Current sexual health care has not yet succeeded to guide men and their partners sufficiently when it comes to dealing with the consequences of prostate cancer (PCa) diagnosis and treatment. The... Show moreCurrent sexual health care has not yet succeeded to guide men and their partners sufficiently when it comes to dealing with the consequences of prostate cancer (PCa) diagnosis and treatment. The majority of men need a standardized consultation with a specialized healthcare provider (HCP) to discuss sexual health issues preferably within three months after treatment. Although current written information provision coming from urology departments discusses sexual health more often than radiotherapy departments; sexual dysfunction (SD) is still not routinely addressed. Focus during consultations is mostly on men while most of the partners also experience difficulties when dealing with sexual side effects. Regarding HCPs, urology residents experience lack of knowledge and competence to treat SD after PCa treatment and an unmet need exists for additional education and training. A symposium on sexual health care in PCa led to an increase of awareness to discuss SD more often during consultations. In case HCPs feel lack of knowledge, competence, time or tools to discuss sexual health after PCa treatment, referral to a specialized HCP should occur; according to the needs and preferences of men and their partners. However, management of outpatient clinics and availability of referral options are still in need of melioration. Show less
Wang, W.; Nier, C.R. de; Wuhrer, M.; Lageveen-Kammeijer, G.S.M. 2023
Prostate-specific antigen (PSA) is a well-known clinical biomarker in prostate cancer (PCa) diagnosis, but a better test is still needed, as the serum-level-based PSA quantification exhibits... Show moreProstate-specific antigen (PSA) is a well-known clinical biomarker in prostate cancer (PCa) diagnosis, but a better test is still needed, as the serum-level-based PSA quantification exhibits limited specificity and comes with poor predictive value. Prior to PSA, prostatic acid phosphatase (PAP) was used, but it was replaced by PSA because PSA improved the early detection of PCa. Upon revisiting PAP and its glycosylation specifically, it appears to be a promising new biomarker candidate. Namely, previous studies have indicated that PAP glycoforms differ between PCa and non-PCa individuals. However, an in-depth characterization of PAP glycosylation is still lacking. In this study, we established an in-depth glycoproteomic assay for urinary PAP by characterizing both the micro- and macroheterogeneity of the PAP glycoprofile. For this purpose, PAP samples were analyzed by capillary electrophoresis coupled to mass spectrometry after affinity purification from urine and proteolytic digestion. The developed urinary PAP assay was applied on a pooled DRE (digital rectal examination) urine sample from nine individuals. Three glycosylation sites were characterized, namely N-94, N-220, and N-333, via N-glycopeptide analysis. Taking sialic acid linkage isomers into account, a total of 63, 27, and 4 N-glycan structures were identified, respectively. The presented PAP glycoproteomic assay will enable the determination of potential glycomic biomarkers for the early detection and prognosis of PCa in cohort studies. Show less
The use of T-cell receptor (TCR) gene transfer for the treatment of both hematological and solid tumors is increasing. Using TCR gene transfer T cells can be redirected to target tumor or lineage... Show moreThe use of T-cell receptor (TCR) gene transfer for the treatment of both hematological and solid tumors is increasing. Using TCR gene transfer T cells can be redirected to target tumor or lineage-specific antigens. Especially for poor immunogenic tumors this offers the potential to circumvent limitations of the endogenous T-cell repertoire. Still, the broad use of TCR-based therapy is hampered by a limited number of targeted antigens and HLA class I binding restrictions of TCRs. Furthermore, several of the pioneering T-cell based therapies have demonstrated that the balance between therapeutic efficacy and safety remains a challenge as T-cell mediated toxicities have occurred. In this thesis we identified novel targets, peptides and TCRs in order to treat a broader patient population, among others ovarian and prostate cancer patients. We stringently selected appropriate tumor- and lineage-specific targets using a differential gene expression analysis, and identified naturally expressed peptides from the HLA class I associated ligandome. We isolated peptide-specific T cells, sequenced their TCRs and carefully selected the most promising TCRs. Overall, we selected ten TCRs that demonstrated an effective and safe reactivity pattern based on the performed T-cell reactivity screenings. These TCRs demonstrated reactivity against broad panels of patient-derived tumor samples and/or tumor cell lines, without reactivity against a broad variety of healthy cell subsets or other antigen negative cells. Furthermore, in this thesis we set up human induced pluripotent stem cell (hiPSC)-derived models to additionally examine toxicity risks of T cells against vital organs or specialized cell subsets. We demonstrated added value of these models in determining toxicity risks in the preclinical pipeline of TCRs. Show less
Berrens, A.C.; Scheltema, M.; Maurer, T.; Hermann, K.; Hamdy, F.C.; Knipper, S.; ... ; Leeuwen, F.W.B. van 2023
Purpose Prostate-specific membrane antigen (PSMA) is increasingly considered as a molecular target to achieve precision surgery for prostate cancer. A Delphi consensus was conducted to explore... Show morePurpose Prostate-specific membrane antigen (PSMA) is increasingly considered as a molecular target to achieve precision surgery for prostate cancer. A Delphi consensus was conducted to explore expert views in this emerging field and to identify knowledge and evidence gaps as well as unmet research needs that may help change practice and improve oncological outcomes for patients.Methods One hundred and five statements (scored by a 9-point Likert scale) were distributed through SurveyMonkey (R). Following evaluation, a consecutive second round was performed to evaluate consensus (16 statements; 89% response rate). Consensus was defined using the disagreement index, assessed by the research and development project/University of California, Los Angeles appropriateness method.Results Eighty-six panel participants (72.1% clinician, 8.1% industry, 15.1% scientists, and 4.7% other) participated, most with a urological background (57.0%), followed by nuclear medicine (22.1%). Consensus was obtained on the following: (1) The diagnostic PSMA-ligand PET/CT should ideally be taken < 1 month before surgery, 1-3 months is acceptable; (2) a 16-20-h interval between injection of the tracer and surgery seems to be preferred; (3) PSMA targeting is most valuable for identification of nodal metastases; (4) gamma, fluorescence, and hybrid imaging are the preferred guidance technologies; and (5) randomized controlled clinical trials are required to define oncological value. Regarding surgical margin assessment, the view on the value of PSMA-targeted surgery was neutral or inconclusive. A high rate of "cannot answer" responses indicates further study is necessary to address knowledge gaps (e.g., Cerenkov or beta-emissions).Conclusions This Delphi consensus provides guidance for clinicians and researchers that implement or develop PSMA-targeted surgery technologies. Ultimately, however, the consensus should be backed by randomized clinical trial data before it may be implemented within the guidelines. Show less
Schepens, M.H.J.; Hooff, M.L. van; Galien, O. van der; Plantes, C.M.P.Z. des; Somford, D.M.; Leeuwen, P.J. van; ... ; Limbeek, J. van 2023
BackgroundOn the basis of previous analyses of the incidence of urinary incontinence (UI) after radical prostatectomy (RP), the hospital RP volume threshold in the Netherlands was gradually... Show moreBackgroundOn the basis of previous analyses of the incidence of urinary incontinence (UI) after radical prostatectomy (RP), the hospital RP volume threshold in the Netherlands was gradually increased from 20 per year in 2017, to 50 in 2018 and 100 from 2019 onwards.ObjectiveTo evaluate the impact of hospital RP volumes on the incidence and risk of UI after RP (RP-UI).Design, setting, and participantsPatients who underwent RP during 2016–2020 were identified in the claims database of the largest health insurance company in the Netherlands. Incontinence was defined as an insurance claim for ≥1 pads/d.Outcome measurements and statistical analysisThe relationship between hospital RP volume (HV) and RP-UI was assessed via multivariable analysis adjusted for age, comorbidity, postoperative radiotherapy, and lymph node dissection.Results and limitationsRP-UI incidence nationwide and by RP volume category did not decrease significantly during the study period, and 5-yr RP-UI rates varied greatly among hospitals (19–85%). However, low-volume hospitals (≤120 RPs/yr) had a higher percentage of patients with RP-UI and higher variation in comparison to high-volume hospitals (>120 RPs/yr). In comparison to hospitals with low RP volumes throughout the study period, the risk of RP-UI was 29% lower in hospitals shifting from the low-volume to the high-volume category (>120 RPs/yr) and 52% lower in hospitals with a high RP volume throughout the study period (>120 RPs/yr for 5 yr).ConclusionsA focus on increasing hospital RP volumes alone does not seem to be sufficient to reduce the incidence of RP-UI, at least in the short term. Measurement of outcomes, preferably per surgeon, and the introduction of quality assurance programs are recommended.Patient summaryIn the Netherlands, centralization of surgery to remove the prostate (RP) because of cancer has not yet improved the occurrence of urinary incontinence (UI) after surgery. Hospitals performing more than 120 RP operations per year had better UI outcomes. However, there was a big difference in UI outcomes between hospitals. Show less
In prostate (PCa) and colorectal (CRC) cancer, there is a need to improve patient stratification techniques that aid diagnostic and prognostic decision-making. To fulfill this unmet clinical need,... Show moreIn prostate (PCa) and colorectal (CRC) cancer, there is a need to improve patient stratification techniques that aid diagnostic and prognostic decision-making. To fulfill this unmet clinical need, the measurement of disease-related biological parameters known as “biomarkers” from biofluids is an approach with the potential to develop noninvasive tests as well as achieve greater clinical accuracy and personalized medicine. Thus, this thesis focused on developing a better understanding of biomarkers relevant to PCa and CRC as well as advancing analytical methodology and achieving methodological advancements for the purpose of biomarker discovery. In chapters two and three, a large diversity of prostate-specific antigen (PSA) cleaved and non-cleaved proteoforms (PCa) with different N-glycosylation patterns were determined in urine and seminal fluid using capillary electrophoresis-electrospray ionization-mass spectrometry (CE-ESI-MS), some of which are relevant for PCa patient stratification. In addition, the data processing workflow was improved in chapter three in order to enable larger studies of intact proteoforms to be performed. Furthermore, chapter four developed a reversed phase-liquid chromatography (RPLC)-MS method whereby it was possible to determine sialic acid linkages and positional isomers in released N-glycans following fluorescent labeling and sialic acid derivatization. This method was applied in chapter five to study serum N-glycosylation profiles in CRC and it was demonstrated that specific N-glycan isomers are implicated in the disease and differences between histological types were eradicated following surgery. Show less
In this thesis, different preclinical strategies were explored aiming at the identification of putative novel therapies for prostate and bladder cancer. The first part of this thesis (Chapter 2 and... Show moreIn this thesis, different preclinical strategies were explored aiming at the identification of putative novel therapies for prostate and bladder cancer. The first part of this thesis (Chapter 2 and Chapter 3) describes the generationof preclinical, patient-derived model systems of prostate and bladder cancer. In Chapter 2, an overview is provided of the most commonly used patient-derived model systems for urological tumors, and a framework on how these patient derived tumor models can be employed to address preclinical and clinical unmet needs is presented. In Chapter 3, we developed and optimized the culture of ex vivo tumor tissue slices and employed this model to detect anti-tumor responses of chemotherapeutic agents Docetaxel and Gemicitabin. Subsequently in Chapters 4, 5 and 6, we describe the use of multiple preclinical translational models, including patient-derived tumor models. In Chapter 4 and 5 the translational potential of the approved antipsychotic drug penfluridol was determined in bladder and prostate cancer. In Chapter 6, the use of oncolytic reovirus jin-3 as putative novel therapeutic strategy for the treatment of prostate is investigated. Finally, in Chapter 7, we describe a novel preclinical screening strategy based on E-cadherin (re)induction and inhibition of invasion for the identification of a new class of small molecules for the treatment of aggressive epithelial cancers. Show less
Dassen, M.G.; Janssen, T.; Kusters, M.; Pos, F.; Kerkmeijer, L.G.W.; Heide, U.A. van der; Bijl, E. van der 2023
PurposeTo quantify the difference in accuracy of adapt-to-position (ATP), adapt-to-rotation (ATR) and adapt-to-shape (ATS) workflows used in MRI-guided online adaptive radiotherapy for prostate... Show morePurposeTo quantify the difference in accuracy of adapt-to-position (ATP), adapt-to-rotation (ATR) and adapt-to-shape (ATS) workflows used in MRI-guided online adaptive radiotherapy for prostate carcinoma (PCa) by evaluating the margins required to accommodate intra-fraction motion of the clinical target volumes for prostate (CTVpros), prostate including seminal vesicles (CTVpros + sv) and gross tumor volume (GTV).Materials and methodsClinical delineations of the CTVpros, CTVpros + sv and GTV of 24 patients with intermediate- and high-risk PCa, treated using ATS on a 1.5 T MR-Linac, were used for analysis. Delineations were available pre- and during beam-on. To simulate ATP and ATR workflows, we automatically generated the structures associated with these workflows using rigid transformations from the planning-MRI to the daily online MRIs. Clinical GTVs were analyzed as ATR GTVs and only ATP GTVs were simulated. Planning target volumes (PTVs) were generated with isotropic margins ranging 0.0–5.0 mm. The volumetric overlap was calculated between these PTVs and their corresponding clinical delineation on the MRI acquired during beam-on and averaged over all treatment fractions.ResultsThe PTV margin required to cover > 95% of the CTVpros was equal (2.5 mm) for all workflows. For the CTVpros + sv, this margin increased to 5.0, 4.0 and 3.5 mm in the ATP, ATR and ATS workflow, respectively. GTV coverage improved from ATP to ATR for margins up to 4.0 mm.ConclusionATP, ATR and ATS workflows ensure equal coverage of the CTVpros for the current clinical margins. For the CTVpros + sv, ATS showed optimal performance. GTV coverage improves by additional adaptations to prostate rotations. Show less
Newly introduced hybrid systems that combine an MRI scanner with a linear accelerator for radiation treatment, called MR-linacs, provide an opportunity for the daily acquisition of quantitative MRI... Show moreNewly introduced hybrid systems that combine an MRI scanner with a linear accelerator for radiation treatment, called MR-linacs, provide an opportunity for the daily acquisition of quantitative MRI (qMRI) without increasing patient burden. This allows for the measurement of changes in quantitative MRI biomarkers over time, that may indicate a response to the radiation treatment. In this thesis, the performance of the Unity MR-linac with regards to several qMRI sequences was characterized, showing results similar to diagnostic systems in terms of accuracy and repeatability. Additionally, we found changes in qMRI parameters in patients early during treatment, which indicates potential as biomarkers for treatment outcome. Show less
Non-metastatic prostate cancer (PCa) patients are at increased risk for osteoporosis and fractures mainly due to androgen deprivation therapy (ADT)-associated hypogonadism, but this remains largely... Show moreNon-metastatic prostate cancer (PCa) patients are at increased risk for osteoporosis and fractures mainly due to androgen deprivation therapy (ADT)-associated hypogonadism, but this remains largely underdiagnosed and untreated. In this study, we examine the value of pre-screening calcaneal QUS in identifying patients who should be referred for screening for osteoporosis using dual-energy X-Ray absorptiometry (DXA). In a single-center retrospective cross-sectional cohort study, we analysed data on DXA and calcaneal QUS measurements systematically collected between 2011 and 2013 in all non-metastatic PCa patients attending our Uro-Oncological Clinic at the Leiden University Medical Center. Receiver operating characteristic curves were used to assess the positive (PPV) and negative (NPV) predictive values of QUS T-scores of 0, -1.0, and - 1.8 in identifying DXAdiagnosed osteoporosis (T-scores < - 2.5 and < -2) at lumbar spine and/or femoral neck. Complete sets of data were available in 256 patients, median age 70.9 (53.6-89.5) years; 93.0 % had received local treatment, 84.4 % with additional ADT. Prevalence of osteoporosis and osteopenia was respectively 10.5 % and 53 %. Mean QUS Tscore was -0.54 +/- 1.58. Whereas PPV at any QUS T-score was <25 %, precluding the use of QUS as surrogate for DXA in screening for osteoporosis, QUS T-scores of -1.0 to 0.0 had a NPV of >= 94.5 % for DXA T-scores < 2.5 and < -2 at any site, confidently identifying patients least likely to have osteoporosis, thereby significantly reducing the number of patients requiring DXA screening for diagnosing osteoporosis by up to two-third. Osteoporosis screening is a significant unmet need in non-metastatic prostate cancer patients treated with ADT, and QUS may represent a valuable alternative pre-screening strategy to overcome logistics, time demands, and economic barriers encountered with current strategies for osteoporosis screening in these patients. Summary: Osteoporosis and associated increased fracture risk are common in non-metastatic prostate carcinoma, mainly due to androgen deprivation therapy, but these often remain underdiagnosed and untreated. We demonstrate that QUS is a safe, less costly pre-screen tool that reduces by up to two-third the number of patients requiring referral for DXA for osteoporosis screening. Show less
Bone and joint disorders have an enormous personal- and societal impact. Diagnosis and treatment of these disorders are most efficient if targeted screening, accurate diagnosis, and targeted... Show moreBone and joint disorders have an enormous personal- and societal impact. Diagnosis and treatment of these disorders are most efficient if targeted screening, accurate diagnosis, and targeted treatment are available. To enable targeted screening, the population at risk must be well-defined, and categorized if required. Subsequently, screening- and diagnostic methods must have good, or excellent predictive value and finally, treatment must target the disease, thus spare healthy tissues and processes and thereby avoid adverse events.The aim of this thesis is to gain new insights about the diagnostic process- and treatment of pathological conditions of the bone and joints, namely male urological cancer-induced bone loss and inflammatory arthritis. Show less
Background: Extended pelvic nodal dissection (ePLND) represents the gold standard for nodal staging in prostate cancer (PCa). Prostate-specific membrane antigen (PSMA) radioguided surgery (RGS)... Show moreBackground: Extended pelvic nodal dissection (ePLND) represents the gold standard for nodal staging in prostate cancer (PCa). Prostate-specific membrane antigen (PSMA) radioguided surgery (RGS) could identify lymph node invasion (LNI) during robotassisted radical prostatectomy (RARP).Objective: To report the planned interim analyses of a phase 2 prospective study (NCT04832958) aimed at describing PSMA-RGS during RARP.Design, setting, and participants: A phase 2 trial aimed at enrolling 100 patients with intermediate- or high-risk cN0cM0 PCa at conventional imaging with a risk of LNI of >5% was conducted. Overall, 18 patients were enrolled between June 2021 and March 2022. Among them, 12 patients underwent PSMA-RGS and represented the study cohort.Surgical procedure: All patients received Ga-68-PSMA positron emission tomography (PET)/magnetic resonance imaging; Tc-99m-PSMA-I&S was synthesised and administered intravenously the day before surgery, followed by single-photon emission computed tomography/computed tomography. A Drop-In gamma probe was used for in vivo measurements. All positive lesions (count rate >= 2 compared with background) were excised and ePLND was performed.Measurements: Side effects, perioperative outcomes, and performance characteristics of robot-assisted PSMA-RGS for LNI were measured.Results and limitations: Overall, four (33%), six (50%), and two (17%) patients had intermediate-risk, high-risk, and locally advanced PCa. Overall, two (17%) patients had pathologic nodal uptake at PSMA PET. The median operative time, blood loss, and length of stay were 230 min, 100 ml, and 5 d, respectively. No adverse events and intraoperative complications were recorded. One patient experienced a 30-d complication (ClavienDindo 2; 8.3%). Overall, three (25%) patients had LNI at ePLND. At per-region analyses on 96 nodal areas, sensitivity, specificity, positive predictive value, and negative predictive value of PSMA-RGS were 63%, 99%, 83%, and 96%, respectively. On a per-patient level, sensitivity, specificity, positive predictive value, and negative predictive values of PSMA-RGS were 67%, 100%, 100%, and 90%, respectively.Conclusions: Robot-assisted PSMA-RGS in primary staging is a safe and feasible procedure characterised by acceptable specificity but suboptimal sensitivity, missing micrometastatic nodal disease.Patient summary: Prostate-specific membrane antigen radioguided robot-assisted surgery is a safe and feasible procedure for the intraoperative identification of nodal metastases in cN0cM0 prostate cancer patients undergoing robot-assisted radical prostatectomy with extended pelvic lymph node dissection. However, this approach might still miss micrometastatic nodal dissemination. (c) 2022 The Author(s). Published by Elsevier B.V. on behalf of European Association of Urology. Show less
Background: It has been proven that intraoperative prostate-specific membrane antigen (PSMA)-targeted radioguidance is valuable for the detection of prostate cancer (PCa) lesions during open... Show moreBackground: It has been proven that intraoperative prostate-specific membrane antigen (PSMA)-targeted radioguidance is valuable for the detection of prostate cancer (PCa) lesions during open surgery. Rapid extension of robot-assisted, minimally invasive surgery has increased the need to make PSMA-radioguided surgery (RGS) robot-compliant.Objective: To evaluate whether the miniaturized DROP-IN gamma probe facilitates translation of PSMA-RGS to robotic surgery in men with recurrent PCa.Design, setting, and participants: This prospective feasibility study included 20 patients with up to three pelvic PCa recurrences (nodal or local) on staging PSMA positron emission tomography (PET) after previous curative-intent therapy.Surgical procedure: Robot-assisted PSMA-RGS using the DROP-IN gamma probe was carried out 19-23 h after intravenous injection of (99m)technetium PSMA-Investigation & Surgery (Tc-99m-PSMA-I&S).Measurements: The primary endpoint was the feasibility of robot-assisted PSMA-RGS. Secondary endpoints were a comparison of the radioactive status (positive or negative) of resected specimens and final histopathology results, prostate-specific antigen (PSA) response following PSMA-RGS, and complications according to the Clavien-Dindo classification.Results and limitations: Using the DROP-IN probe, 19/21 (90%) PSMA-avid lesions could be resected robotically. On a per-lesion basis, the sensitivity and specificity of robot-assisted PSMA-RGS was 86% and 100%, respectively. A prostate-specific antigen (PSA) reduction of >50% and a complete biochemical response (PSA <0.2 ng/ml) were seen in 12/18 (67%) and 4/18 (22%) patients, respectively. During follow-up of up to 15 mo,* Corresponding author. Department of Urology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, Amsterdam 1066 CX, The Netherlands. Tel. +31 205126988. E-mail address: h.d.barros@nki.nl (H.A. de Barros) Show less
Background: With the rise of prostate-specific membrane antigen (PSMA) radioguided surgery, which is performed using a microdosing regime, demand for visual target confirmation via fluorescence... Show moreBackground: With the rise of prostate-specific membrane antigen (PSMA) radioguided surgery, which is performed using a microdosing regime, demand for visual target confirmation via fluorescence guidance is growing. While proven very effective for radiotracers, microdosing approaches the detection limit for fluorescence imaging. Thus, utility will be highly dependent on the tracer performance, the sensitivity of the fluorescence camera used, and the degree of background signal. Using a porcine model the ability to perform robot-assisted radical prostatectomy under fluorescence guidance using the bimodal or rather hybrid PSMA tracer (Tc-99m-EuK-(SO3)Cy5-mas(3)) was studied, while employing the tracer in a microdosing regime. This was followed by ex vivo evaluation in surgical specimens obtained from prostate cancer patients. Results: T-50% blood and T-50% urine were reached at 85 min and 390 min, in, respectively, blood and urine. Surgical fluorescence imaging allowed visualization of the prostate gland based on the basal PSMA-expression in porcine prostate. Together, in vivo visualization of the prostate and urinary excretion suggests at least an interval of > 7 h between tracer administration and surgery. Confocal microscopy of excised tissues confirmed tracer uptake in kidney and prostate, which was confirmed with PSMA IHC. No fluorescence was detected in other excised tissues. Tumor identification based on ex vivo fluorescence imaging of human prostate cancer specimens correlated with PSMA IHC. Conclusion: Intraoperative PSMA-mediated fluorescence imaging with a microdosing approach was shown to be feasible. Furthermore, EuK-(SO3)Cy5-mas(3) allowed tumor identification in human prostate samples, underlining the translational potential of this novel tracer. Trial registration Approval for use of biological material for research purposes was provided by the Translational Research Board of the Netherlands Cancer Institute-Antoni van Leeuwenhoek hospital (NKI-AvL) under reference IRBm19-273 (22/10/2019). Show less
Moschovas, M.C.; Chew, C.; Bhat, S.; Sandri, M.; Rogers, T.; Dell'Oglio, P.; ... ; Patel, V. 2022
Background: The Oncotype DX assay is a clinically validated 17-gene genomic assay that provides a genomic prostate score (GPS; scale 0-100) measuring the heterogeneous nature of prostate tumors.... Show moreBackground: The Oncotype DX assay is a clinically validated 17-gene genomic assay that provides a genomic prostate score (GPS; scale 0-100) measuring the heterogeneous nature of prostate tumors. The test is performed on prostate tissue collected during biopsy. There is a lack of data on the association between the GPS and tumor pathology after radical prostatectomy (RP). Objective: To investigate the association between GPS and final pathology, including extra prostatic extension (EPE), positive surgical margin (PSM), and seminal vesicle invasion (SVI). Design, setting, and participants: Data for the 749 patients who underwent Oncotype DX assay and RP at a referral prostate cancer center between 2015 and 2019 were retrospectively assessed to evaluate the association between GPS and unfavorable pathology parameters. Intervention: After a GPS genetic test, patients underwent robotic RP performed by the same surgeon. Outcome measurement and statistical analysis: Multivariable logistic regression analyses were performed to assess the association between GPS and EPE, PSM, and SVI. The models were adjusted for age, clinical stage, prostate-specific antigen (PSA) level, Gleason score, and time between the genomic assay and surgery. The median time between Oncotype DX assay and surgery was 176 d (interquartile range [IQR] 141-226). The median age was 63 yr (IQR 58-68), median GPS was 29 (IQR 21-39), and median PSA was 5.7 ng/ml (IQR 4.6-7.7). In multivariable analyses assessing the odds ratio (OR) per 20-point change in GPS, GPS was an independent predictor of EPE (OR 1.8, 95% confidence interval [CI] 1.4-2.3) and SVI (OR 2.1, 95% CI 1.3-3.4). In addition, when patients were grouped by GPS quartile, the percentage of cases with EPE and SVI increased with the GPS quartile. Conclusions: We provide evidence that the Oncotype DX GPS is significantly associated with adverse pathology after RP. Specifically, the risk of EPE and SVI increases with the GPS. Therefore, use of the Oncotype DX GPS may help clinicians to improve preoperative patient counseling and develop surgical strategies for patients with a higher chance of EPE or unfavorable pathological features. Patient summary: We studied whether the score for a prostate genetic test was associated with prostate cancer pathology findings for patients who had their prostate removed. We found that the risk of prostate cancer spread outside the gland and to the seminal vesicle increases with higher test scores. These findings may help surgeons in counseling patients on surgical options for prostate cancer. (C) 2021 European Association of Urology. Published by Elsevier B.V. All rights reserved. Show less
Groen, V.H.; Schie, M. van; Zuithoff, N.P.A.; Monninkhof, E.M.; Kunze-Busch, M.; Boer, J.C.J. de; ... ; Kerkmeijer, L.G.W. 2022
Purpose or objectives: The FLAME trial (NCT01168479) showed that by adding a focal boost to conventional fractionated EBRT in the treatment of localized prostate cancer, the five-year biochemical... Show morePurpose or objectives: The FLAME trial (NCT01168479) showed that by adding a focal boost to conventional fractionated EBRT in the treatment of localized prostate cancer, the five-year biochemical disease-free survival increased, without significantly increasing toxicity. The aim of the present study was to investigate the association between radiation dose to the bladder and urethra and genitourinary (GU) toxicity grade >= 2 in the entire cohort.Material and methods: The dose-effect relations of the urethra and bladder dose, separately, and GU toxicity grade >= 2 (CTCAE 3.0) up to five years after treatment were assessed. A mixed model analysis for repeated measurements was used, adjusting for age, diabetes mellitus, T-stage, baseline GU toxicity grade >= 1 and institute. Additionally, the association between the dose and separate GU toxicity subdomains were investigated.Results: Dose-effect relations were observed for the dose (Gy) to the bladder D2 cm(3) and urethra D0.1 cm(3), with adjusted odds ratios of 1.14 (95% CI 1.12-1.16, p < 0.0001) and 1.12 (95% CI 1.11-1.14, p < 0.0001), respectively. Additionally, associations between the dose to the urethra and bladder and the subdomains urinary frequency, urinary retention and urinary incontinence were observed.Conclusion: Further increasing the dose to the bladder and urethra will result in a significant increase in GU toxicity following EBRT. Focal boost treatment plans should incorporate a urethral dose-constraint. Further treatment optimization to increase the focal boost dose without increasing the dose to the urethra and other organs at risk should be a focus for future research, as we have shown that a focal boost is beneficial in the treatment of prostate cancer. (C) 2021 The Author(s). Published by Elsevier B.V. Show less
The work included in this thesis is aimed at developing novel tools to advance our understanding of prostate cancer. The clinical problem of prostate cancer is presented and discussed in the wider... Show moreThe work included in this thesis is aimed at developing novel tools to advance our understanding of prostate cancer. The clinical problem of prostate cancer is presented and discussed in the wider context of the current clinical knowledge, highlighting the genetic mechanisms at its base. A dedicated chapter focuses on bone metastases, highly morbid feature of advanced prostate cancer, discussing the known mechanisms and the available models to study it in translational research. Then, moving from the molecular analysis of clinical specimens of bone metastasis, a biochemical pathway is identified and further studied in vitro, ex vivo and in vivo, validating the initial findings. A novel, early-stage prostate cancer patient-derived xenograft is presented and extensively characterized and implemented in a drug screening. This allowed to screen the effect of over 70 known drugs on prostate cancer models, using three-dimensional cultures and a semi-automated platform. As all research builds on previously established findings, a bibliometric analysis tool is presented, to assist in the generation of a knowledge network arranged by topic and impact of research. All these aspects and findings are then discussed in the context of the current direction of prostate cancer research, its emerging tools and its long-known challenges. Show less
The relation between prostate-specific antigen (PSA) and other relevant prebiopsy information is often combined in a risk calculator (RC). If the setting for RC use differs from that in which it... Show moreThe relation between prostate-specific antigen (PSA) and other relevant prebiopsy information is often combined in a risk calculator (RC). If the setting for RC use differs from that in which it was developed, there is a risk of making clinical decisions based on incorrect estimates of the absolute risk. The ERSPC-MRI RC predicts clinically significant prostate cancer (csPC; Gleason >= 3 + 4) on targeted and systematic biopsy using information on PSA, digital rectal examination, prostate volume, age, previous negative biopsy, and Prostate Imaging-Recording and Data System score. This calculator was developed on a clinical cohort of 961 men (2012-2017) with a csPC prevalence of 36%. Discrimination was good (area under the receiver operating characteristic curve 0.84). With the increasing use of multiparametric magnetic resonance imaging, we foresee that this RC will also be used for men with a lower a priori likelihood of PC. We investigated the effect of such a scenario on individual risk predictions. A small update of the intercept for the calculator can restore the accuracy to support decision-making with locally valid risk estimates.Patient summary: Decisions on who to refer for a prostate biopsy with its risk of sepsis and overdiagnosis require more than a prostate-specific antigen test. A prediction tool may take other relevant prebiopsy information into account, but may need to be updated to contemporary center-specific settings to provide accurate estimates of the risk of having prostate cancer. (C) 2019 Published by Elsevier B.V. on behalf of European Association of Urology. Show less
The recent FLAME trial has demonstrated improved local control of intermediate to high-risk prostate cancer after focal dose escalation of the visible tumor. To visualize the tumor, MRI... Show moreThe recent FLAME trial has demonstrated improved local control of intermediate to high-risk prostate cancer after focal dose escalation of the visible tumor. To visualize the tumor, MRI examinations were taken in which prostate tissue characteristics were visualized. Since this treatment strategy improves the clinical outcome of the patient, a technical analysis of the FLAME dataset is useful for the further optimization of focal dose escalation strategies.Delineation of the prostate tumor appeared to be performed differently in the participating radiotherapy departments. Considering the impact on the realized tumor dose, this analysis demonstrated the need for guidelines of tumor delineation on MRI. Due to the complex nature of the treatment plans, in addition a prediction model was developed, which identified patients for which a higher tumor dose could be planned.The application of MRI was also investigated for ‘dose painting by numbers’, in which MRI values are translated to prescription dose without interference of manual tumor delineations. Dose prescription based on MRI appeared robust to daily patient variations, a prerequisite for further development of ‘dose painting by numbers’. However, because of the absence of significant tumor changes during the treatment course, MRI was considered not suitable for early adaptive treatment. Show less
Over recent years, several new anti-cancer agents, like enzalutamide, abiraterone and radium-223 were introduced for treatment of patients with metastatic castration-resistant prostate cancer ... Show moreOver recent years, several new anti-cancer agents, like enzalutamide, abiraterone and radium-223 were introduced for treatment of patients with metastatic castration-resistant prostate cancer (mCRPC). The phase-3 studies evaluating these agents were primarily performed in patients only treated with docetaxel, because the studies were performed in parallel to each other. The efficacy and safety of sequentially treating patients with these new agents was unknown. This thesis describes the efficacy and tolerability of enzalutamide in patients pretreated with docetaxel and abiraterone. Because the response chance of enzalutamide in this cohort was significantly lower, an analysis of patient- and disease characteristics was performed to identify the responders. Also, the efficacy and tolerability of enzalutamide in heavily pretreated patients was also evaluated.Radium-223 is the first radionuclide with a survival benefit in mCRPC patients, this was concluded based on a study performed in patients treated with docetaxel or treatment-naïve patients. Even though painful bone metastases are the main reason for treatment with radionuclides, the effect of radium-223 on pain was not properly evaluated. This thesis describes the results of the observational ROTOR-registry, which evaluated the efficacy, tolerability, effect on pain and quality of life of Radium-223 in contemporary extensively pretreated mCRPC patients. Show less
