[A case of advanced gastric cancer that was resectable after asctic fluid had disappeared following administration of TS-1].

A 60-year-old man who had suffered from epigastic pain and general malaise from November 1999 was admitted to our hospital due to Borrmann type 3 gastric cancer with ascites on December 7, 1999. We considered a radical B operation impossible, and placed the patient on neoadjuvant TS-1 chemotherapy consisting of 1 M tegafur, 0.4 M gimestat, and 1 M otastat potassium. There were no side effects other than Grade 1 nausea and mild loss of appetite throughout the chemotherapy. After 8 weeks of administration, the primary lesion was reduced in size, and ascitic fluid had disappeared on abdominal computed tomography images. Therefore, a total gastrectomy with splenectomy and D2 lymph node dissection was performed on March 31, 2000. This was a radical B operation that was not possible earlier. The pathological diagnosis was tub2, SE, N1, CY0, H0, P0, M0, INF gamma, ly1, v1, PM (-), DM (-) and the antitumor efficacy of TS-1 was Grade 2 histologically. The patient remains alive and in good condition with no relapse of the gastric cancer 8 months after surgery.

[An effective case of intraperitoneal and intra-arterial combined chemotherapy for unresectably advanced Borrmann type IV gastric carcinoma].

We report an effective case of intraperitoneal and intra-arterial combined chemotherapy for unresectably advanced Borrmann type IV gastric carcinoma. A 59-year-old man was admitted with advanced Borrmann type IV gastric carcinoma in June 1999. With informed consent, the patient underwent laparotomy, which revealed far advanced Stage IV gastric carcinoma of T4, N3, P1, H0, M1, CY1 for resection. Three ports to both subphrenic pouches and Douglas' pouch were placed for intraperitoneal infusion chemotherapy. Pathological findings of omental lesions were metastatic gastric carcinomas of por 2-histological type. Intraperitoneal and intravenous infusion combined chemotherapy with a modified low-dose CDDP and 5-FU regimen were started. The artery-side port was placed in the aorta at the Th. 9/10 levels for arterial infusion chemotherapy in September 1999. The patient was followed-up as an outpatient and continued to receive the intraperitoneal and intra-arterial combined chemotherapy. We report an effective case of intraperitoneal and intra-arterial combined chemotherapy for unresectably advanced Borrmann type IV gastric carcinoma, who could be followed-up as an outpatient while maintaining his quality of life.

[Intraperitoneal and intrathoracic administration of hydroxyapatite-carboplatin (HAp-CBDCA)].

We have investigated the efficacy of intraperitoneal or intrathoracic administration of hydroxyapatite particles (HAp) loaded carboplatin (CBDCA). HAp-CBDCA (HAp; 200 mg, CBDCA; 4 mg) was administered intraperitoneally to rats with peritoneal carcinomatosis. The area under the curve of the ascitic platinum (Pt) increased significantly with rats given HAp-CBDCA, and the omental Pt levels in the HAp-CBDCA group remained higher and longer. Additionally, the HAp-CBDCA group showed a trend toward longer survival when compared with the CBDCA alone group. In clinical use, HAp-CBDCA (HAp; 5 g, CBDCA; 150 mg) was administered intrathoracically to a patient who had undergone esophagectomy. The Pt in serum was detected until 7 days after administration of HAp-CBDCA.

[An effective case of arterial infusion therapy of low-dose CDDP and continuous 5-FU for isolated hepatic recurrence of gastric carcinoma].

We report an effective case of arterial infusion therapy of low-dose CDDP and continuous 5-FU for isolated hepatic recurrence of gastric carcinoma. An 83-year-old man was admitted for epigastric pain and vomiting due to a huge liver metastasis of gastric carcinoma in May, 1997. Nineteen months earlier, in October of 1995, he had undergone distal gastrectomy and D2 lymph node dissection with Billroth I reconstruction. His conclusive stage and pathological findings were as follows. The conclusive stage was stage II: t3, n0, P0, H0. Histological typing was tub 2. Lymph node involvement was not detected, but venous invasion was found in the surrounding regional lymph nodes. CEA had been getting elevated from November, 1996. But he had been well until March, 1997, when CT scans revealed huge hepatic recurrence. The artery-side port was placed for hepatic arterial infusion therapy for liver metastasis. Intra-arterial bolus injection of low-dose CDDP (5 mg) and continuous intra-arterial infusion of 5-FU (250 mg/day for 7 days) were started. Through 4 courses of this arterial infusion therapy, the patient improved. CT scans revealed shrinking of liver metastasis after 3 months of this therapy. The patient was followed in an outpatient clinic and continued to receive this arterial infusion therapy once every 4 weeks. New lung metastasis was detected 9 months after the start, but liver metastasis continued to be responded. The patient died from bleeding into the bile duct from the liver metastasis 16 months after the start of arterial infusion therapy, when metastatic lesions of liver continued to shrink. Arterial infusion therapy of low-dose CDDP and continuous 5-FU may be effective for isolated hepatic recurrence of gastric carcinoma.

[A case of gastric cancer with decreased dihydropyrimidine dehydrogenase activity].

We analyzed the pyrimidine metabolite in the urine of a patient with severe mucositis and hand and foot syndrome, who was administered 5-fluorouracil for recurrence of gastric cancer. From our analysis, it was suggested that the patient had decreased dihydropyrimidine dehydrogenase activity. Dihydropyrimidine dehydrogenase activity is usually measured in peripheral blood mononuclear cells, but this time it was estimated from the analysis of uracil, dihydrouracil, thymine, and dihydrothymine in the urine. We concluded that urinary analysis of the pyrimidine metabolism is effective as screening for the prediction and prevention of 5-fluorouracil toxicity.

[Chemotherapy targeting regional lymph nodes by gastric submucosal injection of liposomal adriamycin in patients with gastric cancer].

We investigated the delivery of adriamycin (ADR) to the regional lymph nodes of the stomach following the gastric submucosal injection of liposomal adriamycin (Lipo-ADR) in 34 gastric carcinoma patients, as well as following intravenous administration of free ADR (F-ADR) in 18 patients, then followed these patients for a minimum of 5 years or until death. Prior to radical gastrectomy. Lipo-ADR was endoscopically injected into the gastric submucosa adjacent to the primary tumor via a needle-tipped catheter. After Lipo-ADR injection, the ADR concentration in the primary and secondary drainage lymph nodes was higher than in the other regional lymph nodes. Thus, the regional nodes more susceptible to the involvement of metastasis showed higher levels of ADR. In contrast, the intravenous administration of F-ADR produced a similar and far lower ADR concentration in all the nodes. Delivery of ADR to the primary drainage lymph nodes following injection of 5 mg of Lipo-ADR (n = 19) was compared with delivery to the left gastric artery lymph nodes after intravenous administration of an equal dose of Lipo-ADR. The ADR levels (microgram/g) after gastric submucosal injection were 15.1 +/- 8.30 on day 1 (n = 4) and 11.9 +/- 4.80 on day 4 (n = 6), whereas, the ADR levels after intravenous administration were 0.29 +/- 0.10 on day 1 (n = 4) and 0.36 +/- 0.0 on day 4 (n = 2). The differences between the two groups were significant (p < 0.05). The ADR levels after the gastric submucosal injection were far higher than those after intravenous administration. These findings indicate that the gastric submucosal injection of Lipo-ADR can specifically deliver ADR to the regional lymph nodes at high concentrations. Disease-free survival of the stage III a-b patients (n = 7) with this regional lymph nodes-targeted chemotherapy was 71.4% in 5 years, while that with intravenous F-ADR administration (n = 5) was 60.0%. This preoperative adjuvant chemotherapy targeting the regional lymph nodes may be effective in preventing the recurrence of gastric carcinoma.

[Possibility of alpha-tricalcium phosphate (alpha-TCP) particles as a drug carrier for treatment of abdominal carcinomatosis].

It is reported that cancer foci are unevenly distributed in abdominal carcinomatosis after intraperitoneal inoculation of cancer cells in rats. The organs may be briefly classified into two groups in terms of the deposit of cancer cells: one that shows an affinity to the cells includes the greater omentum, mesenterium, and gonadal fat and etc., and the other having lesser affinity the stomach, intestine, and spleen and etc. Such uneven distributions are likely to occur in clinical cases of abdominal carcinomatosis resulting from progressive digestive cancers. We have explored the possibility of alpha-Tricalcium Phosphate (alpha-TCP) particles as a drug carrier in which carboplatin (CBDCA) was incorporated. alpha-TCP, which has chemically similar properties to hydroxyapatite, is known to have an excellent biocompatibility with human tissues and is biodegradable. The present study focused on the localization and the forms of alpha-TCP particles, and the morphological changes of the surrounding tissues after intraperitoneal administration using normal and cancer-bearing rats. The following results were obtained: (1) alpha-TCP particles were taken up to a large extent in the "milky spot" of the greater omentum, followed by the "stomata" of the mesenterium, gonadal fat, diaphragm, peritoneum, and liver in normal rats. No alpha-TCP particles were caught up in the tissues of the stomach, small intestine, colon, and spleen. The margination and emigration of lymphocytes were slightly observed around those organs. (2) alpha-TCP particles were predominantly detected on the cancer mass of the greater omentum in abdominal carcinomatosis-bearing rats. It should be noted that the particles collected in the same place where cancer cells were caught, suggesting that the localization of the drug-containing particles result in higher drug concentrations in the cells possibly for extended times. The alpha-TCP particles system is expected to be a good candidate for targeting chemotherapy and specially for abdominal carcinomatosis.

[Intraperitoneal administration of carboplatin loaded alpha-tricalcium phosphate (alpha-TCP) particles in rats bearing abdominal carcinomatosis].

It is difficult to treat abdominal carcinomatosis with conventional chemotherapy, and many kinds of localized chemotherapy have been attempted. We used alpha-tricalcium phosphate (alpha-TCP) particles as a drug carrier in this study. alpha-TCP, which has chemically similar properties to human bone, has an excellent biocompatibility with human tissues and is biodegradable. The particles measured 50 to 100 microns in diameter, were round in shape and very porous. These particles have many open micro-pores of about 1 to 3 microns, which are beneficial for containing drugs. The compatibility and biodegradation of alpha-TCP particles were studied following intraperitoneal (ip) administration in normal rats. The following results were obtained: (1) alpha-TCP particles were intaken in the great omentum, and dissolved gradually. (2) The efficacy of ip administration of carboplatin-loaded alpha-TCP (alpha-TCP-CBDCA) was examined using a Donryu rat model with AH130 abdominal carcinomatosis. The alpha-TCP-CBDCA contained 200 mg alpha-TCP and 4 mg CBDCA. The pharmacokinetics of CBDCA following ip administration of alpha-TCP-CBDCA were studied. Pt levels in ascites and great omentum were higher in the alpha-TCP-CBDCA ip from 0.5 to 168 hours than those in the free-CBDCA ip and iv groups. These results suggest that the efficacy of CBDCA may be enhanced by utilizing alpha-TCP particles as a drug delivery carrier.

Cine magnetic resonance imaging study of blood flow and wall motion of the aortic arch.

The aortic arch has 3D distortions in the transverse arch in the axial view, and we previously reported that this distortion is a risk factor in the pathogenesis of arch aneurysms. In this study, we evaluated blood flow and movement of the aortic arch. In 10 healthy young volunteers, ECG-gated cine magnetic resonance imaging was carried out in the axial plane of the transverse arch, the coronal plane of the ascending arch, and the long axial plane along the entire arch. 1. Left anterolateral movements around the midpoint of the transverse arch in the systolic phase were observed in all of the men (6.3 +/- 1.59 mm) and women (4.8 +/- 0.73 mm). 2. A jet flow was detected in the systolic phase along the right side of the aortic wall. At the top of the plane, this jet flow turned to the left in a clockwise rotation in the anterior view. 3. In the long axial plane, a turbulent flow in the systolic phase was observed distal to the left subclavian arterial orifice in 6 of the 7 cases. In conclusion, this turbulent flow and left anterolateral wall motion of the transverse arch are due to anatomical three-dimensional distortion of the transverse arch. We propose that these phenomena may be important risk factors in the pathogenesis of arch aneurysms.

[A case of advanced gastric cancer treated effectively with neo-adjuvant chemotherapy using l-leucovorin and 5-FU].

A 59-year old man was diagnosed as having advanced gastric cancer, liver metastasis and lymph node metastases after a closed medical examination. Because Schnitzler metastasis was also suspected, chemotherapy was started pre-operatively. The schedule of administration was as follows. One course was l-LV 250 mg/m2 and 5-FU 600 mg/m2 injected intravenously every week and continued for 6 weeks. The UGI examination showed partial response in stomach cancer, and liver metastasis disappeared on CT-scan after 2 courses. We performed total gastrectomy, lymphadenectomy, splenectomy and partial resection of liver. Histological effects showed Grade 1a on main tumor, Grade 2 on liver metastasis, and No. 3 lymphnode metastasis. The survival time was 476 days.

[Antitumor effects of liposome-entrapped carboplatin (Lipo-CBDCA) after intraperitoneal administration in rats bearing carcinomatous peritonitis].

We examined the distribution of Lipo-CBDCA after intraperitoneal administration and antitumor effects in rats. The serum levels of platinum in Lipo-CBDCA were lower than in free-CBDCA intraperitoneal or intravenous administration at 15 and 30 min. after administration. After 3 hours, Lipo-CBDCA showed higher levels of serum platinum than free-CBDCA. These data showed the slow release of Lipo-CBDCA. The antitumor effects of Lipo-CBDCA were studied in rats with peritoneal dissemination due to AH 130 tumors. Intraperitoneal treatment with Lipo-CBDCA prolonged the life span significantly compared with Lipo-CBDCA. No side effects of chemotherapy were found in the liver, kidney, spleen or small intestine. A gastric cancer patient suffering from carcinomatous peritonitis with remarkable ascites was treated with Lipo-CBDCA intraperitoneally. After several injections of Lipo-CBDCA, the ascites disappeared completely and the CEA level of ascites decreased dramatically. These results indicate that intraperitoneal chemotherapy with Lipo-CBDCA may be more effective than free-CBDCA to manage carcinomatous peritonitis, and may be therapeutically useful without toxic side effects.

Anaplastic large cell lymphomas expressing the novel chimeric protein p80NPM/ALK: a distinct clinicopathologic entity.

Anaplastic large cell lymphoma (ALCL) is a subtype of non-Hodgkin's lymphoma characterized by the CD30+ large neoplastic cells and sometimes carries a t(2;5)(p23;q35). Recently, we found a novel hyperphosphorylated 80-kD protein tyrosine kinase, p80, in ALCLs with t(2;5). Subsequent cDNA cloning showed p80 to be a fusion protein of two genes, the novel tyrosine kinase gene and the nucleophosmin gene, in accordance with the sequence of the NPM/ALK gene (Morris et al, Science 263:1281, 1994). Meanwhile, the clinicopathologic features of p80-carrying ALCLs have remained unclear. Paraffin sections of 105 cases of ALCL were immunostained using anti-p80 antibody, and 30 of them were shown to express p80. Clinicopathologic comparison between p80-positive and -negative ALCLs showed that p80-positive cases occurred in a far younger patient age group (16.2 +/- 12.9 years; p80-negative cases, 51.0 +/- 22.3 years; P < .0001) and the patients showed a far better 5-year survival rate (79.8%; p80-negative group, 32.9%; P < .01). These data showed that p80-positive ALCL is a distinct entity both clinically and pathogenetically and should be differentiated from p80-negative ALCL.

[Postoperative choreoathetosis in a case of tetralogy of Fallot].

We presented a case of severe postoperative choreoathetosis which occurred in a 3-year-old boy with tetralogy of Fallot early postoperatively but almost completely recovered within two years after the operation. Because of the large coronary arterial branch on the right ventricular outflow, a small outflow incision and deep hypothermia (lowest rectal temperature was 13 degrees C) and short duration of circulatory arrest (8 minutes) were adopted. Postoperative course was uneventful till the onset of choreoathetosis on the fifth postoperative day. His symptoms and signs of choreoathetosis, oral-facial dyskinesias, hypotonia, affective changes and also pseudobulbar signs were becoming serious during the first week from the onset, but afterwards his condition started getting better gradually every week, and every month. Now, 20 months after the operation, he is almost completely recovered except for small and slow involuntary movements. Though investiations including CT, MRI and EEG were all almost normal, regional nonspecific low area of the frontal lobe and cerebellum was detected by SPECT (single photon emission computed tomography) on the 32nd and 94th postoperative days, respectively.

Perforated acute appendicitis in a patient with AIDS/HIV infection: report of a case.

We report herein the case of a 40-year-old man with AIDS who was admitted to hospital with severe abdominal pain, fever, and chills. He underwent an emergency laparotomy which revealed a perforated appendix with suppurative peritonitis. An appendectomy with peritoneal drainage was carried out, but the postoperative course was complicated by fever without leukocytosis; however, he gradually improved following treatment with intravenous antibiotics, granulocyte colony-stimulating factor (G-CSF) and immunoglobulins, and made a complete recovery. His postoperative course demonstrates the effectiveness of this treatment regimen for patients with AIDS complicated by infection without an increase in the white blood cell count (WBC).

[A pathological study of primary malignant lymphomas of the thyroid].

Thirty cases of a primary malignant lymphoma (ML) have been studied clinicopathologically and immunohistochemically. The average age of the patients was 59.1 years, and the ratio of males to females was 1:1.7. According to the Kiel classification of MLs, 53.3% had a low grade malignancy and 46.7% were a high grade malignancy. Therefore, the number with a low or a high grade malignancy was almost equal. Most of the low grade malignancies were ML, centroblastic centrocytic, and most of the high grade malignancies were ML, lymphoblastic. From histopathological and immunohistochemical studies, most cases were considered to be of B-cell origin and two thirds of the cases were regarded as being of a follicular center cell origin. Prognosis was better than that of other MLs. Finally, MLs of the thyroid were found combined more frequently with chronic thyroiditis of the Hashimoto type than malignant epithelial neoplasms.

Aryl hydrocarbon hydroxylase activity levels in the hepatic microsomal fraction from MC- or TCDD-treated mice: a comparison between aromatic hydrocarbon responsive and non-responsive strains.

The effects of in vivo administration of polycyclic aromatic hydrocarbons on the levels of aryl hydrocarbon hydroxylase (AHH) activity in aromatic hydrocarbon (Ah) responsive and non-responsive strains of mice were studied using the hepatic microsomal fraction. Injection of 3-methylcholanthrene (MC; 42 mg/kg body wt.) or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; 120 micrograms/kg body wt.) into both strains produced marked enhancement of AHH activity except for MC treatment of Ah non-responsive strains. Addition of 7,8-benzoflavone (BNF) to the microsomal AHH assay mixture prepared from mice previously injected with vehicle (olive oil) alone caused an increase in activity when the mice were responsive, while BNF lowered the activity in non-responsive strains. With regard to MC-injected mice, BNF and 3-methyl-sulphonyl-4,5,3',4'-tetrachlorobiphenyl (3-MSF-TCB) decreased microsomal AHH activity in Ah-responsive mice, whereas these drugs enhanced the activity in Ah-non-responsive strains. 3-MSF-TCB also had inhibitory potency on AHH activity, but the mechanism of inhibition seems to be somewhat different from that of BNF. It may also suggest that cytochrome P-450 isozymes inhibited by BNF are different from those inhibited by 3-MSF-TCB.

In vitro effects of methylsulfonyl polychlorinated biphenyls and 7,8-benzoflavone on aryl hydrocarbon hydroxylase activity in human lymphoblastoid cells.

The effects of 11 isomers of methylsulfonyl polychlorinated biphenyls (MSF-PCBs) on the aryl hydrocarbon hydroxylase (AHH) activity were examined at a fixed dose of 1.5 micrograms/ml by using cultured lymphoblastoid cells. One of the isomers 3-MSF-3',4,4',5-tetraCB, as well as 4-MSF-3,3',4',5-tetraCB and 4-MSF-3,3',4',5,5'-pentaCB, effectively reduced the AHH activity when added to the culture medium, especially that previously treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to induce the AHH activity. However, the inhibitory potencies exerted by the above three MSF-PCB compounds were smaller than that by 7,8-benzoflavone (BNF). When added to the culture medium simultaneously with TCDD or 3-methylcholanthrene (MC), 3-MSF-3',4,4',5-tetraCB blocked the enhancement of the AHH activity by TCDD but did not that by MC. This is in contrast to BNF which blocked the increases due to both TCDD and MC. On the other hand, 3-MSF-3',4,4',5-tetraCB added directly to the reaction mixture for the TCDD-induced AHH activity showed little influence, while BNF decreased the same activity. These results imply that the effect of 3-MSF-3',4,4',5-tetraCB on the AHH activity is different from that of BNF.

Immunohistochemical and histometrical studies of the human thymus with special emphasis on age-related changes in medullary epithelial and dendritic cells.

Age-related changes in medullary epithelial and dendritic cells in the human thymus were examined quantitatively using immunohistochemistry and histometry. The material used was thymic biopsy specimens obtained from 105 patients during cardiac surgery, none of whom had immunological abnormalities. By using keratin and tissue polypeptide antigen markers to identify epithelial cells and S-100 protein and LN-2 markers to identify dendritic cells, the numbers of these cells in the medulla were counted morphometrically. The relative proportions of the cortex, medulla, Hassall's bodies, perivascular space, connective tissue and fatty tissue were evaluated using a computer image-analysis system and the respective relative volumes were calculated. Our results indicate that the number of medullary dendritic cells/mm2 and the relative volume of cortical thymocytes decrease steadily up to the age of 40 years, whereas no major change was found in the number of medullary epithelial cells/mm2.