In this prospective single-center feasibility study, we demonstrate that the use of three-dimensional (3D)-printed prostate models support nerve-sparing radical prostatectomy (RP) and intraoperative frozen sectioning (IFS) in ten men suffering from intermediate- and high-risk prostate cancer (PC), of whom seven harbored pT3 disease. Patient-specific 3D resin models were printed based on preoperative multiparametric magnetic resonance imaging (mpMRI) to provide an exact 3D impression of significant tumor lesions. RP and IFS were planned in a patient-tailored fashion. The 36-region Prostate Imaging Reporting and Data System (PI-RADS) v2.0 scheme was used to compare the MRI/3D print with whole-mount histopathology. In all cases, localization of the index lesion was correctly displayed by MRI and the 3D model. Localization of significant PC lesions correlated significantly (Pearson`s correlation coefficient of 0.88; p <  0.001). In addition, a significant correlation of the width, length, and volume of the tumor and prostate gland, derived from the printed model and histopathology, was found, using Pearson's correlation analyses and Bland-Altman plots. In conclusion, 3D-printed prostate models correlate well with final pathology and can be used to tailor RP. PATIENT SUMMARY: The use of three-dimensional (3D)-printed prostate models based on preoperative magnetic resonance imaging (MRI) may improve prostatectomy outcome. This study confirmed the accuracy of 3D-printed prostates compared with pathology from radical prostatectomy specimens. Thus, MRI-derived 3D-printed prostate models can assist in prostate cancer surgery

Bonekamp, D

Darr, C

Finis, F

Forsting, M

Giganti, F

Hadaschik, BA

Haubold, J

Kesch, C

Krafft, U

Radtke, JP

Reis, H

Tschirdewahn, S

Wetter, A

Wiesenfarth, M

English

UCL Discovery

 1 Three-dimensional MRI-based Printed Models of Prostate Anatomy and Targeted 1 Biopsy-proven Index Tumor to Facilitate Patient-tailored Radical Prostatectomy – a 2 feasibility study 3  4 Christopher Darr1+; Friederike Finis1+; Manuel Wiesenfarth2; Francesco Giganti3,4; 5 Stephan Tschirdewahn1; Ulrich Krafft1; Claudia Kesch1; David Bonekamp5; Michael 6 Forsting6; Axel Wetter6; Henning Reis7; Boris A. Hadaschik1; Johannes Haubold5*; Jan 7 Philipp Radtke1,5* 8 1Department of Urology, University Hospital Essen, Essen, Germany and German Cancer Consortium 9 (DKTK)-University Hospital Essen, Essen, Germany 10 2Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany 11 3 Department of Radiology, University College London Hospitals NHS Foundation Trust, London, UK 12 4 Division of Surgery and Interventional Science, University College London, London, UK 13 5Department of Radiology, German Cancer Research Center (DKFZ), Heidelberg, Germany 14 6Institute of Diagnostic and Interventional Radiology, University Hospital Essen, Essen, Germany and 15 German Cancer Consortium (DKTK)-University Hospital Essen, Essen, Germany 16 7Institute of Pathology, University Hospital Essen, Essen, Germany and German Cancer Consortium 17 (DKTK)-University Hospital Essen, Essen, Germany 18 +shared first authorship 19 *contributed equally as senior authors 20  21  22  23  24  25  26 MeSH keywords: 27 Prostate cancer, MRI, 3D model, MRI-derived printed prostate model, radical 28 prostatectomy, patient-tailored prostatectomy 29  2 Corresponding author: 30 PD Dr. med. Jan Philipp Radtke 31 Department of Urology 32 University Hospital Essen 33 Hufelandstr. 55 34 45147 Essen, Germany 35 E-mail: j.radtke@dkfz-heidelberg.de 36 Phone.: 0049 201-723/83069 37 Fax.: 0049 201-723/3151 38  39 Abbreviations: 40  41 DCE: Dynamic contrast-enhanced Imaging  42 DRE: Digital-rectal examination 43 EPE: Extraprostatic extension 44 ESUR: European Society of Urogenital Radiology 45 GGG: Gleason Grade group 46 IFS: Intraoperative frozen sectioning 47 mpMRI: multiparametric Magnetic Resonance Imaging 48 MRI: Magnetic Resonance Imaging 49 NSM: Negative surgical margins 50 PC: Prostate cancer 51 PI-RADS: Prostate Imaging - Reporting and Data System 52 PSA: Prostate specific antigen 53 PSM: Positive surgical margins 54 PV: Prostate volume 55 RP: Radical prostatectomy 56 SB: Systematic biopsy 57 sPC: Significant prostate cancer 58 STARD: Standards of Reporting of Diagnostic Accuracy 59 TRUS: Transrectal ultrasound 60  3 TV: Tumor volume  61  4 Abstract  62 In this prospective single center feasibility study, we demonstrate that the use of 3D-63 printed prostate-models support nerve-sparing radical prostatectomy (RP) and 64 intraoperative frozen-sectioning (IFS) in ten men suffering from intermediate- and high-65 risk prostate cancer (PC), of whom seven harbored pT3-disease. Patient-specific 3D 66 resin models were printed based on preoperative multiparametric MRI (mpMRI) to 67 provide an exact 3D impression of significant tumor lesions. RP and IFS were planned 68 in a patient-tailored fashion. 69 The 36-region PI-RADSv2.0 scheme was used to compare the MRI/3D-print with 70 whole-mount histopathology. In all cases, the localization of the index lesion was 71 correctly displayed by MRI and the 3D-model. Localization of significant PC lesions 72 correlated significantly (Pearson`s correlation coefficient of 0.88 (p<0.001). In addition, 73 a significant correlation of the width, length and volume of the tumor and prostate gland 74 derived from the printed model and histopathology was found, using Pearson`s 75 correlation analyses and Bland-Altman plots.  76 In conclusion, 3D-printed prostate-models correlate well with final pathology and can 77 be used to tailor RP.  78  79 Patient summary  80 The use of 3D printed prostate-models based on preoperative MRI may improve 81 prostatectomy outcome. This study confirmed accuracy of 3D printed prostates 82 compared to pathology from RP specimens. Thus, MRI-derived 3D printed prostate-83 models can assist prostate cancer surgery. 84   85  5 Main report: 86 Multiparametric MRI (mpMRI) and transrectal ultrasound (TRUS)-fusion targeted 87 biopsy detect significantly more significant prostate cancers (sPC) than standard 88 TRUS-biopsy [1,2]. In addition, high spatial resolution of MRI facilitates precise 89 knowledge of the localization of sPC before nerve-sparing radical prostatectomy (RP), 90 to gain maximum security while reducing burden of erectile dysfunction after RP [3]. 91 Another possible tool is intraoperative frozen sectioning (IFS).Schlomm et al. 92 described that IFS has the potential to significantly increase nerve-sparing and to 93 reduce positive margins (PSM) [4]. In addition, Petralia et al. combined both 94 approaches and could demonstrate that preoperative MRI can guide IFS to 95 significantly reduce PSM [5]. This is of specific interest, as unfavourable PSM (>3 mm 96 and/or multifocal) confer a higher oncologic risk of developing metastasis [6]. Another 97 promising step might be utilization of MRI-derived 3D printed prostate models [3].  98 In our feasibility study we used customized, patient-specific 3D printed prostates. The 99 main purpose was to evaluate the correlation of the index tumor lesion and of all sPC 100 lesions between the 3D-prints and RP specimens. Differences in index lesion 101 dimensions (length, width, volume) and whole gland between MRI-based print models 102 and RP specimens were analysed, as underestimation of the lesion volume by MRI of 103 up to 30% has been demonstrated [7]. Lastly, we investigated the role of MRI/3D-104 model-directed IFS to decrease the rate of PSM after RP [5].  105  106 In this feasibility study (review board-approval, 19-TEMP579281-BO, 03/2019-107 06/2019), ten consecutive patients with clinically localized intermediate- and high-risk 108 PC underwent a 3-Tesla mpMRI using a Prostate Imaging-Reporting and Data System 109 (PI-RADS)v2.0-conform protocol and subsequent MRI/TRUS-fusion biopsy. [8].  110  6 The 3D printed prostates were outlined based on the mpMRI, manually marking the 111 boundaries of the prostate gland and seminal vesicles using the open source software 112 3D-Slicer (version: 4.10.2). Index lesions were defined as the lesion with the highest 113 International Society of Urological Pathology (ISUP) Gleason grading groups (GGG) 114 or the largest volume within a prostate. sPC was defined as ISUP ≥2. Biopsy-proven 115 index lesions on mpMRI and all sPC lesions were contoured manually marked under 116 supervision of a dedicated uro-radiologist with experience > 1000 image reports in 117 prostate MRI (AW). A 3D printer (Anycubic Photon, Shenzhen, China) printed the 118 specimens out of resin whereas the index lesion was left blank or filled with a different 119 color. 120 RP was performed by one experienced surgeon (BAH, >500 cases) using a retropubic 121 or robot-assisted technique. Based on National Comprehensive Cancer Network risk-122 groups (intermediate- and high-risk in the present cohort) and with aid of the 3D-printed 123 models, a nerve-sparing approach and IFS were planned and performed. Specifically, 124 IFS was performed for each index lesion and other sPC lesions. Pathological work-up 125 was performed according to current clinical standards by a dedicated pathologist with 126 12 years of experience in genitourinary-pathology (HR). For the analysis, quarters 127 were digitally reconstructed to whole-mounts. Tumor dimensions were measured using 128 MITK software (Medical Imaging Interaction Toolkit, v2018.04.02). The 3D-printed 129 prostate was sliced at the index lesion with a commercial hacksaw. The correct 130 orientation was achieved by interdisciplinary workup between clinicians and 131 pathologists on an individual case-basis and according to anatomical landmarks of the 132 prostate. Histopathologic slides with the greatest cross-section of the specific lesion 133 were used for agreement analysis of location on T2-weighted images. The slides as 134 well as the T2-weighted images had a 90° flip-angle which was transferred accordingly 135 to the anatomical preparation. Agreement and true positivity of the MRI lesion were 136  7 considered if there was exact agreement or a discrepancy with the pathologic lesion in 137 up to one region in any direction [7]; correlation was assessed using Pearson`s 138 correlation coefficient. 139 Correlation of the dimensions of the index lesion and the prostate volume on 3D-140 printed model and RP specimen was analysed by Pearson`s correlation coefficient and 141 graphically by scatter plots and Bland-Altman plots (Figure 1). Statistical analyses were 142 performed using R version 3.5.0 (R Foundation for Statistical Computing, Vienna, 143 Austria) and GraphPad Prism (GraphPad Software, San Diego, USA). 144  145 Patients’ demographic and histopathological data are given in Table 1. In all 10 cases, 146 the index lesion of the 3D-print was correctly located considering the 36-region PI-147 RADS scheme compared to histopathology. 13/14 sPC lesions (93%) were also 148 correctly located, resulting in a significant correlation with a Pearson’s coefficient of 149 0.88 (p<0.001). Histopathology proved negative surgical margins (NSM) in 7 patients. 150 PSM was found in three men suffering from locally advanced pT3 disease. These 151 matched with the suspected extraprostatic extension (EPE) of MRI and the 3D-printed 152 models. Out of the 3 cases with positive IFS, in two repeat resection demonstrated 153 cancer free tissue out of which final pathology demonstrated PSM in one. In the last 154 case a further resection was not possible due to infiltration of the urethral sphincter. 155  156 Measurements of tumor and prostate dimensions showed a significant correlation 157 between the 3D-print and histopathology (length: r2=0.59, p=0.01; width: r2=0.64, 158 p=0.005; tumor volume (TV): r2=0.52, p=0.045; prostate volume: r2=0.70, p=0.002). 159 Pathology measurements were multiplied by a correction factor of 1.15 to compensate 160 for tissue shrinkage due to formalin-fixation. Bland-Altman plots emphasize differences 161 on TV between printed models and histopathology. Particularly, large tumors were 162  8 underestimated on MRI/3D-print as compared to pathology by up to 30%. Of note, the 163 deviation increased with increasing TV, whereas smaller tumor dimensions had an 164 accurate correlation. These results are in the line with findings by Baco et al., 165 suggesting that mpMRI is able to predict the presence of extra-prostatic disease, rather 166 than representing the EPE by means of volume [9]. Contrary the prostate volume is 167 overrated in the MRI compared to histopathology (Figure 1). 168  169 Discrepancies of these volume measurements might be caused through different 170 measurement types. Whereas the TV was measured using MITK software, the 171 prostate volume was measured manually using the GE RIS/PACS software (Version 172 3.0, Chicago, Illinois, USA). Recent literature suggests that computer-assisted TV 173 calculation might attenuate underestimation [10]. Comparison between the 174 histopathologic slide and the sliced 3D-model might be influenced through marginally 175 different heights of the MRI slide and the corresponding histopathologic slide.   176 Nonetheless, the visual and haptic aid of a 3D-model in an intraoperative setting can 177 lead to more precise IFS. Pre- and intraoperative benefits of a 3D-model approach 178 have been described, namely planning of a patient-tailored RP and training of 179 surgeons undergoing the learning-curve [11,12]. The significant correlation of both, 180 localization and lesion volume between histopathology and 3D-print in our study is 181 crucial for the assumption that applying MRI-derived 3D-models might correctly guide 182 IFS and increase the rate of NSM [6]. 183 Chen et al. have recently shown that the use of a fused-deposition-modelling-printer is 184 possible, resulting in much lower cost. Certainly, cost-efficient models which are 185 printed in a short turnaround are favourable for the surgeon [13].  186 Some limitations of our manuscript merit discussion. Firstly, the number of patients in 187 this feasibility study is limited. This small number of patients seems justifiable, due to 188  9 oncologic safety purposes. A strength of the study is that for the first time statistical 189 analyses using correlation coefficients are presented to demonstrate not only 190 feasibility, but also precision of preoperative imaging and 3D-models as compared to 191 RP specimen. Secondly, we investigated only the PSM-rate, and not the more 192 sophisticated surrogate of biochemical recurrence-free survival. However, for a direct 193 analysis of an accurate application of MRI-guided IFS, the SM-status may be sufficient. 194 We did not account for a comparison of a preoperative MRI alone versus MRI-derived 195 3D-models. In view of the recently updated European Association of Urology (EAU) 196 guidelines, knowledge of the preoperative MRI results alone might be sufficient to 197 facilitate patient-tailored RP as recently demonstrated [14,15]. For accurate prediction 198 of EPE, standardized reading using ESUR classification is crucial, as accuracy is 199 decreased by unstandardized MR-reading [14,16]. Lastly, the single-surgeon 200 experience in this feasibility study limits generalizability of the results for cohorts 201 consisting of multiple surgeons with different expertise.  202  10 Conflict of interest: 203 All authors of this manuscript indicate no conflicts of interest regarding the present 204 work.  205  11 References 206 [1] van der Leest M, Cornel E, Israël B, Hendriks R, Padhani AR, Hoogenboom M, 207 et al. Head-to-head Comparison of Transrectal Ultrasound-guided Prostate 208 Biopsy Versus Multiparametric Prostate Resonance Imaging with Subsequent 209 Magnetic Resonance-guided Biopsy in Biopsy-naïve Men with Elevated 210 Prostate-specific Antigen: A Large Prospective Mu. Eur Urol 2019;75:570–8. 211 doi:10.1016/j.eururo.2018.11.023. 212 [2] Kasivisvanathan V, Rannikko AS, Borghi M, Panebianco V, Mynderse LA, 213 Vaarala MH, et al. MRI-Targeted or Standard Biopsy for Prostate-Cancer 214 Diagnosis. N Engl J Med 2018;318:1767–77. doi:10.1056/NEJMoa1801993. 215 [3] Shin T, Ukimura O, Gill IS. Three-dimensional Printed Model of Prostate 216 Anatomy and Targeted Biopsy-proven Index Tumor to Facilitate Nerve-sparing 217 Prostatectomy. 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Combined Clinical Parameters and Multiparametric 269 Magnetic Resonance Imaging for the Prediction of Extraprostatic Disease—A 270 Risk Model for Patient-tailored Risk Stratification When Planning Radical 271 Prostatectomy. Eur Urol Focus 2018:4–11. doi:10.1016/j.euf.2018.11.004. 272   273  14 Table legends:  274 Table 1: 275 Patient demographics and histopathologic characteristics. 276  277 Supplementary Material legends: 278 Supplementary Material 1: 279 Standards of Reporting of Diagnostic Accuracy (STARD) checklist 280  281 Figure legends: 282 Figure 1: 283 Figure 1A. Evaluation of different dimension modalities of the tumor and prostate 284 comparing 3D-print/MRI with histopathology. For each analysis Scatter plots (left) and 285 Bland-Altman plots have been performed. The red line shows the ideal line. The black 286 line displays the balancing line. 1: Length of the tumor (r2 = 0.59; p = 0.01), 2: Width of 287 the tumor (r2 = 0.64; p = 0.005), 3: Volume of the tumor (r2 = 0.52; p = 0.045), 4: Volume 288 of the prostate (r2 = 0.70; p = 0.002).  289 Figure 1B. All four images are taken from the same prostate. This prostate is printed 290 out of liquid photopolymer cured through UV light, the tumor is presented in red 291 photopolymer and more cured than the rest of the prostate. 1: mpMRI of the prostate 292 with index lesion (caudal view), 2: 3D printed prostate with index lesion (photo is taken 293 from caudal), 3: histopathology of the prostate with index lesion (caudal view) 4: 3D 294 printed prostate with index lesion (cranio-dorsal view). 295  296 

Three-dimensional Magnetic Resonance Imaging–based Printed Models of Prostate Anatomy and Targeted Biopsy-proven Index Tumor to Facilitate Patient-tailored Radical Prostatectomy—A Feasibility Study

https://discovery.ucl.ac.uk/id/eprint/10110883/3/Giganti_22072020_Manuscript_Revision_CD_FF_JPR_CD_JPR_BH_FF.pdf

Three-dimensional Magnetic Resonance Imaging–based Printed Models of Prostate Anatomy and Targeted Biopsy-proven Index Tumor to Facilitate Patient-tailored Radical Prostatectomy—A Feasibility Study

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