Randomized phase III trial of treatment duration for oral uracil and tegafur plus leucovorin as adjuvant chemotherapy for patients with stage IIB/III colon cancer: final results of JFMC33-0502.

BACKGROUND: While adjuvant chemotherapy is preferable for high-risk colon cancer, treatment duration is controversial. Oral uracil and tegafur (UFT)/leucovorin (LV) is widely used as a standard adjuvant chemotherapy for colon cancer in Japan. We conducted a phase III trial to investigate the optimal duration of adjuvant chemotherapy for stage IIB/III colon cancer. PATIENTS AND METHODS: Patients with curatively resected stage IIB/III colon cancer were eligible for enrollment in this trial. Patients were registered within 6 weeks after surgery and were randomly assigned to receive UFT/LV for 28 of 35 days for 6 months in the control group or for 5 consecutive days per week for 18 months in the study group. The primary end point was the disease-free survival (DFS), and the secondary end points were overall survival (OS) and safety. RESULT: A total of 1071 patients were registered from 233 centers. A statistically significant difference in DFS was not observed between the study group and the control group; the 5-year DFS was 69% in the study group and 69% in the control group. The 5-year OS was 85% in the study group and 85% in the control group. CONCLUSION: Eighteen-month treatment with UFT/LV did not improve DFS or OS compared with 6-month UFT/LV treatment in patients with stage IIB/III colon cancer. The important finding from this study is that not 18 months but 6 months of treatment is enough for postoperative UFT/LV for stage IIB/III colon cancer. CLINICAL TRIAL NUMBER: UMIN-CTR C000000245.

The inhibitory effects of TNP470 on tumour growth of head and neck carcinoma cell producing interleukin-8.

The anti-tumour effect of the angiogenic inhibitor TNP470, sigma-(chloro-acetyl-carbamoyl) fumagillol, a synthetic analogue of fumagillin, was studied in vitro and in vivo using KB cells, one of the human head and neck carcinoma cell lines that produce interleukin(IL)-8. In the in vitro study, the combination treatment of TNP470 and anti-IL-8 antibody significantly reduced the proliferation of KB cells. In the in vivo studies, TNP470 administration by any route (intratumoral: i.t., intraperitoneal: i.p., intravenous: i.v.) reduced the tumour volume significantly, compared to the control group. Among the groups administered TNP470, the anti-tumour effect was strongest in the it group. Furthermore, the concurrent treatment of anti-IL-8 antibody and TNP470 also maximally reduced the tumour volume. The combination therapy of TNP470 and anti-IL-8 antibody was very effective. These results suggest that combination therapy of TNP470 and anti-IL-8 antibody could be beneficial for solid tumours, such as head and neck cancer.

Immunization against intestinal bacterial endotoxin prevents alcoholic fatty liver in rats.

Accumulating evidences indicate that an endotoxin originating from intestinal gram-negative bacteria may be involved in alcohol-induced liver injury including fatty liver. Therefore, whether immunization against intestinal bacterial endotoxin blocked fatty liver induced by chronic alcohol and diet including much-unsaturated fatty acid was investigated in rats. The titer of antibody against the endotoxin increased significantly after 13 weeks of continuous immunization. Daily alcohol treatment was initiated at 12 weeks and continued for 4 weeks. Plasma glutamic pyruvic transaminase (GPT), glutamic oxaloacetic transaminase (GOT) and triglyceride (TG) levels increased significantly in non-immunized rats receiving alcohol, but not in immunized rats. Continuous alcohol treatment gradually decreased the survival rate to 60% from 13 days after beginning administration in non-immunized, but not immunized, rats. A histochemical study revealed that continuous treatment with alcohol and unsaturated fatty acids caused fatty liver in non-immunized, but not immunized, rats. This study strongly supports the hypothesis that alcohol-induced fatty liver is due to a circulating endotoxin, and suggests that immunization for endotoxin prevent the alcoholic fatty liver.

[Antitumor effect of the angiogenesis inhibitor, TNP470, on squamous cell carcinoma cells in head and neck cancer].

The antitumor effect of the angiogenesis inhibitor TNP470, O-(chloro-acetyl-carbamoyl) fumagillol, a synthetic analogue of fumagillin, was studied in vitro and in vivo on, cell line KB which produced interleukin (IL)-8. In vitro, TNP470 reduced the production of IL-8 from KB cells, the same as anti-IL-8 antibody (Ab.) The combination of anti-IL-8 Ab (10 micrograms/ml) and TNP470 (10 ng/ml) significantly inhibited the proliferation of KB cells, compared to no treatment (p < 0.05). Proliferation of KB cells was also significantly more suppressed by simultaneous treatment of cisplatin and TNP470 (1 mg/ml), than cisplatin alone. The in vivo antitumor effect of TNP470 was studied using anti-IL-8 Ab, anti-vascular endothel growth factor (VEGF) Ab, and TNP470, in administered by different routes, i.e., intratumoral (i.t.), intraperitoneal (i.p.), and intravenous. TNP470 (10 mg/ml) showed an antitumor effect, and intratumoral administration of TNP470 was the most effective route. Combined administration of anti-IL-8 Ab (i.p.) and TNP470 (i.t.) reduced tumor volume more than anti-IL-8 Ab alone did. These results suggest that the combination of TNP470, cisplatin, and anti-IL-8 Ab could be a beneficial treatment for solid tumors of the head and neck.

Subtotal peritonectomy with chemohyperthermic peritoneal perfusion for peritonitis carcinomatosa in gastrointestinal cancer.

Treatment for peritonitis carcinomatosa in gastrointestinal cancer remains to be established though it is one of the commonest causes of cancer death. Subtotal peritonectomy (SP) with chemohyperthermic peritoneal perfusion (CHPP) was developed for the new therapeutic strategy for peritoneal dissemination in gastrointestinal cancer in our department. SP includes resection of stomach, colon, small bowel, spleen, gall bladder, and parietal peritoneum. CHPP was carried out by heated saline containing 25 mg/l cisplatin, 10 mg/l mitomycin C, and 20 mg/l etoposide. Intraperitoneal temperature was maintained at 42 degrees C for 60 min. Fifteen gastric cancer and three colon cancer patients with severe peritoneal dissemination underwent these procedures. The averages of operating time, intraoperative bleeding volume, and total perioperative transfused blood volume were 9 h, 4400 ml, and 5600 ml, respectively. The patients estimated as complete resection and residual disease by histopathological study numbered 11 and 7. There was no treatment-related deaths though bleeding occurred in 5 patients; perforation in 2 patients; and abscesses in 2 patients. The 1-year survival rate (1ysr) and the 2-year survival rate (2-ysr) of all the patients were 57% and 21%, respectively. The 1-ysr and the 2-ysr of the patients who underwent complete resection were 67% and 40% significantly greater than the 43% and 0% of the patients who had residual tumors (p=0.02). The combination therapy of SP and CHPP is feasible in spite of its morbidity and has great possibilities in complete resection of peritoneal dissemination and prolongation of patient's survival.

Chemohyperthermic peritoneal perfusion for peritoneal dissemination in various intra-abdominal malignancies.

A total of 25 patients with severe peritoneal dissemination underwent chemohyperthermic peritoneal perfusion (CHPP). The primary tumors in these patients comprised colorectal cancer (n = 14), ovarian cancer (n = 6), cervical cancer, (n = 1), small bowel cancer (n = 1), pseudomyxoma retroperitonei (n = 1), cystoadenocarcinoma of liver (n = 1), and pancreas cancer (n = 1). The intraperitoneal perfusion was carried out with a magnet pump for 60 min. The heated perfusate contained anticancer drugs to act synergistically with the hyperthermia. The intraperitoneal temperature was maintained at 42.0-42.5 degrees C. Eight of 25 patients showed CR, four PR, ten NC, and three PD, and the percentage (CR+PR) representing the overall efficacy rate was 48.0%. The morbidity rate was 8% (2/25) and there was no treatment-associated mortality. The percentage (CR+PR) of the patients with colorectal cancer was 57%; ovarian cancer, 50%; and other malignancies, 20%. The 1 year-and 3 year-survival rates of all the patients were 55% and 26%, respectively. The median survival periods of the CR, PR, NC, and PD groups were 4.0, 1.0, 1.0, and 0.7 years, respectively. The survival curve of the CR group was the best of all the groups (P = 0.02). These results indicated that CHPP was a feasible therapy and exerted a direct anticancer effect on peritoneal dissemination especially in the case of ovarian cancer, and the prognosis of complete responders was improved.

A new surgical approach (peritonectomy) for the treatment of peritoneal dissemination.

BACKGROUND/AIMS: Despite the improvements of chemotherapy and surgical techniques, treatment results of peritoneal dissemination still remain pessimistic. METHODOLOGY: During a 10-year period, 106 patients with peritoneal dissemination from gastric cancer were treated with chemo-hyperthermic peritoneal perfusion (CHPP), peritonectomy + CHPP, systemic PMUE therapy, and surgery alone in 51, 15, 13, and 27 patients, respectively. In peritonectomy, disseminated nodules were resected as much as possible in combination with the combined resection of the abdominal organs and parietal peritoneum covering diaphragm, pelvis and abdominal wall. After resection, the abdominal cavity was treated with heated saline at 42-43 degrees, containing cisplatinum (CDDP), Mitomycin C (MMC), and etoposide for 1 hour. PMUE therapy was administered with one course of i.v. infusion of 75 mg/m2 of CDDP and 30 mg/body of MMC on the 1st day, followed by etoposide 50 mg/body on the 3rd, 4th, and 5th day, and with oral intake of 400 mg/body of UFT every day from the 1st day. RESULTS: No post-operative or chemotherapeutic deaths were observed. Systemic PMUE therapy showed no survival improvement, and survival of the peritonectomy + CHPP group was the best, following CHPP, systemic PMUE and surgery alone. CONCLUSIONS: Peritonectomy and CHPP may be the best choice for the treatment of peritoneal dissemination.

[Thymidylate synthase expression in patients with hypopharyngeal carcinoma].

We analyzed the relationship between clinical response to neo-adjuvant chemotherapy including 5-fluorouracil (5-FU) in patients with hypopharyngeal carcinoma (HPC) and thymidylate synthase (TS) expression in their tumors. TS expression was evaluated with immunohistochemical staining techniques on biopsy specimens from HPC patients. TS immunostaining was divided into four levels (TS0-TS3) according to its level and pattern. The relationship between prognosis, tumor size, nodal status, differentiation of tumor cells and TS expression were also investigated. There was a statistically significant association between the level of TS expression and tumor size (p < 0.01). In terms of the effectiveness of chemotherapy, tumor differentiation, nodal status and prognosis, a statistical difference was not found in TS expression. These results suggest that the level of TS expression may show the degree of tumor proliferation, but may not necessarily be useful to obtain a response to chemotherapy including other drugs, e.g., cisplatin and other derivatives of platinum.

Axial spondylometaphyseal dysplasia.

UNLABELLED: We present a previously undescribed skeletal dysplasia characterized by mild platyspondyly, small thorax with cupping of the anterior ends of the ribs, irregular proximal femoral metaphyses, and lacy appearance of the iliac wings. Two of the three cases were siblings. Retinitis pigmentosa and optic atrophy are associated findings. CONCLUSION: We describe a new type of spondylometaphyseal dysplasia (SMD) and propose the name axial SMD.

Generalized metaphyseal modification with cone-shaped epiphyses following long-term administration of 13-cis-retinoic acid.

UNLABELLED: We report on a 6-year-old girl with short stature which developed following the administration of 13-cis-retinoic acid (a synthetic derivative of vitamin A or retinoid) for 40 months as adjunct chemotherapy for neuroblastoma. Radiographic examination suggested osteophyte formation in the cervical spine, which is the most common skeletal manifestation of retinoid toxicity [10, 11]. In addition, severe metaphyseal cupping with a cone-shaped epiphysis primarily affecting rapidly growing long bones was found, which represented impaired enchondral ossification. This epi-metaphyseal alteration, though unusually severe, was reminiscent of the premature epiphyseal closure which has been described as an adverse effect of 13-cis-retinoic acid [10-12]. Other minor skeletal changes included posterior scalloping of the vertebral bodies and increased interpediculate distances, which were related to a widened spinal canal found on CT. A literature search disclosed several primary skeletal dysplasias with superficial radiological similarities to those of the present patient. However, these entities showed significant clinical and radiological differences from our patient. CONCLUSION: The precise cause of the generalized skeletal alteration in the present patient remained unknown, but it conceivably resulted from the administration of 13-cis-retinoic acid.

[Chemohyperthermic peritoneal perfusion and high-dose chemotherapy followed by peripheral blood stem cell transplantation in advanced colon cancer--a case report].

A 49-year-old woman who suffered from caecal cancer in 1988 underwent chemohyperthermic peritoneal perfusion for peritoneal and ovarian metastases in 1990, and high dose chemotherapy (HDC) with peripheral blood stem cell transplantation (PBSCT) for lung metastases in 1995. Heated saline containing anticancer drugs such as cisplatin, mitomycin C, etoposide (ETP), and pirarubicin, was intraperitoneally perfused at 43 degrees C for 60 minutes. The CD34 positive cells were mobilized by intravenous 500 micrograms G-CSF administration on five consecutive days. These cells were transplanted three days after the last day in the course of HDC, which included intravenous administration of 475 mg carboplatin, 2,020 mg cyclophosphamide, and 540 mg etoposide. The patient has survived with no sign of the disease.

Effects of intraoperative chemohyperthermia in patients with gastric cancer with peritoneal dissemination.

BACKGROUND: The most common cause of noncurative resection and recurrence is gastric cancer is peritoneal seeding. However, the results of treatment of peritoneal dissemination with chemotherapy have been poor with 5-year survival rates of 0%. METHODS: A new in vitro thermochemosensitivity test was performed on gastric cancer cells obtained from 19 surgically resected specimens by using tetrazolium-based colorimetric assay (MTT assay). A novel treatment of the intraoperative chemohyperthermia was undertaken in 83 patients with gastric cancer with peritoneal dissemination. After aggressive resection of primary tumor, lymph nodes, and peritoneal metastases, warmed saline solution containing mitomycin C 30 mg, etoposide 150 mg, and cisplatin 300 mg was introduced into the peritoneal cavity via a closed circuit continuous hyperthermic peritoneal perfusion (CHPP) for 60 minutes to keep the abdominal temperature at 42 degree to 43 degrees C by means of a heat exchange mechanism. RESULTS: The in vitro thermochemosensitivity test that 43 degrees C enhanced the cytotoxin effects on gastric cancer cells under clinically achievable drug concentrations. During CHPP, drug concentrations of cisplatin, mitomycin C, and etoposide in the perfusate remained statistically higher than in the peripheral venous circulation. Among 43 evaluable patients with residual peritoneal seeding, eight (19%) and nine (21%) exhibited complete response and partial response, respectively. The overall 1- and 5-year survival rates were 43% and 11%, respectively. Patients who underwent complete resection survived significantly longer than those with residual disease, and those with complete response had a significantly better prognosis than did those with partial response, and nonresponders. One-year survival rates with complete response, partial response or nonresponders were 88%, 27% and 22%, respectively. Five patients survived longer than 5 years. CONCLUSIONS: Our triple treatment combining surgery and CHPP is an effective therapy for selected patients with gastric cancer with peritoneal dissemination.

Intrathoracic hyperthermochemotherapeutic perfusion for the intrathoracic malignancies in gastric cancer.

BACKGROUND/AIMS: We introduced intrathoracic hyperthermochemotherapeutic perfusion to two patients with intrathoracic lesions in gastric cancer, one patient with pleural dissemination and the other with left lung metastases. MATERIALS AND METHODS: Heated saline containing cisplatin, mitomycin C, and etoposide was circulated through the patient's thorax by a magnetic pump for an hour. RESULTS: The effects of this procedure were estimated complete respose in the former and no change in the latter. There were no complications. While the intrathoracic temperatures were stable between 42.0 and 42.5 degrees C, systemic temperatures measured at esophagus, urinary bladder, pulmonary artery, and tympanic membrane very gradually increased and peaked under 38.6 degrees C. The drug concentration in the perfusate was much lower than the peak plasma concentration, though concentration in the plasma was higher than the peak plasma concentration. CONCLUSIONS: This procedure is one of the preferable methods for treatment of intrathoracic lesions in gastric cancer because of easy temperature control, pharmacological advantage, and lack of side effects.

Colovesical fistula due to sigmoid colon diverticulitis: a case report.

We present a case of colovesical fistula due to sigmoid colon diverticulitis. A 63-year-old woman was referred to our department with the complaints of dysuria, turbid and foul smelling urine. She was treated twice for acute cystitis at the referral hospitals. A diagnosis of colovesical fistula was confirmed on barium enema. She underwent partial resection of sigmoid colon with primary anastomosis and partial cystectomy with repair of bladder wall and covered with omentum. Retrograde cytography taken on the 20th post-operative day revealed no leakage of contrast medium. She was asymptomatic at 3 months of follow-up.

[Successful neoadjuvant chemotherapy in a patient with advanced gastric cancer with multiple liver metastases].

We described a case of advanced gastric cancer with multiple liver metastases, who was placed on neoadjuvant chemotherapy using CDDP and 5-FU (FP therapy) with a marked reduction in tumor load. The case was a 67-year-old male, who was admitted with a Borrmann III type advanced gastric cancer with multiple liver metastases. FP chemotherapy was carried out two times as neoadjuvant chemotherapy. As a result, both primary cancer and the metastatic tumors showed a remarkable reduction. Then, total gastrectomy with combined resections of spleen and transverse colon was done, and a reservoir was inserted into the hepatic artery. Postoperatively, intrahepatic arterial infusion of CDDP with oral administration of 5-FU was done in the outpatient clinic for about eleven months. But thirteen months later, he died from the rapid recurrence of the tumor.

[A case of parotid tumor showing remarkable regression following hyperthermo-chemo-radiotherapy].

A 72-year-old woman developed adenocarcinoma of the left parotid gland. Because of the excessive size of her tumor and the fact that she suffered from severe liver dysfunction, she was treated by hyperthermo-chemo-radiotherapy (HCR therapy). After ten sessions of radiofrequency hyperthermia with HEH 500 (13.56 MHz radiofrequency wave), 50-Gy irradiation from a linac and administration of 33.0g of tegafur in suppository form, the tumor mass showed remarkable regression decreasing in size by as much as 84% on computed tomography. Histologically the tumor which was resected under local anesthesia, showed almost total necrosis. The multidisciplinary HCR therapy was well tolerated and effective as a therapy for cancer in this case.

[Huge Virchow's metastasis in gastric cancer made resectable by hyperthermochemoradiotherapy].

A 75-year-old woman who had undergone gastrectomy for gastric cancer at the age of 61 developed a huge left supraclavicular tumor (15 X 10 X 10 cm) suspected of being Virchow's node. She was treated with hyperthermochemoradiotherapy (HCT-therapy). After 10 sessions of radiofrequency hyperthermia by a Thermotron RF8, irradiation with 52.8 Gy of 60Co and injection of 8 mg of MMC, the tumor mass decreased by 77% on CT. The histologically resected specimen revealed coagulation necrosis in almost all areas. This case, which was considered HCR-therapy-effective, was estimated as Grade 3 according to The General Rules for the Gastric Cancer Study (The 11th edition.)