Serum levels of the IL-6 family of cytokines predict prognosis in renal cell carcinoma (RCC).

PURPOSE: An improved understanding of RCC immunology should shed further light on RCC tumor biology. Our objective was to study to what extent serum levels of the IL-6 family of cytokines at diagnosis were relevant to survival. METHODS: A total of 118 consecutively patients with RCC, in which the tumor was surgically removed at Haukeland University Hospital during the period from 2007 to 2010, were included. The patients were followed-up for 10 years. The morning before surgery blood was sampled and serum frozen, with levels of IL-6, IL-27, IL-31, OSM, CNTF, IL-6Rα and gp130 determined. RESULTS: Among patients with the highest quartile of IL-6 (> 8 pg/ml) (n = 29), six of nine who had metastasis at diagnosis had such high IL-6 values. Among presumed radically treated patients, a high IL-6 and IL-27 strongly predicted recurrence. In particular, the predictions among patients with large (diameter > 7 cm) tumors were excellent regarding both IL-6 and IL-27 values. High gp130 serum levels predicted an overall survival (OS) among RCC patients with large tumors. Patients with a high IL-6 exhibited a strong expression of IL-6 in endothelial- and vascular smooth muscle cells. Moreover, the level of intra-tumoral CD3-positive cells predicted survival. CONCLUSIONS: IL-6 and IL-27 seem to play a role in RCC biology. IL-6 enables the pinpointing of metastatic condition at diagnosis, as well as together with IL-27, the predicting of survival and recurrence. Endothelial cells and vascular smooth muscle cells are both suggested as important sources of IL-6.

The levels of IL-6 and soluble IL-33R are increased in the renal vein during surgery for clear cell renal cell carcinoma.

PURPOSE: The main aim was to map serum levels of IL-1/IL-6 family cytokines and relevant receptors from serum samples taken across treatment in patients with Renal Cell Carcinoma (RCC). Additionally, we explored the possible interactions between these measurements, immunohistochemistry and intratumoral blood flow. METHODS: We included 40 patients undergoing open surgery for renal tumors. Blood samples were collected before, during (taken simultaneously from a peripheral site and the renal vein (RV) before clamping) and after surgery. Samples were analyzed for IL-6, IL-27, IL-31, OSM, TNF-α, serum (s)-gp130, s-IL-6Rα, s-IL-33R, IL-1Rα and VEGF. All 35 RCC tumors were histologically subtyped as clear cell (CCRCC), papillary or chromophobe. Immunohistochemistry for the CCRCC group included expression of IL-6/IL-6R. Intratumoral blood flow was determined by calculating intratumoral contrast enhancement on preoperative computerized tomography (CT) imaging. RESULTS: In the CCRCC patients, the intraoperative RV concentration of IL-6 was significantly higher than in both the preoperative and postoperative samples (p = 0.005 and p = 0.032, respectively). Furthermore, the intraoperative ratio showed significantly higher levels of IL-6 in the RV than in the simultaneously drawn peripheral sample. Immunohistochemistry showed general expression of IL-6 (23/24) in both tumor cells and the vasculature (20/23). Moreover, s-IL-6R was expressed in tumor cells in 23/24 studied patients. Increased blood flow in the CCRCC tumors predicted increased IL-6 levels in the RV (p < 0.001). The other cytokines and receptors showed an overall stability across the measurements. However, the intraoperative ratios of IL-33R and gp130 showed significantly higher levels in the RV. CONCLUSION: Serum levels of IL-6 increased during surgery. Intraoperative IL-6 and s-IL-33R values were higher in the RV compared to the periphery, suggesting secretion from the tumor or tumor microenvironment itself. Supportive of this is an almost general expression of IL-6/s-IL-6R in tumor cells and IL-6 in vasculature in the tumor microenvironment. Other studied cytokines/receptors were remarkably stable across all measurements.

Development of a disease-specific health-related quality of life (HRQoL) questionnaire intended to be used in conjunction with the general European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) in renal cell carcinoma patients.

BACKGROUND: Studying health-related quality of life (HRQoL) following cancer treatment has become part of a growing number of standardized treatment protocols. The European Organization for Research and Treatment of Cancer (EORTC) has developed HRQoL questionnaires aimed at cancer patients. A disease-specific part is not available for renal cell carcinoma (RCC) patients, and the present aim was to develop an EORTC-compatible RCC-specific HRQoL questionnaire. MATERIAL AND METHODS: In total 413 RCC patients were treated with radical or partial nephrectomies in Western Norway during the period from 1997 to 2010. Three hundred and nine patients with histologically proven cancer were still alive at the inclusion time point and 185 RCC patients (71% response rate) returned the questionnaires. We determined HRQoL by the EORTC-QLQ C30 questionnaire. We also asked 13 candidates questions aimed at constituting a disease-specific part. Furthermore, we tested parts of personality by the Eysenck Personality Inventory and coping by the COPE questionnaire. Given tumor treatment, TNM stage, alcohol consumption level and smoking levels were also determined from the hospital records. RESULTS: A factor analysis showed that five factors were formed: one general symptomatic, one general functional, one with disease-specific questions (flank pain, blood in the urine, flank edema, urinary tract infection), one about sexuality and one about weight loss or gain. Ten RCC-specific HRQoL questions were derived from a factor analysis, including four questions related particularly to pain, mobility and social functioning, also representing a short version of the EORTC C30. The psychometric properties and the relation to other psychological and clinical variables were further determined to be satisfactory. CONCLUSIONS: The suggested disease-specific EORTC-QLQ-style RCC10 version adds important information about the HRQoL of RCC patients, providing additional apparent value to the general questionnaire and personality variables, as well as being psychometrically satisfactory. The questionnaire has a potential as a "stand alone" HRQoL questionnaire among RCC patients.

Longevity of B-cell and T-cell responses after live attenuated influenza vaccination in children.

BACKGROUND: The live attenuated influenza vaccine (LAIV) is the preferred vaccine for children, but the mechanisms behind protective immune responses are unclear, and the duration of immunity remains to be elucidated. This study reports on the longevity of B-cell and T-cell responses elicited by the LAIV. METHODS: Thirty-eight children (3-17 years old) were administered seasonal LAIV. Blood samples were collected before vaccination with sequential sampling up to 1 year after vaccination. Humoral responses were evaluated by a hemagglutination inhibition assay, and memory B-cell responses were evaluated by an enzyme-linked immunosorbent spot assay (ELISpot). T-cell responses were evaluated by interferon γ (IFN-γ) ELISpot analysis, and intracellular cytokine staining of CD4(+) T cells for detection of IFN-γ, interleukin 2, and tumor necrosis factor α was performed using flow cytometry. RESULTS: LAIV induced significant increases in B-cell and T-cell responses, which were sustained at least 1 year after vaccination. Strain variations were observed, in which the B strain elicited stronger responses. IFN-γ-expressing T cell counts increased significantly, and remained higher than prevaccination levels 1 year later. Expression of T-helper type 1 intracellular cytokines (interleukin 2, IFN-γ, and tumor necrosis factor α) increased after 1 dose and were boosted after the second dose. Hemagglutination inhibition titers were sustained for 1 year. Vaccine-induced memory B cell counts were significantly increased, and the response persisted for one year. CONCLUSIONS: LAIV elicited B-cell and T-cell responses that persisted for at least 1 year in children. This is a novel finding that will aid future vaccine policy.

Hearing, Balance, and Mortality: Sex-Specific Patterns in a Longitudinal Study.

OBJECTIVES: Assess the association of hearing on sex-specific overall mortality and death from acute cardiovascular disease and evaluate if these effects are modulated by postural balance. STUDY DESIGN: Cohort study. SETTING: Otolaryngology department at an academic hospital. METHODS: Patients underwent standard clinical examination, laboratory examination including stabilometry and audiometry. Pure tone average on the best hearing ear was calculated from 0.5, 1, 2, and 3 kHz. Cause of death was retrieved from the Norwegian Cause of Death Registry. RESULTS: A total of 1036 patients (58.8% women) were followed for 26 ± 3 years. In Cox regression analyses for overall mortality adjusted for age, past medical history, and vestibular disease, 10 dB increase in hearing threshold was associated with a 14% increase in mortality among men (hazard ratio 95% confidence interval: 1.02-1.28, P = .02), but no significant association was seen between hearing and mortality in women (0.92-1.15, P = .60). The same analyses for acute cardiovascular death found that a 10 dB increase in hearing threshold was associated with a 57% increase in hazard ratio in men (1.21-2.05, P < .001), but no significant effect of hearing on survival was seen in women (P = .71). Adjusting for postural balance did not change the association between hearing and mortality. CONCLUSION: This study finds hearing threshold is associated with overall mortality and acute cardiovascular death among men, with no such association observed among women. Our findings indicate important differences between men and women and suggest that such differences should be taken into consideration in audiological research.

Comorbidity is an independent predictor of health-related quality of life in a longitudinal cohort of head and neck cancer patients.

The aims of this study were to evaluate the validity and reliability of self-reported measurements of comorbidity, as well as the impact of comorbidity on health-related quality of life (HRQoL) scores, obtained at the time of diagnosis and at 18 months follow-up, among head and neck squamous cell carcinoma (HNSCC) patients treated with curative intent. One hundred and six (106) patients were available for analyses at the time of diagnosis and 72 patients at 18 months follow-up. HRQoL was assessed with the EORTC QLQ-C30/H&N35 inventories. The presence of comorbidities was assessed with a self-reported eight-question-based questionnaire at the time of diagnosis and after 18 months, as well as retrospectively with the Adult Comorbidity Evaluation (ACE-27) scale. The self-reported eight-question-based assessments of comorbidity showed high reliability with the chart-based ACE-27 inventory at both time points (r = 0.611, p < 0.001 and r = 0.612, p < 0.001). Significant correlations with comorbidity were determined for the functional (r = -0.194, r = -0.269) and the general symptom HRQoL sum score (r = 0.257 and r = 0.334) at the time of diagnosis and after 18 months; in particular present lung disease explained these associations. The covariates marital status, smoking status, alcohol consumption, and tumor stage were also found to be significantly associated with HRQoL sum scores at both time points. In conclusion, we have demonstrated that it is possible to assess comorbidity in HNSCC patients by self-reported questionnaires. Moreover, comorbidities, in particular present lung disease, appear to have an important and unique influence on HRQoL scores.

Personality, choice of coping and T stage predict level of distress in head and neck cancer patients during follow-up.

The aim of the present study was to investigate to what extent TNM stage, treatment level, personality, choice of coping, mood and health-related quality of life (HRQoL) scores predicted distress as measured by general health questionnaire (GHQ) in successfully treated head and neck squamous cell carcinoma (HNSCC) patients. All patients younger than 80 years who had been diagnosed with HNSCC in western Norway in the period from 1992 to 1997, and who had survived until 1999, were sampled. Ninety-six patients (90% response rate) were included 48 ± 2 months after diagnosis. We determined personality by the Eysenck personality inventory, coping by the COPE questionnaire; HRQoL by EORTC QLQ questionnaire; and mood by Beck depression inventory (BDI). Fifty-five of 58 eligible patients were interviewed a second time 47 ± 1 months after the first interview where neuroticism and GHQ-30 questionnaires were answered. Both HRQoL [explained variance (EV), 9-40%] and BDI (EV 26-30%) scores predicted the GHQ scores. Numerical T stage was inversely associated with GHQ scores (EV ~10%). High neuroticism generally predicted high GHQ scores (EV 16-28%). Avoidance focused, problem focused, drinking to cope predicted GHQ scores (EV 8-14%) and high alcohol consumption (EV ~8%) predicted GHQ scores. The present association pattern could still be shown when adjusted for gender, age and educational level when studied by multiple regression analyses. In conclusion, lowered HRQoL, low mood, a high T stage, high alcohol consumption, high neuroticism, coping by avoidance and coping by problem solving directly predicted worse distress as measured by high GHQ scores, whereas neuroticism was also associated with GHQ through choice of coping.

Tumor HPV Status, Level of Regulatory T Cells and Macrophage Infiltration Predict up to 20-Year Non-Disease-Specific Survival in Oropharynx Squamous Cell Carcinoma Patients.

Oropharynx squamous cell carcinoma (OPSCC) is of special interest because human papilloma virus (HPV) and/or smoking cause this disease. Influxes of inflammatory cells into such tumors are known to vary with prognoses. AIMS: To study whether the density of tumor-infiltrating T lymphocytes and tumor-infiltrating macrophages predicted general 20-year overall survival (OS), as well as OS with only disease-specific survival (DSS) patients included. METHODS: Biopsies from patients treated for OPSCC (n = 180) were stained by immunohistochemistry and the tumor cell macrophage (CD68), pan T lymphocytes (CD3), and regulatory T lymphocytes (Foxp3) densities were determined. The HE-determined percentage of matured tumor cells and the rate of invasion were calculated, and stromal desmoplasia were performed. Tumor HPV presence was studied by PCR. Twenty-year OS and five-year DSS patients were determined. RESULTS: Tumor HPV status strongly predicted survival. High tumor infiltration of CD3, Foxp3 and CD68-positive cells predicted better twenty-year OS, with and without HPV stratification. Foxp3 and CD68 levels predicted OS, and 20-year among DSS patients, primarily among HPV(+) patients. Tumor HE-derived variables did not predict such survival. CONCLUSIONS: Tumor HPV status, level of Foxp3 tumor-infiltrating lymphocytes and CD68 tumor-infiltrating macrophages predicted up to 20-year OS of both all patients and disease-specific survived patients.

Distress, quality of life, neuroticism and psychological coping are related in head and neck cancer patients during follow-up.

UNLABELLED: The aim of the present study was to study the relation between distress, quality of life (QoL), personality and choice of coping in successfully treated head and neck squamous cell carcinoma (HNSCC) patients, and to study whether distress could be regarded as a QoL variable. MATERIAL AND METHODS: We determined present distress by the general health questionnaire (GHQ), QoL by the European Organization for Research and Treatment of Cancer Quality of life Questionnaire (EORTC-QLQ) C30/H&N35, personality by the Eysenck Personality Inventory and coping by the COPE questionnaire. All patients younger than 80 years who had been diagnosed with HNSCC in Western Norway in the period from 1992 to October 2001, and who had survived at least 12 months without evidence of disease were interviewed. In addition, treatment level, TNM stage, alcohol consumption level as well as smoking level were determined. One hundred and thirty-nine patients (96.5% response rate) were included. RESULTS: Distress and QoL indexes were scored with a common variance (CV) between 20% and 35%. The measured variables account for 40-48% of the variance of the QoL/GHQ scores. Between 3% and 10% of the GHQ/general QoL scores and 10% of the variance of the H&N35 QoL scores were predicted by the TNM stage. The measured psychological factors accounted for 20% of the H&N35 QoL scores and 40% of the measured variance of the general QoL and GHQ responses. High neuroticism (CV≈20-35%), present avoidance coping (CV≈10-30%) and coping by suppression of competing activity (CV≈10-20%) were associated with low QoL and high distress. CONCLUSION: GHQ and QoL scores are scored similar, and are to some extent predicted by treatment related factors, but between 2.5 and 10 times more closely associated with psychological factors. Distress may possibly also be regarded as a QoL variable.

Personality and educational level determine self-reported health-related quality-of-life and distress in patients with renal tumors awaiting radical surgery.

Objective: Data on preoperative distress and health-related quality-of-life (HRQoL) is lacking for patients with newly diagnosed renal tumors. This study aims to compare HRQoL within this group with the general population and to study the relationship between distress, HRQoL, personality, coping, and patient/tumor-related factors.Materials and methods: Between January 2011 and June 2014, 153 patients (100 males/53 females), scheduled for surgery were prospectively included. Distress was determined by the General Health Questionnaire (GHQ), HRQoL by EORTC-QLQ-C30 questionnaire, personality by Eysenck Personality Inventory and coping by COPE questionnaire. HRQoL-data from an age and gender matched Norwegian reference population was used for comparison.Results: The study patients had significantly poorer HRQoL than the reference population. GHQ and HRQoL sum scores had a common variance (CV = r2) of 29-35%. In regression models, the measured variables accounted for 33% of the variance for the GHQ score. Significant predictors of the measured variance were neuroticism (18%), education level (3%) and avoidant coping (2%). Similarly, the measured variables accounted for 33-44% of the variance for the HRQoL sum scores. For all HRQoL sum scores, neuroticism predicted 17-28%, while education predicted 4-11% of the measured variance. Large tumor size, comorbidity, performance status and CRP predicted 2-7% of individual sum scores.Conclusions: For both preoperative distress and HRQoL, personality traits such as neuroticism and education level were the most important predictors. Tumor-related factors and other preexisting conditions seemed to be of lesser importance. Thus, preoperatively screening of psychological factors could be helpful to identify those at risk of poor outcomes.

Chemokines are secreted by monocytes following OK-432 (lyophilized Streptococcus pyogenes) stimulation.

BACKGROUND: OK-432, penicillin-killed Streptococcus pyogenes, is used in treating lymphangiomas and carcinomas. We have studied in vitro the role of mononuclear phagocytes (MNPs), including purified monocytes (MOs), in the immune response to OK-432. MIP-1alpha/beta and MCP-1 secretions were assessed in whole blood (WB), peripheral blood mononuclear cells (PBMCs) and purified MOs, after in vitro stimulation with OK-432 with or without adherence for 24 hours. RESULTS: OK-432 stimulated MNPs to secrete MCP-1 and MIP-1alpha/beta in healthy individuals and in head and neck squamous cell carcinoma (HNSCC) patients, except for OK-432 stimulation of WB giving a minimal MIP-1alpha/beta response. Upon culture on low-attachment wells, a spontaneous chemokine secretion was observed, with an unchanged secretion following OK-432 stimulation. Inhibition of Syk kinase and/or PI-3 kinase did not significantly change the chemokine response to OK-432, except for MIP-1alpha production being increased upon Syk inhibitor addition and an increased MCP-1 response upon addition of both inhibitors. Adhesion may possibly involve beta1 and/or beta3 integrins, not beta2, whereas beta(1-3) integrins may act as co-stimulatory receptors for OK-432. Based on direct blockage of CD36 or CD18 by antibodies, MCP-1 production may be mediated by CD18 while MIP-1beta and MCP-1 production may occur upon binding to CD36. CONCLUSION: Adherent human MOs produce MCP-1 and MIP-1alpha/beta upon stimulation with OK-432. CD36 modulates MIP-1beta and MCP-1 response. Thus, to some extent OK-432 acts as a substance whereby only MOs adhered to surfaces secrete MCP-1 and MIP-1alpha/beta, in part explaining why OK-432 is suited as a biological response modifying drug.

Audiovisual assessment of exercise-induced laryngeal obstruction: reliability and validity of observations.

Variable obstruction to airflow at the laryngeal level may cause respiratory distress during exercise. The Continuous Laryngoscopy Exercise (CLE)-test enables direct visualization of the larynx during ongoing exercise. The aims of this study were to establish a scoring system for laryngeal obstruction as visualized during the CLE-test as well as to assess reliability and validity of this scoring system. Continuous video recording of the larynx was performed in parallel with continuous video recording of the upper part of the body, and recording of breath sounds in 80 patients and 20 symptom-negative volunteers, running on a treadmill to respiratory maximal tolerable distress or exhaustion. Each participant scored the degree of symptoms during exercise. The scoring system contains four sub-scores, each graded from 0 to 3. Two independent laryngologists, blinded to clinical data, scored the video recordings of the larynx twice. The proportion of inter- and intra-observer agreement (equal scores) for each sub-score through these four sessions varied between 70 and 100% (weighted kappa values varied from 0.49 to 1.00 correspondingly). A positive correlation was found between CLE-test sum score and symptom score (rho = 0.75, P < 0.001). There was a significant difference in CLE-test sum score between patients (3.34 +/- 1.34) and volunteers (0.65 +/- 0.66) (P < 0.001). The single CLE-test sub-score that correlated most strongly with symptom score was glottic adduction at maximal effort (rho = 0.75, P < 0.001). The presented scoring system is reliable and valid, and we suggest that it can be used when laryngeal function during exercise is evaluated.

Personality and choice of coping predict quality of life in head and neck cancer patients during follow-up.

INTRODUCTION: The aim of the present study was to investigate to what extent personality and choice of coping predicted self-reported quality of life (QoL) in successfully treated head and neck squamous cell carcinoma (HNSCC) patients. MATERIALS AND METHODS: We determined QoL by the European Organization for Research and Treatment of Cancer Quality of life Questionnaire (EORTC-QLQ) C30/H&N35, personality by the Eysenck Personality Inventory and coping by the COPE questionnaire. All patients younger than 80 years who had been diagnosed with HNSCC in Western Norway in the period from 1992 to1997, and who had survived until 1999, were sampled. Ninety-six patients (90% response rate) were included 48+/-2 months after diagnosis. Fifty-five of 58 eligible patients were interviewed a second time 47+/-1 months after the first interview where neuroticism and QoL questionnaires were answered. RESULTS: Numerical T stage was inversely associated with the second QoL scores (CV: 10-24%). High neuroticism generally predicted low secondary QoL scores both directly (common variance: 17-25%) and adjusted by the QoL values measured simultaneously as the neuroticism (CV: 11-25%). Avoidance focused, problem focused, drinking to cope and coping by humor all predicted QoL scores (CV: 8.5-15%). The present association pattern could still be shown when adjusted for gender, age and educational level when studied by multiple regression analyses. CONCLUSION: In conclusion, a high T stage, high neuroticism, coping by humor and coping by problem solving directly predicted low QoL whereas neuroticism was also associated with QoL through avoidance coping.

Gene expression profiles of head and neck carcinomas from Sudanese and Norwegian patients reveal common biological pathways regardless of race and lifestyle.

PURPOSE: To explore possible range of gene expression profiles in head and neck squamous cell carcinomas (HNSCC) and pairwised normal controls from Sudanese (n = 72) and Norwegian (n = 45) patients using a 15K cDNA microarray and to correlate the findings with clinicopathologic variables. EXPERIMENTAL DESIGN: Samples from Sudan were grouped according to anatomic location/patients' habit of toombak (snuff) use, and 37 pools of 2 to 11 tumors matched to 37 pools of their normal controls from the same patients, respectively, were prepared. For Norway, eight pools of 3 to 11 tumors matched to eight pools of their normal controls from the same patients, respectively, were prepared according to anatomic location. Pools (n = 45) were hybridized to microarrays. For controls, 33 of the pools were hybridized against Human Reference RNA. Scanned array images were recorded, and data analysis was done in groups. For verification, results for selected genes were analyzed using quantitative real-time PCR/immunohistochemistry. RESULTS: We identified 136 genes from Sudan and 154 from Norway as differentially expressed between tumors and controls. Changes of the genes found were confirmed in >70% of the pools by hybridization against Reference RNA. Seventy-three genes and three main pathways (signal transduction, cell communication, and ligand-receptor interaction) were of relevance to the HNSCCs from both countries. Hierarchical clustering of the 73 genes identified subclasses of mixed tumors from the two populations, two independent subgroups for Norwegian tumors by their anatomic sites, and five subgroups for Sudanese tumors by their toombak habits. Quantitative real-time PCR/immunohistochemistry validated the microarray-based data. CONCLUSIONS: Differences in gene expression between tumor and nontumor tissues were identified in HNSCCs. Analysis of the two population groups revealed a common set of 73 genes within three main biological pathways. This indicates that the development of HNSCCs is mediated by similar biological pathways regardless of differences related to race, ethnicity, lifestyle, and/or exposure to environmental carcinogens. Of particular interest, however, was the valuable association of gene expression signature found with toombak use and anatomic site of the tumors.

Quality of life, drinking to cope, alcohol consumption and smoking in successfully treated HNSCC patients.

CONCLUSION: The level of coping by alcohol consumption is broadly associated with level of general quality of life (QoL) in patients with successfully treated head and neck squamous cell carcinoma (HNSCC). OBJECTIVE: The aim of this study was to investigate the association between self-reported level of general coping, drinking to cope (DTC), reported alcohol and tobacco use as well as QoL in successfully treated HNSCC patients. PATIENTS AND METHODS: We employed a cross-sectional design. Sample I included all patients <80 years old who had been diagnosed with HNSCC in Western Norway in the period from 1992 to 1997, and who were disease-free in the year 2000. The patients were interviewed at a routine follow-up visit. Sample II included all Norwegian laryngectomized patients. General coping and DTC were assessed by the COPE questionnaire and the QoL was assessed by the EORTC-QLQ (C30/H&N35) questionnaire. Reported level of alcohol consumption was associated with global QoL (r = -0.22) and with DTC (r = 0.31). Reported smoking level was associated with DTC (r = 0.26) and inversely with C30 functional/symptom sum QoL scores (r = -0.31/0.27). Level of DTC was associated with C30 global (r = -0.30) and C30 functional/symptom sum QoL scores (r = -0.31/0.27) and this association was still present after adjustment for gender, age, levels of neuroticism and avoidance coping.

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

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.

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

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.

Health-related quality of life in long-term survivors after renal cancer treatment.

OBJECTIVE: The most important outcome of renal cell carcinoma (RCC) treatment is survival. However, all cancer treatment should evaluate the health-related quality of life (HRQoL) outcome of the treatment. This has not been sufficiently documented in RCC. The aim of this investigation was therefore to document the HRQoL outcome of RCC. MATERIAL AND METHODS: All 413 RCC patients treated with radical or partial nephrectomy at Haukeland University Hospital, Norway, during the period 1997--2010 were included. After exclusions, invitations to participate were mailed to 260 patients; 185 patients (71%) returned the questionnaires. In addition, a cohort of general head and neck squamous cell carcinoma (HNSCC) patients, a cohort of laryngectomized HNSCC patients, and a cohort from the general population of Norway, were used to compare the RCC patients' HRQoL scores. RESULTS: Performance status as measured by the American Society of Anesthesiologists (ASA) score and Eastern Cooperative Oncology Group (ECOG) classification at diagnosis showed an inverse relation to HRQoL [maximum coefficient of variation (CVmax) = 5.3%, p < 0.05]. Flank and open transabdominal approaches to RCC tumour resection were followed by reduced HRQoL compared with a general cohort of Norwegian citizens. However, the laparoscopically treated RCC patients had HRQoL scores at the level of the population. The indices "general health/QoL", the functional indices, and the symptom indices "fatigue", "pain", "sleep", "nausea and vomiting", "constipation" and "diarrhoea" were particularly affected. CONCLUSION: The results show that RCC patients, and in particular those treated by a flank approach but not those treated by minimal invasive surgery, have a multifacetedly reduced HRQoL compared to a general population cohort.

OK-432-stimulated chemokine secretion from human monocytes depends on MEK1/2, and involves p38 MAPK and NF-κB phosphorylation, in vitro.

Interaction between the immune system and cancer cells allows for the use of biological response modifiers, like OK-432, in cancer therapy. We have studied the involvement of monocytes (MOs) in the immune response to OK-432 by examining MCP-1, MIP-1α and MIP-1ß secretion, in vitro. OK-432-induced IL-6/TNF-α secretion has previously been shown to depend on mitogen-activated protein kinases (MAPKs) ERK1/2 and p38, and we therefore investigated the role of these MAPKs in OK-432-induced chemokine secretion. Here we demonstrate that pharmacological MEK1/2 kinase inhibition generally impaired chemokine secretion from MOs, whereas p38 MAPK inhibition in particular reduced MIP-1α production. Furthermore, simultaneous inhibition of MEK1/2 and Syk kinase was seen to have an additive impact on reduced MCP-1, MIP-1α and MIP-1ß secretion. Based on single cell flow cytometry analyses, OK-432, lipoteichoic acid (LTA) and lipopolysaccharide (LPS) were seen to induce p38 MAPK and NF-κB phosphorylation in MOs with different time kinetics. LTA and LPS have been shown to induce ERK1/2 phosphorylation, whereas the levels of phosphorylated ERK1/2 remained constant following OK-432 treatment at the time points tested. Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns, and we demonstrate increased TLR2 cell surface levels on the MO population, most profoundly following stimulation with LTA and OK-432. Together these results indicate that modulation of MEK1/2 and p38 MAPK signalling could affect the response to OK-432 treatment, having the potential to improve its therapeutic potential within cancer and lymphangioma treatment.