[Questionnaire surveys of clinical genetic specialists on the medical genetics for patients with myotonic dystrophy type 1].

We conducted nationwide questionnaire surveys of medical genetics for patients with myotonic dystrophy type 1 to certified medical geneticists. Explanations about the patient's problems were influenced by geneticist's specialties and central nervous system disorders. Many geneticists answered that male patients are also eligible for prenatal/preimplantation genetic diagnosis, and they perform prenatal genetic diagnosis for men if asked. About 40% of respondents answered that criteria for preimplantation genetic diagnosis should be relaxed. Thus, we investigated the implementation status of prenatal/preimplantation genetic diagnosis at the participating facilities of the national liaison council for clinical sections of medical genetics. No facility had an experience of prenatal/preimplantation genetic diagnosis for male patients. Still, one facility was applying for preimplantation genetic diagnosis. The social consensus of reproductive medicine is influenced by technological progress and historical background. It is essential to eliminate the eugenic's idea and form a social consensus through sufficient discussions with participants from many areas, including the patients and their families.

Ovarian metastasis from breast cancer mimicking a primary ovarian neoplasm: A case report.

Ovarian metastasis (OM) from breast cancer accounts for 3-38% of all ovarian neoplasms and is associated with various characteristic clinical presentations, such as pseudo-Meigs syndrome and Krukenberg tumor. Accurate diagnosis of OM may be challenging, as such lesions are frequently asymptomatic until they reach a large size. Occasionally, metastatic ovarian cancer is detected prior to the diagnosis of the primary tumor. Immunohistochemistry plays an important role in distinguishing primary ovarian tumors from extraovarian tumor metastases and may be helpful for identifying the primary tumor site. We herein report a case of OM from breast cancer masquerading as primary ovarian cancer. However, the correct diagnosis was made based on histopathological and immunohistochemical examinations. The patient had bilateral breast cancer, namely invasive lobular carcinoma of the left breast and ductal carcinoma of the right breast. Due to the presence of bilateral synchronous breast tumors, the possibility that the patient had hereditary breast and ovarian cancer syndrome or other relevant genetic factors was considered. Immunohistochemistry plays a key role in distinguishing between primary ovarian tumors and OM, and it was also important for confirming the metastatic nature of the ovarian lesion and diagnosing the primary tumor in the present study.

A Case of Unsuspected Low-grade Endometrial Stromal Sarcoma Successfully Treated with Two Minimally Invasive Surgeries.

It is relatively uncommon to treat patients with a preoperative diagnosis of benign leiomyoma that is then unexpectedly rediagnosed as malignant in postoperative histology. We report the case of a 55-year-old woman with low-grade endometrial stromal sarcoma who had been diagnosed as having uterine leiomyoma with myxoid degeneration by preoperative magnetic resonance imaging (MRI). She underwent a laparoscopic hysterectomy. The uterus, after being placed in a retrieval bag, was transvaginally morcellated to prevent spillage of the contents, as the MRI image appeared somewhat atypical. A retrospective survey of MRI findings affirmed that the muscle tissue had the appearance of a low-intensity band-like structure: bag of worms appearance. She underwent a laparoscopic bilateral salpingo-oophorectomy and remains recurrence-free. With somewhat atypical preoperative MRI, it is essential to prevent the spillage of the tumor content as no definitive preoperative exclusion of unsuspected mesenchymal malignancies is feasible.

Two primary cancers: Primary squamous cell carcinoma with extensive ichthyosis uteri and cervical endometrioid carcinoma: A case report.

Squamous cell carcinoma of the endometrium is extremely rare, accounting for approximately 1% of uterine body malignancies. The present report describes a case of squamous cell carcinoma of the uterine body arising from ichthyosis due to persistent pyometra. A 68-year-old Japanese woman, gravida 1 para 1, was referred to the Gynecological Department of Tokyo Women's Medical University, due to watery brown vaginal discharge which had persisted for 10 days. Pelvic magnetic resonance (MRI) imaging revealed a tumorous lesion occupying the cervical uteri, measuring 3 cm in diameter, and pyometra. The endometrial biopsy specimen obtained after drainage of the purulent fluid in the uterus was insufficient for obtaining a definitive pathological diagnosis. Under a clinical diagnosis of cervical tumor and pyometra, total transabdominal hysterectomy with bilateral salpingo-oophorectomy was performed. Histopathologically, two primary cancers were diagnosed, i.e., cervical endometrioid carcinoma and squamous cell carcinoma of the endometrium. The patient was treated with additional chemotherapy with carboplatin (area under the curve, 6) and paclitaxel (175 mg/m2). The patient has remained alive, without recurrence, for 1 year to date. In this case, preexisting cervical endometrioid carcinoma caused stenosis of the uterine orifice and also resulted in pyometra. The uterine body squamous cell carcinoma appeared to have been caused by persistent inflammatory stimuli to the endometrium. One must be cautious regarding cancer in elderly postmenopausal females presenting with pyometra. The findings in this case report suggest that chronic inflammation of the endometrium may be associated with primary squamous cell carcinoma of the endometrium.

Evaluation of cellular adequacy in endometrial liquid-based cytology.

OBJECTIVE: This study evaluated cellular adequacy in endometrial liquid-based cytology (LBC) specimens. METHODS: In total, 1267 cases were obtained and the rate of unsatisfactory specimen and diagnostic accuracy for malignancy were assessed. If ≥10 cellular clusters composed of ≤30 endometrial cells were found per specimen, then the sample was provisionally considered adequate. RESULTS: The unsatisfactory rate (with fewer than 10 clusters) was 15.4%. Diagnostic accuracy in specimens with ≥10 clusters was significantly higher (90.5% vs 36.4%) than that in specimens with fewer than10 clusters. Moreover, the unsatisfactory rate in patients aged ≥60 years was significantly higher (33.8% vs 13.2%) than that in patients younger than 60 years. Although the unsatisfactory rate was decreased, significant differences were not found between cases with fewer than five clusters (22.6%) and fewer than 10 clusters (33.8%) in patients aged ≥60 years. Diagnostic accuracy in cases with five or more clusters was significantly higher (90.3% vs 0%) than that in cases with fewer than five clusters. CONCLUSIONS: We propose that ≥10 clusters with ≥30 endometrial cells per cluster could be used as a specimen adequacy criterion for endometrial LBC. If ≥10 clusters cannot be found in patients aged ≥60 years, then the use of the alternative criterion of five or more clusters may yield satisfactory specimen adequacy.

A case of ovarian teratoma with nephroblastoma presenting spontaneous rupture.

Nephroblastoma (also known as Wilms' tumor) mainly occurs in the kidneys of children. Nephroblastoma outside the kidneys may be observed in three situations: primary disease, metastatic disease and nephroblastoma arising in teratoma. Teratoma with nephroblastoma (TWN) of the adult ovary is a rare tumor and only one case has been reported. We report an unusual adult case of ovarian TWN presented to us with acute abdomen due to the spontaneous rupture of the ovary. The rupture occurred at the site of TWN, while contralateral ovary with only mature cystic teratoma component had no rupture. After one and a half months of the ovary sparing surgery, the tumor disseminated to the splenic hilum and the omentum. A complete staging with maximum cytoreduction followed by adjuvant chemotherapy were performed. She remains disease free until present.

Treatment results of the second-line chemotherapy regimen for patients with low-risk gestational trophoblastic neoplasia treated with 5-day methotrexate and 5-day etoposide.

OBJECTIVE: Highly effective chemotherapy for patients with low-risk gestational trophoblastic neoplasia (GTN) is associated with almost a 100% cure rate. However, 20%-30% of patients treated with chemotherapy need to change their regimens due to severe adverse events (SAEs) or drug resistance. We examined the treatment outcomes of second-line chemotherapy for patients with low-risk GTN. METHODS: Between 1980 and 2015, 281 patients with low-risk GTN were treated. Of these 281 patients, 178 patients were primarily treated with 5-day intramuscular methotrexate (MTX; n=114) or 5-day drip infusion etoposide (ETP; n=64). We examined the remission rates, the drug change rates, and the outcomes of second-line chemotherapy. RESULTS: The primary remission rates and drug resistant rates of 5-day ETP were significantly higher (p<0.001) and significantly lower (p=0.002) than those of 5-day MTX, respectively. Forty-seven patients (26.4%) required a change in their chemotherapy regimen due to the SAEs (n=16) and drug resistance (n=31), respectively. Of these 47 patients failed the first-line regimen, 39 patients (39/47, 82.9%) were re-treated with single-agent chemotherapy, and 35 patients (35/39, 89.7%) achieved remission. Four patients failed second-line, single-agent chemotherapy and eight patients (17.0%) who failed first-line regimens were treated with combined or multi-agent chemotherapy and achieved remission. CONCLUSIONS: Patients with low-risk GTN were usually treated with single-agent chemotherapy, while 20%-30% patients had to change their chemotherapy regimen due to SAEs or drug resistance. The second-line regimens of single-agent chemotherapy were effective; however, there were several patients who needed multiple agents and combined chemotherapy to achieve remission.

A novel MLH1 mutation in a Japanese family with Lynch syndrome associated with small bowel cancer.

Lynch syndrome is a genetic disorder related to cancer predisposition, including colorectal cancer, endometrial cancer, and ovarian cancer. Germline mutations in mismatch repair genes, including MLH1, MSH2, MSH6, and PMS2, are responsible for this condition. Cancer tissue specimens resected from small bowel adenocarcinoma in a Japanese patient showed decreased expression of MLH1 and PMS2 by immunohistochemistry testing. Finally, a novel MLH1 mutation, c.1833dup, was identified in this patient.

Possible Application of Ascites-infiltrating Gamma-delta T Cells for Adoptive Immunotherapy.

BACKGROUND/AIM: Malignant ascites contain many tumour-infiltrating lymphocytes. γδ T cells with antitumour activity have attracted attention as effector cells in cancer immunotherapy. Vδ2+ T cells were cultured from peripheral blood mononuclear cells (PBMCs) and ascites-infiltrating lymphocytes (AILs) to compare the differences in response to 2-methyl-3-butenyl-1-pyrophosphate (2M3B1-PP) and zoledronate (Zol) as antigens in vitro. MATERIALS AND METHODS: To expand Vδ2+ T cells from PBMCs and AILs from 29 patients with cancer, these cells were cultured and subjected to analysis. RESULTS: The proliferation rate of Vδ2+ T cells was higher in both PBMCs and AILs when cultured with Zol than with 2M3B1-PP. Although Vδ2+ T cells show a higher rate of expansion in AILs compared to PBMCs, the number of mixed tumour cells in ascites was decreased when cultured with Zol. CONCLUSION: Vδ2+ T cells in AILs are cytotoxic to tumour cells in ascites and may be considered in adoptive immunotherapy.

Laparoscopically Removed Streak Gonad Revealed Gonadoblastoma in Frasier Syndrome.

BACKGROUND: Frasier syndrome (FS) is characterized by gonadal dysgenesis and progressive nephropathy caused by mutation in the Wilm's tumor gene (WT1). We report a case of FS in which diagnosis was based on amenorrhea with nephropathy, and laparoscopically-removed streak gonad which revealed gonadoblastoma. CASE REPORT: At the age of 3 years, the patient developed nephrotic syndrome. This later became steroid-resistant and, by the age of 16 years, had progressed to end-stage renal failure with peritoneal dialysis. At the age of 17 years, the patient presented primary amenorrhea and was referred to our department. Physical examination was consistent with Tanner 1 development and external genitalia were female phenotype. Speculum examination showed uterine cervix and uterine body and bilateral ovaries were not palpable on pelvic examination. Multi-sliced computed tomography of abdomen and pelvis revealed streaked structure along the bilateral external iliac artery at pelvic wall and hypoplastic uterus. Serum testing revealed primary hypogonadism pattern, elevated follicle-stimulating hormone and luteinizing hormone with low concentrations of estradiol and testosterone. The patient underwent genetic counseling with her parents. Chromosomal status was 46XY karyotype and DNA sequencing confirmed FS due to a heterozygous WT1 mutation (IVS9+5G>A). Elective laparoscopic bilateral salpingo-oophorectomy was performed to avoid increased risk for gonadoblastoma. Pathological examination revealed gonadoblastoma in the right gonad. CONCLUSION: Although a rare disease, the diagnosis of FS should be considered in the case of primary amenorrhea with nephropathy. Prophylatic gonadectomy is recommended due to the high risk of gonadoblastoma in the dysgenetic gonad.

Gorlin syndrome with an ovarian leiomyoma associated with a PTCH1 second hit.

We describe a Gorlin syndrome (GS) case with two different second hit mutations of PTCH1, one in a keratocystic odontogenic tumor (KCOT) and the other in an ovarian leiomyoma. GS is a rare genetic condition manifesting as multiple basal cell nevi associated with other features such as medulloblastomas, skeletal abnormalities, and ovarian fibromas. A 21-year-old Japanese woman with a history of two KCOTs was diagnosed with GS according to clinical criteria. A PTCH1 mutation, c.1427del T, was detected in peripheral blood. A novel PTCH1 mutation, c.264_265insAATA, had been found in the maxillary KCOT as a second hit mutation. More recently, the ovarian tumor was detected during a gynecological examination. Laparoscopic adnexectomy was performed, and the pathological diagnosis of the ovarian tumor was leiomyoma. Interestingly, another novel mutation, loss of heterozygosity spanning from 9q22.32 to 9q31.2, including PTCH1 and 89 other genes, was detected in this ovarian tumor, providing evidence of a second hit mutation. This is the first report describing a GS-associated ovarian tumor carrying a second hit in the PTCH1 region. We anticipate that accumulation of more cases will clarify the importance of second hit mutations in ovarian tumor formation in GS.

Ritodrine Should Be Carefully Administered during Antenatal Glucocorticoid Therapy Even in Nondiabetic Pregnancies.

Aim. Antenatal glucocorticoid therapy (AGT) has been commonly used recently. However, this therapy has severe harmful effects such as maternal hyperglycemia. In Japan, ritodrine hydrochloride has been used as a tocolytic agent. In this study, we performed retrospective casecontrol study to clarify whether concomitant use of ritodrine and glucocorticoid was safe to pregnant women without diabetes mellitus. Methods. We reviewed the computerized records of pregnant women with pregestational diabetes (n = 9) and nondiabetes (n = 45) who gave birth at our hospital between 2002 and 2011. Cases and controls received AGT. Blood glucose after the therapy was analyzed, and additional volume of insulin was compared to that before the therapy. Results. From this study, 30 units of insulin were necessary when performing AGT in diabetic pregnant women. And also, an increase in blood glucose of 40 mg/dL was seen after the therapy even in nondiabetic pregnant women. Blood glucose increased significantly in the group that also received ritodrine, and it was shown that the number of pregnant women who might develop ketoacidosis might increase 11-fold. Conclusions. Ritodrine should be carefully administered during antenatal glucocorticoid therapy. It may be necessary to adequately monitor blood glucose, when performing the therapy, even in nondiabetic pregnant women.

Enhanced expression of myogenic differentiation factors and skeletal muscle proteins in human amnion-derived cells via the forced expression of MYOD1.

OBJECTIVES: Mesenchymal stem cells are expected to be an ideal cell source for cellular and gene therapy. We previously showed that cells derived from the human placenta can be induced to differentiate into myotubes in vitro and to express dystrophin in mdx/scid mice in vivo. In this study, we examined whether amnion-derived cells can be efficiently transduced and differentiated using lentiviral vectors carrying human MYOD1. METHODS: The amnion-derived cells were isolated from human preterm placentas. They were transduced with the MYOD1 vector, and mRNA levels for MYOD1, MYF5, MYOG, MYH2 and DMD were determined by quantitative-reverse transcriptase-polymerase chain reaction, and also examined immunocytochemically. RESULTS: Approximately 70% of amnion-derived cells were efficiently transduced by the lentiviral vectors. MYOD1 activates MYF5 and MYOG, MYH2 and DMD after a 7-day culture. The concerted upregulations of these myogenic regulatory factors enhanced MYH2 and DMD expressions. PAX7 was below the detectable level. Both myosin heavy chain and dystrophin were demonstrated by immunocytochemistry. CONCLUSIONS: MYOD1 activates MYF5 and MYOG, the transcription factor genes essential for myogenic differentiation, and the concerted upregulation of these myogenic regulatory factors enhanced MYH2 and DMD expressions. The amniotic membrane is an immune-privileged tissue, making MYOD1-transduced amnion-derived cells an ideal cell source for cellular and gene therapy for muscle disorders. This is the first report showing that amnion-derived cells can be modified by exogenous genes using lentiviral vectors. Furthermore, MYOD1-transduced amnion-derived cells are capable of the dystrophin expression necessary for myogenic differentiation.

Prenatal diagnosis of osteogenesis imperfecta type II by three-dimensional computed tomography: the current state of fetal computed tomography.

We report a case of osteogenesis imperfecta (OI) (OMIM166210) type II, in which a prenatal diagnosis was made by three-dimensional computed tomography (3D-CT). Subsequent molecular analysis revealed a recurrent, heterozygous mutation in COL1A2. Fetal CT is a powerful tool for visualizing the fetal skeleton and can provide a definitive diagnosis of fetal skeletal dysplasias; however, whether or not its employment for prenatal diagnosis is warranted in terms of fetal radiation risks remains controversial, both medically and ethically. Based on our experience, we review the current state of fetal CT for the diagnosis of skeletal dysplasias, with a discussion of the relevant literature.

Levels of soluble endothelial selectin in umbilical cord serum are influenced by gestational age and histological chorioamnionitis, but not by pre-eclampsia.

AIMS: The aim of this study was to examine the factors that influence soluble endothelial selectin (sE-selectin) levels in umbilical cord serum. MATERIALS AND METHODS: sE-selectin levels in umbilical cord serum were measured in 144 patients using enzyme-linked immunosorbent assay. We examined the association of sE-selectin levels with gestational age, pre-eclampsia (PE), histological chorioamnionitis (HCAM), preterm premature rupture of membranes, magnesium sulfate use, birthweight, and placental weight. RESULTS: A significant positive correlation was observed between sE-selectin levels and gestational age in the patients who had neither PE nor HCAM (r = 0.559, P < 0.0001). This statistically positive correlation persisted in patients with PE without HCAM (n = 25, r = 0.644, P < 0.001), but not in patients with HCAM without PE (n = 58, r = 0.102, P = 0.448). In matched gestational age analysis, sE-selectin levels were increased in the presence of HCAM (P = 0.0006), but were not influenced by the presence of PE (P = 0.127), preterm premature rupture of membranes (P = 0.352) or magnesium sulfate use (P = 0.337). CONCLUSION: sE-selectin levels in umbilical cord serum were positively correlated with gestational weeks. sE-selectin levels in umbilical cord serum were higher in mothers with HCAM but not with PE, when compared with gestational-age-matched controls.

Case of asymptomatic portal vein thrombosis after cesarean delivery.

We report a case of acute portal vein thrombosis (PVT) after a cesarean delivery. The patient was admitted for treatment of severe pre-eclampsia. On the second day after cesarean delivery, the elevations of aspartic aminotransferase and alanine aminotransferase were observed. Thereafter, acute PVT was diagnosed with ultrasonography. Although early anticoagulant therapy seems to be effective in the treatment of acute PVT, close observation must be made due to the risk of bleeding.

Clinical features of fetal growth restriction complicated later by preeclampsia.

OBJECTIVE: To assess the maternal and perinatal outcome of preeclampsia with fetal growth restriction (FGR) and to assess the risk factors of FGR complicated later by preeclampsia. SUBJECTS AND METHODS: A cohort of women with preeclampsia and/or FGR (n = 306) were retrospectively reviewed. First, the maternal and perinatal outcome were compared between preeclampsia with FGR (n = 37) and preeclampsia without FGR (n = 96). Second, the clinical findings of FGR followed later by preeclampsia (n = 24) were compared to FGR without preeclampsia (n = 149). RESULTS: The incidence of severe hypertension and critical maternal complications in women with preeclampsia with FGR was significantly higher than in those with preeclampsia without FGR. In women diagnosed with FGR, 13.8% (24/173) developed preeclampsia later. In this group, FGR was diagnosed at 28.8 gestational weeks, which was then complicated by preeclampsia at a mean of 32.6 gestational weeks, and delivered at 33.3 gestational weeks. The diagnosis of FGR was earlier and the incidence of proteinuria at entry was more common in women with FGR complicated later by preeclampsia than in those with FGR without preeclampsia (45.8% vs 4.7%; P < 0.001). CONCLUSIONS: Preeclampsia with FGR is severe condition which can possibly adversely affect the maternal condition. About 15% of all mothers diagnosed with FGR developed preeclampsia afterwards; therefore, those with FGR are considered to be candidates for close monitoring for the clinical manifestation of preeclampsia, and those with early-onset FGR with proteinuria may represent a high-risk group for preeclampsia.

Prognosis in cervical insufficiency at less than 32 weeks of gestation.

OBJECTIVE: To identify prenatal events associated with adverse outcome in babies at less than 32 weeks of gestation in cases of cervical insufficiency and preterm labor (PTL)/premature rupture of the membranes (PROM). STUDY DESIGN: A case-control study was performed using a logistic regression model at 17 tertiary hospitals in Japan. Adverse outcome was defined as neonatal death or abnormal cerebral ultrasound scans (intraventricular hemorrhage [IVH] and periventricular leukomalacia [PVL]) prior to discharge from hospital. RESULTS: Data were analyzed for 307 cases (74 for cervical insufficiency and 233 for PTL/PROM). Neonatal death and IVH/PVL were noted in 25 and 29 cases, respectively. A significant association of cervical insufficiency (odds ratio (OR) 1.32, 95% confidence interval (CI) 1.02-1.68), gestational age at delivery (<26 weeks) (OR 4.64, 95% CI 1.73-12.44), and Apgar score <7 at 5 min (OR 3.3, 95% CI 1.42-7.64) with combined neonatal death or IVH and PVL was found in a logistic regression model that controlled for in utero transportation, gestational age on admission, clinical chorioamnionitis, and histopathologic chorioamnionitis. CONCLUSION: Cervical insufficiency is a significant factor related to the occurrence of adverse outcome.

Serum ionized magnesium during magnesium sulfate administration for preterm labor and preeclampsia.

OBJECTIVE: The purpose of this study is to estimate the relations between ionized and total Mg levels during MgSO4 administration in patients with preterm labor and preeclampsia. METHODS: Forty-three pregnant patients who were candidates for MgSO4 were studied (preterm labor, 27; preeclampsia, 16). The administration method was intravenous injection of MgSO4 4 g over 30 min followed by 1-2 g/h. Ionized Mg was measured by the selective ion electrode method at bedside, and compared it with total Mg levels. RESULTS: Significant correlation was existed between levels of ionized and total Mg throughout therapy for both preterm labor (ionized Mg=0.19 x total Mg+0.19; r=0.61, p<0.001) and preeclampsia (ionized Mg=0.20 x total Mg+0.14; r=0.60, p<0.001). CONCLUSION: There are correlations between ionized and total Mg levels during administration of MgSO4 for both preterm labor and preeclampsia.

A case of fetal subdural hematoma at 31 weeks of gestation in a woman on warfarin therapy after Cabrol's operation.

The case of a complicated pregnancy of a woman who had undergone Cabrol's operation, and whose baby suffered from subdural hematoma is presented. Although the outcome of this case was not so severe, we would like to inform about the risk to both the mother and her fetus as a result of serious complications.