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Background: Young women with breast cancer (BC) have an increased chance of carrying germline BRCA pathogenic variants (PVs). Limited data exist on the prognostic impact of tumor histology (i.e. ductal versus lobular) in hereditary breast cancer., Methods: This multicenter retrospective cohort study included women aged ≤40 years with early-stage breast cancer diagnosed between January 2000 and December 2020 and known to carry germline PVs in BRCA1/2. Histology was locally assessed in each center. The Kaplan-Meier method and Cox regression analysis were used to assess disease-free survival and overall survival., Results: Of 4628 patients included from 78 centers worldwide, 3969 (86%) had pure ductal, 135 (3%) pure lobular, and 524 (11%) other histologies. Compared with ductal tumors, lobular tumors were more often grade 1/2 (57.7% versus 22.1%), stage III (29.6% versus 18.5%), and luminal A-like (42.2% versus 12.2%). Lobular tumors were more often associated with BRCA2 PVs (71.1% BRCA2), while ductal tumors were more often associated with BRCA1 PVs (65.7% BRCA1). Patients with lobular tumors more often had mastectomy (68.9% versus 58.3%), and less often received chemotherapy (83.7% versus 92.9%). With a median follow-up of 7.8 years, no significant differences were observed in disease-free survival (adjusted hazard ratio 1.01, 95% confidence interval 0.74-1.37) or overall survival (hazard ratio 0.96, 95% confidence interval 0.62-1.50) between patients with ductal versus lobular tumors. No significant survival differences were observed according to specific BRCA gene, breast cancer subtype, or body mass index., Conclusions: In this large global cohort of young BRCA carriers with breast cancer, the incidence of pure lobular histology was low and associated with higher disease stage at diagnosis, luminal-like disease and BRCA2 PVs. Histology did not appear to impact prognosis., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Hormone receptor expression is a known positive prognostic and predictive factor in breast cancer; however, limited evidence exists on its prognostic impact on prognosis of young patients harboring a pathogenic variant (PV) in the BRCA1 and/or BRCA2 genes., Patients and Methods: This international, multicenter, retrospective cohort study included young patients (aged ≤40 years) diagnosed with invasive breast cancer and harboring germline PVs in BRCA genes. We investigated the impact of hormone receptor status on clinical behavior and outcomes of breast cancer. Outcomes of interest [disease-free survival (DFS), breast cancer-specific survival (BCSS), and overall survival (OS)] were first investigated according to hormone receptor expression (positive versus negative), and then according to breast cancer subtype [luminal A-like versus luminal B-like versus triple-negative versus human epidermal growth factor receptor 2 (HER2)-positive breast cancer]., Results: From 78 centers worldwide, 4709 BRCA carriers were included, of whom 2143 (45.5%) had hormone receptor-positive and 2566 (54.5%) hormone receptor-negative breast cancer. Median follow-up was 7.9 years. The rate of distant recurrences was higher in patients with hormone receptor-positive disease (13.1% versus 9.6%, P < 0.001), while the rate of second primary breast cancer was lower (9.1% versus 14.7%, P < 0.001) compared to patients with hormone receptor-negative disease. The 8-year DFS was 65.8% and 63.4% in patients with hormone receptor-positive and negative disease, respectively. The hazard ratio of hormone receptor-positive versus negative disease changed over time for DFS, BCSS, and OS (P < 0.05 for interaction of hormone receptor status and survival time). Patients with luminal A-like breast cancer had the worst long-term prognosis in terms of DFS compared to all the other subgroups (8-year DFS: 60.8% in luminal A-like versus 63.5% in triple-negative versus 65.5% in HER2-positive and 69.7% in luminal B-like subtype)., Conclusions: In young BRCA carriers, differences in recurrence pattern and second primary breast cancer among hormone receptor-positive versus negative disease warrant consideration in counseling patients on treatment, follow-up, and risk-reducing surgery., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: The CLEOPATRA trial (NCT00567190) established a dual anti-HER2 blockade in combination with docetaxel as the first-line standard of care for patients with metastatic HER2-positive breast cancer. While this treatment is overall associated with significant improvement in progression-free survival (PFS) and overall survival (OS), not all patients respond equally. We hypothesized that a radiological complete response (CR) at week 9 (i.e., first disease re-evaluation) is associated with prolonged OS and PFS compared to radiological partial response (PR) or stable disease (SD)., Methods: We performed an exploratory analysis of the CLEOPATRA study to address this question., Results: Out of 362 patients treated with docetaxel, trastuzumab, and pertuzumab eligible for our analysis, 46 (12.7%) had radiological CR at week 9, 243 (67.1%) PR, and 73 (20.2%) SD per central RECIST v1.0. Radiological CR at first tumor re-evaluation was associated with a 60% risk reduction for death compared to SD (adjusted HR = 0.40 95% confidence interval (CI) 0.23-0.70), whereas no significant impact on survival was observed for PR (adjusted HR = 0.85 95% CI 0.60-1.20). The same was observed for PFS with adjusted HR = 0.30 (95% CI 0.18-0.48) for the CR subgroup and adjusted HR = 0.81 (95% CI 0.60-1.09) for the PR subgroup. In multivariate analysis, no variables were associated with radiological CR., Conclusions: Our findings suggest that radiological CR at first disease re-evaluation is associated with more prolonged survival; this might result from stronger dependence on HER2 pathway addiction, supporting the need for further translational research., Competing Interests: Disclosure VD, MB, MC, FJ: none; EA: consultancy fee/honoraria from Eli Lilly, Sandoz, AstraZeneca. Research grant to my Institution from Gilead; Support to attend medical conferences (travel/accommodation/expenses) from Novartis, Roche, Eli Lilly, Genetic, IstitutoGentili, Daiichi Sankyo (all outside the submitted work); CM: honoraria from Novartis and Lilly; DMB: declares full-time employment from the European Society for Medical Oncology since September 1, 2023; speaker's engagement from AstraZeneca, Daiichi Sankyo; meeting/travel grant from Novartis; institutional research funding from Eli Lilly, F. Hoffmann-La Roche Ltd, Novartis; non-remunerated activity as a member of the board of directors for Associaҫão de Investigaҫão e Cuidados de Suporte em Oncologia; non-remunerated leadership role as prior Portuguese Young Oncologists; Committee Chair of Sociedade Portuguesa de Oncologia; GNM: support to attend medical conferences: Roche and Bayer (all outside the submitted work); ML: honoraria and/or advisory board from Roche, Novartis, Lilly, Pfizer, AstraZeneca, Daiichi Sankyo, Gilead, Seagen, MSD, Exact Sciences, Takeda, Ipsen, Sandoz, Libbsand Knight, a travel grant from Gilead and research support (to the Institution) from Gilead (all outside the submitted work); EdA: honoraria and/or advisory board from Roche/GNE, Novartis, Seattle Genetics, Zodiac, Libbsand Pierre Fabre. Travel grants from Roche/GNE and GSK/Novartis. Research grant to his institution from Roche/GNE, Astra-Zeneca, GSK/Novartis, and Servier(all outside the submitted work)., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Despite increasing evidence on the safety of pregnancy after anticancer treatments in breast cancer survivors, many physicians and patients remain concerned about a potential risk of pregnancy specifically in the case of hormone receptor-positive breast cancer., Materials and Methods: A systematic literature search of Medline, Embase and Cochrane library with no language or date restriction up to 31 March 2023 was carried out. To be included, articles had to be retrospective and prospective case-control and cohort studies as well as clinical trials comparing survival outcomes of premenopausal women with or without a pregnancy after prior diagnosis of hormone receptor-positive breast cancer. Disease-free survival (DFS) and overall survival (OS) were the outcomes of interest. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated. Study protocol is registered in PROSPERO (n. CRD42023394232)., Results: Out of 7796 screened studies, 8 were eligible to be included in the final analysis. A total of 3805 patients with hormone receptor-positive invasive early breast cancer were included in these studies, of whom 1285 had a pregnancy after breast cancer diagnosis. Median follow-up time ranged from 3.8 to 15.8 years and was similar in the pregnancy and non-pregnancy cohorts. In three studies (n = 987 patients) reporting on DFS, no difference was observed between patients with and those without a subsequent pregnancy (HR 0.96, 95% CI 0.75-1.24, P = 0.781). In the six studies (n = 3504 patients) reporting on OS, patients with a pregnancy after breast cancer had a statistically significant better OS than those without a pregnancy (HR 0.46, 95% CI 0.27-0.77, P < 0.05)., Conclusions: This systematic review and meta-analysis of retrospective cohort studies provides updated evidence that having a pregnancy in patients with prior history of hormone receptor-positive invasive early breast cancer appears safe without detrimental effect on prognosis., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

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., Competing Interests: Disclosure CM reports support to attend medical conferences from Gilead and honoraria from Novartis and Lilly (all outside the submitted work). EA reports consultancy fees/honoraria from Eli Lilly, Sandoz, AstraZeneca, research grant to her institution from Gilead and support for attending medical conferences from Novartis, Roche, Eli Lilly, Genetic, Istituto Gentili, Daiichi Sankyo, AstraZeneca. GNM reports support to attend medical conferences from Roche and Bayer (all outside the submitted work). AP reports advisory and consulting fees from Roche, Pfizer, Novartis, Amgen, BMS, Puma, Oncolytics Biotech, MSD, Guardant Health, Peptomyc and Lilly, lecture fees from Roche, Pfizer, Novartis, Amgen, BMS, Nanostring Technologies and Daiichi Sankyo, institutional financial interests from Boehringer, Novartis, Roche, Nanostring, Sysmex Europe GmbH, Medica Scientia inno. Re-search, SL, Celgene, Astellas and Pfizer; and shares ownership and a leadership role in Reveal Genomics, SL. EB reports funding to her institution from Gilead Science. FS declares personal fees for educational activities from Novartis and Gilead and travel expenses from Gilead, Novartis and Daiichy Sankyo. GV received honoraria for advisory boards and consulting fees from Roche, AstraZeneca, Daiichi Sankyo, MSD Oncology and Pfizer. LDM reports institutional research grant from Eli Lilly, Novartis, Roche, Daiichi Sankyo and Seagen, consulting fees from Eli Lilly; honoraria from Roche, Novartis, Pfizer, Eli Lilly, AstraZeneca, Merck Sharp and Dohme, Seagen, Gilead, Pierre Fabre, Eisa, Exact Sciences and Ipsen and support for attending meetings from Roche, Pfizer and Eisai; and fees for participation on a data safety monitoring board or advisory board from Novartis, Roche, Eli Lilly, Pfizer, Daiichi-Sankyo, Exact Sciences, Gilead, Pierre Fabre, Eisai, AstraZeneca and Agendia. ML played an advisory role for Roche, Lilly, Novartis, Astrazeneca, Pfizer, Seagen, Gilead, MSD and Exact Sciences and received speaker honoraria from Roche, Daiichi Sankyo, Lilly, Novartis, Pfizer, Sandoz, Libbs and Takeda and travel grants from Gilead outside the submitted work. EDA received honoraria and/or participated to advisory board from Roche/GNE, Novartis, Seattle Genetics, Zodiac, Libbs and Pierre Fabre; received travel grants from Roche/GNE and GSK/Novartis; and received research grant to his institution from Roche/GNE, AstraZeneca, GSK/Novartis and Servier. All other authors have declared no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Brain metastases (BMs) are frequent events in patients with HER2-positive metastatic breast cancer (MBC) and are associated with poor prognosis. Small-molecule anti-HER2 tyrosine kinase inhibitors (TKIs) are promising agents for the treatment of BM. In this study, we assess the clinical outcomes of patients with HER2-positive MBC and BM treated with TKI-containing regimens compared with those treated with non-TKI-containing regimens., Materials and Methods: PubMed, Embase, Cochrane Library, and conference proceedings (ASCO, SABCS, ESMO, and ESMO Breast) were searched up to June 2021. The primary endpoint was progression-free survival (PFS) in patients with BM. Secondary endpoints included PFS in patients without BM and overall survival (OS). The study was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Overall effects were pooled using random-effects models., Results: This systematic review and meta-analysis included data from 2437 patients (490 with and 1947 without BM at baseline) enrolled in five trials assessing tucatinib-, lapatinib-, pyrotinib-, or afatinib-based combinations. A nonstatistically significant PFS benefit favoring TKI-containing regimens was observed in both patients with BM [hazard ratio (HR) 0.67, 95% confidence interval (CI) 0.41-1.12; P = 0.13] and without BM (HR 0.55, 95% CI 0.24-1.26; P = 0.16). Sensitivity analysis, excluding each study singly, demonstrated a significant PFS benefit favoring TKI-containing regimens in patients with BM after the exclusion of afatinib from the analysis (HR 0.56, 95% CI 0.35-0.90; P = 0.016). No statistically significant differences in OS were observed between the comparison groups., Conclusions: A trend in PFS favoring TKI-containing regimens was observed in patients with BM. Sensitivity analysis including only trials that evaluated regimens containing tucatinib, lapatinib, or pyrotinib demonstrated a significant PFS benefit favoring TKI-containing regimens in patients with BM., Competing Interests: Disclosure GNM reports support to attend medical conferences from Roche and Bayer (all outside the submitted work). DMB reports honoraria and advisory board fees from Janssen, Pfizer, Merck Sharp & Dohme, Angelini, AstraZeneca, and Novartis; meeting/travel grants from LEO Farmacêuticos, Merck Sharp & Dohme, Ipsen, Janssen, Roche, Laboratórios Vitória, and Novartis; and institutional grant from F. Hoffmann-La Roche Ltd (all outside the submitted work). EA reports speaking fee from Lilly; support to attend medical conferences from Lilly, Novartis, Roche, Genetic, and Istituto Gentili (all outside the submitted work). ML plays advisory role for Roche, Lilly, Novartis, AstraZeneca, MSD, Seagen, Gilead, Pfizer, and Exact Sciences; and receives speaker honoraria from Roche, Lilly, Novartis, Pfizer, Sandoz, Takeda, Knight, Libbs, and Ipsen (all outside the submitted work). NK reports honoraria and advisory board fees from Erytech, Innate Pharma, Seattle Genetics, and LEO Pharma; and support to attend medical conferences from AstraZeneca, Pfizer, and OSE Immunotherapeutics (all outside the submitted work). AA reports support from Roche, Lilly, Amgen, EISAI, BMS, Pfizer, Novartis, MSD, Genomic Health, Ipsen, AstraZeneca, Bayer, LEO Pharma, Merck, Daiichi, Seattle Genetics, and Pierre Fabre (all outside the submitted work). EdA reports honoraria and/or advisory board fees from Roche/GNE, Novartis, Seattle Genetics, Zodiac, Libbs, and Pierre Fabre; travel grants from Roche/GNE and GSK/Novartis; research grant to institution from Roche/GNE, Astra-Zeneca, GSK/Novartis, and Servier (all outside the submitted work). All other authors have declared no conflicts of interest., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Knowledge is growing on the safety of assisted reproductive techniques (ART) in cancer survivors. No data exist, however, for the specific population of breast cancer patients harboring germline BRCA1/2 pathogenic variants., Patients and Methods: This is a multicenter retrospective cohort study across 30 centers worldwide including women diagnosed at ≤40 years with stage I-III breast cancer, between January 2000 and December 2012, harboring known germline BRCA1/2 pathogenic variants. Patients included in this analysis had a post-treatment pregnancy either achieved through use of ART (ART group) or naturally (non-ART group). ART procedures included ovulation induction, ovarian stimulation for in vitro fertilization or intracytoplasmic sperm injection, and embryo transfer under hormonal replacement therapy., Results: Among the 1424 patients registered in the study, 168 were eligible for inclusion in the present analysis, of whom 22 were in the ART group and 146 in the non-ART group. Survivors in the ART group conceived at an older age compared with those in the non-ART group (median age: 39.7 versus 35.4 years, respectively). Women in the ART group experienced more delivery complications compared with those in the non-ART group (22.1% versus 4.1%, respectively). No other apparent differences in obstetrical outcomes were observed between cohorts. The median follow-up from pregnancy was 3.4 years (range: 0.8-8.6 years) in the ART group and 5.0 years (range: 0.8-17.6 years) in the non-ART group. Two patients (9.1%) in the ART group experienced a disease-free survival event (specifically, a locoregional recurrence) compared with 40 patients (27.4%) in the non-ART group. In the ART group, no patients deceased compared with 10 patients (6.9%) in the non-ART group., Conclusion: This study provides encouraging safety data on the use of ART in breast cancer survivors harboring germline pathogenic variants in BRCA1/2, when natural conception fails or when they opt for ART in order to carry out preimplantation genetic testing., Competing Interests: Disclosure EdA has acted as a scientific advisory board member and has received honoraria from Roche/Genentech, Novartis, Seattle Genetics, Zodiacs, Libbs, Pierre Fabre, and Lilly; has received travel grants from Roche/GNE and GlaxoSmithKline (GSK)/Novartis; and has received research grants through his institution from Roche/GNE, AstraZeneca, GSK/Novartis, and Servier, outside the submitted work. FAP has acted as consultant for Ipsen, Roche Diagnostic, and Merck outside the submitted work. CRJ has acted as a scientific advisory board member and her institution has received honoraria from Bristol Myers Squibb (BMS), Theramex, and Roche; and her institution has received speaker's fees from Theramex and BMS, outside the submitted work. AS has acted as a consultant for Eli Lilly, Pfizer, Novartis, and Roche; has received speaker's fees from Teva, Roche, Pfizer, and Novartis; has received travel grants from Neopharm, Celgene, and Medison; and has received grant support from Novartis and Roche, outside the submitted work. CVG has acted as a consultant, as a scientific advisory board member, and has received speaker's fees from Roche, Novartis, Pfizer, Lilly, and Merck Sharp & Dohme (MSD); and has received research funding from AstraZeneca, Roche, and Pfizer, outside the submitted work. OCC has acted as a scientific advisory board member for Ascires Sistemas Genómicos; and has received grant support from Roche Diagnostics, Neomedic, and Takeda, outside the submitted work. KP has acted as a scientific advisory board member for AstraZeneca, Eli Lilly, Gilead Sciences, MSD, Novartis, Pierre Fabre, Roche, Teva, and Vifor Pharma; has acted as a consultant for AstraZeneca, Novartis, Pfizer, and Roche; has received speaker's fees from Eli Lilly, Medscape, MSD, Mundi Pharma, Novartis, Pfizer, and Roche; has received travel grants from AstraZeneca, Novartis, Pfizer, PharmaMar, and Roche, outside the submitted work. FP has acted as a scientific advisory board member and has received speaker's fees from Amgen, AstraZeneca, Daichi-Sankyo, Eisai, Eli Lilly, Ipsen, MSD, Novartis, Pierre-Fabre, Pfizer, Roche, Seagen, and Takeda; has received travel grants from Celgene, GlaxoSmithKline, and Roche; and has received research funding from AstraZeneca, Eisai, and Roche, outside the submitted work. ARF has received honoraria from Bayer, Daiichi Sankyo, Novartis, and Roche; and has received travel grants from Roche, outside the submitted work. JB has acted as consultant for AstraZeneca and Pfizer outside the submitted work. ID has acted as a scientific advisory board member and received grant from Roche; has received speaker's fees from Novartis; and has received travel grants from Theramex and Ferring, outside the submitted work. ML has acted as a consultant for Roche, Lilly, AstraZeneca, Exact Sciences, and Novartis; and has received honoraria from Sandoz, Roche, Lilly, Pfizer, Novartis, Ipsen, and Takeda, outside the submitted work. The remaining authors have no conflicts of interest to declare., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The role of tumour infiltrating lymphocytes (TILs) as a biomarker in non-invasive breast cancer is unclear. This meta-analysis assessed the prognostic impact of TIL levels in patients with non-invasive breast cancer., Methods: Systematic literature search was performed to identify studies assessing local recurrence in patients with non-invasive breast cancer according to TIL levels (high vs. low). Subgroup analyses per local recurrence (invasive and non-invasive) were performed. Secondary objectives were the association between TIL levels and non-invasive breast cancer subtypes, age, grade and necrosis. Odds ratios (ORs) and 95% confidence intervals (CI) were extracted from each study and a pooled analysis was conducted with random-effect model., Results: Seven studies (N = 3437) were included in the present meta-analysis. High-TILs were associated with a higher likelihood of local recurrence (invasive or non-invasive, N = 2941; OR 2.05; 95%CI, 1.03-4.08; p = 0.042), although with a lower likelihood of invasive local recurrence (N = 1722; OR 0.69; 95%CI, 0.49-0.99; p = 0.042). High-TIL levels were associated with triple-negative (OR 3.84; 95%CI, 2.23-6.61; p < 0.001) and HER2-positive (OR 6.27; 95%CI, 4.93-7.97; p < 0.001) subtypes, high grade (OR 5.15; 95%CI, 3.69-7.19; p < 0.001) and necrosis (OR 3.09; 95%CI, 2.33-4.10; p < 0.001)., Conclusions: High-TIL levels were associated with more aggressive tumours, a higher likelihood of local recurrence (invasive or non-invasive) but a lower likelihood of invasive local recurrence in patients with non-invasive breast cancer., Competing Interests: Declaration of competing interest RC received speaker honoraria from Boehringer-Ingelheim, AstraZeneca, and Janssen; and travel grants from Pfizer and AstraZeneca, none related to the present work. EdA has received honoraria from Roche-Genentech, Libbs, Seattle Genetics, Novartis, Pierre Fabre; research grant from Roche-Genentech, Astra Zeneca, GSK/Novartis, Servier (to the institution), and travel grants from Roche-Genentech and GlaxoSmithKline, none related to the present work. All other authors declare no disclosures related to the present work. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Preclinical and retrospective studies suggest that beta-blockers are active against breast cancer. We carried out a systematic review and meta-analysis to assess the impact of beta-blockers on the outcomes of patients with early-stage breast cancer., Methods: A systematic literature search was performed to identify studies comparing outcomes of patients with early-stage breast cancer according to beta-blocker use (yes versus no). The primary endpoint was recurrence-free survival (RFS), defined as the occurrence of breast cancer recurrence or death. Secondary objectives were pathologic complete response (pCR), breast cancer recurrence, breast cancer-specific mortality and overall survival (OS). Hazard ratios (HRs) or odds ratios (ORs) and 95% confidence intervals (CIs) were extracted from each study and a pooled analysis with the random-effect model was conducted. The Higgins' I-squared test was used to quantify heterogeneity. Egger's test was applied to assess publication bias. All P values were two-sided and considered significant if ≤0.05., Results: Overall, 13 studies were included as follows: RFS (6), pCR (2), breast cancer recurrence (6), breast cancer-specific mortality (7) and OS (5). The use of beta-blockers was associated with a significant RFS improvement in the overall population (N = 21 570; HR 0.73; 95% CI, 0.56-0.96; P = 0.025) and in patients with triple-negative disease (N = 1212; HR 0.53; 95% CI, 0.35-0.81; P = 0.003). No significant differences in terms of pCR (N = 1554; OR 0.77; 95% CI, 0.44-1.36; P = 0.371), breast cancer recurrence (N = 37 957; OR 0.66; 95% CI, 0.42-1.03; P = 0.065), breast cancer-specific mortality (N = 64 830; HR 0.77; 95% CI, 0.56-1.08; P = 0.130) or OS (N = 103 065; HR 1.03; 95% CI, 0.87-1.23; P = 0.692) were observed according to beta-blocker use., Discussion: In this meta-analysis, beta-blocker use was associated with a longer RFS in patients with early-stage breast cancer, with a more pronounced effect observed in those with triple-negative disease. Beta-blockers arise as an interesting option to be explored in prospective studies for patients with early-stage breast cancer., Competing Interests: Disclosure RC has received speaker honoraria from Boehringer Ingelheim, Astra Zeneca and Janssen, and travel grants from AstraZeneca and Pfizer, none related to the present work. EdA has received honoraria from Roche-Genentech, Libbs, Seattle Genetics, Novartis, Pierre Fabre; research grant from Roche-Genentech, AstraZeneca, GlaxoSmithKline/Novartis, Servier (to the institution), and travel grants from Roche-Genentech and GlaxoSmithKline, none related to the present work. All the other authors declare no conflicts of interest., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The combination of cyclin-dependent kinases 4/6 inhibitors (CDK4/6is) and endocrine therapy (ET) is standard of care for patients with hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer (BC). However, studies evaluating adjuvant CDK4/6is provided contradictory results thus far., Materials and Methods: We conducted a systematic review and meta-analysis to assess if the addition of CDK4/6is to adjuvant ET impacts on survival's outcomes and safety of patients with HR+/HER2- early BC (EBC). This study was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines and was registered in the PROSPERO database (ID: CRD42020218597). A systematic review of PubMed, Cochrane and EMBASE databases and major conference proceedings was performed up to 15 December 2020. All randomized controlled trials including patients with HR+/HER2- EBC treated with CDK4/6is plus ET versus ET alone in the adjuvant setting were included. Pooled hazard ratios (HRs) and odds ratios (ORs) for survival and safety outcomes, respectively, were calculated with 95% confidence intervals (95% CIs) using random effect models., Results: With data available from three studies (N = 12 647), the addition of CDK4/6is to adjuvant ET showed a trend for a benefit in terms of invasive disease-free survival (IDFS; HR 0.85, 95% CI 0.71-1.01; P = 0.071). No significant improvement in distant relapse-free survival was observed (HR 0.83, 95% CI 0.58-1.19; P = 0.311). The risk of all-grade toxicities and early treatment discontinuation increased significantly with the addition of CDK4/6is to ET (OR 9.36, 95% CI 3.46-25.33, P < 0.001, and OR 22.11, 95% CI 9.45-51.69, P < 0.001, respectively)., Conclusion: The administration of adjuvant CDK4/6is to patients with HR+/HER2- EBC showed a trend for an IDFS benefit and an increase in the risk of toxicities and treatment discontinuation. The role of adjuvant CDK4/6is remains controversial and a longer follow-up of these randomized controlled trials is needed before supporting a straightforward change in clinical practice., Competing Interests: Disclosure RC received speaker honoraria from Boehringer Ingelheim, AstraZeneca and Janssen; and travel grants from AstraZeneca and Pfizer (outside the submitted work). ML acted as a consultant for Roche, AstraZeneca, Lilly and Novartis; and received honoraria from Sandoz, Takeda, Roche, Lilly, Pfizer and Novartis (outside the submitted work). NP acted as a consultant for Lilly; and has received honoraria from Roche, Lilly, Novartis and AstraZeneca (outside the submitted work). EdA has received honoraria and serves on the advisory board of Roche/GNE, Novartis, Seattle Genetics, Zodiacs, Libbs and Pierre Fabre; has received travel grants from Roche/GNE, GSK/Novartis; and has also received research grant for his institute from Roche/GNE, Astra-Zeneca, Novartis and Servier (outside the submitted work). All other authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

In Argentina, Shiga toxin producing Escherichia coli (STEC) serogroups O157, O26, O103, O111, O145 and O121 are adulterant in ground beef. In other countries, the zero-tolerance approach to all STEC is implemented for chilled beef. Argentinean abattoirs are interested in implementing effective interventions against STEC on carcasses. Pre-rigor beef carcasses were used to determine whether nine antimicrobial strategies effectively reduced aerobic plate, coliform and E. coli counts and stx and eae gene prevalence. These strategies were: citric acid (2%; automated), acetic acid (2%; manual and automated), lactic acid (LA 2%; manual and automated), LA (3%; automated), electrolytically-generated hypochlorous acid (400 ppm; manual), hot water (82 °C; automated) and INSPEXX (0.2%; automated). Automated application of 2% LA after 30-60-min aeration and 3% LA at 55 °C were the most effective interventions. Automated application was more effective than manual application. Decontamination of beef carcasses through automated application of lactic acid and hot water would reduce public health risks associated with STEC contamination., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: The role of platinum-based neoadjuvant chemotherapy in triple-negative breast cancer (TNBC) patients is highly controversial and it is not endorsed by current guidelines. Our meta-analysis aimed to better elucidate its activity, efficacy and safety., Material and Methods: A systematic search of Medline, Web of Science and conferences proceedings up to 30 October 2017 was carried out to identify randomized controlled trials (RCTs) investigating platinum-based versus platinum-free neoadjuvant chemotherapy in TNBC patients. Using the fixed and random effects models, pooled odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (CI) were calculated for pathological complete response (pCR, defined as ypT0/is pN0), event-free survival (EFS), overall survival (OS) and grade 3 and 4 adverse events (AEs: neutropenia, anemia, thrombocytopenia and neuropathy)., Results: Nine RCTs (N = 2109) were included. Overall, platinum-based neoadjuvant chemotherapy significantly increased pCR rate from 37.0% to 52.1% (OR 1.96, 95% CI 1.46-2.62, P < 0.001). Platinum-based neoadjuvant chemotherapy remained significantly associated with increased pCR rate also after restricting the analysis to the three RCTs (N = 611) that used the same standard regimen in both groups of weekly paclitaxel (with or without carboplatin) followed by anthracycline and cyclophosphamide (OR 2.53, 95% CI 1.37-4.66, P = 0.003). Conversely, among the 96 BRCA-mutated patients included in two RCTs, the addition of carboplatin was not associated with significantly increased pCR rate (OR 1.17, 95% CI 0.51-2.67, P = 0.711). Two RCTs (N = 748) reported survival outcomes: no significant difference in EFS (HR 0.72, 95% CI 0.49-1.06, P = 0.094) and OS (HR 0.86, 95% CI 0.46-1.63, P = 0.651) was observed. A significant higher risk of grade 3 and 4 hematological AEs, with no increased risk of grade 3 and 4 neuropathy was observed with platinum-based neoadjuvant chemotherapy., Conclusion: In TNBC patients, platinum-based neoadjuvant chemotherapy is associated with significantly increased pCR rates at the cost of worse hematological toxicities. Platinum-based neoadjuvant chemotherapy may be considered an option in TNBC patients., Prospero Registration Number: CRD42018080042.

Single-agent poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) have been approved as the first targeted therapy available for patients with BRCA -mutated HER2-negative metastatic breast cancer. This meta-analysis aimed to better evaluate activity, efficacy and safety of single-agent PARPi in this population. A systematic search of Medline, Embase and conference proceedings up to 31 January 2018 was conducted to identify randomised controlled trials (RCTs) investigating single-agent PARPi versus monochemotherapy in patients with BRCA -mutated HER2-negative metastatic breast cancer. Using the random-effect model, we calculated summary risk estimates (pooled HR and OR with 95% CI) for progression-free survival (PFS), overall survival (OS), objective response rate (ORR), any grade and grade 3-4 adverse events (AEs), treatment discontinuation rate and time to deterioration in quality of life (QoL). Two RCTs (n=733) were included. As compared with monochemotherapy, single-agent PARPi significantly improved PFS (HR 0.56(95% CI 0.45 to 0.70)) and ORR (OR 4.15 (95% CI 2.82 to 6.10)), with no difference in OS (HR 0.82 (95% CI 0.64 to 1.05)). Single-agent PARPi significantly increased risk of anaemia and any grade headache, but reduced risk of neutropenia and any grade palmar-plantar erythrodysesthesia syndrome as compared with monochemotherapy. No significant differences in other AEs and treatment discontinuation rate were observed. Patients treated with PARPi experienced a significant delayed time to QoL deterioration (HR 0.40 (95% CI 0.29 to 0.54)). Single-agent PARPi showed to be an effective, well tolerated and useful treatment in maintaining QoL of patients with BRCA -mutated HER2-negative metastatic breast cancer., Competing Interests: Competing interests: LDM received personal fees from Novartis Pharma AG, Roche-Genentech, Ipsen, Astrazeneca, Takeda, Eli Lilly outside the submitted work. EdA received honoraria from Roche-Genentech, research grant from Roche-Genentech (to the institution) and travel grants from Roche-Genentech and GlaxoSmithKline outside the submitted work. ML served as a consultant for Teva outside the submitted work.

Background: Combining targeted agents and endocrine therapy (ET) improves outcomes in hormone receptor-positive metastatic breast cancer patients but increases the risk of adverse events (AEs). This meta-analysis aims to estimate the comparative risk of AEs with ET in addition to targeted agents in this setting., Methods: A systematic literature search of MEDLINE, EMBASE, Cochrane Library and conference proceedings up to July 17th 2017 was conducted to identify randomized controlled trials investigating ET with or without CDK4/6, mTOR, PI3K inhibitors and anti-HER2 agents. We calculated summary risk estimates (odds ratio, OR) and 95% confidence intervals (CI) for each AE within each class of targeted agents for each trial, and pooled analysis using the random and fixed effect models., Results: Sixteen studies (n=8529 patients) were included. The addition of targeted agents to ET was associated with a significant higher risk of grade 3-4 AEs: OR 2.86 (95% CI 2.49-3.27) for CDK4/6 inhibitors, 1.88 (95% CI 1.39-2.53) for mTOR inhibitors, 2.05 (95% CI 1.63-2.58) for PI3K inhibitors, and 2.48 (95% CI 1.09-5.66) for anti-HER2 agents. The highest class-specific risks were neutropenia grade 3-4 for CDK4/6 inhibitors (OR 40.77; 95% CI 19.52-85.19), stomatitis grade 3-4 for mTOR inhibitors (OR 11.92; 95% CI 3.68-38.57), hyperglycemia grade 3-4 for PI3K inhibitors (OR 40.93; 95% CI 10.08-166.22) and diarrhea for anti-HER2 agents (OR 9.93; 95% CI 4.71-20.95)., Conclusions: Adding targeted agents to ET is associated with a significant increased risk of AEs. The risk of developing different AEs varies largely according to the type of agent used., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Worldwide, lung cancer is the leading cause of cancer death. DNA adducts are considered a reliable biomarker that reflects carcinogen exposure to tobacco smoke, but the central question is what is the relationship of DNA adducts and cancer? Therefore, we investigated this relationship by a meta-analysis of twenty-two studies with bronchial adducts for a total of 1091 subjects, 887 lung cancer cases and 204 apparently healthy individuals with no evidence of lung cancer. Our study shows that these adducts are significantly associated to increase lung cancer risk. The value of Mean Ratio lung-cancer (MR) of bronchial adducts resulting from the random effects model was 2.64, 95% C.I. 2.00-3.50, in overall lung cancer cases as compared to controls. The significant difference, with lung cancer patients having significant higher levels of bronchial adducts than controls, persisted after stratification for smoking habits. The MR lung-cancer value between lung cancer patients and controls for smokers was 2.03, 95% C.I. 1.42-2.91, for ex-smokers 3.27, 95% C.I. 1.49-7.18, and for non-smokers was 3.81, 95% C.I. 1.85-7.85. Next, we found that the generation of bronchial adducts is significantly related to inhalation exposure to tobacco smoke carcinogens confirming its association with volatile carcinogens. The MR smoking estimate of bronchial adducts resulting from meta-regression was 2.28, 95% Confidence Interval (C.I.) 1.10-4.73, in overall smokers in respect to non-smokers. The present work provides strengthening of the hypothesis that bronchial adducts are not simply relate to exposure, but are a cause of chemical-induced lung cancer., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The present study tested the hypothesis that a pan-allergen sensitization may affect the sensitization pattern. For this reason, 22 sensitization pattern allergens (SPA), common in Genoa (Italy), were selected for analyses. Successively, five of them, such as Pru p 3 as representative for LTP family, Bet v 1 and Pru p 1 for PR-10, and Bet v 2 and Pru p 4 for Profilin, were used as target allergens (TA). This retrospective study included 1059 subjects, (396 males and 663 females, mean age 42.8 years). The current study showed that sensitization to a pan-allergen entails higher odds to have other sensitizations. In addition, the co-sensitization pattern depends on the basis of the sensitizing pan-allergen family. LTP-sensitization is strongly associated with peanut sensitization, PR10 and profiling sensitization with hazelnut positivity. This study shows that a pan-allergen sensitization is frequently associated with co-sensitizations and the sensitization pattern depends on the sensitizing pan-allergen., (Copyright © 2017 Elsevier GmbH. All rights reserved.)

Purpose: Patients with pre-existing cervical spinal canal stenosis (CSCS) may have minimal or no symptoms. However, performing preventive decompression is controversial as the incidence of CSCS leading to severe cord injury is unknown. Hence, this study aims to revisit the threshold for surgery in "silent" CSCS by reviewing the neurologic outcomes of patients with undiagnosed CSCS who sustained a cervical spinal cord injury (CSCI)., Methods: Two groups of subjects were recruited for analysis. Firstly, patients with trauma-induced CSCI without fracture or dislocation were included. Pre-existing CSCS was diagnosed by MRI measurements. The second group consisted of asymptomatic subjects recruited from the general population who also had MRIs performed. Canal sizes were compared between this control group and the patient group. Within the patient group, neurological assessments and outcomes by Frankel classification were performed in patients treated surgically or conservatively., Results: 32 patients with CSCS were recruited. The mean spinal canal sagittal diameter (disc-level) of all CSCS cases was 5.3 ± 1.4 mm (1.3-8.2). In comparison, the diameter was 10.5 ± 1.7 mm (6.6-14.6) in the 47 asymptomatic individuals recruited from the general population. Decompression was performed in 17 patients and conservative treatment in 15. Mean follow-up was 19.3 ± 17.0 months (6-84). At the final follow-up, 3 patients (9.3%) returned to their pre-injury Frankel grade, whereas 26 patients (83.3%) lost one or more neurological grade. Three patients (9.3%) died., Conclusions: Majority of patients with "silent" CSCS who sustained cervical cord injuries did not return to their pre-injury neurological status. All of these subjects have pre-existing canal stenosis hence the risk of cord injury. Given the poor neurological outcome of CSCS, a lower threshold for surgery could be indicated to avoid these disastrous injuries. However, before making any conclusive recommendation we must first identify the prevalence of "silent" CSCS in the general population and the risk of developing spinal cord injury with more prospective population-based studies., (Copyright © 2016 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

The aim of this study was to assess whether surgery delay and other variables are associated with an increased mortality rate after surgical treatment of hip fractures in the elderly. Patients treated for a proximal femoral fracture at our Orthopaedic Department between 2005 and 2012 were included in this study. A logistic regression was performed to evaluate the relationship between mortality rate at different follow-up times (30 days, six months and one year) and different patient or treatment variables. A total of 1448 consecutive patients with 1558 proximal femoral fractures (55 bilateral) were enrolled in this study (mean age 80.3 years, 75.8% female). The postoperative mortality rate was 4% at 30 days, 14.1% at six months, and 18.8% at one year after surgery. Logistic regression revealed an increased mortality at all the endpoints in patients affected by more than two co-morbidities (respectively OR 30-day =2.003, OR 6-month =1.8654 and OR 1-year =1.5965). Male sex was associated with an increased six-month (OR=1.7158) and one-year (OR=1.9362) mortality. Patients aged under 74 years had a decreased mortality at all endpoints (OR 30-day =0.0703, OR 6-month =0.2191 and OR1-year=0.2486). In this study, the surgery delay influenced mortality at one-year follow-up: operating within 48hours was associated with a decreased mortality rate (OR=0.7341; p=0.0392). Additionally, the patients who were operated on within 72hours were specifically analysed to understand if the option of 'operating within day 3' was acceptable. In the logistic regression, operating between 48 and 72hours was not reported as a risk factor for mortality, both compared to early surgery (within 48 hours) and to late surgery (after 72hours). This study showed that age, sex and number of co-morbidities influenced both early and late mortality in patients affected by proximal hip fractures. Early surgery influenced late mortality, with a decreased risk in patients operated on within 48hours. The option of operating within day 3 is not a valid alternative., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Decreased muscle damage is reported as an advantage of minimally invasive surgical (MIS) approaches in total knee arthroplasty (TKA). The purpose of this study was to evaluate the anatomy of vastus medialis obliquus (VMO) tendon at its patellar insertion as well as to determine the amount and location of muscle damage comparing traditional subvastus approach and optimized subvastus approach. TKAs were performed in ten human cadavers (20 knees). In each specimen, one knee underwent the traditional subvastus approach and the contralateral knee the optimized subvastus approach. The risk of tearing and damaging the VMO muscle during the traditional subvastus approach is significantly higher (70% of the cases) compared to the optimized technique (30%). The amount of damage to the VMO muscle using the traditional subvastus approach was: 80% of the muscle's width in two cases, 60% in three cases, and 30% in two. The damage created by the optimized subvastus approach occurred along the edge of the tendon and the first fibers of the VMO muscle close to the muscle-tendon junction (less than 20% of muscle's width). Clinical studies are needed to determine the functional implications of these findings., (Copyright © 2010 Elsevier B.V. All rights reserved.)

CNF1, a toxin produced by pathogenic Escherichia coli strains, deamidates the RhoA GTP-binding protein glutamine 63 and impairs RhoGAP-mediated GTP hydrolysis resulting in RhoA permanent activation. Using peptides derived from the RhoA sequence, we found that DTAGQEDYDRL (corresponding to RhoA 59-69 residues) was the minimum RhoA-derived peptide which could be deamidated in vitro by the CNF1 catalytic domain (CNF1-Cter). Site-directed mutagenesis outside the RhoA 59-69 sequence had no influence on glutamine 63 deamidation by CNF1-Cter. RhoA proteins with substitutions L57G, D65G, Y66G, or R70G were not affected in their ability to be deamidated by CNF1-Cter, whereas this was abolished by the R68G substitution. Arginine 68 is part of the DYDRL motif that is strictly conserved in Rho, Rac, and Cdc42 but not in other small GTP-binding proteins consistent with the observation that only Rho, Rac, and Cdc42 can be modified by CNF1., (Copyright 2000 Academic Press.)

Renal ammonia production and distribution and ammonia precursor utilization were evaluated in eight patients with chronic potassium depletion (CPD) and aldosterone-producing adenoma and in 20 controls. In CPD, urinary ammonia excretion and ammonia added to renal venous blood were about twofold higher than in controls; thus, total ammonia production was significantly augmented (88.0 +/- 10.3 mumol/min.1.73 m2 vs. 45.0 +/- 2.6 in controls). Total ammonia production was inversely correlated with serum potassium and directly correlated with urine flow. Stepwise multiple regression analysis showed that both factors, mainly serum potassium, significantly influence ammonia production and account for 61.4% of variations in ammonia production. Renal extraction of glutamine was significantly increased (56.6 +/- 5.9 mumol/min.1.73 m2 vs. 34.6 +/- 3.1 in controls), and this could account for ammonia production. The ratio of urinary ammonia excretion to total ammonia production, an index of the intrarenal ammonia distribution, was similar in patients and controls, and was significantly correlated with urine pH and true renal blood flow (RBF). Stepwise multiple regression analysis showed that RBF, urine pH and urine flow also significantly affected ammonia distribution. However, these factors accounted for only 41.7% of variations in intrarenal ammonia partition, urine pH having a minor role. We conclude that in patients with CPD other factors besides urine pH, urine flow and RBF intervene in the ammonia partition between urine and blood.

Epidemiologic studies of the incidence of emesis induced by narcotic analgesics are lacking. The histories of 260 cancer patients receiving oral narcotic analgesics prescribed at the Pain Clinic of our Institute from December 1988 to December 1989 were reviewed. Of the 260 patients, 120 were women, median age 61 (range 30-90) yr and 140 were men, median age 62 (range 30-82) yr. Nausea and vomiting associated with assumption of the various narcotics were buprenorphine 8.3% and 22.7%, morphine 18.3% and 28%, codeine 16.2% and 29.7%, and oxycodone 10% and 40%, respectively. Since the use of narcotic analgesics can effectively relieve pain and improve quality of life in cancer patients, it is important to be aware of the incidence of narcotic-induced emesis in order to use appropriate prophylactic antiemetic therapy.