GMP production of [18F]FE-PE2I on a TRACERLab FX2 N synthesis module, a radiotracer for in vivo PET imaging of the dopamine transport.

BACKGROUND: Parkinson's disease is a neurodegenerative disorder that is characterized by a degeneration of the dopaminergic system. Dopamine transporter (DAT) positron emission tomography (PET) imaging has emerged as a powerful and non-invasive method to quantify dopaminergic function in the living brain. The PET radioligand, [18F]FE-PE2I, a cocaine chemical derivative, has shown promising properties for in vivo PET imaging of DAT, including high affinity and selectivity for DAT, excellent brain permeability, and favorable metabolism. The aim of the current study was to scale up the production of [18F]FE-PE2I to fulfil the increasing clinical demand for this tracer. RESULTS: Thus, a fully automated and GMP-compliant production procedure has been developed using a commercially available radiosynthesis module GE TRACERLab FX2 N. [18F]FE-PE2I was produced with a radiochemical yield of 39 ± 8% (n = 4, relative [18F]F- delivered to the module). The synthesis time was 70 min, and the molar activity was 925.3 ± 763 GBq/µmol (250 ± 20 Ci/µmol). The produced [18F]FE-PE2I was stable over 6 h at room temperature. CONCLUSION: The protocol reliably provides a sterile and pyrogen-free GMP-compliant product.

Successful treatment of paediatric refractory Hodgkin lymphoma with immunotherapy - A case report and literature review.

AIM: To describe a rare case of primary refractory Hodgkin lymphoma nodular sclerosis syncytial variant in a child and review immunotherapy in relapsed/refractory Hodgkin lymphoma. METHODS: We described the treatment course of a child with primary refractory classic Hodgkin lymphoma and discussed different options for salvage therapy, with an emphasis on immunotherapy. We searched PubMed for all published clinical trials investigating immunotherapy in classic Hodgkin lymphoma written in English until 31 June, 2023. The reference list of each identified paper was searched for additional publications. RESULTS: Our patient was salvaged with anti-programmed cell death 1 (PD-1) antibody therapy followed by high-dose chemotherapy with autologous stem cell rescue. Radiotherapy was avoided. We identified five one-armed phase II trials investigating anti-PD-1 therapy in first relapse/refractory disease in a total of 254 patients aged 9-71 years, of which one included 31 children. The complete remission rate before high-dose chemotherapy was 59%-95% overall and 67%-89% among those with refractory disease. CONCLUSION: Although it remains to be proven in randomised trials, anti-PD-1 therapy may provide higher complete response rates than traditional chemotherapy. Anti-PD-1 therapy has the potential to increase the chance of cure while decreasing the risk of late effects from chemotherapy and radiotherapy.

Dilated Virchow-Robin spaces are a marker for arterial disease in multiple sclerosis.

BACKGROUND: Virchow-Robin spaces (VRS) have been associated with neurodegeneration and neuroinflammation. However, it remains uncertain to what degree non-dilated or dilated VRS reflect specific features of neuroinflammatory pathology. Thus, we aimed at investigating the clinical relevance of VRS as imaging biomarker in multiple sclerosis (MS) and to correlate VRS to their histopathologic signature. METHODS: In a cohort study comprising 142 MS patients and 30 control subjects, we assessed the association of non-dilated and dilated VRS to clinical and magnetic resonance imaging (MRI) outcomes. Findings were corroborated in a validation cohort comprising 63 MS patients. Brain blocks from 6 MS patients and 3 non-MS controls were histopathologically processed to correlate VRS to their tissue substrate. FINDINGS: In our actively treated clinical cohort, the count of dilated centrum semiovale VRS was associated with increased T1 and T2 lesion volumes. There was no systematic spatial colocalization of dilated VRS with MS lesions. At tissue level, VRS mostly corresponded to arteries and were not associated with MS pathological hallmarks. Interestingly, in our ex vivo cohort comprising mostly progressive MS patients, dilated VRS in MS were associated with signs of small vessel disease. INTERPRETATION: Contrary to prior beliefs, these observations suggest that VRS in MS do not associate with an accumulation of immune cells. But instead, these findings indicate vascular pathology as a driver and/or consequence of neuroinflammatory pathology for this imaging feature. FUNDING: NIH, Swedish Society for Medical Research, Swiss National Science Foundation and University of Zurich.

Dilated Virchow-Robin Spaces are a Marker for Arterial Disease in Multiple Sclerosis.

Virchow-Robin spaces (VRS) have been associated with neurodegeneration and neuroinflammation. However, it remains uncertain to what degree non-dilated or dilated VRS reflect specific features of neuroinflammatory pathology. Thus, we aimed at investigating the clinical relevance of VRS as imaging biomarker in multiple sclerosis (MS) and to correlate VRS to their histopathologic signature. In a cohort study comprising 205 MS patients (including a validation cohort) and 30 control subjects, we assessed the association of non-dilated and dilated VRS to clinical and magnetic resonance imaging (MRI) out-comes. Brain blocks from 6 MS patients and 3 non-MS controls were histopathologically processed to correlate VRS to their tissue substrate. The count of dilated centrum semiovale VRS was associated with increased T1 and T2 lesion volumes. There was no systematic spatial colocalization of dilated VRS with MS lesions. At tissue level, VRS mostly corresponded to arteries and were not associated with MS pathological hallmarks. Interestingly, dilated VRS in MS were associated with signs of small vessel disease. Contrary to prior beliefs, these observations suggest that VRS in MS do not associate with accumulation of immune cells. But instead, these findings indicate vascular pathology as a driver and/or consequence of neuroinflammatory pathology for this imaging feature.

MRI detection of brain gadolinium retention in multiple sclerosis: Magnetization transfer vs. T1-weighted imaging.

BACKGROUND AND PURPOSE: Evidence of brain gadolinium retention has affected gadolinium-based contrast agent usage. It is, however, unclear to what extent macrocyclic agents are retained and whether their in vivo detection may necessitate nonconventional MRI. Magnetization transfer (MT) could prove suitable to detect gadolinium-related signal changes since dechelated gadolinium ions bind to macromolecules. Therefore, this study aimed to investigate associations of prior gadolinium administrations with MT and T1 signal abnormalities. METHODS: A cohort of 23 persons with multiple sclerosis (MS) (18 females, 5 males, 57 ± 8.0 years) with multiple past gadolinium administrations (median 6, range 3-12) and 23 age- and sex-matched healthy controls underwent 1.5 Tesla MRI with MT, T1-weighted 2-dimensional spin echo, and T1-weighted 3-dimensional gradient echo. The signal intensity index was assessed by MRI in gadolinium retention predilection sites. RESULTS: There were dose-dependent associations of the globus pallidus signal on gradient echo (r = .55, p < .001) and spin echo (r = .38, p = .013) T1-weighted imaging, but not on MT. Relative to controls, MS patients had higher signal intensity index in the dentate nucleus on T1-weighted gradient echo (1.037 ± 0.040 vs. 1.016 ± 0.023, p = .04) with a similar trend in the globus pallidus on T1-weighted spin echo (1.091 ± 0.034 vs. 1.076 ± 0.014, p = .06). MT detected no group differences. CONCLUSIONS: Conventional T1-weighted imaging provided dose-dependent associations with gadolinium administrations in MS, while these could not be detected with 2-dimensional MT. Future studies could explore newer MT techniques like 3D and inhomogenous MT. Notably, these associations were identified with conventional MRI even though most patients had not received gadolinium administrations in the preceding 9 years, suggestive of long-term retention.

The cerebellar phenotype of Charcot-Marie-Tooth neuropathy type 4C.

BACKGROUND: Friedreich ataxia (FRDA) is the most common familial ataxia syndrome in Central and Southern Europe but rare in Scandinavia. Biallelic mutations in SH3 domain and tetratricopeptide repeats 2 (SH3TC2) cause Charcot-Marie-Tooth disease type 4C (CMT4C), one of the most common autosomal recessive polyneuropathies associated with early onset, slow disease progression and scoliosis. Beyond nystagmus reported in some patients, neither ataxia nor cerebellar atrophy has been documented as part of the CMT4C phenotype. METHODS: Here we describe a single centre CMT4C cohort. All patients underwent a comprehensive characterization that included physical examination, neurophysiological studies, neuroimaging and genetic testing. In a patient with cerebellar features, an evaluation of the vestibular system was performed. RESULTS: All five patients in this cohort harbored the R954X mutation in SH3TC2 suggesting a founder effect. Two patients had been diagnosed as FRDA. One of them, an 80-year-old woman had onset of unsteadiness during childhood leading to gradual loss of mobility. She also had scoliosis and hearing loss. On examination she had generalized muscle atrophy, leg flaccidity, pes cavus, facial myokymia, limb dysmetria, dysarthria and gaze-evoked nystagmus. She exhibited bilateral vestibular areflexia. Neuroimaging demonstrated atrophy in the frontoparietal regions and cerebellar hemispheres. CONCLUSIONS: CMTC4A may present with a cerebellar phenotype and mimic a flaccid-ataxic form of FRDA. Absence of cardiomyopathy or endocrine abnormalities and lack of pathological dentate iron accumulation in CMT4C distinguish it from FRDA.

Peritoneal dialysis impairs nitric oxide homeostasis and may predispose infants with low systolic blood pressure to cerebral ischemia.

BACKGROUND & PURPOSE: Infants on chronic peritoneal dialysis (PD) have an increased risk of developing neurological morbidities; however, the underlying biological mechanisms are poorly understood. In this clinical study, we investigated whether PD-mediated impairment of nitric oxide (NO) bioavailability and signaling, in patients with persistently low systolic blood pressure (SBP), can explain the occurrence of cerebral ischemia. METHODS & RESULTS: Repeated blood pressure measurements, serial neuroimaging studies, and investigations of systemic nitrate and nitrite levels, as well as NO signaling, were performed in ten pediatric patients on PD. We consistently observed the loss of both inorganic nitrate (-17 ± 3%, P < 0.05) and nitrite (-34 ± 4%, P < 0.05) during PD, which may result in impairment of the nitrate-nitrite-NO pathway. Indeed, PD was associated with significant reduction of cyclic guanosine monophosphate levels (-59.4 ± 15%, P < 0.05). This reduction in NO signaling was partly prevented by using a commercially available PD solution supplemented with l-arginine. Although PD compromised nitrate-nitrite-NO signaling in all cases, only infants with persistently low SBP developed ischemic cerebral complications. CONCLUSIONS: Our data suggests that PD impairs NO homeostasis and predisposes infants with persistently low SBP to cerebral ischemia. These findings improve current understanding of the pathogenesis of infantile cerebral ischemia induced by PD and may lead to the new treatment strategies to reduce neurological morbidities.

Plasma nitrate/nitrite removal by peritoneal dialysis might predispose infants with low blood pressure to cerebral ischaemia.

The underlying pathogenic mechanisms of neurological complications in infants undergoing peritoneal dialysis (PD) are poorly understood. We report on four male infants treated with PD who developed symptomatic cerebral ischaemia. Blood pressure (BP) levels were low both before the event and at presentation. In two patients, we observed that the removal of nitrate and nitrite by PD could have impaired the nitrate/nitrite--nitrite oxide (NO) pathway, a system that generates NO independently of NO synthase. Our observation suggests that low BP and reduced NO bioavailability puts infants treated with PD at risk for impaired cerebral blood flow and consequently for brain ischaemia.