Adherence to oral anticancer treatment: focus on quality of execution during continuous schema of treatment

Background and objective: Oral anti-cancer treatments have expanded rapidly over the last years. While taking oral tablets at home ensures a better quality of life, it also exposes patients to the risk of sub-optimal adherence. The objective of this study is to assess how well ambulatory cancer patients execute their prescribed dosing regimen while they are engaged with continuous anti-cancer treatments. Design: This is an on-going longitudinal study. Consecutive patients starting an oral treatment are proposed to enter the study by the oncologist. Then they are referred to the pharmacy, where their oral anticancer treatment is dispensed in a Medication Event Monitoring System (MEMSTM), which records date and time of each opening of the drug container. Electronically compiled dosing history data from the MEMS are summarized and used as feedback during semistructured interviews with the pharmacist, which are dedicated to prevention and management of side effects. Interviews are scheduled before each medical visit. Report of the interview is available to the oncologist via an on-line secured portal. Setting: Seamless care approach between a Multidisciplinary Oncology Center and the Pharmacy of an Ambulatory Care and Community Medicine Department. Main outcome measures: For each patient, the comparison between the electronically compiled dosing history and the prescribed regimen was summarized using a daily binary indicator indicating whether yes or no the patient has taken the medication as prescribed. Results: Study started in March 2008. Among 22 eligible patients, 19 were included (11 men, median age 63 years old) and 3 (14%) refused to participate. 15 patients were prescribed a QD regimen, 3 patients a BID and 1 patient switched from QD to BID during follow-up. Median follow up was 182 days (IQR 72-252). Early discontinuation happened in four patients: side effects (n = 1), psychiatric reasons (n = 1), cancer progression (n = 1) and death (n = 1). On average, the daily number of medications was taken as prescribed in 99% of the follow-up days. Conclusions: Execution of the prescribed dosing regimens was almost perfect during the first 6 months. Maintaining this high degree of regimen execution and persistence over time might however be challenging in this population and need therefore to be confirmed in larger and longer follow-up cohort studies.

EORTC topics in neurooncology: The long path from a focus on neurological complications of cancer towards molecularly defined trials and therapies in neurooncology

Over the past decade a series of trials of the EORTC Brain Tumor Group (BTG) has substantially influenced and shaped the standard-of-care of primary brain tumors. All these trials were coupled with biological research that has allowed for better understanding of the biology of these tumors. In glioblastoma, EORTC trial 26981/22981 conducted jointly with the National Cancer Institute of Canada Clinical Trials Group showed superiority of concomitant radiochemotherapy with temozolomide over radiotherapy alone. It also identified the first predictive marker for benefit from alkylating agent chemotherapy in glioblastoma, the methylation of the O6-methyl-guanyl-methly-transferase (MGMT) gene promoter. In another large randomized trial, EORTC 26951, adjuvant chemotherapy in anaplastic oligodendroglial tumors was investigated. Despite an improvement in progression-free survival this did not translate into a survival benefit. The third example of a landmark trial is the EORTC 22845 trial. This trial led by the EORTC Radiation Oncology Group forms the basis for an expectative approach to patients with low-grade glioma, as early radiotherapy indeed prolongs time to tumor progression but with no benefit in overall survival. This trial is the key reference in deciding at what time in their disease adult patients with low-grade glioma should be irradiated. Future initiatives will continue to focus on the conduct of controlled trials, rational academic drug development as well as systematic evaluation of tumor tissue including biomarker development for personalized therapy. Important lessons learned in neurooncology are to dare to ask real questions rather than merely rapidly testing new compounds, and the value of well designed trials, including the presence of controls, central pathology review, strict radiology protocols and biobanking. Structurally, the EORTC BTG has evolved into a multidisciplinary group with strong transatlantic alliances. It has contributed to the maturation of neurooncology within the oncological sciences.

Effect of religion on suicide attempts in outpatients with schizophrenia or schizo-affective disorders compared with inpatients with non-psychotic disorders

Little is known of the relations between psychosis, religion and suicide. One hundred and fifteen outpatients with schizophrenia or schizo-affective disorder and 30 inpatients without psychotic symptoms were studied using a semi-structured interview assessing religiousness/spirituality. Their past suicide attempts were examined. Additionally, they were asked about the role (protective or incentive) of religion in their decision to commit suicide. Forty-three percent of the patients with psychosis had previously attempted suicide. Religiousness was not associated with the rate of patients who attempted suicide. Twenty-five percent of all subjects acknowledged a protective role of religion, mostly through ethical condemnation of suicide and religious coping. One out of ten patients reported an incentive role of religion, not only due to negatively connotated issues but also to the hope for something better after death. There were no differences between groups (i.e. psychotic vs. non-psychotic patients). Religion may play a specific role in the decisions patients make about suicide, both in psychotic and non-psychotic patients. This role may be protective, a finding particularly important for patients with psychosis who are known to be at high risk of severe suicide attempts. Interventions aiming to lower the number of suicide attempts in patients with schizophrenia should take these data into account.

Impact of enhanced compliance initiatives on the efficacy of rosuvastatin in reducing low density lipoprotein cholesterol levels in patients with primary hypercholesterolaemia.

The effectiveness of lipid-lowering medication critically depends on the patients' compliance and the efficacy of the prescribed drug. The primary objective of this multicentre study was to compare the efficacy of rosuvastatin with or without access to compliance initiatives, in bringing patients to the Joint European Task Force's (1998) recommended low-density lipoprotein cholesterol (LDL-C) level goal (LDL-C, <3.0 mmol/L) at week 24. Secondary objectives were comparison of the number and percentage of patients achieving European goals (1998, 2003) for LDL-C and other lipid parameters. Patients with primary hypercholesterolaemia and a 10-year coronary heart disease risk of >20% received open label rosuvastatin treatment for 24 weeks with or without access to compliance enhancement tools. The initial daily dosage of 10 mg could be doubled at week 12. Compliance tools included: a) a starter pack for subjects containing a videotape, an educational leaflet, a passport/goal diary and details of the helpline and/or website; b) regular personalised letters to provide message reinforcement; c) a toll-free helpline and a website. The majority of patients (67%) achieved the 1998 European goal for LDL-C at week 24. 31% required an increase in dosage of rosuvastatin to 20 mg at week 12. Compliance enhancement tools did not increase the number of patients achieving either the 1998 or the 2003 European target for plasma lipids. Rosuvastatin was well tolerated during this study. The safety profile was comparable with other drugs of the same class. 63 patients in the 10 mg group and 58 in the 10 mg Plus group discontinued treatment. The main reasons for discontinuation were adverse events (39 patients in the 10 mg group; 35 patients in the 10 mg Plus group) and loss to follow-up (13 patients in the 10 mg group; 9 patients in the 10 mg Plus group). The two most frequently reported adverse events were myalgia (34 patients, 3% respectively) and back pain (23 patients, 2% respectively). The overall rate of temporary or permanent study discontinuation due to adverse events was 9% (n = 101) in patients receiving 10 mg rosuvastatin and 3% (n = 9) in patients titrated up to 20 mg rosuvastatin. Rosuvastatin was effective in lowering LDL-C values in patients with hypercholesterolaemia to the 1998 European target at week 24. However, compliance enhancement tools did not increase the number of patients achieving any European targets for plasma lipids.

European cancer mortality predictions for the year 2016 with focus on leukemias.

BACKGROUND: Current cancer mortality statistics are important for public health decision making and resource allocation. Age standardized rates and numbers of deaths are predicted for 2016 in the European Union. PATIENTS AND METHODS: Population and death certification data for stomach, colorectum, pancreas, lung, breast, uterus, prostate, leukemia and total cancers were obtained from the World Health Organisation database and Eurostat. Figures were derived for the EU, France, Germany, Italy, Poland, Spain and the UK. Projected numbers of deaths by age group were obtained for 2016 by linear regression on estimated numbers of deaths over the most recent time period identified by a joinpoint regression model. RESULTS: Projected total cancer mortality trends for 2016 in the EU are favourable in both sexes with rates of 133.5/100,000 men and 85.2/100,000 women (8% and 3% falls since 2011, due to population ageing) corresponding to 753,600 and 605,900 deaths in men and women for a total number of 1,359,500 projected cancer deaths (+3% compared to 2011). In men lung, colorectal and prostate cancer fell 11%, 5% and 8% since 2011. Breast and colorectal cancer trends in women are favourable (8% and 7% falls, respectively), but lung and Pancreatic cancer rates rose 5% and 4% since 2011 reaching rates of 14.4 and 5.6/100,000 women. Leukemia shows favourable projected mortality for both sexes and all age groups with stronger falls in the younger age groups, rates are 4.0/100,000 men and 2.5/100,000 women, with respectively falls of 14% and 12%. CONCLUSION: The 2016 predictions for EU cancer mortality confirm the favourable trends in rates particularly for men. Lung cancer is likely to remain the leading site for female cancer rates. Continuing falls in mortality, larger in children and young adults, are predicted in leukemia, essentially due to advancements in management and therapy, and their subsequent adoption across Europe.

Cognition and psychopathology in nonagenarians and centenarians living in geriatric nursing homes in Switzerland: a focus on anosognosia.

BACKGROUND: The number of nonagenarians and centenarians is rising dramatically, and many of them live in nursing homes. Very little is known about psychiatric symptoms and cognitive abilities other than memory in this population. This exploratory study focuses on anosognosia and its relationship with common psychiatric and cognitive symptoms. METHODS: Fifty-eight subjects aged 90 years or older were recruited from geriatric nursing homes and divided into five groups according to Mini-Mental State Examination scores. Assessment included the five-word test, executive clock-drawing task, lexical and categorical fluencies, Anosognosia Questionnaire-Dementia, Neuropsychiatric Inventory, and Charlson Comorbidity Index. RESULTS: Subjects had moderate cognitive impairment, with mean ± SD Mini-Mental State Examination being 15.41 ± 7.04. Anosognosia increased with cognitive impairment and was associated with all cognitive domains, as well as with apathy and agitation. Subjects with mild global cognitive decline seemed less anosognosic than subjects with the least or no impairment. Neither anosognosia nor psychopathological features were related to physical conditions. CONCLUSIONS: Anosognosia in oldest-old nursing home residents was mostly mild. It was associated with both cognitive and psychopathological changes, but whether anosognosia is causal to the observed psychopathological features requires further investigation.

Treatment of atypical hemolytic uremic syndrome and thrombotic microangiopathies: a focus on eculizumab.

Uncontrolled complement activation is central to the occurrence of atypical hemolytic uremic syndrome (aHUS) and can result in thrombotic microangiopathies (TMAs).These terms encompass a group of heterogenic inherited or acquired diseases that recent research suggests may be triggered by the complement cascade. Pathogenetic triggers of complement activation include immunologic disorders, genetics, infections, systemic diseases, pregnancy, drug administration, metabolic diseases, transplantation, or triggers of mixed cause. Hallmarks of aHUS and other TMAs include increased vascular endothelium thromboresistance, leukocyte adhesion to damaged endothelium, complement consumption, coagulation abnormalities, and vascular shear stress, whereas common end points of these mechanisms include hemolytic anemia, thrombocytopenia with microvascular infarction, and predisposition for decreased kidney function and other organ involvement. The central role of the complement cascade as a disease trigger suggests a possible therapeutic target. Eculizumab, a first-in-class humanized monoclonal anti-C5 antibody that has been successful in the treatment of paroxysmal nocturnal hemoglobinuria, a disorder of complement-induced hemolytic anemia, received approval for the treatment of aHUS in the United States and Europe in late 2011. We review the treatment of aHUS and other TMAs, focusing on the role of eculizumab, including its pharmacology, mechanism of action, and approved dosing recommendations and health economic considerations. Finally, the potential for future indications for eculizumab use in other complement-driven diseases is discussed.

Effect of immunisation against angiotensin II with CYT006-AngQb on ambulatory blood pressure: a double-blind, randomised, placebo-controlled phase IIa study.

BACKGROUND: Hypertension can be controlled adequately with existing drugs such as angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers. Nevertheless, treatment success is often restricted by patients not adhering to treatment. Immunisation against angiotensin II could solve this problem. We investigated the safety and efficacy of CYT006-AngQb-a vaccine based on a virus-like particle-that targets angiotensin II to reduce ambulatory blood pressure. METHODS: In this multicentre, double-blind, randomised, placebo-controlled phase IIa trial, 72 patients with mild-to-moderate hypertension were randomly assigned with a computer-generated randomisation list to receive subcutaneous injections of either 100 mug CYT006-AngQb (n=24), 300 mug CYT006-AngQb (24), or placebo (24), at weeks 0, 4, and 12. 24-h ambulatory blood pressure was measured before treatment and at week 14. The primary outcomes were safety and tolerability. Analyses were done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00500786. FINDINGS: Two patients in the 100 mug group, three in the 300 mug group, and none in the placebo group discontinued study treatment. All patients were included in safety analyses; efficacy analyses did not include the five dropouts, for whom no data were available at week 14. Five serious adverse events were reported (two in the 100 mug group, two in the 300 mug group, and one in the placebo group); none were deemed to be treatment related. Most side-effects were mild, transient reactions at the injection site. Mild, transient influenza-like symptoms were seen in three patients in the 100 mug group, seven in the 300 mug group, and none in the placebo group. In the 300 mug group, there was a reduction from baseline in mean ambulatory daytime blood pressure at week 14 by -9.0/-4.0 mm Hg compared with placebo (p=0.015 for systolic and 0.064 for diastolic). The 300 mug dose reduced the early morning blood-pressure surge compared with placebo (change at 0800 h -25/-13 mm Hg; p<0.0001 for systolic, p=0.0035 for diastolic). INTERPRETATION: Immunisation with CYT006-AngQb was associated with no serious adverse events; most observed adverse events were consistent with local or systemic responses similar to those seen with other vaccines. The 300 mug dose reduced blood pressure in patients with mild-to-moderate hypertension during the daytime, especially in the early morning. FUNDING: Cytos Biotechnology AG.

The future key role of LC-high-resolution-MS analyses in clinical laboratories: a focus on quantification.

For the last decade, high-resolution (HR)-MS has been associated with qualitative analyses while triple quadrupole MS has been associated with routine quantitative analyses. However, a shift of this paradigm is taking place: quantitative and qualitative analyses will be increasingly performed by HR-MS, and it will become the common 'language' for most mass spectrometrists. Most analyses will be performed by full-scan acquisitions recording 'all' ions entering the HR-MS with subsequent construction of narrow-width extracted-ion chromatograms. Ions will be available for absolute quantification, profiling and data mining. In parallel to quantification, metabotyping will be the next step in clinical LC-MS analyses because it should help in personalized medicine. This article is aimed to help analytical chemists who perform targeted quantitative acquisitions with triple quadrupole MS make the transition to quantitative and qualitative analyses using HR-MS. Guidelines for the acceptance criteria of mass accuracy and for the determination of mass extraction windows in quantitative analyses are proposed.

Epidémiologie des cancers épithéliaux de la peau [Epidemiology of epithelial skin cancers]

With no less than 15,000 estimated new cases diagnosed per year, non melanomatous carcinomas are the commonest cutaneous cancers in the Swiss population. About 1 in 3 new cancer case is a basal (BCC) or a squamous cell carcinoma (SCC). Incidence rates are steadily increasing, faster for BCC than SCC. Rates are higher for men than women and increase exponentially with age. Systematic population-based registration of non melanomatous skin cancers faces many challenges that few cancer registries can meet. Rates of these cancers in Switzerland are among the highest in Europe. Primary and secondary nationwide prevention campaigns have been carried out for nearly 20 years with a focus on the deadliest cutaneous cancer: melanoma. However, detection of non melanomatous skin cancers benefits from these campaigns since prevention messages and means of early detection are similar for melanomas and other skin cancers.

Prediction of myocardial infarction size using the SYNTAX score in patients treated with primary percutaneous coronary intervention for acute ST- segment elevation myocardial infarction

Objectives The relevance of the SYNTAX score for the particular case of patients with acute ST- segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI)  has previously only been studied in the setting of post hoc analysis of large prospective randomized clinical trials. A "real-life" population approach has never been explored before. The aim of this study was to evaluate the impact of the SYNTAX score for the prediction of the myocardial infarction size, estimated by the creatin-kinase (CK) peak value, using the SYNTAX score in patients treated with primary coronary intervention for acute ST-segment elevation myocardial infarction. Methods The primary endpoint of the study was myocardial infarction size as measured by the CK peak value. The SYNTAX score was calculated retrospectively in 253 consecutive patients with acute ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI) in a large tertiary referral center in Switzerland, between January 2009 and June 2010. Linear regression analysis was performed to compare myocardial infarction size with the SYNTAX score. This same endpoint was then stratified according to SYNTAX score tertiles: low <22 (n=178), intermediate [22-32] (n=60), and high >=33 (n=15). Results There were no significant differences in terms of clinical characteristics between the three groups. When stratified according to the SYNTAX score tertiles, average CK peak values of 1985 (low<22), 3336 (intermediate [22-32]) and 3684 (high>=33) were obtained with a p-value <0.0001. Bartlett's test for equal variances between the three groups was 9.999 (p-value <0.0067). A moderate Pearson product-moment correlation coefficient (r=0.4074) with a high statistical significance level (p-value <0.0001) was found. The coefficient of determination (R^2=0.1660) showed that approximately 17% of the variation of CK peak value (myocardial infarction size) could be explained by the SYNTAX score, i.e. by the coronary disease complexity. Conclusion In an all-comers population, the SYNTAX score is an additional tool in predicting myocardial infarction size in patients treated with primary percutaneous coronary intervention (PPCI). The stratification of patients in different risk groups according to SYNTAX enables to identify a high-risk population that may warrant particular patient care.

Levetiracetam and pregabalin for antiepileptic monotherapy in patients with primary brain tumors. A phase II randomized study.

BACKGROUND: In patients with brain tumors, the choice of antiepileptic medication is guided by tolerability and pharmacokinetic interactions. This study investigated the effectiveness of levetiracetam (LEV) and pregabalin (PGB), 2 non-enzyme-inducing agents, in this setting. METHODS: In this pragmatic, randomized, unblinded phase II trial (NCT00629889), patients with primary brain tumors and epilepsy were titrated to a monotherapy of LEV or PGB. Efficacy and tolerability were assessed using structured questionnaires. The primary composite endpoint was the need to discontinue the study drug, add-on of a further antiepileptic treatment, or occurrence of at least 2 seizures with impaired consciousness during 1 year follow-up. RESULTS: Over 40 months, 25 patients were randomized to LEV, and 27 to PGB. Most were middle-aged men, with a high-grade tumor and at least one generalized convulsion. Mean daily doses were 1125 mg (LEV) and 294 mg (PGB). Retention rates were 59% in the LEV group, and 41% in the PGB group. The composite endpoint was reached in 9 LEV and 12 PGB patients-need to discontinue: side effects, 6 LEV, 3 PGB; lack of efficacy, 1 and 2; impaired oral administration, 0 and 2; add-on of another agent: 1 LEV, 4 PGB; and seizures impairing consciousness: 1 in each. Seven LEV and 5 PGB subjects died of tumor progression. CONCLUSIONS: This study shows that LEV and PGB represent valuable monotherapy options in this setting, with very good antiepileptic efficacy and an acceptable tolerability profile, and provides important data for the design of a phase III trial.

Expertises croisées dans la dégénérescence maculaire liée à l'âge. Focus sur la physiopathologie, l'angiogenèse, les données pharmacologiques et cliniques [Review and expert opinion in age related macular degeneration. Focus on the pathophysiology, angiogenesis and pharmacological and clinical data].

Age related macular degeneration (AMD) is a pathological aging of the macula, brought about by the interaction of genetic and environmental factors. It induces geographic atrophy of the retina and/or choroidal neovascularization. In the latter, abnormal vessels develop from the choriocapillaris, with the involvement of VEGF (vascular endothelial growth factor). The VEGF family includes several factors, including VEGF-A, B, C, D, F and PlGF (placental growth factor). Their biological properties and their affinities to the VEGFR1, VEGFR2 and VEGFR3 receptors found on endothelial cells differ. Exudative AMD involves mainly VEGF-A and VEGF-R2. Anti-VEGF agents used in ophthalmology (ranibizumab, bevacizumab and aflibercept) are designed to primarily target this pathway. In vitro, all have sufficient affinity to their ligands. Their therapeutic efficacy must therefore be judged based on clinical criteria. In clinical practice, the minimum number of injections required for a satisfactory result appears to be comparable with all the three. The few available studies on therapeutic substitutions of anti-VEGF compounds suggest that some patients may benefit from substituting the anti-VEGF in cases of an unsatisfactory response to an initial molecule. Although local side effects, including increased risk of geographic atrophy, and systemic effects, including vascular accidents, have been suggested, these risks remain low, specially compared to the benefits of the treatment. Differences in safety between anti-VEGF are theoretically possible but unproven.