SARS-CoV-2 Infects Human Engineered Heart Tissues and Models COVID-19 Myocarditis.

There is ongoing debate as to whether cardiac complications of coronavirus disease-2019 (COVID-19) result from myocardial viral infection or are secondary to systemic inflammation and/or thrombosis. We provide evidence that cardiomyocytes are infected in patients with COVID-19 myocarditis and are susceptible to severe acute respiratory syndrome coronavirus 2. We establish an engineered heart tissue model of COVID-19 myocardial pathology, define mechanisms of viral pathogenesis, and demonstrate that cardiomyocyte severe acute respiratory syndrome coronavirus 2 infection results in contractile deficits, cytokine production, sarcomere disassembly, and cell death. These findings implicate direct infection of cardiomyocytes in the pathogenesis of COVID-19 myocardial pathology and provides a model system to study this emerging disease.

The concurrence of multiple sclerosis and glioblastoma.

INTRODUCTION: Glioblastoma rarely coincides with multiple sclerosis. Although registries have reported a higher proportion of brain tumors-most of which are glial-these events appear to be underreported. The relative contribution of JC virus (an oncogenic virus) and disease modifying therapies that may facilitate JC virus neurotropism and tumor-specific immune evasion remain unknown. CASE REPORT: We present the case of a 64-year-old woman who developed a primary glioblastoma eight years after diagnosis of multiple sclerosis while on dimethyl fumarate. CONCLUSION: Systematic reporting may help answer whether JC virus seropositivity and certain disease modifying therapies confer higher risk for glioblastoma in patients with multiple sclerosis.

SARS-CoV-2 Infects Human Engineered Heart Tissues and Models COVID-19 Myocarditis.

Epidemiological studies of the COVID-19 pandemic have revealed evidence of cardiac involvement and documented that myocardial injury and myocarditis are predictors of poor outcomes. Nonetheless, little is understood regarding SARS-CoV-2 tropism within the heart and whether cardiac complications result directly from myocardial infection. Here, we develop a human engineered heart tissue model and demonstrate that SARS-CoV-2 selectively infects cardiomyocytes. Viral infection is dependent on expression of angiotensin-I converting enzyme 2 (ACE2) and endosomal cysteine proteases, suggesting an endosomal mechanism of cell entry. After infection with SARS-CoV-2, engineered tissues display typical features of myocarditis, including cardiomyocyte cell death, impaired cardiac contractility, and innate immune cell activation. Consistent with these findings, autopsy tissue obtained from individuals with COVID-19 myocarditis demonstrated cardiomyocyte infection, cell death, and macrophage-predominate immune cell infiltrate. These findings establish human cardiomyocyte tropism for SARS-CoV-2 and provide an experimental platform for interrogating and mitigating cardiac complications of COVID-19.

A Remarkable Response of Granulomatous Hypophysitis to Infliximab in a Patient With a Background of Crohn's Disease-A Case Report.

Background: Hypophysitis is primary or idiopathic or secondary to another disease process. The histologic subtypes of hypophysitis are lymphocytic, granulomatous, xanthomatous, xanthogranulomatous, or IgG4-related. Granulomatous hypophysitis is the second most common form and is characterized by multinucleated giant cells with granulomas and histiocytes. It can be idiopathic or secondary to another process such as infection, sarcoidosis, vasculitis, dendritic cell disorders, Crohn's disease (CD) or a reaction to rupture of a Rathke's cyst or pituitary adenoma. We present a case of granulomatous hypophysitis in a patient with CD who had resistance to corticosteroids but a dramatic response to immunosuppressive therapy with anti-tumor necrosis factor (TNF)-α therapy. Case description: A 43-year-old woman with a 9-year history of ileal and colonic CD presented to the Pituitary Center with headaches, visual disturbance, fatigue, nausea, and secondary amenorrhea. She was not on active therapy for her CD at the time of presentation and had no gastrointestinal symptoms. Hormonal evaluation revealed hyperprolactinemia, secondary hypothyroidism and adrenal insufficiency. MRI revealed a 12 × 12 × 19 mm sellar lesion abutting the optic chiasm, reported as a macroadenoma. The patient underwent endoscopic transsphenoidal biopsy of the pituitary mass. Pathology revealed granulomatous hypophysitis. Evaluation for secondary causes of hypophysitis, apart from CD, was negative. Despite a course of high dose prednisone, her symptoms and MRI findings worsened and she developed symptoms consistent with diabetes insipidus. Using a personalized medicine approach, she was started on anti-(TNF)-α therapy with infliximab combined with azathioprine, which are indicated for treatment of CD. Her headaches and polyuria resolved and her menstrual cycles resumed. MRI at 3 months and more than 1.5 years after initiation of anti-TNF-α therapy revealed durable resolution of the pituitary mass. Conclusion: To our knowledge, this is the first report of successful use of anti-TNF-α therapy for a patient with granulomatous hypophysitis, in this case associated with a previous diagnosis of CD. Although glucocorticoids are used frequently as first-line therapy for primary hypophysitis, granulomatous hypophysitis can be corticosteroid resistant and other immunosuppressive approaches may need to be considered within the context of the patient.

Patient-Derived Orthotopic Xenograft (PDOX) Mouse Models of Primary and Recurrent Meningioma.

BACKGROUND: Meningiomas constitute one-third of all primary brain tumors. Although typically benign, about 20% of these tumors recur despite surgery and radiation, and may ultimately prove fatal. There are currently no effective chemotherapies for meningioma. We, therefore, set out to develop patient-derived orthotopic xenograft (PDOX) mouse models of human meningioma using tumor. METHOD: Of nine patients, four had World Health Organization (WHO) grade I tumors, five had WHO grade II tumors, and in this second group two patients also had recurrent (WHO grade III) meningioma. We also classified the tumors according to our recently developed molecular classification system (Types A, B, and C, with C being the most aggressive). We transplanted all 11 surgical samples into the skull base of immunodeficient (SCID) mice. Only the primary and recurrent tumor cells from one patient-both molecular Type C, despite being WHO grades II and III, respectively-led to the formation of meningioma in the resulting mouse models. We characterized the xenografts by histopathology and RNA-seq and compared them with the original tumors. We performed an in vitro drug screen using 60 anti-cancer drugs followed by in vivo validation. RESULTS: The PDOX models established from the primary and recurrent tumors from patient K29 (K29P-PDOX and K29R-PDOX, respectively) replicated the histopathology and key gene expression profiles of the original samples. Although these xenografts could not be subtransplanted, the cryopreserved primary tumor cells were able to reliably generate PDOX tumors. Drug screening in K29P and K29R tumor cell lines revealed eight compounds that were active on both tumors, including three histone deacetylase (HDAC) inhibitors. We tested the HDAC inhibitor Panobinostat in K29R-PDOX mice, and it significantly prolonged mouse survival (p < 0.05) by inducing histone H3 acetylation and apoptosis. CONCLUSION: Meningiomas are not very amenable to PDOX modeling, for reasons that remain unclear. Yet at least some of the most malignant tumors can be modeled, and cryopreserved primary tumor cells can create large panels of tumors that can be used for preclinical drug testing.

Gastrointestinal stromal tumor with intracranial metastasis: case presentation and systematic review of literature.

BACKGROUND: Intracranial metastasis of Gastrointestinal Stromal Tumors (GISTs) is rare but presents unique treatment challenges. We present a case of intracranial metastasis of GIST with a systematic review of the literature. A literature search using key terms "'gastrointestinal stromal tumor' AND brain AND metastasis"" was conducted through May 2019 via Embase and Pubmed according to PRISMA guidelines. Only cases describing intradural metastases rather than calvarial or intraorbital metastases were included. CASE PRESENTATION: A 57-year-old woman with history of GIST metastatic to the liver presented with a six-week history of left facial weakness, left hearing loss, and left facial numbness, and a one-week history of headaches, gait disturbance, and dizziness. MRI revealed a contrast-enhancing dural-based left middle cranial fossa mass measuring 2.9 cm × 3.1 cm × 3.4 cm with extension into the internal auditory canal and cerebral edema. A left temporal craniotomy was performed to excise the lesion, and the patient was discharged to a rehabilitation facility at her preoperative baseline. Intraoperative pathology revealed a spindle cell neoplasm, postoperative MRI demonstrated gross total resection of the lesion, and microscopic analysis demonstrated sheets of spindled tumor cells with short ovoid, irregular, hyperchromatic nuclei and scattered large atypical nuclei without extensive necrosis. Immunohistochemical staining was positive for KIT proto-oncogene (CD117, c-KIT), and the patient was put on imatinib (400 mg/day). CONCLUSIONS: Of the 18 cases analyzed and our present case, metastasis typically involved the cerebrum with only one in infratentorial elements. The tumors in seven of the cases involved the dura, and one case metastasized to the pituitary. Eight patients died following treatment. Surgery remains the mainstay of intracranial metastatic GIST, however there are many reports of good responses to radiation or chemotherapy alone. More investigation is required to determine the best treatment course for these patients.

Molecular profiling predicts meningioma recurrence and reveals loss of DREAM complex repression in aggressive tumors.

Meningiomas account for one-third of all primary brain tumors. Although typically benign, about 20% of meningiomas are aggressive, and despite the rigor of the current histopathological classification system there remains considerable uncertainty in predicting tumor behavior. Here, we analyzed 160 tumors from all 3 World Health Organization (WHO) grades (I through III) using clinical, gene expression, and sequencing data. Unsupervised clustering analysis identified 3 molecular types (A, B, and C) that reliably predicted recurrence. These groups did not directly correlate with the WHO grading system, which classifies more than half of the tumors in the most aggressive molecular type as benign. Transcriptional and biochemical analyses revealed that aggressive meningiomas involve loss of the repressor function of the DREAM complex, which results in cell-cycle activation; only tumors in this category tend to recur after full resection. These findings should improve our ability to predict recurrence and develop targeted treatments for these clinically challenging tumors.

Spinal Epidermoid Tumors: Case Report and Review of the Literature.

Spinal epidermoid tumors are rare, benign tumors that are either acquired from trauma, surgery, or lumbar puncture or arise as congenital lesions, particularly spinal dysraphisms. We report a case of a massive spinal epidermoid tumor and review the literature with a focus on the surgical outcomes. A 71-year-old female patient presented after a fall with subsequent symptoms of severe back and hip pain, as well as loss of motor strength in the left leg. Her magnetic resonance imaging demonstrated a T2/short tau inversion recovery hyperintense mass extending from the level of the T10-11 disc caudally through S2. A biopsy was recommended to determine whether the tumor was radio- or chemo-sensitive. The patient underwent a L4 laminectomy and a pearly-white tumor was encountered, with a subsequent biopsy confirming it to be an epidermoid tumor. The following conclusions can be drawn from a review of the literature. Spinal epidermoid tumors are more common in women and tend to present in younger patients (median age of 23). The majority of patients had acquired lesions (46%). In terms of surgical outcomes for adherent tumors, gross total resection was found to provide optimal outcomes, with 90% of patients improving clinically after surgery.

Intraventricular Cavernomas of the Third Ventricle: Report of 2 Cases and a Systematic Review of the Literature.

BACKGROUND: Intraventricular cavernous malformations are relatively rare benign vascular malformations. Patients may be asymptomatic or present with headache, seizure, hemorrhage, or neurologic deficits. We report 2 cases of patients with cavernomas in the third ventricle and at the foramen of Monro. We also performed a systematic review of the literature to examine the clinical features and efficacy of the current standard of care for these lesions. METHODS: We performed the systematic review according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Multiple databases were queried; the title/abstract and MeSH keywords used included "cavernous malformation," "cavernoma," "cavernous hemangioma," "cavernous angioma," "foramen of Monro," "third ventricle," and "intraventricular," along with "AND" and "OR" operators. Patient demographic and clinical data were collected for qualitative synthesis. RESULTS: Patients presented at a median age of 38 years; the most common symptom was headaches. Gross total resection was performed in 84.6% of patients, and 81.8% had clinical improvement with intervention. The incidence of intraventricular hemorrhage and hydrocephalus was 15.4% and 59%, respectively. CONCLUSIONS: The specific location of the cavernoma determines clinical features seen and approach used in surgical resection. Ventriculoperitoneal shunting was not required in most cases, as hydrocephalus improved with removal of the obstruction at the foramen of Monro. Gross total resection appears to be the optimal management strategy in symptomatic patients and leads to a good outcome in most cases.

Total artificial heart implantation for biventricular failure due to eosinophilic myocarditis.

Idiopathic hypereosinophilic syndrome is a condition of unknown etiology characterized by proliferation of eosinophils and their infiltration into tissues. Although cardiac involvement is rare, eosinophilic myocarditis can lead to life-threating fulminant congestive heart failure. Treatment of patients with eosinophilic myocarditis is challenging as heart failure can be caused by biventricular dysfunction. To our knowledge, this is the first case reported in the literature describing a patient with acute severe biventricular heart failure caused by eosinophilic myocarditis with mural left ventricular apical thrombus who was successfully treated with implantation of a total artificial heart as a bridge to heart transplant.