Purpose
To estimate the maximum tolerated dose (MTD) and/or identify the recommended Phase II dose (RP2D) for combined INC280 and buparlisib in patients with recurrent glioblastoma with homozygous ...phosphatase and tensin homolog (PTEN) deletion, mutation or protein loss.
Methods
This multicenter, open-label, Phase Ib/II study included adult patients with glioblastoma with mesenchymal-epithelial transcription factor (c-Met) amplification. In Phase Ib, patients received INC280 as capsules or tablets in combination with buparlisib. In Phase II, patients received INC280 only. Response was assessed centrally using Response Assessment in Neuro-Oncology response criteria for high-grade gliomas. All adverse events (AEs) were recorded and graded.
Results
33 patients entered Phase Ib, 32 with altered PTEN. RP2D was not declared due to potential drug–drug interactions, which may have resulted in lack of efficacy; thus, Phase II, including 10 patients, was continued with INC280 monotherapy only. Best response was stable disease in 30% of patients. In the selected patient population, enrollment was halted due to limited activity with INC280 monotherapy. In Phase Ib, the most common treatment-related AEs were fatigue (36.4%), nausea (30.3%) and increased alanine aminotransferase (30.3%). MTD was identified at INC280 Tab 300 mg twice daily + buparlisib 80 mg once daily. In Phase II, the most common AEs were headache (40.0%), constipation (30.0%), fatigue (30.0%) and increased lipase (30.0%).
Conclusion
The combination of INC280/buparlisib resulted in no clear activity in patients with recurrent PTEN-deficient glioblastoma. More stringent molecular selection strategies might produce better outcomes.
Trial registration
: NCT01870726.
The current diagnostics of fish allergy lack sufficient accuracy such that more reliable tests such as component-resolved diagnosis (CRD) are urgently needed. This study aimed at identifying fish ...allergens of salmon and grass carp and evaluating the sensitization pattern in fish allergic subjects from two distinct populations in Asia.
One hundred and three fish allergic subjects were recruited from Hong Kong (67 subjects) and Japan (46 subjects). Western blot and mass spectrometry were used to identify allergens from salmon and grass carp. Fish allergens were purified and tested against 96 sera on ELISA to analyze patients’ sensitization pattern. The protein profiles of salmon meat prepared under different cooking methods until core temperature reached 80 °C were evaluated by SDS-PAGE and mass spectrometry.
Three common allergens between salmon and grass carp, namely enolase, glycerldehyde-3-phosphate dehydrogenase (GAPDH) and parvalbumin, and two salmon-specific allergens collagen and aldolase were identified. Parvalbumin was the major allergen for both fishes showing an overall sensitization rate of 74.7%, followed by collagen (38.9%), aldolase (38.5%) and enolase (17.8%). Japanese subjects showed more diverse allergen sensitization pattern and more frequent IgE-binding to heat-labile salmon allergens. Compared with steaming and boiling, cooking by baking and frying retained more fish proteins inclusive of heat-labile allergens.
Fish allergic patients from different Asian populations show varying fish allergen sensitization profiles. The relevant extracts and components for diagnosis are population-dependent but parvalbumin and collagen are important biomarkers. Cooking methods modify allergen composition of salmon and appear to influence patients’ allergic manifestations.
Wide-field optical coherence tomographic angiography (OCTA) may provide insights to peripheral capillary dropout in eyes with diabetic retinopathy (DR).
To describe the diagnostic performance of ...wide-field OCTA with and without large vessel removal for assessment of DR in persons with diabetes.
This case-control study was performed from April 26, 2018, to April 8, 2019, at a single tertiary eye center in Singapore. Case patients were those with type 2 diabetes for more than 5 years and bilateral DR diagnosed by fundus imaging; control participants included those with no self-reported history of diabetes, a fasting glucose level within the normal range in the past year, and no ocular pathologic findings. A wide-field (12 × 12-mm2) fovea-centered scan was performed using a prototype swept source OCTA system. Retinal microvasculature was examined by separating the angiograms into large vessels, capillaries, and capillary dropout regions.
Area under the receiver operating characteristic curve (AUC) for DR severity discrimination using wide-field vascular metrics. Retinal perfusion density (RPD), capillary perfusion density (CPD), large vessel density (LVD), and capillary dropout density (CDD) were calculated. Low-contrast regions were excluded from the calculation.
A total of 49 eyes in 27 control participants (17 male 63.0%; mean SD age, 59.96 7.63 years; age range, 44-79 years) and 76 eyes in 47 patients with diabetes (29 male 61.7%; mean SD age, 64.36 8.08 years; range, 41-79 years) were included. Among eyes in patients with diabetes, 23 were in those with diabetes but no DR, 25 in those with mild nonproliferative DR, and 28 in those with moderate to severe nonproliferative DR. There was no difference in RPD, CPD, LVD, and CDD between the control group and the group with diabetes and no DR. There was a stepwise decrease in RPD, CPD, and CDD in the diabetes with no DR, mild nonproliferative DR, and moderate to severe nonproliferative DR groups, whereas LVD was not associated with DR staging. The nonproliferative DR group had decreased RPD, CPD, and CDD compared with the control group. The CPD had higher AUCs than RPD for discriminating diabetes with nonproliferative DR (combined mild and moderate to severe nonproliferative DR) vs no DM (AUC, 0.92 95% CI, 0.87-0.98 vs 0.89 95% CI, 0.83-0.95, P = .01), diabetes with no DR vs mild nonproliferative DR (AUC, 0.81 95% CI, 0.68-0.94 vs 0.77 95% CI, 0.64-0.91, P = .18), and mild nonproliferative DR vs moderate to severe nonproliferative DR (AUC, 0.82 95% CI, 0.71-0.94 vs 0.78 95% CI, 0.65-0.91, P = .01) but similar AUCs for no DM vs diabetes with no DR. The total perfusion density and CPD in wide-field OCTA had better discriminative power than the central 6 × 6-mm2 field (CPD, 0.89 95% CI, 0.83-0.95 vs 0.84 95% CI, 0.77-0.92, P = .06; total perfusion density, 0.93 95% CI, 0.87-0.98 vs 0.90 95% CI, 0.83-0.96, P = .06).
The findings suggest that wide-field OCTA provides information on microvascular perfusion and may be useful for detecting predominant peripheral capillary dropout in eyes with nonproliferative DR. A vascular selectivity approach excluding the large vessels may improve the discriminative power for different stages of DR.
Abstract Background The aim of this study is to determine whether preoperative portal vein flow velocity or size has any correlative effect on hemodynamic changes during clamping of the inferior vena ...cava in liver transplantation. Patients and Methods A total of 42 anesthesia charts of adult patients who underwent living donor liver transplantation (LDLT) were analyzed and compared retrospectively. Preoperative portal vein (PV) flow velocity and sizes were obtained using Doppler ultrasound. All changes in the hemodynamic data before and after clamping of the portal vein (PV) and inferior vena cava (IVC) were recorded and analyzed by linear regression. A P value of <.05 was considered significant. Results Heart rate (HR), mean arterial blood pressure (MAP), central venous pressure (CVP), cardiac output (CO), cardiac index (CI), and stroke volume (SV) before and after clamping of the PV and IVC were significantly different for as long as the PV and IVC were clamped. Linear regression analysis indicated that R2 of HR, MAP, CVP, CO, and CI in correlation with the PV velocity were 0.002, 0.035, 0.024, and 0.001; R2 of the PV diameter for HR, MAP, CVP, CO, and CI were 0.028, 0.01, 0.034, and 0.004. The changes in the percentages of cardiac output at 1- and 5-minute intervals after IVC clamping were not correlated significantly with either the preoperative flow velocity or the size of the PV. Conclusion Preoperative PV flow velocity and size are not correlated or associated with hemodynamic changes during IVC clamping in liver transplantation.
It is widely recognised that sorafenib inhibits a range of molecular targets in renal cell carcinoma (RCC). In this study, we aim to use patient-derived RCC xenografts to delineate the angiogenic and ...non-angiogenic molecular targets of sorafenib therapy for advanced RCC (aRCC).
We successfully generated three patient RCC-derived xenografts in severe combined immunodeficient mice, consisting of three different RCC histological subtypes: conventional clear cell, poorly differentiated clear cell RCC with sarcomatoid changes, and papillary RCC. This study also used clear cell RCC cells (786-0/EV) harbouring mutant VHL to investigate the clonogenic survival of cells transfected with survivin sense and antisense oligonucleotides.
All three xenografts retain their original histological characteristics. We reported that sorafenib inhibited all three RCC xenograft lines regardless of histological subtypes in a dose-dependant manner. Sorafenib-induced growth suppression was associated with not only inhibition of angiogenic targets p-PDGFR-β, p-VEGFR-2, and their downstream signalling pathways p-Akt and p-ERK, cell cycle, and anti-apoptotic proteins that include cyclin D1, cyclin B1, and survivin but also upregulation of proapoptotic Bim. Survivin knockdown by survivin-specific antisense-oligonucleotides inhibited colony formation and induced cell death in clear cell RCC cells.
This study has shed light on the molecular mechanisms of sorafenib in RCC. Inhibition of non-angiogenic molecules by sorafenib could contribute in part to its anti-tumour activities observed in vivo, in addition to its anti-angiogenic effects.
Abstract We describe the anesthetic management in a 56-year old man with hepatocellular carcinoma and cirrhosis who underwent liver transplantation (LT). Pretransplantation workup showed a 3-cm wide ...by 10-cm long infrarenal abdominal aortic aneurysm (AAA) with chronic dissection. He subsequently underwent living donor LT. The total operative time was 12 hours. The systolic blood pressure was maintained at normal levels. Severe hypertension was not noted. Hypotension noted during the anhepatic phase was managed with increased volume infusion and small doses (0.1 mg) of intravenous phenylephrine. Metabolic acidosis and ionized hypocalcemia were corrected accordingly. Total blood loss was 460 mL. Blood or blood products were not given. The intravascular volume was replaced with 1400 mL of 5% albumin and 10,610 mL of crystalloid. Extubation was performed in the intensive care unit at 12 hours after the operation. The postoperative course was unremarkable. The patient is alive at 3 years after LT. Patients with AAA undergoing LT present a challenge to the anesthesiologist because among the risk factors for rupture, blood pressure is the only factor under his or her control during the operation. If blood loss can be kept to a minimum and hemodynamic stability achieved, a chronically small dissected AAA may not be a contraindication to LT.
ABSTRACT Aims/Introduction Two Hong Kong Chinese non‐laboratory‐based prediabetes/diabetes mellitus (pre‐DM/DM) risk models were developed using logistic regression (LR) and machine learning, ...respectively. We aimed to evaluate the models' validity in case finding of pre‐DM/DM in a Chinese primary care (PC) population. We also evaluated the validity of a risk‐scoring algorithm derived from the LR model. Materials and Methods This was a cross‐sectional external validation study on Chinese adults, without a prior DM diagnosis, who were recruited from public/private PC clinics in Hong Kong. A total of 1,237 participants completed a questionnaire on the models' predictors. Of that, 919 underwent blood glucose testing. The primary outcome was the models' and the algorithm's sensitivity in finding pre‐DM/DM cases. The secondary outcomes were the models' and the algorithm's specificity, positive/negative predictive values, discrimination and calibration. Results The models' sensitivity were 0.70 (machine learning) and 0.72 (LR). Both showed good external discrimination (area under the receiver operating characteristic curve: machine learning 0.744, LR 0.739). The risks estimated by the models were lower than the observed incidence, indicating poor calibration. Both models were more effective among participants with lower pretest probabilities; that is, age 18–44 years. The algorithm's sensitivity was 0.77 at the cut‐off score of ≥16 out of 41. Conclusion This study showed the validity of the models and the algorithm for finding pre‐DM/DM cases in a Chinese PC population in Hong Kong. They can facilitate more cost‐effective identification of high‐risk individuals for blood testing to diagnose pre‐DM/DM in PC. Further studies should recalibrate the models for more precise risk estimation in PC populations.
The purpose of this study is to examine the reliability and validity of “Perceived Physical Literacy Instrument” (PPLI) questionnaire in adolescents.
Based on physical literacy literature, a 9-item ...instrument was developed for initial tests. The self-report measure was administered to 1945 adolescents in Hong Kong. Confirmatory factor analysis (CFA) was used to examine a three-factor structure of physical literacy. A chi-square difference test analysed several competing models and compared the results between the proposed models (i.e., a three-factor solution) and other alternative models (i.e., a one-factor or two-factor solution). Furthermore, the measurement invariance across gender groups was examined by using multiple-group confirmatory factor analysis. Mean scores for physical literacy factors were also examined by demographic characteristics.
Confirmatory factor analysis (CFA) showed that the construct demonstrated a good fit to the model. For convergent validity, our results, evaluating the factor loading of each items, the values of composite reliability (CR) and the average variance extracted (AVE) of the three factors, revealed that the three-factor validity of physical literacy was satisfactory. The chi-square difference test between models was significant indicating that all the latent variables had satisfactory discriminant validity. Moreover, the findings of measurement invariance showed that the PPLI is invariant across gender.
The PPLI thus appeared to be reliable and valid as a measure of the perceived physical literacy of adolescents. Thus, along with other validated instruments, protocols and research designs, the PPLI could be widely used to test adolescents' self-perception of physical literacy and their own physical and mental health conditions and thereby health. Physical education professionals may thus recommend appropriate intervention programmes for younger generations.
The ultrafast quasiparticle dynamics of Fe1+ySe1−xTex single crystals were investigated by dual-color transient reflectivity measurements (ΔR R) from 4.3 to 290 K. The electron-phonon coupling ...strength λ (=0.16-0.01) and the temperature-dependent energy of longitudinal-acoustic phonons were, respectively, obtained from the relaxation time of a fast component and the period of an oscillation component in ΔR R. Such a small λ demonstrates the unconventional origin of superconductivity in FeSe. Moreover, the temperature-dependent ΔR R exhibits anomalous changes at Tc, 90 K and 230 K, unambiguously revealing the phase transition as well as the phonon softening via the magnetoelastic effect.
PDF
