Research

12 pages, 6072 KiB

Open AccessArticle

The New Radiolabeled Peptide ^99mTcEDDA/HYNIC-TOC: Is It a Feasible Choice for Diagnosing Gastroenteropancreatic NETs?

by Mirela Gherghe, Alexandra Maria Lazăr, Adina Elena Stanciu, Mario-Demian Mutuleanu, Maria-Carla Sterea, Cristina Petroiu and Laurenția Nicoleta Galeș

Cancers 2022, 14(11), 2725; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14112725 - 31 May 2022

Cited by 3 | Viewed by 2670

Abstract

(1) Background: The aim of our study is to reveal the advantages and limitations of the use of ^99mTcEDDA/HYNIC-TOC (Tektrotyd^®, Polatom) in the diagnosis of gastroenteropancreatic neuroendocrine tumors and to compare our results with the values obtained for ¹¹¹In-pentetreotide [...] Read more.

(1) Background: The aim of our study is to reveal the advantages and limitations of the use of ^99mTcEDDA/HYNIC-TOC (Tektrotyd^®, Polatom) in the diagnosis of gastroenteropancreatic neuroendocrine tumors and to compare our results with the values obtained for ¹¹¹In-pentetreotide and ⁶⁸Ga-DOTA-peptides, routinely used in medical practice. (2) Methods: This retrospective monocentric study included 173 patients with gastroenteropancreatic neuroendocrine tumors who underwent ^99mTcEDDA/HYNIC-TOC scans as part of their clinical management. The examination protocol included a whole-body scan acquired 2 h after the radiotracer’s administration, with the SPECT/CT performed 4 h post-injection. Physiological and abnormal uptake were established by two experienced physicians and, based on the obtained results, sensitivity, specificity, accuracy, positive predictive value and negative predictive value were calculated. (3) Results: Our method presented a sensitivity of 90.5%, a specificity of 71.9%, and an accuracy of 84.3%, with a positive predictive value of 86.7% and a negative predictive value of 78.8%. (4) Conclusions: ^99mTc-EDDA/HYNIC-TOC, a receptor-based radiopharmaceutical, could represent a competitor for ⁶⁸Ga-labeled peptides in the diagnosis and management of patients with gastroenteropancreatic neuroendocrine tumors. Our results show a lower sensitivity (90.5%) than ⁶⁸Ga-DOTA-peptides, but with great specificity, accuracy, positive, and negative predictive values. Full article

(This article belongs to the Special Issue Current Status of Neuroendocrine Tumors with a Special Focus on Diagnosis and Novel Treatments)

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12 pages, 1809 KiB

Open AccessArticle

Fate of Surgical Patients with Small Nonfunctioning Pancreatic Neuroendocrine Tumors: An International Study Using Multi-Institutional Registries

by In Woong Han, Jangho Park, Eun Young Park, So Jeong Yoon, Gang Jin, Dae Wook Hwang, Kuirong Jiang, Wooil Kwon, Xuefeng Xu, Jin Seok Heo, De-Liang Fu, Woo Jung Lee, Xueli Bai, Yoo-Seok Yoon, Yin-Mo Yang, Keun Soo Ahn, Chunhui Yuan, Hyeon Kook Lee, Bei Sun, Eun Kyu Park, Seung Eun Lee, Sunghwa Kang, Wenhui Lou and Sang-Jae Park Show full author list Hide full author list

Cancers 2022, 14(4), 1038; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14041038 - 18 Feb 2022

Cited by 4 | Viewed by 1824

Abstract

Several treatment guidelines for sporadic, nonmetastatic nonfunctioning neuroendocrine tumors of the pancreas (NF-pNETs) have recommended resection, however, tumors ≤ 2 cm do not necessarily need surgery. This study aims to establish a surgical treatment plan for NF-pNETs ≤ 2 cm. From 2000 to [...] Read more.

Several treatment guidelines for sporadic, nonmetastatic nonfunctioning neuroendocrine tumors of the pancreas (NF-pNETs) have recommended resection, however, tumors ≤ 2 cm do not necessarily need surgery. This study aims to establish a surgical treatment plan for NF-pNETs ≤ 2 cm. From 2000 to 2017, 483 patients who underwent resection for NF-pNETs ≤ 2 cm in 18 institutions from Korea and China were enrolled and their medical records were reviewed. The median age was 56 (range 16–80) years. The 10-year overall survival rate (10Y-OS) and recurrence-free survival rate (10Y-RFS) were 89.8 and 93.1%, respectively. In multivariable analysis, tumor size (>1.5 cm; HR 4.28, 95% CI 1.80–10.18, p = 0.001) and nodal metastasis (HR 3.32, 95% CI 1.29–8.50, p = 0.013) were independent adverse prognostic factors for OS. Perineural invasion (HR 4.36, 95% CI 1.48–12.87, p = 0.008) and high Ki-67 index (≥3%; HR 9.06, 95% CI 3.01–27.30, p < 0.001) were independent prognostic factors for poor RFS. NF-pNETs ≤ 2 cm showed unfavorable prognosis after resection when the tumor was larger than 1.5 cm, Ki-67 index ≥ 3%, or nodal metastasis was present. NF-pNET patients with tumors ≤ 1.5 cm can be observed if the preoperative Ki-67 index is under 3%, and if nodal metastasis is not suspected in preoperative radiologic studies. These findings support the clinical use to make decisions about small NF-pNETs. Full article

(This article belongs to the Special Issue Current Status of Neuroendocrine Tumors with a Special Focus on Diagnosis and Novel Treatments)

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15 pages, 3971 KiB

Open AccessArticle

Correlation of Somatostatin Receptor 1–5 Expression, [⁶⁸Ga]Ga-DOTANOC, [¹⁸F]F-FDG PET/CT and Clinical Outcome in a Prospective Cohort of Pancreatic Neuroendocrine Neoplasms

by Susanna Majala, Tiina Vesterinen, Hanna Seppänen, Harri Mustonen, Jari Sundström, Camilla Schalin-Jäntti, Risto Gullichsen, Jukka Schildt, Jukka Kemppainen, Johanna Arola and Saila Kauhanen

Cancers 2022, 14(1), 162; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14010162 - 29 Dec 2021

Cited by 7 | Viewed by 1592

Abstract

Purpose: The aim of this study was to correlate immunohistochemical (IHC) tissue levels of SSTR1-5 with the receptor density generated from [⁶⁸Ga]Ga-DOTANOC uptake in a prospective series of NF-PNENs. Methods: Twenty-one patients with a total of thirty-five NF-PNEN-lesions and twenty-one histologically [...] Read more.

Purpose: The aim of this study was to correlate immunohistochemical (IHC) tissue levels of SSTR1-5 with the receptor density generated from [⁶⁸Ga]Ga-DOTANOC uptake in a prospective series of NF-PNENs. Methods: Twenty-one patients with a total of thirty-five NF-PNEN-lesions and twenty-one histologically confirmed lymph node metastases (LN+) were included in this prospective study. Twenty patients were operated on, and one underwent endoscopic ultrasonography and core-needle biopsy. PET/CT with both [⁶⁸Ga]Ga-DOTANOC and [¹⁸F]F-FDG was performed on all patients. All histological samples were re-classified and IHC-stained with monoclonal SSTR1-5 antibodies and Ki-67 and correlated with [⁶⁸Ga]Ga-DOTANOC and [¹⁸F]F-FDG PET/CT. Results: Expression of SSTR1-5 was detected in 74%, 91%, 80%, 14%, and 77% of NF-PNENs. There was a concordance of SSTR2 IHC with positive/negative [⁶⁸Ga]Ga-DOTANOC finding (Spearman’s rho 0.382, p = 0.043). All [⁶⁸Ga]Ga-DOTANOC-avid tumors expressed SSTR2 or SSTR3 or SSTR5. Expression of SSTR5 was higher in tumors with a low Ki-67 proliferation index (PI) (−0.353, 95% CI −0.654–0.039, p = 0.038). The mean Ki-67 PI for SSTR5 positive tumors was 2.44 (SD 2.56, CI 1.0–3.0) and 6.38 (SD 7.25, CI 2.25–8.75) for negative tumors. Conclusion: SSTR2 was the only SSTR subtype to correlate with [⁶⁸Ga]Ga-DOTANOC PET/CT. Our prospective study confirms SSTR2 to be of the highest impact for SST PET/CT signal. Full article

(This article belongs to the Special Issue Current Status of Neuroendocrine Tumors with a Special Focus on Diagnosis and Novel Treatments)

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19 pages, 4998 KiB

Open AccessArticle

Gender-Specific Efficacy Revealed by Head-to-Head Comparison of Pasireotide and Octreotide in a Representative In Vivo Model of Nonfunctioning Pituitary Tumors

by Sebastian Gulde, Tobias Wiedemann, Mathias Schillmaier, Isabel Valença, Amelie Lupp, Katja Steiger, Hsi-Yu Yen, Stephen Bäuerle, Johannes Notni, Raul Luque, Herbert Schmid, Stefan Schulz, Donna P. Ankerst, Franz Schilling and Natalia S. Pellegata

Cancers 2021, 13(12), 3097; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13123097 - 21 Jun 2021

Cited by 8 | Viewed by 2854

Abstract

Invasive nonfunctioning pituitary tumors (NFPTs) are non-resectable neoplasms associated with frequent relapse and significant comorbidities. Current treatments, including somatostatin receptor 2 (SSTR2)-directed somatostatin analogs (SSAs), often fail against NFPTs. Thus, identifying effective therapies is clinically relevant. As NFPTs express SSTR3 at high levels, [...] Read more.

Invasive nonfunctioning pituitary tumors (NFPTs) are non-resectable neoplasms associated with frequent relapse and significant comorbidities. Current treatments, including somatostatin receptor 2 (SSTR2)-directed somatostatin analogs (SSAs), often fail against NFPTs. Thus, identifying effective therapies is clinically relevant. As NFPTs express SSTR3 at high levels, pasireotide, a multireceptor-targeted SSA, might be beneficial. Here we evaluated pasireotide in the only representative model of spontaneous NFPTs (MENX rats) in vivo. Octreotide long-acting release (LAR), pasireotide LAR, or placebo, were administered to age-matched, tumor-bearing MENX rats of both sexes for 28 d or 56 d. Longitudinal high-resolution magnetic resonance imaging monitored tumor growth. While tumors in placebo-treated rats increased in volume over time, PTs in drug-treated rats displayed significant growth suppression, and occasional tumor shrinkage. Pasireotide elicited stronger growth inhibition. Radiological responses correlated with tumors’ proliferation rates. Both SSAs, but especially pasireotide, were more effective in female vs. male rats. Basal Sstr3 expression was significantly higher in the former group. It is noteworthy that female human NFPTs patients also have a trend towards higher SSTR3 expression. Altogether, our studies provide the rationale for testing pasireotide in patients with residual/recurrent NFPTs. If confirmed, the sex-related SSTR3 expression might be used as criteria to stratify NFPTs patients for treatment with pasireotide. Full article

(This article belongs to the Special Issue Current Status of Neuroendocrine Tumors with a Special Focus on Diagnosis and Novel Treatments)

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Review

Jump to: Research, Other

21 pages, 3645 KiB

Open AccessReview

Diagnosis in Neuroendocrine Neoplasms: From Molecular Biology to Molecular Imaging

by Ray Manneh Kopp, Paula Espinosa-Olarte and Teresa Alonso-Gordoa

Cancers 2022, 14(10), 2514; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14102514 - 19 May 2022

Cited by 1 | Viewed by 1886

Abstract

Neuroendocrine neoplasms (NENs) are a heterogeneous group of tumours with a diverse behaviour, biology and prognosis, whose incidence is gradually increasing. Their diagnosis is challenging and a multidisciplinary approach is often required. The combination of pathology, molecular biomarkers, and the use of novel [...] Read more.

Neuroendocrine neoplasms (NENs) are a heterogeneous group of tumours with a diverse behaviour, biology and prognosis, whose incidence is gradually increasing. Their diagnosis is challenging and a multidisciplinary approach is often required. The combination of pathology, molecular biomarkers, and the use of novel imaging techniques leads to an accurate diagnosis and a better treatment approach. To determine the functionality of the tumour, somatostatin receptor expression, differentiation, and primary tumour origin are the main determining tumour-dependent factors to guide treatment, both in local and metastatic stages. Until recently, little was known about the biological behaviour of these tumours. However, in recent years, many advances have been achieved in the molecular characterization and diagnosis of NENs. The incorporation of novel radiotracer-based imaging techniques, such as ⁶⁸Gallium-DOTATATE PET-CT, has significantly increased diagnostic sensitivity, while introducing the theragnosis concept, offering new treatment strategies. Here, we will review current knowledge and novelties in the diagnosis of NENs, including molecular biology, pathology, and new radiotracers. Full article

(This article belongs to the Special Issue Current Status of Neuroendocrine Tumors with a Special Focus on Diagnosis and Novel Treatments)

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15 pages, 8800 KiB

Open AccessReview

Metastatic Neuroendocrine Neoplasms of Unknown Primary: Clues from Pathology Workup

by Carl Christofer Juhlin, Jan Zedenius and Anders Höög

Cancers 2022, 14(9), 2210; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14092210 - 28 Apr 2022

Cited by 7 | Viewed by 3308

Abstract

Neuroendocrine neoplasms (NENs) are diverse tumors arising in various anatomical locations and may therefore cause a variety of symptoms leading to their discovery. However, there are instances in which a NEN first presents clinically as a metastatic deposit, while the associated primary tumor [...] Read more.

Neuroendocrine neoplasms (NENs) are diverse tumors arising in various anatomical locations and may therefore cause a variety of symptoms leading to their discovery. However, there are instances in which a NEN first presents clinically as a metastatic deposit, while the associated primary tumor is not easily identified using conventional imaging techniques because of small primary tumor sizes. In this setting (which is referred to as a “NEN of unknown primary”; NEN-UP), a tissue biopsy is often procured to allow the surgical pathologist to diagnose the metastatic lesion. If indeed a metastatic NEN-UP is found, several clues can be obtained from morphological assessment and immunohistochemical staining patterns that individually or in concert may help identify the primary tumor site. Herein, histological and auxiliary analyses of value in this context are discussed in order to aid the pathologist when encountering these lesions in clinical practice. Full article

(This article belongs to the Special Issue Current Status of Neuroendocrine Tumors with a Special Focus on Diagnosis and Novel Treatments)

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Graphical abstract

22 pages, 2916 KiB

Open AccessReview

Pheochromocytomas and Abdominal Paragangliomas: A Practical Guidance

by Jan Calissendorff, Carl Christofer Juhlin, Irina Bancos and Henrik Falhammar

Cancers 2022, 14(4), 917; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14040917 - 12 Feb 2022

Cited by 17 | Viewed by 6452

Abstract

Pheochromocytomas and abdominal paragangliomas (PPGLs) are rare tumors arising from the adrenal medulla or the sympathetic nervous system. This review presents a practical guidance for clinicians dealing with PPGLs. The incidence of PPGLs has risen. Most cases are detected via imaging and less [...] Read more.

Pheochromocytomas and abdominal paragangliomas (PPGLs) are rare tumors arising from the adrenal medulla or the sympathetic nervous system. This review presents a practical guidance for clinicians dealing with PPGLs. The incidence of PPGLs has risen. Most cases are detected via imaging and less present with symptoms of catecholamine excess. Most PPGLs secrete catecholamines, with diffuse symptoms. Diagnosis is made by imaging and tests of catecholamines. Localized disease can be cured by surgery. PPGLs are the most heritable of all human tumors, and germline variants are found in approximately 30–50% of cases. Such variants can give information regarding the risk of developing recurrence or metastases as well as the risk of developing other tumors and may identify relatives at risk for disease. All PPGLs harbor malignant potential, and current histological and immunohistochemical algorithms can aid in the identification of indolent vs. aggressive tumors. While most patients with metastatic PPGL have slowly progressive disease, a proportion of patients present with an aggressive course, highlighting the need for more effective therapies in these cases. We conclude that PPGLs are rare but increasing in incidence and management should be guided by a multidisciplinary team. Full article

(This article belongs to the Special Issue Current Status of Neuroendocrine Tumors with a Special Focus on Diagnosis and Novel Treatments)

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18 pages, 896 KiB

Open AccessReview

Chemotherapy in Neuroendocrine Tumors

by Satya Das, Taymeyah Al-Toubah and Jonathan Strosberg

Cancers 2021, 13(19), 4872; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13194872 - 29 Sep 2021

Cited by 13 | Viewed by 5387

Abstract

The role for cytotoxic chemotherapy in patients with well-differentiated neuroendocrine tumors (NETs) remains debated. Compared to patients with poorly differentiated neuroendocrine carcinomas (NECs) where chemotherapy is utilized ubiquitously, chemotherapy may play a more select role in patients with certain types of NETs (e.g., [...] Read more.

The role for cytotoxic chemotherapy in patients with well-differentiated neuroendocrine tumors (NETs) remains debated. Compared to patients with poorly differentiated neuroendocrine carcinomas (NECs) where chemotherapy is utilized ubiquitously, chemotherapy may play a more select role in patients with certain types of NETs (e.g., pancreatic tumors, higher grade tumors, and tumors possessing DNA damage repair defects). The primary types of chemotherapy that have been tested in patients with NETs include alkylating agent- and platinum agent-based combinations. Across regimens, chemotherapy appears to elicit greater antitumor activity in patients with pancreatic or grade 3 NETs. The role for chemotherapy in lower grade extra-pancreatic NETs remains undefined. Furthermore, while chemotherapy has demonstrated clinically meaningful benefit for patients in the systemic setting, its role in the adjuvant or neoadjuvant setting is as-of-yet undetermined. Finally, efforts to combine chemotherapy with targeted therapy and peptide receptor radionuclide therapy are ongoing, in hopes of improving the cytoreductive treatment options for patients with NETs. Full article

(This article belongs to the Special Issue Current Status of Neuroendocrine Tumors with a Special Focus on Diagnosis and Novel Treatments)

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Other

Jump to: Research, Review

16 pages, 2436 KiB

Open AccessSystematic Review

Efficacy of Immune Checkpoint Inhibitors against Advanced or Metastatic Neuroendocrine Neoplasms: A Systematic Review and Meta-Analysis

by Eun-Joo Park, Hyo-Jung Park, Kyung-Won Kim, Chong-Hyun Suh, Changhoon Yoo, Young-Kwang Chae, Sree Harsha Tirumani and Nikhil H. Ramaiya

Cancers 2022, 14(3), 794; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14030794 - 04 Feb 2022

Cited by 7 | Viewed by 2048

Abstract

We performed a systematic review and meta-analysis of the treatment efficacy of immune checkpoint inhibitors (ICIs) in advanced/metastatic neuroendocrine neoplasms (NENs). MEDLINE and EMBASE were searched to identify studies that provide data on treatment response and/or survival outcomes of advanced/metastatic NEN patients treated [...] Read more.

We performed a systematic review and meta-analysis of the treatment efficacy of immune checkpoint inhibitors (ICIs) in advanced/metastatic neuroendocrine neoplasms (NENs). MEDLINE and EMBASE were searched to identify studies that provide data on treatment response and/or survival outcomes of advanced/metastatic NEN patients treated with ICIs. The overall response rate (ORR) was pooled using a random-effects model. Meta-regression was performed to explore factors influencing the ORR. Individual patient data (IPD) meta-analysis of survival was performed using stratified Cox regression. Ten studies (464 patients) were included. The overall pooled ORR was 15.5% (95% confidence interval (CI), 9.5–24.3%), and it varied according to the primary site (thoracic, 24.7%; gastro–entero–pancreatic, 9.5%), tumor differentiation (poorly differentiated, 22.7%; well-differentiated, 10.4%), and drug regimen (combination, 25.3%; monotherapy, 10.1%). All these variables significantly influenced the ORR. Tumor differentiation was associated with both overall survival and progression-free survival (hazard ratio of poorly differentiated tumors, 4.2 (95% CI, 2.0–8.7) and 2.6 (95% CI, 1.6–4.4), respectively). Thus, the treatment efficacy of ICIs for advanced/metastatic NENs varied according to primary site, tumor differentiation, and drug regimen. Poorly differentiated NENs showed a better ORR than well-differentiated NENs but had a negative impact on survival. Full article

(This article belongs to the Special Issue Current Status of Neuroendocrine Tumors with a Special Focus on Diagnosis and Novel Treatments)

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