scholarly journals Dosimetric impact of Ac-227 in accelerator-produced Ac-225 for alpha-emitter radiopharmaceutical therapy of patients with hematological malignancies: a pharmacokinetic modeling analysis

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
George Sgouros ◽  
Bin He ◽  
Nitya Ray ◽  
Dale L. Ludwig ◽  
Eric C. Frey
Keyword(s):  
Absorbed Dose ◽  
Pharmacokinetic Modeling ◽  
Hematological Cancer ◽  
Small Component ◽  
Alpha Emitter ◽  
Red Marrow ◽  
Modeling Analysis ◽  
Hematological Cancers ◽  
Dosimetric Analysis ◽  
Radiopharmaceutical Therapy

Abstract Background Actinium-225 is an alpha-particle emitter under investigation for use in radiopharmaceutical therapy. To address limited supply, accelerator-produced 225Ac has been recently made available. Accelerator-produced 225Ac via 232Th irradiation (denoted 225/7Ac) contains a low percentage (0.1–0.3%) of 227Ac (21.77-year half-life) activity at end of bombardment. Using pharmacokinetic modeling, we have examined the dosimetric impact of 227Ac on the use of accelerator-produced 225Ac for radiopharmaceutical therapy. We examine the contribution of 227Ac and its daughters to tissue absorbed doses. The dosimetric analysis was performed for antibody-conjugated 225/7Ac administered intravenously to treat patients with hematological cancers. Published pharmacokinetic models are used to obtain the distribution of 225/7Ac-labeled antibody and also the distribution of either free or antibody-conjugated 227Th. Results Based on our modeling, the tissue specific absorbed dose from 227Ac would be negligible in the context of therapy, less than 0.02 mGy/MBq for the top 6 highest absorbed tissues and less than 0.007 mGy/MBq for all other tissues. Compared to that from 225Ac, the absorbed dose from 227Ac makes up a very small component (less than 0.04%) of the total absorbed dose delivered to the 6 highest dose tissues: red marrow, spleen, endosteal cells, liver, lungs and kidneys when accelerator produced 225/7Ac-conjugated anti-CD33 antibody is used to treat leukemia patients. For all tissues, the dominant contributor to the absorbed dose arising from the 227Ac is 227Th, the first daughter of 227Ac which has the potential to deliver absorbed dose both while it is antibody-bound and while it is free. CONCLUSIONS: These results suggest that the absorbed dose arising from 227Ac to normal organs would be negligible for an 225/7Ac-labeled antibody that targets hematological cancer.

The relationship between methionine synthase rs1805087 polymorphism and hematological cancers risk

2020 ◽  
Vol 16 (28) ◽  
pp. 2219-2233
Author(s):  
Yanliang Bai ◽  
Emmanuel Kwateng Drokow ◽  
Hafiz Abdul Waqas Ahmed ◽  
Juanjuan Song ◽  
Gloria Selorm Akpabla ◽  
...  
Keyword(s):  
Odds Ratio ◽  
Cancer Susceptibility ◽  
Meta Analysis ◽  
Recessive Model ◽  
Methionine Synthase ◽  
Hematological Cancer ◽  
Methionine Synthase Reductase ◽  
Hematological Cancers ◽  
The Relationship ◽  
Allele Model

Background: The relationship between hematological cancer susceptibility and methionine synthase MTR A2756G (rs1805087) polymorphism is inconclusive based on data from past studies. Hence, this updated meta-analysis was conducted to investigate the relationship between methionine synthase reductase (MTR) rs1805087 polymorphism and hematological cancers. Method: We searched EMBASE, Google Scholar, Ovid and PubMed databases for possible relevant articles up to December 31, 2019. Results: The overall pooled outcome of our analysis showed lack of association between the risk of hematological malignancies and MTR A2756G polymorphism under the allele model (G vs A: odds ratio = 1.001, 95% CI: 0.944–1.061; p = 0.983), recessive model (GG vs GA + AA: odds ratio = 1.050, 95% CI: 0.942–1.170; p = 0.382). Conclusion: The findings in this study demonstrate a lack of relationship between hematological cancers and MTR A2756G.

ORGAN ABSORBED DOSE ESTIMATION REFLECTING SPECIFIC ORGAN MASSES WITH SIMPLE SCALING OF REFERENCE DOSES USING THE ORGAN MASSES

2020 ◽  
Vol 189 (4) ◽  
pp. 489-496
Author(s):  
Kentaro Manabe ◽  
Shuji Koyama
Keyword(s):  
Absorbed Dose ◽  
Organ Dose ◽  
Wide Distribution ◽  
Organ Doses ◽  
Organ Mass ◽  
Red Marrow ◽  
Straightforward Method ◽  
Simple Scaling ◽  
Specific Organ ◽  
Reference Doses

Abstract Estimating organ absorbed doses in consideration of person-specific parameters is important for radiation protection in diagnostic nuclear medicine. This study proposes a straightforward method for estimating the organ dose that reflects a specific organ mass by scaling the reference organ dose using the inverse ratio of the specific organ mass to the reference organ mass. For the administration of radiopharmaceuticals labelled by 99mTc or 123I, the organ doses for the liver, spleen, red marrow and thyroid obtained by the method were compared with those generated by a Monte Carlo simulation. The discrepancies were less than 14% for the liver, spleen and thyroid. Conversely, in some cases, the red marrow discrepancies were greater than 30% due to the wide distribution of red marrow in the trunk and head regions. This study confirms that the method of scaling organ doses can be effective for estimating mass-specific doses for solid organs.

scholarly journals 3-D Cell Culture Systems in Bone Marrow Tissue and Organoid Engineering, and BM Phantoms as In Vitro Models of Hematological Cancer Therapeutics—A Review

Materials ◽  
2020 ◽  
Vol 13 (24) ◽  
pp. 5609
Author(s):  
Dasharatham Janagama ◽  
Susanta K. Hui
Keyword(s):  
Tissue Engineering ◽  
Bone Marrow ◽  
Large Scale ◽  
Cancer Therapeutics ◽  
In Vitro Models ◽  
Cancer Tissue ◽  
Hematological Cancer ◽  
Culture Systems ◽  
Hematological Cancers

We review the state-of-the-art in bone and marrow tissue engineering (BMTE) and hematological cancer tissue engineering (HCTE) in light of the recent interest in bone marrow environment and pathophysiology of hematological cancers. This review focuses on engineered BM tissue and organoids as in vitro models of hematological cancer therapeutics, along with identification of BM components and their integration as synthetically engineered BM mimetic scaffolds. In addition, the review details interaction dynamics of various BM and hematologic cancer (HC) cell types in co-culture systems of engineered BM tissues/phantoms as well as their relation to drug resistance and cytotoxicity. Interaction between hematological cancer cells and their niche, and the difference with respect to the healthy niche microenvironment narrated. Future perspectives of BMTE for in vitro disease models, BM regeneration and large scale ex vivo expansion of hematopoietic and mesenchymal stem cells for transplantation and therapy are explained. We conclude by overviewing the clinical application of biomaterials in BM and HC pathophysiology and its challenges and opportunities.

scholarly journals Expert Curation of Somatic Variants in Hematological Malignancies By the Clingen Somatic Hematological Cancer Taskforce (ClinGen HCT)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 23-23
Author(s):  
Rashmi Kanagal-Shamanna ◽  
Shruti Rao ◽  
Panieh Terraf ◽  
Gordana Raca ◽  
Jason Saliba ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Hematological Malignancies ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Hematological Cancer ◽  
Clinical Interpretation ◽  
Hematological Cancers

Hematological malignancies comprise a genetically heterogeneous spectrum of diseases caused by abnormal proliferation or maturation of a variety of hematological cell lineages. Genomic abnormalities including chromosomal translocations, copy number variations and sequence level gene mutations underlie the pathogenesis of these disorders and frequently serve as important diagnostic, prognostic and/or therapeutic markers. However, the substantial discrepancy in interpretation and reporting of these genomic abnormalities among testing labs creates challenges for patient management. Therefore, standardizing the curation, clinical interpretation and reporting of somatic alterations within the context of their diagnostic, prognostic and therapeutic significance in hematological cancers is critical. In January 2020, the ClinGen Somatic Cancer Clinical Domain working group formed the Hematological Cancer Taskforce (HCT) with a goal to undertake systematic curation and evidence-based clinical interpretation of genes/somatic variants associated with hematological malignancies. The HCT has recruited 32 multi-disciplinary experts including oncologists, molecular pathologists, clinical lab directors, genomic scientists and biocurators with expertise in hematological malignancies. In collaboration with the Clinical Interpretation of Variants in Cancer (CIViC) (civicdb.org) knowledgebase, variants from peer-reviewed publications are curated with editor review for clinical utility as evidence items. Monthly discussions based on these evidence items lead to the creation of summary variant assertions using the AMP/ASCO/CAP guidelines (Li M, et al., Journal of Molecular Diagnostics, 2017). The HCT is currently focused on expert curation and clinical interpretation of somatic variants in FLT3 (internal tandem duplication, tyrosine kinase domain and non tyrosine kinase domain variants) in acute myeloid leukemia (AML). Expert curation of gene fusions in Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) in collaboration with the ClinGen somatic pediatric cancer taskforce is currently underway. To date, the HCT has curated 45 evidence items from clinical and pre-clinical studies on the aforementioned genes/variants. In addition, three AMP Tier I, level A variant assertions of FLT3-ITD, D835 and I836, which predict response to Gilteritinib, an FDA-approved drug for relapsed or refractory AML, have been curated. In the future, the HCT plans to extend its focus on curation of BCR-ABL1 kinase domain mutations in chronic myeloid leukemia (CML). Based on the initial pilot curation phase, the HCT will develop gene-specific recommendations to standardize the reporting and interpretation of somatic variants to better assist clinical decisions and apply to become official ClinGen Somatic Expert Panels in each of these gene-disease domains. Disclosures Blombery: Novartis: Consultancy; Invivoscribe: Honoraria; Amgen: Consultancy; Janssen: Honoraria.

scholarly journals Pivotal Role of Dosimetry in High Activity 131i Mibg Therapy in Patients Affected by High Risk Relapsed Refractory Neuroblastoma: Towards a Deeper Metastatic Response Understanding

2021 ◽  
Author(s):  
Bartolomeo Cassano ◽  
Milena Pizzoferro ◽  
Silvio Valeri ◽  
Claudia Polito ◽  
Salvatore Donatiello ◽  
...  
Keyword(s):  
High Risk ◽  
Clinical Outcome ◽  
High Activity ◽  
Absorbed Dose ◽  
Complete Response ◽  
Whole Body ◽  
High Dose ◽  
Red Marrow ◽  
Activity Therapy ◽  
Mibg Therapy

Abstract Background: Dosimetry in molecular radiotherapy for personalized treatment is assuming a central role in clinical management of aggressive/relapsed tumors. High-Risk relapsed/refractory metastatic Neuroblastoma (HRrrm-NBL) has a poor prognosis and high-activity 131I-mIBG therapy could represent a promising strategy.The aim of this study was to report the absorbed dose to whole-body (DWB), red marrow (DRM) and lesions (DLesion) correlated to clinical outcome.Methods: 14 patients affected by HRrrm-NBL were treated with high-activity 131I-mIBG therapy (two administrations separated by 15 days). The first administration was weight-based whereas the second one was dosimetry-based (achieving 4 Gy to whole-body). In all patients DWB and DRM has been assessed; 9/14 patients were selected for DLesion evaluation (for a total of 13 lesions). Treatment response was classified in Progression and Stable Disease (PD and SD), Partial and Complete Response (PR and CR) and correlated to the value of DLesion value.Results: The cumulative DWB, DRM and DLesion ranged from [1.49; 4.45], [0.99; 2.56] and [44.17; 585.75] Gy. After treatment 3, 2, 4 and 5 patients showed CR, PR, SD and PD respectively showing a correlation between the clinical outcome and DLesion with a threshold at 80 Gy.Conclusions: Our experience shows feasibility of high activity therapy of 131I MIBG in rrmHR-NBL children as two administration intensive strategy. Dosimetric approach allowed a tailored high dose treatment maximizing the benefits of radionuclide therapy for pediatric patients with a safety profile. The assesment of DLesion contributed to have a deeper understaning of metabolic treatment effects.

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