EUROPEAN UROLOGY 60 (2011)

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1 EUROPEAN UROLOGY 60 (2011) available at journal homepage: Prostate Cancer The Optimal Rebiopsy Prostatic Scheme Depends on Patient Clinical Characteristics: Results of a Recursive Partitioning Analysis Based on a 24-Core Systematic Scheme Vincenzo Scattoni a, *, Marco Raber a, Umberto Capitanio a, Firas Abdollah a, Marco Roscigno a, Diego Angiolilli a, Carmen Maccagnano a, Andrea Gallina a, Antonio Saccà a, Massimo Freschi b, Claudio Doglioni b, Patrizio Rigatti a, Francesco Montorsi a a Department of Urology, University Vita-Salute, Scientific Institute San Raffaele, Milan, Italy; b Department of Pathology, University Vita-Salute, Scientific Institute San Raffaele, Milan, Italy Article info Article history: Accepted July 8, 2011 Published online ahead of print on July 30, 2011 Keywords: Prostatic neoplasms Prostate biopsy Diagnosis Transrectal ultrasound Abstract Background: The most beneficial number and the location of prostate biopsies remain matters of debate, especially after an initial negative biopsy. Objective: To identify the optimal combination of sampling sites (number and location) to detect prostate cancer (PCa) in patients previously submitted to an initial negative prostatic biopsy. Design, setting, and participants: A transrectal ultrasound guided systematic 24-core prostate biopsy (24PBx) was performed prospectively in 340 consecutive patients after a first negative biopsy (at least 12 cores). Measurements: We relied on a classification and regression tree analysis to identify three clinically different subgroups of patients at dissimilar risk of harboring PCa at second biopsy. Subsequently, we set the cancer-positive rate of the 24PBx at 100% and calculated PCa detection rates for 255 possible combinations of sampling sites. We selected the optimal biopsy scheme (defined as the combination of sampling sites that detected 95% of all the cancers with the minimal number of biopsy cores) for each patient subgroup. Results and limitations: After an initial negative biopsy, cancer was detected at rebiopsy in 95 men (27.9%). At a given number of cores, the cancer detection rates varied significantly according to the different combination of sites considered. Three different PCa risk groups were identified: (1) previous report of atypical small acinar proliferation of the prostate (ASAP), (2) no previous ASAP and ratio of free prostate-specific antigen (fpsa) to total PSA (%fpsa) 10%, and (3) no previous ASAP and %fpsa >10%. For patients with previous ASAP or patients with no previous ASAP and %fpsa 10%, two schemes with different combinations of 14 cores were most favorable. The optimal sampling in patients with no previous ASAP and %fpsa >10% was a scheme with a combination of 20 cores. Conclusions: Both the number and the location of biopsy cores taken affect cancer detection rates in a repeated biopsy setting. We developed an internally validated flowchart to identify the most advantageous set of sampling sites according to patient characteristics. Published by Elsevier B.V. on behalf of European Association of Urology. * Corresponding author. Department of Urology, University Vita-Salute, Scientific Institute H San Raffaele, Via Olgettina 60, Milan, Italy. Tel ; Fax: address: scattoni.vincenzo@hsr.it (V. Scattoni) /$ see back matter. Published by Elsevier B.V. on behalf of European Association of Urology. doi: /j.eururo

2 EUROPEAN UROLOGY 60 (2011) [(Fig._1)TD$FIG] 1. Introduction Patients with a prior negative prostate biopsy but a persistent suspicion of prostate cancer (PCa) on the basis of abnormal digital rectal examination (DRE), prostatespecific antigen (PSA) measurements, and histologic findings, namely, atypical small acinar proliferation of prostate (ASAP) and high-grade prostatic intraepithelial neoplasia (HGPIN), should be considered for a repeated biopsy [1]. Because initial 10- to 12-core biopsy schemes may miss almost a third of cancers [1,2], a saturation prostate biopsy (SPBx) has been adopted to improve PCa detection rate in the repeat setting. Several authors showed that SPBx increases the detection rate of PCa in patients with suspicious clinical findings following previous negative standard prostate biopsy compared with repeat standard biopsy strategies using up to 12 cores [1 6]. Nevertheless, the most efficient scheme with the optimal number and location of the cores has not yet been defined [1]. It is not clear whether it is critical to perform the same sampling protocol in each patient or to modify the protocol according to the different clinical parameters, such as PSA value, DRE findings, or prostatic volume [7]. It is still contentious whether the detection rate may vary simply with additional biopsies or it is due to the different locations from which the cores are taken [1,2,4]. We evaluated cancer detection rates on an individualcore basis after a 24-core prostate biopsy (24PBx) and investigated the ability of various biopsy regimens, which are characterized by the number and anatomic location of cores taken, to detect PCa. We also attempted to identify the optimal number and location of the cores to detect the maximum number of PCas with the minimum number of cores according to different clinical parameters. 2. Patients and methods 2.1. Procedure Following institutional review board approval, from September 2005 to June 2008 we prospectively performed a saturation 24PBx in 340 consecutive patients suspected of harboring PCa after a first negative biopsy sampling (at least 12 cores taken) [8]. The indications to perform a rebiopsy were PSA >4.0 ng/ml and/or abnormal DRE (n = 229) and/or initial HGPIN (n = 78) or ASAP (n = 33). Five dedicated urologists performed the procedures during this period. Each physician used a TRUS (transrectal ultrasound) end-fired probe at a variable frequency of MHz to guide the 18-gauge transrectal needle for prostate biopsy. SPBx was done on an outpatient basis using topical prilocaine-lidocainecream combinedwith a peripheral nerveblock that included the endorectal injection of 5 ml lidocaine (2%) bilaterally [9,10]. The biopsy patterns targeted six sectors (apex, lateral, and base, bilaterally) and the transition zone (TZ) to ensure a broad sampling area (Fig. 1). Three or four cores were taken from a specific zone of the sector for a total of 24 cores, and each single core was individually marked. The scheme (Fig. 1) consisted of the overlapping oftheclassicalsextant scheme of Hodge (white points), the more lateral sextant scheme of Stamey (black points), eight more lateral and subcapsular cores (blue-green points), and four cores from the TZ [2]. The 24 cores were immediately put on sponge Fig. 1 The figure shows the exact position of the 24 cores. The white cores belong to the classic Hodge scheme, the black cores to the Stamey scheme, and the blue-green cores to the more lateral and subcapsular cores. The number on the core represents the exact sequence and order of how the cores were taken and put in the sponge tissue on the sandwich cassette. The figure also shows the three sectors (apex, lateral, and base) and the transition zone from which the cores were taken and the colors used to mark each single core on the cassette (black, green, and blue). We started from the right lobe to the left lobe, from the apex to the base (A, apex; L, lateral; B, base). (A) Two transition zone (TZ) cores (No. 2 and No. 4) were directed through the adenomas to the anterior capsule; the other two posterior TZ cores were directed into the adenoma. (B) The arrows show the direction and the position of the biopsies in each lobe. tissue in seven different sandwich cassettes and individually inked with different colors to mark the sites from which they were collected [11]. All slides were reviewed by a single experienced uropathologist (MF) using contemporary diagnostic criteria for HGPIN, ASAP, and PCa Statistical analysis One-way analysis of variance and chi-square analyses were used to compare means and proportions, respectively. The sextant scheme of Stamey was set as the baseline. We added one single core from each side of the prostate, and we calculated the cancer detection rates for each scheme with 8, 10, 12, 14, 16, 18, 20, and 24 cores (considering all the biopsies of the TZ taken together). A total of 255 possible combinations were created, based on the sites of the cores. Because the exact prevalence of cancer cannot be assessed, to define how many cancers

3 836 [(Fig._2)TD$FIG] EUROPEAN UROLOGY 60 (2011) Fig. 2 Internally validated flowchart showing location and number of cores of the scheme that detects >95% of cancers with the minimum number of cores, in three different risk groups (see Fig. 1 for the position of the cores). The risk groups were identified by using a classification and regression tree analysis depicting the risk to detect prostate cancer at rebiopsy. ASAP = atypical small acinar proliferation of prostate; fpsa = free prostate-specific antigen; tpsa = total prostate-specific antigen. were detected with the different schemes (number and sites), we assumed that virtually all PCa was detected by the 24PBx. Consequently, we calculated the percentage of cancer detected by every scheme in all 255 possible combinations. Recursive partitioning analysis was used to evaluate all possible combinations of sampling sites and to choose a combination providing the highest cancer detection rate at a given number of cores [12,13]. We selected the most advantageous combination of sampling sites that detected >95% of the cancer detected with the minimum number of cores. Because patients with different baseline characteristics have dissimilar PCa detection rates, we identified subgroups of patients according to the risk of having PCa at initial biopsy and then repeated all analyses in each subgroup. To split the population, we relied on a classification and regression tree analysis in which all the available clinical variables were included in the tree modeling to predict the presence of tumor at rebiopsy. Previous ASAP report was forced as a main variable because it represents a universally recognized indication for rebiopsy. The computer-based modeling automatically proceeded to the selection and categorization of the variables included. The overall population was automatically split in three subgroups with different PCa detection risks (Fig. 2): (1) previous ASAP, (2) no previous ASAP and ratio of free prostate-specific antigen (fpsa) to total PSA (%fpsa) 10%, and (3) no previous ASAP and %fpsa >10%. Finally, we validated the tumor detection rates using the 10-fold cross-validation method. 3. Results In all cases, the planned numbers of cores were obtained (Table 1). After an initial negative biopsy with at least 12 cores, cancer was detected in 95 men (27.9%) at rebiopsy. The cancer detection rate was significantly higher in patients with ASAP (17 of 33; 51.5%) than in patients with an initial benign diagnosis (55 of 229; 24.0%; p = 0.002) or in patients with HGPIN (23 of 78, 29.5%; p = 0.04). No significant difference was found between patients without or with HGPIN at initial biopsy ( p = 0.4). At a given number of cores, the overall cancer detection rates varied significantly according to the different combinations of sites considered (Table 2). The mean cancer detection rates were 18.0%, 19.5%, 20.9%, 22.15, 23.1%, 24.1%, and 24.1% Table 1 Patient characteristics of the study population * Parameter Initial negative 24-core PBx (all patients, n = 340) Initial benign histology (n = 229) HGPIN (n = 78) ASAP (n = 33) Age, yr 64.9 (7.0) 65.7 (7.2) 63.9 (6.4) 62.0 (5.4) Abnormal DRE, % PSA, ng/ml 9.1 (16.1) 9.8 (19.3) 7.2 (4.0) 8.3 (5.0) Free PSA/Total PSA (%) 0.18 (0.07) 0.17 (0.06) 0.19 (0.09) 0.16 (0.08) Prostate volume, cm (32.7) 75.0 (32.4) 62.7 (30.1) 71.6 (36.7) Transition zone volume, cm (27.5) 47.7 (26.7) 37.8 (26.3) 45.8 (32.9) PSA density 0.13 (0.18) 0.14 (0.21) 0.12 (0.08) 0.13 (0.09) PSA density transition zone 0.27 (0.37) 0.26 (0.41) 0.28 (0.26) 0.29 (0.31) No. of cores at initial biopsy 13.4 (1.1) HGPIN (%) 78 (22.9) ASAP (%) 33 (9.7) PBx = prostate biopsy; HGPIN = high-grade prostatic intraepithelial neoplasia; ASAP = atypical small acinar proliferation of prostate; DRE = digital rectal examination. * The results were stratified according to the pathologic findings at initial biopsy (mean plus or minus standard deviation).

4 EUROPEAN UROLOGY 60 (2011) Table 2 Mean percentage of cancer detected (plus or minus standard deviation) at initial biopsy according to different clinical parameters and number and location of cores No. of cores All ASAP %fpsa >10% %fpsa <10% (2.5) 75.0 (3.3) 65.2 (3.9) 83.9 (4.3) (3.3) 80.3 (4.0) 71.8 (4.4) 88.4 (5.7) (3.5) 84.9 (4.4) 77.8 (4.7) 91.4 (5.7) (3.4) 88.8 (4.5) 83.2 (4.6) 93.8 (5.3) (3.1) 92.1 (4.3) 88.1 (4.4) 95.8 (4.8) (2.7) 95.0 (3.9) 92.5 (3.8) 97.4 (4.1) (3.3) 95.8 (3.9) 93.2 (4.3) 96.0 (4.7) cores different from p < 0.05 <16 <12 <16 <12 ASAP = atypical small acinar proliferation of prostate; fpsa = free prostate-specific antigen. for 8-, 10-, 12-, 14-, 16-, 18-, and 20-core schemes, respectively. There was no statistically significant difference between patients with and without PCa at rebiopsy for PSA values (8.1 vs 11.7 ng/ml; p = 0.07), %fpsa (0.19 vs 0.17; p = 0.06), and DRE (9.3% vs 11.0%; p = 0.09). Conversely, age, prostate volume, and PSA density were all significantly different ( p < 0.05). Multivariate analysis showed that ASAP at initial biopsy was the strongest predictor for PCa, whereas HGPIN did not reach a significant level (Table 3). We then determined the best combination of sampling sites that detected >95% of the cancers with the minimum number of biopsy cores, according to the clinical characteristics of the patients. As shown in Fig. 2 and 3a 3c, the flowchart allows clinicians to choose the most advantageous schemes. For patients with a previous ASAP or with no previous ASAP and %fpsa 10%, two different combinations of a 14-core biopsy scheme were the most advantageous. Sampling that allowed detection of 95% of cancers in patients with no previous ASAP and %fpsa >10% was a combination of a 20-core biopsy (Fig. 2). Fig. 3a 3c show the core locations according to the proposed schemes. The different site-specific cancer-positive rates are shown in Table 4. The median number of cores positive for cancer was two cores (mean positive cores: 3.2). One single microscopic focus of cancer (<5% of the length of the cores) was detected in 10 patients (10.5%), and one single core (focus >5% of the length of the cores) was Table 3 Univariable logistic regression analyses predicting the presence of cancer at rebiopsy after an initial negative extended biopsy OR (95% CI) p value Age ( ) PSA ( ) 0.2 Free PSA/Total PSA ( ) 0.05 Prostate volume ( ) Transitional zone volume ( ) Abnormal DRE findings ( ) 0.3 HGPIN ( ) 0.4 ASAP ( ) CI = confidence interval; OR = odds ratio; PSA = prostate-specific antigen; DRE = digital rectal examination; HGPIN = high-grade prostatic intraepithelial neoplasia; ASAP = atypical small acinar proliferation of prostate. detected in 22 patients (23.1%). Cancer was present in 2 cores from 25 patients (26.3%) and in 3 13 cores from the remaining 38 patients (40.0%). Cancer was detected on the basis of TZ cores in only seven patients (7.3%). A total of 66 patients (69%) underwent radical prostatectomy. Table 5 shows the pathologic findings of the surgical specimens. Pathologic stage was organ confined Table 4 The different site-specific cancer-positive rates (mean value between left and right lobe) and the mean percentage of cancer on the cores Core Proportion of positivity, % Mean percentage of cancer on the cores, % (95% CI) A (4 25) A (8 42) A (7 17) L (8 54) L (5 27) L (9 39) L (4 28) B (4 15) B (14 37 B (8 34) TZ (4 cores) (7 36) CI = confidence interval; TZ = transition zone. Table 5 Pathologic characteristics of the 66 patients submitted to radial prostatectomy after diagnosis of prostate cancer at 24-core prostate biopsy Parameter No. of cases (%) T stage pt2a 15 (23) pt2c 43 (65) pt3a 6 (9) pt3b 2 (2) N stage N0 59 (89) N+ 1 (2) Nx 6 (9) Gleason score 5 7 (10) Gleason score 6 (3 + 3) 33 (51) Gleason score 7 24 (37) (26) (10) Mean Gleason score 6.6 Mean tumor volume, cm Mean tumor volume, % 7.3 (1 35)

5 838 [(Fig._3)TD$FIG] EUROPEAN UROLOGY 60 (2011) Fig. 3 The overall population was automatically split in three subgroups with different prostate cancer (PCa) detection risks. The figures show the location and the number of cores of the scheme that detects >95% of the cancers with the minimum number of cores, in three different risk groups: (1) previous atypical small acinar proliferation of prostate [ASAP] diagnosis, (2) no previous ASAP diagnosis and free prostate-specific antigen/total prostate-specific antigen (fpsa/tpsa) =10%, and (3) no previous ASAP diagnosis and fpsa/tpsa >10%. (a) Previous ASAP diagnosis (14 cores; transition zone [TZ] can be omitted); (b) no previous ASAP diagnosis and fpsa/tpsa =10% (14 cores; TZ should not be omitted); (c) no previous ASAP diagnosis and fpsa/ tpsa >10% (20 cores; TZ should not be omitted). (pt2a c) in 88% of the patients and was locally advanced in only 11% of the patients. Tumor volume ranged from 0.2 to 3.1 cm 3 (mean: 1.23 cm 3 ). Clinically significant PCa, defined as tumor volume >0.5 cm 3 and Gleason score 6, was detected in 57 cases (60%). 4. Discussion Although SPBx has been shown to be appropriate in the rebiopsy setting in men with an initial negative extended biopsy, its regular use in clinical practice is not approved [1,2,4,5,14]. The National Comprehensive Cancer Network (NCCN) suggests performing a second extended protocol after an initial negative extended protocol and suggests considering SPBx only in patients with a high risk of cancer after multiple negative biopsies [14]. Thus the ideal strategy for prostate biopsy procedure in the repeat biopsy setting has yet to be fully elucidated. In recent years, a significant effort was made to define more efficient biopsy schemes for PCa detection with the minimum number of cores [15 17]. Intuitively, adding more biopsies to prostatic areas not sampled by common extended schemes should increase the detection rate; however, it should be noted that the relationship between the number of biopsy cores and the resultant cancer detection rate does not correlate linearly. Kawakami et al. analyzed the cancer detection rate of prostate biopsy by using a three-dimensional (3D; transrectal-transperineal) 26-core systematic superextended biopsy protocol [12]. They were able to extract a 3D 14-core biopsy protocol that could detect 95% of cancers with the fewest number of cores. Adopting a scheme that is able to maximize the detection rate with the fewest number of cores seems more appealing than adopting a saturation scheme that does not increase the cancer detection rate in proportion to the increase in the number of cores. In our study, we analyzed the performance of a SPBx in 340 patients who had previously received only one negative extended biopsy procedure with at least 12 cores. Our overall diagnostic yield was 27.9%, which is in line with the

6 EUROPEAN UROLOGY 60 (2011) % yield reported in other series [1,2,4,5,14]; however, an important difference is that most of the series included patients who had only prior sextant or <12 sample biopsies. Campos-Fernandes et al. performed a second extended 21-sample needle biopsy, and they reported an overall cancer detection rate of 18% [18]. They also reported cancer detection rates of 16%, 42%, and 17% in patients with prior HGPIN, prior ASAP, and prior benign biopsy, respectively [18]. Their detection rates are slightly lower than ours because they adopted a scheme with a lower number of cores in the peripheral gland (15 vs 20 cores). Similarly to Campos-Fernandes et al, we have reported a similar detection rate between patients with a benign initial biopsy and patients with prior HGPIN, and we have confirmed that HGPIN is not a significant predictive factor for a positive second biopsy [18]. The odds ratio (OR) between these two groups was similar in our multivariate analysis, and the classification and regression tree analysis identified three groups with different characteristics, although none included HGPIN. ASAP was a relevant predictive factor associated with the highest risk of harboring PCa in the study by Campos-Fernandes et al. (42%) as well as in our study (51%), with an OR of 3.1 [18]. In our series we showed for the first time that the best rebiopsy scheme varies according to the clinical characteristics of the patients. Our analysis revealed that for patients with previous ASAP diagnosis, the most advantageous scheme was a combination of a 14-core biopsy (without TZ biopsies). For patients with no previous ASAP and %fpsa 10%, the most advantageous scheme was a 14-core biopsy (including 4 TZ biopsies). The most advantageous sampling scheme for patients with no previous ASAP and %fpsa >10% was a combination of a 20-core biopsy (including 4 TZ biopsies). Isolated ASAP is a well-known risk factor for a positive second biopsy. The overall recent risk of harboring a cancer is about 40% in the recent series, slightly <45% observed more than a decade ago [19,20]. In other studies as well as in the study by Campos-Fernandes et al, the overall risk of finding cancer is about 42% [18]. For the first time, we have demonstrated that a specific combination of a 14-core biopsy is sufficient to detect 95% of cancers. In this group of patients, the TZ biopsies were not necessary because they only slightly increased cancer detection, and most of the cancers were situated in the peripheral gland. In this situation, the site of the ASAP did not seem to be so important, probably due to the multifocality of the PCa. We previously reported that, in a multisite study, a precise spatial concordance between ASAP and cancer was present in only 33% of the cases, similar to the likelihood of finding cancer in an adjacent or a nonadjacent site [21,22]. There is a debate in the literature on the role and the number of cores of the TZ biopsies in patients with an initial benign histology [1,2,4,5]. According to published reports, PCa is diagnosed on the basis of TZ biopsies in only 1.8 8% of cases [1,2,4,5]. Campos-Fernandes et al. reported that only one case (1.7%) was identified from the TZ-only cores, and they concluded that the indication of TZ biopsies alone could be discussed in their cases [18]. It should be noted that the cancer detection rate was particularly low in their study, in which TZ biopsies were systematically performed as the initial biopsy procedure. Pepe et al. recently reported that sampling from the prostatic TZ by directed needle biopsies at repeated SPBx was associated with a very low incidence of PCa (2.5%), especially if compared with TRUS (19% detection rate) [23]. In our study, we included TZ biopsies in our most advantageous schemes because most of our patients were submitted to an extended approach without TZ biopsies. Thus we strongly suggest adding fourcore TZ biopsies in the repeat setting in those patients. Walz et al. reported a high PCa detection rate of 41% with a 24-core protocol [24]. Similarly to the initial biopsy protocol, it has been proven that more time and effort should be spent on lateral biopsies, which increase the cancer detection rate, whereas parasagittal biopsy provides a low yield on repeat biopsy [24]. For this reason, we selected two different schemes with different locations and numbers of cores in two groups of patients with different risks of having cancer, according to %fpsa values. The NCCN guidelines strongly suggest performing a rebiopsy if the %fpsa is <10% [25]. Because the risk of finding cancer in our population is significantly higher in patients with %fpsa <10% than in patients with %fpsa >10%, we selected a 14-core scheme to optimize the cancer detection rates with the fewest cores. As is evident from Fig. 3b, the parasagittal and posterior zone has been omitted, and two very apical biopsies were included in this scheme. Recent publications about radical prostatectomy specimens have confirmed the prevalence of tumors in the apex. Takashima et al. found that more than half of the apical tumors were located in the anterior half of the prostate [26]. Bott et al. reported that 21% of PCas were located in the anterior zone and that those cancers required additional sets of biopsies before detection [27]. Moussa et al. recently reported that apical cores, especially the extreme apical cores like our two apical cores (Fig. 3c), increase PCa detection [28]. We suggest increasing the cores of the apex and anterior part of the prostate when performing a second biopsy after an extended protocol. In patients with %fpsa >10%, a 20-core scheme is necessary to detect 95% of the cancers. This scheme included the TZ cores and omitted only a lateral core from the original 24-core scheme. Similar to our report, Kawakami et al. selected an optimal combination with a 3D 16-core (8 transrectal cores plus 8 transperineal cores) biopsy scheme [12]. The proposed 3D 16-core biopsy scheme, which included sampling from the anterior and posterior part of the prostatic apex, has the disadvantage of the two different approaches. Even if a TRUS 20-core scheme rather than a 3D 16-core scheme is necessary to detect 95% of the cancers, we believe it is more convenient to use our TRUS single approach with 20 cores. Because the %fpsa is also correlated with prostate volume, it is probable that a higher number of cores is necessary in larger prostates that have higher %fpsa values. The present study is not devoid of limitations. The most obvious was that, unfortunately, we do not know how many cancers were missed by our 24PBx scheme. It is mainly influenced by verification bias because we cannot define the real diagnostic accuracy of our combinations of schemes. It is

7 840 EUROPEAN UROLOGY 60 (2011) not possible to generalize our results because they were not validated in an independent data set. Finally, because about 60% of the patients had undergone radical surgery at study presentation, we are unable to verify how many cancers were really insignificant. The question of the clinical significance of any diagnosed PCa is beyond the scope of the current study. 5. Conclusions Both the number and the location of biopsy cores taken affect cancer detection rates in a repeated biopsy setting. The optimal scheme varies according to the clinical characteristics of the patients. Our analysis revealed that for patients with previous ASAP diagnosis or no previous ASAP diagnosis and %fpsa 10%, two different combinations of a 14-core biopsy scheme were most advantageous. The optimal sampling in patients with no previous ASAP diagnosis and %fpsa>10% was a combination of a 20-core biopsy. We developed an internally validated flowchart that identifies the most advantageous set of sampling sites according to patient characteristics. It still needs to be validated in an independent data set before adopting it in clinical practice. Author contributions: Vincenzo Scattoni had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Scattoni, Raber, Roscigno, Doglioni, Maccagnano. Acquisition of data: Abdollah, Angiolilli, Freschi. Analysis and interpretation of data: Scattoni, Capitanio. Drafting of the manuscript: Scattoni, Rigatti. Critical revision of the manuscript for important intellectual content: Roscigno. Statistical analysis: Capitanio, Gallina. Obtaining funding: None. Administrative, technical, or material support: None. Supervision: Montorsi. Other (specify): None. Financial disclosures: I certify that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None. Funding/Support and role of the sponsor: None. References [1] Heidenreich A, Bellmunt J, Bolla M, et al. EAU guidelines on prostate cancer. Part 1: screening, diagnosis, and treatment of clinically localised disease. Eur Urol 2011;59: [2] Scattoni V, Raber M, Abdollah F, et al. Biopsy schemes with the fewest cores for detecting 95% of the prostate cancers detected by a 24-core biopsy. Eur Urol 2010;57:1 8. [3] Falzarano SM, Zhou M, Hernandez AV, et al. 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