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.

Absorbed Dose-Response Relationship in Patients with Gastroenteropancreatic Neuroendocrine Tumors Treated with [177Lu]Lu-DOTATATE: One Step Closer to Personalized Medicine.

[177Lu]Lu-DOTATATE has been approved for progressive and inoperable gastroenteropancreatic neuroendocrine tumors (GEP-NETs) that overexpress somatostatin receptors. The absorbed doses by limiting organs and tumors can be quantified by serial postinfusion scintigraphy measurements of the γ-emissions from 177Lu. The objective of this work was to explore how postinfusion [177Lu]Lu-DOTATATE dosimetry could influence clinical management by predicting treatment efficacy (tumor shrinkage and survival) and toxicity. Methods: Patients with GEP-NETs treated with [177Lu]Lu-DOTATATE between 2016 and 2022 and who underwent dosimetry were included. Absorbed doses were calculated for healthy organs (liver, kidneys, bone marrow, and spleen) and tumors using PLANET Dose and the local energy deposition method based on serial posttreatment SPECT/CT. Up to 5 lesions per site were selected and measured on images collected at baseline and 3 mo after treatment end (measurement masked to the somatostatin receptor imaging uptake). For toxicity assessment, laboratory parameters were regularly monitored. Clinical data, including time to death or progression, were collected from the patients' health records. Correlations between absorbed doses by organs and toxicity and between absorbed doses by lesions and tumor volume variation were studied using regression models. Results: In total, 35 dosimetric studies were performed in patients with mostly grade 2 (77%) tumors and metastases in liver (89%), lymph nodes (77%), and bone (34%), and 146 lesions were analyzed: 1-9 lesions per patient, mostly liver metastases (65%) and lymph nodes (25%). The median total absorbed dose by tumors was 94.4 Gy. The absorbed doses by tumors significantly decreased between cycles. The absorbed dose by tumors was significantly associated with tumor volume variation (P < 0.001) 3 mo after treatment end, and it was a significant prognostic factor for survival. Toxicity analysis showed a correlation between the decrease of hematologic parameters such as lymphocytes or platelet concentrations and the absorbed doses by the spleen or bone marrow. The mean absorbed dose by the kidneys was not correlated with nephrotoxicity during the studied period. Conclusion: In patients treated with [177Lu]Lu-DOTATATE for GEP-NETs, tumor and healthy organ dosimetry can predict survival and toxicities, thus influencing clinical management.

Capsule endoscopy diagnosis of gastrointestinal melanoma.

Melanoma is a cancer that frequently metastasises to the small bowel, but most cases are asymptomatic and are diagnosed postmortem. Therefore, CT and PET CT cannot detect all lesions and conventional endoscopic study only detects 10-20% of lesions. In this study, we present the case of a 68-year-old patient with a history of cutaneous melanoma and a diagnosis of intestinal melanoma. Thanks to capsule endoscopy, two lesions compatible with cutaneous melanoma metastasis to the small bowel were detected, allowing a much more effective surgical planning. Capsule endoscopy is an innovative technique that improves preoperative diagnosis, as it is able to detect bowel segments that cannot be inspected by conventional endoscopy. It also has a better resolution than conventional CT, improving sensitivity in the detection of lesions.

Updates in the diagnosis and management of small-bowel tumors.

Small-bowel tumors represent a rare entity comprising 0.6% of all new cancer cases in the US, and only 3% of all gastrointestinal neoplasms. They are a heterogenous group of neoplasms comprising of about forty different histological subtypes with the most common being adenocarcinoma, neuroendocrine tumors, stromal tumors and lymphomas. Their incidence has been reportedly increasing over recent years, partly owing to the advances and developments in the diagnostic modalities. Small-bowel capsule endoscopy, device assisted enteroscopy and dedicated small-bowel cross-sectional imaging are complimentary tools, supplementing each other in the diagnostic process. Therapeutic management of small-bowel tumors largely depends on the histological type and staging at diagnosis. The aim of the present review article is to discuss relevant advances in the diagnosis and management of small-bowel tumors.

Symptoms Contributing to the Diagnosis of Small Bowel Tumors.

INTRODUCTION: Small bowel tumors (SBTs) are difficult to diagnose because of limited opportunities and technical difficulties in evaluating the small bowel. Asymptomatic conditions or nonspecific symptoms make SBT diagnosis more challenging. In Asia, SBTs are reported to be more frequently malignant lymphoma (ML), adenocarcinoma, and gastrointestinal stromal tumor (GIST). In this study, we examined 66 patients diagnosed with SBTs and determined their clinical characteristics. METHODS: This retrospective study was conducted from January 2013 to July 2020 at Kurume University Hospital. The modalities used to detect SBTs were computed tomography (CT), positron emission tomography, magnetic resonance imaging, and ultrasonography. Endoscopy was also performed in some cases to confirm SBT diagnosis. The study included 66 patients. The medical data collected included presenting symptoms, tumor location, underlying condition, diagnostic modalities, pathologic diagnosis, and treatment. RESULTS: ML and adenocarcinoma were the most common tumors (22.7%), followed by GIST (21.2%) and metastatic SBT (18.2%). Symptoms that led to SBT detection were abdominal pain (44.5%), asymptomatic conditions (28.8%), hematochezia (12.1%), and anemia (10.6%). CT was the most used modality to detect SBTs. Nineteen patients were asymptomatic, and SBTs were incidentally detected in them. GISTs and benign tumors were more often asymptomatic than other malignant tumors. CONCLUSION: Abdominal pain was the main symptom for SBTs in particular adenocarcinoma, ML, and metastatic SBT. In addition, GIST, which was highly prevalent in Asia, had fewer symptoms. An understanding of these characteristics may be helpful in the clinical practice of SBTs.

Lower gastrointestinal bleeding as an uncommon form of presentation in a small intestine neuroendocrine tumor.

Neuroendocrine tumors (NETs) are rare, with an annual incidence of 10/100,000 inhabitants, with an increase in incidence in the last 30 years that probably is due to an improvement in diagnostic techniques. However, NETs the second neoplasia most prevalent advanced disease of the gastrointestinal tract due to its high survival. It´s way of presentation is usually with vague symptoms and often without an incidental diagnosis from the use of imaging techniques. A correct differential diagnosis will allow us its early diagnosis and its treatment. We present the case of a patient diagnosed with NET whose symptoms of presentation was lower gastrointestinal bleeding with a negative endoscopic study.

Fully-automated detection of small bowel carcinoid tumors in CT scans using deep learning.

BACKGROUND: Small bowel carcinoid tumor is a rare neoplasm and increasing in incidence. Patients with small bowel carcinoid tumors often experience long delays in diagnosis due to the vague symptoms, slow growth of tumors, and lack of clinician awareness. Computed tomography (CT) is the most common imaging study for diagnosis of small bowel carcinoid tumor. It is often used with positron emission tomography (PET) to capture anatomical and functional aspects of carcinoid tumors and thus to increase the sensitivity. PURPOSE: We compared three different kinds of methods for the automatic detection of small bowel carcinoid tumors on CT scans, which is the first to the best of our knowledge. METHODS: Thirty-three preoperative CT scans of 33 unique patients with surgically-proven carcinoid tumors within the small bowel were collected. Ground-truth segmentation of tumors was drawn on CT scans by referring to available 18 F-DOPA PET scans and the corresponding radiology report. These scans were split into the trainval set (n = 24) and the test positive set (n= 9). Additionally, 22 CT scans of 22 unique patients who had no evidence of the tumor were collected to comprise the test negative set. We compared three different kinds of detection methods, which are detection network, patch-based classification, and segmentation-based methods. We also investigated the usefulness of small bowel segmentation for reduction of false positives (FPs) for each method. Free-response receiver operating characteristic (FROC) curves and receiver operating characteristic (ROC) curves were used for lesion- and patient-level evaluations, respectively. Statistical analyses comparing the FROC and ROC curves were also performed. RESULTS: The detection network method performed the best among the compared methods. For lesion-level detection, the detection network method, without the small bowel segmentation-based filtering, achieved sensitivity values of (60.8%, 81.1%, 82.4%, 86.5%) at per-scan FP rates of (1, 2, 4 ,8), respectively. The use of the small bowel segmentation did not improve the performance ( p = 0.742 $p=0.742$ ). For patient-level detection, again the detection network method, but with the small bowel segmentation-based filtering, achieved the highest AUC of 0.86 with a sensitivity of 78% and specificity of 82% at the Youden point. CONCLUSIONS: The carcinoid tumors in this patient population were very small and potentially difficult to diagnose. The presented method showed reasonable sensitivity at small numbers of FPs for lesion-level detection. It also achieved a promising AUC for patient-level detection. The method may have clinical application in patients with this rare and difficult to detect disease.

Imaging of Small-Bowel Neuroendocrine Neoplasms: AJR Expert Panel Narrative Review.

Neuroendocrine neoplasms (NENs) of the small bowel are typically slow-growing lesions that remain asymptomatic until reaching an advanced stage. Imaging modalities for lesion detection, staging, and follow-up in patients with known or suspected NEN include CT enterography, MR enterography, and PET/CT using a somatostatin receptor analog. FDG PET/CT may have a role in the evaluation of poorly differentiated NENs. Liver MRI, ideally with a hepatocyte-specific contrast agent, should be used in the evaluation of hepatic metastases. Imaging informs decisions regarding both surgical approaches and systematic therapy (specifically, peptide receptor radionuclide therapy). This AJR Expert Panel Narrative Review describes the multimodality imaging features of small-bowel NENs; explores the optimal imaging modalities for their diagnosis, staging, and follow-up; and discusses how imaging may be used to guide therapy.

Integrating Functional Imaging and Molecular Profiling for Optimal Treatment Selection in Neuroendocrine Neoplasms (NEN).

PURPOSE OF REVIEW: Gastroenteropancreatic NEN (GEP-NEN) are group of malignancies with significant clinical, anatomical and molecular heterogeneity. High-grade GEP-NEN in particular present unique management challenges. RECENT FINDINGS: In the current era, multidisciplinary management with access to a combination of functional imaging and targeted molecular profiling can provide important disease characterisation, guide individualised management and improve patient outcome. Multiple treatment options are now available, and combination and novel therapies are being explored in clinical trials. Precision medicine is highly relevant for a heterogenous disease like NEN. The integration of dual-tracer functional PET/CT imaging, molecular histopathology and genomic data has the potential to be used to gain a more comprehensive understanding of an individual patient's disease biology for precision diagnosis, prognostication and optimal treatment allocation.

Association between surveillance imaging and survival outcomes in small bowel neuroendocrine tumors.

BACKGROUND: Surveillance guidelines following the resection of small bowel neuroendocrine tumors (SB-NETs) are inconsistent. We evaluated the impact of surveillance imaging on SB-NET recurrence and overall survival (OS). METHODS: Patients with completely resected SB-NETs referred to a provincial cancer center (2004-2015) were reviewed. Associations between imaging frequency, recurrence, post-recurrence treatment, and OS were determined using univariate and Cox-regression analyses. RESULTS: Among 195 completely resected SB-NET patients, 31% were ≥70 years, 43% were female, and 80% had grade 1 disease. Imaging frequency was predictive of recurrence (hazard ratio 2.52, 95% confidence interval 1.84-3.46, p < 0.001). 72% underwent interventions for recurrent disease. Patients who were treated for the recurrent disease had comparable OS to those who did not recur (median 152 vs. 164 months; p = 0.25). Imaging frequency was not associated with OS in those with treated recurrent disease (p = 0.65). Patients who recurred underwent more computerized tomography (CT) scans than those who did not recur (CT: 1.47 ± 0.89 vs. 1.02 ± 0.81 scans/year, p < 0.001). Detection of disease recurrence was 5%-7% per year during the first 6 years of surveillance and peaked at 17% in Year 9. CONCLUSION: Less frequent imaging over a longer duration should be emphasized to capture clinically relevant recurrences that can be treated to improve OS.

Primary hepatic neuroendocrine carcinoma with subsequent cerebral and spinal metastases

A 72-year-old man was referred to us for evaluation of asymptomatic masses in the liver that had been detected on ultrasonography performed during a physical screening. The level of neuron-specific enolase was elevated (56.97 ng/mL; normal level, 15.7-17.0 ng/mL). Other tumor markers were normal, including alpha fetoprotein, carcinoembryonic antigen and cancer antigen 199. No tumor was found through chest CT scan, gastroscopy and colonoscopy. Abdominal MR demonstrated multiple masses with irregular central necrosis, which appeared as marked hyperintensity on T2WI. Most lesions showed rim-like enhancement at portal venous phase. Pathological examination of tissue obtained by means of percutaneous biopsy indicated that the tumor was composed of small cells which were arranged in nests and trabeculae, the nuclei were round with little cytoplasm, and nuclear division was present (hematoxylin-eosin stain (AU)

Advances in the imaging of gastroenteropancreatic neuroendocrine neoplasms.

Gastroenteropancreatic neuroendocrine neoplasms comprise a heterogeneous group of tumors that differ in their pathogenesis, hormonal syndromes produced, biological behavior and consequently, in their requirement for and/or response to specific chemotherapeutic agents and molecular targeted therapies. Various imaging techniques are available for functional and morphological evaluation of these neoplasms and the selection of investigations performed in each patient should be customized to the clinical question. Also, with the increased availability of cross sectional imaging, these neoplasms are increasingly being detected incidentally in routine radiology practice. This article is a review of the various imaging modalities currently used in the evaluation of neuroendocrine neoplasms, along with a discussion of the role of advanced imaging techniques and a glimpse into the newer imaging horizons, mostly in the research stage.

Endoscopic techniques for diagnosis and treatment of gastro-entero-pancreatic neuroendocrine neoplasms: Where we are.

BACKGROUND: The correct localization of the primary tumor site and a complete histological diagnosis represent the milestones for the proper management of gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs). AIM: To analyze current evidence on the role of endoscopy in the diagnosis/treatment of GEP-NENs. METHODS: An extensive bibliographical search was performed in PubMed to identify guidelines and primary literature (retrospective and prospective studies, systematic reviews, case series) published in the last 15 years, using both medical subject heading (MeSH) terms and free-language keywords: gastro-entero-pancreatic neuroendocrine neoplasms; endoscopy; ultrasound endoscopy; capsule endoscopy; double-balloon enteroscopy; diagnosis; therapy; staging. RESULTS: In the diagnostic setting, endoscopic ultrasonography (EUS) represents the diagnostic gold standard for pancreatic NENs and the technique of choice for the locoregional staging of gastric, duodenal and rectal NENs. The diagnosis of small bowel NENs (sbNENs) has been improved with the advent of video capsule endoscopy and double-balloon enteroscopy, which allow for direct visualization of the entire small bowel; however, data regarding the efficacy/safety of these techniques in the detection of sbNENs are scanty and often inconclusive. From a therapeutic point of view, endoscopic removal is the treatment of choice for the majority of gastric NENs (type 1/2), for well-differentiated localized nonmetastatic duodenal NENs < 1 cm, confined to the submucosa layer and for < 10 mm, stage T1-T2, rectal NENs. EUS-guided pancreatic locoregional ablative treatments have been proposed in recent studies with promising results in order to control symptoms or reduce tumor burden in selected patients. CONCLUSION: Standard axial endoscopy and EUS still play a pivotal role in several GEP-NENs. Advanced techniques for increasing the rate of R0 resection should be reserved for high-volume referral centers.

Diagnosis, treatment, and current concepts in the endoscopic management of gastroenteropancreatic neuroendocrine neoplasms.

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are rare tumors derived from the neuroendocrine cell system, which that have increased in incidence and prevalence in recent years. Despite improvements in radiological and metabolic imaging, endoscopy still plays a pivotal role in the number of GEP-NENs. Tumor detection, characterization, and staging are essential in management and treatment planning. Upper and lower gastrointestinal (GI) endoscopy is essential for correct localization of the primary tumor site of GI NENs. Endoscopic ultrasonography (EUS) has an important role in the imaging and tissue acquisition of pancreatic NENs and locoregional staging of GI neuroendocrine tumors. Correct staging and histological diagnosis have important prognostic implications. Endoscopic operating techniques allow the removal of small GI NENs in the early stage of mucosal or submucosal invasion of the intestinal wall. Preoperative EUS-guided techniques may help the surgeon locate small and deep tumors, thus avoiding formal pancreatic resections in favor of parenchymal-sparing surgery. Finally, locoregional ablative treatments have been proposed in recent studies with promising results in selected patients.

Bichromatic Imaging with Hemicyanine Fluorophores Enables Simultaneous Visualization of Non-alcoholic Fatty Liver Disease and Metastatic Intestinal Cancer.

Simultaneous detection of different diseases via a single fluorophore is challenging. We herein report a bichromatic fluorophore named Cy-914 for the simultaneous diagnosis of non-alcoholic fatty liver disease (NAFLD) and metastatic intestinal cancer by leveraging its NIR-I/NIR-II dual-color imaging capability. Cy-914 with a pKa of 6.98 exhibits high sensitivity to pH and viscosity, showing turn-on NIR-I fluorescence at 795 nm in an acidic tumor microenvironment, meanwhile displaying intense NIR-II fluorescence at 914/1030 nm under neutral to slightly basic viscous conditions. Notably, Cy-914 could sensitively and noninvasively monitor viscosity variations in the progression of NAFLD. More importantly, it was able to simultaneously visualize NAFLD (ex/em = 808/1000-1700 nm) and intestinal metastases (ex/em = 570/810-875 nm) in two independent channels without spectral cross interference after topical spraying, further improving fluorescence-guided surgery of tiny metastases less than 3 mm. This strategy may provide an understanding for developing multi-color fluorophores for multi-disease diagnosis.