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PURPOSE: Hypofractionated radiation therapy can be used to treat patients with muscle-invasive bladder cancer unable to have radical therapy. Toxicity is a key concern, but adaptive plan-of the day (POD) image-guided radiation therapy delivery could improve outcomes by minimizing the volume of normal tissue irradiated. The HYBRID trial assessed the multicenter implementation, safety, and efficacy of this strategy.METHODS: HYBRID is a Phase II randomized trial that was conducted at 14 UK hospitals. Patients with T2-T4aN0M0 muscle-invasive bladder cancer unsuitable for radical therapy received 36 Gy in 6 weekly fractions, randomized (1:1) to standard planning (SP) or adaptive planning (AP) using a minimization algorithm. For AP, a pretreatment cone beam computed tomography (CT) was used to select the POD from 3 plans (small, medium, and large). Follow-up included standard cystoscopic, radiologic, and clinical assessments. The primary endpoint was nongenitourinary Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 3 (≥G3) toxicity within 3 months of radiation therapy. A noncomparative single stage design aimed to exclude ≥30% toxicity rate in each planning group in patients who received ≥1 fraction of radiation therapy. Local control at 3-months (both groups combined) was a key secondary endpoint.RESULTS: Between April 15, 2014, and August 10, 2016, 65 patients were enrolled (SP, n = 32; AP, n = 33). The median follow-up time was 38.8 months (interquartile range [IQR], 36.8-51.3). The median age was 85 years (IQR, 81-89); 68% of participants (44 of 65) were male; and 98% of participants had grade 3 urothelial cancer. In 63 evaluable participants, CTCAE ≥G3 nongenitourinary toxicity rates were 6% (2 of 33; 95% confidence interval [CI], 0.7%-20.2%) for the AP group and 13% (4 of 30; 95% CI, 3.8%-30.7%) for the SP group. Disease was present in 9/48 participants assessed at 3 months, giving a local control rate of 81.3% (95% CI, 67.4%-91.1%).CONCLUSIONS: POD adaptive radiation therapy was successfully implemented across multiple centers. Weekly ultrahypofractionated 36 Gy/6 fraction radiation therapy is safe and provides good local control rates in this older patient population.

Significance Clearance of surgical margins in early cervical cancer prevents the need for adjuvant chemoradiation and associated morbidity and allows fertility preservation. Clearance of disease is also crucial in the surgical management of local recurrence of cervical tumors with exenterative surgery. In this study intelligent knife technology was able to discriminate healthy from abnormal lesions on the cervix with high accuracy, highlighting the potential to improve intraoperative management of women treated surgically for cervical cancer and, as a result, patient outcomes. While pilot experiments in vivo are encouraging, accuracy remains to be validated in larger patient cohorts. Future studies could also explore whether this technology could be used for management of cervical preinvasive disease., Clearance of surgical margins in cervical cancer prevents the need for adjuvant chemoradiation and allows fertility preservation. In this study, we determined the capacity of the rapid evaporative ionization mass spectrometry (REIMS), also known as intelligent knife (iKnife), to discriminate between healthy, preinvasive, and invasive cervical tissue. Cervical tissue samples were collected from women with healthy, human papilloma virus (HPV) ± cervical intraepithelial neoplasia (CIN), or cervical cancer. A handheld diathermy device generated surgical aerosol, which was transferred into a mass spectrometer for subsequent chemical analysis. Combination of principal component and linear discriminant analysis and least absolute shrinkage and selection operator was employed to study the spectral differences between groups. Significance of discriminatory m/z features was tested using univariate statistics and tandem MS performed to elucidate the structure of the significant peaks allowing separation of the two classes. We analyzed 87 samples (normal = 16, HPV ± CIN = 50, cancer = 21 patients). The iKnife discriminated with 100% accuracy normal (100%) vs. HPV ± CIN (100%) vs. cancer (100%) when compared to histology as the gold standard. When comparing normal vs. cancer samples, the accuracy was 100% with a sensitivity of 100% (95% CI 83.9 to 100) and specificity 100% (79.4 to 100). Univariate analysis revealed significant MS peaks in the cancer-to-normal separation belonging to various classes of complex lipids. The iKnife discriminates healthy from premalignant and invasive cervical lesions with high accuracy and can improve oncological outcomes and fertility preservation of women treated surgically for cervical cancer. Larger in vivo research cohorts are required to validate these findings.

BackgroundObesity and vaginal microbiome (VMB) dysbiosis are each risk factors for adverse reproductive and oncological health outcomes in women. Here, we investigated the relationship between obesity, vaginal bacterial composition, local inflammation and bariatric surgery.MethodsVaginal bacterial composition assessed by high-throughput sequencing of bacterial 16S rRNA genes and local cytokine levels measured using a multiplexed Magnetic Luminex Screening Assay were compared between 67 obese and 42 non-obese women. We further assessed temporal changes in the microbiota and cytokines in a subset of 27 women who underwent bariatric surgery.ResultsThe bacterial component of the vaginal microbiota in obese women was characterised by a lower prevalence of aLactobacillus-dominant VMB and higher prevalence of a high diversity (Lactobacillusspp., andGardnerella- spp. depleted) VMB, compared with non-obese subjects (pDialisterspecies (pAnaerococcus vaginalis(p=0.021), andPrevotella timonensis(p=0.020) and decreased relative abundance ofLactobacillus crispatus(p=0.014). Local vaginal IL-1β, IL-4, IL-6, IL-8, IFNγ, MIP-1α and TNFα levels were all higher among obese women, however, only IL-1β and IL-8 correlated with VMB species diversity. In a subset of obese women undergoing bariatric surgery, there were no significant overall differences in VMB following surgery; however, 75% of these women remained obese at 6 months. Prior to surgery, there was no relationship between body mass index (BMI) and VMB structure; however, post-surgery women with aLactobacillus-dominant VMB had a significantly lower BMI than those with a high diversity VMB.ConclusionsObese women have a significantly different vaginal microbiota composition with increased levels of local inflammation compared to non-obese women. Bariatric surgery does not change the VMB; however, those with the greatest weight loss 6-month post-surgery are most likely to have aLactobacillus-dominant VMB.

Objectives To assess the efficacy and tolerability of cabazitaxel in relapsed penile cancer. Methods This Phase II single-arm trial was designed to recruit 17 patients with relapsed penile cancer. The primary endpoint was objective (complete + partial) response rate (ORR; Response Evaluation Criteria in Solid Tumours [RECIST] v1.1). Treatment comprised six 21-day cycles of cabazitaxel with restaging after cycles 2 and 4. The planned interim analysis was based upon the premise that if none of the first nine patients achieved ORR, trial would be stopped (α = 0.05, Simon’s 2-stage design). Results Nine patients were recruited from four UK centres between December 2014 and August 2016. The median age was 61 (range, 27–73.6) years, and seven patients had metastases. Patients received a median of two chemotherapy cycles (range, 2–5). None of the nine patients achieved ORR and the trial was stopped. Cabazitaxel was well tolerated with no dose reductions or delays. Three patients had grade 3/4 adverse events (anaemia, vomiting, or neutropenic sepsis). The median progression-free and overall survival were 1.3 and 5.6 months, respectively. Conclusions The trial did not reach the threshold for further continuation of single-agent cabazitaxel. However, the observed tolerability profile supports its further investigation in combination with other agents to improve patient outcomes.

Highlights • In response to the dramatic impact of the COVID-19 pandemic on health care pathways and delivery, including delays in management of aggressive cancers, an international expert panel was convened to address the management pathways for patients with penile cancer. • This study reports the statements developed by the panel to reconfigure the management pathways for penile cancer patients during the COVID-19 acute waves. • The adaptation of the EAU and NCCN penile cancer guidelines for use in the setting of COVID-19 acute waves was guided mainly by 2 necessities: To minimize the numbers of hospital visits and hospitalization and to prevent COVID-19-related complications attributed to cancer treatment • A consensus was reached regarding multiple items related to the diagnosis and management of penile cancer throughout the COVID-19 acute waves. • Non-urgent procedures should be postponed and non-invasive procedures should be encouraged to delay or avoid the need for procedures that require general anesthesia because of the morbidity associated with perioperative severe acute respiratory syndrome coronavirus 2 infection., Objectives To develop an international consensus on managing penile cancer patients during the COVID-19 acute waves. A major concern for patients with penile cancer during the coronavirus disease 2019 (COVID-19) pandemic is how the enforced safety measures will affect their disease management. Delays in diagnosis and treatment initiation may have an impact on the extent of the primary lesion as well as the cancer-specific survival because of the development and progression of inguinal lymph node metastases. Materials and methods A review of the COVID-19 literature was conducted in conjunction with analysis of current international guidelines on the management of penile cancer. Results were presented to an international panel of experts on penile cancer and infection control by a virtual accelerated Delphi process using 4 survey rounds. Consensus opinion was defined as an agreement of ≥80%, which was used to reconfigure management pathways for penile cancer. Results Limited evidence is available for delaying penile cancer management. The consensus rate of agreement was 100% that penile cancer pathways should be reconfigured, and measures should be developed to prevent perioperative nosocomial transmission of COVID-19. The panel also reached a consensus on several statements aimed at reconfiguring the management of penile cancer patients during the COVID-19 pandemic. Conclusions The international consensus panel proposed a framework for the diagnostic and invasive therapeutic procedures for penile cancer within a low-risk environment for COVID-19.

Objectives\ud To establish current uro‐oncology practice in the management of sexual dysfunction (SD) following radiotherapy (RT) and/or androgen deprivation therapy (ADT) to treat prostate cancer. To identify differences in approach to the management of SD according to disease stage.\ud \ud Subjects and methods\ud A 14‐question mixed methods survey was designed to assess the current UK practice. Closed‐ and open‐ended questions were used to quantify results while allowing participants to expand on answers. The survey was distributed to members of the British Uro‐Oncology Group at the 2019 annual meeting.\ud \ud Results\ud Surveys were completed by 63 uro‐oncologists attending the annual meeting of the British Uro‐Oncology Group (response rate 66%). The major issue highlighted was a difference in approach to managing SD according to disease stage. More than half of the participants (56%) said ‘advanced stage of disease’ was a barrier to discussing SD. Clinicians were less likely to discuss SD, take baseline assessments, refer to a specialist clinic or offer rehabilitation when dealing with patients with advanced disease. Only a minority said that the management of SD was primarily their responsibility (11%). Nearly all clinicians (92%) had access to SD clinics; however, the majority of clinicians did not routinely refer patients.\ud \ud Conclusions\ud This study shows that men with advanced prostate cancer need better support in managing SD. Patients receiving long‐term ADT are less likely to be offered any kind of help or intervention. Specific guidance on managing SD in this cohort may result in improvements in sexual function, emotional well‐being, quality of life, mental health and confidence.

Transvaginal ultrasound (TVUS) is the initial investigation of choice for postmenopausal bleeding (PMB), followed by diagnostic hysteroscopy and endometrial sampling if abnormalities are detected. Saline contrast sonohysterography (SCSH) - injection of saline through the cervix into the uterine cavity prior to TVUS - allowed increased diagnostic accuracy in women with PMB in several small, heterogeneous studies. The objectives of the current study were to evaluate the diagnostic accuracy of SCSH in women with PMB, comparing findings with surgical and pathological reports, highlight the necessity of SCSH in guiding clinical decision-making, and establish if there is an increase/decrease in the number of hysteroscopies performed for PMB and, hence, the adherence of clinicians to imaging referral guidelines. The search strategy included formulating search terms identifying all synonyms of SCSH and postmenopause. The databases searched were MEDLINE, Embase, and the Cochrane Library. Only studies comparing SCSH to an alternative method were selected. The studies were screened and data analysis performed using content analysis. Data reduction was performed through systematic coding and the generation of themes We identified 18 studies, comprising 974 women, using SCSH to evaluate the endometrial cavity in women with PMB; most support SCSH improving diagnostic accuracy through delineating intracavitary structures. In effect, SCSH could be a first-line investigative modality to assess the uterine cavity once a larger, well-designed study has been conducted to clarify its specificity, sensitivity, and positive predictive value (PPV). Owing to its relatively non-invasive nature and potentially high diagnostic accuracy, SCSH could allow for more accurate decisions regarding the need for further investigation and subsequent management. Tweetable abstract "Saline contrast sonohysterography improves the diagnostic accuracy of the endometrium in postmenopausal bleeding."

Background\ud The introduction of high-risk human papillomavirus (hrHPV) testing as part of primary cervical screening is anticipated to improve sensitivity, but also the number of women who will screen positive. Reflex cytology is the preferred triage test in most settings but has limitations including moderate diagnostic accuracy, lack of automation, inter-observer variability and the need for clinician-collected sample. Novel, objective and cost-effective approaches are needed.\ud \ud Methods\ud In this study, we assessed the potential use of an automated metabolomic robotic platform, employing the principle of laser-assisted Rapid Evaporative Ionisation Mass Spectrometry (LA-REIMS) in cervical cancer screening.\ud \ud Findings\ud In a population of 130 women, LA-REIMS achieved 94% sensitivity and 83% specificity (AUC: 91.6%) in distinguishing women testing positive (n = 65) or negative (n = 65) for hrHPV. We performed further analysis according to disease severity with LA-REIMS achieving sensitivity and specificity of 91% and 73% respectively (AUC: 86.7%) in discriminating normal from high-grade pre-invasive disease.\ud \ud Interpretation\ud This automated high-throughput technology holds promise as a low-cost and rapid test for cervical cancer screening and triage. The use of platforms like LA-REIMS has the potential to further improve the accuracy and efficiency of the current national screening programme.\ud \ud Funding\ud Work was funded by the MRC Imperial Confidence in Concept Scheme, Imperial College Healthcare Charity, British Society for Colposcopy and Cervical Pathology, National Research Development and Innovation Office of Hungary, Waters corporation and NIHR BRC.

Emerging evidence suggests associations between the vaginal microbiota (VMB) composition, human papillomavirus (HPV) infection, and cervical intraepithelial neoplasia (CIN); however, causal inference remains uncertain. Here, we use bacterial DNA sequencing from serially collected vaginal samples from a cohort of 87 adolescent and young women aged 16–26 years with histologically confirmed, untreated CIN2 lesions to determine whether VMB composition affects rates of regression over 24 months. We show that women with a Lactobacillus-dominant microbiome at baseline are more likely to have regressive disease at 12 months. Lactobacillus spp. depletion and presence of specific anaerobic taxa including Megasphaera, Prevotella timonensis and Gardnerella vaginalis are associated with CIN2 persistence and slower regression. These findings suggest that VMB composition may be a future useful biomarker in predicting disease outcome and tailoring surveillance, whilst it may offer rational targets for the development of new prevention and treatment strategies., Persistent infection with human papillomavirus can lead to cervical intraepithelial neoplasia (CIN). Here, the authors profile the vaginal microbiota in a cohort of non-pregnant young women diagnosed with CIN2 and find that absence of Lactobacillusspp. and presence of a diverse population of strict anaerobes associates with a decreased regression of untreated CIN2 lesions.

Background Methylation of the human papillomavirus (HPV) DNA has been proposed as a novel biomarker. Here, we correlated the mean methylation level of 12 CpG sites within the L1 gene, to the histological grade of cervical precancer and cancer. We assessed whether HPV L1 gene methylation can predict the presence of high-grade disease at histology in women testing positive for HPV16 genotype. Methods Pyrosequencing was used for DNA methylation quantification and 145 women were recruited. Results We found that the L1 HPV16 mean methylation (±SD) significantly increased with disease severity (cervical intraepithelial neoplasia [CIN] 3, 17.9% [±7.2] vs CIN2, 11.6% [±6.5], P < .001 or vs CIN1, 9.0% [±3.5], P < .001). Mean methylation was a good predictor of CIN3+ cases; the area under the curve was higher for sites 5611 in the prediction of CIN2+ and higher for position 7145 for CIN3+. The evaluation of different methylation thresholds for the prediction of CIN3+ showed that the optimal balance of sensitivity and specificity (75.7% and 77.5%, respectively) and positive and negative predictive values (74.7% and 78.5%, respectively) was achieved for a methylation of 14.0% with overall accuracy of 76.7%. Conclusions Elevated methylation level is associated with increased disease severity and has good ability to discriminate HPV16-positive women that have high-grade disease or worse.

Background Methylation of viral DNA has been proposed as a novel biomarker for triage of human papillomavirus (HPV) positive women at screening. This systematic review and meta-analysis aims to assess how methylation levels change with disease severity and to determine diagnostic test accuracy (DTA) in detecting high-grade cervical intra-epithelial neoplasia (CIN). Methods We performed searches in MEDLINE, EMBASE and CENTRAL from inception to October 2019. Studies were eligible if they explored HPV methylation levels in HPV positive women. Data were extracted in duplicate and requested from authors where necessary. Random-effects models and a bivariate mixed-effects binary regression model were applied to determine pooled effect estimates. Findings 44 studies with 8819 high-risk HPV positive women were eligible. The pooled estimates for positive methylation rate in HPV16 L1 gene were higher for high-grade CIN (≥CIN2/high-grade squamous intra-epithelial lesion (HSIL) (95% confidence interval (95%CI:72·7% (47·8–92·2))) vs. low-grade CIN (≤CIN1/low-grade squamous intra-epithelial lesion (LSIL) (44·4% (95%CI:16·0–74·1))). Pooled difference in mean methylation level was significantly higher in ≥CIN2/HSIL vs. ≤CIN1/LSIL for HPV16 L1 (11·3% (95%CI:6·5–16·1)). Pooled odds ratio of HPV16 L1 methylation was 5·5 (95%CI:3·5–8·5) for ≥CIN2/HSIL vs. ≤CIN1/LSIL (p

Persistent infection with oncogenic Human Papillomavirus (HPV) is necessary but not sufficient for the development of cervical cancer. The factors promoting persistence as well those triggering carcinogenetic pathways are incompletely understood. Rapidly evolving evidence indicates that the vaginal microbiome (VM) may play a functional role (both protective and harmful) in the acquisition and persistence of HPV, and subsequent development of cervical cancer. The first studies examining the vaginal microbiome and the presence of an HPV infection using next generation sequencing techniques (NGS) identified higher microbial diversity in HPV-positive as opposed to HPV-negative women. Furthermore, there appears to be a temporal relationship between the VM and HPV infection in that specific community state types (CSTs) may be correlated with a higher chance of progression or regression of the infection. Studies describing the VM in women with pre-invasive disease (squamous intra-epithelial neoplasia – SIL) consistently demonstrate a dysbiosis in women with the more severe disease. Although it is plausible that the composition of the VM may influence the host innate immune response, susceptibility to infection and the development of cervical disease, the studies to date do not prove causality. Future studies should explore the causal link between the VM and the clinical outcome in longitudinal samples from existing biobanks.

We performed a systematic review and meta-analysis to explore the optimum management strategy for women with atypical squamous cells of undetermined significance (ASCUS/borderline) or low-grade squamous intra-epithelial lesions (LSIL/mild dyskaryosis) cytological abnormalities at primary screening in the absence of HPV DNA test. We searched MEDLINE, EMBASE and CENTRAL and included randomised controlled trials comparing immediate colposcopy to cytological surveillance in women with ASCUS/LSIL. The outcomes of interest were occurrence of different histological grades of cervical intraepithelial neoplasia (CIN) and default rates during follow-up. Pooled risk ratios (RR) and 95% confidence intervals (CI) were calculated using a random-effect model and with inverse variance weighting. Interstudy heterogeneity was assessed using I2 statistics. Six RCTs were included. Immediate colposcopy significantly increased detection of unimportant abnormalities as opposed to repeat cytology (koilocytosis: 32 vs. 21%, RR: 1.49, 95% CI = 1.17–1.90); CIN1: 21 vs. 8%, RR: 2.58, 95% CI = 1.69–3.94). Although immediate colposcopy detected CIN2, CIN2+, and CIN3+ earlier than cytology, the differences were no longer observed at 24 months (CIN3+: 10.3 vs.11.9%, RR: 1.02, 95% CI = 0.53–1.97), with significant interstudy heterogeneity (p

Purpose To develop multi-institutional consensus clinical target volumes (CTVs) and organs at risk (OARs) for male and female bladder cancer patients undergoing adjuvant radiation therapy (RT) in clinical trials. Methods and Materials We convened a multidisciplinary group of bladder cancer specialists from 15 centers and 5 countries. Six radiation oncologists and 7 urologists participated in the development of the initial contours. The group proposed initial language for the CTVs and OARs, and each radiation oncologist contoured them on computed tomography scans of a male and female cystectomy patient with input from ≥1 urologist. On the basis of the initial contouring, the group updated its CTV and OAR descriptions. The cystectomy bed, the area of greatest controversy, was contoured by another 6 radiation oncologists, and the cystectomy bed contouring language was again updated. To determine whether the revised language produced consistent contours, CTVs and OARs were redrawn by 6 additional radiation oncologists. We evaluated their contours for level of agreement using the Landis-Koch interpretation of the κ statistic. Results The group proposed that patients at elevated risk for local-regional failure with negative margins should be treated to the pelvic nodes alone (internal/external iliac, distal common iliac, obturator, and presacral), whereas patients with positive margins should be treated to the pelvic nodes and cystectomy bed. Proposed OARs included the rectum, bowel space, bone marrow, and urinary diversion. Consensus language describing the CTVs and OARs was developed and externally validated. The revised instructions were found to produce consistent contours. Conclusions Consensus descriptions of CTVs and OARs were successfully developed and can be used in clinical trials of adjuvant radiation therapy for bladder cancer.

Aims Multi-parametric magnetic resonance imaging (mpMRI) may identify radio-recurrent intra-prostatic cancer accurately. We aimed to compare visually directed MRI-targeted biopsies (MRI-TB) to an accurate reference standard – transperineal prostate mapping (TPM) biopsies with 5 mm sampling – in the detection of clinically significant cancer in men with biochemical failure after radiotherapy. Materials and methods A retrospective registry analysis between 2006 and 2014 identified 77 men who had undergone mpMRI followed by MRI-TB and TPM. Clinical significance was set at two definitions of disease. Definition 1 was Gleason ≥ 4+3 and/or maximum cancer core length ≥ 6 mm. Definition 2 was Gleason ≥ 3+4 and/or maximum cancer core length ≥ 4 mm. Results Of the 77 patients included, the mean age was 70 years (range 61–82; standard deviation 5.03). The median prostate-specific antigen (PSA) at the time of external beam radiotherapy (EBRT) was 14 ng/ml (interquartile range 7.83–32.50). The most frequent EBRT dose given was 74 Gy over 37 fractions. Eight patients had iodine-seed implant brachytherapy or high dose rate brachytherapy. Neoadjuvant/adjuvant hormonal therapy use was reported in 38. The time from EBRT to biochemical recurrence was a median of 60 months (interquartile range 36.75–85.00). The median PSA at the time of mpMRI was 4.68 ng/ml (interquartile range 2.68–7.60). The median time between mpMRI and biopsy was 2.76 months (interquartile range 1.58–4.34). In total, 2392 TPM and 381 MRI-TB cores were taken with 18% and 50% cancer detection, respectively. Detection rates of definition 1 clinically significant cancer were 52/77 (68%) versus 55/77 (71%) for MRI-TB and TPM, respectively. MRI-TB was more efficient requiring 1 core versus 2.8 cores to detect definition 2 cancer. Conclusion MRI-TB seems to have encouraging detection rates for clinically significant cancer with fewer cores compared with TPM, although TPM had higher detection rates for smaller lower grade lesions.

Introduction Daily radiotherapy delivered with radiosensitisation offers patients with muscle invasive bladder cancer (MIBC) comparable outcomes to cystectomy with functional organ preservation. Most recurrences following radiotherapy occur within the bladder. Increasing the delivered radiotherapy dose to the tumour may further improve local control. Developments in image-guided radiotherapy have allowed bladder tumour-focused ‘plan of the day’ radiotherapy delivery. We aim to test within a randomised multicentre phase II trial whether this technique will enable dose escalation with acceptable rates of toxicity. Methods and analysis Patients with T2-T4aN0M0 unifocal MIBC will be randomised (1:1:2) between standard/control whole bladder single plan radiotherapy, standard dose adaptive tumour-focused radiotherapy or dose-escalated adaptive tumour-focused radiotherapy (DART). Adaptive tumour-focused radiotherapy will use a library of three plans (small, medium and large) for treatment. A cone beam CT taken prior to each treatment will be used to visualise the anatomy and inform selection of the most appropriate plan for treatment. Two radiotherapy fractionation schedules (32f and 20f) are permitted. A minimum of 120 participants will be randomised in each fractionation cohort (to ensure 57 evaluable DART patients per cohort). A comprehensive radiotherapy quality assurance programme including pretrial and on-trial components is instituted to ensure standardisation of radiotherapy planning and delivery. The trial has a two-stage non-comparative design. The primary end point of stage I is the proportion of patients meeting predefined normal tissue constraints in the DART group. The primary end point of stage II is late Common Terminology Criteria for Adverse Events grade 3 or worse toxicity aiming to exclude a rate of >20% (80% power and 5% alpha, one sided) in each DART fractionation cohort. Secondary end points include locoregional MIBC control, progression-free survival overall survival and patient-reported outcomes. Ethics and dissemination This clinical trial is approved by the London-Surrey Borders Research Ethics Committee (15/LO/0539). The results when available will be disseminated via peer-reviewed scientific journals, conference presentations and submission to regulatory authorities. Trial registration number NCT02447549

503 Background: Level 1 evidence exists for the use of both neoadjuvant chemotherapy (NAC) and concomitant radiosensitization (CRS) to improve outcomes in patients receiving radical radiotherapy (RT) for muscle invasive bladder cancer, but uptake has been patchy. We report here the current patterns of usage in an ongoing trial of adaptive radiotherapy. Methods: RAIDER is an international randomized phase II trial recruiting patients with unifocal T2-T4a urothelial carcinoma of the bladder suitable for RT (ISCRTN:26779187). Patients are randomized in a 1:1:2 ratio to one of 3 arms: Standard whole bladder RT (control); Standard dose adaptive tumour focused RT; Dose escalated (DE) adaptive tumour boost RT. Standard dose patients are treated to either 64Gy/32f or 55Gy/20f and DE patients to 70Gy in 32f or 60Gy in 20f. Patients are encouraged to receive NAC and CRS. The primary endpoint is the rate of late toxicity 6-18 months post treatment in arm 3, with secondary endpoints of patient reported and disease related outcomes. Results: To August 2019, 285 patients had been recruited. Median age is 72 years (IQR 67-79). Stage of disease is T2 79%, T3 19%, T4 2%; 19% have hydronephrosis. Patients receiving NAC were more likely to be PS 0 at trial entry (70% v 45%). Variation in frequency of CRS use is seen across sites, with some offering to >90% of participants and some

Background Primary squamous cell carcinoma (SCC) of the male proximal urethra is an aggressive and rare urogenital malignancy. Objective To review the surgical management and outcomes for male proximal urethral SCCs within a single centre and to suggest an algorithm for the surgical management of these rare tumours. Design, setting, and participants This was a retrospective study of patients undergoing surgery for male proximal urethral SCC within a single tertiary academic centre managing rare genital tumours. Ten patients with a histological diagnosis of proximal urethral SCC were identified from an institutional database over a period of 10 yr with a median follow-up of 22.5 mo (standard deviation ± 25.77 mo). Outcome measurements and statistical analysis Pathological staging, surgical treatment, and neoadjuvant and adjuvant treatment were recorded. Complications according to the Clavien-Dindo classification and overall survival rates were recorded. Kaplan-Meier curves were used for overall survival. Results and limitations A total of 10 patients were identified of whom eight underwent panurethrectomy and radical prostatectomy. Radical inguinal lymphadenectomy was performed in five patients, which confirmed bilateral metastatic disease. Perioperative complications were reported in six patients (Clavien I and II). Within 6 mo of surgery, 90% of patients developed distant metastatic disease. Nine patients died of urethra cancer during the follow-up. One patient is still on follow-up. The median overall follow-up was 13.92 mo (range: 5–91 mo). At 5 yr, cancer-specific/overall survival was 10%. A limitation of this study is the retrospective design, which is unavoidable for such a rare disease. Conclusions Radical surgery allows local disease control, but despite neo/adjuvant treatment, proximal urethral SCC is associated with poor survival outcomes and progression to distant metastatic disease within 6 mo. Patient summary Proximal urethral squamous cell carcinoma is a rare cancer in men which is often detected late. Patients often present with problems such as voiding, urethral bleeding, or a palpable mass. Aggressive surgery allows local control, but despite this the overall survival is poor. Adjuvant and neoadjuvant radiochemotherapy can improve survival. Multicentric randomised trials are needed to identify the correct treatment modality.

Introduction We reviewed the medical and surgical management and long-term outcomes for patients diagnosed with penoscrotal extramammary Pagets disease (EMPD) within an eUROGEN centre. Patients and Methods Retrospective review of cases from an institutional database with biopsy proven penoscrotal EMPD. Results A total of 10 patients were identified with penoscrotal EMPD over a 10-year period. Two patients had a previous history of gastrointestinal and urogenital cancers (20%) and no synchronous or metachronous cancers were identified. Eight patients with non-invasive EMPD (80%) underwent wide local excision of the affected skin, with at least a 5mm macroscopic resection margin and in selected cases simultaneous multiple mapping biopsies around the lesion were performed. Residual disease was present at the margins in seven patients (87.5%), of which three required further surgical excision or adjuvant topical immunotherapy (42.8%). Recurrence after complete excision was 12.5% and was successfully treated with topical imiquimod immunotherapy and CO2 laser therapy. Two patients (20%) had invasive carcinoma and metastatic disease at diagnosis. Conclusion Reported recurrence rates of non-invasive penoscrotal EMPD are high and residual disease is present in most cases requiring either close clinical surveillance or adjuvant treatment. We propose an algorithm in the management of this rare disease.

Background: This is a feasibility study to determine whether circulating tumour cells (CTCs) are detectable and suitable for molecular profiling in advanced endometrial cancer (aEC). Method: Between October 2012 and February 2014, 30 patients with aEC had baseline and up to 3 follow-up samples. CTCs and stathmin expression were evaluated using the CellSearch platform. Epithelial cell adhesion molecule (EpCAM) and stathmin immunohistochemistry were performed on FFPE tumour tissue. Results: Eighteen from 30 (60%) patients had detectable CTCs during study [1 CTC (n = 7), 2 (n = 4), 3 (n = 1), 4 (n = 2), 7 (n = 1), 8 (n = 1), 22 (n = 1), 172 (n = 1) in 7.5 ml blood]. Ten from 18 patients had between 50 and 100% of detectable CTCs that were stathmin positive. More CTC-positive than CTC-negative patients had non-endometrioid versus endometrioid histology, tumour size ≥5 versus 0.05, 95% confidence interval 0.7-16.2]. Twenty-one tumour blocks were tested for EpCAM and stathmin immunohistochemistry (IHC). Stathmin tumour immunostaining scores (TIS) on IHC were higher in CTC-positive patients. Conclusion: CTC enumeration and molecular profiling with stathmin on the CellSearch platform is feasible in aEC. Stathmin TIS on IHC, a known prognostic marker in EC, was associated with CTC positivity.

Background The mean age of women undergoing local treatment for pre-invasive cervical disease (cervical intra-epithelial neoplasia; CIN) or early cervical cancer (stage IA1) is around their 30s and similar to the age of women having their first child. Local cervical treatment has been correlated to adverse reproductive morbidity in a subsequent pregnancy, however, published studies and meta-analyses have reached contradictory conclusions. Objectives To assess the effect of local cervical treatment for CIN and early cervical cancer on obstetric outcomes (after 24 weeks of gestation) and to correlate these to the cone depth and comparison group used. Search methods We searched the following databases: Cochrane Central Register of Controlled Trials (CENTRAL; the Cochrane Library, 2017, Issue 5), MEDLINE (up to June week 4, 2017) and Embase (up to week 26, 2017). In an attempt to identify articles missed by the search or unpublished data, we contacted experts in the field and we handsearched the references of the retrieved articles and conference proceedings. Selection criteria We included all studies reporting on obstetric outcomes (more than 24 weeks of gestation) in women with or without a previous local cervical treatment for any grade of CIN or early cervical cancer (stage IA1). Treatment included both excisional and ablative methods. We excluded studies that had no untreated reference population, reported outcomes in women who had undergone treatment during pregnancy or had a high-risk treated or comparison group, or both Data collection and analysis We classified studies according to the type of treatment and the obstetric endpoint. Studies were classified according to method and obstetric endpoint. Pooled risk ratios (RR) and 95% confidence intervals (CIs) were calculated using a random-effects model and inverse variance. Inter-study heterogeneity was assessed with I2 statistics. We assessed maternal outcomes that included preterm birth (PTB) (spontaneous and threatened), preterm premature rupture of the membranes (pPROM), chorioamnionitis, mode of delivery, length of labour, induction of delivery, oxytocin use, haemorrhage, analgesia, cervical cerclage and cervical stenosis. The neonatal outcomes included low birth weight (LBW), neonatal intensive care unit (NICU) admission, stillbirth, perinatal mortality and Apgar scores. Main results We included 69 studies (6,357,823 pregnancies: 65,098 pregnancies of treated and 6,292,725 pregnancies of untreated women). Many of the studies included only small numbers of women, were of heterogenous design and in their majority retrospective and therefore at high risk of bias. Many outcomes were assessed to be of low or very low quality (GRADE assessment) and therefore results should be interpreted with caution. Women who had treatment were at increased overall risk of preterm birth (PTB) (less than 37 weeks) (10.7% versus 5.4%, RR 1.75, 95% CI 1.57 to 1.96, 59 studies, 5,242,917 participants, very low quality), severe (less than 32 to 34 weeks) (3.5% versus 1.4%, RR 2.25, 95% CI 1.79 to 2.82), 24 studies, 3,793,874 participants, very low quality), and extreme prematurity (less than 28 to 30 weeks) (1.0% versus 0.3%, (RR 2.23, 95% CI 1.55 to 3.22, 8 studies, 3,910,629 participants, very low quality), as compared to women who had no treatment. The risk of overall prematurity was higher for excisional (excision versus no treatment: 11.2% versus 5.5%, RR 1.87, 95% CI 1.64 to 2.12, 53 studies, 4,599,416 participants) than ablative (ablation versus no treatment: 7.7% versus 4.6%, RR 1.35, 95% CI 1.20 to 1.52, 14 studies, 602,370 participants) treatments and the effect was higher for more radical excisional techniques (less than 37 weeks: cold knife conisation (CKC) (RR 2.70, 95% CI 2.14 to 3.40, 12 studies, 39,102 participants), laser conisation (LC) (RR 2.11, 95% CI 1.26 to 3.54, 9 studies, 1509 participants), large loop excision of the transformation zone (LLETZ) (RR 1.58, 95% CI 1.37 to 1.81, 25 studies, 1,445,104 participants). Repeat treatment multiplied the risk of overall prematurity (repeat versus no treatment: 13.2% versus 4.1%, RR 3.78, 95% CI 2.65 to 5.39, 11 studies, 1,317,284 participants, very low quality). The risk of overall prematurity increased with increasing cone depth (less than 10 mm to 12 mm versus no treatment: 7.1% versus 3.4%, RR 1.54, 95% CI 1.09 to 2.18, 8 studies, 550,929 participants, very low quality; more than 10 mm to 12 mm versus no treatment: 9.8% versus 3.4%, RR 1.93, 95% CI 1.62 to 2.31, 8 studies, 552,711 participants, low quality; more than 15 mm to 17 mm versus no treatment: 10.1 versus 3.4%, RR 2.77, 95% CI 1.95 to 3.93, 4 studies, 544,986 participants, very low quality; 20 mm or more versus no treatment: 10.2% versus 3.4%, RR 4.91, 95% CI 2.06 to 11.68, 3 studies, 543,750 participants, very low quality). The comparison group affected the magnitude of effect that was higher for external, followed by internal comparators and ultimately women with disease, but no treatment. Untreated women with disease and the pre-treatment pregnancies of the women who were treated subsequently had higher risk of overall prematurity than the general population (5.9% versus 5.6%, RR 1.24, 95% CI 1.14 to 1.34, 15 studies, 4,357,998 participants, very low quality). pPROM (6.1% versus 3.4%, RR 2.36, 95% CI 1.76 to 3.17, 21 studies, 477,011 participants, very low quality), low birth weight (7.9% versus 3.7%, RR 1.81, 95% CI 1.58 to 2.07, 30 studies, 1,348,206 participants, very low quality), NICU admission rate (12.6% versus 8.9%, RR 1.45, 95% CI 1.16 to 1.81, 8 studies, 2557 participants, low quality) and perinatal mortality (0.9% versus 0.7%, RR 1.51, 95% CI 1.13 to 2.03, 23 studies, 1,659,433 participants, low quality) were also increased after treatment. Authors' conclusions Women with CIN have a higher baseline risk for prematurity. Excisional and ablative treatment appears to further increases that risk. The frequency and severity of adverse sequelae increases with increasing cone depth and is higher for excision than it is for ablation. However, the results should be interpreted with caution as they were based on low or very low quality (GRADE assessment) observational studies, most of which were retrospective.

131 Background: In primary treatment of localised prostate cancer, minimally invasive ablative therapies such as HIFU aim to achieve cancer control whilst offering a potentially favourable toxicity profile. At 5 years median follow up, 12% of patients treated with focal HIFU require salvage therapy. PROMS using Expanded Prostate Cancer Index Composite for Clinical Practice (EPIC‐CP) provide a validated and clinically relevant tool to assess and quantify side effects from pelvic radiotherapy. There is limited data on late toxicity using PROMs with salvage radiotherapy in this setting. Methods: Retrospective analysis from prospectively collected data of 28 patients who received salvage radiotherapy at our institution 2010-2018 was performed. Late bowel and urinary toxicity measured by EPIC-CP is reported. Results: Gleason score at diagnosis: 3+3 4/28; 3+4 22/28; 4+3 2/28. HIFU treatment received: focal: 9/28; whole gland: 6/28; focal and redo focal: 7/28; focal and redo whole gland: 1/28; whole gland and redo: 5/28. All patients had mpMRI and biopsy proven recurrence with median PSA 6.6 ng/ml (0.57- 30.89). Median age at radiation was 67 years (55-80). Patients received 74 Gy to the prostate and 4 patients received additional pelvic lymph node irradiation. Three men received conformal radiotherapy (multiphase technique) and 25 arcing intensity modulated radiotherapy with hormone therapy as per risk stratification. Cumulative incidence of toxicity is reported at median follow-up of 43 months (7-99). Overall urinary function: no problem 8/28; very small problem 4/28; small problem 7/28; moderate problem 5/28; big problem 4/28 Urinary Incontinence Symptom Score: 2.5/12 (0-12) Urinary Irritation /Obstructive Symptom Score: 3.1/12 (0-12) Bowel Symptom Score: 3.5/12 (0-11) Biochemical relapse has occurred in 2/28 patients. Conclusions: Functional and oncological outcomes for a greater number of patients treated with minimally invasive ablative therapies followed by salvage radiation are required, however this data suggests radiation is a well-tolerated and effective salvage option following primary HIFU.

Background A significant number of women are diagnosed with minor cytologi cal abnormalities on cervical screening. Many authorities recom mend surveillance as spontaneous regression might occur. However, attendance for cytological follow-up decreases with time and mig ht put some women at risk of developing invasive disease. Objectives To assess the optimum management strategy for women with min or cervical cytological abnormalities (atypical squamous cells of undetermined significance - ASCUS or low-grade squamous intra-e pithelial lesions - LSIL) at primary screening in the absence o f HPV (human papillomavirus) DNA test. Search methods We searched the following electronic databases: Cochrane Cent ral Register of Controlled Trials (CENTRAL Issue 4 2016), MEDL INE, and Embase from inception to 21 April 2016. Selection criteria We included randomised controlled trials (RCTs) comparing imme diate colposcopy to cytological surveillance in women with atyp- ical squamous cells of undetermined significance (ASCUS/borderl ine) or low-grade squamous intra-epithelial lesions (LSIL/mi ld dyskaryosis). Data collection and analysis The primary outcome measure studied was the occurrence of cervical intra-epithelial neoplasia (CIN). The secondary outcome measur es studied included default rate, clinically significant anxiety a nd depression, and other self-reported adverse effects. We classified studies according to period of surveillance, at 6, 1 2, 24 or 36 months, as well as at 18 months, excluding a possible exit-examination. We calculated pooled risk ratios (RR) and 95% confidence intervals (CI) using a random-effects model with inver se variance weighting. Inter-study heterogeneity was assessed with I 2 statistics. Main results We identified five RCTs with 11,466 participants that fulfilled the inclusion criteria. There were 18 cases of invasive cervical ca ncer, seven in the immediate colposcopy and 11 in the cytological surve illance groups, respectively. Although immediate colposcopy d etects CIN2+ and CIN3+ earlier than cytology, the differences were no longer observed at 24 months (CIN2+: 3 studies, 4331 women; 17.9% versus 18.3%, RR 1.14, CI 0.66 to 1.97; CIN3+: 3 studies , 4331 women; 10.3% versus 11.9%, RR 1.02, CI 0.53 to 1.97). The inter-study heterogeneity was considerable (I 2 greater than 90%). Furthermore, the inclusion of the results o f the exit examinations at 24 months, which could inflate the CIN detection rate of cytolog ical surveillance, may have led to study design-derived bias; w e therefore considered the evidence to be of low quality. When we excluded the exit examination, the detection rate of hig h-grade lesions at the 18-month follow-up was higher after imme diate colposcopy (CIN2+: 2 studies, 4028 women; 14.3% versus 10.1%, R R 1.50, CI 1.12 to 2.01; CIN3+: 2 studies, 4028 women, 7.8% versus 6.9%, RR 1.24, CI 0.77 to 1.98) both had substantial in ter-study heterogeneity (I 2 greater than 60%) and we considered the evidence to be of moderate quality). The meta-analysis revealed that immediate referral to colpos copy significantly increased the detection of clinically insignifi cant cervical abnormalities, as opposed to repeat cytology after 24 months of surveillance (presence of koilocytosis: 2 studies, 656 women ; 32% versus 21%, RR 1.49, 95% CI 1.17 to 1.90; moderate-quality evi dence); incidence of any CIN: 2 studies, 656 women; 64% versus 32%, RR 2.02, 95% CI 1.33 to 3.08, low-quality evidence; inciden ce of CIN1: 2 studies, 656 women; 21% versus 8%, RR 2.58, 95% CI 1.69 to 3.94, moderate-quality evidence). Due to differences in trial designs and settings, there was la rge variation in default rates between the included studies. The risk for default was higher for the repeat cytology group, with a four-f old increase at 6 months, a six-fold at 12 and a 19-fold at 24 month s (6 months: 3 studies, 5117 women; 6.3% versus 13.3%, RR 3.85, 9 5% CI 1.27 to 11.63, moderate-quality evidence; 12 months: 3 studies, 5115 women; 6.3% versus 14.8%, RR 6.39, 95% CI 1.24 t o 32.95, moderate-quality evidence; 24 months: 3 studies, 433 1 women; 0.9% versus 16.1%, RR 19.1, 95% CI 9.02 to 40.43, moder ate-quality evidence). Authors’ conclusions Based on low- or moderate-quality evidence using the GRADE app roach and generally low risk of bias, the detection rate of CIN2 + or CIN3+ after two years does not appear to differ between imm ediate colposcopy and cytological surveillance in the absence of H PV testing, although women may default from follow-up. Immedia te colposcopy probably leads to earlier detection of high-grade lesions, but also detects more clinically insignificant low-grade lesions . Colposcopy may therefore be the first choice when good compliance is not assured. These results emphasize the need for an accurate r eflex HPV triage test to distinguish women who need diagnosti c follow- up from those who can return safely to routine recall.

International audience; PURPOSE: Dutasteride, which is licensed for symptomatic benign prostatic hyperplasia, has been associated with a lower progression rate of low risk prostate cancer. We evaluated the effect of dutasteride on prostate cancer volume as assessed by T2-weighted magnetic resonance imaging.MATERIALS AND METHODS: In this randomized, double-blind, placebo controlled trial, men with biopsy proven, low-intermediate risk prostate cancer (up to Gleason 3 + 4 and PSA up to 15 ng/ml) who had visible lesion of 0.2 ml or greater on T2-weighted magnetic resonance imaging sequences were randomized to daily dutasteride 0.5 mg or placebo for 6 months. Lesion volume was assessed at baseline, and 3 and 6 months with image guided biopsy to the lesion at study exit. The primary end point was the percent reduction in lesion volume over 6 months. This trial was registered with the European Clinical Trials register (EudraCT 2009-102405-18).RESULTS: A total of 42 men were recruited between June 2010 and January 2012. In the dutasteride group, the average volumes at baseline and 6 months were 0.55 and 0.38 ml, respectively and the average reduction was 36%. In the placebo group, the average volumes at baseline and 6 months were 0.65 and 0.76 ml, respectively, and the average reduction was -12%. The difference in percent reductions between the groups was 48% (95% CI 27.4-68.3, p

Local excisional treatment for cervical intra-epithelial neoplasia (CIN) is linked to significant adverse sequelae including preterm birth, with cone depth and radicality of treatment correlating to the frequency and severity of adverse events. Attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy can detect underlying cervical disease more accurately than conventional cytology. The chemical profile of cells pre- and post-treatment may differ as a result of altered biochemical processes due to excision, or treatment of the disease. Since pre-treatment cervical length varies amongst women, the percentage of cervix excised may correlate more accurately to risk than absolute dimensions. We show that treatment for CIN significantly alters the biochemistry of the cervix, compared with women who have not had treatment; this is due to the removal of cervical tissue rather than the removal of the disease. However, the spectra do not seem to correlate to the cone depth or proportion of cervical length excised. Future research should aim to explore the impact of treatment in a larger cohort.

Clinical Question: Does local conservative treatment for cervical intraepithelial neoplasia and early invasive cervical cancer adversely affect successful conception and early pregnancy outcomes in the first and second trimester (

Background: Port-site metastases (PSMs) are a rare occurrence after robotic surgery. For robot-assisted radical cystectomy (RARC), isolated cases have been reported but management has not been previously described. We present a case of PSM that occurred after RARC and report the results of our systematic review of previously reported PSMs and describe the treatment options. Search Criteria and Methods: We describe a case of a PSM in a 55-year-old man who had undergone intracorporeal RARC. We performed a systematic review of MEDLINE and Embase databases for previously reported PSMs, detailing the stage and grade of the primary tumor, time to presentation of PSM, treatment offered, and outcomes for the identified cases. Results: We identified 4 cases of PSMs after RARC in published studies and also included our case for analysis. All 5 patients had muscle-invasive bladder cancer at cystectomy (stage ≥ T2) and 3 had local lymph node-positive disease. Our aggressive treatment of chemotherapy, wide surgical excision of PSM, and radiotherapy provided our patient with a 2-year disease-free status. Conclusion: PSMs are a rare event in RARC, with only 4 other cases reported in published studies. The outcomes have not been well reported for these cases. We propose that multimodality treatment consisting of salvage chemotherapy, surgery, and radiotherapy should be considered, although concessions could be needed after consideration of patient factors.

547 Background: Platinum-based combination chemotherapy regimens are used in the treatment of carcinoma of the penis, but toxicity limits their value for patients with metastatic disease. This trial aims to define both the toxicity and the rate of disease control for the non-platinum cytotoxic agent Vinflunine. Methods: A phase II single-arm trial was designed to demonstrate a clinical benefit rate of at least 40% and to exclude a rate of less than 15% (p0 = 0.15, p1 = 0.40, α = 0.05, β = 0.80, Fleming-A’hern exact design). 22 evaluable patients were required. Key eligibility criteria included measurable, histologically-proven squamous cell carcinoma of the penis staged as M1; or M0, Tx, N3; or M0, Tx, N2 and deemed inoperable by multidisciplinary team; or M0, T4 any N. Patients were required to have ECOG performance status of 0, 1 or 2 and adequate hepatic and renal function. Treatment comprised four 21-day cycles of vinflunine (320mg/m2) with RECIST v1.1 restaging following cycle 4 (response primary endpoint). Patients deemed to be benefitting from treatment were permitted to continue vinflunine at the discretion of the treating clinician until progression or unacceptable toxicity. Results: 25 patients were recruited from 8 UK centres between June 2014 and May 2017. Median age was 68 years; 19 patients had metastatic (M1) disease. All patients have completed trial treatment and primary endpoint assessment. Data cleaning for the primary analysis is currently in progress, with the snapshot for the primary analysis due in October 2017 and primary analysis to be presented to the trial oversight committees in November 2017. Conclusions: It is hoped that single-agent vinflunine will be associated with a favourable toxicity profile combined with meaningful clinical responses. The results will be available for presentation at the meeting. Clinical trial information: NCT02057913.

Persistent infection with oncogenic Human Papillomavirus (HPV) is necessary for cervical carcinogenesis. Although evidence suggests that the vaginal microbiome plays a functional role in the persistence or regression of HPV infections, this has yet to be described in women with cervical intra-epithelial neoplasia (CIN). We hypothesised that increasing microbiome diversity is associated with increasing CIN severity. llumina MiSeq sequencing of 16S rRNA gene amplicons was used to characterise the vaginal microbiota of women with low-grade squamous intra-epithelial lesions (LSIL; n = 52), high-grade (HSIL; n = 92), invasive cervical cancer (ICC; n = 5) and healthy controls (n = 20). Hierarchical clustering analysis revealed an increased prevalence of microbiomes characterised by high-diversity and low levels of Lactobacillus spp. (community state type-CST IV) with increasing disease severity, irrespective of HPV status (Normal = 2/20,10%; LSIL = 11/52,21%; HSIL = 25/92,27%; ICC = 2/5,40%). Increasing disease severity was associated with decreasing relative abundance of Lactobacillus spp. The vaginal microbiome in HSIL was characterised by higher levels of Sneathia sanguinegens (P

OBJECTIVE:\ud To determine the impact of cervical excision for cervical intraepithelial neoplasia on fertility and early pregnancy outcomes.\ud \ud DESIGN:\ud Systematic review and meta-analysis of cohort studies.\ud \ud DATA SOURCES:\ud Medline and Embase.\ud \ud ELIGIBILITY CRITERIA:\ud Studies assessing fertility and early pregnancy outcomes in women with a history of treatment for cervical intraepithelial neoplasia versus untreated women. We classified the included studies according to treatment type and fertility or early pregnancy endpoint.\ud \ud ANALYSIS:\ud Pooled relative risks and 95% confidence intervals using a random effect model, and interstudy heterogeneity with I(2) statistics.\ud \ud RESULTS:\ud 15 studies fulfilled the inclusion criteria and were included. The meta-analysis did not provide any evidence that treatment for cervical intraepithelial neoplasia adversely affected the chances of conception. The overall pregnancy rate was higher for treated women than for untreated women (four studies; 43% v 38%, pooled relative risk 1.29, 95% confidence interval 1.02 to 1.64), although the heterogeneity between studies was high (P

409 Background: Several organizations are developing clinical trials to evaluate adjuvant radiotherapy (RT) for bladder cancer patients at elevated risk of locoregional failure (LF). However, the clinical target volumes (CTVs) & organs at risk (OARs) for this treatment have not been defined in detail. Our purpose was to define multi-institutional consensus CTVs & OARs for male & female bladder cancer patients undergoing adjuvant RT in clinical trials. Methods: We convened a multi-disciplinary group of bladder cancer specialists from 9 centers in 3 countries. 5 radiation oncologists (ROs) & 7 urologists participated in the development of the proposed contours. The group proposed initial language for the CTVs & OARs and contoured them on CT scans of a male & female cystectomy patient with input from ≥ 1 urologist at each center. Using the binomial maximum-likelihood estimates method, we generated 95% level initial contours. We evaluated the contours for level of agreement using the Landis & Koch interpretation of the K statistic. Based on the initial contouring, the group updated its descriptions of the CTVs & OARs. To determine if the revised language produced consistent contours, the cystectomy bed (CB) contour was redrawn on the CT sets by an additional 5 ROs. Results: The group proposed that patients at elevated risk for LF with R0 resections should be treated to the pelvic nodes alone (internal/external iliac, distal common iliac & presacral) whereas patients with ≥ R1 resections should be treated to the pelvic nodes & CB. The group proposed the rectum, bowel space, bone marrow & urinary diversion as OARs. The level of agreement for the initial CTVs & OARs from the group varied substantially (Table). Consensus language to describe CTV & OAR structures where the initial contours varied was successfully developed. Contours & feedback from the validation group are being analyzed. Conclusions: Initial descriptions of CTVs & OARs have been successfully developed. External validation & feedback are pending. The results will be applicable to clinical trials of adjuvant RT in bladder cancer. [Table: see text]

International audience; OBJECTIVE: To evaluate the percentage change in volume of prostate cancer, as assessed by T2-weighted MRI, following exposure to dutasteride (Avodart) 0.5mg daily for six months. PATIENTS AND METHODS: MRI in Primary Prostate cancer after Exposure to Dutasteride (MAPPED) is a double-blind, placebo-controlled trial, supported by GlaxoSmithKline (GSK). Men with prostate cancer suitable for active surveillance (low-intermediate risk prostate cancer on biopsy), and a visible lesion on T2-weighted MRI of at least 0.2 cc, were eligible for consideration. Forty-two men were randomised to 6 months of daily dutasteride 0.5mg or placebo. Multi-parametric MRI (mpMRI) scans were performed at baseline, 3 and 6 months. The percentage changes in cancer volume over time will be compared between the dutasteride and placebo groups. Planned analyses will examine the association between tumour volume and characteristics (perfusion and contrast washout) as seen on mpMRI, HistoScan ultrasound and biopsy histopathology in both groups. DISCUSSION: MAPPED is the first randomised controlled trial to use mpMRI to look at the effect of dutasteride on the volume of prostate cancer. If dutasteride is shown to reduce the volume of prostate cancer, it might be considered as an adjunct for men on active surveillance. Analysis of the placebo arm will allow us to comment on the short-term natural variability of the MR appearance in men who are not receiving any treatment. CONCLUSION: MAPPED will evaluate the short-term effect of dutasteride on prostate cancer volume, as assessed by mpMRI, in men undergoing active surveillance for low or intermediate risk prostate cancer. The study completed recruitment in January 2012.

Purpose: Cabazitaxel (CBZ) improves overall survival in patients withmCRPC previously treated with docetaxel chemotherapy. Prior to cancer drugs fund access of CBZ, patients at University College London Hospital were treated with ECarboF. We report our experiences of CBZ compared with ECarboF. Methods: A retrospective analysis comparing CBZ (10/2013-2/2015) and ECarboF (3/2007-10/2010) was performed. Patients were identified through an electronic prescribing system. Patients’ records were used to identify demographics, treatment responses and toxicities. Survival was estimated using the methods of KaplaneMeier and compared by Cox proportional hazards. Biochemical response rates (BRR; end of treatment PSA > 30% reduction from baseline) and toxicity were compared by chi-squared tests. Results: 23 and 35 patients were identified in the CBZ and ECarboF groups, respectively. CBZ patients were more heavily pre-treated than ECarboF patients (96% versus 0% received second generation hormone therapy). Treatment was generally well tolerated although therewas 1 neutropenic death in each group. Grade 3/4 haematological toxicity was comparable in both groups and grade 3/4 non-haematological toxicities were more frequent in those treated with CBZ. The BRR was similar in the CBZ and ECarboF groups (36% versus 38%, P 1⁄4 0.89). Median progression-free survival (PFS) was 2.7 months (95% CI 2.0e4.9) for CBZ versus 5.3 months (95% CI 2.6e8.0) for ECarboF. Median overall survival (OS) was 9.3 months (95% CI 6.1e17.6) for CBZ versus 13.1 months (95% CI 7.6e27.2) for ECarboF. Therewas a significant difference in PFS in the ECarboF group (HR 1⁄4 0.42; 95% CI 1⁄4 0.24e0.75; P 1⁄4 0.004), and a non-significant trend towards better OS (HR 1⁄4 0.58; 95% CI 1⁄4 0.29e1.14; P 1⁄4 0.114). Conclusion: Patients in the CBZ group were more heavily pre-treated than those in the ECarboF group, probably contributing to improved PFS and OS in ECarboF patients. However, both chemotherapy regimens have activity in the post-docetaxel setting.

Background Persistent infection with oncogenic human papillomavirus (HPV) is necessary for the development of cervical cancer. Although evidence indicates that the vaginal microbiome can have a functional role in the persistence or regression of HPV infections, this possibility has yet to be described in women with cervical intraepithelial neoplasia (CIN). We aimed to test the hypothesis that increasing microbiome diversity is associated with increasing CIN severity. Methods Vaginal swabs were collected, and vaginal microbiome characterised by 16S rRNA gene sequencing (MiSeq, Illumina, San Diego, CA, USA). Women were categorised according to disease severity (invasive cervical cancer [ICC], high-grade squamous intraepithelial lesions [HSIL], low-grade squamous intraepithelial lesions [LSIL], and healthy controls) and HPV status and genotype. Multivariate modelling of sequence data was used to examine bacterial species classification data, and correlated to disease severity and HPV status and genotype. Findings Hierarchical clustering analysis of bacterial species data revealed an association between increased disease severity and increased prevalence of microbiomes characterised by high-diversity and low levels of Lactobacillus spp (community state type CST IV), irrespective of HPV status (2 [10%] of 20 controls, 11 [21%] of 52 LSIL, 25 [27%]of 92 HSIL, ICC 2 [40%] of 5 ICC). Increasing disease severity was associated with decreasing relative abundance of Lactobacillus spp. The vaginal microbiome in women with HSIL was characterised by higher relative abundance of Sneathia sanguinegens (p Anaerococcus tetradius (p Peptostreptococcus anaerobius (p L jensenii (p Interpretation We show that women with CIN have a more diverse Lactobacillus -depleted vaginal microbiome, compared with healthy women. This finding supports previous reports indicating that a dysbiotic microbiome could be involved in HPV persistence. The vaginal microbiome can have a role in carcinogenesis and warrants further investigation. Future therapeutic strategies might allow modulation of the vaginal microbiome towards a vaginal community structure that promotes HPV clearance. Funding Imperial College Healthcare Charity, British Society for Colposcopy and Cervical Pathology.