Molecular pathways and cellular subsets associated with adverse clinical outcomes in overlapping immune-related myocarditis and myositis.

Immune checkpoint therapies (ICTs) can induce life-threatening immune-related adverse events, including myocarditis and myositis, which are rare but often concurrent. The molecular pathways and immune subsets underlying these toxicities remain poorly understood. To address this need, we obtained heart and skeletal muscle biopsies for single-cell RNA sequencing in living patients with cancers treated with ICTs admitted to the hospital with myocarditis and/or myositis (overlapping myocarditis plus myositis, n=10; myocarditis-only, n=1) compared to ICT-exposed patients ruled out for toxicity utilized as controls (n=9) within 96 hours of clinical presentation. Analyses of 58,523 cells revealed CD8+ T cells with a cytotoxic phenotype expressing activation/exhaustion markers in both myocarditis and myositis. Furthermore, the analyses identified a population of myeloid cells expressing tissue-resident signatures and FcγRIIIa (CD16a), which is known to bind IgG and regulate complement activation. Immunohistochemistry of affected cardiac and skeletal muscle tissues revealed protein expression of pan-IgG and complement product C4d that were associated with the presence of high-titer serum autoantibodies against muscle antigens in a subset of patients. We further identified a population of inflammatory IL-1B+TNF+ myeloid cells specifically enriched in myocarditis and associated with greater toxicity severity and poorer clinical outcomes. These results are the first to recognize these myeloid subsets in human immune-related myocarditis and myositis tissues and nominate new targets for investigation into rational treatments to overcome these high-mortality toxicities.

Early recurrence in standard-risk medulloblastoma patients with the common idic(17)(p11.2) rearrangement.

Medulloblastoma is diagnosed histologically; treatment depends on staging and age of onset. Whereas clinical factors identify a standard- and a high-risk population, these findings cannot differentiate which standard-risk patients will relapse and die. Outcome is thought to be influenced by tumor subtype and molecular alterations. Poor prognosis has been associated with isochromosome (i)17q in some but not all studies. In most instances, molecular investigations document that i17q is not a true isochromosome but rather an isodicentric chromosome, idic(17)(p11.2), with rearrangement breakpoints mapping within the REPA/REPB region on 17p11.2. This study explores the clinical utility of testing for idic(17)(p11.2) rearrangements using an assay based on fluorescent in situ hybridization (FISH). This test was applied to 58 consecutive standard- and high-risk medulloblastomas with a 5-year minimum of clinical follow-up. The presence of i17q (ie, including cases not involving the common breakpoint), idic(17)(p11.2), and histologic subtype was correlated with clinical outcome. Overall survival (OS) and disease-free survival (DFS) were consistent with literature reports. Fourteen patients (25%) had i17q, with 10 (18%) involving the common isodicentric rearrangement. The presence of i17q was associated with a poor prognosis. OS and DFS were poor in all cases with anaplasia (4), unresectable disease (7), and metastases at presentation (10); however, patients with standard-risk tumors fared better. Of these 44 cases, tumors with idic(17)(p11.2) were associated with significantly worse patient outcomes and shorter mean DFS. FISH detection of idic(17)(p11.2) may be useful for risk stratification in standard-risk patients. The presence of this abnormal chromosome is associated with early recurrence of medulloblastoma.

Crosstalk between medulloblastoma cells and endothelium triggers a strong chemotactic signal recruiting T lymphocytes to the tumor microenvironment.

Cancer cells can live and grow if they succeed in creating a favorable niche that often includes elements from the immune system. While T lymphocytes play an important role in the host response to tumor growth, the mechanism of their trafficking to the tumor remains poorly understood. We show here that T lymphocytes consistently infiltrate the primary brain cancer, medulloblastoma. We demonstrate, both in vitro and in vivo, that these T lymphocytes are attracted to tumor deposits only after the tumor cells have interacted with tumor vascular endothelium. Macrophage Migration Inhibitory Factor (MIF)" is the key chemokine molecule secreted by tumor cells which induces the tumor vascular endothelial cells to secrete the potent T lymphocyte attractant "Regulated upon Activation, Normal T-cell Expressed, and Secreted (RANTES)." This in turn creates a chemotactic gradient for RANTES-receptor bearing T lymphocytes. Manipulation of this pathway could have important therapeutic implications.

Medulloblastoma and juvenile pilocytic astrocytoma presenting as synchronous primary brain tumors in a child: case report.

Multiple metastatic brain tumors and multifocal primary brain tumors of a single histological type have been published in the adult and pediatric literature. However, the simultaneous occurrence of multiple primary brain tumors with different cell types is rare. Even more rare is the pediatric presentation of multiple primary brain tumors with different cell types. The authors describe the case of an 8-year-old boy who presented with a 2-week history of progressive headache, nausea and vomiting, and imbalance. Brain MR imaging demonstrated a heterogeneously enhancing mixed solid/cystic mass of the left cerebellar hemisphere and a larger, midline, more homogeneously enhancing lesion of the superior vermis. Spinal MR imaging was unremarkable. The patient underwent a suboccipital craniotomy and subsequent gross-total resection of both mass lesions. Pathological examination revealed the left cerebellar and superior vermian lesions to be a juvenile pilocytic astrocytoma and a medulloblastoma, respectively. The patient did well in the immediate postoperative period, was discharged home, and underwent neurooncological follow-up. To the best of the authors' knowledge, they describe the first known pediatric case in which a medulloblastoma and a juvenile pilocytic astrocytoma presented as synchronous primary brain tumors. They review the literature on multiple primary brain tumors with different histological characteristics and rehash potential mechanisms for their development.

Postoperative cranial fasciitis. Report of two cases and review of the literature.

The authors report two cases of cranial fasciitis occurring at prior craniotomy sites. They review the presentation and pathological features associated with cranial fasciitis and describe two unusual cases and their treatment. The first case is that of a 16-year-old girl who underwent suboccipital craniectomy for resection of medulloblastoma and 14 months later was found to have a 4-cm nontender mass at the incision site, with evidence of skull erosion on neuroimaging. Resection of the mass revealed cranial fasciitis. The patient later developed two more lesions in the cranial region, as well as lesions on the chest wall and abdomen consistent with nodular fasciitis; all of the lesions were resected. The second case is that of a 61-year-old man who underwent suboccipital craniectomy for hypertensive hemorrhage and 2 years later was found to have an enlarging mass at the incision site, causing compression of the cerebellum. The mass was resected and found to be consistent with cranial fasciitis. Cranial fasciitis is a rare, benign lesion of the cranial region. It is histologically identical to nodular fasciitis, a self-limiting fibroblastic process of the superficial and deep fascia. Although most cases of cranial fasciitis are reported to occur spontaneously in the very young, the two cases reported here involved older patients and lesions that developed at prior craniotomy sites in a delayed fashion, a phenomenon not previously reported. Interestingly, one patient exhibited lesions in other areas as well.

Activation of caspase-6 in aging and mild cognitive impairment.

Active caspase-6 (Csp6) and Tau cleaved by Csp6 (TauDeltaCsp6) are abundant in neuritic plaques (NPs), neuropil threads (NPTs), and neurofibrillary tangles (NFTs) in end-stage Alzheimer's disease (AD) (Guo H, Albrecht S, Bourdeau M, Petzke T, Bergeron C, LeBlanc AC: Active caspase-6 and caspase-6 cleaved Tau in neuropil threads, neuritic plaques and neurofibrillary tangles of Alzheimer's disease. Am J Pathol 2004, 165:523-531). The goal of this study was to determine whether active Csp6 is present in young and aged noncognitively impaired (NCI); aged mild cognitively impaired (MCI); and aged mild, moderate, severe, and very severe AD individuals. Csp6 activity was assessed with anti-p20Csp6 and TauDeltaCsp6 immunoreactivity. Active Csp6 is present in NFTs, NPTs, and NPs at all stages of AD. Active Csp6 is present in NFTs of all MCI cases and present in NPTs and NPs of some MCI cases. Active Csp6 is present in NFTs and NPTs of all NCI cases but is absent in younger cases. The level of TauDeltaCsp6-positive NFTs and NPTs correlates inversely with global cognitive scores in NCI individuals. Therefore, Csp6 activity can occur with aging in the absence of AD and is always associated with clinical and pathological features of confirmed AD cases. Given the ability of active Csp6 to increase amyloid-beta peptide production and cleave Tau and several synaptic proteins (LeBlanc AC, Liu H, Goodyer C, Bergeron C, Hammond J: Caspase-6 role in apoptosis of human neurons, amyloidogenesis and Alzheimer's disease. J Biol Chem 1999, 274:23426-23436; Petzke TL, Rousselet E, Goodyer C, LeBlanc AC: Substrates of caspase-6 in human primary neurons: a proteomic study. Program No. 80.9. 2005 Abstract Viewer/Itinerary Planner. Washington, DC: Society for Neuroscience. Online), we suggest that active Csp6 could be an early instigator of neuronal dysfunction.

Predisposition to atypical teratoid/rhabdoid tumor due to an inherited INI1 mutation.

BACKGROUND: Germline mutations of the INI1 gene predispose children to the development of rhabdoid tumors. Reports of familial cases, however, are extremely rare. PROCEDURE: We have identified a three-generation family in which two half-brothers were diagnosed with central nervous system atypical teratoid/rhabdoid tumors (AT/RT). The two boys, diagnosed at 2 months and 17 months of age, had a germline insertion mutation in exon 4 of the INI1 gene that was inherited from their healthy mother. A maternal uncle died in childhood from a brain tumor and a malignant rhabdoid tumor of the kidney, and presumably carried the same germline mutation. As the mother and uncle had different fathers, the grandmother is also an obligate carrier of the mutation. CONCLUSION: The identification of two unaffected carriers in a family segregating a germline mutation and rhabdoid tumor supports the hypothesis that there may be variable risks of development of rhabdoid tumor in the context of a germline mutation. There may be a developmental window in which most rhabdoid tumors occur. This family highlights the importance of mutation analysis in all patients with a suspected rhabdoid tumor.

Childhood autism: a circuit syndrome?

BACKGROUND: Autism is a disorder that can lead to life-long disability. Currently, the etiology of autism is unknown, and although there are treatments for some of the behavioral abnormalities, there is no cure. REVIEW SUMMARY: While this article will review the clinical, anatomic, and pathologic features seen in autism, the primary focus will be to present a new and provocative unifying theory regarding the underlying mechanisms causing this disorder. Current research advances, some controversial, will be discussed, and a novel definition of autism as a "circuit syndrome" will be presented. The work elaborated here will tie many of the disparate findings together, based on the idea that autism arises from abnormalities of the cerebellolimbic circuitry. Some of the more alternative theories of autism, such as mercury toxicity, linkage to the measles, mumps, and rubella vaccine, and the use of secretin will be discussed. Finally, pharmacologic treatment options will be reviewed. CONCLUSIONS: Autism is not single disorder but represents dysfunction of the cerebellolimbic circuitry that can arise from many different etiologies.

Atypical features of medulloblastoma on magnetic resonance imaging: case report and review of the literature.

Magnetic resonance imaging (MRI) is the radiologic modality of choice used to evaluate suspected lesions in the posterior fossa, given its greater sensitivity compared with other neuroimaging techniques. The case of a 9-year-old girl with progressive ataxia is presented. MRI of the brain demonstrated nonspecific T2-weighted abnormalities involving the cerebellar vermis with minimal mass effect suggested by asymmetric enlargement of the left superior cerebellar peduncle. Postgadolinium studies showed only minimal enhancement of the left superior cerebellar peduncle. After an MRI of the spine demonstrated drop metastases, a cerebellar biopsy was performed, which revealed an infiltrating medulloblastoma confined to the granular layer and leptomeninges. Hence, MRI is an important ancillary tool in the diagnosis of medulloblastoma, but caution needs to be taken when interpreting imaging studies.

Diffuse neuroendocrine differentiation in a morphologically composite mammary infiltrating ductal carcinoma: a case report and review of the literature.

Neuroendocrine differentiation has been reported in both in situ and infiltrating breast cancers. The prognostic significance of neuroendocrine differentiation in mammary carcinoma is unclear. We report a case of infiltrating ductal carcinoma in which there was a morphologically conventional-appearing infiltrating ductal component admixed with nests of cells that resembled a carcinoid tumor and initially mimicked the appearance of intraductal carcinoma. Immunohistochemical stains for synaptophysin and chromogranin demonstrated diffuse, strong positivity uniformly throughout the tumor, even in the more conventional-appearing areas. Electron microscopic examination of tissue retrieved from paraffin blocks was attempted unsuccessfully. We concluded that this was an infiltrating ductal carcinoma with morphologic and immunohistochemical evidence of neuroendocrine differentiation. The case is discussed with a review of the literature and a discussion of nomenclature for tumors of the breast showing variable degrees of neuroendocrine differentiation.

Facial nerve schwannoma.

Facial nerve schwannomas are clinically challenging tumors. This is a case study of a young woman with an extensive facial nerve schwannoma. The clinical presentation, radiographic diagnosis, pathological confirmation, and treatment options for this relatively rare tumor are discussed.