Myositis ossificans : another condition with USP6 rearrangement, providing evidence of a relationship with nodular fasciitis and aneurysmal bone cyst

Myositis ossificans is defined as a self-limiting pseudotumor composed of reactive hypercellular fibrous tissue and bone. USP6 rearrangements have been identified as a consistent genetic driving event in aneurysmal bone cyst and nodular fasciitis. It is therefore an integral part of the diagnostic workup when dealing with (myo)fibroblastic lesions of soft tissue and bone. Two cases of myositis ossificans with USP6 rearrangement were published so far. We determine herein the incidence of USP6 rearrangement in myositis ossificans using USP6 fluorescence in situ hybridization analysis (FISH). Of the 11 cases included, seven patients were female and four were male. Age ranged from 6 to 56 years (mean 27 years). Lesions were located in the thigh (n = 5), knee (n = 1), lower leg (n = 1), lower arm (n = 1), perineum (n = 1), gluteal (n = 1) and thoracic wall (n = 1). All assessable cases except one (8/9) showed rearrangement of USP6 providing evidence that myositis ossificans is genetically related to nodular fasciitis and aneurysmal bone cyst

The accuracy and intra- and interobserver variability of PSMA PET/CT for the local staging of primary prostate cancer

PURPOSE: Prostate-specific membrane antigen (PSMA) positron emission tomography/ computed tomography (PET/CT) is recognized as the most accurate imaging modality for detection of metastatic high-risk prostate cancer (PCa). Its role in the local staging of disease is yet unclear. We assessed the intra- and interobserver variability, as well as the diagnostic accuracy of the PSMA PET/CT based molecular imaging local tumour stage (miT-stage) for the local tumour stage assessment in a large, multicentre cohort of patients with intermediate and high-risk primary PCa, with the radical prostatectomy specimen (pT-stage) serving as the reference standard.METHODS: A total of 600 patients who underwent staging PSMA PET/CT before robot-assisted radical prostatectomy was studied. In 579 PSMA positive primary prostate tumours a comparison was made between miT-stage as assessed by four nuclear physicians and the pT-stage according to ISUP protocol. Sensitivity, specificity and diagnostic accuracy were determined. In a representative subset of 100 patients, the intra-and interobserver variability were assessed using Kappa-estimates.RESULTS: The sensitivity and specificity of the PSMA PET/CT based miT-stage were 58% and 59% for pT3a-stage, 30% and 97% for ≥ pT3b-stage, and 68% and 61% for overall ≥ pT3-stage, respectively. No statistically significant differences in diagnostic accuracy were found between tracers. We found a substantial intra-observer agreement for PSMA PET/CT assessment of ≥ T3-stage (k 0.70) and ≥ T3b-stage (k 0.75), whereas the interobserver agreement for the assessment of ≥ T3-stage (k 0.47) and ≥ T3b-stage (k 0.41) were moderate.CONCLUSION: In a large, multicentre study evaluating 600 patients with newly diagnosed intermediate and high-risk PCa, we showed that PSMA PET/CT may have a value in local tumour staging when pathological tumour stage in the radical prostatectomy specimen was used as the reference standard. The intra-observer and interobserver variability of assessment of tumour extent on PSMA PET/CT was moderate to substantial.</p

The accuracy and intra- and interobserver variability of PSMA PET/CT for the local staging of primary prostate cancer

PURPOSE: Prostate-specific membrane antigen (PSMA) positron emission tomography/ computed tomography (PET/CT) is recognized as the most accurate imaging modality for detection of metastatic high-risk prostate cancer (PCa). Its role in the local staging of disease is yet unclear. We assessed the intra- and interobserver variability, as well as the diagnostic accuracy of the PSMA PET/CT based molecular imaging local tumour stage (miT-stage) for the local tumour stage assessment in a large, multicentre cohort of patients with intermediate and high-risk primary PCa, with the radical prostatectomy specimen (pT-stage) serving as the reference standard.METHODS: A total of 600 patients who underwent staging PSMA PET/CT before robot-assisted radical prostatectomy was studied. In 579 PSMA positive primary prostate tumours a comparison was made between miT-stage as assessed by four nuclear physicians and the pT-stage according to ISUP protocol. Sensitivity, specificity and diagnostic accuracy were determined. In a representative subset of 100 patients, the intra-and interobserver variability were assessed using Kappa-estimates.RESULTS: The sensitivity and specificity of the PSMA PET/CT based miT-stage were 58% and 59% for pT3a-stage, 30% and 97% for ≥ pT3b-stage, and 68% and 61% for overall ≥ pT3-stage, respectively. No statistically significant differences in diagnostic accuracy were found between tracers. We found a substantial intra-observer agreement for PSMA PET/CT assessment of ≥ T3-stage (k 0.70) and ≥ T3b-stage (k 0.75), whereas the interobserver agreement for the assessment of ≥ T3-stage (k 0.47) and ≥ T3b-stage (k 0.41) were moderate.CONCLUSION: In a large, multicentre study evaluating 600 patients with newly diagnosed intermediate and high-risk PCa, we showed that PSMA PET/CT may have a value in local tumour staging when pathological tumour stage in the radical prostatectomy specimen was used as the reference standard. The intra-observer and interobserver variability of assessment of tumour extent on PSMA PET/CT was moderate to substantial.</p

The prognostic potential of human prostate cancer-associated macrophage subtypes as revealed by single-cell transcriptomics

Macrophages in the tumor microenvironment are causally linked with prostate cancer development and progression, yet little is known about their composition in neoplastic human tissue. By performing single cell transcriptomic analysis of human prostate cancer resident macrophages, three distinct populations were identified in the diseased prostate. Unexpectedly, no differences were observed between macrophages isolated from the tumorous and nontumorous portions of the prostatectomy specimens. Markers associated with canonical M1 and M2 macrophage phenotypes were identifiable, however these were not the main factors defining unique subtypes. The genes selectively associated with each macrophage cluster were used to develop a gene signature which was highly associated with both recurrence-free and metastasis-free survival. These results highlight the relevance of tissue-specific macrophage subtypes in the tumor microenvironment for prostate cancer progression and demonstrates the utility of profiling single-cell transcriptomics in human tumor samples as a strategy to design gene classifiers for patient prognostication. Implications: The specific macrophage subtypes present in a diseased human prostate have prognostic value, suggesting that the relative proportions of these populations are related to patient outcome. Understanding the relative contributions of these subtypes will not only inform patient prognostication, but will enable personalized immunotherapeutic strategies to increase beneficial populations or reduce detrimental populations

The accuracy and intra- and interobserver variability of PSMA PET/CT for the local staging of primary prostate cancer

Purpose: Prostate-specific membrane antigen (PSMA) positron emission tomography/ computed tomography (PET/CT) is recognized as the most accurate imaging modality for detection of metastatic high-risk prostate cancer (PCa). Its role in the local staging of disease is yet unclear. We assessed the intra- and interobserver variability, as well as the diagnostic accuracy of the PSMA PET/CT based molecular imaging local tumour stage (miT-stage) for the local tumour stage assessment in a large, multicentre cohort of patients with intermediate and high-risk primary PCa, with the radical prostatectomy specimen (pT-stage) serving as the reference standard. Methods: A total of 600 patients who underwent staging PSMA PET/CT before robot-assisted radical prostatectomy was studied. In 579 PSMA positive primary prostate tumours a comparison was made between miT-stage as assessed by four nuclear physicians and the pT-stage according to ISUP protocol. Sensitivity, specificity and diagnostic accuracy were determined. In a representative subset of 100 patients, the intra-and interobserver variability were assessed using Kappa-estimates. Results: The sensitivity and specificity of the PSMA PET/CT based miT-stage were 58% and 59% for pT3a-stage, 30% and 97% for ≥ pT3b-stage, and 68% and 61% for overall ≥ pT3-stage, respectively. No statistically significant differences in diagnostic accuracy were found between tracers. We found a substantial intra-observer agreement for PSMA PET/CT assessment of ≥ T3-stage (k 0.70) and ≥ T3b-stage (k 0.75), whereas the interobserver agreement for the assessment of ≥ T3-stage (k 0.47) and ≥ T3b-stage (k 0.41) were moderate. Conclusion: In a large, multicentre study evaluating 600 patients with newly diagnosed intermediate and high-risk PCa, we showed that PSMA PET/CT may have a value in local tumour staging when pathological tumour stage in the radical prostatectomy specimen was used as the reference standard. The intra-observer and interobserver variability of assessment of tumour extent on PSMA PET/CT was moderate to substantial

Cribriform architecture in radical prostatectomies predicts oncological outcome in Gleason score 8 prostate cancer patients

The Gleason score is an important parameter for clinical outcome in prostate cancer patients. Gleason score 8 is a heterogeneous disease including Gleason score 3 + 5, 4 + 4, and 5 + 3 tumors, and encompasses a broad range of tumor growth patterns. Our objective was to characterize individual growth patterns and identify prognostic parameters in Gleason score 8 prostate cancer patients. We reviewed 1064 radical prostatectomy specimens, recorded individual Gleason 4 and 5 growth patterns as well as presence of intraductal carcinoma, and evaluated biochemical recurrence- and metastasis-free survival. Gleason score 8 disease was identified in 140 (13%) patients, of whom 76 (54%) had Gleason score 3 + 5, 46 (33%) 4 + 4, and 18 (13%) 5 + 3 disease. Invasive cribriform and/or intraductal carcinoma (n = 87, 62%) was observed more frequently in Gleason score 4 + 4 (93%) than 3 + 5 (47%; P < 0.001) and 5 + 3 (44%; P < 0.001) patients. Gleason pattern 5 was present in 110 (79%) men: as single cells and/or cords in 99 (90%) and solid fields in 32 (29%) cases. Solid field pattern 5 coexisted with cribriform architecture (23/32, 72%) more frequently than nonsolid pattern 5 cases (36/78, 46%, P = 0.02). In multivariable analysis including age, prostate-specific antigen, pT-stage, surgical margin status, and lymph node metastases, presence of cribriform architecture was an independent parameter for biochemical recurrence-free (hazard ratio (HR) 2.0, 95% confidence interval (CI) 1.0–3.7; P = 0.04) and metastasis-free (HR 3.5, 95% CI 1.0–12.3; P = 0.05) survival. In conclusion, invasive cribriform and/or intraductal carcinoma occurs more frequently in Gleason score 4 + 4 prostate cancer patients than in Gleason score 3 + 5 and 5 + 3, and is an independent parameter for biochemical recurrence and metastasis. Therefore, cribriform architecture has added value in risk stratification of Gleason score 8 prostate cancer patients

Reliable Visualization of the Treatment Effect of Transperineal Focal Laser Ablation in Prostate Cancer Patients by Magnetic Resonance Imaging and Contrast-enhanced Ultrasound Imaging

Background: Transperineal focal laser ablation (TPLA) treatment for prostate cancer (PCa) is an experimental focal ablative therapy modality with low morbidity. However, a dosimetry model for TPLA is lacking. Objective: To determine (1) the three-dimensional (3D) histologically defined ablation zone of single- and multifiber TPLA treatment for PCa correlated with magnetic resonance imaging (MRI) and contrast-enhanced ultrasound (CEUS) and (2) a reliable imaging modality of ablation zone volumetry. Design, setting, and participants: This was a prospective, multicenter, and interventional phase I/II pilot study with an ablate-and-resect design. TPLA was performed in 12 patients with localized prostate cancer divided over four treatment regimens to evaluate potential variation in outcomes. Intervention: TPLA was performed approximately 4 wk prior to robot-assisted radical prostatectomy (RARP) in a daycare setting using local anesthesia. Outcome measurements and statistical analysis: Four weeks after TPLA, ablation zone volumetry was determined on prostate MRI and CEUS by delineation and segmentation into 3D models and correlated with whole-mount RARP histology using the Pearson correlation index. Results and limitations: Twelve office-based TPLA procedures were performed successfully under continuous transrectal ultrasound guidance using local perineal anesthesia. No serious adverse events occurred. A qualitative analysis showed a clear demarcation of the ablation zone on T2-weighted MRI, dynamic contrast-enhanced MRI, and CEUS. On pathological evaluation, no remnant cancer was observed within the ablation zone. Ablation zone volumetry on CEUS and T2-weighted MRI compared with histology had a Pearson correlation index of r = 0.94 (95% confidence interval [CI] 0.74–0.99, p < 0.001) and r = 0.93 (95% CI 0.73–0.98, p < 0.001), respectively. Conclusions: CEUS and prostate MRI could reliably visualize TPLA ablative effects after minimally invasive PCa treatment with a high concordance with histopathological findings and showed no remnant cancer. Patient summary: The treatment effects of a novel minimally invasive ablation therapy device can reliably be visualized with radiological examinations. These results will improve planning and performance of future procedures

Fibro-osseous pseudotumor of digits - Expanding the spectrum of clonal transient neoplasms harboring USP6 rearrangement

Fibro-osseous pseudotumors of the digits (FOPD) is a rare self-limiting lesion composed of bland looking hypercellular fibrous tissue and bone. USP6 rearrangement is a consistent genetic finding in aneurysmal bone cyst, nodular fasciitis, myositis ossificans and giant cell lesions of small bones. We report herein the occurrence of USP6 rearrangement in fibro-osseous pseudotumors of the digits using fluorescence in situ hybridization analysis (FISH). Of the five patients included, three were female and two were male. The age ranged from 33 to 72 years (mean 48 years). Lesions arose in the palm (n = 2), thenar (n = 1), middle finger (n = 1) and great toe (n = 1). All patients underwent resection. Four cases (80%) harbored USP6 rearrangements showing that fibro-osseous pseudotumors of digits belongs to the spectrum of clonal transient neoplasms including aneurysmal bone cyst, nodular fasciitis, myositis ossificans and giant cell lesion of small bones

Agent-based modeling of the prostate tumor microenvironment uncovers spatial tumor growth constraints and immunomodulatory properties

Abstract Inhibiting androgen receptor (AR) signaling through androgen deprivation therapy (ADT) reduces prostate cancer (PCa) growth in virtually all patients, but response may be temporary, in which case resistance develops, ultimately leading to lethal castration-resistant prostate cancer (CRPC). The tumor microenvironment (TME) plays an important role in the development and progression of PCa. In addition to tumor cells, TME-resident macrophages and fibroblasts express AR and are therefore also affected by ADT. However, the interplay of different TME cell types in the development of CRPC remains largely unexplored. To understand the complex stochastic nature of cell-cell interactions, we created a PCa-specific agent-based model (PCABM) based on in vitro cell proliferation data. PCa cells, fibroblasts, “pro-inflammatory” M1-like and “pro-tumor” M2-like polarized macrophages are modeled as agents from a simple set of validated base assumptions. PCABM allows us to simulate the effect of ADT on the interplay between various prostate TME cell types. The resulting in vitro growth patterns mimic human PCa. Our PCABM can effectively model hormonal perturbations by ADT, in which PCABM suggests that CRPC arises in clusters of resistant cells, as is observed in multifocal PCa. In addition, fibroblasts compete for cellular space in the TME while simultaneously creating niches for tumor cells to proliferate in. Finally, PCABM predicts that ADT has immunomodulatory effects on macrophages that may enhance tumor survival. Taken together, these results suggest that AR plays a critical role in the cellular interplay and stochastic interactions in the TME that influence tumor cell behavior and CRPC development