Nobusada Shinoura’s research while affiliated with Tokyo Metropolitan Cancer and Infectious Diseases Center and other places

Background The cognitive dysfunction associated with cerebellar tumors in adults is not well understood. We herein evaluated the effect of cerebellar tumors and surgery on cognitive function in adult patients before and after resection. Methods Eighteen patients who underwent resection of a cerebellar tumor at the study center between 2016 and 2022 were retrospectively analyzed. Their clinical characteristics, surgical complications, and neuropsychological test scores were thoroughly reviewed. Results Of the 18 patients, nine were male, and the median age at surgery was 73 years. A high tumor volume (> 10 cm³) was associated with significantly low preoperative cognitive function scores on the Frontal Assessment Battery (FAB) (P = 0.024), the copying task on the Rey-Osterrieth Complex Figure Test (P = 0.020), and the verbal sequential commands on the Standard Language Test of Aphasia (SLTA) (P = 0.030). The preoperative scores for the verbal sequential commands on the SLTA improved postoperatively in patients with a high tumor volume (P = 0.04). A negative correlation was found between tumor volume and the preoperative score on the FAB (r = -0.50) and the verbal sequential commands on the SLTA (r = -0.58). The difference between the postoperative and preoperative scores for the verbal sequential commands on SLTA positively correlated with tumor volume (r = 0.57). Conclusion The present study found that the executive function, visuospatial cognitive function, and part of the language function were able to be influenced by cerebellar tumors in adult patients.

Intratumor heterogeneity has been analyzed in brain tumors, and it has revealed that clonal evolution results in the formation of genetically diverse cell populations, which is a major factor in treatment resistance and recurrence. However, intratumoral heterogeneity has not been analyzed in routine clinical practice and remains at the research level. Here, we developed a novel tumor sampler to establish the analysis of intratumoral heterogeneity as a routine clinical procedure and to clarify its clinical significance in brain tumors. Our novel tumor sampler consists of a hollow cylinder with a lid, which enabled us to obtain a cylindrical tumor sample cross-sectionally by inserting from the tumor surface to the depth, like the geological borehole test. The obtained cylindrical sample was divided vertically into two, one for pathological analysis and one for genetic analysis, which allowed us to compare genetic findings and pathological findings in arbitrary site of the sample. The sampling procedure was simple and completed in a short time, allowing comparison of heterogeneity among a large number of cases. We collected samples from four cases of Glioblastoma and three cases of brain metastasis using the sampler, and analyzed intratumoral heterogeneity by identifying somatic mutations at multiple sites by whole exome sequencing. We evaluated genetic and morphological heterogeneity among each site, generated a phylogenetic tree of clonal evolution within the tumor, and confirmed that these data could be compared among the cases. Using our novel tumor sampler could establish the analysis of intratumoral heterogeneity as a routine clinical procedure, and it expected to have a significant impact on treatment strategies for brain tumors.

Objectives Hyper- and hyposensitivity in multiple modalities have been well-documented in subjects with autistic spectrum disorder (ASD) but not in subjects with acquired brain injury (ABI). The purpose of this study was to determine whether subjects with ABI experience altered sensory processing in multiple sensory modalities, and to examine the relationships between impaired sensory processing and the emotional state. Methods and procedures Sixty-eight patients with brain or spinal cord tumors participated in the study. Cognitive ability and emotional function were tested, and subjective changes were evaluated in two directions (hyper- and hyposensitivity) and five modalities (visual, auditory, tactile, olfactory, and gustatory) at two time points (after disease onset and after surgery). Results One-fifth of the participants complained of hypersensitivity in the visual domain, and a similar proportion complained of hyposensitivity in the auditory and tactile domains. Additionally, one-third of participants complained of two or more sensory abnormalities after disease onset. A hierarchical regression analysis indicated that auditory and tactile sensory changes predicted a depressive state. Conclusion In conclusion, multimodal sensory changes occurred in patients with brain tumors, manifesting as hyper- or hyposensitivity. Sensory changes might be related to depressive state, but the results were inconclusive.

Mismatch repair (MMR) gene deficiency is rarely observed in gliomas, a constitutional defect is associated with tumorigenesis in Lynch syndrome, and an acquired defect is associated with hypermutation after temozolomide treatment. However, the meaning of MMR gene deficiency in gliomas is unclear. Two cases of MMR-deficient glioblastomas are reported, and mutational status of oncogenes was compared between primary and recurrent tumor samples in a glioblastoma patient with Lynch syndrome. Additionally, the characteristics of MMR-deficient glioblastomas were analyzed using public glioma datasets to determine the meaning of MMR deficiency in gliomas. Case 1 was a glioblastoma patient with Lynch syndrome, and treatment with pembrolizumab for the recurrent tumor was temporarily effective for a short period. Comparison of mutational changes between primary and recurrent tumor samples showed many additional mutated genes associated with multiple signaling pathways in the recurrent tumor. Tumor recurrence and chemoresistance could be associated with intratumoral heterogeneity and accelerated tumor progression due to defects of multiple signaling pathways. Case 2 was a glioblastoma patient with acquired MMR gene deficiency, and she died of rapid progression of bone marrow metastases. This rare clinical course was considered to be associated with gene expression changes and heterogeneity that resulted from MMR gene deficiency. Two cases of MMR gene-deficient glioblastomas were presented, and their genetic characteristics suggested that their clinical courses could be associated with MMR gene deficiency.

Awake craniotomy is an established procedure for resecting brain tumors in eloquent lesions, and intraoperative seizure is one of the most important complications. Phenytoin is normally used to control intraoperative seizures. Recently, phenytoin was replaced with levetiracetam at our institution because the latter has fewer side effects. While the phenytoin dose is calibrated in accordance with the serum concentration, there is currently no consensus on a method of monitoring the serum concentration of levetiracetam or the effective concentration range needed to control intraoperative seizures during awake craniotomy. The present study therefore aimed to determine whether monitoring the serum levetiracetam concentration is useful for controlling intraoperative seizures during awake craniotomy. The intraoperative serum concentration of levetiracetam during awake craniotomy was measured in 34 patients and compared with that of phenytoin in 33 patients undergoing the same procedure. The levetiracetam concentration inversely correlated with body surface area (BSA) and estimated glomerular filtration rate (eGFR). Levetiracetam was superior to phenytoin in terms of the correlation between the serum concentration and the dose adjusted for BSA and eGFR (correlation coefficient, 0.49 vs 0.21). Furthermore, the serum levetiracetam concentration in patients with intraoperative seizures was below the 95% confidence interval (CI) of the regression line whereas the serum phenytoin concentration of two patients with seizures was within the 95% CI, indicating that evaluating the serum levetiracetam concentration against the BSA and eGFR-adjusted dosage may be useful in preventing intraoperative seizures during awake craniotomy by allowing prediction of the seizure risk and enabling more accurate dosage calibration.

Background Tumors trigger both depression and anxiety about death because they can be terminal. However, the relationship between depression and time perspective in patients with life-threatening diseases remains unclear. In this study, we examined the effects of depression on time perspective in patients with brain tumors using a projective method, i.e., the Circle Test. Methods Participants (40 depressed patients, Dp; 35 non-depressed patients, NDp; and 40 healthy non-depressed controls, NDc) were administered the Circle Test of time perspectives and self-rating depression scales before and after surgery. The Circle Test data were analyzed using traditional indices, i.e., time dominance and relatedness, and novel measurements, i.e., time area and proportion. Results Although the traditional indices showed no differences, the results for the novel measurements differed among the Dp, NDp, and NDc groups. The overall time perspective was smaller in the Dp group than in the NDc group; furthermore, the proportions of the future and past perspectives were higher and lower, respectively, in the Dp group compared to the NDp group. Limitations Patients with brain tumors and depressed controls could not be compared, because no healthy control was depressed. Differences in depression-related changes in time perspective between patients with brain tumors and healthy controls should be examined in future studies. Conclusions Depressed patients with brain tumors may experience changes in time perspectives according to the results for our novel measurements, and this might play an important role in treatment adherence.

A 46-year-old female patient with glioblastoma multiforme (GBM), IDH wild type developed severe pancytopenia 5 months after postoperative chemoradiotherapy. Bone marrow aspirate showed normocellular marrow with 70.0% abnormal cells, which suggested the possibility of acute myeloid leukemia. Immunophenotypic analysis did not show any hematological lineage markers, except for cluster of differentiation 56. The results of immunohistochemical staining of glial fibrillary acidic protein and oligodendrocyte transcription Factor 2 were positive. Based on these findings, the patient was diagnosed with bone marrow metastasis from GBM. Bone marrow metastasis from GBM is rare and little is known about the morphological characteristics of bone marrow aspiration smear findings. We experienced a rare case with marrow metastasis from GBM mimicking acute myeloid leukemia.

Purpose: This study aimed to explore the genetic alterations and to identify good responders in the experimental arm in the tumor samples from newly diagnosed glioblastoma (GBM) patients enrolled in JCOG0911; a randomized phase II trial was conducted to compare the efficacy of interferonβ (IFNβ) plus temozolomide (TMZ) with that of TMZ alone. Experimental: DESIGN: Of 122 tumors, we performed deep targeted sequencing to determine the somatic mutations, copy number variations, and tumor mutation burden; pyrosequencing for O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation; Sanger sequencing for the telomerase reverse transcriptase (TERT) promoter; and microsatellite instability (MSI) testing in 95, 91, 91 and 72 tumors, respectively. We performed a multivariable Cox regression analysis using backward stepwise selection of variables including clinical factors (sex, age, performance status, residual tumor after resection, tumor location) and genetic alterations. Results: Deep sequencing detected an IDH1 mutation in 13 tumors (14%). The MGMT promoter methylation by quantitative pyrosequencing was observed in 41% of the tumors. A mutation in the TERT promoter was observed in 69% of the tumors. While high tumor mutation burden (> 10 mutations per megabase) was seen in four tumors, none of the tumors displayed MSI-high. The clinical and genetic factors considered as independent favorable prognostic factors were gross total resection (hazard ratio [HR]: 0.49, 95% confidence interval, 0.30-0.81, P = 0.0049) and MGMT promoter methylation (HR: 0.43, 0.21-0.88, P = 0.023). However, tumor location at the temporal lobe (HR: 1.90, 1.22-2.95, P = 0.0046) was an independent unfavorable prognostic factor. No predictive factors specific to the TMZ + IFNβ + Radiotherapy (RT) group were found. Conclusion: This additional sub-analytical study of JCOG0911 among patients with newly diagnosed GBM showed that tumor location at the temporal lobe, gross total resection, and MGMT promoter methylation were significant prognostic factors, although no factors specific to IFNβ addition were identified.

An out‐of‐body experience (OBE) is a phenomenon whereby an individual views his/her body and the world from a location outside the physical body. Previous studies have suggested that the temporoparietal junction (TPJ), the brain region responsible for integrating multisensory signals, is responsible for OBE development. Here, however, we first present a case of OBE after brain tumour development in the posterior cingulate cortex (PCC). The patient was a 46‐year‐old right‐handed female; she underwent brain surgery. She reported that she had experienced OBEs several times monthly (during daily life) before surgery but never after surgery. She defined her OBEs explicitly; she drew pictures. Her OBEs exhibited phenomenological, overt dissociation of the subjective and objective bodies. We discuss the mechanisms underlying this phenomenon and the relationship between OBEs and the PCC in terms of anatomical and functional brain connectivity. Our case sheds some light on the mechanism involved in creating spatial (dis)unity between the self and the body.