[Ischemia is not an independent predictive factor of chronic renal failure after partial nephrectomy in a solitary kidney in patients without pre-operative renal insufficiency]. / L'ischémie a un impact limité sur la fonction rénale après néphrectomie partielle sur rein unique chez les patients sans insuffisance rénale préopératoire.

OBJECTIVE: To assess the influence of vascular clamping and ischemia time on long-term post-operative renal function following partial nephrectomy (PN) for cancer in a solitary kidney. PATIENTS AND METHODS: This is a retrospective study including 259 patients managed by PN between 1979 and 2010 in 13 centers. Clamping use, technique choice (pedicular or parenchymal clamping), ischemia time, and peri-operative data were collected. Pre-operative and last follow-up glomerular filtration rates were compared. A multivariate analysis using a Cox model was performed to assess the impact of ischemia on post-operative chronic renal failure risk. RESULTS: Mean tumor size was 4.0±2.3cm and mean pre-operative glomerular filtration rate was 60.8±18.9mL/min. One hundred and six patients were managed with warm ischemia (40.9%) and 53 patients with cold ischemia (20.5%). Thirty patients (11.6%) have had a chronic kidney disease. In multivariate analysis, neither vascular clamping (P=0.44) nor warm ischemia time (P=0.1) were associated with a pejorative evolution of renal function. Pre-operative glomerular filtration rate (P<0.0001) and blood loss volume (P=0.02) were significant independent predictive factors of long-term renal failure. CONCLUSION: Renal function following PN in a solitary kidney seems to depend on non-reversible factors such as pre-operative glomerular filtration rate. Our findings minimize the role of vascular clamping and ischemia time, which were not significantly associated with chronic renal failure risk in our study. LEVEL OF EVIDENCE: 5.

Adherence to the Mediterranean diet and risk of bladder cancer in the EPIC cohort study.

There is growing evidence of the protective role of the Mediterranean diet (MD) on cancer. However, to date no epidemiological study has investigated the influence of the MD on bladder cancer. We evaluated the association between adherence to the MD and risk of urothelial cell bladder cancer (UCC), according to tumor aggressiveness, in the European Prospective Investigation into Cancer and Nutrition (EPIC). The analysis included 477,312 participants, recruited from ten European countries between 1991 and 2000. Information from validated dietary questionnaires was used to develop a relative Mediterranean diet score (rMED), including nine dietary components. Cox regression models were used to assess the effect of the rMED on UCC risk, while adjusting for dietary energy and tobacco smoking of any kind. Stratified analyses were performed by sex, BMI, smoking status, European region and age at diagnosis. During an average follow-up of 11 years, 1,425 participants (70.9% male) were diagnosed with a first primary UCC. There was a negative but non-significant association between a high versus low rMED score and risk of UCC overall (HR: 0.84 [95% CI 0.69, 1.03]) and risk of aggressive (HR: 0.88 [95% CI 0.61, 1.28]) and non-aggressive tumors (HR: 0.78 [95% CI 0.54, 1.14]). Although there was no effect modification in the stratified analyses, there was a significant 34% (p = 0.043) decreased risk of UCC in current smokers with a high rMED score. In EPIC, the MD was not significantly associated with risk of UCC, although we cannot exclude that a MD may reduce risk in current smokers.

Treatment and overall survival in renal cell carcinoma: a Swedish population-based study (2000-2008).

BACKGROUND: This retrospective register study assessed overall survival (OS) and influential factors on OS in Swedish renal cell carcinoma (RCC) patients. METHODS: Using three merged national health registers, Cox proportional-hazards analysis was conducted and, in three models, it was used to assess the impact of cytokine (interferon-α and tyrosine kinase inhibitor (TKI; sunitinib or sorafenib) treatment on OS in metastatic (m)RCC. RESULTS: From 2000 to 2008, 8009 patients were diagnosed with RCC and 2753 with mRCC (2002-2008). Median OS in RCC patients diagnosed from 2006 to 2008 compared with 2000-2005 was not reached vs 47.9 months (P<0.001), and in mRCC patients diagnosed from 2006 to 2008 compared with 2002-2005, was 12.4 vs 9.6 months, respectively (P=0.004). Factors associated with significantly improved OS in RCC were female gender, lower age, and previous nephrectomy, and, in mRCC female gender, previous nephrectomy, and any TKI prescription (Model 1: median-adjusted OS, 19.4 months (TKI patients) vs 9.7 months (non-TKI patients); hazard ratio, 0.621; P<0.001). CONCLUSION: OS was improved in Swedish patients diagnosed with RCC and mRCC in the period 2006-2008 compared with 2000-2005 (RCC) and 2002-2005 (mRCC). Although multifactorial in origin, results suggest that increased nephrectomy rates and the use of TKIs contributed to the improvement seen in mRCC patients.

Treatment of haemophilia A and B and von Willebrand's disease: summary and conclusions of a systematic review as part of a Swedish health-technology assessment.

In an ongoing health-technology assessment of haemophilia treatment in Sweden, performed by the governmental agency Dental and Pharmaceutical Benefits Agency (TLV; tandvårds-och lakemedelsförmånsverket), the Swedish Council on Health Technology Assessment (SBU; statens beredning för medicinsk utvardering) was called upon to evaluate treatment of haemophilia A and B and von Willebrand's disease (VWD) with clotting factor concentrates. To evaluate the following questions: What are the short-term and long-term effects of different treatment strategies? What methods are available to treat haemophilia patients that have developed inhibitors against factor concentrates? Based on the questions addressed by the project, a systematic database search was conducted in PubMed, NHSEED, Cochrane Library, EMBASE and other relevant databases. The literature search covered all studies in the field published from 1985 up to the spring of 2010. In most instances, the scientific evidence is insufficient for the questions raised in the review. Concentrates of coagulation factors have good haemostatic effects on acute bleeding and surgical intervention in haemophilia A and B and VWD, but conclusions cannot be drawn about possible differences in the effects of different dosing strategies for acute bleeding and surgery. Prophylaxis initiated at a young age can prevent future joint damage in persons with haemophilia. The available treatment options for inhibitors have been insufficiently assessed. The economic consequences of various treatment regimens have been insufficiently analysed. Introduction of national and international registries is important.

Wilms' tumour 1 can suppress hTERT gene expression and telomerase activity in clear cell renal cell carcinoma via multiple pathways.

BACKGROUND: Wilms' tumour 1 (WT1) gene was discovered as a tumour suppressor gene. Later findings have suggested that WT1 also can be oncogenic. This complexity is partly explained by the fact that WT1 has a number of target genes. METHOD: WT1 and its target gene human telomerase reverse transcriptase (hTERT) were analysed in clear cell renal cell carcinoma (ccRCC). In vitro experiments were performed to examine the functional link between WT1 and hTERT by overexpression of WT1 isoforms in the ccRCC cell line, TK-10. RESULTS: WT1 demonstrated lower RNA expression in ccRCC compared with renal cortical tissue, whereas hTERT was increased, showing a negative correlation between WT1 and hTERT (P=0.005). These findings were experimentally confirmed in vitro. The WT1 generated effect on hTERT promoter activity seemed complex, as several negative regulators of hTERT transcription, such as SMAD3, JUN (AP-1) and ETS1, were activated by WT1 overexpression. Downregulation of potential positive hTERT regulators, such as cMyc, AP-2α, AP-2γ, IRF1, NFX1 and GM-CSF, were also observed. Chromatin immunoprecipitation analysis verified WT1 binding to the hTERT, cMyc and SMAD3 promoters. CONCLUSION: The collected data strongly indicate multiple pathways for hTERT regulation by WT1 in ccRCC.

Alcohol consumption and the risk of renal cancers in the European Prospective Investigation into Cancer and Nutrition (EPIC). Wozniak MB, Brennan P, Brenner DR, Overvad K, Olsen A, Tjønneland A, Boutron-Ruault MC, Clavel-Chapelon F, Fagherazzi G, Katzke V, Kühn T, Boeing H, Bergmann MM, Steffen A, Naska A, Trichopoulou A, Trichopoulos D, Saieva C, Grioni S, Panico S, Tumino R, Vineis P, Bueno-de-Mesquita HB, Peeters PH, Hjartåker A, Weiderpass E, Arriola L, Molina-Montes E, Duell EJ, Santiuste C, Alonso de la Torre R, Barricarte Gurrea A, Stocks T, Johansson M, Ljungberg B, Wareham N, Khaw KT, Travis RC, Cross AJ, Murphy N, Riboli E, Scelo G.Int J Cancer. 2015 Oct 15;137(8):1953-66. [Epub 2015 Apr 28]. doi: 10.1002/ijc.29559.

Epidemiologic studies have reported that moderate alcohol consumption is inversely associated with the risk of renal cancer. However, there is no information available on the associations in renal cancer subsites. From 1992 to 2010, 477,325 men and women in the European Prospective Investigation into Cancer and Nutrition cohort were followed for incident renal cancers (n = 931). Baseline and lifetime alcohol consumption was assessed by country-specific, validated dietary questionnaires. Information on past alcohol consumption was collected by lifestyle questionnaires. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated from Cox proportional hazard models. In multivariate analysis, total alcohol consumption at baseline was inversely associated with renal cancer; the HR and 95% CI for the increasing categories of total alcohol consumption at recruitment vs. the light drinkers category were 0.78 (0.62-0.99), 0.82 (0.64-1.04), 0.70 (0.55-0.90), and 0.91 (0.63-1.30), respectively, (ptrend = 0.001). A similar relationship was observed for average lifetime alcohol consumption and for all renal cancer subsites combined or for renal parenchyma subsite. The trend was not observed in hypertensive individuals and not significant in smokers. In conclusion, moderate alcohol consumption was associated with a decreased risk of renal cancer.

Post-thrombotic syndrome, recurrence, and death 10 years after the first episode of venous thromboembolism treated with warfarin for 6 weeks or 6 months.

BACKGROUND: The influence of the duration of anticoagulant therapy after venous thromboembolism (VTE) on the long-term morbidity and mortality is unclear. AIM: To investigate the long-term sequelae of VTE in patients randomized to different duration of secondary prophylaxis. METHODS: In a multicenter trial comparing secondary prophylaxis with vitamin K antagonists for 6 weeks or 6 months, we extended the originally planned 2 years follow-up to 10 years. The patients had annual visits and at the last visit clinical assessment of the post-thrombotic syndrome (PTS) was performed. Recurrent thromboembolism was adjudicated by a radiologist, blinded to treatment allocation. Causes of death were obtained from the Swedish Death Registry. RESULTS: Of the 897 patients randomized, 545 could be evaluated at the 10 years follow-up. The probability of developing severe PTS was 6% and any sign of PTS was seen in 56.3% of the evaluated patients. In multivariate analysis, old age and signs of impaired circulation at discharge from the hospital were independent risk factors at baseline for development of PTS after 10 years. Recurrent thromboembolism occurred in 29.1% of the patients with a higher rate among males, older patients, those with permanent triggering risk factor - especially with venous insufficiency at baseline - signs of impaired venous circulation at discharge, proximal deep vein thrombosis, or pulmonary embolism. Death occurred in 28.5%, which was a higher mortality than expected with a standardized incidence ratio (SIR) of 1.43 (95% CI 1.28-1.58), mainly because of a higher mortality than expected from cancer (SIR 1.83; 95% CI 1.44-2.23) or from myocardial infarction or stroke (SIR 1.28; 95% CI 1.00-1.56). The duration of anticoagulation did not have a statistically significant effect on any of the long-term outcomes. CONCLUSION: The morbidity and mortality during 10 years after the first episode of VTE is high and not reduced by extension of secondary prophylaxis from 6 weeks to 6 months. A strategy to reduce recurrence of VTE as well as mortality from arterial disease is needed.

Tumor spread and DNA content in human renal cell carcinoma.

Local and distant tumor spread was evaluated and compared with DNA content analyzed by flow cytometry of eight samples from each of 71 renal cell carcinomas. Twenty-six tumors were homogenously diploid while 45 tumors contained at least one aneuploid tumor sample. Diploid tumors generally respected the surrounding tissues and only three of 26 tumors (12%) had evidence of local tumor invasion. In contrast, 33 of 45 patients (73%) with aneuploid tumors had local invasion (p less than 0.001). Local metastases in lymph nodes and adrenal was found only in patients with aneuploid tumors. However, distant metastases appeared in about the same frequency in patients with diploid and aneuploid tumors (35 and 29%, respectively). Patients with diploid tumors had significantly more often solitary metastases and, most interestingly, the occurrence of lung metastases was a characteristic feature for patients with aneuploid tumors (p less than 0.02). The diploid primary tumors with distant metastases generally were devoid of local invasion while all aneuploid tumors with distant metastases had local invasion and mostly also local metastases. Thus, different characteristics of tumor spread were shown for diploid and aneuploid tumors and the pathways for spread with distant metastases might also differ between these tumors.

Telomere shortening in renal cell carcinoma.

The ends of human chromosomes consist of a specialized structure, the telomere, composed of repeats of TTAGGG making up a total of 5-15 kilobase pairs, depending on age and proliferative activity of the tissue. The major function of telomeres is to provide stability to chromosomes and protect underlying unique coding sequences from degradation. There is a loss of telomeric sequences following every cell division estimated to be between 50 and 65 basepairs/cell division in human fibroblasts and embryonic kidney cells in vitro. This loss is due to the fact that DNA replication is incomplete for one strand at each telomere end. In lower eukaryotes there is a compensation mechanism provided by the enzyme telomerase, which is inactive in human somatic cells. Telomerase activation has also been detected in vitro immortalized human cells. In this study we analyzed renal cell carcinoma for the occurrence of telomere shortening using the probe (TTAGGG)4. Southern blots of HinfI-digested DNA revealed a shortening of mean telomere restriction fragment (TRF) length of 0.4 to 2.5 kilobase pairs in 2 or 3 intratumoral samples in all 10 tumors analyzed. No obvious intratumoral heterogeneity was found in mean TRF length values. However, heterogeneity was shown by the occurrence of at least two separate peak TRF values in 7 of 10 tumors, indicating the presence of different tumor cell clones. A conflicting observation was made when we evaluated the intensity of the hybridization signals, where three of the tumors showed an increase in hybridization signals despite concomitant TRF reduction. We found no correlation between tumor size and calculated tumor cell divisions undergone. In two tumors, the calculated cell division cycles were unrealistically low compared to the tumor size. These data suggest that telomerase activation might occur in human renal cell carcinoma.

Telomerase activity in human renal cell carcinoma.

Telomeres have a vital role in maintaining chromosome stability and are essential for long term viability. Since the very ends of linear chromosomes cannot replicate, telomeres shorten in normal somatic cells eventually resulting in growth inhibition. However, most immortal cell lines maintain stable telomeres indicating that mechanisms exist to compensate for the end replication problem. Telomerase activity, leading to synthesis of telomeric DNA repeats, has been proposed to be an important step in the immortalization process of tumor cells. In the present study, 56 renal cell carcinomas were tested for telomerase activity using the sensitive TRAP (telomeric repeat amplification protocol). Forty of the analysed tumors (71%) were positive for telomerase activity, whereas none of the 56 corresponding normal kidney samples showed telomerase activity. All telomerase negative tumors had a reduction in mean telomere restriction fragment (TRF) length and a decrease in total telomere repeat hybridization signal, though cases were observed with an increase in peak TRF lengths. No obvious association between the presence of telomerase activity and clinicopathological parameters (histopathologic grade, DNA-ploidy, stage and clinical outcome) was found. The high frequency of detection of telomerase activity in the renal cell carcinomas indicates that this enzyme is likely to be an important factor involved in the evolution of this tumor type.

Dual-modality probe intended for prostate cancer detection combining Raman spectroscopy and tactile resonance technology--discrimination of normal human prostate tissues ex vivo.

Prostate cancer is the most common cancer for men in the western world. For the first time, a dual-modality probe, combining Raman spectroscopy and tactile resonance technology, has been used for assessment of fresh human prostate tissue. The study investigates the potential of the dual-modality probe by testing its ability to differentiate prostate tissue types ex vivo. Measurements on four prostates show that the tactile resonance modality was able to discriminate soft epithelial tissue and stiff stroma (p < 0.05). The Raman spectra exhibited a strong fluorescent background at the current experimental settings. However, stroma could be discerned from epithelia by integrating the value of the spectral background. Combining both parameters by a stepwise analysis resulted in 100% sensitivity and 91% specificity. Although no cancer tissue was analysed, the results are promising for further development of the instrument and method for discriminating prostate tissues and cancer.

Renal cell carcinoma in tissue culture secretes nondialyzable product that stimulates bone resorption in organ-cultured mouse calvaria.

The bone-resorbing capacity of human renal cell carcinomas in vitro has been examined. Bone resorption in cultures of mouse calvarial bones was assessed by the release of 45Ca from bones prelabeled in vivo and the mobilization of stable calcium and inorganic phosphate from nonlabeled bones. In addition, bone organic matrix degradation was determined either by the release of 3H from [3H]proline-labeled bones or by the loss of hydroxyproline from bone explants during culture. Tumor tissue-conditioned media (TCM) from 13 of 13 renal cell carcinomas stimulated bone resorption in a dose-dependent manner. From 5 of 13 kidneys with renal cell carcinoma, normal kidney cortex tissue was cultured and 4 of these 5 also produced bone-resorbing activity, but the amount was much less compared with the tumor tissue. The stimulatory effect of TCM on 45Ca release could be observed first after 12-24 h of culture. The effect could be inhibited by calcitonin but not by inhibitors of prostaglandin synthesis. The production of bone-resorbing activity by tumor cells could be inhibited by indomethacin and meclofenamic acid. In some tumors, the inhibition by indomethacin was total, whereas in other tumors only partial inhibition could be obtained. In 3 of 4, TCM bone-resorbing activity could be found in the retentate after dialysis. The results show that fresh human renal cell carcinoma tissue can elaborate prostanoid as well as nonprostanoid products that can stimulate bone resorption.

HIV prevention among injecting drug users: three years of experience from a syringe exchange program in Sweden.

Exchange of syringes and needles has for the last 3 years been offered to injecting drug users as part of an HIV prevention project in a small university town in south Sweden. The program at the local hospital has been visited by 979 drug users, of which 182 have participated on a more regular basis. The typical participant is a 30-year-old male who has injected amphetamine or heroin for at least 10 years. The seroprevalence for HIV among drug users in south Sweden has been maintained at approximately 1% in contrast to up to 60% in subpopulations from other Scandinavian regions with a comparable drug problem. No project participant has become HIV infected during the study period and a reduction in risk behavior has been noted among local drug injectors. The HIV prevention project has attracted many individuals with no previous contact with drug rehabilitation programs; for a number of drug users, the syringe exchange has served as an introduction to such treatment efforts.

Serum interleukin-6 in relation to acute-phase reactants and survival in patients with renal cell carcinoma.

Patients with malignancies often present with signs of inflammatory reactions such as elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Since interleukin-6 (IL-6) is a possible regulator of these reactions and has been proposed as a predictor of prognosis, the aim of the study was to analyse its clinical significance in patients with renal cell carcinoma. Serum samples were collected from 196 patients before any treatment. IL-6 was analysed by an enzyme-linked immunoassay and compared with tumour grade, stage, acute-phase reactants and survival. Patients with renal cell carcinoma had significantly higher IL-6 levels (mean 28.1 +/- 63.4 ng/l; median 8.3 ng/l) compared with controls (mean 1.7 +/- 2.6 ng/l; median 0.5 ng/l; P < 0.001). Serum IL-6 levels in patients with distant metastases were significantly higher than for patients with tumours confined to the kidney (P = 0.02). This difference was more pronounced when serum IL-6 levels in patients with poorly differentiated tumours were compared with well-differentiated tumours (P < 0.001). A significant correlation between the acute-phase reactants CRP, ESR and IL-6 levels was found. Survival time was significantly shorter (P = 0.001) for patients with IL-6 levels above the median serum level compared with patients with lower levels. Similar significant prognostic results were obtained in the group of patients with metastatic disease, but not in group of patients with stage I-III. Serum levels of IL-6 correlated to tumour stage, grade and acute-phase reactants. Increased levels were related to the presence of metastases and adverse survival. Serum IL-6 proved univariate prognostic information but this prognostic significance was lost using a multivariate analysis.

Impact of serum basic fibroblast growth factor on prognosis in human renal cell carcinoma.

Renal cell carcinoma is often characterised by extensive vascularity and angiogenic factors may be of importance for disease progression. Using a sandwich enzyme immunoassay, basic fibroblast growth factor (bFGF) was analysed in the sera from 206 patients with renal cell carcinoma before the initiation of therapy. The median bFGF level was 3.0 pg/ml (range <1.0-70.9 pg/ml). The serum levels were significantly correlated to tumour stage and nuclear grade. Patients with tumour thrombus to the renal or the inferior caval vein had significantly higher serum bFGF levels compared with those with non-invading tumours (P=0.007). Patients with serum bFGF levels above 3.0 pg/ml had a worse prognosis, compared with those with lower levels (P=0.001). Furthermore, patients with tumours with vein invasion had a worse prognosis compared with those without invasion. After multivariate analysis, only tumour stage and grade remained as independent prognostic factors.

In vivo effects of a low molecular weight heparin fragment on platelet aggregation and platelet dependent hemostasis in dogs.

Plasma defibrinogenated dogs were used to study the influence of conventional heparin and a low molecular weight heparin fragment (Fragmin, mean MW 5,000 d) on platelet dependent hemostasis. The heparins were given intravenously in gravimetrically equal doses. The bleeding from standardized skin flap wounds and platelet aggregation (ADP and thrombin) was studied. In comparison, higher doses of the fragment than of heparin were required to increase the bleeding. ADP-induced aggregation in defibrinogenated platelet rich plasma (after addition of normal dog plasma) was potentiated by both heparins. After injection of heparin or the fragment, ADP induced platelet aggregation without prior addition of normal plasma to the test-tube. In conclusion the heparin fragment affected bleeding to a less extent than conventional heparin. One explanation might be a weaker inhibition of thrombin-induced platelet aggregation.

Loss of heterozygosity at chromosome 3p correlates with telomerase activity in renal cell carcinoma.

Acquired loss of the entire or parts of the short arm of chromosome 3 is a frequent aberration in renal cell carcinoma as well as in other tumour types, indicating the presence of at least one tumour suppressor gene on 3p. Previous studies have defined the distal and proximal ends of one critical region to reside between 3p21 and 3p11, and one gene involved in von Hippel-Lindau disease has been identified at 3p25. Experimental in vitro data has suggested a negative regulator of telomerase activity on chromosome 3. In the present study we investigated the relationship between telomerase activity and loss of heterozygosity (LOH) on 3p in a series of renal cell carcinomas. Telomerase activity was evaluated using the telomeric repeat amplification protocol assay and LOH, by analysis of 17 polymorphic microsatellite markers. Twenty-nine out of 45 tumours (64%) demonstrated telomerase activity and 37 tumours (82%) showed allelic loss of single or multiple areas of chromosome 3p. A significant correlation between LOH of at least one of three markers localised within 4 cM in the region of 3p21.2-3p14.2 and telomerase activity was demonstrated (p=0.0031), as well as for three distal markers within 3 cM at 3p24.3-3p24.1 (p=0.0287). These data suggest the presence of at least two genes with regulatory function on the expression of telomerase. These genes can encode proteins of importance for senescence and/or immortalisation or have a more direct effect on activation of telomerase.