Somatostatin receptors and the associated intracellular machinery: the two sides of the coin.

Somatostatin receptors (SSTs) are widely expressed in pituitary tumors and neuroendocrine neoplasms (NENs) of different origins, i.e. the gastrointestinal tract and the thorax (lungs and thymus), thus representing a well-established target for medical treatment with SST ligands (SRLs). However, the response to SRLs is highly heterogeneous between tumors. Two main factors can contribute to this variability: (i) the differential SST expression among tumor types and (ii) the differential expression/modulation of the SST-related intracellular machinery. In this literature review, we provide an overview of available data on the variable expression of SSTs in pituitary tumors and NENs, together with the resulting clinical implications. Moreover, we aim to describe the complex intracellular machinery involved in SST signaling and trafficking. Particularly, we will focus on ß-arrestins and describe their role in receptor internalization and recycling, as well as the various functions of these scaffold molecules in tumor pathogenesis and progression. This review highlights the interplay between membrane receptors and intracellular machinery, together with its role in determining the clinical behavior of the tumor and the response to treatment in patients with pituitary tumors or NENs.

Predictors of Response to Treatment with First-Generation Somatostatin Receptor Ligands in Patients with Acromegaly.

BACKGROUND AND AIMS: Predictors of first-generation somatostatin receptor ligands (fgSRLs) response in acromegaly have been studied for over 30 years, but they are still not recommended in clinical guidelines. Is there not enough evidence to support their use? This systematic review aims to describe the current knowledge of the main predictors of fgSRLs response and discuss their current usefulness, as well as future research directions. METHODS: A systematic search was performed in the Scopus and PubMed databases for functional, imaging, and molecular predictive factors. RESULTS: A total of 282 articles were detected, of which 64 were included. Most of them are retrospective studies performed between 1990 and 2023 focused on the predictive response to fgSRLs in acromegaly. The usefulness of the predictive factors is confirmed, with good response identified by the most replicated factors, specifically low GH nadir in the acute octreotide test, T2 MRI hypointensity, high Somatostatin receptor 2 (SSTR2) and E-cadherin expression, and a densely granulated pattern. Even if these biomarkers are interrelated, the association is quite heterogeneous. With classical statistical methods, it is complex to define reliable and generalizable cut-off values worth recommending in clinical guidelines. Machine-learning models involving omics are a promising approach to achieve the highest accuracy values to date. CONCLUSIONS: This survey confirms a sufficiently robust level of evidence to apply knowledge of predictive factors for greater efficiency in the treatment decision process. The irruption of artificial intelligence in this field is providing definitive answers to such long-standing questions that may change clinical guidelines and make personalized medicine a reality.

Computational prediction of analog compounds of the membrane protein MCHR1 antagonists ALB-127158 and KRX-104130.

Obesity, which is already pervasive throughout the world, endangers public health by raising the prevalence of metabolic disorders and making their treatment more difficult. The development of drugs to treat obesity is a focus of effort. Melanin concentrated hormone receptor 1 (MCHR1) is the target of some of these therapeutic possibilities since as increased levels of melanin concentrated hormone have been found in obesity models. Known MCHR1 antagonists include BMS-830216, GW-856464, NGD-4715, ALB-127158, and AMG 076, but many have failed phase-I clinical studies. As a potential treatment for cardiotoxicity, KRX-104130 has only recently been identified. As MCH system is potentially effective target for treatment of obesity, in silico research into interaction between MCHR1 and its antagonists at molecular level was the primary goal of this study. Analogues ALB-127158 and KRX-104130 were screened among the RealEnamine library. The complexes obtained by molecular docking were embedded in mimics brain-cell membrane and simulated for 540 ns, and then MM-GBSA were calculated with MMPBSA.py. With all these computational studies, similar or different aspects of selected analogous compounds to ALB-127158 and KRX-104130 were investigated. The specificity of this study was that it analyzed MCHR1 protein as embedded in membrane. It was concluded that KRX-104130's analogue Z1922310273 and ALB-127158's analogue PV-002757495233 did not cause a difference in terms of phospholipid membrane properties. In addition, all ligands remained stable in putative binding site. It has been suggested that PV-002757495233 and Z1922310273 compounds can be evaluated as MCHR1 antagonists when all these outputs are considered in melting pots.

Pharmacological Treatment of Non-Functioning Pituitary Adenomas.

Treatment strategies for NFPA include surgery, radiotherapy, medical treatment, or follow-up. The treatment of NFPAs with compressive symptoms is surgical. However, in case of post-surgical tumor remnants, there may be treatment strategies that include observation and radiotherapy. Recently, medical treatment with cabergoline (CAB) has been recommended to contain and/or reduce the size of the tumor remnant. Based on the findings that many NFPAs show a dopamine receptor (DR) and somatostatin receptor (SR) expression, medical therapy with dopamine agonists (DAs) and somatostatin receptor ligands (SSRLs) has been tested as an alternative to prevent recurrence after surgery. The DAs have been the most extensively studied, showing some potential in terms of tumor shrinkage. SSRLs and other emerging medical options are much less studied. We will review and critically evaluate the current data on the medical therapy of NFPAs to elucidate their role in the management of this tumor type. In the case of actively growing remnants (more than 10% growth per year) and high-risk pituitary adenomas, treatment with CAB at a dose of 1.5-3.0 mg is indicated for tumor containment and/or reduction. In relation to combined chemotherapy with CAB, there is little information in the literature to support its use. In our experience, CAB treatment can be used after radiotherapy as an adjuvant treatment.

Key Device Attributes for Injectable Somatostatin Receptor Ligand Therapy in Acromegaly and Neuroendocrine Tumours.

INTRODUCTION: People living with acromegaly and neuroendocrine tumours (NETs) may be treated with injectable somatostatin receptor ligands (SRLs), administered by either a caregiver or as self-injection via a proprietary or generic device. Injection device attributes that contribute to ease of use and storage, minimise preparation requirements, and reduce injection pain are associated with improved adherence and more favourable therapeutic outcomes. The aim of this study was to assess current opinion surrounding favourable SRL device attributes for people living with acromegaly and NETs as well as that of their caregivers. METHODS: Participants (healthcare professionals [HCPs] and patients/non-HCP caregivers) from 11 countries were invited to answer survey questions related to their demographic, experience, and preferences as they relate to the real-world use of injectable SRL devices. Questions were developed based on review of available literature and meetings with a Scientific Committee. RESULTS: Device attributes preferred by the patient/non-HCP caregiver group (n = 211) included confidence that the correct drug amount is delivered (76%), quick administration with minimal pain/discomfort (68%), and device safety (needle-safety and low risk of contamination; 53%). Device attributes preferred by HCPs (n = 52) were quick administration with minimal pain/discomfort (69%), correct use is easy to learn, confidence in handling the device (63%), and confidence that the correct drug amount is delivered (62%). CONCLUSION: The results identified key features of injection devices for SRL therapy which merit consideration for optimal management and underscore the importance of patient partnership in treatment decisions.

Partial Response Upon Peptide Receptor Radionuclide Therapy in a Highly Proliferative Pancreatic Neuroendocrine Tumor.

ABSTRACT: We report on a patient diagnosed with an aggressive pancreatic neuroendocrine tumor (NET G3; Ki67 = 60%), who underwent pancreatic resection with partial removal of liver lesions. The patient refused chemotherapy. Dual-tracer imaging with 18 F-FDG and somatostatin receptor (SSTR)-targeted PET/CT was conducted. Radiotracer accumulation on both imaging modalities in bilobar hepatic lesions was observed. "Cold" somatostatin analogues with four cycles of peptide receptor radionuclide therapy (PRRT) were initiated, leading to partial response. Even in highly proliferative but differentiated G3 NET (Ki67>55%), SSTR expression in sites of disease should be evaluated, which may then allow PRRT, even as first-line systemic treatment.

Somatostatin receptors in congenital hyperinsulinism: Biology to bedside.

Congenital hyperinsulinism (CHI), although a rare disease, is an important cause of severe hypoglycemia in early infancy and childhood, causing preventable morbidity and mortality. Prompt diagnosis and appropriate treatment is necessary to prevent hypoglycaemia mediated brain damage. At present, the medical treatment of CHI is limited to diazoxide as first line and synthetic somatostatin receptor ligands (SRLs) as second line options; therefore understanding somatostatin biology and treatment perspectives is important. Under healthy conditions, somatostatin secreted from pancreatic islet δ-cells reduces insulin release through somatostatin receptor induced cAMP-mediated downregulation and paracrine inhibition of ß- cells. Several SRLs with extended duration of action are now commercially available and are being used off-label in CHI patients. Efficacy remains variable with the present generation of SRLs, with treatment effect often being compromised by loss of initial response and adverse effects such as bowel ischaemia and hepatobiliary dysfunction. In this review we have addressed the biology of the somatostatin system contexualised to CHI. We have discussed the clinical use, limitations, and complications of somatostatin agonists and new and emerging therapies for CHI.

Clinical, hormonal and pathomorphological markers of somatotroph pituitary neuroendocrine tumors predicting the treatment outcome in acromegaly.

Background: Transsphenoidal adenomectomy (TSS) of somatotroph pituitary neuroendocrine tumor (PitNET) is the first-line treatment of acromegaly. Pharmacological treatment is recommended if surgery is contraindicated or did not lead to disease remission. The choice of treatment best fitting each patient should be based on thorough investigation of patients' characteristics. The current analysis attempts to create a tool for personalized treatment planning. Aim: This study aimed to assess whether clinical, biochemical, imaging and pathological characteristics can predict surgical remission and response to first-generation somatostatin receptor ligands (SRLs) and pasireotide-LAR in acromegaly. Patients and methods: A retrospective study of 153 acromegaly patients, treated in the Department of Endocrinology in Bielanski Hospital in Warsaw, Poland was performed. Data on demographics, hormonal and imaging results, pathological evaluation, and treatment outcome was extracted from the Polish Acromegaly Registry collecting information from 11 endocrinology centers in Poland and analyzed. Results: Patients with surgical remission had lower GH and IGF-1 concentrations at diagnosis (median GH 5.5 µg/L [IQR: 3.1-16.0] vs. 19.9 µg/L [IQR: 9.8-42.4], p=<0.001 and mean IGF-1 3.1xULN ± SD=1.2 vs. 3.7xULN ± SD=1.2, p=0.007, respectively) and smaller tumors (median 12.5mm [IQR: 9-19] vs. 23mm [IQR: 18-30], p<0.001). These tumors were more often densely granulated (DG) (73.2% vs. 40.0%, p=0.001) with positive staining for alpha-subunit (α-SU) (58.3% vs. 35.5%, p=0.021) and lower Ki-67 index (p=0.002). Patients responding well to SRLs were more often male (55.6% vs 44.4%, p=0.026), presented lower GH concentration (median GH 17.2 µg/L [IQR: 6.2-29.0] vs. 23.8 µg/L [IQR: 11.2-49.5], p=0.048) and had more often DG tumors (63.0% vs. 14.3%, p<0.001). No significant differences between good and poor-response to pasireotide-LAR groups were found. In multivariate logistic regression analysis fasting GH concentration <8.63 µg/L, maximal tumor diameter <15.5mm, normoprolactinemia and DG tumor turned out to be independent predictors of surgical remission (OR=0.92, p=0.026; OR=0.87, p=0.069, OR=3.86, p=0.096 and OR=3.05, p=0.181, respectively). Fasting GH concentration <36.6 µg/L and DG tumor turned out to be independent predictors of good response to first-generation SRLs (OR=0.96, p=0.06 and OR=10.68, p=0.002, respectively). Conclusions: Younger age at diagnosis, male sex, lower GH, IGF-1 and PRL concentrations, smaller tumor size at diagnosis as well as positive α-SU staining, lower Ki-67 index and DG tumors predicted better treatment outcome in acromegaly patients.

Factors associated with therapeutic response in acromegaly diagnosed in the elderly in Spain.

Context: Some reports suggest that acromegaly in elderly patients has a more benign clinical behavior and could have a better response to first-generation long-acting somatostatin receptor ligands (SRL). However, there is no specific therapeutic protocol for this special subgroup of patients. Objective: This study aimed at identifying predictors of response to SRL in elderly patients. Design: Multicentric retrospective nationwide study of patients diagnosed with acromegaly at or over the age of 65 years. Results: One-hundred and eighteen patients (34 men, 84 women, mean age at diagnosis 71.7 ± 5.4 years old) were included. Basal insulin-like growth factor type 1 (IGF-1) above the upper limit of normal (ULN) and growth hormone (GH) levels (mean ± SD) were 2.7 ± 1.4 and 11.0 ± 11.9 ng/ml, respectively. The mean maximal tumor diameter was 12.3 ± 6.4 mm, and up to 68.6% were macroadenoma. Seventy-two out of 118 patients (61.0%) underwent surgery as primary treatment. One-third of patients required first-line medical treatment due to a rejection of surgical treatment or non-suitability because of high surgical risk. After first-line surgery, 45/72 (63.9%) were in disease remission, and 16/34 (46.7%) of those treated with SRL had controlled disease. Patients with basal GH at diagnosis ≤6 ng/ml had lower IGF-1 levels and had smaller tumors, and more patients in this group reached control with SRL (72.7% vs. 33.3%; p < 0.04) [OR: 21.3, IC: 95% (2.4-91.1)], while male patients had a worse response [OR: 0.09, IC 95% (0.01-0.75)]. The predictive model curve obtained for SRL response showed an AUC of 0.82 CI (0.71-0.94). Conclusions: The most frequent phenotype in newly diagnosed acromegaly in the elderly includes small adenomas and moderately high IGF-1 levels. GH at diagnosis ≤6 ng/ml and female gender, but not age per se, were associated with a greater chance of response to SRL.

Somatostatin analogues in treatment-refractory meningioma: a systematic review with meta-analysis of individual patient data.

Treatment-refractory meningiomas have a dismal prognosis and limited treatment options. Meningiomas express high-densities of somatostatin receptors (SSTR), thus potentially susceptible to antitumorigenic effects of somatostatin analogues (SSA). Evidence for SSA in meningiomas is scarce, and it is unclear if published literature would either (1) support wider use of SSA, if (2) more evidence is desirable, or if (3) available evidence is sufficient to discard SSA. We addressed the need for more evidence with a systematic review and meta-analysis. We performed an individual patient data (IPD) meta-analysis. Main outcomes were toxicity, best radiological response, progression-free survival, and overall survival. We applied multivariable logistic regression models to estimate the effect of SSA on the probability of obtaining radiological disease control. The predictive performance was evaluated using area under the curve and Brier scores. We included 16 studies and compiled IPD from 8/9 of all previous cohorts. Quality of evidence was overall ranked "very low." Stable disease was reported in 58% of patients as best radiological response. Per 100 mg increase in total SSA dosage, the odds ratios for obtaining radiological disease control was 1.42 (1.11 to 1.81, P = 0.005) and 1.44 (1.00 to 2.08, P = 0.05) for patients treated with SSA as monodrug therapy vs SSA in combination with everolimus, respectively. Low quality of evidence impeded exact quantification of treatment efficacy, and the association between response and treatment may represent reverse causality. Yet, the SSA treatment was well tolerated, and beneficial effect cannot be disqualified. A prospective trial without bias from inconsistent study designs is warranted to assess SSA therapy for well-defined meningioma subgroups.

[Theranostics for Well and Moderately Differentiated GEP-NEN]. / Theranostics bei gut bis mäßig differenzierten GEP-NEN.

Neuroendocrine neoplasms (NEN) are rare, heterogeneous, and typically slowly growing tumours. The most common location is the gastro-entero-pancreatic system (GEP-NEN). NENs are classified according to their proliferative activity (Ki-67 index, G1-3). In this context, well-differentiated tumours typically express somatostatin receptors (SSTR), thus serving as targets for nuclear medicine theranostics. In this approach, diagnostic molecular imaging, usually by positron emission tomography/computed tomography (PET/CT), can be followed by individually tailored peptide radioreceptor therapy (PRRT) with a ß-emitter labeled radiopharmaceutical. In meta-analyses, diagnostics using SSTR-directed PET/CT showed a sensitivity of 93% and a specificity of 96%. SSTR-directed diagnostics can also be used to trace tumours in-vivo, enabling radioguided surgery. The decision to initiate PRRT should always be made in an interdisciplinary tumour conference and tumour progression during previous therapy should be documented. This treatment is administered intravenously for 4 times at 8-week intervals in specialised nuclear medicine centres. PRRT efficacy was prospectively evaluated in the NETTER-1 study and demonstrated a significant improvement in progression-free survival (primary endpoint). Based on these results, Lutathera (177Lu-DOTATATE) is now available as a radiopharmaceutical approved in Germany for the treatment of non-resectable or metastatic or progressive, well-differentiated (G1 and G2), SSTR-positive GEP-NEN.

Clinical Management of Acromegaly: Therapeutic Frontiers and New Perspectives for Somatostatin Receptor Ligands (SRLs).

Somatostatin receptor ligands (SRLs) represent a true milestone in the medical therapy for acromegaly. The first-generation SRLs (FG-SRLs), octreotide and lanreotide, have demonstrated good efficacy in disease control and tumor shrinkage, and are still considered first-line medical therapies. The development of long-acting release (LAR) formulations has certainly improved the therapeutic tolerability of these drugs, although many patients still experience therapy-related burden. As such, new formulations have recently been developed to improve adherence and therapeutic efficacy and more solutions are on the way. In the case of FG-SRL-resistant disease, pasireotide, the only second generation SRL currently available, demonstrated superiority in disease control and tumor shrinkage compared to FG-SRLs. However, its use in clinical practice is still limited due to concern for impairment in glucose homeostasis. In this review, we discuss the news about the present and future role of SRLs in acromegaly, exploring the therapeutical frontiers of this drug class. Moreover, we provide practical guidance on the use of pasireotide, based on the data in the literature and our clinical experience.

Peptide Receptor Radionuclide Therapy in Thyroid Cancer.

The treatment options that are currently available for management of metastatic, progressive radioactive iodine (RAI)-refractory differentiated thyroid cancers (DTCs), and medullary thyroid cancers (MTCs) are limited. While there are several systemic targeted therapies, such as tyrosine kinase inhibitors, that are being evaluated and implemented in the treatment of these cancers, such therapies are associated with serious, sometimes life-threatening, adverse events. Peptide receptor radionuclide therapy (PRRT) has the potential to be an effective and safe modality for treating patients with somatostatin receptor (SSTR)+ RAI-refractory DTCs and MTCs. MTCs and certain sub-types of RAI-refractory DTCs, such as Hürthle cell cancers which are less responsive to conventional modalities of treatment, have demonstrated a favorable response to treatment with PRRT. While the current literature offers hope for utilization of PRRT in thyroid cancer, several areas of this field remain to be investigated further, especially head-to-head comparisons with other systemic targeted therapies. In this review, we provide a comprehensive outlook on the current translational and clinical data on the use of various PRRTs, including diagnostic utility of somatostatin analogs, theranostic properties of PRRT, and the potential areas for future research.

Phase II trial demonstrates the efficacy and safety of individualized, dosimetry-based 177Lu-DOTATATE treatment of NET patients.

PURPOSE: Radionuclide therapy with 177Lu-DOTATATE is well established for patients with advanced somatostatin receptor-positive neuroendocrine tumors with a standard schedule of 7.4 GBq at four occasions. However, this approach does not consider individual variability affecting the tumor radiation dose or dose to organs at risk. Therefore, it is important to assess more personalized strategies. The aim of this phase II trial was to evaluate individualized 177Lu-DOTATATE for which the number of cycles varied based on renal dosimetry. METHODS: Patients were eligible if they had a progressive, somatostatin receptor-positive neuroendocrine tumor with a Ki 67 labeling index < 20%. They received cycles of 7.4 GBq of 177Lu-DOTATATE at 10 ± 2-week intervals until a predefined radiation dose to the kidneys was reached. The primary endpoint was objective tumor response (RECIST v 1.1). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity (CTCAE v. 4.0). RESULTS: Ninety-six patients who had received a median of 5 cycles (range 1-9) were evaluable for efficacy. The objective tumor response was 16% partial response, 66% stable disease, and 19% progressive disease. The median PFS and OS were 29 months and 47 months, respectively, and were significantly associated with kidney dose, performance status, and Ki 67 levels but not with tumor origin. The overall toxicity was mild, and the most common events were grade 1-2 anemia, thrombocytopenia, fatigue, nausea, and diarrhea. Grade 3-4 toxicity occurred in < 10% of patients and was mostly hematological, with no grade 3-4 renal toxicity. CONCLUSION: Individualized treatment with 177Lu-DOTATATE based on renal dosimetry is clearly feasible with low toxicity and promising efficacy, showing the potential to further improve outcome beyond the standard approach, and should be further assessed in randomized trials. TRIAL REGISTRATION: EudraCT 2011-000,240-16. NCT01456078. https://clinicaltrials.gov/ct2/show/NCT01456078.

Terapia con péptidos radiomarcados con [177Lu]Lu-DOTA-TATE / Peptide receptor radionuclide therapy with [177Lu]Lu-DOTA-TATE

Esta formación pretende presentar, de forma clara y de fácil comprensión, la biología de los tumores neuroendocrinos (TNE), las características de los receptores de somatostatina, cómo debe realizarse la selección de pacientes candidatos a terapia con péptidos radiomarcados (PRRT), si el paciente cumple los criterios para beneficiarse del tratamiento con los mínimos efectos adversos posibles, el protocolo de administración, seguimiento y evaluación de respuesta. También, se desarrollan los estudios de imagen funcional necesarios para explorar la biología del tumor e individualizar el tratamiento, que constituyen la piedra angular para el desarrollo de la teragnosis.Se están desarrollando ensayos clínicos para definir mejor la posición de PRRT dentro del amplio panorama terapéutico y, entre las perspectivas de futuro, hay varias líneas de investigación para mejorar la tasa de respuesta objetiva y la supervivencia con PRRT, centradas en el desarrollo de nuevos agonistas y antagonistas del receptor de somatostatina, nuevos radionúclidos y terapias combinadas radiosensibilizantes.En conclusión, la PRRT es un tratamiento bien tolerado, seguro y con efectos secundarios agudos, generalmente leves y autolimitados, que constituye una gran herramienta terapéutica que debe secuenciarse en el mejor momento de la evolución de la enfermedad de los pacientes con TNE. Los pacientes candidatos a la PRRT deben ser valorados siempre por un comité clínico multidisciplinar (AU)

This continuing education aims to present in a clear and easy-to-understand way, the biology of neuroendocrine tumors (NETs), the characteristics of somatostatin receptors, the selection of patients for radiolabelled peptide therapy (PRRT), the inclusion criteria to benefit from treatment with the minimum possible adverse effects, the administration protocol, follow-up and response evaluation. The functional imaging studies necessary to explore the biology of the tumor and to individualize the treatment are also carried out, and constitute the cornerstone for the development of teragnosis.Clinical trials are being developed to better define the position of PRRT within the broad therapeutic options, and among the future perspectives, there are several lines of research to improve the objective response rate and survival with PRRT, focused on the development of new agonists and somatostatin receptor antagonists, new radionuclides and radiosensitizing combination therapies.In conclusion, PRRT is a great therapeutic, well-tolerated and safe tool with generally mild and self-limited acute side effects, that must be sequenced at the best moment of the evolution of the disease of patients with NET. Candidate patients for PRRT should always be evaluated by an multidisciplinary clinical committee (AU)

Personalized Medical Treatment of Patients With Acromegaly: A Review.

Acromegaly is associated with significant morbidity and mortality if it is not appropriately treated. In addition to insulin-like growth factor 1 and growth hormone normalization as well as tumor shrinkage, the treatment goals include relieving symptoms, managing complications, and improving patients' quality of life. Surgical resection is a first-line treatment option for most patients, with few being pretreated preoperatively with medications. Somatostatin receptor ligands (SRLs), injectable and, more recently, oral capsules, have been the cornerstone of first-line medical therapy for persistent disease. However, several factors, including sparsely granulated adenomas, absent or low somatostatin receptor status, T2-hyperintensity imaging, young age, and aryl hydrocarbon receptor-interacting protein mutations, can predict first-generation SRL resistance. Patients with these characteristics may be better candidates for the growth hormone receptor antagonist pegvisomant, or in cases of large tumors, the second-generation SRL pasireotide. Combination therapy should be further pursued in patients who remain biochemically uncontrolled or have a high remnant tumor after monotherapy. An efficacious and cost-effective pegvisomant dose-sparing effect of SRLs when used in combination has been demonstrated. With such a wide array of medical treatment options, it is becoming increasingly important to tailor treatment to patients' unique characteristics and preferences, with a goal of personalizing management to achieve high-quality outcomes.

Maintenance of response to oral octreotide compared with injectable somatostatin receptor ligands in patients with acromegaly: a phase 3, multicentre, randomised controlled trial.

BACKGROUND: Despite biochemically responding to injectable somatostatin receptor ligands (iSRLs), many patients with acromegaly experience treatment burdens. We aimed to assess maintenance of biochemical response and symptomatic control with oral octreotide capsules versus iSRLs in patients with acromegaly who previously tolerated and responded to both. METHODS: This global, open-label, randomised controlled phase 3 trial was done in 29 clinical sites in Austria, France, Germany, Hungary, Italy, Lithuania, Russia, Serbia, Spain, and the USA. Eligible patients were adults aged 18-75 years with acromegaly who were receiving iSRLs (long-acting octreotide or lanreotide autogel) for at least 6 months before baseline with a stable dose for at least 4 months, and were deemed to be biochemically responding (insulin-like growth factor I [IGF-I] <1·3 × upper limit of normal [ULN] and mean integrated growth hormone <2·5 ng/mL). In the 26-week run-in phase, all patients received oral octreotide (40 mg a day, optional titration to 60 or 80 mg a day). Eligibility for the randomised treatment phase was completion of the run-in phase as a biochemical responder (IGF-I <1·3 × ULN and mean integrated growth hormone <2·5 ng/mL at week 24) and investigator assessment of acromegaly being adequately controlled. Patients were randomly assigned (3:2) to oral octreotide capsules or iSRL at the same dose and interval as before enrolment. Randomisation and drug dispensing were conducted through a qualified randomisation service provider (eg, interactive web or voice response system). The primary endpoint was a non-inferiority assessment (margin -20 percentage points) of proportion of participants maintaining biochemical response throughout the randomised treatment phase (IGF-I <1·3 × ULN using time-weighted average; assessed by comparing the lower bound of the 2-sided 95% CI for the difference in biochemical response between groups). IGF-I was assessed once a month during the run-in and randomised treatment phases (single sample). Efficacy and safety assessments were performed on the randomised population. This trial is registered with ClinicalTrials.gov, NCT02685709. FINDINGS: Between Feb 11, 2016, and Aug 20, 2020, 218 patients were assessed for eligibility. 72 patients were excluded, and 146 participants were enrolled into the run-in phase. 116 patients completed the run-in phase and 30 participants discontinued treatment. 92 participants were randomly assigned to oral octreotide (n=55) or iSRL (n=37). 50 (91%) of 55 participants who received oral octreotide (95% CI 44-53) and 37 (100%) of 37 participants who received iSRLs (34-37) maintained biochemical response. The lower bound of the 2-sided 95% CI for the adjusted difference in proportions between the two treatment groups achieved the prespecified non-inferiority criterion of -20% (95% CI -19·9 to 0·5). 19 (35%) of 55 participants in the oral octreotide group and 15 (41%) of 37 participants in the iSRL group had treatment-related adverse events; the most common of which in both groups were gastrointestinal. INTERPRETATION: Oral octreotide was non-inferior to iSRL treatment, and might be a favourable alternative to iSRLs for many patients with acromegaly. FUNDING: Chiasma. TRANSLATION: For the Russian translation of the abstract see Supplementary Materials section.

Metastatic Medullary Thyroid Cancer: The Role of 68Gallium-DOTA-Somatostatin Analogue PET/CT and Peptide Receptor Radionuclide Therapy.

CONTEXT: Metastatic medullary thyroid cancer (MTC) is a rare malignancy with minimal treatment options. Many, but not all, MTCs express somatostatin receptors. OBJECTIVE: Our aim was to explore the role of 68Ga-DOTA-somatostatin analogue (SSA) positron emission tomography (PET)/computed tomography (CT) in patients with metastatic MTC and to determine their eligibility for peptide receptor radionuclide therapy (PRRT). METHODS: We retrospectively identified patients with metastatic MTC who had 68Ga-DOTA-SSA PET/CT at 5 centers. We collected characteristics on contrast-enhanced CT, 68Ga-DOTA-SSA and 18F-FDG PET/CT. The efficacy of PRRT was explored in a subgroup of patients. Kaplan-Meier analysis was used to estimate time to treatment failure (TTF) and overall survival (OS). RESULTS: Seventy-one patients were included (10 local recurrence, 61 distant disease). Of the patients with distant disease, 16 (26%) had ≥50% of disease sites with tracer avidity greater than background liver, including 10 (10/61, 16%) with >90%. In 19 patients with contemporaneous contrast-enhanced CT, no disease regions were independently identified on 68Ga-DOTA-SSA PET/CT. Thirty-five patients had an 18F-FDG PET/CT, with 18F-FDG positive/68Ga-DOTA-SSA negative metastases identified in 15 (43%). Twenty-one patients had PRRT with a median TTF of 14 months (95% CI 8-25) and a median OS of 63 months (95% CI 21-not reached). Of the entire cohort, the median OS was 323 months (95% CI 152-not reached). Predictors of poorer OS included a short calcitonin doubling-time (≤24 months), strong 18F-FDG avidity, and age ≥60 years. CONCLUSIONS: The prevalence of high tumor avidity on 68Ga-DOTA-SSA PET/CT is low in the setting of metastatic MTC; nevertheless, PRRT may still be a viable treatment option in select patients.

Case Report: Irreversible Watery Diarrhea, Severe Metabolic Acidosis, Hypokalemia and Achloridria Syndrome Related to Vasoactive Intestinal Peptide Secreting Malignant Pheochromocytoma.

Background: Pheochromocytoma (PHEO) clinical manifestations generally mirror excessive catecholamines secretion; rarely the clinical picture may reflect secretion of other hormones. Watery diarrhea, hypokalemia and achlorhydria (WDHA) is a rare syndrome related to excessive secretion of vasoactive intestinal peptide (VIP). Clinical Case: A 73-year-old hypotensive man affected by adrenal PHEO presented with weight loss and watery diarrhea associated with hypokalemia, hyperchloremic metabolic acidosis (anion gap 15 mmol/l) and a negative urinary anion gap. Abdominal computed tomography scan showed a right adrenal PHEO, 8.1 cm in maximum diameter, with tracer uptake on 68GaDOTA-octreotate positron emission tomography. Metastasis in lumbar region and lung were present. Both chromogranin A and VIP levels were high (more than10 times the normal value) with slightly elevated urine normetanephrine and metanephrine excretion. Right adrenalectomy was performed and a somatostatin analogue therapy with lanreotide started. Immunostaining showed chromogranin A and VIP co-expression, with weak somatostatin-receptor-2A positivity. In two months, patient clinical conditions deteriorated with severe WDHA and multiple liver and lung metastasis. Metabolic acidosis and hypokalemia worsened, leading to hemodynamic shock and exitus. Conclusions: A rare case of WDHA syndrome caused by malignant VIP-secreting PHEO was diagnosed. High levels of circulating VIP were responsible of the rapidly evolving clinical picture with massive dehydration and weight loss along with severe hyperchloremic metabolic acidosis and hypokalemia due to the profuse untreatable diarrhea. The rescue treatment with lanreotide was unsuccessful because of the paucity of somatostatin-receptor-2A on VIP-secreting PHEO chromaffin cells.

Somatostatin receptor ligands induce TSH deficiency in thyrotropin-secreting pituitary adenoma.

OBJECTIVE: Somatostatin receptor ligands (SRL) are useful to control central hyperthyroidism in patients with thyrotropin-secreting pituitary adenoma (TSH pituitary adenoma). The aim of this study was to describe the frequency of thyrotropin deficiency (TSH deficiency) in patients with TSH pituitary adenoma treated by SRL. DESIGN: Retrospective study. METHODS: Patients with central hyperthyroidism due to TSH pituitary adenoma treated by short or long-acting SRL were retrospectively included. TSH deficiency was defined by a low FT4 associated with non-elevated TSH concentrations during SRL therapy. We analysed the frequency of TSH deficiency and the characteristics of patients with or without TSH deficiency. RESULTS: Forty-six patients were included. SRL were used as the first-line therapy in 21 of 46 patients (46%). Central hyperthyroidism was controlled in 36 of 46 patients (78%). TSH deficiency appeared in 7 of 46 patients (15%) after a median time of 4 weeks (4-7) and for a median duration of 3 months (2.5-3). The TSH deficiency occurred after one to three injections of long-acting SRL used as first-line therapy in 6/7 cases. There were no differences in terms of clinical and hormonal features, size of adenomas or doses of SRL between patients with or without TSH deficiency. CONCLUSIONS: SRL can induce TSH deficiency in patients with central hyperthyroidism due to TSH pituitary adenoma. Thyrotropic function should be assessed before the first three injections of SRL in order to track TSH deficiency and reduce the frequency of injections when control of thyrotoxicosis rather than tumour reduction is the aim of the treatment.