Gastroenteropancreatic Tumors Research Articles

Improving susceptibility of neuroendocrine tumors to radionuclide therapies: personalized approaches towards complementary treatments.

Radionuclide therapies are an important tool for the management of patients with neuroendocrine neoplasms (NENs). Especially [131I]MIBG and [177Lu]Lu-DOTA-TATE are routinely used for the treatment of a subset of NENs, including pheochromocytomas, paragangliomas and gastroenteropancreatic tumors. Some patients suffering from other forms of NENs, such as medullary thyroid carcinoma or neuroblastoma, were shown to respond to radionuclide therapy; however, no general recommendations exist. Although [131I]MIBG and [177Lu]Lu-DOTA-TATE can delay disease progression and improve quality of life, complete remissions are achieved rarely. Hence, better individually tailored combination regimes are required. This review summarizes currently applied radionuclide therapies in the context of NENs and informs about recent advances in the development of theranostic agents that might enable targeting subgroups of NENs that previously did not respond to [131I]MIBG or [177Lu]Lu-DOTA-TATE. Moreover, molecular pathways involved in NEN tumorigenesis and progression that mediate features of radioresistance and are particularly related to the stemness of cancer cells are discussed. Pharmacological inhibition of such pathways might result in radiosensitization or general complementary antitumor effects in patients with certain genetic, transcriptomic, or metabolic characteristics. Finally, we provide an overview of approved targeted agents that might be beneficial in combination with radionuclide therapies in the context of a personalized molecular profiling approach.

Survival rates in metastatic gastroenteropancreatic neoplasms after multidisciplinary approach

Survival rates in metastatic gastroenteropancreatic neoplasms after multidisciplinary approach

Efficacy of [177Lu]Lu-DOTATATE in metastatic neuroendocrine neoplasms of different locations: data from the SEPTRALU study

BackgroundPeptide receptor radionuclide therapy (PRRT) is one of the most promising therapeutic strategies in neuroendocrine neoplasms (NENs). Nevertheless, its role in certain tumor sites remains unclear. This study sought to elucidate the efficacy and safety of [177Lu]Lu-DOTATATE in NENs with different locations and evaluate the effect of the tumor origin, bearing in mind other prognostic variables. Advanced NENs overexpressing somatostatin receptors (SSTRs) on functional imaging, of any grade or location, treated at 24 centers were enrolled. The protocol consisted of four cycles of 177Lu-DOTATATE 7.4 GBq iv every 8 weeks (NCT04949282).ResultsThe sample comprised 522 subjects with pancreatic (35%), midgut (28%), bronchopulmonary (11%), pheochromocytoma/ paraganglioma (PPGL) (6%), other gastroenteropancreatic (GEP) (11%), and other non-gastroenteropancreatic (NGEP) (9%) NENs. The best RECIST 1.1 responses were complete response, 0.7%; partial response, 33.2%; stable disease, 52.1%; and tumor progression, 14%, with activity conditioned by the tumor subtype, but with benefit in all strata. Median progression-free survival (PFS) was 31.3 months (95% CI, 25.7–not reached [NR]) in midgut, 30.6 months (14.4-NR) in PPGL, 24.3 months (18.0-NR) in other GEP, 20.5 months (11.8-NR) in other NGEP, 19.8 months (16.8–28.1) in pancreatic, and 17.6 months (14.4–33.1) in bronchopulmonary NENs. [177Lu]Lu-DOTATATE exhibited scant severe toxicity.ConclusionThis study confirms the efficacy and safety of [177Lu]Lu-DOTATATE in a wide range of SSTR-expressing NENs, regardless of location, with clinical benefit and superimposable survival outcomes between pNENs and other GEP and NGEP tumor subtypes different from midgut NENs.

Evaluation of chromatin remodelers in pancreatic neuroendocrine neoplasms.

652 Background: Pancreatic neuroendocrine neoplasms (PanNENs) are rare entities comprising 1-2% of gastroenteropancreatic neoplasms with an annual incidence of 0.48/100,000 population in the world. The molecular pathways underpinning the entity are less explored owing to its rarity. We aimed to analyse and correlate the expression of chromatin remodelers in PanNENs from Indian subcontinent. Methods: An ambispective study (prospective 2014-2018 as well as retrospective 2018-2021) was conducted. Haematoxylin and eosin stained slides with immunohistochemistry slides (chromogranin, synaptophysin) of 73 cases of PanNENs were retrieved from archives of Department of Pathology, AlIMS, New Delhi and evaluated for assessment of histopathological parameters. Following slide review, grading and staging were done based on WHO 2017 Classification and AJCC eighth edition respectively. Representative formalin fixed paraffin embedded block was selected after slide review and retrieved for performing immunohistochemical staining with antibodies against ATRX, DAXX, SETD2, H3K36Me3 and ARID1A using Ultra Vision Quanto polymer detection system by Thermo Fisher Scientific. Data was analysed using STATA version SE14. Results: Study cohort of 73 PanNENs had a mean age of presentation 41 years (Range: 8 years -70 years) and male to female ratio of 1.43:1. Majority of the tumors in our study were non functional (63.01%). Loss of nuclear expression of ATRX/DAXX (at least one marker) was seen in 26/73 (35.62%) cases. Loss of expression had significant correlation with pathological stage of the tumor, presence of distant metastasis and adverse prognostic outcome (p value-<0.05). Lower grade tumors with low to intermediate ki67 index had higher preponderance for loss of expression of ARID1A. Loss of expression of any of the chromatin remodelers (ATRX/DAXX/ARID1A/H3K36Me3) was noted in 44/73 cases (60.27%) and was more frequently associated with advanced stage of tumor or recurrence/metastasis/death (p value-0.005). Conclusions: Loss of chromatin remodelers such as ATRX, DAXX, ARID1A, SETD2 and H3K36ME3 is involved in the pathogenesis of pancreatic neuroendocrine neoplasms and are associated with adverse outcomes, so loss or lower immunohistochemical expression for these can serve as a poor prognostic factor and guide for adjuvant therapy.

Characterization of circulating immune cells and correlation with Tie2/Angiopoietins level in well differentiated neuroendocrine gastroenteropancreatic tumors: a cross-sectional analysis.

The immune environment represents a new, but little explored, tool for understanding neuroendocrine neoplasms (NENs) behavior. An immunosuppressed microenvironment is hypothesized to promote NENs progression. A missing profiling of circulating leukocyte and peripheral blood mononuclear cells (PBMCs) subpopulations would open new perspectives in the still limited diagnostic-therapeutic management of NENs. A cross-sectional case-control pilot study was performed recruiting 30 consecutive subjects: 15 patients naïve to treatment, with histologically proven gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) and 15 healthy controls, matched for age and sex. PBMCs subpopulations were studied by flow cytometry. Soluble Tie2 (sTie2), Angiopoietin-1 (Ang-1), Angiopoietin-2 (Ang-2) were evaluated by ELISA. Immune cell profiling revealed a significant lower CD3-CD56+ natural killer (NK) cell count in NETs vs controls (p = 0.04). NK subset analysis showed a reduced relative count of CD56+CD16+ NK cells (p =0.002) in NETs vs controls. Patients with NET showed a higher percentage of CD14+CD16++ non-classical monocytes (p = 0.01), and a lower percentage of CD14+CD16+ intermediate monocytes (p = 0.04). A decrease in percentage (p = 0.004) of CD4+ T-helper lymphocytes was found in NET patients. Evaluation of cellular and serum angiopoietin pathway mediators revealed in NET patients a higher relative count of Tie2-expressing monocytes (TEMs) (p < 0.001), and high levels of Ang-1 (p = 0.003) and Ang-2 (p = 0.002). Patients with GEP-NET presented an immunosuppressed environment characterized by a low count of cytotoxic NK cells, a high count of anti-inflammatory non-classical monocytes, and a low count of T-helper lymphocytes. Higher levels of TEMs and angiopoietins suggest a crosstalk between innate immunity and angiogenic pathways in NETs.

Targeted treatment with somatostatin analogues: widening horizons of clinical practice

Targeted treatment with somatostatin analogues (SA) in acromegaly and neuroendocrine neoplasms may have some benefits compared to curative treatments, because these agents decrease excessive hormone secretion and exert a tumor-suppressive effect. Monotherapy and combination therapy with SA is well tolerated and bears no risk of debilitating iatrogenic complications. In acromegaly caused by somatotropin producing pituitary tumor, first generation SA are treatment of choice after non-radical adenomectomy, as well as in the cases when patients reject surgery. Treatment efficacy depends on the pathomorphological types of somatotropic tumors, which are different in their receptor phenotype, clinical scenario and proliferative activity. The first generation SA are successfully used for medical treatment of other pituitary tumors (thyrotropic, corticotropic, gonadotropic, lactotropic with resistance to dopamine agonists), as well as for adjuvant therapy of neuroendocrine and non-endocrine neoplasms and elimination of various gastrointestinal disorders. The anti-secretory and anti-tumor effects of SA have been proven for gastroenteropancreatic tumors (carcinoid syndrome, vipomas, gastrinomas, insulinomas, glucagonomas, somatostatinomas). Targeted selection of patients for treatment with first generation SA based on the receptor phenotypes of malignant cells would facilitate more rapid achievement of biochemical remission, improvement of quality of life and survival.

Morphological and immunohistochemical features of neuroendocrine neoplasms in gastroenteropancreatic tract

Background and AimsNeuroendocrine neoplasms (NENs) result from neuroendocrine cell neoplastic proliferation, with both characteristics of endocrine and nerve cells. NENs arise in different localizations but the most common site is the gastrointestinal tract, including the pancreas. The morphology and frequency of NENs in our hospital were evaluated, as well as the correlation between lymph node status and Ki67 proliferative index. Materials and MethodsRetrospectively, we analyzed NEN pathohistological reports of patients who underwent surgical excision of gastroenteropancreatic tumors in the Clinical Center of Vojvodina in Novi Sad, from 2011 to 2018. The descriptive and correlation statistics were done. Chromogranin A, synaptophysin, CD56, and Ki67 were usually used as immunohistochemical markers. ResultsThe study registered 78 surgical specimens. The average age of patients was 58.88 (±17) years, whereby 53.8% were males. The most frequent site was the pancreas (29.5%), followed by the large intestine (26.9%). The mean tumor size was 3.71 (±3.13) cm. No significance was found in tumor differentiation degree (G1 = 32.1%, G2 = 26.9%, and G3 = 29.5%). Lymph node metastases were found in 47.44%. Positive correlation was found between the Ki67 index and the percentage of positive lymph nodes (r = 0.343, p = 0.046, p < 0.05, respectively). The correlation between tumor size and lymph node metastases revealed no significance in our study (r = 0.015, p = 0.480, p > 0.05, respectively). ConclusionMost NENs lymph node metastases originated from tumors with a high Ki67 index. The results confirm the use of proliferative index Ki67 as a prognostic marker for the presence of metastases, disease progression, and neuroendocrine tumor prognosis.

GFAP-directed Inactivation of Men1 Exploits Glial Cell Plasticity in Favor of Neuroendocrine Reprogramming.

Background & AimsEfforts to characterize the signaling mechanisms that underlie gastroenteropancreatic neoplasms (GEP-NENs) are precluded by a lack of comprehensive models that recapitulate pathogenesis. Investigation into a potential cell-of-origin for gastrin-secreting NENs revealed a non-cell autonomous role for loss of menin in neuroendocrine cell specification, resulting in an induction of gastrin in enteric glia. Here, we investigated the hypothesis that cell autonomous Men1 inactivation in glial fibrillary acidic protein (GFAP)-expressing cells induced neuroendocrine differentiation and tumorigenesis.MethodsTransgenic GFAPΔMen1 mice were generated by conditional GFAP-directed Men1 deletion in GFAP-expressing cells. Cre specificity was confirmed using a tdTomato reporter. GFAPΔMen1 mice were evaluated for GEP-NEN development and neuroendocrine cell hyperplasia. Small interfering RNA-mediated Men1 silencing in a rat enteric glial cell line was performed in parallel.ResultsGFAPΔMen1 mice developed pancreatic NENs, in addition to pituitary prolactinomas that phenocopied the human MEN1 syndrome. GFAPΔMen1 mice exhibited gastric neuroendocrine hyperplasia that coincided with a significant loss of GFAP expression. Men1 deletion induced loss of glial-restricted progenitor lineage markers and an increase in neuroendocrine genes, suggesting a reprogramming of GFAP+ cells. Deleting Kif3a, a mediator of Hedgehog signaling, in GFAP-expressing cells attenuated neuroendocrine hyperplasia by restricting the neuroendocrine cell fate. Similar results in the pancreas were observed when Sox10 was used to delete Men1.ConclusionsGFAP-directed Men1 inactivation exploits glial cell plasticity in favor of neuroendocrine differentiation.

Increase of Ki-67 index and influence on mortality in patients with neuroendocrine neoplasms.

An increase in the Ki-67 index in neuroendocrine neoplasms over time in relation to prognosis has scarcely been investigated. We aimed to assess whether the Ki-67 index changed over time and also whether a change influenced prognosis. Second, we investigated the difference in the Ki-67 index between primary tumour and metastases. From 1 January 1995 to 31 December 2019, 108 consecutive patients with gastroenteropancreatic tumours were included. Patients were followed with regard to an increase in the Ki-67 index and all-cause mortality. Ki-67 determination of the primary tumour at diagnosis and at the time of radiological progression, including developed metastases, was performed. A significant increase in the Ki-67 index was defined as a doubling of the value at disease progression compared to the value at diagnosis. In addition, in 14 patients, the Ki-67 index of the primary tumour and present metastases at the time of diagnosis was investigated. At diagnosis, there were no differences in the Ki-67 index between primary tumours and metastases (P=.41). Sixty-five patients had a doubling of the Ki-67 index. The median Ki-67 index at the time of progression 17% (1%-90%) vs 5% (1%-60%) at the time of diagnosis (P=.006). A doubling of the Ki-67 index was independently associated with all-cause mortality (hazard ratio = 2.7 [1.3-6.3], P=0.02), after adjustment for relevant co-variables including the Ki-67 index at baseline. Doubling of the Ki-67 index at the time of disease progression was associated with a significantly higher risk of all-cause mortality. We recommend that a Ki-67 index is obtained whenever disease progression is recorded by demonstrated progression because it may have impact on the choice of treatment.

Progress in diagnosing and treating gastroenteropancreatic neoplasms

<p indent=0mm>Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are a group of highly heterogeneous malignancies originating from the diffuse neuroendocrine system, and their incidence has gradually increased in the past <sc>30 years.</sc> The results of molecular biological studies indicate that NENs of different grades and primary sites have distinct molecular characteristics and are responsible for the heterogeneity of clinical manifestations. Surgery remains the method to cure localized GEP-NENs, and prospective clinical study results support no adjuvant therapy. Treating advanced GEP-NENs requires multidisciplinary collaboration, including symptom and tumor proliferation control. Systemic treatment options for patients with metastatic well-differentiated neuroendocrine tumors (NETs) have expanded considerably. However, treating advanced poorly-differentiated neuroendocrine carcinomas (NECs) lacks prospective randomized controlled study outcomes. Platinum-based chemotherapy is the preferred first-line treatment, and the role of immune checkpoint inhibitors still needs to be confirmed by further studies. The present report reviews the recent research progress in GEP-NENs.

P124 Gastroenteropancreatic Neuroendocrine Neoplasms in patients with Inflammatory Bowel Disease: An ECCO CONFER Multicentre Case Series

Abstract Background Neuroendocrine Neoplasms (NENs) are a heterogeneous group of tumours deriving from the diffuse endocrine system. NENs may occur almost everywhere in the body but are most common in the gastrointestinal tract, the pancreas, and the lungs, with gastroenteropancreatic (GEP) tumours representing 70% of all NENs. GEP-NENs have rarely been reported in association with inflammatory bowel diseases (IBDs) but no definitive relationship between these tumours and IBD has been established Methods This was an ECCO COllaborative Network For Exceptionally Rare case reports project (ECCO-CONFER). We included cases of GEP-NENs diagnosed in patients with IBD that met the diagnostic criteria for NEN according to the European Neuroendocrine Tumour Society. Data were retrospectively collected in a standardized case report form and analysed for event association with patient’s and IBD-related factors Results GEP-NEN was diagnosed in 100 patients with IBD [61% female, 55% Crohn’s disease, median age 48 years (IQR 37–59)]. Overall the most common location was the appendix (39/100) followed by the colon (22/100). Complete IBD-related data was available for 50 individuals with a median follow-up of 30.5 months (IQR 11.2–70) following NEN diagnosis. At the last follow-up data, 47/50 patients were alive. Three deaths occurred, of which 2 were related to NEN. Median duration of IBD at NEN diagnosis was 84 months (IQR 10–151), and in 18% of cases NEN and IBD were diagnosed concomitantly. 20/50 of NENs were at stage I (T1N0M0) and 28/50 graded G1 (ki 67 ≤2 %) at diagnosis. Incidental diagnosis of NEN either during follow-up or during surgery as well as receiving diagnosis of NEN concomitantly with IBD was significantly associated with an earlier NEN stage (p&amp;lt; 0.01 and p&amp;lt;0.02, respectively). Exposure to immunomodulatory and/or biologic therapy was not associated with advanced NEN stage or grade. Interestingly, primary GEP-NEN sites significantly correlated to the segment affected by IBD (62% vs 38% p = 0.02) Conclusion In the largest case series to date, prognosis of patients with concomitant GEP-NEN and IBD seems favorable. Incidental NEN diagnosis correlates with an earlier NEN stage and IBD-related therapies are independent of NEN stage and grade. The association of GEP-NEN location and the segment affected by IBD may suggest a possible role of inflammation in NEN tumorigenesis

Apparent Diffusion Coefficient Values for Neuroendocrine Liver Metastases

We aimed to investigate whether there are any differences in apparent diffusion coefficient (ADC) values obtained from liver metastases due to gastroenteropancreatic neuroendocrine tumors (GEP-NET) and adenocarcinomas. We included 54 patients with 167 liver metastases due to gastroenteropancreatic tumors. We divided the patients into two groups as liver metastases due to GEP-NETs (seven patients with 51 lesions, mean age: 48) and adenocarcinomas (47 patients with 116 lesions, mean age: 61.2). We used the independent samples t-test to compare the ADC and ADCmean values of the two groups and performed a receiver-operating characteristic analysis. ADC and ADCmean values were significantly lower in the GEP-NET group compared with the adenocarcinoma group. Receiver-operating characteristic curve analysis showed a significant difference for ADC and ADCmean values, and area under the curve values were 0.733 and 0.790, respectively. The cut-off values were 933x10-6 mm2/s for ADC and 801x10-6 mm2/s for ADCmean. Diagnostic accuracies of ADC (Sensitivity = 80.2, Specificity = 64.7, PPV = 83.8, NPV = 58.9) and ADCmean (Sensitivity = 63.8, Specificity = 82.4, PPV = 89.2, NPV = 50) were calculated in differentiating adenocarcinoma metastases from GEP-NET metastases. The lower ADC and ADCmean values of liver metastases suggest GEP-NET rather than adenocarcinomas. ADC and ADCmean values obtained from liver metastases may be used to differentiate NETs from adenocarcinomas.

Quality of life in patients with gastroenteropancreatic tumours: A systematic literature review.

BACKGROUNDGastroenteropancreatic neuroendocrine tumours (GEP-NETs) are slow-growing cancers that arise from diffuse endocrine cells in the gastrointestinal tract (GI-NETs) or the pancreas (P-NETs). They are relatively uncommon, accounting for 2% of all gastrointestinal malignancies. The usual treatment options in advanced GEP-NET patients with metastatic disease include chemotherapy, biological therapies, and peptide receptor radionuclide therapy. Understanding the impact of treatment on GEP-NET patients is paramount given the nature of the disease. Health-related quality of life (HRQoL) is increasingly important as a concept reflecting the patients’ perspective in conjunction with the disease presentation, severity and treatment.AIMTo conduct a systematic literature review to identify literature reporting HRQoL data in patients with GEP-NETs between January 1985 and November 2019.METHODSThe PRISMA guiding principles were applied. MEDLINE, Embase and the Cochrane library were searched. Data extracted from the publications included type of study, patient population data (mid-gut/hind-gut/GI-NET/P-NET), sample size, intervention/comparators, HRQoL instruments, average and data spread of overall and sub-scores, and follow-up time for data collection.RESULTSForty-three publications met the inclusion criteria. The heterogeneous nature of the different study populations was evident; the percentage of female participants ranged between 30%-60%, whilst average age ranged from 53.8 to 67.0 years. Eight studies investigated GI-NET patients only, six studies focused exclusively on P-NET patients and the remaining studies involved both patient populations or did not report the location of the primary tumour. The most commonly used instrument was the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (n = 28) with consistent results across studies; the GI-NET-specific module Quality of Life Questionnaire-GINET21 was used in six of these studies. A number of randomised trials demonstrated no HRQoL changes between active treatment and placebo arms. The Phase III NETTER-1 study provides the best data available for advanced GEP-NET patients; it shows that peptide receptor radionuclide therapy can significantly improve GEP-NET patients’ HRQoL.CONCLUSIONHRQoL instruments offer a means to monitor patients’ general disease condition, disease progression and their physical and mental well-being. Instruments including the commonly used European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 and GINET21 lack, however, validation and a defined minimal clinical important difference specifically for GI-NET and P-NET patients.

Immunohistochemistry in the diagnosis and classification of neuroendocrine neoplasms: what can brown do for you?

This review is based on a presentation given at the Hans Popper Hepatopathology Society companion meeting at the 2019 United States and Canadian Academy of Pathology Annual Meeting. It presents updates on the diagnosis and classification of neuroendocrine neoplasms, with an emphasis on the role of immunohistochemistry. Neuroendocrine neoplasms often present in liver biopsies as metastases of occult origin. Specific topics covered include 1. general features of neuroendocrine neoplasms, 2. general neuroendocrine marker immunohistochemistry, with discussion of the emerging marker INSM1, 3. non-small cell carcinoma with (occult) neuroendocrine differentiation, 4. the WHO Classification of neuroendocrine neoplasms, with discussion of the 2019 classification of gastroenteropancreatic neoplasms, 5. use of Ki-67 immunohistochemistry, 6. immunohistochemistry to assign site of origin in neuroendocrine metastasis of occult origin, 7. immunohistochemistry to distinguish well-differentiated neuroendocrine tumor G3 from poorly differentiated neuroendocrine carcinoma, 8. lesions frequently misdiagnosed as well-differentiated neuroendocrine tumor, and 9. required and recommended data elements for biopsies and resections with associated immunohistochemical stains. Next-generation immunohistochemistry, including lineage-restricted transcription factors (e.g., CDX2, islet 1, OTP, SATB2) and protein correlates of molecular genetic events (e.g., p53, Rb), is indispensable for the accurate diagnosis and classification of these neoplasms.

Specific and Non-Specific Biomarkers in Neuroendocrine Gastroenteropancreatic Tumors.

The diagnosis of neuroendocrine tumors (NETs) is a challenging task: Symptoms are rarely specific, and clinical manifestations are often evident only when metastases are already present. However, several bioactive substances secreted by NETs can be included for diagnostic, prognostic, and predictive purposes. Expression of these substances differs between different NETs according to the tumor hormone production. Gastroenteropancreatic (GEP) NETs originate from the diffuse neuroendocrine system of the gastrointestinal tract and pancreatic islets cells: These tumors may produce many non-specific and specific substances, such as chromogranin A, insulin, gastrin, glucagon, and serotonin, which shape the clinical manifestations of the NETs. To provide an up-to-date reference concerning the different biomarkers, as well as their main limitations, we reviewed and summarized existing literature.

Peptide Receptor Radionuclide Therapy for Advanced Gastroenteropancreatic Neuroendocrine Tumors - from oncology perspective.

Peptide Receptor Radionuclide Therapy (PRRT) is a form of molecular targeted therapy which is performed by using a small peptide (somatostatin analogue - SSA) that is coupled with a radionuclide beta emitting radiation. PRRT is a nuclear medicine for the systemic treatment of non-resectable, metastasized well/moderately differentiated, neuroendocrine tumours (NET) with overexpression of somatostatin receptor. These types of tumours include gastroenteropancreatic neoplasm (GEP-NENs), e.g. arising from the small bowel (often called carcinoid tumours), the pancreas, duodenum or stomach, but also from the large bowel or the lung and many other tissues (so called diffuse neuroendocrine system). The goal of PRRT is irradiation of tumour cells, via direct binding into specific receptor, somatostatin receptors (SSTR) family, overexpressed on the cell membrane of the primary tumours as well as on the metastasis. Over many years of clinical use of PRRT with ⁹⁰Y and current with ¹⁷⁷Lu DOTA conjugated somatostatin analogues proved to be efficient therapy option for NETs, with tumour responses, base on radiological evaluation. Also, a clinical response with symptoms relief and improvement in quality of life based on standard EORTC questioners is seen. Additional, common NET biomarker reduction and, ultimately, an impact on overall survival (OS) of patients with advanced non-resectable often progressive NEN can be expected. PRRT with ⁹⁰Y or ¹⁷⁷Lu-labelled peptides is generally well tolerated by most of the patients. The acute side effects (Adverse Events - AEs) are usually mild; most of them are related to the co-administration of amino acids (AA), such as nausea and vomiting. Others are related to the radioisotopes, such as fatigue or the exacerbation of endocrine syndromes, which are very rarely and they occurs, only in patients with functional tumours and large tumours burden. Chronic and permanent damage has an effect on target organs, particularly the kidneys and the bone marrow, which are generally mild. Currently, when ¹⁷⁷Lu DOTATATE is used, the potential risk to kidney damage is significantly reduced, compared to the previous usage of ⁹⁰Y labelled analogues. Up to now, kidney and bone marrow toxicity limits the dose of radioactivity of PRRT.

The Role of Chromogranin A in Adrenal Tumors

Chromogranin A (CgA) is part of the family of granins, which are acidic glycoproteins that represent an important part of secretory dense core granules. They are specific to various neuroendocrine and endocrine tissues, as components of diffuse neuroendocrine system and endocrine glands. CgA is co-secreted and co-released in the circulation along with hormones, bioamines and peptides secreted from the neuroendocrine cells . In the last decade, studies have emphasized the major importance of serum CgA in the diagnosis and follow-up of neuroendocrine tumors such as gastroenteropancreatic tumors, pheochromocytoma, medullary thyroid carcinoma. But its diagnostic value for adrenocortical adenomas or for adrenal malignancy, is still controversial. The current study aims to provide a comprehensive review , for synthesizing current knowledge regarding corelations between plasma CgA concentration and various adrenal tumors. Furthermore, there will be also analyzed and synthesized the clinical applicability and the diagnostic usefulness of dosing CgA in adrenal pathology, both medullary and cortical benign and malignant lesions.

How should incidental NEN of the pancreas and gastrointestinal tract be followed?

Neuroendocrine gastro-entero-pancreatic neoplasms (GEP-NENs) constitute a heterogeneous group of tumors, whose incidence has increased over the years. The most frequent site for primary disease is the stomach followed by small and large intestine, and pancreas. In the last decade, a dramatic growing in the incidence of small, incidental GEP-NENs has been recorded. In parallel, an increasing attitude toward more conservative approaches instead of surgical management has being widely spreading. This is particularly true for small, asymptomatic, pancreatic NEN as for these tumor forms an active surveillance has proven to be safe and feasible. Primary site and biological features of the neoplasms lead to different strategies and indications for surveillance and follow-up. This review focuses on the current evidence on modality and timing of surveillance and conservative treatment of incidentally discovered lesions.

Synchronous association of two neuroendocrine gastroenteropancreatic tumors, an adenocarcinoma of the cecum, and a Meckel's diverticulum: a case report.

Neuroendocrine gastroenteropancreatic tumors constitute a heterogeneous group of neoplasms, with the primary tumors being located in the gastric mucosa, pancreas, and small and large intestine. The development of a second primary malignancy in patients with these tumors is a well-described phenomenon, and the reported incidence ranges from 12% to 46%. The most common site of associated noncarcinoid malignancies is the gastrointestinal tract, which involves from 30% to 60% of the tumors. We report a case of concurrent colon carcinoma and two neuroendocrine tumors of the duodenum.

The Clinicopathological Aspects of Primary Presacral Neuroendocrine Neoplasms: One Center Experience.

Presacral neuroendocrine neoplasms (NENs) are rare entities that are found at the presacral space. We report our experience in the diagnosis, management, and outcomes of primary presacral NENs. This was an institutional review board-approved retrospective review of medical records and surgical pathology specimens of patients with a diagnosis of NENs at Cedars-Sinai Medical Center between January 2000 and April 2016. Ten patients were identified. The median age at presentation was 38 years (range, 20-77 years), and 8 were women. One patient presented with carcinoid-like symptoms, 2 were diagnosed incidentally, and 7 presented with symptoms related to mass effect. The median size of the tumor was 7.0 cm (range, 3-12 cm). On pathologic review, 3 of 10 were low-grade and well-differentiated, 5 of 10 were intermediate-grade and well-differentiated, 2 of 10 were grade 3 and classified as high-grade and poorly differentiated neuroendocrine tumors. Seven cases were metastatic on presentation with lymph node, liver, lung, or skeletal metastasis. Seven of 8 cases were detectable using Octreoscan. Eight patients were treated with a somatostatin analog and 5 patients were treated surgically. Presacral NENs are clinically similar to gastroenteropancreatic tumors. Octreoscan imaging and somatostatin analog therapies were frequently applied. Further biologic characterization of this rare subtype is needed.