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As part of the Human Functional Genomics Project, which aims to understand the factors that determine the variability of immune responses, we investigated genetic variants affecting cytokine production in response to ex vivo stimulation in two independent cohorts of 500 and 200 healthy individuals. We demonstrate a strong impact of genetic heritability on cytokine production capacity after challenge with bacterial, fungal, viral, and non-microbial stimuli. In addition to 17 novel genome-wide significant cytokine QTLs (cQTLs), our study provides a comprehensive picture of the genetic variants that influence six different cytokines in whole blood, blood mononuclear cells, and macrophages. Important biological pathways that contain cytokine QTLs map to pattern recognition receptors (TLR1-6-10 cluster), cytokine and complement inhibitors, and the kallikrein system. The cytokine QTLs show enrichment for monocyte-specific enhancers, are more often located in regions under positive selection, and are significantly enriched among SNPs associated with infections and immune-mediated diseases. PAPERCLIP.
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Citocinas/genética , Citocinas/imunologia , Infecções/imunologia , Adolescente , Adulto , Idoso , Sangue/imunologia , Feminino , Estudo de Associação Genômica Ampla , Projeto Genoma Humano , Humanos , Infecções/microbiologia , Infecções/virologia , Leucócitos Mononucleares/imunologia , Macrófagos/imunologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Locos de Características QuantitativasRESUMO
Differences in susceptibility to immune-mediated diseases are determined by variability in immune responses. In three studies within the Human Functional Genomics Project, we assessed the effect of environmental and non-genetic host factors of the genetic make-up of the host and of the intestinal microbiome on the cytokine responses in humans. We analyzed the association of these factors with circulating mediators and with six cytokines after stimulation with 19 bacterial, fungal, viral, and non-microbial metabolic stimuli in 534 healthy subjects. In this first study, we show a strong impact of non-genetic host factors (e.g., age and gender) on cytokine production and circulating mediators. Additionally, annual seasonality is found to be an important environmental factor influencing cytokine production. Alpha-1-antitrypsin concentrations partially mediate the seasonality of cytokine responses, whereas the effect of vitamin D levels is limited. The complete dataset has been made publicly available as a comprehensive resource for future studies. PAPERCLIP.
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Citocinas/genética , Citocinas/imunologia , Interação Gene-Ambiente , Adolescente , Adulto , Idoso , Envelhecimento , Animais , Artrite/imunologia , Sangue/imunologia , Índice de Massa Corporal , Feminino , Projeto Genoma Humano , Humanos , Infecções/imunologia , Infecções/microbiologia , Infecções/virologia , Inflamação/imunologia , Inflamação/microbiologia , Leucócitos Mononucleares/imunologia , Macrófagos/imunologia , Masculino , Camundongos , Pessoa de Meia-Idade , Estações do Ano , Caracteres SexuaisRESUMO
In the Drug Rediscovery Protocol (DRUP), patients with cancer are treated based on their tumor molecular profile with approved targeted and immunotherapies outside the labeled indication. Importantly, patients undergo a tumor biopsy for whole-genome sequencing (WGS) which allows for a WGS-based evaluation of routine diagnostics. Notably, we observed that not all biopsies of patients with dMMR/MSI-positive tumors as determined by routine diagnostics were classified as microsatellite-unstable by subsequent WGS. Therefore, we aimed to evaluate the discordance rate between routine dMMR/MSI diagnostics and WGS and to further characterize discordant cases. We assessed patients enrolled in DRUP with dMMR/MSI-positive tumors identified by routine diagnostics, who were treated with immune checkpoint blockade (ICB) and for whom WGS data were available. Patient and tumor characteristics, study treatment outcomes, and material from routine care were retrieved from the patient medical records and via Palga (the Dutch Pathology Registry), and were compared with WGS results. Initially, discordance between routine dMMR/MSI diagnostics and WGS was observed in 13 patients (13/121; 11%). The majority of these patients did not benefit from ICB (11/13; 85%). After further characterization, we found that in six patients (5%) discordance was caused by dMMR tumors that did not harbor an MSI molecular phenotype by WGS. In six patients (5%), discordance was false due to the presence of multiple primary tumors (n = 3, 2%) and misdiagnosis of dMMR status by immunohistochemistry (n = 3, 2%). In one patient (1%), the exact underlying cause of discordance could not be identified. Thus, in this group of patients limited to those initially diagnosed with dMMR/MSI tumors by current routine diagnostics, the true assay-based discordance rate between routine dMMR/MSI-positive diagnostics and WGS was 5%. To prevent inappropriate ICB treatment, clinicians and pathologists should be aware of the risk of multiple primary tumors and the limitations of different tests. © 2024 The Pathological Society of Great Britain and Ireland.
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Reparo de Erro de Pareamento de DNA , Inibidores de Checkpoint Imunológico , Instabilidade de Microssatélites , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia/métodos , Sequenciamento Completo do Genoma , Adulto , Biomarcadores Tumorais/genética , Neoplasias/genética , Neoplasias/terapia , Neoplasias/patologia , Idoso de 80 Anos ou mais , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapiaRESUMO
Osteosarcoma is a primary bone tumor that exhibits a complex genomic landscape characterized by gross chromosomal abnormalities. Osteosarcoma patients often develop metastatic disease, resulting in limited therapeutic options and poor survival rates. To gain knowledge on the mechanisms underlying osteosarcoma heterogeneity and metastatic process, it is important to obtain a detailed profile of the genomic alterations that accompany osteosarcoma progression. We performed WGS on multiple tissue samples from six patients with osteosarcoma, including the treatment naïve biopsy of the primary tumor, resection of the primary tumor after neoadjuvant chemotherapy, local recurrence, and distant metastases. A comprehensive analysis of single-nucleotide variants (SNVs), structural variants, copy number alterations (CNAs), and chromothripsis events revealed the genomic heterogeneity during osteosarcoma progression. SNVs and structural variants were found to accumulate over time, contributing to an increased complexity of the genome of osteosarcoma during disease progression. Phylogenetic trees based on SNVs and structural variants reveal distinct evolutionary patterns between patients, including linear, neutral, and branched patterns. The majority of osteosarcomas showed variable copy number profiles or gained whole-genome doubling in later occurrences. Large proportions of the genome were affected by loss of heterozygosity (LOH), although these regions remain stable during progression. Additionally, chromothripsis is not confined to a single early event, as multiple other chromothripsis events may appear in later occurrences. Together, we provide a detailed analysis of the complex genome of osteosarcomas and show that five of six osteosarcoma genomes are highly dynamic and variable during progression.
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Neoplasias Ósseas , Variações do Número de Cópias de DNA , Progressão da Doença , Osteossarcoma , Humanos , Osteossarcoma/genética , Osteossarcoma/patologia , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Masculino , Feminino , Adulto , Polimorfismo de Nucleotídeo Único , Perda de Heterozigosidade , Sequenciamento Completo do Genoma , Cromotripsia , Adolescente , Genoma HumanoRESUMO
BACKGROUND: The prognosis of malignant primary high-grade brain tumors, predominantly glioblastomas, is poor despite intensive multimodality treatment options. In more than 50% of patients with glioblastomas, potentially targetable mutations are present, including rearrangements, altered splicing, and/or focal amplifications of epidermal growth factor receptor (EGFR) by signaling through the RAF/RAS pathway. We studied whether treatment with the clinically available anti-EGFR monoclonal antibody panitumumab provides clinical benefit for patients with RAF/RAS-wild-type (wt) glioblastomas in the Drug Rediscovery Protocol (DRUP). METHODS: Patients with progression of treatment refractory RAF/RASwt glioblastoma were included for treatment with panitumumab in DRUP when measurable according to RANO criteria. The primary endpoints of this study are clinical benefit (CB: defined as confirmed objective response [OR] or stable disease [SD] ≥ 16 weeks) and safety. Patients were enrolled using a Simon-like 2-stage model, with 8 patients in stage 1 and up to 24 patients in stage 2 if at least 1 in 8 patients had CB in stage 1. RESULTS: Between 03-2018 and 02-2022, 24 evaluable patients were treated. CB was observed in 5 patients (21%), including 2 patients with partial response (8.3%) and 3 patients with SD ≥ 16 weeks (12.5%). After median follow-up of 15 months, median progression-free survival and overall survival were 1.7 months (95% CI 1.6-2.1 months) and 4.5 months (95% CI 2.9-8.6 months), respectively. No unexpected toxicities were observed. CONCLUSIONS: Panitumumab treatment provides limited CB in patients with recurrent RAF/RASwt glioblastoma precluding further development of this therapeutic strategy.
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Glioblastoma , Panitumumabe , Humanos , Panitumumabe/uso terapêutico , Panitumumabe/efeitos adversos , Panitumumabe/farmacologia , Feminino , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Glioblastoma/patologia , Glioblastoma/mortalidade , Masculino , Pessoa de Meia-Idade , Idoso , Adulto , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Antineoplásicos Imunológicos/uso terapêutico , Antineoplásicos Imunológicos/efeitos adversos , Proteínas ras/genética , Quinases raf/genética , Quinases raf/antagonistas & inibidoresRESUMO
Melanocytic neoplasms with spitzoid histomorphology are often difficult to classify without identifying genetic drivers such as kinase fusions. Traditional diagnostic methods, such as immunohistochemistry, can yield inconclusive results, and advanced techniques such as the Archer fusion assay are often inaccessible and costly. The Idylla GeneFusion Assay might offer a rapid and cost-effective alternative. This study compared Idylla and Archer in identifying ALK, pan-NTRK, RET, and ROS1 gene fusions. Of the 147 samples where next-generation sequencing did not detect genetic drivers, 89 (60.5%) meeting the tissue requirements were further analyzed using Idylla (Cohort A). Idylla demonstrated a sensitivity of 75% and a specificity of 100% in detecting these fusions. Additionally, among 27 randomly selected cases (Cohort B) that failed to meet the inclusion criteria, Idylla maintained the same levels of sensitivity and specificity. Our findings also show that Idylla can be effectively conducted with isolated RNA, broadening its applicability beyond tissue samples. Although the Idylla assay may not replace more comprehensive molecular assays such as Archer, it could serve as a valuable initial screening tool in diagnosing spitzoid melanocytic tumors.
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BACKGROUND: The WHO advocates patient and public involvement as an ethical imperative, due to the value of the lived experience of patients. A deeper understanding of the shared meanings and underlying beliefs of healthcare professionals and managers for and against including patients in care pathway development. OBJECTIVE: To explore the considerations of healthcare professionals and managers on the involvement of patients and public in care pathway development. METHODS: In a medical rehabilitation centre we conducted a single case study that was part of a 2-year action research programme on blended care pathway development. Following 14 semistructured interviews with healthcare professionals and managers, we analysed their discourses on the value of patient involvement as well as the potential threats and opportunities. RESULTS: We identified four discourses. Patient as expert frames involvement as relevant, as adding new perspectives and as required to fully understand the patient's needs. Skills and representation is based on the construct that obtaining valuable insights from patients requires certain skills and competences. Self-protection focusses on personal, interprofessional objections to patient involvement. Professional knows best reveals expertise-related reasons for avoiding or postponing involvement. CONCLUSION: These discourses explain why patient and public involvement in care pathway development is sometimes postponed, limited in scope and level of participation, and/or avoided. The following strategies might minimise the paralysing effect of these discourses: strengthen the capabilities of all stakeholders involved; use a mix of complementary techniques to gain involvement in distinct phases of care pathway development; and create/facilitate a safe environment. Put together, these strategies would foster ongoing, reciprocal learning that could enhance patient involvement. PATIENT OR PUBLIC CONTRIBUTION: This study belonged to an action research programme on blended care pathway development (developing an integrated, coordinated patient care plan that combines remote, digital telehealth applications, self-management tools and face-to-face care). Multidisciplinary teams took a quality collaborative approach to quality improvement (considering patients as stakeholders) to develop 11 blended care pathways. Although professionals and managers were instructed to invite patients onto their teams and to attend care pathway design workshops, few teams (3/11) actually did. Unravelling why this happened will help improve patient and public involvement in care pathway development.
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Procedimentos Clínicos , Pessoal de Saúde , Participação do Paciente , Humanos , Pessoal de Saúde/psicologia , Entrevistas como Assunto , Atitude do Pessoal de Saúde , Pesquisa QualitativaRESUMO
BACKGROUND: The global nursing shortages exacerbated by the COVID-19 pandemic necessitated a drastic reorganization in nursing practices. Work routines, the composition of teams and subsequently mundane nursing practices were all altered to sustain the accessibility and quality of care. These dramatic changes demanded a reshaping of the nurses' work environment. The aim of this study was to explore how nurses reshaped their work environment in the early stages of the COVID-19 pandemic. METHODS: A descriptive study comprising 26 semi-structured interviews conducted in a large Dutch teaching hospital between June and September 2020. Participants were nurses (including intensive care unit nurses), outpatient clinic assistants, nurse managers, and management (including one member of the Nurse Practice Council). The interviews were analysed with open, axial, and selective coding. RESULTS: We identified five themes: 1) the Nursing Staff Deployment Plan created new micro-teams with complementary roles to meet the care needs of COVID-19 infected patients; 2) nurse-led adaptations effectively managed the increased workload, thereby ensuring the quality of care; 3) continuous professional development ensured adequate competence levels for all roles; 4) interprofessional collaboration resulted in experienced solidarity, a positive atmosphere, and increased autonomy for nurses; and, 5) supportive managers reduced nurses' stress and improved work conditions. CONCLUSIONS: This study showed that nurses positively reshaped their work environment during the COVID-19 pandemic. They contributed to innovative solutions in an environment of equal interprofessional collaboration, which led to greater respect for their knowledge and competencies, enhanced their autonomy and improved management support.
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The Dutch Drug Rediscovery Protocol (DRUP) and the Australian Cancer Molecular Screening and Therapeutic (MoST) Program are similar nonrandomized, multidrug, pan-cancer trial platforms that aim to identify signals of clinical activity of molecularly matched targeted therapies or immunotherapies outside their approved indications. Here, we report results for advanced or metastatic cancer patients with tumors harboring cyclin D-CDK4/6 pathway alterations treated with CDK4/6 inhibitors palbociclib or ribociclib. We included adult patients that had therapy-refractory solid malignancies with the following alterations: amplifications of CDK4, CDK6, CCND1, CCND2 or CCND3, or complete loss of CDKN2A or SMARCA4. Within MoST, all patients were treated with palbociclib, whereas in DRUP, palbociclib and ribociclib were assigned to different cohorts (defined by tumor type and alteration). The primary endpoint for this combined analysis was clinical benefit, defined as confirmed objective response or stable disease ≥16 weeks. We treated 139 patients with a broad variety of tumor types; 116 with palbociclib and 23 with ribociclib. In 112 evaluable patients, the objective response rate was 0% and clinical benefit rate at 16 weeks was 15%. Median progression-free survival was 4 months (95% CI: 3-5 months), and median overall survival 5 months (95% CI: 4-6 months). In conclusion, only limited clinical activity of palbociclib and ribociclib monotherapy in patients with pretreated cancers harboring cyclin D-CDK4/6 pathway alterations was observed. Our findings indicate that monotherapy use of palbociclib or ribociclib is not recommended and that merging data of two similar precision oncology trials is feasible.
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Neoplasias da Mama , Neoplasias , Humanos , Feminino , Neoplasias/tratamento farmacológico , Ciclinas , Austrália , Medicina de Precisão , Aminopiridinas/uso terapêutico , Ciclina D , Quinase 4 Dependente de Ciclina , Neoplasias da Mama/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Quinase 6 Dependente de Ciclina , DNA Helicases , Proteínas NuclearesRESUMO
AIMS: Simple Bone Cysts (SBCs) predominantly occur in long bones and 59% harbour NFATC2 rearrangements. Jaw SBC is rare and was previously referred to as traumatic bone cyst. It can rarely occur in association with cemento-osseous dysplasia (COD). To determine whether jaw SBCs represent the same entity as SBC of the long bones, or if they have a different molecular signature, we collected 48 jaw SBC cases of 47 patients to assess NFATC2 rearrangement. METHODS AND RESULTS: Out of the 48 cases, 36 could be used for fluorescence in-situ hybridization (FISH), of which nine (two of which associated with COD) were successful using an NFATC2 split probe. The remaining cases failed to show adequate FISH signals. All nine cases lacked NFATC2 rearrangement and five of these showed no detectable gene fusions using Archer FusionPlex. CONCLUSION: In our study, NFATC2 rearrangement is absent in solitary jaw SBC (n = 7) and COD-associated SBC (n = 2). Our findings suggest that SBC presenting in the jaw is molecularly different from SBC in long bones. Future molecular studies may confirm the absence of clonal molecular aberrations in SBC of the jaw which would support a non-neoplastic, reactive origin.
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Cistos Ósseos , Fatores de Transcrição NFATC , Tumores Odontogênicos , Humanos , Cistos Ósseos/genética , Tumores Odontogênicos/genética , Fatores de Transcrição NFATC/genéticaRESUMO
BACKGROUND: In this study we aimed to evaluate the efficacy and safety of the PD-L1 inhibitor durvalumab across various mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) tumours in the Drug Rediscovery Protocol (DRUP). This is a clinical study in which patients are treated with drugs outside their labeled indication, based on their tumour molecular profile. PATIENTS AND METHODS: Patients with dMMR/MSI-H solid tumours who had exhausted all standard of care options were eligible. Patients were treated with durvalumab. The primary endpoints were clinical benefit ((CB): objective response (OR) or stable disease ≥16 weeks) and safety. Patients were enrolled using a Simon like 2-stage model, with 8 patients in stage 1, up to 24 patients in stage 2 if at least 1/8 patients had CB in stage 1. At baseline, fresh frozen biopsies were obtained for biomarker analyses. RESULTS: Twenty-six patients with 10 different cancer types were included. Two patients (2/26, 8%) were considered as non-evaluable for the primary endpoint. CB was observed in 13 patients (13/26, 50%) with an OR in 7 patients (7/26, 27%). The remaining 11 patients (11/26, 42%) had progressive disease. Median progression-free survival and median overall survival were 5 months (95% CI, 2-not reached) and 14 months (95% CI, 5-not reached), respectively. No unexpected toxicity was observed. We found a significantly higher structural variant (SV) burden in patients without CB. Additionally, we observed a significant enrichment of JAK1 frameshift mutations and a significantly lower IFN-γ expression in patients without CB. CONCLUSION: Durvalumab was generally well-tolerated and provided durable responses in pre-treated patients with dMMR/MSI-H solid tumours. High SV burden, JAK1 frameshift mutations and low IFN-γ expression were associated with a lack of CB; this provides a rationale for larger studies to validate these findings. TRIAL REGISTRATION: Clinical trial registration: NCT02925234. First registration date: 05/10/2016.
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Neoplasias Encefálicas , Instabilidade de Microssatélites , Humanos , BiomarcadoresRESUMO
INTRODUCTION: We developed Eforto®, an innovative system for (self-)monitoring of grip strength (GS) and muscle fatigability (Fatigue Resistance (FR = time until GS decreased to 50% of maximum during sustained contraction) and grip work (GW = area under the strength-time curve)). The Eforto® system consists of a rubber bulb that is wirelessly connected to a smartphone-based application, and a telemonitoring platform. The aim was to evaluate the validity and reliability of Eforto® to measure muscle fatigability. METHODS: Community-dwelling older persons (n = 61), geriatric inpatients (n = 26) and hip fracture patients (n = 25) were evaluated for GS and muscle fatigability. In community dwellers fatigability was tested twice in the clinic (once with Eforto®, once with Martin Vigorimeter (MV), standard analog handgrip system) and for six consecutive days as a self-assessment at home with Eforto®. In hospitalized participants, fatigability was tested twice using Eforto®, once by a researcher and once by a health professional. RESULTS: Criterion validity was supported by good to excellent correlations between Eforto® and MV for GS (r = 0.95) and muscle fatigability (FR r = 0.81 and GW r = 0.73), and no significant differences in measurements between both systems. Inter-rater and intra-rater reliability for GW were moderate to excellent (intra-class correlation: 0.59-0.94). The standard error of measurement for GW was small for geriatric inpatients and hip fracture patients (224.5 and 386.5 kPa*s) and higher for community-dwellers (661.5 kPa*s). DISCUSSION/CONCLUSION: We established the criterion validity and reliability of Eforto® in older community-dwelling persons and hospitalized patients, supporting the implementation of Eforto® for (self-)monitoring of muscle fatigability.
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Força da Mão , Vida Independente , Humanos , Idoso , Idoso de 80 Anos ou mais , Força da Mão/fisiologia , Reprodutibilidade dos Testes , Músculos , Força MuscularRESUMO
Osteosarcoma is a high-grade bone-forming neoplasm, with a complex genome. Tumours frequently show chromothripsis, many deletions, translocations and copy number alterations. Alterations in the p53 or Rb pathway are the most common genetic alterations identified in osteosarcoma. Using spontaneously transformed murine mesenchymal stem cells (MSCs) which formed sarcoma after subcutaneous injection into mice, it was previously demonstrated that p53 is most often involved in the transformation towards sarcomas with complex genomics, including osteosarcoma. In the current study, not only loss of p53 but also loss of p16Ink4a is shown to be a driver of osteosarcomagenesis: murine MSCs with deficient p15Ink4b, p16Ink4a, or p19Arf transform earlier compared to wild-type murine MSCs. Furthermore, in a panel of nine spontaneously transformed murine MSCs, alterations in p15Ink4b, p16Ink4a, or p19Arf were observed in eight out of nine cases. Alterations in the Rb/p16 pathway could indicate that osteosarcoma cells are vulnerable to CDK4/CDK6 inhibitor treatment. Indeed, using two-dimensional (n = 7) and three-dimensional (n = 3) cultures of human osteosarcoma cell lines, it was shown that osteosarcoma cells with defective p16INK4A are sensitive to the CDK4/CDK6 inhibitor palbociclib after 72-hour treatment. A tissue microarray analysis of 109 primary tumour biopsies revealed a subset of patients (20-23%) with intact Rb, but defective p16 or overexpression of CDK4 and/or CDK6. These patients might benefit from CDK4/CDK6 inhibition, therefore our results are promising and might be translated to the clinic.
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Neoplasias Ósseas , Células-Tronco Mesenquimais , Osteossarcoma , Animais , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/genética , Quinase 4 Dependente de Ciclina/genética , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/genética , Quinase 6 Dependente de Ciclina/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Humanos , Células-Tronco Mesenquimais/metabolismo , Camundongos , Osteossarcoma/tratamento farmacológico , Proteína Supressora de Tumor p14ARF/genética , Proteína Supressora de Tumor p14ARF/metabolismo , Proteína Supressora de Tumor p53/genéticaRESUMO
Cutaneous deep penetrating melanocytic neoplasms frequently simulate melanoma and might occasionally progress to metastatic melanoma. Distinguishing deep penetrating nevi (DPN) and deep penetrating melanocytomas (DPM) from malignant deep penetrating tumors (MDPT) is difficult based on histopathology alone, and diagnostic criteria for MDPT are currently lacking. Using a molecular workup, we aimed to provide readily available diagnostic tools for classification of deep penetrating tumors. We used clinical follow-up and Single Nucleotide Polymorphism (SNP) array for tumor classification of 20 deep penetrating neoplasms to identify associations with histopathological, immunohistochemistry, and NGS findings. Ten neoplasms were classified as MDPT, four as DPM, and six as DPN. Two MDPT showed metastases. The following parameters were statistically significantly associated with MDPT: severe nuclear atypia (risk ratio [RR] 2.9, p < 0.05), absence of a nevus component (RR 10.0, p = 0.04), positive PRAME expression (RR 9.0, p = 0.02), complete loss of p16 expression (RR 3.5, p = 0.003), TERT-p and APC mutations (RR 11.0, p = 0.01 and RR 2.7, p = 0.002, respectively), and ≥1 additional pathogenic mutation (RR 9.0, p = 0.02). Ki-67 expression ≥ 5% was not significantly associated with MDPTs, although it was <5% in all DPNs. Three MDPT did not show nuclear ß-catenin expression despite having a CTNNB1 (n = 2) or an APC mutation (n = 1). Our findings suggest that complete loss of p16 and positive PRAME expression, a driver mutation in APC, ≥ 1 additional pathogenic mutation, especially in TERT-p, support an MDPT diagnosis in deep penetrating neoplasms. Besides severe nuclear atypia and possibly severe inflammation, we did not identify specific histopathological criteria for malignancy. Non-aberrant nuclear ß-catenin expression might not exclude a deep penetrating signature in MDPT.
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Melanoma , Nevo de Células Epitelioides e Fusiformes , Nevo Pigmentado , Neoplasias Cutâneas , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Melanoma/diagnóstico , Melanoma/genética , Melanoma/patologia , Nevo Pigmentado/diagnóstico , Nevo Pigmentado/genética , Nevo Pigmentado/patologia , Polimorfismo de Nucleotídeo Único , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , beta Catenina/genética , beta Catenina/metabolismoRESUMO
The phase III clinical study of adjuvant liposomal muramyl tripeptide (MTP-PE) in resected high-grade osteosarcoma (OS) documented positive results that have been translated into regulatory approval, supporting initial promise for innate immune therapies in OS. There remains, however, no new approved treatment such as MTP-PE for either metastatic or recurrent OS. Whilst the addition of different agents, including liposomal MTP-PE, to surgery for metastatic or recurrent high-grade osteosarcoma has tried to improve response rates, a mechanistic hiatus exists in terms of a detailed understanding the therapeutic strategies required in advanced disease. Here we report a Bayesian designed multi-arm, multi-centre, open-label phase II study with randomisation in patients with metastatic and/or recurrent OS, designed to investigate how patients with OS might respond to liposomal MTP-PE, either given alone or in combination with ifosfamide. Despite the trial closing because of poor recruitment within the allocated funding period, with no objective responses in eight patients, we report the design and feasibility outcomes for patients registered into the trial. We demonstrate the feasibility of the Bayesian design, European collaboration, tissue collection with genomic analysis and serum cytokine characterisation. Further mechanistic investigation of liposomal MTP-PE alone and in combination with other agents remains warranted in metastatic OS.
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Neoplasias Ósseas , Osteossarcoma , Acetilmuramil-Alanil-Isoglutamina/análogos & derivados , Teorema de Bayes , Biomarcadores , Neoplasias Ósseas/patologia , Humanos , Lipossomos , Recidiva Local de Neoplasia/tratamento farmacológico , Osteossarcoma/patologia , FosfatidiletanolaminasRESUMO
Multiple sclerosis (MS) is a degenerative disease of the central nervous system in which auto-immunity-induced demyelination occurs. MS is thought to be caused by a complex interplay of environmental and genetic risk factors. While most genetic studies have focused on identifying common genetic variants for MS through genome-wide association studies, the objective of the present study was to identify rare genetic variants contributing to MS susceptibility. We used whole exome sequencing (WES) followed by co-segregation analyses in nine multi-incident families with two to four affected individuals. WES was performed in 31 family members with and without MS. After applying a suite of selection criteria, co-segregation analyses for a number of rare variants selected from the WES results were performed, adding 24 family members. This approach resulted in 12 exonic rare variants that showed acceptable co-segregation with MS within the nine families, implicating the genes MBP, PLK1, MECP2, MTMR7, TOX3, CPT1A, SORCS1, TRIM66, ITPR3, TTC28, CACNA1F, and PRAM1. Of these, three genes (MBP, MECP2, and CPT1A) have been previously reported as carrying MS-related rare variants. Six additional genes (MTMR7, TOX3, SORCS1, ITPR3, TTC28, and PRAM1) have also been implicated in MS through common genetic variants. The proteins encoded by all twelve genes containing rare variants interact in a molecular framework that points to biological processes involved in (de-/re-)myelination and auto-immunity. Our approach provides clues to possible molecular mechanisms underlying MS that should be studied further in cellular and/or animal models.
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Estudo de Associação Genômica Ampla , Esclerose Múltipla , Família , Predisposição Genética para Doença , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Esclerose Múltipla/genética , Linhagem , Sequenciamento do ExomaRESUMO
AIMS: Because of the efficacy of tropomyosin receptor kinase (Trk) inhibitor therapy in tumours with rearrangements of the neurotrophic tyrosine kinase receptor genes (NRTK genes), there has been a surge in demand for NTRK fusion screening. To date, most studies involving mesenchymal tumours have focused on soft tissue tumours, and data on bone tumours are sparse. Hence, we aimed to explore the frequency of NTRK fusions in a large series of primary bone tumours. METHODS AND RESULTS: Immunohistochemical expression of pan-Trk was successfully assessed in 354 primary bone tumours by the use of tissue microarrays. In a selection of positive cases, additional molecular analysis for NTRK fusions was performed with anchored multiplex polymerase chain reaction-based targeted next-generation sequencing. Positivity was found in 19 cases (5%), which comprised Ewing sarcoma (n = 6, 33%), osteosarcoma (n = 11, 13%), and giant-cell tumour of bone (n = 2, 3%). In all except one case, cytoplasmic staining was observed. Weak staining was most often observed (n = 13), although five cases showed moderate staining and one case showed focal strong staining. Molecular analysis was successful in six cases, all of which were negative for NTRK fusions. CONCLUSION: The likelihood of finding an NTRK fusion in bone tumours in clinical practice is extremely low. This may imply that, if more comprehensive large-scale molecular studies confirm this, routine predictive NTRK testing in bone tumour patients with advanced disease may be reconsidered.
Assuntos
Neoplasias Ósseas , Proteínas de Fusão Oncogênica , Receptor trkA , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Humanos , Imuno-Histoquímica , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Receptor trkA/genética , Receptor trkA/metabolismoRESUMO
BACKGROUND: Patients in a range of health care sectors can access their medical health records using a patient portal. In mental health care, the use of patient portals among mental health care professionals remains low. Mental health care professionals are concerned that patient access to electronic health records (EHRs) will negatively affect the patient's well-being and privacy as well as the professional's own workload. OBJECTIVE: This study aims to provide insights into the appraisal work of mental health care professionals to assess and understand patient access to their EHRs through a patient portal. METHODS: We conducted a qualitative study that included 10 semistructured interviews (n=11) and a focus group (n=10). Participants in both the interviews and the focus group were mental health care professionals from different professional backgrounds and staff employees (eg, team leaders and communication advisors). We collected data on their opinions and experiences with the recently implemented patient portal and their attempts to modify work practices. RESULTS: Our study provides insights into mental health care professionals' appraisal work to assess and understand patient access to the EHR through a patient portal. A total of four topics emerged from our data analysis: appraising the effect on the patient-professional relationship, appraising the challenge of sharing and registering delicate information, appraising patient vulnerability, and redefining consultation routines and registration practices. CONCLUSIONS: Mental health care professionals struggle with the effects of web-based patient access and are searching for the best ways to modify their registration and consultation practices. Our participants seem to appraise the effects of web-based patient access individually. Our study signals the lack of systematization and communal appraisal. It also suggests various solutions to the challenges faced by mental health care professionals. To optimize the effects of web-based patient access to EHRs, mental health care professionals need to be involved in the process of developing, implementing, and embedding patient portals.
Assuntos
Registros Eletrônicos de Saúde , Portais do Paciente , Pessoal de Saúde , Humanos , Internet , Pesquisa QualitativaRESUMO
BACKGROUND: eHealth applications are constantly increasing and are frequently considered to constitute a promising strategy for cost containment in health care, particularly if the applications aim to support older persons. Older persons are, however, not the only major eHealth stakeholder. eHealth suppliers, caregivers, funding bodies, and health authorities are also likely to attribute value to eHealth applications, but they can differ in their value attribution because they are affected differently by eHealth costs and benefits. Therefore, any assessment of the value of eHealth applications requires the consideration of multiple stakeholders in a holistic and integrated manner. Such a holistic and reliable value assessment requires a profound understanding of the application's costs and benefits. The first step in measuring costs and benefits is identifying the relevant costs and benefit categories that the eHealth application affects. OBJECTIVE: The aim of this study is to support the conceptual phase of an economic evaluation by providing an overview of the relevant direct and indirect costs and benefits incorporated in economic evaluations so far. METHODS: We conducted a systematic literature search covering papers published until December 2019 by using the Embase, Medline Ovid, Web of Science, and CINAHL EBSCOhost databases. We included papers on eHealth applications with web-based contact possibilities between clients and health care providers (mobile health apps) and applications for self-management, telehomecare, telemedicine, telemonitoring, telerehabilitation, and active healthy aging technologies for older persons. We included studies that focused on any type of economic evaluation, including costs and benefit measures. RESULTS: We identified 55 papers with economic evaluations. These studies considered a range of different types of costs and benefits. Costs pertained to implementation activities and operational activities related to eHealth applications. Benefits (or consequences) could be categorized according to stakeholder groups, that is, older persons, caregivers, and health care providers. These benefits can further be divided into stakeholder-specific outcomes and resource usage. Some cost and benefit types have received more attention than others. For instance, patient outcomes have been predominantly captured via quality-of-life considerations and various types of physical health status indicators. From the perspective of resource usage, a strong emphasis has been placed on home care visits and hospital usage. CONCLUSIONS: Economic evaluations of eHealth applications are gaining momentum, and studies have shown considerable variation regarding the costs and benefits that they include. We contribute to the body of literature by providing a detailed and up-to-date framework of cost and benefit categories that any interested stakeholder can use as a starting point to conduct an economic evaluation in the context of independent living of older persons.
Assuntos
Serviços de Assistência Domiciliar , Telemedicina , Idoso , Idoso de 80 Anos ou mais , Análise Custo-Benefício , Atenção à Saúde , Humanos , Vida IndependenteRESUMO
AIMS: To (1) give an overview of rebel nurse leadership by summarising descriptions of positive deviance, tempered radicals and healthcare rebels; (2) examine the competences of nurse rebel leadership; and (3) describe factors that stimulate or hinder the development of rebel nurse leadership. BACKGROUND: Research shows nurses have lower intention to leave their jobs when they can control their work practices, show leadership and provide the best care. However, organisational rules and regulations do not always fit the provision of good care, which challenges nurses to show leadership and deviate from the rules and regulations to benefit the patient. Three concepts describe this practice: positive deviance, healthcare rebels and tempered radicals. DESIGN: Scoping review using the Joanna Briggs Institute methodology and PRISMA-ScR checklist. METHODS: Papers describing positive deviance, healthcare rebels and tempered radicals in nursing were identified by searching Scopus, CINAHL, PubMed and PsycINFO. After data extraction, these three concepts were analysed to study the content of descriptions and definitions, competences and stimulating and hindering factors. RESULTS: Of 2705 identified papers, 25 were included. The concept descriptions yielded three aspects: (1) positive deviance approach, (2) unconventional and non-confirmative behaviour and (3) relevance of networks and relationships. The competences were the ability to: (1) collaborate in/outside the organisation, (2) gain and share expert (evidence-based) knowledge, (3) critically reflect on working habits/problems in daily care and dare to challenge the status quo and (4) generate ideas to improve care. The factors that stimulate or hinder the development of rebel nurse leadership are as follows: (1) dialogue and reflection, (2) networking conditions and (3) the managers' role. CONCLUSIONS: Based on our analysis, we summarise the descriptions given of rebel nurse leadership, the mentioned competences and provide an overview of the factors that stimulate or hinder rebel nurse leadership. RELEVANCE TO CLINICAL PRACTICE: The descriptions produced in this review of rebel nurse leadership and the stimulating or hindering factors listed should help nurses and managers encourage rebel leadership.