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UNLABELLED Hepatocarcinogenesis is a multistep process characterized by hepatocyte inflammation, regeneration, and proliferation. These changes are believed to depend on the aberrant expression of various tumor suppressor genes, oncogenes and growth factors. Several studies have shown the involvement of cyclooxygenase-2 (COX-2), the inducible isoform of the enzymes that catalyze prostaglandin synthesis in various aspects of carcinogenesis. COX-2 has been described as being overexpressed in hepatocellular carcinoma (HCC) patients. Using immunohistochemistry, we studied COX-2 expression in different chronic liver diseases (CLD) including nonalcoholic steatohepatitis (NASH), chronic hepatitis (CH), liver cirrhosis (LC), and HCC in a population referred to a tertiary center in western Sicily, an area moderately endemic for CLD. Sixteen NASH, 35 CH, 15 LC, and 21 HCC samples were analyzed. Positive signs of COX-2 were observed in the cytoplasm of hepatocytes and median values were 6 (3-9) for NASH, 7 (3-9) for CH, 6 (4-9) for LC, and 4 (0-7) for HCC. COX-2 expression was significantly lower in HCC than in NASH (P < 0.001), CH (P < 0.0001), and LC (P < 0.0001). In HCC we found a wide range of COX-2 expression: from no expression in poorly differentiated areas to a high expression in well-differentiated ones, with an inverse correlation between COX-2 and tumor grading, according to Edmonson (rho=-0.67, P < 0.0001). IN CONCLUSION (a) COX-2 expression was significantly lower in HCC than in the other CLD; (b) COX-2 expression inversely correlated with tumor differentiation status. These results suggest that COX-2 expression could be related to the inflammatory phenomena present in the early phases of CLD and eventually to the induction of hepatocarcinogenesis.

This study, performed on behalf of the Italian Registry of Thrombocythaemias (Registro Italiano Trombocitemie), aimed to test the inter-observer reproducibility of the histological parameters proposed by the WHO classification for the diagnosis of the Philadelphia chromosome-negative myeloproliferative neoplasms. A series of 103 bone marrow biopsy samples of Philadelphia chromosome-negative myeloproliferative neoplasms consecutively collected in 2004 were classified according to the WHO criteria as follows: essential thrombocythaemia (n=34), primary myelofibrosis (n=44) and polycythaemia vera (n=25). Two independent groups of pathologists reviewed the bone marrow biopsies. The first group was asked to reach a collegial 'consensus' diagnosis. The second group reviewed individually all the cases to recognize the main morphological parameters indicated by the WHO classification and report their results in a database. They were subsequently instructed to individually build a 'personal' diagnosis of myeloproliferative neoplasms subtype just assembling the parameters collected in the database. Our results indicate that high levels of agreement (≥70%) have been reached for about all of the morphological features. Moreover, among the 18 evaluated histological features, 11 resulted statistically more useful for the differential diagnosis among the different Philadelphia chromosome-negative myeloproliferative neoplasms. Finally, we found a high percentage of agreement (76%) between the 'personal' and 'consensus' diagnosis (Cohen's kappa statistic >0.40). In conclusion, our results support the use of the histological criteria proposed by the WHO classification for the Philadelphia chromosome-negative myeloproliferative neoplasms to ensure a more precise and early diagnosis for these patients.

Splenic marginal zone lymphoma (SMZL) is a mature B-cell neoplasm characterized by rather indolent clinical course. However, nearly one third of patients experience a rapidly progressive disease with a dismal outcome. Despite the characterization of clone geneticsandthe recognition of deregulated immunologic stimulation in the pathogenesis of SMZL, little is known about microenvironment dynamics and their potential biological influence on disease outcome. Here we investigate the effect of stroma-intrinsic features on SMZL disease progression by focusing on the microenvironment of the bone marrow (BM), which represents an elective disease localization endorsing diagnostic and prognostic relevance. We show that the quality of the BM stromal meshwork of SMZL infiltrates correlates with time to progression. In particular, we describe the unfavorable prognostic influence of dense CD40 expression by BM stromal cells, which involves the contribution of CD40 ligand (CD40L)-expressing bystander mast cells infiltrating SMZL BM aggregates. The CD40/CD40L-assisted crosstalk between mesenchymal stromal cells and mast cells populating the SMZL microenvironment finds correlation in p53-/- mice developing SMZL and contributes to the engendering of detrimental proinflammatory conditions. Our study highlights a dynamic interaction, playing between nonneoplastic elements within the SMZL niche, toward disease progression. © 2014 by The American Society of Hematology.

Background: Surrogate markers of colorectal inflammation are increasingly being recognized as important in differentiating organic from functional intestinal disorders. Fecal calprotectin (FC) can be easily measured in the stool, being released by leukocytes in inflammatory conditions. Aim: We evaluated FC as an index of inflammation in consecutive outpatients referred for colonoscopy for chronic, nonbloody diarrhea. Methods: Stool specimens of 346 outpatients with chronic, nonbloody diarrhea, referred for colonoscopy, were measured for FC levels. The proportion of patients correctly diagnosed with the test and the relationship with endoscopic and histologic findings were measured. Results: Abnormal endoscopic findings were detected in 104 patients (30.1%). Histologic findings included 142 patients (41.0%) with inflammation and 204 (59.0%) without inflammation. Fecal excretion of calprotectin significantly correlated with the finding of inflammation at endoscopy and histology (P

Primary thyroid schwannomas are extremely rare tumors and there are very few reports of such tumors in the literature. This report presents a rare case of schwannoma involving the isthmus of the thyroid in a 47-year-old male, presenting as a symptomatic predominating cold nodule within a multinodular goiter. The patient underwent total thyroidectomy. The histological examination indicated an Antoni A-type schwannoma. The clinical, radiological and pathological findings of the tumor are discussed, emphasizing the difficulty in reaching a correct preoperative diagnosis. Only 18 cases of primary schwannoma of the thyroid gland have so far been described in the literature and, this is only the second report of thyroid schwannoma localized in the isthmus.

Introduction The incidence of cancer compared for age groups is 3–4 times higher in transplant recipients than the general population. The increased risk is related to immunosuppressive therapy as well as the use of increasingly older donors and recipients. Although cardiovascular disease with a functioning transplant is the leading cause of death (47%), cancer mortality is significant especially among older patients. However, the most frequent posttransplantation cancers relate to hemolymphopoietic organs and skin, whereas the occurrence of solid tumors elsewhere is rare. Herein we have described a rare case of synchronous double malignancy of endocrine organs (thyroid-adrenal) in a young woman who underwent renal transplantation. Case Report A 37-year-old woman with end-stage renal disease for 18 years underwent transplantation when she was 30 years old with a 17-year-old standard cadaveric donor receiving immunosuppressive therapy with mycophenolate mofetil, cyclosporine, and steroids. Follow-up demonstrated good indices of renal function with negative tumor pathology at 79 months when, at an annual ultrasound monitoring, we found a lesion in the right lobe of the thyroid and left adrenal neoplasm of dubious interpretation. The cytology for the thyroid was highly suspicious of papillary carcinoma, whereas the histological examination after surgery diagnosed a thyroid multifocal papillary microcarcinoma (mpT1NxMx) and an oxyphil cell adrenocortical carcinoma (pT2, N0). Results Six months after total thyroidectomy with central lymphadenectomy and left kidney and adrenal gland removal the patient showed no evidence of recurrent lesions and stable graft function. Conclusions The rare occurrence of solid tumors after transplantation has no known etiopathogenetic relation. Despite the young age of the patient and the double neoplasm that could have produced an unfavorable outcome for the patient and the graft, careful follow-up for tumor pathologies and multidisciplinary management achieved an early diagnosis of both tumors with a surgical eradication without adjuvant therapy, preserving the life of the patient and the function of the graft.

5-Fluorouracil (5-FU) is currently used for treatment of oral squamous cell carcinoma (OSCC). 5-FU is given by i.v. although the systemic administration is associated with severe toxic effects and no topical formulations of 5-FU for buccal drug delivery have been reported. In this study we would report the development of buccal tablets suitable for direct application of low-doses of 5-FU on cancer lesions. The topical administration could be effective on tumor area while systemic undesired side effects are avoided. Preliminarily, the limited tendency of 5-FU to cross the buccal tissue was established using reconstituted human oral epithelium (RHOE, in vitro) and porcine buccal mucosa (ex vivo) as mucosal models. The values of steady-state flux and permeability coefficient suggested the scarce aptitude of 5-FU to reach the systemic circulation. Matrix buccal tablets, were designed for 5-FU local delivery, developed and prepared. Release tests showed a highly reproducible Higuchian drug discharge. After tablet administration on buccal tissue specimens, the occurrence of histomorphological effects of 5-FU was highlighted. Apoptotic events were registered in all samples treated while only negligible amounts of 5-FU permeated the buccal membrane and reached the simulated plasma. The results suggest that loaded matrix tablets containing 5% of 5-FU could be a useful means in topical treatment of OSCC.

The transbuccal delivery of drugs could assist several categories of chronic, especially elderly, patients in adhering to a correct dosage regimen. In particular, patients suffering from dementia have several difficulties in following the prescribed dosage, in addition to problems associated with swallowing tablets. Galantamine is currently used for treating patients with mild to moderate Alzheimer's-type dementia. The transbuccal delivery of this drug could be an interesting non- invasive and safe administration route. Several studies have been performed in vitro and ex vivo within the framework of a European Commission funded Project (IntelliDrug-FP6), aimed at developing a device which would be fitted for controlled delivery of drugs by an electronic and software-driven system. The primary objective of this study was to evaluate the efficacy of a prototype of the IntelliDrug device in vivo on 6 pigs, following a single Galantamine dose to be delivered through the buccal mucosae, as compared to intravenous drug injection. The secondary objectives were: a) to verify Galantamine bioavailability through buccal delivery; b) to evaluate the permeation enhancement effect of iontophoresis; and, finally, c) to assess any histomorphological changes in the buccal mucosae after transbuccal delivery. The results suggested that transbuccal delivery has the potential to cause long-lasting and controlled blood levels of Galantamine. The latter crosses the entire buccal mucosae, reaching systemic circulation after about 30 minutes and its plasmatic peak approximately 120 minutes after administration. The histological analysis of the buccal mucosae did not reveal any evidence of flogosis or tissue injury. Our results have clearly confirmed that the buccal delivery of Galantamine is a reliable tool with which to overcome the drawbacks associated with the conventional administration route. In general, transbuccal drug delivery has been shown to be an interesting, non-invasive and safe administration route for delivering systemically-acting drugs.

OBJECTIVES: The aims of this study were to investigate the expression of cyclooxygenase-1 and cyclooxygenase-2 (COX-1 and COX-2) in chronic hepatitis C (CHC) by immunohistochemistry, based on the hypothesis that COXs expression could vary according to genotype, viral load, liver steatosis, BMI and response to therapy and to determine whether the addition of selective COX inhibitors could have a rationale in increasing the efficacy of antiviral therapy. METHODS: We used 35 formalin-fixed, paraffin-embedded liver tissue samples obtained by needle biopsy from patients with CHC (17F/18M) with one of two types of genotype (1b and 3a). The presence of COX-1 and COX-2 in the cytoplasm of hepatocytes was scored on the basis of: (i) maximum intensity; (ii) dominant intensity; and (iii) extent. RESULTS: No significant differences were found in COX-1 and COX-2 expression in CHC patients divided according to genotype or according to the type of response to combination therapy with pegylated-interferon and ribavirin. The only significant correlations were observed between the dominant intensity of COX-2 and the presence of histological steatosis (P

Study design: Case reports and review of the literature. Objective: Intramedullary spinal cord metastases (ISCMs) are rare type of central nervous system (CNS) involvement of systemic malignant tumors. Since the advent of new neuroradiological techniques, their detection have become increasingly diagnosed in recent years and, although somewhat controversial, surgical treatment has been considered a valid option. Setting: Neurosurgical Clinic, Department of Clinic Neuroscience, University of Palermo, Italy. Method: The authors describe the case of a 61-year-old woman who was admitted presenting withprogres sive tetraplegia. Investigations revealed an intramedullary spinal cord lesion at the cervical level. Magnetic resonance imaging of the brain did not reveal other CNS metastatic lesions. Result: Patient underwent surgical treatment. The tumor was resected and the patient’s neurologic deficits slowly improved. Histological examination of the lesion showed the typical features of a colon carcinoma metastasis. Patient was referred for proper oncological treatment but, unfortunately, she died of disseminated disease within 2 months. Conclusion: Although uncommon, spinal cord metastases should be considered in the differential diagnosis of ISCM in order to rationalize the decisional-making process and improve the quality of life for these patients.

Summary: Solitary fibrous tumor (SFT) is a rare neoplasm that commonly originates in the pleura. Extrapleural locations are rare and for this reason sometimes difficult to diagnose. Malignant forms with local recurrence or distant metastases have been reported, also as a consequence of inappropriate treatment. In this article, we report the case of an SFT of the lower leg in a 37-year-old man. Leg SFT is a rare occurrence, and differential diagnosis may be difficult because they can mimic a variety of benign and malignant mesenchymal tumors; immunohistochemical analysis for CD34, CD99, vimentin, and Bcl-2 is necessary. Misdiagnosis carries a significant risk of inadequate removal with subsequent increased risk of recurrence and distant metastases.

Objectives: Solid second primary cancers (SPC) have become an issue of extensive research. The purpose of the present study was to estimate the standardised incidence ratio (SIR) and the absolute excess risk (AER) of SPC in patients with splenic marginal zone lymphoma (SMZL). Methods: We investigated the incidence of additional cancers in 129 patients consecutively diagnosed with SMZL in three Italian haematological centres, asking the cooperating doctors for additional information on initial and subsequent therapies and on the onset and type of second cancers. Results: Twelve SPC were recorded (9.3%); the 3- and 5-yr cumulative incidence rates were 5.5% and 18.3% respectively, with an SIR of 2.03 [95% confidence interval (CI): 1.05–3.56; P < 0.05; AER ¼ 145.81]. Of 12 SPC observed, four were urinary tract neoplasms (SIR, 3.70; 95% CI: 1.01–9.48; P < 0.05; AER ¼ 70.06), four were lung cancers (SIR, 9.16; 95% CI: 1.41–13.25; P < 0.05; AER ¼ 85.50) and the other four were hepatic carcinoma, endometrial cancer, breast cancer and colorectal cancer. Conclusions: Our findings evidence a high frequency of additional cancers in patients with SMZL and suggest that the incidence rate of SPC is significantly different from that expected in the general population. The frequency of cases with urinary tract and lung malignancies in our series is higher than expected. Although confirmatory data are needed, it is our opinion that SMZL patients are at risk of second cancer and should be carefully investigated on diagnosis and monitored during the follow-up.

Bipolar disorder (BD) is a psychiatric disease characterized by recurrent and alternated episodes of depression and mania. For the treatment of BD, anticonvulsants drugs as lithium, carbamazepine and oxcarbazepine can be used. These drugs can be associated with potential adverse effects: weight gain, tremors, thyroid abnormalities, and cognitive, gastrointestinal, cardiac or dermatological problems. We describe a case of BD with oral lichenoid drug reaction probably because of the mood stabilizers.

REFERENCES 1 . Carroccio A , Mansueto P , Iacono G et al. Nonceliac wheat sensitivity diagnosed by doubleblind placebo-controlled challenge: exploring a new clinical entity . Am J Gastroenterol 2013 (this issue) . 2 . Ludvigsson JF , Le$ er DA , Bai JC et al. " e Oslo de! nitions for coeliac disease and related terms . Gut 2013 ; 62 : 43 – 52 . 3 . Sapone A , Bai JC , Ciacci C et al. Spectrum of gluten-related disorders: consensus on new nomenclature and classi! cation . BMC Med 2012 ; 10 – 13 . 4 . Ferch CC , Chey WD . Irritable bowel syndrome and gluten sensitivity without celiac disease: separating the wheat from the cha% . Gastroenterology 2012 ; 142 : 664 – 6 . 5 . Biesiekierski JR , Newnham ED , Muir JG et al. Failure to con! rm the existence of non-coeliac gluten sensitivity (NCGS): a non-condition or inappropriate study design? J Gastroenterol Hepatol 2012 ; 27 (Suppl 4) : 124 – 5 . 6 . Hayat M , Cairns A , Dixon MF et al. Quantitation of intraepithelial lymphocytes in human duodenum: what is normal? J Clin Pathol 2002 ; 55 : 393 – 4 .

Celiac disease (CD) is a gluten-triggered enteropathy, presenting with insidious clinical patterns. It can occasionally be diagnosed in asymptomatic subjects. Our aim was to define the relationship among symptoms at diagnosis, serological markers [tissue transglutaminase antibodies (tTGA), anti-endomysium antibodies (EMA) anti-actin antibodies (AAA)] and degree of mucosal damage. A total of 68 consecutive adult patients with CD were enrolled. Intestinal biopsies were scored according to the Marsh classification modified by Oberhuber: I–II minimal lesions or absent villous atrophy; IIIA partial villous atrophy; IIIB–C total villous atrophy (TVA). HLA-typing was done for all patients. No association between clinical presentation and severity of mucosal damage was found. Presence of EMA or tTGA was significantly associated with more severe mucosal damage (P < 0.001). Of 12 patients, 11 with AAA were also positive for TVA. The severity of mucosal damage is the main factor governing the detectability of serological markers of CD. The sensitivity of serological testing is questionable in patients with minimal lesions.

Background Celiac disease (CD) diagnosis is becoming more difficult as patients with no intestinal histology lesions may also be suffering from CD. Aim To evaluate the diagnostic accuracy of antiendomysium (EmA) assay in the culture medium of intestinal biopsies for CD diagnosis. Patients and methods The clinical charts of 418 patients with CD and 705 non-CD controls who had all undergone EmA assay in the culture medium were reviewed. Results EmA assay in the culture medium had a higher sensitivity (98 vs. 80%) and specificity (99 vs. 95%) than serum EmA/antibodies to tissue transglutaminase (anti-tTG) assay. All patients with CD who were tested as false-negatives for serum EmA and/or anti-tTG (32 adults and 39 children) carried the human leukocyte antigen alleles associated to CD. Furthermore, during the follow-up, four patients with negative-serum EmA/anti-tTG, normal villi architecture, and positive-EmAs in the culture medium, developed villous atrophy and underwent gluten-free diet with consequent resolution of the symptoms and complete intestinal histology recovery. Conclusion EmA assay in the culture medium should be included in the diagnostic criteria for CD diagnosis in 'seronegative' patients. Eur J Gastroenterol Hepatol 23:1018-1023 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

Aims: Essential thrombocythaemia (ET) and primary myelofibrosis (PMF) share some clinical and pathological features, but show different biological behaviour and prognosis. The latest contributions to understanding the nature of these disorders have focused on bone marrow microenvironment remodelling and proliferative stress, recognising megakaryocytes (MKCs) as “key-cells”. The aim of this study was to investigate the apoptotic profile of ET and PMF MKCs in order to further characterise the biology of these disorders. Methods: Bone marrow biopsy samples from 30 patients with ET, and 30 patients with PMF, were immunophenotypically studied for the expression of pro-apoptotic (Fas, Fas-L, Bax, Bad) and anti-apoptotic (Bcl-2, Bcl-XL, hTERT (human telomerase reverse transcriptase)) molecules and the “executioner” molecule caspase-3. The fraction of MKCs undergoing apoptosis was assessed by deoxynucleotidyl transferase-mediated dUTP nick-end labelling. Results: Only the mitochondrial pathway seemed to be involved in MKC apoptosis. The anti-apoptotic molecule Bcl-XL was predominantly found in ET MKCs (50.5% of ET MKCs versus 35% of PMF MKCs; p = 0.036), while pro-apoptotic molecules Bax and Bad showed a prevalent expression in PMF MKCs (30.5% of ET MKCs versus 55% of PMF MKCs; 41% of ET MKCs versus 52% of PMF MKCs; p = 0.001 and p = 0.068, respectively). A significant fraction of PMF MKCs were committed to apoptosis according to caspase-3 expression and TUNEL, while only few ET cells were committed to apoptosis. hTERT was significantly more expressed in PMF (32% of ET MKCs versus 46% of PMF MKCs; p = 0.022), in agreement with the proliferative nature of this disease. Conclusions: It was found that ET and PMF MKCs, which barely differ in terms of morphology and aggregation, are characterised by markedly different apoptotic profiles. The rather high apoptotic fraction of PMF was able to support the fibrotic nature of this process, while the anti-apoptotic profile of ET cells fits well with their “steady” maturative state.

Clinical presentation of Crohn’s disease (CD) may be variable according to the location and the intensity of the inflammation. Some patients may have atypical symptoms which could delay the diagnosis. We report the first case of chronic urticaria related to a subclinical, complicated CD. Although the pathologic mechanism of this association was unclear in our patient, this case suggests that in patients with unexplained chronic urticaria it is opportune to investigate for a possible CD, even if there are no or few specific symptoms of intestinal inflammatory disease.

Aim To evaluate the reliability of the bright liver (BL) echo pattern on ultrasound to detect histological steatosis in chronic cryptogenic hypertransaminasaemia (CCH) and hepatitis C virus (HCV)-related forms of hypertransaminasaemia. Materials and methods One hundred and fifty patients, 54 with CCH and 96 with HCV hypertransaminasaemia (76 genotype 1/2 and 20 genotype 3), were enrolled. Histological steatosis was measured as the percentage of hepatocytes involved. The reliability of the BL sign was estimated using the sensitivity, specificity, positive and negative predictive values. Results Histological steatosis was present in 102/150 patients (68%) divided into 59/96 (62%) in the HCV group and 43/54 (79.6%) in the CCH group (χ 2 =4.4; p =0.035). In a multivariate analysis, the variable associated with the BL echo pattern was steatosis percentage ( p =0.0018). Steatosis percentage was higher in CCH group than in the HCV genotype 1/2 and 3 groups ( p =0.02). The sensitivity of the BL echo pattern was 88% in the CCH group [confidence interval (CI) 95% 74–95] versus 61% (CI 95% 44–73) in the HCV genotype 1/2 group. The CI indicates that ultrasound can provide evidence for steatosis in a statistically significant way in the CCH versus HCV genotype 1/2 patients. In the genotype 3 group, the sensitivity was high (90%), but the limited number of cases limited the statistical significance due to the high CI. Conclusion In CCH the BL echo pattern has excellent reliability in diagnosing steatosis, better than in HCV hypertransaminasaemia because of the higher prevalence and extent of steatosis.

CD146+ bone marrow stromal cells have been recently recognized as clonogenic osteoprogenitors able to organize a complete hematopoietic microenvironment. In this study we used immunohistochemical analysis to investigate the contribution of CD146+ bone marrow osteoprogenitors to the stromal remodeling occurring in the different stages of primary myelofibrosis. We found that CD146+ cells sited at the abluminal side of the bone marrow vessels and branching among hematopoietic cells significantly increased in the advanced stages of primary myelofibrosis (p

OBJECTIVE: Persistent villous atrophy in patients with celiac disease (CD) on a gluten-free diet (GFD) is reported with increasing frequency. The aim of this study was to evaluate a possible association between persistent damage of the villi and "atypical" gastrointestinal symptoms in CD patients on a GFD. MATERIAL AND METHODS: Sixty-nine CD patients on a GFD were divided into two groups: Group A included 42 patients (6 M, 36 F, age range 17-62 years) undergoing esophagogastroduodenoscopies (EGDs) due to the presence of symptoms; Group B included 27 control patients (6 M, 21 F, age range 24-71 years) who were asymptomatic at the time of the study. Both groups underwent EGDs and a duodenal histologic study. RESULTS: Persistent endoscopic lesions were more frequent in Group A (30/42) than in Group B (12/27; p=0.01). Villous atrophy was significantly more frequent in Group A than in Group B: 85% versus 33% (p

Objective: We aimed to investigate the existence of associations between well-established and newly recognized biological and phenotypic features of breast cancer involved in tumor progression and prognosis. Methods: Ninety-eight cases of invasive breast cancer were assessed for the immunohistochemical expression of estrogen and progesterone receptors, Ki-67, HER2, Akt-1, and Notch-2, using the tissue microarray technique. Data regarding tumor histotype, histological grade, tumor size and lymph node status were collected for each patient and included in the analysis. Results: Several significant associations between histological and/or immunophenotypic features came from the analysis of our data. Positive associations were observed between estrogen and progesterone receptors, tumor grade and proliferation index, tumor grade and HER2, Akt-1 and estrogen receptors, and Notch-2 and HER2. Inverse associations were noted between hormone receptors and tumor grade, hormone receptors and HER2, Akt-1 and tumor grade, and Akt-1 and nodal invasion. Conclusions: Our results, showing the existence of a number of estrogen receptor-positive tumors with Akt-1 expression, better degree of differentiation, and no lymph node involvement, along with the presence of HER2-positive tumors with strong Notch-2 expression, support the role of Notch and Akt in breast cancer progression and suggest that they may also represent new appealing therapeutic targets.

AIM: To evaluate the immunohistochemical localization of interleukin-6 (IL-6) and IL-6 receptor (IL-6R) on tumor tissue specimens from patients with hepatocellular carcinoma (HCC) and the serum levels of IL-6 and sIL-6R in a group of patients with HCC as well as liver cirrhosis (LC) in a group of patients with LC alone and in a control group. METHODS: Three groups of subjects were studied: group I (n = 83) suffering from HCC and LC, group II (n = 72) suffering from LC alone and group III (n = 42) as healthy controls. All patients had hepatitis C virus infection. Serum IL-6 and IL-6R levels were determined using a commercially available ELISA kit. Immunohistochemistry was performed using the streptavidin-biotin complex and rabbit polyclonal antibodies against IL-6 and IL-6R. RESULTS: Immunohistochemistry analysis showed a medium to strong cytoplasmic and membrane reactivity for IL-6 and IL-6R respectively, in at least 40% of cases of HCC, whereas liver cirrhosis patients and controls were negative for IL-6 or showed a very mild and focal dot-like cytoplasmic reaction for IL-6R. Serum IL-6 levels in HCC group were significantly higher than those in LC and control groups (P < 0.0001). There was no significant difference in sIL-6R concentrations among 3 groups. When the patients with HCC were divided into groups according to Okuda's classification, a significant serum increase of IL-6 and sIL-6R level was observed from stage I to stage III (P < 0.02, P < 0.0005). When HCC and LC patients were divided into 3 classes of cirrhosis severity according to Child-Pugh, values in HCC patients were significantly higher than those in LC patients for each corresponding class (P < 0.01). CONCLUSION: IL-6 serum levels in HCC patients are higher than those in LC patients and controls, suggesting an increased production of this cytokine by neoplastic cells. sIL-6R values are similar in all groups, increasing only in stage III HCC patients. These data suggest that they have a closer relationship with the neoplastic mass rather than with the residual functioning hepatic mass.

Although CD95 and its ligand are expressed in thyroid cancer, the tumor cell mass does not seem to be affected by such expression. We have recently shown that thyroid carcinomas produce interleukin (IL)-4 and IL-10, which promote resistance to chemotherapy through the up-regulation of Bcl-xL. Here, we show that freshly purified thyroid cancer cells were completely refractory to CD95-induced apoptosis despite the consistent expression of Fas-associated death domain and caspase-8. The analysis of potential molecules able to prevent caspase-8 activation in thyroid cancer cells revealed a remarkable up-regulation of cellular FLIPL (cFLIPL) and PED/PEA-15, two antiapoptotic proteins whose exogenous expression in normal thyrocytes inhibited the death-inducing signaling complex of CD95. Additionally, small interfering RNA FLIP and PED antisense sensitized thyroid cancer cells to CD95-mediated apoptosis. Exposure of normal thyrocytes to IL-4 and IL-10 potently up-regulated cFLIP and PED/PEA-15, suggesting that these cytokines are responsible for thyroid cancer cell resistance to CD95 stimulation. Moreover, treatment with neutralizing antibodies against IL-4 and IL-10 or exogenous expression of suppressor of cytokine signaling-1 of thyroid cancer cells resulted in cFLIP and PED/PEA-15 down-regulation and CD95 sensitization. More importantly, prolonged IL-4 and IL-10 neutralization induced cancer cell growth inhibition and apoptosis, which were prevented by blocking antibodies against CD95 ligand. Altogether, autocrine production of IL-4 and IL-10 neutralizes CD95-generated signals and allows survival and growth of thyroid cancer cells. Thus, IL-4 and IL-10 may represent key targets for the treatment of thyroid cancer. (Cancer Res 2006; 66(3): 1491-9)

Background: Splenic marginal zone lymphoma (SMZL) is an infrequent B-cell neoplasm that pursues an indolent course. Signs and symptoms, mostly related to hypersplenism, are successfully managed by splenectomy. However, the therapy of patients who are not fit for a surgical procedure or who relapse after splenectomy, is still an unsettled issue. Patients and methods: We report a phase-II study on 16 patients with SMZL, three therapy naive and 13 pretreated, all showing systemic symptoms or progressive worsening of peripheral cytopenia, who were treated with pentostatin at a dose of 4 mg/m2 every other week for 6–10 wk. In relapsed patients, the median interval between diagnosis and treatment was 26 month (range: 8–49). Results: Overall, 68% of the patients showed a clinical response. Two out three patients, who received pentostatin as first line therapy, attained a complete response (CR). One CR and seven minor or good haematological responses were recorded in relapsed patients. Treatment toxicity, mostly haematological, proved manageable. With a median follow-up of 35 month the median overall survival (OS) is 40 month and the median progression free survival (PFS) is 18 month. Conclusion: Our data show that pentostatin administered every other week has a good degree of activity in the treatment of SMZL and suggest that this schedule could be considered a possible therapeutic option for patients who are not fit for splenectomy or have relapsed.

Our aim was to evaluate in oral squamous cell carcinoma (OSCC) the relationship between some cell cycle markers and HPV infection, conditionally to age, gender and certain habits of patients, and to assess the ability of fuzzy neural networks (FNNs) in building up an adequate predictive model based on logic inference rules. Eighteen cases of OSCC were examined by immunohistochemistry for MIB-1, PCNA and survivin expression; presence of HPV DNA was investigated in exfoliated oral mucosa cells by nested PCR (nPCR, MY09-MY11/GP5-GP6), and HPV genotype was determined by direct DNA sequencing. Data were analyzed by traditional statistics (TS) and FNNs. HPV DNA was found in 9/18 OSCCs (50.0 %) without any significant higher risk of HPV infection with respect to the sociodemographic variables considered (p > 0.2), apart from tobacco smoking, reported in 44.4% of OSCC HPV-positive vs. 100% HPV-negative subjects (p = 0.029). Regarding cell cycle markers, TS and FNN revealed that survivin was expressed significantly more in HPV-negative than in HPV-positive OSCC [root mean-square error (RMSE) = 5.89 × 10–6, % predicted 100.0]; furthermore, smoking played a protective role for survivin expression in HPV-positive cases (OR = 0.019, 95%CI 0.001–0.723, RMSE = 0.20, % of prevision 94.4). FNN, although on a small sample size, allowed us to confirm data by TS and to hypothesize a different cell cycle pattern for HPV-positive vs. HPV-negative OSCC. In the latter cases, the relevance of apoptotic vs. proliferative markers suggested that they may be related to the different supposed outcome of HPV-negative OSCC and that HPV may have a protective role in the expression level of survivin, especially in tobacco smokers. © 2005 Wiley-Liss, Inc.

Primary hepatic lymphoma is a rare but well-defined lymphoma entity that often pursues an aggressive clinical course. Most cases have been described in hepatitis C virus (HCV)-related chronic liver disease patients. Although anthracycline-based chemotherapy has been reported to be highly effective, the best therapeutic strategy has not been defined yet. The prognosis is dismal especially in patients treated with chemotherapy alone or when an advanced liver disease is present. Herein, we describe a case of primary hepatic large B-cell non-Hodgkin’s lymphoma, in a patient with HCV chronic infection. After a minor response with eight cycles of CHOP chemotherapy, a complete and sustained remission was obtained with a-interferon at the daily dose of 3 MU. HCV-RNA clearance pace from the blood almost paralleled the response of the lymphoma and both diseases went in remission within 1 year of therapy. The possible place of a-Interferon in the treatment of primary hepatic lymphoma is discussed. The Hematology Journal (2004) 5, 530–533. doi:10.1038/sj.thj.6200408

Aims: To investigate CD27 expression in splenic marginal zone lymphoma (SMZL), an indolent low-grade B-cell lymphoma with constant involvement of the bone marrow, especially with an intrasinusoidal pattern. It is not clear if the neoplastic clone is composed of virgin or somatically mutated B cells. CD27 is reported to be a hallmark of memory B cells. Methods and results: We evaluated 64 bone marrow biopsy specimens (BMBs) from 36 patients with SMZL for the expression of CD27. For comparison, splenectomy specimens of patients with traumatic splenic rupture or with SMZL were used. All BMBs showed lymphomatous infiltration. When located in the marrow sinusoids, neoplastic cells were CD27– in all cases and therefore corresponded to naive B cells. In nodular/interstitial infiltration, the cells were CD27+ and therefore corresponded to memory B cells. No difference in immunohistochemical expression of B and T antibodies was found between intrasinusoidal and interstitial/nodular infiltration. CD27 was constantly expressed in the splenic marginal zone of normal spleen, surgically removed for trauma, and in seven out of 10 spleens with SMZL. Conclusion: We propose the existence of two different phases of neoplastic progression with, first, expansion of a virgin B clone in the bone marrow and, following exposure to antigen, a re-colonization of the bone marrow.

Marburg's disease (MD) is an extremely rare and aggressive form of multiple sclerosis (MS). In some cases, MD presents with tumefactive demyelinating lesions with a “tumor-like” appearance in MRI images, for which it may be difficult to achieve a form of differential diagnosis between definitive tumors or abscesses. Here we report a case of MD histopathologically confirmed after neuronavigationguided biopsy. Postoperative course was uneventful and following discharge, the patient attended outpatient follow-up appointments and received i.v. cyclophopsphamide, achieving progressive clinical remission. A nine-month follow-up brain MRI scan with gadolinium showed no signs of progressing demyelinating disease with an evident reduction of the biopsied lesion, and almost complete retrogression of the other two lesions. In our opinion, and through the analysis of currently available literature, early neuronavigation-guided biopsy is a highly recommend, valuable, and safe diagnostic tool; it is also preferable to stereotactic biopsy, since its benefits include a very low bleeding rate and brain damage risk, with minimum mortality and morbidity rates. It also allows the identification of the specific histological pattern, helping to select the best medical treatment approach and contributing to increase patient outcome and life expectancy.

Splenic Marginal Zone Lymphoma (SMZL), with or without villous lymphocytes (VL+/-), is a low-grade lymphoproliferative disorder with constant involvement of the bone marrow (BM). Different BM infiltration patterns, mainly intra-sinusoidal, interstitial and nodular, have been described. Adhesion molecules (AMs) constitute a heterogeneous group of antigenic receptors playing a major role in leukocyte recruitment, in lymphocyte homing and in cellular-mediated immune response. Evolution and pattern of the BM infiltrate could be influenced by a variable expression of AM on SMZL lymphocytes. The degree and pattern of BM infiltration and the immunohistochemical expression of AM (H-CAM, BL-CAM, L-selectin, PSGL-1, E-selectin, ICAM-1, VCAM-1 and Beta-1 integrin) among the different infiltration patterns were evaluated in BM biopsies of 38 patients with SMZL and graded according to a semi-quantitative score ranging from 0-4 and based on the percentage of positive cells. An intra-sinusoidal infiltration was constantly observed, alone or in conjunction with other patterns. H-CAM and BL-CAM showed a moderate-to-high degree of positivity in the intra-sinusoidal infiltrate (median expression grade-3) and were expressed in the neoplastic lymphocytes independently from the pattern. PSGL-1 was mostly expressed in the perisinusoidal region and in case of interstitial infiltration (grade-2). ICAM-1 and VCAM-1 were selectively expressed in the nodules as a reticular meshwork located in the core region (grade-2); VCAM-1 was also expressed in the perinodular endothelia. E-selectin, L-selectin and beta-1 integrin proved constantly negative. These data suggest that different expression of AM can influence the modality of BM infiltration in SMZL.

Primary plasma cell leukemia (PCL) is a rare variant of multiple myeloma that occurs de novo in patients without a history of plasma cell disorder. We describe a case of λ PCL that showed a prolonged survival of 2 years and 6 months associated with a generalized dysfunction of the proximal renal tubule. On presentation, the patient had anemia (hemoglobin level, 11 g/dL), thrombocytopenia (platelet count, 102,000/μL), and renal insufficiency (creatinine level, 2.75 mg/dL; creatinine clearance, 19 mL per minute; urea, 71 mg/dL). In addition to the common clinical picture, our case showed proteinuria (30 mg/dL), glycosuria (150 mg/dL) with normal glycemia, low uric acid concentration (2.9 mg/dL), and ion loss from the proximal renal tubule (P, 2.1 mg/dL). These findings were compatible with the clinical picture of adult-acquired Fanconi syndrome, which can be observed in PCL/multiple myeloma but is almost exclusively associated with κ-chain restriction.

im: To investigate the association of cyclooxygenase-2 (COX-2) expression with angiogenesis and the number and type of inflammatory cells (macrophages/Kupffer cells; mast cells) within primary hepatocellular carcinoma (HCC) tissues and adjacent non-tumorous (NT) tissues. Methods: Immunohistochemistry for COX-2, CD34, CD68 and mast cell tryptase (MCT) was performed on 14 well-characterized series of liver-cirrhosis-associated HCC patients. COX-2 expression and the number of inflammatory cells in tumor lesions and surrounding liver tissues of each specimen were compared. Moreover, COX-2, CD34 staining and the number of inflammatory cells in areas with different histological degrees within each tumor sample were comparatively analyzed. Results: The percentage of COX-2 positive cells was significantly higher in NT tissues than in tumors. COX-2 expression was higher in well-differentiated HCC than in poorly-differentiated tissues. Few mast cells were observed within the tumor mass, whereas a higher number was observed in the surrounding tissue, especially in peri-portal spaces of NT tissues. Abundant macrophages/Kupffer cells were observed in NT tissues, whereas the number of cells was significantly lower in the tumor mass. However, a higher cell number was observed in the well-differentiated tumor and progressively decreased in relation to the differentiation grade. Within the tumor, a positive correlation was found between COX-2 expression and the number of macrophages/Kupffer cells and mast cells. Moreover, there was a positive correlation between CD34 and COX-2 expression in tumor tissues. Comparison between well- and poorly-differentiated HCC showed that the number of CD34-positive cells decreased with dedifferentiation. However, COX-2 was the only independent variable showing a positive correlation with CD34 in a multivariate analysis. Conclusion: The presence of inflammatory cells and COX-2 expression in liver tumor suggests a possible relationship with tumor angiogenesis. COX-2 expressing cells and the number of macrophages/Kupffer cells and mast cells decrease with progression of the disease