Successful Treatment with 177Lutetium-Dotatate and Maintenance Octreotide in a Patient with Esthesioneuroblastoma with Central Nervous System Invasion: Case Report and Review of the Literature

This article presents a case of a patient with relapsed esthesioneuroblastoma (ENB), an aggressive rare tumor that arises from the specialized sensory epithelial olfactory cells in the skull base area, which was initially treated with endoscopic surgery, followed by adjuvant radiotherapy. After local relapse, new surgical approaches and subsequent lines of platin-based chemotherapy were performed. A PET-CT with 68GALIUM DOTATATOC (PET-DOTATOC) showed intense uptake of disease, compatible with the presence of somatostatin receptors, in the face, nodes, liver, bones, and meningeal area. Treatment with 4 cycles of 177Lutetium-Dotatate was performed, followed by maintenance octreotide, with a major radiological and clinical response that is lasting more than 1 year after treatment. This article describes a rare case of a skull-base tumor, with multiple recurrences, in which disease control was achieved with a targeted Peptide Receptor Radionuclide Therapy (PRRT) with 177Lutetium-Dotatate, and discusses factors that could influence the incorporation of this form of therapy. Previous case reports proved the potential efficacy of this therapy usually given for low-grade neuroendocrine tumors and will be carefully reviewed.

Synthesis and Crystal Structure of Lutetium Complex withTriethylenetetraaminehexaacetic Acid (H_6ttha):{[Lu_2 (ttha) (H_2O)_6Lu_2 (ttha) (H_2O)_4]·21H_2O}_n

The title complex was synthesized in an aqueous solution and its crystal structure was determined by X-raydiffraction method. It crystalizes in triclinic crystal system, space group P1, formula C36H110N8O55Lu4, Mr=2235.2,a=1.09787(7) nm, b=1.27603(10) nm, c=1.45903(10) nm; α=75.769(6)°, β=85.288(5)°, γ=71.577(6)°, V=1.8797(2) nm3,Z=1, Dc= 1.975 g·cm-3, F(000)=1106, μ=5.312 mm-1; R1=0.0239, wR2=0.0527 for 7156 reflections with I>2σ (I). In the complex, the lutetium ion is coordinated by two nitrogen atoms andsix oxygen atoms and the coordination number is 8. Its coordination polyhedron can be described as a distorted squareantiprism. The complex is of an infinite chain structure. The complex was characterized by elemental analysis, IR spectra and thermal analysis.

Extraction Separation of Scandium，Iron and Lutetium with Isopropyl Phosphonic Acid Mono（1－hexyl－4－ethyl）OctylEster

The extraction and stripping of scandium from its sulfate solutions by isopropyl phosphonic acid mono (1-hexyl-4-ethyl) octyl ester (PT-2, HL) diluted with n-hexane are reported. A high efficiency of separation between scandium, iron and lutetium can be achieved by controlling aqueous acidity. Different mechanisms of Sc3+ with PT-2 in various acid range have been proposed.At lower aqueous acidity, it is a cation exchange reaction, while at higher acidity. a solvation reaction was ascertained. Its IR and NMR spectra have been discussed. The effect of temperature on extraction of Sc3+ was observed and thermodynamic functions were calculated.

Adsorption of Iminodiacetic Acid Resin for Lutetium

The adsorption behavior and mechanism of a novel chelate resin, iminodiacetic acid resin (IDAAR) for Lu(Ⅲ) were investigated. The statically saturated adsorption capacity is 210.8 mg·g^(-1) at 298 K in HAc-NaAc medium. The Lu(Ⅲ) adsorbed on IDAAR can be eluted by 0.5 mol·L^(-1) HCl and the elution percentage reaches 96.5%. The resin can be regenerated and reused without obvious decrease in adsorption capacity. The apparent adsorption rate constant is k_(298)=2.0×10^(-5) s^(-1). The adsorption behavior of IDAAR for Lu(Ⅲ) obeys the Freundlich isotherm. The thermodynamic adsorption parameters, enthalpy change ΔH, free energy change ΔG and entropy change ΔS of IDAAR for Lu(Ⅲ) are 13.1 kJ·mol^(-1), -1.37 kJ·mol^(-1) and 48.4 J·mol^(-1)·K^(-1), respectively. The apparent activation energy is E_a=31.3 kJ·mol^(-1). The molar coordination ratio of the functional group of IDAAR to Lu(Ⅲ) is about 3∶1. The adsorption mechanism of IDAAR for Lu(Ⅲ) was examined by chemical method and IR spectrometry.

Quality Assurance in SPECT/CT for Radionuclide Therapy with Lutetium-177

This study was done to quality assure the Hawkeye SPECT/CT at the St. Olav’s hospital and create a clinical method for doing individual dosimetry with 177Lu-octreotate in targeted radionuclide therapy for neuroendocrine tumors. Various quality control parameters were performed on Infinia Hawkeye SPECT/CT. A calibration dose of 160% ± 2% MBq was ordered and first calibrated for all the dose calibrators. The uniformity test was obtained using a 40 MBq Tc-99m point source positioned 2.5 m away from the two detectors. A 200 MBq Tc-99m was diluted in 70 ml of water, dispersed in six syringes for the registration test. A Lu-177 point source was placed in front of the detectors, one at a time, to check the energy peaks. The Jaczczak phantom with a hollow sphere set (volumes: 0.5, 1, 2, 4, 8, and 16) ml with an additional 60 ml sphere was used for the 3D sensitivity and recovery with Lu-177. Total activity of 945.3 MBq was added to 160 ml of water yielding an activity concentration of 5.908 MBq/ml in the spheres. The phantom was then scanned at various time intervals. A cylindrical phantom with a volume of 6283 ml was also used to obtain the cross-calibration measurement (cps/MBq). Total activity of 995.6 MBq was added and the phantom was scanned at days 0, 6, 13 and 23. The dose calibration factor was changed from 762 to 760 to achieve correct doses. The 2D mean sensitivity factor was 5.56 cps/MBq. Uniformities for both detectors were approved after iteration calibration of the PM tubes. The X-ray to SPECT registration was found to be accurate and within specifications. The energy peak test revealed off-centered 208 keV energy peaks for the two detectors. Quality assurance of imaging devices using radiation is essential for radiation protection and ensures a high-quality image.

Lutetium in prostate cancer: Reconstruction of patient-level data from published trials and generation of a multi-trial Kaplan-Meier curve

BACKGROUND Lutetium has been shown to be an important potential innovation in pre-treated metastatic castration-resistant prostate cancer.Two clinical trials have evaluated lutetium thus far(therap and vision with 99 and 385 patients,respectively),but their results are discordant.AIM To synthetize the available evidence on the effectiveness of lutetium in pre-treated metastatic castration-resistant prostate cancer;and to test the application of a new artificial intelligence technique that synthetizes effectiveness based on reconstructed patient-level data.METHODS We employed a new artificial intelligence method(shiny method)to pool the survival data of these two trials and evaluate to what extent the lutetium cohorts differed from one another.The shiny technique employs an original reconstruction of individual patient data from the Kaplan-Meier curves.The progression-free survival graphs of the two lutetium cohorts were analyzed and compared.RESULTS The hazard ratio estimated was in favor of the vision trial;the difference was statistically significant(P<0.001).These results indicate that further studies on lutetium are needed because the survival data of the two trials published thus far are conflicting.CONCLUSION Our study confirms the feasibility of reconstructing patient-level data from survival graphs in order to generate a survival statistics.

FDA批准抗肿瘤药Lutetium Lu 177 Dotatate上市

美国FDA于2018年1月26日批准Advanced Accelerator Applications USA公司的Lutetium Lu 177Dotatate(商品名:Lutathera)注射液上市,用于治疗生长抑素受体阳性的胃肠胰腺神经内分泌肿瘤。本药可与生长抑素受体结合,且对生长抑素受体2(SSRT2)亲和力最高。

Lutetium Lu 177 vipivotide tetraxetan不良事件信号挖掘与分析

目的 基于美国食品药品监督管理局不良事件报告系统(FAERS),对新型放射性治疗药物lutetium Lu 177 vipivotide tetraxetan的不良事件信号进行挖掘和分析。方法 检索FAERS中2022年第2季度—2022年第4季度以lutetium Lu 177vipivotidetetraxetan为首要怀疑的不良事件报告,分析报告特征、人口学特征及不良事件的诱发时间。采用报告比值(reporting odds ratio,ROR)法、比例报告比值比(proportional reporting ratio,PRR)法、贝叶斯置信传播神经网络(Bayesian confidence propagation neural network,BCPNN)法和多项伽马泊松分布缩减(multi-item gamma Poisson shrinker,MGPS)法挖掘有效信号。结果 共获得以lutetium Lu 177 vipivotide tetraxetan为首要怀疑药物的不良事件报告634例,报告数量整体呈逐月增长趋势,其中568例(89.6%)发生在美国。在所统计的报告中,常见年龄为61~80岁(75.4%),体质量为61~80 kg(50.9%)。不良事件的诱发时间主要集中于0~30 d,占41.5%。基于ROR、PRR、BCPNN、MGPS 4种算法,在首选术语(preferred term,PT)层级共获得6个有效信号,分别为贫血(PT:10002034)、血小板减少症(PT:10043554)、实验室检查异常(PT:10023547)、血小板计数降低(PT:10035528)、全血细胞计数减少(PT:10017413)、口干(PT:10013781)。结论在使用lutetium Lu 177 vipivotide tetraxetan时,应重点加强用药1个月内的临床监护,并关注全血细胞、血小板计数相关实验室检查结果。

Superconductivity above 70 K observed in lutetium polyhydrides

The binary polyhydrides of heavy rare earth lutetium that shares a similar valence electron configuration to lanthanum have been experimentally discovered to be superconductive.The lutetium polyhydrides were successfully synthesized at high pressure and high temperature conditions using a diamond anvil cell in combinations with the in-situ high pressure laser heating technique.The resistance measurements as a function of temperature were performed at the same pressure of synthesis in order to study the transitions of superconductivity(SC).The superconducting transition with a maximum onset temperature(Tc)71 K was observed at pressure of 218 GPa in the experiments.The Tcdecreased to 65 K when pressure was at 181 GPa.From the evolution of SC at applied magnetic fields,the upper critical field at zero temperatureμ0Hc2(0)was obtained to be~36 T.The in-situ high pressure X-ray diffraction experiments imply that the high TcSC should arise from the Lu4H23phase with Pm3n symmetry that forms a new type of hydrogen cage framework different from those reported for previous light rare earth polyhydride superconductors.

Pressure induced color change and evolution of metallic behavior in nitrogen-doped lutetium hydride

By applying pressures up to 42 GPa on the nitrogen-doped lutetium hydride(LuH2_(±x)N_(y)),we have found a gradual change of color from dark-blue to pink-violet in the pressure region of about 12 to 21 GPa.The temperature dependence of resistivity under pressures up to 50.5 GPa shows progressively optimized metallic behavior with pressure.Interestingly,in the pressure region for the color change,a clear decrease of resistivity is observed with the increase of pressure,which is accompanied by a clear increase of the residual resistivity ratio(RRR).Fitting to the low temperature resistivity gives exponents of about 2,suggesting a Fermi-liquid behavior in the low temperature region.The general behavior in a wide temperature region suggests that the electron-phonon scattering is still the dominant one.The magnetoresistance up to 9 T in the state under a pressure of 50.5 GPa shows an almost negligible effect,which suggests that the electric conduction in the pink-violet state is dominated by a single band.It is highly desired to have theoretical efforts in understanding the evolution of color and resistivity in this interesting system.

Development of lutetium oxide continuous fibers with excellent mechanical properties

The difficulty of reducing the diameter of lutetium oxide(Lu_(2)O_(3))continuous fibers below 50μm not only limits the flexibility of the sample but also seriously affects their application and development in high-energy lasers.In this work,a Lu-containing precursor with high ceramic yield was used as raw material,fiberized into precursor fibers by dry spinning.The pressure-assisted water vapor pretreatment(PAWVT)method was creatively proposed,and the effect of pretreatment temperature on the ceramization behavior of the precursor fibers was studied.By regulating the decomposition behavior of organic components in the precursor,the problem of fiber pulverization during heat treatment was effectively solved,and the Lu_(2)O_(3) continuous fibers with a diameter of 40μm were obtained.Compared with the current reported results,the diameter was reduced by about 50%,successfully breaking through the diameter limitation of Lu_(2)O_(3) continuous fibers.In addition,the tensile strength,elastic modulus,flexibility,and temperature resistance of Lu_(2)O_(3) continuous fibers were researched for the first time.The tensile strength and elastic modulus of Lu_(2)O_(3) continuous fibers were 373.23 MPa and 31.55 GPa,respectively.The as-obtained flexible Lu_(2)O_(3) continuous fibers with a limit radius of curvature of 3.5-4.5 mm had a temperature resistance of not lower than 1300℃,which established a solid foundation for the expansion of their application form in the field of high-energy lasers.

国产无载体镥[^(177)Lu]的制备及标记DOTA⁃TOC在神经内分泌肿瘤中的初步临床应用探讨

目的:阐述国产无载体镥[^(177)Lu]制备工艺及^(177)Lu标记1,4,7,10⁃四氮杂环十二烷⁃1,4,7,10⁃四乙酸⁃酪氨酸3⁃奥曲肽(1,4,7,10⁃tetraazacyclododecane⁃1,4,7,10⁃tetraacetic acid conjugated Tyr3⁃octreotide,DOTA⁃TOC)的方法,探讨国产^(177)Lu⁃DO⁃TA⁃TOC初步临床应用的安全性及有效性。方法:采用多级连续分离纯化制备国产无载体镥[^(177)Lu],全自动化模块标记合成^(177)Lu⁃DOTA⁃TOC,回顾分析南京医科大学附属南京医院4例仅接受了国产无载体镥[^(177)Lu]标记DOTA⁃TOC的肽受体放射性核素靶向治疗(peptide receptor radionuclide therapy,PRRT)神经内分泌肿瘤(neuroendocrine neoplasm,NEN)患者资料。结果:国产无载体镥[^(177)Lu]质控良好,铜<0.01,锌<0.01,铁<0.01,铅<0.15,镱未检出,放化纯>99%,细菌内毒素<2 EU/mL。国产^(177)Lu⁃DOTA⁃TOC自动化标记产率为(98.85±0.97)%,产品比活度为(80.96±7.47)GBq/μmol,无菌和内毒素检测均符合规定标准,标记产物中乙醇含量为0,放化纯大于99%。仅接受国产^(177)Lu⁃DOTA⁃TOC治疗的4例患者中,1例仅1次治疗后原发灶及转移灶几乎完全消失,1例治疗后1个月出现3级骨髓毒性,治疗后3个月恢复至正常,所有患者均未出现肾毒性。结论:国产无载体镥[^(177)Lu]标记DOTA⁃TOC质控合格,产率高,安全、耐受性好,对于无法手术切除的NEN患者具有较好疗效。无载体镥[^(177)Lu]的国产化和批量化生产将推动我国核医学诊疗一体化的发展。

Thermodynamics and kinetics of lutetium extraction with HEH(EHP) in hydrochloric acid medium

Solvent extraction has been the most widely used technique for rare earths separation. In this study, thermodynamics and kinetics of lutetium extraction with HEH（EHP） in hydrochloric acid medium were investigated. The extraction mechanism and the relevant parameters were determined by experiment research which can guide the practical extraction process. The data indicated that chloride ion had no effect on lutetium extraction, the rate constant increased when stirring speed was enhanced. Effects of temperature, HEH（EHP） concentration, acidity, and chloride concentration were also studied. Thickness of the diffusion film was also calculated to be 4.66×10^（-3） cm at 150 r/min.

Renewable β-Myrcene Polymerization Initiated by Lutetium Alkyl Complexes Ligated by Imidophosphonamido Ligand

β-Imidophosphonamido ligated lutetium alkyl complex（NPNDipp）Lu（CH2Si Me3）2（THF）（NPNDipp = Ph2P（NC6H3iPr2-2,6）2） with the activation of AliBu3 and [Ph3C][B（C6F5）4] exhibited high catalytic activity, medium syndio-（rr = 66%） but remarkably high 3,4-regioselectivity for the polymerization of β-myrcene（MY）. In sharp contrast, high isotactic 3,4-polymyrcene（PMY）（mm = 95%） was obtained by the precursor（NPN^Et）Lu（CH2Si Me3）2（THF）（NPN^Et = PPh2（NC6H3^iPr2-2,6）（NC6H4-Et-2）） with less bulky substituents on the N-aryl ring.

A preliminary study of polymer inclusion membrane for lutetium(Ⅲ)separation and membrane regeneration

This paper reports on the selective transport of Lu(Ⅲ)from La(III)and Sm(III)through a polymer inclusion membrane(PIM)composed of 40 wt%di(2-ethylhexyl)phosphinic acid(P227)and 60 wt%poly(vinylidene fluoride)(PVDF).Basically,the changes in surface morphology,thickness and water contact angle of this PVDF-based PIM containing P227(P227@PVDF PIM)with different polymer concentrations were investigated.By solvent extraction experiments,it is found that Lu(Ⅲ)can be selectively extracted from La(Ⅲ)and Sm(Ⅲ)at pH 1.5 in hydrochloric acid solution.According to this result,P227@PVDF PIM was used to selectively transport Lu(Ⅲ)from hydrochloric acid feed solution containing similar concentration of La(Ⅲ)and Sm(Ⅲ).The recovery factor of Lu(III)is 91% after 36 h,and about 5%of Sm(Ⅲ)was also transported through the PIM.The concentration of La(III)in the feed solution and the stripping solution does not change.Furthermore,to overcome the ubiquitous decline of transport efficiency caused by the loss of carrier or the damage of membrane structure after long-term use of PIMs,a process for regenerating PIMs was first proposed and implemented.By comparison of the regenerated PIM with the normal PIM,there is almost no difference in the SEM image,ATR-FTIR spectrum and Lu(III)transport efficiency.It is expected that P227@PVDF PIMs have the potential to be applied to the grouped separation of rare earth elements(REEs),and this study also can be as an inspiration for the further study on the PIMs regeneration process.

Synthesis, structural model and vibrational spectroscopy of lutetium tricalcium phosphate Ca9Lu(PO4)7

Lutetium β-tricalcium phosphate Ca9Lu（PO4）7 was synthesized by solid-state reaction at 1200 ℃, and investigated by means of a combination of scanning electron microscopy （SEM） equipped with energy dispersive X-ray spectroscopy （EDS）, X-ray diffraction （XRD）, Fourier transform infrared （FTIR） and Raman spectroscopies. SEM morphological analysis reveals the presence of sub spherical and prismatic micro crystalline aggregates, while EDS semi-quantitative analysis confirms the nominal Lu/Ca compo- sition. The unit cell and the space group were determined by X-ray powder diffraction data showing that the compound crystallizes in the rhombohedral R3c wfiitlockite-type structure, with unit cell constants a - b 1.04164（1） nm, c 3.7302（1） nm and cell volume V 3.5051（1） nm^3. The investigation was completed with the structural refinement by the Rietveld method, and discussion of the distribution of Lu within cationic sites according to the results of the Rietveld refinement. The FIIR and Raman spectra, correlated to isostructural rare earth phosphates from literature, show slight band shifts of the phosphate modes correlated to the evolving size of the rare earth elements.

Nanometric polishing of lutetium oxide by plasma-assisted etching

Plasma-assisted etching,in which the irradiation of hydrogen plasma and inorganic acid etching are integrated,is proposed as a novel polishing method for sesquioxide crystals.By means of this approach,low damage and even damage-free surfaces with a high material removal rate can be achieved in lutetium oxide surface finishing.Analysis of transmission electron microscopy and X-ray photoelectron spectroscopy reveal that plasma hydrogenation converts the sesquioxide into hydroxide,which leads a high efficient way to polish the surfaces.The influences of process conditions on the etching boundary and surface roughness are also qualitatively investigated using scanning electron microscope and white light interferometry.The newly developed process is verified by a systematic experiment.

Structural and Electronic Properties of Lutetium Doped Germanium Clusters LuGen^((+/0/-))(n=6~19):A Density Functional Theory Investigation

Structural growth mechanism,energetics,and electronic properties of cationic,neutral,and anionic lutetium doped germanium cluster LuGen^((+/0/-))(n=6~19)were comprehensively studied by the ABCluster unbiased global search technique with a hybrid density functional theory approach.Compared to the experimental PES,the anion evolution of structure can be clearly defined as four-phase:from the adsorbed to the link structure,then to the half cage motif,and finally to the endohedral structure.The results revealed that the LuGe16-as Frank-Kasper structure with high symmetry of Td can greatly enhance the stabilities.Doped structures have shown thermodynamic stability and appropriate energy gap.These materials are suitable semiconductors.Various approaches,including quasi-spherical geometry with closed-shell model,aromaticity,UV-Vis spectra,density of states(DOS)and partial density of states(PDOS)were applied to further support the results.

Lower temperature synthesis of cerium-doped polycrystalline lutetium pyrosilicate powders by a novel sol-gel processing

A novel sol-gel processing was developed to synthesize polycrystalline cerium-doped lutetium pyrosilicate(Lu2Si2O7:Ce,LPS:Ce)powders under low temperature.It was found that the addition of propylene oxide(PPO)could promote the formation of Lu-O-Si bonds in precursor,which was beneficial to the formation of LPS phase.X-ray diffraction(XRD)patterns indicated that the single-phased LPS powder was well crystallized at 1050°C.Microstructure observation demonstrated that the synthetic LPS powder was composed of ellipsoidal grains with the mean size of 40 nm.The luminescent properties were characterized by photoluminescence(PL),X-ray excited luminescence(XEL)and vacuum ultraviolet(VUV)spectroscopy at room temperature.The synthetic LPS:Ce powder emitted a broad emission spectrum centered at about 380 nm,which should be ascribed to the 5d→4f transition of Ce3+.Decay time of the synthetic LPS:Ce powder was measured to be only 32 ns.

国产^(177)Lu标记DOTATATE最佳条件及其产物的性质

目的观察以国产^(177)Lu标记DOTATATE的最佳条件及其产物的性质。方法采用国产^(177)Lu标记DOTATATE,观察DOTATATE用量、pH、反应温度及反应时间对标记产物^(177)Lu-DOTATATE的影响,以确定最佳标记条件;检测最佳标记条件下产物^(177)Lu-DOTATATE的放射化学纯度(简称放化纯度)、其在小鼠体内外的稳定性、于小鼠体内分布特征及SPECT显像特点。结果国产^(177)Lu标记DOTATATE最佳条件为以1μg/μlDOTATATE 20μl、37 MBq/μl国产^(177)LuCl3原溶液40μl、醋酸(0.5 mol/L)-醋酸钠(0.5 mol/L)缓冲液40μl及生理盐水200μl于80℃恒温条件下反应30 min;上述条件下产物^(177)Lu-DOTATATE的放化纯度>99%、比活度4.9 MBq/μl,在小鼠体内外稳定性良好;对小鼠注射后主要滞留于其肝脏及肾脏,并经肾脏排泄。结论采用国产^(177)Lu标记DOTATATE时,以醋酸(0.5 mol/L)-醋酸钠(0.5 mol/L)缓冲液代替0.25 mol/L醋酸钠缓冲液可提高标记效率,其产物^(177)Lu-DOTATATE的放化纯度、比活度及稳定性均较佳,且对小鼠注射后主要滞留于其肝、肾并经肾脏排泄。