AR visualizations in laparoscopy: surgeon preferences and depth assessment of vascular anatomy.

Introduction: This study compares five augmented reality (AR) vasculature visualization techniques in a mixed-reality laparoscopy simulator with 50 medical professionals and analyzes their impact on the surgeon. Material and methods: ​​The different visualization techniques' abilities to convey depth were measured using the participant's accuracy in an objective depth sorting task. Demographic data and subjective measures, such as the preference of each AR visualization technique and potential application areas, were collected with questionnaires. Results: Despite measuring differences in objective measurements across the visualization techniques, they were not statistically significant. In the subjective measures, however, 55% of the participants rated visualization technique II, 'Opaque with single-color Fresnel highlights', as their favorite. Participants felt that AR could be useful for various surgeries, especially complex surgeries (100%). Almost all participants agreed that AR could potentially improve surgical parameters, such as patient safety (88%), complication rate (84%), and identifying risk structures (96%). Conclusions: More studies are needed on the effect of different visualizations on task performance, as well as more sophisticated and effective visualization techniques for the operating room. With the findings of this study, we encourage the development of new study setups to advance surgical AR.

Phantom study on surgical performance in augmented reality laparoscopy.

PURPOSE: Only a few studies have evaluated Augmented Reality (AR) in in vivo simulations compared to traditional laparoscopy; further research is especially needed regarding the most effective AR visualization technique. This pilot study aims to determine, under controlled conditions on a 3D-printed phantom, whether an AR laparoscope improves surgical outcomes over conventional laparoscopy without augmentation. METHODS: We selected six surgical residents at a similar level of training and had them perform a laparoscopic task. The participants repeated the experiment three times, using different 3D phantoms and visualizations: Floating AR, Occlusion AR, and without any AR visualization (Control). Surgical performance was determined using objective measurements. Subjective measures, such as task load and potential application areas, were collected with questionnaires. RESULTS: Differences in operative time, total touching time, and SurgTLX scores showed no statistical significance ([Formula: see text]). However, when assessing the invasiveness of the simulated intervention, the comparison revealed a statistically significant difference ([Formula: see text]). Participants felt AR could be useful for various surgeries, especially for liver, sigmoid, and pancreatic resections (100%). Almost all participants agreed that AR could potentially lead to improved surgical parameters, such as operative time (83%), complication rate (83%), and identifying risk structures (83%). CONCLUSION: According to our results, AR may have great potential in visceral surgery and based on the objective measures of the study, may improve surgeons' performance in terms of an atraumatic approach. In this pilot study, participants consistently took more time to complete the task, had more contact with the vascular tree, were significantly more invasive, and scored higher on the SurgTLX survey than with AR.

Performance variability of radiomics machine learning models for the detection of clinically significant prostate cancer in heterogeneous MRI datasets.

Background: Radiomics promises to enhance the discriminative performance for clinically significant prostate cancer (csPCa), but still lacks validation in real-life scenarios. This study investigates the classification performance and robustness of machine learning radiomics models in heterogeneous MRI datasets to characterize suspicious prostate lesions for non-invasive prediction of prostate cancer (PCa) aggressiveness compared to conventional imaging biomarkers. Methods: A total of 142 patients with clinical suspicion of PCa underwent 1.5T or 3T biparametric MRI (7 scanner types, 14 institutions) and exhibited suspicious lesions [prostate Imaging Reporting and Data System (PI-RADS) score ≥3] in peripheral or transitional zones. Whole-gland and index-lesion segmentations were performed semi-automatically. A total of 1,482 quantitative morphologic, shape, texture, and intensity-based radiomics features were extracted from T2-weighted and apparent diffusion coefficient (ADC)-images and assessed using random forest and logistic regression models. Five-fold cross-validation performance in terms of area under the ROC curve was compared to mean ADC (mADC), PI-RADS and prostate-specific antigen density (PSAD). Bias mitigation techniques targeting the high-dimensional feature space and inherent class imbalance were applied and robustness of results was systematically evaluated. Results: Trained models showed mean area under the curves (AUCs) ranging from 0.78 to 0.83 in csPCa classification. Despite using mitigation techniques, high performance variability of results could be demonstrated. Trained models achieved on average numerically higher classification performance compared to clinical parameters PI-RADS (AUC =0.78), mADC (AUC =0.71) and PSAD (AUC =0.63). Conclusions: Radiomics models' classification performance of csPCa was numerically but not significantly higher than PI-RADS scoring. Overall, clinical applicability in heterogeneous MRI datasets is limited because of high variability of results. Performance variability, robustness and reproducibility of radiomics-based measures should be addressed more transparently in future research to enable broad clinical application.

Local Shape Preserving Deformations for Augmented Reality Assisted Laparoscopic Surgery.

Image registration is a commonly required task in computer assisted surgical procedures. Existing registration methods in laparoscopic navigation systems suffer from several constraints, such as lack of deformation compensation. The proposed algorithm aims to provide the surgeons with updated navigational information about the deep-seated anatomy, which considers the continuous deformations in the operating environment. We extended an initial rigid registration to a shape-preserving deformable registration pathway by incorporating user interaction and an iterative mesh editing scheme which preserves local details. The proposed deformable registration workflow was tested with phantom and animal trial datasets. A qualitative evaluation based on expert feedback demonstrated satisfactory outcome, and an commensurate execution efficiency was achieved. The improvements offered by the method, couples with its relatively easy implementation, makes it an attractive method for adoption in future pre-clinical and clinical applications of augmented reality assisted surgeries.

Accuracy and prognostic value of radiological lymph node features in variant histologies of bladder cancer.

PURPOSE: To provide first evidence of lymph node (LN) staging using CT scan and its prognostic value in variant histologies of bladder cancer. This knowledge may optimize patient management with variant histologies based on CT morphological findings. METHODS: Preoperative CT scans of patients with variant histologies who underwent RC between 2004 and 2019 were reanalyzed by two independent radiologists in a blinded review process. Specificity, sensitivity, and accuracy for LN staging as well as LN characteristics were evaluated. Correlation with survival was investigated by Kaplan-Meier method, log-rank test and multivariate analysis. RESULTS: 1361 patients with primary tumor of the bladder underwent RC, of which 163 (12%) patients revealed variant histologies. 65 (47.8%) patients have shown an urothelial variant (UV) and 71 (52.2%) a non-urothelial variant (NUV). LN metastases were found in 18 (27.7%) patients with UV and 21 (29.6%) patients with NUV. The accuracy to detect LN metastasis for all variant histologies was 62% with a sensitivity of 46% and a specificity of 70%. Subgroups of UV and NUV revealed an accuracy of 67% and 57%. An increased number of regional LN (HR 2.8; 1.34-6.18) and the loss of fatty hilum (HR 0.36, 0.17-0.76) were prognostic parameters. In multivariate analysis, a fatty hilum (HR 0.313, 0.104-0.945) and the presence of lymph node metastases (HR 2.866, 1.140-7.207) were prognostic. CONCLUSION: This first study on CT morphological behavior of variant histologies revealed an accuracy of UV and NUV comparable to UC with low specificity for all variant histologies. CT scan prior RC should be interpreted in regard to histological subtypes.

Semi-Automatic MRI Feature Assessment in Small- and Medium-Volume Benign Prostatic Hyperplasia after Prostatic Artery Embolization.

(1) Background: To assess the treatment response of benign prostatic syndrome (BPS) following prostatic artery embolization (PAE) using a semi-automatic software analysis of magnetic resonance imaging (MRI) features and clinical indexes. (2) Methods: Prospective, monocenter study of MRI and clinical data of n = 27 patients with symptomatic BPS before and (1, 6, 12 months) after PAE. MRI analysis was performed using a dedicated semi-automatic software for segmentation of the central and the total gland (CG, TG), respectively; signal intensities (SIs) of T1-weighted (T1w), T2-weighted (T2w), and diffusion-weighted images (DWI), as well as intravesical prostatic protrusion (IPP) and prostatic volumes (CGV, TGV), were evaluated at each time point. The semi-automatic assessed TGV was compared to conventional TGV by an ellipse formula. International prostate symptom score (IPSS) and international consultation on incontinence questionnaire−urinary incontinence short form (ICIQ-UI SF) questionnaires were used as clinical indexes. Statistical testing in the form of ANOVA, pairwise comparisons using Bonferroni correction, and multiple linear correlations, were conducted using SPSS. (3) Results: TGV was significantly reduced one, six, and 12 months after PAE as assessed by the semi-automatic approach and conventional ellipse formula (p = 0.005; p = 0.025). CGV significantly decreased after one month (p = 0.038), but showed no significant differences six and 12 months after PAE (p = 0.191; p = 0.283). IPP at baseline was demonstrated by 25/27 patients (92.6%) with a significant decrease one, six, and 12 months after treatment (p = 0.028; p = 0.010; p = 0.008). Significant improvement in IPSS and ICIQ-UI SF (p = 0.002; p = 0.016) after one month correlated moderately with TGV reduction (p = 0.031; p = 0.05, correlation coefficients 0.52; 0.69). Apparent diffusion coefficient (ADC) values of CG significantly decreased one month after embolization (p < 0.001), while there were no significant differences in T1w and T2w SIs before and after treatment at each time point. (4) Conclusions: The semi-automatic approach is appropriate for the assessment of volumetric and morphological changes in prostate MRI following PAE, able to identify significantly different ADC values post-treatment without the need for manual identification of infarct areas. Semi-automatic measured TGV reduction is significant and comparable to the TGV calculated by the conventional ellipse formula, confirming the clinical response after PAE.

Computed-tomography based scoring system predicts outcome for clinical lymph node-positive patients undergoing radical cystectomy

ABSTRACT Purpose: Contrast-enhanced CT scan is the standard staging modality for patients with bladder cancer undergoing radical cystectomy (RC). Involvement of lymph nodes (LN) determines prognosis of patients with bladder cancer. The detection of LN metastasis by CT scan is still insufficient. Therefore, we investigated various CT scan characteristics to predict lymph node ratio (LNR) and its impact on survival. Also, pre-operative CT scan characteristics might hold potential to risk stratify cN+ patients. Materials and Methods: We analyzed preoperative CT scans of patients undergoing RC in a tertiary high volume center. Retrospectively, local tumor stage and LN characteristics such as size, morphology (MLN) and number of loco-regional LN (NLN) were investigated and correlation to LNR and survival was analyzed. CT scan characteristics were used to develop a risk stratification using Kaplan-Maier and multivariate analysis. Results: 764 cN0 and 166 cN+ patients with complete follow-up and imaging data were included in the study. Accuracy to detect LN metastasis and locally advanced tumor stage in CT scan was 72% and 62%. LN larger than 15mm in diameter were significantly associated with higher LNR (p=0.002). Increased NLN correlated with decreased CSS and OS (p=0.001: p=0.002). Furthermore, CT scan based scoring system precisely differentiates low-risk and high-risk profiles to predict oncological outcome (p <0.001). Conclusion: In our study, solely LN size >15mm significantly correlated with higher LNR. Identification of increased loco-regional LN was associated with worse survival. For the first time, precise risk stratification based on computed-tomography findings was developed to predict oncological outcome for clinical lymph node-positive patients undergoing RC.

Computed-tomography based scoring system predicts outcome for clinical lymph node-positive patients undergoing radical cystectomy.

PURPOSE: Contrast-enhanced CT scan is the standard staging modality for patients with bladder cancer undergoing radical cystectomy (RC). Involvement of lymph nodes (LN) determines prognosis of patients with bladder cancer. The detection of LN metastasis by CT scan is still insufficient. Therefore, we investigated various CT scan characteristics to predict lymph node ratio (LNR) and its impact on survival. Also, pre-operative CT scan characteristics might hold potential to risk stratify cN+ patients. MATERIALS AND METHODS: We analyzed preoperative CT scans of patients undergoing RC in a tertiary high volume center. Retrospectively, local tumor stage and LN characteristics such as size, morphology (MLN) and number of loco-regional LN (NLN) were investigated and correlation to LNR and survival was analyzed. CT scan characteristics were used to develop a risk stratification using Kaplan-Maier and multivariate analysis. RESULTS: 764 cN0 and 166 cN+ patients with complete follow-up and imaging data were included in the study. Accuracy to detect LN metastasis and locally advanced tumor stage in CT scan was 72% and 62%. LN larger than 15mm in diameter were significantly associated with higher LNR (p=0.002). Increased NLN correlated with decreased CSS and OS (p=0.001: p=0.002). Furthermore, CT scan based scoring system precisely differentiates low-risk and high-risk profiles to predict oncological outcome (p < 0.001). CONCLUSION: In our study, solely LN size >15mm significantly correlated with higher LNR. Identification of increased loco-regional LN was associated with worse survival. For the first time, precise risk stratification based on computed-tomography findings was developed to predict oncological outcome for clinical lymph node-positive patients undergoing RC.

Cost-effectiveness of short-protocol emergency brain MRI after negative non-contrast CT for minor stroke detection.

OBJECTIVES: To investigate the cost-effectiveness of supplemental short-protocol brain MRI after negative non-contrast CT for the detection of minor strokes in emergency patients with mild and unspecific neurological symptoms. METHODS: The economic evaluation was centered around a prospective single-center diagnostic accuracy study validating the use of short-protocol brain MRI in the emergency setting. A decision-analytic Markov model distinguished the strategies "no additional imaging" and "additional short-protocol MRI" for evaluation. Minor stroke was assumed to be missed in the initial evaluation in 40% of patients without short-protocol MRI. Specialized post-stroke care with immediate secondary prophylaxis was assumed for patients with detected minor stroke. Utilities and quality-of-life measures were estimated as quality-adjusted life years (QALYs). Input parameters were obtained from the literature. The Markov model simulated a follow-up period of up to 30 years. Willingness to pay was set to $100,000 per QALY. Cost-effectiveness was calculated and deterministic and probabilistic sensitivity analysis was performed. RESULTS: Additional short-protocol MRI was the dominant strategy with overall costs of $26,304 (CT only: $27,109). Cumulative calculated effectiveness in the CT-only group was 14.25 QALYs (short-protocol MRI group: 14.31 QALYs). In the deterministic sensitivity analysis, additional short-protocol MRI remained the dominant strategy in all investigated ranges. Probabilistic sensitivity analysis results from the base case analysis were confirmed, and additional short-protocol MRI resulted in lower costs and higher effectiveness. CONCLUSION: Additional short-protocol MRI in emergency patients with mild and unspecific neurological symptoms enables timely secondary prophylaxis through detection of minor strokes, resulting in lower costs and higher cumulative QALYs. KEY POINTS: • Short-protocol brain MRI after negative head CT in selected emergency patients with mild and unspecific neurological symptoms allows for timely detection of minor strokes. • This strategy supports clinical decision-making with regard to immediate initiation of secondary prophylactic treatment, potentially preventing subsequent major strokes with associated high costs and reduced QALY. • According to the Markov model, additional short-protocol MRI remained the dominant strategy over wide variations of input parameters, even when assuming disproportionally high costs of the supplemental MRI scan.

[Clinical impact of abbreviated unenhanced prostate protocols in magnetic resonance imaging]. / Klinischer Stellenwert kontrastmittelfreier Kurzprotokolle in der Magnetresonanztomographie.

BACKGROUND: According to the Prostate Imaging Reporting and Data System (PI-RADS) v2.1 multiparametric magnetic resonance imaging (mpMRI) with gadolinium-(Gd)-based contrast agents is the diagnostic standard of care in the detection of prostate cancer (PCa). Recent data suggest equivalent performance of biparametric MRI (bpMRI) and mpMRI in defined indications. OBJECTIVES: Evaluation of the current role of abbreviated or unenhanced protocols in MRI of the prostate in various clinical settings. MATERIALS AND METHODS: Evaluation of clinical trials, guidelines and expert opinions. RESULTS: The use of dynamic contrast-enhanced (DCE) MRI sequences is associated with contrast agent-associated risks and has significant impact on the imaging procedure and costs. Arguments for and against the use of contrast agent in prostate protocols as well as equivalence from bpMRI and mpMRI are discussed. CONCLUSIONS: Currently, bpMRI can only be performed if very good image quality is available and in the hands of a radiologist with extensive experience in reading prostate MRI. There is a need for prospective studies to qualify bpMRI as the diagnostic method for the primary diagnosis of PCa.

Diagnostic accuracy of magnetic resonance imaging for the detection of pulmonary nodules simulated in a dedicated porcine chest phantom.

OBJECTIVE: CT serves as gold standard for the evaluation of pulmonary nodules. However, CT exposes patients to ionizing radiation, a concern especially in screening scenarios with repeated examinations. Due to recent technological advances, MRI emerges as a potential alternative for lung imaging using 3D steady state free precession and ultra-short echo-time sequences. Therefore, in this study we assessed the performance of three state-of-the-art MRI sequences for the evaluation of pulmonary nodules. METHODS: Lesions of variable sizes were simulated in porcine lungs placed in a dedicated chest phantom mimicking a human thorax, followed by CT and MRI examinations. Two blinded readers evaluated the acquired MR-images locating and measuring every suspect lesion. Using the CT-images as reference, logistic regression was performed to investigate the sensitivity of the tested MRI-sequences for the detection of pulmonary nodules. RESULTS: For nodules with a diameter of 6 mm, all three sequences achieved high sensitivity values above 0.91. However, the sensitivity dropped for smaller nodules, yielding an average of 0.83 for lesions with 4 mm in diameter and less than 0.69 for lesions with 2 mm in diameter. The positive predictive values ranged between 0.91 and 0.96, indicating a low amount of false positive findings. Furthermore, the size measurements done on the MR-images were subject to a bias ranging from 0.83 mm to -1.77 mm with standard deviations ranging from 1.40 mm to 2.11 mm. There was no statistically significant difference between the three tested sequences. CONCLUSION: While showing promising sensitivity values for lesions larger than 4 mm, MRI appears to be not yet suited for lung cancer screening. Nonetheless, the three tested MRI sequences yielded high positive predictive values and accurate size measurements; therefore, MRI could potentially figure as imaging method of the chest in selected follow-up scenarios, e.g. of incidental findings subject to the Fleischner Criteria.

Agrin Promotes Coordinated Therapeutic Processes Leading to Improved Cardiac Repair in Pigs.

BACKGROUND: Ischemic heart diseases are leading causes of death and reduced life quality worldwide. Although revascularization strategies significantly reduce mortality after acute myocardial infarction (MI), a large number of patients with MI develop chronic heart failure over time. We previously reported that a fragment of the extracellular matrix protein agrin promotes cardiac regeneration after MI in adult mice. METHODS: To test the therapeutic potential of agrin in a preclinical porcine model, we performed ischemia-reperfusion injuries using balloon occlusion for 60 minutes followed by a 3-, 7-, or 28-day reperfusion period. RESULTS: We demonstrated that local (antegrade) delivery of recombinant human agrin to the infarcted pig heart can target the affected regions in an efficient and clinically relevant manner. A single dose of recombinant human agrin improved heart function, infarct size, fibrosis, and adverse remodeling parameters 28 days after MI. Short-term MI experiments along with complementary murine studies revealed myocardial protection, improved angiogenesis, inflammatory suppression, and cell cycle reentry as agrin's mechanisms of action. CONCLUSIONS: A single dose of agrin is capable of reducing ischemia-reperfusion injury and improving heart function, demonstrating that agrin could serve as a therapy for patients with acute MI and potentially heart failure.

Ultrafast Brain Magnetic Resonance Imaging in Acute Neurological Emergencies: Diagnostic Accuracy and Impact on Patient Management.

OBJECTIVES: The aim of this study was to investigate diagnostic accuracy and impact on patient management of an ultrafast (4:33 minutes/5 sequences) brain magnetic resonance imaging (MRI) protocol for the detection of intracranial pathologies in acute neurological emergencies. MATERIALS AND METHODS: Four hundred forty-nine consecutive emergency patients with acute nontraumatic neurological symptoms were evaluated for this institutional review board-approved prospective single-center trial. Sixty patients (30 female, 30 male; mean age, 61 years) with negative head CT were included and underwent emergency brain MRI at 3 T subsequent to CT. MRI included the ultrafast protocol (ultrafast-MRI; sag T1 GRE, ax T2 TSE, ax T2 TSE Flair, ax T2* EPI-GRE, ax DWI SS-EPI; TA, 5 minutes) and an equivalent standard-length protocol (TA, 15 minutes) as reference standard. Two blinded board-certified neuroradiologists independently analyzed the MRI with regard to image quality (1, nondiagnostic; 2, substantial artifacts; 3, satisfactory; 4, minor artifacts; 5, no artifacts) and intracranial pathologies. Sensitivity and specificity for the detection of intracranial pathologies were calculated accordingly. RESULTS: Ninety-three additional intracranial lesions (acute ischemia, n = 21; intracranial hemorrhage/microbleeds, n = 27; edema, n = 2; white matter lesion, n = 38; chronic infarction, n = 3; others, n = 2) were detected by ultrafast-MRI, whereas 101 additional intracranial lesions were detected by the standard-length protocol (acute ischemia, n = 24; intracranial hemorrhage/microbleeds, n = 32; edema, n = 2; white matter lesion, n = 38; chronic infarction, n = 3; others, n = 2). Image quality was equivalent to the standard-length protocol. Ultrafast-MRI demonstrated high diagnostic accuracy (sensitivity, 0.939 [0.881-0.972]; specificity, 1.000 [0.895-1.000]) for the detection of intracranial pathologies. MRI led to a change in patient management in 10% compared with the initial CT. CONCLUSIONS: Ultrafast-MRI enables time-optimized diagnostic workup in acute neurological emergencies at high sensitivity and specificity compared with a standard-length protocol, with direct impact on patient management. Ultrafast MRI protocols are a powerful tool in the emergency setting and may be implemented on various scanner types based on the optimization of individual acquisition parameters.

Improved prediction of nephron-sparing surgery versus radical nephrectomy by the optimized R.E.N.A.L. Score in patients undergoing surgery for renal masses.

BACKGROUND: One major objective of currently available morphometric scores (MS) for renal masses, i.e., R.E.N.A.L., PADUA classification, Centrality-Index, is the prediction of type of surgery (nephron-sparin surgery [NSS] or radical nephrectomy [RN]). METHODS: Based on a prospective study protocol, various MS were assigned and calculated for 108 patients undergoing surgical treatment for renal masses at a single academic center. MS calculation was based on preoperative computed-tomography or magnet-resonance-imaging and performed by two independent readers blinded for surgical approach and outcome. Multivariable logistic-regression- and ROC-analyses were performed to assess the predictive value of various MS for surgical approach and the correlation of clinical parameters with nephrectomy type. Furthermore, the association with perioperative outcome parameters was evaluated. RESULTS: None of the tested MS was significantly superior to tumor size alone (area under the curve [AUC]=0.82) in predicting RN, with Centrality-Index showing the best association (AUC=0.88). Based on these findings, a simplified and optimized R.E.N.A.L. Score (optR.E.N.A.L.) was developed with different weightings of included parameters, which did not only show a significantly enhanced association with surgery type (AUC=0.93) than tumor size, but also outperformed all 1st and 2nd generation MS tested in the study cohort. Besides a modest correlation with postoperative change in renal function, no association with perioperative outcome variables was found for all MS including optR.E.N.A.L. CONCLUSIONS: optR.E.N.A.L. represents a promising improvement of the preexisting R.E.N.A.L. Score with higher predictive ability for nephrectomy type than established MS and may serve as a benchmarking tool for nephrectomy assessment and comparison of surgical strategies.

Integrin-targeted quantitative optoacoustic imaging with MRI correlation for monitoring a BRAF/MEK inhibitor combination therapy in a murine model of human melanoma.

PURPOSE: To investigate αvß3-integrin-targeted optoacoustic imaging and MRI for monitoring a BRAF/MEK inhibitor combination therapy in a murine model of human melanoma. MATERIALS AND METHODS: Human BRAF V600E-positive melanoma xenograft (A375)-bearing Balb/c nude mice (n = 10) were imaged before (day 0) and after (day 7) a BRAF/MEK inhibitor combination therapy (encorafenib, 1.3 mg/kg/d; binimetinib, 0.6 mg/kg/d, n = 5) or placebo (n = 5), respectively. Optoacoustic imaging was performed on a preclinical system unenhanced and 5 h after i. v. injection of an αvß3-integrin-targeted fluorescent probe. The αvß3-integrin-specific tumor signal was derived by spectral unmixing. For morphology-based tumor response assessments, T2w MRI data sets were acquired on a clinical 3 Tesla scanner. The imaging results were validated by multiparametric immunohistochemistry (ß3 -integrin expression, CD31 -microvascular density, Ki-67 -proliferation). RESULTS: The αvß3-integrin-specific tumor signal was significantly reduced under therapy, showing a unidirectional decline in all animals (from 7.98±2.22 to 1.67±1.30; p = 0.043). No significant signal change was observed in the control group (from 6.60±6.51 to 3.67±1.93; p = 0.500). Immunohistochemistry revealed a significantly lower integrin expression (ß3: 0.20±0.02 vs. 0.39±0.05; p = 0.008) and microvascular density (CD31: 119±15 vs. 292±49; p = 0.008) in the therapy group. Tumor volumes increased with no significant intergroup difference (therapy: +107±42 mm3; control +112±44mm3, p = 0.841). In vivo blocking studies with αvß3-integrin antagonist cilengitide confirmed the target specificity of the fluorescent probe. CONCLUSIONS: αvß3-integrin-targeted optoacoustic imaging allowed for the early non-invasive monitoring of a BRAF/MEK inhibitor combination therapy in a murine model of human melanoma, adding molecular information on tumor receptor status to morphology-based tumor response criteria.

18F-FDG-PET/CT and diffusion-weighted MRI for monitoring a BRAF and CDK 4/6 inhibitor combination therapy in a murine model of human melanoma.

BACKGROUND: The purpose of the study was to investigate a novel BRAF and CDK 4/6 inhibitor combination therapy in a murine model of BRAF-V600-mutant human melanoma monitored by 18F-FDG-PET/CT and diffusion-weighted MRI (DW-MRI). METHODS: Human BRAF-V600-mutant melanoma (A375) xenograft-bearing balb/c nude mice (n = 21) were imaged by 18F-FDG-PET/CT and DW-MRI before (day 0) and after (day 7) a 1-week BRAF and CDK 4/6 inhibitor combination therapy (n = 12; dabrafenib, 20 mg/kg/d; ribociclib, 100 mg/kg/d) or placebo (n = 9). Animals were scanned on a small animal PET after intravenous administration of 20 MBq 18F-FDG. Tumor glucose uptake was calculated as the tumor-to-liver-ratio (TTL). Unenhanced CT data sets were subsequently acquired for anatomic coregistration. Tumor diffusivity was assessed by DW-MRI using the apparent diffusion coefficient (ADC). Anti-tumor therapy effects were assessed by ex vivo immunohistochemistry for validation purposes (microvascular density - CD31; tumor cell proliferation - Ki-67). RESULTS: Tumor glucose uptake was significantly suppressed under therapy (∆TTLTherapy - 1.00 ± 0.53 vs. ∆TTLControl 0.85 ± 1.21; p < 0.001). In addition, tumor diffusivity was significantly elevated following the BRAF and CDK 4/6 inhibitor combination therapy (∆ADCTherapy 0.12 ± 0.14 × 10-3 mm2/s; ∆ADCControl - 0.12 ± 0.06 × 10-3 mm2/s; p < 0.001). Immunohistochemistry revealed a significant suppression of microvascular density (CD31, 147 ± 48 vs. 287 ± 92; p = 0.001) and proliferation (Ki-67, 3718 ± 998 vs. 5389 ± 1332; p = 0.007) in the therapy compared to the control group. CONCLUSION: A novel BRAF and CDK 4/6 inhibitor combination therapy exhibited significant anti-angiogenic and anti-proliferative effects in experimental human melanomas, monitored by 18F-FDG-PET/CT and DW-MRI.

Quantification of Pathologic Air Trapping in Lung Transplant Patients Using CT Density Mapping: Comparison with Other CT Air Trapping Measures.

To determine whether density mapping (DM) is more accurate for detection and quantification of pathologic air trapping (pAT) in patients after lung transplantation compared to other CT air trapping measures. One-hundred forty-seven lung and heart-lung transplant recipients underwent CT-examinations at functional residual capacity (FRC) and total lung capacity (TLC) and PFT six months after lung transplantation. Quantification of air trapping was performed with the threshold-based method in expiration (EXP), density mapping (DM) and the expiratory to inspiratory ratio of the mean lung density (E/I-ratio MLD). A non-rigid registration of inspiration-expiration CT-data with a following voxel-to-voxel mapping was carried out for DM. Systematic variation of attenuation ranges was performed for EXP and DM and correlated with the ratio of residual volume to total lung capacity (RV/TLC) by Spearman rank correlation test. AT was considered pathologic if RV/TLC was above the 95th percentile of the predicted upper limit of normal values. Receiver operating characteristic (ROC) analysis was performed. The optimal attenuation range for the EXP method was from -790 HU to -950 HU (EXP(-790 to -950HU)) (r = 0.524, p<0.001) to detect air trapping. Within the segmented lung parenchyma, AT was best defined as voxel difference less than 80 HU between expiration and registered inspiration using the DM method. DM correlated best with RV/TLC (r = 0.663, p<0.001). DM and E/I-ratio MLD showed a larger AUC (0.78; 95% CI 0.69-0.86; 0.76, 95% CI 0.67-0.85) than EXP(-790 HU to -950 HU) (0.71, 95% CI 0.63-0.78). DM and E/I-ratio MLD showed better correlation with RV/TLC and are more suited quantitative CT-methods to detect pAT in lung transplant patients than the EXP(-790HU to -950HU).

The extent of changes in the membranous urethra angle is associated with the outcome of retrourethral transobturator sling procedure.

PURPOSE: To evaluate the outcome of the retrourethral transobturator sling (RTS) by functional magnetic resonance imaging (MRI) and to identify parameters associated with sling failure. METHODS: Of thirty recruited men with postprostatectomy stress urinary incontinence (SUI), 26 consecutively underwent functional MRI before sling procedure and 12 months thereafter in a prospective clinical cohort observational study. Periurethral/urethral fibrosis and sling visualization were evaluated on static sequences. The angle of the membranous urethra, position of the bladder neck and external urethral sphincter were assessed during Valsalva's maneuver and voiding. Sling success was defined as no or one dry "security" pad. RESULTS: The success and failure rates were 58 % (15/26 patients) and 42 % (11/26 patients), respectively. The sling leads to reduction in the membranous urethra angle during Valsalva's maneuver (39.55° vs. 36.82°, p = 0.025) and voiding (38.25° vs. 34.83°, p = 0.001) and elevation of the external urethral sphincter (2.9 vs. 4.8 mm, p = 0.017). Preoperative wider angle of the membranous urethra was significantly correlated with severe preoperative incontinence. Sling failure (p = 0.001) and severe preoperative incontinence (p = 0.001) were significantly related to only small changes of the membranous urethra angle. The interrater and intrarater reliability for membranous urethra angle was excellent (intraclass correlation coefficient ≥0.75). CONCLUSIONS: The RTS leads to reduction in the membranous urethra angle. The extent of the changes in the membranous urethra angle is associated with RTS outcome. Functional MRI is a reliable noninvasive visualization tool of interactions between the sling and pelvic floor for further research on the complex nature of postprostatectomy SUI.

Is a wider angle of the membranous urethra associated with incontinence after radical prostatectomy?

PURPOSE: To investigate whether differences in the anatomy and dynamics of the pelvic floor (PF) in patients after radical prostatectomy (RP) depicted on magnetic resonance imaging (MRI) are associated with continence status. METHODS: In the prospective designed study, 24 patients with post-prostatectomy stress urinary incontinence were enrolled. Additionally, 10 continent patients after RP were matched for age, body mass index and perioperative parameters. All patients underwent continence assessment and MRI (TrueFISP sequence; TR 4.57 ms; TE 2.29 ms; slice thickness 7 mm; FOV 270 mm) 12 months after RP. Images were analyzed for membranous urethra length (MUL), angle of the membranous urethra (AMU), severity of periurethral/urethral fibrosis, lifting of the levator ani muscle, lowering of the posterior bladder wall (BPW), bladder neck (BN) and external urinary sphincter (EUS), and symphyseal rotation of these structures during the Valsalva maneuver and voiding. RESULTS: Compared to continent controls, incontinent patients showed a significant wider AMU during voiding (p = 0.002) and more pronounced lowering of the BN and EUS (p < 0.001). No differences between the groups were found in symphyseal rotation of the analyzed structures, MUL and severity of periurethral/urethral fibrosis. CONCLUSIONS: The angle of the membranous urethra as a result of anchoring of the BN and EUS in the PF appears to be an important functional factor with an essential impact on continence after RP. Functional MRI seems to be a helpful imaging tool for morphologic and dynamic evaluation of the PF.