Randomized controlled double-blind trial of methylprednisolone versus placebo in patients with post-COVID-19 syndrome and cognitive deficits: study protocol of the post-corona-virus immune treatment (PoCoVIT) trial.

INTRODUCTION: Post-COVID-19 Syndrome (PCS) includes neurological manifestations, especially fatigue and cognitive deficits. Immune dysregulation, autoimmunity, endothelial dysfunction, viral persistence, and viral reactivation are discussed as potential pathophysiological mechanisms. The post-corona-virus immune treatment (PoCoVIT) trial is a phase 2a randomized, controlled, double-blind trial designed to evaluate the effect of methylprednisolone versus placebo on cognitive impairment in PCS. This trial is designed based on the hypothesised autoimmunological pathogenesis and positive aberrations, employing a series of off-label applications. METHODS: Recruitment criteria include a diagnosis of PCS, a minimum age of 18 years and self-reported cognitive deficits at screening. A total of 418 participants will be randomly assigned to either verum or placebo intervention in the first phase of the trial. The trial will consist of a first trial phase intervention with methylprednisolone versus placebo for six weeks, followed by a six-week treatment interruption period. Subsequently, an open second phase will offer methylprednisolone to all participants for six weeks. Outpatient follow-up visits will take place two weeks after each trial medication cessation. The third and final follow-up, at week 52, will be conducted through a telephone interview. The primary outcome measures an intra-patient change of 15 or more points in the memory satisfaction subscale of the Multifactorial Memory Questionnaire (MMQ) from baseline to follow-up 1 (week 8). Key secondary outcomes include long-term intra-patient changes in memory satisfaction from baseline to follow-up 2 (week 20), changes in other MMQ subscales (follow-up 1 and 2), and changes in neuropsychological and cognitive scores, along with assessments through questionnaires focusing on quality of life, fatigue, and mood over the same periods. Exploratory outcomes involve molecular biomarkers variations in serum and cerebrospinal fluid, as well as structural and functional brain magnetic resonance imaging (MRI) parameters changes related to cognition. PERSPECTIVE: This trial aims to contribute novel evidence for treating patients with PCS, with a primary focus on those manifesting cognitive deficits. By doing so, it may enhance comprehension of the underlying pathophysiological mechanisms, thereby facilitating biomarker research to advance our understanding and treatment of patients with PCS.

Successful Systemic Lysis Therapy of a Floating Carotid Thrombus in an Acute Stroke Patient with Known Immune Thrombocytopenia (ITP) on Ongoing Eltrombopag Therapy and Acute COVID-19 Infection: a Case Report.

Patients with immune thrombocytopenia (ITP) under eltrombopag therapy are vulnerable to thrombotic disbalance, both due to the disease itself and therapy-related hypercoagulability. Vascular events such as the development of a free-floating carotid thrombus are known rare complications of acute COVID-19 infections due to endothelial inflammation and presumptive underlying hypercoagulable state. In patients at risk, the onset of new focal neurological symptoms should prompt immediate angiographic diagnostics and, if necessary, appropriate treatment. Here, we report a case of a 38-year-old female with a medical history of ITP and the presence of COVID-19 infection presenting an acute sensorimotor hemiparesis of the right side while on eltrombopag therapy. Initial CT angiography revealed a free-floating thrombus in the left common carotid artery. Upon admission, the patient's platelet count was significantly elevated at 896 × 109/l. After systemic lysis therapy, the thrombus was fully dissolved. Follow-up diffusion-weighted imaging revealed multilocular cortical infarction of the left MCA territory. The patient soon recovered and was discharged with residual mild sensorimotor deficits in the right arm. Eltrombopag was paused at admission, and the patient's platelet count was quickly returning to normal. She was discharged with a daily intake of acetylsalicylic acid, a reduced daily dose of eltrombopag, and weekly monitoring of her platelet count for the next three months. This unique case highlights the need for caution in patients at vascular risk who contract COVID-19 and discusses thrombocytic derailment under thrombopoietin receptor agonist therapy in the context of an acute COVID-19 infection.

Response assessment methods for patients with hepatic metastasis from rare tumor primaries undergoing transarterial chemoembolization.

PURPOSE: This study assessed the response to conventional transarterial chemoembolization (cTACE) in patients with liver metastases from rare tumor primaries using one-dimensional (1D) and three-dimensional (3D) quantitative response assessment methods, and investigate the relationship of lipiodol deposition in predicting response. MATERIALS AND METHODS: This retrospective bicentric study included 16 patients with hepatic metastases from rare tumors treated with cTACE between 2002 and 2017. Multi-phasic MR imaging obtained before and after cTACE was used for assessment of response. Response evaluation criteria in solid tumors (RECIST) and modified-RECIST (mRECIST) were utilized for 1D response assessment, and volumetric RECIST (vRECIST) and enhancement-based quantitative European Association for Study of the Liver EASL (qEASL) were used for 3D response assessment. The same day post-cTACE CT scan was analyzed to quantify intratumoral lipiodol deposition (%). RESULTS: The mean and standard deviation (SD) of diameter of treated lesions per targeted area was 7.5 ± 5.4 cm, and the mean and SD of number of metastases in each targeted area was 4.2 ± 4.6. cTACE was technically successful in all patients, without major complications. While RECIST and vRECIST methods did not allocate patients with partial response, mRECIST and qEASL identified patients with partial response. Intratumoral lipiodol deposition significantly predicted treatment response according qEASL (R2 = 0.470, p < 0.01), while no association was shown between lipiodol deposition within treated tumor area and RECIST or mRECIST (p > 0.212). CONCLUSION: 3D quantitative volumetric response analysis can be used for stratification of response to cTACE in patients with hepatic metastases originating from rare primary tumors. Lipiodol deposition could potentially be used as an early surrogate to predict response to cTACE.

Memory enhancement with stimulants: Differential neural effects of methylphenidate, modafinil, and caffeine. A pilot study.

Human memory is susceptible to manipulation in many respects. While consolidation is well known to be prone to disruption, there is also growing evidence for the enhancement of memory function. Beside cognitive strategies and mnemonic training, the use of stimulants may improve memory processing in healthy adults. In this single-dose, double-blind, within-subject, randomized, placebo-controlled pilot study, 20 mg methylphenidate (N = 13) or 200 mg modafinil (N = 12) or 200 mg caffeine (N = 14) were administrated to in total 39 healthy participants while performing a declarative memory task. Each participant received only one substance and functional magnetic resonance imaging (fMRI) was used to assess drug-dependent memory effects of the substance for encoding and recognition compared to task-related activation under placebo. While methylphenidate showed some behavioral effect regarding memory recall performance, on the neural level, methylphenidate-dependent deactivations were found in fronto-parietal and temporal regions during recognition of previously learned words. No BOLD alterations were seen during encoding. Caffeine led to deactivations in the precentral gyrus during encoding whereas modafinil did not show any BOLD signal alterations at all. These results should be interpreted with caution since this a pilot study with several limitations, most importantly the small number of participants per group. However, our main finding of task-related deactivations may point to a drug-dependent increase of efficiency in physiological response to memory processing.

Imaging Hallmarks of the Tumor Microenvironment in Glioblastoma Progression.

Glioblastoma progression involves multifaceted changes in vascularity, cellularity, and metabolism. Capturing such complexities of the tumor niche, from the tumor core to the periphery, by magnetic resonance imaging (MRI) and spectroscopic imaging (MRSI) methods has translational impact. In human-derived glioblastoma models (U87, U251) we made simultaneous and longitudinal measurements of tumor perfusion (Fp), permeability (Ktrans), and volume fractions of extracellular (ve) and blood (vp) spaces from dynamic contrast enhanced (DCE) MRI, cellularity from apparent diffusion coefficient (ADC) MRI, and extracellular pH (pHe) from an MRSI method called Biosensor Imaging of Redundant Deviation in Shifts (BIRDS). Spatiotemporal patterns of these parameters during tumorigenesis were unique for each tumor. While U87 tumors grew faster, Fp, Ktrans, and vp increased with tumor growth in both tumors but these trends were more pronounced for U251 tumors. Perfused regions between tumor periphery and core with U87 tumors exhibited higher Fp, but Ktrans of U251 tumors remained lowest at the tumor margin, suggesting primitive vascularization. Tumor growth was uncorrelated with ve, ADC, and pHe. U87 tumors showed correlated regions of reduced ve and lower ADC (higher cellularity), suggesting ongoing proliferation. U251 tumors revealed that the tumor core had higher ve and elevated ADC (lower cellularity), suggesting necrosis development. The entire tumor was uniformly acidic (pHe 6.1-6.8) early and throughout progression, but U251 tumors were more acidic, suggesting lower aerobic glycolysis in U87 tumors. Characterizing these cancer hallmarks with DCE-MRI, ADC-MRI, and BIRDS-MRSI will be useful for exploring tumorigenesis as well as timely therapies targeted to specific vascular and metabolic aspects of the tumor microenvironment.

Cryotherapy for nodal metastasis in NSCLC with acquired resistance to immunotherapy.

Novel approaches with checkpoint inhibitors in immunotherapy continue to be essential in the treatment of non-small cell lung cancer (NSCLC). However, the low rate of primary response and the development of acquired resistance during the immunotherapy limit their long-term effectiveness. The underlying cause of acquired resistance is poorly understood; potential management strategies for patients with acquired resistance are even less clear. Here, we report the case of a 75-year-old female smoker with cough, fatigue, and weight loss that was found to have an 8.6 cm right upper lobe lung lesion with local invasion, adenopathy, and a malignant pericardial effusion. This lesion was biopsied and identified to be cT3N3M1b squamous cell cancer of the lung without any recognizable PD-L1 expression on tumor cells. For her metastatic NSCLC, the patient underwent two lines of conventional chemotherapy before initiation of combination immunotherapy with an anti-PD-L1 and anti-CTLA-4 antibody. Though she initially achieved a response, she thereafter progressed and developed immunotherapy resistant lymph nodal metastasis. While cervical lymph nodes could be surgically removed, another metastasis in an aortocaval area required a more sensitive therapy like thermal ablation. The aortocaval node was partially treated with a single treatment of cryotherapy and demonstrated durable complete response. Cryotherapy for checkpoint immunotherapy resistant metastasis appears to be a safe and feasible treatment for treating metastatic disease in non-small cell lung cancer. The prospect of cryotherapy adjuvancy may enable local control of metastatic disease after initial response to immune checkpoint immunotherapy and may impact on overall outcomes.