Armin Gerger

Increased neutrophil-lymphocyte ratio is a poor prognostic factor in patients with primary operable and inoperable pancreatic cancer

Background:The neutrophil-lymphocyte ratio (NLR) has been proposed as an indicator of systemic inflammatory response. Previous findings from small-scale studies revealed conflicting results about its independent prognostic significance with regard to different clinical end points in pancreatic cancer (PC) patients. Therefore, the aim of our study was the external validation of the prognostic significance of NLR in a large cohort of PC patients.Methods:Data from 371 consecutive PC patients, treated between 2004 and 2010 at a single centre, were evaluated retrospectively. The whole cohort was stratified into two groups according to the treatment modality. Group 1 comprised 261 patients with inoperable PC at diagnosis and group 2 comprised 110 patients with surgically resected PC. Cancer-specific survival (CSS) was assessed using the Kaplan–Meier method. To evaluate the independent prognostic significance of the NLR, the modified Glasgow prognostic score (mGPS) and the platelet-lymphocyte ratio univariate and multivariate Cox regression models were applied.Results:Multivariate analysis identified increased NLR as an independent prognostic factor for inoperable PC patients (hazard ratio (HR)=2.53, confidence interval (CI)=1.64–3.91, P<0.001) and surgically resected PC patients (HR=1.61, CI=1.02–2.53, P=0.039). In inoperable PC patients, the mGPS was associated with poor CSS only in univariate analysis (HR=1.44, CI=1.04–1.98).Conclusion:Risk prediction for cancer-related end points using NLR does add independent prognostic information to other well-established prognostic factors in patients with PC, regardless of the undergoing therapeutic modality. Thus, the NLR should be considered for future individual risk assessment in patients with PC.

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 preoperative lymphocyte to monocyte ratio predicts clinical outcome in patients with stage III colon cancer

Background:Inflammation has a critical role in the pathogenesis and progression of cancer. The lymphocyte to monocyte ratio (LMR) could be shown to be prognostic in haematologic neoplasia. In this study, we analysed the LMR with clinical outcome in stage II and III colon cancer patients.Methods:Three hundred and seventy-two patients with stage II and III colon cancer were included in this retrospective study. Kaplan–Meier curves and multivariate Cox-regression analyses were calculated for time to recurrence (TTR) and overall survival (OS).Results:Including all patients, the elevated preoperative LMR was significantly associated with increased TTR and OS in multivariate analysis (HR: 0.47, 95%CI: 0.29–0.76, P=0.002; HR: 0.51, 95%CI: 0.31–0.83, P=0.007; respectively). In subanalyses, the association was limited to patients with stage III (HR: 0.40, 95%CI: 0.22–0.72, P=0.002), in contrast to patients with stage II (HR: 0.40, 95%CI: 0.28–1.66, P=0.397). When the subgroup of patients with ‘high-risk’ LMR⩽2.83 was analysed, no benefit of adjuvant 5-FU-based chemotherapy could be found (HR: 0.99; 95%CI: 0.60–1.63; P=0.953).Conclusion:The LMR might be an independent prognostic marker for TTR in stage III colon cancer patients. Our results further suggest that high-risk patients based on the LMR do not benefit from adjuvant chemotherapy. Independent validation of our findings is warranted.

Changes in Colorectal Carcinoma Genomes under Anti-EGFR Therapy Identified by Whole-Genome Plasma DNA Sequencing

Monoclonal antibodies targeting the Epidermal Growth Factor Receptor (EGFR), such as cetuximab and panitumumab, have evolved to important therapeutic options in metastatic colorectal cancer (CRC). However, almost all patients with clinical response to anti-EGFR therapies show disease progression within a few months and little is known about mechanism and timing of resistance evolution. Here we analyzed plasma DNA from ten patients treated with anti-EGFR therapy by whole genome sequencing (plasma-Seq) and ultra-sensitive deep sequencing of genes associated with resistance to anti-EGFR treatment such as KRAS, BRAF, PIK3CA, and EGFR. Surprisingly, we observed that the development of resistance to anti-EGFR therapies was associated with acquired gains of KRAS in four patients (40%), which occurred either as novel focal amplifications (n = 3) or as high level polysomy of 12p (n = 1). In addition, we observed focal amplifications of other genes recently shown to be involved in acquired resistance to anti-EGFR therapies, such as MET (n = 2) and ERBB2 (n = 1). Overrepresentation of the EGFR gene was associated with a good initial anti-EGFR efficacy. Overall, we identified predictive biomarkers associated with anti-EGFR efficacy in seven patients (70%), which correlated well with treatment response. In contrast, ultra-sensitive deep sequencing of KRAS, BRAF, PIK3CA, and EGFR did not reveal the occurrence of novel, acquired mutations. Thus, plasma-Seq enables the identification of novel mutant clones and may therefore facilitate early adjustments of therapies that may delay or prevent disease progression.

Platelet-to-Lymphocyte Ratio: A Novel Marker for Critical Limb Ischemia in Peripheral Arterial Occlusive Disease Patients

Background Platelet-to-Lymphocyte Ratio (PLR) is an easily applicable blood test. An elevated PLR has been associated with poor prognosis in patients with different oncologic disorder. As platelets play a key role in atherosclerosis and atherothrombosis, we investigated PLR and its association with critical limb ischemia (CLI) and other vascular endpoints in peripheral arterial occlusive disease (PAOD) patients. Methods and Findings We evaluated 2121 PAOD patients treated at our institution from 2005 to 2010. PLR was calculated and the cohort was categorized into tertiles according to the PLR. An optimal cut-off value for the continuous PLR was calculated by applying a receiver operating curve analysis to discriminate between CLI and non-CLI. In our cohort occurrence of CLI significantly increased with an increase in PLR. As an optimal cut-off value, a PLR of 150 was identified. Two groups were categorized, one containing 1228 patients (PLR≤150) and a second group with 893 patients (PLR>150). CLI was more frequent in PLR>150 patients (410(45.9%)) compared to PLR≤150 patients (270(22.0%)) (p<0.001), as was prior myocardial infarction (51(5.7%) vs. 42(3.5%), p = 0.02). Regarding inflammatory parameters, C-reactive protein (median 7.0 mg/l (3.0–24.25) vs. median 5.0 mg/l (2.0–10.0)) and fibrinogen (median 457 mg/dl (359.0–583.0) vs. 372 mg/dl (317.25–455.75)) also significantly differed in the two patient groups (both p<0.001). Finally, a PLR>150 was associated with an OR of 1.9 (95%CI 1.7–2.1) for CLI even after adjustment for other well-established vascular risk factors. Conclusions An increased PLR is significantly associated with patients at high risk for CLI and other cardiovascular endpoints. The PLR is a broadly available and cheap marker, which could be used to highlight patients at high risk for vascular endpoints.

A derived neutrophil to lymphocyte ratio predicts clinical outcome in stage II and III colon cancer patients

Background:Inflammation has a critical role in the pathogenesis and progression of cancer. Recently, the derived neutrophil to lymphocyte ratio (absolute count of neutrophils divided by the absolute white cell count minus the absolute count of neutrophils; dNLR) has been shown to influence clinical outcome in various cancer entities. In this study, we analysed the dNLR with clinical outcome in stage II and III colon cancer patients.Methods:Three-hundred and seventy-two patients with stage II and III colon cancer were included in this retrospective study. Kaplan–Meier curves and multivariate Cox proportion analyses were calculated for time to recurrence (TTR) and overall survival (OS).Results:In univariate analysis, the elevated preoperative dNLR was significantly associated with decreased TTR (hazard ratio (HR) 2.38, 95% confidence interval (CI) 1.57–3.6, P<0.001) and remained significant in multivariate analysis. Patients with dNLR >3 had a median TTR of 83 months, and patients with dNLR ⩽3 showed a median TTR of 132 months. In OS analysis, a dNLR >2.2 was significantly associated with decreased OS in univariate (HR 1.85, 95% CI 1.11–3.08, P=0.018) and multivariate analysis. Patients with dNLR >2.2 showed a median OS of 121 months, and patients with dNLR ⩽2.2 had a median OS of 147 months.Conclusion:The dNLR may be an independent prognostic marker for TTR and OS in patients with stage II and III colon cancer. Independent validation of our findings is warranted.

The elevated preoperative platelet-to-lymphocyte ratio predicts poor prognosis in breast cancer patients

Background:The elevation of the platelet-to-lymphocyte ratio (PLR), an easily applicable blood test based on platelet and lymphocyte counts has been associated with poor prognosis in patients with different types of cancer. The present study was aimed to investigate the prognostic significance of the preoperative PLR in a large cohort of breast cancer patients.Methods:Data from 793 consecutive non-metastatic breast cancer patients, treated between 1999 and 2004, were evaluated retrospectively. The optimal cutoff values for the PLR were calculated using receiver operating curve analysis. Cancer-specific survival (CSS), overall survival (OS) as well as distant metastasis-free survival (DMFS) were assessed using the Kaplan–Meier method. To evaluate the independent prognostic significance of PLR, multivariable Cox regression models were applied for all three different end points.Results:Univariable analysis revealed a significant association between the elevated preoperative PLR and CSS (hazard ratio (HR): 2.75, 95% confidence interval (CI): 1.57–4.83, P<0.001) that remained statistically significant in multivariable analysis (HR: 2.03, 95% CI: 1.03–4.02, P=0.042). An increased PLR was also significantly associated with decreased OS in univariable (HR: 2.45, 95% CI: 1.43–4.20, P=0.001) and in multivariable analysis (HR: 1.92, 95% CI: 1.01–3.67, P=0.047). Furthermore, univariable analysis showed a significant impact of increased PLR on DMFS (HR: 2.02, 95% CI: 1.18–3.44, P=0.010). Subgroup analysis revealed significant associations of the elevated PLR on the primary end point CSS for all breast cancer subtypes. This association retained its significance in multivariable analysis in patients with luminal B tumours (HR: 2.538, 95% CI: 1.043–6.177, P=0.040).Conclusions:In this study, we identified the preoperative PLR as an independent prognostic marker for survival in breast cancer patients. Independent validation of our findings is needed.

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.

Validation of C-reactive protein levels as a prognostic indicator for survival in a large cohort of pancreatic cancer patients

Background:Recent evidence indicates that the host inflammatory response has an important role in the tumour progression. Elevated C-reactive protein (CRP) levels have been previously associated with poor prognosis in several cancer types including small-scale studies in pancreatic cancer (PC) patients. The purpose of the present study was to validate the prognostic impact of plasma CRP levels at date of diagnosis on cancer-specific survival (CSS) in a large cohort of PC patients.Methods:Data from 474 consecutive patients with adenocarcinoma of the pancreas, treated between 2004 and 2012 at a single centre, were evaluated retrospectively. CSS was analysed using the Kaplan–Meier method. To evaluate the prognostic significance of plasma CRP levels, univariate and multivariate Cox analyses were applied.Results:High plasma CRP levels at diagnosis were significantly associated with well-established prognostic factors, including high tumour stage and tumour grade and the administration of chemotherapy (P<0.05). In univariate analysis, we observed that a high plasma CRP level was a consistent factor for poor CSS in PC patients (hazard ratio (HR)=2.21; 95% confidence interval (CI)=1.68–2.92, P<0.001). In multivariate analysis, tumour stage, grade, administration of chemotherapy, a high neutrophil–lymphocyte ratio and the highest quartile of CRP levels (HR=1.60, 95% CI=1.16–2.21; P=0.005) were identified as independent prognostic factors in PC patients.Conclusion:In conclusion, we confirmed a significant association of elevated CRP levels with poor clinical outcome in PC patients. Our results indicate that the plasma CRP level might represent a useful marker for patient stratification in PC management.

Elevated preoperative neutrophil/lymphocyte ratio is associated with poor prognosis in soft-tissue sarcoma patients.

Background:Recent data indicate that tumour microenvironment, which is influenced by inflammatory cells, has a crucial role in cancer progression and clinical outcome of patients. In the present study, we investigated the prognostic relevance of preoperative neutrophil/lymphocyte (N/L) ratio on time to tumour recurrence (TTR) and overall survival (OS) in soft-tissue sarcoma (STS) patients who underwent curative surgical resection.Methods:In all, 260 STS patients were included in this retrospective study. Kaplan–Meier curves and multivariate Cox proportional models were calculated for TTR and OS.Results:In univariate analysis, elevated N/L ratio was significantly associated with decreased TTR (hazard ratio (HR), 2.32; 95% confidence interval (CI), 1.30–4.14; P=0.005) and remained significant in the multivariate analysis (HR, 1.98; 95%CI, 1.05–3.71; P=0.035). Patients with elevated N/L ratio showed a median TTR of 77.9 months. In contrast, patients with low N/L ratio had a median TTR of 99.1 months. Regarding OS, elevated N/L ratio was also significantly associated with decreased survival in univariate analysis (HR, 2.90; 95%CI, 1.82–4.61; P=0.001) and remained significant in multivariate analysis (HR, 1.88; 95%CI, 1.14–3.12; P=0.014).Conclusion:In conclusion, our findings suggest that an elevated preoperative N/L ratio predicts poor clinical outcome in STS patients and may serve as a cost-effective and broadly available independent prognostic biomarker.