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Introduction: Leptin is a proteohormone produced predominantly by white adipocytes and primarily known for its key role in the control of food intake and sense of satiety. From its discover leptin has been found in different body districts, involved in always new functions and processes. In the last years numerous relationships between leptin and cancer has been found. The aim of this study is to test the leptin positivity in human primitive laryngeal squamous cell carcinoma (SCC) and in its lymph node metastasis. Materials and methods: Leptin positivity was detected by immunohistochemical analysis on pathological samples from 18 patients subjected to laryngectomy and neck dissection for SCC. Results: During the study we pointed out a statistically significant relationship (p < 0.05) between leptin positivity levels and tumor differentiation grade, in particular we observed that a decrease in tumor leptin production correlates with higher level of cancer histological dedifferentiation. Conclusion: Our research on leptin expression in laryngeal squamous neoplastic pathology is aimed to the attempt of establishing a more precise patient risk stratification thanks to a new marker able to give a contribution to the identification of patient with poor prognosis and at risk of failure of actual standard therapy.

Reports focusing on the immunological microenvironment of peripheral T-cell lymphomas (PTCL) are rare. Here we studied the reciprocal contribution of regulatory (Treg) and interleukin-17-producing (Th17) T-cells to the composition of the lymphoma-associated microenvironment of angioimmunoblastic T-cell lymphoma (AITL) and PTCL not otherwise specified on tissue microarrays from 30 PTCLs not otherwise specified and 37 AITLs. We found that Th17 but not Treg cells were differently represented in the two lymphomas and correlated with the amount of mast cells (MCs) and granulocytes, which preferentially occurred in the cellular milieu of AITL cases. We observed that MCs directly synthesized interleukin-6 and thus contribute to the establishment of a proinflammatory, Th17 permissive environment in AITL. We further hypothesized that the AITL clone itself could be responsible for the preferential accumulation of MCs at sites of infiltration through the synthesis of CXCL-13 and its interaction with the CXCR3 and CXCR5 receptors expressed on MCs. Consistent with this hypothesis, we observed MCs efficiently migrating in response to CXCL-13. On these bases, we conclude that MCs have a role in molding the immunological microenvironment of AITL toward the maintenance of pro-inflammatory conditions prone to Th17 generation and autoimmunity. Copyright © American Society for Investigative Pathology.

Monoclonal antibodies (mAbs), successfully adopted in the treatment of several haematological malignancies, have proved almost ineffective in multiple myeloma (MM), because of the lack of an appropriate antigen for targeting and killing MM cells. Here, we demonstrate that PSGL1, the major ligand of P-Selectin, a marker of plasmacytic differentiation expressed at high levels on normal and neoplastic plasma cells, may represent a novel target for mAb-mediated MM immunotherapy. The primary effectors of mAb-induced cell-death, complement-mediated lysis (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC), were investigated using U266B1 and LP1 cell-lines as models. Along with immunological mechanisms, the induction of apoptosis by PSGL1 cross-linking was assessed. The anti-PSGL1 murine mAb KPL1 induced death of MM cells in a dose- and time-dependent fashion and mediated a significant amount of ADCC. KPL1 alone mediated C1q deposition on target cells but proved unable to induce CDC due to inhibition of the lytic activity of complement by membrane complement regulators (mCRP) expressed on the cell surface. Consistently, CDC was induced by KPL1 upon mCRP blockage. Our results suggest a role for PSGL1 in MM humoral immunotherapy and support further in vivo studies assessing the effects of anti-PSGL1 mAbs on MM growth and interaction with the bone marrow microenvironment.

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.

The transcription factor Yin Yang 1 (YY1) can favor several aspects of tumorigenesis. In turn, Raf-1 Kinase Inhibitor Protein (RKIP) inhibits the oncogenic activities of MAPK and NF-κB pathways and promotes drug-induced apoptosis. Mutual influences between YY1 and RKIP may exist, and there are already separate evidences that relevant increases in YY1 and reductions in RKIP occur in hepatocellular carcinoma (HCC). However, the levels of the two factors have never been concomitantly examined in HCC. We evaluated by RT-PCR the mRNA levels of YY1, YY1AP, RKIP, and survivin in 35 clinical HCCs (91% HCV-related), in their adjacent cirrhotic tissues and in 6 healthy livers. Immunohistochemical analyses were also performed. The ratio of YY1 to RKIP mRNA was constantly profoundly inverted in the tumors compared with the adjacent nontumoral tissues. A similar result occurred frequently at protein level. Hyperactivation of YY1 in tumors was corroborated by its nuclear localization and the finding that in the tumors there were also increases in YY1AP, a YY1 coactivator not expressed in normal liver, and in survivin, as a possible target of YY1. The frequent alteration in the YY1-RKIP balance might represent a marker of malignant progression and be exploited for therapeutic interventions in HCC.

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.

We focus on to the role of the transcription factors NF-κB and Yin Yang 1 (YY1) and of Raf-1 kinase inhibitory protein (RKIP) in hepatocellular carcinoma (HCC). YY1, whose expression is enhanced by NF-κB, favors tumorigenesis. RKIP inhibits the oncogenic activities of MAPK and NF-κB pathways and promotes drug-induced apoptosis. Mutual influences between YY1 and RKIP may exist and there is separate evidence that relevant increases in YY1 and reductions in RKIP occur in HCC. In a recent study on clinical HCC, we found that, indeed, the ratio of YY1 to RKIP mRNA and protein expression is very frequently profoundly inverted in tumors compared with adjacent tissues. Hyperactivation of YY1 in tumors was corroborated by its nuclear localization and by concomitant increases in the coactivator YY1AP. Overall, the alteration in the YY1-RKIP balance might represent, beside a marker of malignant progression, a target of therapeutic interventions in HCC, which will include application of NF-κB inhibitors, also in conjunction with the active agent sorafenib

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

Transbuccal drug delivery has got several well-known advantages especially with respect to peroral way. Since a major limitation in buccal drug delivery could be the low permeability of the epithelium, the aptitude of NLX to penetrate the mucosal barrier was assessed. Ex vivo permeation across porcine buccal mucosa 800 microm thick was investigated using Franz type diffusion cells and compared with in vitro data previously obtained by reconstituted human oral epithelium 100 microm thick. Both fluxes (Js) and permeability coefficients (K(p)) are in accordance, using either buffer solution simulating saliva or natural human saliva. Permeation was evaluated also in presence of chemical enhancers or iontophoresis. No significant differences in penetration rate were observed using chemical enhancers; in contrast, Js and K(p) were extensively affected by application of electric fields. Tablets, designed for Naltrexone hydrochloride (NLX) administration on buccal mucosa, were developed and prepared by direct compression of drug loaded (56%) poly-octylcyanocrylate (poly-OCA) matrices. NLX is slowly discharged from buccal tablets following Higuchian kinetic. Histologically, no signs of flogosis ascribable to NLX and/or poly-OCA were observed, while cytoarchitectural changes due to iontophoresis were detected. Buccal tablets containing NLX may represent a potential alternative dosage form in addiction management.

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.

Hypereosinophilia is a systemic condition that has several possible etiologies: allergies, medications, infectious, autoimmune or other systemic diseases, and finally idiopathic forms. Skin involvement seems to relate to subcutaneous inflammatory infiltration in this condition, as can be observed in parasitic, autoimmune and bullous diseases, as well as in drug reactions. Generalizing, a severe adverse drug-induced reaction may cause a systemic inflammatory disease: Drug Rash with Eosinophilia and Systemic Symptoms (DRESS). Its diagnosis requires the application of a complex diagnostic algorithm and immediate identification to prevent inauspicious evolution. The prognosis is severe; drug discontinuation is sometimes not enough and so far the proposed therapies are not always valid. We describe a case of fatal DRESS in which we report: a) difficulties in the management and therapy of the syndrome in its most severe form, and b) need for caution in prescribing drugs potentially inducing DRESS, especially in elderly patients.

IMPORTANCE OF THE FIELDS Multiple myeloma (MM) is a hematological malignancy still remaining incurable despite the various therapies available, mainly because of the high fraction of refractory/relapsing cases. Therefore, the development of novel therapeutic approaches is urgently needed to overcome conventional treatment resistance. AREAS COVERED IN THIS REVIEW: In the era of targeted therapies, treatments combining a high specificity for neoplastic cells and the capability to interfere with environmental signals should be regarded as the weapons of choice. Monoclonal antibody (mAb)-based humoral immunotherapy could satisfy both these requirements when applied to MM. Indeed, many of the molecules expressed on MM cells, such as CD38, CD40, CD49d, CD138 and CD162 are involved in the adhesive dynamics regulating the crosstalk between MM and the BM-microenvironment. WHAT THE READER WILL GAIN: In this study we review those MM-associated molecules that have shown promising antitumor effects as targets of specific mAbs in preclinical settings, thus deserving to be considered for clinical investigation. TAKE HOME MESSAGE: mAbs directed against MM-associated adhesion markers should be taken into account in clinical practice, since they could possibly represent the best available combination of tumor cytotoxicity, environmental signal deprivation and immune system redirection.

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.

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of lymphoid neoplasms characterized by aggressive clinical behavior and dismal prognosis. Hepatosplenic γδ T-cell lymphoma (γδ-HSTL) is a particular form of PTCL that arises from a small subset of γ/δ T-cell receptor-expressing lymphocytes. γδ-HSTL has a rapidly progressive course and poor outcome due also to its refractoriness to conventional chemotherapy regimens. The very low incidence of γδ-HSTL, along with its propensity to mimic different pathological entities, makes this lymphoma a true diagnostic challenge. In this review, we highlight the biological and clinical features of γδ-HSTL that contribute to making this lymphoma a mostly incurable disease. Moreover, we provide a new insight into the crosstalk between HSTL clones and the bone marrow, liver and spleen vascular microenvironment, in which neoplastic cells reside and proliferate. We further discuss γδ-HSTL associated molecules that might be proposed as potential targets for novel therapeutic approaches.

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.

SCOPO DEL LAVORO Presentiamo un caso di una paziente di 24 anni che giunge alla nostra attenzione per la comparsa di disartria come quadro clinico d’esordio di una forma aggressiva di malattia demielinizzante di cui si valuta l’atipica evoluzione neuroradiologica delle lesioni pseudotumorali che la caratterizzano e le possibili diagnosi differenziali. MATERIALI E METODI La paziente dopo una prima valutazione in PS è stata sottoposta a TC encefalo, ricoverata presso l’U.O. di Neurologia, sottoposta a controlli RM seriati (anche con tecniche avanzate); durante la degenza è stata inoltre effettuata una biopsia stereotassica. RISULTATI La TC ha rilevato almeno tre lesioni ipodense: a sinistra, nella sostanza bianca sottocorticale frontale e nella sostanza bianca parietale profonda, a destra, in sede paratrigonale. Le ultime due, ad un approfondimento diagnostico con esame RM, mostravano un aspetto leggermente rigonfio, segnale elevato nelle sequenze a lungo TR ed un cercine di enhancement incompleto dopo contrasto. L’area lesionale frontale, invece, notevolmente più estesa delle altre, mostrava un segnale più disomogeneo nelle pesature a lungo TR (come costituita da più lesioni focali tendenti alla confluenza), restrizione della diffusione in ADC in assenza di enhancement dopo contrasto. Quest’ultima lesione, ai successivi controlli si è infine appalesata, intorno al primo mese dall’esordio clinico, come una grossa lesione pseudotumorale con enhancement tuttavia atipico per malattia demielinizzante. CONCLUSIONI La clinica di presentazione, la rachicentesi e la semeiotica RM delle lesioni di dimensioni minori erano compatibili con un quadro di malattia demielinizzante; tuttavia, non è stato possibile escludere che la grossa lesione in sede frontale sinistra potesse avere altra natura. L’ipotesi diagnostica di una forma di malattia demielinizzante nel nostro caso fu confermata dalla biopsia stereotassica, eseguita in considerazione della mancata risposta alla terapia medica steroidea e della peculiare severità del quadro clinico inesorabilmente ingravescente. All’esame istologico, nei frammenti di tessuto cerebrale bioptizzato, sono state individuate aree di demielinizzazione, negative per la proteina basica della mielina (MBP), isolati linfociti T (CD3+) ed astrocitosi reattiva. Le lesioni demielinizzanti pseudotumorali pongono non pochi problemi di diagnosi differenziale. Il nostro caso, appare eccezionale in letteratura per la singolare evoluzione della lesione di maggior dimensioni, che da un aspetto iniziale di lesione “stroke-like”, in un periodo non superiore ad un mese, si appalesa nei successivi controlli come una lesione pseudotumorale con enhancement atipico, verosimile espressione di una atipica presentazione di una variante di sclerosi multipla (Marburg?).

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Aggressive B-cell lymphomas share high proliferative and invasive attitudes and dismal prognosis despite heterogeneous biological features. In the interchained sequence of events leading to cancer progression, neoplastic clone-intrinsic molecular events play a major role. Nevertheless, microenvironment-related cues have progressively come into focus as true determinants for this process. The cancer-associated microenvironment is a complex network of nonneoplastic immune and stromal cells embedded in extracellular components, giving rise to a multifarious crosstalk with neoplastic cells towards the induction of a supportive milieu. The immunological and stromal microenvironments have been classically regarded as essential partners of indolent lymphomas, while considered mainly negligible in the setting of aggressive B-cell lymphomas that, by their nature, are less reliant on external stimuli. By this paper we try to delineate the cardinal microenvironment-centred dynamics exerting an influence over lymphoid clone progression in aggressive B-cell lymphomas.

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.

Peripheral T-cell lymphomas (TCLs) are uncommon neoplasms, accounting for about 12% of all lymphoid tumors worldwide. TCLs in which gammadelta T-cell receptors are expressed (gammadelta TCLs) are extremely aggressive and rare (

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

BACKGROUND: The incidence of central nervous system involvement has increased in the setting of acquired immune deficiency syndrome (AIDS). Although rarely reported, spinal cord compression, in the setting of AIDS, has been associated with primary lymphoma or opportunistic infections. CASE REPORT: The authors describe the case of a young man who was admitted to our institution with rapid and progressive paraplegia. Imaging studies revealed an extramedullary lesion compressing the spinal cord spanning 3 thoracic levels. Surgical treatment was performed, and the compressing process completely excised. Histologic examination of the lesion showed a chronic inflammatory tissue with many necrotic areas without signs of infection or lymphoma. The patient progressively regained normal strength in his legs and was discharged home. CONCLUSIONS: In patients with HIV, chronic inflammation can lead to a lesion that compresses the spinal cord and should be considered in the differential diagnosis. Knowledge of this entity gains importance with the increasing incidence of HIV because timely excision can restore neurologic deficits. This condition may be considered a new clinical entity, the true incidence of which will be established using the diagnostic protocols provided and further case reports

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.