An oncogenic form of the Flt-1 kinase has a tubulogenic potential in a sinusoidal endothelial cell line.

We have previously reported a constitutively activated form of the Flt-1 kinase (BCR-FLTm) molecularly engineered based on the structural backbone of the activated tyrosine kinase BCR-ABL. Here we show that it can induce not only growth stimulation but also tubulogenic differentiation of non-tubulogenic NP31 (non parenchymal) sinusoidal endothelial cells of rat liver in basement membrane matrix. Tubules formed in vitro were accompanied by fenestration structures and allowed circulation when transplanted into syngeneic animals. This biological response was not observed in other activated forms of kinases constructed in a similar fashion, which include Trk (BCR-TRK), KDR (BCR-KDR), and the parental BCR-ABL. Interestingly, formation of fine tubules was accomplished with lower but not higher expression levels of BCR-FLTm. Compared to NP cells in primary culture NP31 is deficient in expression of alpha1 integrin subunit, which was restored by expression of BCR-FLTm that had tubulogenic ability. Matrix-induced tyrosine phosphorylation of an adaptor protein Shc with recruitment of Grb-2 was observed even when tubulogenesis was nearly completed at G1 stage of the cell cycle in 2-3 weeks. Activation of matrix metalloproteinase 2 (MMP-2) and expression of urokinase type plasminogen activator (uPA) was observed with cellular invasion into matrix at the depth of 200-300 microm. Inhibitors for MAP kinase activator MEK1 and for serine proteases showed deleterious effects on the tubulogenesis. We suppose that matrix ligand-induced integrin signals cooperate with a low level of Flt-1 kinase activity to promote tubulogenic behaviors of endothelial cells in this system.

[Experimental and clinical studies on BRL 25000 (clavulanic acid-amoxicillin) granules in pediatric infections].

BRL 25000, granules preparation containing 2 parts of amoxicillin (AMPC) and 1 part of clavulanic acid (CVA, beta-lactamase inhibitor) as its potassium salt, has been investigated fundamentally and clinically. An in vitro study of the antibacterial activity of BRL 25000 against clinically isolated S. aureus (34 strains) showed higher activity than for AMPC alone and demonstrated that CVA potentiated the activity of AMPC, showing a synergistic effect against beta-lactamase producing organisms. A total of 27 pediatric patients aged between 6 months and 13 years 8 months (23 with respiratory infections and 4 with urinary tract infections) were treated with a daily dose ranging from 31.7 to 54.5 mg/kg, divided into 3 or 4 doses a day for periods of 4-18 days. The clinical effect was evaluated as excellent in 26 cases, poor in 1 case and the efficacy ratio was therefore 96.3% (26/27). The bacteriological effect against 12 organisms isolated from 9 patients was studied and all were eradicated (12/12). A drug-related side effect was observed in only 1 patient who developed diarrhea on the 4th day of treatment which continued during the treatment for 10 days. However, no severe side effect and no abnormality related to the drug in laboratory findings were observed. From these results it is concluded that BRL 25000 will be a clinically effective drug in the treatment of mild and moderate infections in the pediatric field.

[Clinical evaluation of imipenem/cilastatin sodium in the pediatric field].

Imipenem/cilastatin sodium (MK-0787/MK-0791) was evaluated for its safety and efficacy in 7 pediatric patients with infections. The clinical efficacy ratio was 100 percent. No side effect was observed except for elevations of S-GOT and S-GPT and eosinophilia in 1 patient. It may be considered that MK-0787/MK-0791 is a safe and useful antibiotic for the treatment of pediatric infections.

[Clinical evaluation of ceftriaxone in the pediatric field].

Ceftriaxone CTRX was evaluated about its antibacterial activity against clinical isolates at our department and tried clinically in 10 children of 6 months to 10 years and 6 months of age. The antibacterial activity was equal to cefotaxime or higher while the clinical results were almost satisfactory. Three out of 4 strains were eradicated (75%). As to the adverse reaction, eosinophilia was observed only in 1 case.

[Clinical studies on sulbactam/cefoperazone in the pediatric field].

Sulbactam, a new beta-lactamase inhibitor, in combination with cefoperazone was administered to 18 pediatric patients, 7 months to 10 years 6 months of age, at a daily dose of 56-320 mg/kg divided into 4 times by intravenous bolus infusion for 3 to 11 days, and the sum of 2.6-74.0 g of the drug was given. A total of 18 cases comprised 8 with RTI, 1 with gastric tract infection, 4 with UTI and 5 with sepsis (suspected). Clinical efficacy was excellent in 10 cases, good in 3 cases, fair in 1 case and poor in 4 cases, and efficacy rate was 72.2%. Out of 8 strains (1 of S. aureus, 1 of P. aeruginosa, 1 of Salmonella subgenus I, 2 of E. coli, 2 of P. mirabilis and 1 of K. pneumoniae), possible causative organisms isolated before the treatment, 6 strains were disappeared, 1 strain of K. pneumoniae persisted, and 1 strain of P. aeruginosa was replaced by S. aureus. Diarrhea was noted in 1 case as subjective side effect, and as abnormal laboratory findings, GOT and GPT elevations in 1 case, GPT elevation in 1 case and eosinophil elevation in 1 case were observed.

[Studies on efficacy, safety and dosage of rokitamycin in the treatment of pediatric infections].

The usefulness of a new macrolide antibiotic rokitamycin (RKM, TMS-19-Q) was evaluated in the field of pediatrics. 1. Twenty seven patients were enrolled in the study. One patient was excluded from the study because the illness was due to a viral infection. They included 14 boys and 13 girls with ages 7 months to 9 years 11 months. 2. The patients were treated with RKM at daily doses ranging 19.2-41.1 mg/kg, divided into 3 equal portions. The administration was done orally at fasting, lasting 2-15 days, with total doses of 22.2-500.0 mg/kg. 3. The patients were diagnostically classified into the following categories: 9 with acute pharyngitis, 15 with acute bronchitis, and one each with pneumonia, purulent lymphadenitis and Campylobacter enteritis. 4. The clinical response to the treatment was good or excellent in 22 of the patients with an overall efficacy rate of 81.5%. An efficacy rate of 88.9% was achieved for the patients with acute pharyngitis, 80.0% for those with acute bronchitis, and 100% for the patient with purulent lymphadenitis and the patient with Campylobacter enteritis. From the patient with pneumonia whose response was evaluated "fair" was Haemophilus influenzae isolated by culturing pharyngeal material. This organism was found resistant to RKM by the disk method. 5. Bacteriological responses were as follows; of 26 isolates presumed to be pathogens, 9 were eradicated, 5 decreased, 7 unchanged and 5 unknown, with an eradication rate of 42.9%. 6. Neither adverse reactions nor abnormal changes in laboratory findings were observed with the medication in any patients during and after the end of the treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

[Clinical evaluation of cefdinir in pediatric field].

We studied the clinical efficacy of cefdinir (CFDN), a new oral cephalosporin, in 18 children with ages 2 years and 4 months to 11 years and 4 months with pediatric infections. The diagnoses consisted of respiratory tract infections in 15 cases, impetigo in 2 and balanoposthitis in 1. Clinical efficacies were excellent in 11 patients and good in 7, with an efficacy rate of 100%. Bacteriologically, 9 (64.3%) of the 14 strains of clinical isolates were eradicated. No side effects nor abnormal laboratory findings were observed. We have concluded that CFDN is a useful antibiotic for the treatment of mild to moderate pediatric infections.

[Study of efficacy, safety and dosage on cefpodoxime proxetil in pediatric infections].

Cefpodoxime proxetil (CS-807, CPDX-PR), a new cephalosporin antibiotic, was investigated for its usefulness in pediatrics. 1. The total number of patients treated were 21 with their ages ranging from 3 months to 9 years and 1 month, consisting of 5 male and 16 female infants. 2. Single dosages of the drug ranged between 4.4 mg and 5.8 mg/kg with oral administration for 3 times daily in fasting. A total aggregated dosage was between 46.4 mg/kg and 200.0 mg/kg. The length of administration was 3 to 12 days. 3. The breakdown of symptoms were 9 cases of acute pharyngitis, 5 cases of acute tonsillitis, 3 cases of acute bronchitis, and 1 case each of impetigo + purulent rhinitis, cervical lymphadenitis, scarlet fever, and urinary tract infection. 4. The clinical efficacy rate was 100% with 18 excellent responses and 3 good responses. 5. The bacteriological efficacy rate was 90.9% in eradication rate, based on results on 17 strains of suspected causative microorganism among which 10 strains were eradicated, 1 strain was decreased, and 6 strains were unknown. 6. There was no side effect during the treatment and after the discontinuation, while, in clinical laboratory tests, GOT and GPT were elevated in 1 case which was judged as abnormal. No patient refused the drug. CPDX-PR was considered to be very useful drug because of its excellent efficacy and safety in pediatrics in treating infectious diseases.

[Clinical studies of cefteram pivoxil in pediatric infection].

The usefulness of a new cephem antibiotic, cefteram pivoxil (CFTM-PI, T-2588), was evaluated in the field of pediatrics. 1. Thirty-one patients were enrolled in the study. They included 20 boys and 11 girls with ages 8 months to 8 years 7 months. 2. The patients were treated with CFTM-PI at a dose levels ranging 3.0-4.2 mg/kg in 3 divided portions. The administration was done orally for a duration between 3 and 13 days, with a total dose between 27.3 and 130.0 mg/kg. 3. The patients were diagnostically classified into the following categories: 11 with acute pharyngitis, 1 with acute nasopharyngitis, 6 with acute tonsillitis, 9 with acute bronchitis, 2 with scarlet fever, 1 with purulent parotitis and 1 with purulent cervical lymphadenitis. 4. Clinical responses to the treatment were excellent in 14, good in 13, fair in 1 and poor in 3 patients with an overall efficacy rate of 87.1%. 5. Bacteriological responses were as follows: of 29 bacterial strains presumed to be pathogens, 23 were eradicated, 2 unchanged and 4 unknown, with an eradication rate of 92.0%. 6. Neither adverse reactions nor abnormal changes in laboratory test values were observed with the medication in any patients during and after the end of the treatment. None of the patients refused the medication. CFTM-PI was found very effective and safe in treating pediatric infections: it is a useful drug in the field of pediatrics.

[Infections during induction chemotherapy of acute leukemia and their control V. Clinical evaluation of a large dose of amikacin injected intravenously].

In this study, we treated severe infections (21 cases) accompanied with induction chemotherapy in 20 patients with acute leukemia by the combination of a large dose (600 approximately 1,200 mg/day) of amikacin with other antibiotics. Infections during induction chemotherapy of acute leukemia consisted of sepsis (8 cases), pneumonia (7) and others (6), and most of causative organisms were Gram-negative bacteria, such as Ps. aeruginosa (7 strains), Flavobacterium (5), Serratia (3), Ps. cepacia (2), E. coli (2) and others. The combination chemotherapy of a large dose of amikacin with other antibiotics was found to be effective (71.4%) for such infections. Side effects were negligible except for drug eruption. Therefore, a large dose of amikacin should be given for the treatment of severe infections accompanied with induction chemotherapy of acute leukemia.

[A case of advanced esophageal carcinoma successfully treated with chemoradiation therapy with low-dose cisplatin and 5-fluorouracil].

We have experienced a case of advanced esophageal carcinoma successfully treated with chemoradiation therapy together with low-dose cisplatin and 5-fluorouracil, having only minor toxicity. A 55-year-old man was admitted to our hospital because of dysphagia. Cervical esophageal carcinoma was found to have invaded the larynx through endoscopy, and invasion to thyroid gland and trachea was suspected from a cervical CT. We diagnosed the condition as advanced esophageal carcinoma (A2N(-)M0Pl0 Stage III). We then treated the patient by chemoradiation therapy. After the treatment, the carcinoma could not be detected by CT and endoscopy, and endoscopic biopsy revealed there were no active carcinoma cells. The side effects of the therapy were very mild, therefore the patient could be discharged after a short time. No evidence of a tumor relapse was found 5 months after the therapy. We treated 4 patients with esophageal carcinoma using the same regimen, and the results of the therapy were 2 CR, 1 PR, and 1 PD, with an overall response rate of 75%.

[Effect of PMU hepatic arterial chemotherapy for liver metastases of gastric cancer. Hokuriku Cisplatin Round-table Conference].

We performed PMU hepatic arterial chemotherapy (a combination therapy consisting of intra-hepatic arterial infusion of CDDP and MMC, oral administration of UFT) in 20 patients with gastric cancer and liver metastases. In this method, 1-6 courses of one infusion of CDDP at 70-100 mg/body and MMC of 10 mg/body into the proper hepatic artery were administered at intervals of 3-4 weeks. UFT of 300-400 mg/day was orally administered with the infusion. The primary response for hepatic metastatic lesions was observed in one case of CR, 14 cases of PR, 4 cases of NC, and one case of PD. The efficacy for CR and PR was high at 75%. The median disease-free interval was 56 weeks in responders. The 50% survival period was 11.1 months; one-year survival rate, 42.1%; two-year survival rate, 12.3%; the longest survival period was 108 weeks. Mild and transient side effects were recognized in 17 cases (85%): gastrointestinal symptoms, sense of general malaise, fever, leukocytopenia, and elevated BUN. Thus, the results indicated that this combination chemotherapy was effective for liver metastases of gastric cancer.

[A case of gastric cancer with multiple liver metastases effectively treated with PMUE (CDDP, MMC, UFT, etoposide) hepatic arterial chemotherapy].

A 62-year-old male patient with progressive gastric cancer and multiple liver metastases (H3, P0, ss gamma, n4) underwent total gastrectomy (R1). After 2 years and 2 months, he was re-hospitalized with epigastric tumor caused by re-manifestation of liver metastasis as well as inappetence. Since a large focus of liver metastasis and intraportal tumor embolism was identified, a continuous intraarterial infusion tube utilizing Infuse-A-Port was inserted in the hepatic artery. After conducting 2 cycles of PMUE intra-arterial chemotherapy, the tumor size was reduced by 84% (PR); and CEA, which had been high upon rehospitalization, recovered to the normal level. After discharge, the patient has been receiving 5-FU arterial infusion as an outpatient and undergoing UFT oral chemotherapy. The efficacy has continued and he has been well for 3 years since operation. Often operations for gastric cancer accompanied with multiple liver metastasis meet with little success, and almost no case of prolonged survival has been reported. In this case, the effectiveness of PMUE arterial infusion chemotherapy was clear, the patient has been well for 3 years since operation, and is an interesting example with seemingly good prospects for long-survival.

[An in vitro chemotherapy sensitivity test on leukemic colony-forming cells (L-CFU) and its clinical evaluation].

The sensitivity of leukemic progenitor cells (L-CFU) to cytosine arabinoside (Ara-C) and daunomycin (DM) in vitro was studied using PHA -LCM two step assay for L-CFU. Continuous exposure of leukemic and normal bone marrow cells to DM as well as Ara-C in vitro appeared to be more effective than pulse exposure because colony formation was suppressed by a dose dependent fashion. The relationship between in vitro sensitivity to DM and Ara-C and that of in vivo to chemotherapy was investigated in 17 untreated and 5 relapsed patients with acute nonlymphocytic leukemia. The sensitivity of L-CFU to the two chemotherapeutic agents varied from patient to patient. These studies indicated a clear-cut relationship between in vitro drug sensitivity and in vivo response to patients whose L-CFU were sensitive to both agents and entered complete remission, whereas patients whose L-CFU were insensitive to one or both drugs in vitro failed to enter remission. This assay system appears to be useful in predicting response of patients to chemotherapy and in selecting the most effective drugs for an individual patient use.

[A case of advanced gastric cancer showing complete disappearance of cancer cells in multiple liver metastases due to low-dose PMUE therapy].

A case of gastric cancer with liver metastasis who responded well to low-dose PMUE (CDDP, MMC, UFT, etoposide) therapy is reported. A 65-year-old man underwent distal partial gastrectomy with D2 lymph node dissection under the diagnosis of type 5 gastric cancer with multiple liver metastases. Pathological findings revealed papillary adenocarcinoma in the primary lesion and metastatic lymph nodes (No. 8a). Low-dose PMUE therapy after resection of primary lesion was effective for the liver metastases. Exacerbation was suspected, so the lesions of metastases were resected again after 2 years and 11 months postoperative course. All 4 resected lesions of metastases became old fibrous tissue with hyalinization, and 2 of 4 lesions were necrotic and surrounded by fibrous connective tissue. None of these 4 lesions included viable cancer cells. The patient has now been followed with no evidence of exacerbation. It was suggested that low-dose PMUE therapy was effective for liver metastasis of gastric cancer, especially the differentiated type.

[Therapeutic results of DCMP therapy (2M-80) in acute non-lymphocytic leukemia--the relationship between the residual leukemic cells and duration of remission].

In this study the duration of complete remission by daunomycin, cytosine arabinoside (Ara-C), 6MP and prednisolone (DCMP) therapy using a large dose of Ara-C (200 mg) (protocol 2M-80) was compared with that of DCMP therapy with a low dose of Ara-C (80-160 mg) in acute non-lymphocytic leukemia (ANLL). In protocol 2M-80, the chemotherapy was continued until leukemic blasts in marrow were attained below 3%. Complete remission was induced in about 80% of ANLL patients in both chemotherapies. However, the duration of remission in protocol 2M-80 appeared to be much longer than that of DCMP therapy with a low, dose of Ara-C. This difference was dependent not on the consolidation and maintenance therapy, but on the total dose of Ara-C used and leukemic blasts left in marrow at the end of chemotherapy. This suggests that it is important to reduce leukemic blasts in marrow as low as possible by induction chemotherapy to obtain a long-term remission in ANLL.

[Clinical study of ileus like symptom due to eating of raw firefly squid, Watasenia scintillans].

We report 12 patients who ate raw firefly squid, Watasenia scintillans. The patients experienced abdominal pain one or two days after eating them. Ileus was suspected by abdominal X-ray, but abdominal muscle guarding was not recognized. No specific findings was revealed on laboratory data. Patients were recovered two or three days after admission by only drip infusion. Recently, type X larva of the suborder Spirurina is recognized in 3.3% of firefly squid viscus. Indirect fluorescent antibody test using antigen of the type X larva was evaluated for the sera of the 8 ileus patients who were admitted in 1993. The antibody titers were positive in 5 patients and were negative in 3 patients. These results suggested that the ileus like symptom we reported here was attributed to the type X larva of the suborder Spirurina.