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Colon cancer represents a paradigm for the connection between inflammation and cancer in terms of epidemiology and mechanistic studies in preclinical models. Key components of cancer promoting inflammation include master transcription factors (for example, nuclear factor κB, STAT3), proinflammatory cytokines (for example, tumor necrosis factor, interleukin-6 (IL-6)), cyclooxygenase-2 and selected chemokines (for example, CCL2). Of no less importance are mediators that keep inflammation in check, including IL-10, transforming growth factorβ, toll-like receptor and the IL-1 receptor inhibitor TIR8/SIGIRR, and the chemokine decoy and scavenger receptor D6. Dissection of molecular pathways involved in colitis-associated cancer may offer opportunities for innovative therapeutic strategies.

BackgroundCrohn's disease (CD) is a chronic disabling and progressive IBD. Only strategies looking beyond symptoms and based on tight monitoring of objective signs of inflammation such as mucosal lesions may have the potential for disease modification. Endoscopic evaluation is currently the gold standard to assess mucosal lesions and has become a major therapeutic endpoint in clinical trials. Several endoscopic indices have been proposed to evaluate disease activity; unvalidated and arbitrary definitions have been used in clinical trials for defining endoscopic response and endoscopic remission in CD.MethodsIn these recommendations from the International Organization for the Study of Inflammatory Bowel Disease, we first reviewed all technical aspects of available endoscopic scoring systems in the literature. Second, in order to achieve consensus on endoscopic definitions of remission and response in trials, a two-round vote based on a Delphi method was performed among 14 specialists in the field of IBDs.ResultsAt the end of the voting process, the investigators ranked first a >50% decrease in Simple Endoscopic Score for Crohn's Disease (SES-CD) or Crohn's Disease Endoscopic Index of Severity for the definition of endoscopic response, and an SES-CD 0–2 for the definition of endoscopic remission in CD. All experts agreed on a Rutgeerts’ score i0–i1 for the definition of endoscopic remission after surgery.

The Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) program was initiated by the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD). It examined potential treatment targets for inflammatory bowel disease (IBD) to be used for a \"treat-to-target\" clinical management strategy using an evidence-based expert consensus process. A Steering Committee of 28 IBD specialists developed recommendations based on a systematic literature review and expert opinion. Consensus was gained if ≥75% of participants scored the recommendation as 7-10 on a 10-point rating scale (where 10=agree completely). The group agreed upon 12 recommendations for ulcerative colitis (UC) and Crohn's disease (CD). The agreed target for UC was clinical/patient-reported outcome (PRO) remission (defined as resolution of rectal bleeding and diarrhea/altered bowel habit) and endoscopic remission (defined as a Mayo endoscopic subscore of 0-1). Histological remission was considered as an adjunctive goal. Clinical/PRO remission was also agreed upon as a target for CD and defined as resolution of abdominal pain and diarrhea/altered bowel habit; and endoscopic remission, defined as resolution of ulceration at ileocolonoscopy, or resolution of findings of inflammation on cross-sectional imaging in patients who cannot be adequately assessed with ileocolonoscopy. Biomarker remission (normal C-reactive protein (CRP) and calprotectin) was considered as an adjunctive target. Evidence- and consensus-based recommendations for selecting the goals for treat-to-target strategies in patients with IBD are made available. Prospective studies are needed to determine how these targets will change disease course and patients' quality of life.

Studies comparing magnetic resonance enterography (MRE) and computerized tomography enterography (CTE) for Crohn's disease (CD) are scarce.MethodsThe aim of this study was to prospectively compare the sensitivity, specificity, and accuracy of abdominal MRE and CTE to assess disease activity and complications (fistulas, strictures) in ileocolonic CD. A total of 44 patients (23 male; 21 female; mean age 44) with ileocolonic CD underwent both MR and CT in a short time interval (mean 5 days). A 16-slice CT with intravenous contrast and an MRI with oral and paramagnetic intravenous contrast were performed. Ileocolonoscopy was used as the reference standard. Sensitivity values of CT and MR for detection of extraenteric signs of disease were compared with the McNemar test, with results of imaging studies, surgery, and physical examination as reference standards.ResultsNo significant differences in sensitivity, specificity, and accuracy were observed between MRE and CTE regarding the following parameters at the patient level: localization of CD (P = 1.0), bowel wall thickening (P = 1.0), bowel wall enhancement (P = 1.0), enteroenteric fistulas (P = 0.08), detection of abdominal nodes (P = 1.0), and perivisceral fat enhancement (P = 0.31). MR was significantly superior compared to CT in detecting strictures (P = 0.04). Per segment analysis showed that MRE was significantly superior to CTE in detecting ileal wall enhancement (P = 0.02).ConclusionsMR and CT are equally accurate to assess disease activity and bowel damage in CD. MR may be superior to CT in detecting intestinal strictures and ileal wall enhancement. MR may represent an alternative technique to CT in assessing ileocolonic CD.

Although defects in intestinal barrier function are a key pathogenic factor in patients with inflammatory bowel diseases (IBDs), the molecular pathways driving disease-specific alterations of intestinal epithelial cells (IECs) are largely unknown. Here, we addressed this issue by characterizing the transcriptome of IECs from IBD patients using a genome-wide approach. We observed disease-specific alterations in IECs with markedly impaired Rho-A signaling in active IBD patients. Localization of epithelial Rho-A was shifted to the cytosol in IBDs, and inflammation was associated with suppressed Rho-A activation due to reduced expression of the Rho-A prenylation enzyme geranylgeranyltransferase-I (GGTase-I). Functionally, we found that mice with conditional loss of Rhoa or the gene encoding GGTase-I, Pggt1b, in IECs exhibit spontaneous chronic intestinal inflammation with accumulation of granulocytes and CD4+ T cells. This phenotype was associated with cytoskeleton rearrangement and aberrant cell shedding, ultimately leading to loss of epithelial integrity and subsequent inflammation. These findings uncover deficient prenylation of Rho-A as a key player in the pathogenesis of IBDs. As therapeutic triggering of Rho-A signaling suppressed intestinal inflammation in mice with GGTase-I-deficient IECs, our findings suggest new avenues for treatment of epithelial injury and mucosal inflammation in IBD patients.

The VERSIFY phase 3 trial in patients with Crohn's disease (CD) treated with vedolizumab was the first to include a substudy that used a standardized magnetic resonance enterography (MRE) protocol to assess features of transmural inflammation (bowel edema and wall thickness) and extramural disease activity (enlarged lymph nodes). Patients received intravenous vedolizumab (300 mg) at weeks 0 (baseline), 2, and 6, and then every 8 weeks for 26 or 52 weeks. Post hoc analyses included a subpopulation with a Magnetic Resonance Index of Activity score of ≥7 in at least one bowel segment at baseline and at least one postbaseline MRE assessment. Changes in transmural inflammation, including intramural bowel edema and wall thickness, were evaluated. Patient-level and segment-level analyses were performed. MRE images were evaluated in 27 patients with 83 evaluable bowel segments at baseline and week 26, and 13 patients with 38 evaluable segments at baseline, week 26, and week 52. At baseline, all patients had bowel wall edema and wall thickness of >3 mm in at least one bowel segment. The proportion of patients with edema decreased at weeks 26 (17/27 [63.0%]) and 52 (4/13 [30.8%]) and the proportion with bowel wall thickness of >3 mm decreased at weeks 26 (25/27 [92.6%]) and 52 (10/13 [76.9%]). In patients with CD treated with vedolizumab for 26 and 52 weeks, the number of patients, and bowel segments, with MRE-detected transmural inflammation was reduced. These results highlight the impact of vedolizumab on components of transmural inflammation in CD and demonstrate that using MRE in CD multicenter clinical trials is feasible. ClinicalTrials.gov NCT02425111, April 23, 2015, http://www.clinicaltrials.gov NCT02425111; EU Clinical Trials Register EudraCT 2014-003509-13, https://www.clinicaltrialsregister.eu.

Background: The CD40/CD40L system, a key regulator and amplifier of immune reactivity, is activated in inflammatory bowel disease (IBD) mucosa. Aims: To determine whether plasma levels of sCD40L are elevated in Crohn’s disease (CD) and ulcerative colitis (UC) patients compared with normal controls, to investigate the cellular source of sCD40L, and to explore CD40L induction mechanisms. Patients: CD, UC, and normal control subjects were studied. Methods: The concentration of sCD40L in plasma and supernatants of freshly isolated platelets and autologous peripheral blood T cells (PBT) was measured by ELISA. Surface CD40L expression level was measured by flow cytometry in resting and thrombin activated platelets, and unstimulated and CD3/CD28 stimulated PBT before and after coculture with human intestinal microvascular endothelial cells (HIMEC). Results: Compared with normal controls, plasma sCD40L levels were significantly higher in both CD and UC patients and proportional to the extent of mucosal inflammation. Platelets from IBD patients displayed a significantly higher surface CD40L expression than those from control subjects, and released greater amounts of sCD40L than autologous PBT. Contact with IL-1β activated HIMEC induced significant upregulation of CD40L surface expression and release by platelets. Conclusions: Elevated levels of sCD40L in the circulation of IBD patients reflect enhanced surface expression and release of CD40L by platelets. This phenomenon translates to an increased platelet activation state apparently induced by passage through an inflamed mucosal microvascular bed, a conclusion supported by the positive correlation of plasma sCD40L levels with the extent of anatomical involvement by IBD. These results suggest that platelet-endothelial interactions critically contribute to activation of the CD40 pathway in IBD.

In the absence of the second signal, lymphocytes fail to respond effectively and become functionally deactivated and incapable of responding to subsequent antigen exposure (anergy). [...]the one-two costimulatory punch is fundamentally important in determining whether a T cell is enabled or not to competently respond to a specific antigen and ultimately mediate an appropriate immune response. [...]the strength of the TCR signal influences the degree of T cell activation and differentiation, and T cells may become activated even in the absence of a second signal, like in the case of direct stimulation by superantigens (for instance, staphylococcus enterotoxin A).

Introduction/BackgroundHigh-risk endometrial cancer represents a heterogeneous group of patients with an increased risk of pelvic and distant recurrences and worse outcome. The standard adjuvant treatment has not been established; controversy exists regarding the combination of chemotherapy (CT) and radiotherapy (RT) and their optimal timing. The ‘sandwich’ approach involves adjuvant CT followed by RT and subsequent CT; previous studies investigated different treatment modalities in a limited number of patients. Aim of this study is to assess efficacy and tolerability of a standardized ‘sandwich’ approach in high risk endometrial cancer.MethodologyA retrospective study was conducted in two Gynaecological Oncology Units (Mauriziano and Sant'Anna Hospitals) in Torino, Italy, from 01/01/2003 until 31/12/2016. High risk patients according to histological type, FIGO stage, grade and lymphovascular invasion, with available clinical data were included. The ‘sandwich’ method consisted of three cycles of platinum based CT, followed by (external and brachy) RT and than three cycles of platinum based CT. Compliance to treatment, CT and RT toxicities, Disease Free Survival (DFS), Cancer Specific Survival (CSS) and Overall Survival (OS) were analyzed.Results98 patients (median age 65 years, 36–77) were selected: 55 hystological type1 and 43 type 2; 27 FIGO I–II stages and 71 III–IV. Most of the patients (70.4%) received a Carboplatin-Paclitaxel combination. 558 (94.9%) CT cycles were completed and only 3 required a dose reduction. Grade 2 and 3 hematological toxicity rates were 3.1 and 4.1%. Grade 2 gastrointestinal and grade 2 genitourinary toxicity were reported in 8.2% and 2% of cases. With a median follow-up of 52 months, DFS was 77.6%, CSS 82.7% and OS 69.4%.ConclusionIn our experience ‘sandwich’ chemotherapy and radiotherapy combination is an effective adjuvant treatment with a low toxicity in high risk endometrial cancer.DisclosureNothing to disclose.

Introduction/Background*Enhanced Recovery After Surgery (ERAS) is currently considered as a global surgical quality improvement initiative. There is a paucity of data, however, concerning its application in advanced ovarian cancer (AOC) patients. The present analysis shows the results of a survey aimed at gathering detailed information on current perioperative management of AOC patients within MITO-ManGO Groups.MethodologyA 60-item questionnaire, covering the ERAS items for perioperative care in cytoreductive surgery, was sent to the responsible for each MITO/ManGO centre. Only questionnaires from centres reporting to operate >20 AOC per year were considered for the present analysis.Result(s)*Thirty/30 (100%) questionnaires from eligible centres were analysed. Survey main outcomes were presented and compared with the recommendations from the ERAS Society in table 1. Figure 1 graphically shows concordance between centres’ current behaviour and ERAS recommendations, expressed by rate of concordance. In particular, ≥70% concordance (rate of centres behaving in agreement with ERAS recommendations) was observed in 2/10, 8/12, and 5/9 items, respectively for the pre, intra and postoperative phase.Abstract 93 Figure 1Concordance between centres‘ behaviour and ERAS recommendations, expressed by rate of centres behaving in agreement with ERAS recommendations (agreement green; disagreement : red)Abstract 93 Table 1Survey outcomes compared with the recommendations from the ERAS societyConclusion*Although the recent attempts by the health providers to improve the management of AOC patients, this survey shows that further efforts should be made in order to optimize the perioperative pathway. This is true even in selected centres belonging to national oncological networks. There is a need for a structured peri-operative program specifically targeting AOC patients candidate to cytoreductive surgery.