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.     

A case report of complete obstruction of the left main bronchus caused by recurrent esophageal carcinoma with pulmonary embolism of right lung after surgery for esophageal cancer

A 54-year-old woman complained of dyspnea, due to complete obstruction of the left main bronchus caused by recurrent esophageal carcinoma, was transferred to our department about two months after curative resection (with preoperative chemotherapy for T4 cancer) in July 2004. She suddenly developed a severe shortness of breath with anxiety, and arterial blood gas analysis revealed a PaO2 of 25 mmHg (FiO2 1.0). The presence of pulmonary embolism was diagnosed by pulmonary perfusion scintigraphy. Thrombolytic therapy with urokinase was started to keep the air way. Fogarty catheter and bronchoscopic Nd-YAG laser treatment was performed. After that, an expandable metallic stent (EMS) was placed at the site of obstruction without any troubles, and there was a striking improvement in her condition of respiration and atelectasis. The radiation therapy was initiated and completed safely. The tumor lesion had disappeared on CT scan after the radiation therapy (a total dose of 50 Gy). We experienced a case that could be rescued from an advanced respiratory failure caused by one side air way obstruction and another side's blood circulation disorder.     

Enhancement of cytotoxicity of NK cells by D-Fraction, a polysaccharide from Grifola frondosa

In innate immunity, activated natural killer (NK) cells attack and damage pathogens such as bacteria and virus without restriction by the MHC antigen. NK cells activated by IL-12 have been reported to recognize and kill tumor cells in perforin-mediated apoptosis. We have reported that D-Fraction, a polysaccharide extracted from the maitake mushroom (Grifola frondosa), activates macrophages, dendritic cells, and T cells and inhibits the growth of tumor cells. However, the effects of D-Fraction on NK cell function in the innate immune response are not well known. In the present study, we administered D-Fraction to MM-46 mammary tumor-bearing C3H/HeJ mice intraperitoneally for 3 consecutive days and investigated its effects on the activation and cytotoxicity of NK cells. D-Fraction significantly enhanced the cytotoxicity against NK-sensitive YAC-1 cells and the expression of CD223 on NK cells. D-Fraction also increased the expression of CD86 on macrophages. In addition, the levels of IL-12 in the culture supernatant of whole spleen cells and in serum increased, compared with the control corresponding to an increase in expression of IL-12 receptor betaI on NK cells. These results suggest that D-Fraction enhances the cytotoxicity of NK cells through the production of IL-12 by macrophages activated by D-Fraction.     

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.     

Determination of cellularly processed HLA-A2402-restricted novel CTL epitopes derived from two cancer germ line genes, MAGE-A4 and SAGE.

PURPOSE: For identification of CTL epitopes useful for cancer vaccines, it is crucial to determine whether cognate epitopes are presented on the cell surface of target cancer cells through natural processing of endogenous proteins. For this purpose, we tried to use the cellular machinery of both mice and human to define naturally processed CTL epitopes derived from two "cancer germ line" genes, MAGE-A4 and SAGE. EXPERIMENTAL DESIGN: We vaccinated newly produced HLA-A2402 transgenic mice with DNA plasmids encoding target antigens. Following screening of synthesized peptides by splenic CD8(+) T cells of vaccinated mice, we selected candidate epitopes bound to HLA-A2402. We then examined whether human CD8(+) T cells sensitized with autologous CD4(+) PHA blasts transduced by mRNA for the cognate antigens could react with these selected peptides in an HLA-A2402-restricted manner. RESULTS: After DNA vaccination, murine CD8(+) T cells recognizing MAGE-A4(143-151) or SAGE(715-723) in an HLA-A2402-restricted manner became detectable. Human CTLs specific for these two peptides were generated after sensitization of HLA-A2402-positive CD8(+) T cells with autologous CD4(+) PHA blasts transduced with respective mRNA. CTL clones were cytotoxic toward tumor cell lines expressing HLA-A2402 and cognate genes. Taken together, these CTL epitopes defined in HLA-A24 transgenic mice are also processed and expressed with HLA-A2402 in human cells. The presence of SAGE(715-723)-specific precursors was observed in HLA-A2402-positive healthy individuals. CONCLUSIONS: Two novel HLA-A2402-restricted CTL epitopes, MAGE-A4(143-151) and SAGE(715-723), were identified. Our approach assisted by cellular machinery of both mice and human could be widely applicable to identify naturally processed CTL epitopes.     

Prediction of early and late recurrence in patients with breast carcinoma

BACKGROUND: The clinical course of patients with recurrent breast carcinoma varies greatly. Better characterization of an individual's clinical course for recurrent patients may aid in their clinical management. However, less attention has been paid to evaluating factors associated with the timing of recurrence in those patients. We investigated the clinicopathological indicators that determined the timing of recurrence by univariate and multivariate analysis. METHODS: We retrospectively examined data on 1428 curatively treated Japanese patients who had been surgically treated for breast cancer between 1983 and 2002. From these, 244(17.1%)who had clearly died of recurrence were entered into this study. RESULTS: By univariate analysis, tumor size, estrogen receptor(ER), and progesterone receptor(PgR)were significantly correlated with time to recurrence. Multivariate analysis indicated that the time between operation and recurrence was independently influenced by ER and PR. CONCLUSIONS: Our research shows that ER and PgR are independent factors influencing the timing of recurrence of breast carcinoma after curative resection. The combined analysis of these independent factors facilitates prediction of the time to recurrence for each patient.     

Species differences in the tissue distribution of catechol and methylsulphonyl metabolites of 2,4,5,2',5'-penta- and 2,3,4,2',3',6'-hexachlorobiphenyls in rats, mice, hamsters and guinea pigs

Polychlorinated biphenyls (PCBs) are metabolized to phenolic or methylsulphonyl PCBs (MeSO(2)-CBs) in animal species. The study determined the species differences in the tissue distribution of persistent PCB metabolites in rats, mice, hamsters and guinea pigs 4 days after exposure to 2,4,5,2('),5(')-pentachlorobiphenyl (CB101) or 2,3,4,2('),3('),6(')-hexachlorobiphenyl (CB132). For CB101 metabolism, the hydroxylation in rats, mice and hamsters occurred primarily at the 3(')-position in the 2('),5(')-dichlorinated phenyl ring, whereas the hydroxylation in guinea pigs occurred preferentially at the 3-position. Metabolite profiles in tissues of hamsters were dominated by 3('),4(')-catechol-CB101, whereas metabolite profiles in rats and mice were dominated by 3(')- or 4(')-MeSO(2)-CBs. For CB132 metabolism, rats and mice produced 4(')- and 5(')-MeSO(2)-CBs at similar concentration ratios, whereas guinea pigs produced MeSO(2)-CBs at higher levels and selectively retained 5(')-MeSO(2)-CB in liver. In contrast, hamsters preferentially produced 4('),5(')-catechol-CB132 that was retained in serum. Consequently, hamsters produced catechols, whereas guinea pigs produced meta-substituted MeSO(2)-CBs, preferentially from CB132. These findings indicate that PCBs with 2,3,6-chlorine substitution are preferred substrates for the formation of catechols or MeSO(2)-CBs and the differences in metabolite profiles are related to species-dependent metabolic capacities.