IL1R1 gene variants associate with disease susceptibility to IgG4-related periaortitis/periarteritis in IgG4-related disease.

BACKGROUND: IgG4-related disease (IgG4-RD) is an immune-mediated disorder characterized by high serum IgG4 concentration and IgG4-bearing plasma cell infiltration in affected organs. IgG4-related periaortitis/periarteritis is a recently identified disease entity in IgG4-RD that affects the cardiovascular system. Since the genetic factors related to disease onset are unclear, we examined the genetic associations with IgG4-related periaortitis/periarteritis susceptibility. METHODS: A small scale of genome-wide association analysis identified that interleukin 1 receptor type 1 (IL1R1) gene variants were correlated with the development of IgG4-related periaortitis/periarteritis in 75 patients with IgG4-RD. Accordingly, 8 single nucleotide polymorphisms (SNPs) in the IL1R1 gene were selected and genotyped in 124 patients with IgG4-RD (43 with periaortitis/periarteritis and 81 without periaortitis/periarteritis) and 344 healthy subjects. RESULTS: The minor allele frequencies of 6 SNPs (rs2287049, rs3917273, rs2160227, rs951192, rs3917318, rs7582198) were significantly increased in IgG4-related periaortitis/periarteritis patients compared with those without periaortitis/periarteritis (corrected P < 0.05). In addition, the frequency of the AGAAA haplotype, comprised of 5 SNPs (rs3917273, rs2160227, rs951192, rs3917318, rs7582198), was significantly higher in patients with periaortitis/periarteritis (OR = 2.41, 95% CI:1.42-4.10). CONCLUSION: Our findings indicated that IL1R1 genetic polymorphisms contributed to IgG4-related periaortitis/periarteritis and the possibility of certain genetic factors influencing the risk of specific IgG4-RD manifestations.

Impact of CYP2D6 Polymorphisms on Tamoxifen Treatment in Patients With Retroperitoneal Fibrosis: A First Step Towards Tailored Therapy?

OBJECTIVE: To investigate the influence of CYP2D6 polymorphisms on outcomes and health-related quality of life of patients with retroperitoneal fibrosis (RPF) receiving tamoxifen (TMX). TMX is an effective alternative to corticosteroids for patients with RPF. Conversion of TMX to more potent endoxifen is dependent on enzyme activity of CYP2D6. MATERIALS AND METHODS: CYP2D6 genotyping and phenotype prediction of all patients treated with TMX between 02/2007 and 01/2018 was assessed using multiplex polymerase chain reaction (PCR). Groups were classified by phenotype: extensive (EM) vs poor and intermediate (PM + IM) vs ultrarapid metabolizer (UM). Retrospective evaluation of outcome (including magnetic resonance imaging and positron emission tomography-computed tomography) and health-related quality of life using the SF-36 was performed. RESULTS: A total of 63/194 patients received TMX, 40/63 with complete follow-up were sequenced: Twenty-nine patients with EM phenotype, 8 PM + IM and 3 UM. The median therapy duration was 364.5 days with a mean follow-up of 62.9 months. Seven therapy terminations occurred due to lack of response (17.5%), including all UM patients (P <.001). Magnetic resonance imagings showed a regression of fibrosis for EM and PM + IM in 69% and 62.5% of cases and a progression for UM in 100% (P = .004). In positron emission tomography-computed tomography, glucose utilization of RPF decreased significantly for EM and PM + IM. The physical sum-score of SF-36 improved for EM and PM + IM and decreased for UM (P <.05). The removal of DJ-stents was successful for EM, PM + IM, and UM in 48.3%, 75%, and 0% of cases (P = .0581). CONCLUSION: Contrary to expectations, UM showed the lowest success rate, which concludes that genotyping of RPF-patients may be useful in the sense of a tailored-therapy.

Interleukin-10 gene polymorphisms and chronic periodontitis susceptibility: Evidence based on 33 studies.

The purpose of the meta-analysis was to investigate the potential association of interleukin-10 (IL-10) polymorphisms with susceptibility to chronic periodontitis (CP). A total of 33 studies involving 3487 cases and 4356 controls were identified through a search of multiple electronic databases (last search was updated on 19 July 2018). Three single nucleotide polymorphisms (SNPs) were included in the meta-analysis: -1082A>G(rs1800896), -819C>T(rs1800871), and -592C>A(rs1800872). Odds ratios (ORs) and their 95% confidence intervals (CIs) using allele, dominant, and recessive genetic models were computed to assess the strength of the association. The -1082A>G(rs1800896) polymorphism was found to be associated with decreased CP risk in both Caucasians and Latinos under the dominant model. The -819C>T(rs1800871) and -592C>A(rs1800872) polymorphisms were both associated with increased CP risk in Latinos under the allele and dominant models. In Asians, no associations were observed for any of the polymorphisms under all comparison models. The present meta-analysis suggests that the -1082A>G(rs1800896) polymorphism might be a protective factor for CP in both Caucasians and Latinos, but the -819C>T(rs1800871) and -592C>A(rs1800872) polymorphisms might contribute to CP pathogenesis in Latinos.

Association of a polymorphism of the Fcγ-receptor 2A (FCGR2A) gene with chronic periaortitis.

OBJECTIVES: Chronic periaortitis (CP) is an inflammatory disease associated in 20-60% of the cases with IgG4 related disease. Current evidence supports an autoimmune nature for CP. Fc gamma receptors (FcγRs) are involved in several immune system activities and are associated with autoimmunity in general. We explored the influence of genetic variants within this region on susceptibility to CP. METHODS: Genotyping of 4 candidate single nucleotide polymorphisms (SNPs) of the FCGR region was performed in CP patients and controls. RESULTS: One hundred and eighty-three cases and 181 controls were included. An association between the SNP rs1801274 of the FCGR2A and CP was detected (OR 1.6, 95%CI 1.18-2.16;corrected p-value, pcorr=0.0085). After stratification of the population according to clinical characteristics, the association was restricted to cases of idiopathic retroperitoneal fibrosis (OR 1.66, 95%CI 1.21-2.29;pcorr=0.028), without involvement of the thoracic aorta (OR 1.77, 95%CI 1.21-2.57;pcorr=0.043), with deep vein thrombosis at onset (OR 3.96, 95%CI 1.81-8.66;pcorr=0.0021) and with normal IgG4 levels (OR 2.67, 95%CI 1.39-5.12;pcorr=0.031). CONCLUSIONS: In the largest candidate gene approach study performed so far in CP, we demonstrated an association for CP with a gene hallmark of autoimmunity. The association appears restricted to typical cases of CP without increase of IgG4 levels.

Liposarcoma masquerading as an inflammatory pseudotumor: a case report.

BACKGROUND: Distinguishing an atypical lipomatous tumor/well-differentiated liposarcoma from a benign lipomatous tumor on morphology alone can be difficult and there is an established role for MDM2 fluorescent in situ hybridization studies in making this differential diagnosis. There is no literature on the role for MDM2 fluorescent in situ hybridization studies in distinguishing between a well-differentiated liposarcoma with extreme fibrosis and a fibrosing inflammatory pseudotumor. CASE PRESENTATION: We report the case of a 76-year-old Australian woman initially diagnosed by an excision biopsy with a retroperitoneal fibrosing inflammatory pseudotumor. She was then diagnosed 5 years later with a pleomorphic undifferentiated sarcoma. Upon review of the original resection specimen, we were able to show that the tumor demonstrated MDM2 amplification. MDM2 amplification was also present in some adjacent bland adipose tissue, and also in the tumor recurrence as a pleomorphic undifferentiated sarcoma. CONCLUSION: Taken together, our findings provide strong evidence that the original tumor was a misdiagnosed well-differentiated liposarcoma with extreme fibrosis, and the pleomorphic undifferentiated sarcoma represented a recurrence of the same tumor with dedifferentiation.

Case of H syndrome with massive skin involvement, retroperitoneal fibrosis and Raynaud's phenomenon with a novel mutation in the SLC29A3 gene.

We describe a case of H syndrome with massive skin involvement, retroperitoneal fibrosis and Raynaud's phenomenon. A 48-year-old man with parents of a consanguineous marriage, first appeared with decreased urine output, skin sclerosis on his inner thighs and short stature (142 cm, 47 kg). The patient had suffered from hearing loss since the age of 1 year, and his secondary sexual characteristics had not developed. Computed tomography showed periaortic fibrosis, bilateral ureteral stenosis, hydronephrosis and sclerosis of the germinal cords. A biopsy from the retroperitoneal mass revealed remarkable fibrosis with chronic inflammatory cells. Biopsies from the skin lesion showed thick collagen bundles through the dermis and lymphohistiocytic infiltration with numerous plasma cells. Serum inflammatory markers, such as C-reactive protein, vascular endothelial factor, transforming growth factor-ß and soluble interleukin-2 receptor, were elevated. Prednisolone was effective in treating skin lesions and in lowering serum inflammatory markers. After a long period of follow up, genomic DNA of the patient was obtained, and we identified a homozygous mutation in exon 5, c.625G>A, which caused transition of glycine to arginine, p.Gly208Arg, in the patient, but not in DNA samples from another 50 healthy individuals. This is the first case of H syndrome with Raynaud's phenomenon and retroperitoneal fibrosis, and the first Japanese case of H syndrome reported in the English published work with a novel mutation in the SLC29A3 gene.

Immunology of IgG4-related disease.

Immunoglobulin G4-related disease (IgG4-RD) is a fibroinflammatory condition that derives its name from the characteristic finding of abundant IgG4(+) plasma cells in affected tissues, as well as the presence of elevated serum IgG4 concentrations in many patients. In contrast to fibrotic disorders, such as systemic sclerosis or idiopathic pulmonary fibrosis in which the tissues fibrosis has remained largely intractable to treatment, many IgG4-RD patients appear to have a condition in which the collagen deposition is reversible. The mechanisms underlying this peculiar feature remain unknown, but the remarkable efficacy of B cell depletion in these patients supports an important pathogenic role of B cell/T cell collaboration. In particular, aberrant T helper type 2 (Th2)/regulatory T cells sustained by putative autoreactive B cells have been proposed to drive collagen deposition through the production of profibrotic cytokines, but definitive demonstrations of this hypothesis are lacking. Indeed, a number of unsolved questions need to be addressed in order to fully understand the pathogenesis of IgG4-RD. These include the identification of an antigenic trigger(s), the implications (if any) of IgG4 antibodies for pathophysiology and the precise immunological mechanisms leading to fibrosis. Recent investigations have also raised the possibility that innate immunity might precede adaptive immunity, thus further complicating the pathological scenario. Here, we aim to review the most recent insights on the immunology of IgG4-RD, focusing on the relative contribution of innate and adaptive immune responses to the full pathological phenotype of this fibrotic condition. Clinical, histological and therapeutic features are also addressed.

TLR-4 and VEGF polymorphisms in chronic periaortitis.

OBJECTIVE: Chronic periaortitis (CP) is a rare disease that is characterised by fibro-inflammatory tissue surrounding the abdominal aorta and has both non-aneurysmal (idiopathic retroperitoneal fibrosis [IRF]) and aneurysmal forms (inflammatory abdominal aortic aneurysm [IAAA]). We investigated whether toll-like receptor 4 (TLR-4) and vascular endothelial growth factor (VEGF) polymorphisms were associated with susceptibility to, and the clinical features of CP. METHODS: One hundred and two CP patients and 200 healthy controls were molecularly genotyped for TLR-4 gene polymorphism (+896 A/G) (rs4986790), VEGF mutations +936 C/T (rs3025039) and -634 C/G (rs2010963), and an 18 base pair (bp) insertion/deletion (I/D) polymorphism at -2549 of the VEGF promoter region. The patients were grouped on the basis of the type of CP (IRF or IAAA), and the presence or absence of established atherosclerotic disease (ischemic heart disease, cerebrovascular disease, and peripheral arterial disease). RESULTS: There were no significant differences in the distribution of the studied polymorphisms between the patients and controls. However, carriage of the +936 T allele was significantly more frequent in the patients with IRF than in those with IAAA (26.5% vs 5.3%; p = 0.046; OR 6.49 [95% CI 0.82-51.54]). There were significantly more carriers of the I allele among the patients with ureteral obstruction (83.8% vs 58.8%; p = 0.006; OR 3.63 [95% CI 1.42-9.28]) and those who received conservative treatment (48.5% vs 23.5%; p = 0.015; OR 3.06 [95% CI 1.22-7.721]) than among those without, and II homozygosity was significantly more frequent in the patients with deep vein thrombosis than in those without (30.4% vs 11.7%, p = 0.031; OR 3.31 [95% CI 1.07-10.21]). CONCLUSION: The VEGF +936 C/T polymorphism may be associated with an increased risk of developing the non-aneurysmal IRF form of CP. Carriers of the I allele and II homozygosity are respectively at increased risk of developing ureteral obstruction and deep vein thrombosis.

ß-catenin (CTNNB1) mutations and clinicopathological features of mesenteric desmoid-type fibromatosis.

AIMS AND METHODS: Desmoid-type fibromatosis (desmoid) is a fibroblastic tumour that shows locally aggressive growth. Mesenteric desmoid is a rare lesion that shares morphological and biological features with fibromatoses occurring in the abdominal wall or in extraabdominal sites, but differs in terms of gross appearance and clinical presentation. We report on a series of 56 cases of mesenteric desmoids from our consultation files and compare them with cases of non-mesenteric desmoids and retroperitoneal fibrosis. RESULTS: Primary diagnosis of desmoid-type fibromatosis was correct in 42%, and gastrointestinal stromal tumour was a common misdiagnosis. Nuclear expression of ß-catenin was detected in 91.6% of all desmoids. Mutational analysis of exon 3 of the ß-catenin gene (CTNNB1) revealed that mesenteric desmoids carried mutations significantly more often (51/56, 91.1%) than non-mesenteric tumours (20/28; 71.4%; P = 0.027). p.T41A occurred significantly more frequently in mesenteric fibromatoses (80.4%) than in abdominal wall and extra-abdominal fibromatoses (46.4%; P = 0.002). Two novel mutations (p.S45C and p.D32G) were found. In retroperitoneal fibrosis, mutations and nuclear ß-catenin expression were absent. ß-Catenin-negative desmoids either carried a CTNNB1 mutation or were associated with Gardner syndrome. CONCLUSIONS: Our study provides evidence that some clinical and genetic features of mesenteric desmoids differ from those of non-mesenteric fibromatosis, and corroborates the usefulness of mutational analysis, especially in diagnosing ß-catenin-negative mesenteric desmoids.

Eotaxin/CCL11 in idiopathic retroperitoneal fibrosis.

BACKGROUND: Idiopathic retroperitoneal fibrosis (IRF) is a rare fibro-inflammatory disorder characterized by a periaortic tissue which often encases the ureters causing acute renal failure. IRF histology shows fibrosis and a chronic inflammatory infiltrate with frequent tissue eosinophilia. We assessed a panel of molecules promoting eosinophilia and fibrosis in IRF patients and performed an immunogenetic study. METHODS: Serum levels of eotaxin/CCL11, regulated and normal T-cell expressed and secreted (RANTES), granulocyte colony-stimulating factor (G-CSF), interleukin (IL)-5, platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) were measured using a multiplex assay in 24 newly diagnosed, untreated IRF patients and 14 healthy controls. Retroperitoneal biopsies (available in 8/24 patients) were histologically evaluated to assess eosinophil infiltration, whereas mast cells (MCs) were identified by immunohistochemical analysis for human tryptase. Immunohistochemistry for eotaxin/CCL11 and its receptor CCR3 was also performed. Six single nucleotide polymorphisms (SNPs) within the CCL11 gene (rs6505403, rs1860184, rs4795896, rs17735961, rs16969415 and rs17809012) were investigated in 142 IRF patients and 214 healthy controls. RESULTS: Serum levels of eotaxin/CCL11 were higher in IRF patients than in controls (P = 0.009). Eotaxin/CCL11 drives tissue infiltration of eosinophils and MCs, which can promote fibrosis. Eosinophilic infiltration was prominent (>5 cells/hpf) in five (62.5%) cases, and abundant tryptase-positive MCs were found in all cases; notably, MCs were in a degranulating state. Immunohistochemistry showed that CCL11 was highly produced by infiltrating mononuclear cells and that its receptor CCR3 was expressed by infiltrating eosinophils, MCs, lymphocytes and fibroblasts. None of the tested CCL11 SNPs showed disease association, but the TTCCAT haplotype was significantly associated with IRF (P = 0.0005). CONCLUSIONS: These findings suggest that the eotaxin/CCL11-CCR3 axis is active in IRF and may contribute to its pathogenesis; the TTCCAT haplotype within the CCL11 gene is significantly associated with IRF.

Evidence for clonal fibroblast proliferation and autoimmune process in idiopathic retroperitoneal fibrosis.

Idiopathic retroperitoneal fibrosis is an uncommon disease characterized by encasement of retroperitoneal structures by fibrosis and chronic inflammation. Multiple etiologies have been proposed. First, we investigated if idiopathic retroperitoneal fibrosis is a clonal fibroblast proliferation by performing X-chromosome inactivation analyses. Second, we sought to determine if idiopathic retroperitoneal fibrosis is an autoimmune or immunoglobulin G4-driven process. Thirty cases of idiopathic retroperitoneal fibrosis, in whom known causes of retroperitoneal fibrosis were excluded and those for which paraffin blocks were available, were included in this study. We performed clonality analysis in 16 female patients. Genomic DNA samples were prepared from formalin-fixed, paraffin-embedded tissue sections using laser capture microdissection. Of the 16 cases, 15 were informative. Of 15 informative cases, 8 (53%) showed nonrandom X-chromosome inactivation or a clonal process. Of the 26 patients for which immunoglobulin G4 analysis was performed, 14 (54%) were positive for immunoglobulin G4-positive plasma cells, and all were negative for anaplastic lymphoma kinase. Of cases positive for immunoglobulin G4, the immunoglobulin G4:immunoglobulin G ratio ranged from 0.30 to 1.00 (mean, 0.80). Of the 12 patients for which both clonality analysis and immunoglobulin G4 analysis were performed, 4 (33%) were clonal and immunoglobulin G4 negative; 2 (17%), clonal and immunoglobulin G4 positive; 2 (17%), nonclonal and immunoglobulin G4 positive; and 4 (33%), nonclonal and immunoglobulin G4 negative. Our data indicate that a significant proportion (53%) of idiopathic retroperitoneal fibrosis cases in women is associated with a clonal expansion of fibroblasts. In addition, a subset of idiopathic retroperitoneal fibrosis cases could be classified in the immunoglobulin G4-related sclerosing disease spectrum.

Idiopathic retroperitoneal fibrosis mimicking malignant lymphoma.

We present a case of atypical idiopathic retroperitoneal fibrosis (iRPF) presenting as a large pelvic tumor, for which it proved difficult to exclude T-cell malignant lymphoma. Histopathological examination of biopsy material showed collagenous tissue and fat with an exuberant and predominant T-cell infiltrate, largely consisting of CD4(+) cells expressing the IL-2 receptor-α chain (CD25). Focal plasma cells were negative for the immunoglobulin G4 (IgG4) isotype. T-cell receptor gene rearrangement (TRGR) pattern showed a Gaussian distribution, in keeping with a polyclonal T-cell population. Awareness of the sometimes exuberant and predominant T-cell infiltrate in iRPF should lead to earlier consideration of this disorder. This is particularly the case where there is an atypically localized and/or extensive mass, for which early exclusion of monoclonality with TRGR may provide helpful. Immunohistochemical findings suggest that CD4(+) CD25(+) cells, which are part of a naturally occurring population of regulatory T-cells, may be involved in the pathogenesis of iRPF.

CC chemokine receptor 5 polymorphism in chronic periaortitis.

OBJECTIVE: Chronic periaortitis (CP) is a rare disease characterized by a fibro-inflammatory tissue surrounding the abdominal aorta, and includes non-aneurysmal [idiopathic retroperitoneal fibrosis (IRF)] and aneurysmal forms [inflammatory abdominal aortic aneurysm (IAAA)]. We investigated whether CC chemokine receptor 5 (CCR5)Δ32 polymorphism confers susceptibility to CP. METHODS: One hundred CP patients and 180 healthy controls were genotyped for CCR5Δ32 polymorphism by molecular methods. The patients were subgrouped according to the type of CP (IRF or IAAA) and the presence of established atherosclerotic disease (ischaemic heart disease, cerebrovascular disease and peripheral arterial disease). RESULTS: The distribution of the CCR5Δ32 genotype differed between CP patients and controls (P = 0.01). The CCR5Δ32 allele was more frequent in CP patients than in controls [P = 0.02, odds ratio (OR) 2.8 (95% CI 1.2, 6.4)]. The distribution of the CCR5Δ32 genotype did not differ significantly between IRF patients and controls, whereas the CCR5Δ32 allele was more frequent in IAAA patients than in controls [P = 0.0001, OR 10.0 (95% CI 3.7, 27.3)]. Furthermore, the CCR5Δ32 allele occurred more frequently in IAAA than in IRF patients [P = 0.001, OR 6.4 (95% CI 2.1, 19.1)]. The CCR5Δ32 allele frequency was higher in IAAA patients without established atherosclerotic disease compared with controls [66.7 vs 5.6%, P = 0.00001, OR 34.0 (95% CI 7.4, 156.3)], but not in IAAA patients with atherosclerotic disease and IRF patients with or without atherosclerotic disease. CONCLUSIONS: The CCR5Δ32 polymorphism might be associated with an increased risk of developing the aneurysmal form of CP, IAAA, particularly in patients without established atherosclerotic disease. Chemokines may have a role in the pathophysiology of CP.

Characterization of a hemophore-like protein from Porphyromonas gingivalis.

The porphyrin auxotrophic pathogen Porphyromonas gingivalis obtains the majority of essential iron and porphyrin from host hemoproteins. To achieve this, the organism expresses outer membrane gingipains containing cysteine proteinase domains linked to hemagglutinin domains. Heme mobilized in this way is taken up by P. gingivalis through a variety of potential portals where HmuY/HmuR of the hmu locus are best described. These receptors have relatively low binding affinities for heme. In this report, we describe a novel P. gingivalis protein, HusA, the product of PG2227, which rapidly bound heme with a high binding constant at equilibrium of 7 × 10(-10) M. HusA is both expressed on the outer membrane and released from the organism. Spectral analysis indicated an unusual pattern of binding where heme was ligated preferentially as a dimer. Further, the presence of dimeric heme induced protein dimer formation. Deletional inactivation of husA showed that expression of this moiety was essential for growth of P. gingivalis under conditions of heme limitation. This finding was in accord with the pronounced increase in gene expression levels for husA with progressive reduction of heme supplementation. Antibodies reactive against HusA were detected in patients with chronic periodontitis, suggesting that the protein is expressed during the course of infection by P. gingivalis. It is predicted that HusA efficiently sequesters heme from gingipains and fulfills the function of a high affinity hemophore-like protein to meet the heme requirement for growth of P. gingivalis during establishment of infection.

Detection of MDM2 gene amplification or protein expression distinguishes sclerosing mesenteritis and retroperitoneal fibrosis from inflammatory well-differentiated liposarcoma.

Inflammatory liposarcoma is a variant of well-differentiated liposarcoma/atypical lipomatous tumor that consists of a mixture of lymphocytes, histiocytes, scattered atypical stromal cells, mature adipocytes, and rarely lipoblasts. When the inflammatory infiltrate predominates, the morphological features overlap with various fibroinflammatory disorders including sclerosing mesenteritis and retroperitoneal fibrosis, making the diagnosis difficult. Well-differentiated liposarcoma/atypical lipomatous tumor and dedifferentiated liposarcoma have characteristic molecular markers in the form of giant marker and ring chromosomes consisting of amplicons of 12q13-15, which includes MDM2. MDM2 immunohistochemistry (IHC) (Zymed; clone IF2) and dual color fluorescence in situ hybridization utilizing MDM2 (12q15) and chromosome 12 centromeric probes were performed on formalin-fixed and paraffin-embedded specimens from inflammatory well-differentiated liposarcoma (17 cases), sclerosing mesenteritis (14 cases), and idiopathic retroperitoneal fibrosis (10 cases). MDM2 expression as detected by IHC is a very sensitive tool in recognizing inflammatory well-differentiated liposarcoma (17 of 17); however, 21% (3 of 14) and 10% (1 of 10) of sclerosing mesenteritis and retroperitoneal fibrosis, respectively, displayed weak MDM2 immunoexpression. The MDM2 fluorescence in situ hybridization assay was very specific for inflammatory well-differentiated liposarcoma as 15 of 17 (88%) cases showed MDM2 amplification, whereas none of the cases of sclerosing mesenteritis or idiopathic retroperitoneal fibrosis showed amplification. Five cases of retroperitoneal fibrosis were noncontributory secondary to autofluorescence, potentially limiting the usefulness of the assay in certain situations such as inappropriate fixation. Increased MDM2 expression and/or MDM2 amplification can be employed to aid discrimination of inflammatory well-differentiated liposarcoma from fibroinflammatory mimics. MDM2 fluorescence in situ hybridization is a very specific method (100%), but less sensitive (88%), whereas MDM2 expression by IHC is very sensitive (100%), but less specific (83%). Therefore, a positive screen of difficult cases with MDM2 IHC would require confirmation by the fluorescence in situ hybridization. However, lack of MDM2 immunoexpression would rule out the possibility of inflammatory well-differentiated liposarcoma.

Retroperitoneal fibrosis: evolving concepts.

Retroperitoneal fibrosis (RPF) is a rare fibro-inflammatory condition that is idiopathic in most cases, but may be secondary to various causes. Although the cause and pathogenesis of the idiopathic form are unknown, immunogenetic factors and immunopathologic/autoimmune mechanisms are probably involved. Idiopathic RPF usually develops around the abdominal aorta and iliac arteries but in some cases may also involve the thoracic aorta and the origin of its major branches, with a pattern similar to that of other forms of large-vessel vasculitis. In addition, the disease is frequently associated with autoimmune conditions affecting other organs. Glucocorticoids alone or in combination with immunosuppressive agents are usually effective treatment options, but the disease frequently has a chronic relapsing course.

Chronic periaortitis and HLA-DRB1*03: another clue to an autoimmune origin.

OBJECTIVE: Patients with chronic periaortitis (CP) often show clinical and laboratory findings of a systemic autoimmune disorder. The aim of the present study was to investigate the role of the HLA system in CP. METHODS: Low-resolution genotyping for HLA-A, HLA-B, and HLA-DRB1 loci and genotyping of TNFA(-238)A/G and TNFA(-308)A/G single nucleotide polymorphisms were performed in 35 consecutive patients with CP and 350 healthy controls. RESULTS: The HLA-DRB1*03 allele frequency was strikingly higher in patients with CP than in controls (24.28% versus 9.14%; chi(2) = 15.50, P = 0.000084, corrected P [P(corr)] = 0.0012, odds ratio [OR] 3.187, 95% confidence interval [95% CI] 1.74-5.83); the HLA-B*08 allele frequency was also higher in patients than in controls (17.14% versus 6.28%; chi(2)=11.12, P = 0.0008, P(corr) = 0.0269, OR 3.085, 95% CI 1.54-6.16). The A*01 allele frequency was significantly different (P = 0.0463), but the statistical significance was lost after correction for multiple testing (P(corr) = 0.5088). TNFA(-238)A allele and TNFA(-308)A allele frequencies were not significantly different (P = 0.512 and P = 0.445, respectively). Comparison of the main clinical and laboratory findings suggestive of a systemic autoimmune disease (e.g., acute-phase reactants, constitutional symptoms, other autoimmune diseases associated with CP) between the HLA-DRB1*03-positive and the HLA-DRB1*03-negative patients showed that the former group had significantly higher levels of C-reactive protein (P = 0.045) at disease onset, although this difference was not statistically significant after correction for multiple tests (P(corr) = 0.369). CONCLUSION: The HLA system plays a role in susceptibility to CP. The strong association between CP and HLA-DRB1*03, an allele linked to a wide range of autoimmune conditions, further supports the view that CP may represent a clinical manifestation of an autoimmune disease.