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1.
Ann Surg ; 274(6): e980-e987, 2021 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-31804389

RESUMEN

OBJECTIVE: To evaluate the influence of consensus guidelines on the management of intraductal papillary mucinous neoplasms (IPMN) and the subsequent changes in pathologic outcomes. BACKGROUND: Over time, multiple guidelines have been developed to identify high-risk IPMN. We hypothesized that the development and implementation of guidelines should have increased the percentage of resected IPMN with high-risk disease. METHODS: Memorial Sloan-Kettering (MSK), Johns Hopkins (JH), and Massachusetts General Hospital (MGH) databases were queried for resected IPMN (2000-2015). Patients were categorized into main-duct (MD-IPMN) versus branch-duct (BD-IPMN). Guideline-specific radiographic/endoscopic features were recorded. High-risk disease was defined as high-grade dysplasia/carcinoma. Fisher's exact test was used to detect differences between institutions. Logistic regression evaluated differences between time-points [preguidelines (pre-GL, before 2006), Sendai (SCG, 2006-2012), Fukuoka (FCG, after 2012)]. RESULTS: The study included 1210 patients. The percentage of BD-IPMN with ≥1 high-risk radiographic feature differed between centers (MSK 69%, JH 60%, MGH 45%; P < 0.001). In MD-IPMN cohort, the presence of radiographic features such as solid component and main pancreatic duct diameter ≥10 mm also differed (solid component: MSK 38%, JH 30%, MGH 18%; P < 0.001; duct ≥10 mm: MSK 49%, JH 32%, MGH 44%; P < 0.001). The percentage of high-risk disease on pathology, however, was similar between institutions (BD-IPMN: P = 0.36, MD-IPMN: P = 0.48). During the study period, the percentage of BD-IPMN resected with ≥1 high-risk feature increased (52% pre-GL vs 67% FCG; P = 0.005), whereas the percentage of high-risk disease decreased (pre-GL vs FCG: 30% vs 20%). For MD-IPMN, there was not a clear trend towards guideline adherence, and the rate of high-risk disease was similar over the time (pre-GL vs FCG: 69% vs 67%; P = 0.63). CONCLUSION: Surgical management of IPMN based on radiographic criteria is variable between institutions, with similar percentages of high-risk disease. Over the 15-year study period, the rate of BD-IPMN resected with high-risk radiographic features increased; however, the rate of high-risk disease decreased. Better predictors are needed.


Asunto(s)
Adenocarcinoma Mucinoso/cirugía , Adenocarcinoma Papilar/cirugía , Carcinoma Ductal Pancreático/cirugía , Neoplasias Pancreáticas/cirugía , Guías de Práctica Clínica como Asunto , Adenocarcinoma Mucinoso/diagnóstico por imagen , Adenocarcinoma Mucinoso/patología , Adenocarcinoma Papilar/diagnóstico por imagen , Adenocarcinoma Papilar/patología , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Ductal Pancreático/diagnóstico por imagen , Carcinoma Ductal Pancreático/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Neoplasias Pancreáticas/diagnóstico por imagen , Neoplasias Pancreáticas/patología
2.
Cancer ; 126(17): 3939-3949, 2020 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-32573775

RESUMEN

BACKGROUND: KRAS, TP53, CDKN2A, and SMAD4 are established driver genes in pancreatic ductal adenocarcinoma (PDAC). This study was aimed at determining whether the mutational status of driver genes and those involved in DNA repair pathways are associated with clinical outcomes for individuals who undergo resection. METHODS: Eligible individuals were those who underwent resection of PDAC and consented to targeted sequencing of their primary tumor via Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT). Genomic alterations were determined on the basis of MSK-IMPACT results from formalin-fixed, paraffin-embedded samples. Associations between genomic alterations and clinical outcomes were assessed. RESULTS: Targeted sequencing was performed on 283 primary tumors resected between 2004 and 2017. The median follow-up was 23 months among survivors. Alterations in KRAS and TP53 were associated with worse overall survival (OS) in comparison to wild type (median for KRAS, 38.8 months [95% CI, 33.0-45.5 months] vs 91.0 months [95% CI, 34.8 months to not available (NA)]; P = .043; median for TP53, 37.4 months [95% CI, 32.1-42.8 months] vs 65.0 months [95% CI, 33.0 months to NA]; P = .035). KRAS G12D mutations were associated with worse OS (median, 31.6 months [95% CI, 25.3-45.5 months] vs 39.2 months [95% CI, 37.4-75.2 months]; P = .012). TP53 truncating mutations (median, 39.6 months [95% CI, 32.4-75.2 months] vs 33.9 months [95% CI, 24.0-39.0 months]; P = .020) and those associated with loss of heterozygosity (median, 26.6 months [95% CI, 21.6-44.2 months] vs 39.2 months [95% CI, 34.5-49.1 months]; P = .048) had decreased OS. TP53 alterations were independently associated with OS in a multivariate analysis (hazard ratio, 1.54; 95% CI, 1.01-2.33; P = .042). Individuals with germline alterations in homologous recombination deficiency (HRD) genes had improved OS in comparison with those without them (median, not reached vs 37.0 months; 95% CI, 33.0-49.8 months; P = .035). CONCLUSIONS: In patients with resected PDAC, genomic alterations in KRAS and TP53 are associated with worse outcomes, whereas alterations in HRD genes are associated with a favorable prognosis. Further studies are needed to better define these alterations as biomarkers in resected PDAC.


Asunto(s)
Adenocarcinoma/cirugía , Carcinoma Ductal Pancreático/cirugía , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteína Smad4/genética , Proteína p53 Supresora de Tumor/genética , Adenocarcinoma/epidemiología , Adenocarcinoma/genética , Adenocarcinoma/patología , Adulto , Anciano , Biomarcadores de Tumor/genética , Carcinoma Ductal Pancreático/epidemiología , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patología , Humanos , Masculino , Persona de Mediana Edad , Mutación/genética , Pancreatectomía/efectos adversos , Pronóstico , Supervivencia sin Progresión , Resultado del Tratamiento
3.
Transpl Infect Dis ; 21(3): e13085, 2019 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-30925010

RESUMEN

BACKGROUND: Invasive fungal infections (IFI) are common after lung transplantation with reported incidence of 8.1% to 16% at 12 months post-transplant, and 3-month all-cause mortality after IFI of 21.7%. METHODS: We performed a retrospective study of IFI and fungal colonization in lung transplants (LTs) from November 2004 to February 2017. RESULTS: 137 LTs were followed for a median 4.1 years (IQR 2.1-6.2 years). In addition to nebulized amphotericin for the transplant admission to all LTs, systemic mold-active azole was given to 80/130 (61.5%) LTs in the first 6 months post-transplant, 57/121 (47.1%) in the period 6-12 months after transplant, and 93/124 (75%) in the period more than 12 months post-transplant. Mold airways colonization was found in 81 (59.1%) LTs before and 110 (80.3%) LTs after transplantation. There were 13 IFIs for an overall incidence of 2.1 per 100 person-years, occurring at a median 583 days (IQR 182-1110 days) post-transplant, a cumulative incidence of 3.8% at 1 year, 7.6% at 3 years and 10.1% at 5 years post-transplant. All-cause 3-month mortality after IFI was 7.7%. Aspergillus species followed by Scedosporium apiospermum and Cryptococcus species were the commonest fungi causing IFI. CONCLUSIONS: In our cohort the rate of IFI was comparatively low, likely because of comprehensive early antifungal use and preemptive therapy at any time after transplant. Prospective studies of fungal colonization late after LT are required to determine the risks and benefits of watchful waiting compared to preemptive therapy.


Asunto(s)
Infecciones Fúngicas Invasoras/epidemiología , Trasplante de Pulmón/efectos adversos , Receptores de Trasplantes/estadística & datos numéricos , Adulto , Antifúngicos/uso terapéutico , Aspergilosis/epidemiología , Aspergillus/aislamiento & purificación , Criptococosis/epidemiología , Cryptococcus/aislamiento & purificación , Femenino , Humanos , Incidencia , Infecciones Fúngicas Invasoras/tratamiento farmacológico , Infecciones Fúngicas Invasoras/mortalidad , Trasplante de Pulmón/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Estudios Retrospectivos , Factores de Riesgo , Australia Occidental/epidemiología
4.
Transpl Infect Dis ; 21(3): e13069, 2019 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-30884067

RESUMEN

BACKGROUND: Lung transplantation has a high risk of cytomegalovirus (CMV) viremia and disease. METHODS: Valganciclovir was planned for 6 months in CMV recipient seropositive (R+) lung transplants (LTs) and given long-term in D+R- LTs. CMV viremia was monitored regularly during and after prophylaxis in all patients. RESULTS: Of 137 LTs, 22 were D+R-, 49 D+R+, 43 D-R+, and 23 D-R-, with median follow up 4.1 years (IQR 2.1-6.2 years). CMV viremia at any time occurred in 44.5% of LTs. CMV viral load >103  c/mL was uncommon (9/77 episodes). CMV viremia occurred at median 665 days (IQR 271-1411 days), in 5.1% LTs <6 months, 20.3% LTs 6-12 months, and 35.8% LTs >12 months. CMV disease occurred in 6 (4.4%) LTs at an overall rate of 1.0 episode per 100 person-years: two of these cases were organ-specific disease, four were CMV syndrome. One case of ganciclovir-resistant CMV was diagnosed. D+R+ and D+R- LTs had higher viremia rates than the D-R+ group. No viremia occurred in D-R- LTs. CMV viremia was not associated with age, gender, type of LT, indication for LT, acute rejection, bronchiolitis obliterans syndrome, or mortality. CONCLUSIONS: Prophylaxis for 6 months in D+R+ and D-R+, and past 12 months in D+R- LTs, with long-term monitoring in all patients using a sensitive assay, and reinstitution of valganciclovir for low-level viremia was effective at markedly reducing the incidence of CMV disease. CMV D-R- LTs do not need routine CMV monitoring.


Asunto(s)
Antivirales/uso terapéutico , Infecciones por Citomegalovirus/tratamiento farmacológico , Trasplante de Pulmón/efectos adversos , Viremia/tratamiento farmacológico , Adulto , Australia , Citomegalovirus , Infecciones por Citomegalovirus/prevención & control , Femenino , Ganciclovir/uso terapéutico , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Valganciclovir/uso terapéutico , Carga Viral/efectos de los fármacos , Viremia/prevención & control
5.
Intern Med J ; 48(11): 1337-1345, 2018 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-29923278

RESUMEN

BACKGROUND: The Western Australian lung transplant programme commenced in 2004 to serve the growing demand of patients with end-stage lung disease. AIM: This report summarises our 11-year experience in lung transplantation. METHODS: Data on 115 consecutive patients and their respective donors transplanted between 2004 and 2015 were collected. The Kaplan-Meier method was used to estimate survival. Cox regression was used to analyse the impact of donor and recipient characteristics on survival. RESULTS: A total of 88 bilateral, 22 single-lung and 5 heart-lung transplants were performed in Western Australia during the first 11 years of the lung transplant programme. The most common indications for transplantation were interstitial lung disease (30.4%), cystic fibrosis (27.8%) and chronic obstructive pulmonary disease (excluding alpha-1 antitrypsin deficiency) (22.6%). Median recipient age was 50 years. Overall survival rates were 96% at 3 months, 93% at 1 year, 84% at 3 years and 70% at 5 years. Older age and higher BMI negatively impacted survival. Chronic lung allograft dysfunction was the leading cause of late mortality. CONCLUSION: Lung transplantation is a treatment option in end-stage lung disease, with annual transplant rates in Western Australia continuing to rise. Our patients enjoy survival rates that compare favourably against international standards.


Asunto(s)
Trasplante de Pulmón/mortalidad , Donantes de Tejidos/estadística & datos numéricos , Receptores de Trasplantes/estadística & datos numéricos , Adulto , Factores de Edad , Índice de Masa Corporal , Fibrosis Quística/cirugía , Femenino , Humanos , Estimación de Kaplan-Meier , Enfermedades Pulmonares Intersticiales/cirugía , Trasplante de Pulmón/métodos , Masculino , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Enfermedad Pulmonar Obstructiva Crónica/cirugía , Sistema de Registros , Factores de Tiempo , Australia Occidental/epidemiología , Adulto Joven
6.
Ann Surg ; 266(3): 536-544, 2017 09.
Artículo en Inglés | MEDLINE | ID: mdl-28657939

RESUMEN

OBJECTIVE: In 2015, the American Gastroenterological Association recommended the discontinuation of radiographic surveillance after 5 years for patients with stable pancreatic cysts. The current study evaluated the yield of continued surveillance of pancreatic cysts up to and after 5 years of follow up. METHODS: A prospectively maintained registry of patients evaluated for pancreatic cysts was queried (1995-2016). Patients who initially underwent radiographic surveillance were divided into those with <5 years and ≥5 years of follow up. Analyses for the presence of cyst growth (>5 mm increase in diameter), cross-over to resection, and development of carcinoma were performed. RESULTS: A total of 3024 patients were identified, with 2472 (82%) undergoing initial surveillance. The ≥5 year group (n = 596) experienced a greater frequency of cyst growth (44% vs. 20%; P < 0.0001), a lower rate of cross-over to resection (8% vs 11%; P = 0.02), and a similar frequency of progression to carcinoma (2% vs 3%; P = 0.07) compared with the <5 year group (n = 1876). Within the ≥5 year group, 412 patients (69%) had demonstrated radiographic stability at the 5-year time point. This subgroup, when compared with the <5 year group, experienced similar rates of cyst growth (19% vs. 20%; P= 0.95) and lower rates of cross-over to resection (5% vs 11%; P< 0.0001) and development of carcinoma (1% vs 3%; P= 0.008). The observed rate of developing cancer in the group that was stable at the 5-year time point was 31.3 per 100,000 per year, whereas the expected national age-adjusted incidence rate for this same group was 7.04 per 100,000 per year. CONCLUSION: Cyst size stability at the 5-year time point did not preclude future growth, cross-over to resection, or carcinoma development. Patients who were stable at 5 years had a nearly 3-fold higher risk of developing cancer compared with the general population and should continue long-term surveillance.


Asunto(s)
Cuidados Posteriores/métodos , Quiste Pancreático/diagnóstico por imagen , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Quiste Pancreático/patología , Quiste Pancreático/cirugía , Neoplasias Pancreáticas/diagnóstico por imagen , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/cirugía , Lesiones Precancerosas/diagnóstico por imagen , Lesiones Precancerosas/patología , Lesiones Precancerosas/cirugía , Radiografía , Sistema de Registros , Estudios Retrospectivos , Adulto Joven
7.
Am J Hum Biol ; 24(1): 68-73, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22131202

RESUMEN

OBJECTIVE: Brachymesophalangia-V (BMP-V), the general term for a short and broad middle phalanx of the 5th digit, presents both alone and in a large number of complex brachydactylies and developmental disorders. Past anthropological and epidemiological studies of growth and development have examined the prevalence of BMP-V because small developmental disorders may signal more complex disruptions of skeletal growth and development. Historically, however, consensus on qualitative phenotype methodology has not been established. In large-scale, non-clinical studies such as the Fels Longitudinal Study and the Jiri Growth Study, quantitative assessment of the hand is not always the most efficient manner of screening for skeletal dysmorphologies. The current study evaluates qualitative phenotyping techniques for BMP-V used in past anthropological studies of growth and development to establish a useful and reliable screening method for large study samples. METHODS: A total of 1,360 radiographs from Jiri Growth Study participants aged 3-18 years were evaluated. BMP-V was assessed using three methods: (1) subjective evaluation of length and width of the bone; (2) comparison with skeletal age-matched radiographs; and (3) subjective evaluation of the length of the middle 4th and 5th phalanges. RESULTS: We found that the method that uses skeletal age-matched reference radiographs is the better tool for assessing BMP-V because it considers the shape, rather than solely the length and width of the bone, which can be difficult to judge accurately without measurement. This study highlights the complexity of phenotypic assessment of BMP-V and by extension other brachydactylies.


Asunto(s)
Antropometría/métodos , Braquidactilia/diagnóstico por imagen , Falanges de los Dedos de la Mano/anomalías , Dedos/anomalías , Adolescente , Braquidactilia/epidemiología , Niño , Preescolar , Femenino , Falanges de los Dedos de la Mano/diagnóstico por imagen , Dedos/diagnóstico por imagen , Humanos , Estudios Longitudinales , Masculino , Nepal/epidemiología , Fenotipo , Prevalencia , Radiografía
8.
Nephrology (Carlton) ; 17 Suppl 1: 12-5, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22497648

RESUMEN

We report a 29 year old male cystic fibrosis patient with end stage lung disease and normal renal function who underwent a sequential double lung transplant. Medical history included: an ileal resection and pancreatic exocrine dysfunction. The postoperative period was complicated with haemorrhage and repeat surgery, requiring multiple blood transfusions and extensive antibiotic cover. Pancreatic supplements were interrupted. Acute renal failure attributed to haemodynamically-mediated acute tubular necrosis was managed expectantly. He remained dialysis dependent 8 weeks post surgery and was maintained on triple immunosuppression with tacrolimus, mycophenolate and prednisolone. A DTPA study was consistent with ATN. Renal biopsy revealed features consistent with tubular injury due to acute oxalate nephropathy (AON). Further biochemical characterization excluded primary hyperoxaluria but confirmed increased 24 hour urinary oxalate. He was maintained on enhanced frequency HDF and subsequently received an uncomplicated live related renal transplant 10 months post lung transplant with only additional basiliximab. Calcium carbonate was continued to manage post transplant hyperoxaluria and an early renal biopsy excluded recurrent oxalate injury. Enteric hyperoxaluria due to malabsorption in patients with CF especially with ileal resection, in addition to loss of gut Oxalobacter formigenes due to prolonged antimicrobials, increases the risk of AON. Increased awareness of this condition and screening prior to lung transplant is recommended.


Asunto(s)
Fibrosis Quística/cirugía , Hiperoxaluria/etiología , Enfermedades Renales/cirugía , Trasplante de Riñón , Trasplante de Pulmón/efectos adversos , Adulto , Antiinfecciosos/efectos adversos , Biomarcadores/orina , Biopsia , Humanos , Hiperoxaluria/orina , Íleon/metabolismo , Íleon/microbiología , Íleon/cirugía , Inmunosupresores/uso terapéutico , Absorción Intestinal , Enfermedades Renales/diagnóstico , Enfermedades Renales/etiología , Enfermedades Renales/orina , Donadores Vivos , Masculino , Oxalatos/orina , Oxalobacter formigenes/efectos de los fármacos , Oxalobacter formigenes/metabolismo , Reoperación , Factores de Riesgo , Resultado del Tratamiento
9.
JCO Clin Cancer Inform ; 5: 679-694, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-34138636

RESUMEN

PURPOSE: The therapeutic management of pancreatic neuroendocrine tumors (PanNETs) is based on pathological tumor grade assessment. A noninvasive imaging method to grade tumors would facilitate treatment selection. This study evaluated the ability of quantitative image analysis derived from computed tomography (CT) images to predict PanNET grade. METHODS: Institutional database was queried for resected PanNET (2000-2017) with a preoperative arterial phase CT scan. Radiomic features were extracted from the primary tumor on the CT scan using quantitative image analysis, and qualitative radiographic descriptors were assessed by two radiologists. Significant features were identified by univariable analysis and used to build multivariable models to predict PanNET grade. RESULTS: Overall, 150 patients were included. The performance of models based on qualitative radiographic descriptors varied between the two radiologists (reader 1: sensitivity, 33%; specificity, 66%; negative predictive value [NPV], 63%; and positive predictive value [PPV], 37%; reader 2: sensitivity, 45%; specificity, 70%; NPV, 72%; and PPV, 47%). The model based on radiomics had a better performance predicting the tumor grade with a sensitivity of 54%, a specificity of 80%, an NPV of 81%, and a PPV of 54%. The inclusion of radiomics in the radiographic descriptor models improved both the radiologists' performance. CONCLUSION: CT quantitative image analysis of PanNETs helps predict tumor grade from routinely acquired scans and should be investigated in future prospective studies.


Asunto(s)
Neoplasias Pancreáticas , Tomografía Computarizada por Rayos X , Humanos , Procesamiento de Imagen Asistido por Computador , Neoplasias Pancreáticas/diagnóstico por imagen , Valor Predictivo de las Pruebas
10.
Abdom Radiol (NY) ; 46(4): 1607-1617, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-32986175

RESUMEN

PURPOSE: To evaluate the associations between computed tomography (CT) imaging features extracted from the structured American Pancreatic Association (APA)/Society of Abdominal Radiology (SAR) template and overall survival in patients with resected pancreatic ductal adenocarcinoma (PDAC). METHODS: This retrospective analysis included consecutive patients with PDAC who consented to genomic tumor testing and underwent preoperative imaging and curative intent surgical resection from December 2006 to July 2017. Two radiologists assessed preoperative CT imaging using the APA/SAR PDAC-reporting template. Univariable associations between overall survival and imaging variables were evaluated using Cox proportional hazards regression. RESULTS: The study included 168 patients (66 years ± 11; 91 women). 126/168 patients (75%) received upfront surgical resection whereas 42/168 (25%) received neoadjuvant therapy prior to surgical resection. In the entire cohort, features associated with decreased overall survival were tumor arterial contact of any kind (hazard ratio (HR) 1.89, 95% CI 1.13-3.14, p = 0.020), tumor contact with the common hepatic artery (HR 2.33, 95% CI 1.35-4.04, p = 0.009), and portal vein deformity (HR 3.22, 95% CI 1.63-6.37, p = 0.003). In the upfront surgical group, larger tumor size was associated with decreased overall survival (HR 2.30, 95% CI 1.19-4.42, p = 0.013). In the neoadjuvant therapy group, the presence of venous collaterals was the only feature associated with decreased overall survival (HR 2.28, 95% CI 1.04-4.99, p = 0.042). CONCLUSION: The application of the APA/SAR pancreatic adenocarcinoma reporting template may identify predictors of survival that can aid in preoperative stratification of patients.


Asunto(s)
Adenocarcinoma , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Adenocarcinoma/diagnóstico por imagen , Adenocarcinoma/cirugía , Carcinoma Ductal Pancreático/diagnóstico por imagen , Carcinoma Ductal Pancreático/cirugía , Femenino , Humanos , Neoplasias Pancreáticas/diagnóstico por imagen , Neoplasias Pancreáticas/cirugía , Pronóstico , Estudios Retrospectivos , Tomografía Computarizada por Rayos X
11.
J Med Imaging (Bellingham) ; 7(3): 031507, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-32613028

RESUMEN

Purpose: Our paper contributes to the burgeoning field of surgical data science. Specifically, multimodal integration of relevant patient data is used to determine who should undergo a complex pancreatic resection. Intraductal papillary mucinous neoplasms (IPMNs) represent cystic precursor lesions of pancreatic cancer with varying risk for malignancy. We combine previously defined individual models of radiomic analysis of diagnostic computed tomography (CT) with protein markers extracted from the cyst fluid to create a unified prediction model to identify high-risk IPMNs. Patients with high-risk IPMN would be sent for resection, whereas patients with low-risk cystic lesions would be spared an invasive procedure. Approach: Retrospective analysis of prospectively acquired cyst fluid and CT scans was undertaken for this study. A predictive model combining clinical features with a cyst fluid inflammatory marker (CFIM) was applied to patient data. Quantitative imaging (QI) features describing radiomic patterns predictive of risk were extracted from scans. The CFIM model and QI model were combined into a single predictive model. An additional model was created with tumor-associated neutrophils (TANs) assessed by a pathologist at the time of resection. Results: Thirty-three patients were analyzed (7 high risk and 26 low risk). The CFIM model yielded an area under the curve (AUC) of 0.74. Adding the QI model improved performance with an AUC of 0.88. Combining the CFIM, QI, and TAN models further increased performance to an AUC of 0.98. Conclusions: Quantitative analysis of routinely acquired CT scans combined with CFIMs provides accurate prediction of risk of pancreatic cancer progression. Although a larger cohort is needed for validation, this model represents a promising tool for preoperative assessment of IPMN.

12.
Cancer Cell ; 38(2): 198-211.e8, 2020 08 10.
Artículo en Inglés | MEDLINE | ID: mdl-32559497

RESUMEN

Pancreatic ductal adenocarcinoma (PDAC) is driven by co-existing mutations in KRAS and TP53. However, how these mutations collaborate to promote this cancer is unknown. Here, we uncover sequence-specific changes in RNA splicing enforced by mutant p53 which enhance KRAS activity. Mutant p53 increases expression of splicing regulator hnRNPK to promote inclusion of cytosine-rich exons within GTPase-activating proteins (GAPs), negative regulators of RAS family members. Mutant p53-enforced GAP isoforms lose cell membrane association, leading to heightened KRAS activity. Preventing cytosine-rich exon inclusion in mutant KRAS/p53 PDACs decreases tumor growth. Moreover, mutant p53 PDACs are sensitized to inhibition of splicing via spliceosome inhibitors. These data provide insight into co-enrichment of KRAS and p53 mutations and therapeutics targeting this mechanism in PDAC.


Asunto(s)
Carcinoma Ductal Pancreático/genética , Mutación , Neoplasias Pancreáticas/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Empalme del ARN , Transducción de Señal/genética , Proteína p53 Supresora de Tumor/genética , Animales , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/terapia , Línea Celular Tumoral , Células Cultivadas , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Estimación de Kaplan-Meier , Ratones Endogámicos C57BL , Ratones Noqueados , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/terapia , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Tratamiento con ARN de Interferencia/métodos , Ensayos Antitumor por Modelo de Xenoinjerto/métodos
13.
Pancreas ; 48(6): 832-836, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-31210665

RESUMEN

OBJECTIVES: Preoperative determination of the grade of dysplasia in intraductal papillary mucinous neoplasms (IPMNs) is necessary for optimal management. Previous data have suggested that serum neutrophil-to-lymphocyte ratio (NLR) can predict invasive disease in patients with IPMN. METHODS: A prospectively maintained database was queried for consecutive patients who underwent resection of IPMN. Exclusion criteria included recent diagnosis of cancer, immunosuppression, and infection or jaundice within 1 month of operation. A complete blood count with differential within 30 days of operation was used to calculate NLR. RESULTS: Within the study period, 446 patients underwent resection for IPMN, and 348 patients (78%) met the inclusion criteria. Low-grade dysplasia was present in 60 patients (17%), 137 patients (39%) had intermediate-grade dysplasia, 76 (22%) had high-grade dysplasia, and 75 (22%) had invasive carcinoma. A higher NLR was associated with invasive carcinoma as compared with noninvasive disease (3.00 vs 2.68, P = 0.039). There was no difference in NLR between patients with high-risk (invasive and high-grade) and low-risk (low-grade and intermediate-grade) lesions (2.80 vs 2.71, P > 0.95). CONCLUSIONS: Neutrophil-to-lymphocyte ratio was significantly higher in patients with IPMN-associated invasive carcinoma as compared with patients with noninvasive disease; however, NLR was not helpful in differentiating between high- and low-grade lesions.


Asunto(s)
Linfocitos/patología , Neutrófilos/patología , Páncreas/cirugía , Pancreatectomía/métodos , Neoplasias Intraductales Pancreáticas/cirugía , Anciano , Recuento de Células Sanguíneas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Páncreas/patología , Neoplasias Intraductales Pancreáticas/sangre , Neoplasias Intraductales Pancreáticas/diagnóstico , Pronóstico , Reproducibilidad de los Resultados , Sensibilidad y Especificidad
14.
J Am Coll Surg ; 228(4): 595-601, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30630087

RESUMEN

BACKGROUND: Pancreaticoduodenectomy is historically associated with incisional surgical site infection (iSSI) rates between 15% and 20%. Prospective studies have been mixed with respect to the benefit of individual interventions directed at decreasing iSSI. We hypothesized that the application of a perioperative bundle during pancreaticoduodenectomy would decrease the rate of iSSIs significantly. METHODS: An initial cohort of 150 consecutive post-pancreaticoduodenectomy patients were assessed within 2 to 4 weeks of operation to determine baseline iSSI rates. The CDC definition of iSSI was used. A 4-part perioperative bundle was then instituted for the second cohort of 150 patients. This bundle consisted of a double-ring wound protector, gown/glove and drape change before fascial closure, irrigation of the wound with bacitracin solution, and a negative-pressure wound dressing that was left in place until postoperative day 7 or day of discharge. Three-hundred patients provided 80% power to detect a 50% risk reduction in iSSIs. RESULTS: Cohorts 1 and 2 were similar with respect to age (68 vs 69 years; p = 0.918), sex (male, 51% vs 55%; p = 0.644), BMI (26 vs 26 kg/m2; p = 0.928), use of neoadjuvant therapy (21% vs 17%; p = 0.377), median operative time (222 vs 215 minutes; p = 0.366), and presence of a preoperative stent (53% vs 41%; p = 0.064). The iSSI rate was 22.3% in the initial cohort. This rate was higher than both our institutional database (13%) and NSQIP reporting (11%). Within the second cohort, the iSSI rate decreased significantly to 10.7% (n = 16; p = 0.012). All 4 components of the bundle were used in 91% of cohort 2 patients. CONCLUSIONS: In this cohort study of 300 consecutive patients who underwent pancreaticoduodenectomy, the implementation of a 4-part bundle decreased iSSI rate from 22% to 11%.


Asunto(s)
Control de Infecciones/métodos , Pancreaticoduodenectomía , Paquetes de Atención al Paciente/métodos , Infección de la Herida Quirúrgica/prevención & control , Adulto , Anciano , Anciano de 80 o más Años , Terapia Combinada , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Infección de la Herida Quirúrgica/epidemiología , Resultado del Tratamiento
15.
Stem Cells Transl Med ; 6(4): 1152-1157, 2017 04.
Artículo en Inglés | MEDLINE | ID: mdl-28186707

RESUMEN

Chronic lung transplant rejection (termed chronic lung allograft dysfunction [CLAD]) is the main impediment to long-term survival after lung transplantation. Bone marrow-derived mesenchymal stromal cells (MSCs) represent an attractive cell therapy in inflammatory diseases, including organ rejection, given their relative immune privilege and immunosuppressive and tolerogenic properties. Preclinical studies in models of obliterative bronchiolitis and human trials in graft versus host disease and renal transplantation suggest potential efficacy in CLAD. The purpose of this phase 1, single-arm study was to explore the feasibility and safety of intravenous delivery of allogeneic MSCs to patients with advanced CLAD. MSCs from unrelated donors were isolated from bone marrow, expanded and cryopreserved in a GMP-compliant facility. Patients had deteriorating CLAD and were bronchiolitis obliterans (BOS) grade ≥ 2 or grade 1 with risk factors for rapid progression. MSCs (2 x 106 cells per kilogram patient weight) were infused via a peripheral vein twice weekly for 2 weeks, with 52 weeks follow-up. Ten Patients (5 male, 8 bilateral, median [interquartile range] age 40 [30-59] years, 3 BOS2, 7 BOS3) participated. MSC treatment was well tolerated with all patients receiving the full dosing schedule without any procedure-related serious adverse events. The rate of decline in forced expiratory volume in one second slowed after the MSC infusions (120 ml/month preinfusion vs. 30 ml/month postinfusion, p = .08). Two patients died at 152 and 270 days post-MSC treatment, both from progressive CLAD. In conclusion, infusion of allogeneic bone marrow-derived MSCs is feasible and safe even in patients with advanced CLAD. Stem Cells Translational Medicine 2017;6:1152-1157.


Asunto(s)
Células de la Médula Ósea/citología , Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Trasplante de Células Madre Mesenquimatosas/métodos , Células Madre Mesenquimatosas/citología , Adulto , Femenino , Rechazo de Injerto/terapia , Enfermedad Injerto contra Huésped/terapia , Humanos , Trasplante de Pulmón/efectos adversos , Masculino , Células Madre Mesenquimatosas/fisiología , Persona de Mediana Edad
16.
Eur J Heart Fail ; 5(6): 783-91, 2003 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-14675857

RESUMEN

BACKGROUND: Patients with heart failure suffer from poor health outcomes and require combinations of medications to treat their disease. Providing patients with knowledge through education is one mechanism to help them improve compliance with complicated treatment regimens. METHODS: We developed and tested two instruments. The first instrument, which we call the measure of educational material acceptability (EMA), was designed to help us differentiate between written educational materials according to patients' subjective responses. The second instrument, the knowledge acquisition questionnaire (KAQ), which measures knowledge gained, was designed to determine whether patients understand the rationale and mechanics of their heart failure management. We explored the measurement properties of both instruments. RESULTS: The internal consistency of the EMA was 0.79 (Cronbach's alpha). The internal consistency of the KAQ was 0.61 and its responsiveness, measured using change scores of knowledge before and after an educational intervention, was 0.75. CONCLUSIONS: We have developed instruments that measure acceptability and knowledge acquisition, and that clinicians and investigators involved in heart failure programs may find useful in developing educational material and measuring the impact of their interventions on patients' knowledge.


Asunto(s)
Evaluación Educacional , Conocimientos, Actitudes y Práctica en Salud , Insuficiencia Cardíaca/psicología , Educación del Paciente como Asunto , Anciano , Evaluación Educacional/métodos , Femenino , Humanos , Masculino , Aceptación de la Atención de Salud , Proyectos Piloto , Ensayos Clínicos Controlados Aleatorios como Asunto , Reproducibilidad de los Resultados , Encuestas y Cuestionarios
17.
Hum Biol ; 79(6): 609-22, 2007 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-18494372

RESUMEN

Brachymesophalangia-V (BMP-V), a short and broad middle phalanx of the fifth digit, is the most common of all skeletal anomalies of the hand. When this feature appears alone, it is clinically known as brachydactyly type A3 (BDA3). A high prevalence of BDA3 has been observed among the children of the Jirel ethnic group in eastern Nepal. As part of the Jiri Growth Study, a hand-wrist radiograph is taken annually of each child to assess skeletal development. For this study the most recent radiographs of 1,357 Jirel children, adolescents, and young adults (676 boys, 681 girls), age 3-20 years, were examined for the presence or absence of BDA3, to report the prevalence and estimate the heritability of BDA3 in the Jirel population. The overall prevalence of BDA3 in this sample was 10.5% (12.9% of the males and 8.9% of the females were classified as BDA3 affected). The additive genetic heritability of BDA3 was statistically significant in this sample (h2 +/- SE = 0.87 +/- 0.16, p < 0.0001). This study is the first to estimate the prevalence and heritability of BDA3 in a large South Asian family-based sample.


Asunto(s)
Falanges de los Dedos de la Mano/anomalías , Genética de Población/métodos , Deformidades Congénitas de la Mano/epidemiología , Deformidades Congénitas de la Mano/genética , Adolescente , Adulto , Niño , Preescolar , Femenino , Falanges de los Dedos de la Mano/diagnóstico por imagen , Deformidades Congénitas de la Mano/diagnóstico por imagen , Humanos , Masculino , Nepal/epidemiología , Fenotipo , Prevalencia , Radiografía
18.
Cell ; 121(6): 823-35, 2005 Jun 17.
Artículo en Inglés | MEDLINE | ID: mdl-15960971

RESUMEN

Injury models have suggested that the lung contains anatomically and functionally distinct epithelial stem cell populations. We have isolated such a regional pulmonary stem cell population, termed bronchioalveolar stem cells (BASCs). Identified at the bronchioalveolar duct junction, BASCs were resistant to bronchiolar and alveolar damage and proliferated during epithelial cell renewal in vivo. BASCs exhibited self-renewal and were multipotent in clonal assays, highlighting their stem cell properties. Furthermore, BASCs expanded in response to oncogenic K-ras in culture and in precursors of lung tumors in vivo. These data support the hypothesis that BASCs are a stem cell population that maintains the bronchiolar Clara cells and alveolar cells of the distal lung and that their transformed counterparts give rise to adenocarcinoma. Although bronchiolar cells and alveolar cells are proposed to be the precursor cells of adenocarcinoma, this work points to BASCs as the putative cells of origin for this subtype of lung cancer.


Asunto(s)
Adenocarcinoma Bronquioloalveolar/patología , Transformación Celular Neoplásica/patología , Neoplasias Pulmonares/patología , Alveolos Pulmonares/patología , Células Madre/patología , Adenocarcinoma Bronquioloalveolar/metabolismo , Animales , Carcinógenos , Proliferación Celular/efectos de los fármacos , Transformación Celular Neoplásica/efectos de los fármacos , Células Cultivadas , Genes ras/fisiología , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/metabolismo , Ratones , Ratones Endogámicos C57BL , Naftalenos , Alveolos Pulmonares/efectos de los fármacos , Proteína C Asociada a Surfactante Pulmonar/metabolismo , Células Madre/metabolismo , Uteroglobina/metabolismo
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