Archive for category: Letters to the Editor

Rights for men! PSA testing

Sir,

I am writing this from a trainee viewpoint.

I was delighted to read your article on rights regarding PSA testing in February [1]. I know it’s not February or Valentine’s Day now, but men’s rights regarding PSA testing is a central issue. When compared to breast cancer, and women’s rights, men’s rights regarding PSA testing are lagging behind.

At a patient conference, prostate cancer survivors made comments on problems getting their PSA levels tested before being diagnosed with prostate cancer. Whilst some had symptoms of LUTS and had been to their GP to be tested, there were patients who had no symptoms and were unable to get a test. These were all patients who, after being tested, required radical intervention. So where do we as healthcare professionals stand?

I was very happy to note the Melbourne Consensus Statement. This clearly advocates PSA testing, especially for those in the younger age groups, and acknowledges its role as part of a multivariate approach towards detecting prostate cancer [2]. At the same time, it also centralises the use of PSA in the older age group as part of a watchful waiting treatment plan [2]. However, no document clearly specifies or reiterates a screening process for prostate cancer. As a result, patients who potentially may have prostate cancer are left in the dark with regards to their rights. This should lead us to the age-old adage of ‘when in doubt, test’. Men clearly presenting to healthcare professionals have been proven to have a high incidence of prostate cancer. So then what happens to the patients who present to healthcare professionals and are refused a PSA test?

At the same time, there have been many screening trials, such as PLCO and ESRPC [3, 4]. This data demonstrates equivocal results between prostate cancer screening and testing. Screening for prostate cancer has always been weighed against treatment priorities of over diagnosis and overtreatment. On the other hand, the extended results of the ESRPC study demonstrated screening does significantly reduce deaths from prostate cancer [4]. However a longer follow-up period is required for this study. Whilst not screening benefits patients by preventing over diagnosis and overtreatment, it does not help the patients struggle to get tested. The inequity is not that PSA is an imperfect test, but the way it is used is far too variable and non-evidence-based as a result. As a biomarker, it currently outperforms cervical screening and mammography.

Cancer campaigns such as the one run by Prostate Cancer UK have helped create awareness about prostate cancer and just how problematic it can be. However, whilst the patient being more aware is a good thing, it does not help if they struggle to get the one test that will allow diagnosis and treatment to occur.

Sanchia S. Goonewardene* and Raj Persad**
*Spr, Urol University of Warwick, **Professor of Urology, Southmead Hospital Bristol

References

  1. Dasgupta P. Valentine’s Day PSA. BJU Int 2014; 113: 177
  2. Murphy DG, Ahlering T, Catalona WJ, et al. The Melbourne Consensus Statement on the early detection of prostate cancer. BJU Int 2014; 113: 186-188
  3. Hayes RB, Sigurdson A, Moore L, et al. Methods for etiologic and early marker investigations in the PLCO trial. Mutat Res 2005; 592: 147-154
  4. Studer UE, Collette L. What can be concluded from the ERSPC and PLCO trial data? Urol Oncol 2010; 28: 668-669

 

Evolution of surgical training methods: the new class

Sir,

I am writing this from a trainee viewpoint.

I was delighted to read the articles by Khan et al. [1] and Elsamra et al. [2]. Both articles highlight how much the role of the surgical trainee has changed in this day and age.

Surgery has always been about precision, control and patient safety. It was interesting to note, with a new generation of trainees, the requirement for immediate information is there. Knowledge is very literally at our fingertips. Making use of modern web-based tools, in the same way, much of surgical training has become standardised, with the arrival of the ISCP log book, and more recently, the robotic surgery curriculum, which was much welcomed. With these tools, we can easily self-audit our practice to see what our learning curve is. However, additional pressures are now put on surgeons with the advent of published surgical outcomes. In some ways, this is both a help and a hindrance to a trainee. It helps that you can easily monitor your learning curve and continuously readjust your technique and skills accordingly. It is a hindrance that training opportunities may be further restricted as a result. This is more so for open surgery, which may result in less training.  

Surgery is a speciality built on apprenticeship. However, in the modern world, the wealth of information available to trainees is vast. Trainees can learn via social media and link to conferences around the world. This emphasises why live cases are central to training. In a busy hospital, there may not often be time for a trainee to be taken through a procedure step-by-step. With live surgery supplementing training, the trainee already knows what to expect. In this age, we are very lucky. Not only can we read the theory behind the operation, but we can then view the procedure on the web and complete simulation training to improve our surgical skills, prior to approaching any patient in hospital. As a result, we can perfect our skills, even before performing the first operation.

Despite all the above, what still remains central and vital to surgery, is the master–apprentice relationship. With all the texts in the world, and all available resources, nothing can teach you quite so much as the voice of experience. To finish off, I know a lot of comments have been made about the BJUI being a journal that nurtures the younger generation, and a number of negative comments made as a result. As one of the younger generation I would like to say, it is nice to have a journal that listens and continues to support surgical training and education.

Sanchia S. Goonewardene* and Raj Persad**
*University of Warwick, **Southmead Hospital Bristol

References

  1. Khan N, Abboudi H, Khan MS, et al. Measuring the surgical ‘learning curve’: Methods, variables and competency. BJU Int 2014; 113: 504–508
  2. Elsamra SE,  Fakhoury M,  Motato H,  et al. The surgical spectacle: a survey of urologists viewing live case demonstrations. BJU Int 2014; 113: 674–678

 

Re: Measuring the surgical ‘learning curve’: methods, variables and competency

Sir,

Khan et al. [1] present a new review of the use of learning curves (LCs) in clinical practice. It is enlightening to see how many confounding factors are involved when constructing a LC. Could LCs eventually provide a supplement to or even replace indicative numbers charting the progress of surgical trainees?

When considering using a LC to demonstrate competence in surgical training, the many measurable factors associated with skill acquisition are different for different procedures, as is the rate at which these skills are attained.

For some, large gains in expertise may be achieved with few simple procedures, producing a short or steep LC. The attainment of competence for a more complex procedure may require much more exposure, a shallow or long LC. The curve described by Khan et al. this month is only one way to learn. Pictured below are differing learning curves.

In addition, some operations lend themselves to an easier assessment of competence than others. Time versus resected, enucleated or vaporized tissue can be plotted for TURP and laser prostatectomy LC, with the efficiency of operator movement a surrogate for surgical expertise.

A LC may be punctuated by several plateaus as surgeons take on more complex cases, or through changes in the frequency and number of cases carried out over a specified period. The levelling out of an individual’s LC may provide an indication that progress has slowed. This would afford trainers to step in and facilitate further skill acquisition through other training means, such as simulation training or individual mentoring.

Or maybe, we have to consider that a learning curve, in fact, develops as outlined in this image from the Incentive Intelligence website?

Hannah Wells, Paul Sturch, Gordon Muir
Urology Department, King’s College Hospital, London, UK

Read the article

Reference

  1. Khan N, Abboudi H, Khan MS, Dasgupta P and Ahmed K. Measuring the surgical ‘learning curve’: methods, variables and competency. BJU Int 2014; 113: 504–508

New evidence for the relationship between PSA value and BMI in diagnosing prostate cancer: obesity should be reckoned

Sir,

We read with great interest the paper by Oh et al. [1] and the paper by Pater et al. [2]. Their study confirmed the previously reported inverse relationship between prostate-specific antigen (PSA) value and body mass index (BMI). Indeed, they indicated a decrease in PSA for an increasing BMI with a 0.026 decrease in PSA for every unit increase in BMI. To date, the detection of prostate cancer (PCa) has become more common since the introduction of PSA, but overall mortality remains high with an estimated 27,360 deaths in 2009, and relative survival of patients diagnosed with prostate cancer has changed little.

One possible reason that screening for PCa using PSA has not achieved reduced mortality is that PSA can be confounded by weight. In fact, several previous studies have demonstrated an inverse association between PSA and BMI. Kim et al. demonstrated that PSA shows a significant linear trend only in the group with a BMI ≥ 25 kg/m with prostate examination [3].

Pater et al. investigated 767 patients, with mean BMI 28.7 kg/m2; where 78% were overweight or obese (BMI ≥25). Mean PSA was 1.28 ng/ml. Notably, 44 patients had at least 1 PSA level over 4.0 ng/ml [2]. There was a small, but statistically significant trend toward decreasing PSA for an increasing BMI.

However, multiple findings showed that obese men had lower serum PSA concentrations than normal weight men. PSA mass tended to be lower in obese patients, but is unlikely to be a consequence of lower serum testosterone concentrations. Oh et al. declared that the accuracy of PSA in predicting PCa did not change regardless of BMI category in Asian men [1]. Recently it was shown that initial PSA levels of 3471 patients were <30 ng/ml, undergoing multicore (≥12) transrectal ultrasound-guided prostate biopsy. The median PSA level in each BMI category was 7.84, 7.75, 7.33 and 5.79 ng/ml with BMI of <23, 23-24.9, 25-29.9, and ≥30 kg/m2 respectively [1]. Therefore, it may be suggested that the PSA threshold should be lower in obese men to discriminate between PCa and benign conditions in the real clinical situation. Similarly, Yang et al. recruited 20,509 native Korean men and found a statistically significant trend towards a lower likelihood of having a serum PSA level ≥2.5 ng/ml with an increased BMI [4]. These results might affect PCa screening using serum total PSA. Indeed, the relationship between obesity and PSA is confounded by a number of factors, which likely explain the observed inverse association previously reported. These data showed that obesity can help clinical staff to interpret the value of PSA in screening for PCa. Meanwhile, Li et al. demonstrated the inverse relationship between PSA concentration and BMI, and hold that this might be explained by a hemodilution effect among obese men. A value between 3.32 and 3.68 ng/ml might be recommended for PSA screening in middle-aged obese Asian men [5].

Of note, a recent study showed that the result accuracy of PSA as a predictor of PCa in 917 Italian men, performing trans-rectal ultrasound-guided prostate needle biopsy, is not significantly altered by BMI. Bañez et al. highlighted that obesity does not negatively impact the overall ability of PSA to discriminate between PCa and benign conditions [6].

In summary, available evidence has demonstrated an inverse relationship between PSA and BMI. However, much of the data regarding the role of PSA in obese patients with PCa has been obtained from distinct populations and proves controversial. Therefore, further clinical studies may be required to explore comprehensively the accurate diagnosis of prostate cancer in obese men in the real clinical situation.

Chang-ming Lin1,2, Chao-zhao Liang1*

1Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230032, China, 2Department of Urology, The Central Hospital of Maanshan The Affiliated Hospital of Wannan Medical College,Maanshan, Anhui 243011, China

*Correspondence: Chao-zhao Liang, e-mail: [email protected]

Full article: Oh et al.

References

  1. Oh JJ, Jeong SJ, Lee BK et al. Does obesity affect the accuracy of prostate-specific antigen (PSA) for predicting prostate cancer among men undergoing prostate biopsy. BJU Int 2013; 112: E265–E271
  2. Pater LE, Hart KW, Blonigen BJ, Lindsell CJ, Barrett WL. Relationship between prostate-specific antigen, age, and body mass index in a prostate cancer screening population. Am J Clin Oncol 2012; 35: 490–492
  3. Kim JH, Doo SW, Yang WJ, Song YS, Kwon SS. Prostate-specific antigen density: a better index of obesity-related PSA decrease in ostensibly healthy Korean men with a PSA <3.0 ng/mL. Urology 2013; 81: 849–852
  4. Yang WJ. The likelihood of having a serum PSA level of >/=2.5 or >/=4.0 ng ml-1 according to obesity in a screened Korean population. Asian J Androl 2013; 15: 770–772
  5. Li F, Shen Z, Lu Y, Yun J, Fan Y. Serum prostate-specific antigen concentration and hemodilution among Chinese middle-aged obese men: a hematocrit-based equation for plasma volume estimation is induced. Cancer Epidemiol Biomarkers Prev 2012; 21: 1731–1734
  6. Bañez LL, Albisinni S, Freedland SJ, Tubaro A, De Nunzio C. The impact of obesity on the predictive accuracy of PSA in men undergoing prostate biopsy. World J Urol 2012; doi: 10.1007/s00345-012-0919-9

Re: The Protective Role of Coenzyme Q10 in Renal Injury Associated with Extracorporeal Shock Wave Lithotripsy: a Randomized, Placebo Controlled Clinical Trial

Sir,

We read the article by Carrasco et al. [1] with interest. The study is worth attention as it relates to short-term CoQ10 use to prevent renal damage caused by SWL. However, some conflicting points and omissions occur. In addition, it would have been more ethically appropriate to conduct an animal study.

There are studies on the use and effectiveness of CoQ10 in renal diseases. Ishikawa et al., [2] Gokbel et al., [3] Sourris et al., [4] Sato et al. [5] and El-Sheikh et al. [6] state that CoQ10 effectively recovers renal functions and that it can be a treatment option for renal diseases.

Carrasco et al. [1] specifies that SWL was performed at a frequency of 60 waves/minute. Although the related mechanism of action has not been fully explained so far, completing the session at a low frequency is known to cause less damage to the kidney [7]. It could have been possible to apply treatment at various frequencies to identify the efficacy on CoQ10 based on the levels of damage.

It is understood that CoQ10 was used in daily doses of 200 mg over 2 weeks. However, in my opinion, this is a short period of time to determine the effectiveness of the treatment. The ideal blood level of CoQ10 should be more than 5.3 µg/ml [8], so it would have been more appropriate if the term of the study was between 4 to 6 weeks.

There are numerous studies showing that SWL causes oxidative stress. Yilmaz et al. [9] recently reported that SWL affects the oxidant/antioxidant balance in favour of oxidants. The findings in the study by Carrasco et al. [1] seem to be inconsistent with information showing the relationship between SWL and oxidative stress. 

Erdal Yilmaz and Ercan Yuvanc
University of Kirikkale, Faculty of Medicine, Department of Urology, Kirikkale, Turkey

References

  1. Carrasco-Valiente J, Anglada FJ, Campos JP, Muntané J, Requena MJ, Padillo J. The Protective Role of Coenzyme Q10 in Renal Injury Associated with Extracorporeal Shock Wave Lithotripsy: a Randomized, Placebo Controlled Clinical Trial. BJU Int 2013; doi: 10.1111/bju.12485
  2. Ishikawa A, Kawarazaki H, Ando K, Fujita M, Fujita T, Homma Y. Renal preservation effect of ubiquinol, the reduced form of coenzyme Q10. Clin Exp Nephrol 2011; 15: 30-33
  3. Gokbel H, Atalay H, Okudan N, Solak Y, Belviranli M, Turk S. Coenzyme Q10 and its relation with oxidant and antioxidant system markers in patients with end-stage renal disease. Ren Fail 2011; 33: 677-681
  4. Sourris KC, Harcourt BE, Tang PH et al. Ubiquinone (coenzyme Q10) prevents renal mitochondrial dysfunction in an experimental model of type 2 diabetes. Free Radic Biol Med 2012; 52: 716-723
  5. Sato T, Ishikawa A, Homma Y. Effect of reduced form of coenzyme Q10 on cyclosporine nephrotoxicity. Exp Clin Transplant 2013; 11: 17-20
  6. El-Sheikh AA, Morsy MA, Mahmoud MM, Rifaai RA, Abdelrahman AM. Effect of coenzyme-q10 on Doxorubicin-induced nephrotoxicity in rats. Adv Pharmacol Sci 2012; 2012: 981461
  7. Yilmaz E, Batislam E, Basar M, Tuglu D, Mert C, Basar H. Optimal frequency in extracorporeal shock wave lithotripsy: prospective randomized study. Urology 2005; 66: 1160-1164
  8. Bhagavan HN, Chopra RK. Coenzyme Q10: absorption, tissue uptake, metabolism and pharmacokinetics. Free Radic Res 2006; 40: 445-453
  9. Yilmaz E, Haciislamoglu A, Kisa U, Dogan O, Yuvanc E, Batislam E. Ways in which SWL affects oxidant/antioxidant balance. Urolithiasis 2013; 41: 137-141
Read the article

 

Re: Comparative assessment of three standardized robotic surgery training methods

From simulation to reality: the path forward for the trainee robotic surgeon

Sir,

As a trainee, I was delighted to see the articles from Hung et al. [1] and Murphy et al. [2] in the BJUI. They both raised points which trainees encounter in today’s practice. With advances in urology, there are many obstacles facing trainees, most notably robotics. Few advancements related to robotic training methods have been made. Current training courses may be followed by clinical implementation or fellowships [3]. In comparison, validated simulation-based training methods are now standard for laparoscopic surgery. In view of this, there are three issues which need to be addressed directly. The first is of a training programme for robotics, the second is addressing open surgery training in this cohort, and lastly, the position of simulation training in surgery.

A robotic surgery training programme – is it required?

Whilst UK trainees are used to using the Intercollegiate Surgical Curriculum Programme as a tool to further their training up to completion, this has not been extended to training in robotic surgery. At present, no such standard curriculum exists for robotic surgery. However, there are a number of programmes that highlight what a curriculum should cover.

The Yale University laparoscopic camera navigation curriculum is a proficiency-based program. This curriculum covers camera navigation, coordination and target visualization skills. Assessment includes time taken to complete a task, number of targets missed, drift (measure of the angle from the horizontal axis), total path length (measure of excess instrument motion), and the number of times the camera was in contact with tissue [4].

The University of Texas examined efficient and effective skill acquisition, but also the establishment of “standards” in terms of defining proficiency [5]. Inanimate exercises were used with designated skills. For example, peg transfer included hand-eye coordination, instrument to instrument transfer, wrist articulation, depth perception, and atraumatic handling. The curriculum includes an online tutorial, didactics with mandatory completion of multiple-choice questions, interactive sessions designed to teach console robotic instrumentation, and self-practice to proficiency. They concluded that although simulation has been widely accepted in surgical training, a validated curriculum is still needed for robotic surgery.

Cancer-control and quality-of-life outcomes achieved with radical prostatectomy are highly dependent on the surgeon’s technique and skill [6]. As such, appropriate selections of cases are required by educators. This was further examined by Davis et al. [6] and the importance of case difficulty was highlighted with prostate size, median lobe, obesity, previous abdominal surgery, hormonal use, and nerve-sparing strategy noted with the grading of trainees’ performance. The subjective grading and feedback was considered essential for a validated curriculum.

Over 30 reports have been published describing robotic surgical training outside of the operating room. A big part of this is simulation exercises designed to teach robotic skills, with promising results. Surgical training has traditionally been one of apprenticeships, with trainees observing and assisting their seniors, to one day hopefully become like them. However, surgical training has decreased in length due to the European Working Time Directive (EWTD) and the Modernizing Medical Careers (MMC) initiative.

Role of simulation training in surgery

With the da Vinci system, the surgeon sits separately at a console and the first assistant is at the table side. As a result, communication is a big part of robotics training. The first important step in operative surgery is overall perceptual awareness, cognitive understanding and visualisation of operation [7]. The second step is guided learning, with segmental operative steps performed under supervision, with constant and immediate feedback as an essential component. The final stage involves refinement of skills with precision and efficiency [7].

Lessons can be learned from laparoscopic training. Techniques used include operating on human cadavers and live animals to provide alternate methods of learning. Skills used range from basic skills to performing whole procedures. This highlights how simulation training must have good visual and tactile feedback.

Studies have been conducted demonstrating the eventual role of simulation in robotic surgical training [8]. Basic robotic skills can be learned relatively quickly using the da Vinci skills simulator, with a study demonstrating  greater than 10 repetitions is required to reach expert level [9]. It has also been observed apprentices achieve simulator proficiency after relatively short training durations [10] with a steep learning curve. Use of simulators may make the transfer of skills safer and more effective [11], but it does not cover all parameters of the operation itself. In addition, prior studies where a curriculum was used, demonstrated better outcomes than trainees not using one [11]. Whilst simulation is an important part of the initial step in learning an operation, it does not familiarise one with the mechanics of the robotic surgical system. Effective transfer of skills from simulators to real settings requires a structured curriculum [11].

Open surgery for the robotic surgeon – to learn or not to learn?

As Murphy et al. highlight, all training adds value. There is no such thing as wasted knowledge. Whilst focusing on robotic training is important, it is just as important for trainees to be able to perform the procedure as open surgery. There will be a case which must be converted to open and, as such, robotic trainees must be equally competent at open surgery. A robotics curriculum must take this into account and include management of complications as part of training.

A standardised new curriculum – the way forward

A curriculum that assesses both academic and manual dexterity components, in conjunction with each other, is required. The goal of any surgical curriculum should be to assess, train, re-assess and further train students. The required curriculum should be formed on a basis of skills identified through task analysis of actual robotic procedures, with simulator training initially.  

Primary steps would include positioning of patient and port insertion, before moving on to assisting with procedures, and eventually to the console and performing the operation in steps, then in whole. For example, a radical prostatectomy can be broken down into bladder take down, opening the endopelvic fascia, ligating the dorsal venous complex, dissection of anterior and posterior bladder neck, ligation and dissection of vas and seminal vesicles, pedicles, conducting a nerve sparing procedure if required, before urethral anastomosis and lymph node dissection.

Davis et al. grouped the 11 steps of the operation into “skill sets”: basic tissue dissection, advanced tissue dissection, bladder neck and sewing [6]. The authors also highlighted the role of sequential training, with an improvement in outcomes. At the same time, appropriate case selection for trainees is vital for the surgical educator. This paper highlighted at least 40 cases would be needed to get to grips with the procedures, more to refine technique [6].   

In conclusion, a new standardised curriculum needs to be developed, whether as an extension of ISCP or otherwise. Simulator training should be used initially for at least 15 cases, to re-enforce the procedure and skills associated, before moving on to patient cases. When starting robotics on patients, at least 40 cases are needed to gain the basic skills required, with greater numbers required for skills and precision.

Goonewardene SS, Persad R*
Homerton University Hospital, London, *Bristol Urological Institute, Southmead 

References

  1. Hung AJ, Jayaratna IS, Teruya K, Desai MM, Gill IS, Goh AC. Comparative assessment of three standardized robotic surgery training methods. BJU Int 2013; 112: 864–71
  2. Murphy DG, Sundaram CP. Comparative assessment of three standardized robotic surgery training methods. BJU Int 2013; 112: 713–14
  3. Society of American Gastrointestinal and Endoscopic Surgeons. Fundamentals of Laparoscopic Surgery. Available at: https://www.flsprogram.org/. Accessed April 16, 2011
  4. Shetty S, Panait L, Baranoski J et al. Construct and face validity of a virtual reality-based camera navigation curriculum. J Surg Res 2012; 177: 191–95
  5. Dulan G, Rege RV, Hogg DC, Gilberg-Fisher KK, Tesfay ST, Scott DJ. Content and face validity of a comprehensive robotic skills training program for general surgery, urology, and gynecology. Am J Surg 2012; 203: 535–39
  6. Davis JW, Kamat A, Munsell M, Pettaway C, Pisters L, Matin S. Initial experience of teaching robot-assisted radical prostatectomy to surgeons-in-training: can training be evaluated and standardized? BJU Int 2010; 105: 1148–54
  7. Sachdeva AK. Acquiring skills in new procedures and technology: the challenge and the opportunity. Arch Surg 2005; 140: 387–89
  8. Kelly DC, Margules AC, Kundavaram CR et al. Face, content, and construct validation of the da Vinci Skills Simulator. Urology 2012; 79: 1068–72
  9. Brinkman WM, Luursema JM, Kengen B, Schout BM, Witjes JA, Bekkers RL. da Vinci skills simulator for assessing learning curve and criterion-based training of robotic basic skills. Urology 2013; 81: 562–6
  10. Stefanidis D, Scerbo MW, Sechrist C, Mostafavi A, Heniford BT. Do novices display automaticity during simulator training? Am J Surg 2008; 195: 210–13
  11. Abboudi H, Khan MS, Aboumarzouk O, et al. Current status of validation for robotic surgery simulators – a systematic review. BJU Int 2013; 111: 194–205

Prospective randomized double-blind multicenter phase II study comparing chemotherapy with gemcitabine and cisplatin plus sorafenib vs gemcitabine and cisplatin plus placebo in locally advanced and/or metastasized urothelial cancer – SUSE – (AUO-AB 31/05)

Sir,

Krege et al. [1] report on the results of adding sorafenib to standard cisplatin and gemcitabine (CG) in first-line advanced urothelial cancer. Despite reporting on negative findings overall, the results should be discussed because of two major issues.

Firstly, investigators are now asked to delineate the mechanisms behind the clinical benefit of specific targeted compounds, otherwise the probability of succeeding in identifying their add-on effect over what can be expected by standard therapy alone will continue to be a matter of chance rather than the result of a structured methodology. The history of sorafenib in non-small cell lung cancer, where the early clinical benefit was observed in selected patients only, and was lost in a Phase III trial where it was added to CG, is paradigmatic [2]. In bladder cancer, despite two negative Phase II trials added to the present study in a metastatic setting, early signals of positive effects on the rate of pathologic complete responses in combination with CG were recently reported by our group in an ongoing Phase II trial in the neoadjuvant setting for muscle-invasive, node-negative disease (NCT01222676) [3-5]. Although caution is needed and the incongruity might be attributable to the small numbers, this might reflect underlying biological discrepancies between early and advanced disease, as the landscape of molecular alterations in the respective settings is still unrecognized. This is the reason why resources would be best spent fostering the identification of the molecular landscape associated with either response or resistance to the drug, and in different clinical settings. With this aim, a Worldwide Innovative Networking (WIN)-supported project will be conducted as a joint venture between Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan and Memorial Sloan-Kettering Cancer Center (MSKCC). In this project, whole exome sequencing will be used to genomically characterize responders as well as primary progressors identified in sequential INT-sponsored Phase II trials, including the sorafenib plus chemotherapy one. A similar design should be pursued for all cases with available tissue enrolled in the three sorafenib trials reported in urothelial cancer.

Secondly, authors highlight the methodological constraints leading to delay, redundancy, premature closure, and characterizing most of the Phase II trials in bladder cancer, a disease already subject to heavy scrutiny for slow activation and completion of trials over the past and recent years. Dramatic changes are needed in the way we structure support for multicenter, randomized trials in this difficult disease. This would imply reconsidering the concepts of patient molecular characterization, eligibility for trials with targeted agents, harmonizing the relationship between academia and the pharmaceutical companies, utilizing adequate methodological assumptions in the framework of genomically informed clinical trials. From a European perspective, these tasks have been put on the agenda of the Genitourinary Cancers Group of the European Organization for the Research and Treatment of Cancer (EORTC). All these efforts are fostered by the aim to revitalize informed and affordable clinical trials in the area of bladder cancer research.

A. Necchi*, P. Giannatempo*, E. Farè*, D. Raggi* N. Nicolai, M. Maffezzini and R. Salvioni
Department of *Medical Oncology and Surgery-Urology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

Corresponding author:
Andrea Necchi, MD
Department of Medical Oncology
Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
Via G. Venezian 1, 20133 Milan, Italy
Tel. +39-02-2390-2402; Fax. +39-02-2390-3150
Email. [email protected]

References
  1. Krege S, Rexer H, Vom Dorp F et al. Prospective randomized double-blind multicenter phase II study comparing chemotherapy with gemcitabine and cisplatin plus sorafenib vs gemcitabine and cisplatin plus placebo in locally advanced and/or metastasized urothelial cancer – SUSE – (AUO-AB 31/05). BJU Int 2013; epub ahead of print, doi: 10.1111/bju.12437.
  2. Paz-Ares LG, Biesma B, Heigener D et al. Phase III, randomized, double-blind, placebo-controlled trial of gemcitabine/cisplatin alone or with sorafenib for the first-line treatment of advanced, nonsquamous nonsmall-cell lung cancer. J Clin Oncol 2012; 30: 3084-92.
  3. Dreicer R, Li H, Stein M et al. Phase 2 trial of sorafenib in patients with advanced urothelial cancer: a trial of the Eastern Cooperative Oncology Group. Cancer 2009; 115: 4090-5.
  4. Sridhar SS, Winquist E, Eisen A et al. A phase II trial of sorafenib in first-line metastatic urothelial cancer: a study of the PMH Phase II Consortium. Invest New Drugs 2011; 29: 1045-49.
  5. Necchi A, Fina E, Giannatempo P et al. Early results of a phase 2 study of neoadjuvant cisplatin and gemcitabine plus sorafenib (S-CG) for patients with muscle-invasive transitional cell carcinoma of the bladder (INT52/10, NCT01222676). European Cancer Congress 2013 (abstr. 2751).
Read the article

Comparison of candidate scaffolds for tissue engineering for stress urinary incontinence and pelvic organ prolapse repair

Sir,

In the Mangera et al. [1] study various natural and synthetic scaffold materials, potentially applicable for tissue engineering purposes, were carefully compared. Primarily these materials were investigated for their suitability, when seeded with cultured oral fibroblasts, as an in vivo tissue-engineering approach to treat, by restoring the pelvic floor tissue structure, women with pelvic organ prolapse or those with stress urinary incontinence (SUI). Two potential candidate biodegradable scaffold materials were identified to treat these women’s pathological conditions, synthetic poly(L) lactic acid (PLA) and natural small intestinal submucosa (SIS), as they supported good cell attachment and proliferation, and had biomechanical features of the native pelvic floor.

The effectiveness of PLA and SIS as scaffold materials in other tissue engineering areas has been documented since the 1990s, e.g. to obtain a tissue-engineered bladder [2,3]. Recent advances in the preparation of synthetic polymeric scaffolds have shown that electrospun polyethylene terephthalate and polyurethane, given their fibrous microarchitecture similar to extracellular matrix (ECM), can favourably support cell adhesion/growth without the need of co-acting them with ECM-derived proteins [4,5].

Among the complex problems, from bench-to-bedside, concerning the biomechanical and dynamic requirements of a tissue-engineered structure to treat SUI, the main one is its potential for a quick and durable response to the neuronal mechanisms involved in the urinary continence guarding reflex towards sudden increases in intra-abdominal pressure. Indeed, the pontine storage centre-dependent spinal glutamatergic signalling induces the activation of sacral Onuf’s nucleus pudendal motoneurones, that, in turn, promote the acetylcholine-supported stimulation of pelvic floor striated muscle/urethral rhabdosphincter nicotinic receptors, thus efficaciously supporting the ‘guarding reflex’ [6–8].

Presumably the Authors [1], in the course of experimentation, have taken into consideration the response of their tissue-engineered structure to such guarding reflex-related neuromuscular mechanisms; however, this was not discussed in their article.

Contardo Alberti
Surgical Semeiotics, University of Parma, Parma, Italy

References
  1. Mangera A, Bullock AJ, Roman S, Chapple CR, MacNeil S. Comparison of candidate scaffolds for tissue engineering for stress urinary incontinence and pelvic organ prolapse repair. BJU Int 2013; 112: 674–85
  2. Atala A, Vacanti JP, Peters CA, Madnell J, Retik AB, Freeman MR. Formation of urothelial structures in vivo from dissociated cells attached to biodegradable polymer scaffold in vitro. J Urol 1992; 148: 658–62
  3. Oberpenning FO, Meng J, Yoo J, Atala A. De novo reconstruction of a functional urinary bladder by tissue-engineering. Nat Biotechnol 1999; 17: 149-155
  4. Del Gaudio C, Baiguera S, Ajalloueian F, Bianco A, Macchiarini P. Are synthetic scaffolds suitable for the development of clinical tissue-engineered tubular organs? J Biomed Mater Res A 2013 [Epub ahead of print]. DOI: 10.1002/jbm.a.34883.
  5. Alberti C. Tissue engineering as innovative chance for organ replacement in radical tumor surgery. Eur Rev Med Pharmacol Sci 2013; 17: 624–31
  6. Blok BF, Holstege G. The central control of micturition and continence: implications for urology. BJU Int 1999; 83 (Suppl. 2): 1–6
  7. Kitta T, Miyazato M, Chancellor MB, de Groat W, Nonomura K, Yoshimura N. α2-adrenoceptor blockade potentiates the effect of duloxetine on sneeze induced urethral continence reflex in rats. J Urol 2010; 184: 762–8
  8. Alberti C. Coadministration of low-dose serotonin/noradrenaline reuptake inhibitor (SNRI) duloxetine with α 2-adrenoceptor blockers to treat both female and male mild-to-moderate stress urinary incontinence (SUI). G Chir 2013; 34:189–94.
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Inflammatory prognostic markers in clear-cell renal cell carcinoma (RCC): preoperative C-reactive protein does not improve predictive accuracy

Sir,

We read with great interest the paper by Bedke et al. [1], which showed that using C-reactive protein (CRP) as a biomarker, with 0.25mg/dL as a threshold, did not improve predictive accuracy in a clear-cell RCC model. In certain clinical settings where traditional variables, such as TNM stage, grading and performance status are assessed objectively, a prognostic model for clear-cell RCC consisting of such variables would be helpful, especially if it did not require additional variables such as biomarker measurements and blood data.

The model presented by Bedke et al. includes several subjective variables (Fuhrman grade and performance status). It is worth noting that the evaluation of these subjective variables might be affected by interobserver variation [2]. By contrast, CRP is a serum variable which can be measured objectively. If the subjective variables in the Bedke model could be replaced with objective ones that are routinely available at most institutions, this predictive model would become more consistent and more easily generalizable. We have shown that the predictive model known as TNM-C, which includes CRP instead of subjective variables such as Fuhrman nuclear grade, yields an acceptable level of predictive ability [3].

Yet should the utility of a biomarker be evaluated based only on its discriminative accuracy? Although one of the main motivations for identifying biomarkers is the possibility of incorporating them into prognostic models, biomarkers should be evaluated not only for their utility in discrimination but also with regard to other statistical metrics.

Bedke et al. [1] investigated the prognostic impact of CRP as a biomarker, but only in preoperative settings and using a single cohort without external validation, although many studies have shown that CRP is a powerful predictor of outcomes in RCC [3]. Furthermore, many investigators have reported that the availability of CRP data is linked to improved RCC outcomes in a variety of clinical settings. Several papers have indicated that, in advanced disease states, CRP still has prognostic impact in a postoperative setting [4]. Moreover, CRP is useful not only as a static indicator of prognosis, but also as an indicator of change: measuring dynamic changes in CRP concentration permits the observation of the pharmacological response to therapeutic intervention in RCC [5]. Serial measurements of CRP concentration can be used to monitor the response to therapy at any time during treatment, even during surgery or systemic cytokine therapy. These findings show that CRP can serve as a biomarker for RCC in daily practice [6].

Although a single study showed that CRP did not add significant prognostic value to an established prognostic model, the significance of CRP cannot be dismissed in the clinical treatment of RCC.

Junichiro Ishioka, Kazutaka Saito and Kazunori Kihara
Department of Urology, Tokyo Medical and Dental University, Graduate School, Tokyo, Japan

References
  1. Bedke J, Chun FK, Merseburger A et al. Inflammatory prognostic markers in clear cell renal cell carcinoma – preoperative C-reactive protein does not improve predictive accuracy. BJU Int 2012; 110: E771-7.
  2. Novara G, Martignoni G, Artibani W,  Ficarra V. Grading systems in renal cell carcinoma. J Urol 2007; 177: 430-6.
  3. Iimura Y, Saito K, Fujii Y et al. Development and external validation of a new outcome prediction model for patients with clear cell renal cell carcinoma treated with nephrectomy based on preoperative serum C-reactive protein and TNM classification: the TNM-C score. J Urol 2009; 181: 1004-12.
  4. Tatokoro M, Saito K, Iimura Y, Fujii Y, Kawakami S, Kihara K. Prognostic impact of postoperative C-reactive protein level in patients with metastatic renal cell carcinoma undergoing cytoreductive nephrectomy. J Urol 2008; 180: 515-9.
  5. Saito K, Tatokoro M, Fujii Y et al. Impact of C-reactive protein kinetics on survival of patients with metastatic renal cell carcinoma. Eur Urol 2009; 55: 1145-53.
  6. Saito K, Kihara K. C-reactive protein as a biomarker for urological cancers. Nat Rev Urol 2011; 8: 659-66.
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Single-stage preputial skin flap urethroplasty for long-segment urethral stricture: evaluation and determinants of success

Sir,

We read the article by Mathur et al. [1] with interest, in which the authors advocate the use of preputial flap urethroplasty for long-segment urethral stricture. Some points in this article need clarification. The authors mention that the strictures were complex in nature; however, they fail to mention the criteria used for this classification. The sites of stricture also need explanation. How many strictures were extending into the membranous region and what was their aetiology?

Also, it is not clear from the manuscript if urethral ultrasonography was performed only at 3 months or even later. The authors mention that the postoperative median diameter of the urethral lumen on ultrasonography was 4.8 mm. As urethral ultrasonography is not routinely performed, it would have been useful if the authors had highlighted how the urethral lumen size was calculated. Were the lumen diameters calculated at several points and then a mean value obtained in each patient? What is the normal lumen size on ultrasonography?

In the discussion, the authors have highlighted the role of gutka and mention that its use is fairly common in their state; however, they have not highlighted the role of gutka use in their results. The authors found that smoking adversely affected the results of urethroplasty in their study. Could the use of gutka also affect the outcome?

Apul Goel and Manmeet Singh
Department of Urology, King George Medical University, Lucknow, India

Reference
  1. Mathur RK, Nagar M, Mathur R, Khan F, Deshmukh C, Guru N. Single-stage preputial skin flap urethroplasty for long-segment urethral stricture: evaluation and determinants of success. BJU Int, doi:10.1111/bju.12361.
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