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.

[Peripheral cholangiocarcinoma: results of surgical treatment]. / Colangiocarcinoma periférico: resultados del tratamiento quirúrgico.

INTRODUCTION: Peripheral cholangiocarcinoma (PC) is an uncommon primary hepatic tumor that represents 10% of hepatic resections for primary malignant tumors in our experience. PATIENTS AND METHODS: From 1988 to 2004, 29 patients with a diagnosis of PC were treated in our unit. One patient was treated with chemoembolization and the remainder underwent surgery. In 7 patients, hepatectomy was not performed due to the presence of an extrahepatic tumor or massive hepatic invasion. The resectability index was 75%. Twenty-one patients underwent radical excision of PC and comprised the study group. RESULTS: The mean age was 60 years with a slight predominance of women. Sixty-two patients were symptomatic and tumoral markers were elevated in 58%. PC developed in normal liver in 15 patients, in cirrhotic liver in 2 patients and in the context of chronic hepatitis in 4 patients. The mean tumoral size was 7 cm (between 1.6 and 13 cm). Multiple tumors were found in 3 patients, invasion of the hepatic hilum lymph nodes was found in 8 patients and vascular invasion was observed in a further 8 patients. Major hepatectomy was performed in 90% of the patients; radical lymphadenectomy of the hepatic hilum was performed in 15 patients and excision of the extrahepatic biliary tract followed by Roux-en-Y hepaticojejunostomy in 4 patients. Operative mortality occurred in 3 patients (14%); one cirrhotic patient died 4 days after surgery from cardiovascular causes and 2 patients died from liver failure after extensive hepatectomies that included resection of the inferior vena cava and suprahepatic veins. Complications occurred in 33% of the patients. Ten patients (47%) died. Of these, 6 died from tumoral recurrence. Tumoral recurrence occurred in 9 patients (5 hepatic and 4 extrahepatic). Hepatic recurrences were treated with radiofrequency ablation in 2 patients and chemotherapy in 5 patients. The median survival was 11 months. Actuarial survival at 1, 3 and 5 years was 60%, 47% and 47% respectively. Disease-free survival at 1, 3 and 5 years was 50%, 31% and 31% respectively. In univariate analysis, significant risk factors for mortality were lymphatic invasion and a resection margin of less than 1 cm. In multivariate analysis, negative factors for tumoral recurrence were lymphatic invasion, satellitosis, and poor tumoral delimitation. CONCLUSION: Surgical treatment of PC through radical hepatic resection with margins of more than 1 cm in patients without nodal invasion provides good results with a 5-year survival of 79%.

Early pleural effusion in histiocytosis X.

Two cases of histiocytosis X, one of the disseminated form and the other localized to the lung, are reported, in which pleural effusion, probably due to pleural involvement as assessed by biopsy, was one of the initial manifestations of the disease.

Canine dirofilariosis in two cities of southeastern Spain.

Several cases of human subcutaneous/ocular dirofilariosis caused by Dirofilaria repens from an area in the southeastern Spain where previous epidemiological studies have shown a very low prevalence of this species in dogs, have been studied in our laboratory. Since the prevalence of this species in dogs did not correspond to the incidence of human cases in the zone studied, a preliminary epidemiological survey was carried out on 114 dog blood samples from two kennels and one veterinary clinic. Knott, polymerase chain reaction (PCR) with specific primers for Dirofilaria immitis and D. repens, and ELISA with adult E/S D. immitis and adult somatic D. repens antigens for the detection of specific IgG, were used. Fifty-three out of the 114 samples analyzed were positive for Knott and/or PCR to D. immitis or to D. repens. D. repens was the species with the highest prevalence, 84.6 and 37.1%, respectively, in each kennel. IgG antibodies against D. immitis and D. repens, were detected in 11 samples which gave negative results to both Knott and PCR. These results demonstrate a very high prevalence of D. repens that could be associated with the increasing incidence of human subcutaneous/ocular cases recently detected in this zone.

[Histologic evolution of acute alcoholic hepatitis]. / Evolución histológica de la hepatitis alcohólica aguda.

Although acute alcoholic hepatitis is a frequent disease with distinct histologic diagnosis, the prognostic factors of its evolution are largely unknown. The present report analyzes the data of 18 patients with acute alcoholic liver disease submitted to two liver biopsies with a mean interval of 35 months. The results demonstrate a favorable histologic evolution in six of seven patients that abandoned alcohol ingestion, and an evolution to chronic liver disease in the remaining case. Out of six patients with continuous alcohol ingestion the evolution was unfavorable in five, while one case evolved to healing. Centrilobular fibrosis disappeared in the six cases that discontinued alcohol ingestion and who had favorable evolution, and it persisted in four of the six patients that continued drinking. The results suggest that centrilobular fibrosis is not always an unfavorable prognostic marker, and that the evolution of acute alcoholic hepatitis is not exclusively dependent on the continuation of alcohol abuse.

[Improvement in the results of surgical resection of hepatocellular carcinoma]. / Mejoría de los resultados de la resección quirúrgica del hepatocarcinoma.

AIM: To present the results of hepatectomies performed for hepatocellular carcinoma in a specialist unit and to compare the results of an initial period (1987-1993) with those obtained in a second period (1995-2000) in which the indications were limited to Child class A patients without portal hypertension. During the second period technical improvements such as intermittent selective hilar clamping and greater hiliar restrictions on transfusions were introduced. PATIENTS AND METHODS: One hundred and ten hepatectomies were performed in 105 patients with hepatocellular carcinoma in our unit over a 12-year period. Eighty percent of the tumors occurred in cirrhotic livers, mainly caused by hepatitis C virus. In the second period, upper gastrointestinal endoscopy was systematically performed to study the presence of varices. Hemodynamics studies were optionally performed to rule out portal hypertension. RESULTS: In the second period larger tumors were resected, a greater number of major hepatectomies were performed due to the increased frequency of hepatocellular carcinoma in non-cirrhotic liver, and fewer patients underwent transfusion. Early mortality was reduced from 21% to 1.8% and mean survival significantly increased from 37 to 52 months. Actuarial survival increased from 64% to 91% at 1 year and from 23% to 52% at 5 years in the first and second periods, respectively. Disease-free survival also increased significantly from 53% and 84% at 1 year and 27% and 40% at 5 years in the first and second periods, respectively. Analysis of the results in cirrhotic patients also showed a statistically significant improvement in early mortality and survival. Multivariate analysis of prognostic factors for survival demonstrated that the absence of blood transfusion, patients who underwent resection in the second period and the presence of pseudocapsules were independent factors for increased survival. CONCLUSIONS: The results of liver resection for hepatocellular carcinoma improved significantly due to the reduction in early mortality produced by more rigorous patient selection and the introduction of technical improvements.

[Clinical characteristics of chronic autoimmune hepatitis. Study of 51 cases]. / Características clínicas de la hepatitis crónica autoinmune. Estudio de 51 casos.

The clinical and histological features of the 51 patients affected with chronic autoimmuno hepatitis are analyzed. 65% of them were over 50 years old. 41% were without symptoms. The incidence of systemic symptoms was of 25.5%. 84.3% had antinuclear antibodies superior of 1/40 and 53% had positive LMA. The incidence of HCA and CH was similar. 26.7% of the patients had complications.

[Alpha-1-antitrypsin deficiency associated with ruptured aneurysm of the splenic artery]. / Déficit de alfa-1-antitripsina asociado a rotura de aneurisma de la arteria esplénica.

We show a patient with a rupture of splenic artery aneurysm, seven days after liver transplantation for hepatic cirrhosis and portal hypertension secondary to alfa-1-antitrypsin deficiency. We analyse the aneurysm pathology and its relationship with the blood flow through the aneurysm.

Monografía observacional del tronco celiaco / Observational Monograph Of The Celiac Trunk

El tronco celíaco es la primera rama visceral de la aorta abdominal, tiene la función de irrigar al hígado, bazo y estómago, además accesoriamente duodeno y páncreas. Nuestra intención fue describir experiencia en la disección de este ramo arterial, siendo ésta punta pié inicial para la elaboración de una propia casuística. Utilizamos para esta disección un cadáver adulto de sexo femenino conservado en formol al 10 % sin previa selección. El tronco celíaco (TC) fue abordado vía abdomnal, previa incisión medial del abdomen, al igual que sus ramos terminales y respectivos órganos que irriga. Se diseco en conjunto la pieza anatómica formada por el TC, arteria hepática, esplénica y coronaria estomáquica; hígado, estomago, bazo, páncreas y duodeno, con sus respectivas irrigaciones. Esta actividad fue realizad en el año lectivo 2011 por alumnos de primer año en en coordinación y dirección de un superior a cargo.

The celiac trunk is the first brnch of the abdominal nal aorta visceral, has the function of irrigating the liver, spleen and stomach, duodenum and páncreas alsoincidentally. Our intention was to describe the experiencia in the dissection of the arterial branch, this beingstarting point to the preparation of a casuistry own. Usedfor this dissection a female adult cadáver preserved in10% formalin without prior seletion. The celiac artery was approached route abdominal previous incisión medial abdomen, as well as their respective termial branches and organs that irrigates. Was dissected in anatomical piece set consistig of the celiac trunk, hepatic artery, splenic artery and stomachic coronary artery; liver, stomach, spleen pancreas and duodenum, with their irrigation. This activity was conducted in the academicyear 2011 for first years students in coordination and direction of a superior charge.

Intrahepatic biliary stones in children.

Intrahepatic biliary stones in seven non-Oriental patients were studied in all by sonography, in four patients by computed tomography and in four patients by percutaneous transhepatic cholangiography. For patients had extrahepatic biliary atresia treated with portoenterostomies, one patient had undergone partial liver transplantation and of the remaining two, one had cystic fibrosis and the other immunodeficiency syndrome. All sonograms were abnormal and showed echogenic foci within the liver, with or without associated signs of biliary tract dilatation. CT confirmed the biliary tract dilatation yet calculi were identified in one patient only. PTC was particularly helpful in the patient with immunodeficiency in whom features typical of sclerosing cholangitis were found. This report emphasizes the variable radiological appearance of bile stones which to our knowledge have rarely been described in children with entities other than Oriental cholangitis.

Survival after intestinal mucormycosis in acute myelogenous leukemia.

A young woman with acute myelocytic leukemia developed acute lower gastrointestinal bleeding immediately after a first remission induction of her leukemia. After the site of bleeding was located in the descending colon, a necrotic bleeding ulcer was resected. Histologic examination of the ulcer established the diagnosis of gastrointestinal mucormycosis. Treatment with amphotericin B was administered because of the high risk of dissemination. The patient has been followed for 9 months with no evidence of relapse of infection. Survival after gastrointestinal mucormycosis in acute leukemia has not previously been reported in the English language literature. Success in managing mucormycosis depends on the adherence to the recommended principles of early aggressive diagnostic measures, excisional surgery, amphotericin B therapy, and control of the underlying predisposing condition.

Liver involvement in multiple myeloma.

One hundred twenty-eight records of patients with multiple myeloma were reviewed to assess the incidence and manifestations of liver involvement. Histologic study of the liver was available in 21 patients. Diffuse infiltration of the liver by plasma cells was observed in 10 patients, myeloid metaplasia in four, amyloidosis in two, toxic hepatitis in two, and extrahepatic cholestasis secondary to infiltration of the peripancreatic tissue by plasma cells in one. The clinical signs of plasma cell infiltration of the liver consisted of hepatomegaly in seven patients, mild elevation of liver enzymes in five, and portal hypertension in two. Jaundice was only observed in patients with hepatitis or extrahepatic cholestasis. Liver infiltration by plasma cells did not appear to have a major prognostic significance.

Chronic delta hepatitis: detection of hepatitis delta virus antigen in serum by immunoblot and correlation with other markers of delta viral replication.

To investigate the presence of serum hepatitis delta virus antigen by immunoblot and its correlation with other markers of active viral replication (intrahepatic hepatitis D antigen, IgM antibody to hepatitis D and serum hepatitis D virus RNA), we studied serum samples from 50 patients with chronic hepatitis D virus infection (38 with and 12 without intrahepatic hepatitis D antigen). Of the 38 patients with intrahepatic hepatitis D antigen, 27 (71%) had antigen detectable in serum by immunoblot, whereas only two were reactive by conventional enzyme-linked immunosorbent assay. Thirty-one (82%) patients were also positive for serum hepatitis D virus RNA by spot hybridization and 33 (87%) were positive for IgM anti-hepatitis D virus. All markers were simultaneously present in 24 patients. Circulating hepatitis D antigen was detected in one (8%), IgM anti-hepatitis D in seven (58%) and hepatitis D virus RNA in two (17%) of the 12 patients who had anti-hepatitis D in serum but not detectable hepatitis D antigen in liver. Hepatitis D antigen was not detected in serum of any of the 15 control patients. The results suggest that serum hepatitis D antigen as detected by immunoblot and serum hepatitis D virus RNA are similar in sensitivity for detection of active hepatitis D virus replication during chronic infection and constitute useful, sensitive and noninvasive tests for the diagnosis and monitoring of chronic hepatitis D virus infection.