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As medicine is moving toward performance and outcome-based payment and is transitioning away from productivity-based systems, value is now being appraised in healthcare through "performance measures." Over the past few decades, assessment of clinical performance in health care has been essential in ensuring safe and cost-effective patient care. The Centers for Medicare & Medicaid Services is further driving this change with measurable, outcomes-based national payer incentive payment systems. With the continually evolving requirements in health care reform focused on value-based care, there is a growing concern that clinicians, particularly dermatologists, may not understand the scientific rationale of health care quality measurement. As such, in order to help dermatologists understand the health care measurement science landscape to empower them to engage in the performance measure development and implementation process, the first article in this 2-part continuing medical education series reviews the value equation, historic and evolving policy issues, and the American Academy of Dermatology's approach to performance measurement development to provide the required foundational knowledge for performance measure developers.
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Medicare , Calidad de la Atención de Salud , Anciano , Humanos , Estados Unidos , Atención a la Salud , Reforma de la Atención de Salud , Instituciones de SaludRESUMEN
Throughout the 21st century, national and local governments, private health sectors, health insurance companies, healthcare professionals, labor unions, and consumers have been striving to develop an effective approach to evaluate, report, and improve the quality of healthcare. As medicine improves and health systems grow to meet patient needs, the performance measurement system of care effectiveness must also evolve. Continual efforts should be undertaken to effectively measure quality of care to create a more informed public, improve health outcomes, and reduce healthcare costs. As such, recent policy reform has necessitated that performance systems be implemented in healthcare, with the "performance measure" being the foundation of the system in which all of healthcare must be actively engaged in to ensure optimal care for patients. The development of performance measures can be highly complex, particularly when creating specialty-specific performance measures. To help dermatologists understand the process of creating dermatology-specific performance measures to engage in creating or implementing performance measures at the local or national levels, this article in the two-part continuing medical education series reviews the types, components, and process of developing, reviewing, and implementing performance measures.
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Dermatología , Humanos , Atención a la Salud , Seguro de SaludRESUMEN
INTRODUCTION: This study evaluated the treatment of proximal (cervical or upper thoracic) esophageal squamous cell carcinoma (SCC), for which chemoradiation is the recommended therapy. METHODS: Treatment and outcomes of patients with cT1-3N0-1M0 proximal esophageal SCC in the National Cancer Database between 2004 and 2016 was evaluated using logistic regression, Kaplan-Meier analysis, and propensity-score matching. RESULTS: Therapy of 2159 patients was chemoradiation (n = 1500, 69.5%), no treatment (n = 205, 9.5%), surgery (n = 203, 9.4%), radiation alone (n = 190, 8.8%), and chemotherapy alone (n = 61, 2.8%). Factors associated with definitive therapy with either chemoradiation or surgery were younger age, non-Black race, being insured, cervical tumor location, clinical T2 and T3 stage, clinical nodal involvement, and treatment at a research/academic program. Five-year survival was significantly better in patients treated with definitive therapy than patients not treated definitively (34.0% vs. 13.3%, p < 0.001). In multivariable survival analysis, receiving definitive therapy (hazard ratio [HR] 0.39, p = 0.017) was associated with improved survival, while increasing age, male sex, clinical T3 stage, positive clinical nodal involvement, and increasing Charlson Comorbidity Index were associated with worse survival. Esophagectomy was not associated with improved survival in multivariable analysis of the definitive therapy cohort (HR 0.84, p = 0.08) or propensity matched analysis. However, the pathologic complete response was only 33.3% (40/120) for patients who did have an esophagectomy after chemoradiation. CONCLUSIONS: This national analysis supports definitive chemoradiation for not only cervical but also proximal thoracic esophageal SCC. Routine surgery does not appear to be necessary but may have a role in patients with residual disease after chemoradiation.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Humanos , Masculino , Carcinoma de Células Escamosas de Esófago/patología , Neoplasias Esofágicas/patología , Quimioradioterapia , Análisis de Supervivencia , Resultado del Tratamiento , Estudios Retrospectivos , Estadificación de NeoplasiasRESUMEN
INTRODUCTION: The impact of concomitant lung resection during esophagectomy on short-term outcomes is not well characterized. This study tests the hypothesis that lung resection at the time of esophagectomy is not associated with increased perioperative morbidity or mortality. METHODS: Perioperative outcomes for esophageal cancer patients who underwent esophagectomy alone (EA) were compared to patients who had concurrent esophagectomy and lung resection (EL) using the NSQIP database between 2006-2017. Predictors of morbidity and mortality, including combined surgery, were evaluated using multivariable logistic regression. RESULTS: Among the 6,225 study patients, 6,068 (97.5%) underwent EA and 157 (2.5%) underwent EL. There were no differences in baseline characteristics between the two groups. Operating time for EL was longer than EA (median 416 versus 371 minutes, P < 0.01). Median length of stay was 10 d for both groups. Perioperative mortality was not significantly different between EL and EA patients (5.1% versus 2.8%, P = 0.08). EL patients had higher rates of postoperative pneumonia (22.3% versus 16.2%, P = 0.04) and sepsis (11.5% versus 7.1%, P = 0.03), however major complication rates overall were similar (40.8% versus 35.3%, P = 0.16). Combining lung resection with esophagectomy was not independently associated with increased postoperative morbidity (AOR 1.21 [95% CI 0.87-1.69]) or mortality (AOR 1.63 [95% CI 0.74-3.58]). CONCLUSIONS: Concurrent lung resection during esophagectomy is not associated with increased mortality or overall morbidity, but is associated with higher rates of pneumonia beyond esophagectomy alone. Surgeons considering combined lung resection with esophagectomy should carefully evaluate the patient's risk for pulmonary complications and pursue interventions preoperatively to optimize respiratory function.
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Neoplasias Esofágicas , Procedimientos Quirúrgicos Pulmonares , Esofagectomía/efectos adversos , Humanos , Pulmón , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Percutaneous cholecystostomy tubes (PCT) are utilized in the management of acute cholecystitis in patients deemed unsuitable for surgery. However, the drive for these decisions and the outcomes remain understudied. We sought to characterize the practices and utilization of PCT and evaluate associated outcomes at an urban medical center. METHODS: Patients undergoing PCT placement over a 12-y study period ending May 2019 were reviewed. Demographics, clinical presentation, labs, imaging studies, and outcomes were abstracted. The primary and secondary outcomes were 30-d mortality and interval cholecystectomy, respectively. RESULTS: Two hundred and four patients met inclusion criteria: 59.3% were male with a median age of 67.5 y and a National Surgical Quality Improvement Program (NSQIP) risk of serious complication of 8.0%. Overall, 57.8% of patients were located in an intensive care unit setting. The majority (80.9%) had an ultrasound and 48.5% had a hepatobiliary iminodiacetic acid scan. The overall 30-d mortality was 31.9%: 41.5% for intensive care unit and 18.6% for ward patients (P < 0.01). Of patients surviving beyond 30 d (n = 139), the PCT was removed from 106 (76.3%), and a cholecystectomy was performed in 55 (39.6%) at a median interval of 58.0 d. A forward logistic regression identified total bilirubin (Adjusted Odds Ratio: 1.12, adjusted P < 0.01) and NSQIP risk of serious complication (Adjusted Odds Ratio: 1.16, adjusted P < 0.01) as the only predictors for 30-d mortality. CONCLUSIONS: Patients selected for PCT placement have a high mortality risk. Despite subsequent removal of the PCT, the majority of surviving patients did not undergo an interval cholecystectomy. Total bilirubin and NSQIP risk of serious complication are useful adjuncts in predicting 30-d mortality in these patients.
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Colecistitis Aguda , Colecistostomía , Colecistitis Aguda/diagnóstico , Colecistitis Aguda/cirugía , Colecistostomía/efectos adversos , Colecistostomía/métodos , Humanos , Masculino , Pronóstico , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: A Medicare effect has been described to account for increased health care utilization occurring at the age of 65 years. The existence of such an effect in cancer care, where it would be most likely to reduce mortality, has been unclear. METHODS: Patients aged 61 to 69 years who were diagnosed with lung, breast, colon, or prostate cancer from 2004 to 2016 were identified with the Surveillance, Epidemiology, and End Results database and were dichotomized on the basis of eligibility for Medicare (61-64 vs 65-69 years). With age-over-age (AoA) percent change calculations, trends in cancer diagnoses and staging were characterized. After matching, uninsured patients who were 61 to 64 years old (pre-Medicare group) were compared with insured patients who were 65 to 69 years old (post-Medicare group) with respect to cancer-specific mortality. RESULTS: In all, 134,991 patients were identified with lung cancer, 175,558 were identified with breast cancer, 62,721 were identified with colon cancer, and 238,823 were identified with prostate cancer. The AoA growth in the number of cancer diagnoses was highest at the age of 65 years in comparison with all other ages within the decade for all 4 cancers (P < .01, P < .001, P < .01, and P < .001, respectively). In a comparison of diagnoses at the age of 65 years with those in the 61- to 64-year-old cohort, the greatest difference for all 4 cancers was seen in stage I. In matched analyses, the 5-year cancer-specific mortality was worse for lung (86.3% vs 78.5%; P < .001), breast (32.7% vs 11.0%; P < .001), colon (57.1% vs 35.6%; P < .001), and prostate cancer (16.9% vs 4.8%; P < .001) in the uninsured pre-Medicare group than the insured post-Medicare group. CONCLUSIONS: The age threshold of 65 years for Medicare eligibility is associated with more cancer diagnoses (particularly stage I), and this results in lower long-term cancer-specific mortality for all cancers studied. LAY SUMMARY: Contributing to the current debate regarding Medicare for all, this study shows that the expansion of Medicare would improve cancer outcomes for the near elderly.
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Medicare , Neoplasias de la Próstata , Anciano , Humanos , Masculino , Pacientes no Asegurados , Persona de Mediana Edad , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/epidemiología , Programa de VERF , Medicina Estatal , Estados Unidos/epidemiología , Cobertura Universal del Seguro de SaludRESUMEN
BACKGROUND: Strong for Surgery (S4S) is a public health campaign focused on optimizing patient health prior to surgery by identifying evidence-based modifiable risk factors. The potential impact of S4S bundled risk factors on outcomes after major surgery has not been previously studied. This study tested the hypothesis that a higher number of S4S risk factors is associated with an escalating risk of complications and mortality after major elective surgery in the VA population. METHODS: The Veterans Affairs Surgical Quality Improvement Program (VASQIP) database was queried for patients who underwent major non-emergent general, thoracic, vascular, urologic, and orthopedic surgeries between the years 2008 and 2015. Patients with complete data pertaining to S4S risk factors, specifically preoperative smoking status, HbA1c level, and serum albumin level, were stratified by number of positive risk factors, and perioperative outcomes were compared. RESULTS: A total of 31,285 patients comprised the study group, with 16,630 (53.2%) patients having no S4S risk factors (S4S0), 12,323 (39.4%) having one (S4S1), 2,186 (7.0%) having two (S4S2), and 146 (0.5%) having three (S4S3). In the S4S1 group, 60.3% were actively smoking, 35.2% had HbA1c > 7, and 4.4% had serum albumin < 3. In the S4S2 group, 87.8% were smokers, 84.8% had HbA1c > 7, and 27.4% had albumin < 3. Major complications, reoperations, length of stay, and 30-day mortality increased progressively from S4S0 to S4S3 groups. S4S3 had the greatest adjusted mortality risk (adjusted odds radio [AOR] 2.56, p = 0.04) followed by S4S2 (AOR 1.58, p = 0.02) and S4S1 (AOR 1.34, p = 0.02). CONCLUSION: In the VA population, patients who had all three S4S risk factors, namely active smoking, suboptimal nutritional status, and poor glycemic control, had the greatest risk of postoperative mortality compared to patients with fewer S4S risk factors.
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Procedimientos Quirúrgicos Electivos , Hospitales de Veteranos , Humanos , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Mejoramiento de la Calidad , Estudios Retrospectivos , Factores de Riesgo , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND: Percutaneous cholecystostomy is performed by interventional radiologists for patients with calculous/acalculous cholecystitis who are poor candidates for cholecystectomy. Two anatomical approaches are widely utilized: transperitoneal and transhepatic. PURPOSE: To compare the clinical outcomes of transperitoneal and transhepatic approaches to cholecystostomy catheter placement. MATERIAL AND METHODS: From December 2007 to August 2015, 165 consecutive patients (97 men, 68 women) underwent either transperitoneal (n = 89) or transhepatic (n = 76) cholecystostomy at a single center. Indications were calculous cholecystitis (n = 21), acalculous cholecystitis (n = 35), hydrops (n = 1), gangrenous cholecystitis (n = 1), and other cholecystitis (n = 107). The most common high-risk co-morbidities were sepsis (n = 53) and cardiac (n = 11). Outcomes were compared using univariate and multivariable analysis. RESULTS: Post-procedure outcomes included tube dislodgement (transperitoneal [n = 6] and transhepatic [n = 3], P = 0.44), bile leak (transperitoneal [n = 5], transhepatic [n = 1], P = 0.14), gallbladder hemorrhage (transperitoneal [n = 2]; transhepatic [n = 3], P = 0.52), duodenal fistula (transperitoneal [n = 0], transhepatic [n = 1], P = 0.27), repeat cholecystostomy (transperitoneal [n = 1], transhepatic [n = 3], P = 0.27), and repeat cholecystitis requiring separate admission (transperitoneal [n = 6], transhepatic [n = 10], P = 0.15). All complications were Common Terminology Criteria for Adverse Events grade <3. Twenty transperitoneal patients underwent post-procedure cholecystectomy: 13 laparoscopic, three open, and four unclear/outside records. The mean time from cholecystostomy to operation was 38 days (range 3-211 days). Twenty-three transhepatic patients underwent cholecystectomy: 14 laparoscopic, eight open, and one unclear/outside records, with the mean time from cholecystostomy being 98 days (range 0-1053 days). One transhepatic and three transperitoneal patients died during admission. CONCLUSION: There were no significant differences in short-term complications after transperitoneal and transhepatic approaches to percutaneous cholecystostomy catheter placement.
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Colecistitis Aguda/diagnóstico por imagen , Colecistitis Aguda/cirugía , Colecistostomía/métodos , Ultrasonografía Intervencional/métodos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Hígado/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Peritoneo/diagnóstico por imagen , Resultado del Tratamiento , Adulto JovenRESUMEN
Parental occupational exposures to pesticides, animals and organic dust have been associated with an increased risk of childhood cancer based mostly on case-control studies. We prospectively evaluated parental occupational exposures and risk of childhood leukemia and central nervous system (CNS) tumors in the International Childhood Cancer Cohort Consortium. We pooled data on 329,658 participants from birth cohorts in five countries (Australia, Denmark, Israel, Norway and United Kingdom). Parental occupational exposures during pregnancy were estimated by linking International Standard Classification of Occupations-1988 job codes to the ALOHA+ job exposure matrix. Risk of childhood (<15 years) acute lymphoblastic leukemia (ALL; n = 129), acute myeloid leukemia (AML; n = 31) and CNS tumors (n = 158) was estimated using Cox proportional hazards models to generate hazard ratios (HR) and 95% confidence intervals (CI). Paternal exposures to pesticides and animals were associated with increased risk of childhood AML (herbicides HR = 3.22, 95% CI = 0.97-10.68; insecticides HR = 2.86, 95% CI = 0.99-8.23; animals HR = 3.89, 95% CI = 1.18-12.90), but not ALL or CNS tumors. Paternal exposure to organic dust was positively associated with AML (HR = 2.38 95% CI = 1.12-5.07), inversely associated with ALL (HR = 0.55, 95% CI = 0.31-0.99) and not associated with CNS tumors. Low exposure prevalence precluded evaluation of maternal pesticide and animal exposures; we observed no significant associations with organic dust exposure. This first prospective analysis of pooled birth cohorts and parental occupational exposures provides evidence for paternal agricultural exposures as childhood AML risk factors. The different risks for childhood ALL associated with maternal and paternal organic dust exposures should be investigated further.
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Neoplasias del Sistema Nervioso Central/epidemiología , Leucemia Mieloide Aguda/epidemiología , Exposición Materna/efectos adversos , Exposición Profesional/efectos adversos , Exposición Paterna/efectos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiología , Efectos Tardíos de la Exposición Prenatal/epidemiología , Adolescente , Adulto , Animales , Animales Domésticos , Australia/epidemiología , Neoplasias del Sistema Nervioso Central/etiología , Niño , Preescolar , Dinamarca/epidemiología , Polvo , Femenino , Estudios de Seguimiento , Humanos , Lactante , Recién Nacido , Israel/epidemiología , Leucemia Mieloide Aguda/etiología , Masculino , Noruega/epidemiología , Plaguicidas/toxicidad , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiología , Embarazo , Efectos Tardíos de la Exposición Prenatal/etiología , Estudios Prospectivos , Factores de Riesgo , Reino Unido/epidemiología , Adulto JovenRESUMEN
OBJECTIVE: To evaluate the overall survival of patients with operable stage IA non-small-cell lung cancer (NSCLC) who undergo "early" SBRT (within 0-30 days after diagnosis) versus "delayed" surgery (90-120 days after diagnosis). SUMMARY OF BACKGROUND DATA: During the COVID-19 pandemic, national guidelines have recommended patients with operable stage IA NSCLC to consider delaying surgery by at least 3 months or, alternatively, to undergo SBRT without delay. It is unknown which strategy is associated with better short- and long-term outcomes. METHODS: Multivariable Cox proportional hazards modeling and propensity score-matched analysis was used to compare the overall survival of patients with stage IA NSCLC in the National Cancer Data Base from 2004 to 2015 who underwent "early" SBRT (0-30 days after diagnosis) versus that of patients who underwent "delayed" wedge resection (90-120 days after diagnosis). RESULTS: During the study period, 570 (55%) patients underwent early SBRT and 475 (45%) underwent delayed wedge resection. In multivariable analysis, delayed resection was associated with improved survival [adjusted hazard ratio 0.61; (95% confidence interval (CI): 0.50-0.76)]. Propensity-score matching was used to create 2 groups of 279 patients each who received early SBRT or delayed resection that were well-matched with regard to baseline characteristics. The 5-year survival associated with delayed resection was 53% (95% CI: 45%-61%) which was better than the 5-year survival associated with early SBRT (31% [95% CI: 24%-37%]). CONCLUSION: In this national analysis, for patients with stage IA NSCLC, extended delay of surgery was associated with improved survival when compared to early treatment with SBRT.
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Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/cirugía , Radiocirugia , COVID-19 , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Estudios de Cohortes , Humanos , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Estadificación de Neoplasias , SARS-CoV-2 , Tasa de Supervivencia , Factores de Tiempo , Tiempo de TratamientoRESUMEN
Magnesium ion (Mg+2) plays an important role in various biological processes. All the commercial indicators available share a common drawback, i.e., they have a higher affinity towards calcium ions (Ca+2) than Mg+2. In this study, we reported a new robust green fluorescent indicator, Mag-520, for detection of Mg+2 in live cells. Our results showed that Mag-520 has 10 fold higher affinity towards Mg+2 than Ca+2, while mag-fluo-4 has less than 0.5 fold affinity to Mg+2 than Ca+2 under the same conditions using flow cytometry and fluorescence microscopy. The results demonstrated that Mag-520 provides a better tool to measure Mg+2 with less interference from Ca+2.
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Colorantes Fluorescentes/química , Magnesio/análisis , Microscopía Fluorescente , Compuestos de Anilina/química , Calcio/química , Citometría de Flujo , Células HL-60 , Humanos , Iones/química , Xantenos/químicaRESUMEN
OBJECTIVE: Hirschsprung-associated enterocolitis (HAEC) is the most frequent complication in Hirschsprung disease (HSCR) patients. Currently HAEC is diagnosed clinically, leaving uncertainty in the diagnosis thereby potentially leading to over- or undertreatment of patients. The aim of this study was to identify immune biomarkers to aid in the diagnosis of HAEC. METHODS: From 2012 to 2017, 43 children with HSCR enrolled in a multicenter study, underwent retrospective evaluation of their medical records, and questionnaire-directed parent interviews. HAEC status was determined using HAEC score with cutoff ≥4. Plasma was collected and analyzed by ELISA for the inflammatory bowel disease-associated antibodies: anti-Saccharomyces cerevisiae mannan antibodies (ASCA), outer membrane porin C (OmpC), CBir1, antineutrophil cytoplasmic antibodies. Data were analyzed using t test, univariate, multivariable, and binomial regression models. RESULTS: Eighteen patients had at least 1 episode of HAEC, 25 had no history of HAEC. The HAEC and NO HAEC groups had similar median ages (3 years) and family histories of HSCR. The HAEC group showed markedly elevated ASCA IgA and OmpC antibody levels compared with the NO HAEC group, whereas CBir1 and antineutrophil cytoplasmic antibodies were similar between the groups. Both univariate and multivariable analysis revealed higher OmpC antibody levels associated with HAEC (odds ratio 1.39, confidence interval 1-1.92, Pâ=â0.048), whereas univariate analysis identified a trend toward elevated IgA and immunoglobulin G ASCA levels with HAEC. CONCLUSIONS: We identified elevated OmpC and ASCA serum antibody levels in HAEC patients, and that increased OmpC antibody levels correlated with HAEC occurrence, suggesting HAEC and Crohn disease share gut microbial-host immune responses. These antibodies may serve as potential biomarkers for HAEC, although prospective study with larger sample size is needed.
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Biomarcadores/sangre , Enterocolitis/diagnóstico , Enfermedad de Hirschsprung/diagnóstico , Adolescente , Adulto , Anticuerpos Anticitoplasma de Neutrófilos/sangre , Anticuerpos Antifúngicos/sangre , Proteínas de la Membrana Bacteriana Externa/inmunología , Niño , Preescolar , Enterocolitis/sangre , Proteínas de Escherichia coli/inmunología , Femenino , Flagelina/inmunología , Enfermedad de Hirschsprung/sangre , Humanos , Lactante , Recién Nacido , Enfermedades Inflamatorias del Intestino/inmunología , Masculino , Mananos/inmunología , Registros Médicos , Porinas/inmunología , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Adulto JovenRESUMEN
Lipids are important nutrients that proliferating cells require to maintain energy homeostasis as well as to build plasma membranes for newly synthesized cells. Previously, we identified nutrient-sensing checkpoints that exist in the latter part of the G1 phase of the cell cycle that are dependent upon essential amino acids, Gln, and finally, a checkpoint mediated by mammalian target of rapamycin (mTOR), which integrates signals from both nutrients and growth factors. In this study, we have identified and temporally mapped a lipid-mediated G1 checkpoint. This checkpoint is located after the Gln checkpoint and before the mTOR-mediated cell cycle checkpoint. Intriguingly, clear cell renal cell carcinoma cells (ccRCC) have a dysregulated lipid-mediated checkpoint due in part to defective phosphatase and tensin homologue (PTEN). When deprived of lipids, instead of arresting in G1, these cells continue to cycle and utilize lipid droplets as a source of lipids. Lipid droplets have been known to maintain endoplasmic reticulum homeostasis and prevent cytotoxic endoplasmic reticulum stress in ccRCC. Dysregulation of the lipid-mediated checkpoint forces these cells to utilize lipid droplets, which could potentially lead to therapeutic opportunities that exploit this property of ccRCC.
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Carcinoma de Células Renales/metabolismo , Membrana Celular/metabolismo , Puntos de Control de la Fase G1 del Ciclo Celular , Metabolismo de los Lípidos , Carcinoma de Células Renales/patología , Membrana Celular/patología , Estrés del Retículo Endoplásmico , Glutamina/metabolismo , Humanos , Neoplasias Renales , Células MCF-7 , Proteínas de Neoplasias/metabolismo , Fosfohidrolasa PTEN/metabolismo , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
During G1-phase of the cell cycle, normal cells respond first to growth factors that indicate that it is appropriate to divide and then later in G1 to the presence of nutrients that indicate sufficient raw material to generate two daughter cells. Dividing cells rely on the "conditionally essential" amino acid glutamine (Q) as an anaplerotic carbon source for TCA cycle intermediates and as a nitrogen source for nucleotide biosynthesis. We previously reported that while non-transformed cells arrest in the latter portion of G1 upon Q deprivation, mutant KRas-driven cancer cells bypass the G1 checkpoint, and instead, arrest in S-phase. In this study, we report that the arrest of KRas-driven cancer cells in S-phase upon Q deprivation is due to the lack of deoxynucleotides needed for DNA synthesis. The lack of deoxynucleotides causes replicative stress leading to activation of the ataxia telangiectasia and Rad3-related protein (ATR)-mediated DNA damage pathway, which arrests cells in S-phase. The key metabolite generated from Q utilization was aspartate, which is generated from a transaminase reaction whereby Q-derived glutamate is converted to α-ketoglutarate with the concomitant conversion of oxaloacetate to aspartate. Aspartate is a critical metabolite for both purine and pyrimidine nucleotide biosynthesis. This study identifies the molecular basis for the S-phase arrest caused by Q deprivation in KRas-driven cancer cells that arrest in S-phase in response to Q deprivation. Given that arresting cells in S-phase sensitizes cells to apoptotic insult, this study suggests novel therapeutic approaches to KRas-driven cancers.
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Ácido Aspártico/metabolismo , Ciclo del Ácido Cítrico , Ácido Glutámico/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Puntos de Control de la Fase S del Ciclo Celular , Ácido Aspártico/genética , Proteínas de la Ataxia Telangiectasia Mutada/genética , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Puntos de Control de la Fase G1 del Ciclo Celular/genética , Ácido Glutámico/genética , Humanos , Células MCF-7 , Proteínas Proto-Oncogénicas p21(ras)/genética , Nucleótidos de Purina/biosíntesis , Nucleótidos de Purina/genética , Nucleótidos de Pirimidina/biosíntesis , Nucleótidos de Pirimidina/genéticaRESUMEN
BACKGROUND: Parental occupational and childhood exposures to farm animals have been positively associated with childhood brain tumors, whereas associations with childhood leukemia are equivocal. The developing immune system may be influenced by allergen, virus, or other exposures from animal sources, which may contribute to childhood cancer incidence. METHODS: Incident cancers (acute lymphoblastic leukemia [ALL], acute myeloid leukemia [AML], central nervous system [CNS], peripheral nervous system [PNS]) for children aged 0-4 diagnosed between 2003 and 2008 were obtained from nine National Cancer Institute Surveillance, Epidemiology and End Results (SEER) registries and were linked to U.S. Census of Agriculture data from 2002 and 2007 by county of diagnosis. Animal densities (animal units [AU]/km2; one animal unit is 1000 pounds of animal weight) were estimated for hogs, cattle, chickens (layers and broilers, separately), equine (horses, ponies, mules, burros, donkeys), goats, sheep, turkeys, and total animals. Animal density was examined in models as both continuous (AU per km2) and categorical variables (quartiles). Animal operation densities (per km2) by size of operation (cattle, hogs, chickens, sheep) were modeled continuously. Rate ratios and 95% confidence intervals were estimated using Poisson regression. RESULTS: We found positive associations between AML and broiler chicken densities (RRper 10AU/km2 = 1.14, 95% CI = 1.02-1.26). ALL rates increased with densities of hog operations (RRper operation/100km2 = 1.06, 95% CI = 1.02-1.11). PNS cancer rates were inversely associated with layer chicken density (RRper log of AU/km2 = 0.94, 95% CI = 0.89-0.99). No association was found between any cancer type and densities of cattle, equine, or goats. CONCLUSIONS: Although limited by the ecologic study design, some of our findings are novel and should be examined in epidemiological studies with individual level data.
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Ganado , Neoplasias/epidemiología , Aves de Corral , Animales , Neoplasias del Sistema Nervioso Central/epidemiología , Preescolar , Femenino , Humanos , Incidencia , Lactante , Recién Nacido , Leucemia Mieloide Aguda/epidemiología , Masculino , Neoplasias del Sistema Nervioso Periférico/epidemiología , Densidad de Población , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiología , Características de la Residencia , Estados Unidos/epidemiologíaAsunto(s)
Servicio de Urgencia en Hospital/estadística & datos numéricos , Asistencia Médica/economía , Cumplimiento de la Medicación , Medicamentos bajo Prescripción/economía , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Medicamentos bajo Prescripción/provisión & distribución , Derivación y Consulta , Estudios RetrospectivosRESUMEN
BACKGROUND: Extra-anatomic ascending-to-descending aortic bypass grafts have historically been utilized as a safe and effective solution for repairs of complex coarctation of the aorta. However, reports on reoperation in these patients remain rare. We present a case of an aortic valve replacement and coronary artery bypass grafting in a patient with an extra-anatomic ascending-to-descending aortic bypass graft. CASE PRESENTATION: The patient is a 59-year-old male with a complex aortic history, including repair of aortic coarctation with an ascending-to-descending aortic bypass graft 13 years prior, was admitted to the hospital for shortness of breath and chest pain that had developed over the past year. On further workup, he was found to have severe bileaflet aortic valve stenosis, non-ST elevation myocardial infarction, and moderate coronary artery disease. He underwent surgical aortic valve replacement and coronary artery bypass grafting. Given his unique anatomy, cardiopulmonary bypass approach involved separate cannulation of the right axillary and left common femoral arteries with cross-clamp of both the aorta and the extra-anatomic graft. Using this approach, the redo operation was successfully performed. CONCLUSIONS: Reports on reoperation after ascending-to-descending aortic bypass grafting are rare. We describe our approach to cardiopulmonary bypass and reoperation in a patient with an extra-anatomic ascending-to-descending aortic bypass graft.