Vitamin D Receptor Antagonist MeTC7 Inhibits PD-L1.

Small-molecule inhibitors of PD-L1 are postulated to control immune evasion in tumors similar to antibodies that target the PD-L1/PD-1 immune checkpoint axis. However, the identity of targetable PD-L1 inducers is required to develop small-molecule PD-L1 inhibitors. In this study, using chromatin immunoprecipitation (ChIP) assay and siRNA, we demonstrate that vitamin D/VDR regulates PD-L1 expression in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) cells. We have examined whether a VDR antagonist, MeTC7, can inhibit PD-L1. To ensure that MeTC7 inhibits VDR/PD-L1 without off-target effects, we examined competitive inhibition of VDR by MeTC7, utilizing ligand-dependent dimerization of VDR-RXR, RXR-RXR, and VDR-coactivators in a mammalian 2-hybrid (M2H) assay. MeTC7 inhibits VDR selectively, suppresses PD-L1 expression sparing PD-L2, and inhibits the cell viability, clonogenicity, and xenograft growth of AML cells. MeTC7 blocks AML/mesenchymal stem cells (MSCs) adhesion and increases the efferocytotic efficiency of THP-1 AML cells. Additionally, utilizing a syngeneic colorectal cancer model in which VDR/PD-L1 co-upregulation occurs in vivo under radiation therapy (RT), MeTC7 inhibits PD-L1 and enhances intra-tumoral CD8+T cells expressing lymphoid activation antigen-CD69. Taken together, MeTC7 is a promising small-molecule inhibitor of PD-L1 with clinical potential.

Model-based image updating in deep brain stimulation with assimilation of deep brain sparse data.

BACKGROUND: Accuracy of electrode placement for deep brain stimulation (DBS) is critical to achieving desired surgical outcomes and impacts the efficacy of treating neurodegenerative diseases. Intraoperative brain shift degrades the accuracy of surgical navigation based on preoperative images. PURPOSE: We extended a model-based image updating scheme to address intraoperative brain shift in DBS surgery and improved its accuracy in deep brain. METHODS: We evaluated 10 patients, retrospectively, who underwent bilateral DBS surgery and classified them into groups of large and small deformation based on a 2 mm subsurface movement threshold and brain shift index of 5%. In each case, sparse brain deformation data were used to estimate whole brain displacements and deform preoperative CT (preCT) to generate updated CT (uCT). Accuracy of uCT was assessed using target registration errors (TREs) at the Anterior Commissure (AC), Posterior Commissure (PC), and four calcification points in the sub-ventricular area by comparing their locations in uCT with their ground truth counterparts in postoperative CT (postCT). RESULTS: In the large deformation group, TREs were reduced from 2.5 mm in preCT to 1.2 mm in uCT (53% compensation); in the small deformation group, errors were reduced from 1.25 to 0.74 mm (41%). Average reduction of TREs at AC, PC and pineal gland were significant, statistically (p ⩽ 0.01). CONCLUSIONS: With more rigorous validation of model results, this study confirms the feasibility of improving the accuracy of model-based image updating in compensating for intraoperative brain shift during DBS procedures by assimilating deep brain sparse data.

First demonstration of a novel nerve-targeting fluorophore in a cohort of ex vivo human tissues.

Iatrogenic nerve injury is a common complication across all surgical specialties. Better nerve visualization and identification during surgery will improve outcomes and reduce nerve injuries. The Gibbs Laboratory at Oregon Health and Science University has developed a library of near-infrared, nerve-specific fluorophores to highlight nerves intraoperatively and aid surgeons in nerve identification and visualization; the current lead agent is LGW16-03. Prior to this study, testing of LGW16-03 was restricted to animal models; therefore, it was unknown how LGW16-03 performs in human tissue. To advance LGW16-03 to clinic, we sought to test this current lead agent in ex vivo human tissues from a cohort of patients and determine if the route of administration affects LGW16-03 fluorescence contrast between nerves and adjacent background tissues (muscle and adipose). LGW16-03 was applied to ex vivo human tissue from lower limb amputations via two strategies: (1) systemic administration of the fluorophore using our first-in-kind model for fluorophore testing, and (2) topical application of the fluorophore. Results showed no statistical difference between topical and systemic administration. However, in vivo human validation of these findings is required.

Digital Spatial Profiling for Characterization of the Microenvironment in Adult-Type Diffusely Infiltrating Glioma.

Diffusely infiltrating gliomas are associated with high morbidity and mortality due to the infiltrative nature of tumor spread. They are morphologically complex tumors, with a high degree of proteomic variability across both the tumor itself and its heterogenous microenvironment. The malignant potential of these tumors is enhanced by the dysregulation of proteins involved in several key pathways, including processes that maintain cellular stability and preserve the structural integrity of the microenvironment. Although there have been numerous bulk and single-cell glioma analyses, there is a relative paucity of spatial stratification of these proteomic data. Understanding differences in spatial distribution of tumorigenic factors and immune cell populations between the intrinsic tumor, invasive edge, and microenvironment offers valuable insight into the mechanisms underlying tumor proliferation and propagation. Digital spatial profiling (DSP) represents a powerful technology that can form the foundation for these important multilayer analyses. DSP is a method that efficiently quantifies protein expression within user-specified spatial regions in a tissue specimen. DSP is ideal for studying the differential expression of multiple proteins within and across regions of distinction, enabling multiple levels of quantitative and qualitative analysis. The DSP protocol is systematic and user-friendly, allowing for customized spatial analysis of proteomic data. In this experiment, tissue microarrays are constructed from archived glioblastoma core biopsies. Next, a panel of antibodies is selected, targeting proteins of interest within the sample. The antibodies, which are preconjugated to UV-photocleavable DNA oligonucleotides, are then incubated with the tissue sample overnight. Under fluorescence microscopy visualization of the antibodies, regions of interest (ROIs) within which to quantify protein expression are defined with the samples. UV light is then directed at each ROI, cleaving the DNA oligonucleotides. The oligonucleotides are microaspirated and counted within each ROI, quantifying the corresponding protein on a spatial basis.

PTEN Regulates Dendritic Arborization by Decreasing Microtubule Polymerization Rate.

Phosphatase and tensin homolog (PTEN) is a major negative regulator of the phosphatidylinositol-3-kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) pathway. Loss-of-function mutations in PTEN have been found in a subset of patients with macrocephaly and autism spectrum disorder (ASD). PTEN loss in neurons leads to somal hypertrophy, aberrant migration, dendritic overgrowth, increased spine density, and hyperactivity of neuronal circuits. These neuronal overgrowth phenotypes are present on Pten knock-out (KO) and reconstitution with autism-associated point mutations. The mechanism underlying dendritic overgrowth in Pten deficient neurons is unclear. In this study, we examined how Pten loss impacts microtubule (MT) dynamics in both sexes using retroviral infection and transfection strategies to manipulate PTEN expression and tag the plus-end MT binding protein, end-binding protein 3 (EB3). We found Pten KO neurons sprout more new processes over time compared with wild-type (WT) neurons. We also found an increase in MT polymerization rate in Pten KO dendritic growth cones. Reducing MT polymerization rate to the WT level was sufficient to reduce dendritic overgrowth in Pten KO neurons in vitro and in vivo Finally, we found that rescue of dendritic overgrowth via inhibition of MT polymerization was sufficient to improve the performance of Pten KO mice in a spatial memory task. Taken together, our data suggests that one factor underlying PTEN loss dependent dendritic overgrowth is increased MT polymerization. This opens the possibility for an intersectional approach targeting MT polymerization and mTOR with low doses of inhibitors to achieve therapeutic gains with minimal side effects in pathologies associated with loss of neuronal PTEN function.SIGNIFICANCE STATEMENT Loss of Pten function because of genetic deletion or expression of mutations associated with autism spectrum disorder (ASD), results in overgrowth of neurons including increased total dendritic length and branching. We have discovered that this overgrowth is accompanied by increased rate of microtubule (MT) polymerization. The increased polymerization rate is insensitive to acute inhibition of mechanistic target of rapamycin (mTOR)C1 or protein synthesis. Direct pharmacological inhibition of MT polymerization can slow the polymerization rate in Pten knock-out (KO) neurons to rates seen in wild-type (WT) neurons. Correction of the MT polymerization rate rescues increased total dendritic arborization and spatial memory. Our studies suggest that phosphatase and tensin homolog (PTEN) inhibits dendritic growth through parallel regulation of protein synthesis and cytoskeletal polymerization.

Durable Response to Brentuximab Vedotin Plus Cyclophosphamide, Doxorubicin, and Prednisone (BV-CHP) in a Patient with CD30-Positive PTCL Arising as a Post-Transplant Lymphoproliferative Disorder (PTLD).

T-cell PTLDs are lymphoid proliferations that develop in recipients of SOT or allogeneic HSCT. They carry an extremely poor prognosis with a reported median survival of only 6 months. The infrequency with which they are encountered makes treatment a challenge due to the lack of prospective trials to guide management. The significantly higher risk of morbidity and mortality in T-cell PTLD, compared to B-cell PTLD, underscores the challenge of treating these patients and the need for new therapeutic options. Brentuximab vedotin, an ADC targeting CD30, is FDA-approved in combination with CHP as front-line treatment for patients with CD30 expressing PTCL. Herein we report a case of CD30-positive T-cell PTLD that was successfully treated with BV-CHP, suggesting the added value of the addition of BV to chemotherapy, contributing to our patient's long and ongoing progression-free survival. To our knowledge, this is the first documented case of successful treatment using BV-CHP for a CD30-positive, EBV-negative, late T-cell PTLD.

Clinical Anatomy of Human Donor C7 Nerve Roots for Surgical Transfer in Patients with Spastic Arm Paralysis.

BACKGROUND: Contralateral C7 (CC7) nerve transfer has successfully restored hand function in patients with spastic hemiplegia from chronic central nervous system injuries. However, little is known about the morphology and anatomy of the donor C7 nerve root in patients undergoing this procedure. This study quantified intraoperative measurements of donor C7 nerve roots during CC7 transfer surgery for spastic hemiplegia in patients treated at a high-volume center to describe observed anatomical variations for successful direct anastomosis. METHODS: A database of images from 21 patients (2 females, 19 males) undergoing CC7 surgery was searched for photographic data that contained a standard ruler measuring donor C7 nerve root length after surgical sectioning and before transfer. Two independent observers analyzed these images and recorded C7 nerve root diameter, length, and branch lengths. RESULTS: Mean (SD) values of donor C7 nerve measurements were length, 53.5 (8.0) mm; diameter, 5.1 (0.9) mm; branch length following surgical sectioning, 18.3 (6.3) mm. Right-sided donor C7 nerve roots yielded significantly longer branches compared with left-sided donor C7 nerve roots (P = 0.01). Other patient factors such as age, sex, or laterality of brain injury did not influence intraoperative anatomy. CONCLUSIONS: We report detailed intraoperative measurements of the donor C7 root during CC7 nerve transfer for spastic hemiplegia. These findings describe existing variation in surgical C7 nerve root anatomy in patients undergoing this procedure and may serve as a general reference for the expected donor C7 length in successful direct anastomosis.

Testosterone Therapy After Prostate Cancer Treatment: A Review of Literature.

INTRODUCTION: Although testosterone therapy (TTh) is the standard practice in otherwise healthy hypogonadal men, this therapy has historically been contraindicated in men with a history of prostate cancer. Recent evidence suggests that there is minimal or no prostate cancer growth in the setting of TTh administration in men definitively treated for non-metastatic prostate cancer. OBJECTIVE: To review the evidence supporting the safety and efficacy of TTh in patients previously treated for localized prostate cancer. METHODS: A literature review of the PubMed database was performed to identify studies evaluating the safety and efficacy of TTh in patients with a history of prostate cancer. Search terms included Testosterone Therapy, Testosterone Replacement Therapy and Radical Prostatectomy, Radiotherapy, External Beam Radiation Therapy, EBRT, Brachytherapy; Prostate Cancer and Hypogonadism, Low Testosterone; Bipolar Androgen Therapy. RESULTS: Available literature provides evidence for the safe application of TTh in patients previously treated for prostate cancer with either radical prostatectomy or radiotherapy. Furthermore, there exists evidence that severely hypogonadal levels of testosterone may lead to worse oncological outcomes. More recent research has begun to elucidate the effectiveness of bipolar androgen deprivation therapy in the treatment of prostate cancer. This mechanism of action increases the level of evidence indicating that the traditional management of maintaining testosterone levels at low levels may no longer be standard of care. TTh likely has a role in improved erectile function and other quality-of-life concerns in patients developing testosterone deficiency after being treated for prostate cancer. CONCLUSIONS: TTh should be offered to select hypogonadal patients who have a history of definitively treated prostate cancer. Adequately designed randomized controlled trials are necessary to confirm the safety and efficacy of TTh in this population. Natale C, Carlos C, Hong J, et al. Testosterone Replacement Therapy After Prostate Cancer Treatment: A Review of Literature. Sex Med Rev 2021;9:393-405.

Juvenile psammomatoid ossifying fibroma of the parietal bone and review of calvarial presentations: illustrative case.

BACKGROUND: Juvenile psammomatoid ossifying fibroma (JPOF) is an uncommon benign fibro-osseous lesion that only rarely presents in the calvaria. OBSERVATIONS: The authors reported a case of JPOF in the left parietal bone of a 20-year-old patient and reviewed the 27 other cases of JPOF occurring in the calvaria as reported in the literature. LESSONS: JPOF rarely presents in the calvaria, and because diagnosis is a histopathologic one, clinicians should consider this entity when presented with a lytic, expansile mass on imaging. Little is known about the molecular mechanisms driving development of JPOF. MDM2 amplification may play a role, although this was not seen in the case presented herein.

Model-Based Image Updating for Brain Shift in Deep Brain Stimulation Electrode Placement Surgery.

OBJECTIVE: The efficacy of deep brain stimulation (DBS) depends on accurate placement of electrodes. Although stereotactic frames enable co-registration of image-based surgical planning and the operative field, the accuracy of electrode placement can be degraded by intra-operative brain shift. In this study, we adapted a biomechanical model to estimate whole brain displacements from which we deformed preoperative CT (preCT) to generate an updated CT (uCT) that compensates for brain shift. METHODS: We drove the deformation model using displacement data derived from deformation in the frontal cortical surface that occurred during the DBS intervention. We evaluated 15 patients, retrospectively, who underwent bilateral DBS surgery, and assessed the accuracy of uCT in terms of target registration error (TRE) relative to a CT acquired post-placement (postCT). We further divided subjects into large (Group L) and small (Group S) deformation groups based on a TRE threshold of 1.6mm. Anterior commissure (AC), posterior commissure (PC) and pineal gland (PG) were identified on preCT and postCT and used to quantify TREs in preCT and uCT. RESULTS: In the group of large brain deformation, average TREs for uCT were 1.11 ± 0.13 and 1.07 ± 0.38 mm at AC and PC, respectively, compared to 1.85 ± 0.17 and 0.92 ± 0.52 mm for preCT. The model updating approach improved AC localization but did not alter TREs at PC. CONCLUSION: This preliminary study suggests that our image updating method may compensate for brain shift around surgical targets of importance during DBS surgery, although further investigation is warranted before conclusive evidence will be available. SIGNIFICANCE: With further development and evaluation, our model-based image updating method using intraoperative sparse data may compensate for brain shift in DBS surgery efficiently, and have utility in updating targeting coordinates.

Surgical management of Bertolotti's syndrome in two adolescents and literature review.

BACKGROUND: Bertolotti's syndrome is defined by back pain and/or radicular symptoms attributed to a congenital lumbosacral transitional vertebra (LSTV). There are few studies that discuss the surgical management of Bertolotti's syndrome. Here, we report long-term outcomes after resecting a pseudoarthrosis between the sacrum and L5 in two teenage patients, along with a review of literature. CASE DESCRIPTIONS: Surgical resection of a lumbosacral bridging articulation (LSTV type IIa) was performed in two patients, 15 and 16 years of age who presented with intractable back pain. The adequacy of surgery was confirmed with postoperative studies. In both patients, pain and functional status improved within 6 weeks and have remained improved at last follow-up. CONCLUSION: Surgical removal of a pathologic L5 transverse process fused to the sacral ala in two young patients with Bertolotti's syndrome improved postoperative pain and increased overall function. Given the progressive nature of Bertolotti's syndrome, surgical intervention in young patients should be considered to mitigate years of chronic pain and attendant morbidity.

First experience imaging short-wave infrared fluorescence in a large animal: indocyanine green angiography of a pig brain.

The potential to image subsurface fluorescent contrast agents at high spatial resolution has facilitated growing interest in short-wave infrared (SWIR) imaging for biomedical applications. The early but growing literature showing improvements in resolution in small animal models suggests this is indeed the case, yet to date, images from larger animal models that more closely recapitulate humans have not been reported. We report the first imaging of SWIR fluorescence in a large animal model. Specifically, we imaged the vascular kinetics of an indocyanine green (ICG) bolus injection during open craniotomy of a mini-pig using a custom SWIR imaging instrument and a clinical-grade surgical microscope that images ICG in the near-infrared-I (NIR-I) window. Fluorescence images in the SWIR were observed to have higher spatial and contrast resolutions throughout the dynamic sequence, particularly in the smallest vessels. Additionally, vessels beneath a surface pool of blood were readily visualized in the SWIR images yet were obscured in the NIR-I channel. These first-in-large-animal observations represent an important translational step and suggest that SWIR imaging may provide higher spatial and contrast resolution images that are robust to the influence of blood.

Laparoscopic-Assisted Intra-Abdominal Section of the Lateral Femoral Cutaneous Nerve for Meralgia Paresthetica Following Anterior Hip Arthroplasty.

BACKGROUND: Meralgia paresthetica, a pain syndrome that is caused by injury to the lateral femoral cutaneous nerve, is a well-documented complication after anterior hip arthroplasty (THA). Traditional treatment of this peripheral nerve entrapment syndrome can be complicated in patients who have had THA via an anterior approach owing to the presence of scar in the postoperative bed. CASE DESCRIPTION: In a 70-year-old man, we performed a novel laparoscopic-assisted intra-abdominal approach to treat meralgia paresthetica in the setting of previous anterior THA. CONCLUSIONS: Minimally invasive intra-abdominal treatment of meralgia paresthetica following anterior THA results in durable pain relief. This approach is a helpful alternative to traditional techniques of decompression or section of the lateral femoral cutaneous nerve below the inguinal ligament.

Heterotopic ossification following suboccipital craniectomy decompression surgery for Chiari malformation type I: case report.

Suboccipital craniectomy with duraplasty is a commonly performed procedure for children with symptomatic Chiari malformation type I (CM-I). Several dural substitutes are used for duraplasty, ranging from pericranium to synthetic materials. When available, autologous pericranium is often preferred due to its low cost, performance in obtaining a watertight closure, ease of suturing, and absence of immune reaction. Long-term follow-up data on the durability of various dural substitutes are lacking. The authors report a rare, long-term complication of duraplasty performed using an autologous pericranial graft, and they conduct a literature review of similar complications. Heterotopic ossification of an autologous pericranial graft is a rare complication of duraplasty. This dystrophic bone growth can be symptomatic due to compression of neural structures, and it requires reoperation for removal. Surgeons should consider this rare long-term complication in patients presenting with unusual symptoms after duraplasty with pericranium.

Chronic Cutaneous Lupus Erythematosus: Depression Burden and Associated Factors.

OBJECTIVES: Depression may occur in up to 30% of individuals with cutaneous lupus erythematosus (CLE), many of whom may also have systemic manifestations. Chronic cutaneous lupus erythematosus (CCLE) conditions are less likely to present systemic involvement than acute and subacute conditions but more often cause permanent scarring and dyspigmentation. However, little is known about depression in those who have CCLE confined to the skin (primary CCLE). As African Americans are at high risk for primary CCLE and depression, we aimed to investigate the prevalence of and explore the risk factors for depression in a population-based cohort of predominantly Black patients with primary CCLE. METHODS: This was a cross-sectional analysis of a cohort of individuals with a documented diagnosis of primary CCLE, established in metropolitan Atlanta, GA, USA. Participants were recruited from the Centers for Disease Control and Prevention (CDC) population-based Georgia Lupus Registry, multicenter dermatology clinics, community practices, and self-referrals. The Patient-Reported Outcomes Measurement Information System (PROMIS) was used to measure the primary outcome: depressive symptoms. Stand-alone questions were used to assess sociodemographics and healthcare utilization. Emotional, informational, and instrumental support were measured with PROMIS short forms, interpersonal processes of care with the IPC-29 survey, and skin-related quality of life with the Skindex-29+ tool. RESULTS: Of 106 patients, 92 (86.8%) were female, 91 (85.8%) were Black, 45 (42.9%) were unemployed or disabled, and 28 (26.4%) reported moderate to severe depressive symptoms. Depression severity was lower in patients who were aged ≥ 60 years, were married, or had graduated from college. Univariate analysis showed that being employed (odds ratio [OR] 0.24; 95% confidence interval [CI] 0.10-0.61), insured (OR 0.23; 95% CI 0.09-0.60), reporting higher instrumental, informational, and emotional support (OR 0.75; 95% CI 0.60-0.94; OR 0.62; 95% CI 0.49-0.78; and OR 0.48; 95% CI 0.35-0.65, respectively), visiting a primary care physician in the last year (OR 0.16; 95% CI 0.04-0.61) and reporting better physician-patient interactions (OR 0.56; 95% CI 0.37-0.87) were negatively associated with depression. Patient's perception of staff disrespect (OR 2.30; 95% CI 1.19-4.47) and worse skin-related quality of life (OR 1.04; 95% CI 1.02-1.06) rendered higher risk. In multivariate analysis, only perception of staff disrespect (OR 2.35; 95% CI 1.06-5.17) and lower emotional support (OR 0.48; 95% CI 0.35-0.66) remained associated with depression. CONCLUSION: Over one-quarter of a predominantly Black population-based cohort of individuals with primary CCLE reported moderate to severe depression, a rate three to five times higher than described previously in the general population from the same metropolitan Atlanta area. Our findings suggest that, while patient's perception of discrimination in the healthcare setting may play a role as a determinant of depression, social support may be protective. In addition to routine mental health screening and depression treatment, interventions directed at providing emotional support and improving office staff interpersonal interactions may contribute to reduce the risk of depression in patients with CCLE.

5-Aminolevulinic Acid-Induced Fluorescence in Focal Cortical Dysplasia: Report of 3 Cases.

BACKGROUND: Three patients enrolled in a clinical trial of 5-aminolevulinic-acid (5-ALA)-induced fluorescence-guidance, which has been demonstrated to facilitate intracranial tumor resection, were found on neuropathological examination to have focal cortical dysplasia (FCD). OBJECTIVE: To evaluate in this case series visible fluorescence and quantitative levels of protoporphyrin IX (PpIX) during surgery and correlate these findings with preoperative magnetic resonance imaging (MRI) and histopathology. METHODS: Patients were administered 5-ALA (20 mg/kg) approximately 3 h prior to surgery and underwent image-guided, microsurgical resection of their MRI- and electrophysiologically identified lesions. Intraoperative visible fluorescence was evaluated using an operating microscope adapted with a commercially available blue light module. Quantitative PpIX levels were assessed using a handheld fiber-optic probe and a wide-field imaging spectrometer. Sites of fluorescence measurements were co-registered with both preoperative MRI and histopathological analysis. RESULTS: Three patients with a pathologically confirmed diagnosis of FCD (Types 1b, 2a, and 2b) underwent surgery. All patients demonstrated some degree of visible fluorescence (faint or moderate), and all patients had quantitatively elevated concentrations of PpIX. No evidence of neoplasia was identified on histopathology, and in 1 patient, the highest concentrations of PpIX were found at a tissue site with marked gliosis but no typical histological features of FCD. CONCLUSION: FCD has been found to be associated with intraoperative 5-ALA-induced visible fluorescence and quantitatively confirmed elevated concentrations of the fluorophore PpIX in 3 patients. This finding suggests that there may be a role for fluorescence-guidance during surgical intervention for epilepsy-associated FCD.

A Cohort Study of the Natural History of Odontoid Pseudoarthrosis Managed Nonoperatively in Elderly Patients.

OBJECTIVE: Although the primary goal of treatment of type II odontoid fracture is bony union, some advocate continued nonsurgical management of minimally symptomatic older patients who have fibrous union or minimal fracture motion. The risk of this strategy is unknown. We reviewed our long-term outcomes after dens nonunion to define the natural history of Type II odontoid fractures in elderly patients managed nonoperatively. METHODS: A retrospective chart review of 50 consecutive adults aged 65 or older with Type II odontoid fracture initially managed nonsurgically from 1998 to 2012 at a single tertiary care institution was conducted. Particular attention was paid to patients who had orthosis removal despite absent bony fusion. Patients were contacted prospectively by telephone and followed until death, surgical intervention, or last known contact. RESULTS: Fifty patients initially were managed nonsurgically; of these, 21 (42.0%) proceeded to bony fusion, 3 (6%) underwent delayed surgery for persistent instability, and 26 (52%) had orthosis removal despite the lack of solid arthrodesis on imaging. The last group had a median follow-up of 25 months (range 4-158 months), with 20 of 26 (76.9%) followed until death. Of these patients, 1 patient developed progressive quadriplegia and dysphagia 11 months after initial injury. Compared with patients with spontaneous union, patients with nonunion had shorter life expectancy, despite no significant differences between the groups with respect to age, sex, injury mechanism, radiographic variables, or follow-up duration. CONCLUSIONS: Orthosis removal despite fracture nonunion may be reasonable in elderly patients with Type II dens fractures.

Long-term outcomes after surgical treatment of pediatric neurogenic thoracic outlet syndrome.

OBJECTIVE Neurogenic thoracic outlet syndrome (nTOS) is an uncommon compression syndrome of the brachial plexus that presents with pain, sensory changes, and motor weakness in the affected limb. The authors reviewed the clinical presentations and outcomes in their series of pediatric patients with surgically treated nTOS over a 6-year period. METHODS Cases of nTOS in patients age 18 years or younger were extracted for analysis from a prospective database of peripheral nerve operations. Baseline patient characteristics, imaging and neurophysiological data, operative findings, and outcomes and complications were assessed. RESULTS Twelve patients with 14 cases of nTOS surgically treated between April 2010 and December 2016 were identified. One-third of the patients were male, and 2 male patients underwent staged, bilateral procedures. Disabling pain (both local and radiating) was the most common presenting symptom (100%), followed by numbness (35.7%), then tingling (28.6%). The mean duration of symptoms prior to surgery was 15.8 ± 6.6 months (mean ± SD). Sports-related onset of symptoms was seen in 78.6% of cases. Imaging revealed cervical ribs in 4 cases, prominent C-7 transverse processes in 4 cases, abnormal first thoracic ribs in 2 cases, and absence of bony anomalies in 4 cases. Neurophysiological testing results were normal in 85.7% of cases. Conservative management failed in all patients, with 5 patients reporting minimal improvement in symptoms with physical therapy. With a mean follow-up after surgery of 22 ± 18.3 months (mean ± SD), pain relief was excellent (> 90%) in 8 cases (57.1%), and good (improved > 50%) in 6 cases (42.9%). On univariate analysis, patients who reported excellent pain resolution following surgery at long-term follow-up were found to be significantly younger, and to have suffered a shorter duration of preoperative symptoms than patients who had worse outcomes. Lack of significant trauma or previous surgery to the affected arm was also associated with excellent outcomes. There were 4 minor complications in 3 patients within 30 days of surgery: 1 patient developed a small pneumothorax that resolved spontaneously; 1 patient suffered a transient increase in pain requiring consultation, followed by hiccups for a period of 3 hours that resolved spontaneously; and 1 patient fell at home, with transient increased pain in the surgically treated extremity. There were no new neurological deficits, wound infections, deep vein thromboses, or readmissions. CONCLUSION Pediatric nTOS commonly presents with disabling pain and is more frequently associated with bony anomalies compared with adult nTOS. In carefully selected patients, surgical decompression of the brachial plexus results in excellent pain relief, which is more likely to be seen in younger patients who present for early surgical evaluation.

Fibronectin in Layer-by-Layer Assembled Films Switches Tumor Cells between 2D and 3D Morphology.

Tumor cells showing a 3D morphology and in coculture with endothelial cells are a valuable in vitro model for studying cell-cell interactions and for the development of pharmaceuticals. Here, we found that HepG2 cells, unlike endothelial cells, show differences in adhesion to fibronectin alone, or in combination with poly(allylamine hydrochloride). This response allowed us to engineer micropatterned heterotypic cultures of the two cell types using microfluidics to pattern cell adhesion. The resulting cocultures exhibit spatially encoded and physiologically relevant cell function. Further, we found that the protrusive, migratory and 3D morphological responses of HepG2 are synergistically modulated by the constituents of the hybrid extracellular matrix. Treating the hybrid material with the cross-linking enzyme transglutaminase inhibited 3D morphogenesis of tumor cells. Our results extend previous work on the role of fibronectin in layer-by-layer assembled films, and demonstrate that cell-specific differences in adhesion to fibronectin can be used to engineer tumor cell cocultures.

Surgical management of arrested hydrocephalus: Case report, literature review, and 18-month follow-up.

OBJECTIVE: Arrested hydrocephalus is stable ventriculomegaly without evidence of neurologic deterioration or symptoms. Management of arrested hydrocephalus in asymptomatic adults is controversial, with little clinical data. This case highlights the potential for decompensation in adults with arrested hydrocephalus and reviews the literature regarding pathophysiology and management of this clinical entity. PATIENTS AND METHODS: A 39 year-old gentleman with arrested hydrocephalus incidentally found during work-up for new-onset seizure and managed conservatively for ten years presented with increasing headache, memory loss, gait instability and urinary and fecal incontinence. Stable massive triventriculomegaly was documented on serial brain imaging, and ophthalmologic exam revealed no papilledema. RESULTS: The patient underwent endoscopic third ventriculostomy with immediate post-operative improvement of headache, resolution of incontinence, and cessation of seizures. At 15 months after surgery, neuropsychiatric testing demonstrated improvement in visuomotor skills, problem solving, verbal fluency and cognitive flexibility compared to his pre-operative baseline. At 18 months after surgery he remained seizure free with full continence and significant improvement in headaches. CONCLUSION: Early recognition of arrested hydrocephalus and its potential for decompensation may prompt surgical treatment and prevent neurologic deterioration.