Activity of a Novel Anti-Inflammatory Agent F-3,6'-dithiopomalidomide as a Treatment for Traumatic Brain Injury.

Traumatic brain injury (TBI) is a major risk factor for several neurodegenerative disorders, including Parkinson's disease (PD) and Alzheimer's disease (AD). Neuroinflammation is a cause of later secondary cell death following TBI, has the potential to aggravate the initial impact, and provides a therapeutic target, albeit that has failed to translate into clinical trial success. Thalidomide-like compounds have neuroinflammation reduction properties across cellular and animal models of TBI and neurodegenerative disorders. They lower the generation of proinflammatory cytokines, particularly TNF-α which is pivotal in microglial cell activation. Unfortunately, thalidomide-like drugs possess adverse effects in humans before achieving anti-inflammatory drug levels. We developed F-3,6'-dithiopomalidomide (F-3,6'-DP) as a novel thalidomide-like compound to ameliorate inflammation. F-3,6'-DP binds to cereblon but does not efficiently trigger the degradation of the transcription factors (SALL4, Ikaros, and Aiolos) associated with the teratogenic and anti-proliferative responses of thalidomide-like drugs. We utilized a phenotypic drug discovery approach that employed cellular and animal models in the selection and development of F-3,6'-DP. F-3,6'-DP significantly mitigated LPS-induced inflammatory markers in RAW 264.7 cells, and lowered proinflammatory cytokine/chemokine levels in the plasma and brain of rats challenged with systemic LPS. We subsequently examined immunohistochemical, biochemical, and behavioral measures following controlled cortical impact (CCI) in mice, a model of moderate TBI known to induce inflammation. F-3,6'-DP decreased CCI-induced neuroinflammation, neuronal loss, and behavioral deficits when administered after TBI. F-3,6'-DP represents a novel class of thalidomide-like drugs that do not lower classical cereblon-associated transcription factors but retain anti-inflammatory actions and possess efficacy in the treatment of TBI and potentially longer-term neurodegenerative disorders.

3,6'- and 1,6'-Dithiopomalidomide Mitigate Ischemic Stroke in Rats and Blunt Inflammation.

(1) Background: An important concomitant of stroke is neuroinflammation. Pomalidomide, a clinically available immunomodulatory imide drug (IMiD) used in cancer therapy, lowers TNF-α generation and thus has potent anti-inflammatory actions. Well-tolerated analogs may provide a stroke treatment and allow evaluation of the role of neuroinflammation in the ischemic brain. (2) Methods: Two novel pomalidomide derivatives, 3,6'-dithiopomalidomide (3,6'-DP) and 1,6'-dithiopomalidomide (1,6'-DP), were evaluated alongside pomalidomide in a rat middle cerebral artery occlusion (MCAo) stroke model, and their anti-inflammatory actions were characterized. (3) Results: Post-MCAo administration of all drugs lowered pro-inflammatory TNF-α and IL1-ß levels, and reduced stroke-induced postural asymmetry and infarct size. Whereas 3,6'- and 1,6'-DP, like pomalidomide, potently bound to cereblon in cellular studies, 3,6'-DP did not lower Ikaros, Aiolos or SALL4 levels-critical intermediates mediating the anticancer/teratogenic actions of pomalidomide and IMiDs. 3,6'-DP and 1,6'-DP lacked activity in mammalian chromosome aberration, AMES and hERG channel assays -critical FDA regulatory tests. Finally, 3,6'- and 1,6'-DP mitigated inflammation across rat primary dopaminergic neuron and microglia mixed cultures challenged with α-synuclein and mouse LPS-challenged RAW 264.7 cells. (4) Conclusion: Neuroinflammation mediated via TNF-α plays a key role in stroke outcome, and 3,6'-DP and 1,6'-DP may prove valuable as stroke therapies and thus warrant further preclinical development.

Detection of tumor-specific DNA methylation markers in the blood of patients with pituitary neuroendocrine tumors.

BACKGROUND: DNA methylation abnormalities are pervasive in pituitary neuroendocrine tumors (PitNETs). The feasibility to detect methylome alterations in circulating cell-free DNA (cfDNA) has been reported for several central nervous system (CNS) tumors but not across PitNETs. The aim of the study was to use the liquid biopsy (LB) approach to detect PitNET-specific methylation signatures to differentiate these tumors from other sellar diseases. METHODS: We profiled the cfDNA methylome (EPIC array) of 59 serum and 41 plasma LB specimens from patients with PitNETs and other CNS diseases (sellar tumors and other pituitary non-neoplastic diseases, lower-grade gliomas, and skull-base meningiomas) or nontumor conditions, grouped as non-PitNET. RESULTS: Our results indicated that despite quantitative and qualitative differences between serum and plasma cfDNA composition, both sources of LB showed that patients with PitNETs presented a distinct methylome landscape compared to non-PitNETs. In addition, LB methylomes captured epigenetic features reported in PitNET tissue and provided information about cell-type composition. Using LB-derived PitNETs-specific signatures as input to develop machine-learning predictive models, we generated scores that distinguished PitNETs from non-PitNETs conditions, including sellar tumor and non-neoplastic pituitary diseases, with accuracies above ~93% in independent cohort sets. CONCLUSIONS: Our results underpin the potential application of methylation-based LB profiling as a noninvasive approach to identify clinically relevant epigenetic markers to diagnose and potentially impact the prognostication and management of patients with PitNETs.

Neurosurgery residency and fellowship education in the United States: 2 decades of system development by the One Neurosurgery Summit organizations.

The purpose of this report is to chronicle a 2-decade period of educational innovation and improvement, as well as governance reform, across the specialty of neurological surgery. Neurological surgery educational and professional governance systems have evolved substantially over the past 2 decades with the goal of improving training outcomes, patient safety, and the quality of US neurosurgical care. Innovations during this period have included the following: creating a consensus national curriculum; standardizing the length and structure of neurosurgical training; introducing educational outcomes milestones and required case minimums; establishing national skills, safety, and professionalism courses; systematically accrediting subspecialty fellowships; expanding professional development for educators; promoting training in research; and coordinating policy and strategy through the cooperation of national stakeholder organizations. A series of education summits held between 2007 and 2009 restructured some aspects of neurosurgical residency training. Since 2010, ongoing meetings of the One Neurosurgery Summit have provided strategic coordination for specialty definition, neurosurgical education, public policy, and governance. The Summit now includes leadership representatives from the Society of Neurological Surgeons, the American Association of Neurological Surgeons, the Congress of Neurological Surgeons, the American Board of Neurological Surgery, the Review Committee for Neurological Surgery of the Accreditation Council for Graduate Medical Education, the American Academy of Neurological Surgery, and the AANS/CNS Joint Washington Committee. Together, these organizations have increased the effectiveness and efficiency of the specialty of neurosurgery in advancing educational best practices, aligning policymaking, and coordinating strategic planning in order to meet the highest standards of professionalism and promote public health.

Drug Repurposing in the Treatment of Traumatic Brain Injury.

Traumatic brain injury (TBI) is the most common cause of morbidity among trauma patients; however, an effective pharmacological treatment has not yet been approved. Individuals with TBI are at greater risk of developing neurological illnesses such as Alzheimer's disease (AD) and Parkinson's disease (PD). The approval process for treatments can be accelerated by repurposing known drugs to treat the growing number of patients with TBI. This review focuses on the repurposing of N-acetyl cysteine (NAC), a drug currently approved to treat hepatotoxic overdose of acetaminophen. NAC also has antioxidant and anti-inflammatory properties that may be suitable for use in therapeutic treatments for TBI. Minocycline (MINO), a tetracycline antibiotic, has been shown to be effective in combination with NAC in preventing oligodendrocyte damage. (-)-phenserine (PHEN), an anti-acetylcholinesterase agent with additional non-cholinergic neuroprotective/neurotrophic properties initially developed to treat AD, has demonstrated efficacy in treating TBI. Recent literature indicates that NAC, MINO, and PHEN may serve as worthwhile repositioned therapeutics in treating TBI.

Back to the future: surgical rehearsal platform technology as a means to improve surgeon-patient alliance, patient satisfaction, and resident experience.

OBJECTIVE: Informed consent, when performed appropriately, serves many roles beyond simply obtaining the prerequisite medicolegal paperwork to perform a surgery. Prior studies have suggested that patient understanding is poor when verbal communication is the sole means of education. Virtual reality platforms have proven effective in enhancing medical education. No studies exist that have demonstrated the utility of virtual reality-facilitated informed consent (VR-IC) in improving the physician-patient alliance. The aim of this study was to determine the utility of VR-IC among patients providing consent for surgery and the impact of this educational and information technology-based strategy on enhancing the physician-patient alliance, patient satisfaction, and resident-physician perception of the consent process. METHODS: Prospective, single-site, pre- and postconsent surveys were administered to assess patient and resident perception of informed consent performed with the aid of VR-IC at a large tertiary academic medical center in the US. Participants were adult patients (n = 50) undergoing elective surgery for tumor resection and neurosurgical residents (n = 19) who obtained patient informed consent for these surgical procedures. Outcome measures included scores on the Patient-Doctor Relationship Questionnaire (PDRQ-9), the modified Satisfaction with Simulation Experience Scale, and the Maslach Burnout Inventory. Patient pre- and postconsent data were recorded in real time using a secure online research data platform (REDCap). RESULTS: A total of 48 patients and 2 family members provided consent using VR-IC and completed the surveys pre- and postconsent; 47.9% of patients were women. The mean patient age was 57.5 years. There was a statistically significant improvement from pre- to post-VR-IC consent in patient satisfaction scores. Measures of patient-physician alliance, trust, and understanding of their illness all increased. Among the 19 trainees, perceived comfort and preparedness with the informed consent process significantly improved. CONCLUSIONS: VR-IC led to improved patient satisfaction, patient-physician alliance, and patient understanding of their illness as measured by the PDRQ-9. Using VR-IC contributed to residents' increased comfort in the consent-gathering process and handling patient questions. In an era in which satisfaction scores are directly linked with hospital and service-line outcomes and reimbursement, positive results from VR-IC may augment physician and hospital satisfaction scores in addition to increasing measures of trust between physicians and patients.

Intratumoral Rathke's Cleft Cyst Remnants Within Craniopharyngioma, Pituitary Adenoma, Suprasellar Dermoid, and Epidermoid Cysts: A Ubiquitous Signature of Ectodermal Lineage or a Transitional Entity?

BACKGROUND: The authors present cystic epithelial masses in the suprasellar region which on histopathology revealed 4 mixed tumors having simple cuboidal epithelium of Rathke's Cleft Cyst (RCC) elements trapped within pituitary adenoma, epidermoid cyst, dermoid cyst, and papillary craniopharyngioma respectively. OBJECTIVE: To highlight the developmental theory of ectodermal continuum in the realm of suprasellar epithelial cystic lesions and examines the cardinal aspects that distinguish RCC from its confounder, ciliary craniopharyngioma. METHODS: The authors performed a medical chart review on 4 patients who had coexisting RCC with craniopharyngioma, pituitary adenoma, suprasellar dermoid, and epidermoid cysts. RESULTS: This series of unique suprasellar lesions elucidate the spectrum of cases from Rathke's cyst to other suprasellar epithelial cysts including a recently identified clinical entity called ciliary craniopharyngioma, which authors feel is a misnomer. The authors also report the first case of ruptured dermoid cyst admixed with elements of Rathke's cyst elements and xanthogranuloma in neurosurgical literature. CONCLUSION: We propose that the new entity of ciliary craniopharyngioma could be just another variant of RCC elements nested within a typical papillary or adamantinomatous lesion. Further study is warranted to understand the implications of natural history with tumors containing RCC elements.

Impact of Resident Involvement in Neurosurgery: An American College of Surgeons' National Surgical Quality Improvement Program Database Analysis of 33,977 Patients.

OBJECTIVE: There is conflicting and limited literature on the effect of intraoperative resident involvement on surgical outcomes. Our study assessed effects of resident involvement on outcomes in patients undergoing neurosurgery. METHODS: We identified 33,977 adult neurosurgical cases from 374 hospitals in the 2006-2012 National Surgical Quality Improvement Program, a prospectively collected national database with established reproducibility and validity. Outcomes were compared according to resident involvement before and after 1:1 matching on procedure and perioperative risk factors. RESULTS: Resident involvement was documented in 13,654 cases. We matched 10,170 resident-involved cases with 10,170 attending-alone. In the matched sample, resident involvement was associated with increased surgery duration (average, 34 minutes) and slight increases in odds for prolonged hospital stay (odds ratio, 1.2; 95% confidence interval [CI], 1.2-1.3) and complications (odds ratio, 1.2; 95% CI, 1.1-1.3) including infections (odds ratio, 1.4; 95% CI, 1.2-1.7). Increased risk for infections persisted after controlling for surgery duration (odds ratio, 1.3; 95% CI, 1.1-1.5). The majority of cases were spine surgeries, and resident involvement was not associated with morbidity or mortality for malignant tumor and aneurysm patients. Training level of residents was not associated with differences in outcomes. CONCLUSION: Resident involvement was more common in sicker patients undergoing complex procedures, consistent with academic centers undertaking more complex cases. After controlling for patient and intraoperative characteristics, resident involvement in neurosurgical cases continued to be associated with longer surgical duration and slightly higher infection rates. Longer surgery duration did not account for differences in infection rates.

The Value of Perioperative Levels of ACTH, DHEA, and DHEA-S and Tumor Size in Predicting Recurrence of Cushing Disease.

Context and Objectives: Despite the development of hypocortisolemia after corticotroph surgical adenomectomy, 15% to 20% patients have recurrence of Cushing disease (CD). In this study, we investigated the effect of tumor size and the value of perioperative assessment of corticotropin (ACTH) and adrenal steroid levels in predicting recurrence. Design: Perioperatively, no glucocorticoids were administered until the serum cortisol was ≤3 µg/dL. Blood samples were obtained before and repeatedly after adenomectomy in 79 patients with CD. Of these, 66 had a nadir serum cortisol of ≤3.0 µg/dL and clinical and biochemical remissions. During a median follow-up of 131 months, 11 of 66 had disease recurrence (REC), whereas 55 of 66 did not (NO-REC). Results: Preoperative hormone levels in the REC and NO-REC groups were similar. After adenomectomy, a brief and similar increase in ACTH, cortisol, and dehydroepiandrosterone (DHEA) levels was observed in both groups followed by gradual decline in those levels. Although REC and NO-REC patients had similar cortisol levels (3.4 ± 1.7 µg/dL vs 2.9 ± 2.2 µg/dL) at the 36th postoperative hour, their respective ACTH (33 ± 7.1 ng/L vs 12.1 ± 5.4 ng/L; P < 0.0001), DHEA (3.8 ± 1.7 ng/mL vs 1.2 ± 1.1 ng/mL; P = 0.005), and dehydroepiandrosterone sulphate (DHEA-S) (143.9 ± 45.2 µg/dL vs 48.9 ± 38.2 µg/dL; P < 0.0001) were higher. At nadir hypocortisolemia, perioperative ACTH levels were >20 in all REC patients and <20 ng/L in the NO-REC group. Patients with REC had larger tumors than those with NO-REC. Conclusion: Recurrent CD is characterized by persistent perioperative ACTH secretion after adenomectomy. Higher perioperative levels of ACTH, DHEA, and DHEA-S are highly predictive of future disease recurrence, particularly in those with profound hypocortisolemia.

The impact of peri-operative dexamethasone administration on the normal hypothalamic pituitary adrenal response to major surgical procedures.

BACKGROUND: Surgical procedures are associated with activation of the hypothalamic-pituitary-adrenal axis (HPA). Studies examining HPA dynamics peri-operatively are limited and the modulating influence of peri-operatively administered glucocorticoids on that is not well established. This investigation examined alterations in HPA function and the impact of dexamethasone (DEX) administration during the peri-operative period. METHODS: We examined HPA function in 297 patients with normal function who had surgical procedures including pituitary mass resection (n = 191), craniotomy (n = 17) and other thoracic/ abdominal/ pelvic surgeries (n = 89). HPA function was assessed by frequent measurements of parameters defining adrenal function: ACTH, cortisol, DHEA and DHEA-S levels for 48 h. DEX was administered as a single dose (2-10 mg) to 30 and as multiple doses (12-36 mg) to 21 patients. The data of DEX-treated subjects within each group were similar and were combined together. RESULTS: Pre-operative data were similar for patients having different surgical procedures. Without DEX exposure, ACTH increased to 225 ± 100 ng/L at 2-4 h and gradually declined to baseline values by 36 h while cortisol levels peaked (39.2 ± 13.2 ug/dL) at 6-8 h declining gradually thereafter. Cortisol rise was paralleled by an equimolar increase in DHEA and a subsequent increase in DHEA-S levels. Single doses of DEX did not influence ACTH or cortisol secretion but suppressed the expected rise in DHEA and DHEA-S levels. Multiple doses of DEX suppressed ACTH and cortisol after the 15th postoperative hour and completely blocked the expected rise in DHEA and DHEA-S levels. CONCLUSIONS: The data provide a detailed overview of HPA function in a large number of subjects who had major surgical procedures. Single and large doses of DEX did not suppress ACTH or cortisol secretion but suppressed adrenal androgen secretion. It took multiple doses of DEX to partially suppress ACTH and cortisol secretion in the peri-operative period.

Utilization of sinus stents as a novel approach for benign cystic lesions of the sella.

Steroid-releasing sinus stents have emerged as a safe and effective tool in endoscopic sinus surgery. In this case report, we present two patients with recurrent cystic sellar masses. Transsphenoidal approach was used to access the sella. Following resection and drainage of the cystic pathology, a Propel (Menlo Park, CA) stent was placed through the corridor of the resection site to stent the cavity open. This is the first report where a steroid-releasing sinus stent was used in the treatment of a sellar lesion. It supports that this technology is safe and effective for use in skull base surgery.

Perioperative hypothalamic pituitary adrenal function in patients with silent corticotroph adenomas.

BACKGROUND: Silent corticotroph adenomas (SCAs) are characterized by strong ACTH immunostaining without clinical manifestations of hypercortisolism. Patients with SCAs often present with mechanical symptoms related to tumor growth. This study investigates the hypothalamic pituitary adrenal axis (HPA) characteristics after adenomectomy in patients with SCAs. METHODS: Biochemical parameters of HPA function were monitored frequently after surgical resection of non-functioning macroadenomas. Levels of ACTH, cortisol, DHEA and DHEA-S were measured frequently for 48 h after adenomectomy. HPA data of patients with SCAs (n = 38) were compared to others (Controls) with non-secreting, ACTH-negative immunostaining adenomas of similar age and gender distribution (n = 182) who had adenomectomy. RESULT: Plasma ACTH increased (P < 0.0001) equally in patients with SCA and controls reaching a peak at 3 h (238 ± 123 vs. 233 ± 96 ng/L, respectively) after extubation declining thereafter to baseline values 24-36 h. Similarly, serum cortisol levels increased (P < 0.0001) equally in both groups reaching a maximum at 7 h (36.8 ± 13.9 vs. 39.3 ± 13.3 ug/dL). Serum DHEA also increased (P < 0.001) equally in both groups in parallel to the rise in serum cortisol. Serum DHEA-S levels similarly increased (P < 0.001) from their respective baseline (105.9 ± 67.5 and 106.5 ± 58.7 ug/dL) reaching their peak (154.5 ± 69.5 and 153.5 ± 68.6 ug/dL; respectively) at 15 h after extubation. None of the patients acquired any hormone deficits. CONCLUSIONS: Under the maximal stimulation of the peri-operative stress, HPA function in patients with SCA behaved in an identical manner to others with ACTH-negative macroadenomas. Thus, despite the strong ACTH-positive immunostaining of these tumors, SCAs are truly non- functional.

Use of a surgical rehearsal platform and improvement in aneurysm clipping measures: results of a prospective, randomized trial.

OBJECTIVE The field of neurosurgery is constantly undergoing improvements and advances, both in technique and technology. Cerebrovascular neurosurgery is no exception, with endovascular treatments changing the treatment paradigm. Clipping of aneurysms is still necessary, however, and advances are still being made to improve patient outcomes within the microsurgical treatment of aneurysms. Surgical rehearsal platforms are surgical simulators that offer the opportunity to rehearse a procedure prior to entering the operative suite. This study is designed to determine whether use of a surgical rehearsal platform in aneurysm surgery is helpful in decreasing aneurysm dissection time and clip manipulation of the aneurysm. METHODS The authors conducted a blinded, prospective, randomized study comparing key effort and time variables in aneurysm clip ligation surgery with and without preoperative use of the SuRgical Planner (SRP) surgical rehearsal platform. Initially, 40 patients were randomly assigned to either of two groups: one in which surgery was performed after use of the SRP (SRP group) and one in which surgery was performed without use of the SRP (control group). All operations were videotaped. After exclusion of 6 patients from the SRP group and 9 from the control group, a total of 25 surgical cases were analyzed by a reviewer blinded to group assignment. The videos were analyzed for total microsurgical time, number of clips used, and number of clip placement attempts. Means and standard deviations (SDs) were calculated and compared between groups. RESULTS The mean (± SD) amount of operative time per clip used was 920 ± 770 seconds in the SRP group and 1294 ± 678 seconds in the control group (p = 0.05). In addition, the mean values for the number of clip attempts, total operative time, ratio of clip attempts to clips used, and time per clip attempt were all lower in the SRP group, although the between-group differences were not statistically significant. CONCLUSIONS Preoperative rehearsal with SRP increased efficiency and safety in aneurysm microsurgery as demonstrated by the statistically significant improvement in time per clip used. Although the rest of the outcomes did not demonstrate statistically significant between-group differences, the fact that the SRP group showed improvement in mean values for all measures studied suggests that preoperative rehearsal may increase the efficiency and safety of aneurysm microsurgery. Future studies aimed at improving patient outcome and safety during surgical clipping of aneurysms will be needed to keep pace with the quickly advancing endovascular field.

Mature salivary gland rests within sonic hedgehog-positive medulloblastoma: case report and insights into the molecular genetics and embryopathology of ectopic intracranial salivary gland analogs.

Intracranial ectopic salivary gland rests within dural-based lesions are reported very infrequently in the literature. The authors report the unique case of a 12-year-old boy with a cerebellar medulloblastoma positive for sonic hedgehog (Shh) that contained intraaxial mature ectopic salivary gland rests. The patient underwent clinical and radiological monitoring postoperatively, until he died of disseminated disease. An autopsy showed no evidence of salivary glands within disseminated lesions. The intraaxial presence of salivary gland rests and concomitant Shh positivity of the described tumor point to a disorder in differentiation as opposed to ectopic developmental foci, which are uniformly dural based in the described literature. The authors demonstrate the characteristic "papilionaceous" appearance of the salivary glands with mucicarmine stain and highlight the role of Shh signaling in explaining the intraaxial presence of seromucous gland analogs. This article reports the first intraaxial posterior fossa tumor with heterotopic salivary gland rests, and it provides molecular and embryopathological insights into the development of these lesions.

Postoperative sellar hematoma after pituitary surgery: clinical and biochemical characteristics.

BACKGROUND: Postoperative sellar hematoma can develop following surgery for pituitary tumors and other sellar masses such a Rathke's cleft cyst (RCC) due to continued blood oozing. Though often mild sellar hematoma can create mass effects that might impair pituitary function. AIM: This study summarizes the clinical and biochemical characteristics of sellar hematoma and explores the potential mechanisms for the associated hypopituitarism. PATIENTS AND METHODS: Sellar hematoma was suspected clinically (worsening headaches, visual impairment, and mental status alterations) and confirmed radiographically in 23 patients (18/279 with macroadenomas and in 5/92 with RCC). Postoperatively, patients were monitored without glucocorticoid therapy and all had appropriately normal HPA function before sellar hematoma diagnosis. RESULTS: The demographics of patients who had sellar hematoma were similar to those who did not. Biochemical changes at diagnosis included decreased plasma ACTH and its dependent steroids (cortisol, DHEA, and DHEA-S), concomitant mild hyperprolactinemia, and mild hyponatremia (P < 0.005 for all parameters). Treatment with glucocorticoids resulted in rapid clinical improvement in most patients. Glucocorticoid therapy was discontinued within 2 weeks and re-testing thereafter showed normal HPA function in 16/23. None of the patients without sellar hematoma had worsening in pituitary function, visual, or neurological symptoms. CONCLUSIONS: When large, sellar hematoma can lead to mass effect that causes headaches, visual symptoms, and acute and often reversible hypopituitarism manifesting initially as impaired HPA function. Rapid resolution is observed in most patients with glucocorticoid administration The rapid onset and reversibility of hypopituitarism associated with mild hyperprolactinemia suggest that compression of pituitary stalk/ portal vessels is likely the dominant mechanism of pituitary dysfunction in this setting.

Postnatal Pancraniosynostosis in a Patient With Infantile Hypophosphatasia.

Hypophosphatasia is a rare metabolic bone disorder that predisposes patients to craniosynostosis. Typically, patients born with hypophosphatasia will exhibit fused cranial sutures at birth. This is the first reported case of delayed onset of pancraniosynostosis in a patient with infantile hypophosphatasia. The severity of onset and delayed presentation in this patient are of interest and should give pause to those care providers who treat and evaluate patients with hypophosphatasia.

The Recent Revolution in the Design and Manufacture of Cranial Implants: Modern Advancements and Future Directions.

Large format (i.e., >25 cm) cranioplasty is a challenging procedure not only from a cosmesis standpoint, but also in terms of ensuring that the patient's brain will be well-protected from direct trauma. Until recently, when a patient's own cranial flap was unavailable, these goals were unattainable. Recent advances in implant computer-aided design and 3-dimensional (3-D) printing are leveraging other advances in regenerative medicine. It is now possible to 3-D-print patient-specific implants from a variety of polymer, ceramic, or metal components. A skull template may be used to design the external shape of an implant that will become well integrated in the skull, while also providing beneficial distribution of mechanical force in the event of trauma. Furthermore, an internal pore geometry can be utilized to facilitate the seeding of banked allograft cells. Implants may be cultured in a bioreactor along with recombinant growth factors to produce implants coated with bone progenitor cells and extracellular matrix that appear to the body as a graft, albeit a tissue-engineered graft. The growth factors would be left behind in the bioreactor and the graft would resorb as new host bone invades the space and is remodeled into strong bone. As we describe in this review, such advancements will lead to optimal replacement of cranial defects that are both patient-specific and regenerative.

Risks associated with preoperative anemia and perioperative blood transfusion in open surgery for intracranial aneurysms.

OBJECT: Preoperative anemia may be treated with a blood transfusion. Both are associated with adverse outcomes in various surgical procedures, but this has not been clearly elucidated in surgery for cerebral aneurysms. In this study the authors assessed the association of preoperative anemia and perioperative blood transfusion, separately, on 30-day morbidity and mortality in patients undergoing open surgery for ruptured and unruptured intracranial aneurysms. METHODS: The authors identified 668 cases (including 400 unruptured and 268 unruptured intracranial aneurysms) of open surgery for treatment of intracranial aneurysms in the 2006-2012 National Surgical Quality Improvement Program, a validated and reproducible prospective clinical database. Anemia was defined as a hematocrit level less than 39% in males and less than 36% in females. Perioperative transfusion was defined as at least 1 unit of packed or whole red blood cells given at any point between the start of surgery to 72 hours postoperatively. The authors separately compared surgical outcome between patients with (n = 198) versus without (n = 470) anemia, and those who underwent (n = 78) versus those who did not receive (n = 521) a transfusion, using a 1:1 match on propensity score. RESULTS: In the matched cohorts, all observed covariates were comparable between anemic (n = 147) versus nonanemic (n = 147) and between transfused (n = 67) versus nontransfused patients (n = 67). Anemia was independently associated with prolonged hospital length of stay (LOS; odds ratio [OR] 2.5, 95% confidence interval [CI] 1.4-4.5), perioperative complications (OR 1.9, 95% CI 1.1-3.1), and return to the operating room (OR 2.1, 95% CI 1.1-4.5). Transfusion was also independently associated with perioperative complications (OR 2.4, 95% CI 1.1-5.3). CONCLUSIONS: Preoperative anemia and transfusion are each independent risk factors for perioperative complications in patients undergoing surgery for cerebral aneurysms. Perioperative anemia is also associated with prolonged hospital LOS and 30-day return to the operating room.