RESUMO
Sleep spindles are burstlike signals in the electroencephalogram (EEG) of the sleeping mammalian brain and electrical surface correlates of neuronal oscillations in thalamus. As one of the most inheritable sleep EEG signatures, sleep spindles probably reflect the strength and malleability of thalamocortical circuits that underlie individual cognitive profiles. We review the characteristics, organization, regulation, and origins of sleep spindles and their implication in non-rapid-eye-movement sleep (NREMS) and its functions, focusing on human and rodent. Spatially, sleep spindle-related neuronal activity appears on scales ranging from small thalamic circuits to functional cortical areas, and generates a cortical state favoring intracortical plasticity while limiting cortical output. Temporally, sleep spindles are discrete events, part of a continuous power band, and elements grouped on an infraslow time scale over which NREMS alternates between continuity and fragility. We synthesize diverse and seemingly unlinked functions of sleep spindles for sleep architecture, sensory processing, synaptic plasticity, memory formation, and cognitive abilities into a unifying sleep spindle concept, according to which sleep spindles 1) generate neural conditions of large-scale functional connectivity and plasticity that outlast their appearance as discrete EEG events, 2) appear preferentially in thalamic circuits engaged in learning and attention-based experience during wakefulness, and 3) enable a selective reactivation and routing of wake-instated neuronal traces between brain areas such as hippocampus and cortex. Their fine spatiotemporal organization reflects NREMS as a physiological state coordinated over brain and body and may indicate, if not anticipate and ultimately differentiate, pathologies in sleep and neurodevelopmental, -degenerative, and -psychiatric conditions.
Assuntos
Ondas Encefálicas , Encéfalo/fisiopatologia , Cognição , Doenças do Sistema Nervoso/fisiopatologia , Periodicidade , Fases do Sono , Transtornos do Sono-Vigília/fisiopatologia , Animais , Atenção , Encéfalo/metabolismo , Humanos , Inteligência , Memória , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/metabolismo , Doenças do Sistema Nervoso/psicologia , Plasticidade Neuronal , Transtornos do Sono-Vigília/genética , Transtornos do Sono-Vigília/metabolismo , Transtornos do Sono-Vigília/psicologia , Fatores de TempoRESUMO
BACKGROUND: A proportion of rectal cancer patients who achieve a clinical complete response may develop local regrowth. Although salvage appears to provide appropriate local control, the risk of distant metastases is less known. OBJECTIVE: To compare the risk of distant metastases between patients who achieve a clinical complete response (watch-and-wait strategy) and subsequent local regrowth and patients managed by surgery after chemoradiation. DESIGN: Retrospective multicenter cohort study. SETTINGS: This study used data of patients from 3 institutions who were treated between 1993 and 2019. PATIENTS: Patients with initial clinical complete response (after neoadjuvant therapy) followed by local regrowth and patients with near-complete pathological response (≤10%) after straightforward surgery after chemoradiation were included. MAIN OUTCOME MEASURES: Univariate and multivariate analyses were performed to identify risk factors for distant metastases. Kaplan-Meier curves were created (log-rank test) to compare survival outcomes. Analyses were performed using time zero as last day of radiation therapy or as date of salvage resection in the local regrowth group. RESULTS: Twenty-one of 79 patients with local regrowth developed distant metastases, whereas only 10 of 74 after upfront total mesorectal excision following neoadjuvant chemoradiation therapy ( p = 0.04). Local regrowth and final pathology (ypT3-4) were the only independent risk factors associated with distant metastases. When using date of salvage resection as time zero, distant metastases-free survival rates were significantly inferior for patients with local regrowth (70% vs 86%; p = 0.01). LIMITATIONS: Small number of patients, many neoadjuvant therapies, and selection bias. CONCLUSIONS: Patients undergoing watch-and-wait strategy who develop local regrowth are at higher risk for development of distant metastases compared to patients with near-complete pathological response managed by upfront surgery after chemoradiation. See Video Abstract. NUEVO CRECIMIENTO LOCAL Y EL RIESGO DE METSTASIS A DISTANCIA ENTRE PACIENTES SOMETIDOS A OBSERVACIN Y ESPERA POR CNCER DE RECTO CUL ES EL MEJOR GRUPO DE CONTROL ESTUDIO RETROSPECTIVO MUTICNTRICO: ANTECEDENTES:Una proporción de pacientes que logran una respuesta clínica completa pueden desarrollar un nuevo crecimiento local. Si bien el rescate parece proporcionar un control local apropiado, el riesgo de metástasis a distancia es menos conocido.OBJETIVO:Comparar el riesgo de metástasis a distancia entre los pacientes que logran una respuesta clínica completa (estrategia de observación y espera) y el nuevo crecimiento local posterior con los pacientes tratados con cirugía después de la quimiorradiación.DISEÑO:Estudio de cohorte multicéntrico retrospectivo.CONFIGURACIÓN:Este estudio utilizó datos de pacientes de 3 instituciones que fueron tratados entre 1993 y 2019.PACIENTES:Pacientes con respuesta clínica completa inicial (después de la terapia neoadyuvante) seguida de crecimiento local nuevo y pacientes con respuesta patológica casi completa (≤10 %) después de cirugía directa después de quimiorradiación.PRINCIPALES MEDIDAS DE RESULTADO:Se realizó un análisis univariante/multivariante para identificar los factores de riesgo de metástasis a distancia. Se crearon curvas de Kaplan-Meier (prueba de rango logarítmico) para comparar los resultados de supervivencia. El análisis se realizó utilizando el tiempo cero como último día de radioterapia (1) o como fecha de resección de rescate (2) en el grupo de recrecimiento local.RESULTADOS:Veintiuno de 79 pacientes con recrecimiento local desarrollaron metástasis a distancia, mientras que solo 10 de 74 después de una cirugía sencilla (p = 0,04). El recrecimiento local y la patología final (ypT3-4) fueron los únicos factores de riesgo independientes asociados con las metástasis a distancia. Cuando se utilizó la fecha de la resección de rescate como tiempo cero, las tasas de supervivencia sin metástasis a distancia fueron significativamente inferiores para los pacientes con recrecimiento local (70 frente a 86 %; p = 0,01).LIMITACIONES:Pequeño número de pacientes, muchas terapias neoadyuvantes, sesgo de selección.CONCLUSIONES:Los pacientes sometidos a observación y espera que desarrollan un nuevo crecimiento local tienen un mayor riesgo de desarrollar metástasis a distancia en comparación con los pacientes con una respuesta patológica casi completa manejados con cirugía por adelantado después de la quimiorradiación. (Traducción-Dr. Xavier Delgadillo ).
Assuntos
Neoplasias Retais , Humanos , Estudos Retrospectivos , Estudos de Coortes , Grupos Controle , Estadiamento de Neoplasias , Neoplasias Retais/patologiaRESUMO
BACKGROUND: Nearly 30% of patients with rectal cancer develop local regrowth after initial clinical complete response managed by watch and wait. These patients might be at higher risk for distant metastases. OBJECTIVE: This study aimed to investigate risk factors for distant metastases using time-dependent analyses. DESIGN: Data from an international watch and wait database were retrospectively reviewed. Cox regression analysis was used to determine risk factors for worse distant metastases-free survival. Conditional survival modeling was used to investigate the impact of risk factors on the development of distant metastases. SETTING: Retrospective, multicenter database. PATIENTS: A total of 793 patients (47 institutions) with rectal cancer and clinical complete response to neoadjuvant treatment from the International Watch & Wait Database were included. MAIN OUTCOME MEASURES: Distant metastases-free survival. RESULTS: Of the 793 patients managed with watch and wait (median follow-up 55.2 mo)' 85 patients (10.7%) had distant metastases. Fifty-one of 85 patients (60%) had local regrowth at any time. Local regrowth was an independent factor associated with worse distant metastases-free survival in the multivariable model. Using conditional estimates, patients with local regrowth without distant metastases for 5 years (from decision to watch and wait) remained at higher risk for development of distant metastases for 1 subsequent year compared to patients without local regrowth (5-year conditional distant metastases-free survival 94.9% vs 98.4%). LIMITATIONS: Lack of information on adjuvant chemotherapy, salvage surgery for local regrowth, and heterogeneity of individual surveillance/follow-up strategies used may have affected results. CONCLUSIONS: In patients with clinical complete response managed by watch and wait, development of local regrowth at any time is a risk factor for distant metastases. The risk of distant metastases remains higher for 5 years after development of local regrowth. See Video Abstract at http://links.lww.com/DCR/C53. EL RIESGO DE METSTASIS A DISTANCIA EN PACIENTES CON RESPUESTA CLNICA COMPLETA MANEJADA POR WATCH AND WAIT DESPUS DE LA TERAPIA NEOADYUVANTE PARA EL CNCER DE RECTO LA INFLUENCIA DEL NUEVO CRECIMIENTO LOCAL EN LA BASE DE DATOS INTERNACIONAL WATCH AND WAIT: ANTECEDENTES:Casi el 30 % de los pacientes con cáncer de recto desarrollan un nuevo crecimiento local después de la respuesta clínica completa inicial manejada por watch and wait. Estos pacientes podrían tener un mayor riesgo de metástasis a distancia.OBJETIVO:Investigar los factores de riesgo de metástasis a distancia mediante análisis dependientes del tiempo.DISEÑO:Se revisó retrospectivamente los datos de la base de datos internacional de Watch and Wait. Se utilizó el análisis de regresión de Cox para determinar los factores de riesgo de peor sobrevida libre de metástasis a distancia. Se utilizó un modelo de sobrevida condicional para investigar el impacto de los factores de riesgo en el desarrollo de metástasis a distancia. El tiempo transcurrido hasta el evento se calculó utilizando la fecha de decisión para watch and wait y la fecha del nuevo crecimiento local para el diagnóstico de metástasis a distancia.ESCENARIOBase de datos multicéntrica retrospectiva.PACIENTES:Se incluyeron un total de 793 pacientes (47 instituciones) con cáncer de recto y respuesta clínica completa al tratamiento neoadyuvante de la base de datos internacional de Watch and Wait.PRINCIPALES MEDIDAS DE RESULTADO:Desarrollo de metástasis a distancia.RESULTADOS:De los 793 pacientes tratados con watch and wait (mediana de seguimiento de 55,2 meses), 85 (10,7%) tenían metástasis a distancia. 51 de 85 (60%) tuvieron recrecimiento local en algún momento. El recrecimiento local fue un factor independiente asociado a una peor supervivencia libre de metástasis a distancia en el modelo multivariable. Además, al usar estimaciones condicionales, los pacientes con recrecimiento local sin metástasis a distancia durante 5 años (desde la decisión de watch and wait) permanecieron en mayor riesgo de desarrollar metástasis a distancia durante un año subsiguiente en comparación con los pacientes sin recrecimiento local (sobrevida libre de metástasis a distancia a 5 años: recrecimiento local 94,9% frente a no recrecimiento local 98,4%).LIMITACIONES:La falta de información relacionada con el uso de quimioterapia adyuvante, las características específicas de la cirugía de rescate para el nuevo crecimient o local y la heterogeneidad de las estrategias individuales de vigilancia/seguimiento utilizadas pueden haber afectado los resultados observados.CONCLUSIONES:En pacientes con respuesta clínica completa manejados por Watch and Wait, el desarrollo de recrecimiento local en cualquier momento es un factor de riesgo para metástasis a distancia. El riesgo de metástasis a distancia sigue siendo mayor durante 5 años después del desarrollo de un nuevo crecimiento local. Consulte Video Resumen en http://links.lww.com/DCR/C53. (Traducción-Dr. Felipe Bellolio).
Assuntos
Terapia Neoadjuvante , Neoplasias Retais , Humanos , Terapia Neoadjuvante/métodos , Estudos Retrospectivos , Estadiamento de Neoplasias , Neoplasias Retais/patologia , Quimioterapia AdjuvanteRESUMO
For decades, numerous seminal studies have built our understanding of the locus coeruleus (LC), the vertebrate brain's principal noradrenergic system. Containing a numerically small but broadly efferent cell population, the LC provides brain-wide noradrenergic modulation that optimizes network function in the context of attentive and flexible interaction with the sensory environment. This review turns attention to the LC's roles during sleep. We show that these roles go beyond down-scaled versions of the ones in wakefulness. Novel dynamic assessments of noradrenaline signaling and LC activity uncover a rich diversity of activity patterns that establish the LC as an integral portion of sleep regulation and function. The LC could be involved in beneficial functions for the sleeping brain, and even minute alterations in its functionality may prove quintessential in sleep disorders.
Assuntos
Locus Cerúleo , Transtornos do Sono-Vigília , Humanos , Norepinefrina , Sono/fisiologia , Vigília/fisiologiaRESUMO
BACKGROUND: Watch and wait is a novel management strategy in patients with rectal cancer who have a clinical complete response after neoadjuvant chemoradiotherapy. Surveillance of these patients is generally intensive, because local regrowth (with the potential for salvage) occurs in 25% of patients, and distant metastases occur in 10% of patients. It is unclear for how long these patients should be followed up. To address this issue, we did conditional survival modelling using the International Watch & Wait Database (IWWD), which is a large-scale registry of patients with a clinical complete response after neoadjuvant chemotherapy who have been managed by a watch-and-wait strategy. METHODS: We did a retrospective, multicentre registry study using a dataset from the IWWD, which includes data from 47 clinics across 15 countries. We selected patients (aged ≥18 years) with rectal cancer who had a clinical complete response after neoadjuvant chemotherapy, and who were subsequently managed by a watch-and-wait strategy between Nov 25, 1991, and Dec 31, 2015. Patients who had not achieved a clinical complete response or who had undergone any surgical procedure were excluded. The criteria used for defining a clinical complete response and the specific surveillance strategies were at the discretion of each participating centre. We used conditional survival modelling to estimate the probability of patients remaining free of local regrowth or distant metastasis for an additional 2 years after sustaining a clinical complete response or being distant metastasis-free for 1, 3, and 5 years from the date of the decision to commence watch and wait. The primary outcomes were conditional local regrowth-free survival at 3 years, and conditional distant metastasis-free survival at 5 years. FINDINGS: We identified 793 patients in the IWWD with clinical complete response who had been managed by a watch-and-wait strategy. Median follow-up was 55·2 months (IQR 36·0-75·6). The probability of remaining free from local regrowth for an additional 2 years if a patient had a sustained clinical complete response for 1 year was 88·1% (95% CI 85·8-90·9), for 3 years was 97·3% (95·2-98·6), and for 5 years was 98·6% (97·6-100·0). The probably of remaining free from distant metastasis for a further 2 years in patients who had a clinical complete response without distant metastasis for 1 year was 93·8% (92·3-95·9), for 3 years was 97·8% (96·6-99·3), and for 5 years was 96·6% (94·0-98·9). INTERPRETATION: These results suggest that the intensity of active surveillance in patients with rectal cancer managed by a watch-and-wait approach could be reduced if they achieve and maintain a clinical complete response within the first 3 years of starting this approach. FUNDING: European Registration of Cancer Care, financed by the European Society of Surgical Oncology, the Champalimaud Foundation Lisbon, the Bas Mulder Award, granted by the Alpe d'HuZes Foundation and the Dutch Cancer Society, the European Research Council Advanced Grant, and the National Institute of Health and Research Manchester Biomedical Research Centre.
Assuntos
Adenocarcinoma/terapia , Quimiorradioterapia Adjuvante , Terapia Neoadjuvante , Neoplasias Retais/terapia , Conduta Expectante , Adenocarcinoma/mortalidade , Adenocarcinoma/secundário , Idoso , Quimiorradioterapia Adjuvante/efeitos adversos , Quimiorradioterapia Adjuvante/mortalidade , Bases de Dados Factuais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/efeitos adversos , Terapia Neoadjuvante/mortalidade , Recidiva Local de Neoplasia , Neoplasias Retais/mortalidade , Neoplasias Retais/patologia , Sistema de Registros , Indução de Remissão , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do TratamentoRESUMO
AIM: The aim of this work was to compare the results of elective minimally invasive surgery between patients with complicated sigmoid diverticulitis and those with uncomplicated disease. METHOD: An institutional review board-approved database was searched for all consecutive patients who underwent elective minimally invasive surgery, including laparoscopic, hand-assisted and robotic sigmoidectomy, for diverticulitis between 2010 and 2017; they were classified according to the modified Hinchey classification as having complicated (abscess, fistula, stricture, obstruction, bleeding or previous perforation) versus uncomplicated disease. Data recorded included baseline demographics, indications for surgery, operative details and complications. RESULTS: Three hundred and twenty-five patients underwent elective sigmoidectomy for complicated (n = 105) and uncomplicated (n = 220) diverticulitis. Surgical indications for complicated disease were abscess (n = 74), stricture (n = 14), fistula (n = 28) and bleeding (n = 7). The two groups were statistically comparable for age, gender, body mass index and American Society of Anesthesiologists score. Patients with complicated disease had higher rates of concomitant loop ileostomy creation (9.5% vs. 0.9%, p < 0.001) and synchronous resections (9.5% vs. 2.7%, p = 0.01), higher volumes of blood loss (177 ± 140 vs. 125 ± 92 ml, p < 0.001), longer length of stay (5.6 ± 3 vs. 4.8 ± 2 days, p = 0.04) and longer operating time (218.2 ± 59 vs. 185.8 ± 63 min, p < 0.001). There were no significant differences in anastomotic leakage (3% vs. 1%, p = 0.3), conversion to laparotomy (4.8% vs. 2.3%, p = 0.3) or overall complications (36% vs. 25.9%, p = 0.06) for complicated versus uncomplicated disease, respectively. CONCLUSION: Minimally invasive surgery for complicated diverticulitis resulted in higher rates of construction of proximal ileostomy and synchronous resections and longer operating times and length of hospital stay. Otherwise, it has outcomes that are not significantly different from the results recorded in patients with uncomplicated disease.
Assuntos
Doença Diverticular do Colo , Diverticulite , Laparoscopia , Colectomia , Colo Sigmoide/cirurgia , Diverticulite/cirurgia , Doença Diverticular do Colo/complicações , Doença Diverticular do Colo/cirurgia , Procedimentos Cirúrgicos Eletivos , Humanos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
OBJECTIVE: Analyze conditional recurrence-free survival (cRFS) for rectal cancer patients with complete clinical response (cCR) after neoadjuvant chemoradiation (nCRT) managed nonoperatively after each year without recurrence. SUMMARY BACKGROUND DATA: Select patients with cCR after nCRT have been managed nonoperatively. Risk factors for local recurrence, the need for prolonged follow-up, and the risk of recurrence over time are not well defined. METHODS: Retrospective review of patients with rectal cancer cT2-4N0-2M0 treated with nCRT. Mean follow-up was 64 months. Patients who achieved cCR were managed nonoperatively. cRFS was used to investigate the evolution of recurrence-odds, as patients remain recurrence-free after completion of nCRT. Three-year cRFS was estimated at "x" years after completion of nCRT based on the formula cRFS3â=âRFS(x+3)/RFS(x). RESULTS: One hundred ninety-seven patients with cCR after nCRT were included. Overall survival and recurrence-free survival (RFS) at 5 years were 81.9% (95% CI 74.0%-87.6%) and 60.4% (95% CI 52.5%-67.4%) respectively. Using cRFS estimates, the probability of remaining disease-free for an additional 3 years if the patient survived without disease at 1, 3, and 5 years, was 77.4% (95% CI 68.8%-83.8%), 91.0% (95% CI 81.9%-95.7%), and 94.3% (95% CI 82.9%-98.2%), respectively. In contrast, actuarial RFS rates for similar intervals were 79.1% (95% CI 72.5%-84.2%), 64.2% (95% CI 56.5%-70.8%), and 60.4% (95% CI 52.5%-67.4%). After 2 years disease-free, 3 year cRFS became similar for T2 and T3 cancers. In contrast, patients undergoing extended nCRT became less likely to develop recurrences only after initial 2 years of successful organ-preservation. CONCLUSIONS: Conditional survival suggests that patients have significantly lower risks (≤10%) of developing recurrences after 2 years of achieving cCR following nCRT.
Assuntos
Quimiorradioterapia , Recidiva Local de Neoplasia/epidemiologia , Neoplasias Retais/mortalidade , Neoplasias Retais/terapia , Conduta Expectante , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Taxa de SobrevidaRESUMO
BACKGROUND: Patients with rectal cancer may undergo neoadjuvant chemoradiation even in early stages in an attempt to achieve complete clinical response and undergo organ preservation. However, prediction of tumor response is unavailable. In this setting, accurate identification of poor responders could spare patients with early stage disease from potentially unnecessary chemoradiation. OBJECTIVE: This study focused on development/test of a score based on DNA repair gene expression to predict response to neoadjuvant chemoradiation in patients with rectal cancer. DESIGN: Pretreatment biopsy samples from patients with rectal cancer undergoing neoadjuvant chemoradiation were collected and underwent gene expression analysis using RNA-Seq (test cohort). A score was constructed using 8 differentially expressed DNA repair genes between good (complete clinical) and poor responders (incomplete clinical) to treatment. The score was validated in 2 independent cohorts of patients undergoing similar treatment strategies and using quantitative polymerase chain reaction and microarray gene expression data. SETTINGS: This was a retrospective analysis of gene expression data from 3 independent institutions. PATIENTS: Patients with rectal cancer undergoing neoadjuvant chemoradiation (50.4-54.0 Gy and 5-fluorouracil-based chemotherapy) were eligible. Patients with complete clinical response, complete pathological response, or ≤10% residual cancer cells were considered good responders. Patients with >10% residual cancer cells were considered poor responders. The test cohort included 25 patients (16 poor responders). Validation cohort 1 included 28 patients (18 poor responders), and validation cohort 2 included 46 patients (22 poor responders). MAIN OUTCOMES MEASURES: Response was correlated with the DNA repair score calculated using the expression levels of 8 DNA repair genes. DNA repair score sensitivity, specificity, and positive and negative predictive values were determined in test and validation cohorts. RESULTS: Poor responders had significantly lower DNA repair scores when compared with good responders across all 3 cohorts, regardless of the gene expression platform used. A low score correctly predicted poor response in 93%, 90%, and 71% in test, validation 1, and validation 2 cohorts. LIMITATIONS: This study was limited by its small sample size, different gene expression platforms, and treatment regimens across different cohorts used. CONCLUSIONS: A DNA repair gene score may predict patients likely to have poor response to chemoradiation. This score may be a relevant tool to be investigated in future studies focused on chemoradiation used in the context of organ preservation. See Video Abstract at http://links.lww.com/DCR/B104. PREDICCIÓN DE RESPUESTA DEFICIENTE A LA RADIO-QUIMIOTERAPIA NEOADYUVANTE EN PACIENTES CON CÁNCER RECTAL UTILIZANDO UNA PUNTUACIÓN DE DESREGULACIÓN DE REPARACIÓN DE ADN: ESCOGER LOS PERDEDORES EN LUGAR DE LOS GANADORES: Los pacientes con cáncer rectal pueden someterse a radio-quimioterapia neoadyuvante incluso en estadios tempranos en el intento por lograr una respuesta clínica completa y permitir una preservación de órgano. Sin embargo, aun no existen herramientas disponible para la prediccion de la respuesta tumoral al tratamiento. En este contexto, la identificación precisa de los tumores con mala respuesta al tratamiento podría evitar que los pacientes con enfermedad en estadio temprano sean sometidos a radio-quimioterapia potencialmente innecesaria.Desarrollo / testeo de una puntuación basada en la expresión genes reparadores del ADN para predecir la respuesta a la nCRT en pacientes con cáncer rectal.Se recogieron muestras de biopsia de pre-tratamiento de pacientes con cáncer rectal sometidos a radio-quimioterapia neoadyuvante y se les realizó un análisis de expresión génica utilizando RNAseq (cohorte de prueba). Se construyó una puntuación utilizando 8 genes de reparación de ADN expresados diferencialmente entre buenos (respuesta clinica completa) y pobres respondedores (respuesta clinica incompleta) al tratamiento. La puntuación se validó en 2 cohortes independientes de pacientes sometidos a estrategias de tratamiento similares y utilizando qPCR y datos de expresión de genes en chips ADN (biotecnología -microarrays).Análisis retrospectivo de los datos de expresión génica de 3 instituciones independientes.Fueron incluidos aquellos pacientes con cáncer rectal sometidos a radio-quimioterapia neoadyuvante (50,4-54 Gy y quimioterapia basada en 5FU). Los pacientes con respuesta clínica completa, respuesta patológica completa o ≤10% de células cancerosas residuales se consideraron buenos respondedores. Los pacientes con> 10% de células cancerosas residuales se consideraron de respuesta deficiente. La cohorte de prueba incluyó a 25 pacientes (16 respondedores pobres). La cohorte de validación n. ° 1 incluyó a 28 pacientes (18 respondedores pobres) y la cohorte de validación n. ° 2 incluyó a 46 pacientes (22 respondedores pobres).La respuesta se correlacionó con la puntuación de reparación de ADN calculada utilizando los niveles de expresión de 8 genes de reparación de ADN. La sensibilidad del puntaje de reparación del ADN, la especificidad, los valores predictivos positivos y negativos se determinaron en las cohortes de prueba y validación.Los malos respondedores tuvieron puntuaciones de reparación de ADN significativamente más bajas en comparación con los buenos respondedores en las 3 cohortes, independientemente de la plataforma de expresión génica utilizada. Una puntuación baja predijo correctamente una respuesta pobre en el 93%, 90% y 71% en las cohortes de prueba, validación n. ° 1 y validación n. ° 2, respectivamente.Pequeño tamaño de la muestra, diferentes plataformas de expresión génica y regímenes de tratamiento en diferentes cohortes utilizadas.La puntuacion basada en genes de reparación del ADN puede predecir los pacientes con respuesta pobre a la radio-quimioterapia. Esta puntuación puede ser una herramienta relevante para investigar en futuros estudios centrados en la radio-quimioterapia utilizada en el contexto de la preservación de órganos. Consulte Video Resumen en http://links.lww.com/DCR/B104. (Traducción-Dr. Xavier Delgadillo and Dr. Laura Melina Fernandez).
Assuntos
Quimiorradioterapia , Reparo do DNA/genética , Perfilação da Expressão Gênica , Terapia Neoadjuvante , Neoplasias Retais/genética , Neoplasias Retais/terapia , Biópsia , Colectomia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
BACKGROUND: Patients with rectal cancer who achieve complete clinical response after neoadjuvant chemoradiation have been managed nonoperatively. Thirty percent of these patients may develop a local regrowth, and salvage resection with radical surgery is usually recommended. However, selected patients could be offered additional organ preservation by local excision. We hypothesized that patients with baseline T2 who underwent neoadjuvant therapy (for the specific purpose of achieving a complete clinical response) were more likely to harbor recurrent disease at an earlier stage and amenable to organ preservation strategies (local excision) when compared with T3/T4 (undergoing neoadjuvant chemoradiation for oncologic reasons). OBJECTIVE: The purpose of this study was to compare patients with local regrowth requiring salvage resection according to their baseline stage. DESIGN: This was a retrospective review of consecutive patients with nonmetastatic distal rectal cancer undergoing neoadjuvant chemoradiation. SETTINGS: The study included 2 independent tertiary centers with institutional watch-and-wait organ preservation programs. PATIENTS: Consecutive patients with distal rectal cancer (cT2-4N1-2M0) managed by watch and wait and local regrowth from 2 institutions were included. MAIN OUTCOMES MEASURES: Final pathologic features and surgical and oncologic outcomes were compared according to baseline staging. RESULTS: A total of 73 of 257 patients experienced local regrowth. cT2 presented similar to ypT, ypN, R0, and abdominal perineal resection rates (p > 0.05) at the time of salvage when compared with cT3 to cT4. Patients with cT2 at baseline were more likely to undergo an organ preservation procedure for salvage (56.2% vs 26.5%; p = 0.03). Overall and disease-free survival after salvage were similar between groups irrespective of the type of surgery for the regrowth. LIMITATIONS: Retrospective study, small sample size, and possible inaccurate baseline staging. CONCLUSIONS: Although patients with baseline cT2 rectal cancer had similar pathologic stage at the time of recurrence, these patients were more likely to continue an organ preservation pathway after local regrowth through transanal local excision when compared with cT3 to cT4. Despite differences in the use of radical salvage resection, there were no differences in oncologic outcomes. See Video Abstract at http://links.lww.com/DCR/B254. CIRUGÍA DE RESCATE CON PRESERVACIÓN DE ORGANO PARA PACIENTES CON RECIDIVA LOCAL LUEGO DE WATCH & WAIT: ¿SIGUE SIENDO POSIBLE?: Los pacientes con cáncer rectal que logran una respuesta clínica completa luego de la quimiorradiación neoadyuvante han sido tratados de forma no quirúrgica. El treinta por ciento de estos pacientes pueden desarrollar un nuevo crecimiento local y generalmente se recomienda la resección de rescate con cirugía radical. Sin embargo, en pacientes seleccionados se podría ofrecer la posibilidad de preservación de órgano mediante escisión local. Se formuló la hipótesis de que los pacientes con estadio clinico inicial T2 y sometidos a terapia neoadyuvante (con el propósito específico de lograr una respuesta clínica completa) tenían más probabilidades de presentar una recurrencia local en una etapa más temprana y suceptibles de estrategias de preservación de órgano (escisión local) en comparación con T3 / T4 (sometidos a nCRT por razones oncológicas).Comparar los pacientes con recidiva local que requirieron cirugia de rescate de acuerdo con su estadio inicial.Revisión retrospectiva de pacientes consecutivos con cáncer de recto distal no metastásico sometidos a quimiorradiación neoadyuvante.Dos centros terciarios independientes con programas institucionales de preservación de órgano - Watch & Wait.Pacientes consecutivos con cáncer rectal distal (cT2-4N1-2M0) manejados por Watch & Wait y recidiva local.Las características patológicas finales, los resultados quirúrgicos y oncológicos se compararon de acuerdo con la estadificación inicial.Un total de 73 de 257 pacientes presentaron recidiva local. cT2 presentaron similares ypT, ypN, R0 y tasas de resección abdominoperineal (p>0,05) en el momento del rescate en comparación con cT3-4.Los pacientes con cT2 de base tuvieron más probabilidades de someterse a un procedimiento de preservación de órgano durante el rescate (56,2% frente a 26,5%; p = 0,03). Supervivencia general y DFS después del rescate fueron similares entre los grupos, independientemente del tipo de cirugía para la recidiva.Estudio retrospectivo, tamaño de muestra pequeño, la posible estadificación basal inexacta.Aunque los pacientes con cáncer rectal cT2 de base presentaron estadio patologico similar en el momento de la recidiva, estos pacientes tuvieron más probabilidades de continuar una vía de preservación de órgano luego de una recidiva local a través de la escisión local transanal en comparación con cT3-4. A pesar de las diferencias en el uso de la resección radical de rescate, no hubo diferencias en los resultados oncológicos. Consulte Video Resumen en http://links.lww.com/DCR/B254.
Assuntos
Quimiorradioterapia/métodos , Recidiva Local de Neoplasia/cirurgia , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/radioterapia , Terapia de Salvação/métodos , Idoso , Estudos de Casos e Controles , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Estadiamento de Neoplasias , Preservação de Órgãos/métodos , Preservação de Órgãos/estatística & dados numéricos , Tratamentos com Preservação do Órgão/métodos , Protectomia/métodos , Protectomia/estatística & dados numéricos , Neoplasias Retais/patologia , Estudos Retrospectivos , Conduta Expectante/métodosRESUMO
BACKGROUND: Select patients with complete clinical response to chemoradiation have been managed without radical surgery. The presence of radiologic evidence of nodal metastases at baseline could be a risk factor for local tumor regrowth, more advanced stage at the time of recurrence, and worse distant metastases-free survival. OBJECTIVE: The purpose of this study was to compare the outcomes of patients with baseline node-positive and node-negative cancer after neoadjuvant chemoradiation and complete clinical response managed nonoperatively. DESIGN: This was a retrospective review of consecutive patients with nonmetastatic distal rectal cancer undergoing neoadjuvant chemoradiation. PATIENTS: Consecutive patients with clinical and radiologic evidence of complete clinical response at 8 to 10 weeks were managed nonoperatively and enrolled in a strict follow-up program (watch and wait). Patients with incomplete clinical response or tumor regrowth after initial complete clinical response were referred to surgery. MAIN OUTCOMES MEASURES: Surgery-free and distant metastases-free survival were compared between patients according to nodal status at baseline. RESULTS: A total of 117 patients with node-positive and 218 with node-negative cancer at baseline were reviewed. Overall, 62 (53.0%; node positive) and 135 (61.9%; node negative) achieved a complete clinical response and were managed nonoperatively (p = 0.13). Patients with baseline node-positive cancer had similar rates of pathologic nodal metastases at the time of recurrence. Five-year surgery-free (39.7% vs 46.8%; p = 0.2) and distant metastases-free survival (77.5% vs 80.5%; p = 0.49) were similar between baseline node-positive and node-negative patients. LIMITATIONS: This was a retrospective study with a small sample size and possible inaccurate nodal staging. CONCLUSIONS: Patients with rectal cancer with node-positive cancer at baseline who develop a complete clinical response after neoadjuvant chemoradiation are not at increased risk for local tumor regrowth or development of more advanced disease at the time of recurrence. These patients seem to be safe candidates for organ-preserving strategies after achieving complete clinical response. See Video Abstract at http://links.lww.com/DCR/A902.
Assuntos
Quimiorradioterapia Adjuvante , Recidiva Local de Neoplasia/epidemiologia , Neoplasias Retais/patologia , Neoplasias Retais/terapia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estadiamento de Neoplasias , Protectomia , Neoplasias Retais/mortalidade , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
BACKGROUND: The observation of inferior oncologic outcomes after surgery for proximal colon cancers has led to the investigation of alternative treatment strategies, including surgical procedures and neoadjuvant systemic chemotherapy in selected patients. OBJECTIVE: The purpose of this study was to determine the accuracy of CT staging in proximal colon cancer in detecting unfavorable pathologic features that may aid in the selection of ideal candidates alternative treatment strategies, including extended lymph node dissection and/or neoadjuvant chemotherapy. DESIGN: This was a retrospective consecutive series. SETTINGS: Trained abdominal radiologists from 2 centers performed a blinded review of CT scans obtained to locally stage proximal colon cancer according to previously defined prognostic groups, including T1/2, T3/4, N+, and extramural venous invasion. CT findings were compared with histopathologic results as a reference standard. Unfavorable pathologic findings included pT3/4, pN+, or extramural venous invasion. PATIENTS: Consecutive patients undergoing right colectomy in 2 institutions between 2011 and 2016 were retrospectively reviewed from a prospectively collected database. MAIN OUTCOME MEASURES: T status, nodal status, and extramural venous invasion status comparing CT with final histologic findings were measured. RESULTS: Of 150 CT scans reviewed, CT failed to identify primary cancer in 18%. Overall accuracy of CT to identify unfavorable pathologic features was 63% with sensitivity, specificity, positive predictive value, and negative predictive value of 63% (95% CI, 54%-71%), 63% (95% CI, 46%-81%), 87% (95% CI, 80%-94%) and 30% (95% CI, 18%-41%). Only cT3/4 (55% vs 45%; p = 0.001) and cN+ (42% vs 58%; p = 0.02) were significantly associated with correct identification of unfavorable features at final pathology. CT scans overstaged and understaged cT in 23.7% and 48.3% and cN in 28.7% and 53.0% of cases. LIMITATIONS: The study was limited by its retrospective design, relatively small sample size, and heterogeneity of CT images performed in different institutions with variable equipment and technical details. CONCLUSIONS: Accuracy of CT scan for identification of pT3/4, pN+, or extramural venous invasion was insufficient to allow for proper identification of patients at high risk for local recurrence and/or in whom to consider alternative treatment strategies. Locoregional overstaging and understaging resulted in inappropriate treatment strategies in <48%. See Video Abstract at http://links.lww.com/DCR/A935.
Assuntos
Neoplasias do Colo/diagnóstico , Estadiamento de Neoplasias/métodos , Tomografia Computadorizada por Raios X/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Reprodutibilidade dos Testes , Estudos RetrospectivosRESUMO
BACKGROUND: Patients with rectal cancer who achieve complete clinical response after neoadjuvant chemoradiation have been managed by organ-preserving strategies and acceptable long-term outcomes. Controversy still exists regarding optimal timing for the assessment of tumor response after neoadjuvant chemoradiation. OBJECTIVE: The purpose of this study was to estimate the time interval for achieving complete clinical response using strict endoscopic and clinical criteria after a single neoadjuvant chemoradiation regimen. DESIGN: This was a retrospective review of consecutive patients managed by 54-Gy and consolidation 5-fluorouracil-based chemotherapy. Assessment of response was performed at 10 weeks after radiation. Patients with suspected complete clinical response were offered watch-and-wait strategy and reassessment every 6 to 8 weeks until achievement of strict criteria of complete clinical response or overt residual cancer. SETTINGS: This study was conducted at a single tertiary care center. PATIENTS: Patients with complete clinical response who underwent a successful watch-and-wait strategy until last follow-up were eligible. Dates of radiation completion and achievement of strict endoscopic and clinical criteria (mucosal whitening, teleangiectasia, and no ulceration or irregularity) were recorded. Patients with incomplete response or with initial complete clinical response followed by local recurrence or regrowth were excluded. MAIN OUTCOMES MEASURES: The distribution of time intervals between completion of radiation and achievement of strict complete clinical response was measured. Patients who achieved early complete clinical response (≤16 wk) were compared with late complete clinical response (>16 wk). RESULTS: A total of 49 patients achieved complete clinical response and were successfully managed nonoperatively. A median interval of 18.7 weeks was observed for achieving strict complete clinical response. Only 38% of patients achieved complete clinical response between 10 and 16 weeks from radiation completion. Patients with earlier cT status (cT2/T3a) achieved a complete clinical response significantly earlier when compared with those patients with more advanced disease (T3b-d/4; 19 vs 26 wk; p = 0.03). LIMITATIONS: This was a retrospective study with a small sample size. CONCLUSIONS: Assessment at 10 to 16 weeks may detect a minority of patients who achieve complete clinical response without additional recurrence after neoadjuvant chemoradiation. Patients suspected for a complete clinical response should be considered for reassessment beyond 16 weeks before definitive management when considered for a watch and wait strategy. See Video Abstract at http://links.lww.com/DCR/A901.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Quimiorradioterapia Adjuvante , Fluoruracila/uso terapêutico , Neoplasias Retais/diagnóstico por imagem , Neoplasias Retais/terapia , Conduta Expectante , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Metástase Neoplásica , Estadiamento de Neoplasias , Tratamentos com Preservação do Órgão , Neoplasias Retais/patologia , Reto , Estudos Retrospectivos , Fatores de TempoRESUMO
INTRODUCTION: Preoperative colonoscopic localization for resection of colonic neoplasia, with or without tattooing for guidance, has been extensively used with variable accuracy. Difficulty in intraoperative identification of the lesion may lead to resection of an incorrect segment or to a more extensive resection than originally planned. The aim of this study was to evaluate the accuracy of preoperative colonoscopy in determining the site of the lesion. METHODS: A prospectively collected IRB-approved institutional database was retrospectively queried for all consecutive patients who underwent an elective colon resection for neoplasia between 2013 and 2016. Excluded were patients without preoperative colonoscopy reports available for comparison or who underwent emergency surgery. Surgical plan based on preoperative colonoscopic localization with or without tattooing was compared to the final surgery and pathology reports. RESULTS: 203 patients were included [mean age 68 (35-92) years; 102 males (50.2%)]. Preoperative colonoscopy was inaccurate in 16.7% (34 patients) leading to a change in the surgical plan. Patients with transverse or distal lesions were more likely to have a change in final surgical management compared to proximal sided lesions (29.7% vs. 3.9%, respectively; p < 0.001). Only 3.8% of the tattooed lesions could not be identified during surgery. Additional intraoperative colonoscopy was needed in 11 patients (5.5%) to verify exact lesion location. Average length of the resected segment was longer in patients who required a change in surgical plan (26.44 cm vs. 22.47 cm; p = 0.02). CONCLUSION: Inaccurate preoperative colonoscopic localization led to a change in surgical management in 16.7% of cases, especially in transverse or left sided lesions. Surgeons should consider these findings when planning colonic resections.
Assuntos
Neoplasias do Colo/patologia , Neoplasias do Colo/cirurgia , Colonoscopia , Cuidados Pré-Operatórios/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Colectomia , Procedimentos Cirúrgicos Eletivos , Feminino , Humanos , Período Intraoperatório , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , TatuagemRESUMO
INTRODUCTION: Lateral node dissection in rectal cancer has been routinely performed in Eastern countries. Technical and anatomical challenges and potential significant postoperative morbidity associated with the procedure have prevented its implementation into clinical practice in Western countries. However, the minimally invasive approach may offer the opportunity of performing this complex procedure with precise anatomical dissection and minimal intraoperative blood loss. In this setting, proper training and standardization of technical steps is highly warranted for surgeons not fully acquainted with the procedure. TECHNIQUE: Access to the lateral nodes along the obturator and internal iliac vessels is described by using specific anatomical landmarks. Opening of the peritoneum along the ureter provides access to the region of interest. Dissection of the medial limit is performed preserving the neurovascular bundle and ureter. The lateral dissection is performed along the external iliac vein to provide access to the obturator muscle. Identification of the obturator nerve with blunt dissection of the fat is a critical part of the procedure. Once the lymphatic connections between the inguinal and iliac nodes are transected, dissection is performed along the internal iliac vessels, and branches are separated from the lymphadenectomy specimen. RESULTS: Evidence supports that lateral node dissection performed for highly selected patients with minimally invasive access leads to less intraoperative blood loss and similar oncological outcomes. Technical steps illustrated in the present video may aid surgeons in performing this procedure with precise anatomical landmarks and minimal risk for intraoperative complications. CONCLUSIONS: Lateral node dissection for rectal cancer is a procedure that may follow standardized technical steps by using precise anatomical landmarks with the use of minimally invasive approach.
Assuntos
Pontos de Referência Anatômicos/cirurgia , Cirurgia Colorretal/normas , Dissecação/métodos , Excisão de Linfonodo/métodos , Procedimentos Cirúrgicos Minimamente Invasivos/métodos , Neoplasias Retais/cirurgia , Humanos , Laparoscopia/métodos , Recuperação de Sangue Operatório/normas , Pelve/irrigação sanguínea , Pelve/cirurgia , Neoplasias Retais/patologiaAssuntos
Neoplasias Colorretais , Cirurgia Colorretal , Procedimentos Cirúrgicos do Sistema Digestório , Laparoscopia , Humanos , Procedimentos Cirúrgicos do Sistema Digestório/efeitos adversos , Laparoscopia/efeitos adversos , Complicações Intraoperatórias/etiologia , Complicações Intraoperatórias/prevenção & controle , Complicações Intraoperatórias/cirurgia , Neoplasias Colorretais/cirurgia , Neoplasias Colorretais/complicações , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controle , Complicações Pós-Operatórias/cirurgiaRESUMO
Although low-frequency (LF < 10 Hz) activities have been considered as a hallmark of nonrapid eye movement (NREM) sleep, several studies have recently reported LF activities in the membrane potential of cortical neurons from different areas in awake mice. However, little is known about the spatiotemporal organization of LF activities across cortical areas during wakefulness and to what extent it differs during NREM sleep. We have thus investigated the dynamics of LF activities across cortical areas in awake and sleeping mice using chronic simultaneous local field potential recordings. We found that LF activities had higher amplitude in somatosensory and motor areas during quiet wakefulness and decreased in most areas during active wakefulness, resulting in a global state change that was overall correlated with motor activity. However, we also observed transient desynchronization of cortical states between areas, indicating a more local state regulation. During NREM sleep, LF activities had higher amplitude in all areas but slow-wave activity was only poorly correlated across cortical areas. Despite a maximal amplitude during NREM sleep, the coherence of LF activities between areas that are not directly connected dropped from wakefulness to NREM sleep, potentially reflecting a breakdown of long-range cortical integration associated with loss of consciousness.
Assuntos
Córtex Cerebral/fisiologia , Atividade Motora/fisiologia , Sono/fisiologia , Vigília/fisiologia , Animais , Estado de Consciência/fisiologia , Sincronização Cortical/fisiologia , Eletrodos Implantados , Masculino , Camundongos Endogâmicos C57BL , Processamento de Sinais Assistido por ComputadorRESUMO
OBJECTIVE: Demonstrate intratumoral genetic heterogeneity in rectal cancer. BACKGROUND: Several clinical management decisions in rectal cancer may be influenced by pretreatment biopsy information. However, in the setting of significant intratumoral heterogeneity, biopsies may not be representative of the entirety of the tumor and limit the reliability of the information provided from them for clinical decision management. METHODS: Three fragments from a single rectal adenocarcinoma were chosen for whole-exome sequencing followed by mutation detection analysis. About 25 Gb of unambiguously mapped sequences were generated for each sample resulting in a median fold-coverage of 35x. Captured sequences mapped to the reference human genome were then used for the detection of somatic point mutations. RESULTS: Overall, 193 unique somatic point mutations were identified. Only 53 (27%) of these were shared by all three fragments, including known genes involved in early phases of the adenoma-carcinoma sequence (such as, APC). Approximately, 115 (59%) mutations were exclusively present in only one of the fragments, including mutations in "driver" genes (DNAH12). Jaccard distances showed a median distance of 0.603 for pair-wise comparison of fragments indicating significant heterogeneity between them. CONCLUSIONS: Considerable intratumoral heterogeneity is present among naive rectal cancers. The majority of point mutations detected in different fragments from rectal cancers are frequently unique to a single fragment. These findings support that gene mutations found on single pretreatment biopsies will not necessarily be representative of mutations present in the entirety of the tumor and therefore may limit the utility of the biological information provided by single biopsy fragments for clinical management decisions.