Abstract Background The MINDACT (Microarray In Node-negative and 1–3 node positive Disease may Avoid ChemoTherapy) trial investigates the clinical utility of the 70-gene profile (MammaPrint) for the ...selection of breast cancer patients for adjuvant chemotherapy (CT) together with standard clinicopathological criteria. We present the results of the pilot phase consisting of first 800 patients included. Methods MINDACT has enrolled 6600 patients, classified into high or low risk by MammaPrint and clinicopathological risk through Adjuvant! Online. Patients with both clinical (C) and genomic (G) high risks are offered adjuvant CT; those with both C and G low risks do not receive CT; patients with discordant risk are randomised for the decision of adjuvant CT based on C or G risk. CT randomisation of anthracycline-based versus docetaxel/capecitabine and endocrine therapy randomisation between letrozole and tamoxifen → letrozole are offered. Results During the pilot phase 46% of screened patients were enrolled. Main reasons for non-enrolment were node positivity before trial amendment, sample quality problems and failure to meet logistic settings. Among the 800 patients, 386 (48%) were C-low/G-low, 198 (24.8%) as C-high/G-high, 75 (9.4%) as C-low/G-high and 141 (17.6%) as C-high/G-low. In total 216 (27%) cases were discordant. The difference between patients with C-high (42%) and G-high risk (34%) is 8.25% (95% confidence interval (CI), 4.7–11.8%; P < .0001). Compliance with the treatment decision was high (>92%). Conclusions The logistically complex MINDACT trial is feasible in a multinational setting. The proportion of discordant patients, the potential reduction in CT by using the genomic signature and compliance to treatment assignment are in accordance with the trial hypotheses.
The present study was designed to describe tumour features and treatments for patients with breast cancer. It also aimed at assessing the risk of distant metastases in relation to biological ...profiles, disease stages and treatment.
Data were analysed from 81,882 patients in the EUSOMA database (disease stages at diagnosis 0-IV; median age 61 years; range 20-100 years). All patients were treated between January 2016 and December 2021 in 53 Breast Centres within the EUSOMA certification process in 13 European countries. Cases were classified as HR+ /HER2-, HR+ /HER2 + , HR-/HER2 + or HR-/HER2- and data were analysed accordingly.
Univariable and multivariable analyses for distant metastases were conducted on a subset of 38,119 cases with information on whether or not they had developed them. Potential determinants included sub-group type, Ki67 value, disease stage, adjuvant systemic therapies and post-operative radiation therapy. In multivariable analysis, the HR-/HER2 + and HR-/HER2- sub-groups were associated with a higher risk of distant metastases than HR+ /HER2-. Ki67 > 20 % and advanced stage disease also carried a high risk. Radiation therapy emerged as a protective factor against distant metastases.
Present results show a large patient database offers an information stream that can be applied to reduce uncertainties in clinical practice. Database parameters need to be updated dynamically for outcome monitoring. Molecular prognostic factors, gene-expression signatures, tumour-infiltrating lymphocytes and circulating tumoral DNA should be added.
We analysed the impact of the SARS-CoV-2 pandemic (COVID-19) on the quality of breast cancer care in certified EUSOMA (European Society of Breast Cancer Specialists) breast centres.
The results of ...the EUSOMA quality indicators were compared, based on pseudonymised individual records, for the periods 1 March 2020 till 30 June 2020 (first COVID-19 peak in most countries in Europe) and 1 March 2019 till 30 June 2019. In addition, a questionnaire was sent to the participating Centres for investigating the impact of the COVID-19 pandemic on the organisation and the quality of breast cancer care.
Forty-five centres provided data and 31 (67%) responded to the questionnaire. The total number of new cases dropped by 19% and there was a small significant higher tumour (p = 0.003) and lymph node (p = 0.011) stage at presentation. Comparing quality indicators (12,736 patients) by multivariable analysis showed mostly non-significant differences. Surgery could be performed in a COVID-free zone in 94% of the centres, COVID testing was performed before surgery in 96% of the centres, and surgical case load was reduced in 55% of the centres. Modifications of the indications for neoadjuvant endocrine therapy, chemotherapy, and targeted therapy were necessary in 23%, 23%, and 10% of the centres; changes in indications for adjuvant endocrine, chemo-, targeted, immune, and radiotherapy in 3%, 19%, 3%, 6%, and 10%, respectively.
Quality of breast cancer care was well maintained in EUSOMA breast centres during the first wave of the COVID-19 pandemic. A small but significantly higher tumour and lymph node stage at presentation was observed.
•Patients registered in eusomaDB dropped by 19% in the first wave of COVID-19.•We found higher tumour (p = 0.003) and lymph node (p = 0.011) stage at presentation.•Changes in locoregional and adjuvant treatment were seen in patients aged >70.•QIs multivariate analysis in two time periods shows no significant differences.•Quality was maintained in EUSOMA breast centres during the first wave of COVID-19.
Objective
The purpose of this study was to describe the feasibility of respiratory oscillometry (RO) in schoolchildren with asthma, and the concordance of its results with those of spirometry, to ...determine its clinical usefulness.
Methods
RO and spirometry were performed in 154 children (6 to 14‐year‐old) with asthma, following strict quality criteria for the tests. Their feasibility (probability of valid test, time of execution, number of maneuvers needed to achieve a valid test, and perceived difficulty) was compared. The factors that influence feasibility were analyzed with multivariate methods. FEV1, FEV1/FVC, FVC and FEF25‐75 for spirometry, and R5, AX and R5‐19 for RO, were converted into z‐scores and their concordance was investigated through intraclass correlation coefficients (ICC) and kappa indices for normal/abnormal values.
Results
There were no differences in the probability of obtaining a valid RO or spirometry (83.1% vs. 81.8%, p = 0.868). RO required a lower number of maneuvers mean (SD) 4.2 (1.8) versus 6.0 (1.6), p < 0.001 and less execution time 5.1 (2.7) versus 7.6 (2.4) minutes, p < 0.001, and patients considered it less difficult. Age increased the probability of obtaining valid RO and spirometry. The concordance of results between RO and spirometry was low, and only between zFEV1 and zAX could it be considered moderate (ICC = 0.412, kappa = 0.427).
Conclusion
RO and spirometry are feasible in children with asthma. RO has some practical advantages, but the concordance of its results with spirometry is low.
PARP inhibitors are active in tumors with defects in DNA homologous recombination (HR) due to BRCA1/2 mutations. The phosphoinositide 3-kinase (PI3K) signaling pathway preserves HR steady state. We ...hypothesized that in BRCA-proficient triple-negative breast cancer (TNBC), PI3K inhibition would result in HR impairment and subsequent sensitization to PARP inhibitors. We show in TNBC cells that PI3K inhibition leads to DNA damage, downregulation of BRCA1/2, gain in poly-ADP-ribosylation, and subsequent sensitization to PARP inhibition. In TNBC patient-derived primary tumor xenografts, dual PI3K and PARP inhibition with BKM120 and olaparib reduced the growth of tumors displaying BRCA1/2 downregulation following PI3K inhibition. PI3K-mediated BRCA downregulation was accompanied by extracellular signal-regulated kinase (ERK) phosphorylation. Overexpression of an active form of MEK1 resulted in ERK activation and downregulation of BRCA1, whereas the MEK inhibitor AZD6244 increased BRCA1/2 expression and reversed the effects of MEK1. We subsequently identified that the ETS1 transcription factor was involved in the ERK-dependent BRCA1/2 downregulation and that knockdown of ETS1 led to increased BRCA1/2 expression, limiting the sensitivity to combined BKM120 and olaparib in 3-dimensional culture.
Treatment options are limited for patients with TNBCs. PARP inhibitors have clinical activity restricted to a small subgroup of patients with BRCA mutations. Here, we show that PI3K blockade results in HR impairment and sensitization to PARP inhibition in TNBCs without BRCA mutations, providing a rationale to combine PI3K and PARP inhibitors in this indication. Our findings could greatly expand the number of patients with breast cancer that would benefit from therapy with PARP inhibitors. On the basis of our findings, a clinical trial with BKM120 and olaparib is being initiated in patients with TNBCs.
Intraductal (IDC) and cribriform (CRIB) histologies in prostate cancer have been associated with germline BRCA2 (gBRCA2) mutations in small retrospective series, leading to the recommendation of ...genetic testing for patients with IDC in the primary tumour.
To examine the association of gBRCA2 mutations and other tumour molecular features with IDC and/or cribriform (CRIB) histologies, we conducted a case–control study in which primary prostate tumours from 58 gBRCA2 carriers were matched (1:2) by Gleason Grade Group and specimen type to 116 non-carriers. Presence/absence of IDC and CRIB morphologies was established by two expert uropathologists blinded to gBRCA2 status. Fluorescent in-situ hybridization (FISH) and next-generation sequencing (NGS) were used to detect BRCA2 alterations, PTEN deletions and TMPRSS2-ERG fusions. Chi-squared tests were used to compare the frequency of IDC and CRIB in gBRCA2 carriers and controls and to assess associations with other variables. Logistic regression models were constructed to identify independent factors associated with both histology patterns.
No significant differences between gBRCA2 carriers and non-carriers were observed in the prevalence of IDC (36% gBRCA2 versus 50% non-carriers, p = 0.085) or CRIB (53% gBRCA2 versus 43% non-carriers p = 0.197) patterns. However, IDC histology was independently associated with bi-allelic BRCA2 alterations (OR 4.3, 95%CI 1.1–16.2) and PTEN homozygous loss (OR 5.2, 95%CI 2.1–13.1). CRIB morphology was also independently associated with bi-allelic BRCA2 alterations (OR 5.6, 95%CI 1.7–19.3).
While we found no association between gBRCA2 mutations and IDC or CRIB histologies, bi-allelic BRCA2 loss in primary prostate tumours was significantly associated with both variant morphologies, independently of other clinical-pathologic factors.
•Presence of gBRCA2 mutations was not associated with IDC and CRIB patterns.•Results do not support germline BRCA2 testing only based on presence of IDC and/or CRIB.•IDC and CRIB patterns were associated with bi-allelic BRCA2 alterations in our study.
Background and Aims
Ductular reaction (DR) expands in chronic liver diseases and correlates with disease severity. Besides its potential role in liver regeneration, DR plays a role in the ...wound‐healing response of the liver, promoting periductular fibrosis and inflammatory cell recruitment. However, there is no information regarding its role in intrahepatic angiogenesis. In the current study we investigated the potential contribution of DR cells to hepatic vascular remodeling during chronic liver disease.
Approach and Results
In mouse models of liver injury, DR cells express genes involved in angiogenesis. Among angiogenesis‐related genes, the expression of Slit2 and its receptor Roundabout 1 (Robo1) was localized in DR cells and neoangiogenic vessels, respectively. The angiogenic role of the Slit2–Robo1 pathway in chronic liver disease was confirmed in ROBO1/2−/+ mice treated with 3,5‐diethoxycarbonyl‐1,4‐dihydrocollidine, which displayed reduced intrahepatic neovascular density compared to wild‐type mice. However, ROBO1/2 deficiency did not affect angiogenesis in partial hepatectomy. In patients with advanced alcohol‐associated disease, angiogenesis was associated with DR, and up‐regulation of SLIT2–ROBO1 correlated with DR and disease severity. In vitro, human liver‐derived organoids produced SLIT2 and induced tube formation of endothelial cells.
Conclusions
Overall, our data indicate that DR expansion promotes angiogenesis through the Slit2–Robo1 pathway and recognize DR cells as key players in the liver wound‐healing response.
Chronic liver diseases are characterized by the expansion of ductular reaction (DR) cells and the expression of liver progenitor cell (LPC) markers. In alcoholic hepatitis (AH), the degree of DR ...expansion correlates with disease progression and short‐term survival. However, little is known about the biological properties of DR cells, their impact on the pathogenesis of human liver disease, and their contribution to tissue repair. In this study, we have evaluated the transcriptomic profile of DR cells by laser capture microdissection in patients with AH and assessed its association with disease progression. The transcriptome analysis of cytokeratin 7‐positive (KRT7+) DR cells uncovered intrinsic gene pathways expressed in DR and genes associated with alcoholic liver disease progression. Importantly, DR presented a proinflammatory profile with expression of neutrophil recruiting C‐X‐C motif chemokine ligand (CXC) and C‐C motif chemokine ligand chemokines. Moreover, LPC markers correlated with liver expression and circulating levels of inflammatory mediators such as CXCL5. Histologically, DR was associated with neutrophil infiltration at the periportal area. In order to model the DR and to assess its functional role, we generated LPC organoids derived from patients with cirrhosis. Liver organoids mimicked the transcriptomic and proinflammatory profile of DR cells. Conditioned medium from organoids induced neutrophil migration and enhanced cytokine expression in neutrophils. Likewise, neutrophils promoted the proinflammatory profile and the expression of chemokines of liver organoids. Conclusion: Transcriptomic and functional analysis of KRT7+ cells indicate that DR has a proinflammatory profile and promote neutrophil recruitment. These results indicate that DR may be involved in the liver inflammatory response in AH, and suggest that therapeutic strategies targeting DR cells may be useful to mitigate the inflammatory cell recruitment in AH.
Recent developments on the production of omega-3 fatty acid concentrates have been reviewed with an emphasis on the scientific articles published from 2000. At first, a description of the role of ...essential fatty acids in the organism and the influence of omega-3 fatty acids in human health is presented. An account of the review articles that have been published in previous years related to the production or isolation of omega-3 fatty acids is then provided. The publications that have appeared over the last 8
years have been reviewed under two groupings, one involving the production of omega-3 from fish, and the other involving the isolation from alternative sources. Fish is the major source of omega-3 fatty acids and the fish oil extraction processes have been considered firstly, then the fish oil refining processes are presented and finally the omega-3 concentration from fish oil. Some considerations on the stability of polyunsaturated fatty acids against hydrolysis and oxidation and the procedures to avoid it are also presented at the end of this review.
Omega-3 polyunsaturated fatty acids are being used quite extensively in the food industry to obtain omega-3 enriched food products.
Most of the commercial concentrates that can be found nowadays are the omega-3 ethyl ester derivatives. However, research is ongoing to obtain the more natural and better digestible triglyceride concentrates.
We present here a review of the most recent advances, regarding the production of omega-3 concentrates from the very first raw material that contains them from which they should be extracted to the omega-3 concentrates stabilization. In between, a good number of different technologies that are being industrially applied, or still under investigation, are reviewed. One of the technologies with high expectation is supercritical fluid technology, and it finds a relevant place in the review here presented.
Industries involved on innovation, require rapid overviews of the different possibilities open for production, and in that sense, this review is expected to be of interest.
► SFE is an advantageous process for obtaining oil from freeze-dried, low fat, fish by-products. ► SFE can prevent lipid oxidation and reduce extraction of certain pollutants. ► Closed circulation ...SFE may provide extracts with high volatile content. ► On-line fractionation SFE can provide enhanced quality fish oil with low FFA and oxidation products content.
Fish and fish by-products are the main natural source of omega-3 polyunsaturated fatty acids, especially EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid), both of them with a great importance in the food and pharmaceutical industries. Comparing to conventional fish oil extraction processes such as cold extraction, wet reduction or enzymatic extraction, supercritical fluid extraction with carbon dioxide under moderate conditions (25MPa and 313K) may be useful for reducing fish oil oxidation, especially when fish oil is rich in omega-3 such as salmon oil, and the amount of certain impurities, such as some species of arsenic. Furthermore, taking profit of the advantages of supercritical carbon dioxide as extractive solvent, a coupled extraction-fractionation process is proposed as a way to remove free fatty acids and improve fish oil quality, alternatively to physical and chemical refining procedures.
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