Toshiharu Yasugi

Tokyo Metropolitan Cancer and Infectious Diseases Center, Edo, Tōkyō, Japan

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Publications (84)290.01 Total impact

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    ABSTRACT: Few reports on malignant transformation of adenomyosis are available, and endometrioid adenocarcinoma arising from cystic adenomyosis is further rarely reported. We report a case of a 67-year-old asymptomatic woman who was referred to our hospital for evaluation of a cystic lesion in the pelvis, which had been diagnosed as cystic degeneration of leiomyoma for 3 years. Magnetic resonance imaging revealed a cystic mass measuring 11 cm in diameter, which was contiguous with uterine myometrium. The lesion contained solid areas enhanced on gadolinium-enhanced T1 -weighted imaging. Transabdominal simple total hysterectomy with bilateral salpingo-oophorectomy was performed. Pathological examination revealed endometrioid adenocarcinoma arising from cystic adenomyosis. The patient underwent six courses of adjuvant combination chemotherapy with paclitaxel and carboplatin. No metastasis or recurrence has been demonstrated for 16 months following surgery. Our case demonstrates that cystic adenomyoma possesses the risk of malignant transformation, indicating the importance of long-term follow-up with imaging examination.
    Journal of Obstetrics and Gynaecology Research 10/2014; · 0.84 Impact Factor
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    ABSTRACT: This is a retrospective study of fifteen cases of primary peritoneal carcinoma who were treated between 2001 and 2010 in our hospital. The median age at the time of diagnosis was 63 years(range, 40 to 79 years). Three patients had clinical stage II disease, eleven patients had stage III disease, and one patient was unstaged. The serum CA125 values at pretreatment were elevated in all patients, with a median value of 4,144. 8 U/mL(range, 102. 8 to 23, 611. 0 U/mL). Optimal debulking was possible in 9 of the 15 patients. All patients were treated with paclitaxel and carboplatin chemotherapy during the preoperative and/or postoperative period. All patients at stage II disease were alive without evidence of disease at the time of evaluation(2 patients>5 years, 1 patient>3 years). Four patients with stage III disease had died from the disease less than 3 years after the first treatment. The results of our study showed poor survival for the group with stage III disease, but good survival for the group with stage II disease.
    Gan to kagaku ryoho. Cancer & chemotherapy 07/2013; 40(7):887-90.
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    ABSTRACT: Background:A phase III trial was conducted to determine whether neoadjuvant chemotherapy (NACT) before radical surgery (RS) improves overall survival.Methods:Patients with stage IB2, IIA2, or IIB squamous cell carcinoma of the uterine cervix were randomly assigned to receive either BOMP (bleomycin 7 mg days 1-5, vincristine 0.7 mg m(-2) day 5, mitomycin 7 mg m(-2) day 5, cisplatin 14 mg m(-2) days 1-5, every 3 weeks for 2 to 4 cycles) plus RS (NACT group) or RS alone (RS group). Patients with pathological high-risk factors received postoperative radiotherapy (RT). The primary end point was overall survival.Results:A total of 134 patients were randomly assigned to treatment. This study was prematurely terminated at the first planned interim analysis because overall survival in the NACT group was inferior to that in the RS group. Patients who received postoperative RT were significantly lower in the NACT group (58%) than in the RS group (80%; P=0.015). The 5-year overall survival was 70.0% in the NACT group and 74.4% in the RS group (P=0.85).Conclusion:Neoadjuvant chemotherapy with BOMP regimen before RS did not improve overall survival, but reduced the number of patients who received postoperative RT.British Journal of Cancer Advance pnline publication 2 May 2013: doi:10.1038/bjc.2013.179 www.bjcancer.com.
    British Journal of Cancer 05/2013; · 5.08 Impact Factor
  • Open Journal of Obstetrics and Gynecology 01/2013; 03(05):5-10.
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    ABSTRACT: BACKGROUND: It has been suggested that micronutrients such as alpha-tocopherol, retinol, lutein, cryptoxanthin, lycopene, and alpha- and beta-carotene may help in the prevention of cervical cancer. Our aim was to investigate whether serum concentrations and/or dietary intake of micronutrients influence the regression or progression of low-grade cervical abnormalities. METHODS: In a prospective cohort study of 391 patients with cervical intraepithelial neoplasia (CIN) grade 1-2 lesions, we measured serum micronutrient concentrations in addition to a self-administered questionnaire about dietary intake. We evaluated the hazard ratio (HR) adjusted for CIN grade, human papillomavirus genotype, total energy intake and smoking status. RESULTS: In non-smoking regression subjects, regression was significantly associated with serum levels of zeaxanthin/lutein (HR 1.25, 0.78-2.01, p = 0.024). This benefit was abolished in current smokers. Regression was inhibited by high serum levels of alpha-tocopherol in smokers (p = 0.042). In progression subjects, a significant protective effect against progression to CIN3 was observed in individuals with a medium level of serum beta-carotene [HR 0.28, 95 % confidence interval (CI) 0.11-0.71, p = 0.007), although any protective effect from a higher level of serum beta-carotene was weaker or abolished (HR 0.52, 95 % CI 0.24-1.13, p = 0.098). Increasing beta-carotene intake did not show a protective effect (HR 2.30, 95 % CI 0.97-5.42, p = 0.058). CONCLUSIONS: Measurements of serum levels of carotenoids suggest that regression is modulated by smoking status. Maintaining a medium serum level of beta-carotene has a protective effect for progression; however, carotene intake is not correlated with serum levels of carotenoids.
    International Journal of Clinical Oncology 10/2012; · 1.41 Impact Factor
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    ABSTRACT: To determine the role of neutralizing antibody generated by human papillomavirus (HPV) infections, baseline levels of serum neutralizing antibodies directed against HPV 16 and cervical HPV DNA were determined in 242 unvaccinated women with low-grade cervical abnormalities, who were then monitored by cytology and colposcopy every 4 months. In women infected with HPV 16 (n = 42), abnormal cytology persisted longer in those positive for HPV 16-specific neutralizing antibodies at baseline (median time to cytological regression: 23.8 vs. 7.2 months). Progression to cervical precancer (cervical intraepithelial neoplasia grade 3) within 5 years occurred only among women carrying HPV 16-specific neutralizing antibodies (P = 0.03, log-rank test). In women infected with types other than HPV 16 (n = 200), detection of HPV 16-specific neutralizing antibodies was not correlated with disease outcome. In conclusion, development of specific neutralizing antibodies following natural HPV 16 infection did not favor a better outcome of low-grade cervical lesions induced by HPV 16 or by other types; rather, detection of neutralizing antibodies generated by current infection may reflect viral persistence and thus help identify those who are at high risk of disease progression.
    Journal of Medical Virology 07/2012; 84(7):1128-34. · 2.37 Impact Factor
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    ABSTRACT: Genetic variations in human leukocyte antigens (HLA) class II regions may influence the risk of cervical cancer by altering the efficiency of the immune responses to human papillomavirus antigens. This prospective study was designed to evaluate the effects of HLA class II alleles on the natural course of cervical precursor lesions. We followed a total of 454 Japanese women with cytological low-grade squamous intraepithelial lesion (LSIL) and histological cervical intraepithelial neoplasia grades 1 to 2 (CIN1-CIN2). Patients were tested for HLA class II alleles and cervical human papillomavirus DNA at the time of entry and then monitored by cytology and colposcopy every 4 months for a mean follow-up of 39.0 months. We analyzed cumulative probabilities of cytological regression to at least 2 consecutive negative Papanicolaou tests and histological progression to biopsy-positive CIN3. During the follow-up period, 39 lesions progressed to CIN3, and 282 lesions regressed to normal cytology. Progression to CIN3 did not occur in DRB1*1302-positive women, and this protective effect of DRB1*1302 was statistically significant (P = 0.03). Low-grade squamous intraepithelial lesion regressed to normal cytology more quickly in DRB1*1302-positive women than in DRB1*1302-negative women (median time, 8.9 months vs 14.2 months), although the difference was not statistically significant (P = 0.16). The risk of LSIL persistence or progression to CIN3 within 5 years was not affected by any other HLA class II alleles. By using a prospective study design, we demonstrated the protective effect of the DRB1*1302 allele against progression to CIN3 among Japanese women with LSIL.
    International Journal of Gynecological Cancer 03/2012; 22(3):471-8. · 1.94 Impact Factor
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    ABSTRACT: To investigate the natural course of low-grade squamous intraepithelial lesions (LSILs) that cannot be histologically confirmed by colposcopy-directed biopsy. In a multicenter, prospective, cohort study of Japanese women with LSILs, we analyzed the follow-up data from 64 women who had a negative biopsy result at the initial colposcopy (biopsy-negative LSIL) in comparison with those from 479 women who had a histologic diagnosis of cervical intraepithelial neoplasia grade 1 (LSIL/CIN1). Patients were monitored by cytology and colposcopy every 4 months for a mean follow-up period of 39.0 months, with cytologic regression defined as two consecutive negative smears and normal colposcopy. In women with biopsy-negative LSILs, there were no cases of CIN3 or worse (CIN3+) diagnosed within 2 years; the difference in the 2-year risk of CIN3+ between the two groups was marginally significant (0 vs. 5.5%; P = 0.07). The cumulative probability of cytologic regression within 12 months was much higher in the biopsy-negative LSIL group (71.2 vs. 48.6%; P = 0.0001). The percentage of women positive for high-risk human papillomaviruses (hrHPVs) was significantly lower in the biopsy-negative LSIL group than in the LSIL/CIN1 group (62.1 vs. 78.4%; P = 0.01); however, the 12-month regression rate of biopsy-negative LSIL was similar between hrHPV-positive and -negative women (67.3 vs. 74.4%, P = 0.73). In women with biopsy-negative LSILs, the risk of CIN3+ diagnosed within 2 years was low; furthermore, approximately 70% underwent cytologic regression within 12 months, regardless of HPV testing results. Biopsy-negative LSILs may represent regressing lesions rather than lesions missed by colposcopy.
    International Journal of Clinical Oncology 07/2011; 17(3):233-9. · 1.41 Impact Factor
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    ABSTRACT: To evaluate the usefulness of intraoperative ultrasonography (IU) in reducing the number of unnecessary para-aortic lymphadenectomy in women with endometrial carcinoma. Computed tomography (CT) and IU were used to assess whether para-aortic lymph nodes were enlarged in 91 women with endometrial carcinoma. All women underwent hysterectomy and systematic pelvic and para-aortic lymphadenectomy. On the basis of the intrauterine pathological findings (IPF) of the removed uterus, the women were classified into low- and high-risk groups. It was assumed that para-aortic lymphadenectomy would be performed only when enlarged nodes were detected by CT or IU or only when women were classified into the high-risk group. The numbers of women who would have had missed metastases and who could have avoided para-aortic lymphadenectomy were calculated. Eighteen women had pathological para-aortic node metastases. Theoretically, the number of women who would have had missed metastases on the basis of CT, IU, and IPF were 11, 2, and 2, respectively; more metastases were missed with CT than with the other 2 methods. The number of women who could have avoided para-aortic lymphadenectomy on the basis of CT, IU, and IPF were 84, 59, and 29, respectively; compared to IPF, IU helped avoid para-aortic lymphadenectomy in more women. Intraoperative ultrasonography is the most efficient method for avoiding both unnecessary para-aortic lymphadenectomy and missed para-aortic node metastases in women with endometrial carcinoma.
    International Journal of Gynecological Cancer 07/2011; 21(5):859-63. · 1.94 Impact Factor
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    ABSTRACT: Only a subset of cervical precursor lesions progress to cervical cancer and because of the lack of the predictive markers, it cannot be ascertained which lesions will progress or not. To estimate the risk of disease progression associated with human papillomavirus (HPV) genotypes, we followed 570 Japanese women with cytological LSIL (low-grade squamous intraepithelial lesion) and histological CIN (cervical intraepithelial neoplasia) grade 1-2 lesions (479 CIN 1; 91 CIN 2) at 3 to 4 month intervals for a mean follow-up period of 39.1 months. At entry, we detected HPV DNA in cervical samples by polymerase chain reaction-based methodology. Over the period of follow-up period, 46 lesions progressed to CIN 3 while 362 regressed to normal cytology. Women with multiple HPV infections were more likely to have persistent lesions (hazard ratio [HR] for regression, 0.65; 95% confidence interval [CI], 0.42-1.02; p = 0.07); however, multiple infections did not increase the risk of progression (HR for progression, 1.04; 95% CI, 0.37-2.94; p = 0.94). After adjusting for CIN grade and women's age, HRs for progression to CIN 3 (vs. women with low-risk types or negative for HPV DNA) varied markedly by HPV genotype: type 16 (11.1, 95% CI: 1.39-88.3); 18 (14.1, 0.65-306); 31 (24.7, 2.51-243); 33 (20.3, 1.78-231); 35 (13.7, 0.75-251); 52 (11.6, 1.45-93.3); 58 (8.85, 1.01-77.6); other high-risk types (4.04, 0.47-34.7). HPV 45 was not detected in our study subjects. The cumulative probability of CIN 3 within 5 years was 20.5% for HPV 16, 18, 31, 33, 35, 52 and 58; 6.0% for other high-risk types; 1.7% for low-risk types (p = 0.0001). In conclusion, type-specific HPV testing for women with LSIL/CIN 1-2 lesions is useful for identifying populations at increased or decreased risk of disease progression.
    International Journal of Cancer 06/2011; 128(12):2898-910. · 6.20 Impact Factor
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    ABSTRACT: We retrospectively evaluated the efficacy and toxicity of docetaxel and carboplatin in patients with platinum and paclitaxel-pretreated recurrent ovarian, fallopian tube, and peritoneal cancer. Forty-two women (38 with ovarian cancer, 1 with fallopian tube cancer, 3 with peritoneal cancer) whose cancer had progressed within 12 months of their last treatment with both a platinum agent and paclitaxel were treated with docetaxel (70 mg/m(2), day 1) and carboplatin (area under the curve of 4-6, day 1). Thirty-four patients had measurable disease. The objective response rate was 23% within 0-6 months of the progression-free interval, 50% within 6-12 months, and 32% (11 of 34 patients) for both groups. The median time to tumor progression was 28, 49, 34 weeks, and the median overall survival time was 94, 224, 111 weeks, respectively. The most common toxicity was grade 3/4 neutropenia (98% of patients), with 15 episodes (8.4% of courses) of neutropenic fever. The main nonhematologic toxicity was hypersensitivity; 7 patients (17%) required discontinuation of the therapy. The results of our study indicate that the combination of docetaxel and carboplatin is effective against recurrent ovarian, fallopian tube, and peritoneal cancer with progression-free interval of 6-12 months from previous treatment by paclitaxel and platinum. On the other hand, single-agent chemotherapy would be better than this regimen considering its low response rate and severe hematological toxicity for patients with progression-free interval less than 6 months.
    Medical Oncology 03/2011; 29(2):1253-4. · 2.14 Impact Factor
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    ABSTRACT: Uterine leiomyoma are very common benign tumors in women of reproductive age. However, the molecular mechanisms of cause and development of these tumors are poorly understood. This study attempts to examine whether or not aberrant DNA methylation occurred in these tumors. We carried out a genome-wide screen for aberrant DNA methylation, adopting methylation-sensitive-representational difference analysis (MS-RDA) using normal adjacent myometria as tester and myoma tissue driver. A total of 192 clones identified by MS-RDA were sequenced, 27 DNA fragments derived from CpG islands (CGIs) were isolated, and seven of them were from CGI in the 5' regions of known genes, which include CHARC1, FAM44B, FLJ33655, HSUP, MLLT3, SLC16A1, and ZNF96. Then, methylation statuses of those CGIs were analyzed by methylation-specific polymerase chain reaction using 5 primary samples of human uterine leiomyoma. Aberrant DNA methylation did not observed in 7 genes in 5 human uterine leiomyoma eventually. This study is insufficient to identify aberrant DNA methylation occurring in the human uterine leiomyoma, a large population of primary samples and more attempts, such as the use of cell lines or primary monolayer cultures established from tissue samples, are warranted to clarify this issue.
    The Tokai journal of experimental and clinical medicine 01/2011; 36(3):84-90.
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    ABSTRACT: Ovarian clear cell adenocarcinoma (OCCA) is known to have a worse prognosis than ovarian serous adenocarcinoma due to its poor response to conventional platinum-based chemotherapy. Idiopathic thrombocytopenic purpura (ITP), which usually reveals severe thrombocytopenia, is a common autoimmune disorder. However, to date very few cases of ovarian cancer associated with ITP have been reported in the literature. We report a case of a 57-year-old woman who developed OCCA 14 years after the diagnosis of ITP. The patient presented with abdominal distention and mild tenderness. We performed the operation with high-dose immunoglobulin therapy preoperatively, and diagnosed OCCA. Postoperatively, six cycles of cytotoxic chemotherapy with irinotecan hydrochloride plus cisplatin were performed every 4-5 weeks without thrombocytopenia. We conclude that combination chemotherapy with irinotecan hydrochloride plus cisplatin is useful for a case of OCCA associated with ITP.
    International Journal of Clinical Oncology 12/2010; 16(4):447-9. · 1.41 Impact Factor
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    ABSTRACT: CD1d and CD1d-restricted natural killer T (NKT) cells serve as a natural bridge between innate and adaptive immune responses to microbes. CD1d downregulation is utilized by a variety of microbes to evade immune detection. We demonstrate here that CD1d is downregulated in human papillomavirus (HPV)-positive cells in vivo and in vitro. CD1d immunoreactivity was strong in HPV-negative normal cervical epithelium but absent in HPV16-positive CIN1 and HPV6-positive condyloma lesions. We used two cell lines for in vitro assay; one was stably CD1d-transfected cells established from an HPV-negative cervical cancer cell line, C33A (C33A/CD1d), and the other was normal human vaginal keratinocyte bearing endogenous CD1d (Vag). Flow cytometry revealed that cell surface CD1d was downregulated in both C33A/CD1d and Vag cells stably transfected with HPV6 E5 and HPV16 E5. Although the steady-state levels of CD1d protein decreased in both E5-expressing cell lines compared to empty retrovirus-infected cells, CD1d mRNA levels were not affected. Confocal microscopy demonstrated that residual CD1d was not trafficked to the E5-expressing cell surface but colocalized with E5 near the endoplasmic reticulum (ER). In the ER, E5 interacted with calnexin, an ER chaperone known to mediate folding of CD1d. CD1d protein levels were rescued by the proteasome inhibitor, MG132, indicating a role for proteasome-mediated degradation in HPV-associated CD1d downregulation. Taken together, our data suggest that E5 targets CD1d to the cytosolic proteolytic pathway by inhibiting calnexin-related CD1d trafficking. Finally, CD1d-mediated production of interleukin-12 from the C33A/CD1d cells was abrogated in both E5-expressing cell lines. Decreased CD1d expression in the presence of HPV E5 may help HPV-infected cells evade protective immunological surveillance.
    Journal of Virology 11/2010; 84(22):11614-23. · 5.08 Impact Factor
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    ABSTRACT: The role of tobacco smoking in the multistage carcinogenesis at the cervix is not fully understood because of a paucity of prospective data. To assess the relationship between smoking and spontaneous regression of cervical precursor lesions, a total of 516 women with low-grade squamous intraepithelial lesion (LSIL) were monitored by cytology and colposcopy every 4 months. Probability of LSIL regression within 2 years was analyzed in relation to smoking behaviors, with regression defined as at least two consecutive negative Pap smears and normal colposcopy. Women's age, initial biopsy results, and human papillomavirus (HPV) genotypes were included in the multivariate models for adjustments. Our study subjects included 258 never-smokers and 258 smokers (179 current and 79 former smokers). During a mean follow-up time of 39.8 months, 320 lesions regressed to normal cytology. Probability of regression within 2 years was significantly lower in smokers than in never-smokers (55.0%vs 68.8%, P = 0.004). The risk of LSIL persistence increased with smoking intensity and duration and with younger age at starting smoking (P = 0.003, P < 0.001, and P = 0.03, respectively). Smokers had twice as high a risk of persistent HPV infection compared to never-smokers (odds ratio, 2.50; 95% confidence interval, 1.30-4.81; P = 0.006). In young women, passive smoking since childhood reduced probability of regression within 2 years (56.7%vs 85.9%, P < 0.001). Further adjustments for a wide range of cervical cancer risk factors did not change the findings. In conclusion, tobacco smoking may interfere with regression of cervical precursor lesions. Childhood exposure to second-hand smoke may increase a risk of persistent cervical abnormalities among young women.
    Cancer Science 09/2010; 101(9):2065-73. · 3.48 Impact Factor
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    ABSTRACT: Low-grade endometrial stromal sarcoma (ESS) is a rare neoplasm and is generally an indolent tumor with estrogen and progesterone receptors. Objective responses by hormonal treatment with progestin or aromatase inhibitor have been reported, however, long-term management of this disease could be difficult if it becomes refractory to one of these hormonal therapies. A 34-year-old woman was diagnosed with stage I low-grade ESS at the time of hysterectomy for presumed uterine fibroma. Five years later, she recurred with multiple tumors in the lower abdomen. After an optimal surgery, she was free from progression for 6 years with progestin treatment (medroxyprogesterone acetate: MPA, 200-600 mg daily). Thereafter, she recurred twice during the MPA treatment and received debulking surgery each time. MPA was discontinued at age of 53, because another recurrent tumor grew up to 13 cm in diameter. Aromatase inhibitor anastrozole was then given at a daily dose of 1 mg with partial response (the tumor size decreased to 7 cm in diameter) for a duration of 9 months. After complete resection of the recurrent tumor, she remains progression-free for 16 months. Anastrozole was effective to recurrent low-grade ESS even after being refractory to progestin therapy. Aromatase inhibitor treatment may be a useful option as a second-line hormonal treatment to low-grade ESS.
    Medical Oncology 03/2010; 28(3):771-4. · 2.14 Impact Factor
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    ABSTRACT: Although many clinical trials on human papillomavirus (HPV) therapeutic vaccines have been performed, clinical responses have not been consistent. We have addressed mucosal cytotoxic cellular immune responses to HPV16 E7 after oral immunization of mice with recombinant Lactobacillus casei expressing HPV16 E7 (LacE7). C57BL/6 mice were orally exposed to 0.1-100mg/head of attenuated LacE7 or vehicle (Lac) vaccines at weeks 1, 2, 4, and 8. Responses to subcutaneous or intramuscular injection of an HPV16 E7 fusion protein using the same timing protocol were used for comparison. Oral immunization with LacE7 elicited E7-specific IFN gamma-producing cells (T cells with E7-type 1 immune responses) among integrin alpha 4 beta 7(+) mucosal lymphocytes collected from gut mucosa. An induction of E7-specific granzyme B-producing cells (E7-CTL) exhibiting killer responses toward HPV16 E7-positive cells was also observed. The induction of T cells with specific mucosal E7-type 1 immune responses was greater after oral immunization with LacE7 when compared to subcutaneous or intramuscular antigen delivery. Oral immunization with Lactobacillus-based vaccines was also able to induce mucosal cytotoxic cellular immune responses. This novel approach at a therapeutic HPV vaccine may achieve more effective clinical responses through its induction of mucosal E7-specific CTL.
    Vaccine 02/2010; 28(16):2810-7. · 3.77 Impact Factor
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    ABSTRACT: The optimal goal of interval debulking surgery (IDS) following neoadjuvant chemotherapy (NAC) remains undefined. The aim of this study was to determine the optimal goal of IDS following NAC on the basis of long-term survival by the disease status at the end of interval look surgery (ILS) or IDS during the treatment in the setting of upfront primary debulking surgery (PDS). From January 1986 through December 2000, we performed treatment in the setting of upfront PDS in 128 patients with Stage III/IV epithelial ovarian cancer. Sixty-six patients with residual disease (RD) at PDS underwent interval surgery (IS) such as ILS or IDS; 4 patients after two cycles of chemotherapy and 62 after three or more cycles. We investigated how disease status at the end of IS was associated with overall survival (OS). The 5-year OS rates for no, minimal and gross RD were not available (n = 0), 67% (n = 3) and 0% (n = 1) after two cycles, and 47% (n = 42), 0% (n = 18) and 0% (n = 2) after three or more cycles, respectively. No visible tumors at the end of IS after three or more cycles of chemotherapy were necessary for 5-year survival. If the optimal goal of IDS is defined as the surgery that is expected to result in long-term survival in the NAC setting treatment, our data on the assessment of peritoneal findings during the upfront PDS setting treatment suggest that only complete resection with no RD could be the optimal goal of IDS in the NAC setting treatment.
    Japanese Journal of Clinical Oncology 10/2009; 40(1):36-41. · 1.90 Impact Factor
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    Kei Kawana, Toshiharu Yasugi, Yuji Taketani
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    ABSTRACT: Cervical cancer is the leading cause of cancer mortality among women in worldwide. Some 99 per cent of cervical cancer cases are linked to genital infection with human papillomaviruses (HPVs) comprised of approximately 15 oncogenic genital HPV types. Most HPV infections resolve spontaneously. But, the remainder persist and may then progress to cervical cancer in some women. In high-resource countries, the best way to prevent cervical cancer is to implement organised gynaecological screening programs with appropriate treatment of the detected pre-cancerous lesions. However, in developing countries, this method is not practicable because of cost and complexity of proper screening. Vaccines against HPV infections hold promise to reduce incidence of cervical cancer cost-effectively. Two Prophylactic HPV vaccines have been thus far developed: Gardasil(R), a quadrivalent vaccine targeting HPV-6, -11, -16 and -18) and Cervarix(R), a bivalent vaccine which targets HPV-16 and -18. Both vaccines contain L1 virus-like particles (VLPs) derived from HPV-16 and -18 which are most frequently associated with cervical cancer. The L1-VLP vaccines are HPV type-specific and therefore can effectively prevent infection of a HPV type in question alone. Therefore, the L1-VLP vaccines are hoped to be multivalent for 15 oncogenic HPV types, which comes at a price. Otherwise, costly cytologic screening for cervical cancer is still necessary. The current HPV vaccines thus may not be ultimate strategy and study on new HPV vaccines is needed. Broad-spectrum prophylactic vaccines against all oncogenic HPV types and therapeutic vaccines for clearance of HPV-related cervical lesion are being developed.
    The Indian Journal of Medical Research 09/2009; 130(3):341-7. · 2.06 Impact Factor
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    ABSTRACT: Efficient and continuous expression of a therapeutic transgene is a key factor for improving the efficacy of gene therapy. Some insulators are known to contribute to continuous high-level expression of a therapeutic transgene. Using the human AAVS1 insulator (DHS) found in the AAVS1 DNase I hypersensitive site, chicken beta-globin insulator (cHS4) and sea urchin arylsufatase insulator (Ars), we newly constructed three recombinant adeno-associated virus vectors (rAAV) and examined their capability of transducing the mouse quadriceps muscle. DHS increased transgene expression from the human elongation factor 1alpha promoter (EF) by 1000-fold, up to the high level achieved by the human cytomegalovirus immediate early promoter/enhancer (CMV), which comprises an extremely strong promoter for driving a transgene. cHS4 enhanced the expression by 100-fold, whereas Ars did not. The enhanced expression was maintained for at least 24 weeks. Vector copy numbers were similar with and without DHS or cHS4; thus, the enhancement is most likely due to up-regulated transcription. Neither DHS, nor cHS4 affected transgene expression from CMV. DHS enhanced expression from the human muscle creatine kinase promoter/enhancer by 100-fold in mice, as did DHS from EF. Although DHS was unable to further enhance high expression from the strong viral enhancer/promoter, it enhanced low expression from the human promoters by 100- to 1000-fold. Thus, DHS may be useful for constructing rAAVs that express a therapeutic transgene from less efficient, tissue specific promoters.
    The Journal of Gene Medicine 05/2009; 11(7):598-604. · 2.16 Impact Factor

Publication Stats

1k Citations
290.01 Total Impact Points

Institutions

  • 2013
    • Tokyo Metropolitan Cancer and Infectious Diseases Center
      Edo, Tōkyō, Japan
  • 1996–2013
    • The University of Tokyo
      • • Department of Obstetrics and Gynecology
      • • Department of Reproductive, Developmental and Aging Sciences
      Edo, Tōkyō, Japan
  • 2012
    • Keio University
      • Department of Obstetrics and Gynecology
      Tokyo, Tokyo-to, Japan
  • 2010–2012
    • University of Tsukuba
      • Institute of Clinical Medicine
      Tsukuba, Ibaraki, Japan
  • 2011
    • Tokai University
      • Department of Obstetrics and Gynecology
      Hiratuka, Kanagawa, Japan
  • 2006–2009
    • National Institute of Infectious Diseases, Tokyo
      Edo, Tōkyō, Japan
  • 2004–2007
    • National Cancer Center
      • Endoscopy Division
      Edo, Tōkyō, Japan
    • Musashino Red Cross Hospital
      Edo, Tōkyō, Japan
  • 2005
    • Tokyo Medical University
      • Division of Radiology
      Edo, Tōkyō, Japan