Rising utilization of preoperative CT and advances in technology coincided with a decrease in the negative appendectomy rate for women 45 years and younger but not in men of any age or women older than 45 years.
Chondrosarcomas (CHS) represent a heterogeneous group of disorders ranging from indolent, low-grade tumors to aggressive, high-grade forms. Surgical resection represents the primary and preferred treatment modality for individuals with localized disease. Radiation therapy is appropriate for the treatment of positive surgical margins or palliation of disease-related symptoms. The treatment of advanced, metastatic disease is particularly challenging given the recognition that conventional chemotherapy has proven to be largely ineffective. Systemic chemotherapy may be considered in variant forms such as mesenchymal or dedifferentiated chondrosarcomas but high-quality data supporting its use is limited. There is universal agreement, however, that novel treatment strategies are desperately needed. This review will highlight the need for a coordinated multidisciplinary approach to optimize the management and care of patients.
Liposarcoma (LS) represents the most common type of soft tissue sarcoma. LS is subdivided into four distinct subtypes: well-differentiated, myxoid/round cell, pleomorphic, and mixed LS. In addition to distinctive morphology, each of the subgroups has a different prognosis and treatment strategy. While subgrouping has traditionally been based on conventional morphology, recent molecular and cytogenetic findings have validated the current classification system. Well-differentiated LS is characterized by overexpression of MDM2, which blocks the tumor suppressor function of p53. Myxoid/round cell LS is characterized by a specific translocation resulting in a fusion protein which interferes with adipocyte differentiation. Pleomorphic LS, like other high grade sarcomas, is characterized by multiple chromosomal abnormalities. Each of these distinctive molecular signatures can be exploited to aid in the subtyping of LS and in distinguishing true sarcomas of lipogenic derivation from benign mimics.
Undifferentiated pleomorphic sarcoma/Malignant Fibrous Histiocytoma (MFH) is one of the most common subtypes of human soft tissue sarcoma. Using cross species genomic analysis, we define a geneset from the LSL-KrasG12D; Trp53Flox/Flox mouse model of soft tissue sarcoma that is highly enriched in human MFH. With this mouse geneset as a filter, we identify expression of the RAS target FOXM1 in human MFH. Expression of Foxm1 is elevated in mouse sarcomas that metastasize to the lung and tissue microarray analysis of human MFH correlates overexpression of FOXM1 with metastasis. These results suggest that genomic alterations present in human MFH are conserved in the LSL-KrasG12D; p53Flox/Flox mouse model of soft tissue sarcoma and demonstrate the utility of this pre-clinical model.
Background
Diff-Quik stained fine-needle aspiration (FNA) smears and touch preparations from biopsies represent alternative specimens for molecular testing when cell block or biopsy material is insufficient. We describe the use of these samples for targeted next-generation sequencing (NGS) of primary and metastatic lung adenocarcinoma and report DNA quality and success rates of FNA smears compared with other specimens from one year of clinical use.
Methods
A validation set of 10 slides from 9 patients with prior clinical EGFR Sanger sequencing and KRAS pyrosequencing (5 KRAS +/EGFR−, 4 KRAS/EGFR−) underwent DNA extraction, quality assessment, and targeted NGS. Subseqently, lung adenocarcinoma specimens submitted for NGS solid tumor mutation panel testing in one calendar year (60 biopsies, 57 resections, 33 FNA cell blocks, 12 FNA smears, 10 body fluid cell blocks) were reviewed for specimen adequacy, sequencing success, and DNA quality.
Results
All 10 validation samples met the DNA quality threshold (ΔCT threshold <8, range −2.2 to 4.9) and yielded 0.5 to 22 μg of DNA. KRAS and EGFR mutation status from FNA smears by NGS were concordant with previous clinical testing for all 10 samples. In the one year review, FNA smears were 100% successful, suggesting performance equivalent to or better than established specimen types, including FNA cell blocks. DNA quality by ΔCT was significantly better from FNA smears than from biopsies, resections, and FNA cell blocks.
Conclusions
We conclude that FNA smears of lung adenocarcinomas are a high quality alternative specimen for a targeted NGS panel with a high success rate in clinical practice.
Soft-tissue sarcomas are a heterogeneous group of tumors arising from connective tissue. Recently, mutations in the neurofibromin 1 (NF1) tumor suppressor gene were identified in multiple subtypes of human soft-tissue sarcomas. To study the effect of NF1 inactivation in the initiation and progression of distinct sarcoma subtypes, we have developed a novel mouse model of temporally and spatially restricted NF1-deleted sarcoma.
To generate primary sarcomas, we inject adenovirus containing Cre recombinase into NF1flox/flox; Ink4a/Arf flox/flox mice at two distinct orthotopic sites: intramuscularly or in the sciatic nerve. The mice develop either high-grade myogenic sarcomas or MPNST-like tumors, respectively. These tumors reflect the histological properties and spectrum of sarcomas found in patients. To explore the utility of this model for preclinical studies, we performed a study of MAPK pathway inhibition with the MEK inhibitor PD325901. Treatment with PD325901 delays tumor growth through decreased cyclin D1 mRNA and cell proliferation. We also examined the effects of MEK inhibition on the native tumor stroma and find that PD325901 decreases VEGFα expression in tumor cells with a corresponding decrease in microvessel density. Taken together, our results utilize a primary tumor model to demonstrate that sarcomas can be generated by loss of NF1 and Ink4a/Arf, and that these tumors are sensitive to MEK inhibition by direct effects on tumor cells and the surrounding microenvironment. These studies suggest that MEK inhibitors should be further explored as potential sarcoma therapies in patients with tumors containing NF1 deletion.
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