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Birt-Hogg-Dubé syndrome (BHD syndrome) is an autosomal dominant multisystem disorder with variable expression due to pathogenic constitutional variants in the FLCN gene. Patients with BHD syndrome are predisposed to benign cutaneous fibrofolliculomas/trichodischomas, pulmonary cysts with an associated risk of spontaneous pneumothorax, and renal cell carcinoma. A requirement for updated International consensus recommendations for the diagnosis and management of BHD syndrome was identified. Based on a comprehensive literature review and expert consensus within the fields of respiratory medicine, urology, radiology, dermatology, clinical oncology and clinical genetics, updated recommendations for diagnosis, surveillance and management in BHD syndrome were developed. With the widespread availability of FLCN genetic testing, clinical scenarios in which a diagnosis should be considered and criteria for genetic testing were defined. Following a clinical and/or molecular diagnosis of BHD syndrome, a multidisciplinary approach to disease management is required. Regular renal cancer surveillance is recommended in adulthood and life-long, but the evidence base for additional tumour surveillance is limited and further research warranted. Recommendations for the treatment of cutaneous, pulmonary and renal manifestations are provided. Awareness of BHD syndrome needs to be raised and better knowledge of the clinical settings in which the diagnosis should be considered should enable earlier diagnosis. Further details, including areas for future research topics are available at: https://www.genturis.eu/l=eng/Guidelines-and-pathways/Clinical-practice-guidelines.html ., Competing Interests: Competing interests: All members of the ERN GENTURIS BHD Guideline Group, including the Core Working Group, have provided disclosure statements on all relationships that they have that might be perceived to be a potential source of a conflict of interest. Core Working Group patient representatives KN and JH were employed by the Myrovlytis Trust. MGM reports receipt of honoraria or consultation fees from Ipsen. CMC reports receipt of research funding from Boehringer Ingelheim, honoraria or consultation fees from Savara Inc, Theravance, AI Therapeutics, Roche, Aerogen as well as grants from Health Research Board, LAM Foundation and Enterprise Ireland. NR reports participation in a company sponsored speaker’s bureau from Takeda UK. MTAW reports receipt of honoraria or consultation fees from Microsoft. All participants of the ERN GENTURIS BHD syndrome Delphi survey have provided disclosure statements on all relationships that they have that might be perceived to be a potential source of competing interests. Patrick Benusiglio reports receipt of honoraria or consultation fees from AstraZeneca, Bristol Myers Squibb and Merck Sharp & Dohme. Raphael Borie reports receipt of grants/research support from Roche and Boehringer Ingelheim, as well as receipt of honoraria or consultation fees from Roche, Boehringer Ingelheim and Sanofi. Jesper Rømhild Davidsen reports receipt of honoraria or consultation fees from Boehringer Ingelheim. Arndt Hartmann reports receipt of grants/research support from AstraZeneca, Biocartis, Biontech, Cepheid, Gilead, Illumina, Janssen, Nanostring, Novartis, Owkin, Qiagen, QUIP GmbH, Roche and Sanofi, as well as receipt of honoraria or consultation fees from Abbvie, AstraZeneca, Biocartis, Biontech, BMS, Boehringer Ingelheim, Cepheid, Diaceutics, Gilead, Illumina, Ipsen, Janssen, Lilly, MSD, Nanostring, Novartis, Qiagen, QUIP GmbH, Roche, Sanofi and 3DHistotech. Arjan C. Houweling reports receipt of a research grant from the Myrovlytis Trust. Stefan J. Marciniak reports receipt of grants/research support from the Myrovlytis Trust, Asthma+Lung UK, Alpha 1 Foundation, the Medical Research Council (MRC) UK, and the Engineering and Physical Sciences Research Council (EPSRC). Maria Molina-Molina reports receipt of grants/research support from Boehringer Ingelheim and Roche, as well as receipt of honoraria or consultation fees from Ferrer, Chiesi, Boehringer Ingelheim, Roche and Esteve-Teijin. Charles Van Praet reports receipt of honoraria or consultation fees from Astellas, IPSEN and Baxter. Robin de Putter reports receipt of honoraria or consultation fees from AstraZeneca. Lore van Riel reports receipt of a research grant from the Myrovlytis Trust. Jacobo Sellarés Torres reports receipt of grants/research support from Roche and Boehringer Ingelheim, receipt of honoraria or consultation fees from Boehringer Ingelheim, as well as participation in a speaker’s bureau sponsored by Boehringer Ingelheim. Grant D. Stewart reports receipt of grants/research support from AstraZeneca and Pfizer, receipt of honoraria or consultation fees from Pfizer, Merck, EUSA Pharma and Eisai, as well as participation in a speaker’s bureau sponsored by Eisai., (© 2024. The Author(s).)

Background: The recent introduction of magnetic resonance-guided radiation therapy (MRgRT) has allowed improved treatment planning and delivery of stereotactic body radiotherapy (SBRT) in prostate cancer (PC). The health-related quality of life (HRQoL) outcomes using this novel approach are important in shared decision making for patients., Objective: To report HRQoL using both patient- and clinician-reported outcomes at 1 yr following stereotactic MRgRT for patients with localized PC., Design, Setting, and Participants: A prospective phase 2 trial included 101 patients with localized PC., Intervention: All patients received 36.25Gy in five fractions of MRgRT delivered within 2 wk., Outcome Measurements and Statistical Analysis: HRQoL was prospectively assessed at baseline, at the last fraction, at 6 wk, and at 3, 6, 9, and 12 mo after treatment, by patient-reported outcome measures using European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-PR25 questionnaires, and International Prostate Symptom Score. At the same time points, clinicians reported on symptomatic adverse events (AEs). Effect sizes for changes in HRQoL were calculated with repeated measures analysis of variance., Results and Limitations: Availability of HRQoL data exceeded 95% at all study time points. From both questionnaires and the recorded AEs, the largest treatment effects on urinary and bowel symptoms were recorded in the first 6 wk of follow-up. Thereafter, all symptoms decreased and returned to baseline values at 12 mo. No grade ≥3 toxicity was reported. No patient reported any relevant limitation due to urinary symptoms, and only 2.2% of patients reported a relevant impact on daily activities due to bowel problems at 1 yr. The majority of patients had intermediate- or high-risk PC for which androgen deprivation therapy (83.2%) was prescribed, thereby precluding study of MRgRT on sexual function. Longer follow-up is awaited in order to evaluate the oncological outcome., Conclusions: Delivery of MRgRT for SBRT resulted in low toxicity at 1 yr., Patient Summary: All patients completed magnetic resonance-guided radiation therapy, which was well tolerated with only transient early urinary and bowel symptoms, which resolved 1 yr after treatment, as confirmed by patient-reported outcome measures., (Copyright © 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Genital gender-affirming surgery (gGAS) with urethral lengthening (UL) in transgender men is associated with high urological complication and reoperation rates. Since 2009, we offer gGAS without UL to avoid these complications., Aim: The aim of this study was to assess what portion of the transgender men opted for gGAS without UL and to assess functional, surgical outcomes, and patient satisfaction after gGAS without UL., Material and Methods: Retrospective data were collected from patients' charts. The International Prostate Symptom Score, uroflowmetry, and 24-hour frequency voiding chart were used to assess voiding, and a self-constructed semistructured questionnaire was used to assess patient-reported outcomes. Transgender men who underwent gGAS without UL between January 2009 and January 2018 were included, and 56 transgender men were approached to complete the patient-reported outcome measurement. The simple statistical analysis combined with the Mann-Whitney U test and the Wilcoxon signed-rank test was used., Outcomes: 68 transgender men were included. Median follow-up time was 24 (6-129) months. Uroflowmetry and the International Prostate Symptom Score were completed by 44 transgender men, whereas 13 completed the frequency voiding chart preoperatively and postoperatively, respectively. The patient-reported outcome measurement was completed by 40 of 56 (71%) transgender men., Result: Postoperative surgical and urological complications occurred in 9 of 68 (13%) and 8 of 68 (12%) patients, respectively. Storage and voiding function remained unchanged. The median quality of life because of urinary symptoms was scored as "pleased." Sexual functioning and voiding were scored satisfactory and very satisfactory in 18 of 40 (45%) and 21 of 40 (53%) patients, respectively. The number of patients satisfied with the penis and neoscrotum was 25 of 40 (63%) and 26 of 40 (65%), respectively. Increased self-esteem was reported by 32 of 40 (80%), 32 of 40 (80%) would undergo the surgery again, and 28 of 40 (70%) would recommend it to others., Clinical Implications: gGAS without UL should be part of the surgical armamentarium in centers performing gender-affirming surgery., Strengths and Limitations: Strengths of this study comprise the number of patients, the completeness of data, incorporation of patient-reported outcomes, and description of a relatively new surgical approach that may be well-suitable for a subgroup of transgender men. Limitations are the retrospective study design and the lack of validated questionnaires., Conclusion: gGAS without UL shows good surgical and urological outcomes. After extensive counseling, the majority of this selective group of patients shows favorable patient-reported outcomes. Pigot GLS, Al-Tamimi M, Nieuwenhuijzen JA, et al. Genital Gender-Affirming Surgery Without Urethral Lengthening in Transgender Men-A Clinical Follow-Up Study on the Surgical and Urological Outcomes and Patient Satisfaction. J Sex Med 2020;17:2478-2487., (Copyright © 2020 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Novel magnetic-resonance-guided radiotherapy (MRgRT) permits real-time soft-tissue visualization, respiratory-gated delivery with minimal safety margins, and time-consuming daily plan re-optimisation. We report on early clinical outcomes of MRgRT and routine plan re-optimization for large primary renal cell cancer (RCC). Thirty-six patients were treated with MRgRT in 40 Gy/5 fractions. Prior to each fraction, re-contouring of tumor and normal organs on a pretreatment MR-scan allowed daily plan re-optimization. Treatment-induced toxicity and radiological responses were scored, which was followed by an offline analysis to evaluate the need for such daily re-optimization in 180 fractions. Mean age and tumor diameter were 78.1 years and 5.6 cm, respectively. All patients completed MRgRT with an average fraction duration of 45 min. Local control (LC) and overall survival rates at one year were 95.2% and 91.2%. No grade ≥3 toxicity was reported. Plans without re-optimization met institutional radiotherapy constraints in 83.9% of 180 fractions. Thus, daily plan re-optimization was required for only a minority of patients, who can be identified upfront by a higher volume of normal organs receiving 25 Gy in baseline plans. In conclusion, stereotactic MRgRT for large primary RCC showed low toxicity and high LC, while daily plan re-optimization was required only in a minority of patients.

DNA methylation analysis of full void urine and urine pellet seems promising for bladder cancer (BC) detection and surveillance. Urinary cell-free DNA from urine supernatant is now gaining interest for other molecular tests in BC. This study aims to evaluate which urine fraction is preferred for BC diagnosis using methylation markers: full void urine, urine pellet or supernatant. Methylation levels of nine markers were determined in the three urine fractions and correlated with their respective tumor tissues in BC patients and compared to controls. For all markers and marker panel GHSR/MAL , diagnostic performance was determined by calculating the area under the curve (AUC) of the respective receiver operating characteristic curves. For most of the markers, there was a significant correlation between the methylation levels in each of the urine fractions and the matched tumor tissues. Urine pellet was the most representative fraction. Generally, AUCs for BC diagnosis were comparable among the fractions. The highest AUC was obtained for GHSR/MAL in urine pellet: AUC 0.87 (95% confidence interval: 0.73-1.00), corresponding to a sensitivity of 78.6% and a specificity of 91.7%. Our results demonstrate that cellular and cell-free DNA in urine can be used for BC diagnosis by urinary methylation analysis. Based on our comparative analysis and for practical reasons, we recommend the use of urine pellet.

Background: Previously, it has been suggested that colorectal polyps and carcinomas might be associated with Birt-Hogg-Dubé syndrome. We aimed to compare the occurrence of colorectal neoplasms between Dutch patients with Birt-Hogg-Dubé syndrome and their relatives without Birt-Hogg-Dubé syndrome., Methods: In all, 399 patients with a pathogenic FLCN mutation and 382 relatives without the familial FLCN mutation were included. Anonymous data on colon and rectum pathology was provided by PALGA: the Dutch Pathology Registry., Results: No significant difference in the percentage of individuals with a history of colorectal carcinoma was found between the two groups (3.6% vs 2.6%, p = 0.54). There was also no significant difference between the age at diagnosis, diameter, differentiation and location of the colorectal carcinomas. Significantly more individuals with Birt-Hogg-Dubé syndrome underwent removal of colorectal polyps (12.2% vs 6.3%, p = 0.005). However, there was no significant difference between the number of polyps per person, the histology, grade of dysplasia and location of the polyps., Conclusion: Our data do not provide evidence for an increased risk for colorectal carcinoma in Birt-Hogg-Dubé syndrome, arguing against the need for colorectal surveillance. The difference in polyps might be due to a bias caused by a higher number of colonoscopies in patients with Birt-Hogg-Dubé syndrome.

Background: The cornerstone of standard treatment for patients with primary bone metastatic prostate cancer (mPCa) is androgen deprivation therapy (ADT). Retrospective studies suggest a survival benefit for treatment of the primary prostatic tumour in mPCa, but to date, no randomised-controlled-trials (RCTs) have been published addressing this issue., Objective: To determine whether overall survival is prolonged by adding local treatment of the primary prostatic tumour with external beam radiation therapy (EBRT) to ADT., Design, Setting, and Participants: The HORRAD trial is a multicentre RCT recruiting 432 patients with prostate-specific antigen (PSA) >20ng/ml and primary bone mPCa on bone scan between 2004 and 2014., Intervention: Patients were randomised to either ADT with EBRT (radiotherapy group) or ADT alone (control group)., Outcome Measurements and Statistical Analysis: Primary endpoint was overall survival. Secondary endpoint was time to PSA progression. Crude and adjusted analyses were applied to evaluate treatment effect., Results and Limitations: Median PSA level was 142ng/ml and 67% of patients had more than five osseous metastases. Median follow up was 47 mo. Median overall survival was 45 mo (95% confidence interval [CI], 40.4-49.6) in the radiotherapy group and 43 mo (95% CI: 32.6-53.4) in the control group (p=0.4). No significant difference was found in overall survival (hazard ratio [HR]: 0.90; 95% CI: 0.70-1.14; p=0.4). Median time to PSA progression in the radiotherapy group was 15 mo (95% CI: 11.8-18.2), compared with 12 mo (95% CI: 10.6-13.4) in the control group. The crude HR (0.78; 95% CI: 0.63-0.97) was statistically significant (p=0.02)., Conclusions: The current RCT comparing ADT to ADT with EBRT to the prostate in patients with primary bone mPCa did not show a significant difference in overall survival, although the CI cannot exclude a substantial survival benefit. Further research is needed to confirm our findings., Patient Summary: This study investigated the effect of adding radiation therapy to the prostate to hormonal therapy in prostate cancer patients with metastasis to the bone at diagnosis. In our patient group, additional radiotherapy did not improve overall survival. Further research is needed to confirm our findings., Twitter Summary: Adding radiotherapy to the prostate in patients with bone metastatic prostate cancer does not improve overall survival., (Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.)