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Background Early onset (≤50y) colorectal carcinomas (EO-CRCs) are increasing in incidence according to epidemiological data. We investigated clinical-pathological, molecular features and outcomes of 62 left sided EO-CRCs (EOLS-CRCs) and compared them to a group of late onset (≥65) LS-CRCs (LOLS-CRCs). Materials and methods Samples were evaluated for pathological features and microsatellite instability (MSI). Overall survival (OS), disease free survival (DFS) and disease specific survival were evaluated in both groups. Results Five out 62 (8%) EOLS-CRCs showed MSI phenotype. Interestingly these cases were aged 26–39y. Most EOLS-CRCs present at advanced stage and this was statistically significant when compared to LOLS-CRCs. OS was better in EOLS-CRCs whilst DFS showed a worst profile in EOLS-CRCs either in low and high stages even though young patients were treated more often with adjuvant chemotherapy compared to older ones at the same disease stage. Conclusions Most EOLS-CRCs are sporadic non Lynch, microsatellite stable (MSS) CRCs. Our data show that when compared with LOLS-CRCs the early group represents an aggressive disease with worst outcome underlining a possible different carcinogenic pathway.

The up-regulation of "tissue" transglutaminase (TG2) gene has been shown to occur in various pathologies and can lead to severe liver injury; however, its role in the onset of liver damage has not yet been clarified. To address this issue, we have used two experimental settings: carbon tetrachloride (CCl(4))-induced liver injury in wild-type and TG2 knockout mice; and liver biopsies obtained from a large cohort of hepatitis C virus (HCV)-infected patients. Mice lacking TG2 failed to clear the hepatic necrotic tissue formed in response to prolonged CCl(4) exposure (5 weeks) and 60% of them died before the end of the treatment. By contrast, wild-type mice were able to recover after the toxic insult. CCl(4)-treated TG2 null mice showed a derangement of the hepatic lobular architecture and a progressive accumulation of extracellular matrix (ECM) components and inflammatory cells which were not observed in the liver of control animals. Consistent with this protective role, we observed that TG2 levels were much higher (up to 15-fold) during the initial stages of liver fibrosis in HCV-infected individuals (METAVIR = F2) compared with uninfected controls, in which the enzyme protein localized in the hepatocytes facing the periportal infiltrate. By contrast, the enzyme levels decreased in the advanced stages (METAVIR = F3 and F4) and their localization was limited to the ECM. Our data demonstrate that TG2 plays a protective role in the liver injury by favoring tissue stability and repair.

Tissue distribution of dendritic cells was investigated in eight cases of papillary carcinoma of the thyroid using immunohistochemistry. Most dendritic cells had an immature phenotype (CD1a++, CD11c+, CD40+, CD86−, HLA-DR−) and were located at the invasion edge of the tumor. This pattern of distribution was profoundly different from that of CD68+ macrophages, which were evenly distributed throughout the tumor. The ability of tumor cells to release chemotactic factors active on dendritic cells was investigated in primary cultures of the same cases of papillary carcinoma, and was compared to that of the corresponding normal thyroid cells obtained from the tumor-free contralateral lobe. Chemotactic activity of culture supernatants was tested against dendritic cells in a chemotaxis chamber. It was found that papillary carcinoma cells were active in releasing chemotactic activity, that hepatocyte growth factor (HGF; 100 ng/ml) or interleukin (IL)-1β (103 U/ml) induced a fourfold increase in the amount of chemotactic activity released, and that normal thyroid cells obtained from the same patients were as effective as tumor cells. Characterization of chemokines at RNA level revealed that unstimulated cells contain large amounts of IL-8 and monocyte chemotactic protein (MCP)-1 RNAs, and that stimulation with HGF or IL-1β induced RNAs for regulated upon activation normal T expressed and secreted (RANTES), macrophage inflammatory protein (MIP)-3α, interferon-γ-inducible protein 10 (IP-10), and, to a lesser extent, MIP-1α and MIP-1β. The possibility that HGF/Met interaction has a biological role in vivo was investigated in serial sections of six tumors immunostained for CD1a+, Met protein, and HGF. It was found that all six tumors were intensely and diffusely positive for Met protein, that HGF staining was present in tumor cells of the advancing edge, and that HGF+/Met+ tumor cell nests were infiltrated by CD1a+ dendritic cells. The foregoing observations are consistent with the possibility that HGF stimulation of Met+ tumor cells is one of the molecular mechanisms involved in the recruitment of dendritic cells.

Chemokines are a superfamily of structurally related cytokines involved in leukocyte recruitment in normal and neoplastic tissues. The availability of non-cross-reacting reagents specific for each member of the C-C and C-X-C family is important for careful characterization of their in vitro and in vivo production and relevance. Here we describe a novel, highly specific, mAb against monocyte chemotactic protein-1 (MCP-1). The 5D3-F7 mAb (IgG1,kappa) recognizes human recombinant and natural MCP-1 in ELISA, immunoprecipitation and immunoblot analysis. As a source of natural MCP-1 we used the 8387 human sarcoma line which produces spontaneously MCP-1 and responds to TNF with increased expression and release. The 5D3-F7 mAb inhibited the chemotactic activity of MCP-1 for monocytes. Using the 5D3-F7 mAb and a polyclonal rabbit anti-MCP-1 serum, a sandwich ELISA was developed. In both the direct and the sandwich ELISA, the 5D3-F7 mAb recognized human MCP-1, but not the closely related C-C chemokines MCP-1, MCP-2, MCP-3, MIP-1 alpha, and RANTES and the C-X-C chemokines IL-8, gro alpha and NAP-2. In culture supernatants the sensitivity of the sandwich ELISA was approximately equal to 30 pg/ml. The sandwich ELISA permitted detection of MCP-1 in resting or cytokine-stimulated endothelial, mesothelial and Kaposi's sarcoma cells. Preliminary immunohistochemical analysis revealed production of MCP-1 by macrophage-like cells at sites of inflammation. The 5D3-F7 mAb provides a novel, highly specific reagent with which to investigate the in vitro and in vivo production and role of MCP-1.

With the aim of assessing the role of surgery in the management of isolated mediastinal lymphoma, we have reviewed the data of 123 operations performed on 102 patients (64 with Hodgkin's disease and 38 with non-Hodgkin's lymphoma). One death and four major complications occurred in these patients. Macroscopically radical resection was performed in 14 patients who are free of disease after 1 to 14 years. Debulking resection was performed in five patients: Three are alive after 5 to 11 years and two died after 36 and 40 months. Ten patients (seven with non-Hodgkin's lymphoma and three with Hodgkin's disease) had residual mediastinal masses of more than 2 cm after chemotherapy; to assess the nature of the lesion (fibrosis or residual disease), we subjected these patients to surgical restaging of the mediastinum: Results were negative in seven and positive in three. We conclude that open biopsy is indispensable to obtain good tissue specimens suitable for histologic and immunohistochemical assessment. Biopsy must be performed as a major surgical procedure to avoid reoperation: Mediastinoscopy and sternal splitting incisions proved the most reliable approaches. Locally radical or debulking resection might be considered in selected cases to enhance long-term results.

Introduction Bevacizumab (BEV) combined with chemotherapy prolongs PFS and OS in metastatic colorectal cancer (mCRC) independently of KRAS status. This study investigated the role of anti-vascular endothelial growth factor therapy on clinical response, mean progression-free survival (mPFS) and mean overall survival (mOS) according to KRAS status and metastatic sites. Methods 108 patients (pts) were treated with first-line FOLFIRI or FOLFOX chemotherapy in combination with BEV. Tissue samples were analyzed for DNA sequencing to identify KRAS mutations. Before therapy and after 3 months of chemotherapy pts were investigated with CT scan. Statistical association was evaluated by chi-square test and logistic regression analysis to objective response rate (RR). Results RR was available in 108 pts while mPFS and mOS in 106 pts. Overall, 45 (41.7%) pts had a stable disease, 43 (39.8%) showed a partial response, 4 (3,7%) complete response and 16 (14.8%) disease progression, accounting for RR of 43.5%. mPFS was 11.3 months and mOS was 26.9 months. 53 pts presented only hepatic metastases. RR was higher in pts with only hepatic metastasis as compared to those with extra-hepatic or multiple metastases, although the difference failed to reach a statistical significant (49% vs 39%; HR: 1.23; 95% CI: 0.79 – 1.90; p=0.36). In pts with only hepatic metastases mPFS was 12 months vs 11 months in pts with multiple metastatic sites or extra-hepatic metastases, while mOS was 24.8 months vs 27.1 months respectively. KRAS mutations were investigated in 108 patients. 69 patients were wild-type (wt 64%) while 39 patients were mutated ( mut 36%). RR was 49.3% in wt group vs 33,3% in mut group (HR: 0,51; 95% CI: 0,23 - 1,16; p=0.11), mPFS was 12.8 months in KRAS wt group vs 10 months in KRAS mut group and mOS was 28.8 months vs 23.9 months respectively. Conclusion RR in KRAS groups was different with an advantage in KRAS wt, but this difference was not statistical significant. mPFS and mOS tended to be higher in KRAS wt pts. There was evidence of not statistical significant advantage, in terms of clinical response to treatment with Bevacizumab, in pts with only hepatic metastases. Therefore in this subset of pts a favorable trend was demonstrated. Unfortunately, despite positive trend, an increase in mPFS and mOS compared to pts with extra-hepatic metastases or multiple metastatic sites was not shown.

A comparative study of antibody response in C3H/HeN and C3H/HeJ mice has demonstrated impairment of antibody formation against T-dependent antigens in C3H/HeJ mice. Antibody responses against sheep red blood cells and trinitrophenylated horse red blood cells were quantitated by number of plaque-forming cells per spleen and found to be about threefold higher in C3H/HeN mice than in C3H/HeJ mice. This difference was not influenced by route of antigen administration and persisted throughout the duration of antibody response. After immunization with 2,4-dinitrophenyl-keyhole limpet hemocyanin, anti-dinitrophenyl (DNP) antibody affinity was found to be about 10-fold higher in C3H/HeN mice as compared to that in C3H/HeJ mice. Moreover, there was no evidence of affinity maturation in mice of the latter strain. Unlike the immune response to T-dependent antigens, antibody production against T-independent antigens such as DNP and trinitrophenol-Ficoll was found quantitatively and qualitatively comparable in C3H/HeN and C3H/HeJ mice.

Summary Signet ring cell lymphoma is a non-Hodgkin's lymphoma, characterized by neoplastic lymphoid signet ring cells very similar to epithelial mucin producing cells. We describe here a case of signet ring cell lymphoma in which the immunophenotypic markers of signet ring cells parallel those of plasma cells, being intensively T10+ (CD 38), weakly HLA-DR+, and To 15 (CD 22) and T200 (CD 45) negative. The morphologic and immunohistochemical features of the case and the main differential diagnosis are preceded by a review of the literature.

After intraperitoneal injection of purified protein derivative of tubercle bacillus (PPD) into mice infected with Mycobacterium bovis , strain bacillus Calmette-Guerin (BCG), peritoneal exudate macrophages were cytotoxic to tumor cells in vitro . Peritoneal macrophages from BCG-immune mice not injected with antigen or from control mice injected with PPD were not cytotoxic. Tumoricidal macrophages were evident by 9 hr after a single injection of PPD into immune mice and persisted for 3 days; peritoneal cells were not cytotoxic on Day 4. A second injection of PPD on Day 2 prolonged the presence of cytotoxic macrophages for more than 6 days. PPD induction of tumoricidal macrophages was evident by 10 days after BCG immunization and in control mice after adoptive transfer of BCG-immune spleen cells. Intraperitoneal inoculation of PPD into immune mice was followed by the appearance of cytotoxic peroxidase-positive mononuclear phagocytes in the peritoneal exudate. Peroxidase-positive cells induced by peritoneal irritants were not cytotoxic. T-cell mitogens, phytohemagglutinin, and concanavalin A, as well as specific antigen, induced tumoricidal macrophages in vivo . Mitogen activation was more efficient in BCG-immune mice than in controls.