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1.
Theranostics ; 14(5): 1829-1840, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38505615

RESUMO

Rationale: Evaluation of alternative radionuclides for use in prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) is currently focusing on 161Tb, which may provide advantages by emitting additional Auger and conversion electrons. In this pilot study, we present preliminary dosimetry data for [161Tb]Tb-PSMA-617 RLT in a direct comparison with [177Lu]Lu-PSMA-617. Method: Six patients with metastatic castration-resistant prostate cancer (mCRPC) underwent treatment with [177Lu]Lu-PSMA-617 and subsequently - after inadequate response - with [161Tb]Tb-PSMA-617. Whole-body planar and SPECT imaging-based dosimetry of organs at risk (kidneys and salivary glands) and tumor lesions were calculated using IDAC for 177Lu and OLINDA/EXM for 161Tb. The therapeutic index (TI) of mean tumor-absorbed doses over relevant organs at risk was calculated. Results: Mean absorbed doses to organs at risk of PSMA-RLT were slightly higher for [161Tb]Tb-PSMA-617 compared to [177Lu]Lu-PSMA-617 (kidneys: 0.643 ± 0.247 vs. 0.545 ± 0.231 Gy/GBq, factor 1.18; parotid gland: 0.367 ± 0.198 vs. 0.329 ± 0.180 Gy/GBq, factor 1.10), but markedly higher regarding tumor lesions (6.10 ± 6.59 vs 2.59 ± 3.30 Gy/GBq, factor 2.40, p < 0.001). Consequently, the mean TI was higher for [161Tb]Tb-PSMA-617 compared to [177Lu]Lu-PSMA-617 for both, the kidneys (11.54 ± 9.74 vs. 5.28 ± 5.13, p = 0.002) and the parotid gland (16.77 ± 13.10 vs. 12.51 ± 18.09, p = 0.008). Conclusion: In this intra-individual head-to-head pilot study, [161Tb]Tb-PSMA-617 delivered higher tumor-absorbed doses and resulted in superior TI compared to [177Lu]Lu-PSMA-617. This preliminary data support 161Tb as a promising radionuclide for PSMA-RLT in mCRPC.


Assuntos
Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Neoplasias de Próstata Resistentes à Castração/radioterapia , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Projetos Piloto , Compostos Radiofarmacêuticos/uso terapêutico , Dipeptídeos/uso terapêutico , Antígeno Prostático Específico , Compostos Heterocíclicos com 1 Anel/uso terapêutico , Radioisótopos/uso terapêutico , Lutécio
2.
Bioorg Chem ; 145: 107193, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38442611

RESUMO

Immunotherapy has brought great benefits to cancer patients, but only some patients benefit from it. Noninvasive, real-time and dynamic monitoring of the effectiveness of immunotherapy through PET imaging may provide assistance for the treatment plan of immunotherapy. In this study, we designed and synthesized a new targeted PD-L1 peptide NOTA-PEG2-Asp2-PDL1P, which was labeled with nuclide 18F to obtain a new imaging agent [18F]AlF-NOTA-PEG2-Asp2-PDL1P. The total radiochemical yield of [18F]AlF-NOTA-PEG2-Asp2-PDL1P was 13.7 % (Uncorrected radiochemical yield, n > 5). [18F]AlF-NOTA-PEG2-Asp2-PDL1P achieved high radiochemical purity (>95 %) with a molar activity more than 51.2 GBq/µmol. [18F]AlF-NOTA-PEG2-Asp2-PDL1P exhibited good hydrophilicity and had good stability both in vivo and in vitro, it can specifically targets B16F10 tumor with PD-L1 expression, and had a relatively high retention in tumor, a relatively fast clearance in vivo and a higher tumor-to-non-target ratio, all of which could make [18F]AlF-NOTA-PEG2-Asp2-PDL1P a potential tracer for PD-L1 prediction before clinical immunotherapy.


Assuntos
Compostos Heterocíclicos com 1 Anel , Compostos Heterocíclicos , Neoplasias , Humanos , Compostos Heterocíclicos/química , Sondas Moleculares , Antígeno B7-H1/metabolismo , Radioisótopos de Flúor/química , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/química , Linhagem Celular Tumoral
5.
Clin Nucl Med ; 49(3): e120-e122, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38306385

RESUMO

ABSTRACT: We present a case of de novo high-volume metastatic prostate cancer with high PSMA expression, partially PSMA-negative, using quadruplet therapy (PROMISE ver. 2 miTNM; miT4N2M1aM1b(dmi) PRIMARY score: 5, PSMA-expression score: 0-3). Because of our patient's partial PSMA negativity and after a multidisciplinary tumor board discussion, we decided to use a modified protocol involving doublet hormonal therapy along with 177Lu-PSMA and radiation therapy to address the PSMA-negative disease. The patient responded well to this treatment, but recurrence was ultimately inevitable. This case represents a typical example of mixed neuroendocrine prostate carcinoma and highlights its resistant phenotype in response to quadruplet therapy.


Assuntos
Lutécio , Neoplasias de Próstata Resistentes à Castração , Radioisótopos , Humanos , Masculino , Dipeptídeos , Compostos Heterocíclicos com 1 Anel , Neoplasias de Próstata Resistentes à Castração/diagnóstico por imagem , Neoplasias de Próstata Resistentes à Castração/radioterapia , Neoplasias de Próstata Resistentes à Castração/patologia , Compostos Radiofarmacêuticos/uso terapêutico , Resultado do Tratamento
6.
Cancer Biother Radiopharm ; 39(1): 92-101, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38335449

RESUMO

Background: Early detection of skeletal metastasis is of great interest to determine the prognosis of cancer. Positron emission tomography-computed tomography (PET-CT) imaging provides a better temporal and spectral resolution than single photon emission computed tomography-computed tomography (SPECT-CT) imaging, and hence is more suitable to detect small metastatic lesions. Although [18F]NaF has been approved by U.S. FDA for a similar purpose, requirement of a medical cyclotron for its regular formulation restricts its extensive utilization. Efforts have been made to find suitable alternative molecules that can be labeled with 68Ga and used in PET-CT imaging. Objective: The main objective of this study is to synthesize and evaluate a new [68Ga]Ga-labeled NOTA-conjugated geminal bisphosphonate for its potential use in early detection of skeletal metastases using PET-CT. Methods: The authors performed a multistep synthesis of a new NOTA-conjugated bisphosphonic acid using thiourea linker and radiolabeled the molecule with 68Ga. The radiolabeled formulation was evaluated for its in vitro stability, affinity for hydroxyapatite (HA) particles, preclinical biodistribution in animal models, and PET-CT imaging in patients. Results: The bifunctional chelator (NOTA)-conjugated bisphosphonate was synthesized with 97.8% purity and radiolabeled with 68Ga in high yield (>98%). The radiolabeled formulation was found to retain its stability in vitro to the extent of >95% up to 4 h in physiological saline and human serum. The formulation also showed high affinity for HA particles in vitro with Kd = 907 ± 14 mL/g. Preclinical biodistribution studies in normal Wistar rats demonstrated rapid and almost exclusive skeletal accumulation of the complex. PET-CT imaging in a patient confirmed its ability to detect small metastatic skeletal lesions. Conclusions: The newly synthesized [68Ga]Ga-labeled NOTA-conjugated bisphosphonate is a promising radiotracer for PET-CT imaging for skeletal metastases.


Assuntos
Radioisótopos de Gálio , Compostos Heterocíclicos com 1 Anel , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Ratos , Animais , Humanos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Difosfonatos , Distribuição Tecidual , Ratos Wistar , Tomografia por Emissão de Pósitrons/métodos , Controle de Qualidade
7.
BMJ Case Rep ; 17(2)2024 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-38395466

RESUMO

We present the case of a patient with heavily pretreated metastatic castration-resistant prostate cancer (mCRPC) who received lutetium Lu-177 vipivotide tetraxetan (also known as 177Lu-PSMA-617) due to progressive disease despite chemotherapy, hormonal therapy and radiation, including palliative mediastinal and central nervous system radiation. He was subsequently hospitalised for worsening acute onset dyspnoea despite clinically responding to therapy. Interval imaging revealed progressive multifocal ground-glass opacities superimposed on a background of underlying peribronchovascular fibrosis. Further workup, including an extensive workup to identify a possible infectious aetiology, ruled out most aetiologies leaving radiation pneumonitis (RP), radiation recall pneumonitis (RRP) and drug-induced pneumonitis as possible diagnoses secondary to 177Lu -PSMA-617. The associated imaging findings of ground-glass opacities and consolidation can be like other aetiologies such as acute infection and subsequently may be treated incorrectly. In the use of theragnostics like 177Lu -PSMA-617, it is fundamental to apply the practices of radioprotection learnt from radiotherapy, as well as to consider prior radiotherapy treatments and their possible side effects when used in conjunction.


Assuntos
Dipeptídeos , Compostos Heterocíclicos com 1 Anel , Pneumonia , Neoplasias de Próstata Resistentes à Castração , Radioisótopos , Masculino , Humanos , Lutécio/efeitos adversos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/radioterapia , Neoplasias de Próstata Resistentes à Castração/patologia , Resultado do Tratamento , Antígeno Prostático Específico , Pneumonia/tratamento farmacológico , Compostos Radiofarmacêuticos/efeitos adversos
8.
PLoS One ; 19(2): e0294940, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38412200

RESUMO

OBJECTIVE: This study aimed to assess the prevalence of Cryptococcal Meningitis (CM), treatment practice, and the associated factors post-introduction of Tenofovir Lamivudine and Dolutegravir (TLD) regimen among People Living with HIV (PLHIV) in Tanzania. METHODS: This was an analytical cross-sectional study, and the data was collected retrospectively in three public regional referral hospitals (RRHs) in Dar es Salaam, Tanzania. A total of 405 files of the PLHIV admitted in the medical wards on the TLD regimen from January 2019 to December 2022 were reviewed. The collected information includes the patient's demographic characteristics, Cryptococcal status, CD4 level at the time of CM diagnosis, status of using ART, CM treatment approach, and outcome. Data was analyzed using SPSS software version 23. RESULTS: Out of 405 patients, the majority 267(65.9%) were female, 224(55.3%) were aged between 36-55 years, and 293(72.3%) were married. ART defaulters were found to be 37(9.1%). The prevalence of CM was found to be 48(11.9%), out of which 42(87.5%) received fluconazole alone. ART defaulter and marital status significantly (p-value < 0.05) were associated with those who tested CM positive. CONCLUSION: The study found the prevalence of CM among PLHIV to be significantly high and the majority were treated with fluconazole alone. ART defaulters and marital status were significantly associated with one being CM positive. Responsible authorities and stakeholders should enforce guideline adherence and PLHIV should be encouraged on medication adherence.


Assuntos
Fármacos Anti-HIV , Infecções por HIV , Meningite Criptocócica , Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Meningite Criptocócica/tratamento farmacológico , Meningite Criptocócica/epidemiologia , Meningite Criptocócica/complicações , Inibidores de Integrase/uso terapêutico , Fluconazol/uso terapêutico , Tanzânia/epidemiologia , Estudos Transversais , Prevalência , Estudos Retrospectivos , Fármacos Anti-HIV/uso terapêutico , Antirretrovirais/uso terapêutico , Lamivudina/uso terapêutico , Tenofovir/uso terapêutico , Compostos Heterocíclicos com 1 Anel
9.
Clin Nucl Med ; 49(4): e149-e155, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38350067

RESUMO

OBJECTIVE: The aim of this study was to assess the biodistribution and dosimetry of 177 Lu-DOTA-trastuzumab in patients with HER2-positive breast carcinoma using whole-body (WB) planar imaging at multiple time points. PATIENTS AND METHODS: This study was a prospective evaluation of HER2-positive metastatic/locally advanced breast carcinoma patients who underwent gamma camera imaging for dosimetry and biodistribution studies by using 177 Lu-DOTA-trastuzumab. The standard diagnostic dosimetry protocol was followed, which included cold trastuzumab injection followed by in-house produced 177 Lu-DOTA-trastuzumab. Serial WB planar images (anterior and posterior) were obtained on gamma camera after the infusion of 177 Lu-DOTA-trastuzumab at multiple time points. Whole-body and organ regions of interest were drawn, and the numbers of disintegrations were obtained. The mean absorbed doses for the liver, spleen, kidneys, heart, red marrow, and tumor were obtained from OLINDA EXM v2.1.1 and ORIGIN software. RESULTS: The study included a cohort of 21 female breast carcinoma patients. Tracer activity ( 177 Lu-DOTA-trastuzumab) was noted in the physiological organs such as the liver, spleen, kidneys, heart, as well as in the tumors. On visual analysis of 177 Lu-DOTA-trastuzumab biodistribution, the liver activity showed gradual clearance over time, and although spleen was comparatively faintly visualized than liver and similarly, kidneys were faintly visualized suggestive of the alternate route of tracer excretion. The maximum number of patients (n = 12) showed 2 components of clearance, namely, fast and slow. The average effective half-life of all the patients (including single and 2 components of clearance) was 106.25 ± 22.14 hours (84.11-128.39 hours). The mean absorbed dose for the liver, spleen, kidneys, heart, whole body, and red marrow was 1.0702 ± 0.731, 1.4114 ± 0.462, 1.4232 ± 0.364, 1.4719 ± 0.602, 0.2412 ± 0.0295, and 0.1485 ± 0.0213 mGy/MBq, respectively, by OLINDA EXM and 0.5741 ± 0.333, 0.8096 ± 0.224, 0.7943 ± 0.235, 1.8971 ± 0.713, and 0.09619 ± 0.0144 for liver, spleen, kidneys, heart and whole body respectively by ORIGIN. The absorbed radiation dose for tumor was 1.94E+2 by OLINDA EXM software and 1.78E+2 by ORIGIN software. In this study, during and after infusion of 177 Lu-DOTA-trastuzumab, no major adverse effects were noted in any patient except 1 patient who had grade 1 nausea and managed conservatively by antiemetic drug. CONCLUSIONS: The results of our study demonstrated expected and favorable biodistribution and dosimetry with 177 Lu-DOTA-trastuzumab in HER2-positive breast carcinoma patients. We noticed the mean absorbed dose to the normal organs within the limits of maximum tolerable dose, and also tumor dose was higher than the normal liver dose. Therefore, we conclude that 177 Lu-DOTA-trastuzumab radioimmunotherapy is feasible and a safe treatment option for treating HER2-positive breast carcinoma patients.


Assuntos
Neoplasias da Mama , Compostos Heterocíclicos com 1 Anel , Lutécio , Radioisótopos , Humanos , Feminino , Distribuição Tecidual , Trastuzumab/uso terapêutico , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/terapia
10.
Cancer Imaging ; 24(1): 27, 2024 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-38389092

RESUMO

BACKGROUND: The state-of-the-art method for imaging men with biochemical recurrence of prostate cancer (BCR) is prostate-specific membrane antigen (PSMA)-targeted positron emission tomography/computed tomography (PET/CT) with tracers containing short-lived radionuclides, e.g., gallium-68 (68Ga; half-life: ∼67.7 min). However, such imaging not infrequently yields indeterminate findings, which remain challenging to characterize. PSMA-targeted tracers labeled with zirconium-89 (89Zr; half-life: ∼78.41 h) permit later scanning, which may help in classifying the level of suspiciousness for prostate cancer of lesions previously indeterminate on conventional PSMA-targeted PET/CT. METHODS: To assess the ability of [89Zr]Zr-PSMA-617 PET/CT to characterize such lesions, we retrospectively analyzed altogether 20 lesions that were indeterminate on prior [68Ga]Ga-PSMA-11 PET/CT, in 15 men with BCR (median prostate-specific antigen: 0.70 ng/mL). The primary endpoint was the lesions' classifications, and secondary endpoints included [89Zr]Zr-PSMA-617 uptake (maximum standardized uptake value [SUVmax]), and lesion-to-background ratio (tumor-to-liver ratio of the SUVmax [TLR]). [89Zr]Zr-PSMA-617 scans were performed 1 h, 24 h, and 48 h post-injection of 123 ± 19 MBq of radiotracer, 35 ± 35 d post-[68Ga]Ga-PSMA-11 PET/CT. RESULTS: Altogether, 6/20 previously-indeterminate lesions (30%) were classified as suspicious (positive) for prostate cancer, 14/20 (70%), as non-suspicious (negative). In these two categories, [89Zr]Zr-PSMA-617 uptake and lesional contrast showed distinctly different patterns. In positive lesions, SUVmax and TLR markedly rose from 1 to 48 h, with SUVmax essentially plateauing at high levels, and TLR further steeply increasing, from 24 to 48 h. In negative lesions, uptake, when present, was very low, and decreasing, while contrast was minimal, from 1 to 48 h. No adverse events or clinically-relevant vital signs changes related to [89Zr]Zr-PSMA-617 PET/CT were noted during or ~ 4 weeks after the procedure. CONCLUSIONS: In men with BCR, [89Zr]Zr-PSMA-617 PET/CT may help characterize as suspicious or non-suspicious for prostate cancer lesions that were previously indeterminate on [68Ga]Ga-PSMA-11 PET/CT. TRIAL REGISTRATION: Not applicable.


Assuntos
Dipeptídeos , Compostos Heterocíclicos com 1 Anel , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Antígeno Prostático Específico , Neoplasias da Próstata , Masculino , Humanos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Radioisótopos de Gálio , Estudos Retrospectivos , Recidiva Local de Neoplasia/diagnóstico por imagem , Oligopeptídeos , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/patologia , Ácido Edético
11.
Phys Med ; 119: 103299, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38367588

RESUMO

Physiologically based pharmacokinetic (PBPK) models offer the ability to simulate and predict the biodistribution of radiopharmaceuticals and have the potential to enable individualised treatment planning in molecular radiotherapy. The objective of this study was to develop and implement a whole-body compartmental PBPK model for peptide receptor radionuclide therapy (PRRT) with [177Lu]Lu-DOTA-TATE in SimBiology to allow for more complex analyses. The correctness of the model implementation was ensured by comparing its outputs, such as the time-integrated activity (TIA), with those of a PBPK model implemented in SAAM II software. METHODS: A combined PBPK model for [68Ga]Ga-DOTA-TATE and [177Lu]Lu-DOTA-TATE was developed and implemented in both SAAM II and SimBiology. A retrospective analysis of 12 patients with metastatic neuroendocrine tumours (NETs) was conducted. First, time-activity curves (TACs) and TIAs from the two software were calculated and compared for identical parameter values. Second, pharmacokinetic parameters were fitted to activity concentrations, analysed and compared. RESULTS: The PBPK model implemented in SimBiology produced TIA results comparable to those generated by the model implemented in SAAM II, with a relative deviation of less than 0.5% when using the same input parameters. The relative deviation of the fitted TIAs was less than 5% when model parameter values were fitted to the measured activity concentrations. CONCLUSION: The proposed PBPK model implemented in SimBiology can be used for dosimetry in radioligand therapy and TIA prediction. Its outputs are similar to those generated by the PBPK model implemented in SAAM II, confirming the correctness of the model implementation in SimBiology.


Assuntos
Compostos Heterocíclicos com 1 Anel , Octreotida , Humanos , Distribuição Tecidual , Estudos Retrospectivos , Octreotida/uso terapêutico , Octreotida/farmacocinética , Compostos Radiofarmacêuticos/uso terapêutico , Compostos Radiofarmacêuticos/farmacocinética
12.
BMC Cancer ; 24(1): 163, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38302933

RESUMO

BACKGROUND: Despite advancements in managing metastatic clear cell renal carcinoma (mccRCC) through antiangiogenic tyrosine kinase inhibitors and immunotherapy, there remains a demand for novel treatments for patients experiencing progression despite the use of these medications. There is currently no established standard treatment for patients receiving third therapy line. Prostate Specific Membrane Antigen (PSMA) whose high expression has been demonstrated in metastatic aggressive prostate adenocarcinoma is also highly expressed in neovessels of various solid tumors including renal cell carcinoma (RCC): 86% of clear cell RCC, 61% of chromophobe RCC, and 28% of papillary RCC. Therefore, PSMA may be a target expressed in metastatic ccRCC for radionuclide therapy using PSMA ligands radiolabeled with Lutetium-177 (PRLT). 177Lu-PSMA delivers ß-particle radiation to PSMA-expressing cells and the surrounding microenvironment with demonstrated efficacy in metastatic prostate cancer. METHODS: This is a multicenter phase I/II study designed to assess the tolerability and effectiveness of 177Lu-PSMA-1 in individuals with PSMA-positive metastatic clear cell renal cell carcinoma (ccRCC), identified through 68Ga-PSMA PET, conducted in France (PRadR). 48 patients will be treated with 4 cycles of 7.4 GBq of 177Lu-PSMA-1 every 6 weeks. The primary objective is to evaluate the safety of 177Lu-PSMA-1 (phase I) and the efficacy of 177Lu-PSMA-1 in mccRCC patients (phase II). Primary endpoints are incidence of Severe Toxicities (ST) occurring during the first cycle (i.e. 6 first weeks) and disease Control Rate after 24 weeks of treatment (DCR24w) as per RECIST V1.1. Secondary objective is to further document the clinical activity of 177Lu-PSMA-1 in mccRCC patients (duration of response (DoR), best overall response rate (BORR), progression fee survival (PFS) and overall survival (OS). DISCUSSION: Our prospective study may lead to new potential indications for the use of 177Lu-PSMA-1 in mccRCC patients and should confirm the efficacy and safety of this radionuclide therapy with limited adverse events. The use of 177Lu-PSMA-1may lead to increase disease control, objective response rate and the quality of life in mccRCC patients. TRIAL REGISTRATION: ClinicalTrials.gov: NCT06059014.


Assuntos
Antígenos de Superfície , Carcinoma de Células Renais , Glutamato Carboxipeptidase II , Neoplasias Renais , Lutécio , Radioisótopos , Compostos Radiofarmacêuticos , Humanos , Masculino , Carcinoma de Células Renais/radioterapia , Carcinoma de Células Renais/tratamento farmacológico , Dipeptídeos/efeitos adversos , Dipeptídeos/uso terapêutico , Compostos Heterocíclicos com 1 Anel/efeitos adversos , Compostos Heterocíclicos com 1 Anel/uso terapêutico , Lutécio/efeitos adversos , Lutécio/uso terapêutico , Estudos Prospectivos , Qualidade de Vida , Radioisótopos/efeitos adversos , Radioisótopos/uso terapêutico , Resultado do Tratamento , Microambiente Tumoral , Feminino , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/radioterapia , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Estudos Multicêntricos como Assunto , Antígenos de Superfície/metabolismo , Glutamato Carboxipeptidase II/antagonistas & inibidores , Compostos Radiofarmacêuticos/efeitos adversos , Compostos Radiofarmacêuticos/uso terapêutico
13.
Mol Pharm ; 21(3): 1515-1525, 2024 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-38291578

RESUMO

Immune checkpoint inhibitors (ICIs) are a powerful treatment modality for various types of cancer. The effectiveness of ICIs is intimately connected to the binding status of antibodies to receptors. However, validated means to accurately evaluate target specificity and predict antibody efficacy in vivo are lacking. A novel peptide-based probe called Al[18F]F-NOTA-PCP1 was developed and validated for its specificity to PD-L1 in A549, U87MG, GL261, and GL261-iPDL1 cell lines, as well as in xenograft models. Then the probe was used in PET/CT scans to determine the binding status of PD-L1 antibodies (atezolizumab, avelumab, and durvalumab) in U87MG xenograft model mice. Moreover, Al[18F]F-NOTA-PCP1 was used to evaluate the impact of different treatment times and doses. Al[18F]F-NOTA-PCP1 PET/CT can be used to evaluate the interaction between PD-L1 and antibodies to determine the effectiveness of immunotherapy. By quantifying target engagement, the probe has the potential to predict the efficacy of immunotherapy and optimize the dose and treatment schedules for PD-L1 immunotherapy. This imaging agent could be a valuable tool in guiding personalized treatment strategies and improving cancer patient outcomes.


Assuntos
Compostos Heterocíclicos com 1 Anel , Neoplasias , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Humanos , Animais , Camundongos , Antígeno B7-H1/metabolismo , Neoplasias/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Peptídeos
15.
Clin Nucl Med ; 49(3): 262-264, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38271240

RESUMO

ABSTRACT: Cerebral and muscular metastases from prostatic adenocarcinoma occur rarely. Patients who develop such metastatic pattern exhibit noticeable symptoms. Herein, we present a 68-year-old man diagnosed with metastatic castrate-resistant prostate cancer. The patient received multiple 177 Lu-PSMA cycles. After the last cycle, a posttreatment SPECT/CT suggested disease progression with uncommon metastatic pattern in the right temporal brain lobe and muscles. 68 Ga-PSMA PET/CT and brain MRI confirmed these findings. Surprisingly, the patient remained asymptomatic up until the conclusion of the follow-up, which lasted for 3 months. This case emphasizes the importance of posttreatment scintigraphic imaging when other biomarkers are inconclusive.


Assuntos
Adenocarcinoma , Neoplasias de Próstata Resistentes à Castração , Neoplasias da Próstata , Radioisótopos , Masculino , Humanos , Idoso , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Próstata/patologia , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/patologia , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único , Antígeno Prostático Específico , Lutécio , Adenocarcinoma/diagnóstico por imagem , Neoplasias de Próstata Resistentes à Castração/diagnóstico por imagem , Neoplasias de Próstata Resistentes à Castração/patologia , Compostos Heterocíclicos com 1 Anel , Dipeptídeos , Resultado do Tratamento
16.
Clin Nucl Med ; 49(3): e105-e110, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38271254

RESUMO

PURPOSE: Prostate-specific membrane antigen (PSMA)-targeted PET/CT is a well-established imaging method in prostate cancer (PC) for both staging and restaging, and also for theranostic applications. An alternative imaging method is crucial for 15% PSMA-negative cases. We aimed to investigate the contribution of 68 Ga-DOTA-FAPI-04 PET/CT to PC imaging. PATIENTS AND METHODS: Thirty-six patients diagnosed with PC were included. Patients underwent both 68 Ga-PSMA PET/CT and 68 Ga-DOTA-FAPI-04 PET/CT imaging within 1 week. In staging group, primary tumor uptake values were compared, and also correlations were done with histopathological findings, MRI findings, and total PSA levels. In biochemical recurrence group, the uptake values in prostatic region and metastases were evaluated to define the local recurrence or metastatic disease. RESULTS: In staging group, PSMA PET showed increased uptake in the primary lesion area in 14/27 (52%) patients, whereas 20/27 (74%) patients were positive in FAPI-04 PET. FAPI-04 positivity was found to be quite high, such as 54%, in PSMA-negative patients. A significant difference was observed between ISUP grade 1-3 patients and ISUP grade 4-5 patients in FAPI-04 PET ( P = 0.03). Local recurrence was detected in 3 patients, pelvic lymph node metastasis in 1 patient, and sacrum metastasis in 1 patient in biochemical recurrence group, and all of the lesions had more intense uptake in PSMA PET than FAPI-04 PET. CONCLUSIONS: FAPI PET imaging seems to have a potential to contribute PSMA PET imaging with FAPI positivity in more than half of PSMA-negative cases. Also, FAPI-targeted radionuclide therapy may be a promising method in patients resistant to PSMA-targeted therapy.


Assuntos
Compostos Heterocíclicos com 1 Anel , Próstata , Neoplasias da Próstata , Quinolinas , Masculino , Humanos , Próstata/patologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Isótopos de Gálio , Radioisótopos de Gálio , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/patologia
17.
Eur Urol ; 85(4): 382-391, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38185538

RESUMO

BACKGROUND AND OBJECTIVE: [177Lu]Lu-PSMA-617 (177Lu-PSMA-617) plus the standard of care (SoC) significantly improved overall survival and radiographic progression-free survival versus SoC alone in patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer in the VISION trial. We evaluated the safety of additional cycles of 177Lu-PSMA-617 and the impact of longer observation time for patients receiving 177Lu-PSMA-617 plus SoC. METHODS: VISION was an international, open-label study. Patients were randomised 2:1 to receive 177Lu-PSMA-617 plus SoC or SoC alone. The incidence of treatment-emergent adverse events (TEAEs) was assessed in prespecified subgroups of patients who received ≤4 cycles versus 5-6 cycles of treatment and during each cycle of treatment. The TEAE incidence was also adjusted for treatment exposure to calculate the incidence per 100 patient-treatment years of observation. This analysis was performed for the first occurrence of TEAEs. KEY FINDINGS AND LIMITATIONS: The any-grade TEAE incidence was similar in cycles 1-4 and cycles 5-6. TEAE frequency was similar across all cycles of 177Lu-PSMA-617 treatment. No additional safety concerns were reported for patients who received >4 cycles. The exposure-adjusted safety analysis revealed that the overall TEAE incidence was similar between arms, but distinct trends for different TEAE types were noted and the incidence of events associated with 177Lu-PSMA-617 remained higher in the 177Lu-PSMA-617 arm. CONCLUSIONS AND CLINICAL IMPLICATIONS: Longer exposure to 177Lu-PSMA-617 plus SoC was not associated with a higher toxicity risk, and the extended time for safety observation could account for the higher TEAE incidence in comparison to SoC alone. The findings support a favourable benefit-risk profile for 6 cycles of 177Lu-PSMA-617 in this setting and the use of up to 6 cycles of 177Lu-PSMA-617 in patients who are clinically benefiting from and tolerating this therapy. PATIENT SUMMARY: For patients with metastatic prostate cancer no longer responding to hormone therapy, an increase in the number of cycles of treatment with a radioactive compound called 177Lu-PSMA-617 from four to six had no additional adverse side effects.


Assuntos
Dipeptídeos , Compostos Heterocíclicos com 1 Anel , Neoplasias de Próstata Resistentes à Castração , Humanos , Masculino , Lutécio/efeitos adversos , Antígeno Prostático Específico/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/radioterapia , Compostos Radiofarmacêuticos/efeitos adversos , Resultado do Tratamento
18.
J Labelled Comp Radiopharm ; 67(3): 111-115, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38296817

RESUMO

While automated modules for F-18 and C-11 radiosyntheses are standardized with features such as multiple reactors, vacuum connection and semi-preparative HPLC, labeling and processing of compounds with radiometals such as Zr-89, Lu-177 and Ac-225 often do not require complex manipulations and are frequently performed manually by a radiochemist. These procedures typically involve transferring solutions to and from vials using pipettes followed by heating of the reaction mixture, and do not require all the features found in most commercial automated synthesis units marketed as F-18 or C-11 modules. Here we present an efficient automated method for performing radiosyntheses involving radiometals by adapting a commercially available robotic pipettor originally developed for high-throughput processing of biological samples. While a robotic pipettor is less costly than a radiosynthesis module, it holds many similar advantages over manual radiosynthesis such as minimization of operator error, lower operator exposure rates, and abbreviated synthesis times, among others. To demonstrate the feasibility of using the OpenTrons OT-2 robotic pipettor to perform automated radiosyntheses, we radiolabeled and formulated 177 Lu-PSMA-617 and 225 Ac-PSMA-617 on the system. The OT-2 was then used to help streamline the quality control process for both products, further minimizing manual handling by and exposure to the radiochemist.


Assuntos
Dipeptídeos , Compostos Heterocíclicos com 1 Anel , Antígeno Prostático Específico , Radioisótopos , Procedimentos Cirúrgicos Robóticos , Actínio , Zircônio
19.
BMC Cancer ; 24(1): 146, 2024 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-38287346

RESUMO

BACKGROUND: Life expectancy of patients with metastatic castration-resistant prostate cancer (mCRPC) is still limited despite several systemic treatments. Within five years after diagnosis of primary prostate cancer, 10-20% of the patients have mCRPC and curation is not an option. Radionuclide therapy (RNT) targeted against prostate-specific membrane antigen (PSMA) emerged as a new treatment option and showed effective results in patients with mCRPC. Survival benefit after [177Lu]Lu-PSMA RNT has already been demonstrated in several clinical trials. However, [225Ac]Ac-PSMA (225Ac-PSMA) appears to be an even more promising radiopharmaceutical for the treatment of mCRPC. The use of alpha emitting radionuclides offers advantages over beta emitting radionuclides due to the high linear energy transfer effective for killing tumor cells and the limited range to reduce the radiation effects on the healthy tissue. However, these results are based on retrospective data and safety data of 225Ac-PSMA are still limited. Therefore, a prospective trial is needed to determine the optimal amount of activity that can be administered. METHODS: The 225Ac-PSMA-Imaging & Therapy (I&T) trial is an investigator-initiated phase I, single-center, open label, repeated dose-escalation and expansion trial. Patient with PSMA-positive mCRPC after at least one line of chemotherapy and/or one line of nonsteroidal antiandrogen will be treated with 225Ac-PSMA-I&T in increasing amount of activity per cycle. Dose-escalation following an accelerated 3 + 3 design which allows to open the next dose-level cohort in the absence of dose limiting toxicity while the previous one is still ongoing. Up to 4 treatment cohorts will be explored including up to 3 dose-escalation cohorts and one expansion cohort where patients will be administered with the recommended dose. A total of up to 30 patients will be enrolled in this trial. All patients will be evaluated for safety. Additionally, dosimetry was performed for the patients in the dose-escalation cohorts after the first 225Ac-PSMA-I&T administration. DISCUSSION: This trial will assess the safety and tolerability of 225Ac-PSMA-I&T in patients with mCRPC to recommend the optimal dose for the phase II trial. TRIAL REGISTRATION: ClinicalTrials.gov, (NCT05902247). Retrospectively registered 13 June 2023.


Assuntos
Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Antígeno Prostático Específico , Estudos Prospectivos , Estudos Retrospectivos , Dipeptídeos/efeitos adversos , Radioisótopos/uso terapêutico , Compostos Radiofarmacêuticos/efeitos adversos , Compostos Heterocíclicos com 1 Anel , Resultado do Tratamento
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