Efficacy of palonosetron plus dexamethasone in preventing chemotherapy-induced nausea and emesis in patients receiving carboplatin-based chemotherapy for gynecologic cancers: a phase II study by the West Japan Gynecologic Oncology Group (WJGOG 131).

OBJECTIVE: Palonosetron is effective for the management of acute and delayed chemotherapy-induced nausea and vomiting (CINV). While emetogenic carboplatin-based chemotherapy is widely used to treat gynecologic cancers, few studies have evaluated the antiemetic effectiveness of palonosetron in this setting. METHODS: A multicenter, single-arm, open-label phase II trial was conducted to evaluate the safety and effectiveness of palonosetron in controlling CINV in patients with gynecologic cancer. Chemotherapy-naïve patients received intravenous palonosetron (0.75 mg/body) and dexamethasone before the infusion of carboplatin-based chemotherapy on day 1. Dexamethasone was administered (orally or intravenously) on days 2-3. The incidence and severity of CINV were evaluated using the patient-completed Multinational Association of Supportive Care in Cancer Antiemesis Tool and treatment diaries. The primary endpoint was the proportion of patients experiencing complete control (CC) of vomiting, with "no rescue antiemetic medication" and "no clinically significant nausea" or "only mild nausea" in the delayed phase (24-120 hours post-chemotherapy). Secondary endpoints were the proportion of patients with a complete response (CR: "no vomiting" and "no rescue antiemetic medication") in the acute (0-24 hours), delayed (24-120 hours), and overall (0-120 hours) phases, and CC in the acute and overall phases. RESULTS: Efficacy was assessable in 77 of 80 patients recruited. In the acute and delayed phases, the CR rates the primary endpoint, were 71.4% and 59.7% and the CC rates, the secondary endpoint, were 97.4% and 96.1%, respectively. CONCLUSION: While palonosetron effectively controls acute CINV, additional antiemetic management is warranted in the delayed phase after carboplatin-based chemotherapy in gynecologic cancer patients (Trial registry at UMIN Clinical Trials Registry, UMIN000012806).

A prospective observational study on chemotherapy-induced nausea and vomiting (CINV) in patients with gynecologic cancer by the CINV Study Group of Japan.

OBJECTIVE: This study was performed to investigate the occurrence of and risk factors for chemotherapy-induced nausea and vomiting (CINV) in patients with gynecologic cancer. METHODS: In total, 214 patients with gynecologic cancer who underwent highly emetogenic (HEC) or moderately emetogenic chemotherapy (MEC) were evaluated. We investigated the relationship between CINV and clinical factors and the accuracy of estimation of CINV by medical staff in the acute and late phases. Vomiting was evaluated in terms of frequency, and nausea was evaluated with a 100-mm visual analog scale on days 1 to 7. We also analyzed the risk factors and changes in CINV over time using a generalized linear mixed (GLM) model. RESULTS: The multivariate analysis revealed no significant risk factors for acute CINV. The independent risk factors for delayed nausea were a morning sickness history (odds ratio [OR], 2.687; 95% confidence interval [95% CI], 1.450-4.976; p=0.0017), age (each 1-year increment) (OR, 0.97; 95% CI, 0.944-0.996; p=0.0235), and HEC (OR, 2.134; 95% CI, 1.039-4.383; p=0.0391). The GLM model demonstrated that the independent factors affecting nausea were significant morning sickness (p=0.0101) and HEC (p=0.0136). These data also showed more severe nausea from days 3 to 5, but the negative predictive value for estimation of delayed nausea by medical staff was 57.8%. CONCLUSION: Our data suggest that improvement of preventive antiemetic administration is needed for patients with risk factors to manage delayed CINV caused by HEC and by MEC.

A pilot study to search possible mechanisms of ultralong gonadotropin-releasing hormone agonist therapy in IVF-ET patients with endometriosis.

BACKGROUND: Additional treatment with a gonadotropin-releasing hormone (GnRH) agonist (GnRHa) before IVF-ET (ultralong GnRHa therapy) has been reported to improve the outcome of IVF-ET in endometriosis patients. However, the mechanism of ultralong GnRHa therapy is unclear. It is suggested that inflammatory cytokines and oxidative stress contribute to infertility in endometriosis patients. Therefore, in order to search a possible mechanism of ultralong GnRHa therapy, we investigated the effect of ultralong GnRHa therapy on intrafollicular concentrations of tumor necrosis factor alpha (TNFα), oxidative stress markers, and antioxidants in patients with endometriosis. METHODS: Twenty-three infertile women with Stage III or IV endometriosis were recruited for this study. Eleven patients received three courses of GnRHa (1.8 mg s.c. every 28 days), followed by a standard controlled ovarian hyperstimulation (COH) for IVF-ET (ultralong group). The other 12 patients received a standard COH with mid-luteal phase GnRHa down-regulation (control group). The numbers of matured follicles and retrieved oocytes, fertilization rates, implantation rates, clinical pregnancy rate, and intrafollicular concentrations of TNFα, 8-hydroxy-2'-deoxyguanosine (8-OHdG) and hexanoyl-lysine adduct (HEL) as oxidative stress markers, and melatonin and Cu,Zu-superoxide dismutase (Cu,Zn-SOD) as antioxidants were compared between the two groups. RESULTS: The numbers of mature follicles and retrieved oocytes, and fertilization rates did not differ between the two groups. Implantation rates and pregnancy rates tended to be higher in the ultralong group (21.4% and 27.3%, respectively) compared with the control group (8.3% and 8.3%, respectively). TNFα concentrations in the follicular fluid were significantly lower in the ultralong group (5.8 ± 3.2 pg/ml) than those in the control group (10.6 ± 3.2 pg/ml). Follicular concentrations of 8-OHdG concentrations were significantly lower in the ultralong group (5.7 ± 1.6 ng/ml) than those in the control group (6.6 ± 1.5 ng/ml), while melatonin concentrations were significantly higher in the ultralong group (139 ± 46 pg/ml) compared with the control group (86 ± 27 pg/ml). CONCLUSIONS: Ultralong GnRHa therapy reduces the detrimental effects of cytotoxic cytokines and oxidative stress in the ovary in patients with endometriosis.

Prenatal diagnosis of right aortic arch with mirror-image branching without associated anomalies.

A pregnant woman at 32 weeks of gestation was referred because of untypical visualization of a three-vessel tracheal view. Detailed ultrasound examination demonstrated an abnormal position of descending aorta, positioned at the right-front side of the spine at the level of four-chamber view. The descending aorta was connected with left pulmonary artery through ductus arteriosus, which configured a vascular ring. Right aortic arch with mirror-image branching without any associated anomaly was suspected prenatally. Amniocentesis showed no chromosomal abnormality. A male, 2440-g infant was delivered vaginally at 37 weeks and 4 days of gestation. Echocardiography confirmed no associated congenital heart defect. Three-dimensional reconstruction using 64-slice spiral computed tomography angiography at 2-months old confirmed the diagnosis of right aortic arch with mirror-image branching. The infant is now 1 year old and well developed without any symptoms.

Clinical impact of systematic pelvic and para-aortic lymphadenectomy for pT1 and pT2 ovarian cancer: a retrospective survey by the Sankai Gynecology Study Group.

BACKGROUND: The therapeutic value of systematic lymphadenectomy for early-stage epithelial ovarian cancer (EOC) is controversial. This study evaluates the survival impact and adverse events of systematic pelvic and para-aortic lymphadenectomy in patients with pT1 and pT2 EOC. METHODS: A retrospective investigation was performed using data from patients with pT1 and pT2 EOC at multi-institutions belonging to the Sankai Gynecologic Study Group (SGSG). We selected patients who had undergone systematic pelvic and para-aortic lymphadenectomy (Group LA) (n = 284) and patients who had not undergone lymph node resection (Group no-LA) (n = 138). Outcomes for patients and peri-operative adverse events were compared between the two groups. RESULTS: The median operation time was significantly longer in Group LA (288 min) than in Group no-LA (128 min) (P < 0.0001). Total blood loss was significantly higher in Group LA, 43.7 % of patients receiving blood transfusions. There were no significant differences between the treatment groups for progression-free survival (PFS) or overall survival (OS). However, for patients with pT2, PFS was significantly longer in Group LA than in Group no-LA (P = 0.0150). Lymph node metastases were detected in 23 cases (8.1 %) and these patients had significantly shorter PFS than those without metastasis (P = 0.0409). The outcome for patients who underwent chemotherapy after surgery was significantly improved in the Group no-LA, but no improvement was observed in Group LA. CONCLUSIONS: Systematic lymphadenectomy may improve outcomes only in pT2 EOC patients with acceptable peri-operative events. Furthermore, accurate surgical staging may avoid unnecessary adjuvant chemotherapy in selected early-stage cases.

Phase II study of intraperitoneal carboplatin with intravenous paclitaxel in patients with suboptimal residual epithelial ovarian or primary peritoneal cancer: a Sankai Gynecology Cancer Study Group Study.

PURPOSE: To assess the antitumor efficacy and safety of 2 treatment modalities: intraperitoneal carboplatin combined with intravenous (IV) paclitaxel. PATIENTS AND METHODS: Eligible patients were those with epithelial ovarian carcinoma or primary peritoneal carcinoma stages II to IV who underwent initial surgery and had a residual tumor size of 2 cm or larger. Patients received IV paclitaxel 175 mg/m followed by intraperitoneal carboplatin AUC6. The primary end point was a response. Secondary end points were toxicity, progression-free survival, and overall survival. RESULTS: Twenty-six patients were enrolled, and 24 patients were eligible for assessment. The response rate was 83.3% (95% CI, 62.6%-95.3%; ). The median progression-free survival was 25 months. The median overall survival had not been reached. Incidences of grade (G) 3/4 hematological toxicities were absolute neutrophil count, 96%; hemoglobin, 29%; and thrombocytopenia, 16%. Nonhematological toxicities included G2 liver function, 4%; G3 sensory neuropathy, 8%; and G3 myalgia and arthralgia, 4%. CONCLUSIONS: Intraperitoneal administration of carboplatin combined with IV paclitaxel was well tolerated and showed satisfactory response in the patients with bulky residual tumor. Large-scale phase III trial comparing with IV carboplatin is warranted in this patient population.

Aneuploidy predicts outcome in patients with endometrial carcinoma and is related to lack of CDH13 hypermethylation.

PURPOSE: Many investigators have reported that aneuploidy detected by flow cytometry is a useful prognostic marker in patients with endometrial cancer. Laser scanning cytometry (LSC) is a technology similar to flow cytometry but is more feasible for clinical laboratory use. We evaluated the usefulness of DNA ploidy detected by LSC as a prognostic marker in patients with endometrial cancer and investigated genetic and epigenetic factors related to aneuploidy. EXPERIMENTAL DESIGN: Endometrial cancer specimens from 106 patients were evaluated. The methylation status of CDH13, Rassf1, SFRP1, SFRP2, SFRP4, SFRP5, p16, hMLH1, MGMT, APC, ATM, and WIF1 and mutations in the p53 and CDC4 genes were investigated. LSC was carried out to determine DNA ploidy. Fluorescence in situ hybridization was done with chromosome-specific centromeric probes to assess chromosomal instability. RESULTS: Univariate and multivariate analyses revealed that p53 mutation and lack of CDH13 hypermethylation associated positively with aneuploidy. Univariate analysis showed that aneuploidy, chromosomal instability, and lack of CDH13 hypermethylation as well as surgical stage were significantly predictive of death from endometrial cancer. Furthermore, multivariate analysis revealed that stage in combination with either DNA aneuploidy or lack of CDH13 hypermethylation was an independent prognostic factor. CONCLUSION: These results suggest that analysis of DNA ploidy and methylation status of CDH13 may help predict clinical outcome in patients with endometrial cancer. Prospective randomized trials are needed to confirm the validity of an individualized approach, including determination of tumor ploidy and methylation status of CDH13, to management of endometrial cancer patients.

Promoter analyses of SCC antigen genes.

SCC antigen (SCCA) has been used as a tumor marker for squamous cell carcinoma. Analyses of the SCCA1 and SCCA2 genes, which are almost identical, and their promoters have been reported. Recently it was found that both SCCAs were stimulated by interleukin (IL)-4 and IL-13. Here we analyzed the promoter activity of both SCCAs in the 5'-flanking region, exon 1, and intron 1 to evaluate a putative STAT6 binding site. The addition of intron 1 to the luciferase assay constructs including the 5'-flanking region significantly augmented the promoter activity of both SCCA1 and SCCA2. Furthermore, deletion analyses of intron 1 revealed that a 50-bp fragment of intron 1 that includes putative STAT6 binding site was responsible for the increased promoter activity. Although the sequences of SCCA1 and SCCA2 are very similar in the 5'-flanking region, the analysis of the -337 single nucleotide polymorphism of SCCA2 indicated that this polymorphism may underlie the difference in promoter activity between SCCA1 and SCCA2.

Regulation of squamous cell carcinoma antigen production by E-cadherin mediated cell-cell adhesion in squamous cell carcinoma cell line.

Squamous cell carcinoma antigen (SCCA) is a useful tumor marker for diagnosis and management of squamous cell carcinoma. It is well known that cell-cell adhesion is important for progression of cancer. However, it is not clarified whether cell-cell adhesion affects SCCA production in squamous cell carcinoma. The present study was, therefore, undertaken to investigate whether E-cadherin-mediated cell-cell adhesion affects SCCA production in squamous cell carcinoma of the uterine cervix. SKG-IIIa cells or CaSki cells, cervical squamous cell carcinoma cell lines, were treated with anti-E-cadherin antibodies (1 microg/ml) up to 72 h. The cells were dissociated, and SCCA content in the cytosol and SCCA mRNA levels were significantly decreased compared to the control group treated with mouse IgG. Secondly, the signaling pathway for SCCA production mediated by E-cadherin was examined. Phosphatidylinositol (PI) 3-kinase is a well-known mediator of E-cadherin-mediated biological events. The treatment with a PI 3-kinase inhibitor suppressed SCCA production in SKG-IIIa cells. It is concluded that E-cadherin mediated cell-cell adhesion maintains SCCA production through PI 3-kinase in squamous cell carcinoma.

A feasibility study on biweekly administration of docetaxel for patients with recurrent ovarian cancer.

OBJECTIVE: A recent study demonstrated that docetaxel (DTX) was an effective agent for second line chemotherapy against ovarian cancer. Weekly administration of taxane compounds had been more effective compared with a 3 week interval administration in ovarian cancer. The role of biweekly administration of DTX has been unknown. We conducted a dose determination and feasibility study of biweekly DTX administration in patients with ovarian cancer. METHODS: Patients with histologically confirmed epithelial ovarian cancer who received one or more regimens of prior chemotherapy with more than 4 weeks of treatment-free interval were eligible. DTX was administered as 1-h intravenous infusion every two weeks for at least four courses. The starting dose was 40 mg/m(2) (level 1) and the dose was escalated to 50 mg/m(2) (level 2) and 60 mg/m(2) (level 3) in consequent patient cohorts. RESULTS: Nine patients were examined in this study. The treatments were completely performed in all cohorts. Mean treatment delay ranged from 0 to 2.0 days. Dose level did not affect treatment delay. At the first dose level, no patients experienced grade 3/4 neutropenia. Two patients in level 2 experienced grade 3/4 neutropenia. In level 3, all patients had grade 4 neutropenia. Nonhematologic toxicities were tolerable. Of eight patients with measurable disease, all patients in level 1 showed progressive disease, and all patients in level 2 were no-change. There were two responders showing complete response and partial response and one case was no-change in level 3. CONCLUSION: The present study showed that biweekly administration of 60 mg/m(2) DTX was feasible for recurrent ovarian cancer.

Electrophoretic analysis of the cleaved form of serpin, squamous cell carcinoma antigen-1 in normal and malignant squamous epithelial tissues.

The aim of this study was to detect the cleaved form of serine proteinase inhibitor (serpin), squamous cell carcinoma (SCC) antigen-1 in normal and malignant squamous epithelial tissues, which implies the presence of its target proteinase. The cleaved SCC antigen-1 in normal squamous epithelium was identified as a single spot with pI 6.35 and M(r) 40,000 by two-dimensional electrophoresis (2-DE) combined with immunoblotting. Interestingly, the cleaved form showed different biochemical properties in heat stability or immunoreactivity with a monoclonal antibody for SCC antigen (Mab 426) compared to intact SCC antigen-1. Furthermore, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis of tissue extracts showed an abundant 40 kDa band of cleaved SCC antigen-1 in tumor tissue compared to normal tissue. Among the potential target proteinase of SCC antigen-1, immunoblotting analyses revealed that cathepsin L2 was remarkably overexpressed in tumor tissue, while cathepsin L was expressed in both normal and tumor tissues. These findings indicate that SCC antigen-1 interacts with specific endogenous proteinases such as cathepsins L and L2 in physiological and pathological states of squamous epithelium.

Genetic alterations related to lymph node metastasis and peritoneal dissemination in epithelial ovarian cancers.

Genetic alterations are assumed to be necessary for the development and progression of ovarian cancer. However, the genetic alterations that occur during lymph node metastasis and peritoneal dissemination are poorly understood. In the present study, we used comparative genomic hybridization to detect genetic alterations in 30 tumors from patients with primary ovarian cancers and analyzed the associations of these genetic alterations with clinical stage and surgical pathological factors, such as histological grade, lymph node metastasis, and peritoneal dissemination. The total number of genetic alterations per tumor ranged from 0 to 39, with an average of 17.7 alterations per tumor. Among the genetic alterations in ovarian cancers, gains on chromosomes 8q and 3q and losses on chromosomes 17p, 18q, and 4q were observed frequently. Although the difference in total numbers of genetic alterations between early-stage tumors and advanced-stage tumors was not significant, the difference was significant when high-grade cancers were compared with low-grade cancers. Eight regions on seven chromosomes showed genetic alterations related to lymph node metastasis or peritoneal dissemination. Gain at 11q13-q14 and loss at 17q11.2-q21 were related not only to lymph node metastasis and peritoneal dissemination but also to clinical stage and histological grade.

Comparative genomic hybridization detects genetic alterations during early stages of cervical cancer progression.

Invasive cervical carcinoma is thought to arise from cervical intraepithelial neoplasm (CIN). Genetic changes that occur during progression of CIN to cervical carcinoma are poorly understood, although they appear to be directly involved in this process. We used comparative genomic hybridization (CGH) with precise microdissection and degenerate oligonucleotide primed-polymerase chain reaction (DOP-PCR) to detect genetic alterations in normal epithelial, CIN, and invasive carcinoma tissues colocalized in tumors from 18 patients with squamous cell carcinoma of the uterine cervix. Gains on chromosome 1 and on 3q and losses on 2q, 3p, 4, 6p, 11q, and 17p were frequent alterations found in CIN and invasive carcinoma lesions. Interestingly, several of these genetic changes were observed in preinvasive carcinoma lesions. The frequency and average number of genetic alterations corresponded directly to the extent to which the cervical carcinoma had progressed. Frequent alterations were found in more than 90% of CIN III lesions. Gains on 3q and losses on 11q were the most prevalent genetic alterations found in association with uterine cervix carcinogenesis. The common regions of alteration were 3q26.1-q28 and 11q23-qter. The majority of tumor samples showed variability in genetic alterations across lesion types within a single specimen.

Syndecan-1 expression in cancer of the uterine cervix: association with lymph node metastasis.

The development of carcinoma is associated with alterations in the expression of many cell adhesion molecules. Syndecan-1 is a cell surface proteoglycan that binds cells to the extracellular matrix and changes its expression following malignant transformation in some tumors. Our purpose was to examine the pattern of syndecan-1 expression in cancer of the uterine cervix and assess the clinicopathological significance of syndecan-1 expression. A total of 106 tissue specimens (6 normal, 19 cervical intraepithelial neoplasia (CIN) and 81 invasive cancer) were analyzed immunohistochemically. In addition, the corresponding expression of mRNA in tumor tissues was evaluated by reverse transcription-polymerase chain reaction (RT/PCR) in comparison with normal counterparts. Syndecan-1 was positive in normal squamous cells except the basal cell layer. The intensity of syndecan-1 staining was the strongest in normal epithelium, followed by CIN, and invasive squamous cell carcinoma. Syndecan-1 expression in cancer tissue tended to be higher in keratinizing type than non-keratinizing type and not found in adenocarcinoma. Syndecan-1 expression was markedly decreased at the mRNA level in invasive squamous cell carcinoma as compared with that of normal uterine cervix. Interestingy, there was an inverse correlation between the expression of syndecan-1 in the primary site and lymph node metastasis, although there was no significant correlation between syndecan-1 expression and the prognosis. The results of the present study suggest that syndecan-1 expression is associated with squamous tissues and plays a key role in the progression of the cancer of the uterine cervix especially in the metastatic process.