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BACKGROUND: In 2016, the International Consortium for Health Outcomes Measurement (ICHOM) defined an international consensus recommendation of the most important outcomes for lung cancer patients. The European Health Outcomes Observatory (H2O) initiative aimed to develop an updated patient-centered core outcome set (COS) for lung cancer, to capture the patient perspective of the impact of lung cancer and (novel) treatments using a combination of patient-reported outcome (PRO) instruments and clinical data as a means to drive value-based health-care. MATERIAL AND METHODS: An international, expert team of patient representatives, multidisciplinary healthcare professionals, academic researchers and pharmaceutical industry representatives (n = 17) reviewed potential outcomes generated through literature review. A broader group of patients/patient representatives (n = 31), healthcare professionals / academic researchers (n = 83), pharmaceutical industry representatives (n = 26), and health authority representatives (n = 6) participated in a Delphi study. In two survey rounds, participants scored the relevance of outcomes from a preliminary list. The threshold for consensus was defined as ≥ 70 % of participants scoring an outcome as 'highly relevant'. In concluding consensus-meeting rounds, the expert multidisciplinary team finalized the COS. RESULTS: The preliminary list defined by the core group consisted of 102 outcomes and was prioritized in the Delphi procedure to 64. The final lung cancer COS includes: 1) case-mix factors (n = 27); 2) PROs related to health-related quality of life (HRQoL) (n = 25); 3) clinical outcomes (n = 12). Patient-reported symptoms beyond domains included in the ICHOM lung cancer set in 2016 were insomnia, nausea, vomiting, anxiety, depression, lack of appetite, gastric problems, constipation, diarrhoea, dysphagia, and haemoptysis. CONCLUSIONS: We will implement the lung cancer COS in Europe within the H2O initiative by collecting the outcomes through a combination of clinician-reported measures and PRO measures. The COS will support the adoption and reporting of lung cancer measures in a standardized way across Europe and empower patients with lung cancer to better manage their health care.
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Neoplasias Pulmonares , Calidad de Vida , Humanos , Técnica Delphi , Neoplasias Pulmonares/epidemiología , Neoplasias Pulmonares/terapia , Consenso , Atención Dirigida al Paciente , Resultado del Tratamiento , Proyectos de InvestigaciónRESUMEN
Electronic patient-reported outcome (ePRO) applications promise great added value for improving symptom management and health-related quality of life. The aim of this narrative review is to describe the collection and use of ePROs for cancer survivorship care, with an emphasis on ePRO-symptom monitoring. It offers many different perspectives from research settings, while current implementation in routine care is ongoing. ePRO collection optimizes survivorship care by providing insight into the patients' well-being and prioritizing their unmet needs during the whole trajectory from diagnosis to end-of-life. ePRO-symptom monitoring can contribute to timely health risk detection and subsequently allow earlier intervention. Detection is optimized by automatically generated alerts that vary from simple to complex and multilayered. Using ePRO-symptoms during in-hospital consultation enhances the patients' conversation with the health care provider before making informed decisions about treatments, other interventions, or self-management. ePRO(-symptoms) entail specific implementation issues and complementary ethics considerations. The latter is due to privacy concerns, digital divide, and scarcity of adequately representative data for particular groups of patients.
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Supervivientes de Cáncer , Neoplasias , Electrónica , Humanos , Neoplasias/terapia , Medición de Resultados Informados por el Paciente , Calidad de Vida , SupervivenciaRESUMEN
INTRODUCTION: Treatment patterns in stage III NSCLC can vary considerably between countries. The PACIFIC trial reported improvements in progression-free and overall survival with adjuvant durvalumab after concurrent chemoradiotherapy (CCRT). We studied treatment decision-making by three Dutch regional thoracic multidisciplinary tumor boards between 2015 and 2019, to identify changes in practice when adjuvant durvalumab became available. METHODS: Details of patients presenting with stage III NSCLC were retrospectively collected. Both CCRT and multimodality schemes incorporating planned surgery were defined as being radical-intent treatment (RIT). RESULTS: Of 855 eligible patients, most (95%) were discussed at a thoracic multidisciplinary tumor board, which recommended a RIT in 63% (n = 510). Only 52% (n = 424) of the patients finally received a RIT. Predictors for not recommending RIT were age greater than or equal to 70 years, WHO performance score greater than or equal to 2, Charlson comorbidity index greater than or equal to 2 (excluding age), forced expiratory volume in 1 second less than 80% of predicted value, N3 disease, and period of diagnosis. Between 2015 to 2017 and 2018 to 2019, the proportion of patients undergoing CCRT increased from 34% to 42% (p = 0.02) and use of sequential chemoradiotherapy declined (21%-16%, p = 0.05). Rates of early toxicity and 1-year mortality were comparable for both periods. After 2018, 57% of the patients who underwent CCRT (90 of 159) received adjuvant durvalumab. CONCLUSIONS: After publication of the PACIFIC trial, a significant increase was observed in the use of CCRT for patients with stage III NSCLC with rates of early toxicity and mortality being unchanged. Since 2018, 57% of the patients undergoing CCRT went on to receive adjuvant durvalumab. Nevertheless, approximately half of the patients were still considered unfit for a RIT.
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OBJECTIVES: Treatment patterns in patients with stage III non-small cell lung cancer (NSCLC) vary considerably between countries, for reasons that are not well understood. We studied factors influencing treatment decision-making at thoracic multidisciplinary tumor boards (MDT's) and outcome for patients treated between 2015-2017, at a regional network comprising 5 hospitals. MATERIALS AND METHODS: Details of all patients, including comorbidities, with stage III NSCLC were collected in an ethics-approved database. Weekly MDT's were conducted. The preferred radical intent treatments (RIT) for suitable patients were assumed to be concurrent chemoradiotherapy and/or surgery and other therapies were non-radical intent treatments (n-RIT). RESULTS: Of 197 patients identified, 95 % were discussed at an MDT. RIT were recommended in 61 % of patients, but only 48 % finally received RIT. The estimated median OS was significantly better for patients undergoing RIT (28.3 months, CI-95 % 17.3-39.3), versus those who did not (11.2 months, CI-95 % 8.0-14.3). Patient age ≥70 years and a WHO-PS ≥2 were the most important predictors of not recommending RIT. Deaths due to progressive lung cancer within 2 years were observed in 36, 26 and 29 % of patients who received RIT, sequential chemoradiotherapy or radical radiotherapy. Corresponding comorbidity related deaths within 2 years were 3, 12 and 38 %. CONCLUSION: A large number of patients who underwent MDT review were considered too old or not fit for RIT. More effective and better tolerated systemic treatments are required for patients presenting with stage III NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Anciano , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/terapia , Quimioradioterapia , Humanos , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/terapia , Estadificación de Neoplasias , Resultado del TratamientoRESUMEN
INTRODUCTION: The NICOLAS study is the first completed single-arm phase II trial in stage III NSCLC evaluating hierarchically first the safety and then the efficacy of adding nivolumab concurrently to standard definitive concurrent chemoradiotherapy. The safety end point was reported earlier; here, we present the efficacy results. METHODS: Stage IIIA-B unresectable treatment-naive patients with NSCLC received three cycles of platinum-based chemotherapy and concurrent radiotherapy (66 Gy, 33 fractions), along with nivolumab (360 mg, 3-weekly). Nivolumab was continued as monotherapy consolidation for a maximum of 1 year (480 mg, 4-weekly). The primary end point was 1-year progression-free survival (PFS), with a target improvement compared with historical data of at least 15%, from 45% to 60%. To test this efficacy hypothesis, a sample size of 74 assessable patients provided a power of 83% with a one-sided alpha of 5%. RESULTS: A total of 79 patients were enrolled with a median follow-up of 21.0 months (interquartile range: 15.8-25.8 mo) for the primary PFS analysis. A total of 35.4% of the patients had stage IIIA, and 63.3% had stage IIIB disease. The 1-year PFS was 53.7% (95% confidence interval [CI]: 42.0%-64.0%) and the median PFS was 12.7 months (95% CI: 10.1-22.8 mo). Because 37 PFS events occurred in the first year posttreatment among the first 74 assessable patients, a 1-year PFS rate of at least 45% could not be rejected (p = 0.23). At an extended follow-up (median 32.6 mo), 37 deaths have been recorded, with a median overall survival (OS) of 38.8 months (95% CI: 26.8 mo-not estimable) and a 2-year OS rate of 63.7% (95% CI: 51.9%-73.4%). The OS of patients with stage IIIA disease was found to be significantly higher than patients with stage IIIB disease, with a 2-year OS of 81% and 56%, respectively (p = 0.037). CONCLUSIONS: PFS and OS are arithmetically higher in studies involving the same population. However, on the basis of the formal hierarchical efficacy analysis, we could not reject that the 1-year PFS rate is at least 45%.
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Neoplasias Pulmonares , Nivolumab , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioradioterapia , Supervivencia sin Enfermedad , Humanos , Neoplasias Pulmonares/patología , Estadificación de Neoplasias , Nivolumab/uso terapéutico , Estándares de ReferenciaRESUMEN
BACKGROUND: Risk information in patient decision aids (PDAs) is often difficult for older patients to process. Providing audiovisual and narrative information may enhance the understanding and use of health-related information. We studied the effects on patients' information processing and use of audiovisual and narrative information of an early-stage non-small-cell lung cancer treatment decision aid explaining surgery and stereotactic ablative radiotherapy. We further investigated differences between older and younger patients. METHODS: We conducted a 2 (modality: textual v. audiovisual) × 2 (narration style: factual v. narrative) online experiment among cancer patients and survivors (N = 305; Mage = 62.42, SD = 11.68 y). Age was included as a potential modifier: younger (<65 y) versus older (≥65 y) age. We assessed 1) perceived cognitive load, 2) satisfaction with information, 3) comprehension, 4) information recall, and 5) decisional conflict. Analysis of variance was used for data analysis. RESULTS: Irrespective of patient age, audiovisual information (compared with textual information) led to lower perceived cognitive load, higher satisfaction with information, and lower decisional conflict (subscale Effective Decision). Narrative information (compared with factual information) led to reduced decisional conflict (subscale Uncertainty) but only in younger patients. Combining audiovisual information with factual information also resulted in lower perceived cognitive load in younger patients as compared with older patients. LIMITATIONS: Patients who actually face the decision, especially older patients, might be more motivated to process our decision-aid information than the present study participants who responded to a hypothetical situation online. CONCLUSIONS: Providing participants with audiovisual information, irrespective of their age, improved their processing and use of information in a decision aid. Narratives did not clearly benefit information processing.
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Técnicas de Apoyo para la Decisión , Procesamiento Automatizado de Datos/normas , Conducta en la Búsqueda de Información , Neoplasias Pulmonares/terapia , Adulto , Anciano , Anciano de 80 o más Años , Procesamiento Automatizado de Datos/métodos , Femenino , Humanos , Neoplasias Pulmonares/psicología , Masculino , Persona de Mediana Edad , Encuestas y CuestionariosRESUMEN
BACKGROUND: The recent emphasis on value-based health care (VBHC) is thought to provide new opportunities for shared decision-making (SDM) in the Netherlands, especially when using patient-reported outcome measures (PROMs) in routine medical encounters. It is still largely unclear about how PROMs could be linked to SDM and what we expect from clinicians in this respect. AIM: To describe approaches and lessons learned in the fields of SDM and VBHC implementation that converge in using PROMs in medical encounters. APPROACH: Based on input from three Dutch forerunner case examples and available evidence about SDM and VBHC, we describe barriers and facilitators regarding the use of PROMs and SDM in the medical encounter. Barriers and facilitators were structured according to a conversational model that included monitoring and managing, team talk, option talk, choice talk, and decision talk. Key lessons learned and recommendations were synthesized. RESULTS: The use of individual, N = 1 PROMs scores in the medical encounter has been largely achieved in the forerunner projects. Conversation on monitoring and managing is relatively well implemented, and option talk to some extent, unlike team talk, and decision talk. Aggregated PROMs information describing outcomes of treatment options seemed to be scarcely used. Experienced barriers largely corresponded to what is known from the literature, eg, perceived lack of time and lack of tools summarizing the options. Some concerns were identified about increasing health care consumption as a result of using PROMs and SDM in the medical encounter. CONCLUSION: Successful implementation of SDM within VBHC initiatives may not be self-evident, even though individual, N = 1 PROMs scores are being used in the medical encounter. Education and staff resources on meso and macro levels may facilitate the more time-consuming SDM aspects. It seems fruitful to especially target team talk and choice talk in redesigning clinical pathways.
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Toma de Decisiones Conjunta , Toma de Decisiones , Atención a la Salud , Humanos , Países Bajos , Participación del Paciente , Medición de Resultados Informados por el PacienteRESUMEN
BACKGROUND: The aim of this study was to evaluate the efficacy of an intervention combining Life Review Therapy (LRT) and Memory Specificity Training (MST) (LRT-MST) to improve ego-integrity and despair among cancer patients in palliative care. METHODS: In this multicentre randomized controlled trial, cancer patients in palliative care were randomized to the intervention group (LRT-MST; n = 55) or waiting-list control group (n = 52). LRT-MST is a 4-session home-based psychological intervention that aims to retrieve specific positive memories, to re-evaluate life events and to reconstruct the story of a patient's life, including the diagnosis of incurable cancer. Outcome measures were ego-integrity and despair (NEIS), psychological distress, anxiety and depression (HADS), quality of life (EORTC QLQ-C15-PAL), and specificity of the autobiographical memory (AMT). NEIS, HADS and EORTC QLQ-C15-PAL were assessed at baseline (T0), 1 month later (post-treatment; T1), and at 1 month follow-up (T2). AMT was assessed at T0 and T1. Linear mixed models (intention to treat) were used to assess group differences in changes over time. Independent samples t-tests were used to assess group differences at T0, T1, and T2, and effect sizes (ES) were calculated at T1 and T2. RESULTS: The course of ego-integrity (not despair) improved significantly over time (p = .007) in the intervention group compared to the waiting-list control group, with moderate, but insignificant, effect sizes at T1 (ES = .42) and T2 (ES = .48). Compliance rate was 69% and total dropout rate was 28%, both primarily related to disease progression and death. CONCLUSIONS: LRT-MST seems effective among cancer patients in palliative care to improve the course of ego-integrity.
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Neoplasias/terapia , Cuidados Paliativos , Psicoterapia/métodos , Adulto , Anciano , Anciano de 80 o más Años , Ansiedad/terapia , Depresión/terapia , Femenino , Estudios de Seguimiento , Humanos , Modelos Lineales , Masculino , Memoria Episódica , Persona de Mediana Edad , Neoplasias/psicología , Calidad de Vida , Estrés Psicológico/terapia , Resultado del TratamientoRESUMEN
BACKGROUND: Progressive loss of muscle mass is a major characteristic of cancer cachexia. Consensus definitions for cachexia provide different options to measure muscle mass. This study describes the effect of different methods to determine muscle mass on the diagnosis of cancer cachexia. In addition, the association of cachexia with other features of cachexia, quality of life, and survival was explored. METHODS: Prior to chemotherapy, cachexia was assessed by weight loss, body mass index, and muscle mass measurements, the latter by mid-upper arm muscle area (MUAMA), computed tomography (CT) scans, and bio-electrical impedance analysis (BIA). In addition, appetite, inflammation, muscle strength, fatigue, quality of life, and survival were measured, and associations with cachexia were explored. RESULTS: Included were 241 patients with advanced cancer of the lung (36%), colon/rectum (31%), prostate (18%), or breast (15%). Mean age was 64 ± 10 years; 54% was male. Prevalence of low muscle mass was as follows: 13% with MUAMA, 59% with CT, and 93% with BIA. In turn, the prevalence of cachexia was 37, 43, and 48%, whereby weight loss >5% was the most prominent component of being defined cachectic. Irrespective of type of muscle measurement, patients with cachexia presented more often with anorexia, inflammation, low muscle strength, and fatigue and had lower quality of life. Patients with cachexia had worse overall survival compared with patients without cachexia: HRs 2.00 (1.42-2.83) with MUAMA, 1.64 (1.15-2.34) with CT, and 1.50 (1.05-2.14) with BIA. CONCLUSIONS: Although the prevalence of low muscle mass in patients with cancer depended largely on the type of muscle measurement, this had little influence on the diagnosis of cancer cachexia (as the majority of patients was already defined cachectic based on weight loss). New studies are warranted to further elucidate the additional role of muscle measurements in the diagnosis of cachexia and the association with clinical outcomes.
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Composición Corporal/fisiología , Caquexia/complicaciones , Caquexia/epidemiología , Músculo Esquelético/patología , Neoplasias/complicaciones , Neoplasias/epidemiología , Anciano , Anciano de 80 o más Años , Anorexia/complicaciones , Anorexia/epidemiología , Anorexia/patología , Apetito/fisiología , Índice de Masa Corporal , Caquexia/diagnóstico , Caquexia/patología , Fatiga/complicaciones , Fatiga/epidemiología , Fatiga/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fuerza Muscular/fisiología , Músculo Esquelético/anatomía & histología , Neoplasias/diagnóstico , Neoplasias/patología , Prevalencia , Calidad de Vida , Pérdida de Peso/fisiologíaRESUMEN
Background and Aims: The ghrelin receptor is one of the new therapeutic targets in the cancer anorexia-cachexia syndrome. Previous studies revealed that plasma ghrelin levels were high in patients with anorexia nervosa and low in obese subjects. We studied to what extent ghrelin levels are related with anorexia and cachexia in patients with cancer. Materials and Methods: Fasted ghrelin levels were determined as well as anorexia and cachexia in patients with stage III/IV non-small cell lung cancer before chemotherapy. Total plasma ghrelin was measured by radioimmunoassay. Anorexia was measured with the FAACT-A/CS questionnaire (cut-off value ≤ 37). Cachexia was determined as >5% weight loss (WL) in 6 months or >2% WL in 6 months in combination with low BMI or low muscle mass. The Kruskal-Wallis test was performed to assess differences in plasma ghrelin levels between four groups: patients with (+) or without (-) anorexia (A) or cachexia (C). Multiple regression analyses were performed to assess differences in plasma ghrelin levels between patients C+ and C- and patients with A+ and A- (adjusted for age and sex). Results: Forty patients with stage III (33%) or stage IV (68%) were recruited, of which 50% was male. Mean age was 59.6 ± 10.3 years. Sixteen patients had no anorexia or cachexia (A-C-), seven patients had both anorexia and cachexia (A+C+), ten patients had anorexia without cachexia (A+C-) and seven patients had cachexia without anorexia (A-C+). The levels of total plasma ghrelin were significantly different between the four groups of patients with or without anorexia or cachexia (p = 0.032): the A+C- patients had significantly higher ghrelin levels [median (IQR): 1,754 (1,404-2,142) compared to the A-C+ patients 1,026 (952-1,357), p = 0.003]. A+ patients had significantly higher ghrelin levels compared A- patients (C+ and C- combined, ß: 304, p = 0.020). Plasma ghrelin levels were not significantly different in C+ patients compared to C- patients (A+ and A- combined, ß: -99, p = 0.450). Conclusions: Patients with anorexia had significantly higher ghrelin levels compared to patients without anorexia. We therefore hypothesize that patients with cancer anorexia might benefit from treatment with a ghrelin receptor agonist to prevent WL and deterioration in physical functioning.
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Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Neoplasias Pulmonares/tratamiento farmacológico , Mutación , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinazolinas/uso terapéutico , Biopsia , Carcinoma de Pulmón de Células no Pequeñas/enzimología , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Células Escamosas/enzimología , Carcinoma de Células Escamosas/genética , Análisis Mutacional de ADN , Progresión de la Enfermedad , Resistencia a Antineoplásicos , Receptores ErbB/metabolismo , Clorhidrato de Erlotinib , Resultado Fatal , Femenino , Predisposición Genética a la Enfermedad , Humanos , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Persona de Mediana Edad , Terapia Molecular Dirigida , Fenotipo , Factores de Tiempo , Resultado del TratamientoRESUMEN
Protein biogenesis integrates multiple finely regulated mechanisms, ensuring nascent polypeptide chains are correctly enzymatically processed, targeted to membranes and folded to native structure. Recent studies show that the cellular translation machinery serves as hub that coordinates the maturation events in space and time at various levels. The ribosome itself serves as docking site for a multitude of nascent chain-interacting factors. The movement of ribosomes along open reading frames is non-uniformous and includes pausing sites, which facilitates nascent chain folding and perhaps factor engagement. Here we summarize current knowledge and discuss emerging concepts underlying the critical interplay between translation and protein maturation in E. coli.
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Biosíntesis de Proteínas , Pliegue de Proteína , Proteínas/química , Proteínas/metabolismo , Animales , Humanos , Modelos Moleculares , Conformación Proteica , Ribosomas/química , Ribosomas/metabolismoRESUMEN
A plethora of factors is involved in the maturation of newly synthesized proteins, including chaperones, membrane targeting factors and enzymes. Many factors act co-translationally through association with ribosome-nascent chain complexes (RNCs), but their target specificities and modes of action remain poorly understood. We developed selective ribosome profiling (SeRP) to identify substrate pools and points of RNC engagement of these factors. SeRP is based on sequencing mRNA fragments covered by translating ribosomes (general ribosome profiling (RP)), combined with a procedure to selectively isolate RNCs whose nascent polypeptides are associated with the factor of interest. Factor-RNC interactions are stabilized by cross-linking; the resulting factor-RNC adducts are nuclease-treated to generate monosomes, and then they are affinity purified. The ribosome-extracted mRNA footprints are converted to DNA libraries for deep sequencing. The protocol is specified for general RP and SeRP in bacteria. It was first applied to the chaperone trigger factor (TF) and is readily adaptable to other co-translationally acting factors, including eukaryotic factors. Factor-RNC purification and sequencing library preparation takes 7-8 d, and sequencing and data analysis can be completed in 5-6 d.
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Bacterias/metabolismo , Proteínas Bacterianas/metabolismo , Chaperonas Moleculares/fisiología , Ribosomas/metabolismo , Bacterias/genética , Proteínas Bacterianas/química , Proteínas Bacterianas/genética , Biblioteca de Genes , Chaperonas Moleculares/metabolismo , Mapas de Interacción de Proteínas , Procesamiento Proteico-PostraduccionalRESUMEN
How nascent polypeptides emerging from ribosomes fold into functional structures is poorly understood. Here, we monitor disulfide bond formation, protease resistance, and enzymatic activity in nascent polypeptides to show that in close proximity to the ribosome, conformational space and kinetics of folding are restricted. Folding constraints decrease incrementally with distance from the ribosome surface. Upon ribosome binding, the chaperone Trigger Factor counters folding also of longer nascent chains, to extents varying between different chain segments. Trigger Factor even binds and unfolds pre-existing folded structures, the unfolding activity being limited by the thermodynamic stability of nascent chains. Folding retardation and unfolding activities are not shared by the DnaK chaperone assisting later folding steps. These ribosome- and Trigger Factor-specific activities together constitute an efficient mechanism to prevent or even revert premature folding, effectively limiting misfolded intermediates during protein synthesis.
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Proteínas de Escherichia coli/metabolismo , Isomerasa de Peptidilprolil/metabolismo , Pliegue de Proteína , Ribosomas/metabolismo , Proteínas Bacterianas , Disulfuros/metabolismo , Proteínas de Escherichia coli/química , Proteínas HSP70 de Choque Térmico/química , Proteínas HSP70 de Choque Térmico/metabolismo , Modelos Biológicos , Modelos Moleculares , Chaperonas Moleculares/química , Chaperonas Moleculares/metabolismo , Isomerasa de Peptidilprolil/química , Conformación Proteica , Estructura Terciaria de Proteína , Ribonucleasas/química , Ribonucleasas/metabolismo , Tetrahidrofolato Deshidrogenasa/química , Tetrahidrofolato Deshidrogenasa/metabolismoRESUMEN
BACKGROUND: Psychological distress is common in cancer survivors. Although there is some evidence on effectiveness of psychosocial care in distressed cancer patients, referral rate is low. Lack of adequate screening instruments in oncology settings and insufficient availability of traditional models of psychosocial care are the main barriers. A stepped care approach has the potential to improve the efficiency of psychosocial care. The aim of the study described herein is to evaluate efficacy of a stepped care strategy targeting psychological distress in cancer survivors. METHODS/DESIGN: The study is designed as a randomized clinical trial with 2 treatment arms: a stepped care intervention programme versus care as usual. Patients treated for head and neck cancer (HNC) or lung cancer (LC) are screened for distress using OncoQuest, a computerized touchscreen system. After stratification for tumour (HNC vs. LC) and stage (stage I/II vs. III/IV), 176 distressed patients are randomly assigned to the intervention or control group. Patients in the intervention group will follow a stepped care model with 4 evidence based steps: 1. Watchful waiting, 2. Guided self-help via Internet or a booklet, 3. Problem Solving Treatment administered by a specialized nurse, and 4. Specialized psychological intervention or antidepressant medication. In the control group, patients receive care as usual which most often is a single interview or referral to specialized intervention. Primary outcome is the Hospital Anxiety and Depression Scale (HADS). Secondary outcome measures are a clinical level of depression or anxiety (CIDI), quality of life (EQ-5D, EORTC QLQ-C30, QLQ-HN35, QLQ-LC13), patient satisfaction with care (EORTC QLQ-PATSAT), and costs (health care utilization and work loss (TIC-P and PRODISQ modules)). Outcomes are evaluated before and after intervention and at 3, 6, 9 and 12 months after intervention. DISCUSSION: Stepped care is a system of delivering and monitoring treatments, such that effective, yet least resource-intensive, treatment is delivered to patients first. The main aim of a stepped care approach is to simplify the patient pathway, provide access to more patients and to improve patient well-being and cost reduction by directing, where appropriate, patients to low cost (self-)management before high cost specialist services. TRIAL REGISTRATION: NTR1868.
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Neoplasias de Cabeza y Cuello/psicología , Neoplasias de Cabeza y Cuello/terapia , Neoplasias Pulmonares/psicología , Neoplasias Pulmonares/terapia , Estrés Psicológico/terapia , Antidepresivos/uso terapéutico , Ansiedad/tratamiento farmacológico , Ansiedad/etiología , Ansiedad/terapia , Terapia Cognitivo-Conductual/métodos , Atención a la Salud , Depresión/tratamiento farmacológico , Depresión/etiología , Depresión/terapia , Neoplasias de Cabeza y Cuello/patología , Humanos , Neoplasias Pulmonares/patología , Estadificación de Neoplasias , Educación del Paciente como Asunto/métodos , Satisfacción del Paciente , Estudios Prospectivos , Calidad de Vida , Autocuidado/métodos , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/etiología , Espera VigilanteRESUMEN
As nascent polypeptides exit ribosomes, they are engaged by a series of processing, targeting, and folding factors. Here, we present a selective ribosome profiling strategy that enables global monitoring of when these factors engage polypeptides in the complex cellular environment. Studies of the Escherichia coli chaperone trigger factor (TF) reveal that, though TF can interact with many polypeptides, ß-barrel outer-membrane proteins are the most prominent substrates. Loss of TF leads to broad outer-membrane defects and premature, cotranslational protein translocation. Whereas in vitro studies suggested that TF is prebound to ribosomes waiting for polypeptides to emerge from the exit channel, we find that in vivo TF engages ribosomes only after ~100 amino acids are translated. Moreover, excess TF interferes with cotranslational removal of the N-terminal formyl methionine. Our studies support a triaging model in which proper protein biogenesis relies on the fine-tuned, sequential engagement of processing, targeting, and folding factors.
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Proteínas de Escherichia coli/metabolismo , Escherichia coli/metabolismo , Isomerasa de Peptidilprolil/metabolismo , Ribosomas/metabolismo , Citoplasma/química , Escherichia coli/citología , Proteínas de la Membrana/química , Proteínas de la Membrana/metabolismo , Chaperonas Moleculares/metabolismo , Datos de Secuencia Molecular , Biosíntesis de Proteínas , Transporte de ProteínasRESUMEN
INTRODUCTION: Currently, the inhibitor of the epidermal growth factor receptor tyrosine kinase erlotinib is widely used for the treatment of non-small cell lung cancer. Patients with a mutation or deletion in the epidermal growth factor receptor gene will benefit most and are likely to receive the drug for long periods and willing to accept side effects if responding. METHODS: Twenty-two cases with prolonged administration of erlotinib (at least 6 months) and side effects are reported. Three cases with specific side effects are described in detail. RESULTS: In addition to the well-known side effects such as folliculitis and diarrhea, patients reported paronychia, fatigue, and hair changes. DISCUSSION: After prolonged administration of erlotinib in most patients, the initial side effects persist while other inconvenient ones may develop. This may lead to dose reductions or even cessation of treatment.
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Adenocarcinoma/tratamiento farmacológico , Neoplasias Encefálicas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/efectos adversos , Quinazolinas/efectos adversos , Adenocarcinoma/complicaciones , Adenocarcinoma/secundario , Adulto , Neoplasias Encefálicas/complicaciones , Neoplasias Encefálicas/secundario , Carcinoma de Pulmón de Células no Pequeñas/complicaciones , Carcinoma de Pulmón de Células no Pequeñas/patología , Diarrea/inducido químicamente , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Clorhidrato de Erlotinib , Fatiga/inducido químicamente , Femenino , Foliculitis/inducido químicamente , Humanos , Neoplasias Pulmonares/complicaciones , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Mutación/genética , Paroniquia/inducido químicamente , Inhibidores de Proteínas Quinasas/farmacología , Quinazolinas/farmacología , Factores de Tiempo , Resultado del TratamientoRESUMEN
The detection of breast carcinoma cells in effusions is associated with rapidly fatal outcome, but these cells are poorly characterized at the molecular level. This study compared the gene array signatures of breast carcinoma cells in primary carcinomas and effusions. The genetic signature of 10 primary tumors and 10 effusions was analyzed using the Array-Ready Oligo set for the Human Genome platform. Results for selected genes were validated using PCR, Western blotting, and immunohistochemistry. Array analysis identified 255 significantly downregulated and 96 upregulated genes in the effusion samples. The majority of differentially expressed genes were part of pathways involved in focal adhesion, extracellular matrix-cell interaction, and the regulation of the actin cytoskeleton. Genes that were upregulated in effusions included KRT8, BCAR1, CLDN4, VIL2, while DCN, CLDN19, ITGA7, and ITGA5 were downregulated at this anatomic site. PCR, Western blotting, and immunohistochemistry confirmed the array findings for BCAR1, CLDN4, VIL2, and DCN. Our data show that breast carcinoma cells in primary carcinomas and effusions have different gene expression signatures, and differentially express a large number of molecules related to adhesion, motility, and metastasis. These differences may have a critical role in designing therapy and in prognostication for patients with metastatic disease localized to the serosal cavities.
RESUMEN
AIMS: Decreased total compliance of the pulmonary vascular bed is associated with increased mortality in patients with pulmonary arterial hypertension (PAH). We investigated whether proximal pulmonary artery stiffness, in terms of area distensibility and noninvasively assessed relative area change (RAC), calculated as relative cross-sectional area change, predicts mortality in patients with PAH. METHODS AND RESULTS: Eighty-six subjects underwent right-heart catheterization and MRI to assess area distensibility and RAC. Patients were followed up to 48 months. Kaplan-Meier plot and Cox proportional hazards regression analyses assessed the predictive value of area distensibility and RAC. In 70 patients, the diagnosis PAH was confirmed, and 16 subjects served as control subjects. In comparison with control subjects, proximal pulmonary arteries of patients were distended (685 +/- 214 mm2 vs 411 +/- 153 mm2, p < 0.001), less distensible (area distensibility = 0.46 +/- 0.38.10(-2) mm Hg(-1) vs 3.69 +/- 1.96.10(-2) mm Hg(-1), p < 0.0001), and RAC was smaller (20 +/- 10% vs 58 +/- 21%, p < 0.0001) [mean +/- SD]. RAC showed an inverse curvilinear relation with mean pulmonary artery pressure (R2 = 0.47). Eighteen patients (26%) died because of cardiopulmonary causes. Patients with a pulmonary artery RAC