Small Intestinal Neuroendocrine Tumors Research Articles

Evolution of the Mesenteric Mass in Small Intestinal Neuroendocrine Tumours.

Simple SummaryAround two-thirds of patients with small intestinal neuroendocrine tumours are present with a metastatic mesenteric mass. This mass is known to cause intestinal complications, however, little is known on its development over time in the era of targeted therapy. Therefore, we conducted a retrospective study to assess the growth and response to therapy. We found that the growth of the mesenteric mass was detectable in 13.5% over a median time of 3.4 years and peptide receptor radionuclide therapy resulted in size reduction in only 3.8%. This site-specific static growth behavior is important to note when assessing disease progression and therapeutic options.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.

Phase II trial of the CDK4/6 inhibitor abemaciclib in patients (pts) with advanced and refractory well‐differentiated gastroenteropancreatic neuroendocrine tumors (GEP NETs).

TPS376 Background: Despite advances in the treatment of advanced GEP NETs, long‐term disease control remains a challenge. Overexpression and altered regulation of cyclin-dependent kinases (CDK) 4 and 6 have been observed in multiple subtypes of GEP NETs. Preclinical studies have demonstrated that the CDK 4/6 inhibitor palbociclib reduces growth of pancreatic NET cell lines and levels of phosphorylated retinoblastoma protein in vitro. Moreover, the drug significantly inhibited tumor growth in vivo in pancreatic NET xenograft models. Abemaciclib is a selective small molecule CDK 4/6 inhibitor, approved for the treatment of HR+ HER2– metastatic breast cancer. Clinical activity and central nervous system penetration of the drug have been observed in several tumor types in clinical trials, including partial response in one pt with metastatic small intestinal NET. We have developed a Phase 2 trial of abemaciclib in GEP NETs to evaluate its efficacy and safety in these rare cancers. Methods: This is an investigator-initiated non-randomized phase 2 trial using a two-stage design. Eligible pts have metastatic or locally advanced unresectable well-differentiated grade 1-2 GEP NETs, ECOG PS 0-2, and must have progressed on at least one line of systemic therapy. Prior or concurrent treatment with somatostatin analogs is allowed,. Abemaciclib is administered at a dose of 200 mg orally every 12 hours continuously in 28-day cycles. Dose reductions for toxicities are allowed to level -1 (150 mg) and -2 (100 mg). Primary endpoint is objective response rate (ORR) by RECIST v1.1. Secondary endpoints include progression free survival (PFS), overall survival (OS), and toxicity. A two‐stage design with 88% power to detect an increase in ORR to 20% with abemaciclib at the 1‐sided 0.05 level would require a total of 37 patients. Stage 1 will include 20 patients, and if one response is seen among these patients, the study will continue to enroll another 17 patients. The trial was activated in January 2020, and 3 patients have been enrolled to date. Available archival tumor tissue and molecular profiling data are collected for future correlative studies including assessment of response biomarkers.

Cell-Free DNA and Clinical Characteristics in Patients with Small Intestinal or Pancreatic Neuroendocrine Tumors

Introduction: Neuroendocrine tumors (NETs) are rare and characterized by a heterogeneous clinical course and an unmet need for better prognostic markers. Plasma cell-free DNA (cfDNA) has prognostic value in other malignancies but is not previously investigated in NETs. We studied cfDNA levels in patients with mainly low-grade small intestinal NET ­(siNET) or pancreatic NET (pNET) and evaluated the prognostic potential of cfDNA. Materials and Methods: We included 70 NET patients, siNET (n = 50) and pNET (n = 20). Plasma cfDNA levels were determined by droplet digital PCR for the beta-2-microglobulin gene every 6 months during a period of 3 years, including in a subgroup of 19 patients during peptide receptor radionuclide therapy (PRRT) therapy. Results: cfDNA levels were higher in both siNET and pNET compared to a previously established healthy cohort (p < 0.0001). ­cfDNA levels did not predict overall survival (crude hazard ratio [HR] 0.95 [0.57–1.58], p = 0.837, adjusted for smoking status HR 0.77 [0.51–1.17], p = 0.22). The impact of cfDNA level on progression-free survival showed different trends in siNET and pNET. There was no effect of PRRT treatment on cfDNA levels and no difference in cfDNA levels between patients with and without progressive disease after PRRT (ANOVA p = 0.66). cfDNA levels were significantly higher in never-smokers and previous smokers than in current smokers (p = 0.029). Discussion/Conclusion: cfDNA levels are higher in NET patients than in healthy controls; however, there was no association with prognosis, and cfDNA levels were unaffected by PRRT. Our observations suggest that cfDNA levels are not associated with the disease course in low-grade NET in contrast to other malignancies.

Prognostic Factors in Curative Resected Locoregional Small Intestine Neuroendocrine Neoplasms.

Small intestinal neuroendocrine neoplasms (SI-NEN) are rare, and only about 40% of patients are diagnosed without distant metastases. Aim of the study was to identify prognostic factors in patients with potentially curative resected locoregional SI-NEN. Patients with curative resected locoregional SI-NEN (ENETS stages I-III) were retrieved from a prospective data base. Demographic, surgical and pathological data of patients with and without disease recurrence were retrospectively analyzed using univariate and multivariate analysis. In a 20-year period, 65 of 203 (32%) patients with SI-NEN were operated for stages I-III disease. Thirty-eight (58.5%) patients were men, and the median age at surgery was 59 (range 37-87) years. After median follow-up of 65months, 14 patients experienced disease relapse median 28.5 (range 6-122) months after initial surgery, of which 2 died due to their disease. Multivariate analysis revealed age ≥ 60years (HR = 6.41, 95% CI 1.38-29.67, p = 0.017), tumor size ≥ 2cm (HR = 26.54, 95% CI 4.46-157.62, p < 0.001), lymph node ratio > 0.5 (HR 7.18, 95% CI 1.74-29.74, p = 0.007) and multifocal tumor growth (HR = 6.98, 95% CI 1.66-29.39, p = 0.008) as independent negative prognostic factors and right hemicolectomy compared to segmental small bowel resection (HR = 0.04, 95% CI 0.01-0.24, p < 0.001) as independent protector against recurrence. Patients with locoregional SI-NEN with an age ≥ 60years, tumor size ≥ 2cm, lymph node ratio > 0.5 and multiple small bowel tumor foci have an increased risk for recurrence and might benefit from adjuvant treatment. In contrast, right hemicolectomy of ileal SI-NEN seems to reduce the risk of recurrence.

Resection of Primary Gastrointestinal Neuroendocrine Tumor Among Patients with Non-Resected Metastases Is Associated with Improved Survival: A SEER-Medicare Analysis

BackgroundThe objective of this study was to analyze whether primary tumor resection (PTR) among patients with stage IV gastrointestinal neuroendocrine tumor (GI-NET) and unresected metastases was associated with improved outcomes. MethodsPatients diagnosed with stage IV GI-NETs were identified in the linked SEER-Medicare database from 2004 to 2015. Overall survival (OS) of patients who did versus did not undergo PTR was examined using bivariate and multivariable cox regression analysis as well as propensity score matching (PSM). ResultsAmong 2219 patients with metastatic GI-NETs, 632 (28.5%) underwent PTR, whereas 1587 (71.5%) did not. The majority of individuals had a NET in the pancreas (n = 969, 43.6%); the most common site of metastatic disease was the liver (n = 1064, 47.9%). Patients with stage IV small intestinal NETs most frequently underwent PTR (62.6%) followed by individuals with colon NETs (56.5%). After adjusting for all competing factors, PTR remained independently associated with improved OS (HR = 0.65, 95% CI: 0.56–0.76). Following PSM (n = 236 per group), patients who underwent PTR had improved OS (median OS: 1.3 years vs 0.8 years, p = 0.016). While PTR of NETs originating from stomach, small intestine, colon, and pancreas was associated with improved OS, PTR of rectal NET did not yield a survival benefit. ConclusionPrimary GI-NET resection was associated with a survival benefit among individuals presenting with metastatic GI-NET with unresected metastases. Resection of primary GI-NET among patients with stage IV disease and unresected metastases should only be performed in selected cases following multi-disciplinary evaluation.

CDKN1B mutation and copy number variation are associated with tumor aggressiveness in luminal breast cancer.

The CDKN1B gene, encoding for the CDK inhibitor p27kip1, is mutated in defined human cancer subtypes, including breast, prostate carcinomas and small intestine neuroendocrine tumors. Lessons learned from small intestine neuroendocrine tumors suggest that CDKN1B mutations could be subclonal, raising the question of whether a deeper sequencing approach could lead to the identification of higher numbers of patients with mutations. Here, we addressed this question and analyzed human cancer biopsies from breast (n = 396), ovarian (n = 110) and head and neck squamous carcinoma (n = 202) patients, using an ultra‐deep sequencing approach. Notwithstanding this effort, the mutation rate of CDKN1B remained substantially aligned with values from the literature, showing that essentially only hormone receptor‐positive breast cancer displayed CDKN1B mutations in a relevant number of cases (3%). However, the analysis of copy number variation showed that another fraction of luminal breast cancer displayed loss (8%) or gain (6%) of the CDKN1B gene, further reinforcing the idea that the function of p27kip1 is important in this type of tumor. Intriguingly, an enrichment for CDKN1B alterations was found in samples from premenopausal luminal breast cancer patients (n = 227, 4%) and in circulating cell‐free DNA from metastatic luminal breast cancer patients (n = 59, 8.5%), suggesting that CDKN1B alterations could correlate with tumor aggressiveness and/or occur later during disease progression. Notably, many of the identified somatic mutations resulted in p27kip1 protein truncation, leading to loss of most of the protein or of its C‐terminal domain. Using a gene‐editing approach in a luminal breast cancer cell line, MCF‐7, we observed that the expression of p27kip1 truncating mutants that lose the C‐terminal domains failed to rescue most of the phenotypes induced by CDKN1B gene knockout, indicating that the functions retained by the C‐terminal portion are critical for its role as an oncosuppressor, at least in luminal breast cancer. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Assessment of hormonal levels as prognostic markers and of their optimal cut-offs in small intestinal neuroendocrine tumours grade 2

PurposeSmall intestinal neuroendocrine tumours (siNETs) with a Ki-67 proliferation index between 3 and 20% belong to WHO grade 2. Response to treatment may be monitored by blood chromogranin A (CgA) and urine 5-hydroxyindoleacetic acid (5HIAA). The aim of this retrospective study was to investigate the prognostic value of baseline CgA and 5HIAA and of the early biochemical response to treatment, and to compare different cut-off values used in the literature.MethodsA retrospective cohort study of 184 patients with siNET Grade 2 treated with somatostatin analogues (SSA), interferon-alpha (IFN) or peptide receptor radionuclide therapy (PRRT).ResultsBaseline CgA was a statistically significant prognostic marker for both cancer-specific survival (CSS) and progression-free survival (PFS). A cut-off of 5 × ULN (upper limit of normal) was best discriminative in most cases, but 2 × ULN discriminated better for SSA. Baseline 5HIAA was a prognostic marker for CSS in treatment with IFN and PRRT, but not for single SSA. Early changes of CgA and 5HIAA correlated well with CSS (HR 3.18, 95% CI 1.82–5.56 and HR 1.47, 95% CI 1.16–1.86) and PFS (HR 3.08, 95% CI 1.86–5.10 and HR 1.37, 95% CI 1.11–1.68) for SSA, but not for PRRT.ConclusionsBaseline CgA and to a lesser extent 5HIAA are associated with CSS irrespective of treatment used, and with PFS after PRRT, and 5 × ULN provides best discrimination in many, but not all, cases. Early reductions of CgA and 5HIAA are prognostic for treatment with SSA, but not PRRT.

Diagnosis and prognostic significance of extramural venous invasion in neuroendocrine tumors of the small intestine

Extramural venous invasion (EMVI) is an established independent prognostic factor in colorectal carcinoma where it is linked to hematogenous spread (i.e., liver metastases), influencing the decision for adjuvant chemotherapy. However, its prognostic significance in small intestinal neuroendocrine tumors (NETs) has not been studied, nor is it routinely assessed or reported. We reviewed primary small bowel NETs (14 jejunum, 82 ileum, 8 not specified) from 104 patients (52 women; median age 60.5, range: 24–84). EMVI was identified in 58 cases (55.8%), including in 13 of 21 equivocal cases using an elastin stain. In univariate analysis, EMVI was associated with lymphovascular and perineural invasion, tumor stage, and lymph node and distant metastases, whereas in multivariate analysis, only distant metastases remained significant (p < 0.001). Liver metastases were present in 55 cases (52.9%) and were significantly associated in univariate analysis with lymphovascular and perineural invasion, tumor stage, lymph node metastases, and EMVI, whereas in multivariate analysis, only EMVI remained significant (p < 0.001; odds ratio (OR) = 59.42). Eight patients developed metachronous liver metastases during follow-up (mean 22.9 ± 22.0 months, range: 4.7–73.2) and all (100%) were positive for EMVI. In contrast, of 49 patients who never developed liver metastases over significantly longer follow-up (mean 71.0 ± 32.4 months, range: 6.6–150.4; p < 0.001), only 7 (14.3%) had EMVI (p < 0.001). In Kaplan–Meier analysis, 8 of 15 patients with EMVI (53.3%) developed metachronous liver metastases, compared with 0 of 42 patients without EMVI (p < 0.001). In contrast, nonhepatic distant metastases, seen in 26 (25.0%) patients, were not associated with EMVI in multivariate or Kaplan–Meier analyses. Our data demonstrate that EMVI is common in small bowel NETs and strongly correlates with development of liver metastases. Therefore, its evaluation is critical and should be assessed in combination with adjuvant techniques such as elastin staining, if necessary. Moreover, inclusion of EMVI in pathology reporting guidelines should be considered.

Racial/Ethnic Disparities and Survival Characteristics in Non-Pancreatic Gastrointestinal Tract Neuroendocrine Tumors

Background: We studied the effect of race and ethnicity on disease characteristics and survival in gastrointestinal neuroendocrine tumors. Methods: The Surveillance, Epidemiology, and End Results database was used to select patients with non-pancreatic gastrointestinal neuroendocrine tumors diagnosed between 2004 and 2015. Trends in survival were evaluated among three groups: Hispanic, non-Hispanic White, and non-Hispanic Black. Kaplan-Meier and Cox regression methods were performed to calculate overall survival and cause-specific survival after adjusting for patient and tumor characteristics. Results: A total of 26,399 patients were included in the study: 65.1% were non-Hispanic White, 19.9% were non-Hispanic Black, and 15% were Hispanic. Non-Hispanic White patients were more likely to be male (50.0%, p < 0.001), older than 60 years (48.0%, p < 0.001), and present with metastatic disease (17.7%, p < 0.001). Non-Hispanic White patients had small intestine neuroendocrine tumors, while Hispanic and non-Hispanic Black patients had rectum neuroendocrine tumors as the most common primary site. Hispanic patients had better overall survival, while non-Hispanic Black patients had better cause-specific survival versus non-Hispanic White patients. This finding was confirmed on multivariable analysis where Hispanic patients had improved overall survival compared to non-Hispanic White patients (Hazard ratio (HR): 0.89 (0.81-0.97)), whereas non-Hispanic Black patients had better cause-specific survival compared to non-Hispanic White patients (HR: 0.89 (0.80-0.98)). Conclusions: Race/ethnicity is an independent prognostic factor in patients with gastrointestinal neuroendocrine tumors.

S1229 Aspirin and the Gastrointestinal Tract: A Review of Risks and Benefits

INTRODUCTION: The beneficial effects of using long-term low-dose aspirin (LDA) in different types of gastrointestinal disorders has been controversial. In this systematic review we describe the potential risks and benefits of ASA in the GI tract with the quality of supporting evidence. METHODS: A systematic search of the literature was conducted using different search engines. Studies looking at the impact of ASA on GI tract and Liver were included. GRADE methodology was used to evaluate the quality of supporting evidence. RESULTS: Low quality of evidence (QOE) suggests mild to moderate benefit in primary CRC prevention. There is weak evidence for risk reduction in esophageal (SCC & adeno), non-cardia gastric & pancreatic cancer. There is no reduction in the risk for Barrett's esophagus small intestine neuroendocrine tumors& secondary prevention of CRC. There is paucity of the data regarding other conditions as listed in the Tables 1 and 2a/b. The QOE of harmful effects of aspirin on gastroduodenal & small bowel erosions and ulcers, erosive esophagitis & diverticular complications are weak to moderate. Aspirin has weak QOE in reducing the fibrosis in chronic viral hepatitis and NAFLD. Upper GI tract and Small intestine (Table 1) Lower GI tract & Liver (Table 2a/b). CONCLUSION: Long-term LDA use has shown to have both beneficial and deleterious effects on the GI tract as well as the Liver. Also, there is paucity of date regarding the dose related risk reduction. There is moderate QOE for deleterious effects of ASA on Upper Gi tract even at a low dose. Some of these side effects can be mitigated with PPI use. Despite recent enthusiasm with potential benefits of LDA in decreasing risk of GI malignancies and hepatic fibrosis, the evidence remains weak except for CRC prevention. This review can serve as a quick reference for physicians considering LDA for their patients.Table 1.: Upper GI, small intestine and PancreasTable 2.: Colon, IBD and Diverticular diseaseTable 3.: Viral hepatitis, Alcoholic hepatitis and NAFLD

Unifocal versus Multiple Ileal Neuroendocrine Tumors Location: An Embryological Origin

Introduction: Small-intestinal neuroendocrine tumors (SI-NET) are situated preferentially within the ileum. The aim was to describe a potential difference in location between unifocal and multiple ileal-NET. Patients and Methods: Between December 2010 and December 2019, all consecutive patients who underwent resection in our European Neuroendocrine Tumor Society Center of Excellence, of at least 1 non-duodenal SI-NET, were retrospectively included. The main objective was to prove that multiple ileal-NET were mostly located on the left side of the superior mesenteric artery (SMA) axis (defined as 40 cm from the ileocecal valve), and unifocal ones on the right side. Results: Ninety-four patients were included, 6 with unifocal jejunal-NET located 35 cm (range, 10–60) from the duodenojejunal angle (DJA), 44 (47%) with unifocal ileal-NET and 44 (47%) with multiple ileal-NET. The median number of tumors in multiple ileal-NET was 7 (range, 2–95), within a median small bowel segment of 105 cm (10–240). The median length between the proximal tumor and the DJA was 428 cm (300–635) and 540 cm (350–725) for the distal one; 40 (91%) of them were located on the left side of the SMA axis. In contrast, unifocal ileal-NET were located at a median distance of 577 cm (305–820) from the DJA (p < 0.001, compared to multiple ileal-NET); 30 (68%) of them were on the right side of the SMA axis (p < 0.001). Conclusion: Multiple ileal-NET are mostly located on the left side of the SMA axis. Further studies are warranted to explore the embryological origin of unifocal versus multiple ileal-NET.

PCSK2 expression in neuroendocrine tumors points to a midgut, pulmonary, or pheochromocytoma-paraganglioma origin.

Neuroendocrine tumors (NETs) are often diagnosed from the metastases of an unknown primary tumor. Specific immunohistochemical (IHC) markers indicating the location of a primary tumor are needed. The proprotein convertase subtilisin/kexin type 2 (PCSK2) is found in normal neural and neuroendocrine cells, and known to express in NETs. We investigated the tissue microarray (TMA) of 86 primary tumors from 13 different organs and 9 metastatic NETs, including primary tumor‐metastasis pairs, for PCSK2 expression with polymer‐based IHC. PCSK2 was strongly positive in all small intestine and appendiceal NETs, the so‐called midgut NETs, in most pheochromocytomas and paragangliomas, and in some of the typical and atypical pulmonary carcinoid tumors. NETs showing strong positivity were re‐evaluated in larger tumor cohorts confirming the primary observation. In the metastases, the expression of PCSK2 mirrored that of the corresponding primary tumors. We found negative or weak staining in NETs from the thymus, gastric mucosa, pancreas, rectum, thyroid, and parathyroid. PCSK2 expression did not correlate with Ki‐67 in well‐differentiated NETs. Our data suggest that PCSK2 positivity can indicate the location of the primary tumor. Thus, PCSK2 could function in the IHC panel determined from screening metastatic NET biopsies of unknown primary origins.

A Real-World, Population-Based Study for the Incidence and Outcomes of Neuroendocrine Neoplasms of Unknown Primary

Objective: The aim of the study was to provide a real-world, population-based assessment of the incidence and outcomes of neuroendocrine neoplasms (NENs) of unknown primary. Methods: Surveillance, Epidemiology, and End Results registry was accessed, and cases with NENs of unknown primary were reviewed. Rates of NENs diagnosis 1975–2017 according to primary tumor site were also reviewed. Survival outcomes of patients with NENs of unknown primary compared to metastatic NENs with known primary were determined through Kaplan-Meier estimates and multivariable Cox regression analysis. Overall and cancer-specific survival analyses were stratified by primary site and histology (neuroendocrine tumor vs. neuroendocrine carcinoma). Results: A total of 3,550 cases (7%) were diagnosed with NENs of unknown primary within the study duration. The annual percent change for NENs of unknown primary was 3.4 (95% CI: 2.6–4.2). Within the cohort of metastatic neuroendocrine tumor patients (carcinoid tumor histology), the following factors were associated with a lower risk of death; younger age (HR: 0.477; 95% CI: 0.443–0.513), female sex (HR: 0.922; 95% CI: 0.860–0.989), and small intestinal primary (HR for unknown primary vs. small intestinal primary: 1.532; 95% CI: 1.408–1.668). Within the cohort of metastatic neuroendocrine carcinoma, the following factors were associated with a lower risk of death in this cohort; younger age (HR: 0.646; 95% CI: 0.612–0.681), female sex (HR: 0.843; 95% CI: 0.801–0.888), and small intestinal primary (HR for unknown primary vs. small intestinal primary: 2.961; 95% CI: 2.586–3.391). Conclusions: The diagnosis of NENs of unknown primary has increased across the past 4 decades. Outcomes of individuals with metastatic small intestinal NENs seem to be better than those with metastatic NENs of unknown primary (for both carcinoid tumors and neuroendocrine carcinomas).

Survival and disease recurrence in patients operated for small intestinal neuroendocrine tumors at a referral hospital

Background and objectivesSmall intestinal neuroendocrine tumors (SI-NETs) are slow growing but have frequently metastasized at the time of diagnosis. Most patients are operated with either curative intent or with intent to prolong overall survival. In the current study we have examined overall and disease-free survival in patients operated for SI-NETs. MethodsAll patients with a histological diagnosis of SI-NET at St Olav's hospital in the period 1998–2018 were reviewed retrospectively. Patient, disease and treatment characteristics including European Neuroendocrine Tumor Society (ENETS) TNM staging classification, surgery type, time to recurrence and survival were recorded. ResultsA total of 186 patients were identified, whereof 54.3% male, median age at operation 68 years. The majority (n = 141 (75.8%)) underwent elective surgery and surgery was considered curative (radical) in 120 (64.5%) patients. Median estimated overall survival was 9.7 years (95% CI 7.6–11.8) for the entire population. Stage of disease, carcinoid heart disease, age, elective surgery, preoperatively known SI-NET, curative surgery and synchronous cancer were associated with survival in a multivariate analysis. Thirty-six of 120 (30%) patients had disease recurrence after a median follow-up time of 5.5 years, with a median estimated recurrence-free survival of 9.1 (5.4–12.9) years. Recurrence free survival was associated with age and synchronous cancer. ConclusionsPatients with SI-NETs had long overall survival which seemed influenced by stage of disease, presence of carcinoid heart disease, an elective surgery, preoperatively known SI-NET, age and synchronous cancer. Appropriate preoperative diagnostic procedures and elective surgeries seem beneficial and should be aimed for.

Home Total Parenteral Nutrition for Intestinal Failure in Patients with Advanced Small Intestinal Neuroendocrine Neoplasms

The role of total parenteral nutrition (TPN) in cancer patients is controversial, but it may be a treatment option for some patients with indolent but advanced small intestinal neuroendocrine neoplasms (SI-NENs). The aim of this study is to investigate whether home TPN was associated with long-term survival and to assess the indications, duration and complications of TPN in patients with advanced SI-NENs. Patients with advanced SI-NENs who received home TPN were retrospectively included. Electronic records were reviewed for clinical information. Five patients receiving home TPN were identified out of 1011 patients with SI-NENs in our center. The median duration of TPN administration was 12 mo. Small bowel obstruction was the most common reason for TPN initiation. TPN-related complications included two catheter infections, one thrombosis and one episode of TPN-related transaminitis. At the last follow-up, three patients had died and two were alive. The median survival was 12 mo. Overall estimated 1-yr probability of survival on home TPN by Kaplan–Meier analysis was 40%. In conclusion, home TPN may be a treatment option in highly selected advanced SI-NEN patients with severe gastrointestinal tract dysfunction. The initiation of home TPN is associated with long-term survival (≥1 yr), and complication rates appear acceptable.

Role of an active reserve stem cell subset of enteroendocrine cells in intestinal stem cell dynamics and the genesis of small intestinal neuroendocrine tumors.

Small intestinal neuroendocrine tumors (SI-NET) are serotonin-secreting well-differentiated neuroendocrine tumors of putative enterochromaffin (EC) cell origin. Recent studies recognize a subset of EC cells that is label-retaining at the +4 position in the crypt and functions as a reserve intestinal stem cell. Importantly, this +4 reserve EC cell subset not only contributes to regeneration of the intestinal epithelium during injury and inflammation but also to basal crypt homeostasis at a constant rate. The latter function suggests that the +4 EC cell subset serves as an active reserve stem cell via a constant rate of dedifferentiation. Characterization of early tumor formation of SI-NET, observed as crypt-based EC cell clusters in many cases of familial SI-NETs, suggests that the +4 active reserve EC cell subset is the cell of origin. This newly discovered active reserve stem cell property of EC cells can account for unique biological mechanisms and processes associated with the genesis and development of SI-NETs. The recognition of this property of the +4 active reserve EC cell subset may provide novel opportunities to explore NETs in the gastrointestinal tract and other organs.

Clinical Routine Application of the Second-generation Neuroendocrine Markers ISL1, INSM1, and Secretagogin in Neuroendocrine Neoplasia: Staining Outcomes and Potential Clues for Determining Tumor Origin

Neuroendocrine neoplasms (NENs) have traditionally been identified via expression of proteins associated to the regulation of secretory vesicles and granules. We report the clinical usage of the “second-generation” proteins ISL LIM homeobox 1 (ISL1), INSM transcriptional repressor 1 (INSM1), and secretagogin (SECG) as immunohistochemical markers of neuroendocrine differentiation since their introduction in clinical routine and compare the results with the established proteins chromogranin A (CGA) and synaptophysin (SYP). In total, 161 tumors, including 139 NENs and 22 “non-NENs” (unrelated tumors with an initial suspicion of NEN), were informatively stained for ISL1, and subsets were also interrogated for INSM1 and/or SECG. Diffuse or focal positive immunoreactivity was noted for ISL1 in 91/139 NENs (65%) and in 6/22 (27%) non-NENs, for INSM1 in 76/85 NENs (89%) and in 2/5 (40%) non-NENs, and for SECG in 49 out of 64 NENs (77%) and in 0/5 non-NENs (0%). Generally, ISL1, INSM1, and SECG exhibited sensitivities in line with or slightly below that of CGA and SYP—largely attributable to tissue-specific patterns regarding tumoral origin. Moreover, for pancreatic and small intestinal NENs, the two largest subgroups, ISL1 staining results were consistent irrespectively of tumor source and WHO grade. We verify previously suggested immunohistochemical schemes of neuroendocrine markers of first- and second-generations to facilitate the diagnostic process for NENs and confirm that the second-generation neuroendocrine markers display tissue-specific patterns. We therefore recommend their implementation in tertiary endocrine pathology centers, not least to aid in the identification of primary tumors when analyzing metastases.

Gastrointestinal neuroendocrine tumors in 2020.

Gastrointestinal neuroendocrine tumors are rare slow-growing tumors with distinct histological, biological, and clinical characteristics that have increased in incidence and prevalence within the last few decades. They contain chromogranin A, synaptophysin and neuron-specific enolase which are necessary for making a diagnosis of neuroendocrine tumor. Ki-67 index and mitotic index correlate with cellular proliferation. Serum chromogranin A is the most commonly used biomarker to assess the bulk of disease and monitor treatment and is raised in both functioning and non-functioning neuroendocrine tumors. Most of the gastrointestinal neuroendocrine tumors are non-functional. World Health Organization updated the classification of neuroendocrine tumors in 2017 and renamed mixed adenoneuroendocrine carcinoma into mixed neuroendocrine neoplasm. Gastric neuroendocrine tumors arise from enterochromaffin like cells. They are classified into 4 types. Only type I and type II are gastrin dependent. Small intestinal neuroendocrine tumor is the most common small bowel malignancy. More than two-third of them occur in the terminal ileum within 60 cm of ileocecal valve. Patients with small intestinal neuroendrocrine tumors frequently show clinical symptoms and develop distant metastases more often than those with neuroendocrine tumors of other organs. Duodenal and jejuno-ileal neuroendocrine tumors are distinct biologically and clinically. Carcinoid syndrome generally occurs when jejuno-ileal neuroendocrine tumors metastasize to the liver. Appendiceal neuroendocrine tumors are generally detected after appendectomy. Colonic neuroendocrine tumors generally present as a large tumor with local or distant metastasis at the time of diagnosis. Rectal neuroendocrine tumors are increasingly being diagnosed since the implementation of screening colonoscopy in 2000. Gastrointestinal neuroendocrine tumors are diagnosed and staged by endoscopy with biopsy, endoscopic ultrasound, serology of biomarkers, imaging studies and functional somatostatin scans. Various treatment options are available for curative and palliative treatment of gastrointestinal neuroendocrine tumors.

A Plasma Protein Biomarker Strategy for Detection of Small Intestinal Neuroendocrine Tumors

Background: Small intestinal neuroendocrine tumors (SI-NETs) are difficult to diagnose in the early stage of disease. Current blood biomarkers such as chromogranin A (CgA) and 5-hydroxyindolacetic acid have low sensitivity (SEN) and specificity (SPE). This is a first preplanned interim analysis (Nordic non-interventional, prospective, exploratory, EXPLAIN study [NCT02630654]). Its objective is to investigate if a plasma protein multi-biomarker strategy can improve diagnostic accuracy (ACC) in SI-NETs. Methods: At the time of diagnosis, before any disease-specific treatment was initiated, blood was collected from patients with advanced SI-NETs and 92 putative cancer-related plasma proteins from 135 patients were analyzed and compared with the results of age- and sex-matched controls (n = 143), using multiplex proximity extension assay and machine learning techniques. Results: Using a random forest model including 12 top ranked plasma proteins in patients with SI-NETs, the multi-biomarker strategy showed SEN and SPE of 89 and 91%, respectively, with negative predictive value (NPV) and positive predictive value (PPV) of 90 and 91%, respectively, to identify patients with regional or metastatic disease with an area under the receiver operator characteristic curve (AUROC) of 99%. In 30 patients with normal CgA concentrations, the model provided a diagnostic SPE of 98%, SEN of 56%, and NPV 90%, PPV of 90%, and AUROC 97%, regardless of proton pump inhibitor intake. Conclusion: This interim analysis demonstrates that a multi-biomarker/machine learning strategy improves diagnostic ACC of patients with SI-NET at the time of diagnosis, especially in patients with normal CgA levels. The results indicate that this multi-biomarker strategy can be useful for early detection of SI-NETs at presentation and conceivably detect recurrence after radical primary resection.

Surgery and Perioperative Management in Small Intestinal Neuroendocrine Tumors

Small-intestinal neuroendocrine tumors (SI-NETs) are the most prevalent small bowel neoplasms with an increasing frequency. In the multimodal management of SI-NETs, surgery plays a key role, either in curative intent, even if R0 resection is feasible in only 20% of patients due to advanced stage at diagnosis, or palliative intent. Surgeons must be informed about the specific surgical management of SI-NETs according to their hormonal secretion, their usual dissemination at the time of diagnosis and the need for bowel-preserving surgery to avoid short bowel syndrome. The aim of this paper is to review the surgical indications and techniques, and perioperative and postoperative management of SI-NETs.