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BACKGROUND: Previous studies have suggested that there is wide variability in cardiac intensive care unit (CICU) length of stay (LOS); however, these studies are limited by the absence of detailed risk assessment at the time of admission. Thus, we evaluated inter-hospital differences in CICU LOS, and the association between LOS and in-hospital mortality. METHODS: Using data from the Critical Care Cardiology Trials Network (CCCTN) registry, we included 22,862 admissions between 2017 and 2022 from 35 primarily tertiary and quaternary CICUs that captured consecutive admissions in annual 2-month snapshots. The primary analysis compared inter-hospital differences in CICU LOS, as well as the association between CICU LOS and all-cause in-hospital mortality using a Fine and Gray competing risk model. RESULTS: The overall median CICU LOS was 2.2 (1.1-4.8) days, and the median hospital LOS was 5.9 (2.8-12.3) days. Admissions in the longest tertile of LOS tended to be younger with higher rates of pre-existing comorbidities, and had higher Sequential Organ Failure Assessment (SOFA) scores, as well as higher rates of mechanical ventilation, intravenous vasopressor use, mechanical circulatory support, and renal replacement therapy. Unadjusted all-cause in-hospital mortality was 9.3%, 6.7%, and 13.4% in the lowest, intermediate, and highest CICU LOS tertiles. In a competing risk analysis, individual patient CICU LOS was correlated (r2 = 0.31) with a higher risk of 30-day in-hospital mortality. The relationship remained significant in admissions with heart failure, ST-elevation myocardial infarction and non-ST segment elevation myocardial infarction. CONCLUSIONS: In a large registry of academic CICUs, we observed significant variation in CICU LOS and report that LOS is independently associated with all-cause in-hospital mortality. These findings could potentially be used to improve CICU resource utilization planning and refine risk prognostication in critically ill cardiovascular patients.
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Unidades de Cuidados Coronarios , Mortalidad Hospitalaria , Tiempo de Internación , Sistema de Registros , Humanos , Mortalidad Hospitalaria/tendencias , Masculino , Femenino , Tiempo de Internación/estadística & datos numéricos , Anciano , Persona de Mediana Edad , Unidades de Cuidados Coronarios/estadística & datos numéricos , Medición de Riesgo/métodos , Cuidados Críticos/estadística & datos numéricos , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND: There are limited data on how patients with cardiogenic shock (CS) die. METHODS: The Critical Care Cardiology Trials Network is a research network of cardiac intensive care units coordinated by the Thrombolysis In Myocardial Infarction (TIMI) Study Group (Boston, MA). Using standardized definitions, site investigators classified direct modes of in-hospital death for CS admissions (October 2021 to September 2022). Mutually exclusive categories included 4 modes of cardiovascular death and 4 modes of noncardiovascular death. Subgroups defined by CS type, preceding cardiac arrest (CA), use of temporary mechanical circulatory support (tMCS), and transition to comfort measures were evaluated. RESULTS: Among 1068 CS cases, 337 (31.6%) died during the index hospitalization. Overall, the mode of death was cardiovascular in 82.2%. Persistent CS was the dominant specific mode of death (66.5%), followed by arrhythmia (12.8%), anoxic brain injury (6.2%), and respiratory failure (4.5%). Patients with preceding CA were more likely to die from anoxic brain injury (17.1% vs 0.9%; P < .001) or arrhythmia (21.6% vs 8.4%; P < .001). Patients managed with tMCS were more likely to die from persistent shock (P < .01), both cardiogenic (73.5% vs 62.0%) and noncardiogenic (6.1% vs 2.9%). CONCLUSIONS: Most deaths in CS are related to direct cardiovascular causes, particularly persistent CS. However, there is important heterogeneity across subgroups defined by preceding CA and the use of tMCS.
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Mortalidad Hospitalaria , Choque Cardiogénico , Humanos , Choque Cardiogénico/mortalidad , Choque Cardiogénico/terapia , Masculino , Femenino , Anciano , Persona de Mediana Edad , Mortalidad Hospitalaria/tendencias , Unidades de Cuidados Coronarios/estadística & datos numéricos , Cuidados Críticos/métodos , Causas de Muerte/tendencias , Unidades de Cuidados IntensivosRESUMEN
BACKGROUND: Breast cancer is the most common non-skin cancer in women and an increasing number of people are living as breast cancer survivors. While the prognosis of breast cancer continues to improve, the rates of sexual dysfunction and the risk related to cancer treatments have not been well characterized in a population-based study. METHODS: We identified a cohort of 19,709 breast cancer survivors diagnosed between 1997 and 2017 from the Utah Cancer Registry, and 93,389 cancer-free women who were matched by age and birth state from the Utah Population Database. Sexual dysfunction diagnoses were identified through ICD-9 and ICD-10 codes from electronic medical records and statewide healthcare facilities data. Cox proportional hazard models were used to estimate hazard ratios for risk of sexual dysfunction. RESULTS: Breast cancer survivors were at higher risk of sexual dysfunction diagnosis (9.1% versus 6.9%, HR 1.60, 95% CI 1.51-1.70) compared to the general population. This risk increased 2.05-fold within 1 to 5 years after cancer diagnosis (95% CI 1.89-2.22) and 3.05-fold in individuals diagnosed with cancer at < 50 years of age (95% CI 2.65-3.51). Cancer treatments including endocrine therapy, chemotherapy and radiation therapy were associated with an increased risk of sexual dysfunction among breast cancer survivors. CONCLUSIONS: Risk of sexual dysfunction in breast cancer survivors is higher than in the general population, but may be underdiagnosed in the clinical setting. Health care professionals should be encouraged to address the topic of sexual health early on in the treatment of breast cancer, and routinely screen patients for symptoms of sexual dysfunction.
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Neoplasias de la Mama , Supervivientes de Cáncer , Humanos , Femenino , Neoplasias de la Mama/complicaciones , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/terapia , Estudios de Cohortes , Sobrevivientes , SupervivenciaRESUMEN
BACKGROUND: Breast cancer survival is increasing, making late effects such as cardiovascular disease (CVD) more relevant. The purpose of this study was to evaluate incident CVD following breast cancer diagnosis among long-term survivors and to investigate possible risk factors for CVD. METHODS: A population-based cohort of 6641 breast cancer survivors diagnosed between 1997 and 2009 who survived at least 10 years was identified within the Utah Cancer Registry. In addition, 36,612 cancer-free women from the general population, matched by birth year and state, were identified within the Utah Population Database. Cox proportional hazards models were used to calculate CVD hazard ratios (HRs) for >10 to 15 and >15 years. RESULTS: Long-term breast cancer survivors had an increased risk of newly diagnosed diseases of the circulatory system (HR, 1.32; 99% confidence interval [CI], 1.00-1.75) from 10 to 15 years following cancer diagnosis compared with the general population. No increased CVD risks were observed after 15 years. Breast cancer survivors with Charlson Comorbidity Index score ≥2 had a significantly higher risk of diseases of the circulatory system (HR, 2.64; 95% CI, 1.08-6.45) beyond 10 years following breast cancer diagnosis. Similarly, older age, obesity, lower education, and family history of CVD and breast cancer were risk factors for heart and circulatory system diseases among long-term breast cancer survivors. CONCLUSION: Risk of CVD compared to the general population was moderate among this cohort of long-term breast cancer survivors between 10 to 15 years since cancer diagnosis. Awareness of CVD risks is important for breast cancer survivors.
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Neoplasias de la Mama , Supervivientes de Cáncer , Enfermedades Cardiovasculares , Neoplasias de la Mama/diagnóstico , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/etiología , Estudios de Cohortes , Femenino , Humanos , Modelos de Riesgos Proporcionales , Factores de RiesgoRESUMEN
The majority of clinical cancer specimens are preserved as formalin-fixed paraffin-embedded (FFPE) samples. For clinical molecular tests to have wide-reaching impact, they must be applicable to FFPE material. Accurate quantitative measurements of RNA derived from FFPE specimens is challenging because of low yields and high amounts of degradation. Here, we present FFPEcap-seq, a method specifically designed for sequencing capped 5' ends of RNA derived from FFPE samples. FFPEcap-seq combines enzymatic enrichment of 5' capped RNAs with template switching to create sequencing libraries. We find that FFPEcap-seq can faithfully capture mRNA expression levels in FFPE specimens while also detecting enhancer RNAs that arise from distal regulatory regions. FFPEcap-seq is a fast and straightforward method for making high-quality 5' end RNA-seq libraries from FFPE-derived RNA.
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Formaldehído , Adhesión en Parafina , Caperuzas de ARN , Análisis de Secuencia de ARN/métodos , Fijación del Tejido , Elementos de Facilitación Genéticos , HumanosRESUMEN
BACKGROUND/PURPOSE: Published data on the performance of the immunohistochemistry (IHC) test for mismatch repair (MMR) protein expression to detect Lynch syndrome (LS) index cases suggests it is highly variable; its performance in our system was unknown. Moreover, a brief family history questionnaire (bFHQ) developed by Eiriksson and colleagues in Canada demonstrated 100% sensitivity for LS case identification thus was of interest to us, but its performance outside of its original setting was unknown. Determination of the performance of these tests requires complete LS case identification in the testing population. METHODS: Two hundred women were recruited during routine care for endometrial cancer (EC) to administer the bFHQ and perform genetic testing for the LS genes. Independently, the IHC test was performed to screen for presumptive LS cases. We determined the sensitivity, specificity, and positive and negative predictive values of the bFHQ and IHC test as well as simulating outcomes of the complete protocols. RESULTS: Genetic testing all participants identified 8 cases of LS out of 200 (4% prevalence), the bFHQ identified 5 of 8 of these cases (62.5%, CI: 31.5%-87.6%), and the IHC test identified 6 or 7 of 8 cases (mean of 75% or 87.5%) depending on interpretation of test results. The specificities of the bFHQ and IHC test were 56.8% (CI: 49.8%-63.7%) and 79.8% (CI: 73.6%-85.1%), respectively. CONCLUSIONS: This study is the first, to our knowledge, to test the effectiveness of the bFHQ in an EC population since its original reporting; our results are consistent with many reports of the challenges of collecting family health history. The performance of the IHC test as a screen falls within ranges reported in the literature but do not provide the confidence to drive a decision for or against continued use of this test as a LS screen.
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Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Neoplasias Endometriales/complicaciones , Anamnesis , Encuestas y Cuestionarios , Adulto , Neoplasias Colorrectales Hereditarias sin Poliposis/complicaciones , Detección Precoz del Cáncer , Femenino , Pruebas Genéticas , Humanos , Inmunohistoquímica , Valor Predictivo de las Pruebas , Sensibilidad y EspecificidadRESUMEN
Treatment for gynecologic cancer is associated with sexual dysfunction, which may present during and/or after treatment. The aim of this study was to investigate the risk of sexual dysfunction among gynecologic cancer survivors compared to cancer-free women in a population-based cohort study. We identified a cohort of 4863 endometrial, ovarian, and cervical cancer survivors diagnosed between 1997 and 2012 in the Utah Cancer Registry. Up to five cancer-free women were matched to cancer survivors (N = 22,693). We used ICD-9 codes to identify sexual dysfunction. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for sexual dysfunction with adjustment for potential confounders. Approximately 6.6% of gynecologic cancer survivors had sexual dysfunction diagnoses 1-5 years after cancer diagnosis. Gynecologic cancer survivors had higher risks of overall sexual dysfunction (HR: 2.51, 95% CI: 2.16, 2.93), dyspareunia (HR: 3.27, 95% CI: 2.63, 4.06), and vaginal dryness (HR: 2.63, 95% CI: 2.21, 3.12) compared to a general population of women, 1-5 years after cancer diagnosis. Sexual dysfunction was associated with advance cancer stage (HRRegional vs. Localized: 1.61, 95% CI: 1.19, 2.31), radiation therapy (HR: 1.73, 95% CI: 1.29, 2.31), and chemotherapy (HR: 1.80, 95% CI: 1.30, 2.50). This large cohort study confirms that there is an increased risk of sexual dysfunction among gynecologic cancer survivors when compared to the general population. Further investigation is needed to address the risk factors for sexual dysfunction and to improve patient-provider communication, diagnosis, documentation, and treatment of sexual dysfunction among gynecologic cancer survivors.
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Supervivientes de Cáncer , Neoplasias de los Genitales Femeninos , Disfunciones Sexuales Fisiológicas , Femenino , Humanos , Estudios de Cohortes , Disfunciones Sexuales Fisiológicas/epidemiología , Disfunciones Sexuales Fisiológicas/etiología , Neoplasias de los Genitales Femeninos/complicaciones , SobrevivientesRESUMEN
Extraskeletal myxoid chondrosarcoma of the vulva is a very rare tumor, with less than 10 cases reported in the literature. We report a case of a 45-yr-old woman with extraskeletal myxoid chondrosarcoma of the vulva confirmed by EWSR1 fluorescence in situ hybridization. Given the unusual site and prominent myxoid morphology, a broad differential diagnosis and a variety of ancillary testing was required. This article aims to review extraskeletal myxoid chondrosarcoma of the vulva, the differential diagnosis of a myxoid spindle cell neoplasm of the vulva, and the diagnostic importance of immunohistochemistry and EWSR1 fluorescence in situ hybridization.
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Condrosarcoma/diagnóstico por imagen , Neoplasias de los Tejidos Conjuntivo y Blando/diagnóstico por imagen , Proteína EWS de Unión a ARN/metabolismo , Neoplasias de la Vulva/diagnóstico por imagen , Condrosarcoma/patología , Diagnóstico Diferencial , Femenino , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Persona de Mediana Edad , Neoplasias de los Tejidos Conjuntivo y Blando/patología , Proteína EWS de Unión a ARN/genética , Vulva/diagnóstico por imagen , Vulva/patología , Neoplasias de la Vulva/patologíaRESUMEN
OBJECTIVE: While genitourinary complications during treatment for ovarian cancer are well-known, long-term adverse outcomes have not been well characterized. The number of ovarian cancer survivors has been increasing. The aim of this study was to investigate long-term adverse genitourinary outcomes in a population-based cohort. METHODS: We identified a cohort of 1270 ovarian cancer survivors diagnosed between 1996 and 2012 from the Utah Cancer Registry, and 5286 cancer-free women were matched on birth year and state from the Utah Population Database. Genitourinary disease diagnoses were identified through ICD-9 codes from electronic medical records and statewide healthcare facilities data. Cox proportional hazards models were used to estimate hazard ratios (HR) for genitourinary outcomes at 1 to <5 years and 5+ years after ovarian cancer diagnosis. RESULTS: Ovarian cancer survivors had increased risks for urinary system disorders (HR: 2.53, 95% CI: 2.12-3.01) and genital organ disorders (HR: 1.88, 95% CI: 1.57-2.27) between 1 and <5 years after cancer diagnosis compared to the general population cohort. Increased risks were observed for acute renal failure, chronic kidney disease, calculus of kidney, hydronephrosis, pelvic peritoneal adhesions, and pelvic organ inflammatory conditions. Increased risks of several of these diseases were observed 5+ years after cancer diagnosis. CONCLUSIONS: Ovarian cancer survivors experience increased risks of various genitourinary diseases compared to women in the general population in the long-term. Understanding the multimorbidity trajectory among ovarian cancer survivors is important to improve clinical care after cancer treatment is completed.
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Supervivientes de Cáncer/estadística & datos numéricos , Enfermedades de los Genitales Femeninos/epidemiología , Neoplasias Ováricas/epidemiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Humanos , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Ováricas/patología , Sistema de Registros , Utah/epidemiología , Adulto JovenRESUMEN
OBJECTIVE: To analyze our institutional experience and oncologic outcomes for salvage treatment for the recurrence of early-stage endometrial cancer patients. METHODS: We included women of all ages diagnosed with FIGO stage I-II, any grade endometrial cancer from 2000 to 2016 at our institutions who were treated with at least a hysterectomy. Recurrences in the pelvis and/or vagina were considered locoregional recurrences (LRR). Overall survival (OS) was assessed using Kaplan-Meier survival analysis. Univariate (UV) and multivariate (MV) Cox proportional hazards modeling was also used. RESULTS: A total of 2691 women were analyzed. The majority had endometrioid histology (91%), stage IA disease (61%), and were grade 1 (57%). With a median follow-up of 6.1â¯years, the overall rate of recurrence was 7.2%, and the rate of LRR was 3.7%. Women with vaginal-only recurrences had a longer median OS after recurrence (14.0â¯years) compared to both pelvic (1.2â¯years) and distant (1.0â¯year) failures. For women with vaginal-only recurrences, salvage radiotherapy (RT) was the only factor associated with improved OS on MVA (HR 0.1, pâ¯=â¯.04). For women with pelvic recurrences, salvage surgery (HR 0.3, pâ¯=â¯.01), salvage RT (HR 0.3, pâ¯<â¯.01), and salvage chemotherapy (HR 0.4, pâ¯=â¯.03) were associated with improved OS. CONCLUSIONS: Failure rates for women with early-stage endometrial cancer are low. Women with vaginal-only recurrences have improved OS compared to pelvic or distant recurrences. Salvage RT appears to be an important factor for treatment of women with vaginal-only recurrences. Aggressive multimodality treatment may be beneficial for women with pelvic recurrences.
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Neoplasias Endometriales/terapia , Recurrencia Local de Neoplasia/terapia , Terapia Recuperativa/métodos , Carcinoma Endometrioide/patología , Carcinoma Endometrioide/terapia , Quimioterapia Adyuvante , Neoplasias Endometriales/patología , Femenino , Humanos , Histerectomía , Estimación de Kaplan-Meier , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Radioterapia Adyuvante , Resultado del TratamientoRESUMEN
OBJECTIVE: We aimed to evaluate the relationship between hyperglycosylated human chorionic gonadotropin (hCG-H) and placenta accreta spectrum (PAS) in the second and third trimesters of pregnancy. STUDY DESIGN: This was a case-control study of PAS and controls. hCG-H was measured in the second and third trimesters of pregnancy in women with pathologically confirmed cases of PAS and in gestational age-matched controls without PAS. We compared serum hCG-H levels in cases and controls, calculated summary statistics for diagnostic accuracy, and used receiver operating characteristic (ROC) curves to define an optimal cut-point for diagnosis of PAS using hCG-H. RESULTS: Thirty case samples and 30 control samples were evaluated for hCG-H. Mean hCG-H was lower in the case compared with control group (7.8 ± 5.9 µg/L vs. 11.8 ± 8.8 µg/L, p = 0.03). At an optimal cut-point for hCG-H of ≤7.6 µg/L, the sensitivity, specificity, positive likelihood ratios, negative likelihood ratios, and area under the ROC curve were 66.7%, 69.7%, 2.20%, 0.48%, and 0.68%, respectively. CONCLUSION: Hyperglycosylated hCG levels in the second and third trimesters of pregnancy were lower in patients with PAS than in controls, but hCG-H showed only modest capability as a diagnostic test for PAS.
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Gonadotropina Coriónica , Placenta Accreta/sangre , Primer Trimestre del Embarazo/sangre , Segundo Trimestre del Embarazo/sangre , Adulto , Estudios de Casos y Controles , Gonadotropina Coriónica/sangre , Gonadotropina Coriónica/metabolismo , Correlación de Datos , Femenino , Glicosilación , Humanos , Placenta Accreta/diagnóstico , Embarazo , Reproducibilidad de los ResultadosRESUMEN
This article provides an overview of pulmonary arterial hypertension (PAH), beginning with the initial pathologic recognition of pulmonary hypertension more than 100 years ago and progressing to the current diagnostic categorization of PAH. It reviews the epidemiology, pathophysiology, genetics, and modern treatment of PAH. The article discusses several important recent studies that have highlighted the importance of new management strategies, including serial risk assessment and combination pharmacotherapy.
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Antihipertensivos/uso terapéutico , Hipertensión Pulmonar/diagnóstico , Quimioterapia Combinada , Femenino , Humanos , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/fisiopatología , Masculino , Terapia Molecular Dirigida/métodos , Factores de Riesgo , Tasa de SupervivenciaRESUMEN
PURPOSE: The increasing incidence of endometrial cancer (EC), in younger age at diagnosis, calls for new tissue-sparing treatment options. This work aims to evaluate the potential of imiquimod (IQ) in the treatment of low-grade EC. METHODS: Effects of IQ on the viabilities of Ishikawa and HEC-1A cells were evaluated using MTT assay. The ability of IQ to induce apoptosis was evaluated by testing changes in caspase 3/7 levels and expression of cleaved caspase-3, using luminescence assay and western blot. Apoptosis was confirmed by flow cytometry and the expression of cleaved PARP. Western blot was used to evaluate the effect of IQ on expression levels of Bcl-2, Bcl-xL, and BAX. Finally, the in vivo efficacy of IQ was tested in an EC mouse model. RESULTS: There was a decrease in EC cell viability following IQ treatment as well as increased caspase 3/7 activities, cleaved caspase-3 expression, and Annexin-V/ 7AAD positive cell population. Western blot results showed the ability of IQ in cleaving PARP, decreasing Bcl-2 and Bcl-xL expressions, but not affecting BAX expression. In vivo study demonstrated IQ's ability to inhibit EC tumor growth and progression without significant toxicity. CONCLUSIONS: IQ induces apoptosis in low-grade EC cells in vitro, probably through its direct effect on Bcl-2 family protein expression. In, vivo, IQ attenuates EC tumor growth and progression, without an obvious toxicity. Our study provides the first building block for the potential role of IQ in the non-surgical management of low-grades EC and encouraging further investigations.
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Aminoquinolinas/farmacología , Apoptosis/efectos de los fármacos , Neoplasias Endometriales/tratamiento farmacológico , Animales , Anexina A5/metabolismo , Caspasa 3/metabolismo , Caspasa 7/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Neoplasias Endometriales/metabolismo , Femenino , Humanos , Imiquimod , Ratones , Ratones Desnudos , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteína X Asociada a bcl-2/metabolismoRESUMEN
OBJECTIVE: High grade histologies of endometrial carcinomas portend a worse prognosis. Previous randomized, prospective studies examining the role of radiation have excluded endometrial cancer patients with FIGO IB with high risk histologies (clear cell, papillary serous, and Grade 3 endometrioid adenocarcinoma). METHODS: We retrospectively identified 51 patients who underwent a hysterectomy for a FIGO IB endometrial carcinoma with clear cell, papillary serous or Grade 3 endometrioid adenocarcinoma histology. Adjuvant radiation therapy was delivered in 44 of 51 patients (86%). We assessed pelvic control, vaginal control, and overall survival using Kaplan Meier estimate and the log rank test. We completed univariate analysis. RESULTS: The 5-year vaginal control rate in patients without and with adjuvant radiation therapy was 67% and 93.3%, respectively (p=0.0066). At 5-years, the pelvic control rate in patients without and with adjuvant radiation therapy was 0% and 81.5%, respectively (p=0.0003). At 5-years, the overall survival was 80% in patients who had adjuvant radiation compared to 21.4% in patients who did not have adjuvant radiation (p=0.0026). Radiation therapy was the only studied variable that was associated with pelvic control. Radiation therapy, advanced age and pelvic lymphadenectomy were associated with overall survival. CONCLUSIONS: Adjuvant radiation therapy in patients with FIGO IB endometrial carcinoma with high risk histologies was associated with improved vaginal control, pelvic control, and overall survival.
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Neoplasias Endometriales/radioterapia , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Supervivencia sin Enfermedad , Neoplasias Endometriales/mortalidad , Neoplasias Endometriales/patología , Neoplasias Endometriales/cirugía , Femenino , Humanos , Histerectomía , Persona de Mediana Edad , Clasificación del Tumor , Radioterapia Adyuvante , Estudios Retrospectivos , Análisis de SupervivenciaRESUMEN
LRRK2 (PARK8) is the most common genetic determinant of Parkinson's disease (PD), with dominant mutations in LRRK2 causing inherited PD and sequence variation at the LRRK2 locus associated with increased risk for sporadic PD. Although LRRK2 has been implicated in diverse cellular processes encompassing almost all cellular compartments, the precise functions of LRRK2 remain unclear. Here, we show that the Drosophila homolog of LRRK2 (Lrrk) localizes to the membranes of late endosomes and lysosomes, physically interacts with the crucial mediator of late endosomal transport Rab7 and negatively regulates rab7-dependent perinuclear localization of lysosomes. We also show that a mutant form of lrrk analogous to the pathogenic LRRK2(G2019S) allele behaves oppositely to wild-type lrrk in that it promotes rather than inhibits rab7-dependent perinuclear lysosome clustering, with these effects of mutant lrrk on lysosome position requiring both microtubules and dynein. These data suggest that LRRK2 normally functions in Rab7-dependent lysosomal positioning, and that this function is disrupted by the most common PD-causing LRRK2 mutation, linking endolysosomal dysfunction to the pathogenesis of LRRK2-mediated PD.
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Proteínas de Drosophila/metabolismo , Drosophila/metabolismo , Fertilidad/fisiología , Lisosomas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas de Unión al GTP rab/metabolismo , Animales , Animales Modificados Genéticamente , Western Blotting , Células Cultivadas , Drosophila/crecimiento & desarrollo , Proteínas de Drosophila/genética , Endosomas/metabolismo , Femenino , Técnica del Anticuerpo Fluorescente , Inmunoprecipitación , Masculino , Mutación/genética , Proteínas Serina-Treonina Quinasas/genética , Proteínas de Unión al GTP rab/genética , Proteínas de Unión a GTP rab7RESUMEN
OBJECTIVE: Unfavorable histology endometrial carcinomas confer worse prognosis. We determined the association of adjuvant radiation on local recurrence and survival for unfavorable, early stage endometrial cancer. METHODS: We retrospectively identified 125 patients who had a hysterectomy for early stage (FIGO IA), unfavorable histology (clear cell, papillary serous or grade 3 endometrioid), endometrial carcinoma treated between 1992 and 2011. Patients were restaged according to current FIGO 2009 guidelines. Primary endpoint was local control and secondary endpoints were distant recurrence and overall survival. RESULTS: The median age of the cohort was 67 years old with a mean follow up 152 months. Adjuvant radiation was delivered in 60 patients (48%). There were a total of 24 recurrences; 5 had local-regional recurrences, 4 local and distant recurrence, 12 distant only recurrences, and 3 had unspecified recurrences. The 5-year local-regional control was 97.8% in patients who received radiation and 80.1% in patients who did not receive radiation (p=0.018). The 5-year overall survival rate was 68.1% if patients did not receive radiation and 84.9% if they did receive radiation (p=0.0062). On univariate analysis, only radiation (HR 0.12, 95% CI: 0.03 to 0.49, p-value=0.018) was associated with a significant increase in local relapse free survival. CONCLUSIONS: Adjuvant radiation therapy was significantly associated with an improvement in local-regional control and overall survival in patients with unfavorable histology, early stage endometrial cancer.
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Adenocarcinoma/radioterapia , Braquiterapia , Neoplasias Endometriales/radioterapia , Histerectomía , Recurrencia Local de Neoplasia/prevención & control , Adenocarcinoma/patología , Adenocarcinoma de Células Claras/patología , Adenocarcinoma de Células Claras/radioterapia , Adenocarcinoma Papilar/patología , Adenocarcinoma Papilar/radioterapia , Anciano , Carcinoma Endometrioide/patología , Carcinoma Endometrioide/radioterapia , Estudios de Cohortes , Supervivencia sin Enfermedad , Neoplasias Endometriales/patología , Femenino , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Pronóstico , Modelos de Riesgos Proporcionales , Radioterapia Adyuvante/métodos , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Wide interhospital variations exist in cardiovascular intensive care unit (CICU) admission practices and the use of critical care restricted therapies (CCRx), but little is known about the differences in patient acuity, CCRx utilization, and the associated outcomes within tertiary centers. METHODS: The Critical Care Cardiology Trials Network is a multicenter registry of tertiary and academic CICUs in the United States and Canada that captured consecutive admissions in 2-month periods between 2017 and 2022. This analysis included 17â 843 admissions across 34 sites and compared interhospital tertiles of CCRx (eg, mechanical ventilation, mechanical circulatory support, continuous renal replacement therapy) utilization and its adjusted association with in-hospital survival using logistic regression. The Pratt index was used to quantify patient-related and institutional factors associated with CCRx variability. RESULTS: The median age of the study population was 66 (56-77) years and 37% were female. CCRx was provided to 62.2% (interhospital range of 21.3%-87.1%) of CICU patients. Admissions to CICUs with the highest tertile of CCRx utilization had a greater burden of comorbidities, had more diagnoses of ST-elevation myocardial infarction, cardiac arrest, or cardiogenic shock, and had higher Sequential Organ Failure Assessment scores. The unadjusted in-hospital mortality (median, 12.7%) was 9.6%, 11.1%, and 18.7% in low, intermediate, and high CCRx tertiles, respectively. No clinically meaningful differences in adjusted mortality were observed across tertiles when admissions were stratified by the provision of CCRx. Baseline patient-level variables and institutional differences accounted for 80% and 5.3% of the observed CCRx variability, respectively. CONCLUSIONS: In a large registry of tertiary and academic CICUs, there was a >4-fold interhospital variation in the provision of CCRx that was primarily driven by differences in patient acuity compared with institutional differences. No differences were observed in adjusted mortality between low, intermediate, and high CCRx utilization sites.
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Cardiología , Monitorización Hemodinámica , Anciano , Femenino , Humanos , Masculino , Unidades de Cuidados Coronarios , Cuidados Críticos , Mortalidad Hospitalaria , Unidades de Cuidados Intensivos , Sistema de Registros , Estados Unidos/epidemiología , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Ensayos Clínicos como AsuntoRESUMEN
OBJECTIVE: Patients with endometrial cancer with positive lymph nodes (International Federation of Gynecology and Obstetrics stage IIIC) have a substantially worse prognosis. This study investigates how tumor characteristics and adjuvant treatments influence overall survival (OS) in stage IIIC patients. METHODS: This multi-institution, institutional review board-approved study is a retrospective review of 116 patients with surgically staged endometrial cancer with positive lymph nodes treated from 1995 to 2008. The study cohort was evaluated using Kaplan-Meier estimates of OS and proportional hazard modeling. RESULTS: The 5-year OS for all patients was 51%. Administration of adjuvant therapy was associated with improved OS when compared with surgery alone (P = 0.007). Five-year OS was 40% for patients treated with surgery alone (n = 26), 50% with surgery and chemotherapy (n = 8), 58% with surgery and radiotherapy (n = 43), and 54% with surgery followed by both radiotherapy and chemotherapy (n = 39). Patients who received radiotherapy (n = 82) had improved OS (57%) when compared with patients who did not (n = 34, OS = 42%; P = 0.001). Radiotherapy was associated with improved OS for patients with endometrioid histology, high-grade tumors, and positive para-aortic lymph nodes. Patients with nonendometrioid histology and low-grade tumors who received radiotherapy had a similar OS as those who did not. High-grade tumors (P < 0.001), nonendometrioid histology (P = 0.004), and more than 2 positive lymph nodes (P = 0.01) were associated with a poorer OS. After controlling for patient demographics and tumor characteristics, patients with high-grade tumors and more than 2 positive lymph nodes had a poorer OS, whereas patients who received radiotherapy had improved OS. CONCLUSIONS: This large institutional study of patients with lymph node-positive endometrial cancer identified prognostic factors associated with a poor OS. Radiotherapy was associated with improved survival and may be specifically indicated for patients with endometrioid histology, high-grade tumors, and positive para-aortic lymph nodes. We recommend further investigation of adjuvant therapies in randomized clinical trials.
Asunto(s)
Neoplasias Endometriales/mortalidad , Ganglios Linfáticos/patología , Recurrencia Local de Neoplasia/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Terapia Combinada , Neoplasias Endometriales/patología , Neoplasias Endometriales/terapia , Femenino , Estudios de Seguimiento , Humanos , Ganglios Linfáticos/cirugía , Metástasis Linfática , Persona de Mediana Edad , Clasificación del Tumor , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/terapia , Estadificación de Neoplasias , Pronóstico , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
The appearance of endometrial cancer in adolescence is uncommon and warrants investigation for an hereditary cancer syndrome. Cowden syndrome is an autosomal dominant cancer syndrome associated with a germline PTEN mutation and increased risk of breast, thyroid, endometrial and colon cancer. In this report we present a case of a 14-year-old nulligravid female diagnosed with grade 1 endometrial adenocarcinoma. She subsequently developed fibrocystic breast disease and colon polyps and was diagnosed with Cowden syndrome at age 20. We therefore recommend formal evaluation for Cowden syndrome to be considered when endometrial cancer is diagnosed in adolescence.