dAcquisition setting optimization and quantitative imaging for 124I studies with the Inveon microPET-CT system

International audienceABSTRACT: BACKGROUND: Noninvasive multimodality imaging is essential for preclinical evaluation of the biodistribution and pharmacokinetics of radionuclide therapy and for monitoring tumor response. Imaging with nonstandard positron-emission tomography [PET] isotopes such as 124I is promising in that context but requires accurate activity quantification. The decay scheme of 124I implies an optimization of both acquisition settings and correction processing. The PET scanner investigated in this study was the Inveon PET/CT system dedicated to small animal imaging. METHODS: The noise equivalent count rate [NECR], the scatter fraction [SF], and the gamma-prompt fraction [GF] were used to determine the best acquisition parameters for mouse- and rat-sized phantoms filled with 124I. An image-quality phantom as specified by the National Electrical Manufacturers Association NU 4-2008 protocol was acquired and reconstructed with two-dimensional filtered back projection, 2D ordered-subset expectation maximization [2DOSEM], and 3DOSEM with maximum a posteriori [3DOSEM/MAP] algorithms, with and without attenuation correction, scatter correction, and gamma-prompt correction (weighted uniform distribution subtraction). RESULTS: Optimal energy windows were established for the rat phantom (390 to 550 keV) and the mouse phantom (400 to 590 keV) by combining the NECR, SF, and GF results. The coincidence time window had no significant impact regarding the NECR curve variation. Activity concentration of 124I measured in the uniform region of an image-quality phantom was underestimated by 9.9% for the 3DOSEM/MAP algorithm with attenuation and scatter corrections, and by 23% with the gamma-prompt correction. Attenuation, scatter, and gamma-prompt corrections decreased the residual signal in the cold insert. CONCLUSIONS: The optimal energy windows were chosen with the NECR, SF, and GF evaluation. Nevertheless, an image quality and an activity quantification assessment were required to establish the most suitable reconstruction algorithm and corrections for 124I small animal imaging

Comparison of Gene Expression in Human Embryonic Stem Cells, hESC-Derived Mesenchymal Stem Cells and Human Mesenchymal Stem Cells

We present a strategy to identify developmental/differentiation and plasma membrane marker genes of the most primitive human Mesenchymal Stem Cells (hMSCs). Using sensitive and quantitative TaqMan Low Density Arrays (TLDA) methodology, we compared the expression of 381 genes in human Embryonic Stem Cells (hESCs), hESC-derived MSCs (hES-MSCs), and hMSCs. Analysis of differentiation genes indicated that hES-MSCs express the sarcomeric muscle lineage in addition to the classical mesenchymal lineages, suggesting they are more primitive than hMSCs. Transcript analysis of membrane antigens suggests that IL1R1low, BMPR1Blow, FLT4low, LRRC32low, and CD34 may be good candidates for the detection and isolation of the most primitive hMSCs. The expression in hMSCs of cytokine genes, such as IL6, IL8, or FLT3LG, without expression of the corresponding receptor, suggests a role for these cytokines in the paracrine control of stem cell niches. Our database may be shared with other laboratories in order to explore the considerable clinical potential of hES-MSCs, which appear to represent an intermediate developmental stage between hESCs and hMSCs

Low-dose hyper-radiosensitivity of progressive and regressive cells isolated from a rat colon tumour: impact of DNA repair.

International audiencePURPOSE: To ask whether highly metastatic sublines show more marked low-dose hyper-radiosensitivity (HRS) response than poorly metastatic ones. MATERIALS AND METHODS: The progressive (PRO) subline showing tumourigenicity and metastatic potential and the regressive (REG) subline showing neither tumourigenicity nor metastatic potential were both isolated from a parental rat colon tumour. Clonogenic survival, micronuclei and apoptosis, cell cycle distribution, DNA single- (SSB) and double-strand breaks (DSB) induction and repair were examined. RESULTS: HRS phenomenon was demonstrated in PRO subline. Before irradiation, PRO cells show more spontaneous damage than REG cells. After 0.1 Gy, PRO cells displayed: (i) More DNA SSB 15 min post-irradiation, (ii) more unrepaired DNA DSB processed by the non-homologous end-joining (NHEJ) and by the RAD51-dependent recombination pathways, (iii) more micronuclei, than REG cells while neither apoptosis nor p53 phosphorylation nor cell cycle arrest was observed in both sublines. CONCLUSIONS: HRS response of PRO subline may be induced by impairments in NHEJ repair that targets G(1) cells and RAD51-dependent repair that targets S-G(2)/M cells. The cellular consequences of such impairments are a failure to arrest in cell cycle, the propagation of damage through cell cycle, mitotic death but not p53-dependent apoptosis. Tumourigenic cells with high metastatic potential may preferentially show HRS response

Improvement of Radioimmunotherapy Using Pretargeting

During the past two decades, considerable research has been devoted to radionuclide therapy using radiolabeled monoclonal antibodies and receptor binding agents. Conventional radioimmunotherapy (RIT) is now an established and important tool in the treatment of hematologic malignancies such as Non-Hodgkin lymphoma. For solid malignancies, the efficacy of RIT has not been as successful due to lower radiosensitivity, difficult penetration of the antibody into the tumor, and potential excessive radiation to normal tissues. Innovative approaches have been developed in order to enhance tumor absorbed dose while limiting toxicity to overcome the different limitations due to the tumor and host characteristics. Pretargeting techniques (pRIT) are a promising approach that consists of decoupling the delivery of a tumor monoclonal antibody (mAb) from the delivery of the radionuclide. This results in a much higher tumor-to-normal tissue ratio and is favorable for therapy as well and imaging. This includes various strategies based on avidin/streptavidin-biotin, DNA-complementary DNA, and bispecific antibody-hapten bindings. pRIT continuously evolves with the investigation of new molecular constructs and the development of radiochemistry. Pharmacokinetics improve dosimetry depending on the radionuclides used (alpha, beta, and Auger emitters) with prediction of tumor response and host toxicities. New constructs such as the Dock and Lock technology allow production of a variety of mABs directed against tumor-associated antigens. Survival benefit has already been shown in medullary thyroid carcinoma. Improvement in delivery of radioactivity to tumors with these pretargeting procedures associated with reduced hematologic toxicity will become the next generation of RIT. The following review addresses actual technical and clinical considerations and future development of pRIT

Contribution of [64Cu]-ATSM PET in molecular imaging of tumour hypoxia compared to classical [18F]-MISO — a selected review

During the carcinogenesis process, tumour cells often have a more rapid proliferation potential than cells that participate in blood capillary formation by neoangiogenesis. As a consequence of the poorly organized vasculature of various solid tumours, a limited oxygen delivery is observed. This hypoxic mechanism frequently occurs in solid cancers and can lead to therapeutic resistance. The present selected literature review is focused on the comparison of two positron emitting radiopharmaceuticals agents, which are currently leaders in tumour hypoxia imaging by PET. {18F}-fluoromisonidazole (= FMISO) is most commonly used as an investigational PET agent with an investigational new drug exemption from the FDA, while {64Cu}-diacetyl-bis(N4-methylthiosemicarbazone) (64Cu-ATSM) has been presented as an alternative radiopharmaceutical not yet readily available. The comparison of these two radiopharmaceutical agents is particularly focused on isotope properties, radiopharmaceutical labelling process, pharmacological mechanisms, dosimetry data in patients, and clinical results in terms of image contrast. PET imaging has demonstrated a good efficacy in tumour hypoxia imaging with both FMISO and Cu-ATSM, but FMISO has presented too slow an in vivo accumulation and a weak image contrast of the hypoxia area. Despite a less favourable dosimetry, 64Cu-ATSM appears superior in terms of imaging performance, calling for industrial and clinical development of this innovative radiopharmaceutical. Nuclear Med Rev 2011; 14, 2: 90–9

Syndecan-1 antigen, a promising new target for triple-negative breast cancer immuno-PET and radioimmunotherapy. A preclinical study on MDA-MB-468 xenograft tumors

International audienceBackgroundOverexpression of syndecan-1 (CD138) in breast carcinoma correlates with a poor prognosis and an aggressive phenotype. The objective of this study was to evaluate the potential of targeting CD138 by immuno-PET imaging and radioimmunotherapy (RIT) using the antihuman syndecan-1 B-B4 mAb radiolabeled with either 124I or 131I in nude mice engrafted with the triple-negative MDA-MB-468 breast cancer cell line.MethodThe immunoreactivity of 125I-B-B4 (80%) was determined, and the affinity of 125I-B-B4 and the expression of CD138 on MDA-MB-468 was measured in vitro by Scatchard analysis. CD138 expression on established tumors was confirmed by immunohistochemistry. A biodistribution study was performed in mice with subcutaneous MDA-MB-468 and 125I-B-B4 at 4, 24, 48, 72, and 96 h after injection and compared with an isotype-matched control. Tumor uptake of B-B4 was evaluated in vivo by immuno-PET imaging using the 124I-B-B4 mAb. The maximum tolerated dose (MTD) was determined from mice treated with 131I-B-B4 and the RIT efficacy evaluated.Results 125I-B-B4 affinity was in the nanomolar range (Kd = 4.39 ± 1.10 nM). CD138 expression on MDA-MB-468 cells was quite low (Bmax = 1.19 × 104 ± 9.27 × 102 epitopes/cell) but all expressed CD138 in vivo as determined by immunohistochemistry. The tumor uptake of 125I-B-B4 peaked at 14% injected dose (ID) per gram at 24 h and was higher than that of the isotype-matched control mAb (5% ID per gram at 24 h). Immuno-PET performed with 124I-B-B4 on tumor-bearing mice confirmed the specificity of B-B4 uptake and its retention within the tumor. The MTD was reached at 22.2 MBq. All mice treated with RIT (n = 8) as a single treatment at the MTD experienced a partial (n = 3) or complete (n = 5) response, with three of them remaining tumor-free 95 days after treatment.ConclusionThese results demonstrate that RIT with 131I-B-B4 could be considered for the treatment of metastatic triple-negative breast cancer that cannot benefit from hormone therapy or anti-Her2/neu immunotherapy. Immuno-PET for visualizing CD138-expressing tumors with 124I-B-B4 reinforces the interest of this mAb for diagnosis and quantitative imaging

Translational molecular imaging in exocrine pancreatic cancer

Effective treatment for pancreatic cancer remains challenging, particularly the treatment of pancreatic ductal adenocarcinoma (PDAC), which makes up more than 95% of all pancreatic cancers. Late diagnosis and failure of chemotherapy and radiotherapy are all too common, and many patients die soon after diagnosis. Here, we make the case for the increased use of molecular imaging in PDAC preclinical research and in patient management

Translational molecular imaging in exocrine pancreatic cancer

Effective treatment for pancreatic cancer remains challenging, particularly the treatment of pancreatic ductal adenocarcinoma (PDAC), which makes up more than 95% of all pancreatic cancers. Late diagnosis and failure of chemotherapy and radiotherapy are all too common, and many patients die soon after diagnosis. Here, we make the case for the increased use of molecular imaging in PDAC preclinical research and in patient management

Experimental discovery of small RNAs in Staphylococcus aureus reveals a riboregulator of central metabolism

Using an experimental approach, we investigated the RNome of the pathogen Staphylococcus aureus to identify 30 small RNAs (sRNAs) including 14 that are newly confirmed. Among the latter, 10 are encoded in intergenic regions, three are generated by premature transcription termination associated with riboswitch activities, and one is expressed from the complementary strand of a transposase gene. The expression of four sRNAs increases during the transition from exponential to stationary phase. We focused our study on RsaE, an sRNA that is highly conserved in the bacillales order and is deleterious when over-expressed. We show that RsaE interacts in vitro with the 5′ region of opp3A mRNA, encoding an ABC transporter component, to prevent formation of the ribosomal initiation complex. A previous report showed that RsaE targets opp3B which is co-transcribed with opp3A. Thus, our results identify an unusual case of riboregulation where the same sRNA controls an operon mRNA by targeting two of its cistrons. A combination of biocomputational and transcriptional analyses revealed a remarkably coordinated RsaE-dependent downregulation of numerous metabolic enzymes involved in the citrate cycle and the folate-dependent one-carbon metabolism. As we observed that RsaE accumulates transiently in late exponential growth, we propose that RsaE functions to ensure a coordinate downregulation of the central metabolism when carbon sources become scarce

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century