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Background: Sunitinib, a multitarget tyrosine kinase inhibitor, showed encouraging antitumor activity and manageable toxicity in patients with advanced midgut neuroendocrine tumors (NETs) in earlier results from phase I and II trials. Patients and methods: In this phase II trial, patients with a nonresectable grade 1 or 2 midgut progressive NET and Eastern Cooperative Oncology Group performance status 0–1 were randomly assigned 1:1 to receive 37.5 mg sunitinib or a placebo, combined with 120 mg lanreotide autogel every 28 days. The planned sample size was 104 patients. The primary outcome was investigator-assessed progression-free survival (PFS). Results: The study was stopped early because of insufficient patient recruitment. Between January 2013 and December 2016, 44 patients were enrolled and received sunitinib (n = 22) or placebo (n = 22). The median age was 63.7 years (Q 1– Q 3 range, 56.6–68.1) and 26 patients (59.1%) were male. The main localization was ileum (N = 37, 84.1%) and the majority were grade 2 (n = 25, 56.8%). The median follow-up was 36.7 months (95% confidence interval (CI) 34.6–48.2). The median PFS was 9.84 months (95% CI 6.8–23.3) with sunitinib and 11.47 months (95% CI 5.4–15.3) with placebo (hazard ratio (HR) = 0.80, 95% CI 0.41–1.56, p = 0.51). There was no difference in overall survival between treatment arms (HR = 0.81, (95% CI 0.32–2.01), p = 0.64). The objective response rate was 9.1% with sunitinib and 0.0% with placebo, and 19 patients (86.4%) had stable disease. Thirty-nine patients (88.6%) completed the baseline QLQ-C30 questionnaire. Baseline health-related quality of life level was similar between treatment arms, except for physical and emotional functioning which were higher (p = 0.089) and lower (p = 0.023) in the sunitinib arm, respectively. Trends toward longer time until a definitive deterioration in favor of the sunitinib arm were observed for 10 out of 15 dimensions (HRs < 1), with a significant result for financial difficulties (HR = 0.31, (90% CI 0.10–0.94)). Twenty-seven patients (61.4%) had at least one adverse event grade ⩾3 (sunitinib: 72.7%, placebo: 50.0%), with only one patient grade 4 for hypertension and vomiting. Eleven deaths non-related to treatment occurred (sunitinib arm: n = 5, placebo arm: n = 6). Conclusion: Our study does not provide enough evidence to conclude the role of sunitinib in advanced midgut NETs, primarily due to a lower-than-expected number of enrolled patients. While we cannot entirely rule out the efficacy of sunitinib, lanreotide alone may play a significant role. Trial registration: EudraCT: 2012-001098-94. Plain language summary: SUNLAND: a randomized, double-blind phase II GERCOR trial of sunitinib versus placebo and lanreotide in patients with advanced progressive midgut neuroendocrine tumors Neuroendocrine tumours of the small intestine are a rare condition with a very different prognosis and treatment from the more "classic" tumours (known as intestinal adenocarcinomas). A wide variety of treatments can be proposed, depending on the extent of the disease, the specific characteristics of the tumour (degree of proliferation) and how far it has progressed. Treatments may include surgical removal of tumours, administration of hormones (somatostatin analogues), "conventional" chemotherapy agents (cytotoxics), targeted systemic treatments, embolisation/chemotherapy applied directly to liver metastases, radioactive agents (PPRT), etc. Sunitinib is a drug that prevents the synthesis of vessels by certain tumours, thereby preventing them from feeding and proliferating. We compared this drug with a placebo, in combination with a somatostatin analog named lanreotide (phase II study). The main objectives studied were the rate and duration of tumor control (named progression free survival or PFS, corresponding to the length of time during the treatment of a tumour that a patient lives with the disease but it does not get worse. In a clinical trials, this is one classical way to see how well a new treatment works) and the quality of life parameters. The full recruitment of 104 patients planned for this study performed in 11 French center could not be reached, no doubt because of the rarity of this disease and the existence, at the same time, of therapeutic trials with other treatments. Despite some favourable trends for sunitinib on quality of life, the study was not conclusive, partly due to the use of octreotide in all patients, which may have interfered with the experimental treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: Somatostatin analogs like lanreotide are considered first-line agents for the treatment of gastroenteropancreatic neuroendocrine tumors (NET). Although its effects on tumor proliferation and hormonal regulation are somewhat understood, its influence on the immune system has not been well elucidated. We used a double-pronged approach to understand the role of lanreotide in immune system regulation in healthy donor T cells in vitro as well as in vivo in cells obtained from 17 NET patients. We looked at cytokine signaling and differential gene expression to elucidate lanreotide's role in the treatment of NET through additional novel immune pathways. The CLARINET trial led to the approval of lanreotide for the treatment of patients with gastroenteropancreatic neuroendocrine tumors (NETs). It is hypothesized that lanreotide regulates proliferation, hormone synthesis, and other cellular functions via binding to somatostatin receptors (SSTR1–5) present in NETs. However, our knowledge of how lanreotide affects the immune system is limited. In vitro studies have investigated functional immune response parameters with lanreotide treatment in healthy donor T cell subsets, encompassing the breadth of SSTR expression, apoptosis induction, cytokine production, and activity of transcription factor signaling pathways. In our study, we characterized in vitro immune mechanisms in healthy donor T cells in response to lanreotide. We also studied the in vivo effects by looking at differential gene expression pre- and post-lanreotide therapy in patients with NET. Immune-focused gene and protein expression profiling was performed on peripheral blood samples from 17 NET patients and correlated with clinical response. In vivo, lanreotide therapy showed reduced effects on wnt, T cell receptor (TCR), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) signaling in CD8+ T cells in responders compared to non-responders. Compared to non-responders, responders showed reduced effects on cytokine and chemokine signaling but greater effects on ubiquitination and proteasome degradation genes. Our results suggest significant lanreotide pharmacodynamic effects on immune function in vivo, which correlate with responses in NET patients. This is not evident from experimental in vitro settings. [ABSTRACT FROM AUTHOR]

Endometriosis is a gynecological disorder among reproductive-aged women. Recent epidemiological investigations suggest endometriosis increases the risk of endometrial cancer. However, the molecular entity leading to endometriosis-to-endometrial cancer is largely unknown. This study aimed to combine a variety of computational approaches to identify the key therapeutic target promoting endometriosis-to-endometrial cancer and screen potential inhibitors against target to prevent cancer development. Our systematic investigations, includes transcriptomic profiling, protein network, pharmacophore modeling, docking, binding free energy calculation, dynamics simulation, and quantum mechanics. The gene expression analysis on endometriosis and endometrial cancer was performed and showed 108 shared upregulated genes in both conditions. Further construction of interaction network with 108 genes showed intercellular adhesion molecule 1 (ICAM1) to be a crucial molecule with a high degree of connectivity that influences vital mechanisms related to cancer pathways. We then generated ligand-based pharmacophore models using established ICAM1 inhibitors. Among the models, the ADRRR_8 pharmacophore exhibited a robust area under curve (AUC = 0.83), was employed to screen 1739 anti-cancer drugs. On screening, 421 anti-cancer drugs displayed ICAM1-inhibiting pharmacophore features. Further, the docking of 421 drugs with ICAM1 showed lanreotide (−7.80 kcal/mol) with better affinity than the reference ICAM1 inhibitor (−3.59 kcal/mol). Further validation though binding free energy and dynamics simulation of the lanreotide-ICAM1 complex showed a high binding affinity of −55.90 kcal/mol and contributed stable confirmation. According to quantum chemical calculations, lanreotide's electronic properties favour ICAM1 binding with highest occupied molecular orbital was −6.91 eV and lowest unoccupied molecular orbital was −3.93 eV. Our study supports using lanreotide to treat endometriosis, which could delay or prevent endometrial cancer. These predictions need to be confirmed and examined to determine the use of lanreotide in endometriosis treatment. [ABSTRACT FROM AUTHOR]

Purpose: A series of consensus guidelines on medical treatment of acromegaly have been produced in the last two decades. However, little information is available on their application in clinical practice. Furthermore, international standards of acromegaly care have not been published. The aim of our study was to report current standards of care for medical therapy of acromegaly, using results collected through an audit performed to validate criteria for definition of Pituitary Tumor Centers of Excellence (PTCOE). Methods: Details of medical treatment approaches to acromegaly were voluntarily provided by nine renowned international centers that participated in this audit. For the period 2018–2020, we assessed overall number of acromegaly patients under medical treatment, distribution of patients on different treatment modalities, overall biochemical control rate with medical therapy, and specific control rates for different medical treatment options. Results: Median number of total patients and median number of new patients with acromegaly managed annually in the endocrinology units of the centers were 206 and 16.3, respectively. Median percentage of acromegaly patients on medical treatment was 48.9%. Among the patients on medical treatment, first-generation somatostatin receptor ligand (SRL) monotherapy was used with a median rate of 48.7%, followed by combination therapies with a median rate of 29.3%. Cabergoline monotherapy was used in 6.9% of patients. Pegvisomant monotherapy was used in 7 centers and pasireotide monotherapy in 5 centers, with median rates of 7.9% and 6.3%, respectively. Conclusions: Current standards of care in PTCOEs include use of first-generation SRLs as the first medical option in about 50% of patients, as recommended by consensus guidelines. However, some patients are kept on this treatment despite inadequate control suggesting that cost-effectiveness, availability, patient preference, side effects, and therapeutic inertia may play a possible role also in PTCOE. Moreover, at odds with consensus guidelines, other monotherapies for acromegaly appear to have a marginal role as compared to combination therapies as extrapolated from PTCOE practice data. Presence of uncontrolled patients in each treatment category suggest that further optimization of medical therapy, as well as use of other therapeutic tools such as radiosurgery may be needed. [ABSTRACT FROM AUTHOR]

The most common cause of persistent hypoglycemia in newborns and children is congenital hyperinsulinism (CHI). Remarkable advancements in diagnostic tools and treatments, including novel imaging and genetic techniques, and continuous subcutaneous octreotide administration, have improved the prognosis of diazoxide-unresponsive CHI; however, in clinical practice, some issues remain. Here, we report a case series consisting of four adenosine triphosphate-sensitive potassium-associated CHI cases, discuss the practical use of new international guidelines published in 2023, and suggest clinical issues associated with CHI management. Based on the clinical experience of two diffuse and two focal CHI cases, we employed an updated treatment strategy, including genetic diagnosis to determine treatment plans, careful catheter management, switching from octreotide to long-acting somatostatin, effective utilization of a continuous glucose monitoring (CGM) device, measures for feeding problems, and individualized and systematic developmental follow-up. Particularly, our cases suggest a safe method of switching from octreotide to lanreotide, elucidate the efficacy of home-based CGM monitoring, and indicate need for personalized support for feeding problems. Severe CHI is a rare and challenging disorder; thus, further accumulation of experience according to new treatment strategies is essential in generating high-quality evidence for the development and approval of new treatment options. [ABSTRACT FROM AUTHOR]

Purpose: Acromegaly is a rare disease associated with chronic multisystem complications. New therapeutic strategies have emerged in the last decades, combining pituitary transsphenoidal surgery (TSS), radiotherapy or radiosurgery (RXT) and medical treatments. Methods: This retrospective monocentric study focused on presentation, management and outcome of acromegaly patients diagnosed between 2000 and 2020, still followed up in 2020, with a minimum follow-up of 1 year, and comparison of the first vs. second decade of the study. Results: 275 patients were included, 50 diagnosed before 2010 and 225 after 2010. 95% of them had normal IGF-1 levels (with or without treatment) at the last follow-up. Transsphenoidal surgery was more successful after 2010 (75% vs. 54%; p < 0.01), while tumor characteristics remained the same over time. The time from first treatment to biochemical control was shorter after 2010 than before (8 vs. 16 months; p = 0.03). Since 2010, RT was used less frequently (10% vs. 32%; p < 0.01) but more rapidly after surgery (26 vs. 53 months; p = 0.03). In patients requiring anti-secretory drugs after TSS, the time from first therapy to biochemical control was shorter after 2010 (16 vs. 29 months; p < 0.01). Tumor size, tumor invasiveness, baseline IGF-1 levels and Trouillas classification were identified as predictors of remission. Conclusion: The vast majority of patients with acromegaly now have successful disease control with a multimodal approach. They reached biochemical control sooner in the most recent half of the study period. Future work should focus on those patients who are still uncontrolled and on the sequelae of the disease. [ABSTRACT FROM AUTHOR]

A dopamine agonist administered for prolactinoma treatment and pituitary stimulation tests are reported as risk factors for pituitary apoplexy. We report a case of an 82‐year‐old patient who suffered from pituitary apoplexy in an endocrinologically silent adenoma during lanreotide administration. The patient was diagnosed with a pancreatic neuroendocrine tumor with lymph node metastasis and treated with lanreotide for two years. An endoscopic endonasal transsphenoidal approach was used for tumor and hematoma removal. The specimen showed growth hormone and prolactin positivity and was diagnosed as pit1‐lineage plurihormonal adenoma. The tumor also showed positivity for somatostatin receptor 2. Thus, lanreotide treatment is a risk factor for pituitary apoplexy even in silent adenoma. [ABSTRACT FROM AUTHOR]

Background In advanced neuroendocrine tumors (NET), antiproliferative treatment options beyond somatostatin analogs remain limited. Temozolomide (TMZ) has shown efficacy in NET alone or combined with other drugs. Materials and Methods SONNET (NCT02231762) was an open, multicenter, prospective, phase II study to evaluate lanreotide autogel 120 mg (LAN) plus TMZ in patients with progressive advanced/metastatic grade 1/2 gastroenteropancreatic (GEP) NET or of unknown primary. Patients could be enrolled at first-line or higher therapy line. The primary endpoint was disease control rate ([DCR], rate of stable disease [SD], partial [PR], and complete response [CR]) at 6 months of LAN and TMZ. Patients with nonfunctioning (NF) NET without progression at 6 months were randomized to 6-month LAN maintenance or watch and wait, patients with functioning (F)-NET with clinical benefit (PR, SD) continued on LAN. Results Fifty-seven patients were recruited. The majority of patients received the study drug at second or higher treatment line and had an NET G2. DCR at 6 months LAN and TMZ was 73.5%. After 6 months of further LAN maintenance, 54.5% of patients with F-NET and 71.4% with NF-NET had SD or PR vs 41.7% with NF-NET on observation only. LAN and TMZ were effective in all subgroups analyzed. At 12 months of follow-up, median progression-free survival was 11.1 months. Median serum chromogranin A decreased except in NF-NET on observation. O6-methylguanine DNA methyltransferase promoter methylation appeared to better reflect TMZ response than loss of gene expression. During combination therapy, the most frequent treatment-emergent adverse events grade 3/4 reported were nausea (14%), thrombocytopenia (12.3%), and neutropenia (8.8%). Four deaths were reported resulting from severe adverse events not considered related to study medication. Conclusions LAN plus TMZ is a treatment option for patients with progressive GEP-NET with more aggressive biological profile showing a manageable safety profile. [ABSTRACT FROM AUTHOR]

Purpose: PREF-NET reported patients’ experience of Somatuline® (lanreotide) Autogel® (LAN) administration at home and in hospital among patients with gastroenteropancreatic neuroendocrine tumours (GEP-NETs). Methods: PREF-NET was a multicentre, cross-sectional study of UK adults (aged ≥ 18 years) with GEP-NETs receiving a stable dose of LAN, which comprised of (1) a quantitative online survey, and (2) qualitative semi-structured interviews conducted with a subgroup of survey respondents. The primary objective was the description of overall patient preference for home versus hospital administration of LAN. Secondary objectives included describing patient-reported opinions on the experience and associated preference for each administration setting, and the impact on healthcare utilisation, societal cost, activities of daily living and health-related quality of life (HRQoL). Results: In the primary analysis (80 patients; mean age 63.9 years), 98.7% (95% confidence interval [CI]: 96.1–100.0) of patients preferred to receive LAN at home, compared with 1.3% (95% CI: 0.0–3.9) who preferred the hospital setting. Among participants, over half (60.3%) received their injection from a non-healthcare professional. Most patients (79.5% [95% CI: 70.5–88.4]) reported a positive effect on HRQoL after the switch from hospital to home administration. Qualitative interviews (20 patients; mean age 63.6 years) highlighted that patients preferred home administration because it improved overall convenience; saved time and costs; made them feel more comfortable and relaxed, and less stressed; and increased confidence in their ability to self-manage their treatment. Conclusion: Almost all patients preferred to receive LAN treatment at home rather than in hospital with increased convenience and psychological benefits reported as key reasons for this preference. [ABSTRACT FROM AUTHOR]

Introduction: Somatostatin analogues (SSAs) are commonly used in the treatment of hormone hypersecretion in neuroendocrine tumors (NETs), however the extent to which they inhibit proliferation is much discussed. Objective: We studied the antiproliferative effects of novel SSA lanreotide in bronchopulmonary NETs (BP-NETs). We focused on assessing whether pretreating cells with inhibitors for phosphatidylinositol 3-kinase (PI3K) and mammalian target for rapamycin (mTOR) could enhance the antiproliferative effects of lanreotide. Methods: BP-NET cell lines NCI-H720 and NCI-H727 were treated with PI3K inhibitor BYL719 (alpelisib), mTOR inhibitor everolimus and SSA lanreotide to determine the effect on NET differentiation markers, cell survival, proliferation and alterations in cancer-associated pathways. NT-3 cells, previously reported to express somatostatin receptors (SSTRs) natively, were used as control for SSTR expression. Results: SSTR2 was upregulated in NCI-H720 and NT-3 cells upon treatment with BYL719. Additionally, combination treatment consisting of BYL719 and everolimus plus lanreotide tested in NCI-H720 and NCI-H727 led to diminished cell proliferation in a dose-dependent manner. Production of proteins activating cell death mechanisms was also induced. Notably, a multiplexed gene expression analysis performed on NCI-H720 revealed that BYL719 plus lanreotide had a stronger effect on the downregulation of mitogens than lanreotide alone. Discussion/Conclusion: We report a widespread analysis of changes in BP-NET cell lines at the genetic/protein expression level in response to combination of lanreotide with pretreatment consisting of BYL719 and everolimus. Interestingly, SSTR expression reinduction could be exploited in therapeutic and diagnostic applications. The overall results of this study support the evaluation of combination-based therapies using lanreotide in preclinical studies to further increase its antiproliferative effect and ultimately facilitate its use in highgrade tumors. [ABSTRACT FROM AUTHOR]

Summary: There are several options for systemic therapy of gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN), including somatostatin analogues (SSA), molecular-targeted agents, cytotoxic agents, and peptide receptor radionuclide therapy. However, the effectiveness of each agent varies according to the primary site. Although SSA and everolimus are key drugs used for systemic therapy of neuroendocrine tumors arising from the gastrointestinal tract (GI-NET), the optimal strategy for selecting among these modalities remains unexplored. Japanese experts on GI-NET discussed and determined optimal first-line treatment strategies based on the results of previously reported pivotal trials. The consensus was reached that tumor aggressiveness and prognosis can be predicted using hepatic tumor load and Ki-67 labeling index, which are thought to be clinically important factors when selecting systemic therapy for unresectable GI-NET. SSA therapy is considered appropriate for patients with a low hepatic tumor load and low Ki-67 value and everolimus for those with contraindications to SSA therapy. There was also agreement that the treatment strategy should be determined according to whether the origin is in the midgut, considering the biological differences. Based on this strategy, the experts have tentatively created treatment maps and applied them in representative cases of unresectable GI-NET. Japanese experts proposed tentative maps for optimal first-line treatment in patients with unresectable GI-NET. Further investigation is warranted to validate the usefulness of these maps. [ABSTRACT FROM AUTHOR]

Background: Well-differentiated (WD) neuroendocrine tumors (NETs) are a group of rare neoplasms with limited therapeutic options. Cabozantinib is an inhibitor of multiple tyrosine kinases with a pivotal role in NET pathogenesis, including c-MET and Vascular Endothelial Growth Factor Receptor 2 (VEGFR2). LOLA is the first prospective phase II trial aiming to assess the safety and activity of cabozantinib combined with lanreotide in WD NETs of gastroenteropancreatic (GEP), thoracic and of unknown origin. Methods: This is a multicenter, open-label, double-cohort, non comparative, non-randomized, three-stage phase II trial. Eligible patients have to meet the following inclusion criteria: diagnosis of advanced or metastatic, progressive, non-functioning WD thoracic NETs, GEP-NETs or NETs of unknown origin with Ki67 ≥ 10%; positive 68 Ga-PET uptake or somatostatin receptor 2 immunohistochemical (IHC) stain; maximum 1 prior systemic regimen for metastatic disease. Two cohorts will be considered: pNETs and carcinoids (typical or atypical lung and thymus NETs, gastro-intestinal NETs or NETs of unknown origin). In stage I, the primary objective is to find the optimal dose of cabozantinib in combination with lanreotide and to evaluate the safety of the combination (percentage of patients experiencing grade 3–5 toxicities according to NCI-CTCAE version 5.0). Starting dose of cabozantinib is 60 mg/day continuously, plus lanreotide 120 mg every 28 days. In stage II and III, co-primary endpoints are safety and overall response rate (ORR) according to RECIST version 1.1. The uninteresting antitumor activity is fixed in ORR ≤ 5%. Secondary endpoints are progression-free survival and overall survival. Exploratory objectives include the assessment of c-MET, AXL and VEGFR2 IHC expression, to identify predictive or prognostic tissue biomarkers. Enrolment started in July 2020, with an expected trial duration of 42 months comprehensive of accrual, treatment and follow-up. Considering a drop-out rate of 5%, the maximum number of enrolled patients will be 69. Discussion: Supported by a solid rationale, the trial has the potential to generate milestone data about the synergistic effects of cabozantinib plus lanreotide in a group of NET patients with relatively aggressive disease and limited therapeutic options. Trial registration: LOLA is registered at ClinicalTrials.gov (NCT04427787) and EudraCT (2019–004506-10). [ABSTRACT FROM AUTHOR]

Key Clinical Message: Kabuki syndrome is a congenital condition characterized by a set of facial dysmorphic features that often help the clinician to suspect the diagnosis. However, more insidious symptoms can rarely occur, such as manifestations of hypoglycemia in newborns with congenital hyperinsulinism hypoglycemia, especially when a variant of the KDM6A gene is found. In those cases, a treatment with diazoxide can be started and can be replaced with lanreotide if a satisfying glycemic control is not achieved. We report the case of a female patient born at 37 weeks of gestational age, without any obvious facial dysmorphic features, after a non‐complicated pregnancy, that presented with feeding difficulties, drowsiness, and irritability revealing a hyperinsulinemic hypoglycemia. Further testing at 6 months old found a KDM6A mutation. The patient was initially treated by diazoxide alone, but its dosage had to be lowered because of the occurrence of treatment side effects, and lanreotide had been added to maintain acceptable blood sugar levels. A congenital hyperinsulinemia hypoglycemia revealed heterozygous truncating variant in the KDM6A gene, also known as X‐linked Kabuki syndrome in a newborn. In cases of neonatal hypoglycemia, the first‐line therapy is diazoxide. Our report shows that analogues of somatostatin such as lanreotide should be considered if the diazoxide regimen is not tolerated. [ABSTRACT FROM AUTHOR]

Lanreotide autogel/depot (LAN) is a somatostatin analog used in first‐line treatment for neuroendocrine tumors (NETs). The aim of HomeLAN was to evaluate the satisfaction with injection experience among patients with NETs receiving at‐home LAN injection via patient support programs (PSPs). This was an international, non‐interventional, cross‐sectional, online survey in adults with NETs enrolled in PSPs, receiving LAN injections at home, administered by a healthcare professional (HCP) or administered independently (self or caregiver administering injection). The primary endpoint was satisfaction with the most recent LAN injection. Secondary endpoints included the level of anxiety prior to injection, impact on daily life, and the extents to which participants felt in control of their life and agreed that home administration met their medical needs. In total, 111 participants from Belgium, Greece, the Netherlands, and Spain completed the survey (50.5% male; mean age, 63.6 years; most common primary tumor site was intestine [47.7%]). For 99 participants, their most recent injection was administered by an HCP. Overall, 95.5% of all participants were satisfied with their most recent injection experience (95% confidence interval: 89.89%–98.06%); 67% reported experiencing no anxiety prior to injection, 91.0% reported that home injection had a "great deal" or "quite a bit" of positive impact on their daily life, and 85.6% strongly agreed that the PSP met their medical needs. In the HCP injection subgroup, 71.7% reported that this mode of administration helped them to feel in control of their lives. In this patient survey, satisfaction levels were high among patients with NETs receiving LAN injections at home via a LAN PSP. Most patients did not experience anxiety prior to their most recent injection and acknowledged that thanks to their treatment they had a good quality of life despite their disease. Most strongly agreed that the PSP met their medical needs, which highlights the valuable service that LAN PSPs provide for patients with NETs. [ABSTRACT FROM AUTHOR]

Purpose: According to IAEA/EANM/SNMMI guidelines, long-acting somatostatin analogues (LA-SSAs) should be discontinued 4–6 weeks prior to peptide receptor radionuclide therapy (PRRT) to prevent somatostatin receptor saturation. The aim of this study was to determine the effect of continued use of long-acting SSAs during PRRT on the uptake of [177Lu]Lu-HA-DOTATATE on SPECT/CT. Methods: Consecutive patients with neuroendocrine tumours who were treated with PRRT receiving 7.4 GBq of [177Lu]Lu-HA-DOTATATE were included. Patients were divided into 3 groups: (1) control (LA-SSA stopped > 6 weeks prior to PRRT), or continued treatment with (2) long-acting octreotide < 6 weeks prior to PRRT, or (3) long-acting lanreotide < 6 weeks prior to PRRT. The uptake of [177Lu]Lu-HA-DOTATATE was quantified in healthy tissues (spleen, liver, kidneys, bone marrow) and tumour lesions on SPECT/CT performed 24 h after PRRT. A Mann–Whitney U test was used to determine differences in uptake between the long-acting octreotide and long-acting lanreotide groups compared to the control group. Results: Forty-two patients with 135 cycles of PRRT were included: 28 with lanreotide, 50 with octreotide, and 57 cycles without LA-SSAs. Uptake of [177Lu]Lu-HA-DOTATATE was significantly decreased in liver parenchyma in patients with lanreotide (p < 0.001) and in the spleen in patients with either octreotide or lanreotide (both p < 0.001). No differences were observed for uptake in kidneys, bone marrow, and blood pool. Uptake of [177Lu]Lu-HA-DOTATATE in tumours was the same in patients with lanreotide compared to the control (p = 0.862) and in patients with octreotide compared to the control (p = 0.201), independent of tumour location. Conclusion: Long-acting octreotide and lanreotide do not interfere with the uptake of [177Lu]Lu-HA-DOTATATE in tumour lesions 24 h post-injection. Uptake in healthy liver parenchyma significantly decreases after lanreotide administration prior to PRRT, while uptake in healthy spleen tissue significantly decreases with both octreotide and lanreotide administration. [ABSTRACT FROM AUTHOR]

Meningioma is the most frequent brain tumor, and the incidence is ever-increasing. Though often benign and slow growth, recurrence rates are substantial and today's surgical and radiation-based treatment are not without complications. No drugs specific for meningiomas are hitherto approved and patients with inoperable or recurrent meningioma are left with few treatment options. Somatostatin receptors are previously detected in meningiomas and may inhibit growth when stimulated by somatostatin. Hence, somatostatin analogs could provide a targeted drug therapy. The aim of this study was to compile the current insights of somatostatin analogs for patients with meningioma. This paper adheres to the PRISMA extension for Scoping Reviews. A systematic search was conducted in the search databases PubMed, Embase via Ovid, and Web of Science. Seventeen papers adhered to the inclusion and exclusion criteria, and critical appraisal was conducted. The overall quality of evidence is low, as none of the studies were randomized or controlled. Various efficacy of somatostatin analogs is reported, and adverse effects are sparse. Due to the beneficial effects reported by some studies, somatostatin analogs may offer a novel last-option treatment for severely ill-patients. Nonetheless, only a controlled study, preferably a randomized clinical trial, could clarify the efficacy of somatostatin analogs. [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]

Purpose: A systematic literature review was conducted to assess the use of home injections (self/partner/healthcare provider [HCP]-administered) of somatostatin analogs (SSAs) as an alternative to healthcare-setting injections in patients with acromegaly and neuroendocrine tumors (NETs). Methods: MEDLINE/Embase/the Cochrane Library (2001–September 2021), key congresses (2019–2021), and bibliographies of relevant systematic reviews were searched. Eligible studies reported on efficacy/effectiveness, safety, adherence, patient-reported outcomes (PROs), and economic outcomes in populations receiving home injections of SSAs. Results: Overall, 12 studies were included, all reporting on SSAs (lanreotide Autogel/Depot or octreotide long-acting release) in acromegaly or NETs. Across four studies, home injection was associated with similar disease control in patients with acromegaly/NETs compared with healthcare-setting administration. High rates of treatment adherence were shown in two studies of patients with acromegaly receiving lanreotide injections at home. Two studies reported non-serious adverse events; incidence of adverse reactions was similar in both the home and healthcare administration settings. Preference for injection setting varied between studies and indications; nonetheless, higher satisfaction/convenience (>75% patients) was reported for home injections. Self- or partner-injection was associated with economic savings compared with administration in the healthcare setting across five studies. Conclusion: Efficacy/effectiveness, adherence, and safety outcomes of SSAs in the home injection setting were similar to those in the healthcare setting, with high reported satisfaction and convenience. Self/partner injection also resulted in cost savings. These findings provide a basis to understand outcomes related to home injection and encourage healthcare providers to discuss optimal treatment choices with their patients. Plain language summary: Acromegaly and neuroendocrine tumors (NETs) are two diseases that affect the production of hormones, leading to a variety of symptoms in different parts of the body. Patients can be treated with medications called somatostatin analogs, which include lanreotide Autogel/Depot (LAN) and octreotide long-acting release (OCT). These treatments are given by injections, usually performed by a doctor or nurse in a healthcare setting such as a hospital or clinic. However, patients can sometimes receive LAN or OCT injections at home by a healthcare professional or—for LAN only—independently by a partner or the patient themself. Home injection may be less disruptive for patients and could free up healthcare resources, but there is limited evidence to support the choice. To address this, we reviewed all publications on home injection of somatostatin analogs in the last 20 years, finding 12 relevant studies. Results generally showed that home injections and injections in the healthcare setting had a similar effect on disease signs and symptoms, and were equally safe. Patients receiving home injections were also successfully able to follow the treatment plan prescribed by their doctor. Although some patients still preferred to receive injections in the healthcare setting, patients generally found injections at home more convenient. Home injections also resulted in lower costs as fewer appointments at the hospital or clinic were needed. The findings of this review indicate that injections of somatostatin analogs at home, instead of in the healthcare setting, could be a potential option for patients whose circumstances allow it. [ABSTRACT FROM AUTHOR]

A common feature shared by most neuroendocrine tumors (NETs) is the expression on their surface of somatostatin receptors (SSTRs) that are essential for their pathophysiological regulation, diagnosis, and management. The first-generation synthetic somatostatin analogs (SSAs), octreotide and lanreotide, constitute the cornerstone of treatment for growth hormone secreting pituitary adenomas and functioning, progressive functioning, and non-functioning gastro-entero-pancreatic (GEP-NETs). SSAs exert their mechanism of action through binding to the SSTRs; however, their therapeutic response is frequently attenuated or diminished by the development of resistance. The phenomenon of resistance is complex implicating the presence of additional epigenetic and genetic mechanisms. We aim to analyze the molecular, genetic, and epigenetic mechanisms of resistance to SSA treatment. We also summarize recent clinical data related to the development of resistance on conventional and non-conventional modes of administration of the first-generation SSAs and the second-generation SSA pasireotide. We explore mechanisms used to counteract the resistance to SSAs using higher doses or more frequent mode of administration of SSAs and/or combination treatments. There is considerable heterogeneity in the development of resistance to SSAs that is tumor-specific necessitating the delineation of the underlying pathophysiological processes to further expand their therapeutic applications. [ABSTRACT FROM AUTHOR]

Neuroendocrine neoplasms (NENs) are a heterogeneous group of malignancies mainly arising in the gastroenteropancreatic (GEP) and bronchopulmonary systems, with steadily increasing incidence. The therapeutic landscape has widened and the therapeutic strategy should be based on new sequences and combinations, still debated. Herein, we provide an overview of current approved pharmacological treatments in patients with NENs, with the aim to summarize evidence of efficacy of the main different options in GEP and pulmonary NENs, principally focusing on somatostatin analogs (SSAs), targeted therapy with everolimus and sunitinib, peptide receptor radionuclide therapy (PRRT) and chemotherapy. We discuss biological rationale and toxicities, including current indications according to differentiation and placement in the therapeutic algorithm, clinical trials, and combinations. Furthermore, we recommend areas for further research. Therapeutic management of patients with NENs represents a challenge for clinicians and the identification of effective sequences and combinations is of utmost importance. Major efforts should be directed to early identify and overcome resistance and to limit toxicity. The progress in the therapeutic management of NENs grows faster and the choice of the best approach should be based on randomized clinical trials, as well as on long-term, real-world data. [ABSTRACT FROM AUTHOR]

Context: Congenital hyperinsulinism (HI) results in severe, persistent hypoglycemia and is associated with high risk of neurodevelopmental deficits. Sixty percent of HI cases are unresponsive to diazoxide, the only Food and Drug Administration–approved drug. Somatostatin analogs are used off-label as second-line treatment; the long-acting somatostatin analogue, lanreotide, has been used to treat HI over the past decade. Existing reports are limited to small case series. Objective: To assess the effectiveness and safety of lanreotide in individuals with HI. Design: Retrospective cohort study of individuals with HI treated with lanreotide between 2015 and 2020. Setting: The Congenital Hyperinsulinism Center at The Children’s Hospital of Philadelphia. Patients: Fifty-four individuals with hyperinsulinism treated with lanreotide. Main Outcome Measures: Fasting duration with plasma glucose > 70 mg/dL; frequency of lanreotide-associated side effects. Results: The median duration of lanreotide therapy was 28.7 (2.8-64.5) months. Thirty-four patients (63%) had HI due to inactivating mutations of the adenosine 5′-triphosphate (ATP) sensitive potassium channel (KATP-HI), and 39% had undergone a pancreatectomy. Of 52 patients receiving other HI therapies, 22 (42%) were able to discontinue other treatments and were managed on lanreotide alone. Fasting duration with plasma glucose > 70 mg/dL was significantly longer during therapy with lanreotide compared to prior to lanreotide initiation (8.6 ± 6.5 vs 5.1 ± 4.7 hours, P = 0.001). The most common side effects were subcutaneous nodules (26%) and gallstones (11%). Conclusions: Lanreotide is a well-tolerated treatment for patients with HI. It results in a longer duration of fasting and a simplification of treatment regimens. [ABSTRACT FROM AUTHOR]

Introduction: Few studies have attempted to evaluate the early efficacy of first‐generation somatostatin analogues in somatotroph macroadenomas. Objective: To investigate the short‐term efficacy of primary therapy with lanreotide 120 mg at 1 and 3 months on tumour shrinkage and ophthalmologic symptoms in newly diagnosed patients with acromegaly. Design and Patients: This single‐centre retrospective study included 21 patients with de novo acromegaly resulting from pituitary macroadenoma, with optic chiasm compression (Grade ≤ 2) and/or cavernous sinus invasion, treated with a monthly injection of lanreotide 120 mg. Clinical, hormonal, ophthalmologic and magnetic resonance imaging scan evaluations were conducted after the first and the third months of treatment. Results: Tumour volume reduction was more pronounced at 1 month; mean volume change: −31.4 ± 19.5%, p <.0001 than between the first and third month of treatment; mean volume reduction: −20.6 ± 13.4%, p =.0009. The mean volume change between baseline and the third month was − 46.4 ± 21.6, (p <.0001). A significant volume reduction (≥25%) was observed in 61.9% of individuals (13/21) at the first month. Among 14 individuals with optic chiasm compression and visual field defects, visual field normalization or improvement were observed in seven cases (50%), stabilization in four cases (28.5%), and mild worsening in three cases (21.4%) at 1 month. The decrease in growth hormone and IGF‐1 serum values was significant at 1 month. Conclusions: Primary treatment with lanreotide 120 mg in patients with somatotroph macroadenomas provides early significant tumour shrinkage with rapid improvement of visual symptoms at the end of the first month in 50% of patients. [ABSTRACT FROM AUTHOR]

Gastrointestinal angiodysplasias (GIADs) are the most common causes for suspected small bowel bleeding. Fifty percent of GIADs do not need treatment due to bleeding cessation, while 45% have high re-bleeding rates, that significantly impact patient outcome and health resource utilization. We suspected that this high re-bleeding rate occurs because not all lesions are detected with present standard of care. This study evaluates whether device-assisted enteroscopy (DAE) utilizing the Endocuff (EC) device could improve GIAD detection. A retrospective chart review of a prospective data collection was performed from January 2006 to December 2018 at VA Loma Linda Healthcare System (VALLHCS) on both inpatients and outpatients referred for active and chronic suspected small bowel bleeding. The patients were initially monitored for bleeding lesions via video capsule endoscopy (VCE) after negative upper and lower endoscopy. GIADs observed between 0% to 40% small bowel transit time (SBTT) were referred for push enteroscopy (PE) with and without (±) the EC device. Twenty-five consecutive patients underwent PE ± EC. No patient had VCE done after PE ± EC. Using PE-EC, GIADs were detected in 9 of 25 (36%) of patients. Importantly, PE+EC detected GIADs in 23 of 25 (92%) patients. The sum of GIADs detected without EC was 26 ± 0.06 vs. 112 ± 0.2 using EC. The average detection rate for PE without EC was significantly lower (1.04 ± 0.06, mean ± SE) as compared to PE with EC (4.48 ± 0.23, mean ± SE, p<0.0005). Additionally, a positive correlation (r=0.51) between capsule enteroscopy (CE) location of GIADs and SBTT was found. The EC device increases the detection of GIADs in the proximal small bowel. We also reconfirm that the location of bleeding GIADs are within the reach of the push enteroscope (PE). Finally, PE + EC may also reduce GIAD miss rates, which may play a role in the reduction of re-bleeding episodes. [ABSTRACT FROM AUTHOR]

Introduction: Long-acting somatostatin analogues such as lanreotide autogel (LAN) and octreotide long-acting release (OCT) are recommended as first-line treatment for patients with neuroendocrine tumors (NETs). However, only few real-world studies have compared the two medications. This retrospective, observational cohort study used a French claims database to compare patterns of use with LAN vs. OCT in patients with NETs. Methods: Data on LAN and OCT patterns of use were obtained retrospectively from the National System of Health Data (SNDS), a national French claims database. Patients 18 years of age or older who initiated treatment for NETs between 2009 and 2016, and who received at least six subsequent dispensings of first-line LAN or OCT during the first year of treatment, were included. A subgroup analysis was performed on patients with gastroenteropancreatic (GEP)-NETs. Results: Patients receiving LAN (n = 2327) vs. OCT (n = 2090) had greater median treatment duration (31.8 months vs. 22.1 months, respectively; p < 0.0001; log-rank test) and were less likely to discontinue treatment; adjusted hazard ratio (HR) 0.74 (95% confidence interval [CI] 0.69–0.80). In year 1, a significantly lower percentage of patients receiving LAN vs. OCT switched treatments (10.4% vs. 22.2%, respectively; p < 0.0001), received an average monthly dose per trimester above recommended dose (3.0% vs. 7.3%, respectively; p < 0.0001), and used rescue medication (3.1% vs. 10.0%, respectively; p < 0.0001). Dispensing of pancreatic enzymes was significantly higher in patients receiving LAN than OCT (16.4% vs. 13.9%, respectively). In the subgroup of patients with GEP-NETs, those receiving LAN (n = 1478) vs. OCT (n = 1278) had greater treatment duration and less treatment discontinuation, switching, dosage above the recommended dose, and rescue medication use, but no significant difference in dispensing of pancreatic enzymes or time to second-line treatment. Conclusion: These real-world data suggest potential clinical and economic advantages of LAN over OCT in the management of patients with NETs in the French population. [ABSTRACT FROM AUTHOR]

Somatostatin analogues (SA) are currently used to prevent postoperative pancreatic fistula (POPF) development. However, its use is controversial. This study investigated the effect of different SA protocols on the incidence of POPF after pancreatoduodenectomy in a nationwide population. All patients undergoing elective open pancreatoduodenectomy were included from the Dutch Pancreatic Cancer Audit (2014–2017). Patients were divided into six groups: no SA, octreotide, lanreotide, pasireotide, octreotide only in high-risk (HR) patients and lanreotide only in HR patients. Primary endpoint was POPF grade B/C. The updated alternative Fistula Risk Score was used to compare POPF rates across various risk scenarios. 1992 patients were included. Overall POPF rate was 13.1%. Lanreotide (10.0%), octreotide-HR (9.4%) and no protocol (12.7%) POPF rates were lower compared to the other protocols (varying from 15.1 to 19.1%, p = 0.001) in crude analysis. Sub-analysis in patients with HR of POPF showed a significantly lower rate of POPF when treated with lanreotide (10.0%) compared to no protocol, octreotide and pasireotide protocol (21.6–26.9%, p = 0.006). Octreotide-HR and lanreotide-HR protocol POPF rates were comparable to lanreotide protocol, however not significantly different from the other protocols. Multivariable regression analysis demonstrated lanreotide protocol to be positively associated with a low odds-ratio (OR) for POPF (OR 0.387, 95% CI 0.180–0.834, p = 0.015). In-hospital mortality rates were not affected. Use of lanreotide in all patients undergoing pancreatoduodenectomy has a potential protective effect on POPF development. Protocols for HR patients only might be favorable too. However, future studies are warranted to confirm these findings. [ABSTRACT FROM AUTHOR]

Simple Summary: Neuroendocrine tumors (NETs) are a group of heterogenous neoplasms arising from the diffuse neuroendocrine system. Several therapies have been added to the treatment landscape that have improved long-term outcomes. Despite therapeutic advancements, the symptom burden of the disease remains high, impacting health-related quality of life (HRQoL). In this study, we reviewed the impact of different treatment modalities on HRQoL in NET patients. Through a thorough literature review, 61 out of 2375 publications met the inclusion criteria. All randomized phase III trials leading to drug approvals showed a lack of deterioration of HRQoL, and one showed improved QoL. Capturing and understanding patient-reported outcome data is of vital importance for both patients and physicians to make treatment-related decisions. Therapeutic advancements in neuroendocrine tumors (NETs) have improved survival outcomes. This study aims to review the impact of the current therapeutics on health-related quality of life (HRQoL) in NET patients. A literature review was performed utilizing PubMed, The Cochrane Library, and EMBASE, using the keywords "Carcinoid", "Neuroendocrine tumor", "NET", "Quality of life", "Chemotherapy", "Chemoembolization", "Radiofrequency ablation", "Peptide receptor radionucleotide therapy", "PRRT", "Surgery", "Everolimus", "Octreotide", "Lanreotide", "Sunitinib", and "Somatostatin analog". Letters, editorials, narrative reviews, case reports, and studies not in English were excluded. Out of 2375 publications, 61 studies met our inclusion criteria. The commonly used instruments were EORTC QLQ-C30, FACT G, and EORTC- QLQ GI.NET-21. HRQoL was assessed in all pivotal trials that led to approvals of systemic therapies. All systemic therapies showed no worsening in HRQoL. The NETTER-1 study was the only study to show a statistically significant improvement in HRQoL in several domains. The trial examining sunitinib versus placebo in pancreatic NETs showed no change in QoL, except for worsening of diarrhea. In addition to clinical outcomes, patient-reported outcomes are a key element in making appropriate treatment decisions. HRQoL data should be readily provided to patients to assist in shared decision-making. [ABSTRACT FROM AUTHOR]

Introduction: Somatostatin analogs (SSA) prolong progression-free survival (PFS) in patients with well-differentiated gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). However, the eligibility criteria in randomized clinical trials (RCTs) have been restricted, which contrasts with the vast heterogeneity found in NENs. Methods: We identified patients with well-differentiated (Ki-67% ≤20%), metastatic GEP-NENs treated in first line with SSA monotherapy from the Spanish R-GETNE registry. The therapeutic effect was evaluated using a Bayesian Cox model. The objective was to compare survival-based outcomes from real-world clinical practice versus RCTs. Results: The dataset contained 535 patients with a median age of 62 years (range: 26–89). The median Ki-67% was 4 (range: 0–20). The most common primary tumor sites were as follows: midgut, 46%; pancreas, 34%; unknown primary, 10%; and colorectal, 10%. Half of the patients received octreotide LAR (n = 266) and half, lanreotide autogel (n = 269). The median PFS was 28.0 months (95% CI: 22.1–32.0) for octreotide versus 30.1 months (95% CI: 23.1–38.0) for lanreotide. The overall hazard ratio for lanreotide versus octreotide was 0.90 (95% credible interval: 0.71–1.12). The probability of effect sizes >30% with lanreotide versus octreotide was 2 and 6% for midgut and foregut NENs, respectively. Conclusion: Our study evaluated the external validity of RCTs examining SSAs in the real world, as well as the main effect-modifying factors (progression status, symptoms, tumor site, specific metastases, and analytical data). Our results indicate that both octreotide LAR and lanreotide autogel had a similar effect on PFS. Consequently, both represent valid alternatives in patients with well-differentiated, metastatic GEP-NENs. [ABSTRACT FROM AUTHOR]

The incidence of high-output stoma (HOS) was reported to be approximately 3 to 16% in the literature, and HOS can cause dehydration. This complication is often severe enough to warrant hospital readmission and may result in renal failure. The aim of this study was to show a decrease of 50% in ileostomy output in the experimental arm using lanreotide treatment. Patients with an ileostomy output ≥ 1.5 l/24 hours were included in this prospective, open, multicentre randomized trial. Patients were randomly allocated between treatment arms with either lanreotide (LAN) and antidiarrhoeal treatments (TAD) (LAN-TAD group) or antidiarrhoeal treatments only (TADS group). The primary outcome was ileostomy output after 72 days. The secondary endpoints were ileostomy output during the first 6 days, blood urea and creatinine values, hospital length of stay and serious adverse events. In the per-protocol analysis, there were nine patients in the control group (TADS) and six patients in the experimental group (TAD-LAN group). The stoma outputs at Day 3 (D3) in the experimental and control groups were 1,900 ± 855.7 mL and 1,728.6 ± 845.5 mL, respectively (p = 0.2). No differences were found concerning stoma output at D6, renal function, or hospital length of stay between the two groups. The trial was prematurely stopped due to the low number of patients included. The question of the usefulness of somatostatin analogues in HOS persists, especially as the cost of this treatment is high, and there is a lack of evidence of its effectiveness. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study was to describe the long‐term safety and efficacy of lanreotide in Japanese patients with neuroendocrine tumors. Methods: The final analyses of a 48‐week open‐label phase II study (n = 32) and its extension study (n = 17) were conducted. Patients received 4‐weekly subcutaneous injections of lanreotide autogel 120 mg. Safety was evaluated by adverse events. Efficacy endpoints included tumor response by RECIST and change in tumor size. Post hoc analyses including tumor growth rate were performed. Results: The median (range) of lanreotide exposure in the safety analysis set (n = 17) and efficacy analysis set (n = 28) were 151.4 (52–181) and 52.7 (12–181) weeks, respectively. Sixteen patients developed adverse drug reaction; of these, upper abdominal pain and urticaria were not reported before 48 weeks. No patient discontinued lanreotide or died from an adverse event. Two serious events of bile duct stones in one patient were drug‐related. Partial response was observed in 2 patients (7.1%; at 60 and 108 weeks), stable disease in 20 (71.4%) and progressive disease in 6 (21.4%). The mean of the greatest change from baseline in the sum of diameters of target lesions was −5.5%. The mean (standard deviation) tumor growth rate before treatment and from baseline to last observation was 25.3% (35.7%)/month and 6.4% (9.6%)/month, respectively. Conclusion: Lanreotide treatment had an acceptable safety profile and was effective over long‐term treatment in Japanese patients with neuroendocrine tumors. No unexpected serious adverse events developed during prolonged use of lanreotide. [ABSTRACT FROM AUTHOR]

Purpose: To compare biochemical and tumor response rates between two reference centers for pituitary diseases in Brazil after primary and adjuvant therapy with somatostatin receptor ligands (SRL) in acromegaly. Methods: Patients were classified as non-responders (NR), partial responders (PR), and full responders (FR) to 12-month SRL therapy according to: [criteria A] normal IGF-I and random GH (rGH) < 1 ng/mL (FR); ≥ 50% decrease of IGF-I and/or rGH (PR); < 50% decrease of IGF-I and rGH (NR); [criteria B] normal IGF-I (FR); ≥ 50% decrease of IGF-I (PR); < 50% decrease of IGF-I (NR). Tumor shrinkage <20% defined poor responders (tPR) and ≥ 20% good responders (tGR). Results: We studied 219 acromegaly patients (59% women, age 43.1 ± 13.9 years; 73 from Center I and 146 from Center II). After SRL therapy, the proportion of FR, PR, and NR by criteria A and B was 30.2 vs 49.1%, 52.8 vs 21.2% and 17 vs 29.7%, respectively (p < 0.001). Considering criteria A or B separately, there was no difference in the proportion of FR, PR and NR between two centers. However, when comparing criteria A and B, the Center I showed a difference of 30.9% in classification of FR in relation to 13.2% observed in Center II (p = 0.006). tGR were 51.4% of patients, with no differences between the centers. Conclusions: IGF-I alone significantly increased positive response rates to SRLs, whereas the inclusion of rGH levels into therapeutic decision might lead to a significant increment on the costs of acromegaly management. [ABSTRACT FROM AUTHOR]

Octreotide acetate (octreotide) is the most prescribed and most studied somatostatin congener, or analog, for gastroenteropancreatic neuroendocrine tumors (GEP‐NETs) and carcinoid syndrome, the latter of which may be characterized by debilitating diarrhea and flushing. Approved in the U.S. more than 30 years ago, octreotide is widely used to control the symptoms of carcinoid syndrome and has been shown to demonstrate antiproliferative activity. The two formulations available in the U.S. include a subcutaneous immediate‐release (IR) injection introduced in 1989 and a long‐acting repeatable (LAR) intramuscular injection approved in 1999. Lanreotide depot (lanreotide), a more recent somatostatin congener, has been available in the U.S. since 2014. Despite widespread use of octreotide LAR, several key challenges exist with the current depot‐based treatment paradigm. Studies indicate that LAR formulations are associated with continued unmet patient needs, owing in part to a loss of bioactivity over time that may necessitate progressive supplemental treatment with IR octreotide to adequately control symptoms. Clinicians should understand the key differences in the pharmacokinetic profiles of the LAR and IR formulations that may contribute to bioactivity loss and somatostatin receptor desensitization. In addition, there is a need to re‐evaluate the role of IR octreotide in combination with depot therapy to provide consistent bioavailability and better control of carcinoid syndrome symptoms. The purpose of this review is to explore all these issues and to re‐establish a rationale for the IR formulation, particularly with respect to novel use cases and its use during the COVID‐19 pandemic. Implications for Practice: There is a need to re‐evaluate the role of immediate‐release octreotide in combination with depot therapy to provide consistent bioavailability and better control of carcinoid syndrome symptoms. This review explores key challenges with depot‐based treatment of gastroenteropancreatic neuroendocrine tumors with octreotide and the key differences between the LAR and IR formulations. [ABSTRACT FROM AUTHOR]

Although combination therapy is not recommended in patients with gastro-entero-pancreatic (GEP) neuroendocrine tumors (NETs), this strategy is widely used in clinical practice. This network meta-analysis of randomized trials evaluates targeted therapies and somatostatin analogues in GEP-advanced NETs, either alone or in combination, comparing the efficacy of different, single or combined treatment strategies in terms of progression-free survival (PFS). Interventions were grouped as analogs, everolimus, everolimus plus SSAs, sunitinib and placebo. In a secondary analysis, we also assessed the efficacy of individual-specific pharmacological treatments vs placebo or each other. From 83 studies identified, 8 randomized controlled trials were selected, with a total of 1849 patients with either functioning or non-functioning NETs. The analysis confirmed the superiority of all treatments over placebo (HR ranging from 0.34, 95% CI: 0.24-0.37 with the combination of everolimus plus SSAs to 0.42, 0.31-0.57 with the analogs; moderate quality of evidence). On ranking analysis, the combination of everolimus plus SSA (P score = 0.86) and then everolimus alone (P score = 0.65) ranked highest in increasing PFS. On comparative evaluation of different interventions, pasireotide (P score = 0.96) and everolimus + octreotide (P score = 0.82) ranked as the best pharmacological treatment options. Our findings support the use of combination therapy in the treatment of functioning and non-functioning GEP NETs. The role of pasireotide should be explored in selected subgroups of patients. Lastly, the combination of everolimus and octreotide appears promising and should be more widely considered in clinical practice. [ABSTRACT FROM AUTHOR]

Background: Above-label doses of somatostatin analogs (SSAs) are increasingly utilized in the management of inoperable/metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs), progressing on standard 4-weekly regimens. Objective: To evaluate the antiproliferative effect of 3-weekly SSA administration in a retrospective GEP-NET cohort. Methods: Patients with advanced GEP-NET, treated with long-acting release (LAR) octreotide 30 mg or lanreotide Autogel 120 mg at a 3-weekly interval, after disease progression on standard 4-weekly doses, were retrospectively identified. Clinicopathologic and treatment response data were collected. Progression-free survival (PFS; dose escalation to radiographic progression or death) was estimated with the Kaplan-Meier method. Factors associated with PFS were identified with the Cox proportional-hazards model. Results: The inclusion criteria were fulfilled by 105 patients. Octreotide LAR was administered to 60 (57%) and lanreotide Autogel to 45 (43%). Indications for dose escalation were breakthrough carcinoid symptoms (58%), radiographic progression (35%) and/or increasing biomarkers (11%). Diarrheal and/or flushing symptomatic improvement was identified in 37/67 cases (55%) and 30/55 cases (55%) with available data, respectively. The disease control rate (radiographic partial response or stable disease) was achieved in 53 patients (50%). Median PFS was 25.0 months (95% CI 16.9–33.1). Patients with radiographic progression <12 months from 4-weekly SSA initiation had worse PFS after dose escalation (7.0 vs. 17.0 months, p = 0.002). In multivariate analysis, pancreatic NETs, a Ki-67 index ≥5% and multiple extrahepatic metastases were independently associated with inferior PFS. Conclusions: Above-label doses of SSAs may offer a considerable prolongation of PFS and could be utilized as a bridge to other more toxic treatments. Patients with small bowel/colorectal primaries, a Ki-67 index <5% and absence of/limited extrahepatic metastases are more likely to benefit from this approach. [ABSTRACT FROM AUTHOR]

Long‐acting somatostatin analogs, including lanreotide slow release (LAN‐SR) and octreotide long‐acting release (OCT‐LAR), can improve hypoglycemia in insulinoma. LAN‐SR may be more beneficial in some patients with insulinoma than OCT‐LAR. [ABSTRACT FROM AUTHOR]

Purpose: Somatostatin receptor ligands (SRL) are the first-line medical treatment for acromegaly. Gallbladder alterations are one of most important SRL side effect, but according to some authors growth hormone hypersecretion itself is a risk factor for gallstones. This single center, longitudinal retrospective study evaluated the incidence and the predictors of biliary adverse events (BAE) in acromegaly during SRL therapy and their response to ursodeoxycholic acid (UDCA). Methods: 91 acromegaly patients with indication to SRL were enrolled. Evaluations of acromegaly activity (GH, IGF-I, IGF-I/ULN) and metabolic profile were collected before starting treatment, yearly during follow-up and at BAE onset. In patients developing BAE we searched for predictors of UDCA effectiveness. Results: 61.5% of patients developed BAE (58.9% cholelithiasis; 41.1% only sludge). IGF-I and IGF-I/ULN proved to be positive predictor of BAE, which occur about 5 years after SRL starting. None of metabolic markers proved to be associated with BAE. Only five patients (5.5%) underwent cholecystectomy for symptomatic cholelithiasis. 71% of patients started UDCA treatment, achieving regression of BAE in 60% of cases (88% in patients developing only sludge and 30% in patients affected by cholelithiasis, p < 0.001). BMI and obesity were negative predictors of UDCA efficacy. In 50% of the subjects BAE resolved after 36 months of therapy with a lower rate if cholelithiasis was present. Conclusion: Biliary stone disease is a frequent SRL adverse event, although it is often symptomless. Ultrasound follow-up mainly in the first 5 years of therapy, early UDCA starting and proper lifestyle represent a valid strategy in their detection and management. [ABSTRACT FROM AUTHOR]

Background: Long‐acting somatostatin analogs (SSAs) are the primary first‐line treatment of well‐differentiated advanced gastroenteropancreatic neuroendocrine tumors (NETs), but data about their efficacy in pancreatic NETs (panNETs) with Ki‐67 ≥10% are still limited. Materials and Methods: To assess the clinical outcomes of advanced, nonfunctioning, well‐differentiated panNETs with Ki‐67 ≥10% receiving first‐line long‐acting SSAs in a real‐world setting, we carried out a retrospective, multicenter study including patients treated between 2014–2018 across 10 centers of the NET CONNECT Network. The primary endpoints were time to next treatment (TNT) and progression‐free survival (PFS), whereas overall survival (OS) and treatment safety were secondary endpoints. Results: A total of 73 patients were included (68 grade [G]2, 5 G3), with liver metastases in 61 cases (84%). After a median follow‐up of 36.4 months (range, 6–173), the median TNT and PFS were 14.2 months (95% confidence interval [CI], 11.6–16.2) and 11.9 months (95% CI, 8.6–14.1) respectively. No statistically significant difference was observed according to the somatostatin analog used (octreotide vs. lanreotide), whereas increased tumor grade (hazard ratio [HR], 4.4; 95% CI, 1.2–16.6; p =.04) and hepatic tumor load (HR, 2; 95% CI, 1–4; p =.03) were independently associated with shortened PFS. The median OS recorded was 86 months (95% CI, 56.8–86 months), with poor outcomes observed when the hepatic tumor burden was >25% (HR, 3.4; 95% CI, 1.2–10; p =.01). Treatment‐related adverse events were reported in 14 patients, most frequently diarrhea. Conclusion: SSAs exert antiproliferative activity in panNETs with Ki‐67 ≥10%, particularly in G2 tumors, as well as when hepatic tumor load is ≤25%. Implications for Practice: The results of the study call into question the antiproliferative activity of somatostatin analogs (SSAs) in pancreatic neuroendocrine tumors with Ki‐67 ≥10%. Patients with grade 2 tumors and with hepatic tumor load ≤25% appear to derive higher benefit from SSAs. Prospective studies are needed to validate these results to optimize tailored therapeutic strategies for this specific patient population. Long‐acting somatostatin analogs (SSAs) are the primary first‐line treatment of advanced gastroenteropancreatic neuroendocrine tumors. This study assessed the clinical outcomes of patients with pancreatic neuroendocrine tumors and a Ki‐67 ≥10% treated with long‐acting SSAs as first‐line antitumor therapy in a real‐world setting. [ABSTRACT FROM AUTHOR]

Neuroendocrine tumors (NETs) are a group of malignancies arising from neuroendocrine cells and frequently originate in the gastrointestinal tract and pancreas. Although curative resection is the main treatment for localized disease, systemic therapy is needed for relapsed or metastatic/unresectable gastroenteropancreatic NETs (GEP-NETs). Although there are several NET treatment guidelines from various countries, the geographical discrepancies between patient clinical characteristics, the regulatory approval status for therapeutic agents, and medical practices necessitate specific guidelines for Korean patients. We here provide a consensus review of the diagnosis, staging and systemic treatment of Korean GEP-NET patients. Systemic therapy options and the current Korean expert consensus on these treatments, including somatostatin analogs, targeted therapies such as everolimus and sunitinib, peptide receptor radionuclide treatments, and cytotoxic chemotherapies are addressed. [ABSTRACT FROM AUTHOR]

Context Acromegaly is a rare disease caused by excessive growth hormone (GH) secretion from pituitary adenomas in most cases. If neurosurgical therapy is contraindicated or not sufficient, medical therapy is the second line therapy. Objective To describe current medical therapy in acromegaly. Design & Methods Retrospective data analysis from 2732 patients treated in 69 centers of the German Acromegaly Registry. 749 patients were seen within the recent 18 months, of which 420 were on medical therapy (56.1%). Results 73% of medically treated acromegalic patients had normal/low IGF-1 levels. 57% of patients with non-normalized IGF-1 levels had an IGF-1 value between 1- and 1.25-fold above the upper limit of normal. Most patients (55%) received somatostatin analogs as monotherapy, 12% GH receptor monotherapy, and 9% dopamine agonist therapy. Doses of each medical therapy varied widely, with 120 mg lanreotide LAR every 4 weeks, 30 mg octreotide LAR every 4 weeks, 140 mg pegvisomant per week and 1mg cabergoline per week being the most frequent used regimens. A combination of different medical regimens was used in almost 25% of the patients. Conclusion The majority of German acromegalic patients receiving medical therapy are controlled according to normal IGF-1 levels. [ABSTRACT FROM AUTHOR]

Background: Somatostatin analogs (SSAs) are the frontline antitumor therapy in advanced well‐differentiated gastroenteropancreatic neuroendocrine tumors (GEP‐NETs). A subset of patients demonstrate early disease progression on SSA therapy, yet the currently known predictors for treatment failure lack specificity to affect therapeutic decision. SSAs target tumor somatostatin receptors, the level of which can be quantitatively assessed with 68Ga‐DOTATATE positron emission tomography‐computed tomography (PET/CT). We investigated the ability of 68Ga‐DOTATATE PET/CT to predict response to SSA therapy. Materials and Methods: The records of 108 consecutive patients with well‐differentiated grade 1–2 GEP‐NETs on SSA monotherapy who received 68Ga‐DOTATATE PET/CT scans were retrospectively reviewed to obtain baseline characteristics, 68Ga‐DOTATATE maximum standardized uptake value (SUVmax), and progression‐free survival (PFS) data. The optimal SUVmax cutoff for patient stratification was obtained with receiver operating characteristic curve analysis. PFS in the high versus low SUVmax groups was compared with Kaplan‐Meier survival analysis. The effects of baseline characteristics and SUVmax on PFS were examined with univariate and multivariate Cox regression. Results: 68Ga‐DOTATATE SUVmax predicted therapeutic failure with sensitivity and specificity of 39% and 98%, respectively. SUVmax of <18.35 was associated with shorter PFS, which was reproduced in the subgroup analysis of SSA‐naïve patients. Low SUVmax was the only predictor of early treatment failure (hazard ratio, 6.85) in multivariate analysis, as well as in the subgroup analysis of grade 2 GEP‐NETs. Conclusion: Low SUVmax on 68Ga‐DOTATATE PET/CT independently predicts early failure on SSA monotherapy in patients with well‐differentiated grade 1–2 GEP‐NET. Patients with lack of expected benefit from SSA therapy can be readily identified using routine 68Ga‐DOTATATE PET/CT with very high specificity. Implications for Practice: Based on 68Ga‐DOTATATE positron emission tomography‐computed tomography imaging, clinicians can better inform patients on the expected benefit of somatostatin analog therapy for gastroenteropancreatic neuroendocrine tumors, especially when access to the therapy is difficult, and offer proactive discussion on alternative management options. Somatostatin analogs (SSAs) are the frontline antitumor therapy for patients with advanced well‐differentiated gastroenteropancreatic neuroendocrine tumors. This study investigated the ability of 68Ga‐DOTATATE PET/CT to predict response to SSA therapy. [ABSTRACT FROM AUTHOR]

Purpose: Recent data indicate that extended dosing intervals (EDIs) with lanreotide autogel 120 mg are effective and well-received among patients with acromegaly who have achieved biochemical control with monthly injections of long-acting somatostatin analogues (SSAs). We further evaluated the effectiveness of lanreotide autogel 120 mg delivered at EDIs (>4 weeks) in routine clinical practice. Methods: Cross-sectional, multicentre, observational study conducted to determine the effectiveness—measured by control of serum insulin-like growth factor 1 (IGF-1)—of lanreotide autogel 120 mg at dosing intervals >4 weeks for ≥6 months in selected patients with acromegaly treated in routine clinical practice (NCT02807233). Secondary assessments included control of growth hormone (GH) levels, treatment adherence, patient satisfaction, and quality of life (QoL) using validated questionnaires (EQ-5D, AcroQoL, and TSQM-9). Patients who received radiotherapy within the last 6 months were excluded. Results: Among 109 patients evaluated, mean (SD) age was 59.1 (13.2) years. IGF-1 values were normal (mean [SD]: 175.0 [74.5], 95% CI: 160.8 –189.1) in 91.7% of cases and normal in 91.4% of patients without previous radiotherapy treatment (n = 81). GH levels were ≤2.5 and ≤1 ng/mL, respectively, in 80.6% and 58.3%. Most patients were treated either every 5–6 (57.8%) or 7–8 weeks (38.5%), with 2.8% treated greater than every 8 weeks. The mean AcroQoL score was 63.0 (20.1). The mean global treatment satisfaction score (TSQM-9) was 75.1 (16.6). Treatment adherence (defined as no missed injections) was 94.5%. Conclusion: Lanreotide autogel 120 mg at intervals of >4 weeks provided IGF-1 control in more than 90% of patients with acromegaly. Treatment satisfaction and adherence were good. These findings support use of extended dosing intervals in patients who have achieved good biochemical control with long-acting SSAs. [ABSTRACT FROM AUTHOR]

Hyperinsulinemic hypoglycemia (HH) is characterized by unregulated insulin release, leading to persistently low blood glucose concentrations with lack of alternative fuels, which increases the risk of neurological damage in these patients. It is the most common cause of persistent and recurrent hypoglycemia in the neonatal period. HH may be primary, Congenital HH (CHH), when it is associated with variants in a number of genes implicated in pancreatic development and function. Alterations in fifteen genes have been recognized to date, being some of the most recently identified mutations in genes HK1, PGM1, PMM2, CACNA1D, FOXA2 and EIF2S3. Alternatively, HH can be secondary when associated with syndromes, intra-uterine growth restriction, maternal diabetes, birth asphyxia, following gastrointestinal surgery, amongst other causes. CHH can be histologically characterized into three groups: diffuse, focal or atypical. Diffuse and focal forms can be determined by scanning using fluorine-18 dihydroxyphenylalanine-positron emission tomography. Newer and improved isotopes are currently in development to provide increased diagnostic accuracy in identifying lesions and performing successful surgical resection with the ultimate aim of curing the condition. Rapid diagnostics and innovative methods of management, including a wider range of treatment options, have resulted in a reduction in co-morbidities associated with HH with improved quality of life and long-term outcomes. Potential future developments in the management of this condition as well as pathways to transition of the care of these highly vulnerable children into adulthood will also be discussed. [ABSTRACT FROM AUTHOR]

Context: Acromegaly registries constitute a valuable source of therapeutic outcome information in real-life.Objective: The objective of this work is to analyze surgical and pharmacological outcomes in the Mexican Acromegaly Registry (MAR).Design and Methods: Data were extracted from the MAR informatic platform. Surgical remission was defined by a postoperative postglucose (GH) of less than 1 ng/mL and an insulin-like growth factor 1 (IGF-1) of less than 1.2 × upper limit of normal (ULN). Pharmacological remission was defined by a basal GH of less than 1 ng/mL and an IGF-1 of less than 1.2 × ULN.Results: A total of 650 surgical outcomes were analyzed (94.6% transsphenoidal). Surgical remission was achieved in 40.15%, whereas 44.15% remained biochemically active. Persistently active disease after surgery was significantly associated with harboring an invasive macroadenoma, a basal GH of greater than 10 ng/mL, and/or an IGF-1 of greater than 2 × ULN at diagnosis on bivariate and multivariate analysis. The outcome of monotherapy with first-generation somatostatin analogs (SSAs) was evaluated in 267 patients (adjunctive in 65%), of whom 28.4% achieved remission. Persistently active disease was significantly associated with harboring an invasive macroadenoma as well as with pretreatment basal GH and IGF-1 levels of greater than 10 ng/mL and greater than 2 × ULN, respectively, on bivariate and multivariate analysis. Combined therapy with SSA and cabergoline was analyzed in 100 patients, of whom 19% achieved remission and 44% remained active; in this subset of patients, only a pretreatment IGF-1 of greater than 2 × ULN was significantly associated with persistent disease activity.Conclusion: Surgical and pharmacological outcomes in acromegaly are highly dependent on tumor size/invasiveness as well as on the degree of hypersomatotropinemia. [ABSTRACT FROM AUTHOR]

Aim: To investigate the protective effect of octreotide and lanreotide on ovarian damage in experimental ovarian ischemia–reperfusion injury. Methods: Fifty‐six rats were separated into seven groups; group 1: sham group, group 2: surgical control group with 3‐h torsion and detorsion, group 3: 0.02 mg/kg s.c. octreotide 30 min before 3‐h torsion, group 4; octreotide just after detorsion for 7 days, group 5: octreotide 30 min before torsion and just after detorsion for 7 days, group 6: single time 20 mg/kg s.c. lanreotide before torsion, group 7: single time lanreotide just after detorsion. Results: All histopathological scores except congestion were significantly lower in group 1 than other groups. In addition, hemorrhage (group 2 vs 4: P < 0.05), degeneration (group 2 vs 4: P < 0.05, group 2 vs 5: P < 0.01 and group 2 vs 6: P < 0.05) and total damage score (group 2 vs 4: P < 0.05, group 2 vs 5: P < 0.05, group 2 vs 6: P < 0.05 and group 2 vs 7: P < 0.05) were significantly lower than other groups. Moreover, ovarian tissue total oxidant status and oxidative stress index levels were significantly decreased in groups 5 (both P < 0.05) and 7 (both P < 0.05) when compared to group 2. Furthermore, tissue levels of peroxynitrite were significantly higher in group 2 than groups 1, 3 and 5 (all P < 0.05). Conclusions: Octreotide and lanreotide have a protective role against ischemia–reperfusion damage in rat torsion detorsion model by improving histopathological and biochemical findings including tissue levels of total oxidant status, oxidative stress index and peroxynitrite. [ABSTRACT FROM AUTHOR]

Everolimus is recognized as one of the standard drugs for the treatment of unresectable or recurrent gastroenteropancreatic neuroendocrine tumors (NET). However, recent evidence has suggested that addition of somatostatin analogs to everolimus may yield better survival outcomes as compared to everolimus alone. In April 2020, we have initiated a randomized phase III trial in Japan, to confirm the superiority of combined everolimus plus lanreotide therapy over everolimus monotherapy in patients with unresectable or recurrent gastroenteropancreatic NETs with poor prognostic factors (Ki-67 labeling index: LI 5%–20% or Ki-67 LI < 5% with diffuse liver metastases). We plan to enroll a total of 250 patients from 76 institutions over an accrual period of 5 years. The primary endpoint is progression-free survival. The key secondary endpoint is overall survival, with response rate, disease control rate, and proportion of patients with adverse events as the other secondary endpoints. This trial is registered with the Japan Registry of Clinical Trials as jRCT1031200023 [ https://jrct.niph.go.jp/en-latest-detail/jRCT1031200023 ]. [ABSTRACT FROM AUTHOR]

Purpose: PRELUDE aimed to assess use and effectiveness/safety of lanreotide autogel/depot (LAN) combined with 177Lu-DOTATOC or 177Lu-DOTATATE (LAN–peptide receptor radionuclide therapy [PRRT]) in patients with progressive neuroendocrine tumours (NETs). Methods: International, non-interventional, retrospective, non-comparative analysis of medical records from patients with progressive metastatic or locally advanced grade 1 or 2 gastroenteropancreatic (GEP)- or lung-NETs. The primary endpoint was progression-free survival (PFS) at end of last LAN–PRRT cycle. Secondary endpoints included PFS at last available follow-up, best overall response, objective response rate (ORR), presence and severity of diarrhoea and flushing, and safety. Post-hoc analyses were conducted to determine pre-treatment tumour growth rate (TGR) cutoffs that best predicted the ORR during treatment. Results: Forty patients were enrolled (GEP-NETs, n = 39; lung-NETs, n = 1). PFS rates were 91.7% at end of last LAN–PRRT cycle and 95.0% at last available follow-up. In the full analysis set, best overall response among patients with GEP-NETs (n = 23) was stable disease (n = 14, 60.9%), partial response (n = 8, 34.8%) and progressive disease (n = 1, 4.3%). The ORR was 27.3% at end of last LAN–PRRT cycle and 36.8% at last available follow-up. Optimal baseline TGR cutoffs for predicting ORR at these time points were 1.18% and 0.33%, respectively. At baseline, 81.0% of patients had diarrhoea or flushing; both remained stable or improved in most cases. No increased adverse drug reactions were reported. Conclusion: Despite the major recruitment shortfall for the PRELUDE study, effectiveness data were encouraging in this selected population, highlighting the potential usefulness and feasibility of LAN combined with and after PRRT in patients with GEP-NETs. The study also identified challenges associated with evaluating clinical practice in a rare-disease setting and highlighted the need for standardisation of PRRT procedures. Trial registration: Trial number: NCT02788578; URL: https://clinicaltrials.gov/ct2/show/NCT02788578 [ABSTRACT FROM AUTHOR]

Purpose: Neuroendocrine tumors (NETs) associated with carcinoid syndrome (CS) overproduce serotonin, mediated by tryptophan hydroxylase-1 (TPH1). The TPH inhibitor telotristat ethyl (TE) reduces peripheral serotonin and relieves CS symptoms. We conducted a real-world clinical practice study to explore the effects of TE on tumor growth in patients with NETs and CS. Patients and Methods: Single-arm, pre/post chart review study of patients with advanced NETs who received TE for ≥ 6 months and had ≥ 2 radiological scans within 12 months before and ≥ 1 scan after TE initiation. Linear regression and longitudinal analyses assessed changes in tumor size controlling for background NET treatment. Results: Two hundred patients were enrolled, most (61%) had well-differentiated gastrointestinal NETs (61%) and received TE for an average of 12 months (SD, 7.3). Mean reduction in tumor size after TE initiation was 0.59 cm (p=0.006). Longitudinal analysis showed an 8.5% reduction in tumor size (p=0.045) from pre- to post-TE periods. Documented NET treatment prior to initiating TE and time between scans were not significant predictors of changes in tumor size. Results were consistent in a subgroup of patients with the same documented NET treatment before and after initiating TE. Conclusion: TE may have antitumor effects consistent with serotonin overproduction in tumor growth. [ABSTRACT FROM AUTHOR]