Immune-Checkpoint Inhibitor-Related Myocarditis: Where We Are and Where We Will Go.

Immune checkpoint inhibitors (ICIs) are specific monoclonal antibodies directed against inhibitory targets of the immune system, mainly represented by programmed death-1 (PD1) ligand-1 (PD-L1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4), thus enabling an amplified T-cell-mediated immune response against cancer cells. These drugs have significantly improved prognosis in patients with advanced metastatic cancer (e.g., melanoma, non-small cell lung cancer, renal cell carcinoma). However, uncontrolled activation of anti-tumor T-cells could trigger an excessive immune response, possibly responsible for multi-organ damage, including, among others, lymphocytic myocarditis. The incidence of ICIs-induced myocarditis is underestimated and the patients affected are poorly characterized. The diagnosis and management of this condition are mainly based on expert opinion and case reports. EKG and ultrasound are tests that can help identify patients at risk of myocarditis during treatment by red flags, such as QRS complex enlargement and narrowing of global longitudinal strain (GLS). Therapy of ICI-related myocarditis is based on immunosuppressors, monoclonal antibodies and fusion proteins. A future strategy could involve the use of microRNAs. This review considers the current state of the art of immune-related adverse cardiovascular events, focusing on histological and clinical features, diagnosis and management, including current treatments and future pharmacological targets.

Late reproduction at lower risk in Sardinia island: a case of reproductive longevity?

Population of Sardinia Island is characterized by geographical and historical isolation, a deep-rooted tendency to postpone childbearing, and a demographic and genetic structure largely different from that of continental Italy and other European countries. Based on such differences we investigated whether the risk of adverse pregnancy outcome associated with late reproduction was different between the Sardinian population and two mainland areas (North+Centre and South+Sicily), representative of different Italian socio-economic contexts. In particular we suggest that parents, who show aptitude to late childbearing associated with a reduced risk of adverse pregnancy outcome, enjoy "reproductive longevity". Data set come from the National Institute of Statistics and concern all 1990-98 Italian birth records (n=4 830 742). We considered three types of adverse pregnancy outcome: i) stillbirths of the total births, ii) very preterm births (<32 gestation weeks) of the live births, iii) very low birthweight births (<1.5 Kg) of the live births after exclusion of very preterm births. Using logistic regression models we investigated whether the risk of adverse pregnancy outcome associated with maternal or paternal ageing followed differing trends between areas. Moreover we evaluated the Odds Ratio of the three types of adverse outcome as a function of maternal and paternal age and education, and delivery rank. We found that in the three areas the risks increase with parental ageing, but in Sardinia the increase is less rapid than in the mainland. In particular with respect to South+Sicily, in Sardinian mothers=35 years and fathers=40 years the OR is 25% lower for stillbirth and preterm birth, and 19% lower for low birthweight. We suggest that the aptitude to late and successful childbearing may be a peculiar trait of the Sardinian population, indicative of "reproductive longevity". The possibility of identifying populations where a relevant proportion of mothers show the character might promote case-control studies focused on the possible determinants and measures of prevention and/or protection against the adverse effect of late reproduction.

Gestational age shortening in single births at term. Italy 1990-1998.

The increasing incidence of moderate preterm births (32-36 gestation weeks) might reflect a more general tendency toward a shortening of the gestational length occurring also in the term births (37 + gestation weeks). We examined all Italian 1st live born singletons (n = 2,356,365) and found that from 1990 to 1998 the births of 40 + gestation weeks decreased from 60.7 to 51.7% and among term births the average gestation weeks decreased from 39.74 to 39.55. In term pregnancies the effect of low education and advanced age of the mother in decreasing the gestational length persisted over time, but, independently of the maternal factors, the pregnancies experienced a progressive shortening. The finding, if confirmed for other countries, should deserve further investigations on possible determinants, as improved estimates of gestational age through the widespread use of prenatal ultrasound or diffusion of hazardous and stressing working and living conditions.

Paternal age and preterm birth in Italy, 1990 to 1998.

BACKGROUND: Advanced paternal age has been reported to impair pregnancy outcome. Here, we investigated the association of advanced paternal age with preterm birth by using a very large national data set. METHODS: We analyzed data from 1990 to 1998 on Italian firstborn singletons to mothers 20-24 and 25-29 years of age (n = 1,510,823). Odds ratios for overall preterm (<37 weeks' gestation), very preterm (<32 weeks), and moderate preterm (32-36 weeks) births were evaluated through logistic regression models in paternal age classes (20-24, 25-29, 30-34, 35-39, 40-44, 45-49, 50+ years) after adjustment for confounders. Nonparametric regression models were used to fit the effect of paternal ageing on the incidence of very preterm births. RESULTS: Odds ratios increased with paternal age more rapidly for very preterm than for moderate preterm births; among 45- to 49-year-old fathers, odds ratios for very preterm births reached 1.91 (95% confidence interval = 1.08-3.38) and 1.72 (1.25-2.36), respectively, in 20- to 24- and 25- to 29-year-old mothers. CONCLUSIONS: This study confirms that paternal age contributes to the risk of preterm birth. The effect is stronger on very preterm births but also influences moderate preterm births.

Birthweight by gestational age in preterm babies according to a Gaussian mixture model.

OBJECTIVE: To provide a statistically sound criterion for identifying implausibly large birthweights for gestational age. DESIGN: Review of ISTAT 1990-1994 national newborn records. SETTING: Italy POPULATION: Forty-two thousand and twenty-nine single first and second liveborn preterm babies. METHODS: Two-component Gaussian mixture models are used to describe the birthweight distributions stratified by gestational age. Implausibly large babies are identified through model-based probabilistic clustering. MAIN OUTCOME MEASURES: Gestational age misclassification and weight-for-gestational age centile curves RESULTS: Gestational age appears under-estimated by about six weeks in 12.3% of the cases. Large babies are equally present in males and females, but are more frequent in second-borns than in first-borns, even when parity-specific models are fitted. CONCLUSIONS: The approach allows for a quantification of the gestational age under-estimate error and for data correction through model-based clustering. Correct birthweight distributions and growth curves are also provided.