An aggressive case of a thoracic undifferentiated SMARCA4-deficient tumor with extensive pleural involvement.

SMARCA4-deficient undifferentiated thoracic tumors are a rare phenomenon. A 40-year-old male was newly diagnosed with SMARCA4-deficient undifferentiated non-small cell lung cancer. He had a history of heavy smoking and job-related exposure to metal dust and melted nickel. CT imaging showed numerous right-sided pleural masses and soft tissue plaques, but no metastases. CT-guided biopsy of a pleural mass confirmed the diagnosis. He was prescribed six cycles of carboplatin paclitaxel, and follow-up imaging showed largely stable disease. Treatment was changed to nivolumab due to shortness of breath, and he received one cycle of nivolumab without considerable side effects. Unfortunately, during the second cycle of his nivolumab, the patient presented with new weakness. Imaging showed spinal cord metastasis and he underwent a laminectomy; he was subsequently followed up as an outpatient. The objective of this publication was to explore SMARCA4-deficient undifferentiated thoracic tumors, other related SMARCA4-deficient tumors, and their overall pattern of presentation. The genetic aberrations of this case are compared to recent publications that also discuss genetic aberrations commonly occurring with this disease process, with an ultimate goal of hastening detection and adding to the library of treatment results.

Clinical utility of whole-genome DNA methylation profiling as a primary molecular diagnostic assay for central nervous system tumors-A prospective study and guidelines for clinical testing.

Background: Central nervous system (CNS) cancer is the 10th leading cause of cancer-associated deaths for adults, but the leading cause in pediatric patients and young adults. The variety and complexity of histologic subtypes can lead to diagnostic errors. DNA methylation is an epigenetic modification that provides a tumor type-specific signature that can be used for diagnosis. Methods: We performed a prospective study using DNA methylation analysis as a primary diagnostic method for 1921 brain tumors. All tumors received a pathology diagnosis and profiling by whole genome DNA methylation, followed by next-generation DNA and RNA sequencing. Results were stratified by concordance between DNA methylation and histopathology, establishing diagnostic utility. Results: Of the 1602 cases with a World Health Organization histologic diagnosis, DNA methylation identified a diagnostic mismatch in 225 cases (14%), 78 cases (5%) did not classify with any class, and in an additional 110 (7%) cases DNA methylation confirmed the diagnosis and provided prognostic information. Of 319 cases carrying 195 different descriptive histologic diagnoses, DNA methylation provided a definitive diagnosis in 273 (86%) cases, separated them into 55 methylation classes, and changed the grading in 58 (18%) cases. Conclusions: DNA methylation analysis is a robust method to diagnose primary CNS tumors, improving diagnostic accuracy, decreasing diagnostic errors and inconclusive diagnoses, and providing prognostic subclassification. This study provides a framework for inclusion of DNA methylation profiling as a primary molecular diagnostic test into professional guidelines for CNS tumors. The benefits include increased diagnostic accuracy, improved patient management, and refinements in clinical trial design.

Expanded analysis of high-grade astrocytoma with piloid features identifies an epigenetically and clinically distinct subtype associated with neurofibromatosis type 1.

High-grade astrocytoma with piloid features (HGAP) is a recently recognized glioma type whose classification is dependent on its global epigenetic signature. HGAP is characterized by alterations in the mitogen-activated protein kinase (MAPK) pathway, often co-occurring with CDKN2A/B homozygous deletion and/or ATRX mutation. Experience with HGAP is limited and to better understand this tumor type, we evaluated an expanded cohort of patients (n = 144) with these tumors, as defined by DNA methylation array testing, with a subset additionally evaluated by next-generation sequencing (NGS). Among evaluable cases, we confirmed the high prevalence CDKN2A/B homozygous deletion, and/or ATRX mutations/loss in this tumor type, along with a subset showing NF1 alterations. Five of 93 (5.4%) cases sequenced harbored TP53 mutations and RNA fusion analysis identified a single tumor containing an NTRK2 gene fusion, neither of which have been previously reported in HGAP. Clustering analysis revealed the presence of three distinct HGAP subtypes (or groups = g) based on whole-genome DNA methylation patterns, which we provisionally designated as gNF1 (n = 18), g1 (n = 72), and g2 (n = 54) (median ages 43.5 years, 47 years, and 32 years, respectively). Subtype gNF1 is notable for enrichment with patients with Neurofibromatosis Type 1 (33.3%, p = 0.0008), confinement to the posterior fossa, hypermethylation in the NF1 enhancer region, a trend towards decreased progression-free survival (p = 0.0579), RNA processing pathway dysregulation, and elevated non-neoplastic glia and neuron cell content (p < 0.0001 and p < 0.0001, respectively). Overall, our expanded cohort broadens the genetic, epigenetic, and clinical phenotype of HGAP and provides evidence for distinct epigenetic subtypes in this tumor type.

Anti-NMDA receptor encephalitis with initial negative markers: diagnostic and therapeutic challenges of a refractory case with 9-month-long follow-up.

Anti-N-methyl-d-aspartate (NMDA) receptor encephalitis is a progressively debilitating, frequently fatal disease caused by autoantibodies against the NMDA receptor. Risk of delayed treatment is high due to variable presentations, lack of awareness and potential false negative diagnostic studies. In this case report, a woman in her 20s presented with psychiatric manifestations and rapidly declined. Dyskinetic movements and dysautonomia were observed. Initial cerebrospinal fluid and serum anti-NMDA receptor antibodies were negative. MRI was inconclusive. Electroencephalography demonstrated extreme delta brush. Pelvic CT revealed an adnexal teratoma. She remained refractory to treatment until day 126 when, after two cycles of cyclophosphamide, she started to improve. She participated in rehabilitation with eventual discharge home on day 269. Recognising the variable presentations of anti-NMDA receptor encephalitis is important in avoiding misdiagnosis and delayed treatment. If clinical suspicion remains high despite negative results, repeat testing should be pursued. Clinical response should guide treatment decisions in refractory cases.

Cytokine responses in nonlesional psoriatic skin as clinical predictor to anti-TNF agents.

BACKGROUND: A major issue with the current management of psoriasis is our inability to predict treatment response. OBJECTIVE: Our aim was to evaluate the ability to use baseline molecular expression profiling to assess treatment outcome for patients with psoriasis. METHODS: We conducted a longitudinal study of 46 patients with chronic plaque psoriasis treated with anti-TNF agent etanercept, and molecular profiles were assessed in more than 200 RNA-seq samples. RESULTS: We demonstrated correlation between clinical response and molecular changes during the course of the treatment, particularly for genes responding to IL-17A/TNF in keratinocytes. Intriguingly, baseline gene expressions in nonlesional, but not lesional, skin were the best marker of treatment response at week 12. We identified USP18, a known regulator of IFN responses, as positively correlated with Psoriasis Area and Severity Index (PASI) improvement (P = 9.8 × 10-4) and demonstrate its role in regulating IFN/TNF responses in keratinocytes. Consistently, cytokine gene signatures enriched in baseline nonlesional skin expression profiles had strong correlations with PASI improvement. Using this information, we developed a statistical model for predicting PASI75 (ie, 75% of PASI improvement) at week 12, achieving area under the receiver-operating characteristic curve value of 0.75 and up to 80% accurate PASI75 prediction among the top predicted responders. CONCLUSIONS: Our results illustrate feasibility of assessing drug response in psoriasis using nonlesional skin and implicate involvement of IFN regulators in anti-TNF responses.

Fatal central nervous system co-infection with SARS-CoV-2 and tuberculosis in a healthy child.

BACKGROUND: Central and peripheral nervous system symptoms and complications are being increasingly recognized among individuals with pandemic SARS-CoV-2 infections, but actual detection of the virus or its RNA in the central nervous system has rarely been sought or demonstrated. Severe or fatal illnesses are attributed to SARS-CoV-2, generally without attempting to evaluate for alternative causes or co-pathogens. CASE PRESENTATION: A five-year-old girl with fever and headache was diagnosed with acute SARS-CoV-2-associated meningoencephalitis based on the detection of its RNA on a nasopharyngeal swab, cerebrospinal fluid analysis, and magnetic resonance imaging findings. Serial serologic tests for SARS-CoV-2 IgG and IgA showed seroconversion, consistent with an acute infection. Mental status and brain imaging findings gradually worsened despite antiviral therapy and intravenous dexamethasone. Decompressive suboccipital craniectomy for brain herniation with cerebellar biopsy on day 30 of illness, shortly before death, revealed SARS-CoV-2 RNA in cerebellar tissue using the Centers for Disease Control and Prevention 2019-nCoV Real-Time Reverse Transcriptase-PCR Diagnostic Panel. On histopathology, necrotizing granulomas with numerous acid-fast bacilli were visualized, and Mycobacterium tuberculosis complex DNA was detected by PCR. Ventricular cerebrospinal fluid that day was negative for mycobacterial DNA. Tracheal aspirate samples for mycobacterial DNA and culture from days 22 and 27 of illness were negative by PCR but grew Mycobacterium tuberculosis after 8 weeks, long after the child's passing. She had no known exposures to tuberculosis and no chest radiographic findings to suggest it. All 6 family members had normal chest radiographs and negative interferon-γ release assay results. The source of her tuberculous infection was not identified, and further investigations by the local health department were not possible because of the State of Michigan-mandated lockdown for control of SARS-CoV-2 spread. CONCLUSION: The detection of SARS-CoV-2 RNA in cerebellar tissue and the demonstration of seroconversion in IgG and IgA assays was consistent with acute SARS-CoV-2 infection of the central nervous infection. However, the cause of death was brain herniation from her rapidly progressive central nervous system tuberculosis. SARS-CoV-2 may mask or worsen occult tuberculous infection with severe or fatal consequences.

IFN-γ enhances cell-mediated cytotoxicity against keratinocytes via JAK2/STAT1 in lichen planus.

Lichen planus (LP) is a chronic debilitating inflammatory disease of unknown etiology affecting the skin, nails, and mucosa with no current FDA-approved treatments. It is histologically characterized by dense infiltration of T cells and epidermal keratinocyte apoptosis. Using global transcriptomic profiling of patient skin samples, we demonstrate that LP is characterized by a type II interferon (IFN) inflammatory response. The type II IFN, IFN-γ, is demonstrated to prime keratinocytes and increase their susceptibility to CD8+ T cell-mediated cytotoxic responses through MHC class I induction in a coculture model. We show that this process is dependent on Janus kinase 2 (JAK2) and signal transducer and activator of transcription 1 (STAT1), but not JAK1 or STAT2 signaling. Last, using drug prediction algorithms, we identify JAK inhibitors as promising therapeutic agents in LP and demonstrate that the JAK1/2 inhibitor baricitinib fully protects keratinocytes against cell-mediated cytotoxic responses in vitro. In summary, this work elucidates the role and mechanisms of IFN-γ in LP pathogenesis and provides evidence for the therapeutic use of JAK inhibitors to limit cell-mediated cytotoxicity in patients with LP.

A rare case of TLE1-positive sclerosing epithelioid fibrosarcoma expanding the differential diagnosis of TLE1-positive tumors: a case report.

Transducin-like enhancer of split 1 (TLE1) is a transcription factor known for its strong overexpression and immunopositivity in synovial sarcoma. Several studies have revealed that its immunopositivity is not always specific to synovial sarcoma, with several cases showing positivity in peripheral nerve sheath tumors and solitary fibrous tumors. Occasional weak staining for TLE1 has also been described in clear cell sarcoma, high-grade chondrosarcoma, Ewing sarcoma, rhabdomyosarcoma, GIST, myxofibrosarcoma, and leiomyosarcoma. Here we present the first unique case of sclerosing epithelioid fibrosarcoma with strong, diffuse TLE1 positivity, resulting in a new consideration for the differential diagnosis of TLE1 positivity.

The female-biased factor VGLL3 drives cutaneous and systemic autoimmunity.

Autoimmune disease is 4 times more common in women than men. This bias is largely unexplained. Female skin is "autoimmunity prone," showing upregulation of many proinflammatory genes, even in healthy women. We previously identified VGLL3 as a putative transcription cofactor enriched in female skin. Here, we demonstrate that skin-directed overexpression of murine VGLL3 causes a severe lupus-like rash and systemic autoimmune disease that involves B cell expansion, autoantibody production, immune complex deposition, and end-organ damage. Excess epidermal VGLL3 drives a proinflammatory gene expression program that overlaps with both female skin and cutaneous lupus. This includes increased B cell-activating factor (BAFF), the only current biologic target in systemic lupus erythematosus (SLE); IFN-κ, a key inflammatory mediator in cutaneous lupus; and CXCL13, a biomarker of early-onset SLE and renal involvement. Our results demonstrate that skin-targeted overexpression of the female-biased factor VGLL3 is sufficient to drive cutaneous and systemic autoimmune disease that is strikingly similar to SLE. This work strongly implicates VGLL3 as a pivotal orchestrator of sex-biased autoimmunity.

Posterior fossa medulloblastoma in an atypical extra-axial location: A case report.

Medulloblastoma is the most common posterior fossa tumor of childhood typically within the fourth ventricle. However, extra-axial medulloblastoma in posterior fossa is an uncommon diagnosis. We report a case in a 33-month-old male who presented with repeated complaints of abdominal pain, intermittent emesis, and diarrhea, and diagnosed with right cerebellar extra-axial medulloblastoma, which was surgically resected. Majority of the reported extra-axial medulloblastoma in posterior fossa in the United States are located in the cerebellopontine angle. However, to the best of our knowledge, our case is the first to document medulloblastoma occurring exclusively in the cerebellar hemispheric extra-axial space rather than the cerebellopontine angle. Although the diagnosis can present as a radiological dilemma, a systematic multimodality imaging approach can aid in narrowing the differential diagnosis and timely management. In this case report, we will discuss the imaging characteristics, differential diagnosis, and management strategies, alongside a brief review of the world literature of extra-axial medulloblastoma.

Extraosseous Intradural Chondrosarcoma of the Cervical Spine: A Case Report with Brief Review of Literature.

Mesenchymal chondrosarcoma (MCS) is a malignant cancer of the cartilage that accounts for less than 1% of all chondrosarcomas and typically occurs within the bone. One-third of all mesenchymal chondrosarcomas are extraosseous soft tissue sarcomas, rendering this as an uncommon entity. We report a rare case of an extraosseous chondrosarcoma with the cervical spinal canal in a 21-year-old male. The purpose of this case report is to discuss the imaging characteristics of this pathology proven diagnosis.

RNA-Seq Analysis of IL-1B and IL-36 Responses in Epidermal Keratinocytes Identifies a Shared MyD88-Dependent Gene Signature.

IL-36 cytokines have recently emerged as mediators of inflammation in autoimmune conditions including psoriasis vulgaris (PsV) and generalized pustular psoriasis (GPP). This study used RNA-seq to profile the transcriptome of primary epidermal keratinocytes (KCs) treated with IL-1B, IL-36A, IL-36B, or IL-36G. We identified some early IL-1B-specific responses (8 h posttreatment), but nearly all late IL-1B responses were replicated by IL-36 cytokines (24 h posttreatment). Type I and II interferon genes exhibited time-dependent response patterns, with early induction (8 h) followed by no response or repression (24 h). Altogether, we identified 225 differentially expressed genes (DEGs) with shared responses to all 4 cytokines at both time points (8 and 24 h). These involved upregulation of ligands (IL1A, IL1B, and IL36G) and activating proteases (CTSS) but also upregulation of inhibitors such as IL1RN and IL36RN. Shared IL-1B/IL-36 DEGs overlapped significantly with genes altered in PsV and GPP skin lesions, as well as genes near GWAS loci linked to autoimmune and autoinflammatory diseases (e.g., PsV, psoriatic arthritis, inflammatory bowel disease, and primary biliary cholangitis). Inactivation of MyD88 adapter protein using CRISPR/Cas9 completely abolished expression responses of such DEGs to IL-1B and IL-36G stimulation. These results provide a global view of IL-1B and IL-36 expression responses in epidermal KCs with fine-scale characterization of time-dependent and cytokine-specific response patterns. Our findings support an important role for IL-1B and IL-36 in autoimmune or autoinflammatory conditions and show that MyD88 adaptor protein mediates shared IL-1B/IL-36 responses.

Squamous Cell Carcinoma of the Thyroid as a Result of Anaplastic Transformation from BRAF-Positive Papillary Thyroid Cancer.

Papillary thyroid carcinoma (PTC) is the most common malignant neoplasm of the thyroid. Majority of the PTC carries an excellent prognosis. However, patients with tall cell variant (TCV) of papillary thyroid carcinoma have a worse prognosis than those with the classic variant. On the other hand, squamous cell carcinoma of the thyroid (SCT) is an unusual neoplasm thought to arise as a primary tumor or as a component of an anaplastic or undifferentiated carcinoma. We report a patient with TCV of PTC presenting years later with squamous transformation. In addition, the patient was found to have BRAF mutation. Such dedifferentiation is considered to be a rare phenomenon and has been reported only in the form of case reports in the literature. The relationship between BRAFV600E mutation and squamous cell transformation of papillary thyroid cancer is unknown at this time. Meticulous pathology is needed to identify such variants. Our patient responded to treatment with concurrent chemotherapy with carboplatin and paclitaxel along with radiation.

Pitfalls in Diagnosis and Management of Testicular Choriocarcinoma Metastatic to the Brain: Report of 2 Cases and Review of Literature.

INTRODUCTION: Pure choriocarcinoma of the testes is a rare, aggressive germ cell tumor that can metastasize to the brain. Although its prognosis has improved with the development of cisplatin-based chemotherapy regimens, cerebral metastases are prone to hemorrhage and associated with high morbidity. Here, we present 2 cases of testicular choriocarcinoma with cerebral metastasis and discuss potential pitfalls in their diagnosis and management. We also review cases in the literature that feature these rare lesions. METHODS: Medline was searched for all publications including the terms "testicular choriocarcinoma" and "cerebral metastasis" or "brain metastasis." Articles that included patients with tumors classified as a mix of choriocarcinoma and other germ cell tumor subtypes were excluded. RESULTS: A total of 15 cases from the literature and our own 2 cases were included in the analysis. The mean age at presentation was 25.5 years. Neurologic symptoms accounted for the initial presentation of 9 patients (60%). Outcomes were predominantly poor, with 10 patients (67%) expiring shortly after their initial diagnosis. Three of these deaths were related to mass effect from metastasis-related hemorrhages. Two patients underwent emergent decompressive craniectomies, and both died from cerebral herniation. CONCLUSION: The potentially catastrophic nature of choriocarcinoma-related cerebral hemorrhages underscores the need for prompt, accurate diagnosis and aggressive surgical management of these lesions. Their highly vascular nature and lack of findings on cerebral angiography may cause them to be confused with occult vascular malformations.

Affinity of Mucormycosis for Basal Ganglia in Intravenous Drug Users: Case Illustration and Review of Literature.

Central nervous system mucormycosis is an aggressive fungal infection often ending in fatality. The usual circumstance is an immunocompromised individual presenting with rapidly progressive rhinocerebral involvement. An extremely rare variant of central nervous system mucormycosis isolated to the basal ganglia in an immunocompetent intravenous drug user is detailed in this manuscript. The patient was aggressively treated with aspiration of the fungal abscess and long-term intravenous antifungal agents.

Hemorrhagic Pilocytic Astrocytomas in Adults: A Case Report and Literature Review.

Pilocytic astrocytomas are histologically benign tumors, generally found in the pediatric population. Onset of symptoms is generally insidious, predominantly stemming from mass effect upon nearby structures. Patients harboring a pilocytic astrocytoma may present with gait disturbance, headaches, cranial nerve deficits, as well as hydrocephalus, depending on the exact location. Although cases of adult pilocytic astrocytomas in the adult population are described, they are quite uncommon. We present a case of an adult female presenting with acute neurological compromise resulting from an acutely hemorrhagic posterior fossa pilocytic astrocytoma. Her initial neurological assessment was consistent with a Glasgow coma scale of 4T, as the patient was experiencing decerebrate posturing. An emergent external ventricular drain was placed in the emergency department for acute hydrocephalus as a temporizing measure, prior to evacuation of the associated subdural and intratumoral hemorrhages, as well as resection of the mass. After a long hospital course and extensive rehabilitation, the patient made a remarkable recovery and eventually gave birth to a child via Caesarean section three years after her initial presentation.

Aberrant detergent-insoluble excitatory amino acid transporter 2 accumulates in Alzheimer disease.

Alzheimer disease (AD) is characterized by deposition of amyloid-beta, tau, and other specific proteins that accumulate in the brain in detergent-insoluble complexes. Alzheimer disease also involves glutamatergic neurotransmitter system disturbances. Excitatory amino acid transporter 2 (EAAT2) is the dominant glutamate transporter in cerebral cortex and hippocampus. We investigated whether accumulation of detergent-insoluble EAAT2 is related to cognitive impairment and neuropathologic changes in AD by quantifying detergent-insoluble EAAT2 levels in hippocampus and frontal cortex of cognitively normal patients, patients with clinical dementia rating of 0.5 (mildly impaired), and AD patients. Parkinson disease patients served as neurodegenerative disease controls. We found that Triton X-100-insoluble EAAT2 levels were significantly increased in patients with AD compared with controls, whereas Triton X-100-insoluble EAAT2 levels inpatients with clinical dementia rating of 0.5 were intermediately elevated between control and AD subjects. Detergent insolubility of presenilin-1, a structurally similar protein, did not differ among the groups, thus arguing that EAAT2 detergent insolubility was not caused by nonspecific cellular injury. These findings demonstrate that detergent-insoluble EAAT2 accumulation is a progressive biochemical lesion that correlates with cognitive impairment and neuropathologic changes in AD. These findings lend further support to the idea that dysregulation of the glutamatergic system may play a significant role in AD pathogenesis.

Enzymes that synthesize the IB4 epitope are not sufficient to impart IB4 binding in dorsal root ganglia of rat.

The isolectin B4 (IB4) stains a subset of small and medium-sized dorsal root ganglion (DRG) neurons by binding to terminal alpha-galactose on glycoproteins and glycolipids. The enzymes alpha(1,3)galactosyltransferase (1,3GT) and isoglobotriaosylceramide synthase (iGb3S) synthesize the galactose-alpha(1,3)-galactose group, which is the most common carbohydrate containing terminal alpha-galactose. 1,3GT preferentially glycosylates proteins whereas iGb3S glycosylates lipids. We generated antibodies against rat 1,3GT and iGb3S that were used for immunohistochemical staining of DRG cells. Virtually all neurons that bound IB4 expressed both enzymes, suggesting that IB4 binds to both glycoproteins and glycolipids in IB4-positive neurons. 1,3GT immunoreactivity was observed in small and medium-sized neurons and satellite cells. iGb3S immunoreactivity was observed in neurons of varying sizes. Many neurons that expressed these enzymes did not bind IB4. Additionally, the majority of neurons that expressed substance P expressed both enzymes but did not bind IB4. Ultrastructual studies revealed that 1,3GT was predominantly associated with the Golgi apparatus, whereas iGb3S was found near the Golgi apparatus and in large, clear vesicles throughout the soma. These data suggest that, although expression of 1,3GT and/or iGb3S appears to be necessary for IB4 binding, expression of these enzymes is not sufficient to impart IB4 binding.

Cone beam computed tomographic findings in refractory chronic suppurative osteomyelitis of the mandible.

AIMS: To report the imaging features of osteomyelitis of the mandible in various two-dimensional multiplanar and three-dimensional reformations using cone beam computed tomography (CBCT). METHODS: The images were 12-bit DICOM files acquired with a 10cm field of view and voxel resolution of 0.4mm. Two-dimensional multiplanar reformatted reconstructions included coronal, "panoramic" (variable thickness), and serial cross-sections. Three-dimensional reconstructions included surface renderings. Images were presented to referring oral and maxillofacial surgeons in "real time" immediately after acquisition. RESULTS: The features of mandibular osteomyelitis seen on CBCT included: a peripheral sclerotic rim, cortical layering (involucrum), central loss of trabecular pattern with internal round radiolucent resorptive tracts, minimal jaw expansion, and reduction of the alveolar cortex. Sequestra were occasionally evident. The history and presentation of each case on CBCT were consistent with osteomyelitis of the mandible; however, the clinical differential diagnosis in each case had included malignancy. The definitive diagnosis was confirmed by histological examination of biopsy specimens. Two of the three cases were patients who had been treated with bisphosphonates. CONCLUSION: CBCT facilitated comprehensive and dynamic imaging of the jaws based on surgical consultation, rather than inflexible imaging protocols. CBCT images guided operative planning.

The possible contribution of anti-Gal to Graves' disease.

Anti-Gal is a natural antibody specific for the alpha-galactosyl epitope. Previous studies suggested that Graves' disease (GD) patients had elevated anti-Gal titers compared to normal controls, but titers returned to normal after treatment. We developed an anti-Gal enzyme-linked immunosorbent assay (ELISA) using the property of anti-Gal to bind tightly to mouse laminin. We found no significant correlations between anti-Gal and thyroidstimulating immunoglobulin (TSI) or free thyroxine (T(4)) in untreated hyperthyroid GD patients (n = 15) without clinical ophthalmopathy or euthyroid, previously treated GD patients with ophthalmopathy. There was a significant regression between TSI and free T(4) in the hyperthyroid patients (p < 0.01). Addition of total anti- Gal antibody to the regression showed a trend toward improved correlation (p = 0.15 for improved correlation relative to TSI and free T(4) alone), suggesting it may stimulate GD thyroid tissue. However, in contrast to previous studies we found hyperthyroid patients (n = 20) had lower levels of anti-Gal immunoglobulin G (IgG) (18.4 +/- 4.0 vs. 41.8 +/- 8.9) than normals (n = 36 p < 0.05). Interestingly, hyperthyroid patients without clinical ophthalmopathy tended to have lower IgG anti-Gal levels than euthyroid patients with ophthalmopathy (p = 0.1). Hyperthyroidism significantly lowers anti-Gal, but the possible increase of anti-Gal in patients with ophthalmopathy suggests anti-Gal may play a role in ophthalmopathy, or may reflect the euthryoid status of these patients. This trend needs further study.