The Notch signaling pathway mediates cell fate decisions1,2 and is tumor suppressive or oncogenic depending on the context2,3. During lung development, Notch pathway activation inhibits the differentiation of precursor cells to a neuroendocrine (NE) fate4–6. In small cell lung cancer (SCLC), an aggressive NE lung cancer7, loss-of-function NOTCH mutations and the inhibitory effects of ectopic Notch activation indicate that Notch signaling is tumor suppressive8,9. Here, we show that Notch signaling can be both tumor suppressive and pro-tumorigenic in SCLC. Endogenous activation of the Notch pathway results in a NE to non-NE fate switch in 10-50% of tumor cells in a mouse model of SCLC and in human tumors. This switch is mediated in part by Rest/Nrsf, a transcriptional repressor that inhibits NE gene expression. Non-NE Notch-active SCLC cells are slow growing, consistent with a tumor suppressive role for Notch, but these cells are also relatively chemoresistant and provide trophic support to NE tumor cells, consistent with a pro-tumorigenic role. Importantly, Notch blockade in combination with chemotherapy suppresses tumor growth and delays relapse. Thus, SCLC tumors generate their own microenvironment via activation of Notch signaling in a subset of tumor cells, and the presence of these cells may serve as a biomarker for the use of Notch pathway inhibitors in combination with chemotherapy in select SCLC patients.
Study Design: Retrospective cohort study. Objective: To evaluate the risks and benefits of crossing the cervicothoracic junction (CTJ) in cervical arthrodesis. Summary of Background Data: Whether the CTJ should be crossed in cervical arthrodesis remains up for debate. Keeping C7 as the distal end of the fusion risks adjacent segment disease (ASD) and can result in myelopathy or radiculopathy. Longer fusions are thought to increase operative risk and complexity but result in lower rates of ASD. Materials and Methods: Patients undergoing cervical spine fusion surgery ending at C7 or T1 with ≥1-year follow-up were included. To evaluate operative risk, estimated blood loss (EBL), operative time, and length of hospital stay were collected. To evaluate patient-reported outcomes (PROs), Neck Disability Index (NDI) and SF-12 questionnaires (PCS12 and MCS12) were obtained at follow-up. Revision surgery data were also obtained. Results: A total of 168 patients were included and divided into a C7 end-of-fusion cohort (NC7=59) and a T1 end-of-fusion cohort (NT1=109). Multivariate regression analysis adjusting for age, sex, race, surgical approach, and number of levels fused showed that EBL (P=0.12), operative time (P=0.07), and length of hospital stay (P=0.06) are not significantly different in the C7 and T1 end-of-fusion cohorts. Multivariate regression of PROs showed no significant difference in NDI (P=0.70), PCS12 (P=0.23), or MCS12 (P=0.15) between cohorts. Fisher analysis showed significantly higher revision rates in the C7 end-of-fusion cohort (7/59 for C7 vs. 2/109 for T1; odds ratio, 6.4; 95% confidence interval, 1.2–65.1; P=0.01). Conclusions: Crossing the CTJ in cervical arthrodesis does not increase operative risk as measured by blood loss, operative time, and length of hospital stay. However, it leads to lower revision rates, likely because of the avoidance of ASD, and comparable PROs. Thus, crossing the CTJ may help prevent ASD without negatively affecting operative risk or long-term PROs.
Supracondylar humerus (SCH) fractures are reported to be approximately twice as common among boys as among girls. Little is known about sex-associated differences in fracture patterns and complications. We compared the incidence of pediatric SCH fractures, injury mechanism (high-energy or low-energy), fracture subtypes, associated neurologic injuries, and treatment types by patient sex. We reviewed 1231 pediatric SCH fractures treated at 1 center from 2008 to 2017, analyzing sex distributions overall and by year and fracture subtype. We noted patient demographic characteristics, injury mechanisms, neurologic injuries, and treatments (nonoperative or operative). Binomial 2-tailed, chi-squared, and Student's t tests were used for analysis. Multiple logistic regression was performed to assess associations between sex, age, and injury mechanism. Alpha = 0.05. We found no significant difference in the distribution of girls (52%) vs boys (48%) in our sample compared with a binomial distribution ( P = .11). Annual percentages of fractures occurring in girls ranged from 46% to 63%, and sex distribution did not change significantly over time. The mean (± standard deviation) age at injury was significantly younger for girls (5.5 ± 2.5 years) than for boys (6.1 ± 2.5 years) (P < .001). High-energy injury mechanism was associated with older age (odds ratio [OR], 1.05; 95% confidence interval [CI], 1.03–1.06) but not male sex (OR, 1.04; 95% CI, 0.98–1.1). The overall incidence of neurologic injury was 9.5% but boys did not have greater odds of sustaining neurologic injury (OR, 1.03; 95% CI, 1.0–1.1). We found no sex-associated differences in the distribution of Gartland fracture subtypes (P = .13) or treatment type (P = .39). Compared with boys, girls sustain SCH fractures at a younger age. SCH fractures were distributed equally among girls and boys in our sample. Patient sex was not associated with fracture subtype, injury mechanism, neurologic injury, or operative treatment. These findings challenge the perception that SCH fracture is more common in boys than girls. Level III, retrospective study.
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