The effect of sorafenib on liver regeneration and angiogenesis after partial hepatectomy in rats.

BACKGROUND: Liver regeneration is vital for the survival of patients submitted to extensive liver resection as a treatment of hepatocellular carcinoma (HCC). Sorafenib is a multikinase inhibitor of angiogenesis and cell division, both of which are integral components of liver regeneration. We investigated the effect of preoperative treatment with sorafenib, a drug used for the treatment of HCC, on liver regeneration and angiogenesis in healthy rats, after two-thirds partial hepatectomy (PH2/3). METHODS: In total 48 Wistar rats received intragastric injections of sorafenib (30 mg/kg/d) or vehicle, underwent PH2/3, and were sacrificed at 48, 96 or 168 hours after that. The regenerative index of the liver remnant was studied, as well as the mitotic index. DNA synthesis and angiogenesis were estimated by immunohistochemistry for the Ki-67 and CD34 antigens, respectively. RESULTS: Sorafenib reduced significantly the regenerative index at all time points but not the mitotic index at 48, 96 or 168 hours. Deoxyribonucleic acid (DNA) synthesis and angiogenesis were not affected significantly either. CONCLUSIONS: Sorafenib, when administered preoperatively, reduces incompletely and transiently the regeneration of the liver after PH2/3 in rats. This could mean that sorafenib can be used as neoadjuvant treatment of patients with HCC prior to liver resection, but further experimental and clinical studies are needed to establish the safety of this treatment. Hippokratia 2015; 19 (3): 249-255.

Severe eosinophilic infiltration in colonic biopsies predicts patients with ulcerative colitis not responding to medical therapy.

AIM: Eosinophils are potent proinflammatory cells that are involved in the pathogenesis of ulcerative colitis (UC). We evaluated the infiltration of eosinophils into the lamina propria in patients with active and inactive ulcerative colitis (UC) and investigated its clinical significance, among other variables, in predicting the outcome of medical treatment in active disease. METHOD: We studied colorectal biopsy specimens from 18 UC patients with disease in long-standing remission, from 22 patients with active disease who responded to therapy (12 with complete response and 10 with partial response) and from 10 patients who were nonresponders. Demographic information was obtained at baseline, and clinical, endoscopic and laboratory data were obtained at baseline and 12 weeks post-treatment. We evaluated five histological features: mucosal ulceration; mucosal erosions; crypt abscesses; cryptitis; and eosinophilic infiltration of the lamina propria. The severity of these lesions was graded as: none or minimal; mild; moderate; or severe. Statistical analyses were performed between responders and nonresponders for differences in demographic, clinical, laboratory, endoscopic and histological parameters. RESULTS: Laboratory, endoscopic and histological parameters were significantly improved after treatment only in the complete responders group. Analyses of baseline data revealed no significant differences in parameters between complete or partial responders and nonresponders, except for a less severe eosinophilic infiltration of lamina propria in complete responders (P < 0.05). Multiple logistic regression analysis showed that severe eosinophilic infiltration in colonic biopsies was the most significant predictor of poor response to medical therapy. CONCLUSION: Assessing the severity of eosinophilic infiltration in the lamina propria of colonic biopsies in patients with ulcerative colitis could be a valuable predictive tool of response to medical therapy.

Hepatic artery thrombosis after orthotopic liver transplantation: 3 patients with collateral formation and conservative treatment.

Hepatic artery thrombosis (HAT), a serious complication after orthotopic liver transplantation (OLT), can lead to patient death in the absence of revascularization or retransplantation. Herein we have presented clinical characteristics, imaging findings, and long-term outcomes of 3 OLT patients with HAT who were treated conservatively and developed hepatic arterial collaterals. These patients underwent transplantation due to hepatitis B cirrhosis, cryptogenic cirrhosis, or hepatitis C infection and alcoholic disease. They presented with bile duct stenosis and/or a bile leak at 1, 3, and 36 months after transplantation, respectively, and were treated with percutaneous drainage and stent placement, endoscopic retrograde cholangio-pancreatography (ERCP), or reanastomosis of the bile duct over a T tube. HAT was confirmed using multidetector computed tomography (MDCT) 3-dimensional (3D) angiography and Doppler sonography. They survive in good condition with normal liver function at 30, 50, and 42 months after OLT, respectively. Development of collateral arterial circulation to the liver graft was detected with MDCT 3D angiography and Doppler sonography. From our experience with 3 patients and a literature review, we believe that there are a number of patients who experience long-term survival after the diagnosis of irreversible HAT and the development of collaterals. Although this group is at high risk for sepsis and biliary complications, these are usually self-limiting complications due to improved treatment regimens. The development of collateral arterial flow may also be beneficial.

Deeply infiltrating rectal endometriosis with lymph node involvement.

BACKGROUND: Sigmoidorectal endometriosis accounts for 70% of the cases of intestinal endometriosis. Symptoms are non-specific, frequently resembling adenocarcinomas. CASE: A 45-year-old woman complaining of recurrent rectal bleeding underwent colonoscopy in which a rectal polypoid mass was found. She underwent anterior rectosigmoidectomy and the histological examination of the resected bowel revealed rectal endometriosis with lymph node involvement. CONCLUSION: Lymphatic infiltration of epicolic lymph nodes raises questions about the benign nature of this presumed innocent disease.

The evolution of the role of liver transplantation in treating alcoholic cirrhosis in Greece.

BACKGROUND: Liver transplantation represents the main treatment for alcoholic cirrhosis. The goal of this article is to review the results of liver transplantation for alcoholic cirrhosis in Greece over the last 2 decades. METHODS: Among 247 patients who underwent liver transplantation between 1991 and 2007, 34 (13.7%) experienced alcoholic cirrhosis as the primary diagnosis. We reviewed their demographic data, stage of liver disease, and outcomes regarding survival via a Kaplan-Meier curve. Also we analyzed the causes of death and the postoperative complications. RESULTS: Mean Model for End-Stage Liver Disease (MELD) score was 18.4. Other diagnoses included hepatitis C virus (HCV; 23.5%), hepatitis B virus (HBV; 14.7%), and hepatocellular carcinoma (8.8%). Eleven patients died the most frequent causes being primary graft nonfunction (n = 3), hepatic artery thrombosis (n = 2), sepsis (n = 2), and portal vein thrombosis (n = 2). Complications included rejection (32.4%), infection (26.5%), hepatic graft dysfunction (11.8%), and recurrent HCV, recurrent HBV, and renal failure (8.8% each). Recurrence of alcoholism was observed in 3 patients (8.8%) with mild effects on liver function tests. There has been a significant increase in the number of liver transplantations for alcoholic cirrhosis in the last 6 years, namely 25 patients versus 9 in the previous 10 years. CONCLUSIONS: We observed a significant increase in the frequency of alcoholic cirrhosis leading to liver transplantation in the last several years in Greece.

Liver transplantation outcomes in patients with cirrhosis and hepatocellular carcinoma: experience of a single center in a viral hepatitis endemic area.

Our center has performed 205 orthotopic liver transplantations (OLT) in 201 patients. Hepatocellular carcinoma (HCC) was discovered in 32 (15%) patients, 5 of whom were diagnosed incidentally in recipient explants. The main underlying diagnosis was viral hepatitis (n = 28; 87.5%). Most patients (17; 53.1%) were diagnosed as having Child class B cirrhosis. Single tumors measuring <3 cm were diagnosed in 29 (90.6%) patients. Downstaging chemoembolization was performed in 7 (21.8%) patients. Preoperative aFP levels were normal in 20 (62.5%) patients. In the rest (n = 12; 37.5%), aFP levels normalized immediately after the OLT. In the latter group, 2 patients had a delayed (2 years) postoperative increase in aFP levels; both patients had tumor recurrence in the graft. All patients with hepatitis B received antiviral treatment with HBIG and lamivudine. There were 9 deaths (28.1%) in the immediate postoperative period (<30 days). One-year survival rate was 62.5% (n = 20). Actuarial 5-year survival rate was 55%, and actuarial 10-year survival rate was 40%. In conclusion, OLT has become the standard treatment for patients diagnosed with HCC in a population that shows cirrhosis most of the time to be secondary to viral hepatitis, provided that recipients are selected according to the size of the neoplasm and that they receive adequate antiviral prophylaxis.

Focal fatty liver sparing lesion presenting as a "pseudotumour": case report.

We are reporting our experience of a case of "focal fatty liver sparing lesion" in a 24-year-old patient, without any evident predisposing factors for fatty infiltration of the liver. Fatty liver infiltration was sparing the posterior part of liver segment VI, defining an area which was mimicking a lesion on US and CT. Fatty liver infiltration is usually diffuse but may be patchy or localized. Occasionally, focal areas of normal parenchyma in an otherwise diffuse fatty liver may simulate mass lesions. Typically, these "pseudolesions" appear as echo-poor areas against a background of bright echoes due to fatty infiltration and may pose a difficult diagnostic problem. We present this case and discuss the investigation process in order to differentiate this lesion from a hepatic tumor.

Low-molecular-weight heparin (enoxaparin) as adjuvant therapy in the treatment of active ulcerative colitis: a randomized, controlled, comparative study.

BACKGROUND: Heparin could be beneficial to the treatment of active ulcerative colitis because of its anticoagulant, anti-inflammatory and immunomodulatory properties. AIM: To evaluate the tolerability, safety and efficacy of low-molecular-weight heparin as adjuvant therapy in patients with active ulcerative colitis. METHODS: Thirty-four adult patients with active ulcerative colitis were consecutively included in a prospective, randomized, comparative study, and were treated for 12 weeks. Eighteen patients in the 'standard therapy' group were treated with aminosalicylates and weekly tapered corticosteroids. Sixteen patients in the 'heparin therapy' group were treated with standard therapy plus enoxaparin 100 Anti-Xa IU/kg/day subcutaneously. RESULTS: Seventeen patients in the 'standard therapy' group and 15 patients in the 'heparin therapy' group completed the study. Tolerability and compliance to therapy were excellent and no withdrawals were noted because of complications. There was a significant improvement in the disease severity in both groups (P<0.001), without any difference between them (P=not significant). Both treatment groups showed similar proportions of disease improvement (65% and 73%, respectively; P=not significant). There were no significant differences in inflammation (fibrinogen, ESR, CRP) and coagulation (thrombin-antithrombin complex, F1+2, D-dimers) parameters during and at the end of the study between treatment groups. CONCLUSION: Adjuvant administration of low-molecular heparin in patients with active ulcerative colitis is safe and well tolerated, but no additive benefit over standard therapy for ulcerative colitis was noted.

Adefovir dipivoxil added to ongoing lamivudine therapy in patients with lamivudine-resistant hepatitis B e antigen-negative chronic hepatitis B.

BACKGROUND: Long-term treatment with lamivudine is required to control viral replication in patients with hepatitis B e antigen-negative chronic hepatitis B, but is associated with a high rate of viral resistance. The role of adefovir dipivoxil in these patients has not been definitively evaluated. AIM: To address the role of adefovir in the management of patients with lamivudine-resistant hepatitis B e antigen-negative chronic hepatitis B. METHODS: Patients were assigned to receive adefovir 10 mg once daily plus ongoing lamivudine 100 mg once daily for 52 weeks. The primary end point was reduction in serum hepatitis B virus DNA level (hepatitis B virus DNA response). Secondary end points included the proportion of patients with undetectable hepatitis B virus DNA at week 52 (complete virological response) and the percentage of patients with normalization of alanine transferase level at week 52 (biochemical response). RESULTS: A total of 49 consecutive patients were enrolled in this study. After 52 weeks of treatment, all patients had an hepatitis B virus DNA response and 57.1% had complete virological response. Biochemical response occurred in 75.6% of patients. CONCLUSIONS: Administration of adefovir in patients with lamivudine-resistant chronic hepatitis B results in significant suppression of viral replication. Nevertheless, continuous therapy will probably be needed in order to maintain remission in these patients.

Glycine N -methyltransferase deficiency: a new patient with a novel mutation.

We report studies of a Greek boy of gypsy origin that show that he has severe deficiency of glycine N -methyltransferase (GNMT) activity due to apparent homozygosity for a novel mutation in the gene encoding this enzyme that changes asparagine-140 to serine. At age 2 years he was found to have mildly elevated serum liver transaminases that have persisted to his present age of 5 years. At age 4 years, hypermethioninaemia was discovered. Plasma methionine concentrations have ranged from 508 to 1049 micro mol/L. Several known causes of hypermethioninaemia were ruled out by studies of plasma metabolites: tyrosinaemia type I by a normal plasma tyrosine and urine succinylacetone; cystathionine beta-synthase deficiency by total homocysteine of 9.4-12.1 micro mol/L; methionine adenosyltransferase I/III deficiency by S -adenosylmethionine (AdoMet) levels elevated to 1643-2222 nmol/L; and S -adenosylhomocysteine (AdoHcy) hydrolase deficiency by normal AdoHcy levels. A normal plasma N -methylglycine concentration in spite of elevated AdoMet strongly suggested GNMT deficiency. Molecular genetic studies identified a missense mutation in the coding region of the boy's GNMT gene, which, upon expression, retained only barely detectable catalytic activity. The mild hepatitis-like manifestations in this boy are similar to those in the only two previously reported children with GNMT deficiency, strengthening the likelihood of a causative association. Although his deficiency of GNMT activity may well be more extreme, his metabolic abnormalities are not strikingly greater. Also discussed is the metabolic role of GNMT; several additional metabolite abnormalities found in these patients; and remaining questions about human GNMT deficiency, such as the long-term prognosis, whether other individuals with this defect are currently going undetected, and means to search for such persons.

Tenoxicam-associated hepatic injury: a case report and review.

A 51-year-old woman developed jaundice while taking tenoxicam. A full evaluation, including ultrasound, computed tomography, endoscopic cholangiography and liver biopsy, confirmed the diagnosis of mixed hepatic injury. The patient's jaundice and all other liver function abnormalities normalized 1 month after she discontinued taking tenoxicam. This is the first case report of mixed hepatic injury, confirmed with biopsy, associated with tenoxicam. Tenoxicam should be considered as a potential cause of hepatic injury when other more common aetiologies have been excluded.

Adenomyosis at hysterectomy: prevalence and relationship to operative findings and reproductive and menstrual factors.

In order to estimate the frequency and risk factors for adenomyosis, the clinical records of 594 women undergoing hysterectomy were retrieved. Data were collected on indications for the intervention, age at surgery, age at menarche, parity, abortions, mode of delivery, abnormal uterine bleeding, dysmenorrhea, and menopausal status at surgery. Adenomyosis was found in 116 of the 594 patients (19.5%). A pathologic condition was present in 63 patients with fibroids (20.5%), 11 with genital prolapse (25.6%), 11 with benign ovarian tumors (17.8%), six with endometrial hyperplasia (13.6%), two with cervical cancer (18.2%), ten with endometrial cancer (16.1%), and 13 with ovarian cancer (21.3%). No relationship was found between adenomyosis and endometriosis. On the contrary, a strong relationship was found between adenomyosis and parity, cesarean section, induced abortions, dysmenorrhea, abnormal uterine bleeding, and late age at menarche. These results show that adenomyosis is a common pathologic finding, significantly related to reproductive and menstrual characteristics of the patients.

Cytokeratin immunostaining for detection of biliary epithelium: its use in counting bile ducts in cases of liver allograft rejection.

AIMS: To see how useful the application of a bile duct specific cytokeratin antibody (AE1) was in identifying and counting bile ducts in liver allograft biopsy specimens. METHODS: Eighteen liver biopsy specimens showing acute rejection and 17 biopsy specimens plus six hepatectomy specimens showing chronic rejection were studied. Serial sections were cut and stained with haematoxylin and eosin and AE1 antibody. Two pathologists (RFH and KP) examined the sections with respect to a range of histological features. RESULTS: Similar numbers of bile ducts were identified on haematoxylin and eosin sections as on corresponding sections stained by AE1 in cases of acute rejection and end stage chronic rejection. Greater numbers of bile ducts were identified by AE1 during the early stages of chronic rejection, especially when dense portal inflammatory infiltrates were present. These were often incomplete structures or individual cells within portal tracts, and bile ducts subsequently disappeared in all cases. Ductular proliferation was clearly shown by AE1 in acute rejection and the extent seemed to correlate with the severity of rejection present. By contrast, no ductular proliferation was observed in chronic rejection. CONCLUSIONS: Haematoxylin and eosin stained sections are adequate for counting bile ducts in most biopsy specimens from patients with suspected chronic rejection. Immunostaining for biliary cytokeratins using AE1 is of limited use in occasional cases where bile ducts are obscured by inflammatory cells.

Abdominal scanning with technetium-99m pertechnetate localizes ectopic gastric mucosa in the jejunum: case report and review of the literature.

A 16-year-old male patient was admitted to hospital because of a fainting episode which was accompanied by diarrhoea that was dark red. All investigations were normal except a low haematocrit, a technetium-99m pertechnetate abdominal scan, which showed a large area of moderate activity in the upper left abdomen, and digital subtraction angiography, which showed bleeding in the same area where the abnormal finding on the pertechnetate scan was found. Ectopic gastric mucosa and a deep ulcer in an otherwise normal jejunum were found during the urgent exploratory laparotomy.