BACKGROUND: The programmed death 1 inhibitor toripalimab plus the angio-immuno kinase inhibitor surufatinib revealed a tolerable safety profile and preliminary efficacy in patients with advanced solid tumours in a phase I study.
METHODS: This was an open-label, single-arm, multi-cohort phase II study in China. Patients with advanced neuroendocrine tumours (NETs) or neuroendocrine carcinomas (NECs) or mixed neuroendocrine non-neuroendocrine neoplasms (MiNENs) who had failed or were intolerable of standard treatment were given surufatinib (250 mg orally, once daily) plus toripalimab (240 mg intravenously, once every 3 weeks). Primary end-point was investigator-assessed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end-points included duration of response (DoR), disease control rate, progression-free survival (PFS), overall survival (OS), and safety.
RESULTS: Forty patients were enrolled into two cohorts by tumour types (NET, n = 19; NEC-MiNEN, n = 21). ORRs (95% CIs) were 21.1% (6.1-45.6) and 23.8% (8.2-47.2) in the NET and NEC-MiNEN cohorts, respectively. Median DoR was 7.1 months (6.9-not evaluable [NE]) and 4.1 months (3.0-NE), respectively. Median PFS was 9.6 months (4.1-NE) and 4.1 months (1.5-5.5); median OS was 27.3 (15.3-NE) and 10.9 months (9.1-14.6), respectively. Overall, grade ≥ 3 treatment-related adverse events occurred in 18 (45.0%) patients.
CONCLUSIONS: Surufatinib plus toripalimab showed antitumour activity and a tolerable safety profile in patients with previously treated NETs/NECs/MiNENs. Further study of this combination regimen is ongoing for advanced NECs, for which current therapeutic options remain limited.
RESULTS: gov: NCT04169672.

BACKGROUND: Claudin 18.2-targeted therapy has shown significant efficacy in treating claudin 18.2-positive cancers. However, limited systematic studies have investigated characteristics of claudin 18.2 expression in neuroendocrine neoplasms (NENs).
METHODS: Data and specimens from 403 cases of digestive NENs were retrospectively collected, and claudin 18.2 expression was detected using immunochemical staining.
RESULTS: Claudin 18.2 was positive in 19.6% (79/403) of the digestive NENs. The highest positive rate of claudin 18.2 was observed in gastric NENs (72/259, 27.8%), accounting for 91.1% (72/79) of all positive cases. The positivity rate was significantly higher in gastric NENs compared to pancreatic (2/78, 2.6%) or colorectal NENs (2/38, 5.3%; p < 0.05). For digestive NENs, claudin 18.2 positivity was significantly higher in neuroendocrine carcinomas (NECs) (37/144, 25.7%) than in neuroendocrine tumours (NETs; 14/160, 8.8%; p < 0.001), but no significant difference was found between gastric NECs (59/213, 27.7%) and gastric NETs (13/46, 28.3%; p > 0.05). The positivity was significantly higher in large-cell NECs (LCNECs; 28/79, 35.4%) and MiNEN (mixed neuroendocrine-non- neuroendocrine neoplasms)-LCNECs (23/66, 34.8%) compared to small-cell NECs (SCNECs; 9/65, 13.8%) and MiNEN-SCNECs (5/33, 15.2%; p < 0.05). Claudin 18.2 expression was more prevalent in gastric NENs than in pancreatic (12.5 ×; p = 0.001) and colorectal NENs (5.9 ×; p = 0.021). Claudin 18.2 staining was a useful method for identify the gastric origins of NETs, with a sensitivity of 28.3% and a specificity of 99.1%.
CONCLUSIONS: The expression characteristics of claudin 18.2 in NENs were characterized, which may provide a clinicopathological reference for targeted therapies in patients with NENs.

Neuroendocrine neoplasms (NENs) originate from neuroendocrine cells, and mainly occur in the gastrointestinal tract and lungs, rarely occurring in the orbit. Here, the clinicopathologic factors, treatments and prognosis of three cases of orbital NENs are described. The mean age of the three patients (two females and one male) was 59 years. Two cases exhibited ocular symptoms, including unilateral proptosis and eyelid mass, while the third case presented systemic symptoms exhibited as Cushing\'s syndrome. The tumours were surgically resected in all three patients. Immunohistochemistry assays revealed positive expression for pan cytokeratin and epithelial membrane antigen in all cases. Additionally, neural cell adhesion molecule 1 (also known as CD56) and synaptophysin were positive in two cases. The pathological diagnosis for case 1 and 2 was \'neuroendocrine carcinoma\' and both patients died three months after diagnosis. Case 3 was diagnosed with a neuroendocrine tumour and the symptoms of Cushing\'s syndrome gradually improved following surgery. In addition, no recurrence was observed during the four-year follow-up period. These cases demonstrate that orbital neuroendocrine tumours show different clinical manifestations due to the different types. Pathology may clarify the diagnosis, classification and grading, and provide a reference value for treatment and prognosis.

Pheochromocytoma is a rare catecholamine-producing neuroendocrine tumour originating from the chromaffin cells of the adrenal medulla or extra-adrenal paraganglia. However, there are few bibliometric studies on Pheochromocytoma. Therefore, this study was employed to summarize the global trends and current status in pheochromocytoma by bibliometric analysis.
The Web of Science (WOS) core collection database was searched for publications relating to pheochromocytoma from 2001 to 2021. Bibliometric analysis was used to examine the data, and Microsoft Excel was utilized to create bar graphs. In addition, VOSviewer was used to carry out co-authorship analysis, co-citation analysis and co-occurrence analysis. CiteSpace was used to analyze the keywords citation bursts.
A total of 8,653 publications published in 1,806 journals by 38,590 authors in 6,117 organizations from 100 countries/regions were included in our study. Among them, USA was the leading countries in terms of total publications and sum of time cited, whereas Eunice Kennedy Shriver Natl Inst Child Hlth & Hum was the leading institutions. The main publications for pheochromocytoma-related articles were Journal of clinical endocrinology &metabolism. Pacak karel and Eisenhofer Graeme were the main contributing authors. The studies on pheochromocytoma could be grouped into five clusters: Treatment, Mechanism, Etiology, Radiology and Hormones study. Moreover, the radiology study, etiology study and some specific keywords such germlines mutation, mesenchymal stem-cells, autophagy, neuroinflammation, neurotoxicity, and hemodynamic instability, may become the hot spots of future.
Although the number of articles on pheochromocytoma has fluctuated slightly over the past 20 years, there has been an overall upward trend. In general, precision medicine research on pheochromocytoma, especially metastatic pheochromocytoma, in terms of diagnosis, treatment, and etiology will be a hot research topic in the future. This study helps to understand the research perspectives, hot spots and trends of pheochromocytoma and provide new insight and a basis for future pheochromocytoma research quickly.

BACKGROUND: No known case of neuroendocrine tumour (NET) with schwannoma has been reported.
METHODS: A 63-year-old female presented to our hospital with nausea and vomiting. Upper gastrointestinal endoscopy revealed a mass in the descending part of the duodenum. Using ultrasound gastroscopy, we found that the tumour originated from the submucosa and showed low echo. We removed the tumour by electrocoagulation and sent it for pathological biopsy.
CONCLUSIONS: Immunohistochemical results showed that the mass was a rare NET with neurilemmoma.

OBJECTIVE: 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.

The aim of this study was to compare 68 Ga-NOTA-3P-TATE-RGD, a dual somatostatin receptor 2- and integrin αVβ3-targeting tracer, to 68 Ga-DOTATATE in a single group of patients with gastroenteropancreatic (GEP)-neuroendocrine tumours (NETs).
Thirty-five patients with histologically confirmed GEP-NETs (5 grade 1, 28 grade 2, and 2 grade 3 tumours) were prospectively enrolled with informed consent. The primary tumour mainly originated from the pancreas and rectum. All patients were scanned with both 68 Ga-NOTA-3P-TATE-RGD PET/CT and 68 Ga-DOTATATE PET/CT within a week and compared on a head-to-head basis. Sixteen patients also had conventional 18F-FDG PET/CT. Images were evaluated semi-quantitatively using maximum standardized uptake values (SUVmax) of tumour and tumour-to-background ratio.
All patients had at least one positive lesion on each of the two scans. A total of 1190 and 1106 lesions were detected on 68 Ga-NOTA-3P-TATE-RGD images and 68 Ga-DOTATATE images, respectively (P = 0.152). 68 Ga-NOTA-3P-TATE-RGD PET/CT revealed significantly more lesions in the liver than 68 Ga-DOTATATE PET/CT (634 vs. 532, P = 0.021). Both tracers produced comparable results for detecting primary tumours (20 vs. 20, P = 1.000), lymph node metastases (101 vs. 102, P = 0.655), and bone metastases (381 vs. 398, P = 0.244). The tumour SUVmax in 12 patients was significantly higher for 68 Ga-NOTA-3P-TATE-RGD than for 68 Ga-DOTATATE (27.2 ± 13.6 vs. 19.5 ± 10.0, P < 0.001); among them, 9 had 18F-FDG PET/CT and all were found to be FDG-positive. The remaining 23 patients had significantly higher 68 Ga-DOTATATE uptake than 68 Ga-NOTA-3P-TATE-RGD uptake (22.3 ± 16.4 vs. 11.9 ± 7.5, P < 0.001); among them, 7 had 18F-FDG PET/CT and 6 were FDG-negative. Generally, 68 Ga-DOTATATE demonstrated higher tumour SUVmax than 68 Ga-NOTA-3P-TATE-RGD (20.8 ± 16.0 vs. 14.2 ± 8.9, P < 0.001), including primary tumours, liver lesions, lymph node lesions, and bone lesions. However, the tumour-to-background ratio of liver lesions was significantly higher when using 68 Ga-NOTA-3P-TATE-RGD compared with that when using 68 Ga-DOTATATE (8.4 ± 5.5 vs. 4.7 ± 3.7, P < 0.001).
68 Ga-NOTA-3P-TATE-RGD performed better than 68 Ga-DOTATATE in detection of liver metastases with a higher tumour-to-background ratio. Moreover, 68 Ga-NOTA-3P-TATE-RGD tended to demonstrate higher uptake over 68 Ga-DOTATATE in FDG-avid NETs.
Dual SSTR2 and Integrin αvβ3 Targeting PET/CT Imaging (NCT02817945, registered 5 November 2018). URL OF REGISTRY: https://clinicaltrials.gov/ct2/show/NCT02817945.

UNASSIGNED: To describe an unusual case with a primary hepatic neuroendocrine tumour (PHNET) with multiple liver metastases.
METHODS: We reported a 65-year-old woman with PHNET with multiple liver metastases. She was highly suspected of having primary liver cancer with multiple intrahepatic metastases before liver biopsy, but was diagnosed with PHNET with multiple liver metastases after histopathology and immunohistochemistry (IHC) examinations. The patient successfully underwent three times of transcatheter arterial chemoembolization (TACE), and is currently living in a good state without related complications.
UNASSIGNED: Neuroendocrine tumors (NETs), also known as carcinoids or argyrophilic tumors, are very rare malignant tumors. The liver is the main metastasis site of NETs, but primary hepatic neuroendocrine tumors (PHNETs) are extremely rare. Histopathology and immunohistochemistry (IHC) examinations are still the main methods used for diagnosing NETs. There are no treatment guidelines for PHNETs, and surgical resection is generally the preferred treatment. For PHNET patients who are not suitable for surgery, TACE has been proven to be an effective alternative treatment that can effectively reduce the tumour burden and relieve symptoms, but the current evidence is still limited.
CONCLUSIONS: The clinical diagnosis of PHNET still faces great challenges, imaging examinations often lead to misdiagnosis, and its diagnosis mainly depends on histopathology and immunohistochemical examinations. For PHNET patients who are not suitable for surgery, TACE may be an effective alternative therapy.

Primary small cell carcinoma (SCC) of the brain is rare, and there have been no reports of small cell carcinoma located at the resection site of a glioma without extracranial tumours. Herein, we report a case of brain SCC in the same intracranial region from which a malignant glioma had been surgically resected a year prior. The patient, a 68-year-old male, had headaches as a symptom, and brain CT and MRI revealed a hyperdense region measuring 5.5×5 centimetres. Blood test results showed no significant changes. H&E staining suggested that these tumour cells had the characteristics of small cell lung carcinoma cells. Immunohistochemical staining for the glioma marker S100 was negative, but immunohistochemical staining for the neuroendocrine marker synaptophysin and for the cell adhesion molecule CD56 was strongly positive; meanwhile, staining for thyroid transcription factor-1 (TTF-1), a relatively specific marker of lung and thyroid carcinoma, was positive, and the Ki67 index was 75%. The pathological examination strongly suggested that the tumour was a small cell lung carcinoma, but CT and MRI scans indicated that there were no extracranial tumours. Hence, the tumour could be a primary small cell brain carcinoma. The patient underwent surgical resection again; the excised tumour was a mass of grey and white tissues with fragmentary morphology, and its dimensions were 3.0 cm×1.5 cm×0.8 cm.

BACKGROUND: 68Ga-labelled peptides targeting somatostatin receptor 2 (SSTR2) have demonstrated encouraging results in managing patients with neuroendocrine tumours (NETs). In addition to metal chelation, bifunctional chelators have also been found to impact imaging outcomes due to their differences in stability, charge, hydrophilicity, etc. In the present work, a comparative pharmacokinetic evaluation and imaging characteristics were performed between 68Ga-labelled somatostatin analogues (TATE) using NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid) and DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) as bifunctional chelating agents (BFCAs).
RESULTS: Both 68Ga-NOTA-TATE and 68Ga-DOTA-TATE were obtained with high radiochemical purity. 68Ga-NOTA-TATE demonstrated higher in vitro stability (≥ 99%) than 68Ga-DOTA-TATE (≥ 95%) after 3 h of incubation. The water solubilities (partition coefficients, - 1.76 ± 0.06 vs. - 2.72 ± 0.16) and plasma protein binding rates (12.12% vs. 30.6%) were lower for 68Ga-NOTA-TATE than for 68Ga-DOTA-TATE. Differential pharmacokinetics and comparable tumour affinities (within 1 h) were observed in AR42J tumour-bearing mice. Healthy volunteer imaging studies showed comparable distribution patterns of these two imaging agents. However, the maximum standardized uptake values (SUVmax) of the two tracers varied in each organ. The two PET agents demonstrated almost identical SUVmax values in the kidneys. 68Ga-NOTA-TATE did have a lower SUVmax in most other organs compared with 68Ga-DOTA-TATE, including the liver (4.2 vs. 10.1), potentially due to the lower protein binding rate.
CONCLUSIONS: 68Ga-NOTA-TATE and 68Ga-DOTA-TATE demonstrated comparable tumour uptake in an AR42J mouse model. An initial clinical study revealed that 68Ga-NOTA-TATE may have reduced background uptake in the major organs such as the liver. Although the subject numbers were limited, further investigation of 68Ga-NOTA-TATE is warranted for detecting SSTR2-positive neuroendocrine tumours.