A new risk stratification system of prostate cancer to identify high-risk biochemical recurrence patients

BackgroundBiochemical recurrence (BCR) is considered a decisive risk factor for clinical recurrence and the metastasis of prostate cancer (PCa). Therefore, we developed and validated a signature which could be used to accurately predict BCR risk and aid in the selection of PCa treatments.MethodsA comprehensive genome-wide analysis of data concerning PCa from previous datasets of the Cancer Genome Atlas (TCGA) and the gene expression omnibus (GEO) was performed. Lasso and Cox regression analyses were performed to develop and validate a novel signature to help predict BCR risk. Moreover, a nomogram was constructed by combining the signature and clinical variables.ResultsA total of 977 patients were involved in the study. This consisted of patients from the TCGA (n=405), {"type":"entrez-geo","attrs":{"text":"GSE21034","term_id":"21034"}}GSE21034 (n=131), {"type":"entrez-geo","attrs":{"text":"GSE70770","term_id":"70770"}}GSE70770 (n=193) and {"type":"entrez-geo","attrs":{"text":"GSE116918","term_id":"116918"}}GSE116918 (n=248) datasets. A 9-mRNA signature was identified in the TCGA dataset (composed of C9orf152, EPHX2, ASPM, MMP11, CENPF, KIF4A, COL1A1, ASPN, and FANCI) which was significantly associated with BCR (HR =3.72, 95% CI: 2.30–6.00, P<0.0001). This signature was validated in the {"type":"entrez-geo","attrs":{"text":"GSE21034","term_id":"21034"}}GSE21034 (HR =7.54, 95% CI: 3.15–18.06, P=0.019), {"type":"entrez-geo","attrs":{"text":"GSE70770","term_id":"70770"}}GSE70770 (HR =2.52, 95% CI: 1.50–4.22, P=0.0025) and {"type":"entrez-geo","attrs":{"text":"GSE116918","term_id":"116918"}}GSE116918 datasets (HR =4.75, 95% CI: 2.51–9.02, P=0.0035). Multivariate Cox regression and stratified analysis showed that the 9-mRNA signature was a clinical factor independent of prostate-specific antigen (PSA), Gleason score (GS), or AJCC T staging. The mean AUC for 5-year BCR-free survival predictions of the 9-mRNA signature (0.81) was higher than the AUC for PSA, GS, or AJCC T staging (0.52–0.73). Furthermore, we combined the 9-mRNA signature with PSA, GS, or AJCC T staging and demonstrated that this could enhance prognostic accuracy.ConclusionsThe proposed 9-mRNA signature is a promising biomarker for predicting BCR-free survival in PCa. However, further controlled trials are needed to validate our results and explore a role in individualized management of PCa.     

Performance characteristics of computed tomography in detecting lymph node metastases in contemporary patients with prostate cancer treated with extended pelvic lymph node dissection

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.     

Low risk prostate cancer in men under age 65: the case for definitive treatment

The management of low risk prostate cancer, defined as Gleason’s sum ≤6, PSA <10 ng/ml, and clinical stage T1c to T2a, remains controversial. There is substantiating evidence to suggest that a subset of early stage, low risk cancers can cause significant patient morbidity and death in the long term. Studies have shown that the natural history of untreated prostate cancer is to progress, particularly after 15 years of followup. The majority of men seeking definitive surgical treatment in contemporary series fall within 55 to 65 years of age and are expected to enjoy an overall life expectancy ranging from about 15 to 30 years, placing these men at long-term risk for disease progression and prostate cancer-specific death if managed expectantly. During the past 2 decades, refinements in surgical technique and in the delivery of external beam radiation have resulted in excellent long-term cancer control and favorable quality of life outcomes following treatment. Active surveillance with selective delayed intervention assumes that an individual’s cancer will not progress outside the window of curability during the surveillance period, that markers for disease progression are reliable, and that patients are compliant. Until we understand better the long-term natural history of untreated prostate cancer, have more reliable and accurate markers to detect disease progression with certainty, and can risk stratify more precisely the subgroup of men with low risk cancers who will eventually succumb to their disease, early definitive therapy seems prudent.     

人组织激肽释放酶6在前列腺癌中的表达和意义

目的初步探讨人组织激肽释放酶6(Kallikrein 6,KLK6)在前列腺癌中的表达和意义。方法搜集徐州医学附属医院泌尿外科2010-06—2013-10行前列腺根治手术患者组织标本共65例,其中40例前列腺癌(Prostate Cancer,PCa),25例为前列腺增生组织,应用免疫组织化学两步法,检测组织中KLK6蛋白表达情况。结果 PCa患者组织中KLK6阳性表达率为75%,前列腺增生(Hyperplasia of prostate,BPH)组织KLK6阳性表达率为24%,两者比较癌组织显著高于增生组织(P0.01);前列腺癌中低危患者KLK6阳性表达率为58.25%,中高危患者为75%,两者比较中高危患者明显高于低危患者(P0.05)。结论 KLK6在前列腺癌组织表达明显高于前列腺增生,中高危患者明显高于低危患者,KLK6基因可能在前列腺癌诊断和预后判断中存在一定价值。     

Mitochondrial DNA in serum of patients with prostate cancer: a predictor of biochemical recurrence after prostatectomy

OBJECTIVE

To investigate the role of circulating mitochondrial DNA (mtDNA) in patients with localized prostate cancer, as recent reports show that patients with advanced cancer have increased levels of mtDNA.

PATIENTS AND METHODS

DNA was isolated from the serum of 100 patients with prostate cancer and 18 with benign prostate hyperplasia (BPH). A quantitative real‐time polymerase chain reaction was used to amplify 79 bp and 230 bp fragments of the mitochondrial 16s‐RNA gene, the short fragment representing total mtDNA, including mtDNA truncated by apoptosis, and the long fragment representing mostly mtDNA from other cell death entities. mtDNA integrity was defined as the ratio of long to short mtDNA fragments.

RESULTS

The short and long mtDNA levels, and mtDNA integrity, were similar in patients with BPH and cancer (P = 0.940, 0.211 and 0.441, respectively), and were not correlated with clinical or pathological variables, e.g. age, prostate‐specific antigen (PSA) level, cT stage, pT stage, seminal vesicle infiltration, lymph node invasion, or Gleason score (P = 0.075 to 0.961). However, patients with high levels of short mtDNA (>75th percentile) had a greater risk of PSA progression and this variable was the strongest predictor of PSA recurrence in a multivariate Cox analysis (P = 0.023; hazard ratio 0.31; 95% confidence interval 0.113–0.851).

CONCLUSION

Circulating mtDNA levels did not distinguish between patients with prostate cancer or BPH. However, there was a significant increase in short mtDNA fragments in patients with early PSA recurrence after radical prostatectomy.     

Pretreatment multiparametric MRI is independently associated with biochemical outcome in men treated with radiation therapy for prostate cancer

Purpose

The purpose of this study was to investigate the utility of pre-treatment multiparametric magnetic resonance imaging (mpMRI) in a modern cohort of intermediate and high-risk prostate cancer patients treated with primary radiotherapy.

Actual change in anxiety and depression among Australian men with prostate cancer

Background

The clinical significance of anxiety and depression in prostate cancer patients remains largely unclear. In particular, the importance of somatic symptoms and their change over time has been largely unaddressed in spite of their immediate relevance to an understanding of these psychosocial aspects of prostate cancer and its treatment.

Methods

Self-reports of current and previous states of anxiety and depression were collected from 183 Australian men with prostate cancer between 9 and 71 months (average = 1 year 10 months) after initial diagnosis. An ‘Actual Change’ methodology was used to overcome the effects of extraneous sources of invalidity. Statistical tests of the total scores and specific item-changes over time were conducted.

Results

Mean anxiety and depression levels reduced from time of diagnosis to time of the survey, with the most prominent changes being associated with reductions in psychomotor agitation, weakness, fatigue and pessimism. Clinically significant anxiety reduced from about 20% to 12%; clinical depression reduced from about 24% to 12.5%.

Conclusion

While many prostate patients reported anxiety and depression at the time of receiving their diagnosis, about half of those for whom these disorders were of clinical significance had lowered their symptomatology 2 years later. Assessment of somatic symptoms remains a key indicator of depression and anxiety among this patient group.     

SPECT与PSA联合检测诊断前列腺癌的临床意义

目的：探讨放射性核素骨显像与血清前列腺特异抗原联合检测在前列腺癌诊断中的临床意义。方法;采用单光子发射型计算机断层摄影术骨显像及血清ＰＳＡ浓度检测诊断ＰＣａ患者６３例。结果：６３例ＰＣａ患者中,血清ＰＳＡ测定阳性率为９６．８３％,ＳＰＥＣＴ骨显像转移率为５７．１４％。结论：ＳＰＥＣＴ骨显像与血清ＰＳＡ浓度联合检测对于ＰＣａ患者的临床诊断及治疗具有重要的指导意义。     

Tumor volume,surgical margin,and the risk of biochemical recurrence in men with organ-confined prostate cancer

ObjectivesWe proposed to investigate predictors of biochemical recurrence (BCR) in pT2 prostate cancer by identifying the interrelationship between the tumor volume and surgical margin status, and their impact on recurrence.Materials and methodsClinical, pathologic, and follow-up data of 404 consecutive patients who were treated with radical prostatectomy alone and were diagnosed as pT2 prostate cancer in our institution were reviewed. Percent tumor volume (PTV) was estimated from the cancer distribution map, and the surgical margin status was reviewed by a single pathologist (JYR). Clinicopathologic variables were analyzed with respect to the risk of BCR.Results and limitationsRecurrence was observed in 39 (9.7%) patients at a mean of 28.9 (5–47) months. Preoperative PSA, biopsy Gleason score, surgical Gleason score, PTV, and surgical margin status were significantly related to BCR in univariate analysis; in multivariate analysis, PTV (P < 0.001) and surgical Gleason score (P = 0.021) were independent predictors of BCR. PTV was also an independent determinant of positive surgical margin (P = 0.035, HR 1.026, 95% CI 1.002–1.050). By combining the 2 predictors 5-year recurrence-free survivals for PTV ≤ 14.5% and surgical Gleason score ≤ 7, PTV >14.5% or surgical Gleason score > 7, and PTV > 14.5% and surgical Gleason score > 7 were 97.5%, 88.7%, and 44.5%, respectively (log-rank test, P < 0.01). Retrospective study nature, use of PTV instead of actual volume, and intermediate follow-up length are the main limitations of the study.ConclusionsIn men with pT2 prostate cancer, percent tumor volume and the surgical Gleason score were independently prognostic of BCR and by combining the 2 factors, risk of BCR could be significantly stratified. Tumor volume further determined surgical margin status undermining its prognostic value as an independent variable.     

Mental health outcomes in elderly men with prostate cancer

ObjectiveTo examine the burden of mental health issues (MHI), namely anxiety, depressive disorders, and suicide, in a population-based cohort of older men with localized prostate cancer and to evaluate associations with primary treatment modality.Patients and methodsA total of 50,856 men, who were 65 years of age or older with clinically localized prostate cancer diagnosed between 1992 and 2005 and without a diagnosis of mental illness at baseline, were abstracted from the Surveillance, Epidemiology, and End Results–Medicare database. The primary outcome of interest was the development of MHI (anxiety, major depressive disorder, depressive disorder not elsewhere classified, neurotic depression, adjustment disorder with depressed mood, and suicide) after the diagnosis of prostate cancer.ResultsA total of 10,389 men (20.4%) developed MHI during the study period. Independent risk factors for MHI included age≥75 years (hazard ratio [HR] = 1.29); higher comorbidity (Charlson comorbidity index≥3, HR = 1.63); rural hospital location (HR = 1.14); being single, divorced, or widowed (HR = 1.12); later year of diagnosis (HR = 1.05); and urinary incontinence (HR = 1.47). Black race (HR = 0.79), very high-income status (HR = 0.87), and definitive treatment (radical prostatectomy [RP], HR = 0.79; radiotherapy [RT], HR= 0.85, all P<0.001) predicted a lower risk of MHI. The rates of MHI at 10 years were 29.7%, 29.0%, and 22.6% in men undergoing watchful waiting (WW), RT, and RP, respectively.ConclusionOlder men with localized prostate cancer had a significant burden of MHI. Men treated with RP or RT were at a lower risk of developing MHI, compared with those undergoing WW, with median time to development of MHI being significantly greater in those undergoing RP compared with those undergoing RT or WW.     

The extent of pelvic lymph node dissection correlates with the biochemical recurrence rate in patients with intermediate- and high-risk prostate cancer

Study Type – Therapy (case series) Level of Evidence 4 What’s known on the subject? and What does the study add? Pelvic lymph‐node dissection during radical prostatectomy for prostate cancer is certainly a fundamental staging procedure but its therapeutic role is yet under debate. This retrospective study suggests that, in patients with intermediate‐ and high‐risk of prostate cancer, the greater the number of lymph‐nodes removed, the lower the risk of biochemical relapse, even in the presence of 1 or 2 lymph‐node metastasis. However, the Will Rogers phenomenon must be considered due to the retrospective nature of the present study.

OBJECTIVE

• ? To assess the impact of pelvic lymph node dissection (PLND) and of the number of lymph nodes (LNs) retrieved during radical prostatectomy (RP) on biochemical relapse (BCR) in pNX/0/1 patients with prostate cancer according to the clinical risk of lymph node invasion (LNI).

PATIENTS AND METHODS

• ? We evaluated 872 pT2‐4 NX/0/1 consecutive patients submitted to RP between October 1995 and June 2009, with the following inclusion criteria: (i) a follow‐up period ≥12 months; (ii) the avoidance of neoadjuvant hormonal therapy or adjuvant hormonal and/or adjuvant radiotherapy; (iii) the availability of complete follow‐up data; (iv) no pathological T0 disease; (v) complete data regarding the clinical stage and Gleason score (Gs), the preoperative prostate‐specific antigen (PSA) level and the pathological stage.
• ? The patients were stratified as having low risk (cT1a‐T2a and cGs ≤6 and PSA level < 10 ng/mL), intermediate risk (cT2b‐T2c or cGs = 7 or PSA level = 10–19.9) or high risk of LNI (cT3 or cGs = 8–10 or PSA level ≥ 20).
• ? The 872 patients were divided into two LN groups according to the number of LNs retrieved: group 1 had no LN or one to nine LNs removed; group 2 had 10 or more LNs.
• ? The variables analysed were LN group, age, PSA level, clinical and pathological stage and Gs, surgical margin status, LN status and number of LN metastases; the primary endpoint was the BCR‐free survival.

RESULTS

• ? The mean follow‐up was 55.8 months.
• ? Of all the patients, 305 (35%) were pNx and 567 (65.0%) were pN0/1.
• ? Of the 567 patients submitted to PLND, the mean number of LNs obtained was 10.9, and 49 (8.6%) were pN1.
• ? In the 402 patients at low risk of LNI, LN group was not a significant predictor of BCR at univariate analysis, while in the 470 patients at intermediate and high risk of LNI, patients with ≥10 LNs removed had a significantly lower BCR‐free survival at univariate and multivariate analysis.

CONCLUSION

• ? In our study population, a more extensive PLND positively affects the BCR‐free survival regardless of the nodal status in intermediate‐ and high‐risk prostate cancer.

     

Associations of telomere length in risk and recurrence of prostate cancer: A meta‐analysis

Over the past decades, there is an increasing number of association studies of telomere length (TL) and the risk and recurrence of prostate cancer (PCa), but the results are inconsistent. Hence, we identify the relevant studies published in English on or before 10 January 2019 conducting a literature review in the electronic databases including PubMed, EMBASE and Cochrane Library. Twelve studies (with 19 data sets) were included in this meta‐analysis, five of which were associated with risk assessment, six of which reported recurrence of PCa and one of which included them. Our meta‐analysis demonstrated a positive association of shorter telomeres in patients with PCa, but without statistical significance (OR, 1.23; 95% CI: 0.91–1.66). Shorter telomeres in stroma (OR, 2.40; 95% CI: 1.61–3.56) and epithelium (OR, 1.70; 95% CI: 1.33–2.16) were positively correlated with PCa, but in leucocyte (OR, 0.81; 95% CI: 0.73–0.91) had negative association with PCa. Furthermore, two studies combined yielded a pooled OR of 2.87 (95% CI: 1.22–6.76) for the association between shorter TL and metastasis. These results are novel and give further strength to formulate eligible individualising treatment and surveillance strategies.     

Prediction of prostate cancer risk: the role of prostate volume and digital rectal examination in the ERSPC risk calculators

Background

The European Randomized Study of Screening for Prostate Cancer (ERSPC) risk calculators (RCs) are validated tools for prostate cancer (PCa) risk assessment and include prostate volume (PV) data from transrectal ultrasound (TRUS).

Objective

Develop and validate an RC based on digital rectal examination (DRE) that circumvents the need for TRUS but still includes information on PV.

Design, setting, and participants

For development of the DRE-based RC, we studied the original ERSPC Rotterdam RC population including 3624 men (885 PCa cases) and 2896 men (547 PCa cases) detected at first and repeat screening 4 yr later, respectively. A validation cohort consisted of 322 men, screened in 2010-2011 as participants in ERSPC Rotterdam.

Measurements

Data on TRUS-assessed PV in the development cohorts were re-coded into three categories (25, 40, and 60 cm³) to assess the loss of information by categorization of volume information. New RCs including PSA, DRE, and PV categories (DRE-based RC) were developed for men with and without a previous negative biopsy to predict overall and clinically significant PCa (high-grade [HG] PCa) defined as T stage >T2b and/or Gleason score ≥7. Predictive accuracy was quantified by the area under the receiver operating curve. We compared performance with the Prostate Cancer Prevention Trial (PCPT) RC in the validation study.

Results and limitations

Areas under the curve (AUC) of prostate-specific antigen (PSA) alone, PSA and DRE, the DRE-based RC, and the original ERSPC RC to predict PCa at initial biopsy were 0.69, 0.73, 0.77, and 0.79, respectively. The corresponding AUCs for predicting HG PCa were higher (0.74, 0.82, 0.85, and 0.86). Similar results were seen in men previously biopsied and in the validation cohort. The DRE-based RC outperformed the PCPT RC (AUC 0.69 vs 0.59; p = 0.0001) and a model based on PSA and DRE only (AUC 0.69 vs 0.63; p = 0.0075) in the relatively small validation cohort. Further validation is required.

Conclusions

An RC should contain volume estimates based either on TRUS or DRE. Replacing TRUS measurements by DRE estimates may enhance implementation in the daily practice of urologists and general practitioners.     

Targeted salvage lymphadenectomy in patients treated with radical prostatectomy with biochemical recurrence: complete biochemical response without adjuvant therapy in patients with low volume lymph node recurrence over a long-term follow-up

Background

Choline positron emission tomography/computed tomography (PET/CT) represents an option in restaging of prostate cancer patients with disease relapse after local treatment. The present study assess whether salvage resection of lymph node metastases detected on choline PET/CT imaging in prostate cancer patients with biochemical recurrence after radical prostatectomy can result in a long-term complete biochemical remission, without adjuvant therapy.

Methods

We analysed 13 patients with prostate specific antigen (PSA) recurrence (PSA median 1.64 ng/ml, range 0.5-9.55) after radical prostatectomy and suspicious lymph nodes (median 1; range 1–3) detected on [11C]choline and [18F]fluoroethylcholine PET/CT scans. An open salvage lymphadenectomy of positive lymph nodes in a PET/CT scan and nearby lymph nodes was carried out. We examined PSA outcome without adjuvant therapy; defined complete biochemical remission as PSA <0.01 ng/ml. Histological and PET/CT findings were compared.

Results

Ten of 11 patients with histologically confirmed lymph node metastases showed a PSA response. Three of ten patients with single lymph node metastases had a complete biochemical remission (median follow-up 72 months, range 31.0-83). In five cases with single lymph node metastasis PSA decreased <0.02 ng/ml. Histologically confirmed 13 of 16 metastasis suspicious lymph nodes. No lymph node metastases were detected in two patients. All of the additionally removed 30 lymph nodes were correctly negative.

Conclusions

This is the first confirmation of a complete biochemical remission after PET/CT guided secondary resection of a single lymph node metastasis in prostate cancer patients with biochemical recurrence after radical prostatectomy, over the long-term (>6.5 years), without adjuvant therapy. In order to improve these promising results, longer-term studies with more patients are required.