Influence of Systemic Chemotherapy on Anti-P-glycoprotein Antibody-dependent Cell-mediated Cytotoxicity in Patients with Small Cell Lung Cancer

Anti-P-glycoprotein antibody (MRK-16)-dependent cell-mediatedcytotoxicity (ADCC by blood mononuclear cells (MNC was examinedin patients with small cell lung cancer (SCLC) before and aftersystemic chemotherapy. The effect of in vitro treatment of MNCwith interleukin (IL)-2 and macrophage-colony-stimulating factor(M-CSF) was also examined. The ADCC reaction was assessed bya 6 h ⁵¹ Cr-release assay using a multidrug-resistant (MDR)SCLC cell line (H69/VP cells). The MRK-16 monoclonal antibodywas able to augment spontaneous cytotoxicity by MNC, even inSCLC patients. Pretreatment of MNC with IL-2 significantly augmentedtheir ADCC ability in SCLC patients, while M-CSF had no effecton ADCC activity. After the first cycle of systemic chemotherapy,the ADCC activity tended to decline, but ADCC of MNC pretreatedwith IL-2 was not affected. The results suggest that anti-P-glycoproteinantibody, in combination with a cytokine such as IL-2, may betherapeutically useful against human SCLC resistant to chemotherapeuticdrugs.     

Effects of local administration of interferon-beta on proliferation of retinal pigment epithelium in rabbit after laser photocoagulation

PURPOSE: To investigate whether local administration of interferon (IFN)-beta promotes proliferation of the retinal pigment epithelium (RPE) in vivo. METHODS: Following local injection of IFN-beta into the sub-Tenon space of rabbit eyes, the penetration of IFN-beta into various intraocular areas was determined by means of enzyme-linked immuno-adsorbent assay. Retinal lesions were produced by laser photocoagulation (PC), and IFN-beta (1 x 10(6) IU, 1 x 10(5) IU, or 1 x 10(4) IU) was administered into the sub-Tenon space. Physiological saline was substituted for IFN-beta in controls. The proliferation of RPE cells was inspected histopathologically. RESULTS: After IFN-beta administration, IFN-beta was found in all intraocular areas examined, with the highest concentration detected in the choroid. After PC, profuse proliferation of RPE cells began earlier in the rabbits that received the highest dose of IFN-beta than in the control rabbits; repair of the central part of the coagulated lesion in those rabbits was complete within 7 days after PC. In control rabbits, the histopathologic wound repair process proceeded more slowly and to a limited extent. Proliferation of RPE cells in the low and medium dose IFN-beta-treated rabbits was similar to that in the control rabbits. CONCLUSION: The present study demonstrates that repair of the PC-induced retinal lesions, particularly the proliferation of RPE cells, is promoted in vivo by local administration of IFN-beta.     

Serum soluble interleukin-2 receptor (IL-2R) and immunohistochemical staining of IL-2R/Tac antigen in colorectal cancer

Background: In the present study, we investigated the significance of serum soluble interleukin-2 receptor (IL-2R) as a tumor marker, and examined the existence and localization of cells positive for IL-2R/Tac antigen in colorectal cancer tissues and their regional lymph nodes. Methods: The study included 155 patients with colorectal cancer. Levels of serum soluble IL-2R were measured by an enzyme-linked immunosorbent assay. In the tissues obtained from 18 patients, immunohistochemical staining was performed, with the use of the avidin-biotin-peroxidase complex technique, in which mouse anti-human IL-2R antibody was used. Results: The preoperative levels of serum soluble IL-2R in patients with colorectal cancer were significantly higher than those of normal controls (P = 0.0065). The levels of serum soluble IL-2R in patients with metastatic lymph nodes were also significantly higher than the levels in those without metastatic lymph nodes (P = 0.0258). Concerning tumor markers, there were significant differences in serum soluble IL-2R levels between patients who were positive and those who were negative for carcinoembryonic antigen (CEA) and between these who were positive and those who were negative for immunosuppressive acidic protein (IAP). In the immunohistochemical staining of IL-2R, 16 of the 18 patients (88.8%) showed IL-2R-positive cells in the colorectal cancer tissues. In regard to the metastatic lymph nodes, all of 5 patients (100%) showed IL-2R-positive cells. On the other hand, IL-2R-positive cells were not recognized in normal colorectal tissues and non-metastatic lymph nodes. Conclusion: These results suggest that activated T lymphocytes infiltrating into cancer tissues to play an antitumor role may release a large amount of the α-chain of IL-2R, resulting in the high levels of serum soluble IL-2R in patients with colorectal cancer. Received: October 18, 2001 / Accepted: June 12, 2002 Acknowledgments This study was supported in part by a Grant-in Aid for Scientific Research (11671269) from the Japanese Ministry of Education, Science, and Culture. Correspondence to:S. Murakami     

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.     

Attenuated nuclear shrinkage in neurons with nuclear aggregates--a morphometric study on pontine neurons of Machado-Joseph disease brains

Nuclear aggregates (NAs) and neurodegeneration in brains from patients with Machado-Joseph disease (MJD) are both triggered by pathological expansion of CAG/polyglutamine repeat in ataxin-3, but it remains to be clarified whether NA formation is associated with accelerated neurodegeneration. In an attempt to clarify a possible influence of NAs on neurons in human brains, we quantified the size and deformity of neuronal nuclei (those with or without NAs, separately) cross-sectioned on pontine preparations of autopsied brains from four patients with MJD and five controls. Nuclear shrinkage and deformity were more marked in MJD brains than in controls, and these changes were attenuated in neurons harboring NAs. NAs of MJD are presumably linked to a mechanism that attenuates rather than accelerates nuclear shrinkage and deformity. This finding leads us to consider that NAs are not necessarily toxic to neurons in diseased human brains.     

Prominent matched hypoperfusion in an intact cerebellum after a solitary middle cerebellar peduncle infarct

We examined the cerebellar metabolism of a 61-year-old man with a small infarct in the left middle cerebellar peduncle and an intact cerebellum. Positron emission tomographic images obtained 28 days after onset showed prominent hypoperfusion and hypometabolism (almost 50% below the normal level) in the left cerebellar hemisphere. This case report shows that neural deafferentation may cause prominent hypometabolism without morphologic changes in the cerebellum. An arrest in synaptic activity may be the most important factor for the adaptive decrease in oxygen metabolism seen in ischemic brain.     

A network system of medical and welfare information service for the patients,their families,hospitals, local governments,and commercial companies in a medical service area

A service information system using the Internet, which connected the various people who are related to medical treatment and nursing welfare, was constructed. An intractable neurological disease patient who lives in the Onga district, Fukuoka, Japan, and the people who are related to the service were chosen as test users in an experimental model. The communicated service information was divided into open-use data (electronic bulletin board, welfare service, medical care service, and link to private company service home page) and closed-use data (the individual patient's hysterics). The open data server was installed in an Internet service provider The open data could be accessed not only by the patient, but also by the family, information center, companies, hospitals, and nursing commodity store related to patient's nursing and medical treatment. Closed data server was installed in an information center (public health center). Only patient and information center staff can access the closed data. Patients should search and collect the service information of various medical and welfare services by themselves. Therefore, services prepared for the patient are difficult to know, and they cannot be sufficiently utilized. With the use of this information system, all usable service information became accessible, and patients could easily use it. The electronic bulletin board system (BBS) was used by patients for knowing each other or each others' family, and was used as a device for exchange of wisdom. Also, the questions for the specialist, such as doctor, dentist, teacher, physical therapist, care manager, welfare office staff member, and public health nurse, and the answers were shown on the BBS. By arranging data file, a reference of various patients in question and answer, which appeared in this BBS, was made as "advisory hints" and was added to the open data. The advisory hints became the new service information for the patients and their family. This BBS discovered the possibility of becoming an important information source for companies, hospital and, administration to know the requirements of patients and their families and the kind of services to be served. Although suppliers provide medical and welfare services for the patient, there is a tendency that the service information is sent by the suppliers at their own convenience. The information system in which various people participated was constructed in order to collect information for the patient, taking a patient-oriented approach. The result of the model test showed that this information system using Internet technology is a good system for both the service supplier and its receiver.     

抑制Src酪氨酸激酶对非小细胞肺癌细胞增殖的影响

目的探讨抑制Src酪氨酸激酶对非小细胞肺癌(non-smalllungcancer,NSCLC)体内外增殖的影响。方法Westernblot和免疫沉淀法检测Src蛋白在NSCLC细胞株中的表达和磷酸化情况;MTT法检测抑制Src酪氨酸激酶活化对NSCLC细胞体外增殖的影响;采用雄性严重联合免疫缺陷(severecombinedimmunitydeficiency,SCID)小鼠,建立肺腺癌PC-9和A549细胞诱导的皮下肿瘤动物模型,研究抑制Src酪氨酸激酶活化对皮下肿瘤增生的影响。结果NSCLC细胞株中Src蛋白明显活化而没有过度表达。Src酪氨酸激酶抑制剂对NSCLC细胞株中Src蛋白的自主磷酸化呈现剂量依赖的抑制作用。亚微摩尔Src酪氨酸激酶抑制剂(<3μmol/L)对PC-9和A549细胞株体外增生表现出剂量依赖性抑制作用,P<0·05。3μmol/LSrc酪氨酸激酶抑制剂也能够显著抑制H226细胞增生,P<0·01。在PC-9细胞诱导的皮下肿瘤模型中,口服Src酪氨酸激酶抑制剂2周后,10和50mg/(kg·d)治疗组对皮下肿瘤体积抑制率分别为73·28%和93·4%,P<0·001。在A549细胞诱导的皮下肿瘤模型中,50mg/(kg·d)治疗3周后差异有统计学意义,抑制率维持在39·4%,P<0·05。结论抑制Src酪氨酸激酶活化能够抑制NSCLC细胞体内外增殖。