HER2-targeting agents have dramatically changed the therapeutic landscape of HER2+ advanced breast cancer (ABC). Within a short time frame, the rapid introduction of new therapeutics has led to the ...approval of pertuzumab combined with trastuzumab and a taxane in first-line, and trastuzumab emtansine (T-DM1) in second-line. Thereby, evidence of T-DM1 efficacy following trastuzumab/pertuzumab combination is limited, with data from some retrospective reports suggesting lower activity. The purpose of the present study is to investigate T-DM1 efficacy in pertuzumab-pretreated and pertuzumab naïve HER2 positive ABC patients. We also aimed to provide evidence on the exposure to different drugs sequences including pertuzumab and T-DM1 in HER2 positive cell lines.
The biology of HER2 was investigated in vitro through sequential exposure of resistant HER2 + breast cancer cell lines to trastuzumab, pertuzumab, and their combination. In vitro experiments were paralleled by the analysis of data from 555 HER2 + ABC patients treated with T-DM1 and evaluation of T-DM1 efficacy in the 371 patients who received it in second line. Survival estimates were graphically displayed in Kaplan Meier curves, compared by log rank test and, when possibile, confirmed in multivariate models.
We herein show evidence of lower activity of T-DM1 in two HER2+ breast cancer cell lines resistant to trastuzumab+pertuzumab, as compared to trastuzumab-resistant cells. Lower T-DM1 efficacy was associated with a marked reduction of HER2 expression on the cell membrane and its nuclear translocation. HER2 downregulation at the membrane level was confirmed in biopsies of four trastuzumab/pertuzumab-pretreated patients. Among the 371 patients treated with second-line T-DM1, median overall survival (mOS) from diagnosis of advanced disease and median progression-free survival to second-line treatment (mPFS2) were 52 and 6 months in 177 patients who received trastuzumab/pertuzumab in first-line, and 74 and 10 months in 194 pertuzumab-naïve patients (p = 0.0006 and 0.03 for OS and PFS2, respectively).
Our data support the hypothesis that the addition of pertuzumab to trastuzumab reduces the amount of available plasma membrane HER2 receptor, limiting the binding of T-DM1 in cancer cells. This may help interpret the less favorable outcomes of second-line T-DM1 in trastuzumab/pertuzumab pre-treated patients compared to their pertuzumab-naïve counterpart.
Abstract BACKGROUND Virtual reality (VR) solutions are emerging as a useful adjunct to the armamentarium of the neurosurgeon. Surprisingly, little data is available in the literature regarding its ...utility in pediatric neurosurgical oncology. We hereby report our preliminary Institutional experience on the application of VR to surgical rehearsal in a series of pediatric brain tumors. METHODS Virtual models were obtained by the Surgical Planner (Surgical Theatre, Inc) in a series of 50 consecutive brain tumor cases treated at Bambino Gesù Children’s Hospital. Utility of VR was scored based on operators’ perception. Explored items included: planning, execution, resection, sparing of eloquent tissue, and overall surgical management. Scoring was performed using a customized Likert scale. RESULTS We prospectively collected 100 consecutive questionnaires from surgeons participating to brain tumor resection procedures. In a multivariate analysis VR was found to be significantly more beneficial in specific surgical settings. Leading surgeons (LS) judged VR significantly more useful in supratentorial tumors, in children younger than 10 years, and in planned partial resections. Assistant surgeons (AS) found VR more useful in supratentorial lesions, particularly in deep seated tumors. Both LS and AS perceived VR to be less useful for in embryonal tumors and epilepsy-associated gliomas (LEAT). CONCLUSIONS Our data suggest that VR technology is useful in the surgical management of children with brain tumors. There might be specific clinical scenarios in which the advantage of VR availability might have a significant clinical impact in planning and performing surgical resection.
Critically ill patients with coronavirus disease 19 (COVID-19) have a high fatality rate likely due to a dysregulated immune response. Corticosteroids could attenuate this inappropriate response, ...although there are still some concerns regarding its use, timing, and dose.
This is a nationwide, prospective, multicenter, observational, cohort study in critically ill adult patients with COVID-19 admitted into Intensive Care Units (ICU) in Spain from 12th March to 29th June 2020. Using a multivariable Cox model with inverse probability weighting, we compared relevant outcomes between patients treated with early corticosteroids (before or within the first 48 h of ICU admission) with those who did not receive early corticosteroids (delayed group) or any corticosteroids at all (never group). Primary endpoint was ICU mortality. Secondary endpoints included 7-day mortality, ventilator-free days, and complications.
A total of 691 patients out of 882 (78.3%) received corticosteroid during their hospital stay. Patients treated with early-corticosteroids (n = 485) had lower ICU mortality (30.3% vs. never 36.6% and delayed 44.2%) and lower 7-day mortality (7.2% vs. never 15.2%) compared to non-early treated patients. They also had higher number of ventilator-free days, less length of ICU stay, and less secondary infections than delayed treated patients. There were no differences in medical complications between groups. Of note, early use of moderate-to-high doses was associated with better outcomes than low dose regimens.
Early use of corticosteroids in critically ill patients with COVID-19 is associated with lower mortality than no or delayed use, and fewer complications than delayed use.
US Food and Drug Administration has issued Emergency Use Authorizations for hundreds of serological assays to support Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) diagnosis. The aim ...of this study is to evaluate, for the first time in children, the performance of three widely utilized SARS-CoV-2 serology commercial assays, Diesse Diagnostics (IgG, IgA, IgM) and Roche Diagnostics, both Roche Nucleocapsid (N) IgG and Roche Spike (S) IgG assays.
Sensitivity and 95% confidence intervals (CIs) were estimated for each of the three different serological tests and mixed and direct comparison were performed. Univariate and multivariate Poisson regression models were fitted to calculate incidence rate ratios and 95% CIs as estimate of the effects of age, gender, time on the serology title. A p-value < 0.05 indicated statistical significance.
Overall, 149 children were enrolled in the study. A low sensitivity was found for Diesse IgA, IgM and IgG. Compare to Diesse, Roche S had a higher sensitivity at 15-28 days from infection (0.94, 95%CI: 0.73-1.0) and Roche N at 28-84 days (0.78, 95%CI: 0.58-0.91). When a direct comparison of IgG tests sensitivity was feasible for patients with pairwise information, Roche S and Roche N showed a statistically significant higher sensitivity compared to Diesse in all the study periods, whereas there was no difference between the two Roche tests.
Roche S and Roche N serology tests seem to better perform in children. Large prospective studies are needed to better define the characteristics of those tests.
The stability limit of an analyte in a biological sample can be defined as the time required until a measured property acquires a bias higher than a defined specification. Many studies assessing ...stability and presenting recommendations of stability limits are available, but differences among them are frequent. The aim of this study was to classify and to grade a set of bibliographic studies on the stability of five common blood measurands and subsequently generate a consensus stability function.
First, a bibliographic search was made for stability studies for five analytes in blood: alanine aminotransferase (ALT), glucose, phosphorus, potassium and prostate specific antigen (PSA). The quality of every study was evaluated using an in-house grading tool. Second, the different conditions of stability were uniformly defined and the percent deviation (PD%) over time for each analyte and condition were scattered while unifying studies with similar conditions.
From the 37 articles considered as valid, up to 130 experiments were evaluated and 629 PD% data were included (106 for ALT, 180 for glucose, 113 for phosphorus, 145 for potassium and 85 for PSA). Consensus stability equations were established for glucose, potassium, phosphorus and PSA, but not for ALT.
Time is the main variable affecting stability in medical laboratory samples. Bibliographic studies differ in recommedations of stability limits mainly because of different specifications for maximum allowable error. Definition of a consensus stability function in specific conditions can help laboratories define stability limits using their own quality specifications.
Urinary tract infections (UTIs) are among the most frequent bacterial diseases in infants and children. Physician adherence to recommendations is notoriously often poor, but no data are available on ...UTIs management in the emergency setting. In this multicenter national study, we investigated the policies regarding UTIs management in children aged 2 months to 3 years in Italian emergency units. Between April and June 2021, directors of the emergency units were invited to answer an online survey on the following items: diagnostic approach to children with fever without an apparent source, therapeutic approach to UTIs, the use of kidney and urinary tract ultrasound, and the criteria for hospitalization. A total of 121 (89%) out of 139 of invited units participated in the study. Overall, units manage children with a suspected or confirmed UTI according to available recommendations for most of the items. However, in almost 80% (
n
= 94) of units, a sterile perineal bag is used to collect urine for culture. When urine is collected by cathether, heterogeneity exists on the threshold of bacterial load considered for UTI diagnosis.
Conclusions:
Available recommendations on UTIs in children are followed by Italian emergency units for most of the items. However, the methods to collect urine specimens for culture, one of the crucial steps of the diagnostic work-up, often do not align with current recommendations and CFU thresholds considered for diagnosis largely vary among centers. Efforts should be addressed to validate and implement new child and family friendly urine collection techniques.
What is Known:
• Several guidelines are published on the management of children with suspected or confirmed urinary tract infection.
•
No data are available on the management of pediatric urinary tract infections in the emergency setting.
What is New:
•
Almost 80% of the Italian emergency units employ a sterile perineal bag to collect urine for culture.
•
Diagnostic CFU thresholds largely vary among centers.
Bronchiolitis is a common cause of hospitalization in infants. The long-lasting impact of hygiene and social behavior changes during the pandemic on this disease is debated. We investigated the ...prevalence of hospitalized cases, clinical severity, and underlying risk factors before and during pandemic. The study was conducted in 27 hospitals in Italy and included infants hospitalized for bronchiolitis during the following four periods: July 2018-March 2019, July 2020-March 2021, July 2021-March 2022, and July 2022-March 2023. Data on demographics, neonatal gestational age, breastfeeding history, underlying chronic diseases, presence of older siblings, etiologic agents, clinical course and outcome were collected. A total of 5330 patients were included in the study. Compared to 2018–19 (n = 1618), the number of hospitalizations decreased in 2020–21 (n = 121). A gradual increase was observed in 2021–22 (n = 1577) and 2022–23 (n = 2014). A higher disease severity (need and length of O
2
-supplementation, need for non-invasive ventilation, hospital stay) occurred in the 2021–22 and, especially, the 2022–23 periods compared to 2018–19. This tendency persisted after adjusting for risk factors associated with bronchiolitis severity.
Conclusions
: Compared to adults, COVID-19 in infants is often asymptomatic or mildly symptomatic and rarely results in hospitalization. This study indicates that the pandemic has indirectly induced an increased burden of bronchiolitis among hospitalized infants. This shift, which is not explained by the recognized risk factors, suggests the existence of higher infant vulnerability during the last two seasons.
What is known:
• The pandemic led to a change in epidemiology of respiratory diseases
• Large data on severity of bronchiolitis and underlying risk factors before and during COVID-19 pandemic are scarce
What is new:
• Compared to pre-pandemic period, hospitalizations for bronchiolitis decreased in 2020–21 and gradually increased in 2021–22 and 2022–23
• Compared to pre-pandemic period, higher disease burden occurred in 2021–22 and, especially, in 2022–23. This tendency persisted after adjusting for risk factors associated with bronchiolitis severity
• The interplay among viruses, preventive measures, and the infant health deserves to be further investigated
Studies have shown that triggering receptor expressed on myeloid cells-1 (TREM-1) is the mediator and activator of neutrophils and monocytes after stimulation with lipopolysaccharide (LPS), ...heat-inactivated Gram (−) bacteria, Gram (+) bacteria or fungi. Different studies have measured the expression of TREM-1 in patients with bacterial infections and critical states. The purpose of this study was to evaluate the expression of TREM-1 in circulating maternal leukocytes in premature rupture of the membranes (PRM). Two groups of patients were included in this case control study: pregnant women with PRM and healthy controls. All patients were free of any infection, including cervix and urinary tract. Although all patients expressed TREM-1 to some extent, there was no statistically significant difference in the expression of different cellularities in both groups; except for the mononuclear leukocytes (p < 0.05). In this study, TREM-1 was not altered in PRM.
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