Long-Term Follow-Up of Peritoneal Interposition Flap in Symptomatic Lymphocele Reduction following Robot-Assisted Radical Prostatectomy: Insights from the PIANOFORTE Trial.

The available randomised controlled trials (RCTs) assessing the influence of peritoneal interposition flaps (PIF) on the reduction of symptomatic lymphoceles (sLCs) post robot-assisted radical prostatectomy (RARP) do not constitute a sufficient follow-up (FU) to assess the long-term effects. The PIANOFORTE trial was the first of these RCTs, showing no sLC reduction at the 3-month FU. Therefore, all 232 patients from the PIANOFORTE trial were invited for long-term FU. One hundred seventy-six patients (76%) presented themselves for FU and constituted the study group (SG). The median FU duration was 43 months. No significant differences in group allocation or LC endpoints at 90 days were observed between SG patients and patients not presenting themselves for the FU. During the FU period, four patients (2.3%) in the SG developed sLCs, and six patients (3.4%) developed asymptomatic lymphoceles (aLCs), which persisted in five patients (2.9%). There were no significant differences between PIF and non-PIF regarding sLC/aLC formation or persistence, newly developed complications, stress urinary incontinence or biochemical/clinical tumour recurrence. Therefore, this long-term FU confirms the primary outcomes of the PIANOFORTE trial that, while PIF does not impact complications or functionality, it does not reduce sLC/aLC rates. Furthermore, it shows the potential occurrence of LC after the third postoperative month.

High BMI, Aggressive Tumours and Long Console Time Are Independent Predictive Factors for Symptomatic Lymphocele Formation after Robot-Assisted Radical Prostatectomy and Pelvic Lymph Node Dissection.

INTRODUCTION: Lymphocele (LC) formation is a common complication which may cause severe symptoms after robot-assisted radical prostatovesiculectomy (RARP) with concomitant pelvic lymph node dissection (PLND). Compared to open radical prostatectomy, the amount of data on potential risk factors for LC formation is still limited. The aim of the present study was to identify risk factors for symptomatic LC formation (sLC) after RARP with PLND. METHODS: We used the data of a prospective multicentre series of 232 RARP patients which were treated between March 2017 and December 2017. The primary endpoint was the presence of sLC within 90 days. Asymptomatic LC (aLC) formation was also recorded. We evaluated clinical, perioperative, and histopathological criteria and compared their distribution in patients with and without post-operative sLC. Uni- and multivariable logistic regression analyses (MVAs) were performed to identify potential predictors for LC formation. Regarding the influence of patients' BMI, 2 models were calculated: BMI continuously (model 1) and BMI dichotomized with cut-off 30 kg/m2 (WHO definition, model 2). RESULTS: Post-operative sLC was present in 21 patients (9.1%), while aLC was detected in 49 patients (21.1%) 90 days after RARP with PLND. Patients with sLC showed higher median baseline PSA levels (9.8 vs. 8.1 ng/mL), higher prevalence of obesity (BMI >30; 42.9 vs. 19.9%), and longer median console time (180 vs. 165 min) compared to patients without sLC. On MVA higher BMI {model 1: OR 1.145 (confidence interval [CI] 1.025-1.278); model 2: OR 2.761 (1.045-7.296)}, longer console time (model 1: OR 1.013 [1.005-1.021]; model 2: OR 1.013 [1.005-1.020]) and an ISUP grade ≥3 (model 1: OR 3.247 [1.182-8.917]; model 2: OR 2.791 [1.050-7.423]) were identified as independent predictors for sLC development. CONCLUSION: Patients with aggressive tumours and higher BMI should be informed about a potentially increased risk for sLC formation. In case of a long console time, a close and regular follow-up should be considered to check for LC development.

A Randomized Phase IIa Trial with Temsirolimus versus Sunitinib in Advanced Non-Clear Cell Renal Cell Carcinoma: An Intergroup Study of the CESAR Central European Society for Anticancer Drug Research-EWIV and the Interdisciplinary Working Group on Renal Cell Cancer (IAGN) of the German Cancer Society.

BACKGROUND: Non-clear cell renal cell cancers (nccRCC) are rare entities, and the optimal therapy in metastatic disease has still to be defined. METHODS: In this small prospectively randomized phase IIa multicenter trial, we investigated temsirolimus (TEM) versus sunitinib (SUN) as first-line therapy in patients with metastatic nccRCC. The patients were randomized 1:1 to either TEM in a dose of 25 mg i.v. once a week or SUN with 50 mg p.o. daily for 4 weeks on and 2 weeks off. Primary endpoint was progression-free survival (PFS). In total, 22 patients were included with predominantly papillary RCC (16/22) followed by chromophobe RCC and others. RESULTS: The male to female ratio was 16:6. The tumor control rate (CR + PR + SD) was 58% for TEM and 90% for SUN-treated patients. There was also a trend for improved PFS with 9.3 versus 13.2 months (HR 1.64; 95% CI 0.65-4.18) in favor of SUN. There was no trend for overall survival. CONCLUSIONS: Despite this trial had to be terminated earlier due to low recruitment, the results match the other studies published so far with the mTOR inhibitor everolimus and SUN, which show a trend in favor of SUN for ORR and PFS.

Peritoneal Flap in Robot-Assisted Radical Prostatectomy.

BACKGROUND: Lymphocele is the most common complication arising after pelvic lymph node dissection (PLND) in the setting of robot-assisted radical prostatectomy (RARP). The only data available until now on the utility of a peritoneal flap to prevent lymphocele were retrospectively acquired. METHODS: A randomized, controlled, multi-center trial with blinded assessment of endpoints was carried out on 232 patients with prostate cancer who underwent RARP with PLND. The patients in the intervention group were given a peritoneal flap; in the control group, surgery was performed without this modification. The two joint primary endpoints were the rates of symptomatic lymphocele during the same hospitalization as the operative procedure (iT1) and within 90 days of surgery (iT2). The secondary endpoints were lymphocele volume, the need for treatment of lymphocele, complications requiring an intervention, and the degree of postoperative stress incontinence. German Clinical Trials Register number: DRKS00011115. RESULTS: The data were evaluated in an intention-to-treat analysis, which, in this trial, was identical to an as-treated analysis. 108 patients (46.6%) were allotted to the intervention group. There were no statistically significant intergroup differences with respect to any clinical or histopathological criteria. A median of 16 lymph nodes were removed (interquartile range, 11-21). A symptomatic lymphocele arose in 1.3% (iT1) and 9.1% (iT2) of the patients, without any statistically significant difference between the two trial groups (p = 0.599 and p = 0.820, respectively). Nor did the groups differ significantly with respect to lymphocele volume (p = 0.670 on hospital discharge [T1], p = 0.650 90 days after surgery [T2]) or the type and frequency of need for subsequent surgical intervention (p = 0.535; iT2). 81.5% of all patients (n = 189) had no complications at all in the first three months after surgery. Nor were there any intergroup differences at 90 days with respect to the degree of stress urinary incontinence (p = 0.306) or complications (p = 0.486). CONCLUSION: A peritoneal flap after RARP was not found to influence the rate of postoperative lymphocele, whether asymptomatic or requiring treatment.

A Stent for Every Stone? Prestenting Habits and Outcomes from a German Multicenter Prospective Study on the Benchmarks of Ureteroroscopic Stone Treatment (BUSTER).

INTRODUCTION: Previous studies have shown that prestenting in ureterorenoscopic stone removal (URS) is carried out more frequently in Germany than in other countries. OBJECTIVE: This investigation evaluated the impact of high prestenting rates on outcomes as well as the influence of stone characteristics and treatment habits on prestenting. METHODS: The dataset from the BUSTER observational study was used. Patient and stone characteristics, as well as treatment outcomes, were analyzed for 307 cases from 14 urological clinics in Germany. RESULTS: The overall prestenting rate was 70.0%. Prestenting rates were significantly higher for renal stones than ureteric stones (84.6 vs. 60.6%, p < 0.0001). Compared to the unstented cases, prestenting for renal stones improved stone-free rates (73.2 vs. 11.1%, p < 0.0001) and increased the rate of completely lesion-free URS (45.4 vs. 16.7%, p = 0.034) while reducing the rate of poststenting (from 100 to 80.8%, p = 0.041). None of these effects could be demonstrated when prestenting for ureteric stones. Prestenting rates were less variable for renal stones (57-100%) than for ureteric stones (0-100%, p < 0.01). CONCLUSIONS: This study confirms the benefits of prestenting in URS for renal stones but not for ureteric stones. There were considerable differences in prestenting rates between the participating clinics.

Obesity leads to a higher rate of positive surgical margins in the context of robot-assisted radical prostatectomy. Results of a prospective multicenter study.

INTRODUCTION: Current results concerning the effect of body mass index (BMI) on positive surgical margins (PSMs) after robot-assisted radical prostatectomy (RARP) in patients with localized prostate cancer are inconsistent. Therefore, the aim of this study was to further analyse the association between BMI and PSMs after RARP. MATERIAL AND METHODS: Between March 2017 and December 2017 a multicentre, prospective, randomised, single-blind series with a blinded outcome assessment of 232 RARP patients was performed. Multivariate logistical regression models were used to analyse the independent effect of obesity, with body-mass-index (BMI) dichotomised at 30 kg/m2 (model-1) and at 90th percentile (model-2), on PSMs. RESULTS: Median BMI was 27.2 kg/m2, PSMs were found in 15.5% (n = 36). In multivariate model-1, obesity did not have a significant effect on PSMs (OR 2.34, p = 0.061). However, if BMI was dichotomized at the 90th percentile (BMI ≥33.7 kg/m²), patients with a higher BMI showed PSMs four-times more frequently (OR 3.99, p = 0.013). In both models, preoperative prostate-specific antigen (PSA) levels and pathological tumour stage had a significant effect on PSMs. There was no significant correlation between BMI and the extent of PSMs, nor a significant difference between the BMI groups and the localisation of PSMs. There was a higher percentage of posteriolateral PSM localisation in obese patients compared to patients with a BMI of less than 30 kg/m2 (58.3% and 25.3% of the localisations were posterolateral in obese and non-obese patients, respectively), however this effect was not statistically significant (p = 0.175). CONCLUSIONS: In addition to a longer operation time and about twice as many complications, patients with a BMI of ≥33.7 kg/m² had a higher PSM rate after RARP. Differences in localization of PSMs in relation to obesity should be evaluated in future research.

Is the Recommendation of a Pelvic Lymphadenectomy in Conjunction with Radical Prostatectomy in Prostate Cancer Patients Justified? Report from a Multidisciplinary Expert Panel Meeting.

INTRODUCTION: Pelvic lymphadenectomy (pLA) in prostate cancer (PCa) is one of the most common uro-oncologic surgical procedures. An increased complication rate is accompanied by unproven oncologic benefit. Extent of pLA and mechanisms of metastasis are discussed controversially. We aimed to explore evidence and knowledge gaps in pLA and mechanisms of metastasis in PCa and to develop further steps to clarify oncologic benefits through an expert panel. METHODS: A multidisciplinary expert meeting was initiated, compiling available facts on pLA and mechanisms of metastasis in PCa. Questions and hypotheses were formulated. The resulting protocol was modeled on priority and consistency in four anonymized voting rounds using the Delphi method (March 2018-June 2018). RESULTS: The oncologic benefit of pLA in PCa is still unclear. Results of randomized trials (RCTs) are pending. Extent and techniques of pLA are differently applied and inconsistently recommended by the guidelines as well as the indication for pLA. Different growth rates for the primaries and metastases and different survival curves for lymph node and organ metastasis at diagnosis argue against metastasis originating from positive nodes. However, results from clinical and basic research support this opportunity in PCa. CONCLUSIONS: The RCTs required to clarify the estimated low oncologic benefit of pLA prove to be difficult because of the great effort (e.g., high case number). Establishing a network of treatment centers for implementation of high-quality cohort studies could be an alternative approach. Future studies with larger panels and international participants based on the presented feasibility should be launched to set this process in motion. Until valid data are available, benefits and harms of pLA should be weighted under consideration of low-invasive techniques (e.g., sentinel pLA).

Ureteroenteric strictures: a single center experience comparing Bricker versus Wallace ureteroileal anastomosis in patients after urinary diversion for bladder cancer.

BACKGROUND: To evaluate the outcome and complication rate in a single institution experience using the two most commonly used techniques of ureteroenteric anastomosis, the Bricker and Wallace anastomosis. METHODS: A total of 137 patients underwent ileal conduit for bladder cancer. Ureters were anastomosed by two experienced surgeons, one performing a Bricker and the other, a Wallace anastomosis. Stricture was identified during clinical follow-up. RESULTS: Seventy-five patients underwent a Bricker anastomotic, and 65 received a Wallace anastomosis. The average age was 70 in both groups, males were predominant (66% Bricker, 70% Wallace). Follow up period was 36.5 months in Bricker group and 17 months in Wallace group. In both groups, the body mass index (BMI) was similar (26.1 kg/m2 Bricker and 26.4 kg/m2 Wallace). We observed that the stricture rate after performing the Bricker anastomosis technique was 25.3% (19/75) as compared to 7.7% (5/65) after Wallace anastomosis technique, which was statistically significant (p = 0.001). In the Bricker group, patients with strictures had higher BMI (28.3 vs. 25.7 kg/m2, p = 0.05). On average it took 8.5 months in the Bricker group and three months in the Wallace group (p = 0.6) to develop stricture. CONCLUSIONS: The stricture rate was significantly higher when Bricker technique was applied. Although the BMI was not different in both groups, patients with a higher BMI were more likely to develop stricture. We believe that the approach of the separate and refluxing technique of Bricker anastomosis especially in obese patients poses a higher risk for anastomotic stricture formation.

One-carbon metabolism biomarkers and risk of urothelial cell carcinoma in the European prospective investigation into cancer and nutrition.

Published associations between dietary folate and bladder cancer risk are inconsistent. Biomarkers may provide more accurate measures of nutrient status. This nested case-control analysis within the European Prospective Investigation into Cancer and Nutrition (EPIC) investigated associations between pre-diagnostic serum folate, homocysteine, vitamins B6 and B12 and the risk of urothelial cell carcinomas of the bladder (UCC). A total of 824 patients with newly diagnosed UCC were matched with 824 cohort members. Serum folate, homocysteine, and vitamins B6 and B12 were measured. Odds ratios (OR) and 95% confidence intervals (CI) for total, aggressive, and non-aggressive UCC were estimated using conditional logistic regression with adjustment for smoking status, smoking duration and intensity, and other potential confounders. Additionally, statistical interaction with smoking status was assessed. A halving in serum folate concentrations was moderately associated with risk of UCC (OR: 1.18; 95% CI: 0.98-1.43), in particular aggressive UCC (OR: 1.34; 95% CI: 1.02-1.75; p-heterogeneity = 0.19). Compared to never smokers in the highest quartile of folate concentrations, this association seemed only apparent among current smokers in the lowest quartile of folate concentrations (OR: 6.26; 95% CI: 3.62-10.81, p-interaction = 0.07). Dietary folate was not associated with aggressive UCC (OR: 1.26; 95% CI: 0.81-1.95; p-heterogeneity = 0.14). No association was observed between serum homocysteine, vitamins B6 and B12 and risk of UCC. This study suggests that lower serum folate concentrations are associated with increased UCC risk, in particular aggressive UCC. Residual confounding by smoking cannot be ruled out and these findings require confirmation in future studies with multiple measurements.

Prostate cancer risk regions at 8q24 and 17q24 are differentially associated with somatic TMPRSS2:ERG fusion status.

Molecular and epidemiological differences have been described between TMPRSS2:ERG fusion-positive and fusion-negative prostate cancer (PrCa). Assuming two molecularly distinct subtypes, we have examined 27 common PrCa risk variants, previously identified in genome-wide association studies, for subtype specific associations in a total of 1221 TMPRSS2:ERG phenotyped PrCa cases. In meta-analyses of a discovery set of 552 cases with TMPRSS2:ERG data and 7650 unaffected men from five centers we have found support for the hypothesis that several common risk variants are associated with one particular subtype rather than with PrCa in general. Risk variants were analyzed in case-case comparisons (296 TMPRSS2:ERG fusion-positive versus 256 fusion-negative cases) and an independent set of 669 cases with TMPRSS2:ERG data was established to replicate the top five candidates. Significant differences (P < 0.00185) between the two subtypes were observed for rs16901979 (8q24) and rs1859962 (17q24), which were enriched in TMPRSS2:ERG fusion-negative (OR = 0.53, P = 0.0007) and TMPRSS2:ERG fusion-positive PrCa (OR = 1.30, P = 0.0016), respectively. Expression quantitative trait locus analysis was performed to investigate mechanistic links between risk variants, fusion status and target gene mRNA levels. For rs1859962 at 17q24, genotype dependent expression was observed for the candidate target gene SOX9 in TMPRSS2:ERG fusion-positive PrCa, which was not evident in TMPRSS2:ERG negative tumors. The present study established evidence for the first two common PrCa risk variants differentially associated with TMPRSS2:ERG fusion status. TMPRSS2:ERG phenotyping of larger studies is required to determine comprehensive sets of variants with subtype-specific roles in PrCa.

IMA901, a multipeptide cancer vaccine, plus sunitinib versus sunitinib alone, as first-line therapy for advanced or metastatic renal cell carcinoma (IMPRINT): a multicentre, open-label, randomised, controlled, phase 3 trial.

BACKGROUND: In a phase 2 study in patients with metastatic renal cell carcinoma, overall survival was associated with T-cell responses against IMA901, a vaccine consisting of ten tumour-associated peptides. In this phase 3 trial, we aimed to determine the clinical effect of adding IMA901 to sunitinib, the standard first-line treatment in metastatic renal cell carcinoma with postulated favourable immunomodulatory effects. METHODS: The IMPRINT study is an open-label, randomised, controlled, phase 3 trial done at 124 clinical sites in 11 countries. HLA-A*02-positive patients (aged ≥18 years) with treatment-naive, histologically confirmed metastatic or locally advanced (or both) clear-cell renal cell carcinoma were randomly assigned (3:2) to receive sunitinib plus up to ten intradermal vaccinations of IMA901 (4·13 mg) and granulocyte macrophage colony-stimulating factor (75 µg), with one dose of cyclophosphamide (300 mg/m2) 3 days before the first vaccination, or to receive sunitinib alone. Sunitinib (50 mg) was given orally once daily, with each cycle defined as 4 weeks on treatment followed by 2 weeks off treatment, until progression of disease as determined by the investigator, death, or withdrawal of consent. Block randomisation (block size five) was done centrally using an interactive web response system, stratified by prognostic risk, geographical region, and previous nephrectomy. Patients and investigators were not masked to treatment allocation. The primary endpoint was overall survival from randomisation until death of any cause as determined by the investigator, analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01265901. FINDINGS: Between Dec 22, 2010, and Dec 15, 2012, we screened 1171 patients, of whom 339 were randomly assigned to receive sunitinib plus IMA901 (n=204) or sunitinib monotherapy (n=135). Patients had a median follow-up of 33·27 months (IQR 29·92-35·64). Median overall survival did not differ significantly between the groups (33·17 months [95% CI 27·81-41·36] in the sunitinib plus IMA901 group vs not reached [33·67-not reached] in the sunitinib monotherapy group; hazard ratio 1·34 [0·96-1·86]; p=0·087). 116 (57%) of 202 patients in the sunitinib plus IMA901 group and 62 (47%) of 132 in the sunitinib group had grade 3 or worse adverse events, the most common of which were hypertension, neutropenia, and anaemia in both groups, and mild-to-moderate transient injection-site reactions (eg, erythema, pruritus) were the most frequent IMA901-related side-effect in the sunitinib plus IMA901 group. Serious adverse events leading to death occurred in four (2%) patients (one respiratory failure and circulatory collapse [possibly related to sunitinib], one oesophageal varices haemorrhage [possibly related to sunitinib], one cardiac arrest [possibly related to sunitinib], and one myocardial infarction) and eight (6%) patients in the sunitinib group (one case each of renal failure, oesophageal varices haemorrhage, circulatory collapse, wound infection, ileus, cerebrovascular accident [possibly treatment related], and sepsis). INTERPRETATION: IMA901 did not improve overall survival when added to sunitinib as first-line treatment in patients with metastatic renal cell carcinoma. The magnitude of immune responses needs to be improved before further development of IMA901 in this disease is indicated. FUNDING: Immatics Biotechnologies.

Doping of Graphene by Low-Energy Ion Beam Implantation: Structural, Electronic, and Transport Properties.

We investigate the structural, electronic, and transport properties of substitutional defects in SiC-graphene by means of scanning tunneling microscopy and magnetotransport experiments. Using ion incorporation via ultralow energy ion implantation, the influence of different ion species (boron, nitrogen, and carbon) can directly be compared. While boron and nitrogen atoms lead to an effective doping of the graphene sheet and can reduce or raise the position of the Fermi level, respectively, (12)C(+) carbon ions are used to study possible defect creation by the bombardment. For low-temperature transport, the implantation leads to an increase in resistance and a decrease in mobility in contrast to undoped samples. For undoped samples, we observe in high magnetic fields a positive magnetoresistance that changes to negative for the doped samples, especially for (11)B(+)- and (12)C(+)-ions. We conclude that the conductivity of the graphene sheet is lowered by impurity atoms and especially by lattice defects, because they result in weak localization effects at low temperatures.

Everolimus in metastatic renal cell carcinoma after failure of initial anti-VEGF therapy: final results of a noninterventional study.

BACKGROUND: Data are limited regarding routine use of everolimus after initial vascular endothelial growth factor (VEGF)-targeted therapy. The aim of this prospective, noninterventional, observational study was to assess efficacy and safety of everolimus after initial VEGF-targeted treatment in patients with metastatic renal cell carcinoma (mRCC) in routine clinical settings. METHODS: Everolimus was administered per routine clinical practice. Patients with mRCC of any histology from 116 active sites in Germany were included. The main objective was to determine everolimus efficacy in time to progression (TTP). Progression-free survival (PFS), treatment duration, tumor response, adherence to everolimus regimen, treatment after everolimus, and safety were also assessed. RESULTS: In the total population (N = 334), median follow-up was 5.2 months (range, 0-32 months). Median treatment duration (safety population, n = 318) was 6.5 months (95% confidence interval [CI], 5-8 months). Median TTP and median PFS were similar in populations investigated. In patients who received everolimus as second-line treatment (n = 211), median (95% CI) TTP was 7.1 months (5-9 months) and median PFS was 6.9 months (5-9 months). Commonly reported adverse events (safety population, n = 318) were dyspnea (17%), anemia (15%), and fatigue (12%). Limitations of the noninterventional design should be considered. CONCLUSIONS: This study reflects routine clinical use of everolimus in a large sample of patients with mRCC. Favorable efficacy and safety were seen for everolimus after previous therapy with one VEGF-targeted agent. Results of this study confirm everolimus as one of the standard options in second-line therapy for patients with mRCC. Novartis study code, CRAD001LD27: VFA registry for noninterventional studies ( http://www.vfa.de/de/forschung/nisdb/).

Meat and fish consumption and the risk of renal cell carcinoma in the European prospective investigation into cancer and nutrition.

Renal cell cancer (RCC) incidence varies worldwide with a higher incidence in developed countries and lifestyle is likely to contribute to the development of this disease. We examined whether meat and fish consumption were related to the risk of RCC in the European Prospective Investigation into Cancer and Nutrition (EPIC). The analysis included 493,179 EPIC participants, recruited between 1992 and 2000. Until December 2008, 691 RCC cases have been identified. Meat and fish consumption was assessed at baseline using country-specific dietary assessment instruments; 24-hour recalls were applied in an 8% subsample for calibration purposes. Cox proportional hazards regression was used to calculate multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CI). Women with a high consumption of red meat (HR = 1.36, 95% CI 1.14-1.62; calibrated, per 50 g/day) and processed meat (HR = 1.78, 95% CI 1.05-3.03; calibrated, per 50 g/day) had a higher risk of RCC, while no association existed in men. For processed meat, the association with RCC incidence was prominent in premenopausal women and was lacking in postmenopausal women (p interaction = 0.02). Neither poultry nor fish consumption were statistically significantly associated with the risk of RCC. The results show a distinct association of red and processed meat consumption with incident RCC in women but not in men. A biological explanation for these findings remains unclear.

Impact of thoracic epidural analgesia on blood loss in radical retropubic prostatectomy.

INTRODUCTION: Radical retropubic prostatectomy (RRP) is associated with an increased risk of intraoperative blood loss and the necessity of transfusions. This prospective randomised clinical study evaluates the influence of thoracic epidural analgesia (TEA) on blood loss in RRP. MATERIALS AND METHODS: 235 patients were randomised: TEA in group 1 (n = 116; general anaesthesia + TEA) comprised continuous administration of 0.25% bupivacaine, while group 2 (n = 119; general anaesthesia alone) received intravenous analgesia with fentanyl (intubation: 2 µg/kg; maintenance: 0.1-0.3 mg). A restrictive infusion regimen (<1,000 ml until specimen removal) was administered in both groups. Blood loss, infusion rates and anaesthesiological parameters were recorded and analysed using regression models and analyses of variance. RESULTS: Haemoglobin difference between the pre- and the first postoperative day (group 1: 3.35 ± 1.16 g/dl; group 2: 3.56 ± 1.42 g/dl; p = 0.19), overall blood loss (group 1: 665 ± 431.5 ml; group 2: 705 ± 881 ml; p = 0.73) and transfusion rates (0.4% intraoperatively; 2.55% postoperatively; p = 1.0) did not show group differences. In regression analysis blood loss was influenced by preoperative haemoglobin levels (p < 0.0001), patients' weight (p = 0.018) and duration of the operation (p = 0.017). CONCLUSIONS: This study did not demonstrate a direct impact of TEA on intraoperative blood loss and transfusion rates in RRP. Further randomised clinical trials are needed to evaluate an impact of the different anaesthetic procedures presented alone or in combination on blood loss.

Therapy of mRCC beyond mTOR-inhibition in clinical practice: results of a retrospective analysis.

PURPOSE: Renal cell carcinoma (RCC) is the most common renal tumor and accounts for nearly 3 % of adult cancers. In the recent years, seven new targeted agents have been approved changing the treatment in metastatic RCC dramatically. So far, however, it remains unclear which sequence is best for those patients. This study analyzed retrospectively the outcome of patients treated with everolimus after failure of a vascular endothelial growth factor receptor-directed therapy and which therapies were used after everolimus. PATIENTS AND METHODS: In a retrospective analysis, patients receiving everolimus after failure of first-line VEGFR-directed therapy have been analyzed in regard to response, duration of treatment and subsequent therapies. In total, the data of 81 patients have been analyzed. RESULTS: The most observed first-line therapy was sunitinib followed by sorafenib. Thirty-two patients received everolimus as second-line therapy, and 49 as third-line therapy. The median duration of treatment with everolimus was 4.5 months. Seventy-seven of eighty-one patients (95 %) received a further therapy after discontinuation of everolimus. The agents administered beyond were sunitinib (28.6 %), sorafenib (28.6 %) and 42.8 % received other therapies. Twenty-seven patients received an additional sequence of therapy (fourth to fifth line). Fifty-eight percentage of patients have still been alive at time of analysis. CONCLUSION: The duration of everolimus therapy beyond failure of anti-VEGF-directed therapy and the reported time to progression was in the range of the RECORD-1 trial in daily practice as well. After failure of everolimus, reexposure to tyrosine kinase inhibitors is a common clinical practice and demonstrates a clinical benefit of therapies beyond everolimus.

Categories of response to first line vascular endothelial growth factor receptor targeted therapy and overall survival in patients with metastatic renal cell carcinoma.

INTRODUCTION: Sequential use of targeted therapy (TT) has improved overall survival (OS) of patients with metastatic renal cell carcinoma (mRCC). The value of objective response (OR) as compared to stable disease (SD) is unclear. We aimed to investigate OR of first-line TT and its impact on OS. MATERIAL AND METHODS: Retrospective analysis of OS among 331 mRCC patients with a first-line assessment according to RECIST 1.0. Characteristics between objective responders (complete response [CR] or partial remission [PR]), patients with SD and non-responders (progressive disease [PD] and toxicity [Tox]) were compared with the Chi-square test and the Kruskal-Wallis test. Kaplan-Meier analysis of OS and progression-free survival (PFS). Cox model analysis of Predictors of OS . RESULTS: Best response was CR, PR, SD, PD and Tox in 9 (2.7%), 61 (18.4%), 167 (50.5%), 80 (24.2%) and 14 (4.2%) patients respectively resulting in an OR rate of 21%. Median OS in months: CR 63.2; PR 37.6; SD 35.9; PD 14.6; TOX 22.5 (p<0.0001). Median PFS for responders was 14.8, 11.5 for patients with SD and 2.5 for non-responders (p<0.0001). Similarly median OS was 38.7, 35.9 and 15.5 (p<0.00001). Primary resistance and a first-line PFS <6months were the strongest independent predictors of OS. The achievement of OR as compared to SD did not impact OS. CONCLUSIONS: In our cohort of unselected patients OR was not associated with superior OS as compared to SD.

Temsirolimus in daily use: results of a prospective multicentre noninterventional study of patients with metastatic kidney cancer.

BACKGROUND: Temsirolimus (TEMSR) was approved for treating advanced renal cell carcinoma (RCC) in 2007. Based on the data from a single phase 3 trial, it is recommended explicitly as first-line therapy for patients with a poor clinical prognosis. OBJECTIVE: The aim of this prospective multicentre trial (STARTOR) was to examine the effectiveness of TEMSR in daily clinical practice with a broader indication in the treatment of metastatic RCC. DESIGN, SETTING, AND PARTICIPANTS: Metastatic RCC patients treated with 25mg of TEMSR weekly were submitted to a prospective systematic evaluation and follow-up in 87 German centres between January 2008 and October 2011 using standardised procedures. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: All data were centrally analysed by an independent clinical research organisation. RESULTS AND LIMITATIONS: This interim analysis of the STARTOR study included 386 patients. The observed toxicity was tolerable, the median dose intensity was 91% (interquartile range: 79-100%), and the median treatment duration was 20.1 wk (95% confidence interval [CI], 17.0-23.3 wk). Clinical benefit was seen in 157 patients (40.7%); the median progression-free and overall survival were 4.9 mo (95% CI, 4.2-5.6) and 11.6 mo (95% CI, 9.3-13.9), respectively. The effectiveness of TEMSR did not differ significantly in relation to the patient's age, histologic RCC subtype, or line of treatment. The major limitations were the noninterventional study design, limited information about Memorial Sloan-Kettering Cancer Center risk factors and detailed toxicity, and the lack of central radiologic review. CONCLUSIONS: TEMSR is an effective and largely well-tolerated treatment alternative for metastatic RCC patients in daily clinical practice, irrespective of the patient's age, histologic RCC subtype, or line of treatment.

N-acetyltransferase 2 phenotype, occupation, and bladder cancer risk: results from the EPIC cohort.

BACKGROUND: An association between N-acetyltransferase 2 (NAT2) slow acetylation and bladder cancer has been consistently observed in epidemiologic studies. However, evidence has been mainly derived from case-control studies and was sparse from cohort studies. We evaluated the association between NAT2 slow acetylation and bladder cancer in a case-control study nested in the European Prospective Investigation into Cancer and Nutrition. METHODS: Exposure to aromatic amines and polycyclic aromatic hydrocarbons (PAH) could be assessed for 754 cases and 833 controls for whom occupational information was documented. A semiquantitative job-exposure matrix was applied to at-risk occupations to estimate the exposure as low, medium, or high based on tertiles of the distribution of the exposure score in controls. Using a comprehensive genotyping, NAT2 acetylation status could be categorized from 6-single-nucleotide polymorphism genotypes as slow or fast in 607 cases and 695 controls with DNA from archived blood samples. RESULTS: Occupational exposure to aromatic amines and PAH was associated with an increased bladder cancer risk [upper tertile of the distribution of the exposure score: OR = 1.37; 95% confidence interval (CI), 1.02-1.84, and OR = 1.50; 95% CI, 1.09-2.05, respectively]. NAT2 slow acetylation did not modify these risk estimates and was not itself associated with bladder cancer risk (OR = 1.02; 95% CI, 0.81-1.29). CONCLUSIONS: These findings confirm established or suspected occupational risk factors but not the anticipated role of NAT2 slow acetylation in bladder cancer. No interaction was detected between NAT2 and any exposure of interest, including smoking. IMPACT: Genetic testing for NAT2 would be inappropriate in occupational settings.