Induction of replicative competence ("priming") in normal liver

We have used a system of nutritional manipulation to investigate whether hepatocytes of the normal liver can be primed for replication in vivo. In this system, rats that are denied protein for 3 days undergo a burst of hepatic DNA synthesis and mitosis when they are refed amino acids, while normally fed or starved rats do not respond. To determine if hepatocytes of protein deprived (PD) rats have been "primed" for replication, we examined changes in protooncogene expression in livers of PD rats to see if they would mimic the pattern of gene expression that is induced early after partial hepatectomy. c-jun, c-myc, and p53 mRNAs were elevated in livers of PD rats, while c-fos and c-ras genes were not expressed. The administration of amino acids to PD rats stimulated hepatic DNA synthesis in a shorter period than is required after partial hepatectomy and induced p53 and c-ras expression. In culture, hepatocytes from PD rats had higher levels of c-myc mRNA, underwent morphological changes more rapidly, and reached maximum rates of DNA synthesis earlier than normal hepatocytes. In both normal and primed hepatocyte cultures, transforming growth factor alpha stimulated DNA synthesis more effectively than epidermal growth factor. We conclude that hepatocytes pass through a priming stage before they proliferate and that replicative competence without DNA synthesis can be induced in hepatocytes in the normal liver.     

Expression of hepatocyte and oval cell antigens in hepatocellular carcinomas produced by oncogene-transfected liver epithelial cells

We have established an in vivo/in vitro system in which epithelial cells ("oval cells") isolated from livers of rats fed a carcinogenic diet for a very brief period are placed in culture and transfected with an oncogene. Injection s.c. into nude mice of oval cells transfected with the activated c-Ha-ras (EJ oncogene) produces tumors with morphological features of differentiated hepatocellular carcinomas. Using monoclonal antibodies that can recognize hepatocyte, oval cell, and tumor antigens, we investigated the expression of these antigens in oval cells in culture, transfected with either the EJ oncogene or the normal c-Ha-ras allele and in tumors derived from the oncogene-transfected cells. We show that EJ-transfected cells and most particularly the tumors they produce expressed hepatocyte and oval cell antigens not detectable in untransfected cells or cells transfected with the normal c-Ha-ras gene. Furthermore, we found that in cloned tumor cells, the expression of hepatocyte antigens could be induced by changes in culture conditions and was accompanied by a decrease in the expression of oval cell markers. Trabecular hepatocellular carcinomas had higher reactivity toward monoclonal antibodies recognizing hepatocyte antigens while tumors with glandular architecture reacted predominantly with monoclonal antibodies against oval cells. We conclude that, in addition to its tumorigenic effect, the EJ oncogene induced the differentiation of tumor cells toward the hepatocyte lineage. In addition, the data provide further confirmation that oval cells can serve as progenitors of differentiated hepatocellular carcinomas.     

Amikacin and ceftazidime as empirical antibiotic therapy in severely neutropenic patients: analysis of prognostic factors

This study aimed to evaluate the efficacy of amikacine and ceftazidime as an empirical antibiotic therapy for neutropenic patients affected by haematological neoplasms and to investigate the presence of prognostic features suggesting a poor outcome with this antibiotic combination at the onset of infection. This could allow the identification of subgroups of patients with a low rate of response to amikacin/ceftazidime therapy; in these patients different initial empirical therapy may be indicated. The study population comprised 166 severely neutropenic (absolute neutrophil count below 500/l) oncohaematological patients with fever or clinical signs of infection. Multivariate analysis confirmed four negative prognostic factors: 3 or more days of hospitalization at the onset of an infectious episode, a diagnosis of acute myeloid leukaemia, a haematological disease status different from complete remission, the presence of pneumonia. Depending on how many factors are present, cases can be stratified into three groups, of significantly different prognosis: favourable (0 or 1 factor) 76% success; intermediate (2 factors) 52% success; unfavourable (3 or 4 factors) 19% success. At the onset of an infectious episode a subgroup of patients with a very low response rate to empirical amikacin/ceftazidime antibiotic therapy is identifiable, for whom a different therapy is indicated. Because of the high rate of proven or probable fungal infections in this group, the immediate administration of a systemic antifungal therapy, in addition to antibacterial agents, could be considered in these high-risk patients. Studies should be specifically addressed to evaluating a stratification of empirical antibiotic therapy according to risk factors present at the onset of infection.     

Improving vaccination coverage in urban areas through a health communication campaign: the 1990 Philippine experience.

From March to September 1990 the Philippine Department of Health, with the assistance of the HEALTHCOM Project, carried out a national mass-media communication campaign to support routine vaccination services. The essential elements of the campaign strategy were as follows: focusing on measles as a way to get mothers to bring their children to the health centre; emphasizing logistic knowledge in the mass-media messages, in particular popularizing a single day of the week as "vaccination day" and giving clear information about the age for measles vaccination; and focusing on urban areas, which had lower vaccination rates than rural areas. Evaluation of the effects of the campaign indicates an increase in vaccination coverage and a substantial increase in the timeliness of vaccination that can be attributed to improvement in carers'' knowledge about vaccination. Furthermore, most of the observed increase in knowledge was related to exposure to the mass-media campaign. There was no evidence of any programmatic change that could account for the increase in vaccination or evidence that increased health education efforts at health centres could account for the change in knowledge. These results indicate that when countries meet certain conditions--a high level of access to the media, sufficient expertise and funds available to develop and produce high-quality radio and television advertisements, and a routine system that is able to serve the increased demand--a mass communication campaign can significantly improve vaccination coverage.     

Cardiac output measurement by the thermodilution method: An in vitro test of accuracy of three commercially available automatic cardiac output computers

Objective To describe the accuracy and the reproducibility of the thermodilution flow measurements obtained using 3 commercially available cardiac output computers commonly used in intensive care units.Design An experimental in vitro study. Twelve different values of control flow (Qctr) were measured (Qmsr) using 3 different cardiac output computers (Abbott Critical Care System, Oximetrix 3 SvO₂/CO Computer, Baxter Oximeter/Cardiac Output Computer SAT-1^TM; American Edwards Laboratories, 9520 A Cardiac Output Computer). Standard equipment and techniques were employed, taking account of the specific weight and heat of warm water relative to blood. In addition, separate sets of measurements were performed in order to investigate the effect on Qmsr of some variables which may influence the indicator loss (time for injection, depth of immersion of the catheter, temperature of the injected fluid).Setting Our laboratory, inside the intensive care unit.Measurements and results The analysis of the linear regression of Qmsr versus Qctr (r values between 0.992 and 0.984; residual standard deviation values comprised between 0.24 and 0.49 l/min; intercepts and slopes not significantly different from identity line), the values of the percentage errors (PE=[Qctr–Qmsr]·100/Qctr; PE mean values 7.9, 5.0 and 13.1), and those of the coefficients of variability (CV=standard deviation mean value, %; CV mean values 5.4, 5.8 and 4.6), show a good level of accuracy and reproducibility of the measurements. Our data confirm previously reported results. Furthermore, the cumulative effect of variables capable of influencing the indicator loss, even if corrected according to the calculation constant the manufacturers provide, was found to result in statistically significant changes of Qmsr.Conclusion The accuracy and reproducibility of the automatic cardiac computers tested is sufficient for practical clinical purpose. It may also depend on the modality of injection of the cooling bolus, which may significantly influence the effective indicator losses.     

Prevalence and clinical relevance of Blastocystis hominis in diverse patient cohorts

The pathogenicity of Blastocystis hominis is extensively debated in the medical literature. Therefore, we did a prevalence study to investigate the association between the presence of several intestinal parasites and gastrointestinal symptoms in diverse patient cohorts. The study population consisted of 1216 adults, including immunocompromised patients, institutionalized psychiatric or elder subjects, immigrants from developing countries, travellers to developing tropical countries and controls. Several variables for each risk group were considered. Stools specimens, collected in triplicate, were processed by the same technicians. Clinical data about each subject were provided by standardized questionnaires. The presence of gastrointestinal symptoms were related to the presence of any parasite. In addition, on the basis of microbiological results, five subgroups of subjects were evaluated. The results showed a high prevalence of parasites in all the risk groups. Immunocompromised status, recent arrival from developing countries and the presence of behavioural aberrations were significantly related to presence of parasites. B. hominis was the parasite most frequently detected in each studied group. B. hominis showed a significant correlation with gastrointestinal symptoms only when detected in the group including subjects with a severe immunodepression. Immunodepression seems to be a factor of primary importance of the pathogenic role of B. hominis.     

Protooncogenes and growth factors associated with normal and abnormal liver growth

Hepatocyte replication during liver regeneration depends on extrinsic (circulating) and intrinsic (intrahepatic) factors. Two important growth factors produced in the regenerating liver are discussed, TGF, an autocrine, stimulatory growth factor, and TGF, a paracrine inhibitory factor. The balance between the activities of these factors is likely to play an important role in regulating hepatocyte proliferation. The experession of some protooncogenes occurs sequentially during the first few hours after partial hepatectomy and is a marker for the entry of hepatocytes into the cell cycle (proliferative competence). As hepatocytes become competent to proliferate, they respond to TGF and other growth factors and enter a proliferative phase. It is possible that TGF1 serves as a stop signal for liver regeneration but the mechanisms by which TGF inhibits hepatocyte DNA synthesis are still unknown.Presented at the Proceedings of the International Meeting on Normal and Neoplastic Growth in Hepatology, Bari, Italy, June 1989.     

Gastrointestinal stromal tumors: experience of an emergency surgery department

BACKGROUND/AIMS: Gastrointestinal stromal tumors (GISTs) are a rare group of neoplasias of the gastrointestinal tract that have not yet been fully investigated. In this article the authors present the experience of an emergency surgery department in the diagnosis and treatment of patients with such neoplasms and discuss the approaches to these 'strange' tumors. METHODS: A review of our 4-year experience in emergency surgery was performed and 9 patients were found with the diagnosis of GIST. The median follow-up was 32.3 (range 18-45) months. RESULTS: 7 patients had evidence of gastrointestinal blood loss, 1 patient had abdominal pain, and the last patient had anorexia, vomiting and fever. Five tumors were located in the stomach and 4 in the small bowel. All the patients underwent complete resection. On histological examination 5 tumors were of myogenic origin, 1 was a gastrointestinal autonomic nerve tumor and 1 was a mixed neural-myoid tumor. The remaining 2 could not be differentiated. Of the 9 patients who underwent curative resections, 1 had a recurrence and died. CONCLUSION: GIST treatment mainly involves surgical resection with the goal of complete removal which can be curative. The histologic grade and tumor size are the most important prognostic factors.     

The oral neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a multinational, randomized, double-blind, placebo-controlled trial in patients receiving high-dose cisplatin--the Aprepitant Protocol 052 Study Group.

PURPOSE: In early clinical trials with patients receiving highly emetogenic chemotherapy, the neurokinin antagonist aprepitant significantly enhanced the efficacy of a standard antiemetic regimen consisting of a type-three 5-hydroxytryptamine antagonist and a corticosteroid. This multicenter, randomized, double-blind, placebo-controlled phase III study was performed to establish definitively the superiority of the aprepitant regimen versus standard therapy in the prevention of chemotherapy-induced nausea and vomiting (CINV). PATIENTS AND METHODS: Patients receiving cisplatin > or = 70 mg/m2 for the first time were given either standard therapy (ondansetron and dexamethasone on day 1; dexamethasone on days 2 to 4) or an aprepitant regimen (aprepitant plus ondansetron and dexamethasone on day 1; aprepitant and dexamethasone on days 2 to 3; dexamethasone on day 4). Patients recorded nausea and vomiting episodes in a diary. The primary end point was complete response (no emesis and no rescue therapy) on days 1 to 5 postcisplatin, analyzed by a modified intent-to-treat approach. Treatment comparisons were made using logistic regression models. Tolerability was assessed by reported adverse events and physical and laboratory assessments. RESULTS: The percentage of patients with complete response on days 1 to 5 was significantly higher in the aprepitant group (72.7% [n = 260] v 52.3% in the standard therapy group [n = 260]), as were the percentages on day 1, and especially on days 2 to 5 (P <.001 for all three comparisons). CONCLUSION: Compared with standard dual therapy, addition of aprepitant was generally well tolerated and provided consistently superior protection against CINV in patients receiving highly emetogenic cisplatin-based chemotherapy.     

ABL mutations in late chronic phase chronic myeloid leukemia patients with up-front cytogenetic resistance to imatinib are associated with a greater likelihood of progression to blast crisis and shorter survival: a study by the GIMEMA Working Party on Chronic Myeloid Leukemia.

PURPOSE: Point mutations within the ABL kinase domain of the BCR-ABL gene have been associated with clinical resistance to imatinib mesylate in chronic myeloid leukemia (CML) patients. To shed further light on the frequency, distribution, and prognostic significance of ABL mutations, we retrospectively analyzed a homogeneous cohort of late chronic phase CML patients who showed primary cytogenetic resistance to imatinib. PATIENTS AND METHODS: Using denaturing high-performance liquid chromatography (D-HPLC) and sequencing, we screened for ABL mutations in a total of 178 bone marrow and/or peripheral blood samples from 40 late chronic phase CML patients homogeneously treated with imatinib 400 mg/d, who did not reach a major cytogenetic response at 12 months. RESULTS: Mutations were found in 19 of 40 patients (48%). Mutations were already detectable by D-HPLC at a median of 3 months from the onset of therapy. The presence of a missense mutation was significantly associated with a greater likelihood of subsequent progression to accelerated phase/blast crisis (P = .0002) and shorter survival (P = .001). Patients carrying mutations falling within the P-loop seemed to have a particularly poor outcome in terms of time to progression (P = .032) and survival (P = .045). CONCLUSION: Our results show that, irrespective of the hematologic response, monitoring for emerging mutations in the first months of therapy may play a role in detecting patients with worse prognosis, for whom a revision of the therapeutic strategy should be considered.