Systematic review and meta-analysis of C-reactive protein as a biomarker in breast cancer.

Inflammation is an enabling characteristic of the hallmarks of cancer. There has therefore been increasing interest in the clinical value of circulating inflammatory biomarkers in cancer. In this review, we summarize results on C-reactive protein (CRP), alone or as part of the Glasgow Prognostic Score (GPS, composed of CRP and serum albumin), as a biomarker of prognosis or prediction and monitoring of therapeutic response in patients with breast cancer. A systematic literature search was performed in Medline and Embase from 1990 to August 2021. The association of serum CRP and overall survival and disease/progression-free survival was summarized in meta-analyses using a random effects model. The results from a total of 35 included studies (20,936 patients) were divided according to three identified patient settings (metastatic, non-metastatic, and general setting). Most of the studies examined prognostic utility. Several larger studies observed associations between high serum CRP and poor survival, but the meta-analyses suggested a limited value in a non-metastatic and general breast cancer setting (populations with unknown or varied disease stage). In metastatic patients, however, more consistent findings supported an association between serum CRP and prognosis (hazard ratio for overall survival: 1.87 (95% CI 1.31-2.67). Only five studies examined a role in prediction or monitoring of therapeutic response. One study reported a significant association between serum CRP levels and response to chemotherapy. Findings regarding serum CRP as a biomarker in breast cancer appear inconsistent, particularly in non-metastatic and general breast cancer, where the prognostic value could not be confirmed. In patients with metastatic breast cancer we suggest that high serum CRP is an indicator of poor prognosis. Too few studies assessed the role of serum CRP in prediction or monitoring of treatment response to allow conclusions.

Clinical Trials of Immune Checkpoint Inhibitors in Hepatocellular Carcinoma.

Introduction: Several immune checkpoint inhibitors (CPIs) are under clinical development in hepatocellular carcinoma (HCC) and the field is advancing rapidly. In this comprehensive review, we discuss published results and report on ongoing clinical trials. Methods: A literature search was carried out using PubMed and EMBASE; data reported at international meetings and clinicaltrials.gov were included as well. The search was updated 5 March 2021. We evaluated studies with monotherapy CPI's, combinations of CPI's and combinations of CPI's with other treatment modalities separately. Only studies with at least 10 included patients were considered. Results: We identified 2649 records published in the English language literature. After review, 29 studies remained, including 12 studies with preliminary data only. The obtained overall response rate of PD-1/PDL-1 monotherapy in phase II studies in the second-line setting was 15-20% with disease control in approximately 60% of patients. The responses were of long duration in a subset of patients. Furthermore, the safety profiles were manageable. However, a phase III study comparing nivolumab with sorafenib in the first-line setting and a phase III study evaluating pembrolizumab versus best supportive care in the second-line setting did not meet their prespecified endpoints. More recently, a phase I/II study of nivolumab and ipilimumab has resulted in a response rate of approximately 30% with a median OS of 22 months in the second-line setting. Multiple trials have been initiated to evaluate CPIs in combination with molecularly targeted drugs, especially anti-angiogenic drugs or local therapy. A phase III study investigating atezolizumab plus bevacizumab versus sorafenib in the first-line setting showed significantly increased survival in the combination arm. Conclusions: The combination of atezolizumab and bevacizumab represents a new standard of care in the first-line setting for fit patients with preserved liver function. CPIs can produce durable tumor remission and induce long-standing anti-tumor immunity in a subgroup of patients with advanced HCC. Although phase III trials of CPI monotherapy have been negative, the combination of PD-1/PD-L1 inhibitors with other anti-angiogenic drugs, CTLA-4 inhibitors or other modalities may result in new treatment options for patients with HCC. Research on predictive biomarkers is crucial for further development of CPIs in HCC.

Myocardial Ischemia Induced by 5-Fluorouracil: A Prospective Electrocardiographic and Cardiac Biomarker Study.

BACKGROUND: Cardiotoxicity induced by 5-fluorouracil (5-FU) is well known but poorly understood. In this study, we undertook ECG recording (Holter) and analyses of the biomarkers troponin and copeptin in patients receiving 5-FU to increase our understanding of the cardiotoxicity. SUBJECTS, MATERIALS, AND METHODS: Patients with colorectal or anal cancer that received first-time treatment with 5-FU-based chemotherapy were prospectively included. Holter recording, clinical evaluation, 12-lead electrocardiogram, and assessment of plasma concentrations of troponin I and copeptin were performed before (control) and during 5-FU treatment (intervention). RESULTS: A total of 108 patients were included, 82 with colorectal and 26 with anal cancer. The proportion of patients with myocardial ischemia on Holter recording was significantly higher during the first 5-FU infusion (14.1%) than before (3.7%; p = .001). The ischemic burden per day (p = .001), the number of ST depression episodes per day (p = .003), and the total duration of ischemic episodes per day (p = .003) were higher during the first 5-FU infusion than before, as was plasma copeptin (p < .001), whereas plasma troponin I was similar (p > 0.999). Six patients (5.6%) developed acute coronary syndromes and two (1.8%) developed symptomatic arrhythmias during 5-FU treatment. CONCLUSION: 5-FU infusion is associated with an increase in the number of patients with myocardial ischemia on Holter recording. According to biomarker analyses, 5-FU is associated with an increase in copeptin, but rarely with increases in cardiac troponin I. However, 5%-6% of the patients developed acute coronary syndromes during treatment with 5-FU. IMPLICATIONS FOR PRACTICE: Symptomatic 5-fluorouracil (5-FU) cardiotoxicity occurs in 0.6%-19% of patients treated with this drug, but a small electrocardiographic (Holter) study has revealed silent myocardial ischemia in asymptomatic patients, suggesting a more prevalent subclinical cardiac influence. This study demonstrated a significant increase in the number of patients with myocardial ischemia on Holter recording during 5-FU treatment and an increase in ischemic burden. Cardiac biomarker analyses suggested that 5-FU infusion results in endogenous stress (increased copeptin) but rarely induces myocyte injury (no change in troponin). These findings suggest a more prevalent cardiac influence from 5-FU and that Holter recording is an important tool in the evaluation of patients with suspected cardiotoxicity from 5-FU.

Wnt5a expression and prognosis in stage II-III colon cancer.

Cancer metastases accounts for most cancer deaths. The secreting glycoprotein Wnt5a impairs tumor cell migration and reduces invasiveness and metastasis. High Wnt5a expression in tumor cells is correlated to better outcomes in patients with breast, prostate and epithelial ovarian cancer. We aimed to investigate the association between the Wnt5a expression and outcomes in patients with colon cancer (CC) stage II/III. We performed a retrospective single-center study evaluating 345 patients with radical resection for primary CC, stage II/III, who started 6 months of adjuvant chemotherapy with 5-FU or capecitabine ±â€¯oxaliplatin between 2001 and 2015. Archived formalin-fixed paraffin embedded tumor tissue from resection specimens were stained with Wnt5a antibody using immunohistochemistry. Cytoplasmatic Wnt5a staining was assessed according to intensity and percentage of stained cells. Patients were divided in groups depending on high (n = 230) or low (n = 115) Wnt5a expression. Disease free survival (DFS) and overall survival (OS) were analyzed for the two groups using Kaplan-Meier plots and Long rank test. Patients with Wnt5a-negative tumors had significantly poorer performance status (PS) than patients with high Wnt5a expression (p = 0.046). No significant difference was seen between patients with low and high Wnt5a expression in terms of 5-year DFS (p = 0.517) or 5-year OS (p = 0.415). Poor PS was associated with lower DFS (p = 0.002) and OS (p < 0.001). In conclusion, we found no significant difference in prognosis for patients with stage II/III CC depending on their Wnt5a expression. Patients with Wnt5a-negative tumors had significant poorer PS than patients with higher levels. Poor PS was associated with lower DFS and OS.

Incidence and risk markers of 5-fluorouracil and capecitabine cardiotoxicity in patients with colorectal cancer.

Background: Fluoropyrimidines are mainstay chemotherapeutics in the treatment of gastrointestinal cancers and are also used to treat breast cancer and head and neck cancers. However, 5-flourouracil (5-FU) and capecitabine may induce cardiotoxicity that mostly presents as acute coronary syndromes. We compared the incidence of cardiotoxicity induced by 5-FU and capecitabine in patients with colorectal cancer and sought to identify risk markers for cardiotoxicity.Methods: We reviewed all consecutive patients with colorectal cancer who received 5-FU or capecitabine at one institution in the neoadjuvant (2007-2016), adjuvant (2000-2016) or metastatic setting (2007-2016).Results: Totally, 995 patients received 5-FU and 1241 received capecitabine. The incidence of cardiotoxicity induced by 5-FU was 5.2% [95% confidence interval (CI): 3.8-6.6%] and 4.1% (95% CI: 3.0-5.2%) induced by capecitabine (p = .21). The most common events were angina without ischemia (5-FU: 1.6%, capecitabine: 1.3%, p = .53), angina with ischemia on ECG (5-FU: 0.9%, capecitabine: 0.8%, p = .53), unspecified chest pain (5-FU: 0.9%, capecitabine: 0.6%, p = .34), ST-elevation myocardial infarction (5-FU: 0.5%; capecitabine: 0.4%, p = .76) and non-ST-elevation myocardial infarction (5-FU: 0.7%, capecitabine: 0.5%, p = .50). Cardiac arrest or sudden death occurred in 0.5 and 0.4%, respectively (p = 1). No risk markers for cardiotoxicity induced by 5-FU were identified. In the capecitabine group, ischemic heart disease was a risk marker (odds ratio: 2.9, 95% CI: 1.2-7.0, p = .016).Conclusions: Five percent of patients treated with 5-FU developed cardiotoxicity and 4% treated with capecitabine. Ischemic heart disease was a risk marker for cardiotoxicity induced by capecitabine.

Checkpoint inhibitors in pancreatic cancer.

INTRODUCTION: Immune checkpoint inhibitors, targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and the programmed cell death protein-1 (PD-1)/programmed cell death ligand-1 (PD-L1) pathways have shown remarkable potential in several types of cancer. In this review we summarize published and ongoing studies on checkpoint inhibitors in pancreatic cancer (PC). METHODS: We conducted a systematic literature search using Medline and Embase up to November 2018; additional data from a search on clinicaltrials.gov were included. Endpoints of interest encompassed overall survival (OS), progression free survival (PFS) and response rates. RESULTS: Full-length articles constituted a minority of included records. Furthermore, few patients were enrolled, and only few phase II studies were identified. Disappointing limited activity was demonstrated with single-agent checkpoint inhibitors in PC. A small number of studies on combination therapy showed promise with regards to response. But overall, PC patients treated with checkpoint inhibitors were not shown to elicit improvement in response rates or overall survival. CONCLUSION: Checkpoint inhibition monotherapy has failed to elicit efficacy in patients with pancreatic cancer. Combination regimens including chemotherapy have shown initial promise, but these results need to be verified. Numerous studies on checkpoint inhibition in PC are ongoing.

PD-L1 expression in breast cancer: expression in subtypes and prognostic significance: a systematic review.

PURPOSE: To systematically review the literature on the expression of PD-L1 in primary BC, variation of expression between subtypes and effect on overall survival (OS), disease-free survival (DFS), and recurrence-free survival (RFS). Additionally, for studies in the neoadjuvant setting, we have reviewed the ability of PD-L1 to predict pathological complete response (pCR). METHODS: Articles included in this review were retrieved by searching PubMed (1966-2018) and EMBASE (1980-2018). The following search terms were used: "PD-L1 expression" and "breast cancer" (PubMed234; EMBASE 161). RESULTS: Thirty-seven articles were found relevant to this study. We summarize important findings from these works, and show that the observed PD-L1 expression in the studies varies greatly, with expression rates ranging from 0 to 83% across subtypes. PD-L1 expression in relation to prognosis both in the adjuvant and neoadjuvant chemotherapy setting remains controversial, with studies finding better, worse, or no effect on prognosis. We also show that a wide variety of strategies are used when evaluating PD-L1 immunohistochemically, e.g., different cut-off points, different cell types evaluated, and different perceptions of when a cell is positive for PD-L1 (cytoplasmic vs membrane staining). CONCLUSION: Further investigation of PD-L1 expression in breast cancer and its effect on prognosis is required. There is little consensus on the methods used to evaluate PD-L1 expression immunohistochemically, and this may contribute to the diverging results found in this study.

Inhibitors targeting CDK4/6, PARP and PI3K in breast cancer: a review.

Breast cancer is the global leading cause of cancer-related death in women and it represents a major health burden worldwide. One of the promising breast cancer therapeutic avenues is through small molecule inhibitors (SMIs) which have undergone rapid progress with successful clinical trials. Recently, three emerging and vital groups of proteins are targeted by SMIs for breast cancer treatment, namely cyclin-dependent kinase 4 and 6 (CDK4/6), poly (adenosine diphosphate-ribose) polymerase (PARP) and phosphoinositide 3-kinase (PI3K). Several of these inhibitors have been approved for the treatment of breast cancer patients or progressed into late-stage clinical trials. Thus, modeling from these successful clinical trials, as well as their limitations, is pivotal for future development and trials of other inhibitors or therapeutic regimens targeting breast cancer patients. In this review, we discuss eight recently approved or novel SMIs against CDK4/6 (palbociclib, ribociclib and abemaciclib), PARP (olaparib, veliparib and talazoparib), and PI3K (buparlisib and alpelisib). The mechanisms of action, series of clinical trials and limitations are described for each inhibitor.

[Management of cardiovascular complications secondary to medical treatment of cancer].

As the prognoses of both heart and cancer patients have improved along with a longer life expectancy in the general population, the prevalence of both heart- and cancer diseases is increasing. Thus, a larger proportion of cancer patients will have cardiovascular co-morbidity and an increased risk of cardiovascular complications during and after cancer treatment. In this article, the current knowledge on the prevention, monitoring and treatment of cardiotoxicity induced by medical anti-cancer treatment with focus on anthracyclines, trastuzumab and 5-fluorouracil is described.

Checkpoint inhibitors in breast cancer - Current status.

INTRODUCTION: An increasing number of compounds directed against immune checkpoints are currently under clinical development. In this review we summarize current research in breast cancer. MATERIAL AND METHODS: A computer-based literature search was carried out using PubMed and EMBASE; data reported at international meetings and clinicaltrials.gov were included as well. RESULTS: The obtained overall response rate of PD-1/PD-L1 monotherapy varied from 5 to 30% in heavily pretreated triple negative breast cancer (TNBC). The median duration of progression free survival and overall survival were either not reported or short. Still responses were of long duration in a subset of patients. In the neoadjuvant setting, preliminary results including a very limited number of patients suggest high pathological response rates after combined blockade of the PD-1 pathway and chemotherapy. Multiple trials have been initiated to evaluate the combination of other anticancer agents and checkpoint inhibitors, especially in TNBC. In addition, ongoing studies aim to identify biomarkers to guide patient selection. CONCLUSION: Immune checkpoint inhibitors have the potential to produce durable tumor remission and induce long standing anti-tumor immunity in a subgroup of breast cancer patients. However, the identification of predictive biomarkers is crucial for further development of this treatment modality.

Efficacy and safety of regorafenib in the treatment of metastatic colorectal cancer: A systematic review.

PURPOSE: Despite advances in the treatment of colorectal cancer, third-line treatment options are still limited. Regorafenib was approved in 2012 for the treatment of patients with metastatic colorectal cancer previously treated with approved standard therapy. The purpose of this review is to present existing clinical data on regorafenib. METHOD: We systematically searched the PubMed and Embase databases, as well as ASCO and ESMO conference abstracts, for studies in English including ≥30 patients, evaluating the efficacy and safety of regorafenib in patients with metastatic colorectal cancer. A meta-analysis was conducted on the published, randomized phase III trials. RESULTS: 24 eligible studies were included. In two phase III trials, regorafenib significantly increased overall survival (OS), progression free survival (PFS), and disease control rate when compared to placebo. Survival benefits of 1.4 and 2.5 months were presented. The meta-analysis indicated a significant greater treatment effect on OS (hazard ratio 0.67) and PFS (hazard ratio 0.40), compared to placebo. The non-randomized studies mostly supported these results. The most frequently reported adverse events were hand-foot-skin reaction (25%-86%), hypertension (11%-47%) and fatigue (2%-73%). CONCLUSION: Large phase III randomized trials indicate that regorafenib provides a benefit in OS and PFS when compared to placebo. Adverse events were common, but manageable and typical of multi-target tyrosine kinase inhibitors. Further research is needed to investigate alternative approaches to the dosing of regorafenib and to explore clinical and molecular biomarkers that can guide patient selection.

Incidence and risk factors for capecitabine-induced symptomatic cardiotoxicity: a retrospective study of 452 consecutive patients with metastatic breast cancer.

OBJECTIVES: Case reports of capecitabine cardiotoxicity resemble those seen with intravenous 5-fluorouracil (5-FU) with chest pain as the predominant manifestation, but few studies of capecitabine cardiotoxicity are available. We aimed to determine the incidence of symptomatic cardiotoxicity from capecitabine in patients with breast cancer and to identify risk factors. METHODS: We reviewed medical records of consecutive women with breast cancer treated with capecitabine (1000 mg/m2 two times per day) from 2002 to 2012 at one institution. RESULTS: 22 of 452 patients (4.9%) (95% CI 2.9% to 6.9%) had symptoms of cardiotoxicity (chest pain: n=13, dyspnoea: n=9, palpitations: n=2). 11 patients had changes on ECG (atrial fibrillation: n=5, ST deviations: n=3, T-wave abnormalities: n=2 and QTc prolongation: n=1). 2 patients (0.4%) sustained acute myocardial infarction. 1 patient (0.2%) developed cardiac arrest with lethal outcome. 4 of 6 patients (66%) retreated with capecitabine had recurrent symptoms at retreatment. Cardiac comorbidity (p=0.001), hypercholesterolaemia (p=0.005) and current smoking (p=0.023) were risk factors for cardiotoxicity in univariate analyses and remained significant when adjusted for age. Patients with cardiac comorbidity were 5.5 times (95% CI 2.0 to 14.8) more likely to develop cardiotoxicity. In the subgroup of patients with apparently no cardiac comorbidity, the incidence of cardiotoxicity was lower (3.7%) and hypercholesterolaemia (p=0.035) and current smoking (p=0.020) were risk factors of cardiotoxicity. CONCLUSIONS: The incidence of cardiotoxicity from capecitabine resembles that of intravenous 5-FU (≈5%). Cardiac comorbidity, hypercholesterolaemia and current smoking were associated with development of cardiotoxicity.

Specific CDK4/6 inhibition in breast cancer: a systematic review of current clinical evidence.

BACKGROUND: Loss of cell cycle control is a hallmark of cancer, and aberrations in the cyclin-dependent kinase-retinoblastoma (CDK-Rb) pathway are common in breast cancer (BC). Consequently, inhibition of this pathway is an attractive therapeutic strategy. The present review addresses efficacy and toxicity of CDK4/6 inhibition in BC. METHODS: A literature search was carried out using PubMed and EMBASE; data reported at international meetings and clinicaltrials.gov were included. RESULTS: Three specific CDK4/6 inhibitors palbociclib, abemaciclib and ribociclib are tested in clinical trials. A randomised phase II trial of palbociclib plus letrozole versus letrozole and a phase III of palbociclib plus fulvestrant versus fulvestrant showed significantly increased progression-free survival when compared with endocrine therapy alone in first-line and second-line treatment for advanced hormone receptor-positive HER2-negative BC. At the moment several phase III studies are ongoing with all three CDK4/6 inhibitors in hormone receptor-positive HER2-negative BC as well as other subtypes of BC. The predominant toxicity of agents was limited neutropenia. Other common adverse events were infections, fatigue and gastrointestinal toxicity. The toxicities seemed manageable. Yet data are too limited to differentiate between the compounds. Retinoblastoma protein (Rb) is considered a promising biomarker. CONCLUSION: CDK4/6 inhibition might represent a substantial advance for patients with hormone receptor-positive HER2-negative BC. Results must be confirmed in phase III trials before any firm conclusions can be made regarding the future influence of CDK4/6 inhibition. There is an urgent need for prospective biomarker-driven trials to identify patients for whom CDK4/6 inhibition is cost-effective.

A systematic review of the pathophysiology of 5-fluorouracil-induced cardiotoxicity.

BACKGROUND: Cardiotoxicity is a serious side effect to treatment with 5-fluorouracil (5-FU), but the underlying mechanisms are not fully understood. The objective of this systematic review was to evaluate the pathophysiology of 5-FU- induced cardiotoxicity. METHODS: We systematically searched PubMed for articles in English using the search terms: 5-FU OR 5-fluorouracil OR capecitabine AND cardiotoxicity. Papers evaluating the pathophysiology of this cardiotoxicity were included. RESULTS: We identified 27 articles of 26 studies concerning the pathophysiology of 5-FU-induced cardiotoxicity. The studies demonstrated 5-FU-induced: hemorrhagic infarction, interstitial fibrosis and inflammatory reaction in the myocardium; damage of the arterial endothelium followed by platelet aggregation; increased myocardial energy metabolism and depletion of high energy phosphate compounds; increased superoxide anion levels and a reduced antioxidant capacity; vasoconstriction of arteries; changes in red blood cell (RBC) structure, function and metabolism; alterations in plasma levels of substances involved in coagulation and fibrinolysis and increased endothelin-1 levels and N-terminal-pro brain natriuretic peptide levels. Based on these findings the proposed mechanisms are: endothelial injury followed by thrombosis, increased metabolism leading to energy depletion and ischemia, oxidative stress causing cellular damage, coronary artery spasm leading to myocardial ischemia and diminished ability of RBCs to transfer oxygen resulting in myocardial ischemia. CONCLUSIONS: There is no evidence for a single mechanism responsible for 5-FU-induced cardiotoxicity, and the underlying mechanisms might be multifactorial. Further research is needed to elucidate the pathogenesis of this side effect.

Patient-reported outcome and risk of revision after shoulder replacement for osteoarthritis. 1,209 cases from the Danish Shoulder Arthroplasty Registry, 2006-2010.

PURPOSE: We used patient-reported outcome and risk of revision to compare hemiarthroplasty (HA) with total shoulder arthroplasty (TSA) and stemmed hemiarthroplasty (SHA) with resurfacing hemiarthroplasty (RHA) in patients with glenohumeral osteoarthritis. PATIENTS AND METHODS: We included all patients reported to the Danish Shoulder Arthroplasty Registry (DSR) between January 2006 and December 2010. 1,209 arthroplasties in 1,109 patients were eligible. Western Ontario Osteoarthritis of the Shoulder index (WOOS) was used to evaluate patient-reported outcome 1 year postoperatively. For simplicity of presentation, the raw scores were converted to a percentage of the maximum score. Revision rates were calculated by checking reported revisions to the DSR until December 2011. WOOS and risk of revision were adjusted for age, sex, previous surgery, and type of osteoarthritis. RESULTS: There were 113 TSAs and 1096 HAs (837 RHAs and 259 SHAs). Patients treated with TSA generally had a better WOOS, exceeding the predefined minimal clinically important difference, at 1 year (mean difference 10, p < 0.001). RHA had a better WOOS than SHA (mean difference 5, p = 0.02), but the difference did not exceed the minimal clinically important difference. There were no statistically significant differences in revision rate or in adjusted risk of revision between any of the groups. INTERPRETATION: Our results are in accordance with the results from other national shoulder registries and the results published in systematic reviews favoring TSA in the treatment of glenohumeral osteoarthritis. Nonetheless, this registry study had certain limitations and the results should be interpreted carefully.

Cardiotoxicity in cancer patients treated with 5-fluorouracil or capecitabine: a systematic review of incidence, manifestations and predisposing factors.

PURPOSE: To systematically review the incidence, manifestations and predisposing factors for cardiovascular toxicity in cancer patients treated with systemic 5-fluorouracil or capecitabine. DESIGN: We searched PubMed, EMBASE and Web of science for studies with ≥ 20 cancer patients evaluating cardiovascular toxicity of 5-fluorouracil and capecitabine. We hand searched the reference lists of all included studies. Study selection and assessment of risk of bias were performed by two authors independently. RESULTS: We identified 30 eligible studies (1 meta-analyses of 4 RCTs, 18 prospective and 11 retrospective). Symptomatic cardiotoxicity occurred in 0-20% of the patients treated with 5-fluorouracil and in 3-35% with capecitabine. The most common symptom was chest pain (0-18.6%) followed by palpitations (0-23.1%), dyspnoea (0-7.6%) and hypotension (0-6%). Severe clinical events such as myocardial infarction, cardiogenic shock and cardiac arrest occurred in 0-2%. Mortality rates ranged from 0 to 8%. Asymptomatic cardiac influence was demonstrated on ECG, in NT-proBNP measurements and with ultrasonic cyclic variation of integrated backscatter. Predisposing factors were mostly tested in univariate analyses. Preexisting cardiac disease was a risk factor in some studies, but there were divergent results. There was some evidence for increased cardiotoxicity during continuous infusion schedules and with concomitant cisplatin treatment. The effects of previous or current chest-radiotherapy were ambiguous. CONCLUSION: Larger studies suggest an incidence of symptomatic cardiotoxicity of 1.2-4.3% during fluorouracil treatment, however subclinical cardiac influence are common. Possible risk factors are cardiac co-morbidity, continuous infusion schedules and concomitant cisplatin treatment, but existing evidence are of insufficient quality.

Reliability of patient-reported functional outcome in a joint replacement registry. A comparison of primary responders and non-responders in the Danish Shoulder Arthroplasty Registry.

BACKGROUND AND PURPOSE: Patient-reported outcome measures (PROMs) are used by some arthroplasty registries to evaluate results after surgery, but non-response may bias the results. The aim was to identify a potential bias in the outcome scores of subgroups in a cohort of patients from the Danish Shoulder Arthroplasty Registry (DSR) and to characterize non-responders. METHODS: Patient-reported outcome of 787 patients operated in 2008 was assessed 12 months postoperatively using the Western Ontario Osteoarthritis of the Shoulder (WOOS) index. In January 2012, non-responders and incomplete responders were sent a postal reminder. Non-responders to the postal reminder were contacted by telephone. Total WOOS score and WOOS subscales were compared for initial responders (n = 509), responders to the postal reminder (n = 156), and responders after telephone contact (n = 27). The predefined variables age, sex, diagnosis, geographical region, and reoperation rate were compared for responding and non-responding cohorts. RESULTS: A postal reminder increased the response rate from 65% (6% incomplete) to 80% (3% incomplete) and telephone contact resulted in a further increase to 82% (2% incomplete). We did not find any statistically significant differences in total WOOS score or in any of the WOOS subscales between responders to the original questionnaire, responders to the postal reminder, and responders after telephone contact. However, a trend of worse outcome for non-responders was found. The response rate was lower in younger patients. INTERPRETATION: Non-responders did not appear to bias the overall results after shoulder replacement despite a trend of worse outcome for a subgroup of non-responders. As response rates rose markedly by the use of postal reminders, we recommend the use of reminders in arthroplasty registries using PROMs.