Prostagram magnetic resonance imaging in a screening population: Prostate Imaging-Reporting and Data System or Likert?

OBJECTIVE: To compare biopsy recommendation rates and accuracy of the Prostate Imaging-Reporting and Data System, version 2 (PI-RADSv2) with the Likert scale for detection of clinically significant and insignificant prostate cancer in men screened within the Imperial Prostate 1 Prostate Cancer Screening Trial Using Imaging (IP1-PROSTAGRAM). PATIENTS AND METHODS: Men aged 50-69 years were screened with Prostagram MRI. Scans were prospectively reported using both PI-RADSv2 (excluding dynamic contrast-enhanced sequence score) and 5-point Likert scores by expert uro-radiologists. Systematic and targeted transperineal biopsy was recommended if the scan was scored ≥ 3, based on either reporting system. The proportion of patients recommended for biopsy and detection rates for Grade Groups (GGs) 1 and ≥ 2 were compared. Receiver operating characteristic (ROC) analysis was performed to compare performance. RESULTS: A total of 406 men underwent Prostagram MRI. The median (interquartile range) age and prostate-specific antigen level were 57 (53-61) years and 0.91 (0.56-1.74) ng/mL, respectively. At MRI score ≥ 3, more patients were recommended for biopsy based on Likert criteria (94/406; 23%, 95% confidence interval [CI] 19.2%-27.6%) compared to PI-RADSv2 (72/406; 18%, 95% CI 14.2%-21.9%; P = 0.03). For MRI scores ≥ 4, PI-RADSv2 and Likert scales led to 43/406 (11%, 95% CI 7.9%-14.1%) and 35/406 (9%, 95% CI 6.2%-11.9%) men recommended for biopsy (P = 0.40). For GG ≥ 2 detection, PIRADSv2 and Likert detected 22% (95% CI 11.4%-30.8%, 14/72) and 16% (95% CI 9.5%-25.3%, 15/94), respectively (P = 0.56). For GG1 cancers detection these were 11% (95% CI 4.3%-19.6%, seven of 72) vs 11% (95% CI 4.7%-17.8%, nine of 94; P = 1.00). The accuracy of PI-RADSv2 and Likert scale was similar (area under the ROC curve 0.64 vs 0.65, P = 0.95). CONCLUSIONS: In reporting non-contrast-enhanced Prostagram MRI in a screening population, the PI-RADSv2 and Likert scoring systems were equally accurate; however, Likert scale use led to more men undergoing biopsy without a subsequent increase in significant cancer detection rates. To improve reporting of Prostagram MRI, either the PI-RADSv2 or a modified Likert scale or a standalone scoring system should be developed.

To B or not to B: the application of uterine compression sutures to reduce blood loss after myomectomy.

Introduction: The aim was to assess the hemostatic impact of B-Lynch sutures following an open myomectomy for efficacy. Material and methods: In this prospective clinical research, performed in Alazhar university hospitals (Al-Hussain, Damietta, Assiut) and Minia University Maternity Hospital, 250 women scheduled for open myomectomy between January 2021 and January 2023 had multiple fibroid uteri with uterine sizes corresponding to 12-22 weeks. There were two groups of women. Group I (125) underwent standard open myomectomy surgery, whereas Group II (125) underwent normal open laparotomy surgery followed by B-Lynch sutures. Certain inclusion and exclusion criteria were applied to every patient. We recorded vital data, length of the procedure, complications (bleeding during the procedure, bleeding from multiple bites, bladder injury, fever, wound infection), complete blood count before and after surgery, need for blood transfusion, postoperative vital data, time until ambulation, passing flatus, and ability to eat and drink, as well as the amount of blood lost during and after the procedure. Results: There was no statistically significant difference between the two groups in age, parity, weight, number of fibroids, or uterine size as measured by ultrasonography. Between groups I and II, there was a significant difference in the average intraoperative blood loss (Group I lost 562.6 ml, whereas Group II lost 411.3 ml) as well as the mean blood loss following surgery (205 ±82 ml in Group I and 117 ±41 ml in Group II). No significant difference was observed in the mean length of hospital stay between groups I and II (2 ±0.3 days and 2 ±0.6 days, respectively). Conclusions: Using a B-Lynch suture can help minimize blood loss during and after an open myomectomy. Therefore, if the uterus is large and has a lot of fibroids, it is recommended to be done frequently.

Regional Histopathology and Prostate MRI Positivity: A Secondary Analysis of the PROMIS Trial.

Background The effects of regional histopathologic changes on prostate MRI scans have not been accurately quantified in men with an elevated prostate-specific antigen (PSA) level and no previous biopsy. Purpose To assess how Gleason grade, maximum cancer core length (MCCL), inflammation, prostatic intraepithelial neoplasia (PIN), or atypical small acinar proliferation within a Barzell zone affects the odds of MRI visibility. Materials and Methods In this secondary analysis of the Prostate MRI Imaging Study (PROMIS; May 2012 to November 2015), consecutive participants who underwent multiparametric MRI followed by a combined biopsy, including 5-mm transperineal mapping (TPM), were evaluated. TPM pathologic findings were reported at the whole-prostate level and for each of 20 Barzell zones per prostate. An expert panel blinded to the pathologic findings reviewed MRI scans and declared which Barzell areas spanned Likert score 3-5 lesions. The relationship of Gleason grade and MCCL to zonal MRI outcome (visible vs nonvisible) was assessed using generalized linear mixed-effects models with random intercepts for individual participants. Inflammation, PIN, and atypical small acinar proliferation were similarly assessed in men who had negative TPM results. Results Overall, 161 men (median age, 62 years [IQR, 11 years]) were evaluated and 3179 Barzell zones were assigned MRI status. Compared with benign areas, the odds of MRI visibility were higher when a zone contained cancer with a Gleason score of 3+4 (odds ratio [OR], 3.1; 95% CI: 1.9, 4.9; P < .001) or Gleason score greater than or equal to 4+3 (OR, 8.7; 95% CI: 4.5, 17.0; P < .001). MCCL also determined visibility (OR, 1.24 per millimeter increase; 95% CI: 1.15, 1.33; P < .001), but odds were lower with each prostate volume doubling (OR, 0.7; 95% CI: 0.5, 0.9). In men who were TPM-negative, the presence of PIN increased the odds of zonal visibility (OR, 3.7; 95% CI: 1.5, 9.1; P = .004). Conclusion An incremental relationship between cancer burden and prostate MRI visibility was observed. Prostatic intraepithelial neoplasia contributed to false-positive MRI findings. ClinicalTrials.gov registration no. NCT01292291 © RSNA, 2022 Supplemental material is available for this article. See also the editorial by Harmath in this issue.

Evaluation of Outcomes Following Focal Ablative Therapy for Treatment of Localized Clinically Significant Prostate Cancer in Patients >70 Years: A Multi-institute, Multi-energy 15-Year Experience.

PURPOSE: In older patients who do not wish to undergo watchful waiting, focal therapy could be an alternative to the more morbid radical treatment. We evaluated the role of focal therapy in patients 70 years and older as an alternative management modality. MATERIALS AND METHODS: A total of 649 patients across 11 UK sites receiving focal high-intensity focused ultrasound or cryotherapy between June 2006 and July 2020 reported within the UK-based HEAT (HIFU Evaluation and Assessment of Treatment) and ICE (International Cryotherapy Evaluation) registries were evaluated. Primary outcome was failure-free survival, defined by need for more than 1 focal reablation, progression to radical treatment, development of metastases, need for systemic treatment, or prostate cancer-specific death. This was compared to the failure-free survival in patients undergoing radical treatment via a propensity score weighted analysis. RESULTS: Median age was 74 years (IQR: 72, 77) and median follow-up 24 months (IQR: 12, 41). Sixty percent had intermediate-risk disease and 35% high-risk disease. A total of 113 patients (17%) required further treatment. Sixteen had radical treatment and 44 required systemic treatment. Failure-free survival was 82% (95% CI: 76%-87%) at 5 years. Comparing patients who had radical therapy to those who had focal therapy, 5-year failure-free survival was 96% (95% CI: 93%-100%) and 82% (95% CI: 75%-91%) respectively (P < .001). Ninety-three percent of those in the radical treatment arm had received radiotherapy as their primary treatment with its associated use of androgen deprivation therapy, thereby leading to potential overestimation of treatment success in the radical treatment arm, especially given the similar metastases-free and overall survival rates seen. CONCLUSIONS: We propose focal therapy to be an effective management option for the older or comorbid patient who is unsuitable for or not willing to undergo radical treatment.

Accurate diagnosis of prostate cancer by combining Proclarix with magnetic resonance imaging.

OBJECTIVES: To assess of the clinical performance of Proclarix® (a novel Conformité Européenne [CE]-marked biomarker test aiding in the identification of clinically significant prostate cancer [csPCa]) alone or in combination with multiparametric magnetic resonance imaging (mpMRI) to predict csPCa (International Society of Urological Pathology Grade Group ≥2). PATIENTS AND METHODS: The study included blood samples from 721 men undergoing mpMRI followed by biopsy at University College London, London, and Vall d'Hebron University Hospital, Barcelona. Samples were tested blindly. The Proclarix-MRI model combining prostate volume, Proclarix and mpMRI results was trained using the UCL cohort (n = 159) and validated in the Vall d'Hebron cohort (n = 562). Its diagnostic performance was established in correlation to biopsy outcome and compared to available clinical parameters and risk calculators. RESULTS: Clinical performance of the Proclarix-MRI model in the validation cohort did not significantly differ from the training cohort and resulted in a sensitivity for csPCa of 90%, 90% negative predictive value and 66% positive predictive value. The Proclarix-MRI score's specificity (68%) was significantly (P < 0.001) better than the MRI-European Randomized study of Screening for Prostate Cancer risk score (51%), Proclarix (27%) or mpMRI (28%) alone. In addition, Proclarix by itself was found to be useful in the MRI Prostate Imaging-Reporting and Data System (PI-RADS) score 3 subgroup by outperforming prostate-specific antigen density in terms of specificity (25% vs 13%, P = 0.004) at 100% sensitivity. CONCLUSION: When combined with mpMRI and prostate volume, Proclarix reliably predicted csPCa and ruled out men with no or indolent cancer. A large reduction of two thirds of unneeded biopsies was achieved. Proclarix can further be used with high confidence to reliably detect csPCa in men with an indeterminate PI-RADS score 3 mpMRI. Despite these encouraging results, further validation is needed.

The rapid assessment for prostate imaging and diagnosis (RAPID) prostate cancer diagnostic pathway.

OBJECTIVE: To report outcomes within the Rapid Assessment for Prostate Imaging and Diagnosis (RAPID) diagnostic pathway, introduced to reduce patient and healthcare burdens and standardize delivery of pre-biopsy multiparametric magnetic resonance imaging (MRI) and transperineal biopsy. PATIENTS AND METHODS: A total of 2130 patients from three centres who completed the RAPID pathway (3 April 2017 to 31 March 2020) were consecutively entered as a prospective registry. These patients were also compared to a pre-RAPID cohort of 2435 patients. Patients on the RAPID pathway with an MRI score 4 or 5 and those with PSA density ≥0.12 and an MRI score 3 were advised to undergo a biopsy. Primary outcomes were rates of biopsy and cancer detection. Secondary outcomes included comparison of transperineal biopsy techniques, patient acceptability and changes in time to diagnosis before and after the introduction of RAPID. RESULTS: The median patient age and PSA level were 66 years and 6.6 ng/mL, respectively. Biopsy could be omitted in 43% of patients (920/2130). A further 7.9% of patients (168/2130) declined a recommendation for biopsy. The percentage of biopsies avoided among sites varied (45% vs 36% vs 51%; P < 0.001). In all, 30% (221/742) had a local anaesthetic (grid and stepper) transperineal biopsy. Clinically significant cancer detection (any Gleason score ≥3 + 4) was 26% (560/2130) and detection of Gleason score 3 + 3 alone constituted 5.8% (124/2130); detection of Gleason score 3 + 3 did not significantly vary among sites (P = 0.7). Among participants who received a transperineal targeted biopsy, there was no difference in cancer detection rates among local anaesthetic, sedation and general anaesthetic groups. In the 2435 patients from the pre-RAPID cohor, time to diagnosis was 32.1 days (95% confidence interval [CI] 29.3-34.9) compared to 15.9 days (95% CI 12.9-34.9) in the RAPID group. A total of 141 consecutive patient satisfaction surveys indicated a high satisfaction rate with the pathway; 50% indicated a preference for having all tests on a single day. CONCLUSIONS: The RAPID prostate cancer diagnostic pathway allows 43% of men to avoid a biopsy while preserving good detection of clinically significant cancers and low detection of insignificant cancers, although there were some centre-level variations.

External validation of a risk model predicting failure of salvage focal ablation for prostate cancer.

OBJECTIVES: To externally validate a published model predicting failure within 2 years after salvage focal ablation in men with localised radiorecurrent prostate cancer using a prospective, UK multicentre dataset. PATIENTS AND METHODS: Patients with biopsy-confirmed ≤T3bN0M0 cancer after previous external beam radiotherapy or brachytherapy were included from the FOcal RECurrent Assessment and Salvage Treatment (FORECAST) trial (NCT01883128; 2014-2018; six centres), and from the high-intensity focussed ultrasound (HIFU) Evaluation and Assessment of Treatment (HEAT) and International Cryotherapy Evaluation (ICE) UK-based registries (2006-2022; nine centres). Eligible patients underwent either salvage focal HIFU or cryotherapy, with the choice based predominantly on anatomical factors. Per the original multivariable Cox regression model, the predicted outcome was a composite failure outcome. Model performance was assessed at 2 years post-salvage with discrimination (concordance index [C-index]), calibration (calibration curve and slope), and decision curve analysis. For the latter, two clinically-reasonable risk threshold ranges of 0.14-0.52 and 0.26-0.36 were considered, corresponding to previously published pooled 2-year recurrence-free survival rates for salvage local treatments. RESULTS: A total of 168 patients were included, of whom 84/168 (50%) experienced the primary outcome in all follow-ups, and 72/168 (43%) within 2 years. The C-index was 0.65 (95% confidence interval 0.58-0.71). On graphical inspection, there was close agreement between predicted and observed failure. The calibration slope was 1.01. In decision curve analysis, there was incremental net benefit vs a 'treat all' strategy at risk thresholds of ≥0.23. The net benefit was therefore higher across the majority of the 0.14-0.52 risk threshold range, and all of the 0.26-0.36 range. CONCLUSION: In external validation using prospective, multicentre data, this model demonstrated modest discrimination but good calibration and clinical utility for predicting failure of salvage focal ablation within 2 years. This model could be reasonably used to improve selection of appropriate treatment candidates for salvage focal ablation, and its use should be considered when discussing salvage options with patients. Further validation in larger, international cohorts with longer follow-up is recommended.

Drug Reprofiling to Identify Potential HIV-1 Protease Inhibitors.

The use of protease inhibitors in human immunodeficiency virus type 1 (HIV-1) treatment is limited by adverse effects, including metabolic complications. To address these challenges, efforts are underway in the pursuit of more potent and less toxic HIV-1 protease inhibitors. Repurposing existing drugs offers a promising avenue to expedite the drug discovery process, saving both time and costs compared to conventional de novo drug development. This study screened FDA-approved and investigational drugs in the DrugBank database for their potential as HIV-1 protease inhibitors. Molecular docking studies and cell-based assays, including anti-HIV-1 in vitro assays and XTT cell viability tests, were conducted to evaluate their efficacy. The study findings revealed that CBR003PS, an antibiotic currently in clinical use, and CBR013PS, an investigational drug for treating endometriosis and uterine fibroids, exhibited significant binding affinity to the HIV-1 protease with high stability. Their EC50 values, measured at 100% cell viability, were 9.4 nM and 36.6 nM, respectively. Furthermore, cell-based assays demonstrated that these two compounds showed promising results, with therapeutic indexes higher than 32. In summary, based on their favorable therapeutic indexes, CBR003PS and CBR013PS show potential for repurposing as HIV-1 protease inhibitors.

Informational video impact before caesarean delivery on anxiety and satisfaction: a systematic review and meta-analysis.

BACKGROUND: Anxiety prior to caesarean section can lead to a negative birth experience, which may affect different aspects of woman's life in the long term. Improving preoperative information may result in lower anxiety leading to a more positive birth experience. Thus, we aimed to evaluate the impact of informational video before planned caesarean delivery on maternal anxiety and satisfaction. METHODS: Four different databases were searched from inception till March 2023. We selected randomised controlled trials (RCTs) that compared educational or informative videos about the aspects of the expected caesarean delivery process versus no preoperative information in the control group. No language restrictions were imposed. We used Revman software during performing our meta-analysis. Our main outcomes were preoperative and postoperative anxiety as well as maternal satisfaction post-procedure. RESULTS: Six RCTs were retrieved with a total number of 702 patients. Informative video significantly reduced the anxiety level before caesarean delivery in comparison with the control group (MD = -4.21, 95% CI [-5.46, -2.95], p<0001). Moreover, the postoperative anxiety level was significantly improved in the informational video group (MD = -4.71, 95% CI [-7.06, -2.36], p<0001). In addition, there was a significant improvement in maternal satisfaction score after caesarean delivery among the informational video group (p = 0.001). CONCLUSIONS: Informational video prior to caesarean delivery decreases preoperative and postoperative anxiety levels with improvement in maternal post-procedure satisfaction. However, the existing evidence is limited by several shortcomings, chiefly small sample size. More trials with larger sample size are required to confirm our findings.

Effects of Whole-Body Stretching Exercise during Lunch Break for Reducing Musculoskeletal Pain and Physical Exertion among Healthcare Professionals.

Background and Objectives: To investigate the effect of whole-body stretching (WBS) exercise during lunch break for reducing musculoskeletal pain and physical exertion among healthcare professionals. Methods: Full-time healthcare professionals working in hospitals with more than one year of experience were invited to participate. Sixty healthcare professionals (age 37.15 ± 3.9 Years, height 1.61 ± 0.04 m, body mass 67.8 ± 6.3 kg, and BMI 26.5 ± 2.1 kg/m2) participated in this single-blinded, two-arm randomized controlled trial (RCT). Participants were divided into WBS (n = 30) and control (n = 30) groups. The WBS group performed a range of stretching exercises targeting the entire body during a lunch break period for 3 times a week for 6 weeks. The control group received an education program. Musculoskeletal pain and physical exertion were assessed using the Nordic musculoskeletal questionnaire and Borg rating of perceived exertion scale, respectively. Results: The 12-month prevalence of musculoskeletal discomfort among all healthcare professionals was highest in the low back region (46.7%), followed by the neck (43.3%), and then the knee (28.3%). About 22% of participants said that their neck discomfort impacted their job, while about 18% reported that their low back pain impacted their job. Results indicate that the WBS and education program had a beneficial impact on pain and physical exertion (p < 0.001). When comparing the two groups, the WBS group experienced a significantly greater decrease in pain intensity (mean difference 3.6 vs. 2.5) and physical exertion (mean difference 5.6 vs. 4.0) compared to an education program only. Conclusions: This study suggests that doing WBS exercises during lunchtime can help lessen musculoskeletal pain and fatigue, making it easier to get through the workday.

Utility of Opportunistic Infections, Joints' Involvement and Accuracy of Various Screening Tests to Diagnose Rheumatoid Arthritis Patients.

Background and Objectives: Rheumatoid Arthritis (RA) is an auto-immune disease in which the body mistakenly considers some parts of its own system as pathogens and attacks them. Prevalence is approximately 0.75% in India. About 40% of the diseased become work disabled within 5 years from the onset of symptoms. The objective of this paper is to assess the sign/symptoms, joints' involvement, difficulties in daily activities and screening accuracy of serology tests of clinically suspected RA patients. Material and Methods: A cross-sectional cohort study design was conducted on two hundred ninety clinically suspected subjects who were referred by different OPDs of hospitals for screening. The profiles of study subjects were carried through a semi-structured, pre-tested schedule method. About 2 mL of blood samples were collected in a plain vial from each patient and tested for diagnostic tests RF, CRP and AntiCCP by using RF-Latex, CRP Latex and ELISA method, respectively, by the laboratory persons. Results: Joint pain shows to be a leading problem in RA as compared to other signs and symptoms. The majority of the study subjects suffer from knee problems (62%). Approximately equal numbers of RA-positive cases were screened by RF and AntiCCP tests. The CRP test screened about one-third of cases. CRP+ AntiCCP, RF+ AntiCCP and RF + CRP all have good sensitivity, and RF+ AntiCCP + CRP has a very high sensitivity for diagnosing RA. Conclusions: This study found that a substantiation of a major proportion of clinically suspected RA patients were suffering from knee pain. Predication of AntiCCP increased the possibility for the diagnosis of RA. However, RF was also moderately related to the diagnosis of RA, and the combination of both tests was more valuable.

Multiparametric ultrasound versus multiparametric MRI to diagnose prostate cancer (CADMUS): a prospective, multicentre, paired-cohort, confirmatory study.

BACKGROUND: Multiparametric MRI of the prostate followed by targeted biopsy is recommended for patients at risk of prostate cancer. However, multiparametric ultrasound is more readily available than multiparametric MRI. Data from paired-cohort validation studies and randomised, controlled trials support the use of multiparametric MRI, whereas the evidence for individual ultrasound methods and multiparametric ultrasound is only derived from case series. We aimed to establish the overall agreement between multiparametric ultrasound and multiparametric MRI to diagnose clinically significant prostate cancer. METHODS: We conducted a prospective, multicentre, paired-cohort, confirmatory study in seven hospitals in the UK. Patients at risk of prostate cancer, aged 18 years or older, with an elevated prostate-specific antigen concentration or abnormal findings on digital rectal examination underwent both multiparametric ultrasound and multiparametric MRI. Multiparametric ultrasound consisted of B-mode, colour Doppler, real-time elastography, and contrast-enhanced ultrasound. Multiparametric MRI included high-resolution T2-weighted images, diffusion-weighted imaging (dedicated high B 1400 s/mm2 or 2000 s/mm2 and apparent diffusion coefficient map), and dynamic contrast-enhanced axial T1-weighted images. Patients with positive findings on multiparametric ultrasound or multiparametric MRI underwent targeted biopsies but were masked to their test results. If both tests yielded positive findings, the order of targeting at biopsy was randomly assigned (1:1) using stratified (according to centre only) block randomisation with randomly varying block sizes. The co-primary endpoints were the proportion of positive lesions on, and agreement between, multiparametric MRI and multiparametric ultrasound in identifying suspicious lesions (Likert score of ≥3), and detection of clinically significant cancer (defined as a Gleason score of ≥4 + 3 in any area or a maximum cancer core length of ≥6 mm of any grade [PROMIS definition 1]) in those patients who underwent a biopsy. Adverse events were defined according to Good Clinical Practice and trial regulatory guidelines. The trial is registered on ISRCTN, 38541912, and ClinicalTrials.gov, NCT02712684, with recruitment and follow-up completed. FINDINGS: Between March 15, 2016, and Nov 7, 2019, 370 eligible patients were enrolled; 306 patients completed both multiparametric ultrasound and multiparametric MRI and 257 underwent a prostate biopsy. Multiparametric ultrasound was positive in 272 (89% [95% CI 85-92]) of 306 patients and multiparametric MRI was positive in 238 patients (78% [73-82]; difference 11·1% [95% CI 5·1-17·1]). Positive test agreement was 73·2% (95% CI 67·9-78·1; κ=0·06 [95% CI -0·56 to 0·17]). Any cancer was detected in 133 (52% [95% CI 45·5-58]) of 257 patients, with 83 (32% [26-38]) of 257 being clinically significant by PROMIS definition 1. Each test alone would result in multiparametric ultrasound detecting PROMIS definition 1 cancer in 66 (26% [95% CI 21-32]) of 257 patients who had biopsies and multiparametric MRI detecting it in 77 (30% [24-36]; difference -4·3% [95% CI -8·3% to -0·3]). Combining both tests detected 83 (32% [95% CI 27-38]) of 257 clinically significant cancers as per PROMIS definition 1; of these 83 cancers, six (7% [95% CI 3-15]) were detected exclusively with multiparametric ultrasound, and 17 (20% [12-31]) were exclusively detected by multiparametric MRI (agreement 91·1% [95% CI 86·9-94·2]; κ=0·78 [95% CI 0·69-0·86]). No serious adverse events were related to trial activity. INTERPRETATION: Multiparametric ultrasound detected 4·3% fewer clinically significant prostate cancers than multiparametric MRI, but it would lead to 11·1% more patients being referred for a biopsy. Multiparametric ultrasound could be an alternative to multiparametric MRI as a first test for patients at risk of prostate cancer, particularly if multiparametric MRI cannot be carried out. Both imaging tests missed clinically significant cancers detected by the other, so the use of both would increase the detection of clinically significant prostate cancers compared with using each test alone. FUNDING: The Jon Moulton Charity Trust, Prostate Cancer UK, and UCLH Charity and Barts Charity.

Prostate cancer in transgender women: what does a urologist need to know?

OBJECTIVE: To review of the existing literature, current guidelines and standard of practice related to prostate cancer in transgender women, as the transgender population share many of the same healthcare needs as their cisgender counterparts, but may have additional specialist needs. MATERIALS AND METHODS: We performed a non-systematic review of the literature, current guidelines and standard of practice related to prostate cancer in transgender women. RESULTS: Our search revealed 10 case reports of prostate cancer in transgender women, four specialist opinion papers, six cohort studies, and four systematic reviews. The information in these publications were assimilated to produce a review of prostate cancer in transgender women. CONCLUSION: The risk of prostate cancer in transgender women who are not on gender-affirming hormone therapy (GAHT) or who have not had gender-affirming surgery (GAS) and gender non-conforming individuals (who may never commence GAHT or have GAS) is the same as that in the cis male population. In these patients, healthcare professionals need to be able to discuss screening, diagnostic and treatment options considering future wishes for gender-affirming treatment. Prostate cancer incidence in transgender women on GAHT or following GAS is lower than age-matched cis-male counterparts, but diagnosis and treatment is more nuanced. The present review discusses the existing literature about development and incidence of prostate cancer in this population, and makes recommendations about screening, the usefulness of diagnostic tools e.g. prostate-specific antigen and magnetic resonance imaging, and considerations when formulating treatment. Potential directions for future research are discussed, which will hopefully lead to development of robust evidence-based guidelines for the diagnosis and management of prostate cancer in transgender women.

Clinical and pathologic characteristics to select patients for focal therapy or partial gland ablation of nonmetastatic prostate cancer.

PURPOSE OF REVIEW: Focal therapy or partial gland ablation for nonmetastatic prostate cancer is gaining popularity not just as an alternative to active surveillance, but as an acceptable alternative to whole gland therapy in appropriate cases. This review summarizes recent evidence to help select patients for optimal outcomes. RECENT FINDINGS: Recommendations by expert panels have become less conservative with each meeting. As experience with older modalities for focal therapy grows, newer modalities continue to be introduced. We are now in a position to offer personalized treatment pathway considering nuances of each focal therapy modality. SUMMARY: The ideal case for focal therapy should be an MRI visible significant lesion (PIRADS score ≥ 3), with a positive biopsy for significant cancer (Gleason grade group 2-3) in the corresponding targeted biopsy area, and insignificant or absent disease in the nontarget random biopsy areas. Multifocal disease can also be selectively treated. Salvage focal ablation is an attractive treatment option for radio-recurrent or index focal therapy failure cases.

Adjusting for verification bias in diagnostic accuracy measures when comparing multiple screening tests - an application to the IP1-PROSTAGRAM study.

INTRODUCTION: Novel screening tests used to detect a target condition are compared against either a reference standard or other existing screening methods. However, as it is not always possible to apply the reference standard on the whole population under study, verification bias is introduced. Statistical methods exist to adjust estimates to account for this bias. We extend common methods to adjust for verification bias when multiple tests are compared to a reference standard using data from a prospective double blind screening study for prostate cancer. METHODS: Begg and Greenes method and multiple imputation are extended to include the results of multiple screening tests which determine condition verification status. These two methods are compared to the complete case analysis using the IP1-PROSTAGRAM study data. IP1-PROSTAGRAM used a paired-cohort double-blind design to evaluate the use of imaging as alternative tests to screen for prostate cancer, compared to a blood test called prostate specific antigen (PSA). Participants with positive imaging (index) and/or PSA (control) underwent a prostate biopsy (reference standard). RESULTS: When comparing complete case results to Begg and Greenes and methods of multiple imputation there is a statistically significant increase in the specificity estimates for all screening tests. Sensitivity estimates remained similar across the methods, with completely overlapping 95% confidence intervals. Negative predictive value (NPV) estimates were higher when adjusting for verification bias, compared to complete case analysis, even though the 95% confidence intervals overlap. Positive predictive value (PPV) estimates were similar across all methods. CONCLUSION: Statistical methods are required to adjust for verification bias in accuracy estimates of screening tests. Expanding Begg and Greenes method to include multiple screening tests can be computationally intensive, hence multiple imputation is recommended, especially as it can be modified for low prevalence of the target condition.

Discovery of Novel HIV Protease Inhibitors Using Modern Computational Techniques.

The human immunodeficiency virus type 1 (HIV-1) has continued to be a global concern. With the new HIV incidence, the emergence of multi-drug resistance and the untoward side effects of currently used anti-HIV drugs, there is an urgent need to discover more efficient anti-HIV drugs. Modern computational tools have played vital roles in facilitating the drug discovery process. This research focuses on a pharmacophore-based similarity search to screen 111,566,735 unique compounds in the PubChem database to discover novel HIV-1 protease inhibitors (PIs). We used an in silico approach involving a 3D-similarity search, physicochemical and ADMET evaluations, HIV protease-inhibitor prediction (IC50/percent inhibition), rigid receptor-molecular docking studies, binding free energy calculations and molecular dynamics (MD) simulations. The 10 FDA-approved HIV PIs (saquinavir, lopinavir, ritonavir, amprenavir, fosamprenavir, atazanavir, nelfinavir, darunavir, tipranavir and indinavir) were used as reference. The in silico analysis revealed that fourteen out of the twenty-eight selected optimized hit molecules were within the acceptable range of all the parameters investigated. The hit molecules demonstrated significant binding affinity to the HIV protease (PR) when compared to the reference drugs. The important amino acid residues involved in hydrogen bonding and п-п stacked interactions include ASP25, GLY27, ASP29, ASP30 and ILE50. These interactions help to stabilize the optimized hit molecules in the active binding site of the HIV-1 PR (PDB ID: 2Q5K). HPS/002 and HPS/004 have been found to be most promising in terms of IC50/percent inhibition (90.15%) of HIV-1 PR, in addition to their drug metabolism and safety profile. These hit candidates should be investigated further as possible HIV-1 PIs with improved efficacy and low toxicity through in vitro experiments and clinical trial investigations.

Available evidence on HIFU for focal treatment of prostate cancer: a systematic review.

PURPOSE: Prostate cancer (PCa) is the second most common oncologic disease among men. Radical treatment with curative intent provides good oncological results for PCa survivors, although definitive therapy is associated with significant number of serious side-effects. In modern-era of medicine tissue-sparing techniques, such as focal HIFU, have been proposed for PCa patients in order to provide cancer control equivalent to the standard-of-care procedures while reducing morbidities and complications. The aim of this systematic review was to summarise the available evidence about focal HIFU therapy as a primary treatment for localized PCa. MATERIAL AND METHODS: We conducted a comprehensive literature review of focal HIFU therapy in the MEDLINE database (PROSPERO: CRD42021235581). Articles published in the English language between 2010 and 2020 with more than 50 patients were included. RESULTS: Clinically significant in-field recurrence and out-of-field progression were detected to 22% and 29% PCa patients, respectively. Higher ISUP grade group, more positive cores at biopsy and bilateral disease were identified as the main risk factors for disease recurrence. The most common strategy for recurrence management was definitive therapy. Six months after focal HIFU therapy 98% of patients were totally continent and 80% of patients retained sufficient erections for sexual intercourse. The majority of complications presented in the early postoperative period and were classified as low-grade. CONCLUSIONS: This review highlights that focal HIFU therapy appears to be a safe procedure, while short-term cancer control rate is encouraging. Though, second-line treatment or active surveillance seems to be necessary in a significant number of patients.

Prostate Radiofrequency Focal Ablation (ProRAFT) Trial: A Prospective Development Study Evaluating a Bipolar Radiofrequency Device to Treat Prostate Cancer.

PURPOSE: We determined the early efficacy of bipolar radiofrequency ablation with a coil design for focal ablation of clinically significant localized prostate cancer visible at multiparametric magnetic resonance imaging. MATERIALS AND METHODS: A prospective IDEAL phase 2 development study (Focal Prostate Radiofrequency Ablation, NCT02294903) recruited treatment-naïve patients with a single focus of significant localized prostate cancer (Gleason 7 or 4 mm or more of Gleason 6) concordant with a lesion visible on multiparametric magnetic resonance imaging. Intervention was a focal ablation with a bipolar radiofrequency system (Encage™) encompassing the lesion and a predefined margin using nonrigid magnetic resonance imaging-ultrasound fusion. Primary outcome was the proportion of men with absence of significant localized disease on biopsy at 6 months. Trial followup consisted of serum prostate specific antigen, multiparametric magnetic resonance imaging at 1 week, and 6 and 12 months post-ablation. Validated patient reported outcome measures for urinary, erectile and bowel functions, and adverse events monitoring system were used. Analyses were done on a per-protocol basis. RESULTS: Of 21 patients recruited 20 received the intervention. Baseline characteristics were median age 66 years (IQR 63-69) and preoperative median prostate specific antigen 7.9 ng/ml (5.3-9.6). A total of 18 patients (90%) had Gleason 7 disease with median maximum cancer 7 mm (IQR 5-10), for a median of 2.8 cc multiparametric magnetic resonance imaging lesions (IQR 1.4-4.8). Targeted biopsy of the treated area (median number of cores 6, IQR 5-8) showed absence of significant localized prostate cancer in 16/20 men (80%), concordant with multiparametric magnetic resonance imaging. There was a low profile of side effects at patient reported outcome measures analysis and there were no serious adverse events. CONCLUSIONS: Focal therapy of significant localized prostate cancer associated with a magnetic resonance imaging lesion using bipolar radiofrequency showed early efficacy to ablate cancer with low rates of genitourinary and rectal side effects.

A Comparison of Prostate Cancer Detection between Visual Estimation (Cognitive Registration) and Image Fusion (Software Registration) Targeted Transperineal Prostate Biopsy.

PURPOSE: We compared clinically significant prostate cancer detection by visual estimation and image fusion targeted transperineal prostate biopsy. MATERIALS AND METHODS: This multicenter study included patients with multiparametric magnetic resonance imaging lesions undergoing visual estimation or image fusion targeted transperineal biopsy (April 2017-March 2020). Propensity score matching was performed using demographics (age and ethnicity), clinical features (prostate specific antigen, prostate volume, prostate specific antigen density and digital rectal examination), multiparametric magnetic resonance imaging variables (number of lesions, PI-RADS® score, index lesion diameter, whether the lesion was diffuse and radiological T stage) and biopsy factors (number of cores, operator experience and anesthetic type). Matched groups were compared overall and by operator grade, PI-RADS score, lesion multiplicity, prostate volume and anesthetic type using targeted-only and targeted plus systematic histology. Multiple clinically significant prostate cancer thresholds were evaluated (primary: Gleason ≥3+4). RESULTS: A total of 1,071 patients with a median age of 67.3 years (IQR 61.3-72.4), median prostate specific antigen of 7.5 ng/ml (IQR 5.3-11.2) and 1,430 total lesions underwent targeted-only biopsies (visual estimation: 372 patients, 494 lesions; image fusion: 699 patients, 936 lesions). A total of 770 patients with a median age of 67.4 years (IQR 61-72.1), median prostate specific antigen of 7.1 ng/ml (IQR 5.2-10.6) and 919 total lesions underwent targeted plus systematic biopsies (visual estimation: 271 patients, 322 lesions; image fusion: 499 patients, 597 lesions). Matched comparisons demonstrated no overall difference in clinically significant prostate cancer detection between visual estimation and image fusion (primary: targeted-only 54% vs 57.4%, p=0.302; targeted plus systematic 51.2% vs 58.2%, p=0.123). Senior urologists had significantly higher detection rates using image fusion (primary: targeted-only 45.4% vs 63.7%, p=0.001; targeted plus systematic 39.4% vs 64.5%, p <0.001). CONCLUSIONS: We found no overall difference in clinically significant prostate cancer detection, although image fusion may be superior in experienced hands.

Outcomes of the RAFT trial: robotic surgery after focal therapy.

OBJECTIVES: To report toxicity of treatment observed in men participating in the Robotic surgery After Focal Therapy (RAFT) clinical trial. PATIENTS AND METHODS: Men were eligible for this prospective single group interventional study if they had histologically confirmed recurrent/residual prostate adenocarcinoma following primary FT. The short-form Expanded Prostate Cancer Index Composite (EPIC-26) measured prior to salvage robotic prostatectomy (S-RARP) and 3-monthly post-operatively together with Clavien-Dindo complications (I-IV). Secondary outcomes included biochemical recurrence-free survival (BCFS) following surgery and need for salvage treatment after surgery. This study is registered with ClinicalTrials.gov NCT03011606. RESULTS: Twenty-four men were recruited between February 2016 and September 2018. 1 patient withdrew from the trial after consenting and before S-RARP. 23 men completed 12-month post S-RARP follow-up. Median EPIC-26 urinary continence scores initially deteriorated after 3 months (82.4 vs 100) but there was no statistically significant difference from baseline at 12 months (100 vs 100, P = 0.31). Median lower urinary tract symptom scores improved after 12 months compared to baseline (93.8 vs 87.5, P = 0.01). At 12 months, 19/23 (83%) were pad-free and 22/23 (96%) required 0/1 pads. Median sexual function subscale scores deteriorated and remained low at 12 months (22.2 vs 58.3, P < 0.001). Utilising a minimally important difference of nine points, at 12 months after surgery 17/23 (74%) reported urinary continence to be 'better' or 'not different' to pre-operative baseline. The corresponding figure for sexual function (utilising a minimally important difference of 12 points) was 7/23 (30%). There was no statistically significant difference on median bowel/hormonal subscale scores. Only a single patient had a post-operative complication (Clavien-Dindo Grade I). BCFS at 12 months after surgery was 82.6% (95% confidence interval [CI]: 60.1-93.1%) while 4/23 (17%) received salvage radiation. CONCLUSIONS: The RAFT clinical trial suggests toxicity of surgery after FT is low, with good urinary function outcomes, albeit sexual function deteriorated overall. Oncological outcomes at 12 months appear acceptable.