Three-year follow-up analysis of phase 1/2 study on tirabrutinib in patients with relapsed or refractory primary central nervous system lymphoma.

Background: The ONO-4059-02 phase 1/2 study showed favorable efficacy and acceptable safety profile of tirabrutinib, a second-generation Bruton's tyrosine kinase inhibitor, for relapsed/refractory primary central nervous system lymphoma (PCNSL). Here, we report the long-term efficacy and safety after a 3-year follow-up. Methods: Eligible patients were aged ≥ 20 years with histologically diagnosed PCNSL and KPS of ≥ 70. Patients received oral tirabrutinib once daily at 320 or 480 mg, or 480 mg under fasted conditions. Results: Between October 19, 2017, and June 13, 2019, 44 patients were enrolled: 33 and 9 had relapsed and refractory, respectively. The 320, 480, and 480 mg fasted groups included 20, 7, and 17 patients, respectively. The median follow-up was 37.1 months. The overall response rate was 63.6% (95% CI: 47.8-77.6) with complete response (CR), unconfirmed CR, and partial response in 9, 7, and 12 patients, respectively. The median duration of response (DOR) was 9.2 months, with a DOR rate of 19.8%; the median progression-free survival (PFS) and median overall survival (OS) were 2.9 months and not reached, respectively, with PFS and OS rates of 13.9% and 56.7%, respectively. Adverse events occurred in 38 patients (86.4%): grade ≥ 3 in 23 (52.3%) including 1 patient with grade 5 events. KPS and quality of life (QoL) scores were well maintained among patients receiving long-term treatment. Conclusions: The results demonstrated the long-term clinical benefit of tirabrutinib, with deep and durable response in a subset of patients and acceptable safety profile, while KPS and QoL scores were maintained.

Spinal Dissemination of Pineal Parenchymal Tumors of Intermediate Differentiation Over 10 Years After Initial Treatment: A Case Report.

Pineal parenchymal tumors (PPTs) are rare, accounting for less than 0.3% of all primary central nervous system (CNS) tumors. Pineal parenchymal tumors of intermediate differentiation (PPTID) (WHO grade 2 or 3) show an intermediate prognosis between pineocytoma and pineoblastoma. The clinical course is unknown, and the optimal treatment for PPTID, especially for recurrence, has not been determined. We report a case of PPTID with spinal dissemination over 10 years after treatment and survival for four years. A 56-year-old woman presented with headaches and diplopia. Computerized tomography (CT) and magnetic resonance imaging (MRI) revealed a pineal mass, but leptomeningeal dissemination was not identified on whole-spine MRI. Microsurgical gross total tumor resection (GTR) was performed, and the pathological diagnosis was PPTID (grade 3). In addition, a later study found it to harbor a KBTBD4 mutation. She underwent whole-brain radiation therapy with a focal boost. The patient was unable to continue chemotherapy for severe myelosuppression after the first course of treatment. Eleven years after the surgery, she was unable to walk, and a whole-spine MRI revealed multiple masses at C3-4, T4, and cauda equina. Fluorodeoxyglucose-positron emission tomography (FDG-PET) revealed accumulations of the same lesions. No recurrence was observed in the brain. A biopsy of the caudal portion was performed, and the histopathological findings were the same as those of the initial surgery. Spinal dissemination was refractory to chemotherapy but responded to whole spine radiotherapy with focal boost, and she remained tumor-free for four years. We considered good local control with a combination of GTR and subsequent radiation therapy to contribute to long-term survival. The timing of spinal radiation administration is controversial because of the tendency for late cerebrospinal dissemination. The importance of long-term follow-up of the spine and head is emphasized. In PPTID cases with good local control, withholding spinal radiation until spinal dissemination occurs may become a long-term treatment plan.

Long-term outcomes of multidisciplinary treatment combining surgery and stereotactic radiotherapy with Novalis for craniopharyngioma.

Craniopharyngiomas are difficult to resect completely, recurrence is frequent, and hypothalamic/pituitary function may be affected after surgery. Therefore, the ideal treatment for craniopharyngiomas is local control with preservation of hypothalamic and pituitary functions. The purpose of this study is to retrospectively evaluate the long-term efficacy and adverse events of stereotactic radiotherapy (SRT) with Novalis for craniopharyngioma. This study included 23 patients with craniopharyngiomas who underwent surgery between 2006 and 2021 and underwent SRT as their first irradiation after surgery. The median post-irradiation observation period was 88 months, with the overall survival rates of 100 % at 10 years and 85.7 % at 20 years. One patient died of adrenal insufficiency 12 years after irradiation. The local control rate of the cystic component was 91.3 % at 5 years, 83.0 % at 15 years, with no increase in the solid component. No delayed impairment of visual or pituitary function due to irradiation was observed. No new hypothalamic dysfunction was observed after radiation therapy. No delayed adverse events such as brain necrosis, cerebral artery stenosis, cerebral infarction, or secondary brain tumors were also observed. SRT was safe and effective over the long term in patients irradiated in childhood as well as adults, with no local recurrence or adverse events. We believe that surgical planning for craniopharyngioma with stereotactic radiotherapy in mind is effective in maintaining a good prognosis and quality of life.

A Rare Case of Adult Poorly Differentiated Chordoma of the Skull Base With Rapid Progression and Systemic Metastasis: A Review of the Literature.

Chordoma is a rare tumor that arises from chordal tissue during fetal life. Recently, the concept of poorly differentiated chordoma, a subtype of chordoma characterized by loss of SMARCB1/INI1 with a poorer prognosis than conventional chordomas, was established. It predominantly occurs in children and is rare in adults. Here, we report a rare adult case of poorly differentiated chordoma of the skull base with a unique course that rapidly systemically metastasized and had the shortest survival time of any adult chordoma reported to date. The patient was a 32-year-old male with a chief complaint of diplopia. MRI showed a widespread neoplastic lesion with the clivus as the main locus. Endoscopic extended transsphenoidal tumor resection was performed. Pathological findings showed that the tumor was malignant, and immunohistochemistry revealed a Ki-67 labeling index of 80%, diffusely positive brachyury, and loss of INI1 expression. The final diagnosis was poorly differentiated chordoma. Postoperatively, the residual tumor in the right cavernous sinus showed rapid growth. The patient was promptly treated with gamma knife three fractions. The residual tumor regressed, but the tumor developed systemic metastasis in a short period, and the patient died seven months after diagnosis. This report of a rapidly progressing and fatal adult poorly differentiated chordoma shows the highest Ki-67 labeling index reported to date. Prompt multidisciplinary treatment should be considered when the Ki-67 labeling index is high.

Postoperative disappearance of leptomeningeal enhancement around the brainstem in glioblastoma.

PURPOSE: Leptomeningeal enhancement (LME) suggests leptomeningeal dissemination (LMD) of tumor cells, which is a complication of end-stage glioblastoma, and is associated with a poor prognosis. However, magnetic resonance imaging (MRI) occasionally indicates the disappearance of peri-brainstem LME after surgical resection of glioblastoma. Since preoperative LMD may affect treatment indications, we aimed to analyze the clinical significance of preoperative LME of the brainstem in glioblastoma. METHODS: We retrospectively collected clinical and radiological data from consecutive patients with glioblastoma and preoperative LME of the brainstem, who were treated at our hospital between 2017 and 2020. RESULTS: Among 112 patients with glioblastoma, nine (8%) showed preoperative LME of the brainstem. In comparison with tumors without LME, tumor size was significantly associated with the preoperative LME of the brainstem (p = 0.016). In addition, there was a trend toward significance for a relationship between deep tumor location and preoperative LME of the brainstem (p = 0.058). Notably, among six patients who underwent surgical resection for glioblastoma with LME of the brainstem, four showed significant radiological disappearance of the LME on postoperative MRI. This suggests that the LME did not result from LMD in these cases. Moreover, these four patients lived longer than would be expected from the presence of LMD. However, this LME disappearance was not observed after biopsy or chemoradiotherapy. CONCLUSIONS: These findings suggest that preoperative LME does not necessarily indicate the presence of untreatable LMD; moreover, LME may disappear after surgical tumor resection. Thus, transient preoperative LME could be attributed to other mechanisms, including impaired venous flow due to intratumoral arteriovenous shunts, which can be resolved by reducing the tumor burden.

Karnofsky Performance Status and quality of life in patients with relapsed or refractory primary CNS lymphoma from a phase I/II study of tirabrutinib.

Background: Tirabrutinib, a second-generation inhibitor of Bruton's tyrosine kinase, was approved in March 2020 for the treatment of relapsed or refractory primary central nervous system lymphoma (r/r PCNSL) based on phase I/II studies in Japan. We previously reported the overall response rate and safety profile. We describe Karnofsky Performance Status (KPS) and the quality of life (QoL) in patients with r/r PCNSL receiving tirabrutinib based on more than 1-year follow-up data. Methods: Patients with r/r PCNSL, age ≥20 years, and KPS ≥70 were treated with tirabrutinib once daily at a dose of 320, 480, or 480 mg under fasted conditions. QoL was assessed using questionnaires issued by the European Organization for Research and Treatment of Cancer (EORTC), namely EORTC QLQ-C30, EORTC QLQ-BN20, and EuroQol 5 dimensions 3-level (EQ-5D-3L) along with KPS. Results: Forty-four patients (mean age, 60 years [range 29-86]) were enrolled. The median follow-up period was 14.9 months (range, 1.4-27.7). The median KPS of the patients at baseline was 80.0 (range, 70-100), and this remained constant during the treatment. The global health status/QoL in the QLQ-C30 showed significant improvements from baseline through cycles 3-17 and remained relatively constant thereafter until cycle 23. Improvements were also seen in emotional functioning and constipation in the QLQ-C30 segments. Other items of QLQ-C30 and QLQ-BN20, EQ-5D visual analog scales, and EQ-5D index were maintained during the treatment. Conclusions: Tirabrutinib generally maintains KPS and QoL scores with some improvements in specific QoL items in patients with r/r PCNSL.

Accelerating TOF-MRA: The impact of the combined use of compressed sensitivity encoding and spiral imaging.

PURPOSE: To evaluate the image quality of the combined technique of compressed sensitivity encoding (CS) and spiral imaging in time-of-flight magnetic resonance angiography (TOF-MRA), which is approximately 2.5 times faster than conventional methods. METHODS: Twenty volunteers underwent four TOF-MRA sequences: sensitivity encoding (SENSE) with acceleration factor of 4 (acquisition time: 4:55 min), CS with acceleration factor of 10.9, and spiral and CS-spiral (both 1:55 min). A quantitative image analysis (signal-to-noise ratio [SNR], contrast, and full width at half maximum [FWHM] edge criterion measurements) was performed on four TOF sequences. For qualitative image analysis, two board-certified radiologists evaluated the overall depiction of the proximal, intermediate, and distal branches in CS, spiral, and CS-spiral images using SENSE as a reference. RESULTS: The SNR of BA in spiral and CS-spiral imaging was significantly lower than that in SENSE (p = 0.009). The contrasts of ACA and BA in CS-spiral were significantly higher and those in spiral were significantly lower than those in SENSE (p < 0.001). The FWHM in the CS image was significantly higher than that of SENSE; however, no significant differences were observed between the spiral or CS-spiral and SENSE. In qualitative analysis, the depiction of proximal vascular branches was significantly impaired in spiral than in others and that of distal vascular branches was significantly impaired in CS than in others (p < 0.001). CONCLUSIONS: In TOF-MRA, which is approximately 2.5 times faster than conventional methods, the combined use of CS and spiral imaging demonstrated an improvement in image quality compared to either CS or spiral imaging alone. SUMMARY STATEMENT: The image quality of Compressed SENSE and spiral imaging is particularly poor in the proximal and distal vascular branches, respectively at an extremely high acceleration factor; however, CS-spiral provided stable image quality in all regions as compared with the SENSE technique.

Clinicopathologic analysis of pineal parenchymal tumors of intermediate differentiation: a multi-institutional cohort study by the Kyushu Neuro-Oncology Study Group.

PURPOSE: Pineal parenchymal tumors of intermediate differentiation (PPTIDs), which were recognized in the 2007 World Health Organization (WHO) classification, are rare, accounting for less than 1% of all central nervous system tumors. This rarity and novelty complicate the diagnosis and treatments of PPTID. We therefore aimed to evaluate the clinicopathological significance of this tumor. METHODS: At 11 institutions participating in the Kyushu Neuro-Oncology Study Group, data for patients diagnosed with PPTID were collected. Central pathology review and KBTBD4 mutation analysis were applied to attain the diagnostically accurate cohort. RESULTS: PPTID was officially diagnosed in 28 patients: 11 (39%) with WHO grade 2 and 17 (61%) with WHO grade 3 tumors. Median age was 49 years, and the male:female ratio was 1:2.1. Surgery was attempted in all 28 patients, and gross total resection (GTR) was achieved in 46% (13/28). Adjuvant radiotherapy and chemotherapy were administered to, respectively, 82% (23/28) and 46% (13/28). The 5-year progression-free survival (PFS) and overall survival rates were 64.9% and 70.4% respectively. Female sex (p = 0.018) and GTR (p < 0.01) were found to be independent prognostic factors for PFS and female sex (p = 0.019) was that for OS. Initial and second recurrences were most often leptomeningeal (67% and 100% respectively). 80% (20/25) of patients harbored a KBTBD4 mutation. CONCLUSIONS: Female sex and GTR were independent prognostic factors in our patients with PPTID. Leptomeningeal recurrence was observed to be particularly characteristic of this tumor. The rate of KBTBD4 mutation observed in our cohort was acceptable and this could prove the accuracy of our PPTID cohort.

Two children with lymphocytic hypophysitis presenting with positive anti-rabphilin-3A antibody.

Lymphocytic hypophysitis (LYH) is a rare chronic inflammatory disease characterized by lymphocytic infiltration of the anterior or posterior pituitary gland and hypothalamus. LYH is subdivided into lymphocytic adenohypophysitis (LAH), lymphocytic infundibulo-neurohypophysitis (LINH), and lymphocytic panhypophysitis (LPH) depending on the primary site. Most cases occur in adults, with few cases reported in children, and it is especially important to distinguish LYH from suprasellar malignancies, such as germ cell tumors and other neoplastic diseases. Although a biopsy is necessary for definitive diagnosis, it is desirable to be able to diagnose the disease without biopsy if possible, especially in children, because of the surgical invasiveness of the procedure. Recently, serum anti-rabphilin-3A antibodies have attracted attention as diagnostic markers for LYH, especially in LINH, but there are only a few reports on pediatric patients. In the present study, we experienced two children with LPH and LAH, respectively, who tested positive for anti-rabphilin-3A antibodies. This is the first report of children with LYH other than LINH positive for anti-rabphilin-3A antibodies, and anti-rabphilin-3A antibodies may be a useful non-invasive diagnostic marker not only for LINH but also for LYH in general. We also discuss the sensitivity and specificity of anti-rabphilin-3A antibody testing in cases where histological diagnosis has been made.

Lynch syndrome-associated chordoma with high tumor mutational burden and significant response to immune checkpoint inhibitors.

Chordoma is a rare malignant bone tumor arising from notochordal tissue. Conventional treatments, such as radical resection and high-dose irradiation, frequently fail to control the tumor, resulting in recurrence and re-growth. In this study, genetic analysis of the tumor in a 72-year-old male patient with refractory conventional chordoma of the skull base revealed a high tumor mutational burden (TMB) and mutations in the MSH6 and MLH1 genes, which are found in Lynch syndrome. The patient and his family had a dense cancer history, and subsequent germline genetic testing revealed Lynch syndrome. This is the first report of a chordoma that has been genetically proven to be Lynch syndrome. Chordomas usually have low TMB; however, this is an unusual case, because the TMB was high, and immune checkpoint inhibitors effectively controlled the tumor. This case provides a basis for determining the indications for immunotherapy of chordoma based on the genetic analysis. Therefore, further extensive genetic analysis in the future will help to stratify the treatment of chordoma.

Importance of Age and Noncontrast-Enhancing Tumor as Biomarkers for Isocitrate Dehydrogenase-Mutant Glioblastoma: A Multicenter Study.

PURPOSE: This study aimed to investigate the most useful clinical and magnetic resonance imaging (MRI) parameters for differentiating isocitrate dehydrogenase (IDH)-mutant and -wildtype glioblastomas in the 2016 World Health Organization Classification of Tumors of the Central Nervous System. METHODS: This multicenter study included 327 patients with IDH-mutant or IDH-wildtype glioblastoma in the 2016 World Health Organization classification who preoperatively underwent MRI. Isocitrate dehydrogenase mutation status was determined by immunohistochemistry, high-resolution melting analysis, and/or IDH1/2 sequencing. Three radiologists independently reviewed the tumor location, tumor contrast enhancement, noncontrast-enhancing tumor (nCET), and peritumoral edema. Two radiologists independently measured the maximum tumor size and mean and minimum apparent diffusion coefficients of the tumor. Univariate and multivariate logistic regression analyses with an odds ratio (OR) were performed. RESULTS: The tumors were IDH-wildtype glioblastoma in 306 cases and IDH-mutant glioblastoma in 21. Interobserver agreement for both qualitative and quantitative evaluations was moderate to excellent. The univariate analyses revealed a significant difference in age, seizure, tumor contrast enhancement, and nCET ( P < 0.05). The multivariate analysis revealed significant difference in age for all 3 readers (reader 1, odds ratio [OR] = 0.960, P = 0.012; reader 2, OR = 0.966, P = 0.048; reader 3, OR = 0.964, P = 0.026) and nCET for 2 readers (reader 1, OR = 3.082, P = 0.080; reader 2, OR = 4.500, P = 0.003; reader 3, OR = 3.078, P = 0.022). CONCLUSIONS: Age and nCET are the most useful parameters among the clinical and MRI parameters for differentiating IDH-mutant and IDH-wildtype glioblastomas.

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).

Macrophage colony-stimulating factor potentially induces recruitment and maturation of macrophages in recurrent pituitary neuroendocrine tumors.

Although pituitary neuroendocrine tumors (PitNETs) are usually benign, some are highly invasive and recurrent. Recurrent PitNETs are often treatment-resistant and there is currently no effective evidence-based treatment. Tumor-associated macrophages (TAMs) promote tumor growth in many cancers, but the effect of TAMs on PitNETs remains unclear. This study investigated the role of TAMs in the incidence of recurrent PitNETs. Immunohistochemical analysis revealed that the densities of CD163- and CD204-positive TAMs tended to increase in recurrent PitNETs. Compared with TAMs in primary lesions, those in recurrent lesions were enlarged. To clarify the cell-cell interactions between TAMs and PitNETs, in vitro experiments were performed using a mouse PitNET cell line AtT20 and the mouse macrophage cell line J774. Several cytokines related to macrophage chemotaxis and differentiation, such as M-CSF, were elevated significantly by stimulation with macrophage conditioned medium. When M-CSF immunohistochemistry analysis was performed using human PitNET samples, M-CSF expression increased significantly in recurrent lesions compared with primary lesions. Although no M-CSF receptor (M-CSFR) expression was observed in tumor cells of primary and recurrent PitNETs, flow cytometric analysis revealed that the mouse PitNET cell line expressed M-CSFR. Cellular proliferation in mouse PitNETs was inhibited by high concentrations of M-CSFR inhibitors, suggesting that cell-to-cell communication between PitNETs and macrophages induces M-CSF expression, which in turn enhances TAM chemotaxis and maturation in the tumor microenvironment. Blocking the M-CSFR signaling pathway might be a novel therapeutic adjuvant in treating recurrent PitNETs.

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.

Gliosarcoma with Systemic Metastasis Showing Favorable Response to Ifosfamide, Carboplatin, and Etoposide Chemotherapy: An Autopsy Case Report.

Gliosarcoma is a rare malignant neoplasm. It accounts for approximately 2% of all glioblastomas. To date, there is no established treatment method for gliosarcoma, and a variety of therapies, such as surgical resection, radiotherapy, and chemotherapy, are typically employed. Here, we describe a patient with gliosarcoma who, despite multiple tumor metastases throughout the body, including the lungs and lymph nodes, achieved a relatively long survival due to salvage therapy with local irradiation and remarkably effective chemotherapy with low-dose ifosfamide, carboplatin, and etoposide therapy. When the patient died, we performed autopsy and confirmed the nature of the primary and metastatic tumor cells that had spread throughout the patient's body. Clinical and systemic histological studies also suggested the possibility of re-metastasis to the brain from systemic metastatic foci. Gliosarcoma appears to have characteristics similar to sarcoma as well as a higher risk of systemic metastasis. Therefore, a careful follow-up is necessary in such patients.

Ribosomal proteins induce stem cell-like characteristics in glioma cells as an "extra-ribosomal function".

The characteristic features of plasticity and heterogeneity in glioblastoma (GB) cells cause therapeutic difficulties. GB cells are exposed to various stimuli from the tumor microenvironment and acquire the potential to resist chemoradiotherapy. To investigate how GB cells acquire stem cell-like phenotypes, we focused on ribosomal proteins, because ribosome incorporation has been reported to induce stem cell-like phenotypes in somatic cells. Furthermore, dysregulation of ribosome biogenesis has been reported in several types of cancer. We focused on ribosomal protein S6, which promotes sphere-forming ability and stem cell marker expression in GB cells. We expect that investigation of dysregulation of ribosome biogenesis and extra-ribosomal function in GB will provide new insights about the plasticity, heterogeneity, and therapeutic resistance of GB cells, which can potentially lead to revolutionary therapeutic strategies.

Diffusely infiltrating glioma with CREBBP-BCORL1 fusion showing overexpression of not only BCORL1 but BCOR: A case report.

BCORL1 encodes a transcriptional corepressor homolog to BCOR. BCORL1 rearrangements have been previously described as rare events, and among them, CREBBP-BCORL1 has been reported only in 2 cases of ossifying fibromyxoid tumors. Herein, we present the first case of diffusely infiltrating glioma with CREBBP-BCORL1 involving a 17-year-old female patient. Histologically, the tumor was composed of a diffusely infiltrative proliferation of small tumor cells with moderate cellularity showing prominent microcystic formation. DNA methylation analysis revealed that the current case and a previously reported anaplastic ependymoma with EP300-BCORL1 were clustered together in close proximity to but distinct from methylation class high-grade neuroepithelial tumor with BCOR alteration. RNA sequencing demonstrated high mRNA expression of not only BCORL1 but BCOR, and the latter was compatible with diffuse nuclear expression of BCOR detected by immunohistochemistry. Our findings suggest that central nervous system tumors with CREBBP/EP300-BCORL1 may exhibit diverse morphologies but form a distinct DNA methylation group and that BCORL1 fusion genes may lead to upregulation of both BCOR and BCORL1.

Hybrid deep-learning-based denoising method for compressed sensing in pituitary MRI: comparison with the conventional wavelet-based denoising method.

OBJECTIVES: This study aimed to evaluate the efficacy of a combined wavelet and deep-learning reconstruction (DLR) method for under-sampled pituitary MRI. METHODS: This retrospective study included 28 consecutive patients who underwent under-sampled pituitary T2-weighted images (T2WI). Images were reconstructed using either the conventional wavelet denoising method (wavelet method) or the wavelet and DLR methods combined (hybrid DLR method) at five denoising levels. The signal-to-noise ratio (SNR) of the CSF, hypothalamic, and pituitary images and the contrast between structures were compared between the two image types. Noise quality, contrast, sharpness, artifacts, and overall image quality were evaluated by two board-certified radiologists. The quantitative and the qualitative analyses were performed with robust two-way repeated analyses of variance. RESULTS: Using the hybrid DLR method, the SNR of the CSF progressively increased as denoising levels increased. By contrast, with the wavelet method, the SNR of the CSF, hypothalamus, and pituitary did not increase at higher denoising levels. There was a significant main effect of denoising methods (p < 0.001) and denoising levels (p < 0.001), and an interaction between denoising methods and denoising levels (p < 0.001). For all five qualitative scores, there was a significant main effect of denoising methods (p < 0.001) and an interaction between denoising methods and denoising levels (p < 0.001). CONCLUSIONS: The hybrid DLR method can provide higher image quality for T2WI of the pituitary with compressed sensing (CS) than the wavelet method alone, especially at higher denoising levels. KEY POINTS: • The signal-to-noise ratios of cerebrospinal fluid progressively increased with the hybrid DLR method, with an increase in the denoising level for cerebrospinal fluid in pituitary T2WI with CS. • The signal-to-noise ratios of cerebrospinal fluid using the conventional wavelet method did not increase at higher denoising levels. • All qualitative scores of hybrid deep-learning reconstructions at all denoising levels were higher than those for the wavelet denoising method.

The Japan Society for Neuro-Oncology guideline on the diagnosis and treatment of central nervous system germ cell tumors.

Primary CNS germ cell tumors (GCTs) are rare neoplasms predominantly observed in the pediatric and young adult populations. In line with the hypothesis that the primordial germ cell is the cell-of-origin, histopathological examinations for this pathology involve a diverse range of components mirroring the embryogenic developmental dimensions. Chemotherapy and radiotherapy are the mainstays of treatment, with surgery having a limited role for diagnosis and debulking of residual tissue after treatment. While better management has been achieved over recent decades by modifying radiation coverage and selecting appropriate chemotherapy, standardization of treatment remains challenging, partly due to the low volume of cases encountered in each institution. As the incidence is higher in East Asia, including Japan, the Japan Society for Neuro-Oncology established a multidisciplinary task force to create an evidence-based guideline for CNS GCTs. This guideline provides recommendations for multiple dimensions of clinical management for CNS GCTs, with particular focus on diagnostic measures including serum markers, treatment algorithms including surgery, radiotherapy, and chemotherapy, and under-investigated but important areas such as treatment for recurrent cases, long-term follow-up protocols, and long-term sequelae. This guideline serves the purpose of helping healthcare professionals keep up to date with current knowledge and standards of management for patients with this rare disease in daily clinical practice, as well as driving future translational and clinical research by recognizing unmet needs concerning this tumor.