Validation of Claims Data for Absorbing Pads as a Measure for Urinary Incontinence after Radical Prostatectomy, a National Cross-Sectional Analysis.

The use of healthcare insurance claims data for urinary incontinence (UI) pads has the potential to serve as an objective measure for assessing post-radical prostatectomy UI rates, but its validity for this purpose has not been established. The aim of this study is to correlate claims data with Patient Reported Outcome Measures (PROMs) for UI pad use. Patients who underwent RP in the Netherlands between September 2019 and February 2020 were included. Incontinence was defined as the daily use of ≥1 pad(s). Claims data for UI pads at 12-15 months after RP were extracted from a nationwide healthcare insurance database in the Netherlands. Participating hospitals provided PROMS data. In total, 1624 patients underwent RP. Corresponding data of 845 patients was provided by nine participating hospitals, of which 416 patients were matched with complete PROMs data. Claims data and PROMs showed 31% and 45% post-RP UI (≥1 pads). UI according to claims data compared with PROMs had a sensitivity of 62%, specificity of 96%, PPV of 92%, NPV of 75% and accuracy of 81%. The agreement between both methods was moderate (κ = 0.60). Claims data for pads moderately align with PROMs in assessing post-prostatectomy urinary incontinence and could be considered as a conservative quality indicator.

A comparison of machine learning models for predicting urinary incontinence in men with localized prostate cancer.

Introduction: Urinary incontinence (UI) is a common side effect of prostate cancer treatment, but in clinical practice, it is difficult to predict. Machine learning (ML) models have shown promising results in predicting outcomes, yet the lack of transparency in complex models known as "black-box" has made clinicians wary of relying on them in sensitive decisions. Therefore, finding a balance between accuracy and explainability is crucial for the implementation of ML models. The aim of this study was to employ three different ML classifiers to predict the probability of experiencing UI in men with localized prostate cancer 1-year and 2-year after treatment and compare their accuracy and explainability. Methods: We used the ProZIB dataset from the Netherlands Comprehensive Cancer Organization (Integraal Kankercentrum Nederland; IKNL) which contained clinical, demographic, and PROM data of 964 patients from 65 Dutch hospitals. Logistic Regression (LR), Random Forest (RF), and Support Vector Machine (SVM) algorithms were applied to predict (in)continence after prostate cancer treatment. Results: All models have been externally validated according to the TRIPOD Type 3 guidelines and their performance was assessed by accuracy, sensitivity, specificity, and AUC. While all three models demonstrated similar performance, LR showed slightly better accuracy than RF and SVM in predicting the risk of UI one year after prostate cancer treatment, achieving an accuracy of 0.75, a sensitivity of 0.82, and an AUC of 0.79. All models for the 2-year outcome performed poorly in the validation set, with an accuracy of 0.6 for LR, 0.65 for RF, and 0.54 for SVM. Conclusion: The outcomes of our study demonstrate the promise of using non-black box models, such as LR, to assist clinicians in recognizing high-risk patients and making informed treatment choices. The coefficients of the LR model show the importance of each feature in predicting results, and the generated nomogram provides an accessible illustration of how each feature impacts the predicted outcome. Additionally, the model's simplicity and interpretability make it a more appropriate option in scenarios where comprehending the model's predictions is essential.

Development and external validation of multivariate prediction models for erectile dysfunction in men with localized prostate cancer.

While the 10-year survival rate for localized prostate cancer patients is very good (>98%), side effects of treatment may limit quality of life significantly. Erectile dysfunction (ED) is a common burden associated with increasing age as well as prostate cancer treatment. Although many studies have investigated the factors affecting erectile dysfunction (ED) after prostate cancer treatment, only limited studies have investigated whether ED can be predicted before the start of treatment. The advent of machine learning (ML) based prediction tools in oncology offers a promising approach to improve the accuracy of prediction and quality of care. Predicting ED may help aid shared decision-making by making the advantages and disadvantages of certain treatments clear, so that a tailored treatment for an individual patient can be chosen. This study aimed to predict ED at 1-year and 2-year post-diagnosis based on patient demographics, clinical data and patient-reported outcomes (PROMs) measured at diagnosis. We used a subset of the ProZIB dataset collected by the Netherlands Comprehensive Cancer Organization (Integraal Kankercentrum Nederland; IKNL) that contained information on 964 localized prostate cancer cases from 69 Dutch hospitals for model training and external validation. Two models were generated using a logistic regression algorithm coupled with Recursive Feature Elimination (RFE). The first predicted ED 1 year post-diagnosis and required 10 pre-treatment variables; the second predicted ED 2 years post-diagnosis with 9 pre-treatment variables. The validation AUCs were 0.84 and 0.81 for 1 year and 2 years post-diagnosis respectively. To immediately allow patients and clinicians to use these models in the clinical decision-making process, nomograms were generated. In conclusion, we successfully developed and validated two models that predicted ED in patients with localized prostate cancer. These models will allow physicians and patients alike to make informed evidence-based decisions about the most suitable treatment with quality of life in mind.

Onset of androgen deprivation therapy leads to rapid deterioration of body composition, physical performance, cardiometabolic health and quality-of-life in prostate cancer patients.

OBJECTIVES: To assess the adverse impact of the first 5 months of androgen deprivation therapy on body composition, physical performance, cardiometabolic health and health-related quality-of-life in prostate cancer patients. MATERIALS AND METHODS: Thirty-four prostate cancer patients (70 ± 7 years) were assessed shortly after initiation of androgen deprivation therapy and again 5 months thereafter. Measurements consisted of whole-body dual-energy x-ray absorptiometry (body composition), computed tomography scanning of the upper leg (muscle mass), one-repetition maximum leg press (muscle strength), cardiopulmonary exercise testing (aerobic capacity), blood draws (metabolic parameters), accelerometry (habitual physical activity) and questionnaires (health-related quality-of-life). Data were analyzed with Student's paired t-tests. RESULTS: Over time, whole-body fat mass (from 26.2 ± 7.7 to 28.4 ± 8.3 kg, p < 0.001) and fasting insulin (from 9.5 ± 5.8 to 11.3 ± 6.9 mU/L, p < 0.001) increased. Declines were observed for quadriceps cross-sectional area (from 66.3 ± 9.1 to 65.0 ± 8.5 cm2, p < 0.01), one-repetition maximum leg press (from 107 ± 27 to 100 ± 27 kg, p < 0.01), peak oxygen uptake (from 23.2 ± 3.7 to 20.3 ± 3.4 mL/min/kg body weight, p < 0.001), step count (from 7,048 ± 2,277 to 5,842 ± 1,749 steps/day, p < 0.01) and health-related quality-of-life (from 84.6 ± 13.5 to 77.0 ± 14.6, p < 0.001). CONCLUSIONS: Androgen deprivation therapy induces adverse changes in body composition, muscle strength, cardiometabolic health and health-related quality-of-life already within 5 months after the start of treatment, possibly largely contributed by diminished habitual physical activity. Prostate cancer patients should, therefore, be stimulated to increase their habitual physical activity immediately after initiation of androgen deprivation therapy, to limit adverse side-effects and to improve health-related quality-of-life.

Resistance Exercise Training Increases Muscle Mass and Strength in Prostate Cancer Patients on Androgen Deprivation Therapy.

PURPOSE: This study aimed to assess the effects of 20 wk resistance exercise training with or without protein supplementation on body composition, muscle mass, muscle strength, physical performance, and aerobic capacity in prostate cancer patients receiving androgen deprivation therapy (ADT). METHODS: Sixty prostate cancer patients receiving ADT were randomly assigned to perform 20 wk of resistance exercise training with supplementation of 31 g whey protein (EX + PRO, n = 30) or placebo (EX + PLA, n = 30), consumed immediately after exercise and every night before sleep. A separate control group (CON, n = 36) only received usual care. At baseline and after 20 wk, body composition (dual-energy x-ray absorptiometry), muscle mass (computed tomography scan), muscle strength (1-repetition maximum strength tests), physical performance (Timed Up and Go Test, 30-Second Chair Stand Test, and Stair Climb Test), aerobic capacity (cardiopulmonary exercise test), and habitual dietary intake (food diary) were assessed. Data were analyzed using a two-factor repeated-measures ANOVA. RESULTS: Over time, muscle mass and strength increased in EX + PRO and EX + PLA and decreased in CON. Total fat mass and fat percentage increased in EX + PRO and CON, but not in EX + PLA. Physical performance did not significantly change over time in either group. Aerobic capacity was maintained in EX + PLA, but it decreased in EX + PRO and CON. Habitual protein intake (without supplements) averaged >1.0 g·kg body weight -1 ·d -1 , with no differences over time or between groups. CONCLUSIONS: In prostate cancer patients, resistance exercise training counteracts the adverse effects of ADT on body composition, muscle mass, muscle strength, and aerobic capacity, with no additional benefits of protein supplementation.

Human polyomaviruses JCPyV and MCPyV in urothelial cell carcinoma: a single institution experience.

Objective: Urothelial cell carcinoma (UCC) is the most common type of urinary bladder. JCPyV and BKPyV have been detected in the urine and tissue of urothelial cell carcinomas (UCC) in immunocompetent patients. Here, we investigated the presence of several HPyVs in UCC samples using diverse molecular techniques to study the prevalence of HPyVs in UCC. Methods: A large single-institution database of urine cytology specimens (UCS; n = 22.867 UCS) has previously been searched for decoy cells (n = 30), suggesting polyomavirus infection. The available urine sediments and formalin-fixed paraffin-embedded (FFPE) tissue samples of UCC patients were tested for the presence of JCPyV-LTAg expression by immunohistochemistry (IHC) labeled with SV40-LTAg antibody (clone: PAb416) and subsequent PCR followed by sequencing. In addition, the presence of the oncogenic Merkel cell polyomavirus (MCPyV) and the presence of human polyomavirus 6 (HPyV6) and 7 (HPyV7) DNA were tested with DNA PCR or IHC. Results: Of the 30 patients harboring decoy cells, 14 were diagnosed with UCC of the urinary bladder (14/30; 46.6%) before presenting with decoy cells in the urine. The SV40-LTAg IHC was positive in all 14 UCC urine sediments and negative in the FFPE tissues. JCPyV-DNA was identified in all five available UCS and in three FFPE samples of UCC (three of 14; 21.4%). Two UCC cases were positive for MCPyV-DNA (two of 14; 14.3%), and one of them showed protein expression by IHC (one of 14; 7.1%). All specimens were HPyV6 and HPyV7 negative. Conclusion: Our findings show the presence of JCPyV in the urine and UCC of immunocompetent patients. Moreover, MCPyV was detected in two UCC cases. In total, five UCC cases showed the presence of either JCPyV or MCPyV. The evidence here supports the hypothesis that these viruses might sporadically be associated with UCC. Further studies are needed to confirm the relevance of JCPyV or MCPyV as a possible risk factor for UCC development.

A Prospective Multicenter Comparison Study of Risk-adapted Ultrasound-directed and Magnetic Resonance Imaging-directed Diagnostic Pathways for Suspected Prostate Cancer in Biopsy-naïve Men.

BACKGROUND: European Association of Urology guidelines recommend a risk-adjusted biopsy strategy for early detection of prostate cancer in biopsy-naïve men. It remains unclear which strategy is most effective. Therefore, we evaluated two risk assessment pathways commonly used in clinical practice. OBJECTIVE: To compare the diagnostic performance of a risk-based ultrasound (US)-directed pathway (Rotterdam Prostate Cancer Risk Calculator [RPCRC] #3; US volume assessment) and a magnetic resonance imaging (MRI)-directed pathway. DESIGN, SETTING, AND PARTICIPANTS: This was a prospective multicenter study (MR-PROPER) with 1:1 allocation among 21 centers (US arm in 11 centers, MRI arm in ten). Biopsy-naïve men with suspicion of prostate cancer (age ≥50 yr, prostate-specific antigen 3.0-50 ng/ml, ± abnormal digital rectal examination) were included. INTERVENTION: Biopsy-naïve men with elevated risk of prostate cancer, determined using RPCRC#3 in the US arm and Prostate Imaging Reporting and Data System scores of 3-5 in the MRI arm, underwent systematic biopsies (US arm) or targeted biopsies (MRI arm). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was the proportion of men with grade group (GG) ≥2 cancer. Secondary outcomes were the proportions of biopsies avoided and GG 1 cancers detected. Categorical (nonparametric) data were assessed using the Mann-Whitney U test and χ2 tests. RESULTS AND LIMITATIONS: A total of 1965 men were included in the intention-to-treat population (US arm n = 950, MRI arm n = 1015). The US and MRI pathways detected GG ≥2 cancers equally well (235/950, 25% vs 239/1015, 24%; difference 1.2%, 95% confidence interval [CI] -2.6% to 5.0%; p = 0.5). The US pathway detected more GG 1 cancers than the MRI pathway (121/950, 13% vs 84/1015, 8.3%; difference 4.5%, 95% CI 1.8-7.2%; p < 0.01). The US pathway avoided fewer biopsies than the MRI pathway (403/950, 42% vs 559/1015, 55%; difference -13%, 95% CI -17% to -8.3%; p < 0.01). Among men with elevated risk, more GG ≥2 cancers were detected in the MRI group than in the US group (52% vs 43%; difference 9.2%, 95% CI 3.0-15%; p < 0.01). CONCLUSIONS: Risk-adapted US-directed and MRI-directed pathways detected GG ≥2 cancers equally well. The risk-adapted US-directed pathway performs well for prostate cancer diagnosis if prostate MRI capacity and expertise are not available. If prostate MRI availability is sufficient, risk assessment should preferably be performed using MRI, as this avoids more biopsies and detects fewer cases of GG 1 cancer. PATIENT SUMMARY: Among men with suspected prostate cancer, relevant cancers were equally well detected by risk-based pathways using either ultrasound or magnetic resonance imaging (MRI) to guide biopsy of the prostate. If prostate MRI availability is sufficient, risk assessment should be performed with MRI to reduce unnecessary biopsies and detect fewer irrelevant cancers.

Development of a Management Algorithm for Acute and Chronic Radiation Urethritis and Cystitis.

OBJECTIVE: The purpose of this review was to summarize the current literature on the assessment and treatment of radiation urethritis and cystitis (RUC) for the development of an evidenced-based management algorithm. MATERIAL AND METHODS: The PubMed/MEDLINE database was searched by a multidisciplinary group of experts in January 2021. RESULTS: In total, 48 publications were identified. Three different types of RUC can be observed in clinical practice: inflammation-predominant, bleeding-predominant, and the combination of inflammation- and bleeding-RUC. There is no consensus on the optimal treatment of RUC. Inflammation-predominant RUC should be treated symptomatically based on the existence of bothersome storage or voiding lower urinary tract symptom as well as on pain. When bleeding-predominant RUC has occurred, hydration and hyperbaric oxygen therapy (HOT) should be used first and, if HOT is not available, oral drugs instead (sodium pentosane polysulfate, aminocaproic acid, immunokine WF 10, conjugated estrogene, or pentoxifylline + vitamin E). If local bleeding persists, focal therapy of bleeding vessels with a laser or electrocoagulation is indicated. In case of generalized bleeding, intravesical installation should be initiated (formalin, aluminium salts, and hyaluronic acid/chondroitin). Vessel embolization is a less invasive treatment with potentially less complications and good clinical outcomes. Open- or robot-assisted surgery is indicated in patients with permanent, life-threatening bleeding, or fistulae. CONCLUSIONS: Treatment of RUC, if not self-limiting, should be done according to the type of RUC and in a stepwise approach. Conservative/medical treatment (oral and topic agents) should primarily be used before invasive (transurethral) treatments.

Management of upper urinary tract problems after radical cystectomy for urothelial carcinoma: tips and tricks.

PURPOSE OF REVIEW: After radical cystectomy (RC) patients are at risk for both benign and malignant problems regarding the upper urinary tract (UUT). This review summarizes the recent literature and provides tips on how to manage problems of the UUT after RC. RECENT FINDINGS: Disease recurrence, kidney stones and ureteroenteric strictures (UES) are common after RC. Endourological techniques can be used to treat low-grade disease recurrence, either with a retrograde or antegrade approach. Treatment success depends on getting access to the UUT and on tumor characteristics; selecting the right approach is key. Kidney stones can be treated endourologically with good results. With use of minimal invasive techniques such as robot cystectomy, a higher incidence of UES is observed. The use of indocyanine green could help to prevent this complication. In case of a stricture, primary reconstruction should be the treatment strategy of choice. SUMMARY: After RC, recurrence of the UUT remains a complicated problem. Choice of treatment method should be tailored to the patient and tumor characteristics. Kidney stones after cystectomy can be successfully managed endourological. Robot assisted RC introduced a higher rate of UES, which should be managed by primary revision.

Is prostate cancer radiotherapy using implantable rectum spacers safe and effective in inflammatory bowel disease patients?

BACKGROUND: Prostate cancer radiotherapy (RT) in patients with (active) inflammatory bowel disease (IBD) remains controversial. We hypothesized that RT in combination with a biodegradable prostate-rectum spacer balloon implantation, might be a safe treatment approach with acceptable toxicities for these high risk for rectal toxicity patients. MATERIALS AND METHODS: We report on a small prospective mono-centric series of 8 patients with all-risk prostate cancer with the comorbidity of an IBD. Four patients had Crohn's disease and 4 patients had ulcerative colitis. One out of four had an active status of IBD. All patients were intended to be treated with curative high-dose RT: 5 patients were treated with external beam RT (70 Gray (Gy) in 28 fractions), and 3 patients were treated with 125I-implant (145 Gy). Toxicities were scored according to the CTCAE v4.03: acute side effects occur up to 3 months after RT, and late side effects start after 3 months. RESULTS: Median follow-up was 13 months (range: 3-42 months). Only one acute grade 2 gastro-intestinal (GI) toxicity was observed: an increased diarrhea (4-6 above baseline) during RT, which resolved completely 6 weeks after treatment. No late grade 3 or more GI toxicity was reported, and no acute and late grade ≥2 genitourinary toxicity events were observed. CONCLUSION: Prostate cancer patients with IBD are a challenge to treat with RT. Our results suggest that RT in combination with a balloon implant in selective patients with (active) IBD may be promising, however additional validation is needed.

Diagnostic DNA Methylation Biomarkers for Renal Cell Carcinoma: A Systematic Review.

CONTEXT: The 5-yr survival of early-stage renal cell carcinoma (RCC) is approximately 93%, but once metastasised, the 5-yr survival plummets to 12%, indicating that early RCC detection is crucial to improvement in survival. DNA methylation biomarkers have been suggested to be of potential diagnostic value; however, their current state of clinical translation is unclear and a comprehensive overview is lacking. OBJECTIVE: To systematically review and summarise all literature regarding diagnostic DNA methylation biomarkers for RCC. EVIDENCE ACQUISITION: We performed a systematic literature review of PubMed, EMBASE, Medline, and Google Scholar up to January 2019, according to the Preferred Reporting Items for Systematic Review and Meta-Analysis of Diagnostic Test Accuracy Studies (PRISMA-DTA) guidelines. Included studies were scored according to the Standards for Reporting of Diagnostic Accuracy Studies (STARD) criteria. Forest plots were generated to summarise diagnostic performance of all biomarkers. Level of evidence (LoE) and potential risk of bias were determined for all included studies. EVIDENCE SYNTHESIS: After selection, 19 articles reporting on 44 diagnostic DNA methylation biomarkers and 11 multimarker panels were included; however, only 15 biomarkers were independently validated. STARD scores varied from 4 to 13 out of 23 points, with a median of 10 points. Large variation in subgroups, methods, and primer locations was observed. None of the reported biomarkers exceeded LoE III, and the majority of studies reported inadequately. CONCLUSIONS: None of the reported biomarkers exceeded LoE III, indicating their limited clinical utility. Moreover, study reproducibility and further development of these RCC biomarkers are greatly hampered by inadequate reporting. PATIENT SUMMARY: In this report, we reviewed whether specific biomarkers could be used to diagnose the most common form of kidney cancer. We conclude that due to limited evidence and reporting inconsistencies, none of these biomarkers can be used in clinical practice, and further development towards clinical use is hindered.

Exhaled-breath Testing for Prostate Cancer Based on Volatile Organic Compound Profiling Using an Electronic Nose Device (Aeonose™): A Preliminary Report.

BACKGROUND: Prostate biopsy, an invasive examination, is the gold standard for diagnosing prostate cancer (PCa). There is a need for a novel noninvasive diagnostic tool that achieves a significantly high pretest probability for PCa, reducing unnecessary biopsy numbers. Recent studies have shown that volatile organic compounds (VOCs) in exhaled breath can be used to detect different types of cancers via training of an artificial neural network (ANN). OBJECTIVE: To determine whether exhaled-breath analysis using a handheld electronic nose device can be used to discriminate between VOC patterns between PCa patients and healthy individuals. DESIGN, SETTING, AND PARTICIPANTS: This prospective pilot study was conducted in the outpatient urology clinic of the Maastricht University Medical Center, the Netherlands. Patients with histologically proven PCa were already included before initial biopsy or during follow-up, with no prior treatment for their PCa. Urological patients with negative biopsies in the past year or patients with prostate enlargement (PE) with low or stable serum prostate-specific antigen were used as controls. Exhaled breath was probed from 85 patients: 32 with PCa and 53 controls (30 having negative biopsies and 23 PE). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Patient characteristics were statistically analyzed using independent sample t test and Pearson's chi-square test. Data analysis was performed by Aethena software after data compression using the TUCKER3 algorithm. ANN models were trained and evaluated using the leave-10%-out cross-validation method. RESULTS AND LIMITATIONS: Our trained ANN showed an accuracy of 0.75, with an area under the curve of 0.79 with sensitivity and specificity of 0.84 (95% confidence interval [CI] 0.66-0.94) and 0.70 (95% CI 0.55-0.81) respectively, comparing PCa with control individuals. The negative predictive value was found to be 0.88. The main limitation is the relatively small sample size. CONCLUSIONS: Our findings imply that the Aeonose allows us to discriminate between patients with untreated, histologically proven primary PCa and control patients based on exhaled-breath analysis. PATIENT SUMMARY: We explored the possibility of exhaled-breath analysis using an electronic nose, to be used as a noninvasive tool in clinical practice, as a pretest for diagnosing prostate cancer. We found that the electronic nose was able to discriminate between prostate cancer patients and control individuals.

Development and validation of a patient decision aid for prostate Cancer therapy: from paternalistic towards participative shared decision making.

BACKGROUND: Patient decision aids (PDAs) can support the treatment decision making process and empower patients to take a proactive role in their treatment pathway while using a shared decision-making (SDM) approach making participatory medicine possible. The aim of this study was to develop a PDA for prostate cancer that is accurate and user-friendly. METHODS: We followed a user-centered design process consisting of five rounds of semi-structured interviews and usability surveys with topics such as informational/decisional needs of users and requirements for PDAs. Our user-base consisted of 8 urologists, 4 radiation oncologists, 2 oncology nurses, 8 general practitioners, 19 former prostate cancer patients, 4 usability experts and 11 healthy volunteers. RESULTS: Informational needs for patients centered on three key factors: treatment experience, post-treatment quality of life, and the impact of side effects. Patients and clinicians valued a PDA that presents balanced information on these factors through simple understandable language and visual aids. Usability questionnaires revealed that patients were more satisfied overall with the PDA than clinicians; however, both groups had concerns that the PDA might lengthen consultation times (42 and 41%, respectively). The PDA is accessible on http://beslissamen.nl/ . CONCLUSIONS: User-centered design provided valuable insights into PDA requirements but challenges in integrating diverse perspectives as clinicians focus on clinical outcomes while patients also consider quality of life. Nevertheless, it is crucial to involve a broad base of clinical users in order to better understand the decision-making process and to develop a PDA that is accurate, usable, and acceptable.

Multifaceted Mechanisms of Cisplatin Resistance in Long-Term Treated Urothelial Carcinoma Cell Lines.

Therapeutic efficacy of cisplatin-based treatment of late stage urothelial carcinoma (UC) is limited by chemoresistance. To elucidate underlying mechanisms and to develop new approaches for overcoming resistance, we generated long-term cisplatin treated (LTT) UC cell lines, characterised their cisplatin response, and determined the expression of molecules involved in cisplatin transport and detoxification, DNA repair, and apoptosis. Inhibitors of metallothioneins and Survivin were applied to investigate their ability to sensitise towards cisplatin. Cell growth, proliferation, and clonogenicity were examined after cisplatin treatment by MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, EdU (5-ethynyl-2'-deoxyuridine) incorporation assay, and Giemsa staining, respectively. Cell cycle distribution and apoptosis were quantified by flow cytometry. mRNA and protein expressions were measured by real-time quantitative (qRT)-PCR, western blot, or immunofluorescence staining. LTTs recovered rapidly from cisplatin stress compared to parental cells. In LTTs, to various extents, cisplatin exporters and metallothioneins were induced, cisplatin adduct levels and DNA damage were decreased, whereas expression of DNA repair factors and specific anti-apoptotic factors was elevated. Pharmacological inhibition of Survivin, but not of metallothioneins, sensitised LTTs to cisplatin, in an additive manner. LTTs minimise cisplatin-induced DNA damage and evade apoptosis by increased expression of anti-apoptotic factors. The observed diversity among the four LTTs highlights the complexity of cisplatin resistance mechanisms even within one tumour entity, explaining heterogeneity in patient responses to chemotherapy.

Prognostic DNA methylation markers for renal cell carcinoma: a systematic review.

AIM: Despite numerous published prognostic methylation markers for renal cell carcinoma (RCC), none of these have yet changed patient management. Our aim is to systematically review and evaluate the literature on prognostic DNA methylation markers for RCC. MATERIALS & METHODS: We conducted an exhaustive search of PubMed, EMBASE and MEDLINE up to April 2017 and identified 49 publications. Studies were reviewed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, assessed for their reporting quality using the Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK) criteria, and were graded to determine the level of evidence (LOE) for each biomarker. RESULTS: We identified promoter methylation of BNC1, SCUBE3, GATA5, SFRP1, GREM1, RASSF1A, PCDH8, LAD1 and NEFH as promising prognostic markers. Extensive methodological heterogeneity across the included studies was observed, which hampers comparability and reproducibility of results, providing a possible explanation why these biomarkers do not reach the clinic. CONCLUSION: Potential prognostic methylation markers for RCC have been identified, but they require further validation in prospective studies to determine their true clinical value.

Prostate Cancer Radiation Therapy: What Do Clinicians Have to Know?

Radiotherapy (RT) for prostate cancer (PC) has steadily evolved over the last decades, with improving biochemical disease-free survival. Recently population based research also revealed an association between overall survival and doses ≥ 75.6 Gray (Gy) in men with intermediate- and high-risk PC. Examples of improved RT techniques are image-guided RT, intensity-modulated RT, volumetric modulated arc therapy, and stereotactic ablative body RT, which could facilitate further dose escalation. Brachytherapy is an internal form of RT that also developed substantially. New devices such as rectum spacers and balloons have been developed to spare rectal structures. Newer techniques like protons and carbon ions have the intrinsic characteristics maximising the dose on the tumour while minimising the effect on the surrounding healthy tissue, but clinical data are needed for confirmation in randomised phase III trials. Furthermore, it provides an overview of an important discussion issue in PC treatment between urologists and radiation oncologists: the comparison between radical prostatectomy and RT. Current literature reveals that all possible treatment modalities have the same cure rate, but a different toxicity pattern. We recommend proposing the possible different treatment modalities with their own advantages and side-effects to the individual patient. Clinicians and patients should make treatment decisions together (shared decision-making) while using patient decision aids.

Phenotype plasticity rather than repopulation from CD90/CK14+ cancer stem cells leads to cisplatin resistance of urothelial carcinoma cell lines.

BACKGROUND: Tumour heterogeneity and resistance to systemic treatment in urothelial carcinoma (UC) may arise from cancer stem cells (CSC). A recent model describes cellular differentiation states within UC based on corresponding expression of surface markers (CD) and cytokeratins (CK) with CD90 and CK14 positive cells representing the least differentiated and most tumourigenic population. Based on the fact that this population is postulated to constitute CSCs and the origin of cisplatin resistance, we enriched urothelial carcinoma cell lines (UCCs) for CD90 and studied the tumour-initiating potential of these separated cells in vitro. METHODS: Magnetic- and fluorescence-activated- cell sorting were used for separation of CD90(+) and CD90(-) UCCs. Distribution of cell surface markers CD90, CD44, and CD49f and cytokeratins CK14, CK5, and CK20 as well as the effects of short- and long-term treatment with cisplatin were assessed in vitro and measured by qRT-PCR, immunocytochemistry, reporter assay and flow cytometry in 11 UCCs. RESULTS: We observed cell populations with surface markers according to those reported in tumour xenografts. However, expression of cytokeratins did not concord regularly with that of the surface markers. In particular, expression of CD90 and CK14 diverged during enrichment of CD90(+) cells by immunomagnetic sorting or following cisplatin treatment. Enriched CD90(+) cells did not exhibit CSC-like characteristics like enhanced clonogenicity and cisplatin resistance. Moreover, selection of cisplatin-resistant sublines by long-term drug treatment did not result in enrichment of CD90(+) cells. Rather, these sublines displayed significant phenotypic plasticity expressing EMT markers, an altered pattern of CKs, and WNT-pathway target genes. CONCLUSIONS: Our findings indicate that the correspondence between CD surface markers and cytokeratins reported in xenografts is not maintained in commonly used UCCs and that CD90 may not be a stable marker of CSC in UC. Moreover, UCCs cells are capable of substantial phenotypic plasticity that may significantly contribute to the emergence of cisplatin resistance.

[Rectal bleeding after radiotherapy for prostate cancer]. / Rectaal bloedverlies na bestraling van prostaatkanker.

This clinical lesson, based on two case histories, illustrates a complication seen after manipulation of the rectal wall in patients who have undergone radiotherapy for localised prostate cancer. Rectal bleeding, which is feared by patients, can be the first sign of radiation proctitis. Manipulation of the rectal wall, for example by taking biopsies or Argon plasma coagulation, should be done with caution and only if absolutely necessary, because it can lead to fistula formation.

Prostate specific antigen bounce is related to overall survival in prostate brachytherapy.

PURPOSE: To investigate the association between prostate specific antigen (PSA) bounce and disease outcome after prostate brachytherapy. METHODS AND MATERIALS: We analyzed 975 patients treated with (125)I implantation monotherapy between 1992 and 2006. All patients had tumor Stage ≤ 2c, Gleason score ≤ 7 prostate cancer, a minimum follow-up of 2 years with at least four PSA measurements, and no biochemical failure in the first 2 years. Median follow-up was 6 years. Bounce was defined as a PSA elevation of +0.2 ng/mL with subsequent decrease to previous nadir. We used the Phoenix +2 ng/mL definition for biochemical failure. Additional endpoints were disease-specific and overall survival. Multivariate Cox regression analysis was performed to adjust for potential confounding factors. RESULTS: Bounce occurred in 32% of patients, with a median time to bounce of 1.6 years. More than 90% of bounces took place in the first 3 years after treatment and had disappeared within 2 years of onset. Ten-year freedom from biochemical failure, disease-specific survival, and overall survival rates were, respectively, 90%, 99%, and 88% for the bounce group and 70%, 93%, and 82% for the no-bounce group. Only 1 patient (0.3%) died of prostate cancer in the bounce group, compared with 40 patients (6.1%) in the no-bounce group. Adjusted for confounding, a 70% biochemical failure risk reduction was observed for patients experiencing a bounce (hazard ratio 0.31; 95% confidence interval 0.20-0.48). CONCLUSIONS: A PSA bounce after prostate brachytherapy is strongly related to better outcome in terms of biochemical failure, disease-specific survival, and overall survival.

Prostate brachytherapy and second primary cancer risk: a competitive risk analysis.

PURPOSE: To assess the risk of second primary cancer (SPC) after [(125)I]iodine prostate cancer brachytherapy compared with prostatectomy and the general population. PATIENTS AND METHODS: In a cohort consisting of 1,888 patients with prostate cancer who received monotherapy with brachytherapy (n = 1,187; 63%) or prostatectomy (n = 701; 37%), SPC incidences were retrieved by linkage with the Dutch Cancer Registry. Standardized incidence rates (SIRs) and absolute excess risks (AERs) were calculated for comparison. RESULTS: A total of 223 patients were diagnosed with SPC, 136 (11%) after brachytherapy and 87 (12%) after prostatectomy, with a median follow-up of 7.5 years. The SIR for all malignancies, bladder cancer, and rectal cancer were 0.94 (95% CI, 0.78 to 1.12), 1.69 (95% CI, 0.98 to 2.70), and 0.90 (95% CI, 0.41 to 1.72) for brachytherapy and 1.04 (95% CI, 0.83 to 2.28), 1.82 (95% CI, 0.87 to 3.35), and 1.50 (95% CI, 0.68 to 2.85) for prostatectomy, respectively. Bladder SPC risk was significantly increased after brachytherapy for patients age 60 years or younger (SIR, 5.84; 95% CI, 2.14 to 12.71; AER, 24.03) and in the first 4 years of follow-up (SIR, 2.14; 95% CI, 1.03 to 3.94; AER, 12.24). Adjusted for age, the hazard ratio (brachytherapy v prostatectomy) for all SPCs combined was 0.87 (95% CI, 0.64 to 1.18). CONCLUSION: Overall, we found no difference in SPC incidence between patients with prostate cancer treated with prostatectomy or brachytherapy. Furthermore, no increased tumor incidence was found compared with the general population. We observed a higher than expected incidence of bladder SPC after brachytherapy in the first 4 years of follow-up, probably resulting from lead time or screening bias. Because of power limitations, a small increased SPC risk cannot be formally excluded.