Tomasz Borkowski

Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial.

BACKGROUND Bone metastases are a major cause of morbidity and mortality in men with prostate cancer. Preclinical studies suggest that osteoclast inhibition might prevent bone metastases. We assessed denosumab, a fully human anti-RANKL monoclonal antibody, for prevention of bone metastasis or death in non-metastatic castration-resistant prostate cancer. METHODS In this phase 3, double-blind, randomised, placebo-controlled study, men with non-metastatic castration-resistant prostate cancer at high risk of bone metastasis (prostate-specific antigen [PSA] ≥8·0 μg/L or PSA doubling time ≤10·0 months, or both) were enrolled at 319 centres from 30 countries. Patients were randomly assigned (1:1) via an interactive voice response system to receive subcutaneous denosumab 120 mg or subcutaneous placebo every 4 weeks. Randomisation was stratified by PSA eligibility criteria and previous or ongoing chemotherapy for prostate cancer. Patients, investigators, and all people involved in study conduct were masked to treatment allocation. The primary endpoint was bone-metastasis-free survival, a composite endpoint determined by time to first occurrence of bone metastasis (symptomatic or asymptomatic) or death from any cause. Efficacy analysis was by intention to treat. The masked treatment phase of the trial has been completed. This trial was registered at ClinicalTrials.gov, number NCT00286091. FINDINGS 1432 patients were randomly assigned to treatment groups (716 denosumab, 716 placebo). Denosumab significantly increased bone-metastasis-free survival by a median of 4·2 months compared with placebo (median 29·5 [95% CI 25·4-33·3] vs 25·2 [22·2-29·5] months; hazard ratio [HR] 0·85, 95% CI 0·73-0·98, p=0·028). Denosumab also significantly delayed time to first bone metastasis (33·2 [95% CI 29·5-38·0] vs 29·5 [22·4-33·1] months; HR 0·84, 95% CI 0·71-0·98, p=0·032). Overall survival did not differ between groups (denosumab, 43·9 [95% CI 40·1-not estimable] months vs placebo, 44·8 [40·1-not estimable] months; HR 1·01, 95% CI 0·85-1·20, p=0·91). Rates of adverse events and serious adverse events were similar in both groups, except for osteonecrosis of the jaw and hypocalcaemia. 33 (5%) patients on denosumab developed osteonecrosis of the jaw versus none on placebo. Hypocalcaemia occurred in 12 (2%) patients on denosumab and two (<1%) on placebo. INTERPRETATION This large randomised study shows that targeting of the bone microenvironment can delay bone metastasis in men with prostate cancer. FUNDING Amgen Inc.

BRCA1 mutations and prostate cancer in Poland

Evidence to date that BRCA1 mutation carriers are at an increased risk of prostate cancer is mixed – both positive and negative studies have been published. To establish whether or not inherited variation in BRCA1 influences prostate cancer risk we genotyped 1793 men with prostate cancer in Poland and 4570 controls for three founder mutations (C61G, 4153delA and 5382insC). A BRCA1 mutation was present in 0.45% of the cases and 0.48% of the controls (odds ratio=0.9; P=1.0). The odds ratios varied substantially by mutation. The 5382insC mutation is the most common of the three founder mutations. It was detected only in one case (0.06%), whereas it was seen in 0.37% of controls (P=0.06). In contrast, the 4153delA was more common in prostate cancer cases (0.22%) than in controls (0.04%) (odds ratio=5.1; 95% confidence interval: 0.9–27.9; P=0.1). The C61G mutation was also found in excess in cases (0.17%) compared with controls (0.07%) (odds ratio=2.6; 95% confidence interval: 0.5–12.7; P=0.5). Eight men with prostate cancer carried a mutation. Only one of these carried the 5382insC mutation, compared with 17 of 22 individuals with mutations in the control population (P=0.003). These data suggest that the 5382insC mutation is unlikely to be pathogenic for prostate cancer in the Polish population. The presence of one of the other alleles was associated with an increased risk for prostate cancer (odds ratio=3.6; 95% confidence interval: 1.1–11.3; P=0.045); in particular for familial prostate cancer (odds ratio=12; 95% confidence interval: 2.9–51; P=0.0004). We consider that the risk of prostate cancer in BRCA1 carriers varies with the position of the mutation.

The G84E mutation in the HOXB13 gene is associated with an increased risk of prostate cancer in Poland

The G84E mutation in the HOXB13 gene has been associated with a high lifetime risk of prostate cancer in North America (about 20‐fold). The geographical and ethnic extent of this recurrent allele has not yet been determined.

A common nonsense mutation of the BLM gene and prostate cancer risk and survival

BACKGROUND Germline mutations of BRCA2 and NBS1 genes cause inherited recessive chromosomal instability syndromes and predispose to prostate cancer of poor prognosis. Mutations of the BLM gene cause another chromosomal instability clinical syndrome, called Bloom syndrome. Recently, a recurrent truncating mutation of BLM (Q548X) has been associated with a 6-fold increased risk of breast cancer in Russia, Belarus and Ukraine, but its role in prostate cancer etiology and survival has not been investigated yet. METHODS To establish whether the Q548X allele of the BLM gene is present in Poland, and whether this allele predisposes to poor prognosis prostate cancer, we genotyped 3337 men with prostate cancer and 2604 controls. RESULTS Q548X was detected in 13 of 3337 (0.4%) men with prostate cancer compared to 15 of 2604 (0.6%) controls (OR=0.7; 95% CI 0.3-1.4). A positive family history of any cancer in a first- or second-degree relative was seen only in 4 of the 13 (30%) mutation positive families, compared to 49% (1485/3001) of the non-carrier families (p=0.3). The mean follow-up was 49months. Survival was similar among carriers of Q548X and non-carriers (HR=1.1; p=0.9). The 5-year survival for men with a BLM mutation was 83%, compared to 72% for mutation-negative cases. CONCLUSIONS BLM Q548X is a common founder mutation in Poland. We found no evidence that this mutation predisposes one to prostate cancer or affect prostate cancer survival. However, based on the observed 0.6% population frequency of the Q548X allele, we estimate that one in 100,000 children should be affected by Bloom syndrome in Poland.

Exogenously Administered Opioids Contract the Female Rat Intrinsic Urethral Sphincter In Vivo

Previous studies have reported immunoreactive opioid nerve fibers in the detrusor and lower urinary tract sphincters. However, there is a paucity of in vivo studies demonstrating the direct effect of endogenous opioids in these structures. In the present study, we investigated the contractile actions of intra‐arterially administered exogenous Dynorphin‐A, Met‐enkephalin, Leu‐enkephalin, morphine, and the opioid antagonist naltrexone on the female rat intrinsic urethral sphincter in vivo.

The presence of prostate cancer at biopsy is predicted by a number of genetic variants

Several single nucleotide polymorphisms (SNPs) have been associated with an elevated risk of prostate cancer risk. It is not established if they are useful in predicting the presence of prostate cancer at biopsy or if they can be used to define a low‐risk group of men. In this study, 4,548 men underwent a prostate biopsy because of an elevated prostate specific antigen (PSA; ≥4 ng/mL) or an abnormal digital rectal examination (DRE). All men were genotyped for 11 selected SNPs. The effect of each SNP, alone and in combination, on prostate cancer prevalence was studied. Of 4,548 men: 1,834 (40.3%) were found to have cancer. A positive association with prostate cancer was seen for 5 of 11 SNPs studied (rs1800629, rs1859962, rs1447295, rs4430796, rs11228565). The cancer detection rate rose with the number of SNP risk alleles from 29% for men with no variant to 63% for men who carried seven or more risk alleles (OR = 4.2; p = 0.002). The SNP data did not improve the predictive power of clinical factors (age, PSA and DRE) for detecting prostate cancer (AUC: 0.726 vs. 0.735; p = 0.4). We were unable to define a group of men with a sufficiently low prevalence of prostate cancer that a biopsy might have been avoided. In conclusion, our data do not support the routine use of SNP polymorphisms as an adjunct test to be used on the context of prostate biopsy for Polish men with an abnormal screening test.

Endoscopic simple prostatectomy.

Introduction Many options exist for the surgical treatment of lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH), including transurethral resection of the prostate (TURP), laser surgery, and open adenomectomy. Recently, endoscopic techniques have been used in the treatment of BPH. Material and methods We reviewed clinical studies in PubMed describing minimally invasive endoscopic procedures for the treatment of BPH. Results Laparoscopic adenomectomy (LA) and robotic–assisted simple prostatectomy (RASP) were introduced in the early 2000s. These operative techniques have been standardized and reproducible, with some individual modifications. Studies analyzing the outcomes of LA and RASP have reported significant improvements in urinary flow and decreases in patient International Prostate Symptom Score (IPSS). These minimally invasive approaches have resulted in a lower rate of complications, shorter hospital stays, smaller scars, faster recoveries, and an earlier return to work. Conclusions Minimally invasive techniques such as LA and RASP for the treatment BPH are safe, efficacious, and allow faster recovery. These procedures have a short learning curve and offer new options for the surgeon treating BPH.

The limitations of multiparametric magnetic resonance imaging also must be borne in mind.

The increasingly widespread use of multiparametric magnetic resonance imaging (mpMRI) in recent years has clearly changed the diagnostic and, as a consequence, the therapeutic capabilities in prostate cancer. In the current literature review, Bjurlin et al. determined the exact role of contemporary research in various scenarios related to the clinical diagnosis of prostate cancer: no previous biopsy, prior negative or positive biopsy [1]. The use of diffusion-weight imaging (DWI) with dynamic contrast-enhanced imaging (DCE) has significantly improved sensitivity up to 90% and specificity to over 70%, with a negative predictive value of over 95% with respect to tumors with a Gleason score above 3+3 [2, 3]. On account of moderate specificity, however, urological scientific societies indicate that the only way to make a diagnosis in the case of cancer remains a biopsy of the prostate [4, 5]. That being said, despite the undoubted improvements that have occurred in recent years in the field of MRI, this technology presents several limitations. So firstly, which factors have a significant impact on obtaining appropriate quality images and data and, secondly, which factors have a significant impact on their correct interpretation? In order to obtain images with the parameters recommended in the PI-RADS 2.0 guidelines, mpMRI testing should be performed on a system with a field strength of at least 1.5 T [6]. If the field strength is any lower, or if the gradient system is weak, then this could prove to be a technical obstacle to achieving the above requirements. Despite the changes taking place in the standardized reporting system, it is still moderately reproducible. The development of clear recommendations as to which lesion score requires a biopsy and at which can safely be observed, is still required. In the case of sequences that make up the mpMRI study, it must be highlighted that the most important, which go beyond the assessment of morphology, i.e. DWI images, apparent diffusion coefficient mapping (ADC) and DCE, are extremely sensitive to motion artifacts. Therefore, the mere susceptibility to prostate spasms and the muscle movements of the surrounding muscle apparatus may have an impact on the images obtained. Another factor that may also have an adverse impact on the quality of the study is intestinal motility. The use of measures limiting intestinal motility is recommended in mpMRI studies to assist in overcoming this limitation. Intrinsic patient characteristics also pose additional limitations to MRI of the prostate. The signal strength of an organ, which determines the quality of the image obtained, is directly dependent on its distance from the receiver coil of the MR apparatus. Therefore, in patients with severe obesity, the sheer thickness of the adipose tissue, resulting in an increased distance between the receiver coil and prostate, may cause deterioration in the quality of the study to such an extent that it often becomes of no diagnostic use. Important factors limiting the performance of the mpMRI test, including metallic foreign bodies, and particularly hip endo-prosthesis (the frequency of which increases with age) should be mentioned. Field distortion caused by a metal endo-prosthesis may even prevent a reliable assessment of the mpMRI study. In order for the mpMRI study to meet expectations, it should be described by an experienced radiologist [7]. Therefore, it is important for such studies to have been performed in referral centers where multiple descriptions improve quality. Moreover, for a proper interpretation of the morphological data to be obtained during mpMRI tests, a complete profile of the patient is required. Comprehensive presentation of clinical data by the urologist clearly facilitates interpretation of morphological images. Therefore, there is a need for close co-operation between the radiologist and the clinical urologist which, thanks to feedback and the exchange of information, leads to the building of mutual experience among both groups of specialists, in that, the radiologist knows what information is required by the urologist, and the urologist in turn is able to interpret the radiologists description. The current results of the research discussed in the article, highlighting the impact of mpMRI on the increase of clinically relevant cancer detection, are optimistic, especially when an undisputedly high – above 95% – negative predictive value of mpMRI research, in relation to a Gleason score above 3+3, has been observed. The authors expect that in the near future, there will be a further increase in mpMRI sensitivity and specificity, the previously described limitations will be overcome, and that further precise standardisation of this technique will be implemented. Already today technological progress has replaced endo-rectal coils – until recently the “gold standard” – with surface coils. These surface coils are not inferior in terms of quality of imaging but are much easier to work with and the testing itself is more readily acceptable to the patient without this endo-rectal coil [8].

Lack of usefulness of ureteral reconstruction with free bladder mucosa flap in dogs confirmed by microangiography

Background There is a paucity of data addressing the blood supply in the surgically reconstructed ureter, and complete lack of microangiographic studies of the reconstructed ureter with the use of a free bladder mucosa flap. The present study evaluated the blood supply in the reconstructed dog ureter after a 5-centimeter segment resection, supplemented by a tube constructed from a free bladder mucosa flap. Material/Methods Female mongrel dogs (n=29) were used in this study. Under general anaesthesia, a 5-centimeter autologous free bladder mucosa flap was used to construct a tube, which was afterwards grafted to replace a 5-centimeter ureter resection. After a period of 3 months (n=2) and after 1 year (n=2), microangiography was performed to assess the revascularization of the grafted ureter. Results In our study, we observed the continuity of the ureter, but the grafted reconstruction was narrowed by the cicatrization in about 86% (n=25) of cases. This resulted in the development of hydronephrosis, as described in previous publications. The ureteral wall was covered by a normal urothelium, but consisted of fibrous connective tissue, which failed to restore a regular (normal) coat. The reconstructed segment showed no smooth muscle cells. A few smooth monocytes were found only at the border with intact portions of the ureter. The microangiography performed at the end of the experiments showed no vascularization of the restored segment of the ureter. Conclusions The experiments showed a whole regeneration of urothelium in the transected and reanastomosed ureters. However, there was no regeneration of the muscular coat and a complete lack of revascularization.

Malignant peripheral nerve sheath tumor of the prostate

The diagnostic and therapeutic approach to prostatic neurosarcoma, currently known as a malignant peripheral nerve sheath tumor (MPNst) of the prostate, due to its rarity, is not well established. Our presenting case was a 73 year old patient, admitted to the Hospital with suspicion of a prostatic tumor. The patient underwent surgical resection of the described pathological mass. Gross appearance of the pathological examination revealed a yellow-gray colored tumor, 12 × 6 × 7 cm in size. On cross-section: tumor heterogeneity, fatty, yellow-gray, with no foci of necrosis, but with a few cysts of 1–3 cm in size, with a gelatinous substance. Microscopic examination — showed neurosarcoma of the prostate. The patient died at six months follow-up, due to cardiovascular insufficiency.