Radiotheranostics, injectable radiopharmaceuticals with antitumour effects, have seen rapid development over the past decade. Although some formulations are already approved for human use, more ...radiopharmaceuticals will enter clinical practice in the next 5 years, potentially introducing new therapeutic choices for patients. Despite these advances, several challenges remain, including logistics, supply chain, regulatory issues, and education and training. By highlighting active developments in the field, this Review aims to alert practitioners to the value of radiotheranostics and to outline a roadmap for future development. Multidisciplinary approaches in clinical trial design and therapeutic administration will become essential to the continued progress of this evolving therapeutic approach.
Integrins are key regulators of communication between cells and with their microenvironment. Eight members of the integrin superfamily recognize the tripeptide motif Arg-Gly-Asp (RGD) within ...extracelluar matrix (ECM) proteins. These integrins constitute an important subfamily and play a major role in cancer progression and metastasis via their tumor biological functions. Such transmembrane adhesion and signaling receptors are thus recognized as promising and well accessible targets for novel diagnostic and therapeutic applications for directly attacking cancer cells and their fatal microenvironment. Recently, specific small peptidic and peptidomimetic ligands as well as antibodies binding to distinct integrin subtypes have been developed and synthesized as new drug candidates for cancer treatment. Understanding the distinct functions and interplay of integrin subtypes is a prerequisite for selective intervention in integrin-mediated diseases. Integrin subtype-specific ligands labelled with radioisotopes or fluorescent molecules allows the characterization of the integrin patterns in vivo and later the medical intervention via subtype specific drugs. The coating of nanoparticles, larger proteins, or encapsulating agents by integrin ligands are being explored to guide cytotoxic reagents directly to the cancer cell surface. These ligands are currently under investigation in clinical studies for their efficacy in interference with tumor cell adhesion, migration/invasion, proliferation, signaling, and survival, opening new treatment approaches in personalized medicine.
The recently released Biograph mMR is the first commercially available integrated whole-body PET/MR scanner. There are considerable advantages to integrating both modalities in a single scanner that ...enables truly simultaneous acquisition. However, there are also concerns about the possible degradation of both PET and MR performance in an integrated system. This paper evaluates the performance of the Biograph mMR during independent and simultaneous acquisition of PET and morphologic MR data.
The NEMA NU 2-2007 protocol was followed for studying the PET performance. The following measurements were performed: spatial resolution; scatter fraction, count losses, and randoms; sensitivity; accuracy of the correction for count losses and randoms; and image quality. The quality control manual of the American College of Radiology was followed for studying the MR performance. The following measurements were performed: geometric accuracy, spatial resolution, low-contrast detectability, signal-to-noise ratio, static field (B(0)) homogeneity, radiofrequency field (B(1)) homogeneity, and radiofrequency noise.
An average spatial resolution of 4.3 mm in full width at half maximum was measured at 1 cm offset from the center of the field of view. The system sensitivity was 15.0 kcps/MBq along the center of the scanner. The scatter fraction was 37.9%, and the peak noise-equivalent count rate was 184 kcps at 23.1 kBq/mL. The maximum absolute value of the relative count rate error due to dead-time losses and randoms was 5.5%. The average residual error in scatter and attenuation correction was 12.1%. All MR parameters were within the tolerances defined by the American College of Radiology. B(0) inhomogeneities below 1 ppm were measured in a 120-mm radius. B(1) homogeneity and signal-to-noise ratio were equivalent to those of a standard MR scanner. No radiofrequency interference was detected.
These results compare favorably with other state-of-the-art PET/CT and PET/MR scanners, indicating that the integration of the PET detectors in the MR scanner and their operation within the magnetic field do not have a perceptible impact on the overall performance. The MR subsystem performs essentially like a standalone system. However, further work is necessary to evaluate the more advanced MR applications, such as functional imaging and spectroscopy.
Deep venous thrombosis (DVT) is one of the most common cardiovascular diseases, but its pathophysiology remains incompletely understood. Although sterile inflammation has recently been shown to boost ...coagulation during DVT, the underlying molecular mechanisms are not fully resolved, which could potentially identify new anti-inflammatory approaches to prophylaxis and therapy of DVT. Using a mouse model of venous thrombosis induced by flow reduction in the vena cava inferior, we identified blood-derived high-mobility group box 1 protein (HMGB1), a prototypical mediator of sterile inflammation, to be a master regulator of the prothrombotic cascade involving platelets and myeloid leukocytes fostering occlusive DVT formation. Transfer of platelets into Hmgb1−/− chimeras showed that this cell type is the major source of HMGB1, exposing reduced HMGB1 on their surface upon activation thereby enhancing the recruitment of monocytes. Activated leukocytes in turn support oxidation of HMGB1 unleashing its prothrombotic activity and promoting platelet aggregation. This potentiates the amount of HMGB1 and further nurtures the accumulation and activation of monocytes through receptor for advanced glycation end products (RAGE) and Toll-like receptor 2, leading to local delivery of monocyte-derived tissue factor and cytokines. Moreover, disulfide HMGB1 facilitates formation of prothrombotic neutrophil extracellular traps (NETs) mediated by RAGE, exposing additional HMGB1 on their extracellular DNA strands. Eventually, a vicious circle of coagulation and inflammation is set in motion leading to obstructive DVT formation. Therefore, platelet-derived disulfide HMGB1 is a central mediator of the sterile inflammatory process in venous thrombosis and could be an attractive target for an anti-inflammatory approach for DVT prophylaxis.
•Sterile inflammation inducing venous thrombosis is coordinated by the damage-associated molecular pattern HMGB1 delivered by platelets.•The effect of HMGB1 depends on the redox form, and disulfide HMGB1 induces NET formation, platelet aggregation, and monocyte activation.
PET/CT and other combined scanners have in the past decade rapidly emerged as important research tools and are proving to be invaluable for improved diagnostics in routine nuclear medicine. The ...design of hybrid PET/MR scanners presented a formidable technical challenge, and only recently were these instruments introduced to the market. Initial expectations of the performance of these scanners have been high, notably because of the potential for superior tissue contrast inherent in the MR modality, as well as the potential for multiparametric functional imaging in conjunction with PET. However, the additional value and potential clinical role that these new systems might bring to the cardiac field have yet to be documented. This review presents a comparative summary of the existing applications for PET and MR in the field of cardiology and suggests potential cardiac applications exploiting unique properties of the newly introduced combined instrumentation.
Abstract
Natural pH regulatory mechanisms can be overruled during several pathologies such as cancer, inflammation and ischaemia, leading to local pH changes in the human body. Here we demonstrate ...that
13
C-labelled zymonic acid (ZA) can be used as hyperpolarized magnetic resonance pH imaging sensor. ZA is synthesized from 1-
13
Cpyruvic acid and its
13
C resonance frequencies shift up to 3.0 p.p.m. per pH unit in the physiological pH range. The long lifetime of the hyperpolarized signal enhancement enables monitoring of pH, independent of concentration, temperature, ionic strength and protein concentration. We show
in vivo
pH maps within rat kidneys and subcutaneously inoculated tumours derived from a mammary adenocarcinoma cell line and characterize ZA as non-toxic compound predominantly present in the extracellular space. We suggest that ZA represents a reliable and non-invasive extracellular imaging sensor to localize and quantify pH, with the potential to improve understanding, diagnosis and therapy of diseases characterized by aberrant acid-base balance.
Deep vein thrombosis (DVT) is a major cause of cardiovascular death. The sequence of events that promote DVT remains obscure, largely as a result of the lack of an appropriate rodent model. We ...describe a novel mouse model of DVT which reproduces a frequent trigger and resembles the time course, histological features, and clinical presentation of DVT in humans. We demonstrate by intravital two-photon and epifluorescence microscopy that blood monocytes and neutrophils crawling along and adhering to the venous endothelium provide the initiating stimulus for DVT development. Using conditional mutants and bone marrow chimeras, we show that intravascular activation of the extrinsic pathway of coagulation via tissue factor (TF) derived from myeloid leukocytes causes the extensive intraluminal fibrin formation characteristic of DVT. We demonstrate that thrombus-resident neutrophils are indispensable for subsequent DVT propagation by binding factor XII (FXII) and by supporting its activation through the release of neutrophil extracellular traps (NETs). Correspondingly, neutropenia, genetic ablation of FXII, or disintegration of NETs each confers protection against DVT amplification. Platelets associate with innate immune cells via glycoprotein Ibα and contribute to DVT progression by promoting leukocyte recruitment and stimulating neutrophil-dependent coagulation. Hence, we identified a cross talk between monocytes, neutrophils, and platelets responsible for the initiation and amplification of DVT and for inducing its unique clinical features.
Summary Background In patients with locally advanced adenocarcinoma of the oesophagogastric junction (AEG), early metabolic response defined by 18-fluorodeoxyglucose-PET (18 FFDG-PET) during ...neoadjuvant chemotherapy is predictive of histopathological response and survival. We aimed to assess the feasibility of a PET-response-guided treatment algorithm and its potential effect on prognosis. Methods Between May 27, 2002, and Aug 4, 2005, 119 patients with locally advanced adenocarcinoma of AEG type 1 (distal oesophageal adenocarcinoma) or type 2 (gastric cardia adenocarcinoma) were recruited into this prospective, single-centre study. All patients were assigned to 2 weeks of platinum and fluorouracil-based induction chemotherapy (evaluation period). Those with decreases in tumour glucose standard uptake values (SUVs), predefined as decreases of 35% or more at the end of the evaluation period and measured by PET, were defined as metabolic responders. Responders continued to receive neoadjuvant chemotherapy of folinic acid and fluorouracil plus cisplatin, or folinic acid and fluorouracil plus cisplatin and paclitaxel, or folinic acid and fluorouracil plus oxaliplatin for 12 weeks and then proceeded to surgery. Metabolic non-responders discontinued chemotherapy after the 2-week evaluation period and proceeded to surgery. The primary endpoint was median overall survival of metabolic responders and non-responders. Secondary endpoints were median event-free survival, postoperative complications and mortality, number of residual tumour-free (R0) resections, and histopathological responses. This study has been registered in the European Clinical Trials Database (EudraCT) as trial 2007-003356-11. Findings 110 patients were evaluable for metabolic responses. 54 of these patients had metabolic responses (ie, decrease of 35% or more in tumour glucose SUV) after 2 weeks of induction chemotherapy, corresponding to a response of 49% (95% CI 39–59). 104 patients had tumour resection (50 in the responder group and 54 in the non-responder group). After a median follow-up of 2·3 years (IQR 1·7–3·0), median overall survival was not reached in metabolic responders, whereas median overall survival was 25·8 months (19·4–32·2) in non-responders (HR 2·13 1·14–3·99, p=0·015). Median event-free survival was 29·7 months (95% CI 23·6–35·7) in metabolic responders and 14·1 months (7·5–20·6) in non-responders (hazard ratio HR 2·18 1·32–3·62, p=0·002). Major histological remissions (<10% residual tumour) were noted in 29 of 50 metabolic responders (58% 95% CI 48–67), but no histological response was noted in metabolic non-responders. Interpretation This study confirmed prospectively the usefulness of early metabolic response evaluation, and shows the feasibility of a PET-guided treatment algorithm. These findings might enable tailoring of multimodal treatment in accordance with individual tumour biology in future randomised trials.
Background
Due to its high expression in prostate cancer, PSMA (prostate-specific membrane antigen) represents an ideal target for both diagnostic imaging and endoradiotherapeutic approaches. Based ...on a previously published highly specific PSMA ligand (
68
GaDOTA-FFK(Sub-KuE)), we developed a corresponding metabolically stable 1,4,7,10-tetraazacyclododececane,1-(glutaric acid)-4,7,10-triacetic acid (DOTAGA) construct for theranostic treatment of prostate cancer.
Methods
All ligands were synthesized by a combined solid phase and solution phase synthesis strategy. The affinity of the
nat
gallium and lutetium complexes to PSMA and the internalization efficiency of the radiotracers were determined on PSMA-expressing LNCaP cells. The
68
Ga- and
177
Lu-labelled ligands were further investigated for lipophilicity, binding specificity, metabolic stability, as well as biodistribution and μPET in LNCaP-tumour-bearing mice.
Results
Radiochemical yields for
68
Ga (3 nmol, 5.0 M NaCl/2.7 M HEPES (approximately 5/1), pH 3.5 to 4.5, 5 min, 95°C) and
177
Lu labelling (0.7 nmol, 0.1 M NH
4
OAc, pH 5.5, 30 min, 95°C) were almost quantitative, resulting in specific activities of 250 to 300 GBq/μmol for the
68
Ga analogues and 38 GBq/μmol for
177
Lu complexes. Due to metabolic instability of
l
-amino acid spacers,
d
-amino acids were implemented resulting in a metabolically stable DOTAGA ligand. Compared to the DOTA ligand, the DOTAGA derivatives showed higher hydrophilicity (log
P
= -3.6 ± 0.1 and -3.9 ± 0.1 for
68
Ga and
177
Lu, respectively) and improved affinity to PSMA resulting in an about twofold increased specific internalization of the
68
Ga- and
177
Lu-labelled DOTAGA analogue. Especially,
68
GaDOTAGA-ffk(Sub-KuE) exhibits favourable pharmacokinetics, low unspecific uptake and high tumour accumulation in LNCaP-tumour-bearing mice.
Conclusions
The pair of diagnostic/therapeutic PSMA-ligands
68
Ga/
177
LuDOTAGA-ffk(Sub-KuE) possess remarkable potential for the management of prostate cancer.
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