In our study, we also found that high NLR ratios in accordance with the literature were poor prognostic. However, unlike the literature, the prognosticvalue of PLR and lymphocytopenia could not be demonstrated in our study. Prognostic factors include ECOG performance status, gender, stage, number and location of metastases, SIADH and treatment response for ED SCLC and recent findings showed that basal NLR maybe one of them. Therefore, the present results, may serve beneficial in further stratification of SCLC patients into different prognostic groups just by using an easy to calculate, reproducible and economically cheap routine laboratory-test based scoring system in addition to other readily available prognostic factors. But before this judgment, additional studies investigating basal NLR role with other serum inflammation markers such as C- reactive protein, IL-6, TNF alfa or tissue inflammation signs such as tumor infiltrating lymphocytes should be performed.
However, this study also has some limitations. First, this was a retrospective study conducted in a single institute, and we did not include an independent and prospective cohort to validate the prognosticvalue of AAPR. Second, we exclu- sively evaluated patients with ED-SCLC, and thus the gen- eralizability of our ﬁ ndings is limited. Third, because we excluded patients who had concurrent liver or renal diseases as these conditions may in ﬂ uence the ALB or ALP, our study ﬁ ndings also cannot be applied for these patients. Lastly, some variables including comorbidity scores (such as the Charlson comorbidity index) and biochemical mar- kers (such as lactate dehydrogenase, C-reactive protein, and coagulation index), that may also in ﬂ uence OS, were not included for analysis due to missing data. Further studies with larger sample sizes and a multi-center and prospective design are needed.
necessary to identify prognostic factors for predicting stage IB NSCLC. At the same time, precise prognosis in patients is very important to ensure that the best treatment plan and follow-up strategy are selected. In recent years, the theory of inflammatory reactions involved in the occurrence and development of various malignant solid tumors has been widely studied and has become a potential and promising prognostic indicator. In addition, as most stage IB patients with NSCLC have long-term survival, only tumor diameter, low-differentiated tumor, angiolymphatic invasions, pleural involvement, and bronchial infiltration have been found to be independent prognostic indicators for the postoperative OS reported. 6,7 Studies so far have found that neutrophil-
Purpose: Sonic hedgehog (Shh) signaling pathway is known to play a crucial role in carcinogenesis in various malignancies, in- cluding lungcancer regarding tumorigenesis, angiogenesis, and cellular differentiation. The aim of this study was to investigate the value of components of Shh pathway as a prognostic marker in extensivestagesmallcelllungcancer (ES-SCLC) patients. Materials and Methods: We retrospectively analyzed data of 36 patients who were diagnosed with ES-SCLC between 2008 and 2012 at a single center. We performed immuo-histochemistry for glioma-associated oncogene homolog zinc finger protein 1 (Gli1), patched, Shh, and Ptch-mediated repression of smoothened (Smo) proteins using formalin-fixed, paraffin-embedded tissue de- rived from primary tumors. We then conducted survival analysis to evaluate the prognostic impact of these markers.
In this study, NLR at diagnosis was an independent prognos- tic factor, and high NLR was significantly associated with shorter OS and PFS in SCLC patients who received standard therapy. As an index of circulating immune cells, NLR could reflect the balance between system inflammation and host immune response for tumor progression, which might account for its predictive value in clinical outcomes. Similar results were also observed in studies on different kinds of cancers, such as esophageal cancer, advanced gastric cancer, colorectal cancer, breast cancer, non-small-celllungcancer, and epithelial ovarian cancer. Recently, Shao and Cai 16
More than 4,000 patients with pathologically confirmed malignant tumors of the esophagus after surgery were recruited. Among these patients, 138 patients were confirmed with SCCE, 133 patients had received no neoadjuvant therapy prior to esophagectomy, and 129 patients had complete clinical data including age, gender, histology, tumor loca- tion and stage, nodal metastasis, complete blood count, and treatment. Finally, 129 patients were included in the study. The study flowchart is shown in Figure 1. The median age for the patients was 60 years (range: 39–78 years). Eighty- five (65.9%) of the patients were men. Forty-eight (37.2%) patients had stage I, 54 (41.9%) had stage II, and 27 (20.9%) had stage III SCCE. At the end of this study (December 31, 2015), 113 (87.6%) patients died. The median follow-up duration for those who were still alive at the final follow-up was 67.5 months (range: 60–81 months).
Immune checkpoint inhibitor therapies have been approved for multiple malig- nancies and have heralded a new era for cancer therapies. New data is rapidly materializing and clinical practices and protocols are changing quickly. Immune checkpoint inhibitors can prevent cancer cells from inhibiting the immune sys- tem’s natural antineoplastic response by blocking inhibitory signaling pathways involving interactions between programmed death 1 (PD-1) receptors and its li- gands (PD-L1 and PD-L2), thus enhancing the activity of T cells within the tu- mor microenvironment . Targeted immunotherapy has been FDA-approved for non-smallcelllungcancer (NSCLC) and has shifted treatment paradigms dramat- ically over the last few years.
However, there are still some limitations in this study. First, this study is a single-center clinical study with only 267 advanced NSCLC patients included. There- fore, a large sample multicenter clinical study is needed to verify the conclusions of this study. Second, this study did not take into account the mutation of EGFR and ALK in patients with advanced NSCLC, because the prognosis of patients receiving targeted therapy was significantly better than that of patients receiving radiotherapy and chemotherapy, which to some extent affected our evalua- tion of the value of TLC, NLR, and PLR in the prognosis of advanced NSCLC. In subsequent studies, the genetic status of patients should be further examined to exclude the effect of gene or targeted therapy on this result. Finally, the survival time of patients with advanced NSCLC is affected by a variety of factors, the influence of those factors on the survival time should be excluded as far as possible in subsequent studies.
Neutrophils are a type of innate immune cells that are involved in the clearance of microbial infection. They are recruited into the microenvironment of tumors depending on chemokines that bind to CXCR1 and CXCR2 which are expressed by neutrophils. 20 The changed microenviron- ment can then accelerate tumor growth, invasion, and metastasis. Studies have con ﬁ rmed that increases in the number of neutrophils are associated with poor prognoses in NSCLC. 21 As an important part of the immune system, lymphocytes play a key role in the immune response to cancer. A low lymphocyte count indicates immunosup- pressing status inside the body. Lymphopenia has been demonstrated to be associated with a poor prognosis in many types of cancer. 22 NLR represents the balance between neutrophils and lymphocytes. An elevated NLR indicates decreasing antitumor effects of T-lymphocytes
Heterogenous role of TANs in tumors ,needs to be more clearly understood. Aberrant accumulation of neutrophils has been observed in a wide variety of malignant tumors, the prognosticvalue of which appears non uniform among patients with same type of cancers. In most cases TAN is often associated with poor prognosis and shows positive correlation with advanced tumor size and grade. Conversely large number of tumor infiltrating neutrophils is found to correlate with enhanced survival in early stagelungcancer and in women but not men with advanced gastric cancer. In uterine epithelial cancer, neutrophils have been shown to slow down early tumor growth and progression by inducing tumor cell detachment from the basement membrane. The multi factorial role played by neutrophils in tumor microenvironment has major implications intumor pathogenesis and progression. Th17 type of CD4+ T cell adaptive immunity in cancer is pivotal in neutrophil recruitment in tumors. IL-17A exerts this effect by orchestrating
In a further investigation, subgroup analyses were per- formed with confounders such as ethnicity, sample size, and cutoff value (Figure 4). Subgroup analyses by ethnic- ity indicated that high PLR predicted poor prognosis for patients both in Caucasian populations (HR = 1.56, 95% CI: 1.19–2.04, P = 0.001) and in Asian cases (HR = 1.62, 95% CI: 1.29–2.04, P0.001) (Figure 4A). When studies were stratified by sample size, we found the combined HRs were 1.56, 95% CI: 1.18–2.06 for studies with less than 200 cases and HR 1.62, 95% CI: 1.30–2.03 for studies with more than 200 cases (Figure 4B). This result demonstrated that high PLR remained to be an unfavorable prognostic
production of cytokines and angiogenic factors signi ﬁ - cantly promotes tumor development. 5,6 As an important defense of the immune system, lymphocytes are related to the body ’ s immune surveillance. 7,8 Preoperative NLR represents the preoperative neutrophil/postoperative lym- phocyte ratio, maybe more helpful for patients with tumor prognosis prediction. Previous studies have shown that preoperative elevation of NLR is an independent predictor of poor prognosis in non-metastatic papillary renal cell carcinoma. 9 In a 16-year follow-up study of 527,124 Korean adults, the NLR was independently associated with an increased risk of lungcancer mortality. 10 However, the predictive role of NLR in SSCC has been unclear due to the lack of literature. Since NLR is an important prognostic factor for multiple tumors, we hypothesized the indicator is also associated with the prog- nosis of SSCC. The purpose of this study was to evaluate the predictability of preoperative NLR to long-term mor- tality after the operation of SSCC patients.
5-year survival in patients with stage I NSCLC. Accordingly, the understanding of preoperative NLR’s predictive role has changed for patients undergoing complete resection of stage I NSCLC. This study results revealed that preoperative NLR was not a predictor of survival in stage I NSCLC, in agree- ment with the report by Miyazaki et al. To the best of our knowledge, there has been no related study on postoperative NLR or ∆ NLR in patients with stage I NSCLC. This study confirmed that postoperative NLR (HR = 2.435, P = 0.001) and ∆ NLR (HR = 2.103, P = 0.012) were independent risk factors that predicted DFS. Furthermore, our results confirm that the significant predictors of OS include postoperative NLR (HR = 2.747, P = 0.001) and ∆ NLR (HR = 2.052, P = 0.018). The results revealed that postoperative NLR and ∆ NLR reflect the postoperative balance or change in the systematic inflammatory response from the preoperative period to the postoperative period, which may provide a more precise reflection of prognosis.
value of the NLR<2.96 groups (PFS = 11.1, 95% CI: 9.5–13.9 months), HR = 2.67 (95% CI: 1.41–5.03) (P = 0.006). Whereas the median PFS of patients with high level of pretreatment MLR ( ≥ 0.38) (n = 32/53) was 7.5 (95% CI: 5.9–8.4) months, the median PFS in patients with low level of MRL was 10.1 (95% CI: 9.0–13.0) months, HR = 1.91 (95% CI: 1.07–3.41) (P = 0.034). However, the crossover between survival curves at the end of the Kaplan–Meier plot (Figure 2C) indicates that the difference of PFS between groups of the lower and higher MLR level might not be significant. We checked this with the proportional hazards assumption tests and confirmed that MLR is not a significant prognostic factor in this situation (the log–log plot shown the crossed lines while the observed values and predicted values are different; figures not shown). No differences of PFS between groups of age, gender, ECOG PS, number of distant metastasis, status of brain metastasis, pleural effusion, EGFR mutation type, EGFR TKI type, and the level of WBC, PLT and PLR were recorded.
Lungcancer is one of the leading causes of cancer-related deaths (1,2). Non-smallcelllungcancer (NSCLC) accounts for approximately 85% of lungcancer cases, and small-celllungcancer (SCLC) accounts for nearly 13% of overall lungcancer cases. Despite continue efforts and progress in diagnosis and treatment, the overall survival (OS) for lungcancerpatients remains poor (1,2). Prognostic factors influencing survival have been previously identified, includ- ing tumor stage, performance status, weight loss, age, sex, histopathology, and plasma lactate dehydrogenase (LDH) and carcinoembryonic antigen (CEA) levels (3-7). Although novel immunological and histological biomarkers such as intercellular adhesion molecule-1 (IDM-1) and epidermal growth factor receptor (EGFR) have been identified (8,9), these marks are expensive and often time-consuming to
Abstract: Numerous studies determined that the neutrophil/lymphocyte (NLR) and platelet/lymphocyte ratios (PLR) had prognosticvalue in several cancer types. This study aimed to evaluate the relationship between NLR and PLR values with the survival time of lungcancerpatients. Patients diagnosed with lungcancer between January 2014 and December 2016, were retrospectively evaluated. Demographic characteristics, disease stages, laboratory parameters recorded, and the relationship of NLR and PLR values with the survival time and the disease stage evaluated. NLR and PLR were categorized into two groups. SPSS 17.0 software package was used for the statistical analysis. ROC analysis, Student T-test, Chi-square, and Mann- Whitney U test were used. Mean age of 62±8 years were included in the study. In the NSCLC group, the average NLR and PLR values were 4±3.35 and 194.6±144.4 respectively. Regarding the NSCLC group, the overall survival time was shorter in the subgroup with an NLR >3.43 (13.1 months) compared to the subgroup with an NLR ≤3.43 (24.3 months). The mean survival time was shorter in the group with a PLR > 136.9 compared to the group with a PLR ≤136.9 (15.9 and 24.6 months respectively). Subgroups consisting of survivors and non-survivors in the NSCLC group showed a statistically significant difference considering neutrophil and lymphocyte count, CRP, NLR, and PLR values (p<0.05). As NLR and PLR values are easily accessible, they have an essential role in the prognosis of lungcancer as well as other cancer types.
Previous reports and meta-analyses [7, 25, 26] found that an elevated NLR was a marker of poor prognosis, and was associated with recurrence of lungcancer. In cancer pa- tients, oxidative stress can be caused by various tumor pro- gression mechanisms, such as malignant conversion; tumor cell survival, proliferation, chemo- and radio-resistance, invasion, angiogenesis, metastasis, and stem cell survival [4, 5] However, it is not possible to evaluate oxidative stress within the tumor microenvironment of living organs. Unlike previous studies that enrolled heterogeneous groups including patients with different NSCLC stages, we focused on patients with stage 1 disease. Tumor progression and/or tumor burden were thus limited, and patients with symp- toms, treatments, or histories that could influence their in- flammatory or nutrition status were excluded. The serum d-ROM results obtained in this study mainly reflected systemic inflammation, with a relatively small contribution by carcinoma-induced inflammation. In patients in good general condition, the level of systemic oxidative stress may correlate with oxidative stress associated with the tumor micro-environment, and vice versa. This oxidative stress-inflammation interaction may induce factors that promote recurrence and tumor progression.
Patient characteristics regarding the disease stage are shown in Table 1. Out of 438 patients diag- nosed with smallcelllungcancer or mixed neu- roendocrine carcinoma between 2012 and 2016, 140 met the inclusion and exclusion criteria and were included in the study. Of those 140 patients, 80 were diagnosed with extensive-stage disease and 60 with limited-stage disease. The mean pa- tient age was 63.1 years with a mean deviation of 9.2 years (42–87 years of age). Slightly more males than females were involved in the study (89 or 63.6%). The majority of the patients were smokers (95.7%), of good performance status, 0–1 according to the ECOG scale (82.9%). Only 14 patients (10%) received less than 4 chemotherapy cycles. Forty- five patients (32%) underwent radiotherapy, most of whom were in the limited-stage disease group. Only twelve patients underwent PCI (8.6%), again significantly more in the limited-stage disease group. Disease control was observed in 119 patients (85%). After two years, 125 patients (89.2%) died. Fifteen out of the total number of patients included in the analysis (10.7%) survived for more than 2 years, and all of them belonged to the limited-stage disease group. According to the statistical analysis, disease control, PFS, OS, and outcome were signifi- cantly better in the limited-stage disease group. Of the laboratory parameters, a significant statistical difference regarding the disease stage was only ob- served for CRP and LDH. The mean NLR and PLR values were higher in the extensive-stage disease group of patients, while the mean LMR value was higher in the limited-stage disease group, but the difference was not statistically significant. In the extensive-stage disease group, a statistically signif- icant difference of LMR values regarding patient
The following items were recorded: first author’s name, year of publication, country, total number of cases and sex, follow-ups, stage, cut-off value, cancer type, and HRs with 95% CIs. The Newcastle–Ottawa Scale (NOS) was used to assess each of the included studies’ quality by two indepen- dent investigators (Qing-Tao Zhao and Yong Yang). 19 The
curves of the NLR and PNI for the prediction of DFS or OS were generated to determine the cutoff value that yielded an optimal sensitivity and specificity. The prognos- tic evaluation was performed by considering the OS and DFS, which was defined as the time until lungcancer re- currence, the occurrence of a second cancer, or non-lungcancer-related death. The survival curves were estimated using the Kaplan-Meier method, and differences among the curves were evaluated using the log-rank test. Univariate and multivariate analyses were per- formed using the Cox proportional hazards model. Two-sided P values of less than 0.05 were considered statistically significant.