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[Introduction] The triple therapy of pertuzumab, trastuzumab and taxanes (docetaxel or paclitaxel) is coming into widespread use, because of the beneficial effects on HER2 positive breast cancer. However, we don't have enough information about the efficacy and safety of other agents with trastuzumab and pertuzumab (TP). We studied triple therapy of pertuzumab, trastuzumab and eribulin (PTE) for advanced HER2 positive breast cancer to assess the efficacy, safety and QOL prospectively (UMIN000012018). [Patients and methods] Responses were assessed by RECIST criteria v1.1. Adverse events (AEs) were graded according to CTCAE v4.0. Patients with advanced HER2 positive breast cancer were treated with pertuzumab (840 mg loading then 420 mg, day 1), trastuzumab (8 mg/kg loading then 6 mg/kg, day 1), and eribulin (1.4 mg/m2, day 1 and 8) every 3 weeks. Dose reduction was allowed when patients developed febrile neutropenia, grade 3-5 non-hematologic toxicity or skipped day 8 eribulin administration because of neutrophil count [Results] Ten patients were enrolled. Median age of patients was 60 years-old (35-75). Median number of prior chemoregimen for metastatic disease was 3 (0-5). Two patients had a history of docetaxel allergy. Median number of PTE cycle was 6 (3-12). Eight patients reduced eribulin doses 1.4 mg/m2 to 1.1 mg/m2 because of AEs (2 patients), skipped day 8 eribulin (4 patients), or physician's choice (2 patients). One complete response, 1 partial response and 5 stable disease were achieved at 3 months. Two patients (1 CR and 1 SD) stopped eribulin and received TP as maintenance therapy. At 3 months, all 3 patients with progressive disease developed brain metastasis. Two patients had extracranial progressive lesions, but 1 patient had partial response for extracranial disease. The common treatment-related AEs were leukopenia, neutropenia, lymphopenia diarrhea, hypokalemia and stomatitis. Grade 3 AEs were leukopenia (7 patients), neutropenia (8 patients), lymphopenia (2 patients), febrile neutropenia (1 patient), hypokalemia (1 patient) and peripheral neuropathy (1 patient). Grade 4/5 AEs were not observed. Nine patients could be assessed QOL. FACT-B TOI, FACT-G and FACT-B total score had a tendency to be improved at 3 months. [Conclusion] The PTE therapy showed appropriate clinical effect for extracranial lesions and maintained QOL of patients with advanced HER2 positive breast cancer. It may be a choice for patients who have taxane-resistant diseases or a history of taxane allergy. Many patients needed to reduce eribulin dosage. When the PTE therapy is referred to advanced HER2 positive breast cancer patients as a palliative chemotherapy, eribulin (1.1mg/m2) might be a reasonable dosage. Citation Format: Ishihara M, Tamaru S, Oda H, Yamashita Y, Tono Y, Mizuno T, Katayama N. A pilot study of pertuzumab, trastuzumab and eribulin for patients with advanced HER2 positive breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-13-21.

Venous thromboembolism (VTE) is a common complication in patients who have undergone major orthopedic surgery, but there are few predictors of VTE after major orthopedic surgery treated with an anticoagulant. We measured levels of fibrin-related markers (FRMs), such as D-dimer, soluble fibrin (SF), and fibrinogen and fibrin degradation products (FDPs) in 66 patients with acute-phase VTE, and 367 patients undergoing major orthopedic surgery. Plasma FDP, D-dimer, and SF levels were significantly higher in patients with acute VTE, but only FDP and D-dimer levels were significantly higher in subclinical VTE. Adequate cut-off levels of D-dimer were 2.2 μg/ml for diagnosing acute VTE and 1.5 μg/ml for diagnosing subclinical VTE. D-dimer of less than 1.9 or 0.7 μg/ml ruled out acute VTE or subclinical VTE. D-dimer of more than 1.3 μg/ml preoperatively showed a moderate risk for postoperative VTE. Measurement of FRMs is useful for evaluating the risk of subclinical or postoperative VTE in patients with major orthopedic surgery. In particular, FDP is the most valuable marker for diagnosing acute VTE, whereas D-dimer is the most valuable for diagnosing subclinical VTE or predicting VTE.

Efficacy of recombinant human soluble thrombomodulin (rhTM), which is frequently used to treat patients with disseminated intravascular coagulation (DIC), was compared with that of gabexate mesilate (GM), which was previously used routinely in the treatment of DIC patients in Japan. Although there was no significant difference in the resolution rates of the patients who were treated with rhTM and GM, the results of our analysis revealed that the mortality rate was significantly higher among infectious disease patients treated with GM than in those treated with rhTM. Levels of fibrinogen and fibrin degradation products (FDP), antithrombin (AT) activity, and thrombin AT complex (TAT) were significantly lower in the DIC patients with infectious diseases, while fibrinogen levels were high. FDP level, D-dimer, platelet count, PT ratio, and DIC score all showed significant improvement following rhTM treatment. There were no significant difference between survivors and non-survivors in terms of DIC score, FDP level, platelet count, AT activity, or in TAT, SF and PPIC levels before rhTM treatment. However, fibrinogen levels were significantly lower in non-survivors than in survivors. These results indicate that rhTM may be superior to GM for the treatment of DIC.

Several studies have reported risk factors for predicting cisplatin-induced acute kidney injury (AKI), including old age, female sex, smoking, hypoalbuminemia, hypokalemia, hypomagnesemia, a high body surface area, advanced cancer and the total dose of cisplatin administered. Recently, some studies have focused on the associations between genetic alterations in the genes coding for renal drug transporters, such as organic cation transporter 2 (OCT2), and the nephrotoxicity of cisplatin. However, genetic variants have not been fully elucidated for clinical use. Patients who had received cisplatin (≥50 mg/m2)-containing chemotherapy as a first-line treatment were considered as eligible for the present study. The occurrence of AKI and its associations with baseline characteristics, conventional biomarkers and single-nucleotide variants (SNV) were assessed. AKI was defined as an increase in the serum creatinine level of >0.3 mg/dl or to 1.5-2 times the baseline level. Genotyping was conducted using the DMET platform (DMET Plus), which characterizes 1,936 genetic variants (1,931 SNV and 5 copy number variations) in 231 genes. Between April 2014 and June 2016, a total of 28 patients (22 men and 6 women) were enrolled. AKI occurred in 8 of the 28 enrolled patients (28.6%). Univariate analyses demonstrated that the urinary β2-microglobulin level and body surface area were significantly higher in the AKI group (P

Gram-negative bacteria import essential nutrients such as iron and vitamin B12 through outer membrane receptors. This process utilizes proton motive force harvested by the Ton system made up of three inner membrane proteins, ExbB, ExbD and TonB. ExbB and ExbD form the proton channel that energizes uptake through TonB. Recently, crystal structures suggest that the ExbB pentamer is the scaffold. Here, we present structures of hexameric complexes of ExbB and ExbD revealed by X-ray crystallography and single particle cryo-EM. Image analysis shows that hexameric and pentameric complexes coexist, with the proportion of hexamer increasing with pH. Channel current measurement and 2D crystallography support the existence and transition of the two oligomeric states in membranes. The hexameric complex consists of six ExbB subunits and three ExbD transmembrane helices enclosed within the central channel. We propose models for activation/inactivation associated with hexamer and pentamer formation and utilization of proton motive force., eLife digest Many biological processes that are essential for life are powered by the flow of ions across the membranes of cells. Similar to how energy is stored in the water behind a dam, energy is also stored when the concentration of ions on one side of a biological membrane is higher than it is on the other. When these ions then flow down this concentration gradient, the energy can be harnessed to power other processes. In many bacteria, the concentration of hydrogen ions, or protons, is higher on the outside of the cell. When the protons flow down the concentration gradient, a protein complex called the Ton system in the bacteria’s inner membrane harnesses the energy to transport various compounds, including essential nutrients, across the outer membrane, which is about 20 nanometres away. Toxins, and viruses that infect bacteria, can also hijack the Ton system to gain entry into these cells. This means that the Ton system could perhaps be targeted via drugs to treat bacterial infections. Though the Ton system is important, structural information on this protein family is limited. The Ton complex is composed of three proteins – ExbB, ExbD and TonB – located in the bacteria’s inner membrane. ExbB and ExbD together form a channel for the protons and the complex made from these two proteins can be thought of as the system’s engine. Maki-Yonekura et al. wanted to understand how the ExbB / ExbD complex works, which was challenging because the complex was not well suited to any single structural biology technique. To get around this issue, a combination of two techniques called X-ray crystallography and single particle cryo-EM were used. This approached revealed that the two proteins form complexes made up of either five or six ExbB subunits with one or three ExbD subunits, respectively. It also showed that the proteins transition between the two forms in a cell’s membrane. More of the larger six-unit complex (also called a “hexamer”) formed at higher pH. This is consistent with the increased flow of protons through the channel when the local conditions inside the cell become less acidic. Based on these results, Maki-Yonekura et al. propose that some subunits in the core of the complex rotate to harness the energy from the flow of protons, and the number of subunits in the complex changes when it switches to become active or inactive. The discoveries may provide a new vision of dynamic membrane biology. Further studies are now needed to see how general this mechanism is in biology, and the new structural information could also be used to help develop more anti-bacterial drugs.

A 64-year-old man visited his physician complaining of bilateral gynecomastia and left shoulder pain. Chest X-ray showed multiple bilateral masses in the lung, and he was referred to our hospital. Radiographical findings, elevation of serum total hCG, and histological findings of the cervical lymph node revealed multiple pulmonary, nodal, and brain metastases of poorly differentiated carcinoma of an unknown primary site with choriocarcinoma components. He was administered a regimen of reduced bleomycin, cisplatin, etoposide combination(reduced BEP regimen)to reduce the risk of acute respiratory failure with intra-alveolar hemorrhage related to post-chemotherapy early tumor necrosis. After chemotherapy, the tumor marker hCG levels were almost restored to normal levels, and radiography showed he had achieved a clinical partial response.

Abstarct The effective atomic number, Z eff , is measured by the ratio of linear attenuation coefficients at two different X-ray energies obtained by monochromatic X-ray computed tomography (CT). However, monochromatic X-rays are available in synchrotron facilities only. By defining narrow energy ranges in energy-resolved CT using a current mode “transXend” detector, Z eff is measured for sugar and K2HPO4 solutions, as well as for water and acrylic. The experimental Z eff values obtained for water and acrylic were in excellent agreement with the theoretical values. The experimental Z eff values obtained for the sugar and K2HPO4 solutions had larger errors.

A novel X-ray Bragg optics is proposed for variable-magnification of an X-ray beam. This X-ray Bragg optics is composed of two magnifiers in a crossed arrangement, and the magnification factor,M, is controlled through the azimuth angle of each magnifier. The basic properties of the X-ray optics such as the magnification factor, image transformation matrix and intrinsic acceptance angle are described based on the dynamical theory of X-ray diffraction. The feasibility of the variable-magnification X-ray Bragg optics was verified at the vertical-wiggler beamline BL-14B of the Photon Factory. For X-ray Bragg magnifiers, Si(220) crystals with an asymmetric angle of 14° were used. The magnification factor was calculated to be tunable between 0.1 and 10.0 at a wavelength of 0.112 nm. At various magnification factors (M≥ 1.0), X-ray images of a nylon mesh were observed with an air-cooled X-ray CCD camera. Image deformation caused by the optics could be corrected by using a 2 × 2 transformation matrix and bilinear interpolation method. Not only absorption-contrast but also edge-contrast due to Fresnel diffraction was observed in the magnified images.

To investigate the effect of moderate to severe endometriosis on mRNA expression of growth differentiation factor-9 (GDF-9) in the granulosa cells of mature follicles. Follicular fluid (FF) was obtained from 13 patients with moderate to severe endometriosis and 11 without endometriosis, as a control group, and GDF-9 protein levels in both were assayed by western blotting. mRNA expression by GDF-9 and LH receptor (LHR) in granulosa cells obtained from all patients in the study were investigated by StepOne Real-Time PCR. Although GDF-9 in FF from patients with endometriosis was no different from that of controls, GDF-9 mRNA expression in granulosa cells of patients with endometriosis was statistically significantly lower than for the control group. The number of oocytes and high-quality embryos was positively correlated with GDF-9 mRNA expression in controls but not in patients with endometriosis Moreover, a negative correlation was identified between GDF-9 mRNA expression and serum estrogen and progesterone levels in the control group, whereas no correlation was observed for the endometriosis group. Moderate to severe endometriosis can significantly reduce GDF-9 mRNA expression in the granulosa cells of patients with the disease compared with those without, thus causing poor oocyte maturation and lower embryo quality.

The “transXend” detector measures X-rays as electric currents and provides the energy distribution of the measured X-rays after analysis. Capabilities of material distinction, effective atomic number measurement, and low-dose exposure computed tomography (CT) with high K-edge contrast agent from the use of the transXend detector in energy-resolved CT have been demonstrated via the first-generation CT measurements. For application of the principle of the transXend detector to the third-generation CT for human subjects in future work, a method for fabrication of a two-dimensional transXend detector is proposed and demonstrated using a commercial two-dimensional detector and two kinds of strip absorbers. The energy-resolved CT is performed by placing a proposed absorber system in front of a two-dimensional detector, which is used for conventional current measurement CT., Published online: 29 Apr 2015

The activated partial thromboplastin time (APTT) waveform includes several parameters that are related to various underlying diseases. The APTT waveform was examined in various diseases. Regarding the pattern of APTT waveform, a biphasic pattern of the first or second derivative curve (DC) was observed in patients with hemophilia and patients positive for antiphospholipid (aPL) antibodies or coagulation factor VIII (FVIII) inhibitors. The time of the first and second DC and fibrin formation at 1/2 height were prolonged in patients with hemophilia, patients with inhibitors, patients positive for aPL, patients treated with anti-Xa agents, and patients with disseminated intravascular coagulation (DIC). These values all tended to decrease in pregnant women (at 28-36 weeks’ gestation). The height of the second derivative peak 1 was significantly lower in patients with hemophilia, patients with FVIII inhibitors, patients positive for aPL, patients treated with anti-Xa agents, and patients with DIC; these values tended to be significantly higher in pregnant women. The height of the first DC was significantly lower in patients who were positive for FVIII inhibitors and was significantly higher in patients treated with anti-Xa agents and pregnant women. The height of the first and second DC was useful for the analysis of hemophilia, FVIII inhibitor, and aPL.

The cutoff values of D-dimer levels for diagnosing or predicting the occurrence of deep vein thrombosis (DVT) were evaluated in preoperative patients and compared to those in non-DVT patients. The levels of 8 different D-dimers were measured using the latex agglutination method or enzyme immunoassay before surgery in 262 orthopedic surgery patients to diagnose subclinical DVT or predict postoperative DVT. There were 15 patients with subclinical DVT and 47 with postoperative DVT, but 200 patients had no DVT at all. All 8 plasma D-dimer values were significantly higher in the patients with subclinical or postoperative DVT than in those without DVT or in healthy volunteers. There were differences in the cutoff values between the assays highly sensitive for low D-dimer levels and wild-range assays of D-dimers. Some D-dimer assays might therefore be more useful than others for diagnosing low levels of D-dimer. Although the measurement of D-dimer levels was useful for diagnosing subclinical DVT and predicting the risk of DVT, the cutoff values for the diagnosis or prediction of DVT varied. The cutoff values for the prediction of postoperative DVT were ≥1.7 µg/mL (D-dimer A-D) and ≥1.0 µg/mL (D-dimer E-H).

OBJECTIVE Oocyte degeneration often occurs after intracytoplasmic sperm injection (ICSI), and the risk factor is low-quality oocytes. The follicular fluid (FF) provides a crucial microenvironment for oocyte development. We investigated the relationships between the FF volume aspirated from individual follicles and oocyte retrieval, oocyte maturity, oolemma stretchability, fertilization, and development. METHODS This retrospective study included data obtained from 229 ICSI cycles. Ovarian stimulation was performed according to a gonadotropin-releasing hormone antagonist protocol. Each follicle was individually aspirated and divided into six groups according to FF volume (

Prevention of deep vein thrombosis (DVT) is important in patients undergoing major orthopedic surgery. Although the detection of an elevated D-dimer level is useful for predicting DVT, it is not efficacious in postoperative patients being treated with anti-Xa agents. The soluble platelet glycoprotein VI (sGPVI) level is a marker of activated platelets, but not bleeding. Therefore, sGPVI levels are usually examined as a predictor of DVT in such patients. In the present study, 83 orthopedic patients were treated with 30 mg of edoxaban for prophylaxis of DVT. Fourteen patients developed DVT and 17 patients discontinued the prophylaxis due to decreased hemoglobin levels. Plasma levels of sGPVI in the patients were significantly higher after surgery than before surgery. On day 1, the sGPVI levels increased, while the platelet counts decreased. There were no significant differences in D-dimer, soluble fibrin, or FDP levels in orthopedic patients with and without DVT before surgery and on days 1, 4, and 8. Plasma sGPVI levels were significantly higher in the patients with DVT than in those without DVT on days 1 and 4. Plasma levels of D-dimer were significantly higher in patients with withdrawal than in those without. However, there were no significant differences in sGPVI levels between those with and without withdrawal. As D-dimer levels are known to increase in patients with withdrawal, this parameter is not useful for evaluating the risk of DVT in these patients. In contrast, the sGPVI level is not increased in those with withdrawal and may therefore be useful for evaluating the risk of DVT in postoperative patients treated with an anticoagulant.

Dienogest, a synthetic progestin, has been shown to be effective against endometriosis, although it is still unclear as to how it affects the ectopic endometrial cells. Decorin has been shown to be a powerful endogenous tumor repressor acting in a paracrine fashion to limit tumor growth. Our objectives were to examine the direct effects of progesterone and dienogest on thein vitroproliferation of the human ectopic endometrial epithelial and stromal cell lines, and evaluate as to how decorin contributes to this effect. We also examinedDCNmRNA expression in 50 endometriosis patients. The growth of both cell lines was inhibited in a dose-dependent manner by both decorin and dienogest. Using a chromatin immunoprecipitation assay, it was noted that progesterone and dienogest directly induced the binding of the decorin promoter in the EMOsis cc/TERT cells (immortalized human ovarian epithelial cells) and CRL-4003 cells (immortalized human endometrial stromal cells). Progesterone and dienogest also led to significant induced cell cycle arrest via decorin by promoting production of p21 in both cell lines in a dose-dependent manner. Decorin also suppressed the expression of MET in both cell lines. We confirmed thatDCNmRNA expression in patients treated with dienogest was higher than that in the control group. In conclusion, decorin induced by dienogest appears to play a crucial role in suppressing endometriosis by exerting anti-proliferative effects and inducing cell cycle arrest via the production of p21 human ectopic endometrial cells and eutopic endometrial stromal cells.

To evaluate how endometriotic cystectomy and vaporization affect ovarian reserve after conservative surgery.Prospective study (Canadian Task Force classification II-1).Hokusetsu General Hospital.Ninety-nine women who underwent conservative surgery to treat endometriotic cysts from June 2011 to July 2013.Vaporization with bipolar current was performed in nulligravid women, and cystectomy in those who had a child. In women with endometriotic cysts, bilateral cystectomy was performed in 28, bilateral vaporization in 15, unilateral cystectomy in 40, and unilateral vaporization in 16. In all patients, preoperative and postoperative serum anti-müllerian hormone (AMH) and follicle-stimulating hormone (FSH) concentrations at the early proliferative phase were assayed, and the change in concentrations was evaluated for each operation.In the bilateral cystectomy group, the mean (SD) postoperative FSH concentration (19.3 [21.8] IU/mL) was statistically higher than the preoperative concentration (9.0 [6.2] IU/mL) (p.01). AMH significantly declined after all operations to treat endometriotic cysts, and the rate of decline in the AMH concentration was50% compared with preoperative concentrations.Whether endometriotic cysts are unilateral or bilateral, both cystectomy and vaporization using bipolar current can lower ovarian reserve. Therefore, it is necessary to develop more effective surgical procedures to prevent ovarian damage.

For ion radiation therapy, the measurement of effective atomic numbers, Z[eff], is necessary to know the material distribution in a human body; the range of ions entering the human body is influenced by the material distribution along their paths. Z[eff], however, cannot be measured at hospitals because monochromatic X-rays with different energies are necessary and are used only at synchrotron facilities. To make Z[eff] measurements at hand, we propose energy-resolved computed tomography (CT) using a “transXend detector”. By assigning two narrow energy ranges in the unfolding process of the data obtained by the transXend detector, Z[eff] for acrylic and aluminum can be estimated by energy-resolved CT. The estimated Z[eff] are compared with those obtained by dual-energy and monochromatic X-ray CT.

Aim To examine the associations between the pre-pregnancy body mass index (BMI) and gestational weight gain (GWG) with pregnancy outcomes in Japanese women. Methods The medical records of 1883 Japanese women who delivered singleton infants from January 2010 to January 2013 at Osaka-Minami Medical Center were retrospectively reviewed. We use the BMI classification which the World Health Organization defined for Asian populations and the GWG classified based on the current 2009 Institute of Medicine (IOM) recommendations. The odds ratio (OR) of each of the groups for the different pregnancy outcomes were compared to the recommended group using a logistic regression analysis adjusted by age, gestational weeks, parity, weight gain, mode of delivery, pregnancy induced hypertension (PIH) and gestational diabetes mellitus. Results Women who were obese (BMI, ≥25 kg/m(2) ) and overweight (BMI, 23-24.9 kg/m(2) ) had a higher rate of developing PIH (adjusted OR, 6.68 and 3.21 [95% confidence interval [CI], 3.31-13.3 and 1.29-7.24]). In contrast, GWG exhibited a correlation with the weight of the infant. The inadequate GWG group had a higher rate of small-for-gestational age (SGA) infants (adjusted OR, 1.72 [95% CI, 1.22-2.46]). The rate of emergency cesarean section was not significantly different between the groups. Conclusion A pre-pregnancy BMI less than 23 kg/m(2) is desirable to prevent Japanese women from developing PIH. GWG within the IOM recommendations also reduced the risk of PIH and SGA.

Background Thrombotic microangiopathy (TMA) is caused by various conditions, such as decreased a ADAMTS13 level, activated or injured vascular endothelial cells or activated platelets. This study examined the soluble platelet glycoprotein VI (sGPVI) levels in patients with TMA to evaluate the activation of platelets in thrombotic states. Materials and Methods The plasma levels of sGPVI, ADAMTS13 activity, von Willebrand factor (VWF) and VWF propeptide (VWFpp) were measured in patients with TMA. Results The plasma levels of sGPVI were significantly higher in postoperative patients, patients with TMA and those with disseminated intravascular coagulation (DIC) than in those without thrombosis. The plasma levels of sGPVI were the highest in patients with TMA without markedly reduced ADAMTS13 and those were significantly reduced after plasma exchange. Conclusion The measurement of sGPVI level is therefore considered to be important for the diagnosis and evaluation of TMA.

Objective Many patients with malignant diseases are frequently complicated with some type of thrombosis, such as venous thromboembolism (VTE) or disseminated intravascular coagulation (DIC). Methods This retrospective study was designed to examine the frequency of thrombosis in 478 patients with malignant diseases in comparison to that observed in 121 patients without malignant diseases and to evaluate the efficacy of fibrin-related markers (FRMs), such as soluble fibrin, fibrinogen and fibrin degradation products and D-dimer, in diagnosing thrombosis. Results The frequency of thrombosis, including 62 cases of VTE, 63 cases of DIC and nine cases of cerebrovascular thrombosis, was significantly higher in the patients with malignant diseases (28.0%) than in the patients without malignant diseases (12.5%). DIC was frequently detected in the patients with hepatic cell cancer and hematopoietic malignancy, while VTE was frequently observed in the patients with colon cancer, breast cancer and urinary tract cancer. The FRMs levels were significantly higher in the patients with thrombosis than in the patients without thrombosis. A receiver operating characteristic analysis showed these markers to be useful for diagnosing thrombosis. Conclusion Patients with malignant diseases have a high risk of thrombosis, and elevated FRMs levels are useful for diagnosing thrombosis in patients with malignant diseases.

The aim of this study was to investigate the effect of laparoscopic endometriotic cystectomy and vaporization on ovarian reserve.We prospectively analyzed the serum level of anti-Mullerian hormone (AMH) in 62 patients at four different time points- preoperatively and at 1 month, 6 months, and 1 year postoperatively. Among the 62 cases, a bilateral cystectomy was performed in 10, bilateral vaporization in 16, a unilateral cystectomy in 24, and unilateral vaporization in 12.The rate of AMH decline after unilateral cystectomy or bilateral cystectomy was higher than that after unilateral vaporization or bilateral vaporization. Age and bilaterality were associated with an AMH decline at 1 month, and age alone was associated with an AMH decline at 1 year. Moreover, being older than 38 years of age and having a revised American Society for Reproductive Medicine score 80 were independent risk factors for the non-recovery of AMH.The rate of AMH decline after laparoscopic endometriotic vaporization is significantly lower than that after cystectomy. Both methods, however, have the potential to lower ovarian reserve, especially in cases of severe endometriosis or in patients older than 38 years of age.

We evaluated the diagnostic criteria for disseminated intravascular coagulation (DIC), which was published by the Japanese Society of Thrombosis and Hemostasis (JSTH), in 232 patients with suspected DIC without hematopoietic injury or infection. The diagnoses of the patients were as follows: DIC (n = 116), pre-DIC (n = 54), and non-DIC (n = 63). The efficacy of the diagnostic criteria for DIC was evaluated using a receiver operating characteristic analysis. The area under the curve and odds ratio for the global coagulation test (GCT) scores in the diagnosis of “DIC” were high, whereas those for the diagnosis of “DIC and pre-DIC” were low, suggesting that the addition of a reduced platelet count (RPC), antithrombin (AT), and soluble fibrin (SF)/thrombin AT (TAT) complex was required to diagnose DIC and pre-DIC. When the GCT score with the RPC, AT, and TAT/SF values was used, the cutoff DIC score for the diagnosis of DIC or DIC and pre-DIC was 6 points. For predicting the outcome, a scoring system that used the GCT result was useful, but the addition of RPC, AT, or SF/TAT was not. The modified diagnostic criteria of JSTH, which included the GCT score and the RPC, AT, and TAT/SF values, were useful for diagnosing both DIC and pre-DIC.

Essentials The activated partial prothrombin time (aPTT) cannot predict the activity of emicizumab (Emi). Adjusted clot waveform analyses using a prothrombin time (PT)/aPTT initiator were developed. Activity of Emi in the co-presence of factor VIII or bypassing agents was quantified. This assay is useful for assessing coagulation potential in Emi-treated hemophilia A. Summary Background Emicizumab is an anti-activated factor IX/FX bispecific antibody that mimics activated FVIII cofactor function. Emicizumab does not require activation by thrombin, and its effect on shortening the activated partial thromboplastin time (APTT) is much greater than that of FVIII. Therefore, the APTT has limited utility in hemophilia A (HA) patients treated with emicizumab. Aim To evaluate the global coagulation potential of emicizumab. Methods Clot waveform analysis (CWA) with prothrombin time (PT)/APTT mixed reagents was used to define hemostatic monitoring protocols in HA patients. A modified parameter, adjusted-|min1| (Ad|min1|), was developed. Maximum and minimum percentage transmittance were defined as 100% and 0% in the precoagulation and postcoagulation phases, respectively. Ad|min1| was calculated as an index of the maximum velocity of the coagulation process. Results Ad|min1| obtained with mixed-trigger reagent (PT/APTT/buffer, 1 : 15 : 135) in the presence of emicizumab optimally corresponded to the conversion rate estimated in animals; 0.2-0.4 IU dL-1 equivalent FVIII per 1 μg mL-1 emicizumab). Ex vivo addition of emicizumab to HA plasma with or without inhibitors resulted in concentration-dependent increases in Ad|min1|, with some individual variations. The addition of various concentrations of FVIII to HA plasma mixed with emicizumab resulted in dose-dependent increases in Ad|min1|. Similarly, mixtures of activated prothrombin complex concentrate and emicizumab added to HA plasma resulted in dose-dependent increases in Ad|min1|. In contrast, enhanced coagulation potential appeared to be better defined by the clot time than by Ad|min1| in experiments using recombinant activated FVII. Conclusion The PT/APTT reagent-triggered adjusted CWA could provide a useful means of assessing global coagulation potential in emicizumab-treated HA patients, with enhanced activity neither masking nor being masked by FVIII or bypassing agents.

We performed TaqMan genotyping assays of anti-Mullerian hormone (AMH) and anti-Mullerian hormone receptor type II (AMHRII) single nucleotide polymorphisms (SNPs) in order to investigate how their frequency and distribution affect infertility treatment outcome.Eighty Japanese women (advanced age: n = 51, endometriosis: n = 18, male infertility as a control: n = 11) who undertook ART were included in the study, and all couples underwent a full infertility investigation protocol. In order to investigate the natural distribution of SNPs, a naturally pregnant group of 28 subjects was recruited from among women who conceived naturally and subsequently delivered in our department. Genomic DNA was extracted from peripheral blood and genotyping was conducted by TaqMan genotyping assay. The relationship of AMH and AMHRII SNPs and treatment outcome in infertile women. Comparison of allele and genotype frequencies of infertile patients with naturally pregnant women.AMHRII -482 AG homozygote mutation was complicated with ISV 5-6 CT homozygote mutation and showed a significantly lower oocyte retrieval rate compared with a wild type. Two of 3 cases of AMHRII -482 AG homozygote mutation were poor responders, and the distribution and frequency of each allele of naturally pregnant women showed no statistical difference compared with infertile women.This study revealed the possible involvement of AMHRII -482 AG polymorphism on the malfunction of follicular development in Japanese women.

X-ray computed tomography (CT) with iodine contrast agent is widely employed to locate cancers. However, this method has shortcomings such as high-radiation dose exposure, iodine side effects, and ...

The authors invented the transXend detector, which measures X-rays as electric currents, and then gives the energy distribution of the X-rays after an unfolding process. In a previous paper, it was shown that the material thickness distributions can be estimated with the transXend detector by using reference points plotted from the electric current ratios, such as the I 2/I 1 − I 3/I 1 graph, where Ii denotes the electric current measured by the i-th segment of the transXend detector. In this paper, the tomographic images of iodine, aluminum, and the acrylic those surround the other two materials are reconstructed from their material thickness distributions, which are estimated from two X-ray incidence directions. The X-ray event ratios are also used to estimate the material thickness distributions.

Objective: To compare mini-laparoscopic surgery and conventional laparoscopic surgery in patients with endometriosis that was conducted to determine the superiority of mini-laparoscopic surgical technique. Design: Retrospective analysis. Settings: Osaka Medical College Hospital, Hokusetsu General Hospital, and Daiichi-Towakai Hospital, Osaka, Japan. Patients: Forty-six patients with endometriosis who underwent conventional or mini-laparoscopic surgery between November 2009 and October 2012. Intervention: Patients were divided into three groups. Group A underwent conventional surgery with one 12-mm port for a 10-mm laparoscope and three 5-mm ports. Groups B and C underwent mini-laparoscopic surgery with one 5-mm port for a 5-mm laparoscope and one 5-mm port as well as two 3-mm ports (Group B) or two 2.3-mm ports for the Mini-Lap Grasper (Group C). Measurements and main results: Operating time was significantly longer in Group C than in Group B (p = 0.01). Serum C-reactive protein levels 1 day after surgery were significantly lower in Groups B and C than in Group A (p

To measure the iron concentration in the human liver, which comprises soft tissue and adipose as well as iron, energy-resolved computed tomography (CT) is applied using a transXend detector. The transXend detector measures X-rays as electric current and gives an energy distribution after analysis. Energy-resolved CT clearly separates iron solution from acrylic, a substitute for soft tissue, whereas conventional current-measurement CT cannot. Using CT values obtained in two different energy ranges, a two-dimensional map of iron, adipose and soft tissue is plotted. With this map, the components in the liver can be identified.

GPR30 is a seven-transmembrane G protein-coupled estrogen receptor that regulates endometrial cellular responses to estrogen. GPR30 is often highly expressed in cancer cells from aggressive tumors. The aim of this study was to evaluate the expression patterns of GPR30 in endometriosis during medical treatment.A total of 38 females, 28 patients with endometriosis and 10 patients with leiomyoma who underwent laparoscopic surgery were included this study.Eutopic endometrial tissue sampling from women without endometriosis and ectopic endometrial tissue sampling from women with endometriosis.A quantitative real-time polymerase chain reaction analysis of the mRNA expression in eutopic and ectopic endometrial tissues with or without GnRH agonist treatment. The expression of GPR30 was confirmed by immunohistochemistry.There was an increased level of GPR30 mRNA in eutopic endometrium during the proliferative phase, whereas higher expression was observed in the ectopic endometrium during the secretory phase. Increased GPR30 mRNA was observed in ectopic endometrium in comparison to eutopic endometrium. GnRH agonist treatment before laparoscopic surgery decreased GPR30 mRNA in ectopic endometrium. The immunohistochemical analysis also revealed that GPR30 was strongly expressed in epithelial cells in ectopic endometrium, whereas GnRH agonist treatment decreased the GPR30 expression.High levels of GPR30 expression can play an important role in the progression of endometriosis.

Aim The purpose of this study was to compare the intraoperative and postoperative parameters among the three approaches used to treat large uterine myomas: laparoscopic assisted vaginal hysterectomy (LAVH), total laparoscopic hysterectomy (TLH) and abdominal hysterectomy, and to evaluate the selection criteria for laparoscopic hysterectomy as determined by magnetic resonance imaging. Material and Methods The medical records of 155 patients who underwent a hysterectomy between January 2007 and April 2010 were examined. We also compared the indications and outcomes of LAVH and TLH for myomas larger than 7 cm. Results Patients who underwent LAVH or TLH had a lower average intraoperative blood loss, less intense postoperative pain, and shorter hospital stays than patients in the TAH group, although the length of the operations in the laparoscopic groups were significantly longer. To evaluate the selection criteria for the large sized myomas, we compared the LAVH and TLH groups for the myomas larger than 7 cm. The greatest uterine transverse diameters and the weight of the uteri were not significantly different between the LAVH and TLH groups (94.7 ± 20.8 and 83.1 ± 17.6 mm, 371.6 ± 160.3 and 286.7 ± 158.0 g, respectively). The average intraoperative blood loss in the TLH group was significantly lower than that in the LAVH (121.3 ± 111.2 vs 379.3 ± 222.4 g, P

Background/Aims: To compare the perinatal outcomes after laparoscopic myomectomy (LM) versus abdominal myomectomy (AM). Methods: The medical records of 105 Japanese females who delivered after myomectomy from 2004 to 2012 at Osaka Medical College were reviewed retrospectively. Results: Of the 105 females who delivered after myomectomy, 48 had undergone LM and 57 had undergone AM. There were no significant differences in the perinatal outcomes including the rates of emergency cesarean sections, preterm deliveries, placental abnormalities, pregnancy-induced hypertension, low Apgar score, non-reassuring fetal heart rate patterns, and intrauterine fetal death. No significant difference was observed in the incidence of post-partum hemorrhage. There was no uterine rupture in either group. 15 (31%) of the females who had LM were candidates for transvaginal delivery, and 14 delivered vaginally (93% success rate). In contrast, 20 (35%) of the females who had AM were candidates for transvaginal delivery, and 19 delivered vaginally (95% success rate). Conclusion: There were no significant differences in the perinatal outcomes between the females who had LM and AM. Moreover, both groups had a high rate of successful transvaginal delivery after selecting the appropriate candidates.

Objective: We evaluated the modified diagnostic criteria for disseminated intravascular coagulation (DIC), which was published by the Japanese Society of Thrombosis and Hemostasis (JSTH) in 108 patients with suspected infectious DIC. Material and methods: The diagnoses of the patients were as follows: DIC (n = 63), pre-DIC (n = 22), and non-DIC (n = 45). The efficacy of the diagnostic criteria for DIC was evaluated using a receiver–operating characteristic analysis. Results: Although the area under the curve for global coagulation test (GCT) scores in the diagnosis of “DIC” was high that for the diagnosis of “DIC and pre-DIC” was low, suggesting that the addition of antithrombin (AT), soluble fibrin (SF)/thrombin–AT complex (TAT), and reduced platelet count (PLT) values was required to diagnose “DIC and pre-DIC.” Using GCT score with the AT, SF/TAT, and reduced PLT values, the cutoff value of the DIC score for the diagnosis of “DIC and pre-DIC” was 5 points. Discussion and conclusion: The modified JSTH’s diagnostic criteria for DIC, which used the GCT score and the reduced PLT, AT, and TAT/SF values, were useful for diagnosing “DIC and pre-DIC.”

It has been estimated that cancer patients have a 4- to 7-fold increased risk of VTE compared with the general population. The prothrombotic state variably results from tumor- and patient-specific factors. The pathophysiology of cancer-associated thrombosis is not entirely understood. The hypercoagulable state in cancer involves several complex interdependent mechanisms, including interaction among cancer cells, host cells, and the coagulation system. Key roles in pathophysiology are played by TF, inflammatory cytokines, and platelets. Many risk factors for cancer-associated thrombosis have been identified, including patient-, cancer-, and treatment-related factors. Several biomarkers have been identified as potentially predictive of VTE in multivariate analyses. Elevations of leukocyte and platelet counts and low hemoglobin levels are all predictive of chemotherapy- associated VTE. The levels of FRMs are significantly higher in patients with than in those without malignant diseases. A recently developed risk score referred to as the Khorana Risk Score can accurately stratify cancer patients into low, intermediate, and high risk for developing VTE. Observed rates of VTE in the development and validation cohorts were 0.8 and 0.3% in the low-risk category, 1.8 and 2% in the intermedi- ate-risk category, and 7.1 and 6.7% in the high-risk category, respectively. This model has now been validated in several other studies, including the prospective Vienna CATS study, which expanded the study and improved prediction by including biomarkers.

The aim of this study was to investigate whether FOXO1 and FOXO3 mRNA expression in granulosa cells is the cause of unexplained infertility.Thirty-one patients aged40 years (13 with unexplained infertility and 18 with male partner infertility as a control group) whose serum anti-Müllerian hormone level was0.5 ng/μL were enrolled in the study. All patients underwent oocyte retrieval under a short protocol from June 2012 to October 2013. Real-time PCR was carried out using mRNA extracted from granulosa cells retrieved from mature follicles. We compared FOXO1 and FOXO3 mRNA expression ratios in granulosa cells between the unexplained infertility group and the male infertility group. The relation between FOXO1 and FOXO3 mRNA expression ratios in granulosa cells and assisted reproduction technology clinical outcome was also examined.FOXO3 mRNA expression ratio was significantly lower in the unexplained infertility group than in the male infertility group. Moreover, FOXO3 mRNA expression ratio showed a positive correlation with both the number of retrieved oocytes and serum anti-Müllerian hormone level. A positive correlation was also identified between FOXO1 mRNA expression and total dose of hMG. As well, the number of retrieved oocytes in the unexplained infertility group was statistically lower than that in the male infertility group.A lower FOXO3 mRNA expression in granulosa cells leads to poor oocyte development in patients with unexplained infertility undergoing controlled ovarian stimulation for in vitro fertilization-embryo transfer.

Over the past decades, 5-Fluorouracil (5-FU) has been widely used to treat several types of carcinoma, including esophageal squamous cell carcinoma. In addition to its common side effects, including diarrhea, mucositis, neutropenia, and anemia, 5-FU treatment has also been reported to cause hyperammonemia. However, the exact mechanism responsible for 5-FU-induced hyperammonemia remains unknown. We encountered an esophageal carcinoma patient who developed hyperammonemia when receiving 5-FU-containing chemotherapy but did not exhibit any of the other common adverse effects of 5-FU treatment. At the onset of hyperammonemia, laboratory tests revealed high dihydropyrimidine dehydrogenase (DPD) activity and rapid 5-FU clearance. Our findings suggested that 5-FU hypermetabolism may be one of the key mechanisms responsible for hyperammonemia during 5-FU treatment.

A novel x-ray Bragg optics was developed for variable-magnification of an x-ray beam, and was combined with a module of the PILATUS pixel detector. A feasibility test of this optical system was carried out at the vertical-wiggler beamline BL-14B of the Photon Factory. By tuning the magnification factor, we could successfully control the spatial resolution of the optical system between 28 μm and 280 μm. X-ray absorption-contrast images of a leaf were observed at various magnification factors.

Objective: The cutoff values of fibrin-related markers (FRMs) diagnosing or predicting the occurrence of a venous thromboembolism (VTE) were evaluated. Materials and Methods: Fibrin-related markers such as fibrin monomer complex (FMC), D-dimer, and fibrinogen and fibrin degradation products (FDPs) before surgery were measured in 326 patients undergoing orthopedic surgery to diagnose subclinical VTE or predict postoperative VTE. Results: Although the FMC, D-dimer, and FDP levels were all useful for the diagnosis of acute VTE, the FDP level was not useful for diagnosing subclinical VTE or predicting postoperative VTE. The results of several D-dimer assays closely correlated with other D-dimer assays. There were various cutoff ranges for diagnosing or predicting VTE. Some D-dimer assays were useful for diagnosing low levels of D-dimer and others were useful for diagnosing moderate to high D-dimer levels. Increased D-dimer levels were useful for diagnosing acute (cutoff values: 2.0-5.9 μg/mL) or about 10% of subclinical VTE (cutoff values: 3.4-5.3 μg/mL), for predicting about 10% of postoperative VTE (cutoff values: 3.4-5.3 μg/mL), and for excluding VTE. Conclusion: Although increased D-dimer levels were useful for diagnosing subclinical VTE and predicting the risk of VTE, there were various cutoff values for the diagnosis or prediction of VTE.

The energy resolved computed tomography (CT), which had advantage over conventional CT (twofold higher CT value for iodine contrast agent and being free from beam hardening effect), was shown practical by employing the transXend detector: it measured X-rays as electric current and gave energy distribution of incident X-rays after analysis. This article shows a new application of the transXend detector for estimating the thicknesses of acrylic, iodine, and aluminum in a phantom. For this purpose, the responses of the segment detectors in the transXend detector are changed intentionally with inserting filters. With previously obtained two-dimensional maps for acrylic–iodine and acrylic–aluminum thicknesses, which are shown by the ratios of electric currents measured by the segment detectors, the thickness of materials on the path of the X-rays are obtained by a transmission measurement.

Introduction Myomectomy for cervical myoma is problematic because cervical myomas are very close to neighboring structures, such as the ureters, uterine artery, bladder and rectum. There are a few reports on laparoscopic myomectomy for cervical myomas to avoid blood loss, such as occlusion of iliac arteries and clipping of the uterine artery. We evaluated the efficacy and safety of bipolar electrode grasping forceps for laparoscopic myomectomy in uterine cervical myoma. Methods From November 2006 to May 2009, eight women with uterine cervical myoma underwent laparoscopic myomectomy. We employed electrode grasping forceps with a combination of two tenaculums for separating and securing hemostatsis. Results Seven of eight cases were successfully treated by laparoscopic myomectomy, but one patient, with a large 900-g myoma was converted to the laparotomy as a result of blood loss (1800 mL). Among the other seven cases, the average weight of the myoma was 132 g (range, 16–310 g) and the operating time was 176 min. (range, 125–255 min). No complications occurred. Of the four cases who wanted to become pregnant postoperatively, two became pregnant and delivered by Caesarean section. Conclusion These findings indicate that bipolar electrode grasping forceps using two tenaculums for traction of the myoma are useful for laparoscopic myomectomy in cervical myomas.

We report the case of a 59-year-old man with thymic adenocarcinoma who was treated with colon cancer chemotherapy. He was referred to our hospital for an anterior mediastinal mass and multiple bone metastases that were found by computed tomography. Needle biopsy of the mediastinal tumor revealed a caudal-type homeobox 2 (CDX2)-positive adenocarcinoma. Neither upper nor lower gastrointestinal endoscopic examinations revealed any evidence of a primary tumor. The patient was administered CapeOX (capecitabine and oxaliplatin) and FOLFIRI (fluorouracil, leucovorin and irinotecan)/cetuximab. He died 6 months after diagnosis. Primary thymic adenocarcinoma was confirmed by autopsy. As far as we know, this is the first report in which colon cancer chemotherapy was used to treat CDX2-positive metastatic thymic adenocarcinoma.

We performed a prenatal diagnosis for 10 fetuses from nine unrelated Japanese xeroderma pigmentosum complementation group A (XP-A) families. All parents had at least one XP-A child (proband) with a homozygous founder mutation (IVS3-1G>C) in the XPA gene. A genetic analysis was performed by a restriction enzyme; AlwNI fragment length polymorphism of polymerase chain reaction (PCR)-amplified DNA, mostly from amniotic fluid (AF) and cultured cells established from AF. However, for the first family, we tried amniocentesis as well as chorionic villus sampling (CVS). Among the 10 cases, we confirmed the results of PCR-based genetic diagnosis by post-ultraviolet survival of amniotic cells in eight cases. Unfortunately, 6 weeks after CVS and 4 days after the amniocentesis in the first case we examined, the fetus died in utero, the reason for which remains unexplained. We prenatally determined two XP-A cases, six XP-A carriers and two wild-type fetuses, which appears to be consistent with Mendel's law.

Interstitial pregnancy, which is a rare form of tubal ectopic pregnancy, can grow larger than those within the fallopian tube because the surrounding myometrium is more expandable than the tube; many cases are advanced and treated with surgical resection or a large amount of methotrexate (MTX). This report presents a case of an advanced interstitial pregnancy treated with systemic MTX and laparoscopic local MTX injection combined with transcervical aspiration of the gestational sac. A 27-year-old nulliparous female presented with an interstitial pregnancy. Serum human chorionic gonadotropin (hCG) level was 90000 IU/L. MTX was given systemically (50 mg/m(2) i.m.) and the gestational sac was aspirated transcervically under laparoscopic guidance followed by local injection of 25 mg MTX. The patient received a total of only 95 mg MTX. The gestational sac disappeared and serum hCG became undetectable. The patient became pregnant spontaneously six months later, and delivered a live 2482-g infant in good condition by planned cesarean section at 36 weeks and 3 days of gestation. No defect of the myometrium was seen during the surgery. This therapy may be effective for interstitial pregnancy and can be performed safely with laparoscopy.

Genomic hypermutation of RNA viruses, including human immunodeficiency virus type 1 (HIV-1), can be provoked by intrinsic and extrinsic pressures, which lead to the inhibition of viral replication and/or the progression of viral diversity. Human APOBEC3G was identified as an HIV-1 restriction factor, which edits nascent HIV-1 DNA by inducing G-to-A hypermutations and debilitates the infectivity of vif -deficient HIV-1. On the other hand, HIV-1 Vif protein has the robust potential to degrade APOBEC3G protein. Although subsequent investigations have revealed that lines of APOBEC3 family proteins have the capacity to mutate HIV-1 DNA, it remains unclear whether these endogenous APOBEC3s, including APOBEC3G, contribute to mutations of vif -proficient HIV-1 provirus in vivo and, if so, what is the significance of these mutations. In this study, we use a human hematopoietic stem cell-transplanted humanized mouse (NOG-hCD34 mouse) model and demonstrate the predominant accumulation of G-to-A mutations in vif -proficient HIV-1 provirus displaying characteristics of APOBEC3-mediated mutagenesis. Notably, the APOBEC3-associated G-to-A mutation of HIV-1 DNA that leads to the termination of translation was significantly observed. We further provide a novel insight suggesting that HIV-1 G-to-A hypermutation is independently induced by individual APOBEC3 proteins. In contrast to the prominent mutation in intracellular proviral DNA, viral RNA in plasma possessed fewer G-to-A mutations. Taken together, these results provide the evidence indicating that endogenous APOBEC3s are associated with G-to-A mutation of HIV-1 provirus in vivo , which can result in the abrogation of HIV-1 infection.