GRECCAR 14 - a multicentric, randomized, phase II-III study evaluating the tailored management of locally advanced rectal carcinoma after a favourable response to induction chemotherapy: Study protocol.

AIM: Total neoadjuvant treatment (TNT) is becoming standard in patients with locally advanced rectal carcinoma (LARC). Preoperative chemoradiotherapy (CRT) has proven side effects on bowel and genitourinary function. An early tumoral response to induction chemotherapy demonstrates its high prognostic value. Tailored management could be used as an alternative to systematic CRT. The GRECCAR 14 trial will attempt to personalize treatment strategy according to the patient's early tumour response to intensive chemotherapy with the aim of achieving the best toxicity-efficiency ratio. METHOD: GRECCAR 14 is a multicentric, randomized, two-arm, phase II-III noninferiority trial. Patients with mid or low LARC with a predictive circumferential resection margin ≤2 mm or T3c-d stage with extramural venous invasion will be included. Evaluation of the tumoral response will be performed after six courses of high-dose FOLFIRINOX chemotherapy. Good responders (GRs) will be defined by a 60% decrease in tumoral volume on magnetic resonance imaging. Patients will be randomized to CRT before surgery. The primary endpoints will be R0 resection for phase II and the 3-year disease-free survival (DFS) for phase III. RESULTS: Tailored management of LARC is becoming an exciting challenge for the modality of neoadjuvant treatment and for the type of surgery or its omission. Neoadjuvant FOLFIRINOX has established efficacy, with a significant increase in the 3-year DFS. Better control of systemic disease must be accompanied by the same locoregional control, with the lowest morbidity. Our previous GRECCAR 4 trial demonstrated the high value of the early tumoral response after induction chemotherapy and the long-term safety of tailored management for GRs. CONCLUSION: If GRECCAR 14 demonstrates the ability to tailor TNT for LARC, this could lead to changes in clinical practice.

Bisphosphonates as Radiopharmaceuticals: Spotlight on the Development and Clinical Use of DOTAZOL in Diagnostics and Palliative Radionuclide Therapy.

Bisphosphonates are therapeutic agents that have been used for almost five decades in the treatment of various bone diseases, such as osteoporosis, Paget disease and prevention of osseous complications in cancer patients. In nuclear medicine, simple bisphosphonates such as 99mTc-radiolabelled oxidronate and medronate remain first-line bone scintigraphic imaging agents for both oncology and non-oncology indications. In line with the growing interest in theranostic molecules, bifunctional bisphosphonates bearing a chelating moiety capable of complexing a variety of radiometals were designed. Among them, DOTA-conjugated zoledronate (DOTAZOL) emerged as an ideal derivative for both PET imaging (when radiolabeled with 68Ga) and management of bone metastases from various types of cancer (when radiolabeled with 177Lu). In this context, this report provides an overview of the main medicinal chemistry aspects concerning bisphosphonates, discussing their roles in molecular oncology imaging and targeted radionuclide therapy with a particular focus on bifunctional bisphosphonates. Particular attention is also paid to the development of DOTAZOL, with emphasis on the radiochemistry and quality control aspects of its preparation, before outlining the preclinical and clinical data obtained so far with this radiopharmaceutical candidate.

A prospective, randomized, phase II study to assess the schemas of retreatment with Lutathera® in patients with new progression of an intestinal, well-differentiated neuroendocrine tumor (ReLUTH).

BACKGROUND: Although neuroendocrine tumors (NET) are classed as rare, they have a high prevalence and their incidence is increasing. Effective treatment with lutetium 17-[177Lu]Lu-oxodotreotide (Lutathera®) is possible in patients with well-differentiated NET, improving progression-free survival (PFS), overall survival (OS), and quality of life (QoL). However, progression does occur. Retreatment with additional Lutathera® cycles is an option to extend PFS and OS. Two retreatment cycles are usually proposed. We aim to compare four versus two Lutathera® retreatment cycles in patients with new progression of a well-differentiated intestinal NET. METHODS: This will be a multicenter, randomized, controlled, open-label, phase II study in France (ReLUTH). The aim is to evaluate the efficacy of retreatment with Lutathera® in patients with progressive intestinal NET (determined by somatostatin-receptor positive imaging) after previous treatment with two cycles of Lutathera®. Before randomization, all patients will have already received two Lutathera® retreatment cycles (7.4 GBq infusion each, 8 weeks apart). A total of 146 patients will be randomized (1:1) to two additional cycles of Lutathera® (7.4 GBq infusion each, separated by 8 weeks) or to no treatment (active surveillance). PRIMARY OBJECTIVE: efficacy of two additional Lutathera® retreatment cycles compared to active surveillance over 6 months. PRIMARY ENDPOINT: disease control rate at 6 months from randomization (defined as Complete Response, Partial Response, and Stable Disease in the Response Evaluation Criteria In Solid Tumours) with an evaluation every 2 months. A secondary objective will be the safety, as well as the PFS, OS, and QoL. It is expected that the efficacy of retreatment will increase after two additional Lutathera® cycles, with no increased safety concerns. DISCUSSION: Our prospective, randomized controlled study may lead to new recommendations for the use of Lutathera® in patients with intestinal progressive NET, and should confirm that four cycles will be more effective than two, with limited adverse impact on safety. Four Lutathera® treatment cycles have the potential to prolong life and improve quality of life in patients. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04954820.

One-tissue compartment model for myocardial perfusion quantification with N-13 ammonia PET provides matching results: A cross-comparison between Carimas, FlowQuant, and PMOD.

PURPOSE: To cross-compare three software packages (SPs)-Carimas, FlowQuant, and PMOD-to quantify myocardial perfusion at global, regional, and segmental levels. MATERIALS AND METHODS: Stress N-13 ammonia PET scans of 48 patients with HCM were analyzed in three centers using Carimas, FlowQuant, and PMOD. Values agreed if they had an ICC > 0.75 and a difference < 20% of the median across all observers. RESULTS: When using 1TCM on the global level, the agreement was good, and the maximum difference between 1TCM MBF values was 17.2% (ICC = 0.83). On the regional level, the agreement was acceptable except in the LCx region (25.5% difference, ICC = 0.74) between FlowQuant and PMOD. Carimas-1TCM agreed well with PMOD-1TCM and FlowQuant-1TCM. Values obtained with FlowQuant-1TCM had a somewhat lesser agreement with PMOD-1TCM, especially at the segmental level. CONCLUSIONS: The global and regional MBF values (with one exception) agree well between the different software packages. There is significant variability in segmental values, mainly located in the LCx region and segments. Out of the studied tools, Carimas can be used interchangeably with both PMOD and FlowQuant for 1TCM implementation on all levels-global, regional, and segmental.

Whole body planar and 3D quantitative imaging after 177Lu-DOTATATE on CZT SPECT/CT device with MEHRS collimator. First report.

Lutetium-177 (177Lu)-based post-therapeutic imaging allows visualization of treated lesions andabsorbed dose measurement. There is an increasing number of cadmium-zinc-telluride (CZT) gamma-cameras in nuclear medicine departments but until now these devices were not adapted to the medium-energy emission of 177Lu photons. We present here in the first reported images acquired with a new collimator designed for CZT gamma-camera compared to a conventional sodium iodide (NaI) (Tl) gamma-camera. Post-therapeutic 177Lu-DOTATATE imaging on a CZT device with a medium energy high resolution (MEHRS)-collimator are promising and support the widespread of both 177Lu-based peptide-receptor radionuclide therapy (PRRT) and CZT gamma-cameras.

Study protocol of the HYPER-LIV01 trial: a multicenter phase II, prospective and randomized study comparing simultaneous portal and hepatic vein embolization to portal vein embolization for hypertrophy of the future liver remnant before major hepatectomy for colo-rectal liver metastases.

BACKGROUND: In patients undergoing major liver resection, portal vein embolization (PVE) has been widely used to induce hypertrophy of the non-embolized liver in order to prevent post-hepatectomy liver failure. PVE is a safe and effective procedure, but does not always lead to sufficient hypertrophy of the future liver remnant (FLR). Hepatic vein(s) embolization has been proposed to improve FLR regeneration when insufficient after PVE. The sequential right hepatic vein embolization (HVE) after right PVE demonstrated an incremental effect on the FLR but it implies two different procedures with no time gain as compared to PVE alone. We have developed the so-called liver venous deprivation (LVD), a combination of PVE and HVE during the same intervention, to optimize the phase of liver preparation before surgery. The main objective of this randomized phase II trial is to compare the percentage of change in FLR volume at 3 weeks after LVD or PVE. METHODS: Patients eligible to this multicenter prospective randomized phase II study are subjects aged from 18 years old suffering from colo-rectal liver metastases considered as resectable and with non-cirrhotic liver parenchyma. The primary objective is the percentage of change in FLR volume at 3 weeks after LVD or PVE using MRI or CT-Scan. Secondary objectives are assessment of tolerance, post-operative morbidity and mortality, post-hepatectomy liver failure, rate of non-respectability due to insufficient FLR or tumor progression, per-operative difficulties, blood loss, R0 resection rate, post-operative liver volume and overall survival. Objectives of translational research studies are evaluation of pre- and post-operative liver function and determination of biomarkers predictive of liver hypertrophy. Sixty-four patients will be included (randomization ratio 1:1) to detect a difference of 12% at 21 days in FLR volumes between PVE and LVD. DISCUSSION: Adding HVE to PVE during the same procedure is an innovative and promising approach that may lead to a rapid and major increase in volume and function of the FLR, thereby increasing the rate of resectable patients and limiting the risk of patient's drop-out. TRIAL REGISTRATION: This study was registered on clinicaltrials.gov on 15th February 2019 (NCT03841305).

Extended liver venous deprivation before major hepatectomy induces marked and very rapid increase in future liver remnant function.

OBJECTIVE: The aim of this study was to assess the safety and efficacy of extended liver venous deprivation (eLVD), i.e. combination of right portal vein embolisation and right (accessory right) and middle hepatic vein embolisation before major hepatectomy for future remnant liver (FRL) functional increase. METHODS: eLVD was performed in non-cirrhotic patients referred for major hepatectomy in a context of small FRL (baseline FRL <25% of the total liver volume or FRL function <2.69%/min/m2). All patients underwent 99mTc-mebrofenin hepatobiliary scintigraphy (HBS) and computed tomographic evaluations. RESULTS: Ten consecutive patients underwent eLVD before surgery for liver metastases (n = 8), Klatskin tumour (n = 1) and gallbladder carcinoma (n = 1). FRL function increased by 64.3% (range = 28.1-107.5%) at day 21. In patients with serial measurements, maximum FRL function was at day 7 (+65.7 ± 16%). The FRL volume increased by +53.4% at 7 days (+25 ± 8 cc/day). Thirty-one days (range = 22-45 days) after eLVD, 9/10 patients were resected. No post-hepatectomy liver failure was reported. Two grade II and one grade III complications (Dindo-Clavien classification) occurred. No patient died with-in 90 days following surgery. CONCLUSIONS: eLVD is safe and provides a marked and very rapid increase in liver function, unprecedented for an interventional radiology procedure. KEY POINTS: • eLVD is safe • eLVD provides a marked and very rapid increase in liver function • After eLVD, the FRL-F increased by 64.3% (28.1-107.5%) at day 21 • After eLVD, the maximum FRL-F was obtained at day 7 (+65.7 ± 16%) • After eLVD, the FRL volume increased by +53.4% at 7 days (+25 ± 8 cc/day).

Evaluation of response after SBRT for liver tumors.

Stereotactic body radiotherapy (SBRT) has developed over the last few years for the treatment of primary and metastatic hepatic tumors. The tumoral and adjacent peritumoral modifications caused by this radiosurgery limit the evaluation of response by anatomic imaging and dimensional criteria alone, such as with RECIST. This suggests that it is of interest to also take into account the residual enhancement and hyper metabolism of these hepatic targets. We have reviewed the English language literature regarding the response of hepatic lesions treated by SBRT, and found that only seven articles were specifically concerned with this problem. The response of the hepatocellular carcinoma after SBRT has been studied specifically with multiphase enhanced CT-scan. Criteria set by the European Association of Study of the Liver better estimate response at each time point of follow up than RECIST does. Non-enhancement, reflecting tumor necrosis, is additionally an early indicator of response with extended response in time and a best non-enhancement percentage is observed at 12 months. The response after treatment by SBRT of cholangiocarcinoma has not yet generated a specific report. Use of RECIST criteria is also inadequate in the evaluation of response after SBRT for hepatic metastases. Response of liver metastases to SBRT is better assessed with a combination of size and enhancement pattern. The occurrence of a lobulated enhancement during follow up is efficient to predict local progression in a specific, reproducible, and sensitive way. Patients with FDG-avid hepatic metastases are also better evaluated with PET-CT and functional criteria than routine imaging and metric evaluation alone.

SBRT planning for liver metastases: A focus on immobilization, motion management and planning imaging techniques.

AIM: To evaluate the different techniques used for liver metastases Stereotactic Body Radiation Therapy (SBRT) planning. We especially focused on immobilization devices, motion management and imaging used for contouring. BACKGROUND: Although some guidelines exist, there is no consensus regarding the minimal requirements for liver SBRT treatments. MATERIALS AND METHODS: We reviewed the main liver metastases SBRT publications and guidelines; and compared the techniques used for immobilization, motion management, margins and imaging. RESULTS: There is a wide variety of techniques used for immobilization, motion management and planning imaging. CONCLUSIONS: We provide a subjective critical analysis of minimal requirements and ideal technique for liver SBRT planning.

"One Method to Label Them All": A Single Fully Automated Protocol for GMP-Compliant 68Ga Radiolabeling of PSMA-11, Transposable to PSMA-I&T and PSMA-617.

BACKGROUND: Prostate-specific membrane antigen (PSMA) is an ideal target for molecular imaging and targeted radionuclide therapy in prostate cancer. Consequently, various PSMA ligands were developed. Some of these molecules are functionalized with a chelator that can host radiometals, such as 68Ga for PET imaging. The 68Ga radiolabeling step benefits from process automation, making it more robust and reducing radiation exposure. OBJECTIVE: To design a single automated radiolabeling protocol for the GMP-compliant preparation of [68Ga]Ga-PSMA-11, transposable to the production of [68Ga]Ga-PSMA-617 and [68Ga]Ga-PSMA-I&T. METHODS: A GAIA® synthesis module and a GALLIAD® generator were used. Radio-TLC and radio-HPLC methods were validated for radiochemical purity (RCP) determination. Three [68Ga]Ga-PSMA-11 validation batches were produced and thoroughly tested for appearance and pH, radionuclide identity and purity, RCP, stability, residual solvent and sterility. Minimal modifications were made to the reagents and disposables for optimal application to other PSMA ligands. RESULTS: [68Ga]Ga-PSMA-11 for clinical application was produced in 27 min. The 3 validation batches met the quality criteria expected by the European Pharmacopoeia to allow routine production. For optimal transposition to PSMA-617, the solid phase extraction cartridge was changed to improve purification of the radiolabeled product. For application to PSMA-I&T, the buffer solution initially used was replaced by HEPES 2.7 M to achieve good radiochemical yields. Residual HEPES content was checked in the final product and was below the Ph. Eur. threshold. CONCLUSION: A single automated radiolabeling method on the GAIA® module was developed and implemented for 68Ga radiolabeling of 3 PSMA ligands, with slight adjustments for each molecule.

LYMPHOSCORE (Lymphoscintigraphy Scoring Reliability) Reliability of a New Qualitative and Semiquantitative Lymphoscintigraphy Scoring System for Primary Lymphedema.

PURPOSE OF THE REPORT: Primary lymphedema (PLE) is a rare chronic disorder. Extremity lymphoscintigraphy offers access for dynamic and functional information on peripheral lymphatics and lymph nodes. We aimed to assess intraobserver and interobserver reliability of a new lymphoscintigraphy quantitative and qualitative scoring system in a homogeneous population of adult patients followed for PLE of the lower limb(s). PATIENTS AND METHODS: This is a monocentric retrospective study. Clinical files of patients who underwent a lymphoscintigraphy were reviewed for inclusion. Lymphoscintigraphies were interpreted twice by 2 observers with a washout period. To assess intraobserver and interobserver reliability for both lower limbs, Cohen κ and Gwet's AC1 reliability coefficients were calculated with 95% confidence interval and P value of the zero-reliability comparison test. To interpret reliability coefficients, we used the orders of magnitude reported by Landis and Koch. RESULTS: One hundred forty-four patients (288 limbs) with PLE were included. For intraobserver reliability, agreement range was 0.87-1 with an almost perfect agreement in all staging items of the score for both limbs with the lower limit of the 95% confidence interval ≥80%. Interobserver reliability was overall strong or almost perfect, ranging from 0.67 to 0.97. CONCLUSIONS: This new scoring system demonstrated excellent intraobserver reliability and a very good interobserver reliability. Lymphoscintigraphy, when performed in a referral center and interpreted by trained nuclear medicine physicians, is a reliable means of investigation in patients with PLE of the lower limbs. This reproducibility advocates for further use of lymphoscintigraphy in multicentric cohorts of PLE patients.

[68Ga]Ga-FAPI-46 synthesis on a GAIA® module system: Thorough study of the automated radiolabeling reaction conditions.

The influence of several parameters involved in the 68Ga radiolabeling of FAPI-46 was studied at the scale of the automated reaction. Among the buffers tested, HEPES 0.3 M pH 4 allowed both high radiochemical purity (RCP) and radiochemical yield (RCY), without prepurification of 68Ga but after final purification of [68Ga]Ga-FAPI-46 on a C18 cartridge. A longer reaction time did not show significant benefit on the RCP, while higher loads of FAPI-46 and gentisic acid as anti-radiolysis compound allowed better RCY.

Prognostic Value of 18F-FDG PET/CT Assessment After Radiotherapy of Squamous Cell Carcinoma of the Anus in Patients from the National Multicentric Cohort FFCD-ANABASE.

This study aimed to evaluate the prognostic value of 18F-FDG PET/CT qualitative assessment in terms of recurrence-free survival (RFS), colostomy-free survival (CFS), and overall survival (OS) after radiation therapy (RT) of squamous cell carcinoma of the anus (SCCA). Secondary objectives were to evaluate the prognostic value of baseline and posttherapeutic quantitative 18F-FDG PET/CT parameters in terms of RFS, CFS, and OS. Methods: We included all consecutive patients from the French multicentric cohort FFCD-ANABASE who had undergone 18F-FDG PET/CT at baseline and 4-6 mo after RT or chemoradiotherapy for a localized SCCA. Qualitative assessments separated patients with complete metabolic response (CMR) and non-CMR. Quantitative parameters were measured on baseline and posttreatment 18F-FDG PET/CT. RFS, CFS, and OS were analyzed using the Kaplan-Meier method. Associations among qualitative assessments, quantitative parameters, and RFS, CFS, and OS were analyzed using univariate and multivariate Cox regression. Results: Among 1,015 patients treated between January 2015 and April 2020, 388 patients (300 women and 88 men) from 36 centers had undergone 18F-FDG PET/CT at diagnosis and after treatment. The median age was 65 y (range, 32-90 y); 147 patients (37.9%) had an early-stage tumor and 241 patients (62.1%) had a locally advanced-stage tumor; 59 patients (15.2%) received RT, and 329 (84.8%) received chemoradiotherapy. The median follow-up was 35.5 mo (95% CI, 32.8-36.6 mo). Patients with CMR had better 3-y RFS, CFS, and OS, at 84.2% (95% CI, 77.8%-88.9%), 84.7% (95% CI, 77.2%-89.3%), and 88.6% (95% CI, 82.5%-92.7%), respectively, than did non-CMR patients, at 42.1% (95% CI, 33.4%-50.6%), 47.9% (95% CI, 38.1%-56.8%), and 63.5 (95% CI, 53.2%-72.1%), respectively (P < 0.0001). Quantitative parameters were available for 154 patients from 3 centers. The following parameters were statistically significantly associated with 3-y RFS: baseline SUVmax (primitive tumor [T]) (hazard ratio [HR], 1.05 [95% CI, 1.01-1.1; P = 0.018]), SUVpeak (T) (HR, 1.09 [95% CI, 1.02-1.15; P = 0.007]), MTV 41% (T) (HR, 1.02 [95% CI, 1-1.03; P = 0.023]), MTV 41% (lymph node [N]) (HR, 1.06 [95% CI, 1.03-1.1; P < 0.001]), MTV 41% (T + N) (HR, 1.02 [95% CI, 1-1.03; P = 0.005]), and posttreatment SUVmax (HR, 1.21 [95% CI, 1.09-1.34; P < 0.001]). Conclusion: Treatment response assessed by 18F-FDG PET/CT after RT for SCCA has a significant prognostic value.18F-FDG PET/CT could be useful for adapting follow-up, especially for patients with locally advanced-stage tumors. Quantitative parameters could permit identification of patients with a worse prognosis but should be evaluated in further trials.

Absorbed Dose-Response Relationship in Patients with Gastroenteropancreatic Neuroendocrine Tumors Treated with [177Lu]Lu-DOTATATE: One Step Closer to Personalized Medicine.

[177Lu]Lu-DOTATATE has been approved for progressive and inoperable gastroenteropancreatic neuroendocrine tumors (GEP-NETs) that overexpress somatostatin receptors. The absorbed doses by limiting organs and tumors can be quantified by serial postinfusion scintigraphy measurements of the γ-emissions from 177Lu. The objective of this work was to explore how postinfusion [177Lu]Lu-DOTATATE dosimetry could influence clinical management by predicting treatment efficacy (tumor shrinkage and survival) and toxicity. Methods: Patients with GEP-NETs treated with [177Lu]Lu-DOTATATE between 2016 and 2022 and who underwent dosimetry were included. Absorbed doses were calculated for healthy organs (liver, kidneys, bone marrow, and spleen) and tumors using PLANET Dose and the local energy deposition method based on serial posttreatment SPECT/CT. Up to 5 lesions per site were selected and measured on images collected at baseline and 3 mo after treatment end (measurement masked to the somatostatin receptor imaging uptake). For toxicity assessment, laboratory parameters were regularly monitored. Clinical data, including time to death or progression, were collected from the patients' health records. Correlations between absorbed doses by organs and toxicity and between absorbed doses by lesions and tumor volume variation were studied using regression models. Results: In total, 35 dosimetric studies were performed in patients with mostly grade 2 (77%) tumors and metastases in liver (89%), lymph nodes (77%), and bone (34%), and 146 lesions were analyzed: 1-9 lesions per patient, mostly liver metastases (65%) and lymph nodes (25%). The median total absorbed dose by tumors was 94.4 Gy. The absorbed doses by tumors significantly decreased between cycles. The absorbed dose by tumors was significantly associated with tumor volume variation (P < 0.001) 3 mo after treatment end, and it was a significant prognostic factor for survival. Toxicity analysis showed a correlation between the decrease of hematologic parameters such as lymphocytes or platelet concentrations and the absorbed doses by the spleen or bone marrow. The mean absorbed dose by the kidneys was not correlated with nephrotoxicity during the studied period. Conclusion: In patients treated with [177Lu]Lu-DOTATATE for GEP-NETs, tumor and healthy organ dosimetry can predict survival and toxicities, thus influencing clinical management.

Innovation in Radionuclide Therapy for the Treatment of Prostate Cancers: Radiochemical Perspective and Recent Therapeutic Practices.

Prostate cancer represents the second cause of death by cancer in males in western countries. While early-stage diseases are accessible to surgery and/or external radiotherapy, advanced metastatic prostate cancers are primarily treated with androgen deprivation therapy, to which new generation androgen receptor antagonists or taxane-based chemotherapies are added in the case of tumor relapse. Nevertheless, patients become invariably resistant to castration with a median survival that rarely exceeds 3 years. This fostered the search for alternative strategies, independent of the androgen receptor signaling pathway. In this line, radionuclide therapies may represent an interesting option as they could target either the microenvironment of sclerotic bone metastases with the use of radiopharmaceuticals containing samarium-153, strontium-89 or radium-223 or tumor cells expressing the prostate-specific membrane antigen (PSMA), a protein found at the surface of prostate cancer cells. This review gives highlights the chemical properties of radioligands targeting prostate cancer cells and recapitulates the clinical trials evaluating the efficacy of radionuclide therapies, alone or in combination with other approved treatments, in patients with castration-resistant prostate tumors. It discusses some of the encouraging results obtained, especially the benefit on overall survival that was reported with [177Lu]-PSMA-617. It also addresses the specific requirements for the use of this particular class of drugs, both in terms of medical staff coordination and adapted infrastructures for efficient radioprotection.

225Ac-Labeled Somatostatin Analogs in the Management of Neuroendocrine Tumors: From Radiochemistry to Clinic.

The widespread use of peptide receptor radionuclide therapy (PRRT) represents a major therapeutic breakthrough in nuclear medicine, particularly since the introduction of 177Lu-radiolabeled somatostatin analogs. These radiopharmaceuticals have especially improved progression-free survival and quality of life in patients with inoperable metastatic gastroenteropancreatic neuroendocrine tumors expressing somatostatin receptors. In the case of aggressive or resistant disease, the use of somatostatin derivatives radiolabeled with an alpha-emitter could provide a promising alternative. Among the currently available alpha-emitting radioelements, actinium-225 has emerged as the most suitable candidate, especially regarding its physical and radiochemical properties. Nevertheless, preclinical and clinical studies on these radiopharmaceuticals are still few and heterogeneous, despite the growing momentum for their future use on a larger scale. In this context, this report provides a comprehensive and extensive overview of the development of 225Ac-labeled somatostatin analogs; particular emphasis is placed on the challenges associated with the production of 225Ac, its physical and radiochemical properties, as well as the place of 225Ac-DOTATOC and 225Ac-DOTATATE in the management of patients with advanced metastatic neuroendocrine tumors.

Fc-engineered monoclonal antibodies to reduce off-target liver uptake.

BACKGROUND: Radiolabeled-antibodies usually display non-specific liver accumulation that may impair image analysis and antibody biodistribution. Here, we investigated whether Fc silencing influenced antibody biodistribution. We compared recombinant 89Zr-labeled antibodies (human IgG1 against different targets) with wild-type Fc and with mutated Fc (LALAPG triple mutation to prevent binding to Fc gamma receptors; FcγR). After antibody injection in mice harboring xenografts of different tumor cell lines or of immortalized human myoblasts, we analyzed antibody biodistribution by PET-CT and conventional biodistribution analysis. RESULTS: Accumulation in liver was strongly reduced and tumor-specific targeting was increased for the antibodies with mutated Fc compared with wild-type Fc. CONCLUSION: Antibodies with reduced binding to FcγR display lower liver accumulation and better tumor-to-liver ratios. These findings need to be taken into account to improve antibody-based theragnostic approaches.

Clinical Pharmacokinetics of Radiopharmaceuticals from SPECT/CT Image Acquisition by Contouring in Patients with Gastroenteropancreatic Neuroendocrine Tumors: Lu-177 DOTATATE (Lutathera®) Case.

BACKGROUND AND OBJECTIVE: Lu-177 DOTATATE (Lutathera®) is a radiolabeled analog of somatostatin administered intravenously in patients with somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors. Biodistribution of Lu-177 DOTATATE in tumor and healthy tissues can be monitored by serial post-injection scintigraphy imaging. Patient exposure to the drug is variable with the recommended fixed dosage, and hence there is a variable response to treatment. The aim of this work was to study the pharmacokinetics of Lu-177 DOTATATE by a population modeling approach, based on single-photon emission computed tomography (SPECT)/computed tomography (CT) images used as surrogate of plasma concentrations to study the interindividual variability and finally optimize an individual dosage. METHODS: From a retrospective study, SPECT/CT images were acquired at 4 h, 24 h, 72 h, and 192 h postadministration. From these images, volumic activities were calculated in blood and bone marrow. An individual non-compartmental pharmacokinetic analysis was performed, and the mean pharmacokinetic parameters of each tissue were compared together and with reference data. Blood volumic activities were then used to perform a population pharmacokinetic analysis (NONMEM). RESULTS: The pharmacokinetic parameters (non-compartmental analysis) obtained from blood (clearance [CL] = 2.65 L/h, volume of distribution at steady state [Vss] = 309 L, elimination half-life [t1/2] = 86.3 h) and bone marrow (CL =1.68 L/h, Vss = 233 L, t1/2 = 98.8 h) were statistically different from each other and from reference values (CL = 4.50 L/h, Vss = 460 L, t1/2 = 71.0 h) published in the literature. SPECT/CT blood images were used as a surrogate of plasma concentrations to develop a population pharmacokinetic model. Weight was identified as covariate on volume of the central compartment, reducing the interindividual variability of all population pharmacokinetic parameters. CONCLUSION: This study is a proof of concept that obtaining pharmacokinetic parameters with image-based blood concentration is possible. Obtaining observed concentrations from SPECT/CT images, without the need for blood sampling, is a real advantage for the patient and the drug monitoring. Pharmacokinetic modeling could be combined with a deep learning model for automatic contouring and allow precise patient-specific dose adjustment in a non-invasive manner.

Identification of 18F-FDG PET/CT Parameters Associated with Weight Loss in Patients with Esophageal Cancer.

18F-FDG PET-CT is routinely performed as part of the initial staging of numerous cancers. Other than having descriptive, predictive and prognostic values for tumors, 18F-FDG PET-CT provides full-body data, which could inform on concurrent pathophysiological processes such as malnutrition. To test this hypothesis, we measured the 18F-FDG uptake in several organs and evaluated their association with weight loss in patients at diagnosis of esophageal cancer. Forty-eight patients were included in this retrospective monocentric study. 18F-FDG uptake quantification was performed in the brain, the liver, the spleen, bone marrow, muscle and the esophageal tumor itself and was compared between patients with different amounts of weight loss. We found that Total Lesion Glycolysis (TLG) and peak Standardized Uptake Values (SUVpeak) measured in the brain correlated with the amount of weight loss: TLG was, on average, higher in patients who had lost more than 5% of their usual weight, whereas brain SUVpeak were, on average, lower in patients who had lost more than 10% of their weight. Higher TLG and lower brain SUVpeak were associated with worse OS in the univariate analysis. This study reports a new and significant association between 18F-FDG uptake in the brain and initial weight loss in patients with esophageal cancer.

Prevention of post-hepatectomy liver failure after major resection of colorectal liver metastases: is hepato-biliary scintigraphy the optimal tool?

Background: Liver failure is the most threatening complication after hepatectomy for colorectal liver metastases. Recent studies indicate that liver functional evaluation by hepatobiliary scintigraphy (HBS) could be more sensitive than volumetry to predict the risk of post-hepatectomy liver failure (PHLF). The aim of this study was to evaluate the performance of 99mTc-mebrofenin HBS, when used as the main preoperative assessment before major hepatectomy in patients with liver metastases from colorectal cancer. Methods: This retrospective study reviewed data from all patients with colorectal liver metastases treated at Montpellier Cancer Institute between 2013 and 2020. Only patients who underwent HBS before surgery were included. The primary aim was to evaluate how the use of this functional imaging modifies the surgical management of patients with colorectal liver metastases. Results: Among the 80 patients included, 26 (32.5%) underwent two-stage hepatectomy and 13 (16.3%) repeated hepatectomies. Severe postoperative complications occurred in 16 patients (20%) and all-grade liver failure occurred in 13 patients (16.3%). Seventeen patients (21.3%) underwent major liver surgery based on sufficient mebrofenin uptake, although the retrospectively evaluated future liver remnant (FLR) volume was insufficient (<30% of total liver). None of these patients had PHLF. Conclusions: This study showed the reliability of HBS for the preoperative functional assessment of patients with colorectal liver metastases. Indeed, it allowed performing major hepatectomy safely in 20% more patients who would not have been considered for surgery on the basis of volumetric assessment.