GTT1/StarD7, a novel phosphatidylcholine transfer protein-like highly expressed in gestational trophoblastic tumour: cloning and characterization

We report the cDNA cloning and characterization of GTT1/StarD7, a novel gestational trophoblastic tumour gene, initially identified by its up-regulated expression in the choriocarcinoma JEG-3 cell line with respect to their nonmalignant counterpart, complete hydatidiform mole and normal trophoblastic tissue. Using the differential display fragment as a probe we screened placenta and HeLa cDNA libraries and isolated a clone carrying a 3315 bp insert (accession number AF270647). This cDNA encodes a protein of 295 amino acid residues with a molecular weight of approximately 34.7 kDa and a pI of 5.79. Computer-mediated homology search revealed that the deduced amino acid sequence had similarity to phosphatidylcholine transfer protein (PCTP) with a conserved StAR-related lipid transfer (START) domain extending between the amino acids 66 to 250. The GTT1 gene contains at least 9 exons spread nearly 30 kb on chromosome 2p12-2p11.2. Northern blot assays of total RNA derived from normal early placenta (NEP), complete hydatidiform mole (CHM) and JEG-3 cell line revealed a 3.5 kb mRNA expressed exclusively in the JEG-3 cell line. However, semiquantitative RT-PCR analysis performed with the same RNA samples demonstrated GTT1 expression throughout all of them with the highest level in JEG-3 cell line. Examination of GTT1 mRNA expression by semiquantitative RT-PCR assays in a series of tumour cell lines indicated wide-spread GTT1 expression with predominance in both choriocarcinoma JEG-3 and JAR cells, colorectal adenocarcinoma HT29 and hepatocellular carcinoma HepG2 cells. In conclusion, the highly GTT1 expression profile in JEG-3 and JAR cell lines and its lipid binding domain suggest that GTT1 may play an important role in the phospholipid-mediated signalling of trophoblastic tumour cellular events.     

X chromosomal and autosomal loss of heterozygosity and microsatellite instability in human cervical carcinoma

The study analyzes tumor material and normal tissue from 27 patients with pure squamous cell carcinoma of the uterine cervix for loss of heterozygosity (LOH) and microsatellite instability (MSI) on 14 autosomal and 11 X chromosomal loci. Overall, 4-40% of the informative cases showed LOH at autosomal regions with the highest frequency at 3p (21-40%) and a marked frequency at 2q35-q37.1 (12.5%) and 17p13.3 (10%), representing regions with putative tumor suppressor gene (TSG) function. The frequency of X chromosomal LOH ranged from 4% to 20%, with a maximum at Xq28 (20%) and Xq11.2-q12 (17%), again indicating alterations in TSG. A 12% LOH was seen at Xq21.33-q22.3, a region encoding a protein with a regulatory function in the cell cycle via cyclin-dependent kinases. MSI was detected in autosomal regions in up to 7% in regions linked to the X chromosome in up to 11%, probably indicating alterations of mismatch repair mechanisms. Our results and those obtained from the literature suggest that autosomal LOH and MSI in carcinomas of the cervix uteri are predominantly found at regions with putative TSG function. Beside TSG alterations, X chromosomal LOH is probably more strongly connected to disturbances in cell cycle regulation.     

Molecular genetic analysis of malignant ovarian germ cell tumors

OBJECTIVE: Relatively little is known about the molecular mechanisms involved in the initiation and progression of ovarian germ cell tumors (OGCTs), in contrast to testicular germ cell tumors (TGCTs) which have been extensively investigated. Ovarian germ cell tumors share many pathological and biological features with TGCTs and it is likely that they share similar molecular genetic alterations, although this has not been studied in detail. The aim of this study was to compare and contrast loss of heterozygosity (LOH) in OGCTs at chromosomal regions that are commonly involved in TGCTs. METHODS: Universal amplification was performed on 35 paired specimens of malignant OGCT and constitutional DNA that had been microdissected from single paraffin-embedded tissue sections in 32 patients. Sixty-two microsatellite markers were used to assess LOH at chromosomal regions mapping to 3q, 5q, 9p, 11p, 11q, 12q, 17p, and 18q as these are commonly involved in testicular germ cell tumors. RESULTS: Assessment of these regions demonstrated common sites of deletion at 3q27-q28 (50%), 5q31 (33%), 5q34-q35 (46%), 9p22-p21 (32%) and 12q22 (53%) in all histological subtypes of OGCT. We and others have previously found these regions to be frequently deleted at early stages of tumor development in TGCTs. CONCLUSIONS: These chromosomal regions may contain tumor suppressor genes that are important in the initiation and progression of both malignant OGCTs and TGCTs.     

Gestational trophoblastic disease

Most women with gestational trophoblastic disease are of reproductive age. Because the disease is readily treatable with favourable prognosis, fertility becomes an important issue. Hydatidiform mole is a relatively benign disease, and most women do not require chemotherapy after uterine evacuation. A single uterine evacuation has no significant effect on future fertility, and pregnancy outcomes in subsequent pregnancies are comparable to that of the general population, despite a slight increased risk of developing molar pregnancy again. If women develop persistent trophoblastic disease, single or combined chemotherapy will be needed. Although ovarian dysfunction after chemotherapy is a theoretical risk, a term live birth rate of higher than 70% has been reported without increased risk of fetal abnormalities. Successful pregnancies have also been reported after choriocarcinoma. Only a few case reports have been published on fertility-sparing treatment in placental-site trophoblastic tumour, and the successful rate is about 67%. Women are advised to refrain from pregnancy for at least 6 months after a molar pregnancy, and at least 12 months after a gestational trophoblastic neoplasia. Most of the contraceptive methods do not have an adverse effect on the return of fertility. Finally, at least one-half of these women suffer from some form of psychological or sexual problems. Careful counselling and involvement of a multi-disciplinary team are mandated.     

Pathology of gestational trophoblastic tumors

Gestational trophoblastic tumours result from an abnormal proliferation of different types of trophoblasts. The morphological pattern, together with the immunohistochemical aspect, the cytogenetic data and the clinical profile, helps identify each pathological entity. Hydatiform moles represent malformed placentas caused by genetic aberrations of the villous trophoblast. A complete hydatiform mole displays an hydropic degeneration of all the chorionic villi with a more or less marked proliferation of trophoblasts. A partial hydatiform mole is made up of molar vesicles interspersed with normal chorionic villi. In an invasive hydatiform mole or chorioma destruens, molar vesicles penetrate the myometrium giving rise to a mass distorting the uterine wall. A choriocarcinoma is a malignant proliferation of atypical villous trophoblasts without villi formation. Necrosis, haemorrhage, vascular invasion and distant metastases strongly compromise its outcome. A trophoblastic implantation site tumor, clearly less frequent, results from a proliferation of extravillous trophoblasts, particular for their secretion of human placental lactogen hormone (hPL). This tumour, exceptionally malignant, should be differentiated from the exaggerated placental site and its variants. Except for the placental site trophoblastic tumour, and whatever the outcome (benign or malignant), all gestational trophoblastic tumours secrete the beta-subunit of the chorionic gonadotropic hormone (beta-hCG) more or less abundantly. The serum or urinary level of this unit is proportional to the tumour volume and represents a fundamental basis for the follow-up of these tumours. Multidisciplinary care of high-risk cases allows us to cure the disease, and helps the patient recover her reproductive uterine function.     

Observations on molar pregnancy in Enugu, Nigeria

Forty-one molar pregnancies seen at the University Teaching Hospital Enugu, Nigeria during the 10-year period 1976-1985 are analyzed. The incidence of hydatidiform mole was 0.82 per 1000 pregnancies. The incidence of molar pregnancy was lowest among teenage women and increased markedly with advancing age over 35 years. Hyperemesis gravidarum, a relatively uncommon finding in Nigerian women during normal pregnancy was a prominent feature of molar pregnancy in the women. The incidence of postmolar gestational trophoblastic disease was 17%; choriocarcinoma occurred in 7% of the subjects. Molar pregnancy and postmolar malignant trophoblastic disease occurred much less frequently among the Igbo women of Enugu than the Yorubas of western Nigeria. Earlier and better recognition and treatment of hydatidiform mole will probably result in a decrease in the high rate of complications found during this study.     

Expression of HOX gene products in normal and abnormal trophoblastic tissue

OBJECTIVE: The expression pattern of three homeobox genes products, HOX A11, HOX B6, and HOX C6, was examined in normal human placental tissue and abnormal trophoblastic tissue derived from complete hydatidiform moles and choriocarcinoma tumors. We sought to determine whether expression of these gene products during different states of trophoblastic differentiation and proliferation is constant or demonstrates variation. Variation in expression of these respective homeobox genes may provide insight into predicting which molar tissues are likely to develop into choriocarcinoma tumors. METHODS: Tissue sections from a total of 12 samples were studied. Among these, six full-term human placentas, three complete hydatidiform moles, and three choriocarcinoma tumors were examined for expression of the homeobox HOX A11, HOX B6, and HOX C6 gene products, using immunohistochemistry staining methods. RESULTS: Expression of HOX homeobox gene products, HOX A11, HOX B6, and HOX C6, was detected in full-term human placenta and tissue from complete hydatiform moles. Abnormal trophoblasts from complete moles demonstrated an immunoreactivity expression pattern comparable to that of normal trophoblasts from term pregnancies. However, definitive expression of these respective homeobox genes was not identified in tissue obtained from choriocarcinoma tumors. CONCLUSION: Variation in expression of HOX homeobox gene products, HOX A11, HOX B6, and HOX C6, was established in trophoblast tissue obtained from full-term human placentas, complete hydatiform moles, and choriocarcinoma tumors. This finding indicates that normal full-term trophoblasts and abnormal molar trophoblasts may share similar fundamental regulatory control mechanisms. The absence of definitive expression of these HOX gene products in trophoblastic cells derived from choriocarcinoma tumors indicates that while HOX A11, HOX B6, and HOX C6 genes may be involved in maintenance of some trophoblastic cell states, they may be either downregulated or have alterations in their expression in trophoblasts from choriocarcinoma tumors.     

Trophoblastic disease: analysis of 342 patients

The registry for trophoblastic disease in Wakayama, Japan was formed and 342 cases were analyzed. The total number of trophoblastic disease was 342 during 6 years (1972-1977). The number of hydatidiform moles, invasive moles, choriocarcinoma and transitional moles was 278 (81.3%), 28 (8.2%), 18 (5.3%) and 12 (3.5%), respectively. The greatest number of hydatidiform moles occurred in the range 25-29 years inclusive. The percentage of patients with hydatidiform moles over 45 years of age was significantly high. The incidence of malignant complications (invasive moles and choriocarcinoma) of hydatidiform moles was 16.5% in 284 molar pregnancies. The frequency of malignant complications was remarkably high in women over 40 years of age. Thus the epidemiologic study of trophoblastic disease might turn up some important data and the importance should be emphasized.     

Current understandings of the molecular genetics of gestational trophoblastic diseases

Gestational trophoblastic disease (GTD) is a heterogeneous group of diseases characterized by abnormally proliferating trophoblastic tissues. This includes partial and complete hydatidiform moles, invasive mole, choriocarcinoma and placental site trophoblastic tumour. Cytogenetic studies revealed that hydatidiform moles contain either solely (as in complete moles) or an excess (as in partial moles) of paternal contribution to the genome. Genomic imprinting is believed to play a pivotal role in the pathogenesis of hydatidiform moles. However its precise role and mechanism remains poorly understood. Hydatidiform mole carries a potential of malignant transformation. Similar to other human cancers, malignant transformation in gestational trophoblastic tumours is likely a multistep process and involves multiple genetic alterations including activation of oncogenes and inactivation of tumour suppressor genes. In addition, expression of telomerase activity, altered expression of cell--cell adhesion molecules and abnormal expression of matrix metalloproteinases have also been reported in GTD. These represent disruption of the delicate balance and regulation of cellular processes including proliferation, differentiation, apoptosis and invasion. The significance of these alterations in the pathogenesis and malignant transformation of gestational trophoblastic diseases is reviewed in this paper.     

Frequent allelic imbalance of tumor suppressor gene loci in cervical dysplasia.

In addition to human papillomavirus (HPV) infection, loss of heterozygosity (LOH) at tumor suppressor gene loci has been frequently observed in cervical cancer. Thus, it may be assumed that detection and characterization of specific LOH profiles in preneoplastic lesions, in addition to HPV typing, might facilitate assessment of progression risk of cervical dysplasia. In this study, the type and frequency of allelic imbalance (allelic loss or allelic reduction) were analyzed in 24 unrelated cervical lesions using 14 polymorphic microsatellite markers at different tumor suppressor gene loci. No allelic loss was observed in four condylomatous lesions, whereas 2 of 13 (15%) CIN I lesions displayed allelic loss at 3p25 and 5q11-13. In high-grade lesions, however, allelic loss occurred in four of six (66%) cases at multiple chromosomal regions (3p14-25, 5p15, 5q11, 5q21, 11p15, and 17q21). Allelic reduction was observed in 4 of 13 (30%) low-grade lesions and 3 of 6 (50%) high-grade lesions. LOH was confined to lesions infected by high-risk HPV types. These data suggest that chromosomal instability is an early event in cervical carcinogenesis. The detection of LOH on multiple chromosome 3p loci in 50% of high-grade lesions suggests that a specific marker panel encompassing this region might enable better assessment of which lesions are likely to regress, persist, or progress.     

Choriocarcinoma diagnostic score: A scoring system to differentiate choriocarcinoma from invasive mole

Okamoto T, Nomura S, Nakanishi T, Goto S, Tomoda Y, Mizutani M. Choriocarcinoma diagnostic score: A scoring system to differentiate choriocarcinoma from invasive mole. Int J Gynecol Cancer 1998; 8 : 128–132.
The histologic diagnosis of choriocarcinoma has been reported to be one of the prognostic factors for the treatment outcome of gestational trophoblastic tumors (GTT). A scoring system, called the choriocarcinoma diagnostic score (CD score), which had been devised to differentiate choriocarcinoma from invasive mole, was reevaluated in patients with GTT treated at Nagoya University Hospital from 1964 to 1996. There were 134 cases with pathologic documentation of choriocarcinoma and 155 cases of invasive mole. Sensitivity of the CD score (ie the true positive rate for the histologic diagnosis of choriocarcinoma) was 94.0%, and specificity of the score (ie true positive rate for the histologic diagnosis of invasive mole) was 97.4%. Thus, the accuracy of the score was very high (95.8%). Seventy-two (91.2%) of 79 cases with high CD scores (10 points or more) were categorized into high-risk or very high-risk groups according to the World Health Organization (WHO) prognostic index score. This unique scoring system should be included in the management of patients with GTT.     

Array comparative genomic hybridization analysis of uterine leiomyosarcoma

PURPOSE: Using a genome-wide array-based comparative genomic hybridization (array-CGH), DNA copy number changes in uterine leiomyosarcoma were analyzed. MATERIALS AND METHODS: We analyzed 4 cases of uterine leiomyoma and 7 cases of uterine leiomyosarcoma. The paraffin-fixed tissue samples were microdissected under microscope and DNA was extracted. Array-based CGH and fluorescence in situ hybridization (FISH) were carried out with Genome database (Gene Ontology). RESULTS: Uterine leiomyoma showed no genetic alterations, while all of 7 cases of uterine leiomyosarcoma showed specific gains and losses. The percentage of average gains and losses were 4.86% and 15.1%, respectively. The regions of high level of gain were 7q36.3, 7q33-q35, 12q13-12q15, and 12q23.3. And the regions of homozygous loss were 1p21.1, 2p22.2, 6p11.2, 9p21.1, 9p21.3, 9p22.1, 14q32.33, and 14q32.33 qter. There were no recurrent regions of gain, but recurrent regions of loss were 1p21.1-p21.2, 1p22.3-p31.1, 9p21.2-p22.2, 10q25-q25.2, 11q24.2-q25, 13q12-q12.13, 14q31.1-q31.3, 14q32.32-q32.33, 15q11-q12, 15q13-q14, 18q12.1-q12.2, 18q22.1-q22.3, 20p12.1, and 21q22.12-q22.13. In the high level of gain regions, BAC clones encoded HMGIC, SAS, MDM2, TIM1 genes. Frequently gained BAC clone-encoded genes were TIM1, PDGFR-beta, REC Q4, VAV2, FGF4, KLK2, PNUTL1, GDNF, FLG, EXT1, WISP1, HER-2, and SOX18. The genes encoded by frequently lost BAC clones were LEU1, ERCC5, THBS1, DCC, MBD2, SCCA1, FVT1, CYB5, and ETS2/E2. A subset of cellular processes from each gene was clustered by Gene Ontology database. CONCLUSION: Using array-CGH, chromosomal aberrations related to uterine leiomyosarcoma were identified. The high resolution of array-CGH combined with human genome database would give a chance to find out possible target genes present in the gained or lost clones.     

Persistent gestational trophoblastic tumor after partial hydatidiform mole

The current study investigates the clinical characteristics of patients with partial molar pregnancy who developed persistent gestational trophoblastic tumor (GTT). Between January 1979 and January 1989, 16 of 240 (6.6%) patients, who were followed for partial mole, developed persistent GTT. Fifteen (94%) patients were diagnosed as having a missed abortion before evacuation and only 1 patient presented with excessive uterine size and theca lutein ovarian cysts and was felt to have molar disease. No patient presented with toxemia, hyperemesis, or hyperthyroidism. All 16 patients developed nonmetastatic GTT. Fifteen patients achieved complete remission with methotrexate-citrovorum factor and only 1 patient required combination chemotherapy to attain remission. None of the patients had histologic evidence of choriocarcinoma. Patients with partial mole who developed persistent GTT did not have clinical or pathological characteristics that distinguished them from other patients with partial mole. All patients with partial mole should be followed with measurement of hCG levels to assure gonadotropin remission.     

恶性滋养细胞肿瘤脑转移的疗效分析

目的 评价恶性滋养细胞肿瘤转移患者的临床特性、预后影响因素、治疗方法及疗效。方法 回顾性分析了1984年12月至1998年12月我院收治的恶性滋养细胞肿瘤患者814例中发生脑转移的69例患者的临床资料。其中,绒毛膜癌382例,发生脑转移者61例（16．0％）;侵蚀性葡萄胎432例,发生脑转移者8例（1．9％）。根据患者曾否接受化学治疗（化疗）及脑转移出现的时间,将所有转移患者分为3组,即诊断脑转移后于本院治疗前未曾接受化疗者共30例（A组）;诊断脑转移后本院治疗前曾接受化疗者共31例（B组）;在我院化疗期间出现脑转移者共8例（C组）。除12例入院时已濒临死亡,未及化疗或仅接受1个疗程化疗即死亡外,其余57例均接受了以5－氟尿嘧啶为主的联合化疗或足叶乙甙、甲氨喋呤、更生霉素／环磷酰胺及长春新碱方案（EMA／CO）3－17个疗程,平均8．2个疗程,同时辅以蛛网膜下腔穿刺鞘内注射甲氨喋呤治疗。69例中有4例患者因颅内压急剧增高,濒临脑疝形成而急诊进行了开颅去骨瓣减压及转移瘤切除术。结果 除12例患者未经正规化疗即死亡外,57例患者化疗后缓解率为71．9％（41／57）。随诊按57例患者的5年累积生存率为45．8％。A、B、C3组患者的缓解率分别为80．0％（24／30）、54．8％（17／31）及8例中0例（A与B组比较,P＜0．05;A或B组比较,P＜0．01）。结论 恶性滋养细胞肿瘤脑转移预后较差,重视早期诊断与及时有效的化疗是改善预后的关键;多药联合全身化陪结合鞘内化疗仍是治疗的主要方法;对颅内压过高濒临脑疝形成的患者,急诊开颅手术结合化疗是挽救患者生命的重要途径。     

Chromosome 4 deletions are frequent in invasive cervical cancer and differ between histologic variants

OBJECTIVE: Patterns of discontinuous deletion of chromosome 4 have been described in histologic variants of lung carcinomas and may represent different "hotspot" targets for gene-environment interactions. Since similar environmental risks exist for cervical cancer, we investigated patterns of discontinuous deletion in two major histologic variants. METHODS: Thirteen archival cases of squamous cell cancer (SCCA) and 11 cases of adenocarcinoma (AC) were precisely microdissected. Matched normal and tumor DNA were used for polymerase chain reaction (PCR) based loss of heterozygosity (LOH) analyses using 19 polymorphic markers spanning chromosome 4. Human papillomavirus (HPV) detection was determined by PCR using general and type-specific primers (HPV 16, 18). Differences in LOH between histologic tumor types and chromosomal regions were determined using Fisher's exact test. RESULTS: Loss at any chromosome 4 locus occurred in 92% of all tumors studied, with the majority of deletions occurring on the long arm of the chromosome. Four discrete minimal regions of discontinuous deletion (R) were identified. For these regions, LOH frequencies were 76% (R1, 4q34-q35), 48% (R2, 4q25-q26), 36% (R3, 4p15.1-p15.3), and 26% (R4, 4p16). Loss in SCCA predominated at 4q (4q34-q35; 83%) and in AC at 4p (4p15.3; 50%). Overall LOH on the p arm was significant in AC (82%) compared to SCCA (31%) (P = 0.02). HPV detection was similar in SCCA (85%) and AC (73%), and HPV 16/18 subtypes were similarly represented in both histologies. CONCLUSIONS: Chromosome 4 deletions are frequent in cervical carcinomas. Different patterns of deletion between SCCA and AC may represent gene regions targeted by different gene-environment interactions in these tumor subtypes.     

Evaluation of a region on chromosome 1p in ovarian serous carcinoma that is frequently deleted in uterine papillary serous carcinoma.

OBJECTIVE: The goal of this study was to assess the involvement of chromosome 1p deletion in ovarian papillary serous carcinoma (OPSC) via high-resolution physical mapping to detect a candidate tumor suppressor gene previously implicated in uterine papillary serous carcinoma (UPSC) tumorigenesis. METHODS: Previous studies have demonstrated a high rate of loss of heterozygosity (LOH) within a critical region of chromosome 1p in UPSC, suggesting the presence of a putative tumor suppressor gene important in the development of UPSC. To compare the genetic changes in OPSC with those in UPSC, seven microsatellite repeat polymorphisms were used to evaluate LOH in primary OPSC specimens. Allelic intensity was compared between normal and tumor DNA from microdissected, formalin-fixed, paraffin-embedded specimens. In addition to the same seven 1p markers used for UPSC, three additional non-1p markers for chromosomes 1q, 11q, and 2p were tested to determine a baseline rate of LOH. RESULTS: Overall, 26.6% (8/30) of OPSC (vs 63.2% of UPSC) were characterized by loss at either of the two loci that define the critical region for UPSC. Rates of LOH at each of the 1p loci in the OPSC tumors ranged from 5.6 to 38.9%, which are compatible with background rates of loss for OPSC. LOH at non-1p loci was 29.2%. CONCLUSION: While a tumor suppressor gene on 1p appears to be an important genetic event in the development of UPSC, a similar rate and pattern of loss on 1p are not identified in OPSC. Thus, despite the striking clinical similarities between UPSC and OPSC, tumorigenesis in these carcinomas appears to occur via distinctly different pathways.     

Levels of placenta-specific tissue protein 12 (PP12) in serum during normal pregnancy and in patients with trophoblastic tumour

A sensitive radioimmunoassay method has been developed to measure soluble placental protein 12. Using this method trace amounts of PP12 have also been detected in the sera of healthy non-pregnant subjects (24.0 +/- 6.15 micrograms/l). During normal pregnancy serum PP12 levels rose rapidly reaching a peak value of 139.90 +/- 40.26 micrograms/l at 18 weeks. Serial determinations of PP12 have been made in 31 patients with trophoblastic tumours (16 hydatidiform moles, 10 invasive moles and five choriocarcinomas). It has been found that in patients with hydatidiform and invasive moles its initial values are extremely high (342.9 +/- 257.9 micrograms/l and 279.3 +/- 103.1 micrograms/l, respectively), much exceeding the non-pregnant and normal pregnant values. After evacuation of hydatidiform moles serum-PP12 rapidly fell to the upper limit of normal at 21-28 days, and to normal values at 8-12 weeks after operation. In patients with invasive mole requiring chemotherapy the rate of fall of PP12 level was slower. In patients with choriocarcinoma serum-PP12 levels were moderately raised (59-132 micrograms/l) and followed the clinical course of the disease. Serum-PP12 levels would seem to be of less value in monitoring patients with trophoblastic tumours than other tumour-markers (hCG, and SP1).     

EMA/EP chemotherapy for chemorefractory gestational trophoblastic tumor

OBJECTIVE: To evaluate the results of etoposide/ methotrexate/actinomycin D/etoposide/cisplatin (EMA/ EP) chemotherapy in patients with chemorefractory gestational trophoblastic tumor (GTT). STUDY DESIGN: Fifteen patients with chemorefractory GTT were treated with EMA/EP. RESULTS: Twelve of the 15 cases were choriocarcinoma, and the last 3 were metastatic placental site trophoblastic tumor (PSTT): International Federation of Gynecology and Obstetrics (FIGO) stage I, 2 cases; stage III, 10 cases; stage IV, 3 cases. Seven cases have FIGO score 7-10; the scores of the remaining 8 cases were > 10. Fifteen patients received a total of 93 cycles of the study regimen. The median number of courses for each patient was 6.2. Eleven cases (73.3%) achieved complete remission, while 3 (20%) had partial remission; 1 case (6.7%) showed no response. The main complications of EMA/EP chemotherapy were myelosuppression and gastrointestinal symptoms. CONCLUSION: The EMA/EP regimen is effective for chemorefractory GTT, and the chemotherapeutic results can be improved when combined with surgery and arterial infusion chemotherapy in selected patients. The EMA/EP regimen should be considered for primary management of metastatic PSTT.     

EMA/EP方案治疗耐药性滋养细胞肿瘤疗效的初步分析

目的 分析足叶乙甙 甲氨蝶呤 放线菌素D／足叶乙甙 顺铂(EMA／EP)方案治疗耐药性恶性滋养细胞肿瘤的疗效。方法 回顾性分析了15例耐药性恶性滋养细胞肿瘤患者,采用EMA／EP方案化疗,部分患者辅以手术或超选择性动脉插管化疗,观察其疗效及毒副反应。结果 15例患者化疗的平均疗程数为6．2个,化疗后11例获完全缓解(73％),3例部分缓解(20％),1例无效(7％)。其中,3例转移性胎盘部位滋养细胞肿瘤(PslTr)经EMA／EP方案治疗后均完全缓解。该方案的主要毒副反应为骨髓抑制及消化道反应。结论 EMA／EP是治疗耐药性恶性滋养细胞肿瘤患者的有效方案。对于转移性PSTT患者EMA／EP可作为首选化疗方案。     

Estrogen and progesterone receptors and telomerase enzyme immunohistochemical detection in gestational trophoblastic tumors

The purpose of this study is to evaluate the immunohistochemical detection of telomerase enzyme and estrogen receptor (ER) and progesterone receptor (PGR) in gestational trophoblastic neoplasia (GTN) and its clinical significance. Formalin-fixed paraffin blocks for 30 patients (24 with molar pregnancy, 3 with choriocarcinoma, and 3 with placental site trophoblastic tumor) as cases and six products of conception samples from patients with incomplete abortion as controls were included in the study. Immunohistochemical detection of the telomerase catalytic protein and ER and PGR was carried out using streptavidin-biotin-peroxidase method. All control tissues were negative for telomerase and ER expression, while five of six were PGR positive. Significant positive telomerase expression was detected in all gestational trophoblastic tumors (three of six partial moles, 12 of 18 complete moles, three of three choriocarcinomas, and two of three placental site trophoblastic tumors). Nine of 24 molar pregnancies were followed by GTN. Molar pregnancies followed by GTN were associated with higher serum beta-hCG (human chorionic gonadotrophic hormone), larger uterine size for gestational age, negative ER expression, negative PGR expression, and positive telomerase expression. All patients with molar pregnancy with negative telomerase expression (9 of 24) showed spontaneous regression after evacuation. Positive telomerase expression and its immunohistochemical detection are associated with the development of GTN. Negative telomerase expression is highly predictive of postmolar spontaneous regression. Patients with molar pregnancies with negative telomerase expression can be saved the long-term follow-up. ER and PGR expression do not show a significantly different pattern in molar tissues, while negative expression is associated with developing GTN. Cautions on the use of postmolar hormonal contraception may be unjustified.