A case of preoperative concurrent chemoradiotherapy and curative resection for locally advanced non-small-cell lung cancer

We report the case of a 58-year-old man who underwent complete resection for locally advanced non-small-cell lung cancer (cT4N2M0). The patient received UFT (400 mg/m2 orally on days 1-14 and 22-35) and cisplatin (80 mg/m2 intravenously on days 8, 29) with a total 40 Gy, delivered in 20 fractions on days 1-26. The tumor reduction rate was 76%, and no remarkable toxicities were observed. The patient underwent complete resection and a pathologic complete response was observed. This induction concurrent chemoradiotherapy (followed by surgery) is considered to be effective and safe.     

Post launch studies

Evidence Based Medicine (EBM) is a growing concept in Japan as it is elsewhere. Central to improving the use of EBM is generation of data through well conducted controlled clinical studies. There are many problems associated with conduct of clinical studies after launch in Japan, and many initiatives are ongoing to improve the situation. Development of Clinical Research Coordinators (CRO) and central Data Management centers are key to improving the quality of clinical research in Japan. Currently Japan has an undeveloped legal system with regard to post-launch trials and off-label use of registered drugs. There is no reimbursement for off-label and various restrictions imposed on the recipients of the Ministry of Health, Labour and Welfare's (MHLW) funds. Maybe the biggest problem is the high cost of post-marketing studies sponsored by pharmaceutical manufacturers. A high quality system to support post launch clinical studies need a solid financial base. There is a need for a suitable review system for investigator initiated multi-centre studies, as the current IRB system is not sufficient. There are also challenges regarding the differences, perceived or real, in treatment practice and available registrations in Japan and in the West, causing problems in choosing suitable comparators and study designs. At the present time it is not clear whether investigator initiated trials will be acceptable for registration purposes in Japan. The agreed first priority is to build a suitable and strong infrastructure within the academic community to support researchers to investigate important questions with or without pharmaceutical company support. Despite all these issues, several groundbreaking projects are under way throughout Japan, in many different areas and by different collaborative groups, some with government support. In fact, researcher-initiated clinical trials achieved a rapid growth in Japan in the past year.     

Pancreatic islet cell carcinoma with multiple hepatic metastases successfully treated with a streptozocin/5-FU regimen--a case report

A 53-year-old woman was hospitalized because of lientery and steatorrhea. CT scans revealed a pancreatic head tumor along with multiple liver tumors. The pancreatic head tumor had spread to the duodenum. Following tumor biopsy with gastrointestinal fiberscopy, we diagnosed a pancreatic malignant islet cell tumor with multiple liver metastases. Since there was no clinical evidence of recognized endocrinopathy, we diagnosed "nonfunctioning" tumor. At first we administered only 5-FU at a dose of 370 mg/m2/day continuously for two weeks. However, neither the pancreatic head tumor nor the metastatic liver tumors changed in size. We then administered streptozocin and 5-FU at doses of 1,000 mg/m2 and 370 mg/m2, respectively, every week. The patient received a total of 10 g/m2 of streptozocin. After this treatment, the enlarged metastatic liver tumors were reduced in size, with marked improvement in liver enzyme. Toxic reactions to this regimen were mild. Only grade 1 nausea and alopecia were observed during the treatment. No hematological toxicity was observed, nor, with sufficient diuresis, was nephrotoxicity, demonstrating that this regimen can be administered safely.     

Increased expression of sialyl Lewis(x) antigen in penetrating growth type A early gastric cancer

Early gastric cancer can be divided morphologically into two categories, penetrating growth type-A (Pen-A type) and other growth types (non-Pen-A types). Sialyl Lewis(x) antigen has been demonstrated to play an important role in tumor metastasis by serving as a functional ligand in the cell adhesion system. The aim of this study is to ascertain whether or not sialyl Le(x) antigen expression correlates with tumor growth patterns of early gastric carcinoma. An immunohistochemical assay was performed using monoclonal antibody CSLEX1 in 12 Pen-A type and 79 non-Pen-A type cancers. Scoring was based on the percentage of immunoreactive cells: negative, low expression (< or = 25%), and high expression (> 25%). Lymph node metastasis was found more frequently in Pen-A type than non-Pen-A type cancers (P=0.0004). Furthermore, sialyl Le(x) antigen high expression was detected more often in Pen-A type cancers (7 out of 12; 58.3%) than non-Pen-A type cancers (13 out of 79; 16.5%) (P=0.0036). Multivariate logistic regression analysis showed that these variables are related independently to the Pen-A type and the non-Pen-A type tumor growth patterns. These data suggest that the difference in sialyl Le(x) antigen expression between the Pen-A type and non-Pen-A type tumor growth patterns of early gastric cancer may, at least partially, reflect different biological behavior during tumor progression.     

Demyelination associated with HSV-1-induced facial paralysis

In 1995, we developed an animal model of transient homolateral facial nerve paralysis by inoculating Herpes simplex virus type 1 (HSV-1) into the auricle of mice. This study examined the mechanism of facial nerve paralysis in this model histopathologically. Using the immunofluorescence technique with anti-HSV-1 antibody, the time course of viral spread and the site of viral replication were investigated over the entire course of the facial nerve. Furthermore, viral replication and nerve degeneration at the site of viral replication were observed by electron microscopy. On the 7th day after inoculation, facial paralysis was observed in more than 60% of mice. Immunofluorescence study revealed HSV-1 in the geniculate ganglion, the descending root, and the facial nucleus at this stage. On the 9th day, the descending root in the sections stained with osmium looked pale, because prominent demyelination had occurred in this region; electron micrographs showed many degenerated oligodendrocytes and large naked axons. In contrast, the facial nucleus neurons showed no remarkable degeneration, despite HSV-1 particles in their cytoplasm. From these findings, we concluded that facial nerve paralysis in this model is caused mainly by facial nerve demyelination in the descending root.     

Cerebral hemispheric differences in memory of emotional and non-emotional words in normal individuals

The present study was designed to examine the cerebral hemispheric differences in memory of positive, negative and non-emotional words using a new method of successive presentation to each visual half-field in which perception of each item was nearly perfect thereby allowing laterality differences for effects of emotion on memory to emerge unconfounded by perception (Experiment 1). This procedure was compared with traditional perceptual identification (Experiment 2). In Experiment 1, 12 words were presented successively in each half field in each trial followed by free recall at the end of the trial. The results showed that recall of positive and negative emotional words was better than that of non-emotional words in both visual fields. Recall of positive and negative emotional words was not different in left and right visual fields (RVFs) although the recall of non-emotional words was better in the RVF than in the left visual field (LVF). The differences in recall between emotional and non-emotional words was greater in the LVF than in the RVF. Experiment 2 used the more traditional method of perceptual identification following each visual half-field presentation of a single item. Perceptual identification was better in the RVF than the LVF in each word condition. There were no visual field differences in perceptual identification between emotional and non-emotional words, as there was for memory in Experiment 1. The results supported the hypothesis that explicit memory for emotional words was dependent more on the right hemisphere, whereas perception of both emotional and non-emotional words was more dependent on the left hemisphere.     

No association of vitamin D-binding protein gene polymorphisms in Japanese patients with MS

Vitamin D-binding protein (DBP) is known to function as an immunomodulatory factor, as well as the main carrier of vitamin D. We analyzed the frequencies of two polymorphisms (codon 416 and codon 420) in the DBP gene through a case-control study involving 107 Japanese patients with multiple sclerosis (MS) and 109 healthy controls. None of these polymorphisms showed any association with the occurrence of MS. Furthermore, no association was observed between the DBP polymorphisms and the age at disease onset. These results suggest that DBP does not contribute to the development of MS in Japanese.     

Estrogen receptor gene polymorphism and multiple sclerosis in Japanese patients: interaction with HLA-DRB1*1501 and disease modulation

We investigated PvuII and XbaI polymorphism in the estrogen receptor gene (ERG) and HLA-DRB1*1501 positivity in 116 conventional multiple sclerosis (MS) patients and 101 healthy controls in a Japanese population. Logistic analysis revealed independent associations of [P] allele in the profiles for PvuII (p=0.0005, adjusted odds ratio (aOR)=3.17) and DRB1*1501 (p=0.0089, aOR=2.61) with conventional MS. Synergistic elevated risk of MS due to interaction between the [P] allele and HLA-DRB1*1501 allele was found among female patients (odds ratio=16.0; 95% CI=3.99-63.8, p<0.0001). The [P] allele-positive patients with disease duration of more than 5 years had a significantly higher progression index (PI) of disability (p=0.0230) and a worse ranked MS severity score (p=0.0152) than their non-[P] counterparts.     

A GDP/GTP exchange protein for the Rab3 small G protein family up-regulates a postdocking step of synaptic exocytosis in central synapses

The Rab3 GDP/GTP exchange protein (Rab3 GEP) activates the Rab3 small GTP-binding protein (G protein) family, including Rab3A that is an important member controlling synaptic vesicle trafficking. Here, we examined the role of Rab3 GEP in regulating neurotransmitter release in autapses of mouse hippocampal neurons in culture. The release probability was markedly reduced in Rab3 GEP-/- neurons, whereas the readily releasable pool size was not different between WT and Rab3 GEP-/- neurons, indicating that Rab3 GEP up-regulates a postdocking step of synaptic exocytosis. Because Rab3A reportedly down-regulates Ca(2+)-triggered fusion of synaptic vesicles, these results provide evidence for a role of Rab3 GEP in the postdocking process distinct from Rab3A activation.