Toshiko Jobo

Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer: a phase 3, open-label, randomised controlled trial

BACKGROUND Paclitaxel and carboplatin given every 3 weeks is standard treatment for advanced ovarian carcinoma. Attempts to improve patient survival by including other drugs have yielded disappointing results. We compared a conventional regimen of paclitaxel and carboplatin with a dose-dense weekly regimen in women with advanced ovarian cancer. METHODS Patients with stage II to IV epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer were eligible for enrolment in this phase 3, open-label, randomised controlled trial at 85 centres in Japan. Patients were randomly assigned by computer-generated randomisation sequence to receive six cycles of either paclitaxel (180 mg/m(2); 3-h intravenous infusion) plus carboplatin (area under the curve [AUC] 6 mg/mL per min), given on day 1 of a 21-day cycle (conventional regimen; n=320), or dose-dense paclitaxel (80 mg/m(2); 1-h intravenous infusion) given on days 1, 8, and 15 plus carboplatin given on day 1 of a 21-day cycle (dose-dense regimen; n=317). The primary endpoint was progression-free survival. Analysis was by intention to treat (ITT). This trial is registered with ClinicalTrials.gov, number NCT00226915. FINDINGS 631 of the 637 enrolled patients were eligible for treatment and were included in the ITT population (dose-dense regimen, n=312; conventional regimen, n=319). Median progression-free survival was longer in the dose-dense treatment group (28.0 months, 95% CI 22.3-35.4) than in the conventional treatment group (17.2 months, 15.7-21.1; hazard ratio [HR] 0.71; 95% CI 0.58-0.88; p=0.0015). Overall survival at 3 years was higher in the dose-dense regimen group (72.1%) than in the conventional treatment group (65.1%; HR 0.75, 0.57-0.98; p=0.03). 165 patients assigned to the dose-dense regimen and 117 assigned to the conventional regimen discontinued treatment early. Reasons for participant dropout were balanced between the groups, apart from withdrawal because of toxicity, which was higher in the dose-dense regimen group than in the conventional regimen group (n=113 vs n=69). The most common adverse event was neutropenia (dose-dense regimen, 286 [92%] of 312; conventional regimen, 276 [88%] of 314). The frequency of grade 3 and 4 anaemia was higher in the dose-dense treatment group (214 [69%]) than in the conventional treatment group (137 [44%]; p<0.0001). The frequencies of other toxic effects were similar between groups. INTERPRETATION Dose-dense weekly paclitaxel plus carboplatin improved survival compared with the conventional regimen and represents a new treatment option in women with advanced epithelial ovarian cancer. FUNDING Bristol-Myers Squibb.

Long-term results of dose-dense paclitaxel and carboplatin versus conventional paclitaxel and carboplatin for treatment of advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer (JGOG 3016): a randomised, controlled, open-label trial

BACKGROUND The primary analysis of the JGOG 3016 trial showed that a dose-dense paclitaxel and carboplatin regimen significantly improves progression-free and overall survival compared with the conventional regimen as first-line chemotherapy for patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer. We report the long-term follow-up results for survival. METHODS This randomised controlled trial was done at 85 centres in Japan. Patients with stage II-IV ovarian cancer were randomly assigned to receive conventional treatment (carboplatin area under the curve [AUC] 6 mg/mL per min and paclitaxel 180 mg/m(2) on day 1) or dose-dense treatment (carboplatin AUC 6 mg/mL per min on day 1 and paclitaxel 80 mg/m(2) on days 1, 8, and 15). The treatments were repeated every 3 weeks for six cycles; responding patients had three additional cycles. The randomisation was done centrally by telephone or fax, stratified by residual disease, stage, and histological type. The primary endpoint was progression-free survival; overall survival was a secondary endpoint. Long-term information on adverse events was not collected. Efficacy analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00226915. FINDINGS 637 patients were enrolled, of whom 631 were analysed (312 assigned to the dose-dense regimen, 319 to the conventional regimen). Median follow-up was 76·8 months (IQR 68·9-85·6). Median progression-free survival was significantly longer in the dose-dense treatment group than in the conventional treatment group (28·2 months [95% CI 22·3-33·8] vs 17·5 months [15·7-21·7]; hazard ratio [HR] 0·76, 95% CI 0·62-0·91; p=0·0037). Median overall survival was 100·5 months (95% CI 65·2-∞) in the dose-dense treatment group and 62·2 months (52·1-82·6) in the conventional treatment group (HR 0·79, 95% CI 0·63-0·99; p=0·039). INTERPRETATION Dose-dense treatment offers better survival than conventional treatment and is a potential new standard of care for first-line chemotherapy for patients with advanced epithelial ovarian cancer.

Significance of progesterone receptor-A and -B expressions in endometrial adenocarcinoma.

The progesterone receptor (PR) has two isoforms, A and B, among which PR-B is mainly involved in regulating proliferation of the uterine endometrium. In this study, immunohistochemical analysis was carried out to investigate the correlation of PR-A and -B expressions with cell cycle-regulatory proteins and clinicopathological parameters in endometrial adenocarcinoma. One hundred and forty-one endometrioid adenocarcinomas [76 with well-differentiated (G1), 35 with moderately differentiated (G2) and 30 with poorly differentiated (G3)] were used. Specimens of formalin-fixed and paraffin-embedded tissue were immunohistochemically stained using the high polymer method (HISTOFINE, NICHIREI). The percentage of positive nuclei of tumor cells observed in three high power fields was expressed as a labeling index (LI). PR-B expression significantly occurred more frequently in G1. It was inversely correlated with p53 gene mutation and p53 over expression, and also with clinicopathological variables, including myometrial and lymph-vascular space invasion and the FIGO stage. Patients with negative PR-B had a poorer prognosis than positive cases. PR-A expression was also significantly higher in G1 and was inversely correlated with Ki-67 expression and myometrial invasion, but not with prognosis. PR-A and -B expressions were significantly correlated with biologically malignant potential. Especially, PR-B expression is useful as a prognostic indicator of endometrial adenocarcinoma.

PTEN immunohistochemical expression is suppressed in G1 endometrioid adenocarcinoma of the uterine corpus

Purpose PTEN is a tumor suppressor gene that inhibits cell proliferation by regulating intracellular signaling pathways, and this activity can be abolished by mutations of the PTEN gene. This study was designed to examine the correlation of PTEN expression with the expression of cell cycle regulators and with clinicopathological parameters in endometrioid adenocarcinoma of the uterine corpus.MethodsTissue samples of 117 endometrioid adenocarcinomas in addition to those of 19 normal endometria and 20 endometrial hyperplasias were used for the study. Immunohistochemical staining for PTEN protein was performed with the labeled streptavidin-biotin method on formalin-fixed and paraffin-embedded tissue samples. PTEN expression was represented as the staining score.Results Immunohistochemistry showed that the nuclei of cells were positive for PTEN. The PTEN staining score of normal endometrium was significantly higher in the proliferative phase than in the secretory phase. The scores of various endometrial hyperplasias were not significantly different from each other, regardless of the type of hyperplasia. The PTEN staining scores of endometrioid adenocarcinomas were 7.6±5.2 in G1, 9.6±5.2 in G2, and 11.9±3.7 in G3, and increased significantly as the histological grade increased. PTEN staining score was not significantly correlated with clinicopathological parameters such as FIGO stage, myometrial invasion, lymph-vascular space invasion (LVSI), lymph node metastasis or group, but was significantly correlated with labeling indices (LIs) of cell cycle regulators such as Ki-67, cdk2, cyclin A, cyclin D1, cyclin E, p27, and p53. The PTEN staining score of p53-wild cases was significantly lower than that of p53-mutant ones, but there was no significant difference of the score in cases with different PTEN gene status. PTEN expression was significantly lower in cases with both high levels of estrogen receptor and progesterone receptor.Conclusion PTEN protein expression was decreased in well-differentiated and less growth-aggressive endometrial carcinoma with wild-type p53 gene and high levels of ER and PR. This suggests that disturbed PTEN expression occurs in an early phase of the tumorigenesis of well-differentiated endometrial carcinoma.

Expression of cyclin A in endometrial adenocarcinoma and its correlation with proliferative activity and clinicopathological variables.

Abstract.Purpose: Cyclin A is known as an S- and G2-M phase regulatory protein and its abnormal expression has been reportedly implicated in cellular proliferation. This study was designed to investigate the correlation of cyclin A expression with tumorigenesis of the endometrium and clinicopathological variables. Methods: Immunohistochemical staining using labeled streptavidin-biotin complex was performed on formalin-fixed, paraffin-embedded tissue of normal endometrium (15 cases), endometrial hyperplasia (23 cases), and endometrial adenocarcinoma (endometrioid type) (112 cases). Results: Immunohistochemistry showed that the nuclei of the cells were positive for cyclin A. In normal endometrium, only proliferative phase was focally positive for cyclin A. Cyclin A was also positive for endometrial hyperplasia. Its expression in hyperplasia was significantly more frequent than that of proliferative phase and less than that of endometrioid adenocarcinoma. The labeling index (LI) of cyclin A in endometrioid adenocarcinoma was 16.3±6.9 in well-differentiated, 18.3±8.8 in moderately differentiated, and 30.2±11.8 in poorly differentiated adenocarcinoma, respectively. Cyclin A expression increased significantly more in high histological grades. The area of squamous metaplasia in endometrioid adenocarcinoma was negative for cyclin A. The LI of cyclin A was positively correlated with that of Ki-67 and cyclin-dependent kinase 2. Cyclin A expression was significantly associated with carcinoma without coexisting endometrial hyperplasia and lymphovascular space involvement (LVSI), but not with FIGO stage, myometrial invasion, lymph node metastasis, estrogen receptor, progesterone receptor, and menopause as well as recurrence. Conclusions: Cyclin A expression was involved in the progression to malignancy of the endometrium and was correlated with proliferative activity and prognostic features including histological grade, without coexisting endometrial hyperplasia and LVSI.

Immunohistochemical expression of cyclin E in endometrial adenocarcinoma (endometrioid type) and its clinicopathological significance

PurposeCyclin E is known as a G1-S phase regulatory protein and its abnormal expression has been implicated in cellular proliferation. This study aimed to investigate the correlation of cyclin E expression with tumorigenesis of the endometrium, proliferative activity, and clinicopathological features of endometrial adenocarcinoma.MethodsImmunohistochemical staining for cyclin E in addition to cyclin-dependent kinase 2 (cdk2), Ki67, p27, and p53 was performed by the labeled streptavidin-biotin method on formalin-fixed, paraffin-embedded tissues of normal endometria (20 cases), endometrial hyperplasias (20 cases), and endometrial adenocarcinomas (endometrioid type) (127 cases). Positive staining was expressed as a labeling index (LI) based on percentages of positive nuclei in tumor cells.ResultsImmunohistochemistry showed that the nuclei of the cells were positive for cyclin E. Both proliferative and secretory endometria, and endometrial hyperplasia regardless of type were negligible for cyclin E expression. The expression in normal endometrium and hyperplasia was significantly less than that in endometrial adenocarcinomas (P<0.0001). LIs of cyclin E in well-differentiated, moderately differentiated, and poorly differentiated endometrial adenocarcinomas were 31.5±33.3%, 37.8±31.9%, and 51.1±30.8%, respectively. Cyclin E expression increased significantly more in histological grades. The LI of cyclin E in carcinoma was positively correlated with that of cdk2, Ki67, and p53 but not with p27. The cyclin E expression was correlated with myometrial invasion and lymph-vascular space involvement, but not with FIGO stage, lymph node metastasis, coexisting endometrial hyperplasia, estrogen receptor, progesterone receptor, and menopause.ConclusionCyclin E as a complex with cdk2 is associated with carcinogenesis and disease progression in endometrial adenocarcinoma, and might be a prognostic indicator of endometrial adenocarcinoma.

A 22/22 translocation carrier with recurrent abortions demonstrated by a Giemsa banding technique

Summarya 22/22 Robertsonian translocation has been identified in a woman with recurrent abortions by a Giemsa banding technique. Cytogenetic studies of the embryonic tissue derived from one of her spontaneous abortions have demonstrated that the aborted fetus had a 46,XX,-22,+t(22q22q) karyotype.

Cytologic scoring of endometrioid adenocarcinoma of the endometrium.

Endometrial carcinoma is one of the most frequent malignancies in the female genital tract, and its incidence has been increasing in Japan. Histologic grade is an important factor for organizing treatment strategies, including hormone therapy, and for predicting the prognosis of the patient. The objective of this study was to evaluate the applicability and usefulness of cytologic scoring in assessing the morphologic differentiation of endometrioid adenocarcinomas of the endometrium using endometrial smears.

Usefulness of Endometrial Aspiration Cytology for the Preoperative Diagnosis of Ovarian Carcinoma

OBJECTIVE To evaluate the usefulness of endometrial aspiration cytology for the preoperative diagnosis of ovarian carcinoma. STUDY DESIGN A total of 210 patients with ovarian carcinoma were investigated by endometrial aspiration cytology. RESULTS Fifty-five of 210 patients (26.2%) had positive endometrial aspiration cytology. The positive rates of endometrial cytology were 3.9% in stage I, 23.8% in stage II, 36.5% in stage III and 53.3% in stage IV. When classified by histologic type, the positive rates of endometrial cytology in patients with serous adenocarcinoma, mucinous adenocarcinoma, clear cell adenocarcinoma, undifferentiated carcinoma and yolk sac tumor were 38.9%, 11.8%, 21.1%, 16.7% and 16.7%, respectively. One hundred twenty-eight of 210 patients (61.0%) were positive on peritoneal cytology, and 54 of these 128 cases (42.2%) were also positive on endometrial cytology. The positive rates of endometrial cytology were especially high in patients with serous adenocarcinoma (51.2%) and those with clear cell adenocarcinoma (40.0%) among those who were positive on peritoneal cytology. Of 74 patients who were negative on peritoneal cytology, only one (1.4%) with mucinous adenocarcinoma had positive endometrial cytology. Hysterectomy was performed on 130 patients, and the positive rate of endometrial cytology was 100% in 4 patients with endometrial invasion and 15.9% in 126 cases without invasion. CONCLUSION Endometrial aspiration cytology can detect ovarian carcinoma cells not only in patients with endometrial involvement but also in patients with positive peritoneal cytology. Endometrial aspiration cytology appears to be useful for the preoperative diagnosis of ovarian carcinoma.

A cytogenetic survey of consecutive liveborn infants-incidence and type of chromosome abnormalities

SummaryCytogenetic investigations have been carried out with particular concern to the frequency of chromosome abnormalities in newborn infants, and this is a preliminary report of data derived from 2,626 consecutive liveborns (1,393 males and 1,233 females) which were collected in one hospital. Of these, 18 infants (0.69%) were found to have a major chromosome abnormality. Eight infants (0.30%) showed sex-chromosome abnormalities: two with 47,XYY, one with 47,XXX, one with 45,X/47,XXX mosaicism, one with 46,XY/47,XYY mosaicism, one with 45,X/46,XX mosaicism, and a pair of twins with 45,X/46, XY/47,XYY mosaicism. Ten infants (0.38%) were carriers of autosomal abnormalities: three with 21-trisomy, one with 13-trisomy by translocation, three with a balanced 13/14 translocation, two with a balanced 14/22 translocation and one with an extra small marker chromosome. Of chromosomally abnormal infants, 14 were phyiscally normal.