Development of transcriptomic tools for predicting the response to individual drug of the mFOLFIRINOX regimen in patients with metastatic pancreatic cancer.

Background: The utilization of modified FOLFIRINOX (mFFX) therapy has shown notable advancements in patient outcomes in both localized and metastatic PDAC. Nevertheless, the effectiveness of mFFX treatment comes at the cost of elevated toxicity, leading to its restriction to patients with adequate performance status. Consequently, the administration of mFFX is contingent upon patient performance rather than rational criteria. The ideal scenario would involve the ability to assess the sensitivity of each drug within the mFFX regimen, minimizing unnecessary toxicity without compromising clinical benefits. Methods: We developed transcriptomic signatures for each drug of the mFFX regimen (5FU, oxaliplatin and irinotecan) by integrating transcriptomic data from PDC, PDO and PDX with their corresponding chemo-response profiles to capture the biological components responsible for the response to each drug. We further validated the signatures in a cohort of 167 patients with advanced and metastatic PDAC. Results: All three signatures captured high responder patients for OS and PFS in the mFFX arm exclusively. We then studied the response of patients to 0, 1, 2 and 3 drugs and we identified a positive correlation between the number of drugs predicted as sensitive and the OS and PFS, and the with objective response rate. Conclusions: We developed three novel transcriptome-based signatures which define sensitivity for each mFFX components that can be used to rationalize the administration of the mFFX regimen in patients with metastatic pancreatic cancer and could help to avoid unnecessary toxic effects.

Metabolomic profiling of pancreatic adenocarcinoma reveals key features driving clinical outcome and drug resistance.

BACKGROUND: Although significant advances have been made recently to characterize the biology of pancreatic ductal adenocarcinoma (PDAC), more efforts are needed to improve our understanding and to face challenges related to the aggressiveness, high mortality rate and chemoresistance of this disease. METHODS: In this study, we perform the metabolomics profiling of 77 PDAC patient-derived tumor xenografts (PDTX) to investigate the relationship of metabolic profiles with overall survival (OS) in PDAC patients, tumor phenotypes and resistance to five anticancer drugs (gemcitabine, oxaliplatin, docetaxel, SN-38 and 5-Fluorouracil). FINDINGS: We identified a metabolic signature that was able to predict the clinical outcome of PDAC patients (p < 0.001, HR=2.68 [95% CI: 1.5-4.9]). The correlation analysis showed that this metabolomic signature was significantly correlated with the PDAC molecular gradient (PAMG) (R = 0.44 and p < 0.001) indicating significant association to the transcriptomic phenotypes of tumors. Resistance score established, based on growth rate inhibition metrics using 35 PDTX-derived primary cells, allowed to identify several metabolites related to drug resistance which was globally accompanied by accumulation of several diacy-phospholipids and decrease in lysophospholipids. Interestingly, targeting glycerophospholipid synthesis improved sensitivity to the three tested cytotoxic drugs indicating that interfering with metabolism could be a promising therapeutic strategy to overcome the challenging resistance of PDAC. INTERPRETATION: In conclusion, this study shows that the metabolomic profile of pancreatic PDTX models is strongly associated to clinical outcome, transcriptomic phenotypes and drug resistance. We also showed that targeting the lipidomic profile could be used in combinatory therapies against chemoresistance in PDAC.

Squamousness gain defines pancreatic ductal adenocarcinoma hepatic metastases phenotype, and gemcitabine response.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a dismal disease with a survival rate of less than 7%, mainly due to the hepatic metastatic spread. Despite the importance of understanding PDAC metastases, central questions remain concerning their biology and chemosensitivity. Moreover, the transcriptomic divergence between primary tumor (PT) and hepatic metastases (HM) has been poorly studied and without a clear dissection of the confounding tumoral-surrounding tissue. METHODS: Here, to unravel key biological features not biased by the surrounding tissue, we implemented a blind source separation based on independent component analysis, ProDenICA, on a treatment-naïve cohort of PDAC paired samples and a cohort of 305 resectable patients. In addition, a time-lapse experiment was performed to assess the gemcitabine chemosensitivity profile between the PT and HM. RESULTS: We identified HM's specific transcriptomic characteristics related to the upregulation of cell cycle checkpoint, mitochondria activity, and extracellular matrix reorganization, which could be associated with metastatic niche adaptation mechanisms. Furthermore, squamous lineage emerged as a key feature linked with a downregulation in the epithelial-to-mesenchymal program that can stratifies PDAC HM independent of the classical/basal-like spectrum. Remarkably, we also demonstrated that gemcitabine response is influenced by the squamous profile, being the HM more refractory to the treatment than the PT. CONCLUSIONS: These results pointed out divergent HM aspects compared to PT and allowed their stratification through the squamous lineage. Moreover, we unravel a clinical actionable squamous signature that predicts the gemcitabine response.

Risk factors of pancreatic fistula and delayed gastric emptying after pancreaticoduodenectomy with pancreaticogastrostomy.

BACKGROUND: Pancreatic fistula (PF) and delayed gastric emptying (DGE) are, respectively, the most frightening and most frequent complications after pancreaticoduodenectomy (PD). This study was undertaken to determine which independent factors influence the development of PF and DGE after PD. STUDY DESIGN: Between January 1996 and December 2005, 131 consecutive patients underwent a PD with pancreaticogastrostomy. A total of 22 items, entered prospectively, were examined with univariate and multivariate analysis. PF was defined as amylase-rich fluid collected by needle aspiration from an intraabdominal collection or from the drainage placed intraoperatively from day 3. DGE was defined as the need for nasogastric decompression beyond the 10(th) postoperative day. RESULTS: PF occurred in 14 patients (10.7%), with a mean length of hospital stay of 40.1+/-16.6 days. DGE occurred in 41 patients (31.3%), with a mean length of hospital stay of 35.5+/-13.6 days. PF and DGE increased postoperative length of stay. Multivariate analysis identified two independent factors for PF: heart disease as a risk factor and arterial hypertension as a protective factor. According to these two predictive factors, the observed rates of PF ranged from 4.1% to 66.6%. Age and early enteral feeding with nasojejunal tube were independent risk factors for DGE. DGE was statistically more frequent when surgical complications occurred or when an intraabdominal collection was present. CONCLUSIONS: Heart disease was a risk factor and arterial hypertension was a protective factor of PF. Age and early enteral feeding were independent risk factors for DGE. DGE is linked to the occurrence of other postoperative intraabdominal complications.

Malignant rhabdoid tumors of the liver: an exceptional tumor in adults - a case report and literature review.

Malignant rhabdoid tumor (MRT) is a very rare liver tumor, with only a few cases reported in the literature. MRT generally occurs in pediatric patients and prognosis is usually very poor. Here we report a very rare case of MRT occurring in a young adult who is still alive with no sign of recurrence at 41 months of follow-up. MRI and computed tomography scans revealed a voluminous heterogeneous mass in the left liver with no specific pattern. The mass included necrotic and fibrous components. Histology showed fusiform, loosely cohesive cells with abundant eosinophilic cytoplasm resulting in eccentric nuclei, thus creating the characteristic rhabdoid appearance. Immunohistochemical studies revealed a lack of nuclear INI1 protein expression. The patient's treatment included a major left liver resection associated with chemotherapy. A thorough search of the literature revealed one case of MRT in a young adult who died at 48 months of follow-up. A less malignant nature of the tumor in young adults may be suspected, but a longer disease-free survival may also be the fruit of aggressive surgical and oncological treatment.

Malignant rhabdoid tumour of the liver in the young adult: report of first two cases.

Few cases of malignant rhabdoid tumour (MRT) of the liver are reported in literature and always in paediatric patients. We report the first two cases of young adults submitted to hepatic resection for MRT of the liver. A major liver resection was performed in both cases. The histology showed round or fusiform, loosely cohesive cells. The cytoplasm contained abundant eosinophilic inclusions, which caused the nuclei to be located in eccentric locations, giving the characteristic rhabdoid appearance. The immunohistochemical study was performed, and characteristic lack of nuclear INI1 protein expression was found. In a case surgery was associated to chemoradiotherapy. One patient died at 48 months followup for tumour recurrence. The other is still alive at 25 months followup. MRTs are rare tumours of pediatric age with poor prognosis. Hypothetical less malignant behaviour in the young adults could be supposed. Therefore an aggressive surgical and oncological treatment seems justified.

Effect of preoperative endoscopic biliary drainage on infectious morbidity after pancreatoduodenectomy: a case-control study.

BACKGROUND: The utility of preoperative endoscopic biliary drainage (PEBD) in jaundiced patients before pancreatoduodenectomy (PD) is still debated. This is in part due to the heterogeneity of the studied population, including different tumor location, drainage techniques, and surgical procedures. The aim of the current study was to report the influence of PEBD on postoperative infectious morbidity of PD. MATERIALS AND METHODS: Between January 1996 and December 2004, 124 patients underwent a PD and 28. Twenty-eight (22.6%) of these patients underwent a PEBD. This group of patients was matched to 28 control patients who underwent PD without PEBD during the same period. The 2 groups were matched for age, sex, indication of surgery, and serum bilirubin levels. RESULTS: The specific morbidity of PEBD before surgery was 10.7% (n = 3). The postoperative overall morbidity, medical morbidity, and surgical morbidity rates were not different between the 2 groups. At the time of surgery, 89.3% (n = 25) of the patients in the PEBD group had positive bile culture in comparison to 19.4% (n = 4) in the control group (P < .001). The number of patients with 1 or more infectious complications was higher in the PEBD group (50%; n = 14) than in the control group (21.4%; n = 6) (P = .05). CONCLUSIONS: Before PD, PEBD should be routinely avoided whenever possible in patients with potentially resectable pancreatic and peripancreatic lesions. In patients with cholangitis, requiring extensive preoperative assessment (such as liver biopsy) or neoadjuvant treatment, PEBD might still be indicated.

Cistoadenocarcinoma de cabeza de páncreas / Cystadenocarcinoma of the head of the pancreas

Se presentan cuatro pacientes operados de un cistoadenocarcinoma mucinoso de cabeza de páncreas, en quienes se practicó una duodenopancreatectomía cefálica ampliada. Llama la atención que en contraposición a lo que manifiesta la literatura, tres casos fueron hombres. Se destaca que a pesar de ser tumores voluminosos con un promedio aproximado de más de 8cm., todos los casos pudieron ser resecados sin mayores dificultades técnicas y no presentaron metástasis ganglionares regionales. Finalmente, se propone una metodología de estudio

Tumores quísticos del páncreas: realidad actual / Pancreatic cystic: our experiencie

Se presentan 14 pacientes portadores de un tumor quístico de páncreas, ocho hombres y seis mujeres. La edad promedio fue de 63,2 años con un rango entre 34 y 79. Cinco tumores estaban localizados en la cabeza, cinco en el cuerpo y tres en la región corporocaudal. Seis lesiones fueron benignas y las restantes malignas, de las cuales el cistoadenocarcinoma mucinoso fue la forma histopatológica más frecuente (53,8 por ciento). Una paciente de 70 años con un cistoadenoma microquístico no fue operada por tratarse de una lesión prácticamente asintomática localizada en cabeza. Los trece restantes fueron explorados quirúrgicamente, sin mortalidad operatoria. Uno de ellos, portador de un cistoadenocarcinoma mucinoso de istmo fue irresecable, por compromiso de la vena porta y de la arteria hepática. En tres cistoadenomas mucinosos de cuerpo, se realizó una pancreatectomía corporo-caudal con conservación del bazo, encontrándose asintomáticos a los 2, 3 y 5 años. A los seis cistoadenocarcinomas mucinosos se les realizó: en dos, una espleno-pancreatectomía distal, ambos actualmente asintomáticos, y en cuatro una duodeno-pancreatectomía cefálica, de los cuales dos viven a los 5 y 8 años. Un quiste congénito fue resecado, evolucionando muy bien. La neoplasia quística papilar fue tratada con una pancreatectomía corporo-caudal con conservación del bazo, encontrándose asintomática a cinco años de la cirugía y el gastrinoma, por medio de una gastrectomía total más espleno-pancreatectomía distal, con buena evolución durante 15 años

Diverticulitis cecal aguda: nuestra conducta terapéutica / Cecal acute diverticulitis: our experience

Antecedentes: La diverticulitis cecal aguda es una enfermedad poco frecuente que simula el cuadro de una apendicitis aguda, y que presenta problemas en el diagnóstico. Objetivo: Evaluación de la conducta terapéutica de acuerdo a las formas clínicas de presentación y los hallazgos intraoperatorios. Lugar de aplicación: Servicio de Guardia del Hospital Nacional de Clínicas U.N.C. y grupo ABC. Diseño: Retrospectivo observacional. Método: Han sido tratados quirúrgicamente veinte pacientes con diverticulitis cecal aguda. Catorce eran del sexo masculino con una edad promedio de 48,2 años. El síntoma principal fue el dolor abdominal especialmente localizado en f.i.d., pero en 2 oportunidades se presentó un cuadro de abdomen agudo perforativo. Los pacientes fueron intervenidos quirúrgicamente con el diagnóstico de apendicitis aguda en nueve, neoplasia de ciego en tres, perforación de víscera hueca en dos, diverticulitis cecal en tres y los restantes sin sospecha diagnóstica. Resultados: Se practicaron catorce hemicolectomías derechas. En los seis restantes se efectuó una cecostomía. De éstos últimos, uno falleció en el postoperatorio por un T.E.P.A. Cinco pacientes presentaron un absceso de pared, tres de ellos tenían una hemicolectomía derecha y dos una cecostomía. En el postoperatorio alejado, tres pacientes presentaron una eventración mediana. Conclusiones: Consideramos que en aquellos pacientes con serias dificultades para decidir la malignidad o benignidad del proceso, aún siendo jóvenes, o cuando estamos frente a la probabilidad de un divertículo cecal perforado con compromiso inflamatorio o infeccioso del ciego, creemos que el mejor tratamiento es la hemicolectomía derecha