Photobiomodulation in the infrared spectrum reverses the expansion of circulating natural killer cells and brain microglial activation in Sanfilippo mice.

Sanfilippo syndrome results from inherited mutations in genes encoding lysosomal enzymes that catabolise heparan sulfate (HS), leading to early childhood-onset neurodegeneration. This study explores the therapeutic potential of photobiomodulation (PBM), which is neuroprotective and anti-inflammatory in several neurodegenerative diseases; it is also safe and PBM devices are readily available. We investigated the effects of 10-14 days transcranial PBM at 670 nm (2 or 4 J/cm2/day) or 904 nm (4 J/cm2/day) in young (3 weeks) and older (15 weeks) Sanfilippo or mucopolysaccharidosis type IIIA (MPS IIIA) mice. Although we found no PBM-induced changes in HS accumulation, astrocyte activation, CD206 (an anti-inflammatory marker) and BDNF expression in the brains of Sanfilippo mice, there was a near-normalisation of microglial activation in older MPS IIIA mice by 904 nm PBM, with decreased IBA1 expression and a return of their morphology towards a resting state. Immune cell immunophenotyping of peripheral blood with mass cytometry revealed increased pro-inflammatory signalling through pSTAT1 and p-p38 in NK and T cells in young but not older MPS IIIA mice (5 weeks of age), and expansion of NK, B and CD8+ T cells in older affected mice (17 weeks of age), highlighting the importance of innate and adaptive lymphocytes in Sanfilippo syndrome. Notably, 670 and 904 nm PBM both reversed the Sanfilippo-induced increase in pSTAT1 and p-p38 expression in multiple leukocyte populations in young mice, while 904 nm reversed the increase in NK cells in older mice. In conclusion, this is the first study to demonstrate the beneficial effects of PBM in Sanfilippo mice. The distinct reduction in microglial activation and NK cell pro-inflammatory signalling and number suggests PBM may alleviate neuroinflammation and lymphocyte activation, encouraging further investigation of PBM as a standalone, or complementary therapy in Sanfilippo syndrome.

Protocol for in vivo elimination of avian auditory hair cells, multiplexed mRNA detection, immunohistochemistry, and S-phase labeling.

The avian inner ear can naturally regenerate sensory hair cells and is therefore an ideal candidate for investigating mechanisms leading to hair cell regeneration and functional recovery. Here, we present a surgical protocol for eliminating auditory hair cells via sisomicin injection into the lateral semicircular canal. We describe steps for multiplex mRNA detection in chicken basilar papilla and utricle sections. We then detail procedures for integrating immunohistochemistry for concurrent mRNA and protein visualization, complemented by S-phase labeling with EdU. For complete details on the use and execution of this protocol, please refer to Benkafadar et al., Benkafadar et al., Sato et al., Janesick et al., Scheibinger et al.1,2,3,4,5.

SoxB1 transcription factors are essential for initiating and maintaining neural plate border gene expression.

SoxB1 transcription factors (Sox2/3) are well known for their role in early neural fate specification in the embryo, but little is known about functional roles for SoxB1 factors in non-neural ectodermal cell types, such as the neural plate border (NPB). Using Xenopus laevis, we set out to determine if SoxB1 transcription factors have a regulatory function in NPB formation. Herein, we show that SoxB1 factors are necessary for NPB formation, and that prolonged SoxB1 factor activity blocks the transition from a NPB to a neural crest state. Using ChIP-seq we demonstrate that Sox3 is enriched upstream of NPB genes in early NPB cells and in blastula stem cells. Depletion of SoxB1 factors in blastula stem cells results in downregulation of NPB genes. Finally, we identify Pou5f3 factors as potential Sox3 partners in regulating the formation of the NPB and show their combined activity is needed for normal NPB gene expression. Together, these data identify a novel role for SoxB1 factors in the establishment and maintenance of the NPB, in part through partnership with Pou5f3 factors.

Interferon regulatory factor 6 (IRF6) determines intestinal epithelial cell development and immunity.

Intestinal epithelial cell (IEC) responses to interferon (IFN) favor antiviral defense with minimal cytotoxicity, but IEC-specific factors that regulate these responses remain poorly understood. Interferon regulatory factors (IRFs) are a family of nine related transcription factors, and IRF6 is preferentially expressed by epithelial cells, but its roles in IEC immunity are unknown. In this study, Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) screens found that Irf6 deficiency enhanced IFN-stimulated antiviral responses in transformed mouse IECs but not macrophages. Furthermore, knockout (KO) of Irf6 in IEC organoids resulted in profound changes to homeostasis and immunity gene expression. Irf6 KO organoids grew more slowly, and single-cell ribonucleic acid sequencing indicated reduced expression of genes in epithelial differentiation and immunity pathways. IFN-stimulated gene expression was also significantly different in Irf6 KO organoids, with increased expression of stress and apoptosis-associated genes. Functionally, the transcriptional changes in Irf6 KO organoids were associated with increased cytotoxicity upon IFN treatment or inflammasome activation. These data indicate a previously unappreciated role for IRF6 in IEC biology, including regulation of epithelial development and moderation of innate immune responses to minimize cytotoxicity and maintain barrier function.

Role of type-I and type-III interferons in gastrointestinal homeostasis and pathogenesis.

Interferon (IFN) was discovered based on interference with virus production, and three types of IFN are now defined. Since its discovery, IFN's roles have expanded beyond viruses to diverse pathogen types, tissue homeostasis, and inflammatory disease. The gastrointestinal (GI) tract is arguably the tissue where the roles of IFN types are most distinct, with a particularly prominent role for type-III IFN in antiviral protection of the intestinal epithelium. Current studies continue to deepen our understanding of the type- and tissue-specific roles of IFN. This review highlights these advances within the GI tract, including discovery of protective roles for type-III IFNs against nonviral GI pathogens, and discovery of an antiviral homeostatic type-III IFN response within the intestinal epithelium.

Speech-in-Noise Assessment in the Routine Audiologic Test Battery: Relationship to Perceived Auditory Disability.

OBJECTIVES: Self-assessment of perceived communication difficulty has been used in clinical and research practices for decades. Such questionnaires routinely assess the perceived ability of an individual to understand speech, particularly in background noise. Despite the emphasis on perceived performance in noise, speech recognition in routine audiologic practice is measured by word recognition in quiet (WRQ). Moreover, surprisingly little data exist that compare speech understanding in noise (SIN) abilities to perceived communication difficulty. Here, we address these issues by examining audiometric thresholds, WRQ scores, QuickSIN signal to noise ratio (SNR) loss, and perceived auditory disability as measured by the five questions on the Speech Spatial Questionnaire-12 (SSQ12) devoted to speech understanding (SSQ12-Speech5). DESIGN: We examined data from 1633 patients who underwent audiometric assessment at the Stanford Ear Institute. All individuals completed the SSQ12 questionnaire, pure-tone audiometry, and speech assessment consisting of ear-specific WRQ, and ear-specific QuickSIN. Only individuals with hearing threshold asymmetries ≤10 dB HL in their high-frequency pure-tone average (HFPTA) were included. Our primary objectives were to (1) examine the relationship between audiometric variables and the SSQ12-Speech5 scores, (2) determine the amount of variance in the SSQ12-Speech5 scores which could be predicted from audiometric variables, and (3) predict which patients were likely to report greater perceived auditory disability according to the SSQ12-Speech5. RESULTS: Performance on the SSQ12-Speech5 indicated greater perceived auditory disability with more severe degrees of hearing loss and greater QuickSIN SNR loss. Degree of hearing loss and QuickSIN SNR loss were found to account for modest but significant variance in SSQ12-Speech5 scores after accounting for age. In contrast, WRQ scores did not significantly contribute to the predictive power of the model. Degree of hearing loss and QuickSIN SNR loss were also found to have moderate diagnostic accuracy for determining which patients were likely to report SSQ12-Speech5 scores indicating greater perceived auditory disability. CONCLUSIONS: Taken together, these data indicate that audiometric factors including degree of hearing loss (i.e., HFPTA) and QuickSIN SNR loss are predictive of SSQ12-Speech5 scores, though notable variance remains unaccounted for after considering these factors. HFPTA and QuickSIN SNR loss-but not WRQ scores-accounted for a significant amount of variance in SSQ12-Speech5 scores and were largely effective at predicting which patients are likely to report greater perceived auditory disability on the SSQ12-Speech5. This provides further evidence for the notion that speech-in-noise measures have greater clinical utility than WRQ in most instances as they relate more closely to measures of perceived auditory disability.

Distinct roles of hematopoietic cytokines in the regulation of leukemia stem cells in murine MLL-AF9 leukemia.

Lymphoid-primed multipotent progenitor (LMPP)-like and granulocyte-monocyte progenitor (GMP)-like leukemia stem cells (LSCs) co-exist in the blood of most patients with acute myeloid leukemia (AML). Complete elimination of both types of LSCs is required to cure AML. Using an MLL-AF9-induced murine AML model, we studied the role of hematopoietic cytokines in the survival of LMPP- and GMP-like LSCs. We found that SCF or FLT3L promotes the survival of LMPP-like LSCs by stimulating Stat5-mediated Mcl1 expression, whereas interleukin-3 (IL-3) or IL-6 induces the survival of GMP-like LSCs by stimulating Stat3/nuclear factor κB (NF-κB)-mediated Bcl2 expression. Functional study demonstrated that, compared to AML cells cultured in IL-3 and IL-6 medium, AML cells in SCF- or Flt3L-only culture are highly clonogenic in in vitro culture and are highly leukemogenic in vivo. Our study suggests that co-inhibition of both STAT5-MCL1 and STAT3/NF-κB-BCL2 signaling might represent an improved treatment strategy against AML, specifically AML cases with a monocytic phenotype and/or FLT3 mutations.

miR-9 utilizes precursor pathways in adaptation to alcohol in mouse striatal neurons.

microRNA-9 (miR-9) is one of the most abundant microRNAs in the mammalian brain, essential for its development and normal function. In neurons, it regulates the expression of several key molecules, ranging from ion channels to enzymes, to transcription factors broadly affecting the expression of many genes. The neuronal effects of alcohol, one of the most abused drugs in the world, seem to be at least partially dependent on regulating the expression of miR-9. We previously observed that molecular mechanisms of the development of alcohol tolerance are miR-9 dependent. Since a critical feature of alcohol action is temporal exposure to the drug, we decided to better understand the time dependence of alcohol regulation of miR-9 biogenesis and expression. We measured the effect of intoxicating concentration of alcohol (20 mM ethanol) on the expression of all major elements of miR-9 biogenesis: three pri-precursors (pri-mir-9-1, pri-mir-9-2, pri-mir-9-3), three pre-precursors (pre-mir-9-1, pre-mir-9-2, pre-mir-9-3), and two mature microRNAs: miR-9-5p and miR-9-3p, using digital PCR and RT-qPCR, and murine primary medium spiny neurons (MSN) cultures. We subjected the neurons to alcohol based on an exposure/withdrawal matrix of different exposure times (from 15 min to 24 h) followed by different withdrawal times (from 0 h to 24 h). We observed that a short exposure increased mature miR-9-5p expression, which was followed by a gradual decrease and subsequent increase of the expression, returning to pre-exposure levels within 24 h. Temporal changes of miR-9-3p expression were complementing miR-9-5p changes. Interestingly, an extended, continuous presence of the drug caused a similar pattern. These results suggest the presence of the adaptive mechanisms of miR-9 expression in the presence and absence of alcohol. Measurement of miR-9 pre- and pri-precursors showed further that the primary effect of alcohol on miR-9 is through the mir-9-2 precursor pathway with a smaller contribution of mir-9-1 and mir-9-3 precursors. Our results provide new insight into the adaptive mechanisms of neurons to alcohol exposure. It would be of interest to determine next which microRNA-based mechanisms are involved in a transition from the acute, intoxicating effects of alcohol to the chronic, addictive effects of the drug.

SoxB1 transcription factors are essential for initiating and maintaining the neural plate border gene expression.

SoxB1 transcription factors (Sox2/3) are well known for their role in early neural fate specification in the embryo, but little is known about functional roles for SoxB1 factors in non-neural ectodermal cell types, such as the neural plate border (NPB). Using Xenopus laevis , we set out to determine if SoxB1 transcription factors have a regulatory function in NPB formation. Herein, we show that SoxB1 factors are necessary for NPB formation, and that prolonged SoxB1 factor activity blocks the transition from a NPB to a neural crest state. Using ChIP-seq we demonstrate that Sox3 is enriched upstream of NPB genes in early NPB cells and, surprisingly, in blastula stem cells. Depletion of SoxB1 factors in blastula stem cells results in downregulation of NPB genes. Finally, we identify Pou5f3 factors as a potential SoxB1 partners in regulating the formation of the NPB and show their combined activity is needed to maintain NPB gene expression. Together, these data identify a novel role for SoxB1 factors in the establishment and maintenance of the NPB, in part through partnership with Pou5f3 factors.

New Tridentate Ligand Affords a Long-Lived 3MLCT Excited State in a Ru(II) Complex: DNA Photocleavage and 1O2 Production.

Two new complexes, [Ru(tpy)(qdppz)](PF6)2 (1; qdppz = 2-(quinolin-8-yl)dipyrido[3,2-a:2',3'-c]phenazine, tpy = 2,2':6',2″-terpyridine) and [Ru(qdppz)2](PF6)2 (2), were investigated for their potential use as phototherapeutic agents through their ability to photosensitize the production of singlet oxygen, 1O2, upon irradiation with visible light. The complexes exhibit strong Ru(dπ) → qdppz(π*) metal-to-ligand charge transfer (MLCT) absorption with maxima at 485 and 495 nm for 1 and 2 in acetone, respectively, red-shifted from the Ru(dπ) → tpy(π*) absorption at 470 nm observed for [Ru(tpy)2]2+ (3) in the same solvent. Complexes 1 and 3 are not luminescent at room temperature, but 3MLCT emission is observed for 2 with maximum at 690 nm (λexc = 480 nm) in acetone. The lifetimes of the 3MLCT states of 1 and 2 were measured using transient absorption spectroscopy to be ∼9 and 310 ns in methanol, respectively, at room temperature (λexc = 490 nm). The bite angle of the qdppz ligand is closer to octahedral geometry than that of tpy, resulting in the longer lifetime of 2 as compared to those of 1 and 3. Arrhenius treatment of the temperature dependence of the luminescence results in similar activation energies, Ea, from the 3MLCT to the 3LF (ligand-field) state for the two complexes, 2520 cm-1 in 1 and 2400 cm-1 in 2. However, the pre-exponential factors differ by approximately two orders of magnitude, 2.3 × 1013 s-1 for 1 and 1.4 × 1011 s-1 for 2, which, together with differences in the Huang-Rhys factors, lead to markedly different 3MLCT lifetimes. Although both 1 and 2 intercalate between the DNA bases, only 2 is able to photocleave DNA owing to its 1O2 production upon irradiation with ΦΔ = 0.69. The present work highlights the profound effect of the ligand bite angle on the electronic structure, providing guidelines for extending the lifetime of 3MLCT Ru(II) complexes with tridentate ligands, a desired property for a number of applications.

The gut protist Tritrichomonas arnold restrains virus-mediated loss of oral tolerance by modulating dietary antigen-presenting dendritic cells.

Loss of oral tolerance (LOT) to gluten, driven by dendritic cell (DC) priming of gluten-specific T helper 1 (Th1) cell immune responses, is a hallmark of celiac disease (CeD) and can be triggered by enteric viral infections. Whether certain commensals can moderate virus-mediated LOT remains elusive. Here, using a mouse model of virus-mediated LOT, we discovered that the gut-colonizing protist Tritrichomonas (T.) arnold promotes oral tolerance and protects against reovirus- and murine norovirus-mediated LOT, independent of the microbiota. Protection was not attributable to antiviral host responses or T. arnold-mediated innate type 2 immunity. Mechanistically, T. arnold directly restrained the proinflammatory program in dietary antigen-presenting DCs, subsequently limiting Th1 and promoting regulatory T cell responses. Finally, analysis of fecal microbiomes showed that T. arnold-related Parabasalid strains are underrepresented in human CeD patients. Altogether, these findings will motivate further exploration of oral-tolerance-promoting protists in CeD and other immune-mediated food sensitivities.

Social network analysis of Twitter interactions: a directed multilayer network approach.

Effective employment of social media for any social influence outcome requires a detailed understanding of the target audience. Social media provides a rich repository of self-reported information that provides insight regarding the sentiments and implied priorities of an online population. Using Social Network Analysis, this research models user interactions on Twitter as a weighted, directed network. Topic modeling through Latent Dirichlet Allocation identifies the topics of discussion in Tweets, which this study uses to induce a directed multilayer network wherein users (in one layer) are connected to the conversations and topics (in a second layer) in which they have participated, with inter-layer connections representing user participation in conversations. Analysis of the resulting network identifies both influential users and highly connected groups of individuals, informing an understanding of group dynamics and individual connectivity. The results demonstrate that the generation of a topically-focused social network to represent conversations yields more robust findings regarding influential users, particularly when analysts collect Tweets from a variety of discussions through more general search queries. Within the analysis, PageRank performed best among four measures used to rank individual influence within this problem context. In contrast, the results of applying both the Greedy Modular Algorithm and the Leiden Algorithm to identify communities were mixed; each method yielded valuable insights, but neither technique was uniformly superior. The demonstrated four-step process is readily replicable, and an interested user can automate the process with relatively low effort or expense.

Simulation of radioactive plume transport in the atmosphere including dynamics of particle aggregation and breakup.

Accurate prediction of the atmospheric transport of debris particles relies heavily on our knowledge of the size distribution of the particles within a debris cloud. Assuming a fixed particle size during simulations is not always viable since the size distribution of the debris can change during transport. Various microphysical processes, such as aggregation and breakup, influence debris particles and dictate any changes to the size distribution. To track those changes that can occur, a population balance model can be adopted and instituted within a model framework. Nonetheless, many of the models that simulate the transport of radioactive debris following a device-driven fission incident have historically neglected to consider these processes. As such, this work describes our effort to develop a modeling framework capable of simulating the transport and deposition of a radioactive plume generated from a fission incident with a dynamic population balance including particle aggregation and breakup. The impact of aggregation and breakup, individually and collectively, on the particle size distribution is explored using the developed framework. When simulating aggregation, for example, six mechanisms, including Brownian coagulation, the convective enhancement to Brownian coagulation, van der Waals-viscous force correction for Brownian coagulation, gravitational collection, turbulent inertial motion, and turbulent shear, are considered. Brownian coagulation and its corrections have, as one would expect, a large impact on relatively small aggregates. Aggregates with a diameter that is less than or equal to 1.0 µm, for instance, comprise 50.6 vol % of all aggregates in the absence of aggregation and 31.2 vol % when Brownian coagulation and its corrections are considered. Gravitational collection and, to a much lesser extent, turbulent shear and turbulent inertial motion are, conversely, of great importance to relatively large aggregates (i.e., diameter greater than 3.0 µm). Additionally, the individual effects of atmospheric and particle parameters, such as wind speed and particle density, are examined. Of the parameters examined, turbulent energy dissipation and aggregate fractal dimension (i.e., aggregate shape with lower values representing more irregular particles) were of substantial importance since both terms directly impact aggregate stability and, by extension, the breakup rate. Large-scale transport and deposition simulations in a dry atmosphere are also presented and discussed as a proof of concept.

American Society of Clinical Oncology 2022 Annual Meeting Highlights for Radiation Oncologists.

The American Society of Clinical Oncology annual meeting is the largest multidisciplinary oncology-focused conference in the world. With almost 5000 total abstracts in 2022, it is difficult for individuals to evaluate all the results. Here we present a review of 28 selected abstracts, across all disease sites, focusing on those of greatest relevance to radiation oncologists.

Trends in Integrated Plastic Surgery Applicant, Resident, and Junior Attending Research Productivity.

INTRODUCTION: Research productivity is critical for matching into integrated plastic surgery residency. This study will identify how pre and intraresidency research productivity correlate with resident/junior attending productivity. MATERIALS AND METHODS: Retrospective review from 2006 to 2015 issues of the American Board of Plastic Surgery's Annual Newsletter to Diplomates was performed to identify newly board certified plastic surgeons. Only surgeons from US medical schools matching directly into integrated programs were included. Residency type/length, graduation year from medical school, and publication counts were recorded for each surgeon. Publications were categorized as preresidency, intraresidency, and junior attending (6 y post residency/fellowship training). RESULTS: Six hundred fifty-five integrated plastic surgery graduates were analyzed. The median number of total publications (preresidency, intraresidency, and junior attending) was 4 (interquartile range [IQR], 1 to 10). Linear regression revealed negligible correlation between preresidency and junior attending publications (r = 0.019, P = 0.002). Total publications and increasing graduation y had a significant correlation of 0.89 (P < 0.001). Graduates of fellowships had significantly increased median total publications compared to those without fellowships (7 IQR, 3 to 18 versus 3 IQR, 1 to 7, respectively, P < 0.001). Dedicated research years during residency were associated with significant (P < 0.001) increases in median total and junior attending publications. Total publications ranged from 3 (IQR, 1 to 6) to 8 (IQR, 7 to 18) for those who completed 5- and 8-y residencies, respectively. CONCLUSIONS: Increased preresidency research productivity is not strongly associated with increased junior attending productivity in integrated plastic surgery. Better markers are completing dedicated research years in residency or fellowship after residency.

Vascular calcification maladaptively participates in acute phosphate homeostasis.

AIMS: Non-renal extravasation of phosphate from the circulation and transient accumulation into tissues and extracellular fluid is a regulated process of acute phosphate homeostasis that is not well understood. This process is especially relevant in the setting of chronic kidney disease (CKD), where exposure to increased phosphate is prolonged due to inefficient kidney excretion. Furthermore, CKD-associated mineral dysregulation induces pathological accumulation of phosphate causing vascular calcification (VC). Our objective was to determine whether the systemic response to acute phosphate challenges is altered by VC. METHODS AND RESULTS: After bolus phosphate administration, circulating and tissue deposition of this challenge was assessed in two rat models of VC using a radiolabelled phosphate tracer. In an adenine-induced model of CKD (N = 70), animals with VC had a blunted elevation of circulating 33PO4 following oral phosphate administration (P < 0.01), and the discordant deposition could be traced to the calcified arteries (11.4 [7.5-13.1] vs.43.0 [35.5-53.7] pmol/ng tissue, P < 0.001). In a non-CKD model of VC, calcification was induced with 0.5 ug/kg calcitriol and then withdrawn (N = 24). New phosphate uptake by the calcified vasculature correlated to the pre-existing burden of calcification (r = 38, P < 0.001) and was substantially attenuated in the absence of calcification stimulus (P < 0.01). Phosphate accrual was stimulated by the phosphate challenge and not present to the same degree during passive disposition of circulating phosphate. Further, the form of phosphate that deposited to the vasculature was predominately amorphous inorganic phosphate and not that which was bound in matured calciprotein particles. CONCLUSIONS: In the process of calcification, arteries acutely deposit substantial amorphous phosphate while blunting the elevation in the circulation, thereby altering the systemic disposition of phosphate and identifying VC as a participatory mineral homeostatic organ. This study demonstrates the negative vascular consequence of acute fluctuations in circulating phosphate, and supports the importance of phosphate bioavailability and diet management in CKD patients as a mediator of cardiovascular risk.

Alteration history of Séítah formation rocks inferred by PIXL x-ray fluorescence, x-ray diffraction, and multispectral imaging on Mars.

Collocated crystal sizes and mineral identities are critical for interpreting textural relationships in rocks and testing geological hypotheses, but it has been previously impossible to unambiguously constrain these properties using in situ instruments on Mars rovers. Here, we demonstrate that diffracted and fluoresced x-rays detected by the PIXL instrument (an x-ray fluorescence microscope on the Perseverance rover) provide information about the presence or absence of coherent crystalline domains in various minerals. X-ray analysis and multispectral imaging of rocks from the Séítah formation on the floor of Jezero crater shows that they were emplaced as coarsely crystalline igneous phases. Olivine grains were then partially dissolved and filled by finely crystalline or amorphous secondary silicate, carbonate, sulfate, and chloride/oxychlorine minerals. These results support the hypothesis that Séítah formation rocks represent olivine cumulates altered by fluids far from chemical equilibrium at low water-rock ratios.

Evaluation of 5 Fraction Stereotactic Body Radiation Therapy (SBRT) for Osseous Renal Cell Carcinoma Metastases.

OBJECTIVES: The best fractionation for stereotactic body radiotherapy (SBRT) in renal cell carcinoma (RCC) metastases has not been well defined. In addition, the literature on outcomes using 5-fraction SBRT in the setting of osseous metastases has not been well reported. MATERIALS AND METHODS: Thirty-nine patients with 69 RCC osseous metastases were treated using 5-fraction SBRT at a single institution using 2 dose-fractionation schemes. Overall survival and local-control (LC) outcomes of the 2 fractionation schemes were studied using Kaplan-Meier curves. RESULTS: Of the 69 lesions included in the study, 20 were treated with 30 grays (Gy) in 5 fractions and 49 were treated with 40 Gy in 5 fractions. The median age of patients at diagnosis was 58.4 years. The 1-year LC rate for all treated lesions was 85.5% (59/69) with an LC of 90% (18/20) for lesions receiving 30 Gy and 83.7% (41/49) in lesions receiving 40 Gy. There was no statistically significant difference in 1-year LC rate between the 2 fractionation schemes (P-value, 0.553). CONCLUSIONS: Patients with osseous RCC metastases undergoing 5 fractions of SBRT had favorable LC outcomes. There was no difference in survival or LC between the 40 Gy and 30 Gy treatment arms.

Radiation Fibrosis After Stereotactic Body Radiation Therapy for Osseous Metastases: A Case Report.

Radiation-induced fibrosis is a potentially severe late complication after high-dose radiotherapy. Over the last decade, there has been increasing use of stereotactic body radiation therapy (SBRT) to treat both primary and metastatic malignancies. While there has been evolving evidence of appropriate dose constraints for certain organs receiving hypofractionated radiotherapy, the risk, and appropriate dose constraints to limit the risk of radiation-induced muscle fibrosis are poorly defined. In this report, two patients are presented who underwent SBRT for osseous oligometastatic renal cell carcinoma. While the treatment was well-tolerated with no acute toxicities and complete local control of the metastasis, both patients experienced late toxicity of radiation-induced fibrosis in the adjacent musculature. In both cases, toxicity was nonresponsive to medical interventions and was severe enough to require surgical resection of the affected tissue. Following surgery, both patients reported improved pain relief and mobility. Further studies are needed to explore the dose constraints that may reduce the risk of radiation-induced muscle fibrosis in five-fraction treatment.

Academic patterns of practice regarding CT simulation scans and radiology review.

OBJECTIVE: Currently, there are no consensus guidelines about handling incidental radiological findings on radiotherapy planning CT simulation scans. Retrospective studies analyzing incidental findings on CT simulations show a small, but not insignificant, rate of both oncologic and non-oncologic findings. These findings may have medico-legal, financial, and clinical implications. Given a lack of guidelines, we obtained a formal survey of multiple academic institutions to evaluate how CT simulations are handled in regard to incidental findings. METHODS: A formal survey was developed consisting of 12 questions related to institutional practices regarding CT simulation scans. From 7/18/21 to 8/27/21 and 5/6/22 to 5/24/22, the survey was administered electronically by REDCap to key personnel at Academic Radiation Oncology Programs identified through the American Society for Radiation Oncology (ASTRO) with inclusion criteria including an active ACGME approved Radiation Oncology residency program. RESULTS: In total, 88 academic radiation oncology programs were surveyed with total of 45 responses (51%). 1 out of 45 departments who responded has formal guidelines regarding workup of incidental findings. There is variability about sending CT simulation scans for official radiology review if an incidental finding is identified. CONCLUSIONS: Based on a measurable rate of incidental findings on radiotherapy planning CT simulations and their possible implications, our survey illustrates a likely need for consensus recommendations for handling such findings to improve patient care and safety.