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IntroductionPalbociclib is a widely used treatment for advanced breast cancer in older adults. However, the existing evidence regarding its safety and tolerability in this age group is inconsistent and limited to retrospective subgroup or pooled analyses.Materials and methodsWe conducted a prospective single-arm multicenter phase 2 study to evaluate the safety and tolerability of palbociclib in participants aged 70 years or older with advanced hormone receptor-positive breast cancer. Participants were given palbociclib in combination with their physician's choice of endocrine therapy (letrozole or fulvestrant). The primary endpoint was the incidence of grade 3+ adverse events (AEs) by six months. Secondary endpoints included AE-related dose delays, dose reductions, early discontinuations, and hospitalizations. Additionally, we compared these endpoints by age groups (70-74 and ≥ 75 years).ResultsOf the 90 participants (median age 74 years [70-87]) enrolled, 75.6% (95% confidence interval [CI], 65.4-84.0) had grade 3+ AEs by six months. The most frequent grade 3+ AEs were neutropenia (61%), fatigue (4%), and nausea (3%). Febrile neutropenia was uncommon (1.1%). Due to AEs, 36% had dose delays, 34% had dose reductions, 10% had early discontinuations, and 10% had hospitalizations. Compared to those aged 70-74 years, participants aged ≥75 years had higher rates of early discontinuations (5.9% vs 15.9%, a difference of 9.5% [95% CI 3.5%-22.5%]).DiscussionPalbociclib has an overall favorable safety profile in adults aged ≥70 with advanced breast cancer. However, adults ≥75 years had a trend toward higher rates of AE-related early discontinuations compared to those 70-74 years. Further research is needed to evaluate tolerability and improve the delivery of palbociclib in older adults.Clinicaltrialsgov:NCT03633331.

Introduction To improve resource allocation within our healthcare system, the Egyptian Authority for Unified Procurement, Medical Supply and the Management of Medical Technology (UPA) and Universal Health Insurance Authority (UHIA) established a joint economic evaluation process to support UHIA reimbursement decisions and UPA procurement decisions. The main objective of this study is to describe the developed national pharmacoeconomic guidelines in Egypt, especially for reimbursement and procurement for new pharmaceuticals. Methods A focus group was formed as a national initiative activity by governmental authorities in Egypt. The aim of this focus group was to develop national pharmacoeconomic guidelines for the evaluation of innovative and high-budget pharmaceutical products. This group consisted of various stakeholders with experience in health economics, outcomes research, public health, and pharmacy practice. To develop our national pharmacoeconomic guidelines, three steps were taken. First, the focus group reviewed the European Network for Health Technology Assessment (EUnetHTA) methods for health economic evaluations for new pharmaceuticals as well as the Canadian Agency for Drugs and Technologies in Health (CADTH) guidelines and the Academy of Managed Care Pharmacy (AMCP) Format for Formulary Submissions. Second, the focus group used the EUnetHTA guideline as a reference and adapted it to our local context. The focus group added the value assessment component, using the CADTH and AMCP guidelines. Third, the focus group collected input and feedback from key stakeholders through a focus group by using the quasi-Delphi panel approach. Results The results of the focus group are a main structure of national pharmacoeconomic guidelines for the evaluation of innovative and high-budget pharmaceutical products, consisting of seven main topics. Conclusion Economic evaluation is a core element of Health Technology Assessment, (HTA); therefore, the UHIA and UPA were encouraged to produce unified joint pharmacoeconomic guidelines for innovative products as an initial step in their commitment to implement the use of HTA in decision-making. This standardization of guidelines not only ensures transparency but also guarantees an accurate and transparent process to support evidence-based decision-making. These guidelines are expected to help decision-makers improve their process and attain better health outcomes for Egyptian patients.

BackgroundThrombocytopenia is a common adverse event on HER2-targeted therapies, fam-trastuzumab deruxtecan (T-DXd) and ado-trastuzumab emtansine (T-DM1). A reported association of Asian ancestry with this event merits investigation to rule out potential confounding.MethodsSubjects in this retrospective cohort were female patients with HER2 positive breast cancer, of Asian or non-Hispanic White ancestry, who initiated T-DM1 or T-DXd from January 2017 through October 2021. Follow-up closed in January 2022. Primary endpoint was dose adjustment for thrombocytopenia. Competing endpoints were discontinuation of drug for other toxicity, disease progression, or for completion of prescribed cycles. The association between Asian ancestry and thrombocytopenia-related dose adjustment was tested at p

Abstract Background Cost-effectiveness analyses rarely offer useful insights to policy decisions unless their results are compared against a benchmark threshold. The cost-effectiveness threshold (CET) represents the maximum acceptable monetary value for achieving a unit of health gain. This study aimed to identify CET values on a global scale, provide an overview of using multiple CETs, and propose a country-specific CET framework specifically tailored for Egypt. The proposed framework aims to consider the globally identified CETs, analyze global trends, and consider the local structure of Egypt’s healthcare system. Methods We conducted a literature review to identify CET values, with a particular focus on understanding the basis of differentiation when multiple thresholds are present. CETs of different countries were reviewed from secondary sources. Additionally, we assembled an expert panel to develop a national CET framework in Egypt and propose an initial design. This was followed by a multistakeholder workshop, bringing together representatives of different governmental bodies to vote on the threshold value and finalize the recommended framework. Results The average CET, expressed as a percentage of the gross domestic product (GDP) per capita across all countries, was 135%, with a range of 21 to 300%. Interestingly, while the absolute value of CET increased with a country’s income level, the average CET/GDP per capita showed an inverse relationship. Some countries applied multiple thresholds based on disease severity or rarity. In the case of Egypt, the consensus workshop recommended a threshold ranging from one to three times the GDP per capita, taking into account the incremental relative quality-adjusted life years (QALY) gain. For orphan medicines, a CET multiplier between 1.5 and 3.0, based on the disease rarity, was recommended. A two-times multiplier was proposed for the private reimbursement threshold compared to the public threshold. Conclusion The CET values in most countries appear to be closely related to the GDP per capita. Higher-income countries tend to use a lower threshold as a percentage of their GDP per capita, contrasted with lower-income countries. In Egypt, experts opted for a multiple CET framework to assess the value of health technologies in terms of reimbursement and pricing.

BackgroundHyperglycemia is recognized as a common adverse event for patients receiving alpelisib but has been little studied outside of clinical trials. We report the frequency of alpelisib-associated hyperglycemia in a real-world setting and evaluate proposed risk factors.Patients and methodsWe retrospectively identified patients with PIK3CA-mutated, hormone receptor-positive, metastatic breast cancer who initiated treatment with alpelisib plus fulvestrant between August 2019 and December 2021. Ordinal logistic regression evaluated 5 characteristics (diabetes, prediabetes, body mass index [BMI], age, and Asian ancestry) as independent risk factors for ALP-associated hyperglycemia grades 2-4. Risk of error from multiple hypothesis testing was controlled using the false discovery rate method.ResultsThe study included n = 92 subjects, all but 1 female, mean age 59.9 (+11.9) years with 50% non-Hispanic White, 15% Hispanic/Latino, 13% Asian, 9% African/Black, and 13% other/unknown. In total 34% of patients had diabetes, 10% had pre-diabetes, and 56% had normoglycemia. Thirty-six percent were obese, 32% were overweight, 25% were normal weight, and 7% were lean. Frequency of grades 1-4 hyperglycemia in current subjects (64.1%) was similar to hyperglycemia reported in the SOLAR-1 trial (63.7%). Our subjects' risk of grades 2-4 hyperglycemia was independently increased by pre-existing diabetes (Odds ratio 3.75, 95% CI, 1.40-10.01), pre-diabetes (6.22, 1.12-34.47), Asian ancestry (7.10, 1.75-28.84), and each unit of BMI above 20 (1.17, 1.07-1.28).ConclusionWhile receiving alpelisib, patients of Asian ancestry, as well as patients with pre-existing hyperglycemia and/or BMI above 20, should be closely monitored for hyperglycemia. The mechanism underlying the current association of alpelisib-associated hyperglycemia with Asian ancestry is independent of BMI and merits further study. The high incidence of hyperglycemia resulted in a change in practice to include consultation with a diabetes nurse educator or endocrinologist at the start of alpelisib.

Glucocorticoids, which are administered with chemotherapy, cause hyperglycemia. Glycemic variability among breast cancer patients without diabetes is not well known. A retrospective cohort study was conducted involving early-stage breast cancer patients without diabetes who received dexamethasone prior to neoadjuvant or adjuvant taxane chemotherapy between August 2017-December 2019. Random blood glucose levels were analyzed, and steroid-induced hyperglycemia (SIH) was defined as a random glucose level of >140 mg/dL. A multivariate proportional hazards model was used to identify the risk factors of SIH. Out of 100 patients, the median age was 53 years (IQR: 45-63.5). A total of 45% of patients were non-Hispanic White, 28% Hispanic, 19% Asian, and 5% African American. The incidence of SIH was 67%, and glycemic fluctuations were highest in those with glucose levels of >200 mg/dL. Non-Hispanic White patients represented a significant predictor for time to SIH, with a hazard ratio of 2.5 (95% CI: 1.04, 5.95, p = 0.039). SIH was transient in over 90% of the patients, and only seven patients remained hyperglycemic after glucocorticoid and chemotherapy completion. Pretaxane dexamethasone-induced hyperglycemia was observed in 67% of the patients, with the greatest glycemic lability in those patients with blood glucose levels of >200 mg/dL. The non-Hispanic White patients had a higher risk of developing SIH.

The article addresses the yet-to-be-studied issue within the social research; i.e. the issue of interrelated study of gender risks, migration processes and human capital reproduction in conditions of social transformations in RA. Based on the “comprehensively precise” approach of study of gender risks developed by the authors and given the importance of adjustment of human capital theory related to Armenia (where the labour emigration bears not an individual but a mass character), the mentioned interrelations are considered to be based on the interacting macro, meso and micro levels of scientific analysis. The contradictions between the individual and social utility of migration are identified. The authors argue that as the gender imbalance, segregation and discrimination are the manifestations of negative risks, then a thorough sociological analysis of specific problems in the areas of employment and labour market of Armenia (including the groups of the unemployed) has been carried out. The latter, together with other factors, contributes to increasing the migration risks and hindering the application, accumulation and reproduction of both the individual and, first of all, total human capital within the country. In this regard, the authors, emphasize the importance of establishment of institutional structures of gender policy (in the narrow meaning of the word), as well as the necessity of elaborating scientific criteria, clear-cut indicators and gender statistics, which would have reflected the real interrelation between macro-processes, accumulation of human capital and managing gender and migration risks.

Abstract Background Sacituzumab govitecan (sacituzumab) emerged as an important agent in metastatic and locally recurrent HER2‐negative breast cancer treatment. UGT1A1 polymorphisms have also been shown to predict sacituzumab toxicity. Methods In this retrospective study, we sought to evaluate the associations between UGT1A1 status, toxicity, and therapeutic outcomes in sacituzumab recipients with advanced breast cancer who underwent genotype testing for UGT1A1 alleles (N = 68). Results We found 17 (25%) of our patients to be homozygous for UGT1A1*28 and 24 (35.3%) were heterozygous. Of seven African American patients with triple‐negative breast cancer, five were homozygous for UGT1A1*28 and two were heterozygous. Patients with a homozygous UGT1A1*28 genotype were significantly more likely to have treatment terminated because of adverse effects. However, the polymorphism was not associated with treatment discontinuation because of disease progression. Conclusion This retrospective, real‐world analysis suggests potential clinical utility in UGT1A1 testing for patients receiving sacituzumab, but future trials are needed to confirm the association between genotypes and treatment outcomes.

Abstract Purpose The purpose of this prospective longitudinal study was to evaluate the changes in brain surface gyrification in older long‐term breast cancer survivors 5–15 years after chemotherapy treatment. Methods Older breast cancer survivors aged ≥ 65 years treated with chemotherapy (C+) or without chemotherapy (C‐) 5–15 years prior and age‐ and sex‐matched healthy controls (HC) were recruited (time point 1 (TP1)) and followed up for 2 years (time point 2 (TP2)). Study assessments for both time points included neuropsychological (NP) testing with the NIH Toolbox cognition battery and cortical gyrification analysis based on brain MRI. Results The study cohort with data for both TP1 and TP2 consisted of the following: 10 participants for the C+ group, 12 participants for the C‐ group, and 13 participants for the HC group. The C+ group had increased gyrification in six local gyral regions including the right fusiform, paracentral, precuneus, superior, middle temporal gyri and left pars opercularis gyrus, and it had decreased gyrification in two local gyral regions from TP1 to TP2 (p

PurposeThe objective of this study was to assess changes in hippocampal volume and shape in older long-term breast cancer survivors who were exposed to chemotherapy 5–15 years prior.MethodsThis study recruited female long-term breast cancer survivors aged 65 years or older with a history of chemotherapy (C+), age-matched breast cancer survivors who did not receive chemotherapy (C−), and healthy controls (HC). The participants were recruited 5–15 years after chemotherapy at time point 1 (TP1) and were followed up for 2 years at time point 2 (TP2). Assessments included hippocampal volume and shape from brain MRI scans and neuropsychological (NP) tests.ResultsAt TP1, each of the three groups was comprised of 20 participants. The C+ group exhibited a hippocampal volume loss estimated in proportion with total intracranial volume (ICV) in both the left and right hemispheres from TP1 to TP2. Regarding the hippocampal shape at TP1, the C+ group displayed inward changes compared to the control groups. Within the C+ group, changes in right hippocampal volume adjusted with ICV were positively correlated with crystalized composite scores (R = 0.450, p = 0.044). Additionally, in C+ groups, chronological age was negatively correlated with right hippocampal volume adjusted with ICV (R = −0.585, p = 0.007).ConclusionThe observed hippocampal volume reduction and inward shape deformation within the C+ group may serve as neural basis for cognitive changes in older long-term breast cancer survivors with history of chemotherapy treatment.

Chemotherapy may impair cognition and contribute to accelerated aging. The purpose of this study was to assess the effects of chemotherapy on the connectivity of the default mode network (DMN) in older women with breast cancer. This prospective longitudinal study enrolled women aged ≥ 60 years with stage I-III breast cancer (CTx group) and matched healthy controls (HC group). Study assessments, consisting of resting-state functional MRI (rs-fMRI) and the Picture Sequence Memory (psm) test for episodic memory from the NIH Toolbox for Cognition, were obtained at baseline and within one month after the completion of chemotherapy for the CTx group and at matched intervals for the HC group. Two-sample t-test and FDR multiple comparison were used for statistical inference. Our analysis of the CTx group (N = 19; 60-82 years of age, mean = 66.6, SD = 5.24) compared to the HC group (N = 14; 60-78 years of age, mean = 68.1, SD = 5.69) revealed weaker DMN subnetwork connectivity in the anterior brain but stronger connectivity in the posterior brain at baseline. After chemotherapy, this pattern was reversed, with stronger anterior connectivity and weaker posterior connectivity. In addition, the meta-level functional network connectivity (FNC) among the DMN subnetworks after chemotherapy was consistently weaker than the baseline FNC as seen in the couplings between anterior cingulate cortex (ACC) and retrosplenial (rSplenia) region, with ΔFNC(ACC,rSplenia)=-0.14, t value=-2.44, 95 %CI=[-0.27,-0.10], pFDR

Abstract Purpose To assess white matter microstructural changes in older long‐term breast cancer survivors 5–15 years post‐chemotherapy treatment. Methods Breast cancer survivors aged 65 years or older who underwent chemotherapy (C+) and who did not undergo chemotherapy (C−) and age‐ and sex‐matched healthy controls (HC) were enrolled at time point 1 (TP1) and followed for 2 years for time point 2 (TP2). All participants underwent brain MRI with diffusion tensor images and neuropsychological (NP) testing with the NIH Toolbox Cognition Battery. Tract‐based spatial statistics (TBSS) analysis was performed on the diffusion tensor images to assess white matter microstructural changes with the fractional anisotropy (FA) parameter. Results There were significant longitudinal alterations in FA within the C+ group over time. The C+ group showed diminished FA in the body and genu of corpus callosum, anterior corona radiate, and external capsule on both the whole brain and region of interest (ROI) based analyses after p

A robust breast cancer prevention strategy requires risk assessment biomarkers for early detection. We show that expression of ELF5, a transcription factor critical for normal mammary development, is downregulated in mammary luminal epithelia with age. DNA methylation of the ELF5 promoter is negatively correlated with expression in an age-dependent manner. Both ELF5 methylation and gene expression were used to build biological clocks to estimate chronological ages of mammary epithelia. ELF5 clock-based estimates of biological age in luminal epithelia from average-risk women were within three years of chronological age. Biological ages of breast epithelia from BRCA1 or BRCA2 mutation carriers, who were high risk for developing breast cancer, suggested they were accelerated by two decades relative to chronological age. The ELF5 DNA methylation clock had better performance at predicting biological age in luminal epithelial cells as compared with two other epigenetic clocks based on whole tissues. We propose that the changes in ELF5 expression or ELF5-proximal DNA methylation in luminal epithelia are emergent properties of at-risk breast tissue and constitute breast-specific biological clocks. PREVENTION RELEVANCE: ELF5 expression or DNA methylation level at the ELF5 promoter region can be used as breast-specific biological clocks to identify women at higher than average risk of breast cancer.

Obsessive-compulsive disorder (OCD), a leading cause of disability, affects ~1-2% of the population, and can be distressing and disabling. About 1/3 of individuals demonstrate poor responsiveness to conventional treatments. A small proportion of these individuals may be deep brain stimulation (DBS) candidates. Candidacy is assessed through a multidisciplinary process including assessment of illness severity, chronicity, and functional impact. Optimization failure, despite multiple treatments, is critical during screening. Few patients nationwide are eligible for OCD DBS and thus a multi-center approach was necessary to obtain adequate sample size. The study was conducted over a six-year period and was a NIH-funded, eight-center sham-controlled trial of DBS targeting the ventral capsule/ventral striatum (VC/VS) region. There were 269 individuals who initially contacted the sites, in order to achieve 27 participants enrolled. Study enrollment required extensive review for eligibility, which was overseen by an independent advisory board. Disabling OCD had to be persistent for ≥5 years despite exhaustive medication and behavioral treatment. The final cohort was derived from a detailed consent process that included consent monitoring. Mean illness duration was 27.2 years. OCD symptom subtypes and psychiatric comorbidities varied, but all had severe disability with impaired quality of life and functioning. Participants were randomized to receive sham or active DBS for three months. Following this period, all participants received active DBS. Treatment assignment was masked to participants and raters and assessments were blinded. The final sample was consistent in demographic characteristics and clinical features when compared to other contemporary published prospective studies of OCD DBS. We report the clinical trial design, methods, and general demographics of this OCD DBS sample.

The development of new HER2-directed therapies has resulted in a significant prolongation of survival for women with metastatic HER2-positive breast cancer. Discoveries in the laboratory inform clinical trials which are the basis for improving the standard of care and are also the backbone for quality improvement. Clinical trials can be completed more rapidly by expanding trial enrollment to community sites. In this article we review some of the challenges in treating metastatic breast cancer with HER2-directed therapies and our strategies for incorporating our community partners into the research network.

OBJECTIVE: We aimed to use diffusion tensor imaging (DTI) to detect alterations in white matter microstructure in older patients with breast cancer receiving chemotherapy. METHODS: We recruited women age ≥60 years with stage I-III breast cancer (chemotherapy [CT] group; n = 19) to undergo two study assessments: at baseline and within one month after chemotherapy. Each assessment consisted of a brain magnetic resonance imaging scan with DTI and neuropsychological (NP) testing using the National Institutes of Health (NIH) Toolbox Cognition Battery. An age- and sex-matched group of healthy controls (HC, n = 14) underwent the same assessments at matched intervals. Four DTI parameters (fractional anisotropy [FA], mean diffusivity [MD], axial diffusivity [AD], and radial diffusivity [RD]) were calculated and correlated with NP testing scores. RESULTS: For CT group but not HCs, we detected statistically significant increases in MD and RD in the genu of the corpus callosum from time point 1 to time point 2 at p  0.05). CONCLUSIONS: We identified alterations in white matter microstructures in older women with breast cancer undergoing chemotherapy. These findings may potentially serve as neuroimaging biomarkers for identifying cognitive impairment in older adults with cancer.

PURPOSE: Older cancer patients are at increased risk of cancer-related cognitive impairment. The purpose of this study was to assess the alterations in intrinsic brain activity associated with adjuvant chemotherapy in older women with breast cancer. METHODS: Chemotherapy treatment (CT) group included sixteen women aged ≥ 60 years (range 60-82 years) with stage I-III breast cancers, who underwent both resting-state functional magnetic resonance imaging (rs-fMRI) and neuropsychological testing with NIH Toolbox for Cognition before adjuvant chemotherapy, at time point 1 (TP1), and again within 1 month after completing chemotherapy, at time point 2 (TP2). Fourteen age- and sex-matched healthy controls (HC) underwent the same assessments at matched intervals. Three voxel-wise rs-fMRI parameters: amplitude of low-frequency fluctuation (ALFF), fractional ALFF (fALFF), and regional homogeneity, were computed at each time point. The changes in rs-fMRI parameters from TP1 to TP2 for each group, the group differences in changes (the CT group vs. the HC group), and the group difference in the baseline rs-fMRI parameters were assessed. In addition, correlative analysis between the rs-fMRI parameters and neuropsychological testing scores was also performed. RESULTS: In the CT group, one brain region, which included parts of the bilateral subcallosal gyri and right anterior cingulate gyrus, displayed increased ALFF from TP1 to TP2 (cluster p-corrected = 0.024); another brain region in the left precuneus displayed decreased fALFF from TP1 to TP2 (cluster level p-corrected = 0.025). No significant changes in the rs-fMRI parameters from TP1 to TP2 were observed in the HC group. Although ALFF and fALFF alterations were observed only in the CT group, none of the between-group differences in rs-fMRI parameter changes reached statistical significance. CONCLUSIONS: Our study results of ALFF and fALFF alterations in the chemotherapy-treated women suggest that adjuvant chemotherapy may affect intrinsic brain activity in older women with breast cancer.

Purpose: The aim of this study was to determine how preoperative health‐related quality of life (HRQoL) is affected by the duration of the wait time (WT) for anterior cruciate ligament reconstruction (ACLR) once a decision is made to proceed with surgery. Methods: This was a multi‐centre prospective cohort study. One hundred and twenty‐two patients 14 years of age and above waiting for ACLR completed the International Knee Documentation Committee (IKDC) demographic, current health assessment and subjective knee evaluation (SKF) forms on the day of decision to operate and the day of surgery. Changes in scores were analyzed for the entire cohort, adjusted for WTs and a subset was compared for patients with isolated anterior cruciate ligament (ACL) tears and ACL tears with concurrent meniscal involvement. Changes in HRQoL scores from the day of the decision to operate to the 9‐month postoperative appointments were also assessed. Results: Energy/Fatigue (p < 0.05), Pain (p < 0.05), General Health (p < 0.05) and the IKDC‐SKF Score (p < 0.05) significantly increased between the day of the decision to operate and the day of surgery. Only the change in IKDC‐SKF score remained significantly higher after adjusting for WT. Baseline HRQoL scores significantly improved by the 9‐month postoperative appointment. Conclusion: The length of time waiting for ACLR did not adversely influence HRQoL in this study. However, low preoperative HRQoL and the significant improvement in HRQoL of patients followed postoperatively suggest that timely surgery is beneficial for this patient population. Level of Evidence: Level II. [ABSTRACT FROM AUTHOR]

Introduction: Older adults with cancer facing competing treatments must prioritize between various outcomes. This study assessed health outcome prioritization among older adults with cancer starting chemotherapy. Methods: Secondary analysis of a randomized trial addressing vulnerabilities in older adults with cancer. Patients completed three validated outcome prioritization tools: 1) Health Outcomes Tool: prioritizes outcomes (survival, independence, symptoms) using a visual analog scale; 2) Now vs. Later Tool: rates the importance of quality of life at three times—today versus 1 or 5 years in the future; and 3) Attitude Scale: rates agreement with outcome‐related statements. The authors measured the proportion of patients prioritizing various outcomes and evaluated their characteristics. Results: A total of 219 patients (median [range] age 71 [65–88], 68% with metastatic disease) were included. On the Health Outcomes Tool, 60.7% prioritized survival over other outcomes. Having localized disease was associated with choosing survival as top priority. On the Now vs. Later Tool, 50% gave equal importance to current versus future quality of life. On the Attitude Scale, 53.4% disagreed with the statement "the most important thing to me is living as long as I can, no matter what my quality of life is"; and 82.2% agreed with the statement "it is more important to me to maintain my thinking ability than to live as long as possible". Conclusion: Although survival was the top priority for most participants, some older individuals with cancer prioritize other outcomes, such as cognition and function. Clinicians should elicit patient‐defined priorities and include them in decision‐making. In this secondary analysis of 219 older participants (median age 71 years) from a randomized trial addressing vulnerabilities in older adults with cancer, 61% prioritized survival over other outcomes such as maintaining their independence or being free from symptoms. Clinicians should elicit patient‐defined priorities and include them in decision‐making when discussing treatment. [ABSTRACT FROM AUTHOR]

Background Multi- criteria decision analysis (MCDA) can assist policymakers in objectively choosing between alternative therapeutic options based on multiple value attributes. Our aim was to create an MCDA tool for the national tenders of off-patent oncology medicines in Egypt. Methods An initial list of criteria was developed through a literature review complemented by local expert interviews. Price or cost-related criteria were excluded to abide by the national regulations of the tender process. Next, a workshop hosting diversified stakeholders representing different governmental bodies was held. Anonymous voting was used to rank and weigh the criteria as well as assigning scores. Price was added as a separate step to identify best option based on price per point. The tool was then tested on a national tender sample of off-patent oncology medicines to assess its performance, and it was readjusted accordingly in a second workshop. Results Seven non-price criteria were selected, including use in reference countries (23.49% weight), equivalence with the reference product (18.79%), manufacturing quality (15.53%), provision of pharmacovigilance services (12.94%), supply reliability (10.78%), previous use in local settings (9.8%) and macroeconomic benefit (8.67%). A medicine receives a score ranging from 0 to 100% of each criterion’s weight. The aggregated score is calculated on a hundred-point scale. Based on participants’ consensus, an overall score of 65 was set as a cut-off for passing the technical eligibility phase of the tendering process. Any product receiving a lower score would be disqualified from the tender. For qualified products, the lower price per point represents preferential option for the national tender. Conclusions The created MCDA tool is capable of objectively comparing similar off-patent oncology medicines by considering multiple value attributes and providing reliable scoring functions for each.

Inflammation promotes adverse ventricular remodeling, a common antecedent of heart failure. Here, we set out to determine how inflammatory cells affect cardiomyocytes in the remodeling heart. Pathogenic cardiac macrophages induced an IFN response in cardiomyocytes, characterized by upregulation of the ubiquitin-like protein IFN-stimulated gene 15 (ISG15), which posttranslationally modifies its targets through a process termed ISGylation. Cardiac ISG15 is controlled by type I IFN signaling, and ISG15 or ISGylation is upregulated in mice with transverse aortic constriction or infused with angiotensin II; rats with uninephrectomy and DOCA-salt, or pulmonary artery banding; cardiomyocytes exposed to IFNs or CD4* T cell-conditioned medium; and ventricular tissue of humans with nonischemic cardiomyopathy. By nanoscale liquid chromatography-tandem mass spectrometry, we identified the myofibrillar protein filamin-C as an ISGylation target. ISG15 deficiency preserved cardiac function in mice with transverse aortic constriction and led to improved recovery of mouse hearts ex vivo. Metabolomics revealed that ISG15 regulates cardiac amino acid metabolism, whereas ISG15 deficiency prevented misfolded filamin-C accumulation and induced cardiomyocyte autophagy. In sum, ISG15 upregulation is a feature of pathological ventricular remodeling, and protein ISGylation is an inflammation-induced posttranslational modification that may contribute to heart failure development by altering cardiomyocyte protein turnover., Introduction Heart failure is the clinical manifestation of a heterogeneous group of often overlapping conditions that impair the effective emptying or filling of the cardiac ventricles. Despite the heterogeneity of [...]