Surgical management of spinal metastases from primary thyroid carcinoma: Demographics, clinical characteristics, and treatment outcomes - A retrospective analysis.

Objective: Metastatic spinal tumors represent a rare but concerning complication of primary thyroid carcinoma. We identified demographics, metastatic features, outcomes, and treatment strategies for these tumors in our institutional cohort. Materials and Methods: We retrospectively reviewed patients surgically treated for spinal metastases of primary thyroid carcinoma. Demographics, tumor characteristics, and treatment modalities were collected. The functional outcomes were quantified using Nurik, Modified Rankin, and Karnofsky Scores. Results: Twelve patients were identified who underwent 17 surgeries for resection of spinal metastases. The primary thyroid tumor pathologies included papillary (4/12), follicular (6/12), and Hurthle cell (2/12) subtypes. The average number of spinal metastases was 2.5. Of the primary tumor subtypes, follicular tumors averaged 2.8 metastases at the highest and Hurthle cell tumors averaged 2.0 spinal metastases at the lowest. Five patients (41.7%) underwent preoperative embolization for their spinal metastases. Seven patients (58.3%) received postoperative radiation. There was no significant difference in progression-free survival between patients receiving surgery with adjuvant radiation and surgery alone (P = 0.0773). Five patients (41.7%) experienced postoperative complications. Two patients (16.7%) succumbed to disease progression and two patients (16.7%) experienced tumor recurrence following resection. Postsurgical mean Nurik scores decreased 0.54 points, mean Modified Rankin scores decreased 0.48 points, and mean Karnofsky scores increased 4.8 points. Conclusion: Surgery presents as an important treatment modality in the management of spinal metastases from thyroid cancer. Further work is needed to understand the predictive factors for survival and outcomes following treatment.

Radiation Induced Cavernomas in the Treatment of Pediatric Medulloblastoma: Comparative Study Between Proton and Photon Radiation Therapy.

Radiation induced cavernomas among children with medulloblastoma are common following external beam radiation (XRT) treatment with either photon or proton beams. However, with the increased utilization of proton beam therapy over the last decade we sought to determine if there was any difference in the development or natural history of these cavernous malformations (CM) or CM-like lesions. We performed a retrospective analysis of 79 patients from 2003 to 2019 who had undergone resection of medulloblastoma and subsequent XRT (30 photon or 49 proton beam therapy). The average age of patients at radiation treatment was 8.7 years old. Average follow up for patients who received photon beam therapy was 105 months compared to 56.8 months for proton beam therapy. A total of 68 patients (86.1%) developed post-radiation CMs, including 26 photon and 42 proton patients (86.7% and 85.7% respectively). The time to cavernoma development was significantly different, with a mean of 40.2 months for photon patients and 18.2 months for proton patients (p = 1.98 x 10-4). Three patients, one who received photon and two who received proton beam radiation, required surgical resection of a cavernoma. Although CM or CM-like lesions are detected significantly earlier in patients after receiving proton beam therapy, there appears to be no significant difference between the two radiation therapy modalities in the development of significant CM requiring surgical resection or intervention other than continued follow up and surveillance.

Slow progress in the visibility of women in neurosurgery in the United States: opportunity for improvement.

OBJECTIVE: The goal of this study was to analyze the visibility of women within organized neurosurgery, including leadership positions, lectureships, and honored guest/award recipients at neurosurgical conferences. METHODS: A cross-sectional study was used to analyze the gender demographics within the five major national neurosurgical societies (Congress of Neurological Surgeons [CNS], American Association of Neurological Surgeons [AANS], Society of Neurological Surgeons [SNS], American Board of Neurological Surgery [ABNS], and Council of State Neurosurgical Societies [CSNS]) from 2000 to 2020. Data for top leadership positions, keynote speakers, honored guests, and invited lectureships at these neurosurgical societies were reviewed. Additionally, national neurosurgical residency match data from 2018 to 2020 were collected. For each aforementioned data point, gender was determined and confirmed via publicly available data. Data from the US News and World Report best hospitals publication for 2020 were applied for analyzing gender trends within neurosurgical residencies specifically. RESULTS: In the past 2 decades (2000-2020), top leadership positions across the neurosurgical organizations were held by 45 individuals, of whom 5 (11.1%) were women. Spanning from 2000 to 2018, just 8.1% (50 of 618) of guests/honored speakers on the national neurosurgical stage of the CNS, AANS, SNS, and CSNS meetings have been female. Excluding the Louise Eisenhardt Lecture (honoring women), the percentage of female guests/honored speakers at the AANS meeting was just 5% (17 of 367). For the CNS annual meetings, 13.4% (20 of 149) of the speakers were women from 2000 to 2018, whereas the CSNS annual meeting data from 2001 to 2018 found that 11.9% (7 of 59) of speakers were women. From 1952 to the present, there have been no female honored guests at the CNS annual meeting. Across the residency match cycles from 2018 to 2020, the percentages of matched applicants identifying as female have been 22.7%, 28.1%, and, most recently, 25.3%. The percentage of female residents is 28.5% (top 20 program) versus 24.3% (non-top 20 program) (p = 0.267). CONCLUSIONS: This study found that for all the data points surveyed, including leadership positions, invited lectureships at national neurosurgical meetings, and successful neurosurgical residency applicants, disproportionate female underrepresentation was evident. Consistent lack of visibility leads to a negative impact on progress in the recruitment and retention of women in neurosurgery. Visibility, mentorship, role models, and sponsorship are highly interrelated processes and are essential for meaningful progress.

Checkpoint inhibitor immunotherapy for glioblastoma: current progress, challenges and future outlook.

INTRODUCTION: Despite maximal surgical resection and chemoradiation, glioblastoma (GBM) continues to be associated with significant morbidity and mortality. Novel therapeutic strategies are urgently needed. Given success in treating multiple other forms of cancer, checkpoint inhibitor immunotherapy remains foremost amongst novel therapeutic strategies that are currently under investigation. AREAS COVERED: Through a systematic review of both published literature and the latest preliminary data available from ongoing clinical studies, we provide an up-to-date discussion on the immune system in the CNS, a detailed mechanistic evaluation of checkpoint biology in the CNS along with evidence for disruption of these pathways in GBM, and a summary of available preclinical and clinical data for checkpoint blockade in GBM. We also include a discussion of novel, emerging targets for checkpoint blockade which may play an important role in GBM immunotherapy. EXPERT OPINION: Evidence indicates that while clinical success of checkpoint blockade for the treatment of GBM has been limited to date, through improved preclinical models, optimization in the context of standard of care therapies, assay standardization and harmonization, and combinatorial approaches which may include novel targets for checkpoint blockade, checkpoint inhibitor immunotherapy may yield a safe and effective therapeutic option for the treatment of GBM.

Targeting PD-L1 Initiates Effective Antitumor Immunity in a Murine Model of Cushing Disease.

PURPOSE: Although pituitary adenoma is classified as benign, Cushing disease is associated with significant morbidity due to the numerous sequelae of elevated cortisol levels. Successful therapy for Cushing disease remains elusive due to high rates of treatment-refractory recurrence. The frequent emergence of lymphocytic hypophysitis following checkpoint blockade for other cancers, as well as the expression of PD-L1 on pituitary adenomas, suggest a role for immunotherapy. EXPERIMENTAL DESIGN: This study confirms PD-L1 expression on functioning pituitary adenomas and is the first to evaluate the efficacy of checkpoint blockade (anti-PD-L1) therapy in a preclinical model of Cushing disease. RESULTS: Herein, treatment with anti-PD-L1 was successful in reducing adrenocorticotropic hormone plasma levels, decreasing tumor growth, and increasing survival in our model. Furthermore, tumor-infiltrating T cells demonstrated a pattern of checkpoint expression similar to other checkpoint blockade-susceptible tumors. CONCLUSIONS: This suggests that immunotherapy, particularly blockade of the PD1/PD-L1 axis, may be a novel therapeutic option for refractory Cushing disease. Clinical investigation is encouraged.

Plasmonic gold nanostar-mediated photothermal immunotherapy for brain tumor ablation and immunologic memory.

Brain tumors present unique therapeutic challenges and they include glioblastoma (GBM) and metastases from cancers of other organs. Current treatment options are limited and include surgical resection, radiation therapy, laser interstitial thermal therapy and chemotherapy. Although much research has been done on the development of immune-based treatment platforms, only limited success has been demonstrated. Herein, we demonstrate a novel treatment of GBM through the use of plasmonic gold nanostars (GNS) as photothermal inducers for synergistic immuno photothermal nanotherapy (SYMPHONY), which combines treatments using gold nanostar and laser-induced photothermal therapy with checkpoint blockade immunotherapy. In the treatment of a murine flank tumor model with the CT-2A glioma cell line, SYMPHONY demonstrated the capability of producing long-term survivors that rejects rechallenge with cancer cells, heralding the successful emergence of immunologic memory. This study is the first to investigate the use of this novel therapy for the treatment of GBM in a murine model.

Author Correction: Sequestration of T cells in bone marrow in the setting of glioblastoma and other intracranial tumors.

In the version of this article originally published, the figure callout in this sentence was incorrect: "Furthermore, in S1P1-KI mice themselves, whereas PD-1 blockade was ineffectual as monotherapy, the effects of 4-1BB agonism and checkpoint blockade proved additive, with the combination prolonging median survival and producing a 50% long-term survival rate (Fig. 6f)." The callout should have been to Supplementary Fig. 6b. The error has been corrected in the PDF and HTML versions of the article.

Upfront Magnetic Resonance Imaging-Guided Stereotactic Laser-Ablation in Newly Diagnosed Glioblastoma: A Multicenter Review of Survival Outcomes Compared to a Matched Cohort of Biopsy-Only Patients.

BACKGROUND: Laser ablation (LA) is used as an upfront treatment in patients with deep seated newly diagnosed Glioblastoma (nGBM). OBJECTIVE: To evaluate the outcomes of LA in patients with nGBM and compare them with a matched biopsy-only cohort. METHODS: Twenty-four nGBM patients underwent upfront LA at Cleveland clinic, Washington University in St. Louis, and Yale University (6/2011-12/2014) followed by chemo/radiotherapy. Also, 24 out of 171 nGBM patients with biopsy followed by chemo/radiotherapy were matched based on age (< 70 vs ≥ 70), gender, tumor location (deep vs lobar), and volume (<11 cc vs ≥11 cc). Progression-free survival (PFS), overall survival (OS), and disease-specific PFS and OS were outcome measures. Three prognostic groups were identified based on extent of tumor ablation by thermal-damage-threshold (TDT)-lines. RESULTS: The median tumor volume in LA (n = 24) and biopsy only (n = 24) groups was 9.3 cm3 and 8.2 cm3 respectively. Overall, median estimate of OS and PFS in LA cohort was 14.4 and 4.3 mo compared to 15.8 mo and 5.9 mo for biopsy only cohort. On multivariate analysis, favorable TDT-line prognostic groups were associated with lower incidence of disease specific death (P = .03) and progression (P = .05) compared to other groups including biopsy only cohort. Only age (<70 yr, P = .02) and tumor volume (<11 cc, P = .03) were favorable prognostic factors for OS. CONCLUSION: The maximum tumor coverage by LA followed by radiation/chemotherapy is an effective treatment modality in patients with nGBM, compared to biopsy only cohort. The TDT-line prognostic groups were independent predictor of disease specific death and progression after LA.

Prevalence and Cost Analysis of Chronic Pain After Hernia Repair: A Potential Alternative Approach With Neurostimulation.

OBJECTIVES: Chronic pain (CP) affects a significant number of patients following hernia repair, ranging from 11 to 54% in the literature. The aim of this study was to assess the prevalence, overall costs, and health care utilization associated with CP after hernia repair. MATERIALS AND METHODS: A retrospective longitudinal study was performed using the Truven MarketScan® data base to identify patients who develop chronic neuropathic posthernia repair pain from 2001 to 2012. Patients were grouped into CP and No Chronic Pain (No CP) cohorts. Patients were excluded if they 1) were under 18 years of age; 2) had a previous pain diagnosis; 3) had CP diagnosed <90 days after the index hernia repair; 4) had less than one year of follow-up; or 5) had less than one-year baseline record before hernia repair. Patients were grouped into the CP cohort if their CP diagnosis was made within the two years following index hernia repair. Total, outpatient, and pain prescription costs were collected in the period of five years prehernia to nine years posthernia repair. A longitudinal multivariate analysis was used to model the effects of chronic neuropathic posthernia repair pain on total inpatient/outpatient and pain prescription costs. RESULTS: We identified 76,173 patients who underwent hernia repair and met inclusion criteria (CP: n = 14,919, No CP: n = 61,254). There was a trend for increased total inpatient/outpatient and pain prescription costs one-year posthernia repair, when compared to baseline costs for both cohorts. In both cohorts, total inpatient/outpatient costs remained elevated from baseline through nine years posthernia repair, with the CP cohort experiencing significantly higher cumulative median costs (CP: $51,334, No CP: $37,388). The CP diagnosis year was associated with a 1.75-fold increase (p < 0.001) in total inpatient/outpatient costs and a 2.26-fold increase (p < 0.001) in pain prescription costs versus all other years. In the longitudinal analysis, the CP cohort had a 1.14-fold increase (p < 0.001) in total inpatient/outpatient costs and 2.00-fold increase (p < 0.001) in pain prescription costs. CONCLUSIONS: Our study demonstrates the prevalence of CP after hernia surgery to be nearly 20%, with significantly increased costs and healthcare resource utilization. While current treatment paradigms are effective for many, there remains a large number of patients that could benefit from an overall approach that includes nonopioid treatments, such as potentially incorporating neurostimulation, for CP that presents posthernia repair.

Independent Associations With 30- and 90-Day Unplanned Readmissions After Elective Lumbar Spine Surgery: A National Trend Analysis of 144 123 Patients.

BACKGROUND: Unplanned hospital readmissions contribute significantly to soaring national healthcare expenditures. To alleviate this burden, Centers for Medicare and Medicaid Services implemented initiatives to penalize hospitals for unplanned 30-d hospital readmissions. There is a paucity of data identifying patient risk factors independently associated with 30- and 90-d readmissions. OBJECTIVE: To investigate similarities in patient risk factors associated with 30- and 90-d unplanned readmissions following elective lumbar spine surgery. METHODS: The National Readmission Database (NRD) was queried to identify patients undergoing elective lumbar spine surgery between 2013 and 2014. Patients were grouped by no readmission (Non-R), unplanned readmission within 30 days (30-R), and unplanned readmission within 31 to 90 days (90-R). Multivariate analysis determined factors associated with 30- and 90-d readmissions. RESULTS: We identified 144 123 patients with 10 592 (7.3%) patients experiencing an unplanned readmission (30-R: n = 7228 [5.0%]; 90-R: n = 3364 [2.3%]; Non-R: n = 133 531). The most common inpatient complication observed in those patients readmitted was dural tear (30-R: 7.7%, 90-R: 4.6%, Non-R: 4.3%). The most prevalent 30- and 90-d complication seen among the readmitted cohort was infection (30-R: 18.5%, 90-R: 7.4%). In multivariate regression analysis, age, insurance status, chronic obstructive pulmonary disorder (COPD), depression, hypertension, diabetes, deficiency anemia, and obesity were independently associated with 30-d readmission; however, age and obesity were not independently associated with 90-d readmission. CONCLUSION: Our study demonstrated national unplanned readmission rates after elective spinal surgery to be 7.3%. With age, insurance status, COPD, depression, hypertension, diabetes, deficiency anemia, obesity, and depression all independently associated with unplanned hospital readmission. Future solutions that focus on reducing preventable readmissions may improve patient outcomes and reduce healthcare costs.

Sequestration of T cells in bone marrow in the setting of glioblastoma and other intracranial tumors.

T cell dysfunction contributes to tumor immune escape in patients with cancer and is particularly severe amidst glioblastoma (GBM). Among other defects, T cell lymphopenia is characteristic, yet often attributed to treatment. We reveal that even treatment-naïve subjects and mice with GBM can harbor AIDS-level CD4 counts, as well as contracted, T cell-deficient lymphoid organs. Missing naïve T cells are instead found sequestered in large numbers in the bone marrow. This phenomenon characterizes not only GBM but a variety of other cancers, although only when tumors are introduced into the intracranial compartment. T cell sequestration is accompanied by tumor-imposed loss of S1P1 from the T cell surface and is reversible upon precluding S1P1 internalization. In murine models of GBM, hindering S1P1 internalization and reversing sequestration licenses T cell-activating therapies that were previously ineffective. Sequestration of T cells in bone marrow is therefore a tumor-adaptive mode of T cell dysfunction, whose reversal may constitute a promising immunotherapeutic adjunct.

Socioeconomic Factors, Perioperative Complications, and 30-Day Readmission Rates Associated With Delayed Cranial Vault Reconstruction for Craniosynostosis.

BACKGROUND: Premature fusion of the cranial sutures can lead to significant neurocognitive, developmental, and esthetic consequences, especially if not corrected within the first year of life. This study aimed to identify the drivers of delayed cranial vault reconstruction (CVR) and its impact on complication and 30-day readmission rates among craniosynostosis patients. METHODS: The medical records of all children who underwent CVR for craniosynostosis between 2005 and 2017 at an academic institution were retrospectively reviewed. A delay in operation was defined by surgery performed >12 months of age. Patient demographics, comorbidities, perioperative complication rates, and 30-day readmission rates were collected. RESULTS: A total of 96 patients underwent primary CVR, with 79 (82.3%) patients undergoing nondelayed surgery and 17 (17.7%) patients undergoing surgery >12 months of age. Children undergoing delayed surgery were significantly more likely to be non-White (P < 0.0001), have Medicaid insurance (P = 0.023), and have a non-English primary language (P < 0.005). There was increased incidence of developmental disability identified at first consult (no-delay: 3.9% vs delay: 41.2%, P < 0.0001) and increased intracranial pressure (no-delay: 6.3% vs delay: 29.4%, P < 0.005) among children undergoing delayed surgery. The delayed cohort had a significantly higher unplanned 30-day readmission rate (no-delay: 0.0% vs delay: 5.9%, P = 0.03). CONCLUSION: Our study suggests that craniosynostosis patients who are non-White, have a non-English primary language, and have Medicaid insurance are at risk for delayed primary surgery, which may lead to increased 30-day readmission. Interventions are necessary to reduce craniosynostosis patients' barriers to care to minimize the sequelae associated with delayed surgery.

Impact of Chronic Obstructive Pulmonary Disease on Postoperative Complication Rates, Ambulation, and Length of Hospital Stay After Elective Spinal Fusion (≥3 Levels) in Elderly Spine Deformity Patients.

OBJECTIVE: To investigate the impact that chronic obstructive pulmonary disease (COPD) has on postoperative complication rates, ambulation, and hospital length of stay for elderly spinal deformity patients after elective spinal fusion (≥3 levels). METHODS: The medical records of 559 elderly (≥60 years old) spine deformity patients undergoing elective spinal fusion (≥3 levels) at a major academic institution from 2005 to 2015 were reviewed. We identified 60 patients with COPD (10.7%) and 499 patients without COPD (89.3%). Patient demographics, comorbidities, postoperative complications, ambulatory status, and readmission rates were collected. The primary outcomes investigated in this study were complication rates and length of hospital stay. RESULTS: Demographics and comorbidities were similar between groups, with a difference in proportion of smokers (COPD group: 25.0% vs. no COPD group: 9.6%, P = 0.0004). The median number of fusion levels (P = 0.840), operative time (P = 0.842), estimated blood loss (P = 0.336), and incidences of durotomy (P = 0.258) was similar between both cohorts. The COPD cohort experienced a higher rate of postoperative fever (10.0% vs. 3.0%, P = 0.007) and pneumonia (5.0% vs. 0.4%, P = 0.0004), respectively. There was a significant difference in the number of feet walked on the first day of ambulation after surgery (COPD group: 58.6 ± 78.4 vs. no COPD group: 84.0 ± 102.8, P = 0.040). Length of hospital stay was significantly longer in the COPD cohort than the no COPD cohort (7.7 ± 6.4 vs. 6.0 ± 4.0 days, respectively; P = 0.0498). CONCLUSIONS: Our study demonstrates that elderly patients with COPD have increased lengths of stay and higher rates of postoperative pneumonia after spinal fusion. This determination identifies a potentially modifiable risk factor for increased utilization of health care resources.

Influence of racial disparities on patient-reported satisfaction and short- and long-term perception of health status after elective lumbar spine surgery.

OBJECTIVE In spine surgery, racial disparities have been shown to impact various aspects of surgical care. Previous studies have associated racial disparities with inferior surgical outcomes, including increased complication and 30-day readmission rates after spine surgery. Recently, patient-reported outcomes (PROs) and satisfaction measures have been proxies for overall quality of care and hospital reimbursements. However, the influence that racial disparities have on short- and long-term PROs and patient satisfaction after spine surgery is relatively unknown. The aim of this study was to investigate the impact of racial disparities on 3- and 12-month PROs and patient satisfaction after elective lumbar spine surgery. METHODS This study was designed as a retrospective analysis of a prospectively maintained database. The medical records of adult (age ≥ 18 years) patients who had undergone elective lumbar spine surgery for spondylolisthesis (grade 1), disc herniation, or stenosis at a major academic institution were included in this study. Patient demographics, comorbidities, postoperative complications, and 30-day readmission rates were collected. Patients had prospectively collected outcome and satisfaction measures. Patient-reported outcome instruments-Oswestry Disability Index (ODI), visual analog scale for back pain (VAS-BP), and VAS for leg pain (VAS-LP)-were completed before surgery and at 3 and 12 months after surgery, as were patient satisfaction measures. RESULTS The authors identified 345 medical records for 53 (15.4%) African American (AA) patients and 292 (84.6%) white patients. Baseline patient demographics and comorbidities were similar between the two cohorts, with AA patients having a greater body mass index (33.1 ± 6.6 vs 30.2 ± 6.4 kg/m2, p = 0.005) and a higher prevalence of diabetes (35.9% vs 16.1%, p = 0.0008). Surgical indications, operative variables, and postoperative variables were similar between the cohorts. Baseline and follow-up PRO measures were worse in the AA cohort, with patients having a greater baseline ODI (p < 0.0001), VAS-BP score (p = 0.0002), and VAS-LP score (p = 0.0007). However, mean changes from baseline to 3- and 12-month PROs were similar between the cohorts for all measures except the 3-month VAS-BP score (p = 0.046). Patient-reported satisfaction measures at 3 and 12 months demonstrated a significantly lower proportion of AA patients stating that surgery met their expectations (3 months: 47.2% vs 65.5%, p = 0.01; 12 months: 35.7% vs 62.7%, p = 0.007). CONCLUSIONS The study data suggest that there is a significant difference in the perception of health, pain, and disability between AA and white patients at baseline and short- and long-term follow-ups, which may influence overall patient satisfaction. Further research is necessary to identify patient-specific factors associated with racial disparities that may be influencing outcomes to adequately measure and assess overall PROs and satisfaction after elective lumbar spine surgery.

T-Cell Exhaustion Signatures Vary with Tumor Type and Are Severe in Glioblastoma.

Purpose: T-cell dysfunction is a hallmark of glioblastoma (GBM). Although anergy and tolerance have been well characterized, T-cell exhaustion remains relatively unexplored. Exhaustion, characterized in part by the upregulation of multiple immune checkpoints, is a known contributor to failures amid immune checkpoint blockade, a strategy that has lacked success thus far in GBM. This study is among the first to examine, and credential as bona fide, exhaustion among T cells infiltrating human and murine GBM.Experimental Design: Tumor-infiltrating and peripheral blood lymphocytes (TILs and PBLs) were isolated from patients with GBM. Levels of exhaustion-associated inhibitory receptors and poststimulation levels of the cytokines IFNγ, TNFα, and IL2 were assessed by flow cytometry. T-cell receptor Vß chain expansion was also assessed in TILs and PBLs. Similar analysis was extended to TILs isolated from intracranial and subcutaneous immunocompetent murine models of glioma, breast, lung, and melanoma cancers.Results: Our data reveal that GBM elicits a particularly severe T-cell exhaustion signature among infiltrating T cells characterized by: (1) prominent upregulation of multiple immune checkpoints; (2) stereotyped T-cell transcriptional programs matching classical virus-induced exhaustion; and (3) notable T-cell hyporesponsiveness in tumor-specific T cells. Exhaustion signatures differ predictably with tumor identity, but remain stable across manipulated tumor locations.Conclusions: Distinct cancers possess similarly distinct mechanisms for exhausting T cells. The poor TIL function and severe exhaustion observed in GBM highlight the need to better understand this tumor-imposed mode of T-cell dysfunction in order to formulate effective immunotherapeutic strategies targeting GBM. Clin Cancer Res; 24(17); 4175-86. ©2018 AACRSee related commentary by Jackson and Lim, p. 4059.

Systemic activation of antigen-presenting cells via RNA-loaded nanoparticles.

While RNA-pulsed dendritic cell (DC) vaccines have shown promise, the advancement of cellular therapeutics is fraught with developmental challenges. To circumvent the challenges of cellular immunotherapeutics, we developed clinically translatable nanoliposomes that can be combined with tumor-derived RNA to generate personalized tumor RNA-nanoparticles (NPs) with considerable scale-up capacity. RNA-NPs bypass MHC restriction, are amenable to central distribution, and can provide near immediate immune induction. We screened commercially available nanoliposomal preparations and identified the cationic lipid 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) as an efficient mRNA courier to antigen-presenting cells (APCs). When administered intravenously, RNA-NPs mediate systemic activation of APCs in reticuloendothelial organs such as the spleen, liver, and bone marrow. RNA-NPs increase percent expression of MHC class I/II, B7 co-stimulatory molecules, and maturation markers on APCs (all vital for T-cell activation). RNA-NPs also increase activation markers on tumor APCs and elicit potent expansion of antigen-specific T-cells superior to peptide vaccines formulated in complete Freund's adjuvant. We demonstrate that both model antigen-encoding and physiologically-relevant tumor-derived RNA-NPs expand potent antitumor T-cell immunity. RNA-NPs were shown to induce antitumor efficacy in a vaccine model and functioned as a suitable alternative to DCs in a stringent cellular immunotherapy model for a radiation/temozolomide resistant invasive murine high-grade glioma. Although cancer vaccines have suffered from weak immunogenicity, we have advanced a RNA-NP formulation that systemically activates host APCs precipitating activated T-cell frequencies necessary to engender antitumor efficacy. RNA-NPs can thus be harnessed as a more feasible and effective immunotherapy to re-program host-immunity.

Risk Factors for Birth Defects.

IMPORTANCE: Major congenital abnormalities, or birth defects, carry significant medical, surgical, cosmetic, or lifestyle consequences. Such abnormalities may be syndromic, involving multiple organ systems, or can be isolated. Overall, 2% to 4% of live births involve congenital abnormalities. Risk factors for birth defects are categorized as modifiable and nonmodifiable. Modifiable risk factors require thorough patient education/counseling. The strongest risk factors, such as age, family history, and a previously affected child, are usually nonmodifiable. OBJECTIVE: This review focuses on risk factors for birth defects including alcohol consumption, illicit drug use, smoking, obesity, pregestational diabetes, maternal phenylketonuria, multiple gestation, advanced maternal age, advanced paternal age, family history/consanguinity, folic acid deficiency, medication exposure, and radiation exposure. EVIDENCE ACQUISITION: Literature review via PubMed. RESULTS: There is a strong link between alcohol use, folic acid deficiency, obesity, uncontrolled maternal diabetes mellitus, uncontrolled maternal phenylketonuria, and monozygotic twins and an increased risk of congenital anomalies. Advanced maternal age confers an increased risk of aneuploidy, as well as nonchromosomal abnormalities. Some medications, including angiotensin converting enzyme inhibitors, retinoic acid, folic acid antagonists, and certain anticonvulsants, are associated with various birth defects. However, there are few proven links between illicit drug use, smoking, advanced paternal age, radiation exposure, and statins with specific birth defects. CONCLUSIONS AND RELEVANCE: Birth defects are associated with multiple modifiable and nonmodifiable risk factors. Obstetrics providers should work with patients to minimize their risk of birth defects if modifiable risk factors are present and to appropriately counsel patients when nonmodifiable risk factors are present.

Novel role of hematopoietic stem cells in immunologic rejection of malignant gliomas.

Adoptive cellular therapy (ACT) after lymphodepletive conditioning can induce dramatic clinical responses, but this approach has been largely limited to melanoma due to a lack of reliable methods for expanding tumor-specific lymphocytes from the majority of other solid cancers. We have employed tumor RNA-pulsed dendritic cells (DCs) to reliably expand CD4+ and CD8+ tumor-reactive T lymphocytes for curative ACT in a highly-invasive, chemotherapy- and radiation-resistant malignant glioma model. Curative treatment of established intracranial tumors involved a synergistic interaction between myeloablative (MA) conditioning, adoptively transferred tumor-specific T cells, and tumor RNA-pulsed DC vaccines. Hematopoietic stem cells (HSCs), administered for salvage from MA conditioning, rapidly migrated to areas of intracranial tumor growth and facilitated the recruitment of tumor-specific lymphocytes through HSC-elaborated chemokines and enhanced immunologic rejection of intracranial tumors during ACT. Furthermore, HSC transplant under non-myeloablative (NMA) conditions also enhanced immunologic tumor rejection, indicating a novel role for the use of HSCs in the immunologic treatment of malignant gliomas and possibly other solid tumors.