Atherosclerosis regression is an important clinical goal. In previous studies of regression in mice, the rapid loss of plaque foam cells was explained by emigration to lymph nodes, a process ...reminiscent of dendritic cells. In the present study, plaque-containing arterial segments from$apoE^{-/-}$mice were transplanted into WT recipient normolipidemic mice or$apoE^{-/-}$mice. Three days after transplant, in the WT regression environment, plaque size decreased by ≈40%, and foam cell content by ≈75%. In contrast, both parameters increased in$apoE^{-/-}$recipients. Foam cells were isolated by laser capture microdissection. In WT recipients, there were 3- to 6-fold increases in foam cells of mRNA for liver X receptor α and cholesterol efflux factors, ABCA1 and SR-BI. Although liver X receptor a was induced, there was no detectable expression of its putative activator, peroxisome proliferator-activated receptor γ. Expression levels of VCAM or MCP-1 were reduced to 25% of levels in pretransplant or$apoE^{-/-}$recipient samples, but there was induction at the mRNA and protein levels of chemokine receptor CCR7, an essential factor for dendritic cell migration. Remarkably, when CCR7 function was abrogated in vivo by treatment of WT recipients with antibodies to CCR7 ligands CCL19 and CCL21, lesion size and foam cell content were substantially preserved. In summary, in foam cells during atherosclerosis regression, there is induction of CCR7 and a requirement for its function. Taken with the other gene expression data, these results in vivo point to complex relationships among the immune system, nuclear hormone receptors, and inflammation during regression.
Salivary duct carcinoma (SDC) is a rare, aggressive malignancy with limited treatment options and poor outcome. Twenty-nine primary resected SDC, including 15 SDC de novo (SDCDN), and 14 SDC ex ...pleomorphic adenoma (SDCXPA) were subjected to the massive parallel sequencing assay (MSK-IMPACT) targeting 287 to 468 cancer-related genes. TP53 was the most frequently altered gene (69%). TP53 mutations and ERBB2 amplification were more frequent in SDCXPA than in SDCDN (P = .0007 and P = .01, respectively). Potentially targetable mutations were detected in 79% (23/29) of SDC involving ERBB2 (31%), PIK3CA (28%), HRAS (21%), ALK (7%) and BRAF (3%), and 22% (5/23) of those cases harbored possible primary resistance mutations involving CCNE1, NF1 and PTEN. A novel HNRNPH3-ALK rearrangement was found in one SDCDN. In another case, EML4-ALK fusion detected in the primary tumor was associated with ALK G1202R secondary resistance mutation in the post-treatment metastasis. A germline analysis of the DNA repair genes revealed a case with a pathogenic BRCA1 E23fs germline variant. SDCDN and SDCXPA are genetically distinct. Although the majority of SDC may be amenable to molecular targeted therapy, concurrent possible resistance mutations may be found in a significant minority of cases. A broad genomic profiling is necessary to ensure detection of rare but clinically actionable somatic alterations in SDC.
•79% SDC harbor targetable somatic mutations.•22% SDC with targetable somatic mutations may harbor concurrent primary resistance mutations.•A novel HNRNPH3-ALK rearrangement is detected in SDC.•ALK inhibition in an EML4-ALK positive SDC can lead to ALK G1202R secondary resistance mutation.•First SDC patient harboring BRCA1 E23fs germline mutation is reported.
TERT gene promoter mutations are known in multiple cancer types. Other TERT alterations remain poorly characterized. Sequencing data from 30,773 tumors analyzed by a hybridization capture ...next-generation sequencing assay (Memorial Sloan Kettering Cancer Center Integrated Mutation Profiling of Actionable Cancer Targets) were analyzed for the presence of TERT alterations. Promoter rearrangements (500 bases upstream of the transcriptional start site), hypermethylation (n = 57), and gene expression (n = 155) were evaluated for a subset of cases. Mutually exclusive and recurrent promoter mutations were identified at three hot spots upstream of the transcriptional start site in 11.3% of cases (−124: 74%; −146: 24%; and −138: <2%). Mutually exclusive amplification events were identified in another 2.3% of cases, whereas mutually exclusive rearrangements proximal to the TERT gene were seen in 24 cases. The highest incidence of TERT promoter mutations was seen in cutaneous melanoma (82%), whereas amplification events significantly outnumbered promoter mutations in well-differentiated/dedifferentiated liposarcoma (14.1% versus 2.4%) and adrenocortical carcinoma (13.6% versus 4.5%). Gene expression analysis suggests that the highest levels of gene expression are seen in cases with amplifications and rearrangements. Hypermethylation events upstream of the TERT coding sequence were not mutually exclusive with known pathogenic alterations. Studies aimed at defining the prevalence and prognostic impact of TERT alterations should incorporate other pathogenic TERT alterations as these may impact telomerase function.
Sinonasal and skull base malignancies represent a rare, heterogenous group of pathologies with an incidence of 0.556 per 100,000 persons in the population. Given the numerous critical anatomic ...structures located adjacent to the sinonasal cavity and skull base, surgery for tumors in this region requires careful pre-operative planning with the assistance of radiological imaging and intraoperative image guidance technologies to reduce the risk of complications. Virtual surgical planning (VSP) and three-dimensional models (3DMs) are adjunctive technologies which assist clinicians to better visualize patient anatomy using enhanced digital radiological images and physical stereolithographic models based on patients' personal imaging. This review summarizes our institutional experience with VSP and 3DMs in sinonasal and skull base surgical oncology. A clinical case series is used to thematically illustrate the application of VSP and 3DMs in surgical ablation, reconstruction, patient communication, medical education, and interdisciplinary teamwork in sinonasal and skull base surgery.
Aims
Metastasis to the thyroid gland is a rare occurrence that may pose a diagnostic challenge. In this study, we aimed to report the clinicopathological features, immunoprofile, molecular ...alterations and outcome of 30 patients treated at our centre from 2003 to 2019.
Methods and results
The most common site of the primary tumour was the kidney, followed by the lung, lower gastrointestinal tract and breast. In seven (23%) patients, the thyroid metastases were resected prior to the diagnosis of the primary tumours. Six patients (20%) had thyroid as the sole metastatic site. Three (10%) patients harboured tumour‐to‐tumour metastasis; 71% had a unilateral unifocal thyroid mass, which might be mistaken for a primary thyroid tumour. Among the 13 cases that were initially diagnosed at an outside hospital, four (31%) were misinterpreted as a thyroid primary. An immunohistochemical panel of thyroid follicular cell markers was most useful to differentiate primary thyroid tumours from metastasis. Molecularly, the metastasis showed alterations characteristic of the primary tumour, which may be helpful in establishing the diagnosis and primary site. Although the prognosis was poor, with a 5‐year disease specific survival of 58%, a long‐term cure was possible in cases with oligometastasis successfully treated with surgery.
Conclusions
Metastasis to the thyroid gland is an uncommon phenomenon, with an incidence of 0.36% in all thyroid malignancies. It may present as a solitary thyroid mass before the discovery of the primary tumour, posing a diagnostic challenge. Although the overall prognosis is poor, a subset of patients with oligometastasis can be managed surgically.
Acinic cell carcinoma (AciCC) is traditionally considered as a low-grade salivary gland carcinoma. However, a subset demonstrates high-grade features with a higher mortality rate and distant ...metastasis. In this large retrospective study of 117 cases, we aimed to establish a histologic grading scheme for AciCC. Adverse independent prognostic factors identified on the multivariate analysis included older age, tumor necrosis, nuclear anaplasia, lymphovascular invasion, absence of tumor-associated lymphoid stroma, and high American Joint Committee on Cancer (AJCC) pT and pN stages. A 3-tiered grading scheme using 4 pathologic parameters (mitotic index, necrosis, tumor border, and fibrosis at the frankly invasive front) was subsequently applied. Compared with low/intermediate-grade, high-grade AciCC defined as a mitotic index ≥5/10 HPFs and/or necrosis was an independently adverse prognostic factor. The 5-year overall survival was 50% in high-grade AciCCs, and 100% in low-grade or intermediate-grade AciCCs. Compared with low-grade or intermediate-grade AciCC, high-grade tumors were associated with older age, larger tumor size, focal rather than diffuse zymogen granules, solid architecture, infiltrative tumor border, fibrosis at the frankly invasive front, lymphovascular invasion, perineural invasion, positive margin, high pT, and pN stages. NR4A3 was a highly sensitive and specific immunohistochemical stain for diagnosing AciCC with a sensitivity and specificity of 96% and 93%, respectively. In conclusion, although we proposed a 2-tiered grading system for AciCC with high-grade tumors defined by a mitotic count ≥5/10 HPFs and/or necrosis, more studies are needed to assess the prognostic value of intermediate grade. NR4A3 immunohistochemical stain is a useful diagnostic marker for AciCC.
The identification of specific genetic alterations as key oncogenic drivers and the development of targeted therapies are together transforming clinical oncology and creating a pressing need for ...increased breadth and throughput of clinical genotyping. Next-generation sequencing assays allow the efficient and unbiased detection of clinically actionable mutations. To enable precision oncology in patients with solid tumors, we developed Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT), a hybridization capture-based next-generation sequencing assay for targeted deep sequencing of all exons and selected introns of 341 key cancer genes in formalin-fixed, paraffin-embedded tumors. Barcoded libraries from patient-matched tumor and normal samples were captured, sequenced, and subjected to a custom analysis pipeline to identify somatic mutations. Sensitivity, specificity, reproducibility of MSK-IMPACT were assessed through extensive analytical validation. We tested 284 tumor samples with previously known point mutations and insertions/deletions in 47 exons of 19 cancer genes. All known variants were accurately detected, and there was high reproducibility of inter- and intrarun replicates. The detection limit for low-frequency variants was approximately 2% for hotspot mutations and 5% for nonhotspot mutations. Copy number alterations and structural rearrangements were also reliably detected. MSK-IMPACT profiles oncogenic DNA alterations in clinical solid tumor samples with high accuracy and sensitivity. Paired analysis of tumors and patient-matched normal samples enables unambiguous detection of somatic mutations to guide treatment decisions.
Tumor molecular profiling is a fundamental component of precision oncology, enabling the identification of genomic alterations in genes and pathways that can be targeted therapeutically. The ...existence of recurrent targetable alterations across distinct histologically defined tumor types, coupled with an expanding portfolio of molecularly targeted therapies, demands flexible and comprehensive approaches to profile clinically relevant genes across the full spectrum of cancers. We established a large-scale, prospective clinical sequencing initiative using a comprehensive assay, MSK-IMPACT, through which we have compiled tumor and matched normal sequence data from a unique cohort of more than 10,000 patients with advanced cancer and available pathological and clinical annotations. Using these data, we identified clinically relevant somatic mutations, novel noncoding alterations, and mutational signatures that were shared by common and rare tumor types. Patients were enrolled on genomically matched clinical trials at a rate of 11%. To enable discovery of novel biomarkers and deeper investigation into rare alterations and tumor types, all results are publicly accessible.
Aims
The diagnosis of thyroid neoplasms relies upon the demonstration of histological parameters that can be focal and prone to subjective interpretation. We evaluated the utility of NRAS Q61R ...immunohistochemistry (IHC) in the diagnosis of thyroid lesions after determining its specificity and sensitivity as a surrogate marker for RAS Q61R mutation.
Method and results
NRAS Q61R IHC was performed on 282 primary or metastatic thyroid lesions from 256 patients. RAS mutation status was collected from patients’ charts. Sensitivity and specificity of NRAS Q61R IHC for detecting a RAS Q61R mutation was calculated. IHC‐positive cases were reviewed to determine the diagnostic utility of NRAS Q61R IHC. NRAS Q61R immunopositivity was seen in non‐neoplastic, benign and malignant thyroid lesions. NRAS Q61R antibody cross‐reactivity led to the detection of NRAS Q61R, KRAS Q61R and HRAS Q61R proteins. Among primary thyroid carcinomas, immunopositivity was most frequent in papillary thyroid carcinomas, follicular variant (48.0%). The sensitivity and specificity of NRAS Q61R IHC in detecting RAS Q61R mutation was 90.6% and 92.3%, respectively. When positive, the NRAS Q61R stain was determined to be helpful in demonstrating infiltration, tumour size, capsular and/or vascular invasion and multifocality.
Conclusion
NRAS Q61R IHC is highly sensitive and specific for the detection of RAS Q61R mutations in thyroid pathology and is particularly relevant in follicular‐patterned neoplasms. When evaluated alongside histological features, NRAS Q61R immunoreactivity can be instrumental in the diagnosis and classification of thyroid nodules.
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