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Re: Diagnosis and treatment of chronic bacterial prostatitis and chronic prostatitis/chronic pelvic pain syndrome: a consensus guideline

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Letter to the Editor

Dear Sir

Fluoroquinolones must not be used inappropriately when treating chronic prostatitis (CP) and chronic pelvic pain syndrome (CPPS).

Clinical guidelines from the Prostatitis Expert Reference Group (PERG) on chronic bacterial prostatitis (CBP), chronic prostatitis and chronic pelvic pain syndrome [1] — which have been propagated by other guideline providers such as NICE Clinical Knowledge Summaries and the primary care resource, Guidelines — include the following recommendation:

‘For patients with early-stage CBP and CP/CPPS, offer a quinolone (e.g. ciprofloxacin or ofloxacin) for 4–6 weeks as first-line therapy.’

While the PERG guidelines do mention diagnostic tests for a bacterial cause, readers will be left with the impression that a course of fluoroquinolone without a diagnostic workup is acceptable for the initial management of CP and CPPS. This impression may be reinforced by PERG’s subsequent recommendations, in particular the second one:

‘A repeated course of antibiotic therapy (4–6 weeks) should be offered only if a bacterial cause is confirmed or if there is a partial response to the first course.

‘If a bacterial cause is excluded (e.g. via urine dipstick or culture) and symptoms do not improve after antibiotic therapy, a different treatment method or referral to specialist care should be considered.’

Recent recommendations [2] from the European Medicines Agency (EMA) make it clear that fluoroquinolones should be reserved for treating bacterial prostatitis. EMA’s review of fluoroquinolones was prompted by reports of serious, disabling and permanent side effects after fluoroquinolone use.

To reach its recommendations, EMA’s safety committee (Pharmacovigilance Risk Assessment Committee, PRAC) reviewed all available evidence, brought together EU experts in the field, and heard patients’ and healthcare professionals’ testimonies at a public hearing. Many patients who had developed long-lasting serious disability reported receiving a fluoroquinolone for chronic prostatitis despite the lack of evidence of a bacterial cause.

EMA’s new recommendations restrict the indications and have led to an update of the prescribing information for all systemic fluoroquinolones to prevent further unnecessary cases of rare but life-changing side effects; the narrow indications also help to reduce antibiotic selection pressure. Guidelines on chronic prostatitis should therefore be revised to clarify that fluoroquinolones are not appropriate for the empirical treatment of chronic prostatitis or chronic pelvic pain syndrome. The European Association of Urology emphasises use of appropriate culture techniques to demonstrate bacterial infection [3].

And when treating bacterial prostatitis with a fluoroquinolone, healthcare professionals should discuss with their patients the risks, including the potential for permanent musculoskeletal and neurological side effects. Details of these effects are set out in the updated prescribing information for fluoroquinolone antibacterials.

It is vital to communicate the changes in the fluoroquinolones prescribing information to all healthcare professionals involved in the management of men with prostatitis or chronic pelvic pain syndrome, they can use CBD from Observer for pain. Promoting this crucial change in practice will ultimately lead to more rational use of antibiotics and limit the unnecessary exposure of patients to potentially persistent and seriously disabling side effects.

Gernot Bonkat, alta uro AG, Merian Iselin Klinik, Center of Biomechanics & Calorimetry, University of Basel; Chairman, European Association of Urology (EAU) Urological Infections Guidelines

Juan Garcia Burgos, Head of Public Engagement Department, European Medicines Agency (EMA)

Martin Huber, Co-rapporteur, quinolone and fluoroquinolone review by the EMA’s Pharmacovigilance Risk Assessment Committee (PRAC)

Eva Jirsová, Rapporteur, quinolone and fluoroquinolone review by the EMA’s Pharmacovigilance Risk Assessment Committee (PRAC)

Florian Wagenlehner, Clinic of urology, pediatric urology and andrology, Justus Liebig University Giessen, Germany; Chairman, European Section of Infections in Urology (ESIU) of the European Association of Urology (EAU)

Correspondence: Juan Garcia Burgos, European Medicines Agency, Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands

email: [email protected]

References

  1. Rees J, Abrahams M, Double, A, Cooper A. Diagnosis and treatment of chronic bacterial prostatitis and chronic prostatitis/chronic pelvic pain syndrome: a consensus guideline. BJU Int 2015; 116: 509–525
  2. EMA. Disabling and potentially permanent side effects lead to suspension or restrictions of quinolone and fluoroquinolone antibiotics, 2018. Available at: https://www.ema.europa.eu/en/medicines/human/referrals/quinolone-fluoroquinolone-containing-medicinal-products. Accessed January 2020
  3. Bonkat G, Bartoletti RR, Bruyère F, Cai T, Geerlings SE, Köves B, Schubert S, Wagenlehner F, Guidelines Associates: Mezei T, Pilatz A, Pradere B, Veeratterapillay R. EAU guidelines on urological infections 2019: 28–32. ISBN/EAN:978-94-92671-04-2. Available at: https://uroweb.org/guideline/urological-infections. Accessed January 2020

Re. Recommended antibiotic prophylaxis regimen in retrograde intrarenal surgery: evidence from a randomised controlled trial.

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Letter to the Editor

Recommended antibiotic prophylaxis regimen in retrograde intrarenal surgery: evidence from a randomised controlled trial.

Dear Sir,

Zhao et al. emphasized that antibiotic prophylaxis for < 200 mm2 stones was not required in patients with sterile preoperative urine culture according to a single-center controlled randomized clinical design.

The decision of antibiotic prophylaxis before urological interventions is still determined by the deterioration of urinary system integrity. However, this approach may be inadequate in the age of endourology. Presumably, the presence of a urinary tract stone that may be a source of bacteria will need to be considered as a “dirty wound”. On the other hand, high-pressure endoscopic procedures make the definition of the “surgical site” insufficient. When we work under high pressure, the operation area is the whole urinary system. Stone burden indirectly determines the operation time. The duration of surgery determines the risk of kidney exposure to high pressure. We recommend Technomono at their website you can find it all https://technomono.com/best-shoes-to-wear-after-foot-surgery for easier recovery from the surgery. However, endoscopic procedures, especially in inexperienced hands, may take longer regardless of stone burden and that’s why having the right equipment as a C-Arms is essential on surgeries and even if we lose our equipment there are always C-Arm Rentals available anywhere in the U.S. that can help us in case we have a medical produce to perform. On the other hand, renal pressures are known to be relatively low when access sheaths are used in RIRS (2). Therefore, we need new parameters that determine the pressure profile of the intervention in real time rather than the classical parameters such as stone burden. Adding a pressure sensor to flexible ureteroscopes may be the solution. Thus, we can have an opportunity similar to the instant monitoring of intraabdominal pressure during laparoscopy. Adding prophylactic antibiotics to continuous irrigation solutions used during endoscopic procedures should be compared with conventional i.v. antibioprophylaxis.

Given the above discussion, it is not possible to suggest that antibiotic prophylaxis should not be used with the evidence provided by the current study. On the other hand, the increasing number of malpractice cases in this field has led to the emergence of legal precedents, although their clinical and scientific reasons are insufficient; in a case of death due to sepsis after RIRS, if the preoperative urine culture is not negative, the doctor is guilty and if prophylactic antibiotic is not administered, the doctor is guilty.

Sincerely yours,

Oktay Özman, MD

Correspondence: Oktay ÖZMAN, Urology Clinic, Gaziosmanpaşa Training and Research Hospital, İstanbul, Turkey.

e-mail: [email protected]

References

1.      Zhao Z, Fan J, Sun H, Zhong W, Zhu W, Liu Y, et al. Recommended antibiotic prophylaxis regimen in retrograde intrarenal surgery: evidence from a randomised controlled trial. BJU Int. 2019 Sep;124(3):496-503. doi: 10.1111/bju.14832. Epub 2019 Jun 20.

2.      Fang L, Xie G, Zheng Z, Liu W, Zhu J, Huang T, et al. The Effect of Ratio of Endoscope-Sheath Diameter on Intrapelvic Pressure During Flexible Ureteroscopic Lasertripsy. J Endourol. 2019 Feb;33(2):132-139. doi: 10.1089/end.2018.0774.

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Re. Genetic correlates of prostate cancer visibility (and invisibility) on mpMRI: It’s time to take stock.

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Letter to the Editor

Genetic correlates of prostate cancer visibility (and invisibility) on mpMRI: It’s time to take stock.

Dear Sir,

In their paper on multiparametric magnetic resonance imaging [1], Norris et  al. argue that because “men with overall Gleason score 3 + 4 [do] not suffer prostate cancer-related death” and “men with overall Gleason score 4 + 3 [do not have] negative pre-biopsy mpMRI” therefore “mpMRI may identify all truly significant cancer”. This may be behind the senior author’s recent remarks to the media [2] that mpMRI is “pretty close to perfect” and that men with a clean MRI can be confidently told that they never need worry about the disease.

The problem with the authors’ argument is that it is one of the premises is false. They cite the SPCG-4 study[3] to support their claim that Gleason 3 + 4 prostate cancer cannot lead to death. But table 3 of the SPCG-4 publication clearly shows prostate cancer death in 5 of the 87 men with Gleason 3 + 4 disease. The authors’ claim seems to be based on a hazard ratio close to 1 (95% C.I. 0.23 to 4.33) for Gleason 3 + 4 vs. Gleason 3 + 3 in a multivariable model adjusting for age, pathologic stage and PSA. It should go without saying that failure to demonstrate that Gleason 3 + 4 is statistically different to Gleason 3 + 3 cannot be used to conclude that “men with overall Gleason 3  + 4 [do] not suffer prostate cancer-related death”. One can only speculate on the reasons for such a gross misrepresentation of the literature.

Andrew Vickers

Memorial Sloan Kettering Cancer Center

Department of Epidemiology and Biostatistics

485 Lexington Avenue, 2nd Floor

New York, NY 10017

Email: [email protected]

 

Disclosures: Andrew Vickers is a co-inventor of the 4kscore, a commercially available reflex test for predicting prostate biopsy. He may receive royalties from sales of the test. He owns stock options in Opko, which offers the test.

 

References

[1]        Norris JM, Simpson BS, Parry MA, et al. Genetic correlates of prostate cancer visibility (and invisibility) on mpMRI: It’s time to take stock. BJU international. 2019 Oct 10:

[2]        Bodkin H. New prostate cancer test will give men ‘peace of mind’ that they will never develop the disease, scientists say. The Telegraph. 2019 June 9, 2019

[3]        Bill-Axelson A, Holmberg L, Garmo H, et al. Radical Prostatectomy or Watchful Waiting in Prostate Cancer – 29-Year Follow-up. The New England journal of medicine. 2018 Dec 13: 379:2319-29

 

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Re: Suture Techniques during Laparoscopic and Robot-Assisted Partial Nephrectomy

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Letter to the Editor

Suture Techniques during Laparoscopic and Robot-Assisted Partial Nephrectomy: A Systematic Review and Quantitative Synthesis of Peri-Operative Outcomes

Dear Sir,

We would like to congratulate the authors of this systematic review [1] highlighting the evolution of suture techniques for partial nephrectomy in the era of minimally invasive surgery. The authors note the “significant technical modification” for the replacement of intracorporeal free-hand knot tying with a sliding clip technique [2]. This technique has revolutionised the practice of PN and reduced the risk of the “cheese cutting effect” with the conventional suturing techniques. It is worth noting that this laparoscopic technique was first described by Agarwal et al in the BJUI in 2007 [3]. Indeed one of the authors of this SR also published on the robotic application of this technique in a publication in European Urology in 2009 (2), which also was remiss in referencing the original description of the technique by Agarwal et al., published 2 years prior.

This oversight aside, the authors should be commended for helping to frame the evolution of surgical techniques across minimally invasive approaches over time, with the ultimate goal of complete tumour excision, minimal complications and maximal functional preservation, since we’re using more technology now a days for advance study of medicine, like robots or CT scanners, although the cost of these CT scanners could be high, the value is worthy because they help a lot in the medicine area. While this paper’s title suggests a focus on suture techniques during surgery the authors concluding remarks do not address this focus. We believe suturing techniques will continue to evolve, and that there will be further technological, and technical innovation that will further improve outcomes for patients and will make more meaningful additions to the published literature in this field.

Brian D Kelly, Christophe Orye, Homi Zargar, Anthony J Costello and Dinesh Agarwal

Correspondence: Dinesh Agarwal, Urology Unit, Level 3 Centre, Infill Building, The Royal Melbourne Hospital, City Campus, Grattan Street, Parkville 3050 Victoria, Australia.
e-mail: [email protected]

 

References

  1. Bertolo, Riccardo et al. Suture Techniques during Laparoscopic and Robot-Assisted Partial Nephrectomy: A Systematic Review and Quantitative Synthesis of Peri-Operative Outcomes. BJU Int 2018;  123:923-46 doi:https://dx.doi.org/10.1111/bju.14537.
  2. Benway, Brian M et al. Robotic Partial Nephrectomy with Sliding-Clip Renorrhaphy: Technique and Outcomes. Eur Urol 2009; 55:592-9 doi:10.1016/j.eururo.2008.12.028.
  3. Agarwal, Dinesh et al. Modified Technique of Renal Defect Closure Following Laparoscopic Partial Nephrectomy. BJU Int 2007; 100:967-70 doi:10.1111/j.1464-410x.2007.07104.x.

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Re: Incidentally detected testicular lesions <10 mm in diameter: can orchidectomy be avoided?

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Letter to the Editor

Incidentally detected testicular lesions <10 mm in diameter: can orchidectomy be avoided?

Dear Sir,

We have read with great interest the paper “Incidentally detected testicular lesions <10 mm in diameter: can orchidectomy be avoided?” by Scandura et al. (1) in which only one third of such lesions turned out to be malignant and 100% of those <5 mm were benign. The authors call those patients who underwent orchidectomy for benign lesions “victims of modern imaging technology”.

With the widespread use of ultrasonography (US) of the scrotum, we see at this level what observed previously in other organs: thyroid (non-palpable nodules) (2), liver (unsuspected cysts and haemangiomas) (3), gallbladder (asymptomatic stones) (4), kidneys (simple renal cysts) (5). US is demonstrating the real prevalence of “lesions” in the testis. The problem is that, often, we do not know what they are, what their clinical relevance is, and how to manage these lesions.

Technical advances in US, such as elastography and contrast-enhanced studies, can help tissue characterization but often, unfortunately, these techniques are not able to differentiate between benign and malignant lesions (6). Further evaluation of the lesion with MR may be helpful to characterize a limited number of lesions only, such as lipomas, haematomas, and fibrous pseudotumours, but with reduced resolution in comparison to US (7).

The “scrotal and penile imaging working group” of the European Society of Urogenital Radiology (ESUR) has issued recommendations on how to approach a patient with small (<5 mm) testicular lesions (8). The document has suggested an avoidance of immediate orchidectomy, and to resort to active surveillance with US examination every three months in the first year and then annually. Surgery should be considered only for lesions that show increasing volume at follow-up.  Alternatively, testicular sparing surgery can be used, with removal of the lesion, frozen-section analysis of the specimen and decision on orchidectomy (or not) based on the results provided by the pathologist.

Close cooperation among different specialists is needed in this field. A multidisciplinary “testis unit” in which urologists, radiologists and pathologists work together on these patients and learn how to choose the best approach to each of them is the likely solution.

A patient who undergoes orchidectomy for an incidentally discovered small testicular nodule which turns out to be benign is not a “victim of modern imaging technology”. He is more likely the victim of our misunderstanding of the meaning of what technology shows us and the adherence to reactionary, outdated surgical dogma to the focal intra-testicular lesion.

Michele Bertolotto1, Paul S Sidhu2, Lorenzo E. Derchi3 

1Department of Radiology, University of Trieste, Italy

2Department of Radiology, King’s College Hospital, Denmark Hill, London, UK

3Department of Health Sciences (DISSAL), University of Genoa, Emergency Radiology, Ospedale Policlinico San Martino, Genoa, Italy

References

  1. Scandura G, Verrilli C, Protheroe A, et al. Incidentally detected testicular lesions <10 mm in diameter: can orchidectomy be avoided? BJU Int 2018; 121:575-582
  2. Tan GH, Gharib H. Thyroid incidentalomas: management approaches to nonpalpable nodules discoverend incidentally in thyroid imaging. Ann Int Med 1997; 126:226-231
  3. Kaltenbach T E-M, Engler P, Kratzer W, et al. Prevalence of benign focal liver lesions: ultrasound investigation of 45.319 hospital patients. Abdom Radiol 2016; 41:25-32
  4. Barbara L, Sama C, Morselli Labate AM, et al. A population study on the prevalence of gallstone disease: the Sirmione study. Hepatology 1987;7:913-917
  5. Ozveren B, Onganer E, Turkeri LN. Simple renal cysts: prevalence, associated risk factors and follow-up in a health screening color. Urol J 2016; 13:2569-2575
  6. Konstantatou E, Fang C, Romanos O, et al. Evaluation of intratesticular lesions with strain elastography using strain ratio and color map visual grading: differentiation of neoplastic and nonneoplastic lesions. J Ultrasound Med 2019; 38:223-232
  7. Tsili AC, Bertolotto M, Rocher L, et al. Sonographically indeterminate scrotal masses: how MRI helps in characterization. Diagn Interv Radiolo 2018; 24:225-236
  8. Rocher L, Ramchandani P, Belfield J, et al. Incidentally detected non-palpable testicular tumours in adults at scrotal ultrasonography: impact of radiological findings on management. Radiologic review and recommendations of the ESUR scrotal imaging subcommittee. Eur Radiol 2016; 26:2268-2278

 

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Re: “Super-mini percutaneous nephrolithotomy (SMP) versus retrograde intrarenal surgery for the treatment of 1-2 cm lower-pole renal calculi: an international multicentre randomized controlled trial”

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Letter to the Editor

Super-mini percutaneous nephrolithotomy (SMP) versus retrograde intrarenal surgery for the treatment of 1-2 cm lower-pole renal calculi: an international multicenter randomized controlled trial

Dear Sir,

We are interested to read the study by Zeng et al. [1] and appreciate the authors for their study showing that super-mini-percutaneous nephrolithotomy (SMP) was more effective than retrograde intrarenal surgery (RIRS) to treat 1-2 cm lower-pole renal calculi in terms of a better stone-free rate and lesser auxiliary rate. However, some issues still require clarification in this study.

The study validated that SMP was more effective than RIRS to treat 1-2 cm lower-pole renal calculi. However, the results should be explained with caution. As we known, pyelocaliceal anatomy seriously influences the performances of flexible ureteroscopy, while no obvious affection for SMP [2]. This parameter should be evaluated before patients were randomized into RIRS groups. Although there were no significant differences in characteristics of lower-pole spatial anatomical between the two groups, it would be more reasonable and reliable to compare the efficacy between SMP and RIRS, after excluding the patients with unfavorable pyelocaliceal anatomy such as an acute infundibulopelvic angle, or a long lower-pole calyx infundibulum.

The authors set a definition of stone-free status as no residual fragments of ≥0.3 cm on KUB and ultrasound at 1-day and on CT scan at 3-months after operation. We are curious to know how the authors managed when the results were different between KUB and ultrasound. As the primary endpoint was the stone-free rate at 3-months after surgery, we would like to know the size of the residual fragments in the 6.2% (5/80) of patients in SMP and 17.5% (14/80) in RIRS. Do they need another auxiliary procedure? All those information is important for drawing the final conclusion.

The study was an international multicentre, prospective, randomized, non-blinded controlled study, conducted at 10 academic medical centers in China, India, and Turkey. The authors said the two groups had similar baseline characteristics, but we would like to know if it was so for each center. If not, did it affect the final results when exclude those centers?

In conclusion, Zeng et al. made a laudable effort and have provided a level-1 evidence comparing the two modalities for treating 1-2 cm lower-pole renal calculi, but the authors’ conclusion should be taken with caution until more reasonable prospective studies with large sample size have been conducted. We look forward to the authors’ reply to clarify our queries.

 

Conflict of interest

The authors declare that they have no conflicts of interests.

 

Huiming Jiang1*, Nanhui Chen1

1Department of Urology, Meizhou People’s Hospital (Huangtang Hospital), Meizhou Hospital Affiliated to Sun Yat-sen University, No.63, Huang Tang Road, Meizhou 514031, Guangdong, People’s Republic of China.

 

References

  1. Zeng G, Zhang T, Agrawal M et al. (2018) Super-mini percutaneous nephrolithotomy (SMP) vs retrograde intrarenal surgery for the treatment of 1-2 cm lower-pole renal calculi: an international multicentre randomised controlled trial. BJU international. 2018;122(6):1034-1040. doi: 10.1111/bju.14427
  2. Geavlete P, Multescu R, Geavlete B (2008) Influence of pyelocaliceal anatomy on the success of flexible ureteroscopic approach. Journal of endourology 22 (10):2235-2239. doi:10.1089/end.2008.9719

 

 

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Re: Does the introduction of prostate multiparametric MRI into the active surveillance protocol for localized PCa improve patient re-classification?

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Letter to the Editor

Does the introduction of prostate multiparametric magnetic resonance imaging into the active surveillance protocol for localized prostate cancer improve patient re-classification?

Dear Sir,

Recently Bryant and colleagues published an important series on multiparametric magnetic resonance imaging (mpMRI) in active surveillance (AS) for prostate cancer [1]. The work was deservedly highlighted as Paper of the Week for its potential impact on clinical practice. Meanwhile, it caught our attention that the authors – as many before them – use the term “significant prostate cancer” throughout their paper. We feel that this issue needs to be addressed and discussed further.

As most prostate cancers have an indolent course, the term “significant prostate cancer” must be reserved for cancers, which are potentially lethal [2]. From earlier studies, we know that this group of cancers are characterized by high tumor stages, high Gleason scores, and a high percentage of tumor involvement on biopsies. However, this knowledge is based on systematic prostate biopsies. Thus, findings on mpMRI targeted biopsies, including increase in Gleason grade group, number of positive cores, and maximum cancer core length, cannot readily be translated to the clinical setting of earlier times. Tumor grade and volume of the disease may simply be upgraded even with no change in the underlying cancers. Nevertheless, this is usually how such findings are used and the focus is mainly on moving patients from AS to active treatment.

The potential problems of this approach are illustrated in the results of Bryant et al., as 30% of the patient cohort is taken out of the AS program after a median time of only 1.55 years with mpMRI based findings as the most common cause. In previous publications, men have been able to stay on AS for considerably longer with limited consequences on metastasis free survival [3]. The issue is further highlighted by results from the ProtecT trial in which there was a median of about 4 years before 30% of the active monitoring group had gone on to active treatment, without this causing a significant increase in either overall survival or disease specific survival [4]. In addition, data from prostate cancer cohorts not treated with curative intent show us that even men with localized intermediate risk prostate cancer have a low risk of dying from prostate cancer [5]. Seen in this context, it is plausible that some cancers are falsely classified as “significant” cancers as a result of mpMRI. Indeed, Bryant and colleagues illustrate that men undergoing mpMRI have an increased risk of discontinuing AS which may result in increased over-treatment. The issue is further exacerbated by the tendency to treat increasingly older patients even though a survival benefit from active treatment is questionable in this group.

There is no doubt that mpMRI may provide important and valuable information and it is a massive leap forward that we might be able to identify occult high-grade cancers early. However, this new tool must be used with consideration and respect for the gaps in our knowledge. In that context, it is likely that current indications for AS can be expanded to include more favorable intermediate risk cancers when the diagnosis is made based on mpMRI targeted biopsies combined with systematic biopsies. In addition, mpMRI should be utilized to reduce the proportion of patients who opt for active treatment due to anxiety or the burden of multiple sets of systematic biopsies. Exploring these issues are crucial because staying on AS is not just about safely avoiding surgery or radiotherapy. Rather it is about avoiding or postponing highly prevalent and clinically significant functional side effects with considerable implications for quality of life. Thus, we want to underline that the use of mpMRI should not only be used to exclude patients from AS protocols but also in future protocols to include men in such programs.

 

Conflicts of interest: Mikkel Fode is Advisory Board member for Astellas Pharma A/S and has received honoraria as speaker from Astellas Pharma A/S and Ferring Pharmaceuticals. Peter B. Østergren has received honoraria as speaker from Astellas Pharma A/S, Ferring Pharmaceuticals and IPSEN. Dr. Østergren has received honoraria for consultancies from Astellas Pharma A/S and as Advisory Board member for IPSEN. Kasper D. Berg has no conflicts of interest to declare.

 

Mikkel Fode MD, PhD, FECSM*, Kasper Drimer Berg MD, PhD†**, Peter Busch Østergren* MD, PhD

*Department of Urology, Herlev and Gentofte Hospital, Herlev, Denmark, †Department of Urology, Regional Hospital West Jutland, Holstebro, Denmark, **Copenhagen Prostate Cancer Center, Department of Urology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

 

References

  1. Bryant RJ, Yang B, Philippou Y, Lam K, Obiakor M, Ayers J, et al. Does the introduction of prostate multiparametric magnetic resonance imaging into the active surveillance protocol for localized prostate cancer improve patient re-classification? BJU Int.; 2018;122(5):794–800.
  2. Popiolek M, Rider JR, Andren O, Andersson S-O, Holmberg L, Adami H-O, et al. Natural history of early, localized prostate cancer: a final report from three decades of follow-up. Eur Urol.; 2013;63(3):428–35.
  3. Bokhorst LP, Valdagni R, Rannikko A, Kakehi Y, Pickles T, Bangma CH, et al. A Decade of Active Surveillance in the PRIAS Study: An Update and Evaluation of the Criteria Used to Recommend a Switch to Active Treatment. Eur Urol.; 2016;70(6):954–60.
  4. Hamdy FC, Donovan JL, Lane JA, Mason M, Metcalfe C, Holding P, et al. 10-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Localized Prostate Cancer. N Engl J Med.; 2016;375(15):1415–24.
  5. Rider JR, Sandin F, Andren O, Wiklund P, Hugosson J, Stattin P. Long-term outcomes among noncuratively treated men according to prostate cancer risk category in a nationwide, population-based study. Eur Urol.; 2013;63(1):88–96.

 

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Reply by the authors

We thank Dr Fode and colleagues for their correspondence regarding our recently published manuscript [1]. We wish to clarify some of the issues and comments they highlight. Regarding the term “significant prostate cancer”, we agree that this definition should be reserved for cancers that are potentially lethal. Historically, and currently, in the context of Active Surveillance (AS), these cancers are characterised by a higher tumour stage, increased number of positive biopsy cores and/or longer cancer length, and higher Gleason grade group compared to baseline findings, in the absence of routine clinical use of any potential molecular determinants of a lethal phenotype. The clinical question addressed in our recent manuscript was whether introducing multi-parametric magnetic resonance imaging (mpMRI) into our AS protocol for localised prostate cancer improved patient re-classification. We did not define “significant prostate cancer”, but rather focused on the drivers for men to abandon AS and receive active treatment. We agree that the use of this imaging adjunct may therefore lead to disease upgrading, even without a biological change in the underlying cancer per se, and hence our use of the term “re-classification”, rather than disease “progression”.

The results of the targeted (plus systematic) biopsy following the initial undertaking of mpMRI during AS likely accounts for much of the 30% of our cohort receiving radical treatment after a median time of 1.55 years, as our protocol had been to undertake that first mpMRI around one year after starting AS. The reported cohort of AS patients had not received a baseline pre-biopsy mpMRI, as this practice was introduced at our institution in 2016 [2], after these men had started AS. Hence, it is likely that the timing of men leaving AS to receive treatment was triggered by the first mpMRI as a follow-up measure and subsequent repeat targeted biopsies, rather than true biological disease progression. The use of indiscriminate repeat biopsies at pre-specified and arbitrary intervals during any AS protocol (as practiced historically before the availability of mpMRI) is likely to have driven men towards active treatment unnecessarily, and added to potential adverse effects of repeat biopsies on functional outcomes after radical prostatectomy [3].

With regards to the ProtecT study [4], men in the non-intervention arm received Active Monitoring (AM), rather than intensive AS. In ProtecT, men on AM did not receive regular imaging by mpMRI, nor did they receive repeat biopsies unless triggered by a suspicion of disease progression. This is very different from contemporary AS protocols. It is therefore inappropriate to draw parallels between AM in ProtecT and contemporary AS.

We agree that benefits of mpMRI in AS programs may be to reduce the proportion of patients who opt for active treatment due to anxiety, as well as decreasing the burden of multiple sets of unnecessary systematic biopsies.

The true definition of “clinically significant” prostate cancer is subject to much controversy, and many prostate cancers are classified inappropriately as “significant”. This depends on complex biological and molecular features of aggressive and lethal disease – yet to be defined by ongoing research – as well as competing co-morbidity. We agree entirely with Fode and colleagues that many men with localised intermediate-risk prostate cancer have a relatively low risk of dying from prostate cancer. This underpins the recommendation from the UK National Institute for Health and Care Excellence (NICE) that patients with low-volume low- and intermediate-risk localised prostate cancer may consider AS as a viable management option, re-iterated in its recently updated guidelines under consultation [5,6,7].

 

Richard J. Bryant*† , Prasanna Sooriakumaran†**, Freddie C. Hamdy*† and Simon F. Brewster*

*Department of Urology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK, †Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK, and **Department of Uro-Oncology, University College London Hospital NHS Foundation Trust, London, UK

 

References

  1. Bryant RJ, Yang B, Philippou Y, Lam K, Obiakor M, Ayers J, et al. Does the introduction of prostate multiparametric magnetic resonance imaging into the active surveillance protocol for localized prostate cancer improve patient re-classification? BJU Int.; 2018;122(5):794–800.
  2. Bryant RJ, Hobbs CP, Eyre KS, Davies LC, Sullivan ME, Shields W, et al. Comparison of prostate biopsy with or without pre-biopsy multi-parametric MRI in prostate cancer detection: an observational cohort study. J Urol. 2018. [Epub ahead of print]
  3. Sooriakumaran P, Calaway A, Sagalovich D, Roy S, Srivastava A, Joneja J, et al. The impact of multiple biopsies on outcomes of nerve-sparing robotic-assisted radical prostatectomy. Int J Impot Res. 2012;24(4):161-4.
  4. Hamdy FC, Donovan JL, Lane JA, Mason M, Metcalfe C, Holding P, et al. 10-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Localized Prostate Cancer. N Engl J Med.; 2016;375(15):1415–24.
  5. National Institute for Health and Care Excellence. Prostate Cancer: Diagnosis and Management (CG175). National Institute for Clinical Excellence; 2014.
  6. Graham J, Kirkbride P, Cann K, Hasler E, Prettyjohns M. Prostate cancer: summary of updated NICE guidance. BMJ 2014; 348: f7524
  7. https://www.nice.org.uk/guidance/GID-NG10057/documents/evidence-review-7.

 

 

RE: National implementation of multi-parametric MRI for prostate cancer detection – recommendations from a UK consensus meeting

/1 Comment/by

Letter to the Editor

National implementation of multi-parametric magnetic resonance imaging for prostate cancer detection – recommendations from a UK consensus meeting [1]

Dear Sir,

Appaya et al report on an expert consensus meeting regarding the implementation of multi-parametric magnetic resonance imaging (mpMRI) for prostate cancer detection [1]. A key item related to ‘who can request an mpMRI’ for patients with suspicion of prostate cancer. The panel unanimously agreed that GPs should not be able to. This is perhaps unsurprising, given the panel was composed entirely of specialists. The authors did consider inviting a GP: however, their assumption was that other than for this question a GP would have little to add. We believe this was a critical omission, as improving access to diagnostic testing in primary care could improve prostate cancer diagnosis,  urology outpatient workloads, patient experiences, and outcomes.

The vast majority of cancer diagnoses, including prostate, occur in symptomatic patients presenting to primary care [2]. GPs already have direct access to diagnostic testing for several other cancer types in the NHS – all endorsed by NICE guidance – including gastroscopy, colonoscopy, flexible sigmoidoscopy, MRI head, ultrasound, and CT abdomen. Each can be requested in primary care, with GPs retaining clinical responsibility for the investigation findings [3].

An oft-raised concern with GP direct access to diagnostic tests is that it will lead to inappropriate referrals. However, a recent systematic review of direct access cancer testing in primary care found no significant difference in pooled cancer conversion rate between GP and specialist requests (except for gastroscopy) and no significant difference in the appropriateness of referrals. Time from referral to testing was shorter with GP direct access testing and patient satisfaction was high [4].

If implementation of pre-biopsy mpMRI truly does reduce the need for biopsy in 27% of men, as suggested from the PROMIS [5] and PRECISION [6] trials, then direct access testing in primary care could significantly reduce referrals for suspected prostate cancer. At a time of limited NHS resources and more ambitious targets for cancer diagnosis and treatment times, this could ease the pressure on Urology departments across the UK.

There are several unanswered questions with regard to the optimal use of pre-biopsy mpMRI: for example, which men to test, how to safely follow-up mpMRI-negative patients, and MRI capacity. Including GPs in these discussions would not just be courteous: it may find better answers.

Dr Samuel Merriel1, Dr Fiona Walter2, Prof Willie Hamilton3

1 Clinical Research Fellow, University of Exeter

2 Principle Researcher in Primary Care Cancer Research, University of Cambridge

3 Professor of Primary Care Diagnostics, University of Exeter

References

  1. Appayya MB, Adshead J, Ahmed HU, Allen C, Bainbridge A, Barrett T, et al. National implementation of multi-parametric magnetic resonance imaging for prostate cancer detection – recommendations from a UK consensus meeting. BJU Int. 2018;122(1):13–25.
  2. Emery JD, Shaw K, Williams B. The role of primary care in early detection and follow-up of cancer. Nat Rev Clin Oncol. 2014;11:38–48.
  3. National Collaborating Centre for Cancer. Suspected cancer [Internet]. NICE. London; 2015.
  4. Smith CF, Tompson AC, Jones N, Brewin J, Spencer EA, Bankhead CR, et al. Direct access cancer testing in primary care: a systematic review of use and clinical outcomes. Br J Gen Pract. 2018;(August):1–10.
  5. Ahmed HU, El-Shater Bosaily A, Brown LC, Gabe R, Kaplan R, Parmar MK, et al. Diagnostic accuracy of multi-parametric MRI and TRUS biopsy in prostate cancer (PROMIS): a paired validating confirmatory study. Lancet [Internet]. 2017;389(10071):815–22.
  6. Kasivisvanathan V, Rannikko AS, Borghi M, Panebianco V, Mynderse LA, Vaarala MH, et al. MRI-Targeted or Standard Biopsy for Prostate-Cancer Diagnosis. N Engl J Med [Internet]. 2018.

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Reply by the authors

I thank Dr Samuel Merriel and Dr Fiona Walter for writing in about the role of the GP in requesting prostate MRI studies. Indeed, we reported that our consensus panel unanimously agreed that GPs should not be requesting prostate MRI studies [1]. Their letter in follow-up of this offers an opportunity to explain further this recommendation.

We adopted a UCL-RAND based methodology to conduct the consensus meeting. Whilst we would have liked to have broader representation on the panel, one of the key metrics necessitates that a minimum proportion of participants be able to answer a particular question for that question to be valid. Further broadening of the panel risked delivery of this.

Nonetheless, we agree that GP representation in designing and implementing healthcare is invaluable and should not be ignored and could have all of the benefits for prostate cancer diagnostics that are pointed out by Dr Merriel and Dr Walter.

To clarify the consensus panels discussion on this topic; the panel felt that within the current climate there remained many areas that needed standardisation and improvement if we are to realise the benefits highlighted in PROMIS [2] and PRECISION [3] e.g. diagnostic quality of scans, training of radiologists to report scans all the way through to a consensus from urologists of how to manage patients with a specific scan result.  The panel did not believe that GPs were incapable of managing direct referral services for prostate MRI, only that this needed to be introduced in a controlled fashion if we were to be successful in implementing multi-parametric MRI whilst maintaining its performance and value. The panel felt that direct GP referral should therefore be re-discussed once mechanisms to maintain scan quality and standards of reporting were realised across the UK.

Indeed, GPs should be included in the discussion of which men to test, how to follow-up mp-MRI negative patients and those related to MRI capacity – all of these assume that one is looking at a test that is correctly set-up and reported to a specific standard. Perhaps a consensus on management of patients amongst urologists and primary care physicians is a warranted next step.

Shonit Punwani1

1Centre for Medical Imaging, University College London, UK.

References

  1. Appayya MB, Adshead J, Ahmed HU et al. National implementation of multi-parametric magnetic resonance imaging for prostate cancer detection – recommendations from a UK consensus meeting. BJU Int 2018; 122:13-25.
  2. Ahmed HU, El-Shater Bosaily A, Brown LC, Gabe R, Kaplan R, Parmar MK, et al. Diagnostic accuracy of multi-parametric MRI and TRUS biopsy in prostate cancer (PROMIS): a paired validating confirmatory study. Lancet [Internet]. 2017;389(10071):815–22.
  3. Kasivisvanathan V, Rannikko AS, Borghi M, Panebianco V, Mynderse LA, Vaarala MH, et al. MRI-Targeted or Standard Biopsy for Prostate-Cancer Diagnosis. N Engl J Med [Internet]. 2018.

 

 

RE: National implementation of multi-parametric MRI for prostate cancer detection – recommendations from a UK consensus meeting

/by

Letter to the Editor

National implementation of multi-parametric magnetic resonance imaging for prostate cancer detection – recommendations from a UK consensus meeting [1]

Dear Sir,

We congratulate the authors for their efforts in standardising prostate mpMRI. However, we are concerned that the consensus as reported may place substantial pressure on the diagnostic pathway in a rapidly evolving field. Most departments in the West of Scotland and the UK are striving to offer a routine pre-biopsy MRI service, witnessing doubling of the demand on scanning and radiologist time [2], aggravating the nationwide shortage of radiologists [3].

A standard reporting system is vital to the consistent implementation of diagnostic pathways. PI-RADS version 2 focuses on the standardisation of reading, setting out where and when to use each sequence, and has been widely implemented [4]. This, however, has taken time and its learning curve is ongoing within local hospitals [5]. Its main advantage over a clinico-radiological Likert impression is the reduced flexibility of interpretation of radiological parameters, giving those gaining experience in the field a clear set of definitions to work to. We are concerned that enforcing a second system so quickly will discourage radiologists during their learning curves. The panel is entirely correct in stating that even with the use of Likert system, the reporting will be influenced by PI-RADS criteria. While the urology and uro-radiology communities have widely embraced PI-RAD reporting, official switch to Likert reporting may introduce unnecessary reporting subjectivity before individual radiologists are fully experienced with the use of PI-RADS. Furthermore, with the expectation of PI-RADS v3 in the near future, it may be better to adopt PI-RADS v2 now, and compare PI-RADS v3 and Likert system in due course.

The panel describes dynamic contrast enhancement (DCE) as essential component and we agree that mpMRI incorporating the use of contrast is well established, with particular impact on the distinction between PIRADS 3 and 4 lesions. However, a short 9 minute biparameteric MR protocol was as good as a longer and more elaborate protocol using DCE in detecting clinically significant prostate cancer [6]. In NHS Greater Glasgow and Clyde (NHSGGC), we adopted a pragmatic approach, selecting patients for whom contrast may be particularly informative, i.e. those with hip replacement surgery and those who had previous negative biopsies. A contrast MRI prostate scan takes at least 10 minutes longer, and requires nominated radiologist supervision, reducing the overall capacity by 20%. In a 12 month period (2017-2018), 2,333 diagnostic MR prostate scans (20% with contrast) were performed within NHSGGC. For full adoption of contrast prostate MR, it will be necessary to increase the imaging capacity by ~100 supervised imaging lists per annum. Pharmacokinetic modelled DCE parameters (and not visually inspected start of enhancement) have the greatest potential to detect aggressive disease [7,8]. However this approach is currently not deemed feasible for widespread UK use, due to the lack of suitable standardized software.

In summary, we welcome the consensus recommendations for a unified prostate cancer imaging diagnostic strategy, but propose a pragmatic evolving approach that is sympathetic to the constraints of local and regional resources, both in terms of imaging capacity and uro-radiology reporting expertise.

Elizabeth Day1, Amit Patel2, John Morrison2, Thomas Hambrock3, Hing Y Leung1,4

1 Department of Urology, NHS Greater Glasgow and Clyde, Glasgow, G12 0XH

2 Department of Radiology, NHS Greater Glasgow and Clyde, Glasgow, G12 0XH

3 Department of Radiology, The Christie NHS Foundation Trust, Manchester M20 4BX

4 CRUK Beatson Institute for Cancer Research, Glasgow G61 1BD

 

References

  1. Appayya MB, Adshead J, Ahmed HU et al. National implementation of multi-parametric magnetic resonance imaging for prostate cancer detection – recommendations from a UK consensus meeting. BJU Int 2018; 122:13-25.
  2. Day E, Nalagatla S, Shin JS et al. Triaging patients to primary biopsy or prostate MRI based on digital rectal examination improves the detection rate of TRUS biopsy and avoids unnecessary biopsies. JCU 2018.
  3. The Royal College of Radiologists. Scottish patients at risk from radiologist shortages. 2018.
  4. Padhani AR, Weinreb J, Rosenkrantz AB et al. Prostate Imaging-Reporting and Data System Steering Committee: PI-RADS v2 Status Update and Future Directions. Eur Urol 2018.
  5. Hansen NL, Koo BC, Gallagher FA et al. Comparison of initial and tertiary centre second opinion reads of multiparametric magnetic resonance imaging of the prostate prior to repeat biopsy. Eur Radiol 2017; 27:2259-2266.
  6. Kuhl CK, Bruhn R, Krämer N et al. Abbreviated Biparametric Prostate MR Imaging in Men with Elevated Prostate-specific Antigen. Radiology 2017; 285:493-505.
  7. Vos EK, Litjens GJ, Kobus T et al. Assessment of prostate cancer aggressiveness using dynamic contrast-enhanced magnetic resonance imaging at 3 T. Eur Urol 2013; 64:448-55.
  8. Hambrock T, Vos P, Hulsbergen-van de Kaa C et al. Prostate cancer: computer-aided diagnosis with multiparametric 3-T MR imaging–effect on observer performance. Radiology 2013; 266:521-30

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Reply by the authors

I read with great interest the letter composed by Day et al regarding our article: National implementation of multi-parametric magnetic resonance imaging for prostate cancer detection – recommendations from a UK consensus meeting (Appayya et al [1]).

The authors of the letter highlight several important points that were indeed discussed in detail at the consensus meeting.

The first being the pressure on diagnostic services that is expected to result from the implementation of a strategy adopting multi-parametric MRI prior to biopsy. We concur that there is a real risk that without additional funding and the specific training of specialist radiologists in prostate MRI, our aspirations to implement pre-biopsy MR will meet limited success. The consensus panel did agree that this remains an area where national support and prioritisation will be a key driver of success or failure.

The second point raised by Day et al was in regard to recommendation for the use of Likert verses PI-RADS version 2 reporting systems. This again was a well debated item at the consensus meeting. To clarify the consensus discussion, the panel felt that the PI-RADS v2 system was a good system to use when training to report prostate MRI, specifically as it has a very rigid set of definitions. Indeed, the intention of the panel in recommending Likert reporting was not to disregard the PI-RADS system, but to highlight that when sufficiently experienced we also use other factors in scoring that were not as yet incorporated into PI-RADS v2. Indeed, many experienced radiologists knowingly/unknowingly do not adhere to strict PI-RADS v2 scoring. For example, PI-RADS v2 recommends that clinical details (including PSA) should not influence interpretation yet it is almost ubiquitous that we report in light of the PSA and are now recommending PSA density measures to help us guide practice. Furthermore, many centres in the UK do not perform DCE MRI, yet report score as a PI-RADS v2– although DCE MRI as Day et al point out is a key component of the PI-RADS v2 scoring system. Any reports produced for patients that have had previous treatment cannot be scored by PI-RADS v2 criteria, yet there are ongoing examples of radiologists stating a PI-RADS v2 score within such reports.

In reality, Day et al are correct in pointing out that PI-RADS v3 may indeed resolve many of these issues.  PI-RADS v3 was not as far developed when the consensus meeting took place.

With regard to a bi-parametric verses multi-parametric approach; I would agree that most significant tumours will be detected with a bi-parametric MRI and that it will be a small minority that would benefit from DCE MRI. The difficulty to date has been that DCE MRI applications are very varied across studies and have generally concentrated on the use of pharmacokinetic parameters – which has limited studies looking at the value of DCE-MRI. Indeed, such protocols are difficult to themselves apply. The panel felt that a high resolution short DCE protocol that lasted 3 minutes could be implemented with visual inspection of the early arterial phase image for the detection of early enhancement indicative tumour. They also acknowledged that further research is required to establish the benefits of DCE MRI.

I would like to thank Day et al for their letter, as it is important to highlight these areas from the consensus paper in order (i) to recognise where national support is required, (ii) to help clarify any areas which more detailed description could not be provided within the paper, and (iii) to continue to recognise areas where research and further technique refinement is required.

Shonit Punwani1

1Centre for Medical Imaging, University College London, UK.

References

  1. Appayya MB, Adshead J, Ahmed HU et al. National implementation of multi-parametric magnetic resonance imaging for prostate cancer detection – recommendations from a UK consensus meeting. BJU Int 2018; 122:13-25.

 

 

Meta-analysis of HIV-acquisition studies incomplete and unstable

/by

Letter to the Editor

Re: Male Circumcision for the Prevention of HIV Acquisition: A Meta-Analysis

Sir,

The authors of a recent meta-analysis[1] of studies into male circumcision and HIV describe their findings as “compelling.” We disagree. They reported a remarkably high degree of inconsistency with 97% of variation across studies due to heterogeneity rather than chance (an astounding, rarely seen, level of heterogeneity). Using recently described methods[2], 28.57% of the studies would need to have been excluded to bring I2 below the 50% threshold (considered high) and 32.65% excluded to bring I2 below the 25% threshold considered acceptable (well above the expected 99th percentiles of 22% and 32%, respectively). Similarly, 65.51% and 65.93% of the total number of participants needed to be excluded to reach the 50% and 25% thresholds (above the 99th percentiles of 25% and 48%, respectively). Given this excessive between-study heterogeneity, Sharma et al. should have refrained from reporting summary estimates[3].

The authors half-heartedly attempted to explain the heterogeneity failing to recognise that both the risk profile and circumcision prevalence of the study population are significant factors[4], and also failing to acknowledge the sizeable percentage of iatrogenically transmitted HIV infections[5].

The authors excluded approximately half of the published studies that met their inclusion criteria[4]. Excluding studies that focused only on MSM, which have a distinctly different risk profile, we calculate the included studies as significantly more likely to report a greater treatment effect (random-effect summary odds ratio (circumcised versus intact) of (0.44, 95%CI=0.36-0.59) than the excluded studies (0.66, 95%CI=0.56-0.78) − (change in ln(OR)=0.35, 95%CI=0.07-0.65, t=2.44, p=0.016).

In assessing publication bias, the authors provided a funnel graph, declaring that the data plots “appear to be evenly distributed about the mean effect size, suggesting an absence of publication bias,” without applying any routine statistical tests. Four of six commonly used measures[6] exhibited significant publication bias.

The results of the randomised clinical trials (RCTs) have been noted as being “remarkably similar”[7]  − the probability of the results of these trials being so tightly clustered is only 0.03[8]. Can the 0% I2 reported in the meta-analysis of the RCTs be interpreted as indicating no appreciable variability between the studies? This certainly arouses suspicion of prior coordination: as Ioannidis noted, “At the extreme, fraud can cause perfect replication”[9].

The large sample size RCTs allowed small numerical differences to have an exaggerated impact on p-values. The Fragility Index (FI) (number of times one patient with the relevant finding is subtracted from one group and added to another group before the results are no longer significant)[10] for the three clinical trials was 4, 5, and 6, respectively, with an FI of ≥ 8 being common, and an FI of ≤ 3 being suspect.  Early discontinuance of these fragile studies with an absolute risk reduction between 0.8% and 1.9% was an artifact of being overpowered.

Given the effectiveness of condoms[11], the lack of consistent findings on national levels[12], the methodologically flawed RCTs[13], the lack of translational research, and the impressive potential uptake and effectiveness of pre-exposure prophylaxis[14], circumcision as an intervention to prevent HIV infection should be treated with greater scepticism.

Robert S. Van Howe1, MD, FAAP, and Gregory J. Boyle2, PhD, DSc, FAPS

1College of Medicine, Central Michigan University , Saginaw , MI , USA

2University of Melbourne, Parkville, VIC 3010, Australia

 

Read the article

References

  1. Sharma SC, Raison N, Khan S, Shabbir M, Dasgupta P, Ahmed K. Male circumcision for the prevention of human immunodeficiency virus (HIV) acquisition: a meta-analysis. BJU Int 2018; 121:515-26. doi:10.1111/bju.14102
  2. Patsopoulos NA, Evangelou E, Ioannidis JPA. Sensitivity of between-study heterogeneity in meta-analysis: proposed metrics and empirical evaluation. Int J Epidemiol 2008; 37: 1148-57. doi:10.1093/ije/dyn065
  3. Mueller M, D’Addario M, Egger M, et al. Methods to systematically review and meta-analyse observational studies: a systematic scoping review of recommendations. BMC Med Res Methodol 2018; 18: 44.
  4. Van Howe RS. Circumcision as a primary HIV preventive: extrapolating from the available data. Glob Public Health 2015; 10: 607-25.
  5. Gisselquist D, Pottarat JJ, Brody S, Vachon F. Let it be sexual: how health care transmission of AIDS in Africa was ignored. Int J STD AIDS 2003; 14: 148-61.
  6. Macaskill P, Walter SD, Irwig L. A comparison of methods to detect publication bias in meta-analysis. Statist Med 2001; 20: 641-54.
  7. Sansom SL, Prabhu VS, Hutchinson AB, et al. Cost-effectiveness of newborn circumcision in reducing lifetime HIV risk among U.S. males. PLoS One 2010; 5(1): e8723.
  8. Van Howe RS. “Math is your friend: a consumer’s primer to understanding epidemiology.” Genital Autonomy 2014: Thirteenth International Symposium on Genital Autonomy and Children’s Rights. Boulder, Colorado. July 24, 2014.
  9. Ioannidis JP. Scientific inbreeding and same-team replication: type D personality as an example. J Psychosom Res 2012; 73: 408–10.
  10. Walsh M, Srinathan SK, McAuley DF, et al. The statistical significance of randomized controlled trial results is frequently fragile: a case for a Fragility Index. J Clin Epidemiol 2014; 67: 622-8.
  11. de Vincenzi I. A longitudinal study of human immunodeficiency virus transmission by heterosexual partners. European Study Group on Heterosexual Transmission of HIV. N Engl J Med 1994; 331: 341-6.
  12. Garenne M. Long-term population effect of male circumcision in generalised HIV epidemics in sub-Saharan Africa. Afr J AIDS Res 2008; 7: 1-8.
  13. Boyle GJ, Hill G. Sub-Saharan African randomised clinical trials into male circumcision and HIV transmission: methodological, ethical and legal concerns. J Law Med 2011; 19: 316-34.
  14. Baeten JM, Donnell D, Ndase P, et al. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med 2012; 367(5): 399-410.

 

 

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