Neuroradiological, genetic and clinical characteristics of histone H3 K27-mutant diffuse midline gliomas in the Kansai Molecular Diagnosis Network for CNS Tumors (Kansai Network): multicenter retrospective cohort.

This study aims to elucidate the clinical and molecular characteristics, treatment outcomes and prognostic factors of patients with histone H3 K27-mutant diffuse midline glioma. We retrospectively analyzed 93 patients with diffuse midline glioma (47 thalamus, 24 brainstem, 12 spinal cord and 10 other midline locations) treated at 24 affiliated hospitals in the Kansai Molecular Diagnosis Network for CNS Tumors. Considering the term "midline" areas, which had been confused in previous reports, we classified four midline locations based on previous reports and anatomical findings. Clinical and molecular characteristics of the study cohort included: age 4-78 years, female sex (41%), lower-grade histology (56%), preoperative Karnofsky performance status (KPS) scores ≥ 80 (49%), resection (36%), adjuvant radiation plus chemotherapy (83%), temozolomide therapy (76%), bevacizumab therapy (42%), HIST1H3B p.K27M mutation (2%), TERT promoter mutation (3%), MGMT promoter methylation (9%), BRAF p.V600E mutation (1%), FGFR1 mutation (14%) and EGFR mutation (3%). Median progression-free and overall survival time was 9.9 ± 1.0 (7.9-11.9, 95% CI) and 16.6 ± 1.4 (13.9-19.3, 95% CI) months, respectively. Female sex, preoperative KPS score ≥ 80, adjuvant radiation + temozolomide and radiation ≥ 50 Gy were associated with favorable prognosis. Female sex and preoperative KPS score ≥ 80 were identified as independent good prognostic factors. This study demonstrated the current state of clinical practice for patients with diffuse midline glioma and molecular analyses of diffuse midline glioma in real-world settings. Further investigation in a larger population would contribute to better understanding of the pathology of diffuse midline glioma.

Cerebral vasospasm occurring immediately after endoscopic transsphenoidal resection of a pituitary adenoma: A case report.

Background: Cerebral vasospasm is a rare postoperative complication of transsphenoidal pituitary adenoma surgery with potentially severe consequences. These vasospasms generally have a delayed presentation at a mean of 8 postoperative days. We report an unusual case of hyperacute onset of cerebral vasospasm that occurred immediately after surgery. Case Description: A 38-year-old man underwent endoscopic transsphenoidal surgery for a nonfunctioning pituitary adenoma. The patient experienced mild subarachnoid hematoma during surgery. Three hours after surgery, he developed rightward conjugate eye deviation and complete paralysis of the left upper and lower extremities. Diagnostic imaging revealed cerebral vasospasm in both middle cerebral arteries, and symptoms improved after intra-arterial administration of fasudil hydrochloride. Conclusion: There is a need for prompt diagnosis and therapeutic intervention when typical symptoms of cerebral vasospasm, such as paralysis, occur at any time during the postoperative course.

Prediction of MGMT promotor methylation status in glioblastoma by contrast-enhanced T1-weighted intensity image.

Background: The study aims to explore MRI phenotypes that predict glioblastoma's (GBM) methylation status of the promoter region of MGMT gene (pMGMT) by qualitatively assessing contrast-enhanced T1-weighted intensity images. Methods: A total of 193 histologically and molecularly confirmed GBMs at the Kansai Network for Molecular Diagnosis of Central Nervous Tumors (KANSAI) were used as an exploratory cohort. From the Cancer Imaging Archive/Cancer Genome Atlas (TCGA) 93 patients were used as validation cohorts. "Thickened structure" was defined as the solid tumor component presenting circumferential extension or occupying >50% of the tumor volume. "Methylated contrast phenotype" was defined as indistinct enhancing circumferential border, heterogenous enhancement, or nodular enhancement. Inter-rater agreement was assessed, followed by an investigation of the relationship between radiological findings and pMGMT methylation status. Results: Fleiss's Kappa coefficient for "Thickened structure" was 0.68 for the exploratory and 0.55 for the validation cohort, and for "Methylated contrast phenotype," 0.30 and 0.39, respectively. The imaging feature, the presence of "Thickened structure" and absence of "Methylated contrast phenotype," was significantly predictive of pMGMT unmethylation both for the exploratory (p = .015, odds ratio = 2.44) and for the validation cohort (p = .006, odds ratio = 7.83). The sensitivities and specificities of the imaging feature, the presence of "Thickened structure," and the absence of "Methylated contrast phenotype" for predicting pMGMT unmethylation were 0.29 and 0.86 for the exploratory and 0.25 and 0.96 for the validation cohort. Conclusions: The present study showed that qualitative assessment of contrast-enhanced T1-weighted intensity images helps predict GBM's pMGMT methylation status.

Giant cell glioblastoma with lipogenic differentiation in a patient with neurofibromatosis type 1: A case report.

A 45-year-old woman with neurofibromatosis type 1 (NF1) developed a tumor in the left frontal lobe that showed features of giant cell glioblastoma (GC-GB). In addition to the typical GC-GB features, the tumor showed lipogenic differentiation, with many atypical lipoblasts and mature adipocytes. Tumor cells, including the lipogenic cells, were immunoreactive for GFAP, S-100 protein, ATRX, and p53. They were negative for IDH1-R132H, BRAF V600E, synaptophysin, NeuN, p16, mismatch repair proteins, and CD34. The patient is free from recurrence at approximately two years postoperatively. This is the fifth reported case of NF1-associated GC-GB (the second adult case). NF1 gene mutation might have played a role in the pathogenesis of lipogenic differentiation of GC-GB. The differential diagnosis of lipidized GC-GB from gliosarcoma or anaplastic pleomorphic xanthoastrocytoma is briefly discussed.

5-Aminolevulinic acid fluorescence-guided endoscopic surgery for deep-seated intraparenchymal tumors.

AIM: The usefulness of 5-aminolevulinic acid (5-ALA) fluorescence-assisted surgery for maximum resection of malignant gliomas has been established. However, its usefulness when combined with endoscopic surgery for deep-seated tumors has not been well established. In this study, whether 5-ALA photodynamic diagnosis (PDD) is feasible and useful for endoscopic surgery was investigated. METHODS: A specially designed endoscope for PDD that delivers white light or blue light (375-440 nm) as excitation light was used. The fluorescence emitted by the tumor was evaluated in the cavity during resection or at the tip of the sheath during biopsy. The intensity of fluorescence was classified into three categories: strong, vague, and negative. RESULTS: A total of 30 intraparenchymal tumors were observed with a neuroendoscope and 5-ALA PDD; 16 patients underwent resection, and 14 underwent biopsy. Overall, 67% (20/30) of tumors showed positive fluorescence of protoporphyrin IX. High-grade gliomas (HGGs) including glioblastoma (GBM) and anaplastic astrocytoma (AA) showed strong fluorescence in 47% (7/15), vague fluorescence in 33% (5/15), and negative fluorescence in 20% (3/15) of cases. Low-grade gliomas (LGGs) showed vague fluorescence in 33% (1/3) and negative fluorescence in 67% (2/3). Diffuse large B-cell lymphoma (DLBCL) showed vague fluorescence in 38% (3/8) and negative fluorescence in 63% (5/8). Metastatic tumors showed strong fluorescence in 25% (1/4) and vague fluorescence in 75% (3/4). In the comparison of fluorescence evaluation, a significant difference was observed only in the comparison between HGGs and DLBCL (p = 0.049). CONCLUSION: These results suggest that 5-ALA PDD-assisted endoscopic surgery is feasible and useful for deep-seated intraparenchymal tumors.

Distinct patterns of copy number alterations may predict poor outcome in central nervous system germ cell tumors.

We have previously reported that 12p gain may predict the presence of malignant components and poor prognosis for CNS germ cell tumor (GCT). Recently, 3p25.3 gain was identified as an independent predictor of poor prognosis for testicular GCT. Eighty-one CNS GCTs were analyzed. Copy number was calculated using methylation arrays. Five cases (6.2%) showed 3p25.3 gain, but only among the 40 non-germinomatous GCTs (NGGCTs) (5/40, 12.5%; p = 0.03). Among NGGCTs, those with a yolk sac tumor component showed a significantly higher frequency of 3p25.3 gain (18.2%) than those without (1.5%; p = 0.048). NGGCTs with gain showed significantly shorter progression-free survival (PFS) than those without (p = 0.047). The 3p25.3 gain and 12p gain were independent from each other. The combination of 3p25.3 gain and/or 12p gain was more frequent among NGGCTs with malignant components (69%) than among those without (29%; p = 0.02). Germinomas containing a higher number of copy number alterations showed shorter PFS than those with fewer (p = 0.03). Taken together, a finding of 3p25.3 gain may be a copy number alteration specific to NGGCTs and in combination with 12p gain could serve as a marker of negative prognosis or treatment resistance. Germinoma with frequent chromosomal instability may constitute an unfavorable subgroup.

Refractory Delayed Pneumocephalus after Transsphenoidal Cyst Drainage for Rathke's Cleft Cyst in a Patient with a Cerebrospinal Fluid Shunt.

A 75-year-old man presented with bilateral lower limb weakness to our hospital from another clinic. Radiological examinations implied the possibilities of idiopathic normal pressure hydrocephalus (iNPH) and a suprasellar cyst, but both were observed conservatively at that time. Due to the progressive gait disturbance, a lumboperitoneal shunt was implanted 1 year later. The clinical symptoms improved, but the cyst had grown after another year, causing visual impairment. Transsphenoidal drainage of the cyst was performed, but delayed pneumocephalus occurred. Repair surgery was performed with temporary suspension of shunt function, but pneumocephalus relapsed two and a half months after the resumption of shunt flow. In the second repair surgery, the shunt was removed because it was assumed that it would prevent closure of the fistula by lowering intracranial pressure. Two and a half months later, after confirming involution of the cyst and no pneumocephalus, a ventriculoperitoneal shunt was implanted, and cerebrospinal fluid (CSF) leakage has not relapsed since then. The coexistence of idiopathic normal pressure hydrocephalus (iNPH) and Rathke's cleft cyst (RCC) is rare, but it can occur. RCC can be cured by simple drainage, but delayed pneumocephalus can occur in cases whose intracranial pressure decreases due to CSF shunting. When simple drainage without sellar reconstruction for RCC is attempted after CSF shunting for coexistent iNPH, attention should be paid to changes in intracranial pressure, and it is desirable to stop the flow of the shunt for a certain period.

Comparison of intraoperative neurophysiological monitoring methods for lumbosacral lipoma surgery in infants.

BACKGROUND: Stable intraoperative neurophysiology monitoring of infants, especially very young infants, is challenging. In this study, motor evoked potentials (MEPs), the bulbocavernosus reflex (BCR), and somatosensory evoked potentials (SEPs) were simultaneously monitored in infants with lumbosacral lipomas, and these methods were compared retrospectively. METHODS: A total of 21 surgeries performed for lumbosacral lipoma in patients less than 1 year old were studied. The mean age at surgery was 133.8 days (range 21-287 days; ≤ 120 days: 9 cases, > 120 days: 12 cases). Transcranial MEPs were measured in the anal sphincter and gastrocnemius, and tibialis anterior and other muscles were added as needed. The BCR was measured by the electromyogram of the anal sphincter muscle with stimulation of the pubic region, and SEPs were measured from the waveforms of stimulation of the posterior tibial nerves. RESULTS: For the BCR, stable potentials could be recorded for all 9 cases at ≤ 120 days of age. In contrast, for MEPs, stable potentials could be recorded in only 4 of 9 cases (p < 0.05). For all patients > 120 days of age, MEPs and the BCR were measurable. SEPs were undetectable in some patients regardless of age. CONCLUSION: The BCR could be more consistently measured than MEPs in infant patients with lumbosacral lipoma at ≤ 120 days of age.

A case of acute hydrocephalus due to a giant prolactinoma rescued by transventricular neuroendoscopic tumorectomy.

Background: A giant prolactinoma extending to the suprasellar area and causing hydrocephalus may be life-threatening and should be treated promptly. A case of a giant prolactinoma with acute hydrocephalus that underwent transventricular neuroendoscopic tumor resection followed by cabergoline administration is presented. Case Description: A 21-year-old man had a headache lasting for about a month. He gradually developed nausea and disturbance of consciousness. Magnetic resonance imaging showed a contrast-enhanced lesion that extended from the intrasellar space to the suprasellar space and into the third ventricle. The tumor obstructed the foramen of Monro and caused hydrocephalus. A blood test showed marked elevation of prolactin (16,790 ng/mL). The tumor was diagnosed as a prolactinoma. The tumor in the third ventricle had formed a cyst, and the cyst wall blocked the right foramen of Monro. The cystic component of the tumor was resected using an Olympus VEF-V flexible neuroendoscope. The histological diagnosis was pituitary adenoma. The hydrocephalus improved rapidly and his consciousness became clear. After the operation, he was started on cabergoline. The tumor size subsequently decreased. Conclusion: Prompt partial resection of the giant prolactinoma by transventricular neuroendoscopy resulted in early improvement of hydrocephalus with less invasiveness, allowing subsequent treatment with cabergoline.

Coexisting filum terminale arteriovenous fistula and filum terminale lipoma treated with single-stage surgery: illustrative case.

BACKGROUND: Both filum terminale arteriovenous fistulas (FTAVFs) and filum terminale lipomas (FTLs) are rare. Because of this rarity, there is a paucity of data regarding concomitant FTAVF and FTL, and the optimal treatment remains to be defined. The authors describe a patient with coexisting FTAVF and FTL treated with single-stage surgery. OBSERVATIONS: A man in his 70s was referred to the authors' department because of a suspected spinal vascular malformation seen on magnetic resonance imaging that was performed to investigate lower limb weakness, intermittent claudication, and urinary incontinence. Previous imaging had shown a terminal lipoma with an internal flow void. Computed tomography angiography and digital subtraction angiography revealed an FTAVF, the feeder being a lateral sacral artery. The patient was treated surgically with curative intent. The FTL and tethered cord that had been identified by imaging were treated in the same procedure. Postoperative digital subtraction angiography showed absence of the abnormal vessels. The patient was discharged home on the 19th postoperative day. LESSONS: When considering treatment, it is important to determine whether symptoms are attributable mainly to FTL, tethered cord, or FTAVF. One-stage treatment is useful because it eliminates both the FTAVF and the factors that led to its development.

5-ALA fluorescence-guided resection of pediatric low-grade glioma using the ORBEYE 3D digital exoscope: a technical report.

OBJECTIVE: A case of low-grade glioma in which 5-aminolevulinic acid (5-ALA) fluorescence was visualized by a digital exoscope is presented. CASE PRESENTATION: A 14-year-old girl with recurrent paroxysmal episodes of a strange smell and nausea underwent magnetic resonance imaging (MRI) for further investigation. The MRI showed a tumor with an enhanced nodule in the right temporal lobe. The patient received 5-ALA preoperatively, and intraoperative observation using a 4 K-3-dimension digital exoscope (Olympus ORBEYE) showed that the tumor was fluorescent, which was useful in determining the extent of tumor removal. Postoperative MRI showed that the tumor was completely removed. The histopathological diagnosis was pleomorphic xanthoastrocytoma. She was discharged without any complications. CONCLUSIONS: 5-ALA-fluorescence-guided resection of low-grade glioma using the ORBEYE was useful for determining the extent of removal.

Current status and challenges of neurosurgical procedures for patients with myelomeningocele in real-world Japan.

BACKGROUND: Little is known about the real-world status of neurosurgical treatment of myelomeningocele patients. OBJECTIVE: To investigate the real-world status of neurosurgical treatment of myelomeningocele patients, medical claims data provided by the Japan Medical Data Center (JMDC) were analyzed. METHODS: The health claims data of 556 patients with myelomeningoceles from January 2005 to March 2020 were examined. The number of neurosurgical procedures, including myelomeningocele repair, tethered cord release, cerebrospinal fluid (CSF) shunt, CSF drainage, and endoscopic third ventriculostomy (ETV), was determined. RESULTS: A total of 313 neurosurgical procedures were performed for 135 patients in 74 institutions during the study period. The shunt survival rate was most affected by shunts that were revised when the patient was less than 1 year old, which had a significantly lower survival rate than all of the initial shunts performed when the patient was less than on1 year old; the 1-year shunt survival rate was 35 vs 64% (P = 0.0102). The survival rate was significantly lower in patients younger than 1 year who had CSF drainage before shunting compared to those younger than 1 year who did not have CSF drainage before shunting; the 1-year shunt survival rate was 27 vs 59% (P = 0.0196), and 81% of patients remained free of tethered cord release 10 years later. CONCLUSIONS: In this study, a revised shunt of less than 1 year of age and CSF drainage before shunting were the factors that lowered the shunt survival rate in the real world for CSF shunts for hydrocephalus associated with myelomeningocele.

Primary central nervous system lymphoma of the tectal plate in adult.

Background: Primary central nervous system lymphoma (PCNSL) originating in the brainstem is uncommon. In particular, PCNSL confined to the tectal plate in adults has never been reported in the past. The case of a 53-year-old man who was diagnosed with PCNSL in the tectal plate is reported. Case Description: The patient was referred to our hospital with a 1-month history of disorientation and magnetic resonance imaging showed hydrocephalus with an enhancing lesion in the tectum. Preoperative blood tests showed a high serum soluble interleukin-2 receptor level of 624 U/ml. Through a single burr hole, endoscopic third ventriculostomy and biopsy of the lesion were simultaneously performed with a flexible endoscope. The histological examination confirmed diffuse large B-cell lymphoma. The patient underwent chemotherapy and radiotherapy. Conclusion: Malignant lymphoma of the tectum may occur in adults. By measuring the soluble interleukin-2 level preoperatively, it was possible to include malignant lymphoma in the differential diagnosis. In addition, the use of a neuroendoscope permits biopsy and hydrocephalus treatment to be performed simultaneously.

5-Aminolevulinic acid fluorescence-guided endoscopic surgery for intraventricular tumors.

Background: In recent years, the efficacy of 5-aminolevulinic acid photodynamic diagnosis (5-ALA PDD) has been reported for various types of brain tumors, including malignant glioma. In addition, many reports have been published on the usefulness of neuroendoscopic surgery for intraventricular lesions. However, no systematic report is available on the combined use of 5-ALA PDD and neuroendoscopy for various intraventricular tumors. Methods: We report 17 consecutive patients with intraventricular tumors. All patients received oral 5-ALA preoperatively and underwent endoscopic surgical treatment (resection or biopsy). We use a rigid endoscope with a built-in PDD system for intraoperative observation. Results: Seven resections and 10 biopsies were performed. Histopathological diagnosis was confirmed in all 17 cases. Gross total resection was achieved in six of seven cases. The fluorescence positivity rates for each tumor were glioblastoma 100% (2/2), low-grade glioma 67% (2/3), subependymoma 0% (0/1), medulloblastoma 100% (1/1), pineoblastoma 0% (0/1), germ cell tumor 75% (3/4), diffuse large B-cell lymphoma 33% (1/3), and metastatic tumor 100% (2/2). Conclusion: Our method has the potential to improve detection of residual tumors in blind spots and deep areas, as well as the accuracy and safety of biopsy procedures for intraventricular lesions that are difficult to view and treat under a microscope.

Treatment of refractory giant suprasellar arachnoid cyst by endoscopic expansion of a fenestrated stoma.

Background: Although endoscopic ventriculo-cysto-cisternostomy is considered to be effective for suprasellar arachnoid cysts, we encountered a giant suprasellar arachnoid cyst that recurred despite surgery using this technique. Case Description: The patient was a 9-month-old boy. Magnetic resonance imaging revealed a huge suprasellar arachnoid cyst extending from the suprasellar region to the anterior skull base and both middle cranial fossa. First, an endoscopic procedure was performed to open the cyst wall between the right ventricle and the cyst and between the cyst and the prepontine cistern. Although the cyst initially shrank, it recurred over the next 2 months, and hence, we performed another endoscopic surgery. At the second surgery, both the previously opened stomas were found to be occluded. To reopen the cyst wall between the ventricle and the cyst, multiple holes were made with monopolar electrodes, and forceps were used to connect the holes by grasping and twisting the cyst wall so that the stoma was much larger than at the previous surgery. Postoperatively, the cyst shrank and the patient's head circumference stopped expanding. Conclusion: Following the treatment of large cysts, the stoma might become narrower as the cyst shrinks, resulting in obstruction. Using the technique reported here might prevent occlusion of large arachnoid cysts.

Transcriptome and methylome analysis of CNS germ cell tumor finds its cell-of-origin in embryogenesis and reveals shared similarities with testicular counterparts.

BACKGROUND: CNS germ cell tumors (GCTs) predominantly develop in pediatric and young adult patients with variable responses to surgery, radiation, and chemotherapy. This study aimed to examine the complex and largely unknown pathogenesis of CNS GCTs. METHODS: We used a combined transcriptomic and methylomic approach in 84 cases and conducted an integrative analysis of the normal cells undergoing embryogenesis and testicular GCTs. RESULTS: Genome-wide transcriptome analysis in CNS GCTs indicated that germinoma had a transcriptomic profile representative of primitive cells during early embryogenesis with high meiosis/mitosis potentials, while nongerminomatous GCTs (NGGCTs) had differentiated phenotypes oriented toward tissue formation and organogenesis. Co-analysis with the transcriptome of human embryonic cells revealed that germinomas had expression profiles similar to those of primordial germ cells, while the expression profiles of NGGCTs were similar to those of embryonic stem cells. Some germinoma cases were characterized by extensive immune-cell infiltration and high expression of cancer-testis antigens. NGGCTs had significantly higher immune-cell infiltration, characterized by immune-suppression phenotype. CNS and testicular GCTs (TGCTs) had similar mutational profiles; TGCTs showed enhanced copy number alterations. Methylation analysis clustered germinoma/seminoma and nongerminoma/nonseminoma separately. Germinoma and seminoma were co-categorized based on the degree of the tumor microenvironment balance. CONCLUSIONS: These results suggested that the pathophysiology of GCTs was less dependent on their site of origin and more dependent on the state of differentiation as well as on the tumor microenvironment balance. This study revealed distinct biological properties of GCTs, which will hopefully lead to future treatment development.

Number of surgeries performed during the lifetime of patients with myelomeningocele.

OBJECTIVE: Patients with myelomeningocele often require multiple surgeries, but no study has clarified the kind of treatment given to these patients throughout their lives. The authors analyzed the type of surgery that was performed and at what age for Japanese patients with myelomeningoceles. METHODS: The Japanese health claims data of 556 patients with myelomeningocele for the period from January 2005 to March 2020 provided by the Japan Medical Data Center Co., Ltd., were examined to investigate the number of surgeries performed and the patient age at surgery for each specialty. The patients were divided into two groups (those ≤ 18 years old [group A] and those > 18 years old [group B]), and the way in which the types of surgery and the percentage of surgeries changed between these two groups was examined. RESULTS: The mean follow-up period was 4.4 years. The mean age at the end of the overall follow-up was 18.6 years (range 0-70.5 years), and 1033 surgeries were performed on 294 patients (0.42 surgeries performed per patient per year) during this period. The number of surgeries for patients in group A was 818 in 192 patients, with 0.62 surgeries per patient per year, and for patients in group B it was 215 in 102 patients, with 0.19 surgeries per patient per year. The number of surgeries and the mean age at the time of surgery were as follows: 313 neurosurgeries, 5.16 years; 280 orthopedic surgeries, 11.36 years; 70 urological surgeries, 14.57 years; and 202 dermatological/plastic surgeries, 16.19 years. In the surgeries related to myelomeningocele, the rates of CSF shunt placement, tethered cord release, muscle and tendon surgery, and other bone and joint surgery decreased significantly in group B, but they continued to undergo these surgeries. In group B, the rates of skin surgery, nephrostomy, ureterostomy, and cystostomy were significantly higher. CONCLUSIONS: A significant number of surgeries in multiple specialties related to myelomeningocele continue to be performed in adulthood, indicating that these patients require continuous care throughout their lives.

12p gain is predominantly observed in non-germinomatous germ cell tumors and identifies an unfavorable subgroup of central nervous system germ cell tumors.

BACKGROUND: Central nervous system (CNS) germ cell tumors (GCTs) are neoplasms predominantly arising in pediatric and young adult populations. While germinomas generally respond to chemotherapy and radiation, non-germinomatous GCTs (NGGCTs) require more intensive treatment. This study aimed to determine whether 12p gain could predict the prognosis of CNS GCTs. METHODS: Eighty-two CNS GCTs were included in this study. The 12p gain was defined by an additional 12p in the background of potential polyploidy or polysomy. Cases were analyzed using an Illumina methylation 450K array for copy number investigations and validated by fluorescence in situ hybridization (FISH). RESULTS: A 12p gain was found in 25-out-of-82 cases (30%) and was more frequent in NGGCTs (12% of germinoma cases and 50% of NGGCT cases), particularly in cases with malignant components, such as immature teratoma, yolk sac tumor, choriocarcinoma, and embryonal carcinoma. 12p gain and KIT mutation were mutually exclusive events. The presence of 12p gain correlated with shorter progression-free (PFS) and overall survival (OS) (10-year OS: 59% vs. 94%, with and without 12p gain, respectively, P = 0.0002), even with histology and tumor markers incorporated in the multivariate analysis. Among NGGCTs, 12p gain still had prognostic significance for PFS and OS (10-year OS: 47% vs. 90%, respectively, P = 0.02). The 12p copy number status was shared among histological components in mixed GCTs. CONCLUSIONS: 12p gain may predict the presence of malignant components of NGGCTs, and poor prognosis of the patients. It may be associated with early tumorigenesis of CNS GCT.

Low tumor cell content predicts favorable prognosis in germinoma patients.

BACKGROUND: Germinoma preferentially occurs in pediatric and young adult age groups. Although they are responsive to treatment with chemotherapy and radiation, the treatment may cause long-term sequelae in their later lives. Here, we searched for clinical and histopathological features to predict the prognosis of germinoma and affect treatment response. METHODS: A total of 114 germinoma cases were included in the analysis. We investigated the association between clinical factors, tumor cell content, and progression-free survival (PFS). RESULTS: The tumor cell content was widely distributed from <5% to 90% in the specimens, with a median value of 50%. Female patients showed higher tumor cell content in the specimens (P = .002). Cases with lesions at atypical sites showed shorter PFS than those with lesions at other sites (P = .03). Patients with a higher tumor cell content (≥50%) showed shorter PFS than those with a lower tumor cell content (<50%) (P = .03). In multivariate analysis, tumor cell content was the only statistically significant prognostic factor (P = .04). Among the 7 cases treated with local radiation and chemotherapy, all 3 cases that recurred (2 outside of the radiation field, 1 unknown) had tumor cell content of ≥50% in the original specimen, whereas all 4 cases without recurrence had tumor cell contents of <50%. CONCLUSIONS: We found that tumor cell content significantly affected the prognosis of germinomas. Although validation of these results using an independent and larger cohort is necessary, this potentially opens the possibility of leveraging this pathological factor in future clinical trials when stratifying the treatment intensity.

Infrequent RAS mutation is not associated with specific histological phenotype in gliomas.

BACKGROUND: Mutations in driver genes such as IDH and BRAF have been identified in gliomas. Meanwhile, dysregulations in the p53, RB1, and MAPK and/or PI3K pathways are involved in the molecular pathogenesis of glioblastoma. RAS family genes activate MAPK through activation of RAF and PI3K to promote cell proliferation. RAS mutations are a well-known driver of mutation in many types of cancers, but knowledge of their significance for glioma is insufficient. The purpose of this study was to reveal the frequency and the clinical phenotype of RAS mutant in gliomas. METHODS: This study analysed RAS mutations and their clinical significance in 242 gliomas that were stored as unfixed or cryopreserved specimens removed at Kyoto University and Osaka National Hospital between May 2006 and October 2017. The hot spots mutation of IDH1/2, H3F3A, HIST1H3B, and TERT promoter and exon 2 and exon 3 of KRAS, HRAS, and NRAS were analysed with Sanger sequencing method, and 1p/19q codeletion was analysed with multiplex ligation-dependent probe amplification. DNA methylation array was performed in some RAS mutant tumours to improve accuracy of diagnosis. RESULTS: RAS mutations were identified in four gliomas with three KRAS mutations and one NRAS mutation in one anaplastic oligodendroglioma, two anaplastic astrocytomas (IDH wild-type in each), and one ganglioglioma. RAS-mutant gliomas were identified with various types of glioma histology. CONCLUSION: RAS mutation appears infrequent, and it is not associated with any specific histological phenotype of glioma.