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Background We investigated the first-line activity of vinflunine in patients with penis cancer. Cisplatin-based combinations are commonly used, but survival is not prolonged; many patients are unfit for such treatment or experience toxicity that outweighs clinical benefit. Methods Twenty-five patients with inoperable squamous carcinoma of the penis were recruited to a single-arm, Fleming–A’Hern exact phase II trial. Treatment comprised 4 cycles of vinflunine 320 mg/m2, given every 21 days. Primary endpoint was clinical benefit rate (CBR: objective responses plus stable disease) assessed after 4 cycles. Seven or more objective responses or disease stabilisations observed in 22 evaluable participants would exclude a CBR of 40% being probable. Results Twenty-two participants were evaluable. Ten objective responses or disease stabilisations were confirmed. CBR was 45.5%, meeting the primary endpoint; partial response rate was 27.3%. Seven patients received >4 cycles of vinflunine. Dose reduction or treatment delay was required for 20% of cycles. In all, 68% of patients experienced at least one grade 3 adverse event. Two deaths on treatment were not caused by disease progression. Conclusions Pre-specified clinical activity threshold was exceeded. Toxicity was in keeping with experience in other tumours. Vinflunine merits further study in this disease. Trial registration NCT02057913.

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.

Background Biopsy after external beam radiotherapy (EBRT) for localised prostate cancer (PCa) is an infrequently used but potentially valuable technique to evaluate local recurrence and predict long-term outcomes. Methods We performed a meta-analysis of studies until March 2020 where a post-EBRT biopsy was performed on patients with low-to intermediate risk PCa, according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement. The primary outcome was the aggregate post-EBRT positive biopsy rate (≥2 years after EBRT) and the associated odds ratio (OR) of a positive biopsy on biochemical failure (BCF), distant metastasis-free survival (DMFS) and prostate cancer-specific mortality (PCSM). A sensitivity analysis was performed which examined biopsy rate as a function of post-EBRT biopsy protocol, PCa risk, ADT usage and radiation dose. Results A total of 22 studies were included, of which 10 were randomised controlled trials and 12 were cohort studies. Nine out of the 22 studies used dosing regimens consistent with the 2020 NCCN radiotherapy guidelines. The weighted-average positive biopsy rate across all 22 studies was 32% (95%-CI: 25–39%, n = 3017). In studies where post-treatment biopsy was part of the study protocol, the rate was 35% (95%-CI: 21–38%, n = 2450). In the subgroup of studies that conformed to the 2020 NCCN radiotherapy guidelines, this rate was 22% (95% CI: 19–41%, n = 832). Patients with positive biopsy had a 10-fold higher odds of developing BCF (OR of 10.3, 95%-CI: 3.7–28.7, p p p Conclusion A positive biopsy after EBRT is associated with a poor prognosis compared to a negative biopsy. The post-EBRT positive biopsy rate is an important measure which provides additional insight when comparing EBRT to other treatment modalities for PCa.

Increasing numbers of females are participating in elite sports, with a record number having competed at the Tokyo Olympic Games. Importantly, the ages of peak performance and fertility are very likely to coincide; as such, it is inevitable that pregnancy will occur during training and competition. Whilst there is considerable evidence to promote regular exercise in pregnancy, with benefits including a reduction in hypertensive disorders, gestational diabetes, and reduced rates of post-natal depression, few studies have been conducted which include elite athletes. Indeed, there are concerns that high-intensity exercise may lead to increased rates of miscarriage and preterm labour, amongst other pregnancy-related complications. There is minimal guidance on the obstetric management of athletes, and consequently, healthcare professionals frequently adopt a very conservative approach to managing such people. This narrative review summarises the evidence on the antenatal, intrapartum, and postpartum outcomes in elite athletes and provides recommendations for healthcare providers, demonstrating that generally, pregnant athletes can continue their training, with a few notable exceptions. It also summarises the physiological changes that occur in pregnancy and reviews the literature base regarding how these changes may impact performance, with benefits arising from pregnancy-associated cardiovascular adaptations at earlier gestations but later changes causing an increased risk of injury and fatigue.

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.

BACKGROUND: Recurrent prostate cancer after radiotherapy occurs in one in five patients. The efficacy of prostate magnetic resonance imaging (MRI) in recurrent cancer has not been established. Furthermore, high-quality data on new minimally invasive salvage focal ablative treatments are needed. OBJECTIVE: To evaluate the role of prostate MRI in detection of prostate cancer recurring after radiotherapy. DESIGN, SETTING, AND PARTICIPANTS: The FORECAST trial was both a paired-cohort diagnostic study evaluating prostate multiparametric MRI (mpMRI) and MRI-targeted biopsies in the detection of recurrent cancer and a cohort study evaluating focal ablation at six UK centres. A total of 181 patients were recruited, with 155 included in the MRI analysis and 93 in the focal ablation analysis. INTERVENTION: Patients underwent choline positron emission tomography/computed tomography and a bone scan, followed by prostate mpMRI and MRI-targeted and transperineal template-mapping (TTPM) biopsies. MRI was reported blind to other tests. Those eligible underwent subsequent focal ablation. An amendment in December 2014 permitted focal ablation in patients with metastases. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Primary outcomes were the sensitivity of MRI and MRI-targeted biopsies for cancer detection, and urinary incontinence after focal ablation. A key secondary outcome was progression-free survival (PFS). RESULTS AND LIMITATIONS: Staging whole-body imaging revealed localised cancer in 128 patients (71%), with involvement of pelvic nodes only in 13 (7%) and metastases in 38 (21%). The sensitivity of MRI-targeted biopsy was 92% (95% confidence interval [CI] 83–97%). The specificity and positive and negative predictive values were 75% (95% CI 45–92%), 94% (95% CI 86–98%), and 65% (95% CI 38–86%), respectively. Four cancer (6%) were missed by TTPM biopsy and six (8%) were missed by MRI-targeted biopsy. The overall MRI sensitivity for detection of any cancer was 94% (95% CI 88–98%). The specificity and positive and negative predictive values were 18% (95% CI 7–35%), 80% (95% CI 73–87%), and 46% (95% CI 19–75%), respectively. Among 93 patients undergoing focal ablation, urinary incontinence occurred in 15 (16%) and five (5%) had a grade ≥3 adverse event, with no rectal injuries. Median follow-up was 27 mo (interquartile range 18–36); overall PFS was 66% (interquartile range 54–75%) at 24 mo. CONCLUSIONS: Patients should undergo prostate MRI with both systematic and targeted biopsies to optimise cancer detection. Focal ablation for areas of intraprostatic recurrence preserves continence in the majority, with good early cancer control. PATIENT SUMMARY: We investigated the role of magnetic resonance imaging (MRI) scans of the prostate and MRI-targeted biopsies in outcomes after cancer-targeted high-intensity ultrasound or cryotherapy in patients with recurrent cancer after radiotherapy. Our findings show that these patients should undergo prostate MRI with both systematic and targeted biopsies and then ablative treatment focused on areas of recurrent cancer to preserve their quality of life.

Introduction: Histoplasmosis is a fungal infection caused by the agent Histoplasma capsulatum,a dimorphic fungus. The spectrum of illness ranges from subclinical infection to progressive disseminated disease. The major bulk of histoplasma infections are asymptomatic or pulmonary histoplasmosis. In immune compromised patients it can cause disseminated infections involving different organs of the body. In immune competent individuals it may cause isolated adrenal histoplasmosis. Material and methods: A retrospective study was done to look for mucocutaneous histoplasmosis. The excised tissue samples were cultured and only culture confirmed cases were included in the study. Result: Here, we present five cases of primary mucocutaneous histoplasmosis in immune competent individuals in a tertiary care centre in India. These patients had no other co-morbidities and had only isolated lesions in oral cavity or penis.The tissue on excision was cultured and showed growth of Histoplasma capsulatum. All the patients improved with treatment. There are limited cases of mucocutaneous ulcerated lesions caused by Histoplasma capsulatum in immune competent people in published literature. Conclusion: This study emphasizes the necessity of a vigilant look out and clinical suspicion of fungal causes like histoplasma in chronic non healing ulcers which should be confirmed by the laboratory investigations. Accurate diagnosis helps in specific management of these cases. Bangladesh Journal of Medical Science Vol.19(1) 2020 p.94-97

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.

Our objectives were to assess the safety and clinical impact of a novel, kit-based formulation of (68)Ga-tris(hydroxypyridinone) ((68)Ga-THP) prostate-specific membrane antigen (PSMA) for PET/CT in guiding the management of patients with prostate cancer. Methods: Patients were prospectively recruited to group A (high-risk untreated prostate cancer; Gleason score ≥ 4 + 3, or prostate-specific antigen (PSA) level > 20 ng/mL or clinical stage > T2c), group B (biochemical recurrence and eligible for salvage treatment after radical prostatectomy with 2 consecutive rises in PSA with a 3-mo interval between reads and a final PSA level > 0.1 ng/mL or a PSA level ≥ 0.5 ng/mL), or group C (biochemical recurrence with radical curative radiotherapy or brachytherapy at least 3 mo before enrollment, and an increase in PSA level > 2.0 ng/mL above the nadir level after radiotherapy or brachytherapy). Patients underwent evaluation with PET/CT 60 min after intravenous administration of 160 ± 30 MBq of (68)Ga-THP PSMA. Safety was assessed through vital signs, cardiovascular profile, serum hematology, biochemistry, urinalysis, PSA, and adverse events (AEs). A change in management was reported when the predefined clinical management of the patient was altered as a result of the (68)Ga-THP PSMA PET/CT findings. Results: Forty-nine patients were evaluated with PET/CT: 20 in group A, 21 in group B, and 8 in group C. No patients experienced serious AEs, discontinued the study because of AEs, or died during the study. Two patients had treatment-emergent AEs attributed to (68)Ga-THP PSMA (pruritus in one patient and a rash at the intravenous catheter site in another). A management change secondary to the PET/CT findings occurred in 42.9% of all patients: 30% in group A, 42.9% in group B, and 75% in group C. Conclusion: (68)Ga-THP PSMA was safe to use, with no serious AEs and no AEs resulting in withdrawal from the study. (68)Ga-THP PSMA PET/CT changed the management of 42.9% of the study population, comparable to studies using other PSMA tracers. These data form the basis of a planned phase III study of (68)Ga-THP PSMA in patients with prostate cancer.

Background Vaginal microbiota (VMB) composition is altered in women with cervical intra-epithelial neoplasia (CIN) compared to healthy controls and is associated with disease progression. However, the impact of CIN excision on the VMB and innate immunity is not known. This observational study aims to explore the impact of CIN excision on the VMB, antimicrobial peptides (AMP) and proinflammatory cytokines. Methods We sampled 103 non-pregnant, premenopausal women at the time of excisional treatment for CIN and at their 6-month follow-up visit. A further 39 untreated controls with normal cytology were also sampled. We used metataxonomics to group vaginal swab samples into community state types (CSTs) and ELISA to quantify cytokine and AMP levels in matched vaginal secretions. Analyses were performed to compare the bacterial composition and immune analyte levels before and after CIN excision and in healthy controls. Results Women with CIN had significantly higher rates of Lactobacillus species depletion pre-treatment compared to healthy controls (CST IV 21/103, 20% vs 1/39, 3%, p = 0.0081). Excision did not change the VMB composition, with CST IV remaining significantly more prevalent after excision compared to untreated, healthy controls (CST IV 19/103, 20% vs 1/39, 3%, p = 0.0142). Prevotella bivia and Sneathia amnii were significantly higher in samples before treatment compared to untreated controls, and Prevotella bivia remained significantly higher amongst the treated, with less Lactobacillus crispatus compared to untreated controls. IL-1β and IL-8 remained significantly elevated pre- (p < 0.0001 and p = 0.0014, respectively) and post-treatment (p < 0.0001 and p = 0.0035, respectively) compared to untreated controls. Levels of human beta-defensin-1 and secretory leukocyte protease inhibitor were both significantly reduced following CIN excision (p < 0.0001); however, their levels remained lower than controls post-treatment. Conclusions Women with CIN have an increased prevalence of Lactobacillus sp. depletion, high-diversity VMB composition, and higher levels of proinflammatory cytokines and AMPs compared to normal controls. Surgical excision of the disease reduces levels of vaginal AMPs but does not alter VMB composition or cytokine levels. These findings suggest that women with CIN have an inherent predisposition to a high-diversity proinflammatory environment that is not corrected by disease excision. The failure to re-establish a Lactobacillus-enriched CST may explain why women remain at high risk of pre-invasive and invasive disease recurrence.

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."

Men in whom external beam radiotherapy fails are usually placed on delayed hormone therapy. Some of these men have localized recurrence that might be suitable for further local therapy. We describe patterns of recurrence and suitability for focal ablative therapy in those undergoing transperineal template prostate mapping biopsies.The study included 145 consecutive patients (December 2007 to May 2014) referred with suspicion of recurrence due to rising prostate specific antigen after external beam radiotherapy or brachytherapy who underwent transperineal template prostate mapping biopsies. Suitability for focal ablative therapy required the cancer to be unifocal or unilateral, or bilateral/multifocal with 1 dominant index lesion and secondary lesions with Gleason score 3+3=6 with no more than 3 mm cancer core involvement.Mean patient age was 70.7 (SD 5.8) years. Median prostate specific antigen at time of transperineal template prostate mapping biopsy was 4.5 ng/ml (IQR 2.5-7.7). Overall 75.9% (110) were suitable for a form of focal salvage treatment, 40.7% (59) were suitable for quadrant ablation, 14.5% (21) hemiablation, 14.5% (21) bilateral focal ablation and 6.2% (9) for index lesion ablation.Three-quarters of patients who have localized radiorecurrent prostate cancer may be suitable for focal ablative therapy to the prostate based on transperineal template prostate mapping biopsies.

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.

There has been a wealth of media coverage regarding venous thromboembolism (VTE) following certain types of COVID-19 vaccines in the mainstream media and online. To put the risk into perspective for the general public, many journalists, authors and even scientific journals have used the risk of VTE associated with ‘the contraceptive pill’ and air travel as comparators. While this may be well-meaning, it is an unjust comparison and may have unintended consequences on contraceptive use and unplanned pregnancies. Such alarming headlines can be emotive to contraceptive users. VTE associated with hormonal contraceptive use generally relates to deep vein thrombosis and pulmonary embolism, which is quite a different clinical picture to the cerebral venous sinus thromboses (CVST) being reported in individuals receiving the AstraZeneca vaccine that also appear to arise by a different mechanism.1 The complications are neither similar conditions, nor have similar outcomes with CVST, …

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.

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.

Publisher's version (útgefin grein)., Background: Mutations in BRCA2 cause a higher risk of early-onset aggressive prostate cancer (PrCa). The IMPACT study is evaluating targeted PrCa screening using prostate-specific-antigen (PSA) in men with germline BRCA1/2 mutations. Objective: To report the utility of PSA screening, PrCa incidence, positive predictive value of PSA, biopsy, and tumour characteristics after 3 yr of screening, by BRCA status. Design, setting, and participants: Men aged 40–69 yr with a germline pathogenic BRCA1/2 mutation and male controls testing negative for a familial BRCA1/2 mutation were recruited. Participants underwent PSA screening for 3 yr, and if PSA > 3.0 ng/ml, men were offered prostate biopsy. Outcome measurements and statistical analysis: PSA levels, PrCa incidence, and tumour characteristics were evaluated. Statistical analyses included Poisson regression offset by person-year follow-up, chi-square tests for proportion t tests for means, and Kruskal-Wallis for medians. Results and limitations: A total of 3027 patients (2932 unique individuals) were recruited (919 BRCA1 carriers, 709 BRCA1 noncarriers, 902 BRCA2 carriers, and 497 BRCA2 noncarriers). After 3 yr of screening, 527 men had PSA > 3.0 ng/ml, 357 biopsies were performed, and 112 PrCa cases were diagnosed (31 BRCA1 carriers, 19 BRCA1 noncarriers, 47 BRCA2 carriers, and 15 BRCA2 noncarriers). Higher compliance with biopsy was observed in BRCA2 carriers compared with noncarriers (73% vs 60%). Cancer incidence rate per 1000 person years was higher in BRCA2 carriers than in noncarriers (19.4 vs 12.0; p = 0.03); BRCA2 carriers were diagnosed at a younger age (61 vs 64 yr; p = 0.04) and were more likely to have clinically significant disease than BRCA2 noncarriers (77% vs 40%; p = 0.01). No differences in age or tumour characteristics were detected between BRCA1 carriers and BRCA1 noncarriers. The 4 kallikrein marker model discriminated better (area under the curve [AUC] = 0.73) for clinically significant cancer at biopsy than PSA alone (AUC = 0.65). Conclusions: After 3 yr of screening, compared with noncarriers, BRCA2 mutation carriers were associated with a higher incidence of PrCa, younger age of diagnosis, and clinically significant tumours. Therefore, systematic PSA screening is indicated for men with a BRCA2 mutation. Further follow-up is required to assess the role of screening in BRCA1 mutation carriers. Patient summary: We demonstrate that after 3 yr of prostate-specific antigen (PSA) testing, we detect more serious prostate cancers in men with BRCA2 mutations than in those without these mutations. We recommend that male BRCA2 carriers are offered systematic PSA screening. © 2019 The Authors We demonstrate that after 3 yr of prostate-specific-antigen (PSA) testing, we detect more serious prostate cancers in men with BRCA2 mutations than those without these mutations. We recommend that male BRCA2 carriers are offered systematic PSA screening., We demonstrate that, after four annual PSA screening rounds, BRCA2 mutation carriers have a higher incidence of PrCa, are diagnosed at a younger age, and present with more clinically significant tumours than BRCA2 noncarriers. Further follow-up is required to assess the role of screening in BRCA1 mutation carriers. Therefore, these data support the use of systematic PSA screening in male BRCA2 carriers. Author contributions : Rosalind A. Eeles had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design : Aaronson, Ardern-Jones, Bancroft, Bangma, Castro, Dearnaley, Eccles, Evans, Eyfjord, Falconer, Foster, Gronberg, Hamdy, Johannsson, Khoo, Kote-Jarai, Lilja, Lindeman, Lubinski, Mahle, Mikropoulos, Mitra, Moynihan, Page, Rennert, Suri. Acquisition of data: All authors. Analysis and interpretation of data: All authors. Drafting of the manuscript: All authors. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis : Page, Bancroft, Brook, Assel, Vickers, Lilja. Obtaining funding : Eeles and all IMPACT collaborating sites obtained their own funding for running the study at their site. Administrative, technical, or material support: All authors. Supervision: Eeles. Other : None. Financial disclosures: Rosalind A. Eeles certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Hans Lilja holds patents for intact PSA assays, and is named, along with Andrew J. Vickers, on a patent application for a statistical method to detect prostate cancer. The patents have been licensed and commercialised as the 4 Kscore by OPKO Health. Drs. Vickers and Lilja receive royalties from sales of this test. Additionally, Dr. Lilja owns stock and Dr. Vickers owns stock options in OPKO. Professor Rosalind Eeles: Royal Marsden Hospital—Nov 2017; support from Janssen; honorarium as speaker £1100; University of Chicago invited talk May 2018; honorarium as speaker Rosalind A. Eeles certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Hans Lilja holds patents for intact PSA assays, and is named, along with Andrew J. Vickers, on a patent application for a statistical method to detect prostate cancer. The patents have been licensed and commercialised as the 4 Kscore by OPKO Health. Drs. Vickers and Lilja receive royalties from sales of this test. Additionally, Dr. Lilja owns stock and Dr. Vickers owns stock options in OPKO. Professor Rosalind Eeles: Royal Marsden Hospital—Nov 2017; support from Janssen; honorarium as speaker £1100; University of Chicago invited talk May 2018; honorarium as speaker $1000. The remaining authors have no other conflict of interest to declare.000. The remaining authors have no other conflict of interest to declare. Funding/Support and role of the sponsor : This research is coordinated by the Institute of Cancer Research, London, UK, and is supported by grants from Cancer Research UK (grant references C5047/A21332, C5047/A13232, and C5047/A17528) and the Ronald and Rita McAulay Foundation. Judith Offman is supported by Cancer Research UK Programme Grant reference C8161/A16892. Mr. and Mrs. Jack Baker are acknowledged for supporting the study in NorthShore University HealthSystem, Evanston, IL, USA and Myriad Genetics Laboratory, Salt Lake City, UT, USA, for providing research BRCA testing rates for NorthShore University HealthSystem patients. We acknowledge funding from the National Institute for Health Research (NIHR) to the Biomedical Research Center at the Institute of Cancer Research and the Royal Marsden NHS Foundation Trust, at Manchester University Foundation Trust (IS-BRC-1215-20007), the Oxford Biomedical Research Centre Program, and the Cambridge Clinical Research Centre, NIHR Cambridge Biomedical Research Centre. We acknowledge that in Australia, this project was cofunded by Cancer Council Tasmania and Cancer Australia (grant number 1006349 [2011–2013]), Prostate Cancer Foundation of Australia (grant number PCFA PRO4 [2008]), Cancer Councils of Victoria and South Australia (grant number 400048 [2006–2008]), the Victorian Cancer Agency Clinical Trial Capacity CTCB08_14, Cancer Australia and Prostate Cancer Foundation of Australia (2014–2016; grant number 1059423), and Translational grants EOI09_50. The Association of International Cancer Research funded data collection in The Netherlands (AICR 10-0596). We acknowledge funding from the Basser Center for BRCA (to Susan Domchek). This work was supported in part by the National Institutes of Health/National Cancer Institute (NIH/NCI) with a Cancer Center Support Grant to Memorial Sloan Kettering Cancer Center (P30 CA008748), a SPORE grant in Prostate Cancer to Dr. H. Scher (P50-CA92629), the Sidney Kimmel Center for Prostate and Urologic Cancers, David H. Koch through the Prostate Cancer Foundation. This work was also supported in part by the NIHR Oxford Biomedical Research Centre Program in UK, the Swedish Cancer Society (CAN 2017/559), the Swedish Research Council (VR-MH project no. 2016-02974), and General Hospital in Malmö Foundation for Combating Cancer. We acknowledge funding from the Slovenian Research Agency, Research programme P3-0352. We thank CERCA Program/Generalitat de Catalunya for their institutional support. Elena Castro acknowledges funding from Prostate Cancer Foundation. We acknowledge the support of the Asociación Española Contra el Cáncer (AECC), the Instituto de Salud Carlos III (organismo adscrito al Ministerio de Economía y Competitividad), “Fondo Europeo de Desarrollo Regional (FEDER), una manera de hacer Europa” (PI10/01422, PI13/00285, PIE13/00022, PI16/00563, JR18/00011 and CIBERONC), and the Institut Català de la Salut and Autonomous Government of Catalonia (2009SGR290, 2014SGR338 and PERIS Project MedPerCan). We acknowledge funding support from Fundação para a Ciência e a Tecnologia to the IPO Porto study (project grant PTDC/DTP-PIC/1308/2014 to Manuel R. Teixeira and fellowship grant SFRH/BD/116557/2016 to Marta Cardoso).

Introduction/Background Several approaches to fertility-sparing surgery in women with cervical cancer exist. Differences in radicality of parametrial excision are thought to exist according to surgical technique. Minimal access approaches may offer benefits in terms of enhanced patient recovery and nerve-sparing, however comparative oncological safety compared to an open approach is highly debated, especially in tumour volume >2cm. Pregnancy outcomes may also vary according to approach. This is the first systematic review and meta-analysis to compare the oncological and reproductive outcomes of simple or radical trachelectomy surgeries. Methodology We searched relevant studies in MEDLINE, PUBMED and CENTRAL from inception to September 2018. Studies were eligible if they investigated oncological and/or reproductive outcomes following any radical trachelectomy surgical approach. Data were extracted in duplicate and additionally requested from authors where necessary. The primary outcome was cervical cancer recurrence rate after treatment. Secondary outcomes were margin involvement rate, residual tumour rate, conception rate and pregnancy outcomes (including 1st and 2nd trimester miscarriage rates, delivery rate, preterm labour rate ( Results We identified 59 eligible studies including over 2150 women. Recurrence rate varied by surgical approach: simple vaginal trachelectomy (SVT) 2% (95%CI 1–3%, I2=NA), vaginal radical trachelectomy (VRT) 3% (95%CI 2–4%, I2=0%) abdominal radical trachelectomy (ART) 1% (95%CI 0–2%, I2=35%), laparoscopic radical trachelectomy (LRT) 2% (95%CI 0–6%, I2=31%), radical robotic trachelectomy (RRT) 0% (95%CI 0–4%, I2=0%). Involved margins rate was lowest for LRT (7%, 95%CI 0–3%, I2=0%) and highest for RRT (7%, 95%CI 0–25%, I2=50.8%). Conception rate was highest for VRT (62%, 95%CI 47–75%, I2=84%) and lowest for ART (34%, 95%CI 25–44%, I2=55%). Conclusion Balancing the oncological and fertility outcomes for fertility preservation techniques is challenging but achievable. Disclosure Nothing to disclose.

Introduction/Background Emerging evidence suggests associations between the vaginal microbiota (VMB) composition, HPV infection, and cervical intra-epithelial neoplasia (CIN), however, causal inference remains uncertain. The use of longitudinal cohorts can enable temporal assessment of the relationship between VMB and the natural history of CIN. We aimed to assess whether VMB composition associates with rates of progression, persistence or clearance in a cohort of young women with histologically confirmed untreated CIN2 lesions. Methodology 16S rRNA was extracted and sequenced from serial collected liquid based cytology samples of young women with histologically-proven CIN2 that was managed conservatively in Northern California, USA over a 24-month period. Results Of the 87 women in the cohort, 48.3% had regressed by 12 months (42/87), 72.4% (63/87) by 24 months. High-diversity, Lactobacillus spp. depleted, VMB composition at time of CIN2 diagnosis was associated with higher rates of disease persistence at 12 months, compared to those with Lactobacillus spp. dominance at baseline. Relative abundances of taxa including Megasphaera spp. (p=0.0004), Prevotella timonensis (p=0.015) and Gardnerella vaginalis (p=0.036) were higher in women with persistent disease at 12 months compared to those who regressed. A similar trend was seen by 24-month follow-up, but was not statistically significant. The rate of CIN2 regression was slower in women with Lactobacillus spp. depletion at baseline. Conclusion Depletion of Lactobacillus spp. and presence of specific anaerobic taxa are associated with CIN2 persistence and slower regression. Further research on the impact of VMB on the natural history of CIN may help identify VMB compositions and specific taxa associated with increased risk of progression and thus offer rational targets for the development of new prevention and treatment strategies. Disclosure Nothing to disclose.

Introduction/Background Surgical management of presumed early stage cervical cancer presents challenges as clearance of surgical margins avoids adjuvant chemoradiotherapy that can substantially increase morbidity and may allow fertility preservation in young women. Improved intra-operative diagnostic tools have the potential to improve outcomes. In this study, we explore whether the Rapid Evaporative Ionization Mass Spectrometry (REIMS), also known as the iKnife (intelligent Knife), can accurately discriminate between healthy, pre-invasive and invasive cervical tissue ex vivo. Methodology We prospectively collected fresh frozen cervical tissue samples in normal controls and women with Human Papilloma Virus (HPV) ± cervical intraepithelial neoplasia (CIN) and cervical cancer (Cancer) between 2006 and 2018. A handheld diathermy device was used to burn the biopsies; the surgical aerosol produced was subsequently transferred into a mass-spectrometer. The tissue was then stained for histopathological validation. We used principal component and linear discriminant analysis to calculate the accuracy of the iKnife in discriminating between the 3 groups. Cancerous and normal tissues were then processed with REIMS tandem MS (REI-MS/MS) to further delineate the most significant peaks allowing separation of the two classes and identify their lipid profile. Results The iKnife had an overall 97.8% accuracy in discriminating accurately normal (100%) vs HPV±CIN (100%) versus cancer (83.3%) when compared to histology as the gold standard. REI-MS/MS and LipidMAPS revealed twelve significant MS peaks in the cancer to normal separation. Conclusion This study shows that REIMS iKnife has the potential to accurately discriminate healthy, from precancerous and invasive lesions on the cervix. The overexperessed lipids in cancer may be used as markers of disease. If these finding are replicated in larger cohorts, the iKnife may allow real-time intra-operative diagnosis of the presence of disease in surgical margins and lymph nodes. Disclosure Nothing to disclose

Introduction/Background The innate immune system is a key factor in the fate of an HPV infection and a proinflammatory environment has been shown to facilitate HPV persistence and cervical carcinogenesis. Antimicrobial peptides (AMPs) have innate antibacterial and antiviral properties, as well as a role in tissue remodelling but have not been studied in cervical intraepithelial neoplasia (CIN). Bacterial vaginosis is known to be associated with HPV infection and CIN, therefore the vaginal microbiota (VMB) may also influence the innate immune response and subsequent disease state. We aimed to investigate changes in VMB composition and expression of Human Beta Defensin-1 (hBD-1), Secretory Leucocyte Protease Inhibitor (SLPI) and inflammatory cytokines according to disease status. Methodology Population: Non-pregnant, premenopausal women attending the colposcopy clinic in London, UK with cytological ± histological disease classification. Analysis: Vaginal swab samples were used for 16s rRNA bacterial sequencing to assess VMB composition and for enzyme-linked immunosorbent assay (ELISA) to determine hBD-1, SLPI, IL-1b and IL-8 levels. Results A total of 232 women were included and classified into three groups; 34 normal, 81 low-grade CIN, and 117 high-grade CIN. Lower levels of Lactobacillus spp. with increased bacterial species diversity, were seen with increasing disease severity. A bacterial vaginosis-like VMB was observed twice as frequently in women with high-grade disease (28%) compared to controls (14%). Higher levels of pro-inflammatory cytokines; IL-1b and IL-8 and AMPs; hBD-1 and SLPI increase with increasing disease severity. Conclusion Lactobacillus spp. are thought to protect the female reproductive tract from pathogens, including viruses and the lower levels observed with increasing disease severity, along with higher levels of pro-inflammatory cytokines may play a role in disease outcomes. AMPs are known to be overexpressed in several cancers, and therefore higher levels may have a deleterious effect due their ability to facilitate tissue remodeling that is required for carcinogenesis. Disclosure Nothing to disclose.

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

Background Local treatment for cervical intraepithelial neoplasia (CIN) by Loop Electrosurgical Excision Procedure (LEEP) has been correlated with reproductive morbidity, while the cervicovaginal microbiota is also known to affect the risk of preterm delivery. CIN and treatment by LEEP might change the cervical microbiota. The main aim of this study was to describe the cervical microbiota before and after LEEP and assess its associaton with cone depth and HPV persistence. Further, we aimed to compare the microbiota to references with normal cervical cytology. Methods Between 2005 and 2007, we prospectively identified 89 women planned for LEEP in a Norwegian hospital and recruited 100 references with a normal cervical cytology. Endocervical swabs were collected prior to treatment and at six (n = 77) and 12 months (n = 72) post LEEP for bacterial culture and PCR, and post LEEP for DNA testing for human papillomavirus (HPV). We compared the cervical microbiota composition before and after treatment and between women planned for LEEP vs references. Results There was a reduction in the number of non-Lactobacillus bacterial species six and 12 months after LEEP compared to before treatment and a tendency towards a concomitant increase in Lactobacillus. No association between the detection of cervical bacteria, HPV persistence or cone depth was found. Women planned for LEEP carried significantly more Bacteroides spp., Gardnerella vaginalis, Mycoplasma hominis and Ureaplasma parvum as well as a greater number of bacterial species than the references. Conclusions Local excisional treatment appears to alter the cervical microbiota towards a less diverse microbiota. Women with CIN have a more diverse cervical microbiota compared to women with normal cervical cytology.