Erratum: Acute cellular and vascular responses to photodynamic therapy using EGFR-targeted nanobody-photosensitizer conjugates studied with intravital optical imaging and magnetic resonance imaging: Erratum.

[This corrects the article DOI: 10.7150/thno.37949.].

Evaluation of a calcium, magnesium and phosphate clinical ordering tool in the emergency department.

OBJECTIVE: We developed a clinical tool comprising patient risk factors for having an abnormal calcium (Ca), magnesium (Mg) or phosphate (PO4) level. We hypothesized that patients without a risk factor do not require testing. This study examined the tool's potential utility for rationalizing Ca, Mg and PO4 ordering in the emergency department (ED). METHODS: We undertook a retrospective observational study in a single metropolitan ED. Patients aged 18 years or more who presented between July and December 2019 were included if they had a Ca, Mg or PO4 test during their ED stay. Demographic and clinical data, including the presence of risk factors, were extracted from the medical record. The primary outcome was a clinically significant abnormal Ca, Mg or PO4 level (>0.2 mmol/l above or below the laboratory reference range). RESULTS: Calcium, Mg and PO4 levels were measured on 1426, 1296 and 1099 patients, respectively. The positive and negative predictive values and likelihood ratios of the tool identifying a patient with a Ca level > 0.2 mmol/l outside the range were 0.05, 0.99, 1.59 and 0.41, respectively. The values for Mg were 0.02, 1.00, 1.44 and 0.35 and those for PO4 were 0.15, 0.93, 1.38 and 0.57, respectively. The majority of patients not identified as having an abnormal level did not receive electrolyte correction treatment. Application of the tool would have resulted in a 35.8% cost reduction. CONCLUSION: The tool failed to predict a very small proportion of patients (approximately 1%) with an abnormal Ca or Mg level and for whom it would have been desirable to have these levels measured. It may help rationalize Ca and Mg ordering and reduce laboratory costs.

Author and journal self-citation in Emergency Medicine original research articles.

OBJECTIVE: To determine author and journal self-citation rates in a sample of original emergency medicine (EM) research articles. METHODS: We undertook a retrospective observational study of original research articles published in 2019 in the top six English language general EM journals. Data comprised the total numbers of articles, citations, authors and self-citations for each author (author self-citations) as well as the number of articles in the reference list that had been previously published in the same journal (journal self-citations). RESULTS: 3213 individual authors and 581 articles were examined. Most authors did not self-cite at all although 62 self-cited five or more times in a single article. The mean (SD) and median (IQR) numbers of individual author self-citations/article/year were 0.6 (1.3) and 0 (0-1), respectively. Overall, author self-citations accounted for 2.4% of all cited articles. There was a weak positive but significant correlation between the number of individual author self-citations/article/year and the number of articles published by the author (r = 0.38, p < 0.001). There was no correlation between the journal impact factor (IF) and the author self-citation rate (r = 0.14, p = 0.79). The journals differed significantly in their author self-citation rates (p < 0.001). Annals of Emergency Medicine had the highest journal self-citation rate at 8.1% (95%CI 7.0%-9.2%) self-citations/100 citations/year, almost twice that of some other journals. There was a large but non-significant positive correlation between the journal IF and journal self-citation rates (r = 0.78, p = 0.07). CONCLUSION: Both author and journal self-citation rates in the articles examined are relatively low compared to other medical and scientific disciplines.

Acute cellular and vascular responses to photodynamic therapy using EGFR-targeted nanobody-photosensitizer conjugates studied with intravital optical imaging and magnetic resonance imaging.

Targeted photodynamic therapy (PDT) has the potential to selectively damage tumor tissue and to increase tumor vessel permeability. Here we characterize the tissue biodistribution of two EGFR-targeted nanobody-photosensitizer conjugates (NB-PS), the monovalent 7D12-PS and the biparatopic 7D12-9G8-PS. In addition, we report on the local and acute phototoxic effects triggered by illumination of these NB-PS which have previously shown to lead to extensive tumor damage. Methods: Intravital microscopy and the skin-fold chamber model, containing OSC-19-luc2-cGFP tumors, were used to investigate: a) the fluorescence kinetics and distribution, b) the vascular response and c) the induction of necrosis after illumination at 1 or 24 h post administration of 7D12-PS and 7D12-9G8-PS. In addition, dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) of a solid tumor model was used to investigate the microvascular status 2 h after 7D12-PS mediated PDT. Results: Image analysis showed significant tumor colocalization for both NB-PS which was higher for 7D12-9G8-PS. Intravital imaging showed clear tumor cell membrane localization 1 and 2 h after administration of 7D12-9G8-PS, and fluorescence in or close to endothelial cells in normal tissue for both NB-PS. PDT lead to vasoconstriction and leakage of tumor and normal tissue vessels in the skin-fold chamber model. DCE-MRI confirmed the reduction of tumor perfusion after 7D12-PS mediated PDT. PDT induced extensive tumor necrosis and moderate normal tissue damage, which was similar for both NB-PS conjugates. This was significantly reduced when illumination was performed at 24 h compared to 1 h after administration. Discussion: Although differences were observed in distribution of the two NB-PS conjugates, both led to similar necrosis. Clearly, the response to PDT using NB-PS conjugates is the result of a complex mixture of tumor cell responses and vascular effects, which is likely to be necessary for a maximally effective treatment.

Detection of Treatment Success after Photodynamic Therapy Using Dynamic Contrast-Enhanced Magnetic Resonance Imaging.

Early evaluation of response to therapy is crucial for selecting the optimal therapeutic follow-up strategy for cancer patients. PDT is a photochemistry-based treatment modality that induces tumor tissue damage by cytotoxic oxygen radicals, generated by a pre-injected photosensitive drug upon light irradiation of tumor tissue. Vascular shutdown is an important mechanism of tumor destruction for most PDT protocols. In this study, we assessed the suitability of Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI) to evaluate treatment efficacy within a day after photodynamic therapy (PDT), using the tumor vascular response as a biomarker for treatment success. Methods: DCE-MRI at 7 T was used to measure the micro-vascular status of subcutaneous colon carcinoma tumors before, right after, and 24 h after PDT in mice. Maps of the area under the curve (AUC) of the contrast agent concentration were calculated from the DCE-MRI data. Besides, tracer kinetic parameters including Ktrans were calculated using the standard Tofts-Kermode model. Viability of tumor tissue at 24 h after PDT was assessed by histological analysis. Results: PDT led to drastic decreases in AUC and Ktrans or complete loss of enhancement immediately after treatment, indicating a vascular shutdown in treated tumor regions. Histological analysis demonstrated that the treatment induced extensive necrosis in the tumors. For PDT-treated tumors, the viable tumor fraction showed a strong correlation (ρ ≥ 0.85) with the tumor fraction with Ktrans > 0.05 min-1 right after PDT. The viable tumor fraction also correlated strongly with the enhanced fraction, the average Ktrans , and the fraction with Ktrans > 0.05 min-1 at 24 h after PDT. Images of the viability stained tumor sections were registered to the DCE-MRI data, demonstrating a good spatial agreement between regions with Ktrans > 0.05 min-1 and viable tissue regions. Finally, 3D post-treatment viability detection maps were constructed for the tumors of three mice by applying a threshold (0.05 min-1) to Ktrans at 24 h after PDT. As a proof of principle, these maps were compared to actual tumor progression after one week. Complete tumor response was correctly assessed in one animal, while residual viable tumor tissue was detected in the other two at the locations where residual tumor tissue was observed after one week. Conclusion: This study demonstrates that DCE-MRI is an effective tool for early evaluation of PDT tumor treatment.

Noninvasive fluence rate mapping in living tissues using magnetic resonance thermometry.

A noninvasive method is introduced for quantification and visualization of fluence rate in light-irradiated biological tissues. The method is based on magnetic resonance thermometry (MRT) measurements of tissue temperature changes resulting from absorption of light. From the spatial­temporal temperature data, the generated heat is calculated. Finally, fluence rate maps are reconstructed by dividing the heat data by the tissue absorption coefficient. Simulations were performed using virtual MRT datasets based on analytically described fluence rate distributions, which could be accurately reconstructed by the method. Next, the approach was tested in gel phantoms. Resulting fluence rate maps matched well with theoretical predictions in a nonscattering phantom ( R 2 = 0.93 ). Experimental validation was further obtained in a scattering phantom, by comparing fluence rates to invasive fluence rate probe measurements along and perpendicular to the optical axis ( R 2 ? 0.71 for both cases). Finally, our technique was applied in vivo in a mouse tumor model. The resulting fluence rates matched invasive probe measurements (Pearson's ? = 0.90 , p = 0.0026 ). The method may be applied to investigate the relation between light dose and biological response in light-based treatments, such as photodynamic therapy. It may also be useful for experimental validation of light transport models.

A MRI-Compatible Combined Mechanical Loading and MR Elastography Setup to Study Deformation-Induced Skeletal Muscle Damage in Rats.

Deformation of skeletal muscle in the proximity of bony structures may lead to deep tissue injury category of pressure ulcers. Changes in mechanical properties have been proposed as a risk factor in the development of deep tissue injury and may be useful as a diagnostic tool for early detection. MRE allows for the estimation of mechanical properties of soft tissue through analysis of shear wave data. The shear waves originate from vibrations induced by an external actuator placed on the tissue surface. In this study a combined Magnetic Resonance (MR) compatible indentation and MR Elastography (MRE) setup is presented to study mechanical properties associated with deep tissue injury in rats. The proposed setup allows for MRE investigations combined with damage-inducing large strain indentation of the Tibialis Anterior muscle in the rat hind leg inside a small animal MR scanner. An alginate cast allowed proper fixation of the animal leg with anatomical perfect fit, provided boundary condition information for FEA and provided good susceptibility matching. MR Elastography data could be recorded for the Tibialis Anterior muscle prior to, during, and after indentation. A decaying shear wave with an average amplitude of approximately 2 µm propagated in the whole muscle. MRE elastograms representing local tissue shear storage modulus Gd showed significant increased mean values due to damage-inducing indentation (from 4.2 ± 0.1 kPa before to 5.1 ± 0.6 kPa after, p<0.05). The proposed setup enables controlled deformation under MRI-guidance, monitoring of the wound development by MRI, and quantification of tissue mechanical properties by MRE. We expect that improved knowledge of changes in soft tissue mechanical properties due to deep tissue injury, will provide new insights in the etiology of deep tissue injuries, skeletal muscle damage and other related muscle pathologies.

Quantitative Multi-Parametric Magnetic Resonance Imaging of Tumor Response to Photodynamic Therapy.

OBJECTIVE: The aim of this study was to characterize response to photodynamic therapy (PDT) in a mouse cancer model using a multi-parametric quantitative MRI protocol and to identify MR parameters as potential biomarkers for early assessment of treatment outcome. METHODS: CT26.WT colon carcinoma tumors were grown subcutaneously in the hind limb of BALB/c mice. Therapy consisted of intravenous injection of the photosensitizer Bremachlorin, followed by 10 min laser illumination (200 mW/cm2) of the tumor 6 h post injection. MRI at 7 T was performed at baseline, directly after PDT, as well as at 24 h, and 72 h. Tumor relaxation time constants (T1 and T2) and apparent diffusion coefficient (ADC) were quantified at each time point. Additionally, Gd-DOTA dynamic contrast-enhanced (DCE) MRI was performed to estimate transfer constants (Ktrans) and volume fractions of the extravascular extracellular space (ve) using standard Tofts-Kermode tracer kinetic modeling. At the end of the experiment, tumor viability was characterized by histology using NADH-diaphorase staining. RESULTS: The therapy induced extensive cell death in the tumor and resulted in significant reduction in tumor growth, as compared to untreated controls. Tumor T1 and T2 relaxation times remained unchanged up to 24 h, but decreased at 72 h after treatment. Tumor ADC values significantly increased at 24 h and 72 h. DCE-MRI derived tracer kinetic parameters displayed an early response to the treatment. Directly after PDT complete vascular shutdown was observed in large parts of the tumors and reduced uptake (decreased Ktrans) in remaining tumor tissue. At 24 h, contrast uptake in most tumors was essentially absent. Out of 5 animals that were monitored for 2 weeks after treatment, 3 had tumor recurrence, in locations that showed strong contrast uptake at 72 h. CONCLUSION: DCE-MRI is an effective tool for visualization of vascular effects directly after PDT. Endogenous contrast parameters T1, T2, and ADC, measured at 24 to 72 h after PDT, are also potential biomarkers for evaluation of therapy outcome.

p(42)Be neutron therapy beams: dose rate and penetration as a function of target thickness and beam filtration.

It is shown that, in the production of p(42)Be neutron beams for clinical use, the use of semithick targets leads to more desirable beam characteristics when appropriate backstop materials are used. Furthermore, an algebraic representation of beam penetration and of dose per unit charge on target, including hardening by polyethylene filters, provides a method for target optimization.

The influence of target thickness and backstop material on proton-produced neutron beams for radiotherapy.

Results are presented of measurements of skin sparing, penetration and total dose per unit of incident charge for various target thicknesses and filtrations for a neutron beam generated by 42 MeV protons on beryllium. These results are contrasted to predictions outlined in a previous paper. The differences from these predictions are attributed to the contribution of low-energy neutrons produced by the residual proton beam in the thick copper target backstop.

Dosimetric properties of neutron beams from the D--D reaction in the energy range from 6.8 to 11.1 MeV.

The tissue kerma in air, the tissue dose at maximum build-up, the relative depth dose on the central axis and the dose build-up characteristics were measured for neutrons produced by 6.8, 8.9 and 11.1 MeV deuterons on deuterium. The neutron beams were produced by a variable-energy cyclotron with a fully stopping deuterium gas target 20 cm long. Measurements were made in a 11.1cm x 11.1 cm field 126 cm from the target entrance window. The dose rate was found to increase rapidly with energy from 0.07 rad min-1 microamperemeter-1 at 6.8MeV to 0.35 rad min-1 muA-1 at 11.1 MeV. The entrance dose is about 50% of the dose maximum for each bombarding energy. The depth of the 95% dose level in the build-up region increased from 50 mg cm-2 at 6.8 MeV to 90 mg cm-2 at 11.1 MeV. The penetration was independent of the bombarding energy in the region investigated. Attenuation of the total dose to 50% of the maximum occurred at 10.2 +/- 0.1 g cm-2 for all three bombarding energies. The dose at the maximum is typically 14% higher than the tissue kerma in air.

Dosimetry measurements of 26, 35 and 45 MeV p-Be and p-Li neutron beams.

Dosimetric properties of neutron beams produced by stopping 26, 35 and 45 MeV protons in beryllium and lithium have been measured. The effects of filtering the p-Be beam with 6 cm of polyethylene have been investigated. The tissue kerma rate in air exhibited an energy dependence of approximately E3 and the rate for p-Be beams was approximately one-fifth of the rate for d-Be beams. The penetrability of the neutrons was significnatly enhanced by the use of the filter, but with a 50% attentuation in tissue kerma rate. The tissue kerma rate for the p-Li beam was nearly the same as that for the p-Be beam.