The European Neuroendocrine Tumor Society (ENETS) promotes practices and procedures that aim to improve the standard of care delivered to patients diagnosed with or suspected of having neuroendocrine ...neoplasia (NEN). At its annual Scientific Advisory Board Meeting in 2018, experts in imaging, pathology and clinical care of patients with NEN drafted guidance for the standardised reporting of diagnostic studies critical to the diagnosis, grading, staging and treatment of NEN. These included pathology, radiology, endoscopy and molecular imaging procedures. In an iterative process, a synoptic reporting template for molecular imaging procedures was developed to guide personalised therapies. Following pilot implementation and refinement within the ENETS Center of Excellence network, harmonisation with specialist imaging societies including the Society of Nuclear Medicine, European Association of Nuclear Medicine and the International Cancer Imaging Society will be pursued.
In an iterative process, a synoptic reporting template for molecular imaging procedures was developed by the European Neuroendocrine Tumor Society (ENETS) to guide personalised therapies. Following pilot implementation and refinement within the ENETS Center of Excellence network, harmonisation with specialist imaging societies including the Society of Nuclear Medicine, European Association of Nuclear Medicine and the International Cancer Imaging Society will be pursued.
Small intestinal neuroendocrine tumours (SI-NETs) are neoplasms characterized by their ability to secrete biogenic amines and peptides. These cause distinct clinical pathology including carcinoid ...syndrome, marked by diarrhoea and flushing, as well as fibrosis, notably mesenteric fibrosis. Mesenteric fibrosis often results in significant morbidity by causing intestinal obstruction, oedema and ischaemia. Although advancements have been made to alleviate symptoms of carcinoid syndrome and prolong the survival of patients with SI-NETs, therapeutic options for patients with mesenteric fibrosis are still limited. As improved insight in the complex pathogenesis of mesenteric fibrosis is key to the development of new therapies, we evaluated the literature for known and putative mediators of fibrosis in SI-NETs. In this review, we discuss the tumour microenvironment, growth factors and signalling pathways involved in the complex process of fibrosis development and tumour progression in SI-NETs, in order to elucidate potential new avenues for scientific research and therapies to improve the management of patients suffering from the complications of mesenteric fibrosis.
Abstract
Context
Patients with adrenocortical carcinoma (ACC) often fail mitotane treatment and deal with severe toxicity, marking the relevance of predictive parameters for treatment outcome.
...Objective
Determine the effects of mitotane in primary ACC cultures, and correlate sensitivity with patient and tumor characteristics.
Methods
In 32 primary ACC cultures, the effects of mitotane on cell growth and cortisol production were determined. RRM1, SOAT1, and CYP2W1 expression were assessed using reverse transcription-polymerase chain reaction and immunohistochemistry.
Results
The median percentage cell amount inhibition in primary ACC cultures at 50 µM mitotane was 57%. Seven patients were classified as nonresponders, 14 as partial responders, and 11 as responders. The mean median effective concentration (EC50) value of mitotane for inhibition of cell amount in responders was 14.2 µM (95% CI, 11.3–17.9), in partial responders 41.6 µM (95% CI, 33.5–51.8), and could not be calculated in nonresponders. The percentage cortisol-producing ACC was 14%, 43%, and 73% for nonresponders, partial responders, and responders (P = 0.068). Mitotane inhibited cortisol production with a mean EC50 of 1.4 µM (95% CI, 0.9–2.1), which was considerably lower than the EC50 on cell growth. RRM1, SOAT1, and CYP2W1 expression levels were not predictive for mitotane sensitivity in vitro.
Conclusion
Direct antitumor effects of mitotane on human primary ACC cultures are highly variable between patients, reflecting heterogeneous responses in patients. Cortisol was inhibited at lower concentrations, compared with its effect on cell amount. Cortisol secretion by ACC might be associated with enhanced mitotane sensitivity due to increased direct antitumor effects of mitotane.
Abstract
Background
Pancreatic neuroendocrine tumors (pNETs) are highly prevalent in patients with multiple endocrine neoplasia type 1 (MEN1), and metastatic disease is an important cause of ...MEN1-related mortality. Especially small nonfunctional (NF) pNETs pose a challenge to the treating physician and more information is needed regarding their natural course. We assessed long-term natural history of small NF-pNETs and its modifiers in the Dutch MEN1 population.
Patients and Methods
Retrospective longitudinal observational cohort study of patients with small (<2 cm) NF-pNETs from the Dutch national MEN1 database, which includes >90% of the Dutch MEN1 population. Modifiers of long-term natural course were analyzed using linear mixed-models analysis.
Results
Growth rate of the 115 included small NF-pNETs from 99 patients was slow (0.4 mm/y; 95% confidence interval, 0.15 to 0.59). Seventy percent of the tumors was stable and a subgroup of 30% of the tumors was growing (1.6 mm/y; 95% confidence interval, 1.1 to 2.0). No differences in clinical characteristics were identified between growing and stable tumors. Within the subgroup of growing tumors, germline missense mutations were significantly associated with accelerated growth compared with nonsense and frameshift mutations.
Conclusion
The majority of small NF-pNETs are stable at long-term follow-up, irrespective of the underlying MEN1 genotype. A subgroup of tumors is slowly growing but cannot be identified on clinical grounds. In this subgroup, tumors with missense mutations exhibited faster growth. Additional events appear necessary for pNETs to progress. Future studies should be aimed at identifying these molecular driving events, which could be used as potential biomarkers.
The size of 115 small NF-pNETs from 99 MEN1 patients was followed over time. Most tumors were stable. In the subgroup of growing tumors a genotype-phenotype correlation was seen.
Context:
Guidelines advise lifelong radiological followup for asymptomatic pituitary adenomas (PITs) because of the risk for growth and subsequent visual field defects. In the context of multiple ...endocrine neoplasia type 1 (MEN1) an even more comprehensive screening is advised because PITs are presumed to manifest more aggressive behavior. We studied the long-term course of MEN1-related PITs, which may be used as a model for sporadically occurring PITs.
Objective:
The aim of our study is to assess the results of systematic pre-symptomatic PIT screening and subsequent long-term followup of PITs with emphasis on nonfunctioning microadenomas diagnosed by screening.
Patients and Methods:
A cohort study was performed using the Dutch national MEN1 database, including greater than 90% of the Dutch MEN1 population older than 16 years (n = 323).
Main Outcome Measures:
Screening results, natural course, and effects of treatment of PIT were assessed.
Results:
PIT was diagnosed in 123 patients with MEN1 (38.1 %), of whom 66 were diagnosed by MEN1-related screening. Ninety-one percent of the nonfunctioning PIT detected during screening (n = 35), did not require intervention during followup (median, 6.0 y). Three microadenomas showed limited growth but did not progress toward macroadenomas. Both screening-detected and prevalent prolactinomas (n = 52) responded well to treatment with dopamine agonists.
Conclusion:
Systematic presymptomatic screening for PIT in patients with MEN1 predominantly results in detection of nonfunctioning microadenomas. Prolactinoma in patients with MEN1 responded well to medical treatment. Microadenomas grew only occasionally and after many years without clinical consequences. Frequent magnetic resonance imaging followup of nonfunctioning microadenomas in the context of MEN1 and sporadically occurring PITs therefore seems debatable.
Summary
Background
Serotonin secretion occurs in approximately 1%‐4% of patients with a pancreatic neuroendocrine tumour (PNET), but the incidence is not well defined. The aim of this study was to ...determine the incidence of serotonin secretion with and without carcinoid syndrome and the prognostic value for overall survival (OS).
Methods
Data were collected from 255 patients with a PNET if 24‐hours urinary 5‐hydroxyindoleacetic acid excretion (5‐HIAA) was assessed. Patients were diagnosed with serotonin secretion if 24‐hours urinary 5‐HIAA excretion was more than 3× the upper limit of normal (ULN) of 50 μmol/24 hours during follow‐up. The effect of serotonin secretion on OS was estimated with uni‐ and multivariate analyses using a Cox regression.
Results
Two (0.8%) patients were diagnosed with carcinoid syndrome, and another 20 (7.8%) had a serotonin‐secreting PNET without symptoms. These patients mostly had ENETS stage IV disease with high chromogranin A (CgA). Serotonin secretion was a negative prognostic factor in univariate analysis (HR 2.2, 95% CI: 1.27‐3.81), but in multivariate analysis, only CgA>10× ULN (HR: 1.81, 95% CI: 1.10‐2.98) and neuron‐specific enolase (NSE) >ULN (HR: 3.51, 95% CI: 2.26‐5.46) were predictors for OS. Immunohistochemical staining for serotonin was positive in 28.6% of serotonin‐secreting PNETs (one with carcinoid syndrome) and negative in all controls.
Conclusion
Carcinoid syndrome is rare in patients with a PNET, but serotonin secretion occurs often. This is a negative prognostic factor for OS, but after correction for CgA and NSE, it is no longer a predictor and probably only a “not‐so innocent bystander” in patients with high tumour burden.
For progressive metastatic medullary thyroid carcinoma (MTC), the available treatment options with tyrosine kinase inhibitors result in grade 3-4 adverse events in a large number of patients. Peptide ...Receptor Radionuclide Therapy (PRRT), which has also been suggested to be a useful treatment for MTC, is usually well tolerated, but evidence on its effectivity is very limited.
Retrospective evaluation of treatment effects of PRRT in a highly selected group of MTC patients, with progressive disease or refractory symptoms. In addition, a retrospective evaluation of uptake on historical
In-DTPA-octreotide scans was performed in patients with detectable tumor size > 1 cm.
Over the last 17 years, 10 MTC patients were treated with PRRT. Four out of 10 patients showed stable disease at first follow-up (8 months after start of therapy) whereas the other 6 were progressive. Patients with stable disease were characterized by a combination of both a high uptake on
In-DTPA-octreotide scan (uptake grade ≥ 3) and a positive somatostatin receptor type 2a (SSTR2a) expression of the tumor by immunohistochemistry. Retrospective evaluation of historical
In-DTPA-octreotide scans of 35 non-treated MTC patients revealed low uptake (uptake grade 1) in the vast majority of patients 31/35 (89%) with intermediate uptake (uptake grade 2) in the remaining 4/35 (11%).
PRRT using
Lu-octreotate could be considered as a treatment in those patients with high uptake on
In-DTPA-octreotide scan (uptake grade 3) and positive SSTR2a expression in tumor histology. Since this high uptake was present in a very limited number of patients, this treatment is only suitable in a selected group of MTC patients.
To determine if urinary 5-hydroxyindoleacetic acid (5-HIAA) excretion is of prognostic value for overall survival (OS) in patients with a gastrointestinal neuroendocrine tumour (NET) and to compare ...the prognostic value with patient characteristics, ENETS/WHO grading, ENETS TNM staging and biomarkers.
Data was collected from patients with a gastrointestinal NET or a NET with gastrointestinal metastases and available 5-HIAA excretion in 24-h urine samples. Laboratory results were stratified for urinary 5-HIAA and chromogranin A (CgA): <2× upper limit of normal (ULN), 2-10× ULN, or >10× ULN. For neuron-specific enolase (NSE), this was the reference range or >1× ULN. OS was compared using Kaplan-Meier and log-rank tests, and hazard ratios were calculated using Cox regression for univariate and multivariate analyses.
A total of 371 patients were included, 46.6% female with a mean age of 59.9 years. OS was shortest in patients with urinary 5-HIAA excretion >10× ULN vs reference range (median 83 months vs 141 months, P = 0.002). In univariate analysis, urinary 5-HIAA excretion >10× ULN was a negative predictor (HR 1.62, 95% CI: 1.09-2.39). However, in multivariate analysis, only age (HR 1.04, 95% CI: 1.01-1.08), grade 3 disease (HR 5.09, 95% CI: 2.20-11.79), NSE >1× ULN (HR 2.36, 95% CI: 1.34-4.14) and CgA >10× ULN (HR 3.61, 95% CI: 1.56-8.34) remained as the predictors.
Urinary 5-HIAA excretion >10× ULN is a negative predictor for OS. However, when added to other biomarkers and grading, it is no longer a predictor for OS. Therefore, it should only be determined to assess carcinoid syndrome and not for prognostic value.
There are few treatment options for patients with metastasized or inoperable endocrine gastroenteropancreatic (GEP) tumors. Chemotherapy can be effective, but the response is usually less than 1 ...year. Here, we present the results of treatment with a radiolabeled somatostatin analog, 177Lu-DOTA0,Tyr3octreotate (177Lu-octreotate).
One hundred thirty-one patients with somatostatin receptor-positive tumors were treated with up to a cumulative dose of 600 to 800 mCi (22.2 to 29.6 GBq) of 177Lu-octreotate.
One patient developed renal insufficiency, and another patient developed hepatorenal syndrome. Creatinine clearance did not change significantly in the other patients. WHO hematologic toxicity grade 3 or 4 occurred after less than 2% of the administrations. We observed complete remission in three patients (2%), partial remission in 32 patients (26%), minor response (tumor diameter decrease of 25% to 50%) in 24 patients (19%), stable disease (SD) in 44 patients (35%), and progressive disease (PD) in 22 patients (18%). Higher remission rates were positively correlated with high uptake on pretherapy somatostatin receptor imaging and a limited number of liver metastases, whereas PD was significantly more frequent in patients with a low performance score and extensive disease. Median time to progression in 103 patients who either had SD or tumor regression was more than 36 months.
Treatment with 177Lu-octreotate results in tumor remission in a high percentage of patients with GEP tumors. Serious side effects are rare. The median time to progression compares favorably with chemotherapy. Results are better in patients with a limited tumor load. Therefore, early treatment, even in patients who have no PD, may be better.
In a prospective clinical proof-of-concept trial involving nine advanced NET patients with low SST expression, we were able to show that epigenetic treatment with the histone deacetylase (HDAC) ...inhibitor valproic acid and the DNA methyltransferase (DNMT) inhibitor hydralazine did not lead to an increase in tumour-uptake of 68Ga-DOTATATE, contradicting the in vitro data. A prerequisite for the treatment of advanced NETs with (radiolabelled) somatostatin analogues (SSA) is the expression of SST2 on the tumour cell surface, providing rationale for the inferior outcome in patients with low uptake on functional SST imaging.3 Several previous in vitro studies and one in vivo study achieved stimulation of SST2 expression levels and binding of SSAs by increasing histone acetylation levels and reducing DNA methylation of the SST2 gene promoter region in NET cells by epigenetic drugs.1,2,4 Despite these promising results, there are only data from one study showing limited increase of 68Ga-DOTATOC uptake by HDAC inhibitor vorinostat in five NET patients already expressing SST at baseline.5 In the present study, which was approved by the Ethics Committee of the Erasmus Medical Center Rotterdam and registered at the Netherlands Trial Register (NL7726), nine patients with advanced NETs (Table 1) and low SST expression at baseline on 68Ga-DOTATATE/PET (Table 2), defined as tumour uptake below or equal to the physiological uptake in the liver, were included and provided written informed consent. Values are shown as median (interquartile range IQR) or number (%) Patient characteristics Total (n = 9) Age, years (IQR) 67 (54, 75) Sex (male), n (%) 5 (56) Origin Pancreas NET, n (%) 2 (22) Small intestinal NET, n (%) 1 (11) Lung NET, n (%) 4 (44) Rectum NET, n (%) 1 (11) Thymus NET, n (%) 1 (11) Metastases Lymph nodes, n (%) 9 (100) Liver, n (%) 5 (56) Mesenterial, n (%) 1 (11) Bone, n (%) 3 (33) Lung, n (%) 1 (11) Other, n (%) 4 (44) Ki67 index 0%–2%, n (%) 3 (33) 5%–10%, n (%) 4 (44) 30% 1 (11) Unknown 1 (11) Grading G1, n (%) 4 (44) G2, n (%) 4 (44) G3, n (%) 1 (11) Previous treatments Surgery, n (%) 3 (33) Somatostatin analogue, n (%) 2 (22) Chemotherapy, n (%) 1 (11) Other, n (%) 3 (33) Abbreviations: Bpm, beats per minute; n, number; NET, neuroendocrine tumour; IQR, interquartile range; SUV, standard uptake values. TABLE 2 Change in study parameters of neuroendocrine tumour patients at baseline and after 1 and 2 weeks of epigenetic treatment Clinical parameters Baseline Week 1 Week 2 p Value Weight, kg (IQR) 76 (68, 86) 77 (68, 88) 77 (69, 88) .05 Blood pressure systolic, mmHg (IQR) 147 (130, 155) 139 (129, 151) 135 (126, 148) .14 Heart rate, bpm (IQR) 69 (62, 81) 77 (67, 109) 76 (65, 96) .34 Laboratory parameters Haemoglobin, mmol/L (IQR) 8.5 (8.1, 9.2) 8.5 (7.7, 9.2) 8.1 (7.6, 8.6) .05 Thrombocytes, ×109/L (IQR) 247 (195, 282) 233 (173, 255) 177 (148, 271) .11 Creatinine, umol/L (IQR) 73 (58, 90) 74 (54, 86) 76 (56, 89) .72 ASAT, U/L (IQR) 27 (23, 32) 23 (21, 30) 28 (24, 36) 1 ALAT, U/L (IQR) 26 (17, 35) 17 (16, 25) 21 (13, 26) .09 GGT, U/L (IQR) 65 (19, 98) 46 (19, 82) 48 (18, 115) .16 Valproic acid drug level, μg/ml (IQR) NA 102 (84, 126) 95 (90, 117) NA Study medication Valproic acid dosage, mg/day (IQR) (n = 9) NA 2300 (1900, 2500) 1900 (1763, 2000) NA Hydralazine dosage, mg/day (IQR) (n = 7) NA 150 (150, 150) 150 (100, 150) NA Tumour uptake of 68Ga-DOTATATE None, n (%) 6 (67) 6 (67) 1 Below liver, n (%) 3 (33) 3 (33) 1 Peak uptake Primary tumour, SUV (IQR)(n = 6) 8.1 (3.0, 11.4) 6.8 (2.8, 9.9) .17 Lymph node metastases, SUV (IQR) (n = 5) 4.8 (3.1, 9.0) 5.8 (2.6, 7.8) .35 Liver metastases, SUV (IQR) (n = 5) 7.5 (5.0, 7.9) 7.3 (4.5, 8.4) .29 Bone metastases, SUV (IQR) (n = 4) 4.1 (2.6, 5.1) 4.2 (2.7, 5.2) .47 Intestinal metastases, SUV (IQR) (n = 2) 9 (7.5, 10.5) 8.7 (6.7, 10.6) .67 Skin metastases, SUV (IQR) (n = 1) 3.5 3.7 NA Liver, SUV (IQR) 10.5 (8.3, 12.6) 10.7 (8.3, 12.3) .95 Kidneys, SUV (IQR) 16.3 (14.3, 19.2) 20.7 (16.1, 26.0) .02 Spleen, SUV (IQR) 25.9 (22.7, 32.7) 27.8 (22.0, 31.9) .68 Note: Values are shown as median (IQR) or number (%) in nine patients, unless otherwise indicated.
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