Immune cell infiltration and inflammatory landscape in primary brain tumours.

BACKGROUND: Primary malignant brain tumours are more than one-third of all brain tumours and despite the molecular investigation to identify cancer driver mutations, the current therapeutic options available are challenging due to high intratumour heterogeneity. In addition, an immunosuppressive and inflammatory tumour microenvironment strengthens cancer progression. Therefore, we defined an immune and inflammatory profiling of meningioma and glial tumours to elucidate the role of the immune infiltration in these cancer types. METHODS: Using tissue microarrays of 158 brain tumour samples, we assessed CD3, CD4, CD8, CD20, CD138, Granzyme B (GzmB), 5-Lipoxygenase (5-LOX), Programmed Death-Ligand 1 (PD-L1), O-6-Methylguanine-DNA Methyltransferase (MGMT) and Transglutaminase 2 (TG2) expression by immunohistochemistry (IHC). IHC results were correlated using a Spearman correlation matrix. Transcript expression, correlation, and overall survival (OS) analyses were evaluated using public datasets available on GEPIA2 in Glioblastoma (GBM) and Lower Grade Glioma (LGG) cohorts. RESULTS: Seven out of ten markers showed a significantly different IHC expression in at least one of the evaluated cohorts whereas CD3, CD4 and 5-LOX were differentially expressed between GBMs and astrocytomas. Correlation matrix analysis revealed that 5-LOX and GzmB expression were associated in both meningiomas and GBMs, whereas 5-LOX expression was significantly and positively correlated to TG2 in both meningioma and astrocytoma cohorts. These findings were confirmed with the correlation analysis of TCGA-GBM and LGG datasets. Profiling of mRNA levels indicated a significant increase in CD3 (CD3D, CD3E), and CD138 (SDC1) expression in GBM compared to control tissues. CD4 and 5-LOX (ALOX5) mRNA levels were significantly more expressed in tumour samples than in normal tissues in both GBM and LGG. In GBM cohort, GzmB (GZMB), SDC1 and MGMT gene expression predicted a poor overall survival (OS). Moreover, in LGG cohort, an increased expression of CD3 (CD3D, CD3E, CD3G), CD8 (CD8A), GZMB, CD20 (MS4A1), SDC1, PD-L1, ALOX5, and TG2 (TGM2) genes was associated with worse OS. CONCLUSIONS: Our data have revealed that there is a positive and significant correlation between the expression of 5-LOX and GzmB, both at RNA and protein level. Further evaluation is needed to understand the interplay of 5-LOX and immune infiltration in glioma progression.

Prediction of placenta accreta spectrum in patients with placenta previa using a clinical, US and MRI combined model: A retrospective study with external validation.

PURPOSE: To build and validate a predictive model of placental accreta spectrum (PAS) in patients with placenta previa (PP) combining clinical risk factors (CRF) with US and MRI signs. METHOD: Our retrospective study included patients with PP from two institutions. All patients underwent US and MRI examinations for suspicion of PAS. CRF consisting of maternal age, cesarean section number, smoking and hypertension were retrieved. US and MRI signs suggestive of PAS were evaluated. Logistic regression analysis was performed to identify CRF and/or US and MRI signs associated with PAS considering histology as the reference standard. A nomogram was created using significant CRF and imaging signs at multivariate analysis, and its diagnostic accuracy was measured using the area under the binomial ROC curve (AUC), and the cut-off point was determined by Youden's J statistic. RESULTS: A total of 171 patients were enrolled from two institutions. Independent predictors of PAS included in the nomogram were: 1) smoking and number of previous CS among CRF; 2) loss of the retroplacental clear space at US; 3) intraplacental dark bands, focal interruption of the myometrial border and placental bulging at MRI. A PAS-prediction nomogram was built including these parameters and an optimal cut-off of 14.5 points was identified, showing the highest sensitivity (91%) and specificity (88%) with an AUC value of 0.95 (AUC of 0.80 in the external validation cohort). CONCLUSION: A nomogram-based model combining CRF with US and MRI signs might help to predict PAS in PP patients, with MRI contributing more than US as imaging evaluation.

RNA-Based Assay for Next-Generation Sequencing of Clinically Relevant Gene Fusions in Non-Small Cell Lung Cancer.

Gene fusions represent novel predictive biomarkers for advanced non-small cell lung cancer (NSCLC). In this study, we validated a narrow NGS gene panel able to cover therapeutically-relevant gene fusions and splicing events in advanced-stage NSCLC patients. To this aim, we first assessed minimal complementary DNA (cDNA) input and the limit of detection (LoD) in different cell lines. Then, to evaluate the feasibility of applying our panel to routine clinical samples, we retrospectively selected archived lung adenocarcinoma histological and cytological (cell blocks) samples. Overall, our SiRe RNA fusion panel was able to detect all fusions and a splicing event harbored in a RNA pool diluted up to 2 ng/µL. It also successfully analyzed 46 (95.8%) out of 48 samples. Among these, 43 (93.5%) out of 46 samples reproduced the same results as those obtained with conventional techniques. Intriguingly, the three discordant results were confirmed by a CE-IVD automated real-time polymerase chain reaction (RT-PCR) analysis (Easy PGX platform, Diatech Pharmacogenetics, Jesi, Italy). Based on these findings, we conclude that our new SiRe RNA fusion panel is a valid and robust tool for the detection of clinically relevant gene fusions and splicing events in advanced NSCLC.

Brain Radionecrosis After Adjuvant Radiation Therapy for a Primary Intracerebral Undifferentiated Sarcoma.

BACKGROUND: Primary intracranial sarcomas of the central nervous system are rare tumors. They mainly arise from intracranial mesenchymal tissue present in the meninges and can occur at any age. Sometimes osteosarcoma can involve the skull rather than long body bones. In this latter case it is the more common subtype. Surgery, when possible, is a mandatory option often associated with radiation therapy (RT) and chemotherapy. Brain radionecrosis (BRN) is commonly observed due to the growing use of radiosurgery and higher cumulative doses of radiation therapy. The combination of perfusion magnetic resonance imaging and 18fluoro-deoxy-glucose positron emission tomography can help to differentiate tumor progression from radiation injury. Steroids, anticoagulants, and bevacizumab usually control BRN. However, BRN can also have an unfavorable course. CASE DESCRIPTION: Here, we present a case of a 60-year-old male who underwent surgery for a brain tumor. The examination showed a primary undifferentiated high-grade sarcoma. Adjuvant RT was given with a total dose of 60 Gy. Six months later, the patient underwent a second surgery that revealed a BRN progressing despite different pharmacologic attempts. CONCLUSIONS: Primary intracranial sarcomas of the central nervous system are less prevalent among older adults with respect to the younger population. The use of RT alone or combined with chemotherapy is aimed at prolonging survival. However, it is not clearly defined if adjuvant treatments affect this parameter in older patients. RT should be carefully discussed owing to its potential severe neurologic toxicity. Indeed, a BRN can have a significant impact on quality of life and lead to death in certain cases.

PD-L1 expression in cell-blocks of non-small cell lung cancer: The impact of prolonged fixation.

INTRODUCTION: In the selection of non-small cell lung cancer (NSCLC) patients for immunotherapy, specimen processed as cell blocks (CBs) may be the only available material to assess PD-L1 expression. Therefore, optimal CB preparation becomes paramount. In this context, here we assessed whether inadequate fixation time might be one of the pre-analytical factors affecting PD-L1 expression. METHODS: Ex vivo CBs from placental (n = 3) and NSCLC (n = 8) resection specimens were obtained. PD-L1 staining was performed on CBs prepared at increasing fixation times (12 hours, 48 hours, 72 hours, 96 hours, 168 hours and 504 hours) using the companion diagnostic SP263 Assay and a validated 22C3 laboratory developed test (LDT). Staining intensity and percentage of positive cells were evaluated. RESULTS: All placental CBs showed moderate to strong PD-L1 positivity in most cells, regardless of the fixation time. Likewise, the percentage of SP263-stained NSCLC cells was similar at all fixation times except for one case, which showed less intense SP263 staining at 168 hours. Conversely, in 5/8 cases, the 22C3 LDT percentage of positive cells and staining intensity decreased at 168 hours and 504 hours. CONCLUSIONS: Our results show that fixation time influences the performance of 22C3 LDT on CBs. Thus, we recommend that the fixation time of cytological materials be carefully checked, especially when PD-L1 testing is delayed until the oncology request. Indeed, delays in tissue processing and paraffin embedding may lead to sub-optimal performance of PD-L1 staining on CBs.

Rapid On-site Molecular Evaluation in thyroid cytopathology: A same-day cytological and molecular diagnosis.

BACKGROUND: Thyroid fine-needle aspirates (FNAs) with undetermined morphology can be outsourced to centralized laboratories for comprehensive molecular profiling. When a local, rapid screening rules out easily detectable BRAF and NRAS mutations outsourcing is minimized, leading to cost savings. The fully automated Idylla technology, that does not require trained staff, is an emerging option. However, Idylla platform has only been validated to process formalin fixed paraffin embedded (FFPE) sections. Here we investigate whether also the FNA needle rinse could be genotyped by the same cytopathologist who performs the FNA, a procedure that can be termed rapid on site molecular evaluation (ROME). METHODS: To validate this approach, the Idylla BRAF and NRAS Test was performed on the rinses from 25 simulated (bench-top) FNAs, in a first part of the study. Genotyping data were compared with those obtained on matched histological FFPE blocks. The second part of the study was carried out on 25 prospectively collected routine FNAs to assess the performance of the Idylla BRAF and NRAS assay against a gold standard real time polymerase chain reaction method. RESULTS: Idylla NRAS-BRAF Mutation Test was performed on needle rinse as well as histological FFPE blocks. A sensitivity of 88.9%, a specificity of 100.0% were obtained comparing the Idylla NRAS-BRAF Mutation Test on needle rinse to the reference method. CONCLUSIONS: The FNA needle rinse can be directly genotyped. This obviates the need of cell block preparation, making possible a rapid combined morphological and molecular evaluation. Since DNA extraction is no longer necessary, the cytopathologist can perform ROME him/herself.

Anomalous Kv 7 channel activity in human malignant hyperthermia syndrome unmasks a key role for H2 S and persulfidation in skeletal muscle.

BACKGROUND AND PURPOSE: Human malignant hyperthermia (MH) syndrome is induced by volatile anaesthetics and involves increased levels of cystathionine ß-synthase (CBS)-derived H2 S within skeletal muscle. This increase contributes to skeletal muscle hypercontractility. Kv 7 channels, expressed in skeletal muscle, may be a molecular target for H2 S. Here, we have investigated the role of Kv 7 channels in MH. EXPERIMENTAL APPROACH: Skeletal muscle biopsies were obtained from MH-susceptible (MHS) and MH-negative (MHN) patients. Immunohistochemistry, RT-PCR, Western blot, and in vitro contracture test (IVCT) were carried out. Development and characterization of primary human skeletal muscle cells (PHSKMC) and evaluation of cell membrane potential were also performed. The persulfidation state of Kv 7 channels and polysulfide levels were measured. KEY RESULTS: Kv 7 channels were similarly expressed in MHN and MHS biopsies. The IVCT revealed an anomalous contractility of MHS biopsies following exposure to the Kv 7 channel opener retigabine. Incubation of negative biopsies with NaHS, prior to retigabine addition, led to an MHS-like positive response. MHS-derived PHSKMC challenged with retigabine showed a paradoxical depolarizing effect, compared with the canonical hyperpolarizing effect. CBS expression and activity were increased in MHS biopsies, resulting in a major polysulfide bioavailability. Persulfidation of Kv 7.4 channels was significantly higher in MHS than in MHN biopsies. CONCLUSIONS AND IMPLICATIONS: In skeletal muscle of MHS patients, CBS-derived H2 S induced persulfidation of Kv 7 channels. This post-translational modification switches the hyperpolarizing activity into depolarizing. This mechanism can contribute to the pathological skeletal muscle hypercontractility typical of MH syndrome. LINKED ARTICLES: This article is part of a themed section on Hydrogen Sulfide in Biology & Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.4/issuetoc.

Coexistent Squamous Cell Carcinoma and Granular Cell Tumor of Head and Neck Region: Report of Two Very Rare Cases and Review of the Literature.

Granular cell tumor (GCT), a relatively rare neuroectodermal tumor occurring most often in the head and neck region, is not uncommonly associated with pseudoepitheliomatous hyperplasia of the overlying surface epithelium, which may be at times nonreadily distinguishable from well-differentiated squamous cell carcinoma (SCC). To the best of our knowledge, only a handful of coexisting SCC and GCT, mostly described in the esophagus, have been reported in (the current) literature so far. We herein report 2 new cases of coexisting GCT and SCC of the head and neck region, located, respectively, in larynx and tongue; comment on their clinical, imaging, and pathologic features; and discuss their management. In the present work, we also review the literature concerning this association to contribute to the head and neck pathologists' and surgeons' awareness regarding the possibility of this association for an adequate surgical excision and a better management of these patients.

The long-term and extensive efficacy of low dose thalidomide in a case of an untransfusable patient with Non-Transfusion-Dependent Thalassemia.

Patients with Non-Transfusion-Dependent Thalassemia may require regular transfusion therapy. However, these patients are at risk of developing irregular antibodies, making them untransfusable. Second line treatment usually includes hydroxyurea, which however is not effective in all patients. Other treatment options include thalidomide, which has been reported to be safe and effective in selected patients. We report the case of a patient who experienced improvement of hemoglobin levels and of a part of NTDT related complications, following 36months of continuous therapy with low doses of thalidomide.

AMP18 interacts with the anion exchanger SLC26A3 and enhances its expression in gastric cancer cells.

AMP18 is a stomach-specific secreted protein expressed in normal gastric mucosa but absent in gastric cancer. AMP18 plays a major role in maintaining gastric mucosa integrity and is characterized by the presence of a BRICHOS domain consisting of about 100 amino acids, present also in several unrelated proteins, and probably endowed with a chaperon-like activity. In this work, we exploited a functional proteomic strategy to identify potential AMP18 interactors with the aim to add knowledge on its functional role within gastric cell lines and tissues. To this purpose, recombinant biotinylated AMP18 was purified and incubated with protein extract from human normal gastric mucosa by applying an affinity chromatography strategy. The interacting proteins were identified by peptide mass fingerprinting using MALDI-TOF mass spectrometry. The pool of interacting proteins contained SLC26A3, a protein expressed in the apical membrane of intestinal epithelial cells, supposed to play a critical role in Cl(-) absorption and fluid homeostasis. The interaction was also confirmed by Western blot with anti-SLC26A3 on transfected AGS cell extract following AMP18 pull-down. Furthermore, the interaction between AMP18 and SLC26A3 was also validated by confocal microscopy that showed a co-localization of both proteins at plasma membrane level. More importantly, for the first time, we showed that SLC26A3 is down-regulated in gastric cancer and that the overexpression of AMP18 in AMP-transfected gastric cancer cells up-regulated the expression of SLC26A3 both at transcriptional and translational level, the latter probably through the activation of the MAP kinases pathway. These findings strongly suggest that AMP18 might play an anti-inflammatory role in maintaining mucosal integrity also by regulating SLC26A3 level.

Thyroid lymphoma: diagnostic pitfalls on pre-operative ago-biopsy.

BACKGROUND: Thyroid cancer has the highest prevalence of all endocrine malignancies. Malignancy can be of thyroid or non-thyroid origin. Sarcomas and primary thyroid lymphomas (PTL) are rare and surgery is treatment of choice in the former but not in latter. OBJECTIVE: To describe thyroid lymphomas histological types of thyroid cancer found in a reference center. METHODS: Medical chart review from admitted patients diagnosed with thyroid cancer in the period from january 2007 to june 2012. Demographic, diagnostic, therapeutic and histopathological information were collected. RESULTS: 1604 records of patients admitted with thyroid disease were reviewed. Among 307 thyroid cancer, the cases diagnosed with rare tumors were: 10 cases of anaplastic carcinoma (3.5%), followed by 4 cases of medullary carcinoma (1.3%), 1 cases of teratoma (0.03%), 2 cases of lymphoma (0.06%). The most frequent clinical presentation was a palpable thyroid nodule. All patients with lymphoma died. CONCLUSION: Thyroid lymphomas are uncommon and tend to worse outcomes.

Helicobacter pylori infection in bleeding peptic ulcer patients after non-steroidal antiinflammatory drug consumption.

AIM: To establish the prevalence of Helicobacter pylori (H. pylori) infection in patients with a bleeding peptic ulcer after consumption of non-steroidal antiinflammatory drugs (NSAIDs). METHODS: A very early upper endoscopy was performed to find the source of upper gastrointestinal bleeding and to take biopsy specimens for analysis of H. pylori infection by the rapid urease (CLO) test, histological examination, and bacterial culture. IgG anti-CagA were also sought. The gold standard for identifying H. pylori infection was positive culture of biopsy specimens or contemporary positivity of the CLO test and the presence of H. pylori on tissue sections. RESULTS: Eighty patients, 61 males (76.3%), mean age 61.2 ± 15.9 years, were consecutively enrolled. Forty-seven (58.8%) patients occasionally consumed NSAIDs, while 33 (41.3%) were on chronic treatment with low-dose aspirin (LD ASA). Forty-four (55.0%) patients were considered infected by H. pylori. The infection rate was not different between patients who occasionally or chronically consumed NSAIDs. The culture of biopsy specimens had a sensitivity of 86.4% and a specificity of 100%; corresponding figures for histological analysis were 65.9% and 77.8%, for the CLO test were 68.2% and 75%, for the combined use of histology and the CLO test were 56.8% and 100%, and for IgG anti-CagA were 90% and 98%. The highest accuracy (92.5%) was obtained with the culture of biopsy specimens. CONCLUSION: Patients with a bleeding peptic ulcer after NSAID/LD ASA consumption frequently have H. pylori infection. Biopsy specimen culture after an early upper gastrointestinal tract endoscopy seems the most efficient test to detect this infection.

Hydrogen sulphide induces mouse paw oedema through activation of phospholipase A2.

BACKGROUND AND PURPOSE: Hydrogen sulphide (H(2)S), considered as a novel gas transmitter, is produced endogenously in mammalian tissue from L-cysteine by two enzymes, cystathionine ß-synthase and cystathionine γ-lyase. Recently, it has been reported that H(2)S contributes to the local and systemic inflammation in several experimental animal models. We conducted this study to investigate on the signalling involved in H(2)S-induced inflammation. EXPERIMENTAL APPROACH: L-cysteine or sodium hydrogen sulphide (NaHS) was injected into the mouse hind paw and oedema formation was evaluated for 60 min. In order to investigate H(2)S-induced oedema formation, we used 5-HT and histamine receptor antagonists, and inhibitors of K(ATP) channels or arachidonic acid cascade. Prostaglandin levels were determined in hind paw exudates by radioimmunoassay. Paws injected with L-cysteine or NaHS were examined by histological methods. KEY RESULTS: Both NaHS and L-cysteine caused oedema characterized by a fast onset which peaked at 30 min. This oedematogenic action was not associated with histamine or 5-HT release or K(ATP) channel activation. However, oedema formation was significantly inhibited by the inhibition of cyclooxygenases and selective inhibition of phospholipase A(2). Prostaglandin levels were significantly increased in exudates of hind paw injected with NaHS or L-cysteine. The histological examination clearly showed an inflammatory state with a loss of tissue organization following NaHS or L-cysteine injection. CONCLUSIONS AND IMPLICATIONS: Phospholipase A(2) and prostaglandin production are involved in pro-inflammatory effects of H(2)S in mouse hind paws. The present study contributes to the understanding of the role of L-cysteine/H(2)S pathway in inflammatory disease.

Hepatoid carcinoma of the ovary with sex cord stromal tumor: a previously unrecognized association.

BACKGROUND: Hepatoid carcinoma (HC) of ovary is a rare type of epithelial tumor composed mainly of epithelioid cells with abundant acidophilic cytoplasm, histologically indistinguishable from hepatocellular carcinoma. We report a previously unrecognized case of HC of ovary concurrent with a Sertoli cell tumor. CASE REPORT: A 42-year-old woman patient with a long-term history of hepatitis C presented with a mass of left ovary without evidence of hepatic tumor. After initial diagnosis of primary ovarian carcinoma (FIGO Stage I), she had experienced a first recurrence in upper abdomen. Histologically, the primary tumor was composed of epithelioid cells with "hepatoid features" in association with a sex cord stromal tumor of Sertoli-type. Immunohistochemistry hepatoid cells stained positively for hepatocyte paraffin-1, alpha-fetoprotein and alpha-1 antitrypsin; moreover, Sertoli-type cells were positive for alpha-inhibin, calretinin and CD99. A final diagnosis of HC concurrent with Sertoli-type tumor was made. CONCLUSION: The occurrence of this unreported association of HC with Sertoli-like tumor, the problems of differential diagnosis and therapeutic management of these tumors are the subject of this presentation. A diagnosis of ovarian metastasis from hepatocellular carcinoma is easy in patients with known primary tumor of liver and should be always excluded in these cases as an hepatoid variant of yolk sac tumor. Immunohistochemistry is not useful in these cases. However, a combination of clinical and pathological features is necessary for a correct diagnosis.

Monotypic epithelioid angiomyolipoma of the adrenal gland: an unusual site for a rare extrarenal tumor.

Epithelioid angiomyolipoma (AML) is an uncommon renal mesenchymal tumor with malignant potential and is frequently associated with tuberous sclerosis. Extrarenal AMLs are rare, and to the best of our knowledge, this is the first reported case of a primary monotypic epithelioid AML of adrenal gland in a patient without evidence of tuberous sclerosis. The patient is a 42-year old man who presented with retroperitoneal hemorrhage resulting from spontaneous rupture of adrenal mass. Histologically, the tumor showed a prominent component of epithelioid smooth muscle cells with slightly pleomorphic nuclei, sometimes with prominent nucleoli and eosinophilic cytoplasm resembling oncocytic tumors. Epithelioid cells were positive for melanoma (HMB45 and positive MelanA) and smooth muscle markers (alpha-smooth muscle-specific actin), but not for epithelial markers (cytokeratin, EMA). Differential diagnosis from renal cell carcinoma, adrenal gland carcinoma, and metastatic carcinoma is often challenging because of its epithelioid morphology. Because primary and secondary malignant tumors are much more common and aggressive neoplasms, establishing the correct diagnosis has important therapeutic and prognostic implications.

Clear cell "sugar" tumors of urethra: a previously undescribed occurrence and review of published data.

Clear cell "sugar" tumor is a rare benign tumor considered as a member of the family of perivascular epithelioid cell tumors. To the best of our knowledge, this is the first case of clear cell "sugar" tumor presented as a mass protruding from the urethra in a 15-year-old girl. Pathologic examination revealed a tumor composed of epithelioid cells with "water" clear cytoplasm that stained positively for melanocytic and smooth muscle-specific markers. Treatment of this tumor included a surgical excision and complete removal of the urethral mass, with examination of surgical margins. Three months after surgery, the patient remains clinically free of disease.

Mucinous carcinoma of thyroid gland. Report of a primary and a metastatic mucinous tumour from ovarian adenocarcinoma with immunohistochemical study and review of literature.

Mucinous carcinoma of the thyroid gland is an uncommon tumour that from the histological point of view, resembles mucinous carcinoma of others sites. Although a mucinous appearance has sometimes been reported in association with cases of typical thyroid carcinoma, true mucinous carcinoma is exceptionally rare. We describe two cases of thyroid tumours with mucinous differentiation studied with immunohistochemistry. Both cases disclosed a similar histological appearance, with small nests and sheets of malignant epithelial cells associated with extensive extracellular mucin that substituted and entrapped the follicular parenchyma of the thyroid. Thyroglobulin and focally thyroid transcription factor (TTF) 1 were positive in one case. From these findings, we classified this tumour as primary mucinous thyroid carcinoma. Thyroglobulin and TTF-1 were negative in tumour cells of second case; on the contrary, positivity to the carcinoembryonic antigen and CA-125 was strong and generalized. However, successfully, the patient presented ascites associated to right ovarian mass. In this case, thyroid tumour represents the first clinical sign of an ovarian mucinous adenocarcinoma, and it has not been previously described in literature. Both patients died after few months to diagnosis. In conclusion, primary and secondary mucinous carcinoma are rare and unusual tumours of the thyroid gland that can be a cause of pitfall in differential diagnosis. In these cases, for a correct diagnosis, a complete clinical history, restricted histological criteria and immunohistochemical panel are necessary.

Human eosinophil chemotaxis and selective in vivo recruitment by sphingosine 1-phosphate.

Sphingosine 1-phosphate (S1P) is a sphingolipid mediator that is involved in diverse biological functions. Local administration of S1P causes inflammation coupled to a large eosinophil (EO) recruitment in the rat-paw tissue. The inflammatory response is accompanied by an increase in S1P receptors, namely S1P(1), S1P(2), S1P(3), and by an enhanced expression of CCR3, which is the main chemokine receptor known to be involved in EO function. Human EOs constitutively express S1P(1) and, at a lower extent, S1P(2), S1P(3) receptors. S1P in vitro causes cultured human EO migration and an increase in S1P receptor mRNA copies and strongly up-regulates CCR3 and RANTES (regulated on activation, normal T cell-expressed and secreted) message levels; in particular CCR3 is up-regulated 18,000-fold by S1P. A blocking anti-CCR3 Ab inhibits S1P-induced chemotaxis, implying that S1P acts as specific recruiting signal for EOs not only through its own receptors but also through CCR3. These results show that S1P is involved in EO chemotaxis and contribute to shed light on the complex mechanisms underlying EO recruitment in several diseases such as asthma and some malignancies.

Multicystic mesothelioma of the liver with secondary involvement of peritoneum and inguinal region.

A case of multicystic mesothelioma of the liver with secondary involvement of the pelvic peritoneum and the inguinal region is presented. The case is of interest because of its unusual location and peculiar biological behavior.