Evaluation of the 'Prostate Interdisciplinary Communication and Mapping Algorithm for Biopsy and Pathology' (PIC-MABP).

INTRODUCTION: Experience from interdisciplinary cooperation revealed the need for a prostate mapping scheme to communicate multiparametric MRI (mpMRI) findings between radiologists, urologists, and pathologists, which should be detailed, yet easy to memorize. For this purpose, the 'Prostate interdisciplinary communication and mapping algorithm for biopsy and pathology' (PIC-MABP) was developed. This study evaluated the accuracy of the PIC-MABP system. METHODS: PIC-MABP was tested and validated in findings of 10 randomly selected patients from routine clinical practise with 18 histologically proven cancer lesions. Patients received an mpMRI of the prostate prior to prostatectomy. After surgery the prostates were prepared as whole-mount step sections. Cancer lesions, which were found suspicious on mpMRI, were assigned to the according PIC-MABP sectors by a radiologist. MpMRI slides were masked and sent to seven urologists from different centres, providing only the PIC-MABP location of each lesion. Urologists marked the accordant regions. Then mpMRI slides were unmasked, and the correctness of each mark was evaluated. RESULTS: One hundred and seventeen of the 126 marks (93%) were correctly assigned. Detection rates differed for lesions >0.5 cc compared with lesions <0.5 cc (p < 0.005): 3/7 (43%) marks were correctly assigned in lesions <0.3 cc, 16/21 (76%) in lesions with 0.3-0.5 cc, and 98/98 (100%) in lesions >0.5 cc. Interobserver agreement was good for lesions >0.5 cc and poor for lesions <0.3 cc (Fleiss Kappa 1 vs. 0.0175). CONCLUSION: PIC-MABP seems to be a reliable system to communicate the location of mpMRI findings >0.5 cc between different disciplines and can be a useful guidance for cognitive mpMRI/TRUS fusion biopsy.

Intensified antineoplastic effect by combining an HDAC-inhibitor, an mTOR-inhibitor and low dosed interferon alpha in prostate cancer cells.

A significant proportion of men diagnosed with prostate cancer (PCa) eventually develop metastatic disease, which progresses to castration resistance, despite initial response to androgen deprivation. As anticancer therapy has become increasingly effective, acquired drug resistance has emerged, limiting efficacy. Combination treatment, utilizing different drug classes, exemplifies a possible strategy to foil resistance development. The effects of the triple application of the histone deacetylase (HDAC) inhibitor valproic acid (VPA), the mammalian target of rapamycin inhibitor everolimus and low dosed interferon alpha (IFNα) on PCa cell growth and dissemination capacity were investigated. For that purpose, the human PCa cell lines, PC-3, DU-145 and LNCaP were treated with the combined regimen or separate single agents. Cell growth was investigated by the MTT dye reduction assay. Flow cytometry served to analyse cell cycle progression. Adhesion to vascular endothelium or immobilized collagen, fibronectin and laminin was quantified. Migration and invasion characteristics were determined by the modified Boyden chamber assay. Integrin α and ß subtypes were investigated by flow cytometry, western blotting and RT-PCR. Integrin related signalling, Epidermal Growth Factor Receptor (EGFr), Akt, p70S6kinase and extracellular signal-regulated kinases (ERK)1/2 activation were also assessed. The triple application of VPA, everolimus and low dosed IFNα blocked tumour cell growth and dissemination significantly better than any agent alone. Antitumour effects were associated with pronounced alteration in the cell cycle machinery, intracellular signalling and integrin expression profile. Combining VPA, everolimus and low dosed IFNα might be a promising option to counteract resistance development and improve outcome in PCa patients.

Significance of apoptotic and non-apoptotic disseminated tumor cells in the bone marrow of patients with clinically localized prostate cancer.

BACKGROUND: Disseminated tumor cells (DTC) can be detected in a high proportion of patients with localized solid malignancies. In prostate cancer (PC), determination of DTCs is critically discussed as there are conflicting results on their prognostic value. The aim of the present study was to evaluate the presence and prognostic role of DTCs in PC patients with a high risk of disease recurrence. METHODS: 248 patients with clinically localized PC undergoing radical prostatectomy with features of increased risk of recurrence (PSA ≥10 ng/ml or Gleason score ≥ 4 + 3 = 7 or pT ≥3) were included. All patients underwent intraoperative bone marrow (BM) aspiration biopsy. BM cells were evaluated by immunocytochemistry for cytokeratines and the apoptosis marker caspase-cleaved cytokeratin 18 (M30). Results of immunocytochemistry were correlated with clinical and pathological parameters and clinical outcome of the patients. RESULTS: Of 248 patients, 47 (19.0%) had evidence of DTCs at time of radical prostatectomy. In 17 of these 47 patients (36.2%), DTCs expressed the apoptosis marker M30. We observed no correlation between the presence of DTCs and tumor stage, nodal stage, prostate-specific antigen, or Gleason score. After a median-follow-up of 58 months (23-76), no differences in rates of biochemical recurrence, development of metastases and cancer-specific death were observed between patients with and without DTCs while apoptosis markers had no role. CONCLUSIONS: In a single-centre cohort of patients with increased risk for disease recurrence, the presence of DTCs at the time of prostatectomy does not influence clinical outcome. For the first time in patients with PC, DTCs were evaluated for immunocytological features indicating apoptosis. Due to conflicting results of studies on DTCs, BM biopsies at time of radical prostatectomy cannot be recommended as a standard procedure in patients with clinically localized PC.

Flow matters 2: How to improve irrigation flow in small-calibre percutaneous procedures-the purging effect.

INTRODUCTION: Aim of this study was to investigate whether the combination of high-pressure irrigation inflow combined with simultaneous sensor-controlled suction could improve irrigation turnover without leading to high peak intrarenal pressure in small-calibre percutaneous instruments (SCPI). M + M: A MIP XS sheath (9.5 Fr. outer diameter and 8.5 Fr. inner diameter) and a 7.5-Fr. nephroscope (3-Fr. irrigation channel; MIP XS by Nagele, Karl Storz, Tuttlingen, Germany) was inserted into the collecting system of a non-perfused cadaveric porcine kidney, an 8-Fr. mono-J catheter was introduced through the ureter. Irrigation was performed using a pressure-controlled, combined irrigation/suction pump (Uromat E.A.S.I., Karl Storz, Tuttlingen, Germany) in either single-flow or continuous-flow (=combination of irrigation and suction) mode. Intrarenal pressure was measured and irrigation fluid turnover was measured by a cystometry catheter inserted trans-parenchymally into the renal pelvis. Pressure changes were recorded by a urodynamic workstation. RESULTS: Applying pressure-controlled suction, irrigation fluid turnover could be increased by 5 % at an inflow pressure of 75 mmHg (80-84 ml/min) and 15 % at an inflow pressure of 110 mmHg (196-110 ml/min). Suction decreased the intrarenal pressure by 14 % at 75 mmHg (19-14.5 cm H2O) and 28 % at 110 mmHg inflow pressure (37-26.5 cm H2O). CONCLUSION: Although combination of pressure irrigation with sensor-controlled suction increases irrigation flow in SCPI, the intrarenal pressure could be reduced with combined suction via a transurethral mono-J catheter. This irrigation method in percutaneous surgery is called purging effect.

The management of the access tract after percutaneous nephrolithotomy.

PURPOSE: To describe the evolution of the current technique in percutaneous nephrolithotomy (PCNL) with a special focus on access tract closure techniques. METHODS: A systematic review of outcomes and complications of tubeless PCNL was conducted using the MEDLINE and Pubmed databases between 1976 and 2014. RESULTS: During the past decade, PCNL underwent fundamental modifications due to miniaturization of the instruments and advancements in technique. The routine use of the nephrostomy tube after PCNL has been subsequently questioned. Currently, the nephrostomy tube is increasingly omitted, and the access tract is usually sealed by haemostatic agents. An additionally ureteric stent is commonly inserted at the end of the procedure. However, the application of haemostatic sealants increases the immediate costs significantly. Still there are inconsistent data because of small study populations, lack of randomization, retrospective character and further more heterogeneous surgical techniques. CONCLUSION: The current body of literature does not provide high-level evidence for the preferred treatment of the access tract in PCNL. However, most authors agree that a tract sealing can be omitted without increasing the risk of complication in uncomplicated procedures.

The vacuum cleaner effect in minimally invasive percutaneous nephrolitholapaxy.

INTRODUCTION: Percutaneous stone removal increasingly plays an important role among the different approaches of interventional stone therapy, particularly since the development of miniaturized instruments is resulting in lower morbidity for the patients. One major drawback of smaller instruments is the increased difficulty of stone retrieval after disintegration due to the reduced tract diameter. This results in longer operation time and the need of additional tools such as disposable retrieval baskets. One of the key factors in the development of minimally invasive percutaneous nephrolitholapaxy (MIP) was the design of an Amplatz sheath which provides a built-in vacuum cleaner effect for stone retrieval. METHODS: A series of flow analyses with the gauges and shapes of the most commonly used nephroscopes and sheaths in percutaneous nephrolitholapaxy was performed by computational fluid dynamics. Flow velocity and direction in front of the nephroscope were computed and visualized by the software. RESULTS: In our study, the vacuum cleaner effect developed exclusively when a round-shaped nephroscope was used (Nagele Miniature Nephroscope System, Karl Storz GmbH & Co. KG) and depended on the relation between nephroscope diameter and inner sheath diameter. The strongest effect was observed with a 12 F nephroscope and an inner sheath diameter of 15 F. It did not develop when an oval- or crescent-shaped nephroscope was used. In front of the distal end of the round-shaped nephroscope, a slipstream develops, induced by the excursive change of width of the fluid flow on the outlet of the flushing canal. This allows the adhesion of a stone fragment in the eddy while the fluid flow is circulating around the stone. CONCLUSION: This study illustrates and explains the vacuum cleaner effect which has been detected in the development of the Nagele Miniature Nephroscope System used in MIP. It combines the reduced morbidity of smaller kidney puncture diameters with the benefit of quick and complete stone removal.

CCL2 promotes integrin-mediated adhesion of prostate cancer cells in vitro.

PURPOSE: Chemokines undergo alterations during neoplasia. However, knowledge about their functional significance in prostate cancer (PCa) progression is still sparse. Since chemokine (C-C motif) ligand 2 (CCL2) is significantly up-regulated in patients with PCa, aim of the current study was to assess whether CCL2 contributes to invasive behavior of prostate cancer cells in vitro. METHODS: The human PCa cell line PC3 was stimulated with CCL2. Cell growth was investigated by MTT dye reduction assay. Cell adhesion was analyzed by measuring attachment to a human endothelial cell (HUVEC) monolayer and immobilized collagen. Cell migration was assessed by a chemotactic assay. Integrin expression on the cell surface was evaluated by Western blot. Blocking studies were performed with anti-integrin α3, anti-integrin α6 and anti-integrin ß4 monoclonal antibodies. RESULTS: PC3 cell growth 72 h after CCL2 exposure was significantly increased, compared to controls. Activation of tumor cells by CCL2 significantly enhanced tumor cell adhesion to HUVEC and immobilized collagen. CCL2, added for 4 or 24 h, elevated α6 and ß4 (4 > 24 h) integrin expression. α3 was enhanced after 4 h, but reduced after 24 h. Blocking either α3, α6 or ß4 led to significant suppression of tumor cell binding to immobilized collagen. CONCLUSIONS: CCL2 stimulates PCa cell adhesion and induces alterations in α3-, α6- and ß4-integrin expression on the cell surface. Blocking these integrins leads to a significant reduction in cell adhesion.

Direct comparison of targeted MRI-guided biopsy with systematic transrectal ultrasound-guided biopsy in patients with previous negative prostate biopsies.

OBJECTIVE: To directly compare the diagnostic performance of targeted MRI-guided biopsy (MR-GB) and systematic transrectal ultrasound-guided biopsy (TRUS-GB). METHODS: Thirty-five patients with at least one negative TRUS-GB, persistently elevated or rising prostate-specific antigen and a lesion suspicious for prostate cancer (PC) on multiparametric MRI (mpMRI) scored by using the Prostate Imaging Reporting and Data System (PI-RADS) were included. A median of three targeted biopsies per lesion were obtained and systematic TRUS-GB was performed subsequently by an independent urologist without knowledge of the MRI findings. Definite pathology reports were analyzed for anatomical location and criteria of clinical significance. RESULTS: The tumor detection rate was significantly higher with MR-GB compared with TRUS-GB (16/35, 46% and 8/35, 23%, respectively, p < 0.05). MR-GB detected PC in all patients with positive TRUS-GB. All tumors detected by MR-GB exhibited at least one criterion of clinical significance. PC lesions showed a significantly higher PI-RADS sum score compared with benign lesions. CONCLUSIONS: MR-GB is more effective compared with TRUS-GB in detecting clinically significant PC in men after previous negative TRUS-GB. PI-RADS scores give additional information and could be part of the decision-making process when considering retrial biopsy. Additional systematic biopsy can be omitted in patients undergoing targeted MR-GB.

Feasibility, complications and oncologic results of a limited inguinal lymph node dissection in the management of penile cancer.

PURPOSE: In patients with penile cancer (PeCa) and increased risk of inguinal lymphatic dissemination, inguinal lymphadenectomy offers a direct histological staging as the most reliable tool for assessment of the nodal metastasic status and a definitive oncologic treatment simultaneously. However, peri- and/or postoperative mutilating sequalae often occurn. We report on clinical outcome and complications of a limited inguinal lymph node (LN) dissection. MATERIALS AND METHODS: Clinical and histopathological data of all patients with PeCa who underwent limited inguinal lymphadenectomy (LIL) at our institution between 1986 and 2012 were comprehensively analyzed. Perioperative results were presented in relation to one-sided procedures, if appropriate, which were assessed without cross comparison with contralateral LILs. RESULTS: 29 consecutive patients with PeCa aged 60±10.3 years were included in the current study with 57 one-sided LIL performed. Mean operative time for one-sided LIL was 89.0±37.3 minutes with 8.1±3.7 LNs removed. A complication rate of 54.4% (n=31), including 16 minor and 15 major complications was found in a total of 57 procedures with leg oedema being the most prevalent morbidity (15.8%). 4 patients with clinically positive LNs developed inguinal lymphatic recurrence within 9 months after surgery. CONCLUSIONS: Our technique of limited inguinal LN dissection provided an acceptable complication rate without aggravating morbidity. We experienced no recurrences in clinically LN negative patients, so that the approach might be a reasonable option in this scenario. In patients with enlarged LNs, radical inguinal lymphadenectomy still appears to represent the gold standard.

Can high-spatial resolution T2-weighted endorectal MRI rule out clinically significant prostate cancer?

PURPOSE: To evaluate whether clinically significant prostate cancer (PCa) can be ruled out by high-spatial resolution T2-weighted endorectal MRI (eMRI) in a cohort of patients with biopsy-proven PCa. PATIENTS AND METHODS: A retrospective analysis was carried out for consecutive patients who underwent 1.5 Tesla eMRI for local staging before open radical prostatectomy. The cohort was dichotomized into patients with apparent or inapparent tumour on eMRI. The results were compared with final histopathology, and an analysis for presence of clinically significance PCa was performed. RESULTS: A total of 385 patients were included in the study; in 85 patients (22 %), no apparent lesion suspicious for PCa was detected on eMRI, still final pathology revealed clinically significant PCa in 61 of these patients (72 %). In contrast, 256 (85 %) of the 300 patients with apparent tumour in eMRI harboured clinically significant PCa. eMRI could not differentiate clinically significant from insignificant PCa in neither of the groups (p > 0.6). CONCLUSIONS: Presence of clinically significant cancer cannot be excluded by high-resolution 1.5 Tesla T2-weighted eMRI. The results of the study suggest that the role of T2-weighted eMRI for selecting patients suitable for AS is limited.

Alterations of the RANKL pathway in blood and bone marrow samples of prostate cancer patients without bone metastases.

OBJECTIVES: The receptor activator of the NF-kB ligand (RANKL) pathway is a key mediator of prostate cancer (PC)-induced bone disease. However, little is known about this pathway in patients with non-metastatic PC. We aimed to investigate whether changes of RANKL, its inhibitor osteoprotegerin (OPG) and bone marrow-mesenchymal stromal cells (BM-MSCs) occur in PC patients without manifest bone metastases. PATIENTS AND METHODS: We determined OPG and soluble RANKL (sRANKL) in serum and corresponding bone marrow (BM) samples of 140 patients before radical prostatectomy by enzyme-linked immunosorbent assay (ELISA). As control serum samples of 50 patients with benign prostate hyperplasia were analyzed. BM mononuclear cells (BMNCs) of 16 PC patients were analyzed for expression of RANKL and CD271 (as marker for MSCs) by flow cytometry. RESULTS: PC patients had significantly lower serum levels of OPG compared to BPH patients (P = 0.007), whereas no differences were observed for serum sRANKL (P = 0.74). Both OPG and sRANKL concentrations of serum and corresponding BM samples correlated significantly (P < 0.0001 each). Interestingly, in PC patients, lower serum and BM OPG levels were associated with a higher proportion of BM-MSCs (P = 0.04 and 0.0016, respectively). No correlations were observed for sRANKL, OPG, BM-MSCs, and established risk parameters of PC. DISCUSSION: The results of the study indicate that localized PC is associated with early specific changes of the RANKL pathway in serum and bone marrow (BM). These changes might be part of the pre-metastatic niche of PC and implicate a potential benefit of RANKL inhibition in patients with localized PC.

Prospective evaluation of a hydrogel spacer for rectal separation in dose-escalated intensity-modulated radiotherapy for clinically localized prostate cancer.

BACKGROUND: As dose-escalation in prostate cancer radiotherapy improves cure rates, a major concern is rectal toxicity. We prospectively assessed an innovative approach of hydrogel injection between prostate and rectum to reduce the radiation dose to the rectum and thus side effects in dose-escalated prostate radiotherapy. METHODS: Acute toxicity and planning parameters were prospectively evaluated in patients with T1-2 N0 M0 prostate cancer receiving dose-escalated radiotherapy after injection of a hydrogel spacer. Before and after hydrogel injection, we performed MRI scans for anatomical assessment of rectal separation. Radiotherapy was planned and administered to 78 Gy in 39 fractions. RESULTS: From eleven patients scheduled for spacer injection the procedure could be performed in ten. In one patient hydrodissection of the Denonvillier space was not possible. Radiation treatment planning showed low rectal doses despite dose-escalation to the target. In accordance with this, acute rectal toxicity was mild without grade 2 events and there was complete resolution within four to twelve weeks. CONCLUSIONS: This prospective study suggests that hydrogel injection is feasible and may prevent rectal toxicity in dose-escalated radiotherapy of prostate cancer. Further evaluation is necessary including the definition of patients who might benefit from this approach. TRIAL REGISTRATION: German Clinical Trials Register DRKS00003273.

Accuracy of preoperative endorectal MRI in predicting extracapsular extension and influence on neurovascular bundle sparing in radical prostatectomy.

PURPOSE: To evaluate the accuracy of presurgical endorectal MRI (eMRI) for local staging before radical prostatectomy (RP) and its influence on neurovascular bundle (NVB) resection during radical prostatectomy. PATIENTS AND METHODS: A total of 385 patients with histologically proven prostate cancer (PCa) have been included in this retrospective study between 2004 and 2008. All patients underwent preoperative eMRI at 1.5 T before open RP. Staging results by eMRI were compared with the histopathological findings. The presence of positive surgical margins and extent of nerve-sparing procedure were evaluated. Subgroup analysis of low-risk group and intermediate to high-risk group based on D'Amico criteria was conducted. RESULTS: In 294 (76.4%) patients, pathological stage was correctly predicted, 69 patients (17.9%) were understaged and 22 (5.7%) overstaged. Overall sensitivity, specificity, negative and positive predictive value for predicting extracapsular extension (ECE) were 41.5, 91.8, 78.0 and 69.0%, respectively. One hundred and fifty-two (48.4%) of the patients classified as stage cT2 by eMRI underwent bilateral NVB sparing, whereas 14 (19.7%) patients with reported ECE underwent bilateral NVB sparing (P < 0.01). Overall positive surgical margin rate was 14.8%. Sensitivity of predicting ECE and positive predictive value were lower in the low-risk group than in the intermediate and high-risk group. CONCLUSIONS: eMRI is effective in predicting extracapsular extension in an intermediate to high-risk group. Preoperative eMRI in patients with low-risk criteria is not recommended as a routine assessment modality. eMRI findings did appear to influence surgical strategy as patients with imaging findings suggesting >cT2 disease were less likely to undergo NVB sparing.

Minimally invasive percutaneous nephrolithotomy: an alternative to retrograde intrarenal surgery and shockwave lithotripsy.

PURPOSE: There is a lack of studies comparing shock wave lithotripsy (SWL), retrograde intrarenal surgery (RIRS) and minimally invasive percutaneous nephrolithotomy (MIP) in renal stone treatment. This study compared treatment outcome, stone-free rate (SFR) and stone-free survival (SFS) with regard to stone size and localization. METHODS: This analysis included 482 first-time-treated patients in the period 2001-2007. Detailed clinical information, stone analysis and metabolic evaluation were evaluated retrospectively. Outcome, SFR and SFS were analyzed with regard to size (<1 vs. ≥1 cm) and localization (lower vs. non-lower pole). RESULTS: Higher SFRs in lower and non-lower pole stones ≥1 cm were confirmed for RIRS and MIP (p < 0.0001). A regression model confirmed a higher risk of non-lower pole stone persistence for SWL versus RIRS (OR: 2.27, p = 0.034, SWL vs. MIP (OR: 3.23, p = 0.009) and larger stone burden ≥1 versus <1 cm (OR: 2.43, p = 0.006). In accordance, a higher risk of residual stones was found in the lower pole for SWL versus RIRS (OR: 2.67, p = 0.009), SWL versus MIP (OR: 4.75, p < 0.0001) and stones ≥1 cm versus <1 cm (OR: 3.02, p = 0.0006). In RIRS and MIP patients, more complications, stenting, prolonged disability, need/duration of hospitalization and analgesia were noticed (p < 0.05). Overall SFS increased from SWL, RIRS, to MIP (p < 0.001). SWL showed lower SFS for non-lower pole (p = 0.006) and lower pole stones (p = 0.007). CONCLUSIONS: RIRS and MIP were shown to have higher stone-free rates and SFS compared to SWL. The price for better outcome was higher, considering tolerable complication rates. Despite larger preoperative stone burden, MIP achieved high and long-term treatment success.

Prospective assessment of histological serial sectioning of pelvic lymph nodes in prostate cancer: a cost-benefit analysis.

UNLABELLED: What's known on the subject? and What does the study add? Metastatic spread to the regional lymph nodes (LNs) is the single worst predictor of survival in prostate cancer. Knowledge of the LN status is crucial, as the treatment strategy is substantially altered in non-organ-confined disease. Current routine pathological protocols for evaluation of LN resection specimens do not demand a minimum of cross-sections per LN to be examined. Depending on the LN size, usually one to two sections are examined. This might lead to underestimation of the true metastatic burden. The present study shows that additional examination of cross-sections in pelvic LNs and applying prostate cancer-specific cytokeratine immunostaining does not lead to significantly increased detection of prostate cancer metastases. However, the work-load and the expenses were significantly higher compared with routine evaluation. OBJECTIVE: To evaluate the diagnostic gain in the detection of lymph node (LN) metastases of prostate cancer and the additional expenses of histological step-section analysis, including immunohistochemistry compared with routine histopathological evaluation. PATIENTS AND METHODS: In a prospective study, 19 patients with prostate cancer at high risk of LN metastases (>cT2c and/or PSA level of >20 ng/mL and/or Gleason score >8) underwent sentinel-guided LN resection. All palpable LNs were submitted to step-section analysis in 200-µm sections and concomitant immunohistochemical staining for cytokeratine (AE1/AE3), in addition to routine histopathology of one or two haematoxylin and eosin-stained sections per LN. The number of positive LNs and LN-positive patients for each method was compared; additional expenses in labour time and material for the extended evaluation were estimated. RESULTS: In all, 413 LNs were resected; 220 LNs were palpable and were included in the study. In seven of the 19 patients routine histopathological evaluation revealed LN metastases in 24 of 220 LNs (10.9%). Extended LN evaluation with step sectioning and cytokeratin immunohistochemistry did not reveal any additional patients with LN metastases. In one patient already diagnosed with LN metastases on routine histology, four additional LN metastases were detected upon extended LN evaluation. Three LNs of two patients, one of them pN0, contained disseminated tumour cells. Compared with conventional histological evaluation, serial-section analysis and immunohistochemistry increased expenses in materials and labour time 18.7-fold. CONCLUSIONS: Serial-section analysis seems to have only a minimal diagnostic gain; however, valid conclusions cannot be drawn, as not all LNs were submitted to extended evaluation. Considering the additional expenses, extensive LN evaluation in prostate cancer cannot generally be recommended.

Exposed proliferation antigen 210 (XPA-210) in renal cell carcinoma (RCC) and oncocytoma: clinical utility and biological implications.

OBJECTIVE: • To determine the clinical role of the exposed proliferation antigen 210 (XPA-210) of the proliferation marker thymidine kinase 1 (TK1) in a large cohort of different renal cell carcinoma (RCC) types, oncocytomas and normal renal tissues samples, as TK1 is reported to be of clinical significance in several cancer entities and is suggested as a prognostic serum biomarker for RCC. PATIENTS AND METHODS: • Expressions of XPA-210 were determined immunohistochemically in 40 clear cell RCCs (ccRCC), 25 papillary RCCs (papRCC), 17 chromophobe RCC (chRCC), 27 oncocytomas and 64 normal renal parenchyma paraffin-embedded specimens. • Immunohistochemistry was performed with a monoclonal anti-XPA-210 antibody. Staining was measured by the percentage of positive cells. • Expression was compared between subgroups and correlated with respective clinical data using one-way analysis of variance with post hoc Tukey-Kramer analyses. RESULTS: • XPA-210 staining in the RCC subgroup was significantly different from the oncocytomas (mean [sem] 4.1 [0.4] vs 2.2 [0.4]; P = 0.004) and from normal renal tissue (1.0 [0.1]; P < 0.001], whereas oncocytomas did not differ from normal renal parenchyma staining (P = 0.18). • Subdivided into RCC groups, only ccRCC (mean [sem] 5.1 [0.6]; P < 0.001) and papRCC (4.4 [0.6]; P < 0.001) varied from normal renal parenchyma, whereas chRCC (1.4 [0.3]; P = 0.99) did not. • RCC XPA-210 staining was significantly associated with higher tumour stage (T = 3, P = 0.002) and grade (G = 3, P = 0.001). CONCLUSIONS: • The malignant character of RCC is reflected by higher XPA-210 expression as compared with oncocytomas and normal kidney. • The ccRCC and papRCC subgroups had higher XPA-210 levels. • XPA-210 could be considered a potential marker for the assessment of the proliferative activity in primary RCC.

Minimally invasive percutaneous nephrolitholapaxy (PCNL) as an effective and safe procedure for large renal stones.

UNLABELLED: Study Type--Therapy (case series) Level of Evidence 4. What's known on the subject? and What does the study add? The minimally invasive percutaneous nephrolitholapaxy (MIP) has shown high efficacy and safety for the management of small renal stones. It was initially developed to overcome a gap between the minimally invasive extracorporeal shockwave lithotripsy and invasive conventional percutaneous nephrolitholapaxy (PCNL) in the management of low stone burden but there is debate as to whether the MIP is also effective for larger stones. The present study shows the high efficacy and safety of MIP, which is comparable to conventional PCNL in the treatment of stones of >20 mm, including complex staghorn stones. OBJECTIVE: • To evaluate the safety and efficacy of minimally invasive percutaneous nephrolitholapaxy (MIP) in the management of large and complex renal calculi. PATIENTS AND METHODS: • From January 2007 to March 2011, 73 patients with 83 renal units with large renal stones (>20 mm in diameter) were retrospectively evaluated. • Stones were classified into simple (isolated renal pelvis or isolated calyceal stones) or complex (partial or complete staghorn stones, renal pelvis stones with accompanying calyceal stones). • Stone-free rate, complications according to the modified Clavien system, decrease in haemoglobin, creatinine level, operative duration and hospital stay were compared for simple and complex renal calculi. RESULTS: • The mean (sd) stone size was 36.7 (23.37) mm and mean operative duration was 99.2 (48.3) min. • In all, 65 cases (78.3%) were stone-free after the first procedure and another 14 needed an auxiliary procedure (four second-look percutaneous nephrolitholapaxy, nine ureterorenoscopy, and one extracorporeal shockwave lithotripsy) to become stone-free, resulting in a 95.2% stone-free rate. • Complications occurred in 22 procedures (26.5%), 17 of them were Clavien Grade 1 or 2 (20.5%), five were Grade 3 (6%). There were no Grade 4 or 5 complications. • The only significant difference between complex and simple stones was the stone-free rate (96.9% vs 66.7%, P = 0.001). CONCLUSION: • The MIP technique is effective and safe for larger stones with low morbidity, good success rate and reasonable operative duration.

Inflammatory prognostic markers in clear cell renal cell carcinoma - preoperative C-reactive protein does not improve predictive accuracy.

UNLABELLED: What's known on the subject? and What does the study add? White blood cell count and C-reactive protein are reliable prognostic RCC Biomarkers.Nevertheless, accepted cut-offs for risk stratifications are missing. Therefore, both parameters were re-evaluated and multivariable analyses revealed an optimal CRP breakpoint at 0.25 mg/dL to be best to stratify patients at risk of cancer-specific mortality. However, this CRP-based prediction added no additional information compared to a clinico-pathological based model. OBJECTIVE: To re-evaluate the prognostic and predictive significance of the preoperative white blood cell (WBC) count and C-reactive protein (CRP) that independently predicts patient prognosis and to determine optimal threshold values for CRP. PATIENTS AND METHODS: From 1996 to 2005, 327 patients with surgery for clear cell renal cell carcinoma were retrospectively evaluated. Cox proportional hazard models were used, adjusted for the effects of tumour stage, size, Fuhrman grade and Karnofsky index, to evaluate the prognostic significance of WBC count and CRP and to identify threshold values. Identified thresholds were correlated with clinicopathological parameters and used to estimate cancer-specific survival. To prove any additional predictive accuracy of the identified threshold it was compared with a clinicopathological base model using the Harrell concordance index (c-index). RESULTS: In univariable analyses WBC count was a significant prognostic marker at a concentration of 9.5/µL (hazard ratio [HR] 1.83) and 11.0/µL (HR 2.09) and supported CRP values of 0.25 mg/dL (HR 6.47, P < 0.001) and 0.5 mg/dL (HR 7.15, P < 0.001) as potential threshold values. If adjusted by the multivariable models WBC count showed no clear breakpoint, but a CRP value of 0.25 mg/dL (HR 2.80, P = 0.027) proved to be optimal. Reduced cancer-specific survival was proved for CRP 0.25 mg/dL (median 69.9 vs 92.3 months). Median follow-up was 57.5 months with 72 (22%) tumour-related deaths. The final model built by the addition of CRP 0.25 mg/dL did not improve predictive accuracy (c-index 0.877) compared with the clinicopathological base model (c-index 0.881) which included TNM stage, grading and Karnofsky index. CONCLUSIONS: Multivariable analyses revealed that an optimal breakpoint of CRP at a value of 0.25 mg/dL was best to stratify patients at risk of cancer-specific mortality, but CRP 0.25 mg/dL added no additional information in the prediction model. Therefore we cannot recommend measuring CRP as the traditional parameters of TNM stage, grading and Karnofsky index are already of high predictive accuracy.

Novel options for the treatment of castration-resistant prostate cancer.

Docetaxel had been the only treatment of castration-resistant prostate cancer (CRPC) that demonstrated a survival benefit for the patients. After its approval, no considerable progress has been made for several years until cabazitaxel and abiraterone acetate demonstrated a significant survival benefit in phase III clinical trials. Apart from that several other new drugs appeared including inhibitors of the androgen receptor (MDV3100), endothelin receptor antagonists (atrasentan, zibotentan), bone-targeted drugs (denosumab, Alpharadin) and immunotherapies (sipuleucel-T) capable of improving the prognosis of patients with CRPC. Here, we review the most recent advances in the treatment of CRPC and highlight the most promising new agents currently being investigated in clinical trials.

XPA-210: a new proliferation marker determines locally advanced prostate cancer and is a predictor of biochemical recurrence.

PURPOSE: XPA-210 is a proliferation marker derived from Thymidine kinase-1. It is of clinical significance in kidney, breast, and bladder cancer. There are no data available for XPA-210 in prostate cancer (PC). Herein, we aim to determine the clinical usefulness of XPA-210 in PC. MATERIALS AND METHODS: In a retrospective study, cancer and benign tissue samples of 103 patients (median age 65 years, median PSA 9.04 ng/ml, median Gleason score 6) who underwent prostatectomy were constructed to a tissue micro array and stained for XPA-210. Semi-quantitative results were correlated with pathological and clinical data by Wilcoxon-Kruskall-Wallis and linear regression analysis. Expression levels in PC were correlated between the time of biochemical recurrence and the time to development of metastasis by the Kaplan-Meier method. Multivariate analysis was done to correlate those with the resection status. RESULTS: Mean staining score was 0.51-0.14 for tumor and benign tissue (P < 0.0001). Tumor staining score was significantly associated with Gleason score <6/≥6 (P < 0.0001) and T2/T >2 (P = 0.0007). When dividing the tumor score by the mean value, higher expression of XPA-210 was associated with a shorter time to biochemical recurrence (P = 0.003) and time to development of metastasis (P = 0.0061). Tumor staining (P = 0.0371) was an independent prognostic factor for biochemical relapse regardless of resection status. CONCLUSIONS: XPA-210 is a new tissue-based prognostic marker for prostate cancer histopathology. It reliably differentiates tumor and normal prostatic tissue predicting biochemical relapse and onset of metastatic disease. XPA-210 might be clinically useful for individual decision-making in PC-treatment.