Treatment strategy at the decision for allogeneic transplantation in patients with myelodysplastic syndrome in the era of azacitidine: A KSGCT prospective study.

The optimal bridge strategy at the decision for allogeneic hematopoietic stem cell transplantation (HSCT) in patients with myelodysplastic syndrome (MDS) is unclear. We performed a prospective observational study in which 110 patients with MDS who were decided to undergo HSCT were enrolled. Among these 110 patients, 77 patients were enrolled in this study within 1 month from the decision for HSCT. Among these 77 patients, 13 patients had a human leukocyte antigen (HLA)-matched sibling, 54 patients started an unrelated donor search, and the other 10 patients directly selected cord blood (CB) at the decision for HSCT, and 13 (100%), 38 (70.4%), and 9 (90%) patients actually underwent HSCT within 1 year, respectively. The overall survival (OS) at 1 year from their enrollment was 70.9%, and the selection of azacitidine use at the decision for HSCT was not associated with OS. Among 60 of the 77 patients who actually underwent HSCT within a year from their enrollment, a lower relapse rate after HSCT was observed in those who selected CB at the decision to undergo HSCT. However, this preferable effect of CB selection disappeared when patients who were enrolled in this study in > 1 month from the decision for HSCT were additionally included in the analyses. In conclusion, the selection of bridge strategy at the decision for HSCT did not affect outcomes in patients with MDS. The immediate performance of HSCT may be associated with better outcomes.

Guideline for Gynecological Practice in Japan: Japan Society of Obstetrics and Gynecology and Japan Association of Obstetricians and Gynecologists 2020 edition.

Nine years after the first edition of The Guideline for Gynecological Practice, which was jointly edited by The Japan Society of Obstetrics and Gynecology and The Japan Association of Obstetricians and Gynecologists, the 4th Revised Edition was published in 2020. The 2020 Guidelines includes 4 additional clinical questions (CQ), which brings the total to 99 CQ (12 on infectious disease, 29 on oncology and benign tumors, 29 on endocrinology and infertility and 29 on healthcare for women). Currently, a consensus has been reached on the Guidelines, and therefore, the objective of this report is to present the general policies regarding diagnostic and treatment methods used in standard gynecological outpatient care that are considered appropriate. At the end of each answer, the corresponding Recommendation Level (A, B, C) is indicated.

Biallelic mutations in LARS2 can cause Perrault syndrome type 2 with neurologic symptoms.

Perrault syndrome represents a genetically heterogeneous disorder characterized by sensorineural hearing loss in males and females and ovarian dysfunction in females. Causative genes include HARS2, HSD17B4, CLPP, C10orf2, and LARS2. Some patients with Perrault syndrome exhibit neurologic features including learning disability, cerebellar ataxia, and peripheral neuropathy and are classified as type 2 and are clinically separate from those without neurological symptoms other than a hearing loss (type 1). To date, all reported patients with LARS2 mutations (15 patients in 8 families) have been classified as type 1. Here, we report female siblings with biallelic mutations in LARS2, p.Glu294Lys, and p.Thr519Met, who were classified as type 2. The proposita developed progressive sensorineural hearing loss at 18 months and pervasive developmental disorder at 8 years, with repetitive behavior, insistence on sameness, attention deficit, tic, irritability, and an ataxic gait. At age 15 years, she was diagnosed as having primary amenorrhea with elevated FSH and LH and a decreased estradiol; ultrasound and magnetic resonance imaging examinations revealed a small uterus and no detectable ovaries. The proposita's younger sister presented with neonatal sensorineural hearing loss and a mild delay in motor and speech development. She was diagnosed as having primary amenorrhea with endocrinologic and radiographic findings that were comparable to those of her sister. She had difficulty with reading comprehension, and had trouble with open-ended test questions at 12 years of age. We concluded that Perrault syndrome patients with LARS2 mutations are at risk for neurologic problems, despite previous notions otherwise.

Prognostic value of pretransplant serum C-reactive protein in patients receiving reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation.

The impact of pre-transplant serum C-reactive protein (CRP) level on the outcome of reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation (RIC allo-SCT) is unclear. This study retrospectively investigated 78 patients who underwent RIC allo-SCT between 2005 and 2013. The conditioning regimen consisted of fludarabine and melphalan with/without total body irradiation. The 3-year overall survival of high CRP (43.6 % of all patients) patients was significantly worse than that of normal CRP patients in whom CRP was ≤0.3 mg/dl (26.7 vs. 74.1 %, P < 0.001). Both the CRP level before transplantation and disease risk status were independent prognostic factors for overall survival by multivariate analysis. CRP was not a significant predictor of NRM by multivariate analysis (hazard ratio 3.2, 95 % confidence interval 0.8-13.1, P = 0.100). These results suggest that measuring the CRP level before transplantation can be useful to predicting the outcome of RIC allo-SCT.

Impact of Human Herpesvirus-6 Reactivation on Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation.

Human herpesvirus-6 (HHV-6) is known to reactivate after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and may be associated with development of acute graft-versus-host disease (GVHD) and nonrelapse mortality (NRM). However, the clinical significance of HHV-6 reactivation after allo-HSCT remains unclear. Therefore, we conducted a retrospective analysis to elucidate the impact of HHV-6 reactivation on transplantation outcomes. Of 236 patients who underwent allo-HSCT, 138 (58.5%) developed HHV-6 reactivation and 98 (41.5%) did not. Univariate analysis indicated that at 3 years, patients with HHV-6 reactivation had significantly higher NRM (27.7% versus 13.7%, P = .003) and worse overall survival (42.1% versus 59.0%, P = .008) than those without reactivation. In multivariate analysis, HHV-6 reactivation was associated with higher incidence of acute GVHD (hazard ratio [HR], 1.87; P = .01), cytomegalovirus reactivation (HR, 2.24; P < .001), and NRM (HR, 2.73; P = .007). Subgroup analysis stratified according to conditioning intensity indicated that a significant impact of HHV-6 reactivation on acute GVHD was observed only in patients who received myeloablative conditioning (MAC). These results indicate that HHV-6 reactivation was associated with development of acute GVHD, cytomegalovirus reactivation, and NRM. Furthermore, adverse impact of HHV-6 reactivation on transplantation outcomes was prominent in the setting of MAC.

Vaginal yolk sac (endodermal sinus) tumors in infancy presenting persistent vaginal bleeding.

Vaginal yolk sac (endodermal sinus) tumors were diagnosed in two girls (ages 12 and 46 months). In both, the only manifestation was persistent vaginal bleeding. Pelvic ultrasonography, computed tomography, and magnetic resonance imaging revealed solitary vaginal masses (diameter, 5 and 2 cm, respectively). Serum alpha-fetoprotein was highly elevated in one patient and normal in the other. Biopsy was performed in the first patient, and a tumor excision, in the second. Combination chemotherapy with cisplatin, etoposide, and bleomycin or carboplatin was administered to the first patient, and shortly thereafter, the tumor size decreased by more than half; serum alpha-fetoprotein was normalized after four chemotherapy cycles. After chemotherapy, magnetic resonance imaging revealed a small residual lesion, however the second biopsy revealed no viable tumor cells. In the second patient, no visible tumor was observed after chemotherapy by vaginoscopy. Both patients are well at 19 and 14 months after diagnosis, respectively.

The measurements of RAGE, VEGF, and AGEs in the plasma and follicular fluid of reproductive women: the influence of aging.

OBJECTIVE: To examine the advanced glycation end products (AGEs), the soluble isoform of the receptor for AGEs (sRAGE), and vascular endothelial growth factor (VEGF) concentrations in plasma and follicular fluid (FF) from reproductive-age women. DESIGN: Clinical preliminary study based on the regulations of the ethical committee at National Center for Child Health and Development (NCCHD). SETTING: Women's health clinical office at NCCHD and Aska clinic. PATIENT(S): Reproductive-age women, young group (<35 yrs) and old group (>or=35 yrs), who agreed to let us use plasma or FF samples for the measurements of AGEs, sRAGE, and VEGF. MAIN OUTCOME MEASURE(S): Measurements of AGEs, sRAGE, and VEGF in plasma and FF by ELISA to examine the difference by aging and reproductive dysfunction. RESULT(S): The plasma concentration of sRAGE was significantly higher in the young group; VEGF in FF was significantly higher in the old group. sRAGE in FF showed a tendency of positive correlation with the number of oocytes. The plasma sRAGE concentration was significantly correlated positively with FF sRAGE and inversely with FF VEGF at the time of egg collection. CONCLUSION(S): The measurement results suggest a possibility that RAGE-VEGF regulation may be related to reproductive dysfunction in aging women, and that plasma sRAGE might be a biologic marker of reproductive condition.

Concentrations of receptor for advanced glycation end products, VEGF and CML in plasma, follicular fluid, and peritoneal fluid in women with and without endometriosis.

The etiology and pathogenesis of endometriosis is largely unknown. It has been reported that advanced glycation end products-receptor for advanced glycation end products regulation relates to oxidative stress, inflammatory reaction, apoptosis, and angiogenesis through vascular endothelial growth factor activation. The purpose of this study was to examine whether advanced glycation end products-receptor for advanced glycation end products regulation contributes to the pathogenesis of endometriosis. Plasma, follicular, and peritoneal fluid samples were collected from women with or without endometriosis, and soluble receptor for advanced glycation end products, vascular endothelial growth factor and carboxymethyl lysine levels were measured by enzyme-linked immunosorbent assay. Vascular endothelial growth factor and soluble receptor for advanced glycation end products concentrations were similar in plasma; however, their concentrations in follicular fluid were significantly increased in endometriosis patients (soluble receptor for advanced glycation end products was 132 + 31 pg/mg of protein vs. 105 + 27 pg/mg; vascular endothelial growth factor was 70 + 3 pg/mg vs. 49 + 18 pg/mg, expressed as the mean + standard deviation). Increased soluble receptor for advanced glycation end products and vascular endothelial growth factor levels in a local environment suggest that the advanced glycation end products-receptor for advanced glycation end products may contribute to the pathogenesis of endometriosis.

Pregnancy implanted in the fibromuscular layer of the cervix: a case report.

BACKGROUND: Implantation sites other than the fallopian tube are rarely encountered in ectopic pregnancies. No cases of an implantation in the cervical muscular layer had been reported at this writing. CASE: A 32-year-old woman, gravida 1, para 0, induced abortion 1, was admitted to our hospital with the suspicion of ectopic pregnancy. Although an explorative laparoscopy and dilation and curettage failed to detect a definite implantation site, postoperative tranvaginal ultrasonography (US) and magnetic resonance imaging (MRI) disclosed a pregnancy implanted in the fibromuscular layer of the cervix. Chemotherapy with methotrexate was successful, and the patient's reproductive potential was preserved. A fine tract connecting the cervical canal to the gestational area, which was observed both before and after treatment, appeared to be involved in the etiology. CONCLUSION: This case demonstrates that the cervical wall can be the site of implantation and that such an unusual ectopic pregnancy can be managed conservatively by early diagnosis with repeat US and MRI.

Correlation of neuron-specific enolase and S100B with histological cerebral damage in fetal sheep after severe asphyxia.

Experimental brain damage was induced in 16 fetal sheep by umbilical cord occlusion, and the correlation of neuron-specific enolase (NSE) or S100B with the damage grade was investigated in seven fetuses. Significant correlations of damage degree with NSE (p = 0.016) and S100B (p = 0.018) in serum 2 h after insult were shown by Spearman's test. These findings suggest that they represent potentially useful markers for detecting brain damage at early stage after ischemic insult.

Hemodynamic changes during complete umbilical cord occlusion in fetal sheep related to hippocampal neuronal damage.

OBJECTIVES: The purpose of our study was to examine the physiologic changes caused by 10 minutes of umbilical cord occlusion in fetal sheep and to determine the correlation between fetal acidemia or cerebral ischemia and hippocampal neuronal damage. STUDY DESIGN: Thirteen fetal sheep were instrumented and catheterized. Carotid artery blood flow (CaF), fetal mean arterial blood pressure (FMABP), pH, PCO (2), base excess, oxygen saturation (SatO(2)), and PO (2) were monitored throughout the occlusion study. Brain sections were examined for the hippocampal neuronal damage. RESULTS: Our data showed severe ischemia (CaF: 10 +/- 7 mL/min; FMABP: 29 +/- 8 mm Hg) and acidemia (pH: 7.0 +/- 0.05; base excess: -9.9 +/- 2.4 mEq/L) at the end of occlusion. The neuronal damage score had significant correlations with ischemia and also with reperfusion, but not with the acidemic or hypoxic parameters. CONCLUSION: We demonstrated that the degree of hippocampal damage was correlated with the degree of ischemia and reperfusion.

Mental health of patients visiting an outpatient menopause clinic.

OBJECTIVE: It is understood that psychological factors affect climacteric disturbances. However, details behind these issues remain unknown. The aim of this study was to investigate the mental health of climacteric patients. SUBJECTS AND METHODS: The subjects were 127 Japanese women who visited our outpatient menopause clinic, complaining chiefly of climacteric disturbances. There were 38 premenopausal patients included. The responses to the HADS (Hospital Anxiety and Depression Scale) and the SDS (Self-rating Depression Scale), obtained at the first examination, were compared with HADS data from 2,943 healthy women and 94 patients hospitalized to receive gynecological surgery. RESULTS: The HADS score and the SDS score of the outpatients of the menopause clinic showed a relatively high (statistically significant) correlation. The average HADS total, anxiety and depression scores for these patients were significantly higher than those for healthy controls. The total and depression scores were also significantly higher than those for patients hospitalized to undergo surgery for benign conditions, and were comparable to those for patients with malignant conditions. The comparison between pre- and postmenopausal patients showed that the premenopausal group was more likely to be depressed. The anxiety score was also high in this group (not significantly). CONCLUSIONS: These results indicate that patients with climacteric disturbances, especially premenopausal patients, often experience psychological discomfort, and that attention should be given not only to their depression but also to their anxiety.

Apoptosis and related proteins during parturition in prostaglandin F receptor-deficient mice.

This study investigated whether apoptosis and related proteins are involved in parturition by comparative observation of FP-deficient mice without labor and wild type mice with vaginal delivery. We examined the expression of apoptosis, Fas, FasL, active caspase-3 and bcl-2 proteins in the amnion, placenta and decidua. DNA laddering in the amnion, placenta and decidua tissue did not significantly differ between FP-deficient and wild type mice on day 18 of pregnancy. Similar TUNEL staining results were found in all tissues of FP-deficient mice compared with those of wild type mice. A higher intensity of apoptotic cells was found in the decidua basalis. The index of TUNEL-positive cells were not significantly different in the amnion, placenta and decidua of FP-deficient mice compared with that of wild type mice on day 18 of pregnancy. Specific bands for Fas were clearly observed in the amnion, placenta and decidua tissue. FasL specific bands were observed in the placenta and decidua, but a few in amnion tissue. A great number of active caspase-3 specific bands were detected in decidua, while a few such bands were detected in the placenta and few bands in the amniotic tissue. Bands for bcl-2 were detected in the amnion, placenta and decidua tissue. The weakest band was in decidual tissue. Fas, FasL, active caspase-3, and bcl-2 specific bands did not show any significant differences between the two groups. These findings demonstrate that apoptosis, Fas, FasL, caspase-3, and Bcl-2 occur in mouse term placenta that is not involved in parturition.

Investigation of intraplacental villous arteries by Doppler flow imaging in growth-restricted fetuses.

OBJECTIVE: The purposes of our study were to assess the ability of color and power Doppler sonography to depict the blood flow in the intraplacental villous arteries and to evaluate whether the blood flow of intraplacental villous arteries in a normal pregnancy is different from that in a pregnancy that is associated with intrauterine growth restriction. STUDY DESIGN: Eighty-five women with uncomplicated pregnancy and 16 women with intrauterine growth-restricted fetuses between 27 and 38 weeks of gestation were examined by color and power Doppler imaging. The blood flow of intraplacental villous arteries was analyzed comparatively. The pulsatility index and peak systolic velocity were measured. RESULTS: A unit of 1 intraplacental villous artery-1 and its branches were seen as 1 cotyledon by color and power Doppler imaging. The cotyledon was easily identified and counted. Each cotyledon contained only 1 intraplacental villous artery-1. This method can visualize the intraplacental villous artery-1 to intraplacental villous artery-4 in normal pregnancies. The terminal villous arteries beyond intraplacental villous artery-4 were not imaged. The number of detectable intraplacental villous artery-1 in 1 placenta in intrauterine growth restriction was significantly lower than that in normal pregnancy. The number of detectable branches in intrauterine growth restriction was also significantly lower than in normal pregnancy. No intraplacental villous artery-4 blood flow was found in women with intrauterine growth restriction. In examined arteries, pulsatility index decreased and peak systolic velocity increased significantly with advancing gestational age (P <.02). At any given gestational age, pulsatility index and peak systolic velocity in the peripheral arteries were significantly lower than those in the upstream arteries in normal pregnancy (P <.001). The pulsatility index value of each intraplacental villous artery was also lower than that of the umbilical artery in the women with intrauterine growth restriction (P <.05). There were no differences in pulsatility index in each artery between the groups, although there were a few high pulsatility index values in intrauterine growth restriction. CONCLUSION: Color Doppler and power flow sonography are valuable tools for the detection of the blood flow of intraplacental villous arteries. The decrease in the number of detectable intraplacental villous artery-1 and branches was associated with intrauterine growth retardation.

Effects of neonatal hypoxic-ischemic brain injury on skilled motor tasks and brainstem function in adult rats.

In an attempt to establish more sensitive long-term neurofunctional measurements for neonatal hypoxic-ischemic brain injury, we examined skilled motor task and brainstem functions in adult rats after neonatal cerebral hypoxia-ischemia (H-I), using a staircase test and auditory brainstem response (ABR), respectively. Seven-day-old rats underwent a combination of left common carotid artery ligation and exposure to 8% O(2) for 1 h (n=16). The control animals only received sham operation (n=16). At 3 months of age, the staircase test and ABR were performed. In the staircase test, H-I animals showed marked impairment of skilled forelimb use in the side contralateral to the occluded artery, and the degree of brain damage correlated significantly to skilled forelimb use. In the ABR, H-I animals showed brainstem dysfunction assessed by measuring interpeak latencies for waves III-V and I-V. We also examined the brainstem with antibodies specific for activated caspase-3, a protein involved in initiation of apoptosis, and observed that caspase-3 was activated in the ipsilateral inferior colliculus at 24 h after H-I. The present study shows that both the staircase test and ABR are sensitive and objective long-term neurofunctional measurements that can be used in future studies to assess therapeutic intervention in this neonatal cerebral H-I model.

[Practical regimens and pitfalls of hormone replacement therapy].

Hormone Replacement Therapy (HRT) is recognized as a gold standard for postmenopausal osteoporosis. Currently, various regimens and types of preparation are available in clinical field. However, there are still some issues remaining, such as risks of cancers, poor-responders, and side effects. We should follow current studies and information, and have a knowledge of advantages and disadvantages of HRT. In practical use, HRT needs to be tailored to the individual patient's risk and benefit, and to be performed under informed consent.