Bone marrow failure and extramedullary hematopoiesis in McCune-Albright syndrome.

In fibrous dysplasia/McCune-Albright syndrome (FD/MAS), bone and bone marrow are, to varying degrees, replaced by fibro-osseous tissue typically devoid of hematopoietic marrow. Despite the extensive marrow replacement in severely affected patients, bone marrow failure is not commonly associated with FD/MAS. We present a 14-year-old girl with FD/MAS, who developed pancytopenia and extramedullary hematopoiesis (EMH) with no identified cause, in the setting of iatrogenic thyrotoxicosis and hyperparathyroidism. Pancytopenia, requiring monthly blood transfusions, persisted despite multiple strategies to correct these endocrinopathies. Due to worsening painful splenomegaly, likely as a result of sequestration, splenectomy was performed. Following splenectomy, pancytopenia resolved and patient has since been transfusion-independent. We report the first detailed case of bone marrow failure and EMH in FD/MAS. The etiology of marrow failure is likely multifactorial and related to the loss of marrow reserve due to extensive polyostotic FD, exacerbated by iatrogenic thyrotoxicosis and hyperparathyroidism. Mini Abstract: A patient with fibrous dysplasia developed bone marrow failure and extramedullary hematopoiesis. The etiology likely involved loss of hematopoetic marrow space and uncontrolled endocrinopathies. Splenectomy was therapeutic.

Comparative analysis of portal hepatic infiltrating leucocytes in acute drug-induced liver injury, idiopathic autoimmune and viral hepatitis.

Drug-induced liver injury (DILI) is often caused by innate and adaptive host immune responses. Characterization of inflammatory infiltrates in the liver may improve understanding of the underlying pathogenesis of DILI. This study aimed to enumerate and characterize leucocytes infiltrating liver tissue from subjects with acute DILI (n = 32) versus non-DILI causes of acute liver injury (n = 25). Immunostains for CD11b/CD4 (Kupffer and T helper cells), CD3/CD20 (T and B cells) and CD8/CD56 [T cytotoxic and natural killer (NK) cells] were evaluated in biopsies from subjects with acute DILI, either immunoallergic (IAD) or autoimmune (AID) and idiopathic autoimmune (AIH) and viral hepatitis (VH) and correlated with clinical and pathological features. All biopsies showed numerous CD8(+) T cells and macrophages. DILI cases had significantly fewer B lymphocytes than AIH and VH and significantly fewer NK cells than VH. Prominent plasma cells were unusual in IAD (three of 10 cases), but were associated strongly with AIH (eight of nine) and also observed in most with AID (six of nine). They were also found in five of 10 cases with VH. Liver biopsies from subjects with DILI were characterized by low counts of mature B cells and NK cells in portal triads in contrast to VH. NK cells were found only in cases of VH, whereas AIH and VH both showed higher counts of B cells than DILI. Plasma cells were associated most strongly with AIH and less so with AID, but were uncommon in IAD.

Structural biochemistry and activation of matrix metalloproteases.

The degradation of the extracellular matrix is part of many pathological and physiological processes. Of the several proteases involved in extracellular matrix turnover, the plasmin/plasminogen activator system and the family of matrix metalloproteases have received the most attention. Recent investigations in the field of matrix metalloprotease biochemistry have focused on the functions of the various enzyme domains and their interactions with inhibitor domains. Research into physiological activation mechanisms has demonstrated a plasmin/plasminogen activator-metalloprotease cascade, as well as providing an initial characterization of cell surface associated metalloprotease activation.

No evidence of ongoing HIV replication or compartmentalization in tissues during combination antiretroviral therapy: Implications for HIV eradication.

HIV persistence during combination antiretroviral therapy (cART) is the principal obstacle to cure. Mechanisms responsible for persistence remain uncertain; infections may be maintained by persistence and clonal expansion of infected cells or by ongoing replication in anatomic locations with poor antiretroviral penetration. These mechanisms require different strategies for eradication, and determining their contributions to HIV persistence is essential. We used phylogenetic approaches to investigate, at the DNA level, HIV populations in blood, lymphoid, and other infected tissues obtained at colonoscopy or autopsy in individuals who were on cART for 8 to 16 years. We found no evidence of ongoing replication or compartmentalization of HIV; we did detect clonal expansion of infected cells that were present before cART. Long-term persistence, and not ongoing replication, is primarily responsible for maintaining HIV. HIV-infected cells present when cART is initiated represent the only identifiable source of persistence and is the appropriate focus for eradication.

Monocyte infiltration and kidney allograft dysfunction during acute rejection.

Multiple cell types infiltrate acutely rejecting renal allografts. Typically, monocytes and T cells predominate. Although T cells are known to be required for acute rejection, the degree to which monocytes influence this process remains incompletely defined. Specifically, it has not been established to what degree monocytes impact the clinical phenotype of rejection or how their influence compares to that of T cells. We therefore investigated the relative impact of T cells and monocytes by correlating their presence as measured by immunohistochemical staining with the magnitude of the acute change in renal function at the time of biopsy in 78 consecutive patients with histological acute rejection. We found that functional impairment was strongly associated with the degree of overall cellular infiltration as scored using Banff criteria. However, when cell types were considered, monocyte infiltration was quantitatively associated with renal dysfunction while T-cell infiltration was not. Similarly, renal tubular stress, as indicated by HLA-DR expression, increased with monocyte but not T-cell infiltration. These data suggest that acute allograft dysfunction is most closely related to monocyte infiltration and that isolated T-cell infiltration has less acute functional impact. This relationship may be useful in assigning acute clinical relevance to biopsy findings.

The Banff 2007 working classification of skin-containing composite tissue allograft pathology.

Composite tissue allotransplantation (CTA) is a recently introduced option for limb replacement and reconstruction of tissue defects. As with other allografts, CTA can undergo immune-mediated rejection; therefore standardized criteria are required for characterizing and reporting severity and types of rejection. This article documents the conclusions of a symposium on CTA rejection held at the Ninth Banff Conference on Allograft Pathology in La-Coruna, Spain, on 26 June 2007, and proposes a working classification, the Banff CTA-07, for the categorization of CTA rejection. This classification was derived from a consensus discussion session attended by the first authors of three published classification systems, pathologists and researchers from international centers where clinical CTA has been performed. It was open to all attendees to the Banff conference. To the extent possible, the format followed the established National Institutes of Health (NIH) guidelines on Consensus Development Programs. By consensus, the defining features to diagnose acute skin rejection include inflammatory cell infiltration with involvement of epidermis and/or adnexal structures, epithelial apoptosis, dyskeratosis and necrosis. Five grades of severity of rejection are defined. This classification refines proposed schemas, represents international consensus on this topic, and establishes a working collective classification system for CTA reporting of rejection in skin-containing CTAs.

Endoluminal Vacuum Therapy for Ivor Lewis Anastomotic Leaks: A Pilot Study in a Swine Model.

Anastomotic leaks are a serious complication associated with Ivor Lewis esophagectomies. Endoluminal negative pressure vacuum devices create a possible treatment alternative to conventional surgical intervention. Ten pigs had an intrathoracic esophageal anastomosis with a 1-cm defect. The experimental group had the device placed intraoperatively across the defect, whereas the control group did not. Once treatment was completed, a contrast fluoroscopic study and necropsy was performed. All control pigs had contrast extravasation on fluoroscopy and contamination on necropsy. The experimental group had no radiologic leak and no contamination on necropsy. The P value for leak is 0.03. This study demonstrated that endoluminal negative pressure vacuum therapy is tolerated in the swine model and is successful in facilitating the healing of anastomotic leaks. Endoluminal negative pressure vacuum therapy has potential clinical benefits, including decreased morbidity and length of hospital stay.

Noninvasive markers for staging fibrosis in chronic delta hepatitis.

BACKGROUND: Serum fibrosis markers are useful in staging chronic hepatitis B (HBV) and C (HCV) virus but have not been evaluated in chronic hepatitis D virus (HDV). AIM: To evaluate the utility of serum fibrosis markers [fibrosis-4 score (FIB-4), aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio, aspartate aminotransferase ratio (AAR), age-platelet index (API), AST-to-platelet-ratio-index (APRI) and Hui score] in HDV infection. METHODS: Clinical and histologic laboratory data from HBV, HCV and HDV patients were evaluated and serum fibrosis markers were calculated. The ability of fibrosis markers to detect advanced fibrosis (Ishak ≥4) and cirrhosis (Ishak = 6) were evaluated and compared between viral infections. RESULTS: A total of 1003 subjects (HCV = 701, HBV = 240 and HDV = 62) with mean age of 46 ± 11 and 66% male were evaluated. HDV subjects had higher ALT and AST than HCV and lower platelets than both HBV and HCV. Histologically, HDV had the greatest percentage of Ishak ≥4 and necroinflammation. FIB-4 performed best in detecting advanced fibrosis and cirrhosis in all viral cohorts. In HDV, area under the receiver operator curve (AUROC) 95% confidence intervals for detecting advanced fibrosis were: FIB-4 = 0.70 (0.55-0.84), API = 0.69 (0.55-0.82), APRI = 0.68 (0.54-0.82), Hui score = 0.63 (0.49-0.78), AAR = 0.63 (0.48-0.77). The AUROC for detecting cirrhosis in HDV were: FIB-4 = 0.83 (0.69-0.97), API = 0.80 (0.66-0.95), APRI = 0.75 (0.61-0.89), Hui score = 0.70 (0.49-0.91) and AAR = 0.70 (0.48-0.93). Adjustment of published cut-offs led to marginal improvements in FIB4 for advanced fibrosis and of APRI for cirrhosis in HDV. CONCLUSIONS: Serum fibrosis markers have lower performance accuracy in chronic HDV infected patients compared to HBV and HCV patients. Other noninvasive fibrosis markers should be explored to assist in the management of these patients.

Complications of percutaneous liver biopsy with Klatskin needles: a 36-year single-centre experience.

BACKGROUND: Liver biopsy is the gold standard in evaluating liver diseases but is susceptible to complications. Safety data on aspiration needle biopsies remain limited. AIM: To evaluate the safety of percutaneous liver biopsy performed with Klatskin needle. METHODS: Clinical and biochemical data were retrospectively retrieved from sequential subjects who underwent liver biopsy with Klatskin needle from 1978 to 2015. Subjects with complications underwent thorough chart reviews for hospital course. RESULTS: Of 3357 biopsies performed, complications occurred in 135 (4%) biopsies with 33 (1%) resulting in major complications. Severe pain occurred in 78 (2.3%) subjects and bleeding occurred in 21 (0.6%) subjects. Biliary injury occurred in 8 (0.2%) biopsies. Three subjects died as a result of massive intraperitoneal bleeding. Compared to viral hepatitis, biopsies performed with certain diagnosis had significantly higher odds of major complications: NRH (OR: 17), DILI (OR: 20), GVHD (OR: 32) and HCC (OR: 34). Subjects with major complications had higher pre-biopsy median AP (153 vs. 78 U/L, P < 0.001), ALT (105 vs. 64 U/L, P < 0.05), AST (62 vs. 47 U/L, P < 0.02), along with marginally lower total bilirubin (1.0 vs. 0.7 mg/dL, P < 0.01) and albumin (3.7 vs. 4.0 g/dL, P < 0.001). By multivariate backward logistic regression, platelets ≤100 K/µL and aPTT >35 were independent risk factors of post-biopsy bleeding. CONCLUSION: Klatskin needle liver biopsies are safe with rare procedural morbidity. Our data suggests certain acutely ill subjects and those with systemic illnesses may be at higher risk of major complications. Clinicians should weigh the risks and benefits of liver biopsy in these patients with other alternative approaches.

Mutations of p53 gene in hepatocellular carcinoma: roles of hepatitis B virus and aflatoxin contamination in the diet.

BACKGROUND: Mutations of the p53 tumor suppressor gene have been reported in 50% of patients with hepatocellular carcinoma (HCC) from China and South Africa. These reports suggested an association of p53 mutations with high levels of aflatoxin in the diet. Most studies of p53 and HCC, however, have not fully evaluated the possible role of the hepatitis B virus (HBV). Aflatoxin is a substance produced by food mold that is known to cause HCC in experimental animals. PURPOSE: The purpose of this study was to evaluate the relationship of p53 gene mutation to high or low levels of aflatoxin in the diet and to HBV infection. METHODS: p53 protein and hepatitis B surface antigen (HBsAg) were evaluated by immunohistochemistry using the avidin-biotin-peroxidase system in paraffin-embedded specimens of HCC and of adjacent nontumorous liver tissue from 43 patients. Tissue specimens from three normal human livers were also evaluated. HCCs and adjacent nontumorous liver tissues were obtained from 23 patients from Qidong, China, where aflatoxin levels in the diet are high, and from 20 patients from two regions in the United States (patients from the National Institutes of Health, Bethesda, Md., and Kuakini Medical Center, Honolulu, Hawaii), where aflatoxin levels in the diet are low. RESULTS: Mutant p53 protein was detected in the nuclei of HCCs from 14 (61%) of 23 patients from China and from three (30%) of 10 patients and six (60%) of 10 patients, respectively, from the two regions of the United States. A statistically significant association between detection of mutant p53 protein in HCC cells and the detection of HBsAg in hepatocytes of the adjacent nontumorous liver tissue was observed in patients from China and the United States considered together. CONCLUSION: Mutations of the tumor suppressor gene p53 in hepatocellular carcinomas are not limited to patients from geographic regions where the ingestion of aflatoxin is high. In many patients, these mutations may be associated with HBV infection. IMPLICATIONS: The possible interaction of chronic HBV infection and p53 gene mutation, suggested by these data, indicates a mechanism by which HBV infection beginning early in life could contribute to the subsequent development of HCC.

Liver injury is associated with mortality in sickle cell disease.

BACKGROUND: Increased life expectancy in sickle cell disease (SCD) has resulted in greater recognition of the consequences of repeated intravascular vaso-occlusion and chronic haemolysis to multiple organ systems. AIM: To report the long-term consequences of liver dysfunction in SCD. METHODS: A cohort of SCD patients was prospectively evaluated at the National Institutes of Health (NIH) Clinical Center. The association of mortality with liver enzymes, parameters of liver synthetic function and iron overload was evaluated using Cox regression. RESULTS: Exactly, 247 SCD patients were followed up for 30 months of whom 22 (9%) died. After controlling for predictors, increased direct bilirubin (DB), ferritin, alkaline phosphatase and decreased albumin were independently associated with mortality. In a multivariable model, only high DB and ferritin remained significant. Ferritin correlated with hepatic iron content and total blood transfusions but not haemolysis markers. Forty patients underwent liver biopsies and 11 (28%) had fibrosis. Twelve of 26 patients (48%) had portal hypertension by hepatic venous pressure gradient (HVPG) measurements. All patients with advanced liver fibrosis had iron overload; however, most patients (69%) with iron overload were without significant hepatic fibrosis. Ferritin did not correlate with left ventricular dysfunction by echocardiography. DB correlated with bile acid levels suggesting liver pathology. Platelet count and soluble CD14 correlated with HVPG indicating portal hypertension. CONCLUSIONS: Ferritin and direct bilirubin are independently associated with mortality in sickle cell disease. Ferritin likely relates to transfusional iron overload, while direct bilirubin suggests impairment of hepatic function, possibly impairing patients' ability to tolerate systemic insults.

A phase II study of TRC105 in patients with hepatocellular carcinoma who have progressed on sorafenib.

BACKGROUND: Endoglin is an endothelial cell membrane receptor essential for angiogenesis and highly expressed on the vasculature of many tumor types, including hepatocellular carcinoma (HCC). TRC105 is a chimeric IgG1 anti-CD105 monoclonal antibody that inhibits angiogenesis and tumor growth by endothelial cell growth inhibition, ADCC and apoptosis, and complements VEGF inhibitors. OBJECTIVE: The aim of this phase II study was to evaluate the efficacy of anti-endoglin therapy with TRC105 in patients with advanced HCC, post-sorafenib. METHODS: Patients with HCC and compensated liver function (Childs-Pugh A/B7), ECOG 0/1, were enrolled to a single-arm, phase II study of TRC105 15 mg/kg IV every two weeks. Patients must have progressed on or been intolerant of prior sorafenib. A Simon optimal two-stage design was employed with a 50% four-month PFS target for progression to the second stage. Correlative biomarkers evaluated included DCE-MRI as well as plasma levels of angiogenic biomarkers and soluble CD105. RESULTS: A total accrual of 27 patients was planned. However, because of lack of efficacy and in accordance with the Simon two-stage design, 11 patients were enrolled. There were no grade 3/4 treatment-related toxicities. Most frequent toxicities were headache (G2; N = 3) and epistaxis (G1; N = 4). One patient had a confirmed partial response by standard RECIST criteria and biologic response on DCE-MRI but the four-month PFS was insufficient to proceed to the second stage of the study. CONCLUSIONS: TRC105 was well tolerated in this HCC population following sorafenib. Although there was evidence of clinical activity, this did not meet prespecified criteria to proceed to the second stage. TRC105 development in HCC continues as combination therapy with sorafenib.

Chemically modified tetracyclines inhibit human melanoma cell invasion and metastasis.

Recent work has shown that chemically modified tetracyclines (CMTs) are potent inhibitors of matrix metalloproteinase (MMP) activity, both in vitro and in vivo, which is distinct from their antimicrobial activities (Golub et al. Crit Rev Oral Biol Med, 2, 297-321, 1991; Ryan et al. Curr Opin Rheumatol, 8, 23847, 1996). The process of tumor cell invasion requires MMP-mediated degradation of extracellular matrix barriers as a key step in the metastasic cascade. In this study, we examined the effect(s) of doxycycline and CMTs on extracellular levels of gelatinase A and B activity from a highly invasive and metastatic human melanoma cell line C8161, and correlated these observations with changes in the cells' biological behavior in an in vitro invasion assay and in an in vivo SCID mouse model. The results indicate that coincident with the ability of these compounds to differentially suppress extracellular levels of gelatinase activity, C8161 cells treated with doxycycline, CMT-1, CMT-3, or CMT-6 were less invasive in vitro in a dose-dependent manner (3-50 microg/ml). Furthermore, data derived from the in vivo model indicate that SCID mice dosed orally with CMT-1 or CMT-3 contained a reduced number of lung metastases following i.v. injection of C8161 cells via tail vein inoculation. These observations suggest that careful screening of different CMTs could lead to the identification of compounds which suppress the formation and magnitude of metastases associated with certain cancers, and if used as an adjunct to other treatment regimes, lead to greater efficacy in the treatment of metastatic cancers.

Adrenocortical neoplasms: role of prognostic markers MIB-1, P53, and RB.

Differentiation between benign and malignant adrenocortical neoplasms is made using a combination of clinical and pathologic parameters. Despite these parameters, it is still difficult to predict the biologic potential of some tumors. Forty adrenocortical lesions, including 10 hyperplasias, 10 adenomas, 12 carcinomas and eight metastatic/recurrent adrenocortical carcinomas were studied for the expression of MiB-1, p53, and the retinoblastoma gene product (RB) utilizing immunohistochemical techniques. The mean tumor proliferating fraction (TPF), expressed as the number of MiB-1-positive nuclei per 1,000 tumor cells, was 14.9 in adenomas, 31.5 in hyperplasias, 208.1 in carcinomas and 166.1 in recurrent or metastatic disease. None of the 20 benign lesions had a TPF of > 80, and only one of the 20 malignancies had a TPF of < 80. Nine of the 20 carcinomas were positive for p53. None of the benign lesions were p53 positive. Thirty-nine cases, including benign and malignant ones, were RB positive, and one was uninterpretable. We conclude that prognostic markers can be of great assistance in recognizing adrenocortical carcinomas. High TPF (> 80), as measured by staining with MiB-1, and positive p53 strongly correlate with malignant behavior and therefore may be useful in distinguishing benign from malignant adrenal lesions. Staining for RB does not appear to be a helpful technique.

Unusual aspects of allergic bronchopulmonary fungal disease: report of two cases due to Curvularia organisms associated with allergic fungal sinusitis.

We report two cases of allergic bronchopulmonary fungal disease (ABPFD) caused by Curvularia sp and associated with allergic fungal sinusitis (AFS). Curvularia lunata was cultured in one case and Curvularia senegalensis was cultured in the other. Based on these cases and a review of the literature, we discuss unusual clinical and pathologic features that can occur in ABPFD. Unusual clinical aspects of ABPFD include associated AFS, absence of asthma, progression to Churg-Strauss angiitis and granulomatosis, concomitant hypersensitivity pneumonitis, and underlying cystic fibrosis. Atypical pathologic features that may occur in ABPFD include follicular bronchiolitis, xanthomatous bronchiolitis, limited tissue invasion, fungus balls, and association with unusual fungi. Prominent follicular bronchiolitis and xanthomatous bronchiolitis were misleading histologic features in one of our cases and led to a delay in recognition of the diagnosis. Both patients presented primarily with AFS; ABPFD was detected subsequently. This suggests that a small subset of patients with AFS may be at risk for ABPFD. The goal of this review is to increase awareness of unusual clinical and pathologic manifestations of ABPFD. It is hoped that this will result in accurate diagnosis and proper therapy, especially for patients who present with atypical features. Unusual fungal species should be considered in patients who have clinical findings compatible with ABPFD but who do not demonstrate immunologic reactivity to Aspergillus sp, especially Aspergillus fumigatus. In addition, ABPFD should be considered in patients with AFS who develop new pulmonary lesions.

Perirenal myelolipoma.

Extra-adrenal myelolipomas are rare, benign tumors composed of hematopoietic and adipose elements. Although these tumors can cause local symptoms or hemorrhage, they are generally asymptomatic. However, when discovered intraoperatively, they pose a diagnostic dilemma to the urologic surgeon. We present a case of perirenal extra-adrenal myelolipoma discovered intraoperatively in a patient with von Hippel-Lindau disease undergoing partial nephrectomy.

Progelatinase A mRNA expression in cell lines derived from tumors in patients with metastatic renal cell carcinoma correlates inversely with survival.

OBJECTIVES: Tumors are thought to metastasize by a process involving tumor cell attachment to extracellular matrix, degradation of matrix components by tumor-associated proteases, and cellular movement into the area modified by protease activity. Type IV collagen comprises the major element tumor cells must degrade to gain access to the rest of the body. Renal cancer cell line progelatinase A (E.C. 3.4.24.24; 72-kDa type IV collagenase; MMP-2) mRNA expression was correlated with patient survival. METHODS: Total cellular mRNA was extracted from tumor cell lines derived from patients with metastatic renal cell carcinoma. The results of the densitometric analysis of Northern blots were correlated with patient survival. Formalin-fixed, paraffin-embedded tissue sections of primary renal cancers were examined for immunohistochemical expression of MMP-2. RESULTS: Cell lines established from 23 primary renal tumors and six metastatic sites in 26 patients with metastatic renal carcinoma were studied. Variable expression of progelatinase A, relative to A2058 melanoma cells (mean +/- SEM, 0.60 +/- 0.21; median, 0.082; range, 0 to 4.78), was found. There was a significant inverse association between patient survival and the log of the MMP-2 expression (P = 0.045 by the Cox proportional-hazards model). Using a cutoff value of 0.10, the closest round number to the median expression of MMP-2, a significant difference between survival of patients with lower and higher MMP-2 expression in their primary renal cell line was found (P = 0.0054). Cell lines with low, intermediate, and high expression of MMP-2 mRNA all had primary tumors with high tissue immunohistochemical expression of MMP-2. CONCLUSIONS: These studies demonstrate an inverse relationship between renal cancer cell line MMP-2 mRNA expression and patient survival. Immunohistochemical studies of the primary tumors from which the cell lines were derived uniformly showed high MMP-2 expression. Previous work suggests local renal factors upregulate cellular expression of MMP-2 in the primary tumor, and are not active at extrarenal sites.

Matrix metalloproteinases and metastasis.

Metastatic disease is responsible for the majority of cancer-related deaths, either directly due to tumor involvement of critical organs or indirectly due to complications of therapy to control tumor growth and spread. An understanding of the mechanisms of tumor cell invasion and metastasis may be important for devising therapies aimed at preventing tumor cell spread. Matrix metalloproteinases (MMPs) are a family of zinc-dependent endoproteinases whose enzymatic activity is directed against components of the extracellular matrix (ECM). In humans, 16 members of this family have been identified by cloning and sequencing. These proteinases are linked by a core of common domain structures and by their relationship to a family of proteinase inhibitors called the tissue inhibitors of metalloproteinases (TIMPs). Four members of the TIMP family have been cloned and sequenced in humans and they inhibit MMPs by forming tight-binding, noncovalent associations with the active site of the MMPs. MMPs facilitate tumor cell invasion and metastasis by at least three distinct mechanisms. First, proteinase action removes physical barriers to invasion through degradation of ECM macromolecules such as collagens, laminins, and proteoglycans. This has been demonstrated in vitro through the use of chemoinvasion assays and in vivo by the presence of active MMPs at the invasive front of tumors. Second, MMPs have the ability to modulate cell adhesion. For cells to move through the ECM, they must be able to form new cell-matrix and cell-cell attachments and break existing ones. Using a cell transfection system that altered the ratio of MMP-2 to TIMP-2 we have demonstrated significant variation in the adhesive phenotype of tumor cells. Finally, MMPs may act on ECM components or other proteins to uncover hidden biologic activities. For example, the angiogenesis inhibitor angiostatin may be produced from plasminogen by MMP action and laminin-5 is specifically degraded by MMP-2 to produce a soluble chemotactic fragment. Thus MMPs play multiple key roles in facilitating the metastasis of tumor cells. Therapies designed to interfere with specific MMP actions may be useful in the control of metastatic disease.

Long-term therapy of chronic delta hepatitis with peginterferon alfa.

BACKGROUND: Chronic delta hepatitis virus (HDV) infection rapidly progresses to cirrhosis. Treatment with peginterferon for up to 2 years is often without durable response. AIM: To examine the efficacy and safety of long-term peginterferon in achieving a durable response. METHODS: Treatment was initiated with 180 µg/week of peginterferon alfa-2a with titration to a maximal tolerable dose, for up to 5 years. Liver biopsies and hepatic venous pressure gradients (HVPG) were evaluated at baseline, 1, 3 and 5 years. The primary endpoint was histological improvement or loss of serum HDV and HBsAg at 3 years. RESULTS: Thirteen patients were treated for a median of 140 weeks (6-260) with an average peginterferon dose of 180 µg/week (90-270). At baseline, most had advanced disease (median Ishak fibrosis = 3) with portal hypertension (HVPG = 10.2 ± 6 mmHg). Five of 13 patients (39%) achieved the primary endpoint, with three seroconverting for HBsAg after 24, 37 and 202 weeks of treatment. Histological inflammation improved after 1 year, (median HAI: 10 vs. 7, P = 0.01) with persistence in 4/5 patients at 3 years (median HAI: 7.5). Greatest improvements occurred in the first year. Baseline bilirubin and HBsAg levels were significantly lower in virological responders than nonresponders. After 12 weeks, virological responders had a significant decline in HBsAg (1.5 log10 IU/mL, P = 0.05). CONCLUSION: Despite increased doses and duration of therapy, treatment of chronic HDV with peginterferon remains unsatisfactory. Quantitative measures of HBsAg may be an important biomarker of early response to peginterferon therapy in chronic delta hepatitis virus infection.

Vitamin E and changes in serum alanine aminotransferase levels in patients with non-alcoholic steatohepatitis.

BACKGROUND: Non-alcoholic steatohepatitis (NASH) is a common cause of serum alanine aminotransferase (ALT) elevations and chronic liver disease, but it is unclear how well ALT elevations reflect the liver injury. AIM: To assess how well changes in ALT elevations reflect improvements in liver histology in response to vitamin E therapy. METHODS: The vitamin E and placebo arms of the Pioglitazone vs. Vitamin E vs. Placebo in Non-alcoholic Steatohepatitis (PIVENS) trial were reassessed for associations among changes in ALT levels, body weight and liver histology. An ALT response was defined as a decrease to ≤40 U/L and by ≥30% of baseline. Liver biopsies taken before and after treatment were scored for non-alcoholic fatty liver disease activity (NAS) and fibrosis. RESULTS: ALT responses were more frequent among vitamin E (48%) than placebo (16%) recipients (P < 0.001). Among vitamin E recipients, ALT responses were associated with decreases in NAS (P < 0.001), but not fibrosis scores (P = 0.34), whereas among placebo recipients, ALT responses were associated with significant decreases in both (P < 0.05). Weight loss (≥2 kg) was also associated with ALT response (P < 0.001), improvements in NAS (P < 0.001) and fibrosis (P < 0.02), but vitamin E had an added effect both with and without weight loss. Weight gain (≥2 kg) was associated with lack of ALT response and worsening NAS and fibrosis scores in patients not on vitamin E. CONCLUSIONS: Decrease of ALT levels to normal in patients with NASH is usually associated with improved histological activity. Management should stress the value of weight loss and strongly discourage weight gain. Vitamin E can improve both ALT levels and histology with and without weight loss. CLINICAL TRIAL NUMBER: NCT00063622.