Katharina Eberhard

Validation of the pre-treatment neutrophil–lymphocyte ratio as a prognostic factor in a large European cohort of renal cell carcinoma patients

Background:The neutrophil–lymphocyte ratio (NLR) has been proposed as an indicator of systemic inflammatory response. Several studies suggest a negative impact of increased NLR for patient’s survival in different types of cancer. However, previous findings from small-scale studies revealed conflicting results about its prognostic significance with regard to different clinical end points in non-metastatic renal cell carcinoma (RCC) patients. Therefore, the aim of our study was the validation of the prognostic significance of NLR in a large cohort of RCC patients.Methods:Data from 678 consecutive non-metastatic clear cell RCC patients, operated between 2000 and 2010 at a single centre, were evaluated retrospectively. Cancer-specific, metastasis-free, as well as overall survival (OS) were assessed using the Kaplan–Meier method. To evaluate the independent prognostic significance of NLR, multivariate Cox regression models were applied for all three different end points. Influence of the NLR on the predictive accuracy of the Leibovich prognosis score was determined by Harrells concordance index.Results:Multivariate analysis identified increased NLR as an independent prognostic factor for overall (hazard ratio (HR)=1.59, 95% confidence interval (CI)=1.10–2.31, P=0.014), but not for cancer-specific (HR=1.59, 95% CI=0.84–2.99, P=0.148), nor for metastasis-free survival (HR=1.39, 95% CI=0.85–2.28, P=0.184). The estimated concordance index was 0.79 using the Leibovich risk score and 0.81 when NLR was added.Conclusion:Regarding patients’ OS, an increased NLR represented an independent risk factor, which might reflect a higher risk for severe cardiovascular and other comorbidities. Adding the NLR to well-established prognostic models such as the Leibovich prognosis score might improve their predictive ability.

The lymphocyte/monocyte ratio predicts poor clinical outcome and improves the predictive accuracy in patients with soft tissue sarcomas

Increasing evidence indicates the involvement of inflammation and coagulation in cancer progression and metastases. Inflammatory biomarkers hold great promise for improving the predictive ability of existing prognostic tools in cancer patients. In the present study, we investigated several inflammatory indices with regard to their prognostic relevance for predicting clinical outcome in soft tissue sarcoma (STS) patients. Three hundred and forty STS patients were divided into a training set (n = 170) and a validation set (n = 170). Besides well‐established clinico‐pathological prognostic factors, we evaluated the prognostic value of the neutrophil/lymphocyte (N/L) ratio, the lymphocyte/monocyte (L/M) ratio and the platelet/lymphocyte (P/L) ratio using Kaplan–Meier curves and univariate as well as multivariate Cox regression models. Additionally, we developed a nomogram by supplementing the L/M ratio to the well‐established Kattan nomogram and evaluated the predictive accuracy of this novel nomogram by applying calibration and Harrells concordance index (c‐index). In multivariate analysis, a low L/M ratio was significantly associated with decreased CSS and DFS (HR = 0.41, 95% CI = 0.18–0.97, p = 0.043; HR = 0.39, 95% CI = 0.16–0.91, p = 0.031, respectively) in the training set. Using the validation set for confirmation, we found also in multivariate analysis an independent value for CSS (HR = 0.33, 95% CI = 0.12–0.90, p = 0.03) and for DFS (HR = 0.36, 95% CI = 0.16–0.79, p = 0.01). The estimated c‐index was 0.74 using the original Kattan nomogram and 0.78 when the L/M ratio was added. Our study reports for the first time that the pre‐operative L/M ratio represents a novel independent prognostic factor for prediction the clinical outcome in STS patients. This easily determinable biomarker might be helpful in improved individual risk assessment.

Down-regulation of KRAS-interacting miRNA-143 predicts poor prognosis but not response to EGFR-targeted agents in colorectal cancer

Background:MicroRNA-143 (miRNA-143) is frequently down-regulated in colorectal cancer (CRC) and may influence CRC cell proliferation, apoptosis and sensitivity to 5-fluorouracil. mRNA encoded by the KRAS oncogene has been identified as a target of miRNA-143. However, the prognostic significance of miRNA-143 expression and the ability to predict patient response to epidermal growth factor receptor (EGFR)-targeted agents have not yet been explored.Methods:We examined 77 CRC patients who were identified by pyrosequencing to have wild-type KRAS and were subsequently treated with EGFR-targeted therapy with the monoclonal antibodies cetuximab or panitumumab. MicroRNA-143 expression was measured in CRC tissue and corresponding non-neoplastic colon tissue by RT–PCR and its expression level was correlated with clinico-pathological characteristics. Univariate and multivariate analyses were used to calculate cancer-specific survival (CSS). The progression-free survival (PFS) and objective response rates on EGFR-targeted therapy were also evaluated.Results:Down-regulation of miRNA-143 was observed in 47 out of 77 (61%) tumours. Multivariate Cox regression analysis identified low levels of miRNA-143 expression as an independent prognostic factor with respect to CSS (hazard ratio=1.92, confidence interval=1.1–3.4, P=0.024). A significant difference was also observed with regard to PFS on EGFR-targeted therapy (P=0.031), but there were no significant differences with regard to the objective response rates.Conclusion:Our data indicate that miRNA-143 expression levels serve as an independent prognostic biomarker for CRC in KRAS wild-type patients. No role for miRNA-143 expression as a predictive biomarker for EGFR-targeted agents could be identified. Given its negative impact on CSS and PFS, miRNA-143 represents a novel prognosticator and a promising drug target for patients with CRC.

Low preoperative lymphocyte-monocyte ratio (LMR) represents a potentially poor prognostic factor in nonmetastatic clear cell renal cell carcinoma

OBJECTIVES To explore the potential prognostic significance of the lymphocyte-monocyte ratio (LMR) in patients with nonmetastatic renal cell carcinoma (RCC), as the LMR has been repeatedly proposed to have a negative effect on patient׳s survival in various hematological and solid cancers. However, findings about LMR׳s prognostic significance in RCC have not been reported yet. METHODS AND MATERIALS We retrospectively evaluated the prognostic significance of the LMR in a cohort comprising 678 patients with nonmetastatic clear cell RCC, who were operated between 2000 and 2010 with curative radical or partial nephrectomy at a single tertiary academic center. Preoperative LMR was calculated 1 day before surgical intervention. Patients were categorized using an LMR cutoff of 3.0. Cancer-specific survival (CSS), metastasis-free survival, and overall survival were assessed using the Kaplan-Meier method. To evaluate the independent prognostic significance of the LMR, multivariate Cox regression models were applied. Additionally, the influence of the LMR on the predictive accuracy of the Leibovich prognosis score was determined using the Harrell concordance index (c-index) and decision curve analysis. RESULTS Low LMR was statistically significantly associated with older patients (≥65 y), high tumor grade (G3+G4), advanced pathologic T category (pT3+pT4), the presence of histologic tumor necrosis, and male gender (P<0.05). Multivariate analysis identified a low LMR as an independent prognostic factor for patients׳ CSS (hazard ratio = 2.33; 95% CI: 1.10-4.94; P = 0.027). The estimated c-index was 0.83 using the Leibovich prognosis score and 0.86 when the LMR was added. CONCLUSIONS Regarding CSS of patients with RCC, a decreased LMR represents an independent prognostic factor. Adding the LMR to well-established prognostic models, such as the Leibovich prognosis score, might improve their predictive ability.

Perception of landslides risk and responsibility: a case study in eastern Styria, Austria

This paper presents a case study about the perception of landslide risk. Following a major set of landslides in the eastern part of Austria in June 2009, we surveyed local experts, residents who had suffered losses from the landslides, and others living in the affected communities. Overall, the risk perception was significantly higher among those who had been personally affected by a landslide, had knowledge of the geology in the study region, had been affected by another natural hazard, or spent a lot of time outdoors and in touch with nature. Non-experts viewed natural factors as the main causes for the occurrence of landslides, while experts viewed anthropogenic factors as more important. Likewise, non-experts placed a greater emphasis on hard measures (such as retaining walls) to reduce the risk, whereas the experts tended to focus on better information and land-use planning. In terms of responsibility for mitigative actions, a majority of inhabitants believed that public authorities should undertake most of the costs, whereby those who had personal experience with landslides were more likely to favor the government paying for it.

Trends of stage, grade, histology and tumour necrosis in renal cell carcinoma in a European centre surgical series from 1984 to 2010

Aims To analyse renal cell carcinoma (RCC) stage, grade, histology and necrosis migration in a large European centre series over the last 27 years. Methods The pathology reports of 2739 consecutive patients with RCC who underwent nephrectomy from 1984 to 2010 at the institution of the authors were systematically re-evaluated. Patients were pooled into five time groups according to the date of surgery: group 1: 1984–1989, group 2: 1990–1994, group 3: 1995–1999, group 4: 2000–2004 and group 5: 2005–2010, respectively. Changes in pT categories according to WHO 2010 classification, tumour grade, histological subtype and presence of tumour necrosis (TN) were evaluated. Results Small pT1a tumours were found in 62/485 (12.8%) and 312/639 (48.8%) patients in groups 1 and 5, respectively (p<0.001). Advanced tumour stages (pT3a-4) were found in 306/485 (63.1%) and 171/639 (26.8%) patients in groups 1 and 5, respectively (p<0.001). The number of grade 3/4 tumours increased from 62/485 (12.7%) and 130/639 (20.3%) in groups 1 and 5, respectively, whereas the number of grade 1 tumours decreased over time (p<0.001). There has been a significant histological migration for the chromophobe subtype from 1.1% to 4.3% (p=0.002). The frequency of the presence TN decreased from 41.7% in group 1 to 32.7% in group 5 (p<0.001). Conclusions In contrast to data from Australia but similar to data from US cohorts, a statistically significant stage migration towards small RCCs was observed in this European cohort. Significant changes in tumour grade, histological subtype and TN were also observed.

The elevated pre‐operative plasma fibrinogen level is an independent negative prognostic factor for cancer‐specific, disease‐free and overall survival in soft‐tissue sarcoma patients

Accumulating evidence indicates an important pathophysiological role of fibrinogen on tumor cell progression and metastases in different types of cancer. The aim of the present study was to evaluate the prognostic relevance of pre‐operative fibrinogen levels on clinical outcome in a large cohort of STS patients.

Neutrophil/Lymphocyte ratio has no predictive or prognostic value in breast cancer patients undergoing preoperative systemic therapy

BackgroundThe primary goal of preoperative systemic treatment (PST) in patients with breast cancer is downsizing of tumors to enhance the rate of breast conserving surgery. Additionally, preoperative systemic treatment offers the possibility to assess for chemosensitivity of early stage disease. In various cancers the prognostic value of neutrophil/lymphocyte ratio (NLR) was demonstrated, indicating that high NLR determines worse prognosis of the patients. The goal of our study was to evaluate the predictive and prognostic value of NLR in early stage breast cancer patients undergoing PST.Methods247 female patients with histologically proven breast cancer were analysed in this retrospective analysis. The NLR before the initiation of PST was documented. Histopathological response in surgically removed specimens was evaluated using a modified Sinn regression score and the pCR defined as no invasive tumor in primary tumor and lymph nodes. NLR was correlated with response to PST and disease free survival.ResultsPST was categorized into five groups (anthracycline containing, anthracycline and taxane containing, taxane containing, hormone treatment and other chemotherapies). pCR rate was defined as no invasive rest of tumor either in primary tumor or (ypT0 = Sinn) or in primary tumor and in lymph nodes (ypT0isypN0). Median NLR in patients without any invasive tumor rest was significantly higher than in patients either with some invasive tumor rest or not responding to chemotherapy. Despite this primary difference, the results were not stable across the analysed treatment groups particularly in the group with highest pCR rates (taxane and anthracycline treatment). Further, no association with disease free survival could be observed.ConclusionsAlthough there was a reverse trend with the higher NLR prior to systemic treatment in patients who achieved pCR, we could not demonstrate predictive or prognostic value of NLR in the cohort of early stage breast cancer patients treated with PST.

Accuracy of commercial kits and published primer pairs for the detection of periodontopathogens

ObjectivesDespite the input of microbiome research, a group of 20 bacteria continues to be the focus of periodontal diagnostics and therapy. The aim of this study was to compare three commercial kits and laboratory-developed primer pairs for effectiveness in detecting such periodontopathogens.Materials and methodsFourteen bacterial mock communities, consisting of 16 randomly assembled bacterial strains, were used as reference standard for testing kits and primers. Extracted DNA from mock communities was analyzed by PCR in-house with specific primers and forwarded for analysis to the manufacturer’s laboratory of each of the following kits: ParoCheck®Kit 20, micro-IDent®plus11, and Carpegen® Perio Diagnostik.ResultsThe kits accurately detected Fusobacterium nucleatum, Prevotella intermedia/Prevotella nigrescens, Parvimonas micra, Aggregatibacter actinomycetemcomitans, Campylobacter rectus/showae, Streptococcus mitis, Streptococcus mutans, and Veillonella parvula. The in-house primers for F.nucleatum were highly specific to subtypes of the respective periopathogen. Other primers repeatedly detected oral pathogens not present in the mock communities, indicating reduced specificity.ConclusionsThe commercial kits used in this study are reliable tools to support periodontal diagnostics. Whereas the detection profile of the kits is fixed at a general specificity level, the design of primers can be adjusted to differentiate between highly specific strains. In-house primers are more error-prone. Bacterial mock communities can be established as a reference standard for any similar testing.Clinical relevanceThe tested kits render good results with selected bacterial species. Primers appear to be less useful for routine clinical diagnostics and of limited applicability in research. Basic information about the periodontopathogens identified in this study supports clinical decision-making.

Angiogenic factors in pregnancies of women with antiphospholipid syndrome and systemic lupus erythematosus

OBJECTIVES An imbalance of angiogenic placental factors such as endoglin, soluble fms-like tyrosine kinase 1(sFlt-1) and placental growth factor (PlGF) has been implicated in the pathophysiology of preeclampsia. This study aimed to evaluate serum levels of sFlt-1, PlGF and endoglin in women with primary and secondary antiphospholipid Syndrome (APS) and systemic lupus erythematosus (SLE) longitudinally through pregnancy. MATERIAL AND METHODS Serum levels of sFlt-1, PlGF and endoglin were measured prospectively at 4-week intervals (from gestational weeks 12-36) in 17 women with primary APS (PAPS), 18 women with secondary APS (SAPS), and 23 women with SLE. RESULTS 6/17 (35%) of women with PAPS, 3/18 (17%) of women with SAPS, and 2/23 (9%) of women with SLE developed early-onset preeclampsia. Women who developed preeclampsia had significantly higher mean sFlt-1 and endoglin levels, higher sFlt-1/PlGF ratios, and lower mean PlGF-levels than women who did not. These changes became statistically significant at 12 weeks for sFlt-1, PlGF and endoglin. DISCUSSION Endoglin, sFlt-1 and PlGF are potential early screening parameters for the development of preeclampsia in pregnant women with autoimmune diseases like APS and SLE.