A case of autoimmune encephalitis in a patient with a solitary intracranial plasmacytoma.

A 65-year-old woman presented with fever and abnormal behavior. Magnetic resonance imaging showed swelling of the left medial temporal lobe and an intracranial extra-axial occipital tumor. While her neurological symptoms improved after the administration of corticosteroid therapy under the suspicion of autoimmune encephalitis, the occipital tumor unexpectedly shrank, and the diagnosis of a solitary plasmacytoma was confirmed by biopsy. Additional examinations revealed elevated anti-glutamate receptor antibodies in the cerebrospinal fluid. The patient was diagnosed with autoimmune encephalitis concurrent with an intracranial solitary plasmacytoma. Central nervous system involvement can be considered a neurological complication in patients with a solitary plasmacytoma.

Longitudinal Changes in Iron and Myelination Within Ischemic Lesions Associate With Neurological Outcomes: A Pilot Study.

BACKGROUND: Combined quantitative susceptibility mapping and R2* relaxometry can distinguish iron and myelin components in ischemic lesions. We aimed to investigate whether longitudinal changes in magnetic susceptibility and R2* values within ischemic lesions were associated with neurological outcomes. METHODS: In this single-center prospective study, we included patients, 20 to 90 years of age, who were consecutively admitted to the stroke care unit between August 2020 and March 2022 due to acute ischemic stroke. The participants underwent 2 instances of quantitative susceptibility mapping and R2* relaxometry scanning before and after stroke rehabilitation. We compared the changes in these quantitative measures across different subtypes of acute ischemic stroke. Multiple linear regression models were used to investigate the associations between the National Institutes of Health Stroke Scale scores and the mean magnetic susceptibility and R2* values in ischemic lesions. RESULTS: Among a total of 112 patients with acute ischemic stroke, 32 participants (aged 73.3±9.4 years; 20 men and 12 women) were evaluated. The median time from stroke onset to the first imaging was 5 days and that to the second imaging was 102 days. The changes in magnetic susceptibility values of branch atheromatous disease were higher than those of cardioembolism (mean difference, 0.018 [95% CI, 0.009-0.027] ppm; P<0.001) and lacunar (mean difference, 0.013 [95% CI, 0.005-0.020] ppm; P=0.004). Across all patients, the changes in National Institutes of Health Stroke Scale scores were associated with those of magnetic susceptibility values (coefficient, 0.311 [95% CI, 0.098-0.520]; P=0.017) but not with R2* values (coefficient, 0.114 [95% CI, -0.127 to 0.345]; P=0.291). CONCLUSIONS: The longitudinal changes in the magnetic susceptibility values within ischemic lesions were associated with neurological outcomes during the restorative stages poststroke in patients experiencing acute ischemic stroke. REGISTRATION: URL: https://www.umin.ac.jp/ctr/; Unique identifier: UMIN000050719.

Relationship between brain iron dynamics and blood-brain barrier function during childhood: a quantitative magnetic resonance imaging study.

BACKGROUND: Mounting evidence suggests that the blood-brain barrier (BBB) plays an important role in the regulation of brain iron homeostasis in normal brain development, but these imaging profiles remain to be elucidated. We aimed to establish a relationship between brain iron dynamics and BBB function during childhood using a combined quantitative magnetic resonance imaging (MRI) to depict both physiological systems along developmental trajectories. METHODS: In this single-center prospective study, consecutive outpatients, 2-180 months of age, who underwent brain MRI (3.0-T scanner; Ingenia; Philips) between January 2020 and January 2021, were included. Children with histories of preterm birth or birth defects, abnormalities on MRI, and diagnoses that included neurological diseases during follow-up examinations through December 2022 were excluded. In addition to clinical MRI, quantitative susceptibility mapping (QSM; iron deposition measure) and diffusion-prepared pseudo-continuous arterial spin labeling (DP-pCASL; BBB function measure) were acquired. Atlas-based analyses for QSM and DP-pCASL were performed to investigate developmental trajectories of regional brain iron deposition and BBB function and their relationships. RESULTS: A total of 78 children (mean age, 73.8 months ± 61.5 [SD]; 43 boys) were evaluated. Rapid magnetic susceptibility progression in the brain (Δsusceptibility value) was observed during the first two years (globus pallidus, 1.26 ± 0.18 [× 10- 3 ppm/month]; substantia nigra, 0.68 ± 0.16; thalamus, 0.15 ± 0.04). The scattergram between the Δsusceptibility value and the water exchange rate across the BBB (kw) divided by the cerebral blood flow was well fitted to the sigmoidal curve model, whose inflection point differed among each deep gray-matter nucleus (globus pallidus, 2.96-3.03 [mL/100 g]-1; substantia nigra, 3.12-3.15; thalamus, 3.64-3.67) in accordance with the regional heterogeneity of brain iron accumulation. CONCLUSIONS: The combined quantitative MRI study of QSM and DP-pCASL for pediatric brains demonstrated the relationship between brain iron dynamics and BBB function during childhood. TRIAL REGISTRATION: UMIN Clinical Trials Registry identifier: UMIN000039047, registered January 6, 2020.

Absence of diffusion-weighted imaging abnormalities in a patient with neuronal intranuclear inclusion disease.

INTRODUCTION: Herein, we report a genetically confirmed case of neuronal intranuclear inclusion disease without characteristic subcortical hyperintensities on diffusion-weighted imaging. CASE PRESENTATION: A 75-year-old man was admitted to our hospital with subacute onset of conscious disturbance. Except for gastric cancer, he had no apparent past medical or family history. He presented with transient fever, vomiting, and urinary retention. On admission, no apparent abnormal intensity was detected on diffusion-weighted imaging. The symptoms improved within 10 days, without any medical treatment. Additional inspections were performed under suspicion of neuronal intranuclear inclusion disease. Intranuclear inclusions were found not only from skin biopsy but also from his stomach specimens, which had been resected 6 years previously. Subsequent genetic testing revealed repeat expansion of GGC amplification in NOTCH2NLC. CONCLUSION: Characteristic neuroimaging and skin biopsy findings are important clues for diagnosing neuronal intranuclear inclusion diseases. Nonetheless, confirming a diagnosis is difficult due to the diversity of clinical manifestations and radiological features. Clinicians should suspect neuronal intranuclear inclusion disease in patients with transient encephalitic episodes, even if no abnormalities are detected on diffusion-weighted imaging.

APOE ɛ4 dose associates with increased brain iron and ß-amyloid via blood-brain barrier dysfunction.

OBJECTIVE: To examine the effect of apolipoprotein E (APOE) ɛ4 dose on blood-brain barrier (BBB) clearance function, evaluated using an advanced MRI technique and analyse its correlation with brain iron and ß-amyloid accumulation in the early stages of the Alzheimer's continuum. METHODS: In this single-centre observational prospective cohort study, 24 APOE ɛ4 non-carriers, 22 heterozygotes and 20 homozygotes in the early stages of the Alzheimer's continuum were scanned with diffusion-prepared arterial spin labelling, which estimates the water exchange rate across the BBB (kw). Participants also underwent quantitative susceptibility mapping, [11C]Pittsburgh compound B-positron emission tomography and neuropsychological testing. Using an atlas-based approach, we compared the regional kw of the whole brain among the groups and analysed its correlation with the neuroradiological and neuropsychological findings. RESULTS: The BBB kw values in the neocortices differed significantly among the groups (APOE ɛ4 non-carriers>heterozygotes>homozygotes). These values correlated with brain iron levels (frontal lobe: r=-0.476, 95% CI=-0.644 to -0.264, p=0.011; medial temporal lobe: r=-0.455, 95% CI=-0.628 to -0.239, p=0.017), ß-amyloid loads (frontal lobe: r=-0.504, 95% CI=-0.731 to -0.176, p=0.015; medial temporal lobe: r=-0.452, 95% CI=-0.699 to -0.110, p=0.036) and neuropsychological scores, after adjusting for age, sex and APOE ɛ4 dose. INTERPRETATION: Our results suggest that an increased APOE ɛ4 dose is associated with decreased effective brain-waste clearance, such as iron and ß-amyloid, through the BBB.

[Anti-voltage-gated potassium channel (VGKC) complex/leucine-rich glioma-inactivated protein 1 (LGI1) antibody-associated limbic encephalitis mimicking dementia with Lewy bodies in a patient with subacute REM sleep behavior disorder].

A 73-year-old woman was admitted to our hospital owing to abnormal diurnal behavior, sudden brief episodes of impaired awareness, and loud nocturnal sleep talking. Her symptoms had developed gradually over several months and had been treated as dementia with Lewy bodies (DLB) at another clinic. Video-polysomnography revealed brief sleep talking and gross movements associated with REM sleep without atonia. 18F-FDG PET revealed increased glucose metabolism in both medial temporal lobes. These findings led to a diagnosis of limbic encephalitis (LE) comorbid with REM sleep behavior disorder (RBD). After two courses of intravenous methylprednisolone pulse therapy, her symptoms gradually improved. Her illness was later confirmed as anti-voltage-gated potassium channel (VGKC) complex/leucine-rich glioma-inactivated protein 1 (LGI1) antibody-associated LE using serum analyses. Clinical features of anti-VGKC complex/LGI1 antibody-associated LE can mimic those of DLB, particularly when comorbid with RBD.

Can Medial Temporal Impairment Be an Imaging Red Flag for Neurodegeneration in Disproportionately Enlarged Subarachnoid Space Hydrocephalus?

BACKGROUND: The differentiation of idiopathic normal pressure hydrocephalus (iNPH) from neurodegenerative diseases such as Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) is often challenging because of their non-specific symptoms. Therefore, various neuroradiological markers other than ventriculomegaly have been proposed. Despite the utility of disproportionately enlarged subarachnoid-space hydrocephalus (DESH) for the appropriate selection of shunt surgery candidates, the specificity and neuropathology of this finding have not been sufficiently evaluated. OBJECTIVE: Investigation of the clinicopathological features and comparison of the neuroradiological findings between DESH with postmortem neuropathological diagnoses (pDESH) and clinically-diagnosed iNPH (ciNPH) patients are the main purposes of this study. METHOD: In addition to the retrospective evaluation of clinicopathological information, quantitative, semiquantitative, and qualitative magnetic resonance imaging (MRI) indices were compared between pathologically-investigated 10 patients with pDESH and 10 patients with ciNPHResults:Excluding one patient with multiple cerebral infarctions, the postmortem neuropathological diagnoses of the pathologically-investigated patients were mainly neurodegenerative diseases (five AD, one DLB with AD pathologies, one DLB, one argyrophilic grain disease, and one Huntington's disease). In addition to the common neuroradiological featuresConclusion:Hippocampal atrophy and deformation with temporal horn enlargement seem to be characteristic neuroradiological findings of long-standing severely demented patients with DESH and neurodegenerative diseases, mainly advanced-stage AD.

Heterozygous Cysteine-sparing NOTCH3 Variant p.Val237Met in a Japanese Patient with Suspected Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy.

A 64-year-old Japanese man with recurrent cerebral ischemic events and cognitive impairment was suspected of having cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) because of a family history and brain magnetic resonance imaging findings of cerebral white matter hyperintensities. The cysteine-sparing variation p.Val237Met was identified in NOTCH3. An intensive skin biopsy showed negative results (no granular osmiophilic material or positive NOTCH3 immunostaining), suggesting that the patient's definite diagnosis and pathogenicity of p.Val237Met were uncertain. We additionally reviewed previous reports of two Japanese families with p.Val237Met.

Iron leakage owing to blood-brain barrier disruption in small vessel disease CADASIL.

OBJECTIVE: To assess the relationship among iron accumulation, blood-brain barrier (BBB) damage, and cognitive function in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). METHODS: We enrolled 21 patients with NOTCH3 mutations and 21 age-matched healthy controls in this cross-sectional study. All participants underwent global physical and cognitive assessments and brain MRI using voxel-based quantitative susceptibility mapping (QSM; iron deposition measure) and dynamic contrast-enhanced MRI (BBB permeability measure). We compared behavioral and imaging data between the groups and analyzed the correlations in each group. RESULTS: Among 21 NOTCH3 mutation carriers, 10 were symptomatic and 11 asymptomatic. Montreal Cognitive Assessment scores were significantly different among the groups (symptomatic < asymptomatic < control participants). Voxel-based QSM analysis revealed that the symptomatic group had higher QSM values than did the asymptomatic group in the putamen, caudate nucleus, temporal pole, and centrum semiovale. These QSM values were positively correlated with regional BBB permeabilities (putamen: r = 0.57, p = 0.006; caudate nucleus: r = 0.51, p = 0.019; temporal pole: r = 0.48, p = 0.030; centrum semiovale: r = 0.45, p = 0.044) and negatively correlated with Montreal Cognitive Assessment scores (caudate nucleus: r = -0.53, p = 0.012; temporal pole: r = -0.56, p = 0.008). CONCLUSIONS: This study showed that cerebral iron burden was associated with regional BBB permeability and cognitive dysfunction in patients with CADASIL, highlighting the potential of these imaging techniques as auxiliary biomarkers to monitor the course of small vessel disease.

Multiple Border-Zone Infarcts Triggered by Influenza A Virus Infection in a Patient With Cerebral Autosomal Dominant Arteriopathy Presenting With Subcortical Infarcts and Leukoencephalopathy.

Patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) can develop multiple border-zone infarcts due to hypotension, hypovolemia, or surgery. We report the case of a 41-year-old woman with CADASIL who developed multiple border-zone infarcts due to influenza A virus infection. The patient had no apparent history or episode of stroke or altered consciousness following the onset of respiratory symptoms, which were due to the influenza A infection. Diffusion-weighted magnetic resonance images of the brain showed multiple acute-phase infarcts in border-zone areas of both cerebral hemispheres and the corpus callosum; fluid-attenuated inversion-recovery magnetic resonance images showed increased signal in the subcortical areas of both temporal poles. Gene analysis identified a heterozygous mutation c.160C>T in exon 2 of the NOTCH3 gene (p.Arg54Cys). A diagnosis of CADASIL was established. Our case demonstrates that infectious conditions such as influenza A can trigger multiple border-zone infarctions in patients with CADASIL.

Imaging spectrum of abnormal subcutaneous and visceral fat distribution.

Adipose tissue plays multiple and complex roles not only in mechanical cushioning and energy storage but also as an important secretory organ that regulates energy balance and homeostasis multilaterally. Fat tissue is categorized into subcutaneous fat tissue (SCAT) or visceral fat tissue (VSA) depending on its distribution, with the two having different metabolic functions. Near-total lack of fat in congenital/acquired generalized lipodystrophy, cachexia, or any other severe malnutrition condition induces severe multi-organ dysfunction due to lack of production of leptin and other adipokines. Increased visceral fat tissue secondary to obesity, hypercortisolism, or multiple symmetric lipomatosis raises the risk of insulin resistance, cardiac complications, and airway or spinal canal stenosis, although the fat distribution pattern differs in each condition. Partial abnormal fat distribution conditions such as HIV/HAART therapy-associated lipodystrophy, familial partial lipodystrophies, and acquired partial lipodystrophy frequently show a mixture of lipoatrophy and lipohypertrophy with metabolic dysfunction. Characteristic imaging features in conditions with local abnormal fat distribution can provide information about a patient's co-existent/unrecognized disease(s), past medical history, or lifestyle. Knowledge of characteristic abnormal fat distribution patterns can contribute to proper and timely therapeutic decision-making and patient education.

[Idiopathic CD4-positive lymphocytopenia-associated progressive multifocal leukoencephalopathy confirmed by brain biopsy following negative results of repeated CSF-JC-virus tests: a case report].

A 75-year-old man presented with dysarthria and left facial paralysis. Brain diffusion-weighted MRI revealed a high-signal intensity in the right precentral gyrus, and he was hospitalized under the diagnosis of cerebral infarction. His symptoms worsened and brain MRI findings were consistent with progressive multifocal leukoencephalopathy (PML). Cerebrospinal fluid (CSF) JC virus (JCV) was undetectable in the DNA polymerase chain reaction (PCR) test four times, but brain biopsy revealed typical PML histopathology. He had no human immunodeficiency virus infection and history of immunosuppressive treatment, but he was found to have CD4+ lymphocytopenia. He was treated with mefloquine and mirtazapine, and died 29 months after symptoms onset. In cases whose repeated DNA PCR results are negative for CSF JCV, brain biopsy may be useful for the diagnosis of PML.

[Misleading cerebral arterial wall gadolinium-enhancement in malignant lymphoma].

A previously healthy, 77-year-old woman presented with gradual cognitive decline and acute gait imbalance. On admission, despite no obvious paralysis, she tilted to the right. Her Mini-Mental State Examination score was slightly low (23/30). Gadolinium-enhanced, high-resolution T1-weighted MRI showed abnormal arterial wall enhancement at the bilateral middle cerebral and right internal carotid arteries. The combination of arterial and parenchymal enhancement limited to the central nervous system (CNS), normal laboratory data including soluble interleukin-2 receptor, and random skin and bone-marrow biopsies was suggested of primary angiitis of the CNS (PACNS). However, a biopsy specimen from the right insula showed CD20-positive lymphoma cells indicative of diffuse large B-cell lymphoma. After receiving chemotherapy, above-mentioned abnormal findings were significantly improved. Considering the increasing clinical application of high resolution MRI, there is a risk that patients may receive a presumptive diagnosis of PACNS and immunosuppressive treatment without biopsy confirmation. It should be noted that a combination of abnormal arterial wall and linear parenchymal enhancement similar to that found for PACNS on high-resolution MRI may occur in patients with primary central nervous system lymphoma.

[Intrasellar xanthogranuloma with abscess formation in a patient with Rathke's cleft cyst].

An 80-year-old woman diagnosed with granulomatosis with polyangiitis (GPA) complained of a sustained, non-pulsatile headache. Her brain MRI diffusion-weighted images revealed a high-signal-intensity, space-occupying lesion in the sellar region that was rim-enhanced on gadolinium-enhanced T1-weighted images. Pituitary involvement of GPA was initially suspected based on her condition; however, an abscess formation within an existing Rathke's cleft cyst was also considered according to a previous MRI finding that had been conducted for an unrelated purpose. A trans-sphenoidal resection of the lesion revealed an abscess with foam cells. These findings were consistent with a diagnosis of a xanthogranuloma with abscess formation in the Rathke's cleft cyst, and her headache was completely resolved without any immune therapy that is required for GPA. Thus, differential diagnosis of space-occupying lesions in the seller region should include xanthogranuloma with abscess formation, especially if a Rathke's cleft cyst is detected as an antecedent finding.

Calcifying aponeurotic fibroma in a girl: MRI findings and their chronological changes.

Calcifying aponeurotic fibroma (CAF) is a rare benign tumor that typically develops in the fascia and tendons. On MRI, CAF usually shows isointensity on T1WI and heterogeneous high intensity on T2WI. We report a case of 17-month-old girl with CAF on her right ankle. MRI showed an usual signal intensity for CAF. At 3 years and 4 months of age, MRI revealed hyperintense nodules on T1WI and T2WI inside of the CAF. These fatty areas corresponded to coarse calcified nodules on CT. Radiologists should be aware of the fact that fat-like signals can appear in CAF on MRI.

Low signal intensity lesions on brain susceptibility-weighted MRI in a patient with intravascular large B-cell lymphoma.

A 71-year-old man was admitted to our hospital because of abnormal behavior and generalized convulsion. Brain MRI revealed no abnormalities upon admission. Levels of serum lactate dehydrogenase and soluble interleukin-2 receptors were significantly elevated, whereas the initial bone marrow puncture and random skin biopsy findings were non-malignant. On the tenth day of admission, brain MRI revealed dot and strip-shaped low signal intensity lesions on susceptibility-weighted images (SWI) disseminated mainly within the cerebral cortex. Administration of high dose methyl-prednisolone improved neither his condition nor these MRI findings. Ground-glass opacities within the bilateral lungs later emerged on the chest CT. The results of a transbronchial lung biopsy and second bone marrow puncture were consistent with a diagnosis of intravascular large B-cell lymphoma (IVLBCL). Despite the lack of histopathological confirmation, the low signal intensities on brain SWI in this case were also considered IVLBCL lesions, reflective of micro-hemorrhagic changes.

Radiological imaging features of glioblastoma with oligodendroglioma component: a comparison with conventional glioblastoma.

BACKGROUND: Glioblastoma with oligodendroglioma component (GBMO) is a subtype of conventional glioblastoma (cGBM), which is categorized as WHO grade IV. GBMO can be histopathologically distinguished from cGBM and the prognosis of GBMO is better than that of cGBM. However, no systematic review of GBMO imaging findings has been published to date. PURPOSE: To clarify the radiological imaging features of GBMO compared with those of cGBM. MATERIAL AND METHODS: The participants were 15 patients with GBMO and 32 patients with cGBM as a control group, all of whom were histopathologically diagnosed. A radiologist retrospectively reviewed the imaging findings of both computed tomography (CT) and magnetic resonance imaging (MRI) for density, signal intensity, contrast medium enhancement (CE), cortical swelling, and cortical swelling without CE. We statistically analyzed the imaging findings by Chi-squared test. RESULTS: Cortical swelling without CE in GBMO was significantly greater than that in cGBM (P = 0.004). Non-CE and heterogeneous solid enhancement were observed significantly more often in GBMO (P = 0.004). No other findings were significant. CONCLUSION: There was significant difference in the findings of the CE, which exhibited solid heterogeneous enhancement in GBMO. Cortical swelling without CE can be considered significantly characteristic of GBMO.

Preoperative transarterial embolization using gelatin sponge for hypervascular bone and soft tissue tumors in the pelvis or extremities.

BACKGROUND: Preoperative transcatheter arterial embolization for hypervascular bone and soft tissue tumors plays an important role in reducing intraoperative blood loss (IBL). PURPOSE: To evaluate the use of a gelatin sponge in preoperative transcatheter arterial embolization for hypervascular bone and soft tissue tumors in the pelvis or extremities. MATERIAL AND METHODS: Thirty-seven patients (21 men, 16 women; median age, 61 years; age range, 23-79 years) underwent preoperative transcatheter arterial embolization between April 2004 and January 2015. Medical records and images were reviewed, and the technical success rate, clinical success rate, and complications were evaluated. Technical success was defined as a devascularization rate of 75% or higher, and clinical success was defined as intraoperative blood loss (IBL) <1500 mL in cases undergoing surgery within 3 days of transarterial embolization and <3000 mL in cases operated 4 or more days later. RESULTS: Tumor sizes were in the range of 2.0-13.0 cm (median, 5.0 cm). The devascularization rate was decreased by >75% at follow-up angiography in all cases, and the technical success rate was 100 % (37/37). The median IBL was 491 mL (range, 30-3800 mL), and the clinical success rate was 89% (33/37). The minor complication of local pain was observed in 13 out of 37 cases (35%) during or after embolization, but was controllable by an analgesic. CONCLUSION: Preoperative transarterial embolization using a gelatin sponge appears to be feasible and safe, and may contribute to decreasing IBL.

Associations between computed tomography features of thymomas and their pathological classification.

Background Thymoma exhibits a range of histological and biological features and their imaging findings varies. Purpose To evaluate the associations between CT findings of thymomas and their classification according to the Masaoka staging system and World Health Organization (WHO) classification. Material and Methods Eighty-four patients with thymoma were evaluated. Comparisons between the CT findings of Masaoka stage I/II and III/IV lesions, and the WHO type A-B1 (low risk) and B2/B3 (high risk) lesions were performed. Results Stage III/IV thymomas (mean size, 60 mm) were significantly larger than stage I/II (45 mm) lesions and had more irregular shape and contour. Necrosis and calcification were observed in 16 (59%) and nine (33%) stage III/IV thymomas, and 16 (28%) and seven (12%) stage I/II lesions, respectively. Regarding the WHO classification, the high-risk thymomas displayed irregular shape and contour more often than low-risk lesions. There were significant differences between the patterns of mediastinal invasion seen in high- and low-risk groups; 21 (68%) vs. six (12%) lesions demonstrated mediastinal fat invasion, seven (23%) vs. two (4%) lesions exhibited great vessel invasion, five (16%) vs. 0 (0%) lesions displayed pericardial invasion, and 18 (58%) vs. 10 (20%) lesions invaded the lungs, respectively. Conclusion Masaoka stage III/IV thymomas were larger in size, had more irregular shape and contour, and exhibited necrosis and calcification more often than the stage I/II lesions. In the WHO classification, high-risk thymomas demonstrated more irregular shape and contour than low-risk thymomas.