Hemosiderin Research Articles

Hemosiderin Detection inside the Mammillary Bodies Using Quantitative Susceptibility Mapping on Patients with Wernicke-Korsakoff Syndrome.

Hemorrhage inside the mammillary bodies (MMBs) is known to be one of the findings of Wernicke encephalopathy. Brain MRI of two patients with Wernicke-Korsakoff syndrome (WKS) demonstrated high susceptibility values representing hemosiderin deposition in MMBs by using quantitative susceptibility mapping (QSM). QSM provided additional information of susceptibility values to susceptibility-weighted imaging in diagnosis of WKS.

Incidence and symptomatology of ARIA

AbstractBackgroundTo summarize available evidence on ARIAs from randomized clinical trials (RCTs) testing anti–β‐amyloid mAbs in patients with AD and to provide a comprehensive update about risk factors, clinical correlates, and implications for withholding and reinitiating treatment.MethodA literature search of MEDLINE/PubMed, Embase, and Cochrane Library and a search of ClinicalTrials.gov were conducted through September 15, 2021. Publications describing RCTs, secondary analyses of RCT data, and case reports of ARIAs were included. Strengths of clinical data were graded according to the Oxford Centre for Evidence‐Based Medicine.ResultTwenty‐two RCTs, 11 secondary analyses of RCTs, and 1 case report, including in total 15 508 adult patients (8483 women [54.7%]; mean [SD] age, 69.6 [8.3] years) were selected for inclusion. Signal alterations that included parenchymal edema and sulcal effusion leading to transient hyperintensities on fluid‐attenuated inversion recovery and T2‐weighted sequences were termed ARIA‐E, whereas those consisting of hemosiderin deposits, including parenchymal microhemorrhages and leptomeningeal superficial siderosis, were termed ARIA‐H. Apolipoprotein E (ApoE) ε4 genotype was the main risk factor for both ARIA types; ARIA‐E incidence was further associated with treatment dose, affecting the 55%of ApoE ε4 carriers in the high‐dose aducanumab treatment group. Both ARIA types manifested early during study course, and symptomatic cases accounted for the 6.1% to 39.3%of ARIA‐E cases at higher treatment doses across RCTs, whereas ARIA‐H cases were generally asymptomatic. Most ARIA‐E cases resolved with treatment withholding, although corticosteroid administration was required anecdotally. ARIA‐E recurrence after dose reinitiation or adjustment varied from 13.8% to 25.6%across RCTs.ConclusionEvidence suggests that ARIAs are frequent, mostly asymptomatic collateral events of amyloid‐modifying therapies, highlighting the need for standardized clinical and neuroradiological management protocols in real‐world clinical settings.

The Histopathological Landscape of Synovitis in Hemophilic Arthropathy

Recurrent joint bleeding leads to chronic arthropathy in severe hemophilia A and B. With the recent introduction of novel therapies and the increased availability of treatments for patients with hemophilia, a very tight control of bleeding is achievable, but some patients still experience synovitis oat target joints. A deeper knowledge of the synovial membranes in hemophilic synovitis may help the personalised treatment. However, very few data are available regarding the histopathological characteristics of the synovial membrane of patients with hemophilic arthropathy. We studied the histopathological aspects of the synovial membranes of nine patients undergoing orthopedic surgery in order to describe the overall characteristics and the immune infiltrate. Hematoxylin-eosin coloration was applied. Immunohistochemical analysis was performed and two synovitis scores currently used for rheumatoid arthritis were applied: the Krenn and the Humby scores. Moreover, we evaluated synovial collagen fibrosis by means of Masson trichromic staining, grading subintimal fibrosis semiquantitatively. Iron deposits were parallelly assessed with Perls histochemical stain and graded semiquantitatively. For each case we also evaluated whether iron deposits were mostly found in the intracellular (mainly siderophages) or extracellular compartment. Nine patients (six affected by severe hemophilia A, one by moderate hemophilia A and two by severe hemophilia B) with a mean age of 41 ± 14 years, were included. All patients were in prophylaxis with replacement drugs. Synovial membrane was collected during surgery (four total knee replacement, one arthroscopic knee synovectomy, two total ankle replacement, two arthroscopic ankle debridement), following good clinical practice. Informed consent was obtained before the procedure. All the synovial membrane samples were characterised by synovial hyperplasia and hemosiderin deposits. In seven out of nine samples a pauci-immune infiltrate was observed, whereas in two samples a lymphoid-myeloid infiltrate with lymphoid aggregates was present. All cases showed ≥1 grade fibrosis, with eight out of nine cases showing moderate to severe subintimal fibrosis and only one case with lympho-myeloid infiltrate exhibiting mild fibrosis. Iron deposition across the cohort was heterogeneous, with equal distribution of cases with mild (33%), moderate (33%) and severe (33%) iron deposition. Iron deposits were observed mostly in the intracellular compartment (i.e siderophages) with scattered extracellular presence, with the exception of one case with mild and almost exclusive extracellular deposition. In hemophilic arthropathy, we fount typical characteristics of the blood-induced synovial hyperplasia in the majority of the studied synovial membranes, with a pauci-immune infiltrate resembling degenerative arthropathies such as osteoarthritis. By contrast, lymphoid aggregates similar to inflammatory arthritis were less frequent. Fibrosis and iron deposition were more frequent than in osteoarthritis. It should be noted that all the samples were collected from patients undergoing orthopedic surgery due to long-lasting synovitis. A larger study including patients at different stages of arthropathy may help clarify if a different histopathological landscape may correlate with a different clinical history and predict the response to different therapeutic approaches.

Surgical closure of spinal cerebrospinal fluid leaks improves symptoms in patients with superficial siderosis.

Spinal cerebrospinal fluid (CSF) leaks may cause a myriad of symptoms, most common being orthostatic headache. In addition, ventral spinal CSF leaks are a possible etiology of superficial siderosis (SS), a rare condition characterized by hemosiderin deposits in the central nervous system (CNS). The classical presentation of SS involves ataxia, bilateral hearing loss, and myelopathy. Unfortunately, treatment options are scarce. This study was undertaken to evaluate whether microsurgical closure of CSF leaks can prevent further clinical deterioration or improve symptoms of SS. This cohort study was conducted using data from a prospectively maintained database in two large spontaneous intracranial hypotension (SIH) referral centers in Germany and Switzerland of patients who meet the modified International Classification of Headache Disorders, 3rd edition criteria for SIH. Patients with spinal CSF leaks were screened for the presence of idiopathic infratentorial symmetric SS of the CNS. Twelve patients were included. The median latency between the onset of orthostatic headaches and symptoms attributed to SS was 9.5 years. After surgical closure of the underlying spinal CSF leak, symptoms attributed to SS improved in seven patients and remained stable in three. Patients who presented within 1 year after the onset of SS symptoms improved, but those who presented in 8-12 years did not improve. We could show a significant association between patients with spinal longitudinal extrathecal collections and SS. Long-standing untreated ventral spinal CSF leaks can lead to SS of the CNS, and microsurgical sealing of spinal CSF leaks might stop progression and improve symptoms in patients with SS in a time-dependent manner.

Intraarticular Delivery of AAV5-Mir-125a-5p Regulates Key Molecular Mediators of Hemophilic Arthropathy

Background: Hemophilic arthropathy (HA) is a major comorbidity in patients with hemophilia characterized by chronic inflammation of the joints, stiffness and loss of function. The expression of microRNAs are known to be altered in various joint diseases such as rheumatoid arthritis and osteoarthritis which share clinical attributes with HA. One such microRNA is miR-125a-5p, known to be involved in regulating inflammatory mediators in the arthritic joints. The current study was designed to investigate the role of miR125a-5p in HA and examine the phenotypic effect of its targeted reconstitution in the joints. Methods: We utilized a chronic arthropathy model in hemophilia A mice to study the impact of miR125a-5p in disease progression. First, we performed a targeted screen of miR125a-5p and its target genes (STAT1 and TRAF6) using digital PCR (dPCR). Further, to validate if reconstitution of miR125a-5p aids in modulating the molecular mediators of HA, we performed the Adeno-associated virus vector (AAV) serotype 5 targeted delivery of miR125a (AAV5-miR125a) either alone (2.13x10 11vgs/joint) or in combination with capsid-modified AAV8-human Factor 8 (F8)(AAV8-F8) gene therapy at a low dose (1x10 11vgs/animal) intravenously in F8 tm1kaz/Jmice. Briefly, the animals were administered with vectors (alone or in combination), and seven days post vector administration, the animals were subjected to multiple bleeding episodes in the right knee (Day 0, 14, and 30) to mimic chronic hemarthrosis. On day 45, blood samples were collected from experimental animals for FVIII specific clotting assay, and joint tissues were isolated to perform further molecular and histochemical analysis. Results: Our dPCR analysis revealed a significant reduction (2-fold) of miR125a-5p (3518 copies/µl vs 7242 copies/µl, p≤0.0001) in injured joints compared to control joints. Absolute quantification of target genes, namely STAT1 and TRAF6 showed significantly higher expression in injured joints (7.6 to 10.6 fold, respectively) when compared to control joints. Further immunohistochemical examination of joint sections from the experimental mice confirmed the elevated expression of these immunological mediators (STAT1, TRAF6). Upon administration of AAV vectors containing miR125a and/or F8, we observed a significantly increased expression of miR125a-5p (~12 fold) in only miR125a vector-administered animals while the combination vector treated group had, ~44-fold higher levels of miR125a-5p. The coagulant assay revealed an increased FVIII activity (~17%) in only F8 vector-treated animals and approximately 20% FVIII levels in mice that received both miR125a and F8 vectors at low doses. Surprisingly, the animals that received only F8 vectors also showed significantly upregulated miR125a-5p expression (~20 fold) signifying the role of miR125a-5p in HA pathology. In line with the above findings, immunohistochemical analysis of joint tissues revealed decreased expression of immunological markers STAT1, TRAF6 (direct targets of miR125a-5p), and the chondro-degenerative matrix metalloproteinases 3, 9, 13 in vector-treated groups when compared to injured joints with no treatment. Hematoxylin and Eosin (H&E) staining of joint tissues from experimental animals was performed which revealed that animals that received both miR125a and F8 vectors showed decreased synovial hyperplasia, villi formation, cartilage erosion, and reduced hemosiderin deposition signifying moderate phenotype rescue. Conclusions: Our data confirms that miR125a-5p is a major molecular target that regulates inflammatory response in chronic HA. Targeted delivery of miR125a in tandem with F8 gene augmentation had an impact on several molecular mediators like STAT1, TRAF6, MMP3,9, and 13. The reconstitution of miR125a and a higher dose of F8 vectors might be beneficial to reverse chronic HA.

Chronic toxicity and liver histopathology of mosquito fish (Gambusia holbrooki) exposed to natural and modified nanoclays

Nanoclays are found in the air, water, and soil, and modified nanoclays are being developed and used in several consumer products. For example, modified nanoclays are used to remove pollutants from wastewater. Ironically, however, nanoclays are now considered emerging contaminants. Indeed, release of modified nanoclays in aquatic systems, even as remediating agents, could adversely affect associated wildlife. However, aquatic organisms have interacted with natural nanoclays for millennia, and it is unclear if modified nanoclays induce stronger effects than the nanoclays that occur naturally. The concentrations over which nanoclays occur and illicit negative effects are not well studied. This study investigated the dose response of a natural nanoclay (Na+montmorillonite) relative to two modified nanoclays (Cloisite®30B and Novaclay™) on survival, body condition, and liver pathomorphology of Gambusia holbrooki after 14 days of exposure. Although none of the nanoclays affected survival and body condition of G. holbrooki over 14 days, each nanoclay induced histopathological changes in liver tissues at very low concentrations (LOAEL: 0.01 mgL−1). The effects of nanoclays on hepatic cell circulatory (blood cell aggregation with increased number of Kupffer cells and hemosiderin deposits), regressive (hepatocyte vacuolization), and degenerative (cell death) changes of mosquito fish varied among nanoclay types. Novaclay™ at low concentrations caused circulatory changes on hepatic tissues of G. holbrooki, whereas both natural nanoclays and Cloisite®30B showed little effect on circulatory endpoints. In contrast, all of the nanoclays induced regressive and degenerative changes on liver tissues of mosquito fish across all concentrations tested. This study clearly reveals that natural and modified nanoclays have important health implications for fish and other aquatic organisms. Consequently, the widespread use of modified nanoclays in several applications and increased release of natural nanoclays through erosion or other processes needs to be evaluated in more detail especially in the context of their safety for aquatic systems.

Three-Year Interim Analysis Results of the AOZORA Study to Evaluate the Long-Term Safety and Joint Health in Children with Hemophilia A without Factor VIII Inhibitors Receiving Emicizumab

Background: Recurrent joint bleeding from a young age in people with hemophilia A (PwHA) may lead to hemophilic arthropathy, resulting in limited movement and chronic pain. Emicizumab is a bispecific monoclonal antibody that bridges activated factor (F) IX and FX to substitute for activated FVIII and provides stable plasma concentrations and maintenance of trough levels within the therapeutic range. Limitations in long-term joint health preservation have been reported with FVIII prophylaxis (Warren et al. Blood Adv 2020); it is expected that emicizumab may overcome these limitations, as joint health improvements have been demonstrated in PwHA aged 12-39 years (Kiialainen et al. Haemophilia 2022). Here, we report the 3-year interim analysis of the ongoing, open-label, Phase IV AOZORA study (JapicCTI-194701), analyzing long-term safety and joint health in pediatric PwHA without FVIII inhibitors receiving emicizumab (Shima et al. BMJ Open 2022). Methods: Eligible participants were aged <12 years with severe hemophilia A (HA) without FVIII inhibitors. Participants entered AOZORA as emicizumab-naïve or following the Phase III HOHOEMI study (Shima et al. Haemophilia 2019). Primary endpoints include adverse events (AEs), and joint health and function assessed by magnetic resonance imaging (MRI) and the Hemophilia Joint Health Score (HJHS) version 2.1. MRI evaluation uses the International Prophylaxis Study Group (IPSG) MRI scale; a positive IPSG score indicates pathological changes in the knee and/or ankle joints. Exploratory endpoints include annualized bleed rate (ABR) for treated bleeds and treated joint bleeds. All participants will receive emicizumab for 6 years from their first dose until study end. Results: Data cut-off was the last day of Week 145 for individual participants. Ten participants entered from HOHOEMI and 20 participants were newly enrolled. The median (range) age was 4.2 (0.7-11.1) years, all participants were male, and 27 (93.1%) participants had been treated with prior FVIII prophylaxis ( Table 1). One participant had 1 target joint (knee) at Week 1. In AOZORA, 5 (16.7%) participants experienced 7 emicizumab-related AEs: 6 injection site reactions in 5 participants and 1 case of anemia in 1 participant. Seven serious AEs, reported as unrelated to emicizumab, occurred in 5 (16.7%) participants. No thrombotic events or thrombotic microangiopathies occurred. Twenty-nine participants at Week 1 and 26 participants at Week 145 were assessed using the IPSG MRI scale. At Week 145, MRI scores remained at 0 for 11 (42.3%) of the 26 participants. Of 116 joints assessed at Week 1, 28 (24.1%) had soft tissue changes (effusion/hemarthrosis, synovial hypertrophy and/or hemosiderin deposition; Table 2). At Week 145, 104 joints were assessed and 33 (31.7%) of those had soft tissue changes. Of 10 (8.6%) joints with synovial hypertrophy and hemosiderin at Week 1, all had improved at Week 145 and synovial hypertrophy and hemosiderin were no longer present in 9 joints. One new joint developed synovial hypertrophy and hemosiderin at Week 145. The rest of the soft tissue changes were effusion/hemarthrosis, present in 21 (18.1%) joints at Week 1 and 31 (29.8%) at Week 145. Thirty participants at Week 1 and 27 participants at Week 145 were assessed using the HJHS v2.1. Eighteen (66.7%) participants' HJHS scores remained at 0 from Week 1 to Week 145 and 1 (3.7%) participant's remained at 4; 6 (22.2%) participants' scores improved; 2 (7.4%) participants' scores worsened. Mean (standard deviation) HJHS total score improved from 0.90 (1.79) at Week 1 to 0.44 (1.05) at Week 145. The mean (95% confidence interval [CI]) ABR for treated bleeds was 3.7 (0.94-9.80) prior to emicizumab and 0.7 (0.01-5.10) while receiving emicizumab. The mean (95% CI) ABR for treated joint bleeds was 0.4 (0.00-4.55) prior to emicizumab and 0.2 (0.00-4.04) while receiving emicizumab. Conclusions: This 3-year interim analysis of the AOZORA study confirmed the safety profile of emicizumab. The proportion of joints with effusion/hemarthrosis increased by Week 145. However, all joints with synovial hypertrophy and hemosiderin, which are strongly associated with the progression of arthropathy (Gualtierotti et al. J Thromb Haemost 2021), improved by Week 145. These results suggest that emicizumab is effective in maintaining and improving joint health in pediatric PwHA.

168 Cases of aneurysmal dermatofibroma and 29 cases of hemosiderotic dermatofibroma: A clinicopathologic study.

Aneurysmal dermatofibroma (ADF) and hemosiderotic dermatofibroma (HDF) are rare variants of dermatofibroma (DF) characterized by distinct histologic features. While HDF is traditionally considered a precursor to ADF, supporting evidence is limited, and the etiology remains unclear. A retrospective analysis of 2128 DF cases (2016-2019) was conducted to investigate the clinicopathologic characteristics of ADF, HDF, and other DFs. Histopathologically diagnosed DF cases were examined for ADF and HDF. Univariate analyses were performed to compare clinicopathologic features. Among the cases, 168 (7.9%) were ADF and 29 (1.4%) were HDF. Aneurysmal dermatofibroma and HDF shared several common characteristics, including lower occurrence in females, larger size, and increased cellularity (all P < .0001). Notably, 29% of ADFs lacked hemosiderin deposition. Aneurysmal dermatofibroma primarily manifested on exposed areas (face and forearm, both P < .001). In contrast, 41% of HDFs occurred on the lower leg (P = .018), and all lower leg HDFs exhibited signs of venous stasis, distinguishing them from other HDFs (P < .0001). Our findings indicate a potential close relationship between ADF and HDF. Contrary to conventional beliefs, we also presented the possibility of ADF progressing into HDFs. Physical trauma may induce ADF, and HDFs may emerge from ADFs in conjunction with venous stasis in the lower extremities.

Quality-Switched Nd:YAG 1064 nm Laser for Management of Hyperpigmentation and Atrophic Scars after Long-Pulsed Nd:YAG Laser for Treatment of Leg Telangiectasias—A Case Report

The correction of leg telangiectasias is one of the most frequently performed interventions in the Western world. While sclerotherapy remains the gold standard of treatment, several studies have shown comparable efficacy and, in some situations, an even more favorable use of lasers as an alternative treatment option. The most frequent side effect of both treatment options is hyperpigmentation, which usually clears spontaneously in most cases but can be challenging to treat if it persists. The origin of this hyperpigmentation is not fully understood; small studies point to hemosiderin as the causative pigment, at least in post-sclerotherapy hyperpigmentation. More rare side effects of the treatment include ulcerations and scarring. Quality-switched (QS) Nd:YAG lasers have demonstrated good efficacy in treating hemosiderin depositions in the skin, post-inflammatory hyperpigmentation and atrophic scars. We present a case of post-inflammatory hyperpigmentation and scarring after laser treatment of leg telangiectasia with a long-pulsed Nd:YAG laser that was successfully treated using a QS Nd:YAG 1064 nm laser. This case suggests the QS Nd:YAG laser as a possible treatment option in cases of hyperpigmentation with various origins, including hemosiderin and melanin, and scarring after laser treatment of leg telangiectasias.

Bone SPECT/CT in Advanced Diffuse Tenosynovial Giant Cell Tumor of the Wrist.

Tenosynovial giant cell tumor, previously known as pigmented villonodular synovitis, is a benign low-grade fibrohistiocytic proliferation with hemosiderin deposits in synovial joints. Mostly affecting the knee, it can also manifest in other synovial joints, infrequently also in the wrist. Tenosynovial giant cell tumor typically causes intense radionuclide uptake in all phases in planar bone scintigraphy, making a differentiation from other bone tumors or osteomyelitis difficult, especially in cases associated with extensive bone destruction. We present a case of an unusually advanced and extended tenosynovial giant cell tumor of the wrist in bone scintigraphy, SPECT/CT, radiograph, and MRI.

Case report: a case of primary intracranial parasagittal meningeal angiosarcoma

BackgroundAngiosarcoma, also known as malignant hemangioendothelioma, is a rare vasogenic malignant tumor, commonly found on the skin of the head and neck, rarely occurring in the intracranial region. As for intracranial meningeal angiosarcoma, only 8 cases have been reported before and there is no clinical study with large sample size. We report here a case of parasagittal meningeal angiosarcoma.Case descriptionA 48-year-old Chinese male patient was admitted to our hospital due to headache accompanied by bilateral lower limb weakness. On admission, CT showed a high-density mass on both sides of the sagittal sinus at the top of the frontal lobe. We performed exploratory surgical resection of the tumor. During the operation, it was found that the tumor originated from the dura mater and extensively invaded the surrounding brain tissue and skull, and the surrounding hemosiderin deposition was observed. Postoperative pathology suggested angiosarcoma.ConclusionsIntracranial meningeal angiosarcoma is difficult to accurately diagnose before surgery, so radiologists and neurosurgeons need to strengthen their understanding of this disease. The presence of extensive superficial hemosiderin deposition during operation may contribute to the diagnosis, and immunohistochemistry is very important for the diagnosis of intracranial angiosarcoma.

A Case of Patient with Bilateral Cochleovestibular Function Loss due to Infratentorial Superficial Siderosis

Superficial siderosis (SS) is a rare neurodegenerative condition characterized by hemosiderin deposition in the central nervous system, which sometimes leads to sensorineural hearing loss and vestibular dysfunction. This case report details the diagnosis and treatment of a 63-year-old female patient presenting with a yearlong history of postural instability and recent symptoms of sudden right-sided hearing loss and imbalance. Physical examination and imaging revealed bilateral deafness and infratentorial SS. Treatment, including medication, vestibular exercises, high-dose steroids, and hyperbaric oxygen therapy, led to a significant alleviation of dizziness but no improvement in hearing. This case emphasizes the need for clinicians to consider SS in patients presenting with sudden-onset hearing loss and dizziness, even without prior any medical history or trauma, to accurately identify the underlying cause.

Histopathological and Behavioral Impairments in Zebrafish (Danio rerio) Chronically Exposed to a Cocktail of Fipronil and Pyriproxyfen.

Lately, the high incidence of pesticide usage has attracted everyone's interest due to the serious effects produced. Fipronil (FIP) is a phenylpyrazole compound that acts on the insect's GABA neurotransmitter by inhibiting its activity. Moreover, the literature reports highlight its implication in neurodevelopmental abnormalities and oxidative stress production in different organisms. Similarly, pyriproxyfen (PYR) is known to affect insect activity by mimicking the natural hormones involved in the maturation of the young insects. The aim of the present study was to investigate the impact of the mixture of these pesticides on the tissues and behavior of zebrafish. To assess the influence of this cocktail on zebrafish, three groups of animals were randomly selected and exposed to 0, 0.05, and 0.1 mg L-1 FIP and PYR mixture for five days. The fish were evaluated daily by the T-maze tests for locomotor activity and the light-dark test and recordings lasted four min. The data were quantified using the EthoVision software. Our results indicated significant changes in locomotor activity parameters that showed increased levels following exposure to the mixture of FIP and PYR. On the other hand, the mixture also triggered anxiety in the zebrafish, which spent more time in the light area than in the dark area. In addition, mixture-induced histological changes were observed in the form of numerous hemosiderin deposits found in various zebrafish tissues. The current findings indicate that the mixture of FIP and PYR can have considerable consequences on adult zebrafish and may promote or cause functional neurological changes in addition to histological ones.

Multiple Bone Cysts Caused by Hyperparathyroidism: A Case Report and Review of the Literature.

Brown tumor, a skeletal complication of severe hyperparathyroidism, comprises reparative granulation tissue and proliferating fibrous tissue with hemosiderin deposition. Multiple brown tumors are extremely rare complications of primary hyperparathyroidism. A 41-year-old woman presented with pain in the left knee. Radiography showed multiple cystic lesions in both femurs and the left proximal tibia, and additional radiography showed multiple cystic lesions in the left humerus and ulna. Magnetic resonance imaging (MRI) revealed multiple cystic lesions in the bilateral femurs, left proximal tibia, and ilium. Laboratory tests revealed hypercalcemia (albumin-corrected calcium level, 13.9 mg/dl), hypophosphatemia (phosphate level, 1.6 mg/dl), elevated level of alkaline phosphatase level (614 U/l), and markedly elevated parathyroid hormone (PTH) level (1,070 pg/ml; normal range=10-65 ng/l). 99mTc-hexakis-2-methoxyisobutyl-isonitrile scintigraphy revealed tracer accumulation in the left upper parathyroid gland, which was consistent with parathyroid tumor. Although resection of the parathyroid tumor was planned, the patient developed parathyroid apoplexy before tumor excision. After the parathyroid apoplexy, serum calcium and PTH levels temporarily normalized. Resurgence of the PTH level was observed 2 years after the diagnosis, and the patient underwent left upper parathyroidectomy. One year after the tumor excision, the patient had no symptoms, and MRI showed shrinkage of the cystic bone lesions. This report emphasizes the importance of considering hyperparathy-roidism as a differential diagnosis for patients with multiple bone lesions.

Superficial siderosis presenting as hemiparesis in a paediatric patient with congenital Factor V deficiency – A case report.

Superficial siderosis is a rare abnormality caused by deposition of hemosiderin in the subpial or subarachnoid spaces of the brain, cranial nerves, and spinal cord. It results from chronic repetitive bleeding in the subpial/subarachnoid space. Magnetic resonance imaging of the brain is the diagnostic modality of choice. We describe a rare case of an 18-month-old male, a known case of congenital Factor V deficiency, who presented with recurrent vomiting, irritability and right-sided hemiparesis. On Magnetic resonance imaging, there was hypointense coating of the surface of the brainstem and cerebellum with ventricular dilatation. This case emphasizes the fact that superficial siderosis should be specifically looked for when evaluating a patient with a history of previous intracranial bleed followed by a thorough search for the source of the hemorrhage.

Amyloid-β (Aβ) immunotherapy induced microhemorrhages are associated with activated perivascular macrophages and peripheral monocyte recruitment in Alzheimer’s disease mice

BackgroundAmyloid-related imaging abnormalities (ARIA) have been identified as the most common and serious adverse events resulting from pathological changes in the cerebral vasculature during several recent anti-amyloid-β (Aβ) immunotherapy trials. However, the precise cellular and molecular mechanisms underlying how amyloid immunotherapy enhances cerebral amyloid angiopathy (CAA)-mediated alterations in vascular permeability and microhemorrhages are not currently understood. Interestingly, brain perivascular macrophages have been implicated in regulating CAA deposition and cerebrovascular function however, further investigations are required to understand how perivascular macrophages play a role in enhancing CAA-related vascular permeability and microhemorrhages associated with amyloid immunotherapy.MethodsIn this study, we examined immune responses induced by amyloid-targeting antibodies and CAA-induced microhemorrhages using histology and gene expression analyses in Alzheimer’s disease (AD) mouse models and primary culture systems.ResultsIn the present study, we demonstrate that anti-Aβ (3D6) immunotherapy leads to the formation of an antibody immune complex with vascular amyloid deposits and induces the activation of CD169+ perivascular macrophages. We show that macrophages activated by antibody mediated Fc receptor signaling have increased expression of inflammatory signaling and extracellular matrix remodeling genes such as Timp1 and MMP9 in vitro and confirm these key findings in vivo. Finally, we demonstrate enhanced vascular permeability of plasma proteins and recruitment of inflammatory monocytes around vascular amyloid deposits, which are associated with hemosiderin deposits from cerebral microhemorrhages, suggesting the multidimensional roles of activated perivascular macrophages in response to Aβ immunotherapy.ConclusionsIn summary, our study establishes a connection between Aβ antibodies engaged at CAA deposits, the activation of perivascular macrophages, and the upregulation of genes involved in vascular permeability. However, the implications of this phenomenon on the susceptibility to microhemorrhages remain to be fully elucidated. Further investigations are warranted to determine the precise role of CD169 + perivascular macrophages in enhancing CAA-mediated vascular permeability, extravasation of plasma proteins, and infiltration of immune cells associated with microhemorrhages.

Post-Surgical Depositions of Blood Products Are No Major Confounder for the Diagnostic and Prognostic Performance of CEST MRI in Patients with Glioma.

Amide proton transfer (APT) and semi-solid magnetization transfer (ssMT) imaging can predict clinical outcomes in patients with glioma. However, the treatment of brain tumors is accompanied by the deposition of blood products within the tumor area in most cases. For this reason, the objective was to assess whether the diagnostic interpretation of the APT and ssMT is affected by methemoglobin (mHb) and hemosiderin (Hs) depositions at the first follow-up MRI 4 to 6 weeks after the completion of radiotherapy. A total of 34 participants underwent APT and ssMT imaging by applying reconstruction methods described by Zhou et al. (APTwasym), Goerke et al. (MTRRexAPT and MTRRexMT) and Mehrabian et al. (MTconst). Contrast-enhancing tumor (CE), whole tumor (WT), mHb and Hs were segmented on contrast-enhanced T1wCE, T2w-FLAIR, T1w and T2*w images. ROC-analysis, Kaplan-Meier analysis and the log rank test were used to test for the association of mean contrast values with therapy response and overall survival (OS) before (WT and CE) and after correcting tumor volumes for mHb and Hs (CEC and WTC). CEC showed higher associations of the MTRRexMT with therapy response (CE: AUC = 0.677, p = 0.081; CEC: AUC = 0.705, p = 0.044) and of the APTwasym with OS (CE: HR = 2.634, p = 0.040; CEC: HR = 2.240, p = 0.095). In contrast, WTC showed a lower association of the APTwasym with survival (WT: HR = 2.304, p = 0.0849; WTC: HR = 2.990, p = 0.020). Overall, a sophisticated correction for blood products did not substantially influence the clinical performance of APT and ssMT imaging in patients with glioma early after radiotherapy.

E69 Localised intraarticular pigmented villonodular synovitis in an adolescent patient: a case-based review of the literature

Abstract Introduction Pigmented villonodular synovitis (PVNS) is a rare, locally aggressive subtype of tenosynovial giant cell tumours that affect the synovium of the joints and tendons, occurring either focally or diffusely associated with the deposition of hemosiderin into the involved joint(s) and soft tissues. Although PVNS is historically considered an inflammatory process, recent evidence suggests the possibility of a neoplastic transformation. In addition, despite being typically found as a monoarticular knee disorder, other large and small joints can also be affected. The disease is rarely reported in African children, with most reported cases not histologically confirmed. We, therefore, present the first histologically proven case of localised intraarticular PVNS in an African teenager who presented with unilateral left knee swelling and pain. Method/Setting We report the case of a 16-year-old male teenager who presented to the rheumatology clinic with a nine-month history of non-traumatic anterior left knee swelling and pain that increased over time with associated difficulty walking and standing without aid. After clinical examination and relevant investigations, Magnetic Resonant Imaging (MRI) was done to confirm our suspicion of PVNS. Findings/Treatment Examination revealed a tender, swollen knee with a fluctuant palpable infrapatellar mass. Knee arthrocentesis yielded about 200mls of non-clotted hemorrhagic effusions. The patient had an open synovectomy following MRI, which was highly suggestive of pigmented villonodular synovitis with extensive suprapatellar bursitis. Specific histological findings (below) further confirmed the diagnosis. He commenced early physiotherapy, and symptoms resolved without recurrence of swelling eleven months after surgery. Conclusion This case highlights the visual presentation of an uncommon joint disorder and suggests it is considered a differential diagnosis of non-traumatic monoarticular pain and swelling in our rheumatology clinic set-up and among teenagers in whom juvenile rheumatoid arthritis would have been the first differential. Key words: Pigmented villonodular synovitis, Synovectomy, Multinucleated giant cells Contribution statement: AA conceived the idea to write the case report, draft the first manuscript, and manage the patient. YA, HO and AF edited the manuscript, while AIL interpreted the histological findings. All the authors approved the final version of the manuscript. Disclosure statement: None declared. Ethics and patient consent: This case report adheres to the Helsinki declaration, and the patient’s parents gave written consent to publish the details of the information. Additional information: Any institution did not fund this publication. Acknowledgements: We thank Dr Isaac Akanbi and Dr Bukar for interpreting the MRI and performing the surgery.

A rare case of bilateral Vanishing Testicle Syndrome

Vanishing testicle syndrome (VTS) is due to regression of already formed testes. This could occur at any stage during or after testicular descent due any insult resulting in testicular atrophy. VTS is estimated to affect 1:1250 males. We present a rare case of a 12-year-old boy presenting with absent secondary sexual characteristics and short stature found to have bilateral vanishing testicle syndrome. His testes were impalpable at neonatal examination. At the age of 1.5 years an ultrasound scan detected the right testis in the inguinal ring, measuring 1.5 x 1 cm with features suggestive of ischaemia with likely acute or subacute torsion. The left testes was seen in the inguinal canal already atrophied by that time. Subsequently, on surgical exploration the right testis was found atrophied in the inguinal canal, and was replaced in the right sub-dartose pouch, but left testis could not be identified. Surprisingly, 4 months later laparoscopic exploration failed to identify either of the testes except for bilateral atrophied gubernaculum, indicating testicular regression. At the age of 7 years, magnetic resonance imaging confirmed the absence of either of the testes, with no remnants. On examination his height was 146.5cm, which was between the 25th and 50th percentile for that age, and below his mid-parental height range. He had no androgenic hair growth, testes were impalpable and had a prepubertal penis accounting to tanner stage of 1. He had hypergonadotrophic hypogonadism. Pubertal induction was done with testosterone injections which resulted in height gain and development of secondary sexual characteristics.Introduction: The entity Vanishing testicle syndrome (VTS) was coined by Abryaratne et al. in 1969, and is also referred to as "Testicular regression syndrome" [1][2]. The two essential diagnostic criteria are; visualizing the blind-ending spermatic vessels within the retro-peritoneum or spermatic vessels and vas deferens exiting a closed internal inguinal ring, and Testis not palpated during examination under anaesthesia[2][3]. A small fibrotic nodule or nubbin with dystrophic calcification and haemosiderin deposition is usually found at the end of the spermatic cord, with or without identifiable testicular or para-testicular structures [2][3]. Cryptorchidism is reported in 1 -4.6% full term and 1.1 -45.3% pre-mature male infants [4]. This prevalence of cryptorchidism decreases to 1 % by the age of 1 year [5]. Testes are non-palpable in 10 -20% cases of cryptorchidism, and of these VTS accounts for 35 - 60% [6] VTS occurs in &lt; 5% cases of cryptorchidism [7]. VTS is estimated to affect 1:1250 males [8]. We present a rare case of bilateral VTS in a 12 year old boy who presented with short stature and absent secondary sexual characteristics with unpalpable testes.

CLRM-09 MAPPING THE DISTRIBUTION AND CLINICAL ASSOCIATIONS OF BRAIN METASTASES IN RENAL CELL CARCINOMA

Abstract Brain metastases (BrM) commonly occur in renal cell carcinoma (RCC) and often present with hemorrhagic features. The distribution patterns of BrM in RCC and their associations with clinical outcomes remain unclear. We conducted a retrospective neuroanatomical distribution analysis combined with clinical review of our surgical RCC BrM cohort. Sixty-seven BrMs from 46patients (age 63±10years, 25males) were included. The majority of BrM (55%) were found in the left hemisphere, with frontal (45%), parietal (21%), and occipital (18%) lobes being the most commonly affected areas. Hemosiderin deposits, as detected by MRI, were present in 82% of BrM, while hemorrhage, as detected by CT, was present in 80% of BrM. Patients with solitary BrM had a higher KPS (p=0.006) and lower disease burden (p=0.004) compared to those with multiple BrM. Mean 1D and 2D(RANO) tumor dimensions were 2.0±1.1cm and 4.7±4.9cm2, respectively, and correlated with the neutrophil count at BrM diagnosis (r=0.3; p=0.01). Hemosiderin deposits were associated with larger tumors (2.6±1.0cm vs. 1.8±0.7cm, p=0.04), lower platelet counts (p=0.01), and higher hemoglobin levels (p=0.08). Shorter Brain Metastasis-Free Survival was associated with hemosiderin deposits on MRI (log-rank p=0.04) and renal vein thrombosis (RVT) in the primary specimen (log-rank p=0.002). RVT at primary diagnosis was associated with both hemosiderin deposits on MRI (p=0.05) and hemorrhage on CT (p=0.03), and CNS progression-free survival was shorter in patients with RVT (7.3±1.7 months vs. 21.0±4.7 months). When including only significant predictors, right hemispheric BrM lateralization (HR 2.6, p=0.06), hemosiderin deposits in BrM (HR 6.5, p=0.02), and IMDC risk groups (intermediate HR=2.9; poor-risk HR=25.6; p&amp;lt;0.04) were independent prognostic factors for shorter OS on multivariable analysis. Our results demonstrate that mapping the BrM distribution o in RCC can provide clinically relevant insights. Hemosiderin deposits in BrM may have prognostic implications. Further analyses are ongoing.