Concurrent chemoradiotherapy for esophageal cancer: comparison between intermittent standard-dose cisplatin with 5-fluorouracil and daily low-dose cisplatin with continuous infusion of 5-fluorouracil

Background Although current standard treatment for advanced esophageal cancer is intermittent standard-dose cisplatin with 5-fluorouracil (5-FU) (ISD-FP), daily low-dose cisplatin with continuous infusion of 5-FU (CLD-FP) is advocated for equivalent effectiveness and lower toxicity. The feasibility of these two concurrent chemoradiotherapeutic protocols was retrospectively reviewed for local control rate, overall survival, toxicity, and compliance in a single institutional situation.Methods Concurrent chemoradiotherapy, using 60Gy of radiation and ISD-FP or CLD-FP was non-randomly scheduled for 29 patients between June 1994 and March 2001.Results Complete response in the irradiated volume at the end of primary treatment was shown by 8 of 15 and 9 of 14 patients in the ISD-FP and CLD-FP groups, respectively. The projected overall survival rate at 2 years was 55% for stage III patients and 13% for stage IV. Median survival times were 14 months versus 15 months in the ISD-FP and CLD-FP groups, with no significant difference. Toxicities were similar, including two treatment-related deaths in each group. Chemotherapy was completed for 10 of 15 and 11 of 14 patients in the ISD-FP and CLD-FP groups, respectively. Modification of the planned regimen was more often required for the CLD-FP group.Conclusion CLD-FP therapy has no apparent advantage over ISD-FP therapy from the perspective of compliance and safety. A randomized phase II clinical trial comparing ISD-FP and CLD-FP, currently being performed, is expected to provide further information.     

Clearance of apoptotic photoreceptors: elimination of apoptotic debris into the subretinal space and macrophage-mediated phagocytosis via phosphatidylserine receptor and integrin alphavbeta3

The effective phagocytotic clearance of apoptotic debris is fundamental to the maintenance of neural tissues during apoptosis. Retinal photoreceptors undergo apoptosis after retinal detachment. Although their induction phase of apoptosis has been well discussed, their phagocytotic process remains quite unclear. We herein demonstrate that apoptotic photoreceptors are selectively eliminated from their physiological localization, the outer nuclear layer, to the subretinal space, and then phagocytosed by monocyte-derived macrophages. This could be shown by an ultrastructural and immunophenotypic analysis. Moreover, in chimera mice expressing transgenic green fluorescent protein in bone marrow-derived cells, the local infiltration of macrophages could be detected after retinal detachment-induced photoreceptor apoptosis. The local injection of an antibody blocking the phosphatidylserine receptor (PSR) or a peptide (GRGDSP)-blocking integrin alphavbeta3 revealed that phagocytotic clearance involves the PSR as well as integrin alphavbeta3 in vivo. Importantly, the level of blockade obtained with these reagents was different. Although anti-PSR increased the frequency of apoptotic cells that fail to bind to macrophages, GRGDSP prevented the engulfment (but not the recognition) of apoptotic photoreceptor cells by macrophages. To our knowledge, this is the first report describing the mechanisms through which apoptotic photoreceptors are selectively eliminated via a directional process in the subretinal space.     

Induction of Complete Remission of Hypoplastic Leukemia with Antithymocyte Globulin

A 13-year-old boy was admitted to a local hospital because of pancytopenia. A bone marrow aspiration and biopsy revealed severely hypocellular marrow with no obvious leukemic cells. The diagnosis was severe aplastic anemia, and the patient was treated with antithymocyte globulin and cyclosporin A. A trilineage response was obtained, and the patient became transfusion-independent within 2 weeks. Two months later, the peripheral blood count normalized with an increased bone marrow cellularity. However, the patient was readmitted 5 months later for recurrence of the pancytopenia. A bone marrow aspiration revealed hypocellular marrow with morphologically blastoid cells. A surface marker study revealed the presence of a single clone that was positive for CD7, CD33, CD34, and HLA-DR. A diagnosis of hypoplastic leukemia was made on the basis of morphology and the surface marker studies. Retrospectively, the laboratory findings were the same as those seen at the onset of the disease. The patient did not respond to combination chemotherapy consisting of vincristine, prednisolone, cyclophosphamide, L-asparaginase, and doxorubicin, but administration of etoposide resulted in complete remission. An in vitro study revealed that >95% of the leukemic cells of this patient could be lysed after an incubation with antithymocyte globulin and human AB serum or baby rabbit serum. These findings suggest the efficacy of antithymocyte globulin in treating certain hypoplastic leukemias.     

Squamous predominance in mixed-epithelial papillary cystadenomas of borderline malignancy of mullerian type arising in endometriotic cysts: a study of four cases

Mixed-epithelial papillary cystadenoma of borderline malignancy of mullerian type (MEBMM) is composed of a mixture of mullerian epithelial types, such as mucinous, serous, endometrioid, and squamous. Four cases of MEBMM with squamous overgrowth (MEBMMSO) were reviewed. The patients' median age was 56 years, and all cases were unilateral. The clinical stages were Ia (two cases), Ic (one case), and IV based on the presence of tumor cells in pleural fluid (one case). No recurrence was seen in three of the cases. In one of those three cases, there was no recurrence after undergoing surgery only; in the other two of those three cases, there was no recurrence after undergoing surgery and receiving postoperative chemotherapy. In the single case that was at stage IV at initial presentation, a recurrent MEBMMSO nodule was found at a second look 17 months after the initial surgery. In terms of gross findings, all of the tumors were cystic with intracystic papillary fronds. In addition, old endometriotic lesions lined the cysts. The tumors were mainly composed of a proliferation of squamous-type epithelium, with minor foci containing a mixture of other mullerian-type epithelia, especially mucinous. Intraepithelial infiltration by neutrophilic leukocytes was prominent. The differential diagnosis of MEBMMSO includes proliferating Brenner tumors.     

Highly enhanced permeability of blood-brain barrier induced by repeated administration of endothelin-1 in dogs and rats

The effects of intracisternal administration of endothelin-1 on blood-brain barrier permeability were examined in dogs and rats. Single doses of endothelin-1 elevated blood-brain barrier permeability about two times compared with control groups in both species. However, repeated dosing with endothelin-1 at a 24 hr intervals caused a highly enhanced disruption of blood-brain barrier permeability in dogs, but not in rats, whereas the repeated administration with a 48 hr interval markedly increased the blood-brain barrier permeability in both species of animals (dogs: 923%, rats: more than 661%). Moreover, this abnormally enhanced permeability of blood-brain barrier in dogs was completely blocked by pretreatment with the endothelin ET-A receptor selective antagonist, S-0139, administered prior to either the first or second dosing with endothelin-1. From these results, we conclude that a repeated attack of endothelin-1 from the adventitial site of brain blood vessels produces a severe disruption of blood-brain barrier permeability through an endothelin ET-A receptor-mediated process.     

Novel nonsynonymous polymorphisms of the CYP1A1 gene in Japanese

We found five novel nonsynonymous polymorphisms of the human CYP1A1 gene from Japanese individuals. The five single nucleotide polymorphisms (SNP) in exon 7 (2346_2347 ins T, 2414T>A, 2461C>T, 2500C>T and 2546C>G causing premature stop codon, Ile(448)Asn, Arg(464)Cys, and Arg(477)Trp and Pro(492)Arg, respectively) were as follows:SNP, 030212Saito001; GENE NAME, CYP1A1; ACCESSION NUMBER, X02612; LENGTH, 25 base; 5'-GTCAACCCATCT-/TGAGTTCCTACCT-3'.SNP, 030212Saito002; GENE NAME, CYP1A1; ACCESSION NUMBER, X02612; LENGTH, 25 base; 5'-GTGAGAAGGTGAT/ATATCTTTGGCAT-3'.SNP, 030212Saito003; GENE NAME, CYP1A1; ACCESSION NUMBER, X02612; LENGTH, 25 base; 5'-GAGACCGTTGCCC/TGCTGGGAGGTCT-3'.SNP, 030212Saito004; GENE NAME, CYP1A1; ACCESSION NUMBER, X02612; LENGTH, 25 base; 5'-ATCCTGCTGCAAC/TGGGTGGAATTCA-3'.SNP, 030212Saito005; GENE NAME, CYP1A1; ACCESSION NUMBER, X02612; LENGTH, 25 base; 5'-TGGACATGACCCC/GCATCTATGGGCT-3'.     

Involvement of hepatic glucocorticoid receptor-mediated functions in steroid-induced cataract formation

Determination of whether the steroid-induced cataract formation is caused through glucocorticoid (GC) receptor-mediated process was conducted by using GC antagonist (RU486) and anti-GC receptor antibody, and by sucrose density gradient ultracentrifugation analysis. (1) When 15 day-old chick embryos were treated with dexamethasone (DEX, 0.025 micromol per egg), their lenses started to form an opaque ring around the peri-nuclear region (stage II-III) after 12 hr and developed into nuclear-like cataract (stage IV-V) after 44 hr. The cataract formation examined at the 44 hr could be effectively prevented by administration of RU486 (0.2 micromol per egg) ranging from 2 hr before to 12 hr after the DEX administration. (2) GC receptor was present in liver, but could not be determined in lens by western blot analysis using monoclonal anti-GC receptor antibody. (3) Sucrose gradient ultracentrifugation analysis indicated that the receptor (9S) in the liver could be transformed to the 4S form after 0.4M NaCl treatment. Combined with our previous data, this suggests that changes in hepatic functions mediated by the GC receptor after the GC administration may be involved in the process of the cataract formation.     

Inhibitory effects of hyssop (Hyssopus officinalis) extracts on intestinal alpha-glucosidase activity and postprandial hyperglycemia

It has been known that Hyssopus officinalis (hyssop) is a herb that grows in the wild and is a source of natural antioxidants. We previously reported that a-glucosidase inhibitors, (2S, 3S)1-O-beta-D-6'-O-cinnamoylglucopyranosyl-3-(3", 5"-dimethoxy-4"-hydroxyphenyl)-1,2,3-propanetriol and (2S, 3S)1-O-beta-D-glucopranosyl-3-(3", 5"-dimethoxy-4"-hydroxyphenyl)-1,2,3-propanetriol, from the dry leaves of hyssop, were isolated. This study examined the alpha-glucosidase inhibitory effects of hyssop extracts on intestinal carbohydrate absorption in rat everted gut sac and carbohydrate-loaded hyperglycemia in mice. In the everted gut sac experiment, 10 mM sucrose- and 5 mM maltose-treated increases in glucose concentration in the serosal compartment were inhibited in the presence of 0.5 and 1.0 mg/ mL hyssop extracts, although a 10 mM glucose-induced increase in serosal glucose was not inhibited by the extracts. Additionally, hyperglycemia in sucrose- and maltose-loaded mice was significantly suppressed at an early stage, within 30 to 60 min by oral pre-administration of 300 and 100 mg/kg hyssop extracts, respectively. These findings suggest that hyssop extracts inhibited the digestion of complex carbohydrates, but not that of absorbable monosaccharide, and might be a useful supplemental food for hyperglycemia.     

Comparison of the effectiveness of psychiatric day care treatment between Japan and western countries: a review

Over the last two decades, day care (DC) treatment for mentally ill patients has come into wide use in Japan, following the precedents get in Western countries providing evidence of effectiveness. Several studies to examine the efficacy of DC treatment have already been performed in Japan. However, they were limited to chronic schizophrenic patients as subjects, and therefore the findings showed only improvement of the negative symptoms of schizophrenia. In contrast, Western studies have included heterogeneous mental disorders, and some showed DC was effective not only for treatment of global mental dysfunction but also for that of antisocial or violent behavior, drug dependence, emotional distress, and other characteristic disorders. Several Japanese and Western studies have shown DC treatment to be superior to outpatient treatment for relieving psychiatric symptoms. Regarding reduction of readmission rate, the Western studies were not supportive, but some Japanese studies showed that DC treatment was preventive against readmission as long as the follow up period was brief (within two or two and a half years). These findings suggested that the effectiveness of DC treatment may be limited. However, recently, medication against negative symptoms of schizophrenia has been revolutionary changing, offering the possibility that the combination of DC treatment and appropriate drug therapy may overcome the great obstacle of rehabilitating mentally ill patients in society. It is also very important that an evidence-based, standardized methodology of DC treatment should be immediately established in Japan.