HCC. Of these techniques, percutaneous ethanol injection therapy (PEIT) is widely used with excellent results for small, encapsulated tumours in livers with less than three HCC. Percutaneous ethanol injection therapy can also be used in cases with portal vein thrombosis, but it is not suitable for patients having coagulopathy or ascites. Using acetic acid, OK-432, interferon or anti-cancer drugs in the injection therapy shows no further benefit over ethanol alone. Transcatheter echoguided thermotherapy or cryotherapy has been reported in small series of patients, as has target therapy with immune or radiotherapy and conformal radiotherapy. Preliminary studies show encouraging results. Systemic therapy with either single drug or multidrugs is ineffective, with a response rate of less than 20%. Immunotherapy, such as with interferon or other cytokines, is not beneficial. Hormone therapy has not been promising, except for treatment with tamoxifen, which has been reported to show some beneficial effect. Gene therapy is still in its infancy. In summary, recent progress in non-surgical treatment of HCC has resulted in a breakthrough of regional therapy looking quite promising. Moreover, a combination of different types of regional therapies may yield better outcomes in selected individuals.     

Multidisciplinary management of hepatocellular carcinoma

BACKGROUND/AIMS: The continuing poor prognosis for patients with hepatocellular carcinoma drives a search for new adjuvant therapies. Targeted locoregional immuno-chemotherapy is one of the most promising. MATERIALS AND METHODS: From 1990 to 1996, 193 patients who were not eligible for liver resection were treated in a prospective randomized study. Ninety-one patients received locoregional targeted chemotherapy only via an arterial catheter (Group A), and 102 received combined locoregional immuno-chemotherapy via two arterial catheters (Group B). RESULTS: Overall survival was significantly different (10.2 months vs 22.3 months), favoring Group B. Complications and side effects of treatment were minimal in Group B and easily handled. Even in Group A, side effects were less severe than effects normally associated with systemic chemotherapy. CONCLUSIONS: Even though the current prognosis for patients with Hepatocellular Carcinoma remains poor, targeted locoregional immuno-chemotherapy has proven to be of benefit in terms of quality of life and survival.     

Therapy of vulvar carcinoma

In this study we report on the establishment of novel conditions which permit efficient retrovirus-mediated gene transfer of human adenosine deaminase (ADA) into murine hematopoietic progenitors. Using Southern blot analysis and an ADA probe, we demonstrated that prestimulation of bone marrow cells over an in vitro culture of adherent stromal cell layers (ACLs) for two days provides favorable conditions for gene transfer in the absence of exogenous growth factors. In bone marrow transplant recipients reconstituted with retrovirally-marked cells, ADA was detected in spleen, thymus and bone marrow cells of the recipients eight months after transplantation. These observations were also seen in transplants of embryonal hematopoietic stem cells. By using different incubation protocols, it was found that the developmental fate of hematopoietic stem cells varied with the presence of exogenous growth factors or an ACL in the prestimulation phase. Polyclonal hematopoiesis with multiple clones appearing simultaneously was revealed in mice reconstituted with growth factor-stimulated cells four months after transplantation. This was detected by multiple integration patterns of ADA integration into the genomes of individual colony forming units-spleen (CFU-S) in transplantation recipient mice. In contrast, two to five months after transplantation, polyclonal hematopoiesis was not observed in mice reconstituted with cells infected in the absence of growth factors. It appears that utilization of the bone marrow microenvironment through the use of an ACL results in a narrower spectrum of integration patterns, suggesting that a type of oligoclonal or monoclonal hematopoiesis is occurring. These studies demonstrate that an ACL provides novel conditions for successful gene transfer and stable integration of the vector into the genome. Use of an ACL may be advantageous for successful hematopoietic stem cell gene therapy.     

Liver transplantation for hepatocellular carcinoma

Liver transplantation (LT) for hepatocellular carcinoma (HCC) has been controversial, however, with increasing experience the results of the procedure in these patients have improved. Earlier reports of poor result may have been secondary to advanced tumor and poor patient selection. Careful patient selection and preoperative assessment of tumor characteristic is essential before offering LT to these patients. Results of LT in carefully selected cases may be similar to patients receiving LT for other reasons. In cirrhotic patients LT may offer a better long-term survival than liver resection.     

Early detection of recurrent hepatocellular carcinoma

BACKGROUND/AIMS: Early detection and treatment of recurrent hepatocellular carcinoma (HCC) are keys to patient survival after hepatic resection. In attempts at early detection, we make use of the alpha-fetoprotein (AFP) test every month and abdominal ultrasound (US) and computed tomography (CT) are carried out every three months after hepatectomy. The objective of the present study was to evaluate the most appropriate interval for follow-up re-examinations after resection for HCC. PATIENTS AND METHODS: Eighty-five patients with recurrent HCC were divided into two groups according to the state of the tumor when recurrence was detected: Group I (n = 70); tumor size < or = 2.0 cm, and group II (n = 15); tumor size > or = 2.1 cm. Clinicopathological comparisons were made between the two groups. RESULTS: AFP positivity in group I was significantly lower than group II at the time of recurrence. Rates of extrahepatic intra-abdominal recurrences, i.e. recurrence at the surgical stump and in the abdominal cavity and lymph nodes around the liver, were more frequent in group II than in group I (47% vs 4%; p < 0.001). The average tumor size was larger in 10 patients with extrahepatic intra-abdominal recurrence than in 75 patients with intrahepatic recurrence (3.4 +/- 2.0 vs 1.6 +/- 0.6 cm; p < 0.0001). There was a statistically significant difference regarding the histological grade of initial HCC between the two patterns of recurrence. CONCLUSIONS: Measurements of AFP were seen to have limited value for detecting recurrence, at an early stage. Close postoperative follow-up, including bedside US in the outpatient clinic, should be carried out when the initial HCC is histologically less differentiated HCC.     

Transient spontaneous regression of hepatocellular carcinoma

We report on 2 patients with liver cirrhosis and biopsy-proven hepatocellular carcinoma who underwent spontaneous regression. In 1 case the tumor became undetectable at ultrasonography, while, in the other, the liver lesions decreased in size and showed inner calcifications. In both patients, alpha-fetoprotein, which was high at first diagnosis, returned to normal values. After a tumor-free period of 4 years and 17 months, respectively, liver cancer reappeared and patients died from complications. We advance the hypothesis that tumor regression, when it occurs in cirrhotic patients, is always transient, with chronic liver disease being the oncogenic triggering factor.     

Noradrenaline-assisted selective chemoembolization of hepatocellular carcinoma

Despite the postulated tumour affinity of Lipiodol is liver dysfunction after chemoembolization of hepatic malignancies common. Vasoconstricting action of noradrenaline to protect non malignant tissue was studied. 70 patients with unresectable HCCs (UICC IV: 61%) were treated via percutaneous catheter. After noradrenaline (0.1-0.8 mg) induced and documented vessel constriction a suspension of Lipiodol (5-8 ml) and Mitomycin C (10-20 mg) was injected. In addition minced dehydrated dura suspended in Lipiodol occluded the major tumour feeding vessels. 120 (73%) of a total of 164 chemoembolizations were performed after intrahepatic noradrenaline (0.1-0.8 mg) bolus injection. Arterial perfusion of non malignant liver parenchyma was significantly reduced in 95%. 24 hours later selective tumor retention of lipiodol was noticed in 67%. Side effects were fever (79%), thoracoabdominal pain (67%), nausea and emesis (43%) and tachycardia (15%). There were two treatment related deaths: one each from liver failure and cardiac arrest. By WHO response criteria there were 17 (23%) partial remissions (PR), 34 (49%) stable diseases (SD) and 20 (28%) patients had progression (PD). The median survival time from initiation of treatment was 312 days. Bilobal and multiple tumors reduced survival time (90 days). These findings suggest that noradrenaline guided chemoembolization is feasible in Europe and even in patients with pylethrombosis well tolerated.     

Comprehensive allelotyping of human hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most common cancers in many parts of the world, however the molecular mechanisms underlying liver cell transformation remain obscure. A genome-wide scan of loss of heterozygosity (LOH) in tumors provides a powerful tool to search for genes involved in neoplastic processes. To identify recurrent genetic alterations in liver tumors, we examined DNAs isolated from 120 HCCs and their adjacent non tumorous parts for LOH using a collection of 195 microsatellite markers located roughly every 20 cM throughout 39 autosomal arms. The mean heterozygosity was 73%. Our findings provide additional support that LOH for loci on chromosomal arms 1p, 4q, 6q, 8p, 13q and 16p is significantly elevated in HCC. The highest percentage of LOH is found for a locus in 8p23 (42% of informative csaes). This corresponds to one of the most common genetic abnormalities reported to date in these tumors. In addition, high ratio of LOH (> or = 35%) is observed on chromosome arms which had not been implicated in previous studies, notably on 1q, 2q and 9q. No correlation was found between LOH of specific chromosomal regions and etiologic factors such as chronic infections with hepatitis B or C viruses. This first report of an extensive allelotypic analysis of HCC should help in identifying new genes whose loss of function contributes to the development of liver cancer.