Tag: Prostate cancer

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Editorial: Robot-assisted radical prostatectomy: getting your ducks in a row!

April 3, 2013/by Khurshid A. Guru

Robot-assisted radical prostatectomy (RARP) has become the technique of choice for clinically localised prostate cancer. However, marked inter-surgeon heterogeneity and an obvious lack of standardisation exist for the indications and technique of the procedure. In this issue of the BJUI, Ficarra et al. conducted a multinational survey seeking opinion from 145 robotic surgeons about individual practices during RARP. These opinions can be compared against the benchmark set by the Pasadena Consensus and can help gauge the impact of its recommendations.

Responses from 116 (79.4%) invited surgeons were analysed. The authors acknowledge the limited participation of non-European surgeons (17.1%), which may limit validity and application of its results at a global level. Most surgeons were in consensus with the Pasadena recommendations for transperitoneal access (88%), antegrade approach (76%) and bladder neck preservation (77%). The opinions on cautery use for the seminal vesicle/vas deferens dissection (51% athermal; 21% bipolar), athermal nerve-sparing approach (90%) and the use of the running suture technique for urethrovesical anastomosis (96.6%) were also in agreement.

Despite wide surgeon and institutional variability regarding the deﬁnition of bladder neck preservation and its role in the return of urinary continence, most preferred to preserve the bladder neck. This may pose diﬃculty in the interpretation of the results in view of the ambiguity about the deﬁnition and technique adopted under the term ‘bladder neck preservation’ (Eur Urol, BJU Int).

Most of the participating surgeons were using anterolateral prostatic fascia dissection (Veil of Aphrodite) towards preserving the cavernous nerves by using an athermal approach. Over the last decade the evolution of robot-assisted surgery, with excellent three-dimensional visualisation, depth perception, and EndoWrist^® technology has made working in the conﬁnes of the pelvis both ubiquitous and a desired skill.

The present study found that 33% of surgeons omitted the internal iliac lymph nodes (LNs) and removed only obturator, with or without the external iliac LNs. The Pasadena Consensus recommends a template that includes the internal iliac, external iliac and obturator LNs. Mattei et al. in an attempt to map primary prostatic lymphatic ‘landing’ zones found that after performing a standard limited LN dissection (dorsal to and along the external iliac vein; medially along the obturator nerve) only 38% of LNs were removed. They recommended a template that retrieves LNs extending up to the ureteric crossing of the common iliac vessels. Meanwhile, Menon et al. evaluated the role of only internal iliac LN dissection (limited) in patients with a low probability of nodal disease (Partin table prediction 0–1%), and surprisingly found positive LNs in the internal iliac/obturator region 13.7 times more often than in the external iliac/obturator region. One of the issues that could be addressed in future surveys would be to evaluate how surgeons view and adapt to changes in the proposed LN template. The Pasadena Consensus further recommends considering performing LN dissection for the low-risk category based on the D’Amico risk stratiﬁcation. The surgeon’s indications for pelvic LN dissection were not addressed in this survey.

Despite signiﬁcant studies, including two randomised controlled trials (RCTs), published in the peer-reviewed literature reporting minimal advantage for early recovery of urinary continence with posterior reconstruction, a signiﬁcant number of the surveyed surgeons still preferred to perform it. Responses to other questions about the posterior/anterior reconstruction also showed marked variability reﬂecting the controversial opinion about the value of these surgical steps.

On the other hand, future surveys should gather opinions about the role of RARP for high-risk disease, standardised evaluation of surgical complications; while addressing continence and potency status along with methods of their measurement. These topics were already addressed in the Pasadena Consensus and obtaining opinions of surgeons will further provide insight as to how surgeons adapt to the ever-changing advances in this ﬁeld.

Over the last decade RARP has gained acceptance despite the absence of high-quality RCTs in robot-assisted surgery. The Pasadena Consensus was meant to meet the need for uniformity and this study educates us on how the surgeons really perform ‘in the trenches’. Until further evidence is available, surgeon experience and institutional volume will remain the main force driving the use of these surgical techniques and their outcomes.

Ahmed A. Aboumohamed and Khurshid A. Guru
Department of Urology, Roswell Park Cancer Institute, Buﬀalo, NY, USA

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A Tale of Four Prostates

March 25, 2013/12 Comments/by Roger Kirby

There was a time when doctors were reluctant to tell patients the truth about a diagnosis of cancer, and even more unwilling to discuss any illness from which they themselves suffered. John Anderson broke the mould last year when he made a public announcement about his newly diagnosed liver metastases, which subsequently turned out to be the result of secondary spread of adenocarcinoma of the prostate.

John was President Elect of the British Association of Urological Surgeons (BAUS) at the time, so sadly had to resign his presidency (the best president we never had!) and subsequently his trusteeship of the Prostate Cancer UK charity. John’s energy and drive are legendary, he is a true surgeon’s surgeon. The stoicism and determination that he has displayed throughout a year in which he has received hormonal treatment, followed by chemotherapy, is awe-inspiring.

My admiration for John, in addition to my own recent diagnosis of localised prostate cancer, requiring robot-assisted radical prostatectomy (https://moreintelligentlife.co.uk/content/ideas/simon-garfield/prof-roger-kirby) led me to approach Sean Vesey and Damian Hanbury, whom I knew were similarly afflicted by a disease that carries a 1 in 9 lifetime risk. It occurred to me that there was a great deal to be gained from frank disclosure and discussion, as opposed to treating this problem as some dark, furtive secret. Women suffering from breast cancer are generally much more open about their problem and consequently receive much more support from friends, relatives and others who have been touched by the disease. This empowers them to make the difficult but smarter choices about their health by opting in to breast cancer treatment. Men need this kind of social encouragement and support so that we can be within reach to them as well.

The result was a publication entitled “a Tale of Four Prostates” in the upcoming issue of Trends in Urology and Men’s Health (www.trendsinurology.com) and a short accompanying video.

In this John, Damian and myself discuss the impact of our respective diagnoses and treatment. We sincerely hope that, by being frank, honest and transparent about our own situation, we can help other patients to help themselves by seeking advice and treatment earlier, and by sharing information about their diagnosis with others in order to mobilize support from their family and friends.

Sadly, John Anderson has since died. You can read an obituary by Roger Kirby here.

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Concurrence of squamous cell carcinoma, sarcomatoid carcinoma and adenocarcinoma in relapsed prostate cancer originated from adenocarcinoma

March 19, 2013/by admin Z.9

Squamous cell carcinoma (SqCC) and sarcomatoid carcinoma (SC) are rare subtypes of prostate cancer. We report a rare case with concurrence of SqCC, SC and adenocarcinoma in a relapsed tumour originated from adenocarcinoma.

Authors: Ruiying Diao^1,2, Kin Lam Fok³, Zhongfu Zhang^1,2, Li Zhao^2,4, Lisha Mou^1,2,5, Shuolei Sun^1,2, Lijun Zhou^1,2 and Zhiming Cai^2,6
¹Department of Urology, Peking University Shenzhen Hospital, Shenzhen, China
²Guangdong Key Laboratory of Male Reproductive Medicine and Genetics, Peking University Shenzhen Hospital, Shenzhen, China
³Epithelial Cell Biology Research Center, Department of Physiology, School of Biomedical Sciences, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong, China
⁴Department of Laboratory Medicine, Peking University Shenzhen Hospital, Shenzhen, China
⁵Institute of Urology, Shenzhen PKU-HKUST Medical Center, Shenzhen, China
⁶Department of Urology, Second People’s Hospital of Shenzhen, Shenzhen, China

Corresponding Author: Zhiming, Cai. Guangdong Key Laboratory of Male Reproductive Medicine and Genetics, Peking University Shenzhen Hospital, and Department of Urology, Second People’s Hospital of Shenzhen, Shenzhen, China. E-mail: [email protected]

Abstract
Squamous cell carcinoma (SqCC) and sarcomatoid carcinoma (SC) are rare subtypes of prostate cancer. We report a rare case with concurrence of SqCC, SC and adenocarcinoma in a relapsed tumour originated from adenocarcinoma. A 62-year-old man diagnosed with prostate adenocarcinoma (Gleason score 5+4=9) received androgen blockade (AB) treatment and 89Sr radiotherapy. An increase in total prostate-specific antigen level was noted 13 months after treatment. Pathological analyses on biopsies from transurethral resection of the prostate revealed the concomitance of SqCC and SC with adenocarcinoma (Gleason score 5+5=10). Expression of the epithelial markers E-cadherin and β-catenin were significantly down-regulated, while the mesenchymal marker vimentin was up-regulated in both SqCC and SC. The expression of androgen receptor (AR) was down-regulated in SqCC but elevated in SC. The altered epithelial and mesenchymal markers and the heterogeneous AR expression in the relapsed tumour suggest that the concurrence of unusual subtypes may arise from the epithelial-to-mesenchymal transition and/or the differential function of AR on prostatic epithelial and stromal cells. The present study raises concerns about antiandrogen therapy regimen for prostate cancer.

Introduction
Prostate cancer is the most common malignant tumour in men > 70 years old and the morbidity of prostate cancer has been markedly increasing in recent years [1, 2]. Prostatic squamous cell carcinoma (SqCC) and sarcomatoid (SC) are rare subtypes of prostate cancer that account for 0.5–1% and < 0.1% of all prostate tumours, respectively [3-5]. The prognosis of patients with SqCC and SC is usually poor. Understanding the origin and initiation of SqCC and SC may benefit the development of an effective therapeutic regimen. SqCC and SC have mainly been observed after endocrine therapy or radiotherapy [4]. It has been postulated that the selection pressure from endocrine therapy is one of the driving forces for clonal selection in SqCC, but the exact mechanism underlying the occurrence of SqCC and SC de novo is not yet understood. The present study reports a rare pathological differentiation from initial adenocarcinoma to the concomitance of three kinds of pathological subtypes, adenocarcinoma, SqCC and SC. The expression of androgen receptor (AR), epithelial markers E-cadherin and β-catenin, and the mesenchymal marker vimentin in specimens before and after therapy were examined to evaluate their possible involvement in the transformation of pathological phenotypes.

Case Report
A 62-year-old patient was admitted to our hospital on 3 February 2010 with a 36-month history of progressive LUTS. Before these symptoms, there had been no previous history of urinary tract disease. His PSA level during admission was 30.5 ng/mL (Fig. 1A). The initial pathological analysis from needle biopsy led to a diagnosis of moderately differentiated adenocarcinoma with small acinar infiltration and proliferation mainly centered in the peri-acinar region (Gleason score 5+4=9, FIG. 1B, i). A bone scan revealed widespread metastases. The patient was treated with androgen deprivation therapy for 10 months as the initial regimen. During this period, 89Sr radionuclide therapy against prostate cancer was used twice, once at 4 months and once at 9 months, and the patient’s total PSA level was initially suppressed but was then elevated at a later stage (FIG. 1A). TURP was undertaken for pathological analysis at 13 months because of the increase in total PSA level (FIG. 1A). Specimens were ﬁxed intact in 4% formalin and then sectioned transversally at regular intervals for random sampling (10 points). Pathological diagnosis showed concurrent adenocarcinoma, SqCC and SC (Gleason score 5+5=10). A 55% area of the TURP specimen showed the pathological structure of adenocarcinoma with abundant clear cytoplasm and enlarged nucleolus (FIG. 1B, ii). An area of ~25% of the TURP specimen showed the differentiation of SqCC with individual cell keratinization (cytokeratin high molecular weight; FIG. 1B, vi), intercellular bridges, and/or keratin pearl formation (FIG. 1B, iii). An area of nearly 20% of the TURP specimen showed bizarre atypia with giant cells and a tumour-induced osteoclastic phenotype with S-100 positive (a marker for osteosarcoma) in SC (FIG. 1B, iv). From the 13th month to time of death, serum total PSA increased rapidly to nearly 400ng/mL (FIG. 1A).
Compared with samples from the needle biopsy, the intensities of AR (FIG. 2B), and E-cadherin and β-catenin (FIG. 3B) immunoreactivity were all significantly lowered in SqCC. Similar to the pattern in the SqCC, the expression of E-cadherin and β-catenin in specimens after therapy was also lower in SC compared with those before therapy. The expression of the mesenchymal marker vimentin was increased after therapy (FIG. 1B, x), but the expression of AR was elevated in SC (FIG. 2B, iv, viii). Moreover, the AR C-terminal ligand-binding domain was mainly located in the cytoplasm of osteosarcomatous cells (FIG. 2B, iv), while the AR N-terminal transcription activation-binding domain was mainly located in the nucleus of osteosarcomatous components (FIG. 2B, viii).

Fig. 1 Serum total PSA levels and diagnosis of prostatic cancer before and after therapy. A, Serum total PSA levels from admission to death. B, (i) prostatic adenocarcinoma from prostate needle biopsy before therapy; (ii) prostatic adenocarcinoma from TURP after therapy; (iii) prostatic sqCC from TURP after therapy; (iv) SC after the TURP after therapy; immunohistochemical staining for (v–vi) cytokeratin high molecular weight, (vii-viii) S-100 and (ix-x) vimentin expressions before and after therapy. Haematoxylin-eosin stain, x200. Admission time was set as 0 month. ADT, androgen deprivation therapy; 89Sr, 89Sr radiation; BT, before therapy; AT, after therapy. i-iv, scale bar=50 μm; v-x, scale bar=200 μm.

Fig. 2 Immunohistochemical staining for AR(C) and AR(N) in the adenocarcinoma, SqCC, and SC specimens before and after therapy. A, Immunohistochemical staining for AR(C) and AR(N) in the adenocarcinoma, SqCC, and SC specimens before and after therapy (i–viii). B, Statistical analysis for immunohistochemical staining of AR.
Note: AR(C), AR C-terminal ligand-binding domain; AR(N): AR N-terminal transcription activation-binding domain. Magnification, X200. BT, before therapy; AT, after therapy, **, compared with BT-adenocarcinoma group (BT-A, AR[C]), P<0.05; ##, compared with BT-adenocarcinoma group (BT-A, AR[N]), P<0.05. i-x, scale bar=50 μm.

Fig. 3 Immunohistochemical staining for E-cadherin and β-catenin expressions before and after therapy . A, Immunohistochemical staining for E-cadherin and β-catenin expression before and after therapy (i-viii). B, Statistical analysis for immunohistochemical staining of E-cadherin and β-catenin. Magnification, X200. BT, before therapy; AT, after therapy; **, compared with BT-adenocarcinoma group (BT-A, E-cadherin), P<0.05; ##, compared with BT-adenocarcinoma group (BT-A, β-catenin), P

Discussion
Sarcomatoid carcinoma and SqCC are unusual histological prostatic tumours with a low incidence rate. About half of them can arise from patients with initial acinar adenocarcinoma after endocrine therapy or radiotherapy [4], but the mechanism underlying the occurrence of histological variants of prostate carcinoma remains unknown. In the present case, the concurrence of SqCC and SC was observed in a relapsed tumour originated from adenocarcinoma. The characteristics of the unusual concurrence of multiple carcinoma may provide some clues as to the pathogenesis of histological variants of prostate cancer.
Serum PSA level is the main indicator for estimating the prognosis of prostate cancer [6]. It has been reported that PSA can regulate and transactivate AR expression in prostate cancer cells [7]. During the initial phase of antiandrogen therapy, serum PSA concentration decreased, then rapidly increased at a later stage (FIG. 1A), indicating insensitivity to the hormone therapy [8]. Pathological analysis of the specimens from the needle biopsies suggested that primary multifocal adenocarcinoma tumour occurred both in the right and left lobes. Even with androgen deprivation therapy and radionuclide therapy, the total PSA level of the patient rose gradually from the 13th month (FIG. 1A), therefore, TURP was undertaken for more precise pathological analysis. Intra-operative localization in the TURP specimen indicated that extensive multifocal carrion-like tissues were found in the the middle, left and right lobes of the prostate. Samples from all the three lobes were found to be tumours, based on histological features and immunohistochemical evidence of epithelial and sarcomatoid-like differentiation, including vimentin (FIG. 1B, x) and PSA (FIG. 1A).
Histological analysis of the relapsed tumour found adenocarcinoma, SqCC and SC and revealed a lower AR expression in the area of SqCC, but a significantly higher AR expression in the SC region. Furthermore, the AR C-terminal domain was mainly localized in the cytoplasm of giant cells and tumour-induced osteoclastic cells in the SC, while the AR N-terminal transcription activation-binding domain was mainly in the nucleus of the above cell types. AR has been shown to exert dual functions in prostate cancer proliferation and metastasis. On the one hand, it acts as a suppressor in prostate epithelium, on the other hand, it promotes proliferation in stroma [9, 10]; therefore, the differential expression of AR in relapsed tumour may contribute to the differential response and insensitivity to antiandrogen therapy in the patient [11].
A number of studies have shown that adenocarcinoma can undergo the epithelial-to-mesenchymal transition (EMT) in order to migrate and invade other tissues [12, 13]. EMT is also considered to be a de-differentiation process, which is associated with the loss of epithelial markers and gain of mesenchymal markers [14]. In the present case, mixed populations of E-cadherin- (FIG. 3A, ii, iii) and β-catenin- (FIG. 3A, vi, vii) negative and positive cells were detected in the region between the junction of adenocarcinoma and SqCC. Moreover, down-regulation of E-cadherin (FIG. 3A, iii, iv) and β-catenin (FIG. 3A, vii, viii) and up-regulation of the mesenchymal marker vimentin (FIG.1.Bx) was found in the areas of both SqCC and SC, suggesting that the relapse of three subtypes of prostate cancer may be partially originated from a stem-like cell from the EMT of initial adenocarcinoma; however, the signal that triggers the EMT process in this case remains unknown. Interestingly, it has been suggested that androgen can trigger EMT in prostate tumour epithelial cells, and the effect is inversely correlated with expression levels of AR [15]. While we proposed that EMT may contribute to SqCC, SC and possibly other undifferentiated histological variants of the prostate cancer, the association between AR and EMT suggest that the occurrence of SqCC and SC from the initial adenocarcinoma may be a consequence of the antiandrogen treatment.

Conclusion
The alteration in epithelial and mesenchymal markers and differential AR expression may underlie the concurrence of multiple carcinoma in this case of prostate cancer. The insensitivity of the patient to antiandrogen treatment with a rapid increase in PSA level and the observed differential expression of AR in SqCC and SC raise doubts about the treatment regime, which warrants future investigation.

Acknowledgement
This work was supported by grants from the national High Technology Research and Development Program of China (863 Program, 2006AA02A302 and 2009AA022707) and Bank of Clinical Data of Major Diseases and Biological Specimens of Shenzhen (CXC201005260001A). The authors wish to thank Prof Hsiao Chang Chan (The Chinese University of Hong Kong, Department of Physiology, Epithelial Cell Biology Research Center, China) for her critical comments on the manuscript.

References
1 Jung KW, Park S, Kong HJ, et al. Cancer statistics in Korea: incidence, mortality and survival in 2006-2007. Journal of Korean medical science. 2010 Aug: 25:1113-21
2 Haberland J, Bertz J, Wolf U, Ziese T, Kurth BM. German cancer statistics 2004. BMC cancer. 2010: 10:52
3 Munoz F, Franco P, Ciammella P, et al. Squamous cell carcinoma of the prostate: long-term survival after combined chemo-radiation. Radiat Oncol. 2007: 2:15
4 Mazzucchelli R, Lopez-Beltran A, Cheng L, Scarpelli M, Kirkali Z, Montironi R. Rare and unusual histological variants of prostatic carcinoma: clinical significance. BJU international. 2008 Nov: 102:1369-74
5 Humphrey PA. Histological variants of prostatic carcinoma and their significance. Histopathology. 2012 Jan: 60:59-74
6 Borley N, Feneley MR. Prostate cancer: diagnosis and staging. Asian journal of andrology. 2009 Jan: 11:74-80
7 Saxena P, Trerotola M, Wang T, et al. PSA regulates androgen receptor expression in prostate cancer cells. The Prostate. 2011 Sep 28:
8 Bruckheimer EM, Kyprianou N. Apoptosis in prostate carcinogenesis. A growth regulator and a therapeutic target. Cell and tissue research. 2000 Jul: 301:153-62
9 Niu Y, Altuwaijri S, Yeh S, et al. Targeting the stromal androgen receptor in primary prostate tumors at earlier stages. Proceedings of the National Academy of Sciences of the United States of America. 2008 Aug 26: 105:12188-93
10 Niu Y, Altuwaijri S, Lai KP, et al. Androgen receptor is a tumor suppressor and proliferator in prostate cancer. Proceedings of the National Academy of Sciences of the United States of America. 2008 Aug 26: 105:12182-7
11 Nantermet PV, Xu J, Yu Y, et al. Identification of genetic pathways activated by the androgen receptor during the induction of proliferation in the ventral prostate gland. The Journal of biological chemistry. 2004 Jan 9: 279:1310-22
12 Yuen HF, Chua CW, Chan YP, Wong YC, Wang X, Chan KW. Significance of TWIST and E-cadherin expression in the metastatic progression of prostatic cancer. Histopathology. 2007 Apr: 50:648-58
13 Acevedo VD, Gangula RD, Freeman KW, et al. Inducible FGFR-1 activation leads to irreversible prostate adenocarcinoma and an epithelial-to-mesenchymal transition. Cancer cell. 2007 Dec: 12:559-71
14 Li Q, Mattingly RR. Restoration of E-cadherin cell-cell junctions requires both expression of E-cadherin and suppression of ERK MAP kinase activation in Ras-transformed breast epithelial cells. Neoplasia. 2008 Dec: 10:1444-58
15 Zhu ML, Kyprianou N. Role of androgens and the androgen receptor in epithelial-mesenchymal transition and invasion of prostate cancer cells. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2010 Mar: 24:769-77

Date added to bjui.org: 19/03/2013

DOI: 10.1002/BJUIw-2012-036-web

Does Michelangelo’s David have an increased risk of prostate cancer?

March 9, 2013/2 Comments/by Amrith Rao

Recently when researching on the Italian Renaissance master Michelangelo and his suffering with kidney stones, I stumbled upon a project on his famous masterpiece David. At the precise time, I was browsing BJUI and came across the article by Motofei et al, on the sexual side effects of finasteride as related to hand preference (right-handed or left-handed) for men undergoing treatment of male pattern baldness. This manuscript reminded me of several articles that measured different parts of the male body and correlated with the risk of prostate cancer. With this paper on my mind and at the same time looking at David, it just occurred to me whether I could predict the possibility him getting prostate cancer!

Let’s start from the beginning. Being born as a male, he had acquired a 1 in 6 chance of being diagnosed with prostate cancer and 1 in 36 chance that he would have died from it. The moment David stood erect as a toddler; the risk of getting prostate cancer became a reality. Indeed, the authors of the study go on to claim the link of erect posture of humans with BPH and infertility. For those interested, the theoretical aspects of erect posture and its effects on the male reproductive tract can be found in this review.

It is worth analyzing the David’s anthropometric measurements and bodily features from head to toe and correlate them to the current available evidence. David’s height has been calculated at being 497 cm. This, in real life would probably make him around 5’ 8” to 6’. According to the findings of the PLCO trial, being tall increased his risk of developing more aggressive prostate cancer and at a younger age. This is supported also by the findings of the ProtecT trial, which demonstrated that for high-grade tumours, there was a 23% increase in risk per 10 cm increase in height. The study group’s meta-analysis of published literature also support the increased risk of prostate cancer with increasing height.

Let us start from his head. Fortunately, David is not bald. Recent evidence suggests a strong correlation between vertex pattern androgenic alopecia and significant risk of prostate cancer. Looking at the elegance of the face, it is quite obvious that he is a clean-shaven man. Fortunately, being white, the age at which he started shaving indicating early or delayed adolescence, does not seem make his chances of getting prostate cancer worse.

Going on to his chest, it is apparent that David did not suffer from Gynaecomastia. There is considerable controversy in the literature regarding the association of gynaecomastia and future risk of prostate cancer. A cohort study following men with histologically proven gynaecomastia did not find any increased risk of prostate cancer but surprisingly showed an increased risk of testicular cancer. David’s chest, abdomen and back lack excess dense body hair. A Japanese study has shown that dense body hair raises the risk of prostate cancer!

A lot of research has gone into determining whether David is a right-handed or a left-handed man. If you take a closer look at the statue, the sling is held by the left hand and a rock on the right, suggesting that he could indeed be left handed, like his creator Michelangelo! Although no specific research has been carried out in prostate cancer, it has been shown in a few studies that women who are left handed are more prone to get breast cancer as compared to those who are right handed. The authors claim the effect of prenatal hormones on the foetus that determines the dominance of the side can also have effects on the breast tissue. A study found that men who were exposed to DES in utero were more likely to be left-handed. Similarly mouse experiments have shown an increased risk of prostate cancer in those exposed to DES. So, there may be a connection between left-handedness and risk of prostate cancer!

Coming to his fingers: The ratio of second to fourth digit length (2D:4D) would allow us to further assess the risk. It is now understood that the 2D:4D ratio is determined by Homeobox (Hox) a and d genes that also regulate urogenital system. What is even more interesting is the study that showed the patients with a lower 2D:4D ratio have higher risks of undergoing prostate biopsy and prostate cancer. The same group indeed went on to prove that a lower digit ratio was related to high percentage core cancer volume and higher Gleason score!

Fortunately, David’s waist circumference (WC) is within reasonable limits, thereby reducing his risk of prostate cancer. A recent study has shown that increased WC seems to be associated with high-grade disease at the time of biopsy.

It is obvious looking at David that he was not circumcised. Although aesthetically pleasing for many, there is considerable debate in the medical as well as philosophical literature whether David was circumcised or not?! Not being circumcised unfortunately increases his risk for prostate cancer.

There is a huge controversy about the size of David’s flaccid penis. Penis size has not (yet) been shown to correlate with risk of prostate cancer. Although, indirectly you conclude that because the 2D:4D digit ratio has been correlated with penis size and as shown above 2D:4D ratio has been correlated with prostate cancer. Therefore, the smaller the penis, greater the risk of prostate cancer! With so many manuscripts being published on 2D:4D ratio, I decided to research more on it and landed up on the Wikipedia page. I was astonished to find the various conclusions that have been reached with the curious case of 2D:4D ratio, including a recent study in Germany that found its correlation with male to female transsexuals!

Although not possible, but of interest would have been to measure David’s anogenital distances from anus to upper penis and from anus to scrotum. A study published in BJUI showed that a higher measurement between the anus and the penis was associated with lower risk of prostate cancer. As you may have guessed, yes there is research going on finding a relationship between anogenital distance and the 2D:4D ratio!

My interest then turned to David’s feet. Looking at it, it does seem that he would have been wearing a shoe size of 10 or 11 at least. Does it matter? Comparing his shoe size and the length of his flaccid penis, I was just reminded of the seminal paper by Jyoti Shah et al, which disproved that shoe size has got to do anything with the size of the penis. However, contrary to this paper, a study confirmed significant evidence of older age at the maximal shoe size (20.1 versus 17.6 years, P <0.05) was associated with increased risk of prostate cancer. Yes, as you may have guessed by now, there is a relationship between the 2D:4D to your penis size!

To conclude on the observations, there are several factors that increased David’s risk and several others that are protective, as shown in Table 1. I would leave it to the reader’s judgment, whether you would recommend a PSA test for David or indeed climb on to him and measure the most important parameter, the 2D:4D ratio!

Amrith Rao is a Consultant Urological Surgeon at Wexham Park Hospital, Wexham, UK. His views are his own. @urorao

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Every Month Matters: Living with Prostate Cancer

March 8, 2013/1 Comment/by admin Z.9

This video tells the story of Matt, who was diagnosed with advanced prostate cancer and told he only had two years to live. Nine years after he was diagnosed, Matt and his family share their experience of living with prostate cancer and how the diagnosis affected their lives.

Every Month Matters is a disease awareness campaign funded by Astellas Pharma Europe Ltd.

Please visit the campaign website Every Month Matters for more information.

BJUI have no conflict of interest. This video is posted for patient awareness.

On the Receiving End!

March 5, 2013/11 Comments/by Roger Kirby

It was weird, having spent a career looking after men with prostate problems, to discover that my own PSA was raised to 4.3ng/mL. A 3 Tesla MRI with gadolinium enhancement revealed a lesion in the right peripheral zone, which a biopsy confirmed as a Gleason 3+4=7 adenocarcinoma. The decision wasn’t difficult for me: I opted for a robot-assisted radical prostatectomy (RARP), to be performed by the Editor-in-Chief of this journal, Professor Prokar Dasgupta, ably assisted by Ben Challacombe and Krishna Patil. Details of my whole journey are available here for those who are interested.

The key point for discussion in this blog is the availability of the latest technology for the care of patients with prostate cancer who are less in the know than me. Shouldn’t we be lobbying for greater access for all to the latest pieces of high tech gear?

3 Tesla MRI imaging, together with the expertise to interpret the findings of diffusion-weighted images, for example, offers the possibility of a “prostate mammogram” which facilitates the targeting of the biopsy and holds the promise of avoiding biopsies in those in whom the MRI images appear blameless.

Da Vinci robotic technology undoubtedly facilitates the surgical procedure, especially the preservation of the neurovascular bundles and the very precise vesico-urethral anastomosis. It certainly was an interesting experience to sit and watch the DVD of my own operation at home, with a catheter still draining my bladder, wondering about my future continence and sexual function, as well as the histopathology report! After an operation like this anybody is going to need assistance to move around the house just to do basic activities like go to the bathroom or even change clothes. That’s why it is very important to check into a nursing home where they offer their professional service. In some cases these nurses don’t work professionally and often neglect their patients needs, so that is why it’s recommended to contact a nursing home neglect attorney for situations like this for legal help.

Am I discombobulated by this experience? Not especially, I genuinely found being on the receiving end of prostate surgery a truly educational experience and I now feel energised to help others get through their journey. In the upcoming issue of Trends in Urology three other of our urological colleagues share their own experiences of prostate cancer, as well as the lessons that can be learned from them. Check out the Trends in Urology website from mid-March onwards.

In the meantime we would be interested in your own thoughts on these issues. Do add a comment or question to this blog.

Roger Kirby
The Prostate Centre, London W1G 8GT

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From Famine to Feast. Systemic Therapy for Prostate Cancer Comes of Age.

February 13, 2013/3 Comments/by Simon Chowdhury

OR The Hare Becomes the Tortoise??

When I was a medical oncology trainee in 2001 looking for an area to specialise in my mentors told me prostate cancer was going to be the next big thing. I must admit I was dubious but now more than 10 years later this is amongst the best advice I have ever received. On a par with support Manchester United and buy property in London! Systemic treatment for prostate cancer has well and truly arrived and we are in a position where at times we are spoilt for choice.

So how did we get here and why did it take so long. To answer the second part first we need to go back to 1941 and Huggins and Hodges ground-breaking work showing the profound effect of castration on metastatic prostate cancer. Both the original paper and the Nobel lecture are fascinating reading. Castration remains a cornerstone of the treatment of prostate cancer. The androgen receptor is one of, if not the, most dominant biological pathway in solid tumour oncology. Apart from chemotherapy for testicular cancer, another urological success, I cannot think of another systemic treatment that has such profound activity both in terms of clinical response and disease control rates. For instance androgen deprivation far surpasses the activity seen with tamoxifen in ER +ve breast cancer. So prostate cancer got off to a flier and perhaps was the hare to the tortoise when compared to other cancers, which have slowly but surely overtaken.

There was a long lull with very little positive data for metastatic prostate cancer. Why was this? Perhaps the activity of androgen deprivation set too high a bar for subsequent treatments and a sense of nihilism for those that followed. This is shown by the negative reaction to the data on docetaxel first published in 2004. The 50% PSA response rate (a decline in PSA of 50% or greater) is impressive particularly in this highly pre-treated population. More importantly docetaxel improves quality of life and provides a small but significant survival advantage against an active comparator. We now have a second chemotherapy, cabazitaxel, which again shows a significant survival advantage. Whilst chemotherapy in prostate cancer remains controversial, and worthy of a future blog, there is no doubt for a significant number of patients it provides real benefit.

Prostate cancer is leading the way for other areas of systemic therapy. Sipuleucel-T is one of the only immunotherapies to show a survival benefit in solid tumour oncology. Whilst Sipuleucel-T is controversial and has many detractors, it does have level 1 evidence to support it. During my fellowship with Phil Kantoff’s group in Boston, I saw several patients who I am convinced benefited from this treatment. Alpharadin is the first radionucleotide to show a survival advantage and is likely to become an integral part of systemic therapy for CRPC.

The drugs that have provided most excitement and the greatest benefit in day-to-day practise are abiraterone and enzalutamide. These drugs build on the work of Huggins and Hodges and show that 70 years of targeting the androgen receptor is still relevant even with castration. These drugs have changed how we describe the disease moving from ‘hormone-refractory’ to ‘castration-refractory’. Abiraterone is now licensed in the pre- and post-chemotherapy setting and it is likely that enzalutamide will follow in the not too distant future. In my own practise these drugs are game changers. Ones that provide real benefits relieving symptoms, controlling disease and allowing some men with prostate cancer to live much longer.

Who should be responsible for all these new drugs? Medical oncologists? Urologists? Nurse specialists? For me this shouldn’t be territorial. I want men with prostate cancer looked after by those with a real interest in this area. The days of people dabbling should be in the past and testicular cancer has shown us that patients do better when looked after in high volume centres. In reality men with metastatic prostate cancer have complex medical needs and only with the input from the whole multidisciplinary team are we able to give them the best care.

So systemic treatment for prostate cancer is suddenly fashionable and my mentors (Ellis and Harper) were proved right! ‘Told you so Chowdhury!’ This is only going to be the beginning with prostate cancer, which is now at the forefront of cancer research. Our understanding of the biology of prostate cancer is likely to grow exponentially and with it our ability to improve treatment. So watch this blog – to be continued…

Simon Chowdhury is Consultant Medical Oncologist at Guy’s, King’s and St Thomas’ Hospitals, London. He is actively involved in clinical trial research into urological cancers.

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Prostate Cancer Outcomes Study Meets Twitter Face to Face

February 11, 2013/6 Comments/by Henry Woo

The International Urology Journal Club on Twitter discussion for February 2103 was based upon the recently published Prostate Cancer Outcomes Study in the New England Journal of Medicine on 31 January 2013.

The originally planned discussion paper that was only hours away from being announced when it became apparent through Twitter notification by @NEJM that the PCOS paper was going to be published that day. With this news, ‘urology twitter’ spoke loud and clearly (well, tweeted to be technically correct), and it was clear that this paper required our urgent attention.

The primary and senior authors of the PCOS manuscript in Matthew Resnick and David Penson, respectively, were kind enough to commit to making themselves available for the twitter discussion and proved to be valuable contributors.

In short, PCOS examined 1655 men who had been diagnosed with prostate cancer in 1994 or 1995, between the ages of 55 and 74 years, and who had either undergone radical prostatectomy (1164 men) or radiotherapy (491 men). Functional status was assessed at ‘baseline’ and at 2, 5 and 15 years after diagnosis. The study found patients undergoing surgery were more likely to have urinary incontinence and erectile dysfunction at 2 and 5 years, but there was no significant difference at 15 years. Patients undergoing surgery were less likely to have bowel urgency at 2 and 5 years, but again, there was no discernible distinction between the two groups at 15 years.

The functional results as stated in the manuscript are poor and this generated discussion that attempted to place these results into context. It was pointed out by Stacey Loeb that with the Massachusetts Male Aging Study (MMAS), 79% of men had ED as defined by IIEF and that there was a concern that, with the present data, the media could interpret it as that all prostate cancer treatments universally cause ED. A later constructive comment was made that if the study had followed matched controls to 15 years, it would allow for meaningful estimation of risk with treatment superimposed on aging.

Discussion shifted to the changes that have occurred over time since men entered the study. A number contributors, including Matt Coward, Rajiv Singal, Quoc Trinh and others commented to the effect that many of the men treated in that era would probably no longer be treated radically and would be managed conservatively. Ben Davies in agreement declared that he would promise never to operate on a man with a Gleason score 2–4 prostate cancer. However, Sean Williamson, Alanna Jacobs and others pointed out that this was not really relevant to the study, which was an examination of functional outcomes.

Is the data applicable to today? In response to Tony Finelli’s tweet of “Why is it that the urologic community always criticizes longterm well designed studies with ’The data are no longer applicable today?’“, Rajiv Singal made a very sobering comment that “Data is very applicable. Study well designed. It’s just that over Tx in many in this group makes side effects more appalling”

Prokar Dasgupta provided some British input with “are patients happier if they are clear of cancer @15 years or would they rather be potent?” Michael Leveridge from Canada provided constructive input with “As rational CaPr treatment shifts toward higher risk (wide fields, less nerve sparing), functional outcomes may actually get worse”

Criticism made that there were many men who missed out on completing their 2 and 5 year questionnaires was responded to by Dave Penson who explained that they were included in the study by using imputed data with a hot deck technique – whilst imperfect, it was the best that they could do to overcome this issue.

Stacey Loeb pointed out that a key strength of the study was that it showed that many short-term differences functional outcomes between RP & RT dissipate over time. From a functional perspective, Tim Averch may have a point when he commented that at 15 years that it may not make any difference as to whether we had performed surgery or radiotherapy.

The question was raised about correlating nerve-sparing surgery and subsequent results. Author Matt Resnick indicated that this was something that was being analysed right now with results forthcoming. On the general issue of improvements in surgery and radiotherapy leading to improved functional outcomes, Matt Resnick indicated that “While tech. improvements in RP and EBRT may incrementally improve outcomes, likely non-differential.” Towards the end of the discussion, it was generally agreed that robotic surgery was the primary manner by which surgery was being performed (at least in the US) and that it was an ‘operative leveler’ in terms of how well surgeons performed a radical prostatectomy.

Helen Nicholson from Australia asked if the late serious effects of radiotherapy were considered and on a similar theme, Matt Cooperberg raised the issue of where only incontinence was reported with regard to urinary function but irritative urinary symptoms were often of greater bother and worse with radiotherapy. Dave Penson responded in that they had data on bother from urinary symptoms and that it was worse at 2 and 5 years for surgery but the same for both radiotherapy and surgery at 15 years.

To complete the round up of the discussion content, the Best Tweet Prize was awarded to Dr Rajiv Singal for the following tweet:-

The Best Tweet Prize was kindly donated by Urology Match.

The above summary only touches upon the discussion, which had 32 participants who made a total of 171 recorded tweets to the hashtag #urojc. This does not include participants and their tweets where the #urojc had been omitted. We had quite a number of new participants this month who were still learning the necessity to include #urojc in all tweets in order for them to be visible to the discussion.

It is also interesting to look at the impact of the Superbowl. The first dip is related to our North American friends signing off to concentrate on the Superbowl and the last dip correlates when the majority of participants are with their heads buried in a robot console/wound or asleep on the other side of the world.

We look forward to seeing your participation in the March #urojc. For further information about what #urojc is all about, see my earlier blog entry on the subject.

Henry Woo is an Associate Professor of Surgery at the Sydney Adventist Hospital Clinical School of the University of Sydney in Australia. He has been appointed as the inaugural BJUI CME Editor. He is currently the coordinator of the International Urology Journal Club on Twitter. Follow him on Twitter @DrHWoo

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Article of the week: An open and shut case: outcomes similar for open and robotic prostatectomy

February 6, 2013/7 Comments/by admin Z.9

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

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

Finally, the third post under the Article of the Week heading on the homepage will consist of additional material or media. This week we feature a video of Jonathan Silberstein discussing his paper.

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

A case-mix-adjusted comparison of early oncological outcomes of open and robotic prostatectomy performed by experienced high volume surgeons

Jonathan L. Silberstein*, Daniel Su*, Leonard Glickman*, Matthew Kent†, Gal Keren-Paz*, Andrew J. Vickers†, Jonathan A. Coleman*‡, James A. Eastham*‡, Peter T. Scardino*‡ and Vincent P. Laudone*‡

*Department of Surgery, Urology Service, and †Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, and ‡Department of Urology,Weill Cornell Medical Center, New York, NY, USA

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OBJECTIVE

• To compare early oncological outcomes of robot assisted laparoscopic prostatectomy (RALP) and open radical prostatectomy (ORP) performed by high volume surgeons in a contemporary cohort.

METHODS

• We reviewed patients who underwent radical prostatectomy for prostate cancer by high volume surgeons performing RALP or ORP.

• Biochemical recurrence (BCR) was defined as PSA 0.1 ng/mL or PSA 0.05 ng/mL with receipt of additional therapy.

• A Cox regression model was used to evaluate the association between surgical approach and BCR using a predictive model (nomogram) based on preoperative stage, grade, volume of disease and PSA.

• To explore the impact of differences between surgeons, multivariable analyses were repeated using surgeon in place of approach.

RESULTS

• Of 1454 patients included, 961 (66%) underwent ORP and 493 (34%) RALP and there were no important differences in cancer characteristics by group.

• Overall, 68% of patients met National Comprehensive Cancer Network (NCCN) criteria for intermediate or high risk disease and 9% had lymph node involvement. Positive margin rates were 15% for both open and robotic groups.

• In a multivariate model adjusting for preoperative risk there was no significant difference in BCR rates for RALP compared with ORP (hazard ratio 0.88; 95% CI 0.56–1.39; P = 0.6). The interaction term between © 2013 The Authors 206 BJU International © 2013 BJU International | 111, 206–212 | doi:10.1111/j.1464-410X.2012.11638.x Urological Oncology nomogram risk and procedure type was not statistically significant.

• Using NCCN risk group as the covariate in a Cox model gave similar results (hazard ratio 0.74; 95% CI 0.47–1.17; P = 0.2). The interaction term between NCCN risk and procedure type was also non-significant.

• Differences in BCR rates between techniques (4.1% vs 3.3% adjusted risk at 2 years) were smaller than those between surgeons (2.5% to 4.8% adjusted risk at 2 years).

CONCLUSIONS

• In this relatively high risk cohort of patients undergoing radical prostatectomy we found no evidence to suggest that ORP resulted in better early oncological outcomes then RALP.

• Oncological outcome after radical prostatectomy may be driven more by surgeon factors than surgical approach.

Read Previous Articles of the Week

Editorial: Oncological outcomes: open vs robotic prostatectomy

February 6, 2013/1 Comment/by John Davis

John W. Davis and Prokar Dasgupta*

Departments of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA and *Guy’s Hospital, Kings College London, London, UK
e-mail: [email protected]

For men at signiﬁcant risk of dying from untreated prostate cancer within reasonably estimated remaining life spans, which technique oﬀers the best disease-free survival: open radical prostatectomy (RP) or robot-assisted RP (RARP)? The practice patterns in many countries suggest RARP, but many concerns have been raised about the RARP technique for high-risk disease, including positive surgical margin rates, adequate lymph node dissections (LNDs), and the learning curve. In this issue of the BJUI, Silberstein et al provide a convincing study, short of a randomised trial, that suggests that in experienced hands both techniques can be eﬀective, and that surgeon experience had a stronger eﬀect than technique. In contrast to large population-based studies, this study sought to take the learning curve and low-volume surgeon variables out of the equation by restricting the inclusion criteria to four high-volume surgeons from a single centre. The follow-up is short (one year), and may underestimate the true biochemical relapse rates, and needs follow-up study, but for now oﬀers no diﬀerence in relapse rates nor pathological staging outcomes.

Beyond the comparative eﬀectiveness research (CER), Silberstein et al also provide a valuable vision for prostate cancer surgeons using any standard technique. Several recent landmark studies on PSA screening, the Prostate cancer Intervention Versus Observation Trial (PIVOT), and comparisons of metastatic progression between RP and radiation, all indicate the need to shift our practice pattern towards active surveillance for lower risk patients (with or without adjunctive focal therapy, but the former still experimental in our view), and curative therapy for intermediate- to high-risk disease. Such a practice pattern is evident when you compare this study (2007–2010) with a similar eﬀort from this institution (2003–2005) comparing RP with laparoscopic RP (LRP). In the former study, >55% had low-risk disease compared with <35% from the current study. As expected, the present study shows higher N1 stage (9%) and positive surgical margin rates (15%) than the former (7% and 11%, respectively). While erectile function recovery was not presented, the authors noted the familiar reality that patients demand nerve sparing whenever feasible, only 2% in this study had bilateral non-nervesparing and 91% had a combination of bilateral or partial nerve sparing. The number of LNs retrieved has increased from 12–13/case to 15–16, and the authors state that even with nomogram-based exclusion of mandatory pelvic LNDs with <2% risk of N1 staging, this modern cohort had a pelvic LND in 94% of cases, including external iliac, obturator, and hypogastric templates.

We fully concur with this practice pattern, and have recently provided a video-based illustration of how to learn the technique, and early experience showing an increase in median LN counts from eight to 16, and an increase in positive LNs from 7% to 18%. By risk group, our positive-LN rate was 3% for low risk, 9% for intermediate risk, and 39% for high risk. We certainly hope that future multi-institutional studies will no longer reﬂect what these authors found, in that RARP surgeons are ﬁve times more likely to omit pelvic LNDs than open, even for high-risk cancers.

Finally, Silberstein et al and related CER publications leave us the question, does each publication on CER in RP have to be comprehensive (i.e. oncological, functional, and morbidity) or can it focus on one question. Members of this authorship line have published the ‘trifecta’ (disease control, potency, and continence) and others the ‘pentafecta’ (the trifecta plus negative surgical margins and no complications). Indeed, Eastham and Scardino stated in an editorial that ‘data on cancer control, continence, or potency in isolation are not suﬃcient for decision making and that patients agreeing to RP should be informed of functional results in the context of cancer control’. We feel that the answer should be no, focused manuscripts have their merit and publication space/word limits create this reality. But we should not discount the sometimes surprising results when one institution using the same surgeons and methodologies publishes on the broader topic: the Touijer et al. paper discussed above found the same oncological equivalence between RP and LRP as this comparison of RP and RARP, but also included functional data showing signiﬁcantly lower recovery of continence with LRP. Nevertheless, the recent body of work in the BJUI now provides a well-rounded picture of modern CER including oncological outcomes, complications, recovery of erectile dysfunction, continence and costs. We feel it is reasonable to conclude that patients should be counselled that RARP has potential beneﬁts in terms of blood loss, hospital stay, and complications (at increased costs), but oncological and functional results are probably based upon surgeon experience.

Abbreviations

CER, comparative eﬀectiveness research; LN(D), lymph node dissection; (RA)(L)RP, (robot-assisted) (laparoscopic) radical prostatectomy

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