Παρασκευή 30 Οκτωβρίου 2020

The Changing Landscape of Therapeutic Cancer Vaccines - Novel Platforms and Neoantigen Identification

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Therapeutic cancer vaccines, an exciting development in cancer immunotherapy, share the goal of creating and amplifying tumor-specific T cell responses, but significant obstacles still remain to their success. Here, we briefly outline the principles underlying cancer vaccine therapy with a focus on novel vaccine platforms and antigens, underscoring the renewed optimism. Numerous strategies have been investigated to overcome immunosuppressive mechanisms of the tumor microenvironment (TME) and counteract tumor escape, including improving antigen selection, refining delivery platforms, and use of combination therapies. Several new cancer vaccine platforms and antigen targets are under development. In an effort to amplify tumor-specific T cell responses, a heterologous prime-boost antigen delivery strategy is increasingly used for virus-based vaccines. Viruses have also been engineered to express targeted antigens and immunomodulatory molecules simultaneously, t o favorably modify the TME. Nanoparticle systems have shown promise as delivery vectors for cancer vaccines in preclinical research. T-win is another platform targeting both tumor cells and the TME, using peptide-based vaccines that engage and activate T cells to target immune regulatory molecules expressed on immune suppressive and malignant cells. With the availability of next-generation sequencing, algorithms for neoantigen selection are emerging, and several bioinformatic platforms are available to select therapeutically relevant neoantigen targets for developing personalized therapies. However, more research is needed before the use of neoepitope prediction and personalized immunotherapy become commonplace. Taken together, the field of therapeutic cancer vaccines is fast evolving, with the promise of potential synergy with existing immunotherapies for long-term cancer treatment.

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Early Response to First-Line Anti-PD-1 Treatment in Hodgkin Lymphoma: A PET-Based Analysis from the Prospective, Randomized Phase II NIVAHL Trial

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Purpose: A primary analysis of the ongoing NIVAHL trial demonstrated unexpectedly high interim complete response rates to nivolumab-based first-line treatment in early-stage unfavorable Hodgkin lymphoma. However, biomarkers such as metabolic tumor volume (MTV) or total lesion glycolysis (TLG) and their change under treatment (MTV and TLG), measured on positron emission tomography (PET), might provide additional relevant information for response assessment in this setting. Hence, the present analysis aimed to investigate early response to checkpoint inhibitor therapy beyond conventional criteria. Patients and Methods: NIVAHL is a prospective, randomized phase II trial that recruited between April 2017 and October 2018. Patients in arm A and B were assessed for early treatment response after 2 courses of doxorubicin, vinblastine, and dacarbazine with 2 concomitant nivolumab infusions per cycle (N-AVD) and 4xnivolumab, respectively. In the present analysis, we included all 59 individuals with PET images available to the central review panel for quantitative analysis before April 30, 2019. Results: At interim restaging, we determined a mean MTV and TLG of -99.8% each in arm A after 2xN-AVD, compared with -91.4% and -91.9%, respectively, for treatment group B undergoing 4xnivolumab. This high decrease in MTV and TLG was observed regardless of the initial lymphoma burden. Conclusions: Our study showed that nivolumab-based first-line treatment leads to rapid near-complete reduction of tumor metabolism in early-stage unfavorable Hodgkin lymphoma. Thus, PET-derived biomarkers might allow reduction or even omission of chemo- and radiotherapy. Furthermore, MTV and TLG could be also used to optimize immune checkpoint-targeting treatments in other cancers.

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Gadolinium-Enhanced 3D T1-Weighted Black-Blood MR Imaging for the Detection of Acute Optic Neuritis [HEAD & NECK]

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BACKGROUND AND PURPOSE:

A 3D T1-weighted black-blood sequence was recently shown to improve the detection of contrast-enhancing lesions in the brain in patients with MS compared with a 3D T1-weighted MPRAGE sequence. We compared a contrast-enhanced 3D T1-weighted black-blood sequence with a dedicated orbital contrast-enhanced T1-weighted Dixon sequence in patients with acute optic neuritis.

MATERIALS AND METHODS:

MR imaging data (3T) of 51 patients showing symptoms of acute optic neuritis were analyzed retrospectively, including whole-brain contrast-enhanced 3D T1-weighted black-blood and dedicated orbital coronal 2D or 3D contrast-enhanced T1-weighted Dixon sequences. Two neuroradiologists assessed the images for overall image quality, artifacts, diagnostic confidence, and visual contrast enhancement. Furthermore, the standardized contrast-to-noise ratio was calculated. The final diagnosis of acute optic neuritis was established on the basis of clinical presentation, vi sually evoked potentials, and optical coherence tomography.

RESULTS:

Thirty of 51 patients were diagnosed with acute optic neuritis. Of those, 21 showed contrast-enhancing lesions in the optic nerves, similarly detectable on contrast-enhanced T1-weighted Dixon and contrast-enhanced T1-weighted black-blood images. Thus, the accuracy for each sequence was identical, with a resulting sensitivity of 70% and specificity of 90% or 100% (depending on the reader). Overall image quality, diagnostic confidence, visual contrast enhancement, and artifacts were rated similarly in contrast-enhanced 3D T1-weighted black-blood and dedicated orbital contrast-enhanced T1-weighted Dixon sequences. There was no significant difference (P = .27) in the mean standardized contrast-to-noise ratio between contrast-enhanced T1-weighted black-blood (1.76 ± 1.07) and contrast-enhanced T1-weighted Dixon (2.29 ± 2.49) sequences.

CONCLUSIONS:

Contrast-enhanced 3D T1-weighted black-blood imaging is comparable in accuracy and qualitative/quantitative features with dedicated orbital contrast-enhanced T1-weighted Dixon imaging for the detection of acute optic neuritis. Therefore, when used, it has the potential to considerably shorten total patient imaging time.

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Selection of Patients for Treatment of Brain Arteriovenous Malformations by the Transvenous Approach: Relationship with Venous Anatomy and Risk of Hemorrhagic Complications [INTERVENTIONAL]

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BACKGROUND AND PURPOSE:

Intracranial hemorrhage represents a severe complication of brain arteriovenous malformation treatment. The aim of this cohort was to report the rate of hemorrhagic complications after transvenous endovascular embolization and analyze the potential angioarchitectural risk factors as well as clinical outcomes.

MATERIALS AND METHODS:

During an 11-year period, 57 patients underwent transvenous endovascular embolization. All cases of hemorrhagic complications were identified. We analyzed the following variables: sex, age, hemorrhagic presentation, Spetzler-Martin grade, size of the AVM before the transvenous treatment, number of venous collectors, pattern of drainage, presence of dilated veins, and technical aspects. Univariate and multivariate multiple regression analyses were performed to evaluate the potential risk factors for procedure-related hemorrhagic complications.

RESULTS:

Hemorrhagic complications (either intraprocedural or periprocedu ral) unrelated to a perforation due to micronavigation occurred in 8 (14.0%) procedures. Significant (mRS > 2) and persistent neurologic deficits were present in 2 (3.5%) patients at 6-month control. Larger nidi, especially >3 cm (P = .03), and a larger number of venous collectors have shown a statistically significant correlation with hemorrhagic complications. Only the number of venous collectors was identified as an independent predictor of hemorrhagic complications in the multivariate analysis (OR, 8.7; 95% confidence interval, 2.2–58.2) (P = .006).

CONCLUSIONS:

Larger nidus sizes and an increased number of venous collectors may increase the risk of hemorrhagic complications when implementing transvenous endovascular treatment of AVMs. The technique is effective and promising, especially with small nidi and single venous collectors.

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Radioanatomic Characteristics of the Posteromedial Intraconal Space: Implications for Endoscopic Resection of Orbital Lesions [HEAD & NECK]

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BACKGROUND AND PURPOSE:

Imaging is essential in the diagnostic work-up of patients with orbital lesions. The position of an orbital lesion relative to the inferomedial muscular trunk of the ophthalmic artery determines endoscopic resectability, anticipated technical difficulty, and patient morbidity. Although the inferomedial muscular trunk is not readily identifiable on preoperative imaging, we hypothesize that it is spatially approximate to the location where the ophthalmic artery crosses the optic nerve. Our aim was to determine whether the ophthalmic artery–optic nerve crosspoint anatomically approximates the inferomedial muscular trunk in a cadaver study and can be appreciated on imaging of known posteromedial orbital lesions.

MATERIALS AND METHODS:

Dissection was performed on 17 fresh-frozen cadaver orbits to assess the relationship between the inferomedial muscular trunk and ophthalmic artery–optic nerve crosspoint. Retrospective review of imaging in 9 patient s with posteromedial orbital lesions assessed posteromedial orbital compartment characteristics and the ability to locate the ophthalmic artery–optic nerve crosspoint.

RESULTS:

In our cadaver study, the mean distance between the ophthalmic artery–optic nerve crosspoint and the inferomedial muscular trunk was 1.21 ± 0.64 mm. Retrospectively, the ophthalmic artery–optic nerve crosspoint was identifiable in 9/9 patients, whereas the inferomedial muscular trunk was not identifiable in any patient. Total or partial effacement of the posteromedial intraconal fat triangle was observed in 9/9 patients.

CONCLUSIONS:

This study of neurovascular relationships within the posteromedial orbit demonstrates that the ophthalmic artery–optic nerve crosspoint closely approximates the inferomedial muscular trunk and can be seen in patients with posteromedial orbital lesions. Posteromedial intraconal fat effacement may help to localize these lesions. These findings may facilitate mult idisciplinary communication and help predict lesion resectability and patient outcomes.

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Risk Factors for Early Brain AVM Rupture: Cohort Study of Pediatric and Adult Patients [PEDIATRICS]

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BACKGROUND AND PURPOSE:

Whether architectural characteristics of ruptured brain AVMs vary across the life span is unknown. We aimed to identify angioarchitectural features associated with brain AVMs ruptured early in life.

MATERIALS AND METHODS:

Patients with ruptured brain AVMs referred to 2 distinct academic centers between 2000 and 2018 were pooled and retrospectively analyzed. Imaging was retrospectively reviewed for angioarchitectural characteristics, including nidus size, location, Spetzler-Martin grade, venous drainage, and arterial or nidal aneurysm. Angioarchitecture variations across age groups were analyzed using uni- and multivariable models; then cohorts were pooled and analyzed using Kaplan-Meier and Cox models to determine factors associated with earlier rupture.

RESULTS:

Among 320 included patients, 122 children (mean age, 9.8 ± 3.8 years) and 198 adults (mean age, 43.3 ± 15.7 years) were analyzed. Pediatric brain AVMs were more frequently deeply l ocated (56.3% versus 21.2%, P < .001), with a larger nidus (24.2 versus 18.9 mm, P = .002), were less frequently nidal (15.9% versus 23.5%, P = .03) and arterial aneurysms (2.7% versus 17.9%, P < .001), and had similar drainage patterns or Spetzler-Martin grades. In the fully adjusted Cox model, supratentorial, deep brain AVM locations (adjusted relative risk, 1.19; 95% CI, 1.01–1.41; P = .03 and adjusted relative risk, 1.43; 95% CI, 1.22–1.67; P < .001, respectively) and exclusively deep venous drainage (adjusted relative risk, 1.46, 95% CI, 1.21–1.76; P < .001) were associated with earlier rupture, whereas arterial or nidal aneurysms were associated with rupture later in life.

CONCLUSIONS:

The angioarchitecture of ruptured brain AVMs significantly varies across the life span. These distinct features may help to guide treatment decisions for patients with unruptured AVMs.

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Longitudinal Assessment of Neuroradiologic Features in Wolfram Syndrome [PEDIATRICS]

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BACKGROUND AND PURPOSE:

Wolfram syndrome is a rare genetic disease with characteristic brain involvement. We reviewed the brain MR images of patients with Wolfram syndrome to determine the frequency and characteristics of common neuroradiologic findings.

MATERIALS AND METHODS:

We retrospectively reviewed the imaging data of patients with genetically-confirmed Wolfram syndrome who had been recruited to the Washington University Wolfram Syndrome Research Clinic. These patients were evaluated between 2010 and 2019 with annual MRIs, along with other measures. MR images were assessed for clinical neuroradiologic signs at each individual's first and last follow-up visits to characterize the frequency, rate of progression, and clinical correlations of these signs.

RESULTS:

We included 30 patients (13 males/17 females; average age at first visit, 14 years; average age at last visit, 19 years). The median duration of follow-up was 5 years (range, 2–9 years). The most com mon findings were an absent or diminished posterior pituitary bright spot (first, 53%; last, 70%), T1/T2 pons signal abnormalities (first, 53%; last, 67%), optic nerve atrophy (first, 30%; last, 80%), white matter T2 hyperintensities (first, 27%; last, 35%), and cerebellar atrophy (first, 23%; last, 70%).

CONCLUSIONS:

Patients with Wolfram syndrome present characteristic neuroradiologic findings that involve the posterior pituitary gland, optic nerves, white matter, brain stem, and cerebellum. These abnormal findings appear at an early age and tend to increase in frequency with time. However, the neurologic significance and neuropathologic mechanisms of each sign require more investigation. Neuroradiologists should be aware of the pattern of these features in Wolfram syndrome.

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Considerations for Antiplatelet Management of Carotid Stenting in the Setting of Mechanical Thrombectomy: A Delphi Consensus Statement [INTERVENTIONAL]

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BACKGROUND AND PURPOSE:

There are only few data and lack of consensus regarding antiplatelet management for carotid stent placement in the setting of endovascular stroke treatment. We aimed to develop a consensus-based algorithm for antiplatelet management in acute ischemic stroke patients undergoing endovascular treatment and simultaneous emergent carotid stent placement.

MATERIALS AND METHODS:

We performed a literature search and a modified Delphi approach used Web-based questionnaires that were sent in several iterations to an international multidisciplinary panel of 19 neurointerventionalists from 7 countries. The first round included open-ended questions and formed the basis for subsequent rounds, in which closed-ended questions were used. Participants continuously received feedback on the results from previous rounds. Consensus was defined as agreement of ≥70% for binary questions and agreement of ≥50% for questions with >2 answer options. The results of the Delphi process were then summarized in a draft manuscript that was circulated among the panel members for feedback.

RESULTS:

A total of 5 Delphi rounds were performed. Panel members preferred a single intravenous aspirin bolus or, in jurisdictions in which intravenous aspirin is not available, a glycoprotein IIb/IIIa receptor inhibitor as intraprocedural antiplatelet regimen and a combination therapy of oral aspirin and a P2Y12 inhibitor in the postprocedural period. There was no consensus on the role of platelet function testing in the postprocedural period.

CONCLUSIONS:

More and better data on antiplatelet management for carotid stent placement in the setting of endovascular treatment are urgently needed. Panel members preferred intravenous aspirin or, alternatively, a glycoprotein IIb/IIIa receptor inhibitor as an intraprocedural antiplatelet agent, followed by a dual oral regimen of aspirin and a P2Y12 inhibitor in the postprocedural period.

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Clinical and Radiologic Findings of Acute Necrotizing Encephalopathy in Young Adults [ADULT BRAIN]

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SUMMARY:

Acute necrotizing encephalopathy after an acute febrile illness, although initially described exclusively in the pediatric age group, has been recently shown to have an adult onset as well. In this study, we describe 10 patients (16 years of age or older) with acute necrotizing encephalopathy. In our study, bilateral thalamic involvement with the trilaminar pattern of diffusion restriction on MR imaging was the predominant finding seen in all of the patients reviewed. Ancillary findings of cerebral white matter, brain stem, and cerebellum involvement with sparing of the basal ganglia were also noted. A poorer outcome was observed in patients with a higher degree of thalamic involvement. The cause of an underlying infection was identified in 4 patients (dengue in 3 and influenza in 1). Overall, a sizeable portion of young adults with acute necrotizing encephalopathy have shown a poorer outcome, with dengue being an important underlying trigger in an endemic region.

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Brain MR Spectroscopic Findings in 3 Consecutive Patients with COVID-19: Preliminary Observations [ADULT BRAIN]

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SUMMARY:

Brain multivoxel MR spectroscopic imaging was performed in 3 consecutive patients with coronavirus disease 2019 (COVID-19). These included 1 patient with COVID-19-associated necrotizing leukoencephalopathy, another patient who had a recent pulseless electrical activity cardiac arrest with subtle white matter changes, and a patient without frank encephalopathy or a recent severe hypoxic episode. The MR spectroscopic imaging findings were compared with those of 2 patients with white matter pathology not related to Severe Acute Respiratory Syndrome coronavirus 2 infection and a healthy control subject. The NAA reduction, choline elevation, and glutamate/glutamine elevation found in the patient with COVID-19-associated necrotizing leukoencephalopathy and, to a lesser degree, the patient with COVID-19 postcardiac arrest, follow a similar pattern as seen with the patient with delayed posthypoxic leukoencephalopathy. Lactate elevation was most pronounced in the patient with COVID-19 necrotizing leukoencephalopathy.

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Perinatal Arterial Ischemic Stroke in Fetal Vascular Malperfusion: A Case Series and Literature Review [PEDIATRICS]

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SUMMARY:

Fetal vascular malperfusion includes a continuum of placental histologic abnormalities increasingly associated with perinatal brain injury, namely arterial ischemic stroke. Here, we describe the clinical-neuroimaging features of 5 neonates with arterial ischemic stroke and histologically proved fetal vascular malperfusion. All infarcts involved the anterior territories and were multiple in 2 patients. In 2 neonates, there were additional signs of marked dural sinus congestion, thrombosis, or both. A mixed pattern of chronic hypoxic-ischemic encephalopathy and acute infarcts was noted in 1 patient at birth. Systemic cardiac or thrombotic complications were present in 2 patients. These peculiar clinical-radiologic patterns may suggest fetal vascular malperfusion and should raise the suspicion of this rare, underdiagnosed condition carrying important implications in patient management, medicolegal actions, and future pregnancy counseling.

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Modified technique of free composite osteocutaneous flap based on half-circumferential fibula with multiple segments

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Complex foot injuries are usually the result of high-energy trauma, and characterized by open fractures or comminution of the tarsometatarsal complex, compromise of soft tissues and skin defects. The free fibular osteocutaneous flap is widely used to repair these defects because of its accessibility, composition of cortical bone and well-vascularized skin.1 Recently, possible complications have been documented, including pain, reduced muscle strength, claw toe, ankle instability, limited range of motion (ROM) of the ankle, contracture of the flexor hallucis longus muscle, and tibial stress fracture.
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