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1.
Nature ; 611(7935): 306-311, 2022 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-36289328

RESUMEN

Characterizing how variation in the tempo and mode of evolution has structured the phenotypic diversity of extant species is a central goal of macroevolution1-3. However, studies are typically limited to a handful of traits4-6, providing incomplete information. We analyse morphological diversification in living birds, an ecologically diverse group7, documenting structural scales from 'pan-skeletal' proportions down to the localized three-dimensional shape changes of individual bones. We find substantial variation in evolutionary modes among avian subgroups and among skeletal parts, indicating widespread mosaicism and possible differences in the structure of the macroevolutionary landscape across Earth's main environments. Water-linked groups, especially Aequorlitornithes (waterbirds), have repeatedly explored a large portion of their total morphospace, emphasizing variation in body proportions and in the shape of bones close to the body core, which are functionally related to the mechanics of locomotion8. By contrast, landbirds (Inopinaves) evolved distinct, group-specific body forms early in the aftermath of the K-Pg and subsequently emphasized local shape variation, especially in the head and distal limb bones, which interact more directly with the environment. Passerines, which comprise more than half of all bird species, show a conservative evolutionary dynamic that resulted in low disparity across all skeletal parts. Evidence for early establishment of the morphospace of living birds is clear for some skeletal parts, including beaks and the combined skeletal morphology. However, we find little evidence for early partitioning of that morphospace, contrary to more specific predictions of 'niche-filling' models1,9. Nevertheless, early divergence among broad environmental types may have caused an early divergence of evolutionary modes, suggesting an important role for environmental divergence in structuring the radiation of crown-group birds.


Asunto(s)
Evolución Biológica , Aves , Ambiente , Fenotipo , Esqueleto , Animales , Aves/anatomía & histología , Aves/clasificación , Extremidades/anatomía & histología , Locomoción , Esqueleto/anatomía & histología , Mosaicismo , Pico
2.
Blood ; 141(17): 2047-2061, 2023 04 27.
Artículo en Inglés | MEDLINE | ID: mdl-36724453

RESUMEN

Myelodysplastic syndromes/myelodysplastic neoplasms (MDS) are associated with variable clinical presentations and outcomes. The initial response criteria developed by the International Working Group (IWG) in 2000 have been used in clinical practice, clinical trials, regulatory reviews, and drug labels. Although the IWG criteria were revised in 2006 and 2018 (the latter focusing on lower-risk disease), limitations persist in their application to higher-risk MDS (HR-MDS) and their ability to fully capture the clinical benefits of novel investigational drugs or serve as valid surrogates for longer-term clinical end points (eg, overall survival). Further, issues related to the ambiguity and practicality of some criteria lead to variability in interpretation and interobserver inconsistency in reporting results from the same sets of data. Thus, we convened an international panel of 36 MDS experts and used an established modified Delphi process to develop consensus recommendations for updated response criteria that would be more reflective of patient-centered and clinically relevant outcomes in HR-MDS. Among others, the IWG 2023 criteria include changes in the hemoglobin threshold for complete remission (CR), the introduction of CR with limited count recovery and CR with partial hematologic recovery as provisional response criteria, the elimination of marrow CR, and specific recommendations for the standardization of time-to-event end points and the derivation and reporting of responses. The updated criteria should lead to a better correlation between patient-centered outcomes and clinical trial results in an era of multiple emerging new agents with novel mechanisms of action.


Asunto(s)
Hematología , Síndromes Mielodisplásicos , Humanos , Resultado del Tratamiento , Consenso , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/tratamiento farmacológico , Evaluación de Resultado en la Atención de Salud
3.
Curr Opin Hematol ; 31(2): 40-46, 2024 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-37982261

RESUMEN

PURPOSE OF REVIEW: Myelodysplastic neoplasms (MDS) are diseases of stem cell aging associated with complications from inadequate hematopoiesis (red cells, neutrophils and platelets) and variable risk for transformation to acute myeloid leukemia. Those with low-risk disease also suffer and die from MDS-related complications. Among the most challenging is development of anemia and transfusion dependence, which impacts quality of life and is associated with reduced survival. Appreciating and measuring the quality-of-life impact, preventing (if possible), treating, and managing the complications from anemia in MDS are of critical importance. RECENT FINDINGS: Recent developments in basic science highlight the potential deleterious impact of iron overload within the developing red cell niche. Iron overload can compromise red cell maturation from healthy as well as malignant clones and produces an environment favoring expansion of mutant clonal cells, potentially driving disease progression. Observational studies in nontransfusion dependent MDS highlight that iron overload occurs even in the nontransfusion dependent. The newly approved (and established) therapies for management of MDS-related anemia work best when begun before patients become heavily transfusion-dependent. SUMMARY: Iron overload is detrimental to hematopoiesis. Understanding the benefit afforded by transfusion is critical to optimal application and patient reported outcomes can inform this. Recently developed therapies are active and optimized application may improve response.


Asunto(s)
Anemia , Sobrecarga de Hierro , Síndromes Mielodisplásicos , Neoplasias , Humanos , Calidad de Vida , Sobrecarga de Hierro/terapia , Sobrecarga de Hierro/prevención & control , Síndromes Mielodisplásicos/terapia , Eritropoyesis , Neoplasias/complicaciones , Quelantes del Hierro
4.
Cancer ; 130(12): 2191-2204, 2024 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-38376917

RESUMEN

BACKGROUND: COVID-19 can have a particularly detrimental effect on patients with cancer, but no studies to date have examined if the presence, or site, of metastatic cancer is related to COVID-19 outcomes. METHODS: Using the COVID-19 and Cancer Consortium (CCC19) registry, the authors identified 10,065 patients with COVID-19 and cancer (2325 with and 7740 without metastasis at the time of COVID-19 diagnosis). The primary ordinal outcome was COVID-19 severity: not hospitalized, hospitalized but did not receive supplemental O2, hospitalized and received supplemental O2, admitted to an intensive care unit, received mechanical ventilation, or died from any cause. The authors used ordinal logistic regression models to compare COVID-19 severity by presence and specific site of metastatic cancer. They used logistic regression models to assess 30-day all-cause mortality. RESULTS: Compared to patients without metastasis, patients with metastases have increased hospitalization rates (59% vs. 49%) and higher 30 day mortality (18% vs. 9%). Patients with metastasis to bone, lung, liver, lymph nodes, and brain have significantly higher COVID-19 severity (adjusted odds ratios [ORs], 1.38, 1.59, 1.38, 1.00, and 2.21) compared to patients without metastases at those sites. Patients with metastasis to the lung have significantly higher odds of 30-day mortality (adjusted OR, 1.53; 95% confidence interval, 1.17-2.00) when adjusting for COVID-19 severity. CONCLUSIONS: Patients with metastatic cancer, especially with metastasis to the brain, are more likely to have severe outcomes after COVID-19 whereas patients with metastasis to the lung, compared to patients with cancer metastasis to other sites, have the highest 30-day mortality after COVID-19.


Asunto(s)
COVID-19 , Hospitalización , Metástasis de la Neoplasia , Neoplasias , Sistema de Registros , SARS-CoV-2 , Humanos , COVID-19/mortalidad , COVID-19/complicaciones , COVID-19/epidemiología , COVID-19/patología , Masculino , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Anciano , Hospitalización/estadística & datos numéricos , Neoplasias/patología , Neoplasias/mortalidad , SARS-CoV-2/aislamiento & purificación , Índice de Severidad de la Enfermedad , Respiración Artificial/estadística & datos numéricos
5.
Int J Technol Assess Health Care ; 39(1): e30, 2023 May 22.
Artículo en Inglés | MEDLINE | ID: mdl-37212053

RESUMEN

OBJECTIVES: Value-based agreements (VBAs) link access, reimbursement, or price to the real-world usage and impact of a medicine, thereby enabling patient access while reducing clinical or financial uncertainty for the payer. VBAs have the potential to support improved patient outcomes, given the value-oriented approach to care, and lead to overall savings, while enabling payers to share risk and reduce uncertainty. METHODS: This commentary outlines the key challenges, enablers, and a framework for successful implementation by comparing the experience of two VBAs for AstraZeneca medicines, aiming to increase confidence in their future use. RESULTS: Engagement by payers, manufacturers, physicians, and provider institutions, and robust data collection systems that are accessible, simple to use, and add little burden to physicians were key to successfully negotiating a VBA that worked for all stakeholders. In both country systems, a legal/policy framework enabled innovative contracting. CONCLUSIONS: These examples demonstrate proof of concept for VBA implementation in different settings, and may inform future VBAs.


Asunto(s)
Compra Basada en Calidad , Humanos , Europa (Continente) , Preparaciones Farmacéuticas
6.
Wiad Lek ; 76(12): 2543-2555, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-38290016

RESUMEN

Marie Sklodowska-Curie Symposia on Cancer Research and Care (MSCS-CRC) promote collaborations between cancer researchers and care providers in the United States, Canada and Central and Eastern European Countries (CEEC), to accelerate the development of new cancer therapies, advance early detection and prevention, increase cancer awareness, and improve cancer care and the quality of life of patients and their families. The third edition of MSCS-CRC, held at Roswell Park Comprehensive Cancer Center, Buffalo, NY, in September 2023, brought together 137 participants from 20 academic institutions in the US, Poland, Ukraine, Lithuania, Croatia and Hungary, together with 16 biotech and pharma entities. The key areas of collaborative opportunity identified during the meeting are a) creating of a database of available collaborative projects in the areas of early-phase clinical trials, preclinical development, and identification of early biomarkers; b) promoting awareness of cancer risks and efforts at cancer prevention; c) laboratory and clinical training; and d) sharing experience in cost-effective delivery of cancer care and improving the quality of life of cancer patients and their families. Examples of ongoing international collaborations in the above areas were discussed. Participation of the representatives of the Warsaw-based Medical Research Agency, National Cancer Institute (NCI) of the United States, National Cancer Research Institutes of Poland and Lithuania, New York State Empire State Development, Ministry of Health of Ukraine and Translational Research Cancer Center Consortium of 13 cancer centers from the US and Canada, facilitated the discussion of available governmental and non-governmental funding initiatives in the above areas.


Asunto(s)
Investigación Biomédica , Neoplasias , Humanos , Estados Unidos , New York , Calidad de Vida , Neoplasias/terapia , Polonia
7.
Blood ; 136(6): 674-683, 2020 08 06.
Artículo en Inglés | MEDLINE | ID: mdl-32285126

RESUMEN

This phase 2 study was designed to compare systemic decitabine exposure, demethylation activity, and safety in the first 2 cycles with cedazuridine 100 mg/decitabine 35 mg vs standard decitabine 20 mg/m2 IV. Adults with International Prognostic Scoring System intermediate-1/2- or high-risk myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) were randomized 1:1 to receive oral cedazuridine/decitabine or IV decitabine in cycle 1, followed by crossover to the other treatment in cycle 2. All patients received oral cedazuridine/decitabine in subsequent cycles. Cedazuridine and decitabine were given initially as separate capsules in a dose-confirmation stage and then as a single fixed-dose combination (FDC) tablet. Primary end points: mean decitabine systemic exposure (geometric least-squares mean [LSM]) of oral/IV 5-day area under curve from time 0 to last measurable concentration (AUClast), percentage long interspersed nuclear element 1 (LINE-1) DNA demethylation for oral cedazuridine/decitabine vs IV decitabine, and clinical response. Eighty patients were randomized and treated. Oral/IV ratios of geometric LSM 5-day AUClast (80% confidence interval) were 93.5% (82.1-106.5) and 97.6% (80.5-118.3) for the dose-confirmation and FDC stages, respectively. Differences in mean %LINE-1 demethylation between oral and IV were ≤1%. Clinical responses were observed in 48 patients (60%), including 17 (21%) with complete response. The most common grade ≥3 adverse events regardless of causality were neutropenia (46%), thrombocytopenia (38%), and febrile neutropenia (29%). Oral cedazuridine/decitabine (100/35 mg) produced similar systemic decitabine exposure, DNA demethylation, and safety vs decitabine 20 mg/m2 IV in the first 2 cycles, with similar efficacy. This study is registered at www.clinicaltrials.gov as #NCT02103478.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Mielomonocítica Crónica/tratamiento farmacológico , Síndromes Mielodisplásicos/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Área Bajo la Curva , Cápsulas , Estudios Cruzados , Metilación de ADN/efectos de los fármacos , ADN-Citosina Metilasas/antagonistas & inhibidores , Decitabina/administración & dosificación , Decitabina/efectos adversos , Decitabina/farmacocinética , Decitabina/farmacología , Progresión de la Enfermedad , Combinación de Medicamentos , Monitoreo de Drogas , Femenino , Enfermedades Gastrointestinales/inducido químicamente , Enfermedades Hematológicas/inducido químicamente , Humanos , Estimación de Kaplan-Meier , Análisis de los Mínimos Cuadrados , Leucemia Mieloide Aguda/prevención & control , Elementos de Nucleótido Esparcido Largo/efectos de los fármacos , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/antagonistas & inhibidores , Comprimidos , Uridina/administración & dosificación , Uridina/efectos adversos , Uridina/análogos & derivados , Uridina/farmacocinética , Uridina/farmacología
8.
J Gen Intern Med ; 37(10): 2489-2495, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35132554

RESUMEN

BACKGROUND: Advocacy is a core value of the medical profession. However, patient advocacy (advocacy) is not uniformly assessed and there are no studies of the behaviors clinical supervisors consider when assessing advocacy. OBJECTIVE: To explore how medical students and supervisors characterize advocacy during an internal medicine clerkship, how assessment of advocacy impacted students and supervisors, and elements that support effective implementation of advocacy assessment. DESIGN: A constructivist qualitative paradigm was used to understand advocacy assessment from the perspectives of students and supervisors. PARTICIPANTS: Medical students who completed the internal medicine clerkship at UCSF during the 2018 and 2019 academic years and supervisors who evaluated students during this period. APPROACH: Supervisor comments from an advocacy assessment item in the medicine clerkship and transcripts of focus groups were used to explore which behaviors students and supervisors deem to be advocacy. Separate focus groups with both students and supervisors examined the impact that advocacy assessment had on students' and supervisors' perceptions of advocacy and what additional context was necessary to effectively implement advocacy assessment. KEY RESULTS: Students and supervisors define advocacy as identifying and addressing social determinants of health, recognizing and addressing patient wishes and concerns, navigating the health care system, conducting appropriate evaluation and treatment, and creating exceptional therapeutic alliances. Effective implementation of advocacy assessment requires the creation of non-hierarchical team environments, supervisor role modeling, and pairing assessment with teaching of advocacy skills. Inclusion of advocacy assessment reflects and dictates institutional priorities, shapes professional identity formation, and enhances advocacy skill development for students and their supervisors. CONCLUSIONS: Students and supervisors consider advocacy to be a variety of behaviors beyond identifying and addressing social determinants of health. Effectively implementing advocacy assessment shapes students' professional identity formation, underscoring the critical importance of formally focusing on this competency in the health professions education.


Asunto(s)
Prácticas Clínicas , Educación de Pregrado en Medicina , Estudiantes de Medicina , Competencia Clínica , Humanos , Defensa del Paciente
9.
J Natl Compr Canc Netw ; 20(5): 436-442, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35545171

RESUMEN

The NCCN Guidelines for Hematopoietic Growth Factors provide recommendations for the appropriate use of growth factors in the clinical management of febrile neutropenia (FN), chemotherapy-induced thrombocytopenia (CIT), and chemotherapy-induced anemia (CIA). Management and prevention of these sequelae are an integral part of supportive care for many patients undergoing cancer treatment. The purpose of these guidelines is to operationalize the evaluation, prevention, and treatment of FN, CIT, and CIA in adult patients with nonmyeloid malignancies and to enable the patient and clinician to assess management options for FN, CIT, and CIA in the context of an individual patient's condition. These NCCN Guidelines Insights provide a summary of the important recent updates to the NCCN Guidelines for Hematopoietic Growth Factors, with particular emphasis on the incorporation of a newly developed section on CIT.


Asunto(s)
Anemia , Antineoplásicos , Neoplasias , Adulto , Anemia/inducido químicamente , Anemia/tratamiento farmacológico , Antineoplásicos/efectos adversos , Factores de Crecimiento de Célula Hematopoyética/uso terapéutico , Humanos , Neoplasias/tratamiento farmacológico
10.
J Natl Compr Canc Netw ; 20(2): 106-117, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-35130502

RESUMEN

The NCCN Guidelines for Myelodysplastic Syndromes (MDS) provide recommendations for the evaluation, diagnosis, and management of patients with MDS based on a review of clinical evidence that has led to important advances in treatment or has yielded new information on biologic factors that may have prognostic significance in MDS. The multidisciplinary panel of MDS experts meets on an annual basis to update the recommendations. These NCCN Guidelines Insights focus on some of the updates for the 2022 version of the NCCN Guidelines, which include treatment recommendations both for lower-risk and higher-risk MDS, emerging therapies, supportive care recommendations, and genetic familial high-risk assessment for hereditary myeloid malignancy predisposition syndromes.


Asunto(s)
Síndromes Mielodisplásicos , Predisposición Genética a la Enfermedad , Humanos , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/terapia , Guías de Práctica Clínica como Asunto , Pronóstico
11.
Med Teach ; 44(2): 149-157, 2022 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-34433360

RESUMEN

To improve health, physicians are increasingly called to advocate. Yet medical schools have only recently focused on health advocacy skill-building. Limited work to date addresses assessing medical student advocacy on behalf of patients. We describe how students and clinical supervisors (CS) in two urban longitudinal integrated clerkships (LIC) experience patient advocacy and how introducing a new advocacy assessment impacts them. Using a thematic approach, we analyzed transcripts of focus groups during 2018-2019. Seventeen of 24 (71%) students and 15 of 21 (71%) CS participated in the focus groups. We describe how students perceive their advocacy role as they accompany the patient, amplify their voice, and facilitate connection. The rationale for advocacy assessment includes that it (1) adds a novel dimension to the written and verbal assessment, (2) drives student learning, (3) aligns with the institutional goal to promote equity, and (4) impacts CS teaching and clinical practice. Challenges are the ambiguity of expectations, pressure to 'perform,' and a moral overlay to advocacy assessment. Findings demonstrate how educational alliances between students and CS and longitudinal relationships between LIC students and patients offer a constructive opportunity for advocacy assessment. We describe suggestions to hone and expand the reach of advocacy assessment.


Asunto(s)
Prácticas Clínicas , Educación de Pregrado en Medicina , Estudiantes de Medicina , Prácticas Clínicas/métodos , Educación de Pregrado en Medicina/métodos , Grupos Focales , Humanos , Facultades de Medicina
12.
Lancet ; 395(10241): 1907-1918, 2020 06 20.
Artículo en Inglés | MEDLINE | ID: mdl-32473681

RESUMEN

BACKGROUND: Data on patients with COVID-19 who have cancer are lacking. Here we characterise the outcomes of a cohort of patients with cancer and COVID-19 and identify potential prognostic factors for mortality and severe illness. METHODS: In this cohort study, we collected de-identified data on patients with active or previous malignancy, aged 18 years and older, with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection from the USA, Canada, and Spain from the COVID-19 and Cancer Consortium (CCC19) database for whom baseline data were added between March 17 and April 16, 2020. We collected data on baseline clinical conditions, medications, cancer diagnosis and treatment, and COVID-19 disease course. The primary endpoint was all-cause mortality within 30 days of diagnosis of COVID-19. We assessed the association between the outcome and potential prognostic variables using logistic regression analyses, partially adjusted for age, sex, smoking status, and obesity. This study is registered with ClinicalTrials.gov, NCT04354701, and is ongoing. FINDINGS: Of 1035 records entered into the CCC19 database during the study period, 928 patients met inclusion criteria for our analysis. Median age was 66 years (IQR 57-76), 279 (30%) were aged 75 years or older, and 468 (50%) patients were male. The most prevalent malignancies were breast (191 [21%]) and prostate (152 [16%]). 366 (39%) patients were on active anticancer treatment, and 396 (43%) had active (measurable) cancer. At analysis (May 7, 2020), 121 (13%) patients had died. In logistic regression analysis, independent factors associated with increased 30-day mortality, after partial adjustment, were: increased age (per 10 years; partially adjusted odds ratio 1·84, 95% CI 1·53-2·21), male sex (1·63, 1·07-2·48), smoking status (former smoker vs never smoked: 1·60, 1·03-2·47), number of comorbidities (two vs none: 4·50, 1·33-15·28), Eastern Cooperative Oncology Group performance status of 2 or higher (status of 2 vs 0 or 1: 3·89, 2·11-7·18), active cancer (progressing vs remission: 5·20, 2·77-9·77), and receipt of azithromycin plus hydroxychloroquine (vs treatment with neither: 2·93, 1·79-4·79; confounding by indication cannot be excluded). Compared with residence in the US-Northeast, residence in Canada (0·24, 0·07-0·84) or the US-Midwest (0·50, 0·28-0·90) were associated with decreased 30-day all-cause mortality. Race and ethnicity, obesity status, cancer type, type of anticancer therapy, and recent surgery were not associated with mortality. INTERPRETATION: Among patients with cancer and COVID-19, 30-day all-cause mortality was high and associated with general risk factors and risk factors unique to patients with cancer. Longer follow-up is needed to better understand the effect of COVID-19 on outcomes in patients with cancer, including the ability to continue specific cancer treatments. FUNDING: American Cancer Society, National Institutes of Health, and Hope Foundation for Cancer Research.


Asunto(s)
Infecciones por Coronavirus/epidemiología , Neoplasias/epidemiología , Neumonía Viral/epidemiología , Anciano , Antivirales/uso terapéutico , Azitromicina/uso terapéutico , Betacoronavirus , COVID-19 , Causas de Muerte , Comorbilidad , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/mortalidad , Bases de Datos Factuales , Femenino , Humanos , Hidroxicloroquina/uso terapéutico , Masculino , Persona de Mediana Edad , Neoplasias/mortalidad , Neoplasias/terapia , Pandemias , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/mortalidad , Pronóstico , Factores de Riesgo , SARS-CoV-2 , Tratamiento Farmacológico de COVID-19
13.
Eur J Haematol ; 107(3): 343-353, 2021 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-34053123

RESUMEN

OBJECTIVES: This study aims to retrospectively assess C-lectin-like molecule 1 (CLL-1) bimodal expression on CD34+ blasts in acute myeloid leukemia (AML) patients (total N = 306) and explore potential CLL-1 bimodal associations with leukemia and patient-specific characteristics. METHODS: Flow cytometry assays were performed to assess the deeper immunophenotyping of CLL-1 bimodality. Cytogenetic analysis was performed to characterize the gene mutation on CLL-1-negative subpopulation of CLL-1 bimodal AML samples. RESULTS: The frequency of a bimodal pattern of CLL-1 expression of CD34+ blasts ranged from 8% to 65% in the different cohorts. Bimodal CLL-1 expression was most prevalent in patients with MDS-related AML (P = .011), ELN adverse risk (P = .002), NPM1 wild type (WT, P = .049), FLT3 WT (P = .035), and relatively low percentages of leukemia-associated immunophenotypes (P = .006). Additional immunophenotyping analysis revealed the CLL-1- subpopulation may consist of pre-B cells, immature myeloblasts, and hematopoietic stem cells. Furthermore, (pre)-leukemic mutations were detected in both CLL-1+ and CLL-1- subfractions of bimodal samples (N = 3). CONCLUSIONS: C-lectin-like molecule 1 bimodality occurs in about 25% of AML patients and the CLL-1- cell population still contains malignant cells, hence it may potentially limit the effectiveness of CLL-1-targeted therapies and warrant further investigation.


Asunto(s)
Biomarcadores de Tumor/genética , Células de la Médula Ósea/metabolismo , Lectinas Tipo C/genética , Leucemia Mieloide Aguda/genética , Mutación , Células Mieloides/metabolismo , Receptores Mitogénicos/genética , Antígenos CD34/genética , Antígenos CD34/inmunología , Biomarcadores de Tumor/inmunología , Células de la Médula Ósea/inmunología , Células de la Médula Ósea/patología , Análisis Citogenético , Femenino , Citometría de Flujo , Perfilación de la Expresión Génica , Regulación Leucémica de la Expresión Génica , Células Madre Hematopoyéticas/inmunología , Células Madre Hematopoyéticas/metabolismo , Células Madre Hematopoyéticas/patología , Humanos , Inmunofenotipificación , Lectinas Tipo C/inmunología , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Células Mieloides/inmunología , Células Mieloides/patología , Células Precursoras de Linfocitos B/inmunología , Células Precursoras de Linfocitos B/metabolismo , Células Precursoras de Linfocitos B/patología , Cultivo Primario de Células , Receptores Mitogénicos/inmunología
14.
Future Oncol ; 17(16): 2077-2087, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-33709786

RESUMEN

Myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) are clonal hematopoietic stem cell disorders. Complex disease biology has posed significant challenge to the development of novel therapeutics. Despite myriad clinical trials, none have been superior to azacitidine and decitabine (DEC) therapy. These therapies present a substantial burden for patients with 5 and 7 days of parenteral treatment in an infusion clinic. To overcome this limitation, a fixed drug combination of oral DEC-cedazuridine (C-DEC), a cytidine deaminase inhibitor with documented safety profile was developed. This drug was recently approved by the US FDA, Australian TGA and Health Canada for newly diagnosed or previously treated intermediate or high risk by international prognostic scoring system, MDS and CMML. In this review, we detail the pharmacokinetic and clinical activity of C-DEC in the management of MDS and CMML.


Lay abstract Myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia are rare types of blood cancers. When treatment for these conditions is required, azacitidine or decitabine are the most commonly used chemotherapies. These medications are administered into blood through a medical port. Since these cancers are common in elderly, management of the port and frequent visits to infusion centers for treatment leads to noncompliance with treatment plan. With addition of a new compound by name cedazuridine to decitabine, now a new US FDA-approved medication, INQOVI® (decitabine and cedazuridine) can be taken by mouth at home. This new treatment has shown to be equally effective with a similar safety profile to decitabine. In this review article, we describe the investigational details and drug development of the oral medication, INQOVI®.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Aprobación de Drogas/métodos , Leucemia Mielomonocítica Crónica/tratamiento farmacológico , Síndromes Mielodisplásicos/tratamiento farmacológico , Animales , Decitabina/administración & dosificación , Manejo de la Enfermedad , Humanos , Leucemia Mielomonocítica Crónica/genética , Leucemia Mielomonocítica Crónica/patología , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/patología , Resultado del Tratamiento , Uridina/administración & dosificación , Uridina/análogos & derivados
15.
Nature ; 523(7559): 183-188, 2015 Jul 09.
Artículo en Inglés | MEDLINE | ID: mdl-26131937

RESUMEN

Lenalidomide is a highly effective treatment for myelodysplastic syndrome (MDS) with deletion of chromosome 5q (del(5q)). Here, we demonstrate that lenalidomide induces the ubiquitination of casein kinase 1A1 (CK1α) by the E3 ubiquitin ligase CUL4-RBX1-DDB1-CRBN (known as CRL4(CRBN)), resulting in CK1α degradation. CK1α is encoded by a gene within the common deleted region for del(5q) MDS and haploinsufficient expression sensitizes cells to lenalidomide therapy, providing a mechanistic basis for the therapeutic window of lenalidomide in del(5q) MDS. We found that mouse cells are resistant to lenalidomide but that changing a single amino acid in mouse Crbn to the corresponding human residue enables lenalidomide-dependent degradation of CK1α. We further demonstrate that minor side chain modifications in thalidomide and a novel analogue, CC-122, can modulate the spectrum of substrates targeted by CRL4(CRBN). These findings have implications for the clinical activity of lenalidomide and related compounds, and demonstrate the therapeutic potential of novel modulators of E3 ubiquitin ligases.


Asunto(s)
Quinasa de la Caseína I/metabolismo , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/fisiopatología , Talidomida/análogos & derivados , Ubiquitinación/efectos de los fármacos , Secuencia de Aminoácidos , Animales , Quinasa de la Caseína I/genética , Línea Celular , Regulación de la Expresión Génica/efectos de los fármacos , Células HEK293 , Humanos , Factores Inmunológicos/farmacología , Células Jurkat , Células K562 , Lenalidomida , Ratones , Datos de Secuencia Molecular , Péptido Hidrolasas/química , Proteolisis/efectos de los fármacos , Alineación de Secuencia , Eliminación de Secuencia , Especificidad de la Especie , Talidomida/farmacología , Ubiquitina-Proteína Ligasas/metabolismo
16.
Med Teach ; 43(11): 1286-1293, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34151706

RESUMEN

PURPOSE: Medical societies have embraced advocacy as a core professional competency, but little is known about how entering medical students view physician advocacy. This study examined how first year medical students define advocacy, their motivations for and anticipated challenges to advocacy, and whether they believe advocacy should be a core competency. METHOD: This study used a qualitative content analysis approach to analyze first year medical student narrative responses about physician advocacy. The analysis included the written responses of 95% of the first-year medical students at the University of California, San Francisco (UCSF) School of Medicine during two academic years. RESULTS: Students shared consensus that physicians should advocate on behalf of their individual patients. Students had varying opinions on whether all physicians should engage in societal level advocacy and whether it should be a core competency in medical school. Students find several compelling reasons for physicians to engage in societal advocacy but nevertheless anticipate challenges to physician advocacy. CONCLUSION: Given increasing consensus that advocacy is a core competency of physicians, providing medical students the skills to successfully engage in advocacy is increasingly important. Any new mandatory curricula will need to focus on how to engage learners with varied views on advocacy.


Asunto(s)
Educación de Pregrado en Medicina , Médicos , Estudiantes de Medicina , Curriculum , Humanos , Facultades de Medicina
19.
Transfusion ; 60(5): 932-939, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32358832

RESUMEN

BACKGROUND: Hemoglobin-Based Oxygen Carriers (HBOCs) can act as an "oxygen bridge" in acute severe anemia when transfusion is indicated, but not possible. We present data on 10 Expanded Access (EA) patients treated with high cumulative doses of Hemopure (HBOC-201), to assess the ability of HBOC-201 to safely treat life threatening anemia in situations where high volumes of product were administered over an extended period of time. STUDY DESIGN AND METHODS: Inclusion in this study required that the patient receive at least 10 units of HBOC-201 between 2014 and 2017 under the FDA-sanctioned EA program. Depending on a patient's geographical location, treatment with HBOC-201 was obtained through either a single patient emergency Investigational New Drug (IND) application, or an intermediate size population IND. Of the 41 patients who were treated during this period, 10 patients received 10 or more units of the product. Data were obtained from medical records. RESULTS: Treatments with HBOC-201 started within 24 hours of signing consent and were administered at an average rate of 1.99 (SD 0.17) units per day over a mean of 8.2 days (SD 2.9), during which patients received on average 16.2 units (SD 5.7 units) of HBOC-201. The median pre-treatment nadir corpuscular hemoglobin (Hb) concentration was 3.3 (SD 0.9) g/dL and post-treatment Hemoglobin was 7.3 (SD 1.7) g/dL. Common side effects included methemoglobinemia, gastrointestinal symptoms, and hypertension. However, no product-related serious adverse events (SAEs) were noted. All patients survived. CONCLUSIONS: Administration of HBOC-201 over an extended period is a feasible and safe oxygen bridge for severely anemic patients who cannot be transfused with RBC.


Asunto(s)
Anemia/tratamiento farmacológico , Transfusión Sanguínea , Contraindicaciones , Hemoglobinas/administración & dosificación , Adulto , Anciano , Anemia/diagnóstico , Anemia/patología , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Hemoglobinas/efectos adversos , Humanos , Cuidados a Largo Plazo/métodos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Factores de Tiempo , Reacción a la Transfusión/prevención & control , Resultado del Tratamiento , Adulto Joven
20.
J Natl Compr Canc Netw ; : 1-4, 2020 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-32871558

RESUMEN

Hematopoietic growth factors, including erythrocyte stimulating agents (ESAs), granulocyte colony-stimulating factors, and thrombopoietin mimetics, can mitigate anemia, neutropenia, and thrombocytopenia resulting from chemotherapy for the treatment of cancer. In the context of pandemic SARS-CoV-2 infection, patients with cancer have been identified as a group at high risk of morbidity and mortality from this infection. Our subcommittee of the NCCN Hematopoietic Growth Factors Panel convened a voluntary group to review the potential value of expanded use of such growth factors in the current high-risk environment. Although recommendations are available on the NCCN website in the COVID-19 Resources Section (https://www.nccn.org/covid-19/), these suggestions are provided without substantial context or reference. Herein we review the rationale and data underlying the suggested alterations to the use of hematopoietic growth factors for patients with cancer in the COVID-19 era.

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