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Meningioma is the most common intracranial tumor, with generally favorable patient prognosis. However, patients with malignant meningioma typically experience recurrence, undergo multiple surgical resections, and ultimately have a poor prognosis. Thus far, effective chemotherapy for malignant meningiomas has not been established. We recently reported the efficacy of eribulin (Halaven ®) for glioblastoma with a telomerase reverse transcriptase (TERT) promoter mutation. This study investigated the anti-tumor effect of eribulin against TERT promoter mutation-harboring human malignant meningioma cell lines in vitro and in vivo. Two meningioma cell lines, IOMM-Lee and HKBMM, were used in this study. The strong inhibition of cell proliferation by eribulin via cell cycle arrest was demonstrated through viability assay and flow cytometry. Apoptotic cell death in malignant meningioma cell lines was determined through vital dye assay and immunoblotting. Moreover, a wound healing assay revealed the suppression of tumor cell migration after eribulin exposure. Intraperitoneal administration of eribulin significantly prolonged the survival of orthotopic xenograft mouse models of both malignant meningioma cell lines implanted in the subdural space (p < 0.0001). Immunohistochemistry confirmed apoptosis in brain tumor tissue treated with eribulin. Overall, these results suggest that eribulin is a potential therapeutic agent for malignant meningiomas.

Glioblastomas (GBM) often acquire resistance against temozolomide (TMZ) after continuous treatment and recur as TMZ‐resistant GBM (TMZ‐R‐GBM). Lomustine (CCNU) and nimustine (ACNU), which were previously used as standard therapeutic agents against GBM before TMZ, have occasionally been used for the salvage therapy of TMZ‐R‐GBM; however, their efficacy has not yet been thoroughly examined. Therefore, we investigated the antitumor effects of CCNU and ACNU against TMZ‐R‐GBM. As a model of TMZ‐R‐GBM, TMZ resistant clones of human GBM cell lines (U87, U251MG, and U343MG) were established (TMZ‐R‐cells) by the culture of each GBM cells under continuous TMZ treatment, and the antitumor effects of TMZ, CCNU, or ACNU against these cells were analyzed in vitro and in vivo. As a result, although growth arrest and apoptosis were triggered in all TMZ‐R‐cells after the administration of each drug, the antitumor effects of TMZ against TMZ‐R‐cells were significantly reduced compared to those of parental cells, whereas CCNU and ACNU demonstrated efficient antitumor effects on TMZ‐R‐cells as well as parental cells. It was also demonstrated that TMZ resistance of TMZ‐R‐cells was regulated at the initiation of DNA damage response. Furthermore, survival in mice was significantly prolonged by systemic treatment with CCNU or ACNU but not TMZ after implantation of TMZ‐R‐cells. These findings suggest that CCNU or ACNU may serve as a therapeutic agent in salvage treatment against TMZ‐R‐GBM., We investigated the antitumor effects of lomustine (CCNU) and nimustine (ACNU), which were previously used as standard therapeutic agents for glioblastomas (GBM), against the model cells of human GBM cases, which gained acquired temozolomide (TMZ) resistance after continuous treatment by TMZ (TMZ‐R‐cells). We discovered that the antitumor effects of TMZ against TMZ‐R‐cells were significantly reduced compared to those of parental cells, whereas CCNU and ACNU demonstrated efficient antitumor effects on TMZ‐R‐cells as well as parental cells both in vitro and in vivo. In addition, it was also demonstrated that TMZ resistance of TMZ‐R‐cells was regulated at the level of DNA damage response initiation. These findings suggest that CCNU or ACNU may serve as a therapeutic agent in salvage treatment against GBM cases with acquired TMZ resistance.

INTELLANCE‐J was a phase 1/2 study of a potent antibody‐drug conjugate targeting epidermal growth factor receptor (EGFR), depatuxizumab mafodotin (Depatux‐M), as a second‐ or first‐line therapy, alone or combined with chemotherapy or chemoradiotherapy in 53 Japanese patients with World Health Organization (WHO) grade III/IV glioma. In second‐line arms, patients with EGFR‐amplified recurrent WHO grade III/IV glioma received Depatux‐M plus chemotherapy (temozolomide) or Depatux‐M alone regardless of EGFR status. In first‐line arms, patients with newly diagnosed WHO grade III/IV glioma received Depatux‐M plus chemoradiotherapy. The study was halted following lack of survival benefit with first‐line Depatux‐M in the global trial INTELLANCE‐1. The primary endpoint was 6‐month progression‐free survival (PFS) in patients with EGFR‐amplified tumors receiving second‐line Depatux‐M plus chemotherapy. Common nonocular treatment‐emergent adverse events (TEAEs) with both second‐line and first‐line Depatux‐M included lymphopenia (42%, 33%, respectively), thrombocytopenia (39%, 47%), alanine aminotransferase increase (29%, 47%), and aspartate aminotransferase increase (24%, 60%); incidence of grade ≥3 TEAEs was 66% and 53%, respectively. Ocular side effects (OSEs) occurred in 93% of patients receiving second‐line Depatux‐M plus chemotherapy and all patients receiving second‐line Depatux‐M alone or first‐line Depatux‐M plus chemoradiotherapy. Most OSEs were manageable with dose modifications and concomitant medications. The 6‐month PFS estimate was 25.6% (95% confidence interval [CI] 11.4‒42.6), and median PFS was 2.1 months (95% CI 1.9‒3.9) with second‐line Depatux‐M plus chemotherapy in the EGFR‐amplified subgroup. This study showed acceptable safety profile of Depatux‐M alone or plus chemotherapy/chemoradiotherapy in Japanese patients with WHO grade III/IV glioma. The study was registered at ClinicalTrials.gov (NCT02590263)., INTELLANCE‐J was a phase 1/2 study of a potent antibody‐drug conjugate targeting epidermal growth factor receptor (EGFR), depatuxizumab mafodotin, as a second‐ or first‐line therapy, alone or combined with chemotherapy or chemoradiotherapy in Japanese patients with World Health Organization grade III/IV glioma. The results of this trial demonstrate an acceptable safety profile of depatuxizumab mafodotin, with ocular side effects being the most common adverse events that were mostly reversible. Second‐line depatuxizumab mafodotin in combination with temozolomide resulted in a 6‐month progression‐free survival estimate of 25.6% (95% confidence interval 11.4‒42.6) in patients with EGFR‐amplified tumors and showed encouraging antitumor activity in this subgroup of patients (NCT02590263).

The current standard of diagnosing central nervous system (CNS) lymphoma is stereotactic biopsy, however the procedure has a risk of surgical complication. Liquid biopsy of the CSF is a less invasive, non‐surgical method that can be used for diagnosing CNS lymphoma. In this study, we established a clinically applicable protocol for determining mutations in MYD88 in the CSF of patients with CNS lymphoma. CSF was collected prior to the start of chemotherapy from 42 patients with CNS lymphoma and matched tumor specimens. Mutations in MYD88 in 33 tumor samples were identified using pyrosequencing. Using 10 ng each of cellular DNA and cell‐free DNA (cfDNA) extracted from the CSF, the MYD88 L265P mutation was detected using digital PCR. The conditions to judge mutation were rigorously determined. The median Target/Total value of cases with MYD88 mutations in the tumors was 5.1% in cellular DNA and 22.0% in cfDNA. The criteria to judge mutation were then determined, with a Target/Total value of 0.25% as the cutoff. When MYD88 mutations were determined based on these criteria, the sensitivity and specificity were 92.2% and 100%, respectively, with cellular DNA; and the sensitivity and specificity were 100% with cfDNA. Therefore, the DNA yield, mutated allele fraction, and accuracy were significantly higher in cfDNA compared with that in cellular DNA. Taken together, this study highlights the importance of detecting the MYD88 L265P mutation in cfDNA of the CSF for diagnosing CNS lymphoma using digital PCR, a highly accurate and clinically applicable method., Development of a liquid biopsy for less invasive diagnosis of CNS lymphoma is in progress. In this study, the conditions for detecting the MYD88 L265P mutation by digital PCR were set, and extremely high accuracy was confirmed. This method is fully clinically feasible.

Background An open-label, non-comparative study assessed the efficacy and safety of nivolumab in Japanese patients with first recurrence glioblastoma. Methods Patients with first recurrence of histologically confirmed World Health Organization Grade IV glioma, after treatment with temozolomide and radiotherapy, received nivolumab 3 mg/kg every 2 weeks until confirmed disease progression (Response Assessment in Neuro-Oncology criteria) or toxicity. Primary endpoint was 1-year overall survival rate assessed by Bayesian approach. The prespecified efficacy criterion was that the Bayesian posterior probability threshold for exceeding the 1-year overall survival of bevacizumab (34.5%) from the Japanese phase 2 study (JO22506) would be 93%. Results Of the 50 enrolled patients, 44 (88.0%) had recurrent malignant glioma (glioblastoma, gliosarcoma), and of these, 26 (59.1%) had at least one measurable lesion at baseline. The Bayesian posterior mean 1-year overall survival (90% Bayesian credible intervals) with nivolumab was 54.4% (42.27–66.21), and the Bayesian posterior probability of exceeding the threshold of the 1-year overall survival rate of bevacizumab (34.5%) was 99.7%. Median (90% confidence interval) overall and progression-free survival was 13.1 (10.4–17.7) and 1.5 (1.4–1.5) months, respectively. One partial response was observed (objective response rate 1/26 evaluable patients [3.8%]). Treatment-related adverse event rates were 14.0% for Grade 3–4 and 2.0% for Grade 5; most adverse events resolved and were manageable. Conclusions The 1-year overall survival with nivolumab monotherapy in Japanese patients with glioblastoma met the prespecified efficacy criterion. The safety profile of nivolumab was consistent with that observed in other tumor types. Clinical Trial Registration JapicCTI-152967.

Glioma is the most common type of central nervous system tumor reported worldwide. Current imaging technologies have limitations in the diagnosis and assessment of glioma. The present study aimed to confirm the diagnostic efficacy and safety of anti-1-amino-3-[18F]fluorocyclobutane carboxylic acid (18F-fluciclovine; anti-[18F]FACBC) as a radiotracer for patients undergoing combined positron emission tomography and computed tomography (PET/CT) for suspected glioma. Combined data from two multicenter, open-label phase III clinical trials were evaluated for this study. The two trials enrolled patients with suspected high- or low-grade glioma on the basis of clinical symptoms, clinical course, and magnetic resonance imaging findings, and who were scheduled for tumor resection surgery. Patients fasted for ≥ 4 h and received 2 mL of 18F-fluciclovine (radioactivity dose 78.3–297.0 MBq), followed by a 10-min PET scan 10–50 min after injection. The primary efficacy endpoint was the positive predictive value (PPV) of the gadolinium contrast-enhanced T1-weighted image negative [Gd (–)] and 18F-fluciclovine PET-positive [PET ( +)] area of the scans, using the histopathological diagnosis of the tissue sampled from that area as the standard of truth. All adverse events reported during the study were recorded for safety analysis. A total of 45 patients aged 23–89 years underwent 18F-fluciclovine PET; 31/45 patients (68.9%) were male, and 30/45 patients (66.7%) were suspected to have high-grade glioma. The PPV of 18F-fluciclovine PET in the Gd (–) PET ( +) area was 88.0% (22/25 areas, 95% confidence interval: 70.0–95.8). The extent of planned tumor resection was modified in 47.2% (17/36 cases) after 18F-fluciclovine PET scan, with an extension of area in 30.6% (11/36 cases) and reduction in 16.7% (6/36 cases). Furthermore, tissue samples collected from PET ( +) areas tended to have a higher malignancy grade compared with those from PET (–) areas. Overall, 18F-fluciclovine was well tolerated. 18F-fluciclovine PET/CT is useful for determining the extent of tumor resection at surgical planning, and may serve as a safe and effective diagnostic tool for patients with suspected glioma. These trials were registered in the Japan Pharmaceutical Information Center Clinical Trials Information (JapicCTI-152986, JapicCTI-152985).

External auditory canal (EAC) carcinoma is a rare and unusual malignancy. The complex anatomy and relationship between the tumor and surrounding tissues in a limited space render it difficult to attain safe resection margins during surgery. A high jugular bulb (HJB) is one such anatomical variation that has important surgical implications that complicate the surgical procedure for EAC carcinoma. A 73-year-old woman presented with a 3-month history of right ear pain. Pathological findings and computed tomography (CT) revealed EAC carcinoma, which was expanding to the middle ear (ME). Although there was no cavity inside the ME, an HJB was detected. Surgical treatment using a temporal incision for temporal craniotomy achieved complete resection of the tumor and preserved facial nerve function. The patient recovered without complications and was discharged 17 days after the operation. Temporal incision and temporal craniotomy is a useful approach for EAC carcinoma with HJB.

This study aimed to improve the understanding of the role of adjuvant radiotherapy (AR) after subtotal resection (STR) of World Health Organization (WHO) grade I meningiomas. We retrospectively reviewed the Brain Tumor Registry of Japan database. Among 7341 patients diagnosed with intracranial meningioma during 2001–2008, we identified 406 patients with WHO grade I meningioma treated with STR as initial treatment. Data on progression-free survival (PFS) were assessed for their relevance to clinical factors including age, sex, tumor location and size, presence of preoperative symptoms, and AR. AR was administered for 73 patients (18.0%). Regrowth occurred in 90 cases (22.2%) during the median follow-up period of 6.0 years (interquartile range, 2.7–7.7 years). Multivariate Cox regression analysis of the entire cohort showed that no AR was associated with significantly shorter PFS (hazard ratio [HR] 2.52, 95% confidence interval [CI] 1.33–5.42, p = 0.004). The therapeutic effect of AR was confirmed for skull base, but not non-skull base, meningiomas (p = 0.003 and 0.69, respectively). Propensity score matching analysis balanced the influence of confounding factors to generate AR+ and AR− cohorts of 73 patients each. PFS was significantly longer in the AR+ cohort than in the AR− cohort (HR 3.46, 95% CI 1.53–8.59, p = 0.003). Subgroup analysis demonstrated the favorable effect of AR only for skull base meningiomas. Our study revealed that AR improves tumor control after STR in WHO grade I meningiomas. However, this beneficial effect might be limited to skull base meningiomas.

Background There is no standard treatment for patients with recurrent high-grade gliomas who progress after bevacizumab treatment. We evaluated the outcomes of re-irradiation combined with bevacizumab for patients refractory to bevacizumab. Methods Between January 2015 and September 2019, patients with progression after bevacizumab treatment were treated with re-irradiation combined with bevacizumab (25 Gy in five fractions). Results Fourteen patients [glioblastoma, isocitrate dehydrogenase (IDH) wild type (N = 6), glioblastoma, IDH mutant (N = 4), anaplastic astrocytoma, IDH wild type (N = 1), anaplastic astrocytoma, IDH mutant (N = 1), glioblastoma, not otherwise specified (N = 1) and radiologically diagnosed brainstem glioma (N = 1)] were included in this study. The median survival and progression-free survival times after re-irradiation combined with bevacizumab were 6.1 and 3.8 months, respectively. The 6-month survival and progression-free survival rates were 54.5 and 15.7%, respectively. Patients with a Karnofsky performance status of ≥70 tended to have longer median survival time (9.3 vs. 5.4 months, respectively; P = 0.058) and had a significantly longer median progression-free survival time (4.2 vs. 3.7 months, respectively; P = 0.046) than those with a Karnofsky performance status of Conclusions Re-irradiation combined with bevacizumab for patients with recurrent high-grade gliomas who progress after bevacizumab treatment was feasible. Re-irradiation combined with bevacizumab is a potential treatment option, especially for patients with a Karnofsky performance status of ≥70.

Surgical resection represents the standard of care in diffuse glioma, and more extensive tumour resection appears to be associated with favourable outcome. Up to now, terminology to describe extent of resection has been inconsistently applied across clinical trials which hampers comparative analysis of cohorts between different studies. Based on a comprehensive literature review, we developed evidence-based expert recommendations on categories for extent of resection. Recommendations are formulated for the categories ‘biopsy’, ‘partial resection’, ‘subtotal resection’, ‘near total resection’, ‘complete resection’ and ‘supramaximal resection’. Definitions rest on reduction of contrast- and non–contrast-enhancing tumour in glioblastoma, and on reduction of T2/FLAIR-hyperintense tumour in gliomas WHO grade 2 or 3. Both relative reduction of tumour volume (in percentage) as a measurement of surgical efficacy and absolute residual tumour volume (in cm3) as a measurement of remaining tumour burden are incorporated into the categories for extent of resection. Class of evidence for the proposed categories ranges from class IIB to IV. Limitations of the suggested categories are discussed. The proposed categories on extent of resection offer a framework to standardize nomenclature based on previous studies, and will need to be evaluated in prospective, molecularly well-defined cohorts. Our categories may eventually help as a stratification factor for future clinical trials.

Homozygous deletion (HD) of CDKN2A is one of the most promising biomarkers for predicting poor prognosis of IDH-mutant diffuse gliomas. The Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) recommendations propose that IDH-mutant lower-grade astrocytomas with CDKN2A/B HD be classified as grade IV tumors. Loss of methylthioadenosine phosphorylase (MTAP) immunohistochemistry staining has been proposed as a surrogate of CDKN2A HD in various tumors but its performance has not been fully investigated in diffuse glioma. This study determined whether MTAP immunoreactivity could serve as a proxy for CDKN2A HD in adult-type diffuse glioma, thereby contributing to stratifying patient outcome. MTAP immunohistochemistry staining using clone EPR6893 was scored in 178 diffuse glioma specimens consisting of 77 IDH-mutant astrocytomas, 13 IDH-mutant oligodendrogliomas, and 88 IDH-wildtype glioblastomas. The use of MTAP immunohistochemical deficiency to predict CDKN2A HD was good for IDH-mutant astrocytomas (sensitivity, 88%; specificity, 98%) and IDH-wildtype glioblastomas (sensitivity, 89%; specificity, 100%), but poor for IDH-mutant oligodendrogliomas (sensitivity, 67%; specificity, 57%). Both CDKN2A HD and MTAP immunohistochemical deficiency were significant adverse prognostic factors of overall survival for IDH-mutant astrocytoma (P

A novel radiological research field pursuing comprehensive quantitative image, namely “Radiomics,” gained traction along with the advancement of computational technology and artificial intelligence. This novel concept for analyzing medical images brought extensive interest to the neuro-oncology and neuroradiology research community to build a diagnostic workflow to detect clinically relevant genetic alteration of gliomas noninvasively. Although quite a few promising results were published regarding MRI-based diagnosis of isocitrate dehydrogenase (IDH) mutation in gliomas, it has become clear that an ample amount of effort is still needed to render this technology clinically applicable. At the same time, many significant insights were discovered through this research project, some of which could be “reverse engineered” to improve conventional non-radiomic MR image acquisition. In this review article, the authors aim to discuss the recent advancements and encountering issues of radiomics, how we can apply the knowledge provided by radiomics to standard clinical images, and further expected technological advances in the realm of radiomics and glioma.

Each year, the Japan Neurosurgical Society (JNS) reports up-to-date statistics from the Japan Neurosurgical Database regarding case volume, patient demographics, and in-hospital outcomes of the overall cohort and neurosurgical subgroup according to the major classifications of main diagnosis. We hereby report patient demographics, in-hospital mortality, length of hospital stay, purpose of admission, number of medical management, direct surgery, endovascular treatment, and radiosurgery of the patients based on the major classifications and/or main diagnosis registered in 2018 and 2019 in the overall cohort (523283 and 571143 patients, respectively) and neurosurgical subgroup (177184 and 191595 patients, respectively). The patient demographics, disease severity, proportion of purpose of admission (e.g., operation, 33.9-33.5%) and emergent admission (68.4-67.8%), and in-hospital mortality (e.g., cerebrovascular diseases, 6.3-6.5%; brain tumor, 3.1-3%; and neurotrauma, 4.3%) in the overall cohort were comparable between 2018 and 2019. In total, 207783 and 225217 neurosurgical procedures were performed in the neurosurgical subgroup in 2018 and 2019, respectively, of which endovascular treatment comprised 19.1% and 20.3%, respectively. Neurosurgical management of chronic subdural hematoma (19.4-18.9%) and cerebral aneurysm (15.4-14.8%) was most common. Notably, the proportion of management of ischemic stroke/transient ischemic attack, including recombinant tissue plasminogen activator infusion and endovascular acute reperfusion therapy, increased from 7.5% in 2018 to 8.8% in 2019. The JNS statistical update represents a critical resource for the lay public, policy makers, media professionals, neurosurgeons, healthcare administrators, researchers, health advocates, and others seeking the best available data on neurosurgical practice.

Purpose Although height and body mass index (BMI) are reported to be positively associated with several common cancers, evidence regarding their association with brain tumor risk remains sparse, particularly in Asian populations. In this study, we analyzed the association between height and BMI and brain tumor risk in a Japanese population using a large population-based prospective cohort study. Methods A total of 102,925 participants (48,213 men and 54,712 women) enrolled in the Japan Public Health Center–based Prospective Study were followed from baseline, namely 1990 for cohort I and 1993 for cohort II, until 2012. Information on participants’ dietary and lifestyle habits, including height and body weight, was collected through survey questionnaires administered at baseline. We used the Cox proportional hazards regression model to estimate hazard ratios and 95% confidence intervals (CIs) for brain tumor incidence, with adjustment for potential confounding variables. Results During an average follow-up of 18.1 years, 157 (70 men and 87 women) cases of brain tumor were newly diagnosed. BMI showed a statistically insignificant positive association with the risk of brain tumor. In addition, statistically significant positive trends were seen for men and meningioma, with multivariable-adjusted hazard ratios for a BMI of 27.5 to less than 40 versus 18.5 to less than 23 kg per m2 of 2.14 (95% CI = 0.99–4.59) (P = 0.03) and 1.98 (95% CI = 0.84–4.67) (P = 0.046), respectively. In contrast, height showed no clear association with brain tumor risk, overall or in subgroup analysis. Conclusions Compared with a BMI of 18 to less than 23.5 kg per m2, a higher BMI was associated with higher risk of brain tumor, particularly in men and with meningioma.

Telomerase reverse transcriptase promoter (TERTp) hotspot mutations are the most frequent mutations in primary glioblastomas (GBM). Previous studies have shown that the combination of TERTp and isocitrate dehydrogenase (IDH) status may serve as a useful diagnostic marker for oligodendroglioma and glioblastoma. In oligodendrogliomas, TERTp and IDH mutations, along with the 1p/19q codeletion, usually coexist and are likely to be founder mutations. However, in contrast to oligodendroglioma, the role of the TERTp status in GBM remains obscure. Here, we used Sanger sequencing, pyrosequencing, and digital PCR (dPCR) to examine the TERTp status in 15 pairs of frozen tissue samples from primary and recurrent IDH wild-type GBM, all of which were operated in a single institute. We showed that the TERTp status was stable between primary and recurrent GBM but this consistency was only detected by dPCR. The results suggest that dPCR is a powerful, highly sensitive tool to detect TERTp mutations, especially in a mixed cell population (e.g., a recurrent GBM tissue) where earlier treatment may have grossly altered the tumor microenvironment.

Background: To determine factors that delay surgical recovery and increase intraoperative hemorrhage in skull base surgery. Methods: Factors related to delayed postoperative recovery were retrospectively reviewed in 33 patients who underwent open skull base surgery. Early and late recovery phases were assessed as “days required to walk around the ward (DWW)” and “length of hospital stay (LHS),” respectively. Intraoperative blood loss was cal­culated every hour and analyzed in 4 steps, i.e., craniotomy and intracranial manipulation, cranial fossa osteotomy, extracranial osteotomy, and reconstruction. Results: More than 4,000 mL of blood loss (B = 2.7392, Exp[B] = 15.4744; 95% CI 1.1828–202.4417) and comorbidi­ty (B = 2.3978, Exp[B]) = 10.9987; 95% CI 1.3534–98.3810) significantly prolonged the DWW; the occurrence of postoperative complications significantly delayed the LHS (p = 0.0316). Tumor invasion to the hard palate, the maxillary sinus, the pterygopalatine fossa, the base of the pterygoid process, the sphenoid sinus, the middle cranial fossa, and the cavernous sinus and a long operation time (>13 h) were associated with increased total hemorrhage. The optimal cut-off hemorrhage volume associated with total massive blood loss in craniotomy and intracranial manipulation (AUC = 0.8364), cranial fossa osteotomy (AUC = 0.8000), and extracranial osteotomy (AUC = 0.8545) was 1,111, 750, and 913 mL, respectively. Persistent infection (6%) and neuropsychiatric disorder (6%) are direct causes of delayed LHS. Conclusion: Blood loss, comorbidity, and postoperative complications were risk factors for delayed surgical recovery. Meticulous preoperative planning, intraoperative surefire hemostasis, and perioperative holistic management are prerequisites for safe skull base surgery.

BackgroundThe safety, tolerability, efficacy, and pharmacokinetics of tirabrutinib, a second-generation, highly selective oral Bruton’s tyrosine kinase inhibitor, were evaluated for relapsed/refractory primary central nervous system lymphoma (PCNSL).MethodsPatients with relapsed/refractory PCNSL, Karnofsky performance status ≥70, and normal end-organ function received tirabrutinib 320 and 480 mg once daily (q.d.) in phase I to evaluate dose-limiting toxicity (DLT) within 28 days using a 3 + 3 dose escalation design and with 480 mg q.d. under fasted conditions in phase II.ResultsForty-four patients were enrolled; 20, 7, and 17 received tirabrutinib at 320, 480, and 480 mg under fasted conditions, respectively. No DLTs were observed, and the maximum tolerated dose was not reached at 480 mg. Common grade ≥3 adverse events (AEs) were neutropenia (9.1%), lymphopenia, leukopenia, and erythema multiforme (6.8% each). One patient with 480 mg q.d. had grade 5 AEs (pneumocystis jirovecii pneumonia and interstitial lung disease). Independent review committee assessed overall response rate (ORR) at 64%: 60% with 5 complete responses (CR)/unconfirmed complete responses (CRu) at 320 mg, 100% with 4 CR/CRu at 480 mg, and 53% with 6 CR/CRu at 480 mg under fasted conditions. Median progression-free survival was 2.9 months: 2.1, 11.1, and 5.8 months at 320, 480, and 480 mg under fasted conditions, respectively. Median overall survival was not reached. ORR was similar among patients harboring CARD11, MYD88, and CD79B mutations, and corresponding wild types.ConclusionThese data indicate favorable efficacy of tirabrutinib in patients with relapsed/refractory PCNSL.Trial registrationJapicCTI-173646.

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. 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. 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. 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.

Objective The MD Anderson Symptom Inventory for Brain Tumor (MDASI-BT) module is a widely used instrument for measuring symptom burden and interference of daily activities in brain tumor patients. This study aims to develop and validate its Japanese version (MDASI-BT-Japanese). Methods Following forward and backward translation of the original MDASI-BT into Japanese, understandability and feasibility were assessed by cognitive debriefing. Subsequently, patients with brain tumors were asked to fill out MDASI-BT-Japanese and European Quality of Life-5 Dimensions (EQ-5D). Feasibility, reliability and validity of MDASI-BT-Japanese were assessed. Results Cognitive debriefing confirmed overall ease of completion and good understandability. The study population composed of 140 patients with brain tumors (most commonly gliomas). The mean symptom severity score and mean interference score were 1.9 ± 1.7 and 2.8 ± 2.7, respectively. The top items included distress and drowsiness for symptom severity and general activity and work for interference. The median time required was 4 minutes (range, 0.5–30), and missing values were seen in 1%. Internal consistency was proven by excellent Cronbach’s coefficient alpha (0.94 for symptom severity, 0.92 for interference). Test–retest reliability was assessed with acceptable intra-class correlation coefficient (mean, 0.76). Correlation efficient ranged between 0.7 and 0.9 for convergent validity. Known-group validity was confirmed by significantly different mean symptom severity score and mean interference score among patients with different performance status. As evidence of concurrent validity, MDASI-BT-Japanese correlated with EQ-5D in the hypothesized magnitude and direction. Conclusions The newly developed MDASI-BT-Japanese has demonstrated feasibility, reliability and validity in evaluation of clinical benefit in Japanese-speaking brain tumor patients.

Human coenurosis is caused by the larval stages of Taenia species, mainly Taenia multiceps and Taenia serialis. T. multiceps has been reported to cause human central nervous system (CNS) infections, but no CNS case caused by T. serialis has been reported. The authors report the first case of human neurocoenurosis caused by T. serialis, which was confirmed by mitochondrial DNA analysis. A 38-year-old man presented with visual disturbance and headache, and subsequent magnetic resonance imaging (MRI) revealed a ring-enhancing cystic lesion in the left occipital lobe. Biopsy was performed, and the resultant histopathological diagnosis was that of low-grade B-cell lymphoma. Chemotherapy was initiated, but a subsequent MRI showed increased ring enhancement. Due to the unexpected clinical course, a surgical resection of the lesion was performed. The lesion was completely removed. Pathological examination showed multiple scolices with hooklets, suckers, and numerous calcareous corpuscles. Therefore, the diagnosis of neurocysticercosis was made. However, mitochondrial DNA analysis showed that the disease was definitively coenurosis caused by T. serialis. Albendazole was administered, with no evidence of recurrence at 12 months following the operation. In this study, we demonstrate that T. serialis can cause CNS infection and that genetic analysis is recommended to establish a definitive diagnosis.

BACKGROUND The importance of detecting the genomic status of gliomas is increasingly recognized and IDH (isocitrate dehydrogenase) mutation and TERT (telomerase reverse transcriptase) promoter mutation have a significant impact on treatment decisions. Noninvasive prediction of these genomic statuses in gliomas is a challenging problem; however, a deep learning model using magnetic resonance imaging (MRI) can be a solution. The image differences among facilities causing performance degradation, called domain shift, have also been reported in other tasks such as brain tumor segmentation. We investigated whether a deep learning model could predict the gene status, and if so, to what extent it would be affected by domain shift. METHOD We used the Multimodal Brain Tumor Segmentation Challenge (BraTS) data and the Japanese cohort (JC) dataset consisted of brain tumor images collected from 544 patients in 10 facilities in Japan. We focused on IDH mutation and TERT promoter mutation. The deep learning models to predict the statuses of these genes were trained by the BraTS dataset or the training portion of the JC dataset, and the test portion of the JC dataset evaluated the accuracy of the models. RESULTS The IDH mutation predicting model trained by the BraTS dataset showed 80.0% accuracy for the validation portion of the BraTS dataset; however, only 67.3% for the test portion of the JC dataset. The TERT promoter mutation predicting model trained by the training portion of the JC dataset showed only 49% accuracy for the test portion of the JC dataset. CONCLUSION IDH mutation can be predicted by deep learning models using MRI, but the performance degeneration by domain shift was significant. On the other hand, TERT promoter mutation could not be predicted accurately enough by current deep learning techniques. In both mutations, further studies are needed.

Objective With an increase in the number of imaging examinations and the development of imaging technology, a small number of glioblastomas (GBMs) are identified by incidental radiological images. These incidentally discovered glioblastomas (iGBMs) are rare, and their clinical features are not well understood. Here, we investigated the clinical characteristics and outcomes of iGBM. Methods Data of newly diagnosed iGBM patients who were treated at our institution between August 2005 and October 2019 were reviewed. An iGBM was defined as a GBM without a focal sign, discovered on radiological images obtained for reasons unrelated to the tumor. Kaplan-Meier analysis was performed to calculate progression-free survival (PFS) and overall survival (OS). Results Of 234 patients with newly diagnosed GBM, four (1.7%) were classified as having iGBM. Health screening was the most common reason for tumor discovery (75.0%). The preoperative Karnofsky performance status score was 100 in three patients. Tumors were found on the right side in three cases. The mean volume of preoperative enhanced tumor lesion was 16.8 cm3. The median duration from confirmation of an enhanced lesion to surgery was 13.5 days. In all cases, either total (100%) or subtotal (95–99%) resections were achieved. The median PFS and OS were 11.5 and 20.0 months, respectively. Conclusions The iGBMs were often small and in the right non-eloquent area, and the patients had good performance status. We found that timely therapeutic intervention provided iGBM patients with favorable outcomes. This report suggests that early detection of GBM may lead to a better prognosis.

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 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.

BACKGROUND Neurocognitive deficits are common among brain tumour patients, and may impact on patient awareness of deficits in instrumental activities in daily life (IADL). This study aimed to examine differences between patient-reported and proxy-reported assessments of the patient’s performance of IADL, and whether the level of (dis)agreement is associated with neurocognitive deficits. MATERIAL AND METHODS A phase III EORTC questionnaire measuring IADL in brain tumour patients (EORTC IADL-BN32) and six neurocognitive test measures were administered as part of a larger multicentre international study designed to develop a brain tumour specific IADL questionnaire. Bland-Altman plots and Mann-Whitney U tests were used to evaluated patient- and proxy-reported IADL on a group level. Subsequently, Mann-Whitney U tests were performed to compare patient-proxy difference scores (patient IADL score - their proxy IADL score) between patients who were considered clearly neurocognitively impaired (≥2 neurocognitive test measures; ≤2.0 SD below healthy controls) and patients who were not. Furthermore, multinomial logistic regression analyses were performed to examined which sociodemgraphic, clinical, and particularly neurocognitive variables were independently associated with patients and proxies differing in their evaluation of patient’s IADL. RESULTS Patients (N=81) and proxies (N=81), on group level, did not significantly differ on either the IADL individual item or scale scores. However, significant differences were found on patient-proxy difference scores between patients who were (N=37) and were not (N=44) considered clearly neurocognitively impaired for 10/32 individual items and one of the scales (i.e. Scale 4: Administrative tasks), all showing that the proxies of clearly neurocognitively impaired patients reported more problems relative to the patients themselves, compared to proxies of patients not clearly neurocognitively impaired. Furthermore, for each scale, a neurocognitive variable, either impaired information processing speed, cognitive flexibility, verbal fluency or the number of neurocognitive test measures impaired, was found to be independently associated with proxies reporting more problems. For 4/5 scales, a clinical variable was additionally independently associated with proxies reporting more problems. Only one variable was independently associated with patient reporting more problems, namely being in active treatment was found to be associated with patients reporting more problems on Scale 4: Administrative tasks. CONCLUSION Results imply a consistent trend of clearly neurocognitively impaired patients underreporting problems with IADL compared to their proxies. It would therefore be advised to administer both the patient- and proxy-version of the EORTC IADL-BN32, particularly if neurocognitive deficits are presumed.

To treat malignant glioma, standard fractionated radiotherapy (RT, 60 Gy/30 fractions over 6 weeks) was performed post-surgery in combination with temozolomide to improve overall survival. Malignant glioblastoma recurrence rate is extremely high, and most recurrent tumors originate from the excision cavity in the high-dose irradiation region. In our previous study, protoporphyrin IX physicochemically enhanced reactive oxygen species generation by ionizing radiation and combined treatment with 5-aminolevulinic acid (5-ALA) and ionizing radiation, while radiodynamic therapy (RDT) improved tumor growth suppression in vivo in a melanoma mouse model. We examined the effect of 5-ALA RDT on the standard fractionated RT protocol using U251MG- or U87MG-bearing mice. 5-ALA was orally administered at 60 or 120 mg/kg, 4 h prior to irradiation. In both models, combined treatment with 5-ALA slowed tumor progression and promoted regression compared to treatment with ionizing radiation alone. The standard fractionated RT protocol of 60 Gy in 30 fractions with oral administration of 120 and 240 mg/kg 5-ALA, the human equivalent dose of photodynamic diagnosis, revealed no significant increase in toxicity to normal skin or brain tissue compared to ionizing radiation alone. Thus, RDT is expected to enhance RT treatment of glioblastoma without severe toxicity under clinically feasible conditions.

“Stroke mimics” mean diseases presenting with acute neurological impairments that are taken for stroke. Discriminating them is crucial to avoid improper treatment or delayed correct treatment. We describe a 48‐year‐old woman presenting with a sudden onset of scintillating scotoma and left‐lower quadrantanopsia. Hyperacute cerebral infarction was suspected. However, brain magnetic resonance imaging (MRI) revealed a mass at the cortico‐medullary junction in the right occipital lobe. We diagnosed her as metastatic melanoma. We suspected that neurological deficits can be attributed to seizure, and therefore introduced levetiracetam. She showed neurological improvement immediately. Our case demonstrated the importance of considering brain tumor as a differential diagnosis in patients presenting with acute‐onset neurological deficits. In addition to appropriate treatment of tumor, the use of newer antiepileptic drugs resulted in good neurological prognosis in metastatic brain tumors., Brain MRI and CT showed a mass lesion 2 cm in diameter at the cortico‐medullary junction in right occipital lobe. The findings were typical characteristics of metastatic melanoma.

Aims Alterations in microenvironments are a hallmark of cancer, and these alterations in germinomas are of particular significance. Germinoma, the most common subtype of central nervous system germ cell tumours, often exhibits massive immune cell infiltration intermingled with tumour cells. The role of these immune cells in germinoma, however, remains unknown. Methods We investigated the cellular constituents of immune microenvironments and their clinical impacts on prognosis in 100 germinoma cases. Results Patients with germinomas lower in tumour cell content (i.e. higher immune cell infiltration) had a significantly longer progression-free survival time than those with higher tumour cell contents (P = 0.03). Transcriptome analyses and RNA in-situ hybridization indicated that infiltrating immune cells comprised a wide variety of cell types, including lymphocytes and myelocyte-lineage cells. High expression of CD4 was significantly associated with good prognosis, whereas elevated nitric oxide synthase 2 was associated with poor prognosis. PD1 (PDCD1) was expressed by immune cells present in most germinomas (93.8%), and PD-L1 (CD274) expression was found in tumour cells in the majority of germinomas examined (73.5%). Conclusions The collective data strongly suggest that infiltrating immune cells play an important role in predicting treatment response. Further investigation should lead to additional categorization of germinoma to safely reduce treatment intensity depending on tumour/immune cell balance and to develop possible future immunotherapies.

Background For brain metastases from non-specific primary tumors, the most frequently used and validated clinical prognostic assessment tool is Karnofsky performance status (KPS). Given the lack of prognostic factors of brain metastases from colorectal cancer (CRC) other than KPS, this study aimed to identify new prognostic factors. Methods This retrospective cohort study was conducted at a tertiary care cancer center. Subjects were patients with brain metastases from CRC among all patients who received initial treatment for CRC at the National Cancer Center Hospital from 1997 to 2015 (n = 7147). Prognostic clinicopathological variables for overall survival (OS) were investigated. Results There were 68 consecutive patients with brain metastases from CRC, corresponding to 1.0% of all patients with CRC during the study period. Median survival time was 6.8 months. One-year and 3-year OS rates were 28.0 and 10.1%, respectively. Among the six covariates tested (age, KPS, presence of extracranial metastases, control of primary lesion, number of brain metastases, and history of chemotherapy), multivariate analysis revealed KPS (score ≥ 70), number of brain metastases (1–3), and no history of chemotherapy to be independent factors associated with better prognosis. Conclusions In addition to KPS, the number of brain lesions and history of chemotherapy were independent prognostic factors for OS in patients with brain metastases from CRC. An awareness of these factors may help gastrointestinal surgeons make appropriate choices in the treatment of these patients.

Glioblastoma is one of the most devastating human malignancies for which a novel efficient treatment is urgently required. This pre–clinical study shows that eribulin, a specific inhibitor of telomerase reverse transcriptase (TERT)‐RNA‐dependent RNA polymerase, is an effective anticancer agent against glioblastoma. Eribulin inhibited the growth of 4 TERT promoter mutation‐harboring glioblastoma cell lines in vitro at subnanomolar concentrations. In addition, it suppressed the growth of glioblastoma cells transplanted subcutaneously or intracerebrally into mice, and significantly prolonged the survival of mice harboring brain tumors at a clinically equivalent dose. A pharmacokinetics study showed that eribulin quickly penetrated brain tumors and remained at a high concentration even when it was washed away from plasma, kidney or liver 24 hours after intravenous injection. Moreover, a matrix‐assisted laser desorption/ionization mass spectrometry imaging analysis revealed that intraperitoneally injected eribulin penetrated the brain tumor and was distributed evenly within the tumor mass at 1 hour after the injection whereas only very low levels of eribulin were detected in surrounding normal brain. Eribulin is an FDA‐approved drug for refractory breast cancer and can be safely repositioned for treatment of glioblastoma patients. Thus, our results suggest that eribulin may serve as a novel therapeutic option for glioblastoma. Based on these data, an investigator‐initiated registration‐directed clinical trial to evaluate the safety and efficacy of eribulin in patients with recurrent GBM (UMIN000030359) has been initiated.

Simple Summary Radiogenomics enables prediction of the status and prognosis of patients using non-invasively obtained imaging data. Current machine learning (ML) methods used in radiogenomics require huge datasets, which involve the handling of large heterogeneous datasets from multiple cohorts/hospitals. In this study, two different glioma datasets were used to test various ML and image pre-processing methods to confirm whether the models trained on one dataset are universally applicable to other datasets. Our result suggested that the ML method that yielded the highest accuracy in a single dataset was likely to be overfitted. We demonstrated that implementation of standardization and dimension reduction procedures prior to classification, enabled the development of ML methods that are less affected by the multiple cohort difference. We advocate using caution in interpreting the results of radiogenomic studies of the training and testing datasets that are small or mixed, with a view to implementing practical ML methods in radiogenomics. Abstract Radiogenomics use non-invasively obtained imaging data, such as magnetic resonance imaging (MRI), to predict critical biomarkers of patients. Developing an accurate machine learning (ML) technique for MRI requires data from hundreds of patients, which cannot be gathered from any single local hospital. Hence, a model universally applicable to multiple cohorts/hospitals is required. We applied various ML and image pre-processing procedures on a glioma dataset from The Cancer Image Archive (TCIA, n = 159). The models that showed a high level of accuracy in predicting glioblastoma or WHO Grade II and III glioma using the TCIA dataset, were then tested for the data from the National Cancer Center Hospital, Japan (NCC, n = 166) whether they could maintain similar levels of high accuracy. Results: we confirmed that our ML procedure achieved a level of accuracy (AUROC = 0.904) comparable to that shown previously by the deep-learning methods using TCIA. However, when we directly applied the model to the NCC dataset, its AUROC dropped to 0.383. Introduction of standardization and dimension reduction procedures before classification without re-training improved the prediction accuracy obtained using NCC (0.804) without a loss in prediction accuracy for the TCIA dataset. Furthermore, we confirmed the same tendency in a model for IDH1/2 mutation prediction with standardization and application of dimension reduction that was also applicable to multiple hospitals. Our results demonstrated that overfitting may occur when an ML method providing the highest accuracy in a small training dataset is used for different heterogeneous data sets, and suggested a promising process for developing an ML method applicable to multiple cohorts.

IMPORTANCE: Patients with cancer and health care workers (HCWs) are at high risk of SARS-CoV-2 infection. Assessing the antibody status of patients with cancer and HCWs can help understand the spread of COVID-19 in cancer care. OBJECTIVE: To evaluate serum SARS-CoV-2 antibody status in patients with cancer and HCWs during the COVID-19 pandemic in Japan. DESIGN, SETTING, AND PARTICIPANTS: Participants were enrolled for this prospective cross-sectional study between August 3 and October 30, 2020, from 2 comprehensive cancer centers in the epidemic area around Tokyo, Japan. Patients with cancer aged 16 years or older and employees were enrolled. Participants with suspected COVID-19 infection at the time of enrollment were excluded. EXPOSURES: Cancer of any type and cancer treatment, including chemotherapy, surgery, immune checkpoint inhibitors, radiotherapy, and targeted molecular therapy. MAIN OUTCOMES AND MEASURES: Seroprevalence and antibody levels in patients with cancer and HCWs. Seropositivity was defined as positivity to nucleocapsid IgG (N-IgG) and/or spike IgG (S-IgG). Serum levels of SARS-CoV-2 IgM and IgG antibodies against the nucleocapsid and spike proteins were measured by chemiluminescent enzyme immunoassay. RESULTS: A total of 500 patients with cancer (median age, 62.5 years [range, 21-88 years]; 265 men [55.4%]) and 1190 HCWs (median age, 40 years [range, 20-70 years]; 382 men [25.4%]) were enrolled. In patients with cancer, 489 (97.8%) had solid tumors, and 355 (71.0%) had received anticancer treatment within 1 month. Among HCWs, 385 (32.3%) were nurses or assistant nurses, 266 (22.4%) were administrative officers, 197 (16.6%) were researchers, 179 (15.0%) were physicians, 113 (9.5%) were technicians, and 50 (4.2%) were pharmacists. The seroprevalence was 1.0% (95% CI, 0.33%-2.32%) in patients and 0.67% (95% CI, 0.29%-1.32%) in HCWs (P = .48). However, the N-IgG and S-IgG antibody levels were significantly lower in patients than in HCWs (N-IgG: β, −0.38; 95% CI, −0.55 to −0.21; P

Isocitrate dehydrogenase-mutant low-grade gliomas (IDHmut-LGG) grow slowly but frequently undergo malignant transformation, which eventually leads to premature death. Chemotherapy and radiotherapy treatments prolong survival, but can also induce genetic (or epigenetic) alterations involved in transformation. Here, we developed a mathematical model of tumor progression based on serial tumor volume data and treatment history of 276 IDHmut-LGGs classified by chromosome 1p/19q codeletion (IDHmut/1p19qcodel and IDHmut/1p19qnoncodel) and performed genome-wide mutational analyses, including targeted sequencing and longitudinal whole-exome sequencing data. These analyses showed that tumor mutational burden correlated positively with malignant transformation rate, and chemotherapy and radiotherapy significantly suppressed tumor growth but increased malignant transformation rate per cell by 1.8 to 2.8 times compared with before treatment. This model revealed that prompt adjuvant chemoradiotherapy prolonged malignant transformation-free survival in small IDHmut-LGGs (≤ 50 cm3). Furthermore, optimal treatment differed according to genetic alterations for large IDHmut-LGGs (> 50 cm3); adjuvant therapies delayed malignant transformation in IDHmut/1p19qnoncodel but often accelerated it in IDHmut/1p19qcodel. Notably, PI3K mutation was not associated with malignant transformation but increased net postoperative proliferation rate and decreased malignant transformation-free survival, prompting the need for adjuvant therapy in IDHmut/1p19qcodel. Overall, this model uncovered therapeutic strategies that could prevent malignant transformation and, consequently, improve overall survival in patients with IDHmut-LGGs. Significance: A mathematical model successfully estimates malignant transformation-free survival and reveals a link between genetic alterations and progression, identifying precision medicine approaches for optimal treatment of IDH-mutant low-grade gliomas.

Background and ObjectivesMutant isocitrate dehydrogenase (IDH) 1/2 gene products gain a new ability to produce D-2-hydroxyglutarate (D2HG). IDH1/2 mutations are thought to be associated with seizures owing to the structural similarity between D2HG and glutamate. However, the effects of D2HG on seizures in clinical settings are not fully understood. We sought to investigate the relationship between tissue 2-hydroxyglutarate (2HG) concentration and preoperative seizures using clinical samples.MethodsWe included 104 consecutive patients with diffuse glioma who underwent surgery from August 2008 to May 2016 and whose clinical presentation and IDH1/2 status were identified. The presence of preoperative seizures, tumor location, histopathologic diagnosis, IDH1/2 status, and 1p/19q codeletion were assessed from the patient charts. Tissue 2HG concentration was measured using liquid chromatography–tandem mass spectrometry. To evaluate 2HG distribution without artefactual tissue disruption, we applied matrix-assisted laser desorption/ionization high-resolution mass spectrometry imaging (MALDI-MSI) in 12 patients' surgically resected samples. We assessed the correlation of preoperative seizures with tissue 2HG concentration, IDH1/2 status, WHO grade, and 1p/19q codeletion.ResultsTissue 2HG concentration was higher in IDH1/2 mutant tumors (IDH-Mut, n = 42) than in IDH1/2 wild-type tumors (IDH-WT, n = 62) (median 4,860 ng/mg vs 75 ng/mg) (p < 0.0001). MALDI-MSI could detect 2HG signals in IDH-Mut, but not in IDH-WT. Preoperative seizures were observed in 64.3% of patients with IDH-Mut and 21.0% patients with IDH-WT (p < 0.0001). The optimal cutoff value of tissue 2HG concentration for predicting preoperative seizures was 1,190 ng/mg, as calculated by the receiver operating characteristic curve. Increased preoperative seizure risk was only observed in tumors with 2HG concentration above the cutoff value among IDH-Mut (IDH-Mut with above the cutoff value: 71.4% vs IDH-Mut with below the cutoff value: 28.6%; p = 0.031). Multivariate analysis, including IDH1/2 mutation status, tissue 2HG concentration, WHO grade, and 1p/19q codeletion, revealed that only increased tissue 2HG concentration was associated with preoperative seizures (odds ratio 5.86, 95% confidence interval 1.02–48.5; p = 0.048).DiscussionWe showed that high tissue 2HG concentration was associated with preoperative seizures, suggesting that excess 2HG increases risk of preoperative seizures in IDH1/2 mutant tumors.

Glioblastoma (GBM) is the most common, but extremely malignant, brain tumor; thus, the development of novel therapeutic strategies for GBMs is imperative. Many tyrosine kinase inhibitors (TKIs) have been approved for various cancers, yet none has demonstrated clinical benefit against GBM. Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) that is confirmed only during the embryonic development period in humans. In addition, various ALK gene alterations are known to act as powerful oncogenes and therapeutic targets in various tumors. The antitumor activity of various TKIs was tested against three human GBM cell lines (U87MG, LN229, and GSC23), which expressed substantially low ALK levels; second‐generation ALK inhibitors, alectinib and ceritinib, effectively induced GBM cell death. In addition, treatment with either alectinib or ceritinib modulated the activation of various molecules downstream of RTK signaling and induced caspase‐dependent/‐independent cell death mainly by inhibiting signal transducer and activator of transcription 3 activation in human GBM cells. In addition, alectinib and ceritinib also showed antitumor activity against a U87MG cell line with acquired temozolomide resistance. Finally, oral administration of alectinib and ceritinib prolonged the survival of mice harboring intracerebral GBM xenografts compared with controls. These results suggested that treatment with the second‐generation ALK inhibitors, alectinib and ceritinib, might serve as a potent therapeutic strategy against GBM., Anaplastic lymphoma kinase (ALK) inhibitors, alectinib and ceritinib, demonstrated antitumor activity for glioblastoma (GBM) cells which expressed substantially low ALK levels in vitro and in vivo. Treatment with either alectinib or ceritinib induced cell death mainly by inhibiting signal transducer and activator of transcription 3 activation in GBM cells. Alectinib and ceritinib might serve as potent therapeutic agents against GBM.

Recurrent C11orf95-RELA fusions (RELAFUS) are the hallmark of supratentorial ependymomas. The presence of RELA as the fusion partner indicates a close association of aberrant NF-κB activity with tumorigenesis. However, the oncogenic role of the C11orf95 has not been determined. Here, we performed ChIP-seq analyses to explore genomic regions bound by RELAFUS and H3K27ac proteins in human 293 T and mouse ependymoma cells. We then utilized published RNA-Seq data from human and mouse RELAFUS tumors and identified target genes that were directly regulated by RELAFUS in these tumors. Subsequent transcription factor motif analyses of RELAFUS target genes detected a unique GC-rich motif recognized by the C11orf95 moiety, that is present in approximately half of RELAFUS target genes. Luciferase assays confirmed that a promoter carrying this motif is sufficient to drive RELAFUS-dependent gene expression. Further, the RELAFUS target genes were found to be overlapped with Rela target genes primarily via non-canonical NF-κB binding sites. Using a series of truncation and substitution mutants of RELAFUS, we also show that the activation domain in the RELAFUS moiety is necessary for the regulation of gene expression of these RELAFUS target genes. Lastly, we performed an anti-cancer drug screening with mouse ependymoma cells and identified potential anti-ependymoma drugs that are related to the oncogenic mechanism of RELAFUS. These findings suggested that RELAFUS might induce ependymoma formation through oncogenic pathways orchestrated by both C11orf95 and RELA target genes. Thus, our study unveils a complex gene function of RELAFUS as an oncogenic transcription factor in RELAFUS positive ependymomas.

Purpose Being able to function independently in society is an important aspect of quality of life. This ability goes beyond self-care, requires higher order cognitive functioning, and is typically measured with instrumental activities of daily living (IADL) questionnaires. Cognitive deficits are frequently observed in brain tumour patients, however, IADL is almost never assessed because no valid and reliable IADL measure is available for this patient group. Therefore, this measure is currently being developed. Methods This international multicentre study followed European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Group module development guidelines. Three out of four phases are completed: phases (I) generation of items, (II) construction of the item list, and (III) pre-testing. This paper reports the item selection procedures and preliminary psychometric properties of the questionnaire. Brain tumour patients (gliomas and brain metastases), their informal caregivers, and health care professionals (HCPs) were included. Results Phase I (n = 44 patient-proxy dyads and 26 HCPs) generated 59 relevant and important activities. In phase II, the activities were converted into items. In phase III (n = 85 dyads), the 59 items were pre-tested. Item selection procedures resulted in 32 items. Exploratory factor analysis revealed a preliminary dimensional structure consisting of five scales with acceptable to excellent internal consistency (α = 0.73–0.94) and two single items. For three scales, patients with cognitive impairments had significantly more IADL problems than patients without impairments. Conclusion A phase IV validation study is needed to confirm the psychometric properties of the EORTC IADL-BN32 questionnaire in a larger international sample.

Background: This study evaluated the outcomes of reirradiation combined with bevacizumab (Bev) for patients with recurrent high-grade gliomas that progressed after treatment with Bev.Methods: Between January 2015 and September 2019, 14 patients who experienced progression after Bev treatment were treated with reirradiation consisting of 25 Gy in five fractions combined with Bev (ReRT/Bev). The isocitrate dehydrogenase (IDH) 1/2 mutation status was analysed by pyrosequencing. Results: The diagnoses of 14 patients at the time of reirradiation included six cases of glioblastoma (GBM) with IDH-wildtype, four cases of GBM with IDH-mutant, one case of anaplastic astrocytoma (AA) with IDH-wildtype, one case of AA with IDH-mutant, and one case of GBM not otherwise specified (NOS), and one case of radiologically diagnosed brainstem glioma. The median overall survival (OS) and progression-free survival (PFS) times with ReRT/Bev were 6.1 months and 3.8 months, respectively. The 6-month OS and PFS rates were 54.5% and 15.7%, respectively. The median OS and PFS did not differ significantly between patients with IDH-wildtype (N=7) and IDH-mutant (N=5) (OS: 7.3 [wildtype] vs 6.0 [mutant] months, p = 0.64; PFS: 3.8 [wildtype] vs 3.7 [mutant] months, p = 0.56). The median OS and PFS did not differ significantly between patients with a diagnosis of GBM (N=6) and those with a diagnosis of non-GBM (N=7) (OS: 9.3 [GBM] vs 6.0 [non-GBM] months, p = 0.19; PFS: 4.0 [GBM] vs 3.8 [non-GBM] months, p = 0.31). Four patients (28.6%) achieved a complete or partial radiological response and three patients (21.4%) experienced improvement after ReRT/Bev. Tumor recurrences were observed in 12 patients, including 3 (21.4%) in-field recurrence; 5 (35.7%) marginal recurrence, 3 (21.4%) out-field recurrence, and 1 (7.1%) had in-field and out-field recurrence. Grade 3/4 toxicities included leukopenia in four patients (28.6%), hypertension in three (21.4%), proteinuria in one (7.1%), and gastrointestinal haemorrhage in one (7.1%) with ReRT/Bev. Conclusions: ReRT/Bev for patients with high-grade glioma who experienced progression after Bev was effective and involved acceptable toxicities.

Introduction: Germ cell tumors (GCTs) are uncommon neoplasms predominantly arising in midline tissues. The prognostic significance of histopathology in predicting metastatic GCT behavior is poorly understood. Methods: Multicenter international cohort study including 29 patients with GCTs metastatic to brain were retrospectively investigated (18 patients from Mayo Clinic and 11 patients from the intracranial germ cell tumor genome analysis consortium in Japan). Clinical characteristics were analyzed using the Chi-square test (two-tailed) for categorical variables and using the log-rank test for survival data. Results: Median age at treatment was 31years (range 14–58). Primary disease sites were testis (71%), mediastinum (18%), and female reproductive organs (11%). Median metastatic interval was 223days (range, 6–6124). Median follow-up was 346days (range, 1–5356), with 16 deaths (57%) occurring after the median overall survival of 455days. Actuarial one-year survival was 51%; 12-of-16 deaths (75%) were attributed to intracranial disease. Appearance of the same GCT subtype at the metastatic site as the primary was high for non-seminomatous GCT (NSGCT, 64–100%), but low for seminoma/dysgerminoma and mature teratoma (MT, 14, 17%, respectively). Gain of a new component was seen in 4 (20%)—3 of which included embryonal carcinoma (EC) at the primary site (75%). Incidence of cases without seminoma/dysgerminoma increased significantly after metastasis (p = 0.02). Metastatic interval was shorter in cases with histological change (199 vs 454days, p = 0.009). Overall survival was associated with MT primary histopathology (p = 0.02). Conclusion: Histological differentiation at the primary GCT site influences metastatic prognosis. Aggressive behavior is associated with NSGCT, while EC frequently demonstrates multi-directional histological differentiation after brain metastasis, and such histological dynamism is associated with shorter metastatic interval. Most metastases occurred within one year of diagnosis, emphasizing the need for close surveillance in newly diagnosed extra-cranial GCT.

Background Cerebrospinal fluid (CSF) cytology and spinal MR imaging are routinely performed for staging before treatment of intracranial germinoma. However, the interpretation of the results of CSF cytology poses 2 unresolved clinical questions: (1) Does positive CSF cytology correlate with the presence of spinal lesion before treatment? and (2) Is craniospinal irradiation (CSI) necessary for patients with positive CSF cytology in the absence of spinal lesion? Methods Multicenter retrospective analyses were performed based on a questionnaire on clinical features, spinal MR imaging finding, results of CSF cytology, treatments, and outcomes which was sent to 86 neurosurgical and 35 pediatrics departments in Japan. Pretreatment frequencies of spinal lesion on MR imaging were compared between the patients with positive and negative cytology. Progression-free survival (PFS) rates were compared between patients with positive CSF cytology without spinal lesion on MR imaging treated with CSI and with whole brain or whole ventricular irradiation (non-CSI). Results A total of 92 germinoma patients from 45 institutes were evaluated by both CSF cytology and spinal MR images, but 26 patients were excluded because of tumor markers, the timing of CSF sampling or incomplete estimation of spinal lesion. Of the remaining 66 germinoma patients, spinal lesions were equally identified in patients with negative CSF cytology and positive cytology (4.9% and 8.0%, respectively). Eleven patients treated with non-CSI had excellent PFS comparable to 11 patients treated with CSI. Conclusion CSI is unnecessary for germinoma patients with positive CSF cytology without spinal lesions on MR imaging.

Background Boron neutron capture therapy (BNCT) utilizes tumor-selective particle radiation. This study aimed to assess the safety and efficacy of accelerator-based BNCT (AB-BNCT) using a cyclotron-based neutron generator (BNCT 30) and 10B-boronophenylalanine (SPM-011) in patients with recurrent malignant glioma (MG) (primarily glioblastoma [GB]). Methods This multi-institutional, open-label, phase II clinical trial involved 27 recurrent MG cases, including 24 GB cases, who were enrolled from February 2016 to June 2018. The study was conducted using the abovementioned AB-BNCT system, with 500 mg/kg SPM-011 (study code: JG002). The patients were bevacizumab-naïve and had recurrent MG after standard treatment. The primary endpoint was the 1-year survival rate, and the secondary endpoints were overall survival (OS) and progression-free survival (PFS). Results were compared to those of a previous Japanese domestic bevacizumab trial for recurrent GB (JO22506). Results The 1-year survival rate and median OS of the recurrent GB cases in this trial were 79.2% (95% CI: 57.0–90.8) and 18.9 months (95% CI: 12.9–not estimable), respectively, whereas those of JO22506 were 34.5% (90% CI: 20.0–49.0) and 10.5 months (95% CI: 8.2–12.4), respectively. The median PFS was 0.9 months (95% CI: 0.8–1.0) by the RANO criteria. The most prominent adverse event was brain edema. Twenty-one of 27 cases were treated with bevacizumab following progressive disease. Conclusions AB-BNCT demonstrated acceptable safety and prolonged survival for recurrent MG. AB-BNCT may increase the risk of brain edema due to re-irradiation for recurrent MG; however, this appears to be controlled well with bevacizumab.

The current research tested the hypothesis that inversion time (TI) shorter than 2,400 ms under 3T for FLAIR can improve the diagnostic accuracy of the T2-FLAIR mismatch sign for identifying IDHmt, non-CODEL astrocytomas. We prepared three different cohorts; 94 MRI from 76 IDHmt, non-CODEL Lower-grade gliomas (LrGGs), 33 MRI from 31 LrGG under the restriction of FLAIR being acquired with TI < 2,400 ms for 3T or 2,016 ms for 1.5T, and 112 MRI from 112 patients from the TCIA/TCGA dataset for LrGG. The presence or absence of the “T2-FLAIR mismatch sign” was evaluated, and we compared diagnostic accuracies according to TI used for FLAIR acquisition. The T2-FLAIR mismatch sign was more frequently positive when TI was shorter than 2,400 ms under 3T for FLAIR acquisition (p = 0.0009, Fisher’s exact test). The T2-FLAIR mismatch sign was positive only for IDHmt, non-CODEL astrocytomas even if we confined the cohort with FLAIR acquired with shorter TI (p = 0.0001, Fisher’s exact test). TCIA/TCGA dataset validated that the sensitivity, specificity, PPV, and NPV of the T2-FLAIR mismatch sign to identify IDHmt, non-CODEL astrocytomas improved from 31, 90, 79, and 51% to 67, 94, 92, and 74%, respectively and the area under the curve of ROC improved from 0.63 to 0.87 when FLAIR was acquired with shorter TI. We revealed that TI for FLAIR impacts the T2-FLAIR mismatch sign’s diagnostic accuracy and that FLAIR scanned with TI < 2,400 ms in 3T is necessary for LrGG imaging.

Although surgical resection is the most preferred treatment for intracranial meningiomas, a detailed analysis of the surgery-related risks based on large population data has not been conducted to date. In this study, we analyzed the nation-wide brain tumor registry to assess the surgical risk factors for intracranial meningiomas to provide information for an optimal treatment strategy. Data of 4081 meningioma patients who underwent initial resection between 2001 and 2008 were extracted from the Brain Tumor Registry of Japan (BTRJ) database and reviewed for postoperative mortality, aggravation of Karnofsky Performance Score (KPS), and complications. The total in-hospital mortality rate was 0.59%. Male sex and tumor size ≥30 mm were independent risk factors for mortality. Among 4081 cases, 4.4% of patients had KPS that were lowered by 20 or more points at the time of discharge after surgery. Age ≥65 years, higher WHO grading, tumor location at the skull base, tumor size ≥30 mm, and non-gross total resections were associated with lowering of KPS scores by 20 or more points. The overall incidence of surgical complications was 19.3%. The rate of occurrence of new postoperative seizure in patients with supratentorial meningioma was 10.9%. All complications except for vascular complications occurred with significantly lower frequencies in asymptomatic patients than in symptomatic patients. Our results provide useful information regarding the surgical risks when surgical intervention is being considered for intracranial meningiomas. Surgery is an important option for asymptomatic meningiomas as the mortality rate and complication rate in the current study were sufficiently low.

Palliative care and advance care planning (ACP) from the first diagnosis of glioblastoma are important. This questionnaire survey was conducted to understand the current status of palliative care for brain tumors in Japan. Representative characteristics of Japan in comparison with Western countries (P

BACKGROUND In BIOMARK trial, patients with newly diagnosed glioblastoma were treated with standard chemoradiotherapy combined with first-line bevacizumab; a subset of patients continued bevacizumab beyond progression (BBP). Neurocognitive function (NCF), symptom burden, and health-related quality of life (HRQoL) were examined as secondary endpoints. PATIENTS AND METHODS In the primary protocol, newly diagnosed glioblastoma patients aged 20-75 received standard 6-week radiotherapy combined with temozolomide and bevacizumab followed by 4-week cycles of temozolomide plus bevacizumab, and then 2-3-week cycles of bevacizumab monotherapy. Upon recurrence, patients were subjected to the secondary protocol with 2-3-week cycles of bevacizumab monotherapy with or without other chemotherapeutic agents. NCF tests (Hopkins verbal learning test-revised, trail making test, and controlled oral word association), EORTC QLQ-C30/BN20, and MDASI-BT were completed by the patients. Time to deterioration (TTD) was defined as the time from randomization until a pre-specified change from baseline without further improvement or death. The Kaplan-Meier method and the log-rank test were used to assess TTD for each subscale of the above tests. RESULTS Overall, 94 patients were enrolled in the study. Analyses were based on the full analysis set cohort (N=90), excluding non-glioblastoma diagnosis by central review. The median overall survival (OS) and progression-free survival (PFS) were 25.0 and 14.9 months, respectively. Baseline HRQoL and symptom burden subscales (emotional functioning, symptom severity score, affective factor, and focal factor) were significantly associated with PFS. The median TTD was 8.7, 7.5, 8.1 months for global health status/QoL, symptom severity score, interference score, respectively. Among patients who experienced recurrence, disease progression was apparently preceded by deterioration in terms of symptom burden. CONCLUSIONS Detailed analysis of HRQoL and symptom burden may aid care of glioblastoma patients throughout the disease trajectory.

BACKGROUND Boron neutron capture therapy (BNCT) is tumor-selective particle radiation and theoretically efficacious especially for tumors with infiltrative nature, such as glioblastoma (GBM). The aim of this study is to assess safety and efficacy of accelerator-based BNCT (AB-BNCT) using cyclotron-based neutron generator, BNCT30, and 10B-boronophenylalanine (borofalan(10B)) agent, SPM-011, in patients with recurrent malignant gliomas, chiefly GBM. METHODS The multi-institutional open-label, phase II clinical trial for recurrent 27 cases of malignant gliomas (MG) (24 cases were GBM) was conducted with above AB-BNCT system, using 500mg/kg of SPM-011 (study code, JG002). The patients were enrolled from February 2016 to June 2018. The inclusion criteria are bevacizumab-naïve MG, recurrent after standard treatment composed of XRT and chemotherapy with TMZ. Neutron-irradiation time were determined not to exceed to 8.5 Gy-Eq for scalp dose. Primary endpoint was 1-year survival rate and secondary ones were median overall survival (mOS), median progression free survival (mPFS). The results were compared to previous Japanese domestic bevacizumab trial for recurrent GBM (JO22506) which had the similar inclusion criteria with JG002. RESULTS 1-year survival rate and mOS of recurrent GBM cases in JG002 was 79.2% (95% CI:57.0–90.8) and 18.7 months (95% CI:12.9–23.4) respectively, while those of JO22506 was 34.5% (90% CI:20.0–49.0) and 10.5 months (95% CI:8.2–12.4), respectively. Median PFS of JG002 and JO22506 were 0.9 and 3.3 months, respectively. Most important adverse event in JG002 was brain edema. Brain edema in 21 out of 27 cases was treated with bevacizumab after progress disease. CONCLUSIONS AB-BNCT demonstrated acceptable safety and prolonged survival for recurrent MG chiefly GBM. AB-BNCT might produce brain edema somewhat after the treatment, which might be the unavoidable adverse event of re-irradiation for recurrent MG, however that seemed to be controlled well with bevacizumab.

Purpose: BAY1436032, an inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1), was active against multiple IDH1-R132X solid tumors in preclinical models. This first-in-human study was designed to determine the safety and pharmacokinetics of BAY1436032, and to evaluate its potential pharmacodynamics and antitumor effects. Patients and Methods: The study comprised of dose escalation and dose expansion cohorts. BAY1436032 tablets were orally administered twice daily on a continuous basis in subjects with mIDH1 solid tumors. Results: In dose escalation, 29 subjects with various tumor types were administered BAY1436032 across five doses (150–1,500 mg twice daily). BAY1432032 exhibited a relatively short half-life. Most evaluable subjects experienced target inhibition as indicated by a median maximal reduction of plasma R-2-hydroxyglutarate levels of 76%. BAY1436032 was well tolerated and an MTD was not identified. A dose of 1,500 mg twice daily was selected for dose expansion, where 52 subjects were treated in cohorts representing four different tumor types [lower grade glioma (LGG), glioblastoma, intrahepatic cholangiocarcinoma, and a basket cohort of other tumor types]. The best clinical outcomes were in subjects with LGG (n = 35), with an objective response rate of 11% (one complete response and three partial responses) and stable disease in 43%. As of August 2020, four of these subjects were in treatment for >2 years and still ongoing. Objective responses were observed only in LGG. Conclusions: BAY1436032 was well tolerated and showed evidence of target inhibition and durable objective responses in a small subset of subjects with LGG.

Background We previously reported that the absolute value of O6-methylguanine-DNA methyltransferase (MGMT) messenger RNA (mRNA) obtained using real-time reverse transcription polymerase chain reaction (RT-PCR) might be useful for predicting both the prognosis and the results of therapy for glioblastoma (GB) treated by temozolomide (TMZ). Methods MGMT mRNA was measured in 55 newly diagnosed cases of GB less than 75 and had a Karnofsky performance status (KPS) of at least 60 by real-time reverse transcription polymerase chain reaction (RT-PCR) using the TaqMan probe. A receiver operating characteristic analysis was performed to determine the cutoff points for progression free survival (PFS) and overall survival (OS). Results In 55 patients with GB, 1200 and 3600 for PFS, 1200, 2100 and 2900 copies/μgRNA for OS were the candidate cutoff points. Significantly longer PFS and OS were observed in patients who did not exceed 1200 copies/μg RNA. Conclusions One thousand and two hundred copies/μg RNA appeared to be the most reasonable cutoff point of MGMTmRNA in GB for deciding to use other anti-tumor drugs such as Bevacizumab together with TMZ.