Devices and systems targeted towards augmented robotic radical prostatectomy

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Original article

Devices and systems targeted towards augmented robotic radical prostatectomy S. Voros a,∗ , A. Moreau-Gaudry b , B. Tamadazte a , G. Custillon b , R. Heus a , M.-P. Montmasson a , F. Giroud a , O. Gaiffe c , C. Pieralli c , G. Fiard d , J.-A. Long d , J.-L. Descotes d , C. Vidal e , A. Nguyen-Dinh f , P. Cinquin g a UJF-Grenoble 1, CNRS, INSERM, TIMC-IMAG UMR 5525, 38041 Grenoble, France Centre d’Investigation Clinique, Innovation Technologique, INSERM, CHU de Grenoble, UJF-Grenoble 1, CIT803, 38041 Grenoble, France c FEMTO-ST, UMR CNRS 6174, Université de Franche-Comté, 25030 Besan¸ con cedex, France d Urology Department, Grenoble University Hospital, Grenoble, France e Endocontrol-Medical S.A., 5, avenue du Grand-Sablon, La Tronche, 38700 Grenoble, France f VERMON S.A., 180, rue du Général-Renault, 37038 Tours cedex, France g UJF-Grenoble 1, CNRS, TIMC-IMAG UMR 5525, Centre d’Investigation Clinique, Innovation Technologique, INSERM, CHU de Grenoble, CIT803, 38041 Grenoble, France b

Received 11 January 2013; received in revised form 11 January 2013; accepted 15 January 2013 Available online 15 March 2013

Abstract Prostate cancer is the most frequent male cancer and the second cause of male cancer mortality in developed countries. Therefore, it represents a major public health issue. Health problem and the development of new therapeutic strategies to address this issue is essential. During a prostatectomy, the surgeon looks for a compromise between an exhaustive removal of pathologic tissue (to achieve the best carcinogenic prognosis) and the functional consequences linked to a wide excision (i.e.: avoid as much as possible urinary incontinence and sexual dysfunction). In this context, the ANR TecSan DEPORRA project regroups French research laboratories (TIMC-IMAG, FEMTO-ST), companies (Endocontrol-Medical, VERMON) and hospital departments (CIC-IT, Urology & pathology Department of the Grenoble University Hospital) to bring innovative tools for radical prostatectomy. These tools will provide to the surgeon new information from several imaging modalities (video, fluorescence and US imaging), and combine them in an augmented environment. We believe that this augmented environment will ultimately help the surgeon to perform his surgical gesture “optimally” and will improve the patient’s carcinogenic and functional prognosis. © 2013 Published by Elsevier Masson SAS.

1. Introduction Prostate cancer is the most frequent male cancer and the second cause of male cancer mortality in developed countries, with 643,000 cases and 20% new cases in 2008 according to the 2008 World Cancer Report of the International Agency for Research Cancer. Its incidence has never stopped increasing in the past 25 years because of the population ageing and individual screening. In 75% of the cases, it is diagnosed at a localized stage within the prostate (T1 or T2). At this localized stage, different treatments are available, among which surgery: radical prostatectomy (or surgical ablation of the prostate) is often considered as the

∗

Corresponding author. E-mail address: [email protected] (S. Voros).

1959-0318/$ – see front matter © 2013 Published by Elsevier Masson SAS. http://dx.doi.org/10.1016/j.irbm.2013.01.014

“gold standard” to treat prostate cancer, in precise indications. Several approaches are in competition: open surgery, laparoscopic surgery or robotic surgery. The laparoscopic approach will probably replace open surgery in the future years notably because it reduces perioperative morbidity. Robotic surgery (the reference robot for this approach being Intuitive Surgical’s da Vinci® robot) offers the surgeons a comfort close to open surgery in a mini-invasive environment. This comfort allows for the reduction of the “learning curve”. However, concerning the benefits for the patient, according to the European Association of Urology (EAU) guidelines [1], “it is not clear which technique is superior in terms of oncological and functional results and cost-effectiveness. Prospective trials are urgently needed”, an argument also shared in two recent Health Technology Assessments on robot assisted surgery (Belgian HTA, 2009; Irish HTA, 2012).

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In the current surgical practice, the surgeon must determine the best compromise between a complete removal of the prostate gland and morbidity. The ideal removal consists in removing completely the prostate within its capsule: a non complete removal may lead to positive surgical margins which are associated to a higher risk of biochemical recurrence [2] (15–20% of the patients). Lesions of the urethral sphincter, situated under the prostate, can lead to incontinence (7% of the patients). Lesions of the neurovascular bundles (immediately in contact with the posterior side of the prostate) may lead to erectile problems of varying intensity. The surgeon can try to spare more or less these organs depending on the preoperative staging, completed by magnetic resonance imaging (MRI). The quality of the prostate removal (absence of positive surgical margins) is determined postoperatively thanks to a histopathology exam at the anatomopathology laboratory. Thus, the surgeon cannot adapt his surgical strategy peroperatively.

2. Objectives In this controversial context regarding robotically assisted prostatectomy, we propose a new robotic navigation concept guided by some of the principal complications of a radical prostatectomy (cancer relapse, incontinence and impotence), based on peroperative multimodal imaging. Surgical navigation systems allow for the combination of several imaging modalities in a common environment, thus providing more useful information to the surgeon during a surgery than a single imaging modality. In most of the existing systems, information from preoperative imaging modalities is combined with the peroperative imaging modality. However, in the case of laparoscopic surgery (soft tissue surgery), the registration of preoperative images with the laparoscopic images is very challenging because the organs can move and deform. To our knowledge, there are only a few navigation systems for laparoscopic navigation [3], none of which are used clinically. Our proposed navigation concept is based on three coupled components that will ultimately “augment” the laparoscopic images and allow the surgeon to see beyond the visible and adapt his surgical strategy peroperatively: • an augmented laparoscope allowing the surgeon to navigate more harmoniously inside the abdominal cavity as he would do in open surgery, and potentially to provide three dimensional information; • peroperative visualization technologies allowing the surgeon to visualize the important anatomical structures for radical prostatectomy: ◦ visualization of the prostate and surrounding organs thanks to an innovative transurethral ultrasound probe, ◦ identification and visualization of the tumor and prostatic cells thanks to bimodal fluorescence probe; • integration of the multimodal information to navigation systems thanks to the registration of the different imaging modalities, when required.

3. Material & methods 3.1. Augmented laparoscopy thanks to an innovative video device Laparoscopic surgery in general can be challenging for a surgeon for several reasons, among which the limited field of view of the endoscope (“keyhole” surgery). In consequence, whether it is displaced by a human assistant or a robotic endoscope holder, the endoscope is mobilized a lot, since it is used to see precisely the operating field, but also to monitor the instruments introduction and displacement inside the abdominal cavity. Movements of the endoscope increase the risk of staining of the lens, which leads to a removal of the endoscope from the patient to clean the lens, increasing the surgery duration and discomfort. To provide a solution to this difficulty, we have developed an innovative vision system that can be used in combination with a traditional endoscope, thanks to an encapsulation in a traditional trocar. Our system is composed of two miniature cameras that are positioned like a pair of glasses around the endoscope (Fig. 1), and provide a panoramic view of the abdominal cavity. These cameras are similar to those present on cell phones and cost only a few US$ in large scale diffusion. The system has been designed for an easy insertion, deployment and removal of the cameras, and has been patented [4]. Since it is positioned around the endoscope, it provides roughly the same view direction as the endoscope, and a registration between the laparoscopic image and the vision system images is unnecessary. The cameras of the innovative vision system are mounted in stereoscopic conditions, which could allow for a local 3D reconstruction of the scene. Our preclinical evaluation of the potential expected medical service of this device is presented in section 4. 3.2. Augmented laparoscopy thanks to an innovative ultrasound system Previous work [5] has already shown that the use of transrectal ultrasound during laparoscopic radical prostatectomies could assist the surgeons in the visualization of specific prostate contour anatomy and of the neurovascular bundles, and in the bladder neck dissection. According to the authors, the use of transrectal ultrasound in laparoscopic prostatectomy compensated for the lack of tactile feedback compared to open surgery, achieved significant decrease in the incidence of positive surgical margins and achieved quicker and superior potency recovery. In this work, the ultrasound images were not fused with the laparoscopic images and the surgeon had to perform a challenging mental registration of the two imaging modalities. Long et al. [6] also showed the potential of a guidance of a transrectal ultrasound probe with a robotic endoscope holder (Endocontrol’s ViKY system). Holmes et al. [7] have developed a 2D transurethral ultrasound probe for brachytherapy that is manually rotated around its axis to provide 3D imaging. They affirm that the endourethral approach permits a better resolution than the transrectal approach for the visualization of the prostate. The transurethral approach also allows avoiding some of the

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Fig. 1. The proposed global vision system. a): the mini-cameras used for the vision system; b): CAD drawing of the augmented endoscope concept: the mini-cameras are inserted into a modified trocar. When the endoscope is inserted, the vision system is deployed like glasses around the endoscope; c) and d) rapid prototyping realization.

intrinsic limitations of transrectal ultrasound imaging (a layer of air forms between the prostate and the rectum during the prostate dissection, making the ultrasound visualization of the prostate impossible after this surgical phase). In light of these previous works, we have developed two transurethral ultrasound probe prototypes (one for 2D imaging and a motorized version where the probe rotates around its axis to provide 3D images) (Fig. 2). The 2D probe is composed of 64 piezoelectric elements, with a frequency of 10 MHz, and a 3 mm diameter semi-rigid catheter for an easy introduction. The 3D probe has the same central frequency, but it is composed of 128 piezoelements and has a 6 mm diameter catheter. They are connected to an Ultrasonix ultrasound machine allowing us to control all the piezoelectric elements. In parallel, we have also developed an endoscopic/ultrasound fusion demonstrator. The registration is based on the POSIT algorithm [8] and is based on the manual localization in both imaging modalities of artificial landmarks. In the frame of this

Fig. 2. The innovative intraurethral ultrasound probe. Top: the 3D transurethral probe, able to rotate around its axis. Bottom: the 2D transurethral probe.

project, two complementary approaches have been investigated: passive landmarks (laparoscopic needles planted in the prostate), and innovative active ultrasound landmarks, that emit an ultrasound signal that can be detected by the transurethral probe, allowing for their precise localization in the ultrasound referential [9] (Fig. 3). Our preliminary results for the registration of ultrasound and laparoscopic images using passive landmarks and for the precise 3D localization of the ultrasound “active” markers are described in section 4. 3.3. Augmented laparoscopy thanks to fluorescence imaging During a radical prostatectomy, the ability to visualize biological characteristics of tissue, (prostatic vs. non-prostatic on the one hand, normal vs. malignant on the other hand), could help the surgeon to respectively determine precisely the location of the prostate capsule and assess the extent of the cancer, and thus allow him or her to adapt his surgical strategy peroperatively. Based on these observations, we have developed a bimodal fluorescence fibered probe for the peroperative characterization of tissue for radical prostatectomy: • the normal/malignant characterization of the tissues is based on the detection of the autofluorescence of the Protoporphyrin IX (PpIX) protein which accumulates in malignant cells. Indeed, the elimination cycle of Protorphyrin is perturbed in case of malignant cells. It causes thus an increase of Protoporphyrin concentration. A first prototype (already

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this spectrum, an intensity image can be created (Fig. 4, right). The analysis of prostate tissue samples gathered in the frame of a biomedical protocol (section 4) will allow us to determine the optimal parameters for the acquisition of the fluorescence spectrum and build discrimination criteria from the measurements between malignant/healthy tissue and prostatic/non-prostatic tissue; • the prostatic/non-prostatic characterization of the tissues is based on the detection of the prostate-specific membrane antigen (PSMA), which is specific of the prostatic membrane. This detection is made possible by the immunofluorescence tagging of the PSMA using a specific anti-PSMA antibody labelled with a fluorescent tracer. When excited by light at a characteristic absorption wavelength, the fluorescent tracer emits light at a characteristic emission wavelength. Two fluorescent tracers are investigated in the DEPORRA project, Fluorescein IsoThioCyanate (FITC) and Cyanine 5. Both FITC and Cyanine 5 have a characteristic emission wavelength different from the autofluorescence wavelength of the Protoporpphyrin IX protein, allowing for the characterization of the tissue type (prostatic vs. non-prostatic) and the tissue status (healthy vs. malignant) with the same testbench (Fig. 5).

Fig. 3. The proposed markers for the registration of ultrasound and endoscopic images. Top: “active” landmark (laparoscopic ultrasound emitter). Bottom: “passive” landmark (laparoscopic needle) used for the registration of ultrasound and laparoscopic images.

available, see Fig. 4, left) comes in the form of a testbench equipped with a laser source emitting at 405 nm (excitation wavelength for the PpIX protein) and with optical fibers and a spectrometer allowing the collection of a fluorescence spectrum of 3648 points in the range 345–1040 mm (the testbench can image a 25 × 25 mm2 area with a spatial resolution of 100 ␮m, and a penetration depth of roughly 300 ␮m). Using

The testbench presented on Fig. 4 has also been equipped with two laser sources emitting at 488 nm and 642 nm, excitation wavelengths respectively for FITC and Cyanine 5 for recognizing prostate tissue from those environing. A bimodal laparoscopic-compliant fluorescence probe based on the miniaturization of the fluorescence testbench will be available in 2013 (Fig. 6, top). Preliminary results based on the analysis of histopathologic slices will be presented in section 4. In order to overlay the probe’s fluorescence measurement on the laparoscopic images, we plan on detecting automatically the position of the tip of the laparoscopic probe using a real-time image analysis approach that we have developed [10] (Fig. 6, bottom). 3.4. Preclinical and clinical evaluation Preliminary evaluation of the devices and the software developed in the frame of this project has already been performed on

Fig. 4. Experimental fluorescence design and results. Left: experimental optical device. Right: typical intensity image obtained.

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Fig. 5. Excitation and emission spectra of Protoporphyrin IX, Fluorescein IsoThioCyanate and Cyanine 5 (Cy5) fluorochromes. A. Overlay of the excitation (blue dashed line) and emission (orange solid line) spectra of Protoporphyrin IX with excitation (green dashed line) and emission (emission spectrum) of Fluorescein IsoThioCyanate. B. Overlay of the excitation (blue dashed line) and emission (orange solid line) spectra of Protoporphyrin IX with excitation (red dashed line) and emission (red solid line) of Cy5.

will insert surgical needles in the prostate, and endorectal ultrasound images and laparoscopic images will be recorded. The data will be processed offline in the laboratory to assess quantitatively the feasibility of the registration of ultrasound and laparoscopic images using passive markers. This protocol, already accepted by the ethical instances will be a pilot, monocentric study with 15 patients; • the second protocol, called COPROST will allow us to obtain fresh prostate chips during transurethral resections in the frame of a pilot monocentric prospective, non-randomized, open and controlled clinical trial. The protocol, with an inclusion period of 24 months is already defined and written following the French Regulation on Biomedical Research and biological tissue collection. It is being submitted to the ethical committee “comité de protection des personnes” and the “agence nationale de sécurité du médicament et des produits de santé” (ANSM). The prostate chips, will be on one hand characterized by anatomopathologists to determine their nature (pathologic vs. healthy, prostatic vs. non-prostatic) and will allow us to validate our immunofluorescence protocol and fine-tune our auto and immunofluorescence measurements protocols on fresh tissue samples. 4. Results Fig. 6. The bimodal fluorescence laparoscopic probe and the image-based analysis approach to localize it in laparoscopic images. Top: the CAD drawing of the bimodal fluorescence laparoscopic probe. Bottom: automatic detection of a laparoscopic instrument which will be used to overlay the probe’s tissue characterization measurements on the laparoscopic images.

laboratory testbenchs and during three cadaver experiments at the anatomy laboratory (section 4). However, in order to acquire the qualitative and quantitative proofs necessary to perform the fist clinical evaluations of our innovative medical devices on patients, we have submitted two biomedical research protocols: • the first one, called “fusion of echographic (ultrasound) and endoscopic images” (FEE) is a pilot, monocentric study on a cohort of 15 patients and is currently running. It aims at validating our ultrasound approach and evaluating its expected medical benefit: during radical prostatectomies, the surgeons

In this section, we present our preclinical evaluation of the different prototypes and software presented in the previous section. 4.1. Augmented laparoscopy thanks to an innovative video device In order to evaluate the potential benefits of the proposed vision system, we asked a surgeon to perform a simple surgical task, once with the traditional endoscope alone, and once with the proposed system alone (although in practice, they can be combined to associate local and global views). The tasks consisted in localizing a suture needle, and bringing it to a fixed target point. The experiment was performed on porcine organs placed in a training box and repeated six times by the surgeon. At each realization, the needle’s initial position was repositioned randomly, at a distance equivalent to its initial position, and the

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Fig. 7. Ultrasound image of a prostate acquired with our innovative transurethral ultrasound probe during a cadaver experiment. The image was acquired with our first prototype (64 piezoelectric elements).

surgeon started randomly with the traditional endoscope or the proposed system. In both cases, a robotic endoscope holder was used to mobilize the endoscope and the vision system, allowing us to record the displacements of the vision systems. The full methodology and results are currently under submission but to summarize: the mean time required to perform the six experiments with the traditional endoscope was of 190 s compared to 24.5 s with the proposed system. Moreover, the surgeon needed to give an average of 23.2 commands to the robotic scope holder to perform one stitch with the endoscope alone, compared to 4.6 commands with the proposed system. These preliminary results suggest that the proposed system could significantly reduce the laparoscopic surgery time and the cognitive load required for the control of the endoscope. We now plan on performing cadaver experiments to evaluate the deployment of the vision system in conditions close to the clinical reality, and to evaluate the system with several surgeons. 4.2. Augmented laparoscopy thanks to an innovative ultrasound system We performed two cadaver experiments, which allowed us to determine the optimal characteristics for the realization of the intraurethral ultrasound probe. During these experiments, we evaluated the (difficult) insertion of the catheter through the urethra and the prostate visualization. It must be noted that our clinicians partners stressed that the rigor mortis made this insertion harder. These experiments allowed us to find the best rigidity for the catheter of the probe: it must be flexible enough to be introduced in the urethra, but rigid enough to avoid the distortions of the catheter. The first ultrasound probe (2D) was designed with 64 piezoelements. It appeared that it was not enough. On the one hand, the probe imaged a too small part of the prostate so that it was difficult to identify what was represented on the ultrasound image (Fig. 7). Furthermore, it was impossible to know in which direction the probe was oriented. On the other hand,

Fig. 8. Demonstration of the fusion of ultrasound and laparoscopic images using passive landmarks on chicken breasts. Top-left: the ultrasound image; top-right: the laparoscopic image. The passive landmarks are indicated with the green arrows in the laparoscopic image. They are selected manually in both modalities to perform the registration. Bottom: the fusion of the two imaging modalities.

we demonstrated [9] that a longer probe increases the precision of the localization of the active ultrasound transducers. That is why the second probe designed for the project (3D) has 128 piezoelements. This second probe has graduations located on its catheter, visible on Fig. 2. They allow the surgeon to know the probe’s insertion depth in the urethra, and a line along the catheter allows appreciating the torsion applied to the catheter. The localization of the active transducers is currently under submission. It is based on a global positioning system (GPS) method. We made some experiments on a testbench, making localization in water to have ideal homogeneous conditions, and localization on a chicken breast to have more realistic conditions. In both cases we were able to localize the active transducer with a precision less than 625 ␮m. Moreover, the computation time is a few hundred milliseconds for a 2D localization. These results demonstrate that the localization is fast enough to be implemented for a prostatectomy. For the moment, only a 2D localization has been made with the active landmarks and the

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Fig. 9. Preliminary experiments of the autofluorescence detection with our testbench. The autofluorescence of chlorophyll, which has optical properties very similar to Protoporphyrin IX, was observed on our testbench. Left: direct image of a leaf; right: fluorescence image of the leaf at 680 nm. As expected, chlorophyll seems absent in the veins.

Fig. 10. Specific fluorescence signal of anti-prostate-specific membrane antigen marker. A. Nuclear counter-staining of prostatic tissue with Hoechst (blue DNA marker). We observe the nuclei of prostate cells regularly organized in the glandular epithelium. Prostatic glands are separated by stroma. B. Fluorescence emission of anti-prostate-specific membrane antigen-Fluorescein IsoThioCyanate on cellular membranes of prostatic cells. C. Overlay of the A and B images. This figure demonstrates the specificity, on fixed prostatic tissue, of a specific anti-PSMA antibody labelled with Fluorescein IsoThioCyanate. We can also detect the contribution of non-specific autofluorescence of prostatic concretions (Fig. 11) (×20 magnification).

3D localization is in progress. Then we will be able to perform a registration with laparoscopic images using “active” markers. Concerning the registration between laparoscopic and ultrasound images, we performed several testbench evaluations of the registration algorithm on chicken breasts. The result

of such a registration, obtained by manually pairing passive markers visible on both the laparoscopic and ultrasound imaging modalities, are presented on Fig. 8. In this example, we obtained a registration root mean square error (RMS) of 0.38 mm.

Fig. 11. Non-specific autofluorescence observed in the prostate fixed tissues. This figure shows the benefits of a near infrared marker like Cyanine 5 (excited at 633 nm) compared to Fluorescein IsoThioCyanate (excited at 488 nm). A. Auto fluorescence under laser excitation at 488 nm. We observe that prostate concretions (calcified material) respond to this excitation by a strong fluorescence signal. B. Auto fluorescence under laser excitation at 633 nm. The use of Cyanine 5 reduces widely autofluorescence of some structures such as prostate concretions (×20 magnification).

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4.3. Augmented laparoscopy thanks to fluorescence imaging First experiments were performed on leaves to demonstrate the feasibility of the detection of chlorophyll autofluorescence, which has optical properties very similar to PpIX (absorption at 405 nm and emission at 680 nm), as described on Fig. 9. Then, experiments were conducted on histology slices of the human prostate with, as we anticipated, inconclusive results because of the expected low signal-to-noise ratio caused by the insufficient thickness of a histology slice (3 ␮m thickness) compared to the optimal use of the device (300 ␮m thickness). These results motivated our biomedical research COPROST on macroscopic fresh prostate samples. Concerning the immunofluorescence protocol, we were able to demonstrate the specificity of the anti-PSMA antibody on fixed tissue samples, labelled with FITC as illustrated by Fig. 10. We observed higher autofluorescence problems when exciting the sample at the FITC specific wavelength compared to an excitation at the Cyanine 5 specific wavelength (Fig. 11). These results motivated the inclusion of both fluorophores in our biomedical research COPROST on macroscopic fresh prostate samples: FITC because it was already used to demonstrate specificity of anti-PSMA antibody and Cyanine 5 because its near infra-red characteristics make it a better candidate on fresh material (higher penetration in tissue) and will improve signal/noise ratio as previously demonstrated. To our knowledge, most of the optical biopsy approaches as previously defined have been validated either on histologic slices or on rat/mice prostate models. However these approaches have limitations: prostatic tissue is impaired by the chemical treatment required for histologic preparation, and animal models do not directly mimic all aspects of human prostate cancer [11]. In short, it has not been proved yet that a successful detection with the investigated devices on histopathology slices or on animal models is sufficient to guarantee a successful detection on fresh human tissues. The experiments that will be performed in the frame of the COPROST protocol in 2013 will be determinant to confirm the feasibility of our approach on fresh tissue samples. 5. Discussion/Conclusion The DEPORRA project allowed for the development of innovative devices and navigation prototypes in the objective of allowing the surgeon to see “beyond the visible” during a radical prostatectomy. First evaluations of the devices and methods have been performed preclinically and are very encouraging for the development of innovative approaches to assist the surgeon during such a complex surgery. Our preliminary results have also shown the limits of preclinical validation and have convinced us of the necessity to launch biomedical researches that will allow us to validate further the devices. This process required a

consequent amount of effort and time, but is mandatory for the fine-tuning of our tissue characterization tools, and to obtain the first clinical proofs of the relevance of the developed medical devices, which are mandatory to perform clinical evaluations of the complete navigation systems. We now need to push further the integration of the devices into such navigation systems, in order to exploit at best the information provided by each modality and to determine the optimal approach for displaying the relevant information to the surgeon in a clinical environment. This will imply a conception and development effort, a definition of qualitative and quantitative parameters for the first assessment of the delivered medical benefit of our developments, risks analysis and biomedical research preparations, in order to meet the ethical instances requirements. Acknowledgments This work has been supported by French National Research Agency (ANR) through TecSan program (project DEPORRA no ANR-09-TECS-006). References [1] Heidenreich A, Bolla M, Joniau S, Mason MD, Matveev V, Mottet N, et al. Guidelines on prostate cancer. Eur Assoc Urol 2011;60(5):1045–54 [www. uroweb. org]. [2] Pfitzenmaier J, Pahernik S, Tremmel T, Haferkamp A, Buse S, Hohenfellner M. Positive surgical margins after radical prostatectomy: do they have an impact on biochemical or clinical progression? BJU Int 2008;102(10):1413–8. [3] Soler L, Nicolau S, Schmid J, Koehl C, Marescaux J, et al. Virtual reality and augmented reality in digestive surgery. In: Third IEEE and ACM International Symposium on Mixed and Augmented Reality (ISMAR). 2004. p. 278–9. [4] S. Voros, B. Tamadazte, P. Cinquin, C. Fouard, Système d’imagerie multivision pour chirurgie laparoscopique, demande de dépôt de brevet #FR 1259489, 10/2012. [5] Ukimura O, Ahlering TE, Gill IS. Transrectal ultrasound-guided, energy-free nerve-sparing laparoscopic radical prostatectomy. J Endourol 2008;22(9):1993–5. [6] Long JA, Lee BH, Guillotreau J, Autorino R, Laydner H, Yakoubi R, et al. Real-time robotic transrectal ultrasound navigation during robotic radical prostatectomy: initial clinical experience. Urology 2012;80(3):608–13. [7] Holmes III DR, Davis BJ, Bruce CJ, Robb RA. 3D visualization, analysis, and treatment of the prostate using trans-urethral ultrasound. Comput Med Imaging Graph 2003;27:339–49 [2003]. [8] Dementhon D. Model-based object pose in 25 lines of code. Int J Comput Vis 1995;15(1–2):123–41. [9] Custillon G, Voros S, Cinquin P, Nguyen-Dinh A, Moreau-Gaudry A. Bidimensional localization of active ultrasound transducers for use in laparoscopic prostate surgery. IEEE Trans Med Imaging 2012. [10] Wolf R, Duchateau J, Cinquin P, Voros S. 3D tracking of laparoscopic instruments using statistical and geometric modeling. Med Image Comput Comput Assist Interv 2011;6891:203–10 [Lecture notes in computer science]. [11] Valkenburg KC, Williams BO. “Mouse models of prostate cancer”. Prostate Cancer 2011;2011:22, http://dx.doi.org/10.1155/2011/895238 [Article ID 895238].