Dosimetry and pharmacokinetics of [177Lu]Lu-satoreotide tetraxetan in patients with progressive neuroendocrine tumours.

PURPOSE: To evaluate the dosimetry and pharmacokinetics of the novel radiolabelled somatostatin receptor antagonist [177Lu]Lu-satoreotide tetraxetan in patients with advanced neuroendocrine tumours (NETs). METHODS: This study was part of a phase I/II trial of [177Lu]Lu-satoreotide tetraxetan, administered at a median cumulative activity of 13.0 GBq over three planned cycles (median activity/cycle: 4.5 GBq), in 40 patients with progressive NETs. Organ absorbed doses were monitored at each cycle using patient-specific dosimetry; the cumulative absorbed-dose limits were set at 23.0 Gy for the kidneys and 1.5 Gy for bone marrow. Absorbed dose coefficients (ADCs) were calculated using both patient-specific and model-based dosimetry for some patients. RESULTS: In all evaluated organs, maximum [177Lu]Lu-satoreotide tetraxetan uptake was observed at the first imaging timepoint (4 h after injection), followed by an exponential decrease. Kidneys were the main route of elimination, with a cumulative excretion of 57-66% within 48 h following the first treatment cycle. At the first treatment cycle, [177Lu]Lu-satoreotide tetraxetan showed a median terminal blood half-life of 127 h and median ADCs of [177Lu]Lu-satoreotide tetraxetan were 5.0 Gy/GBq in tumours, 0.1 Gy/GBq in the bone marrow, 0.9 Gy/GBq in kidneys, 0.2 Gy/GBq in the liver and 0.8 Gy/GBq in the spleen. Using image-based dosimetry, the bone marrow and kidneys received median cumulative absorbed doses of 1.1 and 10.8 Gy, respectively, after three cycles. CONCLUSION: [177Lu]Lu-satoreotide tetraxetan showed a favourable dosimetry profile, with high and prolonged tumour uptake, supporting its acceptable safety profile and promising efficacy. TRIAL REGISTRATION: NCT02592707. Registered October 30, 2015.

Pharmacokinetics and pharmacodynamics of a pasireotide subcutaneous depot (CAM4071) and comparison with immediate and long-acting release pasireotide.

PURPOSE: To assess the pharmacokinetics, pharmacodynamics, safety and tolerability of subcutaneous depot CAM4071, a novel, ready-to-use pasireotide formulation. METHODS: This was a phase 1, randomised, open-label study in healthy volunteers. After a single 600 µg dose of pasireotide immediate release (IR), participants were randomised to one of eight groups to receive either a CAM4071 upper thigh (5, 10, 20, 40 or 80 mg) or buttock (20 mg) injection or multiple pasireotide IR 900 µg upper thigh injections twice daily or a single pasireotide long-acting release (LAR) 60 mg intramuscular buttock injection. RESULTS: Ninety-four participants were randomised. For all CAM4071 doses, initial pasireotide release was relatively rapid compared to pasireotide LAR and sustained over the 2-month observation period, with a slow decay in plasma concentrations. CAM4071 maximum plasma concentrations increased slightly greater than dose proportionally; area under the curve extrapolated to infinity increased approximately dose proportionally. Relative bioavailability of pasireotide for different doses of CAM4071 versus pasireotide IR 600 µg ranged from 0.752 (90% confidence interval [CI]: 0.58, 0.98) to 1.68 (1.32, 2.14), and versus pasireotide LAR: 0.517 (0.37, 0.72) to 1.15 (0.84, 1.58). CAM4071 doses >5 mg exhibited rapid initial reductions of insulin-like growth factor 1 (IGF-1) compared to pasireotide LAR. Maximum IGF-1 inhibition was greatest for CAM4071 80 mg. CAM4071 injections ≤40 mg were well tolerated and comparable with currently available pasireotide formulations. CONCLUSION: CAM4071 provided long-acting release of pasireotide over at least one month, with high bioavailability and onset and duration of IGF-1 suppression similar to pasireotide LAR. TRIAL REGISTRATION: EudraCT: 2014-003783-20.

Altered biodistribution of [68Ga]Ga-DOTA-TOC during somatostatin analogue treatment.

PURPOSE: The need for an interval between the administration of long-acting Somatostatin Receptor Analogues (SSA) and the [68Ga]Ga-DOTA-TATE PET has been questioned based on recent literature in the new EANM guidelines. Here an earlier studies showed that SSA injection immediately before SSTR PET had minimal effect on normal organ and tumor uptake (1). However, data are scarce and there are (small) differences between [68Ga]Ga-DOTA-TATE and [68Ga]Ga-DOTA-TOC binding affinity, and it remains unknown whether these findings can be directly translated to scans with [68Ga]Ga-DOTA-TOC as well. The purpose of this study was to assess the effect of SSA use on the biodistribution in a subsequent [68Ga]Ga-DOTA-TOC PET/CT and compare this intra-individually across several cycles of SSA treatments. METHODS: Retrospectively, 35 patients with NENs were included. [68Ga]Ga-DOTA-TOC PET at staging and after the 1st and 2nd cycle of SSA were included. SUVmean and SUVmax of blood, visceral organs, primary tumor and two metastases were determined. Also, the interval between SSA therapy and the PET scan was registered. RESULTS: Treatment with SSA resulted in a significantly higher bloodpool activity and lower visceral tracer uptake. This effect was maintained after a 2nd cycle of SSA therapy. Furthermore, there was an inverse relationship between bloodpool tracer availability and visceral tracer binding and a positive correlation between bloodpool tracer availability and primary tumor tracer uptake. With an interval of up to 5 days, there was a significantly higher bloodpool activity than at longer intervals. CONCLUSION: Absolute comparison of the SUV on [68Ga]Ga-DOTA-TOC PET should be done with caution as the altered biodistribution of the tracer after SSA treatment should be taken into account. We recommend not to perform a scan within the first 5 days after the injection of lanreotide.

Bioanalysis of lanreotide in dog plasma using liquid chromatography-tandem mass spectrometry and its application in a pharmacokinetic study of beagle dogs after single subcutaneous injection.

Lanreotide is similar to a naturally occurring hormone, somatostatin; thus, it may be used to treat acromegaly or metastatic gastroenteropancreatic neuroendocrine tumours. Here, a bioanalytical method coupling ultra-performance liquid chromatography with tandem mass spectrometry to quantify lanreotide and an internal standard (IS) was developed and validated in dog plasma. The plasma samples were extracted using typical protein precipitation processes. The analyte and internal standard were separated on Phenomenex Kinetex® C18 with 0.1% formic acid and acetonitrile in the mobile phase at a flow rate of 0.4 mL/min. The fragmentation of precursor ions to product ions was optimized at m/z 548.8 â†’ 170.0 for lanreotide [M + 2H]2+ and 472.2 â†’ 436.2 for IS [M + H]+. The peak retention times of lanreotide and IS were 1.09 min and 1.22 min, respectively. The calibration curve samples in dog plasma ranged from 0.3 to 1000 ng/mL and showed good linearity, with a correlation coefficient of r2=0.9996. The lower limit of quantitation was 0.3 ng/mL. The intra- and inter-day precision (relative standard deviation) values for each quality control level were < 9.7 % and < 9.3 %, respectively; intra- and inter-day accuracy were < 109.3% and < 110.4%, respectively. Lanreotide in dog plasma was stable in various conditions. The maximum plasma concentration of lanreotide in male beagle dogs after subcutaneous injection of Somatuline® (lanreotide) Autogel 120 mg was 88.1 ng/mL. The half-life (T1/2) of lanreotide in beagle dogs was long, approximately 198.6 h; the area under the plasma-concentration curve from 0 to 840 h (day 35) was 6,995 ng⋅h/mL. This novel quantification method using UPLC-MS/MS was successfully applied to the pharmacokinetic analysis of lanreotide in dog plasma. The results will assist future studies of drug formulation and repurposing.

Quantification of the endogenous growth hormone and prolactin lowering effects of a somatostatin-dopamine chimera using population PK/PD modeling.

A phase 1 clinical trial in healthy male volunteers was conducted with a somatostatin-dopamine chimera (BIM23B065), from which information could be obtained on the concentration-effect relationship of the inhibition of pulsatile endogenous growth hormone and prolactin secretion. Endogenous growth hormone profiles were analyzed using a two-step deconvolution-analysis-informed population pharmacodynamic modeling approach, which was developed for the analyses of pulsatile profiles. Prolactin concentrations were modelled using a population pool model with a circadian component on the prolactin release. During treatment with BIM23B065, growth hormone secretion was significantly reduced (maximal effect [EMAX] = - 64.8%) with significant reductions in the pulse frequency in two out of three multiple ascending dose cohorts. A circadian component in prolactin secretion was identified, modelled using a combination of two cosine functions with 24 h and 12 h periods. Dosing of BIM23B065 strongly inhibited (EMAX = - 91%) the prolactin release and demonstrated further reduction of prolactin secretion after multiple days of dosing. This study quantified the concentration-effect relationship of BIM23B065 on the release of two pituitary hormones, providing proof of pharmacology of the chimeric actions of BIM23B065.

Intravitreal Pharmacokinetics in Mice: SPECT/CT Imaging and Scaling to Rabbits and Humans.

Preclinical in vivo tests of retinal drug responses are carried out in mice and rats, often after intravitreal injections. However, quantitative pharmacokinetics in the mouse eye is poorly understood. Ocular pharmacokinetics studies are usually done in rabbits. We investigated elimination of three compounds ([99mTc]Tc-pentetate, [111In]In-pentetreotide, [99mTc]Tc-human serum albumin with molecular weights of 510.2 Da, 1506.4 Da, and 66.5 kDa, respectively) from mouse vitreous using imaging with single photon emission computed tomography/computed tomography (SPECT/CT). Increasing molecular weight decreased elimination of the compounds from the mouse eyes. Half-lives of [99mTc]Tc-pentetate, [111In]In-pentetreotide, and [99mTc]Tc-human serum albumin in the mouse eyes were 1.8 ± 0.5 h, 4.3 ± 1.7 h, and 30.0 ± 9.0 h, respectively. These values are 3-12-fold shorter than half-lives of similar compounds in the rabbit vitreous. Dose scaling factors were calculated for mouse-to-rabbit and mouse-to-man translation. They were 27-90 and 38-126, respectively, for intravitreal injections in rabbit and man. We show ocular pharmacokinetic parameters for mice and interspecies scaling factors that may augment ocular drug discovery and development.

The Entrapment of Somatostatin in a Lipid Formulation: Retarded Release and Free Radical Reactivity.

The natural peptide somatostatin has hormonal and cytostatic effects exerted by the binding to specific receptors in various tissues. Therapeutic uses are strongly prevented by its very short biological half-life of 1-2 min due to enzymatic hydrolysis, therefore encapsulation methodologies are explored to overcome the need for continuous infusion regimes. Multilamellar liposomes made of natural phosphatidylcholine were used for the incorporation of a mixture of somatostatin and sorbitol dissolved in citrate buffer at pH = 5. Lyophilization and reconstitution of the suspension were carried out, showing the flexibility of this preparation. Full characterization of this suspension was obtained as particle size, encapsulation efficiency and retarded release properties in aqueous medium and human plasma. Liposomal somatostatin incubated at 37 °C in the presence of Fe(II) and (III) salts were used as a biomimetic model of drug-cell membrane interaction, evidencing the free radical processes of peroxidation and isomerization that transform the unsaturated fatty acid moieties of the lipid vesicles. This study offers new insights into a liposomal delivery system and highlights molecular reactivity of sulfur-containing drugs with its carrier or biological membranes for pharmacological applications.

The Pharmacodynamic Effects of a Dopamine-Somatostatin Chimera Agonist on the Cardiovascular System.

The quantification of the effect of pharmacological treatment on the cardiovascular system is complicated because of the high level of interindividual and circadian variability. Recently, a dopamine-somatostatin chimera, BIM23B065, was under investigation to concurrently target the somatostatin and dopamine D2 receptors for the treatment of neuroendocrine tumors. However, both dopamine and somatostatin interact with different components of the cardiovascular system. This study established the response of the heart rate and the systolic blood pressure after administration of BIM23B065 in healthy male volunteers by analysis of the rate-pressure product (RPP), in a model-informed analysis. The RPP in the supine position of placebo-treated subjects showed a clear circadian component, best described by 2 cosine functions. The pharmacokinetics of BIM23B065 and its metabolite were best described using 2-compartment models with different forms of elimination kinetics. The administration of BIM23B065 gave a statistically significant reduction in the RPP, after which the effect diminished because of the tolerance to the cardiovascular effects after prolonged exposure to BIM23B065. This model provided insight in the circadian rhythm of the RPP in the supine position and the level of interindividual variability in healthy male volunteers. The developed population pharmacokinetic/pharmacodynamic model quantified the interaction between BIM23B065 and the RPP, informing on the clinical pharmacological properties of BIM23B065.

A Prospective Observational Study to Evaluate the Effects of Long-Acting Somatostatin Analogs on 68Ga-DOTATATE Uptake in Patients with Neuroendocrine Tumors.

Patients with neuroendocrine tumors (NETs) are often treated with somatostatin analogs (SSAs) for control of symptoms and tumor growth. Such therapy could theoretically lead to misinterpretation of somatostatin receptor imaging with 68Ga-DOTATATE PET/CT by interfering with tracer-receptor binding. Guidelines recommend an interval of 3-4 wk between the last dose and imaging. The aim of this study was to evaluate if long-acting (LA) SSA treatment changes the uptake of 68Ga-DOTATATE in patients with NETs. Methods: From 2013 to 2016, 296 patients with, or under evaluation for, NETs were included in this prospective observational study. The effect of LA SSA on tracer uptake was evaluated in 2 main patient populations: those undergoing 68Ga-DOTATATE PET/CT before starting LA SSA treatment and at least once afterward, and those receiving ongoing LA SSA therapy, in whom the effect of the interval between the last dose of LA SSA and the PET/CT exam was analyzed. A third, explorative, analysis was performed to evaluate if clinical disease progression, regression, or stable tumor status changed the uptake of 68Ga-DOTATATE. In the 3 analyses, measurements of SUVmax in normal liver and tumor lesions were compared. Results: The median SUVmax in normal liver was significantly higher before treatment (8.6; interquartile range, 7.4-10.2) than after treatment initiation (6.0; 4.7-8.0) (P < 0.001). No significant changes in SUVmax were seen in tumor lesions after treatment initiation. No significant differences in SUVmax were found in normal liver or tumor lesions dependent on the interval between last dose of LA SSA and PET/CT. Conclusion: Treatment with LA SSA does not change SUVmax in tumor lesions, whereas SUVmax in normal liver is significantly lower after treatment. The findings have implications for interpretation of 68Ga-DOTATATE PET/CT for response assessment after SSA therapy and for guidelines on discontinuation of treatment before PET/CT.

A Novel Somatostatin-Dopamine Chimera (BIM23B065) Reduced GH Secretion in a First-in-Human Clinical Trial.

Context: A somatostatin-dopamine chimera (BIM23B065) was under investigation to reduce GH secretion for the treatment of pituitary adenomas. Objective: To determine pharmacokinetics, safety, and tolerability and to monitor hormonal changes after single and multiple subcutaneous BIM23B065 administrations. Design: Randomized, double-blind, placebo-controlled, parallel-group design with five single and three 13-day multiple ascending-dose cohorts. Patients: A total of 63 healthy male white volunteers were enrolled (47 active, 16 placebo). Main Outcome Measures: Pharmacokinetics, GH, prolactin (PRL), IGF-1, GH after GHRH administration, and general clinical safety criteria. Results: The maximum dosage of BIM23B065 administered in this study was 1.5 mg. BIM23B065 reduced the mean GH concentrations after 8 and 13 days of treatment. A decrease in GH release after GHRH administration indicated inhibition of the hypothalamic-pituitary-somatotropic axis. IGF-1 was not altered after single doses but showed a significant change from baseline after multiple dosing. PRL secretion was reduced in all subjects who were treated. Orthostatic hypotension and injection site reactions were commonly observed at high dosages. A 6-day uptitration period was included to successfully lower the cardiovascular effects in the multiple ascending dose part of the study. Conclusions: Proof of pharmacology of BIM23B065 was shown by a reduction in GH, IGF-1, and PRL concentrations in healthy male volunteers, supporting activity of the somatostatin analog and dopamine agonist moieties. The safety and tolerability of the higher dosing regions was limited mainly by orthostatic hypotension.

Somatostatin receptor expression in non-classical locations - clinical relevance?

In-111 pentetreotide (Octreoscan) is a radiolabeled somatostatin analog with high binding affinity to somatostatin receptors (SSTR) used in somatostatin receptor scintigraphy (SRS). Pentetreotide labelled with In-111 is widely used due to its high affinity to SSTR 2 and 5. SSTR are expressed on neuroendocrine cells as well as several non-neural and non-endocrine cells with varying levels of density. We retrospectively reviewed articles and publications related to octreoscan accumulation in sites that classically do not have high concentrations of SSTR as well as in organs and tissues from diseases which are not usually diagnosed by octreoscan. The significance of a positive uptake as assessed by octreoscan in non-somatostatin receptor related diseases is not fully understood yet. Localization of octreotide in non-oncological disease states such as inflammation is due to presence of SSTR in activated immunological cells, over-expression by activated cells in the respective tissue and SSTR expression by blood vessels. In granulomatous diseases, over-expression of SSTR2 preferential binding sites were detected in epitheloid and giant cells. The purpose of the current study is to identify octreoscan localization in non-somatostatin receptor related disease sites to better understand the mechanism of this nonspecific accumulation which may help expand the clinical utilization of functional imaging utilizing somatostatin receptor scintigraphy in diagnosis and perhaps therapy.

Sensitive quantification of the somatostatin analog AP102 in plasma by ultra-high pressure liquid chromatography-tandem mass spectrometry and application to a pharmacokinetic study in rats.

AP102 is a di-iodinated octapeptide somatostatin agonist (SSA) designed to treat acromegaly and neuroendocrine tumors. A sensitive and selective method was validated for the quantification of AP102 in plasma following the European Medicines Agency (EMA) and Food and Drug Administration (FDA) guidelines. Sample preparation was performed using solid-phase extraction microplates. Chromatographic separation was achieved on an ultra-high pressure liquid chromatography (UHPLC) C18 column in 6.0 minutes. The compounds were quantified using multiple reaction monitoring on a tandem quadrupole mass spectrometer with 13 C,15 N-labeled AP102 as internal standard. Calibration ranged from 50 to 10000 pg/mL. The lower limit of quantification (LLOQ) was measured at 20 pg/mL, and robust analytical performances were obtained with trueness at 99.2%-100.0%, intra-assay imprecision at 2.5%-4.4%, and inter-assay imprecision at 8.9%-9.7%. The accuracy profiles (total error) built on the 3 concentrations levels showed accuracy within the 70%-130% range. AP102 is remarkably stable since no proteolytic fragments were detected on plasma samples analyzed by Orbitrap-MS. Pharmacokinetic studies were conducted in rats, after single dose (1, 3, and 10 µg/kg, sc) and continuous subcutaneous administration (osmotic minipumps for 28 days, 3.0 or 10.0 µg/kg/h). AP102 showed a rapid absorption by the subcutaneous route (Tmax : 15-30 minutes) and a fast elimination (t1/2 : 33-86 minutes). The PK profile of AP102 exhibited a mean clearance of 1.67 L/h and a mean distribution volume at steady state of 7.16 L/kg, about 10-fold higher than those observed with other SSA or non- and mono-iodinated AP102. LogD7.4 determination confirmed the lipophilic properties of AP102 that might influence its distribution in tissues.

Safety, Pharmacokinetics, and Dosimetry of a Long-Acting Radiolabeled Somatostatin Analog 177Lu-DOTA-EB-TATE in Patients with Advanced Metastatic Neuroendocrine Tumors.

Radiolabeled somatostatin analog therapy has become an established treatment method for patients with well to moderately differentiated unresectable or metastatic neuroendocrine tumors (NETs). The most frequently used somatostatin analogs in clinical practice are octreotide and octreotate. However, both peptides showed suboptimal retention within tumors. The aim of this first-in-humans study is to explore the safety and dosimetry of a long-acting radiolabeled somatostatin analog, 177Lu-1, 4, 7, 10-tetra-azacyclododecane-1, 4, 7, 10-tetraacetic acid-Evans blue-octreotate (177Lu-DOTA-EB-TATE). Methods: Eight patients (6 men and 2 women; age range, 27-61 y) with advanced metastatic NETs were recruited. Five patients received a single dose, 0.35-0.70 GBq (9.5-18.9 mCi), of 177Lu-DOTA-EB-TATE and underwent serial whole-body planar and SPECT/CT scans at 2, 24, 72, 120, and 168 h after injection. The other 3 patients received intravenous injection of 0.28-0.41 GBq (7.5-11.1 mCi) of 177Lu-DOTATATE for the same imaging acquisition procedures at 1, 3, 4, 24, and 72 h after injection. The dosimetry was calculated using the OLINDA/EXM 1.1 software. Results: Administration of 177Lu-DOTA-EB-TATE was well tolerated, with no adverse symptoms being noticed or reported in any of the patients. Compared with 177Lu-DOTATATE, 177Lu-DOTA-EB-TATE showed extended circulation in the blood and achieved a 7.9-fold increase of tumor dose delivery. The total-body effective doses were 0.205 ± 0.161 mSv/MBq for 177Lu-DOTA-EB-TATE and 0.174 ± 0.072 mSv/MBq for 177Lu-DOTATATE. Significant dose delivery increases to the kidneys and bone marrow were also observed in patients receiving 177Lu-DOTA-EB-TATE compared with those receiving 177Lu-DOTATATE (3.2 and 18.2-fold, respectively). Conclusion: By introducing an albumin-binding moiety, 177Lu-DOTA-EB-TATE showed remarkably higher uptake and retention in NETs as well as significantly increased accumulation in the kidneys and red marrow. It has great potential to be used in peptide receptor radionuclide therapy for NETs with lower dose and less frequency of administration.

Pasireotide - Mechanism of Action and Clinical Applications.

BACKGROUND: Pasireotide (SOM230) is a multi-receptor ligand somatostatin analogue (SSA) developed as the successor of the first-generation SSAs. Currently, pasireotide is recommended for the treatment of patients with Cushing's disease in whom surgery was unsuccessful, and patients with acromegaly who either remain uncontrolled after surgical therapy or in whom tumor resection is not possible. METHODS AND RESULTS: Phase II and III clinical trials have shown pasireotide efficacy in these diseases, with a similar rate of adverse events when compared with first-line SSA, although higher incidence of hyperglycemia has been observed. CONCLUSION: Pasireotide therapy provides biochemical control, tumor volume reduction, and improves the quality of life in patients with those disorders. Furthermore, pasireotide might be considered as second-line therapy in patients with metastatic neuroendocrine tumors, and it also might be effective in other neoplasms with a high expression of somatostatin receptors. In addition, therapy with this novel agent has been effective in prevention of postoperative complications after pancreatectomy. However, considering the diversified responsiveness to this drug in vivo, future studies should identify factors predicting better clinical response to pasireotide.

Population Pharmacokinetics of Subcutaneous Pasireotide in Healthy Volunteers and Cushing's Disease Patients.

BACKGROUND AND OBJECTIVE: Pasireotide (SOM230, Signifor®) is a somatostatin analog approved in a subcutaneous formulation for the treatment of Cushing's disease. This analysis characterizes the population pharmacokinetics (PopPK) of subcutaneous pasireotide jointly in healthy volunteers (HVs) and Cushing's disease patients (CDPs), evaluating the effects of age, body size, and population on pasireotide pharmacokinetics. METHODS: The analysis dataset included five phase I studies and one each from phase II and phase III. A three-compartment, linear structural pharmacokinetic model was used. Models were specified a priori that varied in the relationship between HVs and CDPs, and the model with the lowest value of the Bayes Information Criterion (BIC) was selected. It was then used to illustrate various features of pasireotide pharmacokinetics. RESULTS AND CONCLUSIONS: In the final model, the estimated values of apparent clearance (CL/F), central volume of distribution, and deep peripheral volume of distribution of pasireotide in CDP were 59, 43, and 225% those of HVs at the same age and body size. Clearance increased with body size and decreased with age similarly for CDPs and HVs. The estimated CL/F for a typical CDP (40 years old, lean body weight [LBW] 49 kg) was 3.72 L/h, and for a typical HV (29 years old, LBW 61 kg) was 7.96 L/h. The model was judged adequate by visual predictive checks and diagnostic plots separately for HVs and CDPs and can be used for simulations for deriving exposure-response metrics for pharmacokinetic/pharmacodynamic analyses.

Long-Acting Somatostatin Analog Therapy Differentially Alters 68Ga-DOTATATE Uptake in Normal Tissues Compared with Primary Tumors and Metastatic Lesions.

Synthetic somatostatin analogs have been posed as a potential source of error in somatostatin receptor imaging through interference with tumor detection; however, experimental models and clinical studies have shown a complex mechanism of the effect of octreotide on tumors. The aim of this study was to assess whether 68Ga-DOTATATE uptake before treatment with long-acting somatostatin analogs differs from that after treatment. Methods: Thirty patients (15 men; age [mean ± SD], 64.6 ± 13.4 y) who had intermediately differentiated to well-differentiated neuroendocrine tumors and who underwent 68Ga-DOTATATE PET/CT scanning before and after receiving long-acting repeatable octreotide (Sandostatin LAR) were included in the study. The SUVmax and SUVmean of healthy target organs, residual primary tumor, and up to 5 lesions with the highest SUVmax in each organ were compared before and after octreotide treatment. Results: The mean time interval between the 2 68Ga-DOTATATE studies was 9.6 ± 7.2 mo, and the mean time gap between the last Sandostatin LAR injection and the second 68Ga-DOTATATE study was 25.1 ± 14.8 d. The pretreatment mean SUVmax and SUVmean were both significantly higher in the thyroid, liver, and spleen (P < 0.05) than the values measured after the administration of Sandostatin LAR. No significant differences were found among the uptake indices for residual primary tumor or any metastatic lesions in the liver, bone, lung, or lymph nodes before and after Sandostatin LAR administration (P > 0.05). Conclusion: Long-acting octreotide treatment diminished 68Ga-DOTATATE uptake in the liver, spleen, and thyroid but did not compromise tracer uptake in residual primary tumor and metastatic lesions. These findings have a direct impact on the interpretation of 68Ga-DOTATATE PET/CT scans.

Phase II study of lanreotide autogel in Japanese patients with unresectable or metastatic well-differentiated neuroendocrine tumors.

Background Lanreotide is a long-acting somatostatin analog with demonstrated efficacy against enteropancreatic neuroendocrine tumor (NET) in the phase III (CLARINET) study. Materials and Methods In this single-arm study, Japanese patients with grade (G) 1/G2 NET received lanreotide (120 mg/4 weeks) for 48 weeks. Those who completed the study were enrolled in a long-term extension study. The primary endpoint was the clinical benefit rate (CBR) defined as a complete response, partial response (PR), or stable disease (SD) over 24-weeks. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), safety, and pharmacokinetics. Results Thirty-two patients were recruited at 10 sites. The full analysis set (FAS) comprised 28 patients. Primary tumors were located in pancreas (12 patients), foregut (non-pancreas, lung; 1), midgut (2), hindgut (8), and unknown (5). Four patients had gastrinoma of the functional NET, and 3 had multiple endocrine neoplasia type 1. In the FAS, 39.3% had progressive disease at baseline. The CBR at 24 weeks was 64.3% (95% confidence interval; CI: 44.1-81.4), and median PFS was 36.3 weeks (95% CI: 24.1-53.1). PR was confirmed in 1 patient at 60 weeks during the extension study (ORR: 3.6%). Frequent adverse events related to lanreotide included injection site induration (28.1%), faeces pale (18.8%), flatulence (12.5%), and diabetes mellitus (12.5%). Conclusions The efficacy and safety of lanreotide in this study indicated its usefulness as a treatment option for Japanese NET patients. TRIAL REGISTRATION: JapicCTI-132,375, JapicCTI-142,698.

Radioguided surgery with radiolabeled somatostatin analogs: not only in GEP-NETs.

Radioguided surgery (RGS) is a surgical technique that, using intra-operative probes, enables the surgeon to identify tissues preoperatively "marked" by a radiopharmaceutical. Somatostatin receptors (SSTRs) are present in the majority of neuroendocrine cells and may be over-expressed not only by tumor cells, but also by endothelial cells of peritumoral vessels, inflammatory cells and cells of the immune system, such as activated lymphocytes, monocytes and epithelioid cells. This extra neoplastic uptake is the rationale for the use of radiolabeled somatostatin analogs (SSAs) either in some tumors not expressing SSTRs or in various non-oncological diseases. The crucial point of RGS technique lays in the establishment of a favorable tumor-to-background ratio (TBR). A wide range of probe systems are available with different detectors and many radiopharmaceuticals have been experimented and utilized, mainly using g-detection probes; in order to widen RGS application field, newer approaches with b- or b+ emitting radioisotopes have also been proposed. Together with the consolidated clinical use, a promising and effective employment of RGS may be found in neuroendocrine tumors (NETs) using 111In-pentetreotide (OCT). RGS with OCT has been demonstrated useful in the management of patients with gastroenteropancreatic (GEP) tumors, lung, brain and breast cancer. Preoperative scintigraphy or PET with DOTA-peptides combined with RGS increases the rate of successful surgery. Preliminary studies with b- probes using 90Y-SSA suggest the possible interest of this approach in patients undergoing peptide receptor radiotherapy.

Stem cell-derived interneuron transplants as a treatment for schizophrenia: preclinical validation in a rodent model.

An increasing literature suggests that schizophrenia is associated with a reduction in hippocampal interneuron function. Thus, we posit that stem cell-derived interneuron transplants may be an effective therapeutic strategy to reduce hippocampal hyperactivity and attenuate behavioral deficits in schizophrenia. Here we used a dual-reporter embryonic stem cell line to generate enriched populations of parvalbumin (PV)- or somatostatin (SST)-positive interneurons, which were transplanted into the ventral hippocampus of the methylazoxymethanol rodent model of schizophrenia. These interneuron transplants integrate within the existing circuitry, reduce hippocampal hyperactivity and normalize aberrant dopamine neuron activity. Further, interneuron transplants alleviate behaviors that model negative and cognitive symptoms, including deficits in social interaction and cognitive inflexibility. Interestingly, PV- and SST-enriched transplants produced differential effects on behavior, with PV-enriched populations effectively normalizing all the behaviors examined. These data suggest that the stem cell-derived interneuron transplants may represent a novel therapeutic strategy for schizophrenia.