Nomograms for predicting prognostic value of inflammatory biomarkers in colorectal cancer patients after radical resection

Increasing evidence indicates that inflammation plays a vital role in tumorigenesis and progression. However, the prognostic value of inflammatory biomarkers in colorectal cancer (CRC) has not been established. In this study, a retrospective analysis was conducted in patients with CRC in Fudan University Shanghai Cancer Center (FUSCC) between April 1, 2007 and April 30, 2014, and 5,336 patients were identified eligible. Neutrophil‐to‐lymphocyte ratio (NLR), platelet‐to‐lymphocyte ratio (PLR), lymphocyte‐to‐monocyte ratio (LMR), and albumin/globulin ratio (AGR) were analyzed. Kaplan‐Meier analysis was used to calculate the 5‐year overall survival (OS) and disease‐free survival (DFS). Cox regression analysis was performed to assess the prognostic factors. Nomograms were established to predict OS and DFS, and Harrell's concordance index (c‐index) was adopted to evaluate prediction accuracy. As results, the 5‐year OS was 79.2% and the 5‐year DFS was 56.0% in the cohort. Patients were stratified into 2 groups by NLR (≤2.72 and >2.72), PLR (≤219.00 and >219.00), LMR (≤2.83 and >2.83) and AGR (<1.50 and ≥1.50). Patients with NLR > 2.72, PLR > 219.00, LMR ≤ 2.83 and AGR < 1.50 were significantly associated with decreased OS and DFS (p < 0.001). Multivariate analysis indicated that NLR, LMR and AGR were independent factors of OS (p = 0.047, p = 0.008 and p < 0.001, respectively) and DFS (p = 0.009, p < 0.001 and p = 0.008, respectively). In addition, nomograms on OS and DFS were established according to all significant factors, and c‐indexes were 0.765 (95% CI: 0.744–0.785) and 0.735 (95% CI: 0.721–0.749), respectively. Nomograms based on OS and DFS can be recommended as practical models to evaluate prognosis for CRC patients.     

Usefulness of lymphocyte-to-monocyte,neutrophil-to-monocyte and neutrophil-to-lymphocyte ratios as prognostic markers in breast cancer patients treated with neoadjuvant chemotherapy

Background

Nowadays, neoadjuvant chemotherapy (nCT) in breast cancer is more and more standardized, not only in advanced tumours but also in those for which there is an attempt to achieve breast-conserving surgery. In literature, we can find evidences of the relationship between several types of tumours and systemic inflammatory response. Our objective is to analyse the prognostic value of blood parameters (lymphocytes, neutrophils, monocytes, lymphocyte-to-monocyte ratio (LMR), neutrophil-to-monocyte ratio (NMR) and neutrophil-to-lymphocyte ratio (NLR) in breast cancer (BC) patients treated with nCT.

Methods

A retrospective cohort of 150 breast cancer patients treated with nCT and subsequently with surgery was analysed. Data about the patients, histology, response to chemotherapy and peripheral blood values of lymphocytes, monocytes and neutrophils was collected, and used to calculate the LMR, NMR and NLR. Univariate and multivariate analyses were performed for the variables to see the relationship of the ratios to disease-free survival (DFS) and overall survival (OS).

Results

Patients with high LMR (≥5.46) and low NLR (<3.33) were associated with a lower percentage of relapse (P = 0.048 and P = 0.015, respectively) and, above all, NLR was associated with a better survival (P = 0.024), being those factors that predict a good progress.

Conclusion

High LMR and low NLR can be considered as favourable prognostic factors in BC patients treated with nCT.

     

The relationship between blood IL‐12p40 level and melanoma progression

Cytokines such as Interleukin (IL)?12p70 (“IL‐12”) and IL‐23 can influence tumor progression. We tested the hypothesis that blood levels of IL‐12p40, the common subunit of both cytokines, are associated with melanoma progression. Blood from 2,048 white melanoma patients were collected at a single institution between March 1998 and March 2011. Plasma levels of IL‐12p40 were determined for 573 patients (discovery), 249 patients (Validation 1) and 244 patients (Validation 2). Per 10‐unit change of IL‐12p40 level was used to investigate associations with melanoma patient outcome among all patients or among patients with early or advanced stage. Among stage I/II melanoma patients in the pooled data set, after adjustment for sex, age, stage and blood draw time from diagnosis, elevated IL‐12p40 was associated with melanoma recurrence [hazard ratio (HR) = 1.04 per 10‐unit increase in IL‐12p40, 95% CI 1.02–1.06, p = 8.48 × 10^?5]; Elevated IL‐12p40 was also associated with a poorer melanoma specific survival (HR = 1.06, 95% CI 1.03–1.09, p = 3.35 × 10^?5) and overall survival (HR = 1.05, 95% CI 1.03–1.08, p = 8.78×10^?7) in multivariate analysis. Among stage III/IV melanoma patients in the pooled data set, no significant association was detected between elevated IL‐12p40 and overall survival, or with melanoma specific survival, with or without adjustment for the above covariates. Early stage melanoma patients with elevated IL‐12p40 levels are more likely to develop disease recurrence and have a poorer survival. Further investigation with a larger sample size will be needed to determine the role of IL‐12p40 in advanced stage melanoma patients.     

D‐dimers in malignant melanoma: Association with prognosis and dynamic variation in disease progress

Malignant cells elicit a chronic hemostatic activation in disease progress. This procoagulant activity does not only bear a risk for thromboembolism but also facilitates tumor growth and dissemination. An elevated plasma D‐dimer level indicates an activated coagulation and fibrinolysis. In this study, the association of D‐dimer levels with clinicopathological parameters and patients outcome in melanoma was investigated analyzing in total 533 melanoma patients retrospectively. Using the cut‐off point of 0.6 mg/L D‐dimer 145 of the total 533 patients (27.2%) were identified with elevated plasma D‐dimer levels. This increased D‐dimer level positively correlated with tumor thickness (p = 0.0003), lymph node invasion (p = 0.0004) and metastatic state (p <0.0001). To assess the association of D‐dimer levels with progression‐free survival (PFS) and overall survival (OS), long‐rank test and the Cox proportional hazard model was performed. Univariate analyses revealed that elevated D‐dimer levels were significantly associated with decreased PFS (HR:2.89, 95% CI (2.07‐7.56), p < 0.0001) and OS (HR:2.22, 95% CI (1.06‐4.57), p = 0.035). Moreover, multivariate analyses identified elevated D‐dimer levels being associated with poor disease outcome (PFS:HR:2.47, 95% CI (1.23‐4.98), p = 0.012; OS:HR:2.01, 95% CI (0.09‐4.45), p = 0.087). Additionally, D‐dimer levels were significantly increased in terminal stage patients when comparing plasma levels 0‐8 versus 24‐48 weeks before death (p = 0.0003). In summary, this study presents multiple evidence that elevated D‐dimer levels in melanoma patients associate with poor prognosis and therefore plasma levels of D‐dimers could reveal a more aggressive phenotype of melanoma and may guide the management of anti‐melanoma treatment including the concept of an anti‐coagulatory therapy in tumor patients.     

外周血炎性标志物在甲状腺癌中的应用进展

甲状腺癌是内分泌系统最常见的恶性肿瘤,近年来其发病率在世界范围内呈上升趋势,虽然总体治愈率高,但局部复发或远处转移也较常见,另有部分患者因肿瘤组织分化低,疾病进展较快而死亡。免疫反应和炎症反应在肿瘤的发生、发展中起着重要的作用,研究表明外周血中某些炎性细胞的数目及其比值是恶性肿瘤的重要预后因子,如血小板、中性粒细胞、淋巴细胞、单核细胞等。本文就外周血血小板/淋巴细胞比值(PLR)、中性粒细胞/淋巴细胞比值(NLR)、系统免疫炎症指数(SII)、淋巴细胞/单核细胞比值(LMR)及C反应蛋白(CRP)在甲状腺癌中的应用进展作一综述,旨在为甲状腺癌的综合诊疗提供更全面的参考。     

Prognostic significance of preoperative inflammatory response biomarkers in patients undergoing curative thoracoscopic esophagectomy for esophageal squamous cell carcinoma

Background

Recent studies have revealed significant relationships between the lymphocyte-to-monocyte ratio (LMR), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) and survival in various cancers. The purpose of this study was to confirm whether the LMR, NLR, and PLR have prognostic values, independent of clinicopathological criteria, in patients undergoing curative resection for esophageal cancer.

Prognostic impact of perioperative lymphocyte–monocyte ratio in patients with bladder cancer undergoing radical cystectomy

Various systemic inflammatory response biomarkers are associated with oncological outcome. We evaluated the superiority of prognostic predictive accuracy between neutrophil–lymphocyte ratio (NLR) and lymphocyte–monocyte ratio (LMR), and the prognostic significance of their perioperative change in patients with bladder cancer undergoing radical cystectomy (RC). We retrospectively analyzed 302 patients who had undergone RC in four institutions. Comparison of predictive accuracy between NLR and LMR was performed using receiver operating characteristic curve analysis. Overall survival (OS) and cancer-specific survival (CSS) were assessed with the Kaplan–Meier method and Cox regression analysis. Preoperative and postoperative LMR showed higher predictive accuracy for OS than NLR did (p?=?0.034). Applying a cutoff of 3.41, change in perioperative LMR stratified patients into three groups (low, intermediate, and high risk), showing a significant difference in OS and CSS (p?<?0.001, each), and pathological outcomes. Multivariable analyses for OS and CSS showed that poor changes in LMR (high risk) were an independent prognostic factor (hazard ratio 5.70, 95 % confidence interval 3.49–9.32, p?<?0.001; hazard ratio 4.53, 95 % confidence interval 2.63–7.82, p?<?0.001; respectively). Perioperative LMR is significantly associated with survival in patients with bladder cancer after RC, and it is possibly superior to NLR as a prognostic factor.     

Expression and prognostic significance of iNOS in uveal melanoma

Uveal melanoma (UM) is the most common primary intraocular tumor in adults. Disease metastasis occurs in half of the patients and is uniformly fatal despite systemic therapy. Inducible nitric oxide synthase (iNOS) is associated with disease progression in various malignancies including cutaneous melanoma. In this retrospective cohort, we examined the prognostic value of iNOS in UM by performing immunohistochemistry on paraffin‐embedded sections of primary tumors (90 patients) and matched primary and metastatic hepatic tumors (19 patients) with complete histopathological and clinical data. We show that iNOS is expressed in UM (57% of the patients) and high iNOS levels significantly (p = 0.04; hazard ratio (HR) = 2.3) predict disease‐specific survival (DSS) as assessed by Kaplan‐Meier analysis and univariate Cox's proportional hazards regression model. Furthermore, high iNOS expression in the UM primary tissue was significantly associated with metastatic disease and vice versa. Expression of iNOS in hepatic metastases significantly (p = 0.02) predicted a shortened survival as assessed by Kaplan‐Meier analysis. However, iNOS did not appear to be a significant (p = 0.16; HR = 1.9) factor in the multivariate Cox's regression analysis performed together with the clinical parameters tumor diameter, tumor cell type, and tumor location in which only tumor diameter predicted DSS. In conclusion, iNOS predicts DSS in UM and may play a role in disease progression but it is not an independent prognostic factor.     

NLR、LMR和PLR与骨肉瘤预后的关系

目的 探讨术前中性粒细胞/淋巴细胞比值(NLR)、淋巴细胞/单核细胞比值(LMR)、血小板/淋巴细胞比值(PLR)对预测骨肉瘤患者预后的影响.方法 回顾性分析接受同样治疗方案的70例骨肉瘤患者的临床和生存资料,计算出初次确诊为骨肉瘤时的NLR、PLR和LMR,ROC曲线分析NLR、PLR和LMR的AUC值并确定最佳预测...     

Neutrophil-to-lymphocyte ratio after pazopanib treatment predicts response in patients with advanced soft-tissue sarcoma

Background

Pazopanib is a multi-tyrosine kinase inhibitor that is used to treat advanced soft-tissue sarcoma, and its efficacy has been confirmed in several clinical trials, although no clinically useful biomarkers have been identified. In other cancers, the neutrophil-to-lymphocyte ratio (NLR), the platelet-to-lymphocyte ratio (PLR), and the lymphocyte-to-monocyte ratio (LMR) are associated with chemotherapy response and prognosis. Therefore, we aimed to evaluate the associations of pazopanib response with NLR, PLR, and LMR among patients with advanced soft-tissue sarcoma.

Methods

Data regarding NLR, PLR, and LMR were obtained for 25 patients who received pazopanib for soft-tissue sarcoma. The patients were categorized according to their values for NLR (≥3.8 vs. <3.8), PLR (≥230 vs. <230), and LMR (≥2.4 vs. <2.4), and we evaluated the associations of these markers with progression-free survival and overall survival using Kaplan–Meier curves and Cox proportional models.

Results

No significant differences in progression-free survival or overall survival were observed based on the pre-treatment NLR, PLR, and LMR values. However, decreased NLR values after treatment using pazopanib were independently associated with significantly prolonged progression-free survival (hazard ratio: 0.07, p = 0.001) and overall survival (hazard ratio: 0.17, p = 0.0006).

Conclusions

Decreased NLR values after treatment using pazopanib may predict high efficacy and favorable outcomes among patients with advanced soft-tissue sarcoma.

     

The absolute lymphocyte to monocyte ratio is associated with poor prognosis in classical Hodgkin lymphoma patients younger than 60 years of age

Recent studies suggest that absolute lymphocyte count, absolute monocyte count and their ratio [lymphocyte/monocyte ratio (LMR)] at diagnosis may predict survival in classical Hodgkin lymphoma (cHL). Here, we investigated the prognostic significance of LMR in cHL patients in relation to age of patients. Subjects included 351 cHL patients (age range from 4 to 84 years, median age 34 years, sex ratio 1.58) who had been followed‐up for a median period of 59 months (range, 0.1–245 months). The estimated 5‐year overall survival (OS) rate was 86.8%. Subgroup analysis was performed according to patients' age; non‐elderly group (<60 years of age) versus elderly group (≥60 years of age). There was no significant difference in the level of absolute lymphocyte count, absolute monocyte count or LMR between the age groups. Using receiver operating characteristic curve analysis, the optimal cut‐off value of LMR for the entire cohort was determined at 2.8, whereas the optimal cut‐off for the elderly group was 2.2. In the non‐elderly group (<60 years old), patients with LMR <2.8 had significantly lower OS or lymphoma‐specific survival compared with those with LMR ≥2.8 (p < 0.001, both). In contrast, neither the LMR value of 2.8 or 2.2 predicted survival in the elderly group. In multivariate analysis, LMR remained a significant prognostic factor for OS (p = 0.049). The results of our analysis suggest that low LMR is associated with poor OS in patients of <60 years old. Copyright © 2014 John Wiley & Sons, Ltd.     

Venous thromboembolism risk prediction in ambulatory cancer patients: Clinical significance of neutrophil/lymphocyte ratio and platelet/lymphocyte ratio

Neutrophil/lymphocyte (NLR) and platelet/lymphocyte (PLR) ratios might represent a yet unrecognized risk factor for venous thromboembolism (VTE) in cancer out‐patients receiving chemotherapy. Accordingly, this study was aimed at analyzing the significance of these novel markers in the risk prediction of a first VTE episode in a population representative of a general practice cohort. To this purpose, a mono‐institutional cohort study was conducted to retrospectively analyze NLR and PLR in 810 consecutive cancer out‐patients with primary or relapsing solid cancer at the start of a new chemotherapy regimen. Over a median follow‐up of 9.2 months, VTE occurred in 6.7% of patients. Incidental VTE was diagnosed at time of restaging in 47% of cases. Median pre‐chemotherapy NLR (p = 0.015) and PLR (p = 0.040) were significantly higher in patients with intermediate risk class who developed symptomatic VTE with a twofold increased VTE risk for both inflammation‐based markers (NLR: p = 0.022; PLR: p = 0.037) and a worst 1‐year VTE‐free survival for patients with high NLR or PLR. However, only PLR (HR = 2.4, p = 0.027) confirmed to be an independent predictor of future VTE in patients in the intermediate risk class in multivariate analysis, together with ECOG performance status (HR = 3.4, p = 0.0002) and bevacizumab use (HR = 4.7, p = 0.012). We may, thus, conclude that PLR, but to a lesser extent NLR, could represent useful clinical predictors of VTE, especially in selected categories of patients such as those in the intermediate risk class in whom the assessment of PLR could allow a better risk stratification of VTE without additional costs to the national health systems.     

Systemic Inflammatory Markers of Survival in Epidermal Growth Factor–Mutated Non–Small-Cell Lung Cancer: Single-Institution Analysis,Systematic Review,and Meta-analysis

BackgroundSystemic inflammatory response (SIR) may influence prognosis in epidermal growth factor receptor (EGFR)-mutated (m) non–small-cell lung cancer (NSCLC). Pretreatment SIR markers (neutrophil-to-lymphocyte ratio [NLR], platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio [LMR], lactate dehydrogenase [LDH], and lung immune prognostic index [LIPI]) were assessed as prognostic factors in NSCLC survival.Patients and MethodsRetrospective survival analysis (overall survival [OS] and progression-free survival [PFS]) of EGFR-mutated NSCLC patients at Princess Margaret Cancer Centre were performed separately for early (I-IIIa) and late (IIIb-IV) stage disease for individual SIR variables, dichotomized by optimal cutoff points by Kaplan-Meier survival analysis and multivariable Cox proportional hazard modeling. A systematic review and meta-analysis of known SIR studies in patients with late-stage EGFR-mutated were also performed.ResultsFrom 2012 to 2019, in 530 patients, significant adjusted hazard ratios (aHR) for OS comparing high versus low NLR were 2.12 for early stage and 1.79 for late stage disease. Additionally, late stage cohorts had significant associations, as follows: high versus low derived NLR, aHR = 1.53; LMR, aHR = 0.62; LDH, aHR = 2.04; and LIPI, aHR = 2.04. Similar patterns were found for PFS in early stage NLR (aHR = 1.96) and late stage NLR (aHR = 1.46), while for PFS, only late stage derived NLR (aHR = 1.34), LDH (aHR = 1.75), and LIPI (aHR = 1.66) were significant. A meta-analysis confirmed that NLR, LMR, LDH, and LIPI were all significantly associated with OS and PFS in the late stage.ConclusionThis primary study and meta-analysis demonstrated that LMR and LDH were significantly associated with late stage EGFR-mutated NSCLC outcomes, and the LIPI scoring system was prognostic. NLR remained an independent prognostic factor across all stages and could represent an early marker of immuno-oncology interactions.     

NLR和LMR对EGFR-TKIs治疗EGFR突变阳性非小细胞肺癌预后的预测价值

目的:探讨治疗前血清中性粒细胞与淋巴细胞比值（neutrophil to lymphocyte ratio,NLR）和淋巴细胞与单核细胞比值（lympho cyte to monocyte ratio,LMR）对表皮生长因子受体-酪氨酸激酶抑制剂（epidermal growth factor receptor-tyrosine kinase inhibitors,EGFR-TKIs）治疗EGFR突变阳性非小细胞肺癌（non-small cell lung cancer,NSCLC)患者预后的预测价值。方法:回顾性分析112例EGFR突变阳性并接受了EGFR-TKIs治疗的Ⅳ期NSCLC患者的临床资料,根据接受者操作特征曲线（ROC）分析确定的NLR和LMR的最佳分界值,将患者分为高、低水平两组,比较不同分组之间的无进展生存时间（progression free survival,PFS）和总生存时间（overall survival,OS）,通过Cox比例风险模型分析影响PFS和OS的独立预后因素。结果:根据ROC曲线,NLR=2.92,LMR=3.81作为评价的分界值。低NLR组和高NLR组的PFS分别为15.6个月和10.5个月（P＜0.001）,OS分别为26.9个月和19.3个月（P=0.003）;高LMR组和低LMR组的PFS分别为13.4个月和11.5个月（P=0.024）,OS分别为26.2个月和21.8个月（P=0.020）。通过多因素分析发现,ECOG评分和NLR是影响患者PFS和OS的独立预后因素。结论:治疗前血清NLR水平可作为预测EGFR-TKIs治疗EGFR突变阳性Ⅳ期NSCLC患者的预后因子。     

Elevated neutrophil to lymphocyte ratio predicts poor prognosis in nasopharyngeal carcinoma

Elevated neutrophil to lymphocyte ratio (NLR) has been reported to be associated with worse survival in many malignancies, whereas its role in nasopharyngeal carcinoma (NPC) remains unclear. We retrospectively reviewed 363 consecutively, newly diagnosed, non-disseminated, and biopsy-proven NPC patients. Disease-specific survival (DSS), distant metastasis-free survival (DMFS), and locoregional recurrence-free survival (LRFS) rates were compared according to NLR level. Multivariate analysis was performed to assess the prognostic value of NLR. The 5-year DSS, DMFS, and LRFS rates for patients with elevated or non-elevated NLR (> or ≤3.73) were 59.6% vs. 76.6% (p = 0.03), 69.7% vs. 86.6% (p = 0.002), and 78.5% vs. 87.3% (p = 0.105), respectively. For patients with locoregionally advanced disease, NLR was not only an independent prognostic factor, but also a predictor of response to chemoradiotherapy. The 5-year DSS, DMFS, and LRFS rates for patients with elevated or non-elevated NLR were 47.2% vs. 73.7% (p < 0.001), 59.2% vs. 85.1% (p < 0.001), and 72.3% vs. 84.6% (p = 0.041), respectively. Compared with radiation alone, chemoradiotherapy significantly improved DSS and LRFS for patients with non-elevated NLR, but not for those with elevated NLR. Pre-treatment NLR is a strong prognostic factor for NPC patients. For patients with locoregionally advanced disease, NLR might also be a useful indicator for selection of treatment strategies.     

Leukocytosis and neutrophilia as independent prognostic immunological biomarkers for clinical outcome in the CAO/ARO/AIO-04 randomized phase 3 rectal cancer trial

Peripheral blood leukocytosis and neutrophilia reflect cancer inflammation and have been proposed as prognostic immunological biomarkers in various malignancies. However, previous studies were limited by their retrospective nature and small patient numbers. Baseline peripheral blood leukocytes, neutrophils, hemoglobin, platelets, lactate dehydrogenase and carcinoembryonic antigen (CEA) were correlated with clinicopathologic characteristics, and clinical outcome in 1236 patients with rectal cancer treated with 5-FU-based preoperative chemoradiotherapy (CRT) alone or with oxaliplatin followed by surgery and adjuvant chemotherapy within the CAO/ARO/AIO-04 randomized phase 3 trial. Multivariable analyses were performed using Cox regression models. After a median follow-up of 50 months, baseline leukocytosis remained an independent adverse prognostic factor for disease-free survival (DFS; HR 1.457; 95% CI 1.163–1.825; p = 0.001), distant metastasis (HR 1.696; 95% CI 1.266–2.273; p < 0.001) and overall survival (OS; HR 1.716; 95% CI 1.264–2.329; p = 0.001) in multivariable analysis. Similar significant findings were observed for neutrophilia and high CEA levels. Conversely, treatment-induced leukopenia correlated with favorable DFS (p = 0.037), distant metastasis (p = 0.028) and OS (p = 0.012). Intriguingly, addition of oxaliplatin to 5-FU CRT resulted in a significant DFS improvement only in patients with neutrophilia and leukocytosis (p = 0.028 and p = 0.002). Our findings have important clinical implications and provide high-level evidence on the adverse prognostic role of leukocytes and neutrophils, and the impact of chemotherapy in the context of these biomarkers. These data could help guide patient stratification and should be further validated within prospective studies.     

Inherited functional variants of the lymphocyte receptor CD5 influence melanoma survival

Despite the recent progress in treatment options, malignant melanoma remains a deadly disease. Besides therapy, inherited factors might modulate clinical outcome, explaining in part widely varying survival rates. T‐cell effector function regulators on antitumor immune responses could also influence survival. CD5, a T‐cell receptor inhibitory molecule, contributes to the modulation of antimelanoma immune responses as deduced from genetically modified mouse models. The CD5 SNPs rs2241002 (NM_014207.3:c.671C > T, p.Pro224Leu) and rs2229177 (NM_014207.3:c.1412C > T, p.Ala471Val) constitute an ancestral haplotype (Pro224‐Ala471) that confers T‐cell hyper‐responsiveness and worsens clinical autoimmune outcome. The assessment of these SNPs on survival impact from two melanoma patient cohorts (Barcelona, N = 493 and Essen, N = 215) reveals that p.Ala471 correlates with a better outcome (OR= 0.57, 95% CI = 0.33–0.99, Adj. p = 0.043, in Barcelona OR = 0.63, 95% CI = 0.40–1.01, Adj. p = 0.051, in Essen). While, p.Leu224 was associated with increased melanoma‐associated mortality in both cohorts (OR = 1.87, 95% CI = 1.07–3.24, Adj. p = 0.030 in Barcelona and OR = 1.84, 95% CI = 1.04–3.26, Adj. p = 0.037, in Essen). Furthermore survival analyses showed that the Pro224‐Ala471 haplotype in homozygosis improved melanoma survival in the entire set of patients (HR = 0.27, 95% CI 0.11–0.67, Adj. p = 0.005). These findings highlight the relevance of genetic variability in immune‐related genes for clinical outcome in melanoma.     

Diminished levels of the soluble form of RAGE are related to poor survival in malignant melanoma

RAGE is a central driver of tumorigenesis by sustaining an inflammatory tumor microenvironment. This study links the soluble forms of RAGE (sRAGE and esRAGE) with clinical outcome of melanoma patients. Moreover, tissue expression of RAGE was analyzed using immunohistochemistry on two independent tissue microarrays (TMA) containing 35 or 257 primary melanomas, and 41 or 22 benign nevi, respectively. Serum concentrations of sRAGE and esRAGE were measured in 229 Stage III–IV patients using ELISA and plasma concentrations of sRAGE were analyzed in an independent second cohort with 173 samples of Stage I–IV patients. In this cohort, three well‐described SNPs in the RAGE gene were analyzed. RAGE protein expression was highly upregulated in primary melanomas compared to benign nevi in the two TMA (p < 0.001 and p = 0.005) as well as in sun‐exposed melanomas (p = 0.046). sRAGE and esRAGE were identified as prognostic markers for survival as diminished sRAGE (p = 0.034) and esRAGE (p = 0.012) serum levels correlated with poor overall survival (OS). Multivariate Cox regression analysis showed that diminished serum sRAGE was independently associated with poor survival (p = 0.009). Moreover, diminished sRAGE was strongly associated with impaired OS in the second cohort (p < 0.001). Multivariate Cox regression analysis including the investigated SNPs revealed an independent correlation of the two interacting promoter SNPs with impaired OS. In conclusion, the soluble forms of RAGE and variants in its genetic locus are prognostic markers for survival in melanoma patients with high risk for progression.     

Analysis of local chronic inflammatory cell infiltrate combined with systemic inflammation improves prognostication in stage II colon cancer independent of standard clinicopathologic criteria

In Stage II colon cancer, multiple independent studies have shown that a dense intratumoural immune infiltrate (local inflammation) is associated with improved outcomes, while systemic inflammation, measured by various markers, has been associated with poorer outcomes. However, previous studies have not considered the interaction between local and systemic inflammation, nor have they assessed the type of inflammatory response compared with standard clinicopathologic criteria. In order to evaluate the potential clinical utility of inflammatory markers in Stage II colon cancer, we examined local and systemic inflammation in a consecutive series of patients with resected Stage II colon cancer between 2000 and 2010 who were identified from a prospective clinical database. Increased intratumoural chronic inflammatory cell (CIC) density, as assessed by pathologist review of hematoxylin and eosin stained slides, was used to represent local inflammation. Neutrophil‐to‐lymphocyte ratio (NLR) >5, as calculated from pre‐operative full blood counts, was used to represent systemic inflammation. In 396 eligible patients identified, there was a non‐significant inverse relationship between local and systemic inflammation. Increased CIC density was significantly associated with improved overall (HR 0.45, p = 0.001) and recurrence‐free survival (HR 0.37, p = 0.003). High NLR was significantly associated with poorer overall survival (HR 2.56, p < 0.001). The combination of these markers further stratified prognosis independent of standard high‐risk criteria, with a dominant systemic inflammatory response (low CIC/high NLR) associated with the worst outcome (5‐year overall survival 55.8%). With further validation this simple, inexpensive combined inflammatory biomarker might assist in patient selection for adjuvant chemotherapy in Stage II colon cancer.     

First‐line treatment with FOLFOXIRI for advanced pancreatic cancer in clinical practice: Patients' outcome and analysis of prognostic factors

FOLFIRINOX is a standard first‐line treatment for advanced pancreatic cancer (aPC). The Gruppo Oncologico Nord Ovest (GONO) FOLFOXIRI regimen demonstrated efficacy in metastatic colorectal cancer. We aimed to evaluate activity and tolerability of FOLFOXIRI regimen in patients with aPC and to explore putative prognostic factors. One hundred thirty‐seven consecutive aPC patients were treated with FOLFOXIRI in our institution between 2008 and 2014. Clinical, laboratory and pathological data were collected and their association with activity, progression free survival (PFS) and overall survival (OS) was investigated. After a median follow up of 30 months, median PFS and OS were 8.0 months (95% CI 6.19–9.81) and 12 months (95% CI 9.75–14.25), respectively. Response rate was 38.6%, while disease‐control rate 72.2%. At multivariate analysis liver metastases (p = 0.019; Hazard Ratio, HR, 0.59, 95% Confidence Interval, CI, 0.380.96), Eastern Cooperative Oncology Group (ECOG) performance status (PS) 1 (p = 0.001; HR 2.26, 95%CI 1.42–3.59) and neutrophil‐lymphocyte ratio (NLR)> 4 (p= 0.002; HR: 2.42; 95% CI 1.38–4.25) were associated with poorer OS. We categorized 119 pts with complete available data as good‐risk (0 factors, 38 pts), intermediate‐risk (1 factor, 49 pts) and poor‐risk (≥2 factors, 32 pts). Median OS for these three groups were 17.6, 11.1 and 7.4 months, respectively (p < 0.001). FOLFOXIRI is active and feasible in aPC. Prognosis of aPC pts treated with FOLFOXIRI is influenced by easily available factors: our analysis revealed ECOG PS, liver metastases and NLR as the most important predictors of survival. These factors could be helpful for treatment decision and clinical trial design.