Larotrectinib versus infigratinib for adult patients with both glioma and tyrosine kinase alterations after failure of initial therapies: Efficacy and safety analysis

Abstract Objectives To compare the efficacy and safety of larotrectinib with those of infigratinib in adult glioma patients with tyrosine kinase alterations. Methods Patients received oral infigratinib 125 mg (IN cohort, n = 125) or oral larotrectinib (LB cohort, n = 105) until unacceptable toxicity or disease progression. Results Duration of treatment was longer in the LB cohort than in the IN cohort (8 [9.5-6.25] months vs. 5.5 [6-5.25] months, p < 0.0001). Patients with partial responses (p = 0.0424) and overall survival (p = 0.03) were higher in the IN cohort than those in the LB cohort. The number of patients with disease progression was higher in the LB cohort (p = 0.0015). All the patients reported diarrhea, fatigue, vomiting, constipation, and decreased appetite. Patients in the IN cohort reported hyperphosphatemia, hyperlipasemia, stomatitis, dry skin, alopecia, dyspepsia, onycholysis, palmar-plantar erythrodysesthesia, nail disorders, and dry eyes. Patients in the LB cohort reported upper respiratory tract infections, pyrexia, cough, anemia, bacterial/viral infections, conjunctivitis, urinary tract infections, headaches, ataxia, dizziness, and muscle tremors. A total of 30 (24 %) and 40 (38 %) patients from the IN and the LB cohorts died at the follow-up of 18 months (p = 0.03). Patients who received bevacizumab initial therapy had higher overall survival (p = 0.048). Conclusions Infigratinib has higher efficacy and overall survival than larotrectinib but has higher adverse effects in the management of both glioma and tyrosine kinase alterations after failure of initial therapies. Initial bevacizumab therapy is associated with a higher overall survival.

Study on the serum level of CoQ10B in patients with Moyamoya disease and its mechanism of affecting disease progression / Estudo sobre o nível sérico de CoQ10B em pacientes com doença de Moyamoya e seu mecanismo de afetar a progressão da doença

ABSTRACT Background: At present, the etiology and pathogenesis of Moyamoya disease (MMD) are not completely clear. Patients are usually diagnosed after cerebrovascular events. Therefore, it is of great clinical significance to explore the predictive factors of MMD. Objective: This study aimed to investigate the serum level of CoQ10B, the amount of endothelial progenitor cells (EPCs), and mitochondrial function of EPCs in MMD patients. Methods: Forty-one MMD patients and 20 healthy controls were recruited in this study. Patients with MMD were divided into two groups: Ischemic type (n=23) and hemorrhagic type (n=18). Blood samples were collected from the antecubital vein and analyzed by CoQ10B ELISA and flow cytometry. Measures of mitochondrial function of EPCs include oxygen consumption rate (OCR), mitochondrial membrane potential, Ca2+ concentration, adenosine triphosphatases activity and ROS level. Results: The serum CoQ10B level in MMD patients was significantly lower than that in healthy controls (p<0.001). The relative number of EPCs in MMD patients was significantly higher than that in healthy controls (p<0.001). Moreover, the OCR, mitochondrial membrane potential and ATPase activity were decreased and the Ca2+ and reactive oxygen species levels were increased in MMD patients (p<0.001). Conclusions: Our results showed obviously decreased serum CoQ10B level and increased EPCs number in patients with MMD compared with healthy patients, and the mitochondria function of EPCs in MMD patients was abnormal.

RESUMO Antecedentes: No momento, a etiologia e a patogênese da doença de Moyamoya (DMM) não são completamente claras. Os pacientes geralmente são diagnosticados após eventos cerebrovasculares. Sendo assim, é de grande importância clínica explorar os fatores preditivos de DMM. Objetivo: Este estudo teve como objetivo investigar o nível sérico de CoQ10B, a quantidade de células progenitoras endoteliais (CPE) e a função mitocondrial de CPE em pacientes com DMM. Métodos: Quarenta e um pacientes com DMM e 20 controles saudáveis foram recrutados neste estudo. Aqueles com DMM foram divididos em dois grupos: tipo isquêmico (n=23) e tipo hemorrágico (n=18). Amostras de sangue foram coletadas da veia antecubital e analisadas por CoQ10B Ensaio de Imunoadsorção Enzimática (ELISA) e citometria de fluxo. As medidas da função mitocondrial de CPE incluem taxa de consumo de oxigênio (TCO), potencial de membrana mitocondrial, concentração de Ca2+, atividade de adenosina trifosfatases (ATPase) e nível de espécies reativas de oxigênio (ROS). Resultados: O nível sérico de CoQ10B em pacientes com DMM foi significativamente menor do que em controles saudáveis (p<0,001). O número relativo de CPE em pacientes com MMD foi significativamente maior do que em controles saudáveis (p<0,001). Além disso, a TCO, o potencial de membrana mitocondrial e a atividade ATPase diminuíram e os níveis de Ca2+e ROS aumentaram em pacientes com MMD (p<0,001). Conclusões: Nossos resultados mostraram obviamente diminuição do nível sérico de CoQ10B e aumento do número de CPE em pacientes com DMM em comparação com pacientes saudáveis, e a função mitocondrial de CPE em pacientes com DMM estava anormal.

Use of flash glucose-sensing technology in patients with type 2 diabetes treated with liraglutide combined with CSII: a pilot study

Glycemic variability (GV) may be linked to the development of diabetic complications by inducing inflammation, oxidative stress, and endothelial dysfunction. Flash glucose monitoring (FGM) provides a novel method of continuously monitoring interstitial glucose levels for up to 14 days. This study randomly assigned poorly controlled type 2 diabetes mellitus patients treated with metformin and multiple daily injections of insulin (n=60) to either continuous subcutaneous insulin infusion (CSII) treatment or CSII in combination with liraglutide (CSII+Lira) treatment for 14 days during hospitalization. GV was assessed using a FGM system; weight and cardiometabolic biomarkers were also evaluated. The coefficient of variation was significantly reduced in the CSII+Lira group (P<0.001), while no significant change was observed in the CSII group. The changes differed significantly between the two groups in mean amplitude of glycemic excursions (P=0.004), standard deviation (P=0.006), and the percentage of time in the target range (4-10 mmol/L, P=0.005 and >10 mmol/L, P=0.028). The changes in mean of daily differences, interquartile range, and percentage of time in hypoglycemia (<3.3 mmol/L) and hyperglycemia (>13.9 mmol/L) identified by FGM showed no difference. Treatment with liraglutide increased serum adiponectin [33.5 (3.5, 47.7) pg/mL, P=0.003] and heme oxygenase-1 levels [0.4 (-0.0, 1.8) ng/mL, P=0.001] and reduced serum leptin levels [-2.8 (3.9) pg/mL, P<0.001]. Adding the glucagon-like peptide-1 analog liraglutide improved GV, weight, and some cardiometabolic risk markers. The FGM system is, therefore, shown to be a novel and useful method for glucose monitoring.

Malformation of Wharton′s duct with multiple sialoliths: a case report and literature review / 口腔疾病防治

Objective@#To explore the diagnosis and treatment of ductal malformations of the submandibular gland with multiple stones.@*Methods@# A case of a malformation of Wharton′s duct with multiple sialoliths according to the clinical data, diagnosis and treatment of the patient was analyzed retrospectively.@*Results@#The patient′s physical examination and CBCT showed a tumor on the left floor of the mouth. In this case, it was found that the mass was a malformation of Wharton′s duct with multiple sialoliths according to operative exploration. The postoperative pathological examination showed (left submaxillary) salivation gland tissue, duct dilation and duct epithelia hyperplasia, duct calculus, and a large number of lymphocytes proliferating around the duct; 1 month after the follow-up, the patient had healed well. Through literature review and analysis, it was found that cases of submandibular ductal malformation with multiple stones were rare and should be carefully differentiated from arteriovenous malformation at the base of the mouth. Calculi of the submandibular gland can be removed by incision through the oral submandibular duct or by combined resection of the submandibular gland and ductal calculi, and some smaller calculi can also be treated by endoscopy of the salivary gland. @* Conclusion@# In cases of submandibular ductal malformation with multiple stones, intraoral and extraoral incisions should be performed simultaneously to remove the associated ductal stones.

Clinical Observation of Zikun Decoction in Treatment of Syndrome of Yin Deficiency and Blood Dryness in Delayed Menorrhea Cycle Due to Decreasing Ovarian Reservation / 中国实验方剂学杂志

Objective:To observe the effect of Zikun decoction (ZKD) in treatment of Yin deficiency and blood dryness in delayed menorrhea due to decreasing ovarian reservation．Method:A total of 60 cases were randomly divided into two groups．The observation group was given ZKD orally，and the control group was treated with complex packing estradiol tablets/estradiol and dydrogestero for three months．The control group began to take medicine on the first day of menstruation for 28 days, while the observation group began to take medicine on the fifth day of menstruation, and stopped taking medicine on the first day of the next menstruation. Three menstrual cycles were followed up. The clinical syndrome scores, follicle-stimulating hormone (FSH), luteinizing hormone (LH), inhibin B (INHB), FSH/LH, Estradiol (E2), anti-müllerian hormone (AMH), and antral follicle count (AFC) scores of the patients before and after treatment were compared.Result:After treatment, there was no significant difference in clinical efficiency between observation group and control group, but the traditional Chinese medicine syndrome score of observation group was significantly reduced (P<0.05), observation group and control group had the same curative effect in improvement of FSH, FSH/LH, AMH and AFC (P<0.05), but ZKD was better than complex packing estradiol tablets/estradiol and dydrogestero in improvement of INHB.Conclusion:ZKD has a good treatment effect in the treatment of DOR. It can effectively improve patients' sex hormone levels, increase antral follicle count, improve the ovarian reserve function and promote menstruation.

Progress in evaluating the postoperative effect of cleft lip / 口腔疾病防治

@#The postoperative evaluation of cleft lip is an important means to improve the operation method and the effect of the restoration. In recent years, the methods of cleft lip repair, such as Chinese western rotary propulsion, reconstruction of labial and nasal muscle tension band+trefoil flap, etc., have been developed. However, at present, there are still many secondary deformities, such as obvious scars and alar collapse. In this paper, in a review of the previous literature, the existing methods, advantages and disadvantages, and the application of the evaluation of the postoperative effect of cleft lip were reviewed. To date, there are many methods that can be used to evaluate the effect of cleft lip surgery. These research methods can be divided into subjective evaluation and objective evaluation, such as subjective evaluation, direct measurement, photo measurement, and three-dimensional scanning measurement. Among them, the subjective evaluation is simple, but the reliability is poor, and this method is suitable for all patients with cleft lip. The direct measurement has a low cost and is only suitable for one-dimensional information measurement, but the accuracy is poor, so it is difficult to determine the endpoints. The time of the photo measurement method is short, which can avoid tissue deformation, but it is easy to produce errors; this method is suitable for patients with cleft lip who can cooperate. The three-dimensional scanning measurement has a high accuracy, is time consuming and is a simple method but has a high cost and is suitable for areas with appropriate equipment conditions. Overall, the evaluation of the postoperative effect of cleft lip surgery should combine subjective evaluation with objective evaluation, dynamic evaluation with static evaluation, and utilize long-term follow-up to obtain comprehensive and accurate information and provide a reference for clinicians to carry out cleft lip surgery.

Effect of lncRNA HULC knockdown on rat secreting pituitary adenoma GH3 cells

Pituitary adenoma is one of the most common tumors in the neuroendocrine system. This study investigated the effects of long non-coding RNAs (lncRNAs) highly up-regulated in liver cancer (HULC) on rat secreting pituitary adenoma GH3 cell viability, migration, invasion, apoptosis, and hormone secretion, as well as the underlying potential mechanisms. Cell transfection and qRT-PCR were used to change and measure the expression levels of HULC, miR-130b, and FOXM1. Cell viability, migration, invasion, and apoptosis were assessed using trypan blue staining assay, MTT assay, two-chamber transwell assay, Guava Nexin assay, and western blotting. The concentrations of prolactin (PRL) and growth hormone (GH) in culture supernatant of GH3 cells were assessed using ELISA. The targeting relationship between miR-130b and FOXM1 was verified using dual luciferase activity. Finally, the expression levels of key factors involved in PI3K/AKT/mTOR and JAK1/STAT3 pathways were evaluated using western blotting. We found that HULC was highly expressed in GH3 cells. Overexpression of HULC promoted GH3 cell viability, migration, invasion, PRL and GH secretion, as well as activated PI3K/AKT/mTOR and JAK1/STAT3 pathways. Knockdown of HULC had opposite effects and induced cell apoptosis. HULC negatively regulated the expression of miR-130b, and miR-130b participated in the effects of HULC on GH3 cells. FOXM1 was a target gene of miR-130b, which was involved in the regulation of GH3 cell viability, migration, invasion, and apoptosis, as well as PI3K/AKT/mTOR and JAK1/STAT3 pathways. In conclusion, HULC tumor-promoting roles in secreting pituitary adenoma might be via down-regulating miR-130b, up-regulating FOXM1, and activating PI3K/AKT/mTOR and JAK1/STAT3 pathways.

The characteristics of blood glucose fluctuations in patients with fulminant type 1 diabetes mellitus in the stable stage

ABSTRACT Objective: The aim was to characterize blood glucose fluctuations in patients with fulminant type 1 diabetes (FT1DM) at the stable stage using continuous blood glucose monitoring systems (CGMSs). Subjects and methods: Ten patients with FT1DM and 20 patients with classic type 1 diabetes mellitus (T1DM) (the control group) were monitored using CGMSs for 72 hours. Results: The CGMS data showed that the mean blood glucose (MBG), the standard deviation of the blood glucose (SDBG), the mean amplitude glycemic excursions (MAGE), the blood glucose areas and the percentages of blood glucose levels below 13.9 mmol/L were similar between the two groups. However, the percentage of blood glucose levels below 3.9 mmol/L was significantly higher in the FT1DM group compared to the T1DM group (p < 0.05). The minimum (Min) blood glucose level in the FT1DM group was significantly lower than that of the T1DM group (p < 0.05). Patients with FT1DM had severe dysfunction of the islet beta cells and alpha cells compared to patients with T1DM, as indicated by lower C-peptide values and higher glucagon/C-peptide values. Conclusion: In conclusion, patients with FT1DM at the stable stage were more prone to hypoglycemic episodes as recorded by CGMSs, and they had a greater association with severe dysfunction of both the beta and alpha islet cells compared to patients with T1DM.

Effects of low-dose recombinant human brain natriuretic peptide on anterior myocardial infarction complicated by cardiogenic shock

Abstract INTRODUCTION: The mortality due to cardiogenic shock complicating acute myocardial infarction (AMI) is high even in patients with early revascularization. Infusion of low dose recombinant human brain natriuretic peptide (rhBNP) at the time of AMI is well tolerated and could improve cardiac function. OBJECTIVE: The objective of this study was to evaluate the hemodynamic effects of rhBNP in AMI patients revascularized by emergency percutaneous coronary intervention (PCI) who developed cardiogenic shock. METHODS: A total of 48 patients with acute ST segment elevation myocardial infarction (STEMI) complicated by cardiogenic shock and whose hemodynamic status was improved following emergency PCI were enrolled. Patients were randomly assigned to rhBNP (n=25) and control (n=23) groups. In addition to standard therapy, study group individuals received rhBNP by continuous infusion at 0.005 µg kg−1 min−1 for 72 hours. RESULTS: Baseline characteristics, medications, and peak of cardiac troponin I (cTnI) were similar between both groups. rhBNP treatment resulted in consistently improved pulmonary capillary wedge pressure (PCWP) compared to the control group. Respectively, 7 and 9 patients died in experimental and control groups. No drug-related serious adverse events occurred in either group. CONCLUSION: When added to standard care in stable patients with cardiogenic shock complicating anterior STEMI, low dose rhBNP improves PCWP and is well tolerated.

Risk of congenital anomalies associated with antithyroid treatment during pregnancy: a meta-analysis

To evaluate the association of either propylthiouracil or methimazole treatment for hyperthyroidism during pregnancy with congenital malformations, relevant studies were identified by searching Medline, PubMed, the Cochrane Library and EMBASE. We intended to include randomized controlled trials, but no such trials were identified. Thus, we included cohort studies and case-control studies in this meta-analysis. A total of 7 studies were included in the meta-analyses. The results revealed an increased risk of birth defects among the group of pregnant women with hyperthyroidism treated with methimazole compared with the control group (odds ratio 1.76, 95% confidence interval 1.47-2.10) or the non-exposed group (odds ratio 1.71, 95% confidence interval 1.39-2.10). A maternal shift between methimazole and propylthiouracil was associated with an increased odds ratio of birth defects (odds ratio 1.88, 95% confidence interval 1.27-2.77). An equal risk of birth defects was observed between the group of pregnant women with hyperthyroidism treated with propylthiouracil and the non-exposed group (odds ratio 1.18, 95% confidence interval 0.97-1.42). There was only a slight trend towards an increased risk of congenital malformations in infants whose mothers were treated with propylthiouracil compared with in infants whose mothers were healthy controls (odds ratio 1.29, 95% confidence interval 1.07-1.55). The children of women receiving methimazole treatment showed an increased risk of adverse fetal outcomes relative to those of mothers receiving propylthiouracil treatment. We found that propylthiouracil was a safer choice for treating pregnant women with hyperthyroidism according to the risk of birth defects but that a shift between methimazole and propylthiouracil failed to provide protection against birth defects. .

Predictive value of pediatrics end-stage liver disease or model for end-stage liver disease score in the prognosis of pediatric acute liver failure treated with artificial liver support system / 中华儿科杂志

<p><b>OBJECTIVE</b>To investigate the predictive value of pediatrics end-stage liver disease (PELD) or the model for end-stage liver disease (MELD) in the prognosis of pediatric acute liver failure (PALF) treated with artificial liver support system (ALSS).</p><p><b>METHOD</b>The clinical data of 47 children with acute liver failure seen from August 2008 to July 2013 treated in Children's Hospital, Fudan University were analyzed. Thirty children were treated with ALSS in addition to conventional comprehensive medical treatment (ALSS group). Seventeen children were treated with only conventional comprehensive medical treatment (control group). The main biochemical parameters and coagulation function parameters before and after treatment were compared in the ALSS group and the mortality rates were compared between the two groups. The patients were graded by PELD or MELD when they were hospitalized and the relationship of PELD or MELD scores and mortalities of child patients with the receiver operating characteristic curve (ROC) were analyzed.</p><p><b>RESULT</b>There were significant differences in total bilirubin (TB) ((302 ± 208) vs. (161 ± 129) µmol/L); alanine aminotransferase (ALT) ((161 ± 225) vs. (761 ± 834) U/L); aspartate aminotransferase ( AST) (66 (35, 123 ) vs. 447 (184, 1,129 ) U/L) ; international normalized ratio (INR) ((2.6 ± 1.6) vs. (5.1 ± 4.0)); prothrombin time activity percentage (PTA) ((42 ± 25)% vs. (22 ± 13)%); albumin( ALB) ((35 ± 5) vs. (33 ± 6) g/L) in the ALSS group after treatment. Through the ROC curve analysis, the best PELD/MELD threshold was 25 to predict the patients survival after ALSS therapy, with a sensitivity of 92. 3% , and a specificity of 94.1% at the cutoff point. The area under the ROC curve was 0. 912. The mortality of patients with PELD or MELD score below 25 in the ALSS group (1/13) was lower than the control group (3/4) (P = 0.022), and the mortality of patients with PELD or MELD score over 25 (16/17) was higher than that of the control group (10/13) (P = 0.290).</p><p><b>CONCLUSION</b>PELD or MELD score is a valid index in prognostic evaluation of ALSS therapy, which may provide an evidence for the therapeutic strategies of PALF. Patients with PELD or MELD score below 25 treated with ALSS obtained more benefit.</p>