Optimal doses of paclitaxel and carboplatin combination chemotherapy for ovarian cancer: a phase I modified continual reassessment method study.

BACKGROUND: A multicenter, phase I study of combination therapy with paclitaxel and carboplatin for epithelial ovarian cancer was conducted to determine the safety and recommended dosages for Japanese women. METHODS: Paclitaxel was administered intravenously over a 3-h period, followed by carboplatin administered intravenously over a 1.5-h period. A modified continual reassessment method (mCRM) was used in two treatment arms to establish the maximum tolerated dose (MTD) and recommended doses of the combination. In group A, the dose of paclitaxel (175 mg/m2) was constant and the dose of carboplatin was increased from 4 to 7 in terms of the target area under the plasma concentration-versus-time curve (AUC). In group B, the dose of carboplatin was constant (AUC 6) and paclitaxel was administered at two dose levels (160 and 175 mg/m2). In both groups, the carboplatin dose was limited to a maximum of 800 mg/body for each administration. RESULTS: Because the calculated probability of toxicity was greatest at a dose of paclitaxel 175 mg/m2 and carboplatin AUC 7, this dose was designated the MTD in group A. Based on this result, treatment in group B was initiated at doses of paclitaxel of 160 mg/m2 and carboplatin AUC 6. While the dose of paclitaxel was escalated to 175 mg/m2, the safety of the combination was confirmed. The most frequent adverse effect was neutropenia, which resolved promptly with the appropriate use of granulocyte-colony stimulating factor (G-CSF). No other severe hematologic or nonhematologic toxicities were observed. CONCLUSIONS: Our study demonstrated that the recommended dose for this combination regimen should be paclitaxel 175 mg/m2 plus carboplatin AUC 6 (maximum dose, 800 mg/body).

Randomized trial of cisplatin and carboplatin versus cisplatin, vinblastine and bleomycin in ovarian cancer.

Between January 1992 and July 1997, 202 cases of epithelial ovarian cancer were registered and assigned randomly to a combination of cisplatin and carboplatin (PP group), or cisplatin, vinblastine and bleomycin (PVB group). We analyzed 189 patients whose clinical records were available. The PP chemotherapeutic regimen was advantageous in terms of overall survival compared to the PVB regimen until 4 years after the initial operation. However, the 5-year survival rates were almost the same in both groups. However, in stage III patients, the mean survival time in the PP group was 51.4 months and that in the PVB group was 23.3 months, and there was a statistically significant difference in the survival curves between the two groups (p = 0.0158). The 5-year survival rates were 31.1 and 20.4% in the PP and PVB groups, respectively, in stage III patients. The PP regimen was also significantly superior in patients with macroscopic residual tumor after the initial operation, and the 5-year survival rates were 25.7 and 10.1% in the PP and PVB groups, respectively (p = 0.0128). However, there was no significant difference between the two regimens in patients without macroscopic residual tumor. Cox's proportional hazards regression analysis showed that tumor stage, presence of macroscopic residual tumor, and the chemotherapeutic regimen used were significant prognostic factors. In conclusion, the PP chemotherapeutic regimen is superior to the PVB regimen especially in the treatment of advanced ovarian cancer.

Esophageal achalasia in pregnancy.

Achalasia is rare motor disorder of esophageal smooth muscle. It has been linked to malnutrition during pregnancy leading to maternal and fetal mortality. We report a case of achalasia with intrauterine fetal death who succeeded in following pregnancy with good fetal and maternal outcome after operative treatment. A 34-year-old pregnant woman had intrauterine fetal death at 27 gestational weeks due to severe and persistent maternal malnutrition during pregnancy. Achalasia was diagnosed postpartum and myotomy-fundoplasty was performed. She succeeded in normal delivery with a healthy baby 21 months after the operation. This case suggests the effect of severe achalasia of early onset on poor fetal outcome, and the efficacy of surgical myotomy for the improvement of following pregnant outcome.

Antenatal ultrasonographic appearance of a cloacal anomaly.

BACKGROUND: Cloacal anomalies are rare abnormalities with highly variable forms, which makes them difficult to diagnose antenatally. We present a cloacal anomaly case with interesting antenatal ultrasonographic findings. CASE: A 24-year-old woman, gravida 1, para 0, presented at 23 weeks' gestation with ultrasonographic evidence of fetal ascites. Between 23 and 30 weeks' gestation, serial ultrasounds showed changing features of a cloacal anomaly, consisting of fetal ascites, a cystic pelvic mass, hydronephrosis, and oligohydramnios. CONCLUSION: Serial antenatal ultrasound helped diagnose changing features of a cloacal anomaly in our case, thus allowing directed antenatal counseling and appropriate perinatal treatment.

Structural properties of recombinant ovalbumin and its transformation into a thermostabilized form by alkaline treatment.

The recombinant ovalbumin produced in Escherichia coli was purified from the cytoplasmic fraction and analyzed for its chemical and conformational properties. The recombinant ovalbumin displayed almost exactly the same circular dichroism and intrinsic tryptophan fluorescence spectra as egg white ovalbumin. As in the egg white protein, four cysteine sulfhydryls and one cystine disulfide were contained in the recombinant protein, according to the results of amino acid analyses; the disulfide bond was found by a peptide mapping analysis to correspond to the native cystine, Cys73-Cys120. According to a gel electrophoresis analysis, the presence of the disulfide bond was accounted for by specific oxidation of the corresponding cysteine residues during purification of the cytoplasmic protein. Unlike the identity in the conformational and peptide structures, none of the post-translational modifications (N-terminal acetylation, phosphorylation, and glycosylation) that are known with egg white ovalbumin were detected in the recombinant protein. The recombinant ovalbumin was transformed into a thermostabilized form in a similar manner to the transformation of egg white protein into S-ovalbumin; alkaline treatment increased the temperature for thermostability by 8.7 degrees C. These data strongly suggest that the post-translational modifications of ovalbumin are not related to the formation mechanism for S-ovalbumin.

Ophthalmic artery velocimetry in normotensive and preeclamptic women with or without photophobia.

OBJECTIVE: To compare ophthalmic arterial velocimetry in normotensive and preeclamptic gravidas with and without photophobia. METHODS: Ophthalmic arteries were studied by color-flow Doppler ultrasonography in 118 normotensive pregnant women, 20 gravidas with preeclampsia and no visual symptoms, and 11 with preeclampsia, photophobia, and retinal edema. RESULTS: The ophthalmic arterial pulsatility index (PI) correlated negatively with gestational age (y = -0.01x + 1.84, r = -0.41, P<.01). Pulsatility index in preeclamptics with photophobia (0.71+/-0.17) was lowest among the three groups (P<.01) and was highest in normotensive pregnant women (1.41+/-0.21, P<.01). Mean velocity in normotensive pregnant women (0.19+/-0.05 m/second) was highest among the groups (P<.01) and was not significantly different in preeclamptic women with no visual symptoms (0.27+/-0.03 m/second) and with photophobia (0.30+/-0.02 m/second). CONCLUSION: Preeclamptic women, especially those with photophobia, have orbital vascular vasodilation or hyperperfusion, or both.

Diagnosis of squamous cell carcinoma arising from mature cystic teratoma of the ovary.

BACKGROUND: The prognoses of patients with squamous cell carcinoma of the ovary are quite poor. However, preoperative diagnosis is difficult due to the rarity of this tumor and its similarity to mature cystic teratoma (MCT). The objective of this study was to assess the value of tumor markers and clinical characteristics in making a differential diagnosis between MCT and squamous cell carcinoma arising from MCT. METHODS: Between September 1979 and June 1996, 37 patients with ovarian squamous cell carcinoma arising from MCT were treated by the Tokai Ovarian Tumor Study Group. The authors evaluated tumor markers, tumor size, and age as parameters for differentiation between MCT and squamous cell carcinoma arising from MCT. Diagnostic efficiency was calculated as the sensitivity multiplied by the specificity. RESULTS: There were significant differences (P < or = 0.0002) in age, tumor size, and levels of squamous cell carcinoma antigen (SCC), CA125, and CEA, as well as a significant difference (P < or = 0.0396) in the CA19-9 level between MCT and squamous cell carcinoma arising from MCT. Diagnostic efficiency was highest for SCC (63.0%), followed by CA125 (50.7%). Receiver operating characteristic (ROC) curves demonstrated that CEA was the best screening marker for squamous cell carcinoma arising from MCT, whereas age and tumor size were better markers than CA125 or CA19-9. The optimal cutoff values for age and tumor size were 45 years and 99 mm, respectively, according to ROC analysis. CONCLUSIONS: These findings demonstrate that age and tumor size are important factors in making a differential diagnosis. In addition, SCC and CEA levels should be measured in patients age 45 years or older who have an MCT-like ovarian tumor larger than 99 mm in greatest dimension.

A randomized trial of cisplatin, vinblastine, and bleomycin versus cyclophosphamide, aclacinomycin, and cisplatin in epithelial ovarian cancer.

After primary cytoreductive surgery, a randomized clinical trial was conducted in women with epithelial ovarian cancer to compare the impact on survival between PVB chemotherapy, consisting of cisplatin, vinblastine and bleomycin, and CAP chemotherapy, consisting of cyclophosphamide, aclacinomycin and cisplatin. There were 148 evaluable patients. One hundred and five patients with stage II, III and IV were analyzed in this study, 49 of them received PVB chemotherapy while the remaining 56 patients received CAP chemotherapy. Sixty-four patients fulfilled the criteria for clinical remission set by the Tokai Ovarian Tumor Study Group [Gynecol Oncol 1993;48:342-348]. The remission rate was 73 and 50% in the PVB and CAP groups, respectively, and showed a significant advantage for the PVB group (p = 0.0139). Moreover, the recurrence rate was 44% in the PVB group and 61% in the CAP group after clinical remission, although there was no significant difference between the two groups. The final survival rate was 32% in the PVB group and 24% in the CAP group. There was a significant difference of survival rate between both groups at 24 months (p = 0.0378) and 48 months (p = 0.0450), but finally no significant difference was found at 96 months (p = 0.0660). Compared to the CAP regimen, the PVB combination has a significantly higher efficacy in remission, but there was no significant difference in the long-term survival rate. Furthermore, multivariate analysis demonstrated that the PVB chemotherapy improved the survival, but it was not significant. The authors conclude that PVB chemotherapy may be more effective than CAP chemotherapy for epithelial ovarian cancer.

Interferon alpha-2a therapy for disseminated intravascular coagulation in a patient with blue rubber bleb nevus syndrome. A case report.

The authors present a sixteen-year-old girl with blue rubber bleb nevus syndrome (BRBNS) associated with disseminated hemangiomas involving the skin, oral cavity, skeletal muscle, and cerebrum. Although she denied neurologic symptoms, magnetic resonance imaging of the brain demonstrated dilatated cerebral veins and the Chiari I malformation. Examination of hemostasis revealed disseminated intravascular coagulation (DIC) manifesting as Kasabach-Merritt syndrome, with the potential for life-threatening bleeding or thrombosis in the central nervous system. Since successful management of life-threatening hemangiomas with interferon alpha-2a (IFN alpha-2a) has been reported, the authors administered IFN alpha-2a with an improvement in hemostasis. These findings suggest that IFN alpha-2a therapy is beneficial for relieving the life-threatening consumptive coagulopathy associated with BRBNS.

Clinical behavior of borderline ovarian tumors: a study of 150 cases.

BACKGROUND: We evaluated the clinical features, treatment, and survival status of the patients with borderline ovarian tumors. METHODS: A retrospective review of the charts of 150 patients with borderline ovarian tumor registered at the Tokai Ovarian Tumor Study Group from January 1, 1980, to December 31, 1994, was conducted to obtain clinical and pathological information. RESULTS: In stage II and III disease, the numbers of patients with no residual tumor, residual tumor of <2 cm, 2-5 cm, and >5 cm were 9, 10, 3, and 3, respectively. The sizes of residual tumors and corresponding clinical response to chemotherapy were as follows: residual tumor of <2 cm, complete response (CR), 6 patients; no change (NC), 2; progressive disease (PD), 2; tumors 2-5 cm, NC, 1 patient, PD, 2; tumors >5 cm, PD, 3 patients. The survival for patients with residual tumor <2 cm was significantly better than for those with residual tumor from 2-5 cm and of >5 cm (P < 0.05). The survival for patients with stage II and III serous tumor was significantly longer than that for patients with stage II and III mucinous tumor (P < 0.05). CONCLUSION: In advanced borderline ovarian tumor, the prognosis of patients with gross residual tumor after initial surgery, and especially with mucinous tumor, was poor.

Transcranial assessment of maternal cerebral blood flow velocity in patients with pre-eclampsia.

BACKGROUND: To clarify the cerebral hemodynamics in pre-eclamptic pregnant women, we investigated the blood flow velocity of the cerebral arteries. METHODS: The mean blood flow velocity and pulsatility index (PI) of the middle cerebral artery (MCA) and internal carotid artery (ICA) in normal pregnant women (n = 35) and pre-eclamptic patients (n = 18) were examined transcranially using pulsed-wave Doppler technique with a 2 MHz probe. In two pre-eclamptic women with post-partum visual disturbance, we examined the mean blood flow velocity and PI of the MCA and ICA every day. RESULTS: The mean blood flow velocity of the MCA in the pre-eclamptic patients (89.7 +/- 20.5 cm/s) was significantly higher than that in the normal pregnant women (53.6 +/- 16.9 cm/s) (p < 0.05). PI of the MCA in the former group (0.67 +/- 0.13) was significantly lower than that in the latter (0.78 +/- 0.02) (p < 0.05). There was no significant difference between these two groups in these variables of the ICA. In the two patients with visual disturbance, the mean blood flow velocity of the MCA was increased before the onset of visual disturbance and decreased gradually following the disappearance of this symptom. In these patients, spasm of the MCA was confirmed by magnetic resonance angiography. CONCLUSIONS: In pre-eclamptic patients, we found increased MCA mean velocity before the onset of visual disturbance. Transcranial Doppler may be useful for the evaluation of cerebral hemodynamics and the prediction of eclampsia.

Mucinous carcinoma of the ovary. Clinicopathologic analysis.

Since the incidence of mucinous carcinoma of the ovary is relatively low, with only small numbers of cases at any institution, detailed clinicopathologic studies on the prognosis and the care of patients with mucinous carcinoma are missing. Forty-four patients with mucinous carcinoma were histopathologically subclassified into endocervical (n = 8) and intestinal types (n = 36), and studied for clinical manifestations. All tumors of the endocervical type were stage I, whereas 14 intestinal-type tumors were stage II or higher (p < 0.05). Stromal invasion was not observed in 14 of 44 tumors, 13 of which were stage I. Analysis of prognostic factors disclosed that the clinical stage, maximum residual tumor diameter, volume of ascites, stromal invasion, and preoperative CA125 and CA19-9 levels significantly affected prognosis. However, multivariate analysis (stepwise regression) showed that the only significant factor was clinical stage (p < 0.004). In conclusion it is believed that, pathologically, the endocervical-type mucinous carcinoma is not as aggressive as the intestinal-type cancer. The clinical stage was found to be a significant prognostic factor even by multivariate analysis, and the prognosis at stages III and IV was unfavorable compared to stages I and II.

Effects of calcitonin gene-related peptide and interleukin 6 on myoblast differentiation.

Effects of calcitonin gene-related peptide (CGRP) and interleukin 6 (IL-6) on muscle cell differentiation were studied using cultured rat myoblasts (L6 cells). Cell morphology and the amounts of the messenger RNAs (mRNAs) of myogenin and Myf-5, DNA content, creatine kinase (CK) activity, and myoglobin (Mb) content in the cultured cells were examined serially over 10 days of culture. In the presence of CGRP or IL-6, the mRNAs of myogenin and Myf-5 were expressed earlier and at a higher concentration in the treated cells than in the control cells. The ratios of CK activity to DNA content (CK/DNA) and of Mb content to DNA content (Mb/DNA) on day 10 of culture also were greater than in the control cells. Furthermore, the mRNAs of myogenin and Myf-5 in cultured cells incubated with both CGRP and IL-6 increased more rapidly than in cells cultured with CGRP or IL-6 alone, and the ratios of CK/DNA and Mb/DNA on day 10 were more than twice those in the presence of CGRP or IL-6. These findings indicate that both CGRP and IL-6 facilitate the differentiation of myoblasts and may have an additive effect.

Lymphadenectomy in stage-III serous cystadenocarcinoma of the ovary.

OBJECTIVE: To elucidate the effects of lymphadenectomy on the prognosis for ovarian cancer. METHOD: A retrospective study of 69 patients with stage-III serous cystadenocarcinoma was performed. RESULTS: Among the 69 patients, 36 were not treated by lymphadenectomy. Both pelvic and para-aortic lymphadenectomies were performed on 13 patients at the initial operation and on 11 at the second operation. The group (n = 13) treated by both pelvic and para-aortic lymphadenectomies at the initial operation had a disease-free survival rate that was significantly higher than the non-lymphadenectomy group (n = 36) or the group (n = 5) treated by pelvic or para-aortic lymphadenectomy alone (P < 0.04). These 54 patients were subjected to multivariate analysis for lymphadenectomy at the initial operation, and a significant correlation was found between disease-free survival rate and both pelvic and para-aortic lymphadenectomies (P < 0.05). CONCLUSION: These results suggest that systematic lymphadenectomy can reduce the rate of recurrence.

Prognostic evaluation of lymphadenectomy for epithelial ovarian cancer.

Between 1989 and 1991, 150 patients with ovarian cancer were treated with chemotherapy, including cisplatin, in the Tokai Ovarian Tumor Study Group. Of these patients, 25 underwent cytoreductive surgery with lymphadenectomy, including removal of either pelvic or para-aortic lymph nodes, and 36 underwent both lymphadenectomies. A significant difference was observed between survival curves of the groups with positive and negative lymph nodes, respectively (P = 0.0049). The overall survival was longer in the lymphadenectomy group than in the nonlymphadenectomy group (P = 0.0842), and a significantly longer survival time was noted for stage III patients who underwent lymphadenectomy compared with those who did not (P = 0.0185). Multivariate analysis demonstrated that lymphadenectomy is a positive prognostic factor. The authors conclude that both pelvic and para-aortic lymph nodes should be resected to improve survival as well as to assess exact staging in patients with ovarian cancer.

Umbilical plasma concentration of endothelin-1 in intrapartum fetal stress: effect of fetal heart rate abnormalities.

OBJECTIVE: To measure the umbilical plasma concentration of endothelin (ET)-1 in the presence of labor, fetal heart rate (FHR) abnormalities, and fetal hypoxia. METHODS: Umbilical and maternal plasma concentrations of ET-1 were measured in 100 pregnant women at full-term deliveries (60 with vaginal delivery without induction and 40 with elective cesarean delivery without labor). We assessed the FHR pattern, measured umbilical blood gases and plasma concentration of vasopressin, and investigated the relationships between the umbilical vein-artery ET-1 concentration difference and these variables. RESULTS: The concentration of ET-1 in the umbilical vein was higher than in the umbilical artery and the maternal vein in all cases. The umbilical vein-artery ET-1 concentration difference (mean +/- standard error of the mean) was significantly greater in the vaginal delivery group (4.5 +/- 2.0 pmol/L) than in those delivered by elective cesarean (1.7 +/- 1.5 pmol/L) (P < .05). The umbilical vein-artery ET-1 concentration difference was significantly greater when more than three episodes of severe variable decelerations occurred during the 30-minute period before delivery (7.0 +/- 2.0 pmol/L) than in the absence of any decelerations (1.6 +/- 1.5 pmol/L) (P < .05). The umbilical vein-artery ET-1 concentration difference correlated positively with the umbilical arterial concentration of vasopressin (r = 0.45, P < .05) and negatively with the umbilical arterial oxygen pressure (r = -0.47, P < .05). CONCLUSION: In cases of vaginal delivery with FHR abnormalities and with fetal hypoxia, the fetoplacental concentration of ET-1 was increased.

Long-term follow-up of patients with epithelial carcinoma of the ovary.

OBJECTIVES: To determine the long-term outcomes of patients with epithelial ovarian cancer. METHODS: A group of 298 patients with epithelial ovarian cancer were treated with combination chemotherapy between July 1979 and January 1986 at the Tokai Ovarian Tumor Study Group. Long-term results of these patients were analyzed. RESULTS: Five-year survival and 10-year survival rates of all the patients were 53% and 47%, respectively. Five-year survival and 10-year survival rates for stage I were 89% and 79%, 59% and 56% for stage II, 27% and 22% for stage III, and 9% and 9% for stage IV, respectively. Survival of mucinous and endometrioid cell types were decreased after 5 or more years. In stages II-IV, cisplatin-based chemotherapy produced better results than mitomycin-C, 5-Fu, cytarabine (MFC) therapy. CONCLUSIONS: Long-term results of epithelial ovarian cancer were not favorable even in mucinous and endometrioid cell types. For long-term results, cisplatin-based chemotherapy was effective in advanced ovarian cancer. Long-term follow-up of ovarian cancer is important and necessary.

[Effects of calcitonin gene-related peptide on muscle cell differentiation and development].

We studied the factors which facilitate muscle cell differentiation and development to produce preventive and therapeutic treatment for muscle atrophies. Calcitonin gene-related peptide (CGRP) is present in the nervous system and neuromuscular junction, and acts as either a neurotransmitter or a neuromodulator. In this study, we report the effects of CGRP on the differentiation and development of rat skeletal myoblasts. Rat skeletal myoblasts (L6 cell) were cultured in Dulbecco's modified Eagle's medium containing 2% horse serum and 6 micrograms/ml insulin (control group). CGRP was then added at concentrations of 1, 10, and 100 nM (CGRP groups). Changes in cell morphology, myoglobin (Mb) content, creatine kinase (CK) activity, DNA content, and calcium concentration in the cultured cells were examined on days 3, 6, 8, and 10. In all of the groups, the number of cultured cells increased until myotubes appeared on day 6. The number of myotubes then rapidly increased until day 10. Additional cell culture became impossible because the cells were detached from the culture dish. The short axis length of the cultured cells reached a maximum of 59.4 +/- 5.2 microns on day 8 in the CGRP (10 nM) group. This value was significantly greater than that in the control group (43.7 +/- 3.9 microns). The ratio of Mb content/DNA content in the cultured cells increased in all of the groups and reached a maximum of 13.6 +/- 0.4 x 10(-2) ng.Mb/microgram.DNA in the CGRP (10 nM) group on day 10. This value was approximately 3 times higher than that in the control group (4.7 +/- 0.3 x 10(-2) ng.Mb/microgram.DNA).(ABSTRACT TRUNCATED AT 250 WORDS)

Randomised study of immunotherapy with OK-432 in uterine cervical carcinoma.

OK-432, a streptococcal preparation, was administered to patients with stage Ib and II cervical carcinoma except for adeno- and adenosquamous carcinomas. To evaluate the efficacy of OK-432 precisely, 177 patients were stratified by clinical stage, radiotherapy, and lymph node metastasis after complete radical hysterectomy and pelvic lymphadenectomy. Within each stratum, patients were divided randomly into OK-432 and control groups. 85 patients received OK-432 and 92 patients did not. No significant difference was observed in overall 5-year disease free rates between the OK-432 and the control groups, although the mean diameter of erythema on SU-polysaccharide (SU-PS) skin test was larger in the OK-432 group than in the control group. In stage IIb, a significant difference was observed between the OK-432 and control groups. This difference, however, could be attributed in part to the different incidence of the lymph node metastasis. In stage II without lymph node metastasis, 5-year disease free rate was significantly higher in the OK-432 group.