Matrix metalloproteinases (MMPs) have long been associated with cancer-cell invasion and metastasis. This provided the rationale for clinical trials of MMP inhibitors, unfortunately with disappointing results. We now know, however, that the MMPs have functions other than promotion of invasion, have substrates other than components of the extracellular matrix, and that they function before invasion in the development of cancer. With this knowledge in hand, can we rethink the use of MMP inhibitors in the clinic?

New functions for the matrix metalloproteinases in cancer progression

The integrin family of cell adhesion receptors regulates a diverse array of cellular functions crucial to the initiation, progression and metastasis of solid tumours. The importance of integrins in several cell types that affect tumour progression has made them an appealing target for cancer therapy. Integrin antagonists, including the alphavbeta3 and alphavbeta5 inhibitor cilengitide, have shown encouraging activity in Phase II clinical trials and cilengitide is currently being tested in a Phase III trial in patients with glioblastoma. These exciting clinical developments emphasize the need to identify how integrin antagonists influence the tumour and its microenvironment.

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Integrins in cancer: biological implications and therapeutic opportunities

Depletion of Carcinoma-Associated Fibroblasts and Fibrosis Induces Immunosuppression and Accelerates Pancreas Cancer with Reduced Survival.

The different compartments of the gastrointestinal tract are inhabited by populations of micro-organisms. By far the most important predominant populations are in the colon where a true symbiosis with the host exists that is a key for well-being and health. For such a microbiota, 'normobiosis' characterises a composition of the gut 'ecosystem' in which micro-organisms with potential health benefits predominate in number over potentially harmful ones, in contrast to 'dysbiosis', in which one or a few potentially harmful micro-organisms are dominant, thus creating a disease-prone situation. The present document has been written by a group of both academic and industry experts (in the ILSI Europe Prebiotic Expert Group and Prebiotic Task Force, respectively). It does not aim to propose a new definition of a prebiotic nor to identify which food products are classified as prebiotic but rather to validate and expand the original idea of the prebiotic concept (that can be translated in 'prebiotic effects'), defined as: 'The selective stimulation of growth and/or activity(ies) of one or a limited number of microbial genus(era)/species in the gut microbiota that confer(s) health benefits to the host.' Thanks to the methodological and fundamental research of microbiologists, immense progress has very recently been made in our understanding of the gut microbiota. A large number of human intervention studies have been performed that have demonstrated that dietary consumption of certain food products can result in statistically significant changes in the composition of the gut microbiota in line with the prebiotic concept. Thus the prebiotic effect is now a well-established scientific fact. The more data are accumulating, the more it will be recognised that such changes in the microbiota's composition, especially increase in bifidobacteria, can be regarded as a marker of intestinal health. The review is divided in chapters that cover the major areas of nutrition research where a prebiotic effect has tentatively been investigated for potential health benefits. The prebiotic effect has been shown to associate with modulation of biomarkers and activity(ies) of the immune system. Confirming the studies in adults, it has been demonstrated that, in infant nutrition, the prebiotic effect includes a significant change of gut microbiota composition, especially an increase of faecal concentrations of bifidobacteria. This concomitantly improves stool quality (pH, SCFA, frequency and consistency), reduces the risk of gastroenteritis and infections, improves general well-being and reduces the incidence of allergic symptoms such as atopic eczema. Changes in the gut microbiota composition are classically considered as one of the many factors involved in the pathogenesis of either inflammatory bowel disease or irritable bowel syndrome. The use of particular food products with a prebiotic effect has thus been tested in clinical trials with the objective to improve the clinical activity and well-being of patients with such disorders. Promising beneficial effects have been demonstrated in some preliminary studies, including changes in gut microbiota composition (especially increase in bifidobacteria concentration). Often associated with toxic load and/or miscellaneous risk factors, colon cancer is another pathology for which a possible role of gut microbiota composition has been hypothesised. Numerous experimental studies have reported reduction in incidence of tumours and cancers after feeding specific food products with a prebiotic effect. Some of these studies (including one human trial) have also reported that, in such conditions, gut microbiota composition was modified (especially due to increased concentration of bifidobacteria). Dietary intake of particular food products with a prebiotic effect has been shown, especially in adolescents, but also tentatively in postmenopausal women, to increase Ca absorption as well as bone Ca accretion and bone mineral density. Recent data, both from experimental models and from human studies, support the beneficial effects of particular food products with prebiotic properties on energy homaeostasis, satiety regulation and body weight gain. Together, with data in obese animals and patients, these studies support the hypothesis that gut microbiota composition (especially the number of bifidobacteria) may contribute to modulate metabolic processes associated with syndrome X, especially obesity and diabetes type 2. It is plausible, even though not exclusive, that these effects are linked to the microbiota-induced changes and it is feasible to conclude that their mechanisms fit into the prebiotic effect. However, the role of such changes in these health benefits remains to be definitively proven. As a result of the research activity that followed the publication of the prebiotic concept 15 years ago, it has become clear that products that cause a selective modification in the gut microbiota's composition and/or activity(ies) and thus strengthens normobiosis could either induce beneficial physiological effects in the colon and also in extra-intestinal compartments or contribute towards reducing the risk of dysbiosis and associated intestinal and systemic pathologies.

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Prebiotic effects: metabolic and health benefits.

Cutaneous melanin pigment plays a critical role in camouflage, mimicry, social communication, and protection against harmful effects of solar radiation. Melanogenesis is under complex regulatory control by multiple agents interacting via pathways activated by receptor-dependent and -independent mechanisms, in hormonal, auto-, para-, or intracrine fashion. Because of the multidirectional nature and heterogeneous character of the melanogenesis modifying agents, its controlling factors are not organized into simple linear sequences, but they interphase instead in a multidimensional network, with extensive functional overlapping with connections arranged both in series and in parallel. The most important positive regulator of melanogenesis is the MC1 receptor with its ligands melanocortins and ACTH, whereas among the negative regulators agouti protein stands out, determining intensity of melanogenesis and also the type of melanin synthesized. Within the context of the skin as a stress organ, melanogenic activity serves as a unique molecular sensor and transducer of noxious signals and as regulator of local homeostasis. In keeping with these multiple roles, melanogenesis is controlled by a highly structured system, active since early embryogenesis and capable of superselective functional regulation that may reach down to the cellular level represented by single melanocytes. Indeed, the significance of melanogenesis extends beyond the mere assignment of a color trait.

https://www.physiology.org/doi/pdf/10.1152/physrev.00044.2003

Melanin Pigmentation in Mammalian Skin and Its Hormonal Regulation

Background: Exocrine (acinar) destruction and endocrine (islet) preservation in chronic pancreatitis (CP) is related to differential apoptotic indices within these cellular compartments.

Aim: To define the role of cell cycle regulatory proteins in the control of pancreatic epithelial cell apoptosis.

Methods: Formalin-fixed, paraffin-embedded tissue from six cases of CP and eight normal controls (N) were studied using immunohistochemistry for BCl-2, Bax, retinoblastoma protein (Rb) and Fas ligand (Fas-L). Labelling patterns were assessed using semi-quantitative (intensity-proportion [I-P]) or fully quantitative (labelling index [LI]) analysis.

Results: Rb protein was expressed at a higher level by acinar cells in CP than N (mean acinar cell Rb LI 1.45% in CP and 0.437% in N; p<0.05) but this difference was not observed within islet cells. BCl-2 was more strongly expressed by acinar than islet cells in CP and N (e.g. N mean BCl-2 I-P score 4.88 in acini and 0.375 in islets; p<0.05) while Bax was strongly expressed by a subset of islet cells and weakly by centroacinar cells (e.g. N mean Bax I-P score 1.75 in acini and 4.31 in islets; p<0.05). Fas-L was more strongly expressed by islet than acinar cells in CP and N (e.g. CP mean Fas-L I-P score 5.67 in islets and 2.83 in acini; p<0.01).

Conclusion: Strong BCl-2 expression by acinar cells and of Bax by islet cells was an unexpected result and indicates complex control of apoptosis within these cell populations. Increased Rb protein expression by acinar cells in CP may differentially promote apoptosis within these cells. Fas-L expression by islet cells may protect islets from apoptosis by promoting apoptosis of cytotoxic T-lymphocytes.

# 241. THE EFFECT OF SELECTIVE INHIBITION OF INDUCIBLE NITRIC OXIDE SYNTHASE ON THE OUTCOME OF SEVERE ACUTE PANCREATITIS {#article-title-2}

Background: Nitric oxide (NO), overproduced by inducible NO synthase (iNOS), has been established as a key inflammatory mediator in systemic inflammatory response syndrome leading to multiple organ failure.

Aim: To examine the effect of …

240. fas-ligand protects islet cells from apoptosis in chronic pancreatitis

/pdf/p228-igg4-positive-plasma-cells-in-the-colon-of-patients-39emtamdo1.pdf

P228 IgG4-positive plasma cells in the colon of patients with ulcerative colitis are markers of endoscopic and histological disease activity

Influence of cytokine gene polymorphisms on susceptibility to and prognosis in breast cancer

This report describes a tumour in the ileum with clinical features initially suggestive of a gastrointestinal stromal tumour (GIST). Histopathological examination revealed a biphasic tumour in which the spindle cell component showed immunohistochemical evidence of smooth muscle differentiation but without the characteristic profile of a GIST. A well-differentiated epithelial component was also present, comprising glandular structures with immunohistochemical features suggestive of Mullerian differentiation. Similar glandular differentiation has been described in uterine leiomyomas but not, to our knowledge, in tumours associated with the small bowel. None of the characteristic mutations of GISTs were identified in this case. There were no overt features of malignancy but, because of the unusual nature of the case, we assessed the biological behaviour as uncertain.

https://jcp.bmj.com/content/jclinpath/62/6/555.full.pdf?62%2F6%2F555=

Spindle cell tumour with glandular elements: an unusual ileal neoplasm

Introduction Management of patients with locally advanced (LA) and locally recurrent (LR) colorectal cancer is challenging, with patients frequently requiring complex multimodality interventions. Despite increasing emphasis on evaluation of health related quality of life (HRQoL) in patients having complex interventions, HRQoL information on patients with LA and LR colorectal cancer is sparse. The aim of this study was to prospectively assess outcome measures and HRQoL in a cohort of patients with LA and LR colorectal cancer at our institution. Methods LA disease was defined as tumour requiring extended multi-visceral resection in the abdomen or pelvis to achieve an R0 resection. 45 consecutive patients were prospectively assessed over a 2-year period. Demographic, treatment, and cancer-related outcomes were recorded on all patients. Pelvic disease was staged using Leeds and Royal Marsden Hospital classification systems. HRQoL was prospectively evaluated using the EORTC generic and disease specific instruments QLQ-CR30 and QLQ-CR29. Results Median age was 69 (range 46–89) and 60% were male (27/45). There were 25 cases of LA disease and 20 LR cases. 35 patients underwent surgery while 10 patients had non-surgical palliation. R0 resection rate was 94%. HRQoL data were available on 41 patients. Median global health status was 65 (95% CI 55.5 to 74.1), physical functioning 77 (95% CI 69.9 to 84.5), and social functioning 72 (95% CI 60.3 to 83.8), which compared favourably with published EORTC reference values. Global health status and pain were significantly better in patients having surgery compared to non-surgical palliation (p Conclusion In carefully selected patients, HRQoL after radical multimodality treatment for LA and LR colorectal cancer is acceptable, and gives better results than palliation. Competing interests None declared.

https://gut.bmj.com/content/gutjnl/61/Suppl_2/A337.1.full.pdf

PWE-099 Contribution of surgery and disease subtype to health related quality of life in patients with locally advanced and recurrent colorectal cancer

Adrian C Bateman

Papers

240. fas-ligand protects islet cells from apoptosis in chronic pancreatitis

P228 IgG4-positive plasma cells in the colon of patients with ulcerative colitis are markers of endoscopic and histological disease activity

Influence of cytokine gene polymorphisms on susceptibility to and prognosis in breast cancer

Spindle cell tumour with glandular elements: an unusual ileal neoplasm

PWE-099 Contribution of surgery and disease subtype to health related quality of life in patients with locally advanced and recurrent colorectal cancer