Efficacy and safety of erythropoietin for traumatic brain injury.

BACKGROUND: Recent studies regarding the effects of erythropoietin (EPO) for treating traumatic brain injury (TBI) have been inconsistent. This study conducts a meta-analysis of randomized controlled trials (RCTs) to assess the safety and efficacy of EPO for TBI patients at various follow-up time points. METHODS: A literature search was performed using PubMed, Web of Science, MEDLINE, Embase, Google Scholar and the Cochrane Library for RCTs studying EPO in TBI patients published through March 2019. Non-English manuscripts and non-human studies were excluded. The assessed outcomes include mortality, neurological recovery and associated adverse effects. Dichotomous variables are presented as risk ratios (RR) with a 95% confidence interval (CI). RESULTS: A total of seven RCTs involving 1197 TBI patients (611 treated with EPO, 586 treated with placebo) were included in this study. Compared to the placebo arm, treatment with EPO did not improve acute hospital mortality or short-term mortality. However, there was a significant improvement in mid-term (6 months) follow-up survival rates. EPO administration was not associated with neurological function improvement. Regarding adverse effects, EPO treatment did not increase the incidence of thromboembolic events or other associated adverse events. CONCLUSIONS: This meta-analysis indicates a slight mortality benefit for TBI patients treated with EPO at mid-term follow-up. EPO does not improve in-hospital mortality, nor does it increase adverse events including thrombotic, cardiovascular and other associated complications. Our analysis did not demonstrate a significant beneficial effect of EPO intervention on the recovery of neurological function. Future RCTs are required to further characterize the use of EPO in TBI.

Vagus Nerve Stimulation versus Responsive Neurostimulator System in Patients with Temporal Lobe Epilepsy.

INTRODUCTION: Patients with medically refractory temporal lobe epilepsy (TLE) are candidates for neuromodulation procedures. While vagus nerve stimulation (VNS) was historically the procedure of choice for this condition, the responsive neurostimulation system (RNS) has come into favor for its more targeted approach. While both VNS and RNS have been reported as efficacious treatments for TLE, the outcomes of these 2 procedures have not been directly compared. This study aims to compare outcomes following VNS versus RNS for TLE. METHODS: We retrospectively reviewed the records of all patients with TLE who underwent VNS or RNS placement at our institution from 2003 to 2018. The primary outcome was change in seizure frequency. Other outcomes included Engel score, change in anti-epileptic medications, and complications. RESULTS: Twenty-three patients met inclusion criteria; 11 underwent VNS and 12 underwent RNS. At baseline, the 2 groups were statistically similar regarding age at surgery, epilepsy duration, and preoperative seizure frequency. At last follow-up, both groups displayed reduced seizure frequency (mean reduction of 46.3% for the VNS group and 58.1% for the RNS group, p = 0.49). Responder rate, Engel score, and change in medications were statistically similar between groups. Compared to 0.0% of the VNS group, 13.3% of the RNS group experienced infection requiring re-operation. CONCLUSION: Despite their different mechanisms, VNS and RNS resulted in similar response rates for patients with TLE. We suggest that VNS should not be excluded as a treatment for patients with medically refractory TLE who are not candidates for resective or ablative procedures.

Spine surgeon specialty differences in single-level percutaneous kyphoplasty.

BACKGROUND: Percutaneous kyphoplasty (PKP) is a procedure performed by a spine surgeon who undergoes either orthopedic or neurosurgical training. The relationship between short-term adverse outcomes and spine specialty is presently unknown. To compare short-term adverse outcomes of single-level PKP when performed by neurosurgeons and orthopedic surgeons in order to develop more concretely preventive strategies for patients under consideration for single-level PKP. METHODS: We evaluated patients who underwent single-level PKP from 2012 to 2014 through the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP). We used univariate analysis and multivariate logistic regression to assess the association between spine surgeon specialty and short-term adverse events, including postoperative complication and unplanned readmission, and to identify different independent risk predictors between two specialties. RESULTS: Of 2248 patients who underwent single-level PKP procedure, 1229 patients (54.7%) had their operations completed by a neurosurgeon. There were no significant differences in the development of the majority of postoperative complications and the occurrence of unplanned readmission between the neurosurgical cohort (NC) and the orthopedic cohort (OC). A difference in the postoperative blood transfusion rate (0.7% NS vs. 1.7% OC, P = 0.039) was noted and may due to the differences in comorbidities between patients. Multivariate regression analysis revealed different independent predictors of postoperative adverse events for the two spine specialties. CONCLUSIONS: By comparing a large range of demographic feature, preoperative comorbidities, and intraoperative factors, we find that short-term adverse events in single-level PKP patients does not affect by spine surgeon specialty, except that the OC had higher postoperative blood transfusion rate. In addition, the different perioperative predictors of postoperative complications and unplanned readmissions were identified between the two specialties. These findings can lead to better evidence-based patient counseling and provide valuable information for medical evaluation and potentially devise methods to reduce patients' risk.

A systematic review of nanocarriers for treatment of urologic cancers.

Nanocarriers (NCs) are a form of nanotechnology widely investigated in cancer treatment to improve the safety and efficacy of systemic therapies by increasing tumor specificity. Numerous clinical trials have explored the use of NCs in urologic cancers since the approval of the first NCs for cancer treatment over 20 years ago. The objective of this systematic review is to examine the effectiveness and safety of NCs in treating urological cancers. This paper summarizes the state of the field by investigating peer-reviewed, published results from 43 clinical trials involving the use of NCs in bladder, prostate, and kidney cancer patients with a focus on safety and efficacy data. Among the 43 trials, 16 were phase I, 20 phase II, and 4 phase I/II. No phase III trials have been reported. While both novel and classic NCs have been explored in urologic cancers, NCs already approved for the treatment of other cancers were more widely represented. Trials in prostate cancer and mixed trials involving both urologic and non-urologic cancer patients were the most commonly reported trials. Although NCs have demonstrable efficacy with adequate safety in non-urologic cancer patient populations, current clinical stage NC options appear to be less beneficial in the urologic cancer setting. For example, nab-paclitaxel and liposomal doxorubicin have proven ineffective in the treatment of urologic cancers despite successes in other cancers. However, several ongoing pre-clinical studies using targeted and locally applied improved NCs may eventually improve their utility.

Symptomatic perianeursymal cyst development 20 years after endovascular treatment of a ruptured giant aneurysm: Case report and updated review.

Perianeurysmal cysts are a rare and poorly understood finding in patients both with treated and untreated aneurysms. While the prior literature suggests that a minority of perianeurysmal cysts develop 1-4 years following endovascular aneurysm treatment, this updated review demonstrates that nearly half of perianeurysmal cysts were diagnosed following aneurysm coiling, with the other half diagnosed concurrently with an associated aneurysm prior to treatment. 64% of perianeurysmal cysts were surgically decompressed, with a 39% rate of recurrence requiring re-operation. We report a case of a 71-year-old woman who presented with vertigo and nausea and was found to have a 3.4 cm perianeurysmal cyst 20 years after initial endovascular coiling of a ruptured giant ophthalmic aneurysm. The cyst was treated with endoscopic fenestration followed by open fenestration upon recurrence. The case represents the longest latency from initial aneurysm treatment to cyst diagnosis reported in the literature and indicates that the diagnosis of perianeurysmal cyst should remain on the differential even decades after treatment. Based on a case discussion and updated literature review, this report highlights proposed etiologies of development and management strategies for a challenging lesion.

Endoscopic endonasal approach for olfactory groove meningioma resection: Strategies and outcomes in a retrospective case series.

OBJECTIVE: Though the endoscopic endonasal approach (EEA) is a widely accepted treatment for skull base tumors, the specific use of EEA for olfactory groove meningiomas (OGMs) is debated, with variable outcomes reported in the literature. We review the surgical results of OGM resections for one surgeon including the operative approach, surgical nuances, and outcomes, with a focus on factors relating to patient selection which favor EEA over transcranial approaches. METHODS: We retrospectively reviewed thirteen cases of endoscopic endonasal resection of olfactory groove meningiomas. Patient characteristics, clinical characteristics, surgical outcomes, and complications were analyzed. Extent of resection was determined based on volumetric analysis of pre- and postoperative MRI. RESULTS: Anatomic characteristics that render a tumor difficult to access fully are lateral extension beyond the mid-orbit and anterior extension to the falx. Simpson Grade I resection was achieved in 11/13 (84.6 %) cases. Mean pre-operative tumor volume was 8.99 cm3 (range 2.19-16.79 cm3), and 92 % of tumors were WHO grade I. We demonstrate 2 cases of smell preservation, possible with small unilateral tumors and tumors that are confined to either the anterior or posterior portion of the cribriform plate. The post-operative CSF leak rate was 7.7 %, without prophylactic lumbar CSF drainage. The mortality rate was 7.7 % (n = 1) after infectious complications following CSF leak. CONCLUSIONS: Endoscopic endonasal resection of olfactory groove meningiomas is an effective and safe operative method with outcomes and complication rates comparable to transcranial approaches. Key considerations include careful patient selection and familiarity with technical nuances of endoscopic endonasal approach for this specific tumor type.

Embryonal carcinoma cell induction of miRNA and mRNA changes in co-cultured prostate stromal fibromuscular cells.

The prostate stromal mesenchyme controls organ-specific development. In cancer, the stromal compartment shows altered gene expression compared to non-cancer. The lineage relationship between cancer-associated stromal cells and normal tissue stromal cells is not known. Nor is the cause underlying the expression difference. Previously, the embryonal carcinoma (EC) cell line, NCCIT, was used by us to study the stromal induction property. In the current study, stromal cells from non-cancer (NP) and cancer (CP) were isolated from tissue specimens and co-cultured with NCCIT cells in a trans-well format to preclude heterotypic cell contact. After 3 days, the stromal cells were analyzed by gene arrays for microRNA (miRNA) and mRNA expression. In co-culture, NCCIT cells were found to alter the miRNA and mRNA expression of NP stromal cells to one like that of CP stromal cells. In contrast, NCCIT had no significant effect on the gene expression of CP stromal cells. We conclude that the gene expression changes in stromal cells can be induced by diffusible factors synthesized by EC cells, and suggest that cancer-associated stromal cells represent a more primitive or less differentiated stromal cell type.

Social agent identity cells in the prefrontal cortex of interacting groups of primates.

The ability to interact effectively within social groups is essential to primate and human behavior. Yet understanding the neural processes that underlie the interactive behavior of groups or by which neurons solve the basic problem of coding for multiple agents has remained a challenge. By tracking the interindividual dynamics of groups of three interacting rhesus macaques, we discover detailed representations of the groups' behavior by neurons in the dorsomedial prefrontal cortex, reflecting not only the other agents' identities but also their specific interactions, social context, actions, and outcomes. We show how these cells collectively represent the interaction between specific group members and their reciprocation, retaliation, and past behaviors. We also show how they influence the animals' own upcoming decisions and their ability to form beneficial agent-specific interactions. Together, these findings reveal prefrontal neurons that code for the agency identity of others and a cellular mechanism that could support the interactive behavior of social groups.

Cervical Spine Osteomyelitis: A Systematic Review of Instrumented Fusion in the Modern Era.

OBJECTIVE: For cases of cervical osteomyelitis that require surgery, concern has continued regarding instrumentation owing to the potential for bacterial seeding of the hardware. We performed a systematic review of the current data. METHODS: A search was performed using Medline, Embase, and Ovid for articles using the keywords "cervical osteomyelitis/spondylodiscitis" and "fusion" or "instrumentation" reported from 1980 to 2017. Prospective or retrospective studies describing ≥2 patients with cervical osteomyelitis were included in the analysis; non-English reports were excluded. Individual patients were excluded from the final analysis if they had previously undergone spinal instrumentation. RESULTS: A total of 239 patients from 24 studies met our criteria. Surgical approaches were classified as anterior-only, combined anteroposterior, and posterior-only for 64.8%, 31.9%, and 3.3% of the patients respectively. Of the patients treated using an anterior-only approach, 76.5% had received anterior plating and 85.3%, a cage or spacer implants. Of the patients who had undergone combined approaches, 85.1% underwent circumferential fixation and 14.9%, anterior debridement with posterior instrumentation. The follow-up period ranged from 6 weeks to 11 years (mean, 31.0 months). All the studies reporting the fusion rates, except for 1, reported a 100% fusion rate. The reported rates of pain improvement and neurologic recovery were favorable. The incidence of hardware failure and wound complications was 4.6% and 4.0%, respectively. CONCLUSIONS: Despite placing instrumentation during active infection, the rates of hardware failure and wound complications were comparable to those of elective cervical spine procedures. These results suggest that surgical intervention with instrumentation is a safe treatment option for patients with cervical spine osteomyelitis.

Preoperative Stratification of Transsphenoidal Pituitary Surgery Patients Based on Surgical Urgency.

BACKGROUND: Currently, there is no prioritization scale available to distinguish those patients with pituitary tumors who require urgent surgical intervention from those who are candidates for elective treatment. OBJECTIVE: To develop a classification system that can help primary care physicians, endocrinologists, neurosurgeons, ancillary support staff, and hospital administrators identify high-priority surgical candidates. METHODS: An expert international panel of clinicians consisting of endocrinologists and neurosurgeons who are involved in the diagnosis and management of sellar disease was convened. The panel retrospectively reviewed individual experiences, including a cohort of patients operated upon for pituitary related disease at the Brigham and Women's Hospital from January 2008 to November 2015. A risk stratification schema was developed to streamline patient care pathways. RESULTS: We identified 4 groups of surgical candidates with varying levels of risk, and then assigned treatment timelines and different differential diagnoses to each. The 4 groups were as follows: group A: urgent-immediate; group B: prompt-initiate treatment within 1 to 2 weeks; group C: soon-initiate treatment within 3 months; group D: elective-as soon as indicated. Among 472 patients treated at Brigham and Women's Hospital for pituitary adenomas, each was assigned to 1 of the 4 predetermined subgroups: group A, 6.8%; group B, 30.1%; group C, 31.1%; group D, 32.0%. CONCLUSIONS: We developed a risk stratification schema that may serve as a platform to streamline care to the patients at highest risk. The expert opinions presented provide a basis for future studies regarding the risk prioritization of patients.

History of endonasal skull base surgery.

While the endonasal approach to the skull base continues to advance, this paper invokes its long history. The centuries of medieval neuroanatomy and early neurosurgery enabled the conception of the first transfacial approaches in the late 1800s; Henry Schloffer performed the first transsphenoidal surgery in 1907. Although the procedure was initially met with much interest, Harvey Cushing eventually led the field of neurosurgery to abandon the transsphenoidal approach in the 1920s. The following three generations of neurosurgeons contained several key figures including Norman Dott, Gerard Guiot, and Jules Hardy who were steadfast in preserving the technique as well as in addressing its shortcomings. The endoscopic approach developed simultaneously, and advances in magnifying and fiberoptics further resolved limitations previously inherent to the transsphenoidal approach. At last, in the 1960s, the transsphenoidal approach entered its renaissance. Today, the momentum of its development persists in the endoscopic endonasal approach, which has recently expanded the indications for transsphenoidal surgery across the skull base, far beyond its original jurisdiction of the sella. Continued progress must not take for granted the rich history of the transsphenoidal approach, which was developed over centuries by surgeons around the world. The authors present the evolution of modern endonasal surgery as a dynamic interplay between technology, medicine, and surgery over the past 100 years. Progress can be attributed to courageous surgeons who affirmed their contemporary practices despite gaps in technology or medicine, and to visionary individuals who produced and incorporated new elements into transsphenoidal surgery. And so while the new endoscopic technique brings forth new challenges, its development reaffirms the principles laid down by the pioneers of transsphenoidal surgery.

Modeling pain in vitro using nociceptor neurons reprogrammed from fibroblasts.

Reprogramming somatic cells from one cell fate to another can generate specific neurons suitable for disease modeling. To maximize the utility of patient-derived neurons, they must model not only disease-relevant cell classes, but also the diversity of neuronal subtypes found in vivo and the pathophysiological changes that underlie specific clinical diseases. We identified five transcription factors that reprogram mouse and human fibroblasts into noxious stimulus-detecting (nociceptor) neurons. These recapitulated the expression of quintessential nociceptor-specific functional receptors and channels found in adult mouse nociceptor neurons, as well as native subtype diversity. Moreover, the derived nociceptor neurons exhibited TrpV1 sensitization to the inflammatory mediator prostaglandin E2 and the chemotherapeutic drug oxaliplatin, modeling the inherent mechanisms underlying inflammatory pain hypersensitivity and painful chemotherapy-induced neuropathy. Using fibroblasts from patients with familial dysautonomia (hereditary sensory and autonomic neuropathy type III), we found that the technique was able to reveal previously unknown aspects of human disease phenotypes in vitro.

HIF induces human embryonic stem cell markers in cancer cells.

Low oxygen levels have been shown to promote self-renewal in many stem cells. In tumors, hypoxia is associated with aggressive disease course and poor clinical outcomes. Furthermore, many aggressive tumors have been shown to display gene expression signatures characteristic of human embryonic stem cells (hESC). We now tested whether hypoxia might be responsible for the hESC signature observed in aggressive tumors. We show that hypoxia, through hypoxia-inducible factor (HIF), can induce an hESC-like transcriptional program, including the induced pluripotent stem cell (iPSC) inducers, OCT4, NANOG, SOX2, KLF4, cMYC, and microRNA-302 in 11 cancer cell lines (from prostate, brain, kidney, cervix, lung, colon, liver, and breast tumors). Furthermore, nondegradable forms of HIFα, combined with the traditional iPSC inducers, are highly efficient in generating A549 iPSC-like colonies that have high tumorigenic capacity. To test potential correlation between iPSC inducers and HIF expression in primary tumors, we analyzed primary prostate tumors and found a significant correlation between NANOG-, OCT4-, and HIF1α-positive regions. Furthermore, NANOG and OCT4 expressions positively correlated with increased prostate tumor Gleason score. In primary glioma-derived CD133 negative cells, hypoxia was able to induce neurospheres and hESC markers. Together, these findings suggest that HIF targets may act as key inducers of a dynamic state of stemness in pathologic conditions.