Pathway-based analysis of primary biliary cirrhosis genome-wide association studies.

Genome-wide association studies (GWAS) have successfully identified several loci associated with primary biliary cirrhosis (PBC) risk. Pathway analysis complements conventional GWAS analysis. We applied the recently developed linear combination test for pathways to datasets drawn from independent PBC GWAS in Italian and Canadian subjects. Of the Kyoto Encyclopedia of Genes and Genomes and BioCarta pathways tested, 25 pathways in the Italian dataset (449 cases, 940 controls) and 26 pathways in the Canadian dataset (530 cases, 398 controls) were associated with PBC susceptibility (P<0.05). After correcting for multiple comparisons, only the eight most significant pathways in the Italian dataset had FDR <0.25 with tumor necrosis factor/stress-related signaling emerging as the top pathway (P=7.38 × 10⁻4, FDR=0.18). Two pathways, phosphatidylinositol signaling and hedgehog signaling, were replicated in both datasets (P<0.05), and subjected to two additional complementary pathway tests. Both pathway signals remained significant in the Italian dataset on modified gene set enrichment analysis (P<0.05). In both GWAS, variants nominally associated with PBC were significantly overrepresented in the phosphatidylinositol pathway (Fisher exact P<0.05). These results point to established and novel pathway-level associations with inherited predisposition to PBC that, on further independent replication and functional validation, may provide fresh insights into PBC etiology.

Consensus statement on the pathology of IgG4-related disease.

IgG4-related disease is a newly recognized fibro-inflammatory condition characterized by several features: a tendency to form tumefactive lesions in multiple sites; a characteristic histopathological appearance; and-often but not always-elevated serum IgG4 concentrations. An international symposium on IgG4-related disease was held in Boston, MA, on 4-7 October 2011. The organizing committee comprising 35 IgG4-related disease experts from Japan, Korea, Hong Kong, the United Kingdom, Germany, Italy, Holland, Canada, and the United States, including the clinicians, pathologists, radiologists, and basic scientists. This group represents broad subspecialty expertise in pathology, rheumatology, gastroenterology, allergy, immunology, nephrology, pulmonary medicine, oncology, ophthalmology, and surgery. The histopathology of IgG4-related disease was a specific focus of the international symposium. The primary purpose of this statement is to provide practicing pathologists with a set of guidelines for the diagnosis of IgG4-related disease. The diagnosis of IgG4-related disease rests on the combined presence of the characteristic histopathological appearance and increased numbers of IgG4⁺ plasma cells. The critical histopathological features are a dense lymphoplasmacytic infiltrate, a storiform pattern of fibrosis, and obliterative phlebitis. We propose a terminology scheme for the diagnosis of IgG4-related disease that is based primarily on the morphological appearance on biopsy. Tissue IgG4 counts and IgG4:IgG ratios are secondary in importance. The guidelines proposed in this statement do not supplant careful clinicopathological correlation and sound clinical judgment. As the spectrum of this disease continues to expand, we advocate the use of strict criteria for accepting newly proposed entities or sites as components of the IgG4-related disease spectrum.

Immigrant patients with chronic hepatitis C and advanced fibrosis have a higher risk of hepatocellular carcinoma.

To explore the impact of the differences in baseline characteristics between immigrants with chronic hepatitis C (CHC) and native-born patients on the prognosis of advanced fibrosis. A retrospective cohort study was conducted in 318 patients (including 128 immigrants) with CHC and advanced fibrosis attending a tertiary referral clinic. Patients' medical records were reviewed to collect data describing immigrant status, baseline characteristics, and liver-related clinical outcomes. Kaplan-Meier (KM) analyses and Cox proportional-hazards regression analyses were performed to explore the differences between the two groups with respect to clinical outcomes. Relative to native-born patients, immigrant patients were older, more likely to be female, and more likely to be Asian. Immigrants were less likely to be heavy drinkers, heavy smokers, injection drug users, and more likely to have type 2 diabetes. KM analyses indicated that immigrant patients had a significantly higher risk of hepatocellular carcinoma (HCC) than Canadian-born patients (P = 0.005). Univariate Cox proportional-hazards analyses indicated that immigrant status (hazard ratio (HR) 2.22; P = 0.006), age (HR 1.07; P < 0.001), heavy drinking (HR 2.69; P = 0.001), heavy smoking (HR 2.03; P = 0.019), and type 2 diabetes (HR 2.06; P = 0.011) were significantly associated with the risk of HCC. Multivariable Cox proportional-hazards analyses showed that immigrant status was not an independent risk factor for HCC (HR 1.37; P = 0.318) after adjusting for age and type 2 diabetes. Older age and higher prevalence of type 2 diabetes accounted for the increased risk of HCC among immigrant patients with CHC and advanced fibrosis.

Acute orbital inflammatory syndrome secondary to an ANCA-positive small-vessel vasculitis: a case report and review of the literature.

A 61-year-old man presents with sequential painful bilateral proptosis within 36 h and orbital compartment syndrome resulting in complete loss of vision bilaterally. Sequential urgent lateral canthotomy and cantholysis were performed to reverse the compartment syndrome. Orbital imaging showed non-specific orbital inflammation. Biopsies showed necrotizing inflammation and bloodwork was positive for c-ANCA. The patient was therefore treated with prednisone and cyclophosphomide and showed good recovery of vision in one eye, and had no recurrence of orbital inflammation. ANCA-associated orbital vasculitides are rare, but must be kept in mind in the differential diagnosis of acute orbital inflammatory syndromes.

Apocrine hidrocystoma of the orbit.

Apocrine hidrocystomas are benign cysts of sweat duct origin, originating mainly from the apocrine secretory glands of Moll. They are typically encountered in the head and neck, particularly around the inner canthus of the eyelid. An intraorbital location of this lesion is extremely rare but should be considered in the differential diagnosis of a painless cystic lesion in the ocular adnexa at any age.

Biosynthesis of sulphated macromolecules by rabbit lens epithelium. I. Identification of the major macromolecules synthesized by lens epithelial cells in vitro.

Rabbit lens epithelial cells synthesize and secrete a variety of [35S]sulphate-labeled glycoconjugates in vitro. Associated with the cell layer, and with the medium, was a high molecular weight glycoconjugate(s) that contained heparan sulphate which was apparently covalently linked to sulphated glycoprotein. This component(s) was eluted in the void volume of a Sepharose CL-2B column and could not be fractionated by detergent treatment or extraction with lipid solvents. The cell layer also contained glycosaminoglycans (72% heparan sulphate, 28% chondroitin sulphate), as well as a small proportion of a low molecular weight sulphated glycoprotein. The major 35S-labeled species secreted into the medium were sulphated glycoproteins with approximate molecular weights of 120,000 and 35,000 together with a heparan sulphate proteoglycan. This proteoglycan could be precipitated from the culture medium with 30% saturated (NH4)2SO4 and eluted from Sepharose CL-4B columns at approximately the same position (Kav = 0.15) as heparan sulphate proteoglycans described in the basement membrane of the EHS "sarcoma" (Hassell, J. R., P. G. Robey, H. J. Barrach, J. Wilczek, S. I. Rennard, and G. R. Martin, 1980, Proc. Natl. Acad. Sci. USA, 77:4494-4498) and of the mouse mammary epithelium (David, G., and M. Bernfield, 1981, J. Cell Biol., 91:281-286). Its presence in the culture medium was unanticipated but may be explained by the inability of these cultures to deposit a basement membrane when grown on a plastic surface. The relationship of this heparan sulphate proteoglycan to the lens epithelial basement membrane is the subject of the following paper.

Biosynthesis of sulphated macromolecules by rabbit lens epithelium. II. Relationship to basement membrane formation.

Rabbit lens epithelial cells display a similar "cobblestone" morphology and produce the same complement of sulphated macromolecules (also see Heathcote, J.G., and R.W. Orkin, 1984, J. Cell Biol., 99:852-860) whether grown on plastic or glass, dried films of gelatin or type IV collagen with laminin, or on gels of type I collagen. There was no evidence of basement membrane formation by these cells when they were grown on plastic, glass, or dried films. In contrast, cultures that had been grown on gels deposited a discrete basement membrane that followed the contours of the basal surfaces of the cells and in addition, they secreted amorphous basement membrane-like material that diffused into the interstices of the gel and associated with the collagen fibrils of the gel. A significant proportion (approximately 70%) of the heparan sulphate proteoglycan fraction that was secreted into the culture medium (fraction MI) when the cells were grown on plastic became associated with the cell-gel layer in the gel cultures. Further, when basement membrane was isolated by detergent extraction, greater than 90% of the 35S-labeled material present was in this heparan sulphate proteoglycan.

Ocular involvement in acute febrile neutrophilic dermatosis (Sweet syndrome): new cases and review of the literature.

Sweet syndrome (acute febrile neutrophilic dermatosis) is a dermatologic disorder with accompanying features of systemic inflammation. It is commonly associated with conjunctivitis, but a variety of types of ocular inflammation have been reported. The ocular manifestations of Sweet syndrome include periorbital and orbital inflammation, dacryoadenitis, conjunctivitis, episcleritis, scleritis, limbal nodules, peripheral ulcerative keratitis, iritis, glaucoma, and choroiditis. The ocular inflammation appears concurrently with skin lesions. An overview of Sweet syndrome is presented with a review of cases in the literature describing ocular involvement. We report two additional cases of ocular involvement, one with conjunctivitis and a second with iritis, peripheral ulcerative keratitis, and episcleritis. Of the 20 cases, half were bilateral. Thirteen cases occurred in the setting of classical or idiopathic Sweet syndrome and seven in association with malignancy. Biopsies of ocular tissue were infrequent, but, in the seven cases where ocular tissue was analyzed, the histopathology was similar to that of the cutaneous lesions. The ocular complications of Sweet syndrome resolved with systemic administration of corticosteroid or cyclosporine. Topical ocular steroid treatment was frequently used in conjunction with oral steroid but may not have been valuable.

NUT carcinoma of the sinonasal tract infiltrating the orbit in a man with birdshot chorioretinitis.

A 48-year-old man with a history of birdshot chorioretinitis presented with blurry vision, retro-bulbar pain and sinusitis. Though visual acuity was unaffected, he had left optic disc oedema and mild restriction of left eye abduction. His symptoms progressed quickly, with diplopia in primary gaze, epistaxis from his left nostril, and a left relative afferent pupillary defect (RAPD). On computed tomography, there was a mass in the nasal cavity that extended through the left cribriform plate and lamina papyracea and posteriorly into the optic canal. Pathological examination of biopsy specimens revealed sheets of undifferentiated cells with extensive areas of necrosis and islands of squamous differentiation. The tumour cells expressed monokeratin, p63, CD34, and p16. Molecular testing indicated rearrangement of the NUTM1 (15q14) locus and fusion of the NUTM1 and BRD4 (19p13.12) loci, confirming the diagnosis of NUT carcinoma of the sinonasal tract. This is the first reported case of NUT carcinoma in a patient with birdshot chorioretinitis. The onset of chorioretinitis may have been the earliest sign of the effects of the BRD4-NUTM1 fusion protein, resulting in expression of HLA-A29. There is evidence that bromodomain and extra terminal (BET) family proteins play a role in inflammatory marker expression.

Multicentred international review of orbital exenteration and reconstruction in oculoplastic and orbit practice.

BACKGROUND: Orbital exenteration is a disfiguring procedure reserved for life-threatening malignancies. This study examines the clinical course and outcomes of a large series of patients who underwent orbital exenteration for malignant periocular neoplasms. METHODS: This is a retrospective review of patients who underwent orbital exenteration from 1 July 2005 to 30 June 2015 at four tertiary referral centres in the USA, Australia and Canada. Demographics, indication for surgery, pathology, surgical technique, reconstruction type and outcomes were reviewed. RESULTS: Orbital exenteration was performed on 102 patients. The mean age at surgery was 67.5 years. The most common malignant tumours encountered were squamous cell carcinoma, melanoma and basal cell carcinoma. Seventy-six patients (75%) underwent reconstruction with a local myocutaneous flap, twelve with partial-thickness skin grafts (PTSG), or split skin graft, two had a free flap, and one had a dermis fat graft. Sixteen patients had combined procedures of two of the above. Complete removal of the tumour was achieved with clear margins in 81 cases. Of all patients, 72% were alive at 48 months or more. CONCLUSION: The majority of orbital exenterations performed in this series were secondary to periocular malignancies with unsuccessful/insufficient previous treatments. Regional myocutaneous flaps, PTSG, full-thickness skin grafts and dermis fat grafts were all highly effective and durable reconstructive options, and were able to withstand radiation therapy without complications.

Adenocarcinoma of the Retinal Pigment Epithelium Arising in Conjunction with Late Recurrence and Systemic Metastasis of Retinoblastoma.

In 1974, an 8-month-old male was diagnosed with bilateral retinoblastoma. His left eye was enucleated, while the right eye was salvaged with a combination of external beam radiotherapy (4,000 cGy total, divided in 20 fractions) and retinal laser treatment. Thirty-nine years later, he developed intraocular recurrence of retinoblastoma with extrascleral spread. Histopathological examination also identified a second distinct malignancy, retinal pigment epithelium adenocarcinoma, arising in continuity with the retinoblastoma. Further investigation revealed foci of metastatic retinoblastoma in his parotid gland. He was subsequently treated with a combination of orbital exenteration, extensive neck dissection, and resection of metastatic foci, followed by a high-dose ablative chemotherapeutic regimen consisting of cisplatin, vincristine, and cyclophosphamide. Although very rare, late recurrence of retinoblastoma with systemic metastasis is possible, and continued clinical observation and appropriate long-term follow-up should be considered. Additionally, it is important to consider a second primary intraocular tumor in the differential diagnosis, especially in a patient with heritable retinoblastoma who has undergone radiation therapy.

Positron Emission Tomography/Computerized Tomography in Newly Diagnosed Patients with Giant Cell Arteritis Who Are Taking Glucocorticoids.

OBJECTIVE: Large vessel uptake on positron emission tomography/computerized tomography (PET/CT) supports the diagnosis of giant cell arteritis (GCA). Its value, however, in patients without arteritis on temporal artery biopsy and in those receiving glucocorticoids remains unknown. We compared PET/CT results in GCA patients with positive (TAB+) and negative temporal artery biopsies (TAB-), and controls. METHODS: Patients with new clinically diagnosed GCA starting treatment with glucocorticoids underwent temporal artery biopsy and PET/CT. Using a visual semiquantitative approach, 18F-fluorodeoxyglucose (FDG) uptake was scored in 8 vascular territories and summed overall to give a total score in patients and matched controls. RESULTS: Twenty-eight patients with GCA and 28 controls were enrolled. Eighteen patients with GCA were TAB+. Mean PET/CT scores after an average of 11.9 days of prednisone were higher in patients with GCA compared to controls, for both total uptake (10.34 ± 2.72 vs 7.73 ± 2.56; p = 0.001), and in 6 of 8 specific vascular territories. PET/CT scores were similar between TAB+ and TAB- patients with GCA. The optimal cutoff for distinguishing GCA cases from controls was a total PET/CT score of ≥ 9, with an area under the receiver-operating characteristic curve of 0.75, sensitivity 71.4%, and specificity 64.3%. Among patients with GCA, these measures correlated with greater total PET/CT scores: systemic symptoms (p = 0.015), lower hemoglobin (p = 0.009), and higher platelet count (p = 0.008). CONCLUSION: Vascular FDG uptake scores were increased in most patients with GCA despite exposure to prednisone; however, the sensitivity and specificity of PET/CT in this setting were lower than those previously reported.

Treating chronic hepatitis C with pegylated interferon alfa-2a (40 KD) and ribavirin in clinical practice.

BACKGROUND: Pegylated interferon alfa-2a (40 KD) plus ribavirin therapy induces sustained virological response rates up to 63% in randomized-controlled trials. AIM: To conduct a prospective open-label programme to examine the efficacy and safety of this therapy in routine clinical practice. METHODS: Treatment-naive patients with chronic hepatitis C received, at the discretion of the investigator, pegylated interferon alfa-2a 180 microg/week + ribavirin 800 mg/day for 24 or 48 weeks. In total, 508 patients were enrolled [334 non-cirrhotic; 174 cirrhotic (defined as stage F3 and F4)]. RESULTS: In genotype 1 patients treated for 48 weeks, sustained virological response rates were 41% in non-cirrhotics and 34% in cirrhotics. Sustained virological response rates in genotype 2 or 3 non-cirrhotics were 79% (24 weeks) and 72% (48 weeks). Corresponding values for cirrhotic genotype 2/3 were 66% and 44%. The negative predictive value of an early virological response at week 12 was 94%. Predictive factors for sustained virological response on multivariate analysis were genotype (2/3 vs. 1), low viral load and degree of fibrosis. Rates of serious adverse events (

Twenty-four novel mutations in Wilson disease patients of predominantly European ancestry.

Wilson disease (WND), an autosomal recessive disorder of copper transport, shows wide genotypic and phenotypic variability, with hepatic and/or neurological symptoms. The WND gene, ATP7B, encodes a copper transporting ATPase that is involved in the transport of copper into the plasma protein ceruloplasmin, and in the excretion of copper from the liver. ATP7B mutations result in copper storage in liver and brain. From 247 WND patients worldwide whose DNA has been sequenced in our laboratory, we have identified 24 new mutations. The origins of the patients were European white (one deletion, one nonsense, one splice site, and 18 missense), Chinese (one deletion, one missense) and Bangladeshi (one missense). Most of these had strong support as disease causing mutations, based on conservation between species, structural changes, and absence in controls. One missense mutation in a Chinese patient was considered uncertain because of its conservative nature and position in the protein. We also identified 15 nucleotide substitutions (11 of them new) causing silent or intronic changes, none of which produce an additional splice site that could lead to disease. Characterization of mutations, both disease-causing and normal variants, is essential for accurate molecular diagnosis of this condition.

Hepatic arterial infusion of mitoxantrone in the treatment of primary hepatocellular carcinoma.

Twenty-three patients (16 male, seven female) with hepatocellular carcinoma (HCC) were treated by hepatic arterial infusion (HAI) of mitoxantrone every 4 weeks. At each treatment, a catheter was inserted percutaneously into the main hepatic artery via the femoral artery under image intensification. Treatment consisted of a 24-hour continuous HAI of mitoxantrone, 6 mg/m2/d X 3 (eight patients) or 10 mg/m2/d X 3 (14 patients) without heparin. Eight patients had only one infusion, nine patients four infusions, five patients three infusions, two patients two infusions, and one patient five infusions. A partial response was seen in six patients, with a median duration of 20 weeks (range, 18 to 38 weeks). Five patients achieved stable disease, with a median duration of 20 weeks (range, 11 to 42 weeks). The median survival of the overall group was 22 weeks. Survivals of responding, stable, and nonresponding patients were 32 weeks, 24 weeks, and 9 weeks, respectively. Complications of catheter placement included asymptomatic dissection of the hepatic artery (one patient), and asymptomatic thrombosis of the hepatic artery (five patients). Three patients experienced mild nausea and vomiting, and six patients had mild to moderate alopecia. Granulocytopenia was frequent at both dose schedules. The granulocyte nadir was greater than 1,000/microL in 34% of evaluable courses, 500 to 1,000/microL in 32%, and less than 500/microL in 34% of courses. Two patients developed neutropenia-associated fever. A platelet nadir below 100,000/microL was seen after only 10% of courses, and only two patients had platelets below 50,000/microL. Seven patients received doxorubicin after progression on mitoxantrone. Four received systemic doxorubicin, 50 mg/m2, and three HAI of doxorubicin, 25 mg/m2, for three days. Two patients achieved partial response (18 weeks and 32 weeks) to HAI doxorubicin. Mitoxantrone has activity in HCC and is well tolerated when administered by HAI. It is not entirely cross-resistant with doxorubicin.

The role of interferon in the treatment of viral hepatitis.

Chronic viral hepatitis, frequently an asymptomatic disease, can persist for decades. Despite the lack of symptoms, prolonged infection can lead to the complications of cirrhosis, liver failure and hepatocellular carcinoma. The goal of therapy is to reduce the risk of developing these complications and to eradicate the infectious pool. Patients with ongoing viral replication appear to be at greatest risk for developing complications. These patients have been targeted for treatment. Numerous randomized studies of interferon treatment of chronic hepatitis B and C have been published in the last 8 years. The experience from these studies and more recent developments will be reviewed.

Primary intraocular lymphoma arising during methotrexate treatment of temporal arteritis.

CASE REPORT: Primary intraocular lymphoma arose over a period of 9 months in the left eye of an 81-year-old woman who was blind in both eyes from temporal arteritis. During this period, she was treated with prednisone and methotrexate. Following a sudden total hyphema, the eye was enucleated. Examination revealed that, in addition to iris neovascularisation and central retinal artery occlusion, the neurosensory retina was replaced by atypical lymphocytes. COMMENTS: Histological and immunohistochemical studies confirmed the presence of a lymphoma with features indicative of an immunosuppression-related disorder. The relationship of the lymphoma to the vascular changes within the eye is discussed.

Peginterferon alfa-2a (40 kDa) monotherapy: a novel agent for chronic hepatitis C therapy.

Current therapy for hepatitis C remains far from optimal. The modification of IFN by the attachment of a polyethylene glycol (PEG) moiety has produced long-lasting IFNs. A 40 kDa branched peginterferon alfa-2a (40 kDa) (PEG-IFN alfa-2a) has unique pharmacokinetic and pharmacodynamic properties. PEG-IFN alfa-2a is absorbed in a sustained manner and its clearance is reduced substantially compared with IFN alfa-2a, resulting in sustained serum drug concentrations. These constant serum drug levels stay above the EC(50) values (effective concentration 50%) needed for antiviral, antiproliferative and immunomodulatory actions. Sustained virological responses were significantly greater in patients who received PEG-IFN alfa-2a versus IFN alfa-2a, with a similar side effect profile. Histological improvements were seen in patients who achieved sustained virological responses and were frequently observed among patients who did not achieve a virological response. The advantages of PEG-IFN alfa-2a were also seen in patients with cirrhosis or hepatitis C virus (HCV) genotype 1.