Prostate Cancer Lymph Node Research Articles

Increased Paxillin expression in prostate cancer is associated with advanced pathological features, lymph node metastases and biochemical recurrence

Purpose Paxillin regulates cell-cell adhesion, and altered Paxillin expression has been associated with human carcinogenesis. This study analyzed the association between Paxillin expression in prostate cancer (PCa) tissues with clinicopathological features, lymph node metastasis and biochemical PCa recurrence.Methods A total of 386 tissue specimens from PCa patients who received radical prostatectomy and 60 tissue specimens from benign prostatic hyperplasia (BPH) cases were collected to construct tissue microarrays, which were subsequently immunostained for Paxillin expression. Thirty positive lymph node tissue specimens and 10 healthy prostate tissue specimens were randomly selected for Paxillin immunostaining.Results The association between Paxillin expression, lymph node metastasis and biochemical PCa recurrence was analyzed. Paxillin expression was significantly higher in PCa than both normal and BPH tissues (P<0.001) and was correlated with preoperative prostate-specific antigen level, Gleason score, clinical tumor stage, lymph node metastasis, positive surgical margin, extracapsular extension and seminal vesicle invasion (P<0.05 for all). Logistic regression analysis showed that Paxillin and Gleason score were independent risk factors for PCa lymph node metastasis (P<0.05). The receiver operating characteristic (ROC) curve indicated that Paxillin expression (AUC=0.723) more accurately predicted PCa lymph node metastasis than Gleason score (AUC=0.692). Kaplan-Meier curve analysis showed that increased Paxillin expression was associated with shortened biochemical-free survival (BFS) after radical prostatectomy (P<0.001).Conclusion Paxillin was significantly upregulated in PCa compared with BPH and normal tissues and associated with lymph node metastasis and shortened BFS of PCa. Further study will investigate the underlying molecular mechanism and the role of Paxillin in PCa.

Contemporary Incidence and Outcomes of Prostate Cancer Lymph Node Metastases

The incidence of localized prostate cancer has decreased with shifts in prostate cancer screening. While recent population based studies demonstrated a stable incidence of locoregional prostate cancer, they categorized organ confined, extraprostatic and lymph node positive disease together. However, to our knowledge the contemporary incidence of prostate cancer with pelvic lymph node metastases remains unknown. We used SEER (Surveillance, Epidemiology and End Results) data from 2004 to 2014 to identify men diagnosed with prostate cancer. We analyzed trends in the age standardized prostate cancer incidence by stage. The impact of disease extent on mortality was assessed by adjusted Cox proportional hazard analysis. During the study period the annual incidence of nonmetastatic prostate cancer decreased from 5,119.1 to 2,931.9 per million men (IR 0.57, 95% CI 0.56-0.58, p <0.01) while the incidence of pelvic lymph node metastases increased from 54.1 to 79.5 per million men (IR 1.47, 95% CI 1.33-1.62, p <0.01). The incidence of distant metastases in men 75 years old or older reached a nadir in 2011 compared to 2004 (IR 0.81, 95% CI 0.74-0.90, p <0.01) and it increased in 2012 compared to 2011 (IR 1.13, 95% CI 1.02-1.24, p <0.05). The risk of cancer specific mortality significantly increased in men diagnosed with pelvic lymph node metastases (HR 4.5, 95% CI 4.2-4.9, p <0.01) and distant metastases (HR 21.9, 95% CI 21.2-22.7, p <0.01) compared to men with nonmetastatic disease. The incidence of pelvic lymph node metastases is increasing coincident with a decline in the detection of localized disease. Whether this portends an increase in the burden of advanced disease or simply reflects decreased lead time remains unclear. However, this should be monitored closely as the increase in N1 disease reflects an increase in incurable prostate cancer at diagnosis.

Value of multi-modal image-guided transrectal ultrasonography in the diagnosis of prostatic nodules in elderly patients

Objective To assess the value of multi-modal image-guided transrectal ultrasonography in the diagnosis of prostatic nodules in elderly patients. Methods Sixty-four elderly patients suspected of prostate cancer (PCA) were enrolled from December 2015 to December 2016.Sixty-four patients with 72 nodules underwent transrectal ultrasound (TRUS), contrast-enhanced transrectal ultrasound (CETRUS) and transrectal real-time tissue elastography (TRTE). A combination of systematic biopsy and suspicious site-targeted biopsy was conducted.The accuracies of different detection methods for prostate cancer were assessed against the gold standard of histological examination of prostate biopsy samples. Results Among the 72 nodules, 31 were prostatic hyperplasia, 5 were chronic prostatitis, 35 were prostatic cancer, and one was prostatic lymphoma.There were significant differences in enhancement strength, enhancement time fast-in and degree of elasticity on TRTE and CETRUS between the malignant and benign groups (χ2=28.794, 10.889, 52.898; P=0.000, 0.001, 0.000, respectively). When the 35 PCA nodules were divided into two subgroups based on the Gleason score, there were statistically significant differences in enhancement strength, homogeneity of enhancement, and enhancement time fast-in and fast-out between them (χ2=6.073, 12.315, 4.717, 18.093; P=0.048, 0.001, 0.030, 0.000, respectively). The combination of CETRUS and TRTE in diagnosing prostate nodules produced a sensitivity of 83.3%, a specificity of 86.1%, an accuracy of 84.7%, a positive predictive value of 85.7%, and a negative predictive rate of 83.8%, better than either method alone. Conclusions Multi-modal image-guided transrectal ultrasonography has an advantage in providing information on the perfusion and elasticity of prostate nodules in the elderly patients and thus has important clinical value for the diagnosis of prostate nodules. Key words: Prostatic neoplasms; Ultrasonography; Contrast media; Elasticity imaging techniques

Magnetic Marking and Intraoperative Detection of Primary Draining Lymph Nodes in High-Risk Prostate Cancer Using Superparamagnetic Iron Oxide Nanoparticles: Additional Diagnostic Value.

Sentinel lymph node dissection (sLND) using a magnetometer and superparamagnetic iron oxide nanoparticles (SPIONs) as a tracer was successfully applied in prostate cancer (PCa). Radioisotope-guided sLND combined with extended pelvic LND (ePLND) achieved better node removal, increasing the number of affected nodes or the detection of sentinel lymph nodes outside the established ePLND template. We determined the diagnostic value of additional magnetometer-guided sLND after intraprostatic SPION-injection in high-risk PCa. This retrospective study included 104 high-risk PCa patients (PSA >20 ng/mL and/or Gleason score ≥ 8 and/or cT2c) from a prospective cohort who underwent radical prostatectomy with magnetometer-guided sLND and ePLND. The diagnostic accuracy of sLND was assessed using ePLND as a reference standard. Lymph node metastases were found in 61 of 104 patients (58.7%). sLND had a 100% diagnostic rate, 96.6% sensitivity, 95.6% specificity, 96.6% positive predictive value, 95.6% negative predictive value, 3.4% false negative rate, and 4.4% false positive rate (detecting lymph node metastases outside the ePLND template). These findings demonstrate the high sensitivity and additional diagnostic value of magnetometer-guided sLND, exceeding that of ePLND through the individualized extension of PLND or the detection of sentinel lymph nodes/lymph node metastases outside the established node template in high-risk PCa.

EO5 - 11C-choline PET-guided salvage intensity modulated radiotherapy with simultaneous integrated boost for isolated pelvic and para-aortic prostate cancer nodal recurrences: Minimal adverse effects

EO5 - 11C-choline PET-guided salvage intensity modulated radiotherapy with simultaneous integrated boost for isolated pelvic and para-aortic prostate cancer nodal recurrences: Minimal adverse effects

Re: Near-Infrared Intraoperative Molecular Imaging Can Identify Metastatic Lymph Nodes in Prostate Cancer.

Re: Near-Infrared Intraoperative Molecular Imaging Can Identify Metastatic Lymph Nodes in Prostate Cancer.

Erratum to: An IGRT margin concept for pelvic lymph nodes in high-risk prostate cancer.

Erratum to: An IGRT margin concept for pelvic lymph nodes in high-risk prostate cancer.

Molecular alterations in prostate cancer and association with MRI features.

Multiparametric magnetic resonance imaging (mpMRI) has been increasingly used for prostate cancer (PCa). Recent studies identified distinct molecular subclasses of PCa with recurrent genomic alterations. However, the associations between molecular alterations in PCa and characteristics on mpMRI are unknown. Therefore, the objective of this study was to investigate recurrent molecular alterations in PCa and their associations with mpMRI features. Sixty-two PCa nodules >0.5 cm had a preoperative mpMRI. Nodules were evaluated for ERG rearrangement, PTEN deletion, SPINK1 overexpression, SPOP mutation and CHD1 deletion. Each PCa focus was matched to the corresponding location on mpMRI. Lesions were scored by single observer according to the PI-RADSv2 scale. Of the 62 nodules, 22 (35.5%) were ERG positive, 6 (9.7%) had SPINK1 overexpression, 6 (9.7%) had SPOP mutations, 4 (6.5%) had CHD1 deletions and 1 (1.6%) had PTEN deletion. All of the nodules with CHD1 deletions were not visible on mpMRI (P=0.037). All of the nodules with SPINK1 overexpression were visible on mpMRI, although the association was not statistically significant (P=0.06). There were no significant associations between any molecular alteration with the severity of the PI-RADS scores (all P>0.05). This investigation represents the first description of an association between recurrent molecular alterations and the characterization of PCa nodules on mpMRI. This study can be considered hypothesis-generating for future studies to rigorously evaluate the association of specific PCa molecular subclasses with imaging features and potentially define specific subsets of PCa for which the utility of MRI is higher or lower.

Development of an Activatable Fluorescent Probe for Prostate Cancer Imaging.

Technology to visualize small prostate cancers is urgently needed because of the difficulty of discriminating prostate cancer from normal tissue with the naked eye, and a fluorescence imaging method would be advantageous. Here, we describe the design and synthesis of a fluorogenic probe (Ac-KQLR-HMRG) that is activated by hepsin and matriptase (proteases over-expressed in prostate cancer). Ac-KQLR-HMRG exhibited significant turn-on fluorogenicity in the presence of hepsin (180-fold) and matriptase (80-fold) and allowed specific fluorescence imaging of various prostate cancer cell line in vitro. In addition, the probe enabled rapid imaging (within 1-10 min) of small prostate cancer nodules in mouse models of disseminated peritoneal tumor and orthotopic tumor.

Sensitivity of HOXB13 as a Diagnostic Immunohistochemical Marker of Prostatic Origin in Prostate Cancer Metastases: Comparison to PSA, Prostein, Androgen Receptor, ERG, NKX3.1, PSAP, and PSMA.

Aims: Determining the origin of metastases is an important task of pathologists to allow for the initiation of a tumor-specific therapy. Recently, homeobox protein Hox-B13 (HOXB13) has been suggested as a new marker for the detection of prostatic origin. The aim of this study was to evaluate the diagnostic sensitivity of HOXB13 in comparison to commonly used immunohistochemical markers for prostate cancer. Materials and methods: Histologically confirmed prostate cancer lymph node metastases from 64 cases were used to test the diagnostic value of immunohistochemical markers: prostate specific antigen (PSA), Prostatic acid phosphatase (PSAP), prostate specific membrane antigen (PSMA), homeobox gene NKX3.1, prostein, androgen receptor (AR), HOXB13, and ETS-related gene (ERG). All markers were evaluated semi-quantitatively using Remmele’s immune reactive score. Results: The detection rate of prostate origin of metastasis for single markers was 100% for NKX3.1, 98.1% for AR, 84.3% for PSMA, 80.8% for PSA, 66% for PSAP, 60.4% for HOXB13, 59.6% for prostein, and 50.0% for ERG. Conclusions: Our data suggest that HOXB13 on its own lacks sensitivity for the detection of prostatic origin. Therefore, this marker should be only used in conjunction with other markers, preferably the highly specific PSA. The combination of PSA with NKX3.1 shows a higher sensitivity and thus appears preferable in this setting.

Comprehensive molecular profiling of multi-focal prostate cancer and concomitant lymph node metastasis: Implications for tissue-based prognostic biomarkers.

5061 Background: Current tissue-based prognostic biomarker assays claim that assessment of a single biopsy focus is sufficient to predict disease behavior. We analyzed and compared the genetic profiles of multifocal prostate cancer (PCa) with concordant lymph node metastasis (LNM) to determine if expression-based prognostic tests are robust to multifocality. Methods: This IRB-approved study comprised patients who underwent radical prostatectomy and lymph node dissection that revealed N1 or discordant multifocal (low- and high-grade foci) disease. DNA and RNA were co-isolated from each tumor focus pre-identified on formalin fixed paraffin embedded specimens. High depth, targeted DNA and RNA next generation sequencing was performed to characterize the molecular profile of each sample, using the Oncomine Comprehensive (11 patients) or Comprehensive Cancer (DNA, 3 patients) Panels and a custom targeted RNAseq panel comprising genes for deriving prognostic signatures. Results: A total of 67 primary tumor and 17 LNM foci from 14 patients were analyzed. We observed significant intra- and inter-patient molecular heterogeneity. For example, in patient #1, while all 4 regions of high-grade primary tumor showed TP53 somatic mutations and some copy number alterations (CNAs) with two samples from the LNM, tumor areas near the positive margin showed more complete concordance than intraprostatic regions. Critically, a low-grade primary tumor focus in this case showed no somatic mutation or CNA overlap with the high-grade or LNM samples. In patient #4, all tumor and LNM foci shared a large number of somatic mutations, including a frameshift mutation in PTEN, with no high level CNA, consistent with a hypermutated genotype. By targeted RNAseq, low- and high-grade tumors from the same patient showed distinct expression profiles using genes included in prognostic signatures. Conclusions: Our results challenge the claim that expression-based prognostic tests are robust to multifocality. Further studies are needed to better characterize the biologically dominant lesion in multifocal PCa and hold promise for the development of improved prognostic biomarkers.

EP-1346: Oligorecurrent nodal prostate cancer: long-term results of an elective nodal irradiation approach

EP-1346: Oligorecurrent nodal prostate cancer: long-term results of an elective nodal irradiation approach

Near-infrared Intraoperative Molecular Imaging Can Identify Metastatic Lymph Nodes in Prostate Cancer

To propose a novel method to perform indocyanine green (ICG) based near-infrared (NIR) fluorescence imaging during pelvic lymph node dissection (PLND) for prostate cancer patients with lymph node metastasis (LNM). A prostate cancer cell line PC3 was used to establish xenograft model in NOD/SCID mice. After tumor growth, the mice were injected with ICG through the tail vein. Xenografts and surrounding tissues were imaged with NIR camera 24 hours after intravenous ICG, and tumor-to-background ratios were calculated. We then performed a pilot human study to evaluate the role of NIR imaging in robotic PLND after systemic ICG in 4 patients with prostate cancer and preoperative lymphadenopathy. ICG localized to PC3 xenografts in the mice and all xenografts were highly fluorescent compared with surrounding tissues, with a median tumor-to-background ratio of 2.85 (interquartile range = 2.64-3.90). In the human study, intraoperative in vivo NIR imaging identified 3 of the 4 preoperative lymphadenopathies as fluorescence-positive, and back table ex vivo NIR imaging identified all 4 lymphadenopathies as fluorescence-positive. All the lymphadenopathies were found to be LNMs by pathologic examination. Two of the four cases had additional LNMs, all of which were fluorescence-positive with intraoperative in vivo NIR imaging. Intravenously administered ICG accumulates in prostate cancers in both a murine model and human patients. NIR fluorescence based on intravenous ICG may serve as a useful tool to facilitate the identification of positive nodes during PLND in patients with higher risk of LNMs.

482 - Comprehensive molecular dissection of multi-focal prostate cancer and concomitant lymph node metastasis: Implications for tissue based prognostic biomarkers

482 - Comprehensive molecular dissection of multi-focal prostate cancer and concomitant lymph node metastasis: Implications for tissue based prognostic biomarkers

CyberKnife Stereotactic Ablative Radiotherapy as an Option of Treatment for Patients With Prostate Cancer Having Oligometastatic Lymph Nodes: Single-Center Study Outcome Evaluation.

The aim of this study was to evaluate the effectiveness of CyberKnife-based stereotactic ablative radiotherapy on prostate cancer lymph node metastases. Our material consisted of 18 patients with 31 metastatic lymph nodes irradiated between 2011 and 2014 using CyberKnife-based stereotactic ablative radiotherapy. Patients were irradiated using fraction dose varied from 6 to 15 Gy (median 10), to the total dose of 24 to 45 Gy (median 30). Irradiated lymph node size varied from 0.4 to 4.0 cm. In all, 9 patients had single lymph node metastasis and 9 patients had metastases of 2 to 4 lymph nodes. Prostate-specific antigen concentration before radiotherapy varied from 0.01 to 15.58 (mean 6.97; median 4.66). All patients at the time of radiotherapy and follow-up received androgen deprivation therapy. Mann-Whitney U, Kaplan-Meier method, and log-rank tests were used in statistical analysis. We obtained the following results: after CyberKnife stereotactic ablative radiotherapy, prostate-specific antigen concentration dropped in majority of cases and during the last control varied from 0.00 to 258.00 (median 2.5), and was lower in patients without dissemination to other organs (P = .01). Complete regression was found in 12 lesions, stable disease in 13, and progression in 4. In 7 patients, the dissemination to other organs occurred. Our results allow us to conclude that CyberKnife stereotactic ablative radiotherapy of prostate cancer lymph node oligometastases gives good local control and relatively good prostate-specific antigen response.

Upregulation of Talin-1 expression associates with advanced pathological features and predicts lymph node metastases and biochemical recurrence of prostate cancer

Talin-1 functions to regulate cell–cell adhesion, and its altered expression was reported to be associated with human carcinogenesis.A total of 280 tissue specimens from prostate cancer (PCa) patients who underwent radical prostatectomy, 75 cases of benign prostatic hyperplasia (BPH) tissue, and 6 cases of normal prostate tissue specimens were collected for construction of tissue microarray and subsequently subjected to immunohistochemical staining of Talin-1 expression.Talin-1 expression was significantly higher in PCa than both normal and BPH tissues (P <0.001). Talin-1 expression in PCa tissues was associated with preoperative prostate-specific antigen (PSA) level, Gleason score, tumor stage, lymph node metastasis, positive surgical margin, extracapsular extension and seminal vesicle invasion (all P <0.05). Logistic regression analysis showed that Talin-1 and Gleason score were independent risk factors for lymph node metastasis of PCa (P <0.001). Receiver operating characteristic (ROC) curve indicated that Talin-1 expression (AUC = 0.766) had a better accuracy to predict PCa lymph node metastasis than Gleason score (AUC = 0.697), whereas their combination could further enhance the prediction accuracy (AUC = 0.803). Kaplan–Meier curve analysis showed that increased Talin-1 expression was associated with shortened biochemical-free survival of PCa patients after radical prostatectomy (P <0.001).These findings suggested that Talin-1 protein was significantly upregulated in PCa tissues compared with that of BPH tissue and Talin-1 expression was an independent predictor for lymph node metastasis and biochemical recurrence of PCa. Further study will investigate the underlying molecular mechanism and the role of Talin-1 in PCa.

Stereotactic body radiotherapy in oligometastatic prostate cancer patients with isolated lymph nodes involvement: a two-institution experience.

Stereotactic body radiotherapy (SBRT) is emerging as a treatment option in oligometastatic cancer patients. This retrospective study aimed to analyze local control, biochemical progression-free survival (b-PFS), and toxicity in patients affected by isolated prostate cancer lymph node metastases. Finally, we evaluated androgen deprivation therapy-free survival (ADT-FS). Forty patients with 47 isolated lymph nodes of recurrent prostate cancer were treated with SBRT. Mostly, two different fractionation schemes were used: 5×7Gy in 23 (48.9%) lesions and 5×8Gy in 13 (27.7%) lesions. Response to treatment was assessed with periodical PSA evaluation. Toxicity was registered according to RTOG/EORTC criteria. With a mean follow-up of 30.18months, local control was achieved in 98% of the cases, with a median b-PFS of 24months. We obtained a 2-year b-PFS of 44% with 40% of the patients ADT-free at last follow-up (mean value 26.18months; range 3.96-59.46), whereas 12.5% had a mean ADT-FS of 13.58months (range 2.06-37.13). Late toxicity was observed in one (2.5%) patient who manifested a grade 3 gastrointestinal toxicity 11.76months after the end of SBRT. Our study demonstrates that SBRT is safe, effective, and minimally invasive in the eradication of limited nodal metastases, yielding an important delay in prescribing ADT.

Pattern of Progression after Stereotactic Body Radiotherapy for Oligometastatic Prostate Cancer Nodal Recurrences

AimsTo report the relapse pattern of stereotactic body radiotherapy (SBRT) for oligorecurrent nodal prostate cancer (PCa). Materials and methodsPCa patients with ≤3 lymph nodes (N1/M1a) at the time of recurrence were treated with SBRT. SBRT was defined as a radiotherapy dose of at least 5 Gy per fraction to a biological effective dose of at least 80 Gy to all metastatic sites. Distant progression-free survival was defined as the time interval between the first day of SBRT and appearance of new metastatic lesions, outside the high-dose region. Relapses after SBRT were recorded and compared with the initially treated site. Secondary end points were local control, time to palliative androgen deprivation therapy and toxicity scored using the Common Terminology Criteria for Adverse Events v4.0. ResultsOverall, 89 metastases were treated in 72 patients. The median distant progression-free survival was 21 months (95% confidence interval 16–25 months) with 88% of patients having ≤3 metastases at the time of progression. The median time from first SBRT to the start of palliative androgen deprivation therapy was 44 months (95% confidence interval 17–70 months). Most relapses (68%) occurred in nodal regions. Relapses after pelvic nodal SBRT (n = 36) were located in the pelvis (n = 14), retroperitoneum (n = 1), pelvis and retroperitoneum (n = 8) or in non-nodal regions (n = 13). Relapses after SBRT for extrapelvic nodes (n = 5) were located in the pelvis (n = 1) or the pelvis and retroperitoneum (n = 4). Late grade 1 and 2 toxicity was observed in 17% (n = 12) and 4% of patients (n = 3). ConclusionSBRT for oligometastatic PCa nodal recurrences is safe. Most subsequent relapses are again nodal and oligometastatic.

Single Positive Lymph Node Prostate Cancer Can Be Treated Surgically without Recurrence

Purpose/ObjectivesTo investigate pN1 prostate cancer (PCa) patients treated surgically without immediate adjuvant treatment.Materials and MethodsWe analyzed the database of 2316 patients at our institution who underwent robot-assisted radical prostatectomy (RARP)/radical prostatectomy (RP) between July 2005 and November 2012. 87 patients with pN1 PCa and received no neoadjuvant and immediate adjuvant therapy were included in the study. Included pN1 PCa patients were followed up for median of 60 months. Biochemical recurrence (BCR)-free survival, metastasis-free survival (MFS), cancer specific survival (CSS), and overall survival (OS) rates were determined by using Kaplan-Meier analysis. Cox regression analysis was performed to investigate the impact of prostate-specific antigen (PSA) level, Gleason score, extraprostatic extension, seminal vesicle invasion, perineural invasion, lymphovascular invasion, positive surgical margin, tumor volume, early post-operative PSA(6 weeks), PSA nadir, lymph node yield, and number of pathologically positive lymph nodes on survival.ResultsThe 5-year OS rate of patients was 86.1%, while the CSS rate was 89.6%. The metastasis-free and BCR-free survival rates were 71% and 19.1%, respectively, and each was significantly correlated with the number of positive lymph nodes on log rank tests (p = 0.004 and p = 0.039, respectively). The presence of 2 or more pathologically positive LNs (HR:2.20; 95% CI 1.30–3.72; p = 0.003) and a Gleason score ≥8 (HR: 2.40;95% CI: 1.32–4.38; p = 0.04) were significant negative predictors of BCR free survival on multivariable regression analysis. Furthermore, the presence of 2 or more positive lymph nodes (HR: 1.06; 95% CI 1.01–1.11; p = 0.029) were significant negative predictors of metastasis-free survival on multivariable regression analysis. Additionally, in the patients who had no BCR without adjuvant treatment 9 patients out of 10 (90%) had single positive LN and 5 patients out of 10 (50%) had Gleason score 7. Therefore, single positive LN, and Gleason scores ≤7 have significantly low risk of disease progression.ConclusionspN1 PCa patients have heterogenous clinical courses. Patients with single positive LN, and Gleason scores ≤7 have low risk of recurrence. Close observation with delayed adjuvant hormone therapy can be considered in these patients.

670 Single positive lymph node prostate cancer can be surgically cured in selective cases

670 Single positive lymph node prostate cancer can be surgically cured in selective cases