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BACKGROUND In the literature, there exist conflicting data on the value of fibulin-3 (FBLN3) for the diagnosis of pleural effusion (PE) in malignant pleural mesothelioma (MPM). Therefore we compared the diagnostic performance of FBLN3 against that of soluble mesothelin-related peptide (SMRP) in a cohort of Italian patients. MATERIALS AND METHODS FBLN3 and SMRP were detected in PE from 33 patients with MPM, 64 with pleural benign lesions and 23 with non-MPM pleural metastases using a commercial enzyme-linked-immunosorbent(ELISA)-assay kit according to manufacturers' instructions. RESULTS Levels of FBLN3 were similar in PE from MPM and PE from other pathologies (geometric mean=68.1 vs. 66.2 ng/ml; p=0.872) in contrast to SMRP levels, which were significantly higher in PE from MPM (geometric mean=14.6 vs. 3.2 nM; p

CTLA-4 function as a negative regulator of T cell-mediated immune response is well established, whereas much less is known about the immunoregulatory role of its soluble isoform (sCTLA-4). No data are available on CTLA-4 expression and prognostic impact in malignant pleural mesothelioma (MPM). We investigated, by immunohistochemistry, CTLA-4 expression in tumor tissues and, by ELISA, sCTLA-4 levels in sera and matched pleural effusions from 45 MPM patients. Prognostic effect of CTLA-4 expression on overall survival (OS) was assessed through Cox regression and prognostic significance expressed as death rate ratio (HR). We found that 56.0 % of MPM tissues expressed CTLA-4 with variable intensity and percentage of positive cells estimated by the immunoreactive score. sCTLA-4 levels were significantly higher in sera (S-sCTLA-4) than in pleural effusions (PE-sCTLA-4) (geometric mean ratio = 2.70, P value = 0.020). CTLA-4 expression at the tissue level was higher in the epithelioid histological subtype than in the sarcomatoid, whereas at the serum level, it was higher in the sarcomatoid subtype. A homogeneous favorable prognostic effect was found for CTLA-4 overexpression in tissue, serum and pleural effusion. Interestingly, only the PE-sCTLA-4 was found to be a statistically significant positive prognostic factor (HR = 0.37, 95 % CI = 0.18-0.77, P value = 0.007). Indeed, PE-sCTLA-4 correlated with CTLA-4 expression in tissues, whereas this latter expression showed a weak association with OS. To confirm our findings, further experimental evidences obtained from a larger cohort of MPM patients are required. However, our results would indicate a positive correlation of PE-sCTLA-4 levels and OS in MPM patients.

Soluble mesothelin-related peptide (SMRP) is regarded as an FDA approved biomarker for the diagnosis and monitoring of pleural malignant mesothelioma (MPM). We detected the SMRP levels in pleural effusions (PE) by means of an ELISA and analyzed their diagnostic relevance to differentiate MPM from benign pathology and from non-MPM pleural metastasis. Comparison with cytology in MPM-PE was also performed. We found that SMRP detection in MPM-PE can help the diagnosis of MPM and provide additional diagnostic value to cytology. We concluded that SMRP test may be incorporated into clinical practice of PE from patients suspicious for MPM.

Background human mammaglobin (hMAM) expression has been reported in pleural effusions (PE). The aim of this study was to assess the clinical relevance of hMAM mRNA in PE from patients who underwent thoracoscopy. Material and methods A total of 288 patients with PE were studied, 155 of which were diagnosed with malignant and 133 with non-malignant diseases by thoracoscopy. Cells from PE were analyzed by nested hMAM RT-PCR. Statistical analyses were performed to evaluate the diagnostic performance parameters (DPP), the association between hMAM expression and benign or malignant status and the relative risk of cancer for patients with negative thoracoscopy showing hMAM positivity. Results hMAM mRNA was found in 68/288 (23.6%) PE samples of which 51 were from the 155 patients diagnosed with malignant diseases and 17 were from the 133 patients diagnosed with non-malignant diseases. A significant correlation between hMAM expression and malignancy was found (OR=3.04) and the DPP were as follows: sensitivity=32.9%, specificity=87.2%, accuracy=58.0%, positive predictive value=75.0% and negative predictive value=52.7%. Among the patients with negative thoracoscopy (n=133), 5/17 (29.4%) hMAM-positive patients had or developed a tumor during the 18-month follow up period, as compared to 10/116 (8.6%) hMAM-negative patients (relative risk of 4.6 for developing a malignancy). Conclusion These findings suggest a possible application of hMAM RT-PCR detection in PE as to identify a false-negative thoracoscopy in non-specific pleuritis.

We describe a 70 year old woman affected by diffuse pulmonary lymphoid hyperplasia (DPLH). DPLH is a rare clinical-pathological entity generally associated with connective tissue diseases, but we diagnosed our case as an idiopathic DPLH. To the best of our knowledge, this is the first case of idiopathic DPLH reported in medical literature.

We report a case of acute fibrinous and organising pneumonia in Whipple’s disease with lung improvement after antibiotic therapy. In our knowledge this is the first report of Whipple’s disease with acute fibrinous and organising pneumonia.

Purpose: Dysregulated cytokine/cytokine receptor expression may occur in B-cell lymphoproliferative disorders. Little information is available on interleukin-18 receptor (IL-18R) and IL-18 expression in normal and malignant B cells. Our purpose was to investigate this issue in human naive, germinal center (GC) and memory B cells, and in their neoplastic counterparts. Experimental Design: We have evaluated IL-18 expression and production in tonsil naive, GC, and memory B cells and in their presumed neoplastic counterparts by reverse transcription-PCR and ELISA. Moreover, IL-18Rα and β expression was investigated in the same cells by reverse transcription-PCR, flow cytometry, and immunohistochemistry. Results: We found that: (a) IL-18 mRNA was expressed in tonsil naive, GC, and memory B cells. Bioactive IL-18 was secreted by naive and GC, but not by memory B cells; (b) IL-18Rα and β transcripts were expressed in the three B-cell subsets. IL-18Rα was detected on the surface of naive, GC, and memory B lymphocytes, and IL-18Rβ was detected on GC and memory, but not naive, B cells; (c) mantle zone, follicular, marginal zone, Burkitt lymphoma (BL), and B-cell chronic lymphocytic leukemia (B-CLL) cells expressed IL-18 mRNA. B-CLL and BL cells did not produce bioactive IL-18; and (d) lymphoma B cells displayed heterogeneous expression of either or both IL-18R chain mRNA. In contrast, B-CLL cells expressed both IL-18R chains at the mRNA and protein levels. Conclusions: Dysregulated expression of IL-18 and/or IL-18R in chronic B-cell lymphoproliferative disorders may sometimes contribute to tumor escape from the host immune system.

Splenosis can be considered as a benign condition due to the presence of heterotopic splenic tissue in abdomen, thorax and pelvis because of a massive splenic trauma or surgery. Here we report the case of a patient with an unknown hepatic mass, chronic hepatitis C, liver cirrhosis and a previous splenectomy after abdominal trauma. In our case lesion could not be clearly defined by ultrasound, computed tomography and magnetic resonance. Classical features of malignancy were not demonstrated at computed tomography, while at magnetic resonance imaging the differential diagnosis of the lesion appeared quite difficult and debate. Then an ultrasound-guided biopsy demonstrated the liver mass in left hepatic lobe consisted of splenic tissue and some millimetric accessory spleens in the left upper quadrant. So the possibility of an intra-hepatic splenosis should be taken into account in patients with an unknown liver mass and a history of previous abdominal trauma, followed by splenectomy. The conclusive diagnosis of intra-hepatic splenosis was given by ultrasound-guided biopsy.

In this study, immunoglobulin variable (Ig V) region genes, c-myc re-arrangement and sequence and p53 status were analyzed in clones derived from a Burkitt's lymphoma cell line (LAM) in which it was previously demonstrated that Epstein-Barr virus (EBV) infection occurred late during lymphomagenesis. Such evidence was based on the finding that 2 groups of cellular clones, characterized by the same c-myc re-arrangement but different EBV-fused termini, were obtained from the LAM cell line. The Ig V gene sequences were identical for the 2 groups of clones with different EBV-fused termini. The Ig variable heavy (VH) gene sequence displayed a substantial accumulation of point mutations (but no intra-clonal diversification), whereas the productive Ig V lambda (Vλ) gene sequence was virtually unmutated. Studies on the Ig V kappa (Vκ) locus suggested a receptor revision event (with a switch from κ to λ chain production) prior to EBV infection. Likewise, it was determined that the mutations observed in both p53 alleles and in the re-arranged c-myc gene occurred before EBV infection. Based on these findings, we present a model for the various steps of lymphomagenesis. It is proposed that stimulation by an antigen or a superantigen initially favored the clonal expansion and accumulation of other cytogenetic changes, including those involved in receptor editing. These events occurred prior to or during the germinal center (GC) phase of B-cell maturation. Thereafter, possibly upon exit of the cells from the GC, EBV infection occurred, further promoting lymphomagenesis. Int. J. Cancer 88:744–750, 2000. © 2000 Wiley-Liss, Inc.

This report discusses the association of ovarian lymphoma and hydroureteronephrosis managed by laparoscopic surgery and endoscopy., Introduction: Ovarian lymphoma is a rare entity, and hydronephrosis from lymphoma is even rarer. Most reports describe a laparoscopic approach to the disease, but we report a case of hydroureteronephrosis associated with ovarian lymphoma managed completely by mini-invasive techniques. Case Report: A 51-year-old woman was referred to us for back pain and renal colic and computed tomography scan findings of right hydroureteronephrosis and a mass in the right mesorectum and uterosacral ligament. After magnetic resonance imaging was performed, the patient underwent laparoscopic adnexectomy and ureterolysis after ureteroscopy and stenting. Histology results showed diffuse B-cell lymphoma of the ovary occluding the ureter without infiltration. The patient has undergone 6 cycles of chemotherapy. Discussion: This is the first report to describe ovarian lymphoma and hydroureteronephrosis managed completely by laparoscopic surgery and endoscopy. Frequency in clinical practice, differential diagnosis, and endoscopic approach are discussed. The advantages of a multidisciplinary endoscopic team are underlined.

The aim of this study based on the third phase of the architecture of diagnostic research was to assess the sensitivity and specificity of soluble mesothelin-related peptide (SMRP) in pleural exudative effusions (PE) compared to the histology obtained by medical thoracoscopy as the diagnostic gold standard examination. We assessed 104 consecutive thoracoscopies. SMRP concentrations were obtained using an ELISA test. We had 34 mesotheliomas (25 epithelioid and 9 sarcomatoid), 35 pleural metastases, and 35 benign diseases. PE-SMRP were significantly higher in patients with epitheliomorphic mesothelioma (mean ± SD 46.55 ± 44.29 nM) than in patients with sarcomatoid mesothelioma (16.11 ± 25.02 nM; p = 0.061), pleural metastasis (7.52 ± 10.77 nM; p < 0.0001), or benign diseases (5.82 ± 8.86 nM; p < 0.0001). Using ROC curve analysis, PE-SMRP offered an AUC of 0.767 in its ability to differentiate between patients with mesothelioma and all other diagnoses. The diagnostic sensitivity and specificity of PE-SMRP for distinguishing mesothelioma from all other causes of pleural effusion, at a cut-off value of 19.6 nM, were 58.8 and 97.1 %, respectively. PE-SMRP higher than the assumed cut-off of 19.6 nM were observed in 18/25 (72.0%) epitheliomorphic mesotheliomas, 2/9 (22.2%) sarcomatoid mesotheliomas, 5/35 (14.3%) pleural metastases, and 1/35 (2.9%) benign diseases. We conclude that PE-SMRP adds some clinical information in the work-up of patients with a PE of unknown origin: (1) thoracoscopy should always be done in patients with a positive mesothelin; (2) a negative mesothelin does not exclude a malignant disease.

We investigated the association of circulating tumor cells (CTC) with poor prognostic markers in breast cancer (BC) at time of diagnosis. Peripheral blood (PB) samples from 190 patients with invasive BC, 12 patients with in situ BC, before theraphy and/or surgery, and 330 from patients without BC were tested for CTCs by RT-PCR for human mammaglobin (hMAM). hMAM was expressed only in PB of invasive BC (9.5%) and a significant correlation was found between CTCs with lymph node involvement, tumour size and negative ER. We conclude that CTC detention in invasive BC may be an additional poor prognostic indicator.

HER2 expression or gene amplification is crucial for performing targeted theraphy. We assessed p185HER2 (p185) expression, HER2 amplification and copy number of chromosome 17 centromere (CEP17) in pancreatic adenocarcinoma (PAC). We analyzed 26 tumours at diagnosis, 21 metastatic lymph nodes (mLN) and 38 distant metastases (mTS) by immunohistochemistry and by FISH. p185 overexpression was shown in 4% of primary PAC, 6% of mLN and 29% of mTS. Amplification was found restricted to 10% of the mTS and increased CEP17 in 21% of mTS and 16% of mLN. Overexpression of p185 was present in all amplified cases but in only 36% of increased CEP17. In conclusion HER2 amplification and increased CEP17 were mainly related to mTS or mLN and increased CEP17 was not always linked to overexpression of p185.

As was reported that human mammaglobin (hMAM) may be expressed in malignant pleural effusions (PEs), we investigated the relevance of hMAM reverse-transcriptase polymerase chain reaction (RT-PCR) for their diagnosis and determination of primary origin. Two hundred and twenty-eight malignant (132 male, 96 female) and 185 benign (132 male, 53 female) PEs were investigated. Statistical analyses evaluated the diagnostic performance parameters in all PEs and in cytologically negative malignant PEs, the association between hMAM and benign or malignant status by the direct index of correlation [diagnostic odds ratio (DOR)], chi test, and P value (P). In addition, the discriminative diagnostic power of hMAM expression, independently in breast cancer, lung cancer (LC), malignant mesothelioma (MM), and other cancers was evaluated. In the entire patient population, hMAM was detected in 45.6% and 5.4% of malignant and benign PEs, respectively, in the male group in 41.7% and 4.5% and in the female group in 51.0% and 7.5% of malignant and benign PEs, respectively. A statistically significant correlation between hMAM and malignancy was found in the entire population (DOR=14.68, P

Leptomeningeal (LM) carcinomatosis is an increasing clinical complication in patients with advanced breast cancer (BC). The LM carcinomatosis diagnostic procedures rely mainly on cerebrospinal fluid (CSF) cytology, although both the amount of CSF and the number of malignant cells remain limiting factors. Therefore, efforts should be made to design new highly sensitive diagnostic tools to detect malignant cells in CSF of BC patients with LM carcinomatosis. In this study, the human Mammaglobin (hMAM) mRNA amplification by RT-PCR was employed to detect metastatic cells in CSF and thus, to diagnose LM carcinomatosis in a BC patient. Our data demonstrate that hMAM transcripts are expressed in the CSF of a BC patient with LM carcinomatosis, hence making RT-PCR for hMAM a potentially suitable test to identify occult BC cells in the brain.

In Burkitt's lymphoma (BL) cells due to a t(8;14) chromosomal translocation c-myc is often placed in proximity to the Emu enhancer of the Ig locus and upregulated. We demonstrated that in BL cells a peptide nucleic acid (PNA), complementary to intronic Emu sequences (PNAEmuwt), specifically blocks the expression of the c-myc oncogene under the Emu enhancer control and inhibits BL cell growth in culture. Here, we investigated whether PNAEmuwt was also able to block tumor growth in SCID mice inoculated with human BL cell lines. After subcutaneous inoculum in mice BL cells reproducibly form tumors. Both pre-treatment of BL cells with PNAEmuwt before inoculum and chronic intravenous administration of PNAEmuwt to mice already inoculated with BL cells selectively caused increased latency of tumor appearance and decreased final tumor size. Tumors from PNAEmuwt-treated animals showed substantial areas of cell necrosis and of c-myc downregulation. Inhibition of tumor growth was specific and was not observed with PNAEmumut carrying sequence mutations and in BL cell lines where the translocated c-myc is not under the control of the Emu enhancer. These data confirm the potential therapeutic value of PNA targeted to regulatory non-coding regions.

Four cases of gastric carcinoma are described that are associated with an osteoclast-like giant cell (OGC) stromal component. The patients were all middle-aged men (range 53-63 years). Microscopically, the tumors were characterized by a bland cytologic appearance, and an either solid or cribriform pattern. Osteoclast-like giant cells were found adjacent to, or intimately intermixed with, the neoplastic cells in the primary gastric masses and in the lymph nodal metastases and were often associated with lymphocytes, histiocytes, and desmoplastic stroma. By immunohistochemistry, mononuclear cells and OGCs showed diffuse positivity for alpha-l-antichymotrypsin, alpha-1-antitrypsin, and CD68. Neoplastic cells that were positive for keratin and CEA, also showed reactivity for vimentin and the latent membrane protein of Epstein-Barr virus in one case. At follow-up, three patients had died at 13, 15, and 24 months after diagnosis, and one is still alive, without evidence of disease, after 120 months. This report describes a novel variant of gastric carcinoma with distinctive and histologic features. (Key words : Stomach ; Carcinoma ; Osteoclast-like giant cell ; Immunohistochemistry; Epstein-Barr virus ; Prognosis ; Gastric neoplasm) Am J Clin Pathol 1995 ;103 :453-459.

10534 Background: It has been reported that application of the RT-PCR test for human mammaglobin (hMAM) may provide diagnostic information to evaluate the neoplastic origin of pleural effusion (PE). Our main goal was to assess the value of hMAM RT-PCR as an adjunctive test to thoracoscopic biopsy which represents the conventional gold standard in PE diagnosis. Methods: This study included 288 patients who underwent thoracoscopy. Histological analysis of pleural biopsies showed malignant diseases (MT) in 155/288 (53.8%) patients and non-malignant diseases (NMT) in 133/288 (46.2%) patients. The cells obtained from PE were analyzed by a nested RT-PCR protocol for hMAM mRNA gene detection. We evaluated the association between hMAM expression and MT vs NMT status by the diagnostic odds ratio (DOR). The diagnostic performance parameters of sensitivity (Se), specificity (Sp), accuracy (Ac), predictive positive value (PPV), predictive negative value (PNV) were also analysed. In addition, the relative risk of canc...

BACKGROUND. Risk of basal cell carcinoma (BCC) recurrence appears to be related to tumor location, tumor size, treatment modality, radicalness of excision, and histologic type. Recurrences of BCC on the trunk and extremities are rare, with 97% of all recurrent lesions being located in the head and neck region. OBJECTIVE. This report concerns a man who had a BCC of the back removed with electrodesiccation and curettage in 1980 at the age of 36. In the following 10 years the patient experienced five recurrences and finally developed infiltration of the thoracic spine that precluded further attempts at radical excision of the neoplasm. METHODS AND RESULTS. The pathology of the BCC in our patient revealed a number of histologic features that have been associated with aggressive behaviour. These include an infiltrative growth pattern characterized by an irregular and acute tapered profile of the tumor cell groups and fibroblast-rich stroma, infiltrating invading tumour edges, poorly peripheral palisading, nuclear pleomorphism, and perineural invasion. CONCLUSION. Basal cell carcinomas that occur in sunlight-protected areas of the trunk of middle-aged individuals can occasionally exhibit aggressive and highly invasive features as well as a marked tendency for local uncontrollable recurrences. The prognosis for patients with this variety of BCC is poor, especially when progressive infiltration of deep tissues does not permit, as in our case, any possible further radical surgical procedure.

1112 Background: Detection of breast cancer (BC) cells in pleural effusions (PE) is usually achieved by routine cytomorphology. However, the diagnosis of PE by this methodology shows scarce sensiti...

Three cases of acantholytic squamous-cell carcinoma of the breast are reported. They all had histological features resembling those of angiosarcoma or adenocarcinoma. They were not angiosarcoma, since in all three cases areas of squamous differentiation were present; in addition, the neoplastic cells were negative when stained for factor VIII, but were positive with anti-epidermal keratin. The glandular pattern exhibited, especially in Case 2, was difficult to differentiate from that of an ordinary carcinoma. However, the presence of dyskeratotic cells within the lumina, and the absence of alcian blue/periodic acid-Schiff positive material, and epithelial membrane antigen staining, were evidence against the diagnosis of adenocarcinoma. The patients died 5, 6, and 16 months after the diagnosis. Tumors with these histological features may have a very aggressive clinical course.

Eleven cases of Masson's hemangioendothelioma are reported. This benign condition must be distinguished histologically from numerous malignant endothelial lesions. Two different papillary structures were observed; one defined as « inflammatory papilla » was constantly associated with a thrombus; the other, defined as «fibrous papilla» was observed in 4 cases where no thrombus could be found. It is postulated that the inflammatory papillae are an exuberant endothelial growth during the normal organisation of a thrombus; fibrous papillae, it is suggested, might be reactive to blood or lymph stasis.

A case of primary oat cell carcinoma of the esophagus is described. The oat cell pattern appeared intermingled with small areas of squamous carcinoma. The origin of this mixed tumor is discussed together with the literature on esophageal carcinomas with an oat cell pattern.