Hypofractionated Stereotactic Re-irradiation and Anti-PDL1 Durvalumab Combination in Recurrent Glioblastoma: STERIMGLI Phase I Results.

BACKGROUND: Hypofractionated stereotactic radiotherapy (hFSRT) is a salvage option for recurrent glioblastoma (GB) which may synergize anti-PDL1 treatment. This phase I study evaluated the safety and the recommended phase II dose of anti-PDL1 durvalumab combined with hFSRT in patients with recurrent GB. METHODS: Patients were treated with 24 Gy, 8 Gy per fraction on days 1, 3, and 5 combined with the first 1500 mg Durvalumab dose on day 5, followed by infusions q4weeks until progression or for a maximum of 12 months. A standard 3 + 3 Durvalumab dose de-escalation design was used. Longitudinal lymphocytes count, cytokines analyses on plasma samples, and magnetic resonance imaging (MRI) were collected. RESULTS: Six patients were included. One dose limiting toxicity, an immune-related grade 3 vestibular neuritis related to Durvalumab, was reported. Median progression-free interval (PFI) and overall survival (OS) were 2.3 and 16.7 months, respectively. Multi-modal deep learning-based analysis including MRI, cytokines, and lymphocytes/neutrophil ratio isolated the patients presenting pseudoprogression, the longest PFI and those with the longest OS, but statistical significance cannot be established considering phase I data only. CONCLUSION: Combination of hFSRT and Durvalumab in recurrent GB was well tolerated in this phase I study. These encouraging results led to an ongoing randomized phase II. (ClinicalTrials.gov Identifier: NCT02866747).

Radiomics-Based Detection of Radionecrosis Using Harmonized Multiparametric MRI.

In this study, a radiomics analysis was conducted to provide insights into the differentiation of radionecrosis and tumor progression in multiparametric MRI in the context of a multicentric clinical trial. First, the sensitivity of radiomic features to the unwanted variability caused by different protocol settings was assessed for each modality. Then, the ability of image normalization and ComBat-based harmonization to reduce the scanner-related variability was evaluated. Finally, the performances of several radiomic models dedicated to the classification of MRI examinations were measured. Our results showed that using radiomic models trained on harmonized data achieved better predictive performance for the investigated clinical outcome (balanced accuracy of 0.61 with the model based on raw data and 0.72 with ComBat harmonization). A comparison of several models based on information extracted from different MR modalities showed that the best classification accuracy was achieved with a model based on MR perfusion features in conjunction with clinical observation (balanced accuracy of 0.76 using LASSO feature selection and a Random Forest classifier). Although multimodality did not provide additional benefit in predictive power, the model based on T1-weighted MRI before injection provided an accuracy close to the performance achieved with perfusion.

Pilocytic Astrocytoma-Derived Cells in Peripheral Blood: A Case Report.

Imaging limitations, invasive tissue biopsies and poor information over the course of treatment to evaluate 'real-time' tumor dynamics justify the emerging use of liquid biopsies in the field of brain tumors. Circulating tumor cells (CTCs) from high-grade astrocytomas might reach the circulation by crossing the blood-brain barrier. Here, for the first time, CTCs cytology in a case of pylocitic astrocytoma is described. An obstructive hydrocephalous due to a lateral mesencephalic tectum mass occluding the Silvio Aqueduct was diagnosed in a young, 18 years old, male. Considering the location of the tumor and the rapid deterioration of the neurological status, it has been decided to urgency treat the patient with ventriculoperitoneal shunting. Magnetic resonance imaging showed a nodular shaped lesion localized within the left lateral mesencephalic tectum. Stereotactic biopsy was not approachable due significant risk of neurological consequences. The diagnosis was performed by blood sampling, a non-invasive procedure for the patient, in order to provide tumor information. Cytopathological features on detected circulating atypical GFAP positive cells led to pilocytic diagnosis confirmed by the patient's 68 months outcome.

Depletion of circulating IgM memory B cells predicts unfavourable outcome in COVID-19.

Impaired immune responses have been hypothesised to be a possible trigger of unfavourable outcomes in coronavirus disease 2019 (COVID-19). We aimed to characterise IgM memory B cells in patients with COVID-19 admitted to an internal medicine ward in Northern Italy. Overall, 66 COVID-19 patients (mean age 74 ± 16.6 years; 29 females) were enrolled. Three patients (4.5%; 1 female) had been splenectomised and were excluded from further analyses. Fifty-five patients (87.3%) had IgM memory B cell depletion, and 18 (28.6%) died during hospitalisation (cumulative incidence rate 9.26/100 person-week; 5.8-14.7 95% CI). All patients who died had IgM memory B cell depletion. A superimposed infection was found in 6 patients (9.5%), all of them having IgM memory B cell depletion (cumulative incidence rate 3.08/100 person-week; 1.3-6.8 95% CI). At bivariable analyses, older age, sex, number of comorbidities, and peripheral blood lymphocyte count < 1500/µl were not correlated with IgM memory B cell depletion. A discrete-to-marked reduction of the B-cell compartment was also noticed in autoptic spleen specimens of two COVID-19 patients. We conclude that IgM memory B cells are commonly depleted in COVID-19 patients and this correlates with increased mortality and superimposed infections.

A Phase 1 Randomized Trial of Specific Active α-Synuclein Immunotherapies PD01A and PD03A in Multiple System Atrophy.

Multiple system atrophy (MSA) is a rare and fatal neurodegenerative disease with limited symptomatic treatment options. Aggregation of α-synuclein in oligodendrocytes is believed to be a central mechanism of the neurodegenerative process. PD01A and PD03A are 2 novel therapeutic vaccine candidates containing short peptides as antigenic moieties that are designed to induce a sustained antibody response, specifically targeting pathogenic assemblies of α-synuclein. The objectives of the current study were to evaluate primarily the safety and tolerability of PD01A and PD03A in patients with early MSA. Thirty patients (11 women) were randomized to receive 5 subcutaneous injections of either PD01A (n = 12), PD03A (n = 12), or placebo (n = 6) in this patient- and examiner-blinded, placebo-controlled, 52-week phase 1 clinical trial (ClinicalTrial.gov identifier: NCT02270489). Immunogenicity and clinical scores were assessed as secondary objectives. Twenty-nine patients reported a total of 595 treatment-emergent adverse events (mild or moderate, n = 555; severe, n = 40). Treatment-related adverse events included 190 injection-site reactions typically observed in vaccination trials with similar per-subject incidence in the treatment groups over time. Sustained IgG titers were observed in the PD01A-treated group, and 89% of treated patients developed a PD01-specific antibody response after receiving all injections. Induced antibodies displayed clear reactivity to the α-synuclein target epitope. Titers and antibody responder rate (58%) were lower in the PD03A-treated group. In conclusion, both PD01A and PD03A were safe and well tolerated. PD01A triggered a rapid and long-lasting antibody response that specifically targeted the α-synuclein epitope. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Impact of [64Cu][Cu(ATSM)] PET/CT in the evaluation of hypoxia in a patient with Glioblastoma: a case report.

BACKGROUND: Glioblastoma multiform (GBM), a malignant brain tumour, has a very often poor prognosis. The therapeutic approach is represented by surgery followed by radiotherapy and chemotherapy. Hypoxia is a factor that causes a reduction of both radiotherapy and chemotherapy effectiveness in GBM and other cancers. Through the use of [64Cu][Cu(ATSM)], a hypoxia-targeting positron emission tomography (PET) radiotracer, is possible to identify the presence of hypoxic areas within a lesion and therefore modulate the therapeutic approach according to the findings. CASE PRESENTATION: In this case report, we observed an increase of radiotracer uptake from early acquisition to late acquisition in hypoxia sites and high correlation between [64Cu][Cu(ATSM) PET/CT results and expression of the hypoxia marker HIF-1α. CONCLUSIONS: [64Cu][Cu(ATSM) PET/CT represents a valid opportunity to reveal in vivo hypoxic areas in GBM lesion which can guide clinicians on selecting GMB patient's therapeutic scheme.

Transient effects of tumor location on the functional architecture at rest in glioblastoma patients: three longitudinal case studies.

BACKGROUND: The cognitive function of brain tumor patients is affected during the treatment. There is evidence that gliomas and surgery alter the functional brain connectivity but studies on the longitudinal effects are lacking. METHODS: We acquired longitudinal (pre- and post-radiotherapy) resting-state functional magnetic resonance imaging on three selected glioblastoma patients. These cases were selected to study three models: a lesion involving a functional hub within a central system, a lesion involving a peripheral node within a central system and a lesion involving a peripheral node of a non-central system. RESULTS: We found that, as expected, the tumor lesion affects connections in close vicinity, but when the lesion relates to a functional hub, these changes involve long-range connections leading to diverse connectivity profiles pre- and post-radiotherapy. In particular, a global but temporary improvement in the post-radiotherapy connectivity was obtained when treating a lesion close to a network hub, such as the posterior Cingulate Cortex. CONCLUSIONS: This suggests that this node re-establishes communication to nodes further away in the network. Eventually, these observed effects seem to be transient and on the long-term the tumor burden leads to an overall decline of connectivity following the course of the pathology. Furthermore, we obtained that the link between hubs, such as the Supplementary Motor Area and posterior Cingulate Cortex represents an important backbone by means of which within and across network communication is handled: the disruption of this connection seems to imply a strong decrease in the overall connectivity.

The role of iron in gray matter degeneration in Huntington's disease: a magnetic resonance imaging study.

In Huntington's disease, iron accumulation in basal ganglia accompanies neuronal loss. However, if iron content changes with disease progression and how it relates to gray matter atrophy is not clear yet. We explored iron content in basal ganglia and cortex and its relationship with gray matter volume in 77 mutation carriers [19 presymptomatic, 8 with soft symptoms (SS), and 50 early-stage patients) and 73 matched-controls by T2*relaxometry and T1-weighted imaging on a 3T scanner. The ANCOVA model showed that iron accumulates in the caudate in presymptomatic subjects (P = 0.004) and remains relatively stable along disease stages in this nucleus; while increases in putamen and globus pallidus (P < 0.05). Volume instead decreases in basal ganglia, starting from the caudate (P < 0.0001) and extending to the putamen and globus pallidus (P ≤ 0.001). The longer the disease duration and the higher the CAG repeats, the higher the iron accumulation and the smaller the volume. In the cortex, iron decreases in parieto-occipital areas in SS (P < 0.027); extending to premotor and parieto-temporo-occipital areas in patients (P < 0.003); while volume declines in frontoparietal and temporal areas in presymptomatic (P < 0.023) and SS (P < 0.045), and extends throughout the cortex, with the exception of anterior frontal regions, in patients (P < 0.023). There is an inverse correlation between volume and iron levels in putamen, globus pallidus and the anterior cingulate; and a direct correlation in cortical structures (SMA-sensoriomotor and temporo-occipital). Iron homeostasis is affected in the disease; however, there appear to be differences in the role played by iron in basal ganglia and in cortex.

Urologic dysfunction and neurologic outcome in coma survivors after severe traumatic brain injury in the postacute and chronic phase.

OBJECTIVES: To investigate voiding dysfunction and upper urinary tract status in survivors of coma resulting from traumatic brain injury (TBI), and to compare clinical and urodynamic results with neurologic and psychological features as well as functional outcomes. DESIGN: Observational study focused on urologic dysfunction and neurologic outcome in coma survivors after traumatic brain injury in the postacute and chronic phase. SETTING: A postcoma unit in a rehabilitation hospital. PARTICIPANTS: Consecutive patients (N=57) who recovered from coma of traumatic etiology and who were admitted during a 1-year period to a postcoma unit of a rehabilitation hospital. INTERVENTIONS: Patients underwent clinical urologic assessment, urodynamics with the assessment of the Schafer nomogram and the projected isovolumetric detrusor pressure to evaluate detrusor contractility, ultrasound assessment of the lower and upper urinary tract and voiding cystourethrography, routinely performed, according to the International Continence Society Standards. Neurologic variables assessed were brain injury and disability severity, and neuropsychological status. Neuroimaging identified the site of cerebral lesions. MAIN OUTCOME MEASURES: Urinary symptoms, disability by means of the Glasgow Outcome Scale (GOS), and neuropsychological status by means of the Neurobehavioral Rating Scale (NBRS), and the relationships among them. RESULTS: Of the 57 patients studied, 30 had overactive bladder (urge incontinence) symptoms, 28 had detrusor overactivity, and 18 had detrusor underactivity with associated pseudodyssynergia in 15 of these patients. Eleven patients had hypertrophic bladder; 3, bilateral pyelectasia; and 2, vesicoureteral reflux. Disability measured by GOS was severe in 8 patients and moderate in 27, while recovery was good in 22 patients. The mean NBRS total score indicated a mild cognitive impairment. Neuroimaging showed diffuse brain injury in all patients. Statistically significant relationships were found between urge incontinence, detrusor overactivity, and poor neurologic functional outcome, between detrusor overactivity and right hemisphere damage (P=.0001), and between impaired detrusor contractility and left hemisphere injuries (P=.0001). CONCLUSIONS: Most patients who recovered from coma resulting from TBI have symptoms of overactive bladder syndrome and voiding difficulties. These urinary problems correlate with cerebral involvement and neurologic functional outcome.

Volume and iron content in basal ganglia and thalamus.

Magnetic resonance imaging (MRI) studies have highlighted the possibility to investigate brain iron content in vivo. In this study, we combined T2* relaxometry and automatic segmentation of basal ganglia based on T1-weighted images in healthy subjects, with the aim of characterizing age related changes in volume and iron-related relaxivity values (R2*) of these structures. Thirty healthy subjects underwent MR imaging at 3 Tesla. Mean R2* values and volumes were calculated for the selected subcortical structures (pallidum, putamen, thalamus and caudate nucleus). Our results showed a correlation between R2* values and iron concentration as calculated from published post-mortem data. Furthermore, we observed a shrinkage/iron increase with a different pattern in the anatomical regions selected in this work, suggesting that the age-related changes on these MR parameters are specific to the subcortical structure considered. In particular, the putamen demonstrated a decrease of volume and an increase of iron level, with the posterior region of this structure appearing more disposed to iron deposition. Our work suggests that combining volumetry and iron estimation in MRI permits to investigate in vivo neurophysiological and neuropathological changes of basal ganglia.

Recovery from amnesic confabulatory syndrome after right fornix lesion.

BACKGROUND: Reports of amnesia due to bilateral fornix lesions are rare. A unilateral right fornix lesion is not known to cause an amnestic confabulatory syndrome. OBJECTIVE: To investigate the role of right fornix lesion in amnesia, the association of confabulation with executive disorders, and to evaluate the long-term recovery of memory and executive functions after surgical removal of a pilocytic astrocytoma in the right orbitofrontal region extending to the right fornix. METHODS: Neuropsychological testing was performed 3 and 17 months after surgery. RESULTS: Severe anterograde global amnesia, mild retrograde amnesia, momentary and spontaneous confabulation, and mild executive deficits were found initially and mostly recovered by 17 months. CONCLUSIONS: The authors hypothesize that the lesion of the right fornix was sufficient to cause amnesia by disconnecting the hippocampal formations from the anterior thalamic nuclei and mammillary bodies and interrupting the cholinergic efferents to the hippocampus from the medial septum, according to the extended hippocampal system framework. Sparing of the left fornix may be sufficient to ensure a good recovery of memory. Confabulation is strongly associated with the improvement of executive functions, specifically the ability to suppress irrelevant memory traces.