Original Citation:
Chitosan membranes applied on the prostatic neurovascular bundles after nerve-sparing robot-assisted radical prostatectomy: A phase II study
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Porpiglia, Francesco; Bertolo, Riccardo; Fiori, Cristian; Manfredi, Matteo; De
Cillis, Sabrina; Geuna, Stefano. Chitosan membranes applied on the prostatic
neurovascular bundles after nerve-sparing robot-assisted radical
prostatectomy: A phase II study. BJU INTERNATIONAL. None pp: 1-28.
DOI: 10.1111/bju.13959
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Chitosan Membranes application on the Prostatic Neurovascular Bundles following Robot-assisted Radical
Prostatectomy: a phase II study
Journal: BJU International Manuscript ID BJU-2017-0573.R1 Manuscript Type: Original Article Date Submitted by the Author: 19-Jun-2017
Complete List of Authors: Porpiglia, Francesco; San Luigi Hospital, Dpt of Clinical and Biological Sciences, Division of Urology, University of Turin
Bertolo, Riccardo; San Luigi Hospital, Dpt of Clinical and Biological Sciences, Division of Urology, University of Turin
Fiori, Cristian; Azienda Ospedaliero Universitaria San Luigi Gonzaga Manfredi, Matteo; San Luigi Hospital, Dpt of Clinical and Biological Sciences, Division of Urology, University of Turin
De Cillis, Sabrina; Azienda Ospedaliero Universitaria San Luigi Gonzaga Geuna, Stefano; San Luigi Hospital, Dpt of Clinical and Biological Sciences, Division of Urology, University of Turin
Keywords: Trauma, Nervous System, Chitosan, Prostatic Neoplasms, Prostatectomy, Robotics
Abstract:
Objective: To evaluate the feasibility and the safety of the application of chitosan membranes on the neuro-vascular bundles after nerve-sparing Robot-Assisted Radical Prostatectomy (RARP). The secondary aim of the study was to report preliminary data and more particularly potency recovery data.
Materials and Methods: Single-center, single-arm prospective study. Enrolment from July 2015 to September 2016 of all patients with localized prostate cancer scheduled for RARP with IIEF-5 score > 17 after San Luigi Gonzaga Hospital Ethics Committee (Orbassano) approval (80/2015) and patient’s acceptance. All patients underwent nerve-sparing RARP with application of Chitosan Membranes on the neuro-vascular bundles. Demographics, peri-operative, postoperative data and complications were evaluated. Potency recovery data were particularly evaluated. Specifically for the purpose of the study, any referred sign/symptom of local
allergy/intolerance to the chitosan membranes was recorded and evaluated Results: Hundred-forty patients underwent nerve-sparing RARP with
chitosan membranes application on the neuro-vascular bundles. The application was easy in almost all the cases and did not compromise the safety of the procedure. None of the patients reported signs of
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Conclusion: In our experience chitosan membranes application on the neuro-vascular bundles after nerve-sparing RARP was feasible and safe, without compromising the length, the difficulty and the complications rate of the “standard” procedure. No patients experienced signs of
intolerance/allergy attributable to the membranes. Potency recovery data were encouraging. Comparative cohort would have added value to the study. The present paper was performed pre-CE mark achievement.
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Chitosan Membranes application on the Prostatic Neurovascular
Bundles following Robot-assisted Radical Prostatectomy: a phase II
study
F. Porpiglia1, R. Bertolo1, C. Fiori1, M. Manfredi1, S. De Cillis1, S. Geuna2
1
Division of Urology, Department of Oncology, San Luigi Gonzaga Hospital, University of Turin, Orbassano, Turin, Italy.
2Department of Life Sciences and Systems Biology and Department of Clinical and Biological
Sciences, San Luigi Gonzaga Hospital, University of Turin, Turin, Italy.
Corresponding author:
Francesco Porpiglia, MD
Division of Urology, Department of Oncology, University of Turin “San Luigi Gonzaga” Hospital
Regione Gonzole 10
10043 Orbassano (Turin), Italy Tel. +39 0119026557
Fax. +39 0119026244 e-mail: porpiglia@libero.it
Keywords: Trauma, Nervous System; Chitosan; Prostatic Neoplasms; Prostatectomy; Robotics Abstract: 240
Article Word count: 2771 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59
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Conflict of Interest statement:
None of the Authors has nothing to disclose.
ABSTRACT
Objective: To evaluate the feasibility and the safety of the application of chitosan membranes on the neuro-vascular bundles after nerve-sparing Robot-Assisted Radical Prostatectomy (RARP). The secondary aim of the study was to report preliminary data and more particularly potency recovery data.
Materials and Methods: Single-center, single-arm prospective study. Enrolment from July 2015 to September 2016 of all patients with localized prostate cancer scheduled for RARP with IIEF-5 score > 17 after San Luigi Gonzaga Hospital Ethics Committee (Orbassano) approval (80/2015) and patient’s acceptance. All patients underwent nerve-sparing RARP with application of Chitosan Membranes on the neuro-vascular bundles.
Demographics, peri-operative, postoperative data and complications were evaluated. Potency recovery data were particularly evaluated. Specifically for the purpose of the study, any referred sign/symptom of local allergy/intolerance to the chitosan membranes was recorded and evaluated
Results: Hundred-forty patients underwent nerve-sparing RARP with chitosan membranes
application on the neuro-vascular bundles.The application was easy in almost all the cases and did not compromise the safety of the procedure. None of the patients reported signs of
intolerance/allergy attributable to the membranes.
Conclusion: In our experience chitosan membranes application on the neuro-vascular bundles after nerve-sparing RARP was feasible and safe, without compromising the length, the difficulty and the complications rate of the “standard” procedure. No patients experienced signs of intolerance/allergy attributable to the membranes.Potency recovery data were encouraging. Comparative cohort would have added value to the study. The present paper was performed pre-CE mark achievement.
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INTRODUCTION
Over the last decades, the knowledge of peri-prostatic anatomical structures has increased, together with the development of radical prostatectomy surgical technique.
Robotics has played a crucial role, thanks to its undoubted advantages including the magnification of the anatomical structures. Nevertheless, even in case of meticulous preservation of the peri-prostatic neurovascular bundles (NVBs), in patients undergoing robot-assisted radical
prostatectomy (RARP) still remains a period of convalescence characterized by unrecovered potency [1].
Such a delay is probably due to the stunning of the anatomical structures and due to an
inflammatory response caused by injury from traction of the NVB [2]. Indeed, the physical tractions of the NVB can be minimized by the surgeon with consistent experience but cannot be fully
eliminated during the mobilization of the prostate [3].
In summary, we cannot wait for further innovations of the nerve-sparing (NS) technique; instead, we have to look for biological/bioengineering solutions aimed to protection and neuro-regeneration [4].
Recently, Patel and co-workers [5] published their results about the placement of dehydrated human amnion/chorion membranes around the NVBs after NS-RARP reporting an earlier return of continence and potency with respect to the comparative cohort who did not receive the membranes. Trying to give a contribution in this field, we began in our Centre the experience with chitosan in form of membranes applied on the NVBs after NS-RARP.
Chitosan has been widely used in a variety of biomedical applications, including peripheral nerves repair, due to its excellent biocompatibility, biodegradability, readily availability and antibacterial activity. For its features, chitosan is actually being used in periodontal and orthopedic systems
(either implantable or injectable), as drug-delivery system, as healing agent, as pulmonary
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surfactant additive and, of specific interest, as scaffold for regeneration of various tissues (nerve, skin, bone, cartilage) [6,7].
The primary endpoint of the study was the evaluation of the feasibility and the safety of the application of Chitosan in form of Membranes (ChiMe) on the NVBs after NS-RARP.
The secondary endpoint was to report preliminary data and more particularly potency recovery data after NS-RARP with application of ChiMe on the NVBs.
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MATERIALS AND METHODS
The enrolment phase lasted from July 2015 to September 2016 and was conducted in accordance with the Good Clinical Practice Rules and the ethical principles of the Declaration of Helsinki. The
Institutional Review Board of the San Luigi Gonzaga Hospital (Orbassano, Italy) approved the
study (80/2015).
Inclusion criteria
All males between 45 and 75 years old, with International Index of Erectile Function (IIEF-5) score > 17 [8], referred to our Institution with prostate cancer (T1-2 N0 M0 clinically-staged according to TNM [9], regardless the prostate size) and to whom NS-RARP was proposed.
All patients had preoperatively undergone prostate multi-parametric MRI (mp-MRI) according to the ESUR guidelines [10].
Exclusion criteria
Suspicious digital rectal examination, previous radiation therapy, hormonal therapy and/or previous prostate surgeries. Evidence at mp-MRI of: extra-capsular extension of the disease and/or seminal vesicles invasion [11].
Chitosan Membranes Manufacturing
Briefly, a 1.5% solution of chitosan (degree of acetylation of approximately 5.5%) in 0.5% aqueous acetic acid was poured into plastic dishes, followed by drying at room temperature. The resulting films were treated with a solution of ammonia in methanol/water, followed by intense washing with distilled water, and drying. A defined pattern of holes of approximately 160 µm diameter was made by means of a perforator. These sheets (thickness approximately 30 µm) were then cut into 4 x 3 cm membranes (Figure 1), placed in sterilization bags and sterilized using ethylene oxide.
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Surgical technique
RARP was performed as described in a previously published paper [12]. On the basis of the clinical, histological and radiological features of the disease, intrafascial or interfascial NS technique with lateral/postero-lateral approach was performed [13]. At the end of the total anatomical
reconstruction [12], the 4 x 3 cm ChiMe was cut into 2 rectangular pieces. When satisfactory haemostasis was achieved, one of the cut pieces was introduced by a Johann grasper through the assistant’s port (Figure 2) and then applied on the NVB by the first surgeon (Figure 3). The procedure was repeated contra-laterally.
Functional rehabilitation
All patients were administered phospho-diesterase type 5 inhibitors (PDE5-I) (Tadalafil 20 mg twice per week) for three months after surgery. Afterwards, drugs were continued if subjectively needed.
The following data were prospectively collected and registered in a dedicated database:
Demographic data
Age, body mass index, prostate specific antigen (PSA), biopsy Gleason Score (GS), mp-MRI status and American Society of Anaesthesiologists score.
Intraoperative data
Skin to skin operative time, estimated blood losses, complications and transfusion rate.
Post-operative data
Post-operative complications (as classified according to the Clavien system [14]) until 90 days after the surgery, catheterisation time and hospital stay.
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Membranes side-effects
Specifically for the purpose of the study, any referred sign/symptom of local allergy/intolerance to ChiMe (including itching and flushing) or anaphylaxis was recorded and evaluated.
No specific tests were scheduled, because neither allergic reactions nor other side-effects to chitosan medical devices available on the market have not been reported even in patients with known shellfish allergy [15].
Pathological data
Prostate and tumour volume, pathologic GS, staging according to TNM [8] and positive surgical margins (PSM) rate. Specimens were processed according to Montironi et al. [16].
Oncological follow-up
The oncological follow-up consisted of PSA measurements at 1, 3 and 6 months after surgery. Biochemical recurrence after the intervention was defined as PSA > 0.2 ng/ml.
Functional data
Urinary continence
Urinary continence was evaluated at catheter removal and at 1, 3 and 6 months after surgery. The question from the Expanded Prostatic Index Composite (EPIC) questionnaire: “How many pads of adult diapers per day did you usually use to control leakage?” was used to define pre- and post-operative continence. Patients were defined as continent if they did not use any pads or used one safety pad per day [17].
Erectile function
Preoperative erectile function was evaluated by IIEF-5 [9]. Potency recovery with or without PDE5-I treatment was defined as erection enough for intercourse or masturbation (score > 2 at question 2 of the EPIC questionnaire) and assessed at 1, 3 and 6 months after surgery.
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Statistical analysis
Means and standard deviations were used to report continuous variables with normal distribution. In other case medians and interquartile ranges were reported. Frequencies and proportions were used for categorical variables. Univariable and multivariable regression analyses were used to assess the effect of potential independent variables on potency recovery. P-values < 0.05 were considered significant. Statistical analyses were performed by Statistic 8 software (StatSoft, Tulsa, Oklahoma). 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59
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RESULTS
Hundred-forty patients underwent NS-RARP with ChiMe application. Patients’ demographics were reported in Table 1. Median baseline IIEF-5 score was 24. Perioperative data were detailed in Table 2. ChiMe were easily applied in 131 cases. Median time for application was 10 seconds per side (IQR 9 – 11). In 9 cases one or both the membranes had to be removed for a while: a dedicated suture was performed to control the bleeding occurring from one NVB. The membranes were then applied. Complications were detailed in Table 3.
No patients reported any sign of intolerance/allergy attributable to the membranes. Pathological data were reported in Table 4. Overall potency rate was 32.8, 54.2 and 68.6% at 1, 3 and 6 months postoperatively, respectively. Potency rates after stratification according to degree of NS were detailed in Table 5. Univariable regression analysis for potency (Table 6) revealed age as independent factor (p = 0.022) at 3rd month postoperatively and hypertension at 6th month
postoperatively (p = 0.008). Age was confirmed as independent factor at third month multivariable analysis too (β -0.20; 95% C.I: -0.40 -0.04, p = 0.015).
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DISCUSSION
In the field of peripheral nerves, the chance to recover nerve function after trauma is dependent on the severity of the suffered damage. Spontaneous recovery is possible if the continuity of the nerve is maintained, as in case of neuroapraxia. In case of complete nerve transection
(axonotmesis/neurotmesis), a surgical intervention is required to restore the continuity of the nerve. Autologous nerve grafts (auto-graft) would be the ‘gold standard’ technique for repairing peripheral nerve defects, consisting in the use of healthy nerve fragment of sensory origin for bridging the gap [18]. However, this practice presents some disadvantages: it requires an additional incision for removing the healthy sensory nerve, leading to a residue sensory deficit; yet, graft material is limited especially in case of an extended nerve lesion. As an alternative to auto-graft, a variety of biomaterials for nerve reconstruction have been developed [19]. In particular, chitosan, as a natural polysaccharide, has recently attracted more and more attention due to its good biocompatibility, biodegradability, non-toxicity, readily availability and physicochemical properties [4,6,7,19-24]. Indeed, chitosan has been used in a variety of biomedical applications, including peripheral nerves repair: the use of the chitosan-based nerve tube is already an authorized and CE-certified German medical product (Reaxon® Nerve Guide, Medovent, Germany).
Recent in vitro studies revealed the suitability of ChiMe as substrate for survival and oriented Schwann cell growth [19] as well as survival and differentiation of neuronal cells [20]. based scaffolds have been widely used for neural repair in different animal models [21]. Chitosan-based nerve conduits, alone or in combination with other biomaterials, have been found to bridge efficiently peripheral nerve defects [22,23]. Consistent enhancement in functional and
morphological nerve regeneration has been demonstrated [24]. The matter with prostate surgery is that it’s not a "one-nerve-only" damage: the anatomy of neuronal structures surrounding the
prostate is complex, neuronal fibers are autonomic and it is impossible to identify the single fiber to be reconstructed. Moreover, a complex mix of injuries from stretching, electro-cautery and
transection act on the integrity of NVB during the surgery. 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59
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Nevertheless, previous experiences tried to transfer the concept of sural nerve grafting to radical prostatectomy, with no significant results [25]. In parallel with such attempts, NS techniques improved a lot, reaching their acme with the advent of robotics [26,27]. Moreover, some Authors proposed helpful systems aimed to maximize NS during RARP: to name some of them, Tewari described a nerve stretching monitor [28]; Finley et al. tried regional hypothermia by rectal cooling balloon [29]. But urological community is still waiting for more consistent innovations.
The use of growth factors and anti-inflammatory substances for prostatic NVB regeneration has been proposed: specifically, Patel and co-workers described the use of dehydrated human amniotic/chorionic membrane (dHACM) as a source of implantable neurotrophic factors and cytokines [5]. They applied the membranes in 58 patients who underwent full NS RARP. Patients were matched with a similar group of patients who did not receive the graft: a faster return of potency was showed, with a higher rate of potent patients at 2 months in the grafted group (65.5% vs. 51.7%). Some perplexity could occur about the use of this kind of membranes, because they are applied close to the previous tumor site. Anyway, we have to wait for longer oncological follow-up data to draw definitive conclusions.
Try to give a contribution in this field we looked for an inert scaffold for neural regeneration. After the good results of chitosan in form of a cylinder to promote somatic nerves re-growth we could not avoid to try chitosan. The characteristics of the chitosan supposed to be useful in the
intra-operative field were 1) the neuroprotective/neuroregenerative effect [7], 2) the antitumoral activity [30], 3) the antinflammatory and analgesic effect [31], 4) the hemostatic activity (chitosan is an hemostatic agent actually approved in USA and in Europe, used by the American Marine Corps, and proved to be in pre-clinical studies essential in the survival of pigs with otherwise lethal arterial lesions [32] and 5) Antimicrobial activity [33]. Moreover, we were sponsored by the encouraging results obtained in our Institutional in vitro studies with autonomic nerves (they will be object for future publications in dedicated journals).
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Nevertheless, due to the anatomy of prostatic NVB we had to think about a different shape of the biomaterial. Indeed, it was produced in form of a thin square, with micro holes. This form was used pre-CE mark certification; this is why the study was submitted to and approved by our
Institutional Review Board and notified to the competent body. The application of ChiMe was
easy and safe in almost all the patients. After this preliminary experience, bleedings from the NVB have to be well controlled before placing the membrane. It is not mandatory the perfect adhesion of the membrane to the bundle. Rather, the membrane should be just deposited on the NVB, because it has to work as scaffold and drive the neural regeneration.
After applying ChiMe in 140 patients we did not record any complication or adverse event.
Moreover, the length of the operative time was not significantly affected with respect to a standard procedure. Concerning functional outcomes, in the present study we preliminary reported the potency data after the application of ChiMe on the NVBs after NS RARP: they were satisfactory, with a trend towards a faster recovery of erectile function with respect to our previous experience
even if no definitive conclusions can be drawn as no control arm was included in this pre-CE mark study. Having said this, confirming previous literature findings, age was found to be the
most significant predictor of postoperative potency recovery, even in a selected cohort of patients with high preoperative potency as assessed by IIEF-5 score [34].
No adverse events were recorded but two fevers that were reasonably attributed to infection: in fact, they were successfully managed by antibiotics.
A frequent question on chitosan-based medical products is whether they are able to induce allergic reactions in patients known to have shellfish allergy. To the best of our knowledge, allergic reactions to chitosan medical devices are not known. There have been sporadic reports of cases of allergic reactions to nonmedical products (e.g. dietary supplement, cosmetics) that contain chitosan whereupon in these cases a causal relationship with the ingredient chitosan is not clear.
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The chitosan used for the production of the membranes was prepared in multiple controlled processing steps where the starting material is chitin from Pandalus borealis, which is processed under defined conditions. Chitin is freed of proteins and minerals by treatments with dilute alkaline and acidic solutions, then converted to chitosan by hydrolysis for several hours and at high
temperatures. These hydrolysis conditions cause a denaturation and destruction of proteins and nucleic acids, so that allergic reactions to such treated chitosan can be excluded even in patients with known shellfish allergy who previously had anaphylactic reactions when in contact with shellfish [15].
Our study was not devoid of limitations; it was an observational study with prospective collection of data but no comparative cohort was included. This would have added value to the study but the present paper reported the phase II study pre-CE mark achievement. Designing a study including a
control arm was beyond the aims of the study. We avoid it waiting for the possibility to design a multicentre randomized study after the CE-mark achievement: this kind of study would be more representative of the real life situation, eliminating the bias of the single surgeon / single nerve-sparing technique that would occur in case of a single-center study.
The best candidates for receiving the membrane have yet to be investigated. Indeed, the effect of the membranes can be both neuro-protective and neuro-regenerative. We assume that in patients who underwent bilateral intrafascial NS no loss of neural tissue occurred: these patients would benefit of the eventual neuro-protective property of the ChiMe. Conversely, we would expect a more
consistent contribution in fasting the potency recovery in patients who underwent partial NS
techniques (with loss of neural tissue): in this cohort the neuro-regenerative effect of the membranes could be the key point.
Concerning the factors influencing potency recovery, radiation therapy could affect longer follow-up data. The 6 months long follow-follow-up did not reveal negative impact on potency recovery as the treatment was started since the 5th postoperative month in all the patients who required it. 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59
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Moreover, long-term oncological data are being recorded, and longer follow-up is required to evaluate future outcomes for our cohort.
In summary, in our experience chitosan membranes application on the NVBs after NS-RARP was feasible and safe, without compromising the length, the difficulty and the complications rate of the “standard” procedure. No patients experienced signs of intolerance/allergy attributable to the membranes.
Potency recovery data were encouraging even if no definitive conclusions can be drawn about
the effect of the membranes. After the proved absence of adverse events and the CE mark
certification, an adequately powered, prospective randomized trial of the application of the ChiMe on the prostatic NVB is going to be designed in order to the test the influence of chitosan
membranes on the potency recovery. 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59
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FIGURES LEGEND
Figure 1
The 4 x 3 cm x 30 µm chitosan membrane is ready to be cut into two pieces and used. Please note the micro-holes on the surface of the membrane.
Figure 2
A picture-in-picture showing the assistant introducing the membrane through an operative 10-mm port by using a Johann grasper at the end of a nerve-sparing robot-assisted radical prostatectomy.
Figure 3
After the anastomosis is completed, the membrane is applied on the neuro-vascular bundle by the first surgeon who drives the robotic arms. Please note that the membrane is just deposited on the neuro-vascular bundle without waiting for its perfect adhesion.
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[25] Porpiglia F, Ragni F, Terrone C, et al. Is laparoscopic unilateral sural nerve grafting during radical prostatectomy effective in retaining sexual potency? BJU Int. 2005 Jun;95(9):1267-71. [26] Schiffmann J, Haese A, Boehm K, et al. Ten-year experience of robot-assisted radical
prostatectomy: the road from cherry-picking to standard procedure. Minerva Urol Nefrol 2017 Feb; 69(1):69-75.
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For Peer Review
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[34] Porpiglia F, Morra I, Lucci Chiarissi M, et al. Randomised controlled trial comparing laparoscopic and robot-assisted radical prostatectomy. Eur Urol 2013 Apr; 63(4):606-14. 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59
For Peer Review
Demographics
Age
mean (SD), years median [IQR], years
60.8 (6.9) 61 [56 – 66] BMI median [IQR] 25.5 [23 – 27] PSA mean (SD), ng/ml median [IQR], ng/ml 8.4 (5.8) 6.5 [5 – 9] GS at biopsy No. 6 (%) No. 7 (%) No. 8-10 (%) 58/140 (41.4) 73/140 (52.1) 9/140 (6.5)
ASA score, median [IQR] 2 [2 – 3]
Prostate volume at TRUS mean (SD), ml
median [IQR], ml
44.1 (17.9) 38 [32 – 56] No. positive/suspected for PCa MRI (%) 105/140 (75.0) IIEF-5 score
median [IQR] 24 [21 – 25]
No. patients with previous CVD (%) 10/140 (7.1) No. patients with hypertension (%) 55/140 (39.3)
No. smokers patients (%) 14/140 (10.0)
No. patients with diabetes (%) 7/140 (5.0)
Table 1: Patients’ demographics
SD: Standard Deviation; IQR: Inter-Quartile Range; BMI: Body Mass Index; PSA: Prostate Specific Antigen; GS: Gleason Score; ASA: American Society of Anaesthesiologists; TRUS: Trans-Rectal Ultra-Sound; PCa: Prostate Cancer; MRI: Magnetic Resonance Imaging; IIEF: International Index of Erectile Function; CVD: Cardio-Vascular Disease.
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For Peer Review
Peri-operative Data
Operative time
median [IQR], min 110 (90 – 120)
NS procedures
No. bilateral intrafascial (%) No. intrafascial / interfascial (%) No. bilateral interfascial (%)
21 44 75 Time for application of chitosan membranes, median [IQR], sec
10 [9 - 11] Blood losses
median [IQR], ml 240 [215 – 270]
No. LND (%) 50 (35.7)
No. Intraoperative complications (%) 0 (0) Catheterization time, median [IQR], days 5 [4 - 6] Hospital Stay, median [IQR], days 5 [4 - 6]
Table 2: Peri-operative data.
IQR: Inter-Quartile Range; NS: Nerve-Sparing; LND: Lymph-Nodes Dissection.
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59
For Peer Review
Postoperative Complications Type Management
No. Early [occurred within the 30th POD] (%) 9/140 (6.4) Minor (grade I - II) 8/140 (5.7) - 2 AUR - 1 urine leakage - 2 fever - 2 scrotal oedema - 1 lymphocele Catheterization Catheterization Medical Therapy Medical Therapy Conservative Major
(grade III- IV)
1/140 (0.7)
1 paravesical haematoma Drainage with local anaesthesia
Intermediate [occurred from the 31st to the 90th POD] (%) 0/140 (0)
Table 3: Postoperative Complications as classified according to the Clavien System. POD: post-operative day; AUR: Acute Urinary Retention.
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59
For Peer Review
Pathological Data pT stage no. pT2 (%) no. pT3 (%) 98 (70.0) 42 (30.0) pN stage no. pNx (%) no. pN0 (%) no. pN+ (%) 83 (59.3) 57 (40.7) 0 (0) GS at final pathology no. 6 (%) no. 7 (%) no. 8-10 (%) 21/140 (15.0) 110/140 (78.5) 9/140 (6.5) no. overall PSM (%) no. PSM in pT2 (%) no. PSM in pT3 (%) no. >3 mm PSM (%) 34/140 (24.3) 2/98 (2.0) 11/42 (26.2) 7/140 (5.0)Table 4: Pathological Data.
GS: Gleason Score; PSM: Positive Surgical Margins.
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For Peer Review
Functional Data No. continent* patients (%) 1 month 3 months 6 months 128/140 (91.4%) 134/140 (95.7%) 135/140 (96.4%) No. potent§ patients (%)
Overall 1 month 3 months 6 months 46/140 (32.8) 76/140 (54.2) 96/140 (68.6) Bilateral Intrafascial NS (n=21) 1 month 3 months 6 months 9/21 (42.8) 15/21 (71.4) 17/21 (80.9) Intrafascial/Interfascial NS (n=44) 1 month 3 months 6 months 16/44 (36.4) 24/44 (54.5) 34/44 (77.3) Bilateral Interfascial NS (n=75) 1 month 3 months 6 months 22/75 (29.3) 39/75 (52.0) 49/75 (65.3) Table 5: Functional Data.
NS: Nerve-Sparing.
*continence was defined using a single question from the Expanded Prostatic Index Composite (EPIC) questionnaire: “How many pads of adult diapers per day did you usually use to control leakage?” Patients were defined as continent if they did not use any pads or used one safety pad per day
§
potency was defined as erection enough for intercourse or masturbation (score >2 at question number 2 of EPIC questionnaire) with or without PDE5-I treatment
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For Peer Review
Univariable Regression Analysis – potency recovery at 3rd month
p-value beta 95% C.I.
Age 0.022 -0.21 (-0.39 ; -0.30) BMI 0.706 -0.04 (-0.26 ; 0.17) Prostate Volume 0.266 -0.10 (-0.29 ; -0.08) Diabetes 0.151 0.13 (-0.05 ; 0.32) Hypertension 0.150 -0.13 (-0.32 ; 0.05) Smoking 0.057 -0.18 (-0.36 ; 0.01) CVD 0.326 0.09 (-0.09 ; 0.28) IIEF-5 0.958 0.01 (-0.19 ; 0.20) Bilateral Intrafascial NS 0.152 0.31 (-0.03 ; 0.45)
Univariable Regression Analysis– potency recovery at 6th month
p-value beta 95% C.I.
Age 0.196 -0.13 (-0.33 ; 0.07) BMI 0.614 0.06 (-0.17 ; 0.29) Prostate Volume 0.117 -0.15 (-0.35 ; 0.04) Diabetes 0.691 -0.04 (-0.24 ; 0.16) Hypertension 0.008 -0.26 (-0.46 ; -0.07) Smoking 0.083 -0.17 (-0.37 ; 0.02) CVD 0.854 -0.02 (-0.22 ; 0.18)
External Beam Radiation 0.562 0.29 (-0.21 ; 0.39)
IIEF-5 0.133 0.16 (-0.05 ; 0.37)
Bilateral Intrafascial NS 0.189 0.12 (-0.11 ; 0.23)
Table 6: Univariable Regression Analysis.
BMI: Body Mass Index; CVD: Cardio-Vascular Disease; IIEF: International Index of Erectile Function; NS: Nerve-Sparing. 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59
