Health information quality on the internet in gynecological oncology: a multilingual evaluation.

BACKGROUND: Oncological internet information quality is considered variable, but no comprehensive analysis of gynecological malig- nancies exists. The present authors' objectives were to compare the quality of common malignancy websites and to assess for language or disease differences; and secondly, to perform a quality comparison between medical and layperson terminology. MATERIALS AND METHODS: World Health Organization (WHO) Health on the Net (HON) principles may be applied to websites using an automated toolbar function. Using a search engine (www.Google.com) 8,400 websites were assessed using keywords 'endometrial, 'uterine', 'cervical', 'ovarian', 'vaginal', 'vulvar', plus 'cancer', in English, French, German, and Spanish; repeated for alternate terms e.g. 'cervix', 'womb'. RESULTS: Searches for "vaginal' 'uterine', 'cervical', and 'endometrial' each returned millions of websites. The total percentage of all assessed HON-accredited sites was notably low across all search terms (median 15%; range 3-19%). Significant differences by malignancy type (p < 0.0001), language (p < 0.0001), and tertiles (thirds) of the first 150 websites returned (p < 0.0001). French language had most accredited websites. Using alternate terms demonstrated significant differences (p < 0.001) in accredited websites for most gynecological cancers. CONCLUSIONS: Internet data on gynecological malignancies is overwhelming. Further, a lack of validation of the majority of gynecological oncologic sites should be appreciated with discrepancies in quality and number of websites across diseases, languages, and also between medical and layperson terms. Physicians should encourage and more importantly their professional bodies should participate in the development of informative, ethical, and reliable health websites on the internet and direct patients to them.

First reported clinical pregnancy following heterotopic grafting of cryopreserved ovarian tissue in a woman after a bilateral oophorectomy.

Ovarian tissue cryopreservation and transplantation is a form of fertility preservation offered to young women at high risk of losing ovarian function after cancer treatment. While there have been successful births resulting from orthotopic site grafts, we report the first case of an ongoing pregnancy from a heterotopic graft in a patient who had previously undergone bilateral oopherectomy for a granulosa cell tumour. Frozen-thawed ovarian tissue was transplanted to the anterior abdominal wall. Subsequent ovarian stimulation and transabdominal ultrasound-guided oocyte retrieval from the grafts resulted in two oocytes. These were fertilized with ICSI and two embryos were transferred. Serial ultrasounds have confirmed an ongoing 26-week intrauterine twin pregnancy. Thus, this first demonstration of a pregnancy from a heterotopic graft site provides unequivocal evidence that cryopreservation preserves complete follicle development and that normal ovarian function can occur at a non-ovarian site. This provides optimism for further efforts to assist women who have had oophorectomy and pelvic surgery or radiotherapy, without an appropriate orthotopic site for grafting.

Intraperitoneal distribution imaging in ovarian cancer patients.

BACKGROUND/AIMS: Optimal delivery of intraperitoneal (i.p.) chemotherapy is dependent on adequate drug distribution. An accurate understanding of the limitations of i.p. distribution is critical if we are to improve cytotoxic delivery through this route. METHODS: Using repeated scintigraphic peritoneography we investigated peritoneal fluid distribution in patients receiving i.p. therapy. Both early (1-6 h) and late (24-48 h) images were performed. The peritoneal cavity was divided into six regions; pouch of Douglas, left and right paracolic gutters, left and right subphrenic spaces and the right subhepatic space. The distribution in each region was classified as absent (0), faint (1) or intense (2). A total distribution score was calculated from the summation of distribution values for each of the six regions. Distribution was then graded according to the total distribution score as follows: Grade 0 = 0-3; Grade 1 = 4-6; Grade 2 = 7-9; and Grade 3 = 10-12. RESULTS: Twenty-six participants were included in the study: all 26 patients had early imaging performed and 21 of these also had late imaging. Thirteen (50%) and 15 (71%) patients had grade 1 or 2 i.p. distribution on early and late imaging respectively. The most common abdominal regions to show maldistribution were the subphrenic spaces. CONCLUSIONS: This study highlights the deficiencies of distribution following i.p. drug delivery, with the majority of patients demonstrating multiple regions of faint or absent uptake on scintigraphic peritoneography imaging. Future large clinical studies investigating i.p. chemotherapy should include analyses of i.p. distribution to improve our understanding of optimal drug delivery through this route.

Prognostic significance of several histological features in intermediate and high-risk endometrial cancer patients treated with curative intent using surgery and adjuvant radiotherapy.

The purpose of the present study was to explore the prognostic significance of several histological features with respect to lymph node metastasis, failure-free survival (FFS), and overall survival (OS) in intermediate and high-risk endometrial cancer patients treated with curative intent. One hundred and eighty patients with endometrial cancer were treated with hysterectomy with or without lymphadenectomy and received external beam radiotherapy (EBRT). The mean follow-up period was 4.25 years (range 0.44-10.45 years). In multifactor analysis, fractional myometrial invasion (MI) (P = 0.047), histology (P < 0.001) and lymph-vascular space invasion (LVSI) (P = 0.025) were significant predictors for FFS when nodal status was not included. When lymph node status was known, histology (P = 0.007) and LVSI (P = 0.014) remained significant factors for FFS. For OS, histology (P < 0.001) and fractional MI (P = 0.004) were the significant factors. Lymph node status could be predicted by tumour grading (P = 0.016) and absolute MI (P = 0.002). Histology type and the presence of LVSI were the most important prognostic factors in high-risk endometrial cancer patients treated by surgery and postoperative radiotherapy. Absolute MI and tumour grading were useful predictors of nodal spread.

Molecular characterization of sarcomatous change in a granulosa cell tumor.

Sarcomatous transformation of a granulosa cell tumor (GCT) is a rare event. We describe the development of a rapidly progressive sarcomatous change in a woman who had initially presented with a classical GCT. A first recurrence occurred 23 months after the initial diagnosis when she was treated with external beam radiotherapy to her pelvis. A second recurrence 76 months following her initial surgery was consistent with a GCT. At 92 months, she presented with a further recurrence, outside of the radiotherapy field. This last recurrence had a different histologic appearance with features of sarcomatous change. Molecular analysis, using both reverse transcription-polymerase chain reaction and complementary DNA microarrays, has been used to analyze tissue obtained before and after the observed change in the tumor. The data show that GCT-specific genes, such as inhibin alpha, estrogen receptor, and follicle-stimulating hormone receptor, have been downregulated in the sarcomatous change. Significant upregulation of genes associated with an inflammatory response was also noted in the sarcoma, and this was consistent with the presence of a marked inflammatory infiltrate seen on histopathology. This study represents the novel application of microarray technology and demonstrates the unexpected finding of expression of the fibroblast activation protein gene in normal ovary. Although tumors such as this may be targets for the novel fibroblast activating protein-directed chemotherapeutic monoclonal antibody sibrotuzumab, the finding of expression in the normal ovary suggests the need for caution.

Metastatic malignant melanoma arising in a mature ovarian cystic teratoma: a case report and literature review.

Primary malignant melanoma arising inform the ovary is rare, with only 30 cases described in the literature to date. The case reported here occurred in a 19-year-old woman and was rapidly progressive, resulting in death only 37 days following initial presentation. Management of this case is discussed in the context of the other reported cases. Surgery, ranging from an ovarian cystectomy to a radical debulking procedure, has been the main treatment with adjuvant chemotherapy utilized in only 4 of the previous cases. Key problems in management relate to the ability to make the diagnosis at the time of surgery and the overall poor response rates of melanoma to adjuvant chemotherapy.

The contribution of spirituality and spiritual coping to anxiety and depression in women with a recent diagnosis of gynecological cancer.

The objective of this study was to determine whether, after accounting for illness and demographic variables, spiritual involvement and beliefs and positive and negative spiritual coping could account for any of the variation in anxiety and depression among women within 1 year's diagnosis of gynecological cancer (GC). One hundred patients from outpatient GC clinics at two Melbourne-based hospitals completed a brief structured interview and self-report measures of anxiety, depression, spirituality, and spiritual coping. Using two sequential regression analyses, we found that younger women with more advanced disease, who used more negative spiritual coping, had a greater tendency towards depression and that the use of negative spiritual coping was associated with greater anxiety scores. Although not statistically significant, patients with lower levels of generalized spirituality also tended to be more depressed. The site of disease and phase of treatment were not predictive of either anxiety or depression. We conclude that spirituality and spiritual coping are important to women with GC and that health professionals in the area should consider these issues.

Inhibins/activins as diagnostic markers for ovarian cancer.

It is widely recognised that the early detection and subsequent assessment of recurrence of ovarian cancers are key steps for successful treatment. Available serum markers (e.g. CA125) are sensitive for some epithelial carcinomas (e.g. serous, endometrioid, clear cell), however, these markers are less sensitive for granulosa cell tumours and mucinous carcinomas. Serum inhibin is an ovarian product which decreases to non detectable levels after menopause, however, certain ovarian cancers (mucinous carcinomas and sex cord stromal tumours such as granulosa cell tumours) continue to produce inhibin which provides a basis for a serum diagnostic test. Studies from this and other laboratories have investigated the suitability of inhibin as a diagnostic marker by identifying which inhibin (inhibin A (alphabetaA), inhibin B (alphabetaB), free alpha subunit) or activin (betaAbetaA) form is associated with these cancers. Available data show that inhibin assays which detect all inhibin forms, i.e. assays which detect the alpha subunit both as the free form and as an alphabeta subunit dimer provide the highest sensitivity/specificity characteristics as an ovarian cancer diagnostic test. This review will discuss the data supporting these observations and show recent studies in which a new alpha subunit monoclonal antibody-based ELISA is used as a potential diagnostic test. Furthermore, based on the high sensitivity/specificity characteristics of the respective assays for the various types of ovarian cancer, the combination of the inhibin assay with CA125 detects the majority of all ovarian cancers.

FSH-regulated gene expression profiles in ovarian tumours and normal ovaries.

Development, growth and function of the ovary are controlled by endocrine and paracrine signals. These may also influence the development of ovarian cancer. The aim of this study was to identify the key molecular markers of the unregulated growth and hormone synthesis seen in ovarian tumours, particularly in granulosa cell tumours (GCT). Genes used in this study were chosen on the basis of our understanding of growth and differentiation in the normal ovary. We sought to define the patterns of gene expression in a panel of epithelial and stromal ovarian tumours. Expression was determined by RT-PCR using gene-specific primers for the FSH receptor (FSHR); the FSH early response genes: regulatory subunit of protein kinase A (RII-beta), cyclin D2 (cycD2) and sgk; and late response markers: cyclooxygenase-2 (COX-2) and the LH receptor (LHR). The GCT had high expression of FSHR compared with normal ovaries and the other tumours. cycD2 and RII-beta and COX-2 genes were also highly expressed in the GCT. sgk and LHR expression was lower in all of the tumours than in normal ovaries. Serous cystadenocarcinomas also had an unexpectedly high expression of COX-2. Comparison of the gene expression profiles between each tumour group suggests a molecular phenotype for GCT that is similar to that reported for FSH stimulated pre-ovulatory granulosa cells.

A comparison of MRI and PET scanning in surgically staged loco-regionally advanced cervical cancer: potential impact on treatment.

The aim of this study was to assess whether positron emission tomography (PET) or magnetic resonance imaging (MRI) could obviate the need for surgical staging in patients with locally advanced cervical carcinoma being planned for radiotherapy (RT). Imaging findings were compared to surgical staging in 27 patients including three with recent resection of the primary tumor. Both PET and MRI visualized all 24 residual cervical tumors. Primary tumor volume, as measured by MRI scan, ranged from 1.25 cc to 140 cc. In 24 patients evaluable for pelvic nodal status, PET had sensitivity, specificity, and positive and negative predictive values of 83%, 92%, 91% and 85%, respectively, with 88% accuracy. MRI detected only six in 12 (50%) patients with confirmed pelvic nodal disease, all of which were also seen by CT and PET, with an overall accuracy of 75%. PET detected only four in seven (57%) cases with confirmed para-aortic (PA) involvement. All histologically confirmed sites not visualized on PET were <1 cm. Without surgical staging, six in 10 (60%) patients with histologically proven pelvic nodal disease would not have received pelvic boost if guided by MRI alone, compared to two in 10 (20%) patients guided by PET alone or in combination with MRI. All four patients with positive PA on PET were confirmed on histology or clinical follow-up, including one case that proved to be a false negative one on surgery. However, in three cases, PET would have yielded an inadequate radiation volume. In conclusion, the positive predictive value of PET in the pelvis and para-aortic region appears sufficient to obviate lymph nodal sampling, but sampling is still required to exclude small-volume disease cranial to sites of abnormality on PET. MRI has insufficient accuracy for nodal staging to impact management.

[Inhibin and ovarian cancer]. / Ingibin i rak iaichnikov.

Previous observations from our laboratory have demonstrated that the levels of immunoreactive inhibin (ir-inh) are elevated in almost all patients with granulosa cell tumors and in the majority of postmenopausal women with mucinous ovarian cancers. The present report confirms these findings in a larger group of post-menopausal women. Immunohistochemistry for the inhibin alpha. beta A and beta B sununits shows predominantly epithelial staining in granulosa cell tumors and in the majority of mucinous cancers. Serous cystadenocarcinomas also frequently show positive staining. Studies seeking to identify G alpha i-2 or FSH receptor mutations have provided negative results in contrast to other reports. Further studies of the roles of the inhibin-related family of peptides in ovarian cancer diagnosis and monitoring are clearly indicated.

Inhibin subunit gene expression in ovarian cancer.

OBJECTIVE(S): Granulosa cell tumors (GCT) and mucinous cystadenocarcinoma of the ovary are associated with elevated circulating levels of immunoreactive inhibin. Measurement of serum inhibin levels provides a useful tumor marker in the management of ovarian tumors. Inhibin is a dimeric ovarian glycoprotein hormone consisting of one alpha and one of two beta subunits. The beta subunits can dimerize to form activin. Activin is bound and its action modulated by another gonadal peptide, follistatin. In this study the patterns of expression of the three inhibin subunit genes, the follistatin gene, and the activin receptor type II gene have been determined. METHODS: Gene expression was analyzed in RNA prepared from 16 primary ovarian tumors using reverse transcriptase-polymerase chain reaction (RT-PCR). Gene-specific primes were used for RT-PCR; the products were analyzed by Southern blot analysis with gene-specific 32P-labeled probes. RESULTS: Widespread expression of these genes was found in all of the tumor types examined. Abundant expression of the inhibin alpha subunit gene was observed in the GCT and to a lesser extent in the mucinous and serous tumors. beta subunit expression was also present in the GCT and to a lesser extent in the other tumors. Widespread expression of both the activin receptor type II and the follistatin genes was also observed. CONCLUSIONS: Expression of the inhibin subunit genes in GCT and some epithelial tumors confirms that these tumors are the source of the increased immunoreactive inhibin seen in the circulation of patients with ovarian tumors. Expression of the activin receptor type II and follistatin genes suggests a paracrine role for activin in these tumors which may be modulated by follistatin, particularly in the GCT.

Inhibin and ovarian cancer.

Previous observations from our laboratory have demonstrated that the levels of immunoreactive inhibin (ir-inh) are elevated in almost all patients with granulosa cell tumours and in the majority of postmenopausal women with mucinous ovarian cancers. The present manuscript confirms these findings in a larger group of postmenopausal women. Immunohistochemistry for the inhibin alpha, betaA and betaB subunits shows predominantly epithelial staining in granulosa cell tumours and in the majority of mucinous cancers. Serous cystadenocarcinomas also frequently show positive staining. Studies seeking to identify G alpha(i-2) or FSH receptor mutations have provided negative results in contrast to other reports. Further studies of the roles of the inhibin-related family of peptides in ovarian cancer diagnosis and monitoring are clearly indicated.

No evidence of a role for mutations or polymorphisms of the follicle-stimulating hormone receptor in ovarian granulosa cell tumors.

The molecular pathogenesis of granulosa cell tumors of the ovary is not understood, although recent studies have shown that immunoreactive inhibin secretion by these tumors may be used as a tumor marker. Granulosa cell tumors exhibit many features of normal granulosa cells, including a response to FSH and inhibin secretion. FSH levels are suppressed in patients with inhibin-secreting granulosa cell tumors, suggesting FSH-independent growth of these tumors. Activating mutations of the FSH receptor might, therefore, be involved in tumorigenesis. We sought to identify mutations in the FSH receptor genes of these tumors using PCR to amplify the exon encoding the transmembrane and cytoplasmic domains from the tumor DNA. Analysis of the amplicons for single strand conformational polymorphisms and direct sequencing confirmed a previously reported polymorphism in the C-terminal region of the receptor, but did not identify tumor-specific missense mutations and/or polymorphisms. In addition, ribonucleic acid from 3 granulosa cell tumors was used to confirm expression of the FSH receptor; expression was unexpectedly also observed in several ovarian mucinous cystadenocarcinomas used as controls. In conclusion, our failure to identify activating mutations of the FSH receptor in 15 granulosa cell tumors argues against a role for the FSH receptor in tumorigenesis and suggests that some subsequent component of this signal transduction pathway may be activated.

Absence of the previously reported G protein oncogene (gip2) in ovarian granulosa cell tumors.

The molecular pathogenesis of granulosa cell tumors of the ovary is not understood, although recent studies have shown that authentic inhibin secretion by these tumors may be used as a tumor marker. G proteins are heterotrimeric membrane-based polypeptides that mediate signal transduction. Activating mutations of the alpha-subunit have been reported in several tumors in which the resulting constitutively activated signal transduction pathway may be involved in tumorigenesis. Activating mutations of the G protein, G alpha I-2, have been reported to be present in 30% of ovarian sex cord tumors and in adrenocortical tumors; this activated G alpha I-2 has been designated the gip2 oncogene. We sought to explore the frequency of this oncogene in granulosa cell tumors, the most common of the sex cord tumors. Genomic DNA was obtained from either fresh-frozen tumor tissue or paraffin-embedded sections. Using both allele-specific oligonucleotide hybridization and direct sequencing of a PCR-amplified region of the G alpha I-2 gene, we were unable to confirm the presence of the previously reported mutation in any of the 13 tumors examined. The gip2 oncogene does not appear to be present at high frequency in ovarian granulosa cell tumors.

Combined ovarian serous papillary and hepatoid carcinoma.

Hepatoid carcinoma is a rare type of malignant tumor resembling hepatocellular carcinoma that arises in extrahepatic sites. A case of a combined hepatoid and serous papillary carcinoma of the ovary in a 72-year-old woman is reported. The hepatoid component showed alpha-fetoprotein production. Imperceptible merging of the hepatoid and serous papillary components was seen, supporting the theory of a surface epithelial origin of ovarian hepatoid carcinoma.

Characterization of inhibin immunoreactivity in post-menopausal women with ovarian tumours.

BACKGROUND AND OBJECTIVE: We have previously reported elevated serum immunoreactive inhibin (INH) levels in patients with ovarian malignancies, particularly granulosa cell and mucinous tumours. The present study was designed to compare INH measurements using a heterologous radioimmunoassay with cross-reactivity for inhibin alpha-subunit derived peptides with measurements obtained using a new ELISA specific for dimeric inhibin-A. It was hypothesized that granulosa cell tumours may secrete significant quantities of inhibin-A whereas mucinous tumours were unlikely to do so because of the lack of a relation between INH and FSH measurements in the latter group. DESIGN: Serum samples obtained from women found to have ovarian cancer were assayed using the heterologous radioimmunoassay (the Monash assay) and using an ELISA specific for dimeric inhibin (the Groome assay) and the results were compared. PATIENTS: Samples for assay were available from 69 normal post-menopausal control women, 12 patients with mucinous tumours of the ovary, 26 with serous tumours, 7 with granulosa cell tumours and 8 with various other ovarian tumours. Patients were post-menopausal or had been subjected to bilateral oophorectomy at the time these samples were collected. MEASUREMENTS: The Monash and Groome assays were carried out as described previously. The upper limit of normal for post-menopausal women in the Monash assay was 122 U/l and for the Groome assay was calculated to be 32 ng/l. RESULTS: Among the 69 normal subjects, 4 were found to have elevated inhibin levels using the Monash RIA (133-190 U/l) and 4 were found to have elevated levels in the Groome ELISA (45.5-55.3 ng/l). Among 12 patients with mucinous tumours, 10 (83%) had elevated inhibin levels using the Monash assay but only 3 (25%) had elevated levels with the Groome assay (P < 0.005). Among 26 with serous tumours, 15 (58%) had elevated levels in the Monash assay but only 1 (4%) in the Groome assay (P < 0.001). Among 7 samples from patients with granulosa cell tumours, 100% were elevated in the Monash assay and 71% in the Groome assay (NS, non-significant). In a miscellaneous group of tumours all 8 had elevated levels in the Monash assay and 2 in the Groome assay (P < 0.001). CONCLUSIONS: It was concluded that in normal postmenopausal subjects, INH is generally undetectable or present at low levels, consistent with the loss of ovarian function. The majority of granulosa cell tumours appear to secrete significant amounts of dimeric inhibin-A, whereas mucinous tumours secrete predominantly other forms of INH, presumably related to the alpha-subunit. Serous tumours may also secrete inhibin-related peptides but not dimeric inhibin-A. The nature of the inhibin related peptides produced by epithelial ovarian cancers remains to be characterized.

Inhibin and activin are demonstrable by immunohistochemistry in ovarian tumor tissue.

Elevated serum immunoreactive inhibin concentrations have been reported in patients with mucinous and granulosa cell tumors of the ovary. The present study aimed to determine whether the inhibins and/or the related peptides, the activins, were demonstrable within ovarian tumor tissue. Immunohistochemical analyses were performed on 11 ovarian tumors, 5 mucinous, 3 serous, 1 granulosa, 1 clear cell, and 1 metastatic colonic cancer. Both monoclonal and polyclonal antisera specific for inhibin-A, activin-A, and activin-B, and their alpha-, beta A- and beta B-subunits were used. The mucinous cells of all five mucinous tumors showed positive staining for activin-A and activin-B, and their beta A- and beta B-subunits, and three stained positive for inhibin-A and the alpha-subunit. The granulosa cell tumor also showed positive staining for inhibin-A and the activins. The remaining tumors were negative. The findings are consistent with the hypersecretion of inhibin (and possibly activin) by some ovarian malignancies and suggest that immunohistochemistry for the inhibins and the activins should be explored further in the classification of ovarian malignancies.

A prospective study of inhibin in granulosa cell tumors of the ovary.

Elevated preoperative serum inhibin concentrations have been reported in patients with granulosa cell tumor of the ovary. The aim of this study was to determine if elevations in serum inhibin predated clinical recurrence in patients with a diagnosis of granulosa cell tumor. Twenty-seven consecutive patients with granulosa cell tumor were followed prospectively to assess the relationship between serum inhibin concentrations and disease status. The serum inhibin concentrations in normal postmenopausal women were < 77-130 U/liter. In patients with granulosa cell tumor at initial surgery, mean inhibin concentrations preoperatively were 2831 U/liter in 4 postmenopausal subjects (range 2130-3323 U/liter) and 3680 U/liter in each of 2 premenopausal women. In 5 postmenopausal subjects with a histological diagnosis of granulosa cell tumor who underwent secondary surgery because of a recurrent palpable mass, mean inhibin concentrations were 4216 U/liter (range 2672-7360). In 3 patients with known or suspected residual disease despite a secondary debulking operation the serum inhibin concentrations were 475, 1000, and 2541 U/liter. In 13 subjects who were clinically disease free with a previous diagnosis of granulosa cell tumor, serum inhibin concentrations remained within the normal range for reproductive status. We conclude: (1) Preoperative serum inhibin concentrations are typically elevated sevenfold above the normal premenopausal follicular phase levels in women with granulosa cell tumor; (2) after surgery, serum inhibin levels may become elevated up to 2 years before further surgery is undertaken; and (3) serum inhibin concentrations appear to be a valuable tumor marker for the diagnosis of primary or recurrent granulosa cell tumor.