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Background: Gastric cancer (GC) patients with positive peritoneal lavage cytology (CY1) and/or localized peritoneum metastasis (P1a) are defined as stage IV in the 15th edition of the Japanese Classification of Gastric Cancer. In Japan, the most common treatment for patients with CY1 and/or P1a is gastrectomy followed by postoperative chemotherapy., Patients and Methods: Subjects in this multi-institutional retrospective study were GC patients with CY1 and/or P1a who received surgical resection that leaves no macroscopically visible disease. Patients were selected from 34 institutions in Japan between 2007 and 2012. Selection criteria included adenocarcinoma, no distant metastasis except CY1 and P1a, and no prior treatment for GC before surgery., Results: Among 824 patients registered, 506 were identified as eligible, with a background of P0CY1, P1aCY0, or P1aCY1 (72.5%, 16.0%, and 11.5% of subjects, respectively). Sixty-two patients had not received postoperative chemotherapy (no-Cx), whereas 444 patients had received postoperative chemotherapy: S-1 monotherapy (S-1; n = 267, 52.7%), cisplatin plus S-1 (CS; n = 114, 22.5%), and others (n = 63, 12.6%). Overall survival (OS) was 29.5, 24.7, 25.4 and 9.9 months in the S-1, CS, 'others', and no-Cx groups, respectively [CS vs. S-1: hazard ratio (HR) 1.15, 95% confidence interval (CI) 0.89-1.50; p = 0.275]. In multivariate analysis, OS was similar between the S-1 and CS groups (CS vs. S-1: HR 1.19, 95% CI 0.92-1.55; p = 0.18)., Conclusions: Postoperative chemotherapy after gastrectomy that leaves no macroscopically visible disease may have some survival benefits for GC patients with CY1 and/or P1a. In contrast, S-1 plus cisplatin seems to have no additional benefit over S-1 treatment alone.

The patient-a Jehovah's Witness-was a woman in her 60s, with locally advanced sigmoid colon cancer. She had severe anemia, and a computed tomography scan of her abdomen showed a tumor with abscess formation and perforation that had invaded into the left urinary duct and the left ovary, without distant metastasis. It was difficult to perform curative resections without transfusion; therefore, CapeOX therapy was plannedas the neoadjuvant treatment. After 3 courses of CapeOX therapy, the patient's anemia improved, and the tumor and abscess had shrunk. Subsequently, a sigmoidectomy with D3 lymph node dissection, partial resection of the small intestine, and the left adnexectomy, as a radical surgery, were performed without blood transfusion. In cases of concomitant colon cancer with anemia that are treated with highly invasive surgery, it might be necessary to conduct systematic treatment in order to complete non-transfusion therapy.

The patient was a 68-year-old man who had undergone sigmoidectomy 1 year previously. Adjuvant therapy with tegafur- uraci(l UFT) and Leucovorin( UZEL) was administered. Seven months later, the carcinoembryonic antigen( CEA) level increased to 7.5 ng/mL. Enhanced computed tomography (CT) revealed a 4-cm mass in the mesorectum, and the patient was diagnosed as having local recurrence. Chemotherapy with oxaliplatin, 5-fluorouracil, and Leucovorin( mFOLFOX6) and radiation therapy( 60 Gy) were administered. As the tumor could not be detected after chemoradiotherapy, abdominoperineal resection was performed. Pathological examination showed no cancer and indicated a complete response. The patients CEA level has not increased and no recurrence has been detected on enhanced CT for 3.5 years. The tumor could be decreased in size by chemoradiotherapy and the operation could be safely performed without resecting other organs. Although surgery is generally performed for local recurrence, multidisciplinary therapy could be useful in performing such surgery safely.

We report a case of hyperammonemic encephalopathy related to 5-FU in an aged patient with recurrent colon cancer treated with FOLFIRI therapy. An 80-year-old man underwent right hemicolectomy for cecal cancer. After 10 months, surgical resection was performed for its local recurrence. He was then treated with FOLFIRI therapy, and during the fifth course, he presented with a sudden onset of congestive disturbances. Through radiographic examination and laboratory data, only hyperammonemia was found; he was therefore diagnosed with hyperammonemic encephalopathy. By starting branchedamino acid solutions for its treatment, his consciousness and serum ammonia were promptly improved. Hyperammonemic encephalopathy related 5-FU is caused by increasing ammonia production and its metabolic inhibition, and is worsened by renal dysfunction, dehydration, constipation, infections, or body weight loss. On account of the potential decrease of metabolic function of liver and kidney, an aged person tends to have hyperammonnemia more than a youth. Clinicians should be aware of the adverse events associated with hyperammonemia when then administer a large amount of 5-FU to elderly patients.

The patient was a 62-year-old man with bowel obstruction in a locally advanced rectal cancer. Computed tomography (CT) scan of the abdomen showed tumor enlargement(11.4 × 9.0 cm)that invaded the urinary bladder, but no distant metastasis. XELOX therapy was planned in order to shrink or eliminate the tumor after a sigmoid colostomy. Four courses of XELOX therapy were perfomed. Consequently, the level of the tumor marker had been restored to a normal range. CT scan revealed marked shrinkage of the tumor (6.1 × 5.2 cm) and a sharply-defined border between the tumor and the urinary bladder. Three weeks after chemotherapy, a low anterior resection as a radical surgery, and a temporary ileostomy were performed. The post-operative course was good. The histological effect was judged to be grade 3. There were no viable cancer cells in the rectal tumor and lymph nodes. The patient is alive and has been disease-free for 10 months after the operation. XELOX therapy as pre-operative chemotherapy might be safe and effective for patients with locally advanced rectal cancer.

The standard treatment for T4 locally advanced gastric cancer is gastrectomy with D2 lymph node dissection followed by adjuvant chemotherapy with S-1 for 12 months; however, prognostic outcome in Stage IIIb has been insufficient. It is expected that survival is improved by preoperative treatment with a triplet regimen of docetaxel, cisplatin and S-1 (divided DCS therapy). A multicenter Phase II study has been conducted to evaluate the safety and efficacy of two courses of preoperative chemotherapy followed by gastrectomy. Fifty-five patients are required for this study. The primary endpoint of the study is pathological response rate of primary lesions. Secondary endpoints are overall survival, disease-free survival, R0 resection rate and adverse events.

Objectives: Liver perfusion chemotherapy (LPC) for pancreatic cancer has been rarely undertaken in a postoperative adjuvant setting. We evaluated the feasibility and antitumor efficacy of LPC with 5-fluorouracil (5-FU) followed by gemcitabine treatment., Methods: This prospective study enrolled 27 patients who underwent pancreatic resection and subsequent LPC + gemcitabine treatment during a 3-year period. The liver was infused with 5-FU (125 mg/body per day per route) via both routes of hepatic artery and portal vein for more than 21 days. After that, gemcitabine (1000 mg/m) was administered biweekly., Results: Portal vein thrombosis developed in 1 patient, but 89% patients tolerated LPC for more than 21 days with no life-threatening complication. Systemic administration of gemcitabine was accomplished in 93%; however, 1 patient died of serious capillary leak syndrome. No grade 4 toxicity was recorded, except for that patient. Median survival time and disease-free survival were 27.5 and 24.5 months, respectively. Hepatic relapse was observed in 25.9% (n = 7). Survival was in favor of paraaortic node-negative cases (n = 20) with a 2-year survival of 68.7%., Conclusions: Liver perfusion chemotherapy was feasible with acceptable toxicity. Systemic use of gemcitabine also seems to be safe for the most part. This adjuvant chemotherapy shows promising survival benefit and seems to be indicative to paraaortic node-negative tumors.

Aspergillosis is a common fungal infection in immunocompromised patients undergoing chemotherapy. The incidence of invasive fungal infection in these patients has increased dramatically in recent years. We report a case of small-bowel infarction caused by Aspergillus in a 48-year-old man who was receiving chemotherapy for acute myeloid leukemia. On day 20 after the start of chemotherapy, right lower abdominal pain and rebound tenderness developed, with a high fever. A contrast-enhanced computed tomography scan showed a semicircular perfusion defect in the ileum. Thus, we performed partial resection of the ileum with primary anastomosis. Macroscopically, the ileum had mucosal ulcerations. Microscopically, there was transmural necrosis with microperforation and Aspergillus invading necrotic tissue and blood vessels. The patient had an uneventful postoperative course and was discharged 14 days after the procedure. Intestinal aspergillosis is rare and associated with high mortality. Thus, it should be considered in the differential diagnosis of neutropenic patients with sudden abdominal pain and fever.

Recently, low-dose 5-fluorouracil/cisplatin induction concurrent with radiation (chemoradiation) has been reported to be effective for locally advanced squamous cell carcinoma of the otorhinolaryngologic and gynecologic regions. However, to date, this therapeutic option has not been evaluated for squamous cell carcinoma of the skin. We evaluated chemoradiation therapy using cisplatin and 5-fluorouracil in two patients with locally advanced squamous cell carcinoma of the skin. Administration of cisplatin and 5-fluorouracil was conducted concurrently with conventionally fractionated radiation therapy. Cisplatin (patient 1: 4 mg/m(2)/d on days 1 to 5; patient 2: 15 mg/m(2)/d on days 1 to 5) and 5-fluorouracil (patient 1: 400 mg/m(2)/d for 7 days; patient 2: 850 mg/m(2)/d for 5 days) were administered intravenously for 1 hour and for 24 hours, respectively. Patient 1 underwent two courses of chemotherapy with a 3-week interval, and patient 2 underwent a single course of chemotherapy. The primary tumor of both patients showed complete regression, leaving ulceration. In patient 1, the ulceration completely resolved after 3 months. Patient 2 underwent surgical resection and full-thickness skin grafting. A histopathologic examination confirmed complete tumor regression. Neither patient suffered any serious side effects during this treatment. We conclude that chemoradiation using cisplatin and 5-fluorouracil was effective in these two patients with locally advanced squamous cell carcinoma of the skin. Several randomized studies have shown concurrent chemoradiation to be superior to radiation alone. This regimen is an option in managing patients who have unresectable primary tumors or who require preservation of local function.

We have experienced successful treatment of a multiple hepatic metastasis of rectal cancer with combination chemotherapy. The patient is a 57-year-old male with bowel obstruction accompanied by rectal cancer (SE, N3, P1, H3, M (-) stage IV) who underwent a Hartmann operation with D3 lymph node dissection on July 6, 2000. The histopathological findings revealed a well-differentiated adenocarcinoma (se, INFbeta, n3, ly2, v2, p1). From the 11th postoperative day, combination chemotherapy using 5-FU 750 mg/day and LV 300 mg/day was performed once a week. When he underwent 5 combination chemotherapy treatments, adverse effects of grade 3 occurred, and the serum CEA level rose rapidly. We changed his regimen at that time. He underwent 2 courses of combination chemotherapy with 5-FU 500 mg/day and CDDP 10 mg/day for 5 days. Additional courses of combination chemotherapy with 5-FU 500 mg/day, LV 25 mg/day and CDDP 10 mg/day were performed weekly in the outpatient department. The treatment was effective, and a complete response (CR) was noted 4 months after the chemotherapy. The same combination chemotherapy was performed biweekly for one year after CR. The patient has been receiving a subsequent single administration of UFT and has remained in remission for 3 years and 7 months after surgery.

Thymidylate synthase (EC 2.1.1.45) and thymidine kinase (EC 2.71.21) are key enzymes involved in de novo and salvage pathways for pyrimidine nucleotide synthesis. Both enzyme activities are increased in rapidly proliferating normal, fetal and neoplastic tissues. In a previous study, the activities of thymidylate synthase and thymidine kinase were relatively predominant in the poorly-and well-differentiated types of a gastric cancer. In the present study of patients with colorectal cancer, the serum thymidine kinase activities are elevated in cases at a clinically late stage, and in cases with a recurrence and a distant metastasis associated with abundant blood supply, i.e. metastasis to the liver, lung and bone. Well-differentiated colorectal cancer shows higher thymidine kinase activity than moderately-well-differentiated type as was previously shown in gastric cancer patients. Furthermore, neoadjuvant chemotherapy using the 5-fluorouracil derivative UFT demonstrates a stronger suppression of increased activities of thymidylate synthase in the tumorous tissues than in the non-tumorous mucosa.

A 26-year-old woman was admitted to our hospital for lumbago on November 29, 1995. The white blood cell count was 6,500/microliter with 26.5% myeloblasts and the bone marrow was hyperplastic due to myeloblasts. Myeloblasts were negative for myeloperoxidase and positive for alpha-naphthyl butylate esterase, CD11a (89%), CD11b (38%), CD11c (92%), CD33 (91%) and HLA-DR (58%). Chromosomal abnormalities were recognized: 46, XX, t(9;11) (p22;q23), 45, XX, -7, t(9;11) (p22;q23) and 47, XX, +19, t(9;11) (p22;q23). Acute myeloblastic leukemia (M5a) was diagnosed. Disseminated intravascular coagulation was also present. The patient received induction therapy and achieved remission on January 9, 1996, but myeloblasts increased to 3.6% in bone marrow despite consolidation therapy. Low doses of cytarabine (AraC) and etoposide were instituted on March 7, granulocyte colony-stimulating factor (G-CSF) was started on March 15, and pronounced skin infiltration developed on March 18. The patient received reinduction therapy from April 16 and administration of G-CSF was combined for 2 days, and a marked increment of myeloblasts in the peripheral blood was observed. After discontinuation of G-CSF, myeloblasts decreased and skin infiltration disappeared. However, the patient died of cerebral infiltration on June 30. The response of myeloblasts to G-CSF by in vitro liquid culture was noteworthy. The present case stresses the requirement for great caution to be exercised in the use of G-CSF in patients receiving low dose AraC.

It has been known that a high incidence of adenocarcinoma in distal colon can be induced by s.c. injection of 1, 2-dimethylhydrazine (DMH) into rats at weekly intervals. We investigated effects of radiofrequency hyperthermia (RF-HT) in combination with anti-cancer drug UFT (a combination of tegafur and uracil) on activities of DNA-synthesizing enzymes, using colon carcinomas induced by DMH treatment in rats. 1) Thymidylate synthetase (TS), DNA-synthesizing enzyme in de novo pathway of pyrimidine metabolism, increased to approximately 7-fold that of normal control colon in DMH-induced colon carcinomas in activity, but was markedly reduced to 48% of that in the carcinomas by administration of UFT. 2) Thymidine kinase (TK) in salvage pathway increased to approximately 8-fold that of the control in the carcinomas in activity, but was markedly reduced to 25% of that in the carcinomas by RF-HT treatment. 3) The TK-isozyme, that was thought to be a fetal type in the intracellularly cytoplasmic fraction and closely involved in rapid DNA replication, increased to approximately 24-fold that of the control in the carcinomas in activity, but was reduced to the nearly same level as that of the control by RF-HT treatment. This isozyme was labile in thermostability and easy to be inactivated in low pH. 4) The activities of TS and TK in the carcinomas were extremely suppressed by UFT administration in combination with RF-HT treatment. These results indicate that hyperthermochemotherapy with UFT may serve as an available treatment for colon carcinomas.

Thymidylate synthetase (TS) and thymidine kinase (TK) are known to catalyse the methylation of dUMP for the de novo synthesis of dTMP and the phosphorylation of thymidine for the salvage synthesis of dTMP in the pyrimidine pathway, respectively. High TS and TK activities have been observed in rapidly proliferating tissues such as foetal tissue, regenerating liver and carcinomas. TS and TK activities were measured in histologically normal colon mucosa and colorectal carcinomas with or without neo-adjuvant chemotherapy of an antitumor drug UFT (a combination of tegafur and uracil) in humans. In colorectal carcinomas, 5-FU and uracil levels were increased to 2.6- and 3.2-fold, respectively, those in normal colon mucosa by neo-adjuvant chemotherapy of UFT. In colorectal carcinomas, TS and TK activities were both increased to approximately 2- and 3-fold, respectively, those in normal colon mucosa without UFT treatment. In normal colon mucosa and colorectal carcinomas with neo-adjuvant chemotherapy of UFT, TS activities were reduced to approximately 50% and 40%, respectively, those without UFT treatment. These results indicate that neo-adjuvant chemotherapy with UFT may prevent dissemination of cancer cells during operation, and local recurrence and distant metastasis after operation, inhibiting DNA synthesis via the de novo pathway of pyrimidine synthesis in carcinomas.

Carcinoma of the colon was induced in rats by injection of a carcinogen 1,2-dimethylhydrazine (DMH), and thymidylate synthetase (TS) and thymidine kinase (TK) activities, which catalyze the biosynthesis of dTMP by the de novo pathway and the salvage pathway of pyrimidine synthesis, respectively, were measured in normal control colon, DMH-treated normal colon, and DMH-induced colon carcinoma with or without administration of two doses of an anti-cancer drug UFT (a combination of tegafur and uracil). TS and TK activities were both increased after treatment with DMH, markedly in colon carcinoma tissue, and to a lesser degree in normal-appearing colon tissue. This phenomenon is well explained by the hypothesis that biochemical alterations of DNA-synthesizing enzyme activities occur as a preliminary step prior to the development of overt cancerous transformation. A low dose of UFT inhibited TS activity but enhanced TK activity, therefore, the salvage pathway may compensate for the reduced level of the de novo synthesis. On the other hand, a large dose of UFT reduced both TS and TK activities, perhaps due to cytotoxic effects of UFT incorporation into RNA.