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OBJECTIVES: Somatostatin receptor positron emission tomography/computed tomography (SSTR-PET/CT) using [68Ga]-labeled tracers is a widely used imaging modality for neuroendocrine tumors (NET). Recently, [18F]SiTATE, a SiFAlin tagged [Tyr3]-octreotate (TATE) PET tracer, has shown great potential due to favorable clinical characteristics. We aimed to evaluate the reproducibility of Somatostatin Receptor-Reporting and Data System 1.0 (SSTR-RADS 1.0) for structured interpretation and treatment planning of NET using [18F]SiTATE. METHODS: Four readers assessed [18F]SiTATE-PET/CT of 95 patients according to the SSTR-RADS 1.0 criteria at two different time points. Each reader evaluated up to five target lesions per scan. The overall scan score and the decision on peptide receptor radionuclide therapy (PRRT) were considered. Inter- and intra-reader agreement was determined using the intraclass correlation coefficient (ICC). RESULTS: The ICC analysis on the inter-reader agreement using SSTR-RADS 1.0 for identical target lesions (ICC ≥ 85%), overall scan score (ICC ≥ 90%), and the decision to recommend PRRT (ICC ≥ 85%) showed excellent agreement. However, significant differences were observed in recommending PRRT among experienced readers (ER) (p = 0.020) and inexperienced readers (IR) (p = 0.004). Compartment-based analysis demonstrated good to excellent inter-reader agreement for most organs (ICC ≥ 74%), except for lymph nodes (ICC ≥ 53%). CONCLUSION: SSTR-RADS 1.0 represents a highly reproducible and consistent framework system for stratifying SSTR-targeted PET/CT scans, even using the novel SSTR-ligand [18F]SiTATE. Some inter-reader variability was observed regarding the evaluation of uptake intensity prior to PRRT as well as compartment scoring of lymph nodes, indicating that those categories require special attention during further clinical validation and might be refined in a future SSTR-RADS version 1.1. CLINICAL RELEVANCE STATEMENT: SSTR-RADS 1.0 is a consistent framework for categorizing somatostatin receptor-targeted PET/CT scans when using [18F]SiTATE. The framework serves as a valuable tool for facilitating and improving the management of patients with NET. KEY POINTS: SSTR-RADS 1.0 is a valuable tool for managing patients with NET. SSTR-RADS 1.0 categorizes patients with showing strong agreement across diverse reader expertise. As an alternative to [68Ga]-labeled PET/CT in neuroendocrine tumor imaging, SSTR-RADS 1.0 reliably classifies [18F]SiTATE-PET/CT.

Introduction: The CRISPR/Cas9 system-based gene therapy can fundamentally address the issues of cancer occurrence, development, progression, and metastasis. However, the lack of targeting and effectiveness hinders gene therapy from entering clinical application. Herein, a somatostatin receptor-targeted polymeric nanoplatform is developed for the delivery of a PD-L1-targeted CRISPR/Cas9 system and synergistic treatment of hepatocellular carcinoma. This nanoplatform can effectively incorporate the CRISPR/Cas9 system and the chemotherapeutic drug paclitaxel to simultaneously address the biological safety and packaging capacity issues of viral vectors. After the octreotide-modified polymer (LNA-PEG-OCT) guided the nanoparticle into hepatoma carcinoma cells, the nanoparticle protected the CRISPR/Cas9 ribonucleoprotein complex (RNP) and achieved lysosomal escape. Then, the RNP reached the target gene (PD-L1) under the guidance of the single guide RNA (sgRNA) in the RNP. The PD-L1 gene editing efficiency reached up to 55.8% for HepG2 cells in vitro and 46.0% for tumor tissues in vivo, leading to effective suppression of PD-L1 protein expression. Substantial inhibition of hepatocellular carcinoma cell proliferation and further 79.45% growth repression against subcutaneous xenograft tumors were achieved. Overall, this somatostatin receptor-targeted polymeric nanoplatform system not only provides a promising nanocarrier for CRISPR/Cas9 system delivery, but also expands the potential of combining gene editing and chemotherapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Lymph node dissection (LND) damages the lymphatic pathway, leading to postoperative lymphorrhea and chylorrhea. Treatments for lymphorrhea include conservative treatment (e.g., fasting, total parenteral nutrition), drug therapy, interventional radiology (IR), and surgery. We reviewed the records of 28 patients at Toho University Sakura Medical Center with postoperative lymphorrhea or chylorrhea after LND that did not improve with conservative treatment. Based on our analysis, we partially revised the treatment algorithm for lymphorrhea developed by Rose et al. Octreotide was administered in twenty-seven patients, lymphangiography was performed in three patients, and lymphatic embolization was performed in one patient. Treatment success rates for octreotide and IR were 78.6% and 100%, respectively. The mean duration of drain placement after surgery for primary cancer was 18.3 ± 14.3 days. Patients with lymphorrhea and chylorrhea should be initially treated conservatively, with IR performed if conservative treatment is unsuccessful. Surgical treatment should be a last resort. Background: Lymph node dissection (LND) is often performed in genitourinary cancer to improve accurate staging. However, the resultant lymphatic damage often leads to postoperative lymphorrhea and chylorrhea. Further, since lymphatic fluid lacks platelets, it has very few clotting factors, and it is often difficult to treat postoperative lymphatic leakage. Treatments for lymphorrhea include conservative treatment (e.g., fasting, total parenteral nutrition, and drug therapy), interventional radiology (IR) and surgical treatment. However, there is no guideline of refractory lymphorrhea, and no clear criteria for switching to the next treatment. Methods: We reviewed the records of 28 patients at Toho University Sakura Medical Center with postoperative lymphorrhea or chylorrhea after LND that did not improve with conservative treatment. Based on this analysis, we partially revised the treatment algorithm for lymphorrhea developed by Rose et al. Results: The cases consisted of 26 men and two women, aged 65.0 ± 9.9 years. The mean number of lymph nodes removed was 25.3 ± 15.0. Octreotide was administered in 27 patients, lymphangiography was performed in three patients, and lymphatic embolization was performed in two patients. The mean duration of octreotide administration was 9.7 ± 6.1 days, and the mean dose was 211.1 µg/day. The treatment success rates with octreotide and IR were 78.6% and 100%, respectively. The mean duration of drain placement after surgery for primary cancer was 18.3 ± 14.3 days. Conclusions: Patients with lymphorrhea and chylorrhea should be initially treated conservatively, with IR performed if conservative treatment is unsuccessful. Surgical treatment should be a last resort. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to investigate the treatment patterns and outcomes in two propensity score-matched cohorts of patients with neuroendocrine tumours (NETs) treated with first-line somatostatin analogue (SSA). Methods: Metastatic NET patients treated with first-line SSA (2009–2022) were retrospectively examined. First-line lanreotide vs. octreotide cohorts were matched 1:1 by propensity scores for demographics, tumour characteristics, and diagnosis year. Progression-free survival (PFS) and overall survival (OS) were analysed using Kaplan–Meier analysis and the Cox proportional hazards model. Results: Among 441 patients, 310 were matched (155 in both the octreotide and lanreotide groups). First-line SSA was monotherapy (63.5%) or combination with other medications (36.5%). A total of 77% of second-line patients (188/244) maintained their initial SSA medication in combination with other therapies. Radioligand therapy with lanreotide (N = 72; 29.5%) or octreotide (N = 70; 28.7%) was the most common second-line treatment. First-line lanreotide and octreotide cohorts had similar median PFS (15.5; 95% CI: 13.6–19.1 vs. 14.0; 95% CI: 12.0–15.8 months), despite octreotide having a 36% higher likelihood of moving to the second line than lanreotide (95% CI: 1.05–1.76, p = 0.018). Multiple metastases (HR = 1.45; p = 0.004, 95% CI: 1.13–1.87) and Ki-67 > 20% (HR = 2.34; p < 0.001, 95% CI: 1.43–3.83) were significantly associated with the worst PFS. First-line lanreotide patients had a median OS of 10.4 years (95% CI: 7.5-NA) and octreotide 9.2 years (95% CI: 7.3-NA) (p = 0.537). Bone metastases increased death risk by 91% (p = 0.014; 95% CI: 1.14–3.20). Conclusions: SSA monotherapy is the main first-line treatment and most subsequent treatments include SSA with additional medications. Cohorts had similar PFS/OS, but octreotide demonstrated a 36% significantly higher likelihood of moving to the second-line treatment. [ABSTRACT FROM AUTHOR]

Introduction: Somatostatin analogs (SSAs) were developed as antisecretory agents to palliate hormonal symptoms in patients with functioning neuroendocrine tumors (NETs). Their antiproliferative activity has been established in the phase 3 PROMID and CLARINET trials. SSAs currently represent the standard first-line therapy for the majority of well-differentiated G1/G2 gastroenteropancreatic NETs as well as for pulmonary NETs. Areas covered: An update on the clinical applications of established SSAs for the treatment of NETs is provided. Perspectives on emerging nonpeptide SSAs such as paltusotine and innovative formulations of octreotide (CAM2029) are included. Expert opinion: SSAs represent the cornerstone of treatment for both functioning and nonfunctioning NETs. While standard-dose SSAs have a defined place in the therapeutic algorithm of well-differentiated NETs, uncertainties remain on how to best integrate above-label doses of SSAs in the treatment sequence, particularly when tumor control is the goal. Octreotide and lanreotide appear to be clinically interchangeable, and no signs of superiority of one agent over the other has been observed so far. Whether SSAs may be exploited in the maintenance setting following more aggressive treatments, whether continuing SSAs beyond-progression after first-line therapy could be an effective treatment strategy, and whether new-generation SSAs such as pasireotide could overcome resistance to established SSAs are key areas of investigation. [ABSTRACT FROM AUTHOR]

Acromegaly is a rare endocrine disorder caused by excessive growth hormone (GH) production, due, in the vast majority of cases, to the presence of a GH-secreting pituitary tumour. The chronic elevation of GH and the resulting high circulating levels of insulin-like growth factor-1 (IGF-1) cause the characteristic tissue overgrowth and a number of associated comorbidities, including several metabolic changes, such as glucose intolerance and overt diabetes mellitus (DM). Elevated GH concentrations directly attenuate insulin signalling and stimulate lipolysis, decreasing glucose uptake in peripheral tissues, thus leading to the development of impaired glucose tolerance and DM. Acromegaly treatment aims to normalize plasma GH and IGF-1 levels using surgery, medical treatment, or radiotherapy. The effect of the different medical therapies on glucose homeostasis varies. This literature review explores the impact of the currently available pharmacological therapies for acromegaly (first- and second-generation somatostatin receptor ligands, a GH receptor antagonist, and dopamine agonists) on glucose homeostasis. We also discuss the underlying biological mechanisms through which they impact glucose metabolism. [ABSTRACT FROM AUTHOR]

Octreotide is recommended as a second-line treatment for patients with congenital hyperinsulinism (CHI), especially for those who do not respond to diazoxide or surgical intervention. Studies on the adverse effects of octreotide in large cohorts are still scarce. We evaluated the safety of octreotide in CHI patients by reviewing cases from the two largest centres in China that specialize in the management of this condition. Our study analysed adverse events in 122 CHI patients on octreotide, with a 93% success rate for the therapy alone. The mean maximum dose of octreotide was 13.1 ± 6.5 µg/kg/day, with no difference in required doses between diffuse and focal lesion patients. Common side effects were hepatobiliary injuries (20.5%), gastrointestinal symptoms (31.1%), and transient hyperglycaemia (49.2%), with one case of necrotizing enterocolitis. Adverse event rates increased in patients treated with intermediate octreotide dose to those treated with higher doses, rising from 58% at doses of 5–10 µg/kg/day to 100% at doses exceeding 20 µg/kg/day. Patients experiencing adverse events received significantly higher doses. Conclusion: Octreotide effectively maintained blood glucose levels in diazoxide-unresponsive CHI patients without serious adverse effects, across all subtypes. Our study suggests that intermediate octreotide dosing is associated with a lower incidence of adverse events. We recommend close monitoring of patients receiving octreotide, especially during the initiation phase and when higher doses are administered. What is known: • Octreotide is a commonly used second line treatment for patients with congenital hyperinsulinism. • The administration of octreotide is frequently associated with gastrointestinal adverse events. What is new: • Our study indicates that octreotide is used without serious adverse effects to maintain blood glucose levels in infants with congenital hyperinsulinism who are otherwise in good health. • The incidence of adverse events in patients treated with octreotide is dose-dependent. [ABSTRACT FROM AUTHOR]

Regulatory authorities typically require bioequivalence to be demonstrated by comparing pharmacokinetic parameters like area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax). Because in certain cases, AUC and Cmax alone may not be adequate to identify formulation differences in early and/or late segments of the dosing interval, partial AUCs (pAUCs) have been proposed as additional metrics to evaluate bioequivalence. Even though cut-off points for pAUCs are usually decided based on clinical relevance, the identification of the correct cut-off range remains elusive in many other cases and tends to contribute to increased pAUC estimate variabilities. The choice of meaningful cut-off points in pAUC estimates can be especially difficult in the case of long-acting injectable (LAI) products, where long dosing intervals and complex pharmacokinetic (PK) and pharmacodynamic (PD) profiles apply, but most importantly, because there is not always a clear PK/PD relationship established. In this communication, authors discuss the usefulness and challenges associated with the estimation of pAUCs in the development of generic LAI products through the review of six case studies under the lens of regulatory requirements from the two major authorities, namely the FDA and EMA. [ABSTRACT FROM AUTHOR]

Rare defects in the promoter region of SLC16A1 , the gene encoding monocarboxylate transporter 1 (MCT-1), result in exercise-induced hyperinsulinism. In this disorder, inappropriate insulin secretion is triggered by anaerobic exercise with consequent hypoglycaemia. We describe the case of a 41-year-old man presenting with a generalised tonic–clonic seizure and severe hypoglycaemia following strenuous exercise. A subsequent prolonged fast with incorporation of exercise into the protocol demonstrated hyperinsulinaemic hypoglycaemia; genetic testing revealed a variant of unknown significance in the SLC16A1 gene. Administration of subcutaneous octreotide resulted in dose-dependent reduction in hyperinsulinaemia and hypoglycaemia. [ABSTRACT FROM AUTHOR]

PurposeInflamed, prone-to-rupture coronary plaques are an important cause of myocardial infarction and their early identification is crucial. Atherosclerotic plaques are characterized by overexpression of the type-2 somatostatin receptor (SST2) in activated macrophages. SST2 ligand imaging (e.g. with [68 Ga]Ga-DOTA-TOC) has shown promise in detecting and quantifying the inflammatory activity within atherosclerotic plaques. However, the sensitivity of standard axial field of view (SAFOV) PET scanners may be suboptimal for imaging coronary arteries. Long-axial field of view (LAFOV) PET/CT scanners may help overcome this limitation. We aim to assess the ability of [68 Ga]Ga-DOTA-TOC LAFOV-PET/CT in detecting calcified, SST2 overexpressing coronary artery plaques.MethodsIn this retrospective study, 108 oncological patients underwent [68 Ga]Ga-DOTA-TOC PET/CT on a LAFOV system. [68 Ga]Ga-DOTA-TOC uptake and calcifications in the coronary arteries were evaluated visually and semi-quantitatively. Data on patients' cardiac risk factors and coronary artery calcium score were also collected. Patients were followed up for 21.5 ± 3.4 months.ResultsA total of 66 patients (61.1%) presented with calcified coronary artery plaques. Of these, 32 patients had increased [68 Ga]Ga-DOTA-TOC uptake in at least one coronary vessel (TBR: 1.65 ± 0.53). Patients with single-vessel calcifications showed statistically significantly lower uptake (SUVmax 1.10 ± 0.28) compared to patients with two- (SUVmax 1.31 ± 0.29, p

Abstract Background Neuroendocrine tumors (NETs) are clinically diverse types of tumors that can arise anywhere in the body. Previous studies have shown that somatostatin receptors (SSTRs) are overexpressed on NET cell membranes relative to healthy tissue, allowing for tumor targeting through radiolabeled somatostatin analogs (SSAs). This work aims to develop a novel 89Zr-labeled tracer incorporating the SSA, octreotide (TOC), for positron emission tomography (PET) imaging of SSTR + NETs and predictive dosimetry calculations, leveraging the excellent nuclear (t½ = 3.27 days, β+ = 22.3%, β+ avg = 395.5 keV) and chemical characteristics (+ 4 oxidation state, preferential coordination number of 7/8, favorable aqueous chemistry) of 89Zr. In combination with 89Zr, the known radiochemistry with the chelator deferoxamine (DFO) gives reason to believe that this radiopharmaceutical incorporating an octreotide conjugate will be successful in studying the suitability of detecting SSTR + NETs. Results Radiochemical tracer assessment indicated that amounts as low as 0.1 nmol DFO-TOC can be effectively radiolabeled with 89Zr, while maintaining ≥ 95% radiochemical yield. The stability of the compound was found to maintain radiochemical yields of 89.6% and 88.7% on the benchtop and in mouse serum, respectively, after 9 days. Receptor binding and competitive receptor blocking assays compared AR42J (high SSTR expression), PC-3 (moderate SSTR expression), and PANC-1 (minimal SSTR expression) cell lines at time points up to 6 days. In vitro studies demonstrated highest uptake in AR42J cells, and statistically significant differences in tracer uptake were seen after 1 h. Internalization assays showed maximum internalization after 3 h for all cell lines. Conclusions In this work, [89Zr]Zr-DFO-TOC was synthesized with radiochemical yields ≥ 95% and was found to remain stable in vitro at extended time points. In vitro cell studies demonstrated a statistically significant difference between receptor binding and blocking experiments. The development of this work shows potential to positively impact patient care through the predictive dosimetry calculations for the FDA-approved therapeutic agent [177Lu]Lu-DOTA-TATE, while allowing for imaging at extended timepoints and should be studied further.

Background: The second-line treatment of neuroendocrine tumors (NETs) of unknown primary origin remains uncertain. This report presented a patient who received octreotide plus IBI-318 plus anlotinib as a second-line treatment for multiple metastatic NETs of unknown primary lesions after the failure of octreotide plus everolimus. Case presentation: A 32-year-old male patient presented with elevated CEA (197.83 ng/ml) without specific symptoms. A contrast-enhanced computed tomography (CT) scan showed multiple metastatic lymph nodes and multiple low-density nodules in the liver of undetermined nature. A right supraclavicular lymph node biopsy indicated NET, but the primary tumor origin remained unknown. PD-L1 expression was negative in tumor tissue according to immunohistochemistry. Immunofluorescence indicated the CD4+ T cells, CD8+ T cells, and Treg cells were gathered around blood vessels, with only a few infiltrating lymphocytes in the tumor tissue. Treatment with octreotide (30 mg/28 d) plus everolimus (5 mg qd) led to disease progression after three cycles. Treatment was changed to octreotide (30 mg/28 d) plus IBI318 (400 mg/28 d) plus anlotinib (10 mg/1-14 d/q3w), leading to partial remission, which was sustained up to the last follow-up (June 20, 2023), with a PFS of 11 months. The patient experienced no treatment-related adverse reactions. Conclusions: Octreotide plus IBI318 plus anlotinib achieved benefits in a patient with advanced NETs of unknown primary lesions after first-line treatment failure, even though with low PD-L1 expression. This case suggests that combining SSAs, TKIs and PD-1/PD-L1 inhibitors could be an alternative second-line treatment for patients with advanced, well-differentiated NETs. [ABSTRACT FROM AUTHOR]

Background: Neuroendocrine tumors (NETs) are clinically diverse types of tumors that can arise anywhere in the body. Previous studies have shown that somatostatin receptors (SSTRs) are overexpressed on NET cell membranes relative to healthy tissue, allowing for tumor targeting through radiolabeled somatostatin analogs (SSAs). This work aims to develop a novel 89Zr-labeled tracer incorporating the SSA, octreotide (TOC), for positron emission tomography (PET) imaging of SSTR + NETs and predictive dosimetry calculations, leveraging the excellent nuclear (t½ = 3.27 days, β+ = 22.3%, β+avg = 395.5 keV) and chemical characteristics (+ 4 oxidation state, preferential coordination number of 7/8, favorable aqueous chemistry) of 89Zr. In combination with 89Zr, the known radiochemistry with the chelator deferoxamine (DFO) gives reason to believe that this radiopharmaceutical incorporating an octreotide conjugate will be successful in studying the suitability of detecting SSTR + NETs. Results: Radiochemical tracer assessment indicated that amounts as low as 0.1 nmol DFO-TOC can be effectively radiolabeled with 89Zr, while maintaining ≥ 95% radiochemical yield. The stability of the compound was found to maintain radiochemical yields of 89.6% and 88.7% on the benchtop and in mouse serum, respectively, after 9 days. Receptor binding and competitive receptor blocking assays compared AR42J (high SSTR expression), PC-3 (moderate SSTR expression), and PANC-1 (minimal SSTR expression) cell lines at time points up to 6 days. In vitro studies demonstrated highest uptake in AR42J cells, and statistically significant differences in tracer uptake were seen after 1 h. Internalization assays showed maximum internalization after 3 h for all cell lines. Conclusions: In this work, [89Zr]Zr-DFO-TOC was synthesized with radiochemical yields ≥ 95% and was found to remain stable in vitro at extended time points. In vitro cell studies demonstrated a statistically significant difference between receptor binding and blocking experiments. The development of this work shows potential to positively impact patient care through the predictive dosimetry calculations for the FDA-approved therapeutic agent [177Lu]Lu-DOTA-TATE, while allowing for imaging at extended timepoints and should be studied further. [ABSTRACT FROM AUTHOR]

Objective To observe the effects of octreotide on fecal characteristics and humoral immunity in neonates with necrotizing enterocolitis (NEC). Methods A retrospective study was conducted on 60 newly born NEC patients at Hebei PetroChina Central Hospital from March 2022 to September 2023. The patients were separated into the observation group (30 cases) and the routine group (30 cases) based on treatment methods. The conventional group was treated with total parenteral nutrition and gastrointestinal decompression plus piperacillin sodium and tazobactam sodium for 7 days. The observation group was treated with octreotide in addition to the routine group for 5 days. The treatment efficacy, general clinical data, degree of intestinal microbiota disorder, expression levels of intestinal microbiota markers and immune indicators were compared between the two groups. Results The total effective rate of the observation group was higher than that of the routine group (P＜0.05). After treatment, body weight of the observation group was higher than that of the routine group. The hospitalization time, vomiting relief time, abdominal distension relief time, diarrhea relief time and complete recovery time of fecal characteristics were lower in the observation group than those in the routine group. Compared with before treatment, the degree of intestinal microbiota disorder and high mobility group box protein 1 (HMGB1) were reduced in both groups after treatment, and expression levels of human β defensin 2 (HBD2), autoinducer-2 (AI-2) and serum immunoglobulin (Ig) A, IgG and IgM were increased (P＜0.05). After treatment, HMGB1 was lower in the observation group than that in the routine group, while HBD2, AI-2 and serum IgA, IgG and IgM were higher than those in the routine group (P＜0.05). Conclusion Octreotide can effectively treat children with NEC, improve stool characteristics, and enhance immunity. [ABSTRACT FROM AUTHOR]

Adjuvant therapy for pancreatic neuroendocrine tumors (PanNETs) after radical resection lacks evidence‐based data and remains controversial. This study aimed to validate whether long‐acting octreotide is a potential candidate for adjuvant therapy in patients with G2 PanNETs at high recurrence risk by clustering real‐world data. A retrospective review of patients with nonmetastatic grade 2 PanNETs who underwent radical resection at six research centers between 2008 and 2020 was conducted. Propensity score matching and inverse probability of treatment weight analysis were used to control confounding factors. Overall, 357 patients (octreotide group, n = 82; control group, n = 275) were analyzed. Kaplan–Meier survival analyses showed that the octreotide group had longer disease‐free survival (DFS) compared with the control group (36 months: 93.3% vs. 79.0%, p =.0124; 60 months: 71% vs. 67.6%, p =.0596, respectively), as well as overall survival (OS) (60 months: 98% vs. 83.8%, p =.0117, respectively). Multivariate analyses indicated that octreotide long‐acting repeatable (LAR) adjuvant therapy was associated with higher OS (p =.0270) at 60 months. Propensity score matching analysis showed that octreotide adjuvant therapy was associated with higher DFS (p =.0455) and OS (p =.0190) at 60 months. Similar results were obtained via inverse probability of treatment weight analysis. Subgroup analysis indicated that octreotide LAR was associated with a high DFS in patients with lymph node metastasis or Ki‐67 <10% PanNETs. Adjuvant therapy with long‐acting octreotide following radical resection of nonmetastatic G2 PanNETs may be associated with improved DFS and OS in a real‐world setting. [ABSTRACT FROM AUTHOR]