Advancement study of CancerMath model as prognostic tools for predicting Sentinel lymph node metastasis in clinically negative T1 breast cancer patients

Purpose: Sentinel lymph node biopsy (SLNB) is an invasive surgical procedure and although it has fewer complications and is less severe than axillary lymph node dissection, it is not a risk-free procedure. Large prospective trials have documented SLNB that it is considered non-therapeutic in early stage breast cancer. Methods: Web-calculator CancerMath (CM) allows you to estimate the probability of having positive lymph nodes valued on the basis of tumour size, age, histologic type, grading, expression of estrogen receptor, progesterone receptor. We collected 595 patients referred to our Institute resulting clinically negative T1 breast cancer characterized by sentinel lymph node status, prognostic factors defined by CM and also HER2 and Ki-67. We have compared classification performances obtained by online CM application with those obtained after training its algorithm on our database. Results: By training CM model on our dataset and using the same feature, adding HER2 or ki67 we reached a sensitivity median value of 71.4%, 73%, 70.4%, respectively, whereas the online one was equal to 61%, without losing specificity. The introduction of the prognostic factors Her2 and Ki67 could help improving performances on the classification of particularly type of patients. Conclusions: Although the training of the model on the sample of T1 patients has brought a significant improvement in performance, the general performance does not yet allow a clinical application of the algorithm. However, the experimental results encourage future developments aimed at introducing features of a different nature in the CM model

Accurate Evaluation of Feature Contributions for Sentinel Lymph Node Status Classification in Breast Cancer

The current guidelines recommend the sentinel lymph node biopsy to evaluate the lymph node involvement for breast cancer patients with clinically negative lymph nodes on clinical or radiological examination. Machine learning (ML) models have significantly improved the prediction of lymph nodes status based on clinical features, thus avoiding expensive, time-consuming and invasive procedures. However, the classification of sentinel lymph node status represents a typical example of an unbalanced classification problem. In this work, we developed a ML framework to explore the effects of unbalanced populations on the performance and stability of feature ranking for sentinel lymph node status classification in breast cancer. Our results indicate state-of-the-art AUC (Area under the Receiver Operating Characteristic curve) values on a hold-out set (67%) while providing particularly stable features related to tumor size, histological subtype and estrogen receptor expression, which should therefore be considered as potential biomarkers

Sentinel Lymph Node Metastasis on Clinically Negative Patients: Preliminary Results of a Machine Learning Model Based on Histopathological Features

The reported incidence of node metastasis at sentinel lymph node biopsy is generally low, so that the majority of women underwent unnecessary invasive axilla surgery. Although the sentinel lymph node biopsy is time consuming and expensive, it is still the intra-operative exam with the highest performance, but sometimes surgery is achieved without a clear diagnosis and also with possible serious complications. In this work, we developed a machine learning model to predict the sentinel lymph nodes positivity in clinically negative patients. Breast cancer clinical and immunohistochemical features of 907 patients characterized by a clinically negative lymph node status were collected. We trained different machine learning algorithms on the retrospective collected data and selected an optimal subset of features through a sequential forward procedure. We found comparable performances for different classification algorithms: on a hold-out training set, the logistics regression classifier with seven features, i.e., tumor diameter, age, histologic type, grading, multiplicity, in situ component and Her2-neu status reached an AUC value of 71.5% and showed a better trade-off between sensitivity and specificity (69.4 and 66.9%, respectively) compared to other two classifiers. On the hold-out test set, the performance dropped by five percentage points in terms of accuracy. Overall, the histological characteristics alone did not allow us to develop a support tool suitable for actual clinical application, but it showed the maximum informative power contained in the same for the resolution of the clinical problem. The proposed study represents a starting point for future development of predictive models to obtain the probability for lymph node metastases by using histopathological features combined with other features of a different nature

Protein synthesis inhibition and loss of homeostatic functions in astrocytes from an Alzheimer's disease mouse model: a role for ER-mitochondria interaction

Deregulation of protein synthesis and ER stress/unfolded protein response (ER stress/UPR) have been reported in astrocytes. However, the relationships between protein synthesis deregulation and ER stress/UPR, as well as their role in the altered homeostatic support of Alzheimer's disease (AD) astrocytes remain poorly understood. Previously, we reported that in astrocytic cell lines from 3xTg-AD mice (3Tg-iAstro) protein synthesis was impaired and ER-mitochondria distance was reduced. Here we show that impaired protein synthesis in 3Tg-iAstro is associated with an increase of p-eIF2α and downregulation of GADD34. Although mRNA levels of ER stress/UPR markers were increased two-three-fold, we found neither activation of PERK nor downstream induction of ATF4 protein. Strikingly, the overexpression of a synthetic ER-mitochondrial linker (EML) resulted in a reduced protein synthesis and augmented p-eIF2α without any effect on ER stress/UPR marker genes. In vivo, in hippocampi of 3xTg-AD mice, reduced protein synthesis, increased p-eIF2α and downregulated GADD34 protein were found, while no increase of p-PERK or ATF4 proteins was observed, suggesting that in AD astrocytes, both in vitro and in vivo, phosphorylation of eIF2α and impairment of protein synthesis are PERK-independent. Next, we investigated the ability of 3xTg-AD astrocytes to support metabolism and function of other cells of the central nervous system. Astrocyte-conditioned medium (ACM) from 3Tg-iAstro cells significantly reduced protein synthesis rate in primary hippocampal neurons. When added as a part of pericyte/endothelial cell (EC)/astrocyte 3D co-culture, 3Tg-iAstro, but not WT-iAstro, severely impaired formation and ramification of tubules, the effect, replicated by EML overexpression in WT-iAstro cells. Finally, a chemical chaperone 4-phenylbutyric acid (4-PBA) rescued protein synthesis, p-eIF2α levels in 3Tg-iAstro cells and tubulogenesis in pericyte/EC/3Tg-iAstro co-culture. Collectively, our results suggest that a PERK-independent, p-eIF2α-associated impairment of protein synthesis compromises astrocytic homeostatic functions, and this may be caused by the altered ER-mitochondria interaction

A Cost Decision Model Supporting Treatment Strategy Selection in BRCA1/2 Mutation Carriers in Breast Cancer

In this paper, a cost decision-making model that compares the healthcare costs for diverse treatment strategies is built for BRCA-mutated women with breast cancer. Moreover, this model calculates the cancer treatment costs that could potentially be prevented, if the treatment strategy with the lowest total cost, along the entire lifetime of the patient, is chosen for high-risk women with breast cancer. The benchmark of the healthcare costs for diverse treatment strategies is selected in the presence of uncertainty, i.e., considering, throughout the lifetime of the patient, the risks and complications that may arise in each strategy and, therefore, the costs associated with the management of such events. Our results reveal a clear economic advantage of adopting the cost decision-making model for benchmarking the healthcare costs for various treatment strategies for BRCA-mutated women with breast cancer. The cost savings were higher when all breast cancer patients underwent counseling and genetic testing before deciding on any diagnostic-therapeutic path, with a probability of obtaining savings of over 75%

Breast MRI background parenchymal enhancement as an imaging bridge to molecular cancer sub-type

Purpose: To evaluate the distribution of MRI breast parenchymal enhancement (BPE) among different breast cancer subtypes searching for any significant difference in terms of immunohistochemical and receptorial patterns (Estrogen Receptor -ER, Progesterone Receptor - PR, Human Epidermal Growth Factor Receptor 2 - HER2). Methods: 82 consecutive patients affected by breast cancer underwent breast DCE-MRI. Two radiologists retrospectively evaluated all subtracted MR enhanced images for classifying BPE. ER, PR and HER2 expression was assessed by immunohistochemical analysis. ER and PR status was evaluated using Allred score (positive values: score ≥3). The intensity of the cerbB-2 staining was scored as 0, 1+, 2+, or 3+ (positive values: ≥ 3+; negative:0 and 1+; 2+ value assessed with silver in-situ hybridization). Patients were classified into five categories based on cancer subtypes: Luminal A, Luminal B HER2 negative, Luminal B HER2 positive, HER2 positive non luminal, triple negative. The χ2 test was used for evaluating the significance of BPE type distribution into the five groups of tumor subtypes and the distribution of the five breast cancer subtypes among every single BPE type. The correlation of BPE with factors such as age, menopausal status and lesion diameter was investigated using multivariate regression analysis and logistic regression. Cohen's kappa statistics was used in order to assess inter-observer agreement for classifying BPE. Results: 6/82 cases were Luminal A-like (7.3%), 42/82 Luminal B-like (HER2-) (51.2%), 12/82 Luminal B-like (HER2+) (14.6%), 4/82 Non Luminal (HER+) (4.9%), 18/82 Triple Negative (ductal) (22%). 16/82 cases showed minimal BPE, 28/82 mild BPE, 22/82 moderate BPE, 16/82 marked BPE. Mild BPE pattern was significantly more prevalent (p = 0.0001) than other BPE types only in the luminal B (HER-) tumors. Moderate and marked BPE prevailed over minimal and mild, in triple negatives. Among all patients with mild BPE, luminal B (HER2-) tumors were significantly higher (p = 0.0001). Among all patients with marked BPE, triple negative subtypes were significantly higher (p = 0.0074). No significant confounder to BPE qualitative evaluation was found (p = 0.39). The inter-rater agreement in evaluating BPE patterns on MRI was almost perfect with Cohen's k = 0.83. Conclusions: BPE could play a crucial role as an imaging bridge to molecular breast cancer subtype allowing an additional risk stratification in the field of breast MRI and targeted screening tests. Luminal B (HER2-) tumors could prevail in case of mild BPE on CE-MRI examinations and TN tumors in patients with marked BPE. Further studies on larger series are needed to confirm this hypothesis

Identification and Molecular Characterization of Novel Mycoviruses in Saccharomyces and Non-Saccharomyces Yeasts of Oenological Interest

Wine yeasts can be natural hosts for dsRNA, ssRNA viruses and retrotransposon elements. In this study, high-throughput RNA sequencing combined with bioinformatic analyses unveiled the virome associated to 16 Saccharomyces cerevisiae and 8 non-Saccharomyces strains of oenological interest. Results showed the presence of six viruses and two satellite dsRNAs from four different families, two of which—Partitiviridae and Mitoviridae—were not reported before in yeasts, as well as two ORFan contigs of viral origin. According to phylogenetic analysis, four new putative mycoviruses distributed in Totivirus, Cryspovirus, and Mitovirus genera were identified. The majority of commercial S. cerevisiae strains were confirmed to be the host for helper L-A type totiviruses and satellite M dsRNAs associated with the killer phenotype, both in single and mixed infections with L-BC totiviruses, and two viral sequences belonging to a new cryspovirus putative species discovered here for the first time. Moreover, single infection by a narnavirus 20S-related sequence was also found in one S. cerevisiae strain. Considering the non-Saccharomyces yeasts, Starmerella bacillaris hosted four RNAs of viral origin—two clustering in Totivirus and Mitovirus genera, and two ORFans with putative satellite behavior. This study confirmed the infection of wine yeasts by viruses associated with useful technological characteristics and demonstrated the presence of complex mixed infections with unpredictable biological effects

Lithium alanates as negative electrodes in lithium-ion batteries

Hydride conversion reactions have been recently proposed and verified experimentally on simple binary and ternary H-containing materials. Herein, we show for the first time the incorporation of lithium alanates, that is, LiAlH4 and Li3AlH6, as active materials in negative electrodes in rechargeable lithium cells. Samples were prepared by mechanochemical treatment. Characterization of the samples was performed by X-ray diffraction, transmission electron microscopy, and Fourier-transform infrared spectroscopy. Analysis of the electrochemical features of the conversion process was performed by potentiodynamic cycling with galvanostatic acceleration in close comparison with computational data obtained by density functional theory with the use of pseudopotentials and planewaves. The occurrence of the conversion reactions was proved by ex situ synchrotron radiation diffraction experiments. As a final point, the stability of the electrolyte/electrode interface over time was evaluated by impendence spectroscopy and attenuated total reflectance Fourier-transform infrared spectroscopy

Six-year prospective evaluation of second-look US with volume navigation for MRI-detected additional breast lesions

ObjectiveThe aim of this study is to present a 6-year prospective evaluation of second-look ultrasound (US) using volume navigation (V Nav) for MRI-detected additional breast lesions.MethodsAfter IRB approvals in both institutions, 1930 consecutive prone MRI breast examinations in 1437 patients were prospectively evaluated. All patients with an MRI-detected additional lesion underwent second-look US, and if occult, contrast-enhanced MRI in supine position was performed for US and MRI co-registration. For patients with breast hypertrophy, MRI-guided biopsy was performed directly. Pathologic examination was the standard of reference. One-way ANOVA and chi-square tests were used.ResultsIn 490 MRI examinations (25.4%, 490/1930), at least one additional breast lesion was detected for a total of 722 only MRI-detected lesions. Second-look US identified 549 additional lesions (238mm); 362 (65.9%, 362/549) proved benign at pathology and 187 (34.1%, 187/549) malignant. Second-look US with V Nav identified 151 additional lesions (179mm, p=n.s.); 67 (44.4%, 67/151) proved benign at pathology and 84 (55.6%, 84/151) malignant. MRI-guided biopsy was performed on 22 additional breast lesions (228mm, p=n.s.); pathology revealed 20 (90.9%, 20/22) benign lesions and 2 (9.1%, 2/22) malignant ones. Mass lesions were significantly higher in the second-look US group (p<0.001). No significant difference in lesion dimension was found between the three groups (p=0.729).ConclusionsSecond-look US with V Nav can be effective in detecting a large number of additional breast lesions occult at second-look US and to biopsy a significant number of malignant lesions safely and irrespective of distance from skin or lesion position.Key Points center dot Second-look US with volume navigation is effective in detecting occult additional lesions. center dot Permits safe biopsies irrespective of position and depth center dot Reduces the need for MRI-guided biops

La biopsia ecoguidata Elite con sistema TruVac e sonda da 13 G: risultati preliminari

OBIETTIVO: La tipizzazione di noduli mammari mediante prelievi con ago sottile è talora complicata, per varie ragioni da esiti inconclusivi. Queste problematiche dilatano i tempi diagnostici rendendo necessarie ulteriori biopsie con risultati spesso discordanti. Per questo, in molti centri si stanno utilizzando aghi di calibro maggiore sostituendo la citologia con la microistologia: i sistemi di biopsia vuoto-assistita (vacuum-assisted breast biopsy, VABB) evidenziano performance superiori, risultando, tuttavia, spesso meno maneggevoli e più costosi. Lo scopo di questo studio è di valutare le performance di sistema del prelievo microistologico con ago 13 G e tecnologia VABB senza cavi con una maneggiabilità vicina a quella di un ago tranciante. METODI: Da gennaio 2016 a febbraio 2018, due operatori hanno eseguito complessivamente 86 prelievi microistologici con ago 13 G Elite su lesioni BIRADS 3, 4 e 5, delle quali 30 ripetute dopo precedenti prelievi cito-istologici inconclusivi. Sono state biopsiate lesioni tra 5 e 43 mm di cui 70 noduli, 12 aree di alterazione ecostrutturale non-mass like e tre cisti complex. RISULTATI: Il sistema 13 G ha evidenziato 3,53% casi B1, 41,17% B2, 17,64% B3 e 37,64% B5. Nello stesso periodo i prelievi con ago tranciante 14-16 G con i medesimi operatori hanno evidenziato i seguenti risultati: 2,65% B1, 44,33% B2, 9% B3, 0,48% B4, 43,49% B5. Il prelievo da 13 G Elite ha permesso un cambio di classe istologica nell’83,33% delle procedure ripetute dopo prelievo non dirimente. CONCLUSIONI: La procedura bioptica con sistema TruVac si è dimostrata affidabile e potrebbe essere utilizzata per ridurre i casi con esito cito-istologico non dirimente