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ABSTRACT: This study compared subsequent pregnancy outcome in patients with complete and partial hydatidiform moles. Among 1052 patients with molar pregnancy (complete mole, 801; partial mole, 251) monitored at Chiba University Hospital between 1981 and 1999, 891 patients (84.7%) had spontaneous resolution of human chorionic gonadotrophin (HCG) after mole evacuation, and 161 patients (15.3%) required chemotherapy. Of the 891 patients, 438 (49.2%) had 650 subsequent pregnancies. The pregnancy outcome was not significantly different in patients with complete and partial moles, and was comparable with that in the general Japanese population. The incidence of repeat molar pregnancy in patients with complete and partial mole (1.3 and 1.5% respectively) was 5-fold higher than that of the general population, while no increased risk of persistent gestational trophoblastic tumour (GTT) associated with later molar pregnancy was observed. During HCG follow-up, 10 patients (1.1%) developed secondary high-risk GTT between 14 and 54 months after mole evacuation. The incidence of high-risk GTT in patients with and without subsequent pregnancies was 0.46% (2/438) and 1.8% (8/453) respectively (P = 0.1243). In conclusion, patients with complete and partial mole can anticipate a normal future reproductive outcome, and pregnancies after experiencing hydatidiform mole may not affect the development of high-risk GTT.
Human Reproduction 07/2001; 16(6):1274-7. · 4.47 Impact Factor
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ABSTRACT: To evaluate the efficacy of adjuvant hysterectomy with chemotherapy for women with low-risk gestational trophoblastic disease.
One hundred fifteen consecutive Japanese women (16-52 years old) with low-risk gestational trophoblastic disease (46 with metastatic disease and 69 without) were treated initially with single-agent chemotherapy (etoposide in 85, methotrexate in 27, and actinomycin D in three) with or without adjuvant hysterectomy, and 97 patients (84.3%) achieved primary remission with those treatments. Eight women (9.4%) treated with etoposide required other regimens because of drug resistance or toxicities. The total dose of etoposide given to achieve primary remission was analyzed in 77 women who received etoposide alone or with adjuvant hysterectomy.
In 34 women with metastatic disease, the mean (+/- standard deviation [SD]) total dose of etoposide was not significantly different with and without adjuvant hysterectomy (2857 +/- 842 mg versus 2815 +/- 815 mg; P =.957; Mann-Whitney U test). However, in 43 women without metastases, the total dose of etoposide was significantly less in those who had adjuvant hysterectomies than in those who did not (1750 +/- 635 mg versus 2545 +/- 938 mg; P <.05; Mann-Whitney U test).
Adjuvant hysterectomy decreased the total dose of etoposide given to achieve primary remission in women with nonmetastatic, low-risk gestational trophoblastic disease. If the lesions of gestational trophoblastic disease are confined to the uterus and the woman has no desire to preserve fertility, she should be informed of adjuvant hysterectomy as a treatment option.
Obstetrics and Gynecology 04/2001; 97(3):431-4. · 4.73 Impact Factor
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ABSTRACT: The goal of this study was to evaluate the efficacy, toxicity, and survival of patients with high-risk gestational trophoblastic tumors (GTTs) treated with a methotrexate-etoposide-actinomycin D (MEA) regimen without cyclosphosphamide or vincristine.
Thirty-nine consecutive patients with high-risk GTTs (28 were defined high risk by WHO criteria) were treated with primarily the MEA regimen. Among them, 27 patients had received no prior chemotherapy and 12 had received prior chemotherapy. Survival, causes of treatment failure, and toxicity were analyzed retrospectively.
After treatment with the MEA regimen, 29 of 39 patients achieved primary remission (74.4%), 8 developed resistance (20.5%), and 2 died of widespread metastases and chemotherapy-related toxicity. All 8 patients who developed resistance were treated with high-dose 5-fluorouracil and actinomycin D (FA); 6 were salvaged and 2 died of refractory disease. Three patients relapsed; 2 were controlled with FA or cisplatin-based chemotherapy and 1 who refused further treatment died. The disease-free survival rate was 87%. WHO grade 4 leukocytopenia and thrombocytopenia with the MEA regimen occurred in 5.3 and 6.4%, respectively, of the cycles; other toxic effects were acceptable and manageable.
At present, MEA chemotherapy (without cyclophosphamide or vincristine) is our treatment of choice for patients with high-risk GTT. Its toxicity is predictable and manageable. For patients who become resistant to MEA, new salvage chemotherapy regimens are needed.
Gynecologic Oncology 08/2000; 78(1):28-31. · 3.89 Impact Factor
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ABSTRACT: The Ncx gene encodes a homeobox containing transcription factor that belongs to the Hox11 gene family. We determined specific Ncx protein binding consensus DNA sequences. Optimal Ncx binding sequences were 5'-CGGTAATTGG-3' (TAAT core) and 5'-CGGTAAGTGG-3' (TAAG core), which coincided with the Hox11 binding sequence. Both Ncx and Hox11 could bind to the TAAT and the TAAG core oligonucleotide in vitro. However, they could efficiently transactivate the reporter plasmid linked to the TAAT core sequence but not to the TAAG core sequence. Thus, Ncx and Hox11 act as transcriptional activators via their target sequence, 5'-CGGTAATTGG-3'.
FEBS Letters 07/2000; 475(3):170-4. · 3.54 Impact Factor
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ABSTRACT: The aim of this study was to evaluate the clinical course and the management policy of complete mole coexistent with a twin live fetus confirmed with DNA polymorphism in a single hospital.
From 1981 to 1995, six patients with androgenetic complete hydatidiform mole coexistent with a twin live fetus were diagnosed by DNA polymorphism analysis. The clinical course of these six patients was analyzed.
Two patients chose to terminate pregnancies and four patients desired to continue the pregnancy. However, the pregnancy had to be interrupted in two patients because of severe preeclampsia and sudden intrauterine fetal death. In two patients, fetuses were growing unremarkably and normal babies were delivered at term. The development of persistent trophoblastic tumor (PTT) in these rare pregnancies was higher (50.0%: 3/6) than that of single complete mole. In three patients, serum hCG titers during pregnancy were monitored. Although serum hCG levels progressively decreased during pregnancy in one patient without PTT, hCG levels initially decreased, but subsequently increased or showed a plateau with advancing gestational age in two patients with PTT.
In patients with complete mole coexistent with a live fetus, the pregnancy may be allowed to continue when the fetal karyotype and development are normal and serum hCG titers are constantly falling with advancing gestational age.
Gynecologic Oncology 09/1999; 74(2):217-21. · 3.89 Impact Factor
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ABSTRACT: The murine Ncx (Enx, Hox11L1) gene is specifically expressed in a neuronal subset of neural crest-derived tissues. In attempts to elucidate the regulatory DNA element of the tissue-specific expression, we sequenced the 5'-flanking region of the Ncx gene. The transcriptional initiation site was determined at 297 nucleotides (-297) upstream from the ATG start codon (+1). A retinoic acid response element was located on the region between -1163 and -1150. Transient transfection assays with the 5'-flanking sequences fused to the luciferase gene showed that the region between -1387 and -1368 was crucial for the tissue-specific enhancer activity. Furthermore, nuclear proteins extracted from neural crest-derived cells such as murine and human neuroblastoma cells bind to the DNA region between -1387 and -1368. This DNA element was also conserved in the 5'-flanking region of the human NCX gene. Our observations strongly suggest that the DNA element (between -1387 and -1368) contributes to tissue-specific expression of the Ncx gene in murine and human species.
Journal of Biological Chemistry 09/1999; 274(34):24401-7. · 4.77 Impact Factor
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ABSTRACT: The aim of this study was to evaluate subsequent fertility and pregnancy in patients treated for persistent trophoblastic tumors with single-agent VP-16. Records of all patients treated for persistent trophoblastic tumors at the Chiba University Hospital between January 1, 1986 and December 31, 1997 were reviewed. Of these, 85 patients were initially treated with single-agent VP-16. Subsequent pregnancy outcome of these patients was investigated. After remission with VP-16, 36 patients (92.3%) of those who wished for a pregnancy (45.9% of all patients studied) conceived, and 91.7% had at least one live birth. A total of 56 conceptions resulted in 42 (75.0%) term live births, seven (12.5%) first-trimester spontaneous abortions, one (1.8%) second-trimester spontaneous abortion, four (7.1%) therapeutic abortions, and two (3.6%) repeated moles. There were no congenital anomalies, no stillbirths, and the neonates' physical growth was comparable to that of the standard population in Japan. Single VP-16 regimen for patients with low-risk gestational trophoblastic tumor appears to have no adverse effects on fertility potential and pregnancy outcome.
International Journal of Gynecological Cancer 04/1999; 9(2):166-169. · 1.65 Impact Factor
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ABSTRACT: We applied deoxyribonucleic acid polymorphism analysis on the basis of differences in the number of short tandem repeat sequences to genetically differentiate dizygotic twins with complete hydatidiform moles and normal fetuses from partial moles presenting a similar appearance.
Six pregnant women exhibiting apparent moles and coexisting fetuses were the subjects of this study. Eight polymorphic loci including short tandem repeat sequences were amplified by polymerase chain reaction from deoxyribonucleic acid of peripheral leukocytes of parents, umbilical cord, grossly normal placenta-villi, and molar tissue. The segregation of alleles among samples were determined by comparing band patterns on polyacrylamide gels.
In all 6 cases amplifications of polymorphic loci provided sufficient information to determine the parental origin. At informative loci the alleles of cord and placenta-villi were transmitted from both patients and husbands whereas molar tissue had only paternal alleles. These allele segregations indicated 2 different genetic origins, namely, normal parental for a fetus and androgenetic for molar tissue, and thus the diagnosis of dizygotic twins with a complete hydatidiform mole and a normal fetus was made. Additionally, the molar component was defined as a heterozygous mole in 2 cases.
Short tandem repeat-derived deoxyribonucleic acid polymorphism analysis was demonstrated to be a useful and precise procedure for the differential diagnosis of a complete hydatidiform coexisting with a normal fetus and the determination of its zygosity as well.
American Journal of Obstetrics and Gynecology 10/1998; 179(3 Pt 1):628-34. · 3.47 Impact Factor
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ABSTRACT: To compare the efficiency and toxicity of four chemotherapeutic regimens in low-risk gestational trophoblastic disease.
Since 1974, 247 patients with low-risk gestational trophoblastic disease have been treated with 5-day intramuscular methotrexate (MTX) (conventional MTX), 5-day intravenous drip infusion of VP-16, 5-day intravenous actinomycin-D (Act-D) or 8-day alternating intramuscular MTX-folic acid (MTX-CF) at Chiba University School of Medicine. We compared the primary remission rate, the response of human chorionic gonadotropin and the prevalence of drug toxicities in these 4 regimens.
The primary remission rate was 73.6% in the conventional MTX regimen, 90.1% in VP-16, 84.0% in Act-D, and 60.0% in MTX-CF. The primary remission rate was significantly higher in the VP-16 and Act-D regimens than in the conventional MTX and MTX-CF regimens. The response rate was significantly higher in the VP-16 regimen than in the other 3 regimens. The drug toxicity with VP-16 and Act-D was less than that with conventional MTX and MTX-CF regimens.
The VP-16 regimen was highly effective and less toxic for gestational trophoblastic disease compared with other chemotherapeutic regimens.
Gynecologic and Obstetric Investigation 02/1998; 46(1):5-8. · 1.28 Impact Factor
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ABSTRACT: The Ncx/Hox11L.1 gene, a member of the Hox11 homeobox gene family, is mainly expressed in neural crest-derived tissues. To elucidate the role of Ncx/Hox11L.1, the gene has been inactivated in embryonic stem cells by homologous recombination. The homozygous mutant mice were viable. These mice developed megacolon with enteric ganglia by age 3-5 wk. Histochemical analysis of the ganglia revealed that the enteric neurons hyperinnervated in the narrow segment of megacolon. Some of these neuronal cells degenerated and neuronal cell death occurred in later stages. We propose that Ncx/Hox11L.1 is required for maintenance of proper functions of the enteric nervous system. These mutant mice can be used to elucidate a novel pathogenesis for human neuronal intestinal dysplasia.
Journal of Clinical Investigation 09/1997; 100(4):795-801. · 15.39 Impact Factor
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ABSTRACT: Matsui H, Iitsuka Y, Seki K, Sekiya S. Etoposide (VP-16) as first-line,single agent chemotherapeutic drug in low-risk gestational trophoblasticdisease. Int J Gynecol Cancer 1997; 7: 400–404.We reviewed the records of 73 patients with low-risk gestationaltrophoblastic disease (GTD) treated with etoposide from 1986 to 1995 at ChibaUniversity. All patients received courses of etoposide every 10 to 14 days until their human chorionicgonadotropin (hCG) concentrations had reached <1 mIU/ml or drug resistanceand/or unacceptable toxicityoccurred. Fifty-one patients (69.9%) were treated with chemotherapyalone and 22 patients (30.1%) also underwent planned hysterectomy.Sixty-seven patients (92%) achieved a primary remission, while sixpatients (8%) required a change in drugs due to drug resistance (4patients, 5%) or toxicity (2patients, 3%). All 73 patients achieved complete remission. However, onepatient (1.4%) relapsed later.We have demonstrated that etoposide is one of the most effective drugsagainst GTD and that the short-term toxicity is, except for alopecia,relatively mild and acceptable.Patients should, however, be informed of the possibilities of secondarymalignancies and followed-up cautiously.
International Journal of Gynecological Cancer 08/1997; 7(5):400 - 404. · 1.65 Impact Factor
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ABSTRACT: We have isolated the murine homeobox gene (Ncx) that belong to a Hox11 gene family. Expression of the Ncx gene was analyzed in total RNAs from embryos by reverse transcribed polymerase chain reaction (RT-PCR). The mRNA was detected in embryos after 9.5 days of embryogenesis (E9.5) and was maximal at E12.5. The RT-PCR also detected the message in total RNAs from adrenal glands and intestine in adult mice. The expression was further examined in various tissues from embryos by in situ hybridization. It was detected in dorsal root ganglia, cranial nerve ganglia (V, IX, X), enteric nerve ganglia and adrenal glands from embryos between E9.5 and E13.5. Since its expression is restricted to tissues derived from neural crest cells, Ncx may play a role in differentiation and proliferation of neural crest lineage cells.
Anatomy and Embryology 06/1997; 195(5):419-25. · 1.42 Impact Factor
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ABSTRACT: HOX11 is identified from the breakpoint of human T cell acute lymphoblastic leukemias with t(10;14). Since overexpression of HOX11 in T cells caused leukemias in transgenic mice, the endogenous HOX11 may play a role in proliferation and differentiation of T cells. In order to elucidate the role, we examined the expression of Hox11 in normal lymphocytes by a reverse transcriptase-polymerase chain reaction analysis. Two alternatively spliced Hox11 mRNAs were expressed in fetal spleens. However, lymphocytes did not express Hox11 mRNA during differentiation. Furthermore, it was not induced in primary lymphocytes after activation. These results suggest that ectopic expression of HOX11 in T cells is responsible for leukemogenesis.
Molecular Immunology 12/1995; 32(16):1177-82. · 2.90 Impact Factor
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ABSTRACT: The diagnosis of a complete hydatidiform mole coexisting with a live fetus is often difficult because of the morphological similarity to a partial mole, but it is crucial to management in the postmolar course. We present a recent case in which DNA polymorphism analysis clearly revealed a different genetic origin for the fetal and molar parts. DNA polymorphisms on three different variable number tandem repeat loci, which were detected by polymerase chain reaction, indicated that the cord/placenta and molar tissue were parental and androgenetic, respectively. Subsequently, the patient was admitted for chemotherapy of metastatic trophoblastic disease.
Gynecologic Oncology 02/1995; 56(1):90-3. · 3.89 Impact Factor
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ABSTRACT: Objectives: To evaluate the spontaneous regression curve of serum human chorionic gonadotropin (hCG) in patients with an uneventful course after evacuation of hydatidiform mole and to compare the criteria for initiating chemotherapy in patients after evacuation of mole. Methods: From 1986 to 2001, 608 patients were followed at our department after evacuation of mole. The spontaneous regression curves of serum hCG in 432 patients with an uneventful course were established. Results: After evacuation of mole, the titers of serum hCG decreased constantly, and 90% of patients with an uneventful course were within normal range within 16 weeks. In 432 patients with an uneventful course, the upper 95% confidence limit of serum hCG at 5, 8 and 20 weeks was 753.7, 422.9 and 14.8 mIU/ml, respectively. Moreover, 39 (9.0%) and 15 patients (3.5%) with an uneventful course might have been diagnosed with gestational trophoblastic tumor and received needless chemotherapy based on the normal regression curve established by the Japan Society of Obstetrics and Gynecology or the US criteria of 4 consecutive plateauing or rising hCG values, respectively. Conclusions: Our more selective criteria for initiating chemotherapy in patients after evacuation of mole, i.e. hCG of 10,000 mIU/ml at 5 weeks, 1,000 mIU/ml at 8 weeks and nondetectable levels at 24 weeks after evacuation of mole, may be safe and acceptable in the management of patients after evacuation of mole.
Tumor Biology 08/1970; 24(3):140-146. · 1.94 Impact Factor
