Development and Characterisation of a New Patient-Derived Xenograft Model of AR-Negative Metastatic Castration-Resistant Prostate Cancer.

As the treatment landscape for prostate cancer gradually evolves, the frequency of treatment-induced neuroendocrine prostate cancer (NEPC) and double-negative prostate cancer (DNPC) that is deficient for androgen receptor (AR) and neuroendocrine (NE) markers has increased. These prostate cancer subtypes are typically refractory to AR-directed therapies and exhibit poor clinical outcomes. Only a small range of NEPC/DNPC models exist, limiting our molecular understanding of this disease and hindering our ability to perform preclinical trials exploring novel therapies to treat NEPC/DNPC that are urgently needed in the clinic. Here, we report the development of the CU-PC01 PDX model that represents AR-negative mCRPC with PTEN/RB/PSMA loss and CTNN1B/TP53/BRCA2 genetic variants. The CU-PC01 model lacks classic NE markers, with only focal and/or weak expression of chromogranin A, INSM1 and CD56. Collectively, these findings are most consistent with a DNPC phenotype. Ex vivo and in vivo preclinical studies revealed that CU-PC01 PDX tumours are resistant to mCRPC standard-of-care treatments enzalutamide and docetaxel, mirroring the donor patient's treatment response. Furthermore, short-term CU-PC01 tumour explant cultures indicate this model is initially sensitive to PARP inhibition with olaparib. Thus, the CU-PC01 PDX model provides a valuable opportunity to study AR-negative mCRPC biology and to discover new treatment avenues for this hard-to-treat disease.

Disseminated E. coli urinary tract infection resulting in septic arthritis of the glenohumeral joint.

An 89-year-old male with a background of metastatic transitional cell carcinoma presented acutely with new hydronephrosis and deranged renal function secondary to high pressure chronic urinary retention. A recent urine culture was positive for Escherichia coli (E.coli). Co-incidentally, the patient's primary presenting symptom was right shoulder pain following recent low velocity trauma. X-ray demonstrated air density within the glenohumeral joint, with Magnetic Resonance Imaging (MRI) confirming features of septic arthritis. Surgical debridement was undertaken with tissue microscopy and culture identifying the presence of E. coli, confirming the diagnosis of disseminated urinary tract infection.

Perception of urinary biomarker tests among patients referred with suspected urological malignancy.

Objective: To determine the acceptability of a non-invasive urinary biomarker test in place of conventional flexible cystoscopy for the diagnosis of bladder cancer in patients referred to a Rapid Access Haematuria Clinic (RAHC) with suspected urological malignancy. Patients and methods: Patients attending a RAHC were recruited to a prospective observational study evaluating a novel urinary biomarker (URO17™) for the detection of bladder cancer and invited to complete a two-part structured questionnaire. Questions related to demographics, attitudes towards conventional cystoscopy and the minimal acceptable sensitivity (MAS) at which a urinary biomarker would be considered an alternative to flexible cystoscopy both before and after undergoing the procedure. Results: A total of 250 patients completed the survey; the majority of whom were referred with visible haematuria (75.2%). One hundred seventy-one (68.4%) would be willing to accept a urinary biomarker in place of cystoscopy, with 59 (23.6%) expressing preference for the biomarker with a MAS as low as 85%. Conversely, 74 patients (29.6%) would not be willing to accept a urinary biomarker, regardless of its sensitivity. A significant number of patients reported a change in MAS after undergoing cystoscopy, with 80 (32.0%) and 16 (6.4%) increasing and decreasing the required value respectively (P = 0.001). The greatest increase was seen in the proportion of patients unwilling to accept a urinary biomarker regardless of its sensitivity, rising from 29.6% to 38.4%. Conclusions: Although many patients attending a RAHC would be willing to accept a urinary biomarker test in place of conventional flexible cystoscopy for the detection of bladder cancer, effective patient, public and clinician engagement will be necessary at all stages of implementation if it is to become an established component of the diagnostic pathway.

The PTEN Conundrum: How to Target PTEN-Deficient Prostate Cancer.

Loss of the tumor suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN), which negatively regulates the PI3K-AKT-mTOR pathway, is strongly linked to advanced prostate cancer progression and poor clinical outcome. Accordingly, several therapeutic approaches are currently being explored to combat PTEN-deficient tumors. These include classical inhibition of the PI3K-AKT-mTOR signaling network, as well as new approaches that restore PTEN function, or target PTEN regulation of chromosome stability, DNA damage repair and the tumor microenvironment. While targeting PTEN-deficient prostate cancer remains a clinical challenge, new advances in the field of precision medicine indicate that PTEN loss provides a valuable biomarker to stratify prostate cancer patients for treatments, which may improve overall outcome. Here, we discuss the clinical implications of PTEN loss in the management of prostate cancer and review recent therapeutic advances in targeting PTEN-deficient prostate cancer. Deepening our understanding of how PTEN loss contributes to prostate cancer growth and therapeutic resistance will inform the design of future clinical studies and precision-medicine strategies that will ultimately improve patient care.

Pathological upgrading in prostate cancer treated with surgery in the United Kingdom: trends and risk factors from the British Association of Urological Surgeons Radical Prostatectomy Registry.

BACKGROUND: Accurate grading at the time of diagnosis if fundamental to risk stratification and treatment decision making in patients with prostate cancer. Whilst previous studies have demonstrated significant pathological upgrading and downgrading following radical prostatectomy (RP), these were based on historical cohorts and do not reflect contemporary patient selection and management practices. The aim of this national, multicentre observational study was to characterise contemporary rates and risk factors for pathological upgrading after RP in the United Kingdom (UK). METHODS: All RP entries on the British Association of Urological Surgeons (BAUS) Radical Prostatectomy Registry database of prospectively entered cases undertaken between January 2011 and December 2016 were extracted. Those patients with full preoperative PSA, clinical stage, needle biopsy and subsequent RP pathological grade information were included. Upgrade was defined as any increase in Gleason grade from initial needle biopsy to pathological assessment of the entire surgical specimen. Statistical analysis and multivariate logistic regression were undertaken using R version 3.5 (R Foundation for Statistical Computing, Vienna, Austria). RESULTS: A total of 17,598 patients met full inclusion criteria. Absolute concordance between initial biopsy and pathological grade was 58.9% (n = 10,364), whilst upgrade and downgrade rates were 25.5% (n = 4489) and 15.6% (n = 2745) respectively. Upgrade rate was highest in those with D'Amico low risk compared with intermediate and high-risk disease (55.7% versus 19.1 and 24.3% respectively, P < 0.001). Although rates varied between year of surgery and geographical regions, these differences were not significant after adjusting for other preoperative diagnostic variables using multivariate logistic regression. CONCLUSIONS: Pathological upgrading after RP in the UK is lower than expected when compared with other large contemporary series, despite operating on a generally higher risk patient cohort. As new diagnostic techniques that may reduce rates of pathological upgrading become more widely utilised, this study provides an important benchmark against which to measure future performance.

Implementation of medication-related indicators of potentially preventable hospitalizations in a national chronic disease management program for older patients with multimorbidity.

INITIAL ASSESSMENT: Older people are at increased risk of medication-related potentially preventable hospitalizations (MR-PPH) due to the presence of multiple chronic conditions (multimorbidity) and subsequent polypharmacy. CHOICE OF SOLUTION: A pilot study was conducted, using evidence-based indicators to detect older patients in a chronic disease management program (CDMP) at risk of hospitalization due to sub-optimal medication use. IMPLEMENTATION: Previously validated indicators for MR-PPH were applied to patients with multimorbidity, aged 65 years or older and who were enrolled in a national community-based CDMP. Nurse-led telephone interviews and case note abstraction were used as data sources. EVALUATION: Nineteen patients triggered the MR-PPH indicators 85 times with a median of four per patient. Sub-optimal medication management was identified 34 times (40%) with a median of two per patient. The most common reasons for sub-optimal medication management were exposure to medications associated with falls, underuse of angiotensin-converting enzyme inhibitor/angiotensin-2 receptor blocker medications for cardiovascular disease and low rates of hemoglobin A1c and renal monitoring in patients with diabetes. LESSONS LEARNED: This study has shown the utility of MR-PPH indicators within a CDMP to identify and monitor sub-optimal medication-related care. Implementation and ongoing monitoring of these types of indicators can support the development of targeted programs to reduce the ongoing risk of adverse events in the older population and improve the overall quality of life.

Emergency Management of Priapism in the United Kingdom: A Survey of Current Practice.

BACKGROUND: Despite its importance, current practice in the emergency management of priapism in the United Kingdom is unknown. AIM: To evaluate current practice in the emergency management of priapism in the United Kingdom. METHODS: All "full," "associate urological specialist," and "trainee" members of the British Association of Urological Surgeons (BAUS; leading membership-based organization for practitioners of urologic surgery in the United Kingdom) were invited to participate in an online survey. Questions related to the emergency management of priapism, access to tertiary andrology services, and use of guidelines. OUTCOMES: Key outcome measures included frequency of encountered cases, access to specialist andrology support, confidence in key management steps, and use of current guidelines. RESULTS: 213 of 1,304 (16.3%) eligible members completed the survey. Most reported managing 1 case annually (median = 1, range = 0->10). Only 7.0% transferred patients to a tertiary center and 87.8% believed they could access specialist andrology advice if required. Respondents were less confident in performing intracavernosal phenylephrine instillation (88.7%) compared with corporal aspiration (98.1%), with confidence lowest among trainee members. Only 68.5% reported performing the distal shunt procedure. Of the 212 respondents that chose to answer questions relating to guidelines, only 155 (73.1%) were aware of their existence, with those published by the European Association of Urology being most popular (53.8%). 205 (96.2%) respondents expressed an interest in the development of a UK-specific guideline, with 162 of 212 (76.4%) stating they would use this in practice. CLINICAL IMPLICATIONS: Urologists in the United Kingdom support the development of UK-specific guidance on the emergency management of priapism for use within the context of the National Health Service. STRENGTHS AND LIMITATIONS: This is the first study to assess current practice in the emergency management of priapism in the United Kingdom. Its strength is that most UK urologists were invited to participate through collaboration with the BAUS. Although the response rate of 16.3% is acceptable for a national survey of this nature, responses were self-reported, rendering them susceptible to bias. CONCLUSION: This study demonstrates that some UK urologists lack confidence in key steps in the emergency management of priapism and identifies a strong level of support for the development of up-to-date UK-specific guidance. Bullock N, Steggall M, Brown G. Emergency Management of Priapism in the United Kingdom: A Survey of Current Practice. J Sex Med 2018;15:476-479.

The 100 most cited manuscripts in emergency abdominal surgery: A bibliometric analysis.

BACKGROUND: The number of citations a scientific article receives provides a good indication of its impact within any given field. This bibliometric analysis aimed to identify the 100 most cited articles in Emergency Abdominal Surgery (EAS), to highlight key areas of interest and identify those that have most significantly shaped contemporary clinical practice in this newly evolving surgical specialty. This is of increasing relevance as concerns grow regarding the variable and suboptimal outcomes in Emergency General Surgery. MATERIALS AND METHODS: The Thomson Reuters Web of Science database was used to search using the terms [Emergency AND Abdom* AND Surg*] to identify all English language, full manuscripts. Results were ranked according to citation number. The top 100 articles were further analysed by subject, author, journal, year of publication, institution, and country of origin. RESULTS: The median (range) citation number of the top 100 out of 7433 eligible papers was 131 (1569-97). The most cited paper (by Goldman et al., Massachusetts General Hospital, New England Journal of Medicine; 1569 citations) focused on cardiac risk stratification in non-cardiac surgery. The Journal of Trauma, Injury, Infection and Critical Care published the most papers and received most citations (n = 19; 2954 citations. The majority of papers were published by centres in the USA (n = 52; 9422 citations), followed by the UK (n = 13; 1816 citations). The most common topics of publication concerned abdominal aneurysm management (n = 26) and emergency gastrointestinal surgery (n = 26). CONCLUSION: Vascular surgery, risk assessment and gastrointestinal surgery were the areas of focus for 59% of the contemporary most cited emergency abdominal surgery manuscripts. By providing the most influential references this work serves as a guide to what makes a citable emergency surgery paper.

The many faces of SRPK1.

Serine-arginine protein kinase 1 (SRPK1) phosphorylates proteins involved in the regulation of several mRNA-processing pathways, including alternative splicing. SRPK1 has been recently reported to be overexpressed in multiple cancers, including prostate cancer, breast cancer, lung cancer, and glioma. Several studies have shown that inhibition of SRPK1 has anti-tumoural effects, and SRPK1 has therefore become a new candidate for targeted therapies. Interestingly, in terms of molecular mechanism, SRPK1 seems to act heterogeneously, and has been reported to affect several processes in different cancers, e.g. angiogenesis in prostate and colon cancer, apoptosis in breast and colon cancer, and migration in breast cancer. A recent report adds to this puzzle, showing that the main effect of SRPK1 overexpression in non-small-cell lung carcinoma is to stimulate a stem cell-like phenotype. This pleiotropy might be related to preferential activation of different downstream signalling pathways by SRPK1 in various cancers. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Serine-arginine protein kinase 1 (SRPK1), a determinant of angiogenesis, is upregulated in prostate cancer and correlates with disease stage and invasion.

Vascular endothelial growth factor (VEGF) undergoes alternative splicing to produce both proangiogenic and antiangiogenic isoforms. Preferential splicing of proangiogenic VEGF is determined by serine-arginine protein kinase 1 (SRPK1), which is upregulated in a number of cancers. In the present study, we aimed to investigate SRPK1 expression in prostate cancer (PCa) and its association with cancer progression. SRPK1 expression was assessed using immunohistochemistry of PCa tissue extracted from radical prostatectomy specimens of 110 patients. SRPK1 expression was significantly higher in tumour compared with benign tissue (p<0.00001) and correlated with higher pT stage (p=0.004), extracapsular extension (p=0.003) and extracapsular perineural invasion (p=0.008). Interestingly, the expression did not correlate with Gleason grade (p=0.21), suggesting that SRPK1 facilitates the development of a tumour microenvironment that favours growth and invasion (possibly through stimulating angiogenesis) while having little bearing on the morphology or function of the tumour cells themselves.