Archive for category: Article of the Week

You are here: / Article of the Week

Residents’ podcast: Vaccines for preventing recurrent UTIs

/by


Maria Uloko is a Urology Resident at the University of Minnesota Hospital. In this podcast she discusses the following BJUI Article of the Week:

Vaccines for the prevention of recurrent urinary tract infections: a systematic review

 

Read the full article

Abstract

Objectives

To systematically review the evidence regarding the efficacy of vaccines or immunostimulants in reducing the recurrence rate of urinary tract infections (UTIs).

Materials and Methods

The Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica dataBASE (EMBASE), PubMed, Cochrane Library, World Health Organization (WHO) International Clinical Trials Registry Platform Search Portal, and conference abstracts were searched up to January 2018 for English‐titled citations. Randomised placebo‐controlled trials evaluating UTI recurrence rates in adult patients with recurrent UTIs treated with a vaccine were selected by two independent reviewers according to the Population, Interventions, Comparators, and Outcomes (PICO) criteria. Differences in recurrence rates in study populations for individual trials were calculated and pooled, and risk ratios (RRs) using random effects models were calculated. Risk of bias was assessed using the Cochrane Collaboration’s tool and heterogeneity was assessed using chi‐squared and I2 testing. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to evaluate the quality of evidence (QOE) and summarise findings.

Results

In all, 599 records were identified, of which 10 studies were included. A total of 1537 patients were recruited and analysed, on whom data were presented. Three candidate vaccines were studied: Uro‐Vaxom® (OM Pharma, Myerlin, Switzerland), Urovac® (Solco Basel Ltd, Basel, Switzerland), and ExPEC4V (GlycoVaxyn AG, Schlieren, Switzerland). At trial endpoint, the use of vaccines appeared to reduce UTI recurrence compared to placebo (RR 0.74, 95% confidence interval [CI] 0.67–0.81; low QOE). Uro‐Vaxom showed the greatest reduction in UTI recurrence rate; the maximal effect was seen at 3 months compared with 6 months after initial treatment (RR 0.67, 95% CI 0.57–0.78; and RR 0.78, 95% CI 0.69–0.88, respectively; low QOE). Urovac may also reduce risk of UTI recurrence (RR 0.75, 95% CI 0.63–0.89; low QOE). ExPEC4V does not appear to reduce UTI recurrence compared to placebo at study endpoint (RR 0.82, 95% CI 0.62–1.10; low QOE). Substantial heterogeneity was observed across the included studies (chi‐squared = 54.58; P < 0.001, I2 = 84%).

Conclusions

While there is evidence for the efficacy of vaccines in patients with recurrent UTIs, significant heterogeneity amongst these studies renders interpretation and recommendation for routine clinical use difficult at present. Further randomised trials using consistent definitions and endpoints are needed to study the long‐term efficacy and safety of vaccines for infection prevention in patients with recurrent UTIs.

Read more Articles of the week

 

BJUI Podcasts now available on iTunes, subscribe here https://itunes.apple.com/gb/podcast/bju-international/id1309570262

 

Article of the week: The impact on oncological outcomes after RP for PCa of converting soft tissue margins at the apex and bladder neck from tumour‐positive to ‐negative

/by

Every week, the Editor-in-Chief selects an Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an editorial written by a prominent member of the urological community and the authors have also kindly produced a video describing their work. These are intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation. 

If you only have time to read one article this week, it should be this one.

The impact on oncological outcomes after radical prostatectomy for prostate cancer of converting soft tissue margins at the apex and bladder neck from tumour‐positive to ‐negative

Sahyun Pak*, Sejun Park†, Myong Kim*, Heounjeong Go‡, Yong Mee Cho‡ and Hanjong Ahn*

 

*Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, †Department of Urology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan and ‡Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

 

Read the full article

Abstract

Objectives

To assess the impact of conversion from histologically positive to negative soft tissue margins at the apex and bladder neck on biochemical recurrence‐free survival (BCRFS) and distant metastasis‐free survival (DMFS) after radical prostatectomy (RP) for prostate cancer.

Materials and Methods

The records of 2 013 patients who underwent RP and intra‐operative frozen section (IFS) analysis between July 2007 and June 2016 were reviewed. IFS analysis of the urethra and bladder neck was performed, and if malignant or atypical cells remained, further resection with the aim of achieving histological negativity was carried out. Patients were divided into three groups according to the findings: those with a negative surgical margin (NSM), a positive surgical margin converted to negative (NCSM) and a persistent positive surgical margin (PSM).

Table 4. Impact of converting margins from tumour‐positive to ‐negative on biochemical recurrence

Results

Among the 2 013 patients, rates of NSMs, NCSMs and PSMs were 75.1%, 4.9%, and 20.0%, respectively. The 5‐year BCRFS rates of patients with NSMs, NCSMs and PSMs were 89.6%, 85.1% and 57.1%, respectively (P < 0.001). In both pathological (p)T2 and pT3 cancers, the 5‐year BCRFS rate for patients with NCSMs was similar to that for patients with NSMs, and higher than for patients with PSMs. The 7‐year DMFS rates of patients with NSMs, NCSMs and PSMs were 97.8%, 99.1% and 89.4%, respectively (P < 0.001). Among patients with pT3 cancers, the 7‐year DMFS rate was significantly higher in the NCSM group than in the PSM group (98.0% vs 86.7%; P = 0.023), but not among those with pT2 cancers (100% vs 96.9%; P = 0.616). The 5‐year BCRFS rate for the NCSM group was not significantly different from that of the NSM group among the patients with low‐ (96.3% vs 95.8%) and intermediate‐risk disease (91.1% vs 82.8%), but was lower than that of the NSM group among patients in the high‐risk group (73.2% vs 54.7%).

Conclusions

Conversion of the soft tissue margin at the prostate apex and bladder neck from histologically positive to negative improved the BCRFS and DMFS after RP for prostate cancer; however, the benefit of conversion was not apparent in patients in the high‐risk group.

Read more Articles of the week

 

Editorial: Conversion to negative surgical margin after intraoperative frozen section – (un)necessary effort and relevance in 2019?

/by

The assessment and impact of positive surgical margins (PSMs) at the time of radical prostatectomy (RP) have been discussed for many decades. The determination and reporting should be performed in a standardised fashion according to the International Society of Urological Pathology [1]. The SM is considered positive if tumour cells touch the inked surface of the RP specimen. However, reasons for difficulty in truly differentiating between negative SMs (NSMs) and PSMs include iatrogenic disruption of the prostatic capsule, penetration of ink into small cracks on the outside, or cases in which prostate cancer cells are very close to, but not definitely touching, the inked margins.

A systematic review by Yossepowitch et al. [2] found a contemporary PSM rate of 15% (range 6.5–32%), which increases with extracapsular extension. In addition, the likelihood of PSM is strongly influenced by surgeon experience, independent of the surgical technique. Although PSM is considered an adverse pathological outcome and associated with an increased risk of biochemical recurrence (BCR), the impact on long‐term survival and actual prognostic value remains debatable. The association with other endpoints, such as prostate‐cancer specific mortality and overall survival, is controversial and may be primarily influenced by other risk factors, such as preoperative PSA level, Gleason score, and pathological T‐stage [2].

The role of intraoperative frozen section analysis in order to reduce the PSM rate continues to evolve. In a study by von Bodman et al. [3], 92.3% of patients with a PSM on frozen‐section analysis could ultimately be converted to a NSM. Similar findings were reported by Schlomm et al. [4] in 5392 patients using the intraoperative neurovascular structure‐adjacent frozen section examination (NeuroSAFE) technique, PSMs were detected in 25%, leading to re‐resection and conversion to definitive NSMs in 86% of these patients. In the setting of increasing experience with intraoperative frozen section analysis, a false‐positive SM status was found in only 48 patients (3.3%).

The study by Pak et al. [5], published in this issue of the BJUI, reported that specimens with initial PSMs were converted to NSMs upon permanent specimen evaluation (NCSM) in 4.9% of 2013 men undergoing RP. In this subgroup, the 5‐year BCR‐free survival (BCRFS) rates did not differ from those observed in National Comprehensive Cancer Network (NCCN) low‐ and intermediate‐risk patients with an initially NSM. However, the benefit of conversion from an initial PSM to final NSM was not apparent in high‐risk patients, as the authors found a significantly lower rate of BCRFS amongst this NCSM group. In multivariate analysis, NCSM status was independently associated (hazard ratio 0.624, P = 0.033) with BCR but not distant metastasis. These findings corroborate the findings of the Schlomm et al. [4] study, in which the BCRFS rates of propensity score‐based matched patients with conversion to NSMs did not differ significantly from patients with primarily NSMs.

What is the current role of intraoperative frozen section analysis during RP? How important is it to achieve NSMs in contemporary practice? In whom and how should the assessment be performed? Although it is clearly desirable to completely remove the entire tumour at the time of surgery, and NSMs are a surrogate marker of adequate local excision, the devil is in the details. First, in this study [5], the authors only assessed SMs at the bladder neck and apex. Although the apex is one of the most frequent locations for PSMs, other and/or multiple sites of PSMs are possible and could have been missed. Alternatively, the NeuroSAFE method is able to assess the entire laterorectal circumference albeit with the trade‐off of more extensive pathological involvement and assessment. Second, intraoperative frozen section analysis, and manoeuvers for NCSM, may ultimately be necessary and beneficial in only a small number of patients currently undergoing RP. An increasing proportion of men harbour more aggressive, higher‐risk disease in whom PSMs may have no impact on oncological outcomes or treatment decisions. In these men, long‐term cancer outcomes are probably more related to risks of unsuspected metastatic disease rather than residual, microscopic cancer within the prostatic fossa. As suggested in this study [5], an initial PSM in high‐risk men, independent of ultimate NCSM, may be a surrogate for non‐localised disease and poorer outcomes; PSMs were found in 53% of men with pT3b. In low‐risk men, the issues are whether active surveillance is a more appropriate initial management strategy and that routine intraoperative frozen section analysis may not be worthwhile with a PSM rate of only 10%. How does this alter the decision for adjuvant therapy? Adjuvant radiotherapy is probably under‐utilised in men with PSMs after RP (~11%), and NCSM may spare men from unnecessary treatment, particularly with lower‐risk disease [6]. However, men with PSMs and additional adverse pathological features, such as extraprostatic extension or seminal vesicle invasion, should probably receive adjuvant therapy, primarily driven by T stage.

The incremental value and potential clinical benefit of intraoperative frozen section analysis to achieve NSMs remain to be determined. Although one would suspect that PSM leading to excision of additional tissue could lead to worse functional outcomes, the study from Mirmilstein et al. [7] is reassuring. Despite higher Gleason score and pT stage in those undergoing the NeuroSAFE approach, the PSM rate was lower in this group (9.2%) compared with those undergoing standard intraoperative nerve‐sparing while leading to greater bilateral nerve preservation, higher potency rates at 12 months, and pad‐free continence.

In the future, other methods may guide surgical decision‐making and may eventually alter PSM rate including preoperative MRI of the prostate to evaluate extracapsular extension, genomic risk scores, or real‐time, near‐infrared fluorescent surgical guidance with prostate‐specific membrane antigen ligands [8]. However, one should not forget that outcomes are not solely based on the SM status. Various pathological and clinical factors and patients’ comorbidities and preference should be taken into consideration in the surgical management and that evaluation of validated oncological and functional outcomes is critical.

by Annika Herlemann and Maxwell Meng

References

  1. Tan, PH, Cheng, L, Srigley, JR et al. International Society of Urological Pathology (ISUP) Consensus Conference on Handling and Staging of Radical Prostatectomy Specimens. Working group 5: surgical margins. Mod Pathol 2011; 24: 48– 57
  2. Yossepowitch, O, Briganti, A, Eastham, JA et al. Positive surgical margins after radical prostatectomy: a systematic review and contemporary update. Eur Urol 2014; 65: 303– 13
  3. Bodman, C, Brock, M, Roghmann, F et al. Intraoperative frozen section of the prostate decreases positive margin rate while ensuring nerve sparing procedure during radical prostatectomy. J Urol 2013; 190: 515– 20
  4. Schlomm, T, Tennstedt, P, Huxhold, C et al. Neurovascular structure‐adjacent frozen‐section examination (NeuroSAFE) increases nerve‐sparing frequency and reduces positive surgical margins in open and robot‐assisted laparoscopic radical prostatectomy: experience after 11,069 consecutive patients. Eur Urol 2012; 62: 333– 40
  5. Pak, S, Park, S, Kim, M, Go, H, Cho, YM, Ahn, H. The impact on oncological outcomes after radical prostatectomy for prostate cancer of converting soft tissue margins at the apex and bladder neck from tumour‐positive to ‐negative. BJU Int 2019; 123: 811– 7
  6. Ghabili, K, Nguyen, K, Hsiang, W et al. National trends in the management of patients with positive surgical margins at the time of radical prostatectomy. J Clin Oncol 2018; 36 (Suppl.): 111
  7. Mirmilstein, G, Rai, BP, Gbolahan, O et al. The neurovascular structure‐adjacent frozen‐section examination (NeuroSAFE) approach to nerve sparing in robot‐assisted laparoscopic radical prostatectomy in a British setting – a prospective observational comparative study. BJU Int 2018;121: 854– 62
  8. Neuman, BP, Eifler, JB, Castanares, M et al. Real‐time, near‐infrared fluorescence imaging with an optimized dye/light source/camera combination for surgical guidance of prostate cancer. Clin Cancer Res 2015; 21: 771– 80

 

Video: The impact on oncological outcomes after RP for PCa of converting soft tissue margins at the apex and bladder neck from tumour‐positive to ‐negative

/by

The impact on oncological outcomes after radical prostatectomy for prostate cancer of converting soft tissue margins at the apex and bladder neck from tumour‐positive to ‐negative

Read the full article

Abstract

Objectives

To assess the impact of conversion from histologically positive to negative soft tissue margins at the apex and bladder neck on biochemical recurrence‐free survival (BCRFS) and distant metastasis‐free survival (DMFS) after radical prostatectomy (RP) for prostate cancer.

Materials and Methods

The records of 2 013 patients who underwent RP and intra‐operative frozen section (IFS) analysis between July 2007 and June 2016 were reviewed. IFS analysis of the urethra and bladder neck was performed, and if malignant or atypical cells remained, further resection with the aim of achieving histological negativity was carried out. Patients were divided into three groups according to the findings: those with a negative surgical margin (NSM), a positive surgical margin converted to negative (NCSM) and a persistent positive surgical margin (PSM).

Results

Among the 2 013 patients, rates of NSMs, NCSMs and PSMs were 75.1%, 4.9%, and 20.0%, respectively. The 5‐year BCRFS rates of patients with NSMs, NCSMs and PSMs were 89.6%, 85.1% and 57.1%, respectively (P < 0.001). In both pathological (p)T2 and pT3 cancers, the 5‐year BCRFS rate for patients with NCSMs was similar to that for patients with NSMs, and higher than for patients with PSMs. The 7‐year DMFS rates of patients with NSMs, NCSMs and PSMs were 97.8%, 99.1% and 89.4%, respectively (P < 0.001). Among patients with pT3 cancers, the 7‐year DMFS rate was significantly higher in the NCSM group than in the PSM group (98.0% vs 86.7%; P = 0.023), but not among those with pT2 cancers (100% vs 96.9%; P = 0.616). The 5‐year BCRFS rate for the NCSM group was not significantly different from that of the NSM group among the patients with low‐ (96.3% vs 95.8%) and intermediate‐risk disease (91.1% vs 82.8%), but was lower than that of the NSM group among patients in the high‐risk group (73.2% vs 54.7%).

Conclusions

Conversion of the soft tissue margin at the prostate apex and bladder neck from histologically positive to negative improved the BCRFS and DMFS after RP for prostate cancer; however, the benefit of conversion was not apparent in patients in the high‐risk group.

 

View more videos

Article of the week: Vaccines for the prevention of recurrent urinary tract infections: a systematic review

/by

Every week, the Editor-in-Chief selects an Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an editorial written by a prominent member of the urological community, a podcast, and the authors have also kindly produced a video describing their work. These are intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation. 

If you only have time to read one article this week, it should be this one.

Vaccines for the prevention of recurrent urinary tract infections: a systematic review

Nikoo Aziminia*, Marios Hadjipavlou*†, Yiannis Philippou‡, Shivkumar S. Pandian*, Sachin Malde† and Mohamed Y. Hammadeh*

 

*Department of Urology, Queen Elizabeth Hospital, †Urology Centre, Guy’s Hospital, London and ‡Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK

 

Read the full article

Abstract

Objectives

To systematically review the evidence regarding the efficacy of vaccines or immunostimulants in reducing the recurrence rate of urinary tract infections (UTIs).

Materials and Methods

The Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica dataBASE (EMBASE), PubMed, Cochrane Library, World Health Organization (WHO) International Clinical Trials Registry Platform Search Portal, and conference abstracts were searched up to January 2018 for English‐titled citations. Randomised placebo‐controlled trials evaluating UTI recurrence rates in adult patients with recurrent UTIs treated with a vaccine were selected by two independent reviewers according to the Population, Interventions, Comparators, and Outcomes (PICO) criteria. Differences in recurrence rates in study populations for individual trials were calculated and pooled, and risk ratios (RRs) using random effects models were calculated. Risk of bias was assessed using the Cochrane Collaboration’s tool and heterogeneity was assessed using chi‐squared and I2 testing. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to evaluate the quality of evidence (QOE) and summarise findings.

 

Results

In all, 599 records were identified, of which 10 studies were included. A total of 1537 patients were recruited and analysed, on whom data were presented. Three candidate vaccines were studied: Uro‐Vaxom® (OM Pharma, Myerlin, Switzerland), Urovac® (Solco Basel Ltd, Basel, Switzerland), and ExPEC4V (GlycoVaxyn AG, Schlieren, Switzerland). At trial endpoint, the use of vaccines appeared to reduce UTI recurrence compared to placebo (RR 0.74, 95% confidence interval [CI] 0.67–0.81; low QOE). Uro‐Vaxom showed the greatest reduction in UTI recurrence rate; the maximal effect was seen at 3 months compared with 6 months after initial treatment (RR 0.67, 95% CI 0.57–0.78; and RR 0.78, 95% CI 0.69–0.88, respectively; low QOE). Urovac may also reduce risk of UTI recurrence (RR 0.75, 95% CI 0.63–0.89; low QOE). ExPEC4V does not appear to reduce UTI recurrence compared to placebo at study endpoint (RR 0.82, 95% CI 0.62–1.10; low QOE). Substantial heterogeneity was observed across the included studies (chi‐squared = 54.58; P < 0.001, I2 = 84%).

Conclusions

While there is evidence for the efficacy of vaccines in patients with recurrent UTIs, significant heterogeneity amongst these studies renders interpretation and recommendation for routine clinical use difficult at present. Further randomised trials using consistent definitions and endpoints are needed to study the long‐term efficacy and safety of vaccines for infection prevention in patients with recurrent UTIs.

 

Read more Articles of the week

Editorial: Urinary tract infection vaccines – the ‘burning’ issue

/by

The current ‘hot topic’ in UTI is antibiotic‐free prevention. At the forefront of this is the development of new immunomodulating vaccines, which utilise the most common strains of uropathogens, both surface antigen or inactivated whole bacterium, to induce a host immune response to prevent recurrent infections. Vaccines currently with established randomised control trials (RCTs) are Uro‐Vaxom® (OM Pharma, Myerlin, Switzerland), Urovac® (Solco Basel Ltd, Basel, Switzerland) and ExPEC4V (GlycoVaxyn AG, Schlieren, Switzerland), which have recently been reviewed by Aziminia et al. [1].

Vaccines classically work by inducing a systemic adaptive host immune response by pre‐sensitisation to the bacterial surface antigen. As most uropathogens share similar antigenic structures, a broad spectrum response is possible against other pathogens and not limited solely to the bacteria within the vaccine itself.

UroVaxom® is an oral tablet composed of bacterial extracts from 18 strains of Escherichia coli given daily for 90 days. Its use has been reported in the literature since 1990 and was found in the systematic review to reduce UTI recurrence rates the most (risk ratio [RR] 0.67, 95% CI 0.57–0.78).

Urovac® is composed of 10 inactivated uropathogen strains including six E. coli strains and one Proteus mirabilis, Morganella morganii, Enterococcus faecalis and Klebsiella pneumoniae. It is delivered as a weekly vaginal suppository for three doses, followed by three booster doses at 6, 10 and 14 weeks. Urovac® has also been shown to effectively reduce UTI recurrence rates (RR 0.75, 95% CI 0.63–0.89).

ExPEC4V is composed of O‐antigens of four E. coli serotypes delivered as a single i.m. injection. Whilst effective in initial trials, to date there is only one RCT, which reported no reduction in UTI recurrence rates (RR 0.82, 95% CI 0.62–1.10).

Overall, Aziminia et al. [1] concluded that a firm conclusion about the efficacy of UTI vaccines could not be reached. The studies thus have in general been limited by many factors, including the definition of what constitutes a UTI, the heterogeneity of participants, and variable definitions of trial endpoints, making comparisons difficult [1]. More targeted research is therefore needed.

UTI is a major problem and is one of the most common infections worldwide, affecting disproportionately more women than men. In the UK, 40–50% of women experience at least one episode of UTI in their lifetime, of which 20–30% proceed to develop recurrent UTIs (as defined by three or more episodes of UTI within a 12‐month period) [2,3]. Yet despite its prevalence, mainstream preventative options rely heavily upon long‐term antibiotic usage, either as low‐dose prophylaxis or recurrent rescue courses.

However, the problem is the concurrent and rapid rise in global bacterial multidrug resistance, such that the WHO has declared antibiotic resistance as one of the biggest risks to public health in our lifetimes and created a Global Action Plan to combat this issue. There is, therefore, an urgent need to find antibiotic‐free alternatives.

More recently, site‐targeted immune response has been shown to be effective in delivering a UTI vaccine. In particular, the genitourinary tract harbours both an innate and adaptive mucosal immune system. Within this there is mucosa‐associated lymphoid tissue (MALT) through which immunocytes transit. This is part of a larger mammalian lymphoid organ system. Stimulation at one MALT site induces an activation and dissemination of immunity to other MALT sites. In particular the activation of the sublingual mucosa has been linked with a broad spectrum immune response in the genitourinary tract [4].

Uromune® (Q‐Pharma, Alicante, Spain) is a new sublingual vaccine targeting this pathway. Composed of inactivated E. coli, Klebsiella pneumoniae, Proteus vulgaris and Enterococcus faecalis, it has been shown in two large retrospective Spanish studies to decrease UTI recurrence by up to 90% when compared to antibiotic prophylaxis [5]. A prospective UK observational study found after 3 months of daily administration, 78% of women developed no further UTIs in the 12‐month follow‐up period [6]. To date, there is no RCT available on the efficacy of Uromune®, although one international multicentre phase III RCT is currently underway, due to report in 2019/2020.

In general, whilst initial trials on UTI vaccines show potential, further research is needed to bring UTI vaccinations into mainstream treatment. In particular, future trials need to have robust definitions of the following (which previous studies have often lacked):

  • Definition of UTI – presence of symptoms and bacteriuria, as opposed to asymptomatic bacteriuria, which is often self‐limiting; and
  • Defined eligibility criteria – previous studies included hugely variable populations that included patients with neurogenic bladders, males and females, patients with indwelling catheters, and even immunosuppressed patients.

Furthermore, whilst comparison against placebo is important, comparison against antibiotic prophylaxis, the current ‘gold standard’, is also vital in providing evidence of efficacy.

Finally, the longevity of the vaccines’s effects also needs to be determined, in particular whether and when a booster dose is required in order to maintain the immune memory.

Overall though the future is exciting on tackling this ‘burning issue’ of UTI prevention.

 

References

  1. Aziminia, N, Hadjipavlou, M, Philippou, Y, Pandian, SS, Malde, S, Hammadeh, MY. Vaccines for the prevention of recurrent urinary tract infections: a systematic review. BJU Int 2019; 123: 753– 68
  2. Foxman, B. Urinary tract infection syndromes: occurrence, recurrence, bacteriology, risk factors, and disease burden. Infect Dis Clin North Am 2014; 28: 1– 13
  3. Albert, X, Huertas, I, Pereiró, II, Sanfélix J, Gosalbes V, Perrota C. Antibiotics for preventing recurrent urinary tract infection in non‐pregnant women. Cochrane Database Syst Rev 2004; 3:CD001209
  4. Holmgren, J, Czerkinsky, C. Mucosal immunity and vaccines. Nat Med 2005; 11 ( Suppl.): S45– 53
  5. Yang, B, Foley, S, Toozs‐Hobson, P. Urinary tract infections: current and new preventative options. SM J Clin Med 2016; 2: 1018
  6. Yang, B, Foley, S. First experience in the UK of treating women with recurrent urinary tract infections with the bacterial vaccine Uromune®. BJU Int 2018; 121: 289– 92

 

Video: Vaccines for the prevention of recurrent urinary tract infections: a systematic review

/by

Vaccines for the prevention of recurrent urinary tract infections: a systematic review

Read the full article

Abstract

Objectives

To systematically review the evidence regarding the efficacy of vaccines or immunostimulants in reducing the recurrence rate of urinary tract infections (UTIs).

Materials and Methods

The Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica dataBASE (EMBASE), PubMed, Cochrane Library, World Health Organization (WHO) International Clinical Trials Registry Platform Search Portal, and conference abstracts were searched up to January 2018 for English‐titled citations. Randomised placebo‐controlled trials evaluating UTI recurrence rates in adult patients with recurrent UTIs treated with a vaccine were selected by two independent reviewers according to the Population, Interventions, Comparators, and Outcomes (PICO) criteria. Differences in recurrence rates in study populations for individual trials were calculated and pooled, and risk ratios (RRs) using random effects models were calculated. Risk of bias was assessed using the Cochrane Collaboration’s tool and heterogeneity was assessed using chi‐squared and I2 testing. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to evaluate the quality of evidence (QOE) and summarise findings.

Results

In all, 599 records were identified, of which 10 studies were included. A total of 1537 patients were recruited and analysed, on whom data were presented. Three candidate vaccines were studied: Uro‐Vaxom® (OM Pharma, Myerlin, Switzerland), Urovac® (Solco Basel Ltd, Basel, Switzerland), and ExPEC4V (GlycoVaxyn AG, Schlieren, Switzerland). At trial endpoint, the use of vaccines appeared to reduce UTI recurrence compared to placebo (RR 0.74, 95% confidence interval [CI] 0.67–0.81; low QOE). Uro‐Vaxom showed the greatest reduction in UTI recurrence rate; the maximal effect was seen at 3 months compared with 6 months after initial treatment (RR 0.67, 95% CI 0.57–0.78; and RR 0.78, 95% CI 0.69–0.88, respectively; low QOE). Urovac may also reduce risk of UTI recurrence (RR 0.75, 95% CI 0.63–0.89; low QOE). ExPEC4V does not appear to reduce UTI recurrence compared to placebo at study endpoint (RR 0.82, 95% CI 0.62–1.10; low QOE). Substantial heterogeneity was observed across the included studies (chi‐squared = 54.58; P < 0.001, I2 = 84%).

Conclusions

While there is evidence for the efficacy of vaccines in patients with recurrent UTIs, significant heterogeneity amongst these studies renders interpretation and recommendation for routine clinical use difficult at present. Further randomised trials using consistent definitions and endpoints are needed to study the long‐term efficacy and safety of vaccines for infection prevention in patients with recurrent UTIs.

View more videos

Article of the month: Evaluation of axitinib to downstage cT2a renal tumours and allow partial nephrectomy: a phase II study

/by

Every month, the Editor-in-Chief selects an Article of the Month from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an editorial written by a prominent member of the urological community and the authors have also kindly produced a video describing their work. These are intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation. 

If you only have time to read one article this week, it should be this one.

Evaluation of axitinib to downstage cT2a renal tumours and allow partial nephrectomy: a phase II study

Cedric Lebacle* , Karim Bensalah†, Jean-Christophe Bernhard‡§, Laurence Albiges, Brigitte Laguerre**, Marine Gross-Goupil††, Herve Baumert‡‡, Herve Lang§§, Thibault Tricard§§, Brigitte Duclos¶¶, Armelle Arnoux***, Celine Piedvache***, Jean-Jacques Patard††† and Bernard Escudier

 

*Department of Urology, Bicêtre University Hospital, Assistance Publique-Hôpitaux de Paris, APHP, University Paris-Saclay, Le Kremlin-Bicêtre, †Department of Urology, Pontchaillou University Hospital, Rennes, ‡Department of Urology, Bordeaux University Hospital, Pellegrin Hospital, §French Research Network on Kidney Cancer UroCCR, Bordeaux, Department of Medicine, Gustave Roussy, University Paris-Saclay, Villejuif, **Department of Oncology, Eugene Marquis Centre, Rennes, ††Department of Medical Oncology, Bordeaux University Hospital, Saint-André Hospital, Bordeaux, ‡‡Department of Urology, Saint-Joseph Hospital, Paris, §§Department of Urology, Nouvel Hôpital Civil, ¶¶Department of Oncology, Hautepierre Hospital, Strasbourg University Hospital, Strasbourg, ***Paris-Sud Clinical Research Unit, Department of Statistics, Bicêtre University Hospital, Assistance Publique-Hôpitaux de Paris, Le Kremlin-Bicêtre and †††Department of Urology, Mont de Marsan Hospital, Mont de Marsan, France

 

Read the full article

Abstract

Objective

To evaluate the ability of neoadjuvant axitinib to reduce the size of T2 renal cell carcinoma (RCC) for shifting from a radical nephrectomy (RN) to a partial nephrectomy (PN) indication, offering preservation of renal function.

Patients and Methods

Patients with cT2aN0NxM0 clear‐cell RCC, considered not suitable for PN, were enrolled in a prospective, multicentre, phase II trial (AXIPAN). Axitinib 5 mg, and up to 7–10 mg, was administered twice daily, for 2–6 months before surgery, depending on the radiological response. The primary outcome was the number of patients receiving PN for a tumour <7 cm in size after neoadjuvant axitinib.

Results

Eighteen patients were enrolled. The median (range) tumour size and RENAL nephrometry score were 76.5  (70–98) mm and 11 (7–11), respectively. After axitinib neoadjuvant treatment, 16 tumours decreased in diameter, with a median size reduction of 17% (64.0 vs 76.5 mm; P < 0.001). The primary outcome was considered achieved in 12 patients who underwent PN for tumours <7 cm. Sixteen patients underwent PN. Axitinib was tolerated in the present study, as has been previously shown in the metastatic setting. Five patients had grade 3 adverse events. Five patients experienced Clavien III–V post‐surgery complications. At 2‐year follow‐up, six patients had metastatic progression, and two had a recurrence.

Conclusion

Neoadjuvant axitinib in cT2 ccRCC is feasible and, even with a modest decrease in size, allowed a tumour shrinkage <7 cm in 12 cases; however, PN procedures remained complex, requiring surgical expertise with possible morbidity.

Read more Articles of the week

Editorial: Expanding the feasibility of nephron‐sparing surgery: time for a paradigm shift?

/by

With the rapid implementation of ‘targeted’ therapies, kidney cancer has entered a new era where old paradigms are being challenged, and new ones can be explored. The idea of delivering ‘neoadjuvant’ systemic therapy to alter the surgical treatment of advanced RCC was suggested in this same journal ~10 years ago as a proof‐of‐concept study [1]. Since then, a plethora of small case series has investigated the safety and feasibility of different targeted agents in the preoperative setting to facilitate surgical resection of locally advanced disease, mostly with a ‘cytoreductive’ (rather than ‘curative’) intent.

In this issue of the BJU Int, Lebacle et al. [2] evaluated the role of neoadjuvant axitinib, an oral tyrosine kinase inhibitor currently recommended as a second‐line option for metastatic clear cell RCC, to downstage cT2 kidney cancer and allow a partial nephrectomy (PN). In this multicentre prospective study, 18 patients with RCC (median tumour size 7.6 cm and R.E.N.A.L. [Radius; Exophytic/Endophytic; Nearness; Anterior/Posterior; Location] score 11) were enrolled. A median tumour size reduction of 17% was obtained, and the primary outcome (‘clinical downstaging’ to cT1 to allow PN) was achieved in 12 patients (67%). Overall, 16 patients underwent PN, as this was successfully done also in four of six (67%) patients who were not ‘down‐staged’ by the drug. Notably, about half of the PNs were performed with a robotic approach. Whilst axitinib was well tolerated, five patients experienced a high‐grade complication after surgery, including one death. Interestingly, final pathology showed upstaging to pT3a disease in seven patients, and two positive margins. Moreover, about a third of patients had metastatic progression and two had recurrence at 2 years. Thus, while the authors noted axitinib to be effective in reducing tumour size and achieving a clinical downstaging in most patients, the significant presence of pT3a disease calls into question the overall efficacy (to truly pathologically downstage) or desirability (most of the tumours that were not downstaged still successfully underwent PN) of the study’s main stated aim.

The rapid adoption of robotic surgery and the increasing experience with PN techniques translated into expanding indications for minimally invasive nephron‐sparing surgery (NSS), to include also T1b and T2 renal masses [3], and the field is primed for a possible paradigm shift. Whether or not a PN is doable, regardless of the technique, remains in the hands of the surgeon, who makes that decision based on previous personal experience. This is also the case for the present study, where the primary outcome was simply represented by the number of patients who could get a PN (instead of a radical nephrectomy). As such, is such a subjective endpoint (feasibility of PN) clinically meaningful? While disagreement may occur over the risk of PN in complex and elective cases, the desirability of nephron preservation in imperative and most elective circumstances is supported by evidence that largely suggests that PN translates into better renal function. In addition, recent findings suggest that estimated GFR preservation might translate into better cancer‐specific survival [4]. Certainly, this type of endpoint (whether a PN is feasible) is prone to intrinsic bias and limitations.

Only a limited number of studies have specifically explored the role of neoadjuvant therapy to enable NSS with variable results [5] (Table 1) [2, 6, 7, 8, 9]. Overall, these studies suggest that even a modest tumour size reduction can facilitate kidney preservation in a significant number of cases. Amongst these studies, only one had assessed axitinib in this specific setting [9]. Differences in outcomes between that trial and the present one by Lebacle et al. [2] could be explained by differences in study populations and/or drug regimens. A more recent study by Karam et al. [10], showed that inter‐observer agreement regarding the feasibility of a PN is quite variable, which is not surprising. For this reason, those authors advocated the need for a ‘resectability score’.

In conclusion, utility of neoadjuvant therapy to modify tumour size and facilitate NSS is an active and exciting area of clinical investigation, fuelled by the rapidly changing landscape of systemic therapies for RCC. It is too early to call for a paradigm shift, but a few ongoing studies might provide some meaningful answers soon. Amongst these, the PADRES (Prior Axitinib as a Determinant of Outcome of REnal Surgery) is an ongoing North American multicentre phase II study of axitinib with the aim of recruiting 50 patients [5]. While waiting for more robust evidence, the use of neoadjuvant therapy to facilitate NSS should still be deemed as investigational.

References

  1. Shuch, B, Riggs, SB, LaRochelle, JC et al. Neoadjuvant targeted therapy and advanced kidney cancer: observations and implications for a new treatment paradigm. BJU Int 2008; 102: 692– 6
  2. Lebacle, C, Bensalah, K, Bernhard, JC et al. Evaluation of axitinib to downstage cT2a renal tumours and allow partial nephrectomy: a phase II study. BJU Int 2019; 123: 804– 10
  3. Bertolo, R, Autorino, R, Simone, G et al. Outcomes of robot‐assisted partial nephrectomy for clinical T2 renal tumors: a multicenter analysis (ROSULA Collaborative Group). Eur Urol 2018; 74:226– 32
  4. Antonelli, A, Minervini, A, Sandri, M et al. Below safety limits, every unit of glomerular filtration rate counts: assessing the relationship between renal function and cancer‐specific mortality in renal cell carcinoma. Eur Urol 2018; 74: 661– 7
  5. Bindayi, A, Hamilton, ZA, McDonald, ML et al. Neoadjuvant therapy for localized and locally advanced renal cell carcinoma. Urol Oncol 2018; 36: 31– 7
  6. Silberstein, JL, Millard, F, Mehrazin, R et al. Feasibility and efficacy of neoadjuvant sunitinib before nephron‐sparing surgery. BJU Int 2010; 106: 1270– 6
  7. Rini, BI, Plimack, ER, Takagi, T et al. A phase II study of pazopanib in patients with localized renal cell carcinoma to optimize preservation of renal parenchyma. J Urol 2015; 194: 297– 303
  8. Lane, BR, Derweesh, IH, Kim, HL et al. Presurgical sunitinib reduces tumor size and may facilitate partial nephrectomy in patients with renal cell carcinoma. Urol Oncol 2015; 33: 112.e15–21.
  9. Karam, JA, Devine, CE, Urbauer, DL et al. Phase 2 trial of neoadjuvant axitinib in patients with locally advanced nonmetastatic clear cell renal cell carcinoma. Eur Urol 2014; 66: 874– 80
  10. Karam, JA, Devine, CE, Fellman, BM et al. Variability of inter‐observer agreement on feasibility of partial nephrectomy before and after neoadjuvant axitinib for locally advanced renal cell carcinoma (RCC): independent analysis from a phase II trial. BJU Int 2016; 117: 629– 35

 

Video: Evaluation of axitinib to downstage cT2a renal tumours and allow partial nephrectomy: a phase II study

/by

Evaluation of axitinib to downstage cT2a renal tumours and allow partial nephrectomy: a phase II study

Read the full article

Abstract

Objective

To evaluate the ability of neoadjuvant axitinib to reduce the size of T2 renal cell carcinoma (RCC) for shifting from a radical nephrectomy (RN) to a partial nephrectomy (PN) indication, offering preservation of renal function.

Patients and Methods

Patients with cT2aN0NxM0 clear‐cell RCC, considered not suitable for PN, were enrolled in a prospective, multicentre, phase II trial (AXIPAN). Axitinib 5 mg, and up to 7–10 mg, was administered twice daily, for 2–6 months before surgery, depending on the radiological response. The primary outcome was the number of patients receiving PN for a tumour <7 cm in size after neoadjuvant axitinib.

Results

Eighteen patients were enrolled. The median (range) tumour size and RENAL nephrometry score were 76.5  (70–98) mm and 11 (7–11), respectively. After axitinib neoadjuvant treatment, 16 tumours decreased in diameter, with a median size reduction of 17% (64.0 vs 76.5 mm; P < 0.001). The primary outcome was considered achieved in 12 patients who underwent PN for tumours <7 cm. Sixteen patients underwent PN. Axitinib was tolerated in the present study, as has been previously shown in the metastatic setting. Five patients had grade 3 adverse events. Five patients experienced Clavien III–V post‐surgery complications. At 2‐year follow‐up, six patients had metastatic progression, and two had a recurrence.

Conclusion

Neoadjuvant axitinib in cT2 ccRCC is feasible and, even with a modest decrease in size, allowed a tumour shrinkage <7 cm in 12 cases; however, PN procedures remained complex, requiring surgical expertise with possible morbidity.

View more videos
© 2024 BJU International. All Rights Reserved.