A Case of Malignant Transformation of an Orbital Epidermoid Cyst to Cystic Squamous Cell Carcinoma.

Squamous cell carcinoma of the orbit is uncommon as there is no squamous epithelium in the orbit. Thus, mechanistically squamous cell carcinoma of the orbit most commonly arises from a cutaneous lesion. Although orbital epidermoid cysts are thought to have very low malignant potential, these lesions possess squamous epithelium and theoretically can undergo malignant transformation. Here we present the case of a 63-year-old woman who presented with a 3-month history of diplopia and forehead tenderness with an orbital extraconal lesion on MRI consistent with a ruptured epidermoid cyst. Six months following resection, she suddenly experienced new-onset left upper eyelid ptosis, recurrent diplopia, and left orbital pain. MRI revealed a recurrence of the left orbital mass. Left anterior orbitotomy and biopsy revealed cystic squamous cell carcinoma. This case appears to demonstrate a very rare malignant transformation of an epidermoid cyst to cystic squamous cell carcinoma.

Interfacility Ambulance Versus Helicopter Transport of Traumatic Spinal Cord Injury Patients: Outcomes, Observations, and Utilization.

INTRODUCTION: Traumatic spinal cord injury (tSCI) is a devastating event that can cause permanent loss of function or disability. Time to surgical decompression of the spinal cord affects outcomes and is a critical principle in management of tSCI. One of the major determinants of time to decompression is transport time. To date, no study has compared the neurological outcomes of tSCI patients transported via ground/ambulance versus air/helicopter. OBJECTIVE: This retrospective cohort study sought to assess the association of the mode of transport on the neurological outcomes of tSCI patients. METHODS: Data from 46 ground transport and 29 air transport patients with tSCI requiring surgical decompression were collected. Outcomes were assessed by the change in American Spinal Injury Association Impairment Scale (AIS) grade from admission to discharge. Additionally, the utilization of air versus ground transport was assessed based on the distance from the admitting institution. RESULTS: Among the transport groups, there were no significant differences (PP < 0.05) in patient demographics. Helicopter transport patients demonstrated higher rates of AIS grade improvement (P = 0.004), especially among AIS grade A/grade B patients (P = 0.02; P = 0.02, respectively), compared to the ambulance transport group. Additionally, within the cohort of patients undergoing decompression within 0 to 12 hours, helicopter transport was associated with higher AIS grade improvement (P = 0.04) versus the ambulance transport group. Helicopter transport was used more frequently at distances greater than 80 miles from the admitting institution (P = 0.01). CONCLUSIONS: This study suggests that helicopter transport of tSCI patients requiring surgical decompression was associated with improved neurological outcomes compared to patients transported via ambulance.

EGFRVIII and EGFR targeted chimeric antigen receptor T cell therapy in glioblastoma.

Glioblastoma is the most common primary brain tumor. Although there have been significant advances in surgical techniques, chemo and immunotherapies, and radiation therapy, outcomes continue to be devastating for these patients with minimal improvements in survival. Chimeric antigen receptor T cell therapy is a revolutionary approach that is a new pillar in the treatment of cancer. CAR T cell therapy has produced remarkable results in hematological malignancies; however, multiple limitations currently prevent it from being a first-line therapy, especially for solid tumors. Epidermal growth factor receptor is classically amplified in glioblastoma, and a variant, EGFR variant III, is expressed on glioblastoma, making it an exciting potential target for CAR T cell therapy. Although preclinical has exciting potential, clinical data has been heterogeneous. In this review, we assess the state of field of EGFR-targeted CAR T cells.

Management of a challenging dura-embedded anterior inferior cerebellar artery loop during a retrosigmoid hearing-preserving vestibular schwannoma resection: microsurgical technique and operative video. Illustrative case.

BACKGROUND: Anatomical variants of the anterior inferior cerebellar artery (AICA), such as an anomalous "AICA loop" embedded in the dura and bone of the subarcuate fossa, increase the complexity and risk of vestibular schwannoma resections. Classically, osseous penetrating AICA loops are the most challenging to mobilize, as the dura must be dissected and the surrounding petrous bone must be drilled to mobilize the AICA away from the surgical corridor and out of harm. OBSERVATIONS: The authors present a rare case of a dura-embedded, osseous-penetrating AICA loop encountered during a hearing-preserving retrosigmoid approach in which they demonstrate safe and efficient microdissection and mobilization of the AICA loop without having to drill the surrounding bone. LESSONS: Although preoperative recognition of potentially dangerous AICA loops has been challenging, thin-sliced petrous bone computed tomography scanning and high-quality magnetic resonance imaging can be useful in preoperative diagnosis. Furthermore, this report suggests that a retrosigmoid approach is superior, as it allows early intradural recognition and proximal vascular control and facilitates more versatile mobilization of AICA loops.

Microneurosurgical treatment of a small perimesencephalic pure pial arterial malformation: an under-recognized etiology of angiographically occult subarachnoid hemorrhage. Illustrative case.

BACKGROUND: Pial arterial malformations (PAMs) are rare vascular lesions consisting of dilated tortuous arteries without venous drainage. Current PAM understanding is limited by the lesion's rarity, limited anatomopathological studies, and frequent misclassifications. OBSERVATIONS: A 23-year-old male experienced two spontaneous subarachnoid hemorrhages (SAHs) over 6 months with initially unremarkable diagnostic cerebral angiograms. Magnetic resonance imaging (MRI) and angiography after the second SAH revealed a small perimesencephalic ovoid lesion within the left crural cistern, between the left superior and posterior cerebral arteries, appearing to be an exophytic cavernoma, a thrombosed aneurysm, or a hemorrhagic tumor. Microsurgical resection was achieved with a pterional craniotomy and anterior clinoidectomy. The resected lesion was characteristic of a pure PAM arising from superior cerebellar arterial branches. LESSONS: Small pure PAMs can be deceitfully dynamic lesions causing episodes of hemorrhage, complete thrombosis (angiographically occult), recanalization, and rehemorrhage. Small thrombosed vascular malformations or aneurysms should be included in differential diagnoses of angiographically occult SAH. MRI can be diagnostic, but the true angioarchitecture can only be elucidated with microneurosurgery. The only definitive cure is removal. The microneurosurgical strategy should account for worst-case scenarios, provide adequate skull base exposures, and include bypass revascularization options when thrombosed aneurysms are encountered.

Delays in Presentation After Traumatic Spinal Cord Injury-A Systematic Review.

BACKGROUND: Prompt surgical decompression after traumatic spinal cord injury (TSCI) may be associated with improved sensorimotor outcomes. Delays in presentation may prevent timely decompression after TSCI. OBJECTIVE: To systematically review existing studies investigating delays in presentation after TSCI in low- and middle-income countries (LMICs) and high-income countries (HICs). METHODS: A systematic review was conducted and studies featuring quantitative or qualitative data on prehospital delays in TSCI presentation were included. Studies lacking quantitative or qualitative data on prehospital delays in TSCI presentation, case reports or series with <5 patients, review articles, or animal studies were excluded from our analysis. RESULTS: After exclusion criteria were applied, 24 studies were retained, most of which were retrospective. Eleven studies were from LMICs and 13 were from HICs. Patients with TSCI in LMICs were younger than those in HICs, and most patients were male in both groups. A greater proportion of patients with TSCI in studies from LMICs presented >24 hours after injury (HIC average proportion, 12.0%; LMIC average proportion, 49.9%; P = 0.01). Financial barriers, lack of patient awareness and education, and prehospital transportation barriers were more often cited as reasons for delays in LMICs than in HICs, with prehospital transportation barriers cited as a reason for delay by every LMIC study included in this review. CONCLUSIONS: Disparities in prehospital infrastructure between HICs and LMICs subject more patients in LMICs to increased delays in presentation to care.

Early Decompression and Short Transport Time After Traumatic Spinal Cord Injury are Associated with Higher American Spinal Injury Association Impairment Scale Conversion.

STUDY DEIGN: Retrospective cohort study. OBJECTIVES: This retrospective cohort study aims to determine the association of early decompressive surgery and the impact of transport time on the neurological outcomes of traumatic spinal cord injury (tSCI) patients. SUMMARY OF BACKGROUND DATA: tSCI is a catastrophic event that may result in permanent disability or loss of function. To date, there remains significant controversy over the optimal time for surgical decompression in tSCI patients. The aim of this study is to evaluate the neurological outcomes of tSCI patients undergoing early versus late surgical decompression and the impact of transport time on neurological outcomes. METHODS: Data from 84 patients with tSCI requiring surgical decompression was collected. Regression analysis was used to establish time to decompression classification cutoffs. Patients were classified into the following subgroups: 0 to 12 or >12 hours as a factor of the total or admitting hospital time to decompression. The change in American Spinal Injury Association Impairment (AIS) Grade from admission to discharge was determined. Additionally, the effect of transport time on conversion of AIS grade was assessed as patients were grouped into transport times of <6 or >6 hours. RESULT: Among the time to decompression subgroups there were no significant differences (P > 0.05) in confounding factors such as age, injury severity, and AIS grade. Patients who received decompression within 0 to 12 hours were associated with significantly (P < 0.0001) higher average improvements in ASIA grade (0.76). Patient transport times <6 hours were associated with significantly (P = 0.004) higher conversion of AIS grade to less impaired states. CONCLUSION: The present study suggests an association of decompression within 12 hours and short transport times (<6 hours) with significant improvements in neurological outcomes.Level of Evidence: 4.

Immune effector cell associated neurotoxicity syndrome in chimeric antigen receptor-T cell therapy.

Chimeric antigen receptor (CAR)-T cell therapy is an emerging staple in the treatment of certain hematological malignancies. While CAR-T cells have produced robust responses in certain hematological malignancies, toxicities associated with the therapy have limited their use. Immune Effector Cell Associated Neurotoxicity Syndrome (ICANS) is a potentially life-threatening neurotoxicity that commonly occurs with CAR-T cell therapy. Here we will discuss ICANS, its treatment, possible mechanisms, and potential solutions to this critical limitation of CAR-T cell therapy. As the field of CAR-T cell therapy evolves, improved treatments and methods to circumvent or overcome ICANS are necessary to improve morbidity, mortality, and decrease the cost of CAR-T cell therapy. This serious, life-threatening side effect needs to be studied to better understand its mechanisms and develop treatments and alternative strategies.

Immune response following traumatic spinal cord injury: Pathophysiology and therapies.

Traumatic spinal cord injury (SCI) is a devastating condition that is often associated with significant loss of function and/or permanent disability. The pathophysiology of SCI is complex and occurs in two phases. First, the mechanical damage from the trauma causes immediate acute cell dysfunction and cell death. Then, secondary mechanisms of injury further propagate the cell dysfunction and cell death over the course of days, weeks, or even months. Among the secondary injury mechanisms, inflammation has been shown to be a key determinant of the secondary injury severity and significantly worsens cell death and functional outcomes. Thus, in addition to surgical management of SCI, selectively targeting the immune response following SCI could substantially decrease the progression of secondary injury and improve patient outcomes. In order to develop such therapies, a detailed molecular understanding of the timing of the immune response following SCI is necessary. Recently, several studies have mapped the cytokine/chemokine and cell proliferation patterns following SCI. In this review, we examine the immune response underlying the pathophysiology of SCI and assess both current and future therapies including pharmaceutical therapies, stem cell therapy, and the exciting potential of extracellular vesicle therapy.

Unique Presentation of Bortezomib-Associated Thrombotic Microangiopathy Responsive to Therapeutic Plasma Exchange and Eculizumab Therapy.

Thrombotic microangiopathies (TMA) are a rare group of life-threatening hematological conditions characterized by thrombocytopenia and microangiopathic hemolytic anemia. Although our understanding of the pathophysiology and the availability of diagnostic testing has improved for primary TMAs, such as thrombotic thrombocytopenic purpura, the pathophysiology underlying secondary TMAs, including drug-induced TMAs (DITMAs), remains less clear. In this case report, we present the unique case of a patient with a history of multiple myeloma that presented four months after the initiation of bortezomib therapy with a bortezomib-associated TMA that responded to therapeutic plasma exchange (TPE) with plasma replacement and eculizumab therapy. This case demonstrates the possible utility of TPE with plasma replacement and eculizumab therapy in DITMA patients that fail to respond following a trial of holding the suspected medication.

CAR-T cell therapy: current limitations and potential strategies.

Chimeric antigen receptor (CAR)-T cell therapy is a revolutionary new pillar in cancer treatment. Although treatment with CAR-T cells has produced remarkable clinical responses with certain subsets of B cell leukemia or lymphoma, many challenges limit the therapeutic efficacy of CAR-T cells in solid tumors and hematological malignancies. Barriers to effective CAR-T cell therapy include severe life-threatening toxicities, modest anti-tumor activity, antigen escape, restricted trafficking, and limited tumor infiltration. In addition, the host and tumor microenvironment interactions with CAR-T cells critically alter CAR-T cell function. Furthermore, a complex workforce is required to develop and implement these treatments. In order to overcome these significant challenges, innovative strategies and approaches to engineer more powerful CAR-T cells with improved anti-tumor activity and decreased toxicity are necessary. In this review, we discuss recent innovations in CAR-T cell engineering to improve clinical efficacy in both hematological malignancy and solid tumors and strategies to overcome limitations of CAR-T cell therapy in both hematological malignancy and solid tumors.

Identifying novel ovarian tumor biomarkers through mining of the transcriptome of circulating immune cells: A proof-of-concept study.

OBJECTIVE: Treatment of high-grade serous ovarian cancer (HGSOC) will benefit from early detection of cancer. Here, we provide proof-of-concept data supporting the hypothesis that circulating immune cells, because of their early recognition of tumors and the tumor microenvironment, can be considered for biomarker discovery. METHODS: Longitudinal blood samples from C57BL/6 mice bearing syngeneic ovarian tumors and peripheral blood mononuclear cells (PBMC) from healthy postmenopausal women and newly diagnosed for HGSOC patients were subjected to RNASeq. The results from human immune cells were validated using Affymetrix microarrays. Differentially expressed transcripts in immune cells from tumor-bearing mice and HGSOC patients were compared to matching controls. RESULTS: A total of 1282 transcripts (798 and 484, up- and downregulated, respectively) were differentially expressed in the tumor-bearing mice as compared with controls. Top 100 genes showing longitudinal changes in gene expression 2, 4, 7, and 18 days after tumor implantation were identified. Analysis of the PBMC from healthy post-menopausal women and HGSOC patients identified 4382 differentially expressed genes and 519 of these were validated through Affymetrix microarray analysis. A total of 384 genes, including IL-1R2, CH3L1, Infitm1, FP42, CXC42, Hdc, Spib, and Sema6b, were differentially expressed in the human and mouse datasets. CONCLUSION: The PBMC transcriptome shows longitudinal changes in response to the progressing tumor. Several potential biomarker transcripts were identified in HGSOC patients and mouse models. Monitoring their expression in individual PBMC subsets can serve as additional discriminator for the diagnosis of HGSOC.

Cellular therapies for chronic ischemic heart failure.

The development of stem cell therapies for chronic ischemic heart failure is highly sought after to attempt to improve morbidity and mortality of this prevalent disease. This article reviews clinical trials that investigate stem cell therapy for chronic ischemic heart failure. To generate this review article, PubMed was searched using keywords "stem cell therapy heart failure" with the article type "Clinical Trial" selected on 10/04/2016. The raw search yielded 156 articles; 53 articles were selected for inclusion in the review between the original literature search and manual research/cross-referencing. Additional reviews and original articles were also manually researched and cross-referenced. Cellular-based therapies utilizing peripheral blood progenitor cells, bone marrow cells, mesenchymal stem cells, cells of cardiac origin, and embryonic stem cells have yielded mixed results, but some studies have shown modest efficacy. Skeletal myoblasts raised concerns about safety due to arrhythmias. Optimizing cell type and delivery method will be of critical importance in enhancing efficacy of therapy within various subsets of chronic ischemic heart failure patients. Although much more work needs to be done to optimize treatment strategies, developing stem cell therapies for chronic ischemic heart failure could be of critical importance to lessen the impactful health burden that heart failure has on patients and society.

Backbone and side-chain chemical shift assignments for the C-terminal domain of Tcb2, a cytoskeletal calcium-binding protein from Tetrahymena thermophila.

Tcb2 is a putative calcium-binding protein from the membrane-associated cytoskeleton of the ciliated protozoan Tetrahymena thermophila. It has been hypothesized to participate in several calcium-mediated processes in Tetrahymena, including ciliary movement, cell cortex signaling, and pronuclear exchange. Sequence analysis suggests that the protein belongs to the calmodulin family, with N- and C-terminal domains connected by a central linker, and two helix-loop-helix motifs in each domain. However, its calcium-binding properties, structure and precise biological function remain unknown. Interestingly, Tcb2 is a major component of unique contractile fibers isolated from the Tetrahymena cytoskeleton; in these fibers, addition of calcium triggers an ATP-independent type of contraction. Here we report the (1)H, (13)C and (15)N backbone and side-chain chemical shift assignments of the C-terminal domain of the protein (Tcb2-C) in the absence and presence of calcium ions. (1)H-(15)N HSQC spectra show that the domain is well folded both in the absence and presence of calcium, and undergoes a dramatic conformational change upon calcium addition. Secondary structure prediction from chemical shifts reveals an architecture encountered in other calcium-binding proteins, with paired EF-hand motifs connected by a flexible linker. These studies represent a starting point for the determination of the high-resolution solution structure of Tcb2-C at both low and high calcium levels, and, together with additional structural studies on the full-length protein, will help establish the molecular basis of Tcb2 function and unique contractile properties.