Precociously disseminated cancer cells may seed quiescent sites of future metastasis if they can protect themselves from immune surveillance. However, there is little knowledge about how such sites ...might be achieved. Here, we present evidence that prostate cancer stem-like cells (CSC) can be found in histopathologically negative prostate draining lymph nodes (PDLN) in mice harboring oncogene-driven prostate intraepithelial neoplasia (mPIN). PDLN-derived CSCs were phenotypically and functionally identical to CSC obtained from mPIN lesions, but distinct from CSCs obtained from frank prostate tumors. CSC derived from either PDLN or mPIN used the extracellular matrix protein Tenascin-C (TNC) to inhibit T-cell receptor-dependent T-cell activation, proliferation, and cytokine production. Mechanistically, TNC interacted with α5β1 integrin on the cell surface of T cells, inhibiting reorganization of the actin-based cytoskeleton therein required for proper T-cell activation. CSC from both PDLN and mPIN lesions also expressed CXCR4 and migrated in response to its ligand CXCL12, which was overexpressed in PDLN upon mPIN development. CXCR4 was critical for the development of PDLN-derived CSC, as in vivo administration of CXCR4 inhibitors prevented establishment in PDLN of an immunosuppressive microenvironment. Taken together, our work establishes a pivotal role for TNC in tuning the local immune response to establish equilibrium between disseminated nodal CSC and the immune system.
Abstract Background The management of patients with clinical recurrence of prostate cancer after radical prostatectomy (RP) remains challenging. Objective To determine whether the removal of positive ...lymph nodes at 11Ccholine positron emission tomography/computed tomography (PET/CT) scan may have an impact on the prognosis of patients with biochemical recurrence (BCR) and nodal recurrence after RP. Design, setting, and participants Prospective analysis of 72 patients affected by BCR after RP associated with a nodal pathologic 11Ccholine PET/CT scan. Intervention Patients underwent salvage lymph node dissection (LND). Measurements Biochemical response (BR) to treatment was defined as prostate-specific antigen (PSA) <0.2 ng/ml at 40 d after salvage LND. Kaplan-Meier and Cox regression analyses addressed time to and predictors of clinical recurrence (CR) after salvage LND, respectively. Results and limitations Overall, 56.9% of patients achieved BR. Mean and median follow-up after LND were 39.4 and 39.8 mo, respectively. The 5-yr BCR-free survival rate was 19%. Preoperative PSA <4 ng/ml (hazard ratio HR: 0.12; p = 0.005), time to BCR <24 mo (HR: 7.52; p = 0.005), and negative lymph nodes at previous RP (HR: 0.19; p = 0.04) represented independent predictors of BR. Overall, 5-yr CR-free and cancer-specific survival were 34% and 75%, respectively. At multivariable analyses, only PSA >4 ng/ml (HR: 2.13; p = 0.03) and the presence of retroperitoneal uptake at PET/CT scan (HR = 2.92; p = 0.004) represented independent preoperative predictors of CR. Similarly, the presence of pathologic nodes in the retroperitoneum (HR: 2.78; p = 0.02), higher number of positive lymph nodes (HR: 1.04; p = 0.006), and complete BR to salvage LND (HR: 0.31; p = 0.002) represented postoperative independent predictors of CR. Main limitations consisted of the lack of a control group and the heterogeneity of patients included in the analyses. Conclusions Salvage LND is feasible in patients with BCR after RP and nodal pathologic uptake at 11Ccholine PET/CT scan. Biochemical response after surgery can be achieved in a consistent proportion of patients. Although most patients invariably progressed to BCR after surgery at longer follow-up, 35% of patients showed the absence of CR at 5 yr.
Purpose
The aim of this study is to investigate the role of
68
GaGa-PSMA-11 PET radiomics for the prediction of post-surgical International Society of Urological Pathology (
PS
ISUP) grade in ...primary prostate cancer (PCa).
Methods
This retrospective study included 47 PCa patients who underwent
68
GaGa-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
PS
ISUP 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
68
GaGa-PSMA-11 PET radiomics for the accurate and non-invasive prediction of
PS
ISUP grade.
Abstract Background Currently available predictive models fail to assist clinical decision making in prostate cancer (PCa) patients who are potential candidates for radical prostatectomy (RP). New ...biomarkers would be welcome. Objective To test the hypothesis that prostate-specific antigen (PSA) isoform p2PSA and its derivatives, percentage of p2PSA to free PSA (%p2PSA) and the Prostate Health Index (PHI), predict PCa characteristics at final pathology. Design, setting, and participants An observational prospective multicentre European study was performed in 489 consecutive PCa patients treated with RP. Total PSA (tPSA), free PSA (fPSA), and p2PSA levels were determined. The %fPSA (fPSA / tPSA) × 100, %p2PSA (p2PSA pg/ml) / (fPSA ng/ml × 1000) × 100, and PHI (p2PSA / fPSA) × √tPSA were calculated. Intervention Open or robot-assisted RP. Outcome measurements and statistical analysis Logistic regression models were fitted to test the predictors of pT3 stage and/or pathologic Gleason score (GS) ≥7 and to determine their predictive accuracy. The base multivariable model included tPSA, digital rectal examination, biopsy GS, and percentage of positive biopsy cores. Decision curve analysis provided an estimate of the net benefit obtained using p2PSA, %p2PSA, or PHI. Results and limitations Overall, 344 patients (70%) were affected by pT3 disease or pathologic GS ≥7; pT3 disease and pathologic GS ≥7 were present in 126 patients (26%). At univariable analysis, p2PSA, %p2PSA, and PHI were significant predictors of pT3 disease and/or pathologic GS ≥7 (all p ≤ 0.001). The inclusion of PHI significantly increased the accuracy of the base multivariable model by 2.3% ( p = 0.003) and 2.4% ( p = 0.01) for the prediction of pT3 disease and/or pathologic GS ≥7, respectively. However, at decision curve analysis, models including PHI did not show evidence of a greater clinical net benefit. Conclusions Both %p2PSA and PHI are significant predictors of unfavourable PCa characteristics at final pathology; however, %p2PSA and PHI did not provide a greater net benefit for clinical decision making. Patient summary Prostate-specific antigen (PSA) isoform p2PSA and its derivatives, percentage of p2PSA to free PSA and the Prostate Health Index, are associated with adverse characteristics of prostate cancer; however, these biomarkers provided only a slight net benefit for clinical decision making.
Abstract Background Currently, the 2002 American Joint Committee on Cancer (AJCC) staging system of prostate cancer does not include any stratification of patients according to the number of positive ...nodes. However, node positive (N+) patients share heterogeneous outcomes according to the extent of lymph node invasion (LNI). Objective To test whether the accuracy of cancer specific survival (CSS) predictions may be improved if node positive patients are stratified according to the number of positive nodes. Design, Setting, and Participants The study cohort included 703 N+ M0 patients treated with radical prostatectomy (RP) and extended pelvic lymph node dissection (ePLND) between September 1988 and January 2003 at two large Academic Institutions. Number of positive nodes was dichotomized according to the most informative cut-off predicting CSS. Kaplan-Meier curves assessed cancer specific survival rates. Predictive accuracy of the current N stage and of the new N classification in predicting CSS was quantified with Harrell's concordance index after adjusting for pathological (T) stage and internally validated with 200 boostraps resamples. Differences in predictive accuracy were compared with the Mantel-Haentzel test. Results and Limitations Mean follow-up was 113.7 months (median: 112.5, range 3.5–243). The mean number of nodes removed was 13.9 (range: 2–52). The mean number of positive nodes was 2.3 (range: 1–31). The most informative cut-off of positive nodes in predicting CSS was 2. Of all, 532 (75.7%) patients had 2 or less positive nodes, while 171 (24.3%) had more than 2 positive nodes. Patients with 2 or less positive nodes had significantly better CSS outcome at 15 year follow-up compared to patients with more than 2 positive nodes (84% vs 62%; p < 0.001). After adjusting for pathological stage, multivariable predictive accuracy of the new N staging (≤2 or >2 positive nodes) was 65.0% vs 60.1% when the number of positive nodes was not considered (4.9% gain; p < 0.001). Conclusions We demonstrated that patients with up to 2 positive nodes experienced excellent CSS, which was significantly higher compared to patients with more than 2 positive nodes. Moreover, a significant improvement in CSS prediction was reached when the number of positive nodes was considered. Thus, our results reinforce the need for a stratification of node positive patients according to the number of positive nodes and may warrant consideration in the next revision of the pathologic TNM classification.
The prognostic value of histopathologic features was assessed in 83 patients with stage I-II gastric B-cell lymphomas (PGL). The following histotypes were considered: low-grade mucosa-associated ...lymphoid tissue (MALT)-type lymphoma (LGML; n = 35), diffuse large B-cell lymphoma with areas of MALT-type lymphoma (DLCLML; n = 20) and diffuse large B-cell lymphoma without areas of MALT-type lymphoma (DLCL; n = 28). Low-grade (LG) and high-grade (HG) components, lymphoepithelial lesions (LEL), size of cells giving rise to LEL, and amount and growth pattern of large cells (LC) were analyzed. Five-year cause-specific survival (CSS) for patients with LGML, DLCLML, and DLCL were 94%, 84%, and 64%, respectively (p = 0.05). LG component or LEL were associated with a significantly longer 5-year CSS, whereas the presence of an HG component, defined as clustered LC greater than 10% of neoplastic population, was significantly related to a shorter survival. Lymphomas with LC disposed in clusters were associated with a worse survival in comparison with cases with scattered LC. The presence of scattered LC 5%-10% appeared irrelevant in LGML. When analysis was limited to DLCLML/ DLCL patients, the presence of LG component or LEL was associated with a significantly longer 5-year CSS, whereas the existence of LEL formed by LC (HG LEL) did not modify survival. Multivariate analysis, adjusted by the main prognostic factors, confirmed the independent and significant association between histopathologic categorization and survival. Age, stage, lactate dehydrogenase (LDH) ratio, thrombocytopenia, and use of chemotherapy had independent prognostic value. In conclusion, histopathologic categorization is an independent prognosticator in PGL. The formation of compact clusters by LC, rather than their amount, is a true prognostic variable. The presence of scattered LC 5%-10% appears irrelevant in LGML. LG component and LEL are favorable predictors in HG lymphomas, helping to identify two subsets of DLCL with different prognosis.
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
Abstract Objectives To prospectively evaluate the accuracy of integrated 11 Ccholine-PET/CT in the diagnosis of lymph-node recurrence in prostate cancer patients with biochemical failure after ...surgery. Methods Since October 2002, 25 patients with biochemical recurrence (median PSA: 1.98 ng/ml), based on evidence of lymph-node metastases on 11 Ccholine-PET/CT scan (21 cases) or conventional imaging (4 cases), were scheduled for either bilateral pelvic (12 cases) or both pelvic and retroperitoneal lymph-node dissection (13 patients). Results Sixty-three nodal sites were evaluated histologically. The mean number of nodes removed and positive nodes were 21.92 ± 16.91 (range: 4–74) and 8.84 ± 9.65 (range: 1–31), respectively. Of the four patients with negative 11 Ccholine-PET/CT and positive magnetic resonance, none had nodal metastases. Nineteen of the 21 patients (90%) with positive 11 Ccholine-PET/CT had nodal metastases of prostate adenocarcinoma at histologic evaluation. A lesion-based analysis showed that 11 Ccholine-PET/CT sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 64%, 90%, 86%, 72%, and 77%, respectively. The mean maximum diameter of true positive metastases was larger than false-negative ones (15.0 vs. 6.3 mm; p = 0.0004). Conclusions 11 CCholine-PET/CT is an accurate diagnostic tool for the detection of lymph-node metastases of recurrent prostate cancer. The low negative predictive value seems to depend on the limited capability of 11 Ccholine-PET/CT to detect microscopic lesions. The high positive predictive value, even with low PSA values, provides a basis for further treatment decisions.
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%.
Abstract Background Computed tomography (CT) is a commonly used noninvasive procedure for prostate cancer (PCa) staging. All previous studies addressing the ability of CT scan to predict lymph node ...invasion (LNI) were based on historical patients treated with limited pelvic lymph node dissection (PLND). Objective Assess the value of CT in predicting LNI in contemporary PCa patients treated with extended PLND (ePLND). Design, setting, and participants We evaluated 1541 patients undergoing radical prostatectomy and ePLND between 2003 and 2010 at a single center. All patients were preoperatively staged using abdominopelvic CT scan. All lymph nodes with a short axis diameter ≥10 mm were considered suspicious for metastatic involvement. Intervention All patients underwent preoperative CT scan, radical retropubic prostatectomy, and ePLND, regardless of PCa features at diagnosis. Measurements The performance characteristics of CT scan were tested in the overall patient population, as well as according to the National Comprehensive Cancer Network (NCCN) classification and according to the risk of LNI derived from a nomogram developed on an ePLND series. Logistic regression models tested the relationship between CT scan findings and LNI. Discrimination accuracy was quantified with the area under the curve. Results and limitations Overall, a CT scan that suggested LNI was found in 73 patients (4.7%). Of them, only 24 patients (32.8%) had histologically proven LNI at ePLND. Overall, sensitivity, specificity, and accuracy of CT scan were 13%, 96.0%, and 54.6%, respectively. In patients with low-, intermediate-, or high-risk PCa according to NCCN classification, sensitivity was 8.3%, 96.3%, and 52.3%, respectively; specificity was 3.6%, 97.3%, and 50.5%, respectively; and accuracy was 17.9%, 94.3%, and 56.1%, respectively. Similarly, in patients with a nomogram-derived LNI risk ≥50%, sensitivity, specificity, and accuracy were only 23.9%, 94.7%, and 59.3%, respectively. At multivariable analyses, inclusion of CT scan findings did not improve the accuracy of LNI prediction (81.4% compared with 81.3%; p = 0.8). Lack of a central scan review represents the main limitation of our study. Conclusions In contemporary patients with PCa, the accuracy of CT scan as a preoperative nodal-staging procedure is poor, even in patients with high LNI risk. Therefore, the need for and the extent of PLND should not be based on the results obtained by CT scan.
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