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The patient was a 76-year-old woman who underwent laparoscopic-assisted low anterior resection for rectal cancer. According to the Japanese classification of colorectal carcinoma (8th Edition), the tumor was tub1, ly0, v0, and pStage Ⅰ (pT1bN0M0), Cur A. She received no adjuvant chemotherapy. A chest CT scan obtained 42 months after the surgery revealed 3 lung metastases in the left lung, with the biggest measuring 12 mm; the CA19-9 level was elevated to 72U/mL (normal≦38 U/mL). She declined surgery for the recurrence. She was treated with XELOX plus bevacizumab (Bev) therapy. Before XELOX plus Bev, the 3 lung metastases had enlarged, with the biggest now measuring 15 mm, and the CA19-9 level was elevated to 166 U/mL. After 4 cycles, the lung metastases decreased in size and the CA19-9 level decreased to 4 U/mL. We did not perform pulmonary resection or additional chemotherapy. No progression of the recurrent tumors was detected on CT after 2 years, and the CA19-9 level was within the normal range. XELOX plus Bev therapy may be effective for unresectable pulmonary metastasis from colorectal cancer.

We report 3 cases of advanced gastric cancer with peritoneal dissemination (PD) who underwent oophorectomy for ovarian metastases that occurred during chemotherapy. Case 1: The patient was a 43-year-old woman who had type 4 advanced gastric cancer with PD. After 24 courses of S-1 plus IV and IP paclitaxel (PTX) combination therapy, oophorectomy was performed for a rapidly growing left ovarian metastasis. Thirty-four months after the start of therapy, she has completed 44 courses of S-1 plus IV and IP PTX therapy and she is continuing the treatment. Case 2: The patient was a 77-year-old woman who underwent total gastrectomy with D2-#10 lymph node dissection and cholecystectomy for gastric cancer with PD. Right ovarian resection was performed for an ovarian metastasis 30 months after gastrectomy. She continues receiving chemotherapy 8 months after oophorectomy. Case 3: The patient was a 42-year-old woman who received S-1 plus CDDP combination therapy and 22 courses of S-1 plus IV and IP PTX for gastric cancer with PD, and oophorectomy for bilateral ovarian metastases was performed. After 10 courses of S-1 plus IV and IP PTX therapy, she died of cancer. We discuss the significance of oophorectomy during chemotherapy for advanced gastric cancer with PD.

Peritoneal dissemination (PD) is the most common type of metastasis in advanced gastric cancer. The standard treatment of gastric cancer patients with PD is combination therapy with S-1 and cisplatin (SP therapy). Here, we describe the results of SP therapy for gastric cancer with PD. Sixteen gastric cancer patients with PD were treated with SP therapy as first-line chemotherapy. Second-look staging laparoscopy was performed for 10 patients who showed a good response to SP therapy. Gastrectomy was performed for 5 patients with P0CY0 and 1 case with P0CY1. The median survival time of all 16 patients was 571 days (19 months). The patients, who had surgery, had a significantly better survival time than the others (25 months vs 12.7 months). In conclusion, SP therapy is effective for gastric cancer with PD, and surgery for cases showing a good response to chemotherapy might improve the prognosis of patients with PD.

Here, we report 2 patients with gastric cancer and peritoneal dissemination who were successfully treated with chemotherapy after undergoing treatment for an oncologic emergency caused by peritoneal dissemination. Case 1 involved obstruction of the sigmoid colon caused by peritoneal dissemination. After urgent colostomy, S-1/IP IV paclitaxel chemotherapy was introduced. The patient continued the therapy for 2 years and 2 months. Case 2 involved acute renal failure due to bilateral ureter obstruction and obstructive jaundice caused by peritoneal dissemination. This patient underwent emergency treatment consisting of Double-J ureteral stent insertion and endoscopic nasobiliary drainage. He was successfully started on chemotherapy with S-1/oxaliplatin/IP paclitaxel. He continued the therapy for 8 months without symptoms. Aggressive treatment might be effective for advanced gastric cancer showing oncologic emergency.

Background: A pathologic complete response (pCR) can sometimes be induced by intensive or long-term neoadjuvant chemotherapy (NAC). This prognostic research study based on a systematic review of the literature evaluated the impact of a pCR on the long-term survival of gastric cancer (GC) patients., Methods: Articles were extracted from PubMed and the Japanese medical search engine "Ichu-shi," using the terms "GC," "NAC," and "pCR." Articles were selected based on the following criteria: (1) full-text case report, (2) R0 resection following NAC for locally advanced GC, and (3) pathological complete response in both the primary stomach and in the lymph nodes. A questionnaire regarding the patients' prognoses was sent to the corresponding authors of the articles selected in July 2013., Results: Twenty-four articles met the criteria. Twenty authors responded to the questionnaire. Finally, 22 patients from 20 articles were entered into the present study. The median follow-up time (range) of the survivors was 76 (range 13-161) months. Tumors that were stage III/IV (86%: 19/22) and of an undifferentiated histology (61.9%: 13/21) were dominant. An S1-based regimen was frequently selected for the NAC. All patients underwent R0 resection and D2/D3 lymphadenectomy. The overall survival and recurrence-free survival rates at 3 and 5 years were 96% and 85% and 91% and 75%, respectively., Conclusions: Although a pCR was a relatively rare event, a high pCR rate would be helpful to select the regimen and courses of NAC, especially when the pathological response rates are similar.

A phase III clinical trial to evaluate the efficacy of combination chemotherapy with intraperitoneal administration of paclitaxel for gastric cancer with peritoneal metastasis has been ongoing in Japan. A male patient in his 50s who was diagnosed as having advanced gastric cancer with peritoneal metastasis was enrolled in this trial. The patient was assigned to receive a regimen of intravenous and intraperitoneal paclitaxel combined with S-1. Although an intraperitoneal access port had been implanted to provide access to the peritoneal cavity, tube obstruction occurred twice. Laparoscopic examination revealed that the tube in the abdominal cavity had been totally covered with the great omentum. Therefore, the intraperitoneal regimen was discontinued. Although intraperitoneal chemotherapy for the treatment of peritoneal dissemination in gastric cancer is promising, precaution should be taken to avoid tube obstruction, which is a complication of the intraperitoneal tube placement.

A 64-year-old man was diagnosed as having advanced gastric cancer with peritoneal and para-aortic lymph node metastases. He received 2 courses of chemotherapy with S-1 and cisplatin( CDDP) and 5 courses of combination chemotherapy with capecitabine, CDDP, and trastuzumab. The peritoneal and para-aortic lymph node metastases disappeared after chemotherapy, and subsequently, total gastrectomy was performed (pT2N3aM0, stage IIIA). Although the patient received combination chemotherapy with capecitabine and trastuzumab, para-aortic lymph node recurrence was noted 6 months after the operation. Radiation therapy at a total dose of 50 Gy targeted at the para-aortic lymph node metastasis along with S-1 and trastuzumab chemotherapy was administered. No serious adverse effects were observed during chemoradiotherapy. Following chemoradiation therapy, tumor recurrence was not observed. Therefore, chemoradiotherapy is considered an effective treatment for lymph node metastasis from gastric cancer.

The case was a 70-year-old man with type-2 gastric cancer in the lesser curvature accompanied by multiple liver metastases. He received combination chemotherapy of S-1 and CDDP. S-1 was administered at 100 mg/body/day for 21 days followed by withdrawal for 14 days, and CDDP was prescribed at 80 mg/body/day div on day 8. After 3 courses of treatment, the multiple liver metastases disappeared. The primary gastric lesion had changed to a scar and endoscopic biopsy revealed no cancer cell. After the 4th course, we changed the therapy to S-1 alone and after that to UFT alone. Now, 3 years and 3 months after inducing CR, the patient continues to receive UFT with no regrowth of the tumor.

A 74-year-old male with advanced gastric cancer(cT3N1M0H0P0CY0, cStage III A)was treated with paclitaxel/ CDDP as neoadjuvant chemotherapy. Paclitaxel (80 mg/m(2)) and CDDP (25 mg/m(2)) were administered on days 1, 8 and 15 as one cycle. After the second course, a significant tumor reduction was obtained. Total gastrectomy, splenectomy, and D2 type nodal dissection were performed. The histological diagnosis revealed complete disappearance of cancer cells in the stomach and all of the lymph nodes, a so-called pathologically complete response. The patient has now been in good health without any recurrence for 9 months after surgery. This case suggests that neoadjuvant chemotherapy with paclitaxel/CDDP is a potential regimen for advanced gastric cancer.

Background: The systemic administration of gemcitabine (GEM) has been accepted as a standard treatment for patients with advanced pancreatic cancer. The major mediator of cellular uptake of GEM is the human equilibrative nucleoside transporter 1 (hENT1) whose expression is up-regulated by thymidylate synthase inhibitors, such as 5-fluorouracil (5-FU). S-1 is a novel oral derivative of the 5-FU prodrug tegafur combined with two modulators. Recent clinical trials have reported the promising effect of S-1 in pancreatic cancer. The purpose of this study was to evaluate the relationship between different schedules and the effects of GEM/S-1 combination therapy on pancreatic cancer xenograft models., Materials and Methods: Human pancreatic tumor xenografts were prepared by subcutaneous implantation of MiaPaCa-2 into nude mice. Expression of hENT1 was determined by quantitative RT-PCR. GEM cellular uptake was determined using [3H] GEM., Results: Significant increases in hENT1 expression and GEM cellular uptake were observed after S-1 treatment. Six different treatment schedules (no treatment, single agent of GEM or S-1, combination treatment with GEM either before, simultaneously or following administration of S-1) were compared. Significant tumor growth inhibition was observed in the mice treated with S-1 followed by GEM compared to either untreated mice or the mice treated with the other schedules., Conclusion: Based on the effects of S-1 on the uptake of GEM, S-1 should be used before GEM treatment. The GEM/S-1 combination therapy in patients with pancreatic cancer may be promising and should be tested in clinical trials.

Background: The authors reported previously the beneficial effects of interferon (IFN)-alpha/5-fluorouracil (5-FU) combination therapy for patients with advanced hepatocellular carcinoma (HCC) who have tumor thrombi in the major portal branches. In this report, the authors describe the results from IFN/5-FU chemotherapy for patients who underwent palliative hepatic resection for advanced HCC with tumor thrombus in the main trunk of the portal vein and multiple nodules in the whole liver. In addition, they evaluated the correlation between the response to such therapy and expression of IFN-alpha type 2 receptor (IFNAR2)., Methods: From October 1999 to December 2004, 30 patients with advanced HCC, tumor thrombi in the main trunk of the portal vein, and multiple nodules in the whole liver (Vp4 and grade 3 intrahepatic metastases) were recruited for this study. They underwent palliative hepatic resection followed by at least 2 courses of IFN/5-FU. IFNAR2 expression levels were determined by immunohistochemistry., Results: No major treatment-related complications were noted. An objective response was noted in 10 patients (33.3%) and included a complete response in 6 patients (20%), a partial response in 4 patients (13.3%), no response in 1 patient (3.3%), and progressive disease in 19 patients (63.4%). IFNAR2 expression was detected in 20 of 30 patients (66.7%). There was a significant difference in overall survival between patients with positive and negative IFNAR2 expression cases (P<.0025), and a significant correlation was observed between IFNAR2 expression and response to IFN/5-FU combination therapy (P=.0199)., Conclusions: Adjunct IFN/5-FU therapy is a promising modality for patients with advanced HCC, tumor thrombi in the major trunk, and multiple nodules after palliative hepatic resection. The results from this study indicated that the response to such therapy seemed to be correlated with IFNAR2 expression., (Copyright (c) 2007 American Cancer Society.)

We recently reported that interferon-alpha (IFN-alpha) and 5-fluorouracil (5-FU) combination therapy in advanced hepatocellular carcinoma (HCC) achieved excellent clinical results. However, the mechanism underlying this combination therapy remains to be elucidated. In this study, we examined the anti-tumor effects of IFN-alpha and 5-FU combination therapy in vivo and aimed to reveal its anti-angiogenic effects by investigating the expression of vascular endothelial growth factor (VEGF) and angiopoietins (Ang-1 and Ang-2). Human HCC cells, HuH7, were subcutaneously injected in nude mice. Ten days later, groups of mice received treatment with IFN-alpha alone, 5-FU alone, or with a combination of IFN-alpha and 5-FU for four weeks. Immunohistochemical examinations of proliferating cell nuclear antigen (PCNA), cell differentiation antigen 34 (CD34), Ang-1, -2 and VEGF, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay and quantification of VEGF, Ang-1 and-2 mRNA using real-time RT-PCR were performed. Results showed that IFN-alpha and 5-FU combination therapy significantly inhibited the growth of human HCC cells compared with the control group or single agent treatment. The combination therapy decreased PCNA-positive cells as well as microvessel density (MVD) and induced apoptosis of (TUNEL-positive cells) more than other treatment groups. Immunohistochemical analysis revealed that the combination therapy significantly decreased the expression of VEGF and Ang-2 and increased that of Ang-1. The ANG2/ANG1 mRNA expression ratio was significantly lower in the combination therapy group. In conclusion, our results suggested that IFN-alpha and 5-FU combination therapy has anti-proliferative and anti-angiogenic effects and can induce apoptosis in vivo. The synergistic and anti-angiogenic effects may in part be attributable to the regulation of Ang-1, -2 and VEGF.

We experienced a patient who received successful treatment for multiple hepatocellular carcinoma (HCC) nodules, with tumor thrombi in the major portal branches, with intraarterial 5-fluorouracil perfusion chemotherapy combined with subcutaneous interferon-alpha administration. The patient was a 50-year-old man with hepatitis C virus and HCC. The tumors consisted of a 5-cm main nodule in the right lobe (segment 8) and multiple intrahepatic metastases. The tumor also involved portal vein thrombosis throughout the right portal branch. After two cycles of interferon-alpha/5-fluorouracil combination chemotherapy, tumor markers demonstrated a decreasing tendency. Nine months after the initiation of this therapy, the tumors were limited to the right lobe and were surgically removed by S8 subsegmentectomy, S5 partial hepatectomy, and portal thrombectomy. The serum levels of both alpha-fetoprotein and protein induced by vitamin K absence II fell to normal levels after hepatic resection. Fifty-eight months after the first treatment, he is alive with several recurrent nodules in the liver. In conclusion, the interferon-alpha/5-fluorouracil combination therapy is a useful treatment for HCC in patients who have multiple intrahepatic metastases and portal vein thrombosis. In addition to this therapy, combined modality therapy including, for example, surgical resection, can sometimes have a dramatic therapeutic effect, shown by tumor markers reverting to normal levels.

We report a patient with a case of advanced rectal cancer with unresectable liver metastasis, who received the combination of systemic chemotherapy of 5-FU/l-LV and external radiation therapy. He was alive for 21 months. He had been able to maintain a good quality of life without any complaints of the primary rectal tumor.

Background: We conducted a Phase I/II study to evaluate the local efficacy and toxicity of hyperfractionated accelerated radiotherapy (HART) combined with 5-fluorouracil (5-FU) and cisplatin (CDDP) in patients with unresectable advanced pancreatic cancer., Methods: Thirty-five patients (15 with Stage 4A and 20 with Stage 4B disease according to TNM classification) were enrolled between August 1997 and August 2001 into this Phase I/II trial. All patients received concurrent HART (1.5 Gy twice daily separated by 6 h for 5 days per week), 5-FU (375 mg/m(2) given as continuous intravenous infusion), and CDDP (2 mg/m(2) given as 30-min infusion just before each fraction of irradiation). In the Phase I trial, the total dose of radiation was escalated from 27 to 45 Gy., Results: Twenty-one patients were enrolled in the Phase I study and six patients were given the final planned dose (45 Gy) which did not exceed the maximum tolerated dose. Eleven patients (52.4%) suffered from Grade 3 or worse neutropenia. Vomiting and mucositis were observed in 21 (100%) and 12 (57.1%) patients, respectively. An additional 14 patients were entered in the Phase II trial and received a total dose of 45 Gy, which is recommended in Phase I trial. Concerning the local tumor control of 20 patients with the recommended regimen, 7 patients (35%) achieved partial response, 10 (50%) remained stable and local progressive disease occurred in 3 (15%). The median survival time and the overall 1-year survival rate were 11.2 months and 40.0%, respectively, in 20 patients who received the recommended regimen. In Stage 4A patients, they were 13.0 months and 70.0%, respectively. The trend of toxicities in patients with the recommended regimen was almost the same as that observed in the Phase I study., Conclusion: The chosen combined modality treatment was well tolerated, and showed an expected local efficacy for the treatment of unresectable advanced pancreatic cancer.

Objectives: Gemcitabine is taken up by cells mainly via human equilibrative nucleoside transporter 1 (hENT1). Pretreatment of cancer cell lines with 5-fluorouracil (5-FU) leads to an increase in the expression of hENT1 and augments the effect of single-agent gemcitabine treatment in vitro. The purpose of the present study was to evaluate the relationship between the schedules of gemcitabine/uracil-tegafur (UFT) combination therapy and their effects in pancreatic cancer in vivo., Methods: The expression level of hENT1 mRNA was examined using 6 types of human pancreatic cancer cell lines treated with 5-FU and MiaPaCa-2 xenograft tumors in BALB/c nu/nu mice treated with UFT. A [H] gemcitabine cellular uptake assay was performed using MiaPaCa-2 cells treated with 5-FU. We compared the effects of 6 different schedules of treatment using UFT and/or gemcitabine on MiaPaCa-2 xenograft tumors., Results: MiaPaCa-2 cell line was one of the lines that showed the highest rate of 5-FU-induced increase in the hENT1 mRNA level. Gemcitabine uptake was significantly increased when cells were treated with 5-FU. Treatment with UFT significantly increased the hENT1 mRNA expression in MiaPaCa-2 tumors. A significant growth inhibition of MiaPaCa-2 tumors was observed in the mice treated with UFT followed by gemcitabine as compared with either untreated mice or UFT alone-treated mice., Conclusions: Our results suggest that the schedule in which the gemcitabine is administered after UFT may be the optimal combination for gemcitabine/UFT treatment in pancreatic cancer.

The patient, a 40-year-old woman, underwent total gastrectomy and excision of the pancreatic tail, spleen and gallbladder for gastric cancer in September 2000. The lesion was judged to be P1, SE, H0, N2 and Stage IV and the patient was managed on a regular schedule as an outpatient. In September 2004, she passed blood-stained feces and rectal palpation detected a hard nodule at the anterior rectal wall. A fiber optic examination of the sigmoid colon detected an ulcerous lesion with a hemorrhage at the anterior rectal wall. A biopsy revealed the lesion to be Group V poorly differentiated adenocarcinoma. Starting in October 2004, 100 mg/day of TS-1 was administered for 3 weeks; intravenous drip infusion of 100 mg/body of CDDP was conducted in the second week for a period of 24 hours. After 3 courses of this regimen, a fiber optic examination of the colon conducted in February 2005 no longer detected the rectal tumor, leaving only a cicatrix. Upon a CT examination, the para-aortic lymph nodes that had been enlarged were notably reduced in size and an improvement was eminent in the hypertrophic rectal wall. The patient no longer experienced constipation or melena. Her clinical course is being observed while an oral administration of 100 mg/day of TS-1 continues.

In colorectal cancer, liver metastasis is the most common and most important prognostic factor. Although surgical resection is the first choice of treatment for liver metastasis of colorectal cancer, there are many cases we cannot choose the surgical treatment. The chemotherapy is very important in such cases. We examined 18 cases of unresectable liver metastases from colorectal cancer which were adapted a hepatic arterial infusion of 5-FU (HAI) with a weekly high-dose infusion method (WHF) as the first-line treatment, and then systemic chemotherapy of CPT-11 in combination with 5-FU as the second-line treatment. The response rate of this treatment is 72% (13/18) and the 1-, 2-, 3-year survival rates were 100% (16/16), 83% (10/12), and 50% (5/10), respectively. The combination chemotherapy of HAI with systemic chemotherapy using CPT-11 seemed to be an effective treatment method.

A 44 year-old woman presented with epigastralgia in March 2004 was diagnosed as having type II gastric cancer by gastrofiberscope, and histological diagnosis of biopsy specimens was group V (tub2, por1). Since multiple liver metastases were observed in subsegments 2, 3, and 5 by abdominal ultrasonography, systemic chemotherapy was first conducted for tumor down sizing. The patient was treated by three cycles of the one month regimen (CDDP 70 mg/m2, day 8, for 24hrs, and TS-1 80 mg/m2, day 1-14; 2 week cessation of the drugs). CT scan taken on May 16, 2005 revealed that the tumor diameters in subsegments 2, 3, and 5 were 1 cm, 3 cm, and 1.5 cm, respectively. On September 14, liver tumors were markedly shrunk. Tumor in subsegment 2 became undetectable, and the diameters in those in subsegments 3 and 5 were 1.5 cm, and 0.5 cm, respectively. On September 28, a distal gastrectomy associated with S3 partial hepatectomy and microwave coagulation therapy for S5 tumor was performed without any macroscopic residual lesions. The prognosis of liver metastasis of gastric cancer is generally poor, and there is no comprehensive therapy. The marked clinical response in this patient suggests that this combination therapy with CDDP and TS-1 might be a promising preoperative chemothepapy for unresectable gastric cancer.

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.

We previously reported the beneficial effects of combination therapy of interferon (IFN)-alpha/5-fluorouracil (FU) for advanced hepatocellular carcinoma (HCC) with tumour thrombi in the major portal branches. This report describes the results of longer follow-up and includes more than double the number of patients relative to the original report, and evaluates the role of IFN-alpha/type 2 interferon receptor (IFNAR2) expression on the response to the combination therapy. The study subjects were 55 patients with advanced HCC and tumour thrombi in the major branches of the portal vein (Vp3 or 4). They were treated with at least two courses of IFN-alpha/5-FU without major complication. In the 55 patients, 24 (43.6%) showed objective response (eight (14.5%) showed complete response, 16 (29.1%) partial response), four (7.3%) showed no response, and 27 (49.1%) showed progressive disease. Immunohistochemically, IFNAR2 expression was detected in nine out of 13 (69.2%) patients. There was significant difference in the time-to-progression survival (P = 0.0002) and the overall survival (P < 0.0001) between IFNAR2-positive and -negative cases. There was a significant correlation between IFNAR2 expression and response to IFN-alpha/5-FU combination therapy in univariate analysis (P = 0.0070). IFN-alpha/5-FU combination therapy is a promising modality for advanced HCC with tumour thrombi in the major portal branches and could significantly depend on IFNAR2 expression.

Purpose: Our purpose was to explore the contribution of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/TRAIL receptor pathway to antitumor effects of IFNalpha and 5-fluorouracil (5-FU) combination therapy for hepatocellular carcinoma (HCC)., Experimental Design: Susceptibility of HCC cell lines to TRAIL and/or 5-FU was examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The effects of 5-FU, IFNalpha, or both on the expression of TRAIL receptors (R1, R2, R3, and R4) on HCC cells or TRAIL in peripheral blood mononuclear cells (PBMC) were examined by flow cytometry. IFNalpha-induced cytotoxic effects of PBMC on HCC cell lines were examined by (51)Cr release assay. TRAIL expression in peripheral blood mononuclear cells and liver tissue from patients was examined by real-time reverse transcription-PCR or immunohistochemistry., Results: HLE and HepG2 were sensitive to TRAIL, but HuH7, PLC/PRF/5, and HLF were resistant. 5-FU had synergistic effect on TRAIL in HLF and additive effect in four other HCC cell lines. TRAIL receptors on HCC cells were up-regulated by 5-FU, and IFNalpha induced TRAIL on CD4(+) T cells, CD14(+) monocytes, and CD56(+) NK cells. Treatment of effector cells by IFNalpha and target HCC cells by 5-FU enhanced the cytotoxicity of CD14(+) monocytes and CD56(+) NK cells against HCC cells via a TRAIL-mediated pathway. TRAIL mRNA overexpression was noted in PBMC of HCC patients who clinically responded to IFNalpha/5-FU combination therapy, and TRAIL(+) mononuclear cells were found in cancer tissue of a responder., Conclusion: Our results suggest that modulation of TRAIL/TRAIL receptor-mediated cytotoxic pathway might partially contribute to the anti-HCC effect of IFNalpha and 5-FU combination therapy.

The patients of unresectable cholangiocellular carcinoma (CCC) have extremely poor prognosis. Case 1 was a 72-year-old male who had CCC in the left lobe of liver with intrahepatic metastasis. From June 2003, he received hepatic arterial infusion chemotherapy (FAP: 5-fluorouracil 250 mg/day continuous infusion, day 1-5, adriamycin 10 mg/day, day 1, and CDDP 10 mg/day, day 1). After 5 courses, abdominal CT revealed that the main tumor had regressed. Case 2 was a 66-year-old male who had CCC with portal vein tumor thrombus of anterior branch (Vp2). He received FAP arterial infusion chemotherapy that was a same regimen as with the case 1 patient. After 5 courses were administered, Abdominal CT revealed that the size of the main tumor at S8 had not changed, and that portal vein tumor thrombus had disappeared. In both cases, there was no complication related to the chemotherapy. They are alive for more than 1 year after chemotherapy had started. FAP hepatic arterial infusion chemotherapy might be promising as an effective therapy for non-resectable CCC without extra hepatic metastasis.

The prognosis of unresectable advanced gallbladder cancer is extremely poor. We presented a 61-year-old female with unresectable advanced gallbladder cancer who received FAP therapy, Gemcitabine + UFT therapy, and an intra-arterial FAP therapy that followed. She is still alive 18 months after the first diagnosis. It may be possible to improve the prognosis by maintaining QOL using the combination of chemotherapies such as FAP, Gemcitabine, and UFT.

To investigate the effect of biochemical modulation on antitumor activity shown by the combination of 5-Fluorouracil (5-FU) and interferon-alpha (IFN-alpha), experimental therapy was performed on human hepatocellular carcinoma cell (HuH7, PLC/PLF/5) xenografts inoculated into nude mice, using 5-FU and IFN-alpha, either alone or in combination. These agents showed antitumor activity in different degrees. Although IFN-alpha, given as 100,000 units/mouse/3 times/week subcutaneously x 6, and 5-FU, given as 0.5 mg/mouse/3 times/week intraperitoneally, showed addititive antitumor effect against HuH7 and PLC/PLF/5, the activities of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP), orotate phosphoribosyltransferase (OPRT), uridine phosphorylase (UP) and uridine kinase (UK) were not significantly influenced in the tumors treated with the 5-FU/IFN-alpha combination, compared with those treated with 5-FU or IFN-alpha alone. This suggested that antitumor activity of 5-FU and IFN-alpha in combination was not significantly involved in 5-FU metabolism in two human hepatocellular carcinoma cell lines examined.

Purpose: The prognosis of hepatocellular carcinoma (HCC) is very poor, particularly in patients with tumors that have invaded the major branches of the portal vein. Combination chemotherapy with intra-arterial 5-fluorouracil and subcutaneous interferon-alpha has shown promising results for such advanced HCC, but it is important to develop the ability to accurately predict chemotherapeutic responses., Experimental Design: We analyzed the expression of 3,080 genes using a polymerase chain reaction-based array in 20 HCC patients who were treated with combination chemotherapy after reduction surgery. After unsupervised analyses, a supervised classification method for predicting chemotherapeutic responses was constructed. To minimize the number of predictive genes, we used a random permutation test to select only significant (P < 0.01) genes. A leave-one-out cross-validation confirmed the gene selection. We also prepared an additional 11 cases for validation of predictive performance., Results: Hierarchical clustering analysis and principal component analysis with all 3,080 genes revealed distinct gene expression patterns in responders (those with complete response or partial response) and nonresponders (those with stable disease or progressive disease) to the combination chemotherapy. Using a weighted-voting classification method with either all genes or only significant genes as assessed by permutation testing, the objective responses to treatment were correctly predicted in 17 of 20 cases (accuracy, 85%; positive predictive value, 100%; negative predictive value, 80%). Moreover, patients in the validation dataset could be classified into two distinct prognostic groups using 63 predictive genes., Conclusions: Molecular analysis of 63 genes can predict the response of patients with advanced HCC and major portal vein tumor thrombi to combination chemotherapy with 5-fluorouracil and interferon-alpha.

Previously we reported combined chemo-immunotherapy, using interferon (IFN)-alpha and 5-fluorouracil (5-FU) for patients with advanced hepatocellular carcinoma (HCC), and this regimen improved the prognosis. Recently, we experienced an HCC patient who died of severe interstitial pneumonia during the combined IFN-alpha and 5-FU therapy. This is the first report of the occurrence of interstitial pneumonia during combined IFN-alpha and 5-FU treatment. A 60-year-old-man was admitted to Osaka University Hospital to receive systemic chemo-immunotherapy for recurrent HCC. In the second week of the chemo-immunotherapy, he showed a decreased level of consciousness, and respiratory insufficiency. Emergency roentgenogram revealed diffuse infiltration in both lungs. Respiratory dysfunction due to interstitial pneumonia was suspected, and steroid pulse therapy was started. However, the patient showed respiratory failure, and he died 32 days after the start of the therapy. Autopsy findings showed atelectasis in the bilateral lungs, which showed elastic hard solidity and a dark red color; esophageal varices were also shown, and there was cirrhosis with a large tumor in the liver. Microscopically, the alveolar wall showed marked fibrous thickness and moderate inflammatory change, which is consistent with acute interstitial pneumonia, and the acute pulmonary change was suspected to have been the cause of death. The association of IFN with the development of interstitial pneumonia has been reported. However, the prognosis of IFN-induced interstitial pneumonia has mostly been favorable when the medication was discontinued. It has been postulated that interstitial pneumonia induced by the combination of IFN and 5-FU may be therapy-resistant. The combination of IFN-alpha and 5-FU is a useful therapy for patients with advanced HCC, such as that with portal vein invasion or multiple metastatic foci. Thus, interstitial pneumonia in these patients should be carefully managed.

A phase I study of gemcitabine (GEM) and UFT combination chemotherapy was performed for unresectable pancreatic cancer. The regimen included UFT orally from day 1 through day 6 and from day 8 through 13, GEM intravenously on day 7 and 14, and 1 week rest as 1 course. Administration of more than 2 courses was attempted for each patient, with the same dosage levels at all 3 scheduled steps. Nine patients were enrolled in the study. Leukopenia and neutropenia of grade 3 occurred in 2 of 6 patients at level 2, and maximum tolerated dose (MTD) was considered to be 800 mg/m2 for GEM and 250 mg/m2 for UFT. Clinical effects of the patients included: 2 PR, 4 NC, and 3 PD, for a response rate of 22% (2/9 patients). Reduced CA19-9 level of less than half of that at starting time was observed in 4 of 9 (44%) patients. The recommended dose for the phase II study is GEM 800 mg/m2 and UFT 250 mg/m2 with consideration of application to outpatients and continuing courses.

For the difficulty of the giving sufficient dose because of the poor liver function and low sensitivity for the anti-cancer agents, the chemotherapy may not play a central role for the hepatocellular carcinoma (HCC) patients with liver cirrhosis. However, the chemotherapy must be the one of important possibility as a multimodal treatment for the advanced HCC, for which hepatic resection, TAE and other general therapy would not be effective. The intraarterial perfusion chemotherapy is common as a chemotherapy for HCC and it is not difficult to maintain; the effective rate is not sufficient. Recently, the combination therapy with subcutaneous IFN-alpha and intraarterial 5-FU showed a outstanding effective rate for intractable HCC with Vp3. For the further advance of the HCC treatment and prognosis, this therapy might be the promising treatment modality and expected of the development.

The prognosis of advanced hepatocellular carcinoma (HCC) is extremely poor. Patient 1 was a 43-year-old male with major portal tumor thrombi. He received combination therapy consisting of continuous arterial infusion (MTX 30 mg/m2, day 1, CDDP/5-FU 6 mg/m2: 250 mg/m2, day 1-14) and subcutaneous injection of IFN-alpha (500 x 10(4) U, 3 times a week, 4 weeks). Patient 2 was a 66-year-old male with major hepatic venous tumor thrombi. He received combination therapy consisting of continuous arterial infusion (5-FU 6 mg/m2: 250 mg/m2, day 1-14) and subcutaneous injection of IFN-alpha (500 x 10(4) U, 3 times a week, 4 weeks). Decrease in tumor was observed in both patients markers and marked regression of tumor was observed in both patients. They are still in complete response. This combination therapy is an effective strategy for advanced HCC.

The patient is a 75-year-old male. Abdominal ultrasound tomography in June 2002 revealed hepatocellular carcinoma with intrahepatic metastasis (IM3) and tumor thrombi (Vp4, Vv3) at S4 in the major portal and hepatic vein. From July 2002, he received hepatic arterial infusion therapy (FAP: 5-fluorouracil, CDDP and adriamycin) for these lesions. In December 2002, these lesions had disappeared completely after 6 sessions of arterial infusion therapy. The patient is still alive with no recurrence after 2 years since the beginning of this treatment. Recently, we treated 9 patients with combined arterial infusion chemotherapy (FAP), and the response rate (CR and PR) was 44% and no major side effect was observed. In conclusion, some patients may obtain longer survival through this treatment, even in cases of advanced HCC with tumor thrombus in the major trunks of portal vein and/or hepatic vein.

Peroxisome proliferator-activated receptor gamma (PPARgamma), a ligand activated transcription factor, forms a heterodimer with retinoid X receptor alpha (RXRalpha), and its transcriptional activity is thought to be maximal in the presence of both PPARgamma and RXRalpha ligands. Though previous studies suggested that thiazolidinediones (TZDs), known as PPARgamma ligands, inhibit the growth of certain types of cancer cells, little is known about the growth inhibitory effects mediated though activation of PPARgamma/RXRalpha. We examined the effects of troglitazone (one type of TZDs) and 9-cis retinoic acid, a RXRalpha ligand, on activation of PPARgamma/RXRalpha and growth inhibition of human pancreatic cancer cell lines (AsPC1, BxPC3, PSN1, PCI6, Panc1, KMP-4, and KMP-7). Combined treatment of troglitazone and 9-cis retinoic acid showed enhanced transcriptional activity and enhanced antiproliferative effects. In PSN1 cells, G1 cell cycle arrest and apoptosis were induced by troglitazone and these effects were enhanced with additional 9-cis RA. Our findings suggest that activation of PPARgamma/RXRalpha pathway might play an important role in growth inhibition of pancreatic cancer cells via G1 cell cycle arrest and apoptosis. This nuclear receptor might be a suitable molecular target for treatment of pancreatic cancers.

The prognosis of hepatocellular carcinoma(HCC) invading the major branches of the portal vein(Vp3 or 4) is extremely poor. Recently, we reported the efficacy of the combination therapy with subcutaneous interferon(IFN)-alpha and intra-arterial 5-FU for intractable HCC with Vp3 or Vp4. Forty-eight consecutive patients with HCC and Vp3 or 4 were treated with the combination therapy consisting of continuous arterial infusion of 5-FU(450-500 mg/day, 5 days/week, for the initial 2 weeks) and subcutaneous injection of IFN(5 MIU, 3 times/week, 4 weeks). The treatment outcome of these cases was very good. In addition, it is considered direct antitumor effect, the angiogenesis depression effect, and the indirect antitumor effect through immunocompetent cell, may concerned, as the mechanism. In conclusion, combination therapy with subcutaneous IFN and intra-arterial 5-FU is therefore a promising treatment modality for intractable HCC with Vp3 or 4.

Background: The prognosis of hepatocellular carcinoma (HCC) invading into the major branches of the portal vein (Vp3) is extremely poor., Methods: Eleven consecutive patients with HCC and Vp3 were treated with 2-6 cycles of a "basic" combination therapy consisting of continuous arterial infusion of 5-fluorouracil (450-500 mg/day, for the initial 2 weeks) and subcutaneous injection of interferon-alpha (5 million international units, 3 times/week, 4 weeks). In the first 3 patients, methotrexate (90 mg/day 1 of every week), cisplatin (10 mg/day), and leucovorin (30 mg/days 2 and 3 of every week) also were administered for the initial 2 weeks ("full" regimen)., Results: In 8 (73%) of 11 patients, an objective response (complete response [CR] or partial response [PR]) was observed with marked regression of tumor and decrease in tumor markers. The use of the full regimen was associated with objective response in all patients; instead, they developed thrombocytopenia or leukopenia. In the subsequent 8 patients with basic regimen, 5 patients showed CR (2 cases) or PR (3 cases; objective response rate, 63%), and leukopenia was observed only in 1 patient., Conclusions: Simple combination therapy with subcutaneous interferon-alpha and intraarterial 5-fluorouracil therefore is a promising treatment modality for intractable HCC with Vp3.

A 66-year-old male who underwent radical resection for esophageal cancer (stage IV) was diagnosed with multiple hepatic metastasis 1 year and 3 months after the surgery. He underwent hepatic resection and received systemic chemotherapy (FAP: 5-FU, ADR, CDDP), as the post-operative adjuvant therapy. One year and 3 months later, there was a huge recurrence in the residual liver and hepatic arterial infusion chemotherapy (FAP) was performed. The recurrent lesion disappeared completely after 3 sessions of arterial infusion chemotherapy. The arterial infusion chemotherapy was continued in the outpatient clinic and the recurrent lesion is well controlled. At present, this patient has returned to social life, 2 years and 3 months after the hepatic resection. The utility of hepatic arterial infusion chemotherapy and hepatectomy for postoperative multiple hepatic metastasis from esophageal cancer was shown in the present case.

We report a case of advanced hepatocellular carcinoma (HCC), successfully treated by a combination therapy of alpha-interferon (IFN-alpha) and tegafur/uracil (UFT). A 44-year-old Japanese man who underwent a partial hepatectomy for HCC developed tumor recurrence in the liver 10 months after surgery. Transcatheter arterial chemoembolization (TAE) was performed twice within 7 months, but was ineffective. Later, multiple metastatic lesions appeared in the liver, lung and spine. Following the third TAE, a combination therapy of IFN-alpha (10 x 10(6) units, i.m., t.i.w.) and UFT (300 mg, p.o.d.) was started. The treatment resulted in a fall in serum PIVKA-II (protein induced by vitamin K antagonism) levels from 906 mAU to normal levels and a complete resolution of all lung nodules within 6 months. At the latest follow up 24 months after the initiation of combination treatment, the patient was working full-time and showed no evidence of tumor relapse. A combination therapy of IFN-alpha and UFT may be promising for the treatment of advanced HCC.

Hepatocellular carcinoma (HCC) with vascular invasion and/or intrahepatic metastasis (IM) has a poor prognosis, so advanced HCC may be considered as a contraindication for hepatectomy. We experienced a case of HCC with hepatic venous and portal venous tumor thrombus and multiple IM who survived over 1 year after the operation with combined locoregional chemotherapy. (Case): A 67-year-old male patient was diagnosed with HCC with extracapsular invasion after transarterial embolization (TAE). CT scan revealed the HCC had a right portal venous tumor thrombus and multiple IM. Posterior lobectomy and thrombectomy of hepatic venous and portal venous tumor thrombus and placement of portal venous catheter ware performed. From the first day after operation the patient received continuous intravenous and intraportal 5-FU for 3 weeks. At the first month after operation, TAE and PEIT were given against residual IM. After discharge the patient received hepatic arterial infusion chemotherapy (MTX/CDDP/5-FU/Leucovorin). Fourteen months after operation, the patient is surviving in good physical condition.

Chemotherapy for pancreatic acinar cell carcinoma has not been well studied. We report herein one patient, in whom arterial chemotherapy with 5-FU, CDDP and MMC was extremely effective. He underwent distal pancreatectomy associated with partial resection of transverse colon. Hepatic recurrence was detected by MRI 8 months after the surgery. 5-FU (250 mg/day), CDDP (20 mg/day), and MMC (10 mg) was injected through a catheter introduced into the proper hepatic artery. His tumor became hardly detectable by MRI, and he was discharged about 1 month after admission. 5-FU (250 mg) and CDDP (20 mg) were injected every two weeks, and recurrence was not observed for 5 months.

A 63-year-old female, who had undergone sigmoidectomy for sigmoid carcinoma one year before, was admitted for multiple liver metastases. A urokinase-immobilized catheter was introduced into the proper hepatic artery via the gastroepiploic artery operatively. A daily arterial infusion of 5-FU (250 mg) was combined with a weekly arterial infusion of adriamycin (30 mg) or MMC (10 mg). After discharge, 5-FU (200 mg/day) was given orally and MMC (10 mg) was infused intraarterially every other week at an outpatient clinic. ADR or MMC was infused with angiotensin II, known to increase arterial blood supply to a malignant lesion. Ultrasonography demonstrated 35 to 50% reduction in tumor diameter. The density of metastases seen in computerized tomography became low indicating tumor necrosis. Plasma CEA level, which had initially been as high as 864 ng/ml, decreased rapidly and has remained within normal limits up to the present time. Arterial infusion chemotherapy using 5-FU, ADR or MMC in combination with angiotensin II seems to be effective in the treatment of multiple hepatic metastases from colorectal carcinoma.