Are Guideline Recommendations on Supportive Nutrition and Exercise Therapy for Cancer Patients Implemented in Clinical Routine? A National Survey with Real-Life Data.

Malnutrition and cancer cachexia are highly prevalent comorbidities of cancer, limiting patients' quality of life and being relevant to prognosis. International and national clinical guidelines recommend supportive nutrition and exercise therapy for cancer patients. However, there is little current epidemiological evidence on the implementation of these guideline recommendations in clinical routine. To close this data gap, a national survey in Germany using an online questionnaire was conducted. There were 261 of a total of 5074 contacted hospitals and medical offices who participated in the survey (5.1% response rate). The data indicated that nutrition and exercise therapy for cancer patients is so far inadequately implemented, with 59% of the respondents reporting nutrition therapy as an integral part of oncological treatment, 66.7% having a nutrition specialist/team, and 65.1% routinely conducting a screening for nutritional status. Only half of the participants stated that there are defined goals in nutrition therapy. The majority of respondents (85.8%) generally recommend exercise therapy, but only a few of them provide specific offers at their own institution (19.6%) or at cooperation partners (31.7%). In order to implement the recommended combined nutrition and exercise therapy as part of regular care, there is a need for nationwide availability of multidisciplinary nutrition teams and targeted offers of individualized exercise therapy. Health policy support would be important to create the structural, financial, and staff conditions for appropriate guideline implementation in order to achieve the optimal treatment of cancer patients.

Protein Supplementation Does Not Maximize Adaptations to Low-Volume High-Intensity Interval Training in Sedentary, Healthy Adults: A Placebo-Controlled Double-Blind Randomized Study.

There is ample evidence that specific nutritional strategies can enhance adaptions to resistance and endurance training. However, it is still unclear whether post-session protein supplementation may increase the effects of low-volume high-intensity interval training (LOW-HIIT). We examined the impact of LOW-HIIT combined with protein vs. placebo supplementation on cardiometabolic health indices in sedentary healthy individuals. Forty-seven participants (31.1 ± 8.0 yrs) performed cycle ergometer LOW-HIIT (5−10x1 min at 80−95% maximum heart rate) for eight weeks and randomly received double-blinded 40 g of whey protein (PRO-HIIT, N = 24) or an isocaloric placebo (maltodextrin, PLA-HIIT, N = 23) after each session. The maximum oxygen uptake (VO2max, primary outcome) and several secondary cardiometabolic outcomes were determined pre-/post-intervention. VO2max increased in PRO-HIIT (+2.8 mL/kg/min, p = 0.003) and PLA-HIIT (+3.5 mL/kg/min, p < 0.001). Systolic and diastolic blood pressure decreased in PRO-HIIT (−7/3 mmHg, p < 0.05) and PLA-HIIT (−8/5 mmHg, p < 0.001). Gamma glutamyl transferase (−2 U/L, p = 0.003) decreased in PRO-HIIT and alanine aminotransferase (−3 U/L, p = 0.014) in PLA-HIIT. There were no significant between-group differences in any of the outcome changes. In conclusion, LOW-HIIT improved VO2max and other cardiometabolic markers irrespective of the supplementation condition. Post-session protein supplementation does not seem to provide any additional benefit to LOW-HIIT in improving cardiometabolic health in sedentary healthy individuals.

Smad7 Antisense Oligonucleotide-Based Therapy in Crohn's Disease: Is it Time to Re-Evaluate?

Abundant preclinical work showed that in Crohn's disease (CD), the defective activity of the immunosuppressive cytokine tumor necrosis factor (TGF)-ß1 due to high levels of the intracellular inhibitor Smad7 contributes to amplify the tissue-damaging inflammatory response. Consistently, phase I and II studies documented clinical and endoscopic benefit in active CD patients treated with mongersen, an oral antisense oligonucleotide targeting Smad7. However, a multicenter, randomized, double-blind, placebo-controlled, phase III study was prematurely discontinued as a futility analysis showed that mongersen was not effective in CD patients. The reasons why the phase III study failed despite the fact that previous clinical trials documented the efficacy of the drug remain unknown. The primary objective of this Viewpoint was to provide clues about the factors explaining discrepancies among the clinical trials. We illustrate the recent data indicating that the various batches of mongersen, used during the phase III program, are chemically different, with some of them being unable to downregulate Smad7 expression. Overall, these findings suggest the necessity of new clinical studies to further evaluate the efficacy of chemically homogenous batches of mongersen in patients with inflammatory bowel diseases (IBDs), and, at the same time, they can help understand the failure of other clinical trials with antisense oligonucleotides in IBD (i.e. alicaforsen).

Small but powerful: will nanoparticles be the future state-of-the-art therapy for IBD?

INTRODUCTION: Inflammatory bowel disease (IBD) is the inflammatory condition of the gastrointestinal tract particularly affecting the colon and the ileum. IBD patients can have a very poor quality of life because of the limited therapeutic efficacy and accompanied adverse effects. AREAS COVERED: The potential ways to employ nanoparticles to deliver drugs to a certain site of inflammation are discussed. The focus was set on the microenvironment in the gut as well as the mucosa, epithelial layer and the microbiota. Moreover, experimental animal colitis models were nanoparticles were used as a potential treatment are presented. Lastly, challenges for the potential clinical use in humans are discussed. EXPERT OPINION: Although there still remain many open questions e.g. regarding the toxicity, the metabolism or the pharmacokinetics of nanoparticles further research on this topic could overcome these challenges. For example, instead of synthetically engineered particles, biodegradable components could be used. Since there have been a lot pf promising results in the recent years, we are sure that in the future nanoparticles will be developed in a way to ensure safe and targeted delivery of drugs to the site of inflammation.

Iron Beats Electricity: Resistance Training but Not Whole-Body Electromyostimulation Improves Cardiometabolic Health in Obese Metabolic Syndrome Patients during Caloric Restriction-A Randomized-Controlled Study.

Caloric restriction (CR) and exercise are cornerstones in the treatment of obesity and cardiometabolic disorders. Recently, whole body electromyostimulation (WB-EMS) has emerged as a more time-efficient alternative to traditional resistance training (RT). However, the effects of WB-EMS compared to RT on cardiometabolic health in obese metabolic syndrome (MetS) patients performed during CR are still unclear. In total, 118 obese MetS patients (52.7 ± 11.8 years, BMI: 38.1 ± 6.9 kg/m2) undergoing CR over 12 weeks (aim: -500 kcal deficit/day) were randomly allocated to either WB-EMS, single-set RT (1-RT), 3-set RT (3-RT) or an inactive control group (CON). Primary outcome was MetS severity (MetS z-score). Secondary outcomes were body composition, muscle strength and quality of life (QoL). All groups significantly reduced body weight (~3%) and fat mass (~2.6 kg) but only 1-RT and 3-RT preserved skeletal muscle mass (SMM). All exercise groups increased muscle strength in major muscle groups (20-103%). However, only the two RT-groups improved MetS z-score (1-RT: -1.34, p = 0.003; 3-RT: -2.06, p < 0.001) and QoL (1-RT: +6%, p = 0.027; 3-RT: +12%, p < 0.001), while WB-EMS and CON had no impact on these outcomes. We conclude that traditional RT has superior effects on cardiometabolic health, SMM and QoL in obese MetS patients undergoing CR than WB-EMS.

Seroprevalence of SARS-CoV2 in IBD Patients Treated with Biologic Therapy.

BACKGROUND AND AIMS: A similar course of COVID-19 in patients with inflammatory bowel diseases [IBD] and in the general population has been reported. However, disease prevalence in IBD patients is presently unknown. In this prospective observational study, we aimed at determining SARS-CoV2 infection prevalence in IBD patients treated with biologic therapy. METHODS: From IBD patients under biologic therapy and recruited from three different locations in Italy and Germany, 354 sera were evaluated for antibody presence by RBD ELISA. Control groups were: i] age-matched healthy subjects tested in the same time period in Milan, Italy; ii] healthy subjects collected in the pre-COVID era; iii] IBD patients under biologic therapy collected in the pre-COVID era. RESULTS: Eight out of 354 patients tested positive for the anti-RBD-SARS-CoV2 IgG antibody [prevalence 2.3%]. The percentage of IgG-positive patients among those recruited from Milan was significantly higher than among those recruited from other locations [prevalence 5.4% vs 0.4%, p <0.005]. IgG-positive patients reported a significantly higher incidence of fever, anosmia, and ageusia, and were more likely to have entered into close contact with COVID-19-positive subjects before the study enrolment. CONCLUSIONS: Seroprevalence of SARS-CoV2 in IBD patients treated with biologic therapy reflects values measured in the local general population. Specific symptoms and contact history with SARS-CoV2-infected individuals strongly increase the likelihood of SARS-CoV2 seropositivity.

Complementary roles of murine NaV1.7, NaV1.8 and NaV1.9 in acute itch signalling.

Acute pruritus occurs in various disorders. Despite severe repercussions on quality of life treatment options remain limited. Voltage-gated sodium channels (NaV) are indispensable for transformation and propagation of sensory signals implicating them as drug targets. Here, NaV1.7, 1.8 and 1.9 were compared for their contribution to itch by analysing NaV-specific knockout mice. Acute pruritus was induced by a comprehensive panel of pruritogens (C48/80, endothelin, 5-HT, chloroquine, histamine, lysophosphatidic acid, trypsin, SLIGRL, ß-alanine, BAM8-22), and scratching was assessed using a magnet-based recording technology. We report an unexpected stimulus-dependent diversity in NaV channel-mediated itch signalling. NaV1.7-/- showed substantial scratch reduction mainly towards strong pruritogens. NaV1.8-/- impaired histamine and 5-HT-induced scratching while NaV1.9 was involved in itch signalling towards 5-HT, C48/80 and SLIGRL. Furthermore, similar microfluorimetric calcium responses of sensory neurons and expression of itch-related TRP channels suggest no change in sensory transduction but in action potential transformation and conduction. The cumulative sum of scratching over all pruritogens confirmed a leading role of NaV1.7 and indicated an overall contribution of NaV1.9. Beside the proposed general role of NaV1.7 and 1.9 in itch signalling, scrutiny of time courses suggested NaV1.8 to sustain prolonged itching. Therefore, NaV1.7 and 1.9 may represent targets in pruritus therapy.

Effects of Apremilast, an Oral Inhibitor of Phosphodiesterase 4, in a Randomized Trial of Patients With Active Ulcerative Colitis.

BACKGROUND & AIMS: New oral therapeutic agents are needed for patients with ulcerative colitis (UC) who are unresponsive or intolerant to conventional therapy. METHODS: We performed a double-blind, phase 2 trial of adults with active UC for 3 months or more who were naïve to biologic therapy or had been failed by, could not tolerate, or had contraindications to conventional therapies. The study was performed at 61 sites in 14 countries (screening from January 2015 through May 2017). Patients were randomly assigned to groups given apremilast 30 mg (n = 57), apremilast 40 mg (n = 55), or placebo (n = 58) twice daily for 12 weeks; patients were then randomly assigned to groups that received apremilast, 30 or 40 mg twice daily, for an additional 40 weeks. Endoscopies were performed and biopsies were collected during the screening phase, at week 12, and at week 52. Blood and fecal samples were also collected and analyzed throughout the study. The primary endpoint was clinical remission at week 12, defined as a total Mayo score of 2 or less, with no individual subscore above 1. RESULTS: Clinical remission was achieved at week 12 by 31.6% of patients in the 30 mg apremilast group and 12.1% of patients in the placebo group (P = .01). However, only 21.8% of patients in the 40 mg apremilast group achieved clinical remission at week 12 (P = .27 compared with placebo). Differences in clinical remission between the 30 mg and 40 mg apremilast groups were associated with differences in endoscopic improvement. Both apremilast groups had similar improvements from baseline in Mayo score components (stool frequency score, rectal bleeding score, physician's global assessment). The 30 mg and 40 mg apremilast groups had greater median percent reductions in C-reactive protein (measured by a high-sensitivity blood test) and fecal calprotectin through week 12 than the placebo group. At week 52, clinical remission was achieved by 40.4% of patients initially assigned to the apremilast 30 mg group and 32.7% of patients initially assigned to the apremilast 40 mg group. The most frequent apremilast-associated adverse events were headache and nausea. CONCLUSIONS: Although the primary endpoint of clinical remission was not met in this phase 2 trial, a greater proportion of patients with active UC who received apremilast (30 mg or 40 mg) had improvements in clinical and endoscopic features, and markers of inflammation, at 12 weeks. Clinical remission was maintained to week 52 in up to 40% of patients who continued apremilast until that time point. ClinicalTrials.gov no: NCT02289417.

Assessment of gait parameters and physical function in patients with advanced cancer participating in a 12-week exercise and nutrition programme: A controlled clinical trial.

OBJECTIVE: Gait is a sensitive marker for functional declines commonly seen in patients treated for advanced cancer. We tested the effect of a combined exercise and nutrition programme on gait parameters of advanced-stage cancer patients using a novel wearable gait analysis system. METHODS: Eighty patients were allocated to a control group with nutritional support or to an intervention group additionally receiving whole-body electromyostimulation (WB-EMS) training (2×/week). At baseline and after 12 weeks, physical function was assessed by a biosensor-based gait analysis during a six-minute walk test, a 30-s sit-to-stand test, a hand grip strength test, the Karnofsky Index and EORTC QLQ-C30 questionnaire. Body composition was measured by bioelectrical impedance analysis and inflammation by blood analysis. RESULTS: Final analysis included 41 patients (56.1% male; 60.0 ± 13.0 years). After 12 weeks, the WB-EMS group showed higher stride length, gait velocity (p < .05), six-minute walking distance (p < .01), bodyweight and skeletal muscle mass, and emotional functioning (p < .05) compared with controls. Correlations between changes in gait and in body composition, physical function and inflammation were detected. CONCLUSION: Whole-body electromyostimulation combined with nutrition may help to improve gait and functional status of cancer patients. Sensor-based mobile gait analysis objectively reflects patients' physical status and could support treatment decisions.

Oligonucleotides-A Novel Promising Therapeutic Option for IBD.

Inflammatory Bowel Diseases (IBD), whose denomination comprehends Crohn's Disease (CD) and Ulcerative Colitis (UC), are intestinal chronic diseases that often require lifelong medical therapy. In the last two decades monoclonal antibodies against the cytokine TNF have become integral parts in the treatment of IBD patients, however there are unwanted side-effects and one third of patients show primary non-response while another subgroup loses response over time. Finding novel drugs which could act as therapies against precise pro-inflammatory molecular targets to avoid unwanted systemic side effects and additionally the process of immunization, represents an important aim for subsequent therapeutic approaches. Oligonucleotide based therapies represent a promising novel concept for the treatment of IBD. The molecular action of oligonucleotides ranges from inhibition of the translational process of mRNA transcripts of pro-inflammatory molecules, to mimicking bacterial DNA which can activate cellular targets for immunomodulation. Alicaforsen, selectively targets ICAM-1 mRNA. ICAM-1 is an adhesion molecule which is upregulated on endothelial cells during IBD, thereby mediating the adhesion and migration of leucocytes from blood to sites of active inflammation. In CD parenteral application of alicaforsen did not show therapeutic efficacy in phase II trials, but it demonstrated an improved efficacy as a topical enema in distal UC. Topical application of alicaforsen might represent a therapeutic perspective for refractory pouchitis as well. SMAD7 is a protein that inhibits the signaling of TGFß, which is the mainstay of a regulatory counterpart in cellular immune responses. An antisense oligonucleotide against SMAD7 mRNA (mongersen) demonstrated pre-clinical and phase II efficacy in CD, but a phase III clinical trial was stopped due to lack of efficacy. Cobitolimod is a single strand oligonucleotide, which mimics bacterial DNA as its CpG dinucleotide sequences can be recognized by the Toll-like receptor 9 on different immune cells thereby causing induction of different cytokines, for example IL10 and IFNα. Topical application of cobitolimod was studied in UC patients. We will also discuss two other novel oligonucleotides which act on the GATA3 transcription factor (SB012) and on carbohydrate sulfotransferase 15 (STNM01), which could both represent novel promising therapeutic options for the treatment of UC.

Top-down approach to biological therapy of Crohn's disease.

INTRODUCTION: Crohn's disease (CD) is a chronic, immune-mediated condition with a potentially disabling and destructive course. Despite growing data on when to use a therapeutic 'top-down' strategy, clinical management of this complex disorder is still challenging. Currently, the discussion of 'top-down' strategy in CD mostly includes biological therapy alone or in combination. Areas covered: This article is based on a review of existing literature regarding the use of biological therapy in a 'top-down' approach for the treatment of Crohn's disease. The authors reviewed all the major databases including MEDLINE as well as DDW and ECCO abstracts, respectively. Expert opinion: A 'top-down' therapeutic approach in Crohn's disease is strongly supported by existing data in patients with several risk factors for a severe course of disease. Moreover, there is an increasing amount of published data recommending a more individualised therapeutic strategy to identify candidates for 'top-down' treatment, based on enhanced diagnostics using biomarkers. Emerging therapeutic approaches besides existing therapy concepts using biologicals may possibly redefine the 'top-down' therapeutic strategy for Crohn's disease in the future.

Systemic desensitization through TRPA1 channels by capsazepine and mustard oil - a novel strategy against inflammation and pain.

We demonstrate a novel dual strategy against inflammation and pain through body-wide desensitization of nociceptors via TRPA1. Attenuation of experimental colitis by capsazepine (CPZ) has long been attributed to its antagonistic action on TRPV1 and associated inhibition of neurogenic inflammation. In contrast, we found that CPZ exerts its anti-inflammatory effects via profound desensitization of TRPA1. Micromolar CPZ induced calcium influx in isolated dorsal root ganglion (DRG) neurons from wild-type (WT) but not TRPA1-deficient mice. CPZ-induced calcium transients in human TRPA1-expressing HEK293t cells were blocked by the selective TRPA1 antagonists HC 030031 and A967079 and involved three cysteine residues in the N-terminal domain. Intriguingly, both colonic enemas and drinking water with CPZ led to profound systemic hypoalgesia in WT and TRPV1(-/-) but not TRPA1(-/-) mice. These findings may guide the development of a novel class of disease-modifying drugs with anti-inflammatory and anti-nociceptive effects.

Intravenous infusion of ascorbic acid decreases serum histamine concentrations in patients with allergic and non-allergic diseases.

Histamine plays an important role in the development of symptoms in allergic, infectious, neoplastic and other diseases. Empirical findings have suggested beneficial effects of ascorbic acid supplementation in those diseases, and these effects are assumed to be related to a possible decrease in systemic histamine concentration. In the present study, we systematically investigated for the first time the effect of 7.5 g of intravenously administered ascorbic acid on serum histamine levels (as detected by ELISA) in 89 patients (19 with allergic and 70 with infectious diseases). When all patients were grouped together, there was a significant decline in histamine concentration from 0.83 to 0.57 ng/ml×m2 body surface area (BSA, p<0.0001). The decrease in serum histamine concentration in patients with allergic diseases (1.36 to 0.69 ng/ml×m2 BSA, p=0.0007) was greater than that in patients with infectious diseases (0.73 to 0.56 ng/ml×m2 BSA, p=0.01). Furthermore, the decline in histamine concentration after ascorbic acid administration was positively correlated with the basal, i.e. pre-therapeutic, histamine concentration. Intravenous infusion of ascorbic acid clearly reduced histamine concentrations in serum, and may represent a therapeutic option in patients presenting with symptoms and diseases associated with pathologically increased histamine concentration.

Antiemetic prophylaxis and frequency of chemotherapy-induced nausea and vomiting in palliative first-line treatment of colorectal cancer patients: the Northern Bavarian IVOPAK I Project.

PURPOSE: This study aims to evaluate adherence to guidelines of antiemetic prophylaxis and frequency of chemotherapy-induced nausea and vomiting (CINV) in the palliative first-line treatment of colorectal cancer (CRC) patients in Northern Bavaria. METHODS: We collected detailed information on chemotherapy and supportive drugs in 103 patients within a prospective observational study. The study was conducted to determine quality of care within an interdisciplinary context (first endpoint) and direct costs of palliative treatment for patients with CRC between 2006 and 2010 (second endpoint, Emmert et al. (Eur J Health Econ, 2012) [1]). In this paper, we evaluate adherence to Multinational Association of Supportive Care in Cancer (MASCC) 2006 recommendations for prophylaxis of CINV during the first administration of chemotherapy as well as incidence and grade of CINV within 120 h thereafter. RESULTS: Of the patients studied, 95 patients (92%) received moderately emetogenic (oxaliplatin- and/or irinotecan-containing combined chemotherapy treatment) and eight (8%) received low emetogenic chemotherapy (either 5-fluorouracil (5-FU) or capecitabine monotherapy). Antiemetic prophylaxis could be assessed in 101 out of 103 (98%) of patients. MASCC-recommended antiemetic prophylaxis was prescribed in three patients (3%). Nonadherence was mainly caused by omission of dexamethasone. Nausea and/or vomiting occurred in 18 patients (18%) within a 120-h period. All documented episodes were grade 1 or 2 according to the Common Toxicity Criteria of the National Cancer Institute. None of these patients received the recommended prophylaxis for CINV. In only one patient, antiemetic prophylaxis was intensified during the next chemotherapy application. CONCLUSIONS: In the Integrated Health Care in the Palliative Treatment of Colorectal Carcinoma (IVOPAK) I Project, adherence to the MASCC clinical recommendations was very poor. Extent of CINV in this patient population seems to be underestimated. There is an urgent need to improve clinicians' awareness of this patient-relevant side effect.

Allergen-induced IgE-dependent gut inflammation in a human PBMC-engrafted murine model of allergy.

BACKGROUND: Humanized murine models comprise a new tool to analyze novel therapeutic strategies for allergic diseases of the intestine. OBJECTIVE: In this study we developed a human PBMC-engrafted murine model of allergen-driven gut inflammation and analyzed the underlying immunologic mechanisms. METHODS: Nonobese diabetic (NOD)-scid-γc(-/-) mice were injected intraperitoneally with human PBMCs from allergic donors together with the respective allergen or not. Three weeks later, mice were challenged with the allergen orally or rectally, and gut inflammation was monitored with a high-resolution video miniendoscopic system, as well as histologically. RESULTS: Using the aeroallergens birch or grass pollen as model allergens and, for some donors, also hazelnut allergen, we show that allergen-specific human IgE in murine sera and allergen-specific proliferation and cytokine production of human CD4(+) T cells recovered from spleens after 3 weeks could only be measured in mice treated with PBMCs plus allergen. Importantly, these mice had the highest endoscopic scores evaluating translucent structure, granularity, fibrin, vascularity, and stool after oral or rectal allergen challenge and a strong histologic inflammation of the colon. Analyzing the underlying mechanisms, we demonstrate that allergen-associated colitis was dependent on IgE, human IgE receptor-expressing effector cells, and the mediators histamine and platelet-activating factor. CONCLUSION: These results demonstrate that allergic gut inflammation can be induced in human PBMC-engrafted mice, allowing the investigation of pathophysiologic mechanisms of allergic diseases of the intestine and evaluation of therapeutic interventions.

Palliative first-line therapy with weekly high-dose 5-fluorouracil and sodium folinic acid as a 24-hour infusion (AIO regimen) combined with weekly irinotecan in patients with metastatic adenocarcinoma of the stomach or esophagogastric junction followed by secondary metastatic resection after downsizing.

BACKGROUND: The aim of this retrospective study was to evaluate the efficacy and safety of weekly high-dose 5-fluorouracil (5-FU)/folinic acid (FA) as 24-h infusion (AIO regimen) plus irinotecan in patients with histologically proven metastatic gastroesophageal adenocarcinoma (UICC stage IV). MATERIAL/METHODS: From 08/1999 to 12/2008, 76 registered, previously untreated patients were evaluable. Treatment regimen: irinotecan (80 mg/m²) as 1-h infusion followed by 5-FU (2000 mg/m²) combined with FA (500 mg/m²) as 24-h infusion (d1, 8, 15, 22, 29, 36, qd 57). RESULTS: Median age: 59 years; male/female: 74%/26%; ECOG ≤1: 83%; response: CR: 1%, PR: 16%, SD: 61%, PD: 17%, not evaluable in terms of response: 5%; tumor control: 78%; median OS: 11.2 months; median time-to-progression: 5.3 months; 1-year survival rate: 49%; 2-year survival rate: 17%; no evidence of disease: 6.6%; higher grade toxicities (grade 3/4): anemia: 7%, leucopenia: 1%, ascites: 3%, nausea: 3%, infections: 12%, vomiting: 9%, GI bleeding of the primary tumor: 4%, diarrhea: 17%, thromboembolic events: 4%; secondary metastatic resection after downsizing: 16 patients (21%), R-classification of secondary resections: R0/R1/R2: 81%/6%/13%, median survival of the 16 patients with secondary resection: 23.7 months. CONCLUSIONS: Combined 5-FU/FA as 24-h infusion plus irinotecan may be considered as an active palliative first-line treatment accompanied by tolerable toxicity; thus offering an alternative to cisplatin-based treatment regimens. Thanks to efficient interdisciplinary teamwork, secondary metastatic resections could be performed in 16 patients. In total, the patients who had undergone secondary resection had a median survival of 23.7 months, whereas the median survival of patients without secondary resection was 10.1 months (p≤0.001).

Inflammation, peptides and biological therapy.

Inflammatory bowel diseases are characterized by chronic relapsing inflammations of the gastrointestinal tract that are not caused by specific pathogens. Although the precise aetiology of inflammatory bowel diseases remains unclear, considerable progress has been made in the identification of critical cytokine mediated signalling pathways in the inflammatory process. It could be shown that these pathways induce augmented intestinal T cell resistance against apoptosis, which is a pivotal process in disease pathogenesis. These findings have facilitated our understanding of the disease and the development of new therapies, which aim at restoring mucosal T cell homeostasis based on a sound pathophysiological rationale. This development is best exemplified by the emergence of anti-tumour necrosis factor antibody therapy. The advent of other biological therapies, such as the anti-IL-6R antibody, offers hope for new strategies that may result in more effective and less toxic therapy.

The transcription factor NFATc2 controls IL-6-dependent T cell activation in experimental colitis.

The nuclear factor of activated T cells (NFAT) family of transcription factors controls calcium signaling in T lymphocytes. In this study, we have identified a crucial regulatory role of the transcription factor NFATc2 in T cell-dependent experimental colitis. Similar to ulcerative colitis in humans, the expression of NFATc2 was up-regulated in oxazolone-induced chronic intestinal inflammation. Furthermore, NFATc2 deficiency suppressed colitis induced by oxazolone administration. This finding was associated with enhanced T cell apoptosis in the lamina propria and strikingly reduced production of IL-6, -13, and -17 by mucosal T lymphocytes. Further studies using knockout mice showed that IL-6, rather than IL-23 and -17, are essential for oxazolone colitis induction. Administration of hyper-IL-6 blocked the protective effects of NFATc2 deficiency in experimental colitis, suggesting that IL-6 signal transduction plays a major pathogenic role in vivo. Finally, adoptive transfer of IL-6 and wild-type T cells demonstrated that oxazolone colitis is critically dependent on IL-6 production by T cells. Collectively, these results define a unique regulatory role for NFATc2 in colitis by controlling mucosal T cell activation in an IL-6-dependent manner. NFATc2 in T cells thus emerges as a potentially new therapeutic target for inflammatory bowel diseases.