Neuroendocrine tumours and their microenvironment.

Tumours can escape the immune system by expressing programmed death-ligand-1 (PD-L1), which allows them to bind to PD-1 on T-cells and avoid recognition by the immune system. Regulatory T-cells (Tregs), indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) also play a role in immune suppression. Knowledge about the interaction of neuroendocrine tumours (NETs) with their immune microenvironment and the role of immunotherapy in patients with NET is scarce. Here, we investigated the immune microenvironment of serotonin-producing (SP) and non-serotonin-producing NETs (NSP-NETs). Tumours of 33 patients with SP-NET and 18 patients with NSP-NET were studied. Immunohistochemical analyses were performed for PD-L1, T-cells, IDO, TDO, mismatch repair proteins (MMRp) and activated fibroblasts. PD-L1 expression was seen in < 1% of tumour and T-cells. T-cells were present in 33% of NETs, varying between 1 and 10% T-cells per high power field. IDO was expressed in tumour cells in 55% of SP-NETs and 22% of NSP-NETs (p = 0.039). TDO was expressed in stromal cells in 64% of SP-NETs and 13% of NSP-NETs (p = 0.001). No tumours had loss of MMRp. TDO-expressing stromal cells also strongly expressed α-SMA and were identified as cancer-associated fibroblasts (CAFs). Factors that are associated with a response to checkpoint inhibitor treatment were absent or only present to a limited extent in the tumour microenvironment of NETs. The expression of IDO and TDO in a substantial part of NETs and the presence of CAFs suggest two mechanisms that could be responsible for the cold immune microenvironment, which should be explored to enhance anti-tumour immunity and clinical responses.

Web-based information and support for patients with a newly diagnosed neuroendocrine tumor: a feasibility study.

PURPOSE: Patients with a neuroendocrine tumor (NET) frequently experience physical and psychosocial complaints. Novel strategies to provide information to optimize supportive care in these patients are of interest. The aim of this study was to examine whether the use of a web-based system consisting of self-screening of problems and care needs, patient education, and self-referral to professional health care is feasible in NET patients and to evaluate their opinion on this. METHODS: Newly diagnosed NET patients were randomized between standard care (n = 10) or intervention with additional access to the web-based system (n = 10) during 12 weeks. Patients completed questionnaires regarding received information, distress, quality of life (QoL), and empowerment. The intervention group completed a semi-structured interview to assess patients' opinion on the web-based system. RESULTS: The participation rate was 77% (20/26 invited patients) with no dropouts. The use of the web-based system had a negative effect on patients' perception and satisfaction of received information (range Cohen's d -0.88 to 0.13). Positive effects were found for distress (Cohen's d 0.75), global QoL (subscale European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, Cohen's d 0.46), resolving problems with social functioning and finding information (subscales EORTC QLQ-GINET 21, Cohen's d 0.69, respectively, 1.04), and feeling informed (subscale empowerment questionnaire, Cohen's d 0.51). The interview indicated that the web-based system was of additional value to standard care. CONCLUSIONS: Use of this web-based system is feasible. Contradictory effects on informing and supporting NET patients were found and should be subject of further research. TRIAL REGISTRATION: NCT01849523.

Niacin (Vitamin B3) Supplementation in Patients with Serotonin-Producing Neuroendocrine Tumor.

BACKGROUND/AIMS: Tryptophan is the precursor of serotonin and niacin (vitamin B3). The latter is critical for normal cellular metabolism. Tryptophan and niacin can be deficient in patients with serotonin-producing neuroendocrine tumors (NETs). Niacin deficiency may lead to severe symptoms including pellagra. In patients with serotonin-producing NET, data on niacin status are scarce and niacin supplementation hardly receives attention. We aimed to assess the niacin status before and after supplementation in these patients. METHODS: We identified serotonin-producing NET patients who had received oral niacin supplementation (mean dose 144 mg daily) for tryptophan deficiency and/or pellagra-associated symptoms. Presupplementation plasma tryptophan levels and niacin status based on the urinary niacin metabolite N1-methylnicotinamide (N1-MN) before (n = 42) and after the start of the supplementation (in 34 paired samples) were assessed. Reference values for urinary N1-MN levels were established in 133 healthy individuals. RESULTS: The mean presupplementation plasma tryptophan level was 31.8 ± 9.7 µmol/l (reference value 40.0-70.0). Presupplementation urinary N1-MN levels were lower in patients (median 17.9 µmol/24 h, range 2.6-70.3) compared to healthy controls (median 43.7 µmol/24 h, range 9.5-169.3, p < 0.0001) and below normal in 45% of the patients. Niacin supplementation increased urinary N1-MN levels to high normal levels (median 55.5 µmol/24 h, range 7.4-489.0) in 86% of the niacin-deficient patients. CONCLUSION: In serotonin-producing NET patients, niacin deficiency is prevalent. Therefore, urinary N1-MN deserves to be included in their standard biochemical evaluation. Niacin supplementation normalizes the niacin status in most niacin-deficient serotonin-producing NET patients. A prospective study is warranted.

Web-Based Tailored Psychoeducation for Breast Cancer Patients at the Onset of the Survivorship Phase: A Multicenter Randomized Controlled Trial.

CONTEXT: Many breast cancer patients have unmet informational and psychosocial needs after treatment completion. A psychoeducational intervention may be well suited to support these patients. OBJECTIVES: The purpose of this multicenter randomized controlled trial was to examine the effectiveness of a web-based tailored psychoeducational program (ENCOURAGE) for breast cancer patients, which aims to empower patients to take control over prevailing problems. METHODS: Female breast cancer patients from two hospitals in The Netherlands who recently completed (neo-)adjuvant chemotherapy were randomly assigned to standard care or 12-week access to the ENCOURAGE program providing fully automated information problem-solving strategies, resources, and services for reported problems. At six and 12 weeks, patients completed self-report questions on optimism and control over the future (primary outcome), feelings of being informed, and acceptance of the illness. At baseline and 12 weeks, distress and quality of life questionnaires were completed. RESULTS: About 138 patients were included. Almost all patients (67 of 69) visited ENCOURAGE as requested. No differences between the control and intervention group were observed for primary and secondary outcomes. An unplanned subgroup analysis showed that in clinically distressed patients (N = 57 at baseline; 41%), use of the ENCOURAGE program increased optimism and control over the future at 12 weeks more than in patients in the control group (Cohen's d = 0.65). CONCLUSION: Although the effectiveness was not demonstrated, a subgroup of women treated for breast cancer can probably be supported by the program. The results of the present study are a starting point for further development and use of the program.

Internet-based support programs to alleviate psychosocial and physical symptoms in cancer patients: a literature analysis.

In this review the effect of internet-based support programs on psychosocial and physical symptoms resulting from cancer diagnosis and treatment is analyzed. Selection of studies was based on the following criteria: (non-)randomized controlled trials, performed in adult cancer patients, comparing quantitative psychosocial and/or physical outcomes of an internet-based support program with (a) comparison group(s). Literature search yielded 2032 studies of which 16 fulfilled the eligibility criteria. Three different internet-based support programs were identified: social support groups, online therapy for psychosocial/physical symptoms, and online systems integrating information, support, and coaching services. Outcomes improved by these programs in nine studies. Especially fatigue, social support, and distress improved, regardless of the program type. All online systems showed positive effects, mainly for social support and quality of life. This analysis indicates that internet-based support programs are effective in improving psychosocial and physical symptoms in cancer patients.

[Ileitis following capecitabine use]. / Ileïtis bij gebruik van capecitabine.

BACKGROUND: Over a period of 1 year in our hospital, 3 patients were diagnosed with 'ileitis following capecitabine use'. The case of 1 of these patients is presented in this article. CASE DESCRIPTION: A 73-year-old man known to be suffering from liver metastases from rectal cancer was treated with oxaliplatin, bevacizumab and capecitabine. He was admitted to our hospital with abdominal pain, diarrhoea, nausea and a subfebrile temperature. A CT scan of the abdomen showed marked bowel wall thickening, particularly of the ileum, consistent with terminal ileitis. The diagnosis was 'ileitis following capecitabine use' since other disorders were excluded or seemed less likely, and the Naranjo score was compatible with 'possible adverse reaction'. Capecitabine treatment was discontinued. Following recovery, treatment was resumed without complications. CONCLUSION: Small intestine toxicity during capecitabine use has, to our knowledge, not been described previously. It is important to recognise this side-effect in order to avoid obstruction and perforation. Conservative treatment including an adapted diet and intravenous hydration is the therapy of choice. Surgery does not seem to be indicated.