A case of HCC with inferior caval vein tumor thrombus and multiple pulmonary metastases that remarkably responded to combination therapy of TS-1 and interferon-alpha

A 56-year-old male was admitted to our hospital for hepatoma with portal vein thrombus and multiple intrahepatic metastases. He underwent an extended left lobectomy and a partial resection of the liver in May 2002. After two weeks from the surgery, he received intra arterial 5-FU infusion chemotherapy combined with subcutaneous interferon-alpha injection to treat the lesions in the residual liver. Four months after the surgery, hepatic vein tumor thrombus appeared in the remnant liver and it extended to the inferior caval vein. And another 4 months later, multiple pulmonary metastases were detected with computed tomography and they grew rapidly in the view of their sizes and numbers. Because the combined therapy of 5-FU/interferon-alpha was not effective to distant metastases, we started a new regimen of oral administration of TS-1 and a subcutaneous interferon-alpha injection. After 1 treatment cool, hepatic vein thrombus was markedly reduced the size and vascularity in the CT. Multiple pulmonary metastases also decreased in their sizes and numbers. No adverse effect was seen during this treatment. It was suggested that a combination therapy of TS-1 and interferon-alpha may be one of the most effective treatment modalities against advanced HCC with distant metastasis.     

Successful treatment of combined intraarterial (5-fluorouracil and adriamycin and cisplatin) infusion chemotherapy for advanced hepatocellular carcinoma with multiple intrahepatic metastases and/or portal vein thrombosis--two case reports

Hepatic arterial infusion chemotherapy has been often selected as a therapeutic option for advanced hepatocellular carcinoma with multiple intrahepatic metastases and/or portal vein thrombosis. We successfully treated and obtained CR in the 2 cases of far advanced hepatocellular carcinoma with intraarterial infusion chemotherapy (FAP). Case 1 was a 71-year-old male who had advanced hepatocellular carcinoma with intrahepatic metastasis (IM3) which was recurrent after two surgeries. He received hepatic arterial infusion chemotherapy (FAP: 5-fluorouracil 500 mg/day: continuous infusion, day 1-5, adriamycin 10 mg/day, day 1, CDDP 10 mg/day, day 1). After 10 courses, abdominal CT revealed that the viable lesions had completely disappeared (CR). This patient is still alive with no recurrence after 21 months from the beginning of this treatment. Case 2 was a 74-year-old male who had advanced hepatocellular carcinoma with portal vein thrombi (Vp4) and intrahepatic metastasis (IM3). He received FAP arterial infusion chemotherapy with the same protocol as case 1. After 8 courses of this therapy, CT revealed that these lesions had disappeared (CR). This patient is still alive with no recurrence after 9 months from the beginning of this treatment. For 15 patients with advanced hepatocellular carcinoma using a same protocol, the response rate of this therapy was 33.3% (CR & PR). These findings suggested that combined arterial infusion chemotherapy of FAP may be feasible and a promising modality for the advanced HCC with intrahepatic metastases and/or portal vein thrombosis.     

Thymic cancer effectively treated by combination chemotherapy of carboplatin and etoposide with concurrent radiotherapy

A 63-year-old man was admitted to our hospital for acute heart failure. A chest CT scan revealed a large anterior mediastinal mass and pericardial effusion. Percutaneous needle biopsy showed that the mass was an advanced thymic cancer (squamous cell carcinoma). The patient was treated by combination chemotherapy of carboplatin and etoposide with concurrent radiotherapy (44 Gy). There was no severe toxicity except for grade 4 neutropenia. After 3 courses of chemotherapy, the mass showed an approximately 81% reduction in tumor size and disappearance of the pericardial effusion. Finally, the thymic cancer and small pulmonary metastatic lesions were all resected. This concurrent chemoradiotherapy can be effective against inoperable squamous cell carcinoma of the thymus.     

Gene testing of hereditary cancer on comprehensive gene medical examination support system

It has been estimated that genetic factors or a combination of genetic and environmental factors play a role in the development of 10-15% of all cancers. A genetic cause of hereditary cancer has been identified in more than 40 diseases till now. For preventing this cancer, gene testing is essential because it has no definite clinical marker as in hereditary non-polyposis colorectal cancer: HNPCC. Much more experience must be accumulated in this testing at the clinical base in order to increase specificity and sensitivity while safeguarding ethical, legal and social issues (ELSI). Recently, the Personal Information Protection Law was enforced. Gene inspection involving hereditary cancer should be carried out under a comprehensive gene medical examination organization. It is important for the family doctor, medical specialist, and gene inspection person in charge to cooperate closely with one another, and this will be a subject of future study.     

Apoptosis induced by 5-fluorouracil, cisplatin and paclitaxel are associated with p53 gene status in gastric cancer cell lines

In a recent study, we evaluated the efficacy and toxicity of 5-fluorouracil (5-FU), cisplatin (CDDP), and 5-FU plus CDDP (FP treatment) in gastric cancer cell lines and examined the relationship between the response to FP treatment and apoptosis. Our study indicated that there may be prognostic value in measuring p53 prior to FP treatment, and that cancers with wild-type p53 may be better candidates for FP treatment than those with mutant-type p53 in gastric cancer patients. In the present study, because cells with mutant-type p53 are suggested to be less responsive to FP chemotherapy treatment, we examined the relationship between the response to paclitaxel and apoptosis in MKN45 and MKN28 human gastric cancer cell lines by flow cytometry. In both MKN45 and MKN28 cells, paclitaxel arrested cells in the G2/M phases of the cell cycle after 24 h. Additionally, in both MKN45 and MKN28 cells, paclitaxel produced a significant rise in the number of subG1-phase cells after 72 h by the flow cytometry histogram. From these results, our previous study suggests that cells with mutant-type p53 may be less responsive to FP treatment and the present study indicates that another anti-cancer drug like paclitaxel, which might be mediated by a p53-independent pathway, should be selected. These insights may provide a new strategy for gastric cancer chemotherapy, especially second-line chemotherapy or adjuvant chemotherapy.     

Gonadotropin-releasing hormone retards doxorubicin-induced apoptosis and serine/threonine phosphatase inhibition in ovarian cancer cells

We recently demonstrated serine/threonine phosphatase (protein phosphatase 2A, PP2A), a crucial enzyme in apoptosis control, within the plasma membrane as well as soluble fraction. This study aimed to determine whether gonadotropin-releasing hormone (GnRH) affects the membrane PP2A-associated apoptosis and the enzyme activity in ovarian cancer cells. PP2A activity was assessed by measuring the dephosphorylation of phosphopeptide highly selective for the PP2A in plasma membranes isolated from ovarian cancer SK-Ov-3 and Caov-3 cells. Apoptosis was quantified by nuclear morphology after staining with Hoechst 33342 and by loss of plasma membrane phospholipid asymmetry using Cy3-conjugated annexin-V. Treatment with doxorubicin (1 microM) for 48 h caused parallel increases in the percentage of cells undergoing apoptosis (71.3+/-5.5% vs. 2.2+/-0.8% for control, P<0.01) and decrease in the membrane-associated PP2A activity (to 38.5+/-8.2% of control, P<0.01). In cells simultaneously incubated with GnRH agonist leuprolide (1 microM) for 48 h, the maximum doxorubicine-induced apoptosis and membrane PP2A inhibition were reduced to 38.4+/-6.2% (P<0.01) and to 82.1+/-7.3% of control (P<0.01), respectively. The GnRH agonist alone caused apoptotic cell death accounting for only 6.8+/-2.1% (P<0.01) and had no effect on membrane PP2A activity. These findings demonstrate that PP2A inhibition is closely coupled to the onset of apoptosis in ovarian cancer cells exposed to doxorubicin. GnRH agonist may protect against the inhibition of membrane-associated PP2A activity and thus retard doxorubicin-induced apoptosis, suggesting an additional activity of GnRH to protect ovarian cancer cells from stimulated apoptotic cell death.     

The extending range of the tumor is a more suitable predictive risk factor for lymph node metastases than the location of the deepest tumor invasion in distal thoracic esophageal and cardiac cancer

In the regional lymph node grouping of esophageal cancer by the Japanese Guide Line (the 9th edition), the location of the deepest tumor invasion has precedence in determination. In this study, we investigated the extending range of the tumor and the location of the deepest tumor invasion to ascertain which was the more important factor in predicting lymph node metastases. We examined 52 patients with distal thoracic esophageal and cardiac cancer who had undergone esophagectomy with three-field lymph node dis-section. Among the 52 patients, 16 were found to be positive and 36 negative, for middle-upper mediastinum and cervical lymph node metastases, and the two groups were compared in terms of detailed parameters of the tumor's location. In the result, the distance from the esophagogastric junction (EGJ) to the proximal margin of the tumor was significantly longer in the metastatic group (p=0.005). In univariate logistic regression with this parameter as the independent variable, we obtained a statistically significant result (p=0.0115, odds ratio=1.041, 95% confidence interval=1.009-1.073, R2=0.1169). On the other hand, when the distance from the EGJ to the deepest portion of the tumor was used as the independent variable, p=0.0742, odds ratio=1.045, 95% confidence interval=0.996-1.096 and R2=0.0577. Multiple logistic regression was performed with these two parameters, and the distance from the EGJ to the proximal margin of the tumor was a more important factor than the distance from the EGJ to the deepest portion of the tumor (p=0.0553 vs. 0.9161). We concluded that the extending range of the tumor was a more suitable predictive risk factor of lymph node metastases than the location of the deepest tumor invasion in distal thoracic esophageal and cardiac cancer. We should seriously consider the extending range of the tumor in the regional lymph node grouping of the Japanese Guide Line.     

The modifier subunit of glutamate cysteine ligase relates to cisplatin resistance in human small cell lung cancer xenografts in vivo

Glutamate cysteine ligase (GCL) plays an important role in the intracellular detoxification of cisplatin (CDDP). GCL is composed of a modifier or light chain subunit (GCLM) and a catalytic or heavy chain subunit (GCLC). Previously, we showed that the GCL subunits enhanced CDDP-resistance in non-small cell lung cancer (NSCLC) xenografts. In small cell lung cancer (SCLC), it is unclear whether the GCL subunits are essential to CDDP-resistance. We examined the gene expression of GCLM and GCLC in four human SCLC xenografts with the real-time polymerase chain reaction (PCR). An in vivo drug sensitivity test with CDDP was performed on the SCLC xenografts. CDDP-resistance was examined as the growth ratio of the relative volume of the treated xenografts to the controls (T/C%). The expression level of GCLM gene in SCLC was significantly lower than that in NSCLC (p=0.0026, Welch's t-test). One of four SCLC xenografts showed 62% of T/C and this was evaluated as CDDP-resistance, while the other three xenografts were sensitive to CDDP in vivo (Mann-Whitney U-test, p<0.01, one-sided). The expression level of the GCLM gene was significantly correlated to T/C% (Fisher's test, p=0.0289, correlations = 0.975), while the GCLC gene expression level was not associated with T/C%. These results suggest that the overexpression of GCLM is correlated with CDDP-resistance in SCLC xenografts in vivo.     

Efficacy of lamivudine therapy for decompensated liver cirrhosis due to hepatitis B virus with or without hepatocellular carcinoma

The prognosis for patients with decompensated hepatitis B virus (HBV) related liver cirrhosis (LC-B), especially for those with LC-B complicated with hepatocellular carcinoma (HCC), is poor. We investigated the effects of lamivudine in patients with decompensated LC-B, with and without HCC. Decompensated LC-B patients (n=55) with Child-Pugh classification scores (CPS) >7 points were enrolled. All were admitted to the hospitals of the authors between January 1997 and December 2004. Decompensated cases due to a severe exacerbation of hepatitis with CH-B and patients with HCC showing an extra hepatic metastasis or portal vein tumor thrombus were excluded. Some 19 cases (including 5 cases complicated with HCC at the start of therapy) were treated with lamivudine at 100 mg/day (L group), and 36 (including 7 cases with HCC at time of admittance) were treated without lamivudine (non-L group). The median of CPS points in the L group was higher than that of non-L group (11 points versus 9 points, p<0.02). Prothrombin time (%), albumin, ascites, CPS, and HBV-DNA quantity were each significantly improved after 6 months in the L group (p<0.05). A mutation in the YMDD motif was observed in 5 patients in the L group, however liver function did not deteriorate. Further, the survival rate was significantly higher in the L group (p<0.05). HCC was found in 3 L group and 4 non-L group patients during the study. In the L group, all patients complicated with HCC were treated repeatedly or until cured, whereas 91% of those in the non-L group could not be treated (p<0.01). Our results suggest that lamivudine is a useful and important therapy for patients with decompensated LC-B with and without HCC, as well as those who are restricted from having liver transplantation.