Usefulness of synthetic MRI for differentiation of IDH-mutant diffuse gliomas and its comparison with the T2-FLAIR mismatch sign.

INTRODUCTION: The T2-FLAIR mismatch sign is a characteristic imaging biomarker for astrocytoma, isocitrate dehydrogenase (IDH)-mutant. However, investigators have provided varying interpretations of the positivity/negativity of this sign given for individual cases the nature of qualitative visual assessment. Moreover, MR sequence parameters also influence the appearance of the T2-FLAIR mismatch sign. To resolve these issues, we used synthetic MR technique to quantitatively evaluate and differentiate astrocytoma from oligodendroglioma. METHODS: This study included 20 patients with newly diagnosed non-enhanced IDH-mutant diffuse glioma who underwent preoperative synthetic MRI using the Quantification of Relaxation Times and Proton Density by Multiecho acquisition of a saturation-recovery using Turbo spin-Echo Readout (QRAPMASTER) sequence at our institution. Two independent reviewers evaluated preoperative conventional MR images to determine the presence or absence of the T2-FLAIR mismatch sign. Synthetic MRI was used to measure T1, T2 and proton density (PD) values in the tumor lesion. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic performance. RESULTS: The pathological diagnoses included astrocytoma, IDH-mutant (n = 12) and oligodendroglioma, IDH-mutant and 1p/19q-codeleted (n = 8). The sensitivity and specificity of T2-FLAIR mismatch sign for astrocytoma were 66.7% and 100% [area under the ROC curve (AUC) = 0.833], respectively. Astrocytoma had significantly higher T1, T2, and PD values than did oligodendroglioma (p < 0.0001, < 0.0001, and 0.0154, respectively). A cutoff lesion T1 value of 1580 ms completely differentiated astrocytoma from oligodendroglioma (AUC = 1.00). CONCLUSION: Quantitative evaluation of non-enhanced IDH-mutant diffuse glioma using synthetic MRI allowed for better differentiation between astrocytoma and oligodendroglioma than did conventional T2-FLAIR mismatch sign. Measurement of T1 and T2 value by synthetic MRI could improve the differentiation of IDH-mutant diffuse gliomas.

Pseudocapsular resection to prevent recurrence in nonfunctioning pituitary neuroendocrine tumors: a retrospective, single-center study with more than 5 years of follow-up.

OBJECTIVE: Pseudocapsular resection is a well-recognized, useful approach to achieve endocrinological remission in functioning pituitary neuroendocrine tumors (PitNETs). However, its advantage in nonfunctioning PitNETs (NF-PitNETs) has not been established. This study aimed to clarify the contribution of pseudocapsular resection to the prevention of NF-PitNET recurrence in long-term follow-up. METHODS: This retrospective study included 132 patients who underwent total tumor removal and were followed for more than 5 years after surgery. The patients were categorized into those who underwent total pseudocapsular resection (n = 67) and those who did not (n = 65). The nonpseudocapsule (nonpseudocap) resection group included patients who underwent partial pseudocapsular resection and those in whom the pseudocapsule was not resected, did not exist, or could not be identified during surgery. The main outcome measures were the tumor recurrence rate and site of recurrence. RESULTS: In the nonpseudocap resection group, 2 patients (3.1%) had tumor recurrence in the cavernous sinus and 5 (7.7%) had tumor recurrence in the pituitary fossa. In the pseudocapsule (pseudocap) resection group, only 2 patients (3.0%) had tumor recurrence in the cavernous sinus and 0 patients had tumor recurrence in the pituitary fossa. Tumor recurrence in the pituitary fossa was more likely to occur in the nonpseudocap resection group than in the pseudocap resection group (p = 0.0267). Multivariate regression analysis revealed that pseudocapsular resection was a significant factor for reducing the tumor recurrence rate in the pituitary fossa (p = 0.0107). CONCLUSIONS: Pseudocapsular resection may reduce the rate of tumor recurrence and improve the management of NF-PitNETs in long-term follow-up.

T2-FLAIR mismatch sign, an imaging biomarker for CDKN2A-intact in non-enhancing astrocytoma, IDH-mutant.

INTRODUCTION: The WHO classification of central nervous system tumors (5th edition) classified astrocytoma, IDH-mutant accompanied with CDKN2A/B homozygous deletion as WHO grade 4. Loss of immunohistochemical (IHC) staining for methylthioadenosine phosphorylase (MTAP) was developed as a surrogate marker for CDKN2A-HD. Identification of imaging biomarkers for CDKN2A status is of immense clinical relevance. In this study, we explored the association between radiological characteristics of non-enhancing astrocytoma, IDH-mutant to the CDKN2A/B status. METHODS: Thirty-one cases of astrocytoma, IDH-mutant with MTAP results by IHC were included in this study. The status of CDKN2A was diagnosed by IHC staining for MTAP in all cases, which was further confirmed by comprehensive genomic analysis in 12 cases. The T2-FLAIR mismatch sign, cystic component, calcification, and intratumoral microbleeding were evaluated. The relationship between the radiological features and molecular pathological diagnosis was analyzed. RESULTS: Twenty-six cases were identified as CDKN2A-intact while 5 cases were CDKN2A-HD. The presence of > 33% and > 50% T2-FLAIR mismatch was observed in 23 cases (74.2%) and 14 cases (45.2%), respectively, and was associated with CDKN2A-intact astrocytoma (p = 0.0001, 0.0482). None of the astrocytoma, IDH-mutant with CDKN2A-HD showed T2-FLAIR mismatch sign. Cystic component, calcification, and intratumoral microbleeding were not associated with CDKN2A status. CONCLUSION: In patients with non-enhancing astrocytoma, IDH-mutant, the T2-FLAIR mismatch sign is a potential imaging biomarker for the CDKN2A-intact subtype. This imaging biomarker may enable preoperative prediction of CDKN2A status among astrocytoma, IDH-mutant.

Super T2-FLAIR mismatch sign: a prognostic imaging biomarker for non-enhancing astrocytoma, IDH-mutant.

PURPOSE: The T2-FLAIR mismatch sign is a highly specific diagnostic imaging biomarker for astrocytoma, IDH-mutant. However, a definitive prognostic imaging biomarker has yet to be identified. This study investigated imaging prognostic markers, specifically analyzing T2-weighted and FLAIR images of this tumor. METHODS: We retrospectively analyzed 31 cases of non-enhancing astrocytoma, IDH-mutant treated at our institution, and 30 cases from The Cancer Genome Atlas (TCGA)/The Cancer Imaging Archive (TCIA). We defined "super T2-FLAIR mismatch sign" as having a significantly strong low signal comparable to cerebrospinal fluid at non-cystic lesions rather than just a pale FLAIR low-signal tumor lesion as in conventional T2-FLAIR mismatch sign. Cysts were defined as having a round or oval shape and were excluded from the criteria for the super T2-FLAIR mismatch sign. We evaluated the presence or absence of the T2-FLAIR mismatch sign and super T2-FLAIR mismatch sign using preoperative MRI and analyzed the progression-free survival (PFS) and overall survival (OS) by log-rank test. RESULTS: The T2-FLAIR mismatch sign was present in 17 cases (55%) in our institution and 9 cases (30%) within the TCGA-LGG dataset without any correlation with PFS or OS. However, the super T2-FLAIR mismatch sign was detected in 8 cases (26%) at our institution and 13 cases (43%) in the TCGA-LGG dataset. At our institution, patients displaying the super T2-FLAIR mismatch sign showed significantly extended PFS (122.7 vs. 35.9 months, p = 0.0491) and OS (not reached vs. 116.7 months, p = 0.0232). Similarly, in the TCGA-LGG dataset, those with the super T2-FLAIR mismatch sign exhibited notably longer OS (not reached vs. 44.0 months, p = 0.0177). CONCLUSION: The super T2-FLAIR mismatch is a promising prognostic imaging biomarker for non-enhancing astrocytoma, IDH-mutant.

Characteristics of radiation-induced brain tumors: case series and systematic review.

OBJECTIVE: Radiation therapy (RT) improves the outcome of patients with cancer but introduces the risk of radiation-induced neoplasms in cancer survivors. The most common radiation-induced brain tumors (RIBTs) are gliomas (RIGs), meningiomas (RIMs), and sarcomas (RISs). To investigate the characteristics of these RIBTs, the authors conducted a comprehensive review and analysis of their case series and relevant cases from the literature. METHODS: Sixteen patients in the case series and 941 patients from the literature who previously underwent cranial irradiation were included in this study. The age at irradiation for primary disease was recorded, and the latency period from irradiation to the development of RIBT and the median overall survival (OS) of patients with RIBTs were analyzed using the Kaplan-Meier method. Patients were stratified by age at the time of irradiation (pediatric vs nonpediatric) and the irradiation dose (higher vs lower dose), and latency and OS were compared using the log-rank test. RESULTS: Among patients with RIBTs, 23.4% underwent radiation at < 5 years of age, and 46.6% underwent RT in the 1st decade of life. The median ages at cranial irradiation were 8.4 (IQR 4.1-16) years in patients with RIMs, 9 (IQR 5-23) years in patients with RIGs, and 27.7 (IQR 13.8-40) years in patients with RISs. The median latency period from irradiation to the development of RIM was significantly longer than that to the development of RIG and RIS (RIM: 20 years, RIG: 9 years, RIS: 10 years; p < 0.0001). The latency period was shorter in the nonpediatric patient group with RIMs (p = 0.047). The OS was significantly longer in patients with RIMs than in those with RIGs and RISs (RIM: not reached, RIG: 11 months, RIS: 11 months; p < 0.0001). The OS of patients with RIMs and RIGs was significantly shorter in patients who received higher radiation doses (p = 0.0095 and p = 0.0026, respectively). CONCLUSIONS: The prognosis was poor and worse for patients with RIGs and RISs than for those with RIMs, and patients with RIBTs who underwent higher-dose irradiation for primary disease had poor prognoses. Because RIBTs develop more than a decade after cranial irradiation, long-term follow-up is crucial.

Preventing Post-incisional Dural Shrink in Craniotomy: Introducing the "Roll-up Technique".

Dural dryness makes suturing difficult during dural closure after craniotomy. In this case, dural plasty is often performed using a membrane taken from the surrounding tissue (e.g., fascia or periosteum) or an artificial replacement membrane. Herein, we introduce our novel "roll-up technique" to reduce the utilization of substitute membranes and explore its effectiveness in dural closure. We retrospectively examined the medical records of 50 patients who underwent craniotomy for the first time for supratentorial intracranial lesions between 2015 and 2022. Furthermore, we divided them into two groups: (1) the conventional technique group, which consisted of patients in whom the dura mater was flipped after incision and protected with a moistened gauze (n = 23), and (2) the roll-up technique group, which consisted of patients in whom the dura mater was incised in a U shape, rolled up, and protected with a moist gauze (n = 27). After surgery, we compared the success rates of primary closure, operating time, craniotomy area, and percentage of complications (e.g., cerebrospinal fluid [CSF] leakage or infection) between the groups. Dural closure without dural substitutes using the roll-up technique had a higher success rate than that using the conventional technique (26/27 [96.3%] cases vs. 14/23 [60.9%] cases; P = 0.003). Postoperative CSF leakage or infection did not occur, and no statistically significant difference was observed in the operating time between the groups (P = 0.247). The roll-up technique for dural closure may effectively prevent post-incisional dural shrink after craniotomy.

Clinical practice guidelines for molecular tumor marker, 2nd edition review part 2.

In recent years, rapid advancement in gene/protein analysis technology has resulted in target molecule identification that may be useful in cancer treatment. Therefore, "Clinical Practice Guidelines for Molecular Tumor Marker, Second Edition" was published in Japan in September 2021. These guidelines were established to align the clinical usefulness of external diagnostic products with the evaluation criteria of the Pharmaceuticals and Medical Devices Agency. The guidelines were scoped for each tumor, and a clinical questionnaire was developed based on a serious clinical problem. This guideline was based on a careful review of the evidence obtained through a literature search, and recommendations were identified following the recommended grades of the Medical Information Network Distribution Services (Minds). Therefore, this guideline can be a tool for cancer treatment in clinical practice. We have already reported the review portion of "Clinical Practice Guidelines for Molecular Tumor Marker, Second Edition" as Part 1. Here, we present the English version of each part of the Clinical Practice Guidelines for Molecular Tumor Marker, Second Edition.

Differences in invasiveness and recurrence rate among nonfunctioning pituitary neuroendocrine tumors depending on tumor subtype.

PURPOSE: To clarify the invasiveness to surrounding structures and recurrence rate of each subtype of nonfunctioning pituitary neuroendocrine tumor (Pit-NETs) according to the WHO 2022 classification. METHODS: This retrospective study utilized data from 292 patients with nonfunctioning Pit-NETs treated with initial transsphenoidal surgery. Recurrence was evaluated on 113 patients who were available for a magnetic resonance imaging follow-up ≥ 60 months. All tumors were assessed by immunohistochemical staining for Pit-1, T-PIT, and GATA3. Invasiveness to surrounding structures was evaluated based on intraoperative findings. RESULTS: Cavernous sinus invasion was found in 47.5% of null cell tumors, 50.0% of Pit-1 lineage tumors, 31.8% of corticotroph tumors, and 18.3% of gonadotroph tumors. Dura mater defects in the floor of sellar turcica, indicating dural invasion, were found in 44.3% of null cell tumors, 36.4% of corticotroph tumors, 16.7% of Pit-1 lineage tumors, and 17.3% of gonadotroph tumors. In logistic regression analysis, Pit-1 (OR 5.90, 95% CI 1.71-20.4, P = 0.0050) and null tumors (OR 4.14, 95% CI 1.86-9.23, P = 0.0005) were associated with cavernous sinus invasion. Recurrence was found in 8 (4.9%) patients, but without significant differences between tumor subtypes. The presence of cavernous sinus invasion was correlated with recurrence (HR = 1.95, 95% CI 1.10-3.46, P = 0.0227). CONCLUSION: Among nonfunctioning Pit-NETs, Pit-1 lineage tumors tend to invade the cavernous sinus, corticotroph tumors may produce dura mater defects, and null cell tumors tend to cause both. Pit-NETs with cavernous sinus invasion require a careful attention to recurrence.

Residual diffusion-weighted imaging hyperintense signal in primary central nervous system lymphoma can predict early recurrence.

BACKGROUND: The treatment response of primary central nervous system lymphomas (PCNSLs) is mainly evaluated using postcontrast T1-weighted imaging (T1WI). Because poorly enhanced lesions may contain residual tumors, the combination of evaluation methods will potentially improve the accuracy of determining treatment effectiveness. In this study, we evaluated the usefulness of diffusion-weighted imaging (DWI) in predicting recurrence among patients with PCNSL who achieved complete response (CR)/unconfirmed CR (CRu). METHODS: Fifty-four patients newly diagnosed with PCNSL who were treated at our institution and achieved CR/CRu at the end of treatment were included in this study. The patients were divided into two groups according to the presence or absence of residual DWI hyperintense signal at the tumor site at the end of treatment. Kaplan-Meier analysis was performed to analyze the median overall survival (OS) and progression-free survival (PFS). RESULTS: The mean age of the 54 patients was 66.4 ± 13.3 years. The induction therapies were HD-MTX in 20 patients, R-MPV in 29 patients, and other chemotherapies in five patients. Radiotherapy was performed in 35 patients, high-dose cytarabine therapy in 14 patients, and autologous hematopoietic stem cell transplantation in one patient, and of the 54 patients, 10 had no consolidation therapy. The residual DWI hyperintense signal sign was observed in 18 patients. The R-MPV regimen was statistically associated with a lower rate of residual DWI hyperintense signal (p = 0.0453). The median PFS was statistically shorter in the residual DWI hyperintense signal group than in the non-residual DWI hyperintense signal group (14.0 months vs. 85.1 months) (p < 0.0001, log-rank test). CONCLUSION: A residual DWI hyperintense signal at the end of treatment was statistically associated with shorter PFS. Among patients who achieved CR/CRu evaluated based on postcontrast T1WI, DWI could be a valuable additional sequence to predict the early recurrence of PCNSL.

Characteristics and therapeutic strategies of brain and cranial radiation-induced sarcoma: analysis of 165 cases from our case experience and comprehensive review.

BACKGROUND: Radiation-induced sarcoma (RIS) is among the neoplasms potentially caused by radiation therapy (RT) for brain tumors. However, the clinical characteristics of and ideal treatment for RIS are unclear. We analysed our case experience and conducted a comprehensive literature review to reveal the characteristics of brain and cranial RIS. METHODS: We analysed 165 cases of RIS from the literature together with the RIS case treated at our institution. In each case, the latency period from irradiation to the development of each RIS and the median overall survival (OS) of the patients was analysed by Kaplan-Meier analysis. Spearman's correlation test was used to determine the relationship between the latency period and radiation dose or age at irradiation. RESULTS: The mean age at the development of RIS was 39.63 ± 17.84 years. The mean latency period was 11.79 ± 8.09 years. No factors associated with early development of RIS were detected. The median OS was 11 months, with fibrosarcoma showing significantly shorter OS compared with osteosarcoma and other sarcomas (p = 0.0021), and intracranial RIS showing a worse prognosis than extracranial RIS (p < 0.0001). Patients treated with surgery (p < 0.0001) and postoperative chemotherapy (p = 0.0157) for RIS presented significantly longer OS, whereas RT for RIS was not associated with a survival benefit. CONCLUSIONS: Although prognosis for RIS is universally poor, pathological characteristics and locations are associated with worse prognosis. Surgery and chemotherapy may be the ideal treatment strategies for RIS.

Multidrug chemotherapy, whole-brain radiation and cytarabine therapy for primary central nervous system lymphoma in elderly patients with dose modification based on geriatric assessment: study protocol for a phase II, multicentre, non-randomised study.

INTRODUCTION: Multidrug chemoimmunotherapy with rituximab, high-dose methotrexate, procarbazine and vincristine (R-MPV) is a standard therapy for younger patients with primary central nervous system lymphoma (PCNSL); however, prospective data regarding its use in elderly patients are lacking. This multi-institutional, non-randomised, phase II trial will assess the efficacy and safety of R-MPV and high-dose cytarabine (HD-AraC) for geriatric patients with newly diagnosed PCNSL. METHODS AND ANALYSIS: Forty-five elderly patients will be included. If R-MPV does not achieve complete response, the patients will undergo reduced-dose, whole-brain radiotherapy comprising 23.4 Gy/13 fractions, followed by local boost radiotherapy comprising 21.6 Gy/12 fractions. After achieving complete response using R-MPV with or without radiotherapy, the patients will undergo two courses of HD-AraC. All patients will undergo baseline geriatric 8 (G8) assessment before HD-AraC and after three, five and seven R-MPV courses. Patients with screening scores of ≥14 points that decrease to <14 points during subsequent treatment, or those with screening scores <14 points that decrease from the baseline during subsequent treatment are considered unfit for R-MPV/HD-AraC. The primary endpoint is overall survival, and the secondary endpoints are progression-free survival, treatment failure-free survival and frequency of adverse events. The results will guide a later phase III trial and provide information about the utility of a geriatric assessment for defining chemotherapy ineligibility. ETHICS AND DISSEMINATION: This study complies with the latest Declaration of Helsinki. Written informed consent will be obtained. All participants can quit the study without penalty or impact on treatment. The protocol for the study, statistical analysis plan and informed consent form have been approved by the Certified Review Board at Hiroshima University (CRB6180006) (approval number: CRB2018-0011). The study is ongoing within nine tertiary and two secondary hospitals in Japan. The findings of this trial will be disseminated through national and international presentations and peer-reviewed publications. TRIAL REGISTRATION: jRCTs061180093.

Optic tract edema in craniopharyngioma as a predictor of BRAFV600E mutation presence.

OBJECTIVE: the advent of BRAF inhibitors for preoperative treatment of craniopharyngioma has necessitated the identification of BRAFV600E status. Hence, we investigated predictors of BRAFV600E mutation in craniopharyngiomas. METHODS: this retrospective study utilized data from 30 patients who were newly diagnosed with craniopharyngioma between 2011 and 2021. Magnetic resonance imaging (MRI) and computed tomography were performed within 1 week prior to surgery. Genetic analysis for BRAF mutation was performed using the Oncomine next-generation sequencing panel or Sanger sequencing. The relationship between BRAF mutation and demographic data, endocrinological function and tumour characteristics on imaging was assessed. RESULTS: tumour tissue carried the BRAFV600E mutation in nine patients. There was no significant difference in age, sex, or presence of hormonal dysfunction amongst patients with and without the BRAFV600E mutation in the tumour. Most tumours with the BRAFV600E mutation were histologically categorized as papillary craniopharyngioma (P = 0.0005), and were solid (P = 0.0002) and supra-diaphragmatic (P = 0.0033) on MRI. BRAFV600E tumours were more frequently associated with optic tract edema than wild-type tumour s (55.6 vs. 0%, P = 0.0009) and all tumour s with optic tract edema carried the BRAFV600E mutation. Optic tract edema was not associated with tumour volume, cysts, or preoperative pituitary function. CONCLUSIONS: in craniopharyngiomas, the presence of optic tract edema can predict the presence of BRAFV600E mutation with a positive predictive value of 100%. The finding should be verified in larger prospective cohorts and multivariate regression analysis.

Diagnostic and therapeutic challenges of glioblastoma as an initial malignancy of constitutional mismatch repair deficiency (CMMRD): two case reports and a literature review.

BACKGROUND: Constitutional mismatch repair deficiency (CMMRD) results from a biallelic germline pathogenic variant in a mismatch repair (MMR) gene. The most common CMMRD-associated malignancies are brain tumors; an accurate diagnosis is challenging when a malignant brain tumor is the only tumor at presentation. We describe two cases of glioblastoma as the initial CMMRD malignancy and discuss current diagnostic and therapeutic challenges. CASE PRESENTATION: Two children with brain tumors without remarkable family history had biallelic pathogenic germline variants in PMS2. Patient 1: A 6-year-old girl presented biallelic PMS2 germline pathogenic variants. Glioblastomas at the left frontal lobe and right temporal lobe were resistant to immune-checkpoint inhibitor, temozolomide, and bevacizumab. Patient 2: A 10-year-old boy presented biallelic PMS2 germline variants. His glioblastoma with primitive neuroectodermal tumor-like features responded to chemoradiotherapy, but he developed advanced colon cancer and acute lymphocytic leukemia. In both patients, only a monoallelic PMS2 germline variant was detected by conventional gene tests. PMS2 immunohistochemistry showed lack of staining at both the tumors and normal tissue as vascular endothelial cells. Further gene tests revealed large genomic deletion including the entire PMS2 gene, confirming biallelic PMS2 germline variants. CONCLUSION: Conventional multi-gene panel tests are insufficient for detecting large deletions of MMR genes, resulting in misdiagnoses of CMMRD as Lynch syndrome. PMS2 variants have low cancer penetrance; family histories may thus be absent. Long-range gene analyses or immunohistochemical staining of MMR proteins in normal tissue should be considered for pediatric brain tumors with a single allele MMR variant when CMMRD is suspected.

Safety and efficacy of tumour-treating fields (TTFields) therapy for newly diagnosed glioblastoma in Japanese patients using the Novo-TTF System: a prospective post-approval study.

BACKGROUND: Tumour-treating fields therapy is a locoregional, anti-cancer treatment. Efficacy and safety of tumour-treating fields therapy in adults with newly diagnosed glioblastoma were demonstrated in the pivotal phase 3 EF-14 study (NCT00916409). Here, we report post-approval data of tumour-treating fields therapy in Japanese patients with newly diagnosed glioblastoma. METHODS: Unsolicited post-marketing surveillance data from Japanese patients with newly diagnosed glioblastoma treated with tumour-treating fields therapy (December 2016-June 2020) were retrospectively analysed. The primary endpoints were skin, neurological and psychiatric adverse events. The secondary endpoints were 1- and 2-year overall survival rates, and the 6-month progression-free survival. adverse events were analysed using MedDRA v24.0. The overall survival and progression-free survival were assessed using the Kaplan-Meier survival analysis (log-rank testing). The Cox proportional hazard regression analyses were also performed. RESULTS: Forty patients with newly diagnosed glioblastoma were enrolled (62.5% male; median age 59 years; median baseline Karnofsky Performance Scale score 90). The most common tumour-treating-fields-therapy-related adverse event was beneath-array local skin reaction (60% of patients). The adverse events were mostly mild to moderate in severity. Neurological disorders were observed in 2.5% patients (one patient reported dysesthesia). No psychiatric disorders were reported. The 1- and 2-year overall survival rates were 77.9% (95% CI 60.6-88.3) and 53.6% (35.5-68.7%), respectively. The 6-month progression-free survival was 77.5% (61.2-87.6%). These survival rates compare favourably with those in the EF-14 trial (1- and 2-year overall survival rates: 73% [69-77%] and 43% [39-48%], respectively; 6-month progression-free survival rate: 56% (51-61%). CONCLUSION: This post-approval, real-world evidence study revealed no new safety signals and suggests the safety and efficacy of tumour-treating fields therapy in Japanese patients with newly diagnosed glioblastoma.

The first-in-human phase I study of a brain-penetrant mutant IDH1 inhibitor DS-1001 in patients with recurrent or progressive IDH1-mutant gliomas.

BACKGROUND: Approximately 70% of lower-grade gliomas harbor isocitrate dehydrogenase 1 (IDH1) mutations, resulting in the accumulation of oncometabolite D-2-hydroxyglutarate (D-2-HG); this leads to epigenetic dysregulation, oncogenesis, and subsequent clonal expansion. DS-1001 is an oral brain-penetrant mutant IDH1 selective inhibitor. This first-in-human study investigated the safety, pharmacokinetics, pharmacodynamics, and efficacy of DS-1001. METHODS: This was a multicenter, open-label, dose-escalation, phase I study of DS-1001 for recurrent/progressive IDH1-mutant (R132) glioma (N = 47) (NCT03030066). DS-1001 was administered orally at 125-1400 mg twice daily. Dose-escalation used a modified continual reassessment method. RESULTS: The maximum tolerated dose was not reached. Eight patients were continuing treatment at the data cutoff. Most adverse events (AEs) were grade 1-2. Twenty patients (42.6%) experienced at least 1 grade 3 AE. No grade 4 or 5 AEs or serious drug-related AEs were reported. Common AEs (>20%) were skin hyperpigmentation, diarrhea, pruritus, alopecia, arthralgia, nausea, headache, rash, and dry skin. The objective response rates were 17.1% for enhancing tumors and 33.3% for non-enhancing tumors. Median progression-free survival was 10.4 months (95% confidence interval [CI], 6.1 to 17.7 months) and not reached (95% CI, 24.1 to not reached) for the enhancing and non-enhancing glioma cohorts, respectively. Seven on-treatment brain tumor samples showed a significantly lower amount of D-2-HG compared with pre-study archived samples. CONCLUSIONS: DS-1001 was well tolerated with a favorable brain distribution. Recurrent/progressive IDH1-mutant glioma patients responded to treatment. A study of DS-1001 in patients with chemotherapy- and radiotherapy-naïve IDH1-mutated WHO grade 2 glioma is ongoing (NCT04458272).

Randomized phase III study of high-dose methotrexate and whole-brain radiotherapy with/without temozolomide for newly diagnosed primary CNS lymphoma: JCOG1114C.

BACKGROUND: The goal was to determine whether the addition of temozolomide (TMZ) to the standard treatment of high-dose methotrexate (HD-MTX) and whole-brain radiotherapy (WBRT) for primary central nervous system lymphoma (PCNSL) improves survival. METHODS: An open-label, randomized, phase III trial was conducted in Japan, enrolling immunocompetent patients aged 20-70 years with histologically confirmed, newly diagnosed PCNSL. After administration of HD-MTX, patients were randomly assigned to receive WBRT (30 Gy) ±â€…10 Gy boost (arm A) or WBRT ±â€…boost with concomitant and maintenance TMZ for 2 years (arm B). The primary endpoint was overall survival (OS). RESULTS: Between September 29, 2014 and October 15, 2018, 134 patients were enrolled, of whom 122 were randomly assigned and analyzed. At the planned interim analysis, 2-year OS was 86.8% (95% confidence interval [CI]: 72.5-94.0%) in arm A and 71.4% (56.0-82.2%) in arm B. The hazard ratio was 2.18 (95% CI: 0.95-4.98), with the predicted probability of showing the superiority of arm B at the final analysis estimated to be 1.3%. The study was terminated early due to futility. O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status was measured in 115 tumors, and it was neither prognostic nor predictive of TMZ response. CONCLUSIONS: This study failed to demonstrate the benefit of concomitant and maintenance TMZ in newly diagnosed PCNSL.

Natural course of Rathke's cleft cysts and risk factors for progression.

OBJECTIVE: Rathke's cleft cysts (RCCs) are relatively common and often detected incidentally. They are usually asymptomatic and managed conservatively. However, little is known about their natural history. Thus, the authors aimed to examine the natural course of RCCs and identify the risk factors for their progression. METHODS: This retrospective study examined 229 patients (median age 43.0 years) diagnosed with RCCs by MRI and followed up without surgery (median period 36.6 months). The median cyst height on the initial MRI was 10 mm. Progression or regression of RCC was defined as cyst height changes of ≥ 1 mm. RESULTS: In total, 23 (10.0%) RCCs progressed, whereas 73 (31.9%) RCCs spontaneously regressed. The remaining 133 were noted to be stable throughout the follow-up period. Patients with progressed RCCs were significantly older than those with stable RCCs. In patients with acute headache as an initial symptom, RCCs were significantly more likely to spontaneously regress. New symptoms occurred in 6 patients, 5 of whom underwent surgery for RCC progression. Of these 6 patients, 1 patient had persistent adrenocorticotropic hormone deficiency and 1 patient developed diabetes insipidus. Kaplan-Meier analysis results showed RCC progression and new symptom development rates to be 12.0% and 4.1% at 5 years and 13.7% and 5.7% at 10 years, respectively. CONCLUSIONS: RCCs rarely progress or cause new symptoms in the long term. Patients with asymptomatic RCC should be followed up for at least 5 years to ensure RCC inactivity. RCCs in older adults may require greater surveillance.

Secondary meningioma after cranial irradiation: case series and comprehensive literature review.

BACKGROUND: Secondary meningioma after cranial irradiation, so-called radiation-induced meningioma, is one of the important late effects after cranial radiation therapy. In this report, we analyzed our case series of secondary meningioma after cranial irradiation and conducted a critical review of literature to reveal the characteristics of secondary meningioma. MATERIALS AND METHODS: We performed a comprehensive literature review by using Pubmed, MEDLINE and Google scholar databases and investigated pathologically confirmed individual cases. In our institute, we found pathologically diagnosed seven cases with secondary meningioma between 2000 and 2018. Totally, 364 cases were analyzed based on gender, WHO grade, radiation dose, chemotherapy. The latency years from irradiation to development of secondary meningioma were analyzed with Kaplan-Meier analysis. Spearman's correlation test was used to determine the relationship between age at irradiation and the latency years. RESULTS: The mean age at secondary meningioma development was 35.6 ± 15.7 years and the mean latency periods were 22.6 ± 12.1 years. The latency periods from irradiation to the development of secondary meningioma are significantly shorter in higher WHO grade group (P = 0.0026, generalized Wilcoxon test), higher radiation dose group (P < 0.0001) and concomitant systemic chemotherapy group (P = 0.0003). Age at irradiation was negatively associated with the latency periods (r = -0.23231, P < 0.0001, Spearman's correlation test). CONCLUSION: Cranial irradiation at older ages, at higher doses and concomitant chemotherapy was associated with a shorter latency period to develop secondary meningiomas. However, even low-dose irradiation can cause secondary meningiomas after a long latency period. Long-term follow-up is necessary to minimize the morbidity and mortality caused by secondary meningioma after cranial irradiation.

Usefulness of critical flicker fusion frequency measurement and its laterality for evaluating compressive optic neuropathy due to pituitary neuroendocrine tumors.

Critical flicker fusion frequency (CFF) is a short but sensitive method for evaluating optic nerve function. We measured CFF in patients with pituitary neuroendocrine tumors (Pit-NETs) to assess its usefulness. Data from 184 patients with nonfunctioning Pit-NETs, who had been treated with transsphenoidal surgery and had no medical history of eye diseases, was used in this retrospective study. Visual acuity decline (VAD) was defined as > 0.10 reduction in logMAR visual acuity and CFF decline (CFD) was defined as CFF value < 35 Hz. Visual field defect (VFD) was evaluated by automated perimetry on a Humphrey visual field analyzer. Potential associations between abnormal test results and tumor height from the suprasellar were analyzed. Contact between the optic nerve or chiasma and the tumor was present and absent in 161 and 23 patients, respectively. In patients showing contact, the difference in CFF between the left and right eyes was larger (p = 0.0008), and the optimal cutoff value using the receiver operating characteristic curve was 3 Hz. Therefore, ≥ 3 Hz was considered positive for CFF laterality (CFL), the most prevalent condition. Tumor height was lower in patients with CFL positivity compared to those with VAD or VFD (p < 0.01). The prevalence of test abnormalities was the highest for small tumors compared to those of other tests. Changes in CFL permit early detection of Pit-NETs. Our results indicate that CFF laterality can be seen in the early stages of compressive optic neuropathy due to Pit-NET.