45 research outputs found
Activation of the mTOR Pathway in Primary Medullary Thyroid Carcinoma and Lymph Node Metastases.
No full textUnderstanding the molecular pathogenesis of medullary thyroid carcinoma (MTC) is prerequisite to the design of targeted therapies for patients with advanced disease.We studied by immunohistochemistry the phosphorylation status of proteins of the RAS/MEK/ERK and PI3K/AKT/mTOR pathways in 53 MTC tissues (18 hereditary, 35 sporadic), including 51 primary MTCs and 2 cases with only lymph node metastases (LNM). We also studied 21 autologous LNMs, matched to 21 primary MTCs. Staining was graded on a 0 to 4 scale (S score) based on the percentage of positive cells. We also studied the functional relevance of the mTOR pathway by measuring cell viability, motility, and tumorigenicity upon mTOR chemical blockade.Phosphorylation of ribosomal protein S6 (pS6), a downstream target of mTOR, was evident (S ≥ 1) in 49 (96\%) of 51 primary MTC samples. This was associated with activation of AKT (phospho-Ser473, S > 1) in 79\% of cases studied. Activation of pS6 was also observed (S ≥ 1) in 7 (70\%) of 10 hereditary C-cell hyperplasia specimens, possibly representing an early stage of C-cell transformation. It is noteworthy that 22 (96\%) of 23 LNMs had a high pS6 positivity (S ≥ 3), which was increased compared with autologous matched primary MTCs (P = 0.024). Chemical mTOR blockade blunted viability (P < 0.01), motility (P < 0.01), and tumorigenicity (P < 0.01) of human MTC cells.The AKT/mTOR pathway is activated in MTC, particularly, in LNMs. This pathway sustains malignant features of MTC cell models. These findings suggest that targeting mTOR might be efficacious in patients with advanced MTC. Clin Cancer Res; 18(13); 3532-40. ©2012 AACR
Abstract 3847: Oral cavity squamous cell carcinoma xenografts display conservation of primary tumor genomic heterogeneity
No full textAbstract
Purpose: Patient derived xenograft (PDX) models represent a platform for defining therapeutic opportunities based on their ability to maintain the genomic and molecular features of their respective tumors. We used a comprehensive genomics approach to analyze PDXs for oral squamous cell carcinoma (OSCC), which had not been previously described. This involved confirming that the PDXs conserve the heterogeneous somatic landscape of the primary tumors from which they were derived.
Methods: We established a large panel of OSCC PDX models by engrafting fresh, primary tumor samples into NOD scid gamma (NSG) mice. We performed whole genome sequencing (WGS; n=10), whole exome sequencing (WES; n=15), and transcriptome sequencing (RNAseq; n=15) on matched primary and first passage xenografts. Somatic events, including mutations, copy number alterations (CNAs), loss-of-heterozygosity (LOH) regions, and structural variation (SV), were detected independently in tumors and PDXs. Conservation was defined by the correlation of variant allele frequency (VAF) distributions and gene expression patterns, presence of larger somatic events, and predictions made about the subclonal architecture of the tumor and xenograft.
Results: PDXs were established with an overall success rate of 47% (56/118). The somatic landscape of primary tumors was representative of the published genomic data on OSCC, including amplifications of CCND1 and EGFR family members, inactivating mutations and loss of TP53 and CDKN2A, and chromosome 3q amplification. These somatic events were also strongly conserved in matched xenograft samples. Mutations that were detected in either the xenograft or primary tumor, but not its matched sample, consisted primarily of low-frequency mutations. The predicted clonal architecture, however, revealed correlative subclonal heterogeneity between matched xenograft and primary tumor. This includes maintenance of founding clone mutations and consistent VAF distributions, indicating that a heterogeneous tumor population engrafted.
Conclusions: This comprehensive approach establishes early-passage PDXs as high fidelity models for OSCC. Their ability to maintain the genomic heterogeneity detected in primary OSCC tumors presents a clinically relevant platform for understanding tumor biology and identifying novel therapeutic strategies.
Citation Format: Katie M. Campbell, Tianxiang Lin, Ashley E. Winkler, Paul Zolkind, Zachary L. Skidmore, Erica K. Barnell, Ian Hagemann, Elaine R. Mardis, Malachi Griffith, Rebecca D. Chernock, Obi L. Griffith, Ravindra Uppaluri. Oral cavity squamous cell carcinoma xenografts display conservation of primary tumor genomic heterogeneity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3847. doi:10.1158/1538-7445.AM2017-3847</jats:p
Diagnostic accuracy of fungal identification in histopathology and cytopathology specimens
No full textDiagnostic accuracy of fungal identification in histopathologyand cytopathology specimens
No full textSeromucinous Hamartoma of the Nasal Cavity: A Report of Two Cases and Review of the Literature
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Squamous and Neuroendocrine Specific Immunohistochemical Markers in Head and Neck Squamous Cell Carcinoma: A Tissue Microarray Study
No full textATSC 3.0 Next Generation Digital TV Standard - An Overview and Preview of the Issue
No full text"(c) 2016 IEEE. Personal use of this material is permitted. Permission from IEEE must be obtained for all other users, including reprinting/ republishing this material for advertising or promotional purposes, creating new collective works for resale or redistribution to servers or lists, or reuse of any copyrighted components of this work in other works."The Advanced Television Committee (ATSC) has been working on the next generation broadcast television system, known as ATSC 3.0, to replace the first-generation (ATSC 1.0) A/53 standard, the basic component technologies of which have been in use for 20 years.Chernock, R.; Gómez Barquero, D.; Whitaker, J.; Park, S.; Wu, Y. (2016). ATSC 3.0 Next Generation Digital TV Standard - An Overview and Preview of the Issue. IEEE Transactions on Broadcasting. 62(1):154-158. doi:10.1109/TBC.2016.2515542S15415862
Prevalence of HPV infection in racial-ethnic subgroups of head and neck cancer patients
No full textThe landscape of human papillomavirus (HPV) infection in racial/ethnic subgroups of head and neck cancer (HNC) patients has not been evaluated carefully. In this study, a meta-analysis examined the prevalence of HPV in HNC patients of African ancestry. Additionally, a pooled analysis of subject-level data was also performed to investigate HPV prevalence and patterns of p16 (CDNK2A) expression amongst different racial groups. Eighteen publications (N = 798 Black HNC patients) were examined in the meta-analysis, and the pooled analysis included 29 datasets comprised of 3129 HNC patients of diverse racial/ethnic background. The meta-analysis revealed that the prevalence of HPV16 was higher among Blacks with oropharyngeal cancer than Blacks with non-oropharyngeal cancer. However, there was great heterogeneity observed among studies (Q test P < 0.0001). In the pooled analysis, after adjusting for each study, year of diagnosis, age, gender and smoking status, the prevalence of HPV16,18 in oropharyngeal cancer patients was highest in Whites (61.1%), followed by 58.0% in Blacks and 25.2% in Asians (P < 0.0001). There was no statistically significant difference in HPV16,18 prevalence in nonoropharyngeal cancer by race (P = 0.682). With regard to the pattern of HPV16,18 status and p16 expression, White patients had the highest proportion of HPV16,18+/p16+ oropharyngeal cancer (52.3%), while Asians and Blacks had significantly lower proportions (23.0 and 22.6%, respectively) [P < 0.0001]. Our findings suggest that the pattern of HPV16,18 status and p16 expression in oropharyngeal cancer appears to differ by race and this may contribute to survival disparities
Seven years of Non-invasive Follicular Thyroid Neoplasm with Papillary-like Nuclear Features (NIFTP): Rate of Acceptance and Variation of Diagnostic Approaches Across Different Continents
No full textCONTEXT: Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was introduced as a new entity replacing the diagnosis of noninvasive encapsulated follicular variant of papillary thyroid carcinoma (PTC). Significant variability in the incidence of NIFTP diagnosed in different world regions has been reported. OBJECTIVE: To investigate the rate of adoption of NIFTP, change in practice patterns, and uniformity in applying diagnostic criteria among pathologists practicing in different regions. METHODS: Two surveys distributed to pathologists of the International Endocrine Pathology Discussion Group with multiple-choice questions on NIFTP adoption into pathology practice and whole slide images of 5 tumors to collect information on nuclear score and diagnosis. Forty-eight endocrine pathologists, including 24 from North America, 8 from Europe, and 16 from Asia/Oceania completed the first survey and 38 the second survey. RESULTS: A 94% adoption rate of NIFTP by the pathologists was found. Yet, the frequency of rendering NIFTP diagnosis was significantly higher in North America than in other regions (P = .009). While the highest concordance was found in diagnosing lesions with mildly or well-developed PTC-like nuclei, there was significant variability in nuclear scoring and diagnosing NIFTP for tumors with moderate nuclear changes (nuclear score 2) (case 2, P < .05). Pathologists practicing in North America and Europe showed a tendency for lower thresholds for PTC-like nuclei and NIFTP than those practicing in Asia/Oceania. CONCLUSION: Despite a high adoption rate of NIFTP across geographic regions, NIFTP is diagnosed more often by pathologists in North America. Significant differences remain in diagnosing intermediate PTC-like nuclei and respectively NIFTP, with more conservative nuclear scoring in Asia/Oceania, which may explain the geographic differences in NIFTP incidence
