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The aim of this work was to evaluate the influence of the ripening stage on three fresh-cut fruit (apple, kiwifruit and melon) in terms of quality and tissue metabolism, during accelerated storage (AS) in controlled conditions. For this purpose, two different ripening stages were selected for each fruit. At each ripening stage the fruits were peeled and cut into 10 mm thick slices and stored at 10°C, RH 90%, for 24 hour for apples and 4 days for kiwifruit and melon. During storage, samples were monitored for the main quality indexes and the activity of the main degradative enzymes (polyphenoloxidase, peroxidase and pectinesterase). Production of the endogenous metabolic heat was also monitored using isothermal calorimetry. Results showed that, whether for melon and kiwifruit marked differences were found in the evolution of the parameters considered during storage and in relation to their ripening degree, apple quality and metabolic characteristics proved to be less affected by the ripening degree during storage.

The goal of the study was to determine the effect of thermal treatment and 6-months storage on antioxidant activity and chemical composition of heat-stable apple fillings. The aim was fully accomplished by analyzing apple fillings prepared in laboratory conditions under atmospheric pressure from aseptic apple puree (45 %) in a wide range of soluble solids and with different amounts of inulin and pectin according to the planned 2k factorial design with added central point. A correlation between antioxidant capacity evaluated by 2.2-diphenyl-1-picrylhydrazil radical (DPPH٠) assay and other chemical parameters of apple fillings such as water activity, pH, total polyphenols, 5-hydroxymethylfurfural content and non-enzymatic browning index were reported in the study. Antioxidant activity and the total polyphenols were directly correlated with each other (p

The aim of this work was to evaluate the influence of the ripening stage on fresh-cut kiwifruit tissues in terms of quality and tissue metabolism, during accelerated storage (AS) in controlled conditions. For this purpose three different ripening stages were selected, corresponding to about 11, 13 and 15 °Brix. For each ripening stage the fruits were peeled and cut into 1 cm thick slices and stored in climatic chambers at 10 °C, 90% RH, for 3 days. During storage, quality indices as soluble solid contents, titrable acidity, colour and texture were monitored. Metabolic assessment was carried out evaluating the endogenous metabolic heat using isothermal calorimetry, and monitoring O2 consumption and CO2 production simultaneously. Differences were found in the evolution of the quality indexes during storage; in particular kiwifruit at the lowest ripening stage showed the slowest quality degradation, both in terms of softening and visual quality modifications. Metabolic heat production results were different at the different ripening levels investigated, evidencing a strict connection between the physiological state of the tissue and the entity of its wounding response.

Nonthermal techniques for fruit processing can be a good alternative to heat required methods, in order to produce minimally processed fruit and vegetables. This work presents the state of the art of some applications of osmotic dehydration (OD), vacuum impregnation (VI) and ultrasound (US) treatments on minimally processed apple and kiwifruit, in order to show the potentiality of these techniques to preserve their quality and stability. The application of OD process resulted in several positive effect on kiwifruit overall quality and stability. Despite the texture improvement and the color maintenance, a decrease of water mobility and availability was observed. The application of US promoted the further improvement of water/solutes exchange with the modification of kiwifruit structure. VI instead was applied on apple tissue promoting a considerable weight gain and density changes. The microscopic assessment showed the solutes up-take inside the cells by cell membrane vesiculation.

Two contiguous villages in Tracunhaém county (State of Pernambuco), endemic for schistosomiasis, were studied: Itapinassu (138 inhabitants) and São Joaquim (91 inhabitants). Agriculture predominates in the former region while ceramics is the main activity in the latter. Although no statistical difference was found regarding prevalence, severe infection (>400 epg) predominated in Itapinassu, probably related to the kind of occupation. No association was found between parasite burden and severity of disease, in spite of the high infection rates for Schistosoma mansoni in both communities (approx. 60%). Typical epidemiological features of schistosomiasis such as age-related prevalences and intensities of infection (high in children, low in adults) were also mutual characteristics. Nutritional status determined through anthropometric evaluation was carried out by measuring specific anthropometric indicators. A deficit of energy intake, as well as vitamin A and riboflavin deficiencies were detected. The prevalence of moderate or severe undernutrition in patients under 18 years old was 21.9% in Itapinassu and 24.1% in São Joaquim. In this group an association was found between prevalence of schistosomiasis and chronic undernutrition. Similarly, for patients over 18 year old the prevalence of undernutrition was higher than 20%. However, in this case no association between nutritional status and either prevalence of schistosomiasis or parasite burden could be detected. The two communities had not been treated for eight years.

Trastuzumab deruxtecan (T-DXd) intracranial activity has been observed in small or retrospective patient cohorts with human epidermal growth factor receptor 2-positive (HER2 + ) advanced/metastatic breast cancer (mBC) and stable or active (untreated/previously treated and progressing) brain metastases (BMs). The phase 3b/4 DESTINY-Breast12 study investigated T-DXd in patients with HER2 + mBC and is, to our knowledge, the largest prospective study of T-DXd in patients with BMs in this setting. Patients (stable/active BMs (n = 263) and no BMs (n = 241)) treated with one or more prior anti-HER2-based regimens received T-DXd (5.4 mg per kg). Primary endpoints were progression-free survival (PFS; BMs cohort) and objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (non-BMs cohort). Additional endpoints included central nervous system (CNS) PFS, ORR, time to second progression, CNS ORR (BMs cohort), incidence of new symptomatic CNS metastases (non-BMs cohort), time to progression, duration of response, overall survival and safety (both cohorts). No formal hypothesis testing was conducted for this single-arm, open-label study. In the BMs cohort, 12-month PFS was 61.6% (95% confidence interval (CI): 54.9-67.6), and 12-month CNS PFS was 58.9% (95% CI: 51.9-65.3). In the non-BMs cohort, ORR was 62.7% (95% CI: 56.5-68.8). Grade 3 or higher adverse events occurred in 51% (BMs cohort) and 49% (non-BMs cohort) of patients. Investigator-reported interstitial lung disease/pneumonitis occurred in 16% (grade ≥3: 3%) of patients with BMs and 13% (grade ≥3: 1%) of patients without BMs. These data show substantial and durable overall and intracranial activity for T-DXd, supporting its use in previously treated patients with HER2 + mBC irrespective of stable/active baseline BMs. ClinicalTrials.gov identifier: NCT04739761 ., Competing Interests: Competing interests: N.H. has received lecture honoraria from Art Tempi, AstraZeneca, Daiichi Sankyo, Eli Lilly, Gilead Sciences, Medscape, Merck Sharp & Dohme, Novartis, Onkowissen, Pierre Fabre, Roche, Sanofi, Seagen, Viatris and Zuellig Pharma; has received consulting or advisory honoraria from Aptitude Health, Gileadn Sciences, Pfizer, Sandox-Hexal, Sanofi and Seagen; has received research funding from AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Gilead Sciences, Merck Sharp & Dohme, Roche, Seagen, TRIO and WSG; has participated on independent data monitoring committees/steering committees for Eli Lilly, Pierre Fabre and Roche; and has ownership interest in the West German Study Group. E.C. has received lecture, consulting or advisory honoraria from AstraZeneca, Daiichi Sankyo, Eli lilly, Gilead Sciences, Menarini, Merck Sharp & Dohme, Novartis, Pfizer, Reveal Genomics and Roche; has received support for attending meetings and/or travel from AstraZeneca, Pfizer and Roche; has received research funding from Daiichi Sankyo, Pfizer and Roche; and has participated on steering committees for AstraZeneca, Daiichi Sankyo, Gilead Sciences, Novartis, Reveal Genomics and Roche. G.J. has received consulting honoraria from AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Diaccurate/Evexta Bio, Eli Lilly, Novartis, Pfizer, Roche and Seagen; has received honoraria from AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Novartis, Pfizer, Roche and Seagen; has received support for attending meetings and/or travel from Amgen, AstraZeneca, Bristol Myers Squibb, Eli Lilly, Gilead Sciences, Novartis, Pfizer and Roche; and has received medical writing support from Amgen, AstraZeneca, Bristol Myers Squibb, Eli Lilly, Novartis and Roche. V.M. has received lecture honoraria from AstraZeneca, Daiichi Sankyo, Eisai, Gilead Sciences, high5 Oncology, iMED Institut, Eli Lilly, Medac, Medscape, Merck Sharp & Dohme, Novartis, Onkowissen, Pfizer, Pierre Fabre, Roche and Seagen; has received consulting or advisory honoraria from ClinSol, Daiichi Sankyo, Eisai, Eli Lilly, Gilead Sciences, Menarini Stemline, Merck Sharp & Dohme, Novartis, Pierre Fabre, PINK, Roche and Menarini Stemline; and has received research funding from AstraZeneca, Genentech, Novartis, Roche and Seagen. N.N. has received consulting or advisory honoraria from AstraZeneca, Chugai Pharmaceutical and Daiichi Sankyo; has received lecture honoraria from AstraZeneca, Chugai Pharmaceutical, Eisai, Daiichi Sankyo, Eli Lilly Japan, Nippon Kayaku and Pfizer Japan; and has received research funding from Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly Japan, Nippon Kayaku and Pfizer Japan. G.V. has received research grants from Dako/Agilent Technologies, Roche/Genentech and Ventana Medical Systems and has received honoraria from AstraZeneca, Daiichi Sankyo, Dako/Agilent Technologies, Gilead Sciences, Merck Sharp & Dohme Oncology, Pfizer, Roche and Ventana Medical Systems. R.B. has held advisory roles at AstraZeneca, Daiichi Sankyo, Eisai, Eli Lilly, Gilead Sciences, Grünenthal, Merck Sharp & Dohme, Novartis, Pfizer, Pierre Fabre, Roche, Seagen and Menarini Stemline; has received lecture honoraria from AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Eli Lilly, Gilead Sciences, Grünenthal, Menarini Stemline, Merck Sharp & Dohme, Novartis, Pfizer, Pierre Fabre, Roche and Seagen; and has received research support from Daiichi Sankyo, Merck Sharp & Dohme, Novartis and Roche. C.K. has received lecture honoraria from AstraZeneca, Eli Lilly, Genomic Health/Exact Sciences, Gilead Sciences, GlaxoSmithKline, Novartis, PharmaMar, Pfizer and Roche; has received consulting or advisory honoraria from AstraZeneca, Eli Lilly, Genomic Health/Exact Sciences, Gilead Sciences, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, PharmaMar and Roche; and has participated on steering committees for AstraZeneca. M.J.H. has received lecture honoraria from AstraZeneca. R.M.C. received an unrestricted educational grant from Pfizer; has received research support from AstraZeneca, Daiichi Sankyo, MSD Ireland and Pfizer; has received honoraria from AstraZeneca, Daiichi Sankyo, Eli Lilly, Gilead Sciences and Seagen; and has received support for attending meetings and/or travel from Gilead Sciences, Novartis and Roche. M.G. has received support for attending meetings and/or travel from AstraZeneca, Gilead Sciences, Roche and Pfizer and has received honoraria from AstraZeneca, Gilead Sciences and Pfizer. V.G. has received honoraria from AstraZeneca, Daiichi Sankyo, Eli Lilly, Exact Sciences, Gilead Sciences, Menarini Stemline, Merck Sharp & Dohme, Novartis, Pfizer, Olema Oncology, Pierre Fabre and Roche; has received lecture honoraria from AstraZeneca, Daiichi Sankyo, Eli Lilly, Exact Sciences, Gilead Sciences, GlaxoSmithKline, Menarini Stemline, Novartis, Roche and Zentiva; and has received expert testimony honoraria from Eli Lilly. G.B. has received honoraria from Agendia, Amgen, AstraZeneca, Chugai Pharmaceutical/Roche, Daiichi Sankyo, Eisai, Exact Sciences, Gilead Sciences, Helsinn Lilly, Menarini Stemline, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sanofi and Seagen and received a research grant from Gilead Sciences. H.W. has received lecture honoraria from Seagen; has received consulting or advisory honoraria from AstraZeneca, Augustine Therapeutics, Daiichi Sankyo, E Squared Communications, Eli Lilly, Gilead Sciences, Immutep, MediMix, Menarini Stemline, Novartis, NV Hict, Pfizer, PSI CRO and Roche; has received support for attending meetings and/or travel from Daiichi Sankyo and Pfizer; has received research funding from Novartis, Roche and Syneos Health; and has received subscription fees from Gilead Sciences. S.E.-d.-R. has received honoraria from AstraZeneca, COR2ED, Daiichi Sankyo, Jazz Pharmaceuticals, Medistream, Pierre Fabre, Roche and Seagen; has received research funding from AstraZeneca, Byondis, Daiichi Sankyo, Jazz Pharmaceuticals, MEDSIR, Roche, SOLTI and Zymeworks; and has received support for attending meetings and/or travel from AstraZeneca, Daiichi Sankyo, Kern Pharma, Pfizer, Seagen and SOLTI. M.P., H.B., N.K.-C., N.S. and S.V. are employees of AstraZeneca. N.K.-C. holds stocks in AstraZeneca and AbbVie. N.U.L. has received honoraria from AstraZeneca and has received research funding from AstraZeneca. The other authors declare no competing interests., (© 2024. The Author(s).)

The redirection of T lymphocytes against tumor-associated or tumor-specific antigens, using bispecific antibodies or chimeric antigen receptors (CAR), has shown therapeutic success against certain hematological malignancies. However, this strategy has not been effective against solid tumors. Here, we describe the development of CAR T cells targeting p95HER2, a tumor-specific antigen found in HER2-amplified solid tumors. These CAR T cells display robust activity against p95HER2-expressing cell lines but demonstrate limited efficacy against patient-derived xenografts. As p95HER2 is invariably detectable on tumor cells that overexpress HER2, but not those that express HER2 at normal levels, we arm p95HER2-specific CAR T cells with affinity-tuned bispecific antibodies against HER2 and CD3 in order to redirect them only to HER2-amplified cells. The combination of p95HER2.CAR T cells and HER2 x CD3 bispecific antibodies lead to a complete regression in three HER2-positive, patient-derived mouse xenografts tumor models. This combination represents a promising strategy to redirect T cells against a subset of HER2-positive tumors., Competing Interests: Competing interests J.A. has received research funds from Roche, Byondis, Menarini and Molecular Partners and consultancy honoraria from Menarini, Mnemo and ARKIN. J.A. is an inventor of patent applications EP22382294, EP20382457, EP16191933.7, EP0930183.5 and P200801652. M.R.A., I.R.R., C.K., E.M., are inventors of patent application EP20382457. M.R.A., S.D., A.G.E., I.R.R., V.N. are inventors of patent application EP22382294. C.K. declares employment, patents and stock ownership with Roche. E.M. declares employment with Roche. E.G. reports: research agreements with Novartis, Roche, Thermo Fisher, AstraZeneca, Taiho, BeiGene, Janssen; consultant/advisor at Roche, Ellipses Pharma, Boehringer Ingelheim, Janssen Global Services, Seattle Genetics, Thermo Fisher, MabDiscovery, Anaveon, F-Star Therapeutics, Hengrui, Sanofi, Incyte; and payment or honoraria for speakers’ bureaus from Merck Sharp & Dohme, Roche, Thermo Fisher, Lilly, Novartis, SeaGen. The remaining authors declare no competing interests., (© 2024. The Author(s).)

Climate change has increased interest in the effects of the thermal environment on cardiovascular health. Most studies have focused on mortality data. However, pre-hospital care data are better able to evaluate these effects, as they can register the full spectrum of the disease in real time. This scoping review aims to synthesize the epidemiological evidence regarding the effects of the thermal environment on cardiovascular morbidity in the pre-hospital setting, evaluated through ambulance calls. A staged literature search was performed using the PubMed database for the period between 1st January 2000 and 30th March 2023, using the MeSH terms "Weather" AND "Emergency Medical Services". A total of 987 publications were identified that examined the correlation between the thermal environment and ambulance call-outs for cardiovascular causes. The studies were mostly ecological time series, with significant variability in the methodological aspects employed. An increase in the number of ambulance call-outs has been observed in association with low temperatures, both for overall cardiovascular pathologies and for certain pathological subtypes. For high temperatures, no effect has been observed in overall call-outs, although an increase has been observed during heat waves. The demand for ambulances for cardiac arrests is increased by both low and high temperatures and during heat waves. Ambulance call-outs for cardiovascular causes increase with low temperatures and heat waves, with no significant increase in the overall demand associated with high temperatures. Ambulance call-outs for cardiac arrests are the only subtype that is increased by high temperatures., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Co-published by Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, and American Chemical Society.)

HER2-positive breast cancer is an aggressive disease. As a result of the development of specific HER2-targeted therapies, such as trastuzumab, more than 20 years ago, the prognosis of these patients has improved. Metastatic HER2-positive breast cancer patients are achieving better survival rates upon treatment with anti-HER2 therapies than patients with HER2-negative disease. Double HER2 blockade with trastuzumab and pertuzumab combined with a taxane achieved an unprecedented survival of over 57 months in first-line patients. Trastuzumab emtansine, the first antibody-drug conjugate approved for patients in second-line treatment was a potent cytotoxic agent bound to trastuzumab and is currently a standard therapeutic strategy. Despite the progress in treatment development, most patients develop resistance and eventually relapse. Advances in the design of antibody-drug conjugates have led to the development of new generation drugs with enhanced properties, such as trastuzumab deruxtecan and trastuzumab duocarmazine, which are significantly changing the paradigm in the treatment of HER2-positive metastatic breast cancer., Competing Interests: Escrivá-de-Romaní S: Consultant/speaker/travel grants: Roche, Daiichi Sankyo, Eisai, Pfizer, Pierre Fabre, Seagen, Astra Zeneca, Novartis, Kern. Institutional grants: Roche, Daiichi Sankyo, Zymeworks, Synthon, Solti, Medsir. Saura C: Consultant/speaker/travel grants: AstraZeneca, AX’Consulting, Byondis B.V., Daiichi Sankyo, Eisai, Exact Sciences, Exeter Pharma, F. Hoffmann - La Roche Ltd, ISSECAM, MediTech, Merck Sharp & Dohme, Novartis, Pfizer, Philips, Piere Fabre, PintPharma, Puma, Roche Farma, SeaGen, and Zymeworks. Institutional grants: Aragon Pharmaceuticals, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb (BMS), Cytomx therapeutics, Daiichi Sankyo, F. Hoffmann-la Roche, Genentech, German Breast Group, Glaxosmithkline, Innoup Farma, International Breast Cancer Study Group (IBCSG), Lilly, Macrogenics, Medica Scientia Innovation, Menarini, Merus, Millennium Pharmaceuticals, Novartis, Pfizer, Puma biotechnology, Queen Mary, University of London, Roche, Sanofi-Aventis, Seattle Genetics, Solti and The Netherlands Cancer Institute-Antoni van Leeuwenhoek Ziekenhuis., (© The Author(s) 2023.)

Introduction: Trastuzumab emtansine (T-DM1) significantly improves invasive disease-free survival and reduces the risk of recurrence in patients with HER2-positive early breast cancer (EBC) with residual disease (RD). The KARMA study aimed to describe the characteristics and management of these patients in clinical practice in Spain., Material and Methods: We conducted a multicentre retrospective study in patients with HER2-positive EBC with RD following neoadjuvant treatment (NeoT) and who had received ≥1 dose of T-DM1 as adjuvant treatment. The primary endpoint was the evaluation of sociodemographic and clinicopathological characteristics of these patients., Results: A total of 114 patients were included (March-July 2020). At diagnosis, most tumours were infiltrating ductal carcinoma (IDC) (93.9 %), grade 2 (56.1 %), and hormone receptor (HR)-positive (79.8 %). Over 75 % of patients had disease in operable clinical stages (T1-3 N0-1). In the neoadjuvant setting, 86.8 % of patients received trastuzumab plus pertuzumab, and 23.6 % achieved radiological complete response. Breast-conserving surgery was performed in 55.8 % of patients. Surgical specimens showed that 89.5 % of patients had IDC, 49.1 % grade 2, 84.1 % HR-positive, and 8.3 % HER2-negative disease. Most patients had RD classified as RCB-II and Miller/Payne grade 3/4. Grade 3 treatment-related adverse events (trAEs) occurred in 5.3 % of patients. No grade 4/5 AEs occurred. Over 95 % of patients were free of invasive-disease during T-DM1 adjuvant treatment., Conclusion: The KARMA study describes the characteristics of patients with HER2-positive EBC with RD after NeoT and the real-life management of a T-DM1 adjuvant regimen, which showed a manageable safety profile in line with the KATHERINE trial data., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Silvia Antolín Novoa declares consulting fees from Roche, Daiichi Sankyo, Pierre Fabre, and Lilly; and fees for non-continuing medical education (CME) services received directly from commercial interest or their agents from Roche, Pierre Fabre, and Pfizer. Santiago Escrivá de Romaní Muñoz declares consulting fees from F. Hoffmann-La Roche Ltd, Pierre-Fabre, AstraZeneca/Daiichi-Sankyo, and Seagen; fees for non-CME services received directly from commercial interest from F. Hoffmann-La Roche Ltd, Pierre-Fabre, Novartis, AstraZeneca/Daiichi-Sankyo, and Seagen; and contracted research (for the institution) from F. Hoffmann-La Roche Ltd, AstraZeneca/Daiichi-Sankyo, Byondys, Zymeworks, MedSir, and Solti. Pablo Tolosa Ortega declares consulting fees from AstraZeneca, Daiichi-Sankyo, Novartis, and Seagen; and fees for non-CME services received directly from commercial interest from Pfizer, Novartis, Lilly, AstraZeneca, Daiichi-Sankyo, and Seagen. Rafael López López has received honoraria for participation in Advisory Boards from Roche, AstraZeneca, Merck, MSD, Bayer, BMS, Novartis, Janssen, Lilly, Pfizer, and Leo; travel, accommodations, and expenses from Pharmamar, Roche, BMS, and Pierre Fabre; research funding from Roche and Merck; and is co-founder and shareholder in Nasasbiotech, Diversa Technologies. Ana López González has received consulting fees from Pfizer, Lilly, and Seagen; and non-CME services directly from commercial interest from Pfizer, Novartis, Lilly, and Roche. Pilar de la Morena Barrio declares expert testimony fees from Roche and GSK and honoraria from GSK. Isabel Echavarria Díaz-Guardamino has received fees from Lilly and Astra Zeneca; and fees for non-CME services received directly from commercial interest or their agents from Roche, Pierre Fabre, Novartis, Lilly, and Pfizer. Lucia González-Cortijo declares consulting fees from MSD and GSK; and fees for non-CME services received directly from Roche, MSD, GSK, and Gilead. Lucía Oliva Fernández and José Enrique Alés Martinez declare no conflicts of interest. Zita Garate is a Roche Pharma employee., (Copyright © 2023. Published by Elsevier Ltd.)

Antibody-drug conjugates (ADC) are antineoplastic agents recently introduced into the antitumor arsenal. T-DM1, a trastuzumab-based ADC that relies on lysosomal processing to release the payload, is approved for HER2-positive breast cancer. Next-generation ADCs targeting HER2, such as [vic-]trastuzumab duocarmazine (SYD985), bear linkers cleavable by lysosomal proteases and membrane-permeable drugs, mediating a bystander effect by which neighboring antigen-negative cells are eliminated. Many antitumor therapies, like DNA-damaging agents or CDK4/6 inhibitors, can induce senescence, a cellular state characterized by stable cell-cycle arrest. Another hallmark of cellular senescence is the enlargement of the lysosomal compartment. Given the relevance of the lysosome to the mechanism of action of ADCs, we hypothesized that therapies that induce senescence would potentiate the efficacy of HER2-targeting ADCs. Treatment with the DNA-damaging agent doxorubicin and CDK4/6 inhibitor induced lysosomal enlargement and senescence in several breast cancer cell lines. While senescence-inducing drugs did not increase the cytotoxic effect of ADCs on target cells, the bystander effect was enhanced when HER2-negative cells were cocultured with HER2-low cells. Knockdown experiments demonstrated the importance of cathepsin B in the enhanced bystander effect, suggesting that cathepsin B mediates linker cleavage. In breast cancer patient-derived xenografts, a combination treatment of CDK4/6 inhibitor and SYD985 showed improved antitumor effects over either treatment alone. These data support the strategy of combining next-generation ADCs targeting HER2 with senescence-inducing therapies for tumors with heterogenous and low HER2 expression., Significance: Combining ADCs against HER2-positive breast cancers with therapies that induce cellular senescence may improve their therapeutic efficacy by facilitating a bystander effect against antigen-negative tumor cells., (©2022 The Authors; Published by the American Association for Cancer Research.)

Background: Although the standard of care is to perform surgery of primary breast cancer (BC) after neoadjuvant chemotherapy (NAC), for certain patients achieving clinical complete response (cCR) and pathologic complete response (pCR), omission of surgical treatment may be an option. Levels of circulating tumor DNA (ctDNA) during and after therapy could identify patients achieving minimal residual disease. In this study, we evaluated whether ctDNA clearance during NAC could be a correlate to effective response in human epidermal growth factor receptor 2 positive (HER2+) and triple-negative (TN) BC patients., Methods: A prospective study was conducted to identify patient-specific PIK3CA and TP53 mutations in tissue using next-generation sequencing, which could then be used to track the presence/absence of mutations prior to, during, and following NAC using Sysmex SafeSEQ technology. All patients underwent a surgical excision after NAC, and pCR was assessed., Results: A total of 29 TN and HER2+ BC patients were examined and 20 that carried mutations in the PIK3CA and/or TP53 genes were recruited. Overall, 19 of these 20 patients harbored at least one tumor-specific mutation in their plasma at baseline. After NAC, 15 patients (75.0%) achieved pCR according to the histopathologic evaluation of the surgical specimen, and 15 patients (75.0%) had a cCR; 18 of 20 patients (90.0%) had concordant pCR and cCR. The status of 'no mutation detected' (NMD) following NAC in cCR patients correctly identified the pCR in 14 of 15 patients (93.33%), as well as correctly ruled out pCR in three patients, with an accuracy of 89.47%. During the 12-month follow-up after surgery, 40 plasma samples collected from 15 patients all showed no detectable ctDNA (NMD), and no patient recurred., Conclusion: These findings prompt further research of the value of ctDNA for non-invasive prediction of clinical/pathological response, raising the possibility of sparing surgery following NAC in selected BC patients., Competing Interests: E.Z. has received fees as consultant, participated in advisory boards or received travel grants from Roche/Genentech, Eisai Europe, and Daiichi Sankyo/AstraZeneca; S.E.R has received fees as consultant, participated in advisory boards or had an investigator role from Daiichi Sankyo/AstraZeneca, Pfizer, Roche, Seagen, Byondis, Lilly, MedSIR, and Synthon; C.S has served as consultant, participated in advisory boards or received travel grants from Byondis, AstraZeneca, Daiichi Sankyo, Eisai, Exact Sciences, Exeter Pharma, F. Hoffmann – La Roche Ltd, MediTech, Merck Sharp & Dohme, Novartis, Pfizer, Philips, Pierre Fabre, Puma biotechnology, Sanofi-Aventis, SeaGen and Zymeworks; V.P. has received fees as consultant, participated in advisory boards or received travel grants from Sysmex, Roche, Merck Sharp & Dohme, AstraZeneca, Bayer and Exact Sciences. The remaining authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2022.)

The paper assesses the dose-limiting toxicities and the maximum tolerated dose (MTD) of trastuzumab emtansine (T-DM1) combined with non-pegylated liposomal doxorubicin (NPLD) in HER2-positive (HER2+) metastatic breast cancer (MBC). This single-arm, open-label, phase Ib trial (NCT02562378) enrolled anthracycline-naïve HER2+ MBC patients who had progressed on trastuzumab and taxanes. Patients received a maximum of 6 cycles of NPLD intravenously (IV) at various dose levels (45, 50, and 60 mg/m 2 ) in the "3 plus 3" dose-escalation part. During expansion, they received 60 mg/m 2 of NPLD every 3 weeks (Q3W) plus standard doses of T-DM1. The MTD was T-DM1 3.6 mg/kg plus NPLD 60 mg/m 2 administered IV Q3W. No clinically relevant worsening of cardiac function was observed. Among all evaluable patients, the overall response rate was 40.0% (95%CI, 16.3-67.7) with a median duration of response of 6.9 months (95%CI, 4.8-9.1). Clinical benefit rate was 66.7% (95%CI, 38.4-88.2) and median progression-free survival was 7.2 months (95%CI, 4.5-9.6). No significant influence of NPLD on T-DM1 pharmacokinetics was observed. The addition of NPLD to T-DM1 is feasible but does not seem to improve the antitumor efficacy of T-DM1 in HER2+ MBC patients.

Purpose: To assess palbociclib in combination with trastuzumab with or without endocrine therapy in patients with HER2-positive advanced breast cancer., Patients and Methods: PATRICIA is a prospective, open-label, multicenter phase II trial. Patients had received 2-4 prior lines of anti-HER2-based regimens. Treatment consisted of palbociclib 200 mg daily for 2 weeks and 1 week off plus trastuzumab. The study was based on a Simon two-stage design comprising three cohorts: estrogen receptor (ER)-negative (cohort A), ER-positive (cohort B1), and ER-positive with letrozole (cohort B2). ER-positive patients were randomized to cohorts B1 or B2. Primary endpoint was progression-free survival rate at 6 months (PFS6). Secondary objectives included safety and evaluation of the PAM50 intrinsic subtypes., Results: Seventy-one patients were recruited ( n = 15 in cohort A and 28 in each cohort B). The PFS6 rate in cohorts A, B1, and B2 was 33.3% (5/15), 42.8% (12/28), and 46.4% (13/28), respectively. Regarding safety, grade 1-2 and 3-4 toxicities occurred in 97.7% and 84.4% of patients, respectively. The most common grade 3-4 toxicities were neutropenia (66.4%) and thrombocytopenia (11.3%). Regarding PAM50, 59 (83.1%) tumors were profiled. Luminal disease defined by PAM50 was found independently associated with longer PFS compared with non-luminal disease (10.6 vs. 4.2 months median PFS; adjusted hazard ratio = 0.40; P = 0.003)., Conclusions: Palbociclib in combination with trastuzumab is safe and exhibits promising survival outcomes in trastuzumab pretreated ER-positive/HER2-positive advanced breast cancer with a PAM50 Luminal A or B subtype. The enrollment was stopped prematurely, and a new randomized cohort was opened in this population., (©2020 American Association for Cancer Research.)

A 44-year-old woman diagnosed with a HER2 positive early breast cancer, receiving neoadjuvant treatment with paclitaxel and targeted agents, trastuzumab together with pertuzumab, presented to the emergency room with gait instability and upper right limb weakness. The neurological examination was compatible with cerebellar alteration showing right dissymmetry of the finger-nose and heel-knee manoeuvre. A head CT and a brain MRI were performed and negative. The electromyography showed alterations of the pyramidal pathway and somatosensory pathway. In order to determine the cause of the cerebellar affection, a lumbar puncture was performed. The cerebrospinal fluid analysis was non-specific, but the antineuronal anti-Yo antibody was positive, being diagnosed of a paraneoplastic cerebellar degeneration (PCD). A positron emission tomography CT ruled out metastatic disease. The patient completed four cycles of antiHER2 blockade and weekly paclitaxel, achieving a complete pathological response. One year later, she maintains a complete remission but the PCD still prevails., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Trastuzumab-emtansine (T-DM1) is an antibody-drug conjugate (ADC) approved for the treatment of HER2 (human epidermal growth factor receptor 2)-positive breast cancer. T-DM1 consists of trastuzumab covalently linked to the cytotoxic maytansinoid DM1 via a non-cleavable linker. Despite its efficacy, primary or acquired resistance frequently develops, particularly in advanced stages of the disease. Second generation ADCs targeting HER2 are meant to supersede T-DM1 by using a cleavable linker and a more potent payload with a different mechanism of action. To determine the effect of one of these novel ADCs, SYD985, on tumors resistant to T-DM1, we developed several patient-derived models of resistance to T-DM1. Characterization of these models showed that previously described mechanisms-HER2 downmodulation, impairment of lysosomal function and upregulation of drug efflux pumps-account for the resistances observed, arguing that mechanisms of resistance to T-DM1 are limited, and most of them have already been described. Importantly, SYD985 was effective in these models, showing that the resistance to first generation ADCs can be overcome with an improved design.

Background: The use of poly- l -lactide acid-based bioresorbable scaffolds is limited in daily clinical practice because of safety concerns and lack of physiological benefit. Magnesium-based bioresorbable scaffold (MgBRS) presents a short resorption period (<1 year) and have the potential of being thromboresistant and exhibiting early restoration of vasomotor function. To date, however, no randomized clinical trial has investigated the performance of MgBRS. Therefore, this study aimed to compare the in-stent/scaffold vasomotion between MgBRS and permanent metallic sirolimus-eluting stent (SES) at 12-month follow-up in ST-segment-elevation myocardial infarction patients., Methods: This investigator-driven, multicenter, randomized, single-blind, controlled trial randomized ST-segment-elevation myocardial infarction patients 1:1 to SES or MgBRS at 11 academic centers. The primary end point was the rate of increase (≥3%) after nitroglycerin in mean lumen diameter of the in-stent/scaffold segment at 12 months with superiority of MgBRS over SES in the as-treated population. The main secondary end points included angiographic parameters of restenosis, device-oriented composite end point, their individual components, and device thrombosis rate. Besides, endothelial-dependent vasomotor response to acetylcholine (ie, endothelial function) was also assessed in a subgroup of patients (n=69)., Results: Between June 2017 and June 2018, 150 ST-segment-elevation myocardial infarction patients were randomized (MgBRS, n=74; SES, n=76). At 1 year, the primary end point was significantly higher in the MgBRS arm (56.5% versus 33.8%; P =0.010). Conversely, late lumen loss was significantly lower in the SES group (in-segment: 0.39±0.49mm versus 0.02±0.27mm, P <0.001; in-device: 0.61±0.55mm versus 0.06±0.21mm; P <0.001). The device-oriented composite end point was higher in the MgBRS arm driven by an increase in ischemia-driven target lesion revascularization rate (12[16.2%] versus 4[5.2%], P =0.030). Definite thrombosis rate was similar between groups (1[1.4%] in the MgBRS arm versus 2[2.6%] in the SES group; P =1.0). Endothelial function assessment at device segment evidenced a more pronounced vasoconstrictive response to maximal dose of acetylcholine in the MgBRS arm (-8.3±3.5% versus -2.4±1.3% in the SES group, P =0.003)., Conclusions: When compared to SES, MgBRS demonstrated a higher capacity of vasomotor response to pharmacological agents (either endothelium-independent or endothelium-dependent) at 1 year. However, MgBRS was associated with a lower angiographic efficacy, a higher rate of target lesion revascularization, without thrombotic safety concerns., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03234348.

Drug-drug interactions are of significant concern in clinical practice in oncology, particularly in patients receiving Cyclin-dependent kinase (CDK) 4/6 inhibitors, which are typically exposed to long-term regimens. This article presents the highlights from the 'First Workshop on Pharmacology and Management of CDK4/6 Inhibitors: Consensus about Concomitant Medications'. The article is structured into two modules. The educational module includes background information regarding drug metabolism, corrected QT (QTc) interval abnormalities, management of psychotropic drugs and a comprehensive review of selected adverse effects of palbociclib and ribociclib. The collaborative module presents the conclusions of the five working groups, each of which comprised five experts from different fields. From these conclusions positive lists of drugs for treating common comorbid conditions that can be safely administered concomitantly with palbociclib and/or ribociclib were developed., Competing Interests: Conflict of interest statement: MB has received grants for attending meetings/conferences from Pfizer, Roche and Glaxo, fees as a scientific consultant from Novartis, Pfizer and Lilly and has participated in sponsored speakers bureau or educational activities with Novartis and Pfizer. RV has participated in sponsored speakers bureau or educational activities with Roche and Novartis. CV has received grants for attending meetings/conferences from Roche, Amgen, Janssen and Daiichi Sankyo. XG has received grants for attending meetings/conferences from Roche, fees as a scientific consultant from BMS and has participated in sponsored speakers bureau or educational activities with Roche. EA has received grants for attending meetings/conferences from Roche, Pfizer and Celgene and has participated in sponsored speakers bureau or educational activities with Roche, Novartis, Celgene, AstraZeneca and Glaxo. MV has participated in sponsored speakers bureau or educational activities with Roche and Celgene. JG has received fees as a scientific consultant from Roche and has participated in sponsored speakers bureau or educational activities with Pfizer, AstraZeneca, Novartis and Roche. SER has received grants for attending meetings/conferences from Roche and Daiichi Sankyo, fees as a scientific consultant from Roche and Laboratoires Pierre Fabre and has participated in sponsored speakers bureau or educational activities with Roche. AP has participated in sponsored speakers bureau or educational activities with Novartis and Roche. AL has participated in sponsored speakers bureau or educational activities with Roche, BMS, Eisai, Novartis and AstraZeneca. PZ has received grants for attending meetings/conferences from Roche and has participated in sponsored speakers bureau or educational activities with Roche. IR has received fees as a scientific consultant from Gilead, Pfizer and Merck Sharp & Dohme and has participated in sponsored speakers bureau or educational activities with Astellas, Celgene, Gilead, Merck Sharp & Dohme and Pfizer. MG has received fees as a scientific consultant from Pfizer and has participated in sponsored speakers bureau or educational activities with Novartis, Pfizer and Roche. MAS has received fees as a scientific consultant from Pfizer and has participated in sponsored speakers bureau or educational activities with Novartis, Pfizer and Roche.

For decades, the neoadjuvant setting has provided a useful scenario for research in breast cancer. Historically, neoadjuvant clinical trials, either hormone therapy-based or chemotherapy-based, have tried to recapitulate the results of their counterpart adjuvant studies, but with smaller patient numbers, more rapid outcomes (clinical response and/or pathologic complete response (pCR)), together with additional biologic information. As for neoadjuvant chemotherapy trials, the increase in pCR rates has been recently accepted as an appropriate surrogate marker to accelerate drug approval in high-risk breast cancer patients. In this setting, with the exception of luminal A tumors, pCR has been associated with improved long-term outcomes, particularly when the analysis is based on specific trials for each breast cancer subtype. For luminal tumors receiving neoadjuvant endocrine therapy, Ki67 at 2-4 weeks and the preoperative endocrine prognostic index score are the most accepted intermediate markers of efficacy, which will be validated in ongoing larger trials. In this review, we describe the different neoadjuvant designs: from the classical randomized trials in which treatment is delivered for 6 or more months to short non-therapeutic presurgical studies lasting just 2 or 3 weeks. We also review the main neoadjuvant trials, either ongoing or completed, for luminal, triple-negative, and HER2-positive breast cancer. The translational effort and research of biomarkers conducted in these studies will be particularly addressed.

Objectives: Given the increasing focus on early mortality and readmission rates among patients with acute coronary syndrome (ACS), this study was designed to evaluate the accuracy of the GRACE risk score for identifying patients at high risk of 30-day post-discharge mortality and cardiovascular readmission., Methods: This was a retrospective study carried out in a single center with 4229 ACS patients discharged between 2004 and 2010. The study endpoint was the combination of 30-day post-discharge mortality and readmission due to reinfarction, heart failure or stroke., Results: One hundred and fourteen patients had 30-day events: 0.7% mortality, 1% reinfarction, 1.3% heart failure, and 0.2% stroke. After multivariate analysis, the six-month GRACE risk score was associated with an increased risk of 30-day events (HR 1.03, 95% CI 1.02-1.04; p<0.001), demonstrating good discrimination (C-statistic: 0.79 ± 0.02) and optimal fit (Hosmer-Lemeshow p=0.83). The sensitivity and specificity were adequate (78.1% and 63.3%, respectively), and negative predictive value was excellent (99.1%). In separate analyses for each event of interest (all-cause mortality, reinfarction, heart failure and stroke), assessment of the six-month GRACE risk score also demonstrated good discrimination and fit, as well as adequate predictive values., Conclusions: The six-month GRACE risk score is a useful tool to predict 30-day post-discharge death and early cardiovascular readmission. Clinicians may find it simple to use with the online and mobile app score calculator and applicable to clinical daily practice., (Copyright © 2014 Sociedade Portuguesa de Cardiologia. Published by Elsevier España. All rights reserved.)

Objectives: The risk of stroke after an acute coronary syndrome (ACS) has increased. The aim of this study was to do a comparative validation of the 6-month GRACE (Global Registry of Acute Coronary Events) risk score and CH2DS2VASc risk score to predict the risk of post-ACS ischaemic stroke., Methods: This was a retrospective study carried out in a single centre with 4229 patients with ACS discharged between 2004 and 2010 (66.9±12.8 years, 27.9% women, 64.2% underwent percutaneous coronary intervention). The primary end point is the occurrence of an ischaemic stroke during follow-up (median 4.6 years, IQR 2.7-7.1 years)., Results: 184 (4.4%) patients developed an ischaemic stroke; 153 (83.2%) had sinus rhythm and 31 (16.9%) had atrial fibrillation. Patients with stroke were older, with higher rates of hypertension, diabetes, previous stroke and previous coronary artery disease. The HR for CHA2DS2VASc was 1.36 (95% CI, 1.27 to 1.48, p<0.001) and for GRACE, HR was 1.02(95% CI, 1.01 to 1.03, p<0.001). Both risk scores show adequate discriminative ability (c-index 0.63±0.02 and 0.60±0.02 for CHA2DS2VASc and GRACE, respectively). In the reclassification method there was no difference (Net Reclassification Improvement 1.98%, p=0.69). Comparing moderate-risk/high-risk patients with low-risk patients, both risk scores showed very high negative predictive value (98.5% for CHA2DS2VASc, 98.1% for GRACE). The sensitivity of CHA2DS2VASc score was higher than the GRACE risk score (95.1% vs 87.0%), whereas specificity was lower (14.4% vs 30.2%)., Conclusions: The 6-month GRACE model is a clinical risk score that facilitates the identification of individual patients who are at high risk of ischaemic stroke after ACS discharge.

Relatively little is known on how the Doppler method compares with oscillometric measurement using a conventional automatic blood pressure device to determine the ankle-brachial index, when determinations are performed by physicians with little experience. To assess the diagnostic efficacy of both methods in this professional group, we calculated their sensitivity, specificity, and positive and negative predictive value in 158 legs of 85 patients with symptoms of intermittent claudication. Angiography was used as the gold standard. Of the legs examined, 131 showed significant arterial obstruction. The oscillometric method showed 97% sensitivity, 89% specificity, 98% positive predictive value, and 86% negative predictive value. The Doppler method showed 95% sensitivity, 56% specificity, 91% positive predictive value, and 68% negative predictive value. This study suggests that the automatic blood pressure equipment has greater diagnostic accuracy when the test is performed by physicians not specifically trained to use the Doppler probe. Full English text available from: www.revespcardiol.org., (Copyright © 2010 Sociedad Española de Cardiología. Published by Elsevier Espana. All rights reserved.)

There are anatomical differences between right and left radial artery approaches for coronary catheterization that could influence application of the technique. We present the results of a randomized study that compared the effectiveness of the two approaches and identified factors associated with failure of the procedure. The study involved 351 consecutive patients: a left radial approach was used in 180, and a right radial approach, in 171. The procedure could not be completed using the initial approach selected in 15 patients (11 right radial vs. 4 left radial; P=.007). Use of a right radial approach, lack of catheterization experience, patient age >70 years, and the absence of hypertension were found to be independently associated with prolonged fluoroscopy duration and failure using the initial approach. Use of the right radial approach in patients aged over 70 years was associated with a 6-fold increase in the risk of an adverse event. Consequently, use of the right radial approach should be avoided in patients aged over 70 years when trainee practitioners are on the learning curve.