Impact of Dynamic Contrast Enhanced and Diffusion-Weighted MR Imaging on Detection of Early Local Recurrence of Soft Tissue Sarcoma.

BACKGROUND: Diagnosis of residual or recurrent tumor in soft-tissue sarcomas (STS) is a differential diagnostic challenge since post-therapeutic changes impede diagnosis. PURPOSE: To evaluate the diagnostic accuracy of quantitative dynamic contrast enhanced (DCE)-MRI and diffusion-weighted imaging (DWI) to detect local recurrence of STS of the limb. STUDY TYPE: Prospective. POPULATION: A totalof 64 consecutive patients with primary STS of the limbs were prospectively included 3-6 months after surgery between January 2016 and July 2021. FIELD STRENGTH/SEQUENCE: A 1.5 T; axial DWI echo-planar imaging sequences and DCE-MRI using a 3D T1-weighted spoiled gradient-echo sequence. ASSESSMENT: The quantitative DCE-MRI parameters relative plasma flow (rPF) and relative mean transit time (rMTT) were calculated and ADC mapping was used to quantify diffusion restriction. Regions of interest of tumor growth and postoperative changes were drawn in consensus by two experts for diffusion and perfusion analysis. An additional morphological assessment was done by three independent and blinded radiologists. STATISTICAL TEST: Unpaired t-test, ROC-analysis, and a logistic regression model were applied. Interobserver reliability was calculated using Fleiss kappa statistics. A P value of 0.05 was considered statistically significant. RESULTS: A total of 11 patients turned out to have local recurrence. rPF was significantly higher in cases of local recurrence when compared to cases without local recurrence (61.1-4.5) while rMTT was slightly and significantly lower in local recurrence. ROC-analysis showed an area under the curve (AUC) of 0.95 (SEM ± 0.05) for rPF while a three-factor multivariate logistic regression model showed a high diagnostic accuracy of rPF (R2  = 0.71). Compared with morphological assessment, rPF had a distinct higher specificity and true positive value in detection of LR. DATA CONCLUSION: DCE-MRI is a promising additional method to differentiate local recurrence from benign postoperative changes in STS of the limb. Especially specificity in detection of LR is increased compared to morphological assessment. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 2.

Regulation of cardiac myocyte cohesion and gap junctions via desmosomal adhesion.

AIMS: Mutations in desmosomal proteins can induce arrhythmogenic cardiomyopathy with life-threatening arrhythmia. Previous data demonstrated adrenergic signalling to be important to regulate desmosomal cohesion in cardiac myocytes. Here, we investigated how signalling pathways including adrenergic signalling, PKC and SERCA regulate desmosomal adhesion and how this controls gap junctions (GJs) in cardiac myocytes. METHODS: Immunostaining, Western blot, dissociation assay and multi-electrode array were applied in HL-1 cardiac myocytes to evaluate localization, expression and function of desmosomal and GJ components. cAMP levels were determined by ELISA. RESULTS: Activation of PKC by PMA or adrenergic signalling increased cell cohesion and desmoglein-2 and desmoplakin localization at cell-cell junctions, whereas tryptophan (Trp) treatment to inhibit cadherin binding or inhibition of SERCA by thapsigargin reduced cell cohesion, while cAMP elevation rescued this effect. Despite no changes in protein expression, accumulation of GJ protein connexin-43 was detectable at cell-cell contacts in parallel to increased cohesion. Disruption of cell cohesion by Trp, PMA or thapsigargin impaired conduction of excitation comparable to GJ inhibition. cAMP elevation was effective to improve arrhythmia after Trp treatment. Weakened cell cohesion by Trp or depletion of desmoglein-2 or plakoglobin blocked signalling via the ß1-adrenergic receptor. Moreover, silencing of desmosomal proteins increased arrhythmia and reduced conduction velocity, which were rescued by cAMP elevation. CONCLUSION: These data demonstrate the interplay of GJs, desmosomes and the ß1-adrenergic receptor with regulation of their function by cell cohesion, adrenergic and PKC signalling or SERCA inhibition. These results support the identification of new targets to treat arrhythmogenic cardiomyopathy.