THE VALUE OF NEW INFLAMMATORY PARAMETERS IN MALIGNANT MESOTHELIOMA PROGNOSIS

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1 Acta Medica Mediterranea, 2015, 31: 9 THE VALUE OF NEW INFLAMMATORY PARAMETERS IN MALIGNANT MESOTHELIOMA PROGNOSIS ABDULLAH CETIN TANRIKULU A, ICLAL HOCANLI A, AHMET YILMAZ B, FATIH METEROGLU C, MAHŞUK TAYLAN A, MELIKE DEMIR A, HALIDE KAYA A, ABDURRAHMAN ABAKAY A, OZLEM ABAKAY A, HADICE SELIMOGLU ŞEN A, M ALI KAPLAN D a Department of Chest Diseases Faculty of Medicine Dicle University Diyarbakir - b Department of Family Medicine Faculty of medicine Dicle University Diyarbakir - c Department of Thoracic Surgery Faculty of Medicine Dicle University Diyarbakir, - d Department of Oncology Faculty of Medicine Dicle University Diyarbakir, Turkey ABSTRACT Aim: Malignant mesothelioma (MM) has a poor prognosis. Inflammation is associated with MM prognosis and symptoms. Several inflammatory markers were investigated to estimate MM prognosis. We investigated the role of available inflammatory index and markers for MM prognosis. We developed the advanced mesothelioma index (AMI) to assess the degree of inflammation in MM. Materials and methods: We performed a retrospective study of 202 MM patients (116, male, 86 female) evaluated at Dicle University. Demographic parameters and laboratory data were collected. The AMI was calculated as Body Mass Index*serum albumin value (g/dl)/ platelet-to-lymphocyte ratio. Results: The mean age of patients was years. A total of 135 (66.8%) patients showed epithelial-type histopathological subtypes and 177 patients had pleural MM. The mean survival time was 13.1±11.5 months in the all MM patients. Twenty-four potential prognostic factors were associated with a poor outcome and then analyzed in the univariate analysis. Eighteen of them were definitely associated with a poor prognosis. These 18 potential prognostic factors were analyzed in the multivariate analysis. Based on the results of the multivariate analysis, only patients with an AMI<0.5 had an associated poor prognosis. An AMI<0.5 increased the mortality rate by Furthermore, low AMI was associated with other bad inflammatory markers (such as high platelet count, high C reactive protein level, low Body Mass Index, low albumin and low hemoglobin). Conclusion: Our findings indicate that the AMI can be used to assess the degree of systemic inflammation. Key words: Malignant mesothelioma, inflammation, advanced mesothelioma index. Received May 18, 2014; Accepted September 02, 2014 Introduction Malignant Pleural Mesothelioma (MPM) is a rare cancer, but bad prognosis and aggressive tumor originated from pleural mesothelium with limited knowledge of its natural history (1). Malignant Mesothelioma (MM) is common in the Southeast region of Turkey because of environmental asbestos exposure (2-4). Several treatment regimens have been used in MM patients. However, the disease still has a bad prognosis and means survival time is reportedly almost 12 months (4-6). The European Organization for Research and Treatment of Cancer (EORTC) and the Cancer and Leukemia Group B (CALGB) devised two prognostic scoring systems for use in patients with MM (7,8). These scoring systems are based on several signs and symptoms of MM. These systems are not used routinely in MM prognosis because they are relatively unwieldy, time consuming, and require costly equipment. Therefore, in patients with MM, parameters that are useful, easy and inexpensive to measure are needed for predicting prognosis. Furthermore, these parameters may be a useful to estimate the occurrence of MM after asbestos exposure and to predict treatment options and outcomes. The local and systemic inflammatory response is increased in solid tumors and is associated with the patient s prognosis (9-11). Inflammation plays a significant role in the development of MM.

2 10 Abdullah Cetin Tanrikulu, Abdurrahman Abakay et Al Moreover, during the MM period, patients show signs of increased inflammatory responses such as fever, sweats, and weight loss( 12,13). Recent studies have identified the neutrophillymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR) as a measure of systemic inflammation; they are relatively inexpensive and readily obtainable reproducible markers that serve as independent prognostic factors in MM patients (14-16). Another inflammatory parameter, the Modified Glasgow Prognostic score (mgps) was defined as increased C - reactive protein (CRP) and hypoalbuminemia (16). The red cell distribution width (RDW) is a parameter that measures the variability in the size of circulating erythrocytes (17). It is a routinely measured hemogram. The mean platelet volume (MPV) reflects the platelet size, which is correlated with platelet function and activation. A high MPV predicts platelet activity and the intensity of inflammation (18). Yao et al. investigated the role of prognostic nutritional index (PNI) in MM survival (19). In one study advanced lung cancer inflammation index was defined to investigate lung cancer prognosis (20) and this parameter was associated with poor prognosis. This association was no investigated in MM patients. Based on our knowledge, this is first study that compares new inflammatory markers that affect MM prognosis. The goal of this study was to investigate the relationship between the potential inflammatory prognostic indicators such as NLR, PLR, MPV, mgps, RDW and MM prognosis. For this purpose we used the advanced lung cancer inflammation index and we developed advanced mesothelioma index (AMI), which is a basic index based on the following parameters: serum albumin, PLR, weight and height. Materials and methods This retrospective study included 235 MM patients who were diagnosed and treated in Dicle University Hospital, between January 2003 and December The local ethics committee approved the study protocol. Thirty-three patients were excluded from the study because of lack of data. Additional seven were excluded due to active infection, leaving a study group of 202 patients. MM was confirmed by histopathological examination in all the patients. Histochemical or immunohistochemical stains were used if necessary. Demographic data, asbestos exposure type and time, histopathological subtype of MM, and basic laboratory parameters were obtained from the patients files. We used Butchart staging system in our patients because of we could not perform thoracoscopy to all patient (21). Details on potential prognostic parameters measured at the time of diagnosis were also obtained from the patients files. Lactate Dehydrogenase (LDH) level was determined from the serum using heparin and citrate and an autoanalyzer. LDH level was measured in tubes with K2 ethylenediaminetetra-acetic acid EDTA. Hemogram parameters (including WBC, hemoglobin, platelet count, neutrophil and lymphocyte counts) were measured using Cell-Dyn Complete blood cell count was measured using a Cell-Dyn Assays were performed within 1 hourr of collection, after centrifugation (centrifugation was applied at room temperature) of the paired specimens at 1500 g for 10 min. Inflammatory indexes were defined for MM patients based on parameters from patients files which were obtained at the time of diagnosis. The NLR was determined by dividing the absolute neutrophil count by the absolute lymphocyte count. The PLR was determined by dividing the absolute platelet count by the absolute lymphocyte count. The mgps was calculated as previously described (16). Patients with both a normal serum albumin (>3.5 g/dl) and CRP (<10 mg/dl) were given a score of 0. Patients who had only one of these abnormalities were given a score of 1, whereas those with both abnormal CRP and albumin were given a score of 2. PNI was calculated following formula: 10*serum albumin value (g/dl) *peripheral lymphocyte count (per mm3) according previous study (19). Advanced inflammation index (AII) was calculated following formula: Body Mass Index (BMI) * serum albumin value (g/dl) / NLR according previous study (20). We defined Advanced mesothelioma index (AMI) as the following: AMI = BMI * serum albumin value (g/dl) / PLR. The following potential prognostic parameters were employed and median value of biochemical parameters were used to prognostic calculation (Table 1).

3 The value of new inflammatory parameters in malignant mesothelioma prognosis 11 Features N % Number of Patients Gender Male Female Exposure of Asbestos Symptoms at Diagnosis Dyspnea Chest Pain Weight Loss Sub-Type of MM Pleural Peritoneal Pericardial Sub-Type of MM Epithelial Mixed 4 2 Unidentified Sarcomatous 6 3 Stage of Disease (n=134) Stage Stage Median Value of Platelet (n=202) Median Value of age (n=202) Median Value of RDW (n=201) Median Value of MPV Median Value of albumin Median Value of CRP (n=153) Median Value of pni score (n=198) Median Value of WBC (n=202) Median Value of hemoglobin (n=202) Median Value of LDH (n=195) Median Value of NLR Median Value of PLR Advanced inflammation index (n=116) Advanced mesothelioma index (n=116) Table 1: Demographic features of mesothelioma patients. 0.5 Some of these, age 60 and <60, gender, male or female, histopathological subtype, epithelial or non-epithelial, type of mesothelioma pleural and other, median symptom time before diagnosis 3 months and < 3 months, dyspnea yes or no, chest pain yes or no, weight loss yes or no, Stage 1-2 and 3-4, chemotherapy received yes or no and mgps 0, 1 and 2. Statistical analysis The mean values and the standard deviation (SD) were measured for the continuous variables. For continuous variables we used independent t test and for categorical variables we used the X2 test. The duration of survival and the median and mean event times with 95% confidence interval (CI) were estimated according to the Kaplan-Meier method. The duration of survival was defined as the period between the time of diagnosis and the time of death. If patients were still alive, survival was defined as the period between the time of diagnosis until 31 December The proportional hazards regression model with stratification for the clinical trial was used for both the univariate and the multivariate analyses. The univariate analyses examined the prognostic importance of all the aforementioned factors. The Cox proportional hazards model was used to examine the variables. A two-sided test was used, with a 0.05 level of significance. Comparisons of overall survival were made using two-tailed log-rank tests. Only variables with p-values of <0.1 in the univariate analysis were included in the final model for the multivariate analysis. In the Cox regression analysis, the backward conditional method was used. P value <.05 was significant. In the study group, 32 were alive at the time of this study. Statistical analyses were performed using SPSS statistical program version 15. Results A total of 202 MM patients met the inclusion criteria and were included in this study. The mean age of MM patients was ± years. A total of 116 (57.4%) patients were male, and 86 (42.6%) were female. Environmental asbestos exposure was proved in 122 (60.4%) patients, and the mean exposure time was 31.1 years. A total of 135 (66.8 %) patients showed epithelial-type histopathological subtypes and 177 patients had the pleural subtype of MM (Table 1).

4 12 Abdullah Cetin Tanrikulu, Abdurrahman Abakay et Al Dyspnea is the most frequent seen symptom in MM patients. The mean survival time was 13.1 ± 11.5 months in the all MM patients. Patients who received chemotherapy survived month. Patients who did not receive chemotherapy survived 10 months; this difference was statistically significant (p = 0.002) (Table 2). Median Value of NLR was 2.89 and median value of AMI was 0.50 (Table 1). Twenty-four potential prognostic factors associated with a poor outcome were calculated in the univariate analysis and 18 potential prognostic factors were associated with a poor prognosis (Table 2). These 18 potential prognostic factors were also analyzed in the multivariate analysis. The results of multivariate analysis demonstrated that an AMI < 0.5 was associated with poor prognosis of MM in patients. Patients with an AMI < 0.5 had a fold increased mortality rate (Table 2). Figure 1 shows the association between AMI and MM prognosis. Figure 2 shows the association between NLR and MM prognosis. The results of the multivariate analysis demonstrated a more significant relationship between AMI and poor MM prognosis than other inflammatory parameters (NLR, PLR, PNI index and mgps). Figure 1: Kaplan-Meier survival curves according to AMI (p<0.001) (n= 116). Figure 2: Kaplan-Meier survival curves according to NLR (p<0.001) (n= 200). Table 2: Univariate and multivariate analysis for potential prognostic parameters in mesothelioma patients. O: Observed Death Number; N: Total Patient Number; +: Median Survival (Months); HR: Hazard Ratio RDW: Red cell distribution width; MPV: Mean platelet volume PLR: platelet-to-lymphocyte ratio; NLR: neutrophil-lymphocyte ratio LDH: Lactate dehydrogenase; WBC: White blood cell CRP: C- Reactive Protein; LDH: Lactate Dehydrogenase GPS: Glasgow Prognostic Score

5 The value of new inflammatory parameters in malignant mesothelioma prognosis 13 Furthermore, low AMI was associated high platelet count, high CRP level; high PLR, high RDW and high NLR and low AMI associated low AII, low PNI score, low MPV, low Body Mass Index, low albumin and low hemoglobin (Table 3). AMI was associated with other negative inflammatory indexes. AMI correlated AII (p < 0.001). Discussion Previous studies focused on developing a parameter that had the ability to accurately predict MM prognosis. Several models were defined, using measurements that included: symptoms, pathologic factors, stage and some blood parameters. Unfortunately, none of these methods is considerable an ideal parameters. There is no consensus about an optimal prognostic system. Inexpensive and easily detected prognostic parameters have not been developed. EORTC and CALGB analyzed large numbers of patients enrolled in MM studies and identified the following poor prognostic factors for MM (7,8): nonepithelioid histology, bad performance status, presence of chest pain, age older than 75 years, male gender, WBC /L or greater, platelet number over /μL, and an LDH level greater than 500 IU/L. The local and systemic inflammatory response is increased in solid tumors and is associated with the patient survival (9-11). Several studies investigated the role of inflammatory parameters such as the NLR and the PLR in the prognosis of MM (14-16,22). Many studies have reported that the mortality is increased fold in MM patients with an NLR 3 and that this difference is statistically significant (15,22). Using univariate analysis, we found high NLR was associated with poor prognosis. A possible explanation for this finding is that MM patients with more advanced disease at the time of diagnosis may have a more excessive systemic inflammatory response and therefore a higher NLR. In hemogram, the RDW is increased in several inflammatory diseases, but the association between a high RDW and MM prognosis has not been widely investigated. In one investigation of pulmonary embolisms, an RDW greater than 15% was found to be a prognostic parameter in multivariate analysis, and an RDW greater than 15% increased the mortality 1.2-fold (23). We found that high RDW was associated with poor prognosis. In one study, which used univariate analysis, mgps was associated with poor prognosis in MM patients (16). We also found that high mgps was associated with poor prognosis. Yao et al found PNI was associated with poor prognosis of MM (19), data that we confirmed in our study. These parameters were included: hypoalbuminemia, mgps, ALI and AMI. We believe that hypoalbuminemia is a good predictor of prognosis. In one study, advanced lung cancer inflammation index was used to investigate lung cancer prognosis (20) and this parameter was associated with poor prognosis. Hypoalbuminemia is associated with poor prognosis of MM. In one study, albumin < 3.5 g/l was independently associated with a decrease in survival (24). Both hypoalbuminemia and weight loss are related to ongoing systemic inflammation (25). PLR was associated with poor prognosis (16). Low BMI was found to associate with poor cancer prognosis (26). Variable advanced mesothelioma index < 0.5 Mean advanced mesothelioma index 0.5 Mean Age (years) Platelet count <0.001 WBC count Serum LDH level Hemoglobin level <0.001 Albumin <0.001 CRP Body Mass Index <0.001 PLR <0.001 RDW MPV NLR <0.001 PNI score <0.001 Advanced inflammation index <0.001 Table 3: Mesothelioma patients characteristics based on advanced mesothelioma index groups. The AMI was developed using these markers as a simple index that can be easily obtained, calculated and related to inflammatory markers (weight, height, albumin and PLR). Among the twenty-four potential P

6 14 Abdullah Cetin Tanrikulu, Abdurrahman Abakay et Al prognostic factors, only AMI was related to prognosis in multivariate analysis. AMI < 0.5 is an independent factor for MM prognosis. Additionally, AMI is related to other inflammatory markers (Table 3). The pathological role of chronic inflammation in the development of MM is already known (27). Based on our results, inflammatory-based biomarkers may be predictive of survival. The AMI may be viewed as an inexpensive predictor of MM prognosis at the time of diagnosis. Our study was limited due to its retrospective nature. Important information such as patients performance status disease were unavailable. The AMI can be used to assess the degree of systemic inflammation and high systemic inflammation, as an AMI < 0.5 was independently associated with poor survival. This is a useful marker, given the high prevalence and the prognostic importance of increased levels. 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