Search

CSF1 receptor-related leukoencephalopathy is a rare genetic disorder presenting with severe, adult-onset white matter dementia as one of the leading symptoms. Within the central nervous system, the affected CSF1-receptor is expressed exclusively in microglia cells. Growing evidence implicates that replacing the defective microglia with healthy donor cells through hematopoietic stem cell transplant might halt disease progression. Early initiation of that treatment is crucial to limit persistent disability. However, which patients are suitable for this treatment is not clear, and imaging biomarkers that specifically depict lasting structural damage are lacking. In this study, we report on two patients with CSF1R-related leukoencephalopathy in whom allogenic hematopoietic stem cell transplant at advanced disease stages led to clinical stabilization. We compare their disease course with that of two patients admitted in the same timeframe to our hospital, considered too late for treatment, and place our cases in context with the respective literature. We propose that the rate of clinical progression might be a suitable stratification measure for treatment amenability in patients. Furthermore, for the first time we evaluate [18F] florbetaben, a PET tracer known to bind to intact myelin, as a novel MRI-adjunct tool to image white matter damage in CSF1R-related leukoencephalopathy. In conclusion, our data add evidence for allogenic hematopoietic stem cell transplant as a promising treatment in CSF1R-related leukoencephalopathy patients with slow to moderate disease progression.

A 28-year-old female patient with active and difficult-to-treat systemic lupus erythematosus (SLE) was diagnosed with liver-dominant diffused large B-cell lymphoma. Repeated response 18F-FDG-PET studies showed persistently high, and, despite intensified immunochemotherapy, further increasing metabolic activity of one of the hepatic lymphoma residuals, whereas all other initial lymphoma manifestations had achieved complete metabolic remission. As biopsy of the 18F-FDG-PET-positive liver residual turned out to be inconclusive, complete resection was performed. Subsequent histopathological examination, however, revealed only necrotic tissue. Thus, no further lymphoma treatment was scheduled. The patient undergoes regular surveillance and is disease-free 13 months after resection. Similarly, treatment of SLE is no longer required due to lack of activity already after the first two cycles of lymphoma treatment. The case shows how closely SLE and diffused large B-cell lymphoma can be connected and stresses the importance of interdisciplinary treatment approaches. In the future, artificial intelligence may help to further classify 18F-FDG-PET-positive lymphoma residuals. This could lead to an increase of the positive predictive value of interim- and end-of-treatment 18F-FDG-PET. The patient’s point of view enables another instructive perspective on the course of treatment, which often remains hidden to treating physicians due to lack of time in clinical routine.

Up to 60% of patients with aggressive B-cell lymphoma who receive chimeric antigen receptor (CAR) T-cell therapy experience treatment failure and subsequently have a poor prognosis. Allogeneic hematopoietic stem cell transplantation (alloHSCT) remains a potentially curative approach for patients in this situation. Induction of a deep response prior to alloHSCT is crucial for long-term outcomes, but the optimal bridging strategy following relapse after CAR T-cell therapy has not yet been established. Polatuzumab vedotin, an antibody drug conjugate targeting CD79b, is a novel treatment option for use in combination with rituximab and bendamustine (Pola-BR) in relapsed or refractory disease. Patients: We report two heavily pretreated patients with primary refractory diffuse large B-cell lymphoma (DLBCL) and primary mediastinal B-cell lymphoma (PMBCL) respectively who relapsed after therapy with CAR T-cells with both nodal and extranodal manifestations of the disease. After application of three courses of Pola-BR both patients achieved a complete metabolic remission. Both patients underwent alloHSCT from a human leukocyte antigen (HLA)-mismatched donor following conditioning with busulfan and fludarabine and are disease free 362 days and 195 days after alloHSCT respectively. We conclude that Pola-BR can be an effective bridging therapy before alloHSCT of patients relapsing after CAR T-cell therapy. Further studies will be necessary to define the depth and durability of remission of this salvage regimen before alloHSCT.

Objectives: Autoradiography on brain tissue is used to validate binding targets of newly discovered radiotracers. The purpose of this study was to correlate quantification of autoradiography signal using the novel next-generation tau positron emission tomography (PET) radiotracer [18F]PI-2620 with immunohistochemically determined tau-protein load in both formalin-fixed paraffin-embedded (FFPE) and frozen tissue samples of patients with Alzheimer's disease (AD) and Progressive Supranuclear Palsy (PSP).Methods: We applied [18F]PI-2620 autoradiography to postmortem cortical brain samples of six patients with AD, five patients with PSP and five healthy controls, respectively. Binding intensity was compared between both tissue types and different disease entities. Autoradiography signal quantification (CWMR = cortex to white matter ratio) was correlated with the immunohistochemically assessed tau load (AT8-staining, %-area) for FFPE and frozen tissue samples in the different disease entities.Results: In AD tissue, relative cortical tracer binding was higher in frozen samples when compared to FFPE samples (CWMRfrozen vs. CWMRFFPE: 2.5-fold, p < 0.001), whereas the opposite was observed in PSP tissue (CWMRfrozen vs. CWMRFFPE: 0.8-fold, p = 0.004). In FFPE samples, [18F]PI-2620 autoradiography tracer binding and immunohistochemical tau load correlated significantly for both PSP (R = 0.641, p < 0.001) and AD tissue (R = 0.435, p = 0.016), indicating a high agreement of relative tracer binding with underlying pathology. In frozen tissue, the correlation between autoradiography and immunohistochemistry was only present in AD (R = 0.417, p = 0.014) but not in PSP tissue (R = −0.115, p = n.s.).Conclusion: Our head-to-head comparison indicates that FFPE samples show superiority over frozen samples for autoradiography assessment of PSP tau pathology by [18F]PI-2620. The [18F]PI-2620 autoradiography signal in FFPE samples reflects AT8 positive tau in samples of both PSP and AD patients.

Mast cell sarcoma comprises a rare aggressive mast cell neoplasia with histological, clinical, and genetic features distinct from other mast cell neoplasm. Until now, prognosis is still poor due to high rates of progression to mast cell leukemia and failure of conventional chemotherapies. Our here presented first report about successful allogeneic hematopoietic stem cell transplantation leading to remission in a case of tonsillar MCS represents a promising potential curative treatment option for this rare and often fatal disease.

(S)-[18F]fluspidine ((S)-[18F]1) has recently been explored for positron emission tomography (PET) imaging of sigma-1 receptors in humans. In the current report, we have used plasma samples of healthy volunteers to investigate the radiometabolites of (S)-[18F]1 and elucidate their structures with LC-MS/MS. For the latter purpose additional in vitro studies were conducted by incubation of (S)-[18F]1 and (S)-1 with human liver microsomes (HLM). In vitro metabolites were characterized by interpretation of MS/MS fragmentation patterns from collision-induced dissociation or by use of reference compounds. Thereby, structures of corresponding radio-HPLC-detected radiometabolites, both in vitro and in vivo (human), could be identified. By incubation with HLM, mainly debenzylation and hydroxylation occurred, beside further mono- and di-oxygenations. The product hydroxylated at the fluoroethyl side chain was glucuronidated. Plasma samples (10, 20, 30 min p.i., n = 5-6), obtained from human subjects receiving 250–300 MBq (S)-[18F]1 showed 97.2, 95.4, and 91.0% of unchanged radioligand, respectively. In urine samples (90 min p.i.) the fraction of unchanged radioligand was only 2.6% and three major radiometabolites were detected. The one with the highest percentage, also found in plasma, matched the glucuronide formed in vitro. Only a small amount of debenzylated metabolite was detected. In conclusion, our metabolic study, in particular the high fractions of unchanged radioligand in plasma, confirms the suitability of (S)-[18F]1 as PET radioligand for sigma-1 receptor imaging.