BACKGROUND: Inflammation may play an important role in cancer progression, and a high neutrophil-to-lymphocyte ratio (NLR) has been reported to be a poor prognostic indicator in several malignancies. Here we quantify the prognostic impact of this biomarker and assess its consistency in solid tumors. METHODS: A systematic review of electronic databases was conducted to identify publications exploring the association of blood NLR and clinical outcome in solid tumors. Overall survival (OS) was the primary outcome, and cancer-specific survival (CSS), progression-free survival (PFS), and disease-free survival (DFS) were secondary outcomes. Data from studies reporting a hazard ratio and 95% confidence interval (CI) or a P value were pooled in a meta-analysis. Pooled hazard ratios were computed and weighted using generic inverse-variance and random-effect modeling. All statistical tests were two-sided. RESULTS: One hundred studies comprising 40559 patients were included in the analysis, 57 of them published in 2012 or later. Median cutoff for NLR was 4. Overall, NLR greater than the cutoff was associated with a hazard ratio for OS of 1.81 (95% CI = 1.67 to 1.97; P < .001), an effect observed in all disease subgroups, sites, and stages. Hazard ratios for NLR greater than the cutoff for CSS, PFS, and DFS were 1.61, 1.63, and 2.27, respectively (all P < .001). CONCLUSIONS: A high NLR is associated with an adverse OS in many solid tumors. The NLR is a readily available and inexpensive biomarker, and its addition to established prognostic scores for clinical decision making warrants further investigation.

Prognostic Role of Neutrophil-to-Lymphocyte Ratio in Solid Tumors: A Systematic Review and Meta-Analysis

Hepatocellular carcinoma in non-alcoholic fatty liver disease: An emerging menace

Background A growing body of evidence has suggested that metformin potentially reduces the risk of cancer. Our objective was to enhance the precision of estimates of the effect of metformin on the risk of any-site and site-specific cancers in patients with diabetes. Methods/principal findings We performed a search of MEDLINE, EMBASE, ISI Web of Science, Cochrane Library, and ClinicalTrials.gov for pertinent articles published as of October 12, 2011, and included them in a systematic review and meta-analysis. We calculated pooled risk ratios (RRs) for overall cancer mortality and cancer incidence. Of the 21,195 diabetic patients reported in 6 studies (4 cohort studies, 2 RCTs), 991 (4.5%) cases of death from cancer were reported. A total of 11,117 (5.3%) cases of incident cancer at any site were reported among 210,892 patients in 10 studies (2 RCTs, 6 cohort studies, 2 case-control studies). The risks of cancer among metformin users were significantly lower than those among non-metformin users: the pooled RRs (95% confidence interval) were 0.66 (0.49-0.88) for cancer mortality, 0.67 (0.53-0.85) for all-cancer incidence, 0.68 (0.53-0.88) for colorectal cancer (n = 6), 0.20 (0.07-0.59) for hepatocellular cancer (n = 4), 0.67 (0.45-0.99) for lung cancer (n = 3). Conclusion/significance The use of metformin in diabetic patients was associated with significantly lower risks of cancer mortality and incidence. However, this analysis is mainly based on observational studies and our findings underscore the more need for long-term RCTs to confirm this potential benefit for individuals with diabetes.

/pdf/cancer-risk-in-diabetic-patients-treated-with-metformin-a-q3l07t296l.pdf

Cancer risk in diabetic patients treated with metformin: a systematic review and meta-analysis.

Background: Inflammation influences cancer development and progression. An elevated platelet to lymphocyte ratio (PLR), a marker of inflammation, has been linked to poor prognosis in several malignancies. Here, we quantify the prognostic impact of this biomarker.

Methods: A systematic review of databases was conducted to identify publications exploring the association of blood PLR and overall survival (OS) in solid tumors. Data were pooled in a meta-analysis. Pooled HRs for OS by disease group and by PLR cutoff groups were computed and weighted using generic inverse-variance and random-effect modeling.

Results: Twenty studies comprising 12,754 patients were assessed. Cutoffs for PLR defining risk groups ranged from 150 to 300 and were dichotomous (12 studies; group 1) or split into three groups ( 300, 8 studies; group 2). Higher PLR was associated with significantly worse OS in group 1 [HR = 1.87; 95% confidence interval (CI, 1.49–2.34); P < 0.001] and with a nonsignificant association in group 2 (HR per higher category = 1.21; 95%CI, 0.97–1.50; P = 0.10). The size of effect of PLR on OS was greater for metastatic disease (HR[group 1] = 2.0; 95% CI, 1.6–2.7; HR[group 2] = 1.6; 95% CI, 1.1–2.4) than for early-stage disease (HR[group 1] = 1.5; 95% CI, 1.0–2.2; HR[group 2] = 1.0; 95% CI, 0.8–1.3). A significant association was observed for colorectal, hepatocellular, gastroesophageal, ovarian, and pancreatic carcinoma in group 1 and for colorectal cancers in group 2.

Conclusion: A high PLR is associated with worse OS in various solid tumors. Further research of its regulation and relevance in daily practice is warranted.

Impact: PLR is a readily available and inexpensive biomarker with independent prognostic value in solid tumors. Cancer Epidemiol Biomarkers Prev; 23(7); 1204–12. ©2014 AACR .

This article is featured in Highlights of This Issue, [p. 1137][1]

 [1]: /lookup/volpage/23/1137?iss=7

https://cebp.aacrjournals.org/content/cebp/23/7/1204.full.pdf

Prognostic Role of Platelet to Lymphocyte Ratio in Solid Tumors: A Systematic Review and Meta-Analysis

OBJECTIVE Time-related biases in observational studies of drug effects have been described extensively in different therapeutic areas but less so in diabetes. Immortal time bias, time-window bias, and time-lag bias all tend to greatly exaggerate the benefits observed with a drug. RESEARCH DESIGN AND METHODS These time-related biases are described and shown to be prominent in observational studies that have associated metformin with impressive reductions in the incidence of and mortality from cancer. As a consequence, metformin received much attention as a potential anticancer agent; these observational studies sparked the conduction of randomized, controlled trials of metformin as cancer treatment. However, the spectacular effects reported in these studies are compatible with time-related biases. RESULTS We found that 13 observational studies suffered from immortal time bias; 9 studies had not considered time-window bias, whereas other studies did not consider inherent time-lagging issues when comparing the first-line treatment metformin with second- or third-line treatments. These studies, subject to time-related biases that are avoidable with proper study design and data analysis, led to illusory extraordinarily significant effects, with reductions in cancer risk with metformin ranging from 20 to 94%. Three studies that avoided these biases reported no effect of metformin use on cancer incidence. CONCLUSIONS Although observational studies are important to better understand the effects of drugs, their proper design and analysis is essential to avoid major time-related biases. With respect to metformin, the scientific evidence of its potential beneficial effects on cancer would need to be reassessed critically before embarking on further long and expensive trials.

https://care.diabetesjournals.org/content/diacare/35/12/2665.full.pdf

Metformin and the Risk of Cancer: Time-related biases in observational studies

Background and Aim:  Increasing evidence correlates the presence of systemic inflammation with poor survival in patients with hepatocellular carcinoma (HCC) We studied whether peripheral blood neutrophil-to-lymphocyte ratio (NLR), a marker of systemic inflammatory response, would be a useful predictor for outcome in patients with early HCC undergoing radiofrequency ablation (RFA)



Methods:  A total of 158 patients with early HCC underwent RFA Potential prognostic factors such as age, gender, tumoral characteristics, Child-Turcotte-Pugh (CTP) class and NLR were analyzed The study endpoints were overall survival (OS) and new recurrence



Results:  We modeled NLR as a continuous explanatory variable in regression analyses Multivariate analysis revealed that tumor size (P = 0005) and high baseline NLR (P = 0001) were independent explanatory variables associated with unfavorable OS Regarding new recurrence, multivariate analysis showed that CTP class B (P = 0002), α-fetoprotein > 400 ng/mL (P = 0030), tumor size (P = 0002) and tumor multiplicity (P = 0013) were found to be worse prognosticators, but not baseline NLR In a subset analysis of 140 patients whose post-RFA NLR data at first follow-up visit were available, multivariate analysis revealed that high post-RFA NLR was identified as an independent covariate, not only for OS (P = 0006), but for new recurrence (P = 0010) as well



Conclusions:  High baseline NLR was associated with worse OS for patients with early HCC; post-RFA NLR predicted not only OS, but also tumor recurrence

Neutrophil-to-lymphocyte ratio associated with mortality in early hepatocellular carcinoma patients after radiofrequency ablation

Background and Aim:  Type 2 diabetes increases the risk of cancer development and mortality. However, antidiabetic treatment with metformin can reduce the risk of cancer. We studied whether metformin users among diabetic patients with early hepatocellular carcinoma (HCC) undergoing radiofrequency ablation (RFA) would have a favorable survival compared with those without metformin treatment.



Methods:  A total of 135 patients with early stage HCC having 162 tumors underwent RFA. Among them, 53 patients were diabetic, including 21 metformin users and 32 patients without metformin treatment.



Results:  Diabetic patients had an inferior survival rate compared with nondiabetic patients (1 year, 82.8% vs 93.9%; 3 years, 55.1% vs 80.2%; 5 years, 41.3% vs 64.7%; P = 0.004). With regards to antidiabetic treatments, metformin users had better survival outcome (adjusted hazard ratio [HR] 0.24; 95% confidence interval [CI], 0.07–0.80; P = 0.020) compared to patients without metformin treatment after adjustments for potential confounders. Sulfonylureas and insulin exposures did not achieve significant conclusions. For the whole studied population including nondiabetic and diabetic patients, the multivariate analysis revealed that maximum tumor size more than 2.5 cm (HR, 3.49; 95% CI, 1.74–6.99; P < 0.001) and diabetic patients without metformin treatment (HR, 3.34; 95% CI, 1.67–6.71, P = 0.001) were independent explanatory variables associated with unfavorable survival.



Conclusions:  Metformin users among diabetic patients with HCC undergoing RFA had a favorable overall survival compared with patients without metformin treatment.

Metformin associated with lower mortality in diabetic patients with early stage hepatocellular carcinoma after radiofrequency ablation.

Salient studies have investigated the association between host inflammatory response and cancer. This study was conducted to test the hypothesis that peripheral absolute monocyte counts (AMC) could impart an increased risk of hepatocellular carcinoma (HCC) development in hepatitis C virus (HCV)-infected patients after a failed peginterferon/ribavirin (PR) combination therapy. A total of 723 chronic HCV-infected patients were treated with PR, of which 183 (25.3 %) patients did not achieve a sustained virological response (non-SVR). Post-treatment AMC values were measured at 6 months after end of PR treatment. Fifteen (2.8 %) of 540 patients with an SVR developed HCC during a median follow-up period of 41.4 months, and 14 (7.7 %) of 183 non-SVR patients developed HCC during a median follow-up of 36.8 months (log rank test for SVR vs. non-SVR, P = 0.002). Cox regression analysis revealed that post-treatment AFP level (HR 1.070; 95 % CI = 1.024-1.119, P = 0.003) and post-treatment aspartate aminotransferase (AST)-to-platelet ratio index (APRI) ≥0.5 (HR 4.401; 95 % CI = 1.463-13.233, P = 0.008) were independent variables associated with HCC development for SVR patients. For non-SVR patients, diabetes (HR 5.750; 95 % CI = 1.387-23.841, P = 0.016), post treatment AMC ≥370 mm(-3) (HR 5.805; 95 % CI = 1.268-26.573, P = 0.023), and post-treatment APRI ≥1.5 (HR 10.905; 95 % CI = 2.493-47.697, P = 0.002) were independent risks associated with HCC. In conclusion, post-treatment AMC has a role in prognostication of HCC development in HCV-infected patients who failed to achieve an SVR after PR combination therapy.

High post-treatment absolute monocyte count predicted hepatocellular carcinoma risk in HCV patients who failed peginterferon/ribavirin therapy

https://www.onlinelibrary.wiley.com/doi/pdf/10.1016/j.aidm.2014.11.001

Chen-Fan Wen

Papers

Neutrophil-to-lymphocyte ratio associated with mortality in early hepatocellular carcinoma patients after radiofrequency ablation

Metformin associated with lower mortality in diabetic patients with early stage hepatocellular carcinoma after radiofrequency ablation.

High post-treatment absolute monocyte count predicted hepatocellular carcinoma risk in HCV patients who failed peginterferon/ribavirin therapy

Impact of interleukin-28B polymorphism on HCV-1 infected patients treated with response-guided therapy