[The practice guideline 'Urolithiasis' (first revision) from the Dutch College of General Practitioners; a response from the perspective of urology]. / De standaard 'Urinesteenlijden' (eerste herziening) van het Nederlands Huisartsen Genootschap; reactie vanuit de urologie.

The Dutch College of General Practitioners has made a useful revision of its practice guideline 'Urolithiasis', in which new imaging techniques and medical treatment modalities are implemented. Sonography is useful but CT has now become the gold standard imaging technique. CT images should be examined by both the radiologist and the urologist. Therefore, requests for CT should preferably be made by urologists. This guideline should focus more on the differential diagnosis of urolithiasis in the acute phase, and in particular on aortic aneurysm in the elderly patient. Complaints of irritative micturition should be considered to indicate a distal localization ofa ureteral stone rather than a urinary tract infection. When prescribing selective alpha-1 blocking agents, the doctor should inform the patient that both retrograde ejaculation and orthostatic hypotension are side effects.

[The practice guideline 'Urinary incontinence' (first revision) from the Dutch College of General Practitioners; a response from the perspective of urology]. / De standaard 'Incontinentie voor urine' (eerste herziening) van het Nederlands Huisartsen Genootschap; reactie vanuit de urologie.

The revised practice guideline 'Urinary incontinence' of the Dutch College of General Practitioners contains some important changes. Urodynamic investigation is not mandatory for differentiating between types of incontinence in the general practice setting. Physical examination including a valsalva leak point test is considered important. From a urological point ofview it remains to be seen whether the history-taking and the physical examination described in the revised guideline will be enough to accurately differentiate between the possible incontinence types. The practice guideline underlines a role for the general practitioner in teaching bladder training or pelvic floor exercises. The benefits of this compared to exercises taught by specialized physiotherapists will have to be determined. Another new feature is that antimuscarinic drugs are mentioned as proper treatment for people suffering from overactive bladder complaints. The practice guideline advises referral of male incontinence patients only if the incontinence is not related to prostate surgery. However, patients with postoperative incontinence should also be referred as there are good diagnostic and therapeutic options available.

[Guideline 'Renal cell carcinoma']. / Richtlijn 'Niercelcarcinoom'.

Each year, more than 1500 new cases of renal cell carcinoma are diagnosed in the Netherlands, and approximately 850 patients die due to this disease. The guideline 'Renal cell carcinoma' contains clinical practice recommendations on the diagnosis (imaging, pathological assessment, histopathological classification) and treatment (surgery, chemo-, immuno-, and radiotherapy) of renal cell carcinoma. For diagnostic imaging, chest and abdominal CT is recommended. Scintigraphy is not recommended. The term 'Grawitz tumour' is obsolete and should be replaced by 'renal cell carcinoma' with histological subtype specification according to the 2004 WHO classification. Laparoscopic radical nephrectomy is as effective as open surgery for localised tumours (T1 and T2) and possibly also for T3 tumours. The laparoscopic approach is associated with less morbidity due to the less invasive nature of this technique. This operation requires experience. In partial nephrectomy, a small margin of healthy tissue is sufficient. Frozen section examination of the resection edges does not appear to be required. In patients with metastatic renal cell carcinoma who are eligible for immunotherapy, removal of the tumour prolongs survival. Metastasectomy prolongs survival in patients with a solitary metastasis. Most currently available cytotoxic agents are ineffective against renal cell carcinoma. Interferon-alpha may have a role in the treatment of patients with renal cell carcinoma and favourable prognostic factors, given the survival advantage demonstrated with this agent in clinical trials. The guideline is available in English at www.oncoline.nl.

[Angiogenesis inhibitors for the systemic treatment of metastatic renal cell carcinoma: sunitinib, sorafenib, bevacizumab and temsirolimus]. / Angiogeneseremmers voor de systemische behandeling van gemetastaseerd niercelcarcinoom: sunitinib, sorafenib, bevacizumab en temsirolimus.

Treatment of patients with metastatic renal cell carcinoma is evolving rapidly due to the advent of novel targeted therapies. Improved knowledge of the underlying pathogenesis has led to the development of drugs that modulate the dominant signal transduction pathways for this disease, which results in inhibition of angiogenesis. Recent evidence indicates that the receptor tyrosine kinase inhibitor sunitinib prolongs progression-free survival compared with interferon-alpha, especially in patients with intermediate risk. Immunotherapy with interferon-alpha or high-dose interleukin-2 should still be considered for low-risk patients, particularly those with clear-cell tumours and metastases of the lung only. In patients who fail treatment with interferon-alpha, sorafenib has been shown to improve progression-free survival. High-risk patients may benefit from treatment with temsirolimus, which inhibits mammalian target of rapamycin (mTOR) kinase activity and has shown to improve overall survival. These angiogenesis inhibitors did not receive mention in the recently published guideline 'Renal cell carcinoma'.

[The practice guideline 'Urinary-tract infections' (second revision) from the Dutch College of General Practitioners; a response from the perspective of urology]. / De standaard 'Urineweginfecties' (tweede herziening) van het Nederlands Huisartsen Genootschap; reactie vanuit de urologie.

The convenient and clearly organised structure of this second revision of the practice guideline on urinary-tract infections from the Dutch College of General Practitioners provides a clearly described role for the general practitioner in the diagnosis and treatment of such infections. Most striking is the change in the classification of diagnostic patient categories. It seems that pregnant women with urinary-tract infections represent an important group in extramural medicine. This revised guideline shows great promise for ensuring efficient and effective routing of the various patient groups presenting with urinary-tract infections at the office of the general practitioner.

Prediction of residual retroperitoneal mass histology after chemotherapy for metastatic nonseminomatous germ cell tumor: multivariate analysis of individual patient data from six study groups.

PURPOSE: To develop a statistical model that predicts the histology (necrosis, mature teratoma, or cancer) after chemotherapy for metastatic nonseminomatous germ cell tumor (NSGCT). PATIENTS AND METHODS: An international data set was collected comprising individual patient data from six study groups. Logistic regression analysis was used to estimate the probability of necrosis and the ratio of cancer and mature teratoma. RESULTS: Of 556 patients, 250 (45%) had necrosis at resection, 236 (42%) had mature teratoma, and 70 (13%) had cancer. Predictors of necrosis were the absence of teratoma elements in the primary tumor, prechemotherapy normal alfa-fetoprotein (AFP), normal human chorionic gonadotropin (HCG), and elevated lactate dehydrogenase (LDH) levels, a small prechemotherapy or postchemotherapy mass, and a large shrinkage of the mass during chemotherapy. Multivariate combination of predictors yielded reliable models (goodness-of-fit tests, P > .20), which discriminated necrosis well from other histologies (area under the receiver operating characteristic (ROC) curve, .84), but which discriminated cancer only reasonably from mature teratoma (area, .66). Internal and external validation confirmed these findings. CONCLUSION: The validated models estimate with high accuracy the histology at resection, especially necrosis, based on well-known and readily available predictors. The predicted probabilities may help to choose between immediate resection of a residual mass or follow-up, taking into account the expected benefits and risks of resection, feasibility of frequent follow-up, the financial costs, and the patient's individual preferences.

Novel treatments for metastatic renal cell carcinoma.

The mainstay of any curative treatment in renal cell carcinoma (RCC) is surgery. In case of metastatic disease at presentation a radical nephrectomy is recommended to good performance status patients prior to start of interferon-alfa treatment. Interferon-alpha (IFN-alpha) offers in a small but significant percentage of patients advantage in overall survival; interleukin-2 (IL-2) based therapy gives similar survival rates. To date hormonal and chemotherapy do not have a proven impact on survival. The recent new insights in the molecular biology of clear RCC has revealed a key-role for vascular endothelial growth factor (VEGF) in the stimulation of angiogenesis in this highly vascularized tumour. This opens interesting new treatment strategies including: blockage of VEGF with the monoclonal antibody bevacizumab and inhibition of VEGF receptor tyrosine kinases (with small oral molecules such as SU11248 or PTK787). Likewise, inhibition of the Raf kinase pathway (with oral Bay 43-9006) or inhibition of the mTOR pathway (with i.v. CCI-779) are under investigation. Preliminary clinical results with all these compounds are interesting and the results of ongoing phase III studies will become available in the next years.

[The practice guideline 'Lower urinary-tract symptoms in middle-aged and elderly men' (second revision) from the Dutch College of General Practitioners; a response from the perspective of urology]. / De standaard 'Bemoeilijkte mictie bij oudere mannen' (tweede herziening) van het Nederlands Huisartsen Genootschap; reactie vanuit de urologie.

New insights in the fields of terminology, diagnosis and treatment have been successfully implemented in the second revision of the practice guideline 'Lower urinary-tract symptoms in middle-aged and elderly men' from the Dutch College of General Practitioners. The result is a coherent, lucid and moreover practical guideline. It is important to stress that lower urinary-tract symptoms do not increase the patient's risk of prostate cancer. Screening for prostate cancer by the routine measurement of serum prostate-specific antigen is therefore not indicated.

Prognosis and treatment of T1G3 bladder tumours. A prognostic factor analysis of 121 patients. Dutch South Eastern Bladder Cancer Study Group.

Patients with T1G3 bladder cancer have a considerable risk for recurrence and/or progressive disease. Until now no consensus has been achieved on the optimal treatment. Within the Dutch South Eastern Bladder Cancer Study Group, 155 patients with a T1G3 bladder tumour were seen between 1983 and 1988. After review of histology, 121 could be evaluated and recurrence-free interval was studied with regard to prognostic factors. Prognostic factors such as sex, age, blood group, abnormalities on intravenous urography, pretreatment tumour configuration, number of tumours, number of locations involved in the bladder, voided urine cytology, results of random biopsies and mitotic index were evaluated, using a multivariate analysis with the Cox proportional hazard model. During the follow-up period, 70 (58%) patients had recurrent bladder cancer, and of these 30 (43%) had progression into invasive disease. Of the possible prognostic factors analysed, only multiplicity (P = 0.03) and the number of locations of the tumours (P = 0.03) were independent prognostic factors in relation to the risk of recurrence. The recurrence-free interval was influenced by the therapy. For T1G3 tumours, additional intravesical immunotherapy/chemotherapy or radiotherapy after transurethral resection (TUR) increased the recurrence-free interval significantly. Because most other parameters did not show additional prognostic value, the T1G3 tumours can be considered as homogeneous with regard to prognosis. Only multiplicity and the number of locations involved added to the prognostic significance of patients with these bladder tumours. In addition, it is advisable to give patients with T1G3 tumours additional treatment after the initial TUR.

Intravesical therapy in superficial bladder cancer.

OBJECTIVE: To identify the appropriate characteristics of superficial bladder cancer that allow the physician to predict tumor behavior. METHODS: We analyzed 1,745 patients with primary superficial bladder cancer with regard to disease and patient characteristics. RESULTS: With the characteristics we found, the population can be described and prognostic factors can be found. Moreover, with the use of these factors, it appears to be possible to predict tumor behavior on a group level. Prediction on an individual level, however, remains far from ideal. CONCLUSIONS: Three treatment options can be chosen: follow-up after initial transurethral resection, additional instillations with intravesical chemotherapy, or instillations with bacillus Calmette-Guerin (BCG). In case instillations are indicated, most (but not all) superficial bladder cancer trials show superiority of BCG over intravesical chemotherapy, although at the cost of more side effects. However, with intravesical BCG, it seems possible to influence the natural history of superficial bladder cancer, which means that we can delay progression and improve survival.

Treatment strategies in metastatic renal cell carcinoma : cytokines, vaccines, and gene therapy.

In recent years, the incidence of renal cell carcinoma (RCC) has increased dramatically (54% from 1975 to 1990), and in 1996, approx 30,000 new cases were diagnosed in the United States (1). In the same year, an estimated 12,000 RCC-related deaths occurred in the United States. The increased incidence of RCC in recent years may be linked to certain risk factors such as smoking, obesity, high-protein diets, and hypertension (2).

Bilateral ureteral obstruction after appendectomy in children.

Five cases of bilateral ureteral obstruction after appendicectomy are presented. All five patients were boys (age range, 9 to 15 years). All of them had had severe appendicitis. Based on the urethrocystoscopy findings, edema of the posterior bladder wall appeared to be the cause of obstruction of both distal ureters. This is confirmed by the immediate recovery of renal function after installation of bilateral uretercatheters. It is known that contamination of the peritoneal cavity can occur by organisms leaking from a gangrenous or perforated appendix. This can cause localized inflammatory edema of the posterior bladder wall. It is remarkable that through ultrasound investigation, only mild to moderate dilatation of the urinary tract was observed. An explanation can be obtained from animal models, wherein acute obstruction of the ureter leads only to a transient increase in ureteral pressure, followed by a decline toward the preobstruction level. It is important to be aware that this complication can occur after appendectomy; bilateral uretercatheters can be installed, and irreversible renal damage can be avoided.

[Paraneoplastic syndromes in three patients with renal cell carcinoma]. / Paraneoplastische verschijnselen bij 3 patiënten met een niercelcarcinoom.

Renal cell carcinoma was diagnosed in three male patients, 45, 53 and 52 years of age. In addition, they had paraneoplastic symptoms: hypercalcaemia, hyperglycaemia and elevated hepatic enzyme levels, respectively. All three patients underwent tumour nephrectomy, after which the paraneoplastic symptoms disappeared. The first patient died 16 months postoperatively, while the other two were alive and free of symptoms after a follow-up of nine months and four years, respectively. Many patients with renal cell carcinoma remain asymptomatic for a long period of time and 30% of all patients have metastatic disease at the time of diagnosis. The classic triad of flank pain, haematuria and an abdominal mass occurs in only 10% of all cases. However, 20-40% of all patients present with signs of a paraneoplastic syndrome, of which anaemia (20-40%), fever (30%), hypertension (24%), hypercalcaemia (10-15%) and hepatic dysfunction (3-6%) are the most common.

[Immunology in medical practice. XXV. Use of dendritic cells in the immunotherapy of cancer]. / Immunologie in de medische praktijk. XXV. Toepassing van dendritische cellen in de immunotherapie van kanker.

Dendritic cells are among the most efficient antigen-presenting cells of our immune system and they play a crucial role in immunity reactions such as the activation of T and B cells and the induction or maintenance of tolerance. New culture methods allow us to generate dendritic cells in sufficient numbers for further studies and for the preparation of antigen-loaded dendritic cells for clinical application in cancer patients. In animal studies immunization with antigen-loaded dendritic cells offered protection from growth of injected tumour cells. In experimental clinical studies in cancer patients with e.g. metastatic renal carcinoma, melanoma and B cell lymphoma some lasting remissions were observed after administration of antigen-loaded dendritic cells. Side effects were minor. Unanswered questions on tumour vaccines with antigen-loaded dendritic cells concern specific matters, such as optimal culture methods and antigen loading, and general matters, such as dose, frequency, duration and route of administration. Also, no method is currently available by which the in vivo immune response can be measured accurately.

Clinical use of novel urine and blood based prostate cancer biomarkers: a review.

In the era of upcoming techniques for molecular profiling, breakthroughs led to new discoveries in the field of prostate cancer (PCa) biomarkers. Since the early 1990s a tremendous increase in PCa incidence is seen, dedicated to the introduction of prostate specific antigen (PSA) testing. However, due to its lack of specificity many men undergo unnecessary biopsies, resulting in a rising incidence of clinically insignificant PCa. To overcome this drawback, cancer specific biomarkers are needed to identify patients who are at high risk of harbouring PCa and to distinguish patients with aggressive disease from patients with insignificant cancer. The most non-invasive, easy to obtain substrate for biomarker measurement is urine. The most promising markers to date are PCA3 and TMPRSS2-ERG. Both markers demonstrate to have a higher specificity and diagnostic accuracy for PCa outcome compared to serum PSA. This might better predict the presence of PCa and therefore reduce the number of unnecessary biopsies. Combining both markers in a panel might result in an even higher diagnostic accuracy, given the heterogeneity of the disease. In PCa management, circulating tumour cells (CTCs) detected in the blood seem a promising tool to predict treatment response and survival benefit. Although results appear to be encouraging, the biggest challenge about new markers in PCa is to validate them in large clinical trials and subsequently implement these markers into clinical practice. In this review we discuss the clinical usefulness of novel, non-invasive tests in PCa management.

Exploratory analysis of the visceral disease subgroup in a phase III study of abiraterone acetate in metastatic castration-resistant prostate cancer.

BACKGROUND: Visceral disease, non-nodal soft-tissue metastases predominantly involving the lung and liver, is a negative prognostic factor in patients with metastatic castration-resistant prostate cancer (mCRPC). An exploratory analysis of COU-AA-301 assessed whether abiraterone acetate (AA) improved overall survival (OS) in mCRPC patients with visceral disease progressing post docetaxel. METHODS: In COU-AA-301, post-docetaxel mCRPC patients were randomized 2:1 to AA 1000 mg (n=797) or placebo (n=398) once daily, each with prednisone 5 mg b.i.d. The primary end point was OS; secondary end points included radiographic progression-free survival (rPFS), PSA response rate and objective response rate (ORR). Treatment effects in visceral disease (n=352) and non-visceral disease (n=843) subsets were examined using final data (775 OS events). RESULTS: AA plus prednisone produced similar absolute improvement in median OS in patients with (4.6 months) and without (4.8 months) visceral disease versus prednisone; hazard ratios (HRs) were 0.79 (95% confidence interval (CI): 0.60-1.05; P=0.102) and 0.69 (95% CI: 0.58-0.83; P<0.0001), respectively. Treatment with AA plus prednisone significantly and comparably improved secondary endpoint outcomes versus prednisone in both the subsets: the HRs for rPFS were 0.60 (95% CI: 0.46-0.78; P=0.0002) and 0.68 (95% CI: 0.58-0.80; P<0.0001) in visceral and non-visceral disease subsets, respectively. PSA response rates were 28% versus 7% in the visceral disease subsets and 30% versus 5% in the non-visceral disease subsets (both P<0.0001), and ORRs were 11% versus 0% (P=0.0058) and 19% versus 5% (P=0.0010), respectively. The incidence of grade 3/4 adverse events was similar between the subsets and between the treatment arms in each subset. Adverse events related to CYP17 blockade were increased in the AA arms and were similar in patients with or without visceral disease. CONCLUSIONS: AA plus prednisone provides significant clinical benefit, including improvements in OS and secondary end points, in post-docetaxel mCRPC patients with or without baseline visceral disease. The presence of visceral disease does not preclude clinical benefit from abiraterone.

Synchronous penile metastasis from a high-grade adenocarcinoma of the prostate.

Metastasis to the glans penis is a rare phenomenon and usually occurs in a late stage of disease. A 68-year-old man was referred to our clinic because of two indurated lesions of the glans penis and minor lower urinary tract symptoms. Digital rectal examination revealed a hard nodular prostate, and serum prostate-specific antigen (sPSA) level was 13.3 ng/mL. Biopsies of the penile lesions and transrectal ultrasound-guided prostate biopsies were taken. Immunohistochemical staining of formalin-fixed paraffin-embedded tissue exposed a synchronous penile metastasis from a high-grade adenocarcinoma of the prostate. Except a pathologically enlarged lymph node detected with MRI there was no suspicion on other metastases. Currently this patient is being treated with a Gonadoreline (GnRH) antagonist. Nevertheless, the prognosis will be poor.

Kidney injury during VEGF inhibitor therapy.

Antiangiogenic therapy targeting vascular endothelial growth factor (VEGF) or its receptor (VEGFR) has proven its effect in the treatment of several types of cancer, including renal cell carcinoma (RCC). However, treatment can be accompanied by notable adverse effects. Mild proteinuria and hypertension are often seen, but sometimes nephrotic range proteinuria and÷or renal insufficiency develop. In recent years insight into the toxic effects of anti-VEGF therapy in the kidney has increased. A few biopsies have been done and thrombotic microangiopathy is reported in the majority of cases. However, other patterns of kidney injury have been described as illustrated by the case of a 62-year-old patient who presented two years after initiation of the VEGFR inhibitor cediranib with a nephrotic syndrome and acute renal failure. Kidney biopsy disclosed focal segmental glomerulosclerosis (FS GS) and interstitial nephritis. Partial remission was achieved after stopping the cediranib and a short course of prednisone. We review the different forms of kidney injury that could be caused by anti-VEGF therapy.

Functional MRI techniques demonstrate early vascular changes in renal cell cancer patients treated with sunitinib: a pilot study.

OBJECTIVE: To assess the early vascular effects of sunitinib in patients with renal cell carcinoma (RCC) with diffusion-weighted magnetic resonance imaging (DWI), dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) and T2* perfusion MRI. PATIENTS AND METHODS: In 10 patients with abdominal RCC lesions, DWI, DCE-MRI and T2* perfusion MRI measurements at 3 Tesla were performed at baseline, 3 and 10 days after start of sunitinib. VEGF-A plasma levels were measured on days 0, 3 and 10. RESULTS: DWI showed a significant increase in the apparent diffusion coefficient (×10(-6) s/mm(2)) from baseline (mean 1158, range 814-2003) to day 3 (mean 1306, range 1008-2097, P = 0.015) followed by a decrease to baseline levels at day 10 (mean 1132, range 719-2005, P = 0.001). No significant changes were found in mean DCE-MRI parameters. T2* perfusion MRI showed a significant decrease in relative tumor blood volume (rBV) and relative tumor blood flow (rBF) at day 3 (rBV P = 0.037, rBF P = 0.018) and day 10 (rBV P = 0.006, rBF P = 0.009). VEGF-A plasma levels significantly increased after 10 days, but did not correlate with MRI parameters. CONCLUSIONS: Sunitinib induces antiangiogenic effects as measured by DWI and T2*-perfusion MRI, 3 and 10 days after the start of the initial treatment. DCE-MRI did not show significant changes. In the near future, early functional MRI-based evaluation can play an important role in tailoring treatment to the individual patient with RCC. Further investigation is warranted.