Risk stratification for early postoperative infection in Pediatric spinal deformity correction: development and validation of the Pediatric scoliosis infection risk score (PSIR score).

BACKGROUND CONTEXT: Postoperative infection after spinal deformity correction in pediatric patients is associated with significant costs. Identifying risk factors associated with postoperative infection would help surgeons identify high-risk patients that may require interventions to minimize infection risk. PURPOSE: To investigate risk factors associated with 30-day postoperative infection in pediatric patients who have received posterior arthrodesis for spinal deformity correction. STUDY DESIGN/SETTING: Retrospective review of prospectively collected data. PATIENT SAMPLE: The National Surgical Quality Improvement Program Pediatric database for years 2016-2021 was used for this study. Patients were included if they received posterior arthrodesis for scoliosis or kyphosis correction (CPT 22,800, 22,802, 22,804). Anterior only approaches were excluded. OUTCOME MEASURES: TThe outcome of interest was 30-day postoperative infection. METHODS: Patient demographics and outcomes were analyzed using descriptive statistics. Multivariable logistic regression analysis using likelihood ratio backward selection method was used to identify significant risk factors for 30-day infection to create the Pediatric Scoliosis Infection Risk Score (PSIR Score). ROC curve analysis, predicted probabilities, and Hosmer Lemeshow goodness-of-fit test were done to assess the scoring system on a validation cohort. RESULTS: A total of 31,742 patients were included in the study. The mean age was 13.8 years and 68.7% were female. The 30-day infection rate was 2.2%. Reoperation rate in patients who had a post-operative infection was 59.4%. Patients who had post-operative infection had a higher likelihood of non-home discharge (X2 = 124.8, p < 0.001). In our multivariable regression analysis, high BMI (OR = 1.01, p < 0.001), presence of open wound (OR = 3.18, p < 0.001), presence of ostomy (OR = 1.51, p < 0.001), neuromuscular etiology (OR = 1.56, p = 0.009), previous operation (OR = 1.74, p < 0.001), increasing ASA class (OR = 1.43, p < 0.001), increasing operation time in hours (OR = 1.11, p < 0.001), and use of only minimally invasive techniques (OR = 4.26, p < 0.001) were associated with increased risk of 30-day post-operative infection. Idiopathic etiology (OR = 0.53, p < 0.001) and intraoperative topical antibiotic use (B = 0.71, p = 0.003) were associated with reduced risk of 30-day postoperative infection. The area under the curve was 0.780 and 0.740 for the derivation cohort and validation cohort, respectively. CONCLUSIONS: To our knowledge, this is the largest study of risk factors for infection in pediatric spinal deformity surgery. We found 5 patient factors (BMI, ASA, osteotomy, etiology, and previous surgery, and 3 surgeon-controlled factors (surgical time, antibiotics, MIS) associated with risk. The Pediatric Scoliosis Infection Risk Score (PSIR) Score can be applied for risk stratification and to investigate implementation of novel protocols to reduce infection rates in high-risk patients.

Characterizing antibiotic prophylaxis practices in pediatric deformity spinal surgery and impact on 30-day postoperative infection: an NSQIP pediatric database study.

PURPOSE: The aim of this study was to characterize antibiotic prophylaxis practices in pediatric patients who have received posterior arthrodesis for spinal deformity and understand how these practices impact 30-day postoperative infection rates. METHODS: This was a retrospective cohort study using the National Surgical Quality Improvement Program Pediatric database for year 2021. Patients 18 years of age or younger who received posterior arthrodesis for scoliosis or kyphosis correction were included. The outcome of interest was 30-day postoperative infection. Fisher's exact test and multivariable regression analysis were used to analyze the impact of intravenous antibiotic prophylaxis, intraoperative intravenous antibiotic redosing after 4 h, postoperative antibiotic prophylaxis, intraoperative topical antibiotics on 30-day postoperative infection, and various antibiotic prophylaxis regimens. RESULTS: A total of 6974 patients were included in this study. The 30-day infection rate was 2.9%. Presurgical intravenous antibiotic (11.5% vs. 2.7%, p = 0.005), postoperative antibiotic (5.7% vs. 2.4%, p < 0.01), and intraoperative topical antibiotic (4.0% vs. 2.7%, p = 0.019) were associated with significantly reduced infection rates. There was no significant difference in infection rates between patients that received cefazolin versus vancomycin versus clindamycin. The addition of Gram-negative coverage did not result in significant differences in infection rates. Multivariable regression analysis found postoperative intravenous antibiotics and intraoperative topical antibiotics to reduce infection rates. CONCLUSIONS: We found the use of presurgical intravenous antibiotics, postoperative intravenous antibiotics, and intraoperative topical antibiotics to significantly reduce infection rates. Results from this study can be applied to future research on implementation of standardized infection prevention protocols. LEVEL OF EVIDENCE: Level II.

Impact of frailty on 30-day death, stroke, or myocardial infarction in severe carotid stenosis: Endarterectomy versus stenting.

OBJECTIVE: Carotid endarterectomy (CEA) and carotid artery stenting (CAS) are used for stroke prevention in patients with carotid stenosis. It remains unclear which surgical approach produces the best outcomes for elderly and frail patients. We investigated the impact of age and frailty on 30-day combined outcomes of death, stroke, and myocardial infarction (MI) in patients who received CEA or CAS for severe symptomatic carotid stenosis. METHODS: A retrospective analysis of the NSQIP database identified patients with severe carotid stenosis who received either CEA or CAS between 2015 and 2020 for study inclusion. Frailty was measured by the Modified Frailty Index 5-item (mFI-5), which stratified patients as non-frail (score=0), pre-frail (=1), frail (=2), or severely frail (=3). Age was subdivided into 65 years or younger, 66-84 years, and 85 years or older. The primary outcome was 30-day combined rates of death, stroke, and MI, as analyzed by multivariate logistic regression analyses, adjusted for sex, body mass index, smoking status, anesthetic type, and contralateral carotid stenosis. RESULTS: A total of 18,074 patients were included in analyses, of which 14,428 received CEA (80 %) and 3646 received CAS (20 %). Mean age was 70.8 and 70.5 years for CEA and CAS, respectively. The rate of combined outcome of death, stroke or MI at 30 days was significantly higher in CEA (3.3 %) than CAS (1.3 %) (χ2 =41.90, p < 0.001). Increasing frailty was associated with higher rates of the primary outcome in CEA patients (χ2 =30.26, p < 0.001) but not CAS (χ2 =6.95, p = 0.07). A 6-component risk score was constructed for the combined outcomes in CEA, which predicted adverse events with 80.7 % accuracy. CONCLUSIONS: Age and frailty have a significant impact on the risk of death, stroke, and MI at 30 days in patients with severe, symptomatic carotid stenosis who receive CEA, but not CAS. NON-STANDARD ABBREVIATIONS AND ACRONYMS: Body mass index (BMI), carotid artery stenting (CAS), carotid endarterectomy (CEA), current procedural technology (CPT), myocardial infarction (MI), modified Frailty Index 5-item (mFI-5), American College of Surgeons National Surgical Quality Improvement Program (NSQIP).

Cost-Effectiveness of Poly ADP-Ribose Polymerase Inhibitors in Cancer Treatment: A Systematic Review.

Background: PARP inhibitors have shown significant improvement in progression-free survival, but their costs cast a considerable financial burden. In line with value-based oncology, it is important to evaluate whether drug prices justify the outcomes. Objectives: The aim of the study was to systematically evaluate PARP inhibitors on 1) cost-effectiveness against the standard care, 2) impact on cost-effectiveness upon stratification for genetic characteristics, and 3) identify factors determining their cost-effectiveness, in four cancer types. Methods: We systematically searched PubMed, EMBASE, Web of Science, and Cochrane Library using designated search terms, updated to 31 August 2021. Trial-based or modeling cost-effectiveness analyses of four FDA-approved PARP inhibitors were eligible. Other studies known to authors were included. Reference lists of selected articles were screened. Eligible studies were assessed for methodological and reporting quality before review. Results: A total of 20 original articles proceeded to final review. PARP inhibitors were not cost-effective as recurrence maintenance in advanced ovarian cancer despite improved performance upon genetic stratification. Cost-effectiveness was achieved when moved to upfront maintenance in a new diagnosis setting. Limited evidence indicated non-cost-effectiveness in metastatic breast cancer, mixed conclusions in metastatic pancreatic cancer, and cost-effectiveness in metastatic prostate cancer. Stratification by genetic testing displayed an effect on cost-effectiveness, given the plummeting ICER values when compared to the "treat-all" strategy. Drug cost was a strong determinant for cost-effectiveness in most models. Conclusions: In advanced ovarian cancer, drug use should be prioritized for upfront maintenance and for patients with BRCA mutation or BRCAness at recurrence. Additional economic evaluations are anticipated for novel indications.

Resident peripheral nerve surgery competence: An assessment of procedural exposure, self-reported competence and technical ability.

BACKGROUND: Identifying peripheral nerve surgery procedure (PNSP) competencies is crucial to ensure adequate resident training. We examine PNSP training at neurosurgical centers in the US and Canada to compare resident-reported competence, PNSP exposure, and resident technical abilities in performing 3 peripheral nerve coaptations (PNC). METHODS: Resident-reported PNSP competence and PNSP exposure data were collected using questionnaires from neurosurgical residents at North American neurosurgical training centers. Exposure and self-reported competency were correlated with technical skills. Technical PNC variables collected included: time-to-completion, nerve-handling from video-analysis, independent and blinded visual-analog-scale (VAS) PNC quality grading by 3 judges, and training level. RESULTS: A total of 40 neurosurgical residents participated in the study. Although self-reported competency scores correlated with procedural exposure (P < 0.01, rs = 0.88), a discrepancy was found between the degree of self-reported competency and amount of exposure. The discrepancy was greater in senior residents. A significant VAS difference was found between PNC types with the direct-suture and connector-assister groups scoring higher than connector-only (P = 0.02, P < 0.01, respectively). No difference was observed between training level and VAS grading, nor time-to completion (P = 0.33 and 0.25, respectively). No correlation was found between self-reported competency performing PNSPs and PNC VAS scores, nor nerve handling. CONCLUSIONS: Despite more exposure and a higher self-reported PNSP competency in senior residents, no difference was seen between senior/junior residents in PNC quality. A discrepancy in PNSP exposure and self-reported competency exists. This information will provide guidance for the direction of resident PNS training.

Frailty is an important predictor of 30-day morbidity in patients treated for lumbar spondylolisthesis using a posterior surgical approach.

BACKGROUND CONTEXT: Traditionally, a nonoperative approach has been favored for elderly patients with lumbar spondylolisthesis due to a perceived higher risk of morbidity with surgery. However, most studies have used an arbitrary age cut-off to define "elderly" and this research has yielded conflicting results. PURPOSE: The purpose of this study was to investigate the impact of frailty on morbidity after surgery for degenerative lumbar spondylolisthesis treated with a posterior approach. STUDY DESIGN: A retrospective cohort study was performed. PATIENT SAMPLE: The American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database, with years 2010 to 2018 included in this study. Patients who received posterior lumbar spine decompression with or without single level posterior instrumented fusion for degenerative lumbar spondylolisthesis were included. Patients who received anterior and/or lateral approaches were excluded. OUTCOME MEASURES: The primary outcome was Clavien-Dindo grade IV complication. Secondary outcomes were readmission, reoperation, and discharge to location other than home. METHODS: Patient demographics and comorbidities were extracted. Logistic regression analysis was performed to investigate the association between outcomes and the Modified Frailty Index-5, adjusting for age, gender, body mass index, smoking status, and surgical procedure performed. A sub-analysis was done to assess the effect of frailty in three different age groups (18-45 years, 46-65 years, and >65 years) for the two surgical cohorts. RESULTS: There were 15,658 patients in this study. The mean age was 62.5 years. Approximately 70% of the patients received decompression with fusion. Frailty was significantly associated with an increased risk of major complication, unplanned readmission, reoperation, and non-home discharge. The risk increased with increasing frailty. For patients who received decompression, frailty was associated with a higher risk of readmission and non-home discharge in patients >65 years. For patients who received decompression and fusion, frailty was associated with a higher risk of complications, readmission, and non-home discharge in patients >65 years. CONCLUSIONS: Frailty is independently associated with a higher risk of morbidity after posterior surgery in patients with lumbar spondylolisthesis, especially in patients older than 65. These data are of significance to clinicians in planning treatment for these patients.

Frailty adversely affects outcomes of patients undergoing spine surgery: a systematic review.

BACKGROUND: With an aging population, there are an increasing number of elderly patients undergoing spine surgery. Recent literature in other surgical specialties suggest frailty to be an important predictor of outcomes. PURPOSE: The aim of this review was to examine the association between frailty and outcomes after spine surgery. STUDY DESIGN: A systematic review was performed. PATIENT SAMPLE: Electronic databases from 1946 to 2020 were searched to identify articles on frailty and spine surgery. OUTCOME MEASURES: The primary outcome was adverse events. Secondary outcomes included other measures of morbidity, mortality, and patient outcomes. METHODS: Sample size, mean age, age limitation, data source, study design, primary pathology, surgical procedure performed, follow-up period, assessment of frailty used, surgical outcomes, and impact of frailty on outcomes were extracted from eligible studies. Quality and bias were assessed using the PRISMA 27-point item checklist and the QUADAS-2 tool. RESULTS: Thirty-two studies were selected for review, with a total of 127,813 patients. There were eight different frailty indices/measures. Regardless of how frailty was measured, frailty was associated with an increased risk of adverse events, mortality, extended length of stay, readmission, and nonhome discharge. CONCLUSION: There is strong evidence that frailty is associated with an increased risk of morbidity and mortality in patients who received spine surgery. However, it remains inconclusive whether frailty impacts patient outcomes and quality of life after surgery.

Surgical or Endovascular Management of Middle Cerebral Artery Aneurysms: A Randomized Comparison.

OBJECTIVE: There are few randomized data comparing clipping and coiling for middle cerebral artery (MCA) aneurysms. We analyzed results from patients with MCA aneurysms enrolled in the CURES (Collaborative UnRuptured Endovascular vs. Surgery) and ISAT-2 (International Subarachnoid Aneurysm Trial II) randomized trials. METHODS: Both trials are investigator-led parallel-group 1:1 randomized studies. CURES includes patients with 3-mm to 25-mm unruptured intracranial aneurysms (UIAs), and ISAT-2 includes patients with ruptured aneurysms (RA) for whom uncertainty remains after ISAT. The primary outcome measure of CURES is treatment failure: 1) failure to treat the aneurysm, 2) intracranial hemorrhage during follow-up, or 3) residual aneurysm at 1 year. The primary outcome of ISAT-2 is death or dependency (modified Rankin Scale score >2) at 1 year. One-year angiographic outcomes are systematically recorded. RESULTS: There were 100 unruptured and 71 ruptured MCA aneurysms. In CURES, 90 patients with UIA have been treated and 10 await treatment. Surgical and endovascular management of unruptured MCA aneurysms led to treatment failure in 3/42 (7%; 95% confidence interval [CI], 0.02-0.19) for clipping and 13/48 (27%; 95% CI, 0.17-0.41) for coiling (P = 0.025). All 71 patients with RA have been treated. In ISAT-2, patients with ruptured MCA aneurysms managed surgically had died or were dependent (modified Rankin Scale score >2) in 7/38 (18%; 95% CI, 0.09-0.33) cases, and 8/33 (24%; 95% CI, 0.13-0.41) for endovascular. One-year imaging results were available in 80 patients with UIA and 62 with RA. Complete aneurysm occlusion was found in 30/40 (75%; 95% CI, 0.60-0.86) patients with UIA allocated clipping, and 14/40 (35%; 95% CI, 0.22-0.50) patients with UIA allocated coiling. Complete aneurysm occlusion was found in 24/34 (71%; 95% CI, 0.54-0.83) patients with RA allocated clipping, and 15/28 (54%; 95% CI, 0.36-0.70) patients with RA allocated coiling. CONCLUSIONS: Randomized data from 2 trials show that better efficacy may be obtained with surgical management of patients with MCA aneurysms.

Comparison of Clinical Outcomes Between Posterior Instrumented Fusion With and Without Interbody Fusion for Isthmic Spondylolisthesis.

STUDY DESIGN: A multicenter ambispective study using the Canadian Spine Outcomes and Research Network to compare clinical outcomes in adult patients with isthmic spondylolisthesis who received surgery. OBJECTIVE: The purpose of this study is to compare 1-year postoperative clinical outcomes between posterior instrumented fusion with and without interbody fusion in patients with isthmic spondylolisthesis. SUMMARY OF BACKGROUND DATA: Despite the increased use of interbody fusion in patients with isthmic spondylolisthesis, clinical superiority has not been demonstrated. It remains unclear what the optimal surgical approach is for this population. MATERIALS AND METHODS: The primary outcome was changed in leg pain at 1 year. Secondary outcomes were changed in Oswestry Disability Index, Short Form-12 Physical Component Score, and back pain at 1-year postoperative follow-up, estimated intraoperative blood loss, length of surgery, length of stay, number of transfusions, and adverse events. Descriptive statistics, Student t test, χ2 test, and stepwise multivariable regression were used for analysis. RESULTS: In total, 300 patients were included in this study. Of the 300 patients, 252 received posterolateral instrumented fusion with interbody fusion and 48 received posterolateral instrumented fusion alone. There were no significant differences in primary and secondary clinical outcomes at 1-year postoperative follow-up between the 2 groups. There were no significant differences in estimated blood loss (441 vs. 356 mL), length of surgery (210 vs. 224 min), length of stay (4 vs. 4 d), rate of transfusions (5.6% vs. 8.3%), and number of adverse events (33% vs. 23%) between patients who received interbody fusion and patients who did not. The addition of interbody fusion was not a significant variable for primary and secondary clinical outcomes in the stepwise multivariable regression analysis. CONCLUSIONS: There were no significant differences in clinical outcomes at 1 year or in the number of early complications between patients who received posterolateral fusion or posterior/transformational lumbar interbody fusion. LEVEL OF EVIDENCE: Level III.

Multiple recurrences of spindle cell oncocytoma: A case report and literature review.

Spindle cell oncocytoma (SCO) is a rare tumor originating from pituicytes of the neurohypophysis. It typically occurs in the adult population between 50 and 60 years of age and is often misdiagnosed preoperatively as pituitary adenoma because of similar clinical presentation and neuroimaging features. Diffuse nuclear immunoreactivity for TTF-1 (also known as NK2 homeobox 1 factor) is characteristic of SCO and other tumors of the posterior pituitary. We report a case of SCO in a patient who underwent multiple surgical resections for recurrence. The aim of this case report and literature review is to provide an overview of what is currently known about SCO as well as raise the awareness of this entity to endocrinologists, neurologists, neurosurgeons, and neuropathologists. Our case is also unusual in that the tumor displayed immunoreactivity for neuronal markers, which is a very rare occurrence.

Intraventricular atypical teratoid rhabdoid tumour in an adult: a case report and literature review.

We report a case of atypical teratoid/rhabdoid tumour (AT/RT) in an adult patient in the deep grey matter with extension into the lateral ventricle. To our knowledge, this is the first example of AT/RT involving the lateral ventricle in an adult. The patient presented with headache and confusion, and subsequently required emergent surgery. His postoperative course was complicated by hemorrhage into the surgical site. The location and vascularity of the tumour affected the extent of resection achieved and likely contributed to postoperative complications. We discuss radiological features of AT/RT in adults and implications for investigations and management.

Blunt chest trauma: classification and management.

Blunt chest wall injuries are a significant cause of mortality and morbidity in trauma patients. Accurate identification and description of chest wall injuries by the radiologist can aid in guiding proper patient management. The American Association for the Surgery of Trauma (AAST) has devised a classification system based on severity. This article describes the features of each injury grade according to the AAST injury scale and discusses the implications for management. Additionally, common mechanisms of blunt chest trauma and multimodal imaging techniques are discussed.

A Systematic Review of Atypical Teratoid Rhabdoid Tumor in Adults.

Background: Atypical teratoid/rhabdoid tumor in adults is a relatively rare malignant neoplasm. It is characterized by the presence of rhabdoid cells in combination with loss of either the INI1 or BRG1protein from the tumor cells. Methods: A systematic review was conducted using MEDLINE using the terms "atypical teratoid rhabdoid tumor" AND "adult." The systematic review was supplemented with relevant articles from the references. Cases were included if the pathology was confirmed by loss of INI1 or BRG1. We included a case from our institution. The dataset was analyzed using descriptive statistics and log-rank test. Results: A total of 50 cases from 29 articles were included in this study. The average age at diagnosis was 36.7 years. The most common locations reported are the sellar region and cerebral hemispheres (without deep gray matter involvement). Of the 50 cases, 14 were reported to show evidence of dissemination. The average overall survival was 20 months. There was a significant difference in survival between the adjuvant therapy groups (p = < 0.0001). Conclusion: Atypical teratoid rhabdoid tumor of the central nervous system in adults is a rare neoplasm associated with a poor prognosis in a majority of patients. The treatment and clinical course are highly variable, and it remains unclear which factors impact prognosis.

A novel antibody-TCR (AbTCR) platform combines Fab-based antigen recognition with gamma/delta-TCR signaling to facilitate T-cell cytotoxicity with low cytokine release.

The clinical use of genetically modified T-cell therapies has led to unprecedented response rates in leukemia and lymphoma patients treated with anti-CD19 chimeric antigen receptor (CAR)-T. Despite this clinical success, FDA-approved T-cell therapies are currently limited to B-cell malignancies, and challenges remain with managing cytokine-related toxicities. We have designed a novel antibody-T-cell receptor (AbTCR) platform where we combined the Fab domain of an antibody with the γ and δ chains of the TCR as the effector domain. We demonstrate the ability of anti-CD19-AbTCR-T cells to trigger antigen-specific cytokine production, degranulation, and killing of CD19-positive cancer cells in vitro and in xenograft mouse models. By using the same anti-CD19 binding moiety on an AbTCR compared to a CAR platform, we demonstrate that AbTCR activates cytotoxic T-cell responses with a similar dose-response as CD28/CD3ζ CAR, yet does so with less cytokine release and results in T cells with a less exhausted phenotype. Moreover, in comparative studies with the clinically validated CD137 (4-1BB)-based CAR, CTL019, our anti-CD19-AbTCR shows less cytokine release and comparable tumor inhibition in a patient-derived xenograft leukemia model.

Discovery and Optimization of HKT288, a Cadherin-6-Targeting ADC for the Treatment of Ovarian and Renal Cancers.

Despite an improving therapeutic landscape, significant challenges remain in treating the majority of patients with advanced ovarian or renal cancer. We identified the cell-cell adhesion molecule cadherin-6 (CDH6) as a lineage gene having significant differential expression in ovarian and kidney cancers. HKT288 is an optimized CDH6-targeting DM4-based antibody-drug conjugate (ADC) developed for the treatment of these diseases. Our study provides mechanistic evidence supporting the importance of linker choice for optimal antitumor activity and highlights CDH6 as an antigen for biotherapeutic development. To more robustly predict patient benefit of targeting CDH6, we incorporate a population-based patient-derived xenograft (PDX) clinical trial (PCT) to capture the heterogeneity of response across an unselected cohort of 30 models-a novel preclinical approach in ADC development. HKT288 induces durable tumor regressions of ovarian and renal cancer models in vivo, including 40% of models on the PCT, and features a preclinical safety profile supportive of progression toward clinical evaluation.Significance: We identify CDH6 as a target for biotherapeutics development and demonstrate how an integrated pharmacology strategy that incorporates mechanistic pharmacodynamics and toxicology studies provides a rich dataset for optimizing the therapeutic format. We highlight how a population-based PDX clinical trial and retrospective biomarker analysis can provide correlates of activity and response to guide initial patient selection for first-in-human trials of HKT288. Cancer Discov; 7(9); 1030-45. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 920.

Targeting Alpha-Fetoprotein (AFP)-MHC Complex with CAR T-Cell Therapy for Liver Cancer.

PURPOSE: The majority of tumor-specific antigens are intracellular and/or secreted and therefore inaccessible by conventional chimeric antigen receptor (CAR) T-cell therapy. Given that all intracellular/secreted proteins are processed into peptides and presented by class I MHC on the surface of tumor cells, we used alpha-fetoprotein (AFP), a specific liver cancer marker, as an example to determine whether peptide-MHC complexes can be targets for CAR T-cell therapy against solid tumors. EXPERIMENTAL DESIGN: We generated a fully human chimeric antigen receptor, ET1402L1-CAR (AFP-CAR), with exquisite selectivity and specificity for the AFP158-166 peptide complexed with human leukocyte antigen (HLA)-A*02:01. RESULTS: We report that T cells expressing AFP-CAR selectively degranulated, released cytokines, and lysed liver cancer cells that were HLA-A*02:01+/AFP+ while sparing cells from multiple tissue types that were negative for either expressed proteins. In vivo, intratumoral injection of AFP-CAR T cells significantly regressed both Hep G2 and AFP158-expressing SK-HEP-1 tumors in SCID-Beige mice (n = 8 for each). Moreover, intravenous administration of AFP-CAR T cells in Hep G2 tumor-bearing NSG mice lead to rapid and profound tumor growth inhibition (n = 6). Finally, in an established intraperitoneal liver cancer xenograft model, AFP-CAR T cells showed robust antitumor activity (n = 6). CONCLUSIONS: This study demonstrates that CAR T-cell immunotherapy targeting intracellular/secreted solid tumor antigens can elicit a potent antitumor response. Our approach expands the spectrum of antigens available for redirected T-cell therapy against solid malignancies and offers a promising new avenue for liver cancer immunotherapy. Clin Cancer Res; 23(2); 478-88. ©2016 AACR.

Incidence of seizure in adult patients with intracranial metastatic disease.

Seizures have considerable impact on a patient's quality of life. While guidelines have been articulated to direct clinicians in their management of patients with IMD who suffer from seizure, there have been few attempts to identify the seizure rate in IMD and to determine which primary cancers may be associated with an increased seizure incidence. To determine the incidence of seizure in patients with IMD. A systematic review on seizure incidence in patients with IMD from the magnetic resonance imaging (MRI) era was performed. Articles published between January 2000 and July 2014 with thirty or more consecutive adult patients were included in this study. Seizure rate was calculated using a pooled data analysis. Differences between observed and expected seizure rates between primary tumour sites were examined using the Chi square statistic and adjusted standardized residuals. The systematic search produced 18 relevant studies, with a total study population of 2012 patients. 14.6% (n = 294) had seizures. There was a significant association between primary tumour site and seizure rates. The seizure rate in patients with primary melanoma tumours was significantly greater than expected (z = 2.7; p = .006). The seizure rate in patients with primary prostate tumours was significantly lower than expected (z = -2.6; p = .008). Patients with intracranial metastasis are at significant risk for developing seizure, though at a significantly lower incidence than was estimated by studies performed during the CT era. Seizure rates appear to be greater in certain primary tumours, such as melanoma.

Sources of delayed provision of neurosurgical care in a rural kenyan setting.

BACKGROUND: Delay to neurosurgical care can result in significant morbidity and mortality. In this study, we aim to identify and quantify the sources of delay to neurosurgical consultation and care at a rural setting in Kenya. METHODS: A mixed-methods, cross-sectional analysis of all patients admitted to the neurosurgical department at Kijabe Hospital (KH) was conducted: A retrospective analysis of admissions from October 1 to December 31, 2013 and a prospective analysis from June 2 to June 20, 2014. Sources of delay were categorized and quantified. The Kruskal-Wallis test was used to identify an overall significant difference among diagnoses. The Mann-Whitney U test was used for pairwise comparisons within groups; the Bonferroni correction was applied to the alpha level of significance (0.05) according to the number of comparisons conducted. IBM SPSS version 22.0 (SPSS, Chicago, IL) was used for statistical analyses. RESULTS: A total of 332 admissions were reviewed (237 retrospective, 95 prospective). The majority was pediatric admissions (median age: 3 months). Hydrocephalus (35%) and neural tube defects (NTDs; 27%) were most common. At least one source of delay was identified in 192 cases (58%); 39 (12%) were affected by multiple sources. Delay in primary care (PCPs), in isolation or combined with other sources, comprised 137 of total (71%); misdiagnosis or incorrect management comprised 46 (34%) of these. Finances contributed to delays in 25 of 95 prospective cases. At a median delay of 49 and 200.5 days, the diagnoses of hydrocephalus and tumors were associated with a significantly longer delay compared with NTDs (P < 0.001). CONCLUSION: A substantial proportion of patients experienced delays in procuring pediatric neurosurgical care. Improvement in PCP knowledge base, implementation of a triage and referral process, and development of community-based funding strategies can potentially reduce these delays.

Macrophage IL-10 blocks CD8+ T cell-dependent responses to chemotherapy by suppressing IL-12 expression in intratumoral dendritic cells.

Blockade of colony-stimulating factor-1 (CSF-1) limits macrophage infiltration and improves response of mammary carcinomas to chemotherapy. Herein we identify interleukin (IL)-10 expression by macrophages as the critical mediator of this phenotype. Infiltrating macrophages were the primary source of IL-10 within tumors, and therapeutic blockade of IL-10 receptor (IL-10R) was equivalent to CSF-1 neutralization in enhancing primary tumor response to paclitaxel and carboplatin. Improved response to chemotherapy was CD8(+) T cell-dependent, but IL-10 did not directly suppress CD8(+) T cells or alter macrophage polarization. Instead, IL-10R blockade increased intratumoral dendritic cell expression of IL-12, which was necessary for improved outcomes. In human breast cancer, expression of IL12A and cytotoxic effector molecules were predictive of pathological complete response rates to paclitaxel.