Efficacy and safety of ASP1707 for endometriosis-associated pelvic pain: the phase II randomized controlled TERRA study.

STUDY QUESTION: Does the GnRH antagonist, ASP1707, reduce endometriosis-associated pelvic pain? SUMMARY ANSWER: ASP1707 significantly reduced endometriosis-associated pelvic pain in a dose-related manner. WHAT IS KNOWN ALREADY: GnRH agonists are an effective therapeutic option for endometriosis that is refractory to non-steroidal anti-inflammatory drugs, oral contraceptives, and progestins. However, GnRH agonists cause complete suppression of estradiol (E2), resulting in hypoestrogenic side-effects such as bone loss that may increase the future risk of osteoporotic fractures. STUDY DESIGN, SIZE, DURATION: This was a Phase II, multicenter, double-blind, randomized, parallel-group, placebo-controlled study conducted in 540 women from 04 December 2012 to 30 July 2015 in Europe and Japan. A sample size of 504 (84 subjects per group) was calculated to provide ≥80% power to detect a dose-related treatment effect among placebo and ASP1707 doses in change from baseline in pelvic pain, assuming different dose-response curves after 12 weeks of treatment. PARTICIPANTS/MATERIALS, SETTING, METHODS: Of 912 women with endometriosis-associated pelvic pain screened, 540 were enrolled, and 532 received ≥1 dose of study drug (placebo, n = 88; ASP1707 3 mg, n = 86; ASP1707 5 mg, n = 91; ASP1707 10 mg, n = 90; ASP1707 15 mg, n = 88; leuprorelin, n = 89) for 24 weeks. MAIN RESULTS AND THE ROLE OF CHANCE: After 12 weeks of treatment with ASP1707, the mean (95% CI) changes in numeric rating score (NRS) for overall pelvic pain (OPP) were -1.56 (-1.91, -1.21), -1.63 (-1.99, -1.27), -1.93 (-2.27, -1.60), -2.29 (-2.64, -1.94), and -2.13 (-2.47, -1.79) for placebo, ASP1707 3 mg, ASP1707 5 mg, ASP1707 10 mg, and ASP1707 15 mg, respectively. Mean (95% CI) changes in NRS for dysmenorrhea were -1.50 (-2.00, -1.00), -2.72 (-3.22, -2.21), -2.85 (-3.33, -2.38), -3.97 (-4.46, -3.48), and -4.18 (-4.66, -3.70), respectively. Mean (95% CI) changes in NRS for non-menstrual pelvic pain (NMPP) were -1.53 (-1.88, -1.19), -1.51 (-1.87, -1.16), -1.80 (-2.14, -1.47), -2.03 (-2.37, -1.68), and -1.86 (-2.20, -1.52), respectively. Statistically significant dose-related treatment effects in reduction in NRS for OPP (P = 0.001), dysmenorrhea (P < 0.001), and NMPP (P = 0.029) were observed after 12 weeks among ASP1707 doses and were maintained through 24 weeks. Serum estradiol and bone mineral density decreased dose dependently with ASP1707 through 24 weeks, however, to a lesser extent than with leuprorelin. LIMITATIONS, REASON FOR CAUTION: This study was not powered for pairwise comparison of each ASP1707 group versus placebo. WIDER IMPLICATIONS OF THE FINDINGS: All doses of ASP1707 reduced serum E2 levels to within the target range and to a lesser extent than leuprorelin. ASP1707 is a potential alternative treatment to leuprorelin for endometriosis-associated pelvic pain with lower impact on bone health. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by Astellas Pharma Inc. T.D'.H is Vice President and Head of Global Medical Affairs Fertility at Merck, Darmstadt, Germany since October 1, 2015. At the time that the TERRA study was conducted, he served as Principal Investigator in his role as Coordinator of the Leuven University Fertility Center. Since October 2015, T.D'.H has left Leuven University Hospital Gasthuisberg, but continues to serve as Professor in Reproductive Medicine and Biology at KU Leuven (University of Leuven) Belgium and at the Dept of Obstetrics, Gynecology and Reproduction at Yale University, New Haven, USA. T. Fukaya and Y. Osuga report personal consulting fees from Astellas Pharma Inc. during the conduct of the study and outside the submitted work. G.M. Holtkamp, and L. Skillern are employed by Astellas Pharma Europe B.V.; K. Miyazaki is employed by Astellas Pharma Inc.; B. López, was a biostatistician for Astellas Pharma Europe B.V. during conduct of the study; R. Besuyen was a contract Associate Director of Medical Science for Astellas during conduct of the study. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01767090. EudraCT number 2012-002791-14. TRIAL REGISTRATION DATE: 18 December 2012. DATE OF FIRST SUBJECT'S ENROLLMENT: One subject signed informed consent on 04 December 2012; the first subject was randomized on 16 April 2013.

Is it possible to diagnose malignancy from fluid in cystic ovarian tumors?

OBJECTIVE: p53 gene mutations are frequently identified in ovarian cancer tissue. The aim of this study was to investigate whether wild type or mutated genomic DNA can be identified in ovarian cystic fluid specimens. STUDY DESIGN: Forty-eight Japanese patients with cystic ovarian tumors (30 benign cysts, 8 borderline malignant tumors, and 10 cancers) were investigated. Cystic fluid and tumor tissue were obtained during surgery. After DNA extraction from the cystic fluid, polymerase chain reaction (PCR) and sequence analysis for exons 4-9 of the p53 gene was performed. In two cases of mucinous cystic tumor of borderline malignancy and endometrioid adenocarcinoma, the p53 gene sequences were determined. Immunohistochemical staining for abnormal p53 gene product was also performed. RESULTS: DNA was successfully extracted from all cystic fluid specimens. Furthermore, exons 4-9 of the p53 gene could be identified by electrophoresis from all samples. In a mucinous cystic tumor of borderline malignancy, one point mutation was identified at codon 223 in exon 6 (CCT → CTT) of the p53 gene. Aberrant p53 gene product was also observed in the tumor cells by immunohistochemical staining. Moreover, in another case of endometrial adenocarcinoma, a point mutation at codon 245 in exon 7 (GGC → AGC) was detected by the direct sequencing of the amplified Exon. Notably, the mutation was not present in the peripheral blood (PB) sample and tissue specimens from the patient. CONCLUSION: In cystic ovarian tumors, cystic fluid may provide informative material for molecular studies since it reflects the p53 status of tumor tissue in the cyst wall. This system might help to identify ovarian malignancy without resection of the tumor tissues.

Detection of Merkel cell polyomavirus in cervical squamous cell carcinomas and adenocarcinomas from Japanese patients.

BACKGROUND: Merkel cell polyomavirus (MCPyV) was identified originally in Merkel cell carcinoma (MCC), a rare form of human skin neuroendocrine carcinoma. Evidence of MCPyV existence in other forms of malignancy such as cutaneous squamous cell carcinomas (SCCs) is growing. Cervical cancers became the focus of our interest in searching for potentially MCPyV-related tumors because: (i) the major histological type of cervical cancer is the SCC; (ii) the uterine cervix is a common site of neuroendocrine carcinomas histologically similar to MCCs; and (iii) MCPyV might be transmitted during sexual interaction as demonstrated for human papillomavirus (HPV). In this study, we aimed to clarify the possible presence of MCPyV in cervical SCCs from Japanese patients. Cervical adenocarcinomas (ACs) were also studied. RESULTS: Formalin-fixed paraffin-embedded tissue samples from 48 cervical SCCs and 16 cervical ACs were examined for the presence of the MCPyV genome by polymerase chain reaction (PCR) and sequencing analyses. PCR analysis revealed that 9/48 cervical SCCs (19%) and 4/16 cervical ACs (25%) were positive for MCPyV DNA. MCPyV-specific PCR products were sequenced to compare them with reference sequences. The nucleotide sequences in the MCPyV large T (LT)-sequenced region were the same among MCPyV-positive cervical SCCs and AC. Conversely, in the MCPyV viral protein 1 (VP1)-sequenced region, two cervical SCCs and three cervical ACs showed several nucleotide substitutions, of which three caused amino acid substitutions. These sequencing results suggested that three MCPyV variants of the VP1 were identified in our cases. Immunohistochemistry showed that the LT antigen was expressed in tumor cells in MCPyV-positive samples. Genotyping of human HPV in the MCPyV-positive samples revealed that infected HPVs were HPV types 16, 31 and 58 for SCCs and HPV types 16 and 18 for ACs. CONCLUSIONS: This study provides the first observation that MCPyV coexists in a subset of HPV-associated cervical cancers from Japanese patients. The prevalence of MCPyV in these lesions was close to that observed in the cutaneous SCCs. Further worldwide epidemiological surveys are warranted to determine the possible association of MCPyV with pathogenesis of cervical cancers.

Role of NK cells and HLA-G in endometriosis.

Impaired natural killer (NK) activity in women with endometriosis is thought to promote implantation and progression of endometrial tissue, in accord with Sampson's hypothesis. However, the mechanisms responsible for decreased NK cell activity and the antigens recognized by NK cells are not clear.We focused on human leukocyte antigen (HLA)-G, a ligand of NK receptors, expression and its menstrual cycle changes by eutopic endometrium. Interestingly, HLA-G expression was identified on eutopic endometrium only in the menstrual phase but not in the proliferative or secretory phases. Furthermore, HLA-G expressing cells were also detected in peritoneal fluid during the menstrual period. During retrograde menstruation, HLA-G expressing endometrial tissue may enter the peritoneal cavity, and may be reduced by immunosurveillance system. Although peritoneal NK cells play an important role in this system, impairment of NK cytotoxicity via HLA-G may allow peritoneal endometrial cell survival and implantation. In this review, we discuss the pathogenesis of endometriosis from the viewpoint of intraperitoneal immune interaction between NK cell receptors and HLA-G that can enter into peritoneal cavity from eutopic endometrium through retrograde menstruation.

Prophylactic administration of melatonin to the mother throughout pregnancy can protect against oxidative cerebral damage in neonatal rats.

OBJECTIVE: The purpose of this study was to investigate whether prophylactic administration of melatonin to the mother throughout pregnancy could protect against ischemia/reperfusion (I/R)-induced oxidative brain damage in neonatal rats. METHODS: The utero-ovarian arteries were occluded bilaterally for 30 min in female Wistar rats on day 16 of pregnancy to induce fetal ischemia. Reperfusion was achieved by releasing the occlusion and restoring circulation. A sham operation was performed in control rats. Melatonin solution or vehicle alone was administrated orally throughout pregnancy. We collected brain mitochondria from neonatal rats, evaluated mitochondrial structure by electron microscopy, and measured the respiratory control index (RCI) as an indicator of mitochondrial respiratory activity as well as the concentration of thiobarbituric acid-reactive substances (TBARS), a marker of oxidative stress. Histological analysis was performed at the Cornu Ammonis 1 (CA1) and Cornu Ammonis 3 (CA3) regions of the hippocampus. RESULTS: I/R significantly reduced the RCI and significantly elevated the concentration of TBARS. Melatonin treatment reversed these effects, resulting in values similar to that in untreated, sham-ischemic animals. Electron microscopic evaluation showed that the number of intact mitochondria decreased in the I/R group, while melatonin treatment preserved them. Histological analysis revealed a decrease in the ratio of normal to whole pyramidal cell number in the CA1 and CA3 regions in the I/R group. While melatonin administration protected against degeneration. CONCLUSIONS: These results indicate that prophylactic administration of melatonin to the mother throughout pregnancy may prevent I/R-induced oxidative brain damage in neonatal rats.

Therapeutic effects of maternal melatonin administration on ischemia/reperfusion-induced oxidative cerebral damage in neonatal rats.

BACKGROUND: We have previously demonstrated that prophylactic administration of melatonin to pregnant rats can protect against ischemia/reperfusion (I/R)-induced oxidative cerebral damage in fetal rats. However, the effects of maternal administration of melatonin after an ischemic episode on the brains of neonatal rats exposed to oxidative stress in utero have not been evaluated. OBJECTIVES: The purpose of the present study was to investigate whether maternal administration of melatonin after an ischemic episode can prevent oxidative cerebral damage in neonatal rats. METHODS: The utero-ovarian arteries were occluded bilaterally for 30 min in female Wistar rats on day 16 of pregnancy to induce fetal ischemia. Reperfusion was achieved by releasing the occlusion and restoring circulation. Melatonin solution (10 mg/kg) or vehicle was injected intraperitoneally at 0, 1, 3, 6, and 12 h after reperfusion. After surgery, melatonin solution (20 microg/ml) or vehicle was administered freely via drinking water up to vaginal delivery. Control rats underwent a sham operation. We collected brain tissue from neonatal rats that were delivered naturally and measured the respiratory control index (RCI) as indicators of mitochondrial respiratory activity. Histological evaluation was performed on the cornu ammonis (CA1) and CA3 regions of the hippocampus. RESULTS: I/R significantly reduced the RCI, but melatonin administration at postreperfusion hour 0 or 1 reversed I/R-induced reductions in the RCI. In contrast, melatonin administration at postreperfusion hours 3-12 had no protective effect. Histological analysis revealed a decrease in the ratio of normal to whole pyramidal cell number in the CA1 and CA3 regions in the I/R group. While melatonin administration within 3 h protected against degeneration, administration 6 h after reperfusion failed to protect. CONCLUSIONS: These results suggest that maternal administration of melatonin within 1 h after an ischemic/oxidative episode can prevent I/R-induced oxidative cerebral damage in neonatal rats.

Comparison of four malignancy risk indices in the preoperative evaluation of patients with pelvic masses.

OBJECTIVE: The aim of this study was to evaluate the ability of four malignancy risk indices (RMI 1, RMI 2, RMI 3, and RMI 4), incorporating menopausal status, serum CA125 levels, and ultrasound findings, to discriminate a benign from a malignant pelvic mass. STUDY DESIGN: This is a retrospective study of 253 women admitted to the Department of Obstetrics and Gynecology of Kochi Medical School, between January 2002 and April 2005 for surgical exploration of pelvic masses. To diagnose ovarian cancer, the sensitivity, specificity, and positive predictive value of serum CA125, ultrasound findings and menopausal status were taken separately and combined into RMI 1, RMI 2, RMI 3, and RMI 4. RESULTS: This study confirms that, for the diagnosis of malignancy, four malignancy risk indices were more accurate than menopausal status, serum CA125 levels, and ultrasound findings separately. The accuracy of the RMI 4 was better than RMI 1 (P=0.0013), RMI 2 (P=0.0009) and RMI 3 (P=0.0013). The RMI 4 at a cutoff level of 450 yielded a sensitivity of 86.8%, a specificity of 91.0%, a positive predictive value of 63.5%, a negative predictive value of 97.5%, and an accuracy of 90.4%. CONCLUSION: We found that, in the discrimination between benign and malignant pelvic disease, the RMI 4 method was more reliable than RMI 1, RMI 2 and RMI 3. The RMI 4 method is a simple technique that can be used in gynecology clinics as well as less-specialized centers.

Human leukocyte antigen-G, a ligand for the natural killer receptor KIR2DL4, is expressed by eutopic endometrium only in the menstrual phase.

OBJECTIVE: To investigate menstrual cycle changes in expression by eutopic endometrium of a nonclassic human leukocyte antigen, HLA-G, which binds to the killer immunoglobulin-like receptor (KIR) 2DL4 (CD158d) on natural killer (NK) cells. Such antigens have been linked to endometriosis. DESIGN: Case-control study. SETTING: University hospital. PATIENT(S): We examined 20 Japanese women undergoing hysterectomy for endometriosis and 17 undergoing hysterectomy for myoma. INTERVENTION(S): Immunohistochemical HLA-G staining of eutopic endometrium and peritoneal fluid (PF) cells from women with and without endometriosis. Flow cytometric analysis of PF NK cells from women with and without endometriosis. MAIN OUTCOME MEASURE(S): HLA-G staining in eutopic endometrium was quantified by image analysis. The KIR2DL4-expressing NK cells in PF were investigated by flow cytometry. RESULT(S): The HLA-G was expressed by eutopic endometrium only in the menstrual phase and not in the late proliferative or secretory endometrium. Intensity of HLA-G staining did not differ significantly between women with and without endometriosis. The HLA-G- expressing cells were detected in PF during the menstrual period. These cells are morphologically and flow cytometrically different from mesothelial cells and NK cells. CONCLUSION(S): The HLA-G expression is observed in eutopic endometrium only during the menstrual phase, and no differences were observed between women with and without endometriosis. Epithelial cells bearing HLA-G may enter the peritoneal cavity during retrograde menstruation, allowing the antigen to react locally with KIR2DL4.

A long-survived case with solitary splenic metastasis from ovarian carcinoma.

A61-year-old postmenopausal woman with ovarian carcinoma was treated with two surgical operations and a series of platinum-based chemotherapy. A solitary metastasis into the splenic parenchyma was identified 33 months after the second surgery by abdominal computed tomography with an increased serum level of CA-125. She underwent a pancreaticosplenectomy and received platinum-based adjuvant chemotherapy continuously for 2 years. Her serum CA-125 level decreased to a normal range and she has lived without any recurrence for more than 10 years after the splenectomy. Solitary metastases from ovarian cancer into the splenic parenchyma are extremely rare. Among 18 cases previously reported, this present case shows the longest disease-free survival. Because these cases show favorable prognosis after splenectomy, surgical treatment should be considered along with adjuvant chemotherapy.

Melatonin preserves fetal growth in rats by protecting against ischemia/reperfusion-induced oxidative/nitrosative mitochondrial damage in the placenta.

We have previously demonstrated that melatonin protects against ischemia/reperfusion-induced oxidative damage to mitochondria in the fetal rat brain. The purpose of the present study was to evaluate the effects of maternally administered melatonin on ischemia/reperfusion-induced oxidative placental damage and fetal growth restriction in rats. The utero-ovarian arteries were occluded bilaterally for 30 min in rats on day 16 of pregnancy to induce fetal ischemia. Reperfusion was achieved by releasing the occlusion and restoring circulation. Melatonin solution (20 microg/mL) or the vehicle alone was administered orally during pregnancy. A sham operation was performed in control rats, which were treated with vehicle alone. Laparotomy was performed on day 20 of pregnancy and the number and weight of fetal rats and placentas were measured. Placental mitochondrial respiratory control index (RCI), a marker of mitochondrial respiratory activity, was also calculated for each group. Using immunohistochemistry, we investigated the degree of immunostaining of 8-hydroxy-2-deoxyguanosine (8-OHdG), a marker of oxidative DNA damage, and redox factor-1(ref-1), which repairs DNA damage and acts as a redox-modifying factor in rat placenta. Predictably, the ischemia/reperfusion operation significantly decreased the weight of fetal rats and placentas and the RCI. Melatonin prevented ischemia/reperfusion-induced changes in RCI (1.55 +/- 0.05 to 1.83 +/- 0.09, P < 0.05) and fetal growth (3.04 +/- 0.17 to 3.90 +/- 0.1, P < 0.0001). Immunohistochemistry revealed significant positive staining for 8-OHdG and ref-1 following ischemia/reperfusion; these effects were also reduced by melatonin treatment. Results indicated that ischemia/reperfusion-induced oxidative placental DNA and mitochondrial damage and fetal growth restriction can be prevented by maternally administered melatonin.

Preoperative evaluation of pelvic masses with combined 18F-fluorodeoxyglucose positron emission tomography and computed tomography.

OBJECTIVE: To prospectively evaluate the diagnostic value of combined 18F-fluorodeoxyglucose position emission tomography and computed tomography (FDG-PET/CT) to discriminate malignant or borderline malignant tumors from benign pelvic masses. METHODS: A prospective study of 30 women with suspected ovarian cancer who presented from July 2006 through August 2007. Selection was based on evidence from ultrasound, magnetic resonance imaging, and rising tumor marker levels. All patients underwent FDG-PET/CT prior to standard debulking surgery for a pelvic mass. RESULTS: The sensitivity and specificity of FDG-PET/CT to detect malignant or borderline malignant pelvic tumors were 71.4% and 81.3%, respectively. The sensitivity and specificity of FDG-PET/CT to detect ovarian cancer were 100% and 85.0%, respectively. The maximum standardized uptake value in borderline tumors was significantly lower compared with malignant tumors, but not significantly different compared with benign tumors. CONCLUSION: FDG-PET/CT had a high diagnostic value in differentiating between malignant and benign tumors, and a low diagnostic value in differentiating between borderline malignant and benign tumors.

Decreased human leukocyte antigen-DR expression in the lipid raft by peritoneal macrophages from women with endometriosis.

OBJECTIVE: To investigate the macrophage response in endometriosis by determining the expression and localization of human leukocyte antigen (HLA)-ABC and HLA-DR by the peritoneal fluid (PF) macrophages and PF concentrations of interferon (IFN)-gamma that regulate HLA expression. DESIGN: Case-control study. SETTING: University hospital. PATIENT(S): 64 Japanese endometriosis patients, and 65 women with other laparoscopic diagnoses. INTERVENTION(S): Venipuncture and laparoscopic peritoneal fluid collection. MAIN OUTCOME MEASURE(S): Expression and localization of HLA-ABC and HLA-DR in PF macrophages were determined by flow cytometry and confocal microscopy. The concentration of IFN-gamma in PF was determined by enzyme-linked immunosorbent assay. RESULT(S): In women with endometriosis, expression of HLA-ABC and HLA-DR by PF macrophages, and the IFN-gamma concentrations in PF were statistically significantly lower than in controls. Women with endometriosis showed a statistically significant positive correlation between HLA expression and IFN-gamma concentration. By confocal microscopy, HLA-ABC was distributed homogenously on the macrophage surface whereas HLA-DR expression on these cells corresponded to the lipid raft. CONCLUSION(S): In women with endometriosis, low HLA expression and particularly reduced HLA-DR in the lipid raft may be influenced by low IFN-gamma and may compromise antigen presentation, limiting the immune response to peritoneal cavity antigens such as implanted or metaplastic endometrial tissue.

Chemical zona pellucida thinning with acidified Tyrode's solution: comparison between partial and circumferential techniques.

PURPOSE: To compare effectiveness of two different chemical zona thinning techniques. METHOD: We studied 163 patients who had experienced IVF or ICSI failures in two or more cycles. Patients were assigned to one of three groups: zona intact (n=72), partial thinning (n=59), or circumferential thinning (n=73). Before transfer, the zonae pellucidae of embryos were thinned partially or circumferentially using acidified Tyrode's solution. RESULTS: Implantation rates were 8.9% in the intact zona group, 17.6% in the partial thinning group, and 11.9% in the circumferential thinning group: respective clinical pregnancy rates were 16.7% (12/72), 32.2% (19/59), and 27.4% (20/73). Both rates were significantly higher in the partial thinning group than the intact zona group. For circumferential thinning versus zona intact groups, differences fell short of significance. CONCLUSIONS: Following embryo transfer failure, partial thinning would be recommended over circumferential thinning for successful assisted hatching.

Primary yolk sac tumor concomitant with carcinosarcoma originating from the endometrium: case report.

BACKGROUND: A primary yolk sac tumor (YST) with carcinosarcoma originating from the endometrium is extremely rare, to our knowledge, this is the third documented instance. Several hypotheses exist is to its histogenesis. CASE: A 65-year-old Japanese woman was diagnosed with a uterine malignancy and underwent surgical treatment and chemotherapy. The postoperative diagnosis was primary carcinosarcoma concomitant with a YST of the uterus. Immunohistochemical staining revealed that the tumor area suspected to be a YST was positive for alpha-fetoprotein. CONCLUSION: We report a case of carcinosarcoma concomitant with a YST of uterus. This case is the third documented instance of a YST with concomitant with carcinosarcoma originating from the endometrium. The histogenesis in this case is suggests aberrantly differentiated somatic cells.

Killer immunoglobulin-like receptor and human leukocyte antigen expression as immunodiagnostic parameters for pelvic endometriosis.

PROBLEM: We investigated host immunologic responses to endometriosis by comparing immune cell surface antigens in peripheral blood (PB) and peritoneal fluid (PF) from women with endometriosis with those in PB and PF from other patients. METHOD OF STUDY: Japanese women with endometriosis (n = 56) were compared with controls with other laparoscopic diagnoses (n = 68). PB and PF were collected at the time of laparoscopy for flow cytometry. RESULTS: No significant difference in phenotypic parameters of T cells (CD3, CD4, and CD8), B cells (CD19), natural killer (NK) cells (CD56), or monocytes/macrophages (CD14) was seen between women with and without endometriosis. However, increased killer immunoglobulin-like receptor (CD158a) expression by NK cells and decreased human leukocyte antigen (HLA)-ABC and -DR expression by macrophages, all suggesting decreased functional activation were found in endometriosis. These markers showed significant association with endometriosis by odds ratio, logistic regression, and decision tree analyses. CONCLUSIONS: Increased CD158a(+) NK cells in PB and PF indicated decreased NK cell cytotoxicity in endometriosis, while decreased HLA expression on PF macrophages suggested impaired antigen presentation. Thus, aberrant immune responses by NK cells and macrophages may represent risk factors for endometriosis.

Malignant müllerian mixed tumor (carcinosarcoma) of the fallopian tube: an immunohistochemical study of neoplastic cells.

The patient was a 65-year-old woman who complained of lower abdominal pain. Salpingo-oophorectomy and hysterectomy were performed due to suspicion of ovarian cancer. At surgery a polypoid mass was observed in the fimbria of the left fallopian tube. Histologically, proliferation of undifferentiated neoplastic cells with marked cytological atypia predominated in the tumor. Proliferation of rhabdomyoblastic cells or spindle cells, as well as adenocarcinoma arising from the mucosa of the fallopian tube, was observed. A diagnosis of malignant müllerian mixed tumor (MMMT) was made. CD10 was expressed in adenocarcinoma, undifferentiated, spindle and rhabdomyoblastic cells. Furthermore, rhabdomyoblastic cells were positive for desmin and myoglobin. Undifferentiated and spindle neoplastic cells were focally positive for ASMA and negative for h-caldesmon. Finally, our preliminary report suggests that MMMT of the fallopian tube may contain immature smooth muscle cells or cells with the myofibroblast-like immunohistochemical phenotype in the undifferentiated component.