Beyond School Climate: Validating the School as a Protective Factor-Brief Survey.

BACKGROUND: The conceptual framework for School as a Protective Factor approach was presented in a companion article in this issue of the journal. The current article describes the validation of the School as a Protective Factor-Brief (SPF-Brief), a 13-item survey measuring the 3 core constructs and 13 defining characteristics of this framework. METHODS: The SPF-Brief was validated through 2 studies. The developmental study used a longitudinal design including 1349 participants who completed surveys over 5 semesters, while the validation study used a cross-sectional design with 2775 participants. Both studies included middle and high school students. Factor analysis, growth model analysis, criterion-related validation, and outcome analysis were employed. RESULTS: Analyses provided strong evidence supporting the reliability and validity of the instrument and conceptual framework. Higher SPF-Brief scores were associated with higher math grades, English grades, and quality of life, as well as lower rates of anxiety, depression, conduct disorder, alcohol, e-cigarette, tobacco, and cannabis use. Effect size estimates ranged from moderate to strong. CONCLUSIONS: These findings suggest the utility of the SPF-Brief instrument and the School as a Protective Factor framework. Together, they may offer advantages to the traditional school climate approach.

Postoperative shunt failure following hemispherectomy in pediatric patients with pre-existing hydrocephalus.

OBJECTIVE: The risk of hydrocephalus following hemispherectomy for drug resistant epilepsy (DRE) remains high. Patients with pre-existing hydrocephalus pose a postoperative challenge, as maintaining existing shunt patency is necessary but lacks a clearly defined strategy. This study examines the incidence and predictors of shunt failure in pediatric hemispherectomy patients with pre-existing ventricular shunts. METHODS: We performed a retrospective chart review at our center to identify pediatric patients diagnosed with DRE who were treated with ventricular shunt prior to their first hemispherectomy surgery. Demographic and perioperative data were obtained including shunt history, hydrocephalus etiology, epilepsy duration, surgical technique, and postoperative outcomes. Univariate analysis was performed using Fisher's exact test and Pearson correlation, with Bonferroni correction to a = 0.00625 and a = 0.01, respectively. RESULTS: Five of nineteen (26.3%) patients identified with ventriculoperitoneal shunting prior to hemispherectomy experienced postoperative shunt malfunction. All 5 of these patients underwent at least 1 shunt revision prior to hemispherectomy, with a significant association between pre- and post-hemispherectomy shunt revisions. There was no significant association between post-hemispherectomy shunt failure and valve type, intraoperative shunt alteration, postoperative external ventricular drain placement, hemispherectomy revision, lateralization of shunt relative to resection, postoperative complications, or postoperative aseptic meningitis. There was no significant correlation between number of post-hemispherectomy shunt revisions and age at shunt placement, age at hemispherectomy, epilepsy duration, or shunt duration prior to hemispherectomy. CONCLUSIONS: Earlier shunt revision surgery may portend a subsequent need for shunt revision following hemispherectomy. These findings may guide neurosurgeons in counseling patients with pre-existing ventricular shunts prior to hemispherectomy surgery.

Predictive factors of hydrocephalus development in pediatric patients undergoing hemispherectomy for intractable epilepsy.

OBJECTIVE: Hemispherectomy surgery is an effective procedure for pediatric patients with intractable hemispheric epilepsy. Hydrocephalus is a well-documented complication of hemispherectomy contributing substantially to patient morbidity. Despite some clinical and operative factors demonstrating an association with hydrocephalus development, the true mechanism of disease is incompletely understood. The aim of this study was to investigate a range of clinical and surgical factors that may contribute to hydrocephalus to enhance understanding of the development of this complication and to aid the clinician in optimizing peri- and postoperative surgical management. METHODS: A retrospective chart review was conducted on all pediatric patients younger than 21 years who underwent hemispherectomy surgery at the Cleveland Clinic between 2002 and 2016. Data collected for each patient included general demographic information, neurological and surgical history, surgical technique, pathological analysis, presence and duration of perioperative CSF diversion, CSF laboratory values obtained while an external ventricular drain (EVD) was in place, length of hospital stay, postoperative aseptic meningitis, and in-hospital surgical complications (including perioperative stroke, hematoma formation, wound breakdown, and/or infection). Outcomes data included hemispherectomy revision and Engel grade at last follow-up (based on the Engel Epilepsy Surgery Outcome Scale). RESULTS: Data were collected for 204 pediatric patients who underwent hemispherectomy at the authors' institution. Twenty-eight patients (14%) developed hydrocephalus requiring CSF diversion. Of these 28 patients, 13 patients (46%) presented with hydrocephalus during the postoperative period (within 90 days), while the remaining 15 patients (54%) presented later (beyond 90 days after surgery). Multivariate analysis revealed postoperative aseptic meningitis (OR 7.0, p = 0.001), anatomical hemispherectomy surgical technique (OR 16.3 for functional/disconnective hemispherectomy and OR 7.6 for modified anatomical, p = 0.004), male sex (OR 4.2, p = 0.012), and surgical complications (OR 3.8, p = 0.031) were associated with an increased risk of hydrocephalus development, while seizure freedom (OR 0.3, p = 0.038) was associated with a decreased risk of hydrocephalus. CONCLUSIONS: Hydrocephalus remains a prominent complication following hemispherectomy, presenting both in the postoperative period and months to years after surgery. Aseptic meningitis, anatomical hemispherectomy surgical technique, male sex, and surgical complications show an association with an increased rate of hydrocephalus development while seizure freedom postsurgery is associated with a decreased risk of subsequent hydrocephalus. These findings speak to the multifactorial nature of hydrocephalus development and should be considered in the management of pediatric patients undergoing hemispherectomy for medically intractable epilepsy.

The impact of adjuvant EGFR-TKIs and 14-gene molecular assay on stage I non-small cell lung cancer with sensitive EGFR mutations.

Background: Currently, the role of EGFR-TKIs as adjuvant therapy for stage I, especially IA NSCLC, after surgical resection remains unclear. We aimed to compare the effect of adjuvant EGFR-TKIs with observation in such patients by incorporating an established 14-gene molecular assay for risk stratification. Methods: This retrospective cohort study was conducted at the First Affiliated Hospital of Guangzhou Medical University (Study ID: ChNCRCRD-2022-GZ01). From March 2013 to February 2019, completely resected stage I NSCLC (8th TNM staging) patients with sensitive EGFR mutation were included. Patients with eligible samples for molecular risk stratification were subjected to the 14-gene prognostic assay. Inverse probability of treatment weighting (IPTW) was employed to minimize imbalances in baseline characteristics. Findings: A total of 227 stage I NSCLC patients were enrolled, with 55 in EGFR-TKI group and 172 in the observation group. The median duration of follow-up was 78.4 months. After IPTW, the 5-year DFS (HR = 0.30, 95% CI, 0.14-0.67; P = 0.003) and OS (HR = 0.26, 95% CI, 0.07-0.96; P = 0.044) of the EGFR-TKI group were significantly better than the observation group. For subgroup analyses, adjuvant EGFR-TKIs were associated with favorable 5-year DFS rates in both IA (100.0% vs. 84.5%; P = 0.007), and IB group (98.8% vs. 75.3%; P = 0.008). The 14-gene assay was performed in 180 patients. Among intermediate-high-risk patients, EGFR-TKIs were associated with a significant improvement in 5-year DFS rates compared to observation (96.0% vs. 70.5%; P = 0.012), while no difference was found in low-risk patients (100.0% vs. 94.9%; P = 0.360). Interpretation: Our study suggested that adjuvant EGFR-TKI might improve DFS and OS of stage IA and IB EGFR-mutated NSCLC, and the 14-gene molecular assay could help patients that would benefit the most from treatment. Funding: This work was supported by China National Science Foundation (82022048, 82373121).

Possible role of caffeine in nicotine use onset among early adolescents: Evidence from the Young Mountaineer Health Study Cohort.

BACKGROUND: Preventing nicotine use onset among children and youth is an important public health goal. One possible contributor that has received little empirical investigation is caffeine use. The goal of this study was to examine the possible contribution of caffeine to nicotine onset during early adolescence. METHODS: We used data from the Young Mountaineer Health Study Cohort. Survey data were collected from 1,349 (response rate: 80.7%) 6th grade students (mean age at baseline 11.5 years) in 20 middle schools in West Virginia during the fall of 2020 and spring of 2021. We limited our analyses to students reporting never having used any form of nicotine at baseline. Logistic regression was employed in analyses. RESULTS: Approximately 8% of participants reported having used nicotine at least once between baseline and the follow-up, and 4.7% reported solely using electronic nicotine delivery systems (ENDS) and no other forms of nicotine. In multivariable analyses, we controlled for many environmental, social, and behavioral variables known to influence nicotine use such as alcohol use, peer substance use, and perceived access to nicotine. We formulated our main independent variable, caffeine consumption, as continuous deciles. Any nicotine use, as well as ENDS use only at follow-up, were modeled as dependent variables. Caffeine was significantly associated with nicotine use in both models with ORs of 1.15 (1.04-1.27) and 1.13 (1.00-1.28). CONCLUSIONS: Caffeine consumption among 6th grade non-nicotine users was associated with nicotine use at approximately 6-months follow-up.

Preliminary impact of the adoption of the Icelandic Prevention Model in Tarragona City, 2015-2019: A repeated cross-sectional study.

Background: There is a great need for effective primary prevention intervention strategies to reduce and delay onset of adolescent substance use. The Icelandic Prevention Model (IPM) showed great success in Iceland over the past twenty plus years, however, evidence for the transferability of model is still somewhat limited. Using data collected in Tarragona during regional efforts to begin adoption of the IPM in Catalonia, this study tested the transferability and stability of the core risk and protective factor assumptions of the IPM overtime and examined trends of lifetime smoking, e-cigarette-use, alcohol-use, intoxication, and cannabis-use within the same time period. Methods: This study includes responses from 15- to 16-years-olds from two region-wide samples taken in 2015 and 2019 in Tarragona (N = 2,867). Survey questions assessed frequency of lifetime: smoking, e-cigarette-use, alcohol-use, intoxication, and cannabis-use, and the core model assumptions. Demographic data were also collected. Logistic regression models of main effects with and without time interaction were used to test assumptions and their stability across time. Chi-square tests and Wilcoxon-Mann-Whitney U tests were used to compare prevalence of substance use and mean scores of primary prevention variables respectively. Results: Lifetime: smoking (-7%, p < 0.001) and cannabis-use (-4%, p < 0.001) decreased, and e-cigarette-use increased (+33%, p < 0.001) in Tarragona. Lifetime intoxication (-7%, p < 0.001) decreased in a single zone exclusively. Most core model assumptions held in their hypothesised direction across time. The strongest positive association was observed between time spent with parents during weekends and reduced odds of lifetime smoking (OR: 0.62, 95%CI: 0.57-0.67) and the strongest negative association was observed between being outside after midnight and increased odds of lifetime intoxication (OR: 1.41, 95%CI: 1.32-1.51). Mean scores of primary prevention variables also changed disproportionately in Tarragona. Conclusion: This study confirms that the core IPM assumptions are similar in Tarragona as in Iceland and other contexts previously examined. They also indicate that prevalence of lifetime smoking, intoxication, and cannabis-use decreased disproportionately in Tarragona between 2015 and 2019 during the first phase of regional adoption of the model. Thus, targeting model assumptions represents a viable primary prevention strategy for communities that hope to reduce smoking, alcohol-use, intoxication, and cannabis-use among adolescents.

Management of Patients with Spine Tumors Strengthened by a Dedicated Multidisciplinary Spine Tumor Board: A 15-Year Single-Institutional Experience.

BACKGROUND: Patients with spine tumors frequently require timely, multistep, and multidisciplinary care. A Spine Tumor Board (STB) provides a consistent forum wherein diverse specialists can interact, facilitating complex coordinated care for these patients. This study aims to present a single, large academic center's STB experience specifically reviewing case diversity, recommendations, and quantifying growth over time. METHODS: All patient cases discussed at STB from May 2006 (STB inception) to May 2021 were evaluated. Collected data submitted by presenting physicians and formal documentation completed during the STB are summarized. RESULTS: A total of 4549 cases were reviewed by STB over the study period, representing 2618 unique patients. Over the course of the study, a 266% increase in number of cases presented per week was observed (4.1 to 15.0). Cases were presented by surgeons (74%), radiation oncologists (18%), neurologists (2%), and other specialists (6%). The most common pathologic diagnoses discussed were spinal metastases (n = 1832; 40%), intradural extramedullary tumors (n = 798; 18%), and primary glial tumors (n = 567; 12%). Treatment recommendations included surgery, radiation therapy, or systemic therapy for 1743 cases (38%), continued routine follow-up/expectant management for 1592 cases (35%), supplementary imaging to better clarify the diagnosis for 549 cases (12%), and variable tailored recommendations for the remainder of cases (18%). CONCLUSIONS: Care of patients with spine tumors is complex. We believe that the formation of a stand-alone STB is instrumental to accessing multidisciplinary input, enhancing confidence in management decisions for both patients and providers, assisting with care orchestration, and improving quality of care for patients with spine tumors.

Transposon Mutagenesis Reveals RBMS3 Silencing as a Promoter of Malignant Progression of BRAFV600E-Driven Lung Tumorigenesis.

Mutationally activated BRAF is detected in approximately 7% of human lung adenocarcinomas, with BRAFT1799A serving as a predictive biomarker for treatment of patients with FDA-approved inhibitors of BRAFV600E oncoprotein signaling. In genetically engineered mouse (GEM) models, expression of BRAFV600E in the lung epithelium initiates growth of benign lung tumors that, without additional genetic alterations, rarely progress to malignant lung adenocarcinoma. To identify genes that cooperate with BRAFV600E for malignant progression, we used Sleeping Beauty-mediated transposon mutagenesis, which dramatically accelerated the emergence of lethal lung cancers. Among the genes identified was Rbms3, which encodes an RNA-binding protein previously implicated as a putative tumor suppressor. Silencing of RBMS3 via CRISPR/Cas9 gene editing promoted growth of BRAFV600E lung organoids and promoted development of malignant lung cancers with a distinct micropapillary architecture in BRAFV600E and EGFRL858R GEM models. BRAFV600E/RBMS3Null lung tumors displayed elevated expression of Ctnnb1, Ccnd1, Axin2, Lgr5, and c-Myc mRNAs, suggesting that RBMS3 silencing elevates signaling through the WNT/ß-catenin signaling axis. Although RBMS3 silencing rendered BRAFV600E-driven lung tumors resistant to the effects of dabrafenib plus trametinib, the tumors were sensitive to inhibition of porcupine, an acyltransferase of WNT ligands necessary for their secretion. Analysis of The Cancer Genome Atlas patient samples revealed that chromosome 3p24, which encompasses RBMS3, is frequently lost in non-small cell lung cancer and correlates with poor prognosis. Collectively, these data reveal the role of RBMS3 as a lung cancer suppressor and suggest that RBMS3 silencing may contribute to malignant NSCLC progression. SIGNIFICANCE: Loss of RBMS3 cooperates with BRAFV600E to induce lung tumorigenesis, providing a deeper understanding of the molecular mechanisms underlying mutant BRAF-driven lung cancer and potential strategies to more effectively target this disease.

Caffeine consumption and onset of alcohol use among early adolescents.

Preventing or delaying the onset of alcohol use among children and youth is an important public health goal. One possible factor in alcohol use onset among early adolescents is caffeine. The aim of this study was to assess the possible contribution of caffeine to the onset of alcohol use during early adolescence. We used data from the Young Mountaineer Health Study Cohort. Survey data were collected from 1349 (response rate: 80.7%) 6th grade students (mean age at baseline 11.5 years) in 20 middle schools in West Virginia during the fall of 2020, and again approximately 6 months later in spring of 2021. We limited our analyses to students reporting never having used any form of alcohol at baseline. Logistic regression was employed in multivariable analyses and both Odds Ratios and Relative Risks reported. At follow-up, almost 14% of participants reported having consumed alcohol at least once and 57% used caffeine of 100 mg + daily. In multivariable analyses we controlled for social and behavioral variables known to impact tobacco use. Caffeine use was operationalized as a three-level factor: no use, <100 mg per day, and 100 + mg per day, with the latter being the approximate equivalent of the minimum of a typical cup of coffee or can of energy drink. Caffeine use of 100 mg + per day was significantly related to alcohol use at 6-months follow-up (OR: 1.79, RR: 1.56, p = .037). We conclude that caffeine consumption among 11-12-year-old adolescents may be a factor in early onset of alcohol use.

Underrepresentation of Black participants and adverse events in clinical trials of lenalidomide for myeloma.

Adverse events affecting Black patients, including skin hyperpigmentation, may be overlooked using existing clinical trial data on lenalidomide. The objective of this systematic review is to characterize the representation of Black participants and rate of skin hyperpigmentation in clinical trials. In this systematic review and pooled analysis of 21 clinical trials comprising 4539 participants, the proportion of Black participants in trials (6.9%, n = 315) was significantly less than the multiple myeloma population (p < 0.001). The rate of skin hyperpigmentation (0.066%, n = 3) and all skin changes (6.4%, n = 291) was significantly less compared to a 40.8% incidence in a recent retrospective study (p. <0.001). Among participants undergoing treatment with lenalidomide for multiple myeloma, Black patients were underrepresented and the adverse event of skin hyperpigmentation was underreported. Fair representation of Black patients in clinical trials is needed to better describe this adverse event and other events that may be underreported.

Emerging immuno-oncology targets in Myelodysplastic Syndromes (MDS).

Approaches to immunologic therapies in myelodysplastic syndromes (MDS) have generally fallen into 2 categories: therapies that target immune effector cells and enhance or direct an antileukemic effect, and therapies which target immunological markers on MDS progenitors themselves. Examples of the former include immune checkpoint inhibitors, immunomodulatory therapies, and vaccines, among others, while examples of the latter include antibody-drug conjugate therapies and naked antibodies; while bispecific antibodies and modified T-cells (such as CAR-T therapies) bridge both therapeutic modalities. In this review, we will discuss the rationale for the above therapies, clinical results to date, and potential future directions for investigation.

Genetic and immunologic features of recurrent stage I lung adenocarcinoma.

Although surgery for early-stage lung cancer offers the best chance of cure, recurrence still occurs between 30 and 50% of the time. Why patients frequently recur after complete resection of early-stage lung cancer remains unclear. Using a large cohort of stage I lung adenocarcinoma patients, distinct genetic, genomic, epigenetic, and immunologic profiles of recurrent tumors were analyzed using a novel recurrence classifier. To characterize the tumor immune microenvironment of recurrent stage I tumors, unique tumor-infiltrating immune population markers were identified using single cell RNA-seq on a separate cohort of patients undergoing stage I lung adenocarcinoma resection and applied to a large study cohort using digital cytometry. Recurrent stage I lung adenocarcinomas demonstrated higher mutation and lower methylation burden than non-recurrent tumors, as well as widespread activation of known cancer and cell cycle pathways. Simultaneously, recurrent tumors displayed downregulation of immune response pathways including antigen presentation and Th1/Th2 activation. Recurrent tumors were depleted in adaptive immune populations, and depletion of adaptive immune populations and low cytolytic activity were prognostic of stage I recurrence. Genomic instability and impaired adaptive immune responses are key features of stage I lung adenocarcinoma immunosurveillance escape and recurrence after surgery.

Parental support and monitoring as associated with adolescent alcohol and tobacco use by gender and age.

BACKGROUND: Parental support (PS) and parental monitoring (PM) are known protective factors against adolescent substance use (SU). However, little is known about whether PS and PM may affect SU outcomes differently by gender and age. This study examined the relationship between PS and PM and adolescent SU, specifically alcohol and tobacco use, stratified by gender and age group. METHODS: Middle and high school students (n = 2351, 48.5% Female) completed surveys of self-reported SU, perceived PS and PM, and socioeconomic background. Age group was defined dichotomously as grade 7-8 Middle school and grade 9-10 High school students. PS and PM were each measured using previously validated tools. SU was measured by lifetime and past 30 days cigarette/alcohol use. One-way ANOVA and binary logistic regression models were completed. Odds ratios and means were reported. RESULTS: PS and PM were significantly and negatively related to all outcome variables regardless of gender and age group. Mean differences in PS and PM were insignificant between age groups. Between genders, PM scores were significantly higher for girls (14.05) compared to boys (13.48) (p < 0.01). Odds Ratios of all four SU types (for alcohol and tobacco use) increased with higher age group, with ORs ranging from 1.45-2.61 (p < .05). CONCLUSIONS: PS and PM were protective against SU for all participants, consistent with previous literature. Girls reported greater parental monitoring than boys, irrespective of age-group. While girls experienced higher levels of monitoring, they did not report lower SU than boys. This suggests that monitoring girls more closely than boys appears unnecessary in preventing adolescent SU. Finally, PS was a more significant factor in preventing SU for older adolescents (high school aged group) than for younger adolescents, irrespective of gender suggesting that PS may be more impactful and important as adolescents age. As children mature, particularly from middle school to high school, PS may play a larger role in preventing SU for older adolescents compared to younger ones.

Molecular Risk Stratification is Independent of EGFR Mutation Status in Identifying Early-Stage Non-Squamous Non-Small Cell Lung Cancer Patients at Risk for Recurrence and Likely to Benefit From Adjuvant Chemotherapy.

BACKGROUND: A clinically-certified gene expression profile improved survival in a cohort of stage I-IIA NSCLC patients by identifying those likely to benefit from adjuvant intervention. EGFR mutation status has not provided this type of predictive risk discrimination in stage IA NSCLC, and overtreatment of low-risk stage IB patients may have limited the overall benefit seen recently in the adjuvant application of a third-generation TKI. We compared EGFR mutation data to molecular risk stratification in a prospective, early-stage cohort. MATERIALS AND METHODS: Two hundred fifty eligible stage I-IIA non-squamous NSCLC patients underwent prospective molecular risk stratification by the 14-gene prognostic assay. Platinum doublet adjuvant chemotherapy (AC) was recommended for molecular high-risk (MHR). Differences in freedom from recurrence (FFR) and disease-free survival (DFS) were evaluated. RESULTS: At 29 months, prospective molecular testing yielded an estimated FFR of 94.6% and 72.4% in low-risk and untreated MHR patients, respectively, and 97.0% among MHR patients receiving AC (P < .001). In contrast, there was no association between EGFR status and recurrence, while molecular risk predicted survival and response to AC within both the EGFR mutation(+) and mutation(-) populations. Sixty-seven percent of EGFR(+) and 49% of EGFR(-) patients were molecular low-risk. CONCLUSION: This prospective study demonstrates the utility of the 14-gene assay independent of EGFR mutation. Basing adjuvant intervention in early-stage NSCLC on EGFR status alone may undertreat up to 51% of EGFR(-) patients likely to benefit from adjuvant intervention, and overtreat as many as 67% of EGFR(+) patients more likely to be free of residual disease.

Improved outcomes and staging in non-small-cell lung cancer guided by a molecular assay.

There remains a critical need for improved staging of non-small-cell lung cancer, as recurrence and mortality due to undetectable metastases at the time of surgery remain high even after complete resection of tumors currently categorized as 'early stage.' A 14-gene quantitative PCR-based expression profile has been extensively validated to better identify patients at high-risk of 5-year mortality after surgical resection than conventional staging - mortality that almost always results from previously undetectable metastases. Furthermore, prospective studies now suggest a predictive benefit in disease-free survival when the assay is used to guide adjuvant chemotherapy decisions in early-stage non-small-cell lung cancer patients.

Lay abstract There is a need for improvement in the way early-stage non-small-cell lung cancers are staged and treated because many patients with 'early-stage' disease suffer high rates of cancer recurrence after surgery. In recent years, a specialized test has been developed to allow better characterization of a tumor's risk of recurrence based on the genes being expressed by tumor cells. Use of this test, in conjunction with standard staging methods, is better able to identify patients at high risk of cancer recurrence after surgery. Evidence suggests that giving chemotherapy to patients at high risk of recurrence after surgery reduces recurrence rates and improves long-term patient survival.

Transposon mutagenesis identifies cooperating genetic drivers during keratinocyte transformation and cutaneous squamous cell carcinoma progression.

The systematic identification of genetic events driving cellular transformation and tumor progression in the absence of a highly recurrent oncogenic driver mutation is a challenge in cutaneous oncology. In cutaneous squamous cell carcinoma (cuSCC), the high UV-induced mutational burden poses a hurdle to achieve a complete molecular landscape of this disease. Here, we utilized the Sleeping Beauty transposon mutagenesis system to statistically define drivers of keratinocyte transformation and cuSCC progression in vivo in the absence of UV-IR, and identified both known tumor suppressor genes and novel oncogenic drivers of cuSCC. Functional analysis confirms an oncogenic role for the ZMIZ genes, and tumor suppressive roles for KMT2C, CREBBP and NCOA2, in the initiation or progression of human cuSCC. Taken together, our in vivo screen demonstrates an extremely heterogeneous genetic landscape of cuSCC initiation and progression, which can be harnessed to better understand skin oncogenic etiology and prioritize therapeutic candidates.

Resectability, Recurrence, and Risk Stratification of Giant Solitary Fibrous Tumors in the Thoracic Cavity.

BACKGROUND: Solitary fibrous tumors (SFTs) are rare mesenchymal tumors most commonly arising from the pleura in the thoracic cavity. The impact of tumor size on risk of recurrence in thoracic SFTs is not well understood. METHODS: A single institution review was performed on all resected thoracic SFTs (1992-2019) with giant SFT defined as ≥ 15 cm. Clinical information, pathologic characteristics, and long-term survival data were collected, and predictors of recurrence and survival were evaluated with regression and Kaplan-Meier analysis. RESULTS: There were 38 thoracic SFTs resected from patients, with the majority of tumors (n = 23, 60.5%) originating from visceral pleura. There were nine (23.7%) giant SFTs with a mean size 20.4 cm (range 17-30 cm). Mean follow-up time was 81.0 months (range 1-261 months), during which 4 of 38 (10.5%) patients experienced a recurrence within the thorax (range 51-178 months). The presence of tumor necrosis (p = 0.021) and ≥ 4 mitoses per high-powered field (p = 0.010) were associated with SFT recurrence on univariate regression. Overall 5-year, 10-year, and 20-year survival was 78.2%, 72.6%, and 42.4%, respectively, and SFT-related mortality occurred in three patients at 83, 180, and 208 months postoperatively. There were no recurrences or SFT-related mortality among patients with giant SFT. CONCLUSION: This study represents one of the largest contemporary single institution reviews of long-term outcomes of giant thoracic SFT. Our data suggest that size is not a risk factor for recurrence in thoracic SFTs and long-term survival is excellent for giant SFTs.

Testing risk and protective factor assumptions in the Icelandic model of adolescent substance use prevention.

Iceland has witnessed a dramatic decline in adolescent substance use that may be partly the result of efforts related to the Icelandic prevention model (IPM). We sought to test risk and protective factor assumptions of the IPM using a prospective cohort study with 12 months separating baseline from follow-up. Participants were students in grades 8 and 9 in the national Icelandic school system enrolled in the spring of 2018 and 2019 (N=2165). Participants self-reported their experiences of cigarette smoking, alcohol consumption, and cannabis use and seven risk and protective factors. Analyses were conducted with generalized linear modeling with extension to general estimating equations with correlated outcomes data. Both individual main-effects models and collective models including all main-effects were tested. Out of 28 individual main-effects models, 23 produced findings consistent with study premises (P<0.05). Multiple main-effects models largely sustained the findings of the individual main-effects models. Findings support the assumption that the risk and protective factors commonly emphasized in the IPM are associated with the four different substance use outcomes in the hypothesized direction. Communities that plan to implement the IPM among adolescents might consider these factors in their work.

Promoterless Transposon Mutagenesis Drives Solid Cancers via Tumor Suppressor Inactivation.

A central challenge in cancer genomics is the systematic identification of single and cooperating tumor suppressor gene mutations driving cellular transformation and tumor progression in the absence of oncogenic driver mutation(s). Multiple in vitro and in vivo gene inactivation screens have enhanced our understanding of the tumor suppressor gene landscape in various cancers. However, these studies are limited to single or combination gene effects, specific organs, or require sensitizing mutations. In this study, we developed and utilized a Sleeping Beauty transposon mutagenesis system that functions only as a gene trap to exclusively inactivate tumor suppressor genes. Using whole body transposon mobilization in wild type mice, we observed that cumulative gene inactivation can drive tumorigenesis of solid cancers. We provide a quantitative landscape of the tumor suppressor genes inactivated in these cancers and show that, despite the absence of oncogenic drivers, these genes converge on key biological pathways and processes associated with cancer hallmarks.

Noninvasive Assessment of Epidermal Genomic Markers of UV Exposure in Skin.

The measurement of UV-induced DNA damage as a dosimeter of exposure and predictor of skin cancer risk has been proposed by multiple groups. Although UV-induced mutations and adducts are present in normal-appearing UV-exposed epidermis, sampling normal nonlesional skin requires noninvasive methods to extract epidermal DNA for analysis. Here, we demonstrate the feasibility of such an approach, termed surfactant-based tissue acquisition for molecular profiling. Sampling in patients was performed using a felt-tip pen soaked in a mixture of surfactants (Brij-30/N-decyl-N,N-dimethyl-3-ammonio-1-propanesulfonate). In mice, we show that the epidermis can be selectively removed without scarring, with complete healing within 2 weeks. We exposed hairless mice to low-dose UV radiation over a period of 3 months and serially sampled them through up to 2 months following the cessation of UV exposure, observing a progressive increase in a UV signature mutational burden. To test whether surfactant-based tissue acquisition for molecular profiling could be applied to human patients, samples were collected from sun-exposed and sun-protected areas, which were then subjected to high-depth targeted exome sequencing. Extensive UV-driven mosaicism and substantially increased mutational loads in sun-exposed versus sun-protected areas were observed, suggesting that genomic measures, as an integrated readout of DNA damage, repair, and clonal expansion, may be informative markers of UV exposure.