• Gastroenteropancreatic neuroendocrine neoplasm
• Peptide receptor radionuclide therapy
• α-Emitters

• neuroendocrine
• pancreas
• small bowel

• Neuroendocrine Tumors/therapy
• Neuroendocrine Tumors/diagnosis
• Humans
• Iowa
• History, 20th Century
• History, 21st Century
• Endocrinology/organization & administration

• P50 CA174521 NCI NIH HHS
• R01 CA260200 NCI NIH HHS

• Clinical features
• Gallbladder neuroendocrine carcinoma
• Surgical treatment
• Survival time

• Humans
• Gallbladder Neoplasms/therapy
• Gallbladder Neoplasms/pathology
• Gallbladder Neoplasms/mortality
• Gallbladder Neoplasms/surgery
• Gallbladder Neoplasms/diagnosis
• Male
• Female
• Carcinoma, Neuroendocrine/pathology
• Carcinoma, Neuroendocrine/therapy
• Carcinoma, Neuroendocrine/mortality
• Carcinoma, Neuroendocrine/surgery
• Carcinoma, Neuroendocrine/diagnosis
• Middle Aged
• Retrospective Studies
• Aged
• Prognosis
• Survival Rate
• Adult
• Cholecystectomy
• Follow-Up Studies
• Combined Modality Therapy

• SSTR
• SSTR antagonist
• actinium-225
• neuroendocrine tumor
• peptide receptor radionuclide therapy (PRRT)
• targeted α-particle therapy

• Functional imaging
• GEP-NENs
• Genetic mutations
• Immune checkpoint inhibitors
• Peptide receptor radionuclide therapy
• Targeting agents

Theranostics is a term coined by combining the words “therapeutics” and “diagnostics,” referring to single chemical entities developed to deliver therapy and diagnosis simultaneously. Neuroendocrine tumors are rare cancers that occur in various organs of the body, and they express neuroendocrine factors such as chromogranin A and somatostatin receptor. Somatostatin analogs bind to somatostatin receptor, and when combined with diagnostic radionuclides, such as gamma‐emitters, are utilized for diagnosis of neuroendocrine tumor. Somatostatin receptor scintigraphy when combined with therapeutic radionuclides, such as beta‐emitters, are effective in treating neuroendocrine tumor as peptide receptor radionuclide therapy. Somatostatin receptor scintigraphy and peptide receptor radionuclide therapy are some of the most frequently used and successful theranostics for neuroendocrine tumor. In Japan, radiopharmaceuticals are regulated under a complex law system, creating a significant drug lag, which is a major public concern. It took nearly 10 years to obtain the approval for somatostatin receptor scintigraphy and peptide receptor radionuclide therapy use by the Japanese government. In 2021, ¹¹¹Lu‐DOTATATE (Lutathera), a drug for peptide receptor radionuclide therapy, was covered by insurance in Japan. In this review, we summarize the history of the development of neuroendocrine tumor theranostics and theranostics in general, as therapeutic treatment for cancer in the future. Furthermore, we briefly address the Japanese point of view regarding the development of new radiopharmaceuticals.

• Neuroendocrine tumor (NET)
• Somatostatin receptor scintigraphy (SRS)
• Theranostics
• peptide receptor radionuclide therapy (PRRT)
• somatostatin analog (SSA)

Neuroendocrine neoplasms (NENs) of the gallbladder (GB) are extremely rare. We aimed to compare the clinical features of GB-NENs with those of adenocarcinomas (ADCs) of the GB. Among 21 patients with GB-NENs, 20 were diagnosed with poorly differentiated small-cell neuroendocrine carcinoma (NEC), and 1 patient had large-cell NEC. At initial presentation, all patients had advanced stages of cancer, with extensive local extension and/or distant metastasis. Nine patients with GB-NEC who underwent surgical resection had a significantly better progression-free survival (PFS) than those who did not undergo surgery. After a propensity score matching with a 1:1 ratio using the American Joint Committee on Cancer (AJCC) stage, age, sex, and operation status, there was no difference in the overall survival or PFS between AJCC stage-matched patients with GB-NEC or GB-ADC. In conclusion, GB-NEC is difficult to diagnose early and has a prognosis similar to that of GB-ADC.

Neuroendocrine neoplasms (NENs) of the gallbladder (GB) are extremely rare. We aimed to compare the clinical features, disease progression, management, and prognosis of patients with GB-NENs with those of patients with GB-adenocarcinomas (ADCs). A total of 21 patients with GB-NENs and 206 patients with GB-ADCs, treated at three tertiary medical centers between January 2010 and December 2020, were enrolled. Of the 21 patients with GB-NENs, 20 were diagnosed with poorly differentiated small-cell neuroendocrine carcinomas (NECs), and 1 patient had large-cell NEC. All patients presented with advanced stages of cancer with extensive local extension and/or distant metastasis and non-specific symptoms. Tumor-node-metastasis stage IIIB and IV (A/B) tumors were found in 6 and 15 (1/14) patients, respectively. Nine patients with GB-NEC who underwent surgical resection had a significantly better progression-free survival (PFS) than those who did not undergo surgery. After a propensity score matching with a 1:1 ratio using the American Joint Committee on Cancer stage, age, sex, and operation status, 19 pairs of patients were included. Compared with stage-matched patients with GB-ADC, patients with GB-NEC had similar overall survival and PFS. However, as GB-NEC is rarely diagnosed early, further studies investigating methods for the early diagnosis and improvement in the survival of patients with GB-NEC are needed.

• adenocarcinoma
• gallbladder
• neuroendocrine carcinoma
• neuroendocrine neoplasm
• propensity score matching

In the era of precision medicine, novel targets have emerged on the surface of cancer cells, which have been exploited for the purpose of radioligand therapy. However, there have been variations in the way these receptors are expressed, especially in prostate cancers and neuroendocrine tumors. This variable expression of receptors across the grades of cancers led to the concept of ‘target heterogeneity’, which has not just impacted therapeutic decisions but also their outcomes. Radiopharmaceuticals targeting receptors need to be used when there are specific indicators—either clinical, radiological, or at molecular level—warranting their use. In addition, response to these radioligands can be assessed using different techniques, whereby we can prognosticate further outcomes. We shall also discuss, in this review, the conventional as well as novel approaches of detecting heterogeneity in prostate cancers and neuroendocrine tumors.

Tumor or target heterogeneity (TH) implies presence of variable cellular populations having different genomic characteristics within the same tumor, or in different tumor sites of the same patient. The challenge is to identify this heterogeneity, as it has emerged as the most common cause of ‘treatment resistance’, to current therapeutic agents. We have focused our discussion on ‘Prostate Cancer’ and ‘Neuroendocrine Tumors’, and looked at the established methods for demonstrating heterogeneity, each with its advantages and drawbacks. Also, the available theranostic radiotracers targeting PSMA and somatostatin receptors combined with targeted systemic agents, have been described. Lu-177 labeled PSMA and DOTATATE are the ‘standard of care’ radionuclide therapeutic tracers for management of progressive treatment-resistant prostate cancer and NET. These approved therapies have shown reasonable benefit in treatment outcome, with improvement in quality of life parameters. Various biomarkers and predictors of response to radionuclide therapies targeting TH which are currently available and those which can be explored have been elaborated in details. Imaging-based features using artificial intelligence (AI) need to be developed to further predict the presence of TH. Also, novel theranostic tools binding to newer targets on surface of cancer cell should be explored to overcome the treatment resistance to current treatment regimens.

• Ga-68
• PET/CT
• PSMA
• Prostate Cancer
• heterogeneity
• neuroendocrine tumor
• theranostics

• Carcinoid tumor
• Epidemiology
• Gallbladder cancer
• Neuroendocrine carcinomas
• Neuroendocrine neoplasms
• Neuroendocrine tumors

• Computed tomography
• Pancreatic neuroendocrine neoplasms
• Treatment outcome
• extracellular volume fraction

• 177Lu-DOTATATE
• pancreatic neuroendocrine tumors
• peptide receptor radionuclide therapy
• therapy monitoring
• tumor growth rate

• clinical feature
• gallbladder
• neuroendocrine carcinoma
• treatment

• Carcinoma, Neuroendocrine/diagnosis
• Carcinoma, Neuroendocrine/mortality
• Carcinoma, Neuroendocrine/therapy
• Combined Modality Therapy
• Gallbladder Neoplasms/diagnosis
• Gallbladder Neoplasms/mortality
• Gallbladder Neoplasms/therapy
• Humans
• Prognosis
• Survival Rate

• Image Analysis
• Ki67
• Neuroendocrine Tumour
• Pancreas
• Proliferative Index
• QuPath

• Antibodies, Antinuclear
• Antibodies, Monoclonal
• Biomarkers, Tumor/analysis
• Humans
• Image Interpretation, Computer-Assisted/methods
• Immunohistochemistry/methods
• Immunohistochemistry/standards
• Intestinal Neoplasms/pathology
• Ki-67 Antigen/analysis
• Mitotic Index/methods
• Mitotic Index/standards
• Neoplasm Grading/methods
• Neoplasm Grading/standards
• Neuroendocrine Tumors/pathology
• Pancreatic Neoplasms/pathology
• Stomach Neoplasms/pathology

• Neuroendocrine carcinoma
• Neuroendocrine tumors
• Prognosis
• Tumor grade
• Tumor size
• Univariate analysis

• clinical features
• diagnosis
• neuroendocrine tumor of the gallbladder
• pathological classification
• treatment

• Adénome hypophysaire
• Hyperparathyroïdie primaire
• Multiple endocrine Neoplasia type 1
• Neuroendocrine tumor
• Néoplasie endocrinienne multiple de type 1
• Pituitary adenoma
• Primary hyperparathyroidism
• Tumeur neuroendocrine

Background: Therapy monitoring of cancer treatment by contrast-enhanced CT (CECT), applying response evaluation criteria in solid tumors criteria version 1. 1 (RECIST 1.1) is less suitable for neuroendocrine tumors (NETs) which, when responding, tend to show stabilization rather than shrinkage. New methods are needed to further classify patients in order to identify non-responders at an early stage and avoid unnecessary adverse effects and costs. Changes in arterial tumor attenuation and contrast-enhancement could be used to identify the effect of therapy, perhaps even in early stages of treatment.

Methods: Patients with metastatic pancreatic NETs (PNETs) receiving peptide receptor radionuclide therapy (PRRT) with ¹⁷⁷Lu-DOTATATE underwent CECT at baseline, mid-treatment (PRRT cycles 3–5) and at follow-up, 3 months after the last PRRT cycle. At baseline CECT, the liver metastasis with the highest arterial attenuation was identified in each patient. The fold changes in arterial tumor attenuation (Hounsfield Units, HU), contrast-enhancement (HU), and transversal tumor area (cm²) between CECT at baseline, mid-treatment and follow-up were calculated. Correlation of the tumor metrics to outcome parameters such as progression-free survival (PFS) and time to best response was performed.

Results: Fifty-two patients were included (27 men, 25 women), median age 60 years (range 29–80), median Ki-67 8% (range 1–30). Six patients had grade 1 PNETs, forty had grade 2 and four had grade 3 tumors. As an internal control, it was first tested and established that the tumor contrast-enhancement was not merely related to that of the abdominal aorta. The mean ± SD arterial attenuation of the liver metastases was similar at baseline, 217 ± 62 HU and at mid-treatment, 238 ± 80 HU and then decreased to 198 ± 62 HU at follow-up, compared to baseline (p = 0.024, n = 52) and mid-treatment (p = 0.0004, n = 43). The transversal tumor area decreased 25% between baseline and follow-up (p = 0.013, n = 52). Tumor contrast-enhancement increased slightly from baseline to mid-treatment and these fold changes correlated with PFS (R² = 0.33, p = 0.0002, n = 37) and with time to best response (R² = 0.34, p < 0.0001, n = 37).

Conclusions: Early changes in contrast-enhancement and arterial attenuation in PNET liver metastases may for CECT monitoring of PRRT yield complementary information to evaluation by RECIST 1.1.

• 177Lu
• CT
• NET
• PRRT
• computed tomography
• contrast-enhancement
• neuroendocrine tumor
• therapy monitoring

Gastroenteropancreatic neuroendocrine tumours (GEP-NETs) are a heterogeneous group of tumours. An effective diagnosis requires a multimodal approach that combines evaluation of clinical symptoms, hormonelevels, radiological and nuclear imaging, and histological confirmation. Imaging plays a critical role in NETs diagnosis, prognosis and management, so the radiologists are important members of the multidisciplinary team. During diagnostic work-up two critical issues are present: firstly the need to identify tumor presence and secondly to define the primary site and assess regional and distant metastases.

The most appropriate imaging technique depends on the type of neuroendocrine tumour and the availability of specialized imaging techniques and expertise. There is no general consensus on the most efficient imaging pathway, reflecting the challenge in reliably detection of these tumours.

• computed tomography
• contrast-enhanced ultrasound
• magnetic resonance imaging
• neuroendocrine tumours
• ultrasound

• Pancreatic neuroendocrine carcinoma
• Surgical therapy
• Surveillance, Epidemiology, and End Results (SEER) database

• Aged
• Carcinoma, Neuroendocrine/mortality
• Carcinoma, Neuroendocrine/pathology
• Carcinoma, Neuroendocrine/surgery
• Female
• Humans
• Kaplan-Meier Estimate
• Male
• Middle Aged
• Neoplasm Staging
• Palliative Care/methods
• Pancreas/pathology
• Pancreas/surgery
• Pancreatectomy
• Pancreatic Neoplasms/mortality
• Pancreatic Neoplasms/pathology
• Pancreatic Neoplasms/surgery
• Prognosis
• Retrospective Studies
• SEER Program/statistics & numerical data
• Time Factors
• Treatment Outcome
• Pancreatic Neoplasms

• 2019RC130 Projects of medical and health technology program in Zhejiang province
• Projects of medical and health technology program in Zhejiang province

• Gallbladder
• Neuroendocrine carcinoma
• Neuroendocrine tumor
• Surgery

Large-cell neuroendocrine tumors (NETs) are poorly differentiated malignancies of rare incidence and aggressive nature. NETs mostly arise in the lung followed by the gastrointestinal tract, although they are potentially ubiquitous throughout the body. Primary unknown NET has a worse prognosis and shorter survival comparing with other NETs, with limited available data in the literature concerning this subgroup. The authors report the case of large-cell NET with supraclavicular lymph node presentation. Total excisional biopsy revealed an enlarged adenopathy 18 × 15 × 10 mm, which was extensively infiltrated by a solid malignant neoplasm composed of large cells with granular chromatin, nuclear pseudo-inclusions, high mitotic index, and focal necrosis, with a Ki 67 index 25-30% and positive immunohistochemical study for the expression of cytokeratin 8/18, chromogranin, synaptophysin, and thyroid transcriptional factor-1 (TTF-1). There was no evidence of primary location apart from two infracentimetric lung lesions that could not be accessed for biopsy and were negative at both somatostatin receptor scintigraphy and positron emission tomography. The NET relapsed with three mediastinal masses, so the patient was started on chemotherapy with carboplatin and etoposide with initial total response. Early progression showed no response to further chemotherapy regimens (temozolomide, oral etoposide); therefore, the patient was treated with local radiotherapy. This patient has an atypical long survival (54 months) compared to the literature data. In fact, there are few long-term survivors of large-cell NET and they are all related to complete surgical resection.

• Carcinoma, Neuroendocrine
• Neoplasms, Unknown Primary
• Neuroendocrine Tumors

• Appendicitis
• Carcinoid tumor
• Children
• Neuroendocrine tumors

• Leucine-rich repeat-containing G-protein-coupled receptor 5
• RNA in situ hybridization
• colorectal neuroendocrine neoplasms

• Adult
• Aged
• Blood Glucose/analysis
• C-Peptide/blood
• China
• Endosonography
• Female
• Humans
• Hyperinsulinism/complications
• Hypoglycemia/etiology
• Insulin/blood
• Insulinoma/diagnosis
• Insulinoma/physiopathology
• Magnetic Resonance Imaging
• Male
• Middle Aged
• Pancreatic Neoplasms/diagnosis
• Pancreatic Neoplasms/physiopathology
• Retrospective Studies
• Tomography, X-Ray Computed
• Ultrasonography
• Young Adult

• biomarker
• chromogranin A
• diagnosis
• neuroendocrine neoplasm
• prognosis
• response to treatment

• Biomarkers, Tumor/blood
• Chromogranin A/blood
• Disease Management
• Humans
• Neuroendocrine Tumors/blood
• Neuroendocrine Tumors/diagnosis
• Neuroendocrine Tumors/therapy
• Prognosis

• Chemotherapy
• Liver biopsy
• Neuroendocrine tumor
• Somatostatin
• mTor

• Gastroenteropancreatic neuroendocrine tumors
• angiography
• hepatic metastasis
• interventional treatment
• retrospective analysis

• Humans
• Neuroendocrine Tumors/diagnosis
• Neuroendocrine Tumors/therapy
• Practice Guidelines as Topic
• Societies, Medical

• Appendiceal carcinoid
• Carcinoid
• Neuroendocrine tumor
• Oncologic follow-up

• Neuroendocrine neoplasms (NENs)
• liver metastasis
• rectal tumors
• surgery

To provide more information and therapeutic methods about gastric neuroendocrine carcinomas (G-NECs) which occur rarely but are highly malignant and clinically challenging.

We retrospectively analyzed the clinicopathological characteristics, treatments, and prognosis of 43 G-NEC patients at our hospital between January 2007 and December 2014. The diagnosis was based on the 2010 World Health Organization criteria.

Forty-three G-NECs containing 39 small cell carcinomas and 4 large cell NECs with Ki67 > 60% were included in this study, accounting for only 0.95% of all gastric carcinomas. The median patient age was 62 years (range, 33-82) and the male-to-female ratio was 4.4:1. All patients underwent surgery, including 38 curative resections and 5 palliative resections. Among these 43 patients, nearly half (48.84%) of these tumors were located in the cardiac region of the stomach, regional lymph node metastasis was found in 31 cases (72.09%), and liver metastasis was found in 6 cases (13.95%). Follow-up information was got for 40 patients. Twenty-three die of this disease with a median survival of 31 mo (range 1-90). The 1-year, 2-year, 3-year, and 5-year survival rate was 77.50%, 57.04%, 44.51%, and 35.05%, respectively. Survival was better in patients with tumor located in the cardiac region of the stomach, less than 7 lymph nodes metastasis and no liver metastasis. Five patients did not undergo postoperative chemotherapy, and the median survival time for these patients was 15 mo. For the remaining 34 patients who received postoperative chemotherapy, the median survival time was 44 mo and those received etoposide, cisplatin, and Paclitaxel survived the best. One patient with resected liver metastasis who received postoperative Capecitabine plus Oxaliplatin and Paclitaxel systemic chemotherapy plus octreotide LAR (30 mg intramuscularly, every 4 wk, for 2 years) has survived for 74 mo with no recurrence.

G-NECs are mostly nonfunctioning, which lead to a delay in detection. Local and/or distant metastases were noticed in most patients when diagnosed, and they required postoperative medical treatment. Adjuvant etoposide, cisplatin plus Paclitaxel systemic chemotherapy is recommended for these patients.

• Gastric neuroendocrine carcinomas
• Liver metastasis
• Medical treatment
• Surgery
• Prognosis

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents/administration & dosage
• Antineoplastic Agents/therapeutic use
• Antineoplastic Combined Chemotherapy Protocols/administration & dosage
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Carcinoma, Large Cell/drug therapy
• Carcinoma, Large Cell/mortality
• Carcinoma, Large Cell/pathology
• Carcinoma, Large Cell/surgery
• Carcinoma, Neuroendocrine/drug therapy
• Carcinoma, Neuroendocrine/mortality
• Carcinoma, Neuroendocrine/pathology
• Carcinoma, Neuroendocrine/surgery
• Carcinoma, Small Cell/drug therapy
• Carcinoma, Small Cell/mortality
• Carcinoma, Small Cell/pathology
• Carcinoma, Small Cell/surgery
• Chemotherapy, Adjuvant/methods
• Female
• Follow-Up Studies
• Humans
• Liver Neoplasms/drug therapy
• Liver Neoplasms/mortality
• Liver Neoplasms/secondary
• Liver Neoplasms/surgery
• Lymphatic Metastasis
• Male
• Middle Aged
• Neoplasm Recurrence, Local/epidemiology
• Neoplasm Recurrence, Local/therapy
• Prognosis
• Retrospective Studies
• Stomach Neoplasms/drug therapy
• Stomach Neoplasms/mortality
• Stomach Neoplasms/pathology
• Stomach Neoplasms/surgery
• Survival Analysis
• Survival Rate

• Ki-67
• cytology
• fine-needle aspiration cytology
• pancreatic neuroendocrine tumors
• prognostic

• Adult
• Aged
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Endoscopic Ultrasound-Guided Fine Needle Aspiration/standards
• Female
• Humans
• Ki-67 Antigen/genetics
• Ki-67 Antigen/metabolism
• Male
• Middle Aged
• Neuroendocrine Tumors/metabolism
• Neuroendocrine Tumors/pathology
• Pancreatic Neoplasms/metabolism
• Pancreatic Neoplasms/pathology
• Predictive Value of Tests

• Bone metastases
• Duodenum
• Liver metastases
• Neuroendocrine carcinoma
• Poor differentiation

Somatostatin analogues (SSAs) have shown limited and variable antiproliferative effects in neuroendocrine tumours (NETs). Whether tumour control by SSAs depends on grading based on the 2010 WHO NET classification is still unclear. The aim of this study is to evaluate the efficacy of long-acting SSAs in NETs according to Ki67 index.

An observational Italian multicentre study was designed to collect data in patients with gastro-entero-pancreatic or thoracic NETs under SSA treatment. Both retrospective and prospective data were included and they were analysed in line with Ki67 index, immunohistochemically evaluated in tumour samples and graded according to WHO classification (G1 = Ki67 index 0-2%, G2 = Ki67 index 3-20%, G3 = Ki67 index > 20%).

Among 601 patients with NET, 140 with a histologically confirmed gastro-entero-pancreatic or thoracic NET or NET with unknown primary were treated with lanreotide autogel or octreotide LAR. An objective tumour response was observed in 11%, stability in 58% and progression in 31%. Objective response and tumour stability were not significantly different between G1 and G2 NETs. Progression free survival was longer but not significantly different in G1 than G2 NETs (median: 89 vs 43 months, p = 0.15). The median PFS was significantly longer in NETs showing Ki67 < 5% than in those showing Ki67 ≥5% (89 vs 35 months, p = 0.005).

SSA therapy shows significant antiproliferative effects in well differentiated low/intermediate-proliferating NETs, not only G1 but also in G2 type. A Ki67 index of 5% seems to work better than 3% to select the best candidates for SSA therapy.

• Ki67 index
• lanreotide
• neuroendocrine tumours
• octreotide
• somatostatin analogues

• Cytology
• Fine-needle aspiration
• Grading
• Ki-67
• Pancreatic neuroendocrine tumor

• Adult
• Aged
• Cytodiagnosis/methods
• Endoscopic Ultrasound-Guided Fine Needle Aspiration
• Female
• Humans
• Immunohistochemistry
• Ki-67 Antigen/analysis
• Male
• Middle Aged
• Mitotic Index
• Neoplasm Grading/methods
• Neuroendocrine Tumors/pathology
• Pancreatic Neoplasms/pathology
• Reproducibility of Results
• Retrospective Studies