Efficacy and safety of olaparib, olaparib plus bevacizumab and niraparib maintenance treatment in Japanese patients with platinum-sensitive advanced ovarian cancer.

OBJECTIVE: To investigate whether maintenance treatment could be safely and effectively performed with olaparib, olaparib plus bevacizumab and niraparib in platinum-sensitive advanced ovarian cancer at multiple institutions in Japan. METHODS: We investigated progression-free survival and adverse events in 117 patients with platinum-sensitive advanced ovarian cancer treated with maintenance therapy. RESULTS: The median progression-free survival of 117 patients was 20.1 months. Patients with germline BRCA pathogenic variants had a significantly better prognosis than the other groups (P < 0.001). Furthermore, in the multivariate analysis, stage IV (P = 0.016) and germline BRCA wild-type (P ≤ 0.001) were significantly associated with worse progression-free survival in patients with advanced ovarian cancer. Regarding adverse events, all three types of maintenance treatment were significantly worse than chemotherapy given before maintenance treatment with respect to renal function (olaparib, P = 0.037; olaparib plus bevacizumab, P < 0.001; and niraparib, P = 0.016). CONCLUSION: Maintenance treatment was performed effectively and safely. Renal function deterioration is likely to occur during maintenance treatment, and careful administration is important in platinum-sensitive advanced ovarian cancer.

Relationship Between Hematological Toxicities During Maintenance Treatment and During Chemotherapy Before Maintenance Treatment in Patients With Platinum-sensitive Relapsed Ovarian Cancer.

BACKGROUND/AIM: To determine if maintenance treatment can be performed effectively and safely in patients with platinum-sensitive relapsed ovarian cancer. PATIENTS AND METHODS: We carried out a multi-center study to investigate progression-free survival (PFS) and adverse events (AEs) in 229 patients receiving maintenance treatment for platinum-sensitive relapsed ovarian cancer. RESULTS: The median PFS in the 229 patients with maintenance treatment was 14.0 months (95% confidence interval=10.3-17.6 months). The hematological toxicities included ≥grade 3 anemia in 33.2% of cases. Anemia during maintenance treatment was significantly more common than anemia during chemotherapy given before maintenance treatment (p<0.001). Anemia during chemotherapy prior to maintenance treatment significantly increased the risk of anemia during maintenance treatment, compared with other clinical features (p<0.001). CONCLUSION: Maintenance treatment can be performed safely and effectively in patients with platinum-sensitive relapsed ovarian cancer. Anemia during chemotherapy given before maintenance treatment significantly increased the risk of developing anemia during maintenance treatment in patients with platinum-sensitive relapsed ovarian cancer.

Statistical and machine learning approaches to predict the necessity for computed tomography in children with mild traumatic brain injury.

BACKGROUND: Minor head trauma in children is a common reason for emergency department visits, but the risk of traumatic brain injury (TBI) in those children is very low. Therefore, physicians should consider the indication for computed tomography (CT) to avoid unnecessary radiation exposure to children. The purpose of this study was to statistically assess the differences between control and mild TBI (mTBI). In addition, we also investigate the feasibility of machine learning (ML) to predict the necessity of CT scans in children with mTBI. METHODS AND FINDINGS: The study enrolled 1100 children under the age of 2 years to assess pre-verbal children. Other inclusion and exclusion criteria were per the PECARN study. Data such as demographics, injury details, medical history, and neurological assessment were used for statistical evaluation and creation of the ML algorithm. The number of children with clinically important TBI (ciTBI), mTBI on CT, and controls was 28, 30, and 1042, respectively. Statistical significance between the control group and clinically significant TBI requiring hospitalization (csTBI: ciTBI+mTBI on CT) was demonstrated for all nonparametric predictors except severity of the injury mechanism. The comparison between the three groups also showed significance for all predictors (p<0.05). This study showed that supervised ML for predicting the need for CT scan can be generated with 95% accuracy. It also revealed the significance of each predictor in the decision tree, especially the "days of life." CONCLUSIONS: These results confirm the role and importance of each of the predictors mentioned in the PECARN study and show that ML could discriminate between children with csTBI and the control group.

Docosahexaenoic acid and eicosapentaenoic acid strongly inhibit prostanoid TP receptor-dependent contractions of guinea pig gastric fundus smooth muscle.

The inhibitory effects of docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and linoleic acid (LA) on the contractions induced by five prostanoids and U46619 (a TP receptor agonist) were examined in guinea pig gastric fundus smooth muscle (GFSM). Tension changes were isometrically measured, and the mRNA expression of prostanoid receptors was measured by RT-qPCR. DHA and EPA significantly inhibited contractions induced by the prostanoids and U46619, whereas LA inhibited those induced by prostaglandin D2 and U46619. The mRNA expression levels of the prostanoid receptors were TP ≈ EP3  >> FP > EP1 . The inhibition by DHA, EPA, and LA was positively correlated with that by SQ 29,548 (a TP receptor antagonist) but not with that by L-798,106 (an EP3 receptor antagonist). DHA and EPA suppressed high KCl-induced contractions by 35% and 25%, respectively, and the contractions induced by the prostanoids and U46619 were suppressed by verapamil, a voltage-dependent Ca2+ channel (VDCC) inhibitor, by 40%-85%. Although LA did not suppress high KCl-induced contractions, it suppressed U46619-induced contractions in the presence of verapamil. However, LA did not show significant inhibitory effects on U46619-induced Ca2+ increases in TP receptor-expressing cells. In contrast, LA inhibited U46619-induced contractions in the presence of verapamil, which was also suppressed by SKF-96365 (a store-operated Ca2+ channel [SOCC] inhibitor). These findings suggest that the TP receptor and VDCC are targets of DHA and EPA to inhibit prostanoid-induced contractions of guinea pig GFSM, and SOCCs play a significant role in LA-induced inhibition of U46619-induced contractions.

Studies on safety and efficacy of particles containing a mixture of hydroxyapatite-argentum-titanium oxide (HAT) and sheets coated with HAT particles to be used in masks to improve nasal allergy: II. Cellular, in vivo, and clinical studies.

PURPOSE: We report the manufacture of particles containing a mixture of hydroxyapatite-argentum-titanium oxide (HAT), followed by attachment to nonwoven polyester fabrics to produce HAT-coated sheets (HATS) for use in masks. The purpose of the present study was to perform cellular, in vivo, and clinical studies to further examine the safety of HATS for use in masks to improve nasal allergy. METHODS: Reverse mutation tests for HAT were performed using five bacterial strains. A cellular toxicity test was performed using a Chinese hamster cell line incubated with the HATS extracts. Skin reactions after intradermal administration were examined in rabbits. Skin sensitization tests in guinea pigs were performed using the HATS extracts. HAT was administered to the nasal cavity and conjunctival sac of the rabbits. An oral administration study was performed in rats. Finally, a human skin patch test was performed using the HATS. RESULTS: Reverse mutation tests showed negative results. The cellular toxicity test showed that the HATS extract had moderate cytotoxicity. The intradermal skin reaction and skin sensitization tests were all negative. The administration of HAT to the nasal cavity and intraocular administration showed negative results. No toxicity was observed after oral administration of HAT powder up to a dose of 2000 mg/kg. Finally, the skin patch test result was negative. CONCLUSION: Although HAT showed moderate cytotoxicity, in vivo results indicated that HAT is safe because it does not come in direct contact with cells in normal usage, and HATS is safe when used in masks.

Micro-CT assessment of the effect of silver diammine fluoride on inhibition of root dentin demineralization.

This study evaluated the ability of different types of silver diammine fluoride (SDF) to inhibit dentin demineralization using micro-focused X-ray computed-tomography (µCT). Dentin specimens were divided into five groups (n=10); no-treatment (control), 3.8% SDF (RC), 38% SDF, 38% SDF with potassium iodide (SDF/KI), and potassium fluoride (KF). The treated-dentin surfaces were subjected to demineralization for 7-days and assessed using µCT to determine mineral loss (ML) values. Specimens were also analyzed with scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDS). The ML values of the SDF and KF groups were significantly lower than those of the RC and SDF/KI groups. EDS detected fluoride ions in the SDF and KF groups but not in the RC and SDF/KI groups. It was concluded that 38% SDF demonstrated a high ability to inhibit dentin demineralization while additional application of KI may diminish the inhibitory effect of SDF. The amount of dentin demineralization with SDF treatments was material dependent.

Effects of silver diamine fluoride preparations on biofilm formation of Streptococcus mutans.

Effects of silver diamine fluoride preparations (SDFs) on cariogenic biofilm formation on root dentin (RD) were investigated. Streptococcus mutans (S. mutans) biofilms were formed on bovine RD blocks coated with one of three the SDFs (38%-SDF, 3.8%-SDF and 35%-SDF+potassium-iodide; SDF+KI) and a non-coated Control which were quantified (spectrometric-measurement) and thickness measured (optical coherence tomography) after 20 h. Bacterial viability test (BacLight) and biofilm-morphometry (SEM) of 2 h biofilms were also performed. The amounts of biofilms (bacteria and water insoluble glucan) and the thickness of biofilm were minimum on 38%-SDF specimen; 3.8%-SDF and SDF+KI had significantly more than that, but had significantly less than Control (p<0.05). Most S. mutans cells found dead and morphology damaged by 38%-SDF. Some dead bacteria and remarkably damaged biofilms were observed in case of 3.8%-SDF and SDF+KI. Inhibition potential of 3.8%-SDF and SDF+KI on S. mutans biofilm formation is almost similar, although not equivalent to 38%-SDF.

Cerebellar hemorrhage in a newborn: a case report in association with suspected arterial dissection of the posterior inferior cerebellar artery.

We herein report a 5-day-old baby boy presented with a massive cerebellar hemorrhage due to suspected posterior inferior cerebellar artery (PICA) dissection. He was born by vacuum extraction at the gestational age of 41 weeks with 3370 g birth weight. On the fifth day of life, he developed dyspnea with worsening vital signs. CT of the head showed massive cerebellar hemorrhage and then transferred to our hospital. External ventricular drainages were emergently placed for his hydrocephalus on the first day of hospitalization, then cerebellar hematoma was evacuated with suboccipital craniotomy on day 11. Under microscopic observation, the left PICA was swollen with dark red discoloration at the caudal loop, being a confirmative finding of arterial dissection. By these findings, we suspected ruptured arterial dissection as a cause of cerebellar hemorrhage. The right PICA looked intact. He required a ventriculoperitoneal shunt on day 59 due to his persistent hydrocephalus, resulting in remarkable improvement of his neurological condition. An MRI, a CT angiography/venography, or blood tests showed no abnormalities such as tumors, vascular anomalies, or coagulopathies. We discuss the significantly rare case of cerebellar hematoma in a newborn, most likely caused by ruptured PICA dissection.

Can Total Body Resistance Measured Using Bioelectrical Impedance Analysis Be the Index of Dehydration in Older Japanese Patients?

BACKGROUND: Dehydration in older patients has long been considered a significant health problem because it implies increased morbidity and mortality. However, dehydration is detected by a combination of physical signs and blood tests. For older people dwelling at home and in nursing homes, a simple and non-invasive method for detecting dehydration by caregivers is needed. The total body resistance is measured using bioelectrical impedance analysis and is known as an indicator of dehydration. There are no data from older Japanese patients on this issue. We performed this study to examine the relationship between dehydration and total body resistance in Japan. METHODS: We performed blood tests and measured bioelectrical impedance in older outpatients aged ≥ 65 years from the Internal Medicine Department at Mito Kyodo General Hospital. Patients were classified as dehydrated and non-dehydrated using the dehydration index with a blood urea nitrogen/creatinine ratio > 20, and the mean total body resistance was compared between the two groups. RESULTS: Eighty-one patients were recruited in the study. In the dehydrated group, the mean total body resistance was 439 Ω at 50 kHz, which was significantly higher than that in the non-dehydrated group (408 Ω, P = 0.038). CONCLUSIONS: The total body resistance measurements can be used for simple assessment of dehydration among older Japanese patients.

N-acetylglucosamine suppresses osteoclastogenesis in part through the promotion of O-GlcNAcylation.

Osteoclasts are the only cells in an organism capable of resorbing bone. These cells differentiate from monocyte/macrophage lineage cells upon stimulation by receptor activator of NF-κB ligand (RANKL). On the other hand, osteoclastogenesis is reportedly suppressed by glucose via the downregulation of NF-κB activity through suppression of reactive oxygen species generation. To examine whether other sugars might also affect osteoclast development, we compared the effects of monomeric sugars (glucose, galactose, N-acetylglucosamine (GlcNAc), and N-acetylgalactosamine (GalNAc)) on the osteoclastogenesis of murine RAW264 cells. Our results demonstrated that, in addition to glucose, both GlcNAc and GalNAc, which each have little effect on the generation of reactive oxygen species, suppress osteoclastogenesis. We hypothesized that GlcNAc might affect osteoclastogenesis through the upregulation of O-GlcNAcylation and showed that GlcNAc increases global O-GlcNAcylation, thereby suppressing the RANKL-dependent phosphorylation of NF-κB p65. Furthermore, an inhibitor of N-acetyl-ß-D-glucosaminidase, O-(2-acetamido-2-deoxy-D-glucopyranosylidene) amino N-phenylcarbamate (PUGNAc), which also increases O-GlcNAcylation, suppressed the osteoclastogenesis of RAW264 cells and that of human peripheral blood mononuclear cells. Together, these data suggest that GlcNAc suppresses osteoclast differentiation in part through the promotion of O-GlcNAcylation.

A Case of Spontaneous Tumor Lysis Syndrome in a Patient with Ovarian Cancer.

Tumor lysis syndrome (TLS) is a potentially life-threating complication of tumors or chemotherapy treatment. TLS commonly occurs in hematological malignancies, but it is very rare in patients with a solid tumor. In cases of solid tumors, TLS usually occurs spontaneously and after the initiation of anticancer therapy, and it has a high mortality rate. We present the novel case of a 62-year-old woman with an ovarian tumor who spontaneously developed TLS. Surgical reduction of the tumor mass vastly improved her condition. She showed no sign of tumor recurrence 8 months after treatment. As TLS is life-threatening, successful treatments must be seriously considered.

The measurement of axillary moisture for the assessment of dehydration among older patients: a pilot study.

PURPOSE: Dry axilla can sometimes be found among dehydrated older patients. In this study, we measured the axillary moisture and assessed it as possible marker for dehydration. METHODS: Twenty-nine older patients admitted with acute medical conditions participated in this study. Dehydration was diagnosed by the calculated serum osmolality of greater than 295 mOsm/L. The moisture of axilla was measured by a skin moisture impedance meter which was applied at the center of axilla of patients. RESULTS: 11 patients (7 males and 4 females) were diagnosed as dehydrated and 18 patients (10 males and 8 females) were diagnosed as non-dehydrated. The mean axillary moisture (33%) in the dehydrated group was significantly lower than that (42%) in the non-dehydrated group (p<0.05). The axillary moisture ≥50% showed the sensitivity of 88%. The axillary moisture <30% showed the specificity of 91%. Use of a single cutoff value of 40% moisture produced the sensitivity of 59% and the specificity of 9%. As for the physical signs, dry axilla had also moderate sensitivity and excellent specificity to detect dehydration. CONCLUSIONS: The measurement of the axillary moisture could help assess dehydration. Dehydration could be ruled out when the axillary moisture ≥50%, while it could be ruled-in when the axillary moisture is <30%.

Physical signs of dehydration in the elderly.

OBJECTIVE: Dehydration is a common condition and frequent cause of hospitalization in older people, despite the caregiver's high attention in attempt to avoid its occurrence. In this study, various physical signs were examined as clinical signs of dehydration in elderly. METHODS: A prospective observational study was conducted in an acute care teaching hospital. Consecutive elderly patients who were admitted to the Department of Medicine were evaluated. Dehydration was defined as a calculated serum osmolality above 295 mOsm/L. The patients diagnosed as dehydrated or not dehydrated were observed for physical signs of dehydration. Data of blood and urine chemistry analysis were also compared between the two groups. RESULTS: A total of 27 elderly patients admitted with acute medical conditions were included in this study. For the physical signs, dry axilla had moderate sensitivity (44%) and excellent specificity (89%) to detect dehydration. Sunken eyes and delayed capillary refill time also showed relatively good specificity (83%). For laboratory data, the mean concentrations of serum sodium of the dehydrated group (146 mEq/L) was significantly higher (p<0.01) than those of the non-dehydrated group (134 mEq/L). CONCLUSION: Physical signs of dehydration in elderly showed relatively good specificity but poor sensitivity. The evaluation of the axillary moisture could help assess dehydration as well as laboratory data analysis such as serum sodium concentration.

Transcatheter arterial chemoembolization with DSM for primary hepatic malignant carcinoid.

A 66-year-old male with multiple liver tumors was diagnosed as having malignant carcinoid. The case exhibited carcinoid syndrome with wheezing and high urine 5-Hydroxy-Indole Acetic Acid and serum serotonin concentrations. A search for the primary lesion failed to detect tumors except those in the liver, leading to the diagnosis of primary hepatic carcinoid. Repeated transcatheter arterial chemoembolization with degradable starch microspheres decreased the tumors in size and improved the subjective symptoms. Transcatheter arterial chemoembolization with degradable starch microspheres is a useful treatment for unresectable malignant carcinoid of liver origin.

CT and MRI findings with contrast enhancement of small pancreatic adenocarcinoma in the late phase.

A 60-year-old female was found to have high serum amylase concentrations at a medical check-up. Dynamic computed tomography and magnetic resonance imaging demonstrated a mass in the body of the pancreas, which was enhanced in the late phase of the scans by administration of a contrast medium. Endoscopic retrograde pancreatography showed a stenosis of the main pancreatic duct at the body, and brushing cytology from the region revealed adenocarcinoma. Distal pancreatectomy was performed. The tumor was a well-differentiated adenocarcinoma, measuring 15 x l0 mm. Fibrous tissues were sparsely distributed in the tumor, and there was an increase of dilated veins, in particular at the margin. Late-phase enhancement of the tumor with computed tomography or magnetic resonance imaging was considered to be correlated with this abundant vascular structure in the tumor. Marked tumor enhancement in the late phase might be a characteristic finding suggesting an early-stage pancreatic adenocarcinoma, which should be carefully checked.

Endothelin(B) receptor blocker inhibits high glucose-induced synthesis of fibronectin in human peritoneal mesothelial cells.

BACKGROUND: Long-term peritoneal dialysis using glucose-based dialysates is associated with peritoneal fibrosis. The object of this study was to investigate the hypothesis that endothelin (ET)-1, which is known to play an important role in various fibrotic diseases, may also be involved in peritoneal fibrosis using human peritoneal mesothelial cells (HPMC). METHODS: HPMC were cultured with 4% D- or L-glucose, or loaded with 10 nmol/L ET-1. In some experiments, the ETA receptor antagonist BQ-123, the ETB receptor antagonist BQ-788, and antioxidants 4-hydroxy-2,2,6,6-tetramethyl-piperidine 1-oxyl (TEMPOL) and diphenyleneiodium chloride (DPI) were used. mRNA expression of ET-1, ETA receptor, ETB receptor, and fibronectin (FN) was analyzed by real-time polymerase chain reaction (real-time PCR). The protein levels for FN and ET-1 were measured by ELISA. CM-H2DCFDA-sensitive reactive oxygen species (ROS) were evaluated by flow cytometry. RESULTS: D-Glucose significantly induced mRNA expression of ET-1 and the ETB receptor but not the ETA receptor. FN production under high glucose conditions was inhibited by BQ-788. ET-1 directly stimulated H PMC to increase mRNA expression of FN and CM-H2DCFDA-sensitive ROS production. BQ-788, TEMPOL, and DPI inhibited mRNA expression of FN induced by ET-1. CONCLUSION: The present study suggests that high-glucose-induced FN synthesis is mediated by the ET-1/ETB receptor pathway and, therefore, an ETB receptor antagonist may be usefulin preventing FN production in HPMC.

FGF19-FGFR4 signaling elaborates lens induction with the FGF8-L-Maf cascade in the chick embryo.

The fibroblast growth factor (FGF) family is known to be involved in vertebrate eye development. However, distinct roles of individual FGF members during eye development remain largely elusive. Here, we show a detailed expression pattern of Fgf19 in chick lens development. Fgf19 expression initiated in the forebrain, and then became restricted to the distal portion of the optic vesicle abutting the future lens placode, where FGF receptor 4 (Fgfr4), a receptor for FGF19, was expressed. Fgf8, a positive regulator for L-Maf, was expressed in a portion of the optic vesicle. To examine the role of FGF19 signaling during early eye development, Fgf19 was misexpressed near the presumptive lens ectoderm; however, no alteration in the expression of lens marker genes was observed. Conversely, a secreted form of FGFR4 was misexpressed to inhibit an FGF19 signal, resulting in the induction of L-Maf expression. To further define the relationship between L-Maf and Fgf19, L-Maf misexpression was performed, resulting in ectopic induction of Fgf19 expression by Hamburger and Hamilton's stage 12/13. Furthermore, misexpression of Fgf8 induced Fgf19 expression in addition to L-Maf. These results suggest that FGF19-FGFR4 signaling plays a role in early lens development in collaboration with FGF8 signaling and L-Maf transcriptional system.

A dual role of FGF10 in proliferation and coordinated migration of epithelial leading edge cells during mouse eyelid development.

The development of the eyelid requires coordinated cellular processes of proliferation, cell shape changes, migration and cell death. Mutant mice deficient in the fibroblast growth factor 10 (Fgf10) gene exhibit open-eyelids at birth. To elucidate the roles of FGF10 during eyelid formation, we examined the expression pattern of Fgf10 during eyelid formation and the phenotype of Fgf10-null eyelids in detail. Fgf10 is expressed by mesenchymal cells just beneath the protruding epidermal cells of the nascent eyelid. However, Fgf10-null epithelial cells running though the eyelid groove do not exhibit typical cuboid shape or sufficient proliferation. Furthermore, peridermal clumps are not maintained on the eyelid leading edge, and epithelial extension does not occur. At the cellular level, the accumulation of actin fibers is not observed in the mutant epithelial leading edge. The expression of activin/inhibin betaB (ActbetaB/Inhbb) and transforming growth factor alpha (Tgfa), previously reported to be crucial for eyelid development, is down-regulated in the mutant leading edge, while the onset of sonic hedgehog (Shh) expression is delayed on the mutant eyelid margin. Explant cultures of mouse eyelid primordia shows that the open-eyelid phenotype of the mutant is reduced by exogenous FGF10 protein, and that the expression of ActbetaB and Tgfa is ectopically induced in the thickened eyelid epithelium by the FGF10 protein. These results indicate a dual role of FGF10 in mouse eyelid development, for both proliferation and coordinated migration of eyelid epithelial cells by reorganization of the cytoskeleton, through the regulation of activin, TGFalpha and SHH signaling.

Expression of Fibroblast growth factor 19 (Fgf19) during chicken embryogenesis and eye development, compared with Fgf15 expression in the mouse.

The normal development of eyes relies on proper signaling through Fibroblast growth factor (FGF) receptors, but the source and identity of cognate ligands have remained largely unknown. We have found that Fgf19 is expressed in the developing chicken retina. In situ hybridization discloses dynamic expression patterns for Fgf19 in the optic vesicle, lens primordia and retinal horizontal cells. Overall expression pattern of Fgf19 during chicken embryogenesis was also examined: Fgf19 is expressed in the regions associated with cranial placodes induction, boundary regions of rhombomeres, somites, specific groups of neural cells in midbrain, hindbrain, and those derived from epibranchial placodes, and the apical ectodermal ridge of limb buds. Expression pattern of the Fgf19-orthologous gene Fgf15 was further examined in the mouse developing eye. Fgf15 is expressed in the optic vesicle, a subset of progenitor cells of neural retina, and emerging ganglion and amacrine cells during retinogenesis.