Pancreatic cancer heterogeneity and response to Mek inhibition.

Our increasing knowledge of the mechanisms behind the progression of pancreatic cancer (PC) has not yet translated into effective treatments. Many promising drugs have failed in the clinic, highlighting the need for better preclinical models to assess drug efficacy and characterize mechanisms of resistance. Using different experimental models, including patient-derived xenografts (PDXs), we gauged the efficacy of therapies aimed at two hallmark lesions of PCs: activation of signaling pathways by oncogenic KRAS and inactivation of tumor-suppressor genes. Although the drug targeting inactivation of tumor suppressors by DNA methylation had little effect, the inhibition of Mek, a K-Ras effector, in combination with the standard of care (chemotherapy consisting of gemcitabine/Nab-paclitaxel), reduced the growth of three out of five PC-PDXs and impaired metastasis. The two least responding PC-PDXs were composed of genetically diverse cells, which displayed sensitivities to the Mek inhibitor differing by >10-fold. Unexpectedly, our analysis of this genetic diversity unveiled different KRAS mutations. As mutation in KRAS occurs early during progression, this heterogeneity may reflect the simultaneous appearance of different malignant cellular clones or, alternatively, that cells containing two mutations of KRAS are selected during tumor evolution. In vitro and in vivo analyses indicated that the intratumoral heterogeneity, along with the selective pressure imposed by the Mek inhibitor, resulted in rapid selection of resistant cells. Together with the gemcitabine/Nab-paclitaxel backbone, Mek inhibition could be effective in treatment of PC. However, resistance because of intratumoral heterogeneity is likely to develop frequently, pointing to the necessity of identifying the factors and mechanisms of resistance to further develop this therapy.

Initial experience in sentinel lymph node detection in pancreatic cancer / Experiencia inicial en la detección del ganglio centinela en cáncer de páncreas

Background. The local recurrence of pancreatic cancer is around 30% when complete resection can be achieved. Extended lymphatic resections may improve survival, but increases severe morbidity. As accurate patient selection should be mandatory, a new method is presented for pancreatic sentinel lymph node (SLN) detection with lymphoscintigraphy and gamma probe. Materials and methods. Seven patients with cT2N0M0 pancreatic head cancer were enrolled between 2009 and 2012 in this prospective study. One day prior to surgery, preoperative lymphoscintigraphy with echoendoscopic intratumoural administration of Tc99m-labelled nanocolloid was performed, with planar and SPECT-CT images obtained 2h later. Gamma probe detection of SLN was also carried out during surgery. Results. Radiotracer administration was feasible in all patients. Scintigraphy images showed inter-aortocaval lymph nodes in 2 patients, hepatoduodenal ligament lymph nodes in 1, intravascular injection in 3, intestinal transit in 5, and main pancreatic duct visualisation in 1. Surgical resection could only be achieved in 4 patients owing to locally advanced disease. Intraoperative SLN detection was accomplished in 2 patients, both with negative results. Only in one patient could SLN be confirmed as truly negative by final histopathological analysis. Conclusions. This new method of pancreatic SLN detection is technically feasible, but challenging. Our preliminary results with 7 patients are not sufficient for clinical validation (AU)

Objetivo. Tras una resección quirúrgica completa, la recidiva local del cancer de páncreas es de aproximadamente el 30%. La linfadenectomía extendida podría mejorar la supervivencia pero implica una morbilidad grave, por lo que una adecuada selección de los pacientes seria fundamental. Presentamos una nueva técnica de determinación del ganglio centinela (GC) en el cáncer de páncreas mediante el uso de SPECT/TC y sonda gamma. Materiales y Métodos. Siete pacientes con cáncer de páncreas estadío cT2N0M0 fueron incluidos entre 2009 y 2012 en este estudio prospectivo. El día antes de la cirugía se realizó una ecoendoscopia con inyección intratumoral de un nanocoloide marcado con Tc99m y dos horas más tarde se obtuvieron imágenes planares y de SPECT-TC. Intraoperatoriamente se realizó asimismo un rastreo con sonda gamma para detectar el GC. Resultados. La administración del radiotrazador fue posible en todos los pacientes. La linfogammagrafía detectó ganglios interaortocavos en 2 pacientes, ganglios en el ligamento hepatoduodenal en 1 paciente, inyección intravascular en 3 pacientes, tránsito intestinal en 5 pacientes y visualizó el conducto pancreático principal en 1 paciente. Debido a la progresión local, la resección quirúrgica pudo ser completada únicamente en 4 pacientes. La detección intraoperatoria del GC se completo en 2 pacientes, ambos con resultado negativo. Sólo en uno de estos pacientes el resultado pudo confirmarse con el estudio anatomopatológico definitivo. Conclusiones. Este nuevo método de detección del GC en cáncer de páncreas es viable pero complejo. Nuestros resultados preliminares con 7 pacientes no permiten una validación clínica (AU)

Initial experience in sentinel lymph node detection in pancreatic cancer.

BACKGROUND: The local recurrence of pancreatic cancer is around 30% when complete resection can be achieved. Extended lymphatic resections may improve survival, but increases severe morbidity. As accurate patient selection should be mandatory, a new method is presented for pancreatic sentinel lymph node (SLN) detection with lymphoscintigraphy and gamma probe. MATERIALS AND METHODS: Seven patients with cT2N0M0 pancreatic head cancer were enrolled between 2009 and 2012 in this prospective study. One day prior to surgery, preoperative lymphoscintigraphy with echoendoscopic intratumoural administration of Tc(99m)-labelled nanocolloid was performed, with planar and SPECT-CT images obtained 2h later. Gamma probe detection of SLN was also carried out during surgery. RESULTS: Radiotracer administration was feasible in all patients. Scintigraphy images showed inter-aortocaval lymph nodes in 2 patients, hepatoduodenal ligament lymph nodes in 1, intravascular injection in 3, intestinal transit in 5, and main pancreatic duct visualisation in 1. Surgical resection could only be achieved in 4 patients owing to locally advanced disease. Intraoperative SLN detection was accomplished in 2 patients, both with negative results. Only in one patient could SLN be confirmed as truly negative by final histopathological analysis. CONCLUSIONS: This new method of pancreatic SLN detection is technically feasible, but challenging. Our preliminary results with 7 patients are not sufficient for clinical validation.

Non-anatomical intestinal transplantation.

INTRODUCTION: Intestinal transplantation is the only long-range treatment option for patients with intestinal failure. We report an exceptional case of isolated intestinal transplantation with the implant in a non-anatomical position. CLINICAL CASE: The patient was a thirty-eight-year-old man (60 kg weight, 180 cm height, 18.3 body mass index) with intestinal failure and home parenteral nutrition due to a short-bowel syndrome for which intestinal transplantation was indicated. The patient had a vascular malformation with the cava vein located left to the aorta, and the intestine was implanted with a 180 masculine rotation around the mesenteric axis, so that the implant s superior mesenteric artery and vein matched the recipient s cava and aorta. Postoperative follow-up was excellent and the patient was discharged after six weeks with a 10-kg gain in body weight. DISCUSSION: This non-anatomical intestinal implantation of the small bowel, previously unreported, offers technical advantages over other options. Adequate intestinal function represents a unique model to prove the viability of intestinal implants in a non-anatomical position.

Trasplante intestinal en posición no anatómica / Non-anatomical intestinal transplantation

Introducción: el trasplante intestinal es el único tratamiento eficaz a largo plazo de los pacientes con fallo intestinal. Se presenta un caso clínico excepcional de trasplante intestinal aislado en posición no anatómica. Caso clínico: se trata de un varón de 38 años de edad con fallo intestinal y nutrición parenteral domiciliaria por un síndrome de intestino corto al que se le indicó un trasplante intestinal. Fue incluido en lista de espera con un peso de 60 kg, 180 cm de altura y 18,3 de índice de masa corporal. El receptor presentaba una trasposición de los grandes vasos con la vena cava situada a la izquierda de la arteria aorta por lo que el intestino se implantó con una rotación del injerto de 180º sobre su eje mesentérico, con el objetivo de que la vena y la arteria mesentérica superior del injerto coincidieran con la vena cava y la arteria aorta del receptor. El paciente presentó excelente postoperatorio y fue dado de alta a las 6 semanas con un aumento de peso de 10 kg. Discusión: esta implantación no anatómica del intestino, previamente no referida en la literatura, ofrece ventajas técnicas sobre otras alternativas. La adecuada función intestinal constituye un modelo único que prueba la viabilidad del intestino implantado en posición no anatómica(AU)

Introduction: intestinal transplantation is the only long-range treatment option for patients with intestinal failure. We report an exceptional case of isolated intestinal transplantation with the implant in a non-anatomical position. Clinical case: the patient was a thirty-eight-year-old man (60 kg weight, 180 cm height, 18.3 body mass index) with intestinal failure and home parenteral nutrition due to a short-bowel syndrome for which intestinal transplantation was indicated. The patient had a vascular malformation with the cava vein located left to the aorta, and the intestine was implanted with a 180º rotation around the mesenteric axis, so that the implant's superior mesenteric artery and vein matched the recipient's cava and aorta. Postoperative follow-up was excellent and the patient was discharged after six weeks with a 10-kg gain in body weight. Discussion: this non-anatomical intestinal implantation of the small bowel, previously unreported, offers technical advantages over other options. Adequate intestinal function represents a unique model to prove the viability of intestinal implants in a non-anatomical position(AU)

Colocación de sonda de nutrición enteral asistida por clip hemostásico / Hemostatic clip-assisted placement of enteral feeding tubes

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