Dedifferentiated Endometrial Carcinoma Could be A Target for Immune Checkpoint Inhibitors (Anti PD-1/PD-L1 Antibodies).

Dedifferentiated endometrial carcinoma (DDEC) is defined as an undifferentiated carcinoma admixed with differentiated endometrioid carcinoma (Grade 1 or 2). It has poor prognosis compared with Grade 3 endometrioid adenocarcinoma and is often associated with the loss of mismatch repair (MMR) proteins, which is seen in microsatellite instability (MSI)-type endometrial cancer. Recent studies have shown that the effectiveness of immune checkpoint inhibitor therapy is related to MMR deficiency; therefore, we analyzed the immunophenotype (MMR deficient and expression of PD-L1) of 17 DDEC cases. In the undifferentiated component, nine cases (53%) were deficient in MMR proteins and nine cases (53%) expressed PD-L1. PD-L1 expression was significantly associated with MMR deficiency (p = 0.026). In addition, the presence of tumor-infiltrating lymphocytes (CD8+) was significantly associated with MMR deficiency (p = 0.026). In contrast, none of the cases showed PD-L1 expression in the well-differentiated component. Our results show that DDEC could be a target for immune checkpoint inhibitors (anti PD-L1/PD-1 antibodies), especially in the undifferentiated component. As a treatment strategy for DDEC, conventional paclitaxel plus carboplatin and cisplatin plus doxorubicin therapies are effective for those with the well-differentiated component. However, by using immune checkpoint inhibitors in combination with other conventional treatments, it may be possible to control the undifferentiated component and improve prognosis.

High Frequency of PIK3CA Mutations in Low-Grade Serous Ovarian Carcinomas of Japanese Patients.

The frequency of KRAS/BRAF mutations associated with low-grade serous ovarian carcinoma (LGSC)/serous borderline tumors (SBTs) in Japan is unknown. We aimed to identify genetic variations in KRAS, BRAF, PIK3CA, and ERBB2 in LGSC/SBT/serous cystadenomas (SCAs) in a Japanese population. We performed a mutation analysis (by Sanger sequencing) of 33 cases of LGSC/SBT/SCA and 4 cases of LGSC with synchronous SBTs using microdissected paraffin-embedded sections. Immunohistochemistry of p53 and ARID1A was also performed. The frequency of oncogenic mutations in PIK3CA was 60.0% (6/10) in LGSCs, 63.6% (7/11) in SBTs, and 8.3% (1/12) in SCAs. All cases harbored wild-type KRAS. The frequency of BRAF mutations was 20.0% (2/10) in LGSCs, whereas all SBTs and SCAs harbored the wild-type allele. The frequency of ERBB2 mutations was 30.0% (3/10) in LGSCs, 0.0% (0/11) in SBTs, and 16.7% (2/12) in SCAs. ARID1A staining was positive in all cases. p53 staining was positive in 0% (0/10) LGSCs, 9.1% (1/11) SBTs, and 0.0% (0/12) SCAs. One LGSC case had two PIK3CA mutations (G1633A and G3149A) in both LGSC and SBT lesions, but a BRAF mutation was detected only in an LGSC lesion. These results suggest that, compared with the values in Western populations (16-54%), the KRAS mutation frequency in LGSCs/SBTs is lower and that of PIK3CA mutations in LGSCs/SBTs is much higher in Japanese populations. Therefore, the main carcinogenesis signaling pathways may be different between Japanese and Western LGSCs. Molecular therapies targeting the PIK3CA/AKT pathway may be effective in LGSCs in Japan.

The efficacy and safety of dydrogesterone for treatment of dysmenorrhea: An open-label multicenter clinical study.

AIMS: Dydrogesterone is a retro-progesterone preparation widely used for over a half century. We sought to evaluate the efficacy and safety of dydrogesterone in Japanese women with dysmenorrhea. METHODS: This study was conducted as an open-label, single-arm, multicenter study. One dydrogesterone 5-mg tablet (Duphaston) was administered orally twice daily for 21 days from the 5th to 25th day of each menstrual cycle. A total of 44 (safety analysis) and 31 patients (efficacy analysis) were enrolled. Total dysmenorrhea score, dysmenorrhea subscale scores, dysmenorrhea visual analog scale, severity of menstruation-related lower abdominal pain, low back pain, headache, and nausea/vomiting, basal body temperature, and serum estradiol and progesterone levels were evaluated. RESULTS: Baseline of the total dysmenorrhea score was 4.61, which went down over time following the administration of dydrogesterone, and the decrease was statistically significant at and after 2nd cycle of menstruation. Mean change from baseline at the final evaluation point was -1.84 (P < 0.001). Severity of menstruation-related lower abdominal pain, low back pain, headache, and nausea/vomiting, in the evaluated menstruation cycles tended to decrease over time. Basal body temperature showed a biphasic pattern in 70% at baseline, 50% in 2nd menstruation cycle, and 61% in 5th menstruation cycle, and at least half of the patients may have had ovulation during the treatment. Incidence of adverse drug reactions was 31.8%, and the most common adverse event was metrorrhagia. CONCLUSION: Dydrogesterone is efficacious, safe, and clinically beneficial in patients with dysmenorrhea, thereby indicating that dydrogesterone can be considered as a treatment option for patients with dysmenorrhea.

Glucose intolerance in Japanese patients with polycystic ovary syndrome.

BACKGROUND: Hyperinsulinemia, which is related to obesity, played a pathogenic role in polycystic ovary syndrome (PCOS). However, the incidence of obesity in Japanese women with PCOS is different from that reported in patients with PCOS in Europe and USA. We should determine if insulin resistance occurs in Japanese PCOS. The purpose of this study is to assess the presence of insulin resistance in Japanese PCOS, while also considering obesity as a factor. METHODS: We divided the patients with polycystic ovary (PCO) into three groups based on body mass index and levels of gonadotropin. Nine obese PCOS, 34 normal body-weighted PCOS (luteinizing hormone (LH)/follicle stimulating hormone (FSH) >1.0) and 11 normal LH (LH/FSH

Maternal thyroid function during pregnancy and puerperal period.

It has been noted that hypothyroidism in pregnant women can adversely affect the children's subsequent psychoneurotic development. Also, transient elevation of serum free thyroxine is occasionally seen in the first trimester of normal pregnancy. However, normal thyroid function during pregnancy and the puerperal period has not been clearly defined in Japan. The aim of this study was to assess maternal thyroid function during pregnancy and puerperal period in Japan. The concentrations of thyroid stimulating hormone (TSH), free triiodo-thyronine (free T(3)), free thyroxine (free T(4)) and thyroid binding capacity (TBC) of 522 normal pregnant and puerperal women (119 in the first trimester; 132 in the second trimester; 135 in the third trimester and 136 in the early puerperium) were measured by electrochemiluminescence immunoassay. We compared the measured data with those of healthy nonpregnant control. Twenty-six (21.8%) of 119 women in the first trimester had lower TSH levels and 23 (16.9%) of 136 women in the early puerperium had higher TSH levels than the normal range of healthy nonpregnant controls. Free T(3) gradually decreased during pregnancy, although it remained within the normal control range. Eight (6.7%) of 119 women in the first trimester had high free T(4) levels, which gradually decreased during pregnancy. Sixty (44.4%) of 135 women in the third trimester had low free T(4) levels. The values of TBC in the second trimester increased compared with the first trimester and did not change in the third trimester and decreased after delivery. There were no correlations between maternal TSH and levels of thyroid hormones (free T(3) or free T(4)), except for TSH and free T(4) in the first trimester. In conclusion, we showed that maternal thyroid function, especially TSH and free T(4), changed during the course of pregnancy. In assessing the thyroid function associated with pregnancy, one needs to keep in mind the tendency toward low free T(4) levels in the third trimester and high TSH levels in the early puerperal period.

Influence of missense mutation and silent mutation of LHbeta-subunit gene in Japanese patients with ovulatory disorders.

The frequency of variant LHbeta containing two point mutations (T(986)-C and T(1008)-C) and its relationship to reproductive disorders differ widely between ethnic groups. In a Japanese population, variant luteinizing hormone (LH) correlates with ovulatory disorders. Here we examined the relationship between two missense mutations and five silent mutations (C(894)-T, G(1018)-C, C(1036)-A, C(1098)-T and C(1423)-T) in the LHbeta gene, and ovulatory disorders. We studied 43 patients with ovulatory disorders, 79 patients with normal ovulatory cycles, and 23 healthy men who agreed to join our DNA analysis. PCR-amplified LHbeta-subunit gene sequences were compared with a base sequence of wild-type LH reported after direct sequencing. The highest frequency (0.945) of novel allele was observed at the position of the C(1036)-A transition. No homozygotes for wild-type LHbeta (C(1036)) were identified. The frequency of novel allele in patients with polycystic ovary syndrome, endometriosis, premature ovarian failure and luteal insufficiency was significantly different from that of healthy women. The frequencies of novel alleles (C(894)-T, C(1098)-T and C(1423)-T) in patients with ovulatory disorders were significantly higher than those with normal ovulatory cycles. The mean incidence of point mutation in patients with ovulatory disorders was higher than in those with normal ovulatory cycles. Among patients with variant LH, five silent mutations were identified in 87.5% of patients with ovulatory disorders, whereas only a few silent mutations were identified in patients with normal ovulatory cycles. In a Japanese population, five silent mutations of variant LH could have influenced two missense mutations and/or other unknown missense mutations, causing ovulatory disorders.