The Radiosurgery Society Case-Based Discussion of the Management of Head and Neck or Skull Base Paragangliomas with Stereotactic Radiosurgery and Radiotherapy.

Stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (FSRT) have been used for the treatment of head and neck or skull base paraganglioma for a considerable time, demonstrating promising local control rates and a favorable safety profile compared with surgical approaches. Nevertheless, the choice of treatment must be carefully tailored to each patient's preferences, tumor location, and size, as well as anticipated treatment-related morbidity. This case-based review serves as a practical and concise guide for the use of SRS and FSRT in the management of head and neck or skull base paragangliomas, providing information on the diagnosis, treatment, follow-up considerations, and potential pitfalls.

Distance Traveled by Patients Globally to Access Radiation Therapy: A Systematic Review.

PURPOSE: This study aimed to systematically review the literature on the travel patterns of patients seeking radiation therapy globally. It examined the distance patients travel for radiation therapy as well as secondary outcomes, including travel time. METHODS AND MATERIALS: A comprehensive search of 4 databases was conducted from June 2022 to August 2022. Studies were included in the review if they were observational, retrospective, randomized/nonrandomized, published between June 2000 and June 2022, and if they reported on the global distance traveled for radiation therapy in the treatment of malignant or benign disease. Studies were excluded if they did not report travel distance or were not written in English. RESULTS: Of the 168 studies, most were conducted in North America (76.3%), with 90.7% based in the United States. Radiation therapy studies for treating patients with breast cancer were the most common (26.6%), while external beam radiation therapy was the most prevalent treatment modality (16.6%). Forty-six studies reported the mean distance traveled for radiation therapy, with the shortest being 4.8 miles in the United States and the longest being 276.5 miles in Iran. It was observed that patients outside of the United States traveled greater distances than those living within the United States. Geographic location, urban versus rural residence, and patient population characteristics affected the distance patients traveled for radiation therapy. CONCLUSIONS: This systematic review provides the most extensive summary to date of the travel patterns of patients seeking radiation therapy globally. The results suggest that various factors may contribute to the variability in travel distance patterns, including treatment center location, patient residence, and treatment modality. Overall, the study highlights the need for more research to explore these factors and to develop effective strategies for improving radiation therapy access and reducing travel burden.

Online Adaptive Radiation Therapy and Opportunity Cost.

Purpose: Changes in patient anatomy and tumor geometry pose a challenge to ensuring consistent target coverage and organ-at-risk sparing; online adaptive radiation therapy (ART) accounts for these interfractional changes by facilitating replanning before each treatment. This project explored the opportunity cost of computed tomography (CT)-based online ART by evaluating time and human resource requirements. Time-driven activity-based costing (TDABC) was employed to determine the cost of this time to assess if the dosimetric benefit is worthwhile. Methods and Materials: CT-based online ART was recently employed at our institution and has been used to treat pelvic disease sites (prostate, prostate bed, prostate with nodal coverage, bladder, rectum); data points from all adaptively treated patients (415 fractions) were used. Time taken for each adaptive fraction before treatment, which at our facility is best represented by the duration between 2 cone beam CT scans, was used as a broadly applicable and transferable metric, representing the additional time required for ART on top of standard image guided radiation therapy. Dosimetric effect was also considered by taking the difference of planning target volume V100% for the scheduled and adapted plans. Using recently validated TDABC at this facility, the per fraction cost of ART was determined, reflecting the added cost of ART on top of image guided radiation therapy. Results: A median time of 15.97 (interquartile range, 13.23-18.83) additional minutes was required for each adaptive fraction. TDABC demonstrated an average minimum cost per adapted fraction of $103.58. Dosimetric differences between V100% of the scheduled versus adapted plan showed a mean dosimetric difference of 15.8%. Conclusions: Although online ART decreases the uncertainty of anatomic shifts, each adaptive fraction requires more staff time, delaying completion of other tasks and increasing resource utilization. Although toxicity benefits require further studies, the implementation of progressively complex radiation therapy technologies, like ART, requires consideration of the time and human resource requirements and subsequent opportunity cost.

Residents Across the Globe: A Call for Education, Advocacy, and Collaboration.

The fallout from the COVID-19 pandemic and the war in Ukraine have resulted in unprecedented delays in cancer care. The Global Coalition for Radiotherapy (GCR) has been working to alleviate this backlog and has been functioning as an emergency task force in Ukraine. Not only have patients been displaced by the war, but trainees and physicians have been greatly impacted as well. Given that radiation is needed to treat over half of all cancer cases, it is imperative to advocate for radiation oncology as a field and collaborate globally, especially as trainees.

The Use of Low-Dose Radiation Therapy in Osteoarthritis: A Review.

Despite its clinical use and investigation in other countries, low dose radiation therapy (LDRT) in the treatment of osteoarthritis (OA) is minimally used in the United States (US). Numerous recent studies published outside the US have shown moderate to long-term pain relief and improvement of mobility after treatment with LDRT for joints affected by OA. Here, we review the most recent literature published on the use of LDRT in OA. We provide a brief outline on the epidemiology, pathophysiology, current treatments, and health care burden of OA within the US. We provide a brief history of the historic use of LDRT in the US as well as a history of LDRT within the modern era of radiation oncology, discuss criticisms of LDRT including recently published randomized trials questioning its benefit as well as the risk of secondary malignancy from LDRT, and provide an outline of treatment planning considerations and recommendations regarding dose and fractionation, energy, beam arrangements, and immobilization techniques. LDRT has been shown to be a cost-effective, noninvasive treatment with minimal side effects. Further investigation into the potential role in the treatment of OA with modern LDRT is recommended.

Platelet MHC class I mediates CD8+ T-cell suppression during sepsis.

Circulating platelets interact with leukocytes to modulate host immune and thrombotic responses. In sepsis, platelet-leukocyte interactions are increased and have been associated with adverse clinical events, including increased platelet-T-cell interactions. Sepsis is associated with reduced CD8+ T-cell numbers and functional responses, but whether platelets regulate CD8+ T-cell responses during sepsis remains unknown. In our current study, we systemically evaluated platelet antigen internalization and presentation through major histocompatibility complex class I (MHC-I) and their effects on antigen-specific CD8+ T cells in sepsis in vivo and ex vivo. We discovered that both human and murine platelets internalize and proteolyze exogenous antigens, generating peptides that are loaded onto MHC-I. The expression of platelet MHC-I, but not platelet MHC-II, is significantly increased in human and murine platelets during sepsis and in human megakaryocytes stimulated with agonists generated systemically during sepsis (eg, interferon-γ and lipopolysaccharide). Upregulation of platelet MHC-I during sepsis increases antigen cross-presentation and interactions with CD8+ T cells in an antigen-specific manner. Using a platelet lineage-specific MHC-I-deficient mouse strain (B2Mf/f-Pf4Cre), we demonstrate that platelet MHC-I regulates antigen-specific CD8+ T-cell proliferation in vitro, as well as the number and functional responses of CD8+ T cells in vivo, during sepsis. Loss of platelet MHC-I reduces sepsis-associated mortality in mice in an antigen-specific setting. These data identify a new mechanism by which platelets, through MHC-I, process and cross-present antigens, engage antigen-specific CD8+ T cells, and regulate CD8+ T-cell numbers, functional responses, and outcomes during sepsis.

Sequence Changes Modulate Peptoid Self-Association in Water.

Peptoids, N-substituted glycine oligomers, are a class of diverse and sequence-specific peptidomimetics with wide-ranging applications. Advancing the functional repertoire of peptoids to emulate native peptide and protein functions requires engineering peptoids that adopt regular secondary and tertiary structures. An understanding of how changes to peptoid sequence change structural features, particularly in water-soluble systems, is underdeveloped. To address this knowledge gap, five 15-residue water-soluble peptoids that include naphthalene-functionalized side chains were designed, prepared, and subjected to a structural study using a palette of techniques. Peptoid sequence designs were based on a putative amphiphilic helix peptoid bearing structure-promoting (S)-N-(1-naphthylethyl)glycine residues whose self-association in water has been studied previously. New peptoid variants reported here include sequence changes that influenced peptoid conformational flexibility, functional group patterning (amphiphilicity), and hydrophobicity. Peptoid structures were evaluated and compared using circular dichroism spectroscopy, fluorescence spectroscopy, and size exclusion chromatography. Spectral data confirmed that sequence changes alter peptoids' degree of assembly and the organization of self-assembled structures in aqueous solutions. Insights gained in these studies will inform the design of new water-soluble peptoids with regular structural features, including desirable higher-order (tertiary and quaternary) structural features.

The human platelet transcriptome and proteome is altered and pro-thrombotic functional responses are increased during prolonged hypoxia exposure at high altitude.

Exposure to hypoxia, through ascension to high altitudes (HAs), air travel, or human disease, is associated with an increased incidence of thrombosis in some settings. Mechanisms underpinning this increased thrombosis risk remain incompletely understood, and the effects of more sustained hypoxia on the human platelet molecular signature and associated functional responses have never been examined. We examined the effects of prolonged (≥2 months continuously) hypobaric hypoxia on platelets isolated from subjects residing at HA (3,700 meters) and, for comparison, matched subjects residing under normoxia conditions at sea level (50 meters). Using complementary transcriptomic, proteomic, and functional methods, we identified that the human platelet transcriptome is markedly altered under prolonged exposure to hypobaric hypoxia at HA. Among the significantly, differentially expressed genes (mRNA and protein), were those having canonical roles in platelet activation and thrombosis, including membrane glycoproteins (e.g. GP4, GP6, GP9), integrin subunits (e.g. ITGA2B), and alpha-granule chemokines (e.g. SELP, PF4V1). Platelets from subjects residing at HA were hyperactive, as demonstrated by increased engagement and adhesion to fibrinogen, fewer alpha granules by transmission electron microscopy, increased circulating PF4 and ADP, and significantly enhanced clot retraction. In conclusion, we identify that prolonged hypobaric hypoxia exposure due to HA alters the platelet transcriptome and proteome, triggering increased functional activation responses that may contribute to thrombosis. Our findings may also have relevance across a range of human diseases where chronic hypoxia, platelet activation, and thrombosis are increased.

The variable impact of positive lymph nodes in cervical cancer: Implications of the new FIGO staging system.

OBJECTIVE: The 2018 International Federation of Gynecology and Obstetrics (FIGO) staging system for cervical cancer changed from a clinical system to a clinical/pathologic/radiologic system with stages IIIC1 and IIIC2 indicating positive pelvic and para-aortic lymph nodes, respectively. We evaluated the National Cancer Database (NCDB) for the impact on survival of lymph node metastases (LNM). METHODS: The NCDB from 2004 to 2015 was queried for patients with cervical cancer, yielding 115,819 patients. Patients with FIGO IVB (22,569), non-adeno/squamous cell histologies (5,909), unknown nodal status (60,695), or unknown survival time (9,473) were excluded. Survival was compared using Cox proportional hazard model based on nodal status. Univariate (UVA) and multivariate analyses (MVA) were done for the overall cohort, followed by UVA by individual stage. RESULTS: In 17,173 eligible patients, LNM negatively affected survival (UVA IIIC1 Hazard Ratio [HR] 2.0, p < 0.001, IIIC2 HR 3.9, p < 0.001, MVA IIIC1 HR 1.36, p < 0.001, IIIC2 HR 2.14, p < 0.001). In T1B, the effect of IIIC2 was most pronounced (HR 5.38, p < 0.001 versus HR 1.5 p = 0.001 for IIIC1 disease). In T3, the effect of LNM was markedly less: (HR 1.7, p < 0.001 for IIIC2 versus HR 1.2 p = 0.02 for IIIC1). Within T1B, there was no difference in survival for IIIC1 for the smaller T stages (IB1-2). CONCLUSION: In this study, LNM negatively affects prognosis in cervical cancer. The impact on survival varies by T stage with the greatest effect seen in stage T1B with IIIC2 disease.

Solution effects on the self-association of a water-soluble peptoid.

A desire to replicate the structural and functional complexity of proteins with structured, sequence-specific oligomers motivates study of the structural features of water-soluble peptoids (N-substituted glycine oligomers). Understanding the molecular-level details of peptoid self-assembly in water is essential to advance peptoids' application as novel materials. Peptoid 1, an amphiphilic, putatively helical peptoid previously studied in our laboratory, shows evidence of self-association in aqueous solution. In this work, we evaluate how changes to aqueous solution conditions influence the self-association of 1. We report that changes to pH influence the fluorescence and CD spectroscopic features as well as the peptoid's interaction with a solvatochromic fluorophore and its apparent size as estimated by size exclusion chromatography. Addition of guanidine hydrochloride and ammonium sulfate also modulate spectroscopic features of the peptoid, its interaction with a solvatochromic fluorophore, and its elution in size exclusion chromatography. These data suggest that the ordering of the self-assembly changes in response to pH and with solvent additives and is more ordered at higher pH and in the presence of guanidine hydrochloride. The deeper understanding of the self-association of 1 afforded by these studies informs the design of new stimuli-responsive peptoids with stable tertiary or quaternary structures.

Solid-Phase Synthesis of Azole-Comprising Peptidomimetics and Coordination of a Designed Analog to Zn2.

Peptidomimetics that can coordinate transition metals have a variety of potential applications as catalysts, sensors, or materials. A new modular peptidomimetic scaffold, the "azole peptoid", is introduced here. We report methods for the solid-phase synthesis of eleven examples of trimeric N-substituted oligoamides that include oxazole- or thiazole-functionalized backbones. The products prepared comprise a diversity of functionality, including a metal-coordinating terpyridine group. The modular synthetic approach enables ready preparation of analogs for specific applications. To highlight a potential use of this new synthetic scaffold, a trimeric azole peptoid functionalized with a terpyridine residue was prepared and studied. The characteristic 2:1 ligand:metal binding of this terpyridine-functionalized azole peptoid to Zn2+ in aqueous solution was observed. These studies introduce azole peptoids as a useful class of biomimetic molecules for further study and application.

Postoperative Changes in the Systemic Inflammatory Milieu in Older Surgical Patients.

Dysregulated inflammation is a central component of wound healing following surgery. We prospectively enrolled older patients (n = 25, age 65 ± 7 years) undergoing elective total knee arthroplasty or total hip arthroplasty secondary to advanced osteoarthritis (OA) and healthy controls (n = 48). Inflammatory, proangiogenic (vascular endothelial growth factor [VEGF], monocyte chemoattractant protein-1 [MCP-1], and interleukin-8 [IL-8]), and antiangiogenic (interferon γ [IFN-γ] and IL-4) factors were measured using a high-sensitivity biochip. Patients with OA had significantly higher baseline VEGF (10.5 ± 1.2 pg/mL vs 4.8 ± 0.2 pg/mL, P < .001), MCP-1 (130.6 ± 7.7 pg/mL vs 88.6 ± 3.9 pg/mL, P < .0001), and IL-8 (4.0 ± 0.5 pg/mL vs 2.6 ± 0.1 pg/mL, P < .05). Postoperatively, the levels of VEGF (10.5 ± 1.2 pg/mL vs 18.8 ± 1.5 pg/mL, P < .001) and MCP-1 (130.6 ± 7.7 pg/mL vs 153.1 ± 11.5 pg/mL, P < .05) increased significantly. Baseline and postoperative MCP-1 levels correlated positively and significantly with age. The levels of IFN-γ and IL-4 (which has anti-inflammatory properties) did not significantly differ at baseline in patients with OA compared to controls and did not significantly rise postoperatively. We conclude that systemic levels of pro-inflammatory and angiogenic proteins are increased in patients with OA and rise further postoperatively, while proteins that restrain inflammation and angiogenesis do not coordinately rise. These findings implicate imbalance in inflammatory pathways in OA that may contribute to its pathobiology.