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AbstractNitrous oxide is used medically as an anesthetic agent; in the food industry as a propellant for condiments; and recreationally for its euphoric and dissociative effects. We report three cases of nitrous oxide misuse causing severe, symptomatic cobalamin (vitamin B12) deficiency in which signs of nitrous oxide use per se, as well as signs of toxicity, were observed, including characteristic palmar calluses over the metacarpal heads, and frostbite. These signs may assist clinicians in the recognition of nitrous oxide use and the timely diagnosis of nitrous oxide toxicity. [ABSTRACT FROM AUTHOR]

Introduction: Myeloid sarcoma (MS) is also known as chloroma, extramedullary acute myeloid leukemia (AML), or granulocytic sarcoma. MS is a rare extramedullary infiltration of myeloid cells, most commonly collecting in the skin and causing a small number of localized lesions. It is strongly associated with AML; however, MS more commonly occurs after diagnosis of AML is previously established or after previous treatment of AML. Case Presentation: This case describes a patient with an atypical presentation of MS with no known history of AML and up to 18 lesions identified on CT scan that were previously being monitored for months by her primary care physician. She presented with sepsis attributed to choledocholithiasis versus bacteremia from scattered abscesses versus osteomyelitis of her left knee; nonetheless, lactic acid failed to improve after common bile duct stent with biliary sphincterotomy/dilation or with incision and drainage and empiric antibiotics. Core needle biopsy of her left abdominal sidewall was eventually positive for MS, but she unfortunately developed multiorgan failure with symptomatic hypercalcemia refractory to treatment and ultimately decided to go to comfort care rather than pursue further workup and treatment. Although bone marrow biopsy was ultimately not performed to rule out synchronous AML, this is likely a case of isolated MS due to her scattered skin lesions being present for months prior to hospitalization and acute illness. Conclusion: This case highlights the importance of maintaining MS in the differential diagnosis and the importance of early diagnostic core needle biopsy for patients with persistent skin lesions of unknown origin. [ABSTRACT FROM AUTHOR]

Introduction: Until recently, interest in renal function has focused on impairment to limit drug toxicity and increase medication safety. Augmented renal clearance (ARC) has been increasingly studied in multiple patient populations, including oncology, and could lead to decreased drug efficacy from faster elimination resulting in subtherapeutic concentrations. This scoping review sought to summarize ARC literature in cancer and identify areas of research to better inform pharmacy practitioners. Data Sources: Electronic databases were searched for English articles related to augmented/enhanced renal function/clearance following a framework for scoping reviews. Data Synthesis: Fourteen articles were analyzed, divided according to article objective: descriptive studies or ARC's impact on pharmacokinetics/pharmacodynamics. ARC was most defined as creatinine clearance >130 mL/min/1.73 m2, reported in 10%-100% of patients. Febrile neutropenia in adult and pediatric patients, and age <50-65 years, hematologic malignancy, and lower serum creatinine in adult patients were notable risk factors for ARC. The impact of ARC has only been evaluated with antimicrobial agents consistently resulting in lower than anticipated trough levels. Identified gaps include: elucidation of ARC's mechanism and associated biomarkers, an inclusive ARC definition for relative renal enhancement, and study of additional drug classes to ascertain the breadth of ARC impact on drug therapy. Conclusions: ARC is proving to be a frequent phenomenon in patients with cancer which pharmacists could play a vital role. Further research is needed to better understand the impact of ARC in patient care and a potential need to stage ARC based on degree of renal enhancement to establish specific drug dosing recommendations. [ABSTRACT FROM AUTHOR]

Background: The Dynamic Collimation System (DCS) has been shown to produce superior treatment plans to uncollimated pencil beam scanning (PBS) proton therapy using an in‐house treatment planning system (TPS) designed for research. Clinical implementation of the DCS requires the development and benchmarking of a rigorous dose calculation algorithm that accounts for pencil beam trimming, performs monitor unit calculations to produce deliverable plans at all beam energies, and is ideally implemented with a commercially available TPS. Purpose: To present an analytical Pencil bEam TRimming Algorithm (PETRA) for the DCS, with and without its range shifter, implemented in the Astroid TPS (.decimal, Sanford, Florida, USA). Materials: PETRA was derived by generalizing an existing pencil beam dose calculation model to account for the DCS‐specific effects of lateral penumbra blurring due to the nickel trimmers in two different planes, integral depth dose variation due to the trimming process, and the presence and absence of the range shifter. Tuning parameters were introduced to enable agreement between PETRA and a measurement‐validated Dynamic Collimation Monte Carlo (DCMC) model of the Miami Cancer Institute's IBA Proteus Plus system equipped with the DCS. Trimmer position, spot position, beam energy, and the presence or absence of a range shifter were all used as variables for the characterization of the model. The model was calibrated for pencil beam monitor unit calculations using procedures specified by International Atomic Energy Agency Technical Report Series 398 (IAEA TRS‐398). Results: The integral depth dose curves (IDDs) for energies between 70 MeV and 160 MeV among all simulated trimmer combinations, with and without the ranger shifter, agreed between PETRA and DCMC at the 1%/1 mm 1‐D gamma criteria for 99.99% of points. For lateral dose profiles, the median 2‐D gamma pass rate for all profiles at 1.5%/1.5 mm was 99.99% at the water phantom surface, plateau, and Bragg peak depths without the range shifter and at the surface and Bragg peak depths with the range shifter. The minimum 1.5%/1.5 mm gamma pass rates for the 2‐D profiles at the water phantom surface without and with the range shifter were 98.02% and 97.91%, respectively, and, at the Bragg peak, the minimum pass rates were 97.80% and 97.5%, respectively. Conclusion: The PETRA model for DCS dose calculations was successfully defined and benchmarked for use in a commercially available TPS. [ABSTRACT FROM AUTHOR]

Simple Summary: The loss of function of the BRCA1 tumor suppressor is common in breast cancer, but experimentally, the BRCA1 inactivation promotes cell senescence. The overstimulation of RAS signaling via Her2 upregulation is also common in breast cancer, yet it can also lead to senescence. A significant percent of primary breast tumors exhibit both defects. So how do they overcome the senescence response to become successful tumors? Here we show that the RAS senescence effector NORE1A can complex with BRCA1 and that loss of NORE1A abrogates the senescence-inducing effects of Her2 and BRCA1 dysregulation. Database analysis shows that NORE1A loss of expression is common in primary breast tumors and correlates with BRCA1 loss in Her2+ but not Her2− cases. BRCA1 is a tumor suppressor with a complex mode of action. Hereditary mutations in BRCA1 predispose carriers to breast cancer, and spontaneous breast cancers often exhibit defects in BRCA1 expression. However, haploinsufficiency or suppression of BRCA1 expression leads to defects in DNA repair, which can induce DNA damage responses, leading to senescence. Activating mutation or overexpression of the Her2 oncoprotein are also frequent drivers of breast cancer. Yet, over-activation of Her2, working through the RAS oncoprotein, can also induce senescence. It is thought that additional defects in the p53 and Rb tumor suppressor machinery must occur in such tumors to allow an escape from senescence, thus permitting tumor development. Although BRCA1 mutant breast cancers are usually Her2 negative, a significant percentage of Her2 positive tumors also lose their expression of BRCA1. Such Her2+/BRCA1− tumors might be expected to have a particularly high senescence barrier to overcome. An important RAS senescence effector is the protein NORE1A, which can modulate both p53 and Rb. It is an essential senescence effector of the RAS oncoprotein, and it is often downregulated in breast tumors by promotor methylation. Here we show that NORE1A forms a Her2/RAS regulated, endogenous complex with BRCA1 at sites of replication fork arrest. Suppression of NORE1A blocks senescence induction caused by BRCA1 inactivation and Her2 activation. Thus, NORE1A forms a tumor suppressor complex with BRCA1. Its frequent epigenetic inactivation may facilitate the transformation of Her2+/BRCA1− mediated breast cancer by suppressing senescence. [ABSTRACT FROM AUTHOR]

In January 2016, a 40-year-old man sought care at a hospital in Alameda County, California, USA, with a 2-week history of progressive cough, dyspnea, pleuritic chest pain, and headache associated [...]

Objective. Pencil beam scanning (PBS) proton therapy target dose conformity can be improved with energy layer-specific collimation. One such collimator is the dynamic collimation system (DCS), which consists of four nickel trimmer blades that intercept the scanning beam as it approaches the lateral extent of the target. While the dosimetric benefits of the DCS have been demonstrated through computational treatment planning studies, there has yet to be experimental verification of these benefits for composite multi-energy layer fields. The objective of this work is to dosimetrically characterize and experimentally validate the delivery of dynamically collimated proton therapy with the DCS equipped to a clinical PBS system. Approach. Optimized single field, uniform dose treatment plans for 3 × 3 × 3 cm3 target volumes were generated using Monte Carlo dose calculations with depths ranging from 5 to 15 cm, trimmer-to-surface distances ranging from 5 to 18.15 cm, with and without a 4 cm thick polyethylene range shifter. Treatment plans were then delivered to a water phantom using a prototype DCS and an IBA dedicated nozzle system and measured with a Zebra multilayer ionization chamber, a MatriXX PT ionization chamber array, and Gafchromic™ EBT3 film. Main results. For measurements made within the SOBPs, average 2D gamma pass rates exceeded 98.5% for the MatriXX PT and 96.5% for film at the 2%/2 mm criterion across all measured uncollimated and collimated plans, respectively. For verification of the penumbra width reduction with collimation, film agreed with Monte Carlo with differences within 0.3 mm on average compared to 0.9 mm for the MatriXX PT. Significance. We have experimentally verified the delivery of DCS-collimated fields using a clinical PBS system and commonly available dosimeters and have also identified potential weaknesses for dosimeters subject to steep dose gradients. [ABSTRACT FROM AUTHOR]

Background: In a recent study, we reported beam quality correction factors, fQ, in carbon ion beams using Monte Carlo (MC) methods for a cylindrical and a parallel-plate ionization chamber (IC). A non-negligible perturbation effect was observed;however, the magnitude of the perturbation correction due to the specific IC subcomponents was not included. Furthermore, the stopping power data presented in the International Commission on Radiation Units and Measurements (ICRU) report 73 were used, whereas the latest stopping power data have been reported in the ICRU report 90. Purpose: The aim of this study was to extend our previous work by computing fQ correction factors using the ICRU 90 stopping power data and by reporting ICspecific perturbation correction factors. Possible energy or linear energy transfer (LET) dependence of the fQ correction factor was investigated by simulating both pristine beams and spread-out Bragg peaks (SOBPs). Methods: The TOol for PArticle Simulation (TOPAS)/GEANT4 MC code was used in this study. A 30 × 30 × 50 cm3 water phantom was simulated with a uniform 10 × 10 cm2 parallel beam incident on the surface. A Farmer-type cylindrical IC (Exradin A12) and two parallel-plate ICs (Exradin P11 and A11) were simulated in TOPAS using the manufacturer-provided geometrical drawings. The fQ correction factor was calculated in pristine carbon ion beams in the 150-450 MeV/u energy range at 2 cm depth and in the middle of the flat region of four SOBPs. The kQ correction factor was calculated by simulating the fQo correction factor in a 60Co beam at 5 cm depth. The perturbation correction factors due to the presence of the individual IC subcomponents, such as the displacement effect in the air cavity, collecting electrode, chamber wall, and chamber stem, were calculated at 2 cm depth for monoenergetic beams only. Additionally, the mean dose-averaged and track-averaged LET was calculated at the depths at which the fQ was calculated. Results: The ICRU 90 fQ correction factors were reported. The pdis correction factor was found to be significant for the cylindrical IC with magnitudes up to 1.70%. The individual perturbation corrections for the parallel-plate ICs were <1.0% except for the A11 pcel correction at the lowest energy. The fQ correction for the P11 IC exhibited an energy dependence of >1.00% and displayed differences up to 0.87% between pristine beams and SOBPs. Conversely, the fQ for A11 and A12 displayed a minimal energy dependence of <0.50%. The energy dependence was found to manifest in the LET dependence for the P11 IC. A statistically significant LET dependence was found only for the P11 IC in pristine beams only with a magnitude of <1.10%. Conclusions: The perturbation and kQ correction factor should be calculated for the specific IC to be used in carbon ion beam reference dosimetry as a function of beam quality. [ABSTRACT FROM AUTHOR]

Glycogen synthase kinase‐3 α/β is involved in dysregulation of neuronal tau protein in Alzheimer's disease (AD). There is an unmet clinical need for a blood‐brain barrier (BBB) permeable positron emission tomography (PET) probe for imaging of GSK‐3α/β in the brain to understand the pathogenesis of AD. Herein, we synthesized two PET probes, [18F]F‐CNBI and [18F]F‐CNPIFE, and evaluated their BBB permeability and affinity towards GSK‐3α/β. [19F]F‐CNPIFE showed higher in‐vitro binding towards GSK‐3α/β (IC50=19.4±2.5 nM; n=3, for GSK‐3α, IC50=19.4±3.8 nM; n=3, for GSK‐3β) compared to [19F]F‐CNBI (IC50=107.6±26.0 nM; n=4, for GSK‐3α, IC50=105.3±18.2 nM; n=3, for GSK‐3β). [18F]F‐CNPIFE showed 9.5‐fold higher brain uptake than [18F]F‐CNBI, in normal FVB/NJ mice, which was increased by additional 1.5‐fold on co‐administration of [19F]F‐CNPIFE with respect to [18F]F‐CNBI. Overall, [18F]F‐CNPIFE is a promising PET probe for GSK‐3α/β imaging and warrants further evaluation in an AD mouse model. [ABSTRACT FROM AUTHOR]

Purpose: The radiobiological benefits afforded by spatially fractionated (GRID) radiation therapy pairs well with the dosimetric advantages of proton therapy. Inspired by the emergence of energy‐layer specific collimators in pencil beam scanning (PBS), this work investigates how the spot spacing and collimation can be optimized to maximize the therapeutic gains of a GRID treatment while demonstrating the integration of a dynamic collimation system (DCS) within a commercial beamline to deliver GRID treatments and experimentally benchmark Monte Carlo calculation methods. Methods: GRID profiles were experimentally benchmarked using a clinical DCS prototype that was mounted to the nozzle of the IBA‐dedicated nozzle system. Integral depth dose (IDD) curves and lateral profiles were measured for uncollimated and GRID‐collimated beamlets. A library of collimated GRID dose distributions were simulated by placing beamlets within a specified uniform grid and weighting the beamlets to achieve a volume‐averaged tumor cell survival equivalent to an open field delivery. The healthy tissue sparing afforded by the GRID distribution was then estimated across a range of spot spacings and collimation widths, which were later optimized based on the radiosensitivity of the tumor cell line and the nominal spot size of the PBS system. This was accomplished by using validated models of the IBA universal and dedicated nozzles. Results: Excellent agreement was observed between the measured and simulated profiles. The IDDs matched above 98.7% when analyzed using a 1%/1‐mm gamma criterion with some minor deviation observed near the Bragg peak for higher beamlet energies. Lateral profile distributions predicted using Monte Carlo methods agreed well with the measured profiles; a gamma passing rate of 95% or higher was observed for all in‐depth profiles examined using a 3%/2‐mm criteria. Additional collimation was shown to improve PBS GRID treatments by sharpening the lateral penumbra of the beamlets but creates a trade‐off between enhancing the valley‐to‐peak ratio of the GRID delivery and the dose‐volume effect. The optimal collimation width and spot spacing changed as a function of the tumor cell radiosensitivity, dose, and spot size. In general, a spot spacing below 2.0 cm with a collimation less than 1.0 cm provided a superior dose distribution among the specific cases studied. Conclusions: The ability to customize a GRID dose distribution using different collimation sizes and spot spacings is a useful advantage, especially to maximize the overall therapeutic benefit. In this regard, the capabilities of the DCS, and perhaps alternative dynamic collimators, can be used to enhance GRID treatments. Physical dose models calculated using Monte Carlo methods were experimentally benchmarked in water and were found to accurately predict the respective dose distributions of uncollimated and DCS‐collimated GRID profiles. [ABSTRACT FROM AUTHOR]