Prognostic gene expression signature for high-grade serous ovarian cancer.

BACKGROUND: Median overall survival (OS) for women with high-grade serous ovarian cancer (HGSOC) is ∼4 years, yet survival varies widely between patients. There are no well-established, gene expression signatures associated with prognosis. The aim of this study was to develop a robust prognostic signature for OS in patients with HGSOC. PATIENTS AND METHODS: Expression of 513 genes, selected from a meta-analysis of 1455 tumours and other candidates, was measured using NanoString technology from formalin-fixed paraffin-embedded tumour tissue collected from 3769 women with HGSOC from multiple studies. Elastic net regularization for survival analysis was applied to develop a prognostic model for 5-year OS, trained on 2702 tumours from 15 studies and evaluated on an independent set of 1067 tumours from six studies. RESULTS: Expression levels of 276 genes were associated with OS (false discovery rate < 0.05) in covariate-adjusted single-gene analyses. The top five genes were TAP1, ZFHX4, CXCL9, FBN1 and PTGER3 (P < 0.001). The best performing prognostic signature included 101 genes enriched in pathways with treatment implications. Each gain of one standard deviation in the gene expression score conferred a greater than twofold increase in risk of death [hazard ratio (HR) 2.35, 95% confidence interval (CI) 2.02-2.71; P < 0.001]. Median survival [HR (95% CI)] by gene expression score quintile was 9.5 (8.3 to -), 5.4 (4.6-7.0), 3.8 (3.3-4.6), 3.2 (2.9-3.7) and 2.3 (2.1-2.6) years. CONCLUSION: The OTTA-SPOT (Ovarian Tumor Tissue Analysis consortium - Stratified Prognosis of Ovarian Tumours) gene expression signature may improve risk stratification in clinical trials by identifying patients who are least likely to achieve 5-year survival. The identified novel genes associated with the outcome may also yield opportunities for the development of targeted therapeutic approaches.

Hemodynamic evaluation and anti-hypertensive schemes used in puerperal women following pre-eclampsia.

Pre-eclampsia is still a very prevalent disease with critical hemodynamic changes. This study was evaluated the major anti-hypertensive schemes used at the Materno Perinatal Hospital "Monica Pretelini" (HMPMP) hospitalized at the Obstetric Intensive Care Unit (OICU) for at least seven days. In other group of patients we compared hemodynamic monitoring with Swan-Ganz catheter versus transthoracic electrical bioimpedance (TEB) and gasometric formulas. Statistical analysis was done using the Statistical Package for Social Science (SPSS) software, version 17. Amlodipine + temisartan + prazocin was the preferred anti-hypertensive drug combination used in our intensive care unit. Sodium nitroprusside is required in 25% of patients until reaching control. There was no statistically significant difference in cardiac output calculated with gasometric formulas compared to thermodilution with Swan-Ganz catheter. Calcium antagonists + angiotensin II receptor blocker (ARB) + α-blockers offer the best option to control hypertension in puerperal women that followed pre-eclampsia, but oral and IV drugs to control hypertension is required in 20% of cases, in a Mexican Intensive Care Unit specialized in obstetrical patients. Hemodynamic monitoring with gasometric formulas is still usefull in this set of patients, without discarding TEB with a correction factor due to the accumulated extravascular water in these patients.

Progestin and estrogen potency of combination oral contraceptives and endometrial cancer risk.

OBJECTIVE: Using data from a case-control study of endometrial cancer, we investigated the relationship between the progestin and estrogen potency in combination oral contraceptives (OCs) and the risk of developing endometrial cancer. METHODS: Subjects included 434 endometrial cancer cases and 2,557 controls identified from the Cancer and Steroid Hormone (CASH) study. OCs were classified into four categories according to the individual potencies of each hormonal constituent (high versus low estrogen or progestin potency). Logistic regression was used to evaluate associations between endometrial cancer risk and combination OC formulations. RESULTS: With non-users as the referent group, use of OCs with either high potency progestin [odds ratio for endometrial cancer (OR)=0.21, 95% confidence interval (CI)=0.10 to 0.43] or with low potency progestin (OR=0.39, 95% CI=0.25 to 0.60) were both associated with a decreased risk of endometrial cancer. Overall high progestin potency OCs did not confer significantly more protection than low progestin potency OCs (OR=0.52, 95% CI=0.24 to 1.14). However, among women with a body mass index of 22.1 kg/m2 or higher, those who used high progestin potency oral contraceptives had a lower risk of endometrial cancer than those who used low progestin potency oral contraceptives (OR=0.31, 95% CI=0.11 to 0.92) while those with a BMI below 22.1 kg/m2 did not (OR=1.36, 95% CI=0.39 to 4.70). CONCLUSION: The potency of the progestin in most OCs appears adequate to provide a protective effect against endometrial cancer. Higher progestin-potency OCs may be more protective than lower progestin potency OCs among women with a larger body habitus.

Metastatic adenocarcinoma in the lungs of older laying hens.

As part of a study on ovarian and oviductal adenocarcinomas in older laying hens, 676 commercial egg-laying chickens were necropsied at 4 yr of age. Tumors were identified in 305 (45.1%) of the hens. Grossly visible metastatic tumors in the lungs of a few birds prompted collection of lungs from 228 affected hens for histologic examination. Metastatic adenocarcinomas were identified histologically in the lungs of 42 of the 228 hens (18.4%). The number of tumors and extent of involvement of the lung parenchyma varied from minimal to extensive. Tumor emboli were occasionally seen in pulmonary vessels. Metastatic foci showing expansive or invasive growth were identified. These findings indicate that vascular spread of adenocarcinomas is more common than previously thought in chickens, and the lungs are often involved with metastatic tumors, primarily from the reproductive tract.

Thrombospondin-1 expression in epithelial ovarian carcinoma: association with p53 status, tumor angiogenesis, and survival in platinum-treated patients.

OBJECTIVE: The regulation of the metastatic process in epithelial ovarian cancer has not been well defined. Similar to other tumor types, the angiogenic phenotype in ovarian cancer strongly influences clinical outcome, suggesting that the acquisition of a pro-angiogenic environment is essential to the process of ovarian cancer proliferation and metastasis. Thrombospondin-1 (TSP-1) is a potent peptide shown in other tumor systems to be associated with angiogenesis and possibly regulated by p53, a gene which is mutated in as high as 50% of advanced ovarian cancers. The purpose of this study was to investigate TSP-1 expression in invasive epithelial ovarian cancer and to examine the relationship between TSP-1 expression and the degree of angiogenesis. In addition, we examined whether TSP-1 expression was associated with overexpression of p53. METHODS: Frozen sections obtained from 85 patients with invasive epithelial ovarian cancer were examined immunohistochemically for expression of TSP-1 and p53. The sections were examined microscopically by two investigators, who were blinded to the clinicopathologic variables. Outcome variables included the correlation among TSP-1, angiogenesis, and p53, as well as the association between TSP-1 expression and survival. RESULTS: The majority (62%) of cases demonstrated high levels (3+) of TSP-1 expression; 7% demonstrated no TSP-1 expression. p53 was overexpressed in 55% of cases, and expression was inversely correlated with TSP-1 staining. Thirteen cancers had 0 or 1+ TSP-1 staining; 12 (92%) of these overexpressed the p53 protein. In contrast, only 49% of tumors with high expression of TSP-1 have overexpression of p53 (P = 0.02). TSP-1 was suggestive for improved survival in patients with advanced disease; high TSP-1 expression was associated with a median survival of 2.4 years compared to 1.5 years for patients with tumors having a lower degree of TSP-1 expression (P = 0.06). CONCLUSION: These data suggest that TSP-1 may possess a tumor inhibitory function in patients with advanced epithelial ovarian carcinoma. The reduction of TSP-1 expression associated with overexpression of p53 may be coupled with the development of a pro-angiogenic environment and malignant phenotype.

Vacuum-assisted closure for cutaneous gastrointestinal fistula management.

BACKGROUND: Cutaneous gastrointestinal (GI) fistulas are a challenging complication in the oncologic patient population. The fistulous effluent is difficult to manage and adversely alters quality of life. Nonsurgical management of enteric fistulas is successful in 30% of cases, requiring at least 4 to 6 weeks. Recently a new technology has been developed to expedite wound healing. The Vacuum-Assisted Closure (VAC) method is a subatmospheric pressure technique that has been demonstrated in laboratory and clinical studies to significantly improve wound healing. Here we report its use in the successful medical management of a cutaneous GI fistula. CASE: A 63-year-old woman with advanced ovarian cancer developed an extensive complex cutaneous GI fistula in an open healing wound. She was treated with total parental nutrition and the VAC device, which resulted in complete closure of the fistula. CONCLUSION: We propose that the VAC device may be a useful adjunct for the medical management of cutaneous GI fistulas.

Regulation of invasion of epithelial ovarian cancer by transforming growth factor-beta.

OBJECTIVE: The metastatic process in epithelial ovarian cancer is thought to involve surface shedding and subsequent dissemination of ovarian cancer cells, facilitated by localized proteolysis at the interface between ovarian cancer cells and peritoneal surfaces. The factors regulating the metastatic process, however, are not well understood. Transforming growth factor-beta (TGF-beta) is a multifunctional peptide that elicits numerous cellular effects pertinent to the metastatic process. The purpose of this study was to evaluate the regulatory role of TGF-beta on metastasis in ovarian cancer. METHOD: We evaluated the effect of TGF-beta on the metastatic characteristics (adhesion, invasion, motility, proteolysis) of five ovarian cancer cell lines (DOV-13 and OVCA 420, 429, 432, and 433), two short-term primary ovarian cancer cell cultures (OVCA 10 and OVCA 208), and five normal ovarian surface epithelial (NOSE) cell cultures (OSE 133, 185, 186, 188, and 189). The effect of TGF-beta on invasion and proteolysis was quantified using a modified Boyden chamber invasion assay, zymography, a coupled colorimetric activity assay, and an HPLC-based quantitation of synthetic substrate cleavage. RESULTS: TGF-beta significantly increased invasion in five of seven ovarian cancer cell lines in amounts ranging from 2- to 20-fold. In contrast, TGF-beta significantly decreased invasion in two of five NOSE isolates by 50 to 80% and had no significant effect on invasion in three. TGF-beta treatment increased matrix metalloproteinase (MMP) expression in OVCA 420 and 433 and DOV-13, resulting in MMP-dependent collagen cleavage and invasive activity. Addition of the MMP inhibitor GI12947 neutralized the enhancing effect of TGF-beta on invasion. TGF-beta had no effect on ovarian cancer cell motility and only increased adhesion in DOV-13. CONCLUSIONS: These data suggest that TGF-beta may enhance the invasiveness of ovarian cancers through induction of MMP activity.

The prognostic significance of angiogenesis in epithelial ovarian carcinoma.

The molecular biology underlying the metastatic process in ovarian carcinoma remains poorly understood. For other neoplasms, the induction of angiogenesis by malignant cells has been shown to play a pivotal role in the process of tumor proliferation and metastasis. The purpose of this study was to characterize the degree of angiogenesis in epithelial ovarian malignancies and to determine whether the degree of neovascularization has prognostic significance for survival. Tissue sections obtained from 88 ovarian cancer patients were examined immunohistochemically for angiogenesis after staining with anti-human endothelial cell antibodies to von Willebrand factor and CD31. Light microscopy was performed, and individual microvessel counts were quantified at high power (x400). A chart review was completed, collating data regarding age, stage, grade, status of disease, and survival. Statistical exploratory methods were used to find potentially useful prognostic cutpoints for marker values of angiogenesis. Of the total 88 patients, tissue microvessel counts from 85 were evaluated via antibodies to von Willebrand factor and 87 for CD31. Overall, median survival was 2.7 years in women with cancers containing high microvessel counts versus 7.9 years in those with low microvessel counts (P = 0.03). A low microvessel count was associated with better 5-year survival in both early stage (I and II) and advanced stage (III and IV) disease. Our data suggest that the degree of neovascularization may have prognostic significance in epithelial ovarian carcinoma, especially for women with early-stage disease. In this group of women, the degree of angiogenesis may allow the selection of women at high risk for recurrence who may benefit from aggressive adjuvant therapy.

Mucin gene expression in ovarian cancers.

Ovarian cancer is a highly lethal disease with metastases present in the majority of patients at the time of diagnosis. The molecular mechanisms underlying the metastatic process of this cancer are not well understood. One family of cell-associated and secreted glycoproteins, the mucin glycoproteins, has been implicated in events leading to metastasis of several epithelial cancers including gastrointestinal and lung cancers. The purpose of this study was to characterize mucin gene expression in ovarian cancers and relate expression to tumor histology, stage, and patient survival. RNA was isolated from 29 epithelial ovarian cancers, 1 neuroendocrine carcinoma, 3 mixed mesodermal tumors, and two transformed, yet nonmalignant, ovarian epithelial cell lines. The expression of mucin genes, MUC1, 2, 3, 4, 5AC and 5B, was determined by northern analyses. Epithelial ovarian cancers expressed several mucins including MUC1, 2, 4, and 5AC; MUC3 and 5B were rarely expressed. In contrast, the transformed nonmalignant ovarian epithelial cell lines expressed only MUC1 and 5AC. Although there was no correlation of mucin expression with tumor histology, there was a significant decrease in expression of MUC3 and MUC4 with increasing cancer stage (P < 0.05). In addition, a trend toward improved patient survival occurred with increased expression of MUC4. These observations suggest a relationship between mucin gene expression and the metastatic process in epithelial ovarian cancers. Additional investigation of MUC3 and MUC4 in ovarian cancers may lead to new approaches for early detection and therapy.

Effect of progestin on the ovarian epithelium of macaques: cancer prevention through apoptosis?

OBJECTIVE: The apoptosis pathway is a vital mechanism in vivo that functions to eradicate genetically damaged cells prone to malignancy. The purpose of this study was to determine whether oral contraceptives, which confer significant protection against subsequent epithelial ovarian cancer, induce apoptosis in the ovarian epithelium. METHODS: Female cynomolgus macaques (N = 75) were randomized to receive a diet for 35 months containing either no hormones, the oral contraceptive Triphasil (Wyeth-Ayerst Laboratories, Philadelphia, PA), the estrogenic component of Triphasil (ethinyl estradiol) alone, or the progestin component of Triphasil (levonorgestrel) alone, each administered in a cyclic fashion. At study termination, the animals underwent ovariectomy and the ovarian epithelium was examined morphologically and immunohistochemically for apoptosis. The percentage of ovarian epithelial cells undergoing apoptosis was measured in each animal and compared between the treatment groups. RESULTS: The median percentage of ovarian epithelial cells undergoing apoptosis by treatment was control (3.8%), ethinyl estradiol (1.8%), Triphasil (14.5%), and levonorgestrel (24.9%). Compared with control and ethinyl estradiol-treated monkeys, a statistically significant increase in the proportion of apoptotic cells was noted in the ovarian epithelium of monkeys treated with the oral contraceptive Triphasil (P < or = .01) or levonorgestrel (P < .001), with a maximal effect (six-fold) seen in the group treated with levonorgestrel alone. CONCLUSION: Oral contraceptive progestin induces apoptosis in the ovarian epithelium. Given the importance of the apoptosis pathway for cancer prevention, an effective chemopreventive strategy may be possible using progestins or other agents that selectively induce apoptosis in the ovarian epithelium to prevent the development of ovarian cancer.

Characterization of gelatinases linked to extracellular matrix invasion in ovarian adenocarcinoma: purification of matrix metalloproteinase 2.

Substantial evidence indicates that proteolytic degradation of the extracellular matrix is necessary for invasion and metastasis by cancer cells. Our previous work has demonstrated elevated secretion by cultured ovarian adenocarcinoma cells of two gelatinolytic metalloproteinases, a 72-kDa enzyme resembling matrix metalloproteinase 2 (MMP-2) and a 92-kDa enzyme resembling MMP-9 (Moser et al, Int. J. Cancer 56, 552-559, 1994). To assess the potential in vivo relevance of these enzymes, we have examined ovarian carcinoma ascites using gelatin substrate zymography. MMP species identical to those secreted from several well-characterized ovarian adenocarcinoma cell lines were found in the majority of ascites: MMP-2-like gelatinase (23 of 23 cases) and MMP-9-like gelatinase (18 of 23 cases), suggesting a prevalence of these species in the ovarian carcinoma microenvironment and their availability for tumor-associated proteolysis. The contribution of these proteinases to ovarian cancer invasion was further demonstrated by experiments measuring tumor cell-mediated proteolysis of native endothelial cell extracellular matrix (ECM) and tumor cell invasion of reconstituted basement membrane (Matrigel). These data showed that secretion of type IV collagenase activity by a series of independently isolated ovarian adenocarcinoma cell lines correlated well with the ability of these cells to proteolyze the ECM and invade the basement membrane. Furthermore, we have identified and characterized an ovarian carcinoma-associated gelatinase, the 72-kDa MMP found in conditioned media of the DOV 13 cell line, as MMP-2. This enzyme was identical to the previously described MMP-2 from other sources by Western blot, amino terminal sequence, and substrate specificity. Additionally, a large portion of the MMP-2 activity found in DOV 13 conditioned media is active without organomercurial treatment, suggesting that ovarian cancer cells have an endogenous activator of the zymogen. Together, these data suggest that ECM proteolysis mediated by tumor-associated proteinases plays an important role in the invasion and/or metastasis of ovarian carcinoma.

Gestational trophoblastic disease metastatic to the central nervous system.

OBJECTIVE: To evaluate characteristics of patients with central nervous system (CNS) lesions of gestational trophoblastic disease (GTD) and determine prognostic and therapeutic implications applicable to management. METHODS: We retrospectively reviewed the records of 454 patients treated at the Southeastern Regional Trophoblastic Disease Center between 1966 and 1992 with at least 2 years of follow-up, and identified 42 (9.3%) with CNS metastases. Sixteen patients presented for primary therapy and 27 patients had received significant therapy prior to presentation. Three heavily treated moribund patients died before their first cycle of chemotherapy and were excluded from analysis. Brain metastases were documented by physical exam and radionuclide imaging (before 1976), computed tomography scan (after 1976), or magnetic resonance imaging (after 1986). Patients received multiagent chemotherapy with methotrexate, actinomycin D, and chlorambucil (MAC)- or etoposide-based regimens. All patients received radiation therapy. No intrathecal chemotherapy was given. Craniotomy was employed in seven cases. Remission was defined as three weekly hCG levels below assay sensitivity (< 5 mIU/ml). RESULTS: Overall survival was 44%. Twelve of 16 patients (75%) who presented with CNS metastases with no prior therapy (Group A), 5 of 13 (38%) patients who had prior treatment (Group B), and none of 10 patients who developed CNS metastases during therapy (Group C) survived (P < 0.05). Two of four patients who failed in the CNS after treatment for CNS lesions were salvaged. Demographic characteristics of Groups A and B were similar. No significant differences with respect to WHO score, interval from pregnancy to onset of disease, or age among these groups were found. Group B patients had a four-fold higher incidence of liver metastases. Survival of Group A patients was not related to conventional clinical prognostic factors. Inverse (nonsignificant) correlations were found for Group B patients between survival and WHO score, hCG level, size and number of metastatic lesions, but not type of prior therapy. Survival was higher in those with prior molar pregnancies (56%) as contrasted with aborted (50%) or term (27%) gestations. Selective use of craniotomy helped alleviate intracranial pressure and resect refractory foci. CONCLUSIONS: Chemotherapy combined with radiation therapy in GTD patients with CNS metastases yields survival rates comparable to those reported for intrathecal methotrexate regimens. Tumor burden as indicated by hCG level and size/number of metastases in previously treated patients may correlate with survival. Patients who develop CNS metastases during active therapy have a very poor outcome.

Postsurgical surveillance of patients with FIGO stage I/II endometrial adenocarcinoma.

OBJECTIVE: To examine the effect of postsurgical surveillance on survival of patients with FIGO stage I/II endometrial adenocarcinoma. METHODS: We examined the records of 354 patients who underwent primary surgical therapy for FIGO stage I/II endometrial adenocarcinoma. In patients who developed recurrent disease, we determined whether symptoms or signs of disease were present at recurrence and whether there was evidence of disease on Pap smear or chest radiograph. RESULTS: Among the 354 patients in this study, 44 (12%) developed recurrent disease. Sites of recurrence included 12 (27%) isolated vaginal, 12 (27%) pelvic with vagina or abdomen, 4 (10%) isolated lung, 13 (29%) pelvic/abdominal with other distant sites, and 3 (7%) other distant sites. At diagnosis of recurrence 61% of patients had symptoms related to their cancer, 68% had physical exam findings suggestive of recurrence, and 84% had symptoms and/or signs. Findings consistent with recurrent cancer were detected by Pap smear in 25% and on chest radiograph in 20%. Among the 44 patients who developed recurrent disease, 8 (18%) remain alive without evidence of disease, including 6/12 (50%) with isolated vaginal disease and 2/34 (6%) with other patterns of recurrent disease (P = 0.01). Among the 12 patients with isolated vaginal recurrence, 1/3 (33%) in whom recurrent disease was diagnosed by Pap smear alone was salvaged compared to 5/9 (56%) who had symptoms or signs of vaginal recurrence. None of the three patients in whom an abnormal chest radiograph was the only evidence of recurrence survived. CONCLUSIONS: Because of the low recurrence rate of FIGO stage I/II endometrial cancer and the paucity of effective second-line treatment, surveillance Pap smears and chest radiographs appear to have little impact on survival. Although few asymptomatic potentially curable recurrences were detected due to surveillance examinations, the value of psychological reassurance associated with a normal examination is difficult to quantitate.

Relationship between race and interval to treatment in endometrial cancer.

OBJECTIVE: To determine whether the poor prognosis of black women with endometrial adenocarcinoma is due to racial differences in the interval between the onset of abnormal uterine bleeding and hysterectomy. METHODS: Clinical records of all 219 patients (176 white, 39 black, four other) who underwent surgical treatment of endometrial cancer during 1990-1993 at our institution were reviewed to obtain information regarding clinicopathologic features. In addition, the interval between the onset of abnormal uterine bleeding and hysterectomy was noted. RESULTS: Compared with white patients, black women with endometrial cancer had a significantly higher incidence of unfavorable features, including non-endometrioid histology (38 versus 12%), stage III or IV disease (51 versus 19%), grade 3 differentiation (49 versus 18%), and poor survival (P = .003). There was no significant difference in the median interval from onset of abnormal uterine bleeding to hysterectomy between blacks (11.1 weeks) and whites (13.7 weeks), nor was the interval to treatment related to stage, grade, histologic type, myometrial invasion, or survival. In contrast, patients with a history of hormone use had a longer median interval from the onset of abnormal bleeding to treatment compared with patients who had not used hormones (19 versus 10 weeks) (P < .01), and hormone use was associated with favorable clinicopathologic features and survival. Although black women were less likely to have used hormones than white women (13 versus 44%) (P < .001), racial differences in stage, grade, and survival persisted after correcting for hormone use. CONCLUSION: This study confirms that black women with endometrial cancer have a poorer outcome than white women; however, this does not appear to be due to a difference in the interval from onset of abnormal uterine bleeding to hysterectomy.

Chemotherapy-induced apoptosis in epithelial ovarian cancers.

OBJECTIVE: To determine whether chemotherapy drugs elicit programmed cell death (apoptosis) in ovarian cancer cells. METHODS: Monolayers of immortalized ovarian cancer cell lines and primary ovarian cancer cells obtained from ascites were grown in the presence of cisplatin, 4-hydroxyperoxy-cyclophosphamide (the active metabolite of cyclophosphamide) or paclitaxel. Next, DNA was extracted from the cells and subjected to electrophoresis to determine if DNA laddering characteristic of apoptosis was present. RESULTS: In three of six immortalized cell lines (OVCA 420, 429, and 433), apoptosis was not seen in response to any of the three drugs. In contrast, in OVCAR-3 and OVCA 432, DNA laddering consistent with apoptosis was observed in response to all three drugs. In the DOV 13 cell line, apoptosis was seen only with 4-hydroxyperoxycyclophosphamide. Among three primary ovarian cancers, cisplatin elicited apoptosis in one case. Both cell lines with mutant p53 genes (OVCAR-3 and OVCA 432) underwent apoptosis in response to all three drugs, whereas among three cell lines known to have normal p53 genes, one underwent apoptosis in response to 4-hydroxyperoxycyclophosphamide and two were unaffected. CONCLUSION: Ovarian cancer cell death in response to commonly used chemotherapeutic drugs involves the induction of a genetically programmed sequence of events (apoptosis) rather than simply necrosis.

Villoglandular adenocarcinoma of the cervix: a case report.

BACKGROUND: Villoglandular adenocarcinoma of the cervix is a rare neoplasm associated with a favorable outcome and has not been described as a complication of pregnancy. CASE: A gravida at 20 weeks' gestation was found to have a bulky stage-IB adenocarcinoma of the cervix. She was delivered at 32 weeks' gestation by cesarean, then a radical hysterectomy and pelvic and periaortic lymphadenectomies were performed. Pathology revealed a deeply invasive, grade 1 villoglandular adenocarcinoma confined to the cervix. The patient remains free of disease at 14 months follow-up. CONCLUSION: Villoglandular adenocarcinoma of the cervix has a favorable prognosis and can be managed conservatively, even when complicated by pregnancy.

Regulation of apoptosis in normal and malignant ovarian epithelial cells by transforming growth factor beta.

Previously, we found that transforming growth factor beta (TGF-beta) inhibits proliferation of normal human ovarian epithelial cells. In addition, although only 1 of 5 immortalized ovarian cancer cell lines was inhibited, TGF-beta inhibited proliferation of 19 of 20 primary epithelial ovarian cancers. In this study, we examined whether TGF-beta induces apoptosis in normal and malignant ovarian epithelial cells. Among 5 immortalized cell lines, only OVCA 420 is markedly growth inhibited by TGF-beta, and this was the only cell line in which TGF-beta elicited DNA fragmentation characteristic of apoptosis. Induction of apoptosis in OVCA 420 was time and concentration dependent and could be partially inhibited by concurrent treatment with an anti-TGF-beta mAb. Although apoptosis was not seen in normal ovarian epithelial cells (n = 7), [3H]thymidine incorporation was inhibited in all cases [mean = 61.2 +/- 7.2% (SD) of untreated control; P < 0.01]. Similarly, TGF-beta inhibited [3H]thymidine incorporation in all 10 primary ovarian cancers (mean = 40.4 +/- 7.1% of control; P < 0.01), but only 3 of 10 (30%) were found to undergo apoptosis when treated with TGF-beta. There was no relationship between p53 status of the ovarian cancers and the ability of TGF-beta to elicit apoptosis. In conclusion, TGF-beta inhibits proliferation but does not induce apoptosis in normal human ovarian epithelial cells. In contrast, some ovarian cancers that are growth inhibited by TGF-beta also undergo apoptosis. These data are consistent with the hypothesis that malignant cells are more susceptible to apoptosis than their normal nontransformed counterparts.

Serum progesterone for the exclusion of early pregnancy in women at risk for recurrent gestational trophoblastic neoplasia.

OBJECTIVE: To evaluate the utility of the serum progesterone level for discriminating pregnancy from gestational trophoblastic neoplasia. METHODS: Serum progesterone levels were measured in 61 women with histories of trophoblastic disease who developed a re-elevation in hCG during surveillance and underwent a work-up to differentiate pregnancy from gestational trophoblastic neoplasia. Progesterone levels were analyzed in the context of diagnostic outcome (pregnancy versus gestational trophoblastic neoplasia) to identify optimal threshold levels of progesterone to be used for classifying outcome. RESULTS: Of the 61 women, 37 proved to be pregnant and 24 had gestational trophoblastic neoplasia. Progesterone less than 2.5 ng/mL was predictive of trophoblastic malignancy, with a sensitivity of 83% (20 of 24 subjects were classified correctly as having gestational trophoblastic neoplasia) and a specificity of 95% (35 of 37 patients with progesterone levels at or above 2.5 ng/mL were correctly classified as pregnant). Progesterone of at least 10 ng/mL was associated with viable pregnancy in 97% of the cases. Furthermore, the progesterone level predicted outcome regardless of the serum hCG value. CONCLUSION: The serum progesterone level is useful for discriminating early pregnancy from gestational trophoblastic neoplasia.

Transforming growth factor-beta inhibits proliferation of human ovarian cancer cells obtained from ascites.

BACKGROUND: Previously, the authors found that immortalized ovarian cancer cell lines generally were resistant to the growth inhibitory effect of transforming growth factor-beta and frequently had lost the ability to produce or activate this growth factor. In this study, the authors examined whether early passage epithelial ovarian cancer cells obtained from ascites are growth-inhibited by or produce transforming growth factor-beta. METHODS: Ovarian cancer cells were purified from ascites by percoll gradient density centrifugation, and inflammatory cells were removed using anti-CD45 antibody. The effect of transforming growth factor-beta on the proliferation of ovarian cancer cells was assessed using the thymidine incorporation assay. Immunohistochemical staining for transforming growth factor-beta 1 and beta 2 also was performed in these cells. RESULTS: Transforming growth factor-beta (10 ng/ml) significantly inhibited [3H]thymidine incorporation in 19 of 20 (95%) primary ovarian cancers (P < 0.05). In cases in which significant inhibition was seen, the mean thymidine incorporation was 33 plus or minus 28% of control values. In addition, there was no difference in dose-dependent inhibition of proliferation between ovarian cancer cells and normal ovarian epithelial cells. Eleven of 18 ovarian cancers (61%) were found to express immunohistochemically detectable transforming growth factor-beta, but immunostaining was not observed in 39% of cases. CONCLUSIONS: Although most primary ovarian cancer cells remain sensitive to the growth-inhibitory effect of transforming growth factor-beta, loss of production may interrupt the transforming growth factor-beta autocrine inhibitory loop and play a role in the development of some ovarian cancers.