ESFFU: Urodynamics for male lower urinary tract symptoms

Prof. Marcus Drake Bristol Randomised Trial Centre University of Bristol (GB)

Marcus.Drake@ bristol.ac.uk

Dr. Amanda Lewis Bristol Randomised Trial Centre University of Bristol (GB)

amanda.lewis@ bristol.ac.uk

For men who remain bothered by voiding symptoms despite initial treatment, surgery to relieve bladder outlet obstruction (BOO) is commonly considered. Urodynamics (UDS) aims to decide whether an individual would realistically benefit from such surgery, by diagnosing BOO formally, and looking for risk factors for bad outcome. For example, detrusor underactivity during voiding (DUA) may mean that symptoms will not improve even if BOO is treated. Alternatively, detrusor overactivity (DO) during storage might cause subsequent problems such as incontinence.

Value of urodynamics Until recently, it was not clear whether urodynamics truly made a difference to outcomes beyond influencing clinical decision making1. Hence there was a split of opinions among urologists2. Some supported routine use of urodynamics, feeling that surgery to relieve BOO risks bringing more harm than benefit if BOO is not present. In contrast, supporters of selective use of urodynamics point to the lack of evidence, and the costs of providing the service. There was also a presumption about what the patients wanted, with an assumption that undergoing the test would not be popular.

UPSTREAM UPSTREAM (Urodynamics for Prostate Surgery: Randomised Evaluation of Assessment Methods) is a randomised controlled trial (ISRCTN56164274) in men with bothersome lower urinary tract symptoms (LUTS), in whom surgery was an option3 . Participants were randomised to either routine care (RC) diagnostic tests including uroflowmetry, symptom score and bladder diary or RC plus urodynamics (UDS). 820 men were randomised in 26 hospitals in England. The primary outcome was the International Prostate Symptom Score (IPSS) 18 months after randomisation. The UDS arm demonstrated noninferiority relative to RC, with a difference in the mean IPSS of 0.33. Overall IPSS fell from 19 to 13 in both arms. The median BOO index for the UDS arm was 48 and DO was seen in around half of the men4 .

“…UDS did not actually reduce surgery rates”

Effect on surgery rate The study looked to see whether UDS reduced the surgery rates, arguing that DUA could be identified with this additional test, and that this would mean the men would not undergo surgery to relieve BOO. 38% (153/408) in the UDS arm received surgery during the 18-month-period, compared with 36% (138/384) in the routine care arm. Hence it was clear that UDS did not actually reduce surgery rates.

Conclusion The basic conclusion of the USPTREAM study is that UDS was non-inferior to RC for the IPSS but did not reduce surgical rates in this population. Hence, routine use of UDS in the evaluation of uncomplicated LUTS has a limited role and should be used selectively3 . It is vital, however, that urologists understand some key points: • Any indication of neurological disease or a condition that increases the prevalence of DUA (such as diabetes mellitus) makes UDS an important test; • Individual choice by the patient may justify the use of UDS; • Some men suffered a deterioration in symptoms as a result of surgery. The UPSTREAM team is evaluating this further to derive predictors of outcome, and that work will yield the individual patient clinical indications for UDS; • It is essential to consider what type of LUTS the man is experiencing. To have a good chance of benefit from surgery, voiding LUTS must be present, and they should also be causing a substantial degree of bother. If storage LUTS are the principal cause of bad quality of life, outcome of BOO surgery is not good.

ICIQ-MLUTS Alongside the IPSS, the study used the International Consultation on Incontinence Questionnaire (ICIQ). The additional information that this brings compared with only IPSS turned out to be very influential for understanding the quality of life impact of LUTS5. In particular, ICIQ-MLUTS measures the presence of dribble and incontinence, which are absent from the IPSS. Furthermore, it reports the bother associated with each individual symptom. Overall, this symptom score provided a quick and efficient way to capture which symptoms are present and bothersome. It is thus more valuable than IPSS in prioritising the therapy for an individual patient.

Quality of testing The study was careful to ensure proper quality of testing, joining the UNBLOCS study6 in reviewing standards of flow rate testing and urodynamics for a proportion of tests during the set-up phase of the studies7. We identified wrongly-diagnosed BOO in 6%, which has to be considered a serious error since it could lead to unnecessary surgery being done. We also found that 28% of urodynamic centres did not record calibration checks and equipment servicing, meaning that the equipment may not measure accurately. Furthermore, centres sometimes failed to identify a potential recording problem at the crucial moment of maximum flow rate. This is crucial, since the tracing has to be scrutinised to make sure the correct data is used when diagnosing BOO [see Fig. 1]. Hence, centres were at risk of making an error of diagnosis, and again this could place the patient at risk of inappropriate surgery.

Additional study results Extensive qualitative research was undertaken, and this established that Urodynamics is acceptable to men with LUTS and generally well tolerated8, in contrast to the clinicians’ generally held assumptions. We found evidence of clinicians and patients negotiating treatment decisions between them and of patients disagreeing with clinicians’ recommendations9. We also identified that consultations were sometimes rushed, with incomplete discussions of test results and treatment options, as well as misperceptions about LUTS and its treatment. Hence there is some need for units to evaluate the service delivery in this area, which is a crucial component of any urology service.

It is increasingly clear that men prefer conservative and less risky treatment options, but the preference varies depending on baseline symptom severity and the risk/benefit characteristics of the treatment. Men prefer reducing the risk of surgery1, and hence the role of UDS in potentially achieving this is valuable for individual patients. However, UPSTREAM found that UDS does not reduce surgery rates overall, and hence it should not be routine practice in otherwise healthy men with voiding LUTS. Over the next few years, the study will continue to report features to optimise the diagnostic pathway for LUTS in men.

Acknowledgement This project was funded by the UK National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme (project number 12/140/01). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. This study was designed and delivered in collaboration with the BRTC, a UKCRC Registered Clinical Trials Unit (CTU), which, as part of the Bristol Trials Centre (BTC), is in receipt of NIHR CTU support funding. The UPSTREAM trial was sponsored by North Bristol NHS Trust (NBT), Bristol, UK. Study data were collected and managed using REDCap (Research Electronic Data Capture, Harris PA, et al. J Biomed Inform. 2009 Apr;42(2):377-81) hosted at the University of Bristol.

Fig. 1: A spike is present on the flow trace (red arrow). The machine interpreted this as being the patient’s maximum flow rate, and so erroneously derived the bladder outlet obstruction index from here. In fact, such spikes are not generated by bladder contraction, and the patient’s actual function is best indicated by the peak of the phasic flow curve (purple arrow). This is the point where the index should have been calculated. References

1. Clement KD, Burden H, Warren K, Lapitan MCM, Omar

MI, Drake MJ. Invasive urodynamic studies for the management of lower urinary tract symptoms (LUTS) in men with voiding dysfunction. Cochrane Database of

Systematic Reviews: John Wiley & Sons, Ltd; 2015. 2. Drake MJ, Lewis AL, Lane JA. Urodynamic Testing for Men with Voiding Symptoms Considering Interventional

Therapy: The Merits of a Properly Constructed

Randomised Trial. Eur Urol. 2016;69(5):759-60. 3. Drake MJ, Lewis AL, Young GJ, Abrams P, Blair PS,

Chapple C, et al. Diagnostic Assessment of Lower Urinary

Tract Symptoms in Men Considering Prostate Surgery: A

Noninferiority Randomised Controlled Trial of

Urodynamics in 26 Hospitals. Eur Urol. 2020;78(5):701-10. 4. Lewis AL, Young GJ, Abrams P, Blair PS, Chapple C,

Glazener CMA, et al. Clinical and Patient-reported

Outcome Measures in Men Referred for Consideration of

Surgery to Treat Lower Urinary Tract Symptoms: Baseline

Results and Diagnostic Findings of the Urodynamics for

Prostate Surgery Trial; Randomised Evaluation of

Assessment Methods (UPSTREAM). Eur Urol Focus. 2019;5(3):340-50. 5. Ito H, Young G, Lewis A, Blair PS, Cotterill N, Lane A, et al. Grading severity and bother using the IPSS and

ICIQ-MLUTS scores in men seeking lower urinary tract symptoms therapy. Journal of Urology. 2020. 6. Hashim H, Worthington J, Abrams P, Young G, Taylor H,

Noble SM, et al. Thulium laser transurethral vaporesection of the prostate versus transurethral resection of the prostate for men with lower urinary tract symptoms or urinary retention (UNBLOCS): a randomised controlled trial. Lancet. 2020;396(10243):50-61. 7. Aiello M, Jelski J, Lewis A, Worthington J, McDonald C,

Abrams P, et al. Quality control of uroflowmetry and urodynamic data from two large multicenter studies of male lower urinary tract symptoms. Neurourol Urodyn. 2020;39(4):1170-7. 8. Selman LE, Ochieng CA, Lewis AL, Drake MJ, Horwood J.

Recommendations for conducting invasive urodynamics for men with lower urinary tract symptoms: Qualitative interview findings from a large randomized controlled trial (UPSTREAM). Neurourol Urodyn. 2019;38(1):320-9. 9. Selman LE, Clement C, Ochieng CA, Lewis AL, Chapple C,

Abrams P, et al. Treatment decision-making among men with lower urinary tract symptoms: A qualitative study of men's experiences with recommendations for patient-centred practice. Neurourol Urodyn. 2021;40(1):201-10. 10. Malde S, Umbach R, Wheeler JR, Lytvyn L, Cornu JN,

Gacci M, et al. A Systematic Review of Patients' Values,

Preferences, and Expectations for the Diagnosis and

Treatment of Male Lower Urinary Tract Symptoms. Eur

Urol. 2021.

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Prof. Rodolfo Montironi ESUP Chairman Section of Pathological Anatomy School of Medicine Ancona (IT)

r.montironi@ staff.univpm.it

Dr. Alessia Cimadamore ESUP Board Member Section of Pathological Anatomy School of Medicine Ancona (IT)

a.cimadamore@ staff.univpm.it

Prof. Marina Scarpelli Section of Pathological Anatomy School of Medicine Ancona (IT)

m.scarpelli@ univpm.it

In this period of COVID-19 pandemic, uropathologists, and pathologists in general, are reconsidering the approach in examining glass slides with conventional light microscopy (CLM). There are constrains linked to the issues uropathologists are facing, including the need of physical distance with laboratory professionals and colleagues and loss of social interaction.

After the pandemic The question is what uropathology will be like after the resolution of this pandemic. Since medical practices, including pathology, are moving towards an era of global digitalisation, the uropathology practice might not return to what CLM routine was before the pandemic. In particular, uropathologists are becoming more and more enthusiastic about the adoption and application of digital microscopy (DM).

DM originated approximately 40 years ago1. Dr. Peter H. Bartels (US) contributed to the development of DM. Together with others, he developed its theoretical background as well as applications. The recording and merging processes were extended over a large area, using a so-called multi-megapixel array. It corresponds to what we call virtual slide. This included case based reasoning and machine vision, i.e. the current bases of the artificial intelligence (AI)2 . Bartels’ fields of interest focused on digitalisation in uropathology. One of his studies included the cribriformity index of prostate cancer (PCa). This might have appeared of little clinical significance. Nowadays, PCa with a cribriform architecture is considered as the most aggressive form of Gleason pattern 43 .

Virtual slides A glass slide scanner, a computer with webcam, a TV monitor, an internet connection are pieces of equipment we use to reach in real time the goals of sharing images for consultation, teaching, and communication with clinicians, patients and students. Modern equipment can scan whole mount sections (see Figure 1)4. Virtual slides are shared among us or sent over the internet to other colleagues. The procedure is quite fast and simple, considering that the size of a virtual whole mount section is in the range of gigabits.

The goals can also be met through ‘smart working from home’1. Virtual slides are exchanged via a home internet connection and, in real time, shown on a TV home screen, linked to a PC. The examining uropathologist does not feel isolated because he/she, when analysing the slide(s), can simultaneously communicate with others by using one of the platforms available. Such communication and interaction include voice and image of a colleague and/or student, shown, at the same time as the virtual slide, in a window in a corner of the TV. Implementation of AI-based algorithms The use of DM will allow the routine implementation of artificial AI-based algorithms5-12. Algorithms are based on DM as “learn and input associations and links between items such as a diagnosis made by a uropathologist, underlying molecular features and patients’ survival or response to adjuvant/neoadjuvant therapy”7. Such algorithms have the capability of going beyond the visual evaluation of morphological patterns in order to identify tissue features not perceived by human recognition. Nagpal et al13 adopted “a supervised learning method to develop a deep learning system for PCa grading” on radical prostatectomy specimens. Accuracy was assessed for the assignment of PCa grade groups by generalists, in comparison to specialists.

The process of merging data from multiple sources, including DM, diagnostic imaging13 and robotic surgery, “is defined as multi-criteria decision making and information fusion”4,14. The resulting information, including the diagnostic, prognostic and therapeutic decisions when applied to men with PCa examined with whole slide imaging, and with biomarkers deriving from tissue, urine and blood samples, is far more accurate than when the various sources are considered separately”. All this requires the utilisation of AI. Distant teaching using DM will also grow into a mainstream mode of pathology teaching, something that is reinforced by COVID-19.

Slide 1: Virtual slide of a whole mount section of the prostate (Size: 1.42 GB). The cancer area was dotted on the surface of the glass slide before digitalisation. The user can navigate and change magnification in order to define the lesion and its nature. Prof. Liang Cheng Dept. of Pathology and Laboratory Medicine Indiana University School of Medicine Indianapolis (US)

lcheng@iupui.edu

Prof. Antonio LopezBeltran ESUP Honorary member Dept. of Surgery Cordoba University Medical School Cordoba (ES)

em1lobea@gmail.com

2019;475(1):77–83. 9. Bera K, Schalper KA, Rimm DL, Velcheti V, Madabhushi A.

Artificial intelligence in digital pathology - new tools for diagnosis and precision oncology. Nat Rev Clin Oncol. 2019;16(11):703-715. 10. Bulten W, Balkenhol M, Belinga JA, et al. Artificial intelligence assistance significantly improves Gleason

grading of prostate biopsies by pathologists. Mod Pathol. 2021;34(3):660-671 11. Goldenberg SL, Nir G, Salcudean SE. A new era: artificial intelligence and machine learning in prostate cancer. Nat

Rev Urol. 2019;16(7):391-403. 12. Montironi R, Cheng L, Lopez-Beltran A, et al. Decision support systems for morphology-based diagnosis and prognosis of prostate neoplasms: a methodological approach. Cancer. 2009 Jul 1;115(13 Suppl):3068-77. 13. Nagpal K, Foote D, Tan F, Liu Y,et al. Development and

Validation of a Deep Learning Algorithm for Gleason

Grading of Prostate Cancer From Biopsy Specimens. JAMA

Oncol. 2020;6(9):1372-1380. 14. Antonelli M, Johnston EW, Dikaios N, et al. Machine learning classifiers can predict Gleason pattern 4 prostate cancer with greater accuracy than experienced radiologists. Eur Radiol. 2019;29(9):4754-4764. 15. Montironi MA. From image analysis in pathology to robotics and artificial intelligence. Anal Quant Cytopathol

Histol. 2016;38, 268–269

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References

1. Cimadamore A, Lopez-Beltran A, Scarpelli M, Cheng L,

Montironi R. Digital pathology and COVID-19 and future crises: pathologists can safely diagnose cases from home using a consumer monitor and a mini PC. J Clin Pathol. 2020;73(11):695-696 2. Montironi R, Cimadamore A, Lopez-Beltran A, Cheng L,

Scarpelli. Exciting experiences in the 'Rocky road to digital diagnostics'. J Clin Pathol. 2021;74(1):5-6 3. Montironi R, Cimadamore A, Scarpelli M, Cheng L,

Lopez-Beltran A, Mikuz G. Pathology without microscope:

From a projection screen to a virtual slide. Pathol Res

Pract. 2020;216(11):153196. doi: 10.1016/j.prp.2020.153196. 4. Montironi R, Cimadamore A, Massari F, et al. Whole Slide

Imaging of Large Format Histology in Prostate Pathology:

Potential for Information Fusion. Arch Pathol Lab Med. 2017;141:1460-1461 5. Rakha EA, Toss M, Shiino S, et al. Current and future applications of artificial intelligence in pathology: A clinical perspective. J Clin Pathol. 2020;jclinpath-2020-206908 6. Moradi M, Salcudean SE, Chang SD, et al. Multiparametric

MRI maps for detection and grading of dominant prostate tumors. J Magn Reson Imaging. 2012;35(6):1403–13. 7. Janowczyk A, Madabhushi A. Deep learning for digital pathology image analysis: A comprehensive tutorial with selected use cases. J Pathol Inform. 2016;7(1). 8. Lucas M, Jansen I, Savci-Heijink CD, et al. Deep learning for automatic Gleason pattern classification for grade group determination of prostate biopsies. Virchows Arch.