Dynamics of allograft fibrosis in pediatric liver transplantation.

Progressive liver allograft fibrosis (LAF) is well known to occur long term, as shown by its high prevalence in late posttransplant liver biopsies (LBs). To evaluate the influence of clinical variables and immunosuppression on LAF progression, LAF dynamic was assessed in 54 pediatric liver transplantation (LT) recipients at 6 months, 3 and 7 years post-LT, reviewing clinical, biochemical data and protocol LBs using METAVIR and the liver allograft fibrosis score, previously designed and validated specifically for LAF assessment. Scoring evaluations were correlated with fibrosis quantification by morphometric analysis. Progressive LAF was found in 74% of long-term patients, 70% of whom had unaltered liver enzymes. Deceased grafts showed more fibrosis than living-related grafts (p = 0.0001). Portal fibrosis was observed in correlation with prolonged ischemia time, deceased grafts and lymphoproliferative disease (p = 0.001, 0.006 and 0.012, respectively). Sinusoidal fibrosis was correlated with biliary complications (p = 0.01). Centrilobular fibrosis was associated with vascular complications (p = 0.044), positive autoantibodies (p = 0.017) and high gamma-globulins levels (p = 0.028). Steroid therapy was not associated with reduced fibrosis (p = 0.83). LAF could be viewed as a dynamic process with mostly progression along the time. Peri- and post-LT-associated factors may condition fibrosis development in a specific area of the liver parenchyma.

Novel histologic scoring system for long-term allograft fibrosis after liver transplantation in children.

The existing systems for scoring fibrosis were not developed to evaluate transplanted livers. Our aim was to design and validate a novel fibrosis scoring system specifically adapted to assess liver allograft fibrosis (LAF). Clinical data, histology, transient elastography (TE) and AST/platelet ratio index (APRI) were reviewed in 38 pediatric liver transplant (LT) recipients. Protocol liver biopsies performed at 6 months and 7 years post-LT were reviewed by three pathologists who assessed LAF using the METAVIR and Ishak systems. LAF was also scored separately in portal (0-3), sinusoidal (0-3) and centrolobular areas (0-3). Scoring evaluations were correlated with fibrosis quantification using morphometry, and also with TE and APRI. Statistical correlations between morphometry and METAVIR were 0.571 (p < 0.000) and 0.566 (p < 0.000) for the Ishak system. The novel score (0-9) for separate assessment of portal, sinusoidal and centrolobular fibrosis showed a better correlation with morphometry (0.731; p < 0.000) and high intra-/interobserver agreement (0.966; p < 0.000 and 0.794; p < 0.000, respectively). No correlation was found between TE or APRI and morphometry or the three histologic scores. In conclusion, this novel semiquantitative fibrosis scoring system seems to more accurately reflect LAF than the existing scoring system and may become a practical tool for staging fibrosis in LT.

[Neuroimaging and definition of transient ischemic attack]. / Neuroimaging e definizione di attacco ischemico transitorio.

AIM: Transient ischemic attack (TIA) has to be considered an "alarm bell" of a more or less severe organic or systemic vasculopathy. Positive findings at neuroimaging means tissue damage. The purpose of this retrospective study was to assess the role of neuroimaging in the management of patients presenting with TIA, and to consider the relative implications. METHODS: In a consecutive series of 82 patients (53 males, 29 females, mean age: 65.9±13.1 years) admitted for TIA, it was possible to review the history and the clinical data of 66 patients, including ABCD2 score, laboratory including plasmatic D-dimer, and neuroimaging data including computed tomography (CT) and magnetic resonance imaging including diffusion-weighted with apparent diffusion coefficient measure (DWI-ADC) obtained at diagnosis and by a week later (16 by CT, and 50 by DWI-ADC). Thirty-three patients underwent DWI-ADC within 24 hours from symptoms onset. Statistical analysis has been performed by non-parametric tests (χ2 and Mann-Whitney), and logistic regression by a commercially available software. RESULTS: CT and/or DWI-ADC showed signs of acute ischemic lesions in 23/66 (35%) patients. 12 out of the 35 patients with a 24-hour DWI-ADC follow-up were positive. Statistical analysis showed that positive neuroimaging was significantly associated only with familial history of cardiovascular diseases (P<0.012) and previous TIA/stroke (P<0.046). CONCLUSION: In this patients series, at least 35% of patients with TIA had a positive neuroimaging, especially DWI-ADC. Positive neuroimaging seems an independent factor. Patients with TIA need an early assessment by neuroimaging including DWI-ADC, in order to obtain a correct classification and prognosis.

Coaxial biopsy during percutaneous vertebroplasty in patients with presumed osteoporotic vertebral compression fractures: retrospective review of biopsy results.

PURPOSE: This study retrospectively analysed the results of biopsies obtained during percutaneous vertebroplasty (PVP) in patients with presumed osteoporotic vertebral compression fractures, with a view to highlighting the importance of coaxial biopsy in determining the aetiology of vertebral fractures and planning subsequent treatment. MATERIALS AND METHODS: Between November 2003 and March 2009, 98 patients (78 women; 20 men) with a clinical and imaging suspicion of osteoporotic vertebral compression fractures underwent coaxial biopsy in conjunction with PVP of the thoracic and lumbar vertebrae. Mean age at the time of the procedure was 72.6 years. A pathologist interpreted all the biopsy samples. RESULTS: In 83 patients, the biopsy results were consistent with the presumed osteoporotic aetiology. In two patients, a malignancy was identified. Biopsy samples from 13 patients were considered insufficient or unsuitable by the pathologist for evaluation. CONCLUSIONS: Despite the number of biopsy samples considered insufficient or unsuitable, coaxial biopsy during PVP is useful in verifying the presumed aetiology of vertebral compression fractures, which is often unclear on the basis of clinical and imaging examinations. It is therefore both convenient and advisable to perform a vertebral coaxial biopsy in all patients undergoing a PVP.

CT and MRI of Wernicke's encephalopathy.

The purpose of this pictorial essay is to present the computed tomography (CT) and magnetic resonance imaging (MRI) findings of Wernicke's encephalopathy, a rare, severe, acute neurological syndrome due to thiamine (vitamin B1) deficiency, associated with high morbidity and mortality. The classical clinical triad, which includes ocular signs, altered consciousness and ataxia, can be found in only one-third of patients. Although chronic alcoholic patients are the most commonly affected, Wernicke's encephalopathy may complicate malnutrition conditions in nonalcoholic patients, in whom it is greatly underestimated. CT and above all MRI of the brain play a fundamental role in diagnosing the condition and ruling out other diseases. MRI is the most sensitive technique and is required in all patients with a clinical suspicion of Wernicke's encephalopathy. Medial thalami, mamillary bodies, tegmentum, periaqueductal region, and tectal plate are typical sites of abnormal MRI signal. The dorsal medulla, red nuclei, cranial nerve nuclei, cerebellum, corpus callosum, frontal and parietal cerebral cortex are less common sites of involvement although they are more frequently affected in nonalcoholic patients. Paramagnetic contrast material may help to identify lesions not otherwise visible.

No-touch hepatic hilum technique to treat early portal vein thrombosis after pediatric liver transplantation.

A 'no-touch' hilum technique used to treat early portal vein complications post-liver transplantation in five children with body weight <10 kg is described. Four patients developed thrombosis and one portal flow absence secondary to collateral steal flow. A vascular sheath was placed through the previous laparotomy in the ileocolic vein (n = 2), inferior mesenteric vein (n = 1) or graft umbilical vein (n = 1). Portal clots were mechanically fragmented with balloon angioplasty. In addition, coil embolization of competitive collaterals (n = 3) and stent placement (n = 1) were performed. The catheter was left in place and exteriorized through the wound (n = 2) or a different transabdominal wall puncture (n = 3). A continuous transcatheter perfusion of heparin was subsequently administered. One patient developed recurrent thrombosis 24 h later which was resolved with the same technique. Catheters were removed surgically after a mean of 10.6 days. All patients presented portal vein patency at the end of follow-up. Three patients are alive after 5 months, 1.5 and 3.5 years, respectively; one patient required retransplantation 18 days postprocedure and the remaining patient died of adenovirus infection 2 months postprocedure. In conclusion, treatment of early portal vein complications following pediatric liver transplantation with this novel technique is feasible and effective.

[Long term follow-up of bile duct stenosis treated with interventional radiology in pediatric liver transplantation]. / Seguimiento a largo plazo de las estenosis de la vía biliar tratadas con radiología intervencionista en el trasplante hepático pediátrico.

The reported incidence of biliary strictures following pediatric liver transplantation has ranged between 5-34%, with a higher incidence in segmental grafts. Currently, percutaneous transhepatic balloon dilatation of biliary strictures is considered as the first line treatment owing to its minimal invasiveness. Between 1995-2006, 20 children who underwent liver transplantation developed biliary complications treated with interventional radiology. 16/20 developed biliary stricture, of whom 10 were treated with percutaneous transhepatic balloon dilatation. The mean age at the procedure was 6.6 years (range 8 m--14 years). The allograft types included whole (n=4), split (n=3), and reduced (n=3) livers. The procedure was performed at a mean time post-transplantation of 2.6 years. All patients are alive with a mean follow-up post-procedure of 24 months (range: 4 months-11 years). Currently, only 4 have a normal appearing biliary tree by imaging techniques and 6 developed stricture recurrence; of whom 3 developed biliary cirrhosis (2 splits, 1 reduced), one patient underwent successful rescue surgery, one was treated again percutaneously, and the remaining was lost to followup. In conclusion, treatment of percutaneous transhepatic balloon dilatation of biliary strictures is effective avoiding surgical correction. However, stricture recurrence in the medium- long term follow-up is frequent, particularly in segmental grafts. [corrected]

Total occlusion of a conus medullaris pial arteriovenous malformation obtained with one session of superselective embolization.

The authors report about a case of the endovascular treatment of a pial arteriovenous malformation (AVM). The lesion was located on the conus medullaris. This injury is a rare spinal AVM. The diagnostic management and surgical treatment was chosen with a collaboration between neurosurgeons and neuroradiologists. The diagnostic management was based on clinical validation and magnetic resonance with angiographic technique as a gold standard. With regard to the surgical treatment of spinal AVM, endovascular and radiotherapy is a decision which should be taken multidisciplinarily. The treatment is crucial in resolving this lesion. The authors describe the case of a 38-year-old girl with clinical findings of progressive radiculomedullary ischemic process caused by the presence of spinal AVM. The angiographic images showed a pial AVM of the conus medullaris fed by an anterior radiculomedullary artery (Adamckiewiz artery) originated from a left T11 dorsospinal artery and by a posterior radiculopial artery originated from the left L1 artery. The draining veins were posterior pial veins, and accessory anterior subpial veins. Even if the first treatment of a pial arteriovenous malformation (AVM) of conus medullaris can be the surgical treatment for posterior localization, a neurointerventional angiographic and modern materials make it possible to reach pial AVMS of conus medullaris avoiding surgery. The authors describe a successful treatment of conus medullaris arteriovenous malformation with a one session of superselective embolization.

Impact of valganciclovir on Epstein-Barr Virus polymerase chain reaction in pediatric liver transplantation: preliminary report.

UNLABELLED: Preemptive therapy with ganciclovir has been recommended in the pediatric liver transplant strategy to avoid the development of posttransplant lymphoproliferative disorder (PTLD) from an high Epstein-Barr virus (EBV) is detected. We sought viral load to analyze the response to preemptive therapy with valganciclovir (VGC) in children with liver transplantations and an high quantitative EBV-PCR. METHODS: From June 2005 to December 2007, we tested 979 EBV-PCR among 80 pediatric liver transplant recipients, from those 21/80 PCR were tested from the date of transplantation and 59/80 belonged to the historical cohort (7/59 had a prior history of PTLD). Patients were divided into 2 groups depending upon whether they did (n = 22) or did not (n = 19) receive VGC treatment. The response to VGC was considered complete, if the PCR was negative at 30 and 60 days of treatment; and partial, when the PCR decreased at least 50%. Ganciclovir blood levels tested in 109 cases instances and correlated with the EBV-PCR. RESULTS: A total of 369 (33%) positive PCR were detected in 36/80 patients (mean, 75,000 copies; range = 5000-4,200,000). Among the 22 episodes treated for 30 days, 34% showed complete responses, 41%, partial, and 23%, no response. Among the non-treated group the rates were 6%, 25%, and 68%, respectively (P = .01). However, no differences were observed among those episodes treated for 60 days. At the administered doses, hardly any patient reached the recommended ganciclovir therapeutic level at 2 hours (6 micro/mL). However, the mean PCR was lower when the ganciclovir levels were greater than 4 mg/L when compared with lower levels (P = .03). CONCLUSION: After 30 days of treatment there was a response to VGC in the EBV viral load. There was high interpatient variability of ganciclovir serum concentrations, suggesting the need for pharmacokinetic monitoring to optimize treatment. There was a relationship between the concentration of ganciclovir and the EBV viral load.

Cell cycle-dependent binding of yeast heat shock factor to nucleosomes.

In the nucleus, transcription factors must contend with the presence of chromatin in order to gain access to their cognate regulatory sequences. As most nuclear DNA is assembled into nucleosomes, activators must either invade a stable, preassembled nucleosome or preempt the formation of nucleosomes on newly replicated DNA, which is transiently free of histones. We have investigated the mechanism by which heat shock factor (HSF) binds to target nucleosomal heat shock elements (HSEs), using as our model a dinucleosomal heat shock promoter (hsp82-DeltaHSE1). We find that activated HSF cannot bind a stable, sequence-positioned nucleosome in G(1)-arrested cells. It can do so readily, however, following release from G(1) arrest or after the imposition of either an early S- or late G(2)-phase arrest. Surprisingly, despite the S-phase requirement, HSF nucleosomal binding activity is restored in the absence of hsp82 replication. These results contrast with the prevailing paradigm for activator-nucleosome interactions and implicate a nonreplicative, S-phase-specific event as a prerequisite for HSF binding to nucleosomal sites in vivo.

Quantitative 3D investigation of Neuronal network in mouse spinal cord model.

The investigation of the neuronal network in mouse spinal cord models represents the basis for the research on neurodegenerative diseases. In this framework, the quantitative analysis of the single elements in different districts is a crucial task. However, conventional 3D imaging techniques do not have enough spatial resolution and contrast to allow for a quantitative investigation of the neuronal network. Exploiting the high coherence and the high flux of synchrotron sources, X-ray Phase-Contrast multiscale-Tomography allows for the 3D investigation of the neuronal microanatomy without any aggressive sample preparation or sectioning. We investigated healthy-mouse neuronal architecture by imaging the 3D distribution of the neuronal-network with a spatial resolution of 640 nm. The high quality of the obtained images enables a quantitative study of the neuronal structure on a subject-by-subject basis. We developed and applied a spatial statistical analysis on the motor neurons to obtain quantitative information on their 3D arrangement in the healthy-mice spinal cord. Then, we compared the obtained results with a mouse model of multiple sclerosis. Our approach paves the way to the creation of a "database" for the characterization of the neuronal network main features for a comparative investigation of neurodegenerative diseases and therapies.

X-Ray Phase Contrast Tomography Reveals Early Vascular Alterations and Neuronal Loss in a Multiple Sclerosis Model.

The degenerative effects of multiple sclerosis at the level of the vascular and neuronal networks in the central nervous system are currently the object of intensive investigation. Preclinical studies have demonstrated the efficacy of mesenchymal stem cell (MSC) therapy in experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis, but the neuropathology of specific lesions in EAE and the effects of MSC treatment are under debate. Because conventional imaging techniques entail protocols that alter the tissues, limiting the reliability of the results, we have used non-invasive X-ray phase-contrast tomography to obtain an unprecedented direct 3D characterization of EAE lesions at micro-to-nano scales, with simultaneous imaging of the vascular and neuronal networks. We reveal EAE-mediated alterations down to the capillary network. Our findings shed light on how the disease and MSC treatment affect the tissues, and promote X-ray phase-contrast tomography as a powerful tool for studying neurovascular diseases and monitoring advanced therapies.

Phase I study of recombinant beta-interferon given by four-hour infusion.

Twelve patients with advanced malignant disease were entered onto a Phase I study of escalating doses of beta-interferon serine given by 4-h i.v. infusion twice a wk. Three patients each were entered at starting doses of 0.01, 1, 10, and 30 million units (MU)/m2. Doses escalation within individual patients was allowed to a maximum dose of 400 MU/m2. Fever, chills, fatigue, and acral cyanosis were commonly seen and increased in frequency at higher doses. Myalgia, nausea, diarrhea, headache, and confusion were seen at lesser frequencies. Mild leukopenia, paresthesia, infusion site erythema, and hypotension were each seen in one patient. No conventional maximal tolerated dose could be defined, since several patients underwent escalation to the highest allowable dose and seemed to develop tolerance to acute toxicities. However, a maximal starting dose of 10 MU/m2 was identified, such that those begun at this level or below tolerated semiweekly dose escalation, while those begun at 30 MU/m2 could not tolerate continued therapy. Detectable serum interferon levels were noted during treatment at 10 and 30 MU/m2, the levels at which significant toxicity also first appeared. A maximal starting dose of 10 MU/m2, with gradual escalation as tolerance to side effects develops, is suggested if therapy with high-dose beta-interferon serine is given by 4-h infusion.

Long-term outcome of chronic myeloid leukemia patients treated frontline with imatinib.

For almost 10 years imatinib has been the therapeutic standard of chronic myeloid leukemia. The introduction of other tyrosine kinase inhibitors (TKIs) raised a debate on treatment optimization. The debate is still heated: some studies have protocol restrictions or limited follow-up; in other studies, some relevant data are missing. The aim of this report is to provide a comprehensive, long-term, intention-to-treat, analysis of 559 newly diagnosed, chronic-phase, patients treated frontline with imatinib. With a minimum follow-up of 66 months, 65% of patients were still on imatinib, 19% were on alternative treatment, 12% died and 4% were lost to follow-up. The prognostic value of BCR-ABL1 ratio at 3 months (⩽10% in 81% of patients) was confirmed. The prognostic value of complete cytogenetic response and major molecular response at 1 year was confirmed. The 6-year overall survival was 89%, but as 50% of deaths occurred in remission, the 6-year cumulative incidence of leukemia-related death was 5%. The long-term outcome of first-line imatinib was excellent, also because of second-line treatment with other TKIs, but all responses and outcomes were inferior in high-risk patients, suggesting that to optimize treatment results, a specific risk-adapted treatment is needed for such patients.

Celiac disease with cerebral calcium and silica deposits: x-ray spectroscopic findings, an autopsy study.

An increased incidence of seizures and cerebral calcifications, usually bilateral and located in the occipital cortex, has been reported in celiac patients. The histology of cerebral lesions is not well defined, and their pathogenesis is only speculative. We report the autopsy results of a patient with celiac disease, seizures, and cerebral calcifications who died following a cerebral hemorrhage caused by Fisher-Evans syndrome. Calcifications were restricted to the cortical gray matter and composed of aggregates of small calcified spicules. Calcium deposition was present as psammoma-like bodies, along small vessels, and within neurons. X-ray spectroscopy of the calcified areas revealed that calcium (43%) and silica (57%) were present in the lesions. High silica content was also found in the cerebral hemorrhagic fluid. Silica toxicity has to be considered in regard to the pathogenesis of the cerebral lesions and of the seizures.

Cerebrotendinous xanthomatosis (van Bogaert-Scherer-Epstein disease): CT and MR findings.

PURPOSE: To describe the CT and MR findings in the brain and spinal cord of patients with cerebrotendinous xanthomatosis and to seek possible correlations between clinical, biochemical (cholestanol levels), and neuroimaging findings. METHODS: Ten patients with well-defined clinical and biochemical diagnoses of cerebrotendinous xanthomatosis were examined. Brain CT was performed in eight cases. In all patients MR was obtained using spin-echo and gradient-echo sequences. In eight patients spine MR was also performed. RESULTS: Neuroradiologic findings included diffuse cerebral and cerebellar atrophy. In half the cases, atrophy of the brain stem and corpus callosum was also found. In the majority of patients cerebellar bilateral focal lesions and mild white matter signal alterations were present. Spinal cord MR did not show signal abnormalities or atrophy. CONCLUSIONS: We found cranial alterations in patients with severe neurologic impairment, but there was no correlation with cholestanol plasma levels. No spinal cord abnormalities were present.

Relationship between apoptosis, tumour necrosis factor, and cell proliferation in chronic cholestasis.

BACKGROUND: Target of the immune response in chronic autoimmune cholestasis, is the bile duct epithelium. Lymphocytic infiltration and apoptosis have both been suggested to mediate the destruction of hepatocytes and biliary epithelium in primary biliary cirrhosis. AIMS: To further address this issue in two cholestatic liver diseases characterized by an autoimmune pathogenesis and, furthermore, evaluate the relationship between apoptosis and both tumour necrosis factor alpha and cell proliferation. METHODS: Liver tissue specimens from 16 patients with primary biliary cirrhosis, 15 with primary sclerosing cholangitis, and 16 with chronic hepatitis C (controls) were evaluated. DNA-fragmentation of apoptotic cells was ascertained by the TdT-mediated deoxyuridine triphosphate nick-end labelling method. Tumour necrosis factor alpha expression and cell proliferation (Ki-67 antigen) were assayed by immunohistochemistry. RESULTS: Hepatocytes with DNA fragmentation were observed in 75% of patients with primary biliary cirrhosis, in 66.6% with primary sclerosing cholangitis, and in 43.7% with chronic hepatitis C. Biliocytes showed apoptosis in only 3 cases of primary biliary cirrhosis. Biliocytes showed a strong cytoplasmic expression in 4 cases (1 primary biliary cirrhosis, 2 primary sclerosing cholangitis and 1 chronic hepatitis C). A few intralobular and portal inflammatory mononuclear cells expressing tumour necrosis factor alpha were observed in 62.5% of patients with primary biliary cirrhosis, 46.1% with primary sclerosing cholangitis, and 56.2% with hepatitis C virus chronic hepatitis. The amount of intraportal mononuclear cells expressing Ki-67 antigen was significantly higher in primary biliary cirrhosis specimens than in primary sclerosing cholangitis (p<0.001) or hepatitis C virus-related chronic hepatitis (p<0.03). No correlation was found within the 3 groups of patients between the Ki-67 histological score and the severity of liver disease. Moreover, no relationship was found between TdT-mediated deoxyuridine triphosphate nick-end labelling and either tumour necrosis factor alpha or Ki-67 staining. CONCLUSIONS: Apoptosis is a phenomenon which frequently involves hepatocytes in chronic autoimmune cholestasis. This process is apparently parallel, but unrelated to cell proliferation. Cell proliferation mainly involves mononuclear cells in portal tracts of primary biliary cirrhosis specimens. The finding of tumour necrosis factor alpha expression in biliocytes deserves further study to establish whether this cytokine is involved in triggering bile duct lesions.

Prevalence of coeliac disease in primary biliary cirrhosis and of antimitochondrial antibodies in adult coeliac disease patients in Italy.

BACKGROUND: Although an association between primary biliary cirrhosis and coeliac disease has recently been reported in Northern Europe, there are still conflicting data concerning this issue. AIM: To evaluate both the prevalence of coeliac disease in a series of primary biliary cirrhosis patients and that of antimitochondrial antibodies in a series of adult biopsy proven coeliac disease patients from Northern Italy. PATIENTS AND METHODS: A total of 87 primary biliary cirrhosis patients (79 female, 8 male) were screened for both IgA-transglutaminase antibodies and antiendomysium antibodies and, in those with either IgA-transglutaminase antibodies or antiendomysium antibodies positivity, upper endoscopy with distal duodenum biopsy was offered. In those who refused upper endoscopy, the intestinal permeability test with lactulose/mannitol excretion was performed. RESULTS: Antiendomysium antibodies positivity was detected in 3 subjects (3.4%), all of whom had serum IgA-transglutaminase antibodies above the normal range, and fulfilled the diagnosis of coeliac disease. Of 21 other patients with serum IgA-transglutaminase antibodies above the normal range, 17 underwent upper endoscopy which revealed normal duodenum architecture. The remaining 4 patients underwent the lactulose/mannitol excretion test which was within the normal range. Sera from 108 adult coeliac disease patients were tested for antimitochondrial antibodies and positivity was found in 4 patients (3.7%): all had normal liver biochemistry tests, whereas 2 of them also presented thyroid disease. Antibodies directed to the 74-kDa polypeptide of antimitochondrial antibodies were found in 3 out of 4 antimitochondrial antibodies+ve patients. CONCLUSIONS: These results suggest an association between primary biliary cirrhosis and coeliac disease similar to that observed in the Northern European series. In conclusion, screening for coeliac disease with antiendomysium antibodies in primary biliary cirrhosis is justified, and screening for antimitochondrial antibodies is advisable in adult coeliac disease patients.

Cytokine, infiltrating macrophage and T cell-mediated response to development of primary and secondary human liver cancer.

BACKGROUND: Kupffer cells, monocytes and infiltrating T cells have been considered the major source of interleukin-1beta and tumour necrosis factor-alpha in the liver. AIMS; To explore the expression of interleukin-1beta and tumour necrosis factor-alpha and to evaluate the density and the distribution of T lymphocytes and monocytes/macrophages in the liver of patients with primary and secondary tumours. METHODS: Tumoural and peritumoural liver samples were examined from 21 patients with hepatocellular carcinoma, 10 with hepatic metastases, 5 with benign focal liver lesions and 4 healthy adult livers. Interleukin-1beta and tumour necrosis factor-alpha mRNAs were detected by a semiquantitative comparative reverse transcriptase polymerase chain reaction. T lymphocytes and monocytes/macrophages were detected by immunohistochemistry. RESULTS: Higher levels of interleukin-1beta, tumour necrosis factor-alpha, CD3+ and CD68+ cells were found in the tissue surrounding hepatocellular carcinoma and metastases than in the tumour itself. A strong expression of CD68+ and CD3+ cells was found mainly along the tumour-host interface but the highest expression of CD3+ cells was found at the metastasis interfaces. Interleukin-1beta expression, CD3+ and CD68+ cell densities were higher in peritumoural samples than in so-called "normal" liver tissue. CONCLUSIONS: An increased production of interleukin-1beta and, to a lesser extent, of tumour necrosis factor-alpha mRNA coincides with the presence of cancer be it primary or secondary, both in healthy and cirrhotic livers. The presence of cancer, irrespective of the presence of underlying liver damage, appears to play the most important role.