Endoscopic surveillance alone is feasible and safe in type I gastric neuroendocrine neoplasms less than 10 mm in diameter.

PURPOSE: Type I gastric neuroendocrine neoplasms (g-NENs) have a low risk of metastasis and a generally favourable prognosis. Patients with small type I g-NENs (≤10 mm) frequently require no treatment, whereas those with larger polyps usually undergo resection. We evaluated the safety and outcomes of endoscopic surveillance after no initial treatment in selected patients with type I g-NENs. METHODS: Retrospective analysis of type I g-NEN patients across two European Neuroendocrine Tumour Society Centers of Excellence 2003-2019. RESULTS: Following initial assessment, 87 of 115 patients with type I g-NEN (75 with polyps ≤10 mm) received no initial treatment and underwent endoscopic surveillance. 79/87 (91%) demonstrated no clinically meaningful change in tumour size or grade over a median 62 month follow up. Only two patients developed NEN progression that required a change in management and two other patients developed gastric adenocarcinoma/high grade dysplasia; all four initially had ≥11 mm g-NENs. CONCLUSIONS: Patients with ≤10 mm type I g-NENs were unlikely to develop clinically significant tumour progression and in most cases, resection was not needed. The endoscopic surveillance interval could therefore potentially be safely increased to every 2-3 years in such patients. However, lifelong surveillance is still advocated due to the additional risk of developing gastric adenocarcinoma.

New Developments in Gastric Neuroendocrine Neoplasms.

PURPOSE OF REVIEW: Gastric neuroendocrine neoplasms (g-NENs) are a rare type of stomach cancer. The three main subtypes have different pathogeneses, biological behaviours and clinical characteristics, so they require different management strategies. This article will provide an overview of g-NENs and highlight recent advances in the field. RECENT FINDINGS: Molecular profiling has revealed differences between indolent and aggressive g-NENs, as well as a new somatic mutation responsible for some familial type I g-NENs. Novel biomarkers have been developed which will hopefully improve diagnosis, treatment, risk stratification and follow-up. Patient treatment is also changing, as evidence supports the use of less aggressive options (e.g. endoscopic surveillance or resection) in some patients with more indolent tumours. g-NEN heterogeneity poses challenges in understanding and managing this rare disease. More basic science research is needed to investigate molecular pathogenesis, and future larger clinical studies will hopefully also further improve treatment and patient outcomes.

Is local excision sufficient in selected grade 1 or 2 type III gastric neuroendocrine neoplasms?

PURPOSE: Type III gastric neuroendocrine neoplasms (g-NENs) have historically been regarded as aggressive tumours, hence current guidelines advocate radical surgery with lymph node dissection. Data on the roles of endoscopic or less extensive surgical resections are more limited. The aim of our study is to evaluate the clinicopathological features and long-term outcomes of patients undergoing endoscopic or limited surgical resection for localised grade 1 or 2 type III g-NENs when compared to radical surgery. METHODS: Retrospective analysis of all patients diagnosed with a localised grade 1 or 2 type III g-NENs across six tertiary NEN centers between 2006 and 2019. RESULTS: Forty-five patients were diagnosed with a potentially resectable grade 1 or 2 type III g-NEN of whom 36 underwent either endoscopic or surgical resection. No statistically significant differences were found between the three resection groups in terms of patient age, tumour location, grade or size. Only tumour size was found to be significantly associated with poor clinical outcome (p = 0.012) and ROC curve analysis identified tumour size >10 mm as a negative predictor (AUC:0.8030, p = 0.0021). Tumours >10 mm were also more likely to be associated with lymph node metastases on imaging and histology (p = 0.039 and p = 0.026 respectively). CONCLUSIONS: Localised grade 1 or 2 type III g-NENs had a good prognosis in this series. Tumour size >10 mm was the most significant prognostic factor affecting patient outcome. Endoscopic resection or limited surgical resection is feasible and safe in small type III g-NENs which demonstrate favourable grade 1/2, well differentiated histology.

A "Watch and Wait" Strategy Involving Regular Endoscopic Surveillance Is Safe for Many Patients with Small, Sporadic, Grade 1, Non-Ampullary, Non-Functioning Duodenal Neuroendocrine Tumours.

INTRODUCTION: Duodenal neuroendocrine tumours (d-NETs) are rare but are increasing in incidence. Current ENETS guidelines advocate resection of all localized d-NETs. However, "watch and wait" may be appropriate for some localized, small, grade 1, non-functioning, non-ampullary d-NETs. We evaluated whether patients with such d-NETs who chose "watch and wait" involving regular endoscopic surveillance had equivalent disease-related outcomes to patients undergoing endoscopic or surgical resection. METHODS: Retrospective review of patients with histologically confirmed d-NETs at Liverpool ENETS Centre of Excellence 2007-2020. RESULTS: Sixty-nine patients were diagnosed with d-NET of which 50 were sporadic, non-functioning, non-ampullary tumours. Patient treatment groups were similar in terms of age, gender, and tumour location and grade, but unsurprisingly, larger tumours (median diameter 17 mm [p < 0.0001]) were found in the surgically treated group. Five patients underwent surgical resection with no evidence of tumour recurrence or disease-related death. Twelve patients underwent endoscopic resection (ER), with 1 local recurrence detected during follow-up. Thirty patients (28 with d-NETs ≤10 mm) underwent "watch and wait" with resection only if tumours increased in size. The d-NETs in 28/30 patients remained stable or decreased in size over a median 27 months (IQR: 15-48, R: 3-98). In 7 patients, the d-NET was completely removed by avulsion during diagnostic biopsy and was not seen at subsequent endoscopies. Only 2 patients showed increased d-NET size during surveillance, of whom only one was fit for ER. No NET-related deaths were documented during follow-up. CONCLUSIONS: All of the localized, ≤10 mm, grade 1, non-functioning, non-ampullary d-NETs in this cohort behaved indolently with very low risks of progression and no tumour-related deaths. "Watch and wait," therefore, appears to be a safe alternative management strategy for selected d-NETs.

Laparoscopic Surgery Is Safe and Beneficial in True Functional High-Risk Patients with Colorectal Cancer: Utilization of Cardiopulmonary Exercise Test.

Background: Patients with colorectal cancer deemed to be high-risk may be denied an elective laparoscopic resection due to subjective reasons. A comparison of the 30-day outcomes in true functional high-risk patients who underwent either open or laparoscopic colorectal resection was undertaken. Materials and Methods: A retrospective cohort of all functional high-risk patients as assessed by cardiopulmonary exercise test between July 2015 and April 2018 were identified. Anaerobic threshold of <11 mL/kg/minute was used as a physiologic indicator to determine a high-risk patient. Adherence to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) was ensured. P values were computed via two-sided Fisher's exact test, and the exact Mann-Whitney U-test. Forest plots for relative risks with 95% confidence intervals were displayed on a log scale. Results: One hundred forty-six patients were identified as high-risk. Outcomes demonstrated a trend to laparoscopic benefit in all Clavien-Dindo grades of postoperative complications, but especially in severe complications of grades 3-4 (3.5% versus 10.2%). Readmissions demonstrated a trend to laparoscopic surgery benefit (7% versus 11.8%), as did mortality (1.7% versus 3.4%). The rate of surgery-site complications was higher after open surgery (42.1% versus 22.4%, P = .0201). Wound infections were observed more frequently after open surgery (12.5% versus 1.72%, P = .0280). The estimated risk of all-grade complications was significantly higher after open anterior rectal resection (63.0% versus 29.6%, P = .0281) and there was significantly shorter stay after laparoscopic right colectomy (5 v. 7 days, P = .0490). Conclusions: Laparoscopic approach for colorectal resections in high-risk patients is safe and beneficial compared to open surgery, especially in patients undergoing laparoscopic resection of the rectum and right colon.

Systematic review: management of localised low-grade upper gastrointestinal neuroendocrine tumours.

BACKGROUND: Neuroendocrine tumours (NETs) of the stomach and duodenum are rare, but are increasing in incidence. Optimal management of localised, low-grade gastric and duodenal NETs remains controversial. AIMS: To systematically review recent literature that has evaluated the management of localised low-grade gastric and duodenal NETs. METHODS: A systematic literature search was conducted. Articles were screened and eligible articles fully assessed. Additional articles were identified through the included articles' reference lists. RESULTS: Several relevant retrospective case series were identified, but there was considerable heterogeneity between studies and they reported a variety of parameters. Type I gastric NETs had an excellent prognosis and conservative management approaches such as endoscopic surveillance/resection were appropriate in most cases. Many type III gastric NETs were low grade and appeared to have a better prognosis than has previously been appreciated. Endoscopic rather than surgical resection was therefore effective in some patients who had small, low-grade tumours. Duodenal NETs were more heterogenous. Endoscopic resection was generally safe and effective in patients who had small, low-grade, nonfunctional, non-ampullary tumours. However, some patients, especially those with larger or ampullary duodenal NETs, required surgical resection. CONCLUSIONS: Most type I gastric NETs behave indolently and surgical resection is only rarely indicated. Some type III gastric and duodenal NETs have a worse prognosis, but selected patients who have small, localised, nonfunctional, low-grade tumours are adequately and safely treated by endoscopic resection. Due to the complexity of this area, a multidisciplinary approach to management is strongly recommended.

Netazepide Inhibits Expression of Pappalysin 2 in Type 1 Gastric Neuroendocrine Tumors.

BACKGROUND & AIMS: In patients with autoimmune atrophic gastritis and achlorhydria, hypergastrinemia is associated with the development of type 1 gastric neuroendocrine tumors (gNETs). Twelve months of treatment with netazepide (YF476), an antagonist of the cholecystokinin B receptor (CCKBR or CCK2R), eradicated some type 1 gNETs in patients. We investigated the mechanisms by which netazepide induced gNET regression using gene expression profiling. METHODS: We obtained serum samples and gastric corpus biopsy specimens from 8 patients with hypergastrinemia and type 1 gNETs enrolled in a phase 2 trial of netazepide. Control samples were obtained from 10 patients without gastric cancer. We used amplified and biotinylated sense-strand DNA targets from total RNA and Affymetrix (Thermofisher Scientific, UK) Human Gene 2.0 ST microarrays to identify differentially expressed genes in stomach tissues from patients with type 1 gNETs before, during, and after netazepide treatment. Findings were validated in a human AGSGR gastric adenocarcinoma cell line that stably expresses human CCK2R, primary mouse gastroids, transgenic hypergastrinemic INS-GAS mice, and patient samples. RESULTS: Levels of pappalysin 2 (PAPPA2) messenger RNA were reduced significantly in gNET tissues from patients receiving netazepide therapy compared with tissues collected before therapy. PAPPA2 is a metalloproteinase that increases the bioavailability of insulin-like growth factor (IGF) by cleaving IGF binding proteins (IGFBPs). PAPPA2 expression was increased in the gastric corpus of patients with type 1 gNETs, and immunohistochemistry showed localization in the same vicinity as CCK2R-expressing enterochromaffin-like cells. Up-regulation of PAPPA2 also was found in the stomachs of INS-GAS mice. Gastrin increased PAPPA2 expression with time and in a dose-dependent manner in gastric AGSGR cells and mouse gastroids by activating CCK2R. Knockdown of PAPPA2 in AGSGR cells with small interfering RNAs significantly decreased their migratory response and tissue remodeling in response to gastrin. Gastrin altered the expression and cleavage of IGFBP3 and IGFBP5. CONCLUSIONS: In an analysis of human gNETS and mice, we found that gastrin up-regulates the expression of gastric PAPPA2. Increased PAPPA2 alters IGF bioavailability, cell migration, and tissue remodeling, which are involved in type 1 gNET development. These effects are inhibited by netazepide.

The impact of an operative note proforma at a paediatric surgical centre.

RATIONALE, AIMS AND OBJECTIVES: With expectations for standardization and evidence-based practice, the Royal College of Surgeons (RCS) published the 'Good Surgical Practice' in 2008. The document sets standards for operative records anticipating improved documentation, audits, medico-legal review and quality and safety of handover. We evaluated (1) documentation against RCS standards; (2) whether RCS standards are applicable to and adequate for paediatric surgery; and (3) the impact of a standardized operative proforma. METHODS: All general surgery and urology admissions during July 2011 and August 2012 were retrospectively reviewed using 23 set criteria. An operative note proforma was introduced in February 2012. Results were compared and statistically analysed using two-tailed Fisher's exact test, with Bonferroni correction where appropriate (SPSS 20.0, IBM SPSS Statistics, Armonk, NY, USA). RESULTS: There were 345 children admitted; 63.2% underwent an operation (119 in 2011 versus 99 in 2012); 55% of operations were day cases. The initial audit noted poor documentation in 7 of 23 criteria. Following introduction of the operative note proforma, documentation improved significantly: patient identifiers by 12.3%, procedure time 43.3%, assistant's name 31.9%, procedure type 21.4%, closure 6.2%, anaesthetist's name 15.9%, anaesthetic type 56.8% and surgeons grade 65.8% (P<0.05). Subgroup analysis in the latter cohort shows most of these effects to be related to the use of the proforma rather than education alone (P<0.05). Quality of documentation was better by consultants versus trainees in 2 of 23 criteria (P<0.05). CONCLUSION: We have demonstrated a simple and cost-effective way of improving the quality of operative documentation, in line with guidelines set out by the RCS, in a climate of increasing economic austerity.