Evolution of bombesin conjugates for targeted PET imaging of tumors

Bombesin receptors are under intense investigation as molecular targets since they are overexpressed in several prevalent solid tumors. We rationally designed and synthesized a series of modified bombesin (BN) peptide analogs to study the influence of charge and spacers at the N-terminus, as well as amino acid substitutions, on both receptor binding affinity and pharmacokinetics. This enabled development of a novel (64/67)Cu-labeled BN peptide for PET imaging and targeted radiotherapy of BN receptor-positive tumors. Our results show that N-terminally positively charged peptide ligands had significantly higher affinity to human gastrin releasing peptide receptor (GRPr) than negatively charged or uncharged ligands (IC(50): 3.2±0.5 vs 26.3±3.5 vs 41.5±2.5 nM). The replacement of Nle(14) by Met, and deletion of D-Tyr(6), further resulted in 8-fold higher affinity. Contrary to significant changes to human GRPr binding, modifications at the N-terminal and at the 6(th), 11(th), and 14(th) position of BN induced only slight influences on affinity to mouse GRPr. [Cu(II)]-CPTA-[βAla(11)] BN(7-14) ([Cu(II)]-BZH7) showed the highest internalization rate into PC-3 cells with relatively slow efflux because of its subnanomolar affinity to GRPr. Interestingly, [(64/67)Cu]-BZH7 also displayed similar affinities to the other 2 human BN receptor subtypes. In vivo studies showed that [(64/67)Cu]-BZH7 had a high accumulation in PC-3 xenografts and allowed for clear-cut visualization of the tumor in PET imaging. In addition, a CPTA-glycine derivative, forming a hippurane-type spacer, enhanced kidney clearance of the radiotracer. These data indicate that the species variation of BN receptor plays an important role in screening radiolabeled BN. As well, the positive charge from the metallated complex at the N-terminal significantly increases affinity to human GRPr. Application of these observations enabled the novel ligand [(64/67)Cu]-BZH7 to clearly visualize PC-3 tumors in vivo. This study provides a strong starting point for optimizing radiopeptides for targeting carcinomas that express any of the BN receptor subtypes.

Does pet ownership in infancy lead to asthma or allergy at school age? Pooled analysis of individual participant data from 11 European birth cohorts

Objective To examine the associations between pet keeping in early childhood and asthma and allergies in children aged 6–10 years. Design Pooled analysis of individual participant data of 11 prospective European birth cohorts that recruited a total of over 22,000 children in the 1990s. Exposure definition Ownership of only cats, dogs, birds, rodents, or cats/dogs combined during the first 2 years of life. Outcome definition Current asthma (primary outcome), allergic asthma, allergic rhinitis and allergic sensitization during 6–10 years of age. Data synthesis Three-step approach: (i) Common definition of outcome and exposure variables across cohorts; (ii) calculation of adjusted effect estimates for each cohort; (iii) pooling of effect estimates by using random effects meta-analysis models. Results We found no association between furry and feathered pet keeping early in life and asthma in school age. For example, the odds ratio for asthma comparing cat ownership with “no pets” (10 studies, 11489 participants) was 1.00 (95% confidence interval 0.78 to 1.28) (I2 = 9%; p = 0.36). The odds ratio for asthma comparing dog ownership with “no pets” (9 studies, 11433 participants) was 0.77 (0.58 to 1.03) (I2 = 0%, p = 0.89). Owning both cat(s) and dog(s) compared to “no pets” resulted in an odds ratio of 1.04 (0.59 to 1.84) (I2 = 33%, p = 0.18). Similarly, for allergic asthma and for allergic rhinitis we did not find associations regarding any type of pet ownership early in life. However, we found some evidence for an association between ownership of furry pets during the first 2 years of life and reduced likelihood of becoming sensitized to aero-allergens. Conclusions Pet ownership in early life did not appear to either increase or reduce the risk of asthma or allergic rhinitis symptoms in children aged 6–10. Advice from health care practitioners to avoid or to specifically acquire pets for primary prevention of asthma or allergic rhinitis in children should not be given.

Impact of 3,4-dihydroxy-6-18F-fluoro-L-phenylalanine PET/CT on managing patients with brain tumors: the referring physician's perspective

We investigated the impact of (18)F-DOPA brain PET/CT on the clinical management of patients with known or suspected brain tumors.

Is there a need for dedicated bone imaging in addition to 18F-FDG PET/CT imaging in pediatric sarcoma patients?

Many children with sarcomas undergo whole body 2-deoxy-2-((18)F)fluoro-D-glucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) and technetium methylene diphosphonate ((99)Tc-MDP) studies. It is unknown whether the combination of both tests results in more accurate detection of bone lesions than (18)F-FDG- PET/CT alone.

The impact of 18F-FDG PET on the management of patients with suspected large vessel vasculitis

We aimed to assess the impact of (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) on the management of patients with suspected large vessel vasculitis.

Is there an optimal scan time for 6-[F-18]fluoro-L-DOPA PET in pheochromocytomas and paragangliomas?

To define the appropriate scan time for fluorine-18-labeled dihydroxyphenylalanine (F-18 DOPA) PET in oncological imaging of pheochromocytomas and paragangliomas.

Hypodense regions in unenhanced CT identify nonviable myocardium: validation versus 18F-FDG PET

The aim of the present study was to evaluate the accuracy of hypodense regions in non-contrast-enhanced cardiac computed tomography (unenhanced CT) to identify nonviable myocardial scar tissue.

Phylogenetic analysis of "Candidatus Mycoplasma turicensis" isolates from pet cats in the United Kingdom, Australia, and South Africa, with analysis of risk factors for infection

Two hemotropic mycoplasmas have been recognized in cats, Mycoplasma haemofelis and "Candidatus Mycoplasma haemominutum." We recently described a third feline hemoplasma species, designated "Candidatus Mycoplasma turicensis," in a Swiss cat with hemolytic anemia. This isolate induced anemia after experimental transmission to two specific-pathogen-free cats and analysis of the 16S rRNA gene revealed its close relationship to rodent hemotropic mycoplasmas. The agent was recently shown to be prevalent in Swiss pet cats. We sought to investigate the presence and clinical importance of "Candidatus Mycoplasma turicensis" infection in pet cats outside of Switzerland and to perform the molecular characterization of isolates from different countries. A "Candidatus Mycoplasma turicensis"-specific real-time PCR assay was applied to blood samples from 426 United Kingdom (UK), 147 Australian, and 69 South African pet cats. The 16S rRNA genes of isolates from different countries were sequenced and signalment and laboratory data for the cats were evaluated for associations with "Candidatus Mycoplasma turicensis" infection. Infections were detected in samples from UK, Australian, and South African pet cats. Infection was associated with the male gender, and "Candidatus Mycoplasma haemominutum" and M. haemofelis coinfection. Coinfected cats exhibited significantly lower packed cell volume (PCV) values than uninfected cats. Phylogenetic analyses revealed that some Australian and South African "Candidatus Mycoplasma turicensis" isolates branched away from the remaining isolates. In summary, "Candidatus Mycoplasma turicensis" infection in pet cats exists over a wide geographical area and significantly decreased PCV values are observed in cats coinfected with other feline hemoplasmas.

(18)F-Immuno-PET: Determination of Anti-CD66 Biodistribution in a Patient with High-Risk Leukemia

The monoclonal antibody anti-CD66 labeled with (99m)Tc is widely used as Scintimun((R)) granulocyte for bone marrow immunoscintigraphy. Further, recently performed clinical radioimmunotherapy studies with [(90)Y]Y-anti-CD66 proved to be suitable for the treatment of hematologic malignancies. Before radioimmunotherapy with [(90)Y]Y-anti-CD66, dosimetric estimations are required to minimize radiotoxicity and determine individual applicable activities. Planar imaging, using gamma-emitting radionuclides, is conventionally carried out to estimate the absorbed organ doses. In contrast, immuno-PET (positron emission tomography) enables the quantification of anti-CD66 accumulation and provides better spatial and temporal resolution. Therefore, in this study, a semiautomated radiosynthesis of [(18)F] F-anti-CD66 was developed, using the (18)F-acylation agent, N-succinimidyl-4-[(18)F]fluorobenzoate ([(18)F]SFB). As a proof of concept, an intraindividual comparison between PET and conventional scintigraphy, using (18)F- and (99m)Tc-labeled anti-CD66 in 1 patient with high-risk leukemia, is presented. Both labeled antibodies displayed a similar distribution pattern with high preferential uptake in bone marrow. Urinary excretion of [(18)F] F-anti-CD66 was increased and bone marrow uptake reduced, in comparison to [(99m)Tc]Tc-anti-CD66. Nevertheless, PET-based dosimetry with [(18)F] F-anti-CD66 could provide additional information to support conventional scintigraphy. Moreover, [(18)F]F-anti-CD66 is ideally suited for bone marrow imaging using PET.

Prostate carcinoma: diffusion-weighted imaging as potential alternative to conventional MR and 11C-choline PET/CT for detection of bone metastases

In a technical development study approved by the institutional ethics committee, the feasibility of fast diffusion-weighted imaging as a replacement for conventional magnetic resonance (MR) imaging sequences (short inversion time inversion recovery [STIR] and T1-weighted spin echo [SE]) and positron emission tomography (PET)/computed tomography (CT) in the detection of skeletal metastases from prostate cancer was evaluated. MR imaging and carbon 11 ((11)C) choline PET/CT data from 11 consecutive prostate cancer patients with bone metastases were analyzed. Diffusion-weighted imaging appears to be equal, if not superior, to STIR and T1-weighted SE sequences and equally as effective as (11)C-choline PET/CT in detection of bone metastases in these patients. Diffusion-weighted imaging should be considered for further evaluation and comparisons with PET/CT for comprehensive whole-body staging and restaging in prostate and other cancers.