Cells move through perpetual protrusion and retraction cycles at the leading edge. These cycles are coordinated with substrate adhesion and retraction of the cell rear. Here, we tracked spatial and temporal fluctuations in the molecular activities of individual moving cells to elucidate how extracellular regulated kinase (ERK) signaling controlled the dynamics of protrusion and retraction cycles. ERK is activated by many cell-surface receptors and we found that ERK signaling specifically reinforced cellular protrusions so that they translated into rapid, sustained forward motion of the leading edge. Using quantitative fluorescent speckle microscopy (qFSM) and cross-correlation analysis, we showed that ERK controlled the rate and timing of actin polymerization by promoting the recruitment of the actin nucleator Arp2/3 to the leading edge. Arp2/3 activity generates branched actin networks that can produce pushing force. These findings support a model in which surges in ERK activity induced by extracellular cues enhance Arp2/3-mediated actin polymerization to generate protrusion power phases with enough force to counteract increasing membrane tension and to promote sustained motility.
Purpose: To assess the optimal planning target volume (PTV) margins for stereotactic body radiotherapy (SBRT) of prostate cancer based on inter-and intra-fractional prostate motion determined from daily image guidance. Methods and Materials: Two hundred and five patients who were enrolled on two prospective studies of SBRT (8 Gy × 5 fractions) for localized prostate cancer treated at a single institution between 2012 and 2017 had complete inter-and intra-fractional shift data available. All patients had scheduled kilovoltage planar imaging during SBRT with rigid registration to intraprostatic fiducials prior to each of four half-arcs delivered per fraction, as well as cone beam CT verification of anatomy prior to each fraction. Inter-and intra-fractional shift data were obtained to estimate the required PTV margins based on the classic van Herk formula. Inter-and intra-fractional motion were compared between patients with and without severe toxicities using the independent two-sample Wilcoxon test. Results: The margins required to account for inter-fractional motion were estimated to be 0.99, 1.52, and 1.45 cm in lateral (LR), longitudinal (SI), and vertical (AP) directions, respectively. The margins required to account for intra-fractional motion were estimated to be 0.19, 0.27, and 0.31 cm in LR, SI and AP directions, respectively. Large intra-fractional shifts were mostly observed in the SI and AP directions, with 2.0 and 5.4% of patients experiencing average intra-fractional motion >3 mm in the SI and AP directions, respectively, compared with none experiencing mean shifts >3 mm in the LR direction. Six patients experienced grade 3 gastrointestinal or genitourinary toxicity. There were no significant differences in mean inter-or intra-fractional motion in any of the cardinal directions compared to patients without severe toxicity (inter-fractional p = 0.46-0.99, intra-fractional p = 0.10-0.84). Levin-Epstein et al. Prostate Displacement and SBRT Margins Conclusion: The inter-and intra-fractional margins estimated from this study are in line with prior reported values. Intra-fractional prostate motion was generally small with larger margins required for the SI and AP directions, notably just slightly exceeding the commonly used 3 mm posterior PTV margin even with realignment between half-arcs. Development of severe toxicity was not significantly associated with the degree of inter-or intra-fractional motion.
Prostate-specific membrane antigen (PSMA) positron emission tomography (PET)/ computed tomography (CT) is an emerging imaging modality with greater sensitivity and specificity over conventional imaging for prostate cancer (PCa) staging. Using data from two prospective trials (NCT03368547 and NCT04050215), we
Rationale: Standardized staging and quantitative reporting is necessary to demonstrate the association of 18 F-DCFPyL PET/CT (PSMA) imaging with clinical outcome. This work introduces an automated platform to implement and extend the Prostate Cancer Molecular Imaging Standardized Evaluation (PROMISE) criteria -aPROMISE. The objective is to validate the performance of aPROMISE in staging and quantifying disease burden in patients with prostate cancer who undergo PSMA Imaging.Methods: This was a retrospective analysis of 109 Veterans with intermediate and high-risk prostate cancer, who underwent PSMA imaging. To validate the performance of aPROMISE, two independent nuclear-medicine physicians conducted aPROMISEassisted reads, resulting in standardized reports that quantify individual lesions and stage the patients. Patients were staged as having local only disease (miN0M0); regional lymph node only (miN1M0), metastatic disease only (miN0M1), and with both regional and distant metastatic disease (miN1M1). The staging obtained from aPROMISE-assisted reads was compared with the staging by conventional imaging. Cohen's pairwise kappa agreement was used to evaluate the inter-reader variability. Correlation coefficient and ICC was used to evaluate the inter-reader variability of the quantitative assessment (miPSMA-index) in each stage. Kendall Tau and t-test was used to evaluate the association of miPSMA-index with PSA and Gleason Score.Results: All PSMA images of 109 veterans met the DICOM conformity and the requirements for the aPROMISE analysis. Both independent aPROMISE-assisted analyses demonstrated significant upstaging in patients with localized (23%; N=20/87) and regional tumor burden (25%; N=2/8). However, a significant number of patients with bone metastases identified on conventional imaging (NaF PET/CT) were downstaged (29%; N=4/14). The comparison of the two independent aPROMISE-assisted reads demonstrated a high kappa agreement -0.82 (miN0M0), 0.90 (miN1M0), and 0.77 (miN0M1). The Spearman correlation of quantitative miPSMA-index was 0.93, 0.96 and 0.97, respectively. As a continuous variable, miPSMA index in the prostate (miT) was associated with risk groups defined by the PSA and Gleason.. Conclusion:Here we demonstrate consistency of the aPROMISE platform between readers and observed substantial upstaging in PSMA imaging compared to the conventional imaging. aPROMISE may contribute to the broader standardization of PSMA imaging assessment and to its clinical utility in management of prostate cancer patients.
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