Expanded Systematic Evidence Map for Hundreds of Per- and Polyfluoroalkyl Substances (PFAS) and Comprehensive PFAS Human Health Dashboard.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) encompass a class of chemically and structurally diverse compounds that are extensively used in industry and detected in the environment. The US Environmental Protection Agency (US EPA) 2021 PFAS Strategic Roadmap describes national research plans to address the challenge of PFAS. OBJECTIVES: Systematic Evidence Map (SEM) methods were used to survey and summarize available epidemiological and mammalian bioassay evidence that could inform human health hazard identification for a set of 345 PFAS that were identified by the US EPA's Center for Computational Toxicology and Exposure (CCTE) for in vitro toxicity and toxicokinetic assay testing and through interagency discussions on PFAS of interest. This work builds from the 2022 evidence map that collated evidence on a separate set of ∼150 PFAS. Like our previous work, this SEM does not include PFAS that are the subject of ongoing or completed assessments at the US EPA. METHODS: SEM methods were used to search, screen, and inventory mammalian bioassay and epidemiological literature from peer-reviewed and gray literature sources using manual review and machine-learning software. For each included study, study design details and health end points examined were summarized in interactive web-based literature inventories. Some included studies also underwent study evaluation and detailed extraction of health end point data. All underlying data is publicly available online as interactive visuals with downloadable metadata. RESULTS: More than 13,000 studies were identified from scientific databases. Screening processes identified 121 mammalian bioassay and 111 epidemiological studies that met screening criteria. Epidemiological evidence (available for 12 PFAS) mostly assessed the reproductive, endocrine, developmental, metabolic, cardiovascular, and immune systems. Mammalian bioassay evidence (available for 30 PFAS) commonly assessed effects in the reproductive, whole-body, nervous, and hepatic systems. Overall, 41 PFAS had evidence across mammalian bioassay and epidemiology data streams (roughly 11% of searched chemicals). DISCUSSION: No epidemiological and/or mammalian bioassay evidence were identified for most of the PFAS included in our search. Results from this SEM, our 2022 SEM on ∼150 PFAS, and other PFAS assessment products from the US EPA are compiled into a comprehensive PFAS dashboard that provides researchers and regulators an overview of the current PFAS human health landscape including data gaps and can serve as a scoping tool to facilitate prioritization of PFAS-related research and/or risk assessment activities. https://doi.org/10.1289/EHP13423.

Guidance on protocol development for EFSA generic scientific assessments.

EFSA Strategy 2027 outlines the need for fit-for-purpose protocols for EFSA generic scientific assessments to aid in delivering trustworthy scientific advice. This EFSA Scientific Committee guidance document helps address this need by providing a harmonised and flexible framework for developing protocols for EFSA generic assessments. The guidance replaces the 'Draft framework for protocol development for EFSA's scientific assessments' published in 2020. The two main steps in protocol development are described. The first is problem formulation, which illustrates the objectives of the assessment. Here a new approach to translating the mandated Terms of Reference into scientifically answerable assessment questions and sub-questions is proposed: the 'APRIO' paradigm (Agent, Pathway, Receptor, Intervention and Output). Owing to its cross-cutting nature, this paradigm is considered adaptable and broadly applicable within and across the various EFSA domains and, if applied using the definitions given in this guidance, is expected to help harmonise the problem formulation process and outputs and foster consistency in protocol development. APRIO may also overcome the difficulty of implementing some existing frameworks across the multiple EFSA disciplines, e.g. the PICO/PECO approach (Population, Intervention/Exposure, Comparator, Outcome). Therefore, although not mandatory, APRIO is recommended. The second step in protocol development is the specification of the evidence needs and the methods that will be applied for answering the assessment questions and sub-questions, including uncertainty analysis. Five possible approaches to answering individual (sub-)questions are outlined: using evidence from scientific literature and study reports; using data from databases other than bibliographic; using expert judgement informally collected or elicited via semi-formal or formal expert knowledge elicitation processes; using mathematical/statistical models; and - not covered in this guidance - generating empirical evidence ex novo. The guidance is complemented by a standalone 'template' for EFSA protocols that guides the users step by step through the process of planning an EFSA scientific assessment.

Intravascular Lymphoma as a Cause of Recurrent Strokes - Case Report and Review of the Literature.

Background: Intravascular lymphoma is an uncommon cause of ischemic strokes. Because of its rarity and atypical pattern, most diagnoses are made post-mortem. Case study: We present a case of a 68-year-old male with multiple cardiovascular risk factors and recent SARS-CoV-2 infection who presented with recurrent strokes. Because of his stroke risk factors, he was initially managed with a sequentially escalating antithrombotic regimen. A malignant process was low on the differential at this point given his lack of systemic symptoms. When he continued to have new strokes despite these measures, including a spinal cord infarct, a broad workup was sent including for hypercoagulable states, vasculitis, and intravascular lymphoma. Eventually, a skin biopsy of a cherry angioma returned positive for lymphoma cells. He was treated with methotrexate followed by chemotherapy and rituximab. Unfortunately, he did not improve and was made comfort measures only by his family. Conclusion: This case illustrates the importance of considering intravascular lymphoma as a potential etiology of recurrent strokes, as early diagnosis and treatment are important for preventing irreversible neurological damage.

PIM1 phosphorylates ABI2 to enhance actin dynamics and promote tumor invasion.

Distinguishing key factors that drive the switch from indolent to invasive disease will make a significant impact on guiding the treatment of prostate cancer (PCa) patients. Here, we identify a novel signaling pathway linking hypoxia and PIM1 kinase to the actin cytoskeleton and cell motility. An unbiased proteomic screen identified Abl-interactor 2 (ABI2), an integral member of the wave regulatory complex (WRC), as a PIM1 substrate. Phosphorylation of ABI2 at Ser183 by PIM1 increased ABI2 protein levels and enhanced WRC formation, resulting in increased protrusive activity and cell motility. Cell protrusion induced by hypoxia and/or PIM1 was dependent on ABI2. In vivo smooth muscle invasion assays showed that overexpression of PIM1 significantly increased the depth of tumor cell invasion, and treatment with PIM inhibitors significantly reduced intramuscular PCa invasion. This research uncovers a HIF-1-independent signaling axis that is critical for hypoxia-induced invasion and establishes a novel role for PIM1 as a key regulator of the actin cytoskeleton.

An XBP1s-PIM-2 positive feedback loop controls IL-15-mediated survival of natural killer cells.

Spliced X-box-binding protein 1 (XBP1s) is an essential transcription factor downstream of interleukin-15 (IL-15) and AKT signaling, which controls cell survival and effector functions of human natural killer (NK) cells. However, the precise mechanisms, especially the downstream targets of XBP1s, remain unknown. In this study, by using XBP1 conditional knockout mice, we found that XBP1s is critical for IL-15-mediated NK cell survival but not proliferation in vitro and in vivo. Mechanistically, XBP1s regulates homeostatic NK cell survival by targeting PIM-2, a critical anti-apoptotic gene, which in turn stabilizes XBP1s protein by phosphorylating it at Thr58. In addition, XBP1s enhances the effector functions and antitumor immunity of NK cells by recruiting T-bet to the promoter region of Ifng. Collectively, our findings identify a previously unknown mechanism by which IL-15-XBP1s signaling regulates the survival and effector functions of NK cells.

Spoke-administered thrombolysis improves large vessel occlusion early recanalization: the real-world experience of a large academic hub-and-spoke telestroke network.

Introduction: Intravenous thrombolysis (IVT) prior to mechanical thrombectomy (MT) for large vessel occlusion (LVO) stroke is increasingly controversial. Recent trials support MT without IVT for patients presenting directly to MT-capable "hub" centers. However, bypassing IVT has not been evaluated for patients presenting to IVT-capable "spoke" hospitals that require hub transfer for MT. A perceived lack of efficacy of IVT to result in LVO early recanalization (ER) is often cited to support bypassing IVT, but ER data for IVT in patients that require interhospital transfer is limited. Here we examined LVO ER rates after spoke-administered IVT in our hub-and-spoke stroke network. Methods: Patients presenting to 25 spokes before hub transfer for MT consideration from 2018-2020 were retrospectively identified from a prospectively maintained database. Inclusion criteria were pre-transfer CTA-defined LVO, ASPECTS ≥6, and post-transfer repeat vessel imaging. Results: Of 167 patients, median age was 69 and 51% were female. 76 received spoke IVT (+spokeIVT) and 91 did not (-spokeIVT). Alteplase was the only IVT used in this study. Comorbidities and NIHSS were similar between groups. ER frequency was increased 7.2-fold in +spokeIVT patients [12/76 (15.8%) vs. 2/91 (2.2%), P<0.001]. Spoke-administered IVT was independently associated with ER (aOR=11.5, 95% CI=2.2,99.6, p<0.05) after adjusting for timing of last known well, interhospital transfer, and repeat vessel imaging. Interval NIHSS was improved in patients with ER (median -2 (IQR -6.3, -0.8) vs. 0 (-2.5, 1), p<0.05). Conclusion: Within our network, +spokeIVT patients had a 7.2-fold increased ER relative likelihood. This real-world analysis supports IVT use in eligible patients with LVO at spoke hospitals before hub transfer for MT.

In a hub-and-spoke network, spoke-administered thrombolysis reduces mechanical thrombectomy procedure time and number of passes.

BACKGROUND: The utility of intravenous thrombolysis (IVT) prior to mechanical thrombectomy (MT) in large vessel occlusion stroke (LVO) is controversial. Some data suggest IVT increases MT technical difficulty. Within our hub-and-spoke telestroke network, we examined how spoke-administered IVT affected hub MT procedure time and pass number. METHODS: Patients presenting to 25 spoke hospitals who were transferred to the hub and underwent MT from 2018 to 2020 were identified from a prospectively maintained database. MT procedure time, fluoroscopy time, and pass number were obtained from operative reports. RESULTS: Of 107 patients, 48 received IVT at spokes. Baseline characteristics and NIHSS were similar. The last known well (LKW)-to-puncture time was shorter among IVT patients (4.3 ± 1.9 h vs. 10.5 ± 6.5 h, p < 0.0001). In patients that received IVT, mean MT procedure time was decreased by 18.8 min (50.5 ± 29.4 vs. 69.3 ± 46.7 min, p = 0.02) and mean fluoroscopy time was decreased by 11.3 min (21.7 ± 15.8 vs. 33.0 ± 30.9 min, p = 0.03). Furthermore, IVT-treated patients required fewer MT passes (median 1 pass [IQR 1.0, 1.80] vs. 2 passes [1.0, 2.3], p = 0.0002) and were more likely to achieve reperfusion in ≤2 passes (81.3% vs. 59.3%, p = 0.01). An increased proportion of IVT-treated patients achieved TICI 2b-3 reperfusion after MT (93.9% vs. 83.8%, p = 0.045). There were no associations between MT procedural characteristics and LKW-to-puncture time. CONCLUSION: Within our network, hub MT following spoke-administered IVT was faster, required fewer passes, and achieved improved reperfusion. This suggests spoke-administered IVT does not impair MT, but instead may enhance it.

Synthesis of 2-Oxoquinoline Derivatives as Dual Pim and mTORC Protein Kinase Inhibitors.

Compound VBT-5445 was identified as an inhibitor to block the association of Pim and the protein Enhancer of Decapping 3 (EDC3), a Pim substrate, which normally functions to enhance the decapping of messenger RNA (mRNA). It was also shown to inhibit both the Pim and mTORC protein kinases. The activity of this compound class can be fine-tuned by structural modification. A series of VBT analogs were designed, synthesized, and evaluated. These compounds decrease the growth of multiple cancer types, including pancreas, prostate, breast, lung, and leukemia. Notably, 6-methyl (GRG-1-31, 6d), 4-Bromo (GRG-1-34, 6e), 4-Chloro (GRG-1-35, 6f), and phenylthio substituted (GRG-1-104, 6n) derivatives are highly potent at inhibiting tumor growth. The ability of these compounds to block cancer growth in vitro is highly correlated with their activity as mTORC inhibitors. The toxicity of GRG 1-34 is low in mice treated with twice-daily gavage for 30 days and did not induce weight loss. Pharmacokinetics of a single oral dose demonstrated a peak concentration at 0.5 hours after gavage. In summary, further development of this compound class has the potential to inhibit important signaling pathways and impact cancer treatment.

Characterizing reasons for stroke thrombectomy ineligibility among potential candidates transferred in a hub-and-spoke network.

Background: Access to endovascular thrombectomy (EVT) is relatively limited. Hub-and-spoke networks seek to transfer appropriate large vessel occlusion (LVO) candidates to EVT-capable hubs. However, some patients are ineligible upon hub arrival, and factors that drive transfer inefficiencies are not well described. We sought to quantify EVT transfer efficiency and identify reasons for EVT ineligibility. Methods: Consecutive EVT candidates presenting to 25 spokes from 2018-2020 with pre-transfer CTA-defined LVO and ASPECTS ≥6 were identified from a prospectively maintained database. Outcomes of interest included hub EVT, reasons for EVT ineligibility, and 90-day modified Rankin Scale (mRS) ≤2. Results: Among 258 patients, the median age was 70 years (IQR 60-81); 50% were female. 56% were ineligible for EVT after hub arrival. Cited reasons were large established infarct (49%), mild symptoms (33%), recanalization (6%), distal occlusion (5%), sub-occlusive lesion (3%), and goals of care (3%). Late window patients [last known well (LKW) >6 hours] were more likely to be ineligible (67% vs 43%, P<0.0001). EVT ineligible patients were older (73 vs 68 years, p=0.04), had lower NIHSS (10 vs 16, p<0.0001), longer LKW-hub arrival time (8.4 vs 4.6 hours, p<0.0001), longer spoke Telestroke consult-hub arrival time (2.8 vs 2.2 hours, p<0.0001), and received less intravenous thrombolysis (32% vs 45%, p=0.04) compared to eligible patients. EVT ineligibility independently reduced the odds of 90-day mRS≤2 (aOR=0.26, 95%CI=0.12,0.56; p=0.001) when controlling for age, NIHSS, and LKW-hub arrival time. Conclusions: Among patients transferred for EVT, there are multiple reasons for ineligibility upon hub arrival, with most excluded for infarct growth and mild symptoms. Understanding factors that drive transfer inefficiencies is important to improve EVT access and outcomes.

Systematic evidence map (SEM) template: Report format and methods used for the US EPA Integrated Risk Information System (IRIS) program, Provisional Peer Reviewed Toxicity Value (PPRTV) program, and other "fit for purpose" literature-based human health analyses.

BACKGROUND: Systematic evidence maps (SEMs) are gaining visibility in environmental health for their utility to serve as problem formulation tools and assist in decision-making, especially for priority setting. SEMs are now routinely prepared as part of the assessment development process for the US Environmental Protection Agency (EPA) Integrated Risk Information System (IRIS) and Provisional Peer Reviewed Toxicity Value (PPRTV) assessments. SEMs can also be prepared to explore the available literature for an individual chemical or groups of chemicals of emerging interest. OBJECTIVES: This document describes the typical methods used to produce SEMs for the IRIS and PPRTV Programs, as well as "fit for purpose" applications using a variety of examples drawn from existing analyses. It is intended to serve as an example base template that can be adapted as needed for the specific SEM. The presented methods include workflows intended to facilitate rapid production. The Populations, Exposures, Comparators and Outcomes (PECO) criteria are typically kept broad to identify mammalian animal bioassay and epidemiological studies that could be informative for human hazard identification. In addition, a variety of supplemental content is tracked, e.g., studies presenting information on in vitro model systems, non-mammalian model systems, exposure-level-only studies in humans, pharmacokinetic models, and absorption, distribution, metabolism, and excretion (ADME). The availability of New Approach Methods (NAMs) evidence is also tracked (e.g., high throughput, transcriptomic, in silico, etc.). Genotoxicity studies may be considered as PECO relevant or supplemental material, depending on the topic and context of the review. Standard systematic review practices (e.g., two independent reviewers per record) and specialized software applications are used to search and screen the literature and may include the use of machine learning software. Mammalian bioassay and epidemiological studies that meet the PECO criteria after full-text review are briefly summarized using structured web-based extraction forms with respect to study design and health system(s) assessed. Extracted data is available in interactive visual formats and can be downloaded in open access formats. Methods for conducting study evaluation are also presented which is conducted on a case-by-case basis, depending on the usage of the SEM.

Development of an Evidence-Based Risk Assessment Framework.

Assessment of potential human health risks associated with environmental and other agents requires careful evaluation of all available and relevant evidence for the agent of interest, including both data-rich and data-poor agents. With the advent of new approach methodologies in toxicological risk assessment, guidance on integrating evidence from mul-tiple evidence streams is needed to ensure that all available data is given due consideration in both qualitative and quantitative risk assessment. The present report summarizes the discussions among academic, government, and private sector participants from North America and Europe in an international workshop convened to explore the development of an evidence-based risk assessment framework, taking into account all available evidence in an appropriate manner in order to arrive at the best possible characterization of potential human health risks and associated uncertainty. Although consensus among workshop participants was not a specific goal, there was general agreement on the key consider-ations involved in evidence-based risk assessment incorporating 21st century science into human health risk assessment. These considerations have been embodied into an overarching prototype framework for evidence integration that will be explored in more depth in a follow-up meeting.

Use of systematic evidence maps within the US environmental protection agency (EPA) integrated risk information system (IRIS) program: Advancements to date and looking ahead.

Systematic evidence maps (SEMs) are increasingly used to inform decision-making and risk management priority-setting and to serve as problem formulation tools to refine the focus of questions that get addressed in full systematic reviews. Within the U.S. Environmental Protection Agency (EPA) Office of Research and Development (ORD) Integrated Risk Information System (IRIS), SEMs have been used to inform data gaps, determine the need for updated assessments, inform assessment priorities, and inform development of study evaluation considerations, among other uses. Increased utilization of SEMs across the environmental health field has the potential to increase transparency and efficiency for data gathering, problem formulation, read-across, and evidence surveillance. Use of the SEM templates published in the companion text (Thayer et al.) can promote harmonization in the environmental health community and create more opportunities for sharing extracted content.

OER-073: A multicenter phase 2 study evaluating the role of pazopanib in angiosarcoma.

BACKGROUND: Angiosarcomas are rare mesenchymal sarcomas that can present as primary cutaneous or noncutaneous disease. They express a variety of vascular endothelial growth factor receptors. The authors hypothesized that the treatment of angiosarcoma with pazopanib, a multikinase inhibitor with activity against vascular endothelial growth factor receptors, would result in disease response and prolonged disease stabilization. METHODS: This was an open-label, phase 2 trial of pazopanib in patients who had incurable angiosarcoma. The co-primary end points were response according to the Response Evaluation Criteria in Solid Tumors and progression-free survival (PFS) at 3 months. The starting dose of pazopanib was 800 mg daily. RESULTS: Twenty-nine patients were accrued between 2011 and 2018, and 22 patients were evaluable for response. Toxicities were similar to those identified in prior reports. There was one partial response (3%), and the clinical benefit rate (including complete responses, partial responses, and stable disease) was 48%, which was observed more frequently in patients who had cutaneous disease. The median PFS was 14.4 weeks, and the 3-month PFS rate determined by Kaplan-Meier estimate was 54.6% (95% CI, 36.0%-82.9%), meeting the primary study objective. The Kaplan-Meier overall survival estimate was 16.1 months. CONCLUSIONS: Pazopanib therapy in patients who had incurable angiosarcoma was associated with meaningful disease control, especially in those who had cutaneous disease with limited objective responses. LAY SUMMARY: Angiosarcoma is a rare cancer that can be found on the skin or in internal organs. This study tested pazopanib, an oral targeted medication, to determine its benefit in patients with angiosarcoma who could not undergo the removal of their tumors by surgery. Pazopanib treatment was safe, and no new side effects were reported. The study showed that pazopanib controlled tumor growth in one half of patients at 3 months and was more common in angiosarcomas of the skin; it led to tumor shrinkage in a minority of patients (1 of 29).

Homotopic contralesional excitation suppresses spontaneous circuit repair and global network reconnections following ischemic stroke.

Understanding circuit-level manipulations that affect the brain's capacity for plasticity will inform the design of targeted interventions that enhance recovery after stroke. Following stroke, increased contralesional activity (e.g. use of the unaffected limb) can negatively influence recovery, but it is unknown which specific neural connections exert this influence, and to what extent increased contralesional activity affects systems- and molecular-level biomarkers of recovery. Here, we combine optogenetic photostimulation with optical intrinsic signal imaging to examine how contralesional excitatory activity affects cortical remodeling after stroke in mice. Following photothrombosis of left primary somatosensory forepaw (S1FP) cortex, mice either recovered spontaneously or received chronic optogenetic excitation of right S1FP over the course of 4 weeks. Contralesional excitation suppressed perilesional S1FP remapping and was associated with abnormal patterns of stimulus-evoked activity in the unaffected limb. This maneuver also prevented the restoration of resting-state functional connectivity (RSFC) within the S1FP network, RSFC in several networks functionally distinct from somatomotor regions, and resulted in persistent limb-use asymmetry. In stimulated mice, perilesional tissue exhibited transcriptional changes in several genes relevant for recovery. Our results suggest that contralesional excitation impedes local and global circuit reconnection through suppression of cortical activity and several neuroplasticity-related genes after stroke, and highlight the importance of site selection for targeted therapeutic interventions after focal ischemia.

Systematic Evidence Map for Over One Hundred and Fifty Per- and Polyfluoroalkyl Substances (PFAS).

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are a large class of synthetic (man-made) chemicals widely used in consumer products and industrial processes. Thousands of distinct PFAS exist in commerce. The 2019 U.S. Environmental Protection Agency (U.S. EPA) Per- and Polyfluoroalkyl Substances (PFAS) Action Plan outlines a multiprogram national research plan to address the challenge of PFAS. One component of this strategy involves the use of systematic evidence map (SEM) approaches to characterize the evidence base for hundreds of PFAS. OBJECTIVE: SEM methods were used to summarize available epidemiological and animal bioassay evidence for a set of ∼150 PFAS that were prioritized in 2019 by the U.S. EPA's Center for Computational Toxicology and Exposure (CCTE) for in vitro toxicity and toxicokinetic assay testing. METHODS: Systematic review methods were used to identify and screen literature using manual review and machine-learning software. The Populations, Exposures, Comparators, and Outcomes (PECO) criteria were kept broad to identify mammalian animal bioassay and epidemiological studies that could inform human hazard identification. A variety of supplemental content was also tracked, including information on in vitro model systems; exposure measurement-only studies in humans; and absorption, distribution, metabolism, and excretion (ADME). Animal bioassay and epidemiology studies meeting PECO criteria were summarized with respect to study design, and health system(s) were assessed. Because animal bioassay studies with ≥21-d exposure duration (or reproductive/developmental study design) were most useful to CCTE analyses, these studies underwent study evaluation and detailed data extraction. All data extraction is publicly available online as interactive visuals with downloadable metadata. RESULTS: More than 40,000 studies were identified from scientific databases. Screening processes identified 44 animal and 148 epidemiology studies from the peer-reviewed literature and 95 animal and 50 epidemiology studies from gray literature that met PECO criteria. Epidemiological evidence (available for 15 PFAS) mostly assessed the reproductive, endocrine, developmental, metabolic, cardiovascular, and immune systems. Animal evidence (available for 40 PFAS) commonly assessed effects in the reproductive, developmental, urinary, immunological, and hepatic systems. Overall, 45 PFAS had evidence across animal and epidemiology data streams. DISCUSSION: Many of the ∼150 PFAS were data poor. Epidemiological and animal evidence were lacking for most of the PFAS included in our search. By disseminating this information, we hope to facilitate additional assessment work by providing the initial scoping literature survey and identifying key research needs. Future research on data-poor PFAS will help support a more complete understanding of the potential health effects from PFAS exposures. https://doi.org/10.1289/EHP10343.

Dysarthria-Facial Paresis and Rostral Pontine Ischemic Stroke.

We describe an acute, postoperative dysarthria-facial paresis. While the rare stroke syndrome has been described previously, we present an under-described clinical nuance to its presentation with a particularly clear imaging correlation. A 78-year-old, right-handed man with a past medical history of aortic stenosis presented after a transcatheter aortic valve replacement. Immediately postoperatively, no neurological deficits were noted. That evening, he described his speech as "drunken." He was later noted to have a right lower facial droop in addition to the speech change. His speech exhibited labial, lingual, and (to a lesser degree) guttural dysarthria. At the patient's request due to claustrophobia, he received 2 mg of oral lorazepam prior to cranial imaging. Afterwards, he was sleepy but arousable, yet was unable to put pen to paper when asked to write. Right lower facial paresis persisted, but he now demonstrated a right pronator drift, which resolved after 14 h without other evolution to his clinical examination. Brainstem lesions above the level of the pontine facial nucleus may present with central facial paresis contralateral to the lesion. An associated dysarthria may have both labial and lingual features in the absence of tongue or pharyngeal weakness. Our review of reported cases of dysarthria in isolation, dysarthria in combination with facial paresis, and facial paresis finds that all presentations may result from cortical, subcortical, or brainstem involvement. Stroke mechanisms are most commonly thromboembolic or small-vessel-ischemic in either the anterior or posterior circulations.

Transitioning ifosfamide chemotherapy regimens to the ambulatory setting: reviewing cost savings and safety profile.

PURPOSE: To characterize and compare both the outcome and cost of treatment of outpatient (OP) and inpatient (IP) ifosfamide therapy. METHODS: A single-center retrospective chart review of patients 18 years and older receiving ifosfamide therapy. The primary endpoint compares and evaluates the side effect profiles of ifosfamide-treated patients in the OP/IP settings. The adverse event grading system was characterized using the CTCAE Version 5.0. The highest grade was documented per cycle. The secondary endpoint of this study compares the costs of OP/IP therapy. It was assumed that the cost of medication was equivalent for IP/OP treatments. The cost saved with OP administration was determined by the average cost of hospital stay for IP admission. RESULTS: Ifosfamide therapy of 86 patients (57 OP, 29 IP) was reviewed. The predominant OP regimens were doxorobucin-ifosfamide-mesna (AIM) with 43.9% and ifosfamide-etoposide (IE) with 29.8%. Grade 4 anemia, thrombocytopenia, and neutropenia were most frequent in IP vs OP therapies (22.9% IP vs 4.3% OP, 21.6% IP vs 9.2% OP, and 22.8% IP vs 19.6% OP respectively). Neutropenic fever (NF) occurred in 20 OP patients which were predominantly treated with AIM or IE and led to average hospital stay of 6 days. Neurotoxicity, treated with methylene blue (MB) occurred in 4 OP patients. OP therapy saved a total of 783 hospital days, leading to a cost savings of $2,103,921. CONCLUSIONS: Transitioning ifosfamide to the OP setting is feasible for academic and community infusion centers with the OP administration being safe, well-tolerated, and associated with decreased total cost of care. The current processes allow for safe transition of chemotherapy of chemotherapy under times of COVID.