Renal cell carcinoma and tumour thrombus in the inferior vena cava: clinical outcome of 98 consecutive patients and the prognostic value of preoperative parameters.

OBJECTIVES: To evaluate the outcome of patients after nephrectomy and removal of tumour thrombus and to assess the prognostic value of preoperative parameters. PATIENTS AND METHODS: Ninety-eight patients who were surgically treated between 2002 and 2011 were included. Patients' charts were reviewed, and patients with renal cell carcinoma (RCC) and concomitant tumour thrombus in the renal vein (RV) were compared with those with extended inferior vena cava (IVC) thrombus. Wilcoxon rank-sum test, Kaplan-Meier analysis and uni- and multivariate Cox regression analysis were used for statistical evaluation. RESULTS: Follow-up was 36 months (20-122 months), and 5-year disease-specific survival (DSS) and overall survival were 68.4 and 54.1 %, respectively. Patients with extended thrombus (levels 2-4) had higher intraoperative transfusion rates of concentrated red cells (CRC) and fresh-frozen plasma (FFP) compared with patients with thrombus confined to the RV (CRC: 5.8 vs. 1.5, p < 0.0001; FFP: 2.3 vs. 0.4, p = 0.0032). Surgery time (190 vs. 107 min, p < 0.0001), duration of hospitalisation (16 vs. 11 days, p = 0.0269), serum phosphate (3.64 vs. 3.29 mmol/l, p = 0.0369) and CRP levels (6.7 vs. 4.4 mg/dl, p = 0.0194) as well as aPTT were increased (33.7 vs. 29.6 s, p = 0.0059) in extended thrombus disease. In multivariate analysis, the presence of distant metastasis (p = 0.03) and lymphovascular invasion (p = 0.001), high platelet counts (p = 0.001) and high serum potassium levels (p = 0.032) proved to be independent prognostic factors. CONCLUSION: The surgical treatment of RCC with tumour thrombus in the RV or IVC has favourable results. Extended thrombus disease requires multidisciplinary approach. High serum potassium levels and platelet counts are associated with reduced DSS.

High and ultra-high b-value diffusion-weighted imaging in prostate cancer: a quantitative analysis.

BACKGROUND: Diffusion-weighted imaging (DWI) is routinely used in magnetic resonance imaging (MRI) of prostate cancer. However, the routine use of b values higher than 1000 s/mm(2) is not clear up to present. Moreover, the complex diffusion behavior of malignant and benign prostate tissues hampers precise predictions of contrast in DWI images and apparent diffusion coefficient (ADC) maps. PURPOSE: To quantitatively analyze DWI with different b values in prostate cancer and to identify b values best suitable for cancer detection. MATERIAL AND METHODS: Forty-one patients with histologically proven prostate cancer were examined with high resolution T2-weighted imaging and DWI at 3 Tesla. Five different b values (0, 800, 1000, 1500, 2000 s/mm(2)) were applied. ADC values of tumors and reference areas were measured on ADC maps derived from different pairs of b values. Furthermore, signal intensities of DW images of tumors and reference areas were measured. For analysis, contrast ratios of ADC values and signal intensities of DW images were calculated and compared. RESULTS: No significant differences were found between contrast ratios measured on ADC maps of all analyzed b value pairs (P = 0.43). Contrast ratios calculated from signal intensities of DW images were highest at b values of 1500 and 2000 s/mm(2) and differed significantly from contrast ratios at b values of 800 and 1000 s/mm(2) (P < 0.01). CONCLUSION: Whereas contrast in ADC maps does not significantly change with different b values, contrast ratios of DW images are significantly higher at b-values of 1500 and 2000 s/mm(2) in comparison to b values of 800 and 1000 s/mm(2). Therefore, diagnostic performance of DWI in prostate cancer might be increased by application of b values higher than 1000 s/mm(2).

Liver cell death and anemia in Wilson disease involve acid sphingomyelinase and ceramide.

Wilson disease is caused by accumulation of Cu(2+) in cells, which results in liver cirrhosis and, occasionally, anemia. Here, we show that Cu(2+) triggers hepatocyte apoptosis through activation of acid sphingomyelinase (Asm) and release of ceramide. Genetic deficiency or pharmacological inhibition of Asm prevented Cu(2+)-induced hepatocyte apoptosis and protected rats, genetically prone to develop Wilson disease, from acute hepatocyte death, liver failure and early death. Cu(2+) induced the secretion of activated Asm from leukocytes, leading to ceramide release in and phosphatidylserine exposure on erythrocytes, events also prevented by inhibition of Asm. Phosphatidylserine exposure resulted in immediate clearance of affected erythrocytes from the blood in mice. Accordingly, individuals with Wilson disease showed elevated plasma levels of Asm, and displayed a constitutive increase of ceramide- and phosphatidylserine-positive erythrocytes. Our data suggest a previously unidentified mechanism for liver cirrhosis and anemia in Wilson disease.

Pudendal nerve block in HDR-brachytherapy patients: do we really need general or regional anesthesia?

PURPOSE: In male patients, the pudendal block was applied only in rare cases as a therapy of neuralgia of the pudendal nerve. We compared pudendal nerve block (NPB) and combined spinal-epidural anesthesia (CSE) in order to perform a pain-free high-dose-rate (HDR) brachytherapy in a former pilot study in 2010. Regarding this background, in the present study, we only performed the bilateral perineal infiltration of the pudendal nerve. METHODS: In 25 patients (71.8 ± 4.18 years) suffering from a high-risk prostate carcinoma, we performed the HDR-brachytherapy with the NPB. The perioperative compatibility, the subjective feeling (German school marks principle 1-6), subjective pain (VAS 1-10) and the early postoperative course (mobility, complications) were examined. RESULTS: All patients preferred the NPB. There was no change of anesthesia form necessary. The expense time of NPB was 10.68 ± 2.34 min. The hollow needles (mean 24, range 13-27) for the HDR-brachytherapy remained on average 79.92 ± 12.41 min. During and postoperative, pain feeling was between 1.4 ± 1.08 and 1.08 ± 1.00. A transurethral 22 French Foley catheter was left in place for 6 h. All patients felt the bladder catheter as annoying, but they considered postoperative mobility as more important as complete lack of pain. The subjective feeling was described as 2.28 ± 0.74. Any side effects or complications did not appear. CONCLUSIONS: Bilateral NPB is a safe and effective analgesic option in HDR-brachytherapy and can replace CSE. It offers the advantage of almost no impaired mobility of the patient and can be performed by the urologist himself. Using transrectal ultrasound guidance, the method can be learned quickly.

Central venous port implantations via the cephalic vein applying an intravasal electrographic control of the catheter tip position: a single-center experience of 316 cases.

PURPOSE: The aim of this study was the analysis of the feasibility and complication rate of central venous port implantation with the surgical cut-down technique applying an intravasal electrographic control of the catheter tip position performed by urologists. PATIENTS AND METHODS: In the time from December 1999 to November 2010, implantation of 324 subcutaneously implanted venous port systems (NuPort-System) has been performed in 316 patients, 221 men (mean age 59.5 years, range 11-87 years) and 95 women (mean age 57.6 years, range 7-85 years). Two hundred and fifty-nine (79.9%) port systems were placed under electrographic control of the catheter tip position. Duration of procedure, long-term device function, and complications such as infections, occlusions, dislocations, and thrombosis were all retrospectively measured and recorded until removal of the device, patient's death or the last known recorded documentation. RESULTS: In total, 359 devices have been used in 348 surgical procedures, 324 implantations (90.25%), and 35 explantations (9.75%). Port systems were implanted using the cephalic vein in 275 patients (84.9%), and in 49 (15.1%), the subclavian vein was used for insertion of the catheter. Mean surgical implantation time was 38.8 min (15-85 min). The median follow-up was 490.6 days (range 2-2,568); 159,764 catheter days (mean, 234 days, range 2-2,604) were documented. Of 35 explanted devices, the explantation was necessary due to complications in 28 cases (8.6%) with infection n = 6 (1.9%, 0.037 per 1,000 catheter days), occlusion n = 8 (2.5%, 0.050 per 1,000 catheter days), dislocation n = 7 (2.2%, 0.044 per 1,000 catheter days), deep vein thrombosis of the upper extremity n = 6 (1.9%, 0.037 per 1,000 catheter days), and clotting n = 1 (0.3%, 0.006 per 1,000 catheter days). Premature catheter removal (<30d post-operatively) was required in 6 patients (1.9%, 0.037 per 1,000 catheter days) due to complications: 3 catheter dislocations/malfunctions (0.9%, 0.019 per 1,000 catheter days), one port related infection, one pocket port infection, and one deep vein thrombosis of the upper extremity (0.3%, 0.006 per 1,000 catheter days). CONCLUSIONS: The intra-atrial ECG techniques to judge correct tip positioning for central venous port implantations are simple and economical. The exact position can be determined intraoperatively. It can justify a delayed postoperative chest X-ray to confirm CVC line tip placement. Nevertheless, the procedure and handling of the device later on has to be performed with care in order to avoid infections and technical problems.

New standardization of checking the vesicourethral anastomosis for tightness following radical prostatectomy with dynamic transrectal ultrasound: can this new technique replace the traditional postoperative cystogram?

PURPOSE: Urinary extravasation at the anastomosis is common after radical prostatectomies. Nevertheless, no data exist referring to the optimal date of catheter removal at the time of expected complete tightness of the leakage. Thus, we developed over the last 10 years a standardized concept to check the anastomosis, evaluating urinary extravasation using a dynamic transrectal ultrasound (dTRUS). METHODS: From 1999 to 2008, 1,479 radical prostatectomies have been performed. For complete tightness, 752 could be evaluated using the standardized concept of checking the anastomosis. The first 250 patients have been evaluated by cystogram and dTRUS and the following 502 patients only by dTRUS postoperatively. The date of checking the anastomosis was determined by the urine color. RESULTS: Urinary extravasation could be detected 4-8 days postoperatively in 41% (n = 308), 9-12 days in 16% (n = 120), 13-20 days in 8% (n = 60), and in no patient after 21 days. The coefficient of correlation comparing dTRUS versus cystogram was r = 0.99, P < 0.05. The measured volume of urinary extravasation after 4-8 days postoperatively was 15 ml (3-49 ml) using dTRUS and 16 ml (3-45 ml) using cystogram. After 9-20 days, the volume was determined as 9 ml (3-24 ml) by dTRUS and 9 ml (4-23 ml) by cystogram. The macroscopic evaluation of the urinary color was very well correlated with the likelihood of extravasation being still present. When the urine was cloudy or colored by old blood, extravasation was present in 96.9% of the patients. Microscopic evaluation like leukocyturia or hematuria of the urine on the same day shows specificity in only 34.3%. CONCLUSIONS: Following radical prostatectomy, the urine color is essential to assess the chance of a persisting leakage at the anastomosis. The method of dTRUS can replace the cystogram in checking for complete healing of the anastomosis, thus decreasing the exposure to X-rays of the patient of about 60 cGy/cm(2).

Ceramide-induced cell death in malignant cells.

Ceramide has been shown to be capable to trigger apoptosis in almost any cell, including tumor cells. Ceramide is generated by a de novo pathway or by sphingomyelinases. Sphingomyelinases hydrolyze sphingomyelin in biological membranes to release ceramide and they are named acid, neutral and alkaline sphingomyelinase depending on their maximum activity at acid, neutral and alkaline pH values, respectively. Stimuli that trigger a release of ceramide to mediate apoptosis include CD95, TNF-receptor, DR5, gamma-irradiation, cytotoxic drugs, UV-light, bacteria, viruses, some forms of developmental death, anti-CD20 and disruption of the cell's contact with its matrix, to name a few. Here, we will focus on the role of acid sphingomyelinase in malignant tumors, which function in apoptosis is best characterized and documented by genetic models. We will discuss concepts that unify the biological actions of ceramide and describe the role of ceramide in important anti-tumor treatment modalities, such as gamma-irradiation and chemotherapy.

[Therapy of bone metastases with radium-223. German guidelines]. / Radionuklidtherapie von Knochenmetastasen mittels Radium-223. DGN-Handlungsempfehlung.

This document describes the guideline for therapy of bone metastases with radium-223 ((223)Ra) published by the Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften in Germany (AWMF) under the auspices of the Deutsche Gesellschaft für Nuklearmedizin (DGN), Östereichische Gesellschaft für Nuklearmedizin (OGN), and Schweizerische Gesellschaft für Nuklearmedizin (SGNM). This guidance is based on an interdisciplinary consensus. These recommendations are a prerequisite for the quality management in the treatment of patients with bone metastases from prostate cancer using (223)Ra. They are aimed at guiding nuclear medicine specialists in selecting candidates to receive therapy and to deliver the treatment in a safe and effective manner. The document contains background information and definitions. It covers the rationale, indications and contraindications for therapy with (223)Ra. Essential topics are the requirements for institutions performing the therapy, which patient data have to be available prior to performance of therapy, and how treatment has to be carried out technically and organisationally. Moreover, essential elements of follow-up and aftercare are specified. As a matter of principle, the treatment inclusive aftercare has to be realised in close cooperation with the involved medical disciplines.

SWITCH: A Randomised, Sequential, Open-label Study to Evaluate the Efficacy and Safety of Sorafenib-sunitinib Versus Sunitinib-sorafenib in the Treatment of Metastatic Renal Cell Cancer.

BACKGROUND: Understanding how to sequence targeted therapies for metastatic renal cell carcinoma (mRCC) is important for maximisation of clinical benefit. OBJECTIVES: To prospectively evaluate sequential use of the multikinase inhibitors sorafenib followed by sunitinib (So-Su) versus sunitinib followed by sorafenib (Su-So) in patients with mRCC. DESIGN, SETTING, AND PARTICIPANTS: The multicentre, randomised, open-label, phase 3 SWITCH study assessed So-Su versus Su-So in patients with mRCC without prior systemic therapy, and stratified by Memorial Sloan Kettering Cancer Center risk score (favourable or intermediate). INTERVENTION: Patients were randomised to sorafenib 400mg twice daily followed, on progression or intolerable toxicity, by sunitinib 50mg once daily (4 wk on, 2 wk off) (So-Su), or vice versa (Su-So). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was improvement in progression-free survival (PFS) with So-Su versus Su-So, assessed from randomisation to progression or death during second-line therapy. Secondary endpoints included overall survival (OS) and safety. RESULTS AND LIMITATIONS: In total, 365 patients were randomised (So-Su, n=182; Su-So, n=183). There was no significant difference in total PFS between So-Su and Su-So (median 12.5 vs 14.9 mo; hazard ratio [HR] 1.01; 90% confidence interval [CI] 0.81-1.27; p=0.5 for superiority). OS was similar for So-Su and Su-So (median 31.5 and 30.2 mo; HR 1.00, 90% CI 0.77-1.30; p=0.5 for superiority). More So-Su patients than Su-So patients reached protocol-defined second-line therapy (57% vs 42%). Overall, adverse event rates were generally similar between the treatment arms. The most frequent any-grade treatment-emergent first-line adverse events were diarrhoea (54%) and hand-foot skin reaction (39%) for sorafenib; and diarrhoea (40%) and fatigue (40%) for sunitinib. CONCLUSIONS: Total PFS was not superior with So-Su versus Su-So. These results demonstrate that sorafenib followed by sunitinib and vice versa provide similar clinical benefit in mRCC. PATIENT SUMMARY: We investigated if total progression-free survival (PFS) is improved in patients with advanced/metastatic kidney cancer who are treated with sorafenib and then with sunitinib (So-Su), compared with sunitinib and then sorafenib (Su-So). We found that total PFS was not improved with So-Su compared with Su-So, but both treatment options were similarly effective in patients with advanced/metastatic kidney cancer. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00732914, www.clinicaltrials.gov.

Combined PET imaging and diffusion-weighted imaging of intermediate and high-risk primary prostate carcinomas with simultaneous [18F] choline PET/MRI.

PURPOSE: To characterize intermediate and high-risk prostate carcinomas with measurements of standardized uptake values (SUVs) and apparent diffusion coefficient (ADC) values by means of simultaneous [18F] choline PET/MRI. MATERIALS AND METHODS: 35 patients with primary prostate cancer underwent simultaneous [18F] choline PET/MRI. From these, 21 patients with an intermediate and high risk constellation who were not under ongoing hormonal therapy were included. Altogether 32 tumor lesions with a focal uptake of [18F] choline could be identified. Average ADC values (ADCaver) minimum ADC values (ADCmin) as well as maximum and mean SUVs (SUVmax, SUVmean) of tumor lesions were assessed with volume-of-interest (VOI) and Region-of-interest (ROI) measurements. As a reference, also ADCaver, ADCmin and SUVmax and SUVmean of non-tumorous prostate tissue were measured. Statistical analysis comprised calculation of descriptive parameters and calculation of Pearson's product moment correlations between ADC values and SUVs of tumor lesions. RESULTS: Mean ADCaver and ADCmin of tumor lesions were 0.94±0.22×10(-3) mm2/s and 0.65±0.21×10(-3) mm2/s, respectively. Mean SUVmax and SUVmean of tumor lesions were 6.3±2.3 and 2.6±0.8, respectively. These values were in each case significantly different from the reference values (p<0.001). There was no significant correlation between the measured SUVs and ADC values (SUVmax vs. ADCaver: R = -0.24, p = 0.179; SUVmax vs. ADCmin: R = -0.03, p = 0.877; SUVmean vs. ADCaver: R = -0.27, p = 0.136; SUVmean vs. ADCmin: R = -0.08, p = 0.679). CONCLUSION: Both SUVs and ADC values differ significantly between tumor lesions and healthy tissue. However, there is no significant correlation between these two parameters. This might be explained by the fact that SUVs and ADC values characterize different parts of tumor biology.

Myeloid-derived suppressor cells in the peripheral blood of cancer patients contain a subset of immature neutrophils with impaired migratory properties.

In tumor-bearing mice, immunosuppressive granulocytic and monocytic MDSC have been identified. The identity and function of MDSC in cancer patients are less clear and need further characterization. We analyzed the peripheral blood of 103 patients with HNC, lung cancer, or cancers of bladder and ureter. Based on sedimentation properties in density gradients, a subset of LD-PMN was identified and analyzed. LD-PMN were expanded in the peripheral blood of cancer patients, suppressed proliferation, and IFN-γ production of polyclonally stimulated T cells and thus, qualify as human MDSC. Immunophenotyping and morphological analysis revealed the accumulation of immature PMN in the MDSC fraction. Neutrophilic MDSC showed altered surface marker expression, prolonged survival, and impaired effector functions when compared with conventional, mature PMN of regular density. MDSC displayed markedly reduced chemotaxis toward tumor-conditioned medium and lacked expression of chemokine receptors CXCR1 and CXCR2, which are normally required for PMN extravasation from the bloodstream and subsequent tissue infiltration. Collectively, our data suggest the accumulation and persistence of long-lived, immature granulocytic MDSC with T cell-suppressive function and impaired migratory properties in the peripheral blood of cancer patients.

Ceramide: physiological and pathophysiological aspects.

Ceramide generated in the cell membrane has been shown to be central for the induction of apoptosis by death receptors and many stress stimuli such as gamma-irradiation, UV-light or infection with pathogens. Ceramide reorganizes cell membranes and forms large ceramide-enriched membrane domains that serve the spatial and temporal organization of the cellular signalosome upon activation. Thus, ceramide-enriched membrane domains mediate clustering of CD95 and DR5 to facilitate apoptosis, and they are also critically involved in apoptosis after irradiation, UV-light and infection with Pseudomonas aeruginosa. Since ceramide-enriched membrane domains amplify signals, their function is not restricted to the induction of apoptosis and it was shown that ceramide-enriched membrane domains are also involved in internalization of pathogens and the control of cytokine release from infected epithelial cells. Recent studies support the notion that changes of the ceramide metabolism are also critically involved in human diseases, for instance neurological disorders, cancer, infectious diseases and Wilson's disease.