Current best practice in the management of neuroendocrine tumors

Neuroendocrine neoplasms are rare tumors that display marked heterogeneity with varying natural history, biological behavior, response to therapy and prognosis. Their management is complex, particularly as a number of them may be associated with a secretory syndrome and involve a variety of options. A number of factors such as proliferation rate, degree of differentiation, functionality and extent of the disease are mostly utilized to tailor treatment accordingly, ideally in the context of a multidisciplinary team. In addition, a number of relevant scientific societies have published therapeutic guidelines in an attempt to direct and promote evidence-based treatment. Surgery remains the treatment of choice with an intention to cure while it may also be recommended in some cases of metastatic disease and difficult to control secretory syndromes. Long-acting somatostatin analogs constitute the main treatment for the majority of functioning tumors, whereas specific evolving agents such as telotristat may be used for the control of carcinoid syndrome and related sequelae. In patients with advanced disease not amenable to surgical resection, treatment options include locoregional therapies, long-acting somatostatin analogs, molecular targeted agents, radionuclides, chemotherapy and recently immunotherapy, alone or in combination. However, the ideal time of treatment initiation, sequence of administration of different therapies and identification of robust prognostic markers to select the most appropriate treatment for each individual patient still need to be defined.

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Medical Treatment of Advanced Pancreatic Neuroendocrine Neoplasms

Journal of Clinical Medicine ◽

10.3390/jcm9061860 ◽

2020 ◽

Vol 9 (6) ◽

pp. 1860

Author(s):

Lola-Jade Palmieri ◽

Solène Dermine ◽

Amélie Barré ◽

Marion Dhooge ◽

Catherine Brezault ◽

...

Keyword(s):

Medical Treatment ◽

Treatment Options ◽

Somatostatin Analogs ◽

Treatment Algorithm ◽

Proliferation Index ◽

Neuroendocrine Neoplasms ◽

Ki 67 ◽

Pancreatic Neuroendocrine Neoplasms ◽

Histologic Differentiation ◽

Surgical Treatments

Pancreatic neuroendocrine neoplasms (panNENs) are relatively rare but their incidence has increased almost sevenfold over the last four decades. Neuroendocrine neoplasms are classified according to their histologic differentiation and their grade. Their grade is based on their Ki-67 proliferation index and mitotic index. Their prognosis is highly variable according to these elements and treatments also vary according to their classification. Surgery is the only curative treatment for localized and advanced panNENs and offers a better prognosis than non-surgical treatments. In the case of an advanced panNEN without the possibility of resection and/or ablation, medical treatment remains the cornerstone for improving survival and preserving quality-of-life. PanNENs are considered as chemosensitive tumors, unlike midgut neuroendocrine tumors. Thus, panNENs can be treated with chemotherapy, but targeted therapies and somatostatin analogs are also treatment options. The scarcity and heterogeneity of NENs make their management difficult. The present review aims to clarify the medical treatments currently available for advanced panNENs, based on their characteristics, and to propose a treatment algorithm.

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Well-differentiated gastroenteropancreatic G3 NET: findings from a large single centre cohort

Scientific Reports ◽

10.1038/s41598-021-97247-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

K. Lithgow ◽

H. Venkataraman ◽

S. Hughes ◽

H. Shah ◽

J. Kemp-Blake ◽

...

Keyword(s):

Primary Tumour ◽

Somatostatin Receptor ◽

Somatostatin Analogs ◽

Treatment Strategies ◽

Biological Behavior ◽

Queen Elizabeth Hospital ◽

Neuroendocrine Neoplasms ◽

Single Centre ◽

Net G3 ◽

Well Differentiated

AbstractNeuroendocrine neoplasms are known to have heterogeneous biological behavior. G3 neuroendocrine tumours (NET G3) are characterized by well-differentiated morphology and Ki67 > 20%. The prognosis of this disease is understood to be intermediate between NET G2 and neuroendocrine carcinoma (NEC). Clinical management of NET G3 is challenging due to limited data to inform treatment strategies. We describe clinical characteristics, treatment, and outcomes in a large single centre cohort of patients with gastroenteropancreatic NET G3. Data was reviewed from 26 cases managed at Queen Elizabeth Hospital, Birmingham, UK, from 2012 to 2019. Most commonly the site of the primary tumour was unknown and majority of cases with identifiable primaries originated in the GI tract. Majority of cases demonstrated somatostatin receptor avidity. Median Ki67 was 30%, and most cases had stage IV disease at diagnosis. Treatment options included surgery, somatostatin analogs (SSA), and chemotherapy with either platinum-based or temozolomide-based regimens. Estimated progression free survival was 4 months following initiation of SSA and 3 months following initiation of chemotherapy. Disease control was observed following treatment in 5/11 patients treated with chemotherapy. Estimated median survival was 19 months; estimated 1 year survival was 60% and estimated 2 year survival was 13%. NET G3 is a heterogeneous group of tumours and patients which commonly have advanced disease at presentation. Prognosis is typically poor, though select cases may respond to treatment with SSA and/or chemotherapy. Further study is needed to compare efficacy of different treatment strategies for this disease.

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MicroRNAs and Treatment with Somatostatin Analogs in Gastro- Entero-Pancreatic Neuroendocrine Neoplasms: Challenges in Personalized Medicine

Journal of Gastrointestinal and Liver Diseases ◽

10.15403/jgld-2866 ◽

2020 ◽

Vol 29 (4) ◽

pp. 647-659

Author(s):

Ana Maria Curt ◽

Ioana Rada Popa Ilie ◽

Calin Cainap ◽

Ovidiu Balacescu ◽

Cristina Ghervan

Keyword(s):

Signaling Pathway ◽

Molecular Mechanisms ◽

Residual Disease ◽

Somatostatin Analogs ◽

Predictive Biomarkers ◽

Response To Therapy ◽

Neuroendocrine Neoplasms ◽

Clinical Approach ◽

Pancreatic Neuroendocrine Neoplasms ◽

Potential Clinical Benefit

Molecular predictive biomarkers represent an essential tool for the future of personalized oncotherapy. Gastro-entero-pancreatic neuroendocrine neoplasms are a heterogeneous group of epithelial tumors with a steadyincrease in incidence and prevalence. Their effective management depends on early diagnosis, personalizedrisk stratification, and monitoring response to therapy. A crucial element is identifying accurate biomarkers topredict/monitor therapeutic responses, assess drug resistance, and quantify residual disease in a reproducibleand less invasive way. Taking into consideration their role in cell differentiation, cell proliferation, apoptosisand tumor development, microRNAs have gained interest as potential prognostic markers and treatmentresponse predictors in neuroendocrine neoplasms. This review is the first to summarize the available dataon the possible role of microRNAs in evaluating the efficacy of somatostatin analogs treatment in gastro-entero-pancreatic neuroendocrine neoplasms. Although the literature is scarce, the let-7 family targetingphosphoinositide 3 kinase – protein kinase B 1 – mammalian target of rapamycin signaling pathway mightrepresent a promising biomarker with potential clinical benefit, but further research is required beforetheir eventual clinical application. Furthermore, the ambiguous molecular mechanisms of neuroendocrineproliferation and the undefined signaling pathway of somatostatin analogs should encourage future researchin this field that may lead to a different clinical approach to neuroendocrine disease.

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A systematic review and meta-analysis of the efficacy and safety of long-acting release somatostatin analogs in patients with advanced neuroendocrine neoplasms

Translational Cancer Research ◽

10.21037/tcr.2016.09.43 ◽

2016 ◽

Vol 5 (5) ◽

pp. 504-511

Author(s):

Jiabin Zheng ◽

Junjiang Wang ◽

Xingyu Feng ◽

Yong Li

Keyword(s):

Systematic Review ◽

Meta Analysis ◽

Somatostatin Analogs ◽

Neuroendocrine Neoplasms ◽

Efficacy And Safety ◽

Long Acting

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From Rheumatoid Factor to Anti-Citrullinated Protein Antibodies and Anti-Carbamylated Protein Antibodies for Diagnosis and Prognosis Prediction in Patients with Rheumatoid Arthritis

International Journal of Molecular Sciences ◽

10.3390/ijms22020686 ◽

2021 ◽

Vol 22 (2) ◽

pp. 686

Author(s):

Chao-Yi Wu ◽

Huang-Yu Yang ◽

Shue-Fen Luo ◽

Jenn-Haung Lai

Keyword(s):

Rheumatoid Arthritis ◽

Treatment Options ◽

Clinical Manifestations ◽

Bone Destruction ◽

Response To Therapy ◽

Current Evidence ◽

Prognosis Prediction ◽

Diagnosis And Prognosis ◽

Systemic Inflammatory Disease ◽

Citrullinated Protein

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease mainly involving synovial inflammation and articular bone destruction. RA is a heterogeneous disease with diverse clinical presentations, prognoses and therapeutic responses. Following the first discovery of rheumatoid factors (RFs) 80 years ago, the identification of both anti-citrullinated protein antibodies (ACPAs) and anti-carbamylated protein antibodies (anti-CarP Abs) has greatly facilitated approaches toward RA, especially in the fields of early diagnosis and prognosis prediction of the disease. Although these antibodies share many common features and can function synergistically to promote disease progression, they differ mechanistically and have unique clinical relevance. Specifically, these three RA associating auto-antibodies (autoAbs) all precede the development of RA by years. However, while the current evidence suggests a synergic effect of RF and ACPA in predicting the development of RA and an erosive phenotype, controversies exist regarding the additive value of anti-CarP Abs. In the present review, we critically summarize the characteristics of these autoantibodies and focus on their distinct clinical applications in the early identification, clinical manifestations and prognosis prediction of RA. With the advancement of treatment options in the era of biologics, we also discuss the relevance of these autoantibodies in association with RA patient response to therapy.

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Does combination of “cold” and “hot” somatostatin analogs prolong survival of patients with neuroendocrine neoplasms?

Endocrine Journal ◽

10.1507/endocrj.ej16-0219 ◽

2017 ◽

Vol 64 (2) ◽

pp. 171-177 ◽

Cited By ~ 1

Author(s):

Anna Sowa-Staszczak ◽

Agnieszka Stefanska ◽

Pawel Chrapczynski ◽

Malgorzata Trofimiuk-Müldner ◽

Miroslaw Szura ◽

...

Keyword(s):

Somatostatin Analogs ◽

Neuroendocrine Neoplasms

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Octreotide promotes apoptosis in human somatotroph tumor cells by activating somatostatin receptor type 2

Endocrine Related Cancer ◽

10.1677/erc.1.01191 ◽

2006 ◽

Vol 13 (3) ◽

pp. 955-962 ◽

Cited By ~ 67

Author(s):

E Ferrante ◽

C Pellegrini ◽

S Bondioni ◽

E Peverelli ◽

M Locatelli ◽

...

Keyword(s):

Tumor Cells ◽

Cultured Cells ◽

Somatostatin Receptor ◽

Hormone Secretion ◽

Somatostatin Analogs ◽

Receptor Type ◽

Apoptotic Activity ◽

Long Acting ◽

Induced Apoptosis

Somatostatin analogs currently used in the treatment of acromegaly and other neuroendocrine tumors inhibit hormone secretion and cell proliferation by binding to somatostatin receptor type (SST) 2 and 5. The antiproliferative pathways coupled to these receptors have been only partially characterized. The aim of this study was to evaluate the effect of octreotide and super selective SST2 (BIM23120) and SST5 (BIM23206) analogs on apoptotic activity and apoptotic gene expression in human somatotroph tumor cells. Eight somatotroph tumors expressing similar levels of SST2 and SST5 evaluated by real-time PCR and western blot analyses were included in the study. In cultured cells obtained from these tumors, octreotide induced a dose-dependent increase of caspase-3 activity (160 ± 20% vs basal at 10 nM) and cleaved cytokeratin 18 levels (172 ± 25% vs basal) at concentrations higher than 0.1 nM. This effect was due to SST2 activation since BIM23120 elicited comparable responses, while BIM23206 was ineffective. BIM23120-stimulated apoptosis was dependent on phosphatases, since it was abrogated by the inhibitor orthovanadate, and independent from the induction of apoptosis-related genes, such as p53, p63, p73, Bcl-2, Bax, BID, BIK, TNFSF8, and FADD. In somatotroph tumors, both BIM23120 and BIM2306 caused growth arrest as indicated by the increase in p27 and decrease in cyclin D1 expression. In conclusion, the present study showed that octreotide-induced apoptosis in human somatotroph tumor cells by activating SST2. This effect, together with the cytostatic action exerted by both SST2 and SST5 analogs, might account for the tumor shrinkage observed in acromegalic patients treated with long-acting somatostatin analogs.

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An update on the treatment of cutaneous tumours

UK-Vet Equine ◽

10.12968/ukve.2021.5.6.247 ◽

2021 ◽

Vol 5 (6) ◽

pp. 247-252

Author(s):

Anna Hollis

Keyword(s):

Treatment Options ◽

Surgical Excision ◽

Careful Consideration ◽

Limited Data ◽

Clinical Appearance ◽

Clinical Challenge ◽

Number Of Factors ◽

Intralesional Treatment ◽

New Treatment ◽

Number Of Treatment

Cutaneous tumours continue to present a significant clinical challenge in equine practice. There are a large number of treatment options and selecting the appropriate modality requires careful consideration of a number of factors. While sarcoids are the most commonly diagnosed cutaneous tumour, their clinical appearance can have considerable overlap with other types of lesion, so biopsy should be performed where the diagnosis is uncertain. New treatment options for sarcoids include electrosurgery, electrochemotherapy and novel intralesional treatments. Melanomas still have relatively limited treatment options beyond surgical resection, but there are now limited data to support the use of a xenogenic DNA vaccination protocol. Squamous cell carcinomas are generally best treated via surgical excision, but a novel intralesional treatment may prove to be a useful option for further treatment.

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Multistage Openhole Completion Using Integrated Dynamic Diversion Frac Technique in Highly Depleted Well: First Successful Application in West Kuwait Field

10.2118/205531-ms ◽

2021 ◽

Author(s):

Abdullah Abu-Eida ◽

Salem Al-Sabea ◽

Milan Patra ◽

Bader Akbar ◽

Kutbuddin Bhatia ◽

...

Keyword(s):

Best Practice ◽

Treatment Options ◽

High Energy ◽

Lessons Learned ◽

High Potential ◽

Fracture Plane ◽

Fluid Loss ◽

Field Development ◽

Two Fluids

Abstract The Minagish field in West Kuwait is a high potential field which poses several challenges in terms of hydrocarbon flow assurance through highly depleted tight carbonate intervals with uneven reservoir quality and curtailed mobility. These conditions have shifted the field development from vertical to horizontal wellbore completions. Achieving complete wellbore coverage is a challenge for any frac treatment performed in a long openhole lateral with disparities in reservoir characteristics. The fluid will flow into the path of least resistance leaving large portions of the formation untreated. As a result, economic fracturing treatment options dwindle significantly, thus reservoir stimulation results are not always optimum. A multistage fracturing technique using Integrated Dynamic Diversion (IDD) has been performed first time in West Kuwait field well. The process uses active fluid energy to divert flow into a specific fracture point in the lateral, which can initiate and precisely place a fracture. The process uses two self-directed fluid streams: one inside the pipe and one in the annulus. The process mixes the two fluids downhole with high energy to form a consistent controllable mixture. The technique includes pinpoint fluid jetting at the point of interest, followed by in-situ HCL based crosslinked systems employed for improving individual stage targets. The IDD diversion shifts the fracture to unstimulated areas to create complex fractures which increases reservoir contact volume and improved overall conductivity in the lateral. The kinetic and chemical diversion of the IDD methodology is highly critical to control fluid loss in depleted intervals and results in enhanced stimulation. Pumping a frac treatment in openhole without control would tend to initiate a longitudinal fracture along the wellbore and may restrict productivity. By using specialized completion tools with nozzles at the end of the treating string, a new pinpoint process has been employed to initiate a transverse fracture plane in IDD applications. Proper candidate selection and fluid combination with in-situ crosslink acid effectively plug the fracture generated previously and generate pressure high enough to initiate another fracture for further ramification. By combining these processes into one continuous operation, the use of wireline/coiled tubing for jetting, plug setting and milling is eliminated, making the new multistage completion technology economical for these depleted wells. The application of the IDD methodology is a fit-for-purpose solution to address the unique challenges of openhole operations, formation technical difficulties, high-stakes economics, and untapped high potential from intermittent reservoirs. The paper will present post-operation results of this completion from all fractured zones along the lateral and will describe the lessons learned in implementation of this methodology which can be considered as best practice for application in similar challenges in other fields.

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