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Peptide-receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogs such as octreotide is an effective therapy against neuroendocrine tumors. Other radiolabeled peptides and antibody fragments are under investigation. Most of these compounds are cleared through the kidneys and reabsorbed and partially retained in the proximal tubules, causing dose-limiting nephrotoxicity. An overview of renal handling of radiolabeled peptides and resulting nephrotoxicity is presented, and strategies to reduce nephrotoxicity are discussed. Modification of size, charge, or structure of radiolabeled peptides can alter glomerular filtration and tubular reabsorption. Coinfusion of competitive inhibitors of reabsorption also interferes with the interaction of peptides with renal endocytic receptors; coinfusion of basic amino acids is currently used for kidney protection in clinical PRRT. Furthermore, nephrotoxicity may be reduced by dose fractionation, use of radioprotectors, or use of mitigating agents. Decreasing the risk of nephrotoxicity allows for administration of higher radiation doses, increasing the effectiveness of PRRT.

In patients with colorectal peritoneal metastases scheduled for cytoreductive surgery, accurate preoperative estimation of tumor burden and subsequent intraoperative detection of all tumor deposits remains challenging. In this study (ClinicalTrials.gov NCT03699332) we describe the results of a phase I clinical trial evaluating [ 111 In]In-DOTA-labetuzumab-IRDye800CW, a dual-labeled anti-carcinoembryonic antigen (anti-CEA) antibody conjugate that enables both preoperative imaging and intraoperative radioguidance and fluorescence imaging. Primary study outcomes are safety and feasibility of this multimodal imaging approach. Secondary outcomes are determination of the optimal dose, correlation between tracer uptake and histopathology and effects on clinical strategy. Administration of [ 111 In]In-DOTA-labetuzumab-IRDye800CW is well-tolerated and enables sensitive pre- and intraoperative imaging in patients who receive 10 or 50 mg of the tracer. Preoperative imaging revealed previously undetected lymph node metastases in one patient, and intraoperative fluorescence imaging revealed four previously undetected metastases in two patients. Alteration of clinical strategy based on multimodal imaging occurred in three patients. Thus, multimodal image-guided surgery after administration of this dual-labeled tracer is a promising approach that may aid in decision making before and during cytoreductive surgical procedures. Imaging of tumor burden during surgery can lead to better tumor resection. Here, the authors develop a fluorescent probe that binds to carcinoembryonic antigen, expressed on colorectal cancer cells, and describe the results of their phase I clinical trial.

Nuclear medicine imaging procedures play an important role in the assessment of inflammatory diseases. With the advent of 3-dimensional anatomic imaging, there has been a tendency to replace traditional planar scintigraphy by CT or MRI. Furthermore, scintigraphic techniques may have to be combined with other imaging modalities to achieve high sensitivity and specificity, and some may require time-consuming labeling procedures. On the other hand, new developments such as combined SPECT/CT increase the diagnostic power of scintigraphy. Also, the advent of PET had a considerable impact on the use of nuclear medicine imaging techniques. In this review, we aim to provide nuclear medicine specialists and clinicians with the relevant information on rational and efficient use of nuclear medicine imaging techniques in the assessment of patients with osteomyelitis, infected vascular prostheses, metastatic infectious disease, rheumatoid arthritis, vasculitis, inflammatory bowel disease, sarcoidosis, and fever of unknown origin.

Antibody based positron emission tomography (immuno-PET) imaging is of increasing importance to visualize and characterize tumor lesions. Additionally, it can be used to identify patients who may benefit from a particular therapy and monitor the therapy outcome. In recent years the field is focused on 89Zr, a radiometal with near ideal physical and chemical properties for immuno-PET. In this review we will discuss the production of  89Zr, the bioconjugation strategies, and applications in (pre-)clinical studies of  89Zr-based immuno-PET in oncology. To date, 89Zr-based PET imaging has been investigated in a wide variety of cancer-related targets. Moreover, clinical studies have shown the feasibility for 89Zr-based immuno-PET to predict and monitor treatment, which could be used to tailor treatment for the individual patient. Further research should be directed towards the development of standardized and robust conjugation methods and improved chelators to minimize the amount of released Zr4+ from the antibodies. Additionally, further validation of the imaging method is required. The ongoing development of new 89Zr-labeled antibodies directed against novel tumor targets is expected to expand applications of  89Zr-labeled immuno-PET to a valuable method in the medical imaging.

The success of cellular therapies will depend in part on accurate delivery of cells to target organs. In dendritic cell therapy, in particular, delivery and subsequent migration of cells to regional lymph nodes is essential for effective stimulation of the immune system. We show here that in vivo magnetic resonance tracking of magnetically labeled cells is feasible in humans for detecting very low numbers of dendritic cells in conjunction with detailed anatomical information. Autologous dendritic cells were labeled with a clinical superparamagnetic iron oxide formulation or 111 In-oxine and were co-injected intranodally in melanoma patients under ultrasound guidance. In contrast to scintigraphic imaging, magnetic resonance imaging (MRI) allowed assessment of the accuracy of dendritic cell delivery and of inter- and intra-nodal cell migration patterns. MRI cell tracking using iron oxides appears clinically safe and well suited to monitor cellular therapy in humans.

Targeted therapies, including antibodies, are becoming increasingly important in cancer therapy. Important limitations, however, are that not every patient benefits from a specific antibody therapy and that responses could be short-lived due to acquired resistance. In addition, targeted therapies are quite expensive and are not completely devoid of side-effects. This urges the need for accurate patient selection and response monitoring. An important step towards personalizing antibody treatment could be the implementation of theranostics. Antibody theranostics combine the diagnostic and therapeutic potential of an antibody, thereby selecting those patients who are most likely to benefit from antibody treatment. This review focuses on the clinical application of theranostic antibodies in oncology. It provides detailed information concerning the suitability of antibodies for theranostics, the different types of theranostic tests available and summarizes the efficacy of theranostic antibodies used in current clinical practice. Advanced theranostic applications, including radiolabeled antibodies for non-invasive functional imagining, are also addressed. Finally, we discuss the importance of theranostics in the emerging field of personalized medicine and critically evaluate recent data to determine the best way to apply antibody theranostics in the future. •Importance of antibody theranostics in personalizing targeted cancer treatment.•Limitations of conventional theranostic tests.•Advantages of novel, advanced theranostic approaches.•Difference in theranostic applications for conjugated and unconjugated antibodies.

Platinum-based chemotherapeutics exhibit excellent antitumor properties. However, these drugs cause severe side effects including toxicity, drug resistance, and lack of tumor selectivity. Tumor-targeted drug delivery has demonstrated great potential to overcome these drawbacks. Herein, we aimed to design radioactive bisphosphonate-functionalized platinum ( 195m Pt-BP) complexes to confirm preferential accumulation of these Pt-based drugs in metabolically active bone. In vitro NMR studies revealed that release of Pt from Pt BP complexes increased with decreasing pH. Upon systemic administration to mice, Pt-BP exhibited a 4.5-fold higher affinity to bone compared to platinum complexes lacking the bone-seeking bisphosphonate moiety. These Pt-BP complexes formed less Pt-DNA adducts compared to bisphosphonate-free platinum complexes, indicating that in vivo release of Pt from Pt-BP complexes proceeded relatively slow. Subsequently, radioactive 195m Pt-BP complexes were synthesized using 195m Pt(NO 3 ) 2 (en) as precursor and injected intravenously into mice. Specific accumulation of 195m Pt-BP was observed at skeletal sites with high metabolic activity using micro-SPECT/CT imaging. Furthermore, laser ablation-ICP-MS imaging of proximal tibia sections confirmed that 195m Pt BP co-localized with calcium in the trabeculae of mice tibia.

The insulin-like growth factor 1 receptor (IGF-1R) may be involved in the development of resistance against conventional cancer treatment. The aim of this study was to assess whether IGF-1R expression of breast tumors changes during neoadjuvant therapy and to study whether these changes were associated with survival. Paraffin embedded tumor tissue was collected from pretreatment biopsies and surgical resections of 62 breast cancer patients who were treated with neoadjuvant chemotherapy or endocrine therapy. IGF-1R expression was determined immunohistochemically and compared before and after treatment. High membranous IGF-1R expression at diagnosis correlated significantly with ER positivity, low tumor stage (stage I/II) and longer overall survival (p < 0.05). After neoadjuvant treatment, membranous IGF-1R expression remained the same in 41 (65%) tumors, was upregulated in 11 (18%) tumors and downregulated in 11 (18%) tumors. Changes in membranous IGF-1R expression were associated with overall survival (log-rank test: p = 0.013, multivariate cox-regression: p = 0.086). Mean overall survival time for upregulation, no change, and downregulation in IGF-1R expression was 3.0 ± 0.5 years, 7.3 ± 1.0 years and 15.0 ± 1.8 years, respectively. Changes in other parameters were not significantly associated with survival. Neoadjuvant therapy can induce changes in IGF-1R expression. Upregulation of IGF-1R expression after neoadjuvant treatment is a poor prognostic factor in breast cancer patients, providing a rationale for incorporating anti-IGF-1R drugs in the management of these patients.

Current biomarkers are unable to adequately predict vaccine-induced immune protection in humans with infectious disease or cancer. However, timely and adequate assessment of antigen-specific immune responses is critical for successful vaccine development. Therefore, we have developed a method for the direct assessment of immune responses in vivo in a clinical setting. Melanoma patients with lymph node (LN) metastases received dendritic cell (DC) vaccine therapy, injected intranodally, followed by [18F]-labeled 3'-fluoro-3'-deoxy-thymidine ([18F]FLT) PET at varying time points after vaccination. Control LNs received saline or DCs without antigen. De novo immune responses were readily visualized in treated LNs early after the prime vaccination, and these signals persisted for up to 3 wk. This selective [18F]FLT uptake was markedly absent in control LNs, although tracer uptake in treated LNs increased profoundly with as little as 4.5 x 105 DCs. Immunohistochemical staining confirmed injected DC dispersion to T-cell areas and resultant activation of CD4+ and CD8+ T cells. The level of LN tracer uptake significantly correlates to the level of circulating antigen-specific IgG antibodies and antigen-specific proliferation of T cells in peripheral blood. Furthermore, this correlation was not observed with [18F]-labeled fluoro-2-deoxy-2-D-glucose. Therefore, [18F]FLT PET offers a sensitive tool to study the kinetics, localization, and involvement of lymphocyte subsets in response to vaccination. This technique allows for early discrimination of responding from nonresponding patients in anti-cancer vaccination and aid physicians in individualized decisionmaking.

Renal ischemia/reperfusion injury (IRI) frequently complicates shock, renal transplantation and cardiac and aortic surgery, and has prognostic significance. The translocation of phosphatidylserines to cell surfaces is an important pro-inflammatory signal for cell-stress after IRI. We hypothesized that shielding of exposed phosphatidylserines by the annexin A5 (ANXA5) homodimer Diannexin protects against renal IRI. Protective effects of Diannexin on the kidney were studied in a mouse model of mild renal IRI. Diannexin treatment before renal IRI decreased proximal tubule damage and leukocyte influx, decreased transcription and expression of renal injury markers Neutrophil Gelatinase Associated Lipocalin and Kidney Injury Molecule-1 and improved renal function. A mouse model of ischemic hind limb exercise was used to assess Diannexin biodistribution and targeting. When comparing its biodistribution and elimination to ANXA5, Diannexin was found to have a distinct distribution pattern and longer blood half-life. Diannexin targeted specifically to the ischemic muscle and its affinity exceeded that of ANXA5. Targeting of both proteins was inhibited by pre-treatment with unlabeled ANXA5, suggesting that Diannexin targets specifically to ischemic tissues via phosphatidylserine-binding. This study emphasizes the importance of phosphatidylserine translocation in the pathophysiology of IRI. We show for the first time that Diannexin protects against renal IRI, making it a promising therapeutic tool to prevent IRI in a clinical setting. Our results indicate that Diannexin is a potential new imaging agent for the study of phosphatidylserine-exposing organs in vivo.