Esa Kähkönen

In Vivo Imaging of Prostate Cancer Using [68Ga]-Labeled Bombesin Analog BAY86-7548

Purpose: A novel [68Ga]-labeled DOTA-4-amino-1-carboxymethyl-piperidine-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 peptide (BAY86-7548) having high affinity to bombesin receptor subtype II to detect primary and metastatic prostate carcinoma using positron emission tomography/computed tomography (PET/CT) was synthesized and evaluated for prostate cancer. Experimental Design: In this first human study with BAY86-7548, 14 men scheduled for radical prostatectomy (n = 11) or with biochemical recurrence after surgery or hormonal therapy (n = 3) were enrolled. The patients received an intravenous injection of BAY86-7548 followed by over 60-minute dynamic imaging of prostate gland (n = 10) and/or subsequent whole-body imaging (n = 14). The visual assessment of PET/CT images included evaluation of intraprostatic (12 subsextants) and pelvic nodal uptake of BAY86-7548 in 11 surgical patients and detection of potential metastatic foci in all patients. In patients with biochemical recurrence, results were compared with those of either [11C]-acetate (n = 2) or [18F]-fluoromethylcholine (n = 1) PET/CT. Results: We found a sensitivity, specificity, and accuracy of 88%, 81% and 83%, respectively, for detection of primary PCa and sensitivity of 70% for metastatic lymph nodes using histology as gold standard. BAY86-7548 correctly detected local recurrence in prostate bed and showed nodal relapse in accordance with [11C]-acetate PET/CT in 2 patients with biochemical relapse. In the third hormone refractory patient, BAY86-7548 failed to show multiple bone metastases evident on [18F]-fluoromethylcholine PET/CT. Conclusion: BAY86-7548 PET/CT is a promising molecular imaging technique for detecting intraprostatic prostate cancer. Clin Cancer Res; 19(19); 5434–43. ©2013 AACR.

Plasma Pharmacokinetics, Whole-Body Distribution, Metabolism, and Radiation Dosimetry of 68Ga Bombesin Antagonist BAY 86-7548 in Healthy Men

This first-in-human study investigated the safety, tolerability, metabolism, pharmacokinetics, biodistribution, and radiation dosimetry of 68Ga-bombesin antagonist 68Ga-DOTA-4-amino-1-carboxymethylpiperidine-d-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 (BAY 86-7548). Methods: Five healthy men underwent dynamic whole-body PET/CT after an intravenous injection of BAY 86-7548 (138 ± 5 MBq). Besides total radioactivity, plasma samples were analyzed by radio–high-performance liquid chromatography for metabolism of the tracer. Dosimetry was calculated using the OLINDA/EXM software. Results: Three radioactive plasma metabolites were detected. The proportion of unchanged BAY 86-7548 decreased from 92% ± 9% at 1 min after injection to 19% ± 2% at 65 min. The organs with the highest absorbed doses were the urinary bladder wall (0.62 mSv/MBq) and the pancreas (0.51 mSv/MBq). The mean effective dose was 0.051 mSv/MBq. BAY 86-7548 was well tolerated by all subjects. Conclusion: Intravenously injected BAY 86-7548 is safe, and rapid metabolism is demonstrated. A 150-MBq injection of BAY 86-7548 results in an effective dose of 7.7 mSv, which could be reduced to 5.7 mSv with frequent bladder voids.

Prebiopsy multiparametric 3T prostate MRI in patients with elevated PSA, normal digital rectal examination, and no previous biopsy.

To find the diagnostic accuracy of 3T multiparametric magnetic resonance imaging (mpMRI) and mpMRI targeted transrectal ultrasound (TRUS)‐guided biopsy using visual coregistration (TB) in patients with elevated prostate‐specific antigen (PSA), normal digital rectal examination, and no previous biopsy.

Novel biparametric MRI and targeted biopsy improves risk stratification in men with a clinical suspicion of prostate cancer (IMPROD Trial)

To evaluate the role of a 3T biparametric magnetic resonance imaging (bpMRI), T2‐weighted imaging, and three separate diffusion‐weighted imaging acquisitions combined with targeted biopsy (TB) for improving risk stratification of men with elevated prostate‐specific antigen (PSA).

Stratification of aggressive prostate cancer from indolent disease—Prospective controlled trial utilizing expression of 11 genes in apparently benign tissue

BACKGROUND The aim of the study was to evaluate the diagnostic power of molecular markers in men with a clinical suspicion of prostate cancer (PCa) using apparently benign areas as targeted by magnetic resonance imaging (MRI). METHODS In the study, 99 consecutive men with clinical suspicion of PCa in a prospective controlled trial (IMPROD, NCT01864135) were included. In addition to 12-core systematic and MRI-targeted biopsies, cores from normal-appearing prostate areas, based on clinical examination, ultrasound, and biparametric prostate MRI, were obtained. The RNA transcript levels of ACSM1, AMACR, CACNA1D, DLX1, KLK3, PCA3, PLA2G7, RHOU, SPINK1, SPON2, TMPRSS2-ERG, and TDRD1 were measured with quantitative reverse-transcription polymerase chain reaction. RESULTS Of the 99 men, 69 were diagnosed with PCa, 31 with primary Gleason pattern 3 and 38 with primary Gleason 4 or 5. TDRD1 messenger RNA (mRNA) levels were 1.3 times higher (P = 0.029) and the presence of TMPRSS2-ERG mRNAs more frequent in biopsies from men diagnosed with PCa (27/69, 39%) than in men without (5/30, 16%) (P = 0.035). The 2 markers identified aggressive PCa defined as Gleason sum≥7 at biopsy: median TDRD1 mRNA level was 1.4 higher (P = 0.005) and TMPRSS2-ERG expression more frequent (P<0.001) in high-grade cancer. A multivariate analysis of mRNA expression of 11 candidate genes combined with KLK3, serum prostate-specific antigen (PSA), percentage-free PSA, and prostate volume improved the discrimination between aggressive and nonaggressive PCa (area under the curve = 0.77) compared with the use of the candidate genes or clinical parameters alone. However, serum PSA, percentage-free PSA, and prostate volume resulted in the best discrimination between non-organ-confined PCa (T3) from organ-confined PCa (T2) and healthy prostate (area under the curve = 0.86). CONCLUSIONS Of the 11 studied genes, TDRD1 and TMPRSS2-ERG were able to statistically significantly differentiate men with PCa from men without it as single markers. However, a multivariate analysis using 15 features outperformed each individual marker in identifying aggressive PCa.

Lanthanide chelate complementation and hydrolysis enhanced luminescent chelate in real-time reverse transcription polymerase chain reaction assays for KLK3 transcripts

The requirement for high-performance reporter probes in real-time detection of polymerase chain reaction (PCR) has led to the use of time-resolved fluorometry of lanthanide chelates. The aim of this study was to investigate the applicability of the principle of lanthanide chelate complementation (LCC) in comparison with a method based on hydrolysis enhancement and quenching of intact probes. A real-time reverse transcription (RT) PCR assay for kallikrein-related peptidase 3 (KLK3, model analyte) was developed by using the LCC detection method. Both detection methods were tested with a standard series of purified PCR products, 20 prostatic tissues, 20 healthy and prostate cancer patient blood samples, and female blood samples spiked with LNCaP cells. The same limit of detection was obtained with both methods, and two cycles earlier detection with the LCC method was observed. KLK3 messenger RNA (mRNA) was detected in all tissue samples and in 1 of 20 blood samples identically with both methods. The background was 30 times lower, and the signal-to-background (S/B) ratio was 3 times higher, when compared with the reference method. Use of the new reporter method provided similar sensitivity and specificity as the reference method. The lower background, the improved S/B ratio, and the possibility of melting curve analysis and single nucleotide polymorphism (SNP) detection could be advantages for this new reporter probe.

Prevalence of Complications Leading to a Health Care Contact After Transrectal Prostate Biopsies: A Prospective, Controlled, Multicenter Study Based on a Selected Study Cohort

BACKGROUND Transrectal ultrasound-guided prostate biopsy (TRUS-Bx) is typically considered a safe procedure. However, infectious complications have been increasing. OBJECTIVE To determine the contemporary rate of biopsy-related infectious and noninfectious complications after TRUS-Bx, and identify potential risk factors associated with the complications. DESIGN, SETTING, AND PARTICIPANTS This was a prospective multicenter study and a substudy of a trial investigating the role of magnetic resonance imaging (MRI) in prostate cancer diagnosis (multi-IMPROD, NCT02241122). INTERVENTION TRUS-Bx was performed for all patients included in the study. Ciprofloxacin, levofloxacin, or fosfomycin was administered for antibiotic prophylaxis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS On inclusion, patients completed a detailed questionnaire and underwent MRI scanning. Antibiotic prophylaxis was prospectively recorded. After collection of a rectal swab, TRUS-Bx (total of 14-18 biopsy cores) was performed and. The rectal swabs were cultured and the antimicrobial susceptibility profile of Escherichia coli strains was analyzed. Biopsy complications leading to a visit to a health care unit were recorded and potential risk factors for complications were analyzed. RESULTS AND LIMITATIONS Twelve of the 294 patients (4.1%) had a biopsy-related complication, of which two (0.7%) were infectious and managed in the outpatient setting. Some 11% of the patients had an E. coli strain resistant to the prophylactic antibiotic administered. CONCLUSIONS The risk of an infectious or noninfectious complication after TRUS-Bx is very low, although the FQ resistance rate in the study population was significant. Accordingly, the present TRUS-Bx procedure and antibiotic prophylaxis are efficient in guarding against biopsy complications, but regional resistance rates may affect the generalizability of the results. PATIENT SUMMARY We examined the rate of complications after prostate biopsies in 294 patients. The risk of having a biopsy-related complication was low (4.1%). The rate of infectious complications was reasonably low (0.7%) although antibiotic resistance to the prophylactic antibiotic regimen was significant (11%).

Initiation of robot-assisted radical prostatectomies in Finland: Impact on centralization and quality of care

Abstract Objective The aim of this study was to analyze the impact of introduction of robot-assisted prostate surgery and its quality measures in Finland from 2008 to 2012. Materials and methods Registry data were collected for time trends and national distribution of prostate cancer surgery in Finland, while preoperative, operative and follow-up data were collected for quality measures. Results The number and proportion of robot-assisted laparoscopic radical prostatectomies (RALPs) increased rapidly and they accounted for 68% of all radical prostatectomies in 2012. The number of centers performing prostatectomies diminished from 25 to 20 at the expense of low-volume centers. In total, 1996 patients were operated on in the four RALP centers in 2008–2012. As anticipated, the learning curve was uniform between the centers, as were mean blood loss (212 ml), hospitalization (1.8 days) and catheterization times (10.6 days). At 3 and 12 months, 49.4% and 71.2% of patients, respectively, were totally continent (no pads). After unilateral nerve-sparing surgery, 9.9% and 5.1% had partial or normal erection at 3 months postoperatively and 14.8% and 20.4% at 12 months, respectively. If bilateral nerve sparing was done, the figures were 13.0% and 13.5% at 3 months and 14.6% and 34.9% at 12 months. Clavien–Dindo grade 3, 4 or 5 complications were seen in 0.3%, 0.3% and 0.1% of patients, respectively. Limitations of the study include non-standardized collection of outcome parameters. Conclusions This report shows that the main impact of adoption of RALP on a national level was rapid spontaneous centralization of prostate cancer surgery. The main advantages of minimally invasive prostatectomy, i.e. low blood loss and short hospitalization, are easily achieved, while continuous effort is necessary for improvements in surgical outcomes.

Antibiotic susceptibility of intestinal Escherichia coli in men undergoing transrectal prostate biopsies: a prospective, registered, multicentre study

To determine, in a prospective, multicentre setting, the prevalence of fluoroquinolone‐resistant (FQ‐R) and extended‐spectrum β‐lactamase (ESBL)‐producing Escherichia coli (E. coli) strains in men undergoing transrectal ultrasonography‐guided prostate biopsy (TRUS‐Bx) in Finland; and to survey the associated risk factors for having the previously mentioned strains.

Local delivery of a selective androgen receptor modulator failed as an anabolic agent in a rat bone marrow ablation model

Background and purpose — Selective androgen receptor modulators (SARMs) have been developed to have systemic anabolic effects on bones and muscles without the adverse effects of steroidal androgens. One unexplored therapeutic option is the targeted application of SARMs for the enhancement of local new bone formation. We evaluated the osteogenic efficacy of a locally released SARM (ORM-11984). Methods — ORM-11984 was mixed with a copolymer of L-lactide and ɛ-caprolactone (PLCL). An in vitro dissolution test confirmed the sustainable release of ORM-11984 from the matrix. A bone marrow ablation model was used in female Sprague-Dawley rats. Implants containing 10%, 30%, or 50% ORM-11984 by weight or pure PLCL were inserted into the medullary canal of the ablated tibia. At 6 and 12 weeks, the volume of intramedullary new bone and the perimeter of bone-implant contact were measured by micro-computed tomography and histomorphometry. Results — Contrary to our hypothesis, there was a negative correlation between the amount of new bone around the implant and the dose of ORM-11984. There was only a mild (and not statistically significant) enhancement of bone formation in ablated bones subjected to the lowest dose of the SARM (10%). Interpretation — This study suggests that intramedullary/endosteal osteogenesis had a negative, dose-dependent response to locally released SARM. This result highlights the complexity of androgenic effects on bones and also suggests that there are biological limits to the targeted local application of SARMs.