Targeting 11-beta hydroxylase with [ 131I]IMAZA – a novel approach for the treatment of advanced adrenocortical carcinoma

Introduction Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with limited treatment options. Theranostic approaches with adrenal specific radiotracers hold promise for improved diagnostics and treatment. Here, we report a new theranostic approach to advanced ACC applying (R)-1-[1-(4-[ 123I]Iodophenyl)ethyl]-1H-imidazole-5-carboxylic acid azetidinyl amide ([ 123I]IMAZA) for diagnostic imaging and [ 131I]IMAZA for radionuclide therapy. Patients and treatment 69 patients with non-resectable, metastatic ACC were screened, using a diagnostic [ 123I]IMAZA scan. Patients with significant uptake in all tumoral lesions were offered treatment with [ 131I]IMAZA. Tumor response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST version 1.1), and adverse effects were assessed by Common Toxicity Criteria (version 5.0). Results After screening, 13 patients were treated with a median of 25.7 GBq [ 131I]IMAZA (range, 18.1–30.7 GBq). Five individuals received a second treatment course. Best response was a decrease in the RECIST target lesions of 26% in two patients. Five patients with disease stabilization experienced a median progression-free survival of 14.3 months (range, 8.321.9). Median overall survival in all patients was 14.1 months (4.056.5) after therapy. Treatment was well tolerated, i.e. no severe toxicities (CTCAE grade ≥3) were observed. Conclusion In patients with advanced ACC refractory to standard therapeutic regimens, [ 131I]IMAZA treatment was associated with disease stabilization and non-significant tumour size reduction in a significant patient fraction and only limited toxicities. High [ 131I]IMAZA-uptake in tumor lesions was observed in 38.5% of patients with advanced ACC, rendering [131I] IMAZA a potential treatment option in a limited, well-defined patient fraction. Further clinical trials will be necessary to evaluate the full potential of this novel theranostic approach.

Uptake in newly approved antibiotics prescribed to patients with carbapenem-resistant Enterobacterales (CRE)

We assessed trends in treatment of patients with CRE from 2012 through 2018. We detected decreased utilization of aminoglycosides and colistin and increased utilization in extended-spectrum cephalosporins and ceftazidime-avibactam. We found significant uptake of ceftazidime-avibactam, a newly approved antibiotic, to treat CRE infections.

Biosimilar uptake of filgrastim and impact on spending in Medicare Part D from 2015 to 2019.

67 Background: The introduction of a filgrastim biosimilar in 2014 was associated with substantial cost savings in Medicare Part B and Medicaid programs. However, Medicare Part D is unique since it is unable to directly negotiate prices with drug manufacturers. We sought to investigate the uptake of filgrastim biosimilars and impact on spending among Part D beneficiaries. Methods: We evaluated utilization trends for filgrastim (Neupogen), filgrastim-sndz (Zarxio), and tbo-filgrastim (Granix) using the 2015-2019 Medicare Part D Prescription Drug Event data. We conducted a retrospective cross-sectional review of annual spending, number of beneficiaries, number of claims, spending per beneficiary, and spending per dosage unit. We excluded filgrastim-aafi (Nivestym) due to recent approval and adjusted for inflation using 2019 dollars. Results: In 2019, total aggregate Part D spending on filgrastim products was $78 million. From 2015 to 2019, the biosimilar share of total aggregate spending increased from $1.8 million (2%) to $44 million (56%), with combined biosimilar spending (Zarxio and Granix) eclipsing originator Neupogen in 2018 (within 4 years of FDA approval of Zarxio). Total spending on Neupogen reduced 58% from 2015 to 2019. While biosimilar uptake progressively increased every year, total aggregate spending on all filgrastim forms reduced only 7% from 2015 to 2019 ($84 million to $78 million). For all 3 forms, from 2015 to 2019, trends in spending were: average spending per claim ($3193 to $2549, -20%), average spending per beneficiary ($5880 to $6722, +15%), and average spending per dosage unit of filgrastim ($583 vs $571, -2%). Detailed results in Table. Conclusions: We demonstrate that the significant uptake of biosimilar filgrastim products in Medicare Part D from 2015 to 2019 was associated with a small decrease in aggregate spending, essentially unchanged per unit spending, and increased spending per beneficiary on filgrastim products. Our findings contrast with experiences across Medicare Part B and Medicaid, that demonstrated significant cost savings with biosimilar filgrastim uptake. This may be due to inability of Medicare Part D to directly negotiate prices with manufacturers (in contrast to Medicare Part B and Medicaid), supporting ongoing Congressional policy being debated in the United States Senate (H.R. 3).[Table: see text]

Phytomanagement of soil and groundwater at the Niagara Falls Storage Site (NFSS) using hybridized trees

The Manhattan Engineer District previously used the 191-acre Niagara Falls Storage Site (NFSS) in Niagara County, New York, to store radioactive residues and wastes from uranium (U) ore processing. At present, management practices will determine whether enhanced evapotranspiration rates produced by hybridized shrub willow cuttings planted in 2016 will affect groundwater hydrology. Two shrub willow varieties were planted in an approximately one-half acre area to examine growth performance along a U impacted sanitary sewer line. Additionally, control plots will compare the effectiveness of shrub willows to unplanted areas. Observations of the planted area after 18 months showed success of shrub willow growth with increasing biomass. Chemical analysis from tree tissue samples of the field study showed no significant uptake of U or thorium (Th) to date. A greenhouse study conducted in parallel to the field study tested the willows under controlled greenhouse conditions and evaluated their ability to grow and accumulate contaminants under controlled conditions. Results from the greenhouse study demonstrated that U accumulation was minimal. Thus, this study demonstrates that the shrub willows are not accumulators of U or Th, an advantageous characteristic that implies stabilized contaminants in the soil and no translocation of U into the aboveground biomass.

The ‘Netflix Original’ and what it means for the production of European television content

The European audiovisual market has unique contextual characteristics that constrain the sustainability and development of audiovisual content. Among other shifts, the rise of global subscription video-on-demand players like Netflix have been reshaping this market. Although Netflix has been investing in Europe, little is known about their actual investment strategies. This study’s goal is to analyse Netflix original investment in European scripted series and examine their implications for the European market. Based on a mapping of all European Netflix Originals, we identify four investment patterns. The analysis shows a significant uptake of Netflix investment, yet concurrently these reinforce existing discrepancies between large and small states in Europe.

First Comparison between [18f]-FMISO and [18f]-Faza for Preoperative Pet Imaging of Hypoxia in Lung Cancer

Hypoxic areas are typically resistant to treatment. However, the fluorine-18-fluoroazomycin-arabinoside (FAZA) and fluorine 18 misonidazole (FMISO) tracers have never been compared in non small cell lung cancer (NSCLC). This study compares the capability of 18F-FAZA PET/CT with that of 18F-FMISO PET/CT for detecting hypoxic tumour regions in early and locally advanced NSCLC patients. We prospectively evaluated patients who underwent preoperative PET scans before surgery for localised NSCLC (i.e., fluorodeoxyglucose (FDG)-PET, FMISO-PET, and FAZA-PET). The PET data of the three tracers were compared with each other and then compared to immunohistochemical analysis (GLUT-1, CAIX, LDH-5, and HIF1-Alpha) after tumour resection. Overall, 19 patients with a mean age of 68.2 ± 8 years were included. There were 18 lesions with significant uptake (i.e., SUVmax >1.4) for the F-MISO and 17 for FAZA. The mean SUVmax was 3 (±1.4) with a mean volume of 25.8 cc (±25.8) for FMISO and 2.2 (±0.7) with a mean volume of 13.06 cc (±13.76) for FAZA. The SUVmax of F-MISO was greater than that of FAZA (p = 0.0003). The SUVmax of F-MISO shows a good correlation with that of FAZA at 0.86 (0.66–0.94). Immunohistochemical results are not correlated to hypoxia PET regardless of the staining. The two tracers show a good correlation with hypoxia, with FMISO being superior to FAZA. FMISO, therefore, remains the reference tracer for defining hypoxic volumes.

Transfer of Cobalt Nanoparticles in a Simplified Food Web: From Algae to Zooplankton to Fish

Cobalt (Co) nanoparticles (NPs) may be diffusely dispersed into natural ecosystems from various anthropogenic sources such as traffic settings and eventually end up in aquatic systems. As environmentally dispersed Co NPs may be transferred through an aquatic food web, this study investigated this transfer from algae (Scendesmus sp.) to zooplankton (Daphnia magna) to fish (Crucian carp, Carassius carassius). Effects of interactions between naturally excreted biomolecules from D. magna and Co NPs were investigated from an environmental fate perspective. ATR-FTIR measurements showed the adsorption of both algae constituents and excreted biomolecules onto the Co NPs. Less than 5% of the Co NPs formed heteroagglomerates with algae, partly an effect of both agglomeration and settling of the Co NPs. The presence of excreted biomolecules in the solution did not affect the extent of heteroagglomeration. Despite the low extent of heteroagglomeration between Co NPs and algae, the Co NPs were transferred to the next trophic level (D. magna). The Co uptake in D. magna was 300 times larger than the control samples (without Co NP), which were not influenced by the addition of excreted biomolecules to the solution. Significant uptake of Co was observed in the intestine of the fish feeding on D. magna containing Co NPs. No bioaccumulation of Co was observed in the fish. Moreover, 10–20% of the transferred Co NP mass was dissolved after 24 h in the simulated gut solution of the zooplankton (pH 7), and 50–60% was dissolved in the simulated gut solution of the fish (pH 4). The results elucidate that Co NPs gain different properties upon trophic transfer in the food web. Risk assessments should hence be conducted on transformed and weathered NPs rather than on pristine particles.

Human Absorbed Dose Evaluation of [177Lu]Lu-IBA as a Bone Palliative Candidate

The role of lutetium-177 among bone-seeking radionuclides in targeted therapy is noteworthy. The clinical pharmacokinetics of ibandronate (IBA) indicates that this bisphonate has powerful bone mineral affinity. The aim of this study was to evaluate of [177Lu]Lu-IBA efficacy as a new compound.The [177Lu]Lu-IBA was prepared by radiolabeling of IBA ligand to 177LuCl3 that was obtained by thermal neutron irradiation of enriched Lu2O3 sample. Produced [177Lu]Lu-IBA with high radiochemical purity was administered intravenously to mice. Biodistribution data were collected at 1, 4, 24, 48 h and 7 d post injections. With calculating accumulated activities in each organ and extrapolating mouse’s organs to human’s organs by the RADAR method and using OLINDA/EXM software the injected dose in various human organs was achieved.[177Lu]Lu-IBA was produced with radiochemical purity nearly 96 %. Its biodistribution data showed the high uptake and durability in the skeletal tissues without significant uptake in other major organs.The results showed that [177Lu]Lu-IBA has considerably good properties as a bone-seeking radiopharmaceutical and therefore can be a candidate for bone pain palliative therapy in skeletal metastases; however, further biological studies are still needed.

Sub-nanometer confinement enables facile condensation of gas electrolyte for low-temperature batteries

Confining molecules in the nanoscale environment can lead to dramatic changes of their physical and chemical properties, which opens possibilities for new applications. There is a growing interest in liquefied gas electrolytes for electrochemical devices operating at low temperatures due to their low melting point. However, their high vapor pressure still poses potential safety concerns for practical usages. Herein, we report facile capillary condensation of gas electrolyte by strong confinement in sub-nanometer pores of metal-organic framework (MOF). By designing MOF-polymer membranes (MPMs) that present dense and continuous micropore (~0.8 nm) networks, we show significant uptake of hydrofluorocarbon molecules in MOF pores at pressure lower than the bulk counterpart. This unique property enables lithium/fluorinated graphite batteries with MPM-based electrolytes to deliver a significantly higher capacity than those with commercial separator membranes (~500 mAh g−1 vs. <0.03 mAh g−1) at −40 °C under reduced pressure of the electrolyte.

Preparation and Preliminary Evaluation of Neurotensin Radiolabelled with 68Ga and 177Lu as Potential Theranostic Agent for Colon Cancer

The neurotensin is a tridecapeptide involved in the proliferation of colon cancer, the overexpression of neurotensin receptors occurring at an early stage development of many tumours. Targeting neurotensin receptors by using the same biological active molecule is an effective approach for both imaging quantification and treatment. The present work aimed to demonstrate the ability of radiolabelled neurotensin to specifically target colon cancer cells, and substantiate its usefulness in targeted imaging and radiotherapy, depending on the emission of the coupled radioisotope. Syntheses of 68Ga–DOTA–NT and 177Lu–DOTA–NT were developed to obtain a level of quality suitable for preclinical use with consistent high synthesis yields. Radiochemical purity meets the pharmaceutical requirements, and it is maintained 4 h for 68Ga–DOTA–NT and 48 h for 177Lu–DOTA–NT. Extensive in vitro studies were conducted to assess the uptake and retention of 68Ga–DOTA–NT, the amount of non-specific binding of neurotensin and the effect of 177Lu–DOTA–NT on HT–29 cells. In vivo biodistribution of 68Ga–DOTA–NT revealed significant uptake at the tumour site, along with fast clearance evidenced by decreasing activity in kidneys and blood after 60 min p.i. 177Lu–DOTA–NT exhibited similar uptake in the tumour, but also a significant uptake at 14 days p.i. in the bone marrow was reported. These results successfully demonstrated the potential of neurotensin to deliver imaging/therapeutic 68Ga/177Lu radioisotopes pair, but also the need for further evaluation of the possible radiotoxicity effects on the liver, kidneys or bone marrow.