Unusual presentation of gouty tophus in the liver with subsequent appearance in the same site of HCC: a correlate diagnosis? Case report.

BACKGROUND: Although gout is a common disease, the presence of gouty tophi outside joints is rare and in literature, there is to date only one report of hepatic tophaceous nodule. We would like to highlight here the difficult diagnostic workup in a patient with history of cancer and the presence of a tophus inside the liver. Moreover, we address the possible etiologic role of chronic inflammation related to tophi and liver cancer. CASE PRESENTATION: We present the case of a 72-year-old man with a localization of gouty tophus in the liver, who thereafter developed a hepatocellular carcinoma (HCC) in the same site. The patient was followed up after surgery for left renal cancer from 1992 to 2011, when a hepatic nodule was discovered for the first time. After a detailed evaluation, the nodule was classified as a urate tophus of the liver. However, further follow-up showed that the nodule increased in size and changed its characteristics, bringing to the diagnosis of HCC. CONCLUSIONS: With the present case report, we would discuss the possible neoplastic degeneration of a gouty tophus and its etiologic role favouring cellular degeneration linked to chronic inflammation. We would also highlight the importance of histopathological evaluation of hepatic lesions in gouty patients at high risk of liver neoplasm, due to the difficulty in characterizing gouty tophi by imaging.

Effect of immunosuppressive therapy on patients with inflammatory bowel diseases and hepatitis B or C virus infection.

Viral hepatitis reactivation has been widely reported in patients undergoing immunosuppressive therapy; however, few data are available about the risk of HBV and HCV reactivation in patients with inflammatory bowel disease, receiving immunosuppressive drugs. The aim of our study was to assess the prevalence of HBV and HCV infection in a consecutive series of patients with inflammatory bowel disease and to value the effects of immunosuppressive therapy during the course of the infection. Retrospective observational multicenter study included all consecutive patients with inflammatory bowel disease who have attended seven Italian tertiary referral hospitals in the last decade. A total of 5096 patients were consecutively included: 2485 Crohn's disease and 2611 Ulcerative Colitis. 30.5% and 29.7% of the patients were investigated for HBV and HCV infection. A total of 30 HBsAg positive, 17 isolated anti-HBc and 60 anti-HCV-positive patients were identified. In all, 20 patients with HBV or HCV infection received immunosuppressive therapy (six HBsAg+; four isolated anti-HBc+ and 10 anti-HCV+). One of six patients showed HBsAg+ and one of four isolated anti-HBc+ experienced reactivation of hepatitis. Two of six HBsAg patients received prophylactic therapy with lamivudine. Only one of 10 anti-HCV+ patients showed mild increase in viral load and ALT elevation. Screening procedures for HBV and HCV infection at diagnosis have been underused in patients with inflammatory bowel disease. We confirm the role of immunosuppressive therapy in HBV reactivation, but the impact on clinical course seems to be less relevant than previous reported.

Epidermal growth factor receptor (EGFR) gene promoter methylation and cetuximab treatment in colorectal cancer patients.

BACKGROUND: Epidermal growth factor receptor (EGFR) promoter methylation may be responsible for the loss of EGFR expression in neoplastic cells. The primary aim of our study was to verify a possible correlation between EGFR gene promoter methylation and clinical outcome in metastatic colorectal cancer patients receiving chemotherapy with irinotecan and cetuximab. METHODS: Colorectal samples from patients treated with irinotecan-cetuximab were analysed for EGFR promoter methylation and EGFR immunohistochemistry. RESULTS: Fifty-two patients were analysed. Thirty patients (58%) showed EGFR promoter hypermethylation. In EGFR promoter methylated and EGFR promoter unmethylated patients, we observed a partial response in 3 (10%) and 13 (59%) patients, respectively (P=0.03), progressive disease was obtained in 19 (63%) and 2 (9%) patients, respectively, with EGFR promoter methylated and EGFR promoter unmethylated tumours (P=0.0001). Median progression-free survival was 2.4 months in patients showing EGFR promoter methylated tumours and 7.4 months for those who had EGFR promoter unmethylated tumours (P<0.0001; Figure 1). Median overall survival was 6.1 months in patients showing EGFR promoter methylated tumours and 17.8 months for those who had EGFR promoter unmethylated tumours (P<0.0001; Figure 2). CONCLUSION: EGFR promoter hypermethylation, after confirmation in larger data set, may represent a valuable asset in further studies investigating EGFR as a therapeutic target in colorectal cancer.

Identification of CXCL13 as a new marker for follicular dendritic cell sarcoma.

The homeostatic chemokine CXCL13 is preferentially produced in B-follicles and is crucial in the lymphoid organ development by attracting B-lymphocytes that express its selective receptor CXCR5. Follicular dendritic cells (FDCs) have been identified as the main cellular source of this chemokine in lymphoid organs. Recently, genome-wide approaches have suggested follicular CD4 T-helper cells (T(H)F) as additional CXCL13 producers in the germinal centre and the neoplastic counterpart of T(H)F (CD4+ tumour T-cells in angioimmunoblastic T-cell lymphoma) retains the capability of producing this chemokine. In contrast, no data are available on CXCL13 expression on FDC sarcoma (FDC-S) cells. By using multiple approaches, we investigated the expression of CXCL13 at mRNA and protein level in reactive and neoplastic FDCs. In reactive lymph nodes and tonsils, CXCL13 protein is mainly expressed by a subset of FDCs in B-cell follicles. CXCL13 is maintained during FDC transformation, since both dysplastic FDCs from 13 cases of Castleman's disease and neoplastic FDCs from ten cases of FDC-S strongly and diffusely express this chemokine. This observation was confirmed at mRNA level by using RT-PCR and in situ hybridization. Of note, no CXCL13 reactivity was observed in a cohort of epithelial and mesenchymal neoplasms potentially mimicking FDC-S. FDC-S are commonly associated with a dense intratumoural inflammatory infiltrate and immunohistochemistry showed that these lymphocytes express the CXCL13 receptor CXCR5 and are mainly of mantle zone B-cell derivation (IgD+ and TCL1+). In conclusion, this study demonstrates that CXCL13 is produced by dysplastic and neoplastic FDCs and can be instrumental in recruiting intratumoural CXCR5+ lymphocytes. In addition to the potential biological relevance of this expression, the use of reagents directed against CXCL13 can be useful to properly identify the origin of spindle cell and epithelioid neoplasms.

Fully automated chemiluminescence vs RIA aldosterone assay in primary aldosteronism work-up.

Aldosterone and renin measurement is a cornerstone for primary aldosteronism (PA) diagnosis, but different thresholds are used according to different assays. A fully automated chemiluminescence (CL) immunoassay for renin and aldosterone was recently proposed, showing good performance for PA screening by aldosterone to renin ratio (ARR). This study aimed to define the accuracy of this assay in the screening and in the most popular confirmatory test of autonomous aldosterone production, the intravenous saline loading test (ivSLT). We compared aldosterone results obtained by CL vs radioimmunoassay (RIA) in hypertensive patients investigated for PA (102 baseline and 85 after ivSLT). An excellent correlation was observed between RIA and CL in the entire population for aldosterone (r=0.922) and ARR (r=0.977). For ARR, Deming regression proved a good accordance between methods and, consistent with the fit model, our previous institutional ARR cut-off of 32 (pg ml-1)/(pg ml-1) corresponded to 20 pg ml-1 mU-1 l-1 in CL assay. However, the correlation was weaker in the low end of aldosterone concentrations (r=0.676 for aldosterone <100 pg ml-1), with a concordance of ivSLT results in only 68% of patients. CL assay displays a diagnostic performance very similar to RIA for ARR screening, but it is substantially inferior in the setting of confirmatory tests of autonomous aldosterone secretion, that is, ivSLT.

Effect of temperature on the release and remobilization of ecotoxic elements in AMD colloidal precipitates: the example of the Libiola copper mine, Liguria, (Italy).

Due to their characteristics, colloidal particles are able to control the dispersion of many organic and inorganic pollutants in soils and streams. Colloidal precipitates generated by acid mine drainage (AMD) process are usually amorphous or nanocrystalline materials, and their stability plays a crucial role in controlling the fate of metals released by sulphide oxydation. This paper describes a study of elements release (Fe, Al, Mn, Cd, Co, Cr, Cu, Ni, S, Zn) due to desorption or destabilization of three different colloidal precipitates, two ochreous and a greenish-blue precipitate, sampled at the Libiola mine site (northwest Italy). The samples were heated at high temperature in order to verify this treatment as inertization process. At room temperature, the most easily extracted element was S (with released percentages from 8.39 to 29.17 %), but considerable amounts of Cu, Zn and Mn (up to 16.6, 610.6 and 595.6 mg/kg, respectively) were also observed in the leachates for greenish-blue precipitates. The highest release of elements (S > Cu, Zn, Mn, Cd > Co, Ni > Al, Fe, Cr), with minor differences depending on the mineralogical composition of the samples, was observed for heat-treated samples obtained through moderate heating and mainly formed by anhydrous phases. Samples treated at high temperature had the lowest release, with only Cu showing a significant concentration in the leachate of greenish-blue precipitates. The results showed that dissolution/desorption is limited from ochreous natural colloidal precipitates occurring at the Libiola mine site but also that high amounts of some metals can be remobilized from greenish-blue precipitates. The destabilization of all percipitates through dehydratation-dehydroxylation can further remobilize important amounts of ecotoxic elements. Heat treatment at high temperature could be a definitive, although expensive, way to fix heavy metals in the solid fraction, preventing their dispersion in the surrounding environment.

Large-cell medulloblastomas. A distinct variant with highly aggressive behavior.

We present four cases of infantile cerebellar neoplasms composed of cells with large vesicular nuclei with prominent nucleoli. All four cases were strongly immunoreactive for synaptophysin, and one case showed immunoreactivity for neurofilaments. Filter hybridization for N-myc and c-myc oncogenes showed a 27-fold c-myc amplification in one case. The cytogenetic analysis in this case showed Double-Minutes and isochromosome 17q. An intracerebral xenograft in nude mice obtained from one such tumor showed a similar morphology to that of the original tumor as well as strong immunoreactivity for synaptophysin and neurofilaments. All the neoplasms were characterized by highly aggressive behavior leading to early cerebrospinal fluid dissemination despite radiotherapy and chemotherapy. We conclude that large-cell medulloblastoma represents a distinct and more aggressive variant of medulloblastoma that requires more aggressive therapy.

Newly marketed tissue markers for malignant mesothelioma: immunoreactivity of rabbit AMAD-2 antiserum compared with monoclonal antibody HBME-1 and a review of the literature on so-called antimesothelioma antibodies.

A complementary DNA (cDNA) library was constructed from a human malignant mesothelioma (MM) cell line and a cDNA fragment encoding for a cytoplasmic mesothelial protein recognized by the polyclonal antibody AMAD-1 was then cloned and expressed in Escherichia coli. The purified recombinant protein was used to raise a novel antibody, named AMAD-2, in rabbits. This antibody reacted with normal mesothelium and most MM (15 of 17) on paraffin sections and featured a cytoplasmic labeling. Conversely, AMAD-2 immunostaining of normal and tumor tissues from body sites other than serosal membranes was limited with respect to the proportion of positive specimens and usually less conspicuous than in MM. AMAD-2 immunoreactivity was subsequently compared with staining for HBME-1, another newly marketed antimesothelial monoclonal antibody, concerning the ability to distinguish pleural MM from metastatic pleural tumors of epithelial type. A granular cytoplasmic immunoreactivity for AMAD-2 was present in 50% or more of tumor cells in all 84 MM, regardless of histological type, but also in 3 (7%) of 42 pleural metastases, albeit only focally. HBME-1 was shown in 63 of 66 epithelial MM and in the epithelial component of all 8 mixed MM, with a prevailingly membranous pattern, usually homogeneous and strong, whereas none of the 10 sarcomatous MM was positive. HBME-1 was also expressed in 6 (14%) of 42 pleural metastases in a cytoplasmic or membranous pattern. Compared with HBME-1, AMAD-2 showed a higher degree of specificity and sensitivity for MM. AMAD-2 still proved to be superior to HBME-1, also when sarcomatoid MM were excluded from the assessment. This finding supports the view that AMAD-2 is an antibody highly, although not entirely, specific for the mesothelial lineage, whereas HBME-1 is probably a cell marker more closely related to the epithelial differentiation of MM. Therefore, AMAD-2 is preferable as a positive tissue marker to be incorporated in the optimal immunohistochemical panel for the diagnosis of MM.

Histopathological grading of response to induction chemotherapy in non-small cell lung cancer: a preliminary study.

Management of locally advanced NSCLC is controversial. Induction chemotherapy followed by surgery has become an accepted approach for Stage III disease. However, the clinical assessment of the efficacy of preoperative treatment is inaccurate. We propose a four-grade histopathological evaluation of the response to chemotherapy based on the analysis of 20 evaluable cases and compared with clinical outcome. Follow-up ranged from 12 to 68 months. Correlation between different grading of necrosis and survival is statistically significant. Based on these preliminary results, we suggest that grading of response is a valid parameter to evaluate standard regimens and novel drug associations in larger trials.

Inflammatory pseudotumour of the lung presenting as an airway obstructive syndrome.

The inflammatory pseudotumour of the lung is a rare and non-malignant neoplasm, which can be asymptomatic or characterized by variable clinical expressions. This report refers to a case occurring in a young woman and presenting as a persistent airway obstructive syndrome. With regard to histopathologic characterization, the present case can be classified as a fibrous histiocytic subtype.

Intramedullary spinal cord metastases.

The authors report 5 cases of intramedullary metastases, observed in the last 5 years. In 2 cases, the way of spreading was via the CSF, in 2 cases via the systemic circulation, and in 1 case along the perineural sheaths. A comparison with similar studies in the literature is followed by a brief discussion on treatment and prognosis.

Primary carcinoid tumor of the ovary: report of an unusual case.

Carcinoid tumors are endocrine malignancies that are often associated with a characteristic syndrome, the malignant carcinoid syndrome, which is most common in patients with small bowel tumors and liver metastases. In the rare instances when the syndrome is present without liver metastases the primary tumor is usually localized to the bronchus or ovary and secretes hormones directly into the systemic circulation. About two thirds of patients with carcinoid syndrome have evidence of carcinoid heart disease. We report on a case of a primary ovarian carcinoid tumor with an unusual clinical presentation.

Cutaneous metastases from carcinoma of the cervix.

Skin metastases from internal malignancies are rare, particularly those originating from carcinoma of the cervix: only 11 cases have been reported in the medical literature since 1940. We describe the case of a cutaneous metastases from a squamous-cell carcinoma of the cervix that was solitary, unusual for its location, and with the longest survival reported so far.

Endodermal sinus (yolk sac) tumor of the parotid gland: a case report.

Malignant salivary gland neoplasms in children are rare, most common being mucoepidermoid carcinoma, adenoid cystic carcinoma, acinic cell carcinoma and adenocarcinoma. Most germ-cell neoplasms of head and neck in children are teratomas. The authors report a case of endodermal sinus tumor (EST) of the parotid gland in a 2-year-old girl, which recurred after chemotherapy. The role of alpha-fetoprotein (AFP) serum level as a helpful marker in differential diagnosis and in evaluating tumor progression is underlined.

Sarcoidosis in a patient with 5q-myelodysplasia. A possible pathogenetic link between the two diseases.

This study describes the occurrence of sarcoidosis with lung and skin involvements in a 56-yr-old woman who suffered from 5q-myelodysplastic syndrome since the age of 50. The 5q-myelodysplastic syndrome is marked by deletion of the long arm of chromosome 5, which carries the genes coding for T-helper cell 2 cytokines, such as interleukins-3, -4 and -5, and granulocyte-macrophage colony-stimulating factor. Although the aetiology of sarcoidosis remains unclear, sarcoid granulomatous inflammation is marked by predominant expression of T-helper cell 1 cytokines, with reduced expression of T-helper cell 2 cytokines. The authors suggest that 5q-abnormality may have predisposed to sarcoidosis through an imbalance in the cytokine network, caused by the deletion of genes coding for T-helper cell 2 cytokines.

[Multinodular keratoacanthoma]. / Cheratoacantoma multinodulare.

Multinodular Keratoacanthoma is a variant of keratoacanthoma presenting with large annular plaques localized on the photo-exposed surfaces of the aged people. It is characterized by progressive growth of new nodules of keratoacanthoma at the periphery, while partial or complete spontaneous central healing occurs with scar formation. There is no tendency toward spontaneous regression. Multinodular Keratoacanthoma is quite rare. In our opinion only ten cases can be complied from the literature. We report an additional case in a diabetic 87 year old woman. She was previously affected by a vulvar squamous cell carcinoma. No recurrence was observed four months after the surgical excision.

Dynamic weakening of serpentinite gouges and bare surfaces at seismic slip rates.

To investigate differences in the frictional behavior between initially bare rock surfaces of serpentinite and powdered serpentinite ("gouge") at subseismic to seismic slip rates, we conducted single-velocity step and multiple-velocity step friction experiments on an antigorite-rich and lizardite-rich serpentinite at slip rates (V) from 0.003 m/s to 6.5 m/s, sliding displacements up to 1.6 m, and normal stresses (σn ) up to 22 MPa for gouge and 97 MPa for bare surfaces. Nominal steady state friction values (µnss) in gouge at V = 1 m/s are larger than in bare surfaces for all σn tested and demonstrate a strong σn dependence; µnss decreased from 0.51 at 4.0 MPa to 0.39 at 22.4 MPa. Conversely, µnss values for bare surfaces remained ∼0.1 with increasing σn and V. Additionally, the velocity at the onset of frictional weakening and the amount of slip prior to weakening were orders of magnitude larger in gouge than in bare surfaces. Extrapolation of the normal stress dependence for µnss suggests that the behavior of antigorite gouge approaches that of bare surfaces at σn ≥ 60 MPa. X-ray diffraction revealed dehydration reaction products in samples that frictionally weakened. Microstructural analysis revealed highly localized slip zones with melt-like textures in some cases gouge experiments and in all bare surfaces experiments for V ≥ 1 m/s. One-dimensional thermal modeling indicates that flash heating causes frictional weakening in both bare surfaces and gouge. Friction values for gouge decrease at higher velocities and after longer displacements than bare surfaces because strain is more distributed. KEY POINTS: Gouge friction approaches that of bare surfaces at high normal stressDehydration reactions and bulk melting in serpentinite in < 1 m of slipFlash heating causes dynamic frictional weakening in gouge and bare surfaces.

Serum regenerating islet-derived 3-alpha is a biomarker of mucosal enteropathies.

BACKGROUND: The clinical presentation of organic and functional intestinal disorders can overlap and clinicians often rely on invasive and time-consuming procedures to make a final diagnosis. Regenerating islet-derived 3-alpha (Reg3α) is detectable in the circulation of patients with intestinal graft-versus host disease and patients with inflammatory bowel disease (IBD). AIM: To determine whether serum Reg3α testing is useful for discriminating mucosal enteropathies from functional intestinal disorders. METHODS: We prospectively included 47 patients with active coeliac disease (ACD), 13 patients with refractory coeliac disease (RCD), seven patients with common variable immunodeficiency (CVID), 72 patients with active Crohn's disease, 22 patients with active ulcerative colitis (UC) and 28 patients with irritable bowel syndrome (IBS)-related diarrhoea. Sera were also taken from 10 CD patients before and after 6-12 months of a gluten-free diet (GFD) and from 14 patients with IBD before and after induction therapy with Infliximab (IFX). Sera of 119 healthy volunteers were used to determine the cut-off value. Reg3α levels were measured by a commercial ELISA kit. RESULTS: Levels of Reg3α exceeded the cut-off value of the assay in 43/47(91%) ACD patients, 13/13(100%) RCD patients, 7/7(100%) CVID patients, 65/72(90%) Crohn's disease patients, 17/22(77%) UC patients and one patient with IBS(4%). Reg3α levels distinguished mucosal enteropathies from IBS with a sensitivity of 90% and a specificity of 96%. Reg3α levels significantly decreased in CD patients following a GFD and in IBD patients after treatment with IFX. CONCLUSION: Reg3α is a serum biomarker of intestinal damage that, combined with clinical data, identifies patients who should undergo invasive tests for diagnosing enteropathies.

Defective expression of SIRT1 contributes to sustain inflammatory pathways in the gut.

In inflammatory bowel disease (IBD), tissue damage is driven by an excessive immune response, poorly controlled by counter-regulatory mechanisms. SIRT1, a class III NAD+-dependent deacetylase, regulates negatively the expression of various proteins involved in the control of immune-inflammatory pathways, such as Stat3, Smad7, and NF-κB. Here we examined the expression, regulation, and function of SIRT1 in IBD. SIRT1 RNA and protein expression was less pronounced in whole biopsies and lamina propria mononuclear cells (LPMCs) of IBD patients in comparison with normal controls. SIRT1 expression was downregulated in control LPMC by tumor necrosis factor (TNF)-α and interleukin (IL)-21, and upregulated in IBD LPMC by neutralizing TNF-α and IL-21antibodies. Consistently, SIRT1 expression was increased in mucosal samples taken from IBD patients successfully treated with Infliximab. Treatment of IBD LPMC with Cay10591, a specific SIRT1 activator, reduced NF-κB activation and inhibited inflammatory cytokine synthesis, whereas Ex527, an inhibitor of SIRT1, increased interferon (IFN)-γ in control LPMC. SIRT1 was also reduced in mice with colitis induced by 2,4,6-trinitrobenzenesulphonic acid or oxazolone. Cay10591 prevented and cured experimental colitis whereas Ex527 exacerbated disease by modulating T cell-derived cytokine response. Data indicate that SIRT1 is downregulated in IBD patients and colitic mice and suggest that SIRT1 activation can help attenuate inflammatory signals in the gut.