-
Oncogene Feb 2021MicroRNAs (miRs) are small non-coding RNAs that can have large impacts on oncogenic pathways. Possible functions of dysregulated miRs have not been studied in...
MicroRNAs (miRs) are small non-coding RNAs that can have large impacts on oncogenic pathways. Possible functions of dysregulated miRs have not been studied in neurofibromatosis type 1 (NF1) plexiform neurofibromas (PNFs). In PNFs, Schwann cells (SCs) have biallelic NF1 mutations necessary for tumorigenesis. We analyzed a miR microarray comparing with normal and PNF SCs and identified differences in miR expression, and we validated in mouse PNFs versus normal mouse SCs by qRT-PCR. Among these, miR-155 was a top overexpressed miR, and its expression was regulated by RAS/MAPK signaling. Overexpression of miR-155 increased mature Nf1 mouse SC proliferation. In SC precursors, which model tumor-initiating cells, pharmacological and genetic inhibition of miR-155 decreased PNF-derived sphere numbers in vitro, and we identified Maf as a miR-155 target. In vivo, global deletion of miR-155 significantly decreased tumor number and volume, increasing mouse survival. Fluorescent nanoparticles entered PNFs, suggesting that an anti-miR might have therapeutic potential. However, treatment of established PNFs using anti-miR-155 peptide nucleic acid-loaded nanoparticles marginally decreased tumor numbers and did not reduce tumor growth. These results suggest that miR-155 plays a functional role in PNF growth and/or SC proliferation, and that targeting neurofibroma miRs is feasible, and might provide novel therapeutic opportunities.
Topics: Animals; Carcinogenesis; Cell Line, Tumor; Cell Proliferation; Humans; Mice; Mice, Knockout; MicroRNAs; Mitogen-Activated Protein Kinase Kinases; Neurofibroma; Neurofibromin 1; Schwann Cells
PubMed: 33293695
DOI: 10.1038/s41388-020-01581-9 -
BMB Reports Jul 2013microRNAs (miRNAs) are small non-coding RNAs that regulate gene expression by targeting the 3'-untranslated region of multiple target genes. Pathogenesis results from... (Review)
Review
microRNAs (miRNAs) are small non-coding RNAs that regulate gene expression by targeting the 3'-untranslated region of multiple target genes. Pathogenesis results from defects in several gene sets; therefore, disease progression could be prevented using miRNAs targeting multiple genes. Moreover, recent studies suggest that miRNAs reflect the stage of the specific disease, such as carcinogenesis. Cystic diseases, including polycystic kidney disease, polycystic liver disease, pancreatic cystic disease, and ovarian cystic disease, have common processes of cyst formation in the specific organ. Specifically, epithelial cells initiate abnormal cell proliferation and apoptosis as a result of alterations to key genes. Cysts are caused by fluid accumulation in the lumen. However, the molecular mechanisms underlying cyst formation and progression remain unclear. This review aims to introduce the key miRNAs related to cyst formation, and we suggest that miRNAs could be useful biomarkers and potential therapeutic targets in several cystic diseases.
Topics: Biomarkers; Cysts; Female; Humans; Liver Diseases; MicroRNAs; Pancreatic Cyst; Polycystic Kidney Diseases; Polycystic Ovary Syndrome
PubMed: 23884099
DOI: 10.5483/bmbrep.2013.46.7.151 -
Gastrointestinal Endoscopy Jan 2023Recent advances have introduced molecular subtyping of pancreatic cystic lesions (PCLs) as a possible amendment to the diagnostic algorithm. The study evaluated the... (Clinical Trial)
Clinical Trial
BACKGROUND AND AIMS
Recent advances have introduced molecular subtyping of pancreatic cystic lesions (PCLs) as a possible amendment to the diagnostic algorithm. The study evaluated the feasibility and diagnostic accuracy of molecular analysis and subtyping of PCLs using the recently introduced EUS-guided through-the-needle-biopsy (TTNB) sampling.
METHODS
We prospectively included 101 patients in the study who presented with PCLs >15 mm in the largest cross-section. EUS-guided TTNB samples were obtained by a micro-biopsy forceps introduced through a 19-gauge needle. The TTNB samples were analyzed by next-generation sequencing (NGS) for point mutations in tumor suppressors and oncogenes using a 51-gene customized hotspot panel. Sensitivity and specificity were calculated with the histologic diagnosis as reference.
RESULTS
After initial microscopic evaluation of the samples, 91 patients had residual TTNB samples available for NGS. Of these, 49 harbored mutations, most frequently in KRAS and GNAS, reflecting an excess frequency of intraductal papillary mucinous neoplasms (IPMNs) in the study population. A sensitivity and specificity of 83.7% (95% confidence interval [CI], 70.3-92.7) and 81.8% (95% CI, 48.2-97.7), respectively, were demonstrated for the diagnosis of a mucinous cyst and 87.2% (95% CI, 74.2-95.2) and 84.6% (95% CI, 54.5-98.1) for the diagnosis of an IPMN.
CONCLUSIONS
Thus, molecular analysis of TTNB samples by NGS has high sensitivity and specificity for diagnosing mucinous cysts and IPMNs. Although the procedure comes with a risk of adverse events of 9.9%, TTNB samples are a robust alternative to cyst fluid for a combined histologic and molecular diagnosis of PCLs. (Clinical trial registration number: NCT03578445.).
Topics: Humans; Cyst Fluid; Endoscopic Ultrasound-Guided Fine Needle Aspiration; High-Throughput Nucleotide Sequencing; Pancreas; Pancreatic Cyst; Pancreatic Neoplasms
PubMed: 35964683
DOI: 10.1016/j.gie.2022.08.008 -
Acta Obstetricia Et Gynecologica... Nov 2004The treatment of an ovarian cyst relies on its nature, and accurate preoperative discrimination of benign and malignant cysts is therefore of crucial importance. This... (Review)
Review
BACKGROUND
The treatment of an ovarian cyst relies on its nature, and accurate preoperative discrimination of benign and malignant cysts is therefore of crucial importance. This study was undertaken to review the literature concerning the preoperative diagnosis and treatment of ovarian cysts.
METHODS
Articles concerning ovarian cysts from a medline literature search during the period 1985-2003 were included in addition to articles found as references in the initial publications.
RESULTS
Different methods for discriminating between benign and malignant ovarian cysts are discussed. The diagnosis and the treatment are assessed in relation to age, menopausal status, pregnancy, and whether the cyst is presumed to be benign or malignant. In general, expectant management is the choice in premenopausal and pregnant women with non-suspicious cysts and normal levels of CA-125. In postmenopausal women, unilocular, anechoic cysts less than 5 cm in diameter together with a normal CA-125 may be followed up. Operation is recommended in women with cysts larger than 5 cm and/or elevated levels of CA-125. Women with symptoms should be operated regardless of age, menopausal status, or ultrasound findings.
CONCLUSIONS
The preoperative discrimination between benign and malignant ovarian cysts is a challenge. Multimodal methods improve the results of single modalities, but we still need improved preoperative diagnostic tools. Furthermore, these methods should be validated in consecutive patient populations large enough to give a reliable estimate of the method's sensitivity and specificity.
Topics: CA-125 Antigen; Female; Humans; Ovarian Cysts; Ovarian Neoplasms; Practice Guidelines as Topic; Ultrasonography
PubMed: 15488114
DOI: 10.1111/j.0001-6349.2004.00607.x -
Head and Neck Pathology Mar 2015To reappraise the early history of odontogenic ghost cell lesions (OGCL), the extensive world literature published from 1838 to 1962 was reviewed. In light of the long... (Review)
Review
To reappraise the early history of odontogenic ghost cell lesions (OGCL), the extensive world literature published from 1838 to 1962 was reviewed. In light of the long history of OGCL, the term "calcifying epithelioma of Malherbe" first appeared in a 1931 French report, and the term "ghost cells" had its origin in two American seminal articles by Thoma and Goldman in 1946. Although Gorlin et al. coined the term "calcifying odontogenic cyst" (COC) in 1962, this type of cyst was initially reported three decades earlier by Rywkind in Russia, and almost concurrently by Blood good in the United States and Sato in Japan. In 1948, Willis provided the initial histological evidence of a peripheral COC in his British pathology textbook. Credit for the earliest clinical presentation of odontoma associated calcifying cystic odontogenic tumor belongs to the American radiology textbook by Thoma in 1917. A Scandinavian journal report published in 1953 by Husted and Pindborg was the first to address a dentinogenic ghost cell tumor, and its peripheral counterpart was originally reported in the Swiss literature 7 years later. The current concept of COC was undoubtedly established by Gorlin et al. but the history of OGCL really started with Thoma's pioneering work about a century ago.
Topics: History, 19th Century; History, 20th Century; Humans; Odontogenic Cyst, Calcifying
PubMed: 24972654
DOI: 10.1007/s12105-014-0552-6 -
Oncogene Mar 2023Neurofibromatosis type 1 (NF1) patients are predisposed to develop plexiform neurofibromas (PNFs). Three endoplasmic reticulum (ER) stress response pathways restore...
Neurofibromatosis type 1 (NF1) patients are predisposed to develop plexiform neurofibromas (PNFs). Three endoplasmic reticulum (ER) stress response pathways restore cellular homeostasis. The unfolded protein response (UPR) sensors contribute to tumor initiation in many cancers. We found that all three UPR pathways were activated in mouse and human PNFs, with protein kinase RNA [PKR]-like ER kinase (PERK) the most highly expressed. We tested if neurofibroma cells adapt to ER stress, leading to their growth. Pharmacological or genetic inhibition of PERK reduced mouse neurofibroma-sphere number, and genetic inhibition in PERK in Schwann cell precursors (SCPs) decreased tumor-like lesion numbers in a cell transplantation model. Further, in a PNF mouse model, deletion of PERK in Schwann cells (SCs) and SCPs reduced tumor size, number, and increased survival. Mechanistically, loss of Nf1 activated PERK-eIF2α-ATF4 signaling and increased ATF4 downstream target gene p21 translocation from nucleus to cytoplasm. This nucleus-cytoplasm translocation was mediated by exportin-1. Runx transcriptionally activated ribosome gene expression and increased protein synthesis to allow SCs to adapt to ER stress and tumor formation. We propose that targeting proteostasis might provide cytotoxic and/or potentially durable novel therapy for PNFs.
Topics: Animals; Humans; Mice; Core Binding Factor Alpha 2 Subunit; eIF-2 Kinase; Endoplasmic Reticulum Stress; Neurofibroma; Neurofibroma, Plexiform; Neurofibromatosis 1; Unfolded Protein Response
PubMed: 36759572
DOI: 10.1038/s41388-023-02620-x -
BMC Oral Health Nov 2023Dental panoramic radiographs are utilized in computer-aided image analysis, which detects abnormal tissue masses by analyzing the produced image capacity to recognize...
BACKGROUND AND OBJECTIVE
Dental panoramic radiographs are utilized in computer-aided image analysis, which detects abnormal tissue masses by analyzing the produced image capacity to recognize patterns of intensity fluctuations. This is done to reduce the need for invasive biopsies for arriving to a diagnosis. The aim of the current study was to examine and compare the accuracy of several texture analysis techniques, such as Grey Level Run Length Matrix (GLRLM), Grey Level Co-occurrence Matrix (GLCM), and wavelet analysis in recognizing dental cyst, tumor, and abscess lesions.
MATERIALS & METHODS
The current retrospective study retrieved a total of 172 dental panoramic radiographs with lesion including dental cysts, tumors, or abscess. Radiographs that failed to meet technical criteria for diagnostic quality (such as significant overlap of teeth, a diffuse image, or distortion) were excluded from the sample. The methodology adopted in the study comprised of five stages. At first, the radiographs are improved, and the area of interest was segmented manually. A variety of feature extraction techniques, such GLCM, GLRLM, and the wavelet analysis were used to gather information from the area of interest. Later, the lesions were classified as a cyst, tumor, abscess, or using a support vector machine (SVM) classifier. Eventually, the data was transferred into a Microsoft Excel spreadsheet and statistical package for social sciences (SPSS) (version 21) was used to conduct the statistical analysis. Initially descriptive statistics were computed. For inferential analysis, statistical significance was determined by a p value < 0.05. The sensitivity, specificity, and accuracy were used to find the significant difference between assessed and actual diagnosis.
RESULTS
The findings demonstrate that 98% accuracy was achieved using GLCM, 91% accuracy using Wavelet analysis & 95% accuracy using GLRLM in distinguishing between dental cyst, tumor, and abscess lesions. The area under curve (AUC) number indicates that GLCM achieves a high degree of accuracy. The results achieved excellent accuracy (98%) using GLCM.
CONCLUSION
The GLCM features can be used for further research. After improving the performance and training, it can support routine histological diagnosis and can assist the clinicians in arriving at accurate and spontaneous treatment plans.
Topics: Humans; Retrospective Studies; Abscess; Machine Learning; Cysts
PubMed: 37932703
DOI: 10.1186/s12903-023-03571-1 -
Neuro-oncology Aug 2022Nearly one-third of patients with neurofibromatosis type 1-associated optic pathway glioma (NF1-OPG) fail frontline chemotherapy; however, little is known about risk...
BACKGROUND
Nearly one-third of patients with neurofibromatosis type 1-associated optic pathway glioma (NF1-OPG) fail frontline chemotherapy; however, little is known about risk factors for treatment failure.
METHODS
We performed a retrospective multi-institutional cohort study to identify baseline risk factors for treatment-refractory/relapsed disease and poor visual outcome in children with NF1-OPG. Refractory/relapsed NF1-OPG was defined as a requirement of two or more treatment regimens due to progression or relapse.
RESULTS
Of 111 subjects eligible for inclusion, adequate clinical and visual data were available for 103 subjects from 7 institutions. Median follow-up from the initiation of first chemotherapy regimen was 95 months (range 13-185). Eighty-four (82%) subjects received carboplatin-based frontline chemotherapy. Forty-five subjects (44%) experienced refractory/relapsed disease, with a median time of 21.5 months (range 2-149) from the initiation of first treatment to the start of second treatment. The proportion of patients without refractory/relapsed disease at 2 and 5 years was 78% and 60%. In multivariable analyses, age less than 24 months at initial treatment, posterior tumor location, and familial inheritance were associated with refractory/relapsed NF1-OPG by 2 years. Both age less than 24 months and posterior tumor location were associated with refractory/relapsed NF1-OPG by 5 years. Subjects with moderate to severe vision loss at last follow-up were more likely to have posterior tumor location, optic disc abnormalities, or abnormal visual acuity at initial treatment.
CONCLUSION
Young age, posterior tumor location, and optic disc abnormalities may identify patients with the greatest likelihood of refractory/relapsed NF1-OPG and poor visual outcomes, and who may benefit from newer treatment strategies.
Topics: Child; Cohort Studies; Humans; Infant; Neurofibromatosis 1; Optic Nerve Glioma; Retrospective Studies; Risk Factors
PubMed: 35018469
DOI: 10.1093/neuonc/noac013 -
Acta Neuropathologica Mar 2012Neurofibromas, schwannomas and malignant peripheral nerve sheath tumors (MPNSTs) all arise from the Schwann cell lineage. Despite their common origin, these tumor types... (Review)
Review
Neurofibromas, schwannomas and malignant peripheral nerve sheath tumors (MPNSTs) all arise from the Schwann cell lineage. Despite their common origin, these tumor types have distinct pathologies and clinical behaviors; a growing body of evidence indicates that they also arise via distinct pathogenic mechanisms. Identification of the genes that are mutated in genetic diseases characterized by the development of either neurofibromas and MPNSTs [neurofibromatosis type 1 (NF1)] or schwannomas [neurofibromatosis type 2 (NF2), schwannomatosis and Carney complex type 1] has greatly advanced our understanding of these mechanisms. The development of genetically engineered mice with ablation of NF1, NF2, SMARCB1/INI1 or PRKAR1A has confirmed the key role these genes play in peripheral nerve sheath tumorigenesis. Establishing the functions of the NF1, NF2, SMARCB1/INI1 and PRKAR1A gene products has led to the identification of key cytoplasmic signaling pathways promoting Schwann cell neoplasia and identified new therapeutic targets. Analyses of human neoplasms and genetically engineered mouse models have established that interactions with other tumor suppressors such as TP53 and CDKN2A promote neurofibroma-MPNST progression and indicate that intratumoral interactions between neoplastic and non-neoplastic cell types play an essential role in peripheral nerve sheath tumorigenesis. Recent advances have also provided new insights into the identity of the neural crest-derived populations that give rise to different types of peripheral nerve sheath tumors. Based on these findings, we now have an initial outline of the molecular mechanisms driving the pathogenesis of neurofibromas, MPNSTs and schwannomas. However, this improved understanding in turn raises a host of intriguing new questions.
Topics: Cell Transformation, Neoplastic; Humans; Nerve Sheath Neoplasms; Neurilemmoma; Neurofibromatoses; Schwann Cells
PubMed: 22160322
DOI: 10.1007/s00401-011-0928-6 -
Neurology Aug 2020To define the radiologic features and natural history of nonoptic pathway tumors (non-OPTs) in children with neurofibromatosis type 1 (NF1).
OBJECTIVE
To define the radiologic features and natural history of nonoptic pathway tumors (non-OPTs) in children with neurofibromatosis type 1 (NF1).
METHODS
We performed a retrospective cross-sectional analysis of 64 children with NF1 harboring 100 probable non-OPTs. Age at diagnosis, sex, tumor location, number of tumors, symptomology, concurrent OPT, radiographic progression (defined as qualitative and quantitative increases in size), and treatment were assessed. Tumor volumes were measured from initial presentation until treatment or end of disease progression.
RESULTS
Sixty-three percent of probable non-OPTs progressed over time, where radiographic progression was concomitantly associated with clinical progression. Fifty-two percent of patients had incidentally identified probable non-OPTs. Twenty-five percent of patients were symptomatic at initial diagnosis, all of whom harbored tumors that grew on subsequent scans and required tumor-directed therapy. There were no clinical differences between probable non-OPTs localized to the brainstem vs other locations with respect to age, sex, concurrent optic pathway glioma, symptomology, and treatment. The average time from diagnosis to stabilization or decrease in tumor size was 2.34 years (SD, 2.15 years). Nineteen biopsied lesions were all histopathologically confirmed as tumor. Six children (9%) had deep extensive tumors, who presented earlier (mean age at diagnosis, 3.88 years), required multiple treatments, and had a shorter mean progression-free survival (48 months).
CONCLUSIONS
Over half of children with NF1 in this study developed probable non-OPTs, the majority of which were clinically and radiographically progressive. While brainstem and nonbrainstem gliomas share similar clinical features and natural history, deep extensive tumors comprise a distinct aggressive group of tumors that warrant close attention.
Topics: Adolescent; Brain Neoplasms; Child; Child, Preschool; Cross-Sectional Studies; Female; Humans; Infant; Magnetic Resonance Imaging; Male; Neurofibromatosis 1; Retrospective Studies
PubMed: 32300062
DOI: 10.1212/WNL.0000000000009458