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Background TP53 is a master tumor suppressor gene, mutated in approximately half of all human cancers. Given the many regulatory roles of the corresponding p53 protein, it is possible to infer loss of p53 activity – which may occur due to alterations in trans – from gene expression patterns. Several such alterations that phenocopy p53 loss are known, however additional ones may exist, but their identity and prevalence among human tumors are not well characterized. Results We perform a large-scale statistical analysis on transcriptomes of ~ 7,000 tumors and ~ 1,000 cell lines, estimating that 12% and 8% of tumors and cancer cell lines, respectively, phenocopy TP53 loss: they are likely deficient in the activity of the p53 pathway, while not bearing obvious TP53 inactivating mutations. While some of these cases are explained by amplifications in the known phenocopying genes MDM2 , MDM4 and PPM1D , many are not. An association analysis of cancer genomic scores jointly with CRISPR/RNAi genetic screening data identified an additional common TP53 -loss phenocopying gene, USP28 . Deletions in USP28 are associated with a TP53 functional impairment in 2.9–7.6% of breast, bladder, lung, liver and stomach tumors, and have comparable effect size to MDM4 amplifications. Additionally, in the known copy number alteration (CNA) segment harboring MDM2 , we identify an additional co-amplified gene ( CNOT2 ) that may cooperatively boost the TP53 functional inactivation effect of MDM2. An analysis of cancer cell line drug screens using phenocopy scores suggests that TP53 (in)activity commonly modulates associations between anticancer drug effects and various genetic markers, such as PIK3CA and PTEN mutations, and should thus be considered as a drug activity modifying factor in precision medicine. As a resource, we provide the drug-genetic marker associations that differ depending on TP53 functional status. Conclusions Human tumors that do not bear obvious TP53 genetic alterations but that phenocopy p53 activity loss are common, and the USP28 gene deletions are one likely cause.

ObjectiveWe previously reported a characterisation of the hepatocellular carcinoma (HCC) immune contexture and described an immune-specific class. We now aim to further delineate the immunogenomic classification of HCC to incorporate features that explain responses/resistance to immunotherapy.DesignWe performed RNA and whole-exome sequencing, T-cell receptor (TCR)-sequencing, multiplex immunofluorescence and immunohistochemistry in a novel cohort of 240 HCC patients and validated our results in other cohorts comprising 660 patients.ResultsOur integrative analysis led to define: (1) the inflamed class of HCC (37%), which includes the previously reported immune subclass (22%) and a new immune-like subclass (15%) with high interferon signalling, cytolytic activity, expression of immune-effector cytokines and a more diverse T-cell repertoire. A 20-gene signature was able to capture ~90% of these tumours and is associated with response to immunotherapy. Proteins identified in liquid biopsies recapitulated the inflamed class with an area under the ROC curve (AUC) of 0.91; (2) The intermediate class, enriched in TP53 mutations (49% vs 29%, p=0.035), and chromosomal losses involving immune-related genes and; (3) the excluded class, enriched in CTNNB1 mutations (93% vs 27%, p<0.001) and PTK2 overexpression due to gene amplification and promoter hypomethylation. CTNNB1 mutations outside the excluded class led to weak activation of the Wnt-βcatenin pathway or occurred in HCCs dominated by high interferon signalling and type I antigen presenting genes.ConclusionWe have characterised the immunogenomic contexture of HCC and defined inflamed and non-inflamed tumours. Two distinct CTNNB1 patterns associated with a differential role in immune evasion are described. These features may help predict immune response in HCC.

ObjectiveThe diversity of the tumour microenvironment (TME) of intrahepatic cholangiocarcinoma (iCCA) has not been comprehensively assessed. We aimed to generate a novel molecular iCCA classifier that incorporates elements of the stroma, tumour and immune microenvironment (‘STIM’ classification).DesignWe applied virtual deconvolution to transcriptomic data from ~900 iCCAs, enabling us to devise a novel classification by selecting for the most relevant TME components. Murine models were generated through hydrodynamic tail vein injection and compared with the human disease.ResultsiCCA is composed of five robust STIM classes encompassing both inflamed (35%) and non-inflamed profiles (65%). The inflamed classes, named immune classical (~10%) and inflammatory stroma (~25%), differ in oncogenic pathways and extent of desmoplasia, with the inflammatory stroma showing T cell exhaustion, abundant stroma and KRAS mutations (p<0.001). Analysis of cell–cell interactions highlights cancer-associated fibroblast subtypes as potential mediators of immune evasion. Among the non-inflamed classes, the desert-like class (~20%) harbours the lowest immune infiltration with abundant regulatory T cells (p<0.001), whereas the hepatic stem-like class (~35%) is enriched in ‘M2-like’ macrophages, mutations in IDH1/2 and BAP1, and FGFR2 fusions. The remaining class (tumour classical: ~10%) is defined by cell cycle pathways and poor prognosis. Comparative analysis unveils high similarity between a KRAS/p19 murine model and the inflammatory stroma class (p=0.02). The KRAS-SOS inhibitor, BI3406, sensitises a KRAS-mutant iCCA murine model to anti-PD1 therapy.ConclusionsWe describe a comprehensive TME-based stratification of iCCA. Cross-species analysis establishes murine models that align closely to human iCCA for the preclinical testing of combination strategies.

The COVID-19 pandemic and the precautionary measures applied globally (lockdowns and curfews) have impacted homes, including work. Working from home (WFH) has emerged as a growing trend in the post-pandemic era. The research question was: Are our homes ready for teleworking? To respond, a national prospective mixed approach was launched for Spanish households during the spring 2020 lockdown, using two online questionnaires, one quantitative and the other qualitative. Through a survey, photographs, and narratives, the study evaluates the perceived adequacy of telework spaces and their specific characteristics, the availability of digital resources and the internet. A total of 1800 surveys and over 200 images and texts related to telework environments were obtained. The results suggest that the adequacy of these spaces was insufficient for more than a quarter of the homes. Also, strong relations between the perceived workspace adequacy and a social status or stability of homes were shown and validated, despite other sociodemographic features, the home composition or habitat were not related. Some other variables statistically significant were occupation regime, type and surface of dwellings; their indoor environmental quality; the availability of exclusive spaces for teleworking; quality of digital resources; and the specific space features. The analysis was completed with qualitative insights through photos and texts. Telework, lived in this context as an experiment, needs this reflection from an environmental, resource-availability, and ergonomic point of view.

An increasing number of mobile health (mHealth) apps are becoming available for download and use on mobile devices. Even with the increase in availability and use of mHealth apps, there has still not been a lot of research into understanding the intention to use this kind of apps. The purpose of this study was to investigate a technology acceptance model (TAM) that has been specially designed for primary health care applications. The proposed model is an extension of the TAM, and was empirically tested using data obtained from a survey of mHealth app users (n=310). The research analyzed 2 additional external factors: promotion of health and health benefits. Data were analyzed with a PLS-SEM software and confirmed that gender moderates the adoption of mHealth apps in Spain. The explanatory capacity (R for behavioral intention to use) of the proposed model was 76.4%. Likewise, the relationships of the external constructs of the extended TAM were found to be significant. The results show the importance of healthy habits developed by using mHealth apps. In addition, communication campaigns for these apps should be aimed at transferring the usefulness of eHealth as an agent for transforming attitudes; additionally, as more health benefits are obtained, ease of use becomes greater. Perceived usefulness (PU; β=.415, t =3.442, P=.001), attitude toward using (β=.301, t =2.299, P=.02), and promotion of health (β=.210, t =2.108, P=.03) were found to have a statistically significant impact on behavior intention to use eHealth apps (R =76.4%). Perceived ease of use (PEOU; β=.179, t =2.623, P=.009) and PU (β=.755, t =12.888, P<.001) were found to have a statistically significant impact on attitude toward using (R >=78.2%). Furthermore, PEOU (β=.203, t =2.810, P=.005), health benefits (β=.448, t =4.010, P<.001), and promotion of health (β=.281, t =2.393, P=.01) exerted a significant impact on PU (R =72.7%). Finally, health benefits (β=.640, t =14.948, P<.001) had a statistically significant impact on PEOU (R =40.9%), while promotion of health (β=.865, t =29.943, P<.001) significantly influenced health benefits (R =74.7%). mHealth apps could be used to predict the behavior of patients in the face of recommendations to prevent pandemics, such as COVID-19 or SARS, and to track users' symptoms while they stay at home. Gender is a determining factor that influences the intention to use mHealth apps, so perhaps different interfaces and utilities could be designed according to gender.

Adjuvant abemaciclib plus endocrine therapy previously showed a significant improvement in invasive disease-free survival and distant relapse-free survival in hormone receptor-positive, human epidermal growth factor receptor 2 (HER2; also known as ERBB2)-negative, node-positive, high-risk, early breast cancer. Here, we report updated results from an interim analysis to assess overall survival as well as invasive disease-free survival and distant relapse-free survival with additional follow-up. In monarchE, an open-label, randomised, phase 3 trial, adult patients (aged ≥18 years) who had hormone receptor-positive, HER2-negative, node-positive, early breast cancer at a high risk of recurrence with an Eastern Cooperative Oncology Group performance status of 0 or 1 were recruited from 603 sites including hospitals and academic and community centres in 38 countries. Patients were randomly assigned (1:1) by means of an interactive web-based response system (block size of 4), stratified by previous chemotherapy, menopausal status, and region, to receive standard-of-care endocrine therapy of physician's choice for up to 10 years with or without abemaciclib 150 mg orally twice a day for 2 years (treatment period). All therapies were administered in an open-label manner without masking. High-risk disease was defined as either four or more positive axillary lymph nodes, or between one and three positive axillary lymph nodes and either grade 3 disease or tumour size of 5 cm or larger (cohort 1). A smaller group of patients were enrolled with between one and three positive axillary lymph nodes and Ki-67 of at least 20% as an additional risk feature (cohort 2). This was a prespecified overall survival interim analysis planned to occur 2 years after the primary outcome analysis for invasive disease-free survival. Efficacy was assessed in the intention-to-treat population. Safety was assessed in all treated patients. The study is registered with ClinicalTrials.gov, NCT03155997, and is ongoing. Between July 17, 2017, and Aug 12, 2019, 5637 patients were randomly assigned (5601 [99·4%] were women and 36 [0·6%] were men). 2808 were assigned to receive abemaciclib plus endocrine therapy and 2829 were assigned to receive endocrine therapy alone. At a median follow-up of 42 months (IQR 37–47), median invasive disease-free survival was not reached in either group and the invasive disease-free survival benefit previously reported was sustained: HR 0·664 (95% CI 0·578–0·762, nominal p<0·0001). At 4 years, the absolute difference in invasive disease-free survival between the groups was 6·4% (85·8% [95% CI 84·2–87·3] in the abemaciclib plus endocrine therapy group vs 79·4% [77·5–81·1] in the endocrine therapy alone group). 157 (5·6%) of 2808 patients in the abemaciclib plus endocrine therapy group died compared with 173 (6·1%) of 2829 patients in the endocrine therapy alone group (HR 0·929, 95% CI 0·748–1·153; p=0·50). The most common grade 3–4 adverse events were neutropenia (in 548 [19·6%] of 2791 patients receiving abemaciclib plus endocrine therapy vs 24 [0·9%] of 2800 patients in the endocrine therapy alone group), leukopenia (318 [11·4%] vs 11 [0·4%]), and diarrhoea (218 [7·8%] vs six [0·2%]). Serious adverse events occurred in 433 (15·5%) of 2791 patients receiving abemaciclib plus endocrine therapy versus 256 (9·1%) of 2800 receiving endocrine therapy. There were two treatment-related deaths in the abemaciclib plus endocrine therapy group (diarrhoea and pneumonitis) and none in the endocrine therapy alone group. Adjuvant abemaciclib reduces the risk of recurrence. The benefit is sustained beyond the completion of treatment with an absolute increase at 4 years, further supporting the use of abemaciclib in patients with high-risk hormone receptor-positive, HER2-negative early breast cancer. Further follow-up is needed to establish whether overall survival can be improved with abemaciclib plus endocrine therapy in these patients. Eli Lilly.

Among women with previously untreated hormone-receptor–positive advanced breast cancer, the addition of the cyclin-dependent kinase inhibitor palbociclib to letrozole therapy resulted in longer progression-free survival than that with letrozole alone. Hormone-receptor–positive breast cancer represents the largest therapeutic subtype of the disease, accounting for 60 to 65% of all malignant neoplasms of the breast. For more than 50 years, the treatment of hormone-receptor–positive disease has been focused on targeting the estrogen-receptor signaling pathway. 1 However, both new and acquired resistance to hormonal blockade occurs in a large subset of these cancers, and new approaches are needed. 2 The cyclin-dependent kinases (CDKs) are a large family of serine–threonine kinases that play an important role in regulating cell-cycle progression. The interaction of cyclin D with CDK4 and CDK6 facilitates the hyperphosphorylation of the retinoblastoma (Rb) . . .

Objective To identify situations and behaviors occurring during contact visits that are likely to have an impact on a foster child's well‐being. Background It has been argued that contact visits between foster children and birth parents can help to maintain attachment bonds and support the child's development. However, contact continues to be a subject of controversy, and evidence of both benefits and drawbacks has been reported in the literature. Few studies have examined what actually occurs during such visits, how parents and children interact, and what role is played by those involved. Method We conducted an in‐depth qualitative observational analysis of the behavior of participants in contact visits (birth parent, child, and social worker), as well as of the characteristics of the venue. Participants were 20 children in nonkinship foster care and their birth parents. Information regarding the characteristics of visits was provided by the child protection services and the fostering agencies involved. Results The analysis revealed a large number of positive behaviors among parents, children, and social workers, but also the need for improvement in several areas (e.g., family relationships, social/communication skills, and presents). Conclusions This study highlights the need to improve contact visits by developing intervention strategies targeting all those involved. Notably, the support and supervision provided by social workers was not always adequate. Implications The results of this study could be used to develop an instrument for assessing the quality of contact visits and identifying aspects that need to be improved.

Background We recently described the genotype/phenotype features of all Spanish patients diagnosed with McArdle disease as of January 2011 ( n  = 239, prevalence of ~1/167,000) ( J Neurol Neurosurg Psychiatry 2012;83:322–8). Several caveats were however identified suggesting that the prevalence of the disease is actually higher. Methods We have now updated main genotype/phenotype data, as well as potential associations within/between them, of all Spanish individuals currently diagnosed with McArdle disease (December 2016). Results Ninety-four new patients (all Caucasian) have been diagnosed, yielding a prevalence of ~1/139,543 individuals. Around 55% of the mutated alleles have the commonest PYGM pathogenic mutation p.R50X, whereas p.W798R and p.G205S account for 10 and 9% of the allelic variants, respectively. Seven new mutations were identified: p.H35R, p.R70C, p.R94Q, p.L132WfsX163, p.Q176P, p.R576Q, and c.244-3_244-2CA. Almost all patients show exercise intolerance, the second wind phenomenon and high serum creatine kinase activity. There is, however, heterogeneity in clinical severity, with 8% of patients being asymptomatic during normal daily life, and 21% showing limitations during daily activities and fixed muscle weakness. A major remaining challenge is one of diagnosis, which is often delayed until the third decade of life in 72% of new patients despite the vast majority (86%) reporting symptoms before 20 years. An important development is the growing proportion of those reporting a 4-year improvement in disease severity (now 34%) and following an active lifestyle (50%). Physically active patients are more likely to report an improvement after a 4-year period in the clinical course of the disease than their inactive peers (odds ratio: 13.98; 95% confidence interval: 5.6, 34.9; p  < 0.001). Peak oxygen uptake is also higher in the former (20.7 ± 6.0 vs. 16.8 ± 5.3 mL/kg/min, p  = 0.0013). Finally, there is no association between PYGM genotype and phenotype manifestation of the disease. Conclusions The reported prevalence of McArdle disease grows exponentially despite frequent, long delays in genetic diagnosis, suggesting that many patients remain undiagnosed. Until a genetic cure is available (which is not predicted in the near future), current epidemiologic data support that adoption of an active lifestyle is the best medicine for these patients.