Immunotherapy for Pediatric Brain and Spine Tumors: Current State and Future Directions.

BACKGROUND: Brain tumors are the most common solid tumors and the leading cause of cancer-related deaths in children. Incidence in the USA has been on the rise for the last 2 decades. While therapeutic advances in diagnosis and treatment have improved survival and quality of life in many children, prognosis remains poor and current treatments have significant long-term sequelae. SUMMARY: There is a substantial need for the development of new therapeutic approaches, and since the introduction of immunotherapy by immune checkpoint inhibitors, there has been an exponential increase in clinical trials to adopt these and other immunotherapy approaches in children with brain tumors. In this review, we summarize the current immunotherapy landscape for various pediatric brain tumor types including choroid plexus tumors, embryonal tumors (medulloblastoma, AT/RT, PNETs), ependymoma, germ cell tumors, gliomas, glioneuronal and neuronal tumors, and mesenchymal tumors. We discuss the latest clinical trials and noteworthy preclinical studies to treat these pediatric brain tumors using checkpoint inhibitors, cellular therapies (CAR-T, NK, T cell), oncolytic virotherapy, radioimmunotherapy, tumor vaccines, immunomodulators, and other targeted therapies. KEY MESSAGES: The current landscape for immunotherapy in pediatric brain tumors is still emerging, but results in certain tumors have been promising. In the age of targeted therapy, genetic tumor profiling, and many ongoing clinical trials, immunotherapy will likely become an increasingly effective tool in the neuro-oncologist armamentarium.

The Impact of Smoking on Hospital Course and Postoperative Outcomes in Patients With Fracture-Related Infections.

OBJECTIVES: To assess the relationship between patient smoking status and fracture-related infection (FRI) characteristics including patient symptoms at FRI presentation, bacterial species of FRI, and rates of fracture union. DESIGN: Retrospective cohort study. SETTING: Urban level 1 trauma center. PATIENT SELECTION CRITERIA: All patients undergoing reoperation for FRI from January 2013 to April 2021 were identified through manual review of an institutional database. OUTCOME MEASURES AND COMPARISONS: Data including patient demographics, fracture characteristics, infection presentation, and hospital course were collected through review of the electronic medical record. Patients were grouped based on current smoker versus nonsmoker status. Hospital course and postoperative outcomes of these groups were then compared. Risk factors of methicillin-resistant Staphylococcus aureus (MRSA) infection, Staphylococcus epidermidis infection, and sinus tract development were evaluated using multivariable logistic regression. RESULTS: A total of 301 patients, comprising 155 smokers (51%) and 146 nonsmokers (49%), undergoing FRI reoperation were included. Compared with nonsmokers, smokers were more likely male (69% vs. 56%, P = 0.024), were younger at the time of FRI reoperation (41.7 vs. 49.5 years, P < 0.001), and had lower mean body mass index (27.2 vs. 32.0, P < 0.001). Smokers also had lower prevalence of diabetes mellitus (13% vs. 25%, P = 0.008) and had higher Charlson Comorbidity Index 10-year estimated survival (93% vs. 81%, P < 0.001). Smokers had a lower proportion of S. epidermidis infections (11% vs. 20%, P = 0.037), higher risk of nonunion after index fracture surgery (74% vs. 61%, P = 0.018), and higher risk of sinus tracts at FRI presentation (38% vs. 23%, P = 0.004). On multivariable analysis, smoking was not found to be associated with increased odds of MRSA infection. CONCLUSIONS: Among patients who develop a FRI, smokers seemed to have better baseline health regarding age, body mass index, diabetes mellitus, and Charlson Comorbidity Index 10-year estimated survival compared with nonsmokers. Smoking status was not significantly associated with odds of MRSA infection. However, smoking status was associated with increased risk of sinus tract development and nonunion and lower rates of S. epidermidis infection at the time of FRI reoperation. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Lower Extremity Amputation in Fracture-Related Infection.

OBJECTIVES: To analyze demographics, comorbidities, fracture characteristics, presenting characteristics, microbiology, and treatment course of patients with fracture-related infections (FRIs) to determine risk factors leading to amputation. DESIGN: Retrospective cohort. SETTING: Single Level I Trauma Center (2013-2020). PATIENT SELECTION CRITERIA: Adults with lower extremity (femur and tibia) FRIs were identified through a review of an institutional database. Inclusion criteria were operatively managed fracture of the femur or tibia with an FRI and adequate documentation present in the electronic medical record. This included patients whose primary injury was managed at this institution and who were referred to this institution after the onset of FRI as long as all characteristics and risk factors assessed in the analysis were documented. Exclusion criteria were infected chronic osteomyelitis from a non-fracture-related pathology and a follow-up of less than 6 months. OUTCOME MEASURES AND COMPARISONS: Risk factors (demographics, comorbidities, and surgical, injury, and perioperative characteristics) leading to amputation in patients with FRIs were evaluated. RESULTS: A total of 196 patients were included in this study. The average age of the study group was 44±16 years. Most patients were men (63%) and White (71%). The overall amputation rate was 9.2%. There were significantly higher rates of chronic kidney disease (CKD; P = 0.039), open fractures (P = 0.034), transfusion required during open reduction internal fixation (P = 0.033), Gram-negative infections (P = 0.048), and FRI-related operations (P = 0.001) in the amputation cohort. On multivariate, patients with CKD were 28.8 times more likely to undergo amputation (aOR = 28.8 [2.27 to 366, P = 0.010). A subanalysis of 79 patients with either a methicillin-sensitive Staphylococcus aureus or methicillin-resistant S. aureus (MRSA) infection showed that patients with MRSA were significantly more likely to undergo amputation compared with patients with methicillin-sensitive Staphylococcus aureus (P = 0.031). MRSA was present in all cases of amputation in the Staphylococcal subanalysis. CONCLUSIONS: Findings from this study highlight CKD as a risk factor of amputation in the tibia and femur with fracture-related infection. In addition, MRSA was present in all cases of Staphylococcal amputation. Identifying patients and infection patterns that carry a higher risk of amputation can assist surgeons in minimizing the burden on these individuals. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Postoperative Cerebrospinal Fluid-Related Complications After Posterior Fossa and Posterolateral Skull Base Surgeries: Development of a Predictive Model and Clinical Risk Score.

BACKGROUND: Postoperative pseudomeningocele (PMC) and cerebrospinal fluid (CSF) leak are common complications following posterior fossa and posterolateral skull base surgeries. We sought to 1) determine the rate of CSF-related complications and 2) develop a perioperative model and risk score to identify the highest risk patients for these events. METHODS: We performed a retrospective cohort of 450 patients undergoing posterior fossa and posterolateral skull base procedures from 2016 to 2020. Logistic regressions were performed for predictor selection for 3 prespecified models: 1) a priori variables, 2) predictors selected by large effect sizes, and 3) predictors with P ≤ 0.100 on univariable analysis. A final model was created by elimination of nonsignificant predictors, and the integer-based postoperative CSF-related complications (POCC) clinical risk score was derived. Internal validation was done using 10-fold cross-validation and bootstrapping with uniform shrinkage. RESULTS: A total of 115 patients (25.6%) developed PMC and/or CSF leakage. Age >55 years (odds ratio [OR], 0.560; 95% confidence interval [CI], 0.328-0.954), body mass index >30 kg/m2 (OR, 1.88; 95% CI, 1.14-3.10), and postoperative CSF diversion (OR, 2.85; 95% CI, 1.64-5.00) were associated with CSF leak and PMC. Model 2 was the most predictive (cross-validated area under the receiver operating characteristic curve, 0.690). The final risk score was devised using age, body mass index class, dural repair technique, use of bone substitute, and duration of postoperative CSF diversion. The POCC score performed well (cross-validated area under the receiver operating characteristic curve, 0.761) and was highly specific (96.1%). CONCLUSIONS: We created the first generalizable and predictive risk score to identify patients at risk of CSF-related complications. The POCC score could improve surveillance, inform doctor-patient discussions regarding the risks of surgery, and assist in perioperative management.

Morbid Obesity Increases Length of Surgery in Elective Anterior Cervical Discectomy and Fusion Procedures but Not Readmission or Reoperation Rates: A Cohort Study.

BACKGROUND: As the obesity epidemic grows, the number of morbidly obese patients undergoing anterior cervical discectomy and fusion (ACDF) continues to increase. Despite the association of obesity with perioperative complications in anterior cervical surgery, the impact of morbid obesity on ACDF complications remains controversial, and studies examining morbidly obese cohorts are limited. METHODS: A single-institution, retrospective analysis of patients undergoing ACDF from September 2010 to February 2022 was performed. Demographic, intraoperative, and postoperative data were collected via review of the electronic medical record. Patients were categorized as nonobese (body mass index [BMI] <30), obese (BMI 30-39.9), or morbidly obese (BMI ≥40). Associations of BMI class with discharge disposition, length of surgery, and length of stay were assessed using multivariable logistic regression, multivariable linear regression, and negative binomial regression, respectively. RESULTS: The study included 670 patients undergoing single-level or multilevel ACDF: 413 (61.6%) nonobese, 226 (33.7%) obese, and 31 (4.6%) morbidly obese patients. BMI class was associated with prior history of deep venous thrombosis (P < 0.01), pulmonary thromboembolism (P < 0.05), and diabetes mellitus (P < 0.001). In bivariate analysis, there was no significant association between BMI class and reoperation or readmission rates at 30, 60, or 365 days postoperatively. In multivariable analysis, greater BMI class was associated with increased length of surgery (P = 0.03), but not length of stay or discharge disposition. CONCLUSIONS: For patients undergoing ACDF, greater BMI class was associated with increased length of surgery, but not reoperation rate, readmission rate, length of stay, or discharge disposition.

Oncolytic virotherapies for pediatric tumors.

INTRODUCTION: Many pediatric patients with malignant tumors continue to suffer poor outcomes. The current standard of care includes maximum safe surgical resection followed by chemotherapy and radiation which may be associated with considerable long-term morbidity. The emergence of oncolytic virotherapy (OVT) may provide an alternative or adjuvant treatment for pediatric oncology patients. AREAS COVERED: We reviewed seven virus types that have been investigated in past or ongoing pediatric tumor clinical trials: adenovirus (AdV-tk, Celyvir, DNX-2401, VCN-01, Ad-TD-nsIL-12), herpes simplex virus (G207, HSV-1716), vaccinia (JX-594), reovirus (pelareorep), poliovirus (PVSRIPO), measles virus (MV-NIS), and Senecavirus A (SVV-001). For each virus, we discuss the mechanism of tumor-specific replication and cytotoxicity as well as key findings of preclinical and clinical studies. EXPERT OPINION: Substantial progress has been made in the past 10 years regarding the clinical use of OVT. From our review, OVT has favorable safety profiles compared to chemotherapy and radiation treatment. However, the antitumor effects of OVT remain variable depending on tumor type and viral agent used. Although the widespread adoption of OVT faces many challenges, we are optimistic that OVT will play an important role alongside standard chemotherapy and radiotherapy for the treatment of malignant pediatric solid tumors in the future.

Non-catalytic allostery in α-TAT1 by a phospho-switch drives dynamic microtubule acetylation.

Spatiotemporally dynamic microtubule acetylation underlies diverse physiological and pathological events. Despite its ubiquity, the molecular mechanisms that regulate the sole microtubule acetylating agent, α-tubulin-N-acetyltransferase-1 (α-TAT1), remain obscure. Here, we report that dynamic intracellular localization of α-TAT1 along with its catalytic activity determines efficiency of microtubule acetylation. Specifically, we newly identified a conserved signal motif in the intrinsically disordered C-terminus of α-TAT1, consisting of three competing regulatory elements-nuclear export, nuclear import, and cytosolic retention. Their balance is tuned via phosphorylation by CDK1, PKA, and CK2, and dephosphorylation by PP2A. While the unphosphorylated form binds to importins and resides both in cytosol and nucleus, the phosphorylated form binds to specific 14-3-3 adapters and accumulates in the cytosol for maximal substrate access. Unlike other molecules with a similar phospho-regulated signal motif, α-TAT1 uniquely uses the nucleus as a hideout. This allosteric spatial regulation of α-TAT1 function may help uncover a spatiotemporal code of microtubule acetylation in normal and aberrant cell behavior.