Worldwide survey of the results of treating gestational trophoblastic disease.

OBJECTIVE: To determine factors influencing outcome for patients with gestational trophoblastic disease (GTD) from throughout the world. STUDY DESIGN: Physicians known to treat GTD were sent a questionnaire. RESULTS: There were 32 responses from 17 countries, totaling 26,153 patients. Of 14,093 patients with complete mole 20.6% developed trophoblastic neoplasia, and 5.7% died. There were 10,230 patients with partial mole, of whom 6.5% received therapy for neoplasia. There were 548 patients with post-term pregnancy choriocarcinoma, of whom 13.4% died. Of 137 patients with placental site trophoblastic tumor 16.1% died. The remaining 1,165 patients did not fit into a designated diagnostic category. The mortality rate for 2,818 patients with GTD primarily treated at a trophoblast center was 2.1%, as compared with 8% among 1,854 patients referred after failure of primary treatment (p < 0.01). CONCLUSION: Patients treated by physicians experienced in the management of trophoblastic disease have better results and survival.

Uracil mustard and 5-fluorouracil combination chemotherapy: a historic record.

BACKGROUND: Uracil mustard and 5-fluorouracil (UM-FU) combination chemotherapy was used as one of the earliest combination chemotherapies in ovarian carcinoma from 1964 to 1971 at Yale New Haven Medical Center. METHODS: UM-FU was offered to patients with stage III and IV, histologically verified, ovarian carcinoma. Uracyl mustard was administered orally--1 mg/ kg, daily. 5-Fluorouracyl was administered every four weeks at 5 mg/kg for five days by intravenous infusion. RESULTS: Of a total 185 patients with ovarian cancer, 76 received UM-FU. Thirty-five patients had measurable disease. Fifteen (42%) showed objective response lasting three to 95 months, with decrease in size of masses and disappearance of ascites or hydrothorax. Their survival from diagnosis to death was 41 months. Twenty patients showed no response; their mean survival was 18 months. Three of the 76 patients who received UM-FU developed acute nonlymphocytic leukemia. CONCLUSION: UM-FU was effective in controlling ascites and hydrothorax and diminished intraabdominal masses. The discovery of adriamycin and then platinum led to more effective therapy and the use of uracil mustard was superseded. It is no longer available. The experience reported is of historic interest.

Imaging practices in the diagnosis and management of gestational trophoblastic disease: an assessment.

This article discusses several of the problems associated with imaging in gestational trophoblastic disease based on critical assessment of the literature. (1) Ultrasound scanning has revolutionized the diagnosis of abnormalities of the first trimester of pregnancy. Fetal death can now be diagnosed as early as 6 weeks of gestation, resulting in uterine evacuation. Histologic and genetic analysis of the conceptus therefore becomes essential as otherwise the diagnosis of hydatidiform mole and other chromosomal anomalies of the fetus may be missed. If such investigation is not performed, human chorionic gonadotropin should be measured after early pregnancy loss to make sure it is negative. (2) The routine use of ultrasound or Doppler flow to follow hydatidiform mole regression is clinically and fiscally counterproductive. (3) To diagnose lung metastases and assess the FIGO risk factor score, chest X-ray is mandated. However, CT scanning may show lung micrometastases indicative of possible chemotherapy resistance. (4) positron emission tomography scanning in trophoblastic neoplasia needs to be validated. Previous studies have been small, with some 30% false positive and false negative findings. The International Society for the Study of Trophoblastic Disease should undertake carefully designed prospective studies to validate imaging practices in the management of trophoblastic disease.

Neoadjuvant and adjuvant chemotherapy of cervical cancer: mature results of the phase 2 PBM-PFU protocol.

OBJECTIVE: The mature results of the neoadjuvant and adjuvant chemotherapy arms of the nonrandomized, phase 2 Yale University cisplatin, bleomycin, methotrexate, and 5-FU protocol are presented. METHODS: Sixty-seven patients were prospectively accrued with a median follow-up of 5.4 years, and standard parameters of toxicity and efficacy were studied. Both univariate and multivariate analyses were applied. RESULTS: The 5-year disease-free survival of 78% for the 25 patients in the adjuvant group, of which 80% had high-risk features including positive margins, parametria, and lymph nodes and 28% had adenocarcinomas, was comparable to recent relevant literature. Only 64% of patients in this group received consolidation radiation therapy, which did not impact on survival. Only 12% of patients recurred distantly. Notably, those who received 4 months or more of chemotherapy had prolonged survival (P = 0.012). In the neoadjuvant group, chemotherapy response rate among 42 patients (with stages 1B-IIIB cancer) was 79% (50% partial response, 29% complete response), and no patient progressed. In the subgroup of 22 patients who underwent surgery after chemotherapy, 59% had nonsquamous histology. Forty-five percent of patients with stage IIB cancer were deemed operable after chemotherapy. Ninety-five percent received postoperative radiation therapy. There was a 9% pathologic complete response rate, with positive lymph nodes found in 27%. Notably, those who received 3 months or less of chemotherapy had improved overall survival (P = 0.030). Survival rates of these 22 patients at 3 and 5 years were 73% and 63%, respectively. Although not randomized, these survival rates were similar to those achieved with chemoradiation. CONCLUSIONS: Although there are several logistical/design features of the cisplatin, bleomycin, methotrexate, and 5-FU regimen that are not in line with the current chemotherapy era, our experience with this well-tolerated regimen can serve as a proof of principle. Our data suggests that both neoadjuvant and adjuvant cisplatin-based neoadjuvant chemotherapy may have their place. It also raises the possibility that the optimal duration of chemotherapy in adjuvant cases should be longer than in neoadjuvant cases.

John McLean Morris: a career in surgery, gynecology and reproductive physiology.

This biographical sketch of the professional life of Dr. John McLean Morris is presented as part of the history of the Department of Obstetrics and Gynecology of Yale University School of Medicine.

Evolution of the human brain, chorionic gonadotropin and hemochorial implantation of the placenta: insights into origins of pregnancy failures, preeclampsia and choriocarcinoma.

Hyperglycosylated chorionic gonadotropin (CG-H) signals placental cytotrophoblast cell growth and invasion, and chorionic gonadotropin (CG) promotes uterine vascularization. A hypothesis is presented relating the evolution of these molecules to the evolution of human hemochorial implantation and that of the human brain. Deep placental invasion, vascularization and hemochorial placentation, under the influence of CG and CG-H, are a critical part of the nutrition and energy-generating mechanisms needed for human brain development and thus for the evolution of humans. Insufficient CG-H production and the resulting inappropriate implantation is associated with an unduly high incidence of pregnancy failures in humans. Low levels of CG-H and inappropriate hemochorial placentation also appear to be associated with subsequent preeclampsia. It is also of note that human CG-H drives invasion by gestational trophoblastic neoplasms that have been described only in humans.

The need for an hCG assay that appropriately detects trophoblastic disease and other hCG-producing cancers.

This report was conceived at the 13th World Congress of Gestational Trophoblastic Disease after multiple presentations indicated widespread discrepancies in human chorionic gonadotropin (hCG) use and results. There appears to be a need for a discussion to describe the advantages and limitations of commonly used hCG tests in the management of gestational trophoblastic disease, and to monitor testicular, germ cell and other hCG-producing malignancies. In most countries hCG tests are certified only for pregnancy testing. Use in managing gestational trophoblastic diseases and other malignancies is considered an "off-label" use. Tests are not optimized or calibrated for these applications, and their use and the results therefore have to be considered experimental. Widespread variations in results occur and may lead to needless or inappropriate therapy. It therefore seems important for laboratory directors and treating physicians to familiarize themselves with which hCG test their laboratory is using and, if necessary, to contract an external laboratory for measuring hCG in the management of gestational trophoblastic disease and cancer.

Gestational trophoblastic diseases: 1. Pathophysiology of hyperglycosylated hCG.

OBJECTIVE: Hyperglycosylated hCG (hCG-H) is a glycosylation variant of hCG produced by cytotrophoblast cells at implantation of pregnancy and in choriocarcinoma. We investigated the biological function of hCG-H in invasion in vitro and in vivo and the use of hCG-H antibodies in blocking tumorigenesis and cancer growth in vivo. METHODS AND RESULTS: hCG-H accounts for 43% to 100% of total hCG immunoreactivity in the culture fluid of choriocarcinoma cell lines and 100% in primary cultures of pregnancy cytotrophoblast cells. We investigated the action of hCG and hCG-H on isolated cytotrophoblast cell primary cultures and on 3 different lines of choriocarcinoma cells cultured on Matrigel basement membrane inserts (culture models for assessing tumor invasion). The addition of hCG-H to medium significantly promoted invasion of membranes with both pregnancy and cancer cell line sources, while regular hCG had no significant effect. JEG-3 human choriocarcinoma cells were transplanted subcutaneously into athymic nude mice. Tumors rapidly formed. B152, mouse monoclonal antibody against hCG-H, and non-specific mouse IgG (control) were administered twice weekly once tumors were clearly visible. While a correlation between time and growth was observed with the control group (r(2)=0.97), no correlation was observed with the B152-treated mice (r(2)=0.15). B152 blocked tumor growth (t test, IgG vs. B152, P=0.003). In a second experiment, antibody B152 or IgG was administered to mice at the time of choriocarcinoma transplantation. B152 significantly inhibited tumorigenesis (t test P=0.0071). CONCLUSIONS: hCG-H is a critical promoter in human cytotrophoblast and human choriocarcinoma cell invasion in vivo and in vitro, promoting tumor growth and invasion through an autocrine mechanism. hCG-H is a signal for choriocarcinoma cell invasion, making it a biological tumor marker. Antibodies against hCG-H block tumor formation and growth. Human or humanized antibodies against hCG-H may be useful in treating and managing choriocarcinoma and other gestational trophoblastic malignancies.

Gestational trophoblastic diseases: 2. Hyperglycosylated hCG as a reliable marker of active neoplasia.

OBJECTIVES: To determine whether circulating hyperglycosylated human chorionic gonadotropin (hCG-H), a promoter of choriocarcinoma growth and tumorigenesis, is a reliable marker of active gestational trophoblastic neoplasia (GTN) or choriocarcinoma, and whether hCG-H can consistently discriminate quiescent gestational trophoblastic disease (GTD) from neoplasia. METHODS: Patients were those referred to the USA hCG Reference Service for consultation. These included a total of 82 women with GTN, including 30 with histologic choriocarcinoma. They were compared with 26 patients with resolving hydatidiform mole and 69 with quiescent GTD (persistent positive low value of real hCG but no clinical evidence of disease). All were tested for total hCG and hCG-H. hCG-H was calculated as the percentage of total hCG (hCG-H(%)). RESULTS: We compared the utility of total hCG and hCG-H(%) in detecting active GTN and quiescent GTD. There was no significant difference when measuring total hCG (includes regular and hyperglycosylated hCG), between women with quiescent GTD and self-resolving hydatidiform mole compared to choriocarcinoma/GTN cases (P > 0.05 and P > 0.05). In contrast, hCG-H(%) was significantly higher in choriocarcinoma/GTN cases (P < 0.000001, and P < 0.000001). The usefulness of hCG and hCG-H(%) testing was assessed for discriminating between the 69 quiescent GTD cases, which required no therapy, and choriocarcinoma/GTN which need treatment. While hCG would detect 62% and 24% of malignancies at a 5% false positive rate, hCG-H(%) would detect 100% and 84% of malignancies at this same false positive rate. Follow-up data were received and repeat consultations were performed in 23 cases in which active disease was subsequently demonstrated. In 12 of 23 cases, hCG-H(%) results were able to first identify active disease 0.5 to 11 months prior to rapidly rising hCG or detection of clinically active neoplasia. In the remaining 11 cases, hCG-H(%) active disease appeared at the same time as rising hCG or demonstrable clinical tumor. DISCUSSION AND CONCLUSION: hCG-H(%) appears to reliably identify active trophoblastic malignancy. It is a 100% sensitive marker for discriminating quiescent GTD from active GTN/choriocarcinoma. It is also a marker for the early detection of new or recurrent GTN/choriocarcinoma. The data presented appear sufficient to encourage the adoption of hCG-H as a tumor marker in trophoblastic disease. Further studies are now urgently required to confirm and extend our findings.

What we know about low-level hCG: definition, classification and management.

OBJECTIVE: To critically assess the literature on the syndrome of low-level "real" human chorionic gonadotropin (hCG), to add new cases from our practice, to enumerate the investigations that are essential in the management of these patients and to offer a working classificationfor use by physicians encountering the condition. STUDY DESIGN: We report our experience with 9 patients with low-level hCG treated at the Yale Trophoblast Center and discuss London and Sheffield patients as well as reports from the USA hCG Reference Service. RESULTS: One of the 9 Yale patients had developed placental site trophoblastic tumor metastatic to the lung. Following resection and 18 months of observation, she then had a successful pregnancy, has remained without evidence of disease and has negative hCG. The other patients continue to be observed. The experience from England shows that 2 of 14 patients with detectable hCG in urine and serum developed overt trophoblastic neoplasia and were treated successfully. The others are being followed. None have developed gestational trophoblastic neoplasia, 3 have regular menstrual periods, and 1 has had 2 pregnancies. The USA hCG Reference Laboratory has had 114 consultations. Sixty-three patients had real hCG and were followed for 6 months to 6 years. Forty of the 63 (63%) received single agent or combination chemotherapy, and 10 underwent hysterectomy, also. hCG persisted in spite of therapy. Four of the 63 (6%) eventually developed overt trophoblastic neoplasia and were then treated effectively; their hCG became negative. In these 4 patients whose hCG rose significantly and who did require therapy, the proportion of hyperglycosylated hCG became > or =80% of total hCG. In contrast, the proportion of hyperglycosylated hCG was always very low in the 63 quiescent cases. CONCLUSION: Active therapy with chemotherapy or surgery for persistent, elevated, low-level, real hCG is counterproductive. Therapy should be initiated only if overt trophoblastic neoplasia appears. All patients with low-level, real hCG require sophisticated imaging to exclude the presence of extrauterine sites of trophoblast, such as trophoblastic metastases or pituitary adenoma. They require long-term follow-up with periodic clinical examination, imaging and frequent hCG testing with an assay that measures all aspects of the hCG molecule.

A survey of the complications of vaginal prolapse surgery performed by members of the Society Of Gynecologic Surgeons.

This study aimed to examine the frequency and nature of complications of vaginal prolapse surgery performed by members of SGS over a year and to determine the feasibility and the problems associated with prospective, multicentered collaborative data acquisition. A survey form, which included demographics, surgical indications, colpopexy type, concomitant procedures, technique, estimated blood loss (EBL), OR time, and intra/postoperative complications, was distributed to society members. The nature, extent, and solution of the complications were examined. There were 147 members of SGS at the time of the study. Many were reproductive endocrinologists and gynecologic oncologists. Twenty-one (14%) members participated. Three hundred forty-nine (349) completed forms were received: 187 sacrospinous fixations (SSF), 92 colposacropexies (CSP), and 70 high utero sacral suspensions (HUS). There were seven (3.7%) intraoperative complications for SSF, seven (7.6%) for CSP and three (4.3%) for HUS. There were four (2.1%) postoperative complications for SSF, six (6.5%) for CSP and none for HUS (NS). OR time was significantly longer for CSP vs. HUS ( P<.003) and for SSF vs. HUS ( p=.042). The EBL was significantly higher for SSF compared with CSP for the colpopexy procedure ( p=.013) and for entire cases ( p<.003). Analysis showed that all three colpopexies had significant intraoperative and postoperative complications of less than 8%. Intraoperative visceral damage was a concern for all three procedures. With SSF and CSP there was risk of bleeding and with HUS there was a risk of ureteral obstruction. Postoperative CSP complications were bowel obstruction, bleeding or hernia; for SSF neuropathy, and for HUS none. No life-threatening intraoperative or postoperative complications were reported. OR time was significantly shorter for HUS than SSF. The highest EBL was with SSF. Only 14% of the SGS membership responded, despite multiple requests for participation, demonstrating the difficulty of multicenter data gathering.

Assessing sexual function and dyspareunia with the Female Sexual Function Index (FSFI) in women with vulvodynia.

Using the Female Sexual Function Index (FSFI; Rosen et al., 2000), we assessed forty-two women with vulvodynia. Internal consistency was high (Cronbach's alphas = 0.90-0.97) for all scales. We compared scale scores to published healthy and patient sample data and found very large effect sizes (1.15-2.83), which indicated that women with vulvodynia reported significantly worse overall sexual function than women without sexual dysfunction and greater pain with sexual intercourse than women with female sexual arousal disorder. Results highlight difficulties experienced across all domains of sexual function, particularly with regard to dyspareunia, for women with vulvodynia. Findings also support the internal consistency and discriminant validity of the FSFI.