Mairead Mcnamara

Prognostic role of neutrophil-to-lymphocyte ratio in solid tumors: a systematic review and meta-analysis.

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 Platelet to Lymphocyte Ratio in Solid Tumors: 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 (<150/150–300/>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.

Simple prognostic score for metastatic castration-resistant prostate cancer with incorporation of neutrophil-to-lymphocyte ratio

The neutrophil‐to‐lymphocyte ratio (NLR), a marker of inflammation, has been reported to be a poor prognostic indicator in prostate cancer. Here we explore the use of the NLR to establish a simple prognostic score for men with metastatic castration‐resistant prostate cancer (mCRPC) treated with docetaxel. METHODS: In the training cohort, the NLR and other known prognostic variables were evaluated among a cohort of chemotherapy‐naïve patients treated with thrice‐weekly docetaxel at the Princess Margaret Cancer Centre. Significant prognostic variables identified by univariable Cox regression were evaluated by the area under the receiver operating characteristic curves. Multivariable Cox regression was then used to derive a prognostic score where 1 risk point was assigned for each significant variable. The model was externally validated in a cohort of patients treated at the Royal Marsden. RESULTS: Three hudred fifty‐seven patients were analyzed in the training cohort. Median age was 71 years, 12% had liver metastasis, and median overall survival (OS) was 14.7 months. Liver metastases, hemoglobin <12 g/dL, alkaline phosphatase >2.0× upper limit of normal (ULN), lactate dehydrogenase >1.2× ULN, and NLR >3 were associated with significantly worse OS in multivariable analysis. Four risk categories were subsequently established with 0, 1, 2, and 3‐5 points. Two‐year OS rates for these categories were 43%, 37%, 12%, and 3%, respectively. Area under the curve for the training cohort was 0.78 (95% CI, 0.72‐0.84) compared with 0.66 (95% CI, 0.58‐0.74) for the 215 patients in the validation cohort. CONCLUSIONS: This simple risk score provides good prognostic and discriminatory accuracy for men with mCRPC. Cancer 2014;120:3346–3352.

Feasibility and benefits of second-line chemotherapy in advanced biliary tract cancer: a large retrospective study.

INTRODUCTION First-line chemotherapy (CT1) is effective in advanced biliary tract cancer (ABTC). The benefits of second-line chemotherapy (CT2) are unclear. METHODS We retrospectively studied all patients starting at least one line of chemotherapy for ABTC at our institution between 1991 and 2011. We analysed patient and chemotherapy characteristics in order to: (1) characterise patients eligible for CT2; (2) evaluate the efficacy of CT2. RESULTS Three hundred and seventy-eight received CT1 and 96 (25%) patients received CT2. Primary tumour location was the gallbladder (29%), intraphepatic (20%), perihilar (16%), distal common bile duct (19%) and ampulla of Vater (14%). Ninety percent had a baseline performance status (PS) of 0-1 prior to CT1. Females (p=0.03), ages ≤ 60 years (p=0.001) and patients with progression free survival (PFS) ≥ 6 months following CT1 (p=0.01) were more likely to be offered CT2. Objective response rates and stable disease with CT2 were 9% and 34%, respectively. Median PFS and median overall survival (OS) from the beginning of CT2 were 2.8 and 7.5 months, respectively. Prognostic factors impacting PFS with CT2 were the regimen type (doublet versus monotherapy, p=0.001) and PS<2 (p<0.0001). CONCLUSIONS Among patients with ABTC, 25% received CT2, typically younger patients and those with longer PFS following CT1. Disease control occurred in 43% of patients, and more often with a doublet than a single agent. However, clearly more effective therapies must be found.

Swim Stress Increases the Potency of Glycine at the N-Methyl-d-Aspartate Receptor Complex

Abstract: We have previously demonstrated that chronic administration of antidepressants results in a reduction in the potency of glycine to displace 5,7‐[3H]dichlorokynurenic acid (5,7‐[3H]‐DCKA) from the strychnine‐insensitive glycine recognition site of the NMDA receptor complex. We now report that exposure of rats to the forced swim test results in a 56% increase in the potency of glycine to displace 5,7‐[3H]DCKA from frontal cortical homogenates. These data are consistent with the hypothesis that the forced swim test, a preclinical screen sensitive to acute administration of antidepressant drugs and NMDA receptor antagonists, also results in adaptation of the NMDA receptor complex. Moreover, these data lend further support to the hypothesis that glutamatergic pathways are involved in the neurobiological response to stress and, potentially, in the pathophysiology of depression.

Neutrophil/lymphocyte ratio as a prognostic factor in biliary tract cancer

BACKGROUND Biliary tract cancers (BTCs) include intrahepatic (IHC), hilar, distal bile duct (DBD) and gallbladder carcinoma (GBC). Neutrophil/lymphocyte ratio (NLR), a marker of host inflammation, is prognostic in several cancers but has not been reviewed in large BTC series, or advanced BTC (ABTC) at diagnosis. PATIENTS AND METHODS Baseline demographics and NLR at diagnosis were retrospectively evaluated in 864 consecutive patients with BTC treated from January 1987 to December 2012. The association between NLR and overall survival (OS) was determined using a multivariable Cox proportional hazards model. RESULTS Eight hundred and sixty-four patients were included in the analysis, of which 62% had ABTC and 38% had surgery with curative intent. Median age was 65 years, 444 (51%) were male and 727 (84%) had performance status (PS) ⩽ 2. A NLR ⩾ 3.0, PS >2, IHC primary, stage, lack of surgery, haemoglobin <110 g/L and albumin <40 g/L were associated with significantly worse OS on multivariable analysis. A NLR ⩾ 3.0 was an independent prognostic factor for OS for the entire cohort; median OS was 21.6 months versus 12.0 months for patients with NLR <3.0 versus NLR ⩾ 3.0 respectively (adjusted hazard ratio (HR)-1.26, 95% confidence interval (CI); 1.06-1.50, P = 0.01). NLR was also prognostic in patients with ABTC (HR-1.26, 95% CI; 1.02-1.56, P = 0.035) and hilar cancer: overall group (N = 149) (HR-1.70, 95% CI; 1.10-2.50, P = 0.01) and advanced group (N = 111) (HR-1.57, 95% CI; 1.04-2.44, P = 0.048). CONCLUSION Baseline NLR is a readily available and inexpensive prognostic biomarker in patients with BTC and likely warrants validation in large prospective clinical trials.

Emergence of MRSA in positive blood cultures from patients with febrile neutropenia—a cause for concern

Goals of workFebrile neutropenia (FN) causes considerable morbidity in patients on cytotoxic chemotherapy. Recently, there has been a trend towards fewer Gram-negative and more Gram-positive infections with increasing antibiotic resistance. To assess these patterns, data from a supra-regional cancer centre in Ireland were reviewed.Patients and methodsA 5-year review of all positive blood cultures in patients undergoing anti-cancer chemotherapy was carried out.Main resultsEight hundred and ninety-four patients were reviewed. The mean incidence of FN was 64.2 cases per year. Eight hundred and forty-six blood culture specimens were taken and 173 (20.4%) were culture positive. The isolated organisms were Gram positive (71.1%), Gram negative (27.8%) and fungal (1.1%). Of the Gram-positive organisms, 75.6% were staphylococci. Of these, 67.8% were coagulase-negative staphylococci and 30.1% were Staphylococci aureus. Amongst the S. aureus, 89.3% were methicillin-resistant (MRSA). Vancomycin-resistant enterococci were not identified as a cause of positive blood cultures.ConclusionsAmongst patients with cancer who develop FN in our hospital, Gram-positive bacteria account for the largest proportion. The high proportion of MRSA as a cause of positive blood cultures is of concern.

A phase II trial of second‐line axitinib following prior antiangiogenic therapy in advanced hepatocellular carcinoma

Second‐line treatment options in advanced hepatocellular carcinoma (HCC) are limited. Axitinib, a selective potent tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor VEGF) receptors 1, 2, and 3, merits exploration in HCC.

Antiangiogenic therapies in glioblastoma multiforme

Glioblastoma multiforme (GBM) is the most common and lethal of adult gliomas. The prognosis for the great majority of patients with GBM is poor as almost all tumors recur following optimal surgical resection, radiation and standard chemotherapy, resulting in rapid disease-related death. The standard of care for recurrent GBM has not been clearly established. GBMs are highly vascularized brain tumors and growth has been shown to be angiogenesis dependent, thus stimulating interest in developing antiangiogenic therapeutic strategies. Antiangiogenic agents are the most promising novel agents in development for GBM but to date have not substantially changed overall survival. Future antiangiogenic strategies designed to overcome limitations of current antiangiogenic agents will likely involve the use of agent combinations that target pathways mediating resistance to antiangiogenic agents and tumor invasion.

Prognostic factors for progression-free and overall survival in advanced biliary tract cancer

BACKGROUND Biliary tract cancer is an uncommon cancer with a poor outcome. We assembled data from the National Cancer Research Institute (UK) ABC-02 study and 10 international studies to determine prognostic outcome characteristics for patients with advanced disease. METHODS Multivariable analyses of the final dataset from the ABC-02 study were carried out. All variables were simultaneously included in a Cox proportional hazards model, and backward elimination was used to produce the final model (using a significance level of 10%), in which the selected variables were associated independently with outcome. This score was validated externally by receiver operating curve (ROC) analysis using the independent international dataset. RESULTS A total of 410 patients were included from the ABC-02 study and 753 from the international dataset. An overall survival (OS) and progression-free survival (PFS) Cox model was derived from the ABC-02 study. White blood cells, haemoglobin, disease status, bilirubin, neutrophils, gender, and performance status were considered prognostic for survival (all with P < 0.10). Patients with metastatic disease {hazard ratio (HR) 1.56 [95% confidence interval (CI) 1.20-2.02]} and Eastern Cooperative Oncology Group performance status (ECOG PS) 2 had worse survival [HR 2.24 (95% CI 1.53-3.28)]. In a dataset restricted to patients who received cisplatin and gemcitabine with ECOG PS 0 and 1, only haemoglobin, disease status, bilirubin, and neutrophils were associated with PFS and OS. ROC analysis suggested the models generated from the ABC-02 study had a limited prognostic value [6-month PFS: area under the curve (AUC) 62% (95% CI 57-68); 1-year OS: AUC 64% (95% CI 58-69)]. CONCLUSION These data propose a set of prognostic criteria for outcome in advanced biliary tract cancer derived from the ABC-02 study that are validated in an international dataset. Although these findings establish the benchmark for the prognostic evaluation of patients with ABC and confirm the value of longheld clinical observations, the ability of the model to correctly predict prognosis is limited and needs to be improved through identification of additional clinical and molecular markers.