External validation of the Memorial Sloan Kettering Cancer Center preoperative nomogram predicting lymph node invasion in a cohort of high-grade prostate cancer patients.

BACKGROUND: Commonly used preoperative nomograms predicting clinical and pathological outcomes in prostate cancer (PCa) patients have not been yet validated in high-grade only PCa patients. Our objective is to perform an external validation of the Memorial Sloan Kettering Cancer Center (MSKCC) preoperative nomogram as a predictor of lymph node invasion (LNI) in a cohort of high-grade PCa patients. METHODS: We included patients with high-grade PCa (Gleason ≥8) treated at our institution between 2011 and 2020 with radical prostatectomy and pelvic lymph node dissection without receiving neoadjuvant or adjuvant therapy. The area under the curve (AUC) of the receiver operator characteristic (ROC) was used to quantify the accuracy of the model to predict LNI. A calibration plot was used to evaluate the model's precision, and a decision curve analysis was computed to evaluate the net benefit associated with its use. This study was approved by our institution's ethics board. RESULTS: A total of 242 patients with a median age of 66 (60-71) years were included. LNI was observed in 70 (29%) patients with a mean of 16 (median = 15; range = 2-42) resected nodes. The MSKCC nomogram discriminative accuracy, as evaluated by the AUC-ROC was 79.0% (CI: [0.727-0.853]). CONCLUSION: The MSKCC preoperative nomogram is a good predictor of LNI and a useful tool associated with net clinical benefit in this patient population.

Performance of MRI for standardized lymph nodes assessment in breast cancer: are we ready for Node-RADS?

OBJECTIVES: The Node-RADS score was recently introduced to offer a standardized assessment of lymph node invasion (LNI). We tested its diagnostic performance in accurately predicting LNI in breast cancer (BC) patients with magnetic resonance imaging. The study also explores the consistency of the score across three readers. MATERIALS AND METHODS: A retrospective study was conducted on BC patients who underwent preoperative breast contrast-enhanced magnetic resonance imaging and lymph node dissection between January 2020 and January 2023. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value were calculated for different Node-RADS cut-off values. Pathologic results were considered the gold standard. The overall diagnostic performance was evaluated using receiver operating characteristic curves and the area under the curve (AUC). A logistic regression analysis was performed. Cohen's Kappa analysis was used for inter-reader agreement. RESULTS: The final population includes 192 patients and a total of 1134 lymph nodes analyzed (372 metastatic and 762 benign). Increasing the Node-RADS cut-off values, specificity and PPV rose from 71.4% to 100% and 76.7% to 100%, respectively, for Reader 1, 69.4% to 100% and 74.6% to 100% for Reader 2, and from 64.3% to 100% and 72% to 100% for Reader 3. Node-RADS > 2 could be considered the best cut-off value due to its balanced performance. Node-RADS exhibited a similar AUC for the three readers (0.97, 0.93, and 0.93). An excellent inter-reader agreement was found (Kappa values between 0.71 and 0.83). CONCLUSIONS: The Node-RADS score demonstrated moderate-to-high overall accuracy in identifying LNI in patients with BC, suggesting that the scoring system can aid in the identification of suspicious lymph nodes and facilitate appropriate treatment decisions. CLINICAL RELEVANCE STATEMENT: Node-RADS > 2 can be considered the best cut-off for discriminating malignant nodes, suggesting that the scoring system can effectively help identify suspicious lymph nodes by staging the disease and providing a global standardized language for clear communication. KEY POINTS: Axillary lymphadenopathies in breast cancer are crucial for determining the disease stage. Node-RADS was introduced to provide a standardized evaluation of breast cancer lymph nodes. RADS > 2 can be considered the best cut-off for discriminating malignant nodes.

Prognostic Significance of Pathologic Lymph Node Invasion in Metastatic Renal Cell Carcinoma in the Immunotherapy Era.

BACKGROUND: This study aimed to test the prognostic significance of pathologically confirmed lymph node invasion in metastatic renal cell carcinoma (mRCC) patients in this immunotherapy era. METHODS: Surgically treated mRCC patients were identified in the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2018. Kaplan-Meier plots and multivariable Cox-regression models were fitted to test for differences in cancer-specific mortality (CSM) and overall mortality (OM) according to N stage (pN0 vs pN1 vs. pNx). Subgroup analyses addressing pN1 patients tested for CSM and OM differences according to postoperative systemic therapy status. RESULTS: Overall, 3149 surgically treated mRCC patients were identified. Of these patients, 443 (14%) were labeled as pN1, 812 (26%) as pN0, and 1894 (60%) as pNx. In Kaplan-Meier analyses, the median CSM-free survival was 15 months for pN1 versus 40 months for pN0 versus 35 months for pNx (P < 0.001). In multivariable Cox regression analyses, pN1 independently predicted higher CSM (hazard ratio [HR], 1.88; P < 0.01) and OM (HR, 1.95; P < 0.01) relative to pN0. In sensitivity analyses addressing pN1 patients, postoperative systemic therapy use independently predicted lower CSM (HR, 0.73; P < 0.01) and OM (HR, 0.71; P < 0.01). CONCLUSION: Pathologically confirmed lymph node invasion independently predicted higher CSM and OM for surgically treated mRCC patients. For pN1 mRCC patients, use of postoperative systemic therapy was associated with lower CSM and OM. Consequently, N stage should be considered for individual patient counseling and clinical decision-making. Consort diagram of the study population.

Development and external validation of a multivariable [68Ga]Ga-PSMA-11 PET-based prediction model for lymph node involvement in men with intermediate or high-risk prostate cancer.

PURPOSE: To develop and evaluate a lymph node invasion (LNI) prediction model for men staged with [68Ga]Ga-PSMA-11 PET. METHODS: A consecutive sample of intermediate to high-risk prostate cancer (PCa) patients undergoing [68Ga]Ga-PSMA-11 PET, extended pelvic lymph node dissection (ePLND), and radical prostatectomy (RP) at two tertiary referral centers were retrospectively identified. The training cohort comprised 173 patients (treated between 2013 and 2017), the validation cohort 90 patients (treated between 2016 and 2019). Three models for LNI prediction were developed and evaluated using cross-validation. Optimal risk-threshold was determined during model development. The best performing model was evaluated and compared to available conventional and multiparametric magnetic resonance imaging (mpMRI)-based prediction models using area under the receiver operating characteristic curves (AUC), calibration plots, and decision curve analysis (DCA). RESULTS: A combined model including prostate-specific antigen, biopsy Gleason grade group, [68Ga]Ga Ga-PSMA-11 positive volume of the primary tumor, and the assessment of the [68Ga]Ga-PSMA-11 report N-status yielded an AUC of 0.923 (95% CI 0.863-0.984) in the external validation. Using a cutoff of ≥ 17%, 44 (50%) ePLNDs would be spared and LNI missed in one patient (4.8%). Compared to conventional and MRI-based models, the proposed model showed similar calibration, higher AUC (0.923 (95% CI 0.863-0.984) vs. 0.700 (95% CI 0.548-0.852)-0.824 (95% CI 0.710-0.938)) and higher net benefit at DCA. CONCLUSIONS: Our results indicate that information from [68Ga]Ga-PSMA-11 may improve LNI prediction in intermediate to high-risk PCa patients undergoing primary staging especially when combined with clinical parameters. For better LNI prediction, future research should investigate the combination of information from both PSMA PET and mpMRI for LNI prediction in PCa patients before RP.

Transperineal template saturation and conventional biopsy for stage prediction in prostate cancer.

OBJECTIVE: To evaluate the performance of risk calculators (RCs) predicting lymph node invasion (LNI) and extraprostatic extension (EPE) in men undergoing transperineal magnetic resonance imaging/transrectal ultrasound (TRUS)-fusion template saturation biopsy (TTSB) and conventional systematic TRUS-guided biopsy (SB). PATIENTS AND METHODS: The RCs were tested in a consecutive cohort of 645 men undergoing radical prostatectomy with extended pelvic LN dissection between 2005 and 2019. TTSB was performed in 230 (35.7%) and SB in 415 (64.3%) men. Risk of LNI and EPE was calculated using the available RCs. Discrimination, calibration, and clinical usefulness stratified by different biopsy techniques were assessed. RESULTS: Lymph node invasion was observed in 23 (10%) and EPE in 73 (31.8%) of cases with TTSB and 53 (12.8%) and 158 (38%) with SB, respectively. RCs showed an excellent discrimination and acceptable calibration for prediction of LNI based on TTSB (area under the curve [AUC]/risk estimation: Memorial Sloan Kettering Cancer Center [MSKCC]-RC 0.79/-4%, Briganti (2012)-RC 0.82/-4%, Gandaglia-RC 0.81/+6%). These were comparable in SB (MSKCC-RC 0.78/+2%; Briganti (2012)-RC 0.77/-3%). Decision curve analysis (DCA) revealed a net benefit at threshold probabilities between 3% and 6% when TTSB was used. For prediction of EPE based on TTSB an inferior discrimination and variable calibration were observed (AUC/risk estimation: MSKCC-RC 0.71/+8% and Martini (2018)-RC 0.69/+2%) achieving a net benefit on DCA only at risk thresholds of >17%. Performance of RCs for prediction of LNI and EPE based on SB showed comparable results with a better performance in the DCA for LNI (risk thresholds 1-2%) and poorer performance for EPE (risk threshold >20%). This study is limited by its retrospective single-institution design. CONCLUSIONS: The potentially more accurate grading ability of TTSB did not result in improved performance of preoperative RCs. Prediction tools for LNI proved clinical usefulness while RCs for EPE did not.

Mid-term oncologic outcomes of radical prostatectomy in lymph node metastatic prostate cancer patients.

OBJECTIVES: Lymph node invasion (LNI) has been reported in 10-15% of pelvic lymph node dissection during radical prostatectomy (RP). The objective of this study was to describe the mid-term oncological outcomes in prostate cancer (PCa) patients with metastatic lymph node. METHODS: We conducted a retrospective study at two French referral centers including consecutive cN0 PCa patients who underwent RP and extended pelvic lymph node dissection and had lymph node metastases on final pathological analysis (pN1) between January 2000 and May 2020. Follow-up was per institution, which generally included a PSA level measurement every 3 to 12 months for 5 years and annually thereafter. RESULTS: A total of 123 patients were included: two (1.6%) low-risk, 64 (52%) intermediate-risk and 57 (46.4%) high-risk PCa according to the D'Amico risk classification. The median number of nodes removed and metastatic nodes per patient was 15 (IQR 11-22) and 1 (IQR 1-2), respectively. Adverse pathological features, i.e., ≥pT3a stage, ISUP grade ≥3, and positive surgical margins were reported in 113 (91.9%), 103 (83.7%), and 73 (59%) of cases, respectively. Postoperative treatment was administered in 104 patients, including radiotherapy alone (n=6), androgen deprivation therapy alone (n=27) or combination with androgen deprivation therapy and radiotherapy (n=71). The mean follow-up was 42.7 months. The estimated 3-year biochemical-free survival, clinical recurrence-free survival, and cancer-specific survival was 66% and 85% and 98.8%, respectively. In Cox regression analysis, the number of metastatic nodes was associated with clinical recurrence (P=0.04) and a persistently elevated PSA with biochemical recurrence (P<0.001). CONCLUSION: The management of lymph node metastatic PCa patients is challenging. Risk stratification of node-positive patients, based on postoperative PSA levels and pathologic features being identified, should help physicians determine which patient would best benefit from multimodal treatment.

The Influence of Endogenous Testosterone Density on Unfavorable Disease and Tumor Load at Final Pathology in Intermediate-Risk Prostate Cancer: Results in 338 Patients Treated with Radical Prostatectomy and Extended Pelvic Lymph Node Dissection.

OBJECTIVE: The aim of this study is to evaluate the influence of endogenous testosterone density (ETD) on features of aggressive prostate cancer (PCa) in intermediate-risk disease treated with radical prostatectomy and extended pelvic lymph node dissection. MATERIALS AND METHODS: Density measurements included the ratio of endogenous testosterone (ET), prostate-specific antigen (PSA), and percentage of biopsy positive cores (BPC) on prostate volume (ETD, PSAD, and BPCD, respectively). The ratio of percentage of cancer invading the gland (tumor load, TL) on prostate weight (TLD) was also calculated. Unfavorable disease (UD) was defined as tumor upgrading (ISUP >3) and/or upstaging (pT >2) and/or lymph node invasion (LNI). Associations of ETD with features of aggressive PCa, including UD and TLD, were evaluated by logistic and linear regression models. RESULTS: Evaluated cases were 338. Subjects with upgrading, upstaging, and LNI were 61/338 (18%), 73/338 (21%), and 25/338 (7.4%), respectively. TLD correlated with UD (Pearson's correlation coefficient, r = 0.204; p < 0.0001), PSAD (r = 0.342; p < 0.0001), BPCD (r = 0.364; p < 0.0001), and ETD (r = 0.214; p < 0.0001), which also correlated with BMI (r = -0.223; p < 0.0001), PSAD (r = 0.391; p < 0.0001), and BPCD (r = 0.407; p < 0.0001). TLD was the strongest independent predictor of UD (OR = 2.244; 95% CI = 1.146-4.395; p = 0.018). In the multivariate linear regression model predicting BPCD, ETD was an independent predictor (linear regression coefficient, b = 0.026; 95% CI: 0.016-0.036; p < 0.0001) together with PSAD (b = 1.599; 95% CI: 0.863-2.334; p < 0.0001) and TLD (b = 0.489; 95% CI: 0.274-0.706; p < 0.0001). According to models, TLD increased as ETD increased accordingly, but mean ET levels were significantly lower for patients with UD. CONCLUSIONS: As ETD measurements incremented, the risk of large tumors extending beyond the prostate increased accordingly, and patients with lower ET levels were more likely to occult UD. The influence of ETD on PCa biology should be addressed by prospective studies.

Biochemical relapse predictive factors in patients with lymph node metastases during radical prostatectomy.

INTRODUCTION: There are no clear recommendations for the management of patients with lymph node invasion discovered during radical prostatectomy for prostate cancer (PCa). Adequate risk stratification could personalize post-surgical adjuvant treatment. Our objective was to identify predictive factors for biochemical relapse (BCR) in patients with lymph node (LN) invasion at the time of radical prostatectomy(RP). MATERIALS AND METHODS: Patients who underwent RP for high-risk PCa with LN invasion in two academic centres between 2008 and 2019 were included. Patients with metastatic disease or extrapelvic LN involvement were excluded. Following data were collected retrospectively: age, preoperative prostate-specific antigen level, Gleason score, clinical and pathological stage, number of metastatic LN and LN density. Outcome was BCR during follow-up. BCR-free survival was assessed by Kaplan-Meier method and its association with relevant variables was determined with log-rank test. RESULTS: Twenty-six patients were included. Median (IQR) age, PSA and follow-up were 64.5 years (55-78), 9.2ng/mL (4.4-20) and 16.1 months (6-27.5), respectively. Twenty patients (77%) had BCR after surgery, accounting for 24-month BCR-free survival of 65%. Patients with LN density > 15% had better survival rates than those with ≤ 15% (40% vs. 0%, respectively, at 24 months; P=0.06) without reaching significance. Cox proportional Hazards analysis could not evidence predictive factors of BCR free-survival. CONCLUSIONS: LN density seemed associated with BCR-free survival within patients with high-risk PCa and positive LN at RP. However, extraprostatic extension, number of positive LN and positive surgical margins were not independent risk factors for BCR. Larger prospective studies with centralized pathological reviews are needed. LEVEL OF PROOF: 3.

The role of 18F-FAZA PET/CT in detecting lymph node metastases in renal cell carcinoma patients: a prospective pilot trial.

BACKGROUND: The accurate detection of nodal invasion is an unmet need in the clinical staging of renal cancer. Positron emission tomography (PET) with 18F-fluoroazomycin arabinoside (18F-FAZA), a hypoxia specific tracer, is a non-invasive imaging method that detects tumour hypoxia. The aim of this work was to evaluate the role of 18F-FAZA PET/CT in the identification of lymph node metastases in renal cancer. METHODS: A proof-of-concept phase 2 study including 20 kidney cancer patients ( ClinicalTrials.gov Identifier: NCT03955393) was conducted. Inclusion criteria were one or more of the following three criteria: (1) clinical tumour size > 10 cm, (2) evidence of clinical lymphadenopathies at preoperative CT scan and (3) clinical T4 cancer. Before surgery, 18F-FAZA PET/CT was performed, 2 h after the intravenous injection of the radiotracer. An experienced nuclear medicine physician, aware of patient's history and of all available diagnostic imaging, performed a qualitative and semi-quantitative analysis on 18F-FAZA images. Histopathological analysis was obtained in all patients on surgical specimen. RESULTS: Fourteen/19 (74%) patients had a non-organ confined renal cell carcinoma (RCC) at final pathology (either pT3 or pT4). Median number of nodes removed was 12 (IQR 7-15). The rate of lymph node invasion was 16%. No patient with pN1 disease showed positive 18F-FAZA PET, thus suggesting the non-hypoxic behaviour of the lesions. In addition, neither primary tumour nor distant metastases presented a pathological 18F-FAZA uptake. No adverse events were recorded during the study. CONCLUSIONS: 18F-FAZA PET/CT scan did not detect RCC lymph neither nodal nor distant metastases and did not show any uptake in the primary renal tumour.

External validation of the Briganti 2019 nomogram to identify candidates for extended pelvic lymph node dissection among patients with high-risk clinically localized prostate cancer.

BACKGROUND: We aimed to establish an external validation of the Briganti 2019 nomogram in a Japanese cohort to preoperatively evaluate the probability of lymph node invasion in patients with high-risk, clinically localized prostate cancer. METHODS: The cohort consisted of 278 patients with prostate cancer diagnosed using magnetic resonance imaging-targeted biopsy who underwent radical prostatectomy and extended pelvic lymph node dissection from 2012 to 2020. Patients were rated using the Briganti 2019 nomogram, which evaluates the probability of lymph node invasion. We used the area under curve of the receiver operating characteristic analysis to quantify the accuracy of the nomogram. RESULTS: Nineteen (6.8%) patients had lymph node invasion. The median number of lymph nodes removed was 18. The area under the curve for the Briganti 2019 was 0.71. When the cutoff was set at 7%, 84 (30.2%) patients with extended pelvic lymph node dissection could be omitted, and only 1 (1.2%) patient with lymph node invasion would be missed. Sensitivity, specificity, and negative predictive values at the 7% cutoff were 94.7, 32.0, and 98.8%, respectively. CONCLUSION: This external validation showed that the Briganti 2019 nomogram was accurate, although there may still be scope for individual adjustments.

Predictors of Lymph Node Invasion in Patients with Clinically Localized Prostate Cancer Who Undergo Radical Prostatectomy and Extended Pelvic Lymph Node Dissection: The Role of Obesity.

OBJECTIVE: In patients with intermediate- and high-risk localized prostate cancer (PCa), improving the detection of occult lymph node metastases could play a pivotal role for therapeutic counseling and planning. The recent literature shows that several clinical factors may be related to PCa aggressiveness. The aim of this study is to investigate the potential associations between clinical factors and the risk of multiple lymph node invasion (LNI) in patients with intermediate- and high-risk localized PCa (cT1/2, cN0, and ISUP grading group >2 and/or prostate-specific antigen (PSA) >10 ng/mL) who underwent radical prostatectomy (RP) and extended pelvic lymph node dissection (ePLND). MATERIALS AND METHODS: In a period ranging from January 2014 to December 2018, 880 consecutive patients underwent RP with ePLND for PCa. Among these, 481 met the inclusion criteria and were selected. Data were prospectively collected within an institutional dataset and retrospectively analyzed. Age (years), body mass index (BMI; kg/m2), PSA (ng/mL), prostate volume (mL), and biopsy positive cores (BPC; %) were recorded for each case. BMI and BPC were considered continuous and categorical variables, respectively. The logistic regression models evaluated the association of clinical factors with the risk of nodal metastases. RESULTS: LNI was detected in 73/418 patients (15.2%) of whom 40/418 (8.3%) harbored multiple LNI (median 2, IQR: 3-4). On multivariate analysis, BMI was independently associated with the risk of multiple LNI in the pathological specimen when compared with patients without LNI (OR = 1.147; p = 0.018), as well as the percentage of biopsy positive cores (OR = 1.028; p < 0.0001) and European Association of Urology high-risk class (OR = 5.486; p < 0.0001). BMI was the only predictor of multiple LNI when compared with patients with 1 positive node (OR = 1.189, p = 0.027). CONCLUSIONS: In intermediate- and high-risk localized PCa, BMI was an independent predictor of the risk of multiple lymph node metastases. The inclusion of BMI within LNI risk calculators could be helpful, and a detailed counseling in obese patients should be required.

Comparison between Zumsteg classification and Briganti nomogram for the risk of lymph-node invasion before radical prostatectomy.

PURPOSE: To evaluate the performance of the Zumsteg classification to estimate the risk of lymph-node invasion (LNI) compared with the Briganti nomogram (BN) in prostatectomy patients with intermediate-risk prostate cancer (IRPC). METHODS: We included consecutive patients who had extended pelvic lymph-node dissection associated with radical prostatectomy for IRPC. To be classified favorable intermediate risk (FIR), patients could only have one intermediate-risk factor, fewer than 50% positive biopsies and no primary Gleason score of 4. RESULTS: On the 387 patients included, 149 (38.5%) and 238 (54.3%) were classified FIR and unfavorable intermediate risk (UIR), respectively, and 212 (54.8%) had a BN inferior to 5%. Thirty-eight patients (9.8%) had LNI: 6 FIR patients (4.0%) versus 32 UIR patients (13.4%) and 14 patients (6.6%) with a BN inferior to 5% versus 24 patients (13.7%) with a BN superior to 5%. Eight patients with a BN inferior to 5%, but classified UIR, had LNI. Sensitivity to detect LNI was higher with the Zumsteg classification than with the BN: 84.2% (CI 95% [68-93]) versus 63.2% (CI 95% [46-78]). Both screening tests were concordant to predict LNI (kappa coefficient of 0.076, p < 0.05 for Zumsteg and Briganti) CONCLUSIONS: Zumsteg classification appeared to be more sensitive and as effective (despite the impossibility to make decision curve analysis) than the BN to estimate the risk of LNI. Regarding the modest number of pN+ patients, further studies are needed to see the interest of proposing ePLND for UIR patients only.

Challenging the Current Risk Factors of Appendiceal Neuroendocrine Neoplasms: Can They Accurately Predict Local Lymph Nodal Invasion? Results from a Large Case Series.

BACKGROUND: Appendiceal neuroendocrine neoplasms (ANEN) are uncommon entities, which run mostly an indolent course. Appendicectomy alone is usually curative, except for in a selected group of patients that are deemed to be at risk of loco-regional metastases, in whom a completion right hemicolectomy (RHC) is recommended. The current "Guidelines" criteria for the latter have been controversial, and may result in overtreatment, which is concerning for a young patient population. OBJECTIVE: The aim of this study is to evaluate the prognostic value of the current criteria in identifying more accurately those at-risk patients. METHODS: This was a retrospective study of the 263 cases of ANEN referred for advice or management to a tertiary referral unit over a 10-year period. Seventy-two patients underwent RHC, based on criteria, suggested by International Guidelines. Each one of those was assessed to identify whether it correlated with lymph node invasion (LNI) at the RHC surgical specimen. RESULTS: Tumour grade (p < 0.001), vascular (p = 0.044) and lymph vessel invasion (p < 0.001) were all found to be statistically significant independent risk factors for LNI identified following RHC, whilst tumour size (p = 0.375) and mesoappendiceal invasion (MAI) (p = 0.317) were not statistically significant. However, deep MAI and tumour size >2 cm showed a correlation with each other on LNI positive subgroup analysis. Location in appendiceal base made LNI more likely but again was not significant (p = 0.133). CONCLUSIONS: Higher tumour grade and lymphovascular invasion should be considered as the most important risk prognosticators. Surprisingly, tumour size was not found to be significant in our cohort. Further international multicentre studies with large numbers of patients are needed to fully validate those data.

A machine learning-assisted decision-support model to better identify patients with prostate cancer requiring an extended pelvic lymph node dissection.

OBJECTIVES: To develop a machine learning (ML)-assisted model to identify candidates for extended pelvic lymph node dissection (ePLND) in prostate cancer by integrating clinical, biopsy, and precisely defined magnetic resonance imaging (MRI) findings. PATIENTS AND METHODS: In all, 248 patients treated with radical prostatectomy and ePLND or PLND were included. ML-assisted models were developed from 18 integrated features using logistic regression (LR), support vector machine (SVM), and random forests (RFs). The models were compared to the Memorial SloanKettering Cancer Center (MSKCC) nomogram using receiver operating characteristic-derived area under the curve (AUC) calibration plots and decision curve analysis (DCA). RESULTS: A total of 59/248 (23.8%) lymph node invasions (LNIs) were identified at surgery. The predictive accuracy of the ML-based models, with (+) or without (-) MRI-reported LNI, yielded similar AUCs (RFs+ /RFs- : 0.906/0.885; SVM+ /SVM- : 0.891/0.868; LR+ /LR- : 0.886/0.882) and were higher than the MSKCC nomogram (0.816; P < 0.001). The calibration of the MSKCC nomogram tended to underestimate LNI risk across the entire range of predicted probabilities compared to the ML-assisted models. The DCA showed that the ML-assisted models significantly improved risk prediction at a risk threshold of ≤80% compared to the MSKCC nomogram. If ePLNDs missed was controlled at <3%, both RFs+ and RFs- resulted in a higher positive predictive value (51.4%/49.6% vs 40.3%), similar negative predictive value (97.2%/97.8% vs 97.2%), and higher number of ePLNDs spared (56.9%/54.4% vs 43.9%) compared to the MSKCC nomogram. CONCLUSIONS: Our ML-based model, with a 5-15% cutoff, is superior to the MSKCC nomogram, sparing ≥50% of ePLNDs with a risk of missing <3% of LNIs.

The side and the location of the primary tumor does not affect the probability of lymph node invasion in patients with renal cell carcinoma.

PURPOSE: To evaluate the role of side and location of the primary renal cell carcinoma (RCC) on the risk of lymph node invasion (LNI) and/or nodal progression (NP) during follow-up. MATERIALS AND METHODS: We evaluated 2485 patients with unilateral RCC, surgically treated in a single tertiary care referral center. Outcomes were LNI at surgery and/or NP during follow-up. We studied if RCC side (left vs. right) and location (upper vs. middle vs. hilar vs. lower area vs. more than one area) affected the probability of LNI and/or NP at follow-up. RESULTS: Overall, 43 and 15% of patients underwent lymph node dissection and had LNI at surgery, respectively. During follow-up, 2.2% of patients had NP. Higher rates of LNI and NP were observed for patients with primary tumor located in more than one anatomical kidney area relative to patients with tumor in a single area (upper 11% vs. middle 10% vs. hilar 0%, vs. lower 12% vs. more than one area 26%, p < 0.01). cM1, cN1, pT2/pT3/pT4 disease and Fuhrman grade 3/4 were independent predictors of the study outcome (all p ≤ 0.01). Neither the RCC side nor the location reached the independent predictor status (all p > 0.1). CONCLUSIONS: Patients with single-side and more than one anatomical kidney area affected by RCC have higher rate of LNI at surgery and/or NP at follow-up. Neither side nor location of primary RCC tumor is related to the risk of harboring LNI at surgery and/or developing NP at follow-up.

Predictive and prognostic effect of inflammatory lymphadenopathies in renal cell carcinoma.

PURPOSE: A significant proportion of patients affected by renal cell carcinoma (RCC) shows a suspicious lymph node involvement (LNI) at preoperative imaging. We sought to evaluate the effect of lymphadenopathies (cN1) on survival in surgical RCC patients with no evidence of LNI at final pathology (pN0). METHODS: 719 patients underwent either radical or partial nephrectomy and lymph node dissection at a single tertiary care referral centre between 1987 and 2015. All patients had pathologically no LNI (pN0). Outcomes of the study were cancer-specific mortality (CSM) and other-cause mortality. Multivariable competing-risks regression models assessed the impact of inflammatory lymphadenopathies (cN1pN0) on mortality rates, after adjustment for clinical and pathological confounders. RESULTS: 114 (16%) and 605 (84%) patients (16%) were cN1pN0 and cN0pN0, respectively. cN1pN0 patients were more frequently diagnosed with larger tumours (8.4 vs. 6.5 cm), higher pathological tumour stage (pT3-4 in 71 vs. 36%), higher Fuhrman grade (G3-G4 in 64 vs. 31%), more frequently with necrosis (75 vs. 44%), and distant metastases (33 vs. 10%) (all p < 0.0001). At univariable analysis, inflammatory lymphadenopathies resulted associated with worse CSM (HR 2.45; p < 0.0001). However, at multivariable analysis, inflammatory lymphadenopathies were not an independent predictor of CSM (HR 0.81; p = 0.4). The presence of metastases at diagnosis was the most important factor affecting CSM (HR 6.54; p < 0.0001). This study is limited by its retrospective nature. CONCLUSIONS: In RCC patients, inflammatory lymphadenopathies (cN1pN0) are associated with unfavourable clinical and pathological characteristics. However, the presence of inflammatory lymphadenopathies does not affect RCC-specific mortality.

Identifying candidates for super-extended staging pelvic lymph node dissection among patients with high-risk prostate cancer.

OBJECTIVES: To assess if the preoperative lymph node invasion (LNI) risk could be used to tailor the extent of pelvic lymph node dissection (PLND) according to individual profile in patients with prostate cancer (PCa) undergoing radical prostatectomy (RP), and to identify those who would benefit from the removal of the common iliac and pre-sacral nodes. PATIENTS AND METHODS: A total of 471 patients with high-risk PCa treated with RP and a super-extended PLND that included the removal of the pre-sacral and common iliac nodes between 2006 and 2016 were identified. The risk of LNI was calculated according to the Briganti nomogram. Multivariable logistic regression analyses assessed the association between LNI risk and involvement of the common iliac and pre-sacral regions. The risk of positive common iliac and pre-sacral nodes was plotted over the LNI risk using the LOWESS-smoothed fit curve. RESULTS: The median preoperative LNI risk was 25.5%. The median number of nodes removed was 23, and 171 (36.3%) patients had LNI. Overall, 61 (13.0%) and 28 patients (5.9%), respectively, had positive common iliac and pre-sacral nodes alone or in combination with other sites. The LNI risk was associated with the involvement of the common iliac and pre-sacral regions (all P < 0.001). The proportion of patients with positive common iliac and pre-sacral nodes progressively increased according to the LNI risk. The adoption of a 30% threshold would result in avoiding the removal of the common iliac and pre-sacral nodes in >60% cases, with a risk of missing LNI in these regions of <5%. CONCLUSIONS: Fewer than 5% of patients with an LNI risk of <30% harbour positive common iliac and pre-sacral nodes. A super-extended PLND that includes the dissection of these regions should be considered exclusively in patients with an LNI risk ≥30%.

First North American validation and head-to-head comparison of four preoperative nomograms for prediction of lymph node invasion before radical prostatectomy.

OBJECTIVES: To perform a head-to-head comparison of four nomograms; namely, the Cagiannos, the 2012-Briganti, the Godoy and the online-Memorial Sloan Kettering Cancer Center (MSKCC), for prediction of lymph node invasion (LNI) in a North American population. PATIENTS AND METHODS: A total of 19 775 patients with clinically localized prostate cancer (PCa) who had undergone radical prostatectomy and pelvic lymph node dissection (PLND) were identified within the Surveillance Epidemiology and End Results (SEER) database. All four nomograms were tested using Heagerty's concordance index (C-index), calibration plots and decision curve analysis (DCA). In addition, we examined specific nomogram-derived thresholds to compare the number of avoided PLNDs and missed LNI-positive cases. RESULTS: All nomograms were found to have highly comparable C-index values: the Cagiannos, 78.6%; the Godoy, 78.2%; the 2012-Briganti, 79.8%; and the MSKCC, 79.9%. The Cagiannos nomogram showed the best calibration, followed by the 2012-Briganti, the Godoy and the online-MSKCC. In DCA, the 2012-Briganti and the Cagiannos, in that order, provided the best results, followed by the Godoy and the online-MSKCC models. For each nomogram, the threshold associated with ≤10% missed LNI cases avoided 8 693 (46.6%), 8 652 (46.4%), 8 461 (45.4%) and 8 590 (46.1%) PLNDs, respectively, with the use of the Cagiannos (2.6% threshold), the online-MSKCC (4.3% threshold), the Godoy (3.6% threshold) and the 2012-Briganti (4.6% threshold) nomograms. CONCLUSION: The Cagiannos and the 2012-Briganti nomograms exhibited the best calibrations and DCA results. Conversely, C-index values and ability to avoid unnecessary PLNDs were virtually the same for all four nomograms examined.

Prognostic Impact of Extracapsular Lymph Node Invasion on Survival in Non-small-Cell Lung Cancer: A Systematic Review and Meta-analysis.

The extracapsular tumor extension (ECE) of nodal metastasis is an important prognostic factor in different types of malignancies. However, there is a lack of recent data in patients with non-small-cell lung cancer (NSCLC). In addition, the TNM staging system does not include ECE status as a prognostic factor. This systematic review and meta-analysis has been conducted to summarize and pool existing data to determine the prognostic role of ECE in patients with lymph node-positive NSCLC. Two authors performed an independent search in PubMed using a predefined keyword list, without language restrictions with publication date since 1990. Prospective or retrospective studies reporting data on prognostic parameters in subjects with NSCLC with positive ECE or with only intracapsular lymph node metastasis were retrieved. Data were summarized using risk ratios (RR) for the survival with 95% confidence intervals (CI). The data was analyzed using Mix 2 (ref: Bax L: MIX 2.0 - Professional software for meta-analysis in Excel. Version 2.015. BiostatXL, 2016. https://www.meta-analysis-made-easy.com ). There 2,105 studies were reviewed. Five studies covering a total of 828 subjects met the inclusion criteria and were included in the meta-analysis. Two hundred and ninety-eight (35.9%) patients were categorized as ECE+, of whom 54 (18.1%) survived at the end of follow-up. In the ECE-negative group, 257 patients (48.4%) survived by the end of follow-up. Thus, ECE status is associated with a significantly decreased survival rate: pooled RR 0.45 (95% CI 0.35-0.59), Q (4) = 4.06, P value = 0.39, and I 2 = 68.00% (95 CI 0.00-79.55%). In conclusion, ECE has a significant impact on survival in NSCLC patients and should be considered in diagnostic and therapeutic decisions in addition to the current TNM staging. Postoperative radiotherapy may be an option in ECE-positive pN1 NSCLC patients.

North American Population-Based Validation of the National Comprehensive Cancer Network Practice Guideline Recommendation of Pelvic Lymphadenectomy in Contemporary Prostate Cancer.

BACKGROUND: National Comprehensive Cancer Network (NCCN) guidelines recommend a pelvic lymph node dissection (PLND) in prostate cancer (PCa) patients treated with radical prostatectomy (RP) if a nomogram predicted risk of lymph node invasion (LNI) is ≥2%. We examined this and other thresholds, including nomogram validation. METHODS: We examined records of 26,713 patients treated with RP and PLND between 2010 and 2013, within the Surveillance, Epidemiology, and End Results database. Nomogram thresholds of 2-5% were tested and external validation was performed. RESULTS: LNI was recorded in 4.7% of patients. Nomogram accuracy was 80.4% and maintained minimum accuracy of 75.6% in subgroup analyses, according to age, race, and nodal yield >10. With the NCCN recommended 2% nomogram threshold, PLND could be avoided in 22.3% of patients at the expense of missing 3.0% of individuals with LNI. Alternative thresholds of 3%, 4%, and 5% yielded respective PLND avoidance rates of 60.4%, 71.0%, and 79.8% at the expense of missing 17.8%, 27.2%, and 36.6% of patients with LNI. NCCN cut-off recommendation was best satisfied with a threshold of <2.6%, at which PLND could be avoided in 13,234 patients (49.5%) versus missing 141 patients with LNI (11.2%). CONCLUSION: NCCN LNI nomogram remains accurate in contemporary patients. However, the 2% threshold appears to be too strict, since only 22.3% of PLNDs can be avoided, instead of the stipulated 47.7%. The optimal 2.6% threshold allows a higher rate of PLND avoidance (49.5%), at the cost of 11.2% missed instances of LNI, as recommended by NCCN guidelines. PATIENT SUMMARY. External validation in contemporary SEER prostate cancer patients showed that the NCCN nomogram remains accurate for predicting lymph node invasion and seems to be optimal at an alternative 2.6% threshold, with best ratio of avoided pelvic lymph node dissections (49.5%) and missed LNIs (11.2%), as recommended by NCCN guideline. Prostate 77:542-548, 2017. © 2017 Wiley Periodicals, Inc.