Αρχειοθήκη ιστολογίου

Κυριακή 5 Ιουνίου 2022

HGG-23. The presence ofROS1 fusions are not limited only to infantile hemispheric glioma.

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Abstract
INTRODUCTION: Diffuse pediatric-type high-grade gliomas are diffuse gliomas with histological features of malignancy, typically occurring in children, and infants. For these tumors, precise classification, identification of prognostic and predictive factors requires molecular analysis. The ROS proto-oncogene 1 (ROS1) gene encodes a receptor tyrosine kinase that is involved in chromosomal rearrangements in numerous malignancies, and may be an attractive therapeutic target, since specific inhibitors have been approved for several neoplasms. Molecular evaluation including detection of ROS1 fusions in pediatric gliomas are not included in standard diagnostic tests so far, therefore data on its significance is still limited. We present two cases of pediatric ROS1 fusion-positive brain tumors. METHODS AND RESULTS: The patient no.1 was 1 year old boy with disseminated brain lesions. Histopathological examination displayed the presence of a neoplasm, which was composed of round and spindle-shaped cells with palisading necrosis, mitotic activity, and microvascular proliferation. The patient no.2 is 9 years old girl with tumor located in left frontal lobe. Microscopically, the neoplasm revealed the presence of oligodenroglial-like component with microvascular proliferation, and high mitotic activity. Targeted gene sequencing panel - Ampliseq Childhood Cancer Panel for Illumina was used to detect diagnostic and targetable gene fusions. In both of patients ROS1:GOPC gene fusions were detect. Identified fusions allowed to established diagnosis - infant-type hemispheric glioma with ROS1 fusion (patient no 1) and - diffuse pediatric-type high grade glioma with ROS1 fusion (patient no 2). CONCLUSIONS: Ou r results indicate, that the presence of ROS1 fusions are not limited to the infant-type hemispheric gliomas only and may play a role in other glioma entities. It may be worth to include this biomarker in the diagnostic panel of pediatric brain tumors to establish a more precise diagnosis and a potential therapeutic target. Funded by National Science Centre, Poland (2016/23/B/NZ2/03064).
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QOL-12. Relaxation technique of imagery based story telling reduces manifestation of anxiety in children and adolescents undergoing brain tumor surgery

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Abstract
Children and adolescents undergoing surgical resection of brain tumors are prone to marked psychologic burden. Especially fear of surgery and its consequences like pain or neurologic sequelae is an important issue. Techniques of relaxation might reduce the intensity of the experienced anxiety and therefore might improve quality of life. In this study, we aimed at determining the effect of a standardized imagery story telling on experienced anxiety as quantified by the questionaire KAT III and cardiac frequency (CF) before and after intervention at two time points (before and after surgery). 12 patients (age: 6-17 years) undergoing brain tumor resection were included in the study. KAT III-scores and CF were determined and compared before and after interventions using a dependend t-test. Mean KAT III-score before first intervention was 0.23 (SD: 0.23), while it was 0.15 (SD: 0.21) after (p = 0.11). Mean KAT III-score before second intervention was 0.11 (SD: 0.13), after: 0.05 (SD: 0.9), p = 0.07. Mean CF before first intervention was 77.1 (SD: 10.3), after: 68,36 (SD: 6.8), p = 0.003. Mean CF before second intervention was 71.67 (SD: 9.57), after: 65 (SD: 8.72), p = 0.003. CF was significantly lower post-interventionally after the first and the second intervention. KAT III-score showed a trend to be lower post-interventionally after the second intervention. Hence, our study points at an efficacy of the deployed relaxation technique of imagery story telling in children and adolescents undergoing brain tumor surgery, although it was limited by a small patient number. Further studies with larger patient numbers and a comparison of randomized intervention vs. non-intervention groups are warranted.
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DIPG-40. Combined pharmacological and genetic screening to identify dependencies and combinations in ACVR1-mutant diffuse midline glioma

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Abstract
Somatic mutations in ACVR1, which encodes the serine/threonine kinase ALK2, are found in 20-25% of DMG-H3K27 patients. Treatment of ACVR1-mutant patient-derived models with multiple chemotypes of ALK2 inhibitors (ALK2i) results in reduced cell viability in vitro and extended survival in orthotopic xenografts in vivo but, as single agents, these inhibitors were unable to achieve a complete anti-tumour response. Recently we reported that combinatorial treatment of ACVR1-mutant DIPG cells with vandetanib (RTK inhibitor) and everolimus (mTOR/ABC transporter inhibitor) was synergistic both in vitro and in vivo and was shown to be a feasible combination to trial clinically in this setting. To identify specific dependencies in ACVR1-mutant cells which may be translatable with novel synergistic drug combinations alongside ALK2i, we have implemented both candidate and unbiased drug and genetic screening approaches. Using a panel of patient-derived ACVR1-m utant and wild-type models, we identified synergy between multiple chemotypes of ALK2i (M4K2009/LDN-214117) and PI3K/mTOR (AZD8055/everolimus) and MEK inhibitors (trametinib), reflecting the common co-segregation of PIK3CA/PIK3R1 alterations in these tumours. Whole-genome CRISPR/Cas9 screening of ACVR1-mutant SU-DIPG-IV cells in combination with two ALK2i (M4K2009/LDN-193189), confirmed a specific MTOR genetic dependency, as well as for the protein phosphatase regulatory subunit PPP2R1A, known to play a role in MAPK pathway activation. Additional hits include the serine/threonine kinase PKMYT1, a negative regulator of the G2/M checkpoint via a functionally redundant phosphorylation of CDK1/CCNB1 alongside WEE1; confirmatory drug assays with the WEE1 inhibitor AZD1775 resulted in a synergistic interaction with ALK2i in ACVR1-mutant cells. Hits were integrated with DepMap using 'gene-effect' scores (Chronos) enabling filtering of common essential genes. Preliminary pathway enrichm ent analysis (MAGeCKFlute) identified ALK2i-specific vulnerabilities involving TGFB1/SMAD signalling and histone deacetylation. These data highlight functionally rational and novel combinatorial possibilities for children with ACVR1-mutant DMG, with systematic preclinical assessment required for prioritisation for the clinic.
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PragmaTic, prospEctive, randomized, controlled, double-blind, mulTi-centre, multinational study on the safety and efficacy of a 6% HydroxYethyl Starch (HES) solution versus an electrolyte solution in trauma patients: study protocol for the TETHYS study

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Trauma may be associated with significant to life-threatening blood loss, which in turn may increase the risk of complications and death, particularly in the absence of adequate treatment. Hydroxyethyl starch ...
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Management of Neurofibromatosis Type 1-Associated Plexiform Neurofibromas

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Abstract
Plexiform Neurofibromas (PN) are a common manifestation of the genetic disorder neurofibromatosis type 1 (NF1). These benign nerve sheath tumors often cause significant morbidity, with treatment options limited historically to surgery. There have been tremendous advances over the past two decades in our understanding of PN, and the recent regulatory approvals of the MEK inhibitor selumetinib are reshaping the landscape for PN management. At present, there is no agreed upon PN definition, diagnostic evaluation, surveillance strategy, or clear indications for when to initiate treatment and selection of treatment modality. In this review, we address these questions via consensus recommendations from a panel of multi-disciplinary NF1 experts.
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The clinical and bioinformatics analysis for the role of anti‐hypertension drugs on mortality among patients with hypertension hospitalized with COVID‐19

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Abstract

Comorbidities such as hypertension could exacerbate symptoms of COVID-19 infection. Patients with hypertension may receive both anti-COVID-19 and anti-hypertension therapies when infected with COVID-19. However, it is not clear how different classes of anti-hypertension drugs impact the outcome of COVID-19 treatment. Herein, we explore the association between the inpatient use of different classes of anti-hypertension drugs and mortality among patients with hypertension hospitalized with COVID-19. We totally collected data from 278 patients with hypertension diagnosed with COVID-19 admitted to hospitals in Wuhan from February 01 to April 01, 2020. A retrospective study was conducted and single cell RNA-Seq analysis of treatment-related genes was performed. The results showed that angiotensin II receptor blockers (ARB) and calcium channel blockers (CCB) drugs significantly increased the survival rate but the use of ACEI/beta-block/diuretic drugs did not affec t the mortality caused by COVID-19. Based on the analysis of four public datasets of single-cell RNA-seq on COVID-19 patients, we concluded that JUN, LST1 genes may play a role in the effect of ARB on COVID-19 related mortality while CALM1 gene may contribute to the effect of CCB on COVID-19 related mortality. Our results provide guidance on the selection of anti-hypertension drugs for hypertensive patients infected with COVID-19.

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Clinical efficacy and in vitro neutralization capacity of monoclonal antibodies for SARS‐CoV‐2 delta and omicron variants

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Abstract

We aimed to provide in vitro data on the neutralization capacity of different monoclonal antibody (mAb) preparations against the SARS-CoV-2 delta and omicron variant, respectively, and describe the in vivo RNA kinetics of COVID-19 patients treated with the respective mAbs. Virus neutralization assays were performed to assess the neutralizing effect of the mAb formulations casirivimab/imdevimab and sotrovimab on the SARS-CoV-2 delta and omicron variant. Additionally, respiratory tract SARS-CoV-2 RNA kinetics are provided for 25 COVID-19 patients infected with either delta variant (n=18) or omicron variant (n=7) treated with the respective mAb formulations during their hospital stay. In the virus neutralization assay, sotrovimab exhibits neutralizing capacity at therapeutically achievable concentrations against the SARS-CoV-2 delta and omicron variant. In contrast, casivirimab/imdevimab had neutralizing capacity against the delta variant but fail ed neutralization against the omicron variant except for a very high concentration above the currently recommended therapeutic dosage. In patients with delta variant infections treated with casivirimab/imdevimab, we observed a rapid decrease of respiratory viral RNA at day three after mAb therapy. In contrast, no such prompt decline was observed in patients with delta variant or omicron variant infections receiving sotrovimab.

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Successful isavuconazole salvage therapy for cerebral mucormycosis in a child with relapsed leukemia: A light in the dark tunnel

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Polyamine synthesis enzyme AMD1 is closely related to the tumorigenesis and prognosis of human breast cancer

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Publication date: Available online 4 June 2022

Source: Experimental Cell Research

Author(s): Hongyu Gao, Hanjun Li, Jingjie Wang, Cheng Xu, Yueyun Zhu, Dilihumaer Tuluhong, Xinfang Li, Shaohua Wang, Jieshou Li
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Pharyngeal tongue base augmentation for dysphagia therapy: A prospective case series in patients post head and neck cancer treatment

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Abstract

Background

Dysphagia post head and neck cancer (HNC) multimodality treatment is attributed to reduced pharyngeal strength. We hypothesized that pharyngeal tongue base augmentation for dysphagia (PAD therapy) would increase pharyngeal pressures during swallowing thereby improving swallow symptoms.

Methods

Adults with moderate–severe dysphagia post-HNC treatment had PAD therapy using a temporary filler (hyaluronic acid [HA]), with follow-up long-lasting lipofilling. Swallowing preprocedure and postprocedure was assessed with the Sydney Swallow Questionnaire (SSQ), High-Resolution Pharyngeal Manometry (HRPM), and Videofluoroscopic Swallowing Study (VFSS). Statistical comparison utilized paired tests.

Results

Six participants (all male; median age 64 years [IQR 56, 71]) underwent PAD therapy at a median of 47 [IQR 8, 95] months post-treatment. SSQ scores reduced from baseline (mean 1069 [95%CI 703, 1434]) to post-HA (mean 579 [76, 1081], p > 0.05), and post-lipofilling (491 [95%CI 913, 789], p = 0.003, n = 4). Individual participants demonstrated reduced Swallow Risk Index, Bolus Presence Time, and increased Upper Esophageal Sphincter opening, but mesopharyngeal contractile pressures were unchanged. VFSS measures of aspiration, residue, and severity were unchanged.

Conclusions

Novel PAD therapy is safe and improves dysphagia symptoms. Biomechanical swallowing changes are suggestive of more efficacious bolus propulsion with conservative filler volume, but this was unable to resolve residue or aspiration measures.
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