RESUMEN
Physician burnout, a work-related syndrome involving emotional exhaustion, depersonalization and a sense of reduced personal accomplishment, is prevalent internationally. Rates of burnout symptoms that have been associated with adverse effects on patients, the healthcare workforce, costs and physician health exceed 50% in studies of both physicians-in-training and practicing physicians. This problem represents a public health crisis with negative impacts on individual physicians, patients and healthcare organizations and systems. Drivers of this epidemic are largely rooted within healthcare organizations and systems and include excessive workloads, inefficient work processes, clerical burdens, work-home conflicts, lack of input or control for physicians with respect to issues affecting their work lives, organizational support structures and leadership culture. Individual physician-level factors also play a role, with higher rates of burnout commonly reported in female and younger physicians. Effective solutions align with these drivers. For example, organizational efforts such as locally developed practice modifications and increased support for clinical work have demonstrated benefits in reducing burnout. Individually focused solutions such as mindfulness-based stress reduction and small-group programmes to promote community, connectedness and meaning have also been shown to be effective. Regardless of the specific approach taken, the problem of physician burnout is best addressed when viewed as a shared responsibility of both healthcare systems and individual physicians. Although our understanding of physician burnout has advanced considerably in recent years, many gaps in our knowledge remain. Longitudinal studies of burnout's effects and the impact of interventions on both burnout and its effects are needed, as are studies of effective solutions implemented in combination. For medicine to fulfil its mission for patients and for public health, all stakeholders in healthcare delivery must work together to develop and implement effective remedies for physician burnout.
Asunto(s)
Agotamiento Profesional/etiología , Médicos/psicología , Agotamiento Profesional/diagnóstico , Agotamiento Profesional/prevención & control , Costos de la Atención en Salud , Estado de Salud , Fuerza Laboral en Salud , Humanos , Atención al Paciente/normas , Inhabilitación Médica/psicología , Lugar de Trabajo/psicologíaAsunto(s)
Colecalciferol/uso terapéutico , Leucemia Linfocítica Crónica de Células B/complicaciones , Linfoma/complicaciones , Deficiencia de Vitamina D/complicaciones , Deficiencia de Vitamina D/tratamiento farmacológico , Colecalciferol/sangre , Colecalciferol/deficiencia , Humanos , Leucemia Linfocítica Crónica de Células B/sangre , Linfoma/sangreRESUMEN
Previously, we reported that B-cell chronic lymphocytic leukemia (CLL) patients contained elevated levels of microvesicles (MVs). However, given the quiescent nature of CLL B-cells and the relative indolence of the disease, the dynamics of MV generation and their unique phenotypes are not clearly defined. In this study, we find that CLL B-cells generate MVs spontaneously and can be further induced by B-cell receptor-ligation. Most interestingly, CLL B-cells predominantly generate CD52+ MVs, but not CD19+ MVs in vitro, suggesting preferential usage of CD52 into leukemic-MVs and that the CLL plasma MV phenotypes corroborate well with the in vitro findings. Importantly, we detected increased accumulation of CD52+ MVs in previously untreated CLL patients with progressive disease. Finally, sequential studies on MVs in pre- and post-therapy CLL patients demonstrate that although the plasma CD52+ MV levels drop significantly after therapy in most and remain at low levels in some patients, a trend of increased accumulation of CD52+ MVs was detected in majority of post-therapy CLL patients (25 of 33). In total, this study emphasizes that dynamic accumulation of CD52+ MVs in plasma can be used to study CLL progression and may be a useful biomarker for patients as they progress and require therapy.
Asunto(s)
Micropartículas Derivadas de Células/metabolismo , Leucemia Linfocítica Crónica de Células B/metabolismo , Leucemia Linfocítica Crónica de Células B/patología , Antígenos CD/metabolismo , Antígenos CD19/metabolismo , Antígenos de Neoplasias/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfocitos B/metabolismo , Linfocitos B/ultraestructura , Biomarcadores , Antígeno CD52 , Línea Celular Tumoral , Micropartículas Derivadas de Células/ultraestructura , Progresión de la Enfermedad , Glicoproteínas/metabolismo , Humanos , Inmunofenotipificación , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Tiempo de Tratamiento , Resultado del TratamientoRESUMEN
High-count monoclonal B-cell lymphocytosis (MBL) is an asymptomatic expansion of clonal B cells in the peripheral blood without other manifestations of chronic lymphocytic leukemia (CLL). Yearly, 1% of MBLs evolve to CLL requiring therapy; thus being critical to understand the biological events that determine which MBLs progress to intermediate/advanced CLL. In this study, we performed targeted deep sequencing on 48 high-count MBLs, 47 of them with 2-4 sequential samples analyzed, exploring the mutation status of 21 driver genes and evaluating clonal evolution. We found somatic non-synonymous mutations in 25 MBLs (52%) at the initial time point analyzed, including 12 (25%) with >1 mutated gene. In cases that subsequently progressed to CLL, mutations were detected 41 months (median) prior to progression. Excepting NOTCH1, TP53 and XPO1, which showed a lower incidence in MBL, genes were mutated with a similar prevalence to CLL, indicating the early origin of most driver mutations in the MBL/CLL continuum. MBLs with mutations at the initial time point analyzed were associated with shorter time-to-treatment (TTT). Furthermore, MBLs showing subclonal expansion of driver mutations on sequential evaluation had shorter progression time to CLL and shorter TTT. These findings support that clonal evolution has prognostic implications already at the pre-malignant MBL stage, anticipating which individuals will progress earlier to CLL.
Asunto(s)
Linfocitos B/patología , Leucemia Linfocítica Crónica de Células B/patología , Linfocitosis/diagnóstico , Mutación , Adulto , Anciano , Anciano de 80 o más Años , Transformación Celular Neoplásica/patología , Evolución Clonal , Células Clonales/patología , Progresión de la Enfermedad , Femenino , Genómica , Humanos , Recuento de Linfocitos , Linfocitosis/genética , Masculino , Persona de Mediana Edad , Pronóstico , Tiempo de TratamientoAsunto(s)
Biomarcadores de Tumor/análisis , Leucemia Linfocítica Crónica de Células B/mortalidad , Adulto , Anciano , Estudios de Cohortes , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Estudios Observacionales como Asunto , Pronóstico , Modelos de Riesgos Proporcionales , Factores de RiesgoRESUMEN
It is unknown whether individuals with monoclonal B-cell lymphocytosis (MBL) are at risk for adverse outcomes associated with chronic lymphocytic leukemia (CLL), such as the risk of non-hematologic cancer. We identified all locally residing individuals diagnosed with high-count MBL at Mayo Clinic between 1999 and 2009 and compared their rates of non-hematologic cancer with that of patients with CLL and two control cohorts: general medicine patients and patients who underwent clinical evaluation with flow cytometry but who had no hematologic malignancy. After excluding individuals with prior cancers, there were 107 high-count MBL cases, 132 CLL cases, 589 clinic controls and 482 flow cytometry controls. With 4.6 years median follow-up, 14 (13%) individuals with high-count MBL, 21 (4%) clinic controls (comparison MBL P<0.0001), 18 (4%) flow controls (comparison MBL P=0.0001) and 16 (12%) CLL patients (comparison MBL P=0.82) developed non-hematologic cancer. On multivariable Cox regression analysis, individuals with high-count MBL had higher risk of non-hematologic cancer compared with flow controls (hazard ratio (HR)=2.36; P=0.04) and borderline higher risk compared with clinic controls (HR=2.00; P=0.07). Patients with high-count MBL appear to be at increased risk for non-hematologic cancer, further reinforcing that high-count MBL has a distinct clinical phenotype despite low risk of progression to CLL.
Asunto(s)
Linfocitos B , Linfocitosis/complicaciones , Neoplasias/etiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/complicaciones , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , RiesgoAsunto(s)
Regulación Leucémica de la Expresión Génica , Leucemia Linfocítica Crónica de Células B/genética , MicroARNs/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Tirosina Quinasas Receptoras/genética , Proteína p53 Supresora de Tumor/genética , Regiones no Traducidas 3' , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/metabolismo , MicroARNs/metabolismo , Terapia Molecular Dirigida , Proteínas Proto-Oncogénicas/metabolismo , Interferencia de ARN , Proteínas Tirosina Quinasas Receptoras/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Tirosina Quinasa del Receptor AxlRESUMEN
Although the risk of progression from monoclonal B-cell lymphocytosis (MBL) to chronic lymphocytic leukemia (CLL) has been well characterized, it is unknown whether other common complications associated with CLL, such as increased risk of infection, occurs in individuals with MBL. We used the Mayo CLL database to identify cohorts of individuals with newly diagnosed MBL (n=154) or newly diagnosed CLL (n=174) who resided within 50 miles of Mayo Clinic. A cohort of 689 adult patients seen for a general medical examination who resided within 50 miles of Mayo clinic and who enrolled in a case-control study of non-Hodgkin lymphoma (NHL) was used as a comparison cohort. Hospitalization with infection was more common among individuals with MBL (25/154; 16.2%), and CLL (32/174; 18.4%) than controls (18/689; 2.6%). On pooled multivariable Cox proportional hazards analysis of all 1017 patients (controls, MBL and CLL), male sex (hazards ratio (HR)=2.3; P=0.002), major co-morbid health problems (HR=1.7, P=0.04), the presence of CLL (HR=3.2, P<0.001), treatment for progressive CLL (HR=2.4, P=0.001) and the presence of MBL (HR=3.0, P=0.001) were independently associated with risk of hospitalization for infection. These results suggest the risk of serious infection in clinical MBL is substantially greater than the risk of progression requiring treatment.
Asunto(s)
Infecciones/etiología , Leucemia Linfocítica Crónica de Células B/complicaciones , Linfocitosis/complicaciones , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Comorbilidad , Femenino , Estudios de Seguimiento , Hospitalización , Humanos , Infecciones/mortalidad , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/mortalidad , Linfocitosis/diagnóstico , Linfocitosis/mortalidad , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Factores de Riesgo , Tasa de Supervivencia , Adulto JovenAsunto(s)
Linfoma de Células B/patología , Factores de Edad , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores SexualesRESUMEN
INTRODUCTION: Little is known regarding the rate of burnout, career satisfaction, and quality of life (QOL) among surgical oncologists compared with other surgical subspecialties. METHODS: The American College of Surgeons conducted a survey in 2008 involving 7,905 respondents, of whom 407 were surgical oncologists. Demographic variables, practice characteristics, career satisfaction, burnout, and quality of life (QOL) of surgical oncologists were compared with other surgical subspecialties using validated instruments. RESULTS: Surgical oncologists were younger (mean age 49.9 years), more likely to be female (26%), and had younger children than other surgical subspecialties. With respect to practice characteristics, surgical oncologists had been in practice fewer years and had fewer nights on call per week than other surgical disciplines but worked more hours (mean 62.6/week), were more likely to be in an academic practice (59.5%), were more likely to be paid on a salaried basis (68%), and had more time devoted to non-patient activities (e.g., research). Compared with surgeons from all other specialties, surgical oncologists had similar incidence of burnout (36%), suicide ideation (4.9%), and QOL, but lower incidence of depression (24%), and better indices of career satisfaction. CONCLUSIONS: These data provide a frame of reference for valid comparisons of burnout, QOL, and career satisfaction indices for the surgical oncology community relative to all other surgical specialties. Surgical oncologists have higher career satisfaction and lower risk of depression than surgeons in other surgical disciplines but still experience high rates of burnout.
Asunto(s)
Agotamiento Profesional/complicaciones , Satisfacción en el Trabajo , Oncología Médica , Médicos/psicología , Especialidades Quirúrgicas , Estrés Psicológico/complicaciones , Adulto , Anciano , Anciano de 80 o más Años , Actitud del Personal de Salud , Agotamiento Profesional/prevención & control , Selección de Profesión , Femenino , Promoción de la Salud , Humanos , Estilo de Vida , Masculino , Persona de Mediana Edad , Pautas de la Práctica en Medicina , Calidad de Vida , Estrés Psicológico/prevención & control , Encuestas y Cuestionarios , Factores de Tiempo , Adulto JovenRESUMEN
Chronic lymphocytic leukemia (CLL) and the other low-grade non-Hodgkin lymphomas are among the most common lymphoid malignancies. Recent studies suggest that more than 4% of the general population over age 40 harbor a population of clonal B cells with the phenotype of either CLL or another B-cell malignancy, a condition now designated monoclonal B-cell lymphocytosis (MBL). Although all cases of CLL appear to be preceded by MBL, the majority of individuals with MBL will not develop a hematologic malignancy. The biologic characteristics and clinical implications of MBL appear to differ based on whether it is identified during the diagnostic evaluation of lymphocytosis or incidentally discovered through screening of individuals with normal lymphocyte counts as part of research studies using highly sensitive detection methods. In this paper, we provide a state of the art review on the prevalence, nomenclature, biology, natural history and clinical management of MBL.
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Linfocitos B/patología , Linfocitosis/terapia , Progresión de la Enfermedad , Humanos , Leucemia Linfocítica Crónica de Células B/epidemiología , Leucemia Linfocítica Crónica de Células B/etiología , Linfocitosis/complicaciones , Linfocitosis/diagnóstico , Linfocitosis/epidemiología , Prevalencia , Terminología como AsuntoRESUMEN
Green tea or its constituents have long been touted as a health promoting substance including claims it may have cancer prevention properties. We previously reported the in vitro ability of one tea polyphenol, epigallocatechin gallate (EGCG), to induce apoptotic cell death in the leukemic B-cells from a majority of patients with chronic lymphocytic leukemia (CLL). After the publication of our findings many patients with CLL and other low grade lymphomas began using over-the-counter products containing tea polyphenols despite the absence of evidence to suggest clinical benefit, definition of possible toxicities, or information on optimal dose and schedule. We have become aware of four patients with low grade B-cell malignancies seen in our clinical practice at Mayo Clinic who began, on their own initiative, oral ingestion of EGCG containing products and subsequently appeared to have an objective clinical response. Three of these four patients met criteria for partial response (PR) by standard response criteria. Although spontaneous remission/regression is occasionally observed in individuals with low grade B-cell malignancies, such events are rare. Several patients presented here had documented steady clinical, laboratory, and/or radiographic evidence of progression immediately prior to initiation of over-the-counter green tea products and then developed objective responses shortly after self-initiating this therapy. Such anecdotes highlight the need for clinical trials of tea polyphenols to define the optimal dosing, schedule, toxicities, and clinical efficacy before widespread use can be recommended. An NCI sponsored phase I/II trial of de-caffeinated green tea extracts for patients with asymptomatic, early stage CLL opened at Mayo Clinic in August 2005.
Asunto(s)
Anticarcinógenos/uso terapéutico , Camellia sinensis , Catequina/análogos & derivados , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Fitoterapia , Camellia sinensis/química , Catequina/uso terapéutico , Ensayos Clínicos como Asunto , Supervivencia sin Enfermedad , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/diagnóstico por imagen , Persona de Mediana Edad , Regresión Neoplásica Espontánea , Estadificación de Neoplasias , Extractos Vegetales , Radiografía , Inducción de Remisión/métodos , Té/químicaRESUMEN
CD38, a surface protein whose expression increases upon normal B-cell activation, is a marker of disease aggression in B-cell chronic lymphocytic leukemia (B-CLL). Higher percentages of CD38-expressing CLL B cells may be found in lymphoid compartments compared to peripheral blood. Therefore, it is possible that although CLL B cells are resting, CD38 may be a marker of recent cell activation prior to entry into the periphery. To address this hypothesis, we examined the association of CD38 expression with other activation antigens identified in gene expression profiling experiments and include CD18, CD49d, CD20, and subunit 5 of the anaphase-promoting complex/cyclosome. We found that all these markers were more highly expressed in leukemic B cells from CD38-positive CLL patients. Lastly, because interferon is known to modulate CD38 expression, we used IFN-alpha to test the ability of CLL B cells to increase CD38 expression in vitro. Interestingly, IFN stimulation only modulated CD38 expression in CLL B cells that already expressed CD38. Taken together, these data suggest that CD38 is a marker of a more recently activated CLL B cell. This in turn may explain the biological and clinical differences between CD38-positive type B-CLL and CD38-negative type B-CLL.
Asunto(s)
ADP-Ribosil Ciclasa 1/genética , Interferones/farmacología , Leucemia Linfocítica Crónica de Células B/genética , Activación de Linfocitos/efectos de los fármacos , ADP-Ribosil Ciclasa 1/análisis , Adulto , Anciano , Anciano de 80 o más Años , Antígenos CD/análisis , Biomarcadores/análisis , Femenino , Citometría de Flujo , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Humanos , Leucemia Linfocítica Crónica de Células B/patología , Masculino , Persona de Mediana Edad , PronósticoRESUMEN
Translocations involving IGH are common in some lymphoid malignancies but are believed to be rare in chronic lymphocytic leukaemia (CLL). To study the clinical utility of fluorescence in situ hybridization (FISH) for IGH translocations, we reviewed 1032 patients with a presumptive diagnosis of CLL. Seventy-six (7%) patients had IGH translocations. Pathology and clinical data were available for the 24 patients evaluated at the Mayo Clinic. Ten (42%) patients had IGH/cyclin D1 fusion and were diagnosed with mantle cell lymphoma (MCL). The immunophenotype was typical of MCL in three of these patients and atypical for MCL in seven patients. One patient had biclonal disease with typical MCL and CLL with IGH/BCL-2. Eleven (46%) patients had IGH/BCL-2 fusion including the patient with biclonal disease. Two of these patients had leukaemic phase follicular lymphoma and nine patients had CLL. The median progression-free survival of patients with CLL and IGH/BCL-2 translocation was 20.6 months. The two patients with IGH/BCL-3 fusion (one of these also had IGH/BCL-11a) had rapid disease progression. The IGH partner gene was not identified in two patients. We conclude that use of an IGH probe in FISH analysis of monoclonal B-cell lymphocytosis improves diagnostic precision and could have prognostic value in patients with CLL.
Asunto(s)
Genes de Inmunoglobulinas , Cadenas Pesadas de Inmunoglobulina/genética , Interfase , Leucemia Linfocítica Crónica de Células B/diagnóstico , Sondas de Oligonucleótidos , Translocación Genética , Proteínas del Linfoma 3 de Células B , Ciclina D1/genética , Diagnóstico Diferencial , Citometría de Flujo , Genes bcl-2 , Humanos , Inmunofenotipificación , Hibridación Fluorescente in Situ , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/inmunología , Linfoma de Células B/diagnóstico , Linfoma de Células B/genética , Linfoma de Células del Manto/diagnóstico , Linfoma de Células del Manto/genética , Proteínas Proto-Oncogénicas/genética , Factores de TranscripciónRESUMEN
We have previously shown that chronic lymphocytic leukemia (CLL) B cells secrete vascular endothelial growth factor (VEGF) in vitro, have constitutively active VEGF receptors R1 and R2, and respond to exogenous VEGF by specifically upregulating Mcl-1 and XIAP in association with decreased cell death. We found that epigallocatechin (EGCG) decreases VEGF receptor phosphorylation and induces apoptosis in CLL B cells. The mechanism(s) by which VEGF receptor activation increases Mcl-1 and XIAP and promotes survival remains unknown. To further define the signaling pathway mediating VEGF induction of antiapoptotic proteins in CLL B-cells, we investigated downstream effects of VEGF-VEGF receptor binding on the STAT signaling pathway. We find that CLL B cells abundantly express cytoplasmic serine phosphorylated (p)-STAT-1 and p-STAT-3, VEGF-R1/2 are physically associated with p-STAT-1 and p-STAT-3, and p-STAT-3 (but not p-STAT-1) is found in the CLL nucleus. VEGF receptor ligation selectively induces activation and perinuclear translocation of STAT 3 through receptor-mediated endocytosis. The inhibition of VEGF receptor activation with either tyrosine kinase inhibitors or VEGF neutralizing antibodies inhibit VEGF receptor phosphorylation, decrease p-STAT-3 (serine 727), Mcl-1, and induces cell death in CLL B cells. Thus, a VEGF-VEGF receptor pathway in CLL B cells can be linked to activation of STAT proteins that are able to enhance their apoptotic resistance.