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As the incidence of neuroendocrine tumors has been rising, gender differences in epidemiology and clinical behavior have emerged, and interest into a gender-driven management of these tumors has grown with the aim to improve survival and quality of life of these patients. Somatostatin Analogues represent the first line of systemic treatment of both functional and non-functional neuroendocrine tumors, through the expression of somatostatin receptors (SSTRs) in the tumor cells, and proved effective in controlling hormonal hypersecretion and inhibiting tumor growth, improving progression-free survival and overall survival of these patients. Aim of the present review is to investigate any differences by gender in efficacy and safety of SSTS-targeted therapies, that represent the mainstay treatment of neuroendocrine tumors, as they emerge from studies of varying design and intent. Although preclinical studies have provided evidence in favor of differences by gender in tumor expression of SSTR, as well as of the role of sex hormones and related receptors in modulating SSTRs expression and function, the clinical studies conducted so far have not shown substantial differences between males and females in either efficacy or toxicity of SSTR-targeted therapies, even if with sometimes inconsistent results. Moreover, in most studies gender was not a predictor of response to treatment. Studies specifically designed to address this issue are needed to develop gender-specific therapeutic algorithms, improving patients' prognosis and quality of life., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Pasireotide long-acting release (PAS-LAR) is a second-generation somatostatin receptor ligand (SRL) approved for acromegaly treatment. This meta-analysis aimed to evaluate the real-world effectiveness and safety of PAS-LAR in patients with acromegaly resistant to first-generation somatostatin receptor ligands (fgSRL). A systematic literature search was conducted in PubMed and Web of Science for real-world studies on PAS-LAR in acromegaly published between 2014 and 2023. Random-effects meta-analyses were performed on biochemical control rates, tumor shrinkage, and metabolic parameters. Twelve studies comprising 409 patients were included. The pooled rate of insulin-like growth factor 1 (IGF-1) control was 57.9% [95% CI: 48.4-66.8] and the percentage of patients with tumor shrinkage was 33.3% [95%CI: 19.7-50.4]. Significant reductions were observed in growth hormone standardized mean difference (SMD) 0.6 ng/mL [95% CI: 0.3 to 1.0] and IGF-1 levels SMD 0.9 ULN [95% CI: 0.4 to 1.4]. However, as expected, a worsening in glucose metabolism was noted as an increase in fasting glucose SMD - 0.8 mg/dL [95% CI: -1.0 to -0.5, p < 0.01], glycated hemoglobin SMD - 0.5% [95% CI: -0.7 to -0.2]. and type 2 diabetes mellitus prevalence SMD - 11.5% (95% CI: -17.5 to -5.5). PAS-LAR demonstrated higher effectiveness in real-world settings, with over 60% of patients achieving IGF-1 control compared to the around 30% efficacy observed in clinical trials. These findings suggest that PAS-LAR is an effective option for acromegaly patients resistant to fgSRL, but careful monitoring of glucose levels is essential. The high heterogeneity observed across studies emphasizes the need for identifying PAS-LAR response biomarkers to set-up individualized treatment approaches for optimizing patient outcomes., Competing Interests: Declarations. Institutional review board statement: Not applicable. Informed consent: Not applicable. Conflict of interest: B.B., MA, MM and M.P.D. have received consulting fees, research support, or participated in clinical trials supported by Pfizer, Ipsen, and/or Recordati. C.T. has received fees for speaker lectures from Gedeon Richte., (© 2024. The Author(s).)

Background: Pancreatic metastases from medullary thyroid carcinoma (MTC) are exceptional. Imaging and treatment based on somatostatin receptors may play a role, though the evidence is unconvincing., Case Presentation: We have, herein, documented a unique case of metastatic MTC, where pancreatic metastasis was identified by 68Ga-PET/CT, with the disease showing very slow progression during treatment with lanreotide autogel. A 51-year-old woman underwent total thyroidectomy for goiter in 2000, with a postoperative diagnosis of MTC. Due to persistent disease, somatostatin analogues (SSA) treatment commenced in 2005, following a positive acute octreotide test. In 2012, a pathology-confirmed pancreatic metastasis was diagnosed via 68Gallium-positron emission tomography (68Ga-PET/CT). The disease progressed very slowly over 17 years of SSA treatment., Conclusion: This uncommon case of pancreatic metastasis from MTC indicates that nuclear medicine techniques might offer valuable additional information. Extended treatment with lanreotide autogel appears to correlate with very slow disease progression in selected patients., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Somatostatin and its analogues, known as somatostatin receptor ligands (SRLs), have been reported to attenuate weight gain in some clinical settings. However, their direct effects on preadipocytes are barely investigated. Therefore, this study aimed to evaluate the influence of SRLs on preadipocytes and to further explore the potential mechanisms. Cell Counting Kit-8 assay, Oil Red O staining, triglyceride contents measurements, quantitative polymerase chain reaction (qPCR) and western blot were used to investigate the effects of SRLs on preadipocytes. We found that three SRLs (octreotide, TT232 and pasireotide) inhibited cell viability after 8-48 h but not 4 h. Further western blot results showed that they significantly suppressed activation of PI3K/Akt pathway. Besides, lipid accumulation was also significantly inhibited by these SRLs. Moreover, mRNA levels of some critical adipogenic markers, including Pparg, Cebpa, Fasn, Fabp4, Acaca and Lpl, were downregulated by the treatments of all these SRLs. Consistently, the protein expression of peroxisome proliferator-activated receptor γ (PPARγ), CCAAT/enhancer binding protein α (C/EBPα) and fatty acid synthase (FAS) was also suppressed by SRLs. SRLs inhibit the proliferation and lipogenesis in preadipocytes. Their inhibitory effects on cell proliferation may be mediated by the downregulated PI3K/Akt pathway, and the suppressive actions on lipogenesis may be related to the decreased PPARγ and C/EBPα expression., (© 2022 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). Published by John Wiley & Sons Ltd.)

Simple Summary: Carcinoid syndrome in patients with neuroendocrine tumors is a challenging condition that requires accurate diagnostic and therapeutic management by a multidisciplinary team. Therefore, this review intends to detail all clinical aspects of carcinoid syndrome in order to provide clinicians with a definite overview of the effective approach to carcinoid syndrome. In this way, the review aims to improve patient care and treatment outcomes in this patient population. Carcinoid syndrome (CS) is a rare condition associated with neuroendocrine tumors (NETs), particularly those originating in the gastrointestinal tract, which secrete bioactive substances like serotonin. The management of CS requires a multidisciplinary approach due to its complex clinical manifestations, including flushing, diarrhea, bronchospasm, and carcinoid heart disease. Optimal care involves collaboration between several professional figures like oncologists, endocrinologists, gastroenterologists, surgeons, and dietitians. Currently, a wide range of treatments are available, focused on both symptom control and tumor burden reduction. Somatostatin analogs (SSAs) are the first-line therapy for symptom relief. Still, in patients with progressive disease or refractory CS, other options include targeted therapies, peptide receptor radionuclide therapy (PRRT), liver-directed therapies, and surgical resection, when feasible. Furthermore, management of complications related to prolonged serotonin release and malnutrition as a result of exocrine pancreatic insufficiency, post-surgical conditions, vitamin deficit, and chronic diarrhea often requires early detection to mitigate symptoms and improve the quality of life in these patients. The complexity of CS necessitates individualized care and continuous coordination among specialists to optimize outcomes and enhance patient well-being. [ABSTRACT FROM AUTHOR]

Simple Summary: Somatostatin, a growth hormone-release-inhibiting peptide (SST/SRIF), is a widely distributed multifunctional cyclic peptide that acts by activating G protein-coupled receptors (SSTRs, SST1-5). The diagnostic and prognostic role of these peptides in sporadic CRC remains unclear. The current study showed significant differences in the expression of SST and all SSTRs in the tissue material of sporadic CRC, control colorectal mucosa, and in lymph node metastases from the same patients. A significant dependence of the immunoexpression of SST1-5 on the cellular localization pattern was proved. Differences and/or significant correlations of SRIF system components with clinicopathological data (age, histological subtype of CRC, TNM parameters, Ki-67 antigen, and laboratory tests) were found. Interestingly, only control tissue showed differences in SST1-5 expression depending on the colon segment. The coexpression of all SST1-5 and overexpression of not only SST2 and SST5 in CRC may have applications for future therapy based on the SRIF system in sporadic CRC. Background/Objectives: Colorectal cancer (CRC) is one of the most common human malignancies worldwide. The somatotropin-releasing inhibitory factor/somatostatin (SRIF/SST) acts through activation of five membrane receptors (SSTRs, SST1-5). The diagnostic and prognostic role of these peptides in sporadic CRC remains unclear. This study aimed to determine the role of tissue expression of SST and all SSTRs in the pathogenesis, diagnosis, and prognosis of sporadic CRC. Methods: The expression of SST and all SSTRs was assessed in the tissues of CRC patients, control colorectal mucosa and lymph node metastasis from the same patients using real-time quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry (IHC). Results: Decreased SST (mRNA and peptide) and higher SST2 and SST5 (mRNA and peptide) expression in CRC vs. control was noted. A negative correlation between SST mRNA expression and patient's age in CRC and control groups were observed. IHC study confirmed the coexpression of SSTRs in all tissue groups and significant dependence on the cellular localization. Immunoexpression of SST2 and SST3 showed the most correlations with clinicopathological data in CRC patients. Interestingly, only control tissue showed differences in SST1-5 expression depending on the colon segment. Conclusions: Reduced SST expression in CRC indicates a weakening in its antitumor effect in this cancer in vivo. Overexpression of SST2 and SST5 in CRC suggests that these receptors play an important role in the pathogenesis of this cancer. Analysis of SST1-5 tissue expression allows for differentiation between the mucinous and nonmucinous CRC subtypes. The coexpression of all SST1-5 and overexpression of not only SST2 and SST5 in CRC may have applications for future therapy based on the SRIF system in sporadic CRC. [ABSTRACT FROM AUTHOR]

Somatostatin, a somatotropin release inhibiting factor (SST, SRIF), is a widely distributed multifunctional cyclic peptide and acts through a transmembrane G protein-coupled receptor (SST1-SST5). Over the past decades, research has begun to reveal the molecular mechanisms underlying the anticancer activity of this hormonal peptide. Among gastrointestinal tract (GIT) tumors, direct and indirect antitumor effects of SST have been documented best in gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and less well in non-endocrine cancers, including sporadic colorectal cancer (CRC). In the latter, the signaling pathways involved in the antitumor function of SST are primarily MAPK/ERK/AKT and Wnt/β–catenin. Direct (involving the MAPK pathway) and indirect (VEGF production) antiangiogenic effects of SST in CRC have also been described. The anti-inflammatory role of SST in CRC is emphasized, but detailed molecular mechanisms are still being explored. The role of SST in tumor genome/tumor microenvironment (TME)/host's gut microbiome interactions is only partially known. The results of SST analogues (SSAs)' treatment of sporadic CRC in monotherapy in vivo are not spectacular. The current review aims to present the state-of-the-art mechanisms and antitumor activity of endogenous SST and its synthetic analogues in CRC, with particular emphasis on sporadic CRC. [ABSTRACT FROM AUTHOR]

Background Patients with advanced neuroendocrine tumors (NETs) have multiple treatment options. Ideally, treatment decisions are shared between physician and patient; however, previous studies suggest that oncologists and patients place different value on treatment attributes such as adverse event (AE) rates. High-quality information on NET patient treatment preferences may facilitate patient-centered decision making by helping clinicians understand patient priorities. Methods This study used 2 discrete choice experiments (DCE) to elicit preferences of NET patients regarding advanced midgut and pancreatic NET (pNET) treatments. The DCEs used the "potentially all pairwise rankings of all possible alternatives" (PAPRIKA) method. The primary objective was to determine relative utility rankings for treatment attributes, including progression-free survival (PFS), treatment modality, and AE rates. Ranking of attribute profiles matching specific treatments was also determined. Levels for treatment attributes were obtained from randomized clinical trial data of NET treatments. Results One hundred and 10 participants completed the midgut NET DCE, and 132 completed the pNET DCE. Longer PFS was the highest ranked treatment attribute in 64.5% of participants in the midgut NET DCE, and in 59% in the pNET DCE. Approximately, 40% of participants in both scenarios prioritized lower AE rates or less invasive treatment modalities over PFS. Ranking of treatment profiles in the midgut NET scenario identified 60.9% of participants favoring peptide receptor radionuclide therapy (PRRT), and 30.0% somatostatin analogue dose escalation. Conclusion NET patients have heterogeneous priorities when choosing between treatment options based on the results of 2 independent DCEs. These results highlight the importance of shared decision making for NET patients. [ABSTRACT FROM AUTHOR]

Simple Summary: The tissue expression of somatostatin receptor (SSTR) subtypes in neuroendocrine tumors (NETs) holds paramount significance with far-reaching diagnostic and therapeutic implications. SSTRs contribute significantly to localizing NETs, aiding in advanced imaging techniques such as somatostatin receptor scintigraphy and PET scans. Elevated SSTR expression often aligns with less aggressive tumors, impacting tumor grading and influencing treatment decisions. Therapeutically, SSTRs serve as pivotal targets for treatments like targeted radiotherapy and synthetic somatostatin analogs (e.g., octreotide), commonly employed to inhibit hormone secretion and suppress tumor growth. Tailoring treatment strategies based on SSTR subtype expression enhances therapeutic efficacy. SSTR expression serves as a valuable prognostic indicator, predicting treatment response. While challenges like tumor heterogeneity persist, ongoing research explores promising avenues, including combination therapies. In conclusion, a nuanced understanding of SSTR expression in NETs is indispensable for precise diagnosis and the development of tailored therapeutic interventions, offering the potential for improved patient outcomes. Neuroendocrine tumors (NETs) arise from neuroendocrine cells and manifest in diverse organs. Key players in their regulation are somatostatin and its receptors (SSTR1–SSTR5). Understanding receptor–ligand interactions and signaling pathways is vital for elucidating their role in tumor development and therapeutic potential. This review highlights SSTR characteristics, localization, and expression in tissues, impacting physiological functions. Mechanisms of somatostatin and synthetic analogue binding to SSTRs, their selectivity, and their affinity were analyzed. Upon activation, somatostatin initiates intricate intracellular signaling, involving cAMP, PLC, and MAP kinases and influencing growth, differentiation, survival, and hormone secretion in NETs. This review explores SSTR expression in different tumor types, examining receptor activation effects on cancer cells. SSTRs' significance as therapeutic targets is discussed. Additionally, somatostatin and analogues' role in hormone secretion regulation, tumor growth, and survival is emphasized, presenting relevant therapeutic examples. In conclusion, this review advances the knowledge of receptor–ligand interactions and signaling pathways in somatostatin receptors, with potential for improved neuroendocrine tumor treatments. [ABSTRACT FROM AUTHOR]

Neuropeptides are among the most abundant chemical messengers produced in the brain that can function as neurotransmitters or hormones. Neuropeptides are synthesized and used by a neuron. There are over one hundred known neuropeptides, representing the largest and most diverse class of signaling molecules in the nervous system. Neuropeptides are often co-released with other neuropeptides and neurotransmitters in a single neuron, yielding a multitude of effects. The focus of this review is their role in cancer in general and mainly sarcomas. Neuropeptides and their receptors are no exception when it comes to their pro or antitumorigenic diverse functions defined by cellular and disease content. The molecular targets, pathways, and epigenetic regulation of sarcoma growth by neuropeptides are highlighted to better understand the importance of these molecules and suggest future alternative therapies for this challenging disease with unmet cancer needs. [ABSTRACT FROM AUTHOR]

Simple Summary: Few therapies are available for patients with aggressive or metastatic pituitary neuroendocrine tumours (PitNETs). Peptide receptor radionuclide therapy (PRRT), widely used to treat gastroenteropancreatic neuroendocrine tumours, has been emerging as a potential option for aggressive or metastatic PitNETs if other treatment approaches are not feasible or failed in controlling the disease progression. However, the data regarding the use of PRRT in this setting is scarce, and mainly derives from few case reports or small series of cases. Here, we review the published data regarding the effectiveness and safety of PRRT in the management of aggressive or metastatic PitNETs, as well as the effects of PRRT on the pituitary function in other cancer patients. Pituitary neuroendocrine tumours (PitNETs) are usually benign and slow-growing; however, in some cases, they may behave aggressively and become resistant to conventional treatments. Therapeutic options for aggressive or metastatic PitNETs are limited, and currently mainly consist of temozolomide, with little experience of other emerging approaches, including peptide receptor radionuclide therapy (PRRT). Somatostatin receptor expression in PitNETs explains the effectiveness of somatostatin analogues for treating PitNETs, particularly those hypersecreting pituitary hormones, such as growth hormone or adrenocorticotropic hormone. The expression of such receptors in pituitary tumour cells has provided the rationale for using PRRT to treat patients with aggressive or metastatic PitNETs. However, the PRRT efficacy in this setting remains unestablished, as knowledge on this today is based only on few case reports and small series of cases, which are reviewed here. A total of 30 PRRT-treated patients have been thus far reported: 23 aggressive PitNETs, 5 carcinomas, and 2 of malignancy status unspecified. Of the 27 published cases with information regarding the response to PRRT, 5 (18%) showed a partial response, 8 (30%) had stable disease, and 14 (52%) had progressive disease. No major adverse effects have been reported, and there is also no increased risk of clinically relevant hypopituitarism in patients with pituitary or non-pituitary neuroendocrine tumours following PRRT. PRRT may be regarded as a safe option for patients with aggressive or metastatic PitNETs if other treatment approaches are not feasible or have failed in controlling the disease progression, with tumour shrinkage occurring in up to a fifth of cases, while about a third of aggressive pituitary tumours may achieve stable disease. Here, the data on PRRT in the management of patients with aggressive pituitary tumours are reviewed, as well as the effects of PRRT on the pituitary function in other PRRT-treated cancer patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Neuroendocrine tumours, recently reclassified as neuroendocrine neoplasms (NENs), are a heterogeneous group of tumours with variability in their disease course and outcome. Complex mechanisms involving spatial and temporal changes in tumour biology affect their treatment response and survival. Treatment strategies are often based on information regarding tumour stage and grade. Tumour heterogeneity, however, is a common phenomenon in NENs, and it is not uncommon for these neoplasms to show intra- and inter-tumour heterogeneity that may lead to incomplete understanding of their tumour biology and behaviour. This review summarises the available evidence on gastroenteropancreatic NEN heterogeneity and its impact on diagnosis and clinical management. Tumour heterogeneity is a common phenomenon in neuroendocrine neoplasms (NENs) and a significant cause of treatment failure and disease progression. Genetic and epigenetic instability, along with proliferation of cancer stem cells and alterations in the tumour microenvironment, manifest as intra-tumoural variability in tumour biology in primary tumours and metastases. This may change over time, especially under selective pressure during treatment. The gastroenteropancreatic (GEP) tract is the most common site for NENs, and their diagnosis and treatment depends on the specific characteristics of the disease, in particular proliferation activity, expression of somatostatin receptors and grading. Somatostatin receptor expression has a major role in the diagnosis and treatment of GEP-NENs, while Ki-67 is also a valuable prognostic marker. Intra- and inter-tumour heterogeneity in GEP-NENS, however, may lead to inaccurate assessment of the disease and affect the reliability of the available diagnostic, prognostic and predictive tests. In this review, we summarise the current available evidence of the impact of tumour heterogeneity on tumour diagnosis and treatment of GEP-NENs. Understanding and accurately measuring tumour heterogeneity could better inform clinical decision making in NENs. [ABSTRACT FROM AUTHOR]

Background: Accurate response evaluation in patients with neuroendocrine liver metastases (NELM) remains a challenge. Radiomics has shown promising results regarding response assessment. Purpose: To differentiate progressive (PD) from stable disease (SD) with radiomics in patients with NELM undergoing somatostatin analogue (SSA) treatment. Material and Methods: A total of 46 patients with histologically confirmed gastroenteropancreatic neuroendocrine tumors (GEP-NET) with ≥1 NELM and ≥2 computed tomography (CT) scans were included. Response was assessed with Response Evaluation Criteria in Solid Tumors (RECIST1.1). Hepatic target lesions were manually delineated and analyzed with radiomics. Radiomics features were extracted from each NELM on both arterial-phase (AP) and portal-venous-phase (PVP) CT. Multiple instance learning with regularized logistic regression via LASSO penalization (with threefold cross-validation) was used to classify response. Three models were computed: (i) AP model; (ii) PVP model; and (iii) AP + PVP model for a lesion-based and patient-based outcome. Next, clinical features were added to each model. Results: In total, 19 (40%) patients had PD. Median follow-up was 13 months (range 1–50 months). Radiomics models could not accurately classify response (area under the curve 0.44–0.60). Adding clinical variables to the radiomics models did not significantly improve the performance of any model. Conclusion: Radiomics features were not able to accurately classify response of NELM on surveillance CT scans during SSA treatment. [ABSTRACT FROM AUTHOR]

Background: Type 1 gastric neuroendocrine tumors (GC-1) represent an uncommon subtype of neoplasms. Endoscopic resection has been proposed as the treatment of choice; active surveillance may be performed in those smaller than 1 cm, while gastric surgery may be performed for those with frequent recurrences. The antiproliferative effect of somatostatin analogues (SSA) is well known, and their action on GC-1s has been postulated as a chronic treatment to reduce recurrence. Methods: A two-centered, retrospective, observational study that included nine patients (55.6% women) diagnosed with GC-1, receiving long-term treatment with SSA, with a median follow-up from baseline of 22 months, was undertaken. Endoscopic follow-up, extension study, and analytical values of chromogranin A (Cg A) and gastrin were collected. Results: In total, 88.9% of patients presented partial or complete response. Treatment with SSA was the only independent factor with a trend to prevent tumor recurrence (Odds Ratio 0.054; p = 0.005). A nonsignificant tendency toward a decrease in CgA and gastrin was observed; lack of significance was probably related to concomitant treatment with proton pump inhibitors in some patients. Conclusions: Chronic treatment with SSA is a feasible option for recurrent GC-1s that are difficult to manage using endoscopy or gastrectomy. Randomized clinical trials to provide more scientific evidence are still needed. [ABSTRACT FROM AUTHOR]

Background: Somatostatin analogues (SSAs) are the cornerstone of treatment for carcinoid syndrome (CS)-related symptoms. The aim of this systematic review and meta-analysis is to evaluate the percentage of patients achieving partial (PR) or complete response (CR) with the use of long-acting SSAs in patients with CS. Methods: A systematic electronic literature search was conducted in PubMed, Cochrane, and Scopus to identify eligible studies. Any clinical trials reporting data on the efficacy of SSAs to alleviate symptoms in adult patients were considered as potentially eligible. Results: A total of 17 studies reported extractable outcomes (PR/CR) for quantitative synthesis. The pooled percentage of patients with PR/CR for diarrhea was estimated to be 0.67 (95% confidence interval (CI): 0.52–0.79, I2 = 83%). Subgroup analyses of specific drugs provided no evidence of a differential response. With regards to flushing, the pooled percentage of patients with PR/CR was estimated to be 0.68 (95% CI: 0.52–0.81, I2 = 86%). Similarly, no evidence of a significant differential response in flushing control was documented. Conclusions: We estimate there is a 67–68% overall reduction in symptoms of CS associated with SSA treatment. However, significant heterogeneity was detected, possibly revealing differences in the disease course, in management and in outcome definition. [ABSTRACT FROM AUTHOR]

Simple Summary: Advanced neuroendocrine tumors originating in the intestinal tract and pancreas are treated with biologics that activate somatostatin receptors (lanreotide and octreotide), small molecule drugs that target the mTOR (everolimus) and VEGF and other signaling pathways (sunitinib), chemotherapies (temozolomide, capecitabine, fluorouracil, platinums), and receptor-targeted radionuclides (Lu177-DOTATATE). These treatments eventually fail to control tumor progression, but the mechanisms for therapeutic resistance are poorly understood. We will review preclinical and early clinical studies that provide insight into potential etiologies and new therapies and combinations that may address this resistance. Gastroenteropancreatic neuroendocrine tumors (GEP-NETs), although curable when localized, frequently metastasize and require management with systemic therapies, including somatostatin analogues, peptide receptor radiotherapy, small-molecule targeted therapies, and chemotherapy. Although effective for disease control, these therapies eventually fail as a result of primary or secondary resistance. For small-molecule targeted therapies, the feedback activation of the targeted signaling pathways and activation of alternative pathways are prominent mechanisms, whereas the acquisition of additional genetic alterations only rarely occurs. For somatostatin receptor (SSTR)-targeted therapy, the heterogeneity of tumor SSTR expression and dedifferentiation with a downregulated expression of SSTR likely predominate. Hypoxia in the tumor microenvironment and stromal constituents contribute to resistance to all modalities. Current studies on mechanisms underlying therapeutic resistance and options for management in human GEP-NETs are scant; however, preclinical and early-phase human studies have suggested that combination therapy targeting multiple pathways or novel tyrosine kinase inhibitors with broader kinase inhibition may be promising. [ABSTRACT FROM AUTHOR]

Background: The antiproliferative activity of a high dose of somatostatin analogs (HD-SSA) in treating gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs) remains under debate. Methods: A systematic review and proportion meta-analysis were made. The primary endpoint was the efficacy measured as incidence density ratio (IDR) at one year. The secondary endpoints were the disease control rate (DCR) and severe adverse events (SAEs). The heterogeneity (I2), when high (>50%), was interpreted by performing a univariate metaregression analysis, analyzing as covariates: type and design of the study, location (Europe or USA), sample size, grading according to 2017 WHO, the metastatic disease rate, previous therapy including surgery, and quality of the study. Results: A total of 11 studies with 783 patients were included. The IDR was 62 new progressions of 100 patients treated with HD-SSA every one year. The heterogeneity was high. The study's year, type and design, primary tumor, grading, previous treatments, and quality of the studies did not influence the IDR. The IDR was significantly higher in USA centers and studies with more than 50 patients. The IDR was lower when a high rate of metastatic patients was present in the studies. The DCR was 45%. The heterogeneity was high. The DCR was lower in USA studies and in prospective trials. Conclusion: Given the limited efficacy of HD-SSA in preventing the disease progression in unresectable GEP-NENs after failure of standard dose SSA, the use of this therapeutic approach is advisable in selected cases when other antiproliferative treatments are not feasible. [ABSTRACT FROM AUTHOR]

Malignant insulinomas are functional neuroendocrine tumors of the pancreas and the primary cause of tumor-related hypoglycemia. Malignant insulinoma is rare and has a poor prognosis. We report a case of metastatic malignant insulinoma in a 64-year-old female patient with severe and refractory hypoglycemia. After several ineffective locoregional and systemic therapeutic lines for the secretory disease, the introduction of pasireotide, a second-generation somatostatin analog, provided an improved clinical and secretory evolution both quickly and sustainably, with an excellent safety profile. Pasireotide is an effective and well-tolerated therapy in the treatment of refractory hypoglycemia in metastatic insulinoma. [ABSTRACT FROM AUTHOR]

Somatostatin is an inhibitory peptide, which regulates the release of several hormones, and affects neurotransmission and cell proliferation via its five Gi protein-coupled receptors (SST1-5). Although its endocrine regulatory and anti-tumour effects have been thoroughly studied, little is known about its effect on the vascular system. The aim of the present study was to analyse the effects and potential mechanisms of somatostatin on endothelial barrier function. Cultured human umbilical vein endothelial cells (HUVECs) express mainly SST1 and SST5 receptors. Somatostatin did not affect the basal HUVEC permeability, but primed HUVEC monolayers for thrombin-induced hyperpermeability. Western blot data demonstrated that somatostatin activated the phosphoinositide 3-kinases (PI3K)/protein kinase B (Akt) and p42/44 mitogen-activated protein kinase (MAPK) pathways by phosphorylation. The HUVEC barrier destabilizing effects were abrogated by pre-treating HUVECs with mitogen-activated protein kinase kinase/extracellular signal regulated kinase (MEK/ERK), but not the Akt inhibitor. Moreover, somatostatin pre-treatment amplified vascular endothelial growth factor (VEGF)-induced angiogenesis (3D spheroid formation) in HUVECs. In conclusion, the data demonstrate that HUVECs under quiescence conditions express SST1 and SST5 receptors. Moreover, somatostatin primes HUVECs for thrombin-induced hyperpermeability mainly via the activation of MEK/ERK signalling and promotes HUVEC proliferation and angiogenesis in vitro. [ABSTRACT FROM AUTHOR]

Objectives. To analyze and summarize the effect of SSA treatment on EAS due to p-NETs (EAS-p-NETs). Methods. Thirteen patients with EAS-p-NETs treated with SSAs at our center or described in the literature were included in this study. Clinical characteristics, laboratory data, imaging studies, histopathologic results, the effect of SSA treatment, and the prognosis of these EAS-p-NET patients were evaluated. Results. Four males and 9 females with an average age of 42.9 years were included in the study. The mean duration of follow-up was 38.8 ± 28.2 months. As one of the combined treatment measures, SSAs controlled the levels of ACTH and cortisol in 9 of the 13 patients (69.2%). Partial response was observed in 3 patients (23.1%), stable disease in 2 patients (15.4%), and progressive disease in 6 patients (46.2%). The median time to tumor progression was 24 months, and the median overall survival was 61 months. The side effects of SSA treatment included temporary mild abdominal pain, diarrhea, gallstones, and cholecystitis. Conclusions. As a supplemental therapy, SSA treatment led to clinical and biochemical improvement with a good safety profile in patients exhibiting EAS-p-NET with metastasis. However, tumor progression was inhibited by SSA treatment in only a few patients. Combined with other treatments, SSAs may improve the prognosis of patients with EAS-p-NETs. [ABSTRACT FROM AUTHOR]

Simple Summary: Tumor resistance, both primary and acquired, is leading to increased complexity in the nonsurgical treatment of patients with advanced panNENs, which would be greatly helped by reliable prognostic/predictive factors. The importance in identifying resistance is being contributed to by the increased array of possible treatments available for treating resistant advanced disease; the variable clinical course as well as response to any given treatment approach of patients within one staging or grading system, the advances in imaging which are providing increasing promising results/parameters that correlate with grading/outcome/resistance, the increased understanding of the molecular pathogenesis providing promising prognostic markers, all of which can contribute to selecting the best treatment to overcome resistance disease. Several factors have been identified that have prognostic/predictive value for identifying development resistant disease and affecting overall survival (OS)/PFS with various nonsurgical treatments of patients with advanced panNENs. Prognostic factors identified for patients with advanced panNENs for both OS/PFSs include various clinically-related factors (clinical, laboratory/biological markers, imaging, treatment-related factors), pathological factors (histological, classification, grading) and molecular factors. Particularly important prognostic factors for the different treatment modalities studies are the recent grading systems. Most prognostic factors for each treatment modality for OS/PFS are not specific for a given treatment option. These advances have generated several controversies and new unanswered questions, particularly those related to their possible role in predicting the possible sequence of different anti-tumor treatments in patients with different presentations. Each of these areas is reviewed in this paper. Purpose: Recent advances in the diagnosis, management and nonsurgical treatment of patients with advanced pancreatic neuroendocrine neoplasms (panNENs) have led to an emerging need for sensitive and useful prognostic factors for predicting responses/survival. Areas covered: The predictive value of a number of reported prognostic factors including clinically-related factors (clinical/laboratory/imaging/treatment-related factors), pathological factors (histological/classification/grading), and molecular factors, on therapeutic outcomes of anti-tumor medical therapies with molecular targeting agents (everolimus/sunitinib/somatostatin analogues), chemotherapy, radiological therapy with peptide receptor radionuclide therapy, or liver-directed therapies (embolization/chemoembolization/radio-embolization (SIRTs)) are reviewed. Recent findings in each of these areas, as well as remaining controversies and uncertainties, are discussed in detail, particularly from the viewpoint of treatment sequencing. Conclusions: The recent increase in the number of available therapeutic agents for the nonsurgical treatment of patients with advanced panNENs have raised the importance of prognostic factors predictive for therapeutic outcomes of each treatment option. The establishment of sensitive and useful prognostic markers will have a significant impact on optimal treatment selection, as well as in tailoring the therapeutic sequence, and for maximizing the survival benefit of each individual patient. In the paper, the progress in this area, as well as the controversies/uncertainties, are reviewed. [ABSTRACT FROM AUTHOR]

Pituitary tumors (PT) represent in, the majority of cases, benign tumors for which surgical treatment still remains, except for prolactin-secreting PT, the first-line therapeutic option. Nonetheless, the role played by medical therapies for the management of such tumors, before or after surgery, has evolved considerably, due in part to the recent development of well-tolerated and highly efficient molecules. In this review, our aim was to present a state-of-the-art of the current medical therapies used in the field of PT and the benefits and caveats for each of them, and further specify their positioning in the therapeutic algorithm of each phenotype. Finally, we discuss the future of PT medical therapies, based on the most recent studies published in this field. [ABSTRACT FROM AUTHOR]

Simple Summary: Neuroendocrine neoplasms (NENs) are rare and heterogeneous tumors, presenting in often challenging clinical scenarios, and require multidisciplinary discussion for optimal care. The theranostic approach (DOTA peptides labelled with 68Ga for imaging well-differentiated neuroendocrine tumors NETs, and labelled with 90Y or 177Lu for therapy) plays a crucial role in the management of NENs to assess disease extension and criteria for peptide receptor radionuclide therapy (PRRT) eligibility of based on somatostatin receptor (SSTR) expression. The present paper is an overview of currently employed radiolabeled SSTR analogues used for both diagnosis and therapy of NENs. Further emerging radiopharmaceuticals targeting SSTRs (e.g., fluorinated SSTR agonists, radiolabeled SSTR antagonists) as well as strategies to improve PRRT efficacy (by means of implementation of personalized treatment schemes, dosimetry, amelioration of response assessment strategies, and optimization of treatment sequencing) are also discussed. Finally, although very preliminary, some studies employing radiomic features in various kinds of NET are reported. Neuroendocrine neoplasms (NENs) are rare and heterogeneous tumors that require multidisciplinary discussion for optimal care. The theranostic approach (DOTA peptides labelled with 68Ga for diagnosis and with 90Y or 177Lu for therapy) plays a crucial role in the management of NENs to assess disease extension and as a criteria for peptide receptor radionuclide therapy (PRRT) eligibility based on somatostatin receptor (SSTR) expression. On the diagnostic side, [68Ga]Ga-DOTA peptides PET/CT (SSTR PET/CT) is the gold standard for imaging well-differentiated SSTR-expressing neuroendocrine tumors (NETs). [18F]FDG PET/CT is useful in higher grade NENs (NET G2 with Ki-67 > 10% and NET G3; NEC) for more accurate disease characterization and prognostication. Promising emerging radiopharmaceuticals include somatostatin analogues labelled with 18F (to overcome the limits imposed by 68Ga), and SSTR antagonists (for both diagnosis and therapy). On the therapeutic side, the evidence gathered over the past two decades indicates that PRRT is to be considered as an effective and safe treatment option for SSTR-expressing NETs, and is currently included in the therapeutic algorithms of the main scientific societies. The positioning of PRRT in the treatment sequence, as well as treatment personalization (e.g., tailored dosimetry, re-treatment, selection criteria, and combination with other alternative treatment options), is warranted in order to improve its efficacy while reducing toxicity. Although very preliminary (being mostly hampered by lack of methodological standardization, especially regarding feature selection/extraction) and often including small patient cohorts, radiomic studies in NETs are also presented. To date, the implementation of radiomics in clinical practice is still unclear. The purpose of this review is to offer an overview of radiolabeled SSTR analogues for theranostic use in NENs. [ABSTRACT FROM AUTHOR]

Somatostatin (SST) is a small peptide that exerts inhibitory effects on a wide range of neuroendocrine cells. Due to the fact that somatostatin regulates cell growth and hormone secretion, somatostatin receptors (SSTRs) have become valuable targets for the treatment of different types of neuroendocrine tumours (NETs). NETs are a heterogeneous group of tumours that can develop in various parts of the body, including the digestive system, lungs, and pituitary. NETs are usually slow growing, but they are often diagnosed in advanced stages and can display aggressive behaviour. The mortality rate of NETs is not outstandingly increased compared to other malignant tumours, even in the metastatic setting. One of the intrinsic properties of NETs is the expression of SSTRs that serve as drug targets for SST analogues (SSAs), which can delay tumour progression and downregulate hormone overproduction. Additionally, in many NETs, it has been demonstrated that the SSTR expression level provides a prognostic value in predicting a therapeutic response. Furthermore, higher a SSTR expression correlates with a better survival rate in NET patients. In recent studies, other epigenetic regulators affecting SST signalling or SSA–mTOR inhibitor combination therapy in NETs have been considered as novel strategies for tumour control. In conclusion, SST signalling is a relevant regulator of NET functionality. Alongside classical SSA treatment regimens, future advanced therapies and treatment modalities are expected to improve the disease outcomes and overall health of NET patients. [ABSTRACT FROM AUTHOR]