Immune checkpoint inhibition in patients treated with stereotactic radiation for brain metastases.

PURPOSE: Stereotactic radiation therapy (SRT) and immune checkpoint inhibitors (ICI) may act synergistically to improve treatment outcomes but may also increase the risk of symptomatic radiation necrosis (RN). The objective of this study was to compare outcomes for patients undergoing SRT with and without concurrent ICI. METHODS AND MATERIALS: Patients treated for BMs with single or multi-fraction SRT were retrospectively reviewed. Concurrent ICI with SRT (SRT-ICI) was defined as administration within 3 months of SRT. Local control (LC), radiation necrosis (RN) risk and distant brain failure (DBF) were estimated by the Kaplan-Meier method and compared between groups using the log-rank test. Wilcoxon rank sum and Chi-square tests were used to compare covariates. Multivariate cox regression analysis (MVA) was performed. RESULTS: One hundred seventy-nine patients treated with SRT for 385 brain lesions were included; 36 patients with 99 lesions received SRT-ICI. Median follow up was 10.3 months (SRT alone) and 7.7 months (SRT- ICI) (p = 0.08). Lesions treated with SRT-ICI were more commonly squamous histology (17% vs 8%) melanoma (20% vs 2%) or renal cell carcinoma (8% vs 6%), (p < 0.001). Non-small cell lung cancer (NSCLC) compromised 60% of patients receiving ICI (n = 59). Lesions treated with SRT-ICI had significantly improved 1-year local control compared to SRT alone (98 and 89.5%, respectively (p = 0.0078). On subset analysis of NSCLC patients alone, ICI was also associated with improved 1 year local control (100% vs. 90.1%) (p = 0.018). On MVA, only tumor size ≤2 cm was significantly associated with LC (HR 0.38, p = 0.02), whereas the HR for concurrent ICI with SRS was 0.26 (p = 0.08). One year DBF (41% vs. 53%; p = 0.21), OS (58% vs. 56%; p = 0.79) and RN incidence (7% vs. 4%; p = 0.25) were similar for SRT alone versus SRT-ICI, for the population as a whole and those patients with NSCLC. CONCLUSION: These results suggest SRT-ICI may improve local control of brain metastases and is not associated with an increased risk of symptomatic radiation necrosis in a cohort of predominantly NSCLC patients. Larger, prospective studies are necessary to validate these findings and better elucidate the impact of SRT-ICI on other disease outcomes.

A multi-center analysis of single-fraction versus hypofractionated stereotactic radiosurgery for the treatment of brain metastasis.

BACKGROUND: Hypofractionated-SRS (HF-SRS) may allow for improved local control and a reduced risk of radiation necrosis compared to single-fraction-SRS (SF-SRS). However, data comparing these two treatment approaches are limited. The purpose of this study was to compare clinical outcomes between SF-SRS versus HF-SRS across our multi-center academic network. METHODS: Patients treated with SF-SRS or HF-SRS for brain metastasis from 2013 to 2018 across 5 radiation oncology centers were retrospectively reviewed. SF-SRS dosing was standardized, whereas HF-SRS dosing regimens were variable. The co-primary endpoints of local control and radiation necrosis were estimated using the Kaplan Meier method. Multivariate analysis using Cox proportional hazards modeling was performed to evaluate the impact of select independent variables on the outcomes of interest. Propensity score adjustments were used to reduce the effects confounding variables. To assess dose response for HF-SRS, Biologic Effective Dose (BED) assuming an α/ß of 10 (BED10) was used as a surrogate for total dose. RESULTS: One-hundred and fifty six patients with 335 brain metastasis treated with SF-SRS (n = 222 lesions) or HF-SRS (n = 113 lesions) were included. Prior whole brain radiation was given in 33% (n = 74) and 34% (n = 38) of lesions treated with SF-SRS and HF-SRS, respectively (p = 0.30). After a median follow up time of 12 months in each cohort, the adjusted 1-year rate of local control and incidence of radiation necrosis was 91% (95% CI 86-96%) and 85% (95% CI 75-95%) (p = 0.26) and 10% (95% CI 5-15%) and 7% (95% CI 0.1-14%) (p = 0.73) for SF-SRS and HF-SRS, respectively. For lesions > 2 cm, the adjusted 1 year local control was 97% (95% CI 84-100%) for SF-SRS and 64% (95% CI 43-85%) for HF-SRS (p = 0.06). On multivariate analysis, SRS fractionation was not associated with local control and only size ≤2 cm was associated with a decreased risk of developing radiation necrosis (HR 0.21; 95% CI 0.07-0.58, p < 0.01). For HF-SRS, 1 year local control was 100% for lesions treated with a BED10 ≥ 50 compared to 77% (95% CI 65-88%) for lesions that received a BED10 < 50 (p = 0.09). CONCLUSIONS: In this comparison study of dose fractionation for the treatment of brain metastases, there was no difference in local control or radiation necrosis between HF-SRS and SF-SRS. For HF-SRS, a BED10 ≥ 50 may improve local control.

A developmental-based motivational intervention to reduce alcohol and marijuana use among non-treatment-seeking young adults: a randomized controlled trial.

AIMS: To test the hypothesis that among non-treatment-seeking emerging adults (EA) who both use marijuana and have alcohol binges, a brief, longitudinally delivered, developmentally based motivational intervention would show greater reductions in the use of these two substances compared with a health education control condition. DESIGN: Parallel, two-group, randomized controlled trial with follow-up interventions conducted at 1, 3, 6 and 9 months and final assessments at 12 and 15 months. SETTING: Hospital-based research unit in the United States. PARTICIPANTS: Community-based 18-25-year-olds who reported at least monthly binge drinking and at least weekly marijuana use. INTERVENTION: Motivational intervention (EA-MI) focused primarily on themes of emerging adulthood (identity exploration, instability, self-focus, feeling in-between, a sense of possibilities) and the subjects' relationship to substance use (n = 110) compared with an attention-matched health education control condition (n = 116). MEASUREMENTS: The primary outcomes were days of binge alcohol, marijuana and dual use day as measured using the timeline follow-back method analysing the treatment by time interaction to determine relative differences in the rate of change between intervention arms. FINDINGS: At baseline, the mean rate (days/30) of binge drinking was 5.23 (± 4.31) of marijuana use was 19.4 (± 10.0) and of dual (same day) use was 4.11 (± 4.13). Relative to baseline, there were reductions in the rate of binge alcohol use, marijuana use and days of combined binge alcohol and marijuana use (P < 0.001) at all follow-up assessments. However, the treatment × time interaction was not statistically significant for alcohol (P = 0.37), for marijuana (P = 0.07) or for dual use (P = 0.55). Averaged over all follow-ups, mean reductions in binge, marijuana and dual use days were 1.16, 1.45 and 1.08, respectively, in the health education arm, and 1.06, 1.69 and 0.96 in EA-MI. Bayes factors were < 0.01 for frequency of binge alcohol use and frequency of dual binge alcohol and marijuana and 0.016 for marijuana use. CONCLUSIONS: A brief, longitudinally delivered, developmentally based motivational intervention for young adults did not produce reductions in binge alcohol, marijuana use or dual use days relative to a control condition.

Cognitive Functioning After Hematopoietic Cell Transplantation for Hematologic Malignancy: Results From a Prospective Longitudinal Study.

Purpose Cognitive impairment is well-recognized after myeloablative allogeneic hematopoietic cell transplantation (HCT). However, cognitive functioning after reduced-intensity allogeneic or autologous HCT remains unclear. Methods A total of 477 HCT recipients (236 autologous, 128 reduced-intensity allogeneic, 113 myeloablative allogeneic) underwent standardized neuropsychologic testing before HCT and at 6 months and 1, 2, and 3 years after HCT. Ninety-nine frequency-matched healthy controls underwent testing at commensurate time points. Primary outcomes of the study were practice effect-adjusted domain-specific T scores and global deficit scores. Piecewise generalized estimating equation models were used to compare groups and to identify associated variables and post-HCT trends of cognitive impairment. Results Median age was 52 years (range, 18 to 74 years) for HCT recipients and 55 years (range, 19 to 73 years) for controls. Post-HCT scores were comparable between controls and autologous and reduced-intensity HCT recipients. Myeloablative HCT recipients had significantly lower ( P < .001) post-HCT scores than controls for executive function, verbal speed, processing speed, auditory memory, and fine motor dexterity. Pre-HCT to 6 months post-HCT scores did not change after reduced-intensity HCT but declined significantly for fine motor dexterity ( P < .001) after myeloablative HCT. However, pre-HCT to 3 years post-HCT scores declined significantly ( P < .003) in reduced-intensity HCT recipients for executive function, verbal fluency, and working memory. Older age, male sex, and lower education, income, and cognitive reserve were associated with post-HCT cognitive impairment. At 3 years post-HCT, global cognitive impairment was present in 18.7% of autologous and 35.7% of allogeneic HCT recipients. Conclusion Myeloablative allogeneic HCT recipients showed significant cognitive decline compared with healthy controls. Reduced-intensity allogeneic HCT recipients showed evidence of delayed decline. Cognitive functioning in autologous HCT recipients generally was spared. The study identified vulnerable subpopulations that could benefit from targeted interventions.

Dramatic Response of a Large Sacral Chordoma to Intensity Modulated Proton Beam Therapy.

Sacral chordomas are slow-growing, indolent, and locally invasive tumors that typically present with pain and neurologic dysfunction. Wide en-bloc surgical excision is the primary treatment, but achieving adequate margins is difficult and surgery is often associated with significant morbidity. Adjuvant radiation therapy (RT) is utilized to decrease the risk of local recurrence or as definitive treatment for nonsurgical candidates. Although chordomas are considered to be relatively radioresistant tumors, several studies have demonstrated tumor response to high-dose proton therapy. Here, we present a patient with a large sacral chordoma who underwent definitive treatment with intensity-modulated proton therapy (IMPT).

Ethnic variations in parental ethnic socialization and adolescent ethnic identity: a longitudinal study.

Achievement of a positive ethnic identity has been linked to positive outcomes for ethnic minority youth and is fostered by parental ethnic socialization practices. In light of findings of variability in developmental trajectories and outcomes, we examined ethnic group variations in parents' ethnic socialization practices and adolescents' ethnic identity. Within a sample of 370 adolescents who self-identified as White, African American, Latino/a, or Asian American, and their parents, parental ethnic socialization practices (including preparation for bias, promotion of mistrust, and cultural socialization) and adolescent ethnic identity development (including identity exploration and commitment) were assessed at 10th and 11th grades. Consistent with predictions, African American youth reported higher levels of ethnic identity exploration and commitment than youth from other ethnic groups, and parents of African American youth tended to report higher levels of ethnic socialization than other parents. Parental cultural socialization significantly predicted adolescent ethnic identity exploration and commitment 1 year later; ethnicity did not moderate this link. Findings are discussed in the context of the schools and urban community from which the sample was recruited, highlighting the importance of sociocultural context in development.

Preparticipation screening and prevention of sudden cardiac death in athletes: implications for primary care.

PURPOSES: The purposes of this article are to explore the mechanism of sudden cardiac death (SCD) in young athletes and examine how preparticipation screenings help identify precipitating cardiac abnormalities. Electrocardiogram (ECG) testing has been implicated to play an important role in detecting subtle abnormalities that may cause SCD, but the routine implementation of this diagnostic tool remains a debate among experts. DATA SOURCES: This report was compiled by reviewing the scientific literature on SCD in athletes, preparticipation exams, and current screening guidelines using CINAHL, MEDLINE, and PubMed search engines. CONCLUSIONS: Although the American Heart Association guidelines do not include ECG testing for preparticipation screenings, the implementation of routine ECG testing for preparticipation sports physicals is effective in preventing SCD in athletes. IMPLICATIONS FOR PRACTICE: Primary care providers should be aware of current guidelines for screening patients for heart diseases that predispose them to SCD and their legal obligations to be sure these athletes are safe. The implementation of ECG testing will assist in the decision whether to disqualify an athlete from participation as a result of preexisting cardiac conditions, and ultimately preventing the untimely death of a young athlete.

Visual abnormalities associated with enhanced optic nerve myelination.

Expression of the constitutively active serine/threonine kinase Akt in oligodendrocytes results in enhanced myelination in the CNS. Here, we have examined the effects of this Akt overexpression on optic nerve structure and on optic nerve function, assessed using the visual evoked potential (VEP). Transgenic mice have been generated with the Plp promoter driving expression of a modified form of Akt, in which aspartic acids are substituted for Thr308 and Ser473. These Plp-Akt-DD (Akt-DD) mice, and littermate controls, were studied at different ages. Optic nerves were examined anatomically at 2 and 6 months of age. At 2 months of age, optic nerves were substantially thicker in Akt-DD mice, reflecting an increase in myelination of optic nerve axons. By electron microscopy, myelin thickness was increased in Akt-DD optic nerve, with extended paranodal domains having excess paranodal loops, and the density of nodes of Ranvier was reduced, relative to control mice. We recorded VEPs in response to strobe flash ganzfeld stimuli presented after overnight dark- and light-adapted conditions at ages ranging from 1 to 10 months. It was possible to record a clear VEP from Akt-DD mice at all ages examined. At 1 month of age, VEP implicit times were somewhat shorter in Akt-DD transgenic mice than in control animals. Beyond 6months of age, VEP latencies were consistently delayed in Akt-DD transgenic mice. These abnormalities did not reflect an alteration in retinal function as there were no significant differences between ERGs obtained from control or Akt-DD transgenic mice. In young mice, the somewhat faster responses may reflect improved transmission due to increased myelination of optic nerve axons. In older mice, where the Akt-DD optic nerve is markedly thicker than control, it is remarkable that optic nerves continue to function.

Constitutively active Akt induces enhanced myelination in the CNS.

The serine/threonine kinase Akt regulates multiple cellular functions. The current studies identify a new role for Akt in CNS myelination. In earlier studies on cultured oligodendrocytes, we showed that neuregulin signals through phosphatidylinositol-3'-OH kinase and Akt to enhance survival of oligodendrocytes. However, when transgenic animals were generated that overexpressed constitutively active Akt in oligodendrocytes and their progenitor cells, no enhanced survival of oligodendrocytes or progenitors was found. No alteration in the proliferation or death of progenitors was noted. In contrast, the major impact of Akt overexpression in oligodendrocytes was enhanced myelination. Most interestingly, oligodendrocytes in these mice continued actively myelinating throughout life. Thus, expression of constitutively active Akt in oligodendrocytes and their progenitor cells generated no more oligodendrocytes, but dramatically more myelin. The increased myelination continued as these mice aged, resulting in enlarged optic nerves and white matter areas. In older animals with enlarged white matter areas, the density of oligodendrocytes was reduced, but because of the increased area, the total number of oligodendrocytes remained comparable with wild-type controls. Interestingly, in these animals, overexpression of Akt in Schwann cells did not impact myelination. Thus, in vivo, constitutively active Akt enhances CNS myelination but not PNS myelination and has no impact developmentally on oligodendrocyte number. Understanding the unique aspects of Akt signal transduction in oligodendrocytes that lead to myelination rather than uncontrolled proliferation of oligodendrocyte progenitor cells may have important implications for understanding remyelination in the adult nervous system.