Seizure control by adding on other anti-seizure medication on seizure during levetiracetam administration in patients with glioma-related epilepsy.

BACKGROUND: Epilepsy is a major symptom in patients with glioma. Levetiracetam (LEV) is recognized as a first-line treatment for glioma-related epilepsy. Increasing the LEV dose is allowed into patients with seizure occurrence against its initial dose. However, the therapeutic efficacy of increasing the LEV dose in response to seizure occurrence remains unclear. METHODS: We retrospectively analyzed 236 glioma patients who were treated with antiseizure medications (ASMs) internally at our institute between September 2010 and December 2017. Of these, the analysis focused on 156 patients treated with LEV who had a clear history of administration. RESULTS: Seizure occurrences were observed in 21 of 75 patients (26.7%) who received LEV as first-line therapy and in 33 of 81 patients (40.7%) who received LEV as non-first-line treatment. The seizure control rate for seizure occurrence with LEV as first-line treatment was significantly higher in patients treated with addition of other ASMs (72.7%) than in those treated with increasing dose of LEV (20.0%) (p = 0.016). The seizure control rate for seizure occurrence with LEV as non-first-line treatment did not differ significantly between patients with addition of other ASMs (58.3%) and those treated with increasing dose of LEV (47.6%) (p = 0.554). CONCLUSIONS: Adding other ASMs was more effective than increasing the LEV dose for seizure control in patients treated with LEV as first-line treatment, but they demonstrated comparable efficacy in patients treated with LEV as non-first-line treatment.

Intra-cerebellar schwannoma with various degenerative changes: a case report and a systematic review.

BACKGROUND: Intra-cranial schwannomas account for less than 8% of brain tumors, among which more than 80% arise from the vestibular nerve. Intra-cerebellar schwannomas are extremely rare. Several cases have been previously reported but without remarkable degenerative changes on histology. CASE PRESENTATION: A 61-year-old man presented with worsening disorientation, and an imaging study revealed a cystic lesion (6.5 cm in the largest diameter) in the left hemisphere of the cerebellum accompanied by a mural nodule (2.5 cm) located just inside the skull with enhancement and focal calcification, in addition to hydrocephalus. The lesion was more than 5 mm from the left acoustic nerve. The patient underwent gross total resection. Pathological examination revealed remarkable degenerative changes with various morphological features. Tumor cells were pleomorphic with rich cytoplasm containing numerous eosinophilic granules. Blood vessels and extracellular matrix showed remarkable hyalinization. Immunohistochemical staining revealed that the tumor cells were positive for S-100 protein and negative for Olig2. The tumor was diagnosed as a schwannoma with marked degenerative changes. CONCLUSIONS: The present case is discussed with reference to a systematic review of previous reports of intra-cerebellar schwannoma. Intra-cerebellar schwannoma should be included in the differential diagnosis of cystic lesions with heterogeneous histopathological morphology in the cerebellum.

[Treatment of Non-Traumatic Spinal Epidural Hematoma:A Report of Five Cases and a Systematic Review of the Literature].

Objective:Non-traumatic spinal epidural hematoma(SEH)is relatively rare. We report five cases of SEH, review the relevant literature, and discuss the current treatment strategies for non-traumatic SEH in Japan. Methods:Clinical data of cases with non-traumatic SEH treated at our institute from 2008 to 2015 were retrospectively analyzed. In addition, we identified the relevant literature using the Japan Medical Abstracts Society databases for peer-reviewed articles published from Jan 1, 1995 to Aug 31, 2015. The search terms "spinal", "epidural hematoma", and "non-traumatic OR spontaneous" were used. Treatment strategies were summarized according to the treatment criteria. Results:Five patients(1 man and 4 women;age, 59-86 years;mean age, 74 years)were treated for SEH. Hematomas were located in the cervical(n=1), cervicothoracic(n=2), thoracic(n=1), and thoracolumbar(n=1)regions. All patients suffered sudden neck and/or back pain followed by subsequent neurological deterioration. Four patients were under antithrombotic treatment, and underwent laminectomy and drainage of the hematoma due to severe and progressive neurological deficits. All patients demonstrated significant neurological recovery. Seventy-seven articles from domestic institutes and hospitals were identified. Their criteria for conservative and surgical treatments differed based on the time from the onset and severity. Conclusion:Five cases of non-traumatic SEH were treated successfully. Patients with moderate to severe neurological deficit need timely surgical management, while non-surgical treatment may be indicated in mild deficits. To standardize the optimal treatment for non-traumatic SEH, an appropriate assessment system incorporating the time from onset and severity of neurological impairment should be established.

Impact of collagen matrix on reconstructive material selection and postoperative complications in endoscopic endonasal skull base surgery.

OBJECTIVE: The aim of this study was to investigate the impact of collagen matrix on reconstructive material selection and postoperative complications in endoscopic endonasal skull base surgery. METHODS: The authors retrospectively reviewed the data of consecutive patients who underwent purely endoscopic endonasal skull base surgery from January 2015 to March 2023. Intraoperative CSF leakage was classified according to the Esposito grade, and skull base repair was tailored to the leakage grade. The patients were divided into two groups: before (group A) and after (group B) collagen matrix implementation. The rates of autologous graft harvesting (fat, fascia, and nasoseptal flap), postoperative CSF leakage, and donor-site complications were compared between the two groups. RESULTS: In total, 270 patients were included. Group A included 159 patients and group B included 111 patients. There were no differences in patient characteristics, including age, pathology, and Esposito grade, between the two groups. The overall fat usage rate was significantly higher in group A (63.5%) than in group B (39.6%) (p = 0.0001), and the fascia usage rate was also significantly higher in group A (25.8%) than in group B (4.5%) (p < 0.0001). The nasoseptal flap usage rate did not differ between group A (32.7%) and group B (30.6%) (p = 0.79). Postoperative CSF leakage was similar between the two groups (0.63% in group A vs 1.8% in group B, p = 0.57), and the overall rate of CSF leakage was 1.1%. Donor-site complications occurred in 3 patients in group A, including 1 abdominal hematoma, 1 delayed abdominal infection, and 1 fluid collection after fascia lata harvesting. CONCLUSIONS: Collagen matrix implementation significantly decreased autologous graft harvesting without increasing postoperative CSF leakage, contributing to less invasive surgery.

Cone-beam CT-assisted microcatheter tip placement at the shunted pouch entry zone: A technical note for anterior condylar arteriovenous fistula.

Accurate microcatheter placement for anterior condylar arteriovenous fistula (AVF) enables selective transvenous embolization (TVE) and helps to avoid hypoglossal nerve palsy. Anterior condylar AVF has a shunted pouch within the condylar vascular and osseous structures. Detailed anatomical comprehension of the shunted pouch is essential, in addition, we believe that it is important to have a strategy for where in the shunted pouch to start filling with coils. Specifically, we consider that it is important to structurally understand the more upstream location (arterial side) within the shunted pouch (called "shunted pouch entry zone"), guide the microcatheter there, and embolize from that site. Although several studies have discussed the usefulness of intraoperative cone-beam computed tomography (CBCT) for treating anterior condylar AVF, there are no studies which have mentioned the importance of microcatheter position before coil embolization in selective TVE as in this study. Intraoperative localization of the shunted pouch entry zone is often difficult. Herein, the authors report that cone-beam computed tomography (CBCT) can assist accurate microcatheter tip placement at the shunted pouch entry zone before staring embolization. This is the novel application of intraoperative CBCT to treat anterior condylar AVF successfully treated with precise and selective TVE.

High intratumoral susceptibility signal grade on susceptibility-weighted imaging: a risk factor for hemorrhage after stereotactic biopsy.

OBJECTIVE: This study aimed to examine the association of preoperative intratumoral susceptibility signal (ITSS) grade with hemorrhage after stereotactic biopsy (STB). METHODS: The authors retrospectively reviewed 66 patients who underwent STB in their institution. Preoperative factors including age, sex, platelet count, prothrombin time-international normalized ratio, activated thromboplastin time, antiplatelet agent use, history of diabetes mellitus and hypertension, target location, anesthesia type, and ITSS data were recorded. ITSS was defined as a dot-like or fine linear low signal within a tumor on susceptibility-weighted imaging (SWI) and was graded using a 3-point scale: grade 1, no ITSS within the lesion; grade 2, 1-10 ITSSs; and grade 3, ≥ 11 ITSSs. Postoperative final tumor pathology was also reviewed. The association between preoperative variables and the size of postoperative hemorrhage was examined. RESULTS: Thirty-four patients were men and 32 were women. The mean age was 66.6 years. The most common tumor location was the frontal lobe (27.3%, n = 18). The diagnostic yield of STB was 93.9%. The most common pathology was lymphoma (36.4%, n = 24). The ITSS was grade 1 in 37 patients (56.1%), grade 2 in 14 patients (21.2%), and grade 3 in 15 patients (22.7%). Interobserver agreement for ITSS was almost perfect (weighted kappa = 0.87; 95% CI 0.77-0.98). Age was significantly associated with ITSS (p = 0.0075). Postoperative hemorrhage occurred in 17 patients (25.8%). Maximum hemorrhage diameter (mean ± SD) was 1.78 ± 1.35 mm in grade 1 lesions, 2.98 ± 2.2 mm in grade 2 lesions, and 9.51 ± 2.11 mm in grade 3 lesions (p = 0.01). Hemorrhage > 10 mm in diameter occurred in 10 patients (15.2%), being symptomatic in 3 of them. Four of 6 patients with grade 3 ITSS glioblastomas (66.7%) had postoperative hemorrhages > 10 mm in diameter. After adjusting for age, ITSS grade was the only factor significantly associated with hemorrhage > 10 mm (p = 0.029). Compared with patients with grade 1 ITSS, the odds of postoperative hemorrhage > 10 mm in diameter were 2.57 times higher in patients with grade 2 ITSS (95% CI 0.31-21.1) and 9.73 times higher in patients with grade 3 ITSS (95% CI 1.57-60.5). CONCLUSIONS: ITSS grade on SWI is associated with size of postoperative hemorrhage after STB.

Ruptured thrombosed vertebral artery dissecting aneurysm treated with staged flow diverter after prediction of the rupture point by vessel wall MRI.

The safety and feasibility of using staged flow diverter (FD) for ruptured cerebral aneurysms, in which coil embolization is performed in the acute phase and FD is deployed in the subacute phase, has recently been reported. This strategy requires assuming the rupture point and performing coil embolization. Although vessel wall magnetic resonance imaging (VW-MRI) has been reported to be useful in predicting the rupture point of aneurysms, its use with staged FD has not yet been reported. We report the first case of staged FD with preoperative contrast-enhanced VW-MRI to predict the rupture point for partially thrombosed vertebral artery dissecting large aneurysm involving posterior inferior cerebellar artery (PICA) origin. This approach achieved a very good outcome, not only completely occluding the aneurysm, but also reconstructing the parent artery while maintaining the patency of the PICA.

Malignant transformation of central neurocytoma with dissemination 17 years after initial treatment: illustrative case.

BACKGROUND: Central neurocytomas usually have a favorable clinical course, and gross total resection (GTR) results in long-term survival. Recurrences of central neurocytomas are usually local, and dissemination is extremely rare. OBSERVATIONS: A 24-year-old man who presented with vomiting was found to have a mass in the right lateral ventricle. After GTR, he received whole-brain irradiation and chemotherapy and had remained disease-free on follow-up for years. The review of the initial tumor revealed central neurocytoma. Seventeen years later, he presented with deterioration of memory, and magnetic resonance imaging showed an enhanced lesion in the left hippocampus. The enhanced lesion was resected, and the histological examination revealed that the tumor was a disseminated atypical central neurocytoma with frequent mitoses. Although he was treated with chemotherapy, the disseminated tumor slowly grew and invaded the brain. Massive brain invasion occurred without enhanced lesions, and he died 27 months after the tumor recurrence. LESSONS: In this patient, a central neurocytoma disseminated after an extremely long period of time. Once neurocytomas disseminate and show aggressive behavior, patients usually follow a poor course. Patients with central neurocytomas should be followed up for a long time.

Whole-genome sequencing analysis of an atypical teratoid/rhabdoid tumor in a patient with Phelan-McDermid syndrome: a case report and systematic review.

Atypical teratoid/rhabdoid tumor (AT/RT) is a rare pediatric brain tumor with abnormalities in SMARCB1 located in 22q11.2. We report a case of AT/RT associated with Phelan-McDermid syndrome (PMS) characterized by congenital developmental disorder, mental retardation, and ring chromosome 22 with 22q13.3-qter depletion, for which we performed whole-genome sequencing (WGS). A 4-year-old girl with a developmental disability was referred to our hospital due to dysphoria. Brain magnetic resonance imaging showed a 5-cm well-demarcated mass that extended bilaterally in the frontal lobes. G-banding was performed preoperatively due to a history of developmental retardation. Ring chromosome 22 and deletion of 22q13.3-qter were observed, and she was diagnosed with PMS. She underwent gross total resection of the tumor, and the pathological diagnosis was AT/RT. WGS showed somatic SMARCB1 mutation (p.R201X) and somatic loss of the entire chromosome 22 in the tumor, but not in the blood sample. WGS confirmed previously unreported BRCA2 mutations, 6q loss, and 14q acquisition during tumor progression, but no other significant findings associated with tumor progression. The present case is discussed with reference to a systematic review of previous reports of AT/RT associated with PMS. PMS patients with ring chromosome 22 should be carefully followed up for AT/RT occurrence.

Intraoperative Cerebrospinal Fluid Leak Graded by Esposito Grade Is a Predictor for Diabetes Insipidus After Endoscopic Endonasal Pituitary Adenoma Resection.

BACKGROUND: Diabetes insipidus (DI) is a well-known complication of transsphenoidal surgery. However, the risk factors for DI remain controversial. METHODS: We conducted a retrospective study of patients who underwent endoscopic transsphenoidal surgery for pituitary adenoma at our institution during a 5-year period. The patients were divided into a DI group and a non-DI group. Logistic regression analyses were used to identify risk factors for postoperative DI. In subgroup analysis, the DI group was divided into transient DI and permanent DI groups, and perioperative factors were compared between groups. RESULTS: Of 101 patients, 58 were in the non-DI group (57.4%) and 43 were in the DI group (42.6%). Permanent DI occurred in 7 patients (6.9%). In univariate analyses, statistically significant risk factors were suprasellar extension, tumor functionality, and intraoperative cerebrospinal fluid leaks by Esposito grade. In multivariate logistic regression analysis, Esposito grade was the only statistically significant risk factor (P = 0.015). The frequency of DI increased as the Esposito grade increased (P = 0.0002 for the trend). In subgroup analysis, postoperative nadir sodium concentration was lower in the permanent DI group (128.1 ± 2.78 mmol/L) than in the transient DI group (135 ± 1.22 mmol/L; P = 0.035), and the optimal cutoff value was 124.5 mmol/L, with a sensitivity of 57.1% and a specificity of 91.7% (area under the curve = 0.76, P = 0.034). CONCLUSIONS: Intraoperative cerebrospinal fluid leak by Esposito grade is associated with postoperative DI. These data can be applied to help identify high-risk patients who need more aggressive follow-up and fluid management.

A RUNX-targeted gene switch-off approach modulates the BIRC5/PIF1-p21 pathway and reduces glioblastoma growth in mice.

Glioblastoma is the most common adult brain tumour, representing a high degree of malignancy. Transcription factors such as RUNX1 are believed to be involved in the malignancy of glioblastoma. RUNX1 functions as an oncogene or tumour suppressor gene with diverse target genes. Details of the effects of RUNX1 on the acquisition of malignancy in glioblastoma remain unclear. Here, we show that RUNX1 downregulates p21 by enhancing expressions of BIRC5 and PIF1, conferring anti-apoptotic properties on glioblastoma. A gene switch-off therapy using alkylating agent-conjugated pyrrole-imidazole polyamides, designed to fit the RUNX1 DNA groove, decreased expression levels of BIRC5 and PIF1 and induced apoptosis and cell cycle arrest via p21. The RUNX1-BIRC5/PIF1-p21 pathway appears to reflect refractory characteristics of glioblastoma and thus holds promise as a therapeutic target. RUNX gene switch-off therapy may represent a novel treatment for glioblastoma.

Papillary glioneuronal tumor growing slowly for 26 years: illustrative case.

BACKGROUND: Papillary glioneuronal tumors (PGNTs) are classified as a type of World Health Organization grade I mixed neuronal-glial tumor. Most PGNTs involve cystic formations with mural nodules and solid components in the cerebral hemispheres, and PGNTs occur mainly in young adults. The long-term prognosis of PGNTs remains unclear. OBSERVATIONS: A 38-year-old male had been diagnosed with an arachnoid cyst associated with epilepsy in a local hospital. The initial magnetic resonance imaging (MRI) study showed the tumor as a heterogeneously enhanced nodule in the left postcentral gyrus. Subsequent MRI studies showed slow growth of the tumor for 26 years. He underwent gross total resection to control his epilepsy. The histopathological findings revealed pseudopapillary structures involving hyalinized blood vessels with a single or pseudostratified layer of cuboidal glial cells with round nuclei and scant cytoplasm. At the periphery of the lesion, Rosenthal fibers and acidophilic granule bodies were observed in the gliotic brain tissue. Immunohistochemically, some interpapillary cells were positive for NeuN. On the basis of these findings, the tumor was diagnosed as a PGNT. LESSONS: This PGNT showed slow growth for 26 years. When recognizing a slowly growing tumor in the cerebral hemispheres of relatively young people that is associated with epileptic seizures, PGNT should be considered as a differential diagnosis.

Prognostic stratification for IDH-wild-type lower-grade astrocytoma by Sanger sequencing and copy-number alteration analysis with MLPA.

The characteristics of IDH-wild-type lower-grade astrocytoma remain unclear. According to cIMPACT-NOW update 3, IDH-wild-type astrocytomas with any of the following factors show poor prognosis: combination of chromosome 7 gain and 10 loss (+ 7/- 10), and/or EGFR amplification, and/or TERT promoter (TERTp) mutation. Multiplex ligation-dependent probe amplification (MLPA) can detect copy number alterations at reasonable cost. The purpose of this study was to identify a precise, cost-effective method for stratifying the prognosis of IDH-wild-type astrocytoma. Sanger sequencing, MLPA, and quantitative methylation-specific PCR were performed for 42 IDH-wild-type lower-grade astrocytomas surgically treated at Kyoto University Hospital, and overall survival was analysed for 40 patients who underwent first surgery. Of the 42 IDH-wild-type astrocytomas, 21 were classified as grade 4 using cIMPACT-NOW update 3 criteria and all had either TERTp mutation or EGFR amplification. Kaplan-Meier analysis confirmed the prognostic significance of cIMPACT-NOW criteria, and World Health Organization grade was also prognostic. Cox regression hazard model identified independent significant prognostic indicators of PTEN loss (risk ratio, 9.75; p < 0.001) and PDGFRA amplification (risk ratio, 13.9; p = 0.002). The classification recommended by cIMPACT-NOW update 3 could be completed using Sanger sequencing and MLPA. Survival analysis revealed PTEN and PDGFRA were significant prognostic factors for IDH-wild-type lower-grade astrocytoma.

Mixed germ cell tumor infiltrating the pineal gland without elevated tumor markers: illustrative case.

BACKGROUND: Tumors in the pineal region consist of various histological types, and correct diagnosis from biopsy specimens is sometimes difficult. The authors report the case of a patient with a mixed germ cell tumor infiltrating into the pineal gland despite showing no elevation of tumor markers. OBSERVATIONS: An 18-year-old man complained of headache and nausea and showed disturbance of consciousness. Magnetic resonance imaging showed hydrocephalus associated with a cystic pineal tumor. The patient underwent tumor biopsy followed by endoscopic third ventriculostomy for hydrocephalus in a local hospital. A pineocytoma was diagnosed, and the patient was referred to the authors' hospital for treatment. Concentrations of placental alkaline phosphatase, alpha-fetoprotein (AFP), and beta-human chorionic gonadotropin in cerebrospinal fluid were not elevated. However, the authors' review of the tumor specimen revealed some immature cells infiltrating the pineal gland. These cells were positive for AFP, Sal-like protein 4, and octamer-binding transcription factor 3/4; and the diagnosis was changed to mixed germ cell tumor. Chemoradiotherapy was initiated, followed by surgical removal of the residual tumor. LESSONS: Careful examination of all tumor specimens and immunohistochemical analyses are important for accurate diagnosis of pineal tumors.

Hydrocephalus Resulting from Late-Onset Aqueductal Membranous Occlusion: A Case Report and Review of the Literature.

BACKGROUND: Late-onset aqueductal membranous occlusion (LAMO) is 1 of the few causes of noncommunicating hydrocephalus. Here, we report a case of LAMO and review the associated literature. CASE DESCRIPTION: A 36-year-old man had complained of headache and loss of consciousness. Conventional magnetic resonance imaging (MRI) showed dilatation of the lateral and third ventricles but not of the fourth ventricle. Phase-contrast cine MRI confirmed cessation of cerebrospinal fluid (CSF) flow in the aqueduct of Sylvius. Sagittal and coronal turbo spin echo T2-weighted imaging with 3-dimensional driven equilibrium pulse (3D-DRIVE) revealed a membranous occlusion at the aqueduct of Sylvius and LAMO was diagnosed. The patient underwent endoscopic third ventriculostomy. Occlusion of the aqueduct of Sylvius by a thin membrane was observed and endoscopic aqueductoplasty was also conducted. The patient's symptoms were ameliorated shortly after the operation. Postoperative phase-contrast cine and 3D-DRIVE MRI showed restored CSF flow in the aqueduct of Sylvius and at the bottom of the third ventricle. CONCLUSIONS: We treated a case of LAMO, which usually presents with headache as an initial symptom. 3D-DRIVE MRI is useful for detecting membranous occlusions and for evaluating pre- and postoperative CSF flow. LAMO can be cured by endoscopic third ventriculostomy and/or endoscopic aqueductoplasty.

Human Pluripotent Stem Cell-Derived Tumor Model Uncovers the Embryonic Stem Cell Signature as a Key Driver in Atypical Teratoid/Rhabdoid Tumor.

Atypical teratoid/rhabdoid tumor (AT/RT), which harbors SMARCB1 mutation and exhibits a characteristic histology of rhabdoid cells, has a poor prognosis because of the lack of effective treatments. Here, we establish human SMARCB1-deficient pluripotent stem cells (hPSCs). SMARCB1-deficient hPSC-derived neural progenitor-like cells (NPLCs) efficiently give rise to brain tumors when transplanted into the mouse brain. Notably, activation of an embryonic stem cell (ESC)-like signature confers a rhabdoid histology in SMARCB1-deficient NPLC-derived tumors and causes a poor prognosis. Consistently, we find the activation of the ESC-like gene expression signature and an ESC-like DNA methylation landscape in clinical specimens of AT/RT. Finally, we identify candidate genes that maintain the activation of the ESC-like signature and the growth of AT/RT cells. Collectively, SMARCB1-deficient hPSCs offer the human models for AT/RT, which uncover the role of the activated ESC-like signature in the poor prognosis and unique histology of AT/RT.

Reticular Appearance on Gadolinium-enhanced T1- and Diffusion-weighted MRI, and Low Apparent Diffusion Coefficient Values in Microcystic Meningioma Cysts.

PURPOSE: Microcystic meningioma, a rare meningioma subtype, can present diagnostic difficulty. We aimed to investigate the historadiological properties of microcystic meningioma using conventional magnetic resonance imaging (MRI) and diffusion-weighted imaging (DWI) analysis. METHODS: We retrospectively analyzed conventional MRI and DWI results of six microcystic meningioma cases by examining their appearance and determining their apparent diffusion coefficient (ADC) values. The ADC values of the intratumoral components were normalized with ADC values of the cerebrospinal fluid in the lateral ventricle (ADC ratios). As cystic formations are frequently associated with microcystic meningiomas, their MRI characteristics were compared with the imaging data from 11 cystic meningiomas of non-microcystic subtypes. RESULTS: We found that cysts in microcystic meningioma tended to have a reticular appearance on DWI, as they did on gadolinium-enhanced T1-weighted imaging. Additionally, these reticular cysts had significantly lower ADC ratios than microcystic non-reticular and non-microcystic cysts. These DWI characteristics likely reflect the histological properties of microcystic meningioma. CONCLUSION: A reticular appearance on gadolinium-enhanced T1-weighted MRI and DWI, and cyst formation with relatively low ADC values can be diagnostic markers of microcystic meningiomas.

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.

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.