Analysis of miR-29 Serum Levels in Patients with Neuroendocrine Tumors—Results from an Exploratory Study

Background and aims: Due to its involvement in tumor biology as well as tumor-associated stroma cell responses, recent data suggested a potential role of miR-29 as a biomarker for different malignancies. However, its role in neuroendocrine tumors (NETs) is only poorly understood. Methods: We measured circulating levels of miR-29b in 45 patients with NET and compared them to 19 healthy controls. Results were correlated with clinical records. Results: In our cohort of NET patients treated between 2010 and 2019 at our department, miR-29b serum levels were significantly downregulated when compared to healthy control samples. Further, a significant correlation between chromogranin A (CgA) and relative miR-29b levels was noted. However, serum levels of miR-29b were independent of tumor-related factors such as proliferation activity according to Ki-67 index, tumor grading, the TMN stage of malignant tumors, somatostatin receptor expression or clinical features such as functional or non-functional disease and presence of tumor relapse. Finally, in contrast to previous results from other malignancies, miR-29b serum levels were not a significant predictor of overall survival in NET patients. Conclusion: Our data suggest a role for miR-29b serum levels as a previously unrecognized biomarker for diagnosis of NET. However, miR-29 does not allow for predicting tumor stage or patients’ outcome.

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Serum levels of miR-223 but not miR-21 are decreased in patients with neuroendocrine tumors

PLoS ONE ◽

10.1371/journal.pone.0244504 ◽

2020 ◽

Vol 15 (12) ◽

pp. e0244504

Author(s):

Teresa Hellberg ◽

Raphael Mohr ◽

Lukas Geisler ◽

Jana Knorr ◽

Alexander Wree ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Somatostatin Receptor ◽

Serum Levels ◽

Receptor Expression ◽

Ki 67 ◽

Proliferation Activity ◽

Healthy Control ◽

Clinical Records ◽

Circulating Levels

Background and aims MicroRNAs (miRNAs) are profoundly involved into the pathophysiology of manifold cancers. Recent data suggested a pivotal role of miRNAs as biomarkers in different biological processes including carcinogenesis. However, their role in neuroendocrine tumors (NETs) is only poorly understood. Methods We determined circulating levels of miR-21 and miR-223 in 45 samples from patients with NET treated between 2010 and 2019 at our department and compared them to healthy controls. Results were correlated with clinical records. Results In the total cohort of Patients with NET, miR-223 presented significantly lower levels compared to healthy control samples. In contrast, levels of miR-21 indicated no significant changes between the two groups. Interestingly, despite being significantly downregulated in all NET patients, concentrations of miR-223 were independent of clinical or histopathological factors such as proliferation activity according to Ki-67 index, tumor grading, TNM stage, somatostatin receptor expression, presence of functional/ non-functional disease or tumor relapse. Moreover, in contrast to data from recent publications analyzing other tumor entities, levels of miR-223 serum levels did not reflect prognosis of patients with NET. Conclusion Lower concentrations of circulating miR-223 rather reflect the presence of NET itself than certain tumor characteristics. The value of miR-223 as a biomarker in NET might be limited to diagnostic, but not prognostic purposes.

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Soluble Urokinase Plasminogen Activator Receptor (suPAR) Concentrations Are Elevated in Patients with Neuroendocrine Malignancies

Journal of Clinical Medicine ◽

10.3390/jcm9061647 ◽

2020 ◽

Vol 9 (6) ◽

pp. 1647

Author(s):

Burcin Özdirik ◽

Anna Stueven ◽

Jana Knorr ◽

Lukas Geisler ◽

Raphael Mohr ◽

...

Keyword(s):

Plasminogen Activator ◽

Malignant Tumors ◽

Tnm Classification ◽

Somatostatin Receptor ◽

Serum Levels ◽

Receptor Expression ◽

Urokinase Plasminogen Activator Receptor ◽

Related Factors ◽

Ki 67 ◽

Plasminogen Activator Receptor

Neuroendocrine neoplasia (NEN) comprises heterogeneous tumors that are challenging to diagnose and, especially in cases of poorly differentiated (G3) NEN, are associated with very limited survival. Novel biomarkers allowing an early diagnosis as well as an optimal selection of suitable treatment options are urgently needed to improve the outcome of these patients. Recently, alterations of soluble urokinase-type plasminogen activator receptor (suPAR) serum levels were described in various types of cancers. However, the role of circulating suPAR as a biomarker in patients with NEN is unknown. In this study, we measured suPAR serum levels in a large and well-characterized cohort of 187 patients with NEN (neuroendocrine carcinomas (NEC) n = 30; neuroendocrine tumors (NET), n = 157) as well as 44 healthy controls. suPAR concentrations were significantly elevated in patients compared to controls. However, suPAR concentrations were independent of tumor-related factors such as the proliferation activity according to Ki-67, tumor grading, TNM (TNM classification of malignant tumors) stage, somatostatin receptor expression or clinical features such as functional or nonfunctional disease and the presence of tumor relapse. Interestingly, suPAR concentrations in NET patients were similar when compared to those measured in NEC patients. In contrast to previous results from other malignancies, in our analysis suPAR levels were not a significant predictor of overall survival. In conclusion, our data suggests that suPAR serum concentrations are elevated in NEN patients but do not allow prediction of outcome.

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Mixed adenoneuroendocrine carcinoma of the hepatic bile duct: a case report and review of the literature

BMC Gastroenterology ◽

10.1186/s12876-020-01550-2 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Sulai Liu ◽

Zhendong Zhong ◽

Meng Xiao ◽

Yinghui Song ◽

Youye Zhu ◽

...

Keyword(s):

Bile Duct ◽

Neuroendocrine Tumors ◽

Radical Surgery ◽

Malignant Tumors ◽

World Health ◽

Ki 67 ◽

Mixed Adenoneuroendocrine Carcinoma ◽

Hilar Bile Duct ◽

Hilar Tumor

Abstract Background The World Health Organization's updated classification of digestive system neuroendocrine tumors in 2010 first proposed the classification of mixed adenoneuroendocrine carcinoma (MANEC). The incidence of biliary malignant tumors with neuroendocrine tumors accounts for less than 1% of all neuroendocrine tumors. Moreover, the incidence of hilar bile duct with MANEC is very rare. Case presentation A 65-year-old female patient came to our hospital for repeated abdominal pain for more than 4 months and skin sclera yellow staining for 1 week. Contrast-enhanced computed tomography imaging and magnetic resonance results suggested a hilar tumor for Bismuth-Corlette Type II. The patient underwent radical surgery for hilar cholangiocarcinoma. Finally, the patient was diagnosed with hilar bile duct MANEC, staged 1 (pT1N0M0) based on the eighth edition of the AJCC. Histopathology showed that the tumor was a biliary tumor with both adenocarcinoma and neuroendocrine carcinoma. No evidence of recurrence and metastasis after 20 months of follow-up. Conclusions We first reported a MANEC that originated in the hilar bile duct. As far as we known, there were few reports of biliary MANEC, and the overall prognosis was poor. We also found that the higher the Ki-67 index, the worse the prognosis of this type of patient. Radical surgery is the most effective treatment.

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Effect of Peptide Receptor Radionuclide Therapy on Somatostatin Receptor Status and Glucose Metabolism in Neuroendocrine Tumors: Intraindividual Comparison of Ga-68 DOTANOC PET/CT and F-18 FDG PET/CT

International Journal of Molecular Imaging ◽

10.1155/2011/524130 ◽

2011 ◽

Vol 2011 ◽

pp. 1-7 ◽

Cited By ~ 18

Author(s):

Sowon Oh ◽

Vikas Prasad ◽

Dong Soo Lee ◽

R. P. Baum

Keyword(s):

Glucose Metabolism ◽

Neuroendocrine Tumors ◽

Fdg Pet ◽

Radionuclide Therapy ◽

Somatostatin Receptor ◽

Peptide Receptor Radionuclide Therapy ◽

Receptor Expression ◽

Peptide Receptor ◽

Pet Ct ◽

Fdg Pet Ct

The heterogeneous nature of the neuroendocrine tumors (NET) makes it challenging to find one uniformly applicable management protocol which is especially true for diagnosis. The discovery of the overexpression of somatostatin receptors (SMS-R) on neuroendocrine tumor cells lead to the generalized and rapid acceptance of radiolabeled somatostatin receptor analogs for staging and restaging of NET as well as for Peptide Receptor Radionuclide Therapy (PRRNT) using Y-90 and Lu-177 DOTATATE/DOTATOC. In this present work we tried to look in to the effect of PRRNT on the glucose metabolism assessed by F-18 FDG PET/CT and SMS-R density assessed by Ga-68 DOTANOC PET/CT. We observed a complex relationship between the somatostatin receptor expression and glucose metabolism with only 56% (77/138) of the lesions showing match, while the others show mismatch between the receptor status and metabolism. The match between receptor expression and glucose metabolism increases with the grade of NET. In grade 3 NET, there is a concurrence between the changes in glucose metabolism and somatostatin receptor expression. PRRNT was found to be more effective in lesions with higher receptor expression.

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Somatostatin Receptor (SSTR) Expression and Proliferative Index (KI 67) in 100 Patients (PTS) with Gastroenteropancreatic Neuroendocrine Tumors (Gep-Nets). Clinical-Pathological Correlation

Annals of Oncology ◽

10.1016/s0923-7534(20)33717-0 ◽

2012 ◽

Vol 23 ◽

pp. ix379-ix380

Author(s):

J.M. Oconnor ◽

S. Belli ◽

V. Pesce ◽

C. Bestani ◽

G. Mendez ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Somatostatin Receptor ◽

Proliferative Index ◽

Gastroenteropancreatic Neuroendocrine Tumors ◽

Ki 67 ◽

Pathological Correlation

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Asphericity of Somatostatin Receptor Expression in Neuroendocrine Tumors: An Innovative Predictor of Outcome in Everolimus Treatment?

Diagnostics ◽

10.3390/diagnostics10090732 ◽

2020 ◽

Vol 10 (9) ◽

pp. 732

Author(s):

Christoph Wetz ◽

Julian Rogasch ◽

Philipp Genseke ◽

Imke Schatka ◽

Christian Furth ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Cox Regression ◽

Somatostatin Receptor ◽

Peptide Receptor Radionuclide Therapy ◽

Progression Free Survival ◽

Receptor Expression ◽

Gastroenteropancreatic Neuroendocrine Tumors ◽

Primary Tumor Site ◽

Risk Benefit Assessment ◽

Octreotide Scintigraphy

Background: in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NET), the mTOR inhibitor everolimus is associated with significant improvement in progression-free survival (PFS). This study evaluated the lesional asphericity (ASP) in pretherapeutic somatostatin receptor (SSR) imaging as the first imaging-based prognostic marker for PFS. Methods: this retrospective bicentric cohort study included 30 patients (f = 13, median age, 66.5 (48–81) years) with pretherapeutic [111In-DTPA0]octreotide scintigraphy (Octreoscan®). ASP of functional volumes of up to three leading lesions per patient (n = 74) was calculated after semiautomatic, background-adapted segmentation. Uni- and multivariable Cox regression regarding PFS for clinical factors and the maximum ASP per patient was obtained. Results: all 30 patients showed metachronous or progressive liver metastases. ASP, primary tumor site, metastases pattern, and prior peptide receptor radionuclide therapy (PRRT) were significantly associated with PFS in univariable Cox regression. Only ASP > 12.9% (hazard ratio (HR), 3.33; p = 0.024) and prior PRRT (HR, 0.35; p = 0.043) remained significant in multivariable Cox. Median PFS was 6.7 months for ASP > 12.9% (95% confidence interval (CI), 2.1–11.4 months) versus 14.4 (12.5–16.3) months for ASP ≤ 12.9% (log-rank, p = 0.028). Conclusion: pretherapeutic ASP of SSR positive lesions independently predicted PFS for treatment with everolimus in GEP-NET. ASP may supplement risk-benefit assessment before patient inclusion to treatment.

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Outcomes of peptide receptor radionuclide therapy (PRRT) in metastatic grade 3 neuroendocrine tumors (NETs).

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e15694 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e15694-e15694

Author(s):

Mei Sim Lung ◽

Michael Hofman ◽

Grace Kong ◽

Sue-Ping Thang ◽

Michael Michael ◽

...

Keyword(s):

Treatment Option ◽

Treatment Options ◽

Somatostatin Receptor ◽

Peptide Receptor Radionuclide Therapy ◽

Receptor Expression ◽

Unknown Primary ◽

Receptor Imaging ◽

Ki 67 ◽

Prior Chemotherapy ◽

Platinum Based Chemotherapy

e15694 Background:Grade 3 (G3) NETs have a poor prognosis and limited treatment options (usually chemotherapy). PRRT is a potential treatment option if all sites of disease demonstrate high uptake on somatostatin-receptor imaging (SSRI). We retrospectively evaluated the efficacy of PRRT in G3 NETs. Methods: We reviewed records of patients with metastatic G3 NETs (Ki-67 > 20%) who received PRRT at our institution. Patients were treated with up to 5 cycles of PRRT, predominantly 177Lu-DOTA-octreotate. Further maintenance PRRT was administered upon progression if deemed suitable on SSRI. Radio-sensitizing chemotherapy was administered unless contra-indicated. Kaplan-Meier estimate was used to determine median overall survival (OS) and median time to new treatment/death (TNTD) defined from start of PRRT. Subgroup-analysis was performed for patients with Ki67 < 55% and ≥55%. Results: 26 patients with metastatic G3 NET received PRRT; 22 combined with chemotherapy (capecitabine/temozolomide (n = 12), 5-fluorouracil or capecitabine (n = 8), other (n = 2)). 58% were male. The median age was 62 (range 16-78 years). 61% had pancreatic NET, 19% small bowel, 8% lung, 8% unknown primary, 4% rectal. 77% had received at least one line of prior chemotherapy. 54% received prior platinum-based chemotherapy. Median follow-up was 33 months (range 8-83 months). Patients received a median of 4 cycles of PRRT (range 1-15). The estimated median OS from start of PRRT was 18 months: for Ki-67 < 55% (n = 21), 20 months; and Ki-67≥ 55% (n = 5), 9 months. The estimated median TNTD was 12 months: for Ki-67 < 55%, 16 months; and Ki-67≥55%, 4 months. 31% of patients were alive without a change in treatment modality following PRRT. Conclusions: In thispoor prognosis G3 NET cohort of whom 77% had received prior chemotherapy, a median OS of 18 months from start of PRRT is encouraging and warrants further study. PRRT is a promising treatment option for patients with G3 NET with high somatostatin-receptor expression selected by SSRI.

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