No abstract

Mesenteric fibrosis (MF) surrounding a mesenteric mass is a hallmark feature of small intestinal neuroendocrine tumours (SI-NETs). Since this can induce intestinal obstruction, oedema and ischaemia, prophylactic resection of the primary tumour and mesenteric mass is often recommended. This study assessed the predictors for mesenteric metastasis and fibrosis and the effect of MF and palliative surgery on survival. A retrospective analysis of 559 patients with pathologically proven SI-NET and available CT-imaging data was performed. Clinical characteristics, presence of mesenteric mass and fibrosis on CT imaging and the effect of palliative abdominal surgery on overall survival were assessed. We found that MF was present in 41.4%. Older age, 5-HIAA excretion ≥67 μmol/24 h, serum CgA ≥121.5 μg/L and a mesenteric mass ≥27.5 mm were independent predictors of MF. In patients ≤52 years, mesenteric mass was less often found in women than in men (39% vs 64%, = 0.002). Corrected for age, tumour grade, CgA and liver metastasis, MF was not a prognostic factor for overall survival. In patients undergoing palliative surgery, metastasectomy of mesenteric mass or prophylactic surgery did not result in survival benefit. In conclusion, we confirmed known predictors of MF and mesenteric mass and suggest a role for sex hormones as women ≤52 years have less often a mesenteric mass. Furthermore, the presence of MF has no effect on survival in a multivariate analysis, and we found no benefit of metastasectomy of mesenteric mass or prophylactic surgery on overall survival.

Small intestinal neuroendocrine tumours (SI-NETs) are neoplasms characterized by their ability to secrete biogenic amines and peptides. These cause distinct clinical pathology including carcinoid syndrome, marked by diarrhoea and flushing, as well as fibrosis, notably mesenteric fibrosis. Mesenteric fibrosis often results in significant morbidity by causing intestinal obstruction, oedema and ischaemia. Although advancements have been made to alleviate symptoms of carcinoid syndrome and prolong the survival of patients with SI-NETs, therapeutic options for patients with mesenteric fibrosis are still limited. As improved insight in the complex pathogenesis of mesenteric fibrosis is key to the development of new therapies, we evaluated the literature for known and putative mediators of fibrosis in SI-NETs. In this review, we discuss the tumour microenvironment, growth factors and signalling pathways involved in the complex process of fibrosis development and tumour progression in SI-NETs, in order to elucidate potential new avenues for scientific research and therapies to improve the management of patients suffering from the complications of mesenteric fibrosis.

Context Peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE results in an increase of progression-free survival and quality of life in patients with progressive well-differentiated neuroendocrine neoplasms (NENs). Objective To study the effect of 177Lu-DOTATATE in patients with carcinoid syndrome and radiologically stable or newly diagnosed disease treated solely for the purpose of symptom reduction. Design Retrospective cohort study Setting Tertiary care hospital Patients 22 patients with a metastatic midgut NEN, elevated urinary 5-hydroxyindolacetic acid excretion and flushing and/or diarrhea despite treatment with a somatostatin analog, without documented disease progression Intervention PRRT with 177Lu-DOTATATE (intended cumulative dose: 29.6 GBq) with a primary aim to reduce symptoms. Results After PRRT, mean bowel movement frequency (BMF) decreased from 6.1 ± 3.4 to 4.6 ± 3.6 per day (p=0.009). Flushes decreased from 4.3 ± 2.9 to 2.4 ± 2.7 flushes per day (p=0.002). A decrease of BMF of more than 30% occurred in 47% of patients with baseline BMF of 4 or more (n=17). In patients with ≥2 episodes of flushing a day (n=15), 67% of patients had more than 50% decrease of daily flushing. A decrease in urinary 5-hydroxyindolacetic acid excretion of more than 30% was seen in 56% of patients. The EORTC-C30 diarrhea subscale score showed a trend towards improvement by an average of 16.7 ± 33.3 points (p=0.11). Conclusion PRRT with 177Lu-DOTATATE effectively reduced diarrhea and flushing in patients with carcinoid syndrome and can be considered for symptomatic treatment of carcinoid syndrome insufficiently controlled with somatostatin analogs.

Radiomics uses quantitative medical imaging features to predict clinical outcomes. While many radiomics methods have been described in the literature, these are generally designed for a single application. The aim of this study is to generalize radiomics across applications by proposing a framework to automatically construct and optimize the radiomics workflow per application. To this end, we formulate radiomics as a modular workflow, consisting of several components: image and segmentation preprocessing, feature extraction, feature and sample preprocessing, and machine learning. For each component, a collection of common algorithms is included. To optimize the workflow per application, we employ automated machine learning using a random search and ensembling. We evaluate our method in twelve different clinical applications, resulting in the following area under the curves: 1) liposarcoma (0.83); 2) desmoid-type fibromatosis (0.82); 3) primary liver tumors (0.81); 4) gastrointestinal stromal tumors (0.77); 5) colorectal liver metastases (0.68); 6) melanoma metastases (0.51); 7) hepatocellular carcinoma (0.75); 8) mesenteric fibrosis (0.81); 9) prostate cancer (0.72); 10) glioma (0.70); 11) Alzheimer's disease (0.87); and 12) head and neck cancer (0.84). Concluding, our method fully automatically constructs and optimizes the radiomics workflow, thereby streamlining the search for radiomics biomarkers in new applications. To facilitate reproducibility and future research, we publicly release six datasets, the software implementation of our framework (open-source), and the code to reproduce this study.

Background: A metastatic mesenteric mass is a hallmark of small intestinal neuroendocrine tumours (SI-NETs). However, little is known on its development over time. Therefore, we conducted a study to assess the evolution of a SI-NET-associated mesenteric mass over time. Methods: Retrospectively, 530 patients with proven SI-NET were included. The presence and growth of a mesenteric mass was assessed using RECIST 1.1 criteria on every consecutive CT-scan until the end of follow-up or resection. Results: At baseline, a mesenteric mass was present in 64% of the patients, of whom 13.5% showed growth of the mesenteric mass with a median time to growth of 40 months. Male gender was the only independent predictor of growth (OR 2.67). Of the patients without a mesenteric mass at the first evaluation, 2.6% developed a pathological mesenteric mass. Treatment with peptide receptor radionuclide therapy (PRRT; N = 132) resulted in an objective size reduction of the mesenteric mass in 3.8%. Conclusion: The metastatic mesenteric mass in SI-NETs has a static behavior over time. Therefore, site-specific growth behavior should be taken into account when selecting target lesions and assessing disease progression and therapeutic response. PRRT appears not to be effective for size reduction of the mesenteric mass.

Context Small intestinal neuroendocrine tumors (SI-NETs) have a modest but significantly higher prevalence and worse prognosis in male patients. Objective This work aims to increase understanding of this sexual dimorphism in SI-NETs. Patients and Methods Retrospectively, SI-NET patients treated in a single tertiary center were included and analyzed for disease characteristics. Estrogen receptor 1 (ESR1) and 2 (ESR2), progesterone receptor (PGR) and androgen receptor (AR) mRNA expression was assessed in primary tumors and healthy intestine. Estrogen receptor alpha (ERα) and AR protein expression was analyzed by immunohistochemistry in primary tumors and mesenteric metastases. Results Of the 559 patients, 47% were female. Mesenteric metastasis/fibrosis was more prevalent in men (71/46%) than women (58/37%, P=0.001 and P = 0.027). In women, prevalence of mesenteric metastases increased gradually with age from 41.1% in women <50 years to 71.7% in women >70 years. Increased expression of ESR1 and AR mRNA was observed in primary tumors compared to healthy intestine (both P < 0.001). ERα staining was observed in tumor cells and stroma with a strong correlation between tumor cells of primary tumors and mesenteric metastases (rho=0.831, P=0.02), but not in stroma (rho=-0.037, P=0.91). AR expression was only found in stroma. Conclusion Sexual dimorphism in SI-NETs was most pronounced in mesenteric disease and the risk of mesenteric metastasis in women increased around menopause. The combination of increased ERα and AR expression in the SI-NET microenvironment suggests a modulating role of sex steroids in the development of the characteristic SI-NET mesenteric metastasis and associated fibrosis.

Background: Increased levels of serotonin secretion are associated with mesenteric fibrosis (MF) in small intestinal neuroendocrine tumors (SI-NETs). However, the profibrotic potential of serotonin differs between patients and in this study, we aimed to gain an understanding of the mechanisms underlying this variability. To this end, we analyzed the proteins involved in tryptophan metabolism in SI-NETs. Methods: Proteomes of tumor and stroma from primary SI-NETs and paired mesenteric metastases of patients with MF (n=6) and without MF (n=6) were identified by liquid chromatography-mass spectrometry (LC-MS). The differential expression of proteins involved in tryptophan metabolism between patients with and without MF was analyzed. Concurrently, monoamine oxidase A (MAO-A) expression was analyzed in the tumor and stromal compartment by immunohistochemistry (IHC) and reported as intensity over area (I/A). Results: Of the 42 proteins involved in tryptophan metabolism, 20 were detected by LC-MS. Lower abundance of 10 proteins was found in mesenteric metastases stroma in patients with MF. No differential expression was found in primary SI-NETs. In patients with MF, IHC showed lower MAO-A expression in the stroma of the primary SI-NETs (median 4.2 I/A vs. 6.5 I/A in patients without MF, P=0.003) and mesenteric metastases (median 2.1 I/A vs. 2.8 I/A in patients without MF, P=0.019). Conclusion: We found a decreased expression of tryptophan and serotonin metabolizing enzymes in the stroma in patients with MF, most notably in mesenteric stroma. This might account for the increased profibrotic potential of serotonin and explain the variability in the development of SI-NET-associated fibrotic complications.