Tag Archive for: letter to the editor

Letter to the Editor

Anomalous observations with regard to prostate cancer research

Sir,

The article “Anomalous observations with regard to prostate cancer research” [1] was very interesting and informative and I actually agree with all the points raised in that article. Another important observation which may affect the relationship or association between metabolic syndrome (MetS ) and prostate cancer,  is the definition of MetS that is utilized in the various studies. For instance, the WHO definition of MetS uses hyperglycemia or the presence of diabetes mellitus as a mandatory requirement in its definition [2]. If used to define MetS in a study, there would be a very high likelihood of having an inverse relationship between MetS and prostate cancer. This is probably because of the established inverse relationship between diabetes and prostate cancer [3].  On the other hand, if the International Disease Federation (IDF) definition [4], which uses abdominal obesity as a mandatory requirement in its definition of MetS, is used, what would be observed is a more direct proportional relationship between MetS and prostate cancer. This may also be due to the fact that obesity has been associated with increased risk of prostate cancer. In the article by Häggström et al., they actually looked at specific factors of MetS in relation to prostate cancer [5]. They did observe that “hyperglycemia was associated with a decreased risk of prostate cancer while body mass index was associated with increased mortality from prostate cancer”.  Body mass index does correlate positively with measures of central obesity, so if the WHO MetS definition is used to classify their subjects, that inverse relationship comes out but it may not be so if the IDF definition is used. Thank you for your audience.

Dr Iya Eze Bassey

Department of Medical Laboratory Sciences, University of Calabar, Calabar, Nigeria

 

References

1. Hammarsten J. Anomalous observation with regard to prostate cancer in cancer research. BJU Int 2017, 120: 456–457.
2. World Health Organization. Definition, diagnosis and classification of diabetes mellitus and its complications, report of a WHO consultation. Part 1, diagnosis and classification of Diabetes Mellitus. Geneva: WHO publications, 1999.
3. Hsing AW, Sakoda LC, Chua JrSC. Obesity, metabolic syndrome, and prostate cancer. Am J Clin Nutr 2007; 86(3): 843S-857S.
4. Grundy SM, Cleeman JI, Daniels SR et al. American Heart Association; National Heart, Lung, and Blood Institute. Diagnosis and management of the metabolic syndrome, an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 2005; 112: 2735-2752.
5. Häggström C, Stocks T, Ulmert D et al. Prospective study on metabolic factors and risk of prostate cancer. Cancer 2012; 118: 6199–206.

 

Reply by the author

Thank you, Dr Iya Eze Bassey, for your points of view. You are quite right. This is really quite complex. You raise the difficulties which arise when you are testing the link between metabolic syndrome (MetS) and incident prostate cancer (PC) using the definitions put forth by the World Health Organizations. There are several difficulties here regarding surrogate measures for PC and MetS if your intention is to explore the link between MetS and its aspects and incident PC and PC pathophysiology.

Firstly, there is emerging evidence that the links between MetS and its aspects and incident PC are negative due to bias mechanisms in reports dominated by low-stage incident PC as is the case when the PC diagnoses are the results of PSA-driven diagnostic procedures. By contrast, the link between MetS and its aspects and incident PC are positive in reports dominated by high-stage PC which often is the case in studies based on symptom-driven diagnostic procedures [1,2].

Secondly, over the years, as you have pointed out MetS in man has been defined in different ways by several health organizations [3]. The practical use of the composite definitions of MetS focuses on its potential value as a risk factor for the development of cardiovascular diseases. It has been claimed by the American Diabetes Association and the European Association for the study of Diabetes, however, that MetS is imprecisely defined and appears to be of limited independent value as a marker of risk for cardiovascular diseases [2]. The definitions put forth by World Health Organizations include a mixture of clinical, anthropometric, haemodynamic, endocrine and metabolic aberrations typically observed in individuals with MetS. The four generally accepted definitions used to define MetS have been put forth by the World Health Organization, the National Cholesterol Education Program, the European Group for the Study of Insulin Resistance and the International Diabetes Foundation. None of these can yet be considered the gold standard, however, because they emphasize different aspects of MetS.

Given the limitations of MetS when it comes to cardiovascular diseases and other aspects of MetS, it is reasonable not to use composite definitions of MetS in PC research, if you are interested in the link between MetS and its aspects and incident PC and PC pathophysiology, simply because MetS as defined by World Health Organizations with a mixture of variables represents a poor surrogate measure for the underlying promoting factor(s) for PC growth. In our research, these established definitions of MetS have not been used. Instead, we have focused on risk factor analyses linking established aspects of MetS, such as prevalence of Type 2 Diabetes and treated hypertension, systolic and diastolic blood pressure, body weight, BMI, waist and hip measurements, waist/hip ratio, fasting insulin, HDL-cholesterol, triglycerides and others, which we think are more robust surrogate measures for metabolic aberrations when it comes to exploring the link between MetS and its aspects and incident PC and PC pathophysiology.

 

Dr Jan Hammersten

Gothenburg, Sweden

 

References

1. Hammarsten J. Anomalous observation with regard to prostate cancer in cancer research. BJU Int 2017, 120: 456–457.
2. Hammarsten J, Damber J-E, Haghsheno MA et al. A stage-dependent link between metabolic syndrome and incident prostate cancer. Nature Reviews Urology. In principal accepted for publication.
3. Kahn R, Buse J, Ferannini E et al. The metabolic syndrome: time for critical appraisal. Joint statement from the American Diabetes Association and the European Association for the study of Diabetes. Diabetologia 48, 1684-1699 (2005).

 

Letter to the Editor

The Origins of Urinary Stone Disease: Upstream mineral formations initiate downstream Randall’s plaque

Sir,

We have read with great interest the paper by Hsi et al.[5] and we would like to comment on this paper with two aims: Firstly, to congratulate the authors on a new observation that could transform our understanding of mineralization processes in the renal papilla, but secondly to voice caution concerning the new hypothesis that they have put forth to explain the formation of Randall’s (interstitial) plaque.

Hsi et al.[5] took renal papillae from non-stone formers undergoing nephrectomy, and analyzed mineral content using micro CT. This means that they were able to visualize mineral throughout each papilla without using the laborious method of serial section. They found intratubular mineral in the outer medulla of all 12 patient papillae that they examined.

Our own studies [1-3], have focused on biopsies of the papilla tip, so we have little data on the outer medulla. However, we have examined the entire medulla in four patients (non-stone formers with no family history of stones) undergoing nephrectomy (two for renal cell carcinoma and two for benign disease) and we have not seen mineral deposits such as Hsi et al.[5] describe but we did not carry out micro CT on those specimens. A more recent report on mineralization in the renal medulla did state that intratubular mineral was seen in the majority of specimens, but no details on these were provided in that study [4]. The presence of microscopic mineral deposits in tubules of the outer medulla by Hsi et al.[5] is an interesting finding, but since the patients studied were not stone formers the implications of such deposits on nephrocalcinosis and renal stones is unclear. Further work on this is certainly required.

In the meantime, we would caution readers that the connection that Hsi et al.[5] make in their paper between mineral deposits in the outer medulla and the formation of Randall’s plaque at the papillary tip is still quite hypothetical. First of all, mineral in kidneys from cancer patients could reflect that disease more than it would necessarily provide data applicable to kidney stones. Secondly, the linking of intratubular mineral in the outer medulla with interstitial mineral at the papilla tip is based solely on the fact that when Hsi et al.[5] observed Randall’s plaque, the intratubular mineral in the outer medulla was especially prevalent. This coincidence, of course, could simply reflect greater crystallization at both locations due to a shared risk factor (such as increased calcium excretion).   In particular, the association between calcifications in both locations they observed need not imply a causal link whereby mineral in the outer medulla leads to mineral at the papilla tip. Finally, the pressure model used by Hsi et al.[5] to explain the deposition of Randall’s plaque at the papilla tip is one that ignores the normal, homeostatic mechanisms controlling blood flow and nephron filtration rates, which are likely to have more control over flow in the tubules of the medulla than would blockage of peripheral nephrons.

In summary, we recognize the findings of Hsi et al.[5] as novel, but urge appropriate caution toward some of their conclusions. The title of their paper notwithstanding, there is much to do to establish that these observations are relevant to mechanisms of kidney stone formation.

 

James E. Lingeman

Amy E. Krambeck

Department of Urology, Indiana University School of Medicine, Indianapolis, IN, USA

Tarek M. El-Achkar

Division of Nephrology, Indiana University School of Medicine, Indianapolis, IN, USA

Andrew P. Evan

James C. Williams, Jr.

Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA

John C. Lieske

Department of Medicine, Mayo Clinic, Rochester, MN, USA

Elaine M. Worcester

Fredric L. Coe

Renal Section, University of Chicago School of Medicine, Chicago, IL, USA

References

1. Evan AP, Lingeman JE, Coe FL, Parks JH, Bledsoe SB, Shao Y, Sommer AJ, Paterson RF, Kuo RL and Grynpas M. Randall’s plaque of patients with nephrolithiasis begins in basement membranes of thin loops of henle. J Clin Invest 2003; 111:607-616
2. Coe FL, Evan AP, Lingeman JE and Worcester EM. Plaque and deposits in nine human stone diseases. Urol Res 2010; 38:239-247
3. Evan AP, Lingeman JE, Worcester EM, Sommer AJ, Phillips CL, Williams JC, Jr. and Coe FL. Contrasting histopathology and crystal deposits in kidneys of idiopathic stone formers who produce hydroxyapatite, brushite, or calcium oxalate stones. Anat Rec 2014; 297:731-748
4. Verrier C, Bazin D, Huguet L, Stéphan O, Gloter A, Verpont M-C, Frochot V, Haymann J-P, Brocheriou I, Traxer O, Daudon M and Letavernier E. Topography, composition and structure of incipient randall’s plaque at the nanoscale level. J Urol 2016; 196:1566-1574
5. Hsi RS, Ramaswamy K, Ho SP and Stoller ML. The origins of urinary stone disease: upstream mineral formations initiate downstream Randall’s plaque. BJUI 2017

 

Reply by the authors

 

Intratubular minerals that were previously unappreciated have been identified in the proximal regions of the renal papilla using non-invasive high resolution X-ray microscopy/tomography. As also observed by Verrier et al., J Urol., 2016 [1], these proximal intratubular minerals do exist and are real. Many groups focus their research exclusively on the distal interstitial papillary minerals, the classic Randall’s plaque (RP). The proximal intratubular minerals cannot be seen endoscopically in contrast to the distal papillary minerals as illustrated in our manuscript.

It is valid to ask if, and how the intratubular biominerals are related to interstitial biominerals; collectively, are they related to stone pathogenesis? Our proposed model was formulated on consistently observed patterns from over 30 renal papillae excised from human kidneys (from cancer and non-cancer non-stone formers, and stone formers). Intratubular minerals were observed in the absence of interstitial biominerals. Conversely, interstitial biominerals were never found without proximal intratubular biominerals. In the absence of a valid animal model, our observations led us to hypothesize that there could be a temporal evolution of papillary biomineralization starting first in the proximal intratubular regions, and progressively mature into the interstitial minerals which are endoscopically visible and often documented/investigated.

What are Randall plaques? This question often is asked by scientists from different disciplines that hear about kidney stones. How are they formed? Are they precursors to kidney stones? The etiology of RP formation has been asked in urology for close to a century. The constant interrogation of the renal tip may not provide all the critical insights into the initiation of stone disease. Several hypotheses have been proposed regarding stone pathogenesis by others. Intratubular formations are based on fundamentals of diffusion and pressure gradients, and physical chemistry approaches. Fundamentally, physical chemistry can explain the sequestration of inorganic on organic and subsequent aggregation of small nanoparticles forming into larger particles. While these approaches can provide insights into interstitial biomineral formations, they also can be applied to explain the uniquely different intratubular biominerals.

Form and function can be used to help explain the formation of intratubular minerals at the levels of the papilla and the nephron as described by Jean Oliver 1968 [2]. Analogous to a stream, where leaves gather along the edges, particulates within the filtrate gather along the sides of the nephrons while maintaining fluid flow at the center of the nephron. This fundamental related to fluid flow can be leveraged at several length scales. We have applied it to the nephron and clusters of nephrons that form a pyramidal-shaped papilla. The collective aspects of linking intratubular with the commonly known interstitial biominerals unite the fields of two distinct yet overlapping disciplines – urology and nephrology. Urologists center their attention on the renal papilla and nephrologists on the nephron of the same papilla. Merging the structure of the nephron to that of the renal papilla will help understand stone pathogenesis, and this forms the basis for the title of our manuscript.

We thank you for providing this opportunity to further elaborate on our recent findings.

 

Sunita P. Ho, PhD

Division of Biomaterials and Bioengineering

School of Dentistry, UCSF

Ryan Hsi, MD

Urologic Surgery

School of Medicine

Vanderbilt University

Marshall Stoller, MD

Department of Urology, UCSF

 

 

References

1. Verrier C, Bazin D, Huguet L, Stéphan O, Gloter A, Verpont M-C, Frochot V, Haymann J-P, Brocheriou I, Traxer O, Daudon M and Letavernier E. Topography, composition and structure of incipient Randall’s plaque at the nanoscale level. J Urol 2016; 196:1566-1574
2. Oliver J. Nephrons and kidneys: a quantitative study of development and evolutionary mammalian renal architectonics. New York: Harper & Row; 1968.

 

Letter to the Editor

Robot-assisted partial nephrectomy for the treatment of challenging renal tumors: To get the best recommendation (RE: Comparison of robot-assisted and open partial nephrectomy for completely endophytic renal tumours: a single centre experience)

 

Dear Sir,

With the wide application of robotic surgery in partial nephrectomy (PN), urologists became more interested in assessing its efficacy and safety for the treatment of challenging renal tumors [1-5]. In the current study, Kara and colleagues published the first retrospective  report to compare between robot-assisted partial nephrectomy (RAPN) and open partial nephrectomy (OPN) for the treatment of completely endophytic renal tumors [1]. We congratulate the authors for their valuable work.  15

As expected, they found less blood loss, shorter length of hospital stay, and lower  intraoperative transfusion rates in favor of the robotic group. In fact, the safety and superiority of RAPN over OPN in terms of the intraoperative and perioperative outcomes is no longer a matter of debate. In a recent systematic review and met-analysis, RAPN was found to be an efficient alternative to OPN with the advantages of a low perioperative complication rates, short hospital stay and less blood loss [6]. Despite no RCTs present in this meta-analysis, it confirms the minimally invasive advantages of RAPN over OPN. Recently, in a retrospective matched-pair comparative study between RAPN (n=190) and OPN (n=190) for the treatment of complex renal tumors (RENAL score ≥7), the authors concluded that 35 RAPN is associated with less blood loss (p<0.001), shorter hospital stay (p<0.001) and lower postoperative complication rates (p=0.002); on the other hand, the long-term oncological and functional outcomes at median follow-up (49 and 52 months for RAPN and OPN, respectively) were similar [2]. The treatment of completely endophytic tumors is considered a major challenge to the surgeon. The inaccuracy in identification of tumor extension, the increased risk of vascular entry, and the need for reconstruction of a large parenchymal and pelvicalyceal defect might have a negative influence on the oncologic safety and renal function preservation. However, the introduction of robotic technology and increasing experience in RAPN have allowed for a meticulous dissection of endophytic tumors with intraoperative US guidance, renorrhaphy completion within short time, and improved perioperative outcomes. In experienced hands, when comparing the exophytic, mesophytic and totally endophytic renal tumors, RAPN was found to be safe and feasible procedure in terms of complication rates, functional and oncologic outcomes [3,4]. To our knowledge, the length of WIT is considered a crucial factor affecting the postoperative renal function after PN. The continue evolving in RARP techniques, for example, the sliding-clip renorrhaphy [7], had allowed skillful reconstruction of the large parenchymal and pelvicalyceal defect within safe and acceptable WIT [1-5].    And the important question, what about the long-term oncological and functional difference in estimated glomerular filtration preservation rates and latest functional follow-up between RAPN and OPN. These outcomes were assessed at median follow-up of 15 and 18 months for RAPN and OPN, respectively [1]. This period of follow-up might not be long enough to arrive at a meaningful conclusion regarding the oncologic and functional outcomes of both procedures. Being a retrospective study is one of the limitations in this study; however, we believe that to arrange a well-designed prospective randomized study comparing the robotic and open procedures is a dream difficult to be achieved. In summary, the superiority of RAPN over OPN regarding the perioperative safety has been proven even in challenging cases [1,2,6].  Recent guidelines have poor evidence in recommending the ideal approach to treat large-size, high-complex and/or totally endophytic renal tumors. Thus, the future research directions should be focused on evaluating the long-term outcomes of different PN procedures in order to reach a firm recommendation for treatment of these challenging cases.

 

References: 

1. Kara O, Maurice MJ, Malkoc E, et al. Comparison of robot-assisted and open partial nephrectomy for completely endophytic renal tumours: a single centre experience. BJU Int. 2016 Aug 1. doi: 10.1111/bju.13572.

2. Wang Y, Shao J, Ma X, Du Q, Gong H, Zhang X. Robotic and open partial  nephrectomy for complex  renal tumors: a matched-pair comparison with a long-term follow-up. World J Urol. 2016.            doi:10.1007/s00345-016-1849-8.

3. Komninos C, Shin TY, Tuliao P et al. Robotic partial nephrectomy for completely endophytic renal tumors: complications and functional and oncologic outcomes during a 4-year median period of follow-up. Urology 2014; 84: 1367–73.

4. Curtiss KM, Ball MW, Gorin MA, Harris KT, Pierorazio PM, Allaf ME. Perioperative outcomes of robotic partial nephrectomy for intrarenal tumors. J Endourol 2015; 29: 293–6.

5. Abdel Raheem A, Alatawi A, Kim DK, et al. Outcomes of high-complexity renal 36 tumours with a Preoperative Aspects and Dimensions Used for an Anatomical (PADUA) score of ≥10 after robot-assisted partial nephrectomy with a median 46.5-month follow-up: a tertiary centre experience. BJU Int. 2016 Apr 22. doi:10.1111/bju.13501.

6. Wu Z, Li M, Liu B, et al. Robotic versus open partial nephrectomy: a systematic 49 review and meta-analysis.

7. Benway BM, Wang AJ, Cabello JM, Bhayani SB. Robotic partial nephrectomy with sliding-clip renorrhaphy: technique and outcomes. Eur Urol, 55 (2009), pp. 592–599

 

 Ali Abdel Raheem and Koon Ho Rha 

Department of Urology and Urological Science Institute, Yonsei University College of Medicine, Seoul, South Korea