Prognostic value of HER2-low status in breast cancer: a systematic review and meta-analysis.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-low expression in breast cancer has been recently identified as a new therapeutic target. However, it is unclear if HER2-low status has an independent impact on prognosis. MATERIALS AND METHODS: A systematic literature research was carried out to identify studies comparing survival outcomes of patients affected by HER2-low versus HER2-zero breast cancer. Using random-effects models, pooled hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for progression-free survival (PFS) and overall survival (OS) in the metastatic setting as well as disease-free survival (DFS), OS and pathological complete response (pCR) in the early setting. Subgroup analyses by hormone receptor (HoR) status were carried out. The study protocol is registered on PROSPERO (n.CRD42023390777). RESULTS: Among 1916 identified records, 42 studies including 1 797 175 patients were eligible. In the early setting, HER2-low status was associated with significant improved DFS (HR 0.86, 95% CI 0.79-0.92, P < 0.001) and OS (HR 0.90, 95% CI 0.85-0.95, P < 0.001) when compared to HER2-zero status. Improved OS was observed for both HoR-positive and HoR-negative HER2-low populations, while DFS improvement was observed only in the HoR-positive subgroup. HER2-low status was significantly associated with a lower rate of pCR as compared to HER2-zero status both in the overall population (OR 0.74, 95% CI 0.62-0.88, P = 0.001) and in the HoR-positive subgroup (OR 0.77, 95% CI 0.65-0.90, P = 0.001). In the metastatic setting, patients with HER2-low breast cancers showed better OS when compared with those with HER2-zero tumours in the overall population (HR 0.94, 95% CI 0.89-0.98, P = 0.008), regardless of HoR status. No significant PFS differences were found. CONCLUSIONS: Compared with HER2-zero status, HER2-low status appears to be associated with a slightly increased OS both in the advanced and early settings, regardless of HoR expression. In the early setting, HER2-low tumours seem to be associated to lower pCR rates, especially if HoR-positive.

Prognostic value of intrinsic subtypes in hormone-receptor-positive metastatic breast cancer: systematic review and meta-analysis.

BACKGROUND: In hormone receptor-positive (HoR+) breast cancer (BC), gene expression analysis identifies luminal A (LumA), luminal B (LumB), human epidermal growth factor receptor 2 (HER2)-enriched (HER2-E), basal-like (BL) intrinsic subtypes and a normal-like group. This classification has an established prognostic value in early-stage HoR+ BC. Here, we carried out a trial-level meta-analysis to determine the prognostic ability of subtypes in metastatic BC (MBC). MATERIALS AND METHODS: We systematically reviewed all the available prospective phase II/III trials in HoR+ MBC where subtype was assessed. The primary endpoint was progression-free survival (PFS)/time to progression (TTP) of the LumA subtype compared to non-LumA. Secondary endpoints were PFS/TTP of each individual subtype, according to treatment, menopausal and HER2 status and overall survival (OS). The random-effect model was applied, and heterogeneity assessed through Cochran's Q and I2. Threshold for significance was set at P < 0.05. The study was registered in PROSPERO (ID: CRD42021255769). RESULTS: Seven studies were included (2536 patients). Non-LumA represented 55.2% and was associated with worse PFS/TTP than LumA [hazard ratio (HR) 1.77, P < 0.001, I2 = 61%], independently of clinical HER2 status [Psubgroup difference (Psub) = 0.16], systemic treatment (Psub = 0.96) and menopausal status (Psub = 0.12). Non-LumA tumors also showed worse OS (HR 2.00, P < 0.001, I2 = 65%), with significantly different outcomes for LumB (PFS/TTP HR 1.46; OS HR 1.41), HER2-E (PFS/TTP HR 2.39; OS HR 2.08) and BL (PFS/TTP HR 2.67; OS HR 3.26), separately (PFS/TTP Psub = 0.01; OS Psub = 0.005). Sensitivity analyses supported the main result. No publication bias was observed. CONCLUSIONS: In HoR+ MBC, non-LumA disease is associated with poorer PFS/TTP and OS than LumA, independently of HER2, treatment and menopausal status. Future trials in HoR+ MBC should consider this clinically relevant biological classification.

Identification of cell surface targets for CAR-T cell therapies and antibody-drug conjugates in breast cancer.

BACKGROUND: Two promising therapeutic strategies in oncology are chimeric antigen receptor-T cell (CAR-T) therapies and antibody-drug conjugates (ADCs). To be effective and safe, these immunotherapies require surface antigens to be sufficiently expressed in tumors and less or not expressed in normal tissues. To identify new targets for ADCs and CAR-T specifically targeting breast cancer (BC) molecular and pathology-based subtypes, we propose a novel in silico strategy based on multiple publicly available datasets and provide a comprehensive explanation of the workflow for a further implementation. METHODS: We carried out differential gene expression analyses on The Cancer Genome Atlas BC RNA-sequencing data to identify BC subtype-specific upregulated genes. To fully explain the proposed target-discovering methodology, as proof of concept, we selected the 200 most upregulated genes for each subtype and undertook a comprehensive analysis of their protein expression in BC and normal tissues through several publicly available databases to identify the potentially safest and viable targets. RESULTS: We identified 36 potentially suitable and subtype-specific tumor surface antigens (TSAs), including fibroblast growth factor receptor-4 (FGFR4), carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6), GDNF family receptor alpha 1 (GFRA1), integrin beta-6 (ITGB6) and ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1). We also identified 63 potential TSA pairs that might be appropriate for co-targeting strategies. Finally, we validated subtype specificity in a cohort of our patients, multiple BC cell lines and the METABRIC database. CONCLUSIONS: Overall, our in silico analysis provides a framework to identify novel and specific TSAs for the development of new CAR-T and antibody-based therapies in BC.

T-DM1 versus pertuzumab, trastuzumab and a taxane as first-line therapy of early-relapsed HER2-positive metastatic breast cancer: an Italian multicenter observational study.

BACKGROUND: The current standard first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive (+) metastatic breast cancer is the combination of pertuzumab, trastuzumab and a taxane (P + T + taxane), while standard second-line is ado-trastuzumab-emtansine (T-DM1). The registration trial of pertuzumab, however, did not include early-relapsing patients, defined as patients experiencing tumor relapse ≤12 months from the end of (neo)adjuvant anti-HER2 therapy. Conversely, the pivotal trial of T-DM1 included some patients relapsing ≤6 months after the end of (neo)adjuvant trastuzumab. Thus, a proportion of early-relapsing patients are currently eligible to receive T-DM1 as first-line treatment. Nevertheless, no direct comparison exists between the two regimens in this clinical setting. PATIENTS AND METHODS: We retrospectively compared T-DM1 versus P + T + taxane as first-line treatment in two cohorts of early-relapsing patients in an Italian 'real-world' setting, involving 14 public health care institutions. The primary endpoint was progression-free survival. Secondary endpoints included patients' characterization, overall survival and post-progression survival. Univariate and multivariate analyses were carried out. All tests were two-sided and a P ≤ 0.05 was considered statistically significant. RESULTS: Among 1252 screened patients, 75 met the inclusion criteria. Forty-four (58.7%) received P + T + taxane and 31 (41.3%) received T-DM1. The two cohorts showed similar characteristics of aggressiveness and no significant differences in treatment history. T-DM1, compared with P + T + taxane was associated with worse progression-free survival (adjusted hazard ratio: 2.26, 95% confidence interval: 1.13-4.52, P = 0.021) and overall survival (adjusted hazard ratio: 3.95, 95% confidence interval: 1.38-11.32, P = 0.010), irrespective of previous (neo)adjuvant treatment, age, hormone receptors status, time-to-relapse (≤6 months or within 6-12 months) and presence of visceral/brain metastases. No differences were observed in post-progression survival (P = 0.095). CONCLUSIONS: Our study suggests superiority for P + T + taxane over T-DM1 as up-front treatment of early-relapsing HER2+ metastatic breast cancer, which merits further assessment in larger and prospective trials.

Interfacing brain with computer to improve communication and rehabilitation after brain damage.

Communication and control of the external environment can be provided via brain-computer interfaces (BCIs) to replace a lost function in persons with severe diseases and little or no chance of recovery of motor abilities (ie, amyotrophic lateral sclerosis, brainstem stroke). BCIs allow to intentionally modulate brain activity, to train specific brain functions, and to control prosthetic devices, and thus, this technology can also improve the outcome of rehabilitation programs in persons who have suffered from a central nervous system injury (ie, stroke leading to motor or cognitive impairment). Overall, the BCI researcher is challenged to interact with people with severe disabilities and professionals in the field of neurorehabilitation. This implies a deep understanding of the disabled condition on the one hand, and it requires extensive knowledge on the physiology and function of the human brain on the other. For these reasons, a multidisciplinary approach and the continuous involvement of BCI users in the design, development, and testing of new systems are desirable. In this chapter, we will focus on noninvasive EEG-based systems and their clinical applications, highlighting crucial issues to foster BCI translation outside laboratories to eventually become a technology usable in real-life realm.

Influence of P300 latency jitter on event related potential-based brain-computer interface performance.

OBJECTIVE: Several ERP-based brain-computer interfaces (BCIs) that can be controlled even without eye movements (covert attention) have been recently proposed. However, when compared to similar systems based on overt attention, they displayed significantly lower accuracy. In the current interpretation, this is ascribed to the absence of the contribution of short-latency visual evoked potentials (VEPs) in the tasks performed in the covert attention modality. This study aims to investigate if this decrement (i) is fully explained by the lack of VEP contribution to the classification accuracy; (ii) correlates with lower temporal stability of the single-trial P300 potentials elicited in the covert attention modality. APPROACH: We evaluated the latency jitter of P300 evoked potentials in three BCI interfaces exploiting either overt or covert attention modalities in 20 healthy subjects. The effect of attention modality on the P300 jitter, and the relative contribution of VEPs and P300 jitter to the classification accuracy have been analyzed. MAIN RESULTS: The P300 jitter is higher when the BCI is controlled in covert attention. Classification accuracy negatively correlates with jitter. Even disregarding short-latency VEPs, overt-attention BCI yields better accuracy than covert. When the latency jitter is compensated offline, the difference between accuracies is not significant. SIGNIFICANCE: The lower temporal stability of the P300 evoked potential generated during the tasks performed in covert attention modality should be regarded as the main contributing explanation of lower accuracy of covert-attention ERP-based BCIs.

Self-calibration algorithm in an asynchronous P300-based brain-computer interface.

OBJECTIVE: Reliability is a desirable characteristic of brain-computer interface (BCI) systems when they are intended to be used under non-experimental operating conditions. In addition, their overall usability is influenced by the complex and frequent procedures that are required for configuration and calibration. Earlier studies examined the issue of asynchronous control in P300-based BCIs, introducing dynamic stopping and automatic control suspension features. This report proposes and evaluates an algorithm for the automatic recalibration of the classifier's parameters using unsupervised data. APPROACH: Ten healthy subjects participated in five P300-based BCI sessions throughout a single day. First, we examined whether continuous adaptation of control parameters improved the accuracy of the asynchronous system over time. Then, we assessed the performance of the self-calibration algorithm with respect to the no-recalibration and supervised calibration conditions with regard to system accuracy and communication efficiency. MAIN RESULTS: Offline tests demonstrated that continuous adaptation of the control parameters significantly increased the communication efficiency of asynchronous P300-based BCIs. The self-calibration algorithm correctly assigned labels to unsupervised data with 95% accuracy, effecting communication efficiency that was comparable with that of supervised repeated calibration. SIGNIFICANCE: Although additional online tests that involve end-users under non-experimental conditions are needed, these preliminary results are encouraging, from which we conclude that the self-calibration algorithm is a promising solution to improve P300-based BCI usability and reliability.

A comparison of classification techniques for a gaze-independent P300-based brain-computer interface.

This off-line study aims to assess the performance of five classifiers commonly used in the brain-computer interface (BCI) community, when applied to a gaze-independent P300-based BCI. In particular, we compared the results of four linear classifiers and one nonlinear: Fisher's linear discriminant analysis (LDA), stepwise linear discriminant analysis (SWLDA), Bayesian linear discriminant analysis (BLDA), linear support vector machine (LSVM) and Gaussian supported vector machine (GSVM). Moreover, different values for the decimation of the training dataset were tested. The results were evaluated both in terms of accuracy and written symbol rate with the data of 19 healthy subjects. No significant differences among the considered classifiers were found. The optimal decimation factor spanned a range from 3 to 24 (12 to 94 ms long bins). Nevertheless, performance on individually optimized classification parameters is not significantly different from a classification with general parameters (i.e. using an LDA classifier, about 48 ms long bins).

P300-based brain-computer interface for environmental control: an asynchronous approach.

Brain-computer interface (BCI) systems allow people with severe motor disabilities to communicate and interact with the external world. The P300 potential is one of the most used control signals for EEG-based BCIs. Classic P300-based BCIs work in a synchronous mode; the synchronous control assumes that the user is constantly attending to the stimulation, and the number of stimulation sequences is fixed a priori. This issue is an obstacle for the use of these systems in everyday life; users will be engaged in a continuous control state, their distractions will cause misclassification and the speed of selection will not take into account users' current psychophysical condition. An efficient BCI system should be able to understand the user's intentions from the ongoing EEG instead. Also, it has to refrain from making a selection when the user is engaged in a different activity and it should increase or decrease its speed of selection depending on the current user's state. We addressed these issues by introducing an asynchronous BCI and tested its capabilities for effective environmental monitoring, involving 11 volunteers in three recording sessions. Results show that this BCI system can increase the bit rate during control periods while the system is proved to be very efficient in avoiding false negatives when the users are engaged in other tasks.

Early and late failure of noninvasive ventilation in chronic obstructive pulmonary disease with acute exacerbation.

BACKGROUND: Despite recent encouraging results, the use of noninvasive ventilation (NIV) in the management of acute exacerbations in chronic obstructive pulmonary disease (COPD), complicated by acute respiratory failure (ARF), is not always successful. Failure of NIV may require an immediate intubation after a few hours (usually 1-3) of ventilation ('early failure') or may result in clinical deterioration (one or more days later) after an initial improvement of blood gas tension and general conditions ('late failure'). MATERIALS AND METHODS: We enrolled 122 patients affected by COPD complicated by ARF, and treated with NIV. The schedule of NIV provided sessions of 2-6 h twice daily. RESULTS: Ninety-nine (81%) patients showed a progressive improvement of the clinical parameters and were discharged. Among the remaining 23 patients, 13 had an early failure and 10 had a late failure. In the 'success' group and 'late failure' groups we found after an increase of pH 2 h of NIV (from 7.31 +/- 0.05 to 7.38 +/- 0.04 P < 0.001 and from 7.29 +/- 0.03 to 7.36 +/- 0.02 P < 0.001, respectively) and a decrease of PaCO2 (from 80.93 +/- 9.79 to 66.48 +/- 5.95 P < 0.001 and from 85.96 +/- 10.77 to 76.41 +/- 11.02 P < 0.001, respectively). After 2 h of NIV in the 'late failure' group there were no significant changes in terms of pH (from 7.20 +/- 0.10 to 7.28 +/- 0.06) nor PaCO2 (from 92.86 +/- 35.49 to 93.68 +/- 23.68). The 'early failure' group had different characteristics and, owing to more severe conditions, the value of pH, of Glasgow Coma Score, and Apache II Score were the best predictors of the failure; while, among the complications on admission, metabolic alterations were the only independently significant predictor. CONCLUSIONS: Our study confirms that NIV may be useful to avoid intubation in approximately 80% of patients with COPD complicated by moderate-severe hypercapnic respiratory failure.

Plasma protein Z levels in healthy and high-risk newborn infants.

AIM: To evaluate plasma protein Z (PZ) levels in healthy and high-risk newborn infants. METHODS: A longitudinal observational study was conducted. Inclusion criteria were: healthy term and preterm newborns normal for gestational age and newborns belonging to one of the following groups: newborns small for gestational age (SGA), newborns affected by respiratory distress syndrome (RDS), newborns from mothers with pre-eclampsia. Newborns with sepsis, congenital malformation or haemorrhagic disorders were excluded. Plasma PZ levels, protein C (PC) concentration, PC activity and protein-induced vitamin K absence levels were measured. RESULTS: 53 newborns were enrolled into the study. PZ and PC antigen levels varied significantly among analysed subgroups on day 1 (p < 0.01): lower levels of these inhibitors were found in RDS newborns (group C), newborns from mothers affected by pre-eclampsia (group D) and SGA newborns (group E) than in healthy term and preterm newborns (groups A and B). CONCLUSION: PZ deficiency occurs in newborns affected by severe RDS, in newborns from pre-eclamptic mothers and in SGA newborns, probably owing to activated coagulation in the first two conditions and to reduced PZ synthesis in the last condition.

[Nasopharyngeal colonization of Streptococcus pneumoniae in healthy children: percentage of carriers, serotypes distribution and antibiotic resistance]. / Colonizzazione nasofaringea di Streptococcus pneumoniae in bambini sani: percentuale di portatori, distribuzione dei sierotipi e antibiotico-resistenza.

AIM: The nasopharyngeal carriage of Streptococcus pneumoniae is an important risk factor for pneumococcal diseases. Data regarding prevalence and serotype distribution of this pathogen are lacking in our population. EXPERIMENTAL DESIGN: longitudinal observational cohort study. SETTING: healthy children aged 1-7 years attending day-care centers and schools of a district of a Southern Italy city. MEASURES: the nasopharyngeal colonization rate of Streptococcus pneumoniae as well as its antibiotic susceptibility was determined. RESULTS: Of 317 nasopharyngeal cultures obtained, 18.29% of the cultures were positive for Streptococcus pneumoniae; 60.34% of the isolates were serotypes 19A, 19F, 14, 6B, or 23F; 8.62% of the strains were intermediately resistant to penicillin. Erythromycin-resistance was observed in 65.51% of the micro-organisms isolated and particularly serotypes 19, 14, and 6 were more erythromycin-resistant than organisms of other serotypes. Co-trimoxazole resistance was detected in 17.24% of the strains. All the strains resulted uniformly susceptible to cefotaxime and ceftriaxone. CONCLUSION: The high rate of nasopharyngeal carriage of Streptococcus pneumoniae, along with the resistance to antibiotics widely used in the community, suggests the importance of an epidemiological surveillance as well as the application of new vaccine strategies.

Streptococcus pneumoniae nasopharyngeal colonization in young healthy children: rate of carriage, serotype distribution, and antibiotic resistance.

The nasopharyngeal colonization rate of Streptococcus pneumoniae and its antibiotic susceptibility was determined in a given population of 317 young children (ages 1-7 years) in the area of Bari, Italy. 18.29% of the cultures were positive for S. pneumoniae. 8.62% of the strains were intermediately resistant to penicillin. Erythromycin-(65.51%) and cotrimoxazole-(17.24%) resistance was also observed whereas all the strains resulted uniformely susceptible to cefotaxime and ceftriaxone. The high rate of nasopharyngeal carriage of Streptococcus pneumoniae along with the resistance to antibiotics widely used in the community suggests the importance of epidemiological surveillance as well as the application of new vaccine strategies.

Thrombin generation in children with acute lymphoblastic leukemia: effect of leukemia immunophenotypic subgroups.

Elevated plasma concentrations of endogenous thrombin generation markers and thrombotic events have been reported in children with leukemia. The aim of this study was to evaluate the effects of cancer and its treatment on thrombin generation (TAT levels) in children with acute lymphoblastic leukemia (ALL). The authors evaluated 32 children (23 M, 9 F) aged between 1 and 15 years (mean 6) affected by ALL (immunophenotypic subgroups: 16 common, 7 T, and 9 pre-B type). In all patients TAT levels at onset and after 5-6 doses of L-asparaginase were evaluated. TAT levels were higher in patients both at onset (13.04 +/- 10.90 ng/L) and after the 5-6 doses of L-asp (19.41 +/- 11.05 ng/L) with respect to controls (4 +/- 1 ng/L) (p < .001 and p < .001). TAT levels after 5-6 doses of L-asp were higher than those at onset (p < .001). Factorial ANOVA showed that at onset there was a significant effect of leukemia immunophenotypic subgroups upon TAT levels (p < .05) and no effect of inherited thrombotic risk factors. These results indicate that in children with ALL an important role is played by acquired thrombotic risk factors, among which the indirect cancer procoagulant activity has its importance.

Factors influencing effectiveness of deferiprone in a thalassaemia major clinical setting.

The effectiveness of deferiprone (L1) and the influence of other factors were determined in a clinical setting. Patients of Southern Italian origin, affected by beta-thalassaemia major (n = 13: 7 M, 6 F), aged 10-28 years (median 18 years), were treated with L1 within a 'Controlled Programme' of the Italian Ministry of Health. Desferrioxamine could not be administered in these patients because of anaphylactic reactions or other serious side effects. L1 was considered to be effective when the liver iron concentration was reduced or stable as measured by biomagnetic liver susceptometry. L1 proved to be effective in 3 out the 9 evaluable patients. A high pre-L1 iron overload was the main clinical factor influencing L1 effectiveness.

Gilbert's syndrome accounts for the phenotypic variability of congenital dyserythropoietic anemia type II (CDA-II).

The molecular basis for the considerable variation of serum bilirubin levels and the incidence of gallstone formation in patients with congenital dyserythropoietic anemia (CDA) type II are unknown. We show that the combined effect of an increased bilirubin load caused by dyserythropoiesis in CDA II and decreased bilirubin conjugation caused by reduced expression of uridine diphosphate glucuronosyl transferase (UGT1A) would increase the risk of hyperbilirubinemia (P <.005) and gallstone formation (chi(2): P <. 001). The rate of gallstone formation in patients with CDA II is 4. 75-fold the rate of patients without Gilbert's syndrome, and gallstone diagnosis occurs at a younger age (P < 0.01). These findings should be considered during the follow-up of patients with CDA II.

Malignancy: X-Linked Cytochrome B Positive Chronic Granulomatous Disease treated by Bone Marrow Transplantation.

Chronic granulomatous disease is caused by a genetic defect in the oxidase of phagocytic cells which results in increased susceptibility to recurrent infections. Conventional treatment includes the use of antimicrobials and interpheron-gamma. This study was performed to assess the clinical efficacy of allogeneic bone marrow transplantation in definitively correcting the functional underlying defect of chronic granulomatous disease. An 8-year-old boy with a rare type X-linked cytochrome b positive chronic granulomatous disease underwent allogeneic bone marrow transplantation after conditioning with busulfan and cyclophosphamide. The patient's HLA identical sister was marrow donor. The post-transplant outcome was uneventful. During the 9 year follow-up period the patient has been constantly free of infections, maintained an excellent clinical performance with full correction of the granulocyte functional defect. This case confirms that allogeneic bone marrow transplantation is the only treatment capable to cure chronic granulomatous disease to those patients who cannot be optimally treated with conventional therapy.

Resistance to activated protein C in thalassaemic patients: an underlying cause of thrombosis.

We evaluated 81 thalassaemia major and 4 thalassaemia intermedia patients (48 M, 37 F), median age 17 years; 62/85 patients were HCV-positive, 3/85 HIV-positive, 19/85 were splenectomized. Forty normal healthy children were recruited as the control group. The number of thrombotic events was studied retrospectively. Platelet poor plasma was filtered and quick-frozen at -70 degrees C until time of assay. APC resistance was measured in an activated thromboplastin time and results were expressed as normalized ratio. All tests were done with diluted 1 in 5 (v/v) factor V deficient plasma and with undiluted plasma. Molecular genetic investigation of factor V gene was performed with polymerase chain reaction, followed by digestion of amplified products with restriction enzyme Mnl I. Data obtained with molecular investigation revealed the presence of 4 heterozygous subjects for factor V Leiden (4.7%). Functional tests were able to detect all heterozygotes for factor V Leiden both with undiluted and with diluted plasma, and there were no false negative subjects. However, undiluted plasma revealed a greater number of false positive subjects (n=15) than did diluted plasma. Therefore, tests done with undiluted and diluted plasma revealed a 100% sensitivity, while specificity was 81% for undiluted plasma and 97% for diluted plasma. Only one thrombotic event was observed in one of the 85 studied patients, as a case of stroke in a thalassaemia intermedia patient with APC resistance. In the same patient an additional thrombogenic risk factor was represented by a pronounced haematocrit increase at the beginning of her transfusion regimen.