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Vigorita V.,University of Vigo | Ausania F.,University of Vigo | Bertucci Zoccali M.,Catholic University Med School | Alvarez C.F.,University of Vigo | And 2 more authors.
International Journal of Surgery Case Reports | Year: 2015

INTRODUCTION Primary intestinal melanoma is a rare entity, however the gastrointestinal tract, and particularly the small bowel, is a common site of recurrence from cutaneous melanoma.PRESENTATION OF CASE We report the case of a 48 year old woman with small bowel intussusception secondary to metastatic cutaneous melanoma, 15 years after excision of the primary tumor. The patient underwent an emergency small bowel resection with negative margins on final pathology.DISCUSSION Surgical resection is a palliative, yet necessary, procedure in the setting of small bowel obstruction due to intussusception secondary to intestinal metastatic melanoma. In case of bowel metastasis, presenting symptoms are nonspecific and do not provide significant clues to the differential diagnosis of the underlying disease. In some patients, complete surgical resection of early diagnosed bowel metastases is associated with prolonged survival. Systemic chemotherapy in these patients does not provide survival benefit.CONCLUSION The occurrence of bowel relapse after very long disease free interval, while highly unlikely in most tumors, should always be considered in the differential diagnosis of patients with previous history of cutaneous malignant melanoma presenting with gastrointestinal symptoms. © 2014 The Authors. Published by Elsevier Ltd.

Cesario A.,IRCCS San Raffaele Pisana | Rocca B.,Catholic University Med School | Rutella S.,IRCCS San Raffaele Pisana | Rutella S.,Catholic University Med School
Current Medicinal Chemistry | Year: 2011

The enzyme indoleamine 2,3-dioxygenase 1 (IDO1) degrades the essential amino acid tryptophan into kynurenine and other downstream metabolites that suppress effector T-cell function and favor the differentiation of regulatory T cells. IDO1 is traditionally viewed as a general suppressor of T-cell activation and mediator of immune escape in cancer. Recently, evidence has emerged to support a greater functional complexity of IDO1 as modifier of pathogenic inflammation. For instance, IDO1 activity may sustain autoantibody production by B cells, and elicit the development of cancer in the context of chronic inflammation. Cyclooxygenase (COX)-2 metabolizes the first enzymatic step in the conversion of arachidonic acid into prostanoids. In particular, prostaglandin (PG)E2 generated at sites of inflammation and/or immune response is mainly COX-2-derived and has pro-inflammatory and immune regulatory activities. Pharmacological blockade of COX-2 in animal models of cancer translates into down-regulation of IDO1 expression at tumor sites and decreased levels of kynurenine in the circulation, underpinning the view that IDO1 might be downstream of COX-2. This article reviews preclinical studies focusing on IDO1 and COX-2 as inter-related molecular targets for therapeutic intervention in chronic inflammation and cancer. COX-2 inhibition might, in principle, be pursued in cancer-associated inflammation characterized by IDO1 hyper-activity, with the foreseeable aim at altering the immune response within the tumor microenvironment. © 2011 Bentham Science Publishers Ltd.

Filippini P.,Systems Approaches and Non communicable Diseases | Del Papa N.,UOC Rheumatology Out patient Clinic | Sambataro D.,UO Internal Medicine | Del Bufalo A.,Catholic University Med School | And 4 more authors.
Current Medicinal Chemistry | Year: 2012

The enzyme indoleamine 2,3-dioxygenase 1 (IDO1) finely regulates both innate and adaptive immune responses through the degradation of the essential amino acid tryptophan into kynurenine and other downstream metabolites, which suppress effector T-cell function and promote the differentiation of regulatory T cells. A novel role for IDO1 as a signaling molecule and a modifier of innate inflammatory responses is now emerging. In particular, IDO1 can either support or antagonize inflammation in a context- and tissuedependent manner. Studies in experimental arthritis have unravelled a previously unappreciated role for IDO in controlling B-cell activation and autoantibody production. IDO dysregulation has been documented in patients with systemic lupus erythematosus, systemic sclerosis and Sjögren's syndrome, as well as in severe sepsis and chronic kidney disease. This article summarizes the contribution of IDO to the pathophysiology of inflammatory/autoimmune disorders, and discusses whether strategies to restore metabolic equilibrium in the kynurenine pathway might be pursued in diseases states such as rheumatoid arthritis and systemic sclerosis. © 2012 Bentham Science Publishers.

Bonanno G.,Catholic University Med School | Mariotti A.,Catholic University Med School | Procoli A.,Catholic University Med School | Folgiero V.,IRCCS Bambino Gesu Childrens Hospital | And 13 more authors.
Journal of Translational Medicine | Year: 2012

Background: Multiple myeloma (MM) is a plasma cell malignancy with a multifaceted immune dysfunction. Indoleamine 2,3-dioxygenase 1 (IDO1) degrades tryptophan into kynurenine (KYN), which inhibits effector T cells and promote regulatory T-cell (Treg) differentiation. It is presently unknown whether MM cells express IDO1 and whether IDO1 activity correlates with immune system impairment.Methods: We investigated IDO1 expression in 25 consecutive patients with symptomatic MM and in 7 patients with either monoclonal gammopathy of unknown significance (MGUS; n=3) or smoldering MM (SMM; n=4). IDO1-driven tryptophan breakdown was correlated with the release of hepatocyte growth factor (HGF) and with the frequency of Treg cells and NY-ESO-1-specific CD8+ T cells.Results: KYN was increased in 75% of patients with symptomatic MM and correlated with the expansion of CD4+CD25+FoxP3+ Treg cells and the contraction of NY-ESO-1-specific CD8+ T cells. In vitro, primary MM cells promoted the differentiation of allogeneic CD4+ T cells into bona fide CD4+CD25hiFoxP3hi Treg cells and suppressed IFN-γ/IL-2 secretion, while preserving IL-4 and IL-10 production. Both Treg expansion and inhibition of Th1 differentiation by MM cells were reverted, at least in part, by d,l-1-methyl-tryptophan, a chemical inhibitor of IDO. Notably, HGF levels were higher within the BM microenvironment of patients with IDO+ myeloma disease compared with patients having IDO- MM. Mechanistically, the antagonism of MET receptor for HGF with SU11274, a MET inhibitor, prevented HGF-induced AKT phosphorylation in MM cells and translated into reduced IDO protein levels and functional activity.Conclusions: These data suggest that IDO1 expression may contribute to immune suppression in patients with MM and possibly other HGF-producing cancers. © 2012 Bonanno et al.; licensee BioMed Central Ltd.

Bonanno G.,Catholic University Med School | Iudicone P.,Azienda Ospedaliera S. Camillo Forlanini | Mariotti A.,Catholic University Med School | Procoli A.,Catholic University Med School | And 8 more authors.
Journal of Translational Medicine | Year: 2010

Background: Cytokine-induced killer (CIK) cells are typically differentiated in vitro with interferon (IFN)-γ and αCD3 monoclonal antibodies (mAb), followed by the repeated provision of interleukin (IL)-2. It is presently unknown whether thymoglobulin (TG), a preparation of polyclonal rabbit γ immunoglobulins directed against human thymocytes, can improve the generation efficiency of CIK cells compared with αCD3 mAb in a clinical-grade culture protocol.Methods: Peripheral blood mononuclear cells (PBMC) from 10 healthy donors and 4 patients with solid cancer were primed with IFN-γ on day 0 and low (50 ng/ml), intermediate (250 ng/ml) and high (500 ng/ml) concentrations of either αCD3 mAb or TG on day 1, and were fed with IL-2 every 3 days for 21 days. Aliquots of cells were harvested weekly to monitor the expression of representative members of the killer-like immunoglobulin receptor (KIR), NK inhibitory receptor, NK activating receptor and NK triggering receptor families. We also quantified the frequency of bona fide regulatory T cells (Treg), a T-cell subset implicated in the down-regulation of anti-tumor immunity, and tested the in vitro cytotoxic activity of CIK cells against NK-sensitive, chronic myeloid leukaemia K562 cells.Results: CIK cells expanded more vigorously in cultures supplemented with intermediate and high concentrations of TG compared with 50 ng/ml αCD3 mAb. TG-driven CIK cells expressed a constellation of NK activating/inhibitory receptors, such as CD158a and CD158b, NKp46, NKG2D and NKG2A/CD94, released high quantities of IL-12p40 and efficiently lysed K562 target cells. Of interest, the frequency of Treg cells was lower at any time-point compared with PBMC cultures nurtured with αCD3 mAb. Cancer patient-derived CIK cells were also expanded after priming with TG, but they expressed lower levels of the NKp46 triggering receptor and NKG2D activating receptor, thus manifesting a reduced ability to lyse K562 cells.Conclusions: TG fosters the generation of functional CIK cells with no concomitant expansion of tumor-suppressive Treg cells. The culture conditions described herein should be applicable to cancer-bearing individuals, although the differentiation of fully functional CIK cells may be hindered in patients with advanced malignancies. © 2010 Bonanno et al; licensee BioMed Central Ltd.

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