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1.
J Clin Gastroenterol ; 57(6): 574-577, 2023 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-35703261

RESUMEN

GOALS: We aimed to evaluate a novel upper esophageal sphincter (UES) assist device loaner program for the prevention of acute cellular rejection and chronic lung allograft dysfunction among lung transplant (LTx) recipients. BACKGROUND: Laryngopharyngeal reflux can lead to chronic microaspiration and LTx rejection. The UES assist device applies external pressure at the level of UES to decrease reflux. STUDY: We prospectively enrolled and issued UES assist devices to consecutive transplant patients referred for gastrointestinal motility testing from 2016 to 2020. Device tolerability was defined by successful utilization as a bridge to ambulatory pH monitoring and/or antireflux procedure, or as permanent therapy. Incidence of rejection was analyzed before, during, and after device implementation. RESULTS: Twenty-six participants were issued devices (15 pathologic, 5 physiological, 6 unknown reflux status), none of whom developed acute rejection episodes or chronic lung allograft dysfunction while using the device. Thirteen adopted the device promptly after transplantation (mean 1.7 mo) and remained free of rejection episodes over a mean 24.7 months of follow-up. Among those with pathologic reflux, lag time to device adoption strongly correlated with the development of rejection ( r =0.8, P =0.0006). There was no such correlation among those with physiological reflux. Five developed acute rejection after device return. CONCLUSIONS: The device was tolerated by a majority of LTx patients and appears feasible as a barrier measure in the prevention of rejection. Delayed treatment of laryngopharyngeal reflux may lead to early allograft failure; therefore, the UES assist device should be given important consideration in transplant protection.


Asunto(s)
Esfínter Esofágico Superior , Reflujo Laringofaríngeo , Humanos , Receptores de Trasplantes , Estudios de Factibilidad , Pulmón , Aloinjertos
2.
Genes Dev ; 28(17): 1929-39, 2014 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-25184679

RESUMEN

Cell type-specific conditional activation of oncogenic K-Ras is a powerful tool for investigating the cell of origin of adenocarcinomas in the mouse lung. Our previous studies showed that K-Ras activation with a CC10(Scgb1a1)-CreER driver leads to adenocarcinoma in a subset of alveolar type II cells and hyperplasia in the bronchioalveolar duct region. However, no tumors develop in the bronchioles, although recombination occurs throughout this region. To explore underlying mechanisms, we simultaneously modulated either Notch signaling or Sox2 levels in the CC10+ cells along with activation of K-Ras. Inhibition of Notch strongly inhibits adenocarcinoma formation but promotes squamous hyperplasia in the alveoli. In contrast, activation of Notch leads to widespread Sox2+, Sox9+, and CC10+ papillary adenocarcinomas throughout the bronchioles. Chromatin immunoprecipitation demonstrates Sox2 binding to NOTCH1 and NOTCH2 regulatory regions. In transgenic mouse models, overexpression of Sox2 leads to a significant reduction of Notch1 and Notch2 transcripts, while a 50% reduction in Sox2 leads to widespread papillary adenocarcinoma in the bronchioles. Taken together, our data demonstrate that the cell of origin of K-Ras-induced tumors in the lung depends on levels of Sox2 expression affecting Notch signaling. In addition, the subtype of tumors arising from type II cells is determined in part by Notch activation or suppression.


Asunto(s)
Adenocarcinoma/genética , Adenocarcinoma/patología , Genes ras/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Receptores Notch/metabolismo , Factores de Transcripción SOXB1/metabolismo , Animales , Regulación Neoplásica de la Expresión Génica , Ratones , Ratones Transgénicos , Unión Proteica , Alveolos Pulmonares/patología , Receptores Notch/genética , Transducción de Señal , Activación Transcripcional/genética
3.
Ann Surg ; 274(1): e70-e79, 2021 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-31469745

RESUMEN

OBJECTIVE: The aim of this study was to identify independent predictors of hospital readmission for patients undergoing lobectomy for lung cancer. SUMMARY BACKGROUND DATA: Hospital readmission after lobectomy is associated with increased mortality. Greater than 80% of the variability associated with readmission after surgery is at the patient level. This underscores the importance of using a data source that includes detailed clinical information. METHODS: Using the Society of Thoracic Surgeons (STS) General Thoracic Surgery Database (GTSD), we conducted a retrospective cohort study of patients undergoing elective lobectomy for lung cancer. Three separate multivariable logistic regression models were generated: the first included preoperative variables, the second added intraoperative variables, and the third added postoperative variables. The c statistic was calculated for each model. RESULTS: There were 39,734 patients from 277 centers. The 30-day readmission rate was 8.2% (n = 3237). In the final model, postoperative complications had the greatest effect on readmission. Pulmonary embolus {odds ratio [OR] 12.34 [95% confidence interval (CI),7.94-19.18]} and empyema, [OR 11.66 (95% CI, 7.31-18.63)] were associated with the greatest odds of readmission, followed by pleural effusion [OR 7.52 (95% CI, 6.01-9.41)], pneumothorax [OR 5.08 (95% CI, 4.16-6.20)], central neurologic event [OR 3.67 (95% CI, 2.23-6.04)], pneumonia [OR 3.13 (95% CI, 2.43-4.05)], and myocardial infarction [OR 3.16 (95% CI, 1.71-5.82)]. The c statistic for the final model was 0.736. CONCLUSIONS: Complications are the main driver of readmission after lobectomy for lung cancer. The highest risk was related to postoperative events requiring a procedure or medical therapy necessitating inpatient care.


Asunto(s)
Neoplasias Pulmonares/cirugía , Readmisión del Paciente/estadística & datos numéricos , Neumonectomía , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/terapia , Adulto , Anciano , Bases de Datos Factuales , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Periodo Perioperatorio , Estudios Retrospectivos , Factores de Riesgo
4.
Surg Endosc ; 35(8): 4700-4711, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-32940794

RESUMEN

INTRODUCTION: Standard of care for locally advanced esophageal carcinoma is neoadjuvant chemoradiation (nCRT) and surgical resection 4-8 weeks after completion of nCRT. It is recommended that the CRT to surgery interval not exceed 90 days. Many patients do not undergo surgery within this timeframe due to patient/physician preference, complete clinical response, or poor performance status. Select patients are offered salvage esophagectomy (SE), defined in two ways: resection for recurrent/persistent disease after complete response to definitive CRT (dCRT) or esophagectomy performed > 90 days after completion of nCRT. Salvage esophagectomy reportedly has higher postoperative morbidity and poor survival outcomes. In this study, we assessed outcomes, overall, and disease-free survival of patients undergoing salvage esophagectomy by both definitions (recurrent/persistent disease after dCRT and/or > 90 days), compared to planned (resection after nCRT/within 90 days) esophagectomy (PE). MATERIALS AND METHODS: Retrospective review of a prospectively maintained database identified patients who underwent minimally invasive esophagectomy at a single institution from 2009 to 2019. Esophagectomy for benign disease and patients who did not receive nCRT were excluded. Outcomes included postoperative complications, length of stay (LOS), disease-free survival, and overall survival. RESULTS: 97 patients underwent minimally invasive esophageal resection for esophageal carcinoma. 89.7% of patients were male. Mean age was 64.9 years (range 36-85 years). 94.8% of patients had adenocarcinoma, with 16 transthoracic and 81 transhiatal approaches. On comparing planned esophagectomy (n = 87) to esophagectomy after dCRT failure (n = 10), no significant differences were identified in overall survival (p = 0.73), disease-free survival (p = 0.32), 30-day or major complication rate, anastomotic leak, or LOS. Similarly, when comparing esophagectomy < 90 days after CRT (n = 62) to > 90 days after CRT completion (n = 35), no significant differences were identified in overall survival (p = 0.39), disease-free survival (p = 0.71), 30-day or major complication rate, LOS, or anastomotic leak rate between groups. In this comparison, local recurrence was noted to be elevated with SE as compared to PE (64.3% vs. 25.0%, p = 0.04). CONCLUSION: Overall survival and disease-free survival were equivalent between SE and PE. Local recurrence was noted to be increased with SE, though this did not appear to affect survival. Although planned esophagectomy remains the standard of care, salvage esophagectomy has comparable outcomes and is appropriate for selected patients.


Asunto(s)
Neoplasias Esofágicas , Esofagectomía , Adulto , Anciano , Anciano de 80 o más Años , Quimioradioterapia , Neoplasias Esofágicas/cirugía , Humanos , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante , Recurrencia Local de Neoplasia/cirugía , Estudios Retrospectivos , Terapia Recuperativa , Resultado del Tratamiento
5.
Development ; 144(17): 3114-3125, 2017 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-28743796

RESUMEN

Correct myelination is crucial for the function of the peripheral nervous system. Both positive and negative regulators within the axon and Schwann cell function to ensure the correct onset and progression of myelination during both development and following peripheral nerve injury and repair. The Sox2 transcription factor is well known for its roles in the development and maintenance of progenitor and stem cell populations, but has also been proposed in vitro as a negative regulator of myelination in Schwann cells. We wished to test fully whether Sox2 regulates myelination in vivo and show here that, in mice, sustained Sox2 expression in vivo blocks myelination in the peripheral nerves and maintains Schwann cells in a proliferative non-differentiated state, which is also associated with increased inflammation within the nerve. The plasticity of Schwann cells allows them to re-myelinate regenerated axons following injury and we show that re-myelination is also blocked by Sox2 expression in Schwann cells. These findings identify Sox2 as a physiological regulator of Schwann cell myelination in vivo and its potential to play a role in disorders of myelination in the peripheral nervous system.


Asunto(s)
Macrófagos/metabolismo , Vaina de Mielina/metabolismo , Nervios Periféricos/metabolismo , Factores de Transcripción SOXB1/metabolismo , Células de Schwann/metabolismo , Animales , Biomarcadores/metabolismo , Cadherinas/metabolismo , Proliferación Celular , Proteína 2 de la Respuesta de Crecimiento Precoz/metabolismo , Proteínas Fluorescentes Verdes/metabolismo , Ratones Transgénicos , Actividad Motora , Conducción Nerviosa , Traumatismos de los Nervios Periféricos/metabolismo , Traumatismos de los Nervios Periféricos/patología , Nervios Periféricos/patología , Nervios Periféricos/ultraestructura , Proteínas Proto-Oncogénicas c-jun/metabolismo , Ratas , Recuperación de la Función , Células de Schwann/patología , Transgenes , beta Catenina/metabolismo
6.
Carcinogenesis ; 37(3): 280-289, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26905588

RESUMEN

Centrosome abnormalities are often observed in premalignant lesions and in situ tumors and have been associated with aneuploidy and tumor development. We investigated the associations of 9354 single-nucleotide polymorphisms (SNPs) in 106 centrosomal genes with lung cancer risk by first using the summary data from six published genome-wide association studies (GWASs) of the Transdisciplinary Research in Cancer of the Lung (TRICL) (12,160 cases and 16 838 controls) and then conducted in silico replication in two additional independent lung cancer GWASs of Harvard University (984 cases and 970 controls) and deCODE (1319 cases and 26,380 controls). A total of 44 significant SNPs with false discovery rate (FDR) ≤ 0.05 were mapped to one novel gene FGFR1OP and two previously reported genes (TUBB and BRCA2). After combined the results from TRICL with those from Harvard and deCODE, the most significant association (P combined = 8.032 × 10(-6)) was with rs151606 within FGFR1OP. The rs151606 T>G was associated with an increased risk of lung cancer [odds ratio (OR) = 1.10, 95% confidence interval (95% CI) = 1.05-1.14]. Another significant tagSNP rs12212247 T>C (P combined = 9.589 × 10(-6)) was associated with a decreased risk of lung cancer (OR = 0.93, 95% CI = 0.90-0.96). Further in silico functional analyzes revealed that rs151606 might affect transcriptional regulation and result in decreased FGFR1OP expression (P trend = 0.022). The findings shed some new light on the role of centrosome abnormalities in the susceptibility to lung carcinogenesis.


Asunto(s)
Regulación Neoplásica de la Expresión Génica/genética , Predisposición Genética a la Enfermedad/genética , Neoplasias Pulmonares/genética , Proteínas Proto-Oncogénicas/genética , Femenino , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Masculino , Polimorfismo de Nucleótido Simple , Factores de Riesgo
7.
Ann Surg Oncol ; 22(3): 1020-5, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-25234017

RESUMEN

PURPOSE: We examined survival of patients who underwent esophagectomy for locally advanced esophageal cancer with foci that were suspicious for metastatic disease on initial imaging but whose disease did not progress after induction chemoradiation treatment (CRT). METHODS: The impact of pre- and posttherapy staging characteristics on survival of patients who underwent esophagectomy after CRT between 2003 and 2009 was evaluated using multivariable logistic regression. Survival of patients with and without possible metastatic disease on initial imaging was compared with the log-rank test. RESULTS: During the study period, 71 (32%) of 220 patients who underwent CRT followed by esophagectomy had possible distant metastatic disease on initial imaging. Patients with initial suspicion of metastases had a 5-year survival of 24.8%. Overall survival of patients with and without possible metastatic disease on initial imaging was not significantly different (p = 0.4), but pretreatment positron emission tomography (PET) suggesting a liver lesion (hazard ratio [HR] 3.2, p = 0.003) predicted worse survival. Additional predictors of worse survival were clinical T4 status (HR 3.1, p = 0.001), post-CRT pathologic nodal status (HR 1.6, p = 0.04), and pathologically confirmed metastatic disease at or before resection (HR 3.1, p = 0.01). None of 10 patients with pathologic metastatic disease at resection lived longer than 2.5 years. CONCLUSIONS: Patients with possible liver metastases on pretreatment PET and patients with confirmed metastatic disease at the time of surgery do not benefit from resection. However, patients with pretreatment imaging that shows possible metastatic disease in sites other than the liver still have reasonable long-term survival after resection.


Asunto(s)
Adenocarcinoma/mortalidad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/mortalidad , Neoplasias Esofágicas/mortalidad , Esofagectomía/mortalidad , Recurrencia Local de Neoplasia/mortalidad , Tomografía de Emisión de Positrones/métodos , Adenocarcinoma/secundario , Adenocarcinoma/terapia , Anciano , Carcinoma de Células Escamosas/secundario , Carcinoma de Células Escamosas/terapia , Quimioradioterapia/mortalidad , Terapia Combinada , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/terapia , Femenino , Fluorodesoxiglucosa F18 , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/terapia , Estadificación de Neoplasias , Pronóstico , Estudios Prospectivos , Radiofármacos , Estudios Retrospectivos , Tasa de Supervivencia
8.
Proc Natl Acad Sci U S A ; 109(13): 4910-5, 2012 Mar 27.
Artículo en Inglés | MEDLINE | ID: mdl-22411819

RESUMEN

Identifying the cells of origin of lung cancer may lead to new therapeutic strategies. Previous work has focused upon the putative bronchoalveolar stem cell at the bronchioalveolar duct junction as a cancer cell of origin when a codon 12 K-Ras mutant is induced via adenoviral Cre inhalation. In the present study, we use two "knock-in" Cre-estrogen receptor alleles to inducibly express K-RasG12D in CC10(+) epithelial cells and Sftpc(+) type II alveolar cells of the adult mouse lung. Analysis of these mice identifies type II cells, Clara cells in the terminal bronchioles, and putative bronchoalveolar stem cells as cells of origin for K-Ras-induced lung hyperplasia. However, only type II cells appear to progress to adenocarcinoma.


Asunto(s)
Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Células Epiteliales Alveolares/metabolismo , Células Epiteliales Alveolares/patología , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Adenocarcinoma/genética , Adenocarcinoma del Pulmón , Animales , Bronquiolos/metabolismo , Bronquiolos/patología , Proliferación Celular , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Proteínas Fluorescentes Verdes/metabolismo , Hiperplasia , Péptidos y Proteínas de Señalización Intercelular , Neoplasias Pulmonares/genética , Ratones , Modelos Biológicos , Proteínas Mutantes/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Péptidos/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteína C Asociada a Surfactante Pulmonar , Factores de Transcripción SOXB1/metabolismo , Factores de Tiempo , Transcriptoma/genética , Uteroglobina/metabolismo
9.
Curr Oncol Rep ; 16(3): 374, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24488547

RESUMEN

Open surgical resection via transhiatal or transthoracic, including McKeown, access is the most viable option for curing esophageal cancer; however, the extensive nature of open surgery in both the chest and abdomen results in significant rates of morbidity and mortality. A natural response was the introduction of minimally invasive esophagectomy (MIE) and, later, endoscopic resection. In the hands of experienced surgeons, MIE can achieve equivalent or better perioperative mortality, morbidity, and oncologic outcomes as compared to open surgery. This review starts with an overview of open esophagectomy before delving into the evolving body of evidence on MIE outcomes and practices.


Asunto(s)
Neoplasias Esofágicas/cirugía , Esofagectomía/métodos , Neoplasias Esofágicas/mortalidad , Esofagoscopía , Medicina Basada en la Evidencia , Humanos , Laparoscopía/métodos , Calidad de Vida , Robótica
10.
J Laparoendosc Adv Surg Tech A ; 34(4): 291-298, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38407920

RESUMEN

Background: Esophageal diverticula were traditionally treated with open surgery, which is associated with significant morbidity and mortality rates. Management has shifted to minimally invasive approaches with several advantages. We examine outcomes in patients with esophageal diverticula treated with minimally invasive techniques by a multidisciplinary surgical team at a single center. Materials and Methods: A retrospective review of a prospectively maintained database was performed for patients who underwent minimally invasive surgery for esophageal diverticula at our institution from June 2010 to December 2022. Primary outcomes were 30-day morbidity and mortality rates. Secondary outcomes were symptom resolution, length of stay (LOS), readmission, and need for reintervention. Results: A total of 28 patients were identified. Twelve patients had pharyngeal diverticula, 7 patients had midesophageal diverticula, and 9 patients had epiphrenic diverticula. Thirty-day morbidity and readmission rates were 10.7% (3 patients), 1 pharyngeal (sepsis), 1 midesophageal (refractory nausea), and 1 epiphrenic (poor oral intake). There were no esophageal leaks. Average LOS was 2.3 days, with the pharyngeal group experiencing a significantly shorter LOS (1.3 days versus 3.4 days for midesophageal, P < .01 versus 2.8 days for epiphrenic, P < .05). Symptom resolution after initial operation was 78.6%. Reintervention rate was 17.9%, and symptom resolution after reintervention was 100%. There were no mortalities. Conclusion: This study demonstrates that esophageal diverticula can be repaired safely and efficiently when performed by a multidisciplinary team utilizing advanced minimally invasive endoscopic and robotic surgical techniques. We advocate for the management of this rare condition at a high-volume center with extensive experience in foregut surgery.


Asunto(s)
Divertículo Esofágico , Laparoscopía , Humanos , Fundoplicación/métodos , Divertículo Esofágico/cirugía , Esófago/cirugía , Laparoscopía/métodos , Procedimientos Quirúrgicos Mínimamente Invasivos/métodos
12.
J Carcinog ; 12: 6, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23599688

RESUMEN

Lung cancer is the leading cause of cancer deaths worldwide, and current therapies are disappointing. Elucidation of the cell(s) of origin of lung cancer may lead to new therapeutics. In addition, the discovery of putative cancer-initiating cells with stem cell properties in solid tumors has emerged as an important area of cancer research that may explain the resistance of these tumors to currently available therapeutics. Progress in our understanding of normal tissue stem cells, tumor cell of origin, and cancer stem cells has been hampered by the heterogeneity of the disease, the lack of good in vivo transplantation models to assess stem cell behavior, and an overall incomplete understanding of the epithelial stem cell hierarchy. As such, a systematic computerized literature search of the MEDLINE database was used to identify articles discussing current knowledge about normal lung and lung cancer stem cells or progenitor cells. In this review, we discuss what is currently known about the role of cancer-initiating cells and normal stem cells in the development of lung tumors.

13.
Ann Thorac Surg ; 115(1): 43-49, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36404445

RESUMEN

The Society of Thoracic Surgeons General Thoracic Surgery Database (STS GTSD) remains the largest and most robust thoracic surgical database in the world. Participating sites receive risk-adjusted performance reports for benchmarking and quality improvement initiatives. The GTSD also provides several mechanisms for high-quality clinical research using data from 274 participant sites and 781,000 procedures since its inception in 2002. Participant sites are audited at random annually for completeness and accuracy. Over the last year and a half, the GTSD Task Force continued to refine the data collection process, implementing an updated data collection form in July 2021, ensuring high data fidelity while minimizing data entry burden. In addition, the STS Workforce on National Databases has supported a robust GTSD-based research program, which led to eight scholarly publications in 2021. This report provides an update on volume trends, outcomes, and database initiatives as well as a summary of research productivity resulting from the GTSD over the preceding year.


Asunto(s)
Cirujanos , Cirugía Torácica , Procedimientos Quirúrgicos Torácicos , Humanos , Sociedades Médicas , Mejoramiento de la Calidad , Bases de Datos Factuales
14.
Cancer Res Commun ; 3(11): 2400-2411, 2023 11 24.
Artículo en Inglés | MEDLINE | ID: mdl-37882674

RESUMEN

We have previously identified alveolar type II cell as the cell-of-origin of KrasG12D-induced lung adenocarcinoma using cell lineage-specific inducible Cre mouse models. Using gain-of-function and loss-of-function genetic models, we discovered that active Notch signaling and low Sox2 levels dictate the ability of type II cells to proliferate and progress into lung adenocarcinoma upon KrasG12D activation. Here, we examine the phenotype of type II cells after Kras activation and find evidence for proliferation of cells that coexpress type I and type II markers. Three-dimensional organoid culture and transplantation studies determine that these dual-positive cells are highly plastic and tumor initiating in vivo. RNA sequencing analysis reveals that these dual-positive cells are enriched in Ras/MAPK, EGFR, and Notch pathways. Furthermore, the proliferation of these cells requires active Notch signaling and is inhibited by genetic/chemical Sox2 upregulation. Our findings could provide new therapeutic strategies to target KRAS-activated lung adenocarcinomas. SIGNIFICANCE: Identification of progenitor like tumor-initiating cells in KRAS-mutant lung adenocarcinoma may allow development of novel targeted therapeutics.


Asunto(s)
Adenocarcinoma del Pulmón , Adenocarcinoma , Neoplasias Pulmonares , Ratones , Animales , Proteínas Proto-Oncogénicas p21(ras)/genética , Adenocarcinoma/genética , Neoplasias Pulmonares/genética , Plasticidad de la Célula , Proliferación Celular/genética , Adenocarcinoma del Pulmón/genética
15.
Ann Surg ; 256(3): 487-93, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-22868367

RESUMEN

OBJECTIVE: Using a national database, we asked whether video-assisted thoracoscopic surgery (VATS) lobectomy is beneficial in high-risk pulmonary patients. BACKGROUND: Single-institution series demonstrated benefit of VATS lobectomy over lobectomy via thoracotomy in poor pulmonary function patients [FEV1 (forced expiratory volume in 1 second) or DLCO (diffusion capacity of the lung to carbon monoxide) <60% predicted]. METHODS: The STS General Thoracic Database was queried for patients having undergone lobectomy by either thoracotomy or VATS between 2000 and 2010. Postoperative pulmonary complications included those defined by the STS database. RESULTS: In the STS database, 12,970 patients underwent lobectomy (thoracotomy, n = 8439; VATS, n = 4531) and met inclusion criteria. The overall rate of pulmonary complications was 21.7% (1832/8439) and 17.8% (806/4531) in patients undergoing lobectomy with thoracotomy and VATS, respectively (P < 0.0001). In a multivariable model of pulmonary complications, thoracotomy approach (OR = 1.25, P < 0.001), decreasing FEV1% predicted (OR = 1.01 per unit, P < 0.001) and DLCO% predicted (OR = 1.01 per unit, P < 0.001), and increasing age (1.02 per year, P < 0.001) independently predicted pulmonary complications. When examining pulmonary complications in patients with FEV1 less than 60% predicted, thoracotomy patients have markedly increased pulmonary complications when compared with VATS patients (P = 0.023). No significant difference is noted with FEV1 more than 60% predicted. CONCLUSIONS: Poor pulmonary function predicts respiratory complications regardless of approach. Respiratory complications increase at a significantly greater rate in lobectomy patients with poor pulmonary function after thoracotomy compared with VATS. Planned surgical approach should be considered while determining whether a high-risk patient is an appropriate resection candidate.


Asunto(s)
Neoplasias Pulmonares/cirugía , Neumonectomía/métodos , Cirugía Torácica Asistida por Video , Factores de Edad , Anciano , Bases de Datos Factuales , Femenino , Volumen Espiratorio Forzado , Humanos , Modelos Logísticos , Neoplasias Pulmonares/fisiopatología , Masculino , Persona de Mediana Edad , Análisis Multivariante , Complicaciones Posoperatorias/epidemiología , Factores de Riesgo , Sociedades Médicas , Toracotomía , Resultado del Tratamiento , Estados Unidos
16.
Proc Natl Acad Sci U S A ; 106(31): 12771-5, 2009 Aug 04.
Artículo en Inglés | MEDLINE | ID: mdl-19625615

RESUMEN

The pseudostratified epithelium of the mouse trachea and human airways contains a population of basal cells expressing Trp-63 (p63) and cytokeratins 5 (Krt5) and Krt14. Using a KRT5-CreER(T2) transgenic mouse line for lineage tracing, we show that basal cells generate differentiated cells during postnatal growth and in the adult during both steady state and epithelial repair. We have fractionated mouse basal cells by FACS and identified 627 genes preferentially expressed in a basal subpopulation vs. non-BCs. Analysis reveals potential mechanisms regulating basal cells and allows comparison with other epithelial stem cells. To study basal cell behaviors, we describe a simple in vitro clonal sphere-forming assay in which mouse basal cells self-renew and generate luminal cells, including differentiated ciliated cells, in the absence of stroma. The transcriptional profile identified 2 cell-surface markers, ITGA6 and NGFR, which can be used in combination to purify human lung basal cells by FACS. Like those from the mouse trachea, human airway basal cells both self-renew and generate luminal daughters in the sphere-forming assay.


Asunto(s)
Pulmón/citología , Células Madre/citología , Tráquea/citología , Animales , Proliferación Celular , Células Cultivadas , Femenino , Perfilación de la Expresión Génica , Humanos , Masculino , Ratones , Análisis de Secuencia por Matrices de Oligonucleótidos , Receptor de Factor de Crecimiento Nervioso/análisis , Tráquea/metabolismo
17.
Semin Thorac Cardiovasc Surg ; 34(2): 737-746, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-33984482

RESUMEN

To develop a new approach for identifying acute lung injury (ALI) in surgical ward setting and to assess incidence rate, clinical outcomes, and risk factors for ALI cases after esophagectomy. We also compare the degree of lung injury between operative and non-operative sides. Consecutive esophageal cancer patients (n=1022) who underwent esophagectomy from Dec 2012 to Nov 2018 in our hospital were studied. An approach for identifying ALI was proposed that integrated radiographic assessment of lung edema (RALE) score to quantify degree of lung edema. Stepwise logistic regression identified risk factors for postoperative ALI incidence. The degree of bilateral lung injury was compared using the RALE score. The approach for identifying ALI in surgical ward setting was defined as acute onset, PaO2/FiO2≤300 mmHg, bilateral opacities on bedside chest radiograph with a RALE score≥16, and exclusion of cardiogenic pulmonary edema. Incidence rate of ALI was estimated to be 9.7%. ALI diagnosis was associated with multiple clinical complications, prolonged hospital stay, higher medical bills, and higher perioperative mortality. Nine risk factors including BMI, ASA class, DLCO%, duration of surgery, neutrophil percentage, high-density lipoprotein, and electrolyte disorders were identified. The RALE score of the lung lobes of the operative side was higher than the non-operative side. A new approach for identifying ALI in esophageal cancer patients receiving esophagectomy was proposed and several risk factors were identified. ALI is common and has severe outcomes. The lung lobes on the operative side are more likely to be affected than the non-operative side.


Asunto(s)
Lesión Pulmonar Aguda , Neoplasias Esofágicas , Edema Pulmonar , Síndrome de Dificultad Respiratoria , Lesión Pulmonar Aguda/diagnóstico por imagen , Lesión Pulmonar Aguda/epidemiología , Lesión Pulmonar Aguda/etiología , Edema/complicaciones , Edema/cirugía , Neoplasias Esofágicas/complicaciones , Neoplasias Esofágicas/diagnóstico por imagen , Neoplasias Esofágicas/cirugía , Esofagectomía/efectos adversos , Humanos , Edema Pulmonar/diagnóstico por imagen , Edema Pulmonar/epidemiología , Edema Pulmonar/etiología , Ruidos Respiratorios/etiología , Resultado del Tratamiento
18.
Nat Commun ; 13(1): 2965, 2022 05 26.
Artículo en Inglés | MEDLINE | ID: mdl-35618699

RESUMEN

Development of the gastrointestinal system occurs after gut tube closure, guided by spatial and temporal control of gene expression. However, it remains unclear what forces regulate these spatiotemporal gene expression patterns. Here we perform single-cell chromatin profiling of the primitive gut tube to reveal organ-specific chromatin patterns that reflect the anatomical patterns of distinct organs. We generate a comprehensive map of epigenomic changes throughout gut development, demonstrating that dynamic chromatin accessibility patterns associate with lineage-specific transcription factor binding events to regulate organ-specific gene expression. Additionally, we show that loss of Sox2 and Cdx2, foregut and hindgut lineage-specific transcription factors, respectively, leads to fate shifts in epigenomic patterns, linking transcription factor binding, chromatin accessibility, and lineage fate decisions in gut development. Notably, abnormal expression of Sox2 in the pancreas and intestine impairs lineage fate decisions in both development and adult homeostasis. Together, our findings define the chromatin and transcriptional mechanisms of organ identity and lineage plasticity in development and adult homeostasis.


Asunto(s)
Cromatina , Gástrula , Adulto , Cromatina/genética , Endodermo , Epigenómica , Humanos , Factores de Transcripción
19.
JTO Clin Res Rep ; 3(12): 100427, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-36426286

RESUMEN

Introduction: There is a paucity of data on immune checkpoint inhibitors (ICIs) plus doublet chemotherapy (C) in patients with advanced lung cancer whose tumor harbors an actionable mutation. We sought to provide insight into the role of this combination in relation to chemotherapy alone in this patient population. Methods: We conducted a retrospective study at the five University of California National Cancer Institute-designated Comprehensive Cancer Centers. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS) and significant adverse events. Adverse events in patients who received a tyrosine kinase inhibitor (TKI) post-ICI were also captured. Results: A total of 246 patients were identified, 170 treated with C plus ICI and 76 treated with C alone. Driver alterations included EGFR (54.9%), KRAS (32.9%), ALK (5.3%), HER2/ERBB2 (2.9%), ROS1 (1.2%), MET (1.2%), RET (0.8%), and BRAF non-V600 (0.8%). The overall PFS and OS hazard ratios were not significant at 1.12 (95% confidence interval 0.83-1.51; p = 0.472) and 0.86 (95% confidence interval: 0.60-1.24, p = 0.429), respectively. No significant differences in PFS or OS were observed in the mutational subgroups. Grade 3 or greater adverse events were lower in the C plus ICI group. The multivariate analysis for PFS and OS revealed a performance status (Eastern Cooperative Oncology Group) score of 2, and previous TKI treatment was associated with poorer outcomes with C plus ICI. Conclusions: Our study suggests that patients with oncogenic-driven NSCLC, primarily those with EGFR-driven tumors, treated with a TKI should not subsequently receive C plus ICI. Analysis from prospective clinical trials will provide additional information on the role of ICIs in this group of patients.

20.
Thorac Surg Clin ; 21(3): 369-77, 2011 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-21762860

RESUMEN

The incorporation of research into a career in thoracic surgery is a complex process. Ideally, the preparation for a career in academic thoracic surgery begins with a research fellowship during training. In the academic setting, a research portfolio might include clinical research, translational research, or basic research. Using strategies for developing collaboration, thoracic surgeons in community-based programs may also be successful clinical investigators. In addition to the rigors of conducting research, strategies for reserving protected time and obtaining grant support must be considered to be successful in academic surgery.


Asunto(s)
Investigación Biomédica , Cirugía Torácica , Bases de Datos Factuales , Becas , Humanos , Mentores , Apoyo a la Investigación como Asunto , Investigación Biomédica Traslacional
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