Use of Sequential Multiple Assignment Randomized Trials (SMARTs) in oncology: systematic review of published studies.

Sequential multiple assignments randomized trials (SMARTs) are a type of experimental design where patients may be randomised multiple times according to pre-specified decision rules. The present work investigates the state-of-the-art of SMART designs in oncology, focusing on the discrepancy between the available methodological approaches in the statistical literature and the procedures applied within cancer clinical trials. A systematic review was conducted, searching PubMed, Embase and CENTRAL for protocols or reports of results of SMART designs and registrations of SMART designs in clinical trial registries applied to solid tumour research. After title/abstract and full-text screening, 33 records were included. Fifteen were reports of trials' results, four were trials' protocols and fourteen were trials' registrations. The study design was defined as SMART by only one out of fifteen trial reports. Conversely, 13 of 18 study protocols and trial registrations defined the study design SMART. Furthermore, most of the records considered each stage separately in the analysis, without considering treatment regimens embedded in the trial. SMART designs in oncology are still limited. Study powering and analysis is mainly based on statistical approaches traditionally used in single-stage parallel trial designs. Formal reporting guidelines for SMART designs are needed.

Bioactive glass for periodontal regeneration: a systematic review.

BACKGROUND: One of the major clinical challenges of this age could be represented by the possibility to obtain a complete regeneration of infrabony defects. Over the past few years, numerous materials and different approaches have been developed to obtain bone and periodontal healing. Among all biomaterials, bioglasses (BG) are one of the most interesting due to their ability to form a highly reactive carbonate hydroxyapatite layer. Our aim was to systematically review the literature on the use and capability of BG for the treatment of periodontal defects and to perform a meta-analysis of their efficacy. METHODS: A search of MEDLINE/PubMed, Cochrane Library, Embase and DOSS was conducted in March 2021 to identify randomized controlled trials (RCTs) using BG in the treatment of intrabony and furcation defects. Two reviewers selected the articles included in the study considering the inclusion criteria. The outcomes of interest were periodontal and bone regeneration in terms of decrease of probing depth (PD) and gain of clinical attachment level (CAL). A network meta-analysis (NMA) was fitted, according to the graph theory methodology, using a random effect model. RESULTS: Through the digital search, 46 citations were identified. After duplicate removal and screening process, 20 articles were included. All RCTs were retrieved and rated following the Risk of bias 2 scale, revealing several potential sources of bias. The meta-analysis focused on the evaluation at 6 months, with 12 eligible articles for PD and 10 for CAL. As regards the PD at 6 months, AUTOGENOUS CORTICAL BONE, BIOGLASS and PLATELET RICH FIBRIN were more efficacious than open flap debridement alone, with a statistically significant standardized mean difference (SMD) equal to -1.57, -1.06 and - 2.89, respectively. As to CAL at 6 months, the effect of BIOGLASS is reduced and no longer significant (SMD = -0.19, p-value = 0.4) and curiously PLATELET RICH FIBRIN was more efficacious than OFD (SMD =-4.13, p-value < 0.001) in CAL gain, but in indirect evidence. CONCLUSIONS: The present review partially supports the clinical efficacy of BG in periodontal regeneration treatments for periodontal purposes. Indeed, the SMD of 0.5 to 1 in PD and CAL obtained with BG compared to OFD alone seem clinically insignificant even if it is statistically significant. Heterogeneity sources related to periodontal surgery are multiple, difficult to assess and likely hamper a quantitative assessment of BG efficacy.

Oversampling and replacement strategies in propensity score matching: a critical review focused on small sample size in clinical settings.

BACKGROUND: Propensity score matching is a statistical method that is often used to make inferences on the treatment effects in observational studies. In recent years, there has been widespread use of the technique in the cardiothoracic surgery literature to evaluate to potential benefits of new surgical therapies or procedures. However, the small sample size and the strong dependence of the treatment assignment on the baseline covariates that often characterize these studies make such an evaluation challenging from a statistical point of view. In such settings, the use of propensity score matching in combination with oversampling and replacement may provide a solution to these issues by increasing the initial sample size of the study and thus improving the statistical power that is needed to detect the effect of interest. In this study, we review the use of propensity score matching in combination with oversampling and replacement in small sample size settings. METHODS: We performed a series of Monte Carlo simulations to evaluate how the sample size, the proportion of treated, and the assignment mechanism affect the performances of the proposed approaches. We assessed the performances with overall balance, relative bias, root mean squared error and nominal coverage. Moreover, we illustrate the methods using a real case study from the cardiac surgery literature. RESULTS: Matching without replacement produced estimates with lower bias and better nominal coverage than matching with replacement when 1:1 matching was considered. In contrast to that, matching with replacement showed better balance, relative bias, and root mean squared error than matching without replacement for increasing levels of oversampling. The best nominal coverage was obtained by using the estimator that accounts for uncertainty in the matching procedure on sets of units obtained after matching with replacement. CONCLUSIONS: The use of replacement provides the most reliable treatment effect estimates and that no more than 1 or 2 units from the control group should be matched to each treated observation. Moreover, the variance estimator that accounts for the uncertainty in the matching procedure should be used to estimate the treatment effect.

Multidisciplinary education improves school personnel's self-efficacy in managing food allergy and anaphylaxis.

BACKGROUND: Despite a relatively high risk for allergic reactions, including anaphylaxis, schools are not sufficiently trained and confident in handling children suffering from food allergy. This study aimed to measure the improvement of school personnel's self-efficacy in managing food allergy and anaphylaxis at school after a specific multidisciplinary training course. METHODS: A total of 592 teachers and school caretakers completed the School Personnel Self-Efficacy-Food Allergy and Anaphylaxis Questionnaire (S.PER.SE-FAAQ) before and after the course. The median difference, along with I quartile and III quartile, in scores between baseline and post-intervention assessment was calculated. A conditional regression tree was fitted for each outcome measured after the educational intervention. RESULTS: At baseline, school personnel reported low self-efficacy in anaphylaxis management (AM), especially in recognizing anaphylaxis symptoms and administering proper drugs. After the specific multidisciplinary training course, all scores improved. AM scores particularly showed a significant increase. School personnel's post-training self-efficacy was found to be related to initial levels. Some indicative threshold values emerged. Remarkably, participants with a low self-efficacy at baseline seemed to particularly benefit from the training. CONCLUSIONS: Results highlighted the effectiveness of specific multidisciplinary training courses in improving teachers' and school caretakers' self-efficacy in managing food allergy and anaphylaxis. The S.PER.SE-FAAQ is confirmed to be an easy and helpful tool to assess the level of food allergy and anaphylaxis management in the school staff and training effectiveness.

High- and low-inpatients' serum magnesium levels are associated with in-hospital mortality in elderly patients: a neglected marker?

BACKGROUND: Altered serum magnesium (Mg) level in the human body has been hypothesized to have a role in the prediction of hospitalization and mortality; however, the reported outcomes are not conclusive. AIMS: The present study aimed to analyze the relationship between serum Mg and in-hospital mortality (IHM) in patients admitted to the medical ward of two hospitals in the Veneto region (Italy). METHODS: Patients > 18 years hospitalized in the medical wards of the hospitals of Vittorio Veneto and Conegliano, Italy (from January 12, 2011, through December 27, 2016) with at least one measurement of serum Mg were included in the study. A logistic regression model was used to assess the unadjusted and adjusted (by age, gender, Charlson Comorbidity index, discharge diagnosis' class) association of serum Mg and IHM. RESULTS: In total 5024 patients were analyzed, corresponding to 6980 total admissions. The unadjusted analysis showed that IHM risk was significantly higher with 0.2 mg/dl incremental serum Mg level change from 2.4 mg/dl to 2.6, (OR 1.71 95% CI 1.55-1.89) and with 0.2 mg/dl change from serum Mg level of 1.4 mg/dl to 1.2 mg/dl, (OR 1.28 95% CI 1.17-1.40). Such results were confirmed at adjusted analysis. DISCUSSION: Present findings have relevant implications for the clinical management of patients suffering from medical conditions, highlighting the need for analyzing Mg concentration carefully. CONCLUSIONS: Serum Mg levels seem to be a good predictor of IHM.

Bayesian sample size determination for phase IIA clinical trials using historical data and semi-parametric prior's elicitation.

The Simon's two-stage design is the most commonly applied among multi-stage designs in phase IIA clinical trials. It combines the sample sizes at the two stages in order to minimize either the expected or the maximum sample size. When the uncertainty about pre-trial beliefs on the expected or desired response rate is high, a Bayesian alternative should be considered since it allows to deal with the entire distribution of the parameter of interest in a more natural way. In this setting, a crucial issue is how to construct a distribution from the available summaries to use as a clinical prior in a Bayesian design. In this work, we explore the Bayesian counterparts of the Simon's two-stage design based on the predictive version of the single threshold design. This design requires specifying two prior distributions: the analysis prior, which is used to compute the posterior probabilities, and the design prior, which is employed to obtain the prior predictive distribution. While the usual approach is to build beta priors for carrying out a conjugate analysis, we derived both the analysis and the design distributions through linear combinations of B-splines. The motivating example is the planning of the phase IIA two-stage trial on anti-HER2 DNA vaccine in breast cancer, where initial beliefs formed from elicited experts' opinions and historical data showed a high level of uncertainty. In a sample size determination problem, the impact of different priors is evaluated.

A Systematic Review of Case-Identification Algorithms Based on Italian Healthcare Administrative Databases for Three Relevant Diseases of the Cardiovascular System: Hypertension, Heart Failure, and Congenital Heart Diseases.

OBJECTIVES: to identify and describe all hypertension, heart failure (HF), and congenital heart disease case-identification algorithms by means of Italian Healthcare Administrative Databases (HADs), through the review of papers published in the past 10 years. METHODS: this study is part of a project that systematically reviewed case-identification algorithms for 18 acute and chronic conditions by means of HADs in Italy. PubMed was searched for original articles, published between 2007 and 2017, in Italian or English. The search string consisted of a combination of free text and MeSH terms with a common part that focused on HADs and a disease-specific part. All identified papers were screened by two independent reviewers. Pertinent papers were classified according to the objective for which the algorithm had been used, and only articles that used algorithms for primary objectives (I disease occurrence; II population/cohort selection; III outcome identification) were considered for algorithm extraction. The HADs used (hospital discharge records, drug prescriptions, etc.), ICD-9 and ICD-10 codes, ATC classification of drugs, follow-back periods, and age ranges applied by the algorithms have been reported. Further information on specific objective(s), accuracy measures, sensitivity analyses, and the contribution of each HAD have also been recorded. RESULTS: the search strategy identified 429 papers for hypertension, 479 for HF, and 138 for congenital heart diseases. After title/abstract and full-text screening, the review led to the inclusion of 21 articles for hypertension, 24 for HF, and only 1 for congenital heart diseases. Eighteen algorithms had a primary objective (5 hypertension, 12 HF, 1 congenital heart diseases). All the hypertension algorithms were based on the drug prescription database, except for one algorithm that also used the hospital discharge records and the exemption from co-payment database. As for HF, all the algorithms employed the hospital discharge record database and only two algorithms used another information source. The only algorithm identified for congenital heart diseases was based on the hospital discharge database. The algorithm identified for congenital heart diseases was validated, showing excellent performance. Conversely, only one hypertension algorithm was validated, and none of the HF algorithms were validated - even though 5 out of 12 algorithms were based on previous algorithms used at both national and international level. CONCLUSION: the findings of the present study showed wide use of Italian administrative databases for the detection of hypertension and heart failure cases. However, the validity of the algorithms in most cases has not been tested, highlighting the need for introducing stricter requirements to enforce the assessment of the validity of the algorithms used.

A Systematic Review of Case-Identification Algorithms for 18 Conditions Based on Italian Healthcare Administrative Databases: A Study Protocol.

BACKGROUND: there has been a long-standing, consistent use worldwide of Healthcare Administrative Databases (HADs) for epidemiological purposes, especially to identify acute and chronic health conditions. These databases are able to reflect health-related conditions at a population level through disease-specific case-identification algorithms that combine information coded in multiple HADs. In Italy, in the past 10 years, HAD-based case-identification algorithms have experienced a constant increase, with a significant extension of the spectrum of identifiable diseases. Besides estimating incidence and/or prevalence of diseases, these algorithms have been used to enroll cohorts, monitor quality of care, assess the effect of environmental exposure, and identify health outcomes in analytic studies. Despite the rapid increase in the use of case-identification algorithms, information on their accuracy and misclassification rate is currently unavailable for most conditions. OBJECTIVES: to define a protocol to systematically review algorithms used in Italy in the past 10 years for the identification of several chronic and acute diseases, providing an accessible overview to future users in the Italian and international context. METHODS: PubMed will be searched for original research articles, published between 2007 and 2017, in Italian or English. The search string consists of a combination of free text and MeSH terms with a common part on HADs and a disease-specific part. All identified papers will be screened for eligibility by two independent reviewers. All articles that used/defined an algorithm for the identification of each disease of interest using Italian HADs will be included. Algorithms with exclusive use of death certificates, pathology register, general practitioner or pediatrician data will be excluded. Pertinent papers will be classified according to the objective for which the algorithm was used, and only articles that used algorithms with "primary objectives" (I disease occurrence; II population/cohort selection; III outcome identification) will be considered for algorithm extraction. The HADs used (hospital discharge records, drug prescriptions, etc.), ICD-9 and ICD-10 codes, ATC classification of drugs, follow-back periods, and age ranges applied by the algorithms will be collected. Further information on specific accuracy measures from external validations, sensitivity analyses, and the contribution of each source will be recorded. This protocol will be applied for 16 different systematic reviews concerning eighteen diseases (Hypothyroidism, Hyperthyroidism, Diabetes mellitus, Type 1 diabetes mellitus, Acute myocardial infarction, Ischemic heart disease, Stroke, Hypertension, Heart failure, Congenital heart anomalies, Parkinson's disease, Multiple sclerosis, Epilepsy, Chronic obstructive pulmonary disease, Asthma, Inflammatory bowel disease, Celiac disease, Chronic kidney failure). CONCLUSION: this protocol defines a standardized approach to extensively examine and compare all experiences of case identification algorithms in Italy, on the 18 abovementioned diseases. The methodology proposed may be applied to other systematic reviews concerning diseases not included in this project, as well as other settings, including international ones. Considering the increasing availability of healthcare data, developing standard criteria to describe and update characteristics of published algorithms would be of great use to enhance awareness in the choice of algorithms and provide a greater comparability of results.

Use and effectiveness of dapagliflozin in routine clinical practice: An Italian multicentre retrospective study.

In randomized controlled trials (RCTs), sodium-glucose co-transporter-2 (SGLT2) inhibitors have been shown to confer glycaemic and extra-glycaemic benefits. The DARWIN-T2D (DApagliflozin Real World evIdeNce in Type 2 Diabetes) study was a multicentre retrospective study designed to evaluate the baseline characteristics of patients receiving dapagliflozin vs those receiving selected comparators (dipeptidyl peptidase-4 inhibitors, gliclazide, or glucagon-like peptide-1 receptor agonists), and drug effectiveness in routine clinical practice. From a population of 281 217, the analysis included 17 285 patients initiating dapagliflozin or comparator glucose-lowering medications (GLMs), 6751 of whom had a follow-up examination. At baseline, participants starting dapagliflozin were younger, had a longer disease duration, higher glycated haemoglobin (HbA1c) concentration, and a more complex history of previous GLM use, but the clinical profile of patients receiving dapagliflozin changed during the study period. Dapagliflozin reduced HbA1c by 0.7%, body weight by 2.7 kg, and systolic blood pressure by 3.0 mm Hg. Effects of comparator GLMs were also within the expected range, based on RCTs. This real-world study shows an initial channelling of dapagliflozin to difficult-to-treat patients. Nonetheless, dapagliflozin provided significant benefits with regard to glucose control, body weight and blood pressure that were in line with findings from RCTs.

Research in Nursing and Nutrition: Is Randomized Clinical Trial the Actual Gold Standard?

The aim of this study was to assess the quality of reporting of nurse-driven randomized controlled trials involving a direct nutritional intervention. A bibliometric search for randomized controlled trials involving a direct nutritional intervention from 1991 to 2011 in nursing research was conducted. Both quality of the study and design aspects were evaluated. The prevalent randomized controlled trial design used is 2-arm parallel, individual, and randomized with a continuous primary endpoint. Global numbers of randomized controlled trials and the proportion of good-quality randomized controlled trials began a steady and marked rise, more than doubling, from the 1990s to about 2001 and increased slowly thereafter. Studies are overall sufficiently well designed, although there is still room for quality improvement. Additionally, implementation of new randomized controlled trial designs exists and should be advocated.

School personnel's self-efficacy in managing food allergy and anaphylaxis.

BACKGROUND: Food allergy affects up to 4-7% European schoolchildren. Studies identified important shortcomings on food allergy and anaphylaxis management in schools. In social cognitive theory, personal beliefs in own capabilities influence choices, effort levels, perseverance and performance accomplishments. This study aimed to investigate school personnel's self-efficacy in managing food allergy and anaphylaxis, providing a valid instrument to deeply understand how to support schools to effectively manage students at risk of food reactions. METHODS: A total of 440 schoolteachers and caretakers from north-east Italy completed a questionnaire assessing self-efficacy in managing food allergy and anaphylaxis at school. Exploratory factor analysis was performed. Factors' internal consistency was evaluated using Cronbach's alpha. Factors' scores were estimated using Bartlett approach, and kernel density estimate of distributions was provided. Descriptive statistics explored school personnel's self-efficacy. A regression model assessed the influence of gender, school, job and previous experience. RESULTS: Two factors emerged from exploratory factor analysis related to anaphylaxis management (AM) and food allergy management (FAM). The two subscales both showed good internal consistency. School personnel showed lower self-efficacy in recognizing symptoms, administering drugs and guaranteeing full participation to extra-curricular activities to food-allergic students. Participants who previously had food-allergic students showed a significantly increased self-efficacy in AM and a significantly decreased self-efficacy in FAM. CONCLUSIONS: The study supports the use of self-efficacy scale to identify specific areas where teachers' confidence in their ability to care for food-allergic students is especially weak. This would empower the development of training programs specifically tailored to the needs of teachers and caregivers.

Pomalidomide, cyclophosphamide, and prednisone for relapsed/refractory multiple myeloma: a multicenter phase 1/2 open-label study.

We performed a phase 1/2 trial to determine the maximum tolerated dose (MTD) of pomalidomide and to explore its efficacy when combined with cyclophosphamide-prednisone in relapsed/refractory myeloma patients. Pomalidomide was given at 1 to 2.5 mg/d, cyclophosphamide at 50 mg every other day, prednisone at 50 mg every other day, for 6 28-day cycles, followed by pomalidomide-prednisone maintenance therapy. Thromboprophylaxis was recommended. Sixty-nine patients were enrolled, 55 received the MTD (2.5 mg/d) and were evaluated. Best responses included complete response in 3 patients (5%), very good partial response in 10 (18%), partial response in 15 (27%), minimal response in 11 (20%), stable disease in 15 (27%), and progressive disease in 1 (3%), for an overall response rate of 51%. The median time-to-response was 1.83 months. After a median follow-up of 14.8 months, median progression-free survival was 10.4 months and 1-year overall survival was 69%. At the MTD, grade 3 to 4 toxicities included anemia (9%), thrombocytopenia (11%), neutropenia (42%), neurologic events (7%), dermatologic events (7%), and thromboembolism (2%). Grade 3 to 5 infections occurred in 5 patients (9%). Five patients (9%) discontinued treatment for toxicity. New grade 3 to 4 adverse events were low during maintenance. Pomalidomide-cyclophosphamide-prednisone is safe and effective in relapsed/refractory myeloma patients. This trial was registered at www.clinicaltrials.gov as #NCT01166113.

What is the value given by consumers to nutritional label information? Results from a large investigation in Europe.

RATIONALE: Nutrition labels on prepackaged foods have been widely advocated as a medium to foster healthier eating habits in the general population. OBJECTIVE: The study is aimed at understanding how people value nutritional information on food labels, in particular for front-of-pack labeling. METHODS: A phone-assisted survey of 7550 consumers in 16 European countries was conducted. People were asked about their opinion on nutritional information provided at different levels, from the media to public institutions, and their commitment to healthy behavior. The value of pack labeling was estimated using a willingness-to-pay (WTP) elicitation technique. RESULTS: Older age groups (>45 years old), members of a larger family, people of low income or low education, and those who perceived themselves to be obese valued front-of-pack nutritional labeling. WTP estimates across all countries provided an average accepted added price of $4.32 to the overall yearly food expenditure (95% confidence interval, 3.33-3.68). CONCLUSIONS: Overall, perceived value of labeling is low. However, factors affecting the value for consumer of nutritional labeling appear to be strictly linked to the socioeconomic and health status of the respondents.

Lenalidomide plus R-CHOP21 in elderly patients with untreated diffuse large B-cell lymphoma: results of the REAL07 open-label, multicentre, phase 2 trial.

BACKGROUND: Up to 40% of elderly patients with untreated diffuse large B-cell lymphoma (DLBCL) given a regimen of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone every 21 days (R-CHOP21) relapse or develop refractory disease. Lenalidomide has high activity in relapsed or refractory aggressive B-cell lymphomas. In phase 2 of the REAL07 trial, we aimed to establish the safety and efficacy of the combination of lenalidomide and R-CHOP21 in elderly patients with untreated DLBCL. METHODS: REAL07 was an open-label, multicentre trial that was done in 13 centres in Italy and one in Germany. Eligible patients were aged 60-80 years; had newly diagnosed, untreated, CD20-positive, Ann Arbor stage II-IV DLBCL or grade 3b follicular lymphoma; had an Eastern Cooperative Oncology Group performance status of 0-2; had an International Prognostic Index (IPI) risk of low-intermediate, intermediate-high, or high; and were fit according to comprehensive geriatric assessment. Participants were to receive 15 mg oral lenalidomide on days 1-14 of six 21-day cycles, and standard doses of R-CHOP21 chemotherapy (375 mg/m(2) intravenous rituximab, 750 mg/m(2) intravenous cyclophosphamide, 50 mg/m(2) intravenous doxorubicin, and 1·4 mg/m(2) intravenous vincristine on day 1, and 40 mg/m(2) oral prednisone on days 1-5). The primary endpoint was frequency of overall response (complete response [CR] and partial response [PR]), which was assessed by (18)F-fluorodeoxyglucose ((18)F-FDG) PET at the end of the treatment. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00907348. FINDINGS: 49 patients were included in phase 2: nine had been enrolled into phase 1 between Oct 23, 2008, and June 4, 2009, and had received the maximum tolerated dose of 15 mg lenalidomide; and 40 were enrolled into phase 2 between April 28, 2010, and June 3, 2011. 45 patients (92%, 95% CI 81-97) achieved a response (42 [86%] CR; three [6%] PR). Three patients (6%) did not respond and one (2%) died for reasons unrelated to treatment or disease. 277 (94%) of 294 planned cycles of lenalidomide and R-CHOP21 were completed. Grade 3-4 neutropenia was reported in 87 cycles (31%), grade 3-4 leukopenia in 77 (28%), and grade 3-4 thrombocytopenia in 35 (13%). No grade 4 non-haematological adverse events were reported. No patients died during the study as a result of toxic effects. INTERPRETATION: Lenalidomide with R-CHOP21 is effective and safe in elderly patients with untreated DLBCL. FUNDING: Fondazione Italiana Linfomi and Celgene.

MET dysregulation is a hallmark of aggressive disease in multiple myeloma patients.

Abnormal activation of MET/HGF (Hepatocyte Growth Factor) pathway has been described in several tumours and increased HGF plasmatic levels have been detected in patients with aggressive multiple myeloma (MM). MET and HGF mRNA expression was investigated in 105 samples of purified plasma cells derived from newly diagnosed MM patients treated with bortezomib-based induction therapy. Gene expression was compared with response to therapy and clinical outcome. MET gene copy number was also evaluated. MET mRNA expression was higher in CD138(+) than in CD138(-) cells (median 76·90 vs. 11·24; P = 0·0009). Low MET mRNA expression characterized patients with better response (complete response or very good partial response) compared to other patients (median 56·10 vs. 134·83; P = 0·0006). After a median follow-up of 50 months, patients with high MET mRNA expression displayed a worse progression-free survival (PFS; P = 0·0029) and overall survival (OS; P = 0·0023) compared to those with low MET mRNA levels. Patients with both high MET mRNA expression and high ß2-microglobulin level (>5·5 mg/l) had further worse median PFS (P < 0·0001) and OS (P < 0·0001). Patients carrying 4 MET gene copies (8 out of 82, 9·8%) also had a short PFS. High MET mRNA expression identifies patients with dismal PFS and OS and the combination with high ß2-microglobulin further characterizes patients with worse outcome.

The economic burden of caregiving on families of children and adolescents with cancer: a population-based assessment.

BACKGROUND: Childhood cancer represents a relevant economic burden on families. The preferred tool to investigate family expenditure is the retrospective questionnaire, which is subject to recall errors and selection bias. Therefore, in the present study the economic burden of caregiving on families of children and adolescents (0-19 years of age) with cancer was analysed using administrative data as an alternative to retrospective questionnaires. PROCEDURE: Incident cases of cancer diagnosed in children and adolescents in 2000-2005 (N = 917) were identified from the Piedmont Childhood Cancer Registry and linked to available administrative databases to identify episodes of care during the 3 years after diagnosis (N = 13,433). The opportunity cost of informal caregiving was estimated as the value of the time spent by one of the parents, and was assumed to be equal to the number of days during which the child received inpatient care, day-care or outpatient radiotherapy. Factors affecting the level of economic burden of caregiving on families were analysed in a multivariable model. RESULTS: The economic burden of caregiving increased when care was supplied at the Regional Referral Centre, or when treatment complexity was high. Families with younger children had a higher level of economic burden of caregiving. Leukaemia required a higher family commitment than any other cancer considered. CONCLUSIONS: Estimates of the economic burden of caregiving on families of children and adolescents with cancer derived from administrative data should be considered a minimum burden. The estimated effect of the covariates is informative for healthcare decision-makers in planning support programmes.

Dynamic Bayesian Networks to predict sequences of organ failures in patients admitted to ICU.

Multi Organ Dysfunction Syndrome (MODS) represents a continuum of physiologic derangements and is the major cause of death in the Intensive Care Unit (ICU). Scoring systems for organ failure have become an integral part of critical care practice and play an important role in ICU-based research by tracking disease progression and facilitating patient stratification based on evaluation of illness severity during ICU stay. In this study a Dynamic Bayesian Network (DBN) was applied to model SOFA severity score changes in 79 adult critically ill patients consecutively admitted to the general ICU of the Sant'Andrea University hospital (Rome, Italy) from September 2010 to March 2011, with the aim to identify the most probable sequences of organs failures in the first week after the ICU admission. Approximately 56% of patients were admitted into the ICU with lung failure and about 27% of patients with heart failure. Results suggest that, given the first organ failure at the ICU admission, a sequence of organ failures can be predicted with a certain degree of probability. Sequences involving heart, lung, hematologic system and liver turned out to be the more likely to occur, with slightly different probabilities depending on the day of the week they occur. DBNs could be successfully applied for modeling temporal systems in critical care domain. Capability to predict sequences of likely organ failures makes DBNs a promising prognostic tool, intended to help physicians in undertaking therapeutic decisions in a patient-tailored approach.

Trends in RCT nursing research over 20 years: mind the gap.

Randomised controlled trial (RCT) literature plays a fundamental role in informing evidence-based medicine and nursing. This paper aims to track geographical and temporal trends in the publication of RCTs in nursing over the past 20 years by means of a bibliometric analysis. The PubMed database was searched for articles published from 1 January 1991 to 31 October 2011 and satisfying this search strategy: nursing [MeSH Terms] AND (RCT OR trial* OR 'experimental study' OR randomised OR randomisation) AND (English[lang]). Abstracts were reviewed to assess whether they met the criteria for an RCT. A manual search of information on country of origin was carried out and Journal Citation Reports® was used to allocate journals to subject areas. RCT methodology is increasingly drawing the attention of nursing researchers worldwide. However, there is a large disparity in research productivity, at least in terms of number of published RCTs in the English language and listed on PubMed, between the most productive continents, North America and Europe, and the others.

Lenalidomide plus cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab is safe and effective in untreated, elderly patients with diffuse large B-cell lymphoma: a phase I study by the Fondazione Italiana Linfomi.

Despite improvements in standard therapy with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone for patients with untreated, diffuse large B-cell lymphoma, up to 40% of these patients relapse. Lenalidomide alone or in combination with rituximab has been shown to be active in relapsed/refractory aggressive lymphomas. In this phase I study we determined the maximum tolerated dose of lenalidomide plus rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone in untreated, elderly (median age 68 years) patients with diffuse large B-cell lymphoma. Four lenalidomide doses (5, 10, 15, and 20 mg/day on days 1-14) allocated using the continual reassessment method were planned to be administered for 14 days in combination with each course of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone for a total of six courses. Seven cohorts of patients (n=3 in each cohort) were treated (total n=21) at 10, 20, 15, 15, 15, 10, and 10 mg of lenalidomide. Dose-limiting toxicities occurred in seven patients during the first three courses of treatment. The third dose-level of lenalidomide (15 mg/day) was selected as the maximum tolerated dose, with an estimated probability of dose-limiting toxicities of 0.345 (95% credibility interval 0.164-0.553). Grade 3-4 hematologic adverse events were: neutropenia in 28% of the courses, thrombocytopenia in 9%, and anemia in 3%. Non-hematologic toxicities were moderate: grade 4 increase of creatinine phosphokinase (n=1), grade 3 cardiac (n=2), grade 3 neurological (n=3), and grade 3 gastrointestinal (n=1). In this phase I study, the overall response rate was 90%, with 81% achieving complete remission. This combination regimen appears safe in elderly patients with diffuse large B-cell lymphoma and its efficacy will be assessed in the ongoing phase II trial. This trial was registered at www.clinicaltrials.gov as NCT00907348.

Safety of thalidomide in newly diagnosed elderly myeloma patients: a meta-analysis of data from individual patients in six randomized trials.

Treatment with melphalan-prednisone-thalidomide improves the outcome of patients with multiple myeloma and is now considered a standard of care for patients not eligible for transplantation. However, this treatment is a major source of morbidity. A meta-analysis of data from individual patients (n=1680) in six randomized trials was performed, comparing the effects of melphalan-prednisone-thalidomide versus melphalan-prednisone. The main objective was to estimate the risk of serious adverse events and their impact on outcome. The primary endpoints were the 2-year cumulative incidence of grade 3-4 hematologic and non-hematologic toxicities. At least 75% of the grade 3-4 toxicities occurred during the first 6 months of treatment in both treatment groups. The cumulative incidence of grade 3-4 hematologic toxicities was higher in the melphalan-prednisone-thalidomide group than in the melphalan-prednisone group (28% versus 22%; HR 1.32, 95% CI 1.05-1.66) as was the cumulative incidence of non-hematologic toxicities (39% versus 17%, HR 2.78, 95% CI 2.21-3.50). Grade 3-4 non-hematologic toxicities were significantly increased in patients with poor Performance Status. Occurrence of grade 3-4 non-hematologic toxicities had a negative impact on both progression-free survival (HR 1.24, 95% CI 1.07-1.45) and overall survival, (HR 1.23, 95% CI 1.03-1.47). Besides toxicities, progression-free and overall survival were also negatively affected by advanced International Staging System stage, high creatinine levels and poor Performance Status. Age had a negative impact on survival as well. Although melphalan-prednisone-thalidomide improved outcome, it increased toxicities, especially non-hematologic ones. Serious non-hematologic toxicities, older age, poor Performance Status, and high creatinine levels negatively affected survival.