Treatment strategies in patients with gynecological sarcoma: Results of the prospective intergroup real-world registry for gynecological sarcoma in Germany (REGSA-NOGGO RU1).

OBJECTIVE: Gynecological sarcomas account for 3% of all gynecological malignancies and are associated with a poor prognosis. Due to the rarity and heterogeneity of gynecological sarcomas there is still no consensus on optimal therapeutic strategies. This study's objective was to describe the treatment strategies used in patients with gynecological sarcomas in the primary course of disease. METHODS: The German prospective registry for gynecological sarcoma (REGSA) is the largest registry for gynecological sarcomas in Germany, Austria and Switzerland. Primary inclusion criteria for REGSA are histological diagnosis of sarcoma of the female genital tract, sarcoma of the breast or uterine smooth muscle tumors of uncertain malignant potential (STUMP). We evaluated data of the REGSA registry on therapeutic strategies used for primary treatment from August 2015 to February 2021. RESULTS: A total of 723 patients from 120 centers were included. Data on therapeutic strategies for primary treatment were available in 605 cases. Overall, 580 (95.9%) patients underwent primary surgery, 472 (81.4%) of whom underwent only hysterectomy. Morcellation was reported in 11.4% (n=54) of all hysterectomies. A total of 42.8% (n=202) had no further surgical interventions, whereas an additional salpingo-ophorectomy was performed in 54% (n=255) of patients. An additional lymphadenectomy was performed in 12.7% (n=60), an omentectomy in 9.5% (n=45) and intestinal resection in 6.1% (n=29) of all patients. Among 448 patients with available information, 21.4% (n=96) received chemo- or targeted therapies, more commonly as single-agent treatment than as drug combinations. Information about anti-hormonal treatment was available for 423 patients, among which 42 (9.9%) received anti-hormonal treatment, 23 (54.8%) of whom with low-grade endometrial stroma sarcomas. For radiotherapy, data of 437 patients were available, among which 29 (6.6%) patients underwent radiotherapy. CONCLUSION: Our study showed that treatment of patients with gynecologic sarcomas is heterogeneous. Further trials are needed along with more information on treatment modalities, therapy response and patient-reported outcomes to implement new treatment strategies.

Rates of severe complications in patients undergoing colorectal surgery for deep endometriosis-a retrospective multicenter observational study.

INTRODUCTION: Surgical experience and hospital procedure volumes have been associated with the risk of severe complications in expert centers for endometriosis in France. However, little is known about other certified units in Central European countries. MATERIAL AND METHODS: This retrospective observational study included 937 women who underwent surgery for colorectal endometriosis between January 2018 and January 2020 in 19 participating expert centers for endometriosis. All women underwent complete excision of colorectal endometriosis by rectal shaving, discoid or segmental resection. Postoperative severe complications were defined as grades III-IV of the Clavien-Dindo classification system including anastomotic leakage, fistula, pelvic abscess and hematoma. Surgical outcomes of centers performing less than 40 (group 1), 40-59 (group 2) and ≥60 procedures (group 3) over a period of 2 years were compared. RESULTS: The overall complication rate of grade III and IV complications was 5.1% (48/937), with rates of anastomotic leakage, fistula formation, abscess and hemorrhage in segmental resection, discoid resection and rectal shaving, respectively, as follows: anastomotic leakage 3.6% (14/387), 1.4% (3/222), 0.6% (2/328); fistula formation 1.6% (6/387), 0.5% (1/222), 0.9%; (3/328); abscess 0.5% (2/387), 0% (0/222) and 0.6% (2/328); hemorrhage 2.1% (8/387), 0.9% (2/222) and 1.5% (5/328). Higher overall complication rates were observed for segmental resection (30/387, 7.8%) than for discoid (6/222, 2.7%, P = 0.015) or shaving procedures (12/328, 3.7%, P = 0.089). No significant correlation was observed between the number of procedures performed and overall complication rates (rSpearman  = -0.115; P = 0.639) with a high variability of complications in low-volume centers (group 1). However, an intergroup comparison revealed a significantly lower overall severe complication rate in group 3 than in group 2 (2.9% vs 6.9%; P = 0.017) without significant differences between other groups. CONCLUSIONS: A high variability in complication rates does exist in centers with a low volume of activity. Major complications may decrease with an increase in the volume of activity but this effect cannot be generally applied to all institutions and settings.

Evaluating the Use of Circulating MicroRNA Profiles for Lung Cancer Detection in Symptomatic Patients.

Importance: The overall low survival rate of patients with lung cancer calls for improved detection tools to enable better treatment options and improved patient outcomes. Multivariable molecular signatures, such as blood-borne microRNA (miRNA) signatures, may have high rates of sensitivity and specificity but require additional studies with large cohorts and standardized measurements to confirm the generalizability of miRNA signatures. Objective: To investigate the use of blood-borne miRNAs as potential circulating markers for detecting lung cancer in an extended cohort of symptomatic patients and control participants. Design, Setting, and Participants: This multicenter, cohort study included patients from case-control and cohort studies (TREND and COSYCONET) with 3102 patients being enrolled by convenience sampling between March 3, 2009, and March 19, 2018. For the cohort study TREND, population sampling was performed. Clinical diagnoses were obtained for 3046 patients (606 patients with non-small cell and small cell lung cancer, 593 patients with nontumor lung diseases, 883 patients with diseases not affecting the lung, and 964 unaffected control participants). No samples were removed because of experimental issues. The collected data were analyzed between April 2018 and November 2019. Main Outcomes and Measures: Sensitivity and specificity of liquid biopsy using miRNA signatures for detection of lung cancer. Results: A total of 3102 patients with a mean (SD) age of 61.1 (16.2) years were enrolled. Data on the sex of the participants were available for 2856 participants; 1727 (60.5%) were men. Genome-wide miRNA profiles of blood samples from 3046 individuals were evaluated by machine-learning methods. Three classification scenarios were investigated by splitting the samples equally into training and validation sets. First, a 15-miRNA signature from the training set was used to distinguish patients diagnosed with lung cancer from all other individuals in the validation set with an accuracy of 91.4% (95% CI, 91.0%-91.9%), a sensitivity of 82.8% (95% CI, 81.5%-84.1%), and a specificity of 93.5% (95% CI, 93.2%-93.8%). Second, a 14-miRNA signature from the training set was used to distinguish patients with lung cancer from patients with nontumor lung diseases in the validation set with an accuracy of 92.5% (95% CI, 92.1%-92.9%), sensitivity of 96.4% (95% CI, 95.9%-96.9%), and specificity of 88.6% (95% CI, 88.1%-89.2%). Third, a 14-miRNA signature from the training set was used to distinguish patients with early-stage lung cancer from all individuals without lung cancer in the validation set with an accuracy of 95.9% (95% CI, 95.7%-96.2%), sensitivity of 76.3% (95% CI, 74.5%-78.0%), and specificity of 97.5% (95% CI, 97.2%-97.7%). Conclusions and Relevance: The findings of the study suggest that the identified patterns of miRNAs may be used as a component of a minimally invasive lung cancer test, complementing imaging, sputum cytology, and biopsy tests.

Endometriosis Leads to an Increased Trefoil Factor 3 Concentration in the Peritoneal Cavity but Does Not Alter Systemic Levels.

This study analyzed whether trefoil factor 3 (TFF3) is locally elevated and correlated with common biomarkers and inflammatory processes in endometriosis. Peritoneal fluid (PF) was obtained from 50 women and serum from 124 women with or without endometriosis. Experimental endometriosis was induced in female C57BL/6 mice by syngeneic transplantation of uterine tissue to the abdominal wall. Levels of TFF3 in PF of women with endometriosis were significantly increased ( P < .05) and correlated with local levels of known biomarkers for endometriosis: cancer antigen (CA) 125, CA-19-9, interleukin 8, monocyte chemotactic protein 1, and matrix metalloproteinase 7. Serum levels of TFF3 in women were significantly influenced by the menstrual cycle but were independent from disease state. In mice, local TFF3 levels were significantly elevated in early endometriosis (up to 4 weeks after transplantation, P < .001) and corresponded to increases in spleen weight as marker for systemic inflammation. This study provides the first evidence that TFF3 is locally elevated in the peritoneal cavity in endometriosis and might play a role in disease pathogenesis and its associated inflammatory processes. Furthermore, the results show that TFF3 is regulated through the menstrual cycle. With respect to animal models, syngeneic mouse model does reflect local TFF3 upregulation in the peritoneal cavity affected by endometriosis.

Soluble tumor necrosis factor-alpha receptors in the serum of endometriosis patients.

INTRODUCTION: We examine serum levels sTNFR-I and sTNFR-II in endometriosis patients, and their role as biomarkers of endometriosis. MATERIAL AND METHODS: Women were diagnosed with endometriosis during laparoscopy to investigate pelvic pain and/or infertility (N=62). Control group included women with pelvic pain and/or infertility, whose laparoscopy showed no abnormalities (N=55). Serum concentrations of sTNFR-I and sTNFR-II were measured using Bioplex Protein Array system. Non-parametric statistics were used. RESULTS: Endometriosis patients had significantly higher levels of sTNFR-I than controls (257.46pg/ml, IQR=2.37-1048.92 versus 130.39pg/ml, IQR=0.99-361.1 respectively, P value=0.01). For TNFR-II, difference between women with (232pg/ml, IQR=0.0-624.4), and women without (132.93pg/ml, IQR=0.0-312.81) endometriosis was not significant (P value=0.05). Early stage endometriosis patients had significantly higher level of sTNFR-I (559.13, IQR=1.82-1289.86) and sTNFR-II (248.8, IQR=0-644.65) than control women (P value is 0.01 for TNFR-I and 0.04 for TNFR-II). Levels of sTNFR-I and sTNFR-II were comparable for advanced endometriosis and controls, and between early and advanced endometriosis. As a biomarker for all- stage endometriosis, sTNFR-I produces AUC of 0.62, sensitivity of 61%, and specificity of 47.3%, at a cutoff of 81.87pg/ml. For early stage disease, sTNFR-I yields AUC of 0.68, sensitivity of 60.7%, specificity of 75%, at a cutoff of 351.22pg/ml. CONCLUSION: sTNFR-I is significantly higher in serum of endometriosis patients than controls. As an endometriosis biomarker, sTNFR-I achieves better performance for early stage disease.

When sex is not on fire: a prospective multicentre study evaluating the short-term effects of radical resection of endometriosis on quality of sex life and dyspareunia.

OBJECTIVE: The aim of the current study was to evaluate the effect of surgical removal of endometriosis on dyspareunia, sexual function, quality of sex life and interpersonal relationships. STUDY DESIGN: A questionnaire-based multicentre prospective study was conducted in six tertiary referral centres in Austria and Germany. Ninety-six patients with histologically proven endometriosis and dyspareunia were included. Before surgery and averagely 10 months postoperatively (range 9-12 months), the Female Sexual Function Index (FSFI) and the Female Sexual Distress Scale (FSDS) were used to screen women's sexuality. Additionally, we evaluated psychological parameters and pain intensity during/after sexual intercourse via a self-administered questionnaire. RESULTS: Pain scores measured via NAS during/after intercourse decreased significantly after surgery. Frequencies of interrupted sexual intercourse, feelings of guilt towards the partner, being afraid of pain before/during sexual intercourse and feelings of being a burden for the relationship also decreased significantly in patients with peritoneal endometriosis and deep infiltrating endometriosis. Interestingly, sexually related personal distress did not improve in women with peritoneal endometriosis/vaginal resection, but improved in cases of deep infiltrating endometriosis (DIE). CONCLUSION: Radical laparoscopic excision of endometriosis offers an effective treatment option and offers a significant improvement in dyspareunia and quality of sex life.

Differential expression of secretoglobins in normal ovary and in ovarian carcinoma--overexpression of mammaglobin-1 is linked to tumor progression.

Secretoglobins (SCGB), such as mammaglobin 1 (MGB1, SCGB2A2), mammaglobin 2 (MGB2, SCGB2A1) and lipophilin B (LIPB, SCGB1D2), have been related to carcinogenesis. We profiled expression of MGB1, MGB2 and LIPB in human tissues and ovarian carcinoma and explored the impact of SCGB overexpression on cell proliferation. MGB1, MGB2 and LIPB mRNA are expressed at variable levels in most human tissues and we observed significant bilateral correlations between the different secretoglobins. Concerted overexpression of MGB1 and LIPB resulted in significant increase in cell proliferation. In clinical specimens of ovarian carcinoma we measured elevated concentrations of secretoglobin mRNA and for MGB1 this up-regulation was confirmed on the protein level. Overexpression of MGB1 positively correlated with the FIGO stage, the tumor grade and the mitotic index suggesting a patho-physiological role of the protein. Our data indicate that MGB1, MGB2 and LIPB mRNAs are expressed at low levels in human tissues but basal expression is upregulated in ovarian cancer. The in vivo correlation between nuclear MGB1 localization and the mitotic rate in ovarian cancer as well as the increased cell proliferation induced by secretoglobin overexpression in ovarian cancer cell lines suggest a pathophysiological role of these proteins in ovarian cancer.

L1 cell adhesion molecule as a potential therapeutic target in murine models of endometriosis using a monoclonal antibody approach.

BACKGROUND/AIMS: The neural cell adhesion molecule L1CAM is a transmembrane glycoprotein abnormally expressed in tumors and previously associated with cell proliferation, adhesion and invasion, as well as neurite outgrowth in endometriosis. Being an attractive target molecule for antibody-based therapy, the present study assessed the ability of the monoclonal anti-L1 antibody (anti-L1 mAb) to impair the development of endometriotic lesions in vivo and endometriosis-associated nerve fiber growth. METHODS AND RESULTS: Endometriosis was experimentally induced in sexually mature B6C3F1 (n=34) and CD-1 nude (n=21) mice by autologous and heterologous transplantation, respectively, of endometrial fragments into the peritoneal cavity. Transplantation was confirmed four weeks post-surgery by in vivo magnetic resonance imaging and laparotomy, respectively. Mice were then intraperitoneally injected with anti-L1 mAb or an IgG isotype control antibody twice weekly, over a period of four weeks. Upon treatment completion, mice were sacrificed and endometrial implants were excised, measured and fixed. Endometriosis was histologically confirmed and L1CAM was detected by immunohistochemistry. Endometriotic lesion size was significantly reduced in anti-L1-treated B6C3F1 and CD-1 nude mice compared to mice treated with control antibody (P<0.05). Accordingly, a decreased number of PCNA positive epithelial and stromal cells was detected in autologously and heterologously induced endometriotic lesions exposed to anti-L1 mAb treatment. Anti-L1-treated mice also presented a diminished number of intraperitoneal adhesions at implantation sites compared with controls. Furthermore, a double-blind counting of anti-neurofilament L stained nerves revealed significantly reduced nerve density within peritoneal lesions in anti-L1 treated B6C3F1 mice (P=0.0039). CONCLUSIONS: Local anti-L1 mAb treatment suppressed endometriosis growth in B6C3F1 and CD-1 nude mice and exerted a potent anti-neurogenic effect on induced endometriotic lesions in vivo. The findings of this preliminary study in mice provide a strong basis for further testing in in vivo models.

Augmented epithelial multidrug resistance-associated protein 4 expression in peritoneal endometriosis: regulation by lipoxin A(4).

OBJECTIVE: To compare the expression of the prostaglandin (PG) E(2) transporter multidrug resistance-associated protein 4 (MRP4) in eutopic and ectopic endometrial tissue from endometriosis patients with that of control subjects and to examine whether MRP4 is regulated by the antiinflammatory lipid lipoxin A(4) (LXA(4)) in endometriotic epithelial cells. DESIGN: Molecular analysis in human samples and a cell line. SETTING: Two university hospitals and a private clinic. PATIENT(S): A total of 59 endometriosis patients and 32 age- and body mass index-matched control subjects undergoing laparoscopy or hysterectomy. INTERVENTION(S): Normal, eutopic, and ectopic endometrial biopsies as well as peritoneal fluid were obtained during surgery performed during the proliferative phase of the menstrual cycle. 12Z endometriotic epithelial cells were used for in vitro mechanistic studies. MAIN OUTCOME MEASURE(S): Tissue MRP4 mRNA levels were quantified by quantitative reverse-transcription polymerase chain reaction (qRT-PCR), and localization was analyzed with the use of immunohistochemistry. Cellular MRP4 mRNA and protein were quantified by qRT-PCR and Western blot, respectively. PGE(2) was measured in peritoneal fluid and cell supernatants using an enzyme immunoassay (EIA). RESULT(S): MRP4 was expressed in eutopic and ectopic endometrium, where it was overexpressed in peritoneal lesions and localized in the cytoplasm of glandular epithelial cells. LXA(4) attenuated MRP4 mRNA and protein levels in endometriotic epithelial cells in a dose-dependent manner, while not affecting the expression of enzymes involved in PGE(2) metabolism. Investigations employing receptor antagonists and small interfering RNA revealed that this occurred through estrogen receptor α. Accordingly, LXA(4) treatment inhibited extracellular PGE(2) release. CONCLUSION(S): We report for the first time that MRP4 is expressed in human endometrium, elevated in peritoneal endometriosis, and modulated by LXA(4) in endometriotic epithelial cells.

The expression of estrogen receptors as well as GREB1, c-MYC, and cyclin D1, estrogen-regulated genes implicated in proliferation, is increased in peritoneal endometriosis.

OBJECTIVE: To analyze the expression of estrogen receptors α and ß as well as their target genes implicated in proliferation, c-myc, cyclin D1, and GREB1, in the endometrium of women with or without endometriosis. DESIGN: Expression analysis in human tissue. SETTING: University hospitals and a clinic. PATIENT(S): Ninety-one premenopausal women (59 patients with endometriosis and 32 controls) undergoing laparoscopic surgery. INTERVENTION(S): Biopsies were obtained at time of surgery, performed during the proliferative phase of the cycle. MAIN OUTCOME MEASURE(S): Estrogen receptors α and ß as well as c-myc, cyclin D1, and GREB1 mRNA expression levels were determined by quantitative reverse transcriptase-polymerase chain reaction. Tissue localization of these estrogen-regulated genes was analyzed by immunohistochemistry. RESULT(S): Estrogen receptors α and ß as well as c-myc, cyclin D1, and GREB1 mRNA expression levels were increased in ectopic tissue in comparison with both normal and eutopic endometrium. Estrogen receptor mRNA levels also were upregulated in the eutopic peritoneal tissue of patients with endometriosis. Cyclin D1 and GREB1 expression was augmented in eutopic endometrium. c-myc, cyclin D1, and GREB1 proteins exhibited a nuclear localization in ectopic endometrial tissue. CONCLUSION(S): This constitutes the first report of increased expression of GREB1, as well as cyclin D1 and c-myc, in peritoneal endometriotic lesions, implicating these proteins in estrogen-dependent growth in this context.

Loss of secreted frizzled-related protein 4 correlates with an aggressive phenotype and predicts poor outcome in ovarian cancer patients.

BACKGROUND: Activation of the Wnt signaling pathway is implicated in aberrant cellular proliferation in various cancers. In 40% of endometrioid ovarian cancers, constitutive activation of the pathway is due to oncogenic mutations in ß-catenin or other inactivating mutations in key negative regulators. Secreted frizzled-related protein 4 (SFRP4) has been proposed to have inhibitory activity through binding and sequestering Wnt ligands. METHODOLOGY/PRINCIPAL FINDINGS: We performed RT-qPCR and Western-blotting in primary cultures and ovarian cell lines for SFRP4 and its key downstream regulators activated ß-catenin, ß-catenin and GSK3ß. SFRP4 was then examined by immunohistochemistry in a cohort of 721 patients and due to its proposed secretory function, in plasma, presenting the first ELISA for SFRP4. SFRP4 was most highly expressed in tubal epithelium and decreased with malignant transformation, both on RNA and on protein level, where it was even more profound in the membrane fraction (p<0.0001). SFRP4 was expressed on the protein level in all histotypes of ovarian cancer but was decreased from borderline tumors to cancers and with loss of cellular differentiation. Loss of membrane expression was an independent predictor of poor survival in ovarian cancer patients (p = 0.02 unadjusted; p = 0.089 adjusted), which increased the risk of a patient to die from this disease by the factor 1.8. CONCLUSIONS/SIGNIFICANCE: Our results support a role for SFRP4 as a tumor suppressor gene in ovarian cancers via inhibition of the Wnt signaling pathway. This has not only predictive implications but could also facilitate a therapeutic role using epigenetic targets.

Serum 25-hydroxyvitamin D levels in patients with vulvar cancer.

BACKGROUND: The anticarcinogenic potential of vitamin D 25(OH)D has been attributed to the inhibition of proliferation of cells from different carcinomas. Reduced serum levels of 25(OH)D are associated with an increased incidence of various types of cancer. The influence of serum 25(OH)D on the incidence and outcome of patients with vulvar cancer is unknown. PATIENTS AND METHODS: The serum 25(OH)D levels in 24 patients with vulvar cancer and 24 age-matched cancer-free patients was investigated. The blood samples were collected between October 2009 and September 2010 and time of blood collection of each patient and control was matched to avoid seasonal variations between the pairs. RESULTS: The median 25(OH)D serum levels in the under 50 year old group of patients were significantly lower in the vulvar cancer group than the controls. The younger cancer group also had an age-related trend of lower median serum level than the older population. In the control population the trend was vice versa, yet this finding was not statistically significant. CONCLUSION: Serum 25(OH)D has a possible role in the pathogenesis and progression of vulvar cancer, but further investigations of the association of vitamin D and vulvar cancer as well as regarding its influence on patient survival and quality of life are warranted in the future.

The molecular signature of endometriosis-associated endometrioid ovarian cancer differs significantly from endometriosis-independent endometrioid ovarian cancer.

OBJECTIVE: To determine whether endometriosis-associated endometrioid cancer (EAOC) is a specific entity compared with endometrioid cancer not associated with endometriosis (OC). DESIGN: Case-control study. SETTING: University hospital research laboratory. PATIENT(S): Seven patients with endometriosis-associated ovarian cancer EAOC and five patients each with OC, ovarian endometriosis, and benign ovaries. INTERVENTION(S): Ovarian tissue samples were collected from surgical procedures. MAIN OUTCOME MEASURE(S): We hybridized cRNA samples to the Affymetrix HG-U133A microarray chip. Representative genes were validated by real time polymerase chain reaction. RESULT(S): We identified two main groups of genes: The first group contained the genes SICA2, CCL14, and TDGF1. These genes were equally regulated in endometriosis and EAOC but not in OC and benign ovaries. The second group contained the genes StAR, SPINT1, Keratin 8, FoxM1B, FOLR1, CRABP1, and Claudin 7. They were equally regulated in EAOC and OC but not in ovarian endometriosis and benign ovaries. CONCLUSION(S): That the first group is composed of the cytokines SICA2 and CCL14 and the growth factor TDGF1 indicates that the regulation of the autoimmune system and of inflammatory cytokines may be very important in the etiology of endometriosis and EAOC. That the second group is composed of genes that play a central role in cell-cell interaction, differentiation, and cell proliferation indicates that they may be important in the development of ovarian cancer in women with endometriosis.

Apoptosis in endometriosis.

Apoptosis is a physiologic process that eradicates undesired cells without inducing an inflammatory reaction. It is an important regulator of eutopic endometrial function and evidence suggests that apoptosis aids in maintaining cellular homeostasis during the menstrual cycle by eliminating aging cells from the functional layer of the uterine endometrium. Endometriosis, which is characterized by the growth of endometrial tissue outside the uterus, could result from increased cellular proliferation or decreased apoptosis in response to appropriate stimuli. Eutopic endometrium from women with endometriosis has several differences compared with normal endometrium of women without endometriosis. These differences may contribute to the survival of regurgitated endometrial cells into the peritoneal cavity and thus to the development of endometriosis. In this article, we will summarize recent literature concerning apoptosis-related genes such as Bcl-2 and Fas, outline the molecular basis of apoptosis and review the literature focused on the alterations in regulation of apoptosis in eutopic and ectopic endometrium from women with endometriosis.

Immunohistochemical workup of sentinel nodes in endometrial cancer improves diagnostic accuracy.

OBJECTIVE: The purpose of this study was to examine the effect of immunohistochemical (IHC) staining of sentinel (SLN) and non sentinel lymph nodes (NSLN) on the detection of additional metastases in patients with endometrial cancer. PATIENTS AND METHODS: Between April 2004 and March 2006, 25 patients with endometrial cancer were operated on. A new method for labelling SLNs with Patent Blue(R) was used. One additional slice was cut out of each lymph node and immunohistochemically stained (IHC). Sentinel and NSLN nodes were re-evaluated. RESULTS: 673 lymph nodes from 21 patients were available for re-evaluation. With IHC staining significantly more metastases were detected compared to H&E staining. Though more patients with metastases were discovered this was not significant on the basis of affected SLNs or NSLNs. In the conventional evaluation 7 metastases were found in 3 patients. Applying re-evaluation and IHC 6 additional metastases in 5 patients were detected. These additional metastases were evenly distributed among the pelvic and para-aortic area, and among the SLNs or NSLNs. This had an impact on the diagnostic accuracy of the sentinel concept. Sensitivity reduced from 66.7% to 33.3% and the negative predictive value (NPV) fell from 94.7% to 79.0% only if the NSLNs were additionally IHC stained. On the contrary, if the SLNs were also IHC stained, the sensitivity rose to 83.3%, the NPV rose to 93.8%. CONCLUSION: Our results indicate that additional immunohistochemistry staining of one additional block of SLNs improves the validity of sensitivity and the NPV in the sentinel concept.

Gene therapy of benign gynecological diseases.

Gene therapy is the introduction of genetic material into patient's cells to achieve therapeutic benefit. Advances in molecular biology techniques and better understanding of disease pathogenesis have validated the use of a variety of genes as potential molecular targets for gene therapy based approaches. Gene therapy strategies include: mutation compensation of dysregulated genes; replacement of defective tumor-suppressor genes; inactivation of oncogenes; introduction of suicide genes; immunogenic therapy and antiangiogenesis based approaches. Preclinical studies of gene therapy for various gynecological disorders have not only shown to be feasible, but also showed promising results in diseases such as uterine leiomyomas and endometriosis. In recent years, significant improvement in gene transfer technology has led to the development of targetable vectors, which have fewer side-effects without compromising their efficacy. This review provides an update on developing gene therapy approaches to treat common gynecological diseases such as uterine leiomyoma and endometriosis.

Primary peritoneal carcinoma in a young woman with suspected endometriosis.

OBJECTIVE: To describe the treatment of a 23-year-old patient with primary peritoneal carcinoma and preservation of her fertility. DESIGN: Case report. SETTING: University of Schleswig-Holstein, Campus Lübeck, Department of Gynecology and Obstetrics. PATIENT(S): A 23-year-old patient with primary peritoneal carcinoma. INTERVENTION(S): The patient was given treatment by first preserving her fertility with oocyte vitrification and cryoconservation of ovarian biopsy samples. Surgery was performed with radical resection of the peritoneal lesion, ovarian biopsies, omentectomy, and pelvic and para-aortic lymph node sampling before starting chemotherapy with carboplatin and paclitaxel (Taxol). Hysterectomy and bilateral salpingo-oophorectomy were not performed. MAIN OUTCOME MEASURE(S): Treatment of peritoneal carcinoma and number of vitrified oocytes. RESULT(S): Twenty-five oocytes of the patients were vitrified before chemotherapy was performed. CONCLUSION(S): Primary peritoneal carcinoma is a rare disease that laparoscopically resembles peritoneal endometriosis and histologically is very similar to primary epithelial ovarian cancer. The advised therapy is based on ovarian cancer treatment; however, it is unclear whether the radical operation improves prognosis. In this case, a 23-year-old patient underwent treatment preserving her fertility with oocyte vitrification and cryoconservation of ovarian biopsy samples before surgery and chemotherapy were performed.

Isolated pyosalpinx in a 13-year-old virgin.

OBJECTIVE: To describe the successful laparoscopic management of an isolated pyosalpinx in a 13-year-old virgin. DESIGN: Case report. SETTING: University of Schleswig-Holstein, Campus Luebeck, Department of Gynecology and Obstetrics and Department of Pediatric Surgery. PATIENT(S): A 13-year-old virgin with a pyosalpinx. INTERVENTION(S): Salpingotomy and antibiotic treatment. MAIN OUTCOME MEASURE(S): Successful laparoscopic management of an isolated pyosalpinx in a virgin. RESULT(S): A 13-year-old virgin presented with abdominal pain, fever, and a cystic mass in the right lower abdomen. A laparoscopy was performed. The appendix, the uterus, and the left tube appeared normal with no signs of infection. The right tube was swollen, and after incision, purulent liquid poured out of the tube. The swab revealed the presence of Escherichia coli only, without evidence of other bacteria such as Chlamydia. With antibiotic treatment, the infection was adequately treated, and the patient was discharged in a healthy condition. CONCLUSION(S): In a young virgin, a pyosalpinx has to be considered as a differential diagnosis. If there is no evidence of other infections, laparoscopy may help to confirm the diagnosis of pyosalpinx and simultaneously offer minimally invasive therapy.

Mass spectrometry and serum pattern profiling for analyzing the individual risk for endometriosis: promising insights?

OBJECTIVE: To evaluate whether distinct patterns of serum proteins in symptomatic women are of value to predict endometriosis before laparoscopy. DESIGN: Prospective exploratory cohort study. SETTING: Tertiary care center. PATIENT(S): A total of 91 consecutive symptomatic patients suffering from dysmenorrhea, dyspareunia, chronic pelvic pain, or unexplained infertility. INTERVENTION(S): Collection of serum samples and a standardized protocol for patients' history before laparoscopic diagnosis. MAIN OUTCOME MEASURE(S): Protein expression was analyzed by mass spectrometric analysis according to surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) standards. The analysis of data was performed using a genetic algorithm (ClinProTools 2.0 software) and a rule-based decision-tree algorithm (XLminer software). RESULT(S): A total of 90 out of 91 samples were eligible for analysis. At laparoscopy, 51 of 90 patients (56.7%) exhibited endometriosis and 39 of 90 (43.3%) were disease free. Analyzing the serum samples, the software revealed a unique selection of mass peaks between 2,000 and 20,000 Da, which allowed for discrimination between patients suffering from endometriosis and control subjects. Overall recognition capacity was 70.8%, exhibiting a sensitivity of 81.3% (95% confidence interval [CI] 66.5-92.5) and a specificity of 60.3% (95% CI 46.1-74.2]) using the genetic algorithm, and a sensitivity of 78.4% and a specificity of 59.0% using the rule-based decision-tree algorithm. CONCLUSION(S): These findings provide direct evidence that screening for serum protein patterns using SELDI-TOF MS before laparoscopy might be of discriminative value in the prediction of disease and partly confirms recently published data. However, in this prospective setting, we found both low sensitivity and low specificity, which disqualifies the screening for serum protein patterns by SELDI-TOF MS as a "quick fix" diagnostic test.

Combination of CCR1 mRNA, MCP1, and CA125 measurements in peripheral blood as a diagnostic test for endometriosis.

This study investigated the possible use of CCR1 mRNA measurement in peripheral blood leukocytes in combination with measurements of monocyte chemotactic protein-1 (MCP-1) and CA125 protein in serum as a diagnostic test for endometriosis.The expression of CCR1 mRNA in peripheral blood leukocytes was measured by quantitative real-time polymerase chain reaction. MCP-1 and CA125 levels in serum were determined by ELISA and ECLIA.The ratio of CCR1/HPRT mRNA in peripheral blood of patients with endometriosis and adenomyosis was significantly elevated compared with women without endometriosis. Additionally, serum levels of MCP-1 and CA125 were significantly higher in patients with endometriosis. This method showed a sensitivity of 92.2%, a specificity of 81.6%, a negative predictive value of 83.3%, a positive predictive value of 92.3%, a likelihood ratio of a positive test result of 5.017, and a likelihood ratio of a negative test result of 0.096 to predict the presence or absence of endometriosis.The results imply the potential use of CCR1 mRNA, MCP-1, and CA125 protein measurements for the diagnosis or exclusion of endometriosis.