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1.
Ann Surg Oncol ; 31(7): 4271-4280, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38453768

RESUMEN

BACKGROUND: This study assessed the performance of early contrast-enhanced magnetic resonance (ECE-MR) in the detecting of complete tumor response (ypT0) in patients with esophageal squamous cell carcinoma following neoadjuvant therapy. PATIENTS AND METHODS: Preoperative MR images of consecutive patients who underwent neoadjuvant therapy and surgical resection were reviewed retrospectively. The accuracy of ECE-MR and T2WI+DWI was evaluated by comparing the findings with pathological results. Receiver operating characteristic curve analysis was used to assess the diagnostic performance, and DeLong method was applied to compare the areas under the curves (AUC). Chi-squared analysis was conducted to explore the difference in pathological changes. RESULTS: A total of 198 patients (mean age 62.6 ± 7.8 years, 166 men) with 201 lesions were included. The AUC of ECE-MR was 0.85 (95% CI 0.79-0.90) for diagnosing ypT1-4, which was significantly higher than that of T2WI+DWI (AUC 0.69, 95% CI 0.63-0.76, p < 0.001). The diagnostic performance of both T2WI+DWI and ECE-MR improved with increasing tumor stage. The AUCs of ECE-MRI were higher in ypT1 and ypT2 tumors than T2WI+DWI. Degree 2-3 tumor-infiltrating lymphocytes and neutrophils were commonly seen in ypT0 tumors misdiagnosed by ECE-MR. CONCLUSIONS: Visual evaluation of ECE-MR is a promising diagnostic protocol for the detection of complete tumor response, especially for differentiation with early stage tumors. The accurate diagnosis of complete tumor response after neoadjuvant therapy using imaging modalities is of important significance for clinical decision-making for patients with esophageal squamous cell carcinoma. It is hoped that early contrast-enhanced MR will provide supportive advice for the development of individualized treatment options for patients.


Asunto(s)
Medios de Contraste , Neoplasias Esofágicas , Imagen por Resonancia Magnética , Terapia Neoadyuvante , Humanos , Masculino , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Estudios de Seguimiento , Esofagectomía , Carcinoma de Células Escamosas de Esófago/terapia , Carcinoma de Células Escamosas de Esófago/patología , Pronóstico , Anciano , Curva ROC
2.
BMC Cancer ; 24(1): 315, 2024 Mar 07.
Artículo en Inglés | MEDLINE | ID: mdl-38454349

RESUMEN

PURPOSE: Rectal tumor segmentation on post neoadjuvant chemoradiotherapy (nCRT) magnetic resonance imaging (MRI) has great significance for tumor measurement, radiomics analysis, treatment planning, and operative strategy. In this study, we developed and evaluated segmentation potential exclusively on post-chemoradiation T2-weighted MRI using convolutional neural networks, with the aim of reducing the detection workload for radiologists and clinicians. METHODS: A total of 372 consecutive patients with LARC were retrospectively enrolled from October 2015 to December 2017. The standard-of-care neoadjuvant process included 22-fraction intensity-modulated radiation therapy and oral capecitabine. Further, 243 patients (3061 slices) were grouped into training and validation datasets with a random 80:20 split, and 41 patients (408 slices) were used as the test dataset. A symmetric eight-layer deep network was developed using the nnU-Net Framework, which outputs the segmentation result with the same size. The trained deep learning (DL) network was examined using fivefold cross-validation and tumor lesions with different TRGs. RESULTS: At the stage of testing, the Dice similarity coefficient (DSC), 95% Hausdorff distance (HD95), and mean surface distance (MSD) were applied to quantitatively evaluate the performance of generalization. Considering the test dataset (41 patients, 408 slices), the average DSC, HD95, and MSD were 0.700 (95% CI: 0.680-0.720), 17.73 mm (95% CI: 16.08-19.39), and 3.11 mm (95% CI: 2.67-3.56), respectively. Eighty-two percent of the MSD values were less than 5 mm, and fifty-five percent were less than 2 mm (median 1.62 mm, minimum 0.07 mm). CONCLUSIONS: The experimental results indicated that the constructed pipeline could achieve relatively high accuracy. Future work will focus on assessing the performances with multicentre external validation.


Asunto(s)
Aprendizaje Profundo , Neoplasias del Recto , Humanos , Procesamiento de Imagen Asistido por Computador/métodos , Imagen por Resonancia Magnética/métodos , Terapia Neoadyuvante , Neoplasias del Recto/diagnóstico por imagen , Neoplasias del Recto/terapia , Neoplasias del Recto/patología , Estudios Retrospectivos , Semántica
3.
BMC Cancer ; 23(1): 477, 2023 May 25.
Artículo en Inglés | MEDLINE | ID: mdl-37231388

RESUMEN

OBJECTIVE: To investigate the value of CT radiomics features of meso-esophageal fat in the overall survival (OS) prediction of patients with locally advanced esophageal squamous cell carcinoma (ESCC). METHODS: A total of 166 patients with locally advanced ESCC in two medical centers were retrospectively analyzed. The volume of interest (VOI) of meso-esophageal fat and tumor were manually delineated on enhanced chest CT using ITK-SNAP. Radiomics features were extracted from the VOIs by Pyradiomics and then selected using the t-test, the Cox regression analysis, and the least absolute shrinkage and selection operator. The radiomics scores of meso-esophageal fat and tumors for OS were constructed by a linear combination of the selected radiomic features. The performance of both models was evaluated and compared by the C-index. Time-dependent receiver operating characteristic (ROC) analysis was employed to analyze the prognostic value of the meso-esophageal fat-based model. A combined model for risk evaluation was constructed based on multivariate analysis. RESULTS: The CT radiomic model of meso-esophageal fat showed valuable performance for survival analysis, with C-indexes of 0.688, 0.708, and 0.660 in the training, internal, and external validation cohorts, respectively. The 1-year, 2-year, and 3-year ROC curves showed AUCs of 0.640-0.793 in the cohorts. The model performed equivalently compared to the tumor-based radiomic model and performed better compared to the CT features-based model. Multivariate analysis showed that meso-rad-score was the only factor associated with OS. CONCLUSIONS: A baseline CT radiomic model based on the meso-esophagus provide valuable prognostic information for ESCC patients treated with dCRT.


Asunto(s)
Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Humanos , Carcinoma de Células Escamosas de Esófago/diagnóstico por imagen , Carcinoma de Células Escamosas de Esófago/terapia , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/tratamiento farmacológico , Estudios Retrospectivos , Quimioradioterapia , Tomografía Computarizada por Rayos X
4.
Eur Radiol ; 33(1): 380-390, 2023 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-35927466

RESUMEN

OBJECTIVE: To investigate the performance of quantitative CT analysis in predicting the prognosis of patients with locally advanced oesophageal squamous cell carcinoma (ESCC) after two cycles of induction chemotherapy before definitive chemoradiotherapy/radiotherapy. METHODS: A total of 110 patients with locally advanced ESCC were retrospectively analysed. Baseline chest CT and CT after two cycles of induction chemotherapy were analysed. A multivariate Cox proportional-hazard regression model was used to identify independent prognostic markers for survival analysis. Then, a CT scoring system was established. Time-dependent receiver operating characteristic (ROC) curve analysis and the Kaplan-Meier method were employed for analysing the prognostic value of the CT scoring system. RESULTS: Body mass index, treatment strategy, change ratios of thickness (ΔTHmax), CT value of the primary tumour (ΔCTVaxial) and the short diameter (ΔSD-LN), and the presence of an enlarged small lymph node (ESLN) after two cycles of chemotherapy were noted as independent factors for predicting overall survival (OS). The specificity of the presence of ESLN for death after 12 months was up to 100%. Areas under the curve value of the CT scoring system for predicting OS and progression-free survival (PFS) were higher than that of the RECIST (p < 0.05). Responders had significantly longer OS and PFS than non-responders. CONCLUSION: Quantitative CT analysis after two cycles of induction chemotherapy could predict the outcome of locally advanced ESCC patients treated with definitive chemoradiotherapy/radiotherapy. The CT scoring system could contribute to the development of an appropriate strategy for patients with locally advanced ESCC. KEY POINTS: • Quantitative CT evaluation after two cycles of induction chemotherapy can predict the long-term outcome of locally advanced oesophageal cancer treated with definitive chemoradiotherapy/radiotherapy. • A CT scoring system provides valuable imaging support for indicating the prognosis at the early stage of therapy. • Quantitative CT evaluation can assist clinicians in personalising treatment plans.


Asunto(s)
Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Humanos , Carcinoma de Células Escamosas de Esófago/diagnóstico por imagen , Carcinoma de Células Escamosas de Esófago/terapia , Quimioterapia de Inducción , Estudios Retrospectivos , Quimioradioterapia , Pronóstico , Tomografía Computarizada por Rayos X , Neoplasias Esofágicas/diagnóstico por imagen , Neoplasias Esofágicas/terapia
5.
J Magn Reson Imaging ; 56(2): 562-569, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-34913210

RESUMEN

BACKGROUND: Diffusion weighted imaging (DWI) at multiple b-values has been used to predict the pathological complete response (pCR) to neoadjuvant chemoradiotherapy for locally advanced rectal cancer. Non-Gaussian models fit the signal decay of diffusion by several physical values from different approaches of approximation. PURPOSE: To develop a deep learning method to analyze DWI data scanned at multiple b-values independent on Gaussian or non-Gaussian models and to apply to a rectal cancer neoadjuvant chemoradiotherapy model. STUDY TYPE: Retrospective. POPULATION: A total of 472 participants (age: 56.6 ± 10.5 years; 298 males and 174 females) with locally advanced adenocarcinoma were enrolled and chronologically divided into a training group (n = 200; 42 pCR/158 non-pCR), a validation group (n = 72; 11 pCR/61 non-pCR) and a test group (n = 200; 44 pCR/156 non-pCR). FIELD STRENGTH/SEQUENCE: A 3.0 T MRI scanner. DWI with a single-shot spin echo-planar imaging pulse sequence at 12 b-values (0, 20, 50, 100, 200, 400, 600, 800, 1000, 1200, 1400, and 1600 sec/mm2 ). ASSESSMENT: DWI signals from manually delineated tumor region were converted into a signature-like picture by concatenating all histograms from different b-values. Pathological results (pCR/non-pCR) were used as the ground truth for deep learning. Gaussian and non-Gaussian methods were used for comparison. STATISTICAL TESTS: Analysis of variance for age; Chi-square for gender and pCR/non-pCR; area under the receiver operating characteristic (ROC) curve (AUC); DeLong test for AUC. P < 0.05 for significant difference. RESULTS: The AUC in the test group is 0.924 (95% CI: 0.866-0.983) for the signature-like pictures converted from 35 bins, and it is 0.931 (95% CI: 0.884-0.979) for the signature-like pictures converted from 70 bins, which is significantly (Z = 3.258, P < 0.05) larger than Dapp , the best predictor in non-Gaussian methods with AUC = 0.773 (95% CI: 0.682-0.865). DATA CONCLUSION: The proposed signature-like pictures provide more accurate pretreatment prediction of the response to neoadjuvant chemoradiotherapy than the fitted methods for locally advanced rectal cancer. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 2.


Asunto(s)
Quimioradioterapia , Neoplasias del Recto , Anciano , Quimioradioterapia/métodos , Imagen de Difusión por Resonancia Magnética/métodos , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante/métodos , Neoplasias del Recto/tratamiento farmacológico , Neoplasias del Recto/terapia , Estudios Retrospectivos , Resultado del Tratamiento
6.
Dis Colon Rectum ; 65(3): 322-332, 2022 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-34459446

RESUMEN

BACKGROUND: The cT3 substage criteria based on extramural depth of tumor invasion in rectal cancer have several limitations. OBJECTIVE: This study proposed that the distance between the deepest tumor invasion and mesorectal fascia on pretherapy MRI can distinguish the prognosis of patients with cT3 rectal cancer. DESIGN: This is a cohort study. SETTING: This study included a prospective, single-center, observational cohort and a retrospective, multicenter, independent validation cohort. PATIENT: Patients who had cT3 rectal cancer with negative mesorectal fascia undergoing neoadjuvant chemoradiotherapy followed by radical surgery were included in 4 centers in China from January 2013 to September 2014. INTERVENTION: Baseline MRI with the distance between the deepest tumor invasion and mesorectal fascia, extramural depth of tumor invasion, and mesorectum thickness were measured. MAIN OUTCOME MEASURES: The cutoff of the distance between the deepest tumor invasion and mesorectal fascia was determined by time-dependent receiver operating characteristic curves, supported by a 5-year progression rate from the prospective cohort, and was then validated in a retrospective cohort. RESULTS: There were 124 and 274 patients included in the prospective and independent validation cohorts. The distance between the deepest tumor invasion and mesorectal fascia was the only predictor for cancer-specific death (HR, 0.1; 95% CI, 0.0-0.7) and was also a significant predictor for distant recurrence (HR, 0.4; 95% CI, 0.2-0.9). No statistically significant difference was observed in prognosis between patients classified as T3a/b and T3c/d. LIMITATIONS: The sample size is relatively small, and the study focused on cT3 rectal cancers with a negative mesorectal fascia. CONCLUSIONS: A cutoff of 7 mm of the distance between the deepest tumor invasion and mesorectal fascia on baseline MRI can distinguish cT3 rectal cancer from a different prognosis. We recommend using the distance between the deepest tumor invasion and mesorectal fascia on baseline MRI for local and systemic risk assessment and providing a tailored schedule of neoadjuvant treatment. See Video Abstract at http://links.lww.com/DCR/B682.CORRELACIÓN ENTRE LA DISTANCIA DE LA FASCIA MESORRECTAL Y EL PRONÓSTICO DEL CÁNCER DE RECTO cT3: RESULTADOS DE UN ESTUDIO MULTICÉNTRICO DE CHINAANTECEDENTES:Los criterios de subestadificación cT3 basados en la profundidad extramural de invasión tumoral en el cáncer de recto tienen varias limitaciones.OBJETIVO:Este estudio propuso que la distancia entre la invasión tumoral más profunda y la fascia mesorrectal en la resonancia magnética preterapia puede distinguir el pronóstico de los pacientes con cT3.DISEÑO:Estudio de cohorte.ENTORNO CLINICO:El estudio incluyó una cohorte observacional, prospectiva, unicéntrica, y una cohorte de validación retrospectiva, multicéntrica e independiente.PACIENTE:Se incluyeron pacientes con cáncer de recto cT3 con fascia mesorrectal negativa sometidos a quimio-radioterapia neoadyuvante seguida de cirugía radical en cuatro centros de China desde enero de 2013 hasta septiembre de 2014.INTERVENCIÓN:Imágenes de resonancia magnética de referencia fueron medidas con la distancia entre la invasión tumoral más profunda y la fascia mesorrectal; la profundidad extramural de la invasión tumoral y el grosor del mesorrecto.PRINCIPALES MEDIDAS DE VALORACION:El límite de la distancia entre la invasión tumoral más profunda y la fascia mesorrectal se determinó mediante curvas características operativas del receptor dependientes del tiempo y se apoyó en la tasa de progresión a 5 años de la cohorte prospectiva, y luego se validó en una cohorte retrospectiva.RESULTADOS:Se incluyeron 124 y 274 pacientes en la cohorte de validación prospectiva e independiente, respectivamente. La distancia entre la invasión tumoral más profunda de la fascia mesorrectal fue el único predictor de muerte específica por cáncer (Hazard ratio: 0.1, 95% CI, 0,0-0,7); y también fue un predictor significativo de recurrencia distante Hazard ratio: 0,4, 95% CI, 0,2-0,9). No se observaron diferencias estadísticamente significativas en el pronóstico entre los pacientes clasificados como T3a/b y T3c/d.LIMITACIONES:El tamaño de la muestra es relativamente pequeño y el estudio se centró en los cánceres de recto cT3 con fascia mesorrectal negativa.CONCLUSIONES:Un límite de 7 mm de distancia entre la invasión tumoral más profunda y la fascia mesorrectal en la resonancia magnética de referencia puede distinguir el cáncer de recto cT3 de diferentes pronósticos. Recomendamos la distancia entre la invasión tumoral más profunda y la fascia mesorrectal en la resonancia magnética de referencia para la evaluación del riesgo local y sistémico, proporcionando un programa personalizado de tratamiento neoadyuvante. Consulte Video Resumen en http://links.lww.com/DCR/B682. (Traducción- Dr. Francisco M. Abarca-Rendon).


Asunto(s)
Imagen por Resonancia Magnética/métodos , Invasividad Neoplásica , Proctectomía , Neoplasias del Recto , Recto , China/epidemiología , Estudios de Cohortes , Fascia/diagnóstico por imagen , Fascia/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante/métodos , Invasividad Neoplásica/diagnóstico por imagen , Invasividad Neoplásica/patología , Cuidados Preoperatorios/métodos , Proctectomía/efectos adversos , Proctectomía/métodos , Pronóstico , Neoplasias del Recto/patología , Neoplasias del Recto/cirugía , Recto/diagnóstico por imagen , Recto/patología , Reproducibilidad de los Resultados
7.
J Comput Assist Tomogr ; 45(2): 323-329, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33512851

RESUMEN

OBJECTIVES: We investigated the value of radiomics data, extracted from pretreatment computed tomography images of the primary tumor (PT) and lymph node (LN) for predicting LN metastasis in esophageal squamous cell carcinoma (ESCC) patients. MATERIALS AND METHODS: A total 338 ESCC patients were retrospectively assessed. Primary tumor, the largest short-axis diameter LN (LSLN), and PT and LSLN interaction term (IT) radiomic features were calculated. Subsequently, the radiomic signature was combined with clinical risk factors in multivariable logistic regression analysis to build various clinical-radiomic models. Model performance was evaluated with respect to the fit, overall performance, differentiation, and calibration. RESULTS: A clinical-radiomic model, which combined clinical and PT-LSLN-IT radiomic signature, showed favorable discrimination and calibration. The area under curve value was 0.865 and 0.841 in training and test set. CONCLUSIONS: A venous computed tomography radiomic model based on the PT, LSLN, and IT radiomic features represents a novel noninvasive tool for prediction LN metastasis in ESCC.


Asunto(s)
Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Ganglios Linfáticos/diagnóstico por imagen , Metástasis Linfática/diagnóstico por imagen , Tomografía Computarizada por Rayos X , Anciano , Neoplasias Esofágicas/diagnóstico por imagen , Neoplasias Esofágicas/epidemiología , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/diagnóstico por imagen , Carcinoma de Células Escamosas de Esófago/epidemiología , Carcinoma de Células Escamosas de Esófago/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nomogramas , Estudios Retrospectivos
8.
J Appl Clin Med Phys ; 22(9): 324-331, 2021 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-34343402

RESUMEN

PURPOSE: Manual delineation of a rectal tumor on a volumetric image is time-consuming and subjective. Deep learning has been used to segment rectal tumors automatically on T2-weighted images, but automatic segmentation on diffusion-weighted imaging is challenged by noise, artifact, and low resolution. In this study, a volumetric U-shaped neural network (U-Net) is proposed to automatically segment rectal tumors on diffusion-weighted images. METHODS: Three hundred patients of locally advanced rectal cancer were enrolled in this study and divided into a training group, a validation group, and a test group. The region of rectal tumor was delineated on the diffusion-weighted images by experienced radiologists as the ground truth. A U-Net was designed with a volumetric input of the diffusion-weighted images and an output of segmentation with the same size. A semi-automatic segmentation method was used for comparison by manually choosing a threshold of gray level and automatically selecting the largest connected region. Dice similarity coefficient (DSC) was calculated to evaluate the methods. RESULTS: On the test group, deep learning method (DSC = 0.675 ± 0.144, median DSC is 0.702, maximum DSC is 0.893, and minimum DSC is 0.297) showed higher segmentation accuracy than the semi-automatic method (DSC = 0.614 ± 0.225, median DSC is 0.685, maximum DSC is 0.869, and minimum DSC is 0.047). Paired t-test shows significant difference (T = 2.160, p = 0.035) in DSC between the deep learning method and the semi-automatic method in the test group. CONCLUSION: Volumetric U-Net can automatically segment rectal tumor region on DWI images of locally advanced rectal cancer.


Asunto(s)
Aprendizaje Profundo , Neoplasias del Recto , Imagen de Difusión por Resonancia Magnética , Humanos , Procesamiento de Imagen Asistido por Computador , Redes Neurales de la Computación , Neoplasias del Recto/diagnóstico por imagen , Recto/diagnóstico por imagen
9.
Radiology ; 296(1): 56-64, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32315264

RESUMEN

Background Preoperative response evaluation with neoadjuvant chemoradiotherapy remains a challenge in the setting of locally advanced rectal cancer. Recently, deep learning (DL) has been widely used in tumor diagnosis and treatment and has produced exciting results. Purpose To develop and validate a DL method to predict response of rectal cancer to neoadjuvant therapy based on diffusion kurtosis and T2-weighted MRI. Materials and Methods In this prospective study, participants with locally advanced rectal adenocarcinoma (≥cT3 or N+) proved at histopathology and baseline MRI who were scheduled to undergo preoperative chemoradiotherapy were enrolled from October 2015 to December 2017 and were chronologically divided into 308 training samples and 104 test samples. DL models were constructed primarily to predict pathologic complete response (pCR) and secondarily to assess tumor regression grade (TRG) (TRG0 and TRG1 vs TRG2 and TRG3) and T downstaging. Other analysis included comparisons of diffusion kurtosis MRI parameters and subjective evaluation by radiologists. Results A total of 383 participants (mean age, 57 years ± 10 [standard deviation]; 229 men) were evaluated (290 in the training cohort, 93 in the test cohort). The area under the receiver operating characteristic curve (AUC) was 0.99 for the pCR model in the test cohort, which was higher than the AUC for raters 1 and 2 (0.66 and 0.72, respectively; P < .001 for both). AUC for the DL model was 0.70 for TRG and 0.79 for T downstaging. AUC for pCR with the DL model was better than AUC for the best-performing diffusion kurtosis MRI parameters alone (diffusion coefficient in normal diffusion after correcting the non-Gaussian effect [Dapp value] before neoadjuvant therapy, AUC = 0.76). Subjective evaluation by radiologists yielded a higher error rate (1 - accuracy) (25 of 93 [26.9%] and 23 of 93 [24.8%] for raters 1 and 2, respectively) in predicting pCR than did evaluation with the DL model (two of 93 [2.2%]); the radiologists achieved a lower error rate (12 of 93 [12.9%] and 13 of 93 [14.0%] for raters 1 and 2, respectively) when assisted by the DL model. Conclusion A deep learning model based on diffusion kurtosis MRI showed good performance for predicting pathologic complete response and aided the radiologist in assessing response of locally advanced rectal cancer after neoadjuvant chemoradiotherapy. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Koh in this issue.


Asunto(s)
Adenocarcinoma/diagnóstico por imagen , Adenocarcinoma/terapia , Imagen de Difusión por Resonancia Magnética/métodos , Interpretación de Imagen Asistida por Computador/métodos , Neoplasias del Recto/diagnóstico por imagen , Neoplasias del Recto/terapia , Quimioradioterapia , Aprendizaje Profundo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante , Valor Predictivo de las Pruebas , Estudios Prospectivos , Recto/diagnóstico por imagen , Resultado del Tratamiento
10.
Vet Res ; 50(1): 76, 2019 Oct 02.
Artículo en Inglés | MEDLINE | ID: mdl-31578154

RESUMEN

Edwardsiella piscicida is a severe fish pathogen. Haem utilization systems play an important role in bacterial adversity adaptation and pathogenicity. In this study, a speculative haem utilization protein, HutZEp, was characterized in E. piscicida. hutZEp is encoded with two other genes, hutW and hutX, in an operon that is similar to the haem utilization operon hutWXZ identified in V. cholerae. However, protein activity analysis showed that HutZEp is probably not related to hemin utilization. To explore the biological role of HutZEp, a markerless hutZEp in-frame mutant strain, TX01ΔhutZ, was constructed. Deletion of hutZEp did not significantly affect bacterial growth in normal medium, in iron-deficient conditions, or in the presence of haem but significantly retarded bacterial biofilm growth. The expression of known genes related to biofilm growth was not affected by hutZEp deletion, which indicated that HutZEp was probably a novel factor promoting biofilm formation in E. piscicida. Compared to the wild-type TX01, TX01ΔhutZ exhibited markedly compromised tolerance to acid stress and host serum stress. Pathogenicity analysis showed that inactivation of hutZEp significantly impaired the ability of E. piscicida to invade and reproduce in host cells and to infect host tissue. In contrast to TX01, TX01ΔhutZ was defective in blocking host macrophage activation. The expression of hutZEp was directly regulated by the ferric uptake regulator Fur. This study is the first functional characterization of HutZ in a fish pathogen, and these findings suggested that HutZEp is essential for E. piscicida biofilm formation and contributes to host infection.


Asunto(s)
Proteínas Bacterianas/genética , Biopelículas , Edwardsiella/fisiología , Edwardsiella/patogenicidad , Transcriptoma/fisiología , Proteínas Bacterianas/metabolismo , Edwardsiella/genética , Virulencia
11.
Fish Shellfish Immunol ; 95: 248-258, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31654767

RESUMEN

Universal stress proteins (Usps) exist ubiquitously in bacteria and other organisms. Usps play an important role in adaptation of bacteria to a variety of environmental stresses. There is increasing evidence that Usps facilitate pathogens to adapt host environment and are involved in pathogenicity. Edwardsiella piscicida (formerly included in E. tarda) is a severe fish pathogen and infects various important economic fish including tilapia (Oreochromis niloticus). In E. piscicida, a number of systems and factors that are involved in stress resistance and pathogenesis were identified. However, the function of Usps in E. piscicida is totally unknown. In this study, we examined the expressions of 13 usp genes in E. piscicida and found that most of these usp genes were up-regulated expression under high temperature, oxidative stress, acid stress, and host serum stress. Particularly, among these usp genes, usp13, exhibited dramatically high expression level upon several stress conditions. To investigate the biological role of usp13, a markerless usp13 in-frame mutant strain, TX01Δusp13, was constructed. Compared to the wild type TX01, TX01Δusp13 exhibited markedly compromised tolerance to high temperature, hydrogen peroxide, and low pH. Deletion of usp13 significantly retarded bacterial biofilm growth and decreased resistance against serum killing. Pathogenicity analysis showed that the inactivation of usp13 significantly impaired the ability of E. piscicida to invade into host cell and infect host tissue. Introduction of a trans-expressed usp13 gene restored the lost virulence of TX01Δusp13. In support of these results, host immune response induced by TX01 and TX01Δusp13 was examined, and the results showed reactive oxygen species (ROS) levels in TX01Δusp13-infected macrophages were significantly higher than those in TX01-infected cells. The expression level of several cytokines (IL-6, IL-8, IL-10, TNF-α, and CC2) in TX01Δusp13-infected fish was significantly higher than that in TX01-infected fish. These results suggested that the deletion of usp13 attenuated the ability of bacteria to overcome the host immune response to pathogen infection. Taken together, our study indicated Usp13 of E. piscicida was not only important participant in adversity resistance, but also was essential for E. piscicida pathogenicity and contributed to block host immune response to pathogen infection.


Asunto(s)
Proteínas Bacterianas/genética , Cíclidos/inmunología , Edwardsiella/inmunología , Edwardsiella/patogenicidad , Enfermedades de los Peces/inmunología , Inmunidad Innata/inmunología , Animales , Proteínas Bacterianas/inmunología , Edwardsiella/genética , Infecciones por Enterobacteriaceae/inmunología , Infecciones por Enterobacteriaceae/veterinaria , Filogenia , Virulencia
12.
Radiology ; 289(3): 677-685, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30152742

RESUMEN

Purpose To study the relationship between MRI-defined extramural venous invasion (EMVI) prior to treatment and prognosis in patients with locally advanced rectal cancer treated with neoadjuvant chemotherapy-radiation therapy followed by surgery. Materials and Methods This retrospective study included 517 patients with locally advanced rectal cancer evaluated from August 2008 to December 2014. Baseline and posttherapy MRI and follow-up data were retrieved for all patients. After training by using 328 cases with pathologic evaluation of EMVI after therapy, radiologists evaluated baseline MRI for EMVI status in addition to tumor size and characteristics, nodal status, and invasion of the mesorectal fascia. Reader reproducibility was determined by using κ coefficient. Kaplan-Meier curves and adjusted Cox models were used to determine the relationship of baseline MRI parameters to overall survival, metastasis-free survival, and local relapse-free survival. Results Among 517 patients, 335 (64.8%) were men; the mean age was 55.6 years ± 11.5 (standard deviation). At baseline, radiologists identified 259 of 517 (50%) patients with EMVI by using MRI. In adjusted analysis, EMVI and mesorectal fascial invasion at baseline MRI were predictors of metastasis-free survival (hazard ratio, 0.3 and 0.6; P ˂ .01 and P ˂ .02, respectively) and overall survival (hazard ratio, 0.5 and 0.5; P = .01 and P = .02, respectively). EMVI was the only factor associated with local relapse-free survival (hazard ratio, 0.3; P ˂ .01). The κ coefficient for determination of EMVI was 0.80. Conclusion Extramural venous invasion (EMVI) can be reliably evaluated with MRI. The presence of EMVI was associated with greater risk of local and distant tumor recurrence and overall death in patients with locally advanced rectal cancer treated with neoadjuvant chemotherapy-radiation therapy. © RSNA, 2018 Online supplemental material is available for this article.


Asunto(s)
Imagen por Resonancia Magnética/métodos , Recurrencia Local de Neoplasia/diagnóstico por imagen , Recurrencia Local de Neoplasia/patología , Neoplasias del Recto/diagnóstico por imagen , Neoplasias del Recto/patología , Adulto , Anciano , Anciano de 80 o más Años , Quimioradioterapia , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante , Invasividad Neoplásica/patología , Neoplasias del Recto/terapia , Recto/diagnóstico por imagen , Recto/patología , Reproducibilidad de los Resultados , Estudios Retrospectivos , Adulto Joven
13.
J Cancer Res Clin Oncol ; 150(5): 222, 2024 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-38687350

RESUMEN

PURPOSE: The purpose of this research was to investigate the efficacy of the CT-based peritoneal cancer index (PCI) to predict the overall survival of patients with peritoneal metastasis in gastric cancer (GCPM) after two cycles of chemotherapy. METHODS: This retrospective study registered 112 individuals with peritoneal metastasis in gastric cancer in our hospital. Abdominal and pelvic enhanced CT before and after chemotherapy was independently analyzed by two radiologists. The PCI of peritoneal metastasis in gastric cancer was evaluated according to the Sugarbaker classification, considering the size and distribution of the lesions using CT. Then we evaluated the prognostic performance of PCI based on CT, clinical characteristics, and imaging findings for survival analysis using multivariate Cox proportional hazard regression. RESULTS: The PCI change ratio based on CT after treatment (ΔPCI), therapy lines, and change in grade of ascites were independent factors that were associated with overall survival (OS). The area under the curve (AUC) value of ΔPCI for predicting OS with 0.773 was higher than that of RECIST 1.1 with 0.661 (P < 0.05). Patients with ΔPCI less than -15% had significantly longer OS. CONCLUSION: CT analysis after chemotherapy could predict OS in patients with GCPM. The CT-PCI change ratio could contribute to the determination of an appropriate strategy for gastric cancer patients with peritoneal metastasis.


Asunto(s)
Neoplasias Peritoneales , Neoplasias Gástricas , Tomografía Computarizada por Rayos X , Humanos , Neoplasias Gástricas/patología , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/diagnóstico por imagen , Neoplasias Peritoneales/secundario , Neoplasias Peritoneales/mortalidad , Neoplasias Peritoneales/tratamiento farmacológico , Neoplasias Peritoneales/diagnóstico por imagen , Femenino , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Tomografía Computarizada por Rayos X/métodos , Anciano , Pronóstico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico
14.
Clin Imaging ; 96: 15-22, 2023 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-36736182

RESUMEN

PURPOSE: This study aimed to investigate the diagnostic performance of the histogram array and convolutional neural network (CNN) based on diffusion-weighted imaging (DWI) with multiple b-values under magnetic resonance imaging (MRI) to distinguish pancreatic ductal adenocarcinomas (PDACs) from solid pseudopapillary neoplasms (SPNs) and pancreatic neuroendocrine neoplasms (PNENs). METHODS: This retrospective study consisted of patients diagnosed with PDACs (n = 132), PNENs (n = 45) and SPNs (n = 54). All patients underwent 3.0-T MRI including DWI with 10 b values. The regions of interest (ROIs) of pancreatic tumor were manually drawn using ITK-SNAP software, which included entire tumor at DWI (b = 1500 s/m2). The histogram array was obtained through the ROIs from multiple b-value data. PyTorch (version 1.11) was used to construct a CNN classifier to categorize the histogram array into PDACs, PNENs or SPNs. RESULTS: The area under the curves (AUCs) of the histogram array and the CNN model for differentiating PDACs from PNENs and SPNs were 0.896, 0.846, and 0.839 in the training, validation and testing cohorts, respectively. The accuracy, sensitivity and specificity were 90.22%, 96.23%, and 82.05% in the training cohort, 84.78%, 96.15%, and 70.0% in the validation cohort, and 81.72%, 90.57%, and 70.0% in the testing cohort. The performance of CNN with AUC of 0.865 for this differentiation was significantly higher than that of f with AUC = 0.755 (P = 0.0057) and α with AUC = 0.776 (P = 0.0278) in all patients. CONCLUSION: The histogram array and CNN based on DWI data with multiple b-values using MRI provided an accurate diagnostic performance to differentiate PDACs from PNENs and SPNs.


Asunto(s)
Carcinoma Ductal Pancreático , Tumores Neuroendocrinos , Neoplasias Pancreáticas , Humanos , Estudios Retrospectivos , Neoplasias Pancreáticas/patología , Imagen de Difusión por Resonancia Magnética/métodos , Carcinoma Ductal Pancreático/patología , Imagen por Resonancia Magnética/métodos , Tumores Neuroendocrinos/patología , Redes Neurales de la Computación , Neoplasias Pancreáticas
15.
Biomed Res Int ; 2023: 6057196, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36860814

RESUMEN

Objective: The diagnosis of primary malignant melanoma of the esophagus (PMME) before treatment is essential for clinical decision-making. However, PMME may be misdiagnosed as esophageal squamous cell carcinoma (ESCC) sometimes. This research is aimed at devising a radiomics nomogram model of CT for distinguishing PMME from ESCC. Methods: In this retrospective analysis, 122 individuals with proven pathologically PMME (n = 28) and ESCC (n = 94) were registered from our hospital. PyRadiomics was applied to derive radiomics features from plain and enhanced CT images after resampling image into an isotropic resolution of 0.625 × 0.625 × 0.625 mm3. The diagnostic efficiency of the model was evaluated by an independent validation group. Results: For the purpose of differentiation between PMME and ESCC, a radiomics model was constructed using 5 radiomics features obtained from nonenhanced CT and 4 radiomics features derived from enhanced CT. A radiomics model including multiple radiomics features showed excellent discrimination efficiency with AUCs of 0.975 and 0.906 in the primary and validation cohorts, respectively. Then, a radiomics nomogram model was developed. The decision curve analysis has shown remarkable performance of this nomogram model for distinguishing PMME from ESCC. Conclusions: The proposed radiomics nomogram model based on CT could be used for distinguishing PMME from ESCC. Moreover, this model also contributed to helping clinicians determine an appropriate treatment strategy for esophageal neoplasms.


Asunto(s)
Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Melanoma , Humanos , Carcinoma de Células Escamosas de Esófago/diagnóstico por imagen , Neoplasias Esofágicas/diagnóstico por imagen , Nomogramas , Estudios Retrospectivos , Melanoma/diagnóstico por imagen , Tomografía Computarizada por Rayos X , Melanoma Cutáneo Maligno
16.
Quant Imaging Med Surg ; 13(12): 7996-8008, 2023 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-38106287

RESUMEN

Background: Predicting preoperative understaging in patients with clinical stage T1-2N0 (cT1-2N0) esophageal squamous cell carcinoma (ESCC) is critical to customizing patient treatment. Radiomics analysis can provide additional information that reflects potential biological heterogeneity based on computed tomography (CT) images. However, to the best of our knowledge, no studies have focused on identifying CT radiomics features to predict preoperative understaging in patients with cT1-2N0 ESCC. Thus, we sought to develop a CT-based radiomics model to predict preoperative understaging in patients with cT1-2N0 esophageal cancer, and to explore the value of the model in disease-free survival (DFS) prediction. Methods: A total of 196 patients who underwent radical surgery for cT1-2N0 ESCC were retrospectively recruited from two hospitals. Among the 196 patients, 134 from Peking University Cancer Hospital were included in the training cohort, and 62 from Henan Cancer Hospital were included in the external validation cohort. Radiomics features were extracted from patients' CT images. Least absolute shrinkage and selection operator (LASSO) regression was used for feature selection and model construction. A clinical model was also built based on clinical characteristics, and the tumor size [the length, thickness and the thickness-to-length ratio (TLR)] was evaluated on the CT images. A radiomics nomogram was established based on multivariate logistic regression. The diagnostic performance of the models in predicting preoperative understaging was assessed by the area under the receiver operating characteristic curve (AUC). Kaplan-Meier curves with the log-rank test were employed to analyze the correlation between the nomogram and DFS. Results: Of the patients, 50.0% (67/134) and 51.6% (32/62) were understaged in the training and validation groups, respectively. The radiomics scores and the TLRs of the tumors were included in the nomogram. The AUCs of the nomogram for predicting preoperative understaging were 0.874 [95% confidence interval (CI): 0.815-0.933] in the training cohort and 0.812 (95% CI: 0.703-0.912) in the external validation cohort. The diagnostic performance of the nomogram was superior to that of the clinical model (P<0.05). The nomogram was an independent predictor of DFS in patients with cT1-2N0 ESCC. Conclusions: The proposed CT-based radiomics model could be used to predict preoperative understaging in patients with cT1-2N0 ESCC who have undergone radical surgery.

17.
Abdom Radiol (NY) ; 47(8): 2747-2759, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35668195

RESUMEN

PURPOSE: This study aimed to summarize the computed tomography (CT) findings of PMME and differentiate it from esophageal SCC and leiomyoma using CT analysis. METHODS: This was a retrospective study including 23 patients with PMME, 69 patients with SCC, and 21 patients with leiomyoma in our hospital. Qualitative CT morphological characteristics of each lesion included the location, tumor range, ulcer, enhanced pattern, and so on. For quantitative CT analysis, thickness, length and area of tumor, size of largest lymph node, number of metastatic lymph node, and CT value of tumor in plain, arterial, and delayed phases were measured. The associated factors for differentiating PMME from SCC and leiomyoma were examined with univariate and multivariate analysis. Receive operating characteristic curve (ROC) was used to determine the performance of CT models in discriminating PMME from SCC and leiomyoma. RESULTS: The thickness, mean CT value in arterial phase, and range of tumor were the independent factors for diagnosing PMME from SCC. These parameters were used to establish a diagnostic CT model with area under the ROC (AUC) of 0.969, and accuracy of 90.2%. In pathology, interstitial vessels in PMME were more abundant than that of SCC, and the stromal fibrosis was more obvious in SCC. PMME commonly exhibited intraluminal expansively growth pattern and SCC often showed infiltrative pattern. The postcontrast attenuation difference in maximum CT attenuation value between plain and arterial phases was the independent factor for diagnosing PMME from leiomyoma. This parameter was applied to differentiate PMME from leiomyoma with AUC of 0.929 and accuracy of 86.4%. CONCLUSION: The qualitative and quantitative CT analysis had excellent performance for differentiating PMME from SCC and esophageal leiomyoma.


Asunto(s)
Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Leiomioma , Melanoma , Neoplasias Esofágicas/diagnóstico por imagen , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/diagnóstico por imagen , Humanos , Leiomioma/diagnóstico por imagen , Leiomioma/patología , Melanoma/patología , Estudios Retrospectivos , Neoplasias Cutáneas , Tomografía Computarizada por Rayos X/métodos , Melanoma Cutáneo Maligno
18.
Magn Reson Imaging ; 92: 10-18, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-35623418

RESUMEN

PURPOSE: To assess the value of radiomics, apparent diffusion coefficient (ADC), intravoxel incoherent motion (IVIM) and stretched-exponential (SE) MR imaging in prediction of therapeutic response in patients with spinal metastases before chemotherapy. METHODS: Thirty-six patients with 190 osteolytic metastatic lesions from breast cancer were prospectively enrolled and underwent MR imaging before and after 6 months' treatment on a 1.5 T MRI. According to MDA criteria, 68 lesions were categorized as progressive disease (PD) and 122 lesions were categorized as stable or improvement (non-PD). The regions of interest (ROIs) were manually drawn on DWI, T1WI, T2WI and FS-T2WI by two radiologists with ITK-SNAP. The ADCall (multiple b-values method), IVIM parameters (D, D* and f) and SE parameters (DDC and α) were generated. The radiomics features were extracted from the ROIs. RESULTS: The mean values of ADC, DDC, and D before treatment were significantly higher in non-PD group than those in PD group (P = 0.001). The radiomics based on ADCall had the highest AUC value (0.852), followed by that of the T2WI (0.829) and FS-T2WI (0.798). The radiomics model using ADCall and FS-T2WI showed excellent efficiency in predicting treatment response with AUCs of 0.905 and 0.873 in training and validation cohorts. The radiomics model had better performance than that of ADCall, D, and DDC for predicting treatment response of bone metastases. CONCLUSION: Radiomics model based on ADCall and FS-T2WI could predict the treatment response and contribute to assisting clinicians in accurately choosing appropriate management.


Asunto(s)
Neoplasias Óseas , Neoplasias de la Mama , Neoplasias Óseas/diagnóstico por imagen , Neoplasias Óseas/tratamiento farmacológico , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Imagen de Difusión por Resonancia Magnética/métodos , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Estudios Retrospectivos , Columna Vertebral
19.
Cancer Imaging ; 22(1): 62, 2022 Nov 04.
Artículo en Inglés | MEDLINE | ID: mdl-36333763

RESUMEN

BACKGROUND: Esophageal fistula is one of the most serious complications of chemotherapy or chemoradiotherapy (CRT) for advanced esophageal cancer. This study aimed to evaluate the performance of quantitative computed tomography (CT) analysis and to establish a practical imaging model for predicting esophageal fistula in esophageal cancer patients treated with chemotherapy or chemoradiotherapy. METHODS: This study retrospectively enrolled 204 esophageal cancer patients (54 patients with fistula, 150 patients without fistula) and all patients were allocated to the primary and validation cohorts according to the time of inclusion in a 1:1 ratio. Ulcer depth, tumor thickness and length, and minimum and maximum enhanced CT values of esophageal cancer were measured in pretreatment CT imaging. Logistic regression analysis was used to evaluate the associations of CT quantitative measurements with esophageal fistula. Receiver operating characteristic curve (ROC) analysis was also used. RESULTS: Logistic regression analysis showed that independent predictors of esophageal fistula included tumor thickness [odds ratio (OR) = 1.167; p = 0.037], the ratio of ulcer depth to adjacent tumor thickness (OR = 164.947; p < 0.001), and the ratio of minimum to maximum enhanced CT value (OR = 0.006; p = 0.039) in the primary cohort at baseline CT imaging. These predictors were used to establish a predictive model for predicting esophageal fistula, with areas under the receiver operating characteristic curves (AUCs) of 0.946 and 0.841 in the primary and validation cohorts, respectively. The quantitative analysis combined with T stage for predicting esophageal fistula had AUCs of 0.953 and 0.917 in primary and validation cohorts, respectively. CONCLUSION: Quantitative pretreatment CT analysis has excellent performance for predicting fistula formation in esophageal cancer patients who treated by chemotherapy or chemoradiotherapy.


Asunto(s)
Fístula Esofágica , Neoplasias Esofágicas , Humanos , Estudios Retrospectivos , Úlcera , Quimioradioterapia/efectos adversos , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/patología , Tomografía Computarizada por Rayos X , Fístula Esofágica/diagnóstico por imagen , Fístula Esofágica/etiología , Fluorodesoxiglucosa F18
20.
Abdom Radiol (NY) ; 47(9): 3217-3228, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-34800159

RESUMEN

PURPOSE: To evaluate the potential role of MR findings and DWI parameters in predicting small regional lymph nodes metastases (with short-axis diameter < 10 mm) in pancreatic ductal adenocarcinomas (PDACs). METHODS: A total of 127 patients, 82 in training group and 45 in testing group, with histopathologically diagnosed PDACs who underwent pancreatectomy were retrospectively analyzed. PDACs were divided into two groups of positive and negative lymph node metastases (LNM) based on the pathological results. Pancreatic cancer characteristics, short axis of largest lymph node, and DWI parameters of PDACs were evaluated. RESULTS: Univariate and multivariate analyses showed that extrapancreatic distance of tumor invasion, short-axis diameter of the largest lymph node, and mean diffusivity of tumor were independently associated with small LNM in patients with PDACs. The combining MRI diagnostic model yielded AUCs of 0.836 and 0.873, and accuracies of 81.7% and 80% in the training and testing groups. The AUC of the MRI model for predicting LNM was higher than that of subjective MRI diagnosis in the training group (rater 1, P = 0.01; rater 2, 0.008) and in a testing group (rater 1, P = 0.036; rater 2, 0.024). Comparing the subjective diagnosis, the error rate of the MRI model was decreased. The defined LNM-positive group by the MRI model showed significantly inferior overall survival compared to the negative group (P = 0.006). CONCLUSIONS: The MRI model showed excellent performance for individualized and noninvasive prediction of small regional LNM in PDACs. It may be used to identify PDACs with small LNM and contribute to determining an appropriate treatment strategy for PDACs.


Asunto(s)
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Carcinoma Ductal Pancreático/diagnóstico por imagen , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/cirugía , Humanos , Ganglios Linfáticos/diagnóstico por imagen , Ganglios Linfáticos/patología , Metástasis Linfática/diagnóstico por imagen , Metástasis Linfática/patología , Imagen por Resonancia Magnética/métodos , Neoplasias Pancreáticas/diagnóstico por imagen , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/cirugía , Estudios Retrospectivos , Neoplasias Pancreáticas
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