ABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis among all human cancers as it is highly resistant to chemotherapy. K-Ras mutations usually trigger the development and progression of PDAC. We hypothesized that compounds stabilizing the KRas4B/PDE6δ complex could serve as PDAC treatments. Using in silico approaches, we identified the small molecules C14 and P8 that reduced K-Ras activation in primary PDAC cells. Importantly, C14 and P8 significantly prevented tumor growth in patient-derived xenotransplants. Combined treatment with C14 and P8 strongly increased cytotoxicity in PDAC cell lines and primary cultures and showed strong synergistic antineoplastic effects in preclinical murine PDAC models that were superior to conventional therapeutics without causing side effects. Mechanistically, C14 and P8 reduced tumor growth by inhibiting AKT and ERK signaling downstream of K-RAS leading to apoptosis, specifically in PDAC cells. Thus, combined treatment with C14 and P8 may be a superior pharmaceutical strategy to improve the outcome of PDAC.
Subject(s)
Antineoplastic Agents , Carcinoma, Pancreatic Ductal , Pancreatic Neoplasms , Humans , Mice , Animals , Cell Line, Tumor , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/metabolism , Carcinoma, Pancreatic Ductal/drug therapy , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/pathology , Antineoplastic Agents/pharmacology , Pancreatic NeoplasmsABSTRACT
AIM: The aim of this study is to describe our experience in the diagnosis and treatment of gallstone ileus, as well as the morbility and mortality associated to this pathology. BACKGROUND: The first description of gallstone ileus was made by Bartholin in 1645 during a post-mortem study. It is a rare pathology, the preoperative diagnosis is difficult and controversy exists in the management that should be carried out on first instance, whether the extraction of the gallstone or the correction of the fistula which can affect outcome. METHODS: We made a case series study in which we studied a total of 25 patients in a 14 years period (1989-2003) with diagnosis of gallstone ileus, patients excluded were those with cholecystoduodenal fistula without gallstone ileus. The variables analyzed were: age, sex, preoperative and postoperative diagnosis, treatment and postoperative morbidity and mortality. RESULTS: Twenty, five patients were studied with diagnosis of gallstone ileus (20 women and 5 men) The median age was 64 (rage 41 to 99). The cholecystoenteric fistula is the most frequently was the cholecystoduodenal in 23. cases (92%) one coledocoduodenal (4%) and one cholecystogastric (4%). The most common site of obstruction was the terminal ileon in 96%. There was a morbility of 20% and the mortality in 7%. CONCLUSION: Gallstone ileus is a rare entity, with only 25 cases reported in a 14 years period in our hospitals. Initial surgical treatment should be guided to the correction of the obstruction and should be considered in a second stage the correction of the fistula, if the patient does not develop symptoms it is not necessary, decreasing morbidity and mortality.
Subject(s)
Gallstones/surgery , Ileus/surgery , Adult , Aged , Aged, 80 and over , Female , Gallstones/complications , Humans , Ileus/complications , Intestinal Fistula/complications , Male , Middle AgedABSTRACT
El objetivo del estudio fue conocer la frecuencia, estadificación, tratamiento y sobrevida en la Unidad de tumores mamarios en el Servicio de Oncología del Hospital General de Mexico. Se estudiaron 20 pacientes con diagnóstico clínico e histológico de Enfermedad de Paget mamaria, de un total de 1955 neoplasias tratadas entre enero 1990 a diciembre 1997. el diagnóstico por etapas clínicas correspndió a Etapa Clínica 0.3/100; etapa clinica I,5/100; etapa clínica II,20/100; etapa clínica III, 20/100; etapa clínica IV, 10/100 y no fueron clasificadas 15/100. El diagnóstico histopatológico se confirmó siempre por biopsias incisional y el 90/100 de los pacientes fueron tratados con una mastectomía radical modificada. Solo el 10/100 se les practicó cirugía conservadora mas radioterapia. El seguimiento y la sobrevida global fue de 57 meses, en promedio. La mayoria de las pacientes se presentaron con lesiones que se extendían a la areola y con tumor palpable, por lo que el tratamiento radical fue lo indicado. En nuestro medio la cirugía conservadora es poco factible, ya que el diagnóstico se efectúa tardíamente.
