Search

Peter GK Wagstaff,1 Mara Buijs,1 Willemien van den Bos,1 Daniel M de Bruin,2 Patricia J Zondervan,1 Jean JMCH de la Rosette,1 M Pilar Laguna Pes1 1Department of Urology, 2Department of Biomedical Engineering and Physics, Academic Medical Center, Amsterdam, the Netherlands Abstract: The field of focal ablative therapy for the treatment of cancer is characterized by abundance of thermal ablative techniques that provide a minimally invasive treatment option in selected tumors. However, the unselective destruction inflicted by thermal ablation modalities can result in damage to vital structures in the vicinity of the tumor. Furthermore, the efficacy of thermal ablation intensity can be impaired due to thermal sink caused by large blood vessels in the proximity of the tumor. Irreversible electroporation (IRE) is a novel ablation modality based on the principle of electroporation or electropermeabilization, in which electric pulses are used to create nanoscale defects in the cell membrane. In theory, IRE has the potential of overcoming the aforementioned limitations of thermal ablation techniques. This review provides a description of the principle of IRE, combined with an overview of in vivo research performed to date in the liver, pancreas, kidney, and prostate. Keywords: irreversible electroporation, IRE, tumor, ablation, focal therapy, cancer

Background: Focal laser ablation (FLA) serves as a targeted therapy for prostate cancer (PCa). Clinical studies have demonstrated significant variations in ablation volumes with consistent fiber configurations. Consequently, a prediction model is needed for the safe application of FLA in treating PCa., Objective: This study aimed to evaluate the reproducibility of FLA-induced temperature profiles in controlled ex vivo experiments using clinical laser treatment protocols. Additionally, it sought to examine the effectiveness of the CEM43 model in predicting the zone of irreversible damage (ZID) and to compare these findings with outcomes derived from the Arrhenius model., Methods: Freshly excised postmortem human prostate and porcine liver specimens were used for controlled ex vivo ablation. Tissues were secured in a Perspex sample holder for precise placement of the laser fiber and thermocouples. FLA was conducted with a 1064-nm Nd:YAG laser at 3 W in continuous-wave mode for 10 min. Pre- and post-FLA 3D T1-weighted 7 T MRI scans were obtained to assess the treatment area. Whole-mount hematoxylin and eosin histological slides were prepared and digitized. On histology, the ZID was defined as the total of vaporized, carbonized, and coagulated tissue. A 2D thermal development map was created from temperature data, using bi-cubic interpolation. The cumulative equivalent thermal isoeffect dose at 43°C in minutes (CEM43) model was applied to predict the ZID, with 240 equivalent minutes (240-CEM43) used as the damage threshold. Additionally, the Arrhenius thermal model was used for comparison of CEM43 results. Predicted ZIDs were compared to MRI and histology., Results: FLA treatment was performed on ex vivo human prostate samples (n = 2) and porcine liver specimens (n = 5). For human prostate tissue, FLA did not result in an identifiable ZID upon histological macroscopic examination or a lesion on MRI. Ex vivo porcine liver samples showed a clearly demarcated oval-shaped hyperintense lesion surrounding the laser fiber tip on post-FLA MRI. The MRI lesion (range 1.6-2.1 cm 2 ) corresponded with the shape and location of the ZID on histology, but was smaller (median 1.7 vs. 3.2, p = 0.02). Histological examination of porcine liver samples revealed ZIDs ranging from 2.1 to 4.1 cm 2 , whereas 240-CEM43-predicted ZIDs ranged from 3.3 to 3.8 cm 2 . Although the median 240-CEM43-predicted ZID was not significantly larger than the histology ZID (3.8 vs. 3.2 cm 2 , p = 0.22), it tended to overpredict the histological results in most experiments. The median Arrhenius-predicted ZID was similar to the histological ZID (3.2 vs. 3.2 cm 2 , p = 0.56), but varied in size when comparing individual experiments (range 2.5-3.2 cm 2 )., Conclusion: FLA on ex vivo human prostate showed no thermal damage on histopathology or MRI. Ex vivo porcine liver FLA resulted in identifiable ZID on histology and lesions on MRI. 240-CEM43 generally overestimated the ZID and had less variability compared to histology. Results from the Arrhenius model were in better agreement with the histology findings, but still did not predict the individual FLA-induced histological thermal damage. Inter-experiment ZID variability underlines the need for developing a more comprehensive predictive dosimetry model for FLA in PCa treatment., (© 2024 The Author(s). Lasers in Surgery and Medicine published by Wiley Periodicals LLC.)

Purpose: Urothelial bladder cancer (UCB) care requires frequent follow-up cystoscopy and surgery. Confocal laser endomicroscopy (CLE) is a probe-based optical technique that can provide real-time microscopic evaluation with the potential for outpatient grading of UCB. This study aims to investigate the diagnostic accuracy and interobserver variability for the grading of UCB with CLE during flexible cystoscopy (fCLE)., Methods: Participants scheduled for transurethral resection of papillary bladder tumors were prospectively included for intra-operative fCLE. Exclusion criteria were flat lesions, fluorescein allergy or pregnancy. Two independent observers evaluated fCLE, classifying tumors as low- or high-grade urothelial carcinoma (LGUC/HGUC) or benign. Interobserver agreement was calculated with Cohens kappa (κ) and diagnostic accuracy with 2 × 2 tables. Histopathology was the reference test., Results: Histopathology of 34 lesions revealed 14 HGUC, 14 LGUC and 6 benign tumors. Diagnostic yield for fCLE was 80-85% with a κ of 0.75. Respectively, sensitivity, specificity, NPV and PPV were: for benign tumors 0-20%, 96-100%, unmeasureable-50% and 87%, for LGUC 57-64%, 41-58%, 44-53% and 54-69% and for HGUC 38-57%, 56-68%, 38-57% and 56-68%, with an interobserver agreement of κ 0.61., Conclusion: fCLE is currently insufficient to grade UCB., (© 2024. The Author(s).)

Objectives: To systematically assess the current available literature concerning advanced optical imaging methods for the detection and diagnosis of bladder cancer (BCa), focusing particularly on the sensitivity and specificity of these techniques., Methods: First a scoping search was performed to identify all available optical techniques for BCa detection and diagnosis. The optical imaging techniques used for detecting BCa are: the Storz professional image enhancement system (IMAGE1 S), narrow-band imaging (NBI), photoacoustic imaging (PAI), autofluorescence imaging (AFI), photodynamic diagnosis (PDD), and scanning fibre endoscopy (SFE). The staging and grading techniques for BCa are: optical coherence tomography (OCT), confocal laser endomicroscopy (CLE), Raman spectroscopy, endocytoscopy, and non-linear optical microscopy (NLO). Then a systematic literature search was conducted using MEDLINE, EMBASE and Web of Science from inception to 21 November 2023. Articles were screened and selected by two independent reviewers. Inclusion criteria were: reporting on both the sensitivity and specificity of a particular technique and comparison to histopathology, and in the case of a detection technique comparison to white light cystoscopy (WLC)., Results: Out of 6707 articles, 189 underwent full-text review, resulting in 52 inclusions. No articles met criteria for IMAGE1 S, PAI, SFE, Raman spectroscopy, and endocytoscopy. All detection techniques showed higher sensitivity than WLC, with NBI leading (87.8-100%). Overall, detection technique specificity was comparable to WLC, with PDD being most specific (23.3-100%). CLE and OCT varied in sensitivity and specificity, with OCT showing higher specificity for BCa diagnosis, notably for carcinoma in situ (97-99%) compared to CLE (62.5-81.3%). NLO demonstrated high sensitivity and specificity (90-97% and 77-100%, respectively) based on limited data from two small ex vivo studies., Conclusions: Optical techniques with the most potential are PDD for detecting and OCT for staging and grading BCa. Further research is crucial to validate their integration into routine practice and explore the value of other imaging techniques., (© 2024 The Author(s). BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)

Introduction: Despite many technological advances, the diagnostic yield of bronchoscopic peripheral lung nodule analysis remains limited due to frequent mispositioning. Needle-based confocal laser endomicroscopy (nCLE) enables real-time microscopic feedback on needle positioning, potentially improving the sampling location and diagnostic yield. Previous studies have defined and validated nCLE criteria for malignancy, airway and lung parenchyma. Larger studies demonstrating the effect of nCLE on diagnostic yield are lacking. We aim to investigate if nCLE-imaging integrated with conventional bronchoscopy results in a higher diagnostic yield compared with conventional bronchoscopy without nCLE., Methods and Analysis: This is a parallel-group randomised controlled trial. Recruitment is performed at pulmonology outpatient clinics in universities and general hospitals in six different European countries and one hospital in the USA. Consecutive patients with a for malignancy suspected peripheral lung nodule (10-30 mm) with an indication for diagnostic bronchoscopy will be screened, and 208 patients will be included. Web-based randomisation (1:1) between the two procedures will be performed. The primary outcome is diagnostic yield. Secondary outcomes include diagnostic sensitivity for malignancy, needle repositionings, procedure and fluoroscopy duration, and complications. Pathologists will be blinded to procedure type; patients and endoscopists will not., Ethics and Dissemination: Primary approval by the Ethics Committee of the Amsterdam University Medical Center. Dissemination involves publication in a peer-reviewed journal., Support: Financial and material support from Mauna Kea Technologies., Trial Registration Number: NCT06079970., Competing Interests: Competing interests: JTA declares material and financial support to the sponsor’s institution from Mauna Kea Technologies for this study. All Cellvizio equipment needed for the conduct of the study is provided in-kind to participating centers. All other authors declare no other conflicts of interest., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Indocyanine green fluorescence angiography (ICG-FA) may reduce perfusion-related complications of gastrointestinal anastomosis. Software implementations for quantifying ICG-FA are emerging to overcome a subjective interpretation of the technology. Comparison between quantification algorithms is needed to judge its external validity. This study aimed to measure the agreement for visceral perfusion assessment between two independently developed quantification software implementations., Methods: This retrospective cohort analysis included standardized ICG-FA video recordings of patients who underwent esophagectomy with gastric conduit reconstruction between August 2020 until February 2022. Recordings were analyzed by two quantification software implementations: AMS and CPH. The quantitative parameter used to measure visceral perfusion was the normalized maximum slope derived from fluorescence time curves. The agreement between AMS and CPH was evaluated in a Bland-Altman analysis. The relation between the intraoperative measurement of perfusion and the incidence of anastomotic leakage was determined for both software implementations., Results: Seventy pre-anastomosis ICG-FA recordings were included in the study. The Bland-Altman analysis indicated a mean relative difference of + 58.2% in the measurement of the normalized maximum slope when comparing the AMS software to CPH. The agreement between AMS and CPH deteriorated as the magnitude of the measured values increased, revealing a proportional (linear) bias (R 2  = 0.512, p < 0.001). Neither the AMS nor the CPH measurements of the normalized maximum slope held a significant relationship with the occurrence of anastomotic leakage (median of 0.081 versus 0.074, p = 0.32 and 0.041 vs 0.042, p = 0.51, respectively)., Conclusion: This is the first study to demonstrate technical differences in software implementations that can lead to discrepancies in ICG-FA quantification in human clinical cases. The possible variation among software-based quantification methods should be considered when interpreting studies that report quantitative ICG-FA parameters and derived thresholds, as there may be a limited external validity., (© 2024. The Author(s).)

Introduction: There are three common treatment options for kidney stones: extracorporeal shockwave lithotripsy (ESWL), ureterorenoscopy (URS) and percutaneous nephrolithotomy (PNL). The choice of treatment is based on stone- and patient-related characteristics. However, some stones are eligible for several approaches and the decision is made based on patient and urologist's preferences. This study evaluates which approach has the highest workload., Material and Methods: Between March and August 2022, five members of the Amsterdam Endourology Research Group collected data from 22 ESWL, 31 URS and 22 PNL procedures. After each procedure, the SURG-TLX questionnaire was completed by the surgeon to evaluate workload. Six dimensions were scored for each procedure, including: mental demands, physical demands, temporal demands, task complexity, situational stress, and distractions. The total workload, and the median for each dimension, was calculated and compared for the three treatments., Results: ESWL scored significantly lower than URS for mental demands, physical demands, temporal demands, situational stress, distraction and total workload. However, task complexity did not differ significantly between the two techniques. Compared with PNL, ESWL scored significantly lower for all dimensions. Finally, PNL received significantly higher scores for mental demands, physical demands, temporal demands, situational stress, distractions and total workload than URS. Only task complexity showed no significant difference between both groups., Conclusions: Urologists perceive the highest workload during PNL, followed by URS and finally ESWL. A follow-up study is needed to identify stressors that increase perceived workload with the purpose to address these variables and as final objective to improve urologists' workload, patient safety and treatment outcomes., Competing Interests: The authors declare no conflicts of interest., (Copyright by Polish Urological Association.)

Background: Intraoperative perfusion assessment with indocyanine green fluorescence angiography (ICG-FA) may reduce postoperative anastomotic leakage rates after esophagectomy with gastric conduit reconstruction. This study evaluated quantitative parameters derived from fluorescence time curves to determine a threshold for adequate perfusion and predict postoperative anastomotic complications., Methods: This prospective cohort study included consecutive patients who underwent FA-guided esophagectomy with gastric conduit reconstruction between August 2020 and February 2022. After intravenous bolus injection of 0.05-mg/kg ICG, fluorescence intensity was registered over time by PINPOINT camera (Stryker, USA). Fluorescent angiograms were quantitatively analyzed at a region of interest of 1 cm diameter at the anastomotic site on the conduit using tailor-made software. Extracted fluorescence parameters were both inflow (T 0 , T max , F max , slope, Time-to-peak) as outflow parameters (T 90% and T 80% ). Anastomotic complications including anastomotic leakage (AL) and strictures were documented. Fluorescence parameters in patients with AL were compared to those without AL., Results: One hundred and three patients (81 male, 65.7 ± 9.9 years) were included, the majority of whom (88%) underwent an Ivor Lewis procedure. AL occurred in 19% of patients (n = 20/103). Both time to peak as T max were significantly longer for the AL group in comparison to the non-AL group (39 s vs. 26 s, p = 0.04 and 65 vs. 51 s, p = 0.03, respectively). Slope was 1.0 (IQR 0.3-2.5) and 1.7 (IQR 1.0-3.0) for the AL and non-AL group (p = 0.11). Outflow was longer in the AL group, although not significantly, T 90% 30 versus 15 s, respectively, p = 0.20). Univariate analysis indicated that T max might be predictive for AL, although not reaching significance (p = 0.10, area under the curve 0.71) and a cut-off value of 97 s was derived, with a specificity of 92%., Conclusion: This study demonstrated quantitative parameters and identified a fluorescent threshold which could be used for intraoperative decision-making and to identify high-risk patients for anastomotic leakage during esophagectomy with gastric conduit reconstruction. A significant predictive value remains to be determined in future studies., (© 2023. The Author(s).)

Background: Intraoperative indocyanine green fluorescence angiography (ICG-FA) may be of added value during pouch surgery, in particular after vascular ligations as lengthening maneuver. The aim was to determine quantitative perfusion parameters within the efferent/afferent loop and explore the impact of vascular ligation. Perfusion parameters were also compared in patients with and without anastomotic leakage (AL)., Methods: All consenting patients that underwent FA-guided ileal pouch-anal anastomosis (IPAA) between July 2020 and December 2021 were included. After intravenous bolus injection of 0.1 mg/kg ICG, the near-infrared camera (Stryker Aim 1688) registered the fluorescence intensity over time. Quantitative analysis of ICG-FA from standardized regions of interests on the pouch was performed using software. Fluorescence parameters were extracted for inflow (T 0 , T max , F max , slope, Time-to-peak) and outflow (T 90% and T 80% ). Change of management related to FA findings and AL rates were recorded., Results: Twenty-one patients were included, three patients (14%) required vascular ligation to obtain additional length, by ligating terminal ileal branches in two and the ileocolic artery (ICA) in one patient. In nine patients the ICA was already ligated during subtotal colectomy. ICG-FA triggered a change of management in 19% of patients (n = 4/21), all of them had impaired vascular supply (ligated ileocolic/ terminal ileal branches). Overall, patients with intact vascular supply had similar perfusion patterns for the afferent and efferent loop. Pouches with ICA ligation had longer T max in both afferent as efferent loop than pouches with intact ICA (afferent 51 and efferent 53 versus 41 and 43 s respectively). Mean slope of the efferent loop diminished in ICA ligated patients 1.5(IQR 0.8-4.4) versus 2.2 (1.3-3.6) in ICA intact patients., Conclusion: Quantitative analysis of ICG-FA perfusion during IPAA is feasible and reflects the ligation of the supplying vessels., (© 2023. The Author(s).)

Purpose: To review and compare the effectivity of novel minimally invasive treatments (MITs) to transurethral resection of the prostate (TURP) for the treatment of lower urinary tract symptoms (LUTS) in men., Methods: Medline, Embase, and Cochrane databases were searched from January 2010 to December 2022 for randomized controlled trials (RCTs) evaluating MITs, compared to TURP or sham, in men with LUTS. Studies were assessed by risk of bias tool, and evidence by GRADE. Functional outcomes by means of uroflowmetry and IPSS were the primary outcomes, safety and sexual function were secondary outcomes. As part of this review, a network meta-analysis (NMA) was conducted. MITs were ranked based on functional outcome improvement probability., Results: In total, 10 RCTs were included, evaluating aquablation, prostatic urethral lift, prostatic artery embolization (PAE), convective water vapor thermal treatment or temporary implantable nitinol device. All MITs showed a better safety profile compared to TURP. Functional outcome improvement following aquablation were comparable to TURP. In the NMA, aquablation was ranked highest, PAE followed with the second highest probability to improve functional outcomes. Other novel MITs resulted in worse functional outcomes compared to TURP. Level of evidence was low to very low., Conclusions: Five MITs for treatment of LUTS were identified. Aquablation is likely to result in functional outcomes most comparable to TURP. Second in ranking was PAE, a technique that does not require general or spinal anesthesia. MITs have a better safety profile compared to TURP. However, due to high study heterogeneity, results should be interpreted with caution., Competing Interests: None declared., (Copyright® by the International Brazilian Journal of Urology.)

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., (© 2023 The Author(s).)

Objective: To assess the diagnostic accuracy and intra-observer agreement of endoscopic stone recognition (ESR) compared with formal stone analysis. Introduction: Stone analysis is a corner stone in the prevention of stone recurrence. Although X-ray diffraction (XRD) and infrared spectroscopy are the recommended techniques for reliable formal stone analysis, this is not always possible, and the process takes time and is costly. ESR could be an alternative, as it would give immediate information on stone composition. Materials and Methods: Fifteen endourologists predicted stone composition based on 100 videos from ureterorenoscopy. Diagnostic accuracy was evaluated by comparing the prediction from visual assessment with stone analysis by XRD. After 30 days, the videos were reviewed again in a random order to assess intra-observer agreement. Results: The median diagnostic accuracy for calcium oxalate monohydrate was 54% in questionnaire 1 (Q1) and 59% in questionnaire 2 (Q2), whereas calcium oxalate dihydrate had a median diagnostic accuracy of 75% in Q1 and 50% in Q2. The diagnostic accuracy for calcium hydroxyphosphate was 10% in Q1 and 13% in Q2. The median diagnostic accuracy for calcium hydrogen phosphate dihydrate and calcium magnesium phosphate was 0% in both questionnaires. The median diagnostic accuracy for magnesium ammonium phosphate was 20% in Q1 and 40% in Q2. The median diagnostic accuracy for uric acid was 22% in both questionnaires. Finally, there was a diagnostic accuracy of 60% in Q1 and 80% in Q2 for cystine. The intra-observer agreement ranged between 45% and 72%. Conclusion: Diagnostic accuracy of ESR is limited and intra-observer agreement is below the threshold of acceptable agreement.

Background: Soractelite™ transperineal focal laser ablation (TPLA) for the treatment of localized prostate cancer (PCa) using the Echolaser® system is a novel minimally invasive technique that has the potential to induce tissue ablation, while reducing treatment-related morbidity, when compared with robot-assisted radical prostatectomy (RARP) and radiotherapy., Objective: To determine the short-term safety and feasibility of single or multifiber TPLA, its functional outcomes, and quality of life (QoL)., Design Setting and Participants: TPLA was performed in 12 patients, consecutively assigned to four treatment regimens, with localized PCa who were scheduled for RARP ("ablate and resect design"). The treatment regimens were as follows: (1) a single fiber at 3 W, (2) two fibers at 5 mm distance at 3 W, (3) two fibers at 10 mm distance at 3 W, and (4) a single fiber at 5 W. TPLA was scheduled 4 wk prior to RARP., Intervention: TPLA using the Echolaser® system under local anesthesia at the outpatient clinic., Outcome Measurements and Statistical Analysis: Safety and feasibility were determined by the assessment of device-related peri- and postoperative adverse events (AEs), and length of hospital stay. Functional outcomes and QoL were measured using validated questionnaires. Feasibility of RARP was assessed by a questionnaire for the urologist., Results and Limitations: Patients were dismissed after a median (interquartile range) hospital admission of 3.25 (1.25) h. No device-related AEs occurred. AEs that occurred were mostly related to lower urinary tract symptoms and were mild (grade 1-2). Most AEs resolved within 1 wk. A QoL analysis showed no significant differences for all treatment regimens. Functional outcomes remained unchanged, except for erectile function after 1 wk, which returned to baseline after 4 wk. TPLA treatment did not compromise RARP, based on the questionnaires., Conclusions: TPLA for the treatment of PCa at the outpatient clinic appears to be safe and feasible with good short-term QoL and functional outcomes; oncological results are awaited., Patient Summary: Focal treatment of localized prostate cancer can safely be performed in a daycare setting using a new technique, based on laser ablation, without compromising quality of life., (© 2022 The Author(s).)

This study tests fluorescence imaging-derived quantitative parameters for perfusion evaluation of the gastric tube during surgery and correlates these parameters with patient outcomes in terms of anastomotic leakage. Poor fundus perfusion is seen as a major factor for the development of anastomotic leakage and strictures. Fluorescence perfusion imaging may reduce the incidence of complications. Parameters for the quantification of the fluorescence signal are still lacking. Quantitative parameters in terms of maximal intensity, mean slope and influx timepoint were tested for significant differences between four perfusion areas of the gastric tube in 22 patients with a repeated ANOVA test. These parameters were compared with patient outcomes. Maximal intensity, mean slope and influx timepoint were significantly different between the base of the gastric tube and the fundus ( p < 0.0001). Patients who developed anastomotic leakage showed a mean slope of almost 0 in Location 4. The distance of the demarcation of ICG to the fundus was significantly higher in the three patients who developed anastomotic leakage ( p < 0.0001). This study presents quantitative intra-operative perfusion imaging with fluorescence. Quantification of the fluorescence signal allows for early risk stratification of necrosis.

Background: Adequate perfusion of a bone flap is essential for successful reconstruction of osseous defects. Unfortunately, complications related to inadequate bone perfusion are common. Near-infrared fluorescence (NIRF) imaging enables intraoperative visualization of perfusion. NIRF has been investigated in reconstructive surgery to aid the surgeon in clinical perioperative assessment of soft tissue perfusion. However, little is known on the beneficial use of NIRF to assess bone perfusion. Therefore, the aim of this review was to search for studies evaluating NIRF to assess bone perfusion. Methods: A systematic review, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline, was performed. Studies up to October 2021 were included. We extracted data regarding the study population, size and design, reported objective fluorescence parameters and the methodology used for fluorescence imaging and processing. Results: Ten articles were included. Studies reported unevenly on the protocol used for NIRF imaging. Five studies reported objective parameters. Absolute and relative perfusion parameters and parameters derived from maximum fluorescence were reported. The clinical significance of these parameters has not been evaluated in humans. Conclusion: The evidence on bone perfusion as measured with NIRF is limited. More clinical studies are required.

Purpose: To assess the safety and technical feasibility of in-vivo needle-based forward-looking confocal laser endomicroscopy in prostate tissue. Methods: For this feasibility study, 2 patients with a suspicion of prostate cancer underwent transperineal needle-based confocal laser endomicroscopy during ultrasound-guided transperineal template mapping biopsies. After intravenous administration of fluorescein, needle-based confocal laser endomicroscopy imaging was performed with a forward-looking probe (outer diameter 0.9 mm) in 2 trajectories during a manual push-forward and pullback motion. A biopsy was taken in a coregistered parallel adjacent trajectory to the confocal laser endomicroscopy trajectory for histopathologic comparison. Peri- and postprocedural adverse events, confocal laser endomicroscopy device malfunction and procedural failures were recorded. Needle-based confocal laser endomicroscopy image quality assessment, image interpretation, and histology were performed by an experienced confocal laser endomicroscopy rater and uro-pathologist, blinded to any additional information. Results: In both patients, no peri- and post-procedural adverse events were reported following needle-based confocal laser endomicroscopy. No confocal laser endomicroscopy device malfunction nor procedural failures were reported. Within 1.5 min after intravenous administration of fluorescein, needle-based confocal laser endomicroscopy image quality was sufficient for interpretation for at least 14 min, yielding more than 5000 confocal laser endomicroscopy frames per patient. The pullback confocal laser endomicroscopy recordings and most of the push-forward recordings almost only visualized erythrocytes, being classified as non-representative. During the push-forward recordings, prostate tissue was occasionally visualized in single frames, insufficient for histopathologic comparison. Prostate carcinoma was identified by biopsy in one patient (Gleason score 4 + 3 = 7, >50%), while the biopsy from the other patient showed no malignancy. Conclusion: Needle-based confocal laser endomicroscopy imaging of in-vivo prostate tissue with a forward-looking confocal laser endomicroscopy probe is safe without device malfunctions or procedural failures. Needle-based confocal laser endomicroscopy is technically feasible, but the acquired confocal laser endomicroscopy datasets are non-representative. The confocal laser endomicroscopy images' non-representative nature is possibly caused by bleeding artifacts, movement artifacts and a lack of contact time with the tissue of interest. A different confocal laser endomicroscopy probe or procedure might yield representative images of prostatic tissue.

Background: Non-muscle-invasive bladder cancer (NMIBC) is characterized by frequent recurrence of the disease, which is difficult to predict., Objective: To combine digital histopathology slides with clinical data to predict 1- and 5-yr recurrence-free survival of NMIBC patients using deep learning., Design, Setting, and Participants: Data of patients undergoing a transurethral resection of a bladder tumor between 2000 and 2018 at a Dutch academic medical center were selected. Corresponding histological slides were digitized. A three-step approach was used to predict 1- and 5-yr recurrence-free survival. First, a segmentation network was used to detect the urothelium on the digital histopathology slides. Second, a selection network was trained for the selection of patches associated with recurrence. Third, a classification network, combining the information of the selection network with clinical data, was trained to give the probability of 1- and 5-yr recurrence-free survival., Outcome Measurements and Statistical Analysis: The accuracy of the deep learning-based model was compared with a multivariable logistic regression model using clinical data only., Results and Limitations: In the 1- and 5-yr follow-up cohorts, 359 and 281 patients were included with recurrence rates of 27% and 63%, respectively. The areas under the curve (AUCs) of the model combining digital histopathology slide data with clinical data were 0.62 and 0.76 for 1- and 5-yr recurrence predictions, respectively, which were higher than those of the model using digital histopathology slide data only (AUCs of 0.56 and 0.72, respectively) and the multivariable logistic regression (AUCs of 0.58 and 0.57, respectively)., Conclusions: In our population, the deep learning-based model combining digital histopathology slides and clinical data enhances the prediction of recurrence (within 5 yr) compared with models using clinical data or image data only., Patient Summary: By combining histopathology images and patient record data using deep learning, the prediction of recurrence in bladder cancer patients is enhanced., (Copyright © 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Objective: Accurate, high-resolution imaging of articular cartilage thickness is an important clinical challenge in patients with osteoarthritis, especially in small joints. In this study, computed tomography (CT) mediated catheter-based optical coherence tomography (OCT) was utilized to create a digital reconstruction of the articular surface of the trapeziometacarpal (TMC) joint and to assess cartilage thickness in comparison to cryomicrotome data., Design: Using needle-based introduction of the OCT probe, the articular surface of the TMC joint of 5 cadaver wrists was scanned in different probe positions with matching CT scans to record the intraarticular probe trajectory. Subsequently and based on the acquired CT data, 3-dimensional realignment of the OCT data to the curved intraarticular trajectory was performed for all probe positions. The scanned TMC joints were processed using a cryomicrotome imaging system. Finally, cartilage thickness measurements between OCT and cryomicrotome data were compared., Results: Successful visualization of TMC articular cartilage was performed using OCT. The CT-mediated registration yielded a digital reconstruction of the articular surface on which thickness measurements could be performed. A near-perfect agreement between OCT and cryomicrotome thickness measurements was found ( r 2 = 0.989)., Conclusion: The proposed approach enables 3D reconstruction of the TMC articular surface with subsequent accurate cartilage thickness measurements, encouraging the development of intraarticular cartilage OCT for future (clinical) application.

Background: Barrett's esophagus (BE) is a precursor lesion of esophageal adenocarcinoma and may progress from non-dysplastic through low-grade dysplasia (LGD) to high-grade dysplasia (HGD) and cancer. Grading BE is of crucial prognostic value and is currently based on the subjective evaluation of biopsies. This study aims to investigate the potential of machine learning (ML) using spatially resolved molecular data from mass spectrometry imaging (MSI) and histological data from microscopic hematoxylin and eosin (H&E)-stained imaging for computer-aided diagnosis and prognosis of BE., Methods: Biopsies from 57 patients were considered, divided into non-dysplastic (n = 15), LGD non-progressive (n = 14), LGD progressive (n = 14), and HGD (n = 14). MSI experiments were conducted at 50 × 50 μm spatial resolution per pixel corresponding to a tile size of 96x96 pixels in the co-registered H&E images, making a total of 144,823 tiles for the whole dataset., Results: ML models were trained to distinguish epithelial tissue from stroma with area-under-the-curve (AUC) values of 0.89 (MSI) and 0.95 (H&E)) and dysplastic grade (AUC of 0.97 (MSI) and 0.85 (H&E)) on a tile level, and low-grade progressors from non-progressors on a patient level (accuracies of 0.72 (MSI) and 0.48 (H&E))., Conclusions: In summary, while the H&E-based classifier was best at distinguishing tissue types, the MSI-based model was more accurate at distinguishing dysplastic grades and patients at progression risk, which demonstrates the complementarity of both approaches. Data are available via ProteomeXchange with identifier PXD028949., (Copyright © 2021. Published by Elsevier Ltd.)

Purpose: Ablation plays a growing role in the treatment of small renal masses (SRMs) due to its nephron sparing properties and low invasiveness. Irreversible electroporation (IRE) has the potential, although still experimental, to overcome current limitations of thermal ablation. No prospective imaging studies exist of the ablation zone in the follow up after renal IRE in humans. Objectives are to assess computed tomography (CT) and magnetic resonance imaging (MRI) on the ablation zone volume (AZV), enhancement and imaging characteristics after renal IRE., Methods: Prospective phase 2 study of IRE in nine patients with ten SRMs. MRI imaging was performed pre-IRE, 1 week, 3 months, 6 months and 12 months after IRE. CT was performed pre-IRE, perioperatively (direct after ablation), 3 months, 6 months and 12 months after IRE. AZVs were assessed by two independent observers. Observer variation was analyzed. Evolution of AZVs, and relation between the needle configuration volume (NCV; planned AZV) and CT- and MRI volumes were evaluated., Results: Eight SRMs were clear cell renal cell carcinomas, one SRM was a papillary renal cell carcinoma and one patient had a non-diagnostic biopsy. On CT, median AZV increased perioperatively until 3 months post-IRE (respectively, 16.8 cm3 and 6.2 cm3) compared to the NCV (4.8 cm3). On MRI, median AZV increased 1-week post-IRE until 3 months post-IRE (respectively, 14.5 cm3 and 4.6 cm3) compared to the NCV (4.8 cm3). At 6 months the AZV starts decreasing (CT 4.8 cm3; MRI 3.0 cm3), continuing at 12 months (CT 4.2 cm3, MRI 1.1 cm3). Strong correlation was demonstrated between the planning and the post-treatment volumes. Inter-observer agreement between observers was excellent (CT 95% CI 0.82-0.95, MRI 95% CI 0.86-0.96). All SRMs appeared non-enhanced immediately after ablation, except for one residual tumour. Subtraction images confirmed non-enhancement on MRI in unclear enhancement cases (3/9). Directly after IRE, gas bubbles, perinephric stranding and edema were observed in all cases., Conclusion: The AZV increases immediately on CT until 3 months after IRE. On MRI, the AZV increases at 1 week until 3 months post-IRE. At 6 months the AZV starts decreasing until 12 months post-IRE on both CT and MRI. Enhancement was absent post-IRE, except for one residual tumour. Gas bubbles, perinephric stranding and edema are normal findings directly post-IRE.

Background: Fluorescence angiography (FA) assesses anastomotic perfusion during esophagectomy with gastric conduit reconstruction, but its interpretation is subjective. This study evaluated time to fluorescent enhancement in the gastric conduit, with the aim to determine a threshold to predict postoperative anastomotic complications., Methods: In a prospective cohort study, all consecutive patients undergoing esophagectomy with gastric conduit reconstruction from July 2018 to October 2019 were included. FA was performed before anastomotic reconstruction following injection of indocyanine green (ICG). During FA, the following time points were recorded: ICG injection, first fluorescent enhancement in the lung, at the base of the gastric conduit, at the planned anastomotic site, and at ICG watershed or in the tip of the gastric conduit. Anastomotic complications including anastomotic leakage and clinically relevant strictures were documented., Results: Eighty-four patients were included, the majority (67 out of 84, 80%) of which underwent an Ivor Lewis procedure. After a median follow-up of 297 days, anastomotic leakage was observed in 12 out of 84 (14.3%) and anastomotic stricture in 12 out of 82 (14.6%). Time between ICG injection and enhancement in the tip was predictive for anastomotic leakage (P = 0.174, area under the curve = 0.731), and a cut-off value of 98 seconds was derived (specificity: 98%). All times to enhancement at the planned anastomotic site and ICG watershed were significantly predictive for the occurrence of a stricture, however area under the curves were <0.7., Conclusions: The identified fluorescent threshold can be used for intraoperative decision making or to identify potentially high-risk patients for anastomotic leakage after esophagectomy with gastric conduit reconstruction., (© The Author(s) 2020. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus.)

Background: Anastomotic leakage is one of the most severe complications in patients undergoing esophagectomy with gastric tube reconstruction. Transection of the left gastric and gastro-epiploic artery and vein results in compromised perfusion which is seen as the major contributing factor for anastomotic dehiscence. The main objective of this prospective, observational, in-vivo pilot study is to microscopically evaluate gastric tube perfusion with Sidestream Darkfield Microscopy (SDF)., Methods: Intra-operative microscopic images of gastric-microcirculation were obtained with SDF directly after reconstruction in 22 patients. Quantitative perfusion related parameters were: velocity, Microvascular Flow Index(MFI), Total Vessel Density(TVD), Perfusion Vessel Density(PVD), Proportion of Perfused Vessels(PPV) and De Backer Score(DBS). Dedicated software was used to assess parameters predictive for compromised perfusion., Results: SDF was feasible to accurately visualize and evaluate microcirculation in all patients. Velocity(μm/sec) was significantly decreased towards the fundus (p = 0.001). MFI, PVD and PVD were decreased distal of the watershed - between the right and left gastro-epiploic artery and vein - and in the fundus, compared to the base of the gastric tube(p = 0.0002). No differences in TVD and DBS were observed; because of vessel-dilation in the fundus-area. This suggests that venous congestion results in comprised inflow of oxygen rich blood and plays a role in the development of ischaemia., Conclusion: We present quantitative perfusion imaging with SDF of the gastric tube. Velocity, MFI, TVD and PPV are accurate parameters to observe perfusion decrease. Also, venous congestion is visible in the fundus, suggesting an important role in the development of ischaemia. These parameters could allow early risk stratification, and, potentially, can accomplish a reduction in anastomotic leakage., Competing Interests: Declaration of competing interest The authors have no conflict of interests., (Copyright © 2020. Published by Elsevier Ltd.)

Patients with Barrett's esophagus are at an increased risk to develop esophageal cancer and, therefore, undergo regular endoscopic surveillance. Early detection of neoplasia enables endoscopic treatment, which improves outcomes. However, early Barrett's neoplasia is easily missed during endoscopic surveillance. This study investigates multidiameter single fiber reflectance spectroscopy (MDSFR) to improve Barrett's surveillance. Based on the concept of field cancerization, it may be possible to identify the presence of a neoplastic lesion from measurements elsewhere in the esophagus or even the oral cavity. In this study, MDSFR measurements are performed on non-dysplastic Barrett's mucosa, squamous mucosa, oral mucosa, and the neoplastic lesion (if present). Based on logistic regression analysis on the scattering parameters measured by MDSFR, a classifier is developed that can predict the presence of neoplasia elsewhere in the Barrett's segment from measurements on the non-dysplastic Barrett's mucosa (sensitivity 91%, specificity 71%, AUC = 0.77). Classifiers obtained from logistic regression analysis for the squamous and oral mucosa do not result in an AUC significantly different from 0.5., (© 2021 Wiley-VCH GmbH.)

Background: The aim of this systematic review was to identify all methods to quantify intraoperative fluorescence angiography (FA) of the gastrointestinal anastomosis, and to find potential thresholds to predict patient outcomes, including anastomotic leakage and necrosis., Methods: This systematic review adhered to the PRISMA guidelines. A PubMed and Embase literature search was performed. Articles were included when FA with indocyanine green was performed to assess gastrointestinal perfusion in human or animals, and the fluorescence signal was analysed using quantitative parameters. A parameter was defined as quantitative when a diagnostic numeral threshold for patient outcomes could potentially be produced., Results: Some 1317 articles were identified, of which 23 were included. Fourteen studies were done in patients and nine in animals. Eight studies applied FA during upper and 15 during lower gastrointestinal surgery. The quantitative parameters were divided into four categories: time to fluorescence (20 studies); contrast-to-background ratio (3); pixel intensity (2); and numeric classification score (2). The first category was subdivided into manually assessed time (7 studies) and software-derived fluorescence-time curves (13). Cut-off values were derived for manually assessed time (speed in gastric conduit wall) and derivatives of the fluorescence-time curves (Fmax, T1/2, TR and slope) to predict patient outcomes., Conclusion: Time to fluorescence seems the most promising category for quantitation of FA. Future research might focus on fluorescence-time curves, as many different parameters can be derived and the fluorescence intensity can be bypassed. However, consensus on study set-up, calibration of fluorescence imaging systems, and validation of software programs is mandatory to allow future data comparison., (© 2020 The Authors. BJS Open published by John Wiley & Sons Ltd on behalf of British Journal of Surgery Society.)

Accurate grading of non-muscle-invasive urothelial cell carcinoma is of major importance; however, high interobserver variability exists. A fully automated detection and grading network based on deep learning is proposed to enhance reproducibility. A total of 328 transurethral resection specimens from 232 patients were included, and a consensus reading by three specialized pathologists was used. The slides were digitized, and the urothelium was annotated by expert observers. The U-Net-based segmentation network was trained to automatically detect urothelium. This detection was used as input for the classification network. The classification network aimed to grade the tumors according to the World Health Organization grading system adopted in 2004. The automated grading was compared with the consensus and individual grading. The segmentation network resulted in an accurate detection of urothelium. The automated grading shows moderate agreement (κ = 0.48 ± 0.14 SEM) with the consensus reading. The agreement among pathologists ranges between fair (κ = 0.35 ± 0.13 SEM and κ = 0.38 ± 0.11 SEM) and moderate (κ = 0.52 ± 0.13 SEM). The automated classification correctly graded 76% of the low-grade cancers and 71% of the high-grade cancers according to the consensus reading. These results indicate that deep learning can be used for the fully automated detection and grading of urothelial cell carcinoma., (Copyright © 2020 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

The increase histopathological evaluation of prostatectomy specimens rises the workload on pathologists. Automated histopathology systems, preferably directly on unstained specimens, would accelerate the pathology workflow. In this study, we investigate the potential of quantitative analysis of optical coherence tomography (OCT) to separate benign from malignant prostate tissue automatically. Twenty fixated prostates were cut, from which 54 slices were scanned by OCT. Quantitative OCT metrics (attenuation coefficient, residue, goodness-of-fit) were compared for different tissue types, annotated on the histology slides. To avoid misclassification, the poor-quality slides, and edges of annotations were excluded. Accurate registration of OCT data with histology was achieved in 31 slices. After removing outliers, 56% of the OCT data was compared with histopathology. The quantitative data could not separate malignant from benign tissue. Logistic regression resulted in malignant detection with a sensitivity of 0.80 and a specificity of 0.34. Quantitative OCT analysis should be improved before clinical use., (© 2020 The Authors. Journal of Biophotonics published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Standard surgical treatments for lower urinary tract symptoms (LUTS) due to benign prostatic obstruction (BPO) use a transurethral approach. Drawbacks are the need for general or spinal anesthesia and complications such as hematuria, strictures, and cloth retention. Therefore, a minimal invasive technique under local anesthesia is desired to improve patient safety. Recently, SoracteLite transperineal laser ablation (TPLA) has been introduced as a novel minimal invasive treatment for BPO. The system used is unique because 4 laser sources are independently available. This 1064-nm diode laser induces coagulative necrosis. Moreover, TPLA is unique because it has a transperineal approach and can be performed under local anesthesia in an outpatient setting., Objective: The primary objective of this study is to determine the safety and feasibility of TPLA treatment for men, who are fit for standard surgery, with LUTS due to BPO. The secondary objectives are to determine functional outcomes by flowmetry and patient-reported outcome measures (PROMs), side effects, and tissue changes observed on imaging., Methods: This study is a prospective, single center, interventional pilot study IDEAL framework stage 2a and will include 20 patients. Eligible patients are men ≥40 years of age, with a prostate volume of 30 to 120 cc, have urodynamically proven bladder outlet obstruction, and have a peak urinary flow of 5 to 15 mL per second. All patients will undergo TPLA of their prostate under local anesthesia by using the EchoLaser system. Depending on the prostate volume, 2 to 4 laser fibers will be placed bilaterally into the prostate. Patient follow-up consists of uroflowmetry, PROMs, and imaging by using contrast-enhanced ultrasound. Total follow-up is 12 months following treatment., Results: Presently, recruitment of patients is ongoing. Publication of first results is expected by early 2020., Conclusions: TPLA offers the potential to be a novel minimal invasive technique for treatment of LUTS due to BPO in men fit for standard desobstruction. This study will evaluate the safety and feasibility of TPLA and report on functional outcomes and tissue changes observed on imaging following TPLA treatment., International Registered Report Identifier (irrid): DERR1-10.2196/15687., (©Rob A A van Kollenburg, Luigi A M J G van Riel, Paul R Bloemen, Jorg R Oddens, Theo M de Reijke, Harrie P Beerlage, Daniel Martijn de Bruin. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 21.01.2020.)

Background: Cystoscopy enables the visualisation of suspicious bladder lesions but lacks the ability to provide real-time histopathologic information. Confocal laser endomicroscopy (CLE) is a probe-based optical technique that can provide real-time microscopic images. This high-resolution optical imaging technique may enable real-time tumour grading during cystoscopy., Objective: To validate and adapt CLE criteria for bladder cancer diagnosis and grading., Design, Setting, and Participants: Prospectively, 73 patients scheduled for transurethral resection of bladder tumour(s) were included. CLE imaging was performed intraoperatively prior to en bloc resection. Histopathology was the reference standard for comparison., Intervention: Cystoscopic CLE imaging., Outcome Measurements and Statistical Analysis: Three independent observers evaluated the CLE images to classify tumours as low- or high-grade urothelial carcinoma (UC), or benign lesions. Interobserver agreement was calculated with Fleiss kappa analysis and diagnostic accuracy with 2×2 tables., Results and Limitations: Histopathology of 66 lesions (53 patients) revealed 25 low-grade UCs, 27 high-grade UCs, and 14 benign lesions. For low-grade UC, most common features were papillary configuration (100%), distinct cell borders (81%), presence of fibrovascular stalks (79%), cohesiveness of cells (77%), organised cell pattern (76%), and monomorphic cells (67%). A concordance between CLE-based classification and histopathology was found in 19 cases (76%). For high-grade UC, pleomorphic cells (77%), indistinct cell borders (77%), papillary configuration (67%), and disorganised cell pattern (60%) were the most common features. A concordance with histopathology was found in 19 cases (70%). In benign lesions, the most prevalent features were disorganised cell pattern (57%) and pleomorphic cells (52%), and a concordance with histopathology was found in four cases (29%)., Conclusions: The CLE criteria enable identification of UC. CLE features correlate to histopathologic features that may enable real-time tumour grading. However, flat lesions remain difficult to classify., Patient Summary: Confocal laser endomicroscopy may enable real-time cancer differentiation during cystoscopy, which is important for prognosis and disease management., (Copyright © 2018. Published by Elsevier B.V.)

Purpose: Urothelial carcinoma of the bladder (UCB) is the most common urinary cancer. White-light cystoscopy (WLC) forms the corner stone for the diagnosis of UCB. However, histopathological assessment is required for adjuvant treatment selection. Probe-based confocal laser endomicroscopy (pCLE) enables visualization of the microarchitecture of bladder lesions during WLC, which allows for real-time tissue differentiation and grading of UCB. To improve the diagnostic process of UCB, computer-aided classification of pCLE videos of in vivo bladder lesions were evaluated in this study. Materials and Methods: We implemented preprocessing methods to optimize contrast and to reduce striping artifacts in each individual pCLE frame. Subsequently, a semiautomatic frame selection was performed. The selected frames were used to train a feature extractor based on pretrained ImageNet networks. A recurrent neural network, in specific long short-term memory (LSTM), was used to predict the grade of bladder lesions. Differentiation of lesions was performed at two levels, namely (i) healthy and benign vs malignant tissue and (ii) low-grade vs high-grade papillary UCB. A total of 53 patients with 72 lesions were included in this study, resulting in ∼140,000 pCLE frames. Results: The semiautomated frame selection reduced the number of frames to ∼66,500 informative frames. The accuracy for differentiation of (i) healthy and benign vs malignant urothelium was 79% and (ii) high-grade and low-grade papillary UCB was 82%. Conclusions: A feature extractor in combination with LSTM results in proper stratification of pCLE videos of in vivo bladder lesions.

Background: Thoracic and head and neck cancer radiation therapy (RT) can cause damage to nearby healthy organs such as the esophagus, causing acute radiation-induced esophageal damage (ARIED). A non-invasive method to detect and monitor ARIED can facilitate optimizing RT to avoid ARIED while improving local tumor control. Current clinical guidelines are limited to scoring the esophageal damage based on the symptoms of patients. Magnetic resonance imaging (MRI) is a non-invasive imaging modality that may potentially visualize radiation-induced organ damage. We investigated the feasibility of using T2-weighted MRI to detect and monitor ARIED using a two-phased study in mice., Methods: The first phase aimed to establish the optimal dose level at which ARIED is inducible and to determine the time points where ARIED is detectable. Twenty four mice received a single dose delivery of 20 and 40 Gy at proximal and distal spots of 10.0 mm (in diameter) on the esophagus. Mice underwent MRI and histopathology analysis with esophageal resection at two, three, and 4 weeks post-irradiation, or earlier in case mice had to be euthanized due to humane endpoints. In the second phase, 32 mice received a 40 Gy single dose and were studied at two, three, and 7 days post-irradiation. We detected ARIED as a change in signal intensity of the MRI images. We measured the width of the hyperintense area around the esophagus in all mice that underwent MRI prior to and after irradiation. We conducted a blind qualitative comparison between MRI findings and histopathology as the gold standard., Results/conclusions: A dose of 40 Gy was needed to induce substantial ARIED. MRI detected ARIED as high signal intensity, visible from 2 days post-irradiation. Quantitative MRI analysis showed that the hyperintense area around the esophagus with severe ARIED was 1.41 mm wider than with no damage and MRI-only mice. The overall sensitivity and specificity were 56 and 43% respectively to detect any form of ARIED. However, in this study MRI correctly detected 100% of severe ARIED cases. Our two-phased preclinical study showed that MRI has the potential to detect ARIED as a change in signal intensity and width of enhancement around the esophagus.

Purpose: Confocal laser endomicroscopy (CLE) is a fluorescence-based fiber-optic imaging technique with the potential for intraoperative grading of upper tract urothelial carcinoma (UTUC). This study aims to (1) investigate the prevalence of the previously proposed CLE criteria for bladder cancer in papillary UTUC, (2) estimate the diagnostic value of CLE for UTUC grading and (3) propose a scoring system for a more quantifiable approach of CLE-based grading of UTUC., Materials and Methods: Ureteroscopic CLE was performed in patients with UTUC. Following CLE imaging, co-localized biopsies were taken for histopathologic comparison. Postoperatively, two blinded raters assessed the CLE images., Results: Fifty-three papillary UTUCs (34 low grade and 19 high grade) were imaged with CLE in 36 patients. All the previously described CLE criteria were identifiable in varying proportions. After excluding 10 non-diagnostic recordings (5 low grade and 5 high grade) due to insufficient image quality, the histopathologic grade was correctly identified with CLE in 26 low-grade UTUCs (90%) and in 12 high-grade UTUCs (86%). The most prevalent CLE criteria with the highest diagnostic potential were cellular organization, morphology and cohesiveness of cells. A scoring system was proposed with these criteria, which yielded similar diagnostic accuracies., Conclusions: Based on the previously proposed criteria, CLE enables accurate grading of papillary UTUC at a non-diagnostic rate of 19%. The most prevalent CLE criteria with the highest diagnostic potential for grading of papillary UTUC are cellular organization, morphology and cohesiveness of cells. The proposed scoring system may simplify the assessment of CLE images for UTUC grading but external validation is required.

Background: Pleural biopsies in patients with suspected malignant pleural mesothelioma (MPM) are often inconclusive resulting in repeat diagnostic procedures. Confocal laser endomicroscopy (CLE) enables real-time imaging on a cellular level. We investigated pleural CLE imaging as a biopsy guidance technique to distinguish malignant from benign pleural disease., Methods: Prospective, multicenter study in patients with (suspected) MPM based on PET-CT imaging who were scheduled for pleural biopsies. Patients received 2.5 mL fluorescein intravenously preceding the procedure. In vivo through-the-needle CLE imaging of the pleura and ex vivo CLE imaging of the biopsies were correlated with histology. CLE characteristics for various pleural entities were identified, and their interpretability was tested by CLE video scoring by multiple blinded raters., Results: CLE imaging was successfully obtained in 19 of 20 diagnostic pleural biopsy procedures (thoracoscopy: n = 4, surgical excision: n = 3, CT scan: n = 3, ultrasound: n = 9, esophageal ultrasound guided: n = 1) in 15 patients. CLE videos (n = 89) and corresponding pleural biopsies (n = 105) were obtained. No study-related adverse events occurred. Tumor deposits of MPM were distinguished from areas with pleural fibrosis based on CLE imaging and recognized by raters (n = 3) (interobserver agreement, 0.56; 95% CI, 0.49-0.64)., Conclusions: CLE imaging was feasible and safe regardless of the biopsy method. Real-time visualization of pleural abnormalities in epithelial and sarcomatoid MPM could be distinguished from pleural fibrosis. Therefore, CLE has potential as a guidance biopsy tool to reduce the current substantial rate of repeat biopsy procedures by identification of areas with malignant cells in vivo (smart needle)., Trial Registry: ClinicalTrials.gov; No.: NCT02689050; URL: www.clinicaltrials.gov., (Copyright © 2019. Published by Elsevier Inc.)

Most common complications of esophagectomy stem from a perfusion deficiency of the gastric conduit at the anastomosis. Fluorescent tracer imaging allows intraoperative visualization of tissue perfusion. Quantitative assessment of fluorescence dynamics has the potential to identify perfusion deficiency. We developed a perfusion model to analyze the relation between fluorescence dynamics and perfusion deficiency. The model divides the gastric conduit into two well-perfused and two anastomosed sites. Hemodynamics and tracer transport were modeled. We analyzed the value of relative time-to-threshold (RTT) as a predictor of the relative remaining flow (RRF). Intensity thresholds for RTT of 20% to 50% of the maximum fluorescence intensity of the well-perfused site were tested. The relation between RTT and RRF at the anastomosed sites was evaluated over large variations of vascular conductance and volume. The ability of RTT to distinguish between sufficient and impaired perfusion was analyzed using c-statistics. We found that RTT was a valuable estimate for low RRF. The threshold of 20% of the maximum fluorescence intensity provided the best prediction of impaired perfusion on the two anastomosed sites (AUC = 0.89 and 0.86). The presented model showed that for low flows, relative time-to-threshold may be used to estimate perfusion deficiency.

Abnormal growth of infants may indicate disease of the children, thus methods to identify growth disorders are wanted in medicine. We previously showed that two-time-points weight growth velocities at age t, calculated by a commercial software product as [Weight(t) - Weight(t - X)]/X, with X = 448 days, were erroneous due to the long separation of 448 days. We were convinced that shorter X-values would solve this accuracy problem. However, our hypothesis is that: "shorter time separations than 448 days cause a decreased accuracy of numerical weight velocity equations in realistic infant weights until an age of about three years". Supporting evidence comes from analyzing how shorter X-values will affect the accuracy of two-time-points weight velocity calculations. We systematically varied X between 1 and 448 days of various P50/0SD-related standard weight curves: (a) P50/0SD with the weights separated by 1 day and X = 1,28,224,448 days; (b) P50/0SD with the weights at variable ages and X = 14-448 days; and (c) case (b) and incorporating weight fluctuations typically occurring in infants. Cases (b) and (c) include details observed in a clinical case. Our results show that the combination of weight fluctuations and varying time intervals between consecutive weights make weight velocity predictions worse for shorter X values in children younger than three years. Because these two causes of failure occur naturally in infants whose weight is regularly measured, other weight velocity equations face the same causes for inaccuracy. In conclusion, our hypothesis suggests that any software that predicts weight velocities should be abandoned in infants < 3 years. Practically, it should require that when (commercial) software weight velocity prediction suggests a medical problem, careful clinical checking should be mandatory, e.g. by linking predicted and exact weight velocities at age t (the latter from the mathematical first derivative at age t of standard weight curves)., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Patient-reported outcome measures (PROMs) are increasingly used to measure patient's perspective of functional well-being, disease burden, treatment effectiveness, and clinical decision making. Electronic versions are increasingly feasible because of smartphone and tablet usage. However, validation of these electronic PROMs (ePROMs) is warranted for justified implementation. The International Index of Erectile Function (IIEF) 5 and 15 are widely used PROMs in urology to measure erectile dysfunction. Measurement reliability and validity testing of the IIEF ePROMs are essential before clinical application., Objective: The aim of this study was to assess reliability and validity of an ePROM version of both IIEF-5 and 15., Methods: This study included 179 patients from our urology outpatient clinic. It also had a randomized crossover design-participants completed either a paper and electronic IIEF-5 or 15 or twice completed an electronic version-with a 5-day delay. Internal consistency was assessed using Cronbach alpha and Spearman-Brown coefficient, test-retest reliability using the intraclass correlation coefficient (ICC), and convergent validity using the Pearson and Spearman correlation coefficient., Results: A total of 122 participants completed the study. Internal consistency was excellent for the electronic IIEF-5 (ICC 0.902) and good to excellent for the domains of the IIEF-15 (ICC 0.962-0.834). Test-retest reliability was excellent for the IIEF-5 (ICC 0.924) and good to excellent for the domains of the IIEF-15 (ICC 0.950-0.778). Convergent validity was excellent for the IIEF-5 and IIEF-15, with a correlation of r=0.923 and r=0.951, respectively., Conclusions: We successfully introduced patient-acceptable ePROM versions of the IIEF-5 and IIEF-15. This study's results demonstrate that the ePROM versions of the IIEF-5 and IIEF-15 can be reliably implemented, as outcomes are reliable and in accordance with findings of the paper version., Trial Registration: ClinicalTrials.gov NCT03222388; https://clinicaltrials.gov/ct2/show/NCT03222388., (©Rob A A van Kollenburg, Daniel Martijn de Bruin, Hessel Wijkstra. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 02.07.2019.)

Histopathologic grading of prostate cancer using Gleason patterns (GPs) is subject to a large inter-observer variability, which may result in suboptimal treatment of patients. With the introduction of digitization and whole-slide images of prostate biopsies, computer-aided grading becomes feasible. Computer-aided grading has the potential to improve histopathological grading and treatment selection for prostate cancer. Automated detection of GPs and determination of the grade groups (GG) using a convolutional neural network. In total, 96 prostate biopsies from 38 patients are annotated on pixel-level. Automated detection of GP 3 and GP ≥ 4 in digitized prostate biopsies is performed by re-training the Inception-v3 convolutional neural network (CNN). The outcome of the CNN is subsequently converted into probability maps of GP ≥ 3 and GP ≥ 4, and the GG of the whole biopsy is obtained according to these probability maps. Differentiation between non-atypical and malignant (GP ≥ 3) areas resulted in an accuracy of 92% with a sensitivity and specificity of 90 and 93%, respectively. The differentiation between GP ≥ 4 and GP ≤ 3 was accurate for 90%, with a sensitivity and specificity of 77 and 94%, respectively. Concordance of our automated GG determination method with a genitourinary pathologist was obtained in 65% (κ = 0.70), indicating substantial agreement. A CNN allows for accurate differentiation between non-atypical and malignant areas as defined by GPs, leading to a substantial agreement with the pathologist in defining the GG.

Introduction: With catheter based optical coherence tomography (OCT), high resolution images of the upper urinary tract can be obtained, thereby facilitating the detection of upper tract urothelial carcinomas (UTUC). We hypothesized that the attenuation coefficient of the OCT signal (μ OCT ) is related to the histopathologic grade of the tumor., Objectives: In this study, we aimed to define the μ OCT cut-off for discriminating high grade and low grade papillary UTUC., Methods: For this post-hoc analysis, data from OCT imaging of papillary UTUC was obtained from patients during ureterorenoscopy. OCT images and raw data were simultaneously analyzed with in-house developed software. The μ OCT determined in papillary UTUCs and corresponding histopathologic grading from either biopsies or radical resection specimens were compared., Results: Thirty-five papillary UTUC from 35 patients were included. μ OCT analysis was feasible in all cases. The median μ OCT was 3.3 mm -1 (IQR 2.7-3.7 mm -1 ) for low-grade UTUC and 4.9 mm -1 (IQR 4.3-6.1 mm -1 ) for high-grade UTUC (P = 0.004). ROC analysis yielded a μ OCT cut-off value of >4.0 mm -1 (AUC = 0.85, P < 0.001) with a sensitivity of 83% and a specificity of 94% for high-grade papillary UTUC., Conclusions: This study proposes a μ OCT cut-off of 4.0 mm -1 for quantitative grading of UTUC with ureterorenoscopic OCT imaging. The promising diagnostic accuracy calculations justify further studies to validate the proposed cut-off value. Implementation of the software for the μ OCT analysis in OCT systems may allow for μ OCT assessment at real time during ureterorenoscopy. Lasers Surg. Med. 51:399-406, 2019. © 2019 Wiley Periodicals, Inc., (© 2019 Wiley Periodicals, Inc.)

Diagnosing lung cancer in the absence of endobronchial abnormalities is challenging. Needle-based confocal laser endomicroscopy (nCLE) enables real-time microscopic imaging of cells. We assessed the feasibility and safety of using nCLE for real-time identification of lung cancer.In patients with suspected or proven lung cancer scheduled for endoscopic ultrasound (EUS), lung tumours and mediastinal lymph nodes were imaged with nCLE before fine-needle aspiration (FNA) was performed. nCLE lung cancer characteristics were identified by comparison with pathology. Multiple blinded raters validated CLE videos of lung tumours and mediastinal nodes twice.EUS-nCLE-FNA was performed in 22 patients with suspected or proven lung cancer in whom 27 lesions (six tumours, 21 mediastinal nodes) were evaluated without complications. Three nCLE lung cancer criteria (dark enlarged pleomorphic cells, dark clumps and directional streaming) were identified. The accuracy of nCLE imaging for detecting malignancy was 90% in tumours and 89% in metastatic lymph nodes. Both inter-observer agreement (mean κ=0.68, 95% CI 0.66-0.70) and intra-observer agreement (mean±sd κ=0.70±0.15) were substantial.Real-time lung cancer detection by endosonography-guided nCLE was feasible and safe. Lung cancer characteristics were accurately recognised., Competing Interests: Conflict of interest: J. Yared has nothing to disclose. Conflict of interest: D.M. de Bruin has nothing to disclose. Conflict of interest: S.L. Meijer has nothing to disclose. Conflict of interest: P. Baas has nothing to disclose. Conflict of interest: P.I. Bonta has nothing to disclose. Conflict of interest: J.T. Annema reports non-financial material support from Mauna Kea Technologies during the conduct of the study. Conflict of interest: L. Wijmans has nothing to disclose., (Copyright ©ERS 2019.)

Background: At present, it is not possible to predict the ablation zone volume following irreversible electroporation (IRE) for prostate cancer (PCa). This study aimed to determine the necessary electrical field threshold to ablate human prostate tissue in vivo with IRE., Methods: In this prospective multicenter trial, patients with localized PCa were treated with IRE 4 weeks before their scheduled radical prostatectomy. In 13 patients, numerical models of the electrical field were generated and compared with the ablation zone volume on whole-mount pathology and T2-weighted magnetic resonance imaging (MRI) sequences. Volume-generating software was used to calculate the ablation zone volumes on histology and MRI. The electric field threshold to ablate prostate tissue was determined for each patient., Results: A total of 13 patients were included for histological and simulation analysis. The median electrical field threshold was 550 V/cm (interquartile range 383-750 V/cm) for the software-generated histology volumes. The median electrical field threshold was 500 V/cm (interquartile range 386-580 V/cm) when the ablation zone volumes were used from the follow-up MRI., Conclusions: The electrical field threshold to ablate human prostate tissue in vivo was determined using whole-mount pathology and MRI. These thresholds may be used to develop treatment planning or monitoring software for IRE prostate ablation; however, further optimization of simulation methods are required to decrease the variance that was observed between patients., Competing Interests: Conflict of interest statement: Scheltema received a PhD grant from the Cure for Cancer charity foundation. De la Rosette and Neal are consultants to AngioDynamics. Arena, Neal and Davalos have pending and issued patents related to the IRE technology.

Background: Histopathological analysis is the cornerstone in bladder cancer (BCa) diagnosis. These analysis suffer from a moderate observer agreement in the staging of bladder cancer. Three-dimensional reconstructions have the potential to support the pathologists in visualizing spatial arrangements of structures, which may improve the interpretation of specimen. The aim of this study is to present three-dimensional (3D) reconstructions of histology images., Methods: En-bloc specimens of transurethral bladder tumour resections were formalin fixed and paraffin embedded. Specimens were cut into sections of 4 μm and stained with Hematoxylin and Eosin (H&E). With a Phillips IntelliSite UltraFast scanner, glass slides were digitized at 20x magnification. The digital images were aligned by performing rigid and affine image alignment. The tumour and the muscularis propria (MP) were manually delineated to create 3D segmentations. In conjunction with a 3D display, the results were visualized with the Vesalius3D interactive visualization application for a 3D workstation., Results: En-bloc resection was performed in 21 BCa patients. Per case, 26-30 sections were included for the reconstruction into a 3D volume. Five cases were excluded due to export problems, size of the dataset or condition of the tissue block. Qualitative evaluation suggested an accurate registration for 13 out of 16 cases. The segmentations allowed full 3D visualization and evaluation of the spatial relationship of the BCa tumour and the MP., Conclusion: Digital scanning of en-bloc resected specimens allows a full-fledged 3D reconstruction and analysis and has a potential role to support pathologists in the staging of BCa.

Purpose: An increasing interest in percutaneous ablation of renal tumors has been caused by the increasing incidence of SRMs, the trend toward minimally invasive nephron-sparing treatments and the rapid development of local ablative technologies. In the era of shared decision making, patient preference for non-invasive treatments also leads to an increasing demand for image-guided ablation. Although some guidelines still reserve ablation for poor surgical candidates, indications may soon expand as evidence for the use of the two most validated local ablative techniques, cryoablation (CA) and radiofrequency ablation (RFA), is accumulating. Due to the collaboration between experts in the field in biomedical engineering, urologists, interventional radiologists and radiation oncologists, the improvements in ablation technologies have been evolving rapidly in the last decades, resulting in some new emerging types of ablations., Methods: A literature search was conducted to identify original research articles investigating the clinical outcomes of new emerging technologies, percutaneous MWA, percutaneous IRE and SABR, in patients with primary cT1 localized renal cell cancer., Results: Due to the collaboration between experts in the field in biomedical engineering, urologists, interventional radiologists and radiation oncologists, the improvements in ablation technologies have been evolving rapidly in the last decades. New emerging technologies such as microwave ablation (MWA), irreversible electroporation (IRE) and stereotactic ablative radiotherapy (SABR) seem to be getting ready for prime time., Conclusion: This topical paper describes the new emerging technologies for cT1 localized renal cell cancer and investigates how they compare to CA and RFA.

Background: Irreversible electroporation (IRE) has the potential to overcome limitations of thermal ablation, enabling small renal mass (SRM) ablation near vital structures., Purpose: To assess feasibility and safety of percutaneous IRE for the treatment of SRMs., Materials and Methods: This prospective study is a phase 2 trial (NCT02828709) of IRE for patients with SRMs. Primary endpoints are feasibility and safety. Device- and procedural-adverse events were assessed by Clavien-Dindo and Common Terminology Criteria for Adverse Events version 4.0 grading systems. Technical feasibility was assessed by recording the technical success of the procedures. Technical success was evaluated by performing a CT immediately after ablation where complete tumor coverage and nonenhancement were evaluated. Tumor charcateristics and patient characteristics, procedural and anesthesia details, postprocedural events, and perioperative complications were recorded., Results: Ten SRMs were included with a mean tumor size of 2.2 cm (range 1.1-3.9 cm) were treated with IRE. Renal mass biopsies revealed 7 clear cell and 1 papillary renal cell carcinoma. Two renal mass biopsies were nondiagnostic. The median follow-up was 6 months (range 3-12 months). Technical success was achieved in 9 out of 10 cases. One patient had a grade 3 Clavien-Dindo complication (1/10, 95% Confidence interval (CI) 0.0179-0.4041). Mean anesthesia time was 3.7 hours (range 3-5 hours), mean procedural time was 2.1 hours (range 1 hour 45 minutes-2 hours 30 minutes) and mean ablation time was 50 minutes (range 20 minutes-1 hour 45 minutes). The creatinine preoperative and postoperative (1 week, 3 months, 6 months, and 12 months) did not significantly differ. In total, 8 out of 10 cases did not experience postoperative pain., Conclusion: IRE in SRMs is safe and feasible. Renal function is not affected by IRE and postoperative pain is rare. Anesthesia time and procedural time are a potential concern., (Copyright © 2018 Elsevier Inc. All rights reserved.)