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
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
Wit, E.M.K.; KleinJan, G.H.; Berrens, A.C.; Vliet, R. van; Leeuwen, P.J. van; Buckle, T.; ... ; Poel, H.G. van der 2023
ObjectiveTo determine the diagnostic accuracy of the hybrid tracer indocyanine green (ICG)-Technetium-99 m(Tc-99m)-nanocolloid compared to sequential tracers of Tc-99m-nanocolloid and free-ICG in... Show moreObjectiveTo determine the diagnostic accuracy of the hybrid tracer indocyanine green (ICG)-Technetium-99 m(Tc-99m)-nanocolloid compared to sequential tracers of Tc-99m-nanocolloid and free-ICG in detecting tumor-positive lymph nodes (LN) during primary surgery in prostate cancer (PCa) patients.IntroductionImage-guided surgery strategies can help visualize individual lymphatic drainage patterns and sentinel lymph nodes (SLNs) in PCa patients. For lymphatic mapping radioactive, fluorescent and hybrid tracers are being clinically exploited. In this prospective randomized phase II trial, we made a head-to-head comparison between ICG-Tc-99m-nanocolloid (hybrid group) and Tc-99m-nanocolloid and subsequent free-ICG injection (sequential group).MethodsPCa patients with a >5% risk of lymphatic involvement according to the 2012 Briganti nomogram and planned for prostatectomy were included and randomized (1:1) between ultrasound-guided intraprostatic tracer administration of ICG-Tc-99m-nanocolloid (n = 69) or Tc-99m-nanocolloid (n = 69) 5 h before surgery. Preoperative lymphoscintigraphy and SPECT/CT were performed to define the locations of the SLNs. Additionally, all participants in the sequential group received an injection of free-ICG at time of surgery. Subsequently, all (S)LNs were dissected using fluorescence guidance followed by an extended pelvic lymph node dissection (ePLND). The primary outcome was the total number of surgically removed (S)LNs and tumor-positive (S)LNs.ResultsThe total number of surgically removed (S)LN packages was 701 and 733 in the hybrid and sequential groups, respectively (p = 0.727). The total number of fluorescent LNs retrieved was 310 and 665 nodes in the hybrid and sequential groups, respectively (p < 0.001). However, no statistically significant difference was observed in the corresponding number of tumor-positive nodes among the groups (44 vs. 33; p = 0.470). Consequently, the rate of tumor-positive fluorescent LNs was higher in the hybrid group (7.4%) compared to the sequential group (2.6%; p = 0.002), indicating an enhanced positive predictive value for the hybrid approach. There was no difference in complications within 90 days after surgery (p = 0.78).ConclusionsThe hybrid tracer ICG-Tc-99m-nanocolloid improved the positive predictive value for tumor-bearing LNs while minimizing the number of fluorescent nodes compared to the sequential tracer approach. Consequently, the hybrid tracer ICG-Tc-99m-nanocolloid enables the most reliable and minimal invasive method for LN staging in PCa patients. Show less
Mehra, N.; Kloots, I.; Vlaming, M.; Aluwini, S.; Dewulf, E.; Oprea-Lager, D.E.; ... ; Ausems, M. 2023
Background: Germline and tumour genetic testing in prostate cancer (PCa) is becoming more broadly accepted, but testing indications and clinical consequences for carriers in each disease stage are... Show moreBackground: Germline and tumour genetic testing in prostate cancer (PCa) is becoming more broadly accepted, but testing indications and clinical consequences for carriers in each disease stage are not yet well defined.Objective: To determine the consensus of a Dutch multidisciplinary expert panel on the indication and application of germline and tumour genetic testing in PCa.Design, setting, and participants: The panel consisted of 39 specialists involved in PCa management. We used a modified Delphi method consisting of two voting rounds and a virtual consensus meeting.Outcome measurements and statistical analysis: Consensus was reached if >75% of the panellists chose the same option. Appropriateness was assessed by the RAND/UCLA appropriateness method.Results and limitations: Of the multiple-choice questions, 44% reached consensus. For men without PCa having a relevant family history (familial PCa/BRCA-related hered-itary cancer), follow-up by prostate-specific antigen was considered appropriate. For patients with low-risk localised PCa and a family history of PCa, active surveil-lance was considered appropriate, except in case of the patient being a BRCA2 germ -line pathogenic variant carrier. Germline and tumour genetic testing should not be done for nonmetastatic hormone-sensitive PCa in the absence of a relevant family history of cancer. Tumour genetic testing was deemed most appropriate for the identification of actionable variants, with uncertainty for germline testing. For tumour genetic testing in metastatic castration-resistant PCa, consensus was not reached for the timing and panel composition. The principal limitations are as fol-lows: (1) a number of topics discussed lack scientific evidence, and therefore the recommendations are partly opinion based, and (2) there was a small number of experts per discipline.Conclusions: The outcomes of this Dutch consensus meeting may provide further guidance on genetic counselling and molecular testing related to PCa.Patient summary: A group of Dutch specialists discussed the use of germline and tumour genetic testing in prostate cancer (PCa) patients, indication of these tests (which patients and when), and impact of these tests on the management and treatment of PCa.(c) 2022 The Author(s). Published by Elsevier B.V. on behalf of European Association of Urology. This is an open access article under the CC BY license (http://creativecommons. org/licenses/by/4.0/). Show less
Wit, E.M.K.; Beurden, F. van; Kleinjan, G.H.; Grivas, N.; Korne, C.M. de; Buckle, T.; ... ; Poel, H.G. van der 2021
Introduction Previous studies indicated that location and amount of detected sentinel lymph nodes (SLNs) in prostate cancer (PCa) are influenced where SLN-tracer is deposited within the prostate.... Show moreIntroduction Previous studies indicated that location and amount of detected sentinel lymph nodes (SLNs) in prostate cancer (PCa) are influenced where SLN-tracer is deposited within the prostate. To validate whether intratumoral (IT) tracer injection helps to increase identification of tumor-positive lymph nodes (LNs) better than intraprostatic (IP) tracer injection, a prospective randomized phase II trial was performed.Methods PCa patients with a > 5% risk of lymphatic involvement were randomized between ultrasound-guided transrectal injection of indocyanine green-[Tc-99m]Tc-nanocolloid in 2 depots of 1 mL in the tumor (n = 55, IT-group) or in 4 depots of 0.5 mL in the peripheral zone of the prostate (n = 58, IP-group). Preoperative lymphoscintigraphy and SPECT/CT were used to define the location of the SLNs. SLNs were dissected using combination of radio- and fluorescence-guidance, followed by extended pelvic LN dissection and robot-assisted radical prostatectomy. Outcome measurements were number of tumor-bearing SNs, tumor-bearing LNs, removed nodes, number of patients with nodal metastases, and metastasis-free survival (MFS) of 4-7-year follow-up data.Results IT-injection did not result in significant difference of removed SLNs (5.0 vs 6.0, p = 0.317) and histologically positive SLNs (28 vs 22, p = 0.571). However, in IT-group, the SLN-positive nodes were 73.7% of total positive nodes compared to 37.3% in IP-group (p = 0.015). Moreover, significantly more node-positive patients were found in IT-group (42% vs 24%, p = 0.045), which did not result in worse MFS. In two patients (3.6%) from whom the IT-tracer injection only partly covered intraprostatic tumor spread, nodal metastases in ePLND without tumor-positive SNs were yielded.Conclusions The percentage-positive SLNs found after IT-injection were significantly higher compared to IP-injection. Significantly more node-positive patients were found using IT-injection, which did not affect MFS. IT-injection failed to detect nodal metastases from non-index satellite lesions. Therefore, we suggest to combine IT- and IP-tracer injections in men with visible tumor on imaging. 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
Early detection of prostate cancer may lead to the overdiagnosis and overtreatment of patients as well as missing significant cancers. The current diagnostic approach uses elevated serum... Show moreEarly detection of prostate cancer may lead to the overdiagnosis and overtreatment of patients as well as missing significant cancers. The current diagnostic approach uses elevated serum concentrations of prostate-specific antigen (PSA) as an indicator of risk. However, this test has been widely criticized as it shows poor specificity and sensitivity. In order to improve early detection and diagnosis, several studies have investigated whether different PSA proteoforms are correlated to prostate cancer. Until now, studies and methodologies for the comprehensive characterization of PSA proteoforms from biofluids are scarce. For this purpose, we developed an intact protein assay to analyze PSA by capillary electrophoresis-electrospray ionization-mass spectrometry after affinity purification from patients? urine. Here, we determined six proteolytic cleavage variants. In regard to glycosylation, tri-, di-, mono- and non-sialylated complex-type N-glycans were found on non-cleaved PSA, as well as the non-glycosylated variant. The performance of the intact protein assay was assessed using a pooled sample, obtaining an inter-day variability of 15%. Furthermore, urinary patient samples were analyzed by intact protein analysis and a bottom-up approach (glycopeptide analysis). This combined approach revealed complimentary information on both levels, demonstrating the benefit of using two orthogonal techniques to provide a thorough profile of urinary PSA.Significance: The detection of clinically relevant prostate cancer requires a more specific and sensitive biomarker and, in this case, several PSA proteoforms may be able to aid or improve the current PSA test. However, a comprehensive analysis of the intact PSA proteoform profile is still lacking. This study investigated the PSA proteoforms present in urine and, in particular, determined the relative contribution of cleaved PSA and noncleaved PSA forms to the total glycosylation profile. Importantly, intact protein analysis did not require further sample treatment before being measured by CE-ESI-MS. Furthermore, its glycosylation was also assessed in a bottom-up approach to provide complementary information. Overall, these results represent an important basis for future characterization and biomarker studies. Show less
Since cancer survival rates are rising, there is growing attention for longterm side effects of cancer and its treatment. A common side effect is the negative impact of treatment on sexuality of... Show moreSince cancer survival rates are rising, there is growing attention for longterm side effects of cancer and its treatment. A common side effect is the negative impact of treatment on sexuality of patients and their partners. Patient and partners as well as healthcare professionals experience several barriers to discuss this topic, like lack of time and lack of knowlegde. Two-thirds of the cancer patients reported to be in need of information regarding sexual health; especially those who were younger, who reported a negative impact of cancer on sexuality and those who were diagnosed less than two years ago. Patients and partners reported to prefer to discuss sexual health with nurse practitioners throughout the treatment proces. Besides, satisfaction with sexual life after treatment is related to satisfaction before treatment, not only with current sexual function.Widely available information and defining responsibility within the oncology treatment team would be helpful to improve communication around sexual health in cancer care. Additionally, specialized clinics would tackle soms frequently reported barriers of discussing sexuality. More reseach is needed on the implementation of sexual healthcare in oncology practice to deliver continuum of care, which will ultimately improve patient care. Show less
Background: Since the introduction of prostate-specific membrane antigen (PSMA) positron emission tomography (PET) imaging, isolated local recurrence after radical prostatectomy (RP) can be... Show moreBackground: Since the introduction of prostate-specific membrane antigen (PSMA) positron emission tomography (PET) imaging, isolated local recurrence after radical prostatectomy (RP) can be delineated accurately.Objective: To describe and evaluate surgical technique, biochemical response, and therapy-free survival (TFS) after salvage surgery in patients with local recurrence in the seminal vesicle bed.Design, setting, and participants: We retrospectively assessed 40 patients treated with open salvage surgery in two centres (11/2014-02/2020). All patients presented with biochemical recurrence (BCR) after RP with a singular local recurrence at PSMA PET imaging. Thirty-three (82.5%) patients received previous salvage radiation therapy.Surgical procedure: Open salvage surgery with PSMA radioguidance.Measurements: Prostate-specific antigen (PSA) nadir and percentage of patients with complete biochemical response (cBR) without further treatment (PSA < 0.2 ng/ml) after 6-16 wk were assessed. BCR-free survival and TFS were calculated using Kaplan-Meier estimates. Clavien-Dindo complications were evaluated.Results and limitations: Prior to salvage surgery, median PSA was 0.9 ng/ml (interquartile range [IQR]: 0.5-1.7 ng/ml). Postoperatively, median PSA nadir was 0.1 ng/ml (IQR: 0-0.4 ng/ml). In 31 (77.5%) patients, cBR was observed. During the median follow-up of 24.4 months, 22 (55.0%) patients experienced BCR and 12 (30.0%) received further therapy. At 1 yr of follow-up, BCR-free survival rate was 62.2% and TFS rate was 88.3%. Three (7.5%) Clavien-Dindo grade III complications were observed. The main limitations are the retrospective design, short follow-up, and lack of a control group.Conclusions: Salvage surgery of local recurrence within the seminal vesicle bed is feasible. It may present an opportunity in selected, locally recurrent patients to prolong BCR-free survival and increase TFS. Further studies are needed to confirm our findings.Patient summary: We looked at the outcomes from prostate cancer patients with locally recurrent disease after radical prostatectomy and radiotherapy. We found that surgery in well-selected patients may be an opportunity to prolong treatment-free survival. (C) 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved. Show less
Albers, L.F.; Tillier, C.N.; Muilekom, E. van; Werkhoven, E. van; Elzevier, H.W.; Rhijn, B.W.G. van; ... ; Hendricksen, K. 2021
Background: Preservation of erectile function is an important postoperative quality of life concern for patients after robot-assisted radical prostatectomy (RARP) for prostate cancer. Although... Show moreBackground: Preservation of erectile function is an important postoperative quality of life concern for patients after robot-assisted radical prostatectomy (RARP) for prostate cancer. Although erectile function may recover, many men continue to suffer from erectile dysfunction (ED).Aim: This study aims to determine whether satisfaction with sexual life improves in patients with ED after RARP and which factors are associated with satisfaction during follow-up.Methods: A review was carried out of a prospectively maintained database of patients with prostate cancer who underwent a RARP between 2006 and 2019. The 'International Index of Erectile Function' questionnaire was used to describe ED (range 5-25), overall satisfaction with sexual life and sexual desire (range for both: 2-10). Patients with ED due to RARP were compared with those without ED after RARP. Mixed effect model was used to test differences in satisfaction over time. Mann-Whitney U tests and multiple logistic regression were used to assess factors associated with being satisfied at 24 and 36 months.Outcomes: The main outcomes of this study are the overall satisfaction with sexual life score over time and factors which influence sexual satisfaction.Results: Data of 2808 patients were reviewed. Patients whose erectile function was not known (n = 643) or who had ED at the baseline (n = 1281) were excluded. About 884 patients were included for analysis. They had an overall satisfaction score of 8.4. Patients with ED due to RARP had mean overall satisfaction scores of 4.8, 4.8, 4.9, and 4.6 at 6 mo, 12 mo, 24 mo, and 36 mo. These scores were significantly lower than those of patients without ED at every time point. In multiple regression analysis, higher overall satisfaction score at the baseline and higher sexual desire at 24 and 36 months' follow-up were associated with satisfaction with sexual life at 24 and 36 months? follow-up. No association was found for erectile function.Clinical implications: Interventions focusing on adjustment to the changes in sexual functioning might improve sexual satisfaction; especially for those men who continue to suffer from ED.Strengths & Limitations: Strengths of this study are the large number of patients, time of follow-up, and use of multiple validated questionnaires. Our results must be interpreted within the limits of retrospectively collected, observational data.Conclusion: Satisfaction with sexual life in men with ED due to RARP may take a long time to improve. One could counsel patients that sexual satisfaction is based on individual baseline sexual satisfaction and the return of sexual desire after RARP. Copyright (C) 2020, The Authors. Published by Elsevier Inc. on behalf of the International Society for Sexual Medicine. Show less