Karin M. Hjelle

Observation Should be Considered as an Alternative in Management of Renal Masses in Older and Comorbid Patients

BACKGROUND Renal masses diagnosed in older and comorbid patients represent a challenge with regard to treatment. OBJECTIVE To evaluate clinical outcome and tumor progression in patients with renal masses managed by observation due to age and comorbidity. DESIGN, SETTING, AND PARTICIPANTS The medical records of 63 consecutive patients with renal masses primarily managed by observation during 2002-2007 were reviewed retrospectively and analyzed. The mean age for all patients at diagnosis was 76.6 yr, and 59% were male. Mean tumor size was 4.3 cm in diameter at diagnosis. Of these, 30% had Eastern Cooperative Oncology Group performance status (PS) of 2 or 3, 78% were American Society of Anesthesiologists (ASA) class 3, and the patients had a mean of 2.8 other medical conditions. MEASUREMENTS Registration of age, ASA class, PS, comorbid conditions, computed tomography scans, primary tumor size, tumor growth rate, pathology parameters, observation time, survival time. RESULTS AND LIMITATIONS Five-year overall survival (OS) and cancer-specific survival (CSS) rates were 42.8% and 93.3%, respectively. For tumors < or =4.0 cm in size, 5-yr CSS was 100%. Nine patients received delayed radical treatment, none of whom had later progression of the disease. In 18 patients histopathologic diagnosis of the renal masses were available, and in 15 patients (83%) renal cell carcinoma (RCC) was verified. The annual growth rate was <1cm/yr in 85.4% of the cases. In tumors < or =4.0 cm, only 1 of 27 tumors (3.7%) grew faster than 1cm/yr. CONCLUSIONS Management of renal masses by observation among older and comorbid patients seems to give acceptable results with regard to OS and CSS rates after 5 yr. The risk of disease progression is significantly higher in patients with larger sized renal masses (>4 cm). Thus, selection for observation in this group has to be stricter than in a group of patients with smaller sized renal masses (< or =4.0 cm).

Obesity is associated with an improved cancer-specific survival, but an increased rate of postoperative complications after surgery for renal cell carcinoma.

Abstract Objective. This study aimed to assess the impact of preoperative body mass index (BMI) on postoperative complications, cancer-specific survival (CSS) and overall survival (OS) in patients operated for renal cell carcinoma (RCC). Material and methods. The study included 397 patients with BMI values, who underwent surgery for RCC between 1 January 1997 and 31 December 2010. Obese patients (BMI > 30 kg/m2) were compared to non-obese patients (BMI < 30 kg/m2) in regard to CSS and OS. A Cox proportional hazard model was used for the multivariate survival analyses. The mean age of the patients was 62.1 years. There were 259 males (65%) and 325 patients (82%) were non-obese. Mean BMI was 26 kg/m2. Results. In the total material, CSS was 94.7% for obese patients and 74.8% for non-obese patients (p = 0.06). The obese group had significantly better CSS in univariate analysis for presumed radically treated disease (pT1–3N0M0). Obesity was a significant protective prognostic factor in multivariate analysis. An accelerating protective effect for CSS was found with increasing levels of BMI. In regard to OS, no difference was found between the two groups. Obese patients had a significantly lower age, and a higher rate of diabetes mellitus, hypertension and incidental detection. Obese patients had a significantly higher total incidence of postoperative complications, but not surgery-related complications. Conclusions. In this material, increasing BMI was associated with improved CSS for presumed radically treated patients. However, obese patients had a higher total rate of postoperative complications.

Transcriptome Sequencing (RNAseq) Enables Utilization of Formalin-Fixed, Paraffin-Embedded Biopsies with Clear Cell Renal Cell Carcinoma for Exploration of Disease Biology and Biomarker Development.

Formalin-fixed, paraffin-embedded (FFPE) tissues are an underused resource for molecular analyses. This proof of concept study aimed to compare RNAseq results from FFPE biopsies with the corresponding RNAlater® (Qiagen, Germany) stored samples from clear cell renal cell carcinoma (ccRCC) patients to investigate feasibility of RNAseq in archival tissue. From each of 16 patients undergoing partial or full nephrectomy, four core biopsies, such as two specimens with ccRCC and two specimens of adjacent normal tissue, were obtained with a 16g needle. One normal and one ccRCC tissue specimen per patient was stored either in FFPE or RNAlater®. RNA sequencing libraries were generated applying the new Illumina TruSeq® Access library preparation protocol. Comparative analysis was done using voom/Limma R-package. The analysis of the FFPE and RNAlater® datasets yielded similar numbers of detected genes, differentially expressed transcripts and affected pathways. The FFPE and RNAlater datasets shared 80% (n = 1106) differentially expressed genes. The average expression and the log2 fold changes of these transcripts correlated with R2 = 0.97, and R2 = 0.96, respectively. Among transcripts with the highest fold changes in both datasets were carbonic anhydrase 9 (CA9), neuronal pentraxin-2 (NPTX2) and uromodulin (UMOD) that were confirmed by immunohistochemistry. IPA revealed the presence of gene signatures of cancer and nephrotoxicity, renal damage and immune response. To simulate the feasibility of clinical biomarker studies with FFPE samples, a classifier model was developed for the FFPE dataset: expression data for CA9 alone had an accuracy, specificity and sensitivity of 94%, respectively, and achieved similar performance in the RNAlater dataset. Transforming growth factor-ß1 (TGFB1)-regulated genes, epithelial to mesenchymal transition (EMT) and NOTCH signaling cascade may support novel therapeutic strategies. In conclusion, in this proof of concept study, RNAseq data obtained from FFPE kidney biopsies are comparable to data obtained from fresh stored material, thereby expanding the utility of archival tissue specimens.

Incidentally detected renal cell carcinomas are highly associated with comorbidity and mortality unrelated to renal cell carcinoma

Abstract Objective. The aim of this study was to investigate the underlying reasons for symptomatic (SRCC) and incidental diagnosis of renal cell carcinoma (IRCC), and possible differences in cancer-specific (CSS) and overall survival (OS) with regard to reasons for detection. Material and methods. Between 1997 and 2010, 413 patients underwent surgery for renal cell carcinoma (RCC). SRCCs were divided into groups with general and classical symptoms. IRCCs were divided into “true” IRCCs, found owing to investigation of another definitive medical condition, and “unrelated” IRCCs, found owing to investigation for signs and symptoms presumed to be unrelated to RCC. Gender- and age-adjusted estimated overall survival (EOS) rates based on national mortality data were calculated for both the total material and the subgroups. Results. IRCC tumours were smaller, and of lower stage and grade than SRCCs, which was also reflected in the lower CSS in this group. Most IRCCs were found during investigations related to another definitive condition. There was a significantly higher level of comorbidity in the IRCC group, and the “true” IRCC group had the highest rates. The two IRCC subgroups had similar CSS and tumour characteristics. In the SRCC group, however, those with general symptoms had worse tumour characteristics and lower rates of CSS compared to those with classical symptoms. The true IRCC group had significantly inferior OS compared to the unrelated IRCCs (p = 0,040). Only the unrelated IRCC patients had an OS similar to the EOS; for all other subgroups the OS was inferior to the EOS. Conclusions. Most IRCCs were found during investigations for other medical conditions, and the OS rate in this group of patients was lower than expected.

Postoperative 30-day Mortality Rates for Kidney Cancer Are Dependent on Hospital Surgical Volume: Results from a Norwegian Population-based Study

BACKGROUND To improve cancer care in Norway, the government introduced surgical volume requirements for hospitals in 2015. To treat kidney cancer (KC) in Norway, the lower limit is 20 surgical procedures per year. OBJECTIVES To compare the impact of hospital volume on outcome with regard to 30-d mortality (TDM) following KC surgery. DESIGN, SETTING, AND PARTICIPANTS We identified all KC patients from the Cancer Registry of Norway diagnosed during 2008-2013 whose surgical treatment involved partial or radical nephrectomy. Hospitals were divided into three volume groups: low (LVH), intermediate (IVH), and high (HVH) volume. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Relationships with outcome were analysed using multivariate logistic regression. RESULTS AND LIMITATIONS In total, 3273 patients were identified. The TDM rate was 0.89% overall, 0.73% for localised KC, and 2.6% for metastatic KC. The mean (median, interquartile range) numbers of procedures for LVH, IVH and HVH were 5.2 /yr (3, 1.3-8.7), 27 /yr (26, 23-30) and 53 /yr (53, 48-58), with TDM rates of 2.2%, 0.83%, and 0.39%, respectively (p=0.001). In a multivariate logistic regression model, tumour stage, age, and hospital volume remained independent TDM predictors. The odds ratio for TDM was 4.98 (confidence interval 1.72-14.4) for LVH compared to HVH (p=0.003). Study limitations include a lack of data for surgical complications and other possible confounders. CONCLUSIONS TDM is associated with age, stage, and hospital volume. The study supports the new regulation for hospital volume introduced in Norway. PATIENT SUMMARY The risk of dying within 30 d following kidney cancer surgery is low. Advanced disease and older age are risk factors for higher mortality. In this study, we also showed that more patients die within 30 d in hospitals performing fewer operations per year than in hospitals performing many operations.

Nephron Sparing Surgery Associated With Better Survival Than Radical Nephrectomy in Patients Treated for Unforeseen Benign Renal Tumors

OBJECTIVE To evaluate the role of the surgical technique used for the treatment of benign renal tumors, with regard to renal function and overall survival (OS) in patients without cancer-related mortality. PATIENTS AND METHODS The study included 506 patients, mean age of 63.3 years, with histologically proven benign renal lesions originating from 5 European centers. Retrospective data from each hospital were retrieved and merged into a common database for analyses. OS, American Society of Anesthesiology score, and renal functions were measured in relation to surgical technique. The Mann-Witney U-test, the paired t-test, and Coxs multivariate analysis were used. RESULTS Patients treated with radical nephrectomy had significantly reduced renal function postoperatively compared with nephron sparing surgery (NSS). OS was significantly reduced after radical nephrectomy compared with NSS (P = .012), a survival difference that remained significant [hazard ratio (HR) 0.042, 95% confidence interval (CI) 0.221-0.972, P = .042] in multivariate analysis, together with age at diagnosis (HR 1.065, 95% CI 1.026-1.106, P = .001) and American Society of Anesthesiology score (HR 2.361, 95% CI 1.261-4.419, P = .007). Also renal function assessed by estimated glomerular filtration rate significantly correlated to survival in univariate analysis, but did not remain independent after multivariate analysis. Oncocytoma was the most frequent benign lesion, followed by angiomyolipoma. CONCLUSION The present study in patients with benign renal tumors shows that the remaining renal function and OS correspond to the choice of surgical procedure. Our results support the recommendation to perform NSS whenever possible when surgery is performed for patients with renal masses. The limitations of the study are the retrospective design and the selection bias for the surgical approach.

Health-related quality of life, personality and choice of coping are related in renal cell carcinoma patients

Abstract Objective. To investigate whether health-related quality of life (HRQoL) depends on psychosocial factors, rather than on factors related to the cancer treatment, this study explored the associations between HRQoL, personality, choice of coping and clinical parameters in surgically treated renal cell carcinoma (RCC) patients. Materials and methods. After exclusions (e.g. death, dementia), 260 patients were found to be eligible and invited to participate. The response rate was 71%. HRQoL was determined by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), personality by the Eysenck Personality Inventory and coping by the COPE Questionnaire. Given tumour treatment, TNM stage and patient-reported comorbidity were also determined. The HRQoL indices were also summarized in general quality of life/health, functional sum and symptom sum scores. Results. EORTC C30 sum scores were negatively associated with the personality trait of neuroticism [common variance (CV) 19–36%]. Avoidant choice of coping inversely accounted for 9–18% of the total HRQoL variance, while reported coping by humour was to some extent negatively associated with HRQoL score (CVmax 4%). Indeed, all of the quality of life indices except for one were significantly negatively correlated with neuroticism and avoidance coping. Patients with low HRQoL due to treatment, secondary to flank or open surgery, reported a closer association between problem-focused choice of coping and HRQoL than the other patients. Moreover, present comorbidities were uniquely associated with a lowered HRQoL. Conclusions. HRQoL is related to treatment-related factors in RCC patients, but shown here to be more strongly associated with psychological factors and present comorbidity. These findings suggest that attention should be paid to supportive treatment of RCC patients.

Preoperative high levels of serum vascular endothelial growth factor are a prognostic marker for poor outcome after surgical treatment of renal cell carcinoma

Abstract Objective. The aim of this study was to determine whether concentrations of vascular endothelial growth factor (VEGF) in blood taken preoperatively can predict subtype, survival and recurrence in patients with renal cell carcinoma (RCC). Materials and methods. The patient group consisted of 124 patients with an RCC that was surgically removed with nephrectomy or nephron-sparing surgery at Haukeland University Hospital from 2007 to 2010. All subtypes and stages were included. Preoperative blood samples were taken on the day of surgery, and the samples were prepared and frozen at –80°C. The level of VEGF in serum was analysed using Luminex® immunobead technology. The patients were followed until death or to 31 October 2014 (>4.5 years). Results. Patients with higher levels of VEGF were more likely to have clear cell RCC [odds ratio (OR) 2.43, p = 0.046], as were older patients (OR 1.04, p = 0.024). In a multivariate analysis, high VEGF, stage and nuclear grade all had a significant predictive value for cancer-specific survival (OR 4.56, p = 0.017; OR 11.54, p < 0.001; and OR 7.85, p = 0.015, respectively). VEGF, stage and nuclear grade predicted recurrence in patients presumed to have been radically treated (OR 4.37, p = 0.03; OR 5.02, p = 0.011; and OR 6.57, p = 0.008, respectively). Conclusions. Tumour stage and a high level of serum VEGF were predictors for an increased risk of recurrence and cancer-specific death. Furthermore, the study showed that serum VEGF may be used to determine the subtype of RCC preoperatively.

Development and confirmation of potential gene classifiers of human clear cell renal cell carcinoma using next-generation RNA sequencing

Abstract Objective: A previous study by this group demonstrated the feasibility of RNA sequencing (RNAseq) technology for capturing disease biology of clear cell renal cell carcinoma (ccRCC), and presented initial results for carbonic anhydrase-9 (CA9) and tumor necrosis factor-α-induced protein-6 (TNFAIP6) as possible biomarkers of ccRCC (discovery set) [Eikrem et al. PLoS One 2016;11:e0149743]. To confirm these results, the previous study is expanded, and RNAseq data from additional matched ccRCC and normal renal biopsies are analyzed (confirmation set). Materials and methods: Two core biopsies from patients (n = 12) undergoing partial or full nephrectomy were obtained with a 16 g needle. RNA sequencing libraries were generated with the Illumina TruSeq® Access library preparation protocol. Comparative analysis was done using linear modeling (voom/Limma; R Bioconductor). Results: The formalin-fixed and paraffin-embedded discovery and confirmation data yielded 8957 and 11,047 detected transcripts, respectively. The two data sets shared 1193 of differentially expressed genes with each other. The average expression and the log2-fold changes of differentially expressed transcripts in both data sets correlated, with R² = .95 and R² = .94, respectively. Among transcripts with the highest fold changes were CA9, neuronal pentraxin-2 and uromodulin. Epithelial–mesenchymal transition was highlighted by differential expression of, for example, transforming growth factor-β1 and delta-like ligand-4. The diagnostic accuracy of CA9 was 100% and 93.9% when using the discovery set as the training set and the confirmation data as the test set, and vice versa, respectively. These data further support TNFAIP6 as a novel biomarker of ccRCC. TNFAIP6 had combined accuracy of 98.5% in the two data sets. Conclusions: This study provides confirmatory data on the potential use of CA9 and TNFAIP6 as biomarkers of ccRCC. Thus, next-generation sequencing expands the clinical application of tissue analyses.

Contemporary external validation of the Leibovich model for prediction of progression after radical surgery for clear cell renal cell carcinoma

Abstract Objective.The aim of this study was to externally validate in an up-to-date setting the predictive ability of the model for recurrence after radical treatment of clear cell renal cell carcinoma (CCRCC) published by Leibovich in 2003. Materials and methods. The study included a total of 386 consecutive patients with CCRCC between January 1997 and May 2013, treated with partial or radical nephrectomy. All patients were scored with points between 0 and 11, and further subdivided into low-, intermediate- and high-risk groups according to the original paper. Well-recognized statistical methods for the evaluation of Cox’s proportional hazard-based prognostic models were applied. To validate the discriminative ability, Harrell’s concordance (c) index and hazard ratios (HRs) between risk groups were used, and calibration was graphically explored. Results.The 10 year recurrence-free survival rates for the low-, intermediate- and high-risk groups were 87.3%, 63.8% and 19.8%, respectively Harrell’s c index was 0.864. The HRs across risk groups for the intermediate- and high-risk groups were 5.29 and 21.56, respectively, with the low-risk group as a reference category. A gross comparison of the survival estimates between the patients showed an overall similarity. However, differences within the intermediate- and high-risk groups were seen in the first year of follow-up. Conclusions.The Leibovich model seems to discriminate well between risk groups, but for the intermediate- and high-risk groups the calibration is not optimal. This study validates the model in a present-day Nordic patient population. The model can be used as a risk stratification tool for follow-up after radical treatment of CCRCC.