Phase 1 trial of entinostat as monotherapy and combined with exemestane in Japanese patients with hormone receptor-positive advanced breast cancer.

BACKGROUND: Entinostat is an oral inhibitor of class I histone deacetylases intended for endocrine therapy-resistant patients with hormone receptor-positive (HR+) advanced or metastatic breast cancer (BC). We examined the safety, efficacy, and pharmacokinetics of entinostat monotherapy and combined entinostat/exemestane in Japanese patients. METHODS: This phase 1 study (3 + 3 dose-escalation design) enrolled postmenopausal women with advanced/metastatic HR+ BC previously treated with nonsteroidal aromatase inhibitors. Dose-limiting toxicities (DLTs) of entinostat monotherapy (3 mg/qw, 5 mg/qw, or 10 mg/q2w) and entinostat+exemestane (5 mg/qw + 25 mg/qd) were assessed. Pharmacokinetics, lysine acetylation (Ac-K), and T-cell activation markers were measured at multiple time points. RESULTS: Twelve patients were enrolled. No DLTs or grade 3-5 adverse events (AEs) occurred. Drug-related AEs (≥ 2 patients) during DLT observation were hypophosphatemia, nausea, and platelet count decreased. Six patients (50%) achieved stable disease (SD) for ≥ 6 months, including one treated for > 19 months. Median progression-free survival was 13.9 months (95% CI 1.9-not calculable); median overall survival was not reached. Area under the plasma concentration-time curve and Ac-K in peripheral blood CD19+ B cells increased dose-proportionally. The changing patterns of entinostat concentrations and Ac-K levels were well correlated. T-cell activation markers increased over time; CD69 increased more in patients with SD ≥ 6 months vs. SD < 6 months. CONCLUSIONS: Entinostat monotherapy and combined entinostat/exemestane were well tolerated in Japanese patients, with no additional safety concerns compared with previous reports. The correlation between pharmacokinetics and Ac-K in peripheral blood CD19+ B cells, and also T-cell activation markers, merits further investigation. TRIAL REGISTRATION: JAPIC Clinical Trial Information, JapicCTI-153066 . Registered 12 November 2015. ClinicalTrials.gov, NCT02623751 . Registered 8 December 2015.

Concurrent Double Fungal Infections of the Skin Caused by Phialemoniopsis endophytica and Exophiala jeanselmei in a Patient with Microscopic Polyangiitis.

is missing (Short communication).

Predictors of maternal state anxiety on arrival at a Japanese hospital outpatient clinic: a cross-sectional study.

AIMS AND OBJECTIVES: To identify the factors that predict maternal state anxiety when mothers and their sick children visit the outpatient unit of a paediatric hospital. BACKGROUND: While previous studies have focused on predictors of anxiety in mothers with ill children, the existing literature is limited in study design, research timing, respondent characteristics, sample size and data analysis. DESIGN: A cross-sectional design with self-administered questionnaires. METHODS: Mothers were recruited from the outpatient unit of a Japanese paediatric hospital (N = 1077). Participants' state anxiety scores were collected using the Japanese version of Spielberger's State-Trait Anxiety Inventory. The independent variables were the mothers' and sick children's background information. RESULTS: Participants were 1077 mothers; 990 provided valid responses. Mothers' mean state anxiety score was 49·72. Significant predictors of maternal anxiety were mothers' childrearing anxiety, child age, the sick child having a fever, sick child having siblings, having a person providing childrearing support, the mother's first visit to the hospital, out-of-hours visit and severity of the child's illness. The overall model explained 21·6% of the variance (multiple regression analysis). CONCLUSIONS: As various factors predicted maternal anxiety, identifying methods to address these factors may reduce maternal state anxiety. RELEVANCE TO CLINICAL PRACTICE: There is potential for improved understanding of the predictors of maternal state anxiety to aid in the development of materials that would best measure anxiety. The present findings may also suggest some means of providing appropriate information and support to anxious mothers. Our findings cannot demonstrate causation, however, and teaching methods and supportive practices were not investigated; therefore, a qualitative study on the concrete content of maternal anxiety and an intervention study to create support services for anxious mothers is required. In addition, prospective or longitudinal studies are also important for investigating causation.

Comprehensive evaluation of machine learning algorithms for predicting sleep-wake conditions and differentiating between the wake conditions before and after sleep during pregnancy based on heart rate variability.

Introduction: Perinatal women tend to have difficulties with sleep along with autonomic characteristics. This study aimed to identify a machine learning algorithm capable of achieving high accuracy in predicting sleep-wake conditions and differentiating between the wake conditions before and after sleep during pregnancy based on heart rate variability (HRV). Methods: Nine HRV indicators (features) and sleep-wake conditions of 154 pregnant women were measured for 1 week, from the 23rd to the 32nd weeks of pregnancy. Ten machine learning and three deep learning methods were applied to predict three types of sleep-wake conditions (wake, shallow sleep, and deep sleep). In addition, the prediction of four conditions, in which the wake conditions before and after sleep were differentiated-shallow sleep, deep sleep, and the two types of wake conditions-was also tested. Results and Discussion: In the test for predicting three types of sleep-wake conditions, most of the algorithms, except for Naïve Bayes, showed higher areas under the curve (AUCs; 0.82-0.88) and accuracy (0.78-0.81). The test using four types of sleep-wake conditions with differentiation between the wake conditions before and after sleep also resulted in successful prediction by the gated recurrent unit with the highest AUC (0.86) and accuracy (0.79). Among the nine features, seven made major contributions to predicting sleep-wake conditions. Among the seven features, "the number of interval differences of successive RR intervals greater than 50 ms (NN50)" and "the proportion dividing NN50 by the total number of RR intervals (pNN50)" were useful to predict sleep-wake conditions unique to pregnancy. These findings suggest alterations in the vagal tone system specific to pregnancy.

Dual role of basophils in the pathogenesis of bullous pemphigoid elucidated by pathological and ultrastructural studies

Background: Bullous pemphigoid (BP), one of the most common autoimmune blistering disorders, is characterized by early erythematous and bullous lesions. Histopathologically, eosinophilia in the dermal tissue is a common finding in BP. In addition, basophils infiltrate the BP skin lesion. Although basophils are involved in the induction of type 2 immunity along with eosinophils, their role in both the erythema and blister, as well as the chronology of their involvement, have not been investigated. Objectives: To elucidate the role of basophils in BP development and resolution by performing early- and late-phase histopathological analysis of BP. Materials & Methods: A total of 25 patients with BP who underwent biopsy for both erythema and bullous lesions and were not taking oral steroids at the time of biopsy, were selected. Biopsy specimens of the erythematous (inflammatory) and bullous (resolution) phases were compared by histopathology, immunohistochemistry and electron microscopy. Results: During the early phase of BP, the number of basophils positively correlated with the number of eosinophils compared with other immune cells. In the late phase (bullous phase) of BP, the number of basophils significantly increased and more cell-cell contact between the basophils and M2 macrophages was noted, compared to the early phase Conclusions: Basophils are involved in the development of BP and its resolution, in part, via cell-cell contact with eosinophils or M2 macrophages, as demonstrated by pathological analysis.

Increased App expression in a mouse model of Down's syndrome disrupts NGF transport and causes cholinergic neuron degeneration.

Degeneration of basal forebrain cholinergic neurons (BFCNs) contributes to cognitive dysfunction in Alzheimer's disease (AD) and Down's syndrome (DS). We used Ts65Dn and Ts1Cje mouse models of DS to show that the increased dose of the amyloid precursor protein gene, App, acts to markedly decrease NGF retrograde transport and cause degeneration of BFCNs. NGF transport was also decreased in mice expressing wild-type human APP or a familial AD-linked mutant APP; while significant, the decreases were less marked and there was no evident degeneration of BFCNs. Because of evidence suggesting that the NGF transport defect was intra-axonal, we explored within cholinergic axons the status of early endosomes (EEs). NGF-containing EEs were enlarged in Ts65Dn mice and their App content was increased. Our study thus provides evidence for a pathogenic mechanism for DS in which increased expression of App, in the context of trisomy, causes abnormal transport of NGF and cholinergic neurodegeneration.

Differential effects of topically applied formalin and aromatic compounds on neurogenic-mediated microvascular leakage in rat skin.

Various volatile organic compounds (VOCs) act as a causative agent of skin inflammation. We investigated the effect of topical application of several VOCs and formalin on microvascular leakage in rat skin. We tested capsaicin, which is a reagent that specifically causes the skin response via endogenously released tachykinins. Evans blue dye extravasation served as an index of the increase in skin vascular permeability. After shaving the abdomen, we applied formalin, m-xylene, toluene, styrene, benzene, ethylbenzene, acetone, diethyl ether, hexane, heptane, cyclohexane and capsaicin to the skin. At 40min after application, skin samples were collected. Among all of the VOCs tested, all of the aromatic compounds significantly produced skin microvascular leakage that was similar to formalin and capsaicin. We also investigated the skin responses seen after the intravenous administration of CP-99,994 (1.5 or 5mg/kg), which is a tachykinin NK1 receptor antagonist, ketotifen (1 or 3mg/kg), which is a histamine H1 receptor antagonist that stabilizes the mast cells, and the topical application of capsazepine (22.5 or 50mM), which is the transient receptor potential vanilloid 1 (TRPV1) antagonist. The response induced by formalin and capsaicin was completely inhibited by CP-99,994. On the other hand, the antagonist partially reduced the response induced by m-xylene, toluene and styrene by 39%, 50% and 46%, respectively. Capsazepine and ketotifen did not alter the response induced by formalin or any of the aromatic compounds. Like capsaicin, formalin and the aromatic compounds at least partially caused skin microvascular leakage, which was due to tachykinin NK1 receptor activation related to the release of tachykinins from the sensory nerve endings. However, it is unlikely that mast cells and TRPV1 play an important role in the skin response.

Sleep and EEG features in genetic models of Down syndrome.

Down syndrome is characterized by a host of behavioral abnormalities including sleep disturbances. Sleep and EEG was studied at the age of 3 months in two mouse models of the condition, Ts65Dn and Ts1Cje, carrying one extra copy of partially overlapping segments of the mmu chromosome 16 (equivalent to the human chromosome 21). We found that the Ts65Dn mice showed increased waking amounts at the expense of non-REM sleep, increased theta power during sleep and a delayed sleep rebound after sleep deprivation. In contrast, Ts1Cje had limited sleep and EEG abnormalities, showing only a delayed sleep rebound after sleep deprivation and no difference in theta power. We previously found that mice over-expressing the human APPwt transgene, a gene triplicated in Ts65Dn but not Ts1Cje, also show increased wake and theta power during sleep. These results demonstrate abnormalities in sleep and EEG in Ts65Dn mice and underscore a possible correlation between App overexpression and hippocampal theta oscillations.

Early Stage of Pilomatricoma with an Empty Cyst Cavity and Unusual Clinical Appearance.

We present an unusual case of cystic pilomatricoma. A 13-year-old Japanese boy was referred to our department for evaluation of a 10-day history of a small reddish nodule on his right cheek. Histopathological examination showed a well-circumscribed cystic structure showing a central empty cavity in the dermis. The wall of the cyst was composed of basophilic cells. Inner layers of the wall were covered with flattened epithelial cells having trichohyalin granules. Based on these findings, a diagnosis of cystic pilomatricoma was made. To our knowledge, there has been no report of cystic pilomatricoma with an empty cavity. Dermatologists should be aware of pilomatricoma in the early stage showing a central empty cavity.

Squamous Cell Carcinoma Manifested as a Cutaneous Horn: A Key to Early Detection.

We report a case of squamous cell carcinoma manifested as a cutaneous horn. A 92-year-old man was referred to our department for evaluation of a 3-month history of a keratotic cutaneous horn on the left side of his neck. The height of the cutaneous horn was larger than the diameter of erythema at the base. Histopathological examination showed a hyperkeratotic horn developing over a mass of large atypical keratinocytes with large hyperchromatic and pleomorphic nuclei. Based on these findings, a diagnosis of squamous cell carcinoma was made. A recent study showed that cutaneous horns in association with invasive squamous cell carcinoma had a tendency to have less height than the diameter of the base. In our case, however, the height of the cutaneous horn was larger than the diameter of the base, indicating that invasive squamous cell carcinoma sometimes shows a cutaneous horn that is higher than the diameter of the base. Thus, clinical finding of erythema at the base of the cutaneous horn would be a reliable feature for early detection of squamous cell carcinoma.

Legius syndrome: A case report.

Legius syndrome is a rare genetic disorder caused by heterozygous germ line loss-of-function SPRED1 mutation. In Japan, a family with Legius syndrome was first described in 2015 by Sakai et al. We described a first solitary case of Legius syndrome identified by next-generation sequencing in Japan. A 37-year-old woman presented with multiple café-au-lait macules and freckles but has no other features of neurofibromatosis type 1 (NF-1). Sequencing results showed the presence of a mutation in exon 2 of SPRED1 c.70C>T, resulting in the protein at position 24 (p.Arg24X). When a dermatological clinician sees an adult patient showing only pigmented lesions and no other specifically diagnostic features of NF-1, it is important to suspect the possibility of Legius syndrome.

Melanoma of the Umbilicus: A Patient Report, Precaution in Operative Strategy, and the First Histopathological Review of Published Cases.

Umbilical melanoma is extremely rare. Among the past English reports on umbilical melanoma, there are only 8 reports in which histopathology was described in detail, and there has been no report with a review of the histopathology of previously reported cases. We experienced a case of umbilical melanoma and reviewed previously reported cases including our case. Because of the anatomical location, it is difficult to become aware of the umbilical melanoma unless there are some concomitant symptoms such as discharge or swelling. Even with these symptoms, patients tend to postpone a hospital visit for unknown reasons, resulting in increased risk of tumor growth and metastasis. When performing resection of umbilical melanoma, a portion of the peritoneum should also be removed. Sentinel lymph nodes can be axilla or inguinal lymph nodes. There is a possibility of metastasis to the preoperative abdominal cavity or to nearby skin through hematogenous spread. Preoperative evaluation of tumor spread and postoperative observation are important for umbilical melanoma in order to detect recurrence or metastasis because of its unique anatomical location.