Prospective, Multicenter Phase II Trial of Non-Pegylated Liposomal Doxorubicin Combined with Ifosfamide in First-Line Treatment of Advanced/Metastatic Soft Tissue Sarcomas

Simple Summary This clinical investigation reports the results of a prospective, multicenter phase II trial designed to evaluate the activity and safety of combining non-pegylated liposomal doxorubicin (NPLD) with ifosfamide as a first-line treatment for advanced/metastatic STS. The study results demonstrate a remarkable overall response rate (ORR) alongside a satisfactory disease control rate (DCR) while maintaining acceptable levels of toxicity. The addition of NPLD to ifosfamide, showing high activity and a low toxicity profile, makes this drug combination a useful option for patients with advanced/metastatic STS. These findings provide a promising basis for further comprehensive research into the clinical application of this drug combination in this disease setting.Abstract Doxorubicin is a widely used anticancer agent as a first-line treatment for various tumor types, including sarcomas. Its use is hampered by adverse events, among which is the risk of dose dependence. The potential cardiotoxicity, which increases with higher doses, poses a significant challenge to its safe and effective application. To try to overcome these undesired effects, encapsulation of doxorubicin in liposomes has been proposed. Caelyx and Myocet are different formulations of pegylated (PLD) and non-pegylated liposomal doxorubicin (NPLD), respectively. Both PLD and NPLD have shown similar activity compared with free drugs but with reduced cardiotoxicity. While the hand-foot syndrome exhibits a high occurrence among patients treated with PLD, its frequency is notably reduced in those receiving NPLD. In this prospective, multicenter, one-stage, single-arm phase II trial, we assessed the combination of NPLD and ifosfamide as first-line treatment for advanced/metastatic soft tissue sarcoma (STS). Patients received six cycles of NPLD (50 mg/m2) on day 1 along with ifosfamide (3000 mg/m2 on days 1, 2, and 3 with equidose MESNA) administered every 3 weeks. The overall response rate, yielding 40% (95% CI: 0.29-0.51), resulted in statistical significance; the disease control rate stood at 81% (95% CI: 0.73-0.90), while only 16% (95% CI: 0.08-0.24) of patients experienced a progressive disease. These findings indicate that the combination of NPLD and ifosfamide yields a statistically significant response rate in advanced/metastatic STS with limited toxicity

Oral ondansetron versus domperidone for acute gastroenteritis in pediatric emergency departments: Multicenter double blind randomized controlled trial

The use of antiemetics for vomiting in acute gastroenteritis in children is still a matter of debate. We conducted a double-blind randomized trial to evaluate whether a single oral dose of ondansetron vs domperidone or placebo improves outcomes in children with gastroenteritis. After failure of initial oral rehydration administration, children aged 1-6 years admitted for gastroenteritis to the pediatric emergency departments of 15 hospitals in Italy were randomized to receive one oral dose of ondansetron (0.15 mg/kg) or domperidone (0.5 mg/kg) or placebo. The primary outcome was the percentage of children receiving nasogastric or intravenous rehydration. A p value of 0.014 was used to indicate statistical significance (and 98.6% CI were calculated) as a result of having carried out two interim analyses. 1,313 children were eligible for the first attempt with oral rehydration solution, which was successful for 832 (63.4%); 356 underwent randomization (the parents of 125 children did not give consent): 118 to placebo, 119 to domperidone, and 119 to ondansetron. Fourteen (11.8%) needed intravenous rehydration in the ondansetron group vs 30 (25.2%) and 34 (28.8%) in the domperidone and placebo groups, respectively. Ondansetron reduced the risk of intravenous rehydration by over 50%, both vs placebo (RR 0.41, 98.6% CI 0.20-0.83) and domperidone (RR 0.47, 98.6% CI 0.23-0.97). No differences for adverse events were seen among groups. In a context of emergency care, 6 out of 10 children aged 1-6 years with vomiting due to gastroenteritis and without severe dehydration can be managed effectively with administration of oral rehydration solution alone. In children who fail oral rehydration, a single oral dose of ondansetron reduces the need for intravenous rehydration and the percentage of children who continue to vomit, thereby facilitating the success of oral rehydration. Domperidone was not effective for the symptomatic treatment of vomiting during acute gastroenteritis

FRAILTY IN EUROPE: THE ROLE OF SOCIAL NETWORKS AND ACTIVITY PARTICIPATION

Frailty represents a condition of increased vulnerability among elderly people due to losses in one or more domains of the human functioning. Population aging and the consequential increase in the proportion of elderly, are making frailty a public health priority, especially in the European Union, where the proportion of elderly is projected to increase significantly in the next 30 years. Despite the numerous studies on frailty and its determinants, scholarly interest towards the role of the social determinants, specifically, is recent, with most studies focusing on the Asian context. Thus, evidence on the social determinants of frailty in the European context is scarce. In light of this, the study we propose aims at evaluating the role of social connectedness and activity participation on frailty among the elderly in Europe, using suitable regression techniques. We employ data from the Survey on Health, Aging and Retirement in Europe (SHARE), providing information on the health, socioeconomic conditions and social life of community-dwelling individuals aged 50 or older in European countries. Specifically, we study how social networks (SN) and activity participation (AP) in wave 4 affect frailty of people aged 60 and over in wave 5 by gender, separately. We measure SN and AP via two indexes proposed in the literature. To measure frailty, we rely on Romero-Ortuno et al.’s SHARE Frailty Instrument, providing pre-calculated, population-representative and gender-specific frailty indexes. Our findings hint at the existence of a substantial association between both social connectedness and activity participation and frailty. However, this association appears to change across genders. When comparing the role of social connectedness and activity participation, a more prominent association with activity participation emerges

Administrative databases as a tool for identifying healthcare demand and costs in an over-one million population

Background: the aim of this study was to assess healthcare demand of specific groups of population and their costs borne by Italian Health System, using healthcare administrative databases. Methods: demographic, clinical and economic data were obtained from datasets available at the Regional Health System, combined into a data warehouse (DENALI), using a probabilistic record linkage to optimize the data matching process. The study population consisted of more than 1 million people registered in 2005 at one Local Healthcare Unit of Lombardy. Eight different segments were identified. Costs occurring in 2005 for hospital admissions, drug prescriptions, outpatient medical specialist visits were quantified in each segment. Results: healthy people accounted for 53% of the population and cost € 180 per-capita. Subjects with only one chronic disease made up 16% of the population and cost € 916 per-capita, those affected by several chronic diseases accounted for 13% and cost € 3 457 per-capita. Hospitalizations were the cost driver in five segments, ranging from 42% to 89% of total expenditures. Outpatient visits were the cost driver among healthy subjects (54%) and those with a possible chronic disease (42%), while drug costs ranged between 4% (“acute event”) and 32% (“one chronic disease”). Overall, healthcare cost was € 809 per-capita. Conclusions: healthcare costs were mainly determined by people affected by chronic conditions, even if “healthy people” ranked third for total expenditure. These costs need an appropriate identification of healthcare demand, that could be efficiently monitored through the use of administrative databases

Mitochondrial DNA diversity and genetic structure of striped dolphin Stenella coeruleoalba in the Northern Ionian Sea

In the framework of global and EU policies focused on stopping the loss of biodiversity process, deepening the genetic variability, especially of populations species identified as threatened, is crucial for defining conservation units and developing appropriate conservation strategies. This is more urgent for cetacean species in the Mediterranean because they assume a key ecological role in the marine food web and are severely affected by numerous and different anthropogenic pressures. This study aims to increase information on the genetic variability of striped dolphin in the Northern Ionian Sea by investigating the population structure, phylogenetic relationships and phylogeographic patterns using two mtDNA markers. From October 2020 to August 2021, a total of 88 skin tissue samples were collected from free-ranging dolphins in the Gulf of Taranto by applying the non-invasive technique of skin swabbing. An acceptable amount of DNA was extracted from 86 samples and used for subsequent genetic analysis conducted on the partial sequences of 421 and 704 bp in length of the cytb gene and D-loop control region, respectively. In addition, the sequences of the two mtDNA markers were joined together to compose a mtDNA concatenated sequence of 1125 bp for each sampled dolphin in order to investigate the genetic variability of the species population in the study area. Genetic analysis highlighted a low nucleotide diversity and high haplotypic diversity of the striped dolphin of the Gulf of Taranto, suggesting a population in rapid expansion after a period of reduction in size and diversity of the initial population. The phylogenetic analyses revealed the presence of at least two different lineages of Stenella coeruleoalba in the Mediterranean Sea, one specific to the Northern Ionian Sea and one shared with the Mediterranean population, confirming results already obtained for the local unit in the Gulf of Taranto. The results point out a potential problem of hybridization between striped and common dolphins which needs to be further investigated. Therefore, increasing the analysis of several markers may increase understanding of the genetic diversity of the population in the Ionian Sea and represent a useful tool to support the implementation of future effective conservation measures

STABLE CORONONARY ARTERY DISEASE 136 QUESTION AND ANSWERS

STABLE CORONONARY ARTERY DISEASE 136 QUESTION AND ANSWER

Pharmacogenetic score predicts overall survival, progression-free survival and platinum sensitivity in ovarian cancer

Aim:To define the impact of polymorphisms in genes involved in platinum-taxane and estrogen activity in the outcome of platinum-based treated ovarian cancer patients (OCP).Patients & Methods:Two hundred and thirty OCP were analyzed for 124 germ-line polymorphisms to generate a prognostic score for overall survival (OS), progression-free survival (PFS) and platinum-free interval (PFI).Results:ABCG2rs3219191D>I,UGT1Ars10929302G>A andUGT1Ars2741045T>C polymorphisms were significantly associated with all three parameters (OS, PFS and PFI) and were used to generate a score. Patients in high-risk group had a poorer OS (hazard ratio [HR]: 1.8; 95% CI: 1.3-2.7; p = 0.0019), PFS (HR: 2.0; 95% CI: 1.4-2.9; p < 0.0001) and PFI (HR: 1.9; 95% CI: 1.4-2.8; p = 0.0002) compared with those in low-risk group.Conclusion:The prognostic-score including polymorphisms involved in drug and estrogen pathways stratifies OCP according to OS, PFS and PFI

Brief low-workload myocardial ischaemia induces protection against exercise-related increase of platelet reactivity in patients with coronary artery disease

OBJECTIVE:In patients with acute myocardial infarction, pre-infarction angina is associated with smaller infarct size, probably mainly through myocardial protection induced by ischaemic preconditioning. However, in models of recurrent thrombosis myocardial ischaemia also improves arterial patency. This study investigated whether myocardial ischaemia has any effect on platelet function in patients with coronary artery disease. PATIENTS AND DESIGN: Twenty patients with low-workload myocardial ischaemia underwent, in a randomised crossover study, two treadmill exercise stress tests (EST) on two separate days: a single maximal EST (EST-1) and a maximal EST (EST-2) performed 45 minutes after a low-workload EST stopped at 1-mm ST depression (p-EST). Platelet reactivity was evaluated by measuring the closure time in response to ADP/collagen by the PFA-100 method, and monocyte-platelet aggregate (MPA) formation and CD41 platelet expression, with and without ADP stimulation, by flow cytometry. RESULTS: Compared to resting values, closure time decreased at peak EST-1 (p<0.001) but not at peak EST-2. MPA after ADP stimulation increased more significantly at peak EST-1 compared with peak EST-2 (p<0.001). Repetition in seven patients of the pEST/EST-2 protocol after intravenous administration of the adenosine antagonist theophylline showed prevention of the effects of p-EST on exercise-induced platelet reactivity. CONCLUSIONS: A short episode of myocardial ischaemia induces protection against an exercise-induced increase of platelet reactivity. These data also suggest a role for adenosine in this phenomenon