PTPN11 variant may be a prognostic indicator of IDH-wildtype glioblastoma in a comprehensive genomic profiling cohort.

PURPOSE: Glioblastoma (GBM) is the most common type of primary malignant brain tumor and has a poor prognosis. Identifying novel targets and stratification strategies is urgently needed to improve patient survival. The present study aimed to identify clinically relevant genomic alterations in IDH-wildtype GBM using data from comprehensive genomic profiling (CGP) assays performed nationwide in Japan. METHODS: The CGP assay results of 392 IDH-wildtype GBM cases performed between October 2019 and February 2023 obtained from the Center for Cancer Genomics and Advanced Therapeutics were retrospectively analyzed. RESULTS: The median patient age was 52.5 years, and 207 patients (53%) were male. In the 286 patients for whom survival information was available, a protein-tyrosine phosphatase non-receptor type 11 (PTPN11) variant detected in 20 patients (6.8%) was extracted as the gene associated with significantly shorter overall survival (p = 0.002). Multivariate analysis demonstrated that the PTPN11 variant and poor performance status were independent prognostic indicators. In contrast, no prognostic impact was observed in the cohort in The Cancer Genome Atlas data. The discrepancy in the prognostic impact of the PTPN11 variant from these two pools might have resulted from differences in the biases affecting the survival of patients who underwent a CGP assay, including left-truncation and right-censored bias. However, survival simulation done to adjust for these biases showed that the prognostic impact of the PTPN11 variant was also significant. CONCLUSIONS: The PTPN11 variant was a negative prognostic indicator of IDH-wildtype GBM in the patient cohort with the CGP assay.

CHD5 gene variant predicts leptomeningeal metastasis after surgical resection of brain metastases of breast cancer.

PURPOSE: Leptomeningeal metastasis (LM) is a complication of surgery for brain metastasis and is a risk factor of poor prognosis. The risk of LM is particularly high after surgery for a breast cancer metastasis to the brain. If the risk of LM after surgical resection for a brain metastasis were predictable, appropriate adjuvant therapy could be administered to individual patients to improve their prognosis. The present study aimed to reveal the genetic characteristics of brain metastases as means of predicting LM in breast cancer patients. METHODS: Ten patients with brain metastases of breast cancer presented LM after surgical resection were analyzed by whole-exome sequencing. RESULTS: A chromodomain-helicase-DNA-binding protein 5 (CHD5) gene alteration was detected in nine cases (90%), including a nonsynonymous variant in four cases and copy number deletion in five cases. CHD5 protein expression was lost in nine cases and had decreased in one case. The frequency of CHD5 gene alteration in brain metastases with LM was significantly higher than in primary breast cancer (2.3%) or in brain metastases of breast cancer (0%) (p < 0.0001). CONCLUSIONS: These results suggested that the CHD5 gene alteration was associated with LM after surgical resection of breast cancer brain metastases. Searching for the gene alteration might predict the LM risk after surgical resection.

Sensory hypo- and hypersensitivity in patients with 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.

Influence of chronic kidney disease on hospitalization, chronic dialysis, and mortality in Japanese men: a longitudinal analysis.

BACKGROUND: Little is known concerning the risk of hospitalization and the risk of death before receiving dialysis by the stage of chronic kidney disease (CKD) in Japan. METHODS: The subjects comprised a total of 13,911 Japanese men (mean age 49.2 ± 9.9 years). Based on the results of a health checkup performed in 2006, they were divided into 5 groups according to their estimated glomerular filtration rate (GFR) levels and dialysis status: GFR ≥60, 45-59, 30-44, <30 mL/min/1.73 m2, and undergoing dialysis. From 2006 through to 2013, we investigated their hospitalization, dialysis initiation, and cause-specific death. The adjusted hazard ratios (HRs) for each end point were calculated compared with the GFR ≥60 mL/min/1.73 m2 group using a Cox proportional hazard model. RESULTS: A lower GFR was independently associated with higher risks of overall hospitalization, dialysis initiation, and all-cause death. In particular, the HRs for long-term hospitalization (≥1 month a year), dialysis, and cardiovascular disease (CVD) death markedly increased along with a decreased GFR. The rate ratios of dialysis to all-cause death (calculated based on the incidences of dialysis and death per 1000 person-years) were 0.03 (0.11 vs. 3.19), 0.08 (0.29 vs. 3.62), 0.51 (12.5 vs. 24.7), and 4.50 (179.8 vs. 40.0) for GFR ≥60, 45-59, 30-44, and <30 mL/min/1.73 m2, respectively. CONCLUSION: In Japanese men, although the risk of CVD death before dialysis initiation can never be ignored, CKD patients aged <60 years with a GFR of <30 mL/min/1.73 m2 are more likely to undergo dialysis prior to death.

Preservation of hearing following awake surgery via the retrosigmoid approach for vestibular schwannomas in eight consecutive patients.

BACKGROUND: Hearing preservation in patients with vestibular schwannomas remains difficult by microsurgery or radiosurgery. METHOD: In this study, awake surgery via the retrosigmoid approach was performed for vestibular schwannomas (volume, 11.6 ± 11.2 ml; range, 1.3-26.4 ml) in eight consecutive patients with preoperative quartering of pure tone audiometry (PTA) of 53 ± 27 dB. RESULTS: After surgery, hearing was preserved in seven patients and improved in one patient. The postoperative quartering PTA was 51 ± 21 dB. Serviceable hearing (class A + B + C) using the American Association of Otolaryngology-Head and Neck Surgery (AAO-HNS) classification was preserved in all patients. Preoperative useful hearing (AAO-HNS class A + B) was observed in three patients, and useful hearing was preserved in all three of these patients after surgery. In addition, useful facial nerve function (House-Blackmann Grade 1) was preserved in all patients. CONCLUSIONS: These results suggest that awake surgery for vestibular schwannomas is associated with low patient morbidity, including with respect to hearing and facial nerve function.

Imaging findings and pathological correlations of subacute encephalopathy with neuronal intranuclear inclusion disease-Case report.

Neuronal intranuclear inclusion disease (NIID) is a slowly progressive neurodegenerative disease and may sometimes present with symptoms of subacute encephalopathy, including fever, headache, vomiting, and loss of consciousness. We present a case of adult-onset NIID with subacute encephalopathy, which is confirmed by skin and brain biopsied. The magnetic resonance imaging findings show cortical swelling and hyperintensities in the right temporooccipital lobes on T2-weighted images and magnetic resonance angiography demonstrates vasodilatations of the right middle cerebral artery and posterior cerebral artery. Abnormal enhancement is mainly observed in the gyral crowns (crown enhancement). Pathological examinations reveal new infarcts in the deep layers of the cortices. NIID should be considered in the presence of subacute encephalopathy with cortical swelling, contrast enhancement in the temporooccipital lobes, and vasodilation in adult patients. The encephalopathy targeted on the cortices, and the pathological background included infarctions.

Advantages and disadvantages of awake surgery for brain tumours in the primary motor cortex: institutional experience and review of literature.

Patients undergoing awake surgery for resection of brain tumours in the primary motor cortex (M1) are at high risk of developing new motor deficits. Thus, use of this procedure requires consideration of several important points, including the optimal modality to localise M1 on the affected side and the overall advantages and disadvantages of the procedure. In our experience with awake surgery for 21 brain tumours located in the M1 from January 2004 through October 2008, we found that functional magnetic resonance imaging was the most reliable modality in terms of localising the M1 and that the anatomic relationship between motor tracts and brain tumours is a critical determinant of postoperative motor function. Other considerations, including potential complications of this procedure and relative efficacy and safety versus surgery under general anaesthesia for patients with brain tumours in the M1, are discussed.

Utility of monitoring the serum levetiracetam concentration for intraoperative seizure control during awake craniotomy.

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.

Genetic Characteristics of Mismatch Repair-deficient Glioblastoma.

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.

Relationships between brain tumor and optic tract or calcarine fissure are involved in visual field deficits after surgery for brain tumor.

PURPOSE: Diffusion tensor tractography provides useful information regarding the surgical strategy for brain tumors. The goal of the present study was to analyze relationships between visual field deficits and the locations of brain tumors compared with optic tracts as visualized by tractography, and compared with the calcarine fissure. METHODS: Subjects comprised 11 patients with brain tumor in the occipital lobe or atrium of the lateral ventricle who underwent surgery between October 2006 and February 2009. Tumors were categorized as Type A, with almost all the optic tract in the occipital lobe or atrium of the lateral ventricle running close to and stretched by the brain tumor; and Type B, with the optic tract running at least partially distant to the brain tumor and remaining unstretched. RESULTS: Those type A optic tracts that were laterally compressed by brain tumors (Cases 1-3) displayed hemianopsia after surgery. When the brain tumor was located rostro-medial to the calcarine fissure and optic tracts were compressed caudally by the tumor, lower quadrant hemianopsia remained after surgery (Cases 4, 5). In other cases, the visual field remained or improved to normal after surgery. CONCLUSION: The relationship between optic tracts or the calcarine fissure, and brain tumors in the occipital lobe or atrium of the lateral ventricle is related to visual field deficits after surgery. In particular, those Type A optic tracts that are compressed laterally show hemianopsia of the visual field after surgery.

Dissociation of the subjective and objective bodies: Out-of-body experiences following the development of a posterior cingulate lesion.

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.

Bone marrow metastasis of glioblastoma multiforme mimicking acute myeloid leukemia.

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.

Awake surgery with continuous motor testing for resection of brain tumors in the primary motor area.

Resection of brain tumors in the primary motor area (M1) is difficult to achieve without adversely affecting motor function. Between November 2003 and November 2006, 16 patients with 18 brain tumors involving the M1 (11 metastatic, 6 gliomas, 1 cavernous angioma) underwent craniotomy and awake surgery with continuous motor testing at our hospital. Patients were classified as either type A (9 patients), indicating that motor tracts ran in close proximity to the brain tumors, or type B (7 patients), indicating that motor tracts ran distant to the tumor. The relationship between the extent of resection and post-operative motor function was subsequently evaluated. In 17 out of 18 cases, final post-operative motor function was either preserved or improved relative to pre-operative levels, although transient deterioration of motor function and partial removal of the tumor were observed in 7 and 8 cases, respectively. The remaining patients experienced slight deterioration in motor function of the upper extremities. All type A patients experienced suboptimal outcomes, involving transient or permanent deterioration of motor function after surgery or only partial removal of the tumor. By contrast, most type B patients experienced good outcomes (no deterioration of motor function and gross total removal of the tumor). In conclusion, awake surgery with continuous motor testing allowed for resection of brain tumors in the M1 and preservation of motor function, although the patients in whom motor tracts ran in close proximity to the tumors experienced suboptimal outcomes.

Preservation of cranial nerve function following awake surgery for benign brain tumors in 22 consecutive patients.

BACKGROUND: Preservation of cranial nerve function in patients with benign tumors such as meningiomas and vestibular schwannomas remains difficult following microsurgery. METHODS: In this study, awake surgery was performed in 22 consecutive patients with meningiomas or vestibular schwannomas that compressed cranial nerves (I-XII). Improved, unchanged, or deteriorated cranial nerve function after surgery was evaluated. RESULTS: The function of 44 cranial nerves in 22 consecutive patients who underwent awake surgery for meningiomas or vestibular schwannomas improved, was unchanged, or deteriorated in eight, 35, and one nerves, respectively. Regarding the function of the olfactory (Ist) nerve, which is difficult to preserve, hyposmia improved after surgery in two patients with olfactory groove meningiomas. Regarding the auditory (VIIIth) nerve, which is also difficult to preserve, the function was improved, unchanged, or deteriorated after surgery in two, 11, and one patients, respectively, with cerebello-pontine angle meningiomas or vestibular schwannomas. In all patients with serviceable auditory function before surgery, function was preserved after surgery. In the same patients, the function of the facial (VIIth) nerve was also preserved after surgery in all patients. CONCLUSIONS: These results suggest that awake surgery for benign brain tumors such as meningiomas and vestibular schwannomas is associated with low patient morbidity regarding cranial nerve function.

Continuous intrathecal injection therapy of methotrexate is a therapeutic option in primary CNS lymphoma.

Primary central nervous system lymphoma (PCNSL) is a rare subtype of non-Hodgkin's lymphoma, and its prognosis is still very poor despite the conventional therapy of high-dose methotrexate (HD-MTX) followed by whole-brain radiation therapy (WBRT). The purpose of the present study was to evaluate the survival benefit of continuous intrathecal injection therapy of methotrexate (CIT-MTX) combined with the conventional therapy. A total of 26 PCNSL patients treated with CIT-MTX were analyzed. Ten mg of methotrexate were continuously injected into the lateral ventricle via a subcutaneous port over 5 days biweekly for 5 cycles. CIT-MTX was performed with WBRT in addition to HD-MTX in 15 cases, and 11 cases with high risk for HD-MTX were treated with CIT-MTX and WBRT. The response rate of all patients was 92.3%, and median progression-free survival and median overall survival (mOS) were 59.4 months and 93.8 months, respectively. Median OS of patients treated with CIT-MTX in addition to HD-MTX and WBRT was longer than the previously reported mOS with HD-MTX and WBRT (95 vs 33 months). In cases that could not tolerate HD-MTX, mOS of patients treated with CIT-MTX and WBRT was longer than the previously reported mOS with WBRT alone (36.7 vs 18 months). There was no difference in OS between patients with cerebrospinal fluid dissemination and patients without (p = 0.83). Better prognosis in patients treated with CIT-MTX may be derived from stable concentration of methotrexate in the cerebrospinal fluid. CIT-MTX was an effective additional therapeutic option for PCNSL.

Biased Recognition of Surprised Facial Expressions Following Awake Craniotomy of a Right Temporal Lobe Tumor.

Lesion studies have shown that the right temporal lobe is crucial for recognition of facial expressions, particularly fear expressions. However, in previous studies, premorbid abilities of the patients were unknown and the effects of epileptic discharge could not be excluded. Herein, we report a case of a patient who underwent assessments of facial recognition before and after brain surgery and exhibited biased recognition of facial expressions. The patient was a 29-year-old right-handed male who underwent an awake craniotomy. Compared with the preoperative assessment, after the surgery, he showed biased recognition of surprised facial expressions, and his ability to recognize other facial expressions either improved or remained unchanged. These findings support the idea that the right temporal lobe is crucial for the recognition of facial expressions of surprise and that functional connectivity between various brain regions plays an important role in the ability to recognize facial expressions.

[Temozolomide: Temodal].

The oral alkylating agent, temozolomide (Temodal: TMZ), is the only anticancer drug that has been shown in a phase III study to improve survival in glioblastoma (GBM) when administered with concomitant radiotherapy. Pharmacokinetic studies have documented relatively high concentrations of TMZ in brain tumors and cerebrospinal fluid (20-40% of the area under the plasma concentration curve), and other studies have demonstrated that TMZ is effective for treatment of various brain tumors, including recurrent and newly diagnosed glioma, primary CNS lymphoma, metastatic melanoma, and neuroblastoma. Molecular markers that predict a favorable response to TMZ plus concomitant radiotherapy include methylguanine methyltransferase (MGMT) promoter methylation patients with GBM and chromosome 1p/19q deletion in patients with anaplastic oligodendroglioma or low-grade glioma. Myelosuppression, nausea and constipation are relatively frequent in patients undergoing treatment with TMZ, and prophylaxis against Pneumocystis carinii pneumonia should be instituted. This article will summarize and discuss these issues as well as review ongoing and anticipated studies of TMZ in combination with other anti-cancer therapies.

Measuring the sense of self in brain-damaged patients: A STROBE-compliant article.

Recently, researchers have focused on the embodied sense of self (ESS), which consists of the minimal and narrative selves. Although a study demonstrated that the ESS is related to brain dysfunction empirically, the subjective aspects of the ESS, and a systematic approach to it, have not yet been examined in brain-damaged patients. To examine this, we measured the ESS of patients with brain tumors before and after awake craniotomy.A self-reported questionnaire called the Embodied Sense of Self Scale (ESSS) was used to measure the ESS in patients with brain tumors before and after surgery. For comparison, age-matched controls also completed the ESSS.The ESSS scores of the patients with brain tumors before surgery were higher than those of the controls and improved after surgery. Before surgery, patients with left hemispheric lesions had a poorer ESSS than those with right hemispheric lesions. Episodic memory disturbance was highly correlated with malfunction of narrative self and ownership.Brain lesions were associated with anomalous ESSS, associated with hemispheric laterality and cognitive dysfunction.

A case report of adult cerebellar high-grade glioma with H3.1 K27M mutation: a rare example of an H3 K27M mutant cerebellar tumor.

Diffuse midline glioma, H3 K27M mutant, is newly recognized as a distinct category, which usually arises in the brain stem, thalamus or spinal cord of children, and young adults. The oncogenic H3 K27M mutation involves H3.3 (encoded by H3F3A) or H3.1 (encoded by HIST1H3B/HIST1H3C), and the incidence of each mutation differs among the primary sites. Recently, several papers have reported that cerebellar high-grade gliomas in both children and adults also harbor H3 K27 mutation. With the exception of one pediatric case, all of the cases carried the mutation in H3.3. We herein present the case of an adult cerebellar high-grade astrocytic tumor with H3.1 K27M mutation in a 45-year-old man, which also involvedTP53 mutation and was immunonegative for ATRX. Some groups have reported that H3.3 and H3.1 K27M mutations define subgroups of diffuse intrinsic pontine gliomas (DIPGs) with different phenotypes as well as genetic alterations. On comparing the findings of the present case, particularly TP53 mutation status and ATRX expression, to the findings of the previous studies on DIPGs, our case seems unusual among the H3.1 K27M mutant subgroup. Further studies are needed to clarify the exact frequency, clinicopathological characteristics, and genomic alterations of cerebellar gliomas harboring H3 K27M mutation.

Operative Strategies during Awake Surgery Affect Deterioration of Paresis a Month after Surgery for Brain Lesions in the Primary Motor Area.

Introduction We analyzed factors associated with worsened paresis at 1-month follow-up in patients with brain tumors located in the primary motor area (M1) to establish protocols for safe awake craniotomy for M1 lesions. Methods Patients with M1 brain tumors who underwent awake surgery in our hospital (n = 61) were evaluated before, during, and immediately and 1 month after surgery for severity of paresis, tumor location, extent of resection, complications, preoperative motor strength, histology, and operative strategies (surgery stopped or continued after deterioration of motor function). Results Worsened paresis at 1-month follow-up was significantly associated with worsened paresis immediately after surgery and also with operative strategy. Specifically, when motor function deteriorated during awake surgery and did not recover within 5 to 10 minutes, no deterioration was observed at 1-month follow-up in cases where we stopped surgery, whereas 6 of 13 cases showed deteriorated motor function at 1-month follow-up in cases where we continued surgery. Conclusion Stopping tumor resection on deterioration of motor function during awake surgery may help prevent worsened paresis at 1-month follow-up.