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Anaplastic lymphoma kinase (ALK)-positive lymphomas respond to chemotherapy, but relapses, which bear a poor prognosis, occur. Crizotinib inhibits ALK in vitro and in vivo and was administered as monotherapy to 11 ALK+ lymphoma patients who were resistant/refractory to cytotoxic therapy. The overall response rate was 10 of 11 (90.9%; 95% confidence interval [CI] = 58.7% to 99.8%). Disease status at the latest follow-up is as follows: four patients are in complete response (CR) (months >21, >30, >35, >40) under continuous crizotinib administration; 4 patients had progression of disease (months 1, 2, 2, 2); 1 patient obtained CR on crizotinib, received an allogeneic bone marrow transplant, and is in CR; 2 patients (treated before and/or after allogeneic bone marrow transplant) obtained and are still in CR but they have stopped crizotinib. Overall and progression-free survival rates at 2 years are 72.7% (95% CI = 39.1% to 94.0%) and 63.7% (95% CI = 30.8% to 89.1%), respectively. ALK mutations conferring resistance to crizotinib in vitro could be identified in relapsed patients. Crizotinib exerted a potent antitumor activity with durable responses in advanced, heavily pretreated ALK+ lymphoma patients, with a benign safety profile

In 2007 the International Diabetes Federation (IDF) proposed single blood pressure (BP) cutpoints (systolic: ≥130 mm Hg and diastolic: ≥85 mm Hg) for the diagnosis of high blood pressure (HBP) in adolescents. Before this proposal, HBP had been defined as BP at or above the 95th percentile for age, sex, and height percentile (reference standard). In this study, we evaluated the risk for misclassification when using the IDF single-cutpoints criteria. We first applied the IDF criteria to a reconstructed population with the same age, sex, and height distribution as the population used to develop the reference standard. The proposed single cutpoints corresponded to percentiles from the 81.6th to 99.9th for systolic BP and from the 92.9th to 98.9th for diastolic BP in the reconstructed population. Using IDF criteria, there were high false-negative fractions for both systolic and diastolic BP (from 54% to 93%) in 10- to 12-year-olds and a false-positive fraction up to 35% in older subjects. We then applied the IDF criteria to 1,162 overweight/obese adolescents recruited during 1998-2000 from pediatric clinical centers in Milano, Varese, and Modena in Italy and in Zaragoza, Spain. Overall false-negative and false-positive fractions were 22% and 2%, respectively; negative predictive values were especially low for 10- to 12-year-old subjects. The use of IDF's single cutpoints carries a high risk of misclassification, mostly due to false negatives in younger subjects. The effort to simplify diagnosis could be overcome by the risk of undiagnosed HBP.

Background: Mother-infant bonding is of great importance for the development and the well-being of the baby. The aim of this Concurrent Cohort Study was to investigate the effects of mothers singing lullabies on bonding, newborns' behaviour and maternal stress. Methods: Eighty-three (singing cohort) and 85 (concurrent cohort) women were recruited at antenatal classes at 24 weeks g.a. and followed up to 3 months after birth. The Prenatal Attachment Inventory (PAI) and the Mother-to-Infant Bonding Scale (MIBS) were used to assess maternal-foetal attachment and postnatal bonding. Findings: No significant influence was found on Prenatal Attachment; by contrast, Postnatal Bonding was significantly greater (i.e. lower MIBS) in the singing group 3 months after birth (mean 1.28 vs 1.96; p = 0.001). In the same singing group, the incidence of neonatal crying episodes in the first month was significantly lower (18.5% vs 28.2; p. <. 0.0001) as were the infantile colic (64.7% vs 38.3%; p = 0.003) and perceived maternal stress (29.6% vs 36.5%; p. <. 0.05). Infantile colic was reduced in the singing group, even in the second month after birth (22.8% vs 36.5; p = 0.002). At the same time, a reduction was observed in the neonatal nightly awakening (1.5% vs 4.7; p. <. 0.0001). Conclusions: Mothers singing lullabies could improve maternal-infant bonding. It could also have positive effects on neonatal behaviour and maternal stress

The influence of feeding patterns on the growth of infants and how salt is included in the diet are unknown in the area of West Bengal, India. A cross-sectional study was carried on 517 infants (median age 6.5 months). Negative Z-scores were observed for all anthropometric parameters. About 72.7% of infants aged 0–6 months received exclusive breastfeeding. In the 6–12-month-old group (n = 235), 91.5% had salt added to foods. In a regression model adjusted for age, a low salt diet resulted a significant factor in increasing weight-for-length and BMI for age z-scores, with increments equal to 0.637 SD (p = 0.037) and 0.650 SD (p = 0.036), respectively. In West Bengal infants showing poor growth, breastfeeding was associated with better anthropometric indexes, but early in life salt is added to their diet. Early life low weight coupled with high salt intake may be a risk factor for arterial hypertension in Indian children.

Background: In many studies, some information might not be available for the whole cohort, some covariates, or even the outcome, might be ascertained in selected subsamples. These studies are part of a broad category termed two-phase studies. Common examples include the nested case-control and the case-cohort designs. For two-phase studies, appropriate weighted survival estimates have been derived; however, no estimator of cumulative incidence accounting for competing events has been proposed. This is relevant in the presence of multiple types of events, where estimation of event type specific quantities are needed for evaluating outcome. Methods: We develop a non parametric estimator of the cumulative incidence function of events accounting for possible competing events. It handles a general sampling design by weights derived from the sampling probabilities. The variance is derived from the influence function of the subdistribution hazard. Results: The proposed method shows good performance in simulations. It is applied to estimate the crude incidence of relapse in childhood acute lymphoblastic leukemia in groups defined by a genotype not available for everyone in a cohort of nearly 2000 patients, where death due to toxicity acted as a competing event. In a second example the aim was to estimate engagement in care of a cohort of HIV patients in resource limited setting, where for some patients the outcome itself was missing due to lost to follow-up. A sampling based approach was used to identify outcome in a subsample of lost patients and to obtain a valid estimate of connection to care. Conclusions: A valid estimator for cumulative incidence of events accounting for competing risks under a general sampling design from an infinite target population is derived.

ALK-positive Anaplastic Large Cell Lymphoma (ALCL) represents a subset of Non-Hodgkin Lymphoma whose treatment benefited from crizotinib development, a dual ALK/MET inhibitor. Crizotinib blocks ALK-triggered pathways such as PI3K/AKT/ mTOR, indispensable for survival of ALK-driven tumors. Despite the positive impact of targeted treatment in ALCL, resistant clones are often selected during therapy. Strategies to overcome resistance include the design of second generation drugs and the use of combined therapies that simultaneously target multiple nodes essential for cells survival. We investigated the effects of combined ALK/mTOR inhibition. We observed a specific synergistic effect of combining ALK inhibitors with an mTOR inhibitor (temsirolimus), in ALK+ lymphoma cells. The positive cooperation resulted in an increased inhibition of mTOR effectors, compared to single treatments, a block in G0/G1 phase and induction of apoptosis. The combination was able to prevent the selection of resistant clones, while longterm exposure to single agents led to the establishment of resistant cell lines, with either ALK inhibitor or temsirolimus. In vivo, mice injected with Karpas 299 cells and treated with low dose combination showed complete regression of tumors, while only partial inhibition was obtained in single agents-treated mice. Upon treatment stop the combination was able to significantly delay tumor relapses. Re-challenge of relapsed tumors at a higher dose led to full regression of xenografts in the combination group, but not in mice treated with lorlatinib alone. In conclusion, our data suggest that the combination of ALK and mTOR inhibitors could be a valuable therapeutic option for ALK+ ALCL patients.

The 'landmark' and 'Simon and Makuch' non-parametric estimators of the survival function are commonly used to contrast the survival experience of time-dependent treatment groups in applications such as stem cell transplant versus chemotherapy in leukemia. However, the theoretical survival functions corresponding to the second approach were not clearly defined in the literature, and the use of the 'Simon and Makuch' estimator was criticized in the biostatistical community. Here, we review the 'landmark' approach, showing that it focuses on the average survival of patients conditional on being failure free and on the treatment status assessed at the landmark time. We argue that the 'Simon and Makuch' approach represents counterfactual survival probabilities where treatment status is forced to be fixed: the patient is thought as under chemotherapy without possibility to switch treatment or as under transplant since the beginning of the follow-up. We argue that the 'Simon and Makuch' estimator leads to valid estimates only under the Markov assumption, which is however less likely to occur in practical applications. This motivates the development of a novel approach based on time rescaling, which leads to suitable estimates of the counterfactual probabilities in a semi-Markov process. The method is also extended to deal with a fixed landmark time of interest.

Negli studi clinici spesso è di interesse confrontare la sopravvivenza di pazienti appartenenti a due o più gruppi di trattamento. In alcune situazioni, la classificazione non è effettuata all’inizio del follow-up ma cambia nel tempo. Ad esempio, tutti i pazienti sono sottoposti ad un trattamento iniziale ed alcuni lo continuano mentre altri cambiano dopo un certo periodo di tempo. In questo caso il trattamento è rappresentato da una variabile binaria tempo-dipendente. Un contesto tipico è il confronto tra chemioterapia e trapianto di cellule staminali nella Leucemia Linfoblastica Acuta. In questa situazione, il metodo Kaplan-Meier non è utilizzabile in quanto affetto da immortal time bias. Due approcci non-parametrici alternativi sono stati proposti in letteratura. Andersen et al. (1983) suggeriscono di classificare i pazienti ad un tempo “landmark” che corrisponde al punto iniziale della stima della curva di sopravvivenza, includendo solo i pazienti ancora a rischio al landmark. Il secondo metodo, proposto da Simon e Makuch (1984), consiste nell’aggiornamento dinamico dei “risk sets” dei due gruppi di trattamento tempo-dipendenti. Entrambi i metodi sono stati presentati in maniera euristica e senza specificare le quantità teoriche che corrispondono agli stimatori proposti. Perciò, l’interpretazione delle curve stimate dai due metodi non è mai stata chiarita. Quando l’interesse non è rivolto alla sopravvivenza globale ma alla predizione profilo-specifica, ovvero tenendo conto delle caratteristiche individuali dei soggetti, occorre utilizzare metodi di regressione parametrici o semi-parametrici. Il modello di Cox è quello più popolare ma in presenza di effetti tempo-dipendenti e/o di covariate tempo-dipendenti non può essere utilizzato per ottenere delle curve. Tra le possibili alternative sono stati considerati il modello parametrico di Hanley e Miettinen (2009) e il modello di regressione semi-parametrico basato sul landmark di Van Houwelingen (2007)., In clinical studies it is often of interest to compare the survival experience of patients in two or more treatment groups. In some situations the categorization is not fixed at baseline but changes during the follow-up, where patients, for example, start from an initial treatment and either continue it or switch to an alternative one after some time (waiting time). Thus, treatment is a binary non reversible time-dependent variable. A typical problem is comparing outcomes of chemotherapy vs stem-cell transplantation in Acute Lymphoblastic Leukemia (ALL) where patients are treated initially with chemotherapy and during the follow-up they can receive bone marrow transplant. In this context, the standard Kaplan-Meier method is unreliable since it is affected by the immortal time bias. Two alternative non-parametric approaches were proposed in the literature. Andersen et al. (1983) suggests to classify patients at a landmark time which corresponds to the starting point for the estimation of the Kaplan-Meier survival curve, involving only patients still at risk at the landmark. The second, proposed by Simon and Makuch (1984), consists in dynamically updating in time the risk set of the two time-dependent treatment groups. Both methods were presented mostly relying on heuristic bases and without specifying the theoretical quantities corresponding to the proposed estimators. Thus, the interpretations of the curves estimated by the two methods was never clarified. When the focus is not on the overall survival experience but rather on profile-specific prediction, i.e. accounting for the individual characteristics of the subjects, one must resort to semi-parametric or parametric regression models. The Cox model is the most popular one but in the presence of time-varying effects and/or time-dependent covariates it cannot be used to obtain survival curves. Among the possible alternatives we considered the full parametric model by Hanley and Miettinen (2009) and the semi-paramet

Background: Hypertension and obesity in childhood are related to early cardiac damage, as left ventricular hypertrophy. Few studies have analyzed the independent effects of hypertension and weight excess on diastolic function and left ventricular geometry. Objective: We studied the effects of weight, waist circumference (as an index of fat distribution) and blood pressure on left ventricular mass index, the risk of left ventricular hypertrophy, diastolic function and left ventricular geometry in 526 children (237 girls, age range 6-15 years). Methods: Children were divided into normotensive, prehypertensive and hypertensive (US Nomograms) groups, and into normal-weight, overweight, and obese (International Obesity Task Force classification) groups. Left ventricular mass index, diastolic function and left ventricular geometry were assessed. Results: SBP z-scores and blood pressure categories significantly influenced cardiac mass (P < 0.001 and P = 0.02, respectively) and the prevalence of left ventricular hypertrophy (P < 0.001 and P < 0.05, respectively). Obesity, BMI, and waist circumference z-scores were significantly associated with an increment in E/E m ratio (P < 0.001, P < 0.01, and P < 0.01, respectively). Increasing blood pressure values and the presence of prehypertension (P < 0.05) and hypertension (P < 0.003), but not weight excess, were associated with concentric cardiac remodeling. In contrast, concentric hypertrophy was associated with hypertension (P < 0.01), obesity (P < 0.001), and increasing waist circumference (P < 001). Conclusions: Blood pressure values and hypertension are independently associated with an increase of cardiac mass and the presence of cardiac hypertrophy. Obesity and waist circumference, but not hypertension, are associated with a worsening of diastolic function, whereas only hypertensive children show high prevalence of concentric remodeling. Blood pressure and body weight and fat distribution have an independent and different i

Imatinib mesylate radically changed the natural history of chronic myeloid leukemia (CML). The recent availability of alternative tyrosine kinase inhibitors (TKIs) renders the clinical management of CML more complex. In this article, we summarize our long-term single institution experience. From 2003 to 2012, 102 patients with newly diagnosed chronic phase CML were referred to our institution and treated with imatinib mesylate as first-line therapy. All patients were followed inside a dedicated CML clinic. At 1 year, 82/95 patients (86.3%) achieved complete cytogenetic response (CCyR) using a treatment performed analysis (TPA); when using an intention to treat analysis, 85/102 patients (83.3%) obtained CCyR. At 3 months, 58 patients (64.4% TPA) obtained a BCR-ABL transcripts level <10%. A major molecular response (MMR) was obtained by 38% and 53% of patients at 1 and 2 years. Twenty patients (19.6%) discontinued treatment with imatinib; six of them did so in the initial 2 years of treatment (4 for resistance and 2 for adverse events). We observed seven deaths (6.86%). Overall survival (OS) at 6 years is 95.1% (95% C.I. 90-100%) and is not different from that of the general population. No patient experienced progression of disease (95% C.I.: 0-3%). Our results suggest that patient management is a crucial point to obtain a successful therapeutic outcome: at 1 year CCyR and MMR rates are similar to the results obtained with second generation TKIs and OS is not different from that of the general population

Survival analysis is a powerful statistical tool to study failure-time data. In introductory courses students learn how to describe right-censored survival time data using the product-limit estimator of the survival function on a given end-point relying on a product of conditional survival probabilities. In the case of a composite end-point, the next step is to account for the presence of competing risks. The complement to one of the survival function is decomposed into the sum of cause-specific incidences, which are obtained as sum of unconditional probabilities due to the single competing risk. However, this algebraic decomposition is not straightforward, given the difference between the structures of the involved estimators. In addition, one is tempted to use the Kaplan-Meier estimator, leading to an erroneous decomposition of the overall incidence. Here we discuss a simple reinterpretation of the Kaplan-Meier formula in terms of sum of non-conditional probabilities of developing the end-point in time, adjusted for the presence of censoring. This approach could be used for describing survival data through simple frequency tables which are directly generalized to the case of competing risks. In addition, it makes clear how the estimation of the single cause-specific incidence through the Kaplan-Meier estimator, simply considering the occurrence of competing events as censored data, leads to an overestimation of the cause-sj. incidence. Two examples are provided to support the explanation: the first one could to clarify the procedure described by the formulas; the second one simulates real data in order to present graphically the results.

Anaplastic lymphoma kinase (ALK)-positive lymphomas respond to chemotherapy, but relapses, which bear a poor prognosis, occur. Crizotinib inhibits ALK in vitro and in vivo and was administered as monotherapy to 11 ALK+ lymphoma patients who were resistant/refractory to cytotoxic therapy. The overall response rate was 10 of 11 (90.9%; 95% confidence interval [CI] = 58.7% to 99.8%). Disease status at the latest follow-up is as follows: four patients are in complete response (CR) (months >21, >30, >35, >40) under continuous crizotinib administration; 4 patients had progression of disease (months 1, 2, 2, 2); 1 patient obtained CR on crizotinib, received an allogeneic bone marrow transplant, and is in CR; 2 patients (treated before and/or after allogeneic bone marrow transplant) obtained and are still in CR but they have stopped crizotinib. Overall and progression-free survival rates at 2 years are 72.7% (95% CI = 39.1% to 94.0%) and 63.7% (95% CI = 30.8% to 89.1%), respectively. ALK mutations conferring resistance to crizotinib in vitro could be identified in relapsed patients. Crizotinib exerted a potent antitumor activity with durable responses in advanced, heavily pretreated ALK+ lymphoma patients, with a benign safety profile.

Categorization is often needed for clinical decision making when dealing with diagnostic (prognostic) biomarkers and a binary outcome (true disease status). Four common methods used to dichotomize a continuous biomarker X are compared: the minimum P-value, the Youden index, the concordance probability and the point closest-to-(0,1) corner in the ROC plane. These methods are compared from a theoretical point of view under Normal or Gamma biomarker distributions, showing whether or not they lead to the identification of the same true cut-point. The performance of the corresponding non-parametric estimators is then compared by simulation. Two motivating examples are presented. In all simulation scenarios, the point closest-to-(0,1) corner in the ROC plane and concordance probability approaches outperformed the other methods. Both these methods showed good performance in the estimation of the optimal cut-point of a biomarker. However, when methods do not lead to the same optimal cut-point, scientists should focus on which one is truly what they want to estimate, and use it in practice. In addition, to improve communicability, the Youden index or the concordance probability associated to the estimated cut-point could be reported to summarize the associated classification accuracy. The use of the minimum P-value approach for cut-point finding is strongly not recommended because its objective function is computed under the null hypothesis of absence of association between the true disease status and X. This is in contrast with the presence of some discrimination potential of X that leads to the dichotomization issue