ETV4 and ETV5 drive synovial sarcoma through cell cycle and DUX4 embryonic pathway control

Synovial sarcoma is an aggressive malignancy with no effective treatments for patients with metastasis. The synovial sarcoma fusion SS18-SSX, which recruits the SWI/SNF-BAF chromatin remodeling and polycomb repressive complexes, results in epigenetic activation of FGF receptor (FGFR) signaling. In genetic FGFR-knockout models, culture, and xenograft synovial sarcoma models treated with the FGFR inhibitor BGJ398, we show that FGFR1, FGFR2, and FGFR3 were crucial for tumor growth. Transcriptome analyses of BGJ398-treated cells and histological and expression analyses of mouse and human synovial sarcoma tumors revealed prevalent expression of two ETS factors and FGFR targets, ETV4 and ETV5. We further demonstrate that ETV4 and ETV5 acted as drivers of synovial sarcoma growth, most likely through control of the cell cycle. Upon ETV4 and ETV5 knockdown, we observed a striking upregulation of DUX4 and its transcriptional targets that activate the zygotic genome and drive the atrophy program in facioscapulohumeral dystrophy patients. In addition to demonstrating the importance of inhibiting all three FGFRs, the current findings reveal potential nodes of attack for the cancer with the discovery of ETV4 and ETV5 as appropriate biomarkers and molecular targets, and activation of the embryonic DUX4 pathway as a promising approach to block synovial sarcoma tumors

Autologous microsurgical breast reconstruction and coronary artery bypass grafting: an anatomical study and clinical implications

OBJECTIVE: To identify possible avenues of sparing the internal mammary artery (IMA) for coronary artery bypass grafting (CABG) in women undergoing autologous breast reconstruction with deep inferior epigastric artery perforator (DIEP) flaps. BACKGROUND: Optimal autologous reconstruction of the breast and coronary artery bypass grafting (CABG) are often mutually exclusive as they both require utilisation of the IMA as the preferred arterial conduit. Given the prevalence of both breast cancer and coronary artery disease, this is an important issue for women's health as women with DIEP flap reconstructions and women at increased risk of developing coronary artery disease are potentially restricted from receiving this reconstructive option should the other condition arise. METHODS: The largest clinical and cadaveric anatomical study (n=315) to date was performed, investigating four solutions to this predicament by correlating the precise requirements of breast reconstruction and CABG against the anatomical features of the in situ IMAs. This information was supplemented by a thorough literature review. RESULTS: Minimum lengths of the left and right IMA needed for grafting to the left-anterior descending artery are 160.08 and 177.80 mm, respectively. Based on anatomical findings, the suitable options for anastomosis to each intercostals space are offered. In addition, 87-91% of patients have IMA perforator vessels to which DIEP flaps can be anastomosed in the first- and second-intercostal spaces. CONCLUSION: We outline five methods of preserving the IMA for future CABG: (1) lowering the level of DIEP flaps to the fourth- and fifth-intercostals spaces, (2) using the DIEP pedicle as an intermediary for CABG, (3) using IMA perforators to spare the IMA proper, (4) using and end-to-side anastomosis between the DIEP pedicle and IMA and (5) anastomosis of DIEP flaps using retrograde flow from the distal IMA. With careful patient selection, we hypothesize using the IMA for autologous breast reconstruction need not be an absolute contraindication for future CABG

Fine-needle aspiration biopsy for the diagnosis of bone and soft tissue lesions: a systematic review and meta-analysis

The workup of musculoskeletal (MSK) lesions utilizes a range of diagnostic tests including incisional biopsy, core needle biopsy, and fine-needle aspiration (FNA). FNA is the most cost-effective and least invasive biopsy method, but variation in its reported diagnostic performance has constrained its use for MSK lesions. Herein, we undertake a meta-analysis to clarify the diagnostic performance of FNA for bone and soft tissue lesions. A systematic search was run in MEDLINE, EMBASE, and CINAHL. Included studies were aggregated for pooled estimates of adequacy, accuracy, and sensitivity/specificity for all MSK lesions as well as bone and soft tissue independently. Analysis of heterogeneity and risk of bias were assessed across studies. Covariate subgroup analyses were attempted to investigate potential influences on diagnostic accuracy. Twenty-five articles met inclusion criteria, representing 4604 FNAs. Adequacy was 92.3% (range: 59.2%-98.0%, S = 9.4%), and sensitivity/specificity for the nature (malignant or benign) of the lesion was 95.6% (95% CI: 94.5%-96.5%) and 96.9% (95% CI: 95.9%-97.7%). FNA was 75.8% accurate (range: 42.5%-99.3%, S = 17.3%) for definitive diagnosis. FNA provides higher accuracy for benign versus malignant nature in bone lesions but achieves a definitive diagnosis more frequently in soft tissue lesions. The results of this meta-analysis support the expanded use of FNA in the diagnostic workup of bone and soft tissue lesions, particularly in light of a sensitivity and specificity comparable to incisional and core needle biopsy. •Fine-needle aspiration should be considered in the workup of mesenchymal lesions.•Systematic review and meta-analysis show good performance for this technique.•Adequacy is 92.3% with 95.6% sensitivity and 96.9% specificity.•Accuracy for benign versus malignant is better in bone lesions.•Definitive diagnosis is achieved more frequently in soft tissue lesions

A Triumvirate:: Correlating Thyroid Cytopathology, Molecular Testing, and Histopathology

Risk stratification is essential in the preoperative evaluation and management of thyroid nodules, most of which are benign. Advances in DNA and RNA sequencing have shed light on the molecular drivers of thyroid cancer. Molecular testing of cytologically indeterminate nodules has helped refine risk stratification, triage patients for surgery, and determine the extent of surgery. Molecular platforms with high negative predictive values can help identify nodules that may be spared surgery and can be managed conservatively. Here we discuss the importance of integrating cytomorphologic, molecular, and histologic features to help avoid errors and improve patient management