Switching TNF antagonists in patients with chronic arthritis: an observational study of 488 patients over a four-year period

The objective of this work is to analyze the survival of infliximab, etanercept and adalimumab in patients who have switched among tumor necrosis factor (TNF) antagonists for the treatment of chronic arthritis. BIOBADASER is a national registry of patients with different forms of chronic arthritis who are treated with biologics. Using this registry, we have analyzed patient switching of TNF antagonists. The cumulative discontinuation rate was calculated using the actuarial method. The log-rank test was used to compare survival curves, and Cox regression models were used to assess independent factors associated with discontinuing medication. Between February 2000 and September 2004, 4,706 patients were registered in BIOBADASER, of whom 68% had rheumatoid arthritis, 11% ankylosing spondylitis, 10% psoriatic arthritis, and 11% other forms of chronic arthritis. One- and two-year drug survival rates of the TNF antagonist were 0.83 and 0.75, respectively. There were 488 patients treated with more than one TNF antagonist. In this situation, survival of the second TNF antagonist decreased to 0.68 and 0.60 at 1 and 2 years, respectively. Survival was better in patients replacing the first TNF antagonist because of adverse events (hazard ratio (HR) for discontinuation 0.55 (95% confidence interval (CI), 0.34–0.84)), and worse in patients older than 60 years (HR 1.10 (95% CI 0.97–2.49)) or who were treated with infliximab (HR 3.22 (95% CI 2.13–4.87)). In summary, in patients who require continuous therapy and have failed to respond to a TNF antagonist, replacement with a different TNF antagonist may be of use under certain situations. This issue will deserve continuous reassessment with the arrival of new medications.     

Survival of TNF antagonists in spondylarthritis is better than in rheumatoid arthritis. Data from the Spanish registry BIOBADASER

The aim of the present work is to compare drug survival and safety of infliximab, etanercept, and adalimumab (tumor necrosis factor [TNF] antagonists) in spondylarthritis (SpA) with those of rheumatoid arthritis (RA). To this purpose, we analysed the data in BIOBADASER (2000–2005), a drug registry launched in 2000 for long-term follow-up of the safety of these biologics in rheumatic diseases. The rates of drug discontinuation and adverse events (AEs) in SpA (n = 1,524) were estimated and compared with those of RA (n = 4,006). Cox regression analyses were used to adjust for independent factors. Total exposure to TNF antagonists for SpA was 2,430 patient-years and 7,865 for RA. Drug survival in SpA was significantly greater than in RA at 1, 2, and 3 years. The hazard ratio (HR) for discontinuation in SpA compared with RA was 0.66 (95% confidence interval [CI], 0.57–0.76) after adjustment for age, gender, and use of infliximab. The difference remained after controlling for the individual medication and its place in the sequence of treatment. There were fewer SpA patients with AEs (17%) than RA patients (26%; p < 0.001). The HR for AEs in SpA was 0.80 (95% CI, 0.70–0.91) compared with RA after adjustment for age, disease duration, and use of infliximab. In conclusion, due in part to a better safety profile, survival of TNF antagonists in SpA is better than in RA. TNF antagonists are at present a safe and effective therapeutic option for long-term treatment of patients with SpA failing to respond to traditional drugs. Because chronic therapy is necessary, continual review of this issue is necessary.     

Comparative Persistence of the TNF Antagonists in Rheumatoid Arthritis – A Population-Based Cohort Study

Objective

To compare persistence with tumor necrosis factor alpha (TNF) antagonists among rheumatoid arthritis patients in British Columbia. Treatment persistence has been suggested as a proxy for real-world therapeutic benefit and harm of treatments for chronic non-curable diseases, including rheumatoid arthritis. We hypothesized that the different pharmacological characteristics of infliximab, adalimumab and etanercept cause statistically and clinically significant differences in persistence.

Methods

We conducted a population-based cohort study using administrative health data from the Canadian province of British Columbia. The study cohort included rheumatoid arthritis patients who initiated the first course of a TNF antagonist between 2001 and 2008. Persistence was measured as the time between first dispensing to discontinuation. Drug discontinuation was defined as a drug-free interval of 180 days or switching to another TNF antagonist, anakinra, rituximab or abatacept. Persistence was estimated and compared using survival analysis.

Results

The study cohort included 2,923 patients, 63% treated with etanercept. Median persistence in years (95% confidence interval) with infliximab was 3.7 (2.9–4.9), with adalimumab 3.3 (2.6–4.1) and with etanercept 3.8 (3.3–4.3). Similar risk of discontinuation was observed for the three drugs: the hazard ratio (95% confidence interval) was 0.98 (0.85–1.13) comparing infliximab with etanercept, 0.95 (0.78–1.15) comparing infliximab with adalimumab and 1.04 (0.88–1.22) comparing adalimumab with etanercept.

Conclusions

Similar persistence was observed with infliximab, adalimumab and etanercept in rheumatoid arthritis patients during the first 9 years of use. If treatment persistence is a good proxy for the therapeutic benefit and harm of these drugs, then this finding suggests that the three drugs share an overall similar benefit-harm profile in rheumatoid arthritis patients.     

Seven-year follow-up of infliximab therapy in rheumatoid arthritis patients with severe long-standing refractory disease: attrition rate and evolution of disease activity

Introduction

This study is based on the results from a Belgian expanded access program in which patients with active refractory and erosive rheumatoid arthritis (RA) were treated with intravenous infusions of infliximab in combination with methotrexate. The objectives of this study were to evaluate the continuation rate of infliximab and its clinical effect over a 7-year period and to document the reasons for discontinuation.

Methods

Between 2000 and 2001, 511 patients with severe and refractory RA were enrolled and treated with infliximab. After 7 years, apart from routine clinical follow-up, treating rheumatologists were asked to complete a questionnaire designed specifically for the present study to evaluate the current therapy with infliximab, the level of disease activity (Disease Activity Score in 28 joints [DAS28]) and the reasons for infliximab discontinuation.

Results

After 7 years, 160 of 511 patients (31%) were still on infliximab treatment. The major reasons for infliximab discontinuation included lack of efficacy (104 patients), adverse events (107 patients) and elective change of therapy (70 patients). The majority of cases of treatment discontinuation for safety reasons occurred during the first 2 years. In contrast, discontinuation due to ineffectiveness showed a more constant rate over the 7-year period. Mean DAS for patients still on treatment with infliximab decreased from 5.7 (standard error [SE] 0.1) at baseline to 3.0 (SE 0.1) at year 4 and remained that low until year 7 (3.0 [SE 0.1]). Low disease activity (defined as DAS28 <3.2) was present in 60.9% of patients, and 45.5% achieved remission (DAS28 <2.6). DAS28 at the time of treatment discontinuation due to ineffectiveness decreased over the 7-year period from 5.6 (SE 0.3) in 2001 to 4.8 (SE 0.3) in 2008.

Conclusions

This observational study revealed that patients who continue to receive infliximab experience sustained clinical benefit. The majority of safety issues occurred during the first 2 years of infliximab therapy. We observed that the DAS at the time of therapy discontinuation showed a trend to decrease over time.     

Stereotactic radiosurgery for patients with breast cancer brain oligometastases — molecular subtypes and clinical outcomes

BackgroundWe sought to determine the clinical outcomes of patients with breast cancer (BC) who had undergone stereotactic radiosurgery (SRS) for a limited number of brain metastases (BM) and to identify factors influencing overall survival (OS) and local control.Materials and methodsThe records of 45 patients who underwent SRS for 72 brain lesions were retrospectively evaluated. Statistics included the chi-squared test, Kaplan-Meier method, and the multivariate Cox model.ResultsThe median number of treated BM was 2 (range 1–10). Median OS from BM diagnosis and post-SRS were 27.6 [95% confidence interval (CI): 14.8–40.5) and 18.5 months (95% CI: 11.1–25.8), respectively. One-year and two-year survival rates after BM diagnosis were 55% and 41%, respectively. In a univariate analysis, the Luminal-B-human-epidermal-growth-receptor-positive (HER2+) subtype had the longest median OS at 39.1 months (95% CI: 34.1–44.1, p = 0.004). In an adjusted analysis, grade 2 [hazard ratio (HR): 0.1; 95% CI: 0.1–0.6, p = 0.005), craniotomy (HR: 0.3; 95% CI: 0.1–0.7; p = 0.006), and ≥ 2 systemic therapies received (HR: 0.3; 95% CI: 0.1–0.9, p = 0.028) were associated with improved OS. One-year and two-year intracranial progression-free survival rates were 85% and 63%, respectively. Four factors for a higher risk of any intracranial recurrence remained significant in the adjusted analysis, as follows: age < 50 years (HR: 4.2; 95% CI: 1.3–36.3; p = 0.014), grade 3 (HR: 3.7; 95% CI: 1.1–13.2; p = 0.038), HER2+ (HR: 6.9; 95% CI: 1.3–36.3; p = 0.023), and whether the brain was the first metastatic site (HR: 4.7; 95% CI: 1.6–14.5; p = 0.006).ConclusionIntrinsic BC characteristics are important determinants for both survival and intracranial control for patients undergoing SRS for oligometastatic brain disease.     

Encouraging survival rates in patients with acute myocardial infarction treated with an intra-aortic balloon pump

Objective

To evaluate a 30-day and long-term outcome of patients with acute myocardial infarction (AMI) treated with intra-aortic balloon pump (IABP) counterpulsation and to identify predictors of a 30-day and long-term all-cause mortality.

Methods

Retrospective cohort study of 437 consecutive AMI patients treated with IABP between January 1990 and June 2004. A Cox proportional hazards model was used to identify predictors of a 30-day and long-term all-cause mortality.

Results

Mean age of the study population was 61 ± 11 years, 80% of the patients were male, and 68% had cardiogenic shock. Survival until IABP removal after successful haemodynamic stabilisation was 78% (n = 341). Cumulative 30-day survival was 68%. Median follow-up was 2.9 years (range, 6 months to 15 years). In patients who survived until IABP removal, cumulative 1-, 5-, and 10-year survival was 75%, 61%, and 39%, respectively. Independent predictors of higher long-term mortality were prior cerebrovascular accident (hazard ratio (HR), 1.8; 95% confidence interval (CI), 1.0–3.4), need for antiarrhythmic drugs (HR, 2.3; 95% CI, 1.5–3.3), and need for renal replacement therapy (HR, 2.3; 95% CI, 1.2–4.3). Independent predictors of lower long-term mortality were primary percutaneous coronary intervention (PCI; HR, 0.6; 95% CI, 0.4–1.0), failed thrombolysis with rescue PCI (HR, 0.5; 95% CI, 0.3–0.9), and coronary artery bypass grafting (HR, 0.3; 95% CI, 0.1–0.5).

Conclusions

Despite high in-hospital mortality in patients with AMI treated with IABP, a favourable number of patients survived in the long-term. These results underscore the value of aggressive haemodynamic support of patients throughout the acute phase of AMI.     

Impact of concomitant DMARD therapy on adherence to treatment with etanercept and infliximab in rheumatoid arthritis. Results from a six-year observational study in southern Sweden

The objective of this work is to compare the adherence to therapy of patients receiving etanercept and infliximab during first tumour necrosis factor (TNF)-blocking treatment course in rheumatoid arthritis. Special emphasis is placed on potential predictors for treatment termination and the impact of concomitant methotrexate (MTX) or other disease-modifying antirheumatic drugs (DMARDs). Patients (n = 1,161) with active rheumatoid arthritis, not responding to at least two DMARDs including MTX starting etanercept or infliximab therapy for the first time, were included in a structured clinical follow-up protocol. Information on diagnosis, disease duration, previous and ongoing DMARDs, treatment start and termination, as well as cause of withdrawal was prospectively collected during the period of March 1999 through December 2004. Patients were divided into six groups according to TNF-blocking drugs and concomitant DMARDs. Five-year level (one-year) of adherence to therapy was 36% (69%) for patients receiving infliximab in combination with MTX compared with 65% (89%) for patients treated with etanercept and MTX (p < 0.001). Cox regression models showed that the risk for premature treatment termination of patients treated with infliximab was threefold higher than for etanercept (p < 0.001). Also, the regression analysis showed that patients receiving concomitant MTX had better treatment continuation than patients treated solely with TNF blockers (p < 0.001). Moreover, patients receiving concomitant MTX had superior drug survival than patients receiving other concomitant DMARDs (p < 0.010). The superior effect of MTX was associated primarily with fewer treatment terminations because of adverse events. In addition, the study identifies low C-reactive protein level, high age, elevated health assessment questionnaire score, and higher previous number of DMARDs as predictors of premature treatment termination. In summary, treatment with etanercept has higher adherence to therapy than treatment with infliximab. Concomitant MTX is associated with improved treatment continuation of biologics when compared with both TNF blockers as monotherapy and TNF blockers combined with other DMARDs.     

Impact of concomitant DMARD therapy on adherence to treatment with etanercept and infliximab in rheumatoid arthritis. Results from a six-year observational study in southern Sweden

The objective of this work is to compare the adherence to therapy of patients receiving etanercept and infliximab during first tumour necrosis factor (TNF)-blocking treatment course in rheumatoid arthritis. Special emphasis is placed on potential predictors for treatment termination and the impact of concomitant methotrexate (MTX) or other disease-modifying antirheumatic drugs (DMARDs). Patients (n = 1,161) with active rheumatoid arthritis, not responding to at least two DMARDs including MTX starting etanercept or infliximab therapy for the first time, were included in a structured clinical follow-up protocol. Information on diagnosis, disease duration, previous and ongoing DMARDs, treatment start and termination, as well as cause of withdrawal was prospectively collected during the period of March 1999 through December 2004. Patients were divided into six groups according to TNF-blocking drugs and concomitant DMARDs. Five-year level (one-year) of adherence to therapy was 36% (69%) for patients receiving infliximab in combination with MTX compared with 65% (89%) for patients treated with etanercept and MTX (p < 0.001). Cox regression models showed that the risk for premature treatment termination of patients treated with infliximab was threefold higher than for etanercept (p < 0.001). Also, the regression analysis showed that patients receiving concomitant MTX had better treatment continuation than patients treated solely with TNF blockers (p < 0.001). Moreover, patients receiving concomitant MTX had superior drug survival than patients receiving other concomitant DMARDs (p < 0.010). The superior effect of MTX was associated primarily with fewer treatment terminations because of adverse events. In addition, the study identifies low C-reactive protein level, high age, elevated health assessment questionnaire score, and higher previous number of DMARDs as predictors of premature treatment termination. In summary, treatment with etanercept has higher adherence to therapy than treatment with infliximab. Concomitant MTX is associated with improved treatment continuation of biologics when compared with both TNF blockers as monotherapy and TNF blockers combined with other DMARDs.     

Incidence of active mycobacterial infections in Brazilian patients with chronic inflammatory arthritis and negative evaluation for latent tuberculosis infection at baseline - A longitudinal analysis after using TNFα blockers

Several studies point to the increased risk of reactivation of latent tuberculosis infection (LTBI) in patients with chronic inflammatory arthritis (CIAs) after using tumour necrosis factor (TNF)α blockers. To study the incidence of active mycobacterial infections (aMI) in patients starting TNF α blockers, 262 patients were included in this study: 109 with rheumatoid arthritis (RA), 93 with ankylosing spondylitis (AS), 44 with juvenile idiopathic arthritis (JIA) and 16 with psoriatic arthritis (PsA). All patients had indication for anti-TNF α therapy. Epidemiologic and clinical data were evaluated and a simple X-ray and tuberculin skin test (TST) were performed. The control group included 215 healthy individuals. The follow-up was 48 months to identify cases of aMI. TST positivity was higher in patients with AS (37.6%) than in RA (12.8%), PsA (18.8%) and JIA (6.8%) (p < 0.001). In the control group, TST positivity was 32.7%. Nine (3.43%) patients were diagnosed with aMI. The overall incidence rate of aMI was 86.93/100,000 person-years [95% confidence interval (CI) 23.6-217.9] for patients and 35.79/100,000 person-years (95% CI 12.4-69.6) for control group (p < 0.001). All patients who developed aMI had no evidence of LTBI at the baseline evaluation. Patients with CIA starting TNF α blockers and no evidence of LTBI at baseline, particularly with nonreactive TST, may have higher risk of aMI.     

Prognostic Significance of Molecular Analysis of Peritoneal Fluid for Patients with Gastric Cancer: A Meta-Analysis

Background

Accurately distinguishing serosal invasion in patients with gastric cancer (GC) prior to surgery can be difficult. Molecular analysis of peritoneal fluid (MAPF) for free cancer cells with higher sensitivity than other methods; however, its prognostic value for GC remains controversial, precluding its application in clinical practice.

Methods

PubMed, EMBASE and other databases were systematically searched. Thirty-one studies were eligible for the meta-analysis. Hazard ratios (HRs) and 95% confidence intervals (CIs) were pooled for overall survival (OS), disease-free survival (DFS) and peritoneal recurrence-free survival (PRF).

Results

The current meta-analysis focused on patients with GC and negative cytological diagnoses. The results showed that positive MAPF status (MAPF⁺) led to poorer prognoses for OS (HR 2.59, 95% CI 1.99–3.37), DFS (HR 4.92, 95% CI 3.28–7.37) and PRF (HR 2.81, 95% CI 2.12–3.72) compared with negative MAPF status (MAPF^-). Moreover, among the patients with GC who received curative treatment, the MAPF⁺ patients had poorer prognoses for OS (HR 3.27, 95% CI 2.49–4.29), DFS (HR 3.90, 95% CI 2.74–5.57) and PRF (HR 5.45, 95% CI 3.70–8.03). A meta-analysis of multivariate-adjusted HRs demonstrated that MAPF⁺ status was an independent prognostic factor for patients with GC who underwent curative treatment (OS: HR 2.19, 95% CI 1.47–3.28; PRF: HR 3.44, 95% CI 2.01–5.87). Using the identical target genes (CEA, CEA/CK20) as molecular markers, the patients with GC who were MAPF⁺ had significantly worse prognoses for OS (CEA: HR 3.03, 95% CI 2.29–4.01; CEA/CK20: HR 4.24, 95% CI 2.42–7.40), DFS (CEA: HR 3.99, 95% CI 2.24–7.12; CEA/CK20: HR 4.31, 95% CI 1.49–2.48) and PRF (CEA: HR 4.45, 95% CI 2.72–7.31; CEA/CK20: HR 6.46, 95% CI 3.62–11.55) than the patients who were MAPF^-.

Conclusion/Significance

The above results demonstrate that MAPF could be a prognostic indicator for patients with GC who have a negative cytological diagnosis and/or are receiving curative treatment. MAPF could provide clinicians with additional prognostic information that could aid in developing individualized treatment plans prior to surgery. The widely used target genes CEA, CEA/CK20 were confirmed to be valuable MAPF markers for predicting the prognosis of GC.     

Clinical Impact of Pancreatic Metastases from Renal Cell Carcinoma: A Multicenter Retrospective Analysis

Pancreatic metastases from renal cell carcinoma are uncommon and their prognostic significance is not well defined. In this analysis we evaluated the outcome of patients with pancreatic metastases treated with either targeted therapies or local treatment to the pancreas. Patients with pancreatic metastases from renal cell carcinoma treated between 1993 and 2014 were identified from 11 European centers. Clinical records were retrospectively reviewed. Kaplan-Meier method and log-rank test were used to evaluate progression-free survival and overall survival. Cox’s proportional hazard models were used for survival analysis. In total, 276 PM patients were evaluated, including 77 (28%) patients treated by either surgery or radiotherapy to the pancreas, and 256 (93%) who received systemic therapy. Median time from nephrectomy to diagnosis of pancreatic metastases was 91 months (IQR 54–142). Disease control rate after first-line TTs was 84%, with a median progression-free survival of 12 months (95% CI 10–14). Median overall survival was 73 months (95% CI 61–86) with a 5-year OS of 58%. Median OS of patients treated with local treatment was 106 months (95% CI 78–204) with a 5-year overall survival of 75%. On multivariable analysis, nephrectomy (HR 5.31; 95%CI 2.36–11.92; p<0.0001), Memorial Sloan Kettering/International Metastatic RCC Database Consortium prognostic score (HR 1.45, 95% CI 0.94–2.23 for intermediate vs good vs risk; HR 2.76 95%, CI 1.43–5.35 for poor vs good risk p = 0.0099) and pancreatic local treatment (HR 0.48; 95%CI 0.30–0.78 p = 0.0029) were associated with overall survival. Difference in median OS between patients with PM and that reported in a matched-control group of mRCC patients with extrapancreatic metastases was statistically significant (p < .0001). Pancreatic metastases from renal cell carcinoma usually occur years after nephrectomy, are associated with an indolent behavior and a prolonged survival. Targeted therapies and locoregional approaches are active and achieve high disease control rate.     

Hypothesis of Long-Term Outcome after Coronary Revascularization in Japanese Patients Compared to Multiethnic Groups in the US

Background

Ethnicity has a significant impact on coronary artery disease (CAD). This study investigated the long-term outcomes of Japanese patients undergoing revascularization compared with US patients belonging to multiple ethnic groups.

Methods and Results

We evaluated clinical outcomes, based on ethnicity, of patients included in the Coronary Revascularization Demonstrating Outcome (CREDO-Kyoto) and the Texas (US) Heart Institute Research Database (THIRDBase) registries. For the analysis, we included 8871 patients from the CREDO-Kyoto registry (median follow-up period [FU], 3.5 years; interquartile range [IQR], 2.6–4.3) and 6717 patients from the THIRDBase registry (FU, 5.2 years; IQR, 3.8–6.5) who underwent percutaneous coronary intervention or bypass surgery. Cox proportional hazard models were constructed to compare the adjusted long-term outcomes for each ethnic group. A total of 8871 Japanese, 5170 Caucasians, 648 African-Americans, 817 Hispanics, and 82 Asian-Americans were identified. When adjusted, Japanese patients had significantly better outcomes than US patients, classified by ethnicity (Caucasians: hazard ratio [HR], 1.56; 95% confidence interval [CI], 1.35–1.79; Hispanics: HR, 1.53; 95% CI, 1.22–1.93; African-Americans: HR, 2.03; 95% CI, 1.62–2.56), except for Asian-Americans (HR, 0.84; 95% CI. 0.38–1.89) who had outcomes similar to Japanese patients.

Conclusion

Our findings indicate better survival outcomes in re-vascularized Japanese CAD patients compared to major ethnic groups in the US, including Caucasian, Hispanic, and African-American CAD patients. The characteristics and outcomes of Japanese CAD patients were similar to those of Asian-Americans, despite the sample size limitations in the US dataset.     

Prognostic significance of CXCR7 in cancer patients: a meta-analysis

Background

CXC chemokine receptor 7 (CXCR7) is frequently overexpressed in a variety of tumors. Nevertheless, whether CXCR7 can be used as a tumor prognosis marker has not been systematically assessed. The current meta-analysis was performed to obtain an accurate evaluation of the relationship between CXCR7 level and the prognosis of cancer patients.

Methods

Embase, Web of Science, and PubMed were systematically searched according to a defined search strategy up to June 11, 2018. Then, the required data were extracted from all qualified studies which were screened out based on the defined inclusion and exclusion criteria. Finally, the hazard ratios (HR) with 95% confidence intervals (CI) were used to evaluate the prognostic significance of CXCR7 in tumor patients.

Results

A total of 28 original research studies comprising 33 cohorts and 5685 patients were included in this meta-analysis. The results showed that CXCR7 overexpression was significantly related to worse overall survival (OS) (HR 1.72; 95% CI 1.49–1.99), disease-free survival (DFS) (HR 5.58; 95% CI 3.16–9.85), progression-free survival (PFS) (HR 2.83; 95% CI 1.66–4.85) and recurrence-free survival (RFS) (HR 1.58; 95% CI 1.34–1.88) in cancer patients. Furthermore, for certain types of cancer, significant associations between higher CXCR7 expression and worse OS of glioma (HR 1.77; 95% CI 1.43–2.19), breast cancer (HR 1.45; 95% CI 1.28–1.63), esophageal cancer (HR 2.72; 95% CI 1.11–6.66) and pancreatic cancer (HR 1.46; 95% CI 1.12–1.90) were found. However, for lung cancer and hepatocellular cancer, there was no significant relationship between CXCR7 expression level and OS, (HR 2.40; 95% CI 0.34–17.07) and (HR 1.37; 95% CI 0.84–2.24) respectively.

Conclusions

Increased CXCR7 level could predict poor prognosis of tumor patients and might be regarded as a novel prognostic biomarker for tumor patients.

     

Neutrophil-to-eosinophil ratio as a biomarker for clinical outcomes in advanced stage melanoma patients treated with anti-PD-1 therapy

Neutrophil-to-lymphocyte ratios (NLR) and eosinophil counts are associated with improved survival in melanoma patients treated with immune checkpoint inhibitors, but no study has investigated neutrophil-to-eosinophil ratios (NER) as a predictive indicator in this population. In this retrospective study evaluating anti-PD-1 treated patients with advanced melanoma, progression-free survival (PFS), overall survival (OS), objective response rates (ORR), and risk of high-grade (grade ≥3) immune-related adverse events (irAEs) were compared between groups defined by median pretreatment NLR and NER as well as median NLR and NER at 1-month post-treatment. Lower baseline NLR and NER were associated with improved OS [HR: 0.504, 95% CI: 0.328–0.773, p = .002 and HR: 0.442, 95% CI: 0.288–0.681, p < .001, respectively] on univariate testing. After accounting for multiple covariates, our multivariate analysis found that lower pretreatment NER was associated with better ORR (by irRECIST) (OR: 2.199, 95% CI: 1.071–4.582, p = .033) and improved OS (HR: 0.480, 95% CI: 0.296–0.777, p = .003). Baseline NLR, 1-month NLR, and 1-month NER were not associated with ORR, PFS, or OS outcomes; but 1-month NER correlated with lower risk of grade ≥3 irAEs (OR: 0.392, 95% CI: 0.165–0.895, p = .029). Our findings suggest baseline NER merits additional investigation as a novel prognostic marker for advanced melanoma patients receiving anti-PD-1-based regimens.     

Antihypertensive medications and survival in patients with cancer: A population-based retrospective cohort study

Background: The association between antihypertensive medications and survival in cancer patients remains unclear. Objectives: To explore the association between classes of antihypertensive drugs and survival in cancer patients. Methods: Provincial Cancer Registry data was linked with a Provincial Drug Program Information Network (DPIN) for patients with lung (n = 4241), colorectal (n = 3967), breast (n = 4019) or prostate (n = 3355) cancer between the years of 2004 and 2008. Cox regression analyses were used to compare survival of patients using beta blockers (BBs), angiotensin-converting enzyme inhibitors/receptor blockers (ACEi/ARB), calcium channel blockers (CCBs) or thiazide diuretics (TDs) to survival of patients who did not use any of these antihypertensive drugs. Survival of patients using only one class of antihypertensive drugs were compared to each other, with BBs as the reference class. Results: Compared to the antihypertensive drug non-user cohort, BBs had no effect on survival for any of the cancers. ACEi/ARBs use was weakly associated with increased deaths for breast cancer (HR: 1.22, 95% CI: 1.04–1.44) and lung cancer (HR: 1.11, 95% CI: 1.03–1.21) patients. Deaths were also increased with CCB use in patients with breast cancer (HR: 1.22, 95% CI: 1.02–1.47) and with TD use in lung cancer patients (HR: 1.1, 95% CI: 1.01–1.19). There was strong evidence (p-value <0.0001) of an increase in deaths with TD use for colorectal (HR: 1.28, 95% CI: 1.15–1.42), and prostate (HR 1.41, 1.2–1.65) cancer patients. When including only antihypertensive drug users prescribed one drug class, lung cancer patients receiving CCBs had improved survival compared to BBs (HR 0.79, 95% CI: 0.64–0.98). Conclusions: Some classes of antihypertensive agents are associated with a decreased survival in certain cancers. The decrease could be due to more comorbidities in antihypertensive drug users. However, CCB use was associated with improved survival in lung cancer patients.     

The effect of solar-geomagnetic activity during and after admission on survival in patients with acute coronary syndromes

A number of studies have established the effects of solar-geomagnetic activity on the human cardio-vascular system. It is plausible that the heliophysical conditions existing during and after hospital admission may affect survival in patients with acute coronary syndromes (ACS). We analyzed data from 1,413 ACS patients who were admitted to the Hospital of Kaunas University of Medicine, Lithuania, and who survived for more than 4 days. We evaluated the associations between active-stormy geomagnetic activity (GMA), solar proton events (SPE), and solar flares (SF) that occurred 0–3 days before and after admission, and 2-year survival, based on Cox’s proportional-hazards model, controlling for clinical data. After adjustment for clinical variables, active-stormy GMA on the 2nd day after admission was associated with an increased (by 1.58 times) hazard ratio (HR) of cardiovascular death (HR?=?1.58, 95 % CI 1.07–2.32). For women, geomagnetic storm (GS) 2 days after SPE occurred 1 day after admission increased the HR by 3.91 times (HR?=?3.91, 95 % CI 1.31–11.7); active-stormy GMA during the 2nd–3rd day after admission increased the HR by over 2.5 times (HR?=?2.66, 95 % CI 1.40–5.03). In patients aged over 70 years, GS occurring 1 day before or 2 days after admission, increased the HR by 2.5 times, compared to quiet days; GS in conjunction with SF on the previous day, nearly tripled the HR (HR?=?3.08, 95 % CI 1.32–7.20). These findings suggest that the heliophysical conditions before or after the admission affect the hazard ratio of lethal outcome; adjusting for clinical variables, these effects were stronger for women and older patients.     

Four-year follow-up of infliximab therapy in rheumatoid arthritis patients with long-standing refractory disease: attrition and long-term evolution of disease activity

Although there is strong evidence supporting the short-term efficacy and safety of anti-tumour necrosis factor-alpha agents, few studies have examined the long-term effects. We evaluated 511 patients with long-standing refractory rheumatoid arthritis treated with intravenous infusions of infliximab 3 mg/kg at weeks 0, 2, 6, and 14 and every 8 weeks thereafter for 4 years. Among the initial 511 patients included in the study, 479 could be evaluated; of these, 295 (61.6%) were still receiving infliximab treatment at year 4 of follow-up. The most common reasons for treatment discontinuation were lack of efficacy (65 patients, 13.6%), safety (81 patients, 16.9%), and elective change (38 patients, 7.9%). Analysis of disease activity scores (DAS28 [disease activity score based on the 28-joint count]) over time showed that, after the initial rapid improvement during the first 6 to 22 weeks of therapy, a further decrease in disease activity of 0.2 units in the DAS28 score per year was observed. DAS28 scores, measured at week 14 or 22, were found to predict subsequent discontinuation due to lack of efficacy. In conclusion, long-term maintenance therapy with infliximab 3 mg/kg is effective in producing further reductions in disease activity. Disease activity measured by the DAS28 at week 14 or 22 of infliximab therapy was the best predictor of long-term attrition.     

Bilateral versus Single Internal Mammary Coronary Artery Bypass Grafting in Sweden from 1997–2008

Background

Prior observational studies have suggested better outcomes in patients who receive bilateral internal mammary arteries (BIMA) during coronary artery bypass grafting (CABG) compared with patients who receive a single internal mammary artery (SIMA). The aim of this study was to analyze the association between BIMA use and long-term survival in patients who underwent primary isolated CABG.

Methods and Results

Patients who underwent primary isolated non-emergent CABG in Sweden between 1997 and 2008 were identified. The SWEDEHEART registry and other national Swedish registers were used to acquire information about patient characteristics and outcomes. Unadjusted and multivariable adjusted regression models were used to estimate the association between BIMA use and early mortality, long-term survival, and a composite of death from any cause or rehospitalization for myocardial infarction, heart failure, or stroke in the overall cohort and in a propensity score-matched cohort. The study population consisted of 49702 patients who underwent CABG with at least one internal mammary artery, and 559 (1%) of those had BIMA grafting. In the adjusted analyses, BIMA use was not associated with better survival compared with SIMA use in the overall cohort (hazard ratio (HR) for death: 1.16, 95% confidence interval (CI): 0.97 to 1.37) or in the matched cohort (HR: 1.04, 95% CI: 0.78 to 1.40). The results were similar for early mortality and the composite endpoint. Reoperation for sternal wound complications was more common among BIMA patients (odds ratio: 1.71, 95% CI: 1.01 to 2.88).

Conclusions

BIMA grafting was performed infrequently and was not associated with better outcomes compared with SIMA grafting in patients undergoing non-emergent primary isolated CABG in Sweden during 1997–2008.     

Head-to-head comparison of the safety of tocilizumab and tumor necrosis factor inhibitors in rheumatoid arthritis patients (RA) in clinical practice: results from the registry of Japanese RA patients on biologics for long-term safety (REAL) registry

IntroductionThe objective of this study was to directly compare the safety of tocilizumab (TCZ) and TNF inhibitors (TNFIs) in rheumatoid arthritis (RA) patients in clinical practice.MethodsThis prospective cohort study included RA patients starting TCZ [TCZ group, n = 302, 224.68 patient-years (PY)] or TNFIs [TNFI group, n = 304, 231.01 PY] from 2008 to 2011 in the registry of Japanese RA patients on biologics for long-term safety registry. We assessed types and incidence rates (IRs) of serious adverse events (SAEs) and serious infections (SIs) during the first year of treatment. Risks of the biologics for SAEs or SIs were calculated using the Cox regression hazard analysis.ResultsPatients in the TCZ group had longer disease duration (P <0.001), higher disease activity (P = 0.019) and more frequently used concomitant corticosteroids (P <0.001) than those in the TNFI group. The crude IR (/100 PY) of SIs [TCZ 10.68 vs. TNFI 3.03; IR ratio (95% confidence interval [CI]), 3.53 (1.52 to 8.18)], but not SAEs [21.36 vs. 14.72; 1.45 (0.94 to 2.25)], was significantly higher in the TCZ group compared with the TNFI group. However, after adjusting for covariates using the Cox regression hazard analysis, treatment with TCZ was not associated with higher risk for SAEs [hazard ratio (HR) 1.28, 95% CI 0.75 to 2.19] or SIs (HR 2.23, 95% CI 0.93 to 5.37).ConclusionsThe adjusted risks for SAEs and SIs were not significantly different between TCZ and TNFIs, indicating an influence of clinical characteristics of the patients on the safety profile of the biologics in clinical practice.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-015-0583-8) contains supplementary material, which is available to authorized users.     

Survival of breast cancer patients in German-Danish border regions – A registry-based cohort study

Background and AimDenmark reports slightly lower breast cancer survival before 2010 than its neighbouring country Germany. Previous research is limited by lacking stage and treatment information. This study aims to investigate differences in breast cancer survival between the bordering regions Schleswig-Holstein (Germany), Southern Denmark and Zealand (Denmark) using registry data including stage and treatment information.MethodInvasive female breast cancer cases diagnosed during 2004−2013 with follow up through 31st December 2014 were extracted from cancer registries. Cases notified by death certificates only and those aged 90+ years were excluded. Kaplan-Meier curves and log-rank tests were computed. Cox regression analysis was conducted with adjustment for year of diagnosis, age, stage, and treatment.ResultsThe analytical sample included 42,966 cases. Kaplan-Meier curves and log-rank tests show significant survival differences between the regions. The Cox regression model adjusted for year of diagnosis and age shows significantly worse overall survival of breast cancer patients in both Danish regions compared to Schleswig-Holstein with hazard ratios (HR) of 1.09 (95 % CI: 1.04; 1.15) for patients from Southern Denmark (SD) and 1.25 (95 % CI: 1.18; 1.32) for residents of Zealand (ZL). This effect diminished after adjustment for stage and treatment (HR: 1.05 (SD), 1.09 (ZL) 95 % CI: 0.99; 1.10 (SD), 1.03; 1.15 (ZL)).ConclusionSurvival differences can be explained by differing stage distribution and treatment administration, which formerly were more favourable in Schleswig-Holstein. The survival gap will probably close due to Denmark’s national screening program and increased use of adjuvant cancer therapy.