Diminished corneal angiogenesis in gelatinase A-deficient mice.

The goal of the present study was to define the role of gelatinase A in angiogenesis. We performed corneal micropocket assays in gelatinase A-deficient mice and their age-matched wild-type littermates. The corneal neovascular area in gelatinase A-deficient mice (0.15+/-0.14 mm(2)) was significantly less than that of wild-type littermates (0.53+/-0.35 mm(2); P<0.01). Similarly, aortic ring assays showed significant reduction of endothelial outgrowth in gelatinase A-deficient mice (0.26+/-0.14 mm(2)) as compared to wild-type littermates (0.44+/-0.06 mm(2); P<0.05). These results suggest that gelatinase A may play an important role in the regulation of corneal angiogenesis.

Matrilysin cleavage of corneal collagen type XVIII NC1 domain and generation of a 28-kDa fragment.

PURPOSE: To localize endostatin and collagen type XVIII in human corneas and to characterize the enzymatic action of matrix metalloproteinases (MMPs) in the cleavage of collagen type XVIII and generation of endostatin in the cornea. METHODS: Anti-endostatin and anti-hinge antibodies were generated using peptide fragments corresponding to the endostatin region and the adjacent nonendostatin hinge region of collagen XVIII noncollagenous (NC)1 domain, respectively. Confocal immunostaining was performed to localize collagen XVIII in human corneas. SV40-immortalized corneal epithelial cells were immunoprecipitated and incubated with active MMP-1, -2, -3, -7, or -9, and Western blot analysis was performed to study collagen XVIII cleavage. Incubation with MMP-7 was performed at various concentrations (0, 2, 4, and 6 microg/ml) and time intervals (0, 1, 5, and 12 hours). Purified recombinant NC1 fragment of collagen XVIII was also digested with MMP-7, and the cleavage product was sequenced. RESULTS: Collagen XVIII was immunolocalized to the human corneal epithelium, epithelial basement membrane, and Descemet membrane. Western blot analysis demonstrated a 180- to 200-kDa band corresponding to collagen XVIII. MMP-7 (but not MMP-1, -2, -3, and -9) cleaved corneal epithelium-derived collagen XVIII to generate a 28-kDa endostatin-spanning fragment in a time- and concentration-dependent fashion. MMP-7 cleaved purified recombinant 34-kDa NC1 fragment of collagen XVIII in the hinge region to generate a 28-kDa fragment. CONCLUSIONS: Collagen XVIII is present in human cornea. MMP-7 cleaves the collagen XVIII NC1 domain to generate a 28-kDa fragment in the cornea.

[Complement regulatory proteins CR 1, MCP, DAF, and MACIF levels in patients with Behçet's disease].

We previously reported that serum complements in patients with Behçet's disease were extremely low just before the ocular attack. On the other hand, C3a and C5a levels, which have anaphylactic activity and chemotactic activity for polymorphonuclear leucocytes, were higher just before the ocular attack than at the time of the ocular attack, and there was negative correlation between C3a/C5a and CH50. In this report, we evaluated complement regulatory proteins. The results of low levels of C3b/C4b receptor (CR1) and membrane cofactor protein (MCP), and low tendency of decay accelerating factor (DAF) and membrane attack complex inhibition factor (MACIF) suggested that the function of complement regulatory proteins in patients with Behçet's disease decreases as a whole. But mean levels of both CH50 and ACH50 were significantly higher than in the controls. Although it is unclear which is the cause and which is the result, we suppose the function of complement production works excessively and these phenomena are caused by making up for the lack of complement regulatory proteins.

[A case of chronic myelogenous leukemia complicated with nephrotic syndrome].

An 81-year-old woman was admitted, complained general malaise, and edema on face and lower extremities. In the peripheral blood, leucocytosis (17,220/mm3), microcytic hypochromic anemia (RBC 348 x 10(4)/mm3, Hb 9.6 g/dl, Ht 29.2%), and thrombocytosis (130 x 10(4)/mm3) were present, and many myeloid cells containing of myeloblasts, promyelocytes and so on were observed. Bone marrow aspiration revealed increment of the myeloid series without hiatus leukemia . The Neutrophil Alkaline Phosphatase score and rate was low, and on bone marrow scintigram using indium chloride, liver and extremities were shown. On admission, proteinuria (21.5 g/dl) and hypoalbuminemia (2.5 g/day) were pointed out, and the renal biopsy specimen showed membraneous proliferative glomerulonephritis (MPGN), so we diagnosed this case that chronic myelogenous leukemia (CML) complicated with nephrotic syndrome. At first, she was treated with prednisolone, but proteinuria was not entirely improved, then busulfan was given, myeloid cells in peripheral blood were disappeared and proteinuria was gradually decreased. From this coarse, the causality between CML and nephrotic syndrome was verified.

[A case of acute adult T-cell leukemia with long-term remission by cisplatin therapy].

A 37-year-old man was admitted because of general malaise, slight fever, pain in the knee joint and lower extremities, polydypsia, polyuria and skin lesion in September, 1985. The white blood cell count was 16,920/cmm with 41% of abnormal lymphoid cells with convoluted nuclei, which were compatible with adult T-cell leukemia (ATL). The serum calcium level was 15.1 mg/dl, serum LDH 307 IU/l, and the titer of anti-ATLA antibody in serum x 160. The cell surface phenotype of abnormal lymphocyte was OKT-3+, OKT-4+ and OKT-8-. Therefore the diagnosis of acute ATL was made. He was treated with cisplatin because VEPA therapy was not effective. About five months after the start of chemotherapy, he entered remission with almost complete disappearance of abnormal lymphocyte. The remission continued over twenty-nine months with maintenance therapy by cisplatin alone. The clinical course of this patient suggests that cisplatin could be applied to a case of ATL which is refractory to the conventional treatment.

[Combination chemotherapy of UFT with adriamycin (ADM) and cisplatin (CDDP) for advanced gastrointestinal cancer].

Thirty four patients with advanced gastric cancer (GC), colon cancer (CC) biliary tract cancer (BC) and pancreatic cancer (PC) were treated with a combined chemotherapy of UFT with ADM (UFT-A), or UFT with ADM and CDDP (UFT-AC). The UFT-A regimen consisted of UFT, 600 mg/body daily. As for ADM, 10 mg/body was given intravenously from day 1-4 and repeated every two weeks. The UFT-AC regimen consisted of UFT 400-600 mg/body daily. As for ADM, 7.5 mg/m2 was given from day 7-9 and CDDP 50 mg/m2 on day 7, repeated every 3-4 weeks. Partial responses (PR) were seen in 7 cases (36.8%) (5 cases of GC, 1 case of CC and 1 case of BC) out of 19 evaluable patients (8 cases of GC, 4 cases of CC, 4 cases of BC and 3 case of PC) treated with UFT-A. Complete response in a case of CC and PR in 6 cases (47.7%) (3 cases of GC and 3 cases of BC) were observed out of 15 evaluable patients (7 cases of GC, 2 cases of CC, 4 cases of BC and 2 cases of PC) treated with UFT-AC. There was no significant difference of survival curve between the two regimens, however, the median survival of responders for both regimens is longer than non-responders with statistical significance. As for side effects, UGI symptoms were recognized in 37% of UFT-A group and in 73% of UFT-AC group. A leukopenia count of less than 2,000/mm3 appeared in 11% of UFT-A group and in 20% of UFT-AC group. Considering these results, UFT-A and UFT-AC therapy appears to be useful in cases of advanced gastrointestinal cancer, especially gastric cancer.

Hurler-Scheie phenotype with parental consanguinity. Report of an additional case supporting the concept of genetic heterogeneity.

The Hurler-Scheie phenotype in a 27-year-old woman of first-cousin parentage is possibly the first reported in the orthopedic literature. The patient exhibited short stature, coarse facies, corneal clouding, multiple stiff joints, normal intelligence, and a long history of bilateral carpal tunnel syndrome, which has not been relieved after operation. The irreversible nerve damage was apparently produced by the marked thickening of the transverse carpal ligament. Surgical findings in this case and data from published reports emphasize the need for early surgical treatment of the associated carpal tunnel syndrome in patients with the Hurler-Scheie phenotype. Parental consanguinity present in this patient is further evidence supporting the concept of a third mutant allele different from both the Hurler gene and the Scheie gene.

[Alpha-fetoprotein producing gastric cancer responding to combined chemotherapy with UFT and adriamycin].

A case of AFP producing gastric carcinoma with liver metastasis that showed marked response to combined chemotherapy with UFT and Adriamycin (ADM) is reported. A 61-year-old man was admitted because of lassitude and abdominal fullness. An upper GI series and computed tomography revealed gastric cancer (Borrmann III) and multiple liver tumors. He had a remarkably high serum AFP level (90,000 ng/ml) and a high CEA level (270 ng/ml). The presence of AFP in the tumor cells of the biopsy specimen was proved immunohistochemically. He was treated with 600 mg of UFT orally every day and ADM (10 mg, iv, on days 1-4, repeated every 14 days), resulting in marked regression (PR, partial response) of both the primary tumor and liver metastasis on the 33 rd day after the start of treatment, with decreasing of serum levels of AFP and CEA. The patient has been asymptomatic without evidence of recurrence for a follow-up period of more than three months with continuing treatment in our outpatient clinic. UFT-ADM therapy appears to be useful for gastric cancer.

[Intraperitoneal (Ip) administration of cisplatin in combination with systemic chemotherapy in patients with malignant ascites of gastrointestinal cancer: clinical evaluation and pharmacokinetics].

Ten patients with carcinomatous peritonitis of gastrointestinal cancer have been treated with administrations of CDDP-Ip (50-150 mg/body), in combination with systemic chemotherapy simultaneously combined with sodium thiosulfate (STS) iv in 4 patients. All patients received transfusions of specific hydration. The pharmacokinetics of CDDP was studied in 4 patients, and the following results were obtained. (1) As for its effect on malignant ascites, according to Koyama's and Saito's criteria, 2 patients showed a complete response, 3 showed a partial response, and 5 showed no change. (2) As for its effect on the primary site, only one patient showed a partial response, and the others no change. (2) As to its side effects, 6 patients manifested nausea and vomiting, and only one showed a mild kidney dysfunction, and no myelosuppression. No significant difference in the side effects between the STS-combined group and the non-STS-combined group was found. (3) Serum CDDP levels were reached maximum 1-2 hours after Ip, and gradually decreased during the beta-phase of iv administration. Significant levels of non-protein-bound CDDP were found in the serum within 4 hours after Ip. These results indicate that the CDDP Ip is safe and useful for carcinomatous peritonitis of gastrointestinal cancer, however the combination of STS might weaken the systemic anti-cancer effect of CDDP by neutralizing the non-protein-bound CDDP in the serum.

[Combination chemotherapy of UFT with adriamycin in advanced gastrointestinal cancer].

Seventeen patients with advanced gastrointestinal cancer were treated with a combined chemotherapy of UFT with Adriamycin (UFT-A). The UFT-A regimen consisted of UFT, 600 mg/body daily. As for the Adriamycin, 10 mg/body was give intravenously from day 1-4 and was repeated every two weeks. Partial responses were seen in 7 cases (41%) (5 cases of gastric cancer, 1 case of colon cancer, and 1 case of bile-duct cancer) out of 17 evaluable patients (7 cases of gastric cancer, 3 cases of colon cancer, 4 cases of biliary tract cancer, and 3 cases of pancreatic cancer). Two patients had minor responses, and in eight patients their disease had stabilized. As for side effects, nausea and vomiting occurred in seven patients (41%), and anorexia was observed in eight patients (47%). Two patients (12%) showed a leukopenia count of less than 2,000/mm3 and none of these seventeen patients had thrombocytopenia, of less than 5 x 10(4)/mm3. Considering these results, UFT-A therapy appears to be useful in cases of advanced gastrointestinal cancer, especially gastric cancer.