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Δευτέρα 26 Δεκεμβρίου 2022

Mitotic count is prognostic in IDH-mutant astrocytoma without homozygous deletion of CDKN2A/B. Results of consensus panel review of EORTC trials 26053 and EORTC 22033-26033

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Abstract
Background
Gliomas with IDH1/2 mutations without 1p19q codeletion have been identified as the distinct diagnostic entity of IDH mutant astrocytoma (IDHmut astrocytoma). Homozygous deletion of Cyclin-dependent kinase 4 inhibitor A/B (CDKN2A/B) has recently been incorporated in the grading of these tumors. The question of whether histologic parameters still contribute to prognostic information on top of the molecular classification, remains unanswered. Here we evaluated consensus histologic parameters for providing additional prognostic value in IDHmut astrocytomas.
Methods
An international panel of seven neuropathologists scored 13 well-defined histologic features in virtual microscopy images of 192 IDHmut astrocytomas from EORTC trial 22033-26033 (low-grade gliomas) and 263 from EORTC 26053 (CATNON) (1p19q non-codeleted anaplastic glioma). For 192 gliomas the CDKN2A/B status was known. Consensus (agreement ≥ 4/7 panelists) hi stologic features were tested together with homozygous deletion (HD) of CDKN2A/B for independent prognostic power.
Results
Among consensus histologic parameters, the mitotic count (cut-off of 2 mitoses per 10 high power fields standardized to a field diameter of 0.55 mm and an area of 0.24 mm 2) significantly influences PFS (p = 0.0098) and marginally the OS (p = 0.07). Mitotic count also significantly affects the PFS of tumors with HD CDKN2A/B, but not the OS, possibly due to limited follow-up data.
Conclusion
The mitotic index (cut-off 2 per 10 40x HPF) is of prognostic significance in IDHmut astrocytomas without HD CDKN2A/B. Therefore, the mitotic index may direct the therapeutic approach for patients with IDHmut astrocytomas with native CDKN2A/B status.
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Κυριακή 25 Δεκεμβρίου 2022

enzyme replacement therapy followed by stem cell transplantation in children with Gaucher disease type 1 and 3

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Abstract

Background

Gaucher disease (GD) is a lysosomal storage disorder, characterized by hepatosplenomegaly, pancytopenia, bone diseases, with or without neurological symptoms. Plasma glucosylsphingosine (lyso-Gb1), a highly sensitive and specific biomarker for GD, has been used for diagnosis and monitoring the response to treatment. Enzyme replacement therapy (ERT) is an effective treatment for the non-neurologic symptoms of GD. Neuronopathic GD (type 2 and 3) accounts for 60%–70% of the Asian affected population.

Methods

We explored combination therapy of ERT followed by hematopoietic stem cell transplantation (HSCT) and its long-term outcomes in patients with GD type 3 (GD3).

Results

Four patients with GD3 and one with GD type 1 (GD1) underwent HSCT. The types of donor were one matched-related, one matched-unrelated, and three haploidentical. The age at disease onset was 6–18 months and the age at HSCT was 3.8–15 years in the patients with GD3. The latest age at follow-up was 8–22 years, with a post-HSCT duration of 3–14 years. All patients had successful HSCT. Chronic graft-versus-host disease occurred in one patient. The enzyme activities were normalized at 2 weeks post HSCT. Lyso-Gb1 concentrations became lower than the pathological value. All of the patients are still alive and physically independent. Most of them (4/5) returned to school. None of the patients with GD3 had seizures or additional neurological symptoms after HSCT, but showed varying degrees of cognitive impairment.

Conclusions

ERT followed by HSCT could be considered as an alternative treatment for patients with GD3 who have a high risk of fatal neurological progression.

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high‐viscosity glass ionomer restorative systems in small class II restorations

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Abstract

Objective

Evaluate and compare the 5-year clinical performance of three high-viscosity glass ionomer restorative materials in small class II restorations.

Materials and Methods

Forty patients, each with four class II restorations, were enrolled in this trial. A total of 160 restorations were placed, 25% for each material, as follows: three high-viscosity conventional glass ionomer restorative systems (Ketac Universal Aplicap, EQUIA Forte and Riva Self Cure HV) and a microhybrid resin composite system (Filtek Z250). Clinical evaluation was performed at baseline and after 1, 3, and 5 years by two independent examiners using FDI criteria. Epoxy resin replicas were observed under scanning electron microscope (SEM) to examine surface characteristics. Data were analyzed with Kruskal-Wallis, Mann–Whitney U, Friedman, and Wilcoxon signed-rank tests (p < 0.05).

Results

The success rates were 100% for resin composite, 97.4% for Ketac Universal, and 94.9% for both EQUIA Forte and Riva HV restorations. Statistically significant differences were observed between all groups in terms of surface luster and color match criteria (p < 0.05). Statistically significant changes were found over time for all criteria except for fracture of material, postoperative hypersensitivity, recurrence of caries, tooth integrity, periodontal response, adjacent mucosa, and oral health criteria (p > 0.05). SEM evaluations were in accordance with the clinical findings.

Conclusions

Although drawbacks in surface luster and color match appeared over the 5-year evaluation period, the three high-viscosity glass ionomer restorative materials provided successful clinical performance in small to medium sized class II cavities compared to microhybrid resin composite.

Clinical Significance

Glass ionomer restorations exhibited clinical performance similar to that of microhybrid resin composite restorations in small class II cavities subsequent to 5-year evaluation.

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Πέμπτη 22 Δεκεμβρίου 2022

mTOR Signaling Regulates Zika Virus Replication Bidirectionally through Autophagy and Protein Translation

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Abstract

Zika virus (ZIKV) reemerged in 2016 and attracted much more attention worldwide. To date, the limited knowledge of ZIKV interactions with host cells in the early stages of infection impedes the prevention of viral epidemics and the treatment of ZIKV disease. The Mammalian target of rapamycin (mTOR) signaling pathway plays an essential role in the regulation of autophagy and protein synthesis during multiple viral infections. This study aimed to investigate the functional role of mTOR signaling in ZIKV replication in human umbilical vein endothelial cells (HUVECs). Immunoblotting demonstrated that ZIKV infection inhibited mTORC1 signaling, enhancing autophagy but obstructing protein translation. Drugs or siRNA for interfering with mTOR signaling molecules were utilized to demonstrate that AKT/TSC2/mTORC1 signaling was involved in ZIKV infection and that autophagy promoted ZIKV production, but viral protein expression was regulated by mTORC1 signaling. Moreover, confocal microscopy indicated a robust correlation between autophagy and viral RNA transcription. This study clarifies the dual functions of mTOR signaling during ZIKV infection and provides theoretical support for developing potential anti-ZIKV drugs based on mTOR signaling molecules and deeper insights to better understand the mechanism between ZIKV and host cells.

This article is protected by copyright. All rights reserved.

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Omicron infection increases IgG binding to spike protein of predecessor variants

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Abstract

Background

SARS-CoV-2 transmission in India in 2020-2022 was driven predominantly by Wild (Wuhan-Hu-1and D614G), Delta, and Omicron variants. The aim of this study was to examine the effect of infections on the humoral immune response and cross-reactivity to spike proteins of Wuhan-Hu-1, Delta, C.1.2., and Omicron.

Objectives

Residual archival sera (N=81) received between January 2020 and March 2022 were included. Infection status was inferred by a positive SARS-CoV-2 RT-PCR and/or serology (anti-N and anti-S antibodies) and sequencing of contemporaneous samples (N=18) to infer lineage. We estimated the levels and cross-reactivity of infection-induced sera including Wild, Delta, Omicron as well as vaccine breakthrough infections (Delta and Omicron).

Results

We found ~2-fold increase in spike-specific IgG antibody binding in post-Omicron infection compared to the pre-Omicron period, whilst the change in pre- and post-Delta infections were similar. Further investigation of Omicron-specific humoral responses revealed primary Omicron infection as an inducer of cross-reactive antibodies against predecessor variants, in spite of weaker degree of humoral response compared to Wuhan-Hu-1 and Delta infection. Intriguingly, Omicron vaccine-breakthrough infections when compared with primary infections, exhibited increased humoral responses against RBD (7.7-fold) and Trimeric S (Trimeric form of spike protein) (34.6-fold) in addition to increased binding of IgGs towards previously circulating variants (4.2 - 6.5-fold). Despite Delta breakthrough infections showing a higher level of humoral response against RBD (2.9-fold) and Trimeric S (5.7-fold) compared to primary Delta sera, a demonstrably reduced binding (36-49%) was observed to Omicron spike protein.

Conclusions

Omicron vaccine breakthrough infection results in increased intensity of humoral response and wider breadth of IgG binding to spike proteins of antigenically-distinct, predecessor variants.

This article is protected by copyright. All rights reserved.

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Caring for a child with retinoblastoma: Experience of Ethiopian parents

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Abstract

Objective

This study explored the lived experience of parents of children with retinoblastoma.

Design and method

A phenomenological qualitative study design was used, and a purposive sampling technique to recruit parents of children with retinoblastoma. Semi-structured interviews were conducted to document the lived experience of participants, who were asked to narrate their experiences caring for a child with retinoblastoma, thinking back to the day they learned about their child's condition, as well as their thoughts about the future. The interviews were conducted in Amharic and Oromo language, and audio recordings were transcribed and translated to English. Data were analyzed using thematic analysis.

Results

Thirteen parents (seven mothers, six fathers) participated in the study. Collectively, the children of the participants represented all the stages of the retinoblastoma journey (i.e., diagnosis, treatment, remission, and recurrence). Five major themes emerged from the thematic data analysis: (a) reactions when learning the child's condition; (b) receiving health care; (c) costs of caregiving; (d) support; and (e) uncertainties.

Conclusion

The lived experiences of parents of children with retinoblastoma revealed a significant mental health and psychosocial burden. The sources of mental distress were found to be complex and varied. Holistic care for retinoblastoma should include programs that address the biopsychosocial needs of caregivers.

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Ninety‐day mortality following transoral robotic surgery or radiation at Commission on Cancer‐accredited facilities

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Abstract

Background

Postoperative mortality for oropharynx squamous cell carcinoma (OPSCC) with transoral robotic surgery (TORS) varies from 0.2% to 6.5% on trials; the real-world rate is unknown.

Methods

NCDB study from 2010 to 2017 for patients with cT1-2N0-2M0 OPSCC with Charleson–Deyo score 0–1. Ninety-day mortality assessed from start and end of treatment at Commission on Cancer-accredited facilities.

Results

3639 patients were treated with TORS and 1937 with radiotherapy. TORS cohort had more women and higher income, was younger, more often treated at academic centers, and more likely to have private insurance (all p < 0.05). Ninety-day mortality was 1.3% with TORS and 0.7% or 1.4% from start or end of radiotherapy, respectively. From end of therapy, there was no significant difference on MVA between treatment modality.

Conclusions

There is minimal difference between 90-day mortality in patients treated with TORS or radiotherapy for early-stage OPSCC. While overall rates are low, for patients with expectation of cure, work is needed to identify optimal treatment.

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Τετάρτη 21 Δεκεμβρίου 2022

the Musculoskeletal Pain Intensity and Interference Questionnaire for Musicians (MPIIQM‐Pt)

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Abstract

Objectives

We aim to assess the validity and reliability of the Musculoskeletal Pain Intensity and Interference Questionnaire for Musicians (MPIIQM) and to add to its cross-cultural adaptation process by translating, culturally adapting and validating the MPIIQM into European Portuguese language in the population of Portuguese musicians.

Methods

A Portuguese version of the MPIIQM (MPIIQM-Pt) was created through a process of forward and back translation, pilot testing and cultural adaptation by expert panel evaluation. The psychometric evaluation was performed in a validation sample of 134 musicians, at baseline and after seven days.

Results

The high degree of internal consistency and the substantial test-retest reliability coefficients were demonstrated for each subscale (α = 0,896 and ICC = 0,997 for "pain intensity", and α = 0,879 and ICC = 0,999 for "pain interference", respectively). Exploratory factor analysis indicated two-factor structure (pain intensity and interference) that explained 75,5% of the variance. Both convergent and divergent validity are well demonstrated, confirming more than 90% of the previously defined hypotheses regarding correlations with other measures.

Discussion

MPIIQM-Pt is the first validated questionnaire to evaluate pain among Portuguese musicians. It showed excellent psychometric properties, both in terms of internal consistency, test-retest reliability, factor analysis, and construct validity. Therefore, it is a valid and reliable tool suitable for both research and clinical practice purposes. MPIIQM-Pt will allow the development of more robust studies on pain among musicians and the improved assessment and monitoring of pain in this population, filling an important gap in this field of Pain Medicine.

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Development of machine learning models for the prediction of positive surgical margins in transoral robotic surgery (TORS)

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Abstract

Purpose

To develop machine learning (ML) models for predicting positive margins in patients undergoing transoral robotic surgery (TORS).

Methods

Data from 453 patients with laryngeal, hypopharyngeal, and oropharyngeal squamous cell carcinoma were retrospectively collected at a tertiary referral center to train (n = 316) and validate (n = 137) six two-class supervised ML models employing 14 variables available pre-operatively.

Results

The accuracy of the six ML models ranged between 0.67 and 0.75, while the measured AUC between 0.68 and 0.75. The ML algorithms showed high specificity (range: 0.75–0.89) and low sensitivity (range: 0.26–0.64) in detecting patients with positive margins after TORS. NPV was higher (range: 0.73–0.83) compared to PPV (range: 0.45–0.63). T classification and tumor site were the most important predictors of positive surgical margins.

Conclusions

ML algorithms can identify patients with low risk of positive margins and therefore amenable to TORS.

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Speicheldrüsenkarzinome - Monozentrische Erfahrung zu Subtypen und deren Inzidenz über 42 Jahre

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Laryngorhinootologie
DOI: 10.1055/a-1976-9694

Hintergrund Speicheldrüsenkarzinome sind selten und heterogen. Über 20 Subtypen sind anerkannt und Risikofaktoren sind vielfältig. Ziel dieser Arbeit war die Bewertung des Subtyps und weiterer Risikofaktoren bei einem monozentrischen Kollektiv aus über vier Jahrzehnten. Material und Methoden 205 Fälle (Diagnosezeitraum 1972–2014) wurden retrospektiv erhoben und hinsichtlich der Verteilung von Risikofaktoren und deren Einfluss auf die Gesamtüberlebenszeit (overall survival, OS) statistisch ausgewertet. Ergebnisse 19/24 (79,2%) der in der WHO-Klassifikation gelisteten Subtypen kamen in der Kohorte selten vor (< 5%). Davon wurden 10/24 (41,7%) Subtypen nie diagnostiziert. Das Plattenepithelkarzinom (PEC), Adenokarzinom (AdenoCa), Azinuszellkarzinom (AzinusCa), Mukoepidermoidkarzinom (MEC) und adenoidzystische Karzinom (ACC) sind mit zusammen 145/205 (70,7%) die mit Abstand häufigsten Subtypen. Risikofaktoren sind in diesen Gruppen signifikant unterschiedlich vertreten (z.B. lymphogene Metastasierung und Differenzierungsgrad beim AdenoCa und Alter, T- und UICC-Stadium beim PEC). Das 5-Jahres Gesamtüberleben aller Patienten war 66,9% und unterscheidet sich signifikant innerhalb der häufigsten Subtypen. Ein unabhängiger Einfluss auf das Gesamtüberleben war in der multivariaten Analyse feststellbar für das Alter der Patienten (p<0,001), sowie das T- (p=0,003) und N-Stadium (p=0,046). Schlussfolgerungen Die meisten Subtypen traten auch innerhalb von Jahrzehnten ausgesprochen selten oder gar nicht auf. Die häufigsten Diagnosen unterscheiden sich bezüglich der Risikofaktoren als auch hinsichtlich des OS, so dass 3 Risikogruppen gebildet werden können. Schlussfolgernd ist die Betrachtung von TNM alleine für die Prognoseabschätzung beim Speicheldrüsenkarzinom unzureichend.
[...]

Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

Article in Thieme eJournals:
Table of contents  |  Abstract  |  open access Full text

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