Identification of multipotent luminal progenitor cells in human prostate organoid cultures.

The prostate gland consists of basal and luminal cells arranged as pseudostratified epithelium. In tissue recombination models, only basal cells reconstitute a complete prostate gland, yet murine lineage-tracing experiments show that luminal cells generate basal cells. It has remained challenging to address the molecular details of these transitions and whether they apply to humans, due to the lack of culture conditions that recapitulate prostate gland architecture. Here, we describe a 3D culture system that supports long-term expansion of primary mouse and human prostate organoids, composed of fully differentiated CK5+ basal and CK8+ luminal cells. Organoids are genetically stable, reconstitute prostate glands in recombination assays, and can be experimentally manipulated. Single human luminal and basal cells give rise to organoids, yet luminal-cell-derived organoids more closely resemble prostate glands. These data support a luminal multilineage progenitor cell model for prostate tissue and establish a robust, scalable system for mechanistic studies.

Organoid cultures derived from patients with advanced prostate cancer.

The lack of in vitro prostate cancer models that recapitulate the diversity of human prostate cancer has hampered progress in understanding disease pathogenesis and therapy response. Using a 3D organoid system, we report success in long-term culture of prostate cancer from biopsy specimens and circulating tumor cells. The first seven fully characterized organoid lines recapitulate the molecular diversity of prostate cancer subtypes, including TMPRSS2-ERG fusion, SPOP mutation, SPINK1 overexpression, and CHD1 loss. Whole-exome sequencing shows a low mutational burden, consistent with genomics studies, but with mutations in FOXA1 and PIK3R1, as well as in DNA repair and chromatin modifier pathways that have been reported in advanced disease. Loss of p53 and RB tumor suppressor pathway function are the most common feature shared across the organoid lines. The methodology described here should enable the generation of a large repertoire of patient-derived prostate cancer lines amenable to genetic and pharmacologic studies.

Strategies to maximise patient comfort during extracorporeal shockwave lithotripsy - A randomised controlled trial.

BACKGROUND/PURPOSE OF STUDY: We aim to assess if distraction techniques improve patient comfort tolerability of SWL. METHODS: We carried out a prospective randomised controlled trial of SWL-naïve patients attending for treatment. Patients were randomised into three groups and offered oral analgesia as standard of care. Group 1 (n = 19) received stress balls to squeeze during treatment. Group 2 (n = 19) listened to music during treatment. Group 3 (n = 17) received standard of care only. All patients completed a validated health anxiety inventory score prior to treatment. All patients completed a validated pain questionnaire and visual analogue scale (VAS) after treatment. Primary outcomes were completion of SWL treatment and pain score results. RESULTS: 55 patients attending for SWL were randomised. There was no difference in stone size or position, presence of a stent, height or weight between the groups. VAS scores were lower in controls compared to Group 1 (1.93 vs 3.69, p = 0.08). On subgroup analysis of non-anxious patients, pain questionnaire scores were lower in controls compared to Group 1 (2.58 vs 4.77, p = 0.06). VAS scores were lower in patients who received optional analgesia alone than in patients who received stress balls alone (1.92 vs 4.07, p = 0.05). Across all subgroups, pain scores were lower in the control group compared to the distraction groups, but did not achieve significance. CONCLUSIONS: In conclusion, distraction techniques should not replace standard of care for analgesia during SWL. This study was registered with clinicaltrials.gov (identifier NCT03379922).

Evaluation of a Novel Ostomy Barrier Ring with Assisted Flow for Individuals with an Ileostomy.

OBJECTIVE: To determine the performance and user experience of a novel ostomy barrier ring over a 4-week period. METHODS: This single-arm investigation conducted across three clinical sites included 25 adult participants with an ileostomy for 3 months or longer. The participants used their standard ostomy pouching appliance along with a novel barrier ring for a period of 4 weeks. Skin condition was assessed using the Ostomy Skin Tool. Change in skin condition over the study period was recorded for each participant. The participants' experience in using the novel barrier ring was measured using a five-point Likert-type scale. RESULTS: Twenty of the 25 participants (80%) completed the trial. Of those participants, the median Ostomy Skin Tool score at both the beginning (range, 0-8) and end was 0 (range, 0-6). In terms of skin condition, 7 participants experienced an improvement in skin condition, 11 experienced no change, and 2 got worse. A median score of 5 out of 5 was recorded for all questions relating to user experience. CONCLUSIONS: Although not statistically significant, there was a clear trend toward improvements in peristomal skin condition using the novel barrier ring, even for participants who were already using a barrier ring. User feedback was positive with respect to comfort, device handling, and the perception of the device's ability to protect the skin. Further, most participants who already used a barrier ring indicated that the novel barrier ring would result in a longer wear time.

Dimethyl Fumarate Selectively Reduces Memory T Cells and Shifts the Balance between Th1/Th17 and Th2 in Multiple Sclerosis Patients.

Dimethyl fumarate (DMF; trade name Tecfidera) is an oral formulation of the fumaric acid ester that is Food and Drug Administration approved for treatment of relapsing-remitting multiple sclerosis. To better understand the therapeutic effects of Tecfidera and its rare side effect of progressive multifocal leukoencephalopathy, we conducted cross-sectional and longitudinal studies by immunophenotyping cells from peripheral blood (particularly T lymphocytes) derived from untreated and 4-6 and 18-26 mo Tecfidera-treated stable relapsing-remitting multiple sclerosis patients using multiparametric flow cytometry. The absolute numbers of CD4 and CD8 T cells were significantly decreased and the CD4/CD8 ratio was increased with DMF treatment. The proportions of both effector memory T cells and central memory T cells were reduced, whereas naive T cells increased in treated patients. T cell activation was reduced with DMF treatment, especially among effector memory T cells and effector memory RA T cells. Th subsets Th1 (CXCR3+), Th17 (CCR6+), and particularly those expressing both CXCR3 and CD161 were reduced most significantly, whereas the anti-inflammatory Th2 subset (CCR3+) was increased after DMF treatment. A corresponding increase in IL-4 and decrease in IFN-γ and IL-17-expressing CD4+ T cells were observed in DMF-treated patients. DMF in vitro treatment also led to increased T cell apoptosis and decreased activation, proliferation, reactive oxygen species, and CCR7 expression. Our results suggest that DMF acts on specific memory and effector T cell subsets by limiting their survival, proliferation, activation, and cytokine production. Monitoring these subsets could help to evaluate the efficacy and safety of DMF treatment.

Parental awareness of testicular torsion amongst Irish parents.

PURPOSE: Testicular torsion is the most concerning underlying cause of acute scrotal pain that can lead to loss of the affected testicle. Whether a torted testicle can be salvaged surgically is directly affected by prompt presentation and diagnosis. This study aims to evaluate the awareness of testicular torsion amongst Irish parents and evaluate their response to a potential torsion. METHODS: An anonymous questionnaire was distributed to parents attending general paediatric clinics and an acute paediatric unit in two paediatric tertiary referral centres. SPSS statistical analysis software was used to perform multivariant analysis of the data. RESULTS: There were 242 completed surveys. Fifty-six percent of responders had an awareness of torsion. In the event of an episode of severe testicular pain parents who were aware of testicular torsion were 4 times more likely to present immediately than those who had no awareness of torsion (OR 4.2, 95% CI 1.4-12.2, P < 0.01), and those who identified correctly the critical timeframe were 3 times more likely to present immediately than those who did not (OR 3.0, 95% CI 0.85-10.8, P = 0.08). Of those parents with boys only 11% had discussed what to do in the event of acute scrotal pain. CONCLUSIONS: Education of this topic to the general Irish population and in particular to parents and young males is not established. Both knowledge of testicular torsion and awareness of the urgency in presentation are factors that determine parents promptness in seeking medical attention for their child in the setting of acute scrotal pain.

Outcome of deceased donor renal transplantation in patients with an ileal conduit.

Renal transplantation in recipients with an ileal conduit is uncommon and occasionally controversial as it has been associated with high morbidity and mortality rates. We report on 17 patients with an ileal conduit who received a deceased donor renal transplant at our institution between January 1986 and December 2012. We retrospectively reviewed their allograft and surgical outcome. There were four mortalities at five, five, 39, and 66 months post-transplant. Sixteen of 17 grafts functioned immediately; one patient had primary non-function secondary to vascular thrombosis. Thirteen of 17 (76.5%) grafts were functioning at a mean follow-up period of 105 months. The mean serum creatinine at follow-up was 111 µM (±38.62). Five patients had seven episodes of urosepsis requiring hospital admission, and five patients received treatment for renal stone disease. We conclude that given improvements in immunosuppression, surgical technique, infection treatment, and selection criteria, we believe that renal transplantation in the patient with an ileal conduit yields excellent graft survival, although there is a high morbidity rate in this cohort of patients in the long term.

Ex vivo reconstruction of the donor renal artery in renal transplantation: a case-control study.

Transplantation of renal allografts with anatomic variability or injured vasculature poses a challenge to the transplanting surgeon but can be salvaged for transplantation with ex vivo bench reconstruction of the vasculature. We investigated whether renal allograft function is impaired in these reconstructed allografts; compared to the donor-matched, un-reconstructed allograft. Reconstructed allografts were transplanted into 60 patients at our institution between 1986 and 2012. A control group was selected from the matched pair of the recipient in deceased donor transplantation. We found no significant difference in the overall graft and patient survival rates (P = 1.0, P = 0.178). Serum creatinine levels were not significantly higher in the study group at 1, 3 and 12 months postoperatively. There were two cases of vascular thrombosis in the study group that were not related to the ex vivo reconstruction. A significantly greater proportion of reconstructed patients were investigated with a colour duplex ultrasound postoperatively (0.007). Although we have demonstrated a higher index of suspicion of transplant failure in patients with a reconstructed allograft, this practice has proven to be a safe and useful technique with equivocal outcome when compared to normal grafts; increasing the organ pool available for transplantation.

Multiple sclerosis and seizures: A retrospective observational study in a multiple sclerosis autoimmunity center of excellence.

PURPOSE: The prevalence of epilepsy in patients with multiple sclerosis (MS) is three to six times the prevalence in the general population. Mechanisms resulting in increased seizure risk are not fully understood. Our objective is to characterize patients with MS and epilepsy regarding timing of diagnoses, MS and seizure (SZ) type, EEG findings suggesting cortical dysfunction, frequency of status epilepticus (SE), and seizure freedom. METHODS: This was a single center retrospective study. Cases were obtained via DataDirect via the University of Michigan electronic medical record from January 1, 2006 through October, 12, 2016. The University of Michigan Health System is a large academic institute with a tertiary referral center and an Autoimmunity Center of Excellence. Patients were included if chart listed one or more of the top 62 epilepsy, and one or more of the top 2 MS, most frequently entered ICD9 and ICD10 codes. Patients with alternative epilepsy etiology were excluded. 74 of 361 patients were included. We collected information regarding demographics, MS and SZ type, age at diagnosis, imaging, EEG, seizure freedom, medications, and SE. RESULTS: We found a high percentage of patients with SE. Most patients with imaging had multiple lesions at seizure onset. 27/54 of patients with EEG data showed electrographic evidence of cortical dysfunction. 6/8 of EEGs in PPMS showed features consistent with cortical dysfunction, followed by 9/17 in SPMS and 11/23 in RRMS. 7/8 of patients with PPMS showed EEG evidence of temporal lobe dysfunction. CONCLUSION: Time of seizure onset relative to MS diagnosis varied with MS type suggesting distinct pathophysiology. EEG results correspond with reports of increased cortical damage and temporal dysfunction in PPMS, but are unique as a functional modality (EEG) as indicator of gray matter dysfunction. EEG findings differed in RRMS and progressive MS suggesting possibility of supportive diagnostic marker. Our data suggests higher risk of SE in progressive MS and diminished rate of seizure freedom for MS patients with SE. We conclude that early treatment with antiseizure medication would be beneficial for MS patients with SE and with progressive MS forms and SZ, in agreement with previous studies.

Identification of commensal gut microbiota signatures as predictors of clinical severity and disease progression in multiple sclerosis.

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system and a leading cause of neurological disability in young adults. Clinical presentation and disease course are highly heterogeneous. Typically, disease progression occurs over time and is characterized by the gradual accumulation of disability. The risk of developing MS is driven by complex interactions between genetic and environmental factors, including the gut microbiome. How the commensal gut microbiota impacts disease severity and progression over time remains unknown. In a longitudinal study, disability status and associated clinical features in 58 MS patients were tracked over 4.2 ± 0.98 years, and the baseline fecal gut microbiome was characterized via 16S amplicon sequencing. Progressor status, defined as patients with an increase in Expanded Disability Status Scale (EDSS), were correlated with features of the gut microbiome to determine candidate microbiota associated with risk of MS disease progression. We found no overt differences in microbial community diversity and overall structure between MS patients exhibiting disease progression and non-progressors. However, a total of 41 bacterial species were associated with worsening disease, including a marked depletion in Akkermansia, Lachnospiraceae, and Oscillospiraceae, with an expansion of Alloprevotella, Prevotella-9, and Rhodospirillales. Analysis of the metabolic potential of the inferred metagenome from taxa associated with progression revealed enrichment in oxidative stress-inducing aerobic respiration at the expense of microbial vitamin K2 production (linked to Akkermansia), and a depletion in SCFA metabolism (linked to Oscillospiraceae). Further, as a proof of principle, statistical modeling demonstrated that microbiota composition and clinical features were sufficient to predict disease progression. Additionally, we found that constipation, a frequent gastrointestinal comorbidity among MS patients, exhibited a divergent microbial signature compared with progressor status. These results demonstrate a proof of principle for the utility of the gut microbiome for predicting disease progression in MS in a small well-defined cohort. Further, analysis of the inferred metagenome suggested that oxidative stress, vitamin K2, and SCFAs are associated with progression, warranting future functional validation and mechanistic study.

Ureteral diverticulum: a review of the current literature.

INTRODUCTION: Ureteral diverticulum is a rare urological condition with only 45 cases described in the literature. These previously reported cases vary in their presentation, diagnosis and management and there is no consensus in the literature on the best diagnostic tool available. We describe our experience on diagnosing and managing this condition in two patients and provide a descriptive review of the current literature on ureteral diverticulum. MATERIALS AND METHODS: A Medline search was performed to identify all reported cases of ureteral diverticulum. Key words used were: ureteral diverticulum; abortive bifid ureter; congenital diverticulum; acquired diverticulum. We also reviewed the records of two patients who presented consecutively to our institution with a ureteral diverticulum. The clinical and radiological characteristics of this entity were then evaluated. RESULTS: Forty-one manuscripts were identified, encompassing single case reports and case series, the largest of which contained seven patients. Two additional cases were diagnosed in our institution; a true congenital diverticulum and an abortive bifid ureter which is synonymous with a true ureteral diverticulum. Both were uncomplicated cases and were managed conservatively. Retrograde pyelography was used for definitive diagnosis of this lesion. CONCLUSION: Ureteral diverticulum may present as an incidental finding or with a secondary complication. Conservative management is advocated in the literature for non-complicated cases. Retrograde pyelography is our diagnostic tool of choice.

The psychological impact of adverse events on urology trainees.

INTRODUCTION: Adverse events (AE) are an inevitable reality in healthcare, with an incidence of 7.5-14.1% worldwide. AEs are recognised to cause psychological and emotional distress in healthcare workers, with surgeons being particularly susceptible. We report the first data on the emotional impact in relation to adverse events in surgeons in the Republic of Ireland (ROI). METHODS: We distributed a web-based survey to all urology trainees in the ROI. The questionnaire focused on trainees' personal account of AEs, their emotional response, perceived contributing factors and perceived benefit of support systems. The primary care PTSD screen (PC-PTSD-V) assessed for PTSD. RESULTS: A total of 16 responses were received from 12 (75%) registrars and 4 (25%) SHOs. Of the AEs reported, 12 (75%) were ≥ Clavien-Dindo 3b. Contributing factors identified included lapse of judgement (n = 6, 37.5%), risk of procedure (n = 7, 43%), lack of experience (n = 4, 25%). Anxiety (n = 8, 50%), guilt (n = 7, 44%) and sleep problems (n = 4, 25%) were the most reported emotional responses. Physical symptoms were reported in 2 (12%) trainees. A PC-PTSD-V score ≥ 3 was reported in 2 (12%) trainees. Most trainees (n = 13, 81%) reported talking to someone following the event with most (n = 12, 93%) talking to a consultant or NCHD colleague. Most respondents (n = 14, 87%) agreed that their training could better prepare them for the personal impact of AEs. CONCLUSION: Surgical trainees report negative psychological and emotional responses that are consistent with second victim symptoms. Those surveyed felt that their training could better prepare them for the personal impact of such events.

Dysregulation of humoral immunity, iron homeostasis, and lipid metabolism is associated with multiple sclerosis progression.

BACKGROUND: Though most patients with multiple sclerosis (MS) presented earlier on as a relapsing-remitting (RR) disease, disability progression eventually occurred. Uncovering the mechanisms underlying progression may facilitate the unmet need for developing therapies to prevent progression. Benign MS (BMS), a rare form of MS, is the opposite from secondary progressive MS (SPMS) in that it lacks disease progression defined as Expanded Disability Status Scale (EDSS) ≤3 after at least 15 years of disease onset. BMS is characterized by rare and mild relapses with complete remission of clinical symptoms (lower activity of the disease) and lack of progression. Our study aims to identify transcriptomic and immunological differences between BMS and SPMS to unravel the pathogenesis of disease progression. METHODS: We took multi-modal approaches with microarrays, flow cytometry, and lipidomics by three-way comparisons of patients with BMS vs. RRMS (low disease activity vs. moderate or severe activity), RRMS vs. SPMS (continued activity vs. complete transformation into progressive phase) as well as BMS vs. SPMS, matched for age and disease-duration (low disease activity and no progression vs. progression with or without activity). RESULTS: We found that patients with RRMS and SPMS have a significantly higher percentage of B cells than those with BMS. BMS shows a different transcriptomic profile than SPMS. Many of the differentially expressed genes (DEGs) are involved in B cell-mediated immune responses. Additionally, long-chain fatty acids (LCFA), which can act as inflammatory mediators, are also altered in SPMS. Overall, our data suggest a role for the dysregulation of B cell differentiation and function, humoral immunity, and iron and lipid homeostasis in the pathogenesis of MS disease progression. CONCLUSION: BMS has a unique transcriptomic and immunological profile compared to RRMS and SPMS. These differences will allow for personalized precision medicine and may ultimately lead to the discovery of new therapeutic targets for disease progression.

A critical analysis of deficiencies in the quality of information contained in prostate multiparametric MRI requests and reports.

BACKGROUND: Multiparametric magnetic resonance imaging (mpMRI) has been increasingly recognised as an important tool in the diagnosis of prostate cancer. PI-RADSv2 guidelines recommend that important clinical information including prostate-specific antigen (PSA) levels, examination findings, and biopsy information should be included in mpMRI requests. PIRADS score and PSA density (PSAD) are both independent predictors for the presence of a clinically significant prostate cancer. AIMS: This study aims to evaluate the quality of mpMRI requests and reports at our institution in accordance with these parameters. METHODS: All prostate mpMRIs performed by radiology services in Galway University Hospital between 1st September 2019 and 1st March 2020 were reviewed. Exclusion criteria were applied. Requests and reports were analysed for the presence of the following parameters: PSA-results, examination findings, biopsy information, PI-RADS score, prostate volume, and PSAD. RESULTS: A total of 586 mpMRIs were performed, and of these, 546 were included. PSA value was provided in 497 (91%) of requests, exam findings in 355 (65%), and biopsy information in 452 (82%). PIRADS score was included in 224 (41%) of reports, prostate volume in 178 (32.6%), and PSAD in 106 (19%). CONCLUSIONS: Great variation in the quality of information contained in both requests and reports for prostate mpMRIs exists within our service. We aim to improve this by collaborating with our radiology colleagues to develop a proforma for requesting and reporting of mpMRIs for our radiology systems to ensure important clinical and radiological information is provided in future.

Teriflunomide modulates both innate and adaptive immune capacities in multiple sclerosis.

BACKGROUND: Teriflunomide (TER) (Aubagio™) is an FDA-approved disease-modifying therapy (DMT) for relapsing-remitting multiple sclerosis (RRMS). The mechanism of action of TER is thought to be related to the inhibition of dihydroorotate dehydrogenase (DHODH), a key mitochondrial enzyme in the de novo pyrimidine synthesis pathway required by rapidly dividing lymphocytes. Several large pivotal studies have established the efficacy and safety of TER in patients with RRMS. Despite this, little is known about how the adaptive and innate immune cell subsets are affected by the treatment in patients with MS. METHODS: We recruited 20 patients with RRMS who were newly started on TER and performed multicolor flow cytometry and functional assays on peripheral blood samples. A paired t-test was used for the statistical analysis and comparison. RESULTS: Our data showed that TER promoted a tolerogenic environment by shifting the balance between activated pathogenic and naïve or immunosuppressive immune cell subsets. In our cohort, TER increased the expression of the immunosuppressive marker CD39 on regulatory T cells (Tregs) while it decreased the expression of the activation marker CXCR3 on CD4+ T helper cells. TER treatment also reduced switched memory (sm) B cells while it increased naïve B cells and downregulated the expression of co-stimulatory molecules CD80 and CD86. Additionally, TER reduced the percentage and absolute numbers of natural killer T (NKT) cells, as well as the percentage of natural killer (NK) cells and showed a trend toward reducing the CD56dim NK pathogenic subset. CONCLUSION: TER promotes the tolerogenic immune response and suppresses the pathogenic immune response in patients with RRMS.

Identification of commensal gut microbiota signatures as predictors of clinical severity and disease progression in multiple sclerosis.

Background: Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system and a leading cause of neurological disability in young adults. Clinical presentation and disease course are highly heterogeneous. Typically, disease progression occurs over time and is characterized by the gradual accumulation of disability. The risk of developing MS is driven by complex interactions between genetic and environmental factors, including the gut microbiome. How the commensal gut microbiota impacts disease severity and progression over time remains unknown. Methods: In a longitudinal study, disability status and associated clinical features in 60 MS patients were tracked over 4.2 ± 0.97 years, and the baseline fecal gut microbiome was characterized via 16S amplicon sequencing. Progressor status, defined as patients with an increase in Expanded Disability Status Scale (EDSS), were correlated with features of the gut microbiome to determine candidate microbiota associated with risk of MS disease progression. Results: We found no overt differences in microbial community diversity and overall structure between MS patients exhibiting disease progression and non-progressors. However, a total of 45 bacterial species were associated with worsening disease, including a marked depletion in Akkermansia , Lachnospiraceae, and Oscillospiraceae , with an expansion of Alloprevotella , Prevotella-9 , and Rhodospirillales . Analysis of the metabolic potential of the inferred metagenome from taxa associated with progression revealed a significant enrichment in oxidative stress-inducing aerobic respiration at the expense of microbial vitamin K 2 production (linked to Akkermansia ), and a depletion in SCFA metabolism (linked to Lachnospiraceae and Oscillospiraceae ). Further, statistical modeling demonstrated that microbiota composition and clinical features were sufficient to robustly predict disease progression. Additionally, we found that constipation, a frequent gastrointestinal comorbidity among MS patients, exhibited a divergent microbial signature compared with progressor status. Conclusions: These results demonstrate the utility of the gut microbiome for predicting disease progression in MS. Further, analysis of the inferred metagenome revealed that oxidative stress, vitamin K 2 and SCFAs are associated with progression.

Where are the paediatric patients with testicular torsion during the COVID-19 pandemic?

INTRODUCTION: The Irish people were put on lockdown in mid-March 2020 due to concern of the spread of coronavirus. With these societal changes came a notable reduction in emergency department attendance. Our aim was to analyse emergency urological procedures performed during the COVID-19 era versus the previous year. METHODS: A retrospective review of theatre logbooks was undertaken comparing numbers of emergency urological procedures performed between 1 March 2020 and 31 May 2020 (i.e. the COVID-19 era) with the corresponding 3-month period in 2019. RESULTS: A total of 173 cases were analysed between the two time periods. Similar overall numbers of cases were performed in 2019 (n = 90) and 2020 (n = 83). In particular, similar patient case numbers are also noted in both scrotal explorations (13 vs 9) and ureteric stone surgeries (69 vs 70). However, orchidectomies for testicular cancers were reduced by 63% (3/8). On further analysis of the scrotal exploration group, only 3 were performed in the period after lockdown regulations were instated. CONCLUSION: Whilst patients with ureteric colic continue to present, those with acute testis pain requiring exploration attended less frequently, raising the possibility of undiagnosed testicular torsion in the community.

Implications of a diagnosis of atypical small acinar proliferation (ASAP) and high-grade prostatic intraepithelial neoplasia (HGPIN) on prostate biopsy: a 5-year follow-up study.

BACKGROUND: In the era of active surveillance of low- and intermediate-risk prostatic cancer, a reconsideration of the implications of a biopsy report of ASAP and/or HGPIN may be timely. AIMS: We investigated the implications of a diagnosis of atypical small acinar proliferation (ASAP) and high-grade prostatic intraepithelial neoplasia (HGPIN) on prostate biopsy. METHODS: The rate of re-biopsy and the incidence of carcinoma on repeat biopsy for benign, HGPIN, and ASAP groups were compared. Mean PSA and PSA velocity was also compared between groups. RESULTS: There was an increased risk of developing prostate cancer in the following 5 years with a biopsy diagnosis of ASAP compared to benign (20% vs 5.9%, p = 0.009), and with a biopsy of HGPIN compared with benign (14.8% vs 5.9%, p = 0.005). The frequency of repeat biopsy following a diagnosis of ASAP (54.2%) vs. HGPIN (37%) was not significantly different (p = 0.079). The risk of developing prostate cancer was highest following a biopsy with concomitant ASAP and HGPIN compared to benign (50% vs 5.9%, p < 0.001). There was no significant difference in PSA values between the 3 diagnostic groups at the time of initial biopsy (p = 0.206). CONCLUSION: The findings of this study suggest that a biopsy diagnosis of ASAP ± HGPIN, on either initial or surveillance biopsy, provides support for earlier repeat mpMRI and/or re-biopsy. This may assist in directing to early re-biopsy those patients likely to have intermediate- and high-risk prostate cancer.

Assessment of the workload and financial burden of Bosniak IIF renal cyst surveillance in a tertiary referral hospital.

BACKGROUND: The Bosniak classification is a CT classification which stratifies renal cysts based on imaging appearances and therefore associated risk of malignancy. Bosniak IIf cysts are renal which have complex features and therefore require surveillance. AIMS: The aim of this study is to assess the economic and workload burden of diagnosing and following up Bosniak IIf cysts on the urology service in a tertiary hospital in the West of Ireland. METHODS: All patients with a diagnosis of Bosniak IIf renal cysts attending our urology service between 1st of January 2012 and 31st December 2020 were analysed. The following data were collected: number and modality of follow up scans, number of MDT discussions, number and type of outpatient appointments, surgical intervention, and length of follow up. Financial data were provided by the hospital finance department. RESULTS: One hundred and sixty-two patients were included. Total cost of follow up was €164,056, costing €1,012.7 per patient. Cost of outpatient visits was €77,850. Follow-up length ranged from 1 to 109 months, median follow up time 17.5 months. Overall cost of imaging was €74,518. There were a total of 80 MDT discussions at an overall cost of €11,688. CONCLUSIONS: This study demonstrates that surveillance of patients with Bosniak IIf renal cysts represents a significant burden upon both radiology and urology services. Surveillance for these patients could be streamlined in the future through a number of initiatives such as virtual OPDs and dedicated MDTs.

Characterisation and manipulation of docetaxel resistant prostate cancer cell lines.

BACKGROUND: There is no effective treatment strategy for advanced castration-resistant prostate cancer. Although Docetaxel (Taxotere®) represents the most active chemotherapeutic agent it only gives a modest survival advantage with most patients eventually progressing because of inherent or acquired drug resistance. The aims of this study were to further investigate the mechanisms of resistance to Docetaxel. Three Docetaxel resistant sub-lines were generated and confirmed to be resistant to the apoptotic and anti-proliferative effects of increasing concentrations of Docetaxel. RESULTS: The resistant DU-145 R and 22RV1 R had expression of P-glycoprotein and its inhibition with Elacridar partially and totally reversed the resistant phenotype in the two cell lines respectively, which was not seen in the PC-3 resistant sublines. Resistance was also not mediated in the PC-3 cells by cellular senescence or autophagy but multiple changes in pro- and anti-apoptotic genes and proteins were demonstrated. Even though there were lower basal levels of NF-κB activity in the PC-3 D12 cells compared to the Parental PC-3, docetaxel induced higher NF-κB activity and IκB phosphorylation at 3 and 6 hours with only minor changes in the DU-145 cells. Inhibition of NF-κB with the BAY 11-7082 inhibitor reversed the resistance to Docetaxel. CONCLUSION: This study confirms that multiple mechanisms contribute to Docetaxel resistance and the central transcription factor NF-κB plays an immensely important role in determining docetaxel-resistance which may represent an appropriate therapeutic target.