Histopathological concordance between prostate biopsies and radical prostatectomy specimens-implications of transrectal and transperineal biopsy approaches.

BACKGROUND: This study aimed to evaluate the histopathological concordance rates between prostate biopsies and radical prostatectomy specimens according to the applied biopsy approach (transrectal or transperineal). METHODS: We studied patients who had been newly diagnosed with clinically significant prostate cancer and who underwent a radical prostatectomy between 2018 and 2022. Patients were included if they underwent a prebiopsy magnetic resonance imaging and if they had not been previously treated for prostate cancer. Histopathological grading on prostate biopsies was compared with that on radical prostatectomy specimens. Univariable and multivariable logistic regression analyses were performed to assess the effect of the applied biopsy approach on histopathological concordance. Additional analyses were performed to assess the effect of the applied biopsy approach on American Urological Association risk group migration, defined as any change in risk group after radical prostatectomy. RESULTS: In total, 1058 men were studied, of whom 49.3% (522/1058) and 50.7% (536/1058) underwent transrectal and transperineal prostate biopsies, respectively. Histopathological disconcordance was observed in 37.8% (400/1058) of men while American Urological Association risk group migration was observed in 30.2% (320/1058) of men. A transperineal biopsy approach was found to be independently associated with higher histopathological concordance rates (OR 1.33 [95% CI 1.01-1.75], p = 0.04) and less American Urological Association risk group migration (OR 0.70 [95% CI 0.52-0.93], p = 0.01). CONCLUSIONS: The use of a transperineal biopsy approach improved histopathological concordance rates compared to the use of a transrectal biopsy approach. A transperineal biopsy approach may provide more accurate risk stratification for clinical decision-making. Despite recent improvements, histopathologic concordance remains suboptimal and should be considered before initiating management.

A prospective, multicenter head-to-head comparative study in patients with primary high-risk prostate cancer investigating the bone lesion detection of conventional imaging and 18F-PSMA-PET/CT.

PURPOSE: Prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) is an emerging staging tool for patients with primary high-risk prostate cancer (PCa). Patients with primary metastatic disease are staged using PSMA-PET/CT imaging, while previously published randomized clinical trials relied on conventional imaging (i.e., bone scintigraphy (BS) results. The aim of this study was to compare the ability of bone metastatic lesion detection and changes in staging for 18F-PSMA-PET/CT versus BS in high-risk PCa patients. METHODS: 79 patients with high-risk PCa were prospectively staged using BS and subsequent 18F-PSMA-PET/CT before initial therapy. Patients who presented with a BS showing no metastases represented Group 1, and patients with a BS showing low-volume disease according to the CHAARTED criteria (<4 bone metastases, no metastases outside vertebral column or pelvis and no visceral metastases) represented Group 2. Metastatic risk group according to CHAARTED and treatment strategies based on both imaging modalities were assessed. RESULTS: A change of CHAARTED risk group was observed in 9/70 (12.8%) of patients in Group 1. In Group 2, a change of risk group was found in 66.7% of patients, due to either upstaging (4/9 patients (44.4%)) and downstaging (2/9 patients (22.2%)). Treatment changes due to use of a different imaging modality occurred in almost 20% of patients. CONCLUSION: In patients with negative for cancer results on BS, upstaging on 18F-PSMA-PET/CT occurred only infrequently. Moreover, 18F-PSMA-PET/CT resulted in both upstaging and downstaging in a substantial subset of patients with low-volume metastatic disease on BS. Treatment changes occurred in almost 20% of cases depending on imaging results.

Preoperative multiparametric MRI does not lower positive surgical margin rate in a large series of patients undergoing robot-assisted radical prostatectomy.

To optimize functional outcomes after robot-assisted radical prostatectomy (RARP), surgical preservation of the neurovascular bundle is desired. However, nerve-sparing surgery (NSS) is only feasible in the absence of extraprostatic tumour extension (T-stage 3) to avoid the risk of positive surgical margins (PSM). Multiparametric magnetic-resonance imaging (MRI) is increasingly performed for primary prostate cancer and provides information on local tumour stage. In this study, we evaluated whether the availability of information from MRI influenced the incidence of PSM. A total of 523 patients undergoing RARP for localized prostate cancer in a single Dutch reference centre for prostate-cancer surgery were retrospectively evaluated (2013-2017). Patient characteristics and postoperative outcomes were retrieved. Patients were stratified according to the presence of a preoperative MRI. The incidence of PSM and proportion of patients receiving NSS was analysed using Chi-square tests and logistic regression analysis. N = 139 of 523 (26.6%) patients had a preoperative MRI scan available. Patients with MRI had identical preoperative characteristics compared to the patients without MRI, except for a higher percentage of patients having a prostate-specific antigen value ≥ 20 ng/mL (20.1% versus 9.4%, p = 0.004). PSM were present in 107/384 (27.9%) patients without MRI compared to 36/139 (25.9%) patients with an MRI scan before surgery (p = 0.66). Unilateral NSS was performed more often in the MRI group (26.6% vs. 11.7%), but NSS on both sides was more frequently performed in patients without MRI (57.6% versus 69.8%) (p < 0.001). MRI was not associated with PSM in multivariate analysis (p = 0.265). Preoperative mpMRI imaging was not associated with lower rates of positive surgical margins in patients undergoing RARP for localized prostate cancer.

Determining the diagnostic value of PSMA-PET/CT imaging in patients with persistent high prostate specific antigen levels and negative prostate biopsies.

PURPOSE: To assess the diagnostic performance of prostate specific membranous antigen (PSMA) positron emission tomography/computed tomography (PET/CT) imaging to localize primary prostate cancer (PCa) in men with persistent elevated prostate-specific antigen (PSA) levels and previous prostate biopsies that were negative for PCa. METHODS: In this study, 34 men with persistently elevated PSA-levels, previous negative for PCa biopsies and who subsequently underwent diagnostic PSMA-PET/CT imaging were retrospectively evaluated. Men were divided into 3 groups: 1. 12 men with a previous negative mpMRI scan (PI-RADS 1-2) 2. 17 men with a positive mpMRI scan (PI-RADS 3-5), but negative MRI-targeted biopsies and 3. Four men in whom mpMRI was contraindicated. If PSMA-avid lesions were seen, patients underwent 2-4 cognitive targeted biopsies in combination with systematic biopsies. The detection rate of PSMA-PET/CT for PCa, and the accuracy of (possible) targeted biopsies were calculated. RESULTS: Included men had a median PSA-level of 22.8 ng/mL (Interquartile Range 15.6-30.0) at the time of PSMA-PET/CT. Elevated PSMA-ligand uptake in the prostate suspicious for PCa was observed in 22/34 patients (64.7%). In 18/22 patients (54.5%), PSMA-targeted prostate biopsies were performed. In 3/18 patients (16.6%), the targeted biopsies showed International Society of Urological Pathology (ISUP) score 1-2 PCa. The other men had inflammation or benign findings after histopathological examination of the biopsy cores. CONCLUSION: In this study, the clinical value of PSMA-PET/CT for patients with an elevated PSA-level, and negative for PCa biopsies was low. Only very few men were diagnosed with PCa, and no clinically significant PCa was found.

Prediction of pathological response following neoadjuvant chemotherapy in patients with muscle-invasive bladder cancer: the PRE-PREVENCYS trial.

BACKGROUND: The recommended treatment for patients with non-metastatic muscle-invasive bladder cancer (MIBC) is neoadjuvant chemotherapy (NAC) and radical cystectomy (RC). Following NAC, 20-40% of patients experience a complete pathological response (pCR) in the RC specimen and these patients have excellent long-term overall survival. Subject to debate is, however, whether patients with a pCR to NAC benefit from RC, which is a major surgical procedure with substantial morbidity, and if these patients might be candidates for close surveillance instead. However, currently it is not possible to accurately identify patients with a pCR to NAC in whom RC might be withheld. The objective of this study is to assess whether pathological response in the RC specimen after NAC can be predicted based on clinical, radiological, and histological variables and on a wide set of molecular biomarkers assessed in tissue, blood and urine. METHODS: This is a multicentre, prospective cohort study, including patients with cT2a-T4a N0-N1 M0 urothelial cell MIBC who are scheduled to undergo cisplatin-based NAC followed by RC. Prior to start of therapy, a 2-Deoxy-2-[18F] fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) is performed. Response to NAC is evaluated by CT-scan. Blood and urine, including cytology, are prospectively collected for biomarker analyses before and after NAC. Immediately before RC, participants undergo cystoscopy with bimanual examination and a re-staging transurethral resection (TUR) of all visible cancerous lesions or with biopsies from scar tissue. Subsequently, RC is performed in all patients. Tissue from the diagnostic TUR, the re-staging TUR, and the RC specimen is examined for the presence of urothelial cancer carcinoma and DNA and RNA is isolated for molecular analysis. The primary endpoint is the pathological stage (ypTN) in the RC and ePLND specimen and its association with clinical response. DISCUSSION: If the PRE-PREVENCYS trial shows that the absence of residual disease after NAC in patients with MIBC is accurately predicted, a randomized controlled trial is scheduled comparing the overall survival of NAC plus RC versus NAC followed by close surveillance for patients with a clinically complete response (PREVENCYS trial). TRIAL REGISTRATION: Netherlands Trial Register: NL8678; Registered 20 May 2020 https://www.trialregister.nl/trial/8678.

Detection of prostate cancer with 18F-DCFPyL PET/CT compared to final histopathology of radical prostatectomy specimens: is PSMA-targeted biopsy feasible? The DeTeCT trial.

PURPOSE: In primary prostate cancer (PCa) patients, accurate staging and histologic grading are crucial to guide treatment decisions. 18F-DCFPyL (PSMA)-PET/CT has been successfully introduced for (re)staging PCa, showing high accuracy to localise PCa in lymph nodes and/or osseous structures. The diagnostic performance of 18F-DCFPyL-PET/CT in localizing primary PCa within the prostate gland was assessed, allowing for PSMA-guided targeted-prostate biopsy. METHODS: Thirty patients with intermediate-/high-risk primary PCa were prospectively enrolled between May 2018 and May 2019 and underwent 18F-DCFPyL-PET/CT prior to robot-assisted radical prostatectomy (RARP). Two experienced and blinded nuclear medicine physicians assessed tumour localisation within the prostate gland on PET/CT, using a 12-segment mapping model of the prostate. The same model was used by a uro-pathologist for the RARP specimens. Based on PET/CT imaging, a potential biopsy recommendation was given per patient, based on the size and PET-intensity of the suspected PCa localisations. The biopsy recommendation was correlated to final histopathology in the RARP specimen. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for clinically significant PCa (csPCa, Gleason score ≥ 3 + 4 = 7) were assessed. RESULTS: The segments recommended for potential targeted biopsy harboured csPCA in 28/30 patients (93%), and covered the highest Gleason score PCa segment in 26/30 patient (87%). Overall, 122 of 420 segments (29.0%) contained csPCa at final histopathological examination. Sensitivity, specificity, PPV and NPV for csPCa per segment using 18F-DCFPyL-PET/CT were 61.4%, 88.3%, 68.1% and 84.8%, respectively. CONCLUSIONS: When comparing the PCa-localisation on 18F-DCFPyL-PET/CT with the RARP specimens, an accurate per-patient detection (93%) and localisation of csPCa was found. Thus, 18F-DCFPyL-PET/CT potentially allows for accurate PSMA-targeted biopsy.

Pelvic lymph-node staging with 18F-DCFPyL PET/CT prior to extended pelvic lymph-node dissection in primary prostate cancer - the SALT trial.

PURPOSE: The detection of lymph-node metastases (N1) with conventional imaging such as magnetic resonance imaging (MRI) and computed tomography (CT) is inadequate for primarily diagnosed prostate cancer (PCa). Prostate-specific membrane antigen (PSMA) PET/CT is successfully introduced for the staging of (biochemically) recurrent PCa. Besides the frequently used 68gallium-labelled PSMA tracers, 18fluorine-labelled PSMA tracers are available. This study examined the diagnostic accuracy of 18F-DCFPyL (PSMA) PET/CT for lymph-node staging in primary PCa. METHODS: This was a prospective, multicentre cohort study. Patients with primary PCa underwent 18F-DCFPyL PET/CT prior to robot-assisted radical prostatectomy (RARP) with extended pelvic lymph-node dissection (ePLND). Patients were included between October 2017 and January 2020. A Memorial Sloan Kettering Cancer Centre (MSKCC) nomogram risk probability of ≥ 8% of lymph-node metastases was set to perform ePLND. All images were reviewed by two experienced nuclear physicians, and were compared with post-operative histopathologic results. RESULTS: A total of 117 patients was analysed. Lymph-node metastases (N1) were histologically diagnosed in 17/117 patients (14.5%). The sensitivity, specificity, positive predictive value and negative predictive value for the 18F-DCFPyL PET/CT detection of pelvic lymph-node metastases on a patient level were 41.2% (confidence interval (CI): 19.4-66.5%), 94.0% (CI 86.9-97.5%), 53.8% (CI 26.1-79.6%) and 90.4% (CI 82.6-95.0%), respectively. CONCLUSION: 18F-DCFPyL PET/CT showed a high specificity (94.4%), yet a limited sensitivity (41.2%) for the detection of pelvic lymph-node metastases in primary PCa. This implies that current PSMA PET/CT imaging cannot replace diagnostic ePLND. Further research is necessary to define the exact place of PSMA PET/CT imaging in the primary staging of PCa.

Correction to: Letter to the Editor re: Semiquantitative Parameters in PSMA-Targeted PET Imaging with [18F]DCFPyL: Impact of Tumor Burden on Normal Organ Uptake.

The article was updated to correct the following errors due to an error in production.

Early lesion detection with 18F-DCFPyL PET/CT in 248 patients with biochemically recurrent prostate cancer.

PURPOSE: Prostate-specific membrane antigen (PSMA) PET/CT is increasingly used in patients with biochemically recurrent prostate cancer (BCR), mostly using gallium-68 (168Ga)-labelled radiotracers. Alternatively, fluorine-18 (18F)-labelled PSMA tracers are available, such as 18F-DCFPyL, which offer enhanced image quality and therefore potentially increased detection of small metastases. In this study we evaluate the lesion detection efficacy of 18F-DCFPyL PET/CT in patients with BCR and determine the detection efficacy as a function of their PSA value. METHODS: A total of 248 consecutive patients were evaluated and underwent scanning with 18F-DCFPyL PET/CT for BCR between November 2016 and 2018 in two hospitals in the Netherlands. Patients were examined after radical prostatectomy (52%), external-beam radiation therapy (42%) or brachytherapy (6%). Imaging was performed 120 min after injection of a median dose of 311 MBq 18F-DCFPyL. RESULTS: In 214 out of 248 PET/CT scans (86.3%), at least one lesion suggestive of cancer recurrence was detected ('positive scan'). Scan positivity increased with higher PSA values: 17/29 scans (59%) with PSA values <0.5 ng/ml; 20/29 (69%) with PSA 0.5 to <1.0 ng/ml; 35/41 (85%) with PSA 1.0 to <2.0 ng/ml; 69/73 (95%) with PSA 2.0 to <5.0 ng/ml; and 73/76 (96%) with PSA ≥5.0 ng/ml. Interestingly, suspicious lesions outside the prostatic fossa were detected in 39-50% of patients with PSA <1.0 ng/ml after radical prostatectomy (i.e. candidates for salvage radiotherapy). CONCLUSION: 18F-DCFPyL PET/CT offers early detection of lesions in patients with BCR, even at PSA levels <0.5 ng/ml. These results appear to be comparable to those reported for 68Ga-PSMA and 18F-PSMA-1007, with potentially increased detection efficacy compared to 68Ga-PSMA for patients with PSA <2.0.

Linking surgical skills to postoperative outcomes: a Delphi study on the robot-assisted radical prostatectomy.

OBJECTIVE: To develop an assessment instrument for the evaluation of surgical videos to elucidate the association between surgical skills and postoperative outcomes after a robot-assisted radical prostatectomy (RARP). DESIGN: A Delphi study consisting of two consecutive online surveys and a consensus group meeting. SETTING: Urology departments of general, teaching and university hospitals in the Netherlands. PARTICIPANTS: All Dutch urologists with a specialization in RARP. RESULTS: Of 18 invited experts, 12 (67%) participated in the first online survey. In the second round, 9 of the 18 invited experts participated (50%). The Delphi meeting was attended by 5 of the 18 (27%) invited experts. The panel identified seven surgical steps with a possible association to postoperative outcomes. The experts also expected an association between adverse postoperative outcomes and the frequency of camera removals, the number of stitches placed, the amount of bleeding, and the extent of coagulation. These factors were incorporated into an assessment instrument. CONCLUSIONS: Experts in the field of RARP achieved consensus on 7 surgical steps and 4 aspects of the RARP procedure that may be related to adverse postoperative outcomes. The resulting assessment instrument will be tested in future research to determine its validity.

Local staging with multiparametric MRI in daily clinical practice: diagnostic accuracy and evaluation of a radiologic learning curve.

PURPOSE: To estimate the diagnostic accuracy of multiparametric MRI (mpMRI) for the detection of locally advanced prostate cancer (T-stage 3-4) prior to radical prostatectomy, in a multicenter cohort representing daily clinical practice. In addition, the radiologic learning curve for the detection of locally advanced disease is evaluated. METHODS: Preoperative mpMRI findings of 430 patients (2012-2016) were compared to pathology results following radical prostatectomy. The diagnostic accuracy (sensitivity, specificity, PPV, and NPV) for the detection of locally advanced disease was calculated and compared for all years separately, to evaluate the presence of a radiological learning curve. RESULTS: Of all 137 patients with locally advanced disease, 62 patients were preoperatively detected with mpMRI [sensitivity 45.3% (95% CI 36.9-53.6%), specificity 75.8% (CI 70.9-80.7%), PPV 46.6% (CI 38.1-55.1%), and NPV 74.7% (CI 69.8-79.7%)]. The diagnostic accuracy did not improve significantly over time (sensitivity p = 0.12; specificity p = 0.57). CONCLUSIONS: In daily clinical practice, the diagnostic accuracy of mpMRI for the detection of locally advanced prostate cancer remains limited. It, therefore, seems questionable whether mpMRI is adequate to guide preoperative decision-making. No significant radiologic learning curve for the detection of locally advance disease was observed.

Customized Tool for the Validation of Optical Coherence Tomography in Differentiation of Prostate Cancer.

OBJECTIVE: To design and demonstrate a customized tool to generate histologic sections of the prostate that directly correlate with needle-based optical coherence tomography pullback measurements. MATERIALS AND METHODS: A customized tool was created to hold the prostatectomy specimens during optical coherence tomography measurements and formalin fixation. Using the tool, the prostate could be sliced into slices of 4 mm thickness through the optical coherence tomography measurement trajectory. In this way, whole-mount pathology slides were produced in exactly the same location as the optical coherence tomography measurements were performed. Full 3-dimensional optical coherence tomography pullbacks were fused with the histopathology slides using the 3-dimensional imaging software AMIRA, and images were compared. RESULTS: A radical prostatectomy was performed in a patient (age: 68 years, prostate-specific antigen: 6.0 ng/mL) with Gleason score 3 + 4 = 7 in 2/5 biopsy cores on the left side (15%) and Gleason score 3 + 4 = 7 in 1/5 biopsy cores on the right side (5%). Histopathology after radical prostatectomy showed an anterior located pT2cNx adenocarcinoma (Gleason score 3 + 4 = 7). Histopathological prostate slides were produced using the customized tool for optical coherence tomography measurements, fixation, and slicing of the prostate specimens. These slides correlated exactly with the optical coherence tomography images. Various structures, for example, Gleason 3 + 4 prostate cancer, stroma, healthy glands, and cystic atrophy with septae, could be identified both on optical coherence tomography and on the histopathological prostate slides. CONCLUSION: We successfully designed and applied a customized tool to process radical prostatectomy specimens to improve the coregistration of whole mount histology sections to fresh tissue optical coherence tomography pullback measurements. This technique will be crucial in validating the results of optical coherence tomography imaging studies with histology and can easily be applied in other solid tissues as well, for example, lung, kidney, breast, and liver. This will help improve the efficacy of optical coherence tomography in cancer detection and staging in solid organs.

Recurrence after radical prostatectomy for organ-confined prostate cancer.

BACKGROUND: Some patients from our radical prostatectomy (RPx) series with organ-confined (pT2) prostate cancer and negative surgical margins show a PSA (prostate specific antigen) relapse. Aim of the study was to analyze this cohort of patients that otherwise would have been considered to be cured. PATIENTS AND METHODS: Since the introduction of PSA measurement in the follow-up after RPx, 475 pelvic lymph node dissections with subsequent RPx were performed in our department from 1988 to 1997. Of these, 227 were classified as pT2, 34 (15%) exhibited positive surgical margins, and 4 others were excluded due to an inadequate follow-up. Of the remaining 189 patients (study cohort), 19 (10%) developed a biochemical progression, defined as a minimum of 2 consecutive PSA measurements > or = 0.1 ng/ml. Only in one of them a G3 tumor was present. Median follow-up was 19.1 months. RESULTS: The Kaplan-Meier analysis of biochemical progression showed that after 1, 2 and 5 years, 95% (confidence interval (Cl) 91-99%), 91% (Cl 86-96%), and 77% (Cl 55-89%) of the patients were free of progression, respectively. This means that roughly one fourth of pT2 tumors will become progressive despite negative surgical margins. These 19 patients were subdivided into 4 groups: 1: biopsy-proven local recurrence (n = 2); 2: suspected local recurrence defined as slowly rising PSA < or = 2 ng/ml, but negative biopsies (n = 12); 3: distant metastasis proven by radiologic imaging (n = 1); 4: suspected distant metastasis defined as rapidly rising PSA > 9 ng/ml without direct radiologic evidence (n = 4). Preoperatively all patients from groups 3 + 4 had negative bone scans and 4/5 had preoperative PSA values < 10 ng/ml. In total 7 patients with proven recurrence or with proven metastasis had positive biopsies. CONCLUSION: A pathological diagnosis of organ-confined prostate cancer (pT2) and a meticulous analysis of negative surgical margins do not exclude the occurrence of local relapses in 7% (14/189), and there is evidence for suspect hematogenic spread of PC cells in at least 2% (4/189) of patients.

Value of tissue markers p27(kip1), MIB-1, and CD44s for the pre-operative prediction of tumour features in screen-detected prostate cancer.

The pre-operative prediction of prognostic tumour features in the radical prostatectomy specimen using routine clinicopathological variables remains limited. The present study evaluated the predictive value of the cell-cycle protein p27(kip1), the proliferation marker MIB-1, and the cell-adhesion protein CD44s, determined on the diagnostic needle biopsy of asymptomatic men screened for prostate cancer. Of 81 screen-detected prostate cancers, representative biopsy cores and matched radical prostatectomy specimens were immunohistochemically stained for these tissue markers. Conventional pre-operative and post-operative clinicopathological variables were assessed and cancers were divided according to a validated tumour classification model (potentially harmless, clinically significant). Low (<50%) p27(kip1) expression, high (> or = 10%) MIB-1 expression, and low (<25%) CD44s expression were considered adverse prognostic signs. Binary logistic regression analysis was performed to assess the most valuable predictors of clinically significant disease. An adverse prognostic immunostaining assessment on the biopsy was found in 10 (12.3%), 17 (21.0%), and 25 (30.9%) cases for p27(kip1), MIB-1, and CD44s, respectively. The concordance in tissue marker assessment between the biopsy specimen and matched radical prostatectomy specimens was low for all three. The positive predictive value (PPV) of p27(kip1) was 90.0%, remarkably higher than that of MIB-1 and CD44s (41.2% and 52.0%, respectively), indicating that a low radical prostatectomy p27(kip1) score is expected if the biopsy p27(kip1) score is low. Logistic regression analysis revealed that biopsy Gleason score (p<0.01) and p27(kip1) assessment (p<0.01) remained the only significant predictors of clinically significant disease. All cases with low p27(kip1) expression were found to have clinically significant disease after radical prostatectomy. The assessment of p27(kip1) in the biopsy specimen might thus assist in distinguishing between potentially aggressive and potentially non-aggressive disease in prostate cancer screening.

Serendipity in detecting disease in low prostate-specific antigen ranges.

OBJECTIVE: To assess the magnitude of prostate cancer detection by serendipity (the coincidental detection of prostate cancer during the evaluation of an abnormal screening test result) when a digital rectal examination (DRE) and transrectal ultrasonography (TRUS) are used as initial screening tests for prostate cancer in men with low levels of prostate-specific antigen (PSA; 0.0-3.9 ng/mL). PATIENTS AND METHODS: In all, 117 participants of a population-based screening study were diagnosed with prostate cancer after a standard evaluation of an abnormal screening test result; 49 underwent radical prostatectomy. Serendipity was defined as either: (i) the presence of prostate cancer opposite to the side that raised suspicion for cancer on DRE and/or TRUS; (ii) a negative lesion-directed biopsy while cancer was present in one or more of the cores of the sextant biopsy; (iii) a tumour volume of < 0.5 mL on radical prostatectomy. RESULTS: Depending on the definition, 27-63% of prostate cancers detected at low PSA values were detected coincidentally and not as a result of a true-positive test result. The proportion of cancers detected by serendipity was inversely correlated with serum PSA level. CONCLUSION: A relatively high proportion of prostate cancers diagnosed in men with low PSA levels, and in which a biopsy was prompted by a suspicious DRE and/or TRUS, are considered to be detected by chance only. As these cancers are mostly small (< 0.5 mL), with potentially low biological aggressiveness, relying on serendipity seems disadvantageous in prostate-cancer screening. The level of serendipity in prostate cancer detection, the poor performance of the screening test, and high inter-observer variability, casts further doubt on the utility of DRE (and TRUS) as initial screening tests for prostate cancer in population-based screening.

A phase II trial of methotrexate-human serum albumin (MTX-HSA) in patients with metastatic renal cell carcinoma who progressed under immunotherapy.

INTRODUCTION: Renal cell carcinoma (RCC) has a poor prognosis when metastasized to distant sites, although immunotherapy may offer a prolongation of survival in selected patient groups. Unfortunately, no treatment options remain when immunotherapy fails. In this phase IIa trial the tolerability and efficacy of the antifolate drug methotrexate-human serum albumin (MTX-HSA) were evaluated in patients with metastatic RCC who progressed after first-line immunotherapy. PATIENTS AND METHODS: A total of 17 patients started treatment, and 14 (12 men, 2 women) were evaluable for response according to the phase IIa Gehan design. Patients had had prior tumor nephrectomy, were in relatively good general condition, had no impairment of renal, liver or bone marrow function, and had progressive metastatic disease after treatment with interferon-alpha (IFN-alpha) with or without cis-retinoic acid (EORTC protocols 30951 and 30947). MTX-HSA was given once a week intravenously on an outpatient basis at a dose of 50 mg/m(2). The treatment interval was prolonged in those patients who had not yet recovered from previous toxicities. RESULTS: Toxicity was manageable, relatively mild to moderate and reversible in most cases. Grade 2/3 mucositis (10/17) and grade 3 elevated transaminase levels (4/17) were most frequent, and in only one patient was a grade 4 thrombocytopenia reported. Of three inevaluable patients, one discontinued treatment due to drug-related toxicities. The mean administration interval was 12.1 days, and 7 of 14 evaluable patients had treatment intervals of 1 or 2 weeks. No objective responses were seen, although eight patients had stable disease (stabilization >2 months) for up to 8 months (median 121 days). CONCLUSION: MTX-HSA was generally well tolerated and can be given on an outpatient basis, but no objective responses were seen in patients with metastatic RCC who had progressed after previous immunotherapy.

The predictive value for prostate cancer of lesions that raise suspicion of concomitant carcinoma: an evaluation from a randomized, population-based study of screening for prostate cancer.

BACKGROUND: Suspicion of prostate carcinoma may persist after an initial negative biopsy result, and repeated biopsy is suggested. The authors assessed whether diagnostic follow-up of men with an initial diagnosis of isolated, high-grade prostatic intraepithelial neoplasia (HPIN) and a prostate biopsy suspicious for malignancy (PBSM) is needed. METHODS: The frequency of isolated HPIN and PBSM was determined in 4057 participants of a population-based screening study who underwent systematic sextant transrectal biopsy. The predictive value for prostate carcinoma of HPIN and PBSM was determined by performing repeated biopsies at 6-week interval. The additional predictive value for malignant disease within a screened population was assessed by performing repeated biopsies at a 1-year interval in 462 consecutively recruited men with an initial benign biopsy result. Participants were subjected to a second screening at a 4-year interval. The biopsy and radical prostatectomy tumor features were determined. RESULTS: Isolated HPIN and PBSM were diagnosed in 0.8% and 2.6% of biopsied men, respectively. The detection rates on repeated biopsy were 10.0% (3 of 30 men) for isolated HPIN, 38.7% (36 of 93 men) for PBSM, and 11.0% (51 of 462 men) for those with initial benign biopsy results. Except for two men (one with PBSM and one with HPIN), all others remained free of prostate carcinoma at their second screening. Features of the tumors that were detected after PBSM were comparable to those that were detected on initial biopsy, whereas the few tumors that were diagnosed after HPIN had highly favorable features. CONCLUSIONS: Compared with men who have PBSM, men with isolated HPIN on initial biopsy are at no greater risk of being diagnosed with prostate carcinoma than if their initial biopsies were assessed as benign only. Moreover, the features of tumors that are diagnosed after an evaluation of HPIN warrant no early, extensive diagnostic follow-up.

Pathologic features of prostate cancer found at population-based screening with a four-year interval.

BACKGROUND: The currently recommended frequency for prostate-specific antigen (PSA) screening tests for prostate cancer is 1 year, but the optimal screening interval is not known. Our goal was to determine if a longer interval would compromise the detection of curable prostate cancer. METHODS: A cohort of 4491 men aged 55-75 years, all participants in the Rotterdam section of the European Randomized Study of (population-based) Screening for Prostate Cancer, were invited to participate in an initial PSA screening. Men who received that screening were invited for a second screen 4 years later. Pathology findings from needle biopsy cores were compared for men in both rounds. Statistical tests were two-sided. RESULTS: A total of 4133 men were screened in the first round (the prevalence screen), and 2385 were screened in the second round. The median amount of cancer in needle biopsy sets was 7.0 mm (95% confidence interval [CI] = 5.4 mm to 8.6 mm) in the first round and 4.1 mm (95% CI = 2.6 mm to 5.6 mm) in the second round (P =.001). Thirty-six percent of the adenocarcinomas detected in the first round but only 16% of those detected in the second round had a Gleason score of 7 or higher (mean difference = 20% [95% CI = 10% to 30%]; P<.001). Whereas 25% of the adenocarcinomas detected in the first round had adverse prognostic features, only 6% of those detected in the second round did (mean difference = 19% [95% CI = 11% to 26%]; P<.001). Baseline PSA values were predictive for the amount of tumor in biopsies in men with cancer in the first round but not for that in the second round. CONCLUSION: Most large prostate cancers with high serum PSA levels were effectively detected in a prevalence screen. In this population, a screening interval of 4 years appears to be short enough to constrain the development of large tumors, although it is inconclusive whether this will result in a survival benefit.