DNA Methylation Landscapes of Prostate Cancer Brain Metastasis Are Shaped by Early Driver Genetic Alterations.

Metastases from primary prostate cancers to rare locations, such as the brain, are becoming more common due to longer life expectancy resulting from improved treatments. Epigenetic dysregulation is a feature of primary prostate cancer, and distinct DNA methylation profiles have been shown to be associated with the mutually exclusive SPOP-mutant or TMPRSS2-ERG fusion genetic backgrounds. Using a cohort of prostate cancer brain metastases (PCBM) from 42 patients, with matched primary tumors for 17 patients, we carried out a DNA methylation analysis to examine the epigenetic distinction between primary prostate cancer and PCBM, the association between epigenetic alterations and mutational background, and particular epigenetic alterations that may be associated with PCBM. Multiregion sampling of PCBM revealed epigenetic stability within metastases. Aberrant methylation in PCBM was associated with mutational background and PRC2 complex activity, an effect that is particularly pronounced in SPOP-mutant PCBM. While PCBM displayed a CpG island hypermethylator phenotype, hypomethylation at the promoters of genes involved in neuroactive ligand-receptor interaction and cell adhesion molecules such as GABRB3, CLDN8, and CLDN4 was also observed, suggesting that cells from primary tumors may require specific reprogramming to form brain metastasis. This study revealed the DNA methylation landscapes of PCBM and the potential mechanisms and effects of PCBM-associated aberrant DNA methylation. SIGNIFICANCE: DNA methylation analysis reveals the molecular characteristics of PCBM and may serve as a starting point for efforts to identify and target susceptibilities of these rare metastases.

Complement C1s deficiency in a male Caucasian patient with systemic lupus erythematosus: a case report.

Deficiencies of the early complement components of the classical pathway (CP) are well-documented in association with systemic lupus erythematosus (SLE) or SLE-like syndromes and severe pyogenic infections. Among these, complete C1s deficiency has been reported in nine cases so far. Here, we describe a 34-year-old male patient who presented with severe, recurrent infections since childhood, including meningitides with pneumococci and meningococci, erysipelas, subcutaneous abscess, and recurrent infections of the upper airways. The patient also exhibited adult-onset SLE, meeting 7/11 of the ACR criteria and 34 of the 2019 EULAR/ACR classification criteria, along with class IV-G (A) proliferative lupus nephritis (LN). A screening of the complement cascade showed immeasurably low CH50, while the alternative pathway (AP) function was normal. Subsequent determination of complement components revealed undetectable C1s with low levels of C1r and C1q, normal C3, and slightly elevated C4 and C2 concentrations. The patient had no anti-C1q antibodies. Renal biopsy showed class IV-G (A) LN with complement C1q positivity along the glomerular basement membranes (GBMs) and weak deposition of IgG, IgM, and complement C3 and C4 in the mesangium and GBM. In an ELISA-based functional assay determining C4d deposition, the patient's absent complement activity was fully restored by adding C1s. The genome of the patient was analyzed by whole genome sequencing showing two truncating variants in the C1S gene. One mutation was located at nucleotide 514 in exon 5, caused by a nucleotide substitution from G to T, resulting in a nonsense mutation from Gly172 (p.Gly172*). The other mutation was located at nucleotide 750 in exon 7, where C was replaced by a G, resulting in a nonsense mutation from Tyr250 (p.Tyr250*). Both mutations create a premature stop codon and have not previously been reported in the literature. These genetic findings, combined with the absence of C1s in the circulation, strongly suggest a compound heterozygote C1s deficiency in our patient, without additional defect within the complement cascade. As in a previous C1s deficiency case, the patient responded well to rituximab. The present case highlights unanswered questions regarding the CP's role in SLE etiopathogenesis.

Incidence of new onset glomerulonephritis after SARS-CoV-2 mRNA vaccination is not increased.

Numerous cases of glomerulonephritis manifesting shortly after SARS-CoV-2 vaccination have been reported, but causality remains unproven. Here, we studied the association between mRNA-based SARS-CoV-2 vaccination and new-onset glomerulonephritis using a nationwide retrospective cohort and a case-cohort design. Data from all Swiss pathology institutes processing native kidney biopsies served to calculate incidence of IgA nephropathy, pauci-immune necrotizing glomerulonephritis, minimal change disease, and membranous nephropathy in the adult Swiss population. The observed incidence during the vaccination campaign (January to August 2021) was not different from the expected incidence calculated using a Bayesian model based on the years 2015 to 2019 (incidence rate ratio 0.86, 95% credible interval 0.73-1.02) and did not cross the upper boundary of the 95% credible interval for any month. Among 111 patients 18 years and older with newly diagnosed glomerulonephritis between January and August 2021, 38.7% had received at least one vaccine dose before biopsy, compared to 39.5% of the general Swiss population matched for age and calendar-time. The estimated risk ratio for the development of new-onset biopsy-proven glomerulonephritis was not significant at 0.97 (95% confidence interval 0.66-1.42) in vaccinated vs. unvaccinated individuals. Patients with glomerulonephritis manifesting within four weeks after vaccination did not differ clinically from those manifesting temporally unrelated to vaccination. Thus, vaccination against SARS-CoV-2 was not associated with new-onset glomerulonephritis in these two complementary studies with most temporal associations between SARS-CoV-2 vaccination and glomerulonephritis likely coincidental.

Alterations in homologous recombination repair genes in prostate cancer brain metastases.

Improved survival rates for prostate cancer through more effective therapies have also led to an increase in the diagnosis of metastases to infrequent locations such as the brain. Here we investigate the repertoire of somatic genetic alterations present in brain metastases from 51 patients with prostate cancer brain metastases (PCBM). We highlight the clonal evolution occurring in PCBM and demonstrate an increased mutational burden, concomitant with an enrichment of the homologous recombination deficiency mutational signature in PCBM compared to non-brain metastases. Focusing on known pathogenic alterations within homologous recombination repair genes, we find 10 patients (19.6%) fulfilling the inclusion criteria used in the PROfound clinical trial, which assessed the efficacy of PARP inhibitors (PARPi) in homologous recombination deficient prostate cancer. Eight (15.7%) patients show biallelic loss of one of the 15 genes included in the trial, while 5 patients (9.8%) harbor pathogenic alterations in BRCA1/2 specifically. Uncovering these molecular features of PCBM may have therapeutic implications, suggesting the need of clinical trial enrollment of PCBM patients when evaluating potential benefit from PARPi.

Magnetic Resonance Imaging Signal Characteristics of Medishield: Early Postoperative Profile in a Rabbit Interlaminotomy Model.

OBJECTIVE: Application of Medishield to the nerve root is common during spinal surgery to create a mechanical barrier from pain mediators and reduce scar formation. However, Medishield's signal characteristics on magnetic resonance imaging (MRI) have not yet been examined. METHODS: Microsurgical interlaminotomy was performed on 2 lower lumbar segments in 17 adult New Zealand white rabbits. After dural exposure, applications of 1 mL (autologous blood clot or Medishield) were randomized for each level. On postoperative days 1 through 3, various MRI sequences in 1.5T were performed including T1-weighted, T2-w, T1-gadolinium-weighted, susceptibility-weighted and turbo inversion recovery magnitude (TIRM) sequence. Signaling characteristics were analyzed by 3 blinded observers. Inter-rater agreement was calculated using Fleiss's kappa coefficient (κ). Positive and negative likelihood ratios in detecting Medishield by MRI were determined. RESULTS: Of 24 MRIs performed, TIRM sequence identified Medishield with the highest likelihood ratio. Medishield's positive likelihood ratio was highest (5.8) on postoperative day 1 with interobserver agreement of 93% (κ = 0.75); these rates declined to 2.5 and 1.4 on postoperative days 2 and 3 with interobserver agreements of 71% (κ = 0.43) and 83% (κ = 0.67), respectively. Medishield adherence was confirmed in each rabbit by histologic examinations. CONCLUSION: Understanding that radiologic detection of Medishield diminished over time as its signal characteristics became less distinguishable from a blood clot is essential in clinical practice. Medishield was detected on postoperative day 1 but not 2 days later after hemodynamic changes had occurred. These results may provide a guide for postoperative findings, such as differential diagnosis of hematoma.

Sellar Toxoplasmosis and Nonfunctioning Pituitary Adenoma.

BACKGROUND: Sellar toxoplasmosis is associated with congenital infections or immunodeficiency. The finding of Toxoplasma bradycysts in a pituitary adenoma is very unusual. CASE DESCRIPTION: An otherwise healthy 27-year-old woman presented with secondary amenorrhea and moderately elevated prolactin levels. A macroprolactinoma was suspected on magnetic resonance imaging, and cabergoline was initiated. Although dopamine levels decreased, the tumor did not show significant shrinkage; after 2 years, transsphenoidal resection was indicated to clarify the diagnosis and to cure hyperprolactinemia. Histology showed an inactive pituitary adenoma and Toxoplasma bradycysts. Seropositivity for Toxoplasma gondii, but neither immunodeficiency nor intracerebral spread, was found. During a postoperative follow-up period of 15 months, the patient did not show any recurrence. CONCLUSIONS: Sellar toxoplasmosis in conjunction with pituitary adenoma is extremely rare. Nonfunctioning lesions should be suspected in cases of sellar masses and moderate hyperprolactinemia.

Use of fluorescence to guide resection or biopsy of primary brain tumors and brain metastases.

OBJECT: The accurate discrimination between tumor and normal tissue is crucial for determining how much to resect and therefore for the clinical outcome of patients with brain tumors. In recent years, guidance with 5-aminolevulinic acid (5-ALA)-induced intraoperative fluorescence has proven to be a useful surgical adjunct for gross-total resection of high-grade gliomas. The clinical utility of 5-ALA in resection of brain tumors other than glioblastomas has not yet been established. The authors assessed the frequency of positive 5-ALA fluorescence in a cohort of patients with primary brain tumors and metastases. METHODS: The authors conducted a single-center retrospective analysis of 531 patients with intracranial tumors treated by 5-ALA-guided resection or biopsy. They analyzed patient characteristics, preoperative and postoperative liver function test results, intraoperative tumor fluorescence, and histological data. They also screened discharge summaries for clinical adverse effects resulting from the administration of 5-ALA. Intraoperative qualitative 5-ALA fluorescence (none, mild, moderate, and strong) was documented by the surgeon and dichotomized into negative and positive fluorescence. RESULTS: A total of 458 cases qualified for final analysis. The highest percentage of 5-ALA-positive fluorescence in open resection was found in glioblastomas (96%, n = 99/103). Among other tumors, 5-ALA-positive fluorescence was detected in 88% (n = 21/32) of anaplastic gliomas (WHO Grade III), 40% (n = 8/19) of low-grade gliomas (WHO Grade II), no (n = 0/3) WHO Grade I gliomas, and 77% (n = 85/110) of meningiomas. Among metastases, the highest percentage of 5-ALA-positive fluorescence was detected in adenocarcinomas (48%, n = 13/27). Low rates or absence of positive fluorescence was found among pituitary adenomas (8%, n = 1/12) and schwannomas (0%, n = 0/7). Biopsies of high-grade primary brain tumors showed positive rates of fluorescence similar to those recorded for open resection. No clinical adverse effects associated with use of 5-ALA were observed. Only 1 patient had clinically silent transient elevation of liver enzymes. CONCLUSIONS: Study findings suggest that the administration of 5-ALA as a surgical adjunct for resection and biopsy of primary brain tumors and brain metastases is safe. In light of the high rate of positive fluorescence in high-grade gliomas other than glioblastomas, meningiomas, and a variety of metastatic cancers, 5-ALA seems to be a promising tool for enhancing intraoperative identification of neoplastic tissue and optimizing the extent of resection.

Rare suprasellar glioblastoma: report of two cases and review of the literature.

BACKGROUND AND IMPORTANCE: The suprasellar and hypothalamic/chiasmatic regions can harbor a broad range of pathologic conditions, both neoplastic and nonneoplastic; however, malignant gliomas are extremely rare in those regions. CLINICAL PRESENTATIONS: Patient 1 was a 70 year-old man with weight loss and rapidly progressive visual impairment. A mass centered in the hypothalamus was detected on magnetic resonance (MR) imaging. The second patient, a 45 year-old woman, complained of visual symptoms and headaches. MR imaging revealed a combined intra- and suprasellar mass. In both instances, the preoperative differential diagnosis favored craniopharyngioma. Histological examination confirmed the diagnosis of glioblastoma. CONCLUSION: We report two rare adult cases of hypothalamic/chiasmatic glioblastoma. The authors review the literature, highlighting the importance of considering this rare entity in the differential diagnosis of suprasellar and hypothalamic lesions.

State-of-the-art pathology: new WHO classification, implications, and new developments.

To keep up with advances in central nervous system (CNS) tumor diagnosis and discovery of new entities, the classification of these tumors requires periodic review and revision. Since the initial 1979 publication from the World Health Organization (WHO) of Histological Typing of Tumours of the Central Nervous System, 3 further editions have been published, cataloging the advances in CNS tumor classification and diagnosis over the past 3 decades. In this article, we discuss select new additions to the current classification, including new diagnostic tools, differential diagnoses, and management implications.

Molecular tools: biology, prognosis, and therapeutic triage.

Diffuse gliomas in adults continue to have a dismal prognosis with the current standard therapeutic methods, including maximal surgical resection, radiation, and chemotherapy. The pathogenesis of adult glioma is complex, involving the loss of function of tumor suppressor genes and activation of oncogenes, which are involved in a network of interconnected signaling pathways. Through activation of these pathways, characteristics of malignant gliomas, including uncontrolled proliferation and growth, invasion, and angiogenesis, are driven. Evolving therapeutic approaches are focused on specifically targeting these genetic lesions. This content gives an overview of the current knowledge about the pathogenesis of adult diffuse gliomas, emphasizing new targeted treatment approaches.

ALS-associated fused in sarcoma (FUS) mutations disrupt Transportin-mediated nuclear import.

Mutations in fused in sarcoma (FUS) are a cause of familial amyotrophic lateral sclerosis (fALS). Patients carrying point mutations in the C-terminus of FUS show neuronal cytoplasmic FUS-positive inclusions, whereas in healthy controls, FUS is predominantly nuclear. Cytoplasmic FUS inclusions have also been identified in a subset of frontotemporal lobar degeneration (FTLD-FUS). We show that a non-classical PY nuclear localization signal (NLS) in the C-terminus of FUS is necessary for nuclear import. The majority of fALS-associated mutations occur within the NLS and impair nuclear import to a degree that correlates with the age of disease onset. This presents the first case of disease-causing mutations within a PY-NLS. Nuclear import of FUS is dependent on Transportin, and interference with this transport pathway leads to cytoplasmic redistribution and recruitment of FUS into stress granules. Moreover, proteins known to be stress granule markers co-deposit with inclusions in fALS and FTLD-FUS patients, implicating stress granule formation in the pathogenesis of these diseases. We propose that two pathological hits, namely nuclear import defects and cellular stress, are involved in the pathogenesis of FUS-opathies.