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.     

Feasibility study of weekly paclitaxel as second-line chemotherapy against 5-FU-refractory gastric carcinoma

The present study investigated the efficacy and feasibility of weekly paclitaxel for advanced/recurrent gastric cancer. Subjects comprised 23 patients with advanced/recurrent gastric cancer who had been treated using a 5-FU-containing regimen. Paclitaxel was administered at a dose of 80 mg/m(2), 3 times every 4 weeks. Dexamethasone, diphenhydramine and ranitidine chloride were given 30 min before paclitaxel as premedication. The mean number of treatment cycles was 6.4 (range, 1-28). Response rate was 40.0% (4/10) with measurable lesions. Among 13 patients without measurable lesions, 3 cases revealed improvements on colonography, 1 case displayed decreased ascites on abdominal computed tomography, and 1 case recovered from disseminated intravascular coagulopathy due to bone metastases. Median survival time was 258 days, and median time to progression was 140 days. Grade 3 leukocytopenia and neutropenia occurred in 13.0% of patients. All non-hematological toxicity was low-grade, including that involving the gastrointestinal system. Weekly paclitaxel appears effective and safe for 5-FU-refractory gastric cancer.     

Two cases of advanced gastric cancer, successfully treated with TS-1/CDDP combination chemotherapy--case report

We reported 2 cases with advanced gastric cancer, successfully treated with TS-1 and CDDP. Case 1 had Type 3 gastric cancer with left supra-clavicular (Virchow) and para-aortic lymph node metastases. Those distant node metastases completely disappeared after two courses of neoadjuvant chemotherapy (NAC) consisting of TS-1/ CDDP, and radical surgery for cure was conducted. The second case had Type 3 carcinoma with peritoneal dissemination. The primary lesion significantly decreased after four courses of the combination chemotherapy. The patient has been alive for 1 year and a half after 14 courses of TS-1/CDDP with stable disease. Significance of TS-1/CDDP in far advanced gastric cancer was discussed.     

The potential of oncolytic virus therapy for pancreatic cancer

The objective of this paper was to review a new category of gene therapy using oncolytic viruses for the treatment of pancreatic cancer. The eligibility and feasibility of oncolytic virus therapy as a novel therapeutic agent against pancreatic cancer are discussed as well as basic research for clinical trials, including a historical perspective and the current status of these novel agents. Even combination therapy, such as surgery with radiation and chemotherapy, has not significantly improved the survival rate of pancreatic cancer. Recently, a clinical trial (phase I and II) using an oncolytic adenovirus, ONYX-015, was completed in patients with pancreatic cancer. The phase II trial yielded beneficial results (tumor reduction or stabilization) in about 50% of the patients. A phase I study of the efficacy of oncolytic herpes viruses, G207, OncoVEX GM-CSF, and 1716 against a variety of tumors has been completed, and G207 is in phase II trials for use against brain tumors. In addition, a phase I trial using the herpesvirus showed good tolerance at all dosages. We discuss the basic scientific principles and current results of the above clinical trials with respect to these oncolytic viruses, and then compare the relative advantages and disadvantages of adenoviruses and herpesviruses as oncolytic agents. We also review the published literature on newly developed oncolytic viruses. The concept of oncolytic therapy has been studied for a century. Recent technological developments have made these oncolytic viruses more tumor-specific by exploiting the tumor cell environments. In addition, these viruses have been reported to increase the immunosusceptibility of the tumor cells, and have been designed to express other genes to increase the susceptibility of tumor cells to other therapeutic agents. Oncolytic virus therapy certainly appears to be a feasible treatment for pancreatic cancer.     

Safe and efficient transgene expression in rat hepatocytes induced by adenoviral administration into the biliary tract

We examined whether retrograde intrabiliary adenoviral administration could induce safe and efficient transgene expression in hepatocytes. We administered recombinant adenovirus carrying a reporter lacZ gene retrogradely into the common bile duct of rats and evaluated the transduction efficiency of the lacZ gene in the liver histochemically by X-gal staining, and also quantitatively by a chemiluminescent reporter gene assay. Retrograde administration of adenovirus into the common bile duct was shown to successfully induce transgene expression in the liver. Although transgene expression induced by intrabiliary adenoviral administration was observed predominantly at periportal areas, a considerable number of cells expressing the transgene were detectable even in lobular and centrilobular areas. Furthermore, histochemical analysis revealed that intrabiliary adenoviral administration resulted in gene transfer into hepatocytes, but not into biliary epithelial cells. Transgene expression in the liver was transient, and pathological and biochemical analyses revealed that hepatic damage caused by intrabiliary adenoviral administration was not substantial. The results demonstrated in the present study suggest that retrograde administration of adenovirus into the common bile duct can induce safe and efficient transgene expression in hepatocytes without causing considerable adverse effects, supporting the feasibility of adenovirus-mediated gene transfer into hepatocytes in clinical settings by means of endoscopic retrograde cholangiography.     

Adenovirus-mediated gene transfer into rat livers: comparative study of retrograde intrabiliary and antegrade intraportal administration

To examine the feasibility of liver-directed in vivo gene therapy, we administered recombinant adenoviruses carrying a reporter lacZ gene retrogradely into the common bile duct of rats, as well as antegradely into the portal vein. Transduction efficiency of the lacZ gene in the liver was estimated not only histochemically by X-gal staining, but also quantitatively by a chemiluminescent reporter gene assay. Retrograde infusion of adenoviruses into the common bile duct was shown to successfully induce transgene expression in the liver. Transduction efficiency induced by intrabiliary adenoviral administration was not significantly different from that induced by intraportal adenoviral administration. Although transgene expression induced not only by intraportal, but also by intrabiliary adenoviral administration was observed predominantly at periportal areas, a considerable number of cells expressing the transgene were detectable even in lobular and centrilobular areas. Mild infiltration of inflammatory cells into the liver and mild hyperplastic changes of hepatocytes were observed after intrabiliary and intraportal adenoviral administration. However, hepatic damage estimated pathologically was not substantial. Furthermore, although intrabiliary and intraportal adenoviral administration resulted in very mild elevation of liver-related serum biochemical parameters, apparent complications were not observed in any rats. Our results demonstrated in the present study suggest that retrograde administration of adenoviruses into the common bile duct can induce efficient transgene expression in the liver without causing severe adverse effects, supporting the feasibility of adenovirus-mediated gene transfer into the liver in clinical settings by means of endoscopic retrograde cholangiography.     

Improved survival using multi-modality therapy in patients with lung metastases from colorectal cancer: a preliminary study

This retrospective study was conducted to assess the safety, efficacy, and long-term results of multi-modality therapy including radio-frequency thermal ablation (RFA) and radiotherapy as an additional cytoreductive method for eliciting the marked effects of chemotherapy in treating unresectable lung metastases from colorectal cancer. Total of 21 patients with lung metastasis from colorectal cancer were included. They were treated with modified pharmacokinetic modulating chemotherapy (PMC). Eleven were also treated with RFA and/or radiotherapy (multi-modality group), and 10 were treated with chemotherapy alone (chemotherapy group). Characteristics and survival of patients in the multi-modality group were compared with those of the chemotherapy group. The median survival of all patients was 38.6 months after the initial PMC. The cumulative 3-year survival rate of patients in the multi-modality group was 87.5% compared with 33.3% in the chemotherapy group (p=0.0041). The course of multi-modality therapy was uneventful except for pneumothorax in those who received RFA. Although pneumothorax developed in 4 of 11 patients (36.4%) treated with RFA, all were able to receive chemotherapy within 2 weeks after RFA. In conclusion, multi-modality therapy combined with modified PMC, radiation and RFA is a feasible choice of treatment associated with reasonable morbidity and mortality in patients with inoperable lung metastases from colorectal cancer.     

DNA vaccination of HSP105 leads to tumor rejection of colorectal cancer and melanoma in mice through activation of both CD4 T cells and CD8 T cells

We report that HSP105, identified by serological identification of antigens by recombinant expression cloning (SEREX), is overexpressed in a variety of human cancers, including colorectal, pancreatic, thyroid, esophageal, and breast carcinoma, but is not expressed in normal tissues except for the testis. The amino acid sequences and expression patterns of HSP105 are very similar in humans and mice. In this study, we set up a preclinical study to investigate the usefulness of a DNA vaccine producing mouse HSP105 whole protein for cancer immunotherapy in vivo using BALB/c and C57BL/6 mice, Colon26, a syngeneic endogenously HSP105-expressing colorectal cancer cell line, and B16.F10, a melanoma cell line. The DNA vaccine was used to stimulate HSP105-specific T-cell responses. Fifty percent of mice immunized with the HSP105 DNA vaccine completely suppressed the growth of subcutaneous Colon26 or B16.F10 cells accompanied by massive infiltration of both CD4+ T cells and CD8+ T cells into tumors. In cell transfer or depletion experiments we proved that both CD4+ T cells and CD8+ T cells induced by these vaccines play critical roles in the activation of antitumor immunity. Evidence of autoimmune reactions was not present in surviving mice that had rejected tumor cell challenges. We found that HSP105 was highly immunogenic in mice and that the HSP105 DNA vaccination induced antitumor immunity without causing autoimmunity. Therefore, HSP105 is an ideal tumor antigen that could be useful for immunotherapy or the prevention of various human tumors that overexpress HSP105, including colorectal cancer and melanoma.     

Evaluation of TS-1 based treatment and expression of thymidylate synthase and dihydropyrimidine dehydrogenase on oral squamous cell carcinoma

Seventeen oral squamous cell carcinoma (SCC) patients underwent chemotherapy with TS-1 (8 males and 9 females, mean age; 75.1 years, range; 47-102 years). TS-1 permitted five cases of oral chemotherapy on an outpatient basis and 8 cases in elder patients over 80-years of age. Excepting five patients who underwent TS-1 therapy as post-operative adjuvant chemotherapy, the therapeutic efficacy of TS-1 in 12 patients with or without irradiation, surgery or chemotherapy resulted in 3 cases of complete response (CR), 6 cases of partial response (PR), 3 cases of stable disease (SD), with no progressive disease (PD) cases (overall response rate; 75%). SCC samples obtained from biopsy were immunohistochemically stained with anti-TS and DPD polyclonal antibody. Although the statistical significance was not clear, the expression of TS and DPD for CR cases was lower than that for SD cases. TS-1 therapy improved quality of life (QOL) especially in elder patients with oral SCC, and our immunohistochemical results suggested the predictive possibilities of TS and DPD expression in response to TS-1.