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Open access

Matilde Calanchini, Michael Tadman, Jesper Krogh, Andrea Fabbri, Ashley Grossman and Brian Shine


The 24-h urinary output of 5-hydroxyindoleacetic acid (5-HIAA) is used to monitor disease progression and treatment responses of neuroendocrine neoplasms (NENs). Several conditions are required for 5-HIAA assay, involving urine collection/preservation and food/drug restrictions.


To evaluate the correlation between 5-HIAA concentration in a spot urine sample and the output in a 24-h urine collection, and whether spot urine specimens can replace 24-h collection.


Patients with NENs or symptoms suggestive of NENs were asked to provide a separate spot urine at the end of the 24-h urine collection for 5-HIAA assessment. The upper reference limit for 24-h urinary 5-HIAA was 40 µmol/24 h. 5-HIAA measurements in spot urine samples were corrected for variation in urine flow rate by expressing results as a ratio to creatinine concentration.


We included 136 paired urinary samples for 5-HIAA assessment from 111 patients (100 NENs). The correlation between 5-HIAA values measured in 24-h and spot urines was r = +0.863 (P < 0.001) and r = +0.840 (P < 0.001) including only NEN patients. Using the 24-h urinary 5-HIAA as reference method, the AUC on ROC analysis for spot urinary 5-HIAA was 0.948 (95% CI, 0.914–0.983; P < 0.001), attaining a sensitivity of 83% and specificity of 95% using 5.3 mol/mmol as cut-off for the spot urine. The AUC among NEN patients alone was 0.945 (95% CI, 0.904–0.987; P < 0.001).


The ratio of 5-HIAA to creatinine in a spot urine could replace the measurement of 5-HIAA output in a 24-h urine collection, especially for follow-up of patients with known elevated 5-HIAA levels.

Open access

G Giuffrida, F Ferraù, R Laudicella, O R Cotta, E Messina, F Granata, F F Angileri, A Vento, A Alibrandi, S Baldari and S Cannavò

In aggressive pituitary tumors (PT) showing local invasion or growth/recurrence despite multimodal conventional treatment, temozolomide (TMZ) is considered a further therapeutic option, while little data are available on peptide receptor radionuclide therapy (PRRT). We analyzed PRRT effectiveness, safety and long-term outcome in three patients with aggressive PT, also reviewing the current literature. Patient #1 (F, giant prolactinoma) received five cycles (total dose 37 GBq) of 111In-DTPA-octreotide over 23 months, after unsuccessful surgery and long-term dopamine-agonist treatment. Patient #2 (M, giant prolactinoma) underwent two cycles (12.6 GBq) of 177Lu-DOTATOC after multiple surgeries, radiosurgery and TMZ. In patient #3 (F, non-functioning PT), five cycles (29.8 GBq) of 177Lu-DOTATOC followed five surgeries, radiotherapy and TMZ. Eleven more cases of PRRT-treated aggressive PT emerged from literature. Patient #1 showed tumor shrinkage and visual/neurological amelioration over 8-year follow-up, while the other PTs continued to grow causing blindness and neuro-cognitive disorders (patient #2) or monolateral amaurosis (patient #3). No adverse effects were reported. Including the patients from literature, 4/13 presented tumor shrinkage and clinical/biochemical improvement after PRRT. Response did not correlate with patients’ gender or age, neither with used radionuclide/peptide, but PRRT failure was significantly associated with previous TMZ treatment. Overall, adverse effects occurred only in two patients. PRRT was successful in 1/3 of patients with aggressive PT, and in 4/5 of those not previously treated with TMZ, representing a safe option after unsuccessful multimodal treatment. However, at present, considering the few data, PRRT should be considered only in an experimental setting.

Open access

Bregtje C M Hermans, Jules Derks, Harry J M Groen, Jos A Stigt, Robert Jan van Suylen, Lisa M Hillen, Esther C van den Broek, Ernst-Jan M. Speel and Anne-Marie C Dingemans

Introduction: Stage IV large cell neuroendocrine carcinoma (LCNEC) of the lung generally presents as disseminated and aggressive disease with a Ki-67 proliferation index (PI) 40-80%. LCNEC can be subdivided in two main subtypes: the first harboring TP53/RB1 mutations (small cell lung carcinoma (SCLC)-like), the second with mutations in TP53 and STK11/KEAP1 (non-small cell lung carcinoma (NSCLC)-like). Here we evaluated 11 LCNEC patients with only a solitary brain metastasis and evaluate phenotype, genotype and follow-up.

Methods: Eleven LCNEC patients with solitary brain metastases were analyzed. Clinical characteristics and survival data were retrieved from medical records. Pathological analysis included histomorphological analysis, immunohistochemistry (pRB and Ki-67 PI) and next generation sequencing (TP53, RB1, STK11, KEAP1 and MEN1).

Results: All patients had N0 or N1 disease. Median overall survival (OS) was 12 months (95% confidence interval (CI) 5.5-18.5 months). Mean Ki-67 PI was 59% (range 15-100%). In 6/11 LCNEC Ki-67 PI was ≤40%. OS was longer for Ki-67 ≤40% compared to >40% (17 months (95% CI 11-23 months) vs. 5 months (95% CI 0.7-9 months), p=0.007). Two patients were still alive at follow-up after 86 and 103 months, both had Ki-67 ≤40%. 8/11 patients could be subclassified and both SCLC-like (n=6) and NSCLC-like (n=2) subtype were present. No MEN1 mutation was found.

Conclusion: Stage IV LCNEC with a solitary brain metastasis and N0/N1 disease show in the majority of cases Ki-67 PI ≤40% and prolonged survival, distinguishing them from general LCNEC. This unique subgroup can be both of the SCLC-like and NSCLC-like subtype.

Open access

Carina Hasenoehrl, Gert Schwach, Nassim Ghaffari-Tabrizi-Wizsy, Robert Fuchs, Nadine Kretschmer, Rudolf Bauer and Roswitha Pfragner

New treatment options are needed for medullary thyroid carcinoma (MTC), a highly metastasizing neuroendocrine tumor that is resistant to standard radiotherapy and chemotherapy. We show that the following shikonin derivatives inhibit cell proliferation and cell viability of the MTC cell line TT: acetylshikonin, β,β-dimethylacrylshikonin, shikonin and a petroleum ether extract of the roots of Onosma paniculata containing several shikonin derivatives. The unsubstituted shikonin derivative was found to be the most effective compound with an IC50 of 1.1 µM. The cell viability of normal human skin fibroblasts, however, was not affected by the tested substances, indicating that shikonin derivatives might be selectively toxic for cancer cells. We further report that migration and invasion of TT cells were inhibited at non-toxic concentrations. Finally, shikonin was tested in vivo using the chick chorioallantoic membrane assay, where it significantly reduced tumor growth by inhibiting cell proliferation and inducing apoptosis. In summary, our results suggest that shikonin derivatives have the potential for the treatment of medullary thyroid carcinomas.

Open access

Yiqiang Huang, Lin-ang Wang, Qiubo Xie, Jian Pang, Luofu Wang, Yuting Yi, Jun Zhang, Yao Zhang, Rongrong Chen, Weihua Lan, Dianzheng Zhang and Jun Jiang

Pheochromocytoma and paragangliomas (PCC/PGL) are neuroendocrine tumors that arise from chromaffin cells of the adrenal medulla and sympathetic/parasympathetic ganglia, respectively. Of clinical relevance regarding diagnosis is the highly variable presentation of symptoms in PCC/PGL patients. To date, the clear-cut correlations between the genotypes and phenotypes of PCC/PGL have not been entirely established. In this study, we reviewed the medical records of PCC/PGL patients with pertinent clinical, laboratory and genetic information. Next-generation sequencing (NGS) performed on patient samples revealed specific germline mutations in the SDHB (succinate dehydrogenase complex iron-sulfur subunit B) and SDHD (succinate dehydrogenase complex subunit D) genes and these mutations were validated by Sanger sequencing. Of the 119 patients, two were identified with SDHB mutation and one with SDHD mutation. Immunohistochemical (IHC) staining was used to analyze the expression of these mutated genes. The germline mutations identified in the SDH genes were c343C>T and c.541-542A>G in the SDHB gene and c.334-337delACTG in the SDHD gene. IHC staining of tumors from the c.343C>T and c.541-2A>G carriers showed positive expression of SDHB. Tumors from the c.334-337delACTG carrier showed no expression of SDHD and a weak diffused staining pattern for SDHB. We strongly recommend genetic testing for suspected PCC/PGL patients with a positive family history, early onset of age, erratic hypertension, recurrence or multiple tumor sites and loss of SDHB and/or SDHD expression. Tailored personal management should be conducted once a patient is confirmed as an SDHB and/or SDHD mutation carrier or diagnosed with PCC/PGL.

Open access

Adrian F Daly, Liliya Rostomyan, Daniela Betea, Jean-François Bonneville, Chiara Villa, Natalia S Pellegata, Beatrice Waser, Jean-Claude Reubi, Catherine Waeber Stephan, Emanuel Christ and Albert Beckers

Acromegaly is a rare disease due to chronic excess growth hormone (GH) and IGF-1. Aryl hydrocarbon receptor interacting protein (AIP) mutations are associated with an aggressive, inheritable form of acromegaly that responds poorly to SST2-specific somatostatin analogs (SSA). The role of pasireotide, an SSA with affinity for multiple SSTs, in patients with AIP mutations has not been reported. We studied two AIP mutation positive acromegaly patients with early-onset, invasive macroadenomas and inoperable residues after neurosurgery. Patient 1 came from a FIPA kindred and had uncontrolled GH/IGF-1 throughout 10 years of octreotide/lanreotide treatment. When switched to pasireotide LAR, he rapidly experienced hormonal control which was associated with marked regression of his tumor residue. Pasireotide LAR was stopped after >10 years due to low IGF-1 and he maintained hormonal control without tumor regrowth for >18 months off pasireotide LAR. Patient 2 had a pituitary adenoma diagnosed when aged 17 that was not cured by surgery. Chronic pasireotide LAR therapy produced hormonal control and marked tumor shrinkage but control was lost when switched to octreotide. Tumor immunohistochemistry showed absent AIP and SST2 staining and positive SST5. Her AIP mutation positive sister developed a 2.5 cm follicular thyroid carcinoma aged 21 with tumoral loss of heterozygosity at the AIP locus and absent AIP staining. Patients 1 and 2 required multi-modal therapy to control diabetes. On stopping pasireotide LAR after >10 years of treatment, Patient 1’s glucose metabolism returned to baseline levels. Long-term pasireotide LAR therapy can be beneficial in some AIP mutation positive acromegaly patients that are resistant to first-generation SSA.

Open access

Ruth Therese Casey, Deborah Saunders, Benjamin George Challis, Deborah Pitfield, Heok Cheow, Ashley Shaw and Helen Lisa Simpson


Multiple endocrine neoplasia type 1 (MEN1) is a hereditary condition characterised by the predisposition to hyperplasia/tumours of endocrine glands. MEN1-related disease, moreover, malignancy related to MEN1, is increasingly responsible for death in up to two-thirds of patients. Although patients undergo radiological and biochemical surveillance, current recommendations for radiological monitoring are based on non-prospective data with little consensus or evidence demonstrating improved outcome from this approach. Here, we sought to determine whether cumulative radiation exposure as part of the recommended radiological screening programme posed a distinct risk in a cohort of patients with MEN1.

Patients and study design

A retrospective review of 43 patients with MEN1 attending our institution between 2007 and 2015 was performed. Demographic and clinical information including phenotype was obtained for all patients. We also obtained details regarding all radiological procedures performed as part of MEN1 surveillance or disease localisation. An estimated effective radiation dose (ED) for each individual patient was calculated.


The mean ED for the total patient cohort was 121 mSv, and the estimated mean lifetime risk of cancer secondary to radiation exposure was 0.49%. Patients with malignant neuroendocrine tumours (NETS) had significantly higher ED levels compared to patients without metastatic disease (P < 0.0022).


In MEN1, radiological surveillance is associated with clinically significant exposure to ionising radiation. In patients with MEN1, multi-modality imaging strategies designed to minimise this exposure should be considered.

Open access

Rossella Cannarella, Teresa Mattina, Rosita A Condorelli, Laura M Mongioì, Giuseppe Pandini, Sandro La Vignera and Aldo E Calogero

Insulin-like growth factor 1 receptor (IGF1R), mapping on the 15q26.3 chromosome, is required for normal embryonic and postnatal growth. The aim of the present study was to evaluate the IGF1R gene expression and function in three unrelated patients with chromosome 15 structural abnormalities. We report two male patients with the smallest 15q26.3 chromosome duplication described so far, and a female patient with ring chromosome 15 syndrome. Patient one, with a 568 kb pure duplication, had overgrowth, developmental delay, mental and psychomotor retardation, obesity, cryptorchidism, borderline low testis volume, severe oligoasthenoteratozoospermia and gynecomastia. We found a 1.8-fold increase in the IGF1R mRNA and a 1.3-fold increase in the IGF1R protein expression (P < 0.05). Patient two, with a 650 kb impure duplication, showed overgrowth, developmental delay, mild mental retardation, precocious puberty, low testicular volume and severe oligoasthenoteratozoospermia. The IGF1R mRNA and protein expression was similar to that of the control. Patient three, with a 46,XX r(15) (p10q26.2) karyotype, displayed intrauterine growth retardation, developmental delay, mental and psychomotor retardation. We found a <0.5-fold decrease in the IGF1R mRNA expression and an undetectable IGF1R activity. After reviewing the previously 96 published cases of chromosome 15q duplication, we found that neurological disorders, congenital cardiac defects, typical facial traits and gonadal abnormalities are the prominent features in patients with chromosome 15q duplication. Interestingly, patients with 15q deletion syndrome display similar features. We speculate that both the increased and decreased IGF1R gene expression may play a role in the etiology of neurological and gonadal disorders.

Open access

E T Aristizabal Prada and C J Auernhammer

Molecular targeted therapy of advanced neuroendocrine tumours (NETs) of the gastroenteropancreatic (GEP) system currently encompasses approved therapy with the mammalian target of rapamycin (mTOR) inhibitor everolimus and the multi-tyrosinkinase inhibitor sunitinib. However, clinical efficacy of these treatment strategies is limited by low objective response rates and limited progression-free survival due to tumour resistance. Further novel strategies for molecular targeted therapy of NETs of the GEP system are needed. This paper reviews preclinical research models and signalling pathways in NETs of the GEP system. Preclinical and early clinical data on putative novel targets for molecular targeted therapy of NETs of the GEP system are discussed, including PI3K, Akt, mTORC1/mTORC2, GSK3, c-Met, Ras–Raf–MEK–ERK, embryogenic pathways (Hedgehog, Notch, Wnt/beta-catenin, TGF-beta signalling and SMAD proteins), tumour suppressors and cell cycle regulators (p53, cyclin-dependent kinases (CDKs) CDK4/6, CDK inhibitor p27, retinoblastoma protein (Rb)), heat shock protein HSP90, Aurora kinase, Src kinase family, focal adhesion kinase and epigenetic modulation by histone deacetylase inhibitors.

Open access

Kosmas Daskalakis, Marina Tsoli, Anna Angelousi, Evanthia Kassi, Krystallenia I Alexandraki, Denise Kolomodi, Gregory Kaltsas and Anna Koumarianou

Comparisons between everolimus and sunitinib regarding their efficacy and safety in neuroendocrine neoplasms (NENs) are scarce. We retrospectively analysed the clinicopathological characteristics and outcomes in 92 patients with well-differentiated (WD) NEN of different origin (57 pancreatic NENs (PanNENs)), treated with molecular targeted therapy (MTT) with everolimus or sunitinib, first- (73:19) or second-line (sequential; 12:22) for progressive disease. Disease control rates (DCR: partial response or stable disease) at first-line were higher in all patients treated with everolimus than sunitinib (64/73 vs 12/19, P = 0.012). In PanNENs, DCR at first-line everolimus was 36/42 versus 9/15 with sunitinib (P = 0.062). Progression-free survival (PFS) at first-line everolimus was longer than sunitinib (31 months (95% CI: 23.1–38.9) vs 9 months (95% CI: 0–18.5); log-rank P < 0.0001) in the whole cohort and the subset of PanNENs (log-rank P < 0.0001). Median PFS at second-line MTT was 12 months with everolimus (95% CI: 4.1–19.9) vs 13 months with sunitinib (95% CI: 9.3–16.7; log-rank P = 0.951). Treatment with sunitinib (HR: 3.47; 95% CI: 1.5–8.3; P value: 0.005), KI67 >20% (HR: 6.38; 95% CI: 1.3–31.3; P = 0.022) and prior chemotherapy (HR: 2.71; 95% CI: 1.2–6.3; P = 0.021) were negative predictors for PFS at first line in multivariable and also confirmed at multi-state modelling analyses. Side effect (SE) analysis indicated events of serious toxicities (Grades 3 and 4: n = 13/85 for everolimus and n = 4/41 for sunitinib). Discontinuation rate due to SEs was 20/85 for everolimus versus 4/41 for sunitinib (P = 0.065). No additive toxicity of second-line MTT was confirmed. Based on these findings, and until reliable predictors of response become available, everolimus may be preferable to sunitinib when initiating MTT in progressive NENs.