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Abstract The RAD51 test is emerging as a promising biomarker for the assessment of functional homologous recombination deficiency (HRD). Yet, the robustness and reproducibility of the immunofluorescence‐based RAD51 test, in different academic laboratories, have not been systematically investigated. Therefore, we tested the performance of the RAD51 assay in formalin‐fixed paraffin‐embedded (FFPE) high‐grade serous ovarian carcinoma (HGSOC) samples in four European laboratories. Here, we confirm that subtle differences in staining procedures result in low variability of RAD51 and γH2AX scores. However, substantial variability in RAD51 scoring was observed in some samples, likely due to complicating technical and biological features, such as high RAD51 signal‐to‐noise ratio and RAD51 heterogeneity. These results support the need to identify and perform additional quality control steps and/or automating image analysis. Altogether, resolving technical issues should be a priority, as identifying tumours with functional HRD is urgently needed to guide the individual treatment of HGSOC patients. Follow‐up studies are needed to define the key tissue quality requirements to assess HRD by RAD51 in FFPE tumour samples, as this test could help in guiding the individual treatment of HGSOC patients.

Hereditary breast/ovarian cancer (HBOC) syndrome is caused by the inheritance of monoallelic germline BRCA1/2 gene mutations. If BRCA1/2 mutation carriers are identified before the disease develops, effective actions against HBOC can be taken, including intensive screening, risk-reducing mastectomy and salpingo-oophorectomy, and risk-reducing medications. The Italian National Prevention Plan mandates the creation of regional BRCA genetic testing programmes. So far, however, only informal data have been reported on their implementation. We have designed a study aimed at evaluating the results of a population-based programme for risk assessment and genetic counselling and testing for BRCA1/2-related HBOC that is underway in the Emilia-Romagna region (northern Italy). The programme—which is entirely free—includes basic screening with an estimate of the likelihood of carrying a BRCA1/2 mutation using a familial risk assessment tool, a closer examination of women with suspected risk increase, an assessment of the need for further genetic counselling and, if needed, genetic testing and risk-reducing interventions. In this paper, the design of the programme and the protocol of the study are presented. The study has an observational, historical cohort design. Eligible are the women found to be at an increased risk of HBOC (profile 3 women). The main objectives are (i) to determine the precision of the programme in measuring the level of risk of HBOC for profile 3 women; (ii) to determine the characteristics of profile 3 women and their association with the risk management strategy chosen; (iii) to compare the age at onset, histologic type, tumour stage, molecular subtype, and prognosis of breast/ovarian cancers observed in the cohort of profile 3 women with the features of sporadic cancers observed in the general female population; (iv) to determine the level and the determinants of adherence to recommendations; and (v) to determine the appropriateness and timing of risk-reducing surgery and medications. Investigating the quality and results of the programme is necessary because the best practices in risk assessment and genetic counselling and testing for BRCA1/2-related cancer and the challenges they encounter should be identified and shared. The study has the potential to provide sound empirical evidence for the factors affecting the effectiveness of this type of service.

Background It is possible to induce immunomodulation in HER2-positive breast cancer (BC) by modifying the route of administration of trastuzumab.Methods In this multicenter randomized phase II trial, all enrolled patients (pts) with T2–T4d HER2-positive BC received 3 cycles of neoadjuvant treatment (NAT) with fluorouracil, epirubicin and cyclophosphamide every 3 weeks (q21), followed by docetaxel/pertuzumab plus intravenous trastuzumab (arm A) or, docetaxel/pertuzumab plus subcutaneous (SC) trastuzumab (arm B) q21x4 cycles. After surgical operation, each pt was treated with trastuzumab q21x14 cycles using the same SC or intravenous formulation of NAT. Primary endpoint was the proportion of subjects with high stromal tumor-infiltrating lymphocytes (sTILs) in postneoadjuvant residual disease (RD).Results Sixty-three pts (31 (arm A) and 32 (arm B)) were enrolled. Pathological complete response was obtained by 20/31 pts (64.5%; 95% CI 45.4% to 80.1%) in arm A and 19/32 pts (59.4%; 95% CI 40.1% to 76.3%) in arm B. High sTILs were observed in 27% and 46% of postneoadjuvant residual tumors in arms A and B, respectively. CD8+ T cells increased significantly in RDs of both arms (p=0.014 and 0.002 for arm A and B, respectively), whereas a significant decline in the level of CD4+ FoxP3+ regulatory T cells was observed only in arm B (p=0.016). A significant upregulation of PD-1 on sTILs was found in RD of pts enrolled in arm B (p=0.012), while programmed death-ligand 1 (PD-L1) was significantly overexpressed in residual tumors of arm A (p=0.02). A strong negative correlation was reported in arm B between expression of PD-L1 on pretreatment sTILs and CD3 expression on sTILs in RD (τ: −0.73). Grade≥3 AE incidence rates were similar between the two arms.Conclusions SC trastuzumab induced relevant sTILs enrichment, with favorable variations of immune parameters in HER2-positive BC pts with RD after NAT. Novel immunotherapy strategies should be tested to achieve SC-specific, antitumor immune response.Trial registration number NCT03144947, and EudraCT number: 2016-000435-41.

Hormone receptor (HR)-positive/HER2-positive breast cancer represents a distinct subtype expressing estrogen and progesterone receptors with an overexpression of HER2. Approximately 14% of female breast cancer cases are HER2-positive, with the majority being HR-positive. These tumors show a cross-talk between the hormonal and HER2 pathways; the interaction has implications for the treatment options for the disease. In this review, we analyze the biology of HR-positive/HER2-positive breast cancer and summarize the evidence concerning the standard of care options both in neoadjuvant/adjuvant settings and in advanced disease. Additionally, we focus on new trials and drugs for HR-positive/HER2-positive breast cancer and the new entity: HER2-low breast cancer.

Germline variants occurring in BRCA1 and BRCA2 give rise to hereditary breast and ovarian cancer (HBOC) syndrome, predisposing to breast, ovarian, fallopian tube, and peritoneal cancers marked by elevated incidences of genomic aberrations that correspond to poor prognoses. These genes are in fact involved in genetic integrity, particularly in the process of homologous recombination (HR) DNA repair, a high-fidelity repair system for mending DNA double-strand breaks. In addition to its implication in HBOC pathogenesis, the impairment of HR has become a prime target for therapeutic intervention utilizing poly (ADP-ribose) polymerase (PARP) inhibitors. In the present review, we introduce the molecular roles of HR orchestrated by BRCA1 and BRCA2 within the framework of sensitivity to PARP inhibitors. We examine the genetic architecture underneath breast and ovarian cancer ranging from high- and mid- to low-penetrant predisposing genes and taking into account both germline and somatic variations. Finally, we consider higher levels of complexity of the genomic landscape such as polygenic risk scores and other approaches aiming to optimize therapeutic and preventive strategies for breast and ovarian cancer.

In this paper, the experimental validation of an innovative clutch based on magnetorheological fluids (MRFs) excited by permanent magnets is described. The device, used in automotive applications to engage and disengage the vacuum pump, is tested using a standardized Worldwide harmonized Light-duty Test Cycle (WLTC). A test bench is built, and the system is observed in its operation for one hour, considering two consecutive WLTCs. The temperature increase slightly impacts the clutch’s behavior; in particular, the on-state performance of the device, mainly determined by the magnetic field-induced torque, remains largely unaffected by the temperature increase. The results showed that the performance of the proposed MRF-based device is only marginally affected by the phenomena that take place during the actual operation (e.g., temperature increase, shaft slip), confirming the effectiveness of the design.

This paper reports the design and optimization of a permanent magnet-based spring. The aim of the optimization, performed using a particular form of the self-organizing map (SOM) algorithm, was to determine the dimensions of a ring PM-based spring with a force–displacement curve similar to a desired one. For each step in the optimization process, a spring composed of different ring-shaped magnets was analyzed using a semi-analytical model. Its characteristic was compared with the desired one to search for a minimum cost function obtained by subtracting the evaluated and the desired force–displacement curve. The resulting algorithm was efficient in the design of a spring with a desired characteristic. The geometry obtained was used to study an electrodynamic damper based on the exploitation of the interaction between the moving magnet of the spring and a conductive cylinder. A parametric analysis was performed: the damping effect grows when the cylinder thickness increases and decreases with the gap between the cylinder and the magnets. Also, the cylinder thickness needed to reduce to one the number of overshoots in the moving magnet’s position decreases with the gap increase. Computations were performed using the research code EN4EM (Electric Network 4 ElectroMagnetics) developed by the authors.

Abstract Background The number of patients living after a cancer diagnosis is increasing, especially after thyroid cancer (TC). This study aims at evaluating both the risk of a second primary cancer (SPC) in TC patients and the risk of TC as a SPC. Methods We analyzed two population‐based cohorts of individuals with TC or other neoplasms diagnosed between 1998 and 2012, in 28 Italian areas covered by population‐based cancer registries. Standardized incidence ratios (SIRs) of SPC were stratified by sex, age, and time since first cancer. Results A total of 38,535 TC patients and 1,329,624 patients with other primary cancers were included. The overall SIR was 1.16 (95% CI: 1.12–1.21) for SPC in TC patients, though no increase was shown for people with follicular (1.06) and medullary (0.95) TC. SPC with significantly increased SIRs was bone/soft tissue (2.0), breast (1.2), prostate (1.4), kidney (2.2), and hemolymphopoietic (1.4) cancers. The overall SIR for TC as a SPC was 1.49 (95% CI: 1.42–1.55), similar for all TC subtypes, and it was significantly increased for people diagnosed with head and neck (2.1), colon–rectum (1.4), lung (1.8), melanoma (2.0), bone/soft tissue (2.8), breast (1.3), corpus uteri (1.4), prostate (1.5), kidney (3.2), central nervous system (2.3), and hemolymphopoietic (1.8) cancers. Conclusions The increased risk of TC after many other neoplasms and of few SPC after TC questions the best way to follow‐up cancer patients, avoiding overdiagnosis and overtreatment for TC and, possibly, for other malignancies.

Abstract Background The 8th edition of the American Joint Committee on Cancer (AJCC) staging has introduced prognostic stage based on anatomic stage combined with biologic factors. We aimed to validate the prognostic stage in HER2-positive breast cancer patients enrolled in the ShortHER trial. Methods The ShortHER trial randomized 1253 HER2-positive patients to 9 weeks or 1 year of adjuvant trastuzumab combined with chemotherapy. Patients were classified according to the anatomic and the prognostic stage. Distant disease-free survival (DDFS) was calculated from randomization to distant relapse or death. Results A total of 1244 patients were included. Compared to anatomic stage, the prognostic stage downstaged 41.6% (n = 517) of patients to a more favorable stage category. Five-year DDFS based on anatomic stage was as follows: IA 96.6%, IB 94.1%, IIA 92.4%, IIB 87.3%, IIIA 81.3%, IIIC 70.5% (P

(1) Background: Liver cancer in Italy is characterised by one of the highest incidence rates worldwide outside of Asia coupled with comparatively favourable survival figures. The objective of this study was to evaluate the most recent epidemiologic trends of the disease. (2) Methods: Thirteen cancer registries covering a population of about 12,740,000 (21% of the national population) made available the records of 35,574 cases registered between 2003 and 2017. Trends in age-standardised (Europe 2013) incidence rates were analysed using the results of age–drift models. Trends in survival were analysed using 1-year, 2-year, 5-year and 10-year net survival (NS) and 5|1-year and 5|2-year conditional NS. (3) Results: Over the study period, the average annual incidence rates per 100,000 persons were 29.4 (men) and 9.4 (women) for total liver cancer; 14.6 and 3.5 for hepatocellular carcinoma (HCC); 1.8 and 1.1 for intrahepatic cholangiocarcinoma (ICC); and 13.0 and 4.8 for the ‘other liver cancer types’ group. The incidence of total liver cancer and HCC decreased significantly for both sexes. For total liver cancer, the estimated average annual percent change was −1.6% among men and −2.1% among women. For HCC, the change was −1.3% among men and −2.7% among women. ICC followed an opposite trend. For men, the risk of HCC had two peaks, one in the birth cohorts of 1928 and 1933 and another, more moderate peak in the cohort of 1958. Men and women exhibited comparable improvements in both early and mid-term conditional NS from HCC. In 2013–2017, 5-year NS was 28.9% (95% CI: 27.3%; 30.6%) for men and 30.1% (95% CI: 26.9%; 33.5%) for women. The uptrend in survival from ICC was less pronounced and was weakly significant, with a 5-year NS in 2013-2017 of 13.9% (95% CI: 10.8%; 17.3%) for men and 17.4% (95% CI: 13.5%; 21.7%) for women. (4) Conclusions: The opposite incidence trends of HCC and ICC confirm a pattern observed in other populations. The generalised, albeit slow, improvement in survival from HCC indicates a trend towards earlier detection coupled with improvements in treatments.

Breast cancer is still a lethal disease and the leading cause of death in women, undermining patients’ survival and quality of life. Modern techniques of surgery and radiotherapy allow for the obtaining of good results in terms of survival, however they cause long-term side effects that persist over time, such as lymphedema and neuropathy. Similarly, the advent of new therapies such as endocrine therapy revolutionized breast cancer outcomes, but side effects are still present even in years of follow-up after cure. Besides the side effects of medical and surgical therapy, breast cancer is a real disruption in patients’ lives considering quality of life-related aspects such as the distortion of body image, the psychological consequences of the diagnosis, and the impact on family dynamics. Therefore, the doctor-patient relationship is central to providing the best support both during treatment and afterwards. The aim of this review is to summarize the consequences of medical and surgical treatment on breast cancer patients and to emphasize the importance of early prevention of side effects to improve patients’ quality of life.

The immune system plays a fundamental role in neoplastic disease. In the era of immunotherapy, the adaptive immune response has been in the spotlight whereas the role of innate immunity in cancer development and progression is less known. The tumor microenvironment influences the terminal differentiation of innate immune cells, which can explicate their pro-tumor or anti-tumor effect. Different cells are able to recognize and eliminate no self and tumor cells: macrophages, natural killer cells, monocytes, dendritic cells, and neutrophils are, together with the elements of the complement system, the principal players of innate immunity in cancer development and evolution. Metastatic breast cancer is a heterogeneous disease from the stromal, immune, and biological point of view and requires deepened exploration to understand different patient outcomes. In this review, we summarize the evidence about the role of innate immunity in breast cancer metastatic sites and the potential targets for optimizing the innate response as a novel treatment opportunity.

Women with pathogenic germline mutations in BRCA1 and BRCA2 genes have an increased risk to develop breast and ovarian cancer. There is, however, a high interpersonal variability in the modality and timing of tumor onset in those subjects, thus suggesting a potential role of other individual’s genetic, epigenetic, and environmental risk factors in modulating the penetrance of BRCA mutations. MicroRNAs (miRNAs) are small noncoding RNAs that can modulate the expression of several genes involved in cancer initiation and progression. MiRNAs are dysregulated at all stages of breast cancer and although they are accessible and evaluable, a standardized method for miRNA assessment is needed to ensure comparable data analysis and accuracy of results. The aim of this review was to highlight the role of miRNAs as potential biological markers for BRCA mutation carriers. In particular, biological and clinical implications of a link between lifestyle and nutritional modifiable factors, miRNA expression and germline BRCA1 and BRCA2 mutations are discussed with the knowledge of the best available scientific evidence.

Background: Coronavirus disease (COVID-19), an acute respiratory syndrome caused by a novel severe acute respiratory syndrome coronavirus (SARS-CoV-2), has rapidly spread worldwide, significantly affecting the outcome of a highly vulnerable group such as cancer patients. The aim of the present study was to evaluate the clinical impact of COVID-19 infection on outcome and oncologic treatment of cancer patients. Patient and methods: We retrospectively enrolled cancer patients with laboratory and/or radiologic confirmed SARS-CoV-2 infection, admitted to our center from February to April 2020. Descriptive statistics were used to summarize the clinical data and univariate analyses were performed to investigate the impact of anticancer treatment modifications due to COVID-19 outbreak on the short-term overall survival (OS). Results: Among 61 patients enrolled, 49 (80%) were undergoing anticancer treatment and 41 (67%) had metastatic disease. Most patients were men; median age was 68 years. Median OS was 46.6 days (40% of deaths occurred within 20 days from COVID-19 diagnosis). Among 59 patients with available data on therapeutic course, 46 experienced consequences on their anticancer treatment schedule. Interruption or a starting failure of the oncologic therapy correlated with significant shorter OS. Anticancer treatment delays did not negatively affect the OS. Lymphocytopenia development after COVID was significantly associated with worst outcome. Conclusions: COVID-19 diagnosis in cancer patients may affect their short-term OS, especially in case of interruption/starting failure of cancer therapy. Maintaining/delaying cancer therapy seems not to influence the outcome in selected patients with recent COVID-19 diagnosis.

Background: The aim of the present study was to dissect the clinical outcome of GB patients through the integration of molecular, immunophenotypic and MR imaging features. Methods: We enrolled 57 histologically proven and molecularly tested GB patients (5.3% IDH-1 mutant). Two-Dimensional Free ROI on the Biggest Enhancing Tumoral Diameter (TDFRBETD) acquired by MRI sequences were used to perform a manual evaluation of multiple quantitative variables, among which we selected: SD Fluid Attenuated Inversion Recovery (FLAIR), SD and mean Apparent Diffusion Coefficient (ADC). Characterization of the Tumor Immune Microenvironment (TIME) involved the immunohistochemical analysis of PD-L1, and number and distribution of CD3+, CD4+, CD8+ Tumor Infiltrating Lymphocytes (TILs) and CD163+ Tumor Associated Macrophages (TAMs), focusing on immune-vascular localization. Genetic, MR imaging and TIME descriptors were correlated with overall survival (OS). Results: MGMT methylation was associated with a significantly prolonged OS (median OS = 20 months), while no impact of p53 and EGFR status was apparent. GB cases with high mean ADC at MRI, indicative of low cellularity and soft consistency, exhibited increased OS (median OS = 24 months). PD-L1 and the overall number of TILs and CD163+TAMs had a marginal impact on patient outcome. Conversely, the density of vascular-associated (V) CD4+ lymphocytes emerged as the most significant prognostic factor (median OS = 23 months in V-CD4high vs. 13 months in V-CD4low, p = 0.015). High V-CD4+TILs also characterized TIME of MGMTmeth GB, while p53mut appeared to condition a desert immune background. When individual genetic (MGMTunmeth), MR imaging (mean ADClow) and TIME (V-CD4+TILslow) negative predictors were combined, median OS was 21 months (95% CI, 0–47.37) in patients displaying 0–1 risk factor and 13 months (95% CI 7.22–19.22) in the presence of 2–3 risk factors (p = 0.010, HR = 3.39, 95% CI 1.26–9.09). Conclusion: Interlacing MRI–immune–genetic features may provide highly significant risk-stratification models in GB patients.

A patient with HER2-positive early breast cancer (BC) developed dermatomyositis (DM), which disappeared after the first administration of adjuvant trastuzumab. No HER2 overexpression/amplification was observed in DM skin biopsies. Both BC and skin immune infiltrates were composed mostly of CD3+ T-lymphocytes. Interestingly, tumor-infiltrating lymphocytes expressed PD-1, which was negligible in skin-infiltrating lymphocytes, while both BC cells and keratinocytes were PD-L1-positive. High serum levels of endogenous anti-HER2 antibodies were detected, confirming the induction of a HER2-specific adaptive immune response. It may be argued that HER2-specific T-lymphocytes cross-reacted with one or more unknown skin antigens, causing DM. Trastuzumab may have silenced skin cross-reaction by eliminating any residual HER2-positive micrometastatic disease and, thus, inducing DM remission.

Breast cancer stage at diagnosis, patient age and molecular tumor subtype influence disease progression. The aim of this study was to analyze the relationships between these factors and survival in breast cancer patients among the Italian population using data from the AIRTUM national database. We enrolled women with primary breast cancer from 17 population-based cancer registries. Patients were subdivided into older (>69 years), middle (50–69 years) and younger age groups (

The inductive power transfer (IPT) is expected to greatly contribute towards electrification in transportation. In fact, IPT charging technology has the potential to overcome several limitations of conductive charging: in particular, the process can be fully automatable, and both static and dynamic charging are allowed, thus reducing the size of the battery pack. Additionally, safety is increased due to the absence of safety issues related to loss of cable insulation or to the unwanted interruption of the plug-socket connection. This paper presents, from a systematic approach, the design and realization of a prototype for IPT charging of autonomous shuttles in automated warehouses. First of all, the typical mission profile of the shuttle was properly identified, and a storage system based on power-oriented electrochemical cells was sized. Based on that, the architecture of the IPT system was chosen, both for transmitting and receiving sections. The pads were designed for this purpose, by considering the geometric constraints imposed by the manufacturer, through the utilization of the finite elements method. Finally, the power electronic circuitry was also designed. Numerical simulations of the components, as well as of the complete system, were performed and a prototype was built to widely verify the correspondence of the simulation outputs with the results obtained from an experimental measurements campaign.

Sensitivity to endocrine therapy of patients with estrogen receptor (ER)-positive metastatic breast cancer and germline BRCA1/2 mutations is not yet fully elucidated. Furthermore, the registration trials of CDK 4/6 inhibitors in combination with endocrine therapy lacked of a pre-specified subgroup analysis in BRCA1/2 mutation carriers. We report clinical history of two patients with BRCA-mutated, ER-positive metastatic breast cancer treated with letrozole plus the CDK 4/6 inhibitor palbociclib. Biological and clinical implications of the treatment outcome observed in the two cases are discussed with the knowledge of scientific evidence to date available. Overall, biological rationale, preclinical, and clinical data support the prominent role of CDK 4/6 inhibitors plus endocrine therapy, even in combination with PARP inhibitors, in the treatment of BRCA-mutated, ER-positive breast cancers. However, the interaction between Cyclin/CDK pathway, ER and BRCA is complex and evidences reported so far, albeit reliable, await confirmation in the context of future randomized clinical trials.

Multiphysics problems represent an open issue in numerical modeling. Electromagnetic launchers represent typical examples that require a strongly coupled magnetoquasistatic and mechanical approach. This is mainly due to the high velocities which make comparable the electrical and the mechanical response times. The analysis of interacting devices (e.g., a rail launcher and its feeding generator) adds further complexity, since in this context the substitution of one device with an electric circuit does not guarantee the accuracy of the analysis. A simultaneous full 3D electromechanical analysis of the interacting devices is often required. In this paper a numerical 3D analysis of a full launch system, composed by an air-core compulsator which feeds an electromagnetic rail launcher, is presented. The analysis has been performed by using a dedicated, in-house developed research code, named “EN4EM” (Equivalent Network for Electromagnetic Modeling). This code is able to take into account all the relevant electromechanical quantities and phenomena (i.e., eddy currents, velocity skin effect, sliding contacts) in both the devices. A weakly coupled analysis, based on the use of a zero-dimensional model of the launcher (i.e., a single loop electrical equivalent circuit), has been also performed. Its results, compared with those by the simultaneous 3D analysis of interacting devices, show an over-estimate of about 10–15% of the muzzle speed of the armature.

Background: The aberrant expression of microRNAs (miRNAs) has been associated with several diseases, including cancer, inflammatory, and autoimmune conditions. Interest in salivary miRNAs as non-invasive tools for the diagnosis of malignancies and systemic diseases is rapidly increasing. The present systematic review was developed for answering the question: “Are salivary microRNAs reliable biomarkers for diagnosis of cancer and systemic diseases?” Methods: The application of inclusion and exclusion criteria led to the selection of 11 papers. Critical appraisals and quality assessments of the selected studies were performed through the National Institute of Health “Study Quality Assessment Tool” and the classification of the Oxford Center for Evidence-Based Medicine. Results: Seven studies reported statistically significant correlations between one or more salivary miRNAs and the investigated disease. The critical analysis allowed us to classify only two studies (18.2%) as having “good” quality, the rest being scored as “intermediate” (8; 73%) and “poor” (1; 9%). Evidence exists that salivary miR-940 and miR-3679-5p are reliable markers for pancreatic cancer and that miR140-5p and miR301a are promising molecules for the salivary diagnosis of gastric cancer. Conclusions: Further studies, possibly avoiding the risk of bias highlighted here, are necessary to consolidate these findings and to identify new reliable salivary biomarkers.