Evaluation of the Padua Predicting Score (PPS) In Open Partial Nephrectomy (OPN).

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1 ORIGINAL PAPER Evaluation of the Padua Predicting Score (PPS) In Open Partial Nephrectomy (OPN). CAN THE PREDICTION OF POSTOPERATIVE COMPLICATIONS IMPROVE? RESULTS OF THE FIRST UROLOGICAL CLINIC, SCHOOL OF MEDICINE, UNIVERSITY OF ATHENS Stavros I. Tyritzis 1,2,3, I. Adamakis 1, I. Anastasiou 1, X, Alamanis 1, K. Stravodimos 1, D. Mitropoulos 1, K.A. Konstantinidis 1 1. First Urological Clinic, School of Medicine, University of Athens Laiko, University General Hospital of Athens, Greece 2. Department of Molecular Medicine and Surgery, Section of Urology, Karolinska Institutet, Stockholm, Sweden 3. Center for Minimally Invasive Urologic Surgery, Athens Medical Center, Greece Abstract Over the last years, important changes have taken place on the incidence rate and natural course of renal cell carcinoma. Most patients are now diagnosed at T1 stage. These changes are primarily due to the introduction in everyday medical practice of modern imaging methods (ultrasounds, X-ray, MRI) facilitating more and earlier diagnoses. However, the most common treatment choice remains the tumors surgical removal. Partial nephrectomy is a technically challenging procedure in which the anatomy of the kidney and the tumor site affect the perioperative outcomes. In this study we investigated the improvement of Padua score with the introduction of additional parameters. Introduction/Aim: Over the last years, important changes have taken place on the incidence rate and natural course of renal cell carcinoma (RCC). We observe a significant incidence increase rate in new diagnoses, over-doubled from 7.1 cases per of population in the USA to 15.3 and from 2.3% to 4.3% over the last 30 years. Deaths remain practically stable from 3.6 to 3.9; 5-year survivorship related to the disease has increased from 52.1 to 73.5% 1. Most patients are now diagnosed at T1 stage 2. These changes are primarily due to the

2 introduction in everyday medical practice of modern imaging methods (ultrasounds, X-ray, MRI) facilitating more and earlier diagnoses 3. The most common treatment choice is the tumor s surgical removal 4. Radical nephrectomy (RN) used to constitute the gold standard management for RCC, however, the change in the characteristics of newly diagnosed neoplasms, led the surgical technique to also adjust by the gradual application and prevalence of partial nephrectomy (PN). PN oncologic outcomes are equivalent to RN outcomes, yet, they greatly advance over the first given the preservation of the renal unit and the improved quality of life (QOL) in patients 5. These positive outcomes have resulted to the rapid and wide acceptance of the technique which now constitutes a therapeutic approach in treating T1a and T1b tumors, where feasible, according to the guidelines of the European Association of Urology (EUA) 6. PN is a technically challenging procedure in which the anatomy of the kidney and the tumor site affect the perioperative outcomes. The treatment choice for patients who are candidates for PN is mainly based on the radiographic and morphological features of the tumor. For the best preoperative assessment of the patients and the prediction of postoperative outcomes and complications, several scoring systems have been suggested. Namely, in 2009, Ficarra et al presented the preoperative aspects and dimensions used for an anatomical (PADUA) score as a prediction tool for the postoperative complications after PN, utilizing the tumor s morphological parameters as these are available from the preoperative assessment on computed tomography 7. Following a study conducted in our clinic, where we, as external observers, had validated the score with outcomes justifying the initial application of the PADUA score 8, we applied PADUA in a new series of our patients and we tried to investigate on the possibility of its improvement by adding extra parameters either preoperatively available or associated with the surgical procedure. Materials & Methods During , retrospective analysis was performed on 63 consecutive OPNs. All patients were subjected to the same surgical technique. The access was extraperitoneal

3 with lumbar section complete renal immobilization and vascular pedicle preparation preceded. Hot ischemia was accomplished via vessel loop in 60 cases; ischemia was not performed in the rest 3 cases. Tumor localization and resection margins were optically identified without use of fluorescence assay. The surgical resection was performed with cold biopsy forceps unaccompanied by diathermy application and included supra-tumoral en block dissection of the adipose capsule of the kidney (perirenal fat). No resection margins cold biopsies were processed. In cases where a pelvicalyceal system rupture was recognized, this was sutured with a 3-0 Vicryl suture (Johnson & Johnson New Brunswick, NJ, USA) and a figure-of-eight haemostatic suture. On the kidney bed we performed interrupted suturing with a 0 Vicryl stitch via a liver needle (atraumatic). In 49 out of the 63 patients and according to the surgeon s preference, haemostatic materials were used on the kidney bed which included: a Surgicel haemostatic gauze (Ethicon Somerville, NJ, USA) in 37 cases, a Tachosil haemostatic patch (Baxter Healthcare Corporation Westlake Village, CA, USA) in 15 cases and Bioglue haemostatic glue in 4 cases (Cryolife Kennesaw, GA, USA); in 5 cases a combination of the materials was applied. The ischemia time was recorded in 38 cases, mean time minutes (time range 0-25) and the variable was analysed only for these cases. No pigtail ureteric stent was placed either preoperatively or intraoperatively. There were no cases where a switch was made to RN. Out of the 63 cases, one was excluded from total analysis on the basis of insufficient data.

4 The demographic characteristics of the patients, the co-morbidity assessment on the Charlson-age adjusted score (AAC) 9, Body Mass Index (BMI) and estimated glomerular filtration rate (egfr) factors are presented in Table 1. The postoperative complications were recorded for 90 days postoperatively (POD) and were graded according to the Clavien Dindo 10 recording system. In total, 28 complications were observed in 23 patients; only 3 patients manifested Clavien 3 complications. The complications are presented in detail in Table 3 along with their management, according to the EAU guidelines. The primary aim of the study is the evaluation of the PADUA score in predicting the manifestation of postoperative complications for 90 days subsequent to the procedure. The statistics concern the calculation of sensitivity and specificity of the PADUA score on ROC curves for the prediction of Clavien-graded complications. Synchronous to the primary study aim, a qualitative and quantitative analysis was performed on the improvement potential of the predictive power of the PADUA score in combination with a series of preoperative, intraoperative and oncologic parameters via the Wald test. Namely, the parameters assessed were: gender, age, BMI, Age-Adjusted Charlson Comorbidity (AAC) index score and preoperative egfr, hot ischemia time and tumor s histologic subtype and Grade. The secondary study aim was the analysis of the sensitivity and specificity of the PADUA score on mixed effect analysis for the prediction of renal function impact and

5 specifically that of postoperative egfr in 3 and 6 months follow-up. The postoperative egfr values were available only for 33 patients and the statistical analysis is based only on this sample. Results: The distribution of 62 patients based on PADUA score is depicted in Table 4. The relation between the PADUA score and the potential of manifesting postoperative complications was investigated on ROC curves. Graph 1 The ROC curve shows high sensitivity but low specificity with total moderate predictive power. In a further analysis on the increase potential of the PADUA score prognostic value in combination with the preoperative parameters such as gender, age, BMI, Age- AAC index score and preoperative egfr, no significant statistical difference is observed. Similarly, the addition of intraoperative data such as ischemia time and/or postoperative data such as the tumor s morphology delivered no significant statistical difference. Only the tumor s Grade shows a tendency of approaching a statistically significant difference, which however, cannot be well-documented based on the present sample. The

6 Wald test results and p-values are presented in Table 4. As a secondary aim of our study, the PADUA score was investigated as a factor for the prediction of postoperative egfr and its differentiation (decrease) from the preoperative egfr in 3- and 6-month periods. The statistical analysis regards a sample of 33 patients given these were the only ones with complete data of postoperative renal function. The documentation of the value difference of egfr 3 months postoperatively compared to the baseline according to PADUA score is presented in Graph 2. This difference shows a strong correlation, based on the Pearson correlation coefficient, with the PADUA score r=0.524 (p=0.002). The performed mixed effects analysis which considered the egfr values as repeated measurements associated with the baseline (preoperative baseline measurement), revealed that the period between 3 and 6 months did not determine any statistically significant difference between the 3- and 6-months interval. Nevertheless, there is a statistically significant negative correlation between the PADUA score and postoperative egfr, i.e. the bigger the value of the PADUA score, the smaller the egfr postoperatively with regression coefficient (SE 1.13), p=0.004, 95% CI [-5.82, -1.24]. Conclusions - Discussion: The prognostic value of the PADUA score in our results, presents a statistical significance, with high sensitivity but moderate specificity. This fact does not diminish the value of the PADUA score in total, as we had revealed in our initial study on the external validation of the PADUA score 8, but it possibly reflects the increasing surgical experience and the reduced complications in total and especially those of greater importance graded

7 by Clavien 3. In any case, it remains an objective assessment method for the complexity of the tumor preoperatively. It includes all the anatomic aspects, which the surgeon should take into consideration when deciding on the treatment plan for partial nephrectomy (PN), i.e. site, size, depth, relation to the renal hili etc. The clinical importance of its application in every day practice and the need for greater prognostic significance, led to the investigation of the increase potential in combination with other parameters. The choice of the preoperative factors investigatedgender, age, BMI, AAC and preoperative egfr-, constitute factors that may affect the perioperative results. Of the intraoperative factors, we chose the hot ischemia time as a factor related to the complexity of the procedure and the possibility of preserving the renal function. Concluding, we investigated the oncologic parameters, i.e. the histologic subtype and the tumor s Grade as an expression of the neoplasm s aggressiveness. The reason behind our decision to combine a preoperative scoring system with intraoperative and postoperative data, may not contribute to the patient s preoperative assessment, yet, it may result in the increased postoperative awareness for high risk patients. No factor improves the predictive power of the PADUA score. The outcome strengthens the use of the PADUA score as a tool in every day clinical practice since it can provide considerable information on the patient s postoperative course. As a secondary study aim, we addressed the correlation of PADUA score with the affected egfr in 3 and 6 months postoperatively. The statistical analysis revealed a strong correlation between the complexity of the tumor and the decrease in renal function proportionately, i.e. the bigger the PADUA score, the greater the value difference between preoperative and postoperative egfr. The outcome is considered of great importance since it constitutes the basic reason behind a surgeon s decision to opt for PN instead of RN. The protection of the renal function and the possibility of preoperatively assessing the extent to which the renal function may be affected, hold the primary role in choosing the management. At a clinical level, many authors have also widely applied the PADUA score to describe and classify the renal neoplasias according to their complexity and to affect the decision on the applicable treatment, the choice of PN, the prediction of the need for hot ischemia and its time 11,12. Moreover, it is applied in predicting the clinical outcome in terms of positive surgical margins, intraoperative hemorrhage, complications and postoperative renal function 13. To conclude, it has been studied and established as a critical factor in predicting the postoperative course of all types of PNs 14, including laparoscopic 15, single-site laparoscopic 16 and robotically-assisted 17. Given the above, the clinical use of the PADUA score in the preoperative assessment of patients who are candidates for PN is extremely determining and overrides its academic and investigating purpose. Potentially, the PADUA score could be utilized as a preoperative index of the complexity of the surgery, of the risk to manifest postoperative complications and of the eventual renal function in case the patient should undergo PN.

8 The study limitations include its retrospective character and the lack of data for some patients regarding the hot ischemia time and postoperative egfr. Additionally, the relatively small number of postoperative complications, as a result of the increased surgical experience, did not allow for the predictive capacity of the PADUA score and mostly its specificity to fully emerge in this series of patients. It is necessary, in combination with the results of similar clinical studies, to draw up a multicentric prospective study that will designate the clinical importance of the PADUA score in every day practice for the appropriate preoperative assessment of the patients scheduled for PN. Περίληψη Κατά τα τελευταία χρόνια, έχουν λάβει χώρα σημαντικές αλλαγές σχετικά με τη συχνότητα, το ρυθμό και τη φυσική πορεία του νεφροκυτταρικού καρκινώματος. Οι περισσότεροι ασθενείς διαγιγνώσκονται σε στάδιο Τ1. Αυτές οι αλλαγές οφείλονται στην εισαγωγή καθημερινής ιατρικής πρακτικής των σύγχρονων μεθόδων απεικόνισης (υπέρηχοι, X-ray, MRI), διευκολύνοντας και επισπεύδοντας την διάγνωση. Η πλέον κοινή θεραπεία παραμένει η χειρουργική αφαίρεση του όγκου. Η ανοικτή μερική νεφρεκτομή είναι μια απαιτητική επέμβαση στην οποία η ανατομία του νεφρού και η θέση του όγκου επηρεάζουν την έκβαση.στην μελέτη διερευνήσαμε τη βελτίωση του Padua score με εισαγωγή πρόσθετων παραμέτρων. ΕΙΣΑΓΩΓΗ: H μερική νεφρεκτομή θεωρείται ο χρυσός κανόνας στην αντιμετώπιση των νεφρικών μαζών μεγέθους μικρότερου των 4εκ. Οι ελάχιστα επεμβατικές χειρουργικές επεμβάσεις αποτελούν εναλλακτική λύση στις περιπτώσεις αυτές. Η λαπαροσκοπική μερική νεφρεκτομή έχει ισοδύναμα ογκολογικά αποτελέσματα με την ανοιχτή μερική νεφρεκτομή προσφέροντας συγχρόνως όλα τα πλεονεκτήματα της ελάχιστα επεμβατικής χειρουργικής. Ο σκοπός της μελέτης είναι να παρουσιάσουμε την αρχική μας εμπειρία στην λαπαροσκοπική μερική νεφρεκτομή. ΥΛΙΚΟ ΚΑΙ ΜΕΘΟΔΟΣ: Από τον Οκτώβριο του 2012 έως και το Μάρτιο του 2014,9 επιλεγμένοι ασθενείς με σκιαστικώς ενισχυούμενες νεφρικές μάζες στην αξονική τομογραφία, υποβλήθηκαν σε λαπαροσκοπική μερική νεφρεκτομή. Καταγράφησαν δημογραφικά στοιχεία ασθενών, προεγχειρητικά χαρακτηριστικά του όγκου καθώς και λεπτομερή λειτουργικά, μετεγχειρητικά και παθολογοανατομικά στοιχεία. ΑΠΟΤΕΛΕΣΜΑΤΑ: 6 ασθενείς υποβλήθηκαν σε δεξιά μερική νεφρεκτομή και 3 σε αριστερά, χωρίς διεγχειρητικές επιπλοκές. Σε έναν ασθενή η λαπαροσκοπική ριζική νεφρεκτομή έγινε ανοικτά λόγω αιμορραγίας. Ο χειρουργικός χρόνος κυμάνθηκε μεταξύ 120 και 225 λεπτών,

9 η εκτιμώμενη απώλεια αίματος κυμαίνονταν από 30 έως 300 ml και ο χρόνος θερμής ισχαιμίας μεταξύ λεπτών. Σε έναν ασθενή δεν απαιτήθηκε συμπίεση των αγγείων του νεφρού. Συνολικά, δεν απαιτήθηκαν μεταγγίσεις και δεν υπήρξαν σημαντικές διεγχειρητικές ή μετεγχειρητικές επιπλοκές. Σε έναν ασθενή παρατηρήθηκε ένα μικρό υποδόριο αιμάτωμα στην οπή πρόσβασης και σε άλλον παρατηρήθηκε μικρή παροδική αιματουρία που έπαυσε αυτόματα. Σε έναν ασθενή βρέθηκε ένα μικροσκοπικό θετικό χειρουργικό όριο. Όλοι οι ασθενείς είναι ελεύθεροι νόσου στους 6 μήνες παρακολούθησης. ΣΥΜΠΕΡΑΣΜΑ: Η λαπαροσκοπική μερική νεφρεκτομήείναι μια ασφαλής και εφικτή προσέγγιση σε μικρές νεφρικές μάζες, προσφέροντας όλα τα πλεονεκτήματα της ελάχιστα επεμβατικής χειρουργικής Reference 1. SEER Database Update 2. Fergany AF, Hafez KS, Novick AC. Long-term results of nephron sparing surgery for localized renal cell carcinoma: 10-year follow-up. J Urol 2000 ; 163 : Jayson M, Sanders H. Increased incidence of serendipitously discovered renal cell carcinoma. Urology 1998 ; 51(2) : Jansen NK, Kim HL, Figlin RA, et al. Surveillance after radical or partial nephrectomy for localized renal cell carcinoma and management of recurrent disease. Urol Clin Nrth Am 2003 ; 30 : Van Poppel H, Da Pozzo L, Albrecht W, et al. A prospective, randomised EORTC intergroup phase 3 study comparing the oncologic outcome of elective nephron- sparing surgery and radical nephrectomy for low-stage renal cell carcinoma. Eur Urol 2011 ; 59(4) : EAU Guidelines, edition presented at the 29th EAU Annual Congress, Stockholm ISBN Ficarra V, Novara G, Secco S et al. Preoperative aspects and dimensions used for an anatomical (PADUA) classification of renal tumours in patients who are candidates for nephron-sparing surgery. Eur Urol 2009 ; 56 : Tyritzis S, Papadoukakis S, Katafigiotis I et al Implementation and external validation of Preoperative Aspects and Dimensions Used for an Anatomical (PADUA) score for predicting complications in 74 consecutive partial nephrectomies. BJU Int ;109(12) : Charlson M, Szatrowski T, Peterson J, et al. Validation of a combined comorbidity index J ClinEpidimiol 1994; 47(11):

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