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Pathologists' assessment of sentinel lymph nodes (SNs) for breast cancer (BC) metastases is a treatment-guiding yet labor-intensive and costly task because of the performance of immunohistochemistry (IHC) in morphologically negative cases. This non-randomized, single-center clinical trial (International Standard Randomized Controlled Trial Number:14323711) assessed the efficacy of an artificial intelligence (AI)-assisted workflow for detecting BC metastases in SNs while maintaining diagnostic safety standards. From September 2022 to May 2023, 190 SN specimens were consecutively enrolled and allocated biweekly to the intervention arm (n = 100) or control arm (n = 90). In both arms, digital whole-slide images of hematoxylin-eosin sections of SN specimens were assessed by an expert pathologist, who was assisted by the 'Metastasis Detection' app (Visiopharm) in the intervention arm. Our primary endpoint showed a significantly reduced adjusted relative risk of IHC use (0.680, 95% confidence interval: 0.347-0.878) for AI-assisted pathologists, with subsequent cost savings of ~3,000 . Secondary endpoints showed significant time reductions and up to 30% improved sensitivity for AI-assisted pathologists. This trial demonstrates the safety and potential for cost and time savings of AI assistance.
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BACKGROUND: In the absence of prognostic biomarkers, most patients with early-stage triple-negative breast cancer (eTNBC) are treated with combination chemotherapy. The identification of biomarkers to select patients for whom treatment de-escalation or escalation could be considered remains an unmet need. We evaluated the prognostic value of histopathologic traits in a unique cohort of young, (neo)adjuvant chemotherapy-naïve patients with early-stage (stage I or II), node-negative TNBC and long-term follow-up, in relation to stromal tumor-infiltrating lymphocytes (sTILs) for which the prognostic value was recently reported. MATERIALS AND METHODS: We studied all 485 patients with node-negative eTNBC from the population-based PARADIGM cohort which selected women aged <40 years diagnosed between 1989 and 2000. None of the patients had received (neo)adjuvant chemotherapy according to standard practice at the time. Associations between histopathologic traits and breast cancer-specific survival (BCSS) were analyzed with Cox proportional hazard models. RESULTS: With a median follow-up of 20.0 years, an independent prognostic value for BCSS was observed for lymphovascular invasion (LVI) [adjusted (adj.) hazard ratio (HR) 2.35, 95% confidence interval (CI) 1.49-3.69], fibrotic focus (adj. HR 1.61, 95% CI 1.09-2.37) and sTILs (per 10% increment adj. HR 0.75, 95% CI 0.69-0.82). In the sTILs <30% subgroup, the presence of LVI resulted in a higher cumulative incidence of breast cancer death (at 20 years, 58%; 95% CI 41% to 72%) compared with when LVI was absent (at 20 years, 32%; 95% CI 26% to 39%). In the ≥75% sTILs subgroup, the presence of LVI might be associated with poor survival (HR 11.45, 95% CI 0.71-182.36, two deaths). We confirm the lack of prognostic value of androgen receptor expression and human epidermal growth factor receptor 2 -low status. CONCLUSIONS: sTILs, LVI and fibrotic focus provide independent prognostic information in young women with node-negative eTNBC. Our results are of importance for the selection of patients for de-escalation and escalation trials.
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Neoplasias de Mama Triplo Negativas , Humanos , Feminino , Prognóstico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Biomarcadores Tumorais , Quimioterapia AdjuvanteRESUMO
OBJECTIVE: To assess the cost-effectiveness of a cardiac rehabilitation (CR) program specifically designed for cardiac patients with obesity vs standard CR. DESIGN: Cost-effectiveness analysis based on observations in a randomized controlled trial. SETTING: Three regional CR centers in the Netherlands. PARTICIPANTS: Cardiac patients (N=201) with obesity (BMI≥30 kg/m2) referred to CR. INTERVENTIONS: Participants were randomized to a CR program specifically designed for patients with obesity (OPTICARE XL; N=102) or standard CR. OPTICARE XL included aerobic and strength exercise and behavioral coaching on diet and physical activity during 12 weeks, followed by a 9-month after-care program with "booster" educational sessions. Standard CR consisted of a 6- to 12-week aerobic exercise program, supplemented with cardiovascular lifestyle education. MAIN OUTCOME MEASURES: An economic evaluation, with an 18-month time horizon, in terms of quality-adjusted life years (QALYs) and costs from the societal perspective was performed. Costs were reported in 2020 Euros, discounted at a 4% annual rate, and health effects were discounted at a 1.5% annual rate. RESULTS: OPTICARE XL CR and standard CR resulted in comparable health gain per patient (0.958 vs 0.965 QALYs, respectively; P=.96). Overall, OPTICARE XL CR saved costs (-4542) compared with the standard CR group. The direct costs for OPTICARE XL CR were higher than for standard CR (10,712 vs 9951), whereas indirect costs were lower (51,789 vs 57,092), but these differences were not significant. CONCLUSIONS: This economic evaluation showed no differences between OPTICARE XL CR and standard CR in health effects and costs in cardiac patients with obesity.
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Reabilitação Cardíaca , Humanos , Reabilitação Cardíaca/métodos , Análise Custo-Benefício , Obesidade , Estilo de Vida , Exercício FísicoRESUMO
While the beneficial effects of secondary prevention of cardiovascular disease are undisputed, implementation remains challenging. A gap between guideline-mandated risk factor targets and clinical reality was documented as early as the 1990s. To address this issue, research groups in the Netherlands have performed several major projects. These projects address innovative, multidisciplinary strategies to improve medication adherence and to stimulate healthy lifestyles, both in the setting of cardiac rehabilitation and at dedicated outpatient clinics. The findings of these projects have led to changes in prevention and rehabilitation guidelines.
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BACKGROUND: The Temporary Holding Department (toa) is a link between the 7/24 service and the admissions departments. We examined the make-up of the admission cohorts and the use of isolation between 2001 and 2017 in the context of demographic developments and changes in the mental healthcare sector.
METHOD: Comparison of patient data in four cohorts who came in during four consecutive periods.
RESULTS: The number of admissions rose from 408 a year in the period 2001-2003 to 728 in the period 2013-2016. The proportion of voluntary admissions increased from 4 to 33%, while emergency compulsory admissions (ibs) fell from 83 to 54%. The proportion of admissions of Dutch people from outside Amsterdam and of people from other countries rose from 11 to 23%. The percentage of patients with schizophrenic disorder rose from 25 to 32%, the percentage with mood disorder from 14 to 20% and the percentage with drug-related disorders from 3 to 7%. Assessment at a police station and the classification psychotic disorder were predictors of compulsory admissions (under the terms of the Dutch bopz act). Men under the age of 45 who were admitted compulsorily were more likely to be isolated. The percentage of patients isolated during admission fell from 37% to 20%, and the length of the periods of isolation also declined. CONCLUSIONS The increase in the annual number of admissions to the toa indicates, in the context of population growth and the rise in tourism, that there is a shortage of available beds in regular admissions departments in Amsterdam. Over the course of fifteen years, the number of Dutch nationals from outside Amsterdam and foreigners doubled. Due to policy and/or as a result of the increased proportion of patients admitted voluntarily, the use of isolation decreased.
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Transtornos Mentais , Psiquiatria , Internação Compulsória de Doente Mental , Serviço Hospitalar de Emergência , Hospitalização , Humanos , Masculino , Transtornos Mentais/epidemiologia , Transtornos Mentais/terapia , Admissão do PacienteRESUMO
BACKGROUND: Cardiac rehabilitation (CR) has favourable effects on cardiovascular mortality and morbidity. Therefore, it might reasonable to expect that incomplete CR participation will result in suboptimal patient outcomes. METHODS: We studied the 914 post-acute coronary syndrome patients who participated in the OPTImal CArdiac REhabilitation (OPTICARE) trial. They all started a 'standard' CR programme, with physical exercises (group sessions) twice a week for 12 weeks. Incomplete CR was defined as participation in <75% of the scheduled exercise sessions. Patients were followed-up for 2.7 years, and the incidence of cardiac events was recorded. Major adverse cardiac events (MACE) included all-cause mortality, non-fatal myocardial infarction and coronary revascularisation. RESULTS: A total of 142 (16%) patients had incomplete CR. They had a higher incidence of MACE than their counterparts who completed CR (11.3% versus 3.8%, adjusted hazard ratio [aHR] 2.86 and 95% confidence interval [CI] 1.47-5.26). Furthermore, the incidence of any cardiac event, including MACE and coronary revascularisation, was higher (20.4% versus 11.0%, aHR 1.54; 95% CI 0.98-2.44). Patients with incomplete CR were more often persistent smokers than those who completed CR (31.7% versus 11.5%), but clinical characteristics were similar otherwise. CONCLUSION: Post-ACS patients who did not complete a 'standard' 12-week CR programme had a higher incidence of adverse cardiac events during long-term follow-up than those who completed the programme. Since CR is proven beneficial, further research is needed to understand the reasons why patients terminate prematurely.
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DDX3 is a DEAD box RNA helicase with oncogenic properties. RK-33 is developed as a small-molecule inhibitor of DDX3 and showed potent radiosensitizing activity in preclinical tumor models. This study aimed to assess DDX3 as a target in breast cancer and to elucidate how RK-33 exerts its anti-neoplastic effects. High DDX3 expression was present in 35% of breast cancer patient samples and correlated with markers of aggressiveness and shorter survival. With a quantitative proteomics approach, we identified proteins involved in the mitochondrial translation and respiratory electron transport pathways to be significantly downregulated after RK-33 or DDX3 knockdown. DDX3 localized to the mitochondria and DDX3 inhibition with RK-33 reduced mitochondrial translation. As a consequence, oxygen consumption rates and intracellular ATP concentrations decreased and reactive oxygen species (ROS) increased. RK-33 antagonized the increase in oxygen consumption and ATP production observed after exposure to ionizing radiation and reduced DNA repair. Overall, we conclude that DDX3 inhibition with RK-33 causes radiosensitization in breast cancer through inhibition of mitochondrial translation, which results in reduced oxidative phosphorylation capacity and increased ROS levels, culminating in a bioenergetic catastrophe.
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Neoplasias da Mama/patologia , RNA Helicases DEAD-box/metabolismo , Mitocôndrias/metabolismo , Biossíntese de Proteínas/efeitos dos fármacos , Radiossensibilizantes/farmacologia , Azepinas/farmacologia , Azepinas/uso terapêutico , Mama/patologia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/terapia , Linhagem Celular Tumoral , RNA Helicases DEAD-box/antagonistas & inibidores , RNA Helicases DEAD-box/genética , Regulação para Baixo , Feminino , Técnicas de Silenciamento de Genes , Humanos , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/genética , Mitocôndrias/efeitos da radiação , Oncogenes/efeitos dos fármacos , Proteômica , Radiossensibilizantes/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Espécies Reativas de Oxigênio/efeitos da radiação , Análise de SobrevidaRESUMO
BACKGROUND: Hospital length of stay after acute myocardial infarction (AMI) treated with primary percutaneous coronary intervention (pPCI) has reduced, resulting in more limited patient education during admission. Therefore, systematic participation in cardiac rehabilitation (CR) has become more essential. We aimed to identify patient-related factors that are associated with participation in and completion of a CR programme. METHODS: We identified 3,871 consecutive AMI patients who underwent pPCI between 2003 and 2011. These patients were linked to the database of Capri CR, which provides dedicated, multi-disciplinary CR. 'Participation' was defined as registration at Capri CR within 6 months after pPCI. CR was 'complete' if a patient undertook the final exercise test. RESULTS: In total, 1,497 patients (39%) were registered at Capri CR. Factors independently associated with CR participation included age (<50 vs. >70 year: odds ratio (OR) 7.0, 95% confidence interval (CI) 5.1-9.6), gender (men vs. women: OR 1.9, 95% CI 1.3-1.8), index diagnosis (ST-elevation myocardial infarction [STEMI] vs. non-ST-elevation myocardial infarction [NSTEMI]: OR 2.4, 95% CI 2.0-2.7) and socio-economic status (high vs. low: OR 2.0, 95% CI 1.6-2.5). The model based on these factors discriminated well (c-index 0.75). CR programme completion was 80% and was inversely related with diabetes, current smoking and previous MI. The discrimination of the model based on these factors was poor (c-index 0.59). CONCLUSIONS: Only a minority of AMI/pPCI patients participated in a CR programme. Completion rates, however, were better. Increased physician and patient awareness of the benefits of CR are still needed, with focus on the elderly, women and patients with low socio-economic status.
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The majority of cardiac rehabilitation (CR) referrals consist of patients who have survived an acute coronary syndrome (ACS). Although major changes have been implemented in ACS treatment since the 1980s, which highly influenced mortality and morbidity, CR programs have barely changed and only few data are available on the optimal CR format in these patients. We postulated that standard CR programs followed by relatively brief maintenance programs and booster sessions, including behavioural techniques and focusing on incorporating lifestyle changes into daily life, can improve long-term adherence to lifestyle modifications. These strategies might result in improved (cardiac) mortality and morbidity in a cost-effective fashion. In the OPTImal CArdiac REhabilitation (OPTICARE) trial we will assess the effects of two advanced and extended CR programs that are designed to stimulate permanent adaption of a heart-healthy lifestyle, compared with current standard CR, in ACS patients. We will study the effects in terms of cardiac risk profile, levels of daily physical activity, quality of life and health care consumption.