A Patient-Level Meta-Analysis of Intensive Glucose Control in Critically Ill Adults.

BACKGROUND: Whether intensive glucose control reduces mortality in critically ill patients remains uncertain. Patient-level meta-analyses can provide more precise estimates of treatment effects than are currently available. METHODS: We pooled individual patient data from randomized trials investigating intensive glucose control in critically ill adults. The primary outcome was in-hospital mortality. Secondary outcomes included survival to 90 days and time to live cessation of treatment with vasopressors or inotropes, mechanical ventilation, and newly commenced renal replacement. Severe hypoglycemia was a safety outcome. RESULTS: Of 38 eligible trials (n=29,537 participants), 20 (n=14,171 participants) provided individual patient data including in-hospital mortality status for 7059 and 7049 participants allocated to intensive and conventional glucose control, respectively. Of these 1930 (27.3%) and 1891 (26.8%) individuals assigned to intensive and conventional control, respectively, died (risk ratio, 1.02; 95% confidence interval [CI], 0.96 to 1.07; P=0.52; moderate certainty). There was no apparent heterogeneity of treatment effect on in-hospital mortality in any examined subgroups. Intensive glucose control increased the risk of severe hypoglycemia (risk ratio, 3.38; 95% CI, 2.99 to 3.83; P<0.0001). CONCLUSIONS: Intensive glucose control was not associated with reduced mortality risk but increased the risk of severe hypoglycemia. We did not identify a subgroup of patients in whom intensive glucose control was beneficial. (Funded by the Australian National Health and Medical Research Council and others; PROSPERO number CRD42021278869.).

Preliminary studies of 68Ga-NODA-USPION-BBN as a dual-modality contrast agent for use in positron emission tomography/magnetic resonance imaging.

The aim of this study was to propose a new dual-modality nanoprobe for positron emission tomography/magnetic resonance imaging (PET/MRI) for the early diagnosis of breast cancer. For synthesis of the nanoprobe, polyethylene glycol-coated ultra-small superparamagnetic iron-oxide nanoparticles (USPION) armed with NODA-GA chelate and grafted with bombesin (BBN) were radiolabeled with 68Ga. After characterization, in vitro studies to evaluate the cell binding affinity of the nanoprobe were done by performing Perl's Prussian blue cell staining and MRI imaging. Finally, for in vivo studies, magnetic resonance images were taken in SCID mice bearing breast cancer tumor pre- and post-injection, and a multimodal nanoScan PET/computed tomography was used to perform preclinical imaging of the radiolabeled nanoparticles. Afterwards, a biodistribution study was done on sacrificed mice. The results showed that the highest r1 and r2 values were measured for USPIONs at 20 and 60 MHz, respectively. From the in vitro studies, the optical density of the cells after incubation increased with the increase of the iron concentration and the duration of incubation. However, the T2 values decreased when the iron concentration increased. Furthermore, from in vivo studies, the T2 and signal intensity decreased during the elapsed time post-injection in the tumor area. In this study, the in vitro studies showed that the affinity of cancer cells to nanoprobe increases meaningfully after conjugation with BBN, and also by increasing the duration of incubation and the iron concentration. Meanwhile, the in vivo results confirmed that the blood clearance of the nanoprobe happened during the first 120 min post-injection of the radiolabeled nanoprobe and also confirmed the targeting ability of that to a gastrin-releasing peptide receptor positive tumor.

Preclinical Evaluation of 68Ga-MAA from Commercial Available 99mTc-MAA Kit.

99mTc-Macroaggregated Albumin (99mTc-MAA) has been used as a perfusion agent. This study described development of the 68Ga-MAA via commercially available kits from Pars-Isotopes Company as a 99mTc-MAA kit. 68Ge/68Ga generator was eluted with suprapure HCl (0.6 M, 6 mL) in 0.5 mL fractions. The two fractions with the highest 68GaCl3 activity were generally used for labeling purposes. After labeling, the final product was centrifuged 2 times to purify the solution. Five rats were sacrificed at each exact time interval (from 15 min to 2 h post injection) and the percentage of injected dose per gram (%ID/g) of each organ was measured by direct counting from 11 harvested organs of rats. The RTLC showed that labeling yields before centrifuges were 90% and 95% for Pars-Isotopes and GE kits, respectively and after centrifuges, they became 100%. The microscopic size examination showed a shift in the particle sizes post centrifuges and the biodistribution data revealed the efficiency and benefits of centrifuges in terms of preventing the of liver and bone marrow uptakes especially for Pars-Isotopes kits. Our results showed that after centrifuges of the final product, the lung uptakes increased from 89% to more than 97% of %ID/g after 5 min post injections. The whole procedure took less than 25 min from elution to the final product. Since 99mTc-MAA remained longer than 68Ga-MAA in the lung and 68Ga-MAA showed better image qualities, using 68Ga-MAA is recommended.

Dual nano-sized contrast agents in PET/MRI: a systematic review.

Nowadays molecular imaging plays a vital role in achieving a successful targeted and personalized treatment. Hence, the approach of combining two or more medical imaging modalities was developed. The objective of this review is to systematically compare recent dual contrast agents in Positron Emission Tomography (PET)/Magnetic Resonance Imaging (MRI) and in some cases Single photon emission computed tomography (SPECT)/MRI in terms of some their characteristics, such as tumor uptake, and reticuloendothelial system uptake (especially liver) and their relaxivity rates for early detection of primary cancer tumor. To the best of our knowledge, this is the first systematic and integrated overview of this field. Two reviewers individually directed the systematic review search using PubMed, MEDLINE and Google Scholar. Two other reviewers directed quality assessment, using the criteria checklist from the CAMARADES (Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies) tool, and differences were resolved by consensus. After reviewing all 49 studies, we concluded that a size range of 20-200 nm can be used for molecular imaging, although it is better to try to achieve as small a size as it is possible. Also, small nanoparticles with a hydrophilic coating and positive charge are suitable as a T2 contrast agent. According to our selected data, the most successful dual probes in terms of high targeting were with an average size of 40 nm, PEGylated using peptides as a biomarker and radiolabeled with copper 64 and gallium 68. Copyright © 2017 John Wiley & Sons, Ltd.

External magnetic fields affect the biological impacts of superparamagnetic iron nanoparticles.

Superparamagnetic iron oxide nanoparticles (SPIONs) are recognized as one of the promising nanomaterials for applications in various field of nanomedicine such as targeted imaging/drug delivery, tissue engineering, hyperthermia, and gene therapy. Besides their suitable biocompatibility, SPIONs' unique magnetic properties make them an outstanding candidate for theranostic nanomedicine. Very recent progress in the field revealed that the presence of external magnetic fields may cause considerable amount of SPIONs' agglomeration in their colloidal suspension. As variation of physicochemical properties of colloidal nanoparticles has strong effect on their biological outcomes, one can expect that the SPIONs' agglomeration in the presence of external magnetic fields could change their well-recognized biological impacts. In this case, here, we probed the cellular uptake and toxicity of the SPIONs before and after exposure to external magnetic fields. We found that the external magnetic fields can affect the biological outcome of magnetic nanoparticles.

Comparison of estimated human dose of (68)Ga-MAA with (99m)Tc-MAA based on rat data.

OBJECTIVE: (99m)Tc macroaggregated albumin ((99m)Tc-MAA) that had been used as a perfusion agent has been evaluated. In this study, we tried to estimate human absorbed dose of 68Ga-MAA via commercially available kit from Pars-Isotopes, based on biodistribution data in wild-type rats, and compare our estimation with the available absorbed dose data from (99m)Tc-MAA. METHODS: For biodistribution of 68Ga-MAA, three rats were sacrificed at each selected times after injection (15, 30, 45, 60, and 120 min) and the percentage of injected dose per gram of each organ was measured by direct counting from rats data from 11 harvested organs. The medical internal radiation dose formulation was applied to extrapolate from rats to human and to project the absorbed radiation dose for various organs in humans. RESULTS: The biodistribution data for 68Ga-MAA showed that the most of the activity was taken up by the lung (more than 97 %) in no time. Our dose prediction shows that a 185-MBq injection of 68Ga-MAA into humans might result in an estimated absorbed dose of 4.31 mGy in the whole body. The highest absorbed doses are observed in the adrenals, spleen, pancreas, and red marrow with 0.36, 0.34, 0.26, and 0.19 mGy, respectively. CONCLUSION: Since the (99m)Tc-MAA remains longer than 68Ga-MAA in the lung and 68Ga-MAA has good image qualities and results in lower amounts of dose delivery to the critical organs such as gonads, red marrow, and adrenals, the use of 68Ga-MAA is recommended.

Estimated human absorbed dose for (68)Ga-ECC based on mice data: comparison with (67)Ga-ECC.

OBJECTIVE: Nowadays, the efficacies of (68)Ga-based tracers are comparable to that of (18)F-based agents and have stimulated researchers to investigate the potential of (68)Ga-based positron emission tomography (PET) imaging agents. In this study, the human absorbed dose of (68)Ga labeled with ethylenecysteamine cysteine (68)Ga-ECC and (67)Ga-ECC was estimated based on biodistribution data in mice by the medical internal radiation dose (MIRD) method. METHODS: For biodistribution of (67)Ga/(68)Ga-ECC, three mice were killed by CO2 asphyxiation at each selected times after injection (15, 30, 45, 60, 120 min for (68)Ga-ECC and 0.5, 2 and 48 h for (67)Ga-ECC), and then the tissue (heart, lung, brain, intestine, skin, stomach, kidneys, liver, muscle and bone) was removed. RESULTS: (68)Ga-ECC as a new PET renal imaging agent was prepared with radiochemical purity of >97 % in less than 30 min. The biodistribution data for (68)Ga-ECC showed that the most of the activity extracted from the urinary tract very fast. Comparison between human absorbed dose estimation for these two agents indicated that the absorbed dose of the most organs after injection of (67)Ga-ECC is approximately tenfold higher than the amount after (68)Ga-ECC injection. CONCLUSION: The results showed that (68)Ga-ECC is a more appropriate agent rather than (67)Ga-ECC and generally can be a good candidate for PET renal imaging applications.

Assessment of human effective absorbed dose of 67 Ga-ECC based on biodistribution rat data.

OBJECTIVE: In a diagnostic context, determination of absorbed dose is required before the introduction of a new radiopharmaceutical to the market to obtain marketing authorization from the relevant agencies. In this work, the absorbed dose of [67 Ga]-ethylenecysteamine cysteine [(67 Ga)ECC] to human organs was determined by using distribution data for rats. METHODS: For biodistribution data, the animals were sacrificed by CO2 asphyxiation at selected times after injection (0.5, 2 and 48 h, n = 3 for each time interval), then the tissue (blood, heart, lung, brain, intestine, feces, skin, stomach, kidneys, liver, muscle and bone) were removed. The absorbed dose was determined by Medical Internal Radiation Dose (MIRD) method after calculating cumulated activities in each organ. RESULTS: Our prediction shows that a 185-MBq injection of (67)Ga-ECC into the humans might result in an estimated absorbed dose of 0.029 mGy in the whole body. The highest absorbed doses are observed in the spleen and liver with 33.766 and 16.847 mGy, respectively. CONCLUSION: The results show that this radiopharmaceutical can be a good SPECT tracer since it can be produced easily and also the absorbed dose in each organ is less than permitted absorbed dose.

Monoclonal antibody conjugated magnetic nanoparticles could target MUC-1-positive cells in vitro but not in vivo.

MUC1 antigen is recognized as a high-molecular-weight glycoprotein that is unexpectedly over-expressed in human breast and other carcinomas. In contrast, C595 a monoclonal antibody (mAb) against the protein core of the human urinary epithelial machine, is commonly expressed in breast carcinomas. The aim of this study was to conjugate ultra-small super paramagnetic iron oxide nanoparticles (USPIO) with C595 mAb, in order to detect in vivo MUC1 expression. A dual contrast agent (the C595 antibody-conjugated USPIO labeled with 99mTc) was prepared for targeted imaging and therapy of anti-MUC1-expressing cancers. The C595 antibody-conjugated USPIO had good stability and reactivity in the presence of blood plasma at 37 °C. No significant differences were observed in immunoreactivity results between conjugated and nonconjugated nanoparticles. The T1 and T2 measurements show >79 and 29% increments (for 0.02 mg/ml iron concentrations) in T1 and T2 values for USPIO-C595 in comparison with USPIO, respectively. The nanoprobes showed the interesting targeting capability of finding the MUC1-positive cell line in vitro. However, we found disappointing in vivo results (i.e. very low accumulation of nanoprobes in the targeted site while >80% of the injected dose per gram was taken up by the liver and spleen), not only due to the coverage of targeting site by protein corona but also because of absorption of opsonin-based proteins at the surface of nanoprobes.

Assessment of the effective absorbed dose of 4-benzyl-1-(3-[125I]-iodobenzylsulfonyl)piperidine in humans on the basis of biodistribution data of rats.

OBJECTIVES: The aim of this study was to estimate the effective absorbed radiation dose to human organs following promising in-vivo results of intravenous administration of 4-benzyl-1-(3-[125I]-iodobenzylsulfonyl)piperidine (4-B-[125I]-IBSP) using normal biodistribution data obtained from rats. MATERIALS AND METHODS: Five rats were killed at exact time intervals and the percentage of injected dose per gram of each organ was measured by direct counting from rat data. The medical internal radiation dose formulation was applied to extrapolate from rats to humans and to project the absorbed radiation dose for various human organs. RESULTS: The dose estimation shows that the organs that received the highest absorbed dose were the brain, bone surface, and red marrow (10.51, 0.69, and 0.08 µGy/MBq, respectively). Our prediction shows that a 185 MBq injection of 4-B-[125I]-IBSP into humans might result in an estimated absorbed dose of 49.39 µGy for the whole body. The highest effective absorbed dose for 4-B-[125I]-IBSP was in the brain (19.4 µSv) and the organs that received the next highest doses were the bone surface, red marrow, muscle, and thyroid, with magnitudes of 15.27, 1.81, 0.15, and 0.10 µSv, respectively. CONCLUSION: The results of this study suggest that 4-B-[125I]-IBSP is a suitable and safe candidate in clinical studies and in lung malignancies.

Estimated background doses of [67Ga]-DTPA-USPIO in normal Balb/c mice as a potential therapeutic agent for liver and spleen cancers.

INTRODUCTION: The aim of this study was to evaluate the biodistribution of dextran-coated iron oxide nanoparticles labeled with gallium-67 (Ga) in various organs by intravenous injection in Balb/c mice. METHODS: Ultrasmall superparamagnetic iron oxide (USPIO) was successively labeled with Ga-chloride after chelation with freshly prepared cyclic DTPA-dianhydride. The labeling efficiency of USPIOs labeled with Ga is above 98%. Sixty-five mice were killed at 13 different time points. The percentage of injected dose per gram of each organ was measured by direct counting for 19 harvested organs of the mice. The medical internal radiation dose formula was applied to extrapolate data from mouse to human and to predict the absorbed radiation dose for various organs in the human body. RESULTS: The biodistribution of Ga-USPIO in Balb/c mice showed that 75% of the injected dose accumulated in the spleen and liver 15 min after injection. These nanoparticles remained in the liver for more than 7 days after injection, whereas their clearance was very fast from other organs. Extrapolating these data to the intravenous injection of Ga-USPIO in humans gave an estimated absorbed dose of 36.38 mSv/MBq for the total body, and the highest effective absorbed dose was seen in the liver (32.9 mSv/MBq). CONCLUSION: High uptakes of USPIO nanoparticles in the liver and spleen and their fast clearance from other tissues suggest that these nanoparticles labeled with a ß-emitter radioisotope could be suitable as treatment agents for spleen and liver malignancies only if the organ tolerance dose is not exceeded.

Assessment of effective absorbed dose of (111)In-DTPA-Buserelin in human on the basis of biodistribution rat data.

In this study, the effective absorbed dose to human organs was estimated, following intra vascular administration of (111)In-DTPA-Buserelin using biodistribution data from rats. Rats were sacrificed at exact time intervals of 0.25, 0.5, 1, 2, 4 and 24 h post injections. The Medical Internal Radiation Dose formulation was applied to extrapolate from rats to humans and to project the absorbed radiation dose for various human organs. From rat data, it was estimated that a 185-MBq injection of (111)In-DTPA-Buserelin into the human might result in an estimated absorbed dose of 24.27 mGy to the total body and the highest effective absorbed dose was in kidneys, 28.39 mSv. The promising results of this study emphasises the importance of absorbed doses in humans estimated from data on rats.

Estimation of human effective absorbed dose of 67Ga-cDTPA-gonadorelin based on biodistribution rat data.

OBJECTIVE: In this investigation, we estimated the effective absorbed dose of radiation into human organs, after an intravenous administration of gallium-67 (67Ga)-labeled gonadorelin, one of the gonadotropin-releasing hormone (GnRH) agonists, using biodistribution data from injected normal rats. METHODS: Five rats were killed at exact time intervals (0.25, 0.5, 1, 2, 4, 24, and 48 h post injections) and the percentage of injected dose per gram of each organ was measured by direct counting from rat data. The Medical Internal Radiation Dose formulation was applied to extrapolate from rat to human and to project the absorbed radiation dose for various organs in humans. RESULTS: From rat data we estimated that a 185-MBq injection of 67Ga-cDTPA-GnRH into the humans might result in an estimated absorbed dose of 5.26 mGy in the whole body with the highest effective absorbed dose was in the lungs (2.73 mSv), and the organs that received the next highest doses were the bladder wall (1.59 mSv), liver (0.80 mSv), and bone marrow (0.52 mSv). CONCLUSION: The biodistribution of 67Ga-cDTPA-GnRH in rats showed high breast uptake and low muscle and blood uptake. These results suggest that it should be possible to perform early imaging of the breast anomalies and GnRH receptors indicating potential malignant lesions.