Biomedical subjects

Seiji Isonishi

Publications and source records attributed to Seiji Isonishi.

14 recordsLinked to original sources

PubMed2006

Primary chemotherapy-associated effect of second-line chemotherapy on survival of patients with advanced ovarian cancer.

BACKGROUND: The current treatment of patients with recurrent ovarian cancer who have received initial platinum- or taxane-based chemotherapy depends on the results of the initial chemotherapy. The purpose of this study was to evaluate how to make the selection of second-line agents for patients with recurrent ovarian carcinoma initially diagnosed as stage II to IV. METHODS: We conducted a retrospective crossover study in patients who received second-line chemotherapy at Jikei University School of Medicine. We evaluated the responses, progression-free survivals, survivals of second-line chemotherapy, and overall survivals after primary surgery for 51 patients. The treatment cohorts were defined as follows: TC1, patients who were given paclitaxel and carboplatin as first-line chemotherapy and who, upon recurrence, were treated with a platinum-based combination as second-line; and TC2, patients who were given a non-taxane-based platinum combination as first-line chemotherapy, followed, at the time of recurrence, with paclitaxel and carboplatin. RESULTS: The response rates of the second-line chemotherapy for the TC1 and TC2 groups were 44% and 25% (P=0.09). The median progression-free survivals of TC1 and TC2 were 12.9 and 6.4 months (P=0.018; hazard ratio [HR], 2.42; 95% confidence interval [CI], 1.16-5.04). The median survivals after second-line chemotherapy for the two groups were 16.8 and 10.4 months (P=0.007; HR, 2.78; 95% CI, 1.33-5.84) and overall survivals after primary surgery were 36.6 and 27.9 months (P=0.007; HR, 2.36; 95% CI, 1.07-5.21). CONCLUSION: The TC1 group demonstrated a significantly better response and extension of progression-free survival, as well as significantly better survival after crossover and overall survival after primary surgery. As this was a retrospective analysis, this effect should be considered as hypothesis-generating and assessed prospectively in other trials comparing these two chemotherapy schedules.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2006

Characterization of mitochondria in cisplatin-resistant human ovarian carcinoma cells.

One of the mechanisms of cisplatin cell cytotoxicity is the mitochondria-associated induction of apoptosis. The morphological or functional change of mitochondria in cisplatin-resistant cells has already been reported. Herein we present additional data describing the mitochondrial genomic and functional changes in cisplatin- resistant cells. Cisplatin increased the level of apoptotic cells in cisplatin-sensitive human ovarian carcinoma OV 2008 and C13 cells by 3.90+/-1.01 (SD; N=3) (p<0.01)-fold and 2.03+/-0.20 (SD; N=3) (p<0.01)-fold compared to the basal apoptotic level. This indicates a lower level induction of apoptosis by 50% in cisplatin-resistant OV 2008/C13 *5.25 variant (C13) cells. In both cell types, cisplatin cytotoxicity is mostly inhibited by the caspase-9 inhibitor as well as the caspase-3 inhibitor, Ac-DEVD-CHO, suggesting that the mitochondrial downstream event was functioning well in both the C13 cells and in OV 2008 cells. Mitochondrial transmembrane potential (DeltaPsim) determined by flow cytometry using DiOC6-stained cells revealed a significant depolarization of C13 cells as compared to OV 2008 cells. Treatment of these cells with cisplatin or hydrogen peroxide induces complete mitochondrial DNA damage in OV 2008 cells, while only partial DNA-destruction is observed in C13 cells, strongly suggesting that mitochondria are resistant to cisplatin and oxidative stress response. Continuous oxygen consumption of these cells monitored by a multi-channel dissolved oxygen meter is 1.70-fold higher in OV 2008 cells than C13 cells and the oxygen consumption was decreased by 30% in C13 cells, suggesting mitochondrial respiratory malfunction in these cells. The hypothesis generated here is that mitochondrial DNA resistance to cisplatin and oxidative stress response might be one of the main characteristics concerning the lower level of apoptosis induced by cisplatin. However, the mechanism by which the mitochondrial DNA encoded molecule is involved in cisplatin resistance remains to be determined.

Apoptosis↗

PubMed2005

Indoleamine 2,3-dioxygenase serves as a marker of poor prognosis in gene expression profiles of serous ovarian cancer cells.

PURPOSE: We aimed to find key molecules associated with chemoresistance in ovarian cancer using gene expression profiling as a screening tool. EXPERIMENTAL DESIGN: Using two newly established paclitaxel-resistant ovarian cancer cell lines from an original paclitaxel-sensitive cell line and four supersensitive and four refractory surgical ovarian cancer specimens from paclitaxel-based chemotherapy, molecules associated with chemoresistance were screened with gene expression profiling arrays containing 39,000 genes. We further analyzed 44 genes that showed significantly different expressions between paclitaxel-sensitive samples and paclitaxel-resistant samples with permutation tests, which were common in cell lines and patients' tumors. RESULTS: Eight of these genes showed reproducible results with real-time reverse transcription-PCR, of which indoleamine 2,3-dioxygenase gene expression was the most prominent and consistent. Moreover, by immunohistochemical analysis using a total of 24 serous-type ovarian cancer surgical specimens (stage III, n = 21; stage IV, n = 7), excluding samples used for GeneChip analysis, the Kaplan-Meier survival curve showed a clear relationship between indoleamine 2,3-dioxygenase staining patterns and overall survival (log-rank test, P = 0.0001). All patients classified as negative survived without relapse. The 50% survival of patients classified as sporadic, focal, and diffuse was 41, 17, and 11 months, respectively. CONCLUSION: The indoleamine 2,3-dioxygenase screened with the GeneChip was positively associated with paclitaxel resistance and with impaired survival in patients with serous-type ovarian cancer.

Animals↗

PubMed2005

[Cancer screening].

The purpose of cancer screening is to widen the difference between morbidity and mortality of the target cancer. Since 1983 cancer screening has been supported by the Japanese government. Initially it covered gastric and cervical cancer with lung, breast and endometrial cancers supported from 1987 and colorectal cancer in 1992. Since 1998 support for cancer screening has been transferred to local government. It is generally accepted that the uptake of screening services is too low. Estimates for Japan suggest that at best 30% of the eligible population accept the services. In other parts of the world screening is more widely accepted, for example, 67% for breast cancer and 79% for cervical screening in the USA. Barriers within Japan for increasing screening are complex and include, legal, ethical, financial, technical infrastructure, data related matters and the level of understanding and education of the general public. In 2000 the MHLW conducted an evaluation of cancer screening in terms of usefulness and effectiveness. It concluded that fair or better evidence for reduction in mortality existed for cervical cancer (cytology), breast cancer (mammography with clinical examination for women aged > or = 50 years), colorectal cancer (faecal occult blood test), gastric cancer, lung cancer and liver cancer. As a step towards improving screening services and their uptake by the general public a new Research Centre for Cancer Prevention and Screening was established at the National Cancer Centre in October 2003. This and other initiatives will build on the progress of the past 20 years but it is generally agreed that there is still have a long way to go.

Adult↗

PubMed2005

[Cancer prevention].

The 12 th Oncology Forum discussed the progress and future strategy of cancer prevention in Japan. The National Cancer Center has established a research center for screening focusing on the most common six cancer, stomach, lung, liver, colon, breast and uterus cancer. The program so far had a cumulative detection rate of 3.3%, which is high,and may reflect the selection of subjects. Screening and chemoprevention is also being investigated in prostate cancer, but the issues centre on how to make this widely available. High risk subjects can also be identified for breast cancer. Obesity and family history are especially important. In colorectal cancer studies are evaluating different diets, but general application is not yet possible and the infrastructure to implement any general screening and prevention does not exist. Development of pharmaceutical treatments for prevention is difficult because of the need for very safe treatments, and also because of the length of time needed to carry out studies. Overall, cancer prevention is still in evolution. New approaches are needed, and new infrastructure will be needed at a government level to implement this.

Breast Neoplasms↗

PubMed2004

Drug sensitivity-related benefit of systematic lymphadenectomy during cytoreductive surgery in optimally debulked stages IIIc and IV ovarian cancer.

OBJECTIVE: The purpose of this study is to assess the survival experience following systematic lymphadenectomy (LNX) in conjunction with primary but optimal cytoreductive surgery in advanced epithelial ovarian cancer (OC) patients when followed by intensive chemotherapy. METHODS: This is a retrospective analysis of all women with OC who were treated in our institution between 1992 and 2000. A total of 98 patients with stages IIIc-IV of OC underwent primary cytoreductive surgery which was 'optimal' (<1 cm residual disease). All patients subsequently received postoperative platinum-containing chemotherapy. Group I, consisting of 51 patients underwent LNX; Group II, consisting of 47 patients did not undergo LNX. The percentage of patients failing to respond to chemotherapy in each group was similar. Each group had statistically equivalent age, stage, regimens of chemotherapy performed, and all other known prognostic factors. RESULTS: No survival benefit could be seen in platinum-sensitive patients. However, in patients who failed to respond to chemotherapy, the 2-year progression-free survival (PFS) (42.8% vs. 14.3%) and overall survival (OS) (51.2% vs. 28.8%) was quite different. LNX significantly improved those of drug-resistant patients when optimal cytoreductive surgery was performed [P = 0.008, risk ratio (rr) = 2.675, 95% confidence interval (CI) = 1.251-5.724]. Cox's proportional analysis shows that LNX was one of the three most significant covariate with the tumor grade and the number of postoperative residual lesions. CONCLUSIONS: The results show that LNX might be of benefit in patients who have optimal primary cytoreductive surgery and who do not respond to platinum-based chemotherapy.

Adult↗

PubMed2004

[Molecule based diagnosis].

Based on reviews of the concept of diagnostics and in general and in specific tumour areas it was clear that development of diagnostic procedures involving genomics will allow for much better targeted and tailored treatments in the future. This will result in better efficacy and better tolerability of cancer treatments, but will also allow for progress in prediction, diagnosis and dose selection. Large collaborative projects studying the efficacy and safety of drugs on the genome level is promising to bring important benefits to both patients and the national economy by reducing useless drug therapy. In colorectal cancer there are several genetic defects identified that can act as the target for directed therapy in the future. Expressions of tumour specific antigens open the way for immunological targeted therapies. Developments in the understanding of the genomic basis for resistance to anti-tumour therapy is promising to help targeting patients likely to respond and not develop resistance. A Japanese model is being developed to determine the relative risk of breast cancer of Japanese women. Based on this prevention therapies can be instigated. The last four years have seen the introduction of four novel targeted therapies. If this model should become a standard in the future, much stronger collaboration between academic research and pharmaceutical industry need to develop.

Antineoplastic Agents↗

PubMed2004

[Anti angiogenesis].

Based on presentations on the basic concepts and scientific rationale of anti-angiogenic approaches to cancer therapy and the possible applications in the area of prostate cancer, gastrointestinal cancer, lung cancer and breast cancer it is easy to conclude that development of anti-angiogenic approaches into clinical therapies is extremely challenging. It is now well established that cancer growth is increased by angiogenic factors and that inhibition of angiogenesis decreases growth and metastatic potential. Anti-angiogenic effect can be obtained through interference with multiple targets. Further development of new strategies involving such novel cancer therapies requires wide reaching development of translational research abilities. However, for moving new therapies into the clinic same rigorous criteria need to be applied as is done for traditional therapies. Angiogenesis appear to be a critical factor for development of prostate, gastric, lung and breast cancers. Development of new anti-angiogenic treatment modalities might become very important in these diseases. A critical requirement for the successful clinical development will be the development of imaging techniques that can help evaluate the effect on blood vessel functionality. Such surrogate markers of anti-angiogenic effect will be essential for optimising molecules and doses.

Angiogenesis Inhibitors↗

PubMed2004

[Biomarker in gynecologic malignancies].

We selected ovarian cancer as being the most representative of the gynecologic malignancies since it has the largest number of tumor markers now in clinical use. First, variety of serum tumor markers were developed and regularly used to detect the existence of ovarian cancer and its stage. These markers of monoclonal antibodies could detect three different classes of cell surface antigen. CA 125, CA 130, CA 602 are antibodies raised against the core protein of the proteoglycan molecule, whereas CA 19-9, CA 50, KMO-1 and CA 72-4, STN, CA 546 are antibodies against a different portion of the glycosaminoglycan chain from the core protein. These markers, when combined with another group of tumor markers for discriminating the variety of pathological types of ovarian cancer, might have the potential to provide a better predictive value. Second, biomarkers for the detection of early-stage ovarian cancer are urgently needed and developed also in gynecologic tumors. These include a ovarian cancer-specific proteomic patterns generated by mass spectroscopy and single nucleotide polymorphism (SNP) digital analysis combined with assessment of allelic imbalance. Third, for monitoring the effect of treatment with cytostatic drugs, various types of biomarkers could be used as surrogate markers for the treatment depending on the mechanism of the effects of the drug used. For treatment with Bryostatin, a strong protein kinase C (PKC) stimulator, PKC activity promises to be an effective marker. For the trials with bevacizumab, anti-VEGF antibody, VEGF and its associated bFGF, CD-31, and thrombospondin-1 (TSP-1), are leading candidates for monitoring markers.

Antigens, Tumor-Associated, Carbohydrate↗

PubMed2003

Enhancement of sensitivity to cisplatin by orobol is associated with increased mitochondrial cytochrome c release in human ovarian carcinoma cells.

OBJECTIVES: Based on our previous report showing that orobol, a potent phosphatidylinositol 4-kinase (PI4K) inhibitor, produced cisplatin (DDP) sensitivity, we have determined the mechanism of orobol-sensitization effect. METHODS AND RESULTS: Orobol produced >2-fold DDP sensitivity in human ovarian carcinoma 2008 cells and its DDP-resistant variant 2008/C13*5.25 cells (C13). Because orobol had no effect on conventional mechanisms such as DDP accumulation or cellular metallothionein and glutathione content, we have focused on the apoptotic signaling pathway. Orobol induced a significant increase in apoptosis in DDP-treated cells, as estimated by frequency of condensed nuclear chromatin with Hoechst 33342 stain, although orobol alone did not have any effect on apoptotic potential. The caspase-3-inhibiting peptide Ac-DEVD-CHO completely inhibited the orobol sensitization effect but did not block DDP cell cytotoxicity per se. Orobol rendered both of these cells resistant to rhodamine 123 (Rh) by more than 2.5-fold, indicating significant decrease of mitochondrial membrane potential (DeltaPsim). Confocal laser microscopy of cells stained with the mitochondria (MT)-specific dye Rh revealed that orobol decreased Rh-fluorescent intensity. Electron microscopy of these cells showed that orobol induced swelling and condensation of MT. Orobol suppressed both naturally expressed and the DDP-induced Bcl-2 expression significantly. Orobol and DDP treatment reduced cytochrome c level in MT determined by Western blot analysis, indicating increased amount of cytochrome c release from MT, whereas orobol alone did not alter the amount of cytochrome c in MT. CONCLUSIONS: These results indicate that orobol produced DDP sensitivity in human ovarian carcinoma cells by inducing apoptosis through the MT-dependent signaling pathway.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2003

[Globalization of clinical trials].

Based on reviews of the Japanese clinical trial situation in lung cancer, gastric cancer, prostate cancer and breast cancer, it was clear that much progress has been made in short time. There are considerable differences between Japan and the West and also differences between clinical areas in Japan. For regulatory purposes bridging studies have become increasingly important. Use of identical protocols are required for effective bridging. Participations in global phase III trials is the best way of achieving registration in Japan. For successful global trials in Japan it is important to include Japanese investigators in the preparation of the protocol and to recognise the challenges facing such a project. Clinical practice in diagnosis and treatment have many differences, thus it is recommended to have clear and detailed information in the protocol. Hard end points like survival are important since they are not biased by cultural differences. There are clear difficulties with HE or QOL outcomes. The emergence of focus on evidence based medicine is also happening in Japan and will help to harmonize documentation across the world. For large adjuvant or prevention cancer global trials are essential. To facilitate global studies further development of infrastructure is necessary in Japan. Use of electronic data capture web based communication etc. will help overcome communication difficulties. Other improvements that will make Japanese participation in global trials easier and better include establishment of clinical trial centre at each hospital, introduction of trial coordinators or study nurses and an improved collaboration with company staff. A critical issue that also need addressing is agreement of centre target recruitment. We need to introduce a new flexible system in Japan if participation in global trial is to be optimised. If we can address these issues Japanese investigators and collaborative groups should be able to initiate and lead global trials in the future.

Antineoplastic Agents↗

PubMed2002

[Globalization of anti-cancer therapies].

Based on short reviews of lung, gastric, colorectal, prostate, breast and ovarian cancer, there remain significant differences between Japan and the West in the therapeutic regimen for most cancers. Some of the differences are due to differences in stage of disease at diagnosis or historical factors affecting availability of products. In both Japan and the West, there are initiatives to prepare treatment guidelines based on published data. For Japan this initiative is limited by the lack of Japanese clinical trial data or even safety data. When guidelines are prepared from international data, many of the products have limited indications in Japan and therefore not reimbursed. Availability of the most appropriate therapies to Japanese patients will depend on a facilitation of clinical trials in both primary and additional indications. However, the experience in other countries is that, even where data and registration approval are available, guidelines are hard to agree and are not uniformly accepted by prescribers. The ICH E5 guideline on the use of bridging studies to interpolate Western data to Japanese regulatory dossiers provides an opportunity to accelerate availability of new medicines to Japanese prescribers and patients. The use of bridging studies has so far been limited for anti-cancer therapies. Where relevant pharmacodynamic endpoints can be measured, (e.g. aromatase inhibition) there can increase confidence in bridging. The newer types of agent which act to stabilise disease rather than tumour shrinkage present a special problem. In some cases surrogate markers can be valuable but in each case they need to be validated. As globalization continues, an alternative approach is to include a significant cohort of Japanese patients in Japanese patients but this depends on sufficient similarity in the patient population and background therapy. The most significant limitation to either large outcome studies in Japan or for Japanese centers to join international trials has been the environment for conduct of clinical trials. There have been some recent improvements and further progress is expected so that Japanese doctors can play a full role in the evaluation of new therapies.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2002

[Latest information in the diagnoses of ovarian carcinoma].

Despite improvements in median and overall survival from a combination of improved operation techniques and chemotherapy with platinum-compounds and paclitaxel, long-term survival rates for patients with epithelial ovarian carcinoma remain disappointing, and ongoing efforts are aimed at developing more effective primary therapies. In early ovarian carcinoma, conservative management is used to denote surgery that preserves reproductive potential without compromising curability. With some exceptions, such a strategy may be applicable for women younger than 40, who wish to bear children. A major dilemma facing gynecologic oncologists is to determine whether the accurate staging laparotomy is needed for apparent low-risk stage I ovarian carcinoma and how many cycles of chemotherapy will be needed for high-risk stage I ovarian carcinoma. In advanced ovarian carcinoma, main objectives of salvage therapy include: a improvement in quality of life and symptoms; b. tumor load reduction and survival advantage; c. evaluation of potentially active new drugs to be included in first-line treatment. We need to evaluate the potential benefit on survival of systematic pelvic and para-aortic lymphadenectomy during primary or secondary cytoreductive surgery in patients with advanced ovarian carcinoma. Paclitaxel/cisplatin is considered to be the international standard treatment based on the data of GOG 111 trial showing that paclitaxel/cisplatin has provided a survival benefit better than that of cyclophosphamide/cisplatin. This choice of standard therapy might, however, be questioned based on the results of the largest randomised study, ICON3. There were no statistically significant differences in progression-free or overall survival among paclitaxel/carboplatin and carboplatin only or a platinum combination (cyclophosphamide/doxorubicin/cisplatin). The best selection for adjuvant chemotherapy is still controversial and a large number of studies are now ongoing.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2002

[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.

Clinical Trials as Topic↗