Evaluation of the Glasgow Coma Scale-Pupils score for predicting inpatient mortality among patients with traumatic subdural hematoma at United States trauma centers.

OBJECTIVE: The Glasgow Coma Scale-Pupils (GCS-P) score has been suggested to better predict patient outcomes compared with GCS alone, while avoiding the need for more complex clinical models. This study aimed to compare the prognostic ability of GCS-P versus GCS in a national cohort of traumatic subdural hematoma (SDH) patients. METHODS: Patient data were obtained from the National Trauma Data Bank (2017-2019). Inclusion criteria were traumatic SDH diagnosis with available data on presenting GCS score, pupillary reactivity, and discharge disposition. Patients with severe polytrauma or nonsurvivable head injury at presentation were excluded. Sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) of GCS-P versus GCS scores for inpatient mortality prediction were evaluated across the entire cohort, as well as in subgroups based on age and traumatic brain injury (TBI) type (blunt vs penetrating). Calibration curves were plotted based on predicted probabilities and actual outcomes. RESULTS: A total of 196,747 traumatic SDH patients met the study inclusion criteria. Sensitivity (0.707 vs 0.702), specificity (0.821 vs 0.823), and AUC (0.825 vs 0.814, p < 0.001) of GCS-P versus GCS scores for prediction of inpatient mortality were similar. Calibration curve analysis revealed that GCS scores slightly underestimated inpatient mortality risk, whereas GCS-P scores did not. In patients > 65 years of age with blunt TBI (51.9%, n = 102,148), both GCS-P and GCS scores underestimated inpatient mortality risk. In patients with penetrating TBI (2.4%, n = 4,710), the AUC of the GCS-P score was significantly higher (0.902 vs 0.851, p < 0.001). In this subgroup, both GCS-P and GCS scores underestimated inpatient mortality risk among patients with lower rates of observed mortality and overestimated risk among patients with higher rates of observed mortality. This effect was more pronounced in the GCS-P calibration curve. CONCLUSIONS: The GCS-P score provides better short-term prognostication compared with the GCS score alone among traumatic SDH patients with penetrating TBI. The GCS-P score overestimates inpatient mortality risk among penetrating TBI patients with higher rates of observed mortality. For penetrating TBI patients, which comprised 2.4% of our SDH cohort, a low GCS-P score should not justify clinical nihilism or forgoing aggressive treatment.

Cancer therapy with antibodies.

The greatest challenge in cancer therapy is to eradicate cancer cells with minimal damage to normal cells. Targeted therapy has been developed to meet that challenge, showing a substantially increased therapeutic index compared with conventional cancer therapies. Antibodies are important members of the family of targeted therapeutic agents because of their extraordinarily high specificity to the target antigens. Therapeutic antibodies use a range of mechanisms that directly or indirectly kill the cancer cells. Early antibodies were developed to directly antagonize targets on cancer cells. This was followed by advancements in linker technologies that allowed the production of antibody-drug conjugates (ADCs) that guide cytotoxic payloads to the cancer cells. Improvement in our understanding of the biology of T cells led to the production of immune checkpoint-inhibiting antibodies that indirectly kill the cancer cells through activation of the T cells. Even more recently, bispecific antibodies were synthetically designed to redirect the T cells of a patient to kill the cancer cells. In this Review, we summarize the different approaches used by therapeutic antibodies to target cancer cells. We discuss their mechanisms of action, the structural basis for target specificity, clinical applications and the ongoing research to improve efficacy and reduce toxicity.

Characterizing the presentation, management, and clinical outcomes of patients with intradural spinal chordomas: a systematic review.

OBJECTIVE: Chordomas are locally aggressive neoplasms of the spine or skull base that arise from embryonic remnants of the notochord. Intradural chordomas represent a rare subset of these neoplasms, and few studies have described intradural chordomas in the spine. This review evaluates the presentation, management, and outcomes of intradural spinal chordomas. METHODS: A systematic review of PubMed/MEDLINE, EMBASE, Cochrane Library, Scopus, and Web of Science was performed. Studies describing at least 1 case of intradural chordomas anywhere in the spine were included. Extracted details included presenting symptoms, radiological findings, treatment course, follow-up, and disease progression. RESULTS: Thirty-one studies, with a total of 41 patients, were included in this review. Seventy-six percent (31/41) of patients had primary intradural tumors, whereas 24% (10/41) presented with metastasis. The most common signs and symptoms were pain (n = 27, 66%); motor deficits (n = 20, 49%); sensory deficits (n = 17, 42%); and gait disturbance (n = 10, 24%). The most common treatment for intradural chordoma was resection and postoperative radiotherapy. Sixty-six percent (19/29) of patients reported improvement or complete resolution of symptoms after surgery. The recurrence rate was 37% (10/27), and the complication rate was 25% (6/24). The median progression-free survival was 24 months (range 4-72 months). Four patient deaths were reported. The median follow-up time was 12 months (range 13 days-84 months). CONCLUSIONS: Treatment of intradural spinal chordomas primarily involves resection and radiotherapy. A significant challenge and complication in management is spinal tumor seeding after resection, with 9 studies proposing seeding as a mechanism of tumor metastasis in 11 cases. Factors such as tumor size, Ki-67 positivity, and distant metastasis may correlate with worse outcomes and demonstrate potential as prognostic indicators for intradural spinal chordomas. Further research is needed to improve understanding of this tumor and develop optimal treatment paradigms for these patients.

Machine Learning Identifies Variation in Timing of Palliative Care Consultations Among Traumatic Brain Injury Patients.

Background and Objective Timely palliative care involvement offers demonstrable benefits for traumatic brain injury (TBI) patients; however, palliative care consultations (PCCs) are used inconsistently during TBI management. This study aimed to employ advanced machine learning techniques to elucidate the primary drivers of PCC timing variability for TBI patients. Methods Data on admission, hospital course, and outcomes were collected for a cohort of 232 TBI patients who received both PCCs and neurosurgical consultations during the same hospitalization. Principal Component Analysis (PCA) and K-means clustering were used to identify patient phenotypes, which were then compared using Kaplan-Meier analysis. An extreme gradient boosting model (XGBoost) was employed to determine drivers of PCC timing, with model interpretation performed using SHapley Additive exPlanations (SHAP). Results Cluster A (n = 86) consisted mainly of older (median [IQR] = 87 [78, 94] years), White females with mild TBIs and demonstrated the shortest time-to-PCC (2.5 [1.0, 7.0] days). Cluster B (n = 108) also sustained mild TBIs but comprised moderately younger (81 [75, 86] years) married White males with later PCC (5.0 [3.0, 10.8] days). Cluster C (n = 38) represented much younger (46.5 [29.5, 59.8] years), more severely injured, non-White patients with the latest PCC initiation (9.0 [4.2, 17.0] days). The clusters did not differ by discharge disposition (p = 0.4) or frequency inpatient mortality (p > 0.9); however, Kaplan-Meier analysis revealed a significant difference in the time from admission to PCC (p < 0.001), despite no differences in time from admission to mortality (p = 0.18). SHAP analysis of the XGBoost model identified age, sex, and race as the most influential drivers of PCC timing. Conclusions This study highlights crucial disparities in PCC timing for TBI patients and underscores the need for targeted strategies to ensure timely and equitable palliative care integration for this vulnerable population.

Liquid biopsy for improving diagnosis and monitoring of CNS lymphomas: a RANO review.

BACKGROUND: The utility of liquid biopsies is well documented in several extracranial and intracranial (brain/leptomeningeal metastases, gliomas) tumors. METHODS: The RANO (Response Assessment in Neuro-Oncology) group has set up a multidisciplinary Task Force to critically review the role of blood and CSF-liquid biopsy in central nervous system lymphomas, with a main focus on primary central nervous system lymphomas (PCNSL). RESULTS: Several clinical applications are suggested: diagnosis of PCNSL in critical settings (elderly or frail patients, deep locations, steroids responsiveness), definition of minimal residual disease, early indication of tumor response or relapse following treatments and prediction of outcome. CONCLUSIONS: Thus far, no clinically validated circulating biomarkers for managing both primary and secondary CNS lymphomas exist. There is need of standardization of biofluid collection, choice of analytes and type of technique to perform the molecular analysis. The various assays should be evaluated through well organized central testing within clinical trials.

Exploring the impact of primary care utilization and health information exchange upon treatment patterns and clinical outcomes of glioblastoma patients.

PURPOSE: There is limited literature describing care coordination for patients with glioblastoma (GBM). We aimed to investigate the impact of primary care and electronic health information exchange (HIE) between neurosurgeons, oncologists, and primary care providers (PCP) on GBM treatment patterns, postoperative outcomes, and survival. METHODS: We identified adult GBM patients undergoing primary resection at our institution (2007-2020). HIE was defined as shared electronic medical information between PCPs, oncologists, and neurosurgeons. Multivariate logistic regression analyses were used to determine the effect of PCPs and HIE upon initiation and completion of adjuvant therapy. Kaplan-Meier and multivariate Cox regression models were used to evaluate overall survival (OS). RESULTS: Among 374 patients (mean age ± SD: 57.7 ± 13.5, 39.0% female), 81.0% had a PCP and 62.4% had electronic HIE. In multivariate analyses, having a PCP was associated with initiation (OR: 7.9, P < 0.001) and completion (OR: 4.4, P < 0.001) of 6 weeks of concomitant chemoradiation, as well as initiation (OR: 4.0, P < 0.001) and completion (OR: 3.0, P = 0.007) of 6 cycles of maintenance temozolomide thereafter. Having a PCP (median OS [95%CI]: 14.6[13.1-16.1] vs. 10.8[8.2-13.3] months, P = 0.005) and HIE (15.40[12.82-17.98] vs. 13.80[12.51-15.09] months, P = 0.029) were associated with improved OS relative to counterparts in Kaplan-Meier analysis and in multivariate Cox regression analysis (hazard ratio [HR] = 0.7, [95% CI] 0.5-1.0, P = 0.048). In multivariate analyses, chemoradiation (HR = 0.34, [95% CI] 0.2-0.7, P = 0.002) and maintenance temozolomide (HR = 0.5, 95%CI 0.3-0.8, P = 0.002) were associated with improved OS relative to counterparts. CONCLUSION: Effective care coordination between neurosurgeons, oncologists, and PCPs may offer a modifiable avenue to improve GBM outcomes.

External assessment of preoperative scores for predicting outcome after microvascular decompression for trigeminal neuralgia.

OBJECTIVE: Recently, two scoring systems have been developed for predicting pain-free outcomes after microvascular decompression (MVD). Evaluation of these scores on large external datasets has been limited. In this study, the authors aimed to evaluate the performance of published MVD scoring systems in predicting pain-free outcome. METHODS: A total of 458 patients who underwent MVD for trigeminal neuralgia (TN) between 2007 and 2020 and had at least 6 months of follow-up were included in this study. Hardaway and Panczykowski scores were retrospectively computed for each patient and compared with postoperative pain recurrence and pain-free duration. RESULTS: The mean ± SD area under the receiver operating characteristic curve for predicting any pain recurrence after MVD was 0.567 ± 0.081 using the Hardaway score and 0.546 ± 0.085 using the Panczykowski score. On log-rank tests and Kaplan-Meier analysis, the patients with Hardaway scores of 0-2 had significantly shorter pain-free survival times after MVD than did those with a score of 3. Patients with a Panczykowski score of 1 had a significantly shorter pain-free duration after surgery compared with both patients with scores of 2-3 and patients with scores of 4-5. Patients with Panczykowski scores of 2-3 also had significantly shorter pain-free duration compared with patients with scores of 4-5. CONCLUSIONS: Both the Hardaway and Panczykowski scores may be useful for predicting postoperative pain-free duration in TN patients, and their utility may be greatest when scores are clustered. Continued refinement of both scoring systems will help to improve our ability to predict patient outcomes after MVD.

The Johns Hopkins Physician-Scientist Training Program to Enhance Institutional Retention and Entry Into Academic Positions: An Evaluation of Program Effectiveness and Outcomes.

PURPOSE: The Johns Hopkins Physician-Scientist Training Program (PSTP) was implemented to overcome well-documented challenges in training and retaining physician-scientists by providing physician-scientist pathway training for residents and clinical fellows. The program's core tenets include monthly seminars, individualized feedback on project proposals, access to mentors, and institutional funding opportunities. This study evaluated the effectiveness and outcomes of the PTSP and provides a framework for replication. METHOD: A query of institutional demographic data and bibliometric variables of the PSTP participants (2017-2020) at a single academic medical center was conducted in 2021. In addition, a voluntary survey collected personal and program evaluation information. RESULTS: Of 145 PSTP scholars, 59 (41%) were women, and 41 (31%), 8 (6%), and 6 (5%) of scholars self-identified as Asian, Hispanic, and Black, respectively. Thirty-three (23%) scholars received PSTP research support or career development microgrants. Of 66 PSTP graduates, 29 (44%) remained at Johns Hopkins as clinical fellows or faculty. Of 48 PSTP graduates in a post-training position, 42 (88%) were in academia, with the majority, 29 (76%), holding the rank of assistant professor. Fifty-nine of 140 available participants responded to the survey (42% response rate). The top-cited reason for joining the PSTP was exposure to mentors and administration (50/58 respondents, 86%), followed by seeking scholarly opportunities (37/58 respondents, 64%). Most scholars intended to continue a career as a physician-scientist. CONCLUSIONS: The PSTP provides internal research support and institutional oversight. Although establishing close mentor-mentee relationships requires individualized approaches, the PSTP provided structured academic pathways that enhanced participating scholars' ability to apply for grants and jobs. The vast majority continued their careers as physician-scientists after training. In light of the national evidence of a "leaky physician-scientist pipeline," programs such as the PSTP can be critical to entry into early academic career positions and institutional retention.

The Socioeconomic Distressed Communities Index Predicts 90-Day Mortality Among Intracranial Tumor Patients.

BACKGROUND: Socioeconomic status (SES) is a major determinant of quality of life and outcomes. However, SES remains difficult to measure comprehensively. Distress communities index (DCI), a composite of 7 socioeconomic factors, has been increasingly recognized for its correlation with poor outcomes. As a result, the objective of the present study is to determine the predictive value of the DCI on outcomes following intracranial tumor surgery. METHODS: A single institution, retrospective review was conducted to identify adult intracranial tumor patients undergoing resection (2016-2021). Patient ZIP codes were matched to DCI and stratified by DCI quartiles (low:0-24.9, low-intermediate:25-49.9, intermediate-high:50-74.9, high:75-100). Univariate followed by multivariate regressions assessed the effects of DCI on postoperative outcomes. Receiver operating curves were generated for significant outcomes. RESULTS: A total of 2389 patients were included: 1015 patients (42.5%) resided in low distress communities, 689 (28.8%) in low-intermediate distress communities, 445 (18.6%) in intermediate-high distress communities, and 240 (10.0%) in high distress communities. On multivariate analysis, risk of fracture (adjusted odds ratio = 1.60, 95% confidence interval 1.26-2.05, P < 0.001) and 90-day mortality (adjusted odds ratio = 1.58, 95% confidence interval 1.21-2.06, P < 0.001) increased with increasing DCI quartile. Good predictive accuracy was observed for both models, with receiver operating curves of 0.746 (95% CI 0.720-0.766) for fracture and 0.743 (95% CI 0.714-0.772) for 90-day mortality. CONCLUSIONS: Intracranial tumor patients from distressed communities are at increased risk for adverse events and death in the postoperative period. DCI may be a useful, holistic measure of SES that can help risk stratifying patients and should be considered when building healthcare pathways.

Preoperative Opioid Use and Postoperative Outcomes in Patients Undergoing Microvascular Decompression for Trigeminal Neuralgia.

BACKGROUND AND OBJECTIVES: The prescription of opioid analgesics for trigeminal neuralgia (TN) is controversial, and their effect on postoperative outcomes for patients with TN undergoing microvascular decompression (MVD) has not been reported. We aimed to describe the relationship between preoperative opioid use and postoperative outcomes in patients with TN undergoing MVD. METHODS: We reviewed the records of 920 patients with TN at our institution who underwent an MVD between 2007 and 2020. Patients were sorted into 2 groups based on preoperative opioid usage. Demographic information, comorbidities, characteristics of TN, preoperative medications, pain and numbness outcomes, and recurrence data were recorded and compared between groups. Multivariate ordinal regression, Kaplan-Meier survival analysis, and Cox proportional hazards were used to assess differences in pain outcomes between groups. RESULTS: One hundred and forty-five (15.8%) patients in this study used opioids preoperatively. Patients who used opioids preoperatively were younger (P = .04), were more likely to have a smoking history (P < .001), experienced greater pain in modified Barrow Neurological Institute pain score at final follow-up (P = .001), and were more likely to experience pain recurrence (P = .01). In addition, patients who used opioids preoperatively were more likely to also have been prescribed TN medications including muscle relaxants and antidepressants preoperatively (P < .001 and P < .001, respectively). On multivariate regression, opioid use was an independent risk factor for greater postoperative pain at final follow-up (P = .006) after controlling for variables including female sex and age. Opioid use was associated with shorter time to pain recurrence on Kaplan-Meier analysis (P = .005) and was associated with increased risk for recurrence on Cox proportional hazards regression (P = .008). CONCLUSION: Preoperative opioid use in the setting of TN is associated with worse pain outcomes and increased risk for pain recurrence after MVD. These results indicate that opioids should be prescribed cautiously for TN and that worse post-MVD outcomes may occur in patients using opioids preoperatively.

Stereotactic body radiation therapy for spinal metastases: A new standard of care.

Advancements in systemic therapies for patients with metastatic cancer have improved overall survival and, hence, the number of patients living with spinal metastases. As a result, the need for more versatile and personalized treatments for spinal metastases to optimize long-term pain and local control has become increasingly important. Stereotactic body radiation therapy (SBRT) has been developed to meet this need by providing precise and conformal delivery of ablative high-dose-per-fraction radiation in few fractions while minimizing risk of toxicity. Additionally, advances in minimally invasive surgical techniques have also greatly improved care for patients with epidural disease and/or unstable spines, which may then be combined with SBRT for durable local control. In this review, we highlight the indications and controversies of SBRT along with new surgical techniques for the treatment of spinal metastases.

Active Learning in Brain Tumor Segmentation with Uncertainty Sampling and Annotation Redundancy Restriction.

Deep learning models have demonstrated great potential in medical imaging but are limited by the expensive, large volume of annotations required. To address this, we compared different active learning strategies by training models on subsets of the most informative images using real-world clinical datasets for brain tumor segmentation and proposing a framework that minimizes the data needed while maintaining performance. Then, 638 multi-institutional brain tumor magnetic resonance imaging scans were used to train three-dimensional U-net models and compare active learning strategies. Uncertainty estimation techniques including Bayesian estimation with dropout, bootstrapping, and margins sampling were compared to random query. Strategies to avoid annotating similar images were also considered. We determined the minimum data necessary to achieve performance equivalent to the model trained on the full dataset (α = 0.05). Bayesian approximation with dropout at training and testing showed results equivalent to that of the full data model (target) with around 30% of the training data needed by random query to achieve target performance (p = 0.018). Annotation redundancy restriction techniques can reduce the training data needed by random query to achieve target performance by 20%. We investigated various active learning strategies to minimize the annotation burden for three-dimensional brain tumor segmentation. Dropout uncertainty estimation achieved target performance with the least annotated data.

Exploring disparities in surgical recommendations for patients with primary intramedullary spinal cord tumors: an analysis of the Surveillance, Epidemiology, and End Results database from 2000 to 2019.

OBJECTIVE: Factors that may drive recommendations for operative intervention for patients with intramedullary spinal cord tumors (ISCTs) have yet to be extensively studied. The authors investigated racial and socioeconomic disparities in the management of patients with primary spinal cord ependymomas and nonependymal gliomas, with the aim of determining the associations between socioeconomic patient characteristics, survival, and recommendations for the resection of primary ISCTs. METHODS: The Surveillance, Epidemiology, and End Results registry was queried to identify all patients > 18 years of age with ISCTs diagnosed between 2000 and 2019. Univariable and multivariable logistic regression analyses were used to calculate odds ratios for variables associated with receiving a surgical recommendation. Log-rank tests and multivariable Cox proportional hazards models were used to investigate overall survival (OS) and disease-specific survival (DSS). RESULTS: The authors identified 2325 patients (mean age 49 [SD 16] years; 48.8% female; 67.4% non-Hispanic White, 7.8% non-Hispanic Black, 16.2% Hispanic, 6.5% Asian/Pacific Islander, 0.6% Native American; 56.7% married; 64.4% with household income < $75,000; 73.8% with spinal ependymoma; and 26.2% with nonependymal spinal glioma). Eighty-seven percent of patients received a surgical recommendation. In multivariable models, marriage was associated with higher odds of receiving a surgical recommendation for ependymomas (OR 1.80, p = 0.005). In multivariable models for nonependymal spinal gliomas, older age (OR 0.98, p = 0.001) and increased number of tumors (OR 0.62, p = 0.015) were associated with decreased odds of receiving surgical recommendations. Among ependymomas, marriage (HR 0.59, p = 0.001), younger age (HR 0.93, p < 0.001), female sex (HR 0.43, p = 0.006), and decreased number of tumors (HR 0.56, p < 0.001) were associated with improved OS. Among nonependymal spinal gliomas, median household income ≥ $75,000 (HR 0.69, p = 0.020) and younger age (HR 0.98, p < 0.001) were associated with improved DSS, while Black race (HR 4.65, p = 0.027) and older age (HR 1.05, p < 0.001) were associated with worse OS. CONCLUSIONS: In patients with spinal ependymomas and nonependymal spinal gliomas, recommendations for surgery appear to be unaffected by patient sex, race, or income. Survival disparities appear to exist among unmarried, male, Black, and lower-income cohorts. Continued initiatives to identify drivers of disparities while improving health equity in this patient population are needed.

The hospital frailty risk score independently predicts postoperative outcomes in meningioma patients.

OBJECTIVE: The Hospital Frailty Risk Score (HFRS) is a recently developed tool that uses ICD-10 codes to measure patient frailty. However, the effectiveness of HFRS has not yet been assessed in meningioma patients specifically. The present study aimed to evaluate the effectiveness of HFRS in predicting surgical outcomes for patients with meningiomas. METHODS: This retrospective study utilized data from patients undergoing meningioma resection at a single institution (2017-2019). Data were obtained through a combination of automated data retrieval and manual chart review. Bivariate logistic regression was used to assess the prognostic ability of several frailty indices for predicting postoperative outcomes. Further, discrimination for each model was assessed using the area under the receiver operating characteristic curve (AUROC). Generalized linear models with gamma error distributions and a log-link function were used to model hospital length of stay (LOS), total charges, complications, and disposition. RESULTS: A total of 464 meningioma patients (mean age 58.20 years, 72.8 % female, 66.4 % white) were included. HFRS had a significantly greater AUROC when compared to ASA (p = 0.0074) for postoperative complications, and HFRS significantly outperformed ASA (p = 0.0021) and mFI-5 (p = 0.018) when predicting nonroutine discharge. On multivariate analysis, increasing HFRS scores were significantly and independently associated with greater LOS (p < 0.0001), higher hospital charges (p < 0.0001), higher odds of postoperative complications (OR = 1.05, p = 0.019), and nonroutine discharge (OR = 1.12, p < 0.0001). The HFRS was non-inferior compared to the mFI-5, CCI, ASA and mFI-11 in terms of model discrimination. CONCLUSION: HFRS effectively predicts postoperative outcomes for meningiomas and outperforms other indices in predicting complications and nonroutine discharge. This novel index may be used to improve clinical decision-making and reduce adverse postoperative outcomes among meningioma patients.

Preoperative patient-reported physical health-related quality of life predicts short-term postoperative outcomes in brain tumor patients.

BACKGROUND: Patient-reported outcome measures (PROMs) are increasingly used to assess patients' perioperative health. The PROM Information System 29 (PROMIS-29) is a well-validated global health assessment instrument for patient physical health, though its utility in cranial neurosurgery is unclear. OBJECTIVE: To investigate the utility of preoperative PROMIS-29 physical health (PH) summary scores in predicting postoperative outcomes in brain tumor patients. METHODS: Adult brain tumor patients undergoing resection at a single institution (January 2018-December 2021) were identified and prospectively received PROMIS-29 surveys during pre-operative visits. PH summary scores were constructed and optimum prediction thresholds for length of stay (LOS), discharge disposition (DD), and 30-day readmission were approximated by finding the Youden index of the associated receiver operating characteristic curves. Bivariate analyses were used to study the distribution of low (z-score≤-1) versus high (z-score>-1) PH scores according to baseline characteristics. Logistic regression models quantified the association between preoperative PH summary scores and post-operative outcomes. RESULTS: A total of 157 brain tumor patients were identified (mean age 55.4±15.4 years; 58.0% female; mean PH score 45.5+10.5). Outcomes included prolonged LOS (24.8%), non-routine discharge disposition (37.6%), and 30-day readmission (19.1%). On bivariate analysis, patients with low PH scores were significantly more likely to be diagnosed with a high-grade tumor (69.6% vs 38.85%, p=0.010) and less likely to have elective surgery (34.8% vs 70.9%, p=0.002). Low PH score was associated with prolonged LOS (26.1% vs 22%, p<0.001), nonroutine discharge (73.9% vs 31.3%, p<0.001) and 30-day readmission (43.5% vs 14.9%, p=0.003). In multivariate analysis, low PH scores predicted greater LOS (odds ratio [OR]=6.09, p=0.003), nonroutine discharge (OR=4.25, p=0.020), and 30-day readmission (OR=3.93, p=0.020). CONCLUSION: The PROMIS-29 PH summary score predicts short-term postoperative outcomes in brain tumor patients and may be incorporated into prospective clinical workflows.

TRBC1-targeting antibody-drug conjugates for the treatment of T cell cancers.

Antibody and chimeric antigen receptor (CAR) T cell-mediated targeted therapies have improved survival in patients with solid and haematologic malignancies1-9. Adults with T cell leukaemias and lymphomas, collectively called T cell cancers, have short survival10,11 and lack such targeted therapies. Thus, T cell cancers particularly warrant the development of CAR T cells and antibodies to improve patient outcomes. Preclinical studies showed that targeting T cell receptor ß-chain constant region 1 (TRBC1) can kill cancerous T cells while preserving sufficient healthy T cells to maintain immunity12, making TRBC1 an attractive target to treat T cell cancers. However, the first-in-human clinical trial of anti-TRBC1 CAR T cells reported a low response rate and unexplained loss of anti-TRBC1 CAR T cells13,14. Here we demonstrate that CAR T cells are lost due to killing by the patient's normal T cells, reducing their efficacy. To circumvent this issue, we developed an antibody-drug conjugate that could kill TRBC1+ cancer cells in vitro and cure human T cell cancers in mouse models. The anti-TRBC1 antibody-drug conjugate may provide an optimal format for TRBC1 targeting and produce superior responses in patients with T cell cancers.

Response Rate and Molecular Correlates to Encorafenib and Binimetinib in BRAF-V600E Mutant High-Grade Glioma.

PURPOSE: Although fewer than 5% of high-grade gliomas (HGG) are BRAF-V600E mutated, these tumors are notable as BRAF-targeted therapy shows efficacy for some populations. The purpose of this study was to evaluate response to the combination of encorafenib with binimetinib in adults with recurrent BRAF-V600-mutated HGG. PATIENTS AND METHODS: In this phase 2, open-label, Adult Brain Tumor Consortium (ABTC) trial (NCT03973918), encorafenib and binimetinib were administered at their FDA-approved doses continuously in 28-day cycles. Eligible patients were required to have HGG or glioblastoma with a BRAF-V600E alteration that was recurrent following at least one line of therapy, including radiotherapy. RESULTS: Five patients enrolled between January 2020 and administrative termination in November 2021 (due to closure of the ABTC). Enrolled patients received treatment for 2 to 40 months; currently one patient remains on treatment. Centrally determined radiographic response rate was 60%, with one complete response and two partial responses. Methylation profiling revealed that all tumors cluster most closely with anaplastic pleomorphic xanthoastrocytoma (PXA). Transcriptional profile for MAPK-response signature was similar across all tumors at baseline and did not correlate with response in this small population. Circulating tumor DNA measured in plasma samples before treatment, during response, and upon progression showed feasibility of detection for the BRAF-V600E alteration. No new safety signal was detected. CONCLUSIONS: Encorafenib and binimetinib exhibit positive tumor responses in patients with recurrent BRAF-V600E mutant HGG in this small series, warranting therapeutic consideration. Although toxicity remains a concern for BRAF-targeted therapies, no new safety signal was observed in these patients.

The Hospital Frailty Risk Score Independently Predicts Postoperative Outcomes in Glioblastoma Patients.

OBJECTIVE: The Hospital Frailty Risk Score (HFRS) is a tool for quantifying patient frailty using International Classification of Diseases, Tenth Revision codes. This study aimed to determine the utility of the HFRS in predicting surgical outcomes after resection of glioblastoma (GBM) and compare its prognostic ability with other validated indices such as American Society of Anesthesiologists score and Charlson Comorbidity Index. METHODS: A retrospective analysis was conducted using a GBM patient database (2017-2019) at a single institution. HFRS was calculated using International Classification of Diseases, Tenth Revision codes. Bivariate logistic regression was used to model prognostic ability of each frailty index, and model discrimination was assessed using area under the receiver operating characteristic curve. Multivariate linear and logistic regression models were used to assess for significant associations between HFRS and continuous and binary postoperative outcomes, respectively. RESULTS: The study included 263 patients with GBM. The HFRS had a significantly greater area under the receiver operating characteristic curve compared with American Society of Anesthesiologists score (P = 0.016) and Charlson Comorbidity Index (P = 0.037) for predicting 30-day readmission. On multivariate analysis, the HFRS was significantly and independently associated with hospital length of stay (P = 0.0038), nonroutine discharge (P = 0.018), and 30-day readmission (P = 0.0051). CONCLUSIONS: The HFRS has utility in predicting postoperative outcomes for patients with GBM and more effectively predicts 30-day readmission than other frailty indices. The HFRS may be used as a tool for optimizing clinical decision making to reduce adverse postoperative outcomes in patients with GBM.

Machine learning to detect the SINEs of cancer.

We previously described an approach called RealSeqS to evaluate aneuploidy in plasma cell-free DNA through the amplification of ~350,000 repeated elements with a single primer. We hypothesized that an unbiased evaluation of the large amount of sequencing data obtained with RealSeqS might reveal other differences between plasma samples from patients with and without cancer. This hypothesis was tested through the development of a machine learning approach called Alu Profile Learning Using Sequencing (A-PLUS) and its application to 7615 samples from 5178 individuals, 2073 with solid cancer and the remainder without cancer. Samples from patients with cancer and controls were prespecified into four cohorts used for model training, analyte integration, and threshold determination, validation, and reproducibility. A-PLUS alone provided a sensitivity of 40.5% across 11 different cancer types in the validation cohort, at a specificity of 98.5%. Combining A-PLUS with aneuploidy and eight common protein biomarkers detected 51% of the cancers at 98.9% specificity. We found that part of the power of A-PLUS could be ascribed to a single feature-the global reduction of AluS subfamily elements in the circulating DNA of patients with solid cancer. We confirmed this reduction through the analysis of another independent dataset obtained with a different approach (whole-genome sequencing). The evaluation of Alu elements may therefore have the potential to enhance the performance of several methods designed for the earlier detection of cancer.