Low-Grade, Multiple, Ta Non-muscle-Invasive Bladder Tumors: Tumor Recurrence and Worsening Progression

Abstract

Nearly half of newly diagnosed cases of bladder cancer are low grade, noninvasive, and papillary tumors. The standard treatment for non-muscle-invasive bladder cancer (NMIBC) has been transurethral resection of the bladder tumor (TUR-BT) with or without adjuvant intravesical instillation (IVI) of chemotherapy or Bacillus Calmette-Guerin (BCG) therapy. NMIBC is known to be associated with high rates of recurrence and risk of progression. In this study, we have retrospectively analyzed the clinical outcome of initially diagnosed multiple low-grade Ta tumors, with a special focus on tumor recurrence and worsening progression (WP) pattern. We retrospectively reviewed 42 patients with primary, multiple, low-grade Ta bladder cancer. We defined WP as confirmed high-grade Ta, all T1 or Tis/concomitant CIS of bladder recurrence, upper urinary tract recurrence (UTR), or progression to equal to or more than T2. The associations between clinico-pathological factors and tumor recurrence as well as WP pattern were analyzed. Tumor recurrence and WP occurred in 23 (54.76%) and 8 (19.04%) patients during follow-up (median follow-up: 57.38 months), respectively. WP to high grade/stage was seen in 8 patients. Multivariate analysis demonstrated that use of tobacco (p < 0.0001) and absence of IVI (p < 0.0001) were significant risk factors for tumor recurrence. The 5-year recurrence-free survival rate for non-tobacco users (74.0%) was significantly higher than that for tobacco users (42.5%, p = 0.0001), and also higher for patients receiving intravesical instillation (84.2 vs. 30.0% without IVI, p = 0.0001). Recurrence is common in patients with low-grade, Ta bladder cancer, especially in the setting of multiplicity. Recurrences occurred in 54.76% of patients and WP occurred in 19.04% of patients. Use of tobacco and non-use of IVI were strongly associated with high recurrence rate.

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Clinical translation and regulatory aspects of CAR/TCR-based adoptive cell therapies—the German Cancer Consortium approach

Abstract

Adoptive transfer of T cells genetically modified by TCRs or CARs represents a highly attractive novel therapeutic strategy to treat malignant diseases. Various approaches for the development of such gene therapy medicinal products (GTMPs) have been initiated by scientists in recent years. To date, however, the number of clinical trials commenced in Germany and Europe is still low. Several hurdles may contribute to the delay in clinical translation of these therapeutic innovations including the significant complexity of manufacture and non-clinical testing of these novel medicinal products, the limited knowledge about the intricate regulatory requirements of the academic developers as well as limitations of funds for clinical testing. A suitable good manufacturing practice (GMP) environment is a key prerequisite and platform for the development, validation, and manufacture of such cell-based therapies, but may also represent a bottleneck for clinical translation. The German Cancer Consortium (DKTK) and the Paul-Ehrlich-Institut (PEI) have initiated joint efforts of researchers and regulators to facilitate and advance early phase, academia-driven clinical trials. Starting with a workshop held in 2016, stakeholders from academia and regulatory authorities in Germany have entered into continuing discussions on a diversity of scientific, manufacturing, and regulatory aspects, as well as the benefits and risks of clinical application of CAR/TCR-based cell therapies. This review summarizes the current state of discussions of this cooperative approach providing a basis for further policy-making and suitable modification of processes.

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Nuclear pseudoinclusions in melanoma cells: prognostic fact or artifact? The possible role of Golgi phosphoprotein 3 overexpression in nuclear pseudoinclusions generation

Nuclear pseudoinclusions (NPIs) are classically found in papillary thyroid carcinoma and meningioma. Although NPIs have been described in melanocytic lesions, there is no systematic analysis of potential relationship between NPIs and other clinicopathological characteristics of melanoma. We examined the presence of NPIs in H&E-stained tissue sections form 96 melanomas and analyzed statistical associations with important clinicopathological parameters and tissue immunoreactivity for selected proteins involved in epithelial-mesenchymal transition (SPARC, N-cadherin), cell adhesion and mobility (ALCAM, ADAM-10), regulation of mitosis (PLK1), cell survival (FOXP1) and functioning of Golgi apparatus (GOLPH3, GP73). NPIs were observed in 20% of melanomas and their presence correlated with high mitotic rate and ulceration of the tumor, but not with Breslow thickness, histologic type, or presence of metastases. We observed a significant correlation with shorter cancer-specific survival, but not disease-free survival. Presence of NPIs was related to high expression of GOLPH3 in melanoma cells, whereas their absence was linked to enhanced immunoreactivity of GOLPH3 in tumor-associated macrophages. NPIs are not an uncommon finding in skin melanoma and their diagnostic and prognostic utility could be helpful in the daily routine histopathological practice. The possible explanation of NPI generation is associated with enhanced activity of Golgi apparatus in melanoma cells.

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Clinical translation and regulatory aspects of CAR/TCR-based adoptive cell therapies—the German Cancer Consortium approach

Abstract

Adoptive transfer of T cells genetically modified by TCRs or CARs represents a highly attractive novel therapeutic strategy to treat malignant diseases. Various approaches for the development of such gene therapy medicinal products (GTMPs) have been initiated by scientists in recent years. To date, however, the number of clinical trials commenced in Germany and Europe is still low. Several hurdles may contribute to the delay in clinical translation of these therapeutic innovations including the significant complexity of manufacture and non-clinical testing of these novel medicinal products, the limited knowledge about the intricate regulatory requirements of the academic developers as well as limitations of funds for clinical testing. A suitable good manufacturing practice (GMP) environment is a key prerequisite and platform for the development, validation, and manufacture of such cell-based therapies, but may also represent a bottleneck for clinical translation. The German Cancer Consortium (DKTK) and the Paul-Ehrlich-Institut (PEI) have initiated joint efforts of researchers and regulators to facilitate and advance early phase, academia-driven clinical trials. Starting with a workshop held in 2016, stakeholders from academia and regulatory authorities in Germany have entered into continuing discussions on a diversity of scientific, manufacturing, and regulatory aspects, as well as the benefits and risks of clinical application of CAR/TCR-based cell therapies. This review summarizes the current state of discussions of this cooperative approach providing a basis for further policy-making and suitable modification of processes.

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Depression score changes in response to sleep disordered breathing treatment with positive airway pressure in a large clinic-based cohort

Abstract

Objective

The clinical-population impact of positive airway pressure (PAP) on depressive symptoms in sleep disordered breathing (SDB) awaits clear documentation. We hypothesized that depressive symptoms improve in response to PAP treatment in a large clinical setting, and that lower socio-economic status poses barriers to full therapeutic response.

Method

We performed a retrospective cohort study of SDB patients attending a tertiary ambulatory sleep center between January 1, 2010 and December 31, 2015. Data extracted from electronic health records included Patient Health Questionnaire-9 (PHQ-9) scores, demographic characteristics, PAP adherence, and medical history. Paired- and two-sample t tests were utilized to assess changes in PHQ-9 score according to PAP adherence. Linear regression models were constructed to evaluate the association of socioeconomic status (SES) and other clinical variables on PHQ-9 scores.

Results

The cohort consisted of 1981 SDB patients (56.4 ± 13.3 years; 45.7% female; 76.2% Caucasian). Regardless of adherence, PAP therapy improved PHQ-9 scores (− 2.4 ± 4.6, p < 0.0001), with more robust responses in patients with baseline PHQ-9 scores > 10 (− 4.8 ± 5.7; p < 0.0001). Adherent patients had significantly greater improvement (− 2.8 ± 4.4 vs. 1.6 + 4.2, p < 0.0001), and even greater benefit if baseline PHQ-9 was > 10 (−6.0 ± 5.3 vs. − 3.8 ± 4.9, p < 0.001). Patients from lower socioeconomic status and greater depressive symptom had worse post-PAP PHQ-9 scores.

Conclusions

PAP therapy and adherence were associated with improvement in depressive symptom severity in this clinical cohort. Patients with lower socioeconomic status derived less therapeutic benefit, suggesting that they faced additional barriers to treatment effectiveness.

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Commentary on: Survival benefit of mantle cell lymphoma patients enrolled in clinical trials; a joint study from the LYSA group and French cancer registries

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MR arthrographic demonstration of an unusual multiplication anomaly concerning the glenohumeral ligaments

Abstract

The glenohumeral ligaments (GHLs), localized thickenings of the anterior joint capsule, are important passive stabilizers of the shoulder joint. A 29-year-old man was admitted for evaluation of left shoulder pain. The conventional magnetic resonance (MR) imaging showed a thickened anterior labroligamentous complex. MR arthrography revealed a multiplication anomaly of all the GHLs. The purpose of this study was to demonstrate the MR arthrography findings of this unusual anatomic variation of the GHLs.

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Depression score changes in response to sleep disordered breathing treatment with positive airway pressure in a large clinic-based cohort

Abstract

Objective

The clinical-population impact of positive airway pressure (PAP) on depressive symptoms in sleep disordered breathing (SDB) awaits clear documentation. We hypothesized that depressive symptoms improve in response to PAP treatment in a large clinical setting, and that lower socio-economic status poses barriers to full therapeutic response.

Method

We performed a retrospective cohort study of SDB patients attending a tertiary ambulatory sleep center between January 1, 2010 and December 31, 2015. Data extracted from electronic health records included Patient Health Questionnaire-9 (PHQ-9) scores, demographic characteristics, PAP adherence, and medical history. Paired- and two-sample t tests were utilized to assess changes in PHQ-9 score according to PAP adherence. Linear regression models were constructed to evaluate the association of socioeconomic status (SES) and other clinical variables on PHQ-9 scores.

Results

The cohort consisted of 1981 SDB patients (56.4 ± 13.3 years; 45.7% female; 76.2% Caucasian). Regardless of adherence, PAP therapy improved PHQ-9 scores (− 2.4 ± 4.6, p < 0.0001), with more robust responses in patients with baseline PHQ-9 scores > 10 (− 4.8 ± 5.7; p < 0.0001). Adherent patients had significantly greater improvement (− 2.8 ± 4.4 vs. 1.6 + 4.2, p < 0.0001), and even greater benefit if baseline PHQ-9 was > 10 (−6.0 ± 5.3 vs. − 3.8 ± 4.9, p < 0.001). Patients from lower socioeconomic status and greater depressive symptom had worse post-PAP PHQ-9 scores.

Conclusions

PAP therapy and adherence were associated with improvement in depressive symptom severity in this clinical cohort. Patients with lower socioeconomic status derived less therapeutic benefit, suggesting that they faced additional barriers to treatment effectiveness.

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Effect of finish line design on stress distribution in bilayer and monolithic zirconia crowns: a three-dimensional finite element analysis study

This study evaluated the influence of different finish line designs and abutment materials on the stress distribution of bilayer and monolithic zirconia crowns using three-dimensional finite element analysis (FEA). Three-dimensional models of two types of zirconia premolars – a yttria-stabilized zirconia framework with veneering ceramic and a monolithic zirconia ceramic – were used in the analysis. Cylindrical models with the finish line design of the crown abutments were prepared with three types of margin curvature radius (CR): CR = 0 (CR0; shoulder margin), CR = 0.5 (CR0.5; rounded shoulder margin), and CR = 1.0 (CR1.0; deep chamfer margin). Two abutment materials (dentin and brass) were analyzed. In the FEA model, 1 N was loaded perpendicular to the occlusal surface at the center of the crown, and linear static analysis was performed. For all crowns, stress was localized to the occlusal loading area as well as to the axial walls of the proximal region. The lowest maximum principal stress values were observed when the dentin abutment with CR0.5 was used under a monolithic zirconia crown. These results suggest that the rounded shoulder margin and deep chamfer margin, in combination with a monolithic zirconia crown, potentially have optimal geometry to minimize occlusal stress.

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Efficacy, safety and outcome of frameless image-guided robotic radiosurgery for brain metastases after whole brain radiotherapy

Abstract

Estimating efficacy, safety and outcome of frameless image-guided robotic radiosurgery for the treatment of recurrent brain metastases after whole brain radiotherapy (WBRT). We performed a retrospective single-center analysis including patients with recurrent brain metastases after WBRT, who have been treated with single session radiosurgery, using the CyberKnife® Radiosurgery System (CKRS) (Accuray Inc., CA) between 2011 and 2016. The primary end point was local tumor control, whereas secondary end points were distant tumor control, treatment-related toxicity and overall survival. 36 patients with 140 recurrent brain metastases underwent 46 single session CKRS treatments. Twenty one patients had multiple brain metastases (58%). The mean interval between WBRT and CKRS accounted for 2 years (range 0.2–7 years). The median number of treated metastases per treatment session was five (range 1–12) with a tumor volume of 1.26 ccm (mean) and a median tumor dose of 18 Gy prescribed to the 70% isodose line. Two patients experienced local tumor recurrence within the 1st year after treatment and 13 patients (36%) developed novel brain metastases. Nine of these patients underwent additional one to three CKRS treatments. Eight patients (22.2%) showed treatment-related radiation reactions on MRI, three with clinical symptoms. Median overall survival was 19 months after CKRS. The actuarial 1-year local control rate was 94.2%. CKRS has proven to be locally effective and safe due to high local tumor control rates and low toxicity. Thus CKRS offers a reliable salvage treatment option for recurrent brain metastases after WBRT.

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MR arthrographic demonstration of an unusual multiplication anomaly concerning the glenohumeral ligaments

Abstract

The glenohumeral ligaments (GHLs), localized thickenings of the anterior joint capsule, are important passive stabilizers of the shoulder joint. A 29-year-old man was admitted for evaluation of left shoulder pain. The conventional magnetic resonance (MR) imaging showed a thickened anterior labroligamentous complex. MR arthrography revealed a multiplication anomaly of all the GHLs. The purpose of this study was to demonstrate the MR arthrography findings of this unusual anatomic variation of the GHLs.

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Development and assessment of the Quality of Life in Childhood Epilepsy Questionnaire (QOLCE-16)

Summary

Objective

The aim of this study was to develop and validate a brief version of the Quality of Life in Childhood Epilepsy Questionnaire (QOLCE). A secondary aim was to compare the results described in previously published studies using the QOLCE-55 with those obtained using the new brief version.

Methods

Data come from 373 children involved in the Health-related Quality of Life in Children with Epilepsy Study, a multicenter prospective cohort study. Item response theory (IRT) methods were used to assess dimensionality and item properties and to guide the selection of items. Replication of results using the brief measure was conducted with multiple regression, multinomial regression, and latent mixture modeling techniques.

Results

IRT methods identified a bi-factor graded response model that best fits the data. Thirty-nine items were removed, resulting in a 16-item QOLCE (QOLCE-16) with an equal number of items in all 4 domains of functioning (Cognitive, Emotional, Social, and Physical). Model fit was excellent: Comparative Fit Index = 0.99; Tucker-Lewis Index = 0.99; root mean square error of approximation = 0.052 (90% confidence interval [CI] 0.041-0.064); weighted root mean square = 0.76. Results that were reported previously using the QOLCE-55 and QOLCE-76 were comparable to those generated using the QOLCE-16.

Significance

The QOLCE-16 is a multidimensional measure of health-related quality of life (HRQoL) with good psychometric properties and a short-estimated completion time. It is notable that the items were calibrated using multidimensional IRT methods to create a measure that conforms to conventional definitions of HRQoL. The QOLCE-16 is an appropriate measure for both clinicians and researchers wanting to record HRQoL information in children with epilepsy.

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Delayed myelination and neurodevelopment in male seizure-prone versus seizure-resistant rats

Summary

Objective

Aberrant myelination and developmental delay have been reported in epilepsy. However, it is unclear whether these are linked to intrinsic mechanisms that support a predisposition toward seizures and the development of epilepsy. Thus, we compared rates of myelination and neurodevelopment in male rats selectively bred for enhanced susceptibility to kindling epileptogenesis (FAST) with male rats bred for resistance (SLOW).

Methods

Myelin-specific gene expression was compared in the brainstem, cerebellum, and cerebral hemisphere of FAST and SLOW rats on postnatal days (PNDs) 5, 11, 17, 23, and 90 to determine strain-specific myelination rates. Myelin protein levels were also compared at PNDs 5 and 23 in the brainstem. Relative rates of neurodevelopment were evaluated between PNDs 5 and 21 using physical growth landmarks and neuromotor tests including righting reflex, cliff avoidance, negative geotaxis, and locomotor activity.

Results

Myelin-specific mRNA expression was significantly down-regulated in FAST rats on PNDs 5 and 11 in all 3 brain structures, indicating relatively delayed myelination. Likewise, corresponding protein levels were significantly lower in FAST brainstem on PND 5. Developmental delay was evident in the FAST strain such that only 9% of FAST pups, compared to 81% of SLOW, had open eyes by PND 13, locomotor activity was significantly reduced between PNDs 12 and 16, and neuromotor task acquisition was delayed between PNDs 5 and 10.

Significance

Relative delays in myelination and neurodevelopment co-occurred in the seizure-prone FAST strain in the absence of seizures. These findings suggest these symptoms are not seizure-induced and may be mechanistically linked to an underlying pathophysiology supporting a predisposition toward developing epilepsy.

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PCDH19-related epilepsy is associated with a broad neurodevelopmental spectrum

Summary

Objective

To characterize the features associated with PCDH19-related epilepsy, also known as "female-limited epilepsy."

Methods

We analyzed data from participants enrolled in the PCDH19 Registry, focusing on the seizure-related, developmental, neurobehavioral, and sleep-related features. We evaluated variants for pathogenicity based on previous reports, population databases, and in silico predictions, and included individuals with pathogenic or potentially pathogenic variants. We performed a retrospective analysis of medical records and administered a targeted questionnaire to characterize current or past features in probands and genotype-positive family members.

Results

We included 38 individuals with pathogenic or potentially pathogenic variants in PCDH19: 21 de novo, 5 maternally inherited, 7 paternally inherited, and 5 unknown. All 38 had epilepsy; seizure burden varied, but typical features of clustering of seizures and association with fever were present. Thirty individuals had intellectual disability (ID), with a wide range of severity reported; notably, 8/38 (22%) had average intellect. Behavioral and sleep dysregulation were prominent, in 29/38 (76%) and 20/38 (53%), respectively. Autistic features were present in 22/38 (58%), of whom 12 had a formal diagnosis of autism spectrum disorder. We had additional data from 5 genotype-positive mothers, all with average intellect and 3 with epilepsy, and from 1 genotype-positive father.

Significance

Our series represents a robust cohort with carefully curated PCDH19 variants. We observed seizures as a core feature with a range of seizure types and severity. Whereas the majority of individuals had ID, we highlight the possibility of average intellect in the setting of PCDH19-related epilepsy. We also note the high prevalence and severity of neurobehavioral phenotypes associated with likely pathogenic variants in PCDH19. Sleep dysregulation was also a major area of concern. Our data emphasize the importance of appropriate referrals for formal neuropsychological evaluations as well as the need for formal prospective studies to characterize the PCDH19-related neurodevelopmental syndrome in children and their genotype-positive parents.

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Nitrergic signaling via interstitial cells of Cajal and smooth muscle cells influences circular smooth muscle contractility in murine colon

Abstract

Background

Regulation of gastrointestinal motility involves excitatory and inhibitory neurotransmission. Nitric oxide (NO), the major inhibitory neurotransmitter, acts via its receptor NO-sensitive guanylyl cyclase (NO-GC). In the GI tract, NO-GC is expressed in several cell types such as smooth muscle cells (SMC) and interstitial cells of Cajal (ICC). Using cell-specific knockout mice, we have previously shown that NO-GC modulates spontaneous contractions in colonic longitudinal smooth muscle. However, its detailed role in the colonic circular smooth muscle is still unclear.

Methods

Myography was performed to evaluate spontaneous contractions in rings of proximal colon (2.5 mm) from global (GCKO) and cell-specific knockout mice for NO-GC. Immunohistochemistry and in situ hybridization were used to specify NO-GC expression.

Key results

Colonic circular smooth muscle showed three different contraction patterns: high-frequency ripples, slow phasic contractions, and large contractions. Ripples formed independently of NO-GC. Slow phasic contractions occurred intermittently in WT, SMC-GCKO, and ICC-GCKO tissue, whereas they were more prominent and prolonged in GCKO and SMC/ICC-GCKO tissue. Tetrodotoxin and the NO-GC inhibitor ODQ transformed slow phasic contractions of WT and single cell-specific knockout into GCKO-like contractions. ODQ increased the frequency of large contractions in WT and ICC-GCKO colon but not in GCKO, SMC-GCKO, and SMC/ICC-GCKO preparations. Tetrodotoxin and hexamethonium abolished large contractions.

Conclusions and Inferences

We conclude that short rings of murine colon can be effectively used to record spontaneous contractions. Although NO-GC in SMC determines smooth muscle tone, concerted action of NO-GC in both SMC and ICC modulates slow phasic contractions and large contractions.

Murine colonic circular smooth muscle showed three different contraction patterns: high frequency ripples, slow phasic contractions and large contractions. Ripples formed independently of NO/cGMP signaling whereas NO-sensitive guanylyl cyclase in smooth muscle cells and interstitial cells of Cajal modulated slow phasic contractions and large contractions. We conclude that short rings of murine colon can be effectively used to investigate nitrergic effects on spontaneous contractions.

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Quantitative measures of gingival recession and the influence of gender, race, and attrition

Gingival recession in dentitions with otherwise healthy periodontium is a common occurrence in adults. Recession is clinically measured using a periodontal probe to the nearest millimeter. The aim of this stud...

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Papilla-Crown Height Dimensions around Zirconium Dioxide Implants in the Esthetic Area: A 3-Year Follow-Up Study

Abstract

Purpose

Soft tissue interactions with ceramic dental implants have previously been shown to have favorable esthetic outcomes. This study aimed to evaluate the papilla-crown proportion around zirconia implants in a 3-year follow-up study and the correlation between the gingival biotype and changes in papillary height.

Materials and Methods

This was a prospective study of 39 patients with 40 single-gap implants (Straumann PURE Ceramic ZLA Implant). The papilla-crown proportion was assessed after 3 months, 1 year, and 3 years. In addition, correlations between the peri-implant biotypes and changes in papillary heights were evaluated.

Results

The papilla-crown proportion improved from 35.5% after 3 months to 41.7% after 3 years. The gingival biotype was correlated very weakly to papilla height alterations. Significant papillary fill was observed in the interdental space between 3 months and 3 years (p < 0.001).

Conclusions

An ideal papilla-crown proportion of 40% around single implants was observed after 3 years. A thin or thick gingival biotype showed a very weak correlation with soft tissue alterations.

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Clinical Effectiveness of 6.5-mm-Long Implants to Support Two-Implant Fixed Prostheses in Premolar-Molar Region: The Influence of Immediate Loading and the Length of Splinting Implant

Abstract

Purpose

The purpose of this retrospective clinical study was to assess the influence of immediate loading and lengths of splinted implants on the clinical effectiveness of 6.5-mm-long implants supporting two-implant fixed prostheses in the premolar-molar regions.

Materials and Methods

A clinical database was reviewed in a private dental center to select those patients who had 6.5-mm-long implants placed to support two-implant fixed partial prostheses in the premolar-molar regions of the maxilla and the mandible. All implants were immediately loaded. The study groups were defined according to the lengths of the implants. Two groups were identified: the short-short splinted group, when both implants had 6.5 mm lengths, and the short-long splinted group, when one implant was longer than 6.5 mm. A total of 48 dental implants were placed in 16 patients to support 24 two-implant fixed prostheses. The mean follow-up time was 14 ± 5 months. The short-short splinted group included 8 patients with 16 implants; the short-long splinted group included 16 patients with 32 implants. The main variable was implant survival, and secondary outcomes were marginal bone stability and prosthesis survival.

Results

The statistical analyses indicated an absence of significant differences between the two groups in terms of implant and prosthesis survival (100% for both groups and both variables); however, distal bone loss around the splinted implants was significantly higher in the short-long splinted group. Bone loss was 0.37 ± 0.55 mm in the short-short splinted group and 0.94 ± 0.66 mm in the short-long splinted group.

Conclusions

Immediate loading of short (6.5-mm-long) implants in the premolar-molar regions did not jeopardize their survival. Two-implant supported prostheses had the same clinical effectiveness, whether extra-short implants were splinted to another extra-short implant or to a longer one.

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Comparison of Flexural Strength of Different CAD/CAM PMMA-Based Polymers

Abstract

Purpose

To compare the flexural strength of different computer-aided design/computer-aided manufacturing (CAD/CAM) poly(methyl methacrylate)-based (PMMA) polymers and conventional interim resin materials after thermocycling.

Materials and Methods

Rectangular-shaped specimens (n = 15, for each material) (25 × 2 × 2 mm³) were fabricated from 3 CAD/CAM PMMA-based polymers (Telio CAD [T]; M-PM-Disc [M]; Polident–PMMA [P]), 1 bis-acrylate composite resin (Protemp 4 [PT]), and 1 conventional PMMA (ArtConcept Artegral Dentine [C]) according to ISO 10477:2004 Standards (Dentistry-Polymer-Based Crown and Bridge Materials). The specimens were subjected to 10,000 thermocycles (5 to 55°C). Three-point flexural strength of the specimens was tested in a universal testing machine at a 1.0 mm/min crosshead speed, and the flexural strength data (σ) were calculated (MPa). The flexural strength values were statistically analyzed using 1-way ANOVA, and Tukey HSD post-hoc test for multiple comparisons (α = 0.05).

Results

Flexural strength values ranged between 66.1 ± 13.1 and 131.9 ± 19.8 MPa. There were significant differences among the flexural strengths of tested materials, except for between T and P CAD/CAM PMMA-based polymers (p > 0.05). CAD/CAM PMMA-based polymer M had the highest flexural strength and conventional PMMA had the lowest (p < 0.05). CAD/CAM PMMA-based T and P polymers had significantly higher flexural strength than the bis-acrylate composite resin (p < 0.05), and conventional PMMA (p < 0.0001), and significantly lower flexural strength compared to CAD/CAM PMMA-based M (p < 0.05).

Conclusions

The flexural strength of CAD/CAM PMMA-based polymers was greater than the flexural strength of bis-acrylate composite resin, which had a greater flexural strength compared to conventional PMMA resin.

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Adverse effects of anti-epileptics in trigeminal neuralgiform pain

Background

Side effects of anti-epileptic drugs (AEDs) have not been adequately documented in trigeminal neuralgia and its variants. The aim of this observational cross-sectional study was to compare the A-B Neuropsychological Assessment Schedule (ABNAS), which measures cognitive side effects to the Adverse Events Profile (AEP), which looks at a broader range of side effects, and to investigate drug/dosage relationships with questionnaire scores to help determine a point at which a drug change would be indicated.

Methods

One hundred five patients were recruited from a facial pain clinic, over a 10-month period. Self-complete questionnaire scores were compared between patients using different AEDs.

Results

A-B Neuropsychological Assessment Schedule score correlated well with AEP indicating that cognitive side effects were a significant burden. Toxic range on the ABNAS was estimated to occur when scores were >43/72 (95% CI: 37.4-48.6). Polytherapy is weakly associated with the higher scores. Oxcarbazepine dosage was found to linearly correlate with AEP and ABNAS scores, better than carbamazepine dosage. Memory alteration was least common with lamotrigine and oxcarbazepine, and there was less association between fatigues with oxcarbazepine/pregabalin.

Conclusion

Anti-epileptic drugs have significant side effects. The ABNAS questionnaire is a useful tool along with the AEP to recognize and monitor AEDs' side effects and to help to adjust medications to optimal dosage.

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Diagnostic Value of Circulating Free DNA Integrity and Global Methylation Status in Gall Bladder Carcinoma

Abstract

The current study investigates the role of circulating free DNA (cfDNA) as a liquid biopsy in diagnosis gall bladder carcinoma (GBC) utilizing levels of long DNA fragments (ALU247) derived from tumor necrosis, short apoptotic fragments (ALU115) denoting total cfDNA and cfDNA integrity denoting ratio of ALU247 and ALU115. The global methylation status of cfDNA was also estimated with the hypothesis that these parameters provide a diagnostic distinction between cancer and non-cancer subjects, with higher or altered values favoring presence of malignancy. Study group included 60 cases of GBC and 36 controls including diseased controls (cholecystitis) and healthy subjects. Median levels of ALU115, ALU247 and cfDNA integrity were significantly different in GBC at 1790.88, 673.75, 0.4718 vs. controls at 840.73, 165.03, 0.1989 ng/ml respectively. Global DNA methylation was not significantly different between GBC at 0.679% and controls at 0.695%. The sensitivity and specificity of ALU 247 in discriminating GBC from controls was highest with a sensitivity, specificity and diagnostic accuracy of 80.0%, 86.1% and 82.2% respectively. Global DNA methylation showed lowest sensitivity of 55.0% and specificity of 50.0%. Clinico-pathological parameters showing significant association with cfDNA integrity, on ROC curve analysis, showed significant diagnostic discrimination of the tumor stage, lymphovascular invasion, disease stage and grade histology. This is a first time analysis of ALU115, ALU247 and cfDNA integrity in the diagnosis of GBC and confirms that the combination of ALU247 and cfDNA integrity provides good sensitivity, specificity and diagnostic accuracy in discriminating GBC from controls as well correlates with aggressive disease parameters.

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Metastatic Renal Cell Cancer—Systemic Therapy

Abstract

Management of metastatic renal cell carcinoma (mRCC) has evolved considerably in the past 10 years due to better understanding of tumor biology. This development has changed mRCC to a chronic progressive disease with several lines of treatment options. The introduction of several new targeted therapies including immunotherapy has improved median overall survival of approximately 1 year to >2 years in mRCC.

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Ultrasonographic assessment of pubertal breast development in obese children: compliance with the clinic

Journal Name: Journal of Pediatric Endocrinology and Metabolism
Issue: Ahead of print


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Late presentation of glycogen storage disease types Ia and III in children with short stature and hepatomegaly

Journal Name: Journal of Pediatric Endocrinology and Metabolism
Issue: Ahead of print


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Prosthetic energy return during walking increases after 3 weeks of adaptation to a new device

There are many studies that have investigated biomechanical differences among prosthetic feet, but not changes due to adaptation over time. There is a need for objective measures to quantify the process of ada...

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Over-expression of oncigenic pesudogene DUXAP10 promotes cell proliferation and invasion by regulating LATS1 and β-catenin in gastric cancer

Recently, the pesudogenes have emerged as critical regulators in human cancers tumorigenesis and progression, and been identified as a key revelation in post-genomic biology. However, the expression pattern, b...

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"Asian Pac J Cancer Prev"[jour]; +43 new citations

43 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Asian Pac J Cancer Prev"[jour]

These pubmed results were generated on 2018/01/28

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

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"Otolaryngol Head Neck Surg"[jour]; +24 new citations

24 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Otolaryngol Head Neck Surg"[jour]

These pubmed results were generated on 2018/01/28

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

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Blood Collection and Cell-Free DNA Isolation Methods Influence the Sensitivity of Liquid Biopsy Analysis for Colorectal Cancer Detection

Abstract

During colorectal cancer (CRC) development tumor-derived cell-free DNA (cfDNA) can be released into the bloodstream. Many different cfDNA isolation methods and specific blood collection tubes preventing the release of genomic DNA and stabilizing cfDNA with preservative reagents became available. These factors may affect greatly on the further liquid biopsy analyses. Our aim was to test different blood collection tubes and cfDNA isolation methods to determine whether these factors influence the cfDNA amount and the promoter methylation of four previously described hypermethylated biomarkers. Three manual isolation methods (High Pure Viral Nucleic Acid Large Volume Kit; Epi proColon 2.0 Kit; Quick-cfDNA™ Serum & Plasma Kit) and automated sample preparation systems (InviGenius and InviGenius PLUS) were examined. Furthermore, K3EDTA Vacuette tubes and Streck Cell-Free DNA BCT® tubes were compared. After cfDNA isolation and bisulfite conversion of samples, the methylation level of SFRP1, SFRP2, SDC2, and PRIMA1 were defined with MethyLight assays. We have ascertained that there are differences between the cfDNA amounts depending on the isolation methods. Higher cfDNA yield was observed using InviGenius system than column-based manual isolation method; however, InviGenius PLUS has produced lower cfDNA amounts. No remarkable variance could be found between K3EDTA and Streck tubes; slightly higher cfDNA quantity was detected in 60% of plasma samples using Streck tubes. In point of methylation level and frequency, manual column-based isolation produced more consistent results. Automated cfDNA extraction systems are easy-to-use and high-throughput; however, further improvements in the isolation protocols might lead to the increase of the sensitivity of further methylation analysis.

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"Otolaryngol Head Neck Surg"[jour]; +24 new citations

24 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Otolaryngol Head Neck Surg"[jour]

These pubmed results were generated on 2018/01/28

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

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"Asian Pac J Cancer Prev"[jour]; +43 new citations

43 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Asian Pac J Cancer Prev"[jour]

These pubmed results were generated on 2018/01/28

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

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Epstein–Barr virus strain heterogeneity impairs human T-cell immunity

Abstract

The Epstein–Barr virus (EBV) establishes lifelong infections in > 90% of the human population. Although contained as asymptomatic infection by the immune system in most individuals, EBV is associated with the pathogenesis of approximately 1.5% of all cancers in humans. Some of these EBV-associated tumors have been successfully treated by the infusion of virus-specific T-cell lines. Recent sequence analyses of a large number of viral isolates suggested that distinct EBV strains have evolved in different parts of the world. Here, we assessed the impact of such sequence variations on EBV-specific T-cell immunity. With the exceptions of EBNA2 and the EBNA3 family of proteins, an overall low protein sequence disparity of about 1% was noted between Asian viral isolates, including the newly characterized M81 strain, and the prototypic EBV type 1 and type 2 strains. However, when T-cell epitopes including their flanking regions were compared, a substantial proportion was found to be polymorphic in different EBV strains. Importantly, CD4+ and CD8+ T-cell clones specific for viral epitopes from one strain often showed diminished recognition of the corresponding epitopes in other strains. In addition, T-cell recognition of a conserved epitope was affected by amino acid exchanges within the epitope flanking region. Moreover, the CD8+ T-cell response against polymorphic epitopes varied between donors and often ignored antigen variants. These results demonstrate that viral strain heterogeneity may impair antiviral T-cell immunity and suggest that immunotherapeutic approaches against EBV should preferably target broad sets of conserved epitopes including their flanking regions.

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Final results of a phase I dose-escalation, dose-expansion study of adding disulfiram with or without copper to adjuvant temozolomide for newly diagnosed glioblastoma

Abstract

Disulfiram has shown promising activity including proteasome inhibitory properties and synergy with temozolomide in preclinical glioblastoma (GBM) models. In a phase I study for newly diagnosed GBM after chemoradiotherapy, we have previously reported our initial dose-escalation results combining disulfiram with adjuvant temozolomide and established the maximum tolerated dose (MTD) as 500 mg per day. Here we report the final results of the phase I study including an additional dose-expansion cohort of disulfiram with concurrent copper. The phase I study consisted of an initial dose-escalation phase of disulfiram 500–1000 mg daily during adjuvant temozolomide, followed by a dose-expansion phase of disulfiram 500 mg daily with copper 2 mg three times daily. Proteasome inhibition was assessed using fluorometric 20S proteasome assay on peripheral blood cell. A total of 18 patients were enrolled: 7 patients received 500 mg disulfiram, 5 patients received 1000 mg disulfiram, and 6 patients received 500 mg disulfiram with copper. Two dose-limiting toxicities occurred with 1000 mg disulfiram. At disulfiram 500 mg with or without copper, only 1 patient (7%) required dose-reduction during the first month of therapy. Addition of copper to disulfiram did not increase toxicity nor proteasome inhibition. The median progression-free survival was 4.5 months (95% CI 0.8–8.2). The median overall survival (OS) was 14.0 months (95% CI 8.3–19.6), and the 2-year OS was 24%. The MTD of disulfiram at 500 mg daily in combination with adjuvant temozolomide was well tolerated by GBM patients, but 1000 mg daily was not. Toxicity and pharmacodynamic effect of disulfiram were similar with or without concurrent copper. The clinical efficacy appeared to be comparable to historical data. Additional clinical trials to combine disulfiram and copper with chemoradiotherapy or to resensitize recurrent GBM to temozolomide are ongoing.

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Clinical and dosimetric study of radiotherapy for glioblastoma: three-dimensional conformal radiotherapy versus intensity-modulated radiotherapy

Abstract

Background and purpose

We aimed to compare three-dimensional conformal radiotherapy (3D-CRT) with intensity-modulated radiotherapy (IMRT) for the treatment of glioblastoma.

Materials and methods

Retrospective study of 220 patients with glioblastoma, treated with 3D-CRT or IMRT, with or without surgery. Dosimetric parameters as well as clinical and survival data for the two techniques were analyzed and compared.

Results

The median conformity index was 1.53 (range 0–2.69) for 3D-CRT and 1.25 (range 0.97–2.01) for IMRT, p < 10⁻⁴. The median homogeneity index was 0.10 (range 0.03–0.32) for 3D-CRT and 0.07 (range 0.03–0.18) for IMRT, p < 10⁻⁴. There were significantly fewer acute grade 1 and 2 neurological toxicities in the IMRT group especially for edema (1.3 versus 12.4%, p = 0.017), concentration disorders (6.6 versus 19.9%, p = 0.003) and consciousness disorders (2.6 versus 13.2%, p = 0.002) although IMRT patients had a significantly worse pre-treatment neurological status than 3D-CRT patients. Median survival was 16.0 months (range 11.9–17.8) for IMRT and 13.4 months (range 11.7–15.7) for 3D-CRT patients (p = 0.542).

Conclusion

IMRT improved target conformity and reduced neurological toxicities for patients with glioblastomas.

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The Global Spine Care Initiative: a narrative review of psychological and social issues in back pain in low- and middle-income communities

Abstract

Purpose

The purpose of this review was to describe psychological and social factors associated with low back pain that could be applied in spine care programs in medically underserved areas and low- and middle-income countries.

Methods

We performed a narrative review of cohort, cross-sectional, qualitative and mixed methods studies investigating adults with low back pain using Medline and PubMed were searched from January 2000 to June 2015. Eligible studies had at least one of the following outcomes: psychological, social, psychosocial, or cultural/ethnicity factors. Studies met the following criteria: (1) English language, (2) published in peer-reviewed journal, (3) adults with spinal disorders, (4) included treatment, symptom management or prevention.

Results

Out of 58 studies, 29 were included in this review. There are few studies that have evaluated psychological and social factors associated with back pain in low- and middle-income communities, therefore, adapting recommendations from other regions may be needed until further studies can be achieved.

Conclusion

Psychological and social factors are important components to addressing low back pain and health care providers play an important role in empowering patients to take control of their spinal health outcomes. Patients should be included in negotiating their spinal treatment and establishing treatment goals through careful listening, reassurance, and information providing by the health care provider. Instruments need to be developed for people with low literacy in medically underserved areas and low- and middle-income countries, especially where psychological and social factors may be difficult to detect and are poorly addressed.

Graphical abstract

These slides can be retrieved under Electronic Supplementary Material.

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Epstein–Barr virus strain heterogeneity impairs human T-cell immunity

Abstract

The Epstein–Barr virus (EBV) establishes lifelong infections in > 90% of the human population. Although contained as asymptomatic infection by the immune system in most individuals, EBV is associated with the pathogenesis of approximately 1.5% of all cancers in humans. Some of these EBV-associated tumors have been successfully treated by the infusion of virus-specific T-cell lines. Recent sequence analyses of a large number of viral isolates suggested that distinct EBV strains have evolved in different parts of the world. Here, we assessed the impact of such sequence variations on EBV-specific T-cell immunity. With the exceptions of EBNA2 and the EBNA3 family of proteins, an overall low protein sequence disparity of about 1% was noted between Asian viral isolates, including the newly characterized M81 strain, and the prototypic EBV type 1 and type 2 strains. However, when T-cell epitopes including their flanking regions were compared, a substantial proportion was found to be polymorphic in different EBV strains. Importantly, CD4+ and CD8+ T-cell clones specific for viral epitopes from one strain often showed diminished recognition of the corresponding epitopes in other strains. In addition, T-cell recognition of a conserved epitope was affected by amino acid exchanges within the epitope flanking region. Moreover, the CD8+ T-cell response against polymorphic epitopes varied between donors and often ignored antigen variants. These results demonstrate that viral strain heterogeneity may impair antiviral T-cell immunity and suggest that immunotherapeutic approaches against EBV should preferably target broad sets of conserved epitopes including their flanking regions.

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Liraglutide ameliorates palmitate-induced insulin resistance through inhibiting the IRS-1 serine phosphorylation in mouse skeletal muscle cells

Abstract

Objective

A reduction in insulin-stimulated glucose uptake in skeletal muscles is a characteristic of insulin resistance and type 2 diabetes mellitus (T2DM). The glucagon-like peptide (GLP)-1 agonist liraglutide can reduce blood glucose levels in individuals with T2DM. However, its effect on insulin-induced glucose metabolism in the skeletal muscle of insulin resistance is unknown. We investigated the effects and action mechanisms of liraglutide on insulin resistance (IR) in the skeletal muscle cells treatment with palmitic acid (PA).

Methods

The cell-surface GLUT4myc levels were determined by an antibody-coupled colorimetric assay. The phosphorylation levels of Akt, PI3K(p85α), AS160, IRS1, IKK, and JNK were determined by western blotting. The quantifications of mRNA levels of TNFα, IL-1β, and IL-6 were determined by real-time PCR. Analysis of variance was used for data analysis.

Results

PA elevated not only phosphorylation of JNK, IRS1 serines, and IKKα/β, but also the expression of IL-6, TNFα and IL-1β in C2C12–GLUT4myc cells. PA can reduce phosphorylation of IRS1 tyrosine. These effects of PA were reversed by liraglutide. In addition, liraglutide can reverse PA-decreased insulin-stimulated cell-surface GLUT4 levels, Akt, PI3K(p85α), and AS160 phosphorylation.

Conclusions

Liraglutide can enhance insulin-induced GLUT4 translocation by inhibiting IRS1 serine phosphorylation in PA-treated muscle cells.

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Central Nervous System Involvement in Peripheral T Cell Lymphoma

Abstract

Purpose of Review

Central nervous system (CNS) involvement in peripheral T cell lymphoma (PTCL) is a difficult condition to treat, both as a primary and a secondary disease.

Recent Findings

Primary CNS lymphoma (PCNSL) in PTCL is very rare, making up only 2% of all PCNSLs. The incidence of CNS relapse is generally 2–6% in all cases of PTCL, but the risk may vary by histologic subtype, and extranodal involvement > 1 has been consistently found to be a risk factor for CNS relapse.

Summary

Currently, there is no consensus about indications for CNS prophylactic treatment. A high-dose systemic methotrexate-based regimen is the most commonly used treatment, with or without consolidation with high-dose chemotherapy with autologous stem cell transplantation for both primary and secondary CNS involvement. This approach, however, is generally toxic for older patients. New therapeutic approaches against PTCL are therefore needed.

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Metal-free salan-type compound induces apoptosis and overcomes multidrug resistance in leukemic and lymphoma cells in vitro

Abstract

Purpose

We report on our preclinical findings of a simple salicylic diamine compound (THG 1213) which has yielded exceptional results as a potential chemotherapeutic drug. THG 1213 is an easy to synthesize chiral and metal-free salan compound.

Methods

THG 1213 was tested on several leukemia, lymphoma and solid tumor cell lines in vitro. The effects have been studied by LDH release essay, FACS flow cytometry, photometric cell count, immunoblotting, and NMR spectroscopy.

Results

THG 1213 selectively inhibits proliferation and induces apoptosis in leukemia, lymphoma and solid tumor cell lines. Necrosis or effects on healthy leucocytes could not be detected. Apoptosis is induced via the intrinsic and extrinsic pathways. The salan THG 1213 overcomes multidrug resistance in tumor cells and acts synergistically with vincristine and daunorubicin.

Conclusions

THG 1213 displays remarkable antitumor properties. In particular, the lack of metallic components of THG 1213 could prove to be beneficial in future clinical trials, as metal-containing drugs are known to show severe side effects.

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A novel 3D-printed hybrid simulation model for robotic-assisted kidney transplantation (RAKT)

Abstract

Robotic-assisted kidney transplantation (RAKT) offers key benefits for patients that have been demonstrated in several studies. A barrier to the wider uptake of RAKT is surgical skill acquisition. This is exacerbated by the challenges of modern surgery with reduced surgical training time, patient safety concerns and financial pressures. Simulation is a well-established method of developing surgical skill in a safe and controlled environment away from the patient. We have developed a 3D printed simulation model for the key step of the kidney transplant operation which is the vascular anastomosis. The model is anatomically accurate, based on the CT scans of patients and it incorporates deceased donor vascular tissue. Crucially, it was developed to be used in the robotic operating theatre with the operating robot to enhance its fidelity. It is portable and relatively inexpensive when compared with other forms of simulation such as virtual reality or animal lab training. It thus has the potential of being more accessible as a training tool for the safe acquisition of RAKT specific skills. We demonstrate this model here.

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Clinical value of 18FDG PET/CT in screening for distant metastases in head and neck squamous cell carcinoma

Abstract

Objectives

The detection of distant metastases is of major importance in management of head and neck squamous cell carcinoma patients.

Design

All patients underwent 18FDG PET/CT for the detection of distant metastases.

Setting

Retrospective single center study.

Participants

Head and neck squamous cell carcinoma patients with high risk factors for distant metastases.

Main outcome measures

Accuracy of 18FDG PET/CT for the detection of distant metastases using clinical development of distant metastases and a minimal follow-up of twelve months as reference standard. Comparison of overall survival between patients diagnosed with distant metastases during initial screening and patients diagnosed with distant metastases during follow-up.

Results

In 23 (12%) of the 190 patients 18FDG PET/CT detected distant metastases at screening. Sensitivity and negative predictive value were 46.2% (95% CI 32.6 – 59.7) and 82.6% (95% CI 76.8 – 88.5). No difference in median overall survival from the time of distant metastases detection was found between patients diagnosed with DM during work-up or during follow up.

Conclusions

In head and neck squamous cell carcinoma patients with high risk factors 18FDG PET/CT has a high negative predictive value for the detection of distant metastases and should be used in daily clinical practice, although the sensitivity is limited when long term follow-up is used as reference standard.

This article is protected by copyright. All rights reserved.

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Correlation between septal body size and inferior turbinate hypertrophy on computed tomography scans in fifty patients: A radiological analysis

Abstract

The septal body contains expansile tissue that may behave in a similar manner to the inferior turbinate. It is situated in the nasal valve region and, like the inferior turbinate, can cause changes in the nasal cross-sectional area and resistance to airflow.

Septal body hypertrophy combined with inferior turbinate hypertrophy may result in changes to nasal cross-sectional area and resistance to airflow.

Septal body hypertrophy is likely to accompany inferior turbinate hypertrophy.

Septal body thickness demonstrated significant positive correlation with the widths of the anterior turbinate medial mucosa and middle turbinate lateral mucosa. Septal body length demonstrated significant correlation with the widths of the anterior turbinate lateral mucosa and posterior turbinate lateral mucosa.

Septal body hypertrophy is significantly associated with inferior turbinate hypertrophy and narrowed internal nasal valve area. These results indicate that clinicians should check for concomitant septal body hypertrophy in patients with inferior turbinate hypertrophy.

This article is protected by copyright. All rights reserved.

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