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BACKGROUND Patients with diffuse midline gliomas (DMG), including diffuse intrinsic pontine glioma (DIPG), have dismal outcomes. We previously described the H3.3K27M mutation as a shared neoantigen in HLA-A*02.01+ H3.3K27M+ DMGs. Within the Pacific Pediatric Neuro-Oncology Consortium, we assessed the safety and efficacy of an H3.3K27M-targeted peptide vaccine. PATIENTS AND METHODS Newly diagnosed patients aged 3–21 years with positive HLA-A*02.01+ and H3.3K27M+ status were enrolled into two strata after completion of radiation therapy: Stratum A for DIPG (n=19); Stratum B for non-pontine DMG (n=10). Vaccine was administered in combination with poly-ICLC every three weeks for eight cycles, followed by once every six weeks. Immunological responses were assessed in peripheral blood mononuclear cells using mass cytometry. RESULTS 19 patients enrolled in Stratum A (median age=11 years) and 10 in Stratum B (median age=13 years). There were no grade 4 treatment-related adverse events (TRAE). Injection site reaction was the most commonly reported TRAE. Overall survival (OS) at 12 months was 40% (95% CI, 22% to 73%) for Stratum A and 39% (95% CI, 16% to 93%) for Stratum B. The median OS was 16.1 months in patients exhibiting an expansion of H3.3K27M-reactive CD8+ T-cells compared to 9.8 months for their counterparts (p=0.05). DIPG patients with below-median baseline levels of myeloid-derived suppressor cells had prolonged OS compared to their counterparts (p< 0.1). Immediate pre-treatment dexamethasone administration inversely associated with H3.3K27M-reactive CD8+ T-cell responses. However, neither tumor size or bulk CD8+ T-cell status was significantly associated with OS. CONCLUSION Administration of the H3.3K27M-specific vaccine is well tolerated. Patients with H3.3K27M-specific CD8+ immunological responses demonstrated prolonged OS compared to non-responders.

Several bedside approaches used in combination with thoracoabdominal X-ray are widely used to avoid severe complications that have been reported during nasogastric tube management. Although confirmation by X-ray is considered the gold standard, it is not yet perfect. We present 2 cases of rare complications in which the routine verification methods could not detect all the complications related to the nasogastric tube placement. Case 1 was a 17-year-old male who presented with a brain tumor and repeatedly required nasogastric tube placement. Despite normal auscultatory and X-ray findings, the patient's condition deteriorated rapidly after resuming the enteral nutrition (EN). Computed tomography images showed the presence of hepatic portal venous gas (HPVG). Urgent upper gastrointestinal endoscopy showed esophagogastric submucosal tunneling of the tube that required an emergency open total gastrectomy. Case 2 was a 76-year-old man with long-term EN after stroke. While the last auscultatory verification was normal, he suddenly developed extensive HPVG due to gastric mucosal injury following EN, which resulted in progressive intestinal necrosis, general peritonitis, and death. These 2 cases indicated that routine verification methods consisting of auscultation and X-ray may not be completely reliable, and the awareness of the limitations of these methods should be reaffirmed because expeditious examinations and necessary interventions are critical in preventing life-threatening complications.

In acoustic neuroma surgery, the facial nerve (FN) course varies among patients, but a dorsal pattern is rarely observed. We retrospectively reviewed and classified 556 acoustic neuromas operated on via a lateral suboccipital retrosigmoid (LSO) approach into two groups: dorsal (group D) and non-dorsal (group ND). The clinical features and outcomes including functional preservation of the FN, the extent of tumor resection, and the retreatment rate were compared. Among 556 cases, 21 (3.8 %) patients with dorsal patterns were identified. No significant differences in clinical features or preoperative status were noted between groups D and ND. No significant differences in functional FN preservation were found between groups D and ND in the immediate postoperative period (90.5 and 83.0 %, respectively) or 1-year postoperatively (95.2 and 97.0 %, respectively). Compared with group ND, the extent of tumor resection was significantly less (p

BackgroundThere is increasing evidence for the benefit of poly ADP ribose polymerase (PARP) inhibitors in a subset of high-grade serous ovarian carcinoma (HGSC) patients, especially those with homologous recombination (HR)-deficient tumors. However, new treatment strategies, such as immune checkpoint inhibition, are required for patients with HR-proficient tumors.MethodsA total of 80 cases of HGSC were analyzed in this study. Whole exome and RNA sequencing was performed for these tumors. Methylation arrays were also carried out to examineBRCA1andRAD51Cpromoter methylation status. Mutations, neoantigen load, antigen presentation machinery, and local immune profile were investigated, and the relationships of these factors with clinical outcome were also analyzed.ResultsAs expected, the numbers of predicted neoAgs were lower in HR-proficient (n=46) than HR-deficient tumors (n=34). However, 40% of the patients with HR-proficient tumors still had higher than median numbers of neoAgs and better survival than patients with lower numbers of neoAgs. Incorporation of human leukocyte antigen (HLA)-class I expression status into the survival analysis revealed that patients with both high neoAg numbers and high HLA-class I expression (neoAghiHLAhi) had the best progression-free survival (PFS) in HR-proficient HGSC (p=0.0087). Gene set enrichment analysis demonstrated that the genes for effector memory CD8 T cells, TH1 T cells, the interferon-γ response, and other immune-related genes, were enriched in these patients. Interestingly, this subset of patients also had better PFS (p=0.0015) and a more T-cell-inflamed tumor phenotype than patients with the same phenotype (neoAghiHLAhi) in HR-deficient HGSC.ConclusionsOur results suggest that immune checkpoint inhibitors might be an alternative to explore in HR-proficient cases which currently do not benefit from PARP inhibition.

Immunotherapy applications to glioblastoma represent a new treatment frontier. Antigen-targeted immunotherapy approaches hold enormous potential to elicit antigen-specific anti-tumor effects in central nervous system tumors. Still, the paucity of effective antigen targets remains a significant obstacle in safely and effectively treating glioblastoma and other malignant gliomas with relatively low mutation loads. In this review, we highlight the current understanding of and development of immunotherapy to target 1) shared non-mutant antigens 2) shared mutant antigens (neoantigens) derived from cancer-specific mutations 3) personalized neoantigens derived from tumor-specific genetic alterations containing de novo peptide sequences and 4) virus-derived antigens. We also discuss strategies to enhance tumor immunogenicity and neoantigen prediction. Spatial heterogeneity remains a formidable challenge for immunotherapy of glioma; recent advances in targeting multiple antigens and refining the antigen selection pipeline hold great promise to turn the tide against glioma.

Immune-based therapies have shown limited efficacy in glioma thus far. This might be at least in part due to insufficient numbers of neoantigens, thought to be targets of immune attack. In addition, we hypothesized that dynamic genetic and epigenetic tumor evolution in gliomas might also affect the mutation/neoantigen landscape and contribute to treatment resistance through immune evasion. Here, we investigated changes in the neoantigen landscape and immunologic features during glioma progression using exome and RNA-seq of paired primary and recurrent tumor samples obtained from 25 WHO grade II–IV glioma patients (glioblastoma, IDH-wild-type, n = 8; grade II–III astrocytoma, IDH-mutant, n = 9; and grade II–III oligodendroglioma, IDH-mutant, 1p/19q-codeleted, n = 8). The number of missense mutations, predicted neoantigens, or expressed neoantigens was not significantly different between primary and recurrent tumors. However, we found that in individual patients the ratio of expressed neoantigens to predicted neoantigens, designated the “neoantigen expression ratio,” decreased significantly at recurrence (P = 0.003). This phenomenon was particularly pronounced for “high-affinity,” “clonal,” and “passenger gene–derived” neoantigens. Gene expression and IHC analyses suggested that the decreased neoantigen expression ratio was associated with intact antigen presentation machinery, increased tumor-infiltrating immune cells, and ongoing immune responses. Our findings imply that decreased expression of highly immunogenic neoantigens, possibly due to persistent immune selection pressure, might be one of the immune evasion mechanisms along with tumor clonal evolution in some gliomas.

BACKGROUND: Limited success of immune-based therapies in glioma might be in part due to the lack of enough neoantigens (neoAgs) that can be targeted by immune effector cells. In addition, gliomas also show dynamic clonal evolution over time, possibly leading to immunoediting during progression. Here we conducted multiomics analysis on glioma primary and recurrent pair samples to evaluate temporal changes of glioma-immune system interactions and clarify the immune evasion mechanism characteristic of gliomas. MATERIALS AND METHODS: In total, 25 WHO grade II-IV glioma cases with primary and recurrent pair samples were enrolled [8 IDH-wildtype glioblastoma (GBM), 9 IDH-mutant astrocytoma (LGG-A), and 8 oligodendroglioma (LGG-O)]. All cases received only standard therapies, but not immunotheapies. Somatic missense mutations were identified by whole-exome sequencing. Predicted neoAgs (p-neoAgs) derived from missense mutations were identified based on the MHC class I binding prediction algorism NetMHCpan2.8. In addition, “expressed” neoAgs at mRNA levels (e-neoAgs) were specified according to RNA-seq data; the neoAg expression ratio of each sample was calculated by dividing e-neoAg count by p-neoAg. Differential gene expression analyses were performed using Gene Ontology (GO) analysis or pair-designed gene set enrichment analysis (GSEA) for the tumor-infiltrating leukocytes (TILs) and antigen presentation machinery (APM). Finally, immunohistochemistry (IHC) for CD8 and MHC class I on tumor samples was assessed for validation. RESULTS: Mutational load, p- and e-neoAg count did not significantly differ between primary and recurrent tumors. However, the neoAg expression ratio significantly decreased in recurrent tumors (p = 0.003) and was particularly strong in neoAgs with a higher affinity for MHC class I. Similar trends were demonstrated for GBM, LGG-A, and LGG-O, when analyzed separately. GO analysis revealed that a number of GO terms related to active immune response such as including “CXCR chemokine receptor binding” and “leukocyte migration” were significantly upregulated at recurrence in the cases with strongly reduced neoAg expression ratio (top 8 cases). In the same cases, GSEA for TILs demonstrated a few subpopulations including activated CD8+ T cells significantly increased at recurrence. On the other hand, several TIL subpopulations as well as many APM-related gene sets significantly depleted in those with less significantly reduced neoAg expression ratio (bottom 8). These findings were consistent with those of IHC for CD8 and MHC class I. CONCLUSION: These data may suggest that the tumor cells with reduced neoAg expression survived at recurrence as a result of persistent anti-tumor immune responses in some cases under the standard treatment. Reduced neoAg expression and impaired APM during progression may play complementary roles in the immune evasion of gliomas.

The systems that can objectively predict the future trends of a particular research field are always anticipated while conducting medical research. Such systems also provide a considerable aid to researchers while determining and acquiring appropriate research budgets. This study intended to establish a novel and versatile algorithm that can predict the latest trends in neuro-oncology. Seventy-nine neuro-oncological research fields were selected using computational sorting methods, such as text-mining analyses, along with 30 journals that represent the recent trends in the neuro-oncology field. Further, the annual impact (AI) for each year with respect to each journal and field (number of articles published in the journal × the impact factor of the journal) was calculated as a novel concept. Subsequently, the AI index (AII) for the year was defined as the sum of the AIs for the aforementioned 30 journals. With respect to the aforementioned neuro-oncological research fields, the AII trends from 2008 to 2017 were subjected to machine learning predicting analyses. The prediction accuracy of the latest trends in neuro-oncology was validated using actual data obtained from previous studies. In particular, the linear prediction model achieved a relatively good accuracy. The most notable and latest predicted fields in neuro-oncology included some interesting emerging fields, such as microenvironment and anti-mitosis, as well as the already renowned fields, such as immunology and epigenetics. Furthermore, we retrospectively attempted an analysis of the fields different from neuro-oncology. Interestingly, as of 2008, the future emergence of the CRISPR-Cas9 gene editing system has been predicted using this system. Overall, the presented algorithm displays potential to be an effective and versatile tool for the prediction of future trends in a particular medical field.

Diffuse midline glioma (DMG), including diffuse intrinsic pontine glioma (DIPG) constitutes up to 20% of pediatric brain cancer and has a median survival of less than one year. We have identified a novel HLA-A*02:01-restricted neoantigen epitope encompassing the H3.3K27M mutation and implemented a pilot clinical trial through the Pacific Pediatric Neuro-Oncology Consortium (PNOC007). Newly diagnosed DIPG patients who are HLA-A2+ and H3.3K27M+ underwent radiation therapy, and then received the H3.3K27M peptide vaccine and tetanus toxoid (TT) peptide emulsified in Montanide in combination with poly-ICLC every 3 weeks for a total of 24 weeks. Our objective is to characterize vaccine-induced H3.3K27M-specific T-cell subpopulations in peripheral blood mononuclear cells through the evaluation of surface markers correlated with activation, memory, and exhaustion phenotypes utilizing a novel H3.3K27M-specific dextramer-based mass cytometry method. Through this approach, the temporal expansion of vaccine-reactive CD8+ T-cells was observed in all of patients (n = 4) who completed a minimum of 18 weeks on the study. These T-cells were subsequently stratified into discrete clusters on a tSNE plot using canonical CD8+ T-cell markers. Resultant clusters were further classified by their expression profiles, revealing distinct effector memory and exhausted subpopulations. Chronological monitoring of these groups indicates the time course-dependent development and persistence of vaccine-reactive exhausted and effector memory CD8+ T-cells in 75% of patients analyzed. Furthermore, a comparative analysis of myeloid subpopulations revealed an inverse correlation between the expansion of monocytic myeloid-derived suppressor cells (M-MDSCs) and length of enrollment in the trial. Future plans include the analysis of regulatory T-cells (Tregs) and MDSCs of all enrolled patients to solidify the relationship between the length of stay on the study and prevalence of immunosuppressive populations. This methodology offers insight into the progression of vaccine-induced patient immune responses and exhibits promise as a platform that may be extrapolated to other immunotherapies.

Study design Prospective controlled trial. Objective To describe a newly found increased flow signal in phase-contrast magnetic resonance imaging observed in compressed segments of the spinal cord in patients with cervical spondylotic myelopathy (CSM). Summary of background data Derangement of cerebrospinal fluid movement in the spine is a well-known cause of syringomyelia. However, its possible role in CSM has not been studied well, despite the fact that similar derangement takes place in CSM. Methods In a consecutive series of 57 patients with CSM, cardiac-gated phase-contrast magnetic resonance imaging was analyzed. The amplitude of the flow signal obtained in the compressed segment of the spinal cord was compared with that obtained in the lesion-free C2 segment. It was also compared with controls obtained from 10 healthy volunteers. We also studied whether the amplitude was correlated with the severity of cervical canal stenosis, neurological symptoms, indication of surgery, and the presence of intramedullary high-intensity signal on T2-weighted images. In 33 patients who underwent decompression surgical procedures, we compared the amplitude of the flow signal between the preoperative and the postoperative study. Results Increased flow signal on phase-contrast study was seen in compressed segments of the spinal cord in 36 (63%) patients. The mean amplitude of the signal in the compressed segment was 0.64 ± 0.06 cm/s, whereas that in the C2 segment was 0.27 ± 0.01 and that in the controls was 0.28 ± 0.01. The flow signal linearly increased as the severity of canal stenosis increased. It significantly correlated with the symptom of upper-extremity dysesthesia, and the indication of surgery in these patients. The mean amplitude of the signal tended to be higher in those with intramedullary high-intensity signal than in those without. After decompression surgery, the increased flow signal was markedly diminished, and returned to a level comparable with the controls. Conclusion Phase-contrast imaging demonstrated increased flow signal in compressed segments of the spinal cord in a majority of patients with CSM. This suggests a possible role played by derangement of cerebrospinal fluid movement in CSM. It also suggests potential usefulness of phase-contrast study in the management of patients with CSM. Level of evidence 2.

Among diffuse gliomas, oligodendrogliomas show relatively better prognosis, respond well to radiotherapy and chemotherapy, and seldom progress to very aggressive tumors. To elucidate the genetic and epigenetic background for such behavior and tumor evolution during tumor relapse, we comparatively analyzed 12 pairs of primary and recurrent oligodendrogliomas with 1p/19q-codeletion. Initial treatment for these patients was mostly chemotherapy alone. Temozolomide was used for 3, and procarbazine, nimustine and vincristine (PAV chemotherapy) were used for 7 patients. World Health Organization histological grade at recurrence was mostly stable; it was increased in 2, the same in 9, and decreased in 1 cases. Whole-exome sequencing demonstrated that the rate of shared mutation between the primary and recurrent tumors was relatively low, ranging from 3.2-57.9% (average, 33.3%), indicating a branched evolutionary pattern. The trunk alterations that existed throughout the course were restricted to IDH1 mutation, 1p/19q-codeletion, and TERT promoter mutation, and mutation of the known candidate tumor suppressor genes CIC and FUBP1 were not consistently observed between primary and recurrent tumors. Multiple sampling from different regions within a tumor showed marked intratumoral heterogeneity. Notably, in general, the number of mutations was not significantly different after recurrence, remaining under 100, and no hypermutator phenotype was observed. FUBP1 mutation, loss of chr. 9p21, and TCF12 mutation were among a few recurrent de novo alterations that were found at recurrence, indicating that these events were clonally selected at recurrence but were not enough to enhance malignancy. Genome-wide methylation status, measured by Illumina 450 K arrays, was stable between recurrence and the primary tumor. In summary, although oligodendroglioma displays marked mutational heterogeneity, histological malignant transformation accompanying events such as considerable increase in mutation number and epigenetic profile change were not observed at recurrence, indicating that noticeable temporal and spatial genetic heterogeneity in oligodendrogliomas does not result in rapid tumor progression. Electronic supplementary material The online version of this article (doi:10.1186/s40478-017-0422-z) contains supplementary material, which is available to authorized users.

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OBJECTIVE: Creating a machine learning model using diffusion tensor and kurtosis images are effective for malignancy diagnosing of glioma. However, it is unknown whether an IDH mutation, which is the most important mutation in glioma, can be predicted using diffusion tensor and kurtosis images. The purpose of our research was to predict the IDH mutation by using diffusion tensor and kurtosis images based on a machine learning. METHODS: Between August 2014 and July 2017, 38 consecutive patients with suspected glioma and preoperative MRI including diffusion coefficient (ADC), fractional anisotropy (FA), mean kurtosis (MK), were included in the study. All IDH mutations were identified by Sanger sequencing. A volume of interest (VOI) was created manually and applied to T2-weighted images, diffusion-weighted images (DWI), ADC, FA, MK. 476 per imaging sequence and 2856 features were extracted. RESULTS: 39 datasets were obtained. The number of cases for the IDH mutation and wild-type was 21 cases of the IDH1 mutation (3 diffuse astrocytoma, 8 anaplastic astrocytoma, 4 oligodendroglioma, 3 anaplastic oligodendroglioma, 3 glioblastoma, 18 cases of wild-type(2 anaplastic astrocytoma, 16 glioblastoma). An IDH2 mutation was not observed in our cases. Features were selected by using recursive feature elimination (RFE). The most accurate machine learning model was created using the extracted eight features from ADC, Fa, and MK. The best AUC was 0.95 ± 0.02 in a support vector machine (SVM). Discussion: Imaging sequences useful for the IDH1 mutation identification are ADC, MK, FA, similar to malignancy diagnosing of glioma. However, useful features were different. The machine learning models using diffusion images may be useful for identifying the IDH1 mutations.

Anorexia and emaciation result from various conditions, including digestive diseases, metabolic disorders, chronic inflammation, chronic infections, malignancies, and psychiatric problems. Intracranial tumors can also cause a reduction in food intake, thus mimicking anorexia nervosa, through various mechanisms. Fourth ventricular tumors, particularly hemangioblastomas, can cause prolonged appetite loss and extreme body weight loss, without any apparent focal neurologic deficits.

Aneurysms of the basilar trunk perforating artery are rarely described in the literature. Only 13 cases have been reported previously. The recommended treatment for these aneurysms is usually direct surgery such as microsurgical clipping or proximal trapping;endovascular therapy is not preferred because of difficulty to access the aneurysm. Recently however, a case report of treatment of basilar trunk perforating aneurysm with a Pipeline Embolization Device was published. Microsurgical clipping or wrapping has the disadvantage of the deep and narrow operative area and the difficult skull-base technique. Here, we report a case of basilar trunk perforating rupture aneurysm and its treatment with endovascular coil embolization.

Background: It is difficult to intraoperatively confirm the total disappearance of arteriovenous (AV) shunts during surgery for microarteriovenous malformations (micro-AVMs), especially when the nidus is extremely small or diffuse on preoperative angiography. Although intraoperative angiography is effective for evaluating residual shunts, procedure-related risks raise important concerns. The purpose of this study was to assess the usefulness of intraoperative indocyanine green-based videoangiography (ICG–VA) to determine complete disappearance of micro-AVMs during surgery. Methods: We retrospectively analyzed eight patients with ruptured micro-AVMs who were treated using craniotomy with ICG–VA at our institution. Results: Two patients underwent emergency partial evacuation of hematoma and external decompression before the diagnostic angiography. While three patients had a nidus smaller than 1 cm, five patients had only early draining veins without an appreciable nidus. The draining veins were superficial in six cases and deep in two cases. The average interval from onset to surgery was 33 days (range, 2–57). ICG–VA was repetitively conducted until disappearance of the AV shunt was confirmed. No residual AV shunt was observed on postoperative radiological examinations. In all cases, the diagnosis of AVM was confirmed from the results of postoperative pathological examination. Conclusions: ICG–VA could detect early draining veins more clearly in situ than diagnostic angiography. Although it is not as effective for visualizing lesions with deep draining veins, repetitive ICG–VA was safe and effective for confirming the disappearance of AV shunts with superficial drainage.