In situ XAFS-XRD study of the Zr-Y2O3 interaction at extra-high temperatures.

The in situ measurement technique for a metal/metal-oxide mixture at extra-high temperature above 2000 K has been desired in the field of nuclear safety engineering. In the present study, we succeeded in simultaneous XAFS-XRD measurements of the Zr oxidation [Zr + O → Zr(O) + ZrO2] up to 1952 K and ZrO2-Y2O3 reaction from 1952 to 2519 K. The chemical shift during Zr oxidation was observed in the absorption spectra around the Zr K-edge, and the interatomic cation-cation and cation-oxygen distances obtained by the fitting analysis of EXAFS during the Y2O3-ZrO2 reaction are explained. Also, the temperature dependency of the anharmonic effect was investigated by comparing the fitted second- and third-order cumulants with the theoretical ones in which the Morse potential was applied as an interatomic potential, giving a good explanation about the local structure dynamics. Finally, the applicability of the developed system to investigation of nuclear fuel materials, such as UO2-Zr, is discussed.

Fibroblast growth factor receptor 1/Klothoß agonist BFKB8488A improves lipids and liver health markers in patients with diabetes or NAFLD: A phase 1b randomized trial.

BACKGROUND AND AIMS: BFKB8488A is a bispecific antibody targeting fibroblast growth factor receptor 1c and Klothoß. This phase 1b study assessed safety, tolerability, pharmacokinetics, immunogenicity, and pharmacodynamics of BFKB8488A in patients with type 2 diabetes mellitus (T2DM) or NAFLD. APPROACH AND RESULTS: Patients were randomized to receive multiple doses of BFKB8488A at various dose levels and dosing intervals (weekly, every 2 weeks, or every 4 weeks) or placebo for 12 weeks. The primary outcome was the safety of BFKB8488A. Overall, 153 patients (T2DM: 91; NAFLD: 62) were enrolled and received at least one dose of treatment. Of these, 102 patients (62.7%) reported at least one adverse event (BFKB8488A: 83 [68.6%]; placebo: 19 [59.4%]). BFKB8488A exhibited nonlinear pharmacokinetics, with greater than dose-proportional increases in exposure. The treatment-emergent antidrug antibody incidence was 22.7%. Overall, trends in exposure-dependent increases in high-density lipoprotein (HDL) and decreases in triglyceride levels were observed. Decreases in alanine aminotransferase and aspartate aminotransferase were 0.7% and 9.2% for medium exposure and 7.3% and 11.2% for high-exposure tertiles, compared with increases of 7.5% and 17% in the placebo group, respectively, at Day 85. In patients with NAFLD, the mean decrease from baseline liver fat was 13.0%, 34.5%, and 49.0% in the low-, medium-, and high-exposure tertiles, respectively, compared with 0.1% with placebo at Day 85. CONCLUSIONS: BFKB8488A was adequately tolerated in patients with T2DM or NAFLD, leading to triglyceride reduction, HDL improvements, and trends in improvement in markers of liver health for both populations and marked liver fat reduction in patients with NAFLD. ( ClinicalTrials.gov : NCT03060538).

Successful direct pacing of the left bundle branch area with ICD lead using steerable delivery sheath.

Recently, conduction system pacing has been performed in patients with impaired cardiac function. We report a case in which a DF4 implantable cardioverter defibrillator lead was screwed directly into the left bundle branch area with the support of a steerable delivery sheath.

Visceral Adipose Tissue Percentage Compared to Body Mass Index as Better Indicator of Surgical Outcomes in Women With Obesity and Endometrial Cancer.

STUDY OBJECTIVE: To assess the impact visceral adipose tissue percentage (VAT%) on surgical outcomes during minimally invasive surgery in obese women with endometrial cancer. DESIGN: Retrospective observational cohort study. SETTING: Mie University Hospital, Japan. PATIENTS: Of the 73 women (body mass index [BMI] >30 kg/m2) with obesity and primary endometrial cancer, 52 underwent robotic surgery, while 21 underwent laparoscopic surgery between April 2014 and December 2022. INTERVENTIONS: We investigated the correlation between surgical outcomes (operative time and blood loss) and obesity (BMI and visceral adipose tissue percentage [VAT%]). MEASUREMENTS AND MAIN RESULTS: Abdominal fat-related parameters were measured at the level of the umbilicus using preoperative computed tomography. A weak negative correlation was found between BMI and VAT% (CC = -0.313, p = .001). Multivariate analysis showed that VAT% had a stronger correlation to total and practical operative time than BMI (ß = 0.338 vs 0.267, ß = 0.311 vs 0.209, respectively) and was an independent predictor of blood loss. VAT% was an independent predictive marker prolonged for operative time and increased blood loss during lymphadenectomy. CONCLUSION: VAT% could be an indicator of surgical outcomes for patients with obesity and endometrial cancer.

Support to early clinical decisions in drug development and personalised medicine with checkpoint inhibitors using dynamic biomarker-overall survival models.

Longitudinal models of biomarkers such as tumour size dynamics capture treatment efficacy and predict treatment outcome (overall survival) of a variety of anticancer therapies, including chemotherapies, targeted therapies, immunotherapies and their combinations. These pharmacological endpoints like tumour dynamic (tumour growth inhibition) metrics have been proposed as alternative endpoints to complement the classical RECIST endpoints (objective response rate, progression-free survival) to support early decisions both at the study level in drug development as well as at the patients level in personalised therapy with checkpoint inhibitors. This perspective paper presents recent developments and future directions to enable wider and robust use of model-based decision frameworks based on pharmacological endpoints.

Better Peptides via Chemical Glycosylation: Somatostatin Analogues Having a Human Complex-Type N-Glycan with Improved Drug Properties.

Somatostatin (somatotropin release-inhibiting factor, SRIF) is a growth hormone inhibitory factor in the form of a 14- or 28-amino acid peptide. SRIF affects several physiological functions through its action on five distinct SRIF receptor subtypes (sst1-5). Native SRIF has only limited clinical applications due to its rapid degradation in plasma. To overcome this obstacle, we have developed glycosylated SRIF analogues that possess not only metabolic stability but also high affinity to all five receptor subtypes by attaching human complex-type oligosaccharides. Such glycosylated SRIF analogues with improved pharmacokinetic profiles could be potent and novel therapeutic drugs for SRIF-related diseases in which several SRIF receptor subtypes are closely involved, and also shed light on new indications. Our results show that chemical glycosylation can be a powerful tool for the development of peptide and protein analogues superior to the original molecules with enhanced drug properties.

Glycochenodeoxycholate and glycodeoxycholate 3-O-glucuronides, but not hexadecanedioate and tetradecanedioate, detected weak inhibition of OATP1B caused by GDC-0810 in humans.

Endogenous biomarkers of drug transporters are promising tools to evaluate in vivo transporter function and potential alterations in the pharmacokinetics of their substrates. We have previously reported that coproporphyrin I/III captured the weak inhibition of OATP1B transporters by GDC-0810. In this study, we measured plasma concentrations of additional biomarkers, namely fatty acids, bile acids and their sulphate or glucuronide conjugates in the presence and absence of GDC-0810. Concentrations of hexadecanedioate and tetradecanedioate did not increase in the presence of GDC-0810. Among bile acids and their conjugates, glycochenodeoxycholate and glycodeoxycholate 3-O-glucuronides (GCDCA-3G and GDCA-3G) showed Cmax increases with geometric mean ratio (95% confidence interval) of 1.58 (1.13-2.22) and 1.49 (1.21-1.83), consistent with previous reports from low-dose rifampin co-administration and pharmacogenetic studies. These results suggest that GCDCA-3G and GDCA-3G are two more promising biomarkers that may capture weak OATP1B inhibition in addition to coproporphyrin I/III.

Balloon Trocar Is a Suitable Instrument for Retroperitoneal Para-aortic Lymphadenectomy in Gynecologic Malignant Diseases.

OBJECTIVE: To demonstrate the surgical technique of retroperitoneal para-aortic lymphadenectomy to prevent peritoneal rupture in gynecologic malignant disease. In this video, the authors describe how to use a balloon trocar to create a safe and efficient working space without peritoneal rupture. DESIGN: A step-by-step video demonstration of a surgical technique. SETTING: Department of Gynecology and Obstetrics, Mie University, Tsu, Japan. INTERVENTIONS: Para-aortic lymphadenectomy is a part of most gynecologic oncology procedures for primary and recurrent gynecologic malignancies. There are 2 approaches to para-aortic lymphadenectomy: transperitoneal and retroperitoneal approaches. Although there are no significant differences between these approaches (such as in terms of the number of isolated lymph nodes or related complications), they are performed based on the operator's preference. The retroperitoneal approach is an unfamiliar surgical technique compared with usual laparotomy and laparoscopic surgery, and its disadvantages include a steeper learning curve for attaining proficiency. It is also difficult to develop the retroperitoneal space without a peritoneal rupture. In this video, we demonstrate the use of balloon trocars to create a retroperitoneal compartment. The patient was placed in the lithotomy position with the pelvis elevated at 5° to 10°. The left internal iliac approach, which is considered the standard approach, was used in this case (Fig 1). After identifying the left psoas muscles and the ureter crossing the common iliac artery, dissection of the left para-aortic lymph node was initiated (Supplemental Video 1, 2). CONCLUSION: Herein, we demonstrated a successful surgical technique for retroperitoneal para-aortic lymphadenectomy to prevent peritoneal ruptures.

Double-σ-Bonded Close-Shell Dimers and Peroxy-Linked Open-Shell Dimer Derived from a C3 Symmetric Trioxophenalenyl Neutral Diradical.

A novel neutral diradical of π-extended phenalenyl derivative having three oxo-groups, tri-tert-butyl-1,4,7-trioxophenalenyl, and two types of the corresponding σ-dimers were investigated. Quantum chemical calculations showed that the neutral diradical is in triplet ground state having doubly degenerate singly occupied molecular orbitals. The neutral diradical undergoes a σ-dimerization, generating two types of σ-dimers immediately after the preparation. One of the σ-dimers, which was selectively generated in the crystalline state, was a close-shell dimer linked through double-σ-bonds on the phenalenyl skeleton with a long C-C bond length of 1.66 Å. The other σ-dimer, which existed only in the solution state, was a peroxy-linked open-shell dimer in which one σ-bond was formed between two oxygen atoms. Furthermore, the temperature-dependent 1 H NMR and ESR spectra revealed that these σ-dimers are in equilibrium in the solution state by the reversible σ-bond formation/cleavage via the neutral diradical as a key intermediate.

Trends in prognosis after hospitalization for acute heart failure in Kurashiki Central hospital 2015-2018: single-center prospective study.

Recently, we have been working on enhancing the effectiveness of treatment for acute heart failure (HF) through team-based care. This study was designed to assess the benefits of this initiative by quantifying the prognostic impact on HF patients receiving treatment at our hospital. We identified 1977 consecutive HF patients (mean age 78.3 ± 11.9 years) being discharged from our hospital between February 2015 and December 2018, divided them by admission year, and tracked changes over time, with 2015 as a reference. The postdischarge clinical outcome measures were defined as a composite of all-cause death or rehospitalization for HF, all-cause death, and rehospitalization for HF. The risk of a composite of all-cause death or rehospitalization for HF was lower in 2017 (adjusted hazard ratio, 0.72; 95% confidence interval: 0.57 to 0.91; p = 0.005) and 2018 (adjusted hazard ratio, 0.78; 95% confidence interval: 0.61 to 0.99; p = 0.045) than in 2015, and that of all-cause death was lower in 2017 (adjusted hazard ratio, 0.72; 95% confidence interval: 0.53 to 0.98; p = 0.04) and 2018 (adjusted hazard ratio, 0.60; 95% confidence interval: 0.43 to 0.85; p = 0.004) than in 2015, but that of rehospitalization for HF was not significantly different through the study period. The mortality rate decreased at the end of the study period, but the rate of rehospitalization for HF did not. The benefits of team-based care were difficult to evaluate by quantification.

Safety and efficacy of levonorgestrel-releasing intrauterine device in the treatment of atypical endometrial hyperplasia and early endometrial cancer.

AIM: To investigate the recurrence rate, live-birth rate, and treatment outcomes of levonorgestrel-releasing intrauterine device (LNG-IUD) for the management of atypical endometrial hyperplasia (AEH) or Grade-1 endometrial cancer (EC) in patients who desire fertility-sparing treatment and those seeking conservative treatment without fertility preservation. METHODS: We prospectively enrolled nine patients from a single institution between April 2009 and September 2013 who were followed up for 60 months after LNG-IUD insertion. RESULTS: The median patient age was 35 (range: 29-39) years. The overall recurrence rate was 56% (5/9). The median interval between removal of the LNG-IUD and recurrence was 20.5 (range: 2-30) months. Three of the nine patients had Grade-1 EC, and six had AEH. The response rates to the LNG-IUD in patients with Grade-1 EC and AEH were 66% and 100%, respectively. Four patients (three with AEH, one with Grade-1 EC) experienced recurrence 6 months after MPA treatment and all 4 (100%) had complete response. Eight patients desired fertility preservation, of which 37% (3/8) conceived after receiving fertility treatment and 25% (2/8) had a live birth; the remaining three had previously received MPA for 6 months and had a recurrence; of these, 1 had a live birth. CONCLUSION: LNG-IUD is effective for the management of AEH and EC in young patients who desire fertility-sparing treatment, including those ineligible for MPA owing to the presence of comorbidities and those with recurrence after MPA treatment (6-month treatment), and patients seeking conservative treatment without fertility preservation.

Efficacy of minodronic acid for the prevention of osteoporosis in premenopausal women with gynaecologic disease who undergo bilateral oophorectomy: a single-centre, non-randomised controlled, experimental study.

We evaluated the efficacy of minodronic acid for osteoporosis prevention after bilateral oophorectomy for gynaecologic disease in premenopausal women. Bone mineral density (BMD) and young adult mean (YAM) data from the lumbar vertebrae and femur and bone alkaline phosphatase (BAP)/tartrate-resistant acid phosphatase 5 b (TRACP 5 b) data were obtained for 101 patients. The primary endpoint was the efficacy of minodronic acid for osteoporosis prevention. Fifty-five and 31 patients were assigned to medication and no medication groups, respectively. The decrease in BMD and YAM and the increase in BAP/TRACP-5b were significantly more suppressed in the medication group. There were no significant between-group differences in age at oophorectomy, cancer type, body mass index (BMI), and adjuvant therapy. There were no adverse events due to minodronic acid. Minodronic acid may prevent osteoporosis after oophorectomy in premenopausal women with gynaecologic disease, independent of age at oophorectomy, cancer type, BMI, or adjuvant therapy. Impact statementWhat is already known on this subject? Although the current strategy for osteoporosis prevention after premenopausal bilateral oophorectomy (b-OVX) is hormone therapy (HT), there is no consensus on the treatment duration or adverse events.What do the results of this study add? Therefore, we planned a prospective study to evaluate the efficacy of prophylactic treatment for osteoporosis after b-OVX in premenopausal women with gynaecologic disease using minodronic acid, an oral bisphosphonate, which have a strong evidence of the treatment for osteoporosis. The result showed minodronic acid significantly suppressed the decrease in bone mineral density (BMD) and young adult mean (YAM) and the increase in bone alkaline phosphatase (BAP)/tartrate-resistant acid phosphatase 5b (TRACP 5b). Minodronic acid may prevent osteoporosis after oophorectomy in premenopausal women with gynaecologic disease, independent of age at oophorectomy, cancer type, BMI, or adjuvant therapy.What are the implications of these findings for clinical practice and/or further research? Minodronic acid treatment for osteoporosis prevention after premenopausal b-OVX may be effective as a therapeutic agent after the cessation of HT, or alternative for patients who are contraindicated for HT in breast cancer and thrombosis and should be administered with caution with a history of uterine or ovarian cancer.

Laparoscopic repair of segmental obturator nerve injury defect using an artificial nerve conduit: A case report.

Obturator nerve injury is an uncommon complication frequently associated with pelvic gynecologic or urologic cancer surgery. It can lead to disability or adversely affect quality of life. Large segmental defects are particularly difficult to manage as the limited mobility of the nerve prevents tension-free direct end-to-end anastomosis. A 36-year-old woman with cervical cancer underwent sentinel lymph node biopsy, laparoscopic radical hysterectomy, and bilateral adnexectomy. During the procedure, the sentinel lymph node (right obturator node) adherent to the obturator nerve was resected together with the nerve segment leaving a 3 cm defect. Immediate laparoscopic obturator nerve repair was performed using an artificial nerve conduit leading to successful recovery. We report this unique case due to rarity of large segmental obturator nerve defects and present laparoscopic nerve repair with artificial nerve conduits as a useful treatment alternative of these important injuries, without nerve donor site morbidity.

Laparoscopic retroperitoneal para-aortic lymph node biopsy in advanced cervical cancer with pelvic lymph node metastases: A single-center prospective study.

AIM: Extended-field concurrent chemoradiation therapy (Ex-CCRT) has been widely used for para-aortic lymph node (PAN) metastases confirmed by radiographic assessment without surgical exploration. The objective of this prospective study was to evaluate the clinical value of laparoscopic retroperitoneal PAN biopsy in locally advanced cervical cancer (LACC) with pelvic lymph node (PLN) metastases. METHODS: From May 2017 to March 2020, stage IIB-IIIB cervical cancer patients who were diagnosed with PLN metastasis using positron emission tomography-computed tomography (PET-CT) with maximum standardized uptake value (SUVmax) ≥2.0 underwent laparoscopic retroperitoneal PAN biopsy. The radiation fields were extended to PAN areas with pathological metastases. RESULTS: Fourteen patients were diagnosed with cervical squamous cell carcinoma of the International Federation of Gynecology and Obstetrics (FIGO) stage IIB (n = 7) and IIIB (n = 7). The median operating time was 138 min (range, 104-184 min). The median number of harvested PANs was 19 (range, 6-36). Three patients were positive for PAN metastasis on histological analysis. In this study, the sensitivity and specificity of PET-CT were 66.7% and 90.9%, respectively. CONCLUSION: Our study is characterized by the use of more appropriate eligibility criteria for LACC with PLN metastases. Our results revealed that laparoscopic retroperitoneal PAN biopsy may be a useful approach to determine the radiation field for PANs during standard radiotherapy planning.

[Observation of Child Development in a Uterine Cervical Cancer Patient Who Received Chemotherapy during Pregnancy].

This report describes the case of a 36-year-old woman with stage ⅠB1 cervical adenocarcinoma that was diagnosed when her fetus was at 19 weeks of gestation. Both she and her family strongly hoped that her pregnancy could continue. After approval by the Ethics Committee of our hospital, she was treated with paclitaxel and carboplatin. At 32 weeks of gestation, the patient delivered a 1,518 g female newborn via cesarean section. A radical hysterectomy with pelvic lymphadenectomy was performed after delivery. The newborn had Apgar scores of 3 at 1 minute and 5 at 5 minutes. No external malformations were observed. The Kyoto Scale of Psychological Development 2001 was used for cognitive assessment. Although the Language-Social Developmental Quotient score was 65 and developmental delay was observed at 1 year 8 months, the score improved to 98 at 3 years 5 months. The child was followed up until the age of 6 years 2 months and showed no developmental delay. Presentation of this case is important because there are few reports in Japan about the development of children of cancer patients who are exposed to anticancer drugs during pregnancy.

GDC-0810 Pharmacokinetics and Transporter-Mediated Drug Interaction Evaluation with an Endogenous Biomarker in the First-in-Human, Dose Escalation Study.

GDC-0810 (Cheeti et al., 2018) is an orally bioavailable, selective estrogen receptor (ER) degrader developed to treat ER-positive breast cancer. A first-in-human (FIH) dose escalation phase I study (n = 41) was conducted to characterize the pharmacokinetics (PK) of GDC-0810 and its two major metabolites. GDC-0810 demonstrated linear PK from 100 to 600 mg given once daily. The mean terminal half-life following a single 600 mg dose was approximately 8 hours. Since GDC-0810 is a potent in vitro inhibitor of organic anion transporting polypeptide (OATP) 1B1/3, the kinetic profile of coproporphyrin I (CPI), a promising endogenous biomarker for OATP1B1/3, was analyzed retrospectively in a subset of the plasma samples collected in the same FIH study. CPI exhibited a GDC-0810 dose-dependent increase, suggesting in vivo inhibition of OATP1B transporters. To quantitatively predict the magnitude of OATP1B-mediated drug-drug interactions (DDIs) with pravastatin (a known OATP1B substrate), the in vivo unbound inhibition constant was first estimated using a one-compartment model, and then incorporated to a physiologically based pharmacokinetic model. The model showed some underestimation of the magnitude of the DDI when compared with a clinical DDI study result, while prediction had a relatively large uncertainty due to the small effect size, limited sample size, and variability in CPI kinetics. In conclusion, this study characterized the pharmacokinetic profiles of GDC-0810 in breast cancer patients and demonstrated the utility of CPI in detecting OATP1B-mediated DDIs of a new molecular entity as early as FIH study. SIGNIFICANCE STATEMENT: Endogenous biomarkers of transporters have recently been shown to be promising tools in evaluating the risk of clinical transporter-mediated DDIs. This is the first study to report a pharmacokinetic interaction between an investigational molecule and a transporter biomarker in a first-in-human study. The observed interaction and model-based analysis and the prediction provide important insights on the novel approach to quantitatively predict transporter-mediated DDIs as early as FIH studies in the clinical development.

Schlafen-8 is essential for lymphatic endothelial cell activation in experimental autoimmune encephalomyelitis.

Schlafen-8 (Slfn8) is a member of the Schlafen family of proteins, which harbor helicase domains and are induced by LPS and interferons. It has been reported that the Schlafen family are involved in various cellular functions, including proliferation, differentiation and regulation of virus replication. Slfn8 has been implicated in T-cell differentiation in the thymus. However, the roles of Slfn8 in the immune system remains unclear. In this study, we generated Slfn8 knockout mice (Slfn8-/-) and investigated the immunological role of Slfn8 using the T-cell-mediated autoimmune model experimental autoimmune encephalomyelitis (EAE). We found that the clinical score was reduced in Slfn8-/- mice. IL-6 and IL-17A cytokine production, which are associated with EAE onset and progression, were decreased in the lymph nodes of Slfn8-/- mice. Immune cell populations in Slfn8-/- mice, including macrophages, neutrophils, T cells and B cells, did not reveal significant differences compared with wild-type mice. In vitro activation of Slfn8-/- T cells in response to TCR stimulation also did not reveal significant differences. To confirm the involvement of non-hematopoietic cells, we isolated CD45- CD31+ endothelial cells and CD45-CD31- gp38+ fibroblastic reticular cells by FACS sorting. We showed that the levels of IL-6 and Slfn8 mRNA in CD45- CD31+ endothelial cells were increased after EAE induction. In contrast, the level of IL-6 mRNA after EAE induction was markedly decreased in CD31+ endothelial cells from Slfn8-/- mice. These results indicate that Slfn8 may play a role in EAE by regulating inflammation in endothelial cells.

Influence of gas environment and heating on atomic structures of platinum nanoparticle catalysts for proton-exchange membrane fuel cells.

Atomic-scale relaxations of platinum nanoparticles (Pt NPs) for fuel-cell catalysts are evaluated by spherical-aberration corrected environmental transmission electron microscopy (ETEM) under reference high-vacuum and N2 atmospheres, and then under reactive H2, CO and O2 atmospheres, combined with ex situ durability test using an electrochemical half-cell. In high-vacuum, increasing roughness due to continuous relaxation of surface-adsorbed Pt atoms is quantified in real-space. Under H2 and N2 atmospheres at a critical partial pressure of 1 × 10-2 Pa the stability of the surface facets is for the first time found to be improved. The adsorption behaviour of CO molecules is investigated using experimentally measured Pt-Pt bond lengths on the topmost surface layer of Pt NPs. The deactivation of Pt NPs in the anode environment of a proton-exchange-membrane fuel-cell is demonstrated at the atomic-scale in the ETEM, and the transformation of NPs into disordered nanoclusters is systematically quantified using the partial size distribution of Pt atomic clusters under controlled heating experiments at 423, 573 and 723 K.

A Japanese survey of malignant disease in pregnancy.

BACKGROUND: In recent years, the incidence of malignant disease in pregnancy has been increasing, but there are few large-scale surveys of malignant disease in pregnancy in Japan. The aim of this study was to survey malignant disease occurring during pregnancy in Japan. METHODS: Malignant disease in pregnancy was defined as diagnosis or treatment for malignant disease, except in situ carcinoma during pregnancy, or within 1-year postpartum. First, a primary survey questionnaire of the incidence of malignant disease in pregnancy and the number of deliveries over the course of 2014 was sent to 510 medical centers in Japan. Second, the survey questionnaires on the incidence of malignant diseases in pregnancy were collected and analyzed in detail. RESULTS: Of the 510 medical centers, 411 (81%) responded to the survey. There were 215,372 deliveries and 189 incidents (0.09%) of malignant disease in pregnancy. Of the 189 patients with malignancy, 157 detailed responses about the patients were received. The most frequently encountered cancer types were cervical cancer (36%), breast cancer (24%), and ovarian cancer (15%). During the 2 years after delivery, 15 patients (1 with breast cancer, 2 with ovarian cancer, 3 with hematologic malignancy, 4 with intestinal cancer, and 5 with others) died of the disease; most of them had advanced disease. In particular, 88% of the patients with intestinal cancers at diagnosis had advanced disease, and half of them died of disease. CONCLUSIONS: In Japan, the most common malignancies in pregnancy in order of frequency are cervical cancer, breast cancer, and ovarian cancer. Early diagnosis and appropriate management of cancer during pregnancy are important for improving maternal and neonatal outcomes, because advanced diseases have a poor prognosis.

Spontaneously Cleavable Glycosylated Linker Capable of Extended Release of Its Conjugated Peptide.

Reversibly glycosylated conjugates were developed by adding complex-type N-linked oligosaccharides to peptides through self-cleavable linkers with the aim of increasing the solubility and stability of the peptides in plasma. The amino or carboxyl group of the peptide was connected to a glycosylated Ascendis or ester/thioester-type linker, respectively. Use of the linkers enabled extended release of the peptides depending on the pH and temperature of the buffer according to a first order reaction, and their cleavage rate was also affected by the structure of the peptide-linker coupling. This tunability will allow optimization towards the intended use of the peptides to be released. Furthermore, because glycosylation is a reliable method of greatly increasing the solubility of a peptide, the presented glycosylated linkers are expected to permit the preparation of antibodies in aqueous buffers even in the case of sparingly soluble antigen peptides.