Efficacy and safety of olaparib, olaparib plus bevacizumab and niraparib maintenance treatment in Japanese patients with platinum-sensitive advanced ovarian cancer.

OBJECTIVE: To investigate whether maintenance treatment could be safely and effectively performed with olaparib, olaparib plus bevacizumab and niraparib in platinum-sensitive advanced ovarian cancer at multiple institutions in Japan. METHODS: We investigated progression-free survival and adverse events in 117 patients with platinum-sensitive advanced ovarian cancer treated with maintenance therapy. RESULTS: The median progression-free survival of 117 patients was 20.1 months. Patients with germline BRCA pathogenic variants had a significantly better prognosis than the other groups (P < 0.001). Furthermore, in the multivariate analysis, stage IV (P = 0.016) and germline BRCA wild-type (P ≤ 0.001) were significantly associated with worse progression-free survival in patients with advanced ovarian cancer. Regarding adverse events, all three types of maintenance treatment were significantly worse than chemotherapy given before maintenance treatment with respect to renal function (olaparib, P = 0.037; olaparib plus bevacizumab, P < 0.001; and niraparib, P = 0.016). CONCLUSION: Maintenance treatment was performed effectively and safely. Renal function deterioration is likely to occur during maintenance treatment, and careful administration is important in platinum-sensitive advanced ovarian cancer.

Relationship Between Hematological Toxicities During Maintenance Treatment and During Chemotherapy Before Maintenance Treatment in Patients With Platinum-sensitive Relapsed Ovarian Cancer.

BACKGROUND/AIM: To determine if maintenance treatment can be performed effectively and safely in patients with platinum-sensitive relapsed ovarian cancer. PATIENTS AND METHODS: We carried out a multi-center study to investigate progression-free survival (PFS) and adverse events (AEs) in 229 patients receiving maintenance treatment for platinum-sensitive relapsed ovarian cancer. RESULTS: The median PFS in the 229 patients with maintenance treatment was 14.0 months (95% confidence interval=10.3-17.6 months). The hematological toxicities included ≥grade 3 anemia in 33.2% of cases. Anemia during maintenance treatment was significantly more common than anemia during chemotherapy given before maintenance treatment (p<0.001). Anemia during chemotherapy prior to maintenance treatment significantly increased the risk of anemia during maintenance treatment, compared with other clinical features (p<0.001). CONCLUSION: Maintenance treatment can be performed safely and effectively in patients with platinum-sensitive relapsed ovarian cancer. Anemia during chemotherapy given before maintenance treatment significantly increased the risk of developing anemia during maintenance treatment in patients with platinum-sensitive relapsed ovarian cancer.

Lynch syndrome-associated endometrial carcinoma with MLH1 germline mutation and MLH1 promoter hypermethylation: a case report and literature review.

BACKGROUND: Lynch syndrome is an autosomal dominant inherited disease caused by germline mutations in mismatch repair genes. Analysis for microsatellite instability (MSI) and immunohistochemistry (IHC) of protein expressions of disease-associated genes is used to screen for Lynch syndrome in endometrial cancer patients. When losses of both MLH1 and PMS2 proteins are observed by IHC, MLH1 promoter methylation analysis is conducted to distinguish Lynch syndrome-associated endometrial cancer from sporadic cancer. CASE PRESENTATION: Here we report a woman who developed endometrial cancer at the age of 49 years. She had a family history of colorectal cancer (first-degree relative aged 52 years) and stomach cancer (second-degree relative with the age of onset unknown). No other family history was present, and she failed to meet the Amsterdam II criteria for the diagnosis of Lynch syndrome. Losses of MLH1 and PMS2, but not MSH2 and MSH6, proteins were observed by IHC in endometrial cancer tissues. Because MLH1 promoter hypermethylation was detected in endometrial cancer tissue samples, the epigenetic silencing of MLH1 was suspected as the cause of the protein loss. However, because of the early onset of endometrial cancer and the positive family history, a diagnosis of Lynch syndrome was also suspected. Therefore, we provided her with genetic counseling. After obtaining her consent, MLH1 promoter methylation testing and genetic testing of peripheral blood were performed. MLH1 promoter methylation was not observed in peripheral blood. However, genetic testing revealed a large deletion of exon 5 in MLH1; thus, we diagnosed the presence of Lynch syndrome. CONCLUSIONS: Both MLH1 germline mutation and MLH1 promoter hypermethylation may be observed in endometrial cancer. Therefore, even if MLH1 promoter hypermethylation is detected, a diagnosis of Lynch syndrome cannot be excluded.

Long-term outcomes of postoperative taxane/platinum chemotherapy for early stage cervical cancer: a retrospective study.

BACKGROUND: Taxane/platinum (TP)-based combination chemotherapy is standard for the treatment of metastatic or recurrent cervical cancer. The aim of this study was to investigate the efficacy of postoperative TP therapy in early stage cervical cancer. METHODS: A retrospective review of patients with FIGO IB-IIB stage cervical cancer who were treated with radical hysterectomy and displayed surgical-pathological risk factors was performed. 122 patients were identified between 2003 and 2012. Survival was analyzed by Kaplan-Meier method and compared by the log-rank test. The Cox proportional hazards model was used to investigate predictors of survival. RESULTS: The median follow-up period was 82.4 months. The postoperative adjuvant therapy was TP in 82 (67.2%) patients, other chemotherapies in 10 (8.2%), radiotherapy (RT) in 25 (20.5%), and no further therapy (NFT) in 5 (4.1%). Survival was analyzed using 4 subgroups according to the postoperative adjuvant therapy. The estimated 5-year overall survival was 95.1% in the TP group, 90.0% in the other chemotherapy group, 78.9% in the RT group, and 100% in the NFT group. No significant difference of survival was observed in the subgroups. However, when analyzing only patients who displayed high-risk factors, non-TP adjuvant therapy (including RT and other chemotherapies) was independently associated with shorter survival on multivariate analysis. In the TP group, multivariate analysis revealed that a positive surgical margin was a significant predictor of shorter survival. CONCLUSIONS: Postoperative TP is effective in patients with surgically treated early stage cervical cancer. In these populations, a positive surgical margin could be associated with poor prognosis.

[Safety and Efficacy of Cisplatin Treatment after Carboplatin Hypersensitivity Reactions in Gynecologic Malignancies].

To investigate the safety and efficacy of cisplatin(CDDP)treatment after carboplatin(CBDCA)hypersensitivity reactions (CHSR)in gynecologic malignancies, we retrospectively reviewed the clinical records of 544 patients who underwent paclitaxel and CBDCA therapy(TC therapy). CHSR was observed in 18 patients. Eight patients were administered weekly paclitaxel and CDDP therapy(wTP therapy)continuously, to confirm that there was no CDDP hypersensitivity followingintravenous administration of 10 mgCDDP. At the onset of CHSR, the patients had received a median of 9 TC therapy cycles, and the median number of CBDCA administrations was 14. The frequency of CHSR was significantly higher in patients who received 7 cycles or more of TC therapy and CBDCA administration(p<0.0001). The median number of wTP therapy administrations was 8. Although CDDP hypersensitivity reactions were observed in 2 patients, their symptoms were mild(Grade 2, CTCAE v4.0). Of the 6 patients who received wTP therapy and had evaluable disease sites, 1, 2, 2 and 1 patients showed CR, PR, SD, and PD, respectively. The median progression-free survival in these 6 patients was 9.5 months. For patients with the platinum- sensitive disease who have CHSR, CDDP could improve their prognosis.

[Outcomes of Tertiary Debulking Surgery(TDS)for Re-Recurrent Ovarian Cancer].

The survival of patients with recurrent ovarian cancer who have completed secondary debulking surgery (SDS) has been shown to increase. However, whether tertiary debulking surgery (TDS) aimed at complete surgery is useful in patients with a second recurrence is unclear. Eight patients who had undergone SDS were treated after a second recurrence in our hospital. Their medical records were retrospectively reviewed. Consequently, TDS was performed in 4 of the patients (TDSgr). All 4 patients underwent complete debulking surgery, 2 patients received blood transfusions, and none had serious postoperative complications. The median treatment free interval (TFI) from recurrence surgery to the second recurrence was 16 months (range, 9-23 months), and the median TFI after the second recurrence was 30.5 months (range, 15-69 months). Meanwhile, the median TFI after the second recurrence was 7.5 months (range, 1-31 months) in the 4 patients who did not undergo TDS (non-TDSgr). The median survival times after the second recurrence in TDSgr and non-TDSgr were 53 months (range, 41-69 months) and 12 months (range, 2-30 months), respectively. When complete surgery is indicated in patients with a second recurrent ovarian cancer after SDS, in case of good physical condition with single or multiple recurrent lesions, TDS may increase survival and TFI.

Type C2 radical hysterectomy may improve outcomes of locally advanced mucinous adenocarcinoma of the uterine cervix.

BACKGROUND: It is not known whether radiotherapy or surgery is better as initial treatment for locally advanced mucinous adenocarcinoma of the uterine cervix. METHODS: We reviewed the medical records and pathological materials of 32 patients with International Federation of Gynecology and Obstetrics stage IB2-IIB mucinous adenocarcinoma, who had undergone radiotherapy or radical hysterectomy as primary treatment between 2001 and 2010. p16(INK4a) immunohistochemistry was performed as a marker for human papillomavirus-related adenocarcinoma. RESULTS: Thirteen patients received radiotherapy and 19 patients underwent radical hysterectomy. The cumulative 3-year locoregional control rates in the radical hysterectomy and radiotherapy groups were 79.0 and 46.2 % (P = 0.03), and 5-year overall survival rates were 70.7 and 38.5 % (P = 0.09), respectively. Of patients with p16(INK4a)-positive tumors (n = 19), the cumulative 3-year locoregional control rates in the radical hysterectomy and radiotherapy groups were 100 and 60.0 % (P = 0.01), and 5-year overall survival rates were 88.9 and 40.0 % (P = 0.04), respectively. Conversely, the cumulative 3-year locoregional control rates in the human papillomavirus-negative radical hysterectomy group and radiotherapy group were 20.0 and 37.5 % (P = 0.66), and 5-year overall survival rates were 20.0 and 37.5 % (P = 0.60), respectively. CONCLUSIONS: Radical hysterectomy may significantly improve locoregional control and overall survival compared with radiotherapy for stage IB2-IIB mucinous adenocarcinoma patients, especially those with p16(INK4a)-positive mucinous adenocarcinoma.

A case of uterine corpus large cell neuroendocrine carcinoma showing prominent myometrial invasion without any macroscopically clear tumor formation.

Large cell neuroendocrine carcinoma (LCNEC) arising in the uterine corpus is a very rare. Here, we report our experience with a primary LCNEC in the uterine corpus that showed prominent myometrial invasion without exhibiting any macroscopically distinct tumor formation in the uterine cavity. The patient was a 54-year-old woman. She had a past medical history of right breast cancer and was referred to our department with irregular genital bleeding, elevated serum carcinoembryonic antigen in periodic medical examinations and computed tomography (CT) findings of uterine cavity dilation. Endometrial biopsy suggested a poorly differentiated tumor. Although magnetic resonance imaging (MRI) showed hematometra-like findings in the uterine cavity, it did not indicate any clear endometrial lesion. The myometrium was unequally thickened, and the entire muscle layer showed a high signal intensity on diffusion-weighted images. Fluorine-18-deoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) showed strong FDG accumulation in the whole uterus, and on the bottom of the uterus, there was a ring-shaped accumulation mainly in the muscle layer. The postoperative resected specimen did not show any tumor formation in the uterine cavity, whereas the myometrium was hard and thickened, and colored white overall. Histopathological examination revealed prominent myometrial invasion in most layers, cervical stromal invasion and pelvic lymph node metastasis. The diagnosis was a LCNEC of the uterine corpus, at FIGO stage IIIC1 and pT2N1M0. With these patients, we found that functional metabolic images, such as MRI diffusion-weighted images and FDG-PET/CT, were useful in identifying the lesion. Preoperatively, when a poorly differentiated tumor is estimated and characteristic myometrial invasion is suspected, the possibility of LCNEC should be considered.

A case of ependymoma arising from the peritoneum.

Ependymoma arising from the peritoneum is extremely rare. We present the case of a 23-year-old woman who underwent urgent laparoscopic surgery because of a pelvic mass and intraperitoneal bleeding. Although peritoneal carcinoma was suspected, pathological re-examination revealed ependymoma with a perivascular pseudorosette and positive for glial fibrillary acidic protein. Residual tumor extraction indicated that the ependymoma had developed from the peritoneum. This case highlights the need to consider ependymoma as a potential diagnosis in young women with suspected ovarian or peritoneal cancer.

The usefulness of 18F-FDG-PET/CT in discriminating benign from malignant ovarian teratomas.

BACKGROUND: The present study investigates the usefulness of 18F-FDG-PET/CT (PET/CT) in distinguishing between benign and malignant ovarian teratomas. METHODS: This study includes 4 mature teratomas (MTs) with malignant transformation, 8 immature teratomas (ITs), and 16 MTs that were diagnosed after surgical resection. Preoperative tumor marker values, MRI findings, PET/CT SUVmax values, and other clinical parameters were retrospectively compared with those of 14 patients who had MTs. RESULTS: The median CA125 was significantly higher for ITs than for MTs (P = 0.04). The median AFP was significantly higher for ITs than for MTs (P = 0.0034). The median SUVmax values for MTs with malignant transformation, ITs, and MTs were 18.3 (5.3-23.3), 6.0 (3.6-22.6), and 1.1 (1.0-15.5), respectively. SUVmax was significantly higher in MTs with malignant transformation and ITs than in MTs (P = 0.004, P = 0.0007). With a cut-off SUVmax of 3.6 to distinguish between benign and malignant MTs, sensitivity was 100 %, specificity was 81 %, positive predictive value was 80 %, negative predictive value was 100 %, and diagnostic accuracy was 89 % (AUC 0.94). However, one patient with an MT had a high SUVmax corresponding to values in the central nervous system (CNS). CONCLUSIONS: 18F-FDG-PET/CT has a high diagnostic accuracy in distinguishing between benign and malignant ovarian teratomas. Thus, PET/CT may be useful in cases where the diagnosis is unclear on MRI and other clinical findings. However, some MTs with abundant CNS tissue may have a high SUVmax. Therefore, the diagnosis of a benign or malignant lesion should be made carefully in conjunction with other clinical findings.

[A case of platinum-resistant, recurrent ovarian clear cell adenocarcinoma successfully treated with irinotecan (CPT-11) and paclitaxel (PTX) chemotherapy].

A 40-year-old woman presented to a local clinic with abdominal distension. She was referred to our hospital for suspected ovarian cancer. Computed tomography (CT) and magnetic resonance imaging (MRI) revealed an ovarian tumor with mural nodules, ascites, pleural effusion, and peritoneal dissemination. Laparotomy revealed a 20-cm right ovarian tumor with strong adhesion to the uterus and rectum. Bilateral salpingo-oophorectomy was performed as a primary surgery. The histopathological diagnosis was stage IVovarian clear cell adenocarcinoma, and 6 cycles of postoperative chemotherapy with a combination of TC (paclitaxel [PTX] and carboplatin) and the mTOR inhibitor temsirolimus was administered. During maintenance treatment with temsirolimus, the lesion recurred, and progressive disease was confirmed. Because relapse occurred after 5 months from the last TC treatment, the disease was considered platinum-resistant ovarian cancer, and second-line chemotherapy with 6 cycles of irinotecan (CPT-11 ) and PTX was administered. Partial response was observed after 2 cycles, and the response period was 7 months. We suggest that chemotherapy with CPT-11/PTX could be a treatment option for platinum resistant recurrent ovarian clear cell adenocarcinoma.

Monitoring the impact of a national HPV vaccination program in Japan (MINT Study): rationale, design and methods.

We have developed a collaborative hospital-based approach to monitoring the impact of a human papillomavirus vaccine on cervical cancer, its precursor lesions and human papillomavirus type-specific prevalence in Japan. The monitoring will be conducted for a total period of 21 years on women aged <40 who are newly diagnosed with invasive cervical cancer, cervical intraepithelial neoplasia or adenocarcinoma in situ at 21 participating institutes. Women are monitored to determine their vaccine history and will be human papillomavirus-genotyped each year. The primary endpoint is the human papillomavirus16/human papillomavirus18-positive rate in women aged 16-25 who are diagnosed with invasive cervical cancer, cervical intraepithelial neoplasia grade 2/3 and adenocarcinoma in situ. The major secondary endpoints are the number of women aged <40 who are diagnosed with invasive cervical cancer, cervical intraepithelial neoplasia grade 2/3 and adenocarcinoma in situ, the human papillomavirus type-specific prevalence, and the number of deaths from invasive cervical cancer in women aged <40. Long-term surveillance for human papillomavirus-associated cervical diseases in young females is important for the development of future strategies for cervical cancer prevention in Japan.

Maximum standardized uptake value of fluorodeoxyglucose positron emission tomography/computed tomography is a prognostic factor in ovarian clear cell adenocarcinoma.

BACKGROUND: Fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) is useful for diagnosing malignant tumors. Intracellular FDG uptake is measured as the standardized uptake value (SUV), which differs depending on tumor characteristics. This study investigated differences in maximum SUV (SUVmax) according to histologic type in ovarian epithelial cancer and the relationship of SUVmax with prognosis. METHODS: This study included 80 patients with ovarian epithelial cancer based on histopathologic findings at surgery and who had undergone PET/CT before treatment. Maximum SUV on PET/CT of primary lesions and histopathology were compared based on histologic type, and the prognosis associated with different SUVmax was evaluated. RESULTS: Clinical tumor stage was I in 35 patients, II in 8, III in 25, and IV in 12. Histologic type was serous adenocarcinoma (AC) in 33 patients, clear cell AC in 27, endometrioid AC in 15, and mucinous AC in 5. Median SUVmax was lower in mucinous AC (2.76) and clear cell AC (4.9) than in serous AC (11.4) or endometrioid AC (11.4). Overall, median SUVmax was lower in clinical stage I (5.37) than in clinical stage ≥II (10.3). However, in both clear cell AC and endometrioid AC, when histologic evaluation was possible, no difference was seen between stage I and stage ≥II. Moreover, in clear cell AC, the 5-year survival rate was significantly higher in the low-SUVmax group (100%) than in the high-SUVmax group (43.0%, P = 0.009). CONCLUSIONS: Maximum SUV on preoperative FDG-PET/CT in ovarian epithelial cancer differs according to histologic type. In clear cell AC, SUVmax may represent a prognostic factor.

[Genetic counseling and practice of hereditary cancers at Shikoku Cancer Center].

Although the progress in understanding human genetics regarding cancer has been applied to the medical practice of treating hereditary cancers in developed western countries, it is not widely implemented in Japan. We started treating hereditary cancers at NHO Shikoku Cancer Center in November 2000. Our institution has a multidisciplinary team that provides medical care and genetic counseling for patients with hereditary cancers, and their relatives. The team consists of doctors from several related departments, and paramedics including a genetic counselor who participated as of 2009. Medical care of patients with hereditary cancers should not be separated from general oncological practice, but incorporate all medical professionals, including doctors of related departments and paramedic. We have attempted to identify patients with hereditary cancer and their family members and relatives at high risk; we followed them up and provided risk-reducing therapies for them at our cancer center. Here we present the framework of our practice in treating hereditary cancers. We discuss appropriate goals and future perspectives in the field of hereditary cancer in Japan.

Long-term survival in patients with para-aortic lymph node metastasis with systematic retroperitoneal lymphadenectomy followed by adjuvant chemotherapy in endometrial carcinoma.

OBJECTIVE: The purposes of this study were to assess modified radical hysterectomy including systematic pelvic and para-aortic lymphadenectomy followed by adjuvant chemotherapy in patients with para-aortic lymph node (PAN) metastasis in endometrial carcinoma and to identify the multivariate independent prognostic factors for long-term survival during the past 10 years. METHODS: Between December 1987 and December 2002, we performed modified radical hysterectomy with bilateral salpingo-oophorectomy including systematic pelvic and para-aortic lymphadenectomy and peritoneal cytology in 284 endometrial carcinoma patients according to the classification of the International Federation of Gynecology and Obstetrics (stage IA, n = 66; stage IB, n = 96; stage IC, n = 33; stage IIA, n = 5; stage IIB, n = 20; stage IIIA, n = 28; stage IIIC, n = 28; and stage IV, n = 8) who gave informed consents at our institute. Patients with tumor confined to the uterus (stages IC and II) were treated by 3 courses of cyclophosphamide 750 mg/m2, epirubicin 50 mg/m2, and cisplatin 75 mg/m2 regimen 3 to 4 weeks apart, and patients with extrauterine lesions involving adnexa and/or pelvic lymph node (PLN) were treated by 5 courses. In addition, 10 courses were given to patients with PAN metastasis. Patients with PLN metastasis received adjuvant chemotherapy, and adjuvant radiation was not part of our institutional protocol. For multivariate regression modeling with proportional hazards, the regression model of Cox was used. Survival curves were analyzed by the Kaplan-Meier method, and analysis of the differences was performed by the log-rank test. RESULTS: The overall incidence of retroperitoneal lymph node metastasis assessed by systematic pelvic and para-aortic lymphadenectomy was 12.0% (34/284) in stages I to IV endometrial carcinoma, and incidences of PLN and PAN metastases were 9.2% (26/284) and 7.4% (21/284), respectively. However, PAN metastasis rate is 50% (13/26) in patients with PLN metastasis. Univariate analysis of prognostic factors revealed that International Federation of Gynecology and Obstetrics clinical stage (P < 0.0001), histological finding (P = 0.0292), myometrial invasion (P < 0.0001), adnexal metastasis (P < 0.0001), lymphovascular space invasion (P < 0.0001), tumor diameter (P = 0.0108), peritoneal cytology (P = 0.0001), and retroperitoneal lymph node metastasis (P < 0.0001) were significantly associated with 10-year overall survival. Survival was not associated with age (P = 0.1558) or cervical involvement (P = 0.1828). A multivariate analysis showed that adnexal metastasis (P = 0.0418) and lymphovascular space invasion (P = 0.0214) were significantly associated with 10-year overall survival. The 5- and 10-year overall survival rates in patients with negative PAN were 96% and 93% versus 72% and 62% in patients with positive PAN (P = 0.006). CONCLUSIONS: It is suggested that surgery with systematic pelvic and para-aortic lymphadenectomy followed by adjuvant chemotherapy could improve long-term survival in patients with PAN metastasis, although there are only 21 patients with PAN metastasis.

Distribution of platinum in the female genital tract and efficacy of radiotherapy combined with transcatheter arterial infusion of cisplatin for locally advanced stage IIIb carcinoma of the uterine cervix.

The current main treatment for locally advanced stage III/IV cervical cancer involves chemoradiotherapy. In this study, we investigated the distribution of platinum in the female genital tract by intra-arterial infusion of platinum (carboplatin 150 mg) during surgery and examined the therapeutic effects of radiotherapy with transcatheter arterial infusion (TAI) of cisplatin for locally advanced carcinoma of the uterine cervix. From January 1991, we randomly selected 26 patients with locally advanced stage IIIb cervical cancer to receive radiotherapy combined with TAI of 120 mg/body cisplatin twice a month at an interval of 4 weeks. Radiotherapy routinely involved 50 Gy of external beam irradiation to the whole pelvis and 12-24 Gy (point A dose) of intracavitary irradiation using a remote afterloading system. The mean platinum concentration in the cervical cancer was 1.77 microg/g wet tissue (wt) and high value, but the genital tract also contained the same platinum concentration. The platinum concentration in each regional lymph node was 1.10-1.48 microg/g wt, and its level of platinum was equal to that in the female genital tract. The effective histologic response rate was 88.5% (23/26). The median follow-up period was 38 months. The cumulative survival rate was 74.0%. Serious acute adverse reactions interfering with treatment were not observed. Based on these results, intra-arterial infusion of platinum produced a therapeutic effect on the primary cervical cancer site and the other parts of the female genital tract. We concluded that radiotherapy with TAI of cisplatin achieved superior therapeutic efficacy in locally advanced stage IIIb cervical cancer.

Preclinical analysis of the antitumor efficacy of TS-1 using human uterine cervical cancer tumor xenografts.

We investigated the antitumor activity of TS-1 in comparison with that of UFT and cisplatin (CDDP) against cervical cancer using xenografts of a human uterine cervical squamous cell cancer cell line, CaSki, transplanted into female Balb/cA JcL-nu mice. CaSki cell xenografts were prepared by subcutaneous (s.c.) implantation of 3x10(6) cells/animal into the right dorsal region of the mice. The tumor volume was measured twice a week and the relative tumor volume (RTV) was calculated. We divided the animals into four groups according to the treatment administered; TS-1 (10 mg/kg orally, once daily for 14 consecutive days), UFT (24 mg/kg orally, once daily for 14 consecutive days), CDDP (7.6 mg/kg injected intravenously once on the 1st day) and control (no treatment) groups. The antitumor effects of the drugs were measured. On the 35th day after the completion of treatment, the mean tumor volume in the mice treated with TS-1 or CDDP changed from 132.873+/-11.783 mm(3) to 706.401+/-613.122 mm(3) and 133.809+/-19.366 mm(3) to 722.630+/-855.509 mm(3), respectively. The mean tumor volume in the groups treated with TS-1 or CDDP was significantly lower compared to that in the control group (p<0.001; one-tailed Student's t-test). The relative inhibition of the tumor growth was 65.31 in the TS-1 group, 48.31 in the UFT group and 64.51 in the CDDP group. We conclude that TS-1 administered orally for 14 consecutive days showed the highest antitumor activity.

Human papillomavirus DNA status after loop excision for cervical intraepithelial neoplasia grade III - A prospective study.

The aims of the study were to investigate the relationship between human papillomavirus (HPV) DNA status and recurrence of cervical intraepithelial neoplasia (CIN) after loop excision (LEEP/LLETZ). Women (n=161) who underwent loop excision for CIN III and who were followed up prospectively for at least 4 years were the study cohort. Cervical smear cytology and testing for HPV DNA was performed at 3, 6 and 12 months prospectively and thereafter at intervals of 6-12 months, using the PCR method with a consensus primer targeting the L1 region. There has been no recurrence in 141 (81.6%) out of 161 subjects, while squamous intra-epithelial lesions (SIL) of low or high grade on cytology and CIN grade I-III on histology have been detected in 20 subjects. Prior to loop excision, HPV DNA was detected in 17 subjects who developed recurrence (9 had type 16, 2 each had types 18 and 52, and 1 each had types 31, 51, 58, and unknown). Within 3 months postoperatively, 12 (70.7%) subjects became negative for HPV, but 2 remained positive for the same type (1 each had types 16, 18), along with high-grade SIL on cytology, and CIN III on histology within 6 months, so repeat loop excision was performed. On the other hand, cytological findings were normalized in all transiently infected subjects within 18-36 months. Our results suggest that loop excision has improved HPV infection in many cases of CIN III and the persistent infection with a high-risk type of HPV is a predictor of the recurrence of CIN grade III.

Overexpression of cyclooxygenase-2 protein and its relationship to apoptosis in cervical carcinoma treated with neoadjuvant chemotherapy.

The aims of this study were to examine the overexpression of COX-2 protein and its relationship to apoptosis in cervical carcinoma patients treated with neoadjuvant chemo-therapy (NAC), and to assess the potential role of COX-2 as a predictor of the response to NAC in a series of patients with cervical carcinoma. For immunohistochemical analysis, cervical cancer tissue samples were collected before NAC and 3 weeks after NAC using transcatheter arterial infusion of cisplatin from 40 patients who underwent surgery for advanced cervical carcinoma in stages IB, IIA and IIB and from 5 normal cervical tissues between 1991 and 2000 at the Department of Obstetrics and Gynecology, under informed consent. Patients were randomly assigned to receive one or two arterial infusions of cisplatin. COX-2 protein expression was detected by immunohistochemical staining and was classified as no expression for tumors with negative or <10%, while > or =10% positive staining was defined as overexpression. Detection of apoptosis was done by the TUNEL method. The percentage of cells with DNA fragmentation (apoptotic index, AI) was calculated before NAC and 3 weeks after NAC. The AI ratio (AI after NAC/AI before NAC) was also calculated. COX-2 expression was not detected in the normal cervix. Overexpression of COX-2 protein was detected in 18 out of 40 (45.0%) cervical cancers. A higher incidence of COX-2 protein overexpression was observed in patients with adenocarcinoma than in those with squamous cell carcinoma (p=0.1797, Fisher's exact text). The average AI value before and after NAC was 8.85 versus 11.82 respectively. In COX-2 protein-negative patients with squamous cell carcinoma, the AI ratio was 0.96+/-0.46 following one arterial infusion of cisplatin and 3.19+/-2.72 following two infusions of cisplatin. There was a significant positive correlation between apoptosis and the number of infusions of cisplatin (p=0.0098, Mann-Whitney, U-test). Our findings suggest that COX-2 protein expression could be used as a predictor of chemoresistance and that assessment of the COX-2 status could be useful to identify cervical cancer patients who may benefit from NAC.

Expression of cyclooxygenase-2 and its relationship to p53 accumulation in ovarian adenocarcinomas.

To investigate cyclooxygenase-2 (COX-2) expression and its relationship to p53 accumulation in ovarian adenocarcinomas, COX-2 and p53 protein expressions were examined by immunohistochemistry in 86 ovarian adenocarcinomas and six normal ovaries. In addition, COX-2 mRNA expression level was examined by semi-quantitative PCR in 36 ovarian adenocarcinomas. Neither COX-2 expression nor p53 accumulation were detected in normal ovarian surface epithelium or germinal inclusion cyst epithelial cells. In contrast, COX-2 protein expression was detected in 31.4% of adenocarcinomas, and p53 protein accumulation was found in 30.2% of adenocarcinomas. A significantly higher COX-2 expression rate was observed in endometrioid adenocarcinomas than in either mucinous (p=0.019) or clear cell (p=0.021) adenocarcinomas, and a significantly higher p53 accumulation rate was observed in serous adenocarcinomas compared to clear cell adenocarcinomas (p=0.015). p53 accumulation correlated with advanced clinical stage (stage I vs. stage II/III/IV: p=0.007), whereas no correlation was found between COX-2 expression and clinical stage. There was a significant positive correlation between COX-2 expression and p53 accumulation status (p=0.003). Log-rank testing showed that p53 accumulation was significantly correlated with poor patient survival (p=0.004), whereas no correlation was found between COX-2 expression and survival. COX-2 mRNA expression was detected in 72.2% of ovarian adenocarcinomas, and a significant correlation between COX-2 mRNA expression status and immunoreactivity (p=0.023) was observed. These results suggest that COX-2 expression might play an important role in ovarian cancer development and that COX-2 expression in ovarian adenocarcinomas is frequently associated with p53 protein accumulation. COX-2 overexpression in ovarian cancer cells might partly be caused by dysfunctional p53.