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Intermediate to high-grade lung neuroendocrine tumors (NETs; i.e., atypical carcinoid tumors) and neuroendocrine carcinomas (NECs) are currently difficult to cure. These tumors were found to express the CXCR4 G-protein coupled receptor that can be targeted with radioligands. PCR and flow cytometric analysis of lung NET and NEC cell lines using an anti-CXCR4 antibody demonstrated that all cell lines tested expressed CXCR4. PET/CT imaging with 68Galium-pentixafor in mouse xenografts of NETs and NECs verified tumor targeting that was blocked by a CXCR4 agonist. Clonogenic survival analysis demonstrated a more than additive enhancement of killing when 1 μM auranofin (a thioredoxin reductase inhibitor) was used as a radiosensitizer in combination with 177Lu-pentixather (10 μCi). DMS273 small cell lung cancer xenografts in female nude mice treated with 25 μCi/g 177Lu-pentixather induced inhibition of tumor growth and resulted in an increase in overall survival without causing unacceptable normal tissue toxicities. Immunohistochemical staining of 95 retrospective human samples (containing 90 small cell lung carcinomas) demonstrated 84% CXCR4 positivity. In a multivariable analysis of this cohort that included age, gender, stage, primary site, SSTR2 status, and CXCR4 status, Cox regression models determined that only distant metastasis at presentation (P < 0.01) and a CXCR4 H-score >30 (P = 0.04) were significantly associated with reduced survival. Prospective clinical testing of patient tumors identified CXCR4-positivity in 76% of 21 NECs, 67% of 15 lung NETs (including 8 of 10 atypical carcinoids), and 0% of 25 non-lung NETs (including 5 NETS G3s). These data support the hypothesis that CXCR4-targeted theranostics can be utilized effectively for select NETs and NECs., (© 2024 by Radiation Research Society.)

Background: Grade 3 (G3) gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs) are aggressive tumors with poor survival outcomes for which medical management is generally recommended. This study sought to evaluate outcomes of surgically treated G3 GEP-NEN patients., Methods: A single-institutional prospective NEN database was reviewed. Patients with G3 GEP-NENs based on World Health Organization (WHO) 2019 definitions included well-differentiated neuroendocrine tumors (G3NET) and poorly differentiated neuroendocrine carcinomas (G3NEC). Clinicopathologic factors were compared between groups. Overall survival from G3 diagnosis was assessed by the Kaplan-Meier method., Results: Surgical resection was performed for 463 patients (211 G1, 208 G2, 44 G3). Most had metastatic disease at presentation (54% G1, 69% G2, 91% G3; p < 0.001). The G3 cohort included 39 G3NETs and 5 G3NECs, 22 of pancreatic and 22 of midgut origin. Median overall survival (mOS; in months) was 268.1 for G1NETs, 129.9 for G2NETs, 50.5 for G3NETs, and 28.5 for G3NECs (p < 0.001). Over the same period, 31 G3 patients (12 G3NETs, 19 G3NECs) were treated non-surgically, with mOS of 19.0 for G3NETs and 12.4 for G3NECs., Conclusions: Surgical resection of G3 GEP-NENs remains controversial due to poor prognosis, and surgical series are rare. This large, single-institutional study found significantly lower mOS in patients with resected G3NENs than those with G1/G2 tumors, reflecting more aggressive tumor biology and a higher proportion with metastatic disease. The mOS for resected G3NETs and G3NECs exceeded historical non-surgical G3NEN series (mOS 11-19 months), suggesting surgery should be considered in carefully selected patients with G3NENs, especially those with well-differentiated tumors., (© 2022. Society of Surgical Oncology.)

Background: Management of duodenal neuroendocrine tumors (DNETs) is not standardized, with smaller lesions (< 1-2 cm) generally treated by endoscopic mucosal resection (EMR) and larger DNETs by surgical resection (SR). This study reviewed how patients were selected for treatment and compared outcomes., Patients and Methods: Patients with DNETs undergoing resection were identified through institutional databases, and clinicopathologic data recorded. χ 2 and Wilcoxon tests compared variables. Survival was determined by Kaplan-Meier, and Cox regression tested association with survival., Results: Among 104 patients, 64 underwent EMR and 40 had SR. Patients selected for SR had larger tumor size, younger age, and higher T, N, and M stage. There was no difference in progression-free (PFS) or overall survival (OS) between SR and EMR. In 1-2 cm DNETs, there was no difference in PFS between SR and EMR [median not reached (NR), P = 0.1]; however, longer OS was seen in SR (median NR versus 112 months, P = 0.03). In 1-2 cm DNETs, SR patients were more likely to be node-positive and younger. After adjustment for age, resection method did not correlate with survival. Comparison of surgically resected DNETs versus jejunoileal NETs revealed longer PFS (median NR versus 73 months, P < 0.001) and OS (median NR versus 119 months, P = 0.004) DISCUSSION: In 1-2 cm DNETs, there was no difference in survival between EMR and SR after adjustment for age. Recurrences could be salvaged, suggesting that EMR is a reasonable strategy. Compared with jejunoileal NETs, DNETs treated by SR had improved PFS and OS., (© 2021. Society of Surgical Oncology.)

Peptide receptor radionuclide therapy (PRRT) is an effective treatment for metastatic neuroendocrine tumors. Delivering a sufficient tumor radiation dose remains challenging because of critical-organ dose limitations. Adding 131 I-metaiodobenzylguanidine ( 131 I-MIBG) to PRRT may be advantageous in this regard. Methods: A phase 1 clinical trial was initiated for patients with nonoperable progressive neuroendocrine tumors using a combination of 90 Y-DOTATOC plus 131 I-MIBG. Treatment cohorts were defined by radiation dose limits to the kidneys and the bone marrow. Subject-specific dosimetry was used to determine the administered activity levels. Results: The first cohort treated subjects to a dose limit of 1,900 cGy to the kidneys and 150 cGy to the marrow. No dose-limiting toxicities were observed. Tumor dosimetry estimates demonstrated an expected dose increase of 34%-83% using combination therapy as opposed to 90 Y-DOTATOC PRRT alone. Conclusion: These findings demonstrate the feasibility of using organ dose for a phase 1 escalation design and suggest the safety of using 90 Y-DOTATOC and 131 I-MIBG., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

Octreotide acetate (octreotide) is the most prescribed and most studied somatostatin congener, or analog, for gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and carcinoid syndrome, the latter of which may be characterized by debilitating diarrhea and flushing. Approved in the U.S. more than 30 years ago, octreotide is widely used to control the symptoms of carcinoid syndrome and has been shown to demonstrate antiproliferative activity. The two formulations available in the U.S. include a subcutaneous immediate-release (IR) injection introduced in 1989 and a long-acting repeatable (LAR) intramuscular injection approved in 1999. Lanreotide depot (lanreotide), a more recent somatostatin congener, has been available in the U.S. since 2014. Despite widespread use of octreotide LAR, several key challenges exist with the current depot-based treatment paradigm. Studies indicate that LAR formulations are associated with continued unmet patient needs, owing in part to a loss of bioactivity over time that may necessitate progressive supplemental treatment with IR octreotide to adequately control symptoms. Clinicians should understand the key differences in the pharmacokinetic profiles of the LAR and IR formulations that may contribute to bioactivity loss and somatostatin receptor desensitization. In addition, there is a need to re-evaluate the role of IR octreotide in combination with depot therapy to provide consistent bioavailability and better control of carcinoid syndrome symptoms. The purpose of this review is to explore all these issues and to re-establish a rationale for the IR formulation, particularly with respect to novel use cases and its use during the COVID-19 pandemic. IMPLICATIONS FOR PRACTICE: There is a need to re-evaluate the role of immediate-release octreotide in combination with depot therapy to provide consistent bioavailability and better control of carcinoid syndrome symptoms., (© 2021 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press.)

Background: Telotristat ethyl is approved to treat carcinoid syndrome diarrhea in combination with somatostatin analogs. In TELESTAR and TELECAST phase III studies, patients with carcinoid syndrome received telotristat ethyl 250 or 500 mg 3 times per day (tid) or placebo tid in addition to somatostatin analogs. The aim of this prespecified analysis was to examine the time to reductions in bowel movements (BMs) in the TELESTAR and TELECAST studies using survival analysis methods., Methods: First occurrence of sustained response was defined as the time to the first day of 2 consecutive weeks with a mean BM frequency improvement of ≥ 30% from baseline during the 12-week double-blind treatment periods. Time to first ≥ 30% worsening in BM frequency was also measured. Treatments were compared with the log-rank test; Cox regression models provided point and confidence interval estimates of the hazard ratios for each trial., Results: In TELESTAR and TELECAST, majority of patients (69%) on telotristat ethyl experienced a sustained ≥ 30% improvement in BM frequency. The median time to sustained reduction of at least 30% in BM frequency was significantly faster (fewer days to onset) for telotristat ethyl compared with placebo in both TELESTAR (250 mg, HR = 2.3 [95% CI, 1.3-4.1, P = 0.004]; 500 mg, HR = 2.2 [95% CI, 1.2-3.9, P = 0.009]) and TELECAST (250 mg, HR = 3.9 [95% CI, 1.6-11.1, P = 0.003]; 500 mg, HR = 4.2 [95% CI, 1.7-11.7, P = 0.002]). In TELECAST, 42% of patients on placebo experienced sustained worsening in BM frequency compared with 20% on telotristat ethyl; no significant difference was observed in TELESTAR., Conclusion: The time of onset of sustained BM frequency improvement mean and range are important when considering use of telotristat ethyl in patients with carcinoid syndrome diarrhea. Telotristat ethyl may also reduce sustained worsening in BM frequency., Trial Registration: ClinicalTrials.gov Identifiers: NCT01677910, NCT02063659.

Background: Tumor biomarkers (TBMs) reflect disease burden and correlate with survival for small bowel neuroendocrine tumors (SBNETs). This study sought to determine the performance of chromogranin A (CgA), pancreastatin (PST), neurokinin A (NKA), and serotonin (5HT) during follow-up assessment of resected SBNETs., Methods: An institutional database identified patients undergoing surgery for SBNETs. Tumor biomarker levels were assessed as categorical (normal vs elevated) and continuous variables for association with progression-free survival (PFS) and overall survival (OS) via the Kaplan-Meier method with Cox multivariable models adjusted for confounders. Sensitivity, specificity, and predictive values of TBM levels in identifying imaging-confirmed progression were calculated., Results: In 218 patients (44% female, 92% node + , 73% metastatic, 97% G1 or G2), higher levels of CgA, PST, NKA, and 5HT correlated with higher-grade and metastatic disease at presentation (p < 0.05). Elevated pre- and postoperative CgA, PST, and NKA correlated with lower PFS and OS (p < 0.05; median follow-up period, 49.6 months). Normal CgA, PST, and NKA were present in respectively 20.3%, 16.9%, and 72.6% of the patients with progression, whereas elevated levels were present in respectively 69.5%, 24.8%, and 1.3% of the patients without progression. Using TBMs to determine progression showed superiority of PST (78.9% accuracy) over CgA (63.3% accuracy) or CgA and PST together (60.3% accuracy)., Conclusion: Although specific for progression, NKA was rarely elevated, limiting its usefulness. Pre- and postoperative PST and CgA correlated with disease burden and survival, with PST providing better discrimination of outcomes. During the follow-up period, use of PST most accurately detected progression. These results suggest that PST should replace CgA for SBNET surveillance.

Objectives: A prospective clinical trial evaluated the effect of Ga-DOTATOC positron emission tomography-computerized axial tomography (PET-CT) on change in management of patients with lung, pancreatic, and small bowel neuroendocrine tumors. The primary eligibility criterion was a histologically proven tumor with positive somatostatin receptor subtype 2A immunohistochemistry. The primary and secondary end points were change in patient management and safety., Methods: Referring physicians completed questionnaires pre- and post-Ga-DOTATOC PET-CT, stating current and planned patient management, respectively, with tumor board adjudication of final management decisions. Change in management was categorized as follows: no change; minor change (additional imaging, supportive care); or major change (octreotide/lanreotide therapy, tumor biopsy, surgery, peptide receptor radiotherapy, chemotherapy, biological therapy, liver embolization)., Results: A major change in management was recommended for 54 (47.37%) of 114 subjects and a minor change for 6 (5.26%) of 114 subjects, with no change for 54 (47.37%) of 114 subjects. Grade 1 adverse events were observed in 26 of 114 subjects (nausea, headache, back pain, diarrhea); one grade 2 (petechiae) and one grade 3 (abdominal pain) adverse event were observed. No grade 2 or 3 adverse events were related to study drug and none required intervention., Conclusions: Imaging with Ga-DOTATOC PET-CT has a significant impact on management of patients with neuroendocrine tumors.

Purpose: To assess the impact of baseline liver tumour burden, alkaline phosphatase (ALP) elevation, and target lesion size on treatment outcomes with 177 Lu-Dotatate., Methods: In the phase 3 NETTER-1 trial, patients with advanced, progressive midgut neuroendocrine tumours (NET) were randomised to 177Lu-Dotatate (every 8 weeks, four cycles) plus octreotide long-acting release (LAR) or to octreotide LAR 60 mg. Primary endpoint was progression-free survival (PFS). Analyses of PFS by baseline factors, including liver tumour burden, ALP elevation, and target lesion size, were performed using Kaplan-Meier estimates; hazard ratios (HRs) with corresponding 95% CIs were estimated using Cox regression., Results: Significantly prolonged median PFS occurred with 177 Lu-Dotatate versus octreotide LAR 60 mg in patients with low (< 25%), moderate (25-50%), and high (> 50%) liver tumour burden (HR 0.187, 0.216, 0.145), and normal or elevated ALP (HR 0.153, 0.177), and in the presence or absence of a large target lesion (diameter > 30 mm; HR, 0.213, 0.063). Within the 177 Lu-Dotatate arm, no significant difference in PFS was observed amongst patients with low/moderate/high liver tumour burden (P = 0.7225) or with normal/elevated baseline ALP (P = 0.3532), but absence of a large target lesion was associated with improved PFS (P = 0.0222). Grade 3 and 4 liver function abnormalities were rare and did not appear to be associated with high baseline liver tumour burden., Conclusions: 177 Lu-Dotatate demonstrated significant prolongation in PFS versus high-dose octreotide LAR in patients with advanced, progressive midgut NET, regardless of baseline liver tumour burden, elevated ALP, or the presence of a large target lesion. Clinicaltrials.gov : NCT01578239, EudraCT: 2011-005049-11.

This article is the result of the North American Neuroendocrine Tumor Society consensus conference on the medical management of pancreatic neuroendocrine tumors from July 19 to 20, 2018. The guidelines panel consisted of medical oncologists, pathologists, gastroenterologists, endocrinologists, and radiologists. The panel reviewed a series of questions regarding the medical management of patients with pancreatic neuroendocrine tumors as well as questions regarding surveillance after resection. The available literature was reviewed for each of the question and panel members voted on controversial topics, and the recommendations were included in a document circulated to all panel members for a final approval.

Purpose: Pancreatic neuroendocrine tumors (pNETs) are uncommon malignancies noted for their propensity to metastasize and comparatively favorable prognosis. Although both the treatment options and clinical outcomes have improved in the past decades, most patients will die of metastatic disease. New systemic therapies are needed., Experimental Design: Tissues were obtained from 43 patients with well-differentiated pNETs undergoing surgery. Gene expression was compared between primary tumors versus liver and lymph node metastases using RNA-Seq. Genes that were selectively elevated at only one metastatic site were filtered out to reduce tissue-specific effects. Ingenuity pathway analysis (IPA) and the Connectivity Map (CMap) identified drugs likely to antagonize metastasis-specific targets. The biological activity of top identified agents was tested in vitro using two pNET cell lines (BON-1 and QGP-1)., Results: A total of 902 genes were differentially expressed in pNET metastases compared with primary tumors, 626 of which remained in the common metastatic profile after filtering. Analysis with IPA and CMap revealed altered activity of factors involved in survival and proliferation, and identified drugs targeting those pathways, including inhibitors of mTOR, PI3K, MEK, TOP2A, protein kinase C, NF-kB, cyclin-dependent kinase, and histone deacetylase. Inhibitors of MEK and TOP2A were consistently the most active compounds., Conclusions: We employed a complementary bioinformatics approach to identify novel therapeutics for pNETs by analyzing gene expression in metastatic tumors. The potential utility of these drugs was confirmed by in vitro cytotoxicity assays, suggesting drugs targeting MEK and TOP2A may be highly efficacious against metastatic pNETs. This is a promising strategy for discovering more effective treatments for patients with pNETs., (©2020 American Association for Cancer Research.)

To better understand developments in treatment of neuroendocrine tumors of the gastroenteropancreatic system, and the pivotal roles of native somatostatin and its long-acting analogues play in normal peptide regulation and neuropeptide excess associated with neuroendocrine tumors (NETs), this article delineates and defines distinct eras in the history and discovery of gastrointestinal endocrinology. We highlight the collaboration between academia and industry in basic science and the clinical research that advanced Lu-177-DOTATATE to approval as standard of care therapy for low-grade NETs. Examples of new radioisotopes and therapy compounds currently in development for diagnosis and therapy for high-grade NETs are also discussed., Competing Interests: Disclosures This Manuscript was supported, in part, by a NCI SPORE Award # NCI P50 CA 174521, P.I. M Sue O’Dorisio. T.M. O’Dorisio is a Co-Investigator and Director of the SPORE CORE Clinical Trials., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: The small bowel and pancreas are the most common primary sites of neuroendocrine tumors (NETs) giving rise to metastatic disease. Some patients with small bowel NETs (SBNETs) present with synchronous or metachronous pancreatic NETs (PNETs), and it is unclear whether these are separate primaries or metastases from one site to the other., Methods: A surgical NET database including patients undergoing operations for SBNETs or PNETs was reviewed. Patients with synchronous or metachronous tumors in both the small bowel and pancreas were identified, and available tissues from primary tumors and metastases were examined using a 4-gene quantitative polymerase chain reaction (qPCR) and immunohistochemistry (IHC) panel developed for evaluating NETs of unknown primary., Results: Of 338 patients undergoing exploration, 11 had NETs in both the small bowel and pancreas. Tissues from 11 small bowel tumors, 9 pancreatic tumors, and 10 metastases were analyzed. qPCR and IHC data revealed that three patients had separate SBNET and PNET primaries, and five patients had SBNETs that metastasized to the pancreas. Pancreatic tissue was unavailable in two patients, and qPCR and IHC gave discrepant results in one patient., Conclusions: NETs in both the small bowel and pancreas were found in 3% of our patients. In nearly two-thirds of evaluable patients, the pancreatic tumor was a metastasis from the SBNET primary, while in the remaining one-third of patients it represented a separate primary. Determining the origin of these tumors can help guide the choice of systemic therapy and surgical management.

Background: Patients with neuroendocrine tumors (NETs) and carcinoid syndrome experience considerable morbidity and mortality; carcinoid syndrome may be associated with shorter survival. Carcinoid syndrome is linked to tumoral secretion of serotonin and other bioactive substances. The subsequent debilitating diarrhea and urgency to defecate pose significant health risks. In previous studies, telotristat ethyl, a tryptophan hydroxylase inhibitor, was effective and well tolerated in treating carcinoid syndrome diarrhea. We present pooled safety data from five clinical trials with telotristat ethyl in patients with carcinoid syndrome., Subjects, Materials, and Methods: Adverse events reported during telotristat ethyl treatment were pooled from two phase II and three phase III clinical trials in 239 patients with carcinoid syndrome. Long-term safety of telotristat ethyl and causes of hospitalization and death were reviewed; overall survival was estimated., Results: Mean (median; range) duration of exposure and follow-up was 1.3 years (1.1 years; 1 week to 5.7 years), with 309 total patient-years of exposure. Leading causes of hospitalization were gastrointestinal disorders or were related to the underlying tumor and related treatment. Survival estimates at 1, 2, and 3 years were 93%, 88%, and 77%. Nearly all deaths were due to progression or complication of the underlying disease; none were attributable to telotristat ethyl. There was one death in year 4., Conclusion: Based on long-term safety data, telotristat ethyl is well tolerated and has a favorable long-term safety profile in patients with carcinoid syndrome., Implications for Practice: Carcinoid syndrome can cause persistent diarrhea, even in patients treated with somatostatin analogs. Across five clinical trials in patients with carcinoid syndrome, telotristat ethyl has been well tolerated and efficacious, providing clinicians with a new approach to help control carcinoid syndrome diarrhea, in addition to somatostatin analog therapy. By reducing the stool frequency in patients with carcinoid syndrome whose diarrhea is refractory to anticholinergics, such as loperamide and atropine/diphenoxylate, and somatostatin analog dose escalation, improvement in quality of life becomes an achievable goal., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2019.)

Hyperactivated AKT/mTOR signaling is a hallmark of pancreatic neuroendocrine tumors (PNETs). Drugs targeting this pathway are used clinically, but tumor resistance invariably develops. A better understanding of factors regulating AKT/mTOR signaling and PNET pathogenesis is needed to improve current therapies. We discovered that RABL6A, a new oncogenic driver of PNET proliferation, is required for AKT activity. Silencing RABL6A caused PNET cell-cycle arrest that coincided with selective loss of AKT-S473 (not T308) phosphorylation and AKT/mTOR inactivation. Restoration of AKT phosphorylation rescued the G1 phase block triggered by RABL6A silencing. Mechanistically, loss of AKT-S473 phosphorylation in RABL6A-depleted cells was the result of increased protein phosphatase 2A (PP2A) activity. Inhibition of PP2A restored phosphorylation of AKT-S473 in RABL6A-depleted cells, whereas PP2A reactivation using a specific small-molecule activator of PP2A (SMAP) abolished that phosphorylation. Moreover, SMAP treatment effectively killed PNET cells in a RABL6A-dependent manner and suppressed PNET growth in vivo. The present work identifies RABL6A as a new inhibitor of the PP2A tumor suppressor and an essential activator of AKT in PNET cells. Our findings offer what we believe is a novel strategy of PP2A reactivation for treatment of PNETs as well as other human cancers driven by RABL6A overexpression and PP2A inactivation.

Background: Cytoreductive surgery for neuroendocrine tumor liver metastases improves survival and symptomatic control. However, the feasibility of adequate cytoreduction in patients with many liver metastases remains uncertain. We compared patient outcomes based on the number of lesions treated to better define the efficacy of cytoreductive surgery for numerous neuroendocrine tumor liver metastases., Methods: Patients undergoing hepatic cytoreductive surgery for gastroenteropancreatic neuroendocrine tumors were identified in our institutional surgical neuroendocrine tumor database. Imaging studies were reviewed to determine the liver tumor burden and percent cytoreduced. Overall survival and progression-free survival were compared, using the number of lesions treated, percent tumor debulked, and additional clinicopathologic characteristics., Results: A total of 188 hepatic cytoreductive procedures were identified and stratified into groups according to the number of metastases treated: 1-5, 6-10, and >10. Median overall survival and progression-free survival were 89.4 and 22.5 months, respectively, and did not differ significantly between groups. Greater than 70% cytoreduction was associated with significantly better overall survival than <70% cytoreduction (134 months versus 38 months)., Conclusion: In patients with gastroenteropancreatic neuroendocrine tumors and liver metastases, >70% cytoreduction led to improved overall survival and progression-free survival and was achieved reliably in patients undergoing debulking of >10 lesions. These data support an aggressive approach to patients with numerous neuroendocrine tumor liver metastases to achieve >70% cytoreduction., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Pretherapy PET with 86 Y-DOTATOC is considered the ideal dosimetry protocol for 90 Y-DOTATOC therapy; however, its cost, limited availability, and need for infusion of amino acids to mimic the therapy administration limit its use in the clinical setting. The goal of this study was to develop a dosimetric method for 90 Y-DOTATOC using 90 Y-DOTATOC PET/CT and bremsstrahlung SPECT/CT and to determine whether dosimetry-based administered activities differ significantly from standard administered activities. Methods: This was a prospective phase 2 trial of 90 Y-DOTATOC therapy in patients with somatostatin receptor-positive tumors. 90 Y-DOTATOC was given in 3 cycles 6-8 wk apart. In the first cycle of therapy, adults received 4.4 GBq and children received 1.85 GBq/m 2 ; the subsequent administered activities were adjusted according to the dosimetry of the preceding cycle so as not to exceed a total kidney dose of 23 Gy and bone marrow dose of 2 Gy. The radiation dose to the kidneys was determined from serial imaging sessions consisting of time-of-flight 90 Y-DOTATOC PET/CT at 5 h after therapy and 90 Y-DOTATOC bremsstrahlung SPECT/CT at 6, 24, 48, and 72 h. The PET/CT data were used to measure the absolute concentration of 90 Y-DOTATOC and to calibrate the bremsstrahlung SPECT kidney clearance data. The radiation dose to the kidneys was determined by multiplying the time-integrated activity (from the fitted biexponential curve of renal clearance of 90 Y-DOTATOC) with the energy emitted per decay, divided by the mass of the kidneys. Results: The radiation dose to the kidneys per cycle of 90 Y-DOTATOC therapy was highly variable among patients, ranging from 0.32 to 3.0 mGy/MBq. In 17 (85%) of the 20 adult patients who received the second and the third treatment cycles of 90 Y-DOTATOC, the administered activity was modified by at least 20% from the starting administered activity. Conclusion: Renal dosimetry of 90 Y-DOTATOC is feasible using 90 Y-DOTATOC time-of-flight PET/CT and bremsstrahlung SPECT/CT and has a significant impact on the administered activity in treatment cycles., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: The small bowel (SB) is the most common site of neuroendocrine tumors (NETs) of the GI tract. These are described as being predominantly jejunoileal, but their exact locations within the SB have not been well defined. We sought to determine prospectively the spectrum of SBNET locations., Methods: Patients undergoing exploration for SBNET primaries had measurement of bowel length, tumor locations, and resection length recorded. Correlations of clinicopathologic factors were performed, and analysis done utilizing Welch's t test, Chi square test, and the Kaplan-Meier method., Results: Measurements were recorded in 123 patients, 107 of whom had complete information. Multifocal tumors (MTs) were found in 69 (56%) and unifocal (UTs) in 54 (44%) patients. Only 1 of 107 patients had a tumor within 100 cm of the ligament of Treitz (LT), whereas 77 of 107 (72%) had tumors within 100 cm of the ileocecal valve (ICV). No MTs were found within 100 cm of LT, whereas 41 of 60 (68%) patients had all (10) or at least one tumor (31) located within 100 cm of the ICV. MTs required a mean resection length of 108 versus 59 cm for UTs (p < 0.01). Seventy-seven percent of UTs (36/47) were within 100 cm of ICV. Tumors occurring only between > 100 cm from the LT and ICV were seen in 29 of 107 (27%) patients., Conclusions: SBNETs are frequently multifocal and most commonly located within 100 cm of the ICV. SBNETs are less prevalent proximally in the small bowel, which may result from anatomic differences in enterochromaffin cell density, hormonal factors, or environmental exposures in the distal SB.

Objective: Although personalized dosimetry may be desirable for radionuclide therapy treatments, the multiple time samples required to determine the total integrated activity puts a burden on patients and clinic resources. The aim of this paper is to demonstrate that when some prior knowledge is known about the tracer kinetic parameters, the total integrated activity (and thus radiation dose) can be estimated from a single time sample., Methods: Mathematical derivations have been performed to generate equations for the total integrated activity in terms of a single time sample of activity for monoexponential and biexponential clearance. Simulations were performed using both exponential models where the rate constants and associated parameters were randomly sampled from distributions with a known mean. The actual total integrated activity for each random sample was compared with the estimated total integrated activity using the mean value of the parameters. Retrospective analysis of 90 Y DOTATOC data from a clinical trial provided a comparison of actual kidney dose with the estimated kidney dose using the single time point approach., Results: The optimal sampling time for the single point approach was found to be equal to the mean time of the rate constant. The simulation results for the monoexponential and biexpoential models were similar. Regressions comparing the actual and estimated total integrated activity had very high correlations (r 2  > 0.95) along with acceptable standard errors of estimate, especially at the optimal sampling point. The retrospective analysis of the 90 Y DOTATOC data also yielded similar results with an r 2  = 0.95 and a standard error of estimate of 61 cGy., Conclusions: In situations where there is prior knowledge about the population averages of kinetic parameters, these results suggest that the single time point approach can be used to estimate the total integrated activity and dose with sufficient accuracy to manage radionuclide therapy. This will make personalized dosimetry much easier to perform and more available to the community., (© 2018 American Association of Physicists in Medicine.)

Clusterin, a widely expressed, tissue-specific glycoprotein, is a diagnostic marker of several tumor types, including anaplastic large cell lymphoma, follicular dendritic cell sarcoma, and tenosynovial giant cell tumor. A recent study has suggested it is highly expressed by well-differentiated neuroendocrine tumors (NET) arising at most anatomic sites, with the exception of jejunoileal tumors, and that it is similarly not expressed by poorly differentiated neuroendocrine carcinomas (NEC). We sought to validate this result in a large cohort of NETs and NECs. Clusterin immunohistochemistry was performed on tissue microarrays of 255 NETs [45 lung, 4 stomach, 8 duodenum, 75 pancreas (62 primary, 13 metastatic), 107 jejunoileum (69 primary, 38 metastatic), 16 appendix] and 88 NECs (43 visceral, 45 Merkel cell). Extent (%) and intensity (0, 1+, 2+, 3+) of staining were assessed and an H-score (extent x intensity) calculated. An average H-score >5 was considered positive. Clusterin expression was noted in 82.4% of 148 nonjejunoileal NETs (average H-score 183) and only 8.4% of 107 jejunoileal NETs (average H-score, 31), as well as 19.3% of NECs (average H-score, 36). Clusterin is frequently, strongly expressed by NETs of diverse anatomic sites, with the exception of jejunoileal tumors, in which it is only rarely, weakly expressed. It is occasionally, weakly expressed by NECs. Most metastatic NETs of occult origin arise in the pancreas or the jejunoileum. For cases in which an initial site of origin immunopanel (eg, islet 1, PAX6, CDX2) is ambiguous, addition of clusterin may be diagnostically useful, with absence of expression suggesting a jejunoileal origin.

Background: Small bowel neuroendocrine tumors (SBNETs) present frequently with metastases, yet little is known about the molecular basis of this progression. This study sought to identify the serial differential expression of genes between normal small bowel, primary small bowel neuroendocrine tumors, and liver metastases., Methods: RNA isolated from matched normal small bowel tissue, primary small bowel neuroendocrine tumors, and liver metastases in 12 patients was analyzed with whole transcriptome expression microarrays and RNA-Seq. Changes in gene expression between primary small bowel neuroendocrine tumors and normal small bowels, and liver metastases versus primary small bowel neuroendocrine tumors were calculated. Common genes that were differentially expressed serially (increasing or decreasing from normal small bowel to primary small bowel neuroendocrine tumors to liver metastases) were identified, and 10 were validated using qPCR., Results: Use of 2 transcriptome platforms allowed for a robust discrimination of genes important in small bowel neuroendocrine tumors progression. Serial differential expression was validated in 7/10 genes, all of which had been described previously in abdominal cancers, and with several interacting with members of the AKT, MYC, or MAPK3 pathways. Liver metastases had consistent underexpression of PMP22, while high expression of SERPINA10 and SYT13 was characteristic of both pSBTs and liver metastases., Conclusion: Identification of the serial differential expression of genes from normal tissues to primary tumors to metastases lends insight into important pathways for SBNETs progression. Differential expression of various genes, including PMP22, SYT13 and SERPINA10, are associated with the progression of SBNETs and warrant further investigation., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Aims: Paired-like homeobox 2b (PHOX2B) is a transcription factor with expression outside of the central nervous system restricted to neurons and chromaffin cells of the autonomic nervous system. Germline mutations cause congenital central hypoventilation syndrome and predispose to neuroblastoma and Hirschsprung disease. Among paediatric small round cell tumours, PHOX2B is neuroblastoma-specific. Two studies of adult autonomic nervous system tumours (n = 62) produced conflicting results (all tumours stained in one; expression restricted to 40% of paragangliomas in the other). We examined PHOX2B expression in a large cohort of phaeochromocytomas and paragangliomas, as well as well-differentiated neuroendocrine tumours (WDNETs) and poorly differentiated neuroendocrine carcinomas (PDNECs)., Methods and Results: Tissue microarrays (TMAs) were constructed from 609 tumours: 111 phaeochromocytomas, 146 paragangliomas, 250 WDNETs, and 102 PDNECs. PHOX2B immunohistochemistry was scored for extent (%) and intensity (0-3+), and an H-score (extent × intensity) was calculated. PHOX2B expression was seen in 32% of phaeochromocytomas and in 47% of paragangliomas. Mean/median H-scores for these tumours were in the 30-55 range (i.e. weak to moderate staining). No WDNETs and only 7% of PDNECs stained, the latter often strongly. In a representative cohort of corresponding whole sections (n = 55), the results in WDNETs and PDNECs were unchanged, whereas half of the phaeochromocytomas/paragangliomas that were negative on TMAs became focally, weakly positive., Conclusions: We found frequent, weak to moderate PHOX2B expression in phaeochromocytomas/paragangliomas and no expression in WDNETs, which could be diagnostically useful in the distinction of these tumours. Expression in a minority of PDNECs probably reflects the transcription factor lineage infidelity that is characteristic of this tumour class., (© 2017 John Wiley & Sons Ltd.)

Background: Tumor grade is an important predictor of survival in gastroenteropancreatic (GEP) neuroendocrine tumors (NETs), as determined by Ki-67 expression and mitotic rate. NETs generally grow indolently, but some cells may acquire traits facilitating metastasis. It is unclear how frequently metastases differ in grade from their primary tumors, and whether increasing grade in metastases affects prognosis., Methods: Ki-67 immunohistochemistry was performed on resected GEPNET specimens and cases with results for both primary tumors and concurrent metastases were identified. Grade was determined using a modified World Health Organization classification (Ki-67: G1 = 0-2%; G2 > 2-20%; G3 > 20%)., Results: Ki-67 was performed on both the primary tumor and metastases in 103 patients. Tumor grade was higher in metastases from 25 (24%) patients, 24 increased from G1 to G2, and 1 increased from G2 to G3; 68 (66%) patients had no change in grade (42 G1 and 26 G2), and 10 (10%) decreased from G2 to G1. No clinicopathologic factors were predictive of higher grade in metastases. The 5-year progression-free survival (PFS) was 55% for patients with stable grade versus 8% of patients with increased grade, while 5-year overall survival (OS) was 92 and 54%, respectively. The 5-year OS of patients who had stable grade with G1 and G2 primaries was 92 and 64%, respectively., Conclusions: Nearly one-third of patients had metastases with a different grade than their primary, and, when grade increased, both PFS and OS significantly decreased. Determining the grade in both the primary tumor and a metastasis is important for estimating prognosis and to help inform decisions regarding additional therapies.

There have been significant developments in diagnostic and therapeutic options for patients with neuroendocrine tumors (NETs). Key phase 3 studies include the CLARINET trial, which evaluated lanreotide in patients with nonfunctioning enteropancreatic NETs; the RADIANT-2 and RADIANT-4 studies, which evaluated everolimus in functioning and nonfunctioning NETs of the gastrointestinal tract and lungs; the TELESTAR study, which evaluated telotristat ethyl in patients with refractory carcinoid syndrome; and the NETTER-1 trial, which evaluated Lu-DOTATATE in NETs of the small intestine and proximal colon (midgut). Based on these and other advances, the North American Neuroendocrine Tumor Society convened a multidisciplinary panel of experts with the goal of updating consensus-based guidelines for evaluation and treatment of midgut NETs. The medical aspects of these guidelines (focusing on systemic treatment, nonsurgical liver-directed therapy, and postoperative surveillance) are summarized in this article. Surgical guidelines are described in a companion article.

Localization of the site of the unknown primary tumor is critical for surgical treatment of patients presenting with neuroendocrine tumor (NET) with metastases. Methods: Forty patients with metastatic NET and unknown primary site underwent 68 Ga-DOTATOC PET/CT in a single-site prospective study. The 68 Ga-DOTATOC PET/CT was considered true-positive if the positive primary site was confirmed by histology or follow-up imaging. The scan was considered false-positive if no primary lesion was found corresponding to the 68 Ga-DOTATOC-positive site. All negative scans for primary tumor were considered false-negative. A scan was classified unconfirmed if 68 Ga-DOTATOC PET/CT suggested a primary, however, no histology was obtained and imaging follow-up was not confirmatory. Results: The true-positive, false-positive, false-negative, and unconfirmed rates for unknown primary tumor were 38%, 7%, 50%, and 5%, respectively. Conclusion: 68 Ga-DOTATOC PET/CT is an effective modality in the localization of unknown primary in patients with metastatic NET., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: Patients with advanced midgut neuroendocrine tumors who have had disease progression during first-line somatostatin analogue therapy have limited therapeutic options. This randomized, controlled trial evaluated the efficacy and safety of lutetium-177 ( 177 Lu)-Dotatate in patients with advanced, progressive, somatostatin-receptor-positive midgut neuroendocrine tumors., Methods: We randomly assigned 229 patients who had well-differentiated, metastatic midgut neuroendocrine tumors to receive either 177 Lu-Dotatate (116 patients) at a dose of 7.4 GBq every 8 weeks (four intravenous infusions, plus best supportive care including octreotide long-acting repeatable [LAR] administered intramuscularly at a dose of 30 mg) ( 177 Lu-Dotatate group) or octreotide LAR alone (113 patients) administered intramuscularly at a dose of 60 mg every 4 weeks (control group). The primary end point was progression-free survival. Secondary end points included the objective response rate, overall survival, safety, and the side-effect profile. The final analysis of overall survival will be conducted in the future as specified in the protocol; a prespecified interim analysis of overall survival was conducted and is reported here., Results: At the data-cutoff date for the primary analysis, the estimated rate of progression-free survival at month 20 was 65.2% (95% confidence interval [CI], 50.0 to 76.8) in the 177 Lu-Dotatate group and 10.8% (95% CI, 3.5 to 23.0) in the control group. The response rate was 18% in the 177 Lu-Dotatate group versus 3% in the control group (P<0.001). In the planned interim analysis of overall survival, 14 deaths occurred in the 177 Lu-Dotatate group and 26 in the control group (P=0.004). Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia occurred in 1%, 2%, and 9%, respectively, of patients in the 177 Lu-Dotatate group as compared with no patients in the control group, with no evidence of renal toxic effects during the observed time frame., Conclusions: Treatment with 177 Lu-Dotatate resulted in markedly longer progression-free survival and a significantly higher response rate than high-dose octreotide LAR among patients with advanced midgut neuroendocrine tumors. Preliminary evidence of an overall survival benefit was seen in an interim analysis; confirmation will be required in the planned final analysis. Clinically significant myelosuppression occurred in less than 10% of patients in the 177 Lu-Dotatate group. (Funded by Advanced Accelerator Applications; NETTER-1 ClinicalTrials.gov number, NCT01578239 ; EudraCT number 2011-005049-11 .).

Background: Patients with gastroenteropancreatic neuroendocrine tumors often present with metastases. Identification of the primary tumor is important for operative management, and therefore we sought to determine our success at identifying primary tumors with diagnostic testing and operative exploration., Methods: A clinical neuroendocrine tumor database was reviewed to identify patients presenting with metastases and primary tumor in situ. Results of radiologic, endoscopic, and operative procedures were evaluated to determine which correctly identified the primary tumor., Results: There were 197 patients presenting with metastases and unresected primaries, 134 who had an operation and 63 managed nonoperatively. Primaries were identified preoperatively in 168 (84%), at operative exploration in 7, and were not found in 22 patients. Computed tomography found 150/197 primary tumors, somatostatin-receptor scintigraphy 88/155, and endoscopy 43/107. The sensitivity of computed tomography surpassed scintigraphy (76% vs 57%, P < .01). The primary was removed in 130/134 (97%) patients, and hepatic debulking was performed in 67%. Median survival for operative patients with small bowel and pancreatic tumors was 145 and 71 months, respectively., Conclusion: Imaging and endoscopy identified the primary tumor in most patients, and the majority of the others were found at exploration. Preoperative testing facilitated operative planning, allowing for resection of the primary and hepatic debulking in most patients., (Copyright © 2016 Elsevier Inc. All rights reserved.)