Kjell Grankvist

Vascular endothelial growth factor is of high prognostic value in node-negative breast carcinoma.

PURPOSE The prognostic value of vascular endothelial growth factor (VEGF) protein, known to stimulate endothelial growth and angiogenesis, was evaluated in node-negative breast carcinoma (NNBC) and compared with established prognostic factors. PATIENTS AND METHODS In 525 consecutive patients with primary invasive NNBC (T1-2N0M0; tumor, node, metastasis stage), of whom 500 patients did not receive any systemic therapy, the cytosolic levels of VEGF165 were measured by using a quantitative enzyme-linked immunosorbent assay. The median follow-up was 46 months. Univariate and multivariate analyses were performed. RESULTS VEGF level was significantly inversely correlated with estrogen receptor (ER) positivity but positively associated with tumor size and histologic grade. Patients with VEGF levels above the median value (2.40 pg/microg of DNA) showed a significantly shorter survival time (P=.0012) than patients with levels less than the median value, also when analyzed as a continuous variable (P=.0277). Tumor size, grade, and ER expression were all statistically significant for overall survival in univariate analyses (P=.0069, P=.014, and P < .001, respectively). Multivariate analysis showed that VEGF level was the strongest predictor of overall survival (P=.0199). Histologic grade was also an independent predictor of survival (P=.0477). Among the 381 patients with ER-positive tumors, a group in general considered to have a good prognosis, we found a significant reduction in survival for those with levels of VEGF greater than the median value (P=.0009). CONCLUSION The results suggest that the level of VEGF165 protein is an independent, strong prognostic factor for survival in patients with NNBC, especially in the subgroup of patients with ER positivity. Thus, cytosolic VEGF165 might be useful to select patients for adjuvant systemic therapy.

Correlation of Vascular Endothelial Growth Factor Content With Recurrences, Survival, and First Relapse Site in Primary Node-Positive Breast Carcinoma After Adjuvant Treatment

PURPOSE To determine the predictive value of vascular endothelial growth factor (VEGF) for relapse-free survival (RFS) and overall survival (OS) in primary node-positive breast cancer (NPBC) after adjuvant endocrine treatment or adjuvant chemotherapy. MATERIALS AND METHODS VEGF was quantitatively measured in tumor cytosols from 362 consecutive patients with primary NPBC using an enzyme immunoassay for human VEGF(165). Adjuvant treatment was given to all patients, either as endocrine therapy (n = 250) or chemotherapy (n = 112). The median follow-up time was 56 months. RESULTS Univariate analysis showed VEGF to be a significant predictor of RFS (P =.0289) and OS (P =.0004) in the total patient population and in patients who received adjuvant endocrine treatment (RFS, P =.0238; OS, P =.0121). In the group of patients who received adjuvant chemotherapy, no significant difference was seen in RFS, but a difference was seen in OS (P =.0235). Patients with bone recurrences tended to have lower VEGF expression (median, 2.17 pg/microg DNA) than patients with visceral metastasis (4.41 pg/microg), brain metastasis (8.29 pg/microg), or soft tissue recurrences (3.16 pg/microg). Multivariate analysis showed nodal status (P =.0004), estrogen receptor (ER) status (P <.0001), and tumor size (P =.0085) to be independent predictors of RFS. VEGF was found to be an independent predictor of OS (P =.0170; relative risk [RR] = 1.82), as were ER (P <.0001; RR = 5.19) and nodal status (P =.0002; RR = 2.58). For patients receiving adjuvant endocrine treatment, multivariate analysis showed VEGF content to be an independent predictor of OS (P =.0420; RR = 1.90) but not of RFS. CONCLUSION The results suggest that VEGF(165) content in tumor cytosols is a predictor of RFS and OS in primary NPBC. VEGF content might also predict outcome after adjuvant endocrine treatment, but further studies in a prospective setting with homologous treatments are required.

Vascular endothelial growth factor as prognostic factor in renal cell carcinoma.

PURPOSE Vascular endothelial growth factor (VEGF) has been recognized as an important constituent of vascularization and growth of solid tumors. Serum VEGF levels were evaluated and correlated to clinicopathologic findings and clinical outcome in patients with renal cell carcinoma (RCC). MATERIALS AND METHODS Serum samples were collected before surgery in 164 patients with RCC. Levels of VEGF165 protein in sera were measured using a quantitative ELISA. Univariate and multivariate analyses were performed. RESULTS The VEGF165 level in serum was significantly increased (p = 0.0001) in patients with RCC (median 343.4 pg./ml.) compared with the control patients (median 103.8 pg./ml.). The level of VEGF165 in serum correlated to clinical stage and histopathological grade. Patients with VEGF165 levels below median value had significantly longer survival time than patients with higher levels (p = 0.0001). This was also shown when VEGF165 was analyzed in univariate Cox regression (p = 0.0001). The impact of VEGF165 on survival was especially shown in patients having tumors with vein invasion (pT3b-c N0 M0) and in patients with clinical stages I - III (p = 0.0240 and p = 0.0023, respectively). When using multivariate analysis, only tumor stage and grade remained as independent prognostic variables. CONCLUSIONS In RCC, serum VEGF165 level was significantly correlated to tumor stage and grade. Increased levels were correlated to adverse survival. Although, VEGF did not remain as an independent prognostic factor in multivariate analysis the levels of VEGF165 in serum was found useful for the identification of patients with potentially progressive disease especially for those with vein invasion.

Expression of vascular endothelial growth factor protein in human renal cell carcinoma.

To evaluate the effect of vascular endothelial growth factor (VEGF, one of the most important angiogenetic factors) in renal cell carcinoma (RCC) by analysing many RCCs for the expression of immunohistochemical (IHC) VEGF‐staining related to clinicopathological findings and survival.

p53 and vascular-endothelial-growth-factor (VEGF) expression predicts outcome in 833 patients with primary breast carcinoma

The angiogenic factor vascular endothelial growth factor (VEGF) predicts outcome in primary breast carcinoma. Alteration of the p53 gene causes down‐regulation of the expression of thrombospondin‐1, a natural inhibitor of angiogenesis. This study was conducted to investigate the association between mutant p53 protein and VEGF expression, and the prognostic value of these factors. VEGF165 and p53 protein were measured in tumour cytosols by enzyme immunoassays. Recurrence‐free survival (RFS) and overall survival (OS) were estimated in 833 consecutive patients, 485 node‐negative (NNBC) and 348 node‐positive (NPBC) with primary invasive breast cancer. A significant association was found between mutant p53 protein and VEGF expression. Univariate analysis showed both p53 and VEGF to be significant predictors of survival. Similar correlation was seen when p53 was combined with VEGF. Univariate analysis of NNBC showed significant prognostic value of p53 for OS, also when combined with VEGF expression; for NPBC, significant reductions in RFS and OS were seen for p53‐positive patients, and these findings were enhanced when combined with VEGF, also in the sub‐group receiving adjuvant endocrine treatment. Multivariate analysis showed both p53 and VEGF as independent predictors of OS in all groups. When the 2 factors were combined, an increased relative risk of 2.7 was seen for OS in the group with both p53 positivity and high VEGF content, as compared with 1.7 in the group with one risk factor. The results suggest an association between loss of wt‐p53 and increased VEGF expression, indicating that angiogenic activity may depend, at least partly, on altered p53‐protein function. Combination of these 2 biological markers appears to give additional predictive information of survival. A high‐risk group of patients was associated with p53 positivity and higher VEGF content. Int. J. Cancer (Pred. Oncol.) 89:51–62, 2000.

Preanalytical quality improvement: from dream to reality

Abstract Laboratory diagnostics (i.e., the total testing process) develops conventionally through a virtual loop, originally referred to as “the brain to brain cycle” by George Lundberg. Throughout this complex cycle, there is an inherent possibility that a mistake might occur. According to reliable data, preanalytical errors still account for nearly 60%–70% of all problems occurring in laboratory diagnostics, most of them attributable to mishandling procedures during collection, handling, preparing or storing the specimens. Although most of these would be “intercepted” before inappropriate reactions are taken, in nearly one fifth of the cases they can produce inappropriate investigations and unjustifiable increase in costs, while generating inappropriate clinical decisions and causing some unfortunate circumstances. Several steps have already been undertaken to increase awareness and establish a governance of this frequently overlooked aspect of the total testing process. Standardization and monitoring preanalytical variables is of foremost importance and is associated with the most efficient and well-organized laboratories, resulting in reduced operational costs and increased revenues. As such, this article is aimed at providing readers with significant updates on the total quality management of the preanalytical phase to endeavour further improvement for patient safety throughout this phase of the total testing process.

Preanalytical quality improvement: in quality we trust

Abstract Total quality in laboratory medicine should be defined as the guarantee that each activity throughout the total testing process is correctly performed, providing valuable medical decision-making and effective patient care. In the past decades, a 10-fold reduction in the analytical error rate has been achieved thanks to improvements in both reliability and standardization of analytical techniques, reagents, and instrumentation. Notable advances in information technology, quality control and quality assurance methods have also assured a valuable contribution for reducing diagnostic errors. Nevertheless, several lines of evidence still suggest that most errors in laboratory diagnostics fall outside the analytical phase, and the pre- and postanalytical steps have been found to be much more vulnerable. This collective paper, which is the logical continuum of the former already published in this journal 2 years ago, provides additional contribution to risk management in the preanalytical phase and is a synopsis of the lectures of the 2nd European Federation of Clinical Chemistry and Laboratory Medicine (EFLM)-Becton Dickinson (BD) European Conference on Preanalytical Phase meeting entitled “Preanalytical quality improvement: in quality we trust” (Zagreb, Croatia, 1–2 March 2013). The leading topics that will be discussed include quality indicators for preanalytical phase, phlebotomy practices for collection of blood gas analysis and pediatric samples, lipemia and blood collection tube interferences, preanalytical requirements of urinalysis, molecular biology hemostasis and platelet testing, as well as indications on best practices for safe blood collection. Auditing of the preanalytical phase by ISO assessors and external quality assessment for preanalytical phase are also discussed.

Obesity, metabolic factors and risk of different histological types of lung cancer: A Mendelian randomization study.

Background Assessing the relationship between lung cancer and metabolic conditions is challenging because of the confounding effect of tobacco. Mendelian randomization (MR), or the use of genetic instrumental variables to assess causality, may help to identify the metabolic drivers of lung cancer. Methods and findings We identified genetic instruments for potential metabolic risk factors and evaluated these in relation to risk using 29,266 lung cancer cases (including 11,273 adenocarcinomas, 7,426 squamous cell and 2,664 small cell cases) and 56,450 controls. The MR risk analysis suggested a causal effect of body mass index (BMI) on lung cancer risk for two of the three major histological subtypes, with evidence of a risk increase for squamous cell carcinoma (odds ratio (OR) [95% confidence interval (CI)] = 1.20 [1.01–1.43] and for small cell lung cancer (OR [95%CI] = 1.52 [1.15–2.00]) for each standard deviation (SD) increase in BMI [4.6 kg/m2]), but not for adenocarcinoma (OR [95%CI] = 0.93 [0.79–1.08]) (Pheterogeneity = 4.3x10-3). Additional analysis using a genetic instrument for BMI showed that each SD increase in BMI increased cigarette consumption by 1.27 cigarettes per day (P = 2.1x10-3), providing novel evidence that a genetic susceptibility to obesity influences smoking patterns. There was also evidence that low-density lipoprotein cholesterol was inversely associated with lung cancer overall risk (OR [95%CI] = 0.90 [0.84–0.97] per SD of 38 mg/dl), while fasting insulin was positively associated (OR [95%CI] = 1.63 [1.25–2.13] per SD of 44.4 pmol/l). Sensitivity analyses including a weighted-median approach and MR-Egger test did not detect other pleiotropic effects biasing the main results. Conclusions Our results are consistent with a causal role of fasting insulin and low-density lipoprotein cholesterol in lung cancer etiology, as well as for BMI in squamous cell and small cell carcinoma. The latter relation may be mediated by a previously unrecognized effect of obesity on smoking behavior.

Prognostic impact of carbonic anhydrase IX expression in human renal cell carcinoma

To evaluate the prognostic information of carbonic anhydrase (CA) IX expression in patients with renal cell carcinoma (RCC), as increased expression of CA IX is correlated with a worse prognosis in several malignancies.

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

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