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.

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.

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.

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.

Effect of medroxyprogesterone acetate on vascular inflammatory markers in postmenopausal women receiving estrogen.

BACKGROUND: Estrogen increases C-reactive protein (CRP) in postmenopausal women. Estrogen also decreases cell adhesion molecules, whereas elevated CRP stimulates the expression of cell adhesion molecules. Because androgens have antiinflammatory effects, androgenic progestins such as medroxyprogesterone acetate (MPA) may inhibit proinflammatory effects of estrogen. We investigated the effects of MPA on estrogen-induced changes in acute inflammatory proteins and cell adhesion molecules in postmenopausal women. METHODS AND RESULTS: Postmenopausal women were treated daily with conjugated equine estrogen (CEE, 0.625 mg), CEE plus MPA 2.5 mg, or CEE plus MPA 5.0 mg for 3 months. CEE significantly increased CRP concentrations by 320.1+/-210.2% (P<0.05). The addition of MPA to CEE, however, inhibited the increase in CRP in a concentration-dependent manner (MPA 2.5 mg, 169.8+/-66.9%, P<0.05; MPA 5 mg, 55.0+/-30.4%, not significant). Similarly, CEE increased amyloid A protein concentrations, whereas MPA reversed this effect. Interleukin-6 concentration did not change significantly in any treatment group. CEE alone significantly decreased the concentration of E-selectin, but the concentrations of intercellular adhesion molecule and vascular cellular adhesion molecule did not change significantly. The addition of MPA tended to decrease the levels of cell adhesion molecules, and use of 5.0 mg MPA showed significant decreases in all cell-adhesion molecule concentrations. CONCLUSIONS: Concurrent MPA administration may attenuate estrogen's proinflammatory effect. Because MPA in combination with CEE decreased cell adhesion molecule concentrations, the anti-inflammatory effect of MPA may actually be responsible for the favorable effect of estrogen-progestogen combinations on cell adhesion molecules in postmenopausal women.

Different effects of oral conjugated equine estrogen and transdermal estrogen replacement therapy on size and oxidative susceptibility of low-density lipoprotein particles in postmenopausal women.

BACKGROUND: Postmenopausal estrogen replacement therapy (ERT) has an antioxidant effect that opposes the oxidation of LDL particles. Oral ERT-induced increases in plasma triglyceride, however, decrease LDL particle size, which may counteract this antioxidant effect. Because transdermal ERT decreases plasma triglyceride, it may not decrease LDL particle size and may preserve estrogen's antioxidant effect. The present study investigates whether transdermal ERT can eliminate the adverse effects of oral ERT on the size and oxidative susceptibility of LDL in postmenopausal women. METHODS AND RESULTS: Postmenopausal women received no treatment (n=12) or were treated with either 0.625 mg oral conjugated equine estrogen daily (n=16) or with transdermal estradiol (50 microg/d, n=16) for 3 months. Plasma lipids and the diameter of LDL particles were determined. Susceptibility of LDL to oxidation was analyzed by incubation with CuSO4 and subsequent measurement of thiobarbituric acid reactive substance (TBARS) concentrations. Oral ERT significantly increased plasma triglyceride and decreased LDL diameter but did not affect LDL-derived TBARS concentrations. In contrast, transdermal ERT significantly decreased the concentrations of plasma triglyceride and LDL-derived TBARS and significantly increased LDL diameter. Estrogen-induced changes in LDL diameter correlated negatively with changes in plasma triglyceride (r=-0.51, P<0.001) and LDL-derived TBARS (r=-0.50, P<0.001). CONCLUSIONS: Because transdermal, but not oral ERT, decreases plasma triglyceride and produces larger LDL particles that are resistant to oxidation, the antioxidant effect of estrogen can be preserved.

Effect of lower dose of oral conjugated equine estrogen on size and oxidative susceptibility of low-density lipoprotein particles in postmenopausal women.

BACKGROUND: Estrogen replacement therapy (ERT) has an antioxidant effect that opposes the oxidation of LDL. Oral ERT-induced increases in plasma triglyceride, however, are associated with decreased LDL size, which may counteract this antioxidant effect. Because lower doses of oral estrogen do not affect plasma triglyceride concentrations, LDL size might not change, and the antioxidant effect of estrogen might be preserved. We investigated whether a lower dose of oral estrogen could eliminate the adverse effects of high-dose oral ERT on the size and oxidative susceptibility of LDL in postmenopausal women. METHODS AND RESULTS: Postmenopausal women received no treatment or were treated with oral conjugated equine estrogen (CEE) 0.625 or 0.3125 mg/d for 3 months. CEE at a dose of 0.625 mg/d significantly increased plasma triglyceride concentrations and decreased LDL diameter, but the concentrations of LDL-derived thiobarbituric acid reactive substances (TBARS) and lag time for conjugated diene formation did not change. In contrast, 0.3125 mg of CEE did not affect plasma triglyceride concentrations or LDL diameter and significantly decreased LDL-derived TBARS concentrations and significantly prolonged LDL lag time. Estrogen-induced changes in LDL diameter correlated negatively with changes in plasma triglyceride (r=-0.44, P<0.01) and LDL-derived TBARS (r=-0.57, P<0.001) but positively with changes in LDL lag time (r=0.42, P<0.01). CONCLUSIONS: Because oral CEE at a dose of 0.3125 mg/d does not elevate plasma triglyceride, resulting in unchanged size of LDL particles that are resistant to oxidation, the antioxidant effect of estrogen can be preserved.

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.

Human leukocyte antigen expression by peritoneal macrophages from women with pelvic endometriosis is depressed but coordinated with costimulatory molecule expression.

OBJECTIVE: To investigate the macrophage response in endometriosis, we determined expression of human leukocyte antigen (HLA)-ABC, HLA-DR, and their costimulatory molecules by peritoneal fluid (PF) macrophages. DESIGN: Case-control study of immunologic markers. SETTING: University hospital. PATIENT(S): We compared 38 Japanese women with endometriosis with 59 control subjects who were given other laparoscopic diagnoses. INTERVENTION(S): Venipuncture and laparoscopic peritoneal fluid collection. MAIN OUTCOME MEASURE(S): Expression of HLA-ABC, HLA-DR, CD54, CD40, CD58, CD80, and CD86 by peripheral blood (PB) monocytes and PF macrophages was quantitated as mean fluorescence intensities by flow cytometry. Expression of each marker on PF macrophages was divided by that on PB monocytes as an index of macrophage activation (macrophage activation ratio). RESULT(S): In women with endometriosis, PF macrophages showed significant positive correlations between expression of HLA-ABC and other costimulatory molecules and also between HLA-DR and their costimulatory molecules. However, expression of HLA-ABC and DR by PF macrophages, and also their activation ratios, were significantly lower than in controls. CONCLUSION(S): Coordination with costimulatory molecules but relatively low expression of HLA-ABC and HLA-DR indicates a positive but limited immune response (antigen presentation) to events in the peritoneal cavity in women with endometriosis. This may induce immune tolerance to implanted or metaplastic endometrial tissue.

Effect of lower dosage of oral conjugated equine estrogen on inflammatory markers and endothelial function in healthy postmenopausal women.

OBJECTIVE: Although oral estrogen replacement therapy (ERT) in postmenopausal women improves endothelial function, it also increases plasma C-reactive protein (CRP) and interleukin-6 (IL-6) concentration. The proinflammatory effect of oral ERT may explain the increased risk of coronary heart disease (CHD) associated with this treatment. Recent observational studies have demonstrated that a lower dose of oral estrogen reduces the risk for CHD. The purpose of the present study was to investigate the effects of low-dose oral estrogen on vascular inflammatory markers and endothelium-dependent vasodilation in postmenopausal women. METHODS AND RESULTS: Postmenopausal women were randomized into 3 groups to receive no treatment (n=14) or oral conjugated equine estrogen (CEE) at a dosage of 0.625 mg (n=15) or 0.3125 mg (n=15) daily for 3 months. CEE at a dosage of 0.625 mg resulted in significant increases in plasma concentrations of CRP from 690.9+/-749.5 to 1541.9+/-1608.0 ng/mL, serum amyloid A from 6.12+/-4.15 to 8.25+/-4.40 microg/mL, and IL-6 from 1.45+/-0.73 to 2.35+/-1.16 pg/mL. In contrast, CEE at a dosage of 0.3125 mg had no effect on these inflammatory markers. Both dosages of estrogen significantly decreased E-selectin concentration, whereas the concentrations of intercellular and vascular cell adhesion molecules remained unchanged. In both CEE groups, flow-mediated vasodilation in the brachial artery was increased significantly, whereas nitroglycerine-induced vasodilation was unaltered. CONCLUSIONS: Oral CEE at a low dose of 0.3125 mg in postmenopausal women eliminated the adverse effects of high-dosage oral CEE on vascular inflammatory markers in addition to preserving the favorable effects of estrogen on cell adhesion molecules and endothelial function.

Size and oxidative susceptibility of low-density lipoprotein particles in breast cancer patients with tamoxifen-induced fatty liver.

The purpose of the present study was to investigate the effects of tamoxifen on the size and oxidative susceptibility of low-density lipoprotein (LDL) particles in breast cancer patients with tamoxifen-induced fatty liver. We investigated the following breast cancer patients: 13 receiving no tamoxifen (group A), 13 receiving tamoxifen 40 mg daily but without fatty liver (group B), and 13 receiving tamoxifen 40 mg daily with fatty liver (group C). Plasma lipids and diameter of LDL particles were measured. Susceptibility of LDL to oxidation was analyzed by incubation with CuSO(4) while monitoring conjugated diene formation and assaying thiobarbituric acid reactive substances (TBARS). Plasma total and LDL cholesterol concentrations in groups B and C were significantly lower than those in group A. In group C, concentrations of plasma triglyceride (TG) and TBARS were significantly greater, but LDL particle diameter and lag time for LDL oxidation were significantly smaller than those in groups A and B. Plasma TG concentrations correlated negatively with computed tomography ratio of liver to spleen (r = -0.76; P < 0.001). LDL particle diameter correlated negatively with plasma TG (r = -0.62; P < 0.001) and TBARS (r = -0.44; P < 0.01), but positively with LDL lag time (r = 0.47; P < 0.01). Tamoxifen-induced fatty liver in breast cancer patients may be atherogenic, via increased TG and consequent small, easily oxidized LDL particles.

Small low-density lipoprotein particles and endothelium-dependent vasodilation in postmenopausal women.

Low concentrations of estrogen may decrease endothelial function in postmenopausal women. Elevated plasma triglycerides after menopause are frequently associated with a small, dense low-density lipoprotein (LDL) phenotype. Small LDL particles that are more susceptible to oxidation can also inhibit endothelium-dependent vasodilation. The purpose of the present study was to investigate whether hypertriglyceridemia-induced small LDL particles are associated with endothelial dysfunction in postmenopausal women. We studied 15 premenopausal and 41 postmenopausal women. Postmenopausal subjects were divided into those with LDL subclass pattern A (large particles) and those with pattern B (small particles). Plasma lipids, hormones, and diameter and oxidative susceptibility of LDL were measured. Vasodilatory responses of the brachial artery were evaluated by measuring flow-mediated vasodilation (FMD) and nitroglycerin-induced vasodilation (NID). FMD in both postmenopausal groups was significantly lower than in premenopausal women. FMD in subjects with pattern B was significantly smaller than in those with pattern A (4.9 +/- 1.9% versus 8.8 +/- 3.6%). NID did not differ significantly among the groups. Plasma triglyceride concentrations were higher, lag time for LDL oxidation was shortened, and LDL-derived thiobarbituric acid-reactive substance (TBARS) concentrations were significantly greater in subjects with pattern B than in premenopausal or pattern A subjects. LDL diameter correlated negatively with plasma triglycerides (r = -0.51) or LDL-derived TBARS (r = -0.44) and positively with LDL-lag time (r = 0.66). FMD correlated negatively with LDL-derived TBARS (r = -0.36) and positively with LDL diameter (r = 0.44) or LDL-lag time (r = 0.43). Vascular endothelial dysfunction may be associated with elevated triglyceride-induced small LDL particles that have enhanced oxidative susceptibility in postmenopausal women.

Thymidine phosphorylase expression is preserved after radiotherapy in patients with cervical squamous cell carcinoma.

PURPOSE: The aim of this study was to investigate the changes in two of the enzymes involved in fluorouracil metabolism, thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD), in uterine cervical squamous cell cancer tissue after radiotherapy. SUBJECTS AND METHODS: Cervical tissue from 27 patients diagnosed with stage IIIB or IV uterine cervical squamous cell cancer was compared with normal cervical tissue from 33 patients with benign gynecologic diseases. Expression of TP and DPD in the cervical tissues was measured using enzyme-linked immunosorbent assays. TP and DPD expression before and after irradiation with 10 and 20 Gy was measured in 9 of the 27 patients with cervical cancer. RESULTS: Before irradiation, DPD expression in cancer tissue did not differ from that in normal tissue. TP expression and the TP/DPD ratio were significantly higher in cancer tissue than in normal tissue ( P<0.00001). TP and DPD expression and the TP/DPD ratio were not significantly changed by irradiation with 10 and 20 Gy. TP expression and the TP/DPD ratio after irradiation with 10 and 20 Gy were significantly higher than in normal tissue. CONCLUSION: The increased TP expression and the elevated TP/DPD ratio following irradiation with up to 20 Gy may offer an increased clinical advantage to chemoradiotherapy with capecitabine or doxyfluridine over radiotherapy alone.

Aberrant expression of intercellular adhesion molecule-1 and killer inhibitory receptors induces immune tolerance in women with pelvic endometriosis.

OBJECTIVE: To investigate host immunologic response to endometriosis in terms of intercellular adhesion molecule (ICAM)-1 expression by macrophages and killer cell inhibitory receptor (KIR) expression by natural killer (NK) cells. DESIGN: Case-control study of immunologic markers. SETTING: University hospital. PATIENT(S): Twenty-eight Japanese women with endometriosis. Control subjects were 26 women without endometriosis. Diagnoses were made at laparoscopy. INTERVENTION(S): Venipuncture and laparoscopic peritoneal fluid collection. MAIN OUTCOME MEASURE(S): ICAM-1 expression by macrophages and KIR expression by NK cells, measured by flow cytometry. RESULT(S): In women with endometriosis, expression of ICAM-1 by peritoneal macrophages was significantly lower and expression of KIR by NK cells in peritoneal fluid and peripheral blood was significantly higher than in control subjects. CONCLUSION(S): Properties of macrophages and NK cells in women with endometriosis promote immunotolerance to implanted tissue in the peritoneal environment. Increased KIR(+)NK cells in peripheral blood may represent a risk factor for endometriosis.

Coordinated but depressed expression of human leukocyte antigen-DR, intercellular adhesion molecule-1, and CD14 on peritoneal macrophages in women with pelvic endometriosis.

OBJECTIVE: To investigate the macrophage response in endometriosis, we determined the expression of human leukocyte antigen (HLA)-DR, intercellular adhesion molecule (ICAM)-1, and CD14 on peritoneal macrophages. DESIGN: Case-control study of immunologic markers. SETTING: University hospital. PATIENT(S): Forty-five Japanese women with endometriosis were compared with 48 control subjects with other laparoscopic diagnoses. INTERVENTION(S): Venipuncture and laparoscopic peritoneal fluid (PF) collection. MAIN OUTCOME MEASURE(S): Expression of HLA-DR, ICAM-1, and CD14 on peripheral blood (PB) monocytes and PF macrophages were quantitated as mean fluorescence intensities by flow cytometry. Expression of each marker on PF macrophages was divided by that on PB monocytes, as an index of macrophage activation (macrophage activation ratio). RESULT(S): In women with endometriosis, PF macrophages showed significant positive correlations between expression of HLA-DR and ICAM-1, HLA-DR and CD14, and ICAM-1 and CD14. However, expression of individual markers on PF macrophages and their activation ratios were significantly lower than in control. CONCLUSION(S): Coordinated but relatively low expression of HLA-DR, ICAM-1, and CD14 on PF macrophages indicates a positive but limited immune response to events in the peritoneal cavity in women with endometriosis, which may induce immune tolerance to implanted or metaplastic endometrial tissue.

Increased killer inhibitory receptor KIR2DL1 expression among natural killer cells in women with pelvic endometriosis.

OBJECTIVE: To investigate the host immunologic response to endometriosis in terms of killer inhibitory receptor (KIR) expression by natural killer (NK) cells. DESIGN: Case-control study of immunologic markers. SETTING: University hospital. PATIENT(S): We compared cells from Japanese women with laparoscopically diagnosed endometriosis to cells from 40 women with other laparoscopic diagnoses. INTERVENTION(S): Peripheral venous blood sampling and laparoscopic peritoneal fluid collection. MAIN OUTCOME MEASURE(S): Flow cytometry was used to assess expression of KIR by NK cells in the cell samples. RESULT(S): The percentage of cells that expressed KIR2DL1 among NK (KIR2DL1(+)NK) cells in peritoneal fluid and peripheral blood was significantly higher in women with endometriosis than in controls. The proportion of KIR2DL1(+)NK cells in peripheral blood NK cells before and 1 month after laparoscopic surgery did not differ significantly. CONCLUSION(S): The proportion of KIR2DL1(+)NK cells was increased in peritoneal fluid and peripheral blood in women with endometriosis; this difference is probably related to NK cell suppression in endometriosis. This increase in KIR2DL1 expression by NK cells may represent a risk factor in the pathogenesis of endometriosis.

MRI of endocervical glandular disorders: three cases of a deep nabothian cyst and three cases of a minimal-deviation adenocarcinoma.

The incidence of cervical adenocarcinoma is increasing. Nabothian cysts are a common gynecologic condition; if multiple and/or large cysts are present, it is difficult to differentiate them from a minimal-deviation adenocarcinoma (MDA), which is classified as a special type of cervical adenocarcinoma. We report three cases of deep nabothian cysts and three cases of MDAs. Magnetic resonance imaging (MRI) findings, signs, and symptoms of these cases are described. The absence of a watery discharge and an MR image displaying a round or oval cyst without enhancement after intravenous gadolinium are helpful in the diagnosis of a deep nabothian cyst.