RADT-28. RECURRENT MENINGIOMA WITH 1p/22q SOMATIC MUTATION OF GNAS: A CASE REPORT

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi47-vi47
Author(s):  
Weiping Hong ◽  
Lei Wen ◽  
Changguo Shan ◽  
Minting Ye ◽  
yanying Yang ◽  
...  
Keyword(s):  
Somatic Mutation ◽  
Molecular Diagnosis ◽  
Treatment Plan ◽  
Fold Increase ◽  
Chromosome 1 ◽  
High Recurrence Rate ◽  
Driver Gene ◽  
Active Growth ◽  
Disability Rate ◽  
Atypical Meningiomas

Abstract OBJECTIVE Refractory meningioma faces the problems of low total resection rate, high recurrence rate and high disability rate. Here we report a patient with recurrent refractory meningioma who was benefited from precision treatment plan based on molecular diagnosis. METHODS Molecular diagnosis by next generation sequencing (NGS) test was used to test the hybridized captured DNA in the tumor tissue of the patient. RESULTS The 53-year-old female diagnosed with meningioma was admitted to our hospital after tumor progression was observed for 3 weeks. She had received 4 operations for the tumor previously. The first three times of postoperative pathology indicated WHO Ⅰ grade meningioma. The fourth postoperative pathology showed excessive meningioma, with active growth of tumor cells in some areas and small focal necrosis, WHO Ⅰ- fair grade. Somatic mutation GNAS p.F309VFS *25 and deletion of the short arm of chromosome 1 / long arm of chromosome 22 were also found (1P / 22Q) by NGS test. The second recurrent foci showed partial amplification of 17q and 19, except for 1p/22q deletions, compared with the first. Meningiomas with 1p/22q deletion are type C meningiomas (more than half are grade WHO Ⅰ). Meningiomas have been shown to be highly vascularized neoplasms, with a 2-fold increase in VEGF expression in atypical meningiomas and a 10-fold increase in malignant meningiomas. According to the molecular diagnosis results, the precise treatment plan was determined: concurrent chemoradiotherapy, followed by anti-VEGF-targeted drugs combined with temozolomide for 2 months. The residual lesions were significantly reduced after treatment. CONCLUSION This case is the first to report a meningioma with pituitary tumor driver gene GNAS mutation, which is more prone to recurrence due to the combination of 1P / 22Q chromosome mutation. Molecular diagnosis can guide precise treatment to benefit patients.

scholarly journals PATH-50. ROUTINE MOLECULAR DIAGNOSIS OF GLIOMA PATIENTS USING A GLIOMA-SPECIFIC NGS PANEL

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi154-vi155
Author(s):  
Koji Yoshimoto ◽  
Nayuta Higa ◽  
Hajime Yonezawa ◽  
Hiroyuki Uchida ◽  
Toshiaki Akahane ◽  
...  
Keyword(s):  
Molecular Diagnosis ◽  
Gene Mutations ◽  
Chromosome 1 ◽  
Clinical Samples ◽  
Driver Gene ◽  
Driver Genes ◽  
Chromosome 1P ◽  
Ffpe Tumor ◽  
Grade Ii ◽  
Key Driver

Abstract AIM The 2016 WHO classification requires molecular diagnosis in routine glioma diagnostics. However, analysis of key driver gene mutations and chromosome 1p/19q co-deletions cannot be performed in a single platform. In this study, we evaluated the feasibility of a glioma-specific NGS panel for molecular diagnosis of glioma patients. MATERIALS AND METHODS We developed a glioma-specific NGS panel consisting of 48 genes, including glioma-relevant key driver genes and 21 genes mapped to chromosome 1 and 19. DNA was extracted from formaldehyde fixed-paraffin embedded (FFPE) tumor tissues histologically identified by a pathologist, and from patient-derived blood as a control. In this system, we implemented a molecular barcodes method to enhance confidence in clinical samples and analyzed 80 glioma patients (Grade II: 17 cases, Grade III: 16 cases, Grade IV: 47 cases). RESULTS From these 80 cases, IDH1 and H3F3A mutations were detected in 23 cases (29%) and 2 cases (5%), respectively. The 1p/19q co-deletion was detected in 15 cases (19%), with all cases also containing IDH1 mutations. In Grade IV cases, EGFR, PDGFR, and FGFR mutations were detected in 6% (amp 19%), 9%, and 4% (amp 17%) of cases, respectively. PTEN, TP53, NF1, RB1, and CDKN2A mutations were detected in 37% (del 72%), 45% (del 13%), 21% (del 23%), 15% (del 60%), and 2% (del 53%) of cases, respectively. CONCLUSION Diagnosis of glioma patients with this glioma-specific NGS panel is feasible.

scholarly journals Low Glucose Mediated Fluconazole Tolerance in Cryptococcus neoformans

2021 ◽  
Vol 7 (6) ◽  
pp. 489
Author(s):  
Somanon Bhattacharya ◽  
Natalia Kronbauer Oliveira ◽  
Anne G. Savitt ◽  
Vanessa K. A. Silva ◽  
Rachel B. Krausert ◽  
...  
Keyword(s):  
Cryptococcus Neoformans ◽  
Mitochondrial Function ◽  
Efflux Pump ◽  
Nile Red ◽  
Fold Increase ◽  
Growth Conditions ◽  
Chromosome 1 ◽  
Normal Glucose ◽  
Low Glucose ◽  
Synthetic Media

Chronic meningoencephalitis is caused by Cryptococcus neoformans and is treated in many parts of the world with fluconazole (FLC) monotherapy, which is associated with treatment failure and poor outcome. In the host, C. neoformans propagates predominantly under low glucose growth conditions. We investigated whether low glucose, mimicked by growing in synthetic media (SM) with 0.05% glucose (SMlowglu), affects FLC-resistance. A > 4-fold increase in FLC tolerance was observed in seven C. neoformans strains when minimum inhibitory concentration (MIC) was determined in SMlowglu compared to MIC in SM with normal (2%) glucose (SMnlglu). In SMlowglu, C. neoformans cells exhibited upregulation of efflux pump genes AFR1 (8.7-fold) and AFR2 (2.5-fold), as well as decreased accumulation (2.6-fold) of Nile Red, an efflux pump substrate. Elevated intracellular ATP levels (3.2-fold and 3.4-fold), as well as decreased mitochondrial reactive oxygen species levels (12.8-fold and 17-fold), were found in the presence and absence of FLC, indicating that low glucose altered mitochondrial function. Fluorescence microscopy revealed that mitochondria of C. neoformans grown in SMlowglu were fragmented, whereas normal glucose promoted a reticular network of mitochondria. Although mitochondrial membrane potential (MMP) was not markedly affected in SMlowglu, it significantly decreased in the presence of FLC (12.5-fold) in SMnlglu, but remained stable in SMlowglu-growing C. neoformans cells. Our data demonstrate that increased FLC tolerance in low glucose-growing C. neoformans is the result of increased efflux pump activities and altered mitochondrial function, which is more preserved in SMlowglu. This mechanism of resistance is different from FLC heteroresistance, which is associated with aneuploidy of chromosome 1 (Chr1).

scholarly journals Huge keratocystic odontogenic tumour in medically compromised patient–a management dilemma

2019 ◽  
Vol 5 (4) ◽  
pp. 112
Author(s):  
Muhammed Ali T. ◽  
Sobitha G. ◽  
Dibin R.
Keyword(s):  
Cystic Lesion ◽  
Treatment Plan ◽  
Bone Destruction ◽  
The Body ◽  
High Recurrence Rate ◽  
Multiple Drug ◽  
Odontogenic Tumour ◽  
Management Options ◽  
Lower Jaw ◽  
Keratocystic Odontogenic Tumour

<p class="abstract">Keratocystic odontogenic tumour (KCOT) is a cystic lesion of the jaws with tumour behaviour. Its high prevalence rate makes it one of the commonest cystic lesions especially involving the lower jaw. The characteristic histologic features and aggressive nature corresponds to the high recurrence rate associated with KCOT. Lesion expands mostly in an anteroposterior direction and can cause extensive bone destruction before the appearance of any clinical symptoms. The characteristic radiological picture is that of a multilocular cystic lesion with the common differential diagnosis being dentigerous cyst and ameloblastoma. Here we are presenting a case of KCOT of the left lower jaw of size 10.9×7.86×8.54 cm. It is a huge multilocular cystic lesion extending from the right canine region to the left side involving the body, ramus, coronoid and condyle. Various management options are there ranging from enucleation and chemical cauterization to resection and reconstruction depending upon the size of the lesion. In this case we were not able to perform the ideal treatment option for the case because of the multiple drug allergy the patient was having, including most of the general anesthetic agents. Also the patient was not willing for any extensive procedure under general anesthesia. So we had to follow a compromised treatment plan aiming to reduce the size of the lesion, to improve the aesthetics and frequent follow up.</p>

Abstract 485: Enhanced Large Conductance Ca+2 -sensitive K+ Channels (bk) Activity Impairs the Myogenic Response in the Cerebral Vasculature of Fawn Hooded Hypertensive (fhh) Rat

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Mallikarjuna R Pabbidi ◽  
Jerry Farley ◽  
Debebe Gebremedhin ◽  
David R. Harder ◽  
Richard J. Roman
Keyword(s):  
Congenic Strain ◽  
Single Channel ◽  
Cerebral Arteries ◽  
Fold Increase ◽  
Bk Channel ◽  
Chromosome 1 ◽  
K Channel ◽  
Myogenic Response ◽  
Whole Cell Patch Clamp ◽  
Current Densities

Our recent studies have revealed that the myogenic response in cerebral arteries and autoregulation of cerebral blood flow is impaired in FHH and that transfer of a 2.4 Mb region of chromosome 1 from BN into FHH.1 BN congenic strain restores these responses. The present study examined the role of large conductance calcium activated potassium (BK) channel in altering the myogenic response in FHH rats. Whole-cell patch-clamp of cerebral vascular smooth muscle cells (VSMC) revealed a 4.6 fold increase in outward potassium (K) channel current densities (pA/pF) in FHH rats compared to FHH.1 BN congenic strain. Iberiotoxin (IBTX -a selective BK channel inhibitor) sensitive current densities are significantly greater in FHH rats compared with the FHH.1 BN congenic strain (FHH rats: +40mV; pre IBTX 43.1 ± 7.2, after IBTX 11.8 ± 2.2 pA/pF versus pre IBTX 5.6 ± 1 pA/pF and after IBTX 4.1 ± 0.6 pA/pF in the FHH.1 BN congenic strain). In excised patches, the BK channel exhibited similar single-channel slope conductance for FHH and the FHH.1 BN rats (208.9 pS versus 208.7 pS). However, the open channel probability (NP o ) was ~10 fold higher in FHH rats than in FHH.1 BN rats (1μM free (Ca +2 ) i : +40mV: FHH; 0.8 ± 0.04 versus 0.08 ± 0.004 in FHH.1 BN rats). Voltage and Ca 2+ sensitivity of the BK channel is similar in cerebral VSMC isolated from FHH and FHH.1 BN rats. Middle cerebral arterioles (MCA) isolated from FHH rats increased in diameter from 142 ± 16 to 157 ± 19 μm when pressure was increased from 40 to 140 mmHg. In contrast, the diameter of the MCA decreased by 49% in the FHH.1 BN congenic strain from 127 ± 16 to 65 ± 13 μm. Pharmacological block of BK channel by IBTX (100nM) restored myogenic response in FHH rats but had no effect in FHH.1 BN rats. These results indicate that the impaired myogenic response of the cerebral vessels in FHH rats is mediated via a gene and mechanism that enhances BK channel activity.

scholarly journals SAT-555 Can Histology Predict the Presence of KCNJ5 Somatic Mutation in Aldosterone-Producing Adenomas?

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Yuto Yamazaki ◽  
Xin Gao ◽  
Yuta Tezuka ◽  
Kei Omata ◽  
Yoshikiyo Ono ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Somatic Mutation ◽  
Tumor Size ◽  
Scoring System ◽  
Quantitative Methods ◽  
Clear Cell ◽  
Intratumoral Heterogeneity ◽  
Driver Gene ◽  
Wild Type ◽  
Large Tumor

Abstract Aldosterone-producing adenoma (APA) is well known to harbor marked intratumoral heterogeneity in terms of morphology and CYP11B2 (aldosterone synthase) localization. In histology, APA is generally characterized by two distinct cell subtypes, namely “clear cells” and “compact cells”. Clear tumor cells harbor abundant lipid droplets in their cytoplasms and compact tumor cells generally featuring small round shape have abundant intracytoplasmic organelles including mitochondria. Relatively close correlation between these histological characteristics (morphology and CYP11B2 immunohistochemistry) and genotypes of aldosterone-driver gene somatic mutation has been reported. Among them, KCNJ5-mutated APAs have been reported to harbor clear cell predominant features, while APAs with other rare somatic mutations including ATP1A1, ATP2B3 and CACNA1D harbor heterogenous or relatively compact cell predominant morphometry. However, these previous evaluation were based on eyeball analysis with relatively low reproducibility. Therefore, we developed the more quantitative methods using digital image software in order to analyze the widespread area, which can reflect intratumoral heterogeneity, with high reproducibility to analyze the further detailed correlation between histopathological characteristics and genotype in APA. We explored the utility of immunohistochemistry including CYP11B2 and KCNJ5. We further attempted to propose histopathological scoring system to predict the presence of KCNJ5 somatic mutation in APAs. Results of our present study revealed that KCNJ5 was predominantly immunolocalized in zona glomerulosa among adrenal cortex (vs. ZF, P=0.0002, vs. ZR, P=0.0002), furthermore, predominantly in APCCs than in non-APCCs (P=0.0019). Among the tumors, KCNJ5 immunoreactivity was significantly higher in KCNJ5-wild type APAs than in mutated ones (P=0.0037). KCNJ5-mutated APAs had significantly lower nuclear / cytoplasm ratio and abundant clear cell components than those with wild type, harboring large tumor size. In conclusion, we firstly proposed a novel histopathological predicting scoring system for the presence of KCNJ5 somatic mutation, including the following histopathological findings; N/C ratio, clear cell (%), tumor size, CYP11B2 immunoreactivity and KCNJ5 immunoreactivity. It is true that no single histological factors above could precisely predict the presence of KCNJ5 somatic mutation but this newly developed combined histopathological predicting scoring system could provide relatively high accuracy to predict KCNJ5 somatic mutation in APAs (AUC=96%, sensitivity:100%, specificity:90%, 4 points or more). However, further prospective validation by large number of cases is required for clarification.

scholarly journals Archival bone marrow smears are useful in targeted next-generation sequencing for diagnosing myeloid neoplasms

PLoS ONE ◽  
2021 ◽  
Vol 16 (7) ◽  
pp. e0255257
Author(s):  
Daichi Sadato ◽  
Chizuko Hirama ◽  
Ai Kaiho-Soma ◽  
Ayaka Yamaguchi ◽  
Hiroko Kogure ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Next Generation Sequencing ◽  
Molecular Diagnosis ◽  
Driver Gene ◽  
Next Generation ◽  
Sequencing Data ◽  
Dna And Rna ◽  
Myeloid Neoplasms ◽  
Wide Range ◽  
Generation Sequencing

Gene abnormalities, including mutations and fusions, are important determinants in the molecular diagnosis of myeloid neoplasms. The use of bone marrow (BM) smears as a source of DNA and RNA for next-generation sequencing (NGS) enables molecular diagnosis to be done with small amounts of bone marrow and is especially useful for patients without stocked cells, DNA or RNA. The present study aimed to analyze the quality of DNA and RNA derived from smear samples and the utility of NGS for diagnosing myeloid neoplasms. Targeted DNA sequencing using paired BM cells and smears yielded sequencing data of adequate quality for variant calling. The detected variants were analyzed using the bioinformatics approach to detect mutations reliably and increase sensitivity. Noise deriving from variants with extremely low variant allele frequency (VAF) was detected in smear sample data and removed by filtering. Consequently, various driver gene mutations were detected across a wide range of allele frequencies in patients with myeloid neoplasms. Moreover, targeted RNA sequencing successfully detected fusion genes using smear-derived, very low-quality RNA, even in a patient with a normal karyotype. These findings demonstrated that smear samples can be used for clinical molecular diagnosis with adequate noise-reduction methods even if the DNA and RNA quality is inferior.

scholarly journals KERATOCYSTIC ODONTOGENIC TUMOR OF THE MAXILLARY ANTERIOR REGION MASQUERADING AS A RADICULAR CYST

2017 ◽  
Vol 10 (6) ◽  
pp. 3
Author(s):  
Byakodi Sanjay Satappa ◽  
Datar Uma Vasant ◽  
Sampada Kanitkar ◽  
Mamata Kamat
Keyword(s):  
Rare Case ◽  
Treatment Plan ◽  
Accurate Diagnosis ◽  
Odontogenic Tumor ◽  
High Recurrence Rate ◽  
Keratocystic Odontogenic Tumor ◽  
Periapical Lesions ◽  
Multilocular Radiolucency ◽  
Periapical Cyst ◽  
Odontogenic Neoplasm

Keratocystic odontogenic tumor (KCOT) is a benign odontogenic neoplasm which is characterized by aggressive behavior and a high recurrence rate. KCOTs have a predilection for the angle and ascending ramus of the mandible. Maxillary KCOTs are usually associated with nevoid basal cell carcinoma syndrome. Very few cases of non-syndromic KCOT crossing maxillary midline have been reported. In this article, we report a rare case of KCOT which presented as a multilocular radiolucency crossing midline and involving periapical area of maxillary incisors. The lesion thus simulated a periapical cyst. However, the lesion was proved to be a KCOT on histopathology. Thus this report highlights the need for histopathological evaluation of periapical lesions for accurate diagnosis and treatment plan.

scholarly journals The Dynamics of Indicators of Industrial Injuries in Karaganda Region

2021 ◽  
Vol 1 (56) ◽  
pp. 32-37
Author(s):  
Galina Jaxybekova ◽  
◽  
Gazima Bermagambetova ◽  
Berik Tuleubayev ◽  
◽  
...  
Keyword(s):  
Working Conditions ◽  
Occupational Injury ◽  
Mining Industry ◽  
Injury Rate ◽  
Fold Increase ◽  
Work Related ◽  
National Indicator ◽  
Disability Rate ◽  
Industrial Injuries ◽  
Karaganda Region

The aim of the study. To conduct a comparative analysis of the indicators of industrial injuries in Karaganda region for 2015-2019. Methods. The article analyzes the data on industrial injuries in Karaganda region for 2015-2019 years by the method of descriptive statistics, as well as the material consequences of accidents. Results. In Karaganda region, the number of victims in accidents related to labor activity per 100 thousand adult populations is 2.5 times, and the number of deaths is 2.2 times higher than the national indicator. Over the 5-year period, there has been a slight decrease in the number of work-related fatalities from 9.9% in 2015 to 9% for 2019. At the same time, there was a 1.2-fold increase in material costs. Conclusions. In Karaganda region for 2015-2019, the number of people injured at work decreased. Nevertheless, the level of industrial injuries remains quite high, indicating the need to improve the procedure of certification of production facilities on working conditions, as well as the regulatory framework on compliance with working conditions in the mining industry. Keywords: occupational injury rate, fatality rate, disability rate, Karaganda region, Kazakhstan

scholarly journals Intracellular Accumulation of Polyphosphate by the Yeast Candida humicola G-1 in Response to Acid pH

2000 ◽  
Vol 66 (9) ◽  
pp. 4068-4073 ◽  
Author(s):  
John W. McGrath ◽  
John P. Quinn
Keyword(s):  
Kinase Activity ◽  
Phosphate Uptake ◽  
Phosphate Starvation ◽  
Fold Increase ◽  
Physiological Adaptation ◽  
Intracellular Accumulation ◽  
Mineral Salts ◽  
Active Growth ◽  
Environmental Strain ◽  
Acid Ph

ABSTRACT Cells of a newly isolated environmental strain of Candida humicola accumulated 10-fold more polyphosphate (polyP), during active growth, when grown in complete glucose-mineral salts medium at pH 5.5 than when grown at pH 7.5. Neither phosphate starvation, nutrient limitation, nor anaerobiosis was required to induce polyP formation. An increase in intracellular polyP was accompanied by a 4.5-fold increase in phosphate uptake from the medium and sixfold-higher levels of cellular polyphosphate kinase activity. This novel accumulation of polyP by C. humicola G-1 in response to acid pH provides further evidence as to the importance of polyP in the physiological adaptation of microbial cells during growth and development and in their response to environmental stresses.

scholarly journals Whole genome sequencing of skull-base chordoma reveals genomic alterations associated with recurrence and chordoma-specific survival

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jiwei Bai ◽  
Jianxin Shi ◽  
Chuzhong Li ◽  
Shuai Wang ◽  
Tongwu Zhang ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Skull Base ◽  
Genome Sequencing ◽  
Unknown Etiology ◽  
High Recurrence Rate ◽  
Driver Gene ◽  
Whole Genome ◽  
Genomic Alterations ◽  
Skull Base Chordomas ◽  
Skull Base Chordoma

AbstractChordoma is a rare bone tumor with an unknown etiology and high recurrence rate. Here we conduct whole genome sequencing of 80 skull-base chordomas and identify PBRM1, a SWI/SNF (SWItch/Sucrose Non-Fermentable) complex subunit gene, as a significantly mutated driver gene. Genomic alterations in PBRM1 (12.5%) and homozygous deletions of the CDKN2A/2B locus are the most prevalent events. The combination of PBRM1 alterations and the chromosome 22q deletion, which involves another SWI/SNF gene (SMARCB1), shows strong associations with poor chordoma-specific survival (Hazard ratio [HR] = 10.55, 95% confidence interval [CI] = 2.81-39.64, p = 0.001) and recurrence-free survival (HR = 4.30, 95% CI = 2.34-7.91, p = 2.77 × 10−6). Despite the low mutation rate, extensive somatic copy number alterations frequently occur, most of which are clonal and showed highly concordant profiles between paired primary and recurrence/metastasis samples, indicating their importance in chordoma initiation. In this work, our findings provide important biological and clinical insights into skull-base chordoma.

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