Small Intestinal Neuroendocrine Tumors Research Articles

Optimal follow-up with somatostatin receptor PET/CT imaging in patients with small intestinal neuroendocrine tumours.

Somatostatin receptor positron emission tomography with computerised tomography imaging (SRI) has a high sensitivity for the detection of small intestinal neuroendocrine tumors (siNET), which makes it ideal for follow-up. The aim of the present study was to investigate whether follow-up with SRI in patients with siNET led to any change in the treatment of the patient and if patient and/or tumour factors were associated with such change. Adults with siNET who had undergone at least two SRI scans between 2013 and 2021 were identified. Data on age, sex, comorbidities, tumour stage, grade, and most recent levels of serum Chromogranin A (CgA) and 24-h urine 5-hydroxyindoleacetic acid (5-HIAA) before each SRI scan were obtained. The major change was defined as new treatment previously not received or discontinuation of ongoing treatment. Univariate and multivariate mixed models logistic regression on variables with a presumed biological relationship with major change and with backwards stepwise exclusion of variables with p > .1 was performed. A total of 164 patients with siNET diagnosis had undergone 570 SRI scans. The median follow-up was 3.1 years. Only 82 of 570, 14%, of SRI scans led to a major change in treatment. Female sex, age below 75 years, elevated or missing CgA, elevated or missing urine 5-HIAA, progress on last SRI scan and distant extrahepatic disease were all independently associated with increased odds ratios for major change after follow-up with SRI. A small proportion of SRI scans (14%) led to a major change in treatment. Six independent risk factors with increased odds of major change, all available before each SRI scan, were identified. While validation of these risk factors is needed in a separate cohort, these findings could help clinicians individualise follow-up for siNET patients in the future.

Radio-Guided Surgery with a New-Generation β-Probe for Radiolabeled Somatostatin Analog, in Patients with Small Intestinal Neuroendocrine Tumors.

Radio-guided surgery (RGS) holds promise for improving surgical outcomes in neuroendocrine tumors (NETs). Previous studies showed low specificity (SP) using γ-probes to detect radiation emitted by radio-labeled somatostatin analogs. We aimed to assess the sensitivity (SE) and SP of the intraoperative RGS approach using a β-probe with a per-lesion analysis, while assessing safety and feasibility as secondary objectives. This prospective, single-arm, single-center, phase II trial (NCT05448157) enrolled 20 patients diagnosed with small intestine NETs (SI-NETs) with positive lesions detected at 68Ga-DOTA-TOC positron emission tomography/computed tomography (PET/CT). Patients received an intravenous injection of 1.1 MBq/Kg of 68Ga-DOTA-TOC 10min prior to surgery. Invivo measurements were conducted using a β-probe. Receiver operating characteristic (ROC) analysis was performed, with the tumor-to-background ratio (TBR) as the independent variable and pathology result (cancer vs. non-cancer) as the dependent variable. The area under the curve (AUC), optimal TBR, and absorbed dose for the surgery staff were reported. The intraoperative RGS approach was feasible in all cases without adverse effects. Of 134 specimens, the AUC was 0.928, with a TBR cut-off of 1.35 yielding 89.3% SE and 86.4% SP. The median absorbed dose for the surgery staff was 30 µSv (range 12-41 µSv). This study reports optimal accuracy in detecting lesions of SI-NETs using the intraoperative RGS approach with a novel β-probe. The method was found to be safe, feasible, and easily reproducible in daily clinical practice, with minimal radiation exposure for the staff. RGS might potentially improve radical resection rates in SI-NETs. 68Ga-DOTATOC Radio-Guided Surgery with β-Probe in GEP-NET (RGS GEP-NET) [NCT0544815; https://classic. gov/ct2/show/NCT05448157 ].

Mesenteric sparing approach for advanced nodal extent in small intestinal neuroendocrine tumors. Is there a limit to the vascular resection in order to avoid creating a short small bowel syndrome? An anatomic research study.

By selectively perfusing the first three jejunal arteries (JA), we aim to assess the individual perfusion length of small bowel (SB) and its impact on nodal resection in stage III-up small-intestinal neuroendocrine tumors (SI-NET). Our anatomical research protocol implies a midline laparotomy and three measures of the SB length. We then perform a classical anterior approach of the superior mesenteric vessels. We carry on with the complete dissection and checking of the superior mesenteric artery (SMA) in order to identify the first three JA. Then we selectively perfuse each artery with colored latex solutions and measure the length of small bowel perfused respectively. We conducted our protocol on six cadaveric subjects. Mean(SD) SB length was 413(5.7), 535(13.2), 485(15), 353(25.1), 730(17.3) and 525(16° cm respectively from subject one to six. Most JA originated from the left side of the SMA. The first JA originated from its posterior wall in two subjects. Mean(SD) distance of origin of the first three JA was 4.6(1.3)cm, 6(1.1)cm and 7.1(0.9)cm respectively. Mean(SD) diameter of SMA was 10.8(3.3)mm. Mean diameter of the three first JA was 4(1.4)mm, 4(1.5)mm and 5(1.2)mm respectively. Mean(SD) SB length perfused by first and second JA was 224(14.9)cm, 175(8.6)cm, 238.3(7.6)cm, 84.3(5.1)cm, 233.3(5.8)cm and 218.3(10.4)cm respectively from subject one to six. We observed a trend suggesting that the first and second JA may sustain a SB length beyond the viable 1.5m limit, implying the feasibility of stage III-up SI-NET resection with just two JA.

Prevalence of metastases outside the liver and abdominal lymph nodes on 68Ga-DOTATOC-PET/CT in patients with small intestinal and pancreatic neuroendocrine tumours.

Metastases outside the liver and abdominal/retroperitoneal lymph nodes are nowadays detected frequently in patients with neuroendocrine tumours (NETs), owing to the high sensitivity of positron emission tomography (PET) with Gallium-68-DOTA-somatostatin analogues (68Ga-SSA) and concomitant diagnostic computed tomography (CT). Our aim was to determine the prevalence of extra-abdominal metastases on 68Ga-DOTATOC-PET/CT in a cohort of patients with small intestinal (Si-NET) and pancreatic NET (Pan-NET), as well as that of pancreatic metastasis in patients with Si-NET. Among 2090 patients examined by 68Ga-DOTATOC-PET/CT at two tertiary referral centres, a total of 1177 patients with a history of Si- or Pan-NET, were identified. The most recent 68Ga-DOTATOC-PET/CT report for each patient was reviewed, and the location and number of metastases of interest were recorded. Lesions outside the liver and abdominal nodes were found in 26% of patients (n = 310/1177), of whom 21.5% (255/1177) were diagnosed with Si-NET and 4.5% (55/1177) Pan-NET. Bone metastases were found in 18.4% (215/1177), metastases to Virchow's lymph node in 7.1% (83/1177), and lung/pleura in 4.8% (56/1177). In the subset of 255 Si-NET patients, 5.4% (41/255) manifested lesions in the pancreas, 1.5% in the breast (18/255), 1.3% in the heart (15/255) and 1% in the orbita (12/255). In Si-NET patients, the Ki-67 proliferation index was higher in those with ≥2 metastatic sites of interest, than with 1 metastatic site, (p <0.001). Overall, extra-abdominal or pancreatic metastases were more often found in patients with Si-NET (34%) than in those with Pan-NET (13%) (p <0.001). Bone metastases were 2.6 times more frequent in patients with Si-NET compared to Pan-NET patients (p <0.001). Lesions to the breast and orbita were encountered in almost only Si-NET patients. In conclusion, lesions outside the liver and abdominal nodes were detected in as many as 26% of the patients, with different prevalence and metastatic patterns in patients with Si-NET compared to Pan-NET. The impact of such metastases on overall survival and clinical decision-making needs further evaluation.

Abstract 4234: Personalized therapeutic screening in patient derived organoids for gastroenteropancreatic neuroendocrine tumors

Abstract Introduction Gastroenteropancreatic Neuroendocrine Neoplasms (GEP-NENs) are a rare subset of cancers which nevertheless are a rising health burden. Development of new therapies suffers from several bottlenecks, including low patient accrual and poor understanding of tumor characteristics. Patient tumor organoids (PTOs) are a novel model capable of improving screening of patient tissue in an accurate, standardized, and high-throughput capacity. In this study, we utilized patient tumors for creation of high-fidelity PTOs from a variety of GEP-NEN primary origins to evaluate therapy responses. Methods Tumors from patients undergoing clinically guided surgeries were processed within two hours of resection and dissociated into single-cell suspension. Cells were encapsulated into Matrigel and cultured into two groups. The first group was grown for 10 days to assess viability then treated with a panel of clinically approved therapies and novel treatments recommended by high throughput NEN cell line screening for treatment sensitivity using the MIPE 5.0 library. The second group was grown for long-term expansion and biobanking, followed by characterization using immunohistochemistry and genetic profiling to ensure tumor cell maintenance. Results From March 2023-November 2023, 14 patients provided 30 tumors for PTO development. These included small intestine (n=5), pancreatic (n=8), and gastric (n=1) neuroendocrine tumors. Long-term culture (&amp;gt;3 passages) was successful for 23/30 (77%) specimens, with passage timing related to tumor grade. PTOs maintained immunohistochemical characteristics of the parent tumor types and demonstrated similar genetic profiles, including neuroendocrine tumor cell markers synaptophysin, chromogranin A, and matched grade-based Ki67 proliferative index. The early-stage therapeutic screening was performed for 12/14 (86%) patients, demonstrating tumor grade dependent treatment efficacy and showing clinically dose relevant sensitivity towards approved small molecule inhibitor therapies including cabozantinib and sunitinib in a patient and tumor origin-dependent manner. Testing of effective therapy classes recommended by cell line treatment panels suggested high level treatment efficacy for proteosome inhibitors, MEK inhibitors, and topoisomerase inhibitors. Conclusion Development of GEP-NEN PTOs is feasible for long term culture and standard of care therapy testing. Further study demonstrated the successful application of novel therapeutic options in PTOs for patients with GEP-NENs. Citation Format: Steven D. Forsythe, Srujana V. Yellapragada, Stephen G. Andrews, Jaydira del Rivero, Jonathan M. Hernandez, Naris Nilubol, James P. Madigan, Samira M. Sadowski. Personalized therapeutic screening in patient derived organoids for gastroenteropancreatic neuroendocrine tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4234.

Systemic Therapy for Pancreatic Neuroendocrine Tumors.

Pancreatic neuroendocrine tumors (PanNETs) account for approximately 2% of all pancreatic malignancies. Several systemic treatment options have been developed over the last four decades, ranging from cytotoxic chemotherapy and octreotide to newer targeted therapies like sunitinib, cabozantinib, and lenvatinib. Although surgery or liver-directed therapy remains cornerstone for management of metastatic PanNETs, however, they remain unfeasible in majority of cases. PanNETs behave differently than SI-NETs (small intestinal NET); the former is more aggressive and less responsive to somatostatin-based therapies. The optimal sequence of the systemic therapies for the advanced PanNETs depends mainly on the tumor burden, Ki-67 index, and the tempo of the disease. In the end, drawing from ENETS (European Neuroendocrine Tumor Society) and ESMO (European Society for Medical Oncology) guidelines, we propose a working algorithm for the management of advanced PanNETs, not amenable to surgery or liver-directed therapies.

Modified Histopathological Grading Optimizes Prediction of Survival Outcomes in Small Intestinal Neuroendocrine Tumours.

One of the major prognostic indices in neuroendocrine tumours (NETs) is Ki67 proliferation index. To identify optimal grading Ki-67 cut-offs to delineate differences in prognosis of patients with small intestinal NETs (SI-NETs). Multicentre retrospective cohort analysis of 551 SI-NET patients diagnosed from 1993 through 2021 at five European referral centres with a mean(±SD) follow-up time of 51.5(±52.9) months. Overall- and event-free survival (OS and EFS) rates. Median age at baseline was 62.3(range:17-90) years; 252(45.7%) patients were female. All SI-NETs were well-differentiated with 326 being grade 1(G1; 59.2%), 169G2(30.7%), and only 8G3(1.5), while 48 tumours were of unspecified grade (8.7%). The median Ki67 was 2%(range:1-70%). Two-hundred forty-seven patients (44.8%) had distant metastases at baseline (stage IV), 217 locoregional disease (41.1%; stage III), whereas 29(7.1%) and 25(4.5%) presented at stages II and I, respectively. The median OS was 214.7(95%CI:152.7-276.6) months and the median EFS was 79.8(95%CI:68.2-91.5) months, respectively. In multivariable Cox-regression OS analysis, the proposed modified histopathological Ki67 grading system (K67:5-10% group: HR=2.2, 95%CI:1.15-4.31; p=0.018 and K67≥10% group: HR=5.11, 95%CI:2.87-9.09; p<0.001), age (HR=1.07, 95%CI:1.04-1.09; p<0.001), Charlson Comorbidity Index (HR=1.08, 95%CI:1-1.16; p=0.028) and TNM stage (HR=1.79, 95%CI:1.05-3.06; p=0.034) were independent predictors for death. Pertinent EFS analysis, confirmed the proposed modified histopathological Ki67 grading system (K67≥10% group: HR=4.01, 95%CI:2.6-6.37; p<0.001) and age (HR=1.04, 95%CI:1.02-1.05; p<0.001) as independent predictors for recurrence, progression and/or death. Ki-67 proliferation index was a strong and independent predictor of OS and EFS. A modified histopathological grading system applying Ki-67 cut-offs of 5 and 10% could be superior to predict differences in SI-NET patient survival outcomes.

Diagnosis and staging of small intestinal neuroendocrine tumors with CT enterography and PET with Gallium-68: preoperative risk stratification protocol.

Pre-operative diagnosis and staging of small intestine neuroendocrine tumors (SI-NETs) remain sub-optimal, with open palpation during surgery still considered the gold standard. This limits a standardized implementation of minimally invasive surgery (MIS). The aim of this single-center retrospective study was to assess a tailored diagnostic work-up to identify candidates at low risk of undetected disease who may benefit from MIS. Patients diagnosed with SI-NETs between 2013 and 2022 who underwent contrast-enhanced computed tomography enterography (CTE) and Ga68-DOTATOC-positron emission tomography-CT (68Ga DOTATATE PET/CT) preoperatively and subsequently underwent open surgical resection were included. Imaging studies were reassessed by two radiologists. Combined use of CTE and 68Ga DOTATATE PET/CT in determining primary lesion disease burden (number of lesions) and LN disease stage (distal and proximal relative to superior mesenteric vessels) was assessed, using surgical reports and pathology as gold standard. Overall, 56 patients were included. Sensitivity of CTE and 68Ga DOTATATE PET/CT for at least one primary SI-NET was 100% and 94%, respectively. In the presence of concordance between studies, combined use of CTE and 68Ga DOTATATE PET/CT for detection of single primary tumors improved specificity to 89% (n = 25/28) with a positive predictive value of 87.5% (n = 21/24). Distal LN disease was identified in 89.2% of cases (n = 33/37). The association of single lesion and distal LN disease was found pre-operatively in 32% of patients (n = 18). Combined use of CTE and 68Ga DOTATATE PET/CT enables identifying low-risk surgical candidates (single SI-NET lesions with distal LN disease).

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.

Outcome on Mesenteric Mass Response of Small-Intestinal Neuroendocrine Tumors Treated by 177Lu-DOTATATE Peptide Receptor Radionuclide Therapy: The MesenLuth Study, a National Study from the French Group of Endocrine Tumors and Endocan-RENATEN Network.

A mesenteric mass (MM), characterized by fibrotic reaction, is present in most small-intestinal neuroendocrine tumors (SI-NETs). 177Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) has shown its efficacy in patients with progressive SI-NETs. However, because of specific tissue characteristics of desmoplastic MMs, we hypothesize that these lesions may be refractory to 177Lu-DOTATATE PRRT. Methods: From the national French Groupe d'étude des Tumeurs Endocrines database, we identified patients with an advanced SI-NET and a MM (≥2 cm with a retractile aspect) of a SI-NET treated by at least 1 course of 177Lu-DOTATATE PRRT. The primary endpoint was a MM objective response rate (ORR) of less than 5%. Secondary endpoints were metabolic response, MM-related safety, and clinical response, as well as MM progression-free survival (PFS) and non-MM PFS. Results: In total, 52 patients were included. The MM ORR was 4% (n = 2), and the non-MM ORR was 8% (n = 4). No patient had a MM metabolic response, and the non-MM metabolic response rate was 12% (n = 6). Among the 26 patients with baseline MM-related symptoms, 46% had a clinical response. Four patients presented with gastrointestinal complications during PRRT. The median MM-related PFS was not reached, and the non-MM PFS was 50.3 mo (95% CI, 38.2-61.7 mo). Conclusion: This study confirms that 177Lu-DOTATATE PRRT does not lead to morphologic response on MMs (ORR < 5%). However, it allows MM stability, with few MM-related side effects, and has a relevant impact on MM-related symptoms.

Multi-omic dataset of patient-derived tumor organoids of neuroendocrine neoplasms.

Organoids are 3-dimensional experimental models that summarize the anatomical and functional structure of an organ. Although a promising experimental model for precision medicine, patient-derived tumor organoids (PDTOs) have currently been developed only for a fraction of tumor types. We have generated the first multi-omic dataset (whole-genome sequencing [WGS] and RNA-sequencing [RNA-seq]) of PDTOs from the rare and understudied pulmonary neuroendocrine tumors (n = 12; 6 grade 1, 6 grade 2) and provide data from other rare neuroendocrine neoplasms: small intestine (ileal) neuroendocrine tumors (n = 6; 2 grade 1 and 4 grade 2) and large-cell neuroendocrine carcinoma (n = 5; 1 pancreatic and 4 pulmonary). This dataset includes a matched sample from the parental sample (primary tumor or metastasis) for a majority of samples (21/23) and longitudinal sampling of the PDTOs (1 to 2 time points), for a total of n = 47 RNA-seq and n = 33 WGS. We here provide quality control for each technique and the raw and processed data as well as all scripts for genomic analyses to ensure an optimal reuse of the data. In addition, we report gene expression data and somatic small variant calls and describe how they were generated, in particular how we used WGS somatic calls to train a random forest classifier to detect variants in tumor-only RNA-seq. We also report all histopathological images used for medical diagnosis: hematoxylin and eosin-stained slides, brightfield images, and immunohistochemistry images of protein markers of clinical relevance. This dataset will be critical to future studies relying on this PDTO biobank, such as drug screens for novel therapies and experiments investigating the mechanisms of carcinogenesis in these understudied diseases.

Bronchospasm Complicating A Small Intestine Neuroendocrine Tumor Resection: A Case Report

Small intestinal neuroendocrine tumors (SI-NETs) are rare neoplasms with increasing incidence, known for their diverse clinical presentations and potential hormonal complications. We present the case of a 65-year-old male with a history of chronic smoking and alcoholism, who presented with right iliac fossa pain, liquid diarrhea, and weight loss. Imaging revealed a neuroendocrine tumor of the small intestine, and the patient underwent surgical resection. However, postoperatively, he developed respiratory distress suggestive of bronchospasm, requiring intensive care management. Histopathological analysis confirmed a well-differentiated neuroendocrine tumor, Grade 2. This case underscores the importance of early recognition and management of hemodynamic complications following surgical resection of SI-NETs. Preoperative assessment for carcinoid syndrome and optimization of cardiac function are crucial to minimize perioperative risks. Surgical resection with meticulous attention to complete tumor removal and mesenteric dissection remains the mainstay of treatment for SI-NETs. Further research is needed to refine perioperative management strategies and improve long-term outcomes for patients with SI-NETs.

Outlook for 615 Small Intestinal Neuroendocrine Tumor Patients: Recurrence Risk after Surgery and Disease-Specific Survival in Advanced Disease.

Small intestinal neuroendocrine tumors (siNET) are one of the most common neuroendocrine neoplasms. Radical surgery is the only curative treatment. We utilized a single-center study including consecutive patients diagnosed from 2000 to 2020 and followed them until death or the end of study. Disease-specific survival and recurrence-free survival (RFS) were investigated by Cox regression analyses with the inclusion of prognostic factors. Aims/primary outcomes: We identified three groups: (1) disease specific-survival in the total cohort (group1), (2) RFS and disease-specific survival after intended radical surgery (group2), (3) disease specific-survival in patients with unresectable disease or residual tumor after primary resection (group3). In total, 615 patients, with a mean age (SD) 65 ± 11 years were included. Median (IQR) Ki-67 index was 4 (2-7)%. Median disease-specific survival in group1 was 130 months. Median RFS in group2 was 138 months with 5- and 10-year RFS rates of 72% and 59% with age, plasma chromogranin A (p-CgA) and Ki-67 index as prognostic factors. The ten year disease-specific survival rate in group2 was 86%. The median disease-specific survival in group3 was 85 months with age, Ki-67 index, p-CgA and primary tumor resection as prognostic factors. When proliferation was expressed by WHO grade, no difference was observed between G1 vs. G2 for any of the primary outcomes. Recurrence rates remained high 5-10 years after surgery (group2) supporting long-term follow-up. Median disease-specific survival in patient with unresectable disease (group3) was 7 years, with a favorable impact of primary tumor resection. Our data does not support the current grading system since no significant prognostic information was detected in G1 vs. G2 tumors.

Identification of TIMP1-induced dysregulation of epithelial-mesenchymal transition as a key pathway in inflammatory bowel disease and small intestinal neuroendocrine tumors shared pathogenesis.

Inflammatory Bowel Disease (IBD) is believed to be a risk factor for Small Intestinal Neuroendocrine Tumors (SI-NET) development; however, the molecular relationship between IBD and SI-NET has yet to be elucidated. In this study, we use a systems biology approach to uncover such relationships. We identified a more similar transcriptomic-wide expression pattern between Crohn's Disease (CD) and SI-NET whereas a higher proportion of overlapping dysregulated genes between Ulcerative Colitis (UC) and SI-NET. Enrichment analysis indicates that extracellular matrix remodeling, particularly in epithelial-mesenchymal transition and intestinal fibrosis mediated by TIMP1, is the most significantly dysregulated pathway among upregulated genes shared between both IBD subtypes and SI-NET. However, this remodeling occurs through distinct regulatory molecular mechanisms unique to each IBD subtype. Specifically, myofibroblast activation in CD and SI-NET is mediated through IL-6 and ciliary-dependent signaling pathways. Contrarily, in UC and SI-NET, this phenomenon is mainly regulated through immune cells like macrophages and the NCAM signaling pathway, a potential gut-brain axis in the context of these two diseases. In both IBD and SI-NET, intestinal fibrosis resulted in significant metabolic reprogramming of fatty acid and glucose to an inflammatory- and cancer-inducing state. This altered metabolic state, revealed through enrichment analysis of downregulated genes, showed dysfunctions in oxidative phosphorylation, gluconeogenesis, and glycogenesis, indicating a shift towards glycolysis. Also known as the Warburg effect, this glycolytic switch, in return, exacerbates fibrosis. Corresponding to enrichment analysis results, network construction and subsequent topological analysis pinpointed 7 protein complexes, 17 hub genes, 11 microRNA, and 1 transcription factor related to extracellular matrix accumulation and metabolic reprogramming that are candidate biomarkers in both IBD and SI-NET. Together, these biological pathways and candidate biomarkers may serve as potential therapeutic targets for these diseases.

A retrospective study comparing minimally invasive versus open surgical resection of small intestinal neuroendocrine neoplasms at a tertiary referral center

IntroductionNeuroendocrine neoplasms (SI-NEN) are the commonest malignancies of the small intestine. Traditionally, surgical treatment for SI-NEN has been open surgery. PurposeThe purpose of this study was to compare minimally invasive surgery (MIS) with the traditional open surgery approach for treating SI-NEN in a Swedish population. MethodsPatients with histopathological confirmed SI-NEN who underwent open surgery or MIS resection within 2009–2021 were extracted from the hospital's medical records. Results65 patients were included in this study, with 35 (54 %) undergoing MIS and 30 (46 %) undergoing open surgery. We found no statistically significant difference (p = 0.173) in the frequency of R0 resections (MIS group n = 34 (97 %), open surgery group n = 26 (87 %)). Nor was there a significant difference (p = 0.101) when comparing the median number of resected lymph nodes (MIS group n = 13.5, open surgery group n = 10). A post-operative paralytic ileus was more often reported (p = 0.052) in the MIS group (n = 9, 26 %) compared to the open surgery group (n = 2, 7 %). In light of this, the days of hospital stay did not differ significantly (MIS group median = 6, IQR (5–8), open surgery group median = 6, IQR (5–9)). The Kaplan-Meier analysis did not reveal differences concerning cancer-related deaths (p = 0.109). ConclusionThe results from this study support that a MIS approach for the treatment of SI-NEN may not be inferior to open surgery. The higher number of resected lymph nodes and R0 resections may even speak in favor for a MIS approach. More studies with a longer time of observation are needed to further support this conclusion.

Resistant gastroenteropancreatic neuroendocrine tumors: a definition and guideline to medical and surgical management

Gastroenteropancreatic neuroendocrine tumors (NETs), also historically known as carcinoids, are tumors derived of hormone-secreting enteroendocrine cells. Carcinoids may be found in the esophagus, stomach, small intestine, appendix, colon, rectum, or pancreas. The biologic behavior of carcinoids differs based on their location, with gastric and appendiceal NETs among the least aggressive and small intestinal and pancreatic NETs among the most aggressive. Ultimately, however, biologic behavior is most heavily influenced by tumor grade. The incidence of NETs has increased by 6.4 times over the past 40 years. Surgery remains the mainstay for management of most carcinoids. Medical management, however, is a useful adjunct and/or definitive therapy in patients with symptomatic functional carcinoids, in patients with unresectable or incompletely resected carcinoids, in some cases of recurrent carcinoid, and in postoperative patients to prevent recurrence. Functional tumors with persistent symptoms or progressive metastatic carcinoids despite therapy are called “resistant” tumors. In patients with unresectable disease and/or carcinoid syndrome, an array of medical therapies is available, mainly including somatostatin analogues, molecular-targeted therapy, and peptide receptor radionuclide therapy. Active research is ongoing to identify additional targeted therapies for patients with resistant carcinoids.

Plasma or serum 5-hydroxyindoleacetic acid can be used interchangeably in patients with neuroendocrine tumours

5-hydroxyindole acetic acid, a metabolite of serotonin, is used in the diagnosis and monitoring of patients with neuroendocrine tumours, in particular patients with small intestinal neuroendocrine tumours associated with the carcinoid syndrome. Analysis of 5-hydroxyindole acetic acid was commonly performed in urine, but blood-based assays are now becoming available. The objective of this study was to assess how 5-hydroxyindole acetic acid compares in plasma and serum as a biochemical marker of neuroendocrine tumours. Twenty-four-hour urine, plasma and serum samples were obtained from 80 patients with neuroendocrine tumours and 30 healthy volunteers. We developed a liquid chromatography tandem mass spectrometry assay for plasma and serum 5-hydroxyindole acetic acid. Comparison was made between them, and their cut-off was determined using a receiver-operating characteristic curve. A close correlation was shown between plasma and serum 5-hydroxyindole acetic acid. At a cut-off of 135 nmol/l, a sensitivity of 91.2% with a specificity of 61.9% was obtained for both compared to the urinary assay. A statistically significant agreement was shown when plasma and serum 5-hydroxyindole acetic acid were compared with the currently used urine assay in patients with neuroendocrine tumours; κ = 0.675 (95% CI 0.49 to 0.86), p < 0.001 and healthy volunteers; 0.967 (95% CI 0.828 to 0.999), p = <0.001. In conclusion, 5-hydroxyindole acetic acid in plasma and serum were comparable, hence either sample type can be used interchangeably.

Feasibility of home parenteral nutrition in patients with intestinal failure due to small intestinal neuroendocrine tumours: a systematic review

Feasibility of home parenteral nutrition in patients with intestinal failure due to small intestinal neuroendocrine tumours: a systematic review

Application of Machine Learning in Predicting Hepatic Metastasis or Primary Site in Gastroenteropancreatic Neuroendocrine Tumors.

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) account for 80% of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). GEP-NETs are well-differentiated tumors, highly heterogeneous in biology and origin, and are often diagnosed at the metastatic stage. Diagnosis is commonly through clinical symptoms, histopathology, and PET-CT imaging, while molecular markers for metastasis and the primary site are unknown. Here, we report the identification of multi-gene signatures for hepatic metastasis and primary sites through analyses on RNA-SEQ datasets of pancreatic and small intestinal NETs tissue samples. Relevant gene features, identified from the normalized RNA-SEQ data using the mRMRe algorithm, were used to develop seven Machine Learning models (LDA, RF, CART, k-NN, SVM, XGBOOST, GBM). Two multi-gene random forest (RF) models classified primary and metastatic samples with 100% accuracy in training and test cohorts and >90% accuracy in an independent validation cohort. Similarly, three multi-gene RF models identified the pancreas or small intestine as the primary site with 100% accuracy in training and test cohorts, and >95% accuracy in an independent cohort. Multi-label models for concurrent prediction of hepatic metastasis and primary site returned >98.42% and >87.42% accuracies on training and test cohorts, respectively. A robust molecular signature to predict liver metastasis or the primary site for GEP-NETs is reported for the first time and could complement the clinical management of GEP-NETs.

Management Strategies and Outcomes for Small Intestinal Neuroendocrine Tumours with Involvement of the Superior Mesenteric Vessels: A Systematic Review.

Small intestinal neuroendocrine tumours (SI-NETs) are the most common small intestinal tumours. A particularly challenging subset of these tumours is those that involve the superior mesenteric artery or vein for which the role and feasibility of surgery are often questioned. This systematic review aimed to identify and evaluate the management strategies used for these complex SI-NETs. The identified studies showed positive outcomes with surgery and multimodality therapy.