Chordoma cancer stem cell subpopulation characterization may guide targeted immunotherapy approaches to reduce disease recurrence.

Introduction: Cancer stem cells (CSCs), a group of tumor-initiating and tumor-maintaining cells, may be major players in the treatment resistance and recurrence distinctive of chordoma. Characterizing CSCs is crucial to better targeting this subpopulation. Methods: Using flow cytometry, six chordoma cell lines were evaluated for CSC composition. In vitro, cell lines were stained for B7H6, HER2, MICA-B, ULBP1, EGFR, and PD-L1 surface markers. Eighteen resected chordomas were stained using a multispectral immunofluorescence (mIF) antibody panel to identify CSCs in vivo. HALO software was used for quantitative CSC density and spatial analysis. Results: In vitro, chordoma CSCs express more B7H6, MICA-B, and ULBP1, assessed by percent positivity and mean fluorescence intensity (MFI), as compared to non-CSCs in all cell lines. PD- L1 percent positivity is increased by >20% in CSCs compared to non-CSCs in all cell lines except CH22. In vivo, CSCs comprise 1.39% of chordoma cells and most are PD-L1+ (75.18%). A spatial analysis suggests that chordoma CSCs cluster at an average distance of 71.51 mm (SD 73.40 mm) from stroma. Discussion: To our knowledge, this study is the first to identify individual chordoma CSCs and describe their surface phenotypes using in vitro and in vivo methods. PD-L1 is overexpressed on CSCs in chordoma human cell lines and operative tumor samples. Similarly, potential immunotherapeutic targets on CSCs, including B7H6, MICA-B, ULBP1, EGFR, and HER2 are overexpressed across cell lines. Targeting these markers may have a preferential role in combating CSCs, an aggressive subpopulation likely consequential to chordoma's high recurrence rate.

Augmentation of tumor expression of HLA-DR, CXCL9, and CXCL10 may improve olfactory neuroblastoma immunotherapeutic responses.

BACKGROUND: Olfactory neuroblastoma is a rare malignancy of the anterior skull base typically treated with surgery and adjuvant radiation. Although outcomes are fair for low-grade disease, patients with high-grade, recurrent, or metastatic disease oftentimes respond poorly to standard treatment methods. We hypothesized that an in-depth evaluation of the olfactory neuroblastoma tumor immune microenvironment would identify mechanisms of immune evasion in high-grade olfactory neuroblastoma as well as rational targetable mechanisms for future translational immunotherapeutic approaches. METHODS: Multispectral immunofluorescence and RNAScope evaluation of the tumor immune microenvironment was performed on forty-seven clinically annotated olfactory neuroblastoma samples. A retrospective chart review was performed and clinical correlations assessed. RESULTS: A significant T cell infiltration was noted in olfactory neuroblastoma samples with a stromal predilection, presence of myeloid-derived suppressor cells, and sparse natural killer cells. A striking decrease was observed in MHC-I expression in high-grade olfactory neuroblastoma compared to low-grade disease, representing a mechanism of immune evasion in high-grade disease. Mechanistically, the immune effector stromal predilection appears driven by low tumor cell MHC class II (HLA-DR), CXCL9, and CXCL10 expression as those tumors with increased tumor cell expression of each of these mediators correlated with significant increases in T cell infiltration. CONCLUSION: These data suggest that immunotherapeutic strategies that augment tumor cell expression of MHC class II, CXCL9, and CXCL10 may improve parenchymal trafficking of immune effector cells in olfactory neuroblastoma and augment immunotherapeutic responses.

Recurrent Wnt Pathway and ARID1A Alterations in Sinonasal Olfactory Carcinoma.

Sinonasal tumors with neuroepithelial differentiation, defined by neuroectodermal elements reminiscent of olfactory neuroblastoma (ONB) and epithelial features such as keratin expression or gland formation, are a diagnostically challenging group that has never been formally included in sinonasal tumor classifications. Recently, we documented that most of these neuroepithelial neoplasms have distinctive histologic and immunohistochemical findings and proposed the term "olfactory carcinoma" to describe these tumors. However, the molecular characteristics of olfactory carcinoma have not yet been evaluated. In this study, we performed targeted molecular profiling of 23 sinonasal olfactory carcinomas to further clarify their pathogenesis and classification. All tumors included in this study were composed of high-grade neuroectodermal cells that were positive for pankeratin and at least 1 specific neuroendocrine marker. A significant subset of cases also displayed rosettes and neurofibrillary matrix, intermixed glands with variable cilia, peripheral p63/p40 expression, and S100 protein-positive sustentacular cells. Recurrent oncogenic molecular alterations were identified in 20 tumors, including Wnt pathway alterations affecting CTNNB1 (n = 8) and PPP2R1A (n = 2), ARID1A inactivation (n = 5), RUNX1 mutations (n = 3), and IDH2 hotspot mutations (n = 2). Overall, these findings do demonstrate the presence of recurrent molecular alterations in olfactory carcinoma, although this group of tumors does not appear to be defined by any single mutation. Minimal overlap with alterations previously reported in ONB also adds to histologic and immunohistochemical separation between ONB and olfactory carcinoma. Conversely, these molecular findings enhance the overlap between olfactory carcinoma and sinonasal neuroendocrine carcinomas. A small subset of neuroepithelial tumors might better fit into the superseding molecular category of IDH2-mutant sinonasal carcinoma. At this point, sinonasal neuroendocrine and neuroepithelial tumors may best be regarded as a histologic and molecular spectrum that includes core groups of ONB, olfactory carcinoma, neuroendocrine carcinoma, and IDH2-mutant sinonasal carcinoma.

Awake Versus Asleep Craniotomy for Patients With Eloquent Glioma: A Systematic Review and Meta-Analysis.

BACKGROUND AND OBJECTIVES: Awake vs asleep craniotomy for patients with eloquent glioma is debatable. This systematic review and meta-analysis sought to compare awake vs asleep craniotomy for the resection of gliomas in the eloquent regions. METHODS: MEDLINE and PubMed were searched from inception to December 13, 2022. Primary outcomes were the extent of resection (EOR), overall survival (month), progression-free survival (month), and rates of neurological deficit, Karnofsky performance score, and seizure freedom at the 3-month follow-up. Secondary outcomes were duration of operation (minute) and length of hospital stay (LOS) (day). RESULTS: Fifteen studies yielded 2032 patients, from which 800 (39.4%) and 1232 (60.6%) underwent awake and asleep craniotomy, respectively. The meta-analysis concluded that the awake group had greater EOR (mean difference [MD] = MD = 8.52 [4.28, 12.76], P < .00001), overall survival (MD = 2.86 months [1.35, 4.37], P = .0002), progression-free survival (MD = 5.69 months [0.75, 10.64], P = .02), 3-month postoperative Karnofsky performance score (MD = 13.59 [11.08, 16.09], P < .00001), and 3-month postoperative seizure freedom (odds ratio = 8.72 [3.39, 22.39], P < .00001). Furthermore, the awake group had lower 3-month postoperative neurological deficit (odds ratio = 0.47 [0.28, 0.78], P = .004) and shorter LOS (MD = -2.99 days [-5.09, -0.88], P = .005). In addition, the duration of operation was similar between the groups (MD = 37.88 minutes [-34.09, 109.86], P = .30). CONCLUSION: Awake craniotomy for gliomas in the eloquent regions benefits EOR, survival, postoperative neurofunctional outcomes, and LOS. When feasible, the authors recommend awake craniotomy for surgical resection of gliomas in the eloquent regions.

Craniotomy versus craniectomy for traumatic acute subdural hematoma-coarsened exact matched analysis of outcomes.

BACKGROUND AND OBJECTIVES: Acute subdural hematoma (aSDH) after traumatic brain injury frequently requires emergent craniotomy (CO) or decompressive craniectomy (DC). We sought to determine the variables associated with either surgical approach and to compare outcomes between matched patients. METHODS: A multi-center retrospective review was used to identify traumatic aSDH patients who underwent CO or DC. Patient variables independently associated with surgical approach were used for coarsened exact matching.Multivariate logistic regression and multivariate Cox proportional-hazards regression wereconducted on matched patients to determine independent predictors of mortality. RESULTS: Seventy-six patients underwent CO and sixty-two underwent DC for aSDH evacuation. DC patients were21.4 years younger (P < 0.001), more likely to be male (80.6 % vs 60.5 %,P = 0.011), and present with GCS ≤ 8 (64.5 % vs 36.8 %,P = 0.001). Age (P < 0.001), epidural hematoma (P = 0.01), skull fracture (P = 0.001), and cisternal effacement (P = 0.02) were independently associated with surgical approach. After coarsened exact matching, DC (P = 0.008), older age (P = 0.007), male sex (P = 0.04), and intraventricular hemorrhage (P = 0.02), were independently associated with inpatient mortality. Multivariate Cox proportional-hazards regression demonstrated that DC was independently associated with mortality at 90-days (P = 0.001) and 1-year post-operation (P = 0.003). CONCLUSION: aSDH patients who receive surgical evacuation via DC as opposed to CO are younger, more likely to be male, and have worse clinical exam. After controlling for patient differences via coarsened exact matching, DC is independently associated with mortality.

Impact of Antithrombotic Medications and Reversal Strategies on the Surgical Management and Outcomes of Traumatic Acute Subdural Hematoma.

OBJECTIVE: Careful hematologic management is required in surgical patients with traumatic acute subdural hematoma (aSDH) taking antithrombotic medications. We sought to compare outcomes between patients with aSDH taking antithrombotic medications at admission who received antithrombotic reversal with patients with aSDH not taking antithrombotics. METHODS: Retrospective review identified patients with traumatic aSDH requiring surgical evacuation. The cohort was divided based on antithrombotic use and whether pharmacologic reversal agents or platelet transfusions were administered. A 3-way comparison of outcomes was performed between patients taking anticoagulants who received pharmacologic reversal, patients taking antiplatelets who received platelet transfusion, and patients not taking antithrombotics. Multivariable regressions, adjusted for injury severity, further investigated associations with outcomes. RESULTS: Of 138 patients who met inclusion criteria, 13.0% (n = 18) reported taking anticoagulants, 16.7% (n = 23) reported taking antiplatelets, and 3.6% (n = 5) reported taking both. Patients taking antiplatelets who received platelet transfusion had longer intraoperative times (P = 0.040) and higher rates of palliative care consultations (P = 0.046) compared with patients taking anticoagulants who received pharmacologic reversal and patients not taking antithrombotics. Across groups, no significant differences were found in frequency of in-hospital intracranial hemorrhage and venous thromboembolism, length of hospital stay, rate of inpatient mortality, or follow-up health status. In multivariable analysis, intraoperative time remained longest for the antiplatelets with platelet transfusion group. Other outcomes were not associated with patient group. CONCLUSIONS: Among surgical patients with traumatic aSDH, those taking antiplatelet medications who receive platelet transfusions experience longer intraoperative procedure times and higher rates of palliative care consultation. Comparable outcomes were observed between patients receiving antithrombotic reversal and patients not taking antithrombotics.

Risk of Subdural Hematoma Expansion in Patients With End-Stage Renal Disease: Continuous Venovenous Hemodialysis Versus Intermittent Hemodialysis.

BACKGROUND AND OBJECTIVES: Subdural hematoma (SDH) patients with end-stage renal disease (ESRD) require renal replacement therapy in addition to neurological management. We sought to determine whether continuous venovenous hemodialysis (CVVHD) or intermittent hemodialysis (iHD) is associated with higher rates of SDH re-expansion as well as morbidity and mortality. METHODS: Hemodialysis-dependent patients with ESRD who were discovered to have an SDH were retrospectively identified from 2016 to 2022. Rates of SDH expansion during CVVHD vs iHD were compared. Hemodialysis mode was included in a multivariate logistic regression model to test for independent association with SDH expansion and mortality. RESULTS: A total of 123 hemodialysis-dependent patients with ESRD were discovered to have a concomitant SDH during the period of study. Patients who received CVVHD were on average 10.2 years younger ( P < .001), more likely to have traumatic SDH (47.7% vs 19.0%, P < .001), and more likely to have cirrhosis (25.0% vs 10.1%, P = .029). SDH expansion affecting neurological function occurred more frequently during iHD compared with CVVHD (29.7% vs 12.0%, P = .013). Multivariate logistic regression analysis found that CVVHD was independently associated with decreased risk of SDH affecting neurological function (odds ratio 0.25, 95% CI 0.08-0.65). Among patients who experienced in-hospital mortality or were discharged to hospice, 5% suffered a neurologically devastating SDH expansion while on CVVHD compared with 35% on iHD. CONCLUSION: CVVHD was independently associated with decreased risk of neurologically significant SDH expansion. Therefore, receiving renal replacement therapy through a course of CVVHD may increase SDH stability in patients with ESRD.

Effects of In Utero EtOH Exposure on 18S Ribosomal RNA Processing: Contribution to Fetal Alcohol Spectrum Disorder.

Fetal alcohol spectrum disorders (FASD) are leading causes of neurodevelopmental disability. The mechanisms by which alcohol (EtOH) disrupts fetal brain development are incompletely understood, as are the genetic factors that modify individual vulnerability. Because the phenotype abnormalities of FASD are so varied and widespread, we investigated whether fetal exposure to EtOH disrupts ribosome biogenesis and the processing of pre-ribosomal RNAs and ribosome assembly, by determining the effect of exposure to EtOH on the developmental expression of 18S rRNA and its cleaved forms, members of a novel class of short non-coding RNAs (srRNAs). In vitro neuronal cultures and fetal brains (11-22 weeks) were collected according to an IRB-approved protocol. Twenty EtOH-exposed brains from the first and second trimester were compared with ten unexposed controls matched for gestational age and fetal gender. Twenty fetal-brain-derived exosomes (FB-Es) were isolated from matching maternal blood. RNA was isolated using Qiagen RNA isolation kits. Fetal brain srRNA expression was quantified by ddPCR. srRNAs were expressed in the human brain and FB-Es during fetal development. EtOH exposure slightly decreased srRNA expression (1.1-fold; p = 0.03). Addition of srRNAs to in vitro neuronal cultures inhibited EtOH-induced caspase-3 activation (1.6-fold, p = 0.002) and increased cell survival (4.7%, p = 0.034). The addition of exogenous srRNAs reversed the EtOH-mediated downregulation of srRNAs (2-fold, p = 0.002). EtOH exposure suppressed expression of srRNAs in the developing brain, increased activity of caspase-3, and inhibited neuronal survival. Exogenous srRNAs reversed this effect, possibly by stabilizing endogenous srRNAs, or by increasing the association of cellular proteins with srRNAs, modifying gene transcription. Finally, the reduction in 18S rRNA levels correlated closely with the reduction in fetal eye diameter, an anatomical hallmark of FASD. The findings suggest a potential mechanism for EtOH-mediated neurotoxicity via alterations in 18S rRNA processing and the use of FB-Es for early diagnosis of FASD. Ribosome biogenesis may be a novel target to ameliorate FASD in utero or after birth. These findings are consistent with observations that gene-environment interactions contribute to FASD vulnerability.

Seq-ing the SINEs of central nervous system tumors in cerebrospinal fluid.

It is often challenging to distinguish cancerous from non-cancerous lesions in the brain using conventional diagnostic approaches. We introduce an analytic technique called Real-CSF (repetitive element aneuploidy sequencing in CSF) to detect cancers of the central nervous system from evaluation of DNA in the cerebrospinal fluid (CSF). Short interspersed nuclear elements (SINEs) are PCR amplified with a single primer pair, and the PCR products are evaluated by next-generation sequencing. Real-CSF assesses genome-wide copy-number alterations as well as focal amplifications of selected oncogenes. Real-CSF was applied to 280 CSF samples and correctly identified 67% of 184 cancerous and 96% of 96 non-cancerous brain lesions. CSF analysis was considerably more sensitive than standard-of-care cytology and plasma cell-free DNA analysis in the same patients. Real-CSF therefore has the capacity to be used in combination with other clinical, radiologic, and laboratory-based data to inform the diagnosis and management of patients with suspected cancers of the brain.

Reconstruction in open anterior skull base surgery: A review and algorithmic approach.

PURPOSE: Defects resulting from open resection of anterior skull base neoplasms are difficult to reconstruct. Our objective was to review the literature and describe an evidence-based algorithm that can guide surgeons reconstructing anterior skull base defects. METHODS: A research librarian designed database search strategies. Two investigators independently reviewed the resulting abstracts and full text articles. Studies on reconstruction after open anterior skull base resection were included. Studies of lateral and posterior skull base reconstruction, endoscopic endonasal surgery, traumatic and congenital reconstruction were excluded. Based on the review, a reconstructive algorithm was proposed. RESULTS: The search strategy identified 603 unique abstracts. 53 articles were included. Adjacent subsites resected, defect size, radiotherapy history, and contraindications to free tissue transfer were identified as key factors influencing decision making and were used to develop the algorithm. Discussion of the reconstructive ladder as it applies to skull base reconstruction and consideration of patient specific factors are reviewed. Patients with a prior history of radiotherapy or with simultaneous resection of multiple anatomic subsites adjacent to the anterior skull base will likely benefit from free tissue transfer. CONCLUSIONS: Reconstruction of anterior skull base defects requires knowledge of the available reconstructive techniques and consideration of defect-specific and patient-specific factors.

Predictors of surgical site infection in glioblastoma patients undergoing craniotomy for tumor resection.

OBJECTIVE: Surgical site infections (SSIs) burden patients and healthcare systems, often requiring additional intervention. The objective of this study was to identify the relationship between preoperative predictors inclusive of scalp incision type and postoperative SSI following glioblastoma resection. METHODS: The authors retrospectively reviewed cases of glioblastoma resection performed at their institution from December 2006 to December 2019 and noted preoperative demographic and clinical presentations, excluding patients missing these data. Preoperative nutritional indices were available for a subset of cases. Scalp incisions were categorized as linear/curvilinear, reverse question mark, trapdoor, or frontotemporal. Patients were dichotomized by SSI incidence. Multivariable logistic regression was used to determine predictors of SSI. RESULTS: A total of 911 cases of glioblastoma resection were identified, 30 (3.3%) of which demonstrated postoperative SSI. There were no significant differences in preoperative malnutrition or number of surgeries between SSI and non-SSI cases. The SSI cases had a significantly lower preoperative Karnofsky Performance Status (KPS) than the non-SSI cases (63.0 vs 75.1, p < 0.0001), were more likely to have prior radiation history (43.3% vs 26.4%, p = 0.042), and were more likely to have received steroids both preoperatively and postoperatively (83.3% vs 54.5%, p = 0.002). Linear/curvilinear incisions were more common in non-SSI than in SSI cases (56.9% vs 30.0%, p = 0.004). Trapdoor scalp incisions were more frequent in SSI than non-SSI cases (43.3% vs 24.2%, p = 0.012). On multivariable analysis, a lower preoperative KPS (OR 1.04, 95% CI 1.02-1.06), a trapdoor scalp incision (OR 3.34, 95% CI 1.37-8.49), and combined preoperative and postoperative steroid administration (OR 3.52, 95% CI 1.41-10.7) were independently associated with an elevated risk of postoperative SSI. CONCLUSIONS: The study findings indicated that SSI risk following craniotomy for glioblastoma resection may be elevated in patients with a low preoperative KPS, a trapdoor scalp incision during surgery, and steroid treatment both preoperatively and postoperatively. These data may help guide future operative decision-making for these patients.

Patient reported outcomes and treatment satisfaction in patients with cushing syndrome.

PURPOSE: Cushing Syndrome (CS) is a rare endocrine disorder associated with physical and mental symptoms that can drastically affect quality of life (QoL). This study characterizes QoL in patients with CS, describes their treatment experiences, and identifies patient subsets associated with decreased QoL or shared impressions of treatment. METHODS: A 136-question survey addressing QoL factors and treatment experiences was completed by adult patients with CS from the Cushing Support and Research Foundation. Patient demographics, tumor characteristics, and treatment information were collected. Bivariate analyses were conducted to determine if patients' symptoms or treatment experiences were significantly associated with demographics or other variables. RESULTS: A total of 178 patients, predominantly female (94%) with mean age 53 years, completed the survey. Anxiety and/or depression (n = 163, 94%), loss of physical strength (n = 164, 93%), loneliness (n = 156, 90%), fatigue from treatment (n = 142, 89%), memory loss (n = 153, 88%), insomnia (n = 144, 83%), and pain (n = 141, 83%) were symptoms most commonly experienced by respondents. Patients experiencing delay of diagnosis >10 years were more likely to have suicidal thoughts (p = 0.002). Younger patients were more likely to express concerns about hair loss (p = 0.007), loneliness (p = 0.025), pain (p = 0.004), or the impact of CS on their marriage (p = 0.039) or children (p = 0.024). CONCLUSION: This survey demonstrates CS impacts patients across many dimensions, emphasizing the need for holistic support. We identified patient subsets in which QoL may be improved with additional patient resources or provider attention.

A comparative analysis of the Hospital Frailty Risk Score in predicting postoperative outcomes among intracranial tumor patients.

OBJECTIVE: In recent years, frailty indices such as the 11- and 5-factor modified frailty indices (mFI-11 and mFI-5), American Society of Anesthesiologists (ASA) physical status classification, and Charlson Comorbidity Index (CCI) have been shown to be effective predictors of various postoperative outcomes in neurosurgical patients. The Hospital Frailty Risk Score (HFRS) is a well-validated tool for assessing frailty; however, its utility has not been evaluated in intracranial tumor surgery. In the present study, the authors investigated the accuracy of the HFRS in predicting outcomes following intracranial tumor resection and compared its utility to those of other validated frailty indices. METHODS: A retrospective analysis was conducted using an intracranial tumor patient database at a single institution. Patients eligible for study inclusion were those who had undergone resection for an intracranial tumor between January 1, 2017, and December 31, 2019. ICD-10 codes were used to identify HFRS components and subsequently calculate risk scores. In addition to several postoperative variables, ASA class, CCI, and mFI-11 and mFI-5 scores were determined for each patient. Model discrimination was assessed using the area under the receiver operating characteristic curve (AUROC), and the DeLong test was used to assess for significant differences between AUROCs. Multivariate models for continuous outcomes were constructed using linear regression, whereas logistic regression models were used for categorical outcomes. RESULTS: A total of 2518 intracranial tumor patients (mean age 55.3 ± 15.1 years, 53.4% female, 70.4% White) were included in this study. The HFRS had a statistically significant greater AUROC than ASA status, CCI, mFI-11, and mFI-5 for postoperative complications, high hospital charges, nonroutine discharge, and 90-day readmission. In the multivariate analysis, the HFRS was significantly and independently associated with postoperative complications (OR 1.14, p < 0.0001), hospital length of stay (coefficient = 0.50, p < 0.0001), high hospital charges (coefficient = 1917.49, p < 0.0001), nonroutine discharge (OR 1.14, p < 0.0001), and 90-day readmission (OR 1.06, p < 0.0001). CONCLUSIONS: The study findings suggest that the HFRS is an effective predictor of postoperative outcomes in intracranial tumor patients and more effectively predicts adverse outcomes than other frailty indices. The HFRS may serve as an important tool for reducing patient morbidity and mortality in intracranial tumor surgery.

Multi-spectral immunofluorescence evaluation of the myeloid, T cell, and natural killer cell tumor immune microenvironment in chordoma may guide immunotherapeutic strategies.

Background: Chordoma is a rare, invasive, and devastating bone malignancy of residual notochord tissue that arises at the skull base, sacrum, or spine. In order to maximize immunotherapeutic approaches as a potential treatment strategy in chordoma it is important to fully characterize the tumor immune microenvironment (TIME). Multispectral immunofluorescence (MIF) allows for comprehensive evaluation of tumor compartments, molecular co-expression, and immune cell spatial relationships. Here we implement MIF to define the myeloid, T cell, and natural killer (NK) cell compartments in an effort to guide rational design of immunotherapeutic strategies for chordoma. Methods: Chordoma tumor tissue from 57 patients was evaluated using MIF. Three panels were validated to assess myeloid cell, T cell, and NK cell populations. Slides were stained using an automated system and HALO software objective analysis was utilized for quantitative immune cell density and spatial comparisons between tumor and stroma compartments. Results: Chordoma TIME analysis revealed macrophage infiltration of the tumor parenchyma at a significantly higher density than stroma. In contrast, helper T cells, cytotoxic T cells, and T regulatory cells were significantly more abundant in stroma versus tumor. T cell compartment infiltration more commonly demonstrated a tumor parenchymal exclusion pattern, most markedly among cytotoxic T cells. NK cells were sparsely found within the chordoma TIME and few were in an activated state. No immune composition differences were seen in chordomas originating from diverse anatomic sites or between those resected at primary versus advanced disease stage. Conclusion: This is the first comprehensive evaluation of the chordoma TIME including myeloid, T cell, and NK cell appraisal using MIF. Our findings demonstrate that myeloid cells significantly infiltrate chordoma tumor parenchyma while T cells tend to be tumor parenchymal excluded with high stromal infiltration. On average, myeloid cells are found nearer to target tumor cells than T cells, potentially resulting in restriction of T effector cell function. This study suggests that future immunotherapy combinations for chordoma should be aimed at decreasing myeloid cell suppressive function while enhancing cytotoxic T cell and NK cell killing.

A nanoengineered topical transmucosal cisplatin delivery system induces anti-tumor response in animal models and patients with oral cancer.

Despite therapeutic advancements, oral cavity squamous cell carcinoma (OCSCC) remains a difficult disease to treat. Systemic platinum-based chemotherapy often leads to dose-limiting toxicity (DLT), affecting quality of life. PRV111 is a nanotechnology-based system for local delivery of cisplatin loaded chitosan particles, that penetrate tumor tissue and lymphatic channels while avoiding systemic circulation and toxicity. Here we evaluate PRV111 using animal models of oral cancer, followed by a clinical trial in patients with OCSCC. In vivo, PRV111 results in elevated cisplatin retention in tumors and negligible systemic levels, compared to the intravenous, intraperitoneal or intratumoral delivery. Furthermore, PRV111 produces robust anti-tumor responses in subcutaneous and orthotopic cancer models and results in complete regression of carcinogen-induced premalignant lesions. In a phase 1/2, open-label, single-arm trial (NCT03502148), primary endpoints of efficacy (≥30% tumor volume reduction) and safety (incidence of DLTs) of neoadjuvant PRV111 were reached, with 69% tumor reduction in ~7 days and over 87% response rate. Secondary endpoints (cisplatin biodistribution, loco-regional control, and technical success) were achieved. No DLTs or drug-related serious adverse events were reported. No locoregional recurrences were evident in 6 months. Integration of PRV111 with current standard of care may improve health outcomes and survival of patients with OCSCC.

Predictors and Impact of Postoperative 30-Day Readmission in Glioblastoma.

BACKGROUND: Postoperative 30-day readmissions have been shown to negatively affect survival and other important outcomes in patients with glioblastoma (GBM). OBJECTIVE: To further investigate patient readmission risk factors of primary and recurrent patients with GBM. METHODS: The authors retrospectively reviewed records of 418 adult patients undergoing 575 craniotomies for histologically confirmed GBM at an academic medical center. Patient demographics, comorbidities, and clinical characteristics were collected and compared by patient readmission status using chi-square and Mann-Whitney U testing. Multivariable logistic regression was performed to identify risk factors that predicted 30-day readmissions. RESULTS: The cohort included 69 (12%) 30-day readmissions after 575 operations. Readmitted patients experienced significantly lower median overall survival (11.3 vs 16.4 months, P = .014), had a lower mean Karnofsky Performance Scale score (66.9 vs 74.2, P = .005), and had a longer initial length of stay (6.1 vs 5.3 days, P = .007) relative to their nonreadmitted counterparts. Readmitted patients experienced more postoperative deep vein thromboses or pulmonary embolisms (12% vs 4%, P = .006), new motor deficits (29% vs 14%, P = .002), and nonhome discharges (39% vs 22%, P = .005) relative to their nonreadmitted counterparts. Multivariable analysis demonstrated increased odds of 30-day readmission with each 10-point decrease in Karnofsky Performance Scale score (odds ratio [OR] 1.32, P = .002), each single-point increase in 5-factor modified frailty index (OR 1.51, P = .016), and initial presentation with cognitive deficits (OR 2.11, P = .013). CONCLUSION: Preoperatively available clinical characteristics strongly predicted 30-day readmissions in patients undergoing surgery for GBM. Opportunities may exist to optimize preoperative and postoperative management of at-risk patients with GBM, with downstream improvements in clinical outcomes.

High resolution 3D magnetic resonance imaging of Gruber's ligament: a pilot study.

INTRODUCTION: Gruber's ligament (GL), a surgical landmark, extends from the lateral upper clivus to the petrous apex (PA), forming the superior boundary of Dorello's canal (DC). It overlies the interdural segment of the abducens nerve (CN VI). High-resolution 3D skull base MRI (SB-MRI) demonstrates anatomic details visible to the surgeon, but not well seen on traditional cross-sectional imaging. The aim of this study was to demonstrate visualization of the GL and its relationship to CN VI utilizing contrast enhanced high-resolution SB-MRI. METHODS: Two neuroradiologists retrospectively reviewed in consensus the SB-MRIs of 27 skull base sides, among 14 patients. GL detection rate, confidence of detection, and GL length were recorded. When GL was successfully identified, the position of the interdural segment of CN VI within DC was recorded. RESULTS: GL was readily identified in 16 skull base sides (59%), identified with some difficulty in 2 skull base sides (7%), and failed to be identified in 9 skull base sides (33%). The mean GL length was 7.1 mm (4.5-9.3 mm). Among the 18 cases where GL was successfully identified, CN VI was readily identified in all cases (100%), coursing the lateral third of DC in 72% of sides, and middle third in the remaining 28% of sides. CONCLUSION: GL can be identified in approximately two-thirds of cases utilizing 3D high resolution SB-MRI. CN VI passes most commonly along the lateral third of DC. This is the first report demonstrating visualization of GL and its relation to CN VI, on imaging.