Association between Tubulointerstitial Nephritis and Uveitis Syndrome and Small-Vessel CNS Vasculitis: A Case of Polyautoimmunity.

INTRODUCTION: We report a case study of two male pediatric patients presenting with anterior uveitis and elevated renal function parameters. Both were diagnosed with tubulointerstitial nephritis and uveitis syndrome and subsequently developed diffuse cerebral symptoms such as headache, fatigue, and diziness. METHODS: Magnetic resonance images (MRIs) of the brain showed T2-hyperintense lesions with and without gadolinium enhancement leading to brain biopsy and diagnosis of small-vessel central nervous system (CNS) vasculitis in both cases. Both patients were treated according to BrainWorks small-vessel vasculitis protocol and symptoms vanished over the course of treatment. Follow-up MRIs up to 12 months after initiation of therapy showed no signs of recurrence indicating a monophasic disease. CONCLUSION: Small-vessel CNS vasculitis can occur simultaneously to other autoimmune diseases (ADs) in the scope of polyautoimmunity. As clinical findings of CNS vasculitis are often unspecific, neurological symptoms in nonneurological ADs should be adressed thoroughly. Under suspicion of small-vessel CNS vasculitis brain biopsy is still the gold standard and only secure way of definitive diagnosis.

Pre-hospital pulse glucocorticoid therapy in patients with ST-segment elevation myocardial infarction transferred for primary percutaneous coronary intervention: a randomized controlled trial (PULSE-MI).

BACKGROUND: Inflammation in ST-segment elevation myocardial infarction (STEMI) is an important contributor to both acute myocardial ischemia and reperfusion injury after primary percutaneous coronary intervention (PCI). Methylprednisolone is a glucocorticoid with potent anti-inflammatory properties with an acute effect and is used as an effective and safe treatment of a wide range of acute diseases. The trial aims to investigate the cardioprotective effects of pulse-dose methylprednisolone administered in the pre-hospital setting in patients with STEMI transferred for primary PCI. METHODS: This trial is a randomized, blinded, placebo-controlled prospective clinical phase II trial. Inclusion will continue until 378 patients with STEMI have been evaluated for the primary endpoint. Patients will be randomized 1:1 to a bolus of 250 mg methylprednisolone intravenous or matching placebo over a period of 5 min in the pre-hospital setting. All patients with STEMI transferred for primary PCI at Rigshospitalet, Copenhagen University Hospital, Denmark, will be screened for eligibility. The main eligibility criteria are age ≥ 18 years, acute onset of chest pain with < 12 h duration, STEMI on electrocardiogram, no known allergy to glucocorticoids or no previous coronary artery bypass grafting, previous acute myocardial infarction in assumed culprit, or a history with previous maniac/psychotic episodes. Primary outcome is final infarct size measured by late gadolinium enhancement on cardiac magnetic resonance (CMR) 3 months after STEMI. Secondary outcomes comprise key CMR efficacy parameters, clinical endpoints at 3 months, the peak of cardiac biomarkers, and safety. DISCUSSION: We hypothesize that pulse-dose methylprednisolone administrated in the pre-hospital setting decreases inflammation and thus reduces final infarct size in patients with STEMI treated with primary PCI. TRIAL REGISTRATION: EU-CT number: 2022-500762-10-00; Submitted May 5, 2022. CLINICALTRIALS: gov Identifier: NCT05462730; Submitted July 7, 2022, first posted July 18, 2022.

EFFECTIVENESS OF THE PHOTON CAPTURE BEAM TECHNOLOGY AND PHOTODYNAMIC IMPACT ON MALIGNANT HUMAN CELLS ІN A RESTING STATE. / ЕФЕКТИВНІСТЬ ФОТОН/ЗАХВАТНОЇ ПРОМЕНЕВОЇ ТЕХНОЛОГІЇ ТА ФОТОДИНАМІЧНОГО ВПЛИВУ НА ЗЛОЯКІСНІ КЛІТИНИ ЛЮДИНИ, ЩО ЗНАХОДЯТЬСЯ У СТАНІ СПОКОЮ.

OBJECTIVE: to investigate the structural and morphofunctional changes in test system of malignant (cell line A-549) human cells in a resting state exposed to X-rays in the presence of gadolinium-containing photon capture agent «Dotavist¼ and optical light (red spectrum) in combination with «Photolon¼ photosensitizer. METHODS: Passaged malignant human cell culture technology, X-ray and red light exposure, cytological and statistical methods. RESULTS: X-ray exposure at a dose of 10.0 Gy in the presence of photon capture agent «Dotavist¼ (at a 100 µg/ml nutrient medium concentration) led to death of 75-83 % of malignant cells in a resting state on the 6-8th day of cultivation. Photodynamic exposure (630 nm wavelength red light) in the presence of «Photolon¼ photosensitizer (200 µg/ml concentration) resulted in death of 69-73 % of malignant cells, respectively. Combination of the photon-capturing technology and photodynamic exposure resulted in death of 90 % of the malignant cells in a phase of steady-state growth on the 8th day of cultivation. CONCLUSION: Combination of the photon capture technology (X-ray exposure with gadolinium-containing photoncapture agent «Dotavist¼ in cytotoxic concentration) and photodynamic exposure in the presence of «Photolon¼ photosensitizer increased devitalization effectiveness of human non-small cell lung cancer cells (A-549 cell line) being in a steady-state growth phase up to 90 %. Ten percent of cells resistant to the applied technologies retained their proliferative potential, evident as changes in their morphology, genotype and adhesiveness during further cultivation.

The Clinical Evolution of Diffuse Myocardial Fibrosis in Patients With Arterial Hypertension and Heart Failure With Mildly Reduced Ejection Fraction Treated by Olmesartan or Sacubitril / Valsartan.

Aim      A 12-month evaluation of the potentialities of the angiotensin II receptor inhibitor olmesartan (Olme) and the angiotensin receptor and neprilysin inhibitor (ARNI) sacubitril/valsartan in patients with arterial hypertension (AH) and dyslipidemia in the dynamics of the following indicators of chronic heart failure (CHF): N-terminal pro-brain natriuretic peptide (NT-proBNP), left ventricular ejection fraction (LVEF), LV global longitudinal strain (LV GLS) in diffuse myocardial fibrosis (MF) previously diagnosed by magnetic resonance imaging (MRI).Material and methods  Olmesartan medoxomil (n=56) and sacubitril/valsartan (n=63) were used for 12 months in patients with hypertension, dyslipidemia and NYHA functional class II-III CHF with mid-range LVEF (CHFmrEF). MF was diagnosed by the following MRI criteria: late gadolinium enhancement and an increased proportion of extracellular matrix (33% or more). The frequency of persisting late gadolinium enhancement and the increased proportion of extracellular matrix (33% or more) was evaluated at 12 months; changes in systolic blood pressure (SBP), diastolic blood pressure (DBP), NT-proBNP, and LV GLS were evaluated after 3, 6, and 12 months of follow-up.Results Baseline parameters did not differ between groups. The late gadolinium enhancement and increased proportion of extracellular matrix were present at baseline in all patients of both groups (100%; p=1.0). Already at 3 months, statistically significant decreases in SBP and DBP were observed in both groups. In addition, the LV GLS monitoring showed LV GLS significantly increased in both groups after 3 months and continued changing after 6 and 12 months. The NT-proBNP concentration significantly decreased in both groups already after 3 months and continued to decrease after 6 and 12 months. At 6 and 12 months, sacubitril/valsartan was superior to olmesartan in reducing SBP and NT-proBNP and in restoring LV GLS. At 12 months, the incidence of persisting, abnormal late gadolinium enhancement and increased proportion of extracellular matrix was significantly less in the ARNI group.Conclusion      Olmesartan was demonstrated effective in the multi-modality therapy of CHFmrEF and MF in patients with AH and dyslipidemia. ARNI was superior to olmesartan in this regard, but further research of this issue is required.

Tissue factor as a potential coagulative/vascular marker in relapsing-remitting multiple sclerosis.

Objectives: Recent studies supported coagulation involvement in multiple sclerosis, an inflammatory-demyelinating and degenerative disease of the central nervous system. The main objectives of this observational study were to identify the most specific pro-coagulative/vascular factors for multiple sclerosis pathogenesis and to correlate them with brain hemodynamic abnormalities. Methods: We compared i) serum/plasma levels of complement(C)/coagulation/vascular factors, viral/microbiological assays, fat-soluble vitamins and lymphocyte count among people with multiple sclerosis sampled in a clinical remission (n=30; 23F/7M, 40 ± 8.14 years) or a relapse (n=30; 24F/6M, age 41 ± 10.74 years) and age/sex-matched controls (n=30; 23F/7M, 40 ± 8.38 years); ii) brain hemodynamic metrics at dynamic susceptibility contrast-enhanced 3T-MRI during relapse and remission, and iii) laboratory data with MRI perfusion metrics and clinical features of people with multiple sclerosis. Two models by Partial Least Squares Discriminant Analysis were performed using two groups as input: (1) multiple sclerosis vs. controls, and (2) relapsing vs. remitting multiple sclerosis. Results: Compared to controls, multiple sclerosis patients had a higher Body-Mass-Index, Protein-C and activated-C9; and a lower activated-C4. Levels of Tissue-Factor, Tie-2 and P-Selectin/CD62P were lower in relapse compared to remission and HC, whereas Angiopoietin-I was higher in relapsing vs. remitting multiple sclerosis. A lower number of total lymphocytes was found in relapsing multiple sclerosis vs. remitting multiple sclerosis and controls. Cerebral-Blood-Volume was lower in normal-appearing white matter and left caudatum while Cerebral-Blood-Flow was inferior in bilateral putamen in relapsing versus remitting multiple sclerosis. The mean-transit-time of gadolinium-enhancing lesions negatively correlated with Tissue-Factor. The top-5 discriminating variables for model (1) were: EBV-EBNA-1 IgG, Body-Mass-Index, Protein-C, activated-C4 and Tissue-Factor whereas for model (2) were: Tissue-Factor, Angiopoietin-I, MCHC, Vitamin A and T-CD3. Conclusion: Tissue-factor was one of the top-5 variables in the models discriminating either multiple sclerosis from controls or multiple sclerosis relapse from remission and correlated with mean-transit-time of gadolinium-enhancing lesions. Tissue-factor appears a promising pro-coagulative/vascular biomarker and a possible therapeutic target in relapsing-remitting multiple sclerosis. Clinical trial registration: ClinicalTrials.gov, identifier NCT04380220.

A prospective observational longitudinal study with a two-year follow-up of multiple sclerosis patients on Cladribine.

BACKGROUND: Cladribine was approved for the treatment of multiple sclerosis (MS). Real-world data is very limited. OBJECTIVES: To study the effectiveness and the safety of Cladribine treatment in only one group of MS patients after treatment with Cladribine for two years. METHODS: This observational, longitudinal prospective study. Eligible subjects were relapsing remitting MS patients who had at least two-year follow-up after Cladribine treatment. The primary endpoint was the proportion of relapse free patients. Secondary endpoints were ARR, change in EDSS scores, the proportion of patients with CDP, MRI activity, and NEDA-3 status, also the rate of occurrence of AEs. Patients were assessed for primary and secondary endpoints at the end of two years of follow-up. RESULTS: Of a total of seventy-two patients, 59 (81.9 %) were females, mean age of 36.32 + 10.06 years old, mean disease duration 7.21 + 6.19. Most patients (n = 32; 44.4 %) were naïve to any treatment. Forty patients (55.6 %) completed two courses of treatment. The primary endpoint showed that most of our cohort was relapse free (85 % versus 25 %; P < 0.001), Secondary endpoints showed that ARR was significantly reduced 0.15 + 0.36 versus 0.85 + 0.53; P < 0.01). Most of the cohort 90 % have no progression of disability. Few subjects had new T2 lesions (7.5 % versus 70.8 %; P < 0.001 and gadolinium enhancement 5 % versus 66.7 %; P < 0.001) in MRI compared to baseline. No evidence of disease activity 3 (NEDA-3) was achieved in 30 (75 %) patients. It was achieved in 87.5 % of naive patients versus 66.7 % in patients who received prior disease modification drugs before Cladribine initiation. Infections 6 (n = 6; 8.4 %) lymphocytopenia (n = 3; 4.2 %), and elevated liver enzymes (n = 1; 1.4 %) were reported. CONCLUSION: Cladribine treatment reduced significantly relapse rate and MRI activity. It was safe and tolerable. Early initiation of cladribine is associated with favorable outcomes.

SARS-CoV-2, vaccination or autoimmunity as causes of cardiac inflammation. Which form prevails?

The causes of cardiac inflammation during the COVID-19 pandemic are manifold and complex, and may have changed with different virus variants and vaccinations. The underlying viral etiology is self-evident, but its role in the pathogenic process is diverse. The view of many pathologists that myocyte necrosis and cellular infiltrates are indispensable for myocarditis does not suffice and contradicts the clinical criteria of myocarditis, i.e., a combination of serological evidence of necrosis based on troponins or MRI features of necrosis, edema, and inflammation based on prolonged T1 and T2 times and late gadolinium enhancement. The definition of myocarditis is still debated by pathologists and clinicians. We have learned that myocarditis and pericarditis can be induced by the virus via different pathways of action such as direct viral damage to the myocardium through the ACE2 receptor. Indirect damage occurs via immunological effector organs such as the innate immune system by macrophages and cytokines, and then later the acquired immune system via T cells, overactive proinflammatory cytokines, and cardiac autoantibodies. Cardiovascular diseases lead to more severe courses of SARS-CoV­2 disease. Thus, heart failure patients have a double risk for complicated courses and lethal outcome. So do patients with diabetes, hypertension, and renal insufficiency. Independent of the definition, myocarditis patients benefitted from intensive hospital care, ventilation, if needed, and cortisone treatment. Postvaccination myocarditis and pericarditis affect primarily young male patients after the second RNA vaccine. Both are rare events but severe enough to deserve our full attention, because treatment according to current guidelines is available and necessary.

Gadolinium injected concurrently with anesthetic can result in false-negative diagnostic intra-articular hip injections.

PURPOSE: The purpose of this paper was to evaluate the response to intra-articular hip injections with and without concurrent gadolinium administration. Our secondary outcome was to compare post-operative outcomes between patients with an initial false-negative gadolinium-containing injection and a matched control group. METHODS: Patients receiving a series of two hip diagnostic intra-articular injections (DIAI), the first with gadolinium for concurrent MRA and the second without gadolinium, were retrospectively identified. Pain response to DIAI, injectate volume, local anesthetic volume, inclusion of corticosteroids, and method of injection were compared between injections. False-negative injection was defined as < 50% pain relief with concurrent gadolinium, but ≥ 50% pain relief with subsequent anesthetic injection without gadolinium. False-negative injections in patients that ultimately underwent primary hip arthroscopy were identified from this cohort and matched in a 3:1 ratio to a control cohort to compare short-term post-operative single assessment numerical evaluation (SANE) outcomes. RESULTS: Forty-three patients underwent a series of anesthetic injections with and without gadolinium and met inclusion and exclusion criteria. Pain response was significantly different in injections performed with and without gadolinium (18% vs. 81%; p < 0.001). There were significant differences in total injectate volume, local anesthetic volume, corticosteroid use, and method of injection between injections, but these variables were not correlated with pain response. Fifteen patients with false-negative responses to injection underwent primary hip arthroscopy and were matched in a 3:1 ratio to a control cohort. There was no difference in short-term post-operative SANE scores between the gadolinium-sensitive and control groups (81.6 vs. 80.0, n.s.). CONCLUSION: Concurrent administration of intra-articular gadolinium with DIAI may result in a false-negative response to anesthetic. Additionally, in patients with initial false-negative DIAI with gadolinium, short-term post-operative outcomes after hip arthroscopy are similar to a matched cohort. LEVEL OF EVIDENCE: Level III.

Evaluation of Anticancer Activity of Zhubech, a New 5-FU Analog Liposomal Formulation, against Pancreatic Cancer.

Pancreatic cancer is projected to be the second leading cause of cancer-related death by 2030 in the US. The benefits of the most common systemic therapy for various pancreatic cancers have been masked by high drug toxicities, adverse reactions, and resistance. The use of nanocarriers such as liposomes to overcome these unwanted effects has become very popular. This study aims to formulate 1,3-bistertrahydrofuran-2yl-5FU (MFU)-loaded liposomal nanoparticles (Zhubech) and to evaluate itsstability, release kinetics, in vitro and in vivo anticancer activities, and biodistribution in different tissues. Particle size and zeta potential were determined using a particle size analyzer, while cellular uptake of rhodamine-entrapped liposomal nanoparticles (Rho-LnPs) was determined by confocal microscopy. Gadolinium hexanoate (Gd-Hex) was synthesized and entrapped into the liposomal nanoparticle (LnP) (Gd-Hex-LnP), as a model contrast agent, to evaluate gadolinium biodistribution and accumulation by LnPs in vivo using inductively coupled plasma mass spectrometry (ICP-MS). The mean hydrodynamic diameters of blank LnPs and Zhubech were 90.0 ± 0.65 nm and 124.9 ± 3.2 nm, respectively. The hydrodynamic diameter of Zhubech was found to be highly stable at 4 °C and 25 °C for 30 days in solution. In vitro drug release of MFU from Zhubech formulation exhibited the Higuchi model (R2 value = 0.95). Both Miapaca-2 and Panc-1 treated with Zhubech showed reduced viability, two- or four-fold lower than that of MFU-treated cells in 3D spheroid (IC50Zhubech = 3.4 ± 1.0 µM vs. IC50MFU = 6.8 ± 1.1 µM) and organoid (IC50Zhubech = 9.8 ± 1.4 µM vs. IC50MFU = 42.3 ± 1.0 µM) culture models. Confocal imaging confirmed a high uptake of rhodamine-entrapped LnP by Panc-1 cells in a time-dependent manner. Tumor-efficacy studies in a PDX bearing mouse model revealed a more than 9-fold decrease in mean tumor volumes in Zhubech-treated (108 ± 13.5 mm3) compared to 5-FU-treated (1107 ± 116.2 mm3) animals, respectively. This study demonstrates that Zhubech may be a potential candidate for delivering drugs for pancreatic cancer treatment.

Enhanced In Vivo Radiotherapy of Breast Cancer Using Gadolinium Oxide and Gold Hybrid Nanoparticles.

Radiation therapy has demonstrated promising effectiveness against several types of cancers. X-ray radiation therapy can be made further effective by utilizing nanoparticles of high-atomic-number (high-Z) materials that act as radiosensitizers. Here, in purpose of maximizing the radiation therapy within tumors, bovine serum albumin capped gadolinium oxide and gold nanoparticles (Gd2O3@BSA-Au NPs) are developed as a bimetallic radiosensitizer. In this study, we incorporate two high-Z-based nanoparticles, Au and Gd, in a single nanoplatform. The radiosensitizing ability of the nanoparticles was assessed with a series of in vitro tests, following evaluation in vivo in a breast cancer murine model. Enhanced tumor suppression is observed in the group that received radiation after administration of Gd2O3@BSA-Au NPs. As a result, cancer therapy efficacy is significantly improved by applying Gd2O3@BSA-Au NPs under X-ray irradiation, as evidenced by studies evaluating cell viability, proliferation, reactive oxygen species production, and in vivo anti-tumor effect.

SMART syndrome: a case report.

INTRODUCTION: Stroke-like migraine attacks after radiation therapy (SMART) syndrome, is a late complication of brain radiotherapy (1). Symptoms are commonly subacute in onset and involve migraine type of headache, seizures, focal neurologic deficits (2). Magnetic resonance imaging (MRI) findings are usually unilateral and posterior predominant cortical-subcortical hyperintensity, swelling and prominent gyriform (cortical and leptomeningeal) gadolinium enhancement in the areas of the brain that underwent irradiation with or without diffusion restriction (1). There is no standard treatment protocol for SMART syndrome. Antiepileptics and corticosteroids are commonly used drugs. CASE REPORT: A 65 years old woman was diagnosed with breast cancer with brain metastases and treated with more than 50 Gy brain radiotherapy. The patient presented with acute right-sided weakness and numbness, episodic myoclonic jerking of the right arm and leg, and gait instability five months later. MRI and magnetic resonance angiography of the brain with gadolinium revealed left parietooccipital cortical diffusion restriction and accompanying dilatation of the left posterior cerebral artery as new findings. Computed tomography (CT) perfusion revealed increased perfusion in the affected area. The patient was diagnosed with SMART syndrome. MANAGEMENT AND OUTCOME: The patient was treated with dexamethasone (16 mg/day) and anticonvulsant therapy. Myoclonic seizures had almost completely remitted. However, her cognitive impairment persisted, then the patient was arrested because of aspiration a month later. DISCUSSION: Besides confirming SMART syndrome, diagnostic investigations are also important to exclude other etiologies. Posterior reversible encephalopathy syndrome, post-ictal changes, meningoencephalitis, and cerebrovascular diseases are radiological differential diagnoses considered (3). Proper and early diagnosis of SMART syndrome is significant in preventing unnecessary aggressive approaches and appropriate treatment to avoid lesions of sequela.

Bevacizumab for Cerebral Radionecrosis: A Single-Center Experience.

BACKGROUND: Cerebral radionecrosis, a subacute or late effect of radiotherapy, can be debilitating and difficult to treat. Steroids can reduce symptoms, but have significant long-term side effects. Bevacizumab has been shown to reduce edema and other radiologic features associated with radionecrosis and improve patient symptoms. We report our experience using bevacizumab for cerebral radionecrosis. METHODS: We retrospectively reviewed the charts of all patients treated at our institution with bevacizumab for non-glioma-associated cerebral radionecrosis. We recorded change in symptoms, change in steroids, change in performance status, time to tumor progression, and time to death. We delineated the volume of necrosis pre- and post-bevacizumab on T1-post-gadolinium and fluid-attenuated inversion recovery (FLAIR) MRI scans. RESULTS: We identified 15 patients, 8 with brain metastases, 6 with meningioma, and 1 with nasopharyngeal carcinoma. Most received four doses of bevacizumab, 7.5 mg/kg q 3 weeks × 4 doses. Neuroimaging demonstrated a reduced T1 gadolinium-enhancing volume and edema in 14/15 patients (the average reduction in T1-post-gadolinium volume was 3.0 cm3, and average reduction in FLAIR volume was 27.9 cm3). There was no appreciable change in patient performance status. Steroid doses decreased in five of nine patients. There was a high rate (26%) of adverse events, including pulmonary embolism, stroke, and wound dehiscence. The median progression-free survival was 6.5 months. CONCLUSION: Although bevacizumab is commonly prescribed for cerebral radionecrosis, in our retrospective cohort, the clinical benefits were modest and there was significant toxicity.

Sarcoid Heart Disease: Review of Current Knowledge.

Sarcoidosis is a granulomatous disease with the potential of multiple organ system involvement and its etiology remains unknown. Cardiac involvement is associated with worse clinical outcome, and has been reported to be 20-30% in white and as high as 58% in Japanese populations with sarcoidosis. Clinical manifestations of cardiac sarcoidosis highly depend on the extent and location of granulomatous inflammation. The most frequent presentations include heart block, tachyarrhythmia, or heart failure. Endomyocardial biopsy is the most specific diagnostic test, but has poor sensitivity due to often patchy involvement. The diagnosis of cardiac sarcoidosis remains challenging due to nonspecific imaging findings. Both 18 F-fluorodeoxyglucose-positron emission tomography (FDG-PET) and cardiac magnetic resonance imaging can be used to evaluate cardiac sarcoidosis, but evaluate different stages of the disease process. FDG-PET detects metabolically active inflammatory cells while cardiac magnetic resonance imaging with late gadolinium enhancement reveals areas of myocardial necrosis and fibrosis. Aggressive therapy of symptomatic cardiac sarcoidosis is often sought due to the high risk of sudden death and/or progression to heart failure. Prednisone 20-40 mg a day is the recommended initial treatment. In refractory or severe cases, higher doses of prednisone, 1-1.5 mg/kg/d (or its equivalent) and addition of a steroid-sparing agent have been utilized. Methotrexate is added most commonly. Long-term improvement has been reported with the use of a combination of weekly methotrexate and prednisone versus prednisone alone. After initiation of treatment, a cardiac FDG-PET scan may be performed 2-3 months later to assess treatment response.

Standard deviations of MR signal intensities show a consistent trend during imaging follow-ups for glioblastoma patients when corrected for non-biological heterogeneity due to hardware and software variation.

INTRODUCTION: Glioblastoma multiforme (GBM) has a poor prognosis in spite of advanced MRI guided treatments today. Routine MRI using conventional T1 or advanced permeability based MRI of GBM often does not adequately represent changing tumor phases or overall survival. In this work, region of interest (ROI) based tissue MR standard deviation (SD) is demonstrated as an important MRI variable that could be a potential biomarker of GBM heterogeneity and radioresistance. MATERIALS AND METHODS: MRI characterization is often qualitative and lacks reproducibility. Using standardized MRI phantoms we have normalized retrospective records of 12 radioresistant GBM patients that underwent radiation therapy (RT) with concomitant and adjuvant temozolomide (TMZ) chemotherapy followed by serial MR imaging with gadolinium contrast. RESULTS AND DISCUSSION: We have identified key variables like hardware, software and protocol variation and have standardized those using test phantoms at five MR systems. We suggest GBM growth during the treatment period can be linked to normalized MRI signal and its fluctuations from session to session and from magnet to magnet by using an ROI derived standard deviation that corresponds to heterogeneity of the tumor MRI signal and changes in magnetic susceptibility. The time period observed in our patient group for peak standard deviations is approximately halfway through the tumor course and may correspond to a growth of more aggressive MES subtype of cells. To model the GBM heterogeneity we performed in vitro T1 weighted inversion recovery MRI experiments at 3 T for porous media of silicate particles in 1% aq solution of Gadavist and linked SD with particle size and local gadolinium volume within porous media. Such in vitro models mimic the increased SD in radioresistant GBM and as a novel contribution suggest that finer texture with high surface area might arise approximately halfway through the overall survival duration in GBM. CONCLUSION: Standard deviation as a measure of magnetic susceptibility may be collectively linked to the changes in texture, cell fractions (biological) and trapped contrast media (vascular as well as artifactual consequences) and should be evaluated as a potential biomarker of GBM aggressiveness than the overall MRI signal intensity from a GBM.

A case of lymphocytic myocarditis in a patient treated with an immune checkpoint inhibitor, a recent class of chemotherapy agents.

Chemotherapy-associated cardiotoxicity is a common adverse event. Immune checkpoint inhibitors (ICI) - a new class of monoclonal antibodies - have revolutionized the management of various diseases. Their use is expected to increase in the near future and their cardiac side effects have been increasingly recognized. CLINICAL CASE: We describe a case of a 67-year-old female patient with urothelial carcinoma undergoing treatment with pembrolizumab who presented to the emergency department with progressive fatigue, retrosternal pain and palpitations for three days. On admission she was diagnosed with acute heart failure (HF). The electrocardiogram revealed a right bundle branch block and ventricular bigeminy. Blood tests showed elevated troponin I, while transthoracic echocardiography revealed severe left ventricular dysfunction. Coronary angiography excluded coronary artery disease. Cardiac magnetic resonance revealed moderate left ventricular dysfunction and late gadolinium enhancement typical of myocarditis. Endomyocardial biopsy confirmed the diagnosis of lymphocytic myocarditis. In the first 48h of hospitalization, she developed transient complete AV block. Corticoid and HF therapy were initiated, leading to symptom improvement and disappearance of the rhythm disturbances. She was discharged on the 12th day, maintaining moderate LV dysfunction, which improved only mildly at a subsequent outpatient assessment. She died suddenly 35 days after discharge. CONCLUSION: Lymphocytic myocarditis is a serious cardiac side effect of ICI therapy. Pembrolizumab is increasingly used, so it is important to be aware of its effects, in order to perform an early diagnosis and provide adequate treatment. Corticosteroid therapy seems to be crucial in preventing disease progression and enabling ventricular remodeling.

Gadolinium-enhanced brain lesions in multiple sclerosis relapse.

OBJECTIVE: To study the clinico-radiological paradox in multiple sclerosis (MS) relapse by analyzing the number and location of gadolinium-enhanced (Gd+) lesions on brain MRI before methylprednisolone (MP) treatment. METHODS: We analyzed brain MRI from 90 relapsed MS patients in two Phase IV multicenter double-blind randomized clinical trials that showed the noninferiority of different routes and doses of MP administration. A 1.5- or 3-T brain MRI was performed at baseline before MP treatment and within 15 days of symptom onset. The number and location of Gd+ lesions were analyzed. Associations were studied using univariate analysis. RESULTS: Sixty-two percent of patients had at least 1 Gd+ brain lesion; the median number was 1 (interquartile range 0-4), and 41% of patients had 2 or more lesions. The most frequent location of Gd+ lesions was subcortical (41.4%). Gd+ brain lesions were found in 71.4% of patients with brainstem-cerebellum symptoms, 57.1% with spinal cord symptoms and 55.5% with optic neuritis (ON). Thirty percent of patients with brain symptoms did not have Gd+ lesions, and only 43.6% of patients had symptomatic Gd+ lesions. The univariate analysis showed a negative correlation between age and the number of Gd+ lesions (p=0.002). CONCLUSION: Most patients with relapse showed several Gd+ lesions on brain MRI, even when the clinical manifestation was outside of the brain. Our findings illustrate the clinico-radiological paradox in MS relapse and support the value of brain MRI in this scenario.

Efficacy, safety and patient reported outcomes in patients with active relapsing multiple sclerosis treated with ocrelizumab: Final results from the PRO-MSACTIVE study.

BACKGROUND: Ocrelizumab, a humanized anti-CD20 monoclonal antibody, has been approved in Europe for the treatment of adult patients with active relapsing multiple sclerosis (RMS) and primary progressive multiple sclerosis (PPMS), on the basis of previous phase III studies. However, limited data were available on ocrelizumab efficacy in RMS according to the Lublin definition of activity (clinical and/or imaging features) used in the current drug label. The PRO-MSACTIVE study was thus designed to provide additional data on ocrelizumab efficacy according to this definition, and also on safety and patient reported outcomes (PROs). METHODS: PRO-MSACTIVE is a national, multicenter, open-label, single-arm phase IV French study, conducted in patients with active RMS (relapsing-remitting multiple sclerosis, RRMS, or secondary progressive multiple sclerosis, SPMS). The primary endpoint, which was assessed at week (W) 48, was defined as the proportion of patients free of disease activity (defined by no relapses and no T1 gadolinium-enhancing nor new and/or enlarging T2 lesions using brain MRI). Disease activity, disability and PROs using 6 questionnaires for disease severity, quality of life, impact on work productivity, and treatment satisfaction were described at W24 and W48. Adverse events were described until W72. RESULTS: Among the 422 analyzed patients (RRMS: 376, SPMS: 46), 63.3% (95% CI [58.5%; 67.9%]) were free of disease activity at W48 (RRMS: 62.2% [57.1%; 67.2%], SPMS: 71.7% [56.5%; 84.0%]). A total of 358 patients (84.8%; RRMS: 84.6%, SPMS: 87.0%) were relapse-free up to W48, and the overall adjusted annualized relapse rate was 0.14 (RRMS: 0.15, SPMS: 0.09). Overall, 67.8% of patients (RRMS: 66.8%, SPMS: 76.1%) had no evidence of MRI activity (no T1 gadolinium-enhancing lesions [83.4%] and no new/enlarging T2 lesions [75.1%]); 58.5% of patients (RRMS: 57.7%, SPMS: 65.2%) achieved No Evidence of Disease Activity (NEDA: no relapses, no confirmed disability progression, and no MRI activity) at W48. All PRO scores were stable between the first dose of ocrelizumab and W48 and better outcomes were seen for patients having an EDSS score ≥4. Overall, 89.3% of patients reported adverse events, 62.3% adverse events assessed as related to ocrelizumab, and 8.5% serious adverse events. No serious infusion-related reactions, opportunistic infections, progressive multifocal leukoencephalopathy, nor deaths were reported. No new safety signal was identified. CONCLUSION: These data confirm the efficacy of ocrelizumab in a pragmatic setting and its favorable benefit-risk profile in patients with RMS. (ClinicalTrials.gov identifier: NCT03589105; EudraCT identifier: 2018-000780-91).

Myocardial involvement is not rare in anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis/clinically amyopathic dermatomyositis: a retrospective study.

Objectives: Studies concerning myocardial involvement (MI) in patients with anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis/clinically amyopathic dermatomyositis (anti-MDA5 Ab+ DM/CADM) are scarce. We aimed to characterize MI in our anti-MDA5 Ab+ DM/CADM cohort and to investigate its association with prognosis. Methods: In this single-center retrospective study, anti-MDA5 Ab+ hospitalized DM/CADM patients who underwent transthoracic echocardiography (TTE) were enrolled. Myocardial involvement was diagnosed according to abnormal cardiac structure and function detected by TEE. Clinical features and cardiac examination findings of patients with MI were analyzed. Clinical features, laboratory findings, complications, and treatments were compared between MI and non-MI, deceased, and survival patients. Logistic regression analysis was used to explore the independent risk factors for the occurrence of MI and prognostic factors for these patients. Results: Seventy-six hospitalized patients with anti-MDA5 Ab+ DM/CADM were enrolled. Twelve (15.8%) patients were diagnosed with MI. Of the 12 patients, three underwent cardiac magnetic resonance imaging (CMR) and late gadolinium enhancement (LGE) were noted for them. TEE revealed that eight (66.7%) patients had left atrial and/or ventricular enlargement, three (25.0%) had cardiac hypertrophy, six (50.0%) had diffuse ventricular wall dyskinesia, and seven (58.3%) had diastolic dysfunction. Six (50.0%) patients with MI developed heart failure (HF) during treatment. Of the 12 patients, one patient died of HF caused by myocarditis, three died of infection, and four died of exacerbation of rapidly progressive interstitial lung disease (RP-ILD). Logistic regression analysis revealed that dysphagia (OR 3.923, 95% CI 1.085, 14.181), NT-proBNP >600 pg/ml (OR 18.333, 95% CI 1.508, 222.875), and increased peripheral white blood cells (OR 1.201, 95% CI 1.003, 1.438) were risk factors for the occurrence of MI, but plasma albumin (OR 0.892, 95% CI 0.796, 0.999) was a protective factor. Both MI (OR 5.984, 95% CI 1.174, 30.496) and RP-ILD (OR 11.875, 95% CI 2.796, 50.411) were independent risk factors for the mortality of these anti-MDA5 Ab+ DM/CADM patients. Conclusion: Myocardial involvement is not rare and is an independent poor prognostic factor of anti-MDA5 Ab+ DM/CADM patients. Cardiac abnormality screening is necessary for them.

Is It Time for Ocrelizumab Extended Interval Dosing in Relapsing Remitting MS? Evidence from An Italian Multicenter Experience During the COVID-19 Pandemic.

In the COVID-19 pandemic era, safety concerns have been raised regarding the risk of severe infection following administration of ocrelizumab (OCR), a B-cell-depleting therapy. We enrolled all relapsing remitting multiple sclerosis (RRMS) patients who received maintenance doses of OCR from January 2020 to June 2021. Data were extracted in December 2021. Standard interval dosing (SID) was defined as a regular maintenance interval of OCR infusion every 6 months, whereas extended interval dosing (EID) was defined as an OCR infusion delay of at least 4 weeks. Three infusions were considered in defining SID vs. EID (infusions A, B, and C). Infusion A was the last infusion before January 2020. The primary study outcome was a comparison of disease activity during the A-C interval, which was defined as either clinical (new relapses) or radiological (new lesions on T1-gadolinium or T2-weighted magnetic resonance imaging (MRI) sequences). Second, we aimed to assess confirmed disability progression (CDP). A total cohort of 278 patients (174 on SID and 104 on EID) was enrolled. Patients who received OCR on EID had a longer disease duration and a higher rate of vaccination against severe acute respiratory syndrome-coronavirus 2 (p < 0.05). EID was associated with an increased risk of MRI activity during the A-C interval (OR 5.373, 95% CI 1.203-24.001, p = 0.028). Being on SID or EID did not influence CDP (V-Cramer 0.47, p = 0.342). EID seemed to be associated with a higher risk of MRI activity in our cohort. EID needs to be carefully considered for OCR-treated patients.

Ublituximab versus Teriflunomide in Relapsing Multiple Sclerosis.

BACKGROUND: The monoclonal antibody ublituximab enhances antibody-dependent cellular cytolysis and produces B-cell depletion. Ublituximab is being evaluated for the treatment of relapsing multiple sclerosis. METHODS: In two identical, phase 3, double-blind, double-dummy trials (ULTIMATE I and II), participants with relapsing multiple sclerosis were randomly assigned in a 1:1 ratio to receive intravenous ublituximab (150 mg on day 1, followed by 450 mg on day 15 and at weeks 24, 48, and 72) and oral placebo or oral teriflunomide (14 mg once daily) and intravenous placebo. The primary end point was the annualized relapse rate. Secondary end points included the number of gadolinium-enhancing lesions on magnetic resonance imaging (MRI) by 96 weeks and worsening of disability. RESULTS: A total of 549 participants were enrolled in the ULTIMATE I trial, and 545 were enrolled in the ULTIMATE II trial; the median follow-up was 95 weeks. In the ULTIMATE I trial, the annualized relapse rate was 0.08 with ublituximab and 0.19 with teriflunomide (rate ratio, 0.41; 95% confidence interval [CI], 0.27 to 0.62; P<0.001); in the ULTIMATE II trial, the annualized relapse rate was 0.09 and 0.18, respectively (rate ratio, 0.51; 95% CI, 0.33 to 0.78; P = 0.002). The mean number of gadolinium-enhancing lesions was 0.02 in the ublituximab group and 0.49 in the teriflunomide group (rate ratio, 0.03; 95% CI, 0.02 to 0.06; P<0.001) in the ULTIMATE I trial and 0.01 and 0.25, respectively (rate ratio, 0.04; 95% CI, 0.02 to 0.06; P<0.001), in the ULTIMATE II trial. In the pooled analysis of the two trials, 5.2% of the participants in the ublituximab group and 5.9% in the teriflunomide group had worsening of disability at 12 weeks (hazard ratio, 0.84; 95% CI, 0.50 to 1.41; P = 0.51). Infusion-related reactions occurred in 47.7% of the participants in the ublituximab group. Serious infections occurred in 5.0% in the ublituximab group and in 2.9% in the teriflunomide group. CONCLUSIONS: Among participants with relapsing multiple sclerosis, ublituximab resulted in lower annualized relapse rates and fewer brain lesions on MRI than teriflunomide over a period of 96 weeks but did not result in a significantly lower risk of worsening of disability. Ublituximab was associated with infusion-related reactions. (Funded by TG Therapeutics; ULTIMATE I and II ClinicalTrials.gov numbers, NCT03277261 and NCT03277248.).