OBJECT: Although the length of hospital stay is often used as a measure of quality of care, data evaluating the predictors of extended hospital stay after craniotomy for tumor are limited. The goals of this study were to use multivariate regression to examine which preoperative characteristics and postoperative complications predict a prolonged hospital stay and to assess the impact of length of stay on unplanned hospital readmission. METHODS: Data were extracted from the National Surgical Quality Improvement Program (NSQIP) database from 2007 to 2013. Patients who underwent craniotomy for resection of a brain tumor were included. Stratification was based on length of hospital stay, which was dichotomized by the upper quartile of the interquartile range (IQR) for the entire population. Covariates included patient age, sex, race, tumor histology, comorbidities, American Society of Anesthesiologists (ASA) class, functional status, preoperative laboratory values, preoperative neurological deficits, operative time, and postoperative complications. Multivariate logistic regression with forward prediction was used to evaluate independent predictors of extended hospitalization. Thereafter, hierarchical multivariate logistic regression assessed the impact of length of stay on unplanned readmission. RESULTS: The study included 11,510 patients. The median hospital stay was 4 days (IQR 3-8 days), and 27.7% (n = 3185) had a hospital stay of at least 8 days. Independent predictors of extended hospital stay included age greater than 70 years (OR 1.53, 95% CI 1.28%-1.83%, p < 0.001); African American (OR 1.75, 95% CI 1.44%-2.14%, p < 0.001) and Hispanic (OR 1.68, 95% CI 1.36%-2.08%) race or ethnicity; ASA class 3 (OR 1.52, 95% CI 1.34%-1.73%) or 4-5 (OR 2.18, 95% CI 1.82%-2.62%) designation; partially (OR 1.94, 95% CI 1.61%-2.35%) or totally dependent (OR 3.30, 95% CI 1.95%-5.55%) functional status; insulin-dependent diabetes mellitus (OR 1.46, 95% CI 1.16%-1.84%); hematological comorbidities (OR 1.68, 95% CI 1.25%-2.24%); and preoperative hypoalbuminemia (OR 1.78, 95% CI 1.51%-2.09%, all p ≤ 0.009). Several postoperative complications were additional independent predictors of prolonged hospitalization including pulmonary emboli (OR 13.75, 95% CI 4.73%-39.99%), pneumonia (OR 5.40, 95% CI 2.89%-10.07%), and urinary tract infections (OR 11.87, 95% CI 7.09%-19.87%, all p < 0.001). The C-statistic of the model based on preoperative characteristics was 0.79, which increased to 0.83 after the addition of postoperative complications. A length of stay after craniotomy for tumor score was created based on preoperative factors significant in regression models, with a moderate correlation with length of stay (p = 0.43, p < 0.001). Extended hospital stay was not associated with differential odds of an unplanned hospital readmission (OR 0.97, 95% CI 0.89%-1.06%, p = 0.55). CONCLUSIONS: In this NSQIP analysis that evaluated patients who underwent craniotomy for tumor, much of the variance in hospital stay was attributable to baseline patient characteristics, suggesting length of stay may be an imperfect proxy for quality. Additionally, longer hospitalizations were not found to be associated with differential rates of unplanned readmission.

The molecular linkage between neocortical projection neuron subtype and area development, which enables the establishment of functional areas by projection neuron populations appropriate for specific sensory and motor functions, is poorly understood. Here, we report that Ctip1 controls precision of neocortical development by regulating subtype identity in deep-layer projection neurons. Ctip1 is expressed by postmitotic callosal and corticothalamic projection neurons but is excluded over embryonic development from corticospinal motor neurons, which instead express its close relative, Ctip2. Loss of Ctip1 function results in a striking bias in favor of subcerebral projection neuron development in sensory cortex at the expense of corticothalamic and deep-layer callosal development, while misexpression of Ctip1 in vivo represses subcerebral gene expression and projections. As we report in a paired paper, Ctip1 also controls acquisition of sensory area identity. Therefore, Ctip1 couples subtype and area specification, enabling specific functional areas to organize precise ratios of appropriate output projections.

Aberrant chromatin remodeling and activation of the PI3K pathway have been identified as important mediators of pediatric high-grade glioma (pHGG) and diffuse intrinsic pontine glioma (DIPG) pathogenesis. As inhibition of these pathways are promising therapeutic avenues and radiation is the only modality to prolong survival of patients with DIPG, we sought to explore radiosensitizing functions of such inhibition and to explore mechanisms of action of such agents. Here, we demonstrate that combined treatment with radiotherapy and CUDC-907, a novel first-in-class dual inhibitor of histone deacetylases (HDAC) and PI3K, evokes a potent cytotoxic response in pHGG and DIPG models. CUDC-907 modulated DNA damage response by inhibiting radiation-induced DNA repair pathways including homologous recombination and nonhomologous end joining. The radiosensitizing effects of CUDC-907 were mediated by decreased NFκB/Forkhead box M1 (FOXM1) recruitment to promoters of genes involved in the DNA damage response; exogenous expression of NFκB/FOXM1 protected from CUDC-907–induced cytotoxicity. Together, these findings reveal CUDC-907 as a novel radiosensitizer with potent antitumor activity in pHGG and DIPG and provide a preclinical rationale for the combination of CUDC-907 with radiotherapy as a novel therapeutic strategy against pHGG and DIPG. More globally, we have identified NFκB and FOXM1 and their downstream transcriptional elements as critical targets for new treatments for pHGG and DIPG. Significance: These findings describe the radiosensitizing effect of a novel agent in pediatric high-grade gliomas, addressing a critical unmet need of increasing the radiation sensitivity of these highly aggressive tumors. Cancer Res; 78(14); 4007–21. ©2018 AACR.

• Pediatric low-grade glioma (pLGG) is a MAPK pathway-altered disease with novel therapeutic options. • Clinical trials are vital in translation of targeted agents to influence patient care. • Targeted agents have unknown long-term toxicities and unclear impact on pLGG natural history. • Challenges include rapid clinical trial translation, tumor heterogeneity and need to harmonize molecular profiling techniques.

Amyotrophic lateral sclerosis is a devastating neurodegenerative disorder characterized by the progressive loss of spinal motor neurons. While the aetiological mechanisms underlying the disease remain poorly understood, oxidative stress is a central component of amyotrophic lateral sclerosis and contributes to motor neuron injury. Recently, oxidation resistance 1 (OXR1) has emerged as a critical regulator of neuronal survival in response to oxidative stress, and is upregulated in the spinal cord of patients with amyotrophic lateral sclerosis. Here, we tested the hypothesis that OXR1 is a key neuroprotective factor during amyotrophic lateral sclerosis pathogenesis by crossing a new transgenic mouse line that overexpresses OXR1 in neurons with the SOD1^G93A mouse model of amyotrophic lateral sclerosis. Interestingly, we report that overexpression of OXR1 significantly extends survival, improves motor deficits, and delays pathology in the spinal cord and in muscles of SOD1^G93A mice. Furthermore, we find that overexpression of OXR1 in neurons significantly delays non-cell-autonomous neuroinflammatory response, classic complement system activation, and STAT3 activation through transcriptomic analysis of spinal cords of SOD1^G93A mice. Taken together, these data identify OXR1 as the first neuron-specific antioxidant modulator of pathogenesis and disease progression in SOD1-mediated amyotrophic lateral sclerosis, and suggest that OXR1 may serve as a novel target for future therapeutic strategies.