Abstract Background Preoperative assessment of the risk of lymph node invasion (LNI) is mandatory to identify prostate cancer (PCa) patients who should receive an extended pelvic lymph node ...dissection (ePLND). Objective To update a nomogram predicting LNI in contemporary PCa patients with detailed biopsy reports. Design, setting, and participants Overall, 681 patients with detailed biopsy information, evaluated by a high-volume uropathologist, treated with radical prostatectomy and ePLND between 2011 and 2016 were identified. Outcome measurements and statistical analysis A multivariable logistic regression model predicting LNI was fitted and represented the basis for a coefficient-based nomogram. The model was evaluated using the receiver operating characteristic-derived area under the curve (AUC), calibration plot, and decision-curve analyses (DCAs). Results and limitations The median number of nodes removed was 16. Overall, 79 (12%) patients had LNI. A multivariable model that included prostate-specific antigen, clinical stage, biopsy Gleason grade group, percentage of cores with highest-grade PCa, and percentage of cores with lower-grade disease represented the basis for the nomogram. After cross validation, the predictive accuracy of these predictors in our cohort was 90.8% and the DCA demonstrated improved risk prediction against threshold probabilities of LNI ≤20%. Using a cutoff of 7%, 471 (69%) ePLNDs would be spared and LNI would be missed in seven (1.5%) patients. As compared with the Briganti and Memorial Sloan Kettering Cancer Center nomograms, the novel model showed higher AUC (90.8% vs 89.5% vs 89.5%), better calibration characteristics, and a higher net benefit at DCA. Conclusions An ePLND should be avoided in patients with detailed biopsy information and a risk of nodal involvement below 7%, in order to spare approximately 70% ePLNDs at the cost of missing only 1.5% LNIs. Patient summary We developed a novel nomogram to predict lymph node invasion (LNI) in patients with clinically localized prostate cancer based on detailed biopsy reports. A lymph node dissection exclusively in men with a risk of LNI > 7% according to this model would significantly reduce the number of unnecessary pelvic nodal dissections with a risk of missing only 1.5% of patients with LNI.
Irregular blood flow and endothelial cell anergy, which characterize many solid tumors, hinder tumor infiltration by cytotoxic T lymphocytes (CTL). This confers resistance to cancer immunotherapy ...with monoclonal antibodies directed against regulatory pathways in T lymphocytes (i.e., immune checkpoint blockade, ICB). We investigated whether NGR-TNF, a TNF derivative capable of targeting the tumor vasculature, and improving intratumor infiltration by activated CTLs, could sensitize tumors to ICB with antibodies specific for the PD-1 and CTLA-4 receptors.
Transgenic adenocarcinoma of the mouse prostate (TRAMP) mice with autochthonous prostate cancer and C57BL/6 mice with orthotopic B16 melanoma were treated with NGR-TNF, adoptive T-cell therapy (ACT), and ICB, and monitored for immune surveillance and disease progression.
The combination of ACT, NGR-TNF, and ICB was the most effective in delaying disease progression, and in improving overall survival of mice bearing ICB-resistant prostate cancer or melanoma. Mechanistically, the therapeutic effects were associated with potent tumor infiltration, especially by endogenous but also by adoptively transferred PD-1
, granzyme B
, and interferon-γ
CTLs. The therapeutic effects were also associated with favorable T-effector/regulatory T cell ratios.
Targeting the tumor vasculature with low-dose TNF in association with ACT may represent a novel strategy for enhancing T-cell infiltration in tumors and overcoming resistance to immune checkpoint blockers.
.
Abstract Background Strategies to reduce prostate-specific antigen (PSA)–driven prostate cancer (PCa) overdiagnosis and overtreatment seem to be necessary. Objective To test the accuracy of serum ...isoform −2proPSA (p2PSA) and its derivatives, percentage of p2PSA to free PSA (fPSA; %p2PSA) and the Prostate Health Index (PHI)—called index tests —in discriminating between patients with and without PCa. Design, setting, and participants This was an observational, prospective cohort study of patients from five European urologic centers with a total PSA (tPSA) range of 2–10 ng/ml who were subjected to initial prostate biopsy for suspected PCa. Outcome measurements and statistical analysis The primary end point was to evaluate the specificity, sensitivity, and diagnostic accuracy of index tests in determining the presence of PCa at prostate biopsy in comparison to tPSA, fPSA, and percentage of fPSA to tPSA (%fPSA) (standard tests) and the number of prostate biopsies that could be spared using these tests. Multivariable logistic regression models were complemented by predictive accuracy analysis and decision curve analysis. Results and limitations Of >646 patients, PCa was diagnosed in 264 (40.1%). Median tPSA (5.7 vs 5.8 ng/ml; p = 0.942) and p2PSA (15.0 vs 14.7 pg/ml) did not differ between groups; conversely, median fPSA (0.7 vs 1 ng/ml; p < 0.001), %fPSA (0.14 vs 0.17; p < 0.001), %p2PSA (2.1 vs 1.6; p < 0.001), and PHI (48.2 vs 38; p < 0.001) did differ significantly between men with and without PCa. In multivariable logistic regression models, p2PSA, %p2PSA, and PHI significantly increased the accuracy of the base multivariable model by 6.4%, 5.6%, and 6.4%, respectively (all p < 0.001). At a PHI cut-off of 27.6, a total of 100 (15.5%) biopsies could have been avoided. The main limitation is that cases were selected on the basis of their initial tPSA values. Conclusions In patients with a tPSA range of 2–10 ng/ml, %p2PSA and PHI are the strongest predictors of PCa at initial biopsy and are significantly more accurate than tPSA and %fPSA. Trial registration The study is registered at http://www.controlled-trials.com , ref. ISRCTN04707454.
Abstract Background Currently available predictive models fail to assist clinical decision making in prostate cancer (PCa) patients who are possible candidates for radical prostatectomy (RP). New ...biomarkers would be welcome. Objective Test the hypothesis that prostate-specific antigen (PSA) isoform p2PSA and its derivates, percentage of p2PSA to free PSA (%p2PSA) and the Prostate Health Index (PHI), predict PCa characteristics at final pathology after RP. Design, setting, and participants An observational prospective study was performed in 350 consecutive men diagnosed with clinically localised PCa who underwent RP. Measurements We determined the predictive accuracy of serum total PSA (tPSA), free PSA (fPSA), fPSA-to-tPSA ratio (%fPSA), p2PSA, %p2PSA, and PHI. The primary end point was to determine the accuracy of these biomarkers in predicting the presence of pT3 disease, pathologic Gleason sum ≥7, Gleason sum upgrading, and tumour volume <0.5 ml. Intervention Open retropubic and robot-assisted laparoscopic RP was performed. Pelvic lymphadenectomy was performed according to baseline oncologic parameters and the surgeon's judgement. Results and limitations The %p2PSA and PHI levels were significantly higher in patients with pT3 disease, pathologic Gleason sum ≥7, and Gleason sum upgrading (all p values <0.001). Conversely, %p2PSA and PHI levels were significantly lower in patients with tumour volume <0.5 ml ( p < 0.001). By univariate analysis, both %p2PSA and PHI were accurate predictors of pT3 disease, pathologic Gleason sum ≥7, Gleason sum upgrading, and tumour volume <0.5 ml. By multivariate analyses, the inclusion of both %p2PSA and PHI significantly increased the predictive accuracy of a base multivariate model (excluding the tumour volume prediction for both variables, and Gleason sum upgrading for the model including %p2PSA) that included patient age, tPSA, fPSA, f/tPSA, clinical stage, and biopsy Gleason sum. Conclusions We found that p2PSA and its derivatives are predictors of PCa characteristics at final pathology after RP and are more accurate than currently available markers.
To determine the clinical benefit of high-dose early adjuvant radiotherapy (EART) in high-risk prostate cancer (hrCaP) patients submitted to radical retropubic prostatectomy plus pelvic ...lymphadenectomy.
The clinical outcome of 334 hrCaP (pT3-4 and/or positive resection margins) node-negative patients submitted to radical retropubic prostatectomy plus pelvic lymphadenectomy before 2004 was analyzed according to the EART dose delivered to the prostatic bed, <70.2 Gy (lower dose, median 66.6 Gy, n = 153) or >or=70.2 Gy (median 70.2 Gy, n = 181).
The two groups were comparable except for a significant difference in terms of median follow-up (10 vs. 7 years, respectively) owing to the gradual increase of EART doses over time. Nevertheless, median time to prostate-specific antigen (PSA) failure was almost identical, 38 and 36 months, respectively. At univariate analysis, both 5-year biochemical relapse-free survival (bRFS) and disease-free survival (DFS) were significantly higher (83% vs. 71% p = 0.001 and 94% vs. 88% p = 0.005, respectively) in the HD group. Multivariate analysis confirmed EART dose >or=70 Gy to be independently related to both bRFS (hazard ratio 2.5, p = 0.04) and DFS (hazard ratio 3.6, p = 0.004). Similar results were obtained after the exclusion of patients receiving any androgen deprivation. After grouping the hormone-naïve patients by postoperative PSA level the statistically significant impact of high-dose EART on both 5-year bRFS and DFS was maintained only for those with undetectable values, possibly owing to micrometastatic disease outside the irradiated area in case of detectable postoperative PSA values.
This series provides strong support for the use of EART doses >or=70 Gy after radical retropubic prostatectomy in hrCaP patients with undetectable postoperative PSA levels.
Galectin-3 (Gal-3) is an extracellular matrix glycan-binding protein with several immunosuppressive and pro-tumor functions. The role of Galectin-3 in cancer stem-like cells (CSCs) is poorly ...investigated. Here, we show that prostate CSCs also colonizing prostate-draining lymph nodes of transgenic adenocarcinoma of the mouse prostate (TRAMP) mice overexpress Gal-3. Gal-3 contributes to prostate CSC-mediated immune suppression because either Gal-3 silencing in CSCs, or co-culture of CSCs and T cells in the presence of the Gal-3 inhibitor N-Acetyl-D-lactosamine rescued T cell proliferation. N-Acetyl-D-lactosamine also rescued the proliferation of T cells in prostate-draining lymph nodes of TRAMP mice affected by prostate intraepithelial neoplasia. Additionally, Gal-3 impacted prostate CSC tumorigenic and metastatic potential
, as Gal-3 silencing in prostate CSCs reduced both primary tumor growth and secondary invasion. Gal-3 was also found expressed in more differentiated prostate cancer cells, but with different intracellular distribution as compared to CSCs, which suggests different functions of Gal-3 in the two cell populations. In fact, the prevalent nuclear and cytoplasmic distribution of Gal-3 in prostate CSCs made them less susceptible to apoptosis, when compared to more differentiated prostate cancer cells, in which Gal-3 was predominantly intra-cytoplasmic. Finally, we found Gal-3 expressed in human and mouse prostate intraepithelial neoplasia lesions and in metastatic lymph nodes. All together, these findings identify Gal-3 as a key molecule and a potential therapeutic target already in the early phases of prostate cancer progression and metastasis.
Purpose We tested the hypothesis that serum isoform -2proPSA derivatives %p2PSA and Prostate Health Index are accurate predictors of prostate cancer in men scheduled for repeat biopsy. Materials and ...Methods The study was an observational prospective evaluation of a clinical cohort of men with 1 or 2 previous negative prostate biopsies, with persistent suspicion of prostate cancer. They were enrolled in the study to determine the diagnostic accuracy of %p2PSA using the formula, (p2PSA pg/ml)/(free prostate specific antigen ng/ml × 1,000)× 100, and Beckman-Coulter Prostate Health Index using the formula, (p2PSA/free prostate specific antigen) × √total prostate specific antigen), and to compare it with the accuracy of established prostate cancer serum tests (total prostate specific antigen, free prostate specific antigen and percent free prostate specific antigen). Multivariable logistic regression models were complemented by predictive accuracy analysis and decision curve analysis. Results Prostate cancer was found in 71 of 222 (31.9%) subjects. %p2PSA and Prostate Health Index were the most accurate predictors of disease. %p2PSA significantly outperformed total prostate specific antigen, free prostate specific antigen, percent free prostate specific antigen and p2PSA in the prediction of prostate cancer (p ≤0.01), but not Prostate Health Index (p = 0.094). Prostate Health Index significantly outperformed total prostate specific antigen and p2PSA (p ≤0.001) but not free prostate specific antigen (p = 0.109) and free/total prostate specific antigen (p = 0.136). In multivariable logistic regression models %p2PSA and Prostate Health Index achieved independent predictor status, and significantly increased the accuracy of multivariable models including prostate specific antigen and prostate volume with or without percent free prostate specific antigen and prostate specific antigen density by 8% to 11% (p ≤0.034). At a %p2PSA cutoff of 1.23, 153 (68.9%) biopsies could have been avoided, missing prostate cancer in 6 patients. At a Prostate Health Index cutoff of 28.8, 116 (52.25%) biopsies could have been avoided, missing prostate cancer in 6 patients. Conclusions Serum %p2PSA and Prostate Health Index are more accurate than standard reference tests in predicting repeat prostate biopsy outcome, and could avoid unnecessary repeat biopsies.
Abstract Objective To test the expandability of active surveillance (AS) to Gleason score 3+4 cancers by assessing the unfavorable disease risk in a large multi-institutional cohort. Materials and ...methods We performed a retrospective analysis including 2,323 patients with localized Gleason score 3+4 prostate cancer who underwent a radical prostatectomy between 2005 and 2013 from 6 academic centers. We analyzed the rates of biopsy downgrading/upgrading and advanced stage in the overall cohort by employing standardized AS criteria (using biopsy Gleason score 3+4). Results The final pathologic Gleason score was 3+3 = 6 in 8%, 3+4 = 7 in 67%, 4+3 = 7 in 20%, and 8 to 10 in 5% cases. The overall rate of unfavorable disease (upgrading or advanced stage or both) was 46%. In multivariable analysis, prostate-specific antigen (PSA) level>10 ng/ml, PSA density (PSAD) >0.15 ng/ml/g, clinical stage >T1, and>2 positive cores were predictors of unfavorable disease. According to the AS criteria used, the risk of unfavorable disease ranged from 30% to 42%. In patients without any risk factor (PSA level≤10 ng/ml, PSAD ≤0.15 ng/ml/g, T1c, and≤2 positive cores), the unfavorable disease rate was 19%. The main limitations of this study are the retrospective design and nonstandardization of pathologic assessment between centers. Conclusions Approximately half of patients with biopsy Gleason score 3+4 cancer have unfavorable disease at final pathology. Nevertheless, expanding AS eligibility to these patients may be acceptable provided adherence to strict selection criteria leading to a<20% risk of unfavorable disease. Future tools for selection such as magnetic resonance imaging, early rebiopsy, and serum markers may be especially beneficial in this group of patients.
Abstract Objective Positron emission tomography (PET)/computed tomography (CT) has been shown to be a valid tool in detecting lymph node (LN) metastases in men with biochemical recurrence after ...radical prostatectomy. We assessed its validity in detecting a single positive LN at pathologic examination in regard to an increasing interest in lesion-targeted salvage therapies. Methods and materials We included 46 patients with biochemical recurrence after radical prostatectomy and a single positive spot at 11 Ccholine PET/CT who underwent pelvic or pelvic and retroperitoneal LN dissection. The ability of 11 Ccholine PET/CT in identifying the exact positive LN was assessed with the positive predictive value (PPV) in the overall population and according to androgen deprivation therapy, prostate-specific antigen value, and site of PET/CT positivity. Results Overall, 30 patients (65%) had positive LNs at pathologic examination. Of these, only 16 (35%) had pathologically confirmed metastases in the same lymphatic region and 11 (24%) had involvement of 1 single LN. Conversely, 28 patients had positive LNs in other areas and 8 had no evidence of metastases. The overall PPV of PET/CT was 34.8% and 23.9% when exact concordance was defined according to the lymphatic landing site and single positive LN, respectively. The PPV ranged from 33.3% to 44.4% and from 17.9% to 28.6%, in men with and without androgen deprivation therapy, respectively. Conclusions The PPV 11 Ccholine of PET/CT in correctly identifying patients with a single positive LN at salvage LN dissection is poor (24%). Therefore, extensive salvage treatment approaches are needed to maximize the chance of cure.
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