Intraductal Delivery of Adenoviruses Targets Pancreatic Tumors in Transgenic Ela-myc Mice and Orthotopic Xenografts

Gene-based anticancer therapies delivered by adenoviruses are limited by the poor viral distribution into the tumor. In the current work we have explored the feasibility of targeting pancreatic tumors through a loco-regional route.We have taken advantage of the ductal network in the pancreas to retrogradelly inject adenoviruses through the common bile duct in two different mouse models of pancreatic carcinogenesis: The transgenic Ela-myc mice that develop mixed neoplasms displaying both acinar-like and duct-like neoplastic cells affecting the whole pancreas; and mice bearing PANC-1 and BxPC-3 orthotopic xenografts that constitute a model of localized human neoplastic tumors. We studied tumor targeting and the anticancer effects of newly thymidine kinase-engineered adenoviruses both in vitro and in vivo, and conducted comparative studies between intraductal or intravenous administration. Our data indicate that the intraductal delivery of adenovirus efficiently targets pancreatic tumors in the two mouse models. The in vivo application of AduPARTK^T plus ganciclovir (GCV) treatment induced tumor regression in Ela-myc mice. Moreover, the intraductal injection of ICOVIR15-TK^T oncolytic adenoviruses significantly improved mean survival of mice bearing PANC-1 and BxPC-3 pancreatic xenografts from 30 to 52 days and from 20 to 68 days respectively (p<0.0001) when combined with GCV. Of notice, both AduPARTK^T and ICOVIR15-TK^T antitumoral responses were stronger by ductal viral application than intravenously, in line with the 38-fold increase in pancreas transduction observed upon ductal administration.In summary our data show that cytotoxic adenoviruses retrogradelly injected to the pancreas can be a feasible approach to treat localized pancreatic tumors.     

Effects of stimulation and inhibition of acid secretion on gastric damage induced by platelet-activating factor

Intravenous administration of platelet-activating factor (PAF) induces extensive damage in rat gastric mucosa. The aim of the present study was to examine whether the presence or absence of acid in the gastric lumen could modify the PAF-induced gastric damage. The effects of inhibition of basal and pentagastrin-stimulated acid secretion by ranitidine on the deep histological gastric damage induced by 30 min of infusion of PAF (100 ng/kg/min) were assessed by using a histological score. Inhibition of basal gastric acid secretion did not prevent the histological gastric damage induced by PAF. Stimulation of gastric acid secretion by pentagastrin significantly increased PAF-induced gastric damage, and this effect was reversed by a dose of ranitidine that returns acid secretion to baseline levels. This acid-related damage was confined to the deep mucosa, since scanning electron microscope analysis ruled out an additional surface damage in PAF-infused rats when gastric acid was stimulated. The data indicate that a certain amount of acid may worsen the deep gastric mucosal damage induced by PAF.     

Diagnosis of hepatic nodules 20 mm or smaller in cirrhosis: Prospective validation of the noninvasive diagnostic criteria for hepatocellular carcinoma

This study prospectively evaluates the accuracy of contrast-enhanced ultrasound (CEUS) and dynamic magnetic resonance imaging (MRI) for the diagnosis of nodules 20 mm or smaller detected during ultrasound (US) surveillance. We included 89 patients with cirrhosis [median age, 65 years; male 53, hepatitis C virus 68, Child-Pugh A 80] without prior hepatocellular carcinoma (HCC) in whom US detected a small solitary nodule (mean diameter, 14 mm). Hepatic MRI, CEUS, and fine-needle biopsy (gold standard) (FNB) were performed at baseline. Non-HCC cases were followed (median 23 months) by CEUS/3 months and MRI/6 months. FNB was repeated up to 3 times and on detection of change in aspect/size. Intense arterial contrast uptake followed by washout in the delayed/venous phase was registered as conclusive for HCC. Final diagnoses were: HCC (n = 60), cholangiocarcinoma (n = 1), and benign lesions (regenerative/dysplastic nodule, hemangioma, focal nodular hyperplasia) (n = 28). Sex, cirrhosis cause, liver function, and alpha-fetoprotein (AFP) levels were similar between HCC and non-HCC groups. HCC patients were older and their nodules significantly larger (P < 0.0001). First biopsy was positive in 42 of 60 HCC patients. Sensitivity, specificity, and positive and negative predictive values of conclusive profile were 61.7%, 96.6%, 97.4%, and 54.9%, for MRI, 51.7%, 93.1%, 93.9%, and 50.9%, for CEUS. Values for coincidental conclusive findings in both techniques were 33.3%, 100%, 100%, and 42%. Thus, diagnosis of HCC 20 mm or smaller can be established without a positive biopsy if both CEUS and MRI are conclusive. However, sensitivity of these noninvasive criteria is 33% and, as occurs with biopsy, absence of a conclusive pattern does not rule out malignancy. These results validate the American Association for the Study of Liver Disease (AASLD) guidelines.     

Natural history of hepatocellular carcinoma in Spain. Five year's experience in 249 cases

In this study we attempted to define the clinical pattern and prognosis of hepatocellular carcinoma (HCC) patients in Spain. Two hundred and forty-nine patients were included in the study. One hundred and eighty-seven were male and 62 female, with their mean age being 62.5 +/- 0.6 years. The majority of patients (92.8%) had an underlying cirrhosis. In most of the patients, the disease appeared as decompensated liver disease. Only 18.5% of the HCC cases were asymptomatic. Only 8.2% of the cases were HBsAg positive. alpha-Fetoprotein reached diagnostic values in only 37.2% of the patients. Surgical treatment was successfully performed in 14 patients: one underwent orthotopic liver transplantation and the 13 others complete tumor resection. Chemotherapy was administered to 38 subjects, while percutaneous ethanol injection was applied in seven cases. Patients receiving only symptomatic treatment, comprised 76.7%. Survival was related to tumor size and liver function. While the median survival of the whole series was 3.3 +/- 0.4 months, it was 14.5 +/- 2.2 months in patients with preserved liver function and small tumors. These results reflect that in Spain HCC patients are diagnosed at a moderately advanced phase. Since early diagnosis is the only way to increase the proportion of patients suitable for curative treatment, early detection plans are mandatory in the population at risk.     

Histamine‐N‐methyl transferase polymorphism and risk for multiple sclerosis

Background: Histamine N‐methyltransferase (HNMT) is the main metabolizing enzyme of histamine (a mediator of inflammation implicated in the pathogenesis of multiple sclerosis‐MS) in the CNS. We have investigated the possible association between a single nucleotide polymorphism of the HNMT (chromosome 2q22.1), that causes the amino acid substitution Thr105Ile (decreasing enzyme activity) and the risk for MS. Methods: We studied the frequency of the HNMT genotypes and allelic variants in 228 MS patients and 295 healthy controls using a PCR‐RLFP method. Results: The frequencies of the HNMT genotypes and allelic variants did not differ significantly between MS patients and controls, and were unrelated with the age of onset of MS, gender, and course of MS. Conclusion: The HNMT polymorphism is not related with the risk for MS.