Faecal Immunochemical Testing to Detect Colorectal Cancer in Symptomatic Patients: A Diagnostic Accuracy Study.

(1) Background: NHS England recommended faecal immunochemical testing (FIT) for symptomatic patients in June 2020 to rationalise limited diagnostic services during COVID-19. (2) Aim: to investigate the diagnostic performance of FIT, analysing the proportion of FIT-negative colorectal cancers (CRC) missed in symptomatic patients and how this risk could be mitigated. (3) Design and Setting: a retrospective study of biochemistry and cancer databases involving patients referred from primary healthcare with suspected CRC to a single secondary care trust in North East London. (4) Methods: a retrospective cohort diagnostic accuracy study was undertaken to determine the performance of FIT for detecting CRC at 10 µgHb/g. (5) Results: between January and December 2020, 7653 patients provided a stool sample for FIT analysis; 1679 (22%) samples were excluded due to inadequate or incorrect specimens; 48% of suspected CRC referrals completed FIT before evaluation; 86 FIT tested patients were diagnosed with histologically proven CRC. At 10 µgHb/g, FIT performance was comparable with the existing literature with a sensitivity of 0.8140 (95% CI 0.7189-0.8821), a specificity of 0.7704 (95% CI 0.7595-0.7809), a positive predictive value (PPV) of 0.04923 (95% CI 0.03915-0.06174), a negative predictive value (NPV) of 0.9965 (95% CI 0.9943-0.9978), and a likelihood ratio (LR) of 3.545; 16 patients with CRC had an FIT of ≤10 µgHb/g (18.6% 95% CI 11.0-28.4%). (6) Conclusions: this study raises concerns about compliance with FIT testing and the incidence of FIT-negative CRC at the NICE recommended threshold and how this risk can be mitigated without colonic imaging. Whilst FIT may have facilitated prioritisation during COVID-19, we must be cautious about using FIT alone to determine which patients are referred to secondary care or receive further investigation.

Is Panenteric PillcamTM Crohn's Capsule Endoscopy Ready for Widespread Use? A Narrative Review.

Patients diagnosed with Crohn's disease are increasingly subjected to repeat colonoscopic and radiological examinations to assess the extent of the disease severity and the effects of treatment. PillcamTM Crohn's video capsule, a modified colon capsule, was developed to generate a minimally invasive mouth to rectum video of the gastrointestinal tract. The capsule provides a wide-angle panoramic mucosal view to assess inflammation, ulceration, stenosis, disease extent, and effect of treatment. This review summarizes the evidence of its utility in both adult and paediatric Crohn's disease and reviews the scoring systems used to quantify findings. The literature survey indicates that the PillcamTM Crohn's capsule offers high sensitivity and specificity for the detection of inflammatory lesions and the extent and distribution of disease, and it could be considered a reliable imaging modality in both adults and childhood with Crohn's disease.

Colon Capsule Endoscopy in the Diagnosis of Colon Polyps: Who Needs a Colonoscopy?

Colon screening programs have reduced colon cancer mortality. Population screening should be minimally invasive, safe, acceptably sensitive, cost-effective, and scalable. The range of screening modalities include guaiac or immunochemical fecal occult blood testing and CT colonography and colonoscopy. A number of carefully controlled studies concur that second-generation capsule endoscopy has excellent sensitivity for polyp detection and a high negative predictive value. Colon capsules fulfill the screening expectation of safety, high sensitivity for polyp detection, and patient acceptance, and appear to straddle the divide between occult blood testing and colonoscopy. While meeting these criteria, there remains the challenges of scaling, capsule practitioner training, resource allocation, and implementing change of practice. Like CT colonography, capsule screening presents the clinician with a decision on the threshold for colonoscopy referral. Overall, colon capsules are an invaluable tool in polyp detection and colon screening and offer a filter that determines "who needs a colonoscopy?".

Virtual Chromoendoscopy in Capsule Endoscopy: A Narrative Review.

The usefulness of virtual chromoendoscopy (VC) in capsule endoscopy (CE) isa controversial issue, with conflicting studies regarding its efficacy. FICE and a blue filter were embedded in the PillCamTM software, with the aim to assist readers in identifying the source of obscure gastrointestinal (GI) bleeding (OGIB), coeliac disease mucosal changes and other small and large bowel lesions, including polyps and tumors. This review aims to summarize the existing evidence on the value of VC in the visualization and identification of different types of pathology. Overall, VC in CE with FICE 1 and 2 can be a useful adjunctive tool and may increase the visibility of pigmented lesions, such as angiectasias and ulcers. However, it does not appear to improve the detection of polyps or tumors. On the other hand, the role of FICE 3 and the blue filter appears to be limited. FICE may also be helpful in differentiating hyperplastic and adenomatous colonic polyps during colon capsule endoscopy, although more evidence is needed.

What Causes Desmoplastic Reaction in Small Intestinal Neuroendocrine Neoplasms?

PURPOSE OF REVIEW: Mesenteric desmoplasia in small intestinal neuroendocrine neoplasms (SINENs) is associated with increased morbidity and mortality. In this paper, we discuss the development of desmoplasia in SINENs. RECENT FINDINGS: The fibrotic reactions associated with these tumours could be limited to the loco-regional environment of the tumour and/or at distant sites. Mesenteric fibrotic mass forms around a local lymph node. Formation of desmoplasia is mediated by interactions between the neoplastic cells and its microenvironment via number of profibrotic mediators and signalling pathways. Profibrotic molecules that are mainly involved in the desmoplastic reaction include serotonin, TGFß (transforming growth factor ß) and CTGF (connective tissue growth factor), although there is some evidence to suggest that there are a number of other molecules involved in this process. Desmoplasia is a result of autocrine and paracrine effects of multiple molecules and signalling pathways. However, more research is needed to understand these mechanisms and to develop targeted therapy to minimise desmoplasia.

State of the Art in Endoscopic Therapy for the Management of Gastroenteropancreatic Neuroendocrine Tumors.

OPINION STATEMENT: Gastroenteropancreatic neuroendocrine neoplasms (GEP NENs) comprise a heterogeneous group of slow growing tumors arising from the neuroendocrine cells of the gastrointestinal (GI) tract. Although they are considered relatively rare, their incidence is rising and it is believed that the more frequent use of endoscopy and imaging studies have at least in part contributed to the increased diagnosis especially of localized neoplasms. The management of these neoplasms should be guided by a multidisciplinary NEN team following appropriate staging investigations. Localized neoplasms of the GI tract may be suitable for endoscopic therapy, while patients with pancreatic NENs, unsuitable for surgery, should be considered for endoscopic ultrasound (EUS)-guided ablation. In this review, we discuss the evidence regarding endoscopic resection of luminal NENs and EUS-guided therapy of pancreatic NENs. The efficacy, safety, and other longer-term outcomes of these techniques are summarized. In conclusion, this review of endoscopic therapies for localized NENs may be a useful guide for NEN clinicians and endoscopists who are considering these therapeutic options for the management of focal GEP NENs.

Review: Colon Capsule Endoscopy in Inflammatory Bowel Disease.

The COVID-19 pandemic has caused considerable disruption in healthcare services and has had a substantial impact on the care of patients with chronic diseases, such as inflammatory bowel disease. Endoscopy services were significantly restricted, resulting in long waiting lists. There has been a growing interest in the use of capsule endoscopy in the diagnostic pathway and management of these patients. This review explores the published literature on the role of colon capsule endoscopy in ulcerative colitis and Crohn's disease as a method for mucosal assessment of extent, severity, and response to treatment. Colon capsule preparation regimens and scoring systems are reported. The studies indicate that, despite inherent limitations of minimally invasive capsule endoscopy, there is increasing evidence to support the use of the second-generation colon capsule in inflammatory bowel disease evaluation, providing an additional pathway to expedite investigation of appropriate patients especially during and after the pandemic.

Upper gastrointestinal video capsule endoscopy: The state of the art.

BACKGROUND: Video capsule can illuminate the entire gastrointestinal mucosa. Upper gastrointestinal capsule endoscopy (UGICE) has the potential to survey for oesophageal, gastric and duodenal pathology and determine whether biopsy or intervention is indicated. AIMS: This review traces the evolution of foregut video capsule endoscopy. METHODS: A broad literature research was performed independently by two investigators. Extracted articles were organized and evaluated to interpret all current data. RESULTS: In contrast to small bowel capsule, UGICE required sequential innovations to deal with rapid oesophageal transit, the irregular shape of the stomach and unpredictable gastric peristalsis. Oesophageal capsule endoscopy required the development of a two-camera device operating at a high frame rate, and postural change was developed to improve image capture, especially at the level of the Z-line, thus providing good imaging of Barrett's oesophagus, erosive oesophagitis and oesophageal varices, with optimal patients' tolerance. UGICE in patients presenting to the emergency room with acute bleeding has demonstrated accuracy when deciding on the need for emergency intervention. The latest development of a high frame rate UGICE, designed to image the oesophagus, stomach and duodenum has overtaken dedicated oesophageal capsule development. Capsule control is possible by exposing a magnetised capsule to an external magnetic field, and early reports indicate high accuracy in the oesophagus and stomach with high levels of patient acceptability. There is little information on cost-benefit. CONCLUSIONS: Capsule endoscopy offers gastroenterologists a new device to investigate the upper gastrointestinal tract with promising future potential.

Role of Artificial Intelligence in Video Capsule Endoscopy.

Capsule endoscopy (CE) has been increasingly utilised in recent years as a minimally invasive tool to investigate the whole gastrointestinal (GI) tract and a range of capsules are currently available for evaluation of upper GI, small bowel, and lower GI pathology. Although CE is undoubtedly an invaluable test for the investigation of small bowel pathology, it presents considerable challenges and limitations, such as long and laborious reading times, risk of missing lesions, lack of bowel cleansing score and lack of locomotion. Artificial intelligence (AI) seems to be a promising tool that may help improve the performance metrics of CE, and consequently translate to better patient care. In the last decade, significant progress has been made to apply AI in the field of endoscopy, including CE. Although it is certain that AI will find soon its place in day-to-day endoscopy clinical practice, there are still some open questions and barriers limiting its widespread application. In this review, we provide some general information about AI, and outline recent advances in AI and CE, issues around implementation of AI in medical practice and potential future applications of AI-aided CE.

Early Identification of Residual Disease After Neuroendocrine Tumor Resection Using a Liquid Biopsy Multigenomic mRNA Signature (NETest).

INTRODUCTION: Surgery is the only cure for neuroendocrine tumors (NETs), with R0 resection being critical for successful tumor removal. Early detection of residual disease is key for optimal management, but both imaging and current biomarkers are ineffective post-surgery. NETest, a multigene blood biomarker, identifies NETs with >90% accuracy. We hypothesized that surgery would decrease NETest levels and that elevated scores post-surgery would predict recurrence. METHODS: This was a multicenter evaluation of surgically treated primary NETs (n = 153). Blood sampling was performed at day 0 and postoperative day (POD) 30. Follow-up included computed tomography/magnetic resonance imaging (CT/MRI), and messenger RNA (mRNA) quantification was performed by polymerase chain reaction (PCR; NETest score: 0-100; normal ≤20). Statistical analyses were performed using the Mann-Whitney U-test, Chi-square test, Kaplan-Meier survival, and area under the receiver operating characteristic curve (AUROC), as appropriate. Data are presented as mean ± standard deviation. RESULTS: The NET cohort (n = 153) included 57 patients with pancreatic cancer, 62 patients with small bowel cancer, 27 patients with lung cancer, 4 patients with duodenal cancer, and 3 patients with gastric cancer, while the surgical cohort comprised patients with R0 (n = 102) and R1 and R2 (n = 51) resection. The mean follow-up time was 14 months (range 3-68). The NETest was positive in 153/153 (100%) samples preoperatively (mean levels of 68 ± 28). In the R0 cohort, POD30 levels decreased from 62 ± 28 to 22 ± 20 (p < 0.0001), but remained elevated in 30% (31/102) of patients: 28% lung, 29% pancreas, 27% small bowel, and 33% gastric. By 18 months, 25/31 (81%) patients with a POD30 NETest >20 had image-identifiable recurrence. An NETest score of >20 predicted recurrence with 100% sensitivity and correlated with residual disease (Chi-square 17.1, p < 0.0001). AUROC analysis identified an AUC of 0.97 (p < 0.0001) for recurrence-prediction. In the R1 (n = 29) and R2 (n = 22) cohorts, the score decreased (R1: 74 ± 28 to 45 ± 24, p = 0.0012; R2: 72 ± 24 to 60 ± 28, p = non-significant). At POD30, 100% of NETest scores were elevated despite surgery (p < 0.0001). CONCLUSION: The preoperative NETest accurately identified all NETs (100%). All resections decreased NETest levels and a POD30 NETest score >20 predicted radiologically recurrent disease with 94% accuracy and 100% sensitivity. R0 resection appears to be ineffective in approximately 30% of patients. NET mRNA blood levels provide early objective genomic identification of residual disease and may facilitate management.

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.

AIM: Analysis 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. METHODS: An 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. RESULTS: RT 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. CONCLUSION: This 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.

Carcinoid Heart Disease: a Review.

PURPOSE OF REVIEW: The development of carcinoid heart disease (CHD) is a fibrotic complication of neuroendocrine neoplasms (NEN) which is associated with a poor prognosis. This review aims to summarise the clinical features, investigations and management of this condition. RECENT FINDINGS: CHD can affect up to 50% of NET patients with carcinoid syndrome. However, it is often not screened for appropriately and recognised late when patients become symptomatic. A screening strategy with biomarkers and multimodality imaging is necessary for early recognition. Management by an experienced multidisciplinary team with appropriate medical therapeutic strategies and where indicated surgical intervention is needed to optimise clinical outcomes. CHD is a poor prognostic factor, but recently, outcomes have improved due to the multidisciplinary approach and centralised care of CHD-NET patients.

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.

Antiproliferative Effect of Above-Label Doses of Somatostatin Analogs for the Management of Gastroenteropancreatic Neuroendocrine Tumors.

BACKGROUND: Above-label doses of somatostatin analogs (SSAs) are increasingly utilized in the management of inoperable/metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs), progressing on standard 4-weekly regimens. OBJECTIVE: To evaluate the antiproliferative effect of 3-weekly SSA administration in a retrospective GEP-NET cohort. METHODS: Patients with advanced GEP-NET, treated with long-acting release (LAR) octreotide 30 mg or lanreotide Autogel 120 mg at a 3-weekly interval, after disease progression on standard 4-weekly doses, were retrospectively identified. Clinicopathologic and treatment response data were collected. Progression-free survival (PFS; dose escalation to radiographic progression or death) was estimated with the Kaplan-Meier method. Factors associated with PFS were identified with the Cox proportional-hazards model. RESULTS: The inclusion criteria were fulfilled by 105 patients. Octreotide LAR was administered to 60 (57%) and lanreotide Autogel to 45 (43%). Indications for dose escalation were breakthrough carcinoid symptoms (58%), radiographic progression (35%) and/or increasing biomarkers (11%). Diarrheal and/or flushing symptomatic improvement was identified in 37/67 cases (55%) and 30/55 cases (55%) with available data, respectively. The disease control rate (radiographic partial response or stable disease) was achieved in 53 patients (50%). Median PFS was 25.0 months (95% CI 16.9-33.1). Patients with radiographic progression <12 months from 4-weekly SSA initiation had worse PFS after dose escalation (7.0 vs. 17.0 months, p = 0.002). In multivariate analysis, pancreatic NETs, a Ki-67 index ≥5% and multiple extrahepatic metastases were independently associated with inferior PFS. CONCLUSIONS: Above-label doses of SSAs may offer a considerable prolongation of PFS and could be utilized as a bridge to other more toxic treatments. Patients with small bowel/colorectal primaries, a Ki-67 index <5% and absence of/limited extrahepatic metastases are more likely to benefit from this approach.

Somatostatin Analogs for Pancreatic Neuroendocrine Tumors: Any Benefit When Ki-67 Is ≥10%?

BACKGROUND: Long-acting somatostatin analogs (SSAs) are the primary first-line treatment of well-differentiated advanced gastroenteropancreatic neuroendocrine tumors (NETs), but data about their efficacy in pancreatic NETs (panNETs) with Ki-67 ≥10% are still limited. MATERIALS AND METHODS: To assess the clinical outcomes of advanced, nonfunctioning, well-differentiated panNETs with Ki-67 ≥10% receiving first-line long-acting SSAs in a real-world setting, we carried out a retrospective, multicenter study including patients treated between 2014-2018 across 10 centers of the NET CONNECT Network. The primary endpoints were time to next treatment (TNT) and progression-free survival (PFS), whereas overall survival (OS) and treatment safety were secondary endpoints. RESULTS: A total of 73 patients were included (68 grade [G]2, 5 G3), with liver metastases in 61 cases (84%). After a median follow-up of 36.4 months (range, 6-173), the median TNT and PFS were 14.2 months (95% confidence interval [CI], 11.6-16.2) and 11.9 months (95% CI, 8.6-14.1) respectively. No statistically significant difference was observed according to the somatostatin analog used (octreotide vs. lanreotide), whereas increased tumor grade (hazard ratio [HR], 4.4; 95% CI, 1.2-16.6; p = .04) and hepatic tumor load (HR, 2; 95% CI, 1-4; p = .03) were independently associated with shortened PFS. The median OS recorded was 86 months (95% CI, 56.8-86 months), with poor outcomes observed when the hepatic tumor burden was >25% (HR, 3.4; 95% CI, 1.2-10; p = .01). Treatment-related adverse events were reported in 14 patients, most frequently diarrhea. CONCLUSION: SSAs exert antiproliferative activity in panNETs with Ki-67 ≥10%, particularly in G2 tumors, as well as when hepatic tumor load is ≤25%. IMPLICATIONS FOR PRACTICE: The results of the study call into question the antiproliferative activity of somatostatin analogs (SSAs) in pancreatic neuroendocrine tumors with Ki-67 ≥10%. Patients with grade 2 tumors and with hepatic tumor load ≤25% appear to derive higher benefit from SSAs. Prospective studies are needed to validate these results to optimize tailored therapeutic strategies for this specific patient population.

An unusual polypoid lesion in the cecum.

The inverted appendix or appendiceal stump is a rare finding that may be identified at colonoscopy. This may cause diagnostic confusion and be misinterpreted as a polyp with a risk of peritonitis if excised endoscopically.

Evaluation of circulating transcript analysis (NETest) in small intestinal neuroendocrine neoplasms after surgical resection.

PURPOSE: Surgical resection is the only effective curative strategy for small intestinal neuroendocrine neoplasms (SINENs). Nevertheless, the evaluation of residual disease and prediction of disease recurrence/progression remains a problematic issue. METHODS: We evaluated 13 SINENs that underwent surgical resection of the primary tumour and/or mesenteric mass. Patients were divided in three groups: (a) Group 1: SINENs that underwent resection with curative intent, (b) Group 2: SINENs treated with resection in the setting of metastatic disease, which remained stable and (c) Group 3: SINENs treated with resection in the setting of metastatic disease, with evidence of any progression at follow-up. NETest and chromogranin A were measured pre-operatively and post-operatively during a 22-month median follow-up period and compared with imaging studies. NETest score <20% was determined as normal, 20-40% low, 41-79% intermediate and ≥80% high score. RESULTS: NETest score was raised in all (100%) SINENs pre-operatively. Surgery with curative intent resulted in NETest score reduction from 78.25 ± 15.32 to 25.25 ± 1.75 (p < 0.05). Low NETest scores post-operatively were evident in all cases without clinical evidence of residual disease (Group 1). However, the low disease activity score suggested the presence of microscopic residual disease. In three cases (75%) with stable disease (Group 2) the NETest score was low consistent with indolent disease. In the progressive disease group (Group 3), a high NETest score was present in three cases (60%) and an intermediate NETest score in the remainder (40%). CONCLUSIONS: Blood NETest scores accurately identified SINENs and were significantly decreased by curative surgery. Monitoring NETest post-operatively may facilitate management by identifying the presence of residual/progressive disease.