Measurement of perceived pressures in psychiatry: paper-and-pencil and computerized adaptive version of the P-PSY35 scale.

PURPOSE: Formal coercion in psychiatry is widely studied yet much less is known about pressures patients may experience, partly because of the very few measures available. The goal of this study was to validate the P-PSY35 (Pressures in Psychiatry Scale) and provide a paper-and-pencil and a computerised adaptive test (CAT) to measure pressures experienced by patients in psychiatry. METHODS: The P-PSY35 items were developed with users. Patients were evaluated during psychiatric hospitalisation or through an online survey. Mokken scale analysis and Item response theory (IRT) were used to select and estimate the items parameters. A Monte-Carlo simulation was performed to evaluate the number of items needed to transform the paper-and-pencil test into a reliable psychometric CAT. RESULTS: A total of 274 patients were assessed. The P-PSY35 demonstrated good internal validity, internal consistency, convergent and divergent validity. The P-PSY35 could be substantially shortened while maintaining excellent reliability using the CAT procedure. CONCLUSION: The P-PSY35 was developed in collaboration with users. It is a psychometrically rigorous tool designed to measure experienced pressures in French-language. The development and successful validation of the P-PSY35 represent a welcome step towards implementing and evaluating programs aimed at reducing negative consequences of coercion.

[Burden and perceived stress among informal caregivers of people suffering from mental disorders]. / Fardeau et stress perçu chez les proches aidants de personnes souffrant de troubles psychiques.

Informal caregivers of people with severe mental illness are particularly at risk of experiencing high levels of burden and perceived stress, which can worsen their global health. In addition, the semi-confinement in 2020 represented a period of additional difficulties for informal caregivers in French-speaking of Switzerland. The burden represents all the negative consequences linked to the informal caregiver role. Perceived stress is the way in which the informal caregiver will perceive a potentially threatening situation, according to their coping strategies and personal resources. Burden and perceived stress can be rapidly assessed in primary care, to suggest useful and effective support interventions to the informal caregivers.

Les proches aidants de personnes atteintes d'un trouble psychique sont particulièrement à risque de vivre des niveaux élevés de fardeau et de stress perçu, ce qui peut détériorer leur état de santé globale. En outre, le semi-confinement de 2020 a représenté une période de difficultés supplémentaires pour les proches en Suisse romande. Le fardeau représente l'ensemble des conséquences défavorables relatives au rôle d'aidant. Le stress perçu est la façon dont le proche aidant va percevoir une situation potentiellement menaçante, selon ses stratégies de coping et ses ressources personnelles. Fardeau et stress perçu peuvent être évalués de façon rapide déjà en soins de première ligne afin de proposer aux proches aidants une orientation vers des interventions de soutien utiles et efficaces.

[The Ensemble Program: Making sense of your actions through ACT]. / Programme Ensemble : redonner du sens à ses actions grâce à l'ACT.

The Ensemble program supports informal caregivers of people with mental health problems. Tailor-made support is offered in order to target the tools that will be most useful to them in their personal situation. Acceptance and commitment therapy can be used to help them give meaning to their actions.

External quality assessment of serum indices: Spanish SEQC-ML program.

OBJECTIVES: Serum indices included in clinical chemistry instruments are widely used by laboratories to assess the quality of samples. Instruments that report quantitative results allow an evaluation of their diagnostic performance in a similar way to other biochemical tests. The Spanish Society of Laboratory Medicine (SEQC-ML) launched a monthly External Quality program of serum indices in 2018 using three lyophilized materials of simultaneous annual distribution. We present the results of the first three years of the program. METHODS: The use of four different quality control materials with different concentrations in three alternate months allows an annual evaluation of the participant's accuracy. Assigned values are established by consensus among homogeneous groups, considering necessary at least 10 participants for a comparison at instrument level. The average percentage difference results per instrument allow the assessment of bias among groups. RESULTS: The imprecision of the three indices ranges between 3 and 9%, with no major differences among instruments. Significant differences were observed in all indices among instruments with more than 10 participants (Roche Cobas, Abbott Architect, Abbott Alinity and Siemens Advia). The 90th percentile of the distribution of percentage differences was used as the analytical performance specification (APS). An improvement in performance was observed in the first three years of the program, probably due to the learning curve effect. In 2020, APS of 7.8, 12.2 and 9.7% were proposed for hemolytic, icteric and lipemic indices, respectively. CONCLUSIONS: Serum indices have a great impact on the quality and the reliability of laboratory test results. Participation in proficiency testing programs for serum indices is helpful to encourage harmonization among providers and laboratories.

Satisfaction and Perceived Coercion in Voluntary Hospitalisations: Impact of Past Coercive Experiences.

Coercion in psychiatry is associated with several detrimental effects, including in the long term. The effect of past experience of coercion on the perception of subsequent hospitalisations remains less studied. The present study aimed to assess the impact of past experience of coercion on the perception of coercion and satisfaction with subsequent voluntary hospitalisations. A total of 140 patients who were hospitalised on a voluntary basis were included. Fifty-three patients experienced coercion before this hospitalisation and 87 did not. Patients were assessed for treatment satisfaction and perceived coercion. Health status was also evaluated by both patients and carers. Past experience of coercion was the independent variable. Perceived coercion and satisfaction scores were used as different dependent variables in a series of regression models. Results suggested a long-term detrimental impact of past experience of coercion on some aspects of satisfaction and perceived coercion in subsequent voluntary hospitalisations even when controlling for self and carers-rated health status. Overall, this study suggests that special attention should be paid to patients who are voluntarily admitted to hospital but have a history of coercion, as they may still be impacted by their past coercive experiences. Ways to increase satisfaction and reduce perceived coercion of these patients are discussed.

Frequency and spectrum of PIK3CA somatic mutations in breast cancer.

PURPOSE: The therascreen PIK3CA mutation assay and the alpha-specific PI3K inhibitor alpelisib are FDA-approved for identifying and treating patients with advanced PIK3CA-mutated (PIK3CAmut) breast cancer (BC). However, it is currently unknown to what extend this assay detects most PIK3CA mutations in BC. This information is critical as patients and clinicians are using this and other genomic assays to indicate alpelisib. METHODS: Data from 6338 patients with BC was explored across 10 publicly available studies. The primary objective was to evaluate the proportion and distribution of PIK3CA mutations in BC. Secondary objectives were (1) to evaluate in silico the spectrum of PIK3CA mutations in BC that would be captured by the therascreen panel; (2) to evaluate the proportion and distribution of PIK3CA mutations in hormone receptor-positive/HER2-negative (HR+/HER2-), HER2+, and triple-negative BC (TNBC); and (3) to explore the identification of PIK3CA mutations in a cohort of 48 HR+/HER2- advanced BC patients by the Guardant B360 circulating tumor DNA (ctDNA) assay. RESULTS: Patients with PIK3CAmut tumors represented 35.7% (2261/6338). Five PIK3CA mutations comprised 73% of all PIK3CA mutations: H1047R (35%), E545K (17%), E542K (11%), N345K (6%), and H1047L (4%). Therascreen gene list would capture 72% of all PIK3CA mutations and 80% of patients with a known PIK3CAmut BC. Among patients with double PIK3CAmut tumors (12% of all PIK3CAmut), the therascreen panel would capture 78% as harboring 1 single PIK3CA mutation, 17% as PIK3CAmut undetected, and 5% as PIK3CA double-mut. PIK3CA mutation rates were lower in TNBC (16%) compared to HR+/HER2 (42%) and HER2+ (31%) BC; however, the distribution of the 4 main PIK3CA mutations across subtypes was similar. Finally, 28% of PIK3CA mutations identified in ctDNA in 48 patients with advanced HR+/HER2- BC were not part of the therascreen panel. CONCLUSION: PIK3CA mutations in BC are heterogenous and ~ 20% of patients with a known PIK3CA mutation, and 95% with a known double PIK3CAmut tumor, would not be captured by the therascreen panel. Finally, the clinical utility of PIK3CA mutations not present in the therascreen companion diagnostic assay or identified by other sequencing-based assays needs further investigation.

Everolimus plus Exemestane for Hormone Receptor-Positive Advanced Breast Cancer: A PAM50 Intrinsic Subtype Analysis of BOLERO-2.

BACKGROUND: The prognostic and predictive value of the two nonluminal (human epidermal growth factor receptor 2 [HER2]-enriched and basal-like) subtypes within advanced hormone receptor-positive (HR+) breast cancer is currently unknown. MATERIALS AND METHODS: This study retrospectively analyzed 261 tumors (80.7% primary; 19.3% metastatic) from the BOLERO-2 study; BOLERO-2 randomized 724 patients with advanced HR+/HER2-negative breast cancer to everolimus plus exemestane or placebo plus exemestane. Tumors were classified using a PAM50 subtype predictor. Multivariable Cox regression analyses tested the independent prognostic significance of PAM50, and associations between PAM50 subtypes and treatment upon progression-free survival (PFS) were evaluated. RESULTS: Subtype distribution was 46.7% luminal A (n = 122), 21.5% HER2-enriched (n = 56), 15.7% luminal B (n = 41), 14.2% normal-like (n = 37), and 1.9% basal-like (n = 5); HER2-enriched subtypes were more common in metastatic versus primary tumors (32.0% vs. 18.7%; p = .038). Median PFS differences between luminal and nonluminal (6.7 vs. 5.2 months; adjusted hazard ratio, 0.66; 95% confidence interval [CI], 0.47-0.94; p = .020) and HER2-enriched and non-HER2-enriched subtypes (5.2 vs. 6.2 months; adjusted hazard ratio, 1.53; 95% CI, 1.07-2.19; p = .019) were significant. Everolimus plus exemestane significantly improved median PFS versus placebo plus exemestane among patients with HER2-enriched tumors (5.8 vs. 4.1 months; adjusted hazard ratio, 0.49; 95% CI, 0.26-0.90; p = .034); however, the association between HER2-enriched tumors and everolimus benefit was nonsignificant (p = .433). CONCLUSION: The HER2-enriched subtype was identified in a substantial proportion of advanced HR+/HER2-negative breast tumors, and was a consistent biomarker of poor prognosis. Tailored therapies are therefore needed for HER2-enriched tumors in the advanced HR+/HER2-negative breast cancer setting. IMPLICATIONS FOR PRACTICE: Using 261 tumor samples from the BOLERO-2 phase III clinical trial, this study shows that a substantial proportion (20%-30%) of hormone receptor-positive (HR+)/human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancers do not have a luminal A or B gene expression profile. This group of patients with nonluminal disease has a poor survival outcome regardless of the addition of everolimus to exemestane. This is the second study that confirms the prognostic value of this biomarker. Overall, these findings indicate a necessity to design novel clinical trials targeting nonluminal disease within HR+/HER2-negative breast cancer.

Tyrosine oxidation and nitration in transmembrane peptides is connected to lipid peroxidation.

Tyrosine nitration is an oxidative post-translational modification that can occur in proteins associated to hydrophobic bio-structures such as membranes and lipoproteins. In this work, we have studied tyrosine nitration in membranes using a model system consisting of phosphatidylcholine liposomes with pre-incorporated tyrosine-containing 23 amino acid transmembrane peptides. Tyrosine residues were located at positions 4, 8 or 12 of the amino terminal, resulting in different depths in the bilayer. Tyrosine nitration was accomplished by exposure to peroxynitrite and a peroxyl radical donor or hemin in the presence of nitrite. In egg yolk phosphatidylcholine liposomes, nitration was highest for the peptide with tyrosine at position 8 and dramatically increased as a function of oxygen levels. Molecular dynamics studies support that the proximity of the tyrosine phenolic ring to the linoleic acid peroxyl radicals contributes to the efficiency of tyrosine oxidation. In turn, α-tocopherol inhibited both lipid peroxidation and tyrosine nitration. The mechanism of tyrosine nitration involves a "connecting reaction" by which lipid peroxyl radicals oxidize tyrosine to tyrosyl radical and was fully recapitulated by computer-assisted kinetic simulations. Altogether, this work underscores unique characteristics of the tyrosine oxidation and nitration process in lipid-rich milieu that is fueled via the lipid peroxidation process.

Synthesis of Allylic Amines by Asymmetric Transfer Hydrogenation of α,ß-Unsaturated N-(tert-Butylsulfinyl)imines.

Primary allylic amines with enantiomeric excesses from 97 to >99% were prepared by asymmetric transfer hydrogenation of α,ß-unsaturated N-(tert-butylsulfinyl)ketimines followed by removal of the sulfinyl group. The effect caused by different substituents at the C═C bond and at the iminic carbon atom on the chemoselectivity of the reduction was studied. The desired enantiomer of the final allylic amine can be synthesized by choosing the sulfinyl group with the appropriate absolute configuration.

Spanish Preanalytical Quality Monitoring Program (SEQC), an overview of 12 years' experience.

BACKGROUND: Preanalytical variables, such as sample collection, handling and transport, may affect patient results. Preanalytical phase quality monitoring should be established in order to minimize laboratory errors and improve patient safety. METHODS: A retrospective study (2001-2013) of the results obtained through the Spanish Society of Clinical Biochemistry and Molecular Pathology (SEQC) External quality assessment (preanalytical phase) was performed to summarize data regarding the main factors affecting preanalytical phase quality. Our aim was to compare data from 2006 to 2013 with a previously published manuscript assessing the 2001-2005 period. RESULTS: A significant decrease in rejection rates was observed both for blood and urine samples. For serum samples, the most frequent rejection causes in the first period were non-received samples (37.5%), hemolysis (29.3%) and clotted samples (14.4%). Conversely, in the second period, hemolysis was the main rejection cause (36.2%), followed by non-received samples (34.5%) and clotted samples (11.1%). For urine samples, the main rejection cause overall was a non-received sample (up to 86.1% of cases in the second period, and 81.6% in the first). For blood samples with anticoagulant, the number of rejections also decreased. While plasma-citrate-ESR still showed the highest percentages of rejections (0.980% vs. 1.473%, p<0.001), the lowest corresponded to whole-blood EDTA (0.296% vs. 0.381%, p<0.001). CONCLUSIONS: For the majority of sample types, a decrease in preanalytical errors was confirmed. Improvements in organization, implementation of standardized procedures in the preanalytical phase, and participation in a Spanish external quality assessment scheme may have notably contributed to error reduction in this phase.

Evaluation of the toxicity of α-(phenylselanyl) acetophenone in mice.

Selenium is an essential micronutrient with several biological roles in the human body, but supra nutritional consumption can cause toxic effects. The potential deleterious effects of organoselenium compounds are controversial. The compound α-(phenylselanyl) acetophenone (PSAP) exhibits antioxidant, antidepressant-like and glutathione peroxidase-like activity, which makes important the elucidation of any toxic effects. Hence, the present study aims to investigate the in vitro toxicity of PSAP in Chinese Hamster ovary cells (through MTT assay) and analyse its genotoxicity using the comet assay in mice leukocytes after acute or chronic treatments, alongside with biochemical analyses. Our results demonstrate that the oral administration of PSAP in acute (1, 5, 10, 50, 200 mg/kg) and chronic (1, 10, 50, 200 mg/kg) doses did not cause genotoxicity. The compound presented cytotoxic effect in the MTT assay just at 500 µM after 24 h of administration and at 250 and 500 µM after 48 and 72 h of administration. According to biochemical analysis, PSAP presented a minor toxic effect by altering δ-ALA-D activity in liver and catalase activity in kidney at the highest tested concentration. Taking together, these data indicate that PSAP has low toxic effects after chronic administration in mice.

Organochalcogen compounds from glycerol: synthesis of new antioxidants.

We describe here a simple method for the synthesis of glycerol derivatives containing an organochalcogen unit (Se, Te and S) using NaBH4 and PEG-400 as a solvent. The new methodology was used to synthesize a range of new organochalcogen compounds in good yields. Furthermore, four of synthesized compounds were evaluated for their antioxidant activity using different assays, such as 2-azinobis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS), 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical, nitric oxide (NO) and hydroxyl radical (OH) scavenging, ferric ion reducing antioxidant power (FRAP), ferrous ion chelating, superoxide dismutase-like activity and inhibition of linoleic acid lipid peroxidation. The new organotellurium 2,2-dimethyl-4-(phenyltellanylmethyl)-1,3-dioxolane 3 j showed antioxidant activity and was more effective in inhibition of induced lipid peroxidation compared to solketal 4. Selenium and sulfur analogs 3a and 3m and solketal 4 did not present antioxidant effect. These findings suggest that 2,2-dimethyl-4-(phenyltellanylmethyl)-1,3-dioxolane 3 j is a promising antioxidant and that its activity is influenced by the presence of the tellurium atom on the structure.

How do decision making and fairness mediate the relationship between involuntary hospitalisation and perceived coercion among psychiatric inpatients?

BACKGROUND: Coercion perceived by psychiatric inpatients is not exclusively determined by formal measures such as involuntary admissions, seclusion or restraint, but is also associated with patients' characteristics and professionals' attitude. AIMS: This study examined how inpatients' involvement in the decision making process, the respect of their decision making preference, and their feeling of having been treated fairly mediate the relationship between involuntary hospitalisation and perceived coercion both at admission and during hospital stay. METHODS: Mediation analysis were performed in order to study the relationship between involuntary hospitalisation and perceived coercion among 230 patients, voluntarily and involuntarily admitted in six psychiatric hospitals. RESULTS: 32.2% of the participants were involuntarily hospitalised. Taken individually, stronger participants' involvement in decision making process, better respect for their decision making preference and higher level of perceived fairness partially mediated the relationship between involuntary hospitalisation and perceived coercion by reducing the level of the latter both at admission and during the hospitalisation. In multiple mediator models, only involvement and respect played an important role at admission. During the hospitalisation, perceived fairness was the most relevant mediator, followed by involvement in decision making. CONCLUSIONS: During psychiatric hospitalisation patients' involvement in decision making, respect of their decision making preference and perceived fairness determined the relationship between involuntary hospitalisation and perceived coercion, but not in the same way at admission and during the stay. Involving patients in decision making and treating them fairly may be more relevant than taking account of their decision making preference in order to reduce perceived coercion.

Coinfections and comorbidities observed in COVID-19 during the influenza season in the pediatric patient.

OBJECTIVE: To evaluate if the comorbidity and coinfections presented by SARS-CoV-2 infection vs. COVID-19 impact our Mexican children. METHOD: Prospective and observational study that included the 2020-2021 peak influenza season. All patients with a diagnosis of infection by SARS-CoV-2 vs. COVID-19 who were admitted to the Hospital Infantil de Mexico were analyzed. Real-time RT-PCR for SARS-CoV-2 was performed in all patients, determining E, RdRp and RP genes and protein N, as well as RT-PCR for detection of respiratory viruses. RESULTS: The inclusion criteria were met by 163 patients. The group with the highest risk of becoming ill was adolescents (40.4%), followed by schoolchildren and preschoolers (21.4% and 19.6% of the cases, respectively). There were three cases with viral coinfection: two (1.2%) with parvovirus B-19 and one (0.6%) with herpes type I; another two (1.2%) showed bacterial coinfection. The main comorbidity were obesity, acute lymphoblastic leukemia and arterial hypertension. Regarding mortality, we only had four cases (2.4%). CONCLUSIONS: Obesity, cancer, hypertension, heart disease and diabetes are comorbidity present in our patients, as referred to in literature, but not coinfections. In our study, we did not have any associated mortality related to comorbidity.

OBJETIVO: Evaluar el impacto de la comorbilidad y de las coinfecciones presentadas por la infección por SARS-CoV-2 vs. COVID-19 en niños mexicanos. MÉTODO: Estudio prospectivo y observacional que comprendió la temporada alta de influenza 2020-2021, analizando todos los pacientes con diagnóstico de infección vs. enfermedad por SARS-CoV-2 vs. COVID-19 que ingresaron al Hospital Infantil de México. Se realizó en todos RT-PCR en tiempo real para SARS-CoV-2, determinando gen E, gen RdRp, gen RP y proteína N, y RT-PCR multiplex para detección de virus respiratorios. RESULTADOS: Los criterios de inclusión los cumplieron 163 pacientes. El grupo con mayor riesgo de enfermar fueron los adolescentes (40.4%), seguidos de los escolares y preescolares (21.4% y 19.6% de los casos, respectivamente). Hubo tres casos con coinfección viral: dos (1.2%) con parvovirus B-19 y uno (0.6%) con herpes tipo I; hubo otros dos (1.2%) con coinfección bacteriana. La principal comorbilidad correspondió a obesidad, leucemia linfoblástica aguda e hipertensión arterial. En cuanto a mortalidad, solo hubo cuatro casos (2.4%). CONCLUSIONES: Obesidad, cáncer, hipertensión, cardiopatías y diabetes constituyen la comorbilidad en nuestros pacientes, como se refiere en la literatura, no así las coinfecciones. En nuestro estudio no hubo casos de mortalidad relacionada con la comorbilidad.

Women involvement in the informal caregiving field: A perspective review.

The patient recovery process of individual with mental health disorder is reinforced if they are connected with their community and supported by relatives. The literature has shown that caregivers are important, although their roles can lead to alterations in their own health; and women are the most involved in this role. The present review investigated women's involvement in the informal caregiver scientific field. A literature review indicated gender differences; researchers who are women are more interested in this field than men. Even with a good representation of women in this scientific field, the results showed a statistically significant gender difference for the first and second authors, whereas there was no significant gender difference among the last authors. More efforts must be made to recognize the importance of women's involvement in research because they raise a specific important field. Family caregivers are key players in the healthcare system, but to date, there has been little recognition of their enormous contribution. Our results also indicated the informal caregiver role is filled more by women than by men, which creates social inequalities in many domains, especially in opportunities at the professional level. Tailored interventions are required to address the specific needs and issues of family caregivers. A better redistribution of unpaid work, such as informal caregiving, compared to paid work must be made to respect gender in social existence.

Feeling coerced during voluntary and involuntary psychiatric hospitalisation: A review and meta-aggregation of qualitative studies.

Objective: This review aimed to provide an aggregative synthesis of the qualitative evidence on patients' experienced coercion during voluntary and involuntary psychiatric hospitalisation. Design: A qualitative review. Data sources: The search was conducted, in five bibliographic databases: Embase.com, Ovid MEDLINE(R) ALL, APA PsycINFO Ovid, Web of Science Core Collection and the Cochrane Database of Systematic Reviews. Review methods: Following the Joanna Briggs Institute approach, a systematized procedure was applied throughout the review process, from data search to synthesis of results. The reporting of this review was guided by the standards of the PRISMA 2020 statement. The quality of the included studies was critically appraised by two independent reviewers using the JBI Critical Appraisal Checklist. Included findings were synthesized using meta-aggregation. Confidence in the review findings was assessed following the Confidence in the Output of Qualitative research synthesis (ConQual) approach. Results: A total of 423 studies were identified through the literature search and 26 were included in the meta-aggregation. Totally, 151 findings were extracted and aggregated into 27 categories and 7 synthesized findings. The synthesized findings focused on: the patients' experience of the hospitalisation and the associated feeling of coercion; the factors affecting this feeling, such as the involvement in the decision-making process, the relationships with the staff and the perception of the hospital treatment as effective and safe; the coping strategies adopted to deal with it and the patients' suggestions for alternatives. All synthesized findings reached an overall confidence score of "moderate". The seven findings were downgraded one level due to dependability limitations of the included studies. Conclusion: Based on these findings, seven recommendations for clinical practice where developed, such as fostering care ethics, promoting patients' voice and shared decision-making, and enhancing patients' perceived closeness, respect and fairness. Five recommendations for future research were also prompted, for instance improving the methodological quality and cultural variation of future qualitative studies, and exploring the psychosocial impact of experienced coercion on patients. For these recommendations to be effectively implemented, a profound change in the structure and culture of the mental health system should be promoted. The involvement of patients in the design, development and scientific evaluation of this change is strongly recommended.

A randomized controlled trial of a targeted support program for informal caregivers in adult psychiatry.

Background: The importance of informal caregivers for persons with severe mental illness has been demonstrated. However, this role may cause a high care burden that considerably affects caregiver health. The Ensemble program is a five-session brief individual intervention designed to support informal caregivers. This trial aimed to assess the efficacy of the program versus SAU (support as usual) for participants with a high care burden. Methods: A single-center randomized controlled trial including 149 participants was conducted. Caregivers in the intervention arm participated in the Ensemble program. The effects of the intervention were assessed using mixed models for repeated measures analysis of variance on improvements in informal caregivers' psychological health status, optimism levels, burden scores, and quality of life at three time points (T0 = pretest; T1 = posttest at 2 months, and T2 = follow-up at 4 months). Results: Analysis of the Global Psychological Index showed no significant effect at the two endpoints in favor of the Ensemble group. However, the Brief Symptom Inventory-Positive Symptom Distress Index was significantly lower at the two-month follow-up. A significant reduction in burden on the Zarit Burden Interview was observed post-intervention, along with an increase in optimism levels on the Life Orientation Test-Revised at follow-up in the Ensemble group. No significant differences were observed in quality of life. Clinical improvements in both psychological health status and burden levels were also identified. Conclusion: The Ensemble program offers an inclusive approach based on a recovery perspective that significantly reduces symptom distress and burden and increases optimism among informal caregivers.Clinical trial registration: https://clinicaltrials.gov/, NCT04020497.

Circulating tumor DNA reveals complex biological features with clinical relevance in metastatic breast cancer.

Liquid biopsy has proven valuable in identifying individual genetic alterations; however, the ability of plasma ctDNA to capture complex tumor phenotypes with clinical value is unknown. To address this question, we have performed 0.5X shallow whole-genome sequencing in plasma from 459 patients with metastatic breast cancer, including 245 patients treated with endocrine therapy and a CDK4/6 inhibitor (ET + CDK4/6i) from 2 independent cohorts. We demonstrate that machine learning multi-gene signatures, obtained from ctDNA, identify complex biological features, including measures of tumor proliferation and estrogen receptor signaling, similar to what is accomplished using direct tumor tissue DNA or RNA profiling. More importantly, 4 DNA-based subtypes, and a ctDNA-based genomic signature tracking retinoblastoma loss-of-heterozygosity, are significantly associated with poor response and survival outcome following ET + CDK4/6i, independently of plasma tumor fraction. Our approach opens opportunities for the discovery of additional multi-feature genomic predictors coming from ctDNA in breast cancer and other cancer-types.

Targeting HER2-AXL heterodimerization to overcome resistance to HER2 blockade in breast cancer.

Anti-HER2 therapies have markedly improved prognosis of HER2-positive breast cancer. However, different mechanisms play a role in treatment resistance. Here, we identified AXL overexpression as an essential mechanism of trastuzumab resistance. AXL orchestrates epithelial-to-mesenchymal transition and heterodimerizes with HER2, leading to activation of PI3K/AKT and MAPK pathways in a ligand-independent manner. Genetic depletion and pharmacological inhibition of AXL restored trastuzumab response in vitro and in vivo. AXL inhibitor plus trastuzumab achieved complete regression in trastuzumab-resistant patient-derived xenograft models. Moreover, AXL expression in HER2-positive primary tumors was able to predict prognosis. Data from the PAMELA trial showed a change in AXL expression during neoadjuvant dual HER2 blockade, supporting its role in resistance. Therefore, our study highlights the importance of targeting AXL in combination with anti-HER2 drugs across HER2-amplified breast cancer patients with high AXL expression. Furthermore, it unveils the potential value of AXL as a druggable prognostic biomarker in HER2-positive breast cancer.