Obesity in patients with acute lymphoblastic leukemia in childhood

Acute lymphoblastic leukemia is the most common malignancy in childhood. Continuous progress in risk-adapted treatment for childhood acute lymphoblastic leukemia has secured 5-year event-free survival rates of approximately 80% and 8-year survival rates approaching 90%. Almost 75% of survivors, however, have a chronic health condition negatively impacting on cardiovascular morbidity and mortality. Obesity can be considered one of the most important health chronic conditions in the general population, with an increasing incidence in patients treated for childhood cancers and especially in acute lymphoblastic leukemia survivors who are, at the same time, more at risk of experiencing precocious cardiovascular and metabolic co-morbidities. The hypothalamic-pituitary axis damage secondary to cancer therapies (cranial irradiation and chemotherapy) or to primary tumor together with lifestyle modifications and genetic factors could affect long-term outcomes. Nevertheless, the etiology of obesity in acute lymphoblastic leukemia is not yet fully understood. The present review has the aim of summarizing the published data and examining the most accepted mechanisms and main predisposing factors related to weight gain in this particular population

Identification of a prognostic signature based on the expression of genes related to the insulin pathway in early breast cancer

INTRODUCTION: Insulin and the insulin-like growth factor (IGF) family play a key role in breast cancer (BC). OBJECTIVE: In this study, we evaluated on a genomic scale the potential prognostic value of insulin signaling in early BC. METHODS: Candidate genes were selected from the published literature and gene expression profiling experiments. Three publicly available BC datasets, containing gene expression data on 502 cases, were used to test the prognostic ability of the score. The gene signature was developed on GSE1456, containing microarray data from 159 patients, split into a training set (102 breast tumors) and a validation set (n = 57). GSE3494 and GSE2990 (350 patients) were used for external validation. Univariate Mann-Whitney test was used to identify genes differentially expressed between relapsed and nonrelapsed patients. Expression of genes significantly correlated with relapse was combined in a linear score. Patients were classified as low or high risk with respect to the median value. RESULTS: On the training set, 15 genes turned out to be differentially expressed: 8-year disease-free survival (DFS) was 51 and 91% in the high- and low-risk group (p < 0.001), respectively. In the validation set, DFS was 97 and 54% (p = 0.009), respectively. External validation: 8-year DFS was 72 and 61%, respectively, in GSE3494 (p = 0.03) and 74 and 55% in GSE2990 (p = 0.03). By multivariate analyses, the insulin signature was significantly associated with DFS, independently of age, hormone receptor status, nodal status, and grade. CONCLUSIONS: Our findings indicate that the insulin pathway is involved in BC prognosis at a genomic level and provide a window of selectivity for preventive and treatment strategies targeting the insulin/IGF pathway in BC patients

False-positive galactomannan platelia Aspergillus test results for patients receiving piperacillin-tazobactam

At the bone marrow transplantation center of the San Martino Hospital ( Genoa), we observed an increase in the rate of patients with positive Platelia Aspergillus (PA; Bio-Rad) test results, from 10% ( 38 of 386 patients) in the period from January 1999 through January 2003 to 36% ( 21 of 59 patients) in the period from February 2003 through May 2003. Positivity was significantly (P < .001) associated with the administration of piperacillin-tazobactam (PT) (17 [74%] of 23 patients who received PT had positive results vs. 4 [11%] of 36 who did not receive PT). Multivariate analysis found administration of PT (&chi;2 = 34.7; P < .001) and underlying disease (chi(2) = 21.14; P < .001) to be associated with PA positivity. of 15 PT batches tested, 12 had positive PA test results.Natl Inst Canc Res, Infect Dis Unit, I-16132 Genoa, ItalyUniv Genoa, Genoa, ItalyNatl Inst Canc Res, Epidemiol Unit, I-16132 Genoa, ItalyOsped San Martino Genova, Dept Hematol, Genoa, ItalyUniversidade Federal de São Paulo, Infect Dis Unit, São Paulo, BrazilUniversidade Federal de São Paulo, Infect Dis Unit, São Paulo, BrazilWeb of Scienc

The management of achondroplasia in Italy: results from a Delphi panel based on real-world experience

BackgroundAchondroplasia is a rare genetic disorder caused by a mutation in the FGFR3 gene, leading to skeletal changes and other systemic complications that greatly impact the patient's quality of life. There currently are differences in achondroplasia patients' management among countries and centers within the same country.MethodA group of Italian experts discussed the best practice and the current unmet needs in the management of patients with achondroplasia though a two-round Delphi panel, between September and November 2022. The Delphi survey consisted of 32 questions covering organizational aspects, diagnosis and follow-up, and management of achondroplasia patient, and was shared among 54 experts from 25 different centers in Italy. The consensus was determined on the basis of the percentage of agreement or disagreement to each statement on a 5-point Likert scale.ResultsPediatricians (including specialists in pediatrics, medical genetics, and pediatric endocrinology) orthopedics and medical geneticists were the most represented specialists accounting for 64%, 9% and 9% of participants, respectively. The panel highlighted the need for standardized procedures to identify reference centers, the crucial role of multidisciplinary team, and effective communication among centers (Hub and Spoke model) as the essential organizational features; the importance of genetic counseling, presence of a psychologist, and clear communication during prenatal diagnosis as main points for diagnosis; early intervention by different specialists, personalized care, and promotion of a healthy lifestyle as major points for patient management.ConclusionTo ensure an adequate continuity of care over the whole lifespan of a patient with achondroplasia a shared model for patient management is suggested by Italian specialists

Hormonal therapy followed by chemotherapy or the reverse sequence as first-line treatment of hormone-responsive, human epidermal growth factor receptor-2 negative metastatic breast cancer patients: Results of an observational study

Introduction Although hormonal-therapy is the preferred first-line treatment for hormone-responsive, HER2 negative metastatic breast cancer, no data from clinical trials support the choice between hormonal-therapy and chemotherapy. Methods Patients were divided into two groups according to the treatment: chemotherapy or hormonal-therapy. Outcomes in terms of clinical benefit and median overall survival (OS) were retrospectively evaluated in the two groups. To calculate the time spent in chemotherapy with respect to OS in the two groups, the proportion of patients in chemotherapy relative to those present in either group was computed at every day from the start of therapy. Results From 1999 to 2013, 119 patients received first-line hormonal-therapy (HT-first group) and 100 first-line chemotherapy (CT-first group). Patients in the CTfirst group were younger and with poorer prognostic factors as compared to those in HT-first group. Clinical benefit (77 vs 81%) and median OS (50.7 vs 51.1 months) were similar in the two groups. Time spent in chemotherapy was significantly longer during the first 3 years in CT-first group (54-34%) as compared to the HT-first group (11-18%). This difference decreased after the third year and overall was 28% in the CT-first group and 18% in the HT-first group. Conclusions The sequence first-line chemotherapy followed by hormonal-therapy, as compared with the opposite sequence, is associated with a longer time of OS spent in chemotherapy. However, despite the poorer prognostic factors, patients in the CTfirst group had a superimposable OS than those in the HT-first group

Neo-adjuvant chemo/immunotherapy in the treatment of stage III (N2) non-small cell lung cancer: a phase I/II pilot study.

In a previous randomized study, we showed that adjuvant immunotherapy with tumor-infiltrating lymphocytes and recombinant interleukin-2 (rIL-2) significantly improved survival in resected N2-Non Small Cell Lung Cancer (NSCLC) patients. The present study assesses feasibility, safety and potential efficacy of combined neo-adjuvant chemotherapy and immunotherapy with peripheral blood mononuclear cells (PBMC) and rIL-2 in resectable N2-NSCLC patients. Eighty-two consecutive N2-NSCLC patients underwent neo-adjuvant chemotherapy with cisplatin and gemcitabine. Out of the 82 patients, 23 were also subjected to leukapheresis prior to neo-adjuvant chemotherapy while the remaining 59 did not. Collected PBMC were analyzed for viability and phenotype and then stored frozen in liquid nitrogen. Thawed PBMC were infused intravenously, 5 days before surgery. After the infusion, rIL-2 was administered subcutaneously until surgery. Only patients with a partial or complete response to neoadjuvant chemotherapy underwent surgery: 13 patients in the experimental immunotherapy group (A) and 32 in the reference group (B). The two groups were homogeneous for all major prognostic factors. Median leukapheresis yield was 10 billion PBMC, (range 3–24 billions). Two to six billion PBMC were infused. The phenotypic analysis showed that similar proportions of CD4 and CD8 cells were present in leukapheresis products, and thawed PBMC, as well as in T lymphocytes isolated from the removed tumours. No severe adverse effects were observed following immunotherapy. No significant differences in overall survival (OS) and event-free survival (EFS) were seen between the two groups. However, the 5-year OS in group A was almost twice as much compared to group B (59% vs 32%). After adjustment for major prognostic factors, a statistically significant 66% reduction in the hazard of death was seen in patients receiving immunotherapy. The OS benefit was more evident in patients with adenocarcinoma than in those with squamous cell carcinoma. This study supports the favorable toxicity profile and potential efficacy of combining neo-adjuvant chemotherapy and immunotherapy with PBMC and rIL-2 in the treatment of N2-NSCLC patients

A Score-Based Approach to 18F-FDG PET Images as a Tool to Describe Metabolic Predictors of Myocardial Doxorubicin Susceptibility

Purpose: To verify the capability of 18F-fluorodeoxy-glucose positron emission tomography/computed tomography (FDG-PET/CT) to identify patients at higher risk of developing doxorubicin (DXR)-induced cardiotoxicity, using a score-based image approach. Methods: 36 patients underwent FDG-PET/CT. These patients had shown full remission after DXR-based chemotherapy for Hodgkin\u2019s disease (DXR dose: 40\u201350 mg/m2 per cycle), and were retrospectively enrolled. Inclusion criteria implied the presence of both pre- and post-chemotherapy clinical evaluation encompassing electrocardiogram (ECG) and echocardiography. Myocardial metabolism at pre-therapy PET was evaluated according to both standardized uptake value (SUV)- and score-based approaches. The capability of the score-based image assessment to predict the occurrence of cardiac toxicity with respect to SUV measurement was then evaluated. Results: In contrast to the SUV-based approach, the five-point scale method does not linearly stratify the risk of the subsequent development of cardiotoxicity. However, converting the five-points scale to a dichotomic evaluation (low vs. high myocardial metabolism), FDG-PET/CT showed high diagnostic accuracy in the prediction of cardiac toxicity (specificity = 100% and sensitivity = 83.3%). In patients showing high myocardial uptake at baseline, in which the score-based method is not able to definitively exclude the occurrence of cardiac toxicity, myocardial SUV mean quantification is able to further stratify the risk between low and intermediate risk classes. Conclusions: the score-based approach to FDG-PET/CT images is a feasible method for predicting DXR-induced cardiotoxicity. This method might improve the inter-reader and inter-scanner variability, thus allowing the evaluation of FDG-PET/CT images in a multicentral setting

Randomised phase 3 open-label trial of first-line treatment with gemcitabine in association with docetaxel or paclitaxel in women with metastatic breast cancer: a comparison of different schedules and treatments

BACKGROUND: This open-label study compared docetaxel/gemcitabine vs. paclitaxel/gemcitabine and a weekly (W) vs. 3-weekly (3 W) schedule in metastatic breast cancer (MBC). METHODS: Patients relapsed after adjuvant/neoadjuvant anthracycline-containing chemotherapy were randomized to: A) gemcitabine 1000 mg/m(2) Day 1,8 + docetaxel 75 mg/m(2) Day 1 q3W; B) gemcitabine 1250 mg/m(2) Day 1,8 + paclitaxel 175 mg/m(2) Day 1 q3W; C) gemcitabine 800 mg/m(2) Day 1,8,15 + docetaxel 30 mg/m(2) Day 1,8,15 q4W; D) gemcitabine 800 mg/m(2) Day 1,15 + paclitaxel 80 mg/m(2) Day 1,8,15 q4W. Primary endpoint was time-to-progression (TTP). Secondary endpoints were overall survival (OS) and overall response rate (ORR). RESULTS: Interim analysis led to accrual interruption (241 patients enrolled of 360 planned). Median TTP (months) was 8.33 (95% CI: 6.19-10.16) with W and 7.51 (95% CI: 5.93-8.33) with 3 W (p=0.319). No differences were observed in median TTP between docetaxel and paclitaxel, with 85.6% and 87.0% of patients progressing, respectively. OS did not differ between regimens/schedules. ORR was comparable between regimens (HR: 0.882; 95% CI: 0.523-1.488; p=0.639), while it was significantly higher in W than in the 3 W (HR: 0.504; 95% CI: 0.299-0.850; p=0.010) schedule. Grade 3/4 toxicities occurred in 69.2% and 71.9% of patients on docetaxel and paclitaxel, and in 65.8% and 75.2% in W and 3 W. CONCLUSIONS: Both treatment regimens showed similar TTP. W might be associated with a better tumour response compared with 3 W. TRIAL REGISTRATION: Clinicaltrial.gov ID NCT0023689

Effects of L-carnitine administration on left ventricular remodeling after acute anterior myocardial infarction: The L-carnitine Ecocardiografia Digitalizzata Infarto Miocardico (CEDIM) trial

Objectives. This study was performed to evaluate the effects of l-carnitine administration on long-term left ventricular dilation in patients with acute anterior myocardial infarction. Background. Carnitine is a physiologic compound that performs an essential role in myocardial energy production at the mitochondrial level. Myocardial carnitine deprivation occurs during ischemia, acute myocardial infarction and cardiac failure. Experimental studies have suggested that exogenous carnitine administration during these events has a beneficial effect on function. Methods. The l-Carnitine Ecocardiografia Digitalizzata Infarto Miocardico (CEDIM) trial was a randomized, double-blind, placebo-controlled, multicenter trial in which 472 patients with a first acute myocardial infarction and high quality two-dimensional echocardiograms received either placebo (239 patients) or l-carnitine (233 patients) within 24 h of onset of chest pain. Placebo or l-carnitine was given at a dose of 9 g/day intravenously for the first 5 days and then 6 g/day orally for the next 12 months. Left ventricular volumes and ejection fraction were evaluated on admission, at discharge from hospital and at 3, 6 and 12 months after acute myocardial infarction. Results. A significant attenuation of left ventricular dilation in the first year after acute myocardial infarction was observed in patients treated with l-carnitine compared with those receiving placebo. The percent increase in both end-diastolic and endsystolic volumes from admission to 3-, 6- and 12-mouth evaluation was significantly reduced in the l-carnitine group. No significant differences were observed in left ventricular ejection fraction changes over time in the two groups. Although not designed to demonstrate differences in clinical end points, the combined incidence of death and congestive heart failure after discharge was 14 (6%) in the l-carnitine treatment group versus 23 (9.6%) in the placebo group (p = NS). Incidence of ischemic events during follow-up was similar in the two groups of patients. Conclusions. l-Carnitine treatment initiated early after acute myocardial infarction and continued for 12 months can attenuate left ventricular dilation during the first year after an acute myocardial infarction, resulting in smaller left ventricular volumes at 3, 6 and 12 months after the emergent event