Immunohistochemical and histopathological validation of 18 F-PSMA-1007 PET/CT for intraprostatic cancerous lesions.

INTRODUCTION: Prostate-specific membrane antigen (PSMA) is overexpressed in prostate cancer (PCa). In this study, we aim to immunohistochemically and histopathological validate the fluorine-18 (18 F)-PSMA-1007 positron emission tomography/computed tomography (PET/CT) for intraprostatic PCa lesions. METHODS: Between February 2019 and October 2020, patients with biopsy-proven, treatment-naïve intermediate-to-high-risk PCa undergoing an 18 F-PSMA-1007 PET/CT before robot-assisted radical prostatectomy (RARP) were prospectively enrolled. For all PCa lesions found on whole-mount histopathology, location, size, International Society of Urological Pathology (ISUP) grade group (GG), and immune reactive score (IRS) were assessed after PSMA staining. ISUP GG ≥ 3 PCa was defined as clinically significant (cs) PCa. All lesions were matched on PSMA PET/CT and the maximum standardized uptake value (SUVmax) was measured. RESULTS: A total of 125 lesions were analyzed in the 80 RARP specimens, of which 49 (40%) were csPCa and 76 (60%) non-csPCa. Linear multivariable regressions showed that an increase in SUVmax significantly correlated with a higher ISUP GG (p values between 0.021 and 0.001) and a higher IRS (p = 0.017). Logistic multivariable regression showed that csPCa significantly correlated with a higher SUVmax (odds ratio, OR: 1.17 [95% confidence interval, CI: 1.04-1.21, p = 0.005]), an increase in tumor length (OR: 1.05 [95% CI 1.01-1.10, p = 0.020]) and a higher IRS (OR; 1.24 [95% CI 1.07-1.47, p = 0.006]). A SUVmax threshold of 4 would have resulted in one (2%) missed lesion with csPCa. CONCLUSION: This prospective study revealed that 18 F-PSMA-1007 PET/CT SUVmax is correlated with the ISUP GG and IRS, and thereby could be a tool to characterize intraprostatic PCa lesions.

Incidence of significant prostate cancer after negative MRI and systematic biopsy in the FUTURE trial.

OBJECTIVES: To assess the proportion of clinically significant (cs) prostate cancer (PCa) found during follow-up in patients with negative systematic biopsy (SB) followed by non-suspicious multiparametric magnetic resonance imaging (mpMRI) and persistent clinical suspicion of PCa compared to the general population. PATIENTS AND METHODS: A prospective study in a subgroup of patients from a multicentre randomized controlled trial was conducted between 2014 and 2017, including 665 men with prior negative SB with a persistent elevated prostate-specific antigen and/or suspicious digital rectal examination undergoing mpMRI. All patients with negative SB and Prostate Imaging-Reporting and Data System (PI-RADS) ≤2 on mpMRI entered biochemical follow-up. Follow-up data until December 2021 were collected by reviewing institutional hospital records and the Dutch Pathology Registry (PALGA). The primary outcome was the observed number of csPCa (Gleason ≥3 + 4/International Society of Urological Pathology grade group ≥2) cases during follow-up compared to the expected number in the general population (standardized incidence ratio [SIR]). RESULTS: In total, 431 patients had non-suspicious mpMRI and entered biochemical follow-up. After a median (interquartile range) follow-up of 41 (23-57) months, 38 patients were diagnosed with PCa, of whom 13 (3.0%) had csPCa. The SIR for csPCa was 4.3 (95% confidence interval 2.3-7.4; total excess of eight cases). A higher risk of a positive biopsy for (cs)PCa based on the European Randomized Study of Screening for Prostate Cancer risk calculator and a suspicious repeat MRI (PI-RADS ≥3) were significant predictive factors for csPCa. CONCLUSION: After negative prior biopsy and non-suspicious mpMRI the risk of csPCa is low. However, compared to the general population, the risk of csPCa is increased despite the high negative predictive value of mpMRI. More research focusing on biochemical and image-guided risk-adapted diagnostic surveillance strategies is warranted.

Functional and oncological outcomes of salvage cryosurgery for radiorecurrent prostate cancer.

OBJECTIVES: To evaluate the oncological and functional outcomes of salvage cryosurgery (SCS) for radiorecurrent prostate cancer (rrPCa). PATIENTS AND METHODS: A total of 169 consecutive patients with biopsy confirmed rrPCa were retrospectively analysed. All patients underwent SCS in a single referral centre between 2006 and 2018. The primary outcome was biochemical recurrence-free survival (BRFS) according to the Phoenix definition (prostate-specific antigen [PSA] nadir +2 ng/mL). The secondary outcomes were overall survival, BRFS defined as a PSA level of >0.5 ng/mL, metastasis-free survival, androgen-deprivation therapy (ADT)-free survival, and functional outcomes. Complications were classified according to the Clavien-Dindo system. PSA was measured every 3-6 months postoperatively. Functional outcomes were scored as reported by patients at outpatient visits. Kaplan-Meier survival analysis and uni- and multivariable Cox regression were performed. RESULTS: The median (interquartile range) follow-up was 36 (18-66) months. The BRFS after 5 and 8 years was 52% (95% confidence interval [CI] 43-62%) and 45% (95% CI 35-57%), respectively. At multivariable analysis PSA level at initial diagnosis, initial treatment, interval between primary treatment and SCS, age at SCS, and post-SCS PSA nadir were significant factors for BRFS. The 5-year ADT-free survival was 70% (95% CI 62-79%). Clavien-Dindo Grade ≥III complications occurred in 1.2% (two/169) of patients. In all, 19% (29/156) of patients had new-onset urinary incontinence defined as >1 pad/24 h and 92% (57/62) of patients had new-onset erectile dysfunction. Persistent urinary fistula occurred in 6.5% (11/169) of patients. CONCLUSIONS: The present study shows acceptable oncological outcomes of SCS considering the salvage character of the treatment. The occurrence of serious complications such as urinary incontinence and fistula should not be underestimated.

Head-to-Head Comparison of 18F-PSMA-1007 Positron Emission Tomography/Computed Tomography and Multiparametric Magnetic Resonance Imaging with Whole-mount Histopathology as Reference in Localisation and Staging of Primary Prostate Cancer.

BACKGROUND: Accurate local staging is critical for treatment planning and prognosis in prostate cancer (PCa). Although multiparametric magnetic resonance imaging (mpMRI) has high specificity for detection of extraprostatic extension (EPE) and seminal vesicle invasion (SVI), its sensitivity remains limited. 18F-PSMA-1007 positron emission tomography/computed tomography (PET/CT) may be more accurate in determining T stage. OBJECTIVE: To assess the diagnostic performance of 18F-PSMA-1007 PET/CT in comparison to mpMRI for intraprostatic tumour localisation and detection of EPE and SVI in men with primary PCa undergoing robot-assisted radical prostatectomy (RARP). DESIGN, SETTING, AND PARTICIPANTS: Between February 2019 and October 2020, 105 treatment-naïve patients with biopsy-proven intermediate- or high-risk PCa undergoing mpMRI and 18F-PSMA-1007 PET/CT before RARP were prospectively enrolled. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The diagnostic accuracy of 18F-PSMA-1007 PET/CT and mpMRI for intraprostatic tumour localisation and detection of EPE and SVI was assessed via histopathological examination of whole-mount RP specimens. The sensitivity, specificity, negative predictive value, positive predictive value, and accuracy were calculated. The McNemar test was used to compare outcomes between imaging modalities. RESULTS AND LIMITATIONS: In 80 RP specimens, 129 PCa lesions were found, of which 96 were clinically significant PCa (csPCa). Per-lesion sensitivity for localisation of overall PCa was 85% (95% confidence interval [CI] 77-90%) with PSMA PET/CT and 62% (95% CI 53-70%) with mpMRI (p < 0.001). Per-lesion sensitivity for csPCa was 95% (95% CI 88-98%) with PSMA PET/CT and 73% (95% CI 63-81%) with mpMRI (p < 0.001). The diagnostic accuracy of PSMA PET/CT and mpMRI for detection of EPE per lesion did not significantly differ (sensitivity 45%, 95% CI 31-60% vs 55%, 95% CI 40-69%; p = 0.3; specificity 85%, 95% CI 75-92% vs 90%, 95% CI 81-86%; p = 0.5). The sensitivity and specificity of PSMA PET/CT and mpMRI for detection of SVI did not significantly differ (sensitivity 47%, 95% CI 21-73% vs 33%, 95% CI 12-62; p = 0.6; specificity 94%, 95% CI 88-98% vs 96%, 95% CI 90-99%; p = 0.8). CONCLUSIONS: 18F-PSMA-1007 is a promising imaging modality for localising intraprostatic csPCa but did not show additional value in assessing EPE and SVI in comparison to mpMRI. PATIENT SUMMARY: A new imaging technique called PET/CT (positron emission tomography/computed tomography) with the radioactive tracer 18F-PSMA-1007 shows promise in identifying the location of clinically significant prostate cancer. However, it does not seem to be of additional value over magnetic resonance imaging (MRI) for determining the local tumour stage.

Is There Still a Need for Repeated Systematic Biopsies in Patients with Previous Negative Biopsies in the Era of Magnetic Resonance Imaging-targeted Biopsies of the Prostate?

BACKGROUND: The role of targeted prostate biopsies (TBs) in patients with cancer suspicious lesions on multiparametric magnetic resonance imaging (mpMRI) following negative systematic biopsies (SBs) is undebated. However, whether they should be combined with repeated SBs remains unclear. OBJECTIVE: To evaluate the value of repeated SBs in addition to TBs in patients with a prior negative SB and a persistent suspicion of prostate cancer (PCa). DESIGN, SETTING, AND PARTICIPANTS: A prospective study as part of a multicenter randomized controlled trial conducted between 2014 and 2017, including 665 men with a prior negative SB and a persistent suspicion of PCa (suspicious digital rectal examination and/or prostate-specific antigen >4.0ng/ml). INTERVENTION: All patients underwent 3T mpMRI according to Prostate Imaging Reporting and Data System (PI-RADS) v2. Patients with PI-RADS ≥3 were randomized 1:1:1 for three TB techniques: MRI-TRUS fusion TB (FUS-TB), cognitive registration fusion TB (COG-TB), or in-bore MRI TB. FUS-TB and COG-TB were combined with repeated SBs. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Clinically significant prostate cancer (csPCa) was defined as Gleason ≥3+4. Differences in detection rates of csPCa, clinically insignificant PCa (cisPCa), and overall PCa between TBs (FUS-TB and COG-TB) and repeated SBs were compared using McNemar's test. RESULTS AND LIMITATIONS: In the 152 patients who underwent both TB and SB, PCa was detected by TB in 47% and by SB in 32% (p<0.001, 95% confidence interval [CI]: 6.0-22%). TB detected significantly more csPCa than SB (32% vs 16%; p<0.001, 95% CI: 11-25%). Clinically significant PCa was missed by TB in 1.3% (2/152). Combining SB and TB resulted in detection rate differences of 6.0% for PCa, 5.0% for cisPCa, and 1.0% for csPCa compared with TB alone. CONCLUSIONS: In case of a persistent suspicion of PCa following a negative SB, TB detected significantly more csPCa cases than SB. The additional value of SB was limited, and only 1.3% of csPCa would have been missed when SB had been omitted. PATIENT SUMMARY: We evaluated the role of systematic biopsies and magnetic resonance imaging (MRI)-targeted biopsies for the diagnosis of prostate cancer in patients with prior negative systematic biopsies. MRI-targeted biopsies perform better in detecting prostate cancer in these patients. The value of repeated systematic biopsies is limited.

Complications and Adverse Events of Three Magnetic Resonance Imaging-based Target Biopsy Techniques in the Diagnosis of Prostate Cancer Among Men with Prior Negative Biopsies: Results from the FUTURE Trial, a Multicentre Randomised Controlled Trial.

BACKGROUND: Three techniques of magnetic resonance imaging (MRI)-based targeted biopsy (TB) of the prostate exist. There is no superiority regarding diagnostic efficacy of prostate cancer (PCa) detection. OBJECTIVE: To compare adverse events (AEs) among three TB techniques and to evaluate the effect on urinary and erectile function. DESIGN, SETTING, AND PARTICIPANTS: Post hoc analysis of a multicentre randomised controlled trial among men with negative systematic biopsy (SB) and suspicion of PCa. INTERVENTION: In 234 patients, 3-T multiparametric MRI demonstrated PIRADS≥ 3 lesions, and patients were randomised 1:1:1 for TB: transrectal in-bore MRI TB (MRI-TB), transperineal MRI-transrectal ultrasound (TRUS) fusion TB (FUS-TB), and transrectal cognitive TRUS TB (COG-TB). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: AEs (Clavien-Dindo) were compared using Pearson chi-square test. Univariate logistic regression tests were performed for the number of cores, biopsy approach, and usage of anticoagulants. The participants filled in baseline and 30-d postbiopsy International Prostate Symptom Score (IPSS) and International Index of Erectile Function (IIEF-5) questionnaires. The delta between measurements was compared using one-way analysis of variance. RESULTS AND LIMITATIONS: There were significant differences in minor AEs: 53% in MRI-TB, 71% in FUS-TB, and 85% in COG-TB (p < 0.001). The number of cores was associated with AEs (odds ratio [OR] 1.11 per extra biopsy [95% confidence interval {CI} 1.06-1.17, p < 0.001]). Anticoagulants were not associated with bleeding complications (OR 1.24 [95% CI 0.66-2.35, p = 0.5]). Transrectal approach (MRI-TB + COG-TB) increased the risk of any AE (OR 2.54 [95% CI 1.16-5.77, p < 0.05]) and nonsignificantly increased the risk of urinary tract infections (OR 3.69 [95% CI 0.46-168.4, p = 0.3]). Biopsy did not impact urinary (ΔIPSS 0.3, p = 0.1) and erectile function (ΔIIEF-5 -0.4, p = 0.5). The main limitation was that additional SB was performed in FUS-TB and COG-TB, and was omitted in MRI-TB, making comparison difficult. CONCLUSIONS: There was a significant difference in minor AEs among groups. An increase in the number of cores increased the overall risk of AEs. A low AE occurrence in MRI-TB was likely caused by the omission of SB. Prostate biopsy did not impact self-reported urinary and erectile functions. PATIENT SUMMARY: In this study, we compared the complication rates of three techniques of magnetic resonance imaging (MRI)-based targeted biopsy of the prostate. We found a significant difference in the occurrence of minor complication rates among three groups in favour of transrectal in-bore MRI targeted biopsy, likely caused by the omission of additional systematic biopsy in this group.

The FUTURE Trial: A Multicenter Randomised Controlled Trial on Target Biopsy Techniques Based on Magnetic Resonance Imaging in the Diagnosis of Prostate Cancer in Patients with Prior Negative Biopsies.

BACKGROUND: Guidelines advise multiparametric magnetic resonance imaging (mpMRI) before repeat biopsy in patients with negative systematic biopsy (SB) and a suspicion of prostate cancer (PCa), enabling MRI targeted biopsy (TB). No consensus exists regarding which of the three available techniques of TB should be preferred. OBJECTIVE: To compare detection rates of overall PCa and clinically significant PCa (csPCa) for the three MRI-based TB techniques. DESIGN, SETTING, AND PARTICIPANTS: Multicenter randomised controlled trial, including 665 men with prior negative SB and a persistent suspicion of PCa, conducted between 2014 and 2017 in two nonacademic teaching hospitals and an academic hospital. INTERVENTION: All patients underwent 3-T mpMRI evaluated with Prostate Imaging Reporting and Data System (PIRADS) version 2. If imaging demonstrated PIRADS ≥3 lesions, patients were randomised 1:1:1 for one TB technique: MRI-transrectal ultrasound (TRUS) fusion TB (FUS-TB), cognitive registration TRUS TB (COG-TB), or in-bore MRI TB (MRI-TB). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Primary (overall PCa detection) and secondary (csPCa detection [Gleason score ≥3+4]) outcomes were compared using Pearson chi-square test. RESULTS AND LIMITATIONS: On mpMRI, 234/665 (35%) patients had PIRADS ≥3 lesions and underwent TB. There were no significant differences in the detection rates of overall PCa (FUS-TB 49%, COG-TB 44%, MRI-TB 55%, p=0.4). PCa detection rate differences were -5% between FUS-TB and MRI-TB (p=0.5, 95% confidence interval [CI] -21% to 11%), 6% between FUS-TB and COG-TB (p=0.5, 95% CI -10% to 21%), and -11% between COG-TB and MRI-TB (p=0.17, 95% CI -26% to 5%). There were no significant differences in the detection rates of csPCa (FUS-TB 34%, COG-TB 33%, MRI-TB 33%, p>0.9). Differences in csPCa detection rates were 2% between FUS-TB and MRI-TB (p=0.8, 95% CI -13% to 16%), 1% between FUS-TB and COG-TB (p>0.9, 95% CI -14% to 16%), and 1% between COG-TB and MRI-TB (p>0.9, 95% CI -14% to 16%). The main study limitation was a low rate of PIRADS ≥3 lesions on mpMRI, causing underpowering for primary outcome. CONCLUSIONS: We found no significant differences in the detection rates of (cs)PCa among the three MRI-based TB techniques. PATIENT SUMMARY: In this study, we compared the detection rates of (aggressive) prostate cancer among men with prior negative biopsies and a persistent suspicion of cancer using three different techniques of targeted biopsy based on magnetic resonance imaging. We found no significant differences in the detection rates of (aggressive) prostate cancer among the three techniques.

Frailty and Transplantation.

Consequences of aging are gaining clinical relevance. In transplantation, aging and immunosenescence impact treatment and outcomes. The impact of aging, however, will critically depend on distinguishing healthy, chronological aging from biological aging that may result into frailty. Approximately 15% of individuals older than 65 years are frail, and it is expected that this condition will gain more clinical relevance with an expected increase to greater than 20% over the next 5 years. Clearly, frailty impacts various general aspects of health care and organ transplantation in particular including patient selection, waitlist management and treatment after transplantation. In general, frailty has been characterized by a compromised physiological reserve and an augmented vulnerability. In comparison to healthy aging, inflammatory markers and cytokines are increased in frail older adults. Thus, modifications of the immune response, in addition to physical limitations and changes of metabolism, are likely to impact outcomes after transplantation. Here, we provide a risk assessment of frailty at the time of transplant evaluation and review effects on outcomes and recovery after transplantation. Moreover, we summarize our current understanding of the pathophysiology of frailty and consequences on immune responses and metabolism.