Repetitive head impacts and chronic traumatic encephalopathy are associated with TDP-43 inclusions and hippocampal sclerosis.

Hippocampal sclerosis (HS) is associated with advanced age as well as transactive response DNA-binding protein with 43 kDa (TDP-43) deposits. Both hippocampal sclerosis and TDP-43 proteinopathy have also been described in chronic traumatic encephalopathy (CTE), a neurodegenerative disease linked to exposure to repetitive head impacts (RHI). However, the prevalence of HS in CTE, the pattern of TDP-43 pathology, and associations of HS and TDP-43 with RHI are unknown. A group of participants with a history of RHI and CTE at autopsy (n = 401) as well as a group with HS-aging without CTE (n = 33) was examined to determine the prevalence of HS and TDP-43 inclusions in CTE and to compare the clinical and pathological features of HS and TDP-43 inclusions in CTE to HS-aging. In CTE, HS was present in 23.4%, and TDP-43 inclusions were present in 43.3% of participants. HS in CTE occurred at a relatively young age (mean 77.0 years) and was associated with a greater number of years of RHI than CTE without HS adjusting for age (p = 0.029). In CTE, TDP-43 inclusions occurred frequently in the frontal cortex and occurred both with and without limbic TDP-43. Additionally, structural equation modeling demonstrated that RHI exposure years were associated with hippocampal TDP-43 inclusions (p < 0.001) through increased CTE stage (p < 0.001). Overall, RHI and the development of CTE pathology may contribute to TDP-43 deposition and hippocampal sclerosis.

Severe Neurological Toxicity of Immune Checkpoint Inhibitors: Growing Spectrum.

Expanding use of immune-checkpoint inhibitors (ICIs) underscores the importance of accurate diagnosis and timely management of neurological immune-related adverse events (irAE-N). We evaluate the real-world frequency, phenotypes, co-occurring immune-related adverse events (irAEs), and long-term outcomes of severe, grade III to V irAE-N at a tertiary care center over 6 years. We analyze how our experience supports published literature and professional society guidelines. We also discuss these data with regard to common clinical scenarios, such as combination therapy, ICI rechallenge and risk of relapse of irAE-N, and corticosteroid taper, which are not specifically addressed by current guidelines and/or have limited data. Recommendations for management and future irAE-N reporting are outlined. ANN NEUROL 2020;87:659-669.

Clinical presentation, management, and biomarkers of neurotoxicity after adoptive immunotherapy with CAR T cells.

Chimeric antigen receptor (CAR) T cells have emerged as a promising class of cell-based immunotherapy in refractory malignancies. Neurotoxicity represents a common and potentially life-threatening adverse effect of CAR T cells, and clinical experience is limited. Here, we describe the clinical presentation and management of 25 adult patients who presented with neurotoxic syndromes after CAR T-cell therapy at the Massachusetts General Hospital. This cohort includes 24 patients treated with CD19-directed CAR T cells for non-Hodgkin lymphoma (n = 23) and acute lymphoblastic leukemia (n = 1), and 1 patient treated with α-fetoprotein-directed CAR T cells for hepatocellular carcinoma (n = 1). Twelve of the 25 patients (48%) developed grade 1-2 neurotoxicity and 13 patients (52%) presented with grade 3-4 neurotoxicity. We found that lower platelet counts at time of CAR T-cell infusion were associated with more severe neurotoxicity (P = .030). Cytokine release syndrome occurred in 24 of 25 patients (96%). Serum levels of ferritin peaked with onset of neurologic symptoms, and higher ferritin levels were associated with higher neurotoxicity grade. Grade 3-4 neurotoxicity correlated negatively with overall survival (OS) (P = .013). Median OS of the entire cohort was 54.7 weeks. Eight patients (32%) with grade 3-4 neurotoxicity were deceased at database closure, whereas none died with neurotoxicity grade 1-2. High pretreatment lactate dehydrogenase was frequently encountered in lymphoma patients with grade 3-4 neurotoxicity and correlated negatively with progression-free survival (P = .048). We did not find evidence that steroid use ≥7 days altered the patient's outcome when compared with <7 days of steroids. Management of CAR T cell-mediated neurotoxicity warrants evaluation in prospective clinical trials.

A Simplified Brain Blocking Protocol Optimized for the Diagnosis of Neurodegenerative Disease Saves Time and Money While Preserving Anatomic Relationships.

CONTEXT.­: Postmortem evaluation for neurodegenerative disease is expensive in time and materials. These challenges can be met by implementing simpler sampling protocols while preserving anatomic relations. OBJECTIVE.­: To determine the diagnostic effectiveness and cost-effectiveness of a simplified brain blocking protocol compared with the standard blocking protocol used in our Alzheimer's Disease Research Center (ADRC). DESIGN.­: We prospectively compared the neuropathologic diagnoses established from our standard 19-cassette/19 brain sites ADRC protocol to a simplified 6-cassette/12 brain sites protocol in 52 consecutive cases. The simplified protocol generated 14 slides for comparison to 52 slides from our standard protocol. RESULTS.­: Compared with the ADRC protocol the simplified protocol produced Alzheimer Disease Neuropathologic Changes probability scores that were the same in 50 of 52 cases (r = 0.99). Staging for Lewy pathology was equivalent in 45 of 52 (r = 0.98), scoring for cerebral amyloid angiopathy was equivalent in 48 of 52 (r = 0.97), and grading for arteriolosclerosis was the same in 45 of 52 cases (r = 0.92). Progressive supranuclear palsy (n = 4), multiple system atrophy (n = 2), and corticobasal degeneration (n = 1) could be diagnosed by either protocol independently. The estimated savings per case was 72% or $1744.89 ($2436.37 [ADRC] versus $691.48 [simplified]). CONCLUSIONS.­: The diagnosis of neurodegenerative disease at autopsy can be done accurately with a less expensive, simplified protocol. Our protocol is similar to those of previously published approaches, but it has a simpler organization scheme. This method should be valuable to institutions where autopsy cost considerations may be important.

Intradural extramedullary pleomorphic xanthoastrocytoma: A case report.

BACKGROUND: Pleomorphic xanthoastrocytomas (PXAs) are uncommon intradural and typically intramedullary astrocytic central nervous system tumors. Although they commonly occur supratentorially, they are rarely seen in the spine. CASE DESCRIPTION: A 43-year-old male presented with cervical neck pain and right-sided radicular symptoms. He was found to have an intradural extramedullary mass at the C5-C6 level. The lesion was fully excised and proved to be a PXA. Of interest, the lesion did not recur on postoperative MR imaging studies obtained 7 months later. CONCLUSION: While rare, primary intradural extramedullary spinal PXA has been reported. Here, we review such a lesion occurring in a 43-year-old male who did well following gross total excision of the tumor.

Varied phenotypes and management of immune checkpoint inhibitor-associated neuropathies.

OBJECTIVE: To describe the spectrum, clinical course, and management of neuropathies associated with immune checkpoint inhibitors (ICIs). METHODS: Patients with ICI-related neuropathy (irNeuropathy) were identified and their clinical characteristics compared to neuropathy attributed to cytotoxic agents. RESULTS: We identified 19 patients with irNeuropathies. ICIs included anti-programmed death-1 (PD1), 9; anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA4), 2; and combination of anti-CTLA4 and anti-PD1, 8. Median number of ICI doses prior to neuropathy onset was 4. Rate of neuropathies following ICI therapy was 0.7%. Underlying malignancies included melanoma (n = 15), lung adenocarcinoma (n = 3), and cholangiocarcinoma (n = 1). Neuropathy phenotypes were cranial neuropathies with or without meningitis (n = 7), nonlength-dependent polyradiculoneuropathies with and without cranial nerve involvement (n = 6), small-fiber/autonomic neuropathy (n = 2), ANCA-associated mononeuritis multiplex (n = 1), sensory neuronopathy (n = 1), length-dependent sensorimotor axonal polyneuropathy (n = 1), and neuralgic amyotrophy (n = 1). Immune-related adverse events involving other organ systems were common (58%). Corticosteroid use for management of neuropathy was associated with improvement in median modified Rankin Scale score (1 vs 0, p = 0.001) and Inflammatory Neuropathy Cause and Treatment Disability score (2 vs 0.5, p = 0.012) (Class IV). Significantly higher proportion of irNeuropathies had acute or subacute and nonlength-dependent presentations (p < 0.001) and rate of hospitalization for irNeuropathy was also higher (p = 0.002) compared to toxic neuropathy from chemotherapy. CONCLUSION: Neuropathy is a rare complication of ICIs that often responds to immunosuppression. Recognition of its wide phenotypic spectrum and distinct clinical characteristics and prompt management with corticosteroids may lead to favorable outcomes.

Comparison of direct site endovascular repair utilizing expandable polytetrafluoroethylene stent grafts versus standard vascular shunts in a porcine (Sus scrofa) model.

INTRODUCTION: The small diameter of temporary vascular shunts for vascular trauma management may restrict flow and result in ischemia or early thrombosis. We have previously reported a clinical experience with direct, open surgical reconstruction using expandable polytetrafluoroethylene stent grafts to create a "sutureless" anastomosis as an alternative to standard temporary vascular shunts. We sought to characterize patency and flow characteristics of these grafts compared with standard shunts in a survival model of porcine vascular injury. METHODS: Twelve Yorkshire-cross swine received a 2-cm-long near-circumferential defect in the bilateral iliac arteries. A 14 Fr Argyle shunt was inserted into one randomly assigned artery, with a self-expanding expandable polytetrafluoroethylene stent deployed in the other. At 72 hours, conduit patency was evaluated by angiography. Arterial flow measurements were obtained at baseline, immediately after intervention, and after 72 hours via direct measurement with perivascular flow meters. Blood pressure proximal and distal to the conduits and arterial samples for histopathology were obtained during the terminal procedure. RESULTS: Angiography revealed no difference in patency at 72 hours (p = 1.0). While there was no difference in baseline arterial flow between arteries (p = 0.63), the stent grafts demonstrated significantly improved blood flow compared with shunts both immediately after intervention (390 ± 36 mL/min vs. 265 ± 25 mL/min, p = 0.002) and at 72 hours (261 ± 29 mL/min vs. 170 ± 36 mL/min, p = 0.005). The pressure gradient across the shunts was greater than that of the stent grafts (11.5 mm Hg [interquartile range, 3-19 mm Hg] vs. 3 mm Hg [interquartile range, 3-5 mm Hg], p = 0.013). The speed of deployment was similar between the two devices. CONCLUSIONS: Open "sutureless" direct site repair using commercially available stent grafts to treat vascular injury is a technically feasible strategy for damage control management of peripheral vascular injury and offers increased blood flow when compared with temporary shunts. Furthermore, stent grafts may offer improved durability to extend the window until definitive vascular repair. The combination of these traits may improve outcomes after vascular injury. LEVEL OF EVIDENCE: Epidemiologic/Prognostic, level III.

Automated variable aortic control versus complete aortic occlusion in a swine model of hemorrhage.

BACKGROUND: Future endovascular hemorrhage control devices will require features that mitigate the adverse effects of vessel occlusion. Permissive regional hypoperfusion (PRH) with variable aortic control (VAC) is a novel strategy to minimize hemorrhage and reduce the ischemic burden of complete aortic occlusion (AO). The objective of this study was to compare PRH with VAC to AO in a lethal model of hemorrhage. METHODS: Twenty-five swine underwent cannulation of the supraceliac aorta, with diversion of aortic flow through an automated extracorporeal circuit. After creation of uncontrolled liver hemorrhage, animals were randomized to 90 minutes of treatment: Control (full, unregulated flow; n = 5), AO (no flow; n = 10), and PRH with VAC (dynamic distal flow initiated after 20 minutes of AO; n = 10). In the PRH group, distal flow rates were regulated between 100 and 300 mL/min based on a desired, preset range of proximal mean arterial pressure (MAP). At 90 minutes, damage control surgery, resuscitation, and restoration of full flow ensued. Critical care continued for 4.5 hours or until death. Hemodynamic parameters and markers of ischemia were recorded. RESULTS: Study survival was 0%, 50%, and 90% for control, AO, and VAC, respectively (p < 0.01). During intervention, VAC resulted in more physiologic proximal MAP (84 ± 18 mm Hg vs. 105 ± 9 mm Hg, p < 0.01) and higher renal blood flow than AO animals (p = 0.02). During critical care, VAC resulted in higher proximal MAP (73 ± 8 mm Hg vs. 50 ± 6 mm Hg, p < 0.01), carotid and renal blood flow (p < 0.01), lactate clearance (p < 0.01), and urine output (p < 0.01) than AO despite requiring half the volume of crystalloids to maintain proximal MAP ≥50 mm Hg (p < 0.01). CONCLUSION: Permissive regional hypoperfusion with variable aortic control minimizes the adverse effects of distal ischemia, optimizes proximal pressure to the brain and heart, and prevents exsanguination in this model of lethal hemorrhage. These findings provide foundational knowledge for the continued development of this novel paradigm and inform next-generation endovascular designs.

Partial Resuscitative Endovascular Balloon Occlusion of the Aorta in Swine Model of Hemorrhagic Shock.

BACKGROUND: Complete resuscitative endovascular balloon occlusion of the aorta (C-REBOA) increases proximal mean arterial pressure (MAP) at the cost of distal organ ischemia, limiting the duration of intervention. We hypothesized that partial aortic occlusion (P-REBOA) would maintain a more physiologic proximal MAP and reduce distal tissue ischemia. We investigated the hemodynamic and physiologic effects of P-REBOA vs C-REBOA. STUDY DESIGN: Fifteen swine were anesthetized, instrumented, splenectomized, and subjected to rapid 25% blood volume loss. They were randomized to C-REBOA, P-REBOA, or no intervention (controls). Partial REBOA was created by partially inflating an aortic balloon catheter to generate a 50% blood pressure gradient across the balloon. Hemodynamics were recorded and serum makers of ischemia and inflammation were measured. After 90 minutes of treatment, balloons were deflated to evaluate the immediate effects of reperfusion. End organs were histologically examined. RESULTS: Complete REBOA produced supraphysiologic increases in proximal MAP after hemorrhage compared with more modest augmentation in the P-REBOA group (p < 0.01), with both groups significantly greater than controls (p < 0.01). Less rebound hypotension after balloon deflation was seen in the P-REBOA compared with C-REBOA groups. Complete REBOA resulted in higher serum lactate than both P-REBOA and controls (p < 0.01). Histology revealed early necrosis and disruption of duodenal mucosa in all C-REBOA animals, but none in P-REBOA animals. CONCLUSIONS: In a porcine hemorrhagic shock model, P-REBOA resulted in more physiologically tolerable hemodynamic and ischemic changes compared with C-REBOA. Additional work is needed to determine whether the benefits associated with P-REBOA can both extend the duration of intervention and increase survival.

Extending the golden hour: Partial resuscitative endovascular balloon occlusion of the aorta in a highly lethal swine liver injury model.

BACKGROUND: Combat-injured patients may require rapid and sustained support during transport; however, the prolonged aortic occlusion produced by conventional resuscitative endovascular balloon occlusion of the aorta (REBOA) may lead to substantial morbidity. Partial REBOA (P-REBOA) may permit longer periods of occlusion by allowing some degree of distal perfusion. However, the ability of this procedure to limit exsanguination is unclear. We evaluated the impact of P-REBOA on immediate survival and ongoing hemorrhage in a highly lethal swine liver injury model. METHODS: Fifteen Yorkshire-cross swine were anesthetized, instrumented, splenectomized, and subjected to rapid 10% total blood loss followed by 30% liver amputation. Coagulopathy was created through colloid hemodilution. Randomized swine received no intervention (control), P-REBOA, or complete REBOA (C-REBOA). Central mean arterial pressure (cMAP), carotid blood flow, and blood loss were recorded. Balloons remained inflated in the P-REBOA and C-REBOA groups for 90 minutes followed by graded deflation. The study ended at 180 minutes from onset of hemorrhage or death of the animal. Survival analysis was performed, and data were analyzed using repeated-measures analysis of variance with post hoc pairwise comparisons. RESULTS: Mean survival times in the control, P-REBOA, and C-REBOA groups were, 25 ± 21, 86 ± 40, and 163 ± 20 minutes, respectively (p < 0.001). Blood loss was greater in the P-REBOA group than the C-REBOA or control groups, but this difference was not significant (4,722 ± 224, 3,834 ± 319, 3,818 ± 37 mL, respectively, p = 0.10). P-REBOA resulted in maintenance of near-baseline carotid blood flow and cMAP, while C-REBOA generated extreme cMAP and prolonged supraphysiologic carotid blood flow. Both experimental groups experienced profound decreases in cMAP following balloon deflation. CONCLUSION: In the setting of severe ongoing hemorrhage, P-REBOA increased survival time beyond the golden hour while maintaining cMAP and carotid flow at physiologic levels.

High and intermediate grade ductal carcinoma in-situ of the breast: a comparison of pathologic features in core biopsies and excisions and an evaluation of core biopsy features that may predict a close or positive margin in the excision.

Low and high-grade ductal carcinoma in-situ (DCIS) are known to be highly disparate by a multitude of parameters, including progression potential, immunophenotype, gene expression profile and DNA ploidy. In this study, we analyzed a group of intermediate and high-grade DCIS cases to determine how well the core biopsy predicts the maximal pathology in the associated excisions, and to determine if there are any core biopsy morphologic features that may predict a close (< or = 0.2 cm) or positive margin in the subsequent excision. Forty-nine consecutive paired specimens [core biopsies with a maximal diagnosis of DCIS, and their corresponding excisions, which included 20 and 29 specimens from mastectomies and breast conserving surgeries respectively] were evaluated in detail. In 5 (10%) of 49 cases, no residual carcinoma was found in the excision. In another 4 cases, the changes were diagnostic only of atypical ductal hyperplasia. There were 4 and 3 respective cases of invasive and microinvasive carcinoma out of the 49 excision specimens, for an overall invasion frequency of 14%. In 28 cases where a sentinel lymph node evaluation was performed, only 1 was found to be positive. Among the 40 cases with at least residual DCIS in the excision, there were 5 cases in which comedo-pattern DCIS was present in the excision but not in the core biopsy, attributed to the lower maximal nuclear grade in the biopsy proliferation in 4 cases and the absence of central necrosis in the 5th. For the other main histologic patterns, in 8 (20%) of 40 cases, there were more patterns identified in the core biopsy than in the corresponding excision. For the other 32 cases, 100%, 66%, 50%, 33% and 25% of the number of histologic patterns in the excisions were captured in 35%, 5%, 17.5%, 15% and 7.5% of the preceding core biopsies respectively. Therefore, the core biopsy reflected at least half of the non-comedo histologic patterns in 77.5% of cases. In 6(15%) of the 40 cases, the maximum nuclear grade of the excision (grade 3) was higher than that seen in the core biopsy (grade 2). Overall, however, the maximum nuclear grade in the excision was significantly predicted by maximum nuclear grade in the core biopsy (p = 0.028), with a Phi of 0.347, indicating a moderately strong association. At a size threshold of 2.7 cm, there was no significant association between lesional size and core biopsy features. Furthermore, the clear margin width of the cases with lesional size < or = 2.7 cm (mean 0.69 cm) was not significantly different (p = 0.4) from the cases with lesional size > 2.7 cm (mean 0.56 cm). Finally, among a variety of core biopsy features that were evaluated, including maximum nuclear grade, necrosis, cancerization of lobules, number of tissue cores with DCIS, number of DCIS ducts per tissue core, total DCIS ducts, or comedo-pattern, only necrosis was significantly associated with a positive or close (< or = 0.2 cm) margin on multivariate analysis (Phi of 0.350). It is concluded that a significant change [to invasive disease (14%) or to no residual disease (10%)] is seen in approximately 24% of excisions that follow a core biopsy diagnosis of intermediate or high-grade DCIS. Core biopsy features are of limited value in predicting a close or positive margin in these lesions.