Mesenteric Fibrosis Research Articles

Intestinal Adipocytes Transdifferentiate into Myofibroblast-like Cells and Contribute to Fibrosis in Crohn's Disease.

Intestinal fibrotic stenosis is a major reason for surgery in Crohn's disease [CD], but the mechanism is unknown. Thus, we asked whether intestinal adipocytes contribute to intestinal fibrosis. Adipocytes were found to transdifferentiate into myofibroblasts and confirmed to be involved in mesenteric fibrosis in our recent study. Here, we investigated the role and possible mechanisms of intestinal adipocytes in intestinal fibrosis in CD. The intestinal tissue of patients with CD with or without fibrotic stenosis [CDS or CDN] and normal intestinal tissue from individuals without CD were obtained to assess alterations in submucosal adipocytes in CDS and whether these cells transdifferentiated into myofibroblasts and participated in the fibrotic process. Human primary adipocytes and adipose organoids were used to evaluate whether adipocytes could be induced to transdifferentiate into myofibroblasts and to investigate the fibrotic behaviour of adipocytes. LPS/TLR4/TGF-β signalling was also studied to explore the underlying mechanism. Submucosal adipocytes were reduced in number or even absent in CDS tissue, and the extent of the reduction correlated negatively with the degree of submucosal fibrosis. Interestingly, submucosal adipocytes in CDS tissue transdifferentiated into myofibroblast-like cells and expressed collagenous components, possibly due to stimulation by submucosally translocated bacteria. Lipopolysaccharide [LPS]-stimulated human primary adipocytes and adipose organoids also exhibited transdifferentiation and profibrotic behaviour. Mechanistically, TLR4-mediated TGF-β signalling was associated with the transdifferentiation and profibrotic behaviour of intestinal adipocytes in CDS tissue. Intestinal adipocytes transdifferentiate into myofibroblasts and participate in the intestinal fibrosis process in CD, possibly through LPS/TLR4/TGF-β signalling.

Mesenteric fibrosis in patients with small intestinal neuroendocrine tumors is associated with enrichment of alpha-smooth muscle actin-positive fibrosis and COMP-expressing stromal cells.

Neuroendocrine tumors of the small intestine (SI-NETs) often develop lymph node metastasis (LNM)-induced mesenteric fibrosis (MF). MF can cause intestinal obstruction as well as ischemia and render surgical resection technically challenging. The underlying pathomechanisms of MF are still not well understood. We examined mesenteric LNM and the surrounding stroma compartment from 24 SI-NET patients, including 11 with in situ presentation of strong MF (MF+) and 13 without MF (MF-). Differential gene expression was assessed with the HTG EdgeSeq Oncology Biomarker Panel comparing MF+ with MF- within LNM and paired stromal samples, respectively. Most interesting differentially expressed genes were validated by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) in combination with validation of associated protein levels utilizing immunohistochemistry (IHC) staining of MF+ and MF- formalin-fixed, paraffin-embedded (FFPE) patient samples. Overall, 14 genes measured with a 2549-gene expression panel were differentially expressed in MF+ patients compared to MF-. Of those, nine were differentially expressed genes in LNM and five genes in the stromal tissue (>2-fold change, p < .05). The top hits included increased COMP and COL11A1 expression in the stroma of MF+ patients compared to MF-, as well as decreased HMGA2, COL6A6, and SLC22A3 expression in LNM of MF+ patients compared to LNM of MF- patients. RT-qPCR confirmed high levels of COMP and COL11A1 in stroma samples of MF+ compared to MF- patients. IHC staining confirmed the enrichment of α-smooth muscle actin-positive fibrosis in MF+ compared to MF- patients with corresponding increase of COMP-expressing stromal cells in MF+. Since COMP is associated with the known driver for fibrosis development transforming growth factor beta and with a cancer-associated fibroblasts enriched environment, it seems to be a promising new target for MF research.

Viscoelastic properties of small bowel mesentery at MR elastography in Crohn’s disease: a prospective cross-sectional exploratory study

BackgroundCreeping fat is a pathological feature of small bowel Crohn’s disease (CD), with literature suggesting that bowel resection with extended mesenteric resection is related to less postoperative recurrences. Conventional imaging is unable to accurately quantify the disease involvement (i.e., fibrosis) of creeping fat. Quantification of disease involvement could be useful in decision-making for additional extended mesenteric resection. We investigated the feasibility of magnetic resonance elastography (MRE) of the mesentery and if MRE is capable to detect fibrotic disease involvement of mesentery in active CD.MethodsMultifrequency MRE yielded spatial stiffness (shear wave speed, SWS, |G*|) and fluidity maps (φ). Viscoelastic properties of seven CD patients’ mesentery were compared to age- and sex-matched healthy volunteers (HV) (Mann–Whitney U-test). Within CD patients, the affected and “presumably” unaffected mesentery were compared (Wilcoxon-signed rank test). Repeatability was tested in 15 HVs (Bland–Altman analysis, coefficient of variation [CoV]). Spearman rank correlations were used to investigate the relation between microscopically scored amount of mesenteric fibrosis and viscoelastic parameters.ResultsSWS, |G*|, and φ of affected mesentery in CD were higher compared to HV (p = 0.017, p = 0.001, p = 0.017). Strong correlations were found between percentage of area of mesenteric fibrosis and SWS and |G*| (p < 0.010). No differences were found within CD between affected and presumably unaffected mesentery. Repeatability of SWS showed 95% limits of agreement of (-0.09, 0.13 m/s) and within-subject CoV of 5.3%.ConclusionMRE may have the potential to measure fibrotic disease involvement of the mesentery in CD, possibly guiding clinical decision-making with respect to extended mesenteric resection.Trial registrationDutch trial register, NL9105, registered 7 December 2020.Relevance statementMRE may have the potential to measure the amount of mesenteric fibrosis of the affected mesenteric fat in active Crohn’s disease, giving more insight into disease progression and could potentially play a role in clinical decision-making for extended mesenteric resection.Key points• MRE of the mesentery in patients with active CD is feasible.• Fluidity and stiffness of the mesentery increase in active CD, while stiffness correlates with the histopathological amount of mesenteric fibrosis.• MRE provides biomarkers to quantify mesenteric disease activity in active CD.Graphical

Proteomic analysis of small intestinal neuroendocrine tumors and mesenteric fibrosis.

Mesenteric metastases in small intestinal neuroendocrine tumors (SI-NETs) are associated with mesenteric fibrosis (MF) in a proportion of patients. MF can induce severe abdominal complications, and an effective preventive treatment is lacking. To elucidate possible novel therapeutic targets, we performed a proteomics-based analysis of MF. The tumor cell and stromal compartment of primary tumors and paired mesenteric metastases of SI-NET patients with MF (n = 6) and without MF (n = 6) was analyzed by liquid chromatography-mass spectrometry-based proteomics. Analysis of differential protein abundance was performed. Collagen alpha-1(XII) (COL12A1) and complement component C9 (C9) expression was evaluated by immunohistochemistry (IHC) in mesenteric metastases. A total of 2988 proteins were identified. Unsupervised hierarchical clustering showed close clustering of paired primary and mesenteric tumor cell samples. Comparing MF to non-MF samples, we detected differentially protein abundance solely in the mesenteric metastasis stroma group. There was no differential abundance of proteins in tumor cell samples or primary tumor stroma samples. Analysis of the differentially abundant proteins (n = 36) revealed higher abundance in MF samples of C9, various collagens and proteoglycans associated with profibrotic extracellular matrix dysregulation and signaling pathways. Proteins involved in fatty acid oxidation showed a lower abundance. COL12A1 and C9 were confirmed by IHC to have significantly higher expression in MF mesenteric metastases compared to non-MF. In conclusion, proteome profiles of SI-NETs with and without MF differ primarily in the stromal compartment of mesenteric metastases. Analysis of differentially abundant proteins revealed possible new signaling pathways involved in MF development. In conclusion, proteome profiles of SI-NETs with and without MF differ primarily in the stromal compartment of mesenteric metastases. Analysis of differentially abundant proteins revealed possible new signaling pathways involved in MF development.

Carcinoid Syndrome: Preclinical Models and Future Therapeutic Strategies

Carcinoid syndrome represents a debilitating paraneoplastic disease, caused by the secretion of several substances, occurring in about 10-40% of patients with well-differentiated neuroendocrine tumors (NETs). The main signs and symptoms associated with carcinoid syndrome are flushing, diarrhea, hypotension, tachycardia, bronchoconstriction, venous telangiectasia, dyspnea and fibrotic complications (mesenteric and retroperitoneal fibrosis, and carcinoid heart disease). Although there are several drugs available for the treatment of carcinoid syndrome, the lack of therapeutic response, poor tolerance or resistance to drugs are often reported. Preclinical models are indispensable tools for investigating the pathogenesis, mechanisms for tumor progression and new therapeutic approaches for cancer. This paper provides a state-of-the-art overview of in vitro and in vivo models in NETs with carcinoid syndrome, highlighting the future developments and therapeutic approaches in this field.

A small intestine neuroendocrine tumor: case report

Small intestinal neuroendocrine tumors (SI-NETs) are the most common small bowel tumors, they are recognized for their ability to produce hormones causing mesenteric fibrosis and carcinoid syndrome. They tend to have better surgical rate than adenocarcinomas.this work was made as an update on one of the most aggressive small intestine tumors. Presentation of case We discuss here the case of a sixth years old female woman admitted and operated for a small intestine neuroendocrine tumor with peritoneal carcinosis Discussion Neuroendocrine tumors are secreting tumors, locating mainly in the small intestine with a high malignancy risk. At the time of the diagnosis, lymph node, liver metastasis and peritoneal carcinosis are very common. Patients may be asymptomatic or consult for abdominal pain, rarely bowel obstruction, diagnosis is radiologically made and confirmed indeed histologically. Treatment involves surgery, chemotherapy, immunotherapy and radiotherapy and surveillance is assured by biomarkers, endoscopy and Octreoscan when metastatic. Conclusion The SI-NETs are rare but their incidence and prevalence have been increasing. Histologically, diagnosis is confirmed by positive immunohistochemical staining. Treatment and prognosis depend on the grade and stage of the tumor. Immunotherapy will serve as a future treatment modality.

Vessel-Sparing Lymphadenectomy Should Be Performed in Small Intestine Neuroendocrine Neoplasms.

Simple SummaryPrimary tumor resection with lymphadenectomy in small intestine neuroendocrine neoplasms potentially requires extensive small bowel resections due to central lymph node metastases and mesenteric fibrosis. Retrograde vessel-sparing lymphadenectomy (VS-LA) might be a sufficient method for avoiding local recurrence and for sparing the small bowel at the same time. We retrospectively analyzed clinical, surgical and pathological data of 50 patients with SI-NENs who exclusively underwent small bowel resections; half of them received conventional lymphadenectomy and 25 underwent VS-LA. VS-LA resulted in shorter resected bowel segments (median 40 cm vs. 65 cm, p = 0.007) with similar rates of local R0 resections (72% vs. 84%) and number of resected lymph nodes (median 13 vs. 13). Postoperative complications occurred significantly less in the vessel-sparing group. VS-LA should be the preferred surgical method in small bowel resections for SI-NENs.Introduction: The goal of primary tumor resection with lymphadenectomy (PTR) in small intestine neuroendocrine neoplasms (SI-NENs) is to avoid local recurrence while sparing as much of the small bowel as possible, even in the case of extensive mesenteric fibrosis. The results of PTR with retrograde vessel-sparing lymphadenectomy (VS-LA) were compared to those of conventional lymphadenectomy (Con-LA). Methods: Prospectively collected clinical, surgical and pathological data of consecutive patients with SI-NENs who underwent small bowel resections were retrospectively analyzed regarding the resection technique performed. Results: In a 7-year period, 50 of 102 patients with SI-NENs had only small bowel resections; of those, 25 were VS-LA and 25 were Con-LA. Patients with VS-LA had tendentially more advanced diseases with slightly higher rates of abdominal pain, mesenteric shrinkage and more level III lymph node involvement compared to patients with Con-LA. VS-LA, however, resulted in shorter resected bowel segments (median 40 cm vs. 65 cm, p = 0.007) with similar rates of local R0 resections (72% vs. 84%) and resected lymph nodes (median 13 vs. 13). Postoperative clinically relevant complications occurred in 1 of 25 (4%) in the VS-LA and in 7 of 25 (28%) patients in the Con-LA group (p = 0.02). Three months after surgery, 1 of 25 (4%) patients of the VS-LA group and 10 of 25 (40%) patients in the Con-LA group (p = 0.002) complained about abdominal pain. One of eight patients in the VS-LA group and two of thirteen patients in the Con-LA group who had completely resected stage III disease complained about diarrhea (p = 0.31). Conclusion: VS-LA seems to be oncologically safe and should be considered in small bowel resections for SI-NENs.

Leonurine Attenuates Obesity-Related Vascular Dysfunction and Inflammation.

Oxidative stress in adipose tissue is a crucial pathogenic mechanism of obesity-associated cardiovascular diseases. Chronic low-grade inflammation caused by obesity increases ROS production and dysregulation of adipocytokines. Leonurine (LEO) is an active alkaloid extracted from Herba Leonuri and plays a protective role in the cardiovascular system. The present study tested whether LEO alleviates inflammation and oxidative stress, and improves vascular function in an obese mouse model. Here, we found that obesity leads to inflammation and oxidative stress in epididymal white adipose tissue (EWAT), as well as vascular dysfunction. LEO significantly improved inflammation and oxidative stress both in vivo and in vitro. Obesity-induced vascular dysfunction was also improved by LEO as evidenced by the ameliorated vascular tone and decreased mesenteric artery fibrosis. Using mass spectrometry, we identified YTHDF1 as the direct target of LEO. Taken together, we demonstrated that LEO improves oxidative stress and vascular remodeling induced by obesity and targets YTHDF1, raising the possibility of LEO treating other obesity-related metabolic syndromes.

Mesenteric Panniculitis, Sclerosing Mesenteritis and Mesenteric Lipodystrophy: Descriptive Review of a Rare Condition.

Mesenteric panniculitis (MP) is the preferred nomenclature for a continuum of inflammatory diseases of the mesentery. The diagnosis of MP is often based on the appearance of a mass-like structure at the root of the mesentery. Characteristic histology includes focal fat necrosis, chronic inflammation, and sometimes mesenteric fibrosis. At present, robust literature related to diagnosis and management of MP are limited. MP is postulated to be an immune-mediated chronic inflammatory and/or a paraneoplastic disease. A personal or family history of other autoimmune diseases is commonly apparent. Several inciting events have been identified that possibly act as triggers in the development of the disease. Trauma, abdominal surgery, infection, and various cancers have been associated with mesenteric panniculitis. There are several diagnostic and histologic criteria that aid in making the diagnosis of MP. The differential diagnosis for a mesenteric mass includes neoplastic disease, and a biopsy may be indicated to rule out other conditions. While cases of MP with a short duration of symptoms, or spontaneously regression may occur, some patients experience prolonged periods of pain, fever, and alterations in bowel habit, causing significant morbidity. A variety of medical therapies have been suggested for MP. Only two, thalidomide and low-dose naltrexone, have been prospectively evaluated. For patients with chronic MP, good responses to prolonged corticosteroid treatment have been reported. Novel therapies include thalidomide and low-dose naltrexone. Hormonal and immunomodulatory therapies are also used based on small case series, but these treatments may have significant side effects. Surgical intervention is not curative and is avoided except for relief of focal bowel obstruction secondary to fibrotic forms of the disease.

European Neuroendocrine Tumor Society (ENETS) 2022 Guidance Paper for Carcinoid Syndrome and Carcinoid Heart Disease

European Neuroendocrine Tumor Society (<scp>ENETS</scp>) 2022 Guidance Paper for Carcinoid Syndrome and Carcinoid Heart Disease

Aberrant tryptophan metabolism in stromal cells is associated with mesenteric fibrosis in small intestinal neuroendocrine tumors.

BackgroundIncreased 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.MethodsProteomes 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).ResultsOf the 42 proteins involved in tryptophan metabolism, 20 were detected by LC-MS. Lower abundance of ten 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).ConclusionWe found a decreased expression of tryptophan and serotonin-metabolizing enzymes in the stroma in patients with MF, most notably in the 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.

Predicting resectability of primary tumor and mesenteric lymph-node masses in patients with small-intestine neuroendocrine tumors.

Vascular infiltration may jeopardize resection of the primary tumor and mesenteric metastatic masses in small-intestine neuroendocrine tumors (SI-NETs). However, other factors may play a role in predicting resectability. After computed tomography (CT) scan, three radiological parameters were considered: (1) degree of superior mesenteric artery involvement (SMA) according to a previous classification (2) degree of superior mesenteric venous involvement (SMV) as either absent, peripheral or proximal (3) presence or not of mesenteric fibrosis retraction (MF). Pre-surgical parameters were matched to surgical outcome. Forty-nine consecutive patients were submitted to laparotomy. Of them, 37 had complete primary tumor and mesenteric masses resection. SMA (p = 0.001), SMV (p = 0.008), metastasis site (p = 0.001) and MF (p < 0.001) were all significantly associated with the likelihood to receive resection at univariate analysis. All the five patients with infiltration of SMV proximal to middle colic vein were unresectable. At multivariable analysis excluding SMA stage, the absence of MF (HR 13.1, I.C. 1.44-119; p = 0.002) was the only factor associated with the likelihood to receive primary tumor and mesentery radical surgery. SMA stage 3-up and/or signs of MF, as well as infiltration of SMV proximal to middle colic vein at CT scan are predictive of operative failure in patients with SI-NETs. The assessment of such factors should be always considered in the decision-making process of such patients especially in those with asymptomatic disease with synchronous unresectable liver metastases.

Small Bowel Obstruction as a Rare Complication of Progressive Sclerosing Mesenteritis

Abstract Introduction/Objective Sclerosing Mesenteritis is an uncommon, idiopathic, localized inflammatory syndrome involving the small intestine and colonic mesentery. It is considered a benign condition that commonly occurs in elderly with a gender predilection for males, and its etiology remains unknown. Small Bowel Obstruction (SBO) is a rare, unexpected, but detrimental complication of progressive Sclerosing Mesenteritis. Herein, we present a case of an enlarging, progressive Sclerosing Mesenteritis with extensive involvement of the small bowel and mesentery requiring two consecutive major surgical interventions. Methods/Case Report A 72-year-old male with Myelodysplastic Syndrome (MDS) and recent history of loop ileostomy due to distal intestinal obstruction secondary to enlarging Sclerosing Mesenteritis, presented to our institution with non-specific symptoms of worsening abdominal pain and multiple episodes of gastrointestinal bleeding. Radiographic investigation revealed SBO and he subsequently underwent exploratory laparotomy resulting in total enterectomy with excision of mesenteric mass, extended right colectomy, Whipple procedure, and gastrostomy. The specimens were sent to pathology for histopathological evaluation and gross examination revealed several bosselated, tan-white, firm and rubbery, fibrotic lesions with associated lobulated fibroadipose tissue. Microscopic examination showed extensive mesenteric fibrosis with dense bundles of collagen fibers, areas of fat necrosis, mucosal ischemia and calcification involving the small bowel and serosal surface of large intestine and peritoneum. The lesional cells showed minimal atypia, mitoses, and lacked the Beta-catenin nuclear staining seen in mesenteric fibromatosis. Given the clinical history and histopathological findings of the lesion, we favored the diagnosis of Sclerosing Mesenteritis. Results (if a Case Study enter NA) N/A Conclusion The etiology of Sclerosing Mesenteritis is not well-understood and there are cases of Sclerosing Mesenteritis reported in the literature in association with trauma, surgery, malignancy, and IgG4-related disease. Our patient’s post-operative history was complicated by short gut syndrome, and he is currently requiring small bowel transplant. We report this case for its unusual and aggressive clinical presentation, and to heighten clinical awareness for detrimental consequences of this seemingly benign condition.

Reverse translation approach generates a signature of penetrating fibrosis in Crohn’s disease that is associated with anti-TNF response

ObjectiveFibrosis is a common feature of Crohn’s disease (CD) which can involve the mesenteric fat. However, the molecular signature of this process remains unclear. Our goal was to define the...

Gastroenteropancreatic neuroendocrine neoplasms: A clinical snapshot.

Our understanding about the epidemiological aspects, pathogenesis, molecular diagnosis, and targeted therapies of neuroendocrine neoplasms (NENs) have drastically advanced in the past decade. Gastroenteropancreatic (GEP) NENs originate from the enteroendocrine cells of the embryonic gut which share common endocrine and neural differentiation factors. Most NENs are well-differentiated, and slow growing. Specific neuroendocrine biomarkers that are used in the diagnosis of functional NENs include insulin, glucagon, vasoactive intestinal polypeptide, gastrin, somatostatin, adrenocorticotropin, growth hormone releasing hormone, parathyroid hormone-related peptide, serotonin, histamine, and 5-hydroxy indole acetic acid (5-HIAA). Biomarkers such as pancreatic polypeptide, human chorionic gonadotrophin subunits, neurotensin, ghrelin, and calcitonin are used in the diagnosis of non-functional NENs. 5-HIAA levels correlate with tumour burden, prognosis and development of carcinoid heart disease and mesenteric fibrosis, however several diseases, medications and edible products can falsely elevate the 5-HIAA levels. Organ-specific transcription factors are useful in the differential diagnosis of metastasis from an unknown primary of well-differentiated NENs. Emerging novel biomarkers include circulating tumour cells, circulating tumour DNA, circulating micro-RNAs, and neuroendocrine neoplasms test (NETest) (simultaneous measurement of 51 neuroendocrine-specific marker genes in the peripheral blood). NETest has high sensitivity (85%-98%) and specificity (93%-97%) for the detection of gastrointestinal NENs, and is useful for monitoring treatment response, recurrence, and prognosis. In terms of management, surgery, radiofrequency ablation, symptom control with medications, chemotherapy and molecular targeted therapies are all considered as options. Surgery is the mainstay of treatment, but depends on factors including age of the individual, location, stage, grade, functional status, and the heredity of the tumour (sporadic vs inherited). Medical management is helpful to alleviate the symptoms, manage inoperable lesions, suppress postoperative tumour growth, and manage recurrences. Several molecular-targeted therapies are considered second line to somatostatin analogues. This review is a clinical update on the pathophysiological aspects, diagnostic algorithm, and management of GEP NENs.

Transcriptomic Profiling of In Vitro Tumor-Stromal Cell Paracrine Crosstalk Identifies Involvement of the Integrin Signaling Pathway in the Pathogenesis of Mesenteric Fibrosis in Human Small Intestinal Neuroendocrine Neoplasms.

AimAnalysis of the pathophysiology of mesenteric fibrosis (MF) in small intestinal neuroendocrine tumors (SI-NETs) in an in vitro paracrine model and in human SI-NET tissue samples.MethodsAn indirect co-culture model of SI-NET cells KRJ-I and P-STS with stromal cells HEK293 was designed to evaluate the paracrine effects on cell metabolic activity, gene expression by RT2 PCR Profilers to analyse cancer and fibrosis related genes, and RNA sequencing. The integrin signaling pathway, a specific Ingenuity enriched pathway, was further explored in a cohort of human SI-NET tissues by performing protein analysis and immunohistochemistry.ResultsRT Profiler array analysis demonstrated several genes to be significantly up- or down-regulated in a cell specific manner as a result of the paracrine effect. This was further confirmed by employing RNA sequencing revealing multiple signaling pathways involved in carcinogenesis and fibrogenesis that were significantly affected in these cell lines. A significant upregulation in the expression of various integrin pathway – related genes was identified in the mesenteric mass of fibrotic SI-NET as confirmed by RT-qPCR and immunohistochemistry. Protein analysis demonstrated downstream activation of the MAPK and mTOR pathways in some patients with fibrotic SI-NETs.ConclusionThis study has provided the first comprehensive analysis of the crosstalk of SI-NET cells with stromal cells. A novel pathway – the integrin pathway – was identified and further validated and confirmed in a cohort of human SI-NET tissue featured by a dual role in fibrogenesis/carcinogenesis within the neoplastic fibrotic microenvironment.

Management of Locally Advanced and Unresectable Small Bowel Neuroendocrine Tumours.

Three subtypes of small bowel neuroendocrine tumours (SBNETs) have been described: Type A: SBNET with resectable mesenteric disease that does not involve the mesenteric root; Type B: "Borderline resectable" SBNET presenting with mesenteric nodal metastases and fibrosis adjacent but not encasing the main trunk of the superior mesenteric artery (SMA) and superior mesenteric vein (SMV); and Type C: "Locally advanced or irresectable" SBNET where tumour deposits and fibrosis encase the SMA and SMV. Type C SBNETs are rare and constitute around 5% of patients in reported series, although this may underestimate the prevalence. In these patients, almost all will present with symptoms of intestinal ischemia or obstruction and symptom management should be a primary main focus of treatment. All patients should be carefully staged with cross-sectional imaging and 68Ga-dotate positron emission tomography, and discussed at a dedicated neuroendocrine tumour multidisciplinary meeting. Expert surgical review should always be sought as experienced centers have a high rate of successful resection of primary tumours and mesenteric disease. If resection is not feasible, surgical bypass should be considered in patients with a discrete and symptomatic point of obstruction. Non-operative management should emphasize symptomatic treatment with somatostatin analogs, nutritional advice and support and palliative care. Successful neoadjuvant approaches utilizing peptide radionucleide receptor therapy and systemic chemotherapy with everolimus or temazolamide/capecitabine have not been reported.

Role of Primary Tumor Resection for Metastatic Small Bowel Neuroendocrine Tumors.

While small bowel resection is well established as standard of care for curative-intent management of localized and loco-regional small bowel neuroendocrine tumors (SB-NETs), resection of the primary tumor in the setting of metastatic disease is debated. This review addresses the role of primary tumor resection for stage IV well-differentiated grade 1 and 2 SB-NETs. While survival benefits have been reported for primary tumor resection in the setting of metastatic disease, these studies are limited by selection bias and thus controversial. The main clinical benefits of primary tumor resection for stage IV disease involve the prevention of potentially debilitating complications associated with mesenteric fibrosis, including intestinal obstruction, mesenteric ischemia and angina, venous congestion, malabsorption, and malnutrition. Patients with metastases undergoing initial resection of the primary SB-NETs appear to have fewer episodes of care and re-intervention for loco-regional complications than those who do not undergo resection. As recommended by the NANETS and ENETS guidelines, resection of the primary tumor for stage IV SB-NETs should be strongly considered to avoid future loco-regional complications and potentially to improve survival. All patients with stage IV SB-NETs should be assessed by a surgeon experienced in the management of NETs to consider surgical therapies, including resection of the primary tumor despite metastatic disease.

Extent of Lymph Node Dissection for Small Bowel Neuroendocrine Tumors.

The management of nodal disease remains controversial for small bowel neuroendocrine tumors (SB-NETs). Debates remain regarding the therapeutic role and extent of routine lymph node dissection (LND) for localized SB-NETs, as well as the need for aggressive resection of advanced loco-regional SB-NETs with mesenteric nodal masses. This review will address these questions regarding lymph node dissection for well-differentiated WHO grade 1 and 2 SB-NETs. In general, the aggressiveness and radicality of resection should be balanced against the length of bowel resected and post-operative functional outcomes. In localized SB-NETs with clinically negative lymph nodes, a nodal harvest of ≥ 8 lymph nodes provides accurate staging, but has not been shown to confer survival benefit. For loco-regional SB-NETs with clinically positive lymph nodes identified on imaging, 4 stages of nodal extent have been described: stage 1 nodes are located near to the intestinal border, stage 2 on arterial branches close to the origin of the SMA, stage 3 along the SMA itself, and stage 4 extend in the retroperitoneum under the pancreatic neck. In SB-NETs, every attempt should be made at resection of the primary tumor and the nodal mesenteric mass for curative-intent management and to prevent debilitating complications from mesenteric fibrosis. A mesenteric-sparing approach is favored to allow for resection for complex proximal nodal masses while preserving intestinal length and function. All patients with SB-NETs with nodal mesenteric mass should be assessed by a surgeon for resection; if deemed unresectable, consideration should be given to assessment in high-volume NETs centres to confirm proximal mesenteric-sparing resection is not feasible.

Pathogenesis and Clinical Management of Mesenteric Fibrosis in Small Intestinal Neuroendocine Neoplasms: A Systematic Review.

Mesenteric fibrosis (MF) constitutes an underrecognized sequela in patients with small intestinal neuroendocrine neoplasms (SI-NENs), often complicating the disease clinical course. The aim of the present systematic review, carried out by Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology, is to provide an update in evolving aspects of MF pathogenesis and its clinical management in SI-NENs. Complex and dynamic interactions are present in the microenvironment of tumor deposits in the mesentery. Serotonin, as well as the signaling pathways of certain growth factors play a pivotal, yet not fully elucidated role in the pathogenesis of MF. Clinically, MF often results in significant morbidity by causing either acute complications, such as intestinal obstruction and/or acute ischemia or more chronic conditions involving abdominal pain, venous stasis, malabsorption and malnutrition. Surgical resection in patients with locoregional disease only or symptomatic distant stage disease, as well as palliative minimally invasive interventions in advanced inoperable cases seem clinically meaningful, whereas currently available systemic and/or targeted treatments do not unequivocally affect the development of MF in SI-NENs. Increased awareness and improved understanding of the molecular pathogenesis of MF in SI-NENs may provide better diagnostic and predictive tools for its timely recognition and intervention and also facilitates the development of agents targeting MF.