New Drugs for Targeted Radionuclide Therapy in Metastatic Prostate Cancer.

Metastatic prostate cancer is a frequent and fatal disease. Targeted radionuclide therapy (TRT) has become a readily available therapeutic option since the approval of [177Lu]Lu-PSMA-617. Various molecules are currently being studied for TRT in prostate cancer. We review various combinations of isotopes and vectors being used to target prostate cancer cells and optimize pharmacokinetics. Promising innovations include chemical modifications to improve biodistribution, identification of new targets, and the use of novel radioisotopes such as α emitters. PATIENT SUMMARY: Our mini review summarizes research on targeted radioactive drugs for treatment of metastatic prostate cancer. Several promising radioactive pharmaceuticals are being evaluated in clinical trials, but more studies are necessary before these can be used in routine clinical practice.

Clinical Pharmacy Initiatives Contribute to the Excellent Efficacy of the Dabrafenib/Trametinib Combination for Iodine-Refractory Thyroid Carcinoma: A Case Report.

A 76-year-old female patient presented with an iodine-refractory papillary thyroid carcinoma (PTC), diagnosed eight years earlier, with several lymph node recurrences requiring successive surgeries. Fluorodeoxyglucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) imaging revealed a new unresectable loco-regional recurrence. The patient was diagnosed with a somatic BRAF V600E mutation. Therefore, dabrafenib and trametinib combination therapy was introduced and closely monitored by a dedicated multidisciplinary team, involving pharmaceutical consultations. As early as six weeks after treatment initiation, the patient reported multiple adverse events (AEs) to the clinical pharmacy team, who provided advice on resolving AEs or improving tolerance. Close interprofessional collaboration among healthcare workers involved in the care pathway allowed for the identification of the most opportune times for temporary suspension of treatment (four suspensions over seven months) or dose reduction (two reductions over 3.5 months). This resulted in a total treatment duration (one year) longer than the average times reported in the literature. The patient showed a rapid and excellent response to treatment immediately after initiation, culminating in a complete metabolic response assessed by [18F]FDG PET/CT imaging at nine months. Twenty-five months after treatment discontinuation, the disease remained controlled. Overall, dabrafenib and trametinib combination could offer excellent outcomes in selected patients with refractory BRAF-mutated PTC, with additional clinical pharmacy initiatives allowing for the optimized management of AEs and prolonged treatment periods.

Evaluation of parenteral diluent contamination by caprolactam.

DISCLAIMER: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. PURPOSE: A leachable cyclic amide (caprolactam) can be found in normal saline (NS) and 5% dextrose in water (D5W) plastic bags widely used in clinical practice if they contain polyamide in a multilayer sheeting. This contamination and the parameters that could influence its content have never been studied in a public work such as a scientific publication. METHODS: Two independent laboratories validated a caprolactam dosing method and studied contamination levels in several containers. RESULTS: Caprolactam content in multilayer polypropylene/polyamide/polypropylene plastic bags ranged from a mean (SD) of 5.43 (0.21) mg/L (D5W 1,000 mL) to 22.83 (1.26) mg/L (NS 50 mL). NS and D5W can be intravenously administered with a total daily dose of 3 L, corresponding to a minimal daily dose of 16.3 mg of caprolactam. CONCLUSION: The high levels of contamination we have reported and the possibility of administering caprolactam to high-risk patients (eg, neonates, the elderly) should make it imperative for pharmaceutical companies to communicate publicly on the safety of caprolactam.

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.

[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.

"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.

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.

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.

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.

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.

Development and Implementation of a Professional Practices Evaluation during Radiopharmaceuticals Administration.

Securing both the patient and radiopharmaceuticals (RPs) circuit is an essential concern in nuclear medicine (NM). These circuits converge at the RP administration phase, a key step in patient management in NM. In a continuous quality improvement approach, we developed and implemented an evaluation of professional practices (EPPs) methodology focused on RPs injection to identify and correct deviations from good practices. The nuclear medicine technologists (NMTs) of a single center were evaluated. A specific audit grid was designed for this purpose, covering 4 main themes. Following the audit campaign, an improvement action plan was set up to address the non-conformities observed. Nine NMTs were audited on 4 RPs injections each. The mean total score was 93.36% with, on average, 7.01% and 3.00% of unmet and partially met criteria, respectively. In view of the non-compliance rates of hygiene and radiation protection items, theoretical reviews of these themes were included in the improvement action plan. As a part of the quality assurance system of a healthcare unit, EPPs are useful for identifying and correcting practice deviations at an early stage. They should be regularly repeated and combined with rigorous training and qualification of operators involved in RPs injection.

177Lu-Dotatate administration using an infusion pump or a peristaltic pump: comparison of two methods.

OBJECTIVES: 177Lu-oxodotreotide (Lutathera) is an intravenous peptide receptor radionuclide therapy to treat unresectable metastatic digestive neuroendocrine tumours. The recommended method for Lutathera administration is gravity infusion; however, other appropriate and safe techniques are possible. This work compares two infusion methods from a medico-economic, radiation protection, efficiency and practicality point of view. METHODS: Two infusion methods were studied, either involving a volumetric infusion pump (method 1) or a peristaltic pump (method 2). For each method, the mean residual activity per vial and the mean injection time were compared. Occupational radiation exposure was measured. The cost of initial equipment and consumables for one administration was determined. Feedback from operators and past incidents during injections were collected through a survey. RESULTS: Three operators performed 219 Lutathera injections over 70 months: 60.7% (133) with method 1 and 39.3% (86) with method 2. After infusion, the mean residual activity in vial was 124.3±16.9 MBq with method 1 and 80.9±19.3 MBq with method 2 (34.9% decrease). The average administration time was 41±7.2 min with method 1 and 39±8.5 min with method 2. Occupational exposures obtained with both methods were very low and quite similar. Method 1 required an initial investment of 1165.8 US$ plus 4.0 US$ of supplies for each administration. Initial investment for method 2 was comparable (1261.4 US$) but supplies cost per administration was higher (12.5 US$). Two major incidents were recorded with method 1 and none with method 2. From operators' experience, method 2 felt safer and more suitable. CONCLUSIONS: Method 2 appeared to be convenient and secure, despite a higher cost per injection. It could also be applied to new radioligand therapies such as 177Lu-PSMA or 225Ac-Dotatate.

Unusual Focal Lung Uptake without CT Abnormality on a Bone Scan: What Might It Mean?

A 48-year-old woman was referred for a bone scan as an assessment of bone metastasis from breast cancer. Surprisingly, two hot spots of lung uptake were present in the left lung without any abnormality on CT slices. No history of pulmonary disease was observed. An optimized CT scan with fine slices performed the same day was strictly normal (without any micronodule). A lung ventilation/perfusion scintigraphy showed no significant perfusion defect. A follow-up bone scan performed eight months later was normal and without any lung uptake. After exclusion of the main etiologies described in the literature, such as amylosis, sarcoidosis, abscess, or hypercalcemia, radiotracer microembolism seems to be the most likely hypothesis in this patient.

Tailored Media-Fill Test Protocols Inspired by 68Ga Kit-Based Radiopharmaceuticals.

Gallium-68 radiolabeling is an increasingly common activity in radiopharmacy. Single vial cold kits to radiolabel DOTATOC and PSMA-11 with 68Ga were developed, either for manual or automated preparation. Both approaches are very specific and require aseptic compounding skills, raising the need for dedicated training. The aim of this work was to design and implement an integrative media-fill test (MFT) protocol inspired by 68Ga kit-based radiopharmaceuticals for operator qualification, suitable for both manual and automated preparation simulations. Three custom MFT protocols (two manual and one automated simulations) compatible with specific radiopharmacy equipment were designed for operator training. During MFT sessions, the microbiological quality of the working environment was monitored by surface and air sampling. The sensitivity of the tryptic soy broth (TSB) and the influence of the number of punctures performed in each vial on the units positivity were also studied. Four operators were evaluated and carried out in triplicate the three MFTs. None of the 336 incubated units showed turbidity, although 27.8% of surface samples and 11.1% of air samples were positive (1-4 CFU). Over 36 MFT sessions, 15 contaminations of the working area by TSB drops occurred. TSB sensitivity was estimated >3.12 UFC. Units positivity showed a probable relationship with the number of punctures in a vial and, more obviously, with the contamination level of the vial stopper. As a part of a general sterile compounding instruction, these MFT protocols may be useful tools for initial and continuing training of operators carrying out manual and automated 68Ga radiolabeling.

AAZTA-Derived Chelators for the Design of Innovative Radiopharmaceuticals with Theranostic Applications.

With the development of 68Ga and 177Lu radiochemistry, theranostic approaches in modern nuclear medicine enabling patient-centered personalized medicine applications have been growing in the last decade. In conjunction with the search for new relevant molecular targets, the design of innovative chelating agents to easily form stable complexes with various radiometals for theranostic applications has gained evident momentum. Initially conceived for magnetic resonance imaging applications, the chelating agent AAZTA features a mesocyclic seven-membered diazepane ring, conferring some of the properties of both acyclic and macrocyclic chelating agents. Described in the early 2000s, AAZTA and its derivatives exhibited interesting properties once complexed with metals and radiometals, combining a fast kinetic of formation with a slow kinetic of dissociation. Importantly, the extremely short coordination reaction times allowed by AAZTA derivatives were particularly suitable for short half-life radioelements (i.e., 68Ga). In view of these particular characteristics, the scope of this review is to provide a survey on the design, synthesis, and applications in the nuclear medicine/radiopharmacy field of AAZTA-derived chelators.

Update on glasdegib in acute myeloid leukemia - broadening horizons of Hedgehog pathway inhibitors.

Numerous new emerging therapies, including oral targeted chemotherapies, have recently entered the therapeutic arsenal against acute myeloid leukemia (AML). The significant shift toward the use of these novel therapeutics, administered either alone or in combination with intensive or low-intensity chemotherapy, changes the prospects for the control of this disease, especially for elderly patients. Glasdegib, an oral Hedgehog pathway inhibitor, showed satisfactory response rates associated with moderate toxicity and less early mortality than standard induction regimens in this population. It was approved in November 2018 by the FDA and in June 2020 by the EMA for use in combination with low-dose cytarabine as a treatment of newly-diagnosed AML in patients aged ≥ 75 and/or unfit for intensive induction chemotherapy. The current paper proposes an extensive, up-to-date review of the preclinical and clinical development of glasdegib. Elements of its routine clinical use and the landscape of ongoing clinical trials are also stated.

Lumbosacral Plexus Neurolymphomatosis: A Typical 18FDG PET/CT Pattern to Recognize.

ABSTRACT: A 79-year-old man anteriorly treated for primary central nervous system diffuse large B-cell lymphoma with MRI complete response after immunochemotherapy was referred 1 year later for 18FDG PET/CT because of right persistent lombosciatic radicular pain for 6 months with negative medullary and spine MRI and negative cerebrospinal fluid cytology. Linearly intense uptake was observed in several roots of lumbosacral plexus, highly suggestive of peripheral neurolymphomatosis relapse. No specific treatment was engaged because of rapid decrease of performance status leading to death.

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.

Implementation and validation of an in-house combined fluorescein/media-fill test to qualify radiopharmacy operators.

BACKGROUND: The purpose of this work was to design, validate and implement a media-fill test combined with fluorescein (MFT-F) for the specific qualification and training of radiopharmacy operators, in accordance with United States Pharmacopeia General Chapter 797 and European Good Manufacturing Practices. MFT-F was embedded in the quality management system of our radiopharmacy unit. Its validation involved fluorescein concentration choice, media growth promotion test and evaluation protocol controls (with or without intentional aseptic mistakes). Each operator was evaluated following a three-part evaluation form. Evaluation criteria related to garbing and hygiene, fluorescent contamination and bacteriological contamination (pre- and post-evaluation environment controls and MFT-F samples). Combined MFT-F allowed the assessment of aseptic compounding skills and non-contamination of the working area through a single evaluation. It was also designed to fit the constraints of radiopharmacy common practice related to radiation protection equipment and to the small volumes handled. RESULTS: A 0.01% fluorescein concentration was chosen to prepare MFT-F. Addition of fluorescein in the culture medium did not jeopardize its growth properties according to growth promotion test. Eleven operators were evaluated and carried out 3 MFT-F over 3 successive days. Pre- and post-evaluation bacteriological controls of every session showed no CFU of microbiological contaminant above 5. All operators validated the garbing and hygiene evaluation, with an average score of 92.7%. All operators validated the fluorescent contamination evaluation, with an average score of 29.4 out of 30. None of the MFT-F samples showed any visible bacterial growth after incubation. CONCLUSIONS: Combined MFT-F, as a part of a comprehensive sterile compounding training program, appeared as a convenient and promising tool to increase both the sterile compounding safety and awareness of radioactive contamination in radiopharmacy.

Thienopyrimidine: A Promising Scaffold to Access Anti-Infective Agents.

Thienopyrimidines are widely represented in the literature, mainly due to their structural relationship with purine base such as adenine and guanine. This current review presents three isomers-thieno[2,3-d]pyrimidines, thieno[3,2-d]pyrimidines and thieno[3,4-d]pyrimidines-and their anti-infective properties. Broad-spectrum thienopyrimidines with biological properties such as antibacterial, antifungal, antiparasitic and antiviral inspired us to analyze and compile their structure-activity relationship (SAR) and classify their synthetic pathways. This review explains the main access route to synthesize thienopyrimidines from thiophene derivatives or from pyrimidine analogs. In addition, SAR study and promising anti-infective activity of these scaffolds are summarized in figures and explanatory diagrams. Ligand-receptor interactions were modeled when the biological target was identified and the crystal structure was solved.