In vitro reconstitution of epigenetic reprogramming in the human germ line.

Epigenetic reprogramming resets parental epigenetic memories and differentiates primordial germ cells (PGCs) into mitotic pro-spermatogonia or oogonia. This process ensures sexually dimorphic germ cell development for totipotency1. In vitro reconstitution of epigenetic reprogramming in humans remains a fundamental challenge. Here we establish a strategy for inducing epigenetic reprogramming and differentiation of pluripotent stem-cell-derived human PGC-like cells (hPGCLCs) into mitotic pro-spermatogonia or oogonia, coupled with their extensive amplification (about >1010-fold). Bone morphogenetic protein (BMP) signalling is a key driver of these processes. BMP-driven hPGCLC differentiation involves attenuation of the MAPK (ERK) pathway and both de novo and maintenance DNA methyltransferase activities, which probably promote replication-coupled, passive DNA demethylation. hPGCLCs deficient in TET1, an active DNA demethylase abundant in human germ cells2,3, differentiate into extraembryonic cells, including amnion, with de-repression of key genes that bear bivalent promoters. These cells fail to fully activate genes vital for spermatogenesis and oogenesis, and their promoters remain methylated. Our study provides a framework for epigenetic reprogramming in humans and an important advance in human biology. Through the generation of abundant mitotic pro-spermatogonia and oogonia-like cells, our results also represent a milestone for human in vitro gametogenesis research and its potential translation into reproductive medicine.

Transarterial and Transvenous Embolization for Posterior Condylar Canal Dural Arteriovenous Fistula.

Objective: Posterior condylar canal dural arteriovenous fistula (PCC DAVF) is extremely rare, with only four previously reported cases in the English literature. Cases may present tinnitus and radiculopathy. In cases where the drainer is around the brainstem, subarachnoid and intraventricular hemorrhages (IVHs) may occur. We describe the clinical presentation, angiographic imaging, and endovascular treatment strategy of a PCC DAVF. Case Presentation: A 30-year-old woman presented to our hospital with tinnitus and stiffness of the shoulder. Neuroimaging studies showed DAVF with fistulous points around right PCC consisted of a high-flow shunt, fed mainly by the occipital artery, and drained to the suboccipital cavernous sinus (SCS) and internal jugular vein. The lesion was treated with a combination of transvenous coil embolization and transarterial Onyx injection. The patient recovered immediately after intervention and had no neurological deficits in the follow-up visit. Conclusion: In this case, endovascular treatment was performed safely without recurrence so far. A strategy combining transvenous coil embolization and transarterial Onyx injection may be an effective treatment for PCC DAVF with high-flow shunt. Further case accumulation is desired.

Cerebral Amyloidoma Accompanied by Sjögren's Syndrome: A Case Report and Literature Review.

We present a 69-year-old woman with colorectal cancer and a left frontal lobe tumor that was diagnosed as a cerebral amyloidoma after surgical resection. Further postoperative systemic evaluation revealed another amyloidoma in her hip as well as Sjögren's syndrome. Systemic amyloidosis was not present. To the best of our knowledge, this is the first case of cerebral amyloidoma presenting as one of the multiple localized amyloidomas accompanied by Sjögren's syndrome. We also present a systematic review of 65 cerebral amyloidoma cases reported in the literature over the past 40 years and discuss patient characteristics and pathological and imaging findings associated with prognosis.

PD-1/PD-L1 expression in a series of intracranial germinoma and its association with Foxp3+ and CD8+ infiltrating lymphocytes.

One histopathological characteristic of intracranial germinoma is abundant tumor-infiltrating lymphocytes (TILs) showing a two-cell pattern with large undifferentiated tumor cells. The programmed cell death 1 (PD-1)/programmed cell death 1 ligand (PD-L) axis has recently been recognized as an anti-tumor immune system. To evaluate intratumor immune status in intracranial germinoma, we examined expressions of PD-1 and PD-L1 (clone 28-8) and subtypes of TILs. Expressions of PD-1 and PD-L1 were detected immunohistochemically in 25 formalin-fixed, paraffin-embedded tumor specimens from 24 patients with intracranial germinoma consisting of 22 primary and 3 recurrent tumors. To evaluate subtypes of TILs, quantification of lymphocytes with CD3, CD8, CD4, and Foxp3 was performed. Statistical analyses were performed among PD-1, PD-L1 and subtypes of TILs. In 25 tumor tissue, expressions of PD-1 in TILs and PD-L1 in tumor cells were identified in 96% (24/25) and 92% (23/25), respectively. Expression of PD-1 was associated with CD3+ TIL density. Expression of PD-1 correlated with Foxp3+ TIL density and CD8+ TIL density, but not with CD4+ TIL density. Furthermore, expression of PD-1 correlated strongly with Foxp3+/CD4+ ratio. Taken together, increase of PD-1+ expression is associated with accumulation of Foxp3+ and CD8+ TILs. These findings intimate that PD-1/PD-L1 axis might shape the immune infiltration suggesting a modulation of the immune response and subsequent tumor growth in intracranial germinoma. Anti-PD-1 and anti-PD-L1 are potential immune therapeutic strategies in intracranial germinoma.

High programmed cell death 1 ligand-1 expression: association with CD8+ T-cell infiltration and poor prognosis in human medulloblastoma.

OBJECTIVE Medulloblastoma is a type of malignant tumor arising in the cerebellum. The clinical importance of programmed cell death 1 ligand-1 (PD-L1) expression in medulloblastoma remains unknown. The aim of the present study was to examine the expression of PD-L1 and tumor-infiltrating T cells, and to evaluate their relationships to the prognosis of patients with medulloblastoma. METHODS The authors immunohistochemically analyzed PD-L1 expression and CD3+ and CD8+ lymphocyte infiltrations in tumor specimens from 16 patients with medulloblastoma. RESULTS High expression of PD-L1 was observed in 9 (56.3%) of 16 samples studied. High expression of PD-L1 was associated with low infiltrations of CD3+ or CD8+ lymphocytes. Patients with high expression of PD-L1 had shorter progression-free survival and overall survival times than those with low expression (p = 0.076 and p = 0.099, respectively). In addition, patients with high expression of PD-L1 and with low infiltration of CD8+ lymphocytes had a significantly worse outcome, with a 5-year survival rate of 15%, as compared with the other patients, who had a 5-year survival rate of nearly 90% (p = 0.0048 for progression-free survival and p = 0.010 for overall survival). CONCLUSIONS These findings indicate that PD-L1 expression was associated with a reduced infiltration of CD8+ T cells and poor prognosis in human medulloblastoma.

Clinicopathological, Radiological, and Genetic Analyses of Cerebellar Gangliogliomas with Long-Term Survival.

OBJECTIVE: Cerebellar gangliogliomas show different image findings and clinical behaviors from the supratentorial; however, their molecular basis and optimal managements remain to be elucidated. We report 3 children with cerebellar ganglioglioma and long-term survival, focusing on clinicopathological and radiological findings and genetic analyses. PATIENTS AND METHODS: We retrospectively analyzed 3 children with cerebellar ganglioglioma treated in our institute between 2000 and 2010. Immunohistochemical examinations were performed to determine the expression of KI-67, glial fibrillary acidic protein, synaptophysin, BRAFV600E and IDH-1 R132H mutated proteins. Standard Sanger sequencing was used to confirm BRAF, IDH-1/2, and Histone H3.3 mutations. Methylation-specific polymerase chain reaction was used to evaluate MGMT promoter methylation. RESULTS: In all cases, magnetic resonance imaging demonstrated an infiltrative tumor in cerebellar peduncle and hemisphere. All 3 children are alive (>12 years survival), and their residual tumors have been stable for more than 5 years after the treatments. Their tumors showed distinctive features of ganglioglioma with low Ki-67 index (2%-4%), positive for the BRAFV600E mutation, but negative for IDH1/2 mutations. The MGMT promoter methylation was observed in all of them. CONCLUSIONS: Our study showed that all 3 children achieved long-term survival with residual tumors. These tumors might indicate a benign prognosis of pediatric cerebellar gangliogliomas, regardless of the infiltrating manifestation and the presence of BRAF mutation.