Pulmonary lesion after surgery for renal cancer: progression or new primary?

PURPOSE: To investigate clinical and radiological differences between kidney metastases to the lung (RCCM +) and metachronous lung cancer (LC) detected during follow-up in patients surgically treated for Renal Cell Carcinoma (RCC). METHODS: cM0 surgically-treated RCC who harbored a pulmonary mass during follow-up were retrospectively scrutinized. Univariate logistic regression assessed predictive features for differentiating between LC and RCCM + . Multivariable analyses (MVA) were fitted to predict factors that could influence time between detection and histological diagnosis of the pulmonary mass, and how this interval could impact on survivals. RESULTS: 87% had RCCM + and 13% had LC. LC were more likely to have smoking history (75% vs. 29%, p < 0.001) and less aggressive RCC features (cT1-2: 94% vs. 65%, p = 0.01; pT1-2: 88% vs. 41%, p = 0.02; G1-2: 88% vs. 37%, p < 0.001). The median interval between RCC surgery and lung mass detection was longer between LC (55 months [32.8-107.2] vs. 20 months [9.0-45.0], p = 0.01). RCCM + had a higher likelihood of multiple (3[1-4] vs. 1[1-1], p < 0.001) and bilateral (51% vs. 6%, p = 0.002) pulmonary nodules, whereas LC usually presented with a solitary pulmonary nodule, less than 20 mm. Univariate analyses revealed that smoking history (OR:0.79; 95% CI 0.70-0.89; p < 0.001) and interval between RCC surgery and lung mass detection (OR:0.99; 95% CI 0.97-1.00; p = 0.002) predicted a higher risk of LC. Conversely, size (OR:1.02; 95% CI 1.01-1.04; p = 0.003), clinical stage (OR:1.14; 95% CI 1.06-1.23; p < 0.001), pathological stage (OR:1.14; 95% CI 1.07-1.22; p < 0.001), grade (OR:1.15; 95% CI 1.07-1.23; p < 0.001), presence of necrosis (OR:1.17; 95% CI 1.04-1.32; p = 0.01), and lymphovascular invasion (OR:1.18; 95% CI 1.01-1.37; p = 0.03) of primary RCC predicted a higher risk of RCCM + . Furthermore, number (OR:1.08; 95% CI 1.04-1.12; p < 0.001) and bilaterality (OR:1.23; 95% CI 1.09-1.38; p < 0.001) of pulmonary lesions predicted a higher risk of RCCM + . Survival analysis showed a median second PFS of 10.9 years (95% CI 3.3-not reached) for LC and a 3.8 years (95% CI 3.2-8.4) for RCCM + . The median OS time was 6.5 years (95% CI 4.4-not reached) for LC and 6 years (95% CI 4.3-11.6) for RCCM + . CONCLUSIONS: Smoking history, primary grade and stage of RCC, interval between RCC surgery and lung mass detection, and number of pulmonary lesions appear to be the most valuable predictors for differentiating new primary lung cancer from RCC progression.

Role of [68Ga]Ga-PSMA-11 PET radiomics to predict post-surgical ISUP grade in primary prostate cancer.

PURPOSE: The aim of this study is to investigate the role of [68Ga]Ga-PSMA-11 PET radiomics for the prediction of post-surgical International Society of Urological Pathology (PSISUP) grade in primary prostate cancer (PCa). METHODS: This retrospective study included 47 PCa patients who underwent [68Ga]Ga-PSMA-11 PET at IRCCS San Raffaele Scientific Institute before radical prostatectomy. The whole prostate was manually contoured on PET images and 103 image biomarker standardization initiative (IBSI)-compliant radiomic features (RFs) were extracted. Features were then selected using the minimum redundancy maximum relevance algorithm and a combination of the 4 most relevant RFs was used to train 12 radiomics machine learning models for the prediction of PSISUP grade: ISUP ≥ 4 vs ISUP < 4. Machine learning models were validated by means of fivefold repeated cross-validation, and two control models were generated to assess that our findings were not surrogates of spurious associations. Balanced accuracy (bACC) was collected for all generated models and compared with Kruskal-Wallis and Mann-Whitney tests. Sensitivity, specificity, and positive and negative predictive values were also reported to provide a complete overview of models' performance. The predictions of the best performing model were compared against ISUP grade at biopsy. RESULTS: ISUP grade at biopsy was upgraded in 9/47 patients after prostatectomy, resulting in a bACC = 85.9%, SN = 71.9%, SP = 100%, PPV = 100%, and NPV = 62.5%, while the best-performing radiomic model yielded a bACC = 87.6%, SN = 88.6%, SP = 86.7%, PPV = 94%, and NPV = 82.5%. All radiomic models trained with at least 2 RFs (GLSZM-Zone Entropy and Shape-Least Axis Length) outperformed the control models. Conversely, no significant differences were found for radiomic models trained with 2 or more RFs (Mann-Whitney p > 0.05). CONCLUSION: These findings support the role of [68Ga]Ga-PSMA-11 PET radiomics for the accurate and non-invasive prediction of PSISUP grade.

Boosting Interleukin-12 Antitumor Activity and Synergism with Immunotherapy by Targeted Delivery with isoDGR-Tagged Nanogold.

The clinical use of interleukin-12 (IL12), a cytokine endowed with potent immunotherapeutic anticancer activity, is limited by systemic toxicity. The hypothesis is addressed that gold nanoparticles tagged with a tumor-homing peptide containing isoDGR, an αvß3-integrin binding motif, can be exploited for delivering IL12 to tumors and improving its therapeutic index. To this aim, gold nanospheres are functionalized with the head-to-tail cyclized-peptide CGisoDGRG (Iso1) and murine IL12. The resulting nanodrug (Iso1/Au/IL12) is monodispersed, stable, and bifunctional in terms of αvß3 and IL12-receptor recognition. Low-dose Iso1/Au/IL12, equivalent to 18-75 pg of IL12, induces antitumor effects in murine models of fibrosarcomas and mammary adenocarcinomas, with no evidence of toxicity. Equivalent doses of Au/IL12 (a nanodrug lacking Iso1) fail to delay tumor growth, whereas 15 000 pg of free IL12 is necessary to achieve similar effects. Iso1/Au/IL12 significantly increases tumor infiltration by innate immune cells, such as NK and iNKT cells, monocytes, and neutrophils. NK cell depletion completely inhibits its antitumor effects. Low-dose Iso1/Au/IL12 can also increase the therapeutic efficacy of adoptive T-cell therapy in mice with autochthonous prostate cancer. These findings indicate that coupling IL12 to isoDGR-tagged nanogold is a valid strategy for enhancing its therapeutic index and sustaining adoptive T-cell therapy.

Radical Cystectomy in Pathological T4a and T4b Bladder Cancer Patients: Is There Any Space for Sub Stratification?

INTRODUCTION: According to TNM staging, pathological T4ab are comprehensive of the invasion of prostate, seminal vesicles, uterus or vagina and pelvic or abdominal wall. However, few data are available on the perioperative and oncological outcomes of specific organ invasion. MATERIALS AND METHODS: A total of 917 consecutive bladder cancer (BCa) patients treated with radical cystectomy (RC) at a single institution between 1990 and 2015 were studies. Cox regression analyses were used to stratify pT4ab according to the site of invasion and survival. RESULTS: Overall, 176 (19.2%) and 40 (4.4%) patients harbored pT4a or pT4b disease. Specifically, 84 (9.2%) patients reported prostate and/or SVI invasion, 62 (6.8%) prostate only, 16 (1.7%) uterus, 14 (1.5%) vaginal, 24 (2.6%) pelvic wall, and 16 (1.7%) abdominal wall invasion. The median follow-up in pT4 patients was 48 months. The 1-year cancer-specific mortality (CSM) rates were 71, 65, 24, 50, 50, and 72%, for vaginal, uterus, prostate only, prostate and/or seminal vesicles, pelvic wall, and abdominal wall invasions, respectively. At multivariable Cox regression, the invasion of prostate only (hazard ratio [HR] 3.53), prostate and/or SVI (HR 4.98), uterus (HR 7.16), vagina (HR 6.12), pelvic (HR 11.81), abdominal (8.36) were associated with adverse CSM. CONCLUSIONS: Our study described the differences in survival related to invasion site in pT4 patients, confirming poor survival expectancies in this subgroup. Patients with prostate invasion only seem to be associated with better survival than those affected by concomitant invasion of seminal vesicles. Uterus and vaginal invasions were associated with poor survival outcomes. Patients Summary: In this study, we looked at the outcome of locally advanced invasive BCa (stage pT4) in patients treated with RC at a tertiary referral hospital. We analyzed the differences in survival related to the specific organ invasion. We confirmed poor survival in this subgroup of patients. Only patients who had prostate invasion only seem to have a better survival.

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%.

Preoperative multiparametric MRI of the prostate for the prediction of lymph node metastases in prostate cancer patients treated with extended pelvic lymph node dissection.

OBJECTIVES: To assess the role of preoperative multiparametric MRI (mpMRI) of the prostate in the prediction of nodal metastases in patients treated with radical prostatectomy (RP) and extended pelvic lymph node dissection (ePLND). METHODS: We retrospectively analyzed 101 patients who underwent both preoperative mpMRI of the prostate and RP with ePLND at our institution. For each patient, complete preoperative clinical data and tumour characteristics at mpMRI were recorded. Final histopathologic stage was considered the standard of reference. Univariate and multivariate logistic regression analyses were performed. RESULTS: Nodal metastases were found in 23/101 (22.8%) patients. At univariate analyses, all clinical and radiological parameters were significantly associated to nodal invasion (all p<0.03); tumour volume at MRI (mrV), tumour ADC and tumour T-stage at MRI (mrT) were the most accurate predictors (AUC = 0.93, 0.86 and 0.84, respectively). A multivariate model including PSA levels, primary Gleason grade, mrT and mrV showed high predictive accuracy (AUC = 0.956). Observed prevalence of nodal metastases was very low among tumours with mrT2 stage and mrV<1cc (1.8%). CONCLUSION: Preoperative mpMRI of the prostate can predict nodal metastases in prostate cancer patients, potentially allowing a better selection of candidates to ePLND. KEY POINTS: • Multiparametric-MRI of the prostate can predict nodal metastases in prostate cancer • Tumour volume and stage at MRI are the most accurate predictors • Prevalence of nodal metastases is low for T2-stage and <1cc tumours • Preoperative mpMRI may allow a better selection of candidates to lymphadenectomy.

Impact of Prostate Involvement on Outcomes in Patients Treated with Radical Cystoprostatectomy for Bladder Cancer.

OBJECTIVE: The study aimed to evaluate the impact of the different types of prostate involvement at the time of radical cystoprostatectomy (RCP). METHODS: Data from 893 male patients treated with RCP at a referral center for bladder cancer (BCa) were assessed. Prostatic urothelial carcinoma (PUC) was stratified as stromal vs. urethral/duct involvements. Multivariable Cox regression analyses were built to test the impact of the presence of incidental prostate cancer (PCa) and PUC on survival outcomes. RESULTS: PCa was present in 319 (35.7%) RCP patients, of which 45 (14.1%) had significant PCa disease. PUC was identified in 181 patients (20%): 75 (41.1%) with urethral/duct involvement and 106 (58.6%) with stromal. Within a median follow-up of 72 months, stromal PUC, but not the other forms of PUC or PCa, was associated with worse survival outcomes. In multivariable analyses adjusted for the effects of standard features, stromal PUC remained associated with recurrence (hazards ratio [HR] 2.01, p = 0.03), cancer-specific mortality (HR 1.65, p = 0.01), and overall mortality (HR 1.45, p = 0.03). CONCLUSION: Prostatic stromal invasion with urothelial carcinoma confers a poor survival expectation to BCa patients after surgical treatment. Conversely, other type of urothelial prostatic invasions or the presence of concomitant PCa does not seem to be associated with differences in survival outcomes.

Impact of stage migration and practice changes on high-risk prostate cancer: results from patients treated with radical prostatectomy over the last two decades.

OBJECTIVE: To evaluate the impact of year of surgery on clinical, pathological and oncological outcomes of patients with high-risk prostate cancer. PATIENTS AND METHODS: We evaluated 1 033 patients with clinically high-risk prostate cancer, defined as the presence of at least one of the following risk factors: preoperative prostate-specific antigen (PSA) level >20 ng/mL, and/or clinical stage ≥T3, and/or biopsy Gleason score ≥8. Patients were treated between 1990 and 2013 at a single institution. The year-by-year trends in clinical and pathological characteristics were examined. Multivariable Cox regression analysis was used to test the relationship between year of surgery and oncological outcomes. RESULTS: We observed a decrease over time in the proportion of patients with high-risk disease (preoperative PSA >20 ng/mL or clinical stage cT3). A trend in the opposite direction was seen for biopsy Gleason score ≥8 tumours. We observed a considerable increase in the median number of lymph nodes removed, which was associated with an increased rate of lymph node invasion (LNI). On multivariable Cox regression analysis, year of surgery was associated with a reduced risk of biochemical recurrence (hazard ratio [HR] per 5-year interval 0.90, 95% confidence interval [CI] 0.84-0.96; P = 0.01) and distant metastasis (HR per 5-year interval 0.91, 95% CI 0.83-0.99; P = 0.039), after adjusting for age, preoperative PSA, pathological stage, LNI, surgical margin status, and pathological Gleason score. CONCLUSIONS: In this single-centre study, an increased diagnosis of localized and less extensive high-grade prostate cancer was observed over the last two decades. Patients with high-risk disease who were selected for radical prostatectomy showed better cancer control over time. Better definitions of what constitutes high-risk prostate cancer among contemporary patients are needed.

Lymphadenopathies in patients with renal cell carcinoma: clinical and pathological predictors of pathologically confirmed lymph node invasion.

INTRODUCTION: In renal cell carcinoma (RCC), lymph node status at preoperative imaging is affected by a non-negligible false-positive rate. We aimed to investigate which factors are related to a concordance between clinical suspicion and pathological confirmation of lymph node invasion (LNI). METHODS: At a single tertiary care institution, 2954 RCC patients underwent either partial or radical nephrectomy. For the aim of the study, only clinically positive lymph node cases were included (cN1). Statistical analyses assessed the concordance between preoperative and pathological nodal status. RESULTS: Preoperative axial CT scans revealed 424 (14.4 %) patients showing at least one enlarged lymph node suspected for LNI (cN1). All lymphadenopathies were removed at surgery, and LNI was pathologically confirmed (pN1) in 122 patients (28.8 %). When focusing the analyses on clinical characteristics (variables known before surgery), metastases at diagnosis [OR 3.0 (95 %1.9-4.8), p < 0.001] and tumor size [OR 1.1 (95 % 1.1-1.2), p < 0.001] were the two most informative predictors of concordance between clinical and pathological nodal status. Concordance was also more likely in patients with papillary type II tumors (55.6 %) relative to papillary type I (38.1 %), clear cell (27.7 %) and chromophobe (8.3 %) tumors. At multivariable analyses, none of the considered blood markers resulted to be independently associated with LNI. CONCLUSIONS: Roughly 70 % of patients showing a suspected lymph node preoperatively do not show LNI at the final pathological report. Among patients with clinically positive nodes, clinical tumor size and metastases at diagnosis represent the most informative and independent predictors of confirmed LNI at final pathology.

Oncological predictive value of the 2004 World Health Organisation grading classification in primary T1 non-muscle-invasive bladder cancer. A step forward or back?

OBJECTIVE: To compare the clinical reliability of the 1973 and 2004 World Health Organisation (WHO) classification systems in pT1 bladder cancer. PATIENTS AND METHODS: We retrospectively evaluated 291 consecutive patients who had pT1 high grade bladder cancer between 2004 and 2011. All tumours were simultaneously evaluated by a single uro-pathologist as high grade and G2 or G3. All patients underwent a second transurethral resection (TUR) and those confirmed with non-muscle-invasive bladder cancer at second TUR received bacille Calmette-Guérin. Follow-up included urine cytology and cystoscopy 3 months after second TUR and then every 6 months for 5 years. Univariate and multivariate analysis to determine recurrence-free survival (RFS) and progression-free survival (PFS) rates were performed using the Kaplan­Meier method with the log-rank test. RESULTS: G2 tumours were found in 124 (46.6%) and G3 in 142 (53.4%) patients. The mean (median; range) follow-up period was 31.1 (19; 1­93) months. The 5-year RFS rate was 39.1% for the overall high grade population, and 49.1 and 31.8% for G2 and G3 subgroups, respectively. The 5-year PFS was 82% for the overall high grade population and 89 and 73% for G2 and G3 subgroups, respectively. RFS (P < 0.002) and PFS (P < 0.001) rates were significantly different between the G2 and G3 subgroups. In multivariate analysis, only the grade assessed according to the 1973 WHO significantly correlated with both RFS (P = 0.003) and PFS (P < 0.001). CONCLUSION: The results suggest that the 1973 WHO classification system has higher prognostic reliability for patients with T1 disease. If confirmed, these findings should be carefully taken into account when making treatment decisions for patients with T1 bladder cancer.

Clinical performance of the Prostate Health Index (PHI) for the prediction of prostate cancer in obese men: data from the PROMEtheuS project, a multicentre European prospective study.

OBJECTIVES: To test serum prostate-specific antigen (PSA) isoform [-2]proPSA (p2PSA), p2PSA/free PSA (%p2PSA) and Prostate Health Index (PHI) accuracy in predicting prostate cancer in obese men and to test whether PHI is more accurate than PSA in predicting prostate cancer in obese patients. PATIENTS AND METHODS: The analysis consisted of a nested case-control study from the pro-PSA Multicentric European Study (PROMEtheuS) project. The study is registered at http://www.controlled-trials.com/ISRCTN04707454. The primary outcome was to test sensitivity, specificity and accuracy (clinical validity) of serum p2PSA, %p2PSA and PHI, in determining prostate cancer at prostate biopsy in obese men [body mass index (BMI) ≥30 kg/m(2) ], compared with total PSA (tPSA), free PSA (fPSA) and fPSA/tPSA ratio (%fPSA). The number of avoidable prostate biopsies (clinical utility) was also assessed. Multivariable logistic regression models were complemented by predictive accuracy analysis and decision-curve analysis. RESULTS: Of the 965 patients, 383 (39.7%) were normal weight (BMI <25 kg/m(2) ), 440 (45.6%) were overweight (BMI 25-29.9 kg/m(2) ) and 142 (14.7%) were obese (BMI ≥30 kg/m(2) ). Among obese patients, prostate cancer was found in 65 patients (45.8%), with a higher percentage of Gleason score ≥7 diseases (67.7%). PSA, p2PSA, %p2PSA and PHI were significantly higher, and %fPSA significantly lower in patients with prostate cancer (P < 0.001). In multivariable logistic regression models, PHI significantly increased accuracy of the base multivariable model by 8.8% (P = 0.007). At a PHI threshold of 35.7, 46 (32.4%) biopsies could have been avoided. CONCLUSION: In obese patients, PHI is significantly more accurate than current tests in predicting prostate cancer.

Percentage of high-grade tumour volume does not meaningfully improve prediction of early biochemical recurrence after radical prostatectomy compared with Gleason score.

OBJECTIVE: To examine whether percentage of tumour volume (%TV) and percentage of high-grade tumour volume (%HGTV) help to better identify men at higher risk of early biochemical recurrence (BCR) after radical prostatectomy (RP) for non-metastatic high-risk prostate cancer, as early BCR after RP might be associated with higher risk of metastases and cancer-specific mortality. PATIENTS AND METHODS: We examined the data of 595 men treated with RP for non-metastatic high-risk prostate cancer between 1992 and 2011 at two European tertiary care centres. Kaplan-Meier analyses were used to graphically depict 2-year BCR-free survival. Multivariable Cox regression models addressed early BCR. We tested whether addition of %TV and %HGTV to a multivariable Cox regression model helps to increase a model's predictive accuracy (PA) for prediction of early BCR. RESULTS: In all, 32 men (10%) with specimen-confined prostate cancer (pT2-pT3a, negative surgical margin, pN0) and 67 men (24%) with non-specimen-confined prostate cancer had early BCR. After stratification according to %HGTV (%HGTV threshold: ≤33.33 vs >33.33%), the 2-year BCR-free survival rates were respectively 93 vs 60% (log-rank P < 0.001). In multivariable Cox regression models %HGTV emerged as an independent predictor of early BCR (P < 0.001), whereas %TV did not (P > 0.05). However, adding %HGTV (regardless of its coding) to other covariates in multivariable Cox regression analysis did not increase the model's PA in a meaningful fashion compared with the use of the detailed Gleason grading system (6 vs 7a vs 7b vs 8 vs 9-10). CONCLUSIONS: In a large cohort of patients with high-risk prostate cancer, %HGTV and %TV did not improve prediction of early BCR after RP substantially, although %HGTV was an independent predictor of early BCR. Therefore, sophisticated TV/HGTV measurements do not seem to have additional benefit for early BCR prediction relative to the use of Gleason grading. However, these results need to be confirmed in larger, prospective studies.

The number of cores taken in patients diagnosed with a single microfocus at initial biopsy is a major predictor of insignificant prostate cancer.

PURPOSE: Patients with a single microfocus of prostate cancer at initial biopsy represent the ideal candidates for active surveillance. We investigate whether the number of cores taken affects the concordance rate between microfocus of prostate cancer and the confirmation of a pathologically insignificant prostate cancer at radical prostatectomy. MATERIALS AND METHODS: Data were analyzed from 233 patients with a single microfocus of prostate cancer at initial transrectal prostate biopsy (a single focus of Gleason 6 involving 5% or less of the core) subsequently treated with radical prostatectomy. The chi-square test, cubic spline analyses and logistic regression analyses were used to depict the relationship between the number of cores taken and the probability of confirming the presence of an indolent disease (pathologically confirmed insignificant prostate cancer defined as radical prostatectomy Gleason score 6 or less, tumor volume 0.5 ml or less and organ confined disease). RESULTS: Overall 65 patients (27.9%) showed pathologically confirmed insignificant prostate cancer at radical prostatectomy. The rate of pathologically confirmed insignificant prostate cancer was 3.8%, 29.6% and 39.4% in patients who underwent biopsy of 12 or fewer cores, 13 to 18 cores and 19 or more cores, respectively (p <0.001). After adjusting for the available confounders, age (p = 0.04), number of cores taken (p <0.001) and prostate specific antigen density (p <0.02) were independent predictors of pathologically confirmed insignificant prostate cancer. CONCLUSIONS: Of patients diagnosed with a single microfocus of prostate cancer the number of biopsy cores taken was a major independent predictor of having pathologically confirmed insignificant prostate cancer at radical prostatectomy. Therefore, when active surveillance is considered as a possible alternative in patients with microfocus of prostate cancer, the number of cores taken should be taken into account in decision making.

[68Ga]Ga-PSMA and [68Ga]Ga-RM2 PET/MRI vs. Histopathological Images in Prostate Cancer: A New Workflow for Spatial Co-Registration.

This study proposed a new workflow for co-registering prostate PET images from a dual-tracer PET/MRI study with histopathological images of resected prostate specimens. The method aims to establish an accurate correspondence between PET/MRI findings and histology, facilitating a deeper understanding of PET tracer distribution and enabling advanced analyses like radiomics. To achieve this, images derived by three patients who underwent both [68Ga]Ga-PSMA and [68Ga]Ga-RM2 PET/MRI before radical prostatectomy were selected. After surgery, in the resected fresh specimens, fiducial markers visible on both histology and MR images were inserted. An ex vivo MRI of the prostate served as an intermediate step for co-registration between histological specimens and in vivo MRI examinations. The co-registration workflow involved five steps, ensuring alignment between histopathological images and PET/MRI data. The target registration error (TRE) was calculated to assess the precision of the co-registration. Furthermore, the DICE score was computed between the dominant intraprostatic tumor lesions delineated by the pathologist and the nuclear medicine physician. The TRE for the co-registration of histopathology and in vivo images was 1.59 mm, while the DICE score related to the site of increased intraprostatic uptake on [68Ga]Ga-PSMA and [68Ga]Ga-RM2 PET images was 0.54 and 0.75, respectively. This work shows an accurate co-registration method for histopathological and in vivo PET/MRI prostate examinations that allows the quantitative assessment of dual-tracer PET/MRI diagnostic accuracy at a millimetric scale. This approach may unveil radiotracer uptake mechanisms and identify new PET/MRI biomarkers, thus establishing the basis for precision medicine and future analyses, such as radiomics.

Assessing the risk of lymph node invasion in patients with intermediate risk prostate cancer treated with extended pelvic lymph node dissection. A novel prediction tool.

BACKGROUND: Controversy exists regarding the need for extended pelvic lymph node dissection (ePLND) in patients with intermediate risk prostate cancer (PCa). MATERIALS AND METHODS: The study included 982 consecutive men with intermediate risk PCa (PSA 10­20 ng/ml or cT2b-c or biopsy Gleason 3 + 4/ 4 + 3) treated with ePLND and radical prostatectomy (RP) at a single center. All patients underwent an anatomically defined ePLND. A novel risk stratification tool was developed by applying the nonparametric tree modeling technique of classification and regression tree analysis (CART) which relied on pre-operative PSA, clinical stage, biopsy Gleason score, and percentage of positive cores. The area under the receiver characteristic curve (AUC) method was used to quantify the accuracy of the model. RESULTS: Lymph node invasion (LNI) was found in 81 (8.2%) patients. The CART analyses identified three risk groups of having LNI: a) Low risk: Gleason 3 + 3, cT1c/cT2, PSA 10-20 ng/ml, or Gleason 3 + 4/4 + 3, ≤ 63% of positive cores and PSA < 5 ng/ml (risk of LNI:3.7 and 5.2%, respectively; 64.8% of patients included); b) Moderate risk: Gleason 3 + 4/4 + 3, ≤ 63% of positive cores and PSA ≥ 5 ng/ml (risk of LNI:14.4%; 23% of patients included); c)High risk: Gleason 3 + 4/4 + 3, % positive cores >63% (risk of LNI:20.1%; 12.% of patients included; P < 0.001). The accuracy of the model was 71%. CONCLUSIONS: The risk of having LNI varies significantly (3.7­20.1%) in patients with intermediate risk PCa. Our predictive tool might help selecting those patients suitable fore PLND, allowing to spare this approach in about 60% of intermediate risk patients.

Lymphatic spread of nodal metastases in high-risk prostate cancer: The ascending pathway from the pelvis to the retroperitoneum.

BACKGROUND: The aim of this study was to map the nodal metastases distribution in patients with high-risk prostate cancer (PCa) treated with extended pelvic lymph node dissection (ePLND) and retroperitoneal lymph node dissection (rLND) at the time of radical prostatectomy (RP). MATERIALS AND METHODS: This prospective mapping study included 19 patients with high-risk PCa (sharing at least two out of the three following parameters: PSA >20 ng/ml, cT3, biopsy Gleason score ≥8). All patients were treated with RP, ePLND (removal of the obturator, hypogastric, external iliac, presacral, and common iliac lymph nodes) and rLND (removal of para-aortal/para-caval and inter-aorto-caval lymph nodes) by a single surgeon. All patients signed an informed consent highlighting the absence of clinical data supporting the benefit of this surgical approach. RESULTS: Overall, 18 out of 19 patients (94.7%) had pelvic lymph node invasion. The most commonly affected pelvic nodal landing site was obturator (88.8%), followed by external iliac (83.3%), common iliac (77%), hypogastric (44.4%), and presacral (33.3%). Moreover, 14 (77.8%) patients also had involvement of retroperitoneal lymph nodes. Only patients with positive common iliac lymph nodes having at least five positive lower pelvic lymph nodes (n = 14), also had invariably positive retroperitoneal lymph nodes. No patients with negative common iliac lymph nodes had positive retroperitoneal lymph nodes. CONCLUSIONS: PCa lymphatic spread ascends from the pelvis up to the retroperitoneum invariably through common iliac lymph nodes. PCa lymphatic spread can be divided in two main levels: pelvic and common iliac plus retroperitoneal lymph nodes.

There is no way to identify patients who will harbor small volume, unilateral prostate cancer at final pathology. implications for focal therapies.

BACKGROUND: The aim of this study was to assess the clinical characteristics of the potentially ideal candidates for focal therapy, that is, patients with unilateral, small volume (namely, pT2a) prostate cancer (PCa) at radical prostatectomy (RP). MATERIALS AND METHODS: We evaluated 2,503 consecutive pT2 PCa patients treated with RP between 2002 and 2009 at a single center. Within this population, the clinical characteristics of patients with pT2a and pT2b/c disease were compared. Univariable and multivariable logistic regression models were fitted to assess clinical predictors of pT2a at RP. RESULTS: Overall, 349 patients (14%) had pT2a PCa, while the remaining patients had either pT2b (n = 334; 15.5%) or pT2c disease (n = 1,820 patients; 84.5%). Patients with pT2a PCa had a significantly lower mean PSA value, lower mean percentage of positive biopsy cores and lower biopsy Gleason score distribution (all P ≤ 0.03). However, at multivariable analyses, only percentage of positive cores maintained an independent predictor status (P = 0.01). Even when considering only patients sharing all the most favorable PCa characteristics (namely, clinical stage T1, PSA ≤ 4, Gleason score ≤6 and percentage of positive cores ≤25%), the rate of pT2a disease was only 24%. CONCLUSIONS: The rate of small volume, unilateral PCa even among patients with extremely favourable PCa characteristics was remarkably low (roughly 25%). This suggests that: (1) Three quarters of the best candidates for focal therapy would ultimately show adverse pathological features; (2) At present, accurate identification of the ideal candidate for focal therapy is not possible with current clinical-pathologic parameters.

Age-adjusted validation of the most stringent criteria for active surveillance in low-risk prostate cancer patients.

BACKGROUND: The authors tested the performance of the currently used clinical criteria reported in populations studied by van den Bergh et al and Carter et al for the selection of patients with prostate cancer (PCa) for active surveillance (AS) according to age. METHODS: Data were analyzed from 893 patients who underwent with radical prostatectomy (RP). The authors investigated the rates of unfavorable PCa at RP (extracapsular extension, seminal vesicle or lymph node invasion, or Gleason score 7-10) in patients who fulfilled AS criteria according to age tertiles (ages ≤ 63 years, 63.1 to 69 years, and >69 years). Area under the curve (AUC) [corrected] analyses tested the criteria for predicting unfavorable PCa. Then, the patients were stratified according to the cutoff age of 70 years. Multivariate analyses were used to test the role of age in predicting unfavorable PCa. RESULTS: The rate of unfavorable PCa characteristics was between 24% and 27.8%. In the van den Bergh et al population, after age 70 years, the rate of unfavorable PCa characteristics was 41% compared with 23.2% and 24.1% in patients in the previous age tertiles (ages ≤ 63 years and 63.1 to 69 years, respectively). In the Carter et al population, the rate of unfavorable PCa was 41.2% compared with 17.3% and 18.6% in the previous age tertiles (ages ≤ 63 years and 63.1 to 69 years, respectively). When the 70-year age cutoff was used, unfavorable PCa was identified in 17.9% to 23.6% of patients aged <70 years versus 4% to 41.2% of patients aged >70 years (all P < .001). AUC analyses revealed significantly lower performance in older patients. In multivariate analyses, after adjustment for prostate-specific antigen, prostate volume, and the number of cores, age represented an independent predictor of unfavorable PCa. CONCLUSIONS: The currently used AS criteria performed significantly better for patients aged <70 years. The authors concluded that the current results should be taken into account when deciding whether to offer active surveillance to patients with low-risk PCa.