Vertebral Artery to Middle Cerebral Artery Bypass for Flow Augmentation.

BACKGROUND AND IMPORTANCE: Extracranial-intracranial bypass remains an enduring procedure for a select group of patients suffering from steno-occlusive cerebrovascular disease. Although the superficial temporal artery (STA) to middle cerebral artery (MCA) bypass is most familiar among neurosurgeons, particular circumstances preclude the use of an STA donor. In such cases, alternative revascularization strategies must be pursued. CLINICAL PRESENTATION: A 63-year-old female presented with symptoms of hemodynamic insufficiency and was found to have left common carotid artery occlusion at the origin. She experienced progressive watershed ischemia and pressure-dependent fluctuations in her neurological examination despite maximum medical therapy. The ipsilateral STA was unsuitable for use as a donor vessel. We performed an extracranial vertebral artery (VA) to MCA bypass with a radial artery interposition graft. CONCLUSION: This technical case description and accompanying surgical video review the relevant anatomy and surgical technique for a VA-MCA bypass. The patient was ultimately discharged home at her preoperative neurological baseline with patency of the bypass. The VA can serve as a useful donor vessel for cerebral revascularization procedures in pathologies ranging from malignancies of the head and neck to cerebral aneurysms and cerebrovascular steno-occlusive disease.

Hemodynamic outcomes of stenting for vertebrobasilar insufficiency in patients with a low flow state.

INTRODUCTION: The Vertebrobasilar Flow Evaluation and Risk of Transient Ischemic Attack and Stroke (VERiTAS) study determined patients with low flow in their vertebrobasilar (VB) system are at increased risk of recurrent stroke. Endovascular interventions such as angioplasty and stenting are reserved for patients with refractory symptoms; however, few series to date have demonstrated either hemodynamic or clinical outcomes in this high-risk patient group. We present our combined institutional series of patients with symptomatic VB atherosclerotic disease and low-flow state who underwent angioplasty and stenting. METHODS: Retrospective chart review of patients undergoing angioplasty and stenting for symptomatic VB atherosclerotic disease at two institutions was performed. Clinical and radiographical outcomes were collected including flow rates using quantitative MRA (QMRA) pre- and post-stenting. RESULTS: Seventeen patients underwent angioplasty and stenting for symptomatic VB atherosclerotic disease and met VERiTAS low-flow state criteria. There were four cases (23.5%) of periprocedural stroke, two of which were minor and transient. The stent was placed intracranially in 82.4% of patients. Basilar and bilateral posterior cerebral artery (PCA) flows significantly improved post-stenting (p < 0.05) and normalized based upon VERiTAS criteria in all patients. Fourteen patients had delayed QMRA at mean follow-up 20 months demonstrating appropriate patency and flow post-stenting. Two patients (10%) had recurrent stroke, one from medication nonadherence and in-stent thrombosis, and the other from a procedural dissection that subsequently became symptomatic. CONCLUSIONS: Our series demonstrates angioplasty and stenting significantly improve intracranial flow over long-term. Angioplasty and stenting may improve the natural history of low-flow VB atherosclerotic disease.

A persistent trigeminal artery demonstrates cerebrovascular embryologic development.

Background: Cerebrovascular embryologic development is characterized by the presence of four well-described carotid-vertebrobasilar (VB) anastomoses. As the fetal hindbrain matures and the VB system develops, these connections involute, yet some may persist into adulthood. The persistent primitive trigeminal artery (PPTA) is the most common of these anastomoses. In this report, we describe a unique variant of the PPTA and a four-way division of the VB circulation. Case Description: A female in her 70s presented with a Fisher Grade 4 subarachnoid hemorrhage. Catheter angiography revealed a fetal origin of the left posterior cerebral artery (PCA) giving rise to a left P2 aneurysm which was coiled. A PPTA arose from the left internal carotid artery and supplied the distal basilar artery (BA) including the superior cerebellar arteries bilaterally and the right but not left PCA. The mid-BA was atretic and the anterior inferior cerebellar artery-posterior inferior cerebellar artery complexes were fed solely from the right vertebral artery. Conclusion: Our patient's cerebrovascular anatomy represents a unique variant of the PPTA not well described in the literature. This demonstrates how hemodynamic capture of the distal VB territory by a PPTA is sufficient to prevent fusion of the BA.

Transradial flow diversion with an aberrant right subclavian artery.

Transradial access for diagnostic and therapeutic neurointerventional procedures has gained popularity due to a decreased incidence of access site complications and improved patient comfort compared with transfemoral access.1-4 An aberrant right subclavian artery is an aortic arch variant characterized by a right subclavian artery that arises directly from the arch as the most distal great vessel. Transradial access with an aberrant right subclavian artery is anatomically challenging due to the predilection of the catheter system to collapse into the descending aorta. In this (video 1), we describe a step-by-step technique for transradial access in a patient with an aberrant right subclavian artery undergoing endovascular flow diversion for a left superior hypophyseal artery aneurysm. Particular emphasis is placed on the technique for accessing the proximal arch and aortic valve as well as distal catheter navigation while avoiding prolapse into the descending aorta. neurintsurg;15/11/1164/V1F1V1Video 1 .

Accelerated Aging in Cyclophilin B-Deficient Mice Downstream of p21-Cip1/Waf1.

Loss of bone mass and strength is a common problem of advanced age in humans. Defective bone is also a primary finding in osteogenesis imperfecta (OI), a genetic condition most commonly caused by autosomal dominant mutations in the type I collagen genes. Although altered collagen has been proposed to correlate with cellular processes that underlie aging, the causal relationships between them in vivo have not yet been completely explored. Whether aging plays a promoting role in OI development or whether OI contributes to aging, also remains unknown. The PpiB gene encodes cyclophilin B (CypB), a prolyl isomerase residing in the endoplasmic reticulum required for normal assembly of collagen. Germline deletion or mutations of CypB in mice or humans cause autosomal recessive OI (type IX). Here, we show that mice lacking CypB develop early onset of aging-associated phenotypes, including kyphosis, fat reduction and weight loss, as well as abnormal teeth, skin, and muscle. Elevated senescence-associated beta-galactosidase (SA-ß-Gal) activity was observed in fat tissues and in bone marrow-derived multipotent stromal cells. Protein levels of the cyclin-dependent kinase (cdk)-inhibitor p21-Cip1/Waf1, a well known senescence marker, were significantly elevated in CypB-deficient primary cells and mouse tissues. Importantly, loss of p21 in CypB knockout mice attenuated SA-ß-Gal activity and delayed the development of kyphosis. In addition, less adipose tissue depot and higher SA-ß-Gal activity were observed in a second OI model, Cola2 oim mutant mice. A potential upregulation of p21 was also revealed in a limited number of these mice. These findings suggest that some of the features in OI patients may be mediated in part through activation of the p21-dependent pathway, one of which is closely associated with senescence and aging. This study provides new mechanistic insight into relationships between OI and aging and raises the possibility of using senolytics drugs to treat OI in the future. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Phase I trial of sargramostim/pelareorep therapy in pediatric patients with recurrent or refractory high-grade brain tumors.

Background: Brain tumors are the leading cause of cancer death for pediatric patients. Pelareorep, an immunomodulatory oncolytic reovirus, has intravenous efficacy in preclinical glioma models when preconditioned with GM-CSF (sargramostim). We report a phase I trial with the primary goal of evaluating the safety of sargramostim/pelareorep in pediatric patients with recurrent or refractory high-grade brain tumors and a secondary goal of characterizing immunologic responses. Methods: The trial was open to pediatric patients with recurrent or refractory high-grade brain tumors (3 + 3 cohort design). Each cycle included 3 days of subcutaneous sargramostim followed by 2 days of intravenous pelareorep. Laboratory studies and imaging were acquired upon recruitment and periodically thereafter. Results: Six patients participated, including three glioblastoma, two diffuse intrinsic pontine glioma, and one medulloblastoma. Two pelareorep dose levels of 3 × 108 and 5 × 108 tissue culture infectious dose 50 (TCID50) were assessed. One patient experienced a dose limiting toxicity of persistent hyponatremia. Common low-grade (1 or 2) adverse events included transient fatigue, hypocalcemia, fever, flu-like symptoms, thrombocytopenia, and leukopenia. High-grade (3 or 4) adverse events included neutropenia, lymphopenia, leukopenia, hypophosphatemia, depressed level of consciousness, and confusion. All patients progressed on therapy after a median of 32.5 days and died a median of 108 days after recruitment. Imaging at progression did not show evidence of pseudoprogression or inflammation. Correlative assays revealed transient but consistent changes in immune cells across patients. Conclusions: Sargramostim/pelareorep was administered to pediatric patients with recurrent or refractory high-grade brain tumors. Hyponatremia was the only dose limiting toxicity (DLT), though maximum tolerated dose (MTD) was not determined.

Early expression of mature αß TCR in CD4-CD8- T cell progenitors enables MHC to drive development of T-ALL bearing NOTCH mutations.

During normal T cell development in mouse and human, a low-frequency population of immature CD4-CD8- double-negative (DN) thymocytes expresses early, mature αß T cell antigen receptor (TCR). We report that these early αß TCR+ DN (EADN) cells are DN3b-DN4 stage and require CD3δ but not major histocompatibility complex (MHC) for their generation/detection. When MHC - is present, however, EADN cells can respond to it, displaying a degree of coreceptor-independent MHC reactivity not typical of mature, conventional αß T cells. We found these data to be connected with observations that EADN cells were susceptible to T cell acute lymphoblastic leukemia (T-ALL) transformation in both humans and mice. Using the OT-1 TCR transgenic system to model EADN-stage αß TCR expression, we found that EADN leukemogenesis required MHC to induce development of T-ALL bearing NOTCH1 mutations. This leukemia-driving MHC requirement could be lost, however, upon passaging the tumors in vivo, even when matching MHC was continuously present in recipient animals and on the tumor cells themselves. These data demonstrate that MHC:TCR signaling can be required to initiate a cancer phenotype from an understudied developmental state that appears to be represented in the mouse and human disease spectrum.

Microsurgical Clipping of a Ruptured Basilar-P1 Junction Aneurysm.

In current neurosurgical practice, treatment paradigms for posterior circulation aneurysms have shifted away from microsurgical clip ligation toward endovascular therapy. This is largely due to the results of the International Subarachnoid Aneurysm Trial and International Study of Unruptured Intracranial Aneurysms, which, in part, showed that outcomes in patients with ruptured aneurysms were better with coiling and that a location in the posterior circulation was an independent risk factor for poor outcome, respectively.1,2 Nevertheless, there exist certain anatomic features that highlight the importance of a microsurgical approach. These include small size, wide-neck configuration, and the incorporation of perforators, among other factors. In Video 1, we report a case of a 53-year-old male with a ruptured 2 mm × 2 mm right basilar-P1 junction aneurysm. Endovascular options were deemed less favorable due to the small size of the aneurysm and the hemorrhagic complications associated with dual-antiplatelet therapy in the setting of an acute subarachnoid hemorrhage. A standard right-sided orbitozygomatic approach was performed.3 This video highlights the importance of performing microsurgical clipping for posterior circulation aneurysms in an era with increasing reliance on endovascular treatment.

Delayed intracerebral hemorrhage from a traumatic carotid-cavernous fistula associated with an enucleated orbit.

Spontaneous intracerebral hemorrhage (ICH) from a traumatic carotid-cavernous fistula (CCF) is a rare occurrence with few cases reported in the literature. Patients classically present shortly after the inciting trauma with symptoms of ocular venous hypertension. We report a case of an ICH due to delayed rupture of a venous aneurysm from a CCF in a patient with decades-old history of enucleation of the left globe secondary to trauma with no sentinel symptoms. Our patient represents a unique presentation of a rare pathology. This case highlights the need for ongoing surveillance in patients with a history of severe craniofacial trauma, as ICH from ruptured CCF(s) demands emergent treatment due to the potential for rapid neurological deterioration.

TNFRSF13B genotypes control immune-mediated pathology by regulating the functions of innate B cells.

Host genes define the severity of inflammation and immunity but specific loci doing so are unknown. Here we show that TNF receptor superfamily member 13B (TNFRSF13B) variants, which enhance defense against certain pathogens, also control immune-mediated injury of transplants, by regulating innate B cells' functions. Analysis of TNFRSF13B in human kidney transplant recipients revealed that 33% of those with antibody-mediated rejection (AMR) but fewer than 6% of those with stable graft function had TNFRSF13B missense mutations. To explore mechanisms underlying aggressive immune responses, we investigated alloimmunity and rejection in mice. Cardiac allografts in Tnfrsf13b-mutant mice underwent early and severe AMR. The dominance and precocity of AMR in Tnfrsf13b-deficient mice were not caused by increased alloantibodies. Rather, Tnfrsf13b mutations decreased "natural" IgM and compromised complement regulation, leading to complement deposition in allografted hearts and autogenous kidneys. Thus, WT TNFRSF13B and Tnfrsf13b support innate B cell functions that limit complement-associated inflammation; in contrast, common variants of these genes intensify inflammatory responses that help clear microbial infections but allow inadvertent tissue injury to ensue. The wide variation in inflammatory reactions associated with TNFRSF13B diversity suggests polymorphisms could underlie variation in host defense and explosive inflammatory responses that sometimes enhance morbidity associated with immune responses.

TNFRSF13B polymorphisms counter microbial adaptation to enteric IgA.

TNFRSF13B encodes the transmembrane activator and CAML interactor (TACI) receptor, which drives plasma cell differentiation. Although TNFRSF13B supports host defense, dominant-negative TNFRSF13B alleles are common in humans and other species and only rarely associate with disease. We reasoned that the high frequency of disruptive TNFRSF13B alleles reflects balancing selection, the loss of function conferring advantage in some settings. Testing that concept, we investigated how a common human dominant-negative variant, TNFRSF13B A181E, imparts resistance to enteric pathogens. Mice engineered to express mono- or biallelic A144E variants of tnrsf13B, corresponding to A181E, exhibited a striking resistance to pathogenicity and transmission of Citrobacter rodentium, a murine pathogen that models enterohemorrhagic Escherichia coli, and resistance was principally owed to natural IgA deficiency in the intestine. In WT mice with gut IgA and in mutant mice reconstituted with enteric IgA obtained from WT mice, IgA induces LEE expression of encoded virulence genes, which confer pathogenicity and transmission. Taken together, our results show that C. rodentium and most likely other enteric organisms appropriated binding of otherwise protective antibodies to signal induction of the virulence program. Additionally, the high prevalence of TNFRSF13B dominant-negative variants reflects balancing selection.

Intervention for symptomatic vertebrobasilar disease.

Disease of the vertebral (VA) and basilar arteries (BA) can lead to stroke of the posterior circulation and may warrant management strategies which differ from the anterior circulation. The mechanism and location of the disease determine its natural history and therefore affect the relative risks and benefits of the possible treatment options. Vertebrobasilar (VB) atherosclerotic disease is a source of both hemodynamic and embolic posterior circulation stroke. Advances in medical therapy have decreased the rate of stroke after initial symptomatic presentation. Antiplatelet therapy, blood pressure control, and optimization of secondary risk factors can reduce recurrent stroke risk in both intracranial and extracranial VB disease. However, symptomatic intracranial disease is still associated with a high risk of subsequent stroke, particularly those with hemodynamic compromise who represent a higher risk population. Patients with hemodynamic impairment may benefit from judicious application of endovascular and microsurgical interventions to augment blood flow. Stenting, angioplasty alone, bypass surgery, and endarterectomy, represent endovascular and surgical tools available to address medically refractory VB disease. Apart from atherosclerotic disease, dissection is another etiology of VB stroke, most frequently affecting the extracranial VA. Treatment is predominantly antithrombotic therapy although surgical or endovascular intervention can be required in rare cases of persistent embolism or hemodynamic compromise. In contrast, extrinsic compromise of the VA represents a separate extracranial pathology and is best treated with mechanistically targeted surgeries or extracranial bypass.

Cyclophilins A and B oppositely regulate renal tubular epithelial cell phenotype.

Restoration of kidney tubular epithelium following sublethal injury sequentially involves partial epithelial-mesenchymal transition (pEMT), proliferation, and further redifferentiation into specialized tubule epithelial cells (TECs). Because the immunosuppressant cyclosporine-A produces pEMT in TECs and inhibits the peptidyl-prolyl isomerase (PPIase) activity of cyclophilin (Cyp) proteins, we hypothesized that cyclophilins could regulate TEC phenotype. Here we demonstrate that in cultured TECs, CypA silencing triggers loss of epithelial features and enhances transforming growth factor ß (TGFß)-induced EMT in association with upregulation of epithelial repressors Slug and Snail. This pro-epithelial action of CypA relies on its PPIase activity. By contrast, CypB emerges as an epithelial repressor, because CypB silencing promotes epithelial differentiation, prevents TGFß-induced EMT, and induces tubular structures in 3D cultures. In addition, in the kidneys of CypB knockout mice subjected to unilateral ureteral obstruction, inflammatory and pro-fibrotic events were attenuated. CypB silencing/knockout leads to Slug, but not Snail, downregulation. CypB support of Slug expression depends on its endoplasmic reticulum location, where it interacts with calreticulin, a calcium-buffering chaperone related to Slug expression. As CypB silencing reduces ionomycin-induced calcium release and Slug upregulation, we suggest that Slug expression may rely on CypB modulation of calreticulin-dependent calcium signaling. In conclusion, this work uncovers new roles for CypA and CypB in modulating TEC plasticity and identifies CypB as a druggable target potentially relevant in promoting kidney repair.

Chemotherapy-induced cellular senescence suppresses progression of Notch-driven T-ALL.

T cell acute lymphoblastic leukemia (T-ALL) is a serious hematologic malignancy that occurs in children and young adults. Current therapies include intensive chemotherapy and ionizing radiation that preferentially kill malignant cells. Unfortunately, they are frequently accompanied by unintended negative impacts, including the induction of cellular senescence and long-term toxicities in normal host tissues. Whether these senescent cells resulting from therapy increase the susceptibility to relapse or secondary cancers is unknown. Using transgenic and pharmacological approaches to eliminate doxorubicin-induced senescent cells in a Notch-driven T-ALL relapse mouse model, we find that these cells inhibit tumor recurrence, suggesting that senescence in response to treatment suppresses tumorigenesis. This finding, together with extensive evidence from others demonstrating that age-associated health problems develop dramatically earlier among childhood cancer survivors compared to age-matched counterparts, suggests a relationship between therapy-induced senescence and tumorigenesis. Although cancer risk is increased through accelerated premature-aging in the long run, therapy-induced senescence appears to protect survivors from recurrence, at least in the short run.

Immunotherapy in pediatric B-cell acute lymphoblastic leukemia.

Advances in multi-agent chemotherapy and supportive care have dramatically improved survival of children with B-cell acute lymphoblastic leukemia (B-ALL); however, patients with relapsed and refractory disease continue to represent a therapeutic challenge. Hematopoietic stem cell transplant was the first immunotherapeutic approach to be used in the treatment of patients with relapsed or refractory disease. However, novel therapies such as bispecific antibodies that engage T-cells and chimeric antigen receptor T-cells (CAR-T) therapy have emerged as novel FDA-approved options that have the potential to become the new standard of care for these difficult-to-treat leukemias. With multiple immunotherapeutic agents in the drug development pipeline, it is important for cancer researchers and oncologists to be familiar with these agents, including their mechanism of action, side effects and efficacy. In this paper, we review the role of the human immune system in the development and treatment of childhood ALL and provide an overview of current and upcoming immunotherapeutic treatment approaches.