A randomized controlled study on acupuncture for peri-operative pain after open radical prostatectomy.

OBJECTIVES: To evaluate the advantages of adding acupuncture to standard postoperative pain management for open radical prostatectomy (RP). MATERIALS AND METHODS: A randomized controlled trial (1:1:1) comparing routine postoperative analgesic care (control [CON]) vs the addition of press tack needle acupuncture (ACU) or press tack placebo acupressure (SHAM) for pain management after open RP was performed. A total of 126 patients were enrolled between February 2020 and April 2021. After open RP, the CON group received standard postoperative analgesia, the ACU group received long-term acupuncture with press tacks at specific points (P-6, Shenmen and SP-6) along with standard analgesia, and the SHAM group received placebo press tacks at the same acupuncture points alongside standard analgesia. The primary endpoint was postoperative pain measured on a numeric rating scale, the NRS-11, calculated as the area under the curve. The cumulative use of routine postoperative analgesics, time to first defaecation, and quality of life were analysed using the Kruskal-Wallis rank sum test, Fisher's exact test, and Pearson's chi-squared test. RESULTS: The ACU group reported significantly less postoperative pain compared to the SHAM (P = 0.007) and CON groups (P = 0.02). There were no significant difference in median (interquartile range) cumulative pain medication usage, time to first defaecation (CON: 37 [33, 44] h; SHAM: 37 [33, 42] h; ACU: 37 [33, 41] h; P > 0.9), or health status at discharge (EuroQol five-dimension, five-level general health assessment questionnaire: CON: 70 [65-83]; SHAM: 70 [60-80]; ACU: 70 [50-80]). CONCLUSION: Incorporating acupuncture into postoperative pain management can improve patient postoperative outcomes.

[Role of nutrition in urological prehabilitation]. / Rolle der Ernährung in der urologischen Prähabilitation.

Nutritional intervention plays an important role in prehabilitation, a multimodal concept designed to improve the physical condition of the patient prior to treatment in order to influence the outcome of surgery. The focus is on reducing the postoperative complication rate, while simultaneously shortening the hospital stay and the rehabilitation phase. The nutritional status should be optimized through individual counseling and the targeted intake of calories, protein, and nutritional supplements. A good nutritional status contributes to the strengthening of the immune system and improves wound healing. Especially after surgery, muscle mass declines rapidly. Adequate protein intake accompanying strength exercises can best preserve muscle and promote development of muscular fitness during prehabilitation. Despite the positive effects of nutritional interventions, prehabilitation programs with nutritional components in uro-oncology are rare and the evidence of the programs is therefore insufficient. Results from initial studies appear promising, but further prospective, randomized studies of high quality and with defined program content on the various types of cancer are needed.

Feasibility, acceptability, and behavioral outcomes of a multimodal intervention for prostate cancer patients: Experience from the MARTINI lifestyle program.

BACKGROUND: Prostate cancer (PCa) is the most frequently diagnosed malignant tumor in men. The potential benefit of a healthy lifestyle contrasts sharply with the observed poor adherence to current international lifestyle guidelines. Thus, well-designed sustainable interventions of aftercare that can be translated into routine practice are highly recommended. The present pilot study aimed to evaluate the feasibility and acceptability of a multimodal lifestyle intervention program in PCa patients after radical prostatectomy (RP). METHODS: In a single-arm study, carried out at the Martini-Klinik of the University Medical Center Hamburg-Eppendorf, Germany, 59 eligible men with locally advanced PCa were recruited within 3-6 months after RP and assigned to a multimodal lifestyle program. The program consisted of 10 weekly 6-7 h course days, with a focus on dietary control, physical activity (per World Cancer Research Fund recommendations) and psychological support. Primary objectives were feasibility, acceptability, completion rate, and safety. In addition, changes in lifestyle, psychological well-being, clinical and laboratory values were assessed. The study was registered in the German Clinical Trials Register (No. DRK S00015288 [MARTINI-Lifestyle-cohort] [www.germanctr.de]). RESULTS: A high program acceptance was observed. Only three participants (5%) dropped out of the program prematurely. Personal feedback reflected appreciation for participation, personal gain through new knowledge and through the group experience. Without exception, all participants have taken part in follow-up examinations and no adverse events or incidents occurred. In addition, changes in lifestyle habits, clinical parameters and improved quality of life were detected. CONCLUSION: The MARTINI lifestyle program appears feasible and safe, and acceptance of the multimodal intervention was high among PCa patients. These encouraging results favor conducting a large multicenter trial to implement the program into routine practice and to evaluate the effectiveness of the intervention on survival and quality of life.

Histopathological results of radical prostatectomy specimen of men younger than 50 years of age at the time of surgery: possible implications for prostate cancer screening programs?

INTRODUCTION: Prostate cancer (PCa) detection is usually achieved by PSA measurement and, if indicated, further diagnostics. The recent EAU guidelines recommend a first PSA test at the age of 50 years, if no family history of PCa or BRCA2 mutation exists. However, some men might harbor significant PCa at younger age; thus we evaluated the histopathological results of men treated with radical prostatectomy (RP) in their 40 s at our institution. MATERIALS AND METHODS: We relied on the data of all patients who underwent RP in our institution between 1992 and 2020 and were younger than 50 years at the time of surgery. The histopathological results are descriptively presented. Moreover, we tested the effect of a positive family history on the descriptive results. RESULTS: Overall, 1225 patients younger than 50 years underwent RP at our institution. Median age was 47 years. Most patients showed favorable histopathological characteristics. However, 20% of patients had extraprostatic disease (≥ pT3a), 15% had ISUP Gleason grade group ≥ 3, and 7% had positive lymph nodes (pN1). Patients with a known positive family history did not have a higher rate of adverse disease as their counterparts with a negative family history. DISCUSSION: Our data show that the majority of patients who were diagnosed with PCa at a very young age had favorable histopathological RP characteristics. However, a non-negligible proportion of patients already showed locally advanced disease and would have probably benefited from earlier PCa detection. This should be kept in mind when PCa screening recommendations are proposed.

Circulating Vitamin D and Selenium Levels and Outcome in Prostate Cancer Patients: Lessons from the MARTINI-Lifestyle Cohort.

BACKGROUND: Dietary agents, in particular vitamin D (Vit D) and selenium, are widely used by prostate cancer (PCa) patients to improve cancer outcomes. OBJECTIVE: To investigate whether plasma Vit D and selenium levels prior to radical prostatectomy (RP) are associated with worse pathologic tumor characteristics and increased risk of disease recurrence. DESIGN, SETTING, AND PARTICIPANTS: A total of 3849 men with PCa scheduled for RP in the Martini-Klinik at the University Hospital Hamburg-Eppendorf, Hamburg, Germany, between January 2014 and December 2018 were included in this study. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Age, and clinical and laboratory values were collected prior to RP. Biochemical recurrence (BCR) was defined as prostate-specific antigen (PSA) ≥0.2 µg/l and rising after RP. Kaplan-Meier plots depicted BCR-free survival. Cox regression models (adjusted for age, preoperative PSA, pT stage, pN stage, pGG, surgical margin status, and year of surgery) tested the relationship between oncologic outcomes and Vit D and selenium levels. RESULTS AND LIMITATIONS: Median plasma Vit D and selenium levels were 19.3 and 71 µg/l, respectively. Circulating Vit D and selenium levels correlated inversely with PSA values. Histologic grade, pT stage, and pN stage were not associated with Vit D and selenium levels at the time of RP. In the overall cohort, BCR-free survival at 3 yr of follow-up was 82.9%. When stratified according to median Vit D levels, BCR-free survival at 3 yr of follow-up was 82.7% and 83.0% (p ≤ 0.59). Upon stratification according to median selenium levels, BCR-free survival was 82.2% and 83.7% (p = 0.19). In a multivariable Cox regression model predicting BCR, lower Vit D and selenium levels were not independent predictors of BCR. CONCLUSIONS: Plasma Vit D and selenium levels prior to RP were not associated with BCR-free survival. PATIENT SUMMARY: The results of the MARTINI-Lifestyle cohort could not show a correlation between the occurrence of biochemical recurrence of prostate cancer after radical prostatectomy and the serum levels of vitamin D and selenium. A recommendation should therefore be made to compensate for a potential deficiency and not with the expectation of a reduction in the risk of progression.

Poor Adherence to International Cancer Prevention Recommendations Among Patients With Prostate Cancer: First Results From the MARTINI-Lifestyle Cohort.

BACKGROUND: Promotion of a healthy lifestyle in patients with prostate cancer (PCa) has gained traction to increase patient investment in his/her health care practices, improve patient quality of life, and improve survival outcomes. OBJECTIVE: To investigate adherence of patients with PCa to healthy lifestyle recommendations from the World Cancer Research Fund (WCRF) and the American Institute for Cancer Research (AICR). DESIGN, SETTING, AND PARTICIPANTS: A total of 2227 men with PCa scheduled for radical prostatectomy in the Martini-Klinik at the University Hospital Hamburg-Eppendorf, Hamburg, Germany between January 2016 and December 2017. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Age and clinical characteristics were collected at the time of the diagnosis. Assessment of diet and physical activity data were obtained via e-mail surveys using validated questionnaires developed for the European Prospective Investigation into Cancer and Nutrition (EPIC) study [food frequency questionnaire, version 2 (FFQ2), EPIC-Physical Activity Questionnaire (EPIC-PAQ)]. Baseline characteristics were calculated as means and standard deviations for continuous data or counts and percentages for categorical data. RESULTS AND LIMITATIONS: Patients followed 3.3 (±1.5) of the 10 WCRF/AICR recommendations. None of the participants reached all goals; 67.3% of the patients did not fulfill the criteria of a healthy normal weight, 33.5% reported no exercise at all, and 49.6% were characterized as current or ex-smokers. As to nutritional goals, 75.4% did not meet the recommended intake of meat, 88.8% reported a low consumption of fruit and vegetables, and 86% did not achieve the recommended fiber intake. Because these analyses are based on self-reported data of diet and lifestyle, a bias toward underreporting cannot be excluded. CONCLUSIONS: First results of the MARTINI-Lifestyle cohort show that adherence to the AICR/WCRF recommendations for cancer prevention is poor. PATIENT SUMMARY: Patients with prostate cancer scheduled for surgery do not adhere to cancer prevention guidelines. Thus, improving lifestyle habits may provide significant impact on patient health and quality of life.

Prostate cancer prognosis in men with other malignancies prior to radical prostatectomy.

OBJECTIVES: Cancer survivors are often diagnosed with subsequent prostate cancer. To improve medical care of these patients, we examined the oncological outcomes in men with prostate cancer and a cancer history. PATIENTS AND METHODS: We retrospectively analyzed data from 25,422 prostate cancer patients, who underwent a radical prostatectomy between 1992 and 2016. Patients with other malignancies were identified using medical records and self-administrated questionnaires. Cox regression and Kaplan Meier analysis of a propensity score-matched patient cohort were performed to examine biochemical recurrence-free survival, metastasis-free survival, overall survival and prostate cancer-specific survival. Competing risk analysis was used to estimate other-cause mortality, other cancer-specific mortality, and prostate cancer-specific mortality. Statistical analysis was performed using R. RESULTS: Of all patients, 6.4% were diagnosed with other malignancy prior to radical prostatectomy. Patients with tumor history were older (median: 66 years vs. 64 years., P< 0,001) and showed a higher tumor volume (median: 4.0 ml vs. 3.6 ml, P = 0.02) than patients without. The risk of biochemical recurrence and metastasis development after radical prostatectomy was similar. All-cause mortality was significantly increased (hazard ratio 2.0; 95% confidence interval 1.7-2.4), while prostate cancer-specific mortality was lower (hazard ratio 0.4; 95% confidence interval 0.23-0.87) in patients with additional malignancy. In a propensity score-matched cohort overall survival was significantly adverse (P< 0.001) and prostate cancer-specific survival was higher (P= 0.003) in patients with other malignancy prior to surgery. CONCLUSION: A higher other-cause mortality in men with tumor history should be concerned in the decision-making for medical care of prostate cancer patients in favor of reserved care strategies.

Author Correction: Up regulation and nuclear translocation of Y-box binding protein 1 (YB-1) is linked to poor prognosis in ERG-negative prostate cancer.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

Marked Prognostic Impact of Minimal Lymphatic Tumor Spread in Prostate Cancer.

BACKGROUND: Nodal metastasis (N1) is a strong prognostic parameter in prostate cancer; however, lymph node evaluation is always incomplete. OBJECTIVE: To study the prognostic value of lymphatic invasion (L1) and whether it might complement or even replace lymph node analysis in clinical practice. DESIGN, SETTING, AND PARTICIPANTS: Retrospective analysis of pathological and clinical data from 14 528 consecutive patients. INTERVENTION: Radical prostatectomy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The impact of L1 and N1 on patient prognosis was measured with time to biochemical recurrence as the primary endpoint. RESULTS AND LIMITATIONS: Nodal metastases were found in 1602 (12%) of 13 070 patients with lymph node dissection. L1 was seen in 2027 of 14 528 patients (14%) for whom lymphatic vessels had been visualized by immunohistochemistry. N1 and L1 continuously increased with unfavorable Gleason grade, advanced pT stage, and preoperative prostate-specific antigen (PSA) values (p<0.0001 each). N1 was found in 4.3% of 12 501 L0 and in 41% of 2027 L1 carcinomas (p<0.0001). L1 was seen in 11% of 9868 N0 and in 61% of 1360 N1 carcinomas (p<0.0001). Both N1 and L1 were linked to PSA recurrence (p<0.0001 each). This was also true for 17 patients with isolated tumor cells (ie, <200 unequivocal cancer cells without invasive growth) and 193 metastases ≤1mm. Combined analysis of N and L status showed that L1 had no prognostic effect in N1 patients but L1 was strikingly linked to PSA recurrence in N0 patients. N0L1 patients showed a similar outcome as N1 patients. CONCLUSIONS: Analysis of lymphatic invasion provides comparable prognostic information than lymph node analysis. Even minimal involvement of the lymphatic system has pivotal prognostic impact in prostate cancer. Thus, a thorough search for lymphatic involvement helps to identify more patients with an increased risk for disease recurrence. PATIENT SUMMARY: Already minimal amounts of tumor cells inside the lymph nodes or intraprostatic lymphatic vessels have a severe impact on patient prognosis.

Up regulation of the steroid hormone synthesis regulator HSD3B2 is linked to early PSA recurrence in prostate cancer.

HSD3B2 plays a crucial role in steroid hormone biosynthesis and is thus of particular interest in hormone dependent tumors such as prostate cancer. To clarify the clinical relevance of HSD3B2 expression in prostate cancer, we analyzed HSD3B2 protein expression by immunohistochemistry on our preexisting tissue microarray with 12.247 annotated cancers. Compared with normal tissue cytoplasmic HSD3B2 staining was stronger in prostate cancers. In 9371 interpretable cancers, HSD3B2 expression was found in 95.5% of cancers and was considered weak in 29.9%, moderate in 40.7% and strong in 24.9%. HSD3B2 up regulation was linked to advanced pathological tumor stage (pT), high Gleason grade, elevated preoperative PSA levels (p < 0.0001 each), lymph node metastasis (p = 0.0019), accelerated cell proliferation (p < 0.0001), androgen receptor (AR) expression (p < 0.0001), and early biochemical recurrence (p < 0.0001). HSD3B2 up regulation was only marginally more frequent in ERG positive (98%) than in ERG negative cancers (94%; p < 0.0001) and was strongly linked to deletions of 5q and 6q (p < 0.0001 each). Multivariate analyses showed that the prognostic impact of HSD3B2 expression was independent of established preoperative, but not of postoperative prognostic parameters. In summary, the results of our study demonstrate that HSD3B2 is strongly up regulated in a fraction of prostate cancers that are characterized by increased AR signaling, adverse tumor phenotype and early biochemical recurrence.

Integrating Tertiary Gleason 5 Patterns into Quantitative Gleason Grading in Prostate Biopsies and Prostatectomy Specimens.

BACKGROUND: Presence of small (tertiary) Gleason 5 pattern is linked to a higher risk of biochemical recurrence in prostate cancer. It is unclear, however, how to integrate small Gleason 5 elements into clinically relevant Gleason grade groups. OBJECTIVE: To analyze the prognostic impact of Gleason 5 patterns in prostate cancer and to develop a method for integrating tertiary Gleason 5 patterns into a quantitative Gleason grading system. DESIGN, SETTING, AND PARTICIPANTS: Prostatectomy specimens from 13 261 consecutive patients and of 3295 matched preoperative biopsies were available. Percentages of Gleason 3, 4, and 5 had been recorded for each cancer. Outcome measurements and statistical analysis: RESULTS AND LIMITATIONS: Our data demonstrate that minimal Gleason 5 areas have strong prognostic impact in Gleason 7 carcinomas, while further expansion of the Gleason 5 pattern population has less impact. We thus defined an integrated quantitative Gleason score (IQ-Gleason) by adding a lump score of 10 to the percentage of unfavorable Gleason pattern (Gleason 4/5) if any Gleason 5 was present and by adding another 7.5 points in case of a Gleason 5 fraction >20%. There was a continuous increase of the risk of prostate-specific antigen recurrence with increasing IQ-Gleason. This was also true for subgroups with identical Cancer of the Prostate Risk Assessment Postsurgical scores (p<0.0001) or Gleason grade groups (p<0.0001). CONCLUSIONS: The IQ-Gleason represents a simple and efficient approach for combining both quantitative Gleason grading and tertiary Gleason grades in one highly prognostic numerical variable. PATIENT SUMMARY: Prostatectomy specimens (13 261) were analyzed to estimate the relevance of small Gleason 5 elements in prostate cancers. Even the smallest Gleason 5 areas markedly increased the risk of prostate-specific antigen recurrence after surgery. Larger fractions of Gleason 5 patterns had less further impact on prognosis. Based on this, a numerical Gleason score (integrated quantitative Gleason score) was defined by the percentages of Gleason 4 and 5 patterns, enabling a refined estimate of patient prognosis.

Up-regulation of Biglycan is Associated with Poor Prognosis and PTEN Deletion in Patients with Prostate Cancer.

Biglycan (BGN), a proteoglycan of the extracellular matrix, is included in mRNA signatures for prostate cancer aggressiveness. To understand the impact of BGN on prognosis and its relationship to molecularly defined subsets, we analyzed BGN expression by immunohistochemistry on a tissue microarray containing 12,427 prostate cancers. Seventy-eight percent of 11,050 interpretable cancers showed BGN expression, which was considered as low intensity in 47.7% and as high intensity in 31.1% of cancers. BGN protein expression rose with increasing pathological tumor stage, Gleason grade, lymph node metastasis and early PSA recurrence (P<.0001 each). Comparison with our molecular database attached to the TMA revealed that BGN expression was linked to presence of TMPRRS2:ERG fusion and PTEN deletion (P<.0001 each). In addition, BGN was strongly linked to androgen-receptor (AR) levels (P<.0001), suggesting a hormone-depending regulation of BGN. BGN up-regulation is a frequent feature of prostate cancer that parallels tumor progression and may be useful to estimate tumor aggressiveness particularly if combined with other molecular markers.

Increased ERCC1 expression is linked to chromosomal aberrations and adverse tumor biology in prostate cancer.

BACKGROUND: Animal model experiments have suggested a role of the DNA repair protein ERCC1 (Excision Repair Cross-Complementation Group 1) in prostate cancer progression. METHODS: To better understand the impact of ERCC1 protein expression in human prostate cancer, a preexisting tissue microarray (TMA) containing more than 12,000 prostate cancer specimens was analyzed by immunohistochemistry and data were compared with tumor phenotype, PSA recurrence and several of the most common genomic alterations (TMPRSS2:ERG fusions: deletions of PTEN, 6q, 5q, 3p). RESULTS: ERCC1 staining was seen in 64.7% of 10,436 interpretable tissues and was considered weak in 37.1%, moderate in 22.6% and strong in 5% of tumors. High-level ERCC1 staining was linked to advanced pT stage, high Gleason grade, positive lymph nodes, high pre-operative serum PSA, and positive surgical margin status (p < 0.0001 each). High ERCC1 expression was strongly associated with an elevated risk of PSA recurrence (p < 0.0001). This was independent of established prognostic features. A subgroup analysis of cancers defined by comparable quantitative Gleason grades revealed that the prognostic impact was mostly driven by low-grade tumors with a Gleason 3 + 3 or 3 + 4 (Gleason 4: ≤5%). High ERCC1 expression was strongly associated with the presence of genomic alterations and expression levels increased with the number of deletions present in the tumor. These latter data suggest a functional relationship of ERCC1 expression with genomic instability. CONCLUSION: The results of our study demonstrate that expression of ERCC1 - a potential surrogate for genomic instability - is an independent prognostic marker in prostate cancer with particular importance in low-grade tumors.

Up regulation and nuclear translocation of Y-box binding protein 1 (YB-1) is linked to poor prognosis in ERG-negative prostate cancer.

Y-box binding protein 1 (YB-1) is an RNA and DNA binding factor with potential prognostic cancer. To evaluate the clinical impact of YB-1, a tissue microarray with 11,152 prostate cancers was analysed by immunohistochemistry. Cytoplasmic and nuclear staining was separately analysed. Cytoplasmic YB-1 was absent or weak in normal epithelium but seen in 86,3% of carcinomas. Cytoplasmic staining was weak, moderate, and strong in 29.6%, 43.7% and 13.0% of tumours and was accompanied by nuclear YB-1 staining in 32.1% of cases. Particularly nuclear staining was strongly linked to poor patient prognosis (p < 0.0001). YB-1 protein was more abundant in ERG positive (95.1%) than in ERG negative cancers (80.4%; p < 0.0001), but any prognostic impact of YB-1 staining was limited to the ERG-negative subset. Similarly, significant associations with pT stage and Gleason grade (p < 0.0001 each) were driven by the ERG negative subset. The significant association of YB-1 protein detection with deletions of PTEN, 5q21 and 6q15 fits well in the protein's role as an inhibitor of DNA damage dependent cell cycle arrest, a role that is likely to induce genomic instability. In summary, the data show, that the prognostic impact of YB-1 expression is limited to ERG negative prostate cancers.

Apurinic/apyrimidinic endonuclease 1 (APE1/Ref-1) overexpression is an independent prognostic marker in prostate cancer without TMPRSS2:ERG fusion.

Polymorphisms of the base excision repair gene APE1 may be associated with an increased risk for developing prostate cancer. In other cancer types, altered APE1 protein expression is a candidate prognostic marker. Using immunohistochemistry, we thus analyzed APE1 expression in 9763 prostate cancers in a tissue microarray (TMA) with attached clinical and molecular data. The comparison with normal prostate tissue revealed an upregulation of APE1 in cancer samples. APE1 immunostaining was considered weak in 20.2%, moderate in 36.7%, and strong in 33.4% of cancers. Strong APE1 expression was markedly more frequent in prostate cancers harboring the TMPRSS2:ERG fusion (52.9%) than in ERG-negative cancers (19.1%, P < 0.0001). Significant associations with Gleason grade, tumor stage, tumor grade, and early biochemical recurrence (P < 0.0001 each) were largely limited to ERG-negative tumors. Multivariable analysis revealed that the prognostic value of APE1 upregulation in ERG-negative prostate cancers was independent from established histopathological and clinical parameters. In conclusion, the results of our study demonstrate that APE1 overexpression is an independent prognostic marker, but exclusively in ERG-negative prostate cancers.

Overexpression of the A Disintegrin and Metalloproteinase ADAM15 is linked to a Small but Highly Aggressive Subset of Prostate Cancers.

The A Disintegrin and Metalloproteinase (ADAM) family of endopeptidases plays a role in many solid cancers and includes promising targets for anticancer therapies. Deregulation of ADAM15 has been linked to tumor aggressiveness and cell line studies suggest that ADAM15 overexpression may also be implicated in prostate cancer. To evaluate the impact of ADAM15 expression and its relationship with key genomic alterations, a tissue microarray containing 12,427 prostate cancers was analyzed by immunohistochemistry. ADAM15 expression was compared to phenotype, prognosis and molecular features including TMPRSS2:ERG fusion and frequent deletions involving PTEN, 3p, 5q and 6q. Normal prostate epithelium did not show ADAM15 staining. In prostate cancers, negative, weak, moderate, and strong ADAM15 staining was found in 87.7%, 3.7%, 5.6%, and 3.0% of 9826 interpretable tumors. Strong ADAM15 staining was linked to high Gleason grade, advanced pathological tumor stage, positive nodal stage and resection margin. ADAM15 overexpression was also associated with TMPRSS2:ERG fusions and PTEN deletions (P<.0001) but unrelated to deletions of 3p, 5q and 6q. In univariate analysis, high ADAM15 expression was strongly linked to PSA recurrence (P<.0001). However, in multivariate analyses this association was only maintained if the analysis was limited to preoperatively available parameters in ERG-negative cancers. The results of our study demonstrate that ADAM15 is strongly up regulated in a small but highly aggressive fraction of prostate cancers. In these tumors, ADAM15 may represent a suitable drug target. In a preoperative scenario, ADAM15 expression measurement may assist prognosis assessment, either alone or in combination with other markers.

High-Level γ-Glutamyl-Hydrolase (GGH) Expression is Linked to Poor Prognosis in ERG Negative Prostate Cancer.

γ-glutamyl-hydrolase (GGH) is a ubiquitously-expressed enzyme that regulates intracellular folate metabolism for cell proliferation, DNA synthesis, and repair. Employing GGH immunohistochemistry on a tissue microarray with 12,427 prostate cancers, we found that GGH expression was negative to low in normal prostate epithelium, whereas 88.3% of our 10,562 interpretable cancers showed GGH expression. GGH staining was considered as low intensity in 49.6% and as high intensity in 38.6% of cancers. High GGH expression was linked to the TMPRSS2:ERG-fusion positive subset of cancers (p < 0.0001), advanced pathological tumor stage, and high Gleason grade (p < 0.0001 each). Further analysis revealed that these associations were merely driven by the subset of ERG-negative cancers, High GGH expression was weakly linked to early biochemical recurrence in ERG negative cancers (p < 0.0001) and independent from established histo-pathological parameters. Moreover, GGH expression was linked to features of genetic instability, including presence of recurrent deletions at 3p, 5q, 6q, and 10q (PTEN, p ≤ 0.01 each), as well as to accelerated cell proliferation as measured by Ki67 immunohistochemistry (p < 0.0001). In conclusion, the results of our study identify GGH as an ERG subtype specific molecular marker with modest prognostic relevance, which may have clinical relevance if analyzed in combination with other molecular markers.

Functional Outcomes and Quality of Life After Radical Prostatectomy Only Versus a Combination of Prostatectomy with Radiation and Hormonal Therapy.

BACKGROUND: While the optimal use and timing of secondary therapy after radical prostatectomy (RP) remain controversial, there are limited data on patient-reported outcomes following multimodal therapy. OBJECTIVE: To assess the impact of additional radiation therapy (RT) and/or androgen deprivation therapy (ADT) on urinary continence, potency, and quality of life (QoL) after RP. DESIGN, SETTING, AND PARTICIPANTS: Among 13150 men who underwent RP from 1992 to 2013, 905 received RP + RT, 407 RP + ADT and 688 RP + RT + ADT. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES: Urinary function, sexual function, and overall QoL were evaluated annually using self-administered validated questionnaires. Propensity score-matched and bootstrap analyses were performed, and the distributions for all functional outcomes were analyzed as a function of time after RP. RESULTS AND LIMITATIONS: Patients who received RP + RT had a 4% higher overall incontinence rate 3 yr after surgery, and 1% higher rate for severe incontinence (>3 pads/24h) compared to matched RP-only patients. ADT further increased the overall and severe incontinence rates by 4% and 3%, respectively, compared to matched RP + RT patients. RP + RT was associated with an 18% lower rate of potency compared to RP alone, while RP + RT + ADT was associated with a further 17% reduction compared to RP + RT. Additional RT reduced QoL by 10% and additional ADT by a further 12% compared to RP only and RP + RT, respectively. The timing of RT after RP had no influence on continence, but adjuvant compared to salvage RT was associated with significantly lower potency (37% vs 45%), but higher QoL (60% vs 56%). Limitations of our study include the observational study design and potential for selection bias in the treatments received. CONCLUSIONS: Secondary RT and ADT after RP have an additive negative influence on urinary function, potency, and QoL. Patients with high-risk disease should be counseled before RP on the potential net impairment of functional outcomes due to multimodal treatment. PATIENT SUMMARY: Men with high-risk disease choosing surgery upfront should be counseled on the potential need for additional radiation and or androgen deprivation, and the potential net impairment of functional outcomes arising from multimodal treatment.

Use of phosphodiesterase type 5 inhibitors may adversely impact biochemical recurrence after radical prostatectomy.

PURPOSE: Experimental evidence suggests that phosphodiesterase type 5 inhibitors may suppress tumor growth, postpone metastasis and prolong survival, but clinical data are lacking. We studied the effect of phosphodiesterase type 5 inhibitors on biochemical recurrence after radical prostatectomy for prostate cancer. MATERIALS AND METHODS: The study was comprised of 4,752 consecutive patients with localized prostate cancer treated with bilateral nerve sparing radical prostatectomy between January 2000 and December 2010. Of these patients 1,110 (23.4%) received phosphodiesterase type 5 inhibitors postoperatively while 3,642 (76.6%) did not. The risk of biochemical recurrence was compared between the phosphodiesterase type 5 inhibitor group and the nonphosphodiesterase type 5 inhibitor group. Cox multivariate proportional hazard models and confidence intervals were used to estimate the hazard ratio of biochemical recurrence associated with phosphodiesterase type 5 inhibitor use. Propensity score matched analysis was performed. RESULTS: Median followup was 60.3 months (IQR 36.7-84.5). Five-year biochemical recurrence-free survival estimates in the phosphodiesterase type 5 inhibitor vs nonphosphodiesterase type 5 inhibitor groups were 84.7% (95% CI 82.1-87.0) and 89.2% (95% CI 88.1-90.3), respectively (p=0.0006). Multivariate regression analysis showed that phosphodiesterase type 5 inhibitor use was an independent risk factor for biochemical recurrence (HR 1.38, 95% CI 1.11-1.70, p=0.0035) and this was also true after propensity score matching. CONCLUSIONS: Contrary to experimental data, the use of phosphodiesterase type 5 inhibitors after radical prostatectomy may adversely impact biochemical recurrence. Further studies are needed to validate our results.