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The objective of this study was to propose prognostic factors and optimal treatment strategies by analyzing the clinicopathological features and programmed death-ligand 1 (PD-L1) expression. We analyzed 31 patients diagnosed with uterine or ovarian melanoma between 1997 and 2017 in the Kansai Clinical Oncology Group/Intergroup. Twenty-four and seven patients with cervical and ovarian melanomas were included, respectively. Immune checkpoint inhibitors were used in seven patients, and the objective response rate was 40%. Notably, two patients with objective responses had a high PD-L1 expression. Ten and four patients with cervical and ovarian melanomas, respectively, had high PD-L1 immunohistochemical expressions. Multivariate analysis revealed that tumor stage was an independent prognostic factor for progression-free survival in patients with cervical melanomas. In patients with ovarian melanomas, the 1-year cumulative progression-free and overall survival rates were 0 and 29%, respectively. Kaplan-Meier analyses revealed that age <60 years was associated with poorer progression-free and overall survivals in patients with ovarian melanomas. In patients with cervical melanomas, the 1-, 3-, and 5-year cumulative overall survival rates were 53, 32, and 16%, respectively. Histological atypia was associated with a poorer progression-free survival, but there was no difference in survival between patients who underwent radical hysterectomy and those who did not. The present study is a large cohort study of uterine and ovarian melanomas, which are aggressive tumors with a significantly poor prognosis, even after standard surgery and adjuvant therapy. The use of immune checkpoint inhibitors is a promising and effective treatment option., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Allergen-specific immunoglobulin isotype formation associated with immunoglobulin class-switching during the lactation period is the immunological background for food allergy in infants. We analyzed the serial changes in the production of feeding type-related egg- and milk-specific immunoglobulin isotypes from birth to 6 months of age with or without eczema in 84 infants., Methods: Allergen-specific immunoglobulin G1 (IgG1), IgG2, IgG3, IgG4, IgA, and IgE levels of hen's egg and bovine milk were measured in cord blood and blood samples from infants at 2, 4, and 6 months of age by the densely carboxylated protein microarray., Results: Formula and mixed feeding were associated with a rapid increase in cow's milk allergen-specific immunoglobulins and feeding type-related significant differences in casein-specific immunoglobulin levels were detected. Breast and mixed feeding were associated with slow but significant increase in ovalbumin-specific IgG1 and IgE levels, but not other immunoglobulins. We found two different immunoglobulin isotype formation at 6 months of age with low- or high-affinity IgE against ovalbumin. One isotype formation pattern had relatively high ovalbumin-specific IgG1 levels, detectable IgG2, and low-affinity IgE, while the other had low ovalbumin-specific IgG1 levels, undetectable IgG2, and high levels of high-affinity IgE. The incidence of eczema was significantly higher in the latter pattern (84.6%), compared with the remaining infants (42.2%)., Conclusions: Feeding practice-related allergen sensitization and immunoglobulin isotype formation were identified during the lactation period. The development of eczema during the lactation period could potentially modify the immunoglobulin isotype formation with high levels of high-affinity IgE., (© 2019 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.)

Background: The therapeutic value of systematic lymphadenectomy for early-stage epithelial ovarian cancer (EOC) is controversial. This study evaluates the survival impact and adverse events of systematic pelvic and para-aortic lymphadenectomy in patients with pT1 and pT2 EOC., Methods: A retrospective investigation was performed using data from patients with pT1 and pT2 EOC at multi-institutions belonging to the Sankai Gynecologic Study Group (SGSG). We selected patients who had undergone systematic pelvic and para-aortic lymphadenectomy (Group LA) (n = 284) and patients who had not undergone lymph node resection (Group no-LA) (n = 138). Outcomes for patients and peri-operative adverse events were compared between the two groups., Results: The median operation time was significantly longer in Group LA (288 min) than in Group no-LA (128 min) (P < 0.0001). Total blood loss was significantly higher in Group LA, 43.7 % of patients receiving blood transfusions. There were no significant differences between the treatment groups for progression-free survival (PFS) or overall survival (OS). However, for patients with pT2, PFS was significantly longer in Group LA than in Group no-LA (P = 0.0150). Lymph node metastases were detected in 23 cases (8.1 %) and these patients had significantly shorter PFS than those without metastasis (P = 0.0409). The outcome for patients who underwent chemotherapy after surgery was significantly improved in the Group no-LA, but no improvement was observed in Group LA., Conclusions: Systematic lymphadenectomy may improve outcomes only in pT2 EOC patients with acceptable peri-operative events. Furthermore, accurate surgical staging may avoid unnecessary adjuvant chemotherapy in selected early-stage cases.

In the follicles of the mammalian and amphibian ovary, oocyte maturation is arrested at the prophase of the first meiotic division. Prior to ovulation, oocytes reenter the cell cycle, complete the meiotic division, and extrude the first polar body. Work from several laboratories including ours has provided evidence that the cAMP-mediated signal transduction pathway plays an important role in regulation of meiosis, the cyclic nucleotide acting as a negative regulator of maturation. Since cAMP can be regulated both at the level of synthesis and degradation, our laboratory is investigating the role of phosphodiesterases (PDE) in the control of cAMP levels of oocytes. Using pharmacological and molecular tools, we have determined that a PDE3 is the enzyme involved in the control of cAMP levels in the oocytes. In vitro and in vivo studies have established that inhibition of the oocyte PDE3 blocks resumption of a PDE is per se sufficient to cause resumption of meiosis in an amphibian oocyte model. The pathways regulating this PDE isoform expressed in the oocyte is under investigation, as they may uncover the physiological signals controlling meiosis.

Objective: To clarify the mechanism of the suppressive effect of 2-buten-4-olide (2-B4O), an endogenous feeding suppressant, on the pulsatile secretion of luteinizing hormone (LH), by studying whether endogenous opioid peptides are involved in this suppressive effect., Methods: Using ovariectomized (ovx) rats, blood samples were taken every 6 min for 2 h after administration of 2-B4O or saline into the third cerebroventricle (3V) and sequential i.v. injection of naloxone (0. 5 mg/kg per h) or saline. Rats were divided into three experimental groups: group 1: 3V saline + i.v. saline (control); group 2: 3V 2-B4O + i.v. saline; group 3: 3V 2-B4O + i.v. naloxone. Serum LH concentrations were determined by double-antibody RIA. To determine whether 2-B4O affected the biosynthetic activity of the opioidergic neurons within the ovx rat arcuate nucleus, we measured the concentrations of pro-opiomelanocortin (POMC) mRNA, a precursor of beta-endorphin, in the rostral arcuate nucleus using non-radioactive in situ hybridization and a computerized image-analysis system., Results: 2-B4O significantly suppressed the pulse frequency of LH (group 2: 1.5+/-0.33 pulses/2 h, group 1: 2.43+/-0.2 pulses/2 h; P < 0.05), but naloxone blocked its suppressive effect and restored the pulse frequency (group 3: 3.29+/-0.36 pulses/2 h, group 2: 1.5+/-0.33 pulses/2 h: P < 0.01). There were no significant changes in the mean LH concentrations and amplitude. Furthermore, 2-B4O significantly stimulated the expression of POMC mRNA in the rostral arcuate nucleus., Conclusion: These results suggest that 2-B4O may impair the pulsatile secretion of LH by activating the opioid pathway within the hypothalamus.

We developed an assay system for measuring free follistatin by using an anti-follistatin mouse monoclonal antibody and [125I]activin A. The sensitivity of this assay was 0.5 microgram/l and cross-reactivities with inhibin, luteinizing hormone, follicle-stimulating hormone and growth hormone were all less than 0.5%. The dose-response curves of human sera and follicular fluid were parallel to the standard curve, and the follicular fluid contained a large amount of follistatin (6.4 +/- 0.5 mg/l, mean +/- SEM; N = 13). The within- and between-assay coefficients of variation calculated from the analysis of serum samples of four different concentrations were 3.3-7.8% and 3.9-11.0%, respectively. The recovery rates of free follistatin at five different doses were 86.4 - 102.4%. When activin A was added to the same sample, free follistatin recovery rate declined dose-dependently. Gel filtration analyses of human serum and follicular fluid resulted in a single peak corresponding to authentic follistatin. Using this assay, free follistatin concentrations in sera were measured in normal, pregnant and diseased subjects. The free follistatin level in serum of normal adults was 3.5 +/- 0.2 micrograms/l (N = 60), which was significantly elevated in pregnant women (16.7 +/- 1.3 micrograms/l, N = 56), and in patients with chronic liver disease (8.1 +/- 1.1 micrograms/l, N = 20), chronic renal failure (6.7 +/- 0.9 micrograms/l, N = 42), advanced solid cancer (8.5 +/- 1.0 micrograms/l, N = 39) and hematological malignancies (6.8 +/- 1.0 micrograms/l, N = 18). These data indicated that the free follistatin concentration in serum is detectable and varies during pregnancy and in various diseased states.

We developed and validated a RIA for measuring serum activin A. The least detectable value of this assay was 0.1 micrograms/L, and the antibody used cross-reacted slightly with bovine inhibin (3.2%) and porcine activin AB (10.0%) but not with porcine activin B (< 0.5%). Serum activin A was extracted with acetonitrile and trifluoroacetic acid to get rid of the interaction with possible binding proteins in serum. As a result of this extraction procedure, the dose-response curve of serum extract was parallel to the standard curve and a single immunoreactive (ir-) peak was demonstrated on gel chromatographic analysis with constant recovery rates over 80%. Serum ir-activin A level in healthy adults was 1.27 +/- 0.03 micrograms/L (mean +/- SEM, n = 180); being 1.38 +/- 0.05 micrograms/L (n = 90) in male, and 1.16 +/- 0.05 micrograms/L (n = 90) in female subjects, with a tendency to increase with age. Serum ir-activin A level during pregnancy showed a marked increase with the advance of gestation; 1.65 +/- 0.41 micrograms/L (n = 7) in the early, 4.50 +/- 1.13 micrograms/L (n = 21) in the middle, and 16.32 +/- 2.25 micrograms/L (n = 26) in the late trimester, with a rapid decline after delivery. On the other hand, serum ir-activin A level was elevated in patients with hyperthyroidism (1.91 +/- 0.37 micrograms/L, n = 31), liver cirrhosis (2.03 +/- 0.71 micrograms/L, n = 10), chronic renal failure (3.41 +/- 0.34 micrograms/L, n = 41), and advanced solid cancer (2.24 +/- 0.52 micrograms/L, n = 67). These findings indicate that serum ir-activin A level varies with physiological conditions such as aging and pregnancy, and that it may reflect the altered production and metabolism of activin A in certain diseased conditions.

A sensitive and specific immunoradiometric assay for follistatin was developed using antifollistatin mouse monoclonal and rabbit polyclonal antibodies. The sensitivity of the assay was 0.5 micrograms/L, and cross-reactivities with recombinant human activin A and bovine inhibin were less than 0.1%. The intra- and interassay coefficients of variation were less than 10%, and the recovery rate was about 90% in human serum. The addition of activin A to the same sample resulted in a minimal influence on follistatin recovery, indicating that this assay system can measure the total level of activin-bound and unbound follistatin. Gel filtration analysis of human serum showed that the majority of immunoreactivity was eluted in a larger molecular size position than that of free follistatin, suggesting that the large part of follistatin is bound to other proteins, presumably activins, in serum. Using this assay, immunoreactive follistatin levels in various biological fluids and human sera were examined. The dose-response curves of porcine follicular and amniotic fluids were parallel to the standard curve, and porcine follicular fluid contained extremely high follistatin immunoreactivity (5.6 mg/L). The serum follistatin level in normal human volunteers was 13.3 +/- 4.7 micrograms/L (mean +/- SD; n = 60), with a tendency to increase gradually with age. On the other hand, the serum follistatin level was remarkably elevated in pregnant women (62.7 +/- 35.3 micrograms/L; n = 57), with a positive correlation with weeks of pregnancy. These data indicated that circulating immunoreactive follistatin is detectable in human serum, and the levels vary with physiological conditions such as aging and pregnancy.

To eliminate the risks involved in homologous blood transfusion in gynecological surgery, we studied the effect of the combined transfusion of autologous blood as predeposited and preoperatively diluted. Thirty-nine cases were operated on and studied. In 27 cases, a total of 695 ml/person of autoblood was taken during the 15 preoperative days. In 39 cases, an average of 1,038 ml/person of autoblood was collected at the beginning of surgery. In 37 out of 39 cases, we were able to avoid homologous blood transfusion. In the remaining two cases with homologous blood transfusion, although more than 3,000 ml of operative blood loss was observed, only about 700 ml of homologous blood was needed. We did not find any serious side effect with autoblood transfusion. These results demonstrate the usefulness of the combined transfusion of autologous blood as predeposited and preoperatively diluted in gynecological surgery.

The effects of 2-buten-4-olide (2-B40), an endogenous feeding suppressant, on the secretion of luteinizing hormone (LH) were studied in ovariectomized rats. Intraperitoneal (ip) administration of 2-B40: adult female ovariectomized Wistar rats were given daily ip injections of solution containing 2-B40 at 0, 50 or 100 mg/kg body wt for 14 days. This ip treatment with 2-B40 significantly decreased the mean LH concentration and pulse frequency of LH. Intravenous (iv) administration of 2-B40: a solution of 2-B40 (50 or 100 mg/kg body wt) was slowly injected through an intra-atrium catheter and blood samples were taken every 6 min for 2 h. This iv treatment significantly suppressed the LH pulse frequency but had no significant effect on the LH amplitude or mean LH. Injection of 2-B40 into the third cerebroventricle: the injection of 2-B40 into the third cerebroventricle of freely moving rats decreased the mean LH concentration and the frequency and amplitude of LH pulses. Third cerebroventricle injection of a corticotropin-releasing factor (CRF) receptor antagonist before third cerebroventricle injection of 2-B40: the specific CRF receptor antagonist alpha-helical-CRF (9-41) was injected into the third cerebroventricle of ovariectomized rats before injection of 2-B40. Administration of 2-B40 into the third cerebroventricle significantly decreased the mean LH, concentration and pulse frequency. Third cerebroventricle injection of the CRF antagonist at 50 micrograms/rat and then 2-B40 also resulted in significant suppression of the mean LH concentration and pulse frequency.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of insulin-like growth factor-I on gonadotropin release were studied using primary culture of rat anterior pituitary cells incubated with IGF-I (20-5000 micrograms/l) and a hypothalamus-pituitary perifusion system, in which either the mediobasal hypothalamus-pituitary unit or the pituitary were perifused with IGF-I (20-2000 micrograms/l). In primary cultures of rat anterior pituitary cells, IGF-I (2000 micrograms/l) caused a significant increase in the release of both LH (46% increase) and FSH (27% increase). It also caused a significant decrease in the cellular content of LH (9%) and FSH (19%). Its effects in stimulating gonadotropin release were suppressed by administration of anti IGF-I receptor antibody (1 mg/l). In the perifusion system, IGF-I (2000 micrograms/l) did not affect the LH release from the hypothalamus-pituitary or pituitary alone. However, it caused a significant increase in the GnRH (10(-9) mol/l) stimulated LH release from perifused pituitary. These data suggest that IGF-I enhances pituitary gonadotropin release via the IGF-I receptor, but its effect on the hypothalamus was not confirmed.

The effects of 2-buten-4-olide, an endogenous feeding suppressant, on the estrous cycle and LH secretion were studied to determine the influence of this compound on reproductive function. Estrous cycling female Wistar rats were treated ip with 2-buten-4-olide (0, 30 or 100 mg.kg-1.day-1) for 2 weeks. Treatment with 100 mg.kg-1.day-1 delayed the estrous cycle. 2-Buten-4-olide increased the pituitary content of LH (1651.3 +/- 164.4 vs 927.7 +/- 65.1 ng/pituitary; p less than 0.01), and decreased the serum LH level compared with the control level in diestrus (0.16 +/- 0.01 vs 0.26 +/- 0.03 microgram/l; p less than 0.05). However, it did not affect the GnRH content of the mediobasal hypothalamus. The direct effects of 2-buten-4-olide on the pituitary response to GnRH was examined by perifusing the pituitary. Medium containing 2-buten-4-olide (10(-4) mol/l) suppressed the pituitary response to GnRH (2 micrograms/l) (percent increase at 50 min after start of GnRH stimulation: 180 +/- 47 vs 406 +/- 66%; p less than 0.05). These findings suggest that 2-buten-4-olide is involved in the regulation of pituitary gonadotropin secretion directly by suppressing the pituitary responsiveness to GnRH, and that 2-buten-4-olide may play an important role in starvation-induced anestrus.

Thomsen-Friedenreich antigen (T-antigen) is a carbohydrate antigen that is expressed in a variety of cancer tissues. T-antigen is thought to have an antigenicity because circulating T antibodies can be detected as natural antibodies in humans. In this study, we examined the serum T antibody titers in patients with gynecological cancer using the hemagglutination test, and studied the relationship between the expression of T-antigen in cancer tissues and serum TA-4 levels and serum T antibody titers. Serum T antibody titers in patients with gynecological cancer were lower than those in normal controls, especially in endometrial and ovarian cancer (p less than 0.05) in which T-antigen was strongly expressed. Furthermore, the low antibody titers correlated with the expression of T-antigen in cancer tissues. T antibody titers significantly increased (p less than 0.01) after operation and the inverse relationship was found with the levels of circulating TA-4 in cervical cancer patients. These findings suggests that patients with gynecological cancer immunologically responded to T-antigen and the measurement of circulating T antibodies may be useful as an indicator of the progression of cancer in tissues.

The expression of Thomsen-Friedenreich antigen (T-Ag), the precursor of MN blood group antigen, was studied by the ABC method with Arachys Hypogaea lectin (PNA) and the relationship of the results to the histology and clinical behavior of primary gynecologic cancers were examined. The results were as follows: 1. In cervical squamous cell tumors, the incidence of the expression of T-Ag in invasive cancers (52.9%, 37/70) was significantly higher (p less than 0.05) than that in intraepithelial tumors (28.6%, 8/28). No cryptic T-Ag(-) tissue was found in intraepithelial tumors or microinvasive cancers. 2. In squamous cell carcinomas of the cervix, the incidence of cryptic T-Ag(-) tissue was high (36.4%, 4/11) in tissue of the small cell non-keratinizing type, the most undifferentiated type, whereas it was not found in 5 cases of well-differentiated keratinizing carcinoma examined. 3. In stage Ib and II cervical cancers, no relationship was recognized between the expression of T-Ag in primary lesion and extension to the parametrium or the pelvic lymph nodes. 4. The incidence of T-Ag(+) tissue in adenocarcinomas of the uterine cervix (62.5%, 5/8), the endometrium (91.7%, 11/12), and the ovarian (80%, 8/10) was higher than that in squamous cell carcinoma of the uterine cervix (52.5%, 32/61). 5. In endometrial cancers, no relationship was recognized between the expression of T-Ag and hormone receptor status.