DISCUSSION AND CONCLUSION

1. DISCUSSION AND CONCLUSION Alberto Briganti Urological Research Institute Vita Salute San Raffaele University Dept. of Urology, Milan, Italy

2. DISCUSSION : A SINGLE, KEY PRE-REQUISITE ….AS THERE IS NO WAY TO PERFORM A GOOD SURGICAL PROCEDURE IF YOU DO NOT KNOW THE SURGICAL STEPS….. …THERE WILL BE NEVER A GOOD DISCUSSION IF YOU DO NOT KNOW THE LITERATURE RELATED TO YOUR ARTICLE…. THEREFORE…. PLEASE STUDY!!!!!

3. DISCUSSION Length: should not be more than 1/3 of the total length of the manuscript: please be CONCISE! Avoid the temptation to cite all the articles you have read (AVOID ALSO SELF-CITATION…) Pick up no more than 20-25 articles and use them for references Study in details all studies including inclusion criteria, number of patients, methodology applied, length of observation Write down all strengths and limitations of the articles, including differences from yours

4. DISCUSSION : AIMS Discuss your data (results and why are these important?) and your hypothesis: SUMMARY OF YOUR FINDINGS Which are the clinical implications of your findings (do they change clinical practice) ? Discuss (only) the most relevant work and always in relationship with your data Is your data different from the literature and still relevant? Why? Which are the limitations of you study?

5. DISCUSSION: NOT TO DO 1. Do not add new results, do not repeat results IN DETAILS, but discuss actual results and explain conflicting data 2. Do not claim novel theories on small amounts of data 3. Do not claim anything based on other people’s work 4. NOBODY IS INTERESTED IN YOUR PERSONAL OPINION (THIS IS NOT AN EDITORIAL OR COMMENTARY) 5. Hopefully, the era of “in my experience” is over….

6. DISCUSSION Background (what we already know) : NOT MANDATORY This is what we did and why this issue is of importance (HYPOTHESIS which has not been addressed already by previous studies) This is what we found Strengths of the study (including clinical implications) How the paper compares and fits with previous knowledge Limitations of our findings This is the next step to go and future studies to perform in order to answer unaddressed questions

7. DISCUSSION All these section should be linked each other Each reader should understand the flow of your thoughts Be as simple as possible , simple and short sentences

8. DISCUSSION

9. DISCUSSION What we already know: The incidence of nodal metastases in patients affected by prostate cancer and submitted to RP has dramatically decreased in the PSA era. Nevertheless, even in the most selected clinical series, nodal metastases are still diagnosed in up to 40% of patients submitted to ePLND . However, although the presence of nodal metastases represents an adverse pathological characteristic, not all patients with prostate cancer and LNI are at the same risk of BCR ad cancer specific death. Several trials have indeed shown that patients with low volume of lymph node metastases have significantly higher CSS rates compared to patients with more extensive LNI. Thus, the number of positive nodes is key for determining patient prognosis.

10. DISCUSSION What we already know: Despite these evidences, the revised 2002 AJCC staging system for prostate cancer does not provide any stratification of patients with nodal metastases according to the number of positive nodes. Patients are indeed classified as having (N1) or not (N0) nodal metastases. Conversely, the N classification of the 1992 prostate cancer AJCC staging system included a stratification of node positive prostate cancer patients into two different categories (N1 and N2) according to the number and size of nodes involved by metastatic spread. Therefore, the AJCC lymph node staging has been simplified in 2002. However, these changes might not translate into comparable CSS predictive accuracies due to the different outcomes of node positive patients according to the extent of LNI.

11. DISCUSSION What we did (HYPOTHESIS): Based on these controversies, we aimed at quantifying the accuracy of the revised 2002 AJCC staging system in predicting CSS of node positive patients and to compare it with the accuracy of multivariable models including the number of positive nodes as a covariate. We performed our analysis in the largest series of node positive prostate cancer available (n = 703) treated with RP, ePLND and adjuvant treatments. Patients were sub-divided into two groups according to the most-informative cut-off of positive nodes for CSS prediction (namely, 2 vs >2 positive nodes).

12. DISCUSSION What we found: Interestingly, we confirmed the overall excellent cancer specific outcome of LNI patients. Prostate CSS rate at 15 years was as high as 79%. Similarly, about 50% of patients treated with a multimodal approach were free of BCR at 15-year follow-up. Moreover, we confirmed the key role represented by the number of positive nodes in predicting CSS of patients with LNI. Men with more than 2 positive nodes had significantly less favourable cancer characteristics at diagnosis (all p 0.04; Table 3) and lower CSS rates at 15 year follow-up compared to patients with 2 positive nodes (62% vs 84%, respectively; p < 0.001; Fig. 4).

13. DISCUSSION What is new and noteworthy (STRENGHTS + COMPARISONS): Several aspects of our study are noteworthy. First, our results reinforce the need for stratification of node positive prostate cancer patients according to the number of positive nodes. Our results are in line with previous studies supporting extremely favourable long term outcome of patients with low volume of nodal disease compared to patients with more extensive nodal invasion. Bader et al [omissis]. However, none of the previous studies assessed the predictive ability of the number of positive nodes for CSS prediction. Boorjan et al [omissis]. Therefore, we consider patient classification according to number of positive nodes a key variable for CSS predictions of node positive patients.

14. DISCUSSION What is new and noteworthy (STRENGHTS + COMPARISONS): Second, our results are based on the largest series of node positive prostate cancer published to date (n = 703) assessed at a long-term follow-up. Moreover, all our patients were treated with an anatomically defined extended pelvic lymph node dissection in the PSA era, which avoids any bias related to the diagnosis of LNI as well as to the current applicability of our findings.

15. DISCUSSION Limitations: Despite several elements of interest, our study is not devoid of limitations. First, all patients included in the analyses were submitted to adjuvant treatments after surgery. This may be criticized as a confounder of the impact of RP and PLND alone on lymph node positive prostate cancer. However, the use of adjuvant HT reflects a practice that is not uncommon among practicing urologists, based on the evidence of improved overall survival, CSS and progression-free survival of node positive prostate cancer submitted to adjuvant HT. However, it has to be acknowledged that our results might not applicable to node positive patients left untreated after surgery until progression. Nevertheless, even when adjuvant HT was not administered to node positive patients, patients with low volume of nodal burden had significantly better outcome compared to patients with higher number of positive nodes removed. This may suggest a potential curative role of PLND in selected category of patients. However, such hypothesis cannot be confirmed in our series since all patients received adjuvant HT after surgery.

16. DISCUSSION Limitations: Second, the differences in the population characteristics between the two contributing Institutions might represent another limitation of our study (Table 1). However, the two cohorts did not differ in terms of the extent of LNI (i.e. number of positive nodes) which represented the key variable of our study. Moreover, the effect of all these differences was accounted for by including patient characteristics as covariates in multivariable models.

17. DISCUSSION Limitations: Third, our analysis was in part limited by the differences in the way the lymph nodes were sent for pathological assessment between the two contributing Institutions. Indeed, at Mayo Clinic lymph nodes were submitted en bloc from each side of the pelvis. Conversely, at Vita-Salute University lymph nodes were submitted in multiple packages, which has been shown to improve the quality of pathological assessment of the number of lymph nodes that may be involved with metastatic cancer. This may be responsible for the difference in the mean number of lymph nodes examined between the two Centres. In addition, this may also be responsible for the overall relatively low mean number of lymph nodes examined in this series of extensive nodal dissection (Table 1). Nevertheless, the mean number of nodes removed was 13.9 which is significantly higher compared to limited nodal dissection series, where the mean number of nodes removed was as low as 5.8. Moreover, the lack of a central pathological re-assessment may represent another important limitation. Indeed, pathological evaluation of node specimens may account for different number of nodes identified and examined [omissis].

18. Conclusions • Short summary or conclusion regarding the significance of the work based on your results • Few sentences (Be CONCISE!!) • Highlight the possible implications or consequences of your results 18

19. Conclusions Our results showed favorable long-term outcome of patients with LNI. We have demonstrated that the number of positive nodes represents a key variable for CSS predictions. Patients with up to 2 positive nodes experience excellent CSS rate, which was significantly higher compared to patients with more than 2 positive nodes. Moreover, a significant improvement in CSS prediction is reached when the number of positive nodes is considered. These results reinforce the need for a stratification of node positive patients according to the number of positive nodes and may warrant consideration in the next revision of the pathologic TNM classification 19