Decorin and/or biglycan knockdown in aged mouse patellar tendon impacts fibril morphology, scar area, and mechanical properties.

Small leucine-rich proteoglycans, such as decorin and biglycan, play pivotal roles in collagen fibrillogenesis during development, healing, and aging in tendon. Previous work has shown that the absence of decorin and biglycan affects fibril shape and mechanical properties during tendon healing. However, the roles of decorin and biglycan in the healing process of aged tendons are unclear. Therefore the objective of this study was to evaluate the differential roles of decorin and biglycan during healing of patellar tendon injury in aged mice. Aged (300 days old) female Dcn+/+/Bgn+/+ control (WT, n = 52), Dcnflox/flox (I-Dcn-/-, n = 36), Bgnflox/flox (I-Bgn-/-, n = 36), and compound Dcnflox/flox/Bgnflox/flox (I-Dcn-/-/Bgn-/-, n = 36) mice with a tamoxifen-inducible Cre were utilized. Targeted gene expression, collagen fibril diameter distributions, mechanical properties, and histological assays were employed to assess the effects of knockdown of decorin and/or biglycan at the time of injury. Knockdown resulted in alterations in fibril diameter distribution and scar area, but surprisingly did not lead to many differences in mechanical properties. Biglycan played a larger role in early healing stages, while decorin is more significant in later stages, particularly in scar remodeling. This study highlights some of the differential roles of biglycan and decorin in the regulation of fibril structure and scar area, as well as influencing gene expression during healing in aged mice.

Physician Reluctance to Intervene in Addiction: A Systematic Review.

Importance: The overdose epidemic continues in the US, with 107 941 overdose deaths in 2022 and countless lives affected by the addiction crisis. Although widespread efforts to train and support physicians to implement medications and other evidence-based substance use disorder interventions have been ongoing, adoption of these evidence-based practices (EBPs) by physicians remains low. Objective: To describe physician-reported reasons for reluctance to address substance use and addiction in their clinical practices using screening, treatment, harm reduction, or recovery support interventions. Data Sources: A literature search of PubMed, Embase, Scopus, medRxiv, and SSRN Medical Research Network was conducted and returned articles published from January 1, 1960, through October 5, 2021. Study Selection: Publications that included physicians, discussed substance use interventions, and presented data on reasons for reluctance to intervene in addiction were included. Data Extraction and Synthesis: Two reviewers (L.N., M.C., L.F., J.P., C.S., and S.W.) independently reviewed each publication; a third reviewer resolved discordant votes (M.C. and W.C.). This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines and the theoretical domains framework was used to systematically extract reluctance reasons. Main Outcomes and Measures: The primary outcome was reasons for physician reluctance to address substance use disorder. The association of reasons for reluctance with practice setting and drug type was also measured. Reasons and other variables were determined according to predefined criteria. Results: A total of 183 of 9308 returned studies reporting data collected from 66 732 physicians were included. Most studies reported survey data. Alcohol, nicotine, and opioids were the most often studied substances; screening and treatment were the most often studied interventions. The most common reluctance reasons were lack of institutional support (173 of 213 articles [81.2%]), knowledge (174 of 242 articles [71.9%]), skill (170 of 230 articles [73.9%]), and cognitive capacity (136 of 185 articles [73.5%]). Reimbursement concerns were also noted. Bivariate analysis revealed associations between these reasons and physician specialty, intervention type, and drug. Conclusions and Relevance: In this systematic review of reasons for physician reluctance to intervene in addiction, the most common reasons were lack of institutional support, knowledge, skill, and cognitive capacity. Targeting these reasons with education and training, policy development, and program implementation may improve adoption by physicians of EBPs for substance use and addiction care. Future studies of physician-reported reasons for reluctance to adopt EBPs may be improved through use of a theoretical framework and improved adherence to and reporting of survey development best practices; development of a validated survey instrument may further improve study results.

Reproducibility of Air Displacement Plethysmography in Term and Preterm Infants-A Study to Enhance Body Composition Analysis in Clinical Routine.

The quality-initiative analysis of weekly duplicate PEAPOD® body composition measurements was conducted from clinical practice (January to September 2021) on preterm and term infants without respiratory support. Statistical analysis, including regression analysis, Bland-Altman plots and cv-root-mean-square tests, was performed. A total of 188 duplicate (376 individual) measurements were collected from 119 infants (88 preterm, 31 term). The median absolute difference between duplicates was 31.5 g for fat-free mass (FFM). Linear correlation analysis showed R2 = 0.97 for FFM. The absolute differences in FFM and fat mass did not significantly correlate with increasing age. The %FFM differed (p = 0.02) across body weight groups of 1 kg < BW ≤ 2 kg (1.8%; IQR: 0.8, 3.6) and BW > 3 kg (0.9%; IQR: 0.3, 2.1). The median absolute differences were 1 g (IQR: 0.4, 3.1) for body weight and 5.6 mL (IQR: 2.1, 11.8) for body volume. Body volume estimation is charged with a constant absolute error, which is the main factor for differences between repeated body composition assessments. This error becomes more prominent in infants with lower body weights. Nevertheless, reproducibility of weekly PEAPOD testing is sufficient to monitor body compartment changes, offering a foundation for nutritional decisions in both preterm and term infants.

Kratom addiction per DSM-5 SUD criteria, and kratom physical dependence: Insights from dosing amount versus frequency.

BACKGROUND: Kratom products are widely used in the United States, with inadequate understanding of how dosing amounts/frequencies relate to outcomes. METHODS: Between July-November 2022, we enrolled 395 active US adult kratom consumers into a remote study with a baseline survey. We examined self-reported typical dose amounts and frequencies across people and product types, and their associations with outcomes: multiple regression was used to examine whether amounts and frequencies (doses/day) were associated with acute effects, withdrawal symptoms, scores on the Subjective Opioid Withdrawal Scale (SOWS), and addiction (operationalized as DSM-5-based symptoms of kratom-use disorder, KUD). RESULTS: Participants were 54.9% male, aged 38.1 on average, and 81.3% White. Mean length of kratom use was 5.7 years. Most (95.9%) reported regularly using whole-leaf kratom products; 16 (4.1%) reported regular extract use. SOWS scores were mild to moderate on average (13.5, SD 11.9). KUD symptom counts were mostly in the mild/moderate range (80.7%). Withdrawal and KUD symptoms were more closely associated with dose frequency than dose amount. Men reported more acute effects, withdrawal symptoms with cessation, and KUD symptoms than women. CONCLUSIONS: Greater dose amount and frequency were systematically related to the number of withdrawal symptoms upon cessation and to KUD symptoms; the relationship was stronger for dose frequency than amount. Men may have more acute effects and more withdrawal and KUD symptoms than women. Although kratom may be used nonproblematically by some consumers, physical dependence (tolerance, withdrawal, or use to avoid withdrawal) and KUD become more likely with increasing dose frequency.

An update on the clinical pharmacology of kratom: uses, abuse potential, and future considerations.

INTRODUCTION: Kratom (Mitragyna speciosa) has generated substantial clinical and scientific interest as a complex natural product. Its predominant alkaloid mitragynine and several stereoisomers have been studied for activity in opioid, adrenergic, and serotonin receptors. While awaiting clinical trial results, the pre-clinical evidence suggests a range of potential therapeutic applications for kratom with careful consideration of potential adverse effects. AREAS COVERED: The focus of this review is on the pharmacology, pharmacokinetics, and potential drug-drug interactions of kratom and its individual alkaloids. A discussion on the clinical pharmacology and toxicology of kratom is followed by a summary of user surveys and the evolving concepts of tolerance, dependence, and withdrawal associated with kratom use disorder. EXPERT OPINION: With the increasing use of kratom in clinical practice, clinicians should be aware of the potential benefits and adverse effects associated with kratom. While many patients may benefit from kratom use with few or no reported adverse effects, escalating dose and increased use frequency raise the risk for toxic events in the setting of polysubstance use or development of a use disorder.

Responses to a "Typical" Morning Dose of Kratom in People Who Use Kratom Regularly: A Direct-Observation Study.

INTRODUCTION: Use of kratom has outpaced systematic study of its effects, with most studies reliant on retrospective self-report. METHODS: We aimed to assess acute effects following kratom use in adults who use regularly, and quantify alkaloids in the products, urine, and plasma. Between July and November 2022, 10 adults came to our clinic and orally self-administered their typical kratom dose; blinding procedures were not used. Physiological measures included blood pressure, respiratory rate, heart rate, pulse oximetry, temperature, and pupil diameter. Subjective outcomes included Subjective Opioid Withdrawal Scale, Addiction Research Center Inventory, and Drug Effects Questionnaire. Psychomotor performance was also assessed. RESULTS: Participants were 6 men and 4 women, mean age 41.2 years. Nine were non-Hispanic White; 1 was biracial. They had used kratom for 6.6 years (SD, 3.8 years) on average (2.0-14.1). Sessions were 190.89 minutes on average (SD, 15.10 minutes). Mean session dose was 5.16 g (median, 4.38 g; range, 1.1-10.9 g) leaf powder. Relative to baseline, physiological changes were minor. However, pupil diameter decreased (right, b = -0.70, P < 0.01; left, b = -0.73, P < 0.01) 40-80 minutes postdose and remained below baseline >160 minutes. Subjective Opioid Withdrawal Scale pre-dosing was mild (5.5 ± 3.3) and decreased postdose (b = [-4.0, -2.9], P < 0.01). Drug Effects Questionnaire "feeling effects" increased to 40/100 (SD, 30.5) within 40 minutes and remained above baseline 80 to 120 minutes (b = 19.0, P = 0.04), peaking at 72.7/100; 6 participants rated euphoria as mild on the Addiction Research Center Inventory Morphine-Benzedrine-scale. Psychomotor performance did not reliably improve or deteriorate postdosing. CONCLUSIONS: Among regular consumers, we found few clinically significant differences pre- and post-kratom dosing. Alkaloidal contents in products were within expected ranges.

Collagen V haploinsufficiency in female murine patellar tendons results in altered matrix engagement and cellular density, demonstrating decreased healing.

Collagen V (Col5) is a quantitatively minor component of collagen fibrils comprising tendon, however, plays a crucial role in regulation of development and dynamic healing processes. Clinically, patients with COL5a1 haploinsufficiency, known as classic Ehlers-Danlos Syndrome (cEDS), present with hyperextensible skin, joint instability and laxity, with females more likely to be affected. Previous studies in Col5-deficient mice indicated that reduced Col5a1 expression leads to a reduction in stiffness, fibril deposition, and altered fibril structure. Additionally, Col5-deficient male tendons demonstrated altered healing compared to wild-type tendons, however female mice have not yet been studied utilizing this model. Along with clinical differences between sexes in cEDS patient populations, differences in hormone physiology may be a factor influencing tendon health. Therefore, the objective of this study was to utilize a Col5a1+/ - female mouse model, to determine the effect of Col5 on tendon cell morphology, cell density, tissue composition, and mechanical properties throughout healing. We hypothesized that reduction in Col5 expression would result in an abnormal wound matrix post-injury, resulting in reduced mechanical properties compared to normal tendons. Following patellar tendon surgery, mice were euthanized at 1, 3, and 6-week post-injury. Col5-deficient tendons demonstrated altered and decreased healing compared to WT tendons. The lack of resolution in cellularity by 6-week post-injury in Col5-deficient tendons influenced the decreased mechanical properties. Stiffness did not increase post-injury in Col5-deficient mice, and collagen fiber realignment was delayed during mechanical loading. Therefore, increased Col5a1 expression post-injury is necessary to re-establish matrix engagement and cellularity throughout tendon healing.

Novel application of in vivo microdialysis in a rat Achilles tendon acute injury model.

Tendon injury and healing involve intricate changes to tissue metabolism, biology, and inflammation. Current techniques often require animal euthanasia or tissue destruction, limiting assessment of dynamic changes in tendon, including treatment response, disease development, rupture risk, and healing progression. Microdialysis, a minimally invasive technique, offers potential for longitudinal assessment, yet it has not been applied to rat tendon models. Therefore, the objective of this study is to adapt a novel application of an in vivo assay, microdialysis, using acute injury as a model for extreme disruption of the tendon homeostasis. We hypothesize that microdialysis will be able to detect measurable differences in the healing responses of acute injury with high specificity and sensitivity. Overall results suggest that microdialysis is a promising in vivo technique for longitudinal assessment for this system with strong correlations between extracellular fluid (ECF) and dialysate concentrations and reasonable recovery rates considering the limitations of this model. Strong positive correlations were found between dialysate and extracellular fluid (ECF) concentration for each target molecule of interest including metabolites, inflammatory mediators, and collagen synthesis and degradation byproducts. These results suggest that microdialysis is capable of detecting changes in tendon healing following acute tendon injury with high specificity and sensitivity. In summary, this is the first study to apply microdialysis to a rat tendon model and assess its efficacy as a direct measurement of tendon metabolism, biology, and inflammation.NEW & NOTEWORTHY This study adapts a novel application of microdialysis to rat tendon models, offering a minimally invasive avenue for longitudinal tendon assessment. Successfully detecting changes in tendon healing after acute injury, it showcases strong correlations between extracellular fluid and dialysate concentrations. The results highlight the potential of microdialysis as a direct measure of tendon metabolism, biology, and inflammation, bypassing the need for animal euthanasia and tissue destruction.

Neonatal Achilles Tendon Microstructure is Negatively Impacted by Decorin and Biglycan Knockdown After Injury and During Development.

Interest in studying neonatal development and the improved healing response observed in neonates is increasing, with the goal of using this work to create better therapeutics for tendon injury. Decorin and biglycan are two small leucine-rich proteoglycans that play important roles in collagen fibrillogenesis to develop, maintain, and repair tendon structure. However, little is known about the roles of decorin and biglycan in early neonatal development and healing. The goal of this study was to determine the effects of decorin and biglycan knockdown on Achilles tendon structure and mechanics during neonatal development and recovery of these properties after injury of the neonatal tendon. We hypothesized that knockdown of decorin and biglycan would disrupt the neonatal tendon developmental process and produce tendons with impaired mechanical and structural properties. We found that knockdown of decorin and biglycan in an inducible, compound decorin/biglycan knockdown model, both during development and after injury, in neonatal mice produced tendons with reduced mechanical properties. Additionally, the collagen fibril microstructure resembled an immature tendon with a large population of small diameter fibrils and an absence of larger diameter fibrils. Overall, this study demonstrates the importance of decorin and biglycan in facilitating tendon growth and maturation during neonatal development.

Presumed Melanocytoma-Associated Choroidal Neovascular Membrane with Hemorrhage Successfully Treated with Intravitreal Aflibercept Injections.

A patient presented with melanocytoma and associated choroidal neovascular membrane with hemorrhage involving the macula. The patient was treated with monthly aflibercept (Eylea) injections with significant improvement of best corrected visual acuity. In this report, we explore the development of a choroidal neovascular membrane (CNVM) formation in a patient with melanocytoma and the effect of intravitreal aflibercept (Eylea) on disease course. Case report study used patient data obtained from examination and imaging. The patient was treated with monthly intravitreal aflibercept injections leading to complete resolution of CNVM and hemorrhage, with significant improvement of best corrected visual acuity. Awareness and proper monitoring for the sequelae of melanocytoma are important for early detection and prevention of visually threatening outcomes. In cases of melanocytoma-associated CNVM formation with large subretinal hemorrhage, intravitreal aflibercept can be an effective tool for inducing CNVM regression and allowing improvement of visual acuity.

The Subject Is a Patient.

Although it is common in academic and government research settings to speak of study participants as "subjects," this perspective piece argues against doing so. In particular, the relationship of the study physician with study participants is unique and still retains many elements of the usual patient-physician relationship that exists in general clinical practice.

The Opioid Overdose Resuscitation Education for Addiction Counselors and Trainees (Opioid Overdose REACT) naloxone response education pilot project improved confidence and knowledge among addiction counselors and trainees.

INTRODUCTION: Community programs to teach nonmedical laypeople how to recognize an opioid overdose and effectively resuscitate the victim using naloxone have proliferated recently as a significant component of harm-reduction efforts. Although many such programs target laypeople like first responders or friends and family members of people who use drugs, there are currently no programs that specifically target addiction counselors, despite their work with a client population at high risk of an opioid overdose. METHODS: The four-hour curriculum designed by the authors covered opioid agonist and antagonist pharmacology; opioid toxidrome signs; legal implications and indications for using the naloxone kits; and hands-on training. Participants were two cohorts of addiction counselors and addiction counseling trainees at our institution and an affiliated Opioid Treatment Program methadone clinic. Surveys testing participant knowledge and confidence were conducted at baseline, immediately post-training, six months post-training, and 12 months post-training. RESULTS: Overall, opioid and naloxone pharmacology knowledge, as well as the confidence to intervene in an overdose emergency, improved among participants in both cohorts. Knowledge scores at baseline (n = 36, median 5/10) improved significantly immediately post-training (n = 31, median 7/10, P < 0.0001, Wilcoxon signed-rank test) and were sustained six (n = 19) and 12 months (n = 11) later. Two participants reported using their naloxone kits to successfully reverse a client overdose in the 12 months after taking the course. DISCUSSION: These results from our knowledge translation pilot project suggest that our educational program to train addiction counselors in opioid pharmacology and toxicology, allowing them to recognize and respond to an opioid overdose, is feasible and could be effective. Specific barriers to implementing such educational programs include cost, stigma, and unclear best practice for designing and conducting these programs. CONCLUSIONS: Further study of providing opioid pharmacology education and overdose and naloxone training to addiction counselors and counseling trainees appears to be warranted.

Investigating the temporal roles of decorin and biglycan in tendon healing.

The small leucine-rich proteoglycans, decorin and biglycan, are minor components of the tendon extracellular matrix that regulate fibrillogenesis and matrix assembly. Our study objective was to define the temporal roles of decorin and biglycan during tendon healing using inducible knockout mice to include genetic knockdown at specific phases of healing: time of injury, the proliferative phase, and the remodeling phase. We hypothesized that knockdown of decorin or biglycan would adversely affect tendon healing, and that by prescribing the timing of knockdown, we could elucidate the temporal roles of these proteins during healing. Contrary to our hypothesis, decorin knockdown did not affect tendon healing. However, when biglycan was knocked down, either alone or coupled with decorin, tendon modulus was increased relative to wild-type mice, and this finding was consistent among all induction timepoints. At 6 weeks postinjury, we observed increased expression of genes associated with the extracellular matrix and growth factor signaling in the biglycan knockdown and compound decorin-biglycan knockdown tendons. Interestingly, these groups demonstrated opposing trends in gene expression as a function of knockdown-induction timepoint, highlighting distinct temporal roles for decorin and biglycan. In summary, this study finds that biglycan plays multiple functions throughout tendon healing, with the most impactful, detrimental role likely occurring during late-stage healing. Statement of clinical importance: This study helps to define the molecular factors that regulate tendon healing, which may aid in the development of new clinical therapies.

Examining the paradoxical effects of kratom: a narrative inquiry.

Introduction: Surveys and case reports have documented kratom use in the United States (US) for over a decade. However, those reports have generally not examined in depth the role kratom plays in the lives of those who use it regularly for sustained periods. Until there are controlled studies of the pharmacology and subjective effects of kratom alkaloids in humans, one of the best sources of insight on kratom-product use remains qualitative data with nuanced descriptions of kratom effects from those who use it regularly. Method: We conducted semistructured qualitative interviews with adults who regularly use kratom products, as part of a laboratory study of kratom-product self-administration. This qualitative component of the study was conducted as a narrative case-report series (n = 10). Results: Despite some differences among participants, all experienced acute combination effects that were largely, even simultaneously, analgesic and stimulatory. Most participants had decreased their dosages over time, and one planned to quit. Five of the 10 participants met DSM-5-based criteria for kratom-use disorder (3 mild, 1 moderate, 1 severe, by symptoms counts). When kratom was inadvertently taken in larger than intended doses, participants described a constellation of symptoms that they called "the wobbles" (a jittery feeling accompanied by what seemed to be nystagmus); this was rare, but could be of scientific and clinical interest as a possible manifestation of serotonin syndrome. Most participants described tolerance but considered kratom generally safe at low-moderate doses, providing perceived benefits with less potential risk for adverse effects compared to pharmaceuticals or illicit drugs. Discussion: In-depth interview data like these help confirm and clarify findings from larger survey studies and clinician-driven case reports. They are needed to inform the policy practice regarding kratom and may also help inform future experimental designs.

Knockdown of biglycan reveals an important role in maintenance of structural and mechanical properties during tendon aging.

Biglycan, a small leucine-rich proteoglycan (SLRP), is involved in collagen fibrillogenesis and also acts as a signaling molecule. Although decorin has been considered as the primary SLRP in developing and maintaining tendon structure and mechanics, more recent work using inducible knockdown models suggests that biglycan is involved in tendon homeostasis. The purpose of the study was to determine the role of biglycan in tendon homeostasis to maintain mechanical and structural integrity in aged mice. Aged (485 days old) female Bgn+/+ control (wild type [WT], n = 16) and 16 bitransgenic conditional Bgnflox/flox mice (I-Bgn-/- , n = 16) with a tamoxifen-inducible Cre (driven by ROSA) were utilized. After biglycan knockdown, the transgenic model demonstrated effective knockdown of the target gene without any compensation from other SLRPs or type I collagen. Patellar tendon cellularity was not modified after biglycan knockdown. However, biglycan knockdown had an impact on collagen fibrillogenesis with a higher percentage of small diameter fibrils (25-45 nm) and a lower percentage of medium size fibrils (150-165 nm) in I-Bgn-/- tendons. Biglycan knockdown also induced a reduction in the midsubstance modulus and maximum stress compared to WT. Stress relaxation was reduced at 4% strain in I-Bgn-/- tendons but no changes were observed in dynamic modulus and tan delta. As in mature tendons (120 days old), this study showed significant effects of biglycan knockdown on mechanical and structural properties of aged tendons only 30 days after knockdown. These data suggest that biglycan has a major role in maintaining homeostasis in aged tendon.

NCCN Guidelines® Insights: Central Nervous System Cancers, Version 2.2022.

The NCCN Guidelines for Central Nervous System (CNS) Cancers focus on management of the following adult CNS cancers: glioma (WHO grade 1, WHO grade 2-3 oligodendroglioma [1p19q codeleted, IDH-mutant], WHO grade 2-4 IDH-mutant astrocytoma, WHO grade 4 glioblastoma), intracranial and spinal ependymomas, medulloblastoma, limited and extensive brain metastases, leptomeningeal metastases, non-AIDS-related primary CNS lymphomas, metastatic spine tumors, meningiomas, and primary spinal cord tumors. The information contained in the algorithms and principles of management sections in the NCCN Guidelines for CNS Cancers are designed to help clinicians navigate through the complex management of patients with CNS tumors. Several important principles guide surgical management and treatment with radiotherapy and systemic therapy for adults with brain tumors. The NCCN CNS Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel's most recent recommendations regarding molecular profiling of gliomas.

Multicenter analysis of stereotactic radiosurgery for multiple brain metastases from EGFR and ALK driven non-small cell lung cancer.

INTRODUCTION: Patients with brain metastases (BrMs) arising from EGFR and ALK driven non-small cell lung cancer (NSCLC) have favorable prognoses and evolving treatment options. We evaluated multicenter outcomes for stereotactic radiosurgery (SRS) to multiple (≥4) BrMs, where randomized data remain limited. METHODS: Data were collected retrospectively from 5 academic centers on EGFR and ALK NSCLC who received SRS to ≥4 BrMs with their first SRS treatment between 2008 and 2018. Analyzed endpoints included overall survival (OS), freedom from CNS progression (FFCNSP), and freedom from whole-brain radiotherapy (FFWBRT). RESULTS: Eighty-nine patients (50 EGFR, 39 ALK) received a total of 159 SRS treatments to 1,080 BrMs, with a median follow up of 51.3 months. The median number of BrMs treated with SRS treatment-1 was 6 (range 4-26) and median for all treatments was 9 (range 4-47). Sixteen patients (18 %) had received WBRT prior to SRS treatment-1. The median OS was 24.2, 21.2, and 33.2 months for all patients, EGFR, and ALK subsets, respectively. After multivariable adjustment, only receipt of a next-generation tyrosine kinase inhibitor was associated with OS (HR 0.40, p = 0.005). No differences in OS were observed based on number of BrMs treated. The median FFCNSP was 9.4, 11.6, and 7.5 months, for all patients, EGFR, and ALK subsets, respectively. After multivariable adjustment, the number of BrMs (continuous) treated during treatment-1 was the only negative prognostic factor associated with FFCNSP (HR 1.071, p = 0.045). The 5-year FFWBRT was 73.6 %. CONCLUSIONS: This multicenter analysis over a >10-year period demonstrated favorable OS, FFCNSP, and FFWBRT, in patients with EGFR and ALK driven NSCLC receiving SRS to ≥4 BrMs. These data support SRS as an option in the upfront and salvage setting for higher burden CNS disease in this population.