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OBJECTIVE Circumferential minimally invasive surgery (cMIS) may provide incremental benefits compared with open surgery for patients with increasing frailty status by decreasing peri- and postoperative complications. METHODS Operative patients with adult spinal deformity (ASD) ≥ 18 years old with baseline and 2-year postoperative data were assessed. With propensity score matching, patients who underwent cMIS (cMIS group) were matched with similar patients who underwent open surgery (open group) based on baseline BMI, C7–S1 sagittal vertical axis, pelvic incidence to lumbar lordosis mismatch, and S1 pelvic tilt. The Passias modified ASD frailty index (mASD-FI) was used to determine patient frailty stratification as not frail, frail, or severely frail. Baseline and postoperative factors were assessed using two-way analysis of covariance (ANCOVA) and multivariate ANCOVA while controlling for baseline age, Charlson Comorbidity Index (CCI) score, and number of levels fused. RESULTS After propensity score matching, 170 ASD patients (mean age 62.71 ± 13.64 years, 75.0% female, mean BMI 29.25 ± 6.60 kg/m2) were included, split evenly between the cMIS and open groups. Surgically, patients in the open group had higher numbers of posterior levels fused (p = 0.021) and were more likely to undergo three-column osteotomies (p > 0.05). Perioperatively, cMIS patients had lower intraoperative blood loss and decreased use of cell saver across frailty groups (with adjustment for baseline age, CCI score, and levels fused), as well as fewer perioperative complications (p < 0.001). Adjusted analysis also revealed that compared to open patients, increasingly frail patients in the cMIS group were also more likely to demonstrate greater improvement in 1- and 2-year postoperative scores for the Oswestry Disability Index, SRS-36 (total), EQ-5D and SF-36 (all p < 0.05). With regard to postoperative complications, increasingly frail patients in the cMIS group were also noted to experience significantly fewer complications overall (p = 0.036) and fewer major intraoperative complications (p = 0.039). The cMIS patients were also less likely to need a reoperation than their open group counterparts (p = 0.043). CONCLUSIONS Surgery performed with a cMIS technique may offer acceptable outcomes, with diminishment of perioperative complications and mitigation of catastrophic outcomes, in increasingly frail patients who may not be candidates for surgery using traditional open techniques. However, further studies should be performed to investigate the long-term impact of less optimal alignment in this population.

OBJECTIVE Management of adult spinal deformity (ASD) has increasingly favored operative intervention; however, the incidence of complications and reoperations is high, and patients may fail to achieve idealized postsurgical results. This study compared health-related quality of life (HRQOL) metrics between patients with suboptimal surgical outcomes and those who underwent nonoperative management as a proxy for the natural history (NH) of ASD. METHODS ASD patients with 2-year data were included. Patients who were offered surgery but declined were considered nonoperative (i.e., NH) patients. Operative patients with suboptimal outcome (SOp)—defined as any reoperation, major complication, or ≥ 2 severe Scoliosis Research Society (SRS)–Schwab modifiers at follow-up—were selected for comparison. Propensity score matching (PSM) on the basis of baseline age, deformity, SRS-22 Total, and Charlson Comorbidity Index score was used to match the groups. ANCOVA and stepwise logistic regression analysis were used to assess outcomes between groups at 2 years. RESULTS In total, 441 patients were included (267 SOp and 174 NH patients). After PSM, 142 patients remained (71 SOp 71 and 71 NH patients). At baseline, the SOp and NH groups had similar demographic characteristics, HRQOL, and deformity (all p > 0.05). At 2 years, ANCOVA determined that NH patients had worse deformity as measured with sagittal vertical axis (36.7 mm vs 21.3 mm, p = 0.025), mismatch between pelvic incidence and lumbar lordosis (11.9° vs 2.9°, p < 0.001), and pelvic tilt (PT) (23.1° vs 20.7°, p = 0.019). The adjusted regression analysis found that SOp patients had higher odds of reaching the minimal clinically important differences in Oswestry Disability Index score (OR [95% CI] 4.5 [1.7–11.5], p = 0.002), SRS-22 Activity (OR [95% CI] 3.2 [1.5–6.8], p = 0.002), SRS-22 Pain (OR [95% CI] 2.8 [1.4–5.9], p = 0.005), and SRS-22 Total (OR [95% CI] 11.0 [3.5–34.4], p < 0.001). CONCLUSIONS Operative patients with SOp still experience greater improvements in deformity and HRQOL relative to the progressive radiographic and functional deterioration associated with the NH of ASD. The NH of nonoperative management should be accounted for when weighing the risks and benefits of operative intervention for ASD.

OBJECTIVE The purpose of this study was to discern factors that differentiate patients who experience postoperative lower-extremity motor function decline in the early postoperative period. METHODS Adult spinal deformity (ASD) patients who were enrolled in a multicenter, observational, and prospectively collected study from 2018 to 2021 at 18 spinal deformity centers in North America were queried. Eligible participants met at least one of the following radiographic and/or procedural inclusion criteria: pelvic incidence minus lumbar lordosis (PI-LL) ≥ 25°, T1 pelvic angle (T1PA) ≥ 30°, sagittal vertical axis (SVA) ≥ 15 cm, thoracic scoliosis ≥ 70°, thoracolumbar scoliosis ≥ 50°, global coronal malalignment ≥ 7 cm, 3-column osteotomy, spinal fusion ≥ 12 levels, and/or age ≥ 65 years with ≥ 7 levels of instrumentation. Patients with an inflammatory or autoimmune disease and those who were incarcerated or pregnant were excluded, as were non-English speakers. Only patients with baseline and 6-week postoperative lower-extremity motor score (LEMS) were analyzed. Patient information, including demographic data, operative data, patient-reported outcomes, and radiographic parameters, were collected. Univariate and multivariable logistic regression models were built to quantify the degree to which a patient’s postoperative LEMS decline was related to demographic and clinical characteristics. RESULTS In total, 205 patients (mean age 61.5 years, mean total instrumented levels 12.6, 67.3% female, 54.2% primary cases, 79.5% with pelvic fixation) were evaluated. Of these 205 patients, 32 (15.5%) experienced LEMS decline in the perioperative period. These patients were older (p = 0.0014) and had greater BMI (p = 0.0176), higher frailty scores (p = 0.047), longer operating room times (p = 0.033), and greater estimated blood loss (p < 0.0001), and they were more frequently observed to have intraoperative neurophysiological monitoring (IONM) changes (p = 0.018). The deteriorated cohort had greater C7SVA at baseline (p = 0.0028) but were comparable in terms of all other radiographic parameters. No radiographic differences were seen between the groups at the 6-week visit; however, the deteriorated cohort experienced greater change in PI-LL (p < 0.0001), lumbar lordosis (p = 0.0461), C7SVA (p = 0.0004), and T1PA (p < 0.0001). Multivariate logistic regression demonstrated that the presence of IONM changes and each degree of negative change in T1PA conferred 3.71 (95% CI 1.01–13.42) and 1.09 (1.01–1.19) greater odds of postoperative LEMS deterioration, respectively. CONCLUSIONS In this study, 15.6% of ASD patients incurred LEMS decline in the perioperative period. The magnitude of change in global sagittal alignment, specifically T1PA, was the strongest independent predictor of LEMS decline, which has implications for surgical planning, patient counseling, and clinical research.

Machine learning (ML) models, if trained to data sets of high-fidelity quantum simulations, produce accurate and efficient interatomic potentials. Active learning (AL) is a powerful tool to iteratively generate diverse data sets. In this approach, the ML model provides an uncertainty estimate along with its prediction for each new atomic configuration. If the uncertainty estimate passes a certain threshold, then the configuration is included in the data set. Here we develop a strategy to more rapidly discover configurations that meaningfully augment the training data set. The approach, uncertainty-driven dynamics for active learning (UDD-AL), modifies the potential energy surface used in molecular dynamics simulations to favor regions of configuration space for which there is large model uncertainty. The performance of UDD-AL is demonstrated for two AL tasks: sampling the conformational space of glycine and sampling the promotion of proton transfer in acetylacetone. The method is shown to efficiently explore the chemically relevant configuration space, which may be inaccessible using regular dynamical sampling at target temperature conditions.

OBJECTIVE The objective of this study was to evaluate spinopelvic sagittal alignment and spinal compensatory changes in adult cervical kyphotic deformity. METHODS A database composed of 13 US spine centers was retrospectively reviewed for adult patients who underwent cervical reconstruction with radiographic evidence of cervical kyphotic deformity: C2–7 sagittal vertical axis > 4 cm, chin-brow vertical angle > 25°, or cervical kyphosis (T1 slope [T1S] cervical lordosis [CL] > 15°) (n = 129). Sagittal parameters were evaluated preoperatively and in the early postoperative window (6 weeks to 6 months postoperatively) and compared with asymptomatic control patients. Adult cervical deformity patients were further stratified by degree of cervical kyphosis (severe kyphosis, C2–T3 Cobb angle ≤ −30°; moderate kyphosis, ≤ 0°; and minimal kyphosis, > 0°) and severity of sagittal malalignment (severe malalignment, sagittal vertical axis T3–S1 ≤ −60 mm; moderate malalignment, ≤ 20 mm; and minimal malalignment > 20 mm). RESULTS Compared with asymptomatic control patients, cervical deformity was associated with increased C0–2 lordosis (32.9° vs 23.6°), T1S (33.5° vs 28.0°), thoracolumbar junction kyphosis (T10–L2 Cobb angle −7.0° vs −1.7°), and pelvic tilt (PT) (19.7° vs 15.9°) (p < 0.01). Cervicothoracic kyphosis was correlated with C0–2 lordosis (R = −0.57, p < 0.01) and lumbar lordosis (LL) (R = −0.20, p = 0.03). Cervical reconstruction resulted in decreased C0–2 lordosis, increased T1S, and increased thoracic and thoracolumbar junction kyphosis (p < 0.01). Patients with severe cervical kyphosis (n = 34) had greater C0–2 lordosis (p < 0.01) and postoperative reduction of C0–2 lordosis (p = 0.02) but no difference in PT. Severe cervical kyphosis was also associated with a greater increase in thoracic and thoracolumbar junction kyphosis postoperatively (p = 0.01). Patients with severe sagittal malalignment (n = 52) had decreased PT (p = 0.01) and increased LL (p < 0.01), as well as a greater postoperative reduction in LL (p < 0.01). CONCLUSIONS Adult cervical deformity is associated with upper cervical hyperlordotic compensation and thoracic hypokyphosis. In the setting of increased kyphotic deformity and sagittal malalignment, thoracolumbar junction kyphosis and lumbar hyperlordosis develop to restore normal center of gravity. There was no consistent compensatory pelvic retroversion or anteversion among the adult cervical deformity patients in this cohort.

OBJECTIVE The objective of this study was to use an unsupervised cluster approach to identify patterns of operative adult spinal deformity (ASD) and compare the perioperative outcomes of these groups. METHODS A multicenter data set included patients with complex surgical ASD, including those with severe deformities, significant surgical complexity, or advanced age who underwent a multilevel fusion. An unsupervised cluster analysis allowing for 10% outliers was used to identify different deformity patterns. The perioperative outcomes of these clusters were then compared using ANOVA, Kruskal-Wallis, and chi-square tests, with p values < 0.05 considered significant. RESULTS Two hundred eighty-six patients were classified into four clusters of deformity patterns: hyper-thoracic kyphosis (hyper-TK), severe coronal, severe sagittal, and moderate sagittal. Hyper-TK patients had the lowest disability (mean Oswestry Disability Index [ODI] 32.9 ± 17.1) and pain scores (median numeric rating scale [NRS] back score 6, leg score 1). The severe coronal cluster had moderate functional impairment (mean physical component score 34.4 ± 12.3) and pain (median NRS back score 7, leg score 4) scores. The severe sagittal cluster had the highest levels of disability (mean ODI 49.3 ± 15.6) and low appearance scores (mean 2.3 ± 0.7). The moderate cluster (mean 68.8 ± 7.8 years) had the highest pain interference subscores on the Patient-Reported Outcomes Measurement Information System (mean 65.2 ± 5.8). Overall 30-day adverse events were equivalent among the four groups. Fusion to the pelvis was most common in the moderate sagittal (89.4%) and severe sagittal (97.5%) clusters. The severe coronal cluster had more osteotomies per case (median 11, IQR 6.5–14) and a higher rate of 30-day implant-related complications (5.5%). The severe sagittal and hyper-TK clusters had more three-column osteotomies (43% and 32.3%, respectively). Hyper-TK patients had shorter hospital stays. CONCLUSIONS This cohort of patients with complex ASD surgeries contained four natural clusters of deformity, each with distinct perioperative outcomes.

OBJECTIVE Revision surgery is often necessary for adult spinal deformity (ASD) patients. Satisfaction with management is an important component of health-related quality of life. The authors hypothesized that patients who underwent multiple revision surgeries following ASD correction would exhibit lower self-reported satisfaction scores. METHODS This was a retrospective cohort study of 668 patients who underwent ASD surgery and were eligible for a minimum 2-year follow-up. Visits were stratified by occurrence prior to the index surgery (period 0), after the index surgery only (period 1), after the first revision only (period 2), and after the second revision only (period 3). Patients were further stratified by prior spine surgery before their index surgery. Scoliosis Research Society–22 (SRS-22r) health-related quality-of-life satisfaction subscore and total satisfaction scores were evaluated at all periods using multiple linear regression and adjustment for age, sex, and Charlson Comorbidity Index. RESULTS In total, 46.6% of the study patients had undergone prior spine surgery before their index surgery. The overall revision rate was 21.3%. Among patients with no spine surgery prior to the index surgery, SRS-22r satisfaction scores increased from period 0 to 1 (from 2.8 to 4.3, p < 0.0001), decreased after one revision from period 1 to 2 (4.3 to 3.9, p = 0.0004), and decreased further after a second revision from period 2 to 3 (3.9 to 3.3, p = 0.0437). Among patients with spine surgery prior to the index procedure, SRS-22r satisfaction increased from period 0 to 1 (2.8 to 4.2, p < 0.0001) and decreased from period 1 to 2 (4.2 to 3.8, p = 0.0011). No differences in follow-up time from last surgery were observed (all p > 0.3). Among patients with multiple revisions, 40% experienced rod fracture, 40% proximal junctional kyphosis, and 33% pseudarthrosis. CONCLUSIONS Among patients undergoing ASD surgery, revision surgery is associated with decreased satisfaction, and multiple revisions are associated with additive detriment to satisfaction among patients initially undergoing primary surgery. These findings have direct implications for preoperative patient counseling and establishment of postoperative expectations.

Primary spinal cord astrocytomas are rare, fatal, and poorly studied.This study included a 2-center, retrospective analysis of primary spinal cord astrocytoma patients from 1997 to 2020. Patients with drop metastases or without at least one follow-up were excluded.Seven World Health Organization grade I, 6 grade II, 7 grade III, and 4 grade IV astrocytoma patients were included. Older patients had higher grades (median 20 years in grade I vs. 36.5 in grade IV). The median follow-up was 15 months. Thirteen patients were discharged to rehabilitation. Eight patients demonstrated radiographic progression. Adjuvant therapy was utilized more in higher grades (5 of 13 grades III vs. all 11 grades IIIIV). Six patients died (1 death in grades III vs. 5 in grades IIIIV). Ten patients had worsened symptoms at the last follow-up. The median progression-free survival in grade I, II, III, and IV tumors was 116, 36, 8, and 8.5 months, respectively. The median overall survival in grade I, II, III, and IV tumors was 142, 69, 19, and 12 months, respectively. Thrombotic complications occurred in 2 patients, one with isocitrate dehydrogenasewild type glioblastoma.Outcomes worsen with higher grades and lead to difficult postoperative periods. Clinicians should be vigilant for thromboembolic complications. Further research is needed to understand these rare tumors.

As corrective surgery for cervical deformity (CD) increases, so does the rate of complications and reoperations. To minimize suboptimal postoperative outcomes, it is important to develop a tool that allows for proper preoperative risk stratification.To develop a prognostic utility for identification of risk factors that lead to the development of major complications and unplanned reoperations.CD patients age 18 years or older were stratified into 2 groups based on the postoperative occurrence of a revision and/or major complication. Multivariable logistic regressions identified characteristics that were associated with revision or major complication. Decision tree analysis established cutoffs for predictive variables. Models predicting both outcomes were quantified using area under the curve (AUC) and receiver operating curve characteristics.A total of 109 patients with CD were included in this study. By 1 year postoperatively, 26 patients experienced a major complication and 17 patients underwent a revision. Predictive modeling incorporating preoperative and surgical factors identified development of a revision to include upper instrumented vertebraeC5, lowermost instrumented vertebraeT7, number of unfused lordotic cervical vertebrae1, baseline T1 slope25.3°, and number of vertebral levels in maximal kyphosis12 (AUC: 0.82). For developing a major complication, a model included a current smoking history, osteoporosis, upper instrumented vertebrae inclination angle0° or40°, anterior diskectomies3, and a posterior Smith Peterson osteotomy (AUC: 0.81).Revisions were predicted using a predominance of radiographic parameters while the occurrence of major complications relied on baseline bone health, radiographic, and surgical characteristics.

Frailty is influential in determining operative outcomes, including complications, in patients with cervical deformity (CD).To assess whether frailty status limits the highest achievable outcomes of patients with CD.Adult patients with CD with 2-year (2Y) data included. Frailty stratification: not frail (NF)0.2, frail (F) 0.2 to 0.4, and severely frail (SF)0.4. Analysis of covariance established estimated marginal means based on age, invasiveness, and baseline deformity, for improvement, deterioration, or maintenance in Neck Disability Index (NDI), Modified Japanese Orthopaedic Association (mJOA), and Numerical Rating Scale Neck Pain.One hundred twenty-six patients with CD included 29 NF, 83 F, and 14 SF. The NF group had the highest rates of deterioration and lowest rates of improvement in cervical Sagittal Vertical Axis and horizontal gaze modifiers. Two-year improvements in NDI by frailty: NF: -11.2, F: -16.9, and SF: -14.6 ( P = .524). The top quartile of NF patients also had the lowest 1-year (1Y) NDI (7.0) compared with F (11.0) and SF (40.5). Between 1Y and 2Y, 7.9% of patients deteriorated in NDI, 71.1% maintained, and 21.1% improved. Between 1Y and 2Y, SF had the highest rate of improvement (42%), while NF had the highest rate of deterioration (18.5%).Although frail patients improved more often by 1Y, SF patients achieve most of their clinical improvement between 1 and 2Y. Frailty is associated with factors such as osteoporosis, poor alignment, neurological status, sarcopenia, and other medical comorbidities. Similarly, clinical outcomes can be affected by many factors (fusion status, number of pain generators within treated levels, integrity of soft tissues and bone, and deformity correction). Although accounting for such factors will ultimately determine whether frailty alone is an independent risk factor, these preliminary findings may suggest that frailty status affects the clinical outcomes and improvement after CD surgery.

OBJECTIVE The Adult Symptomatic Lumbar Scoliosis–1 (ASLS-1) trial demonstrated the benefit of adult symptomatic lumbar scoliosis (ASLS) surgery. However, the extent to which individuals differ in their postoperative recovery trajectories is unknown. This study’s objective was to evaluate variability in and factors moderating recovery trajectories after ASLS surgery. METHODS The authors used longitudinal, multilevel models to analyze postoperative recovery trajectories following ASLS surgery. Study outcomes included the Oswestry Disability Index (ODI) score and Scoliosis Research Society–22 (SRS-22) subscore, which were measured every 3 months until 2 years postoperatively. The authors evaluated the influence of preoperative disability level, along with other potential trajectory moderators, including radiographic, comorbidity, pain/function, demographic, and surgical factors. The impact of different parameters was measured using the R2, which represented the amount of variability in ODI/SRS-22 explained by each model. The R2 ranged from 0 (no variability explained) to 1 (100% of variability explained). RESULTS Among 178 patients, there was substantial variability in recovery trajectories. Applying the average trajectory to each patient explained only 15% of the variability in ODI and 21% of the variability in SRS-22 subscore. Differences in preoperative disability (ODI/SRS-22) had the strongest influence on recovery trajectories, with patients having moderate disability experiencing the greatest and most rapid improvement after surgery. Reflecting this impact, accounting for the preoperative ODI/SRS-22 level explained an additional 56%–57% of variability in recovery trajectory, while differences in the rate of postoperative change explained another 7%–9%. Among the effect moderators tested, pain/function variables—such as visual analog scale back pain score—had the biggest impact, explaining 21%–25% of variability in trajectories. Radiographic parameters were the least influential, explaining only 3%–6% more variance than models with time alone. The authors identified several significant trajectory moderators in the final model, such as significant adverse events and the number of levels fused. CONCLUSIONS ASLS patients have highly variable postoperative recovery trajectories, although most reach steady state at 12 months. Preoperative disability was the most important influence, although other factors, such as number of levels fused, also impacted recovery.

Patients with less severe adult spinal deformity (ASD) undergo surgical correction and often achieve good clinical outcomes. However, it is not well understood how much clinical improvement is due to sagittal correction rather than treatment of the spondylotic process.Determine baseline thresholds in radiographic parameters that, when exceeded, may result in substantive clinical improvement from surgical correction.Retrospective.ASD patients with BL and two-year data were included. Parameters assessed: sagittal vertical axis, pelvic incidence-lumbar lordosis mismatch, pelvic tilt, T1 pelvic angle, L1 pelvic angle, L4-S1 lordosis, C2-C7 sagittal vertical axis, C2-T3, C2 slope. Outcomes: Good Outcome (GO) at two years: [meeting either: (1) Substantial Clinical Benefit for Oswestry Disability Index (change18.8), or (2) Oswestry Disability Index15 and Scoliosis Research Society Total4.5]. Binary logistic regression assessed each parameter to determine if correction was more likely needed to achieve GO. Conditional inference tree run machine learning analysis generated baseline thresholds for each parameter, above which, correction was necessary to achieve GO.We included 431 ASD patients. There were 223 (50%) that achieved a GO by two years. Binary logistic regression analysis demonstrated, with increasing baseline severity in deformity, sagittal correction was more often seen in those achieving GO for each parameter(all P0.001). Of patients with baseline T1 pelvic angle above the threshold, 95% required correction to meet GO (95% vs. 54%, P0.001). A baseline pelvic incidence-lumbar lordosis10° (74% of patients meeting GO) needed correction to achieve GO (odds ratio: 2.6, 95% confidence interval: 1.4-4.8). A baseline C2 slope15° also necessitated correction to obtain clinical success (odds ratio: 7.7, 95% confidence interval: 3.7-15.7).Our study highlighted point may be present at which sagittal correction has an outsized influence on clinical improvement, reflecting the line where deformity becomes a significant contributor to disability. These new thresholds give us insight into which patients may be more suitable for sagittal correction, as opposed to intervention for the spondylotic process only, leading to a more efficient utility of surgical intervention for ASD.

Literature review.The aim of this review is to summarize recent literature on adult spinal deformity (ASD) treatment failure as well as prevention strategies for these failure modes.There is substantial evidence that ASD surgery can provide significant clinical benefits to patients. The volume of ASD surgery is increasing, and significantly more complex procedures are being performed, especially in the aging population with multiple comorbidities. Although there is potential for significant improvements in pain and disability with ASD surgery, these procedures continue to be associated with major complications and even outright failure.A systematic search of the PubMed database was performed for articles relevant to failure after ASD surgery. Institutional review board approval was not needed.Failure and the potential need for revision surgery generally fall into 1 of 4 well-defined phenotypes: clinical failure, radiographic failure, the need for reoperation, and lack of cost-effectiveness. Revision surgery rates remain relatively high, challenging the overall cost-effectiveness of these procedures.By consolidating the key evidence regarding failure, further research and innovation may be stimulated with the goal of significantly improving the safety and cost-effectiveness of ASD surgery.

Atomistic machine learning focuses on the creation of models that obey fundamental symmetries of atomistic configurations, such as permutation, translation, and rotation invariances. In many of these schemes, translation and rotation invariance are achieved by building on scalar invariants, e.g., distances between atom pairs. There is growing interest in molecular representations that work internally with higher rank rotational tensors, e.g., vector displacements between atoms, and tensor products thereof. Here, we present a framework for extending the Hierarchically Interacting Particle Neural Network (HIP-NN) with Tensor Sensitivity information (HIP-NN-TS) from each local atomic environment. Crucially, the method employs a weight tying strategy that allows direct incorporation of many-body information while adding very few model parameters. We show that HIP-NN-TS is more accurate than HIP-NN, with negligible increase in parameter count, for several datasets and network sizes. As the dataset becomes more complex, tensor sensitivities provide greater improvements to model accuracy. In particular, HIP-NN-TS achieves a record mean absolute error of 0.927 kcalmol for conformational energy variation on the challenging COMP6 benchmark, which includes a broad set of organic molecules. We also compare the computational performance of HIP-NN-TS to HIP-NN and other models in the literature.

HOXA genes encode critical transcriptional regulators of embryonic development that have been implicated in cancer. In this study, we documented functional relevance and mechanism of activation of HOXA9 in glioblastoma (GBM), the most common malignant brain tumor. Expression of HOXA genes was investigated using reverse transcription–PCR in primary gliomas and glioblastoma cell lines and was validated in two sets of expression array data. In a subset of GBM, HOXA genes are aberrently activated within confined chromosomal domains. Transcriptional activation of the HOXA cluster was reversible by a phosphoinostide 3-kinase (PI3K) inhibitor through an epigenetic mechanism involving histone H3K27 trimethylation. Functional studies of HOXA9 showed its capacity to decrease apoptosis and increase cellular proliferation along with tumor necrosis factor–related apoptosis-including ligand resistance. Notably, aberrant expression of HOXA9 was independently predictive of shorter overall and progression-free survival in two GBM patient sets and improved survival prediction by MGMT promoter methylation. Thus, HOXA9 activation is a novel, independent, and negative prognostic marker in GBM that is reversible through a PI3K-associated epigenetic mechanism. Our findings suggest a transcriptional pathway through which PI3K activates oncogenic HOXA expression with implications for mTOR or PI3K targeted therapies. Cancer Res; 70(2); 453–62

Supplementary Table 1 from Reversing HOXA9 Oncogene Activation by PI3K Inhibition: Epigenetic Mechanism and Prognostic Significance in Human Glioblastoma

Supplementary Table 4 from Reversing HOXA9 Oncogene Activation by PI3K Inhibition: Epigenetic Mechanism and Prognostic Significance in Human Glioblastoma

Supplementary Table 2 from Reversing HOXA9 Oncogene Activation by PI3K Inhibition: Epigenetic Mechanism and Prognostic Significance in Human Glioblastoma

Supplementary Figures 1-7 from Reversing HOXA9 Oncogene Activation by PI3K Inhibition: Epigenetic Mechanism and Prognostic Significance in Human Glioblastoma