Efficacy and toxicity of pegylated liposomal doxorubicin as therapy for recurrent ovarian cancer in relation to the number of previous chemotherapy regimens: Comparison with gemcitabine.

AIM: Pegylated liposomal doxorubicin (PLD) is one of the second-line chemotherapy regimens for platinum-resistant recurrent ovarian cancer, but in clinical practice, it is also used for third or subsequent lines of chemotherapy. There is no report on the efficacy and toxicity of PLD in relation to the number of previous chemotherapy regimens. The purpose of this study was to clarify these points and compare with the results of gemcitabine (GEM) therapy we reported previously. METHODS: We retrospectively reviewed the medical records of patients with platinum-resistant recurrent ovarian cancer who underwent two or more cycles of PLD therapy between July 2009 and March 2017 at our institution. We used our reported data of GEM for comparison analysis. RESULTS: Seventy-eight patients were enrolled in this study. The overall response rate was 19.2% and the disease control rate (DCR) was 53.8%. The DCR with 1, 2, 3, and 4 or more previous regimens was 53.8%, 48.6%, 63.6% and 66.7%, respectively. Grade 3/4 neutropenia and anemia developed in 59.0% and 12.8%, respectively. Grade 2 or higher hand -foot syndrome, stomatitis, and liver dysfunction developed in 25.6%, 25.6% and 2.6%, respectively. When the number of previous regimens was 3 or higher, the DCR of PLD was significantly higher than that of GEM (64.7% vs 30.8%, P = 0.037). CONCLUSION: The DCR did not decrease with a greater number of previous regimens. When the number of previous regimens was 3 or higher, PLD therapy had a superior DCR to GEM therapy. Toxicity was tolerable in PLD therapy.

New criteria for the omission of lymphadenectomy in endometrioid carcinoma.

OBJECTIVE: To establish new criteria for the omission of lymphadenectomy in patients with endometrioid carcinoma. METHODS: We retrospectively reviewed 185 cases of histologically confirmed endometrioid carcinoma by hysterectomy at Jichi Medical University Hospital between January 2006 and December 2011. We reviewed patient medical records to detect risk factors for lymph node metastasis to identify the optimum criteria for lymphadenectomy omission. RESULTS: Univariate analysis revealed risk factors for lymph node metastasis to be a large tumor size (volume index ≥40 cm³) (p<0.0001), tumor diameter >2 cm (p=0.0003), myometrial invasion ≥50% based on pre-operative MRI (p=0.0366), elevated serum CA125 (pre-menopausal value ≥70 U/mL, post-menopausal value ≥25 U/mL) (p=0.0004), and lymphadenopathy on pre-operative CT scans (p=0.0002). Multivariate analysis indicated that tumor volume index, tumor diameter, elevated serum CA125, and CT scans positive for lymphadenopathy were independent risk factors for lymph node metastasis. Thus, we set tumor diameter >2 cm, elevated serum CA125, and CT scans positive for lymphadenopathy as risk factors. In cases with no risk factors, the rate of lymph node metastasis was 2.1%, which rose to 8.9%, 30.4%, and 58.3% for those with one, two, and three risk factors, respectively. The rate of para-aortic lymph node metastasis rose from 0% to 2.5%, 10.9%, and 41.7% among those with zero, one, two, and three risk factors, respectively. CONCLUSIONS: We propose that lymphadenectomy can be omitted in cases of endometrioid carcinoma that do not have any of the following risk factors: tumor diameter >2 cm, elevated serum CA125, and a CT scan positive for lymphadenopathy. We believe that these new criteria will limit inter-institutional differences as they are all objective factors. Further, they are useful in predicting lymph node metastasis, including para-aortic lymph node metastasis, based on the number of risk factors present.

Impact of the number of removed lymph nodes on recurrence-free survival in stage I ovarian clear cell carcinoma.

BACKGROUND: Although there have been several reports regarding the significance of staging lymphadenectomy for early stage ovarian clear cell carcinoma (CCC) patients, there have been few reports focusing on the number of removed lymph nodes. The aim of this study was to evaluate the impact of the number of removed lymph nodes on recurrence-free survival (RFS) in stage I ovarian CCC. METHODS: The subjects were patients with ovarian CCC who underwent surgery between January 1988 and December 2013. Clinicopathological variables were obtained from the medical records retrospectively. Statistical analysis using Kaplan-Meier method, log-rank test, and Cox proportional hazards model was performed. RESULTS: A total of 68 patients were entered into this study. The median number of removed lymph nodes was 56.5 (21-135). We calculated that the cutoff value of the number of removed lymph nodes for predicting recurrence was 35. RFS of the group with ≥ 35 removed lymph nodes was significantly better than that of the group with < 35 removed lymph nodes (p = 0.001). Similarly, RFS of stage IA and PS 0 or 1 was significantly better than that of stage IC (p = 0.029) and PS 2 or 3 (p = 0.001), respectively. Multivariate analysis revealed that the number of removed lymph nodes, stage, and PS was independent predictors for RFS. CONCLUSIONS: This study showed that the number of removed lymph nodes ≥ 35 was an independent predictor for improved RFS for stage I ovarian CCC. Sufficient lymphadenectomy may improve prognosis for stage I ovarian CCC.

Response to and toxicity of gemcitabine for recurrent ovarian cancer according to number of previous chemotherapy regimens.

AIM: Gemcitabine is used not only as a second-line, but also as a third-line or higher regimen for taxane/platinum-resistant recurrent ovarian cancer. The purpose of this study was to clarify the response to and toxicity of gemcitabine for recurrent ovarian cancer according to the number of previous chemotherapy regimens. METHODS: The subjects were patients with taxane/platinum-resistant recurrent ovarian cancer on gemcitabine treatment at the present hospital between June 2007 and September 2013. We retrospectively reviewed the medical records. Response and adverse events were assessed using the Response Evaluation Criteria in Solid Tumors version 1.1. and the Common Terminology Criteria for Adverse Events v4.0, respectively. RESULTS: The subjects consisted of 65 patients. The median number of previous chemotherapy regimens was 3 (range, 1-7). Overall response rate was 4.6%, and disease control rate (DCR) was 40.0%. DCR versus one, two, three, and ≥four previous chemotherapy regimens was 83.3%, 45.0%, 36.4%, and 23.5%, respectively. Grade 3/4 neutropenia, anemia, and thrombocytopenia occurred in 52.3%, 9.2%, and 9.2% of patients, respectively. Prevalence of grade 3/4 neutropenia according to one, two, three, and ≥four previous chemotherapy regimens was 66.7%, 55.0%, 54.5%, and 41.2%, respectively. Prevalence of anemia, thrombocytopenia, and almost all the non-hematological toxicities also did not increase with an increase in the number of previous chemotherapy regimens. CONCLUSIONS: Although DCR decreased as the number of previous chemotherapy regimens increased, the toxicities did not increase. Gemcitabine may be relatively safe in heavily pretreated ovarian cancer patients.

Vasohibin-1 expression inhibits advancement of ovarian cancer producing various angiogenic factors.

Vasohibin-1 (VASH1) is a negative feedback regulator of angiogenesis, the first to be discovered, and was identified in vascular endothelial growth factor (VEGF)-stimulated vascular endothelial cells. Vasohibin-1 inhibits abnormal vascularization induced by various angiogenic factors including fibroblast growth factor and platelet-derived growth factor (PDGF), in addition to VEGF. By focusing on this characteristic of VASH1, we investigated the antitumor effects of VASH1 expression on ovarian cancer cells that produce different angiogenic factors. By using a high VEGF-producing ovarian cancer cell line, SHIN-3, and a high PDGF-producing ovarian cancer cell line, KOC-2S, the cells were transfected with either a VEGF antagonist, soluble VEGF receptor-1 (sVEGFR-1, or sFlt-1), or VASH1 genes to establish their respective cellular expression. The characteristics of these transfectants were compared with controls. We previously reported that the expression of sFlt-1 inhibited tumor vascularization and growth of high VEGF-producing ovarian cancer cells, reduced peritoneal dissemination and ascites development, and prolonged the survival time of the host. However, in the current study, the expression of sFlt-1 had no such effect on the high PDGF-producing ovarian cancer cells used here, whereas VASH1 expression inhibited tumor vascularization and growth, not only in high VEGF-producing cells, but also in high PDGF-producing cells, reduced their peritoneal dissemination and ascites, and prolonged the survival time of the host. These results suggest that VASH1 is an effective treatment for ovarian cancer cells that produce different angiogenic factors.

Ovarian nongestational choriocarcinoma and associated adenocarcinoma with the same germ cell origin determined by a molecular genetic approach: A case report.

Ovarian non-gestational choriocarcinomas co-existing with adenocarcinoma are extremely rare and have been reported as epithelial ovarian carcinomas of a "non-germ cell origin" with "choriocarcinomatous differentiation". Although the cellular origin of non-gestational choriocarcinoma may be post-meiotic ovarian germ cells or the dedifferentiation of epithelial ovarian carcinoma, detailed genetic evidence has not yet been obtained to support this. We herein present a case of ovarian non-gestational choriocarcinoma co-existing with adenocarcinoma in a 29-year-old woman. The tumor rapidly increased in size and lung metastases appeared soon after parturition. We genetically demonstrated that the cellular origin of ovarian non-gestational choriocarcinoma was a post-meiotic germ cell derivation using a short tandem repeat analysis. The co-existing adenocarcinoma component was also shown to be of the same germ cell origin. These tumors showed the same homozygous pattern. A molecular genetic approach may be important for understanding the clinicopathological features of such tumors.

Immature ovarian teratoma with hyponatremia and low serum vasopressin level.

Hyponatremia is often caused by the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Hypersecretion of vasopressin from malignant tumors can be considered a cause of SIADH. Most of these ectopic productions of vasopressin are complications of small cell lung cancer. Cases concomitant with ovarian tumors are very rare, and a specific causative substance from the ovary is often unknown. A 16-year-old woman was diagnosed with an ovarian tumor. She developed hyponatremia that was resistant to medical treatment, but immediately improved after surgical resection of the tumor. Her diagnosis was SIADH caused by an ovarian tumor; however, her serum vasopressin level was normal. It is possible that a vasopressin-like substance causing SIADH was secreted by either nervous system tissue within an immature teratoma or small cell lung cancer. We should be cautious when SIADH is a complication of an ovarian tumor.

Prognosis of endometrial cancer patients with and without symptoms at recurrence.

AIM: During routine follow-up for postoperative endometrial cancer, we have encountered patients with and without symptoms at recurrence. In this study, we investigated whether or not there is a difference in the prognosis between patients with and without symptoms at recurrence. METHODS: We reviewed endometrial cancer patients who had been treated in our hospital between 1998 and 2007. Routine follow-up was conducted by our facility criteria. We investigated recurrence-free survival (RFS), presence or absence of symptoms at recurrence, overall survival from recurrence (OSFR), and overall survival (OS). RESULTS: The subjects were 293 patients. Recurrence was detected in 46 patients. The median RFS was 15 (1-103) months. At the time of recurrence, symptoms were present in 14 patients and absent in 32 patients. In groups with and without symptoms at recurrence, the median OSFR were 36 (2-100) and 45 (2-139) months, respectively. The median OS were 55 (6-163) and 100 (11-178) months, respectively. There were no significant differences in either parameter. Independent prognostic factors for OSFR and OS were histopathologic types other than endometrioid carcinoma (vs endometrioid carcinoma, hazard ratio = 3.102 and 3.008, respectively) and RFS of 14 months or shorter (vs 15 months or longer, hazard ratio = 2.378 and 3.739, respectively). CONCLUSION: There was no difference in the prognosis between the groups with and without symptoms at recurrence. Independent prognostic factors of recurrent patients were histopathologic types and RFS. A large-scale study should be conducted to examine the necessity of routine follow-up for detecting recurrence in the absence of symptoms.

Radiation therapy for chemotherapy-resistant recurrent epithelial ovarian cancer.

OBJECTIVES: While radiation therapy is administered as a palliative treatment for recurrent ovarian cancer, it remains unclear whether it improves the prognosis. METHODS: The effects and adverse events of radiation therapy for patients with recurrent epithelial ovarian cancer were investigated using medical records. RESULTS: Herein, 46 subjects comprising 33 patients whose recurrent lesions were contained within the irradiation field (therapeutic radiation group; TRG) and 13 patients with some recurrent lesions outside the irradiation field (palliative radiation group; PRG) were included. The TRG achieved a response rate (RR) of 66%, a disease control rate (DCR) of 100%, a progression-free survival (PFS) of 10 months, and an overall survival (OS) of 20 months. The PFS after radiation therapy was significantly longer than that following chemotherapy received just before radiation therapy. The PFS of patients with recurrent intrapelvic lesions was longer than that of patients with some extrapelvic recurrence. There was no significant association between PFS after radiation therapy and the duration from the previous chemotherapy or histological type. The RR, DCR, PFS, and OS of the PRG were 30 and 90% and 2 and 6 months, respectively. Serious adverse events were rare. CONCLUSIONS: Radiation therapy is a potential option for chemotherapy-resistant, localized recurrent ovarian cancer. © 2014 S. Karger AG, Basel.

Influences of uterine adenomyosis on muscle invasion and prognosis of endometrioid adenocarcinoma.

OBJECTIVE: Endometrial cancer often coexists with uterine adenomyosis. However, little is known about the clinical characteristics of these cases. Thus, cases of endometrial cancer occurring with and without uterine adenomyosis were compared, and the influences of uterine adenomyosis on the clinical progress of endometrial cancer were examined. MATERIALS AND METHODS: Of endometrial cancer patients who underwent hysterectomies in our facility from 2002 to 2011, we included only endometrioid adenocarcinoma patients in our study. The patients were divided into 2 groups, adenomyosis group and nonadenomyosis group, according to the presence/absence of uterine adenomyosis. Patient characteristics, stage, histopathological grade, muscle invasion, recurrence, and mortality were retrospectively compared and examined. RESULTS: There were 362 cases of endometrioid adenocarcinoma of the uterine body, of which 121 (33.4%) and 241 cases (66.6%) were in the adenomyosis and nonadenomyosis group, respectively. There were no significant differences with respect to the disease stages or ratios of the histopathological grade between the 2 groups. In the adenomyosis group/nonadenomyosis group, 5-year progression-free survival for International Federation of Gynecology and Obstetrics (FIGO) stages I and II was 89.9%/93.7% and that for stages III and IV was 70.6%/62.0%; the 5-year overall survival was 100%/95.9% for FIGO stages I and II, and 88.0%/73.5% for stages III and IV. There were no significant between-group differences for either progression-free survival or overall survival. When limiting the results to only FIGO stage I endometrioid adenocarcinoma, despite no grade variance between the 2 groups, a significant difference was observed in the ratios of outer-half muscle invasion between the adenomyosis and nonadenomyosis groups (19.5% [17/87] vs 10.1% [16/158], P < 0.05); however, the prognosis was similar in the 2 groups. CONCLUSIONS: Uterine adenomyosis is associated with deep myometrial invasion in stage I endometrioid adenocarcinoma; however, it did not affect the recurrence or mortality rates.

In vivo delivery of siRNA targeting vasohibin-2 decreases tumor angiogenesis and suppresses tumor growth in ovarian cancer.

Vasohibin-2 (VASH2) is a homolog of vasohibin-1 and exhibits pro-angiogenic activity. We recently reported that VASH2 is expressed in certain ovarian cancers and promotes tumor growth through angiogenesis. To further demonstrate the effectiveness of molecular targeting of VASH2 for anticancer treatment, we applied in vivo delivery of siRNA targeting VASH2 (siVASH2) using atelocollagen to a xenograft model of ovarian cancer. We inoculated mice s.c. with DISS and SKOV-3, two representative human ovarian serous adenocarcinoma cell lines. When tumors were measurable, we initiated treatment with control or siVASH2 mixed with atelocollagen, which enveloped the whole tumor. Treatment with siVASH2 significantly inhibited s.c. tumor growth by abrogating tumor angiogenesis. We confirmed that expression of VASH2 mRNA in the tumor was downregulated by siVASH2 treatment. In addition, the siVASH2-treated tumor contained more blood vessels covered with pericytes, indicating that knockdown of VASH2 contributes to the normalization of tumor blood vessels. Based on these results, VASH2 may be a promising molecular target for ovarian cancer treatment.

Suppression of lymph node and lung metastases of endometrial cancer by muscle-mediated expression of soluble vascular endothelial growth factor receptor-3.

Lymph node metastasis is the most important prognostic factor of endometrial cancer. However, effective therapy has not been established against lymph node metastasis. In this study, we explored the efficacy of gene therapy targeting lymph node metastasis of endometrial cancer by suppressing the action of vascular endothelial growth factor (VEGF)-C through soluble VEGF receptor-3 (sVEGFR-3) expression. For this purpose, we first conducted a model experiment by introducing sVEGFR-3 cDNA into an endometrial cancer cell line HEC1A and established HEC1A/sVEGFR-3 cell line with high sVEGFR-3 expression. The conditioned medium of HEC1A/sVEGFR-3 cells inhibited lymphatic endothelial cell growth in vitro, and sVEGFR-3 expression in HEC1A cells suppressed in vivo lymph node and lung metastases without inhibiting the growth of a subcutaneously inoculated tumor. To validate the therapeutic efficacy, adeno-associated virus vectors encoding sVEGFR-3 were injected into the skeletal muscle of mice with lymph node metastasis. Lymph node and lung metastases of HEC1A cells were completely suppressed by the muscle-mediated expression of sVEGFR-3 using adeno-associated virus vectors. These results suggest the possibility of gene therapy against lymph node and lung metastases of endometrial cancer by using muscle-mediated expression of sVEGFR-3.

Decidualization of ovarian endometriosis during pregnancy mimicking malignancy: report of three cases with a literature review.

BACKGROUND: Intracystic papillary excrescence is a characteristic morphological feature of ovarian malignancy. A few recent reports have demonstrated that ovarian endometriotic cysts, undergoing decidualization during pregnancy, occasionally show excrescence, necessitating surgery during pregnancy; however, this phenomenon is not well recognized among clinicians. CASES: Three pregnant women with decidualized ovarian endometriosis showed excrescence. Both ultrasound and magnetic resonance imaging (MRI) preoperatively suggested the presence of underlying ovarian endometriotic cysts in 2 women, but not in the other. Intracystic papillary excrescence prompted us to perform laparotomy at 14, 14, and 19 weeks of pregnancy, respectively, with 1 woman aborting in the 21st week, and with 2 delivering healthy term infants. Histological examination confirmed the diagnosis of decidualized ovarian endometriotic cysts in all 3 patients. CONCLUSIONS: We provide the first report of pregnant women in whom excrescence occurred from ovarian endometriotic cysts without preoperative evidence. Decidualized ovarian endometriosis, even without preoperative morphological features of endometriosis, should be added to the differential diagnosis of ovarian malignancy during pregnancy.

Gestational choriocarcinoma with uterine serosal metastasis mimicking ruptured ectopic pregnancy: A case report.

Primary gestational choriocarcinoma is commonly present in the uterus in cases of atypical genital bleeding. Symptoms similar to those of an ectopic pregnancy develop when an extra-uterine lesion is present in the abdominal cavity, and lesions have been detected in the ovaries and fallopian tubes in a number of cases. In the present study, we describe a patient with choriocarcinoma that metastasized to the uterine serosa and caused symptoms similar to those of an ectopic pregnancy. The patient was a 30-year-old female who presented to our hospital with atypical genital bleeding and a positive pregnancy test 3 months after missed abortion at 10 weeks of gestation. Transvaginal ultrasonography revealed the absence of a gestational sac in or outside the uterus, and intra-abdominal bleeding was noted. An ectopic pregnancy was suspected based on these findings, and emergency laparotomy was performed. A hemorrhagic mass was present on the uterine serosa, and was subsequently resected. Trophoblastic disease was suspected following histopathological examination, for which intra-uterine curettage was performed and choriocarcinoma was diagnosed. Lung metastasis was detected on computed tomography, and a high serum human chorionic gonadotropin (hCG) level persisted following surgery. The lesion disappeared following five cycles of methotrexate+ etoposide+actinomycin D therapy, which was performed as postoperative chemotherapy, and the patient's serum hCG level decreased to below the detection limit. In this case of choriocarcinoma, the primary lesion was present in the uterus and had metastasized to the uterine serosa, which is a very rare metastatic site. This uterine serosal metastatic lesion bled and caused symptoms similar to those of an ectopic pregnancy. Certain patients who undergo surgery for a suspected peritoneal pregnancy may have gestational choriocarcinoma, similar to this case.

Effect of providing risk information on undergoing cervical cancer screening: a randomized controlled trial.

BACKGROUND: In Japan, the cervical cancer screening rate is extremely low. Towards improving the cervical cancer screening rate, encouraging eligible people to make an informed choice, which is a decision-making process that relies on beliefs informed by adequate information about the possible benefits and risks of screening, has attracted increased attention in the public health domain. However, there is concern that providing information on possible risks of screening might prevent deter from participating. METHODS: In total, 1,912 women aged 20-39 years who had not participated in screening in the fiscal year were selected from a Japanese urban community setting. Participants were randomly divided into 3 groups. Group A received a printed reminder with information about the possible benefits of screening, group B received a printed reminder with information about possible benefits and risks, and group C received a printed reminder with simple information only (control group). RESULTS: Out of 1,912 participants, 169 (8.8%) participated in cervical cancer screening. In the intervention groups, 137 (10.9%) participated in cervical cancer screening, compared to only 32 (4.9%) of the control group (p < 0.001). In addition, logistic regression analysis revealed that there was no significant difference in screening rate between group A and group B (p = 0.372). CONCLUSIONS: Providing information on the possible risks of screening may not prevent people from taking part in cervical cancer screening among a Japanese non-adherent population.

A feasibility study of paclitaxel and carboplatin therapy in Japanese patients with epithelial ovarian cancer.

The aim of this study was clarification of the feasibility, effects, and adverse events of combination chemotherapy with paclitaxel and carboplatin in Japanese women with epithelial ovarian cancer. In patients with stage Ic to IV epithelial ovarian cancer, primary cytoreductive surgery was performed. Paclitaxel (175 mg/m(2)) was intravenously infused for 3 h. Subsequently, carboplatin was infused, with an area under the plasma concentration-time curve of 5. Ninety-one patients were enrolled in this study. The mean dose of paclitaxel at the sixth course was 161 mg/m(2). Of 51 patients, a complete response was observed in 19 patients (37%), and a partial response in 23 patients (45%). The response rate for clear cell adenocarcinoma was 25%. With regard to adverse events, grade 4 granulopenia was observed in 80% of patients, suggesting dose-limiting toxicity. However, none of the patients developed serious infection. With regard to non-hematological toxicity, grade 2 or 3 alopecia, arythralgia/myalgia, and peripheral neurotoxicity were noted in 97, 29, and 20% of the patients, respectively. Although hematological toxicity was relatively marked, this regimen can be applied in Japanese women.

Disseminated intravascular coagulopathy caused by uterine leiomyoma with sarcoma-like findings on magnetic resonance imaging.

A leiomyoma rarely causes disseminated intravascular coagulopathy (DIC). In the present report, we describe a case of DIC caused by leiomyoma. A 36-year-old nulliparous woman presented with hypermenorrhea and a lower abdominal mass. On magnetic resonance imaging, we detected a 14 cm uterine tumor, which was suspected to be a sarcoma. Blood tests at the preoperative examination indicated platelet count of 9.6 × 10(4)/µL, fibrin degradation product level of 107.1 µg/mL (normal value, 0-5.0 µg/mL), and fibrinogen level of 54 mg/dL (normal value, 129-271 mg/dL). Based on these findings, we diagnosed the patient with DIC. The patient was treated with nafamostat mesilate and fresh frozen plasma, but the DIC did not show any improvement. Subsequently, a hysterectomy was performed, after which the DIC improved. Clinicopathological findings indicated the presence of a leiomyoma with multiple vessels containing thromboemboli, and suggested that the DIC was caused by the leiomyoma. Therefore, it is essential to consider that that a benign leiomyoma may be a cause of DIC.

Community-based interventions to improve HPV vaccination coverage among 13- to 15-year-old females: measures implemented by local governments in Japan.

The purpose of this study was to examine the effect of various community-based interventions in support of HPV vaccination implemented by cities and towns within Tochigi prefecture, Japan with a view to identifying useful indicators which might guide future interventions to improve HPV vaccination coverage in the prefecture. A postal questionnaire survey of all 27 local governments in Tochigi Prefecture was conducted in December 2010. All 27 responded, and 22 provided the exact numbers of the targeted and vaccinated populations of 13- to 15-year-old girls from April to December 2010. The local governments also answered questions on the type of interventions implemented including public subsidies, school-based programs, direct mail, free tickets and recalls. Local governments that conducted a school-based vaccination program reported 96.8% coverage for the 1(st) dose, 96.2% for the 2(nd) dose, and 91.2% for the 3(rd) dose. Those that provided subsidies without school-based programs reported a wide range of vaccination rates: 45.7%-95.0% for the 1(st) dose, 41.1%-93.7% for the 2(nd) dose and 3.1%-90.1% for the 3(rd) dose. Among this group, the combination of a free ticket, direct mail and recall was most effective, with 95.0% coverage for the 1(st) dose, 93.7% for the 2(nd) dose, and 90.1% for the 3(rd) dose. The governments that did not offer a subsidy had the lowest vaccination coverage, with 0.8%-1.4% for the 1(st) dose, 0.0%-0.8% for the 2(nd) dose, and 0.1%-0.1% for the 3(rd) dose. The results of this survey indicate that school-based vaccinations and public subsidies are the most effective method to improve HPV vaccination coverage; however, the combination of a free ticket, direct mail, and recalls with public subsidies are also important measures in increasing the vaccination rate. These data may afford important indicators for the successful implementation of future HPV vaccination programs.

Evaluation of a formula for individual dosage of nedaplatin based on renal function.

PURPOSE: Nedaplatin (NDP), a platinum derivative, has been developed to reduce nephrotoxicity and gastrointestinal toxicity of cisplatin. The pharmacokinetic profile of NDP is similar to that of carboplatin (CBDCA). The optimal dosing for CBDCA is determined by the area under the curve (AUC) using Calvert's formula. However, the administration dose of nedaplatin (NDP) is determined based on the body surface area in clinical treatment. Ishibashi et al. reported a formula for predicting NDP clearance based on renal function like Calvert's formula for CBDCA. We conducted the present study to evaluate the Ishibashi's formula. METHODS: A total of 22 patients with cervical or ovarian cancer, who underwent chemotherapy consisting of NDP and irinotecan (CPT-11), were examined in this study. Blood samples were collected at 0, 1, 2, 4, and 6 h after the end of infusion of NDP (48-80 mg/m(2)), and free platinum concentrations were measured. Observed AUCs were compared with predicted AUCs, which were calculated by the Ishibashi's formula. In addition, the relative reduction in platelets (PLTs) was assessed as a parameter of adverse effects. RESULTS: The observed AUC of NDP ranged from 4 to 14 (µg h(-1) ml(-1)) with large variation. The predicted AUC based on renal function was correlated with the observed AUC. There was a relationship between observed AUC and the decrease in PLTs. CONCLUSIONS: Ishibashi's formula would be predictable and useful for estimating the individual dose of NDP.