Pazopanib-Induced Heart Failure in a Metastatic Sarcoma Patient: between Reversible Side Effect and Efficacy

 Introduction: Pazopanib, a multi-target tyrosine-kinase inhibitor (TKI), is a relatively novel anticancer agent registered for advanced renal cell carcinoma recently emerged in the setting of advanced soft-tissue sarcoma (STS). In the early clinical trials pazopanib has been very marginally linked to left ventricular ejection fraction (LVEF) dysfunction as, on contrary, reported for other anti-angiogenesis TKIs, such as Sunitinib and Sorafenib. Presentation of Case: We here present a case of severe, but reversible, congestive cardiac failure in a 37-year old Caucasian man affected by soft-tissue sarcoma during an efficacious treatment with pazopanib. Conclusion: Cardiac damage from novel TKI treatments is still an underestimated phenomenon. In our patient, pazopanib was the only treatment ensuring stability of disease and its discontinuation meant disease progression. Post-approval monitoring of novel TKIs should be taken into account by clinicians including a careful monitoring of LVEF and all symptoms suggestive of cardiac dysfunction, in particular for drugs potentially capable to change the natural history of still uncurable cancer.

Group b streptococcus late-onset disease: 2003-2010

BACKGROUND: There is insufficient population-based data on group B streptococcus (GBS) late-onset disease (LOD). Risk factors and routes of GBS transmission are poorly understood. METHODS: A prospective, cohort study was conducted to collect incidence data on LOD and evaluate GBS infections over an 8-year period (2003-2010). Starting from January 2007, maternal rectovaginal and breast milk cultures were routinely collected on confirmation of the LOD diagnosis to assess maternal GBS culture status. RESULTS: The incidence rate of LOD was 0.32 per 1000 live births (1.4 and 0.24 per 1000 live births for preterm and term newborns, respectively). The registered cases of LOD (n = 100) were classified as sepsis (n = 57), meningitis (n = 36), or focal infection (n = 7). Thirty neonates were preterm (2 had recurrent infection); 68 were term. Four infants died (3 early preterm, 1 term). At the time the LOD diagnosis was confirmed, 3 (6%) of 53 mothers had GBS mastitis, and 30 (64%) of 47 carried GBS at the rectovaginal site. Early (7-30 days) LOD presentation was associated with neonatal brain lesions or death (odds ratio: 0.96 [95% confidence interval: 0.93-0.99]). Intrapartum antibiotic exposure was significantly associated with mild (12 of 22) rather than severe (11 of 45; P = .03) LOD. CONCLUSIONS: Preterm neonates had the highest rates of LOD and mortality. Most mothers carried GBS at the time of the LOD diagnosis, whereas 6% had mastitis. Intrapartum antibiotics were associated both with delayed presentation of symptoms and milder LOD. Pediatrics 2013;131:e361-e368Early neonatal mortality has remained high and unchanged for many years in Tanzania, a resource-limited country. Helping Babies Breathe (HBB), a novel educational program using basic interventions to enhance delivery room stabilization/resuscitation, has been developed to reduce the number of these deaths. METHODS: Master trainers from the 3 major referral hospitals, 4 associated regional hospitals, and 1 district hospital were trained in the HBB program to serve as trainers for national dissemination. A before (n = 8124) and after (n = 78 500) design was used for implementation. The primary outcomes were a reduction in early neonatal deaths within 24 hours and rates of fresh stillbirths (FSB). RESULTS: Implementation was associated with a significant reduction in neonatal deaths (relative risk [RR] with training 0.53; 95% confidence interval [CI] 0.43-0.65; P ≤.0001) and rates of FSB (RR with training 0.76; 95% CI 0.64-0.90; P = .001). The use of stimulation increased from 47% to 88% (RR 1.87; 95% CI 1.82-1.90; P ≤.0001) and suctioning from 15% to 22% (RR 1.40; 95% CI 1.33-1.46; P ≤.0001) whereas face mask ventilation decreased from 8.2% to 5.2% (RR 0.65; 95% CI 0.60- 0.72; P ≤ .0001). Copyright © 2013 by the American Academy of Pediatrics

Direct analysis of thymic function in children with Down's syndrome

BACKGROUND: Down's syndrome (DS) is characterized by several immunological defects, especially regarding T cell compartment. DS is considered the best example of accelerated ageing in humans. Direct observations of the thymus have shown that in DS this organ undergoes severe histological and morphological changes. However, no data on its capacity to generate T cells are present in the literature. Here, using a new technology based upon real time PCR, we have investigated the capacity of the thymus to produce and release newly generated T lymphocytes (the so called "recent thymic emigrants", RTE) in children with DS. METHODS: We studied 8 children affected by DS, aged 2–7 years, compared with 8 age- and sex-matched healthy controls. Flow cytometry was used to determine different lymphocytes subsets. Real time PCR with the Taqman system was used to quantify the amount of RTE, i.e. peripheral blood lymphocytes that express the T cell receptor rearrangement excision circles (TREC). RESULTS: In comparison with control children, those with DS had a significant lower number of TREC+ peripheral blood cells. Moreover, in DS children but not in controls, a strong negative correlation between age and the levels of TREC+ cells was found. CONCLUSIONS: The direct measure of thymic output indicates that the impairment of the organ results in a reduced production of newly generated T cells. This observation could suggest that cytokines able to modulate thymic function, such as interleukins, could be useful to improve the functionality of the organ and to treat the immunodeficiency present in DS subjects

An overview of Alpine and Mediterranean palaeogeography, terrestrial ecosystems and climate history during MIS 3 with focus on the Middle to Upper Palaeolithic transition

This paper summarizes the current state of knowledge about the millennial scale climate variability characterizing Marine Isotope Stage 3 (MIS 3) in S-Europe and the Mediterranean area and its effects on terrestrial ecosystems. The sequence of Dansgaard-Oeschger events, as recorded by Greenland ice cores and recognizable in isotope profiles from speleothems and high-resolution palaeoecological records, led to dramatic variations in glacier extent and sea level configuration with major impacts on the physiography and vegetation patterns, both latitudinally and altitudinally. The recurrent succession of (open) woodlands, including temperate taxa, and grasslands with xerophytic elements, have been tentatively correlated to GIs in Greenland ice cores. Concerning colder phases, the Greenland Stadials (GSs) related to Heinrich events (HEs) appear to have a more pronounced effect than other GSs on woodland withdrawal and xerophytes expansion. Notably, GS 9-HE4 phase corresponds to the most severe reduction of tree cover in a number of Mediterranean records. On a long-term scale, a reduction/opening of forests throughout MIS 3 started from Greenland Interstadials (GIs) 14/13 (ca. 55\u201348 ka), which show a maximum in woodland density. At that time, natural environments were favourable for Anatomically Modern Humans (AMHs) to migrate from Africa into Europe as documented by industries associated with modern hominin remains in the Levant. Afterwards, a variety of early Upper Palaeolithic cultures emerged (e.g., Uluzzian and Proto-Aurignacian). In this chronostratigraphic framework, attention is paid to the Campanian Ignimbrite tephra marker, as a pivotal tool for deciphering and correlating several temporal-spatial issues crucial for understanding the interaction between AMHs and Neandertals at the time of the Middle to Upper Palaeolithic transition

Escherichia coli Is Overtaking Group B Streptococcus in Early-Onset Neonatal Sepsis

The widespread use of intrapartum antibiotic prophylaxis (IAP) to prevent group B streptococcus (GBS) early-onset sepsis (EOS) is changing the epidemiology of EOS. Italian prospective area-based surveillance data (from 1 January 2016 to 31 December 2020) were used, from which we identified 64 cases of culture-proven EOS (E. coli, n = 39; GBS, n = 25) among 159,898 live births (annual incidence rates of 0.24 and 0.16 per 1000, respectively). Approximately 10% of E. coli isolates were resistant to both gentamicin and ampicillin. Five neonates died; among them, four were born very pre-term (E. coli, n = 3; GBS, n = 1) and one was born full-term (E. coli, n = 1). After adjustment for gestational age, IAP-exposed neonates had ≥95% lower risk of death, as compared to IAP-unexposed neonates, both in the whole cohort (OR 0.04, 95% CI 0.00-0.70; p = 0.03) and in the E. coli EOS cohort (OR 0.05, 95% CI 0.00-0.88; p = 0.04). In multi-variable logistic regression analysis, IAP was inversely associated with severe disease (OR = 0.12, 95% CI 0.02-0.76; p = 0.03). E. coli is now the leading pathogen in neonatal EOS, and its incidence is close to that of GBS in full-term neonates. IAP reduces the risk of severe disease and death. Importantly, approximately 10% of E. coli isolates causing EOS were found to be resistant to typical first-line antibiotics

Prednisone vs high-dose dexamethasone in newly diagnosed adult primary immune thrombocytopenia: a randomized trial

A debate exists regarding which type of corticosteroids (standard-dose prednisone [PDN] or high-dose dexamethasone [HD-DXM]) is the best first-line treatment for adult patients with newly diagnosed untreated primary immune thrombocytopenia (pITP). An ad hoc study compared PDN with HD-DXM in newly diagnosed untreated patients with pITP (aged >= 18 but <= 80 years, platelet count of <= 20 or >20 but <50 x 10(9)/L, and bleeding score of >= 8). Patients were randomised to receive PDN 1 mg/kg per day from days 0 to 28 (Arm A) or HD-DXM 40 mg per day for 4 days, every 14 days, for 3 consecutive courses (Arm B). Fifty-nine of 113 patients (52.2%) were randomized to Arm A and 54 of 113 (47.8%) to Arm B. In evaluable patients, total initial responses (complete response [CR], partial response [PR], minimal response [MR]) were 44 of 56 (78.57%) in Arm A and 46 of 49 (93.88%) in Arm B at days 42 and 46, respectively (P = 0.0284). Total final responses (at day 180 from initial response) were 26 of 43 (60.47%) in Arm A and 23 of 39 (58.97%) in Arm B (P = 0.8907). Total persistent responses (at 12 months from initial response) were 25 of 31 (80.65%) in Arm A and 20 of 36 (55.56%) in Arm B (P = 0.0292). Seven relapses occurred. Median follow-up was 44.4 months. Overall survival was 100% at 48 months, overall disease-free survival was 81.11% at 48 months from day 180. PDN and pulsed HD-DXM were well tolerated; HD-DXM allows effective initial responses but less long lasting than PDN. This trial was registered at www.clinicaltrials.gov as #NCT00657410

A regional audit system for stillbirth: A way to better understand the phenomenon

Background: Implementation of high-quality national audits for perinatal mortality are needed to improve the registration of all perinatal deaths and the identification of the causes of death. This study aims to evaluate the implementation of a Regional Audit System for Stillbirth in Emilia-Romagna Region, Italy. Methods: For each stillbirth ( 65 22 weeks of gestation, 65 500 g) occurred between January 1, 2014 to December 1, 2016 (n = 332), the same diagnostic workup was performed and a clinical record with data about mother and stillborn was completed. Every case was discussed in a multidisciplinary local audit to assess both the cause of death (ReCoDe classification) and the quality of care. Data were reviewed by the Regional Audit Group. Stillbirth rates, causes of death and the quality of care were established for each case. Results: Total stillbirth rate was 3.09 per 1000 births (332/107,528). Late stillbirth rate was 2.3 per 1000 (251/107,087). Sixteen stillbirths were not registered by the Regional Birth Register. The most prevalent cause of death was placental disorder (33.3%), followed by fetal (17.6%), cord (14.2%) and maternal disorders (7.6%). Unexplained cases were 14%. Compared to local audits, the regional group attributed different causes of death in 17% of cases. At multivariate analysis, infections were associated with early stillbirths (OR 3.38, CI95% 1.62-7.03) and intrapartum cases (OR 6.64, CI95% 2.61-17.02). Placental disorders were related to growth restriction (OR 1.89, CI95% 1.06-3.36) and were more frequent before term (OR 1.86, CI95% 1.11-3.15). Stillbirths judged possibly/probably preventable with a different management (10.9%) occurred more frequently in non-Italian women and were mainly related to maternal disorders (OR 6.64, CI95% 2.61-17.02). Conclusions: Regional Audit System for Stillbirth improves the registration of stillbirth and allows to define the causes of death. Moreover, sub-optimal care was recognized, allowing to identify populations which could benefit from preventive measures

Early life of Neanderthals

The early onset of weaning in modern humans has been linked to the high nutritional demand of brain development that is intimately connected with infant physiology and growth rate. In Neanderthals, ontogenetic patterns in early life are still debated, with some studies suggesting an accelerated development and others indicating only subtle differences to modern humans. Here we report the onset of weaning and rates of enamel growth using an unprecedented sample set of three late (~70-50 ka) Neanderthals and one Upper Paleolithic modern human from Northeastern-Italy via spatially-resolved chemical/isotopic analyses and histomorphometry of deciduous teeth. Our results reveal that the modern human nursing strategy, with onset of weaning at 5-6 months, was present among these Neanderthals. This evidence, combined with dental development akin to modern humans, highlights their similar metabolic constraints during early life and excludes late weaning as a factor contributing to Neanderthals' demise

Prognostic Value of a Negative Peak Supine Bicycle Stress Echocardiography With or Without Concomitant Ischemic Stress Electrocardiographic Changes: a Cohort Study.

BACKGROUND: a negative peak supine bicycle exercise stress echocardiography (ESE) was shown to have a long-term favourable prognostic value. Data on the long-term prognosis of ischaemic electrocardiographic (ISECG) changes in the setting of a negative peak supine bicycle ESE are lacking. DESIGN: we evaluated the prognostic value of negative peak supine bicycle ESE with or without concomitant ISECG changes in a referral population evaluated for chest pain after an inconclusive first-line work-up including clinical evaluation and exercise ECG stress. METHODS: from 2003 to 2010, patients who underwent a peak supine bicycle ESE and were deemed to be negative were evaluated. Two groups based on concomitant stress ECG tracing were analysed - those with normal stress ECG and those with ISECG changes. The primary endpoint was cumulative incidence of cardiovascular death, hospitalizations for acute coronary syndrome and coronary revascularizations. RESULTS: a total of 371 patients (mean age 59.1 ± 12.1 years, 49.9% women) were studied. Of those, 141 (38.0%) had concomitant ISECG changes. Mean follow-up was 3.46 ± 1.76 years. The primary endpoint occurred in 3.0% of patients, (2.2% in those with normal stress ECG, and in 4.3% with ISECG changes, p = 0.251); with unadjusted hazard ratio for primary endpoint of 2.04 (95%CI 0.62-6.69, p = 0.239) in patients with ISECG changes compared to those with normal stress ECG. CONCLUSIONS: in an outpatient population without known CAD evaluated for chest pain after inconclusive first-line work-up, a negative peak supine bicycle ESE confers an excellent prognosis regardless of the nature of concomitant stress ECG abnormalities