Icon immunoconjugate treatment results in regression of red lesions in a non-human primate (Papio anubis) model of endometriosis.

Endometriosis is a common condition in reproductive-aged women characterized by ectopic endometrial lesions of varied appearance, including red, white, blue, black or powder burn coloration, which contribute to chronic pain and infertility. The immunoconjugate molecule (Icon) targets Tissue Factor, a transmembrane receptor for Factor VII/VIIa that is aberrantly expressed in the endothelium supporting ectopic endometrial tissue. Icon has been shown to cause regression of endometriosis in a murine model of disease but prior to this study had not been tested in non-human primates. This study evaluated Icon as a novel treatment for endometriosis in non-human primates (Papio anubis) using an adenoviral vector (AdIcon) delivery system. Female baboons (n = 15) underwent surgical induction of endometriosis. After laparoscopic confirmation of endometriosis lesions 6-weeks post-surgery, the treatment group (n = 7) received weekly intraperitoneal injections of viral particles carrying the sequence for Icon, resulting in expression of the protein, while the control group (n = 8) received no treatment. Icon preferentially reduced the number and volume of red vascularized lesions. Icon may present a novel treatment for endometriosis by degrading red vascularized lesions, likely by targeting tissue factor aberrantly expressed in the lesion vasculature.

Usefulness of Flow Cytometry in Diagnosis of IgG4-Related Ophthalmic Disease and Extranodal Marginal Zone B-Cell Lymphoma of the Ocular Adnexa.

BACKGROUND/AIM: Although flow cytometry (FCM) is used to evaluate cell surface markers of various leucocyte populations quantitatively, little is known about the usefulness of FCM in lymphoproliferative disorders of the ocular adnexa. The aim of this study was to disclose results of FCM, which were compared among IgG4-related ophthalmic disease (IgG4-ROD), idiopathic orbital inflammation (IOI), and extranodal marginal zone B-cell lymphoma (EMZL). MATERIALS AND METHODS: This is a retrospective observational study. Sixty-nine tumors comprising of 16 IgG4-ROD, 24 IOI, and 29 EMZL were enrolled in the study. All tumors, surgically excised, were diagnosed based on histopathology, immunoglobulin (Ig) heavy chain gene rearrangement, and FCM. In FCM, the percentage of T-cell markers (CD2, CD3, CD4, CD5, CD7, CD8), B-cell markers (CD10, CD19, CD20, CD23), NK cell marker (CD56) and cell surface kappa/lambda was searched based on medical records. Ig light chain restriction was evaluated from results in kappa/lambda deviation by FCM. RESULTS: The percentage of CD2, CD3, CD4, CD7, and CD10 was significantly higher in IgG4-ROD/IOI than EMZL (p<0.05 in every factor). In contrast, CD19 and CD20 percentages were significantly greater in EMZL than IgG4-ROD/IOI (p<0.01). There was no significant difference in any marker between IgG4-ROD and IOI. Kappa-positive cells were significantly greater in EMZL than IgG4-ROD/IOI (p<0.05). In kappa/lambda deviation, false-positive was noted in 3 (7.5%) benign IgG4-ROD/IOI and false-negative was observed in 10 (34.5%) EMZL cases. Sensitivity and specificity of Ig light chain restriction were 65.5 and 92.5%, respectively. CONCLUSION: Analyses of cell surface markers using FCM were useful in differentiating EMZL from IgG4-ROD/IOI. Sensitivity of Ig light chain restriction was relatively low in diagnosis of EMZL using FCM.

IgG4-related ocular adnexal disease mimicking thyroid-associated orbitopathy.

A 72-year-old man presented with bilateral eyelid swelling and redness. An orbital CT scan showed bilateral proptosis, extraocular muscle enlargement and swollen lacrimal glands, mimicking thyroid-associated orbitopathy (TAO) with Hashimoto's thyroiditis (HT). During the patient's clinical course, spontaneous remission of lung consolidation (35 × 26 mm) was seen. A diagnosis of IgG4-related disease (IgG4-RD) was made based on an elevated serum IgG4 level (1,020 mg/dL; normal, 4-108), predominance of IgG4-positive plasma cells (IgG4/IgG: 35/70 in HPF) in the lacrimal glands and typical features of Mikulicz's disease. This report provides a novel description of this unusual disease entity among HT, TAO and IgG4-RD.

Microscopic dysgerminoma associated with anti-Ma2 paraneoplastic encephalitis in a patient with gonadal dysgenesis.

We present a 27-yr-old female with gonadal dysgenesis (46, XY), who presented to our hospital with poor consciousness, aphasia, restlessness, and visual hallucination. Physical examination revealed normal breast development and normal external female genetalia. Computed tomography scan of the head and neck revealed the presence of brain edema, hydrocephalous, and a localized hypodense lesion in the hypothalamus. Her serum was positive for the anti-Ma2, which is associated with paraneoplastic encephalitis syndrome. Computed tomography of the abdomen revealed the presence of a 7.5×5.3×3.0 cm solid pelvic mass. Interestingly, a single microscopic focus of dysgerminoma was identified in a background of stromal fibrosis and focal dystrophic calcifications. No ovarian stroma or testicular tissue was identified. To our knowledge, this is the first case of gonadal dysgenesis presenting with anti-Ma2 paraneoplastic encephalitis with dysgerminoma. A discussion about paraneoplastic encephalitis with a microscopic dysgerminoma associated with anti-Ma2 antibody is presented.

Differential diagnosis of adnexal masses: sequential use of the risk of malignancy index and HistoScanning, a novel computer-aided diagnostic tool.

OBJECTIVE: To assess the value of ovarian Histo-Scanning(™) , a novel computerized technique for interpreting ultrasound data, in combination with the risk of malignancy index (RMI) in improving triage for women with adnexal masses. METHODS: RMI indices were assessed in 199 women enrolled in a prospective study to investigate the use of HistoScanning. Ultrasound scores were obtained by blinded analysis of archived images. The following sequential test was developed: HistoScanning was modeled as a second-line test for RMI between a lower cut-off and an upper cut-off. The optimal combination of these cut-offs that together maximized the Youden index (Sensitivity + Specificity - 1) was determined. RESULTS: Using RMI at the standard cut-off value of 250 resulted in a sensitivity of 74% and a specificity of 86%. When RMI was combined with HistoScanning, the highest accuracy was achieved by using HistoScanning as a sequential second-line test for patients with RMI values between 105 and 2100. At these cut-off values, sequential use of RMI and HistoScanning resulted in mean sensitivity and specificity estimates of 88% and 95%, respectively. CONCLUSIONS: Our data suggest that HistoScanning may have the potential to improve the diagnostic accuracy of RMI, which could result in better triage for women with adnexal masses. Further prospective validation is warranted.

[Antibodies against the chlamydial heat shock protein in women with periadnexal adhesions]. / Protilátky proti proteinu tepelného soku chlamydiového puvodu u zen s periadnexálními adhezemi.

OBJECTIVE: To compare and analyze IgG antibodies against chlamydial heat shock protein (cHSP60) in the blood serum of women with or without periadnexal adhesions in small pelvis. DESIGN: Retrospective study. SETTING: Department of Gynaecology and Obstetrics, Masaryk University, Brno, Veterinary Research Institute, Brno, Department of Clinical Microbiology, Faculty Hospital Brno. METHODS: IgG antibodies against cHSP60 in the blood serum were detected by means of recombinant enzyme immunoanalysis ("cHSP60 - IgG - rELISA medac"). The presence of antibodies was expressed as +, ++ or +++ pozitive. Laparoscopy according to a standard procedure was performed in 76 women (age 28 +/- 43 years) from couples with fertility disorders treated in the Centre of Reproductive Medicine, Department of Gynaecology and Obstetrics. Chí-square test (programme Statcalc - EpiInfo 6) and calculation of OR value were used for statistical analysis. RESULTS: Twenty-four women (31.6%) had normal finding in small pelvis. Periadnexal adhesions were detected in 43 (56.6%) patients, hydrosalpinx in 13 cases (17.1%), endometriosis in 27 (35.5%) patients and uterine myomas in 11 (145%) women. In the group of 33 women without periadnexal adhesions cHSP-60 antibodies were pozitive in 3 women (9.1%), in 43 women with periadnexal adhesions were pozitive in 17 cases (39.5%). In 13 patients with hydrosalpinx cHSP-60 antibodies were pozitive in 61.5%. In patients with periadnexal adhesions semiquantitative pozitivity +++ was detected in 8 cases (18.6%), 4 of them with hydrosalpinx (30.8%). Statistical analysis found significantly higher presence of cHSP-60 antibodies in women with periadnexal adhesions (OR = 654, CI interval = 1.59 - 37.81, chi-square: p = 0.0028) CONCLUSION: Women with periadnexal adhesions have more frequent and stronger pozitivity of IgG antibodies against chlamydial heat shock protein cHSP60.

Expression of adhesion molecules and Ki-67 in female adnexal tumor of probable Wolffian origin (FATWO): report of two cases and review of the literature.

Female adnexal tumor of probable Wolffian origin (FATWO) is a rare entity which is believed to originate from mesonephric (Wolffian) remnants on the basis of its location where the remnants are abundant. Its behavior is usually indolent, although some cases can recur or metastasize. The authors present the clinicopathological features of two cases of FATWO arising in the broad ligament, and focus on the expression of adhesion molecules and proliferative marker. Mesonephric duct remnants are also examined in an attempt to elucidate the histogenesis of FATWOs. The two FATWOs were well-circumscribed solid masses arising in the leaves of the broad ligament and histological examination revealed a mixture of cysts and tubules imparting a sieve-like pattern and mucin-negative eosinophilic secretion within these tubules. Immunohistochemically, the tumors showed the expression of cytokeratin 7 and 20, high-molecular-weight cytokeratin, and calretinin, which closely resembled that of the mesonephric duct remnants. Regarding CK 20, CD 10, EMA, S-100 protein, and vimentin their expression was in part not identical with previous studies. E-cadherin, alpha and beta-catenin were strongly expressed along the cell membrane of the tumor cells. The Ki-67 labeling index of FATWO was 0% and 3.2% in each case. The preservation of the E-cadherin-catenin complex and low Ki-67 labeling index could explain the indolent behavior and low malignant potential of this tumor.

Location and intensity of IL-8 and TGF-beta2 mRNA production in the fimbrial compartment of fallopian tubes and IL-10 in the endometrium in patients with pyoinflammatory adnexal diseases.

The location and level of IL-8 and TGF-beta2 expression in the fimbrial compartment of fallopian tubes and IL-10 expression in the endometrium of women with pyoinflammatory adnexal diseases were studied by in situ hybridization. These diseases are associated with considerable changes in the levels of local production of these cytokines. Inflammatory infiltration and epithelial cells were most active producers of IL-9 and TGF-beta2 in the fimbrial compartment of fallopian tubes, while in the endometrium IL-10 gene was expressed at a high level primarily in the glandular epithelial cells.

Local expression of cytokine genes in uterine adnexa and endometrium of women with pyoinflammatory adnexal diseases.

Changes in the local expression of IL-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-15, IL-18, TNF-alpha, IFN-gamma- and TGF-beta(2) genes in the uterine adnexa and endometrium were studied in women with pyoinflammatory adnexal diseases. Examination of tissue specimens from the uterine adnexa involved in inflammation revealed a direct correlation in the levels of mRNA production between IL-6 and IL-10 (r=0.93, p<0.1), IL-6 and IL-4 (r=0.96, p<0.01), IL-10 and IL-4 (r=0.91, p<0.01), IL-12 and IFN-gamma (r=0.98, p<0.01). Expression of IL-4 gene increased 5.1-fold (p=0.001), IL-6 2-fold (p=0.007), IL-8 90.2-fold (p=0.009), IL-10 2.9-fold (p=0.008), IL-12 2.3-fold (p=0.3), and TGF-beta(2) gene 10.3-fold (p=0.1). In the endometrium of women with pyoinflammatory adnexal diseases only IL-10 gene expression increased (15.6-fold, p=0.007).

[Use of color Doppler technique and estimation of CA 125 amd TPA levels in blood serum for the diagnosis of adnexal masses]. / Zastosowanie techniki kolorowego Dopplera oraz oceny poziomów antygenów Ca 125 i TPA w surowicy krwi w diagnostyce zmian w obrebie przydatków.

OBJECTIVE: The purpose of the study was to compare usefulness of color doppler technique and measurements of Ca 125 and TPA levels in differential diagnosis of adnexal masses. MATERIAL AND METHODS: 122 patients admitted and diagnosed due to presence of adnexal masses. Transvaginal scans with color doppler technique were performed Ca 125 and TPA levels in blood serum were measured. Morphological features of tumor during transvaginal scans were also noticed. Histopathological data after operation were collected and compared with preoperative scores. RESULTS: 22 adnexal masses were malignant. Presence of central vascularisation within the tumor and low Resistance Index and Pulsatility Index values were the best predictors of malignancy. Measurements of Ca 125 and TPA levels had worse predictive value ind diagnosis of adnexal masses. CONCLUSIONS: Color doppler technique is a useful tool in diagnosis of adnexal masses and has higher sensitivity and specificity compared with measurements of Ca125, TPA levels and single tumor features achieved during transvaginal ultrasound.

Diagnosis and management of the adnexal mass.

Adnexal masses are frequently found in both symptomatic and asymptomatic women. In premenopausal women, physiologic follicular cysts and corpus luteum cysts are the most common adnexal masses, but the possibility of ectopic pregnancy must always be considered. Other masses in this age group include endometriomas, polycystic ovaries, tubo-ovarian abscesses and benign neoplasms. Malignant neoplasms are uncommon in younger women but become more frequent with increasing age. In postmenopausal women with adnexal masses, both primary and secondary neoplasms must be considered, along with leiomyomas, ovarian fibromas and other lesions such as diverticular abscesses. Information from the history, physical examination, ultrasound evaluation and selected laboratory tests will enable the physician to find the most likely cause of an adnexal mass. Measurement of serum CA-125 is a useful test for ovarian malignancy in postmenopausal women with pelvic masses. Asymptomatic premenopausal patients with simple ovarian cysts less than 10 cm in diameter can be observed or placed on suppressive therapy with oral contraceptives. Postmenopausal women with simple cysts less than 3 cm in diameter may also be followed, provided the serum CA-125 level is not elevated and the patient has no signs or symptoms suggestive of malignancy.

A multicenter study of laparoscopic management of selected cystic adnexal masses in postmenopausal women.

BACKGROUND: The objective of this study was to determine the ability to predict benign adnexal masses in postmenopausal women and to evaluate the effectiveness of laparoscopic management in selected patients. STUDY DESIGN: Postmenopausal women found to have an adnexal mass were prospectively evaluated with clinical examination, sonography, and serum CA-125 levels. Women with cystic masses greater than 3 cm but less than 10 cm, with distinct borders, without solid parts or septations greater than 2 mm, without ascites or matted bowel, and with serum CA-125 levels less than 35 IU per mL were operated upon by laparoscopy. RESULTS: Sixty-one women gave consent for the study. Cyst size ranged from 3 to 10 cm. All masses were accurately predicted to be benign. Fifty-eight (95 percent) women were successfully managed by operative laparoscopy and three required laparotomy. For the patients managed by laparoscopy, the mean operative time was 63 minutes, the mean postoperative hospitalization period was 12 hours, and the mean return to normal activity was 5.6 days. CONCLUSIONS: The combination of clinical examination, sonographic appearance and serum CA-125 levels can accurately predict benign masses in postmenopausal women. Operative laparoscopy is acceptable for these patients and provides for a short period of hospitalization and a rapid recovery.

Correlation of serum, urinary and salivary CA 125 levels in patients with adnexal masses.

A prospective study was made of 105 consecutive patients admitted to one department of obstetrics and gynaecology for surgery for adnexal masses. The objective was to investigate if CA 125 level is measurable in the urine or saliva and to correlate these measurements with serum CA 125 level in patients presenting with adnexal masses. The final diagnosis and grouping of patients for analysis were based on histopathological examination of the adnexal masses. Serum, urine and salivary samples were collected simultaneously from all patients on the morning before surgery. CA 125 levels in each sample were determined in duplicate using Abbott CA 125-E1A monoclonal test kits (Abbott Laboratories, USA). The mean inter-assay variability was 10%. CA 125 was detectable in the serum, urine and saliva from all the patients and the concentration was highest in the saliva and lowest in urine. There were no discernible differences in the distributions of salivary CA 125 concentrations between patients with ovarian malignancies and those with benign ovarian cysts. In contrast, both serum and urinary CA 125 levels were significantly higher in the ovarian cancer group. There was no correlation in CA 125 concentrations between serum and urine, or between serum and saliva. For detection of ovarian malignancies, the sensitivity, specificity, and positive and negative predictive values for serum CA 125 measurement (> or = 35 U/mL) were 88.9%, 79.2%, 27.6% and 98.7 respectively. The corresponding figures for urinary CA 125 measurement (> or = 10 U/mL) were 88.9%, 66.7%, 19.5% and 98.4% respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of CO2 laser laparoscopy for treatment of pelvic endometriosis on serum concentrations of antiendometrial antibodies.

This study uses antiendometrial antibodies as an indicator for follow-up of patients with endometriosis after surgical treatment. This is a prospective study of 32 patients with endometriosis. The patients were used as their own controls. Serum samples were obtained before surgery and 1 month, 3 months, and 6-9 months following surgery. All patients were treated with CO2 laser laparoscopy. Serum concentrations of antiendometrial antibodies decreased significantly at 1 month, 3 months, and 6-9 months following treatment in each group. There was no correlation between baseline concentration of antibodies and stage of the disease. This study confirms the value of using antiendometrial antibodies as an indicator for follow-up of endometriosis patients. Surgical treatment with CO2 laser laparoscopy is effective in lowering the antigenic effect of the disease in these patients. This beneficial effect is maintained for up to 9 months after treatment.

Management of adnexal masses by operative laparoscopy. Selection criteria.

The management of adnexal masses by operative laparoscopy is controversial. The application of strict criteria for preoperative patient selection and careful intraoperative assessment and management are critical to the appropriate use of this approach. Clinical examination, ultrasound imaging of the pelvis and the addition of the CA-125 tumor marker in postmenopausal women can aid in the selection of a population at low risk for malignancy that may be appropriate for operative laparoscopic adnexal surgery. Recommended procedures include careful intraoperative inspection of the pelvis and abdomen, liberal use of frozen sections, and conversion to immediate-staging laparotomy when malignancy is found.

Management of selected cystic adnexal masses in postmenopausal women by operative laparoscopy: a pilot study.

Twenty-five postmenopausal patients were predicted to have benign masses by screening criteria that included ultrasonographic findings of a cystic adnexal mass less than 10 cm with distinct borders and no evidence of irregular solid parts, thick septa, ascites, or matted bowel, and a normal serum CA 125 value (less than 35 U/ml). All 25 masses were accurately predicted to be benign. The size of the cysts on ultrasonography ranged from 3 to 9 cm with a mean of 5 cm. Twenty-two patients (88%) were successfully managed by operative laparoscopy and adnexectomy. Mean operative time was 70 minutes and mean postoperative hospital stay was 12 hours. Mean time of return to normal activity was 5 days. Three patients required laparotomy. We conclude that removal of these cystic adnexal masses by operative laparoscopy is an acceptable alternative in carefully selected postmenopausal women.

Pretreatment serum levels of CA-125, carcinoembryonic antigen, tissue polypeptide antigen, and placental alkaline phosphatase, in patients with ovarian carcinoma, borderline tumors, or benign adnexal masses: relevance for differential diagnosis.

Pretreatment serum levels of the antigens CA-125, tissue polypeptide Antigen (TPA), carcinoembryonic antigen (CEA), and placental alkaline phosphatase (PLAP) were determined in samples from 295 women with adnexal masses. At laparotomy 48% of patients had epithelial ovarian carcinoma, 9% had tumors of low malignant potential, and 8% suffered from malignancies of other kinds. The sensitivity of CA-125 with 35 U/ml as the cutoff was 88% in women with ovarian carcinoma, but 74% among those with limited disease and 58% in borderline malignancy. Only 6 of 17 mucinous ovarian carcinomas were detected. Specificity was 83%. CEA was elevated above 5.0 micrograms/liter in 15 of 17 patients with mucinous ovarian cancer. TPA detected advanced stages of malignancy, but the sensitivity was low, 53%, in cases with limited disease. PLAP was elevated in 46% of ovarian carcinoma patients. For detecting malignancy overall, the use of a parallel combination of the CA-125 and CEA assays was more sensitive than use of CA-125 as a single marker. This test combination may be of value in the diagnosis of adnexal masses. The predictive value of a positive result was 90%, and that of a negative result, 76%.

Antibodies of ovarian antigens in different diseases of the ovary.

Using the test of antiglobulin serum consumption against the human ovarian antigen, investigations were conducted on the presence of antiovarian antibodies in the blood serum of 432 women with different diseases of the ovary and 50 healthy women as control group. Autoantibodies were found in 12 of 172 patients with inflammatory lesions of the ovary (7.0%), in 18 of 118 patients with ovarian failure (15.3%), and in 21 of 65 patients with malignancies of the ovary (32.3%). No autoantibodies were detected in any of the healthy women from the control group, in any of the 10 patients with tuberculosis of the adnexa, or in any of the 67 women operated upon for benign neoplasms of the ovary. The authors formulate the suppression that there may be a correlation between the occurrence of autoantibodies, lesions of the ovarian tissue, and the malignancy of the neoplastic process.