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.

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.

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.

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.

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.

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.

[Epidemiology for Glioma].

Recently, Japan's population has been aging with a declining birth rate at an unprecedented rate compared to that worldwide, and Kumamoto Prefecture is no exception. In this chapter, we examine whether the recent changes in vital statistics have affected the incidence of glioma based on data from the latest Kumamoto Prefecture Brain Tumor Data Bank. We compare the age-adjusted incidence of glioma extracted from the Brain Tumor Registry of Japan and Central Brain Tumor Registry of the United States(CBTRUS)for the period from 1990 to 2017 when data on the annual transition of the population composition in Kumamoto Prefecture were obtained. This chapter also outlines whether there are differences in survival rates between Japan and the United States. We hope that this chapter will help you determine the future direction of glioma treatment in Japan.

Ribosomal protein S6 promotes stem-like characters in glioma cells.

Glioblastoma multiforme (GBM), a lethal brain tumor developing in the white matter of the adult brain, contains a small population of GBM stem cells (GSCs), which potentially cause chemotherapeutic resistance and tumor recurrence. However, the mechanisms underlying the pathogenesis and maintenance of GSCs remain largely unknown. A recent study reported that incorporation of ribosomes and ribosomal proteins into somatic cells promoted lineage trans-differentiation toward multipotency. This study aimed to investigate the mechanism underlying stemness acquisition in GBM cells by focusing on 40S ribosomal protein S6 (RPS6). RPS6 was significantly upregulated in high-grade glioma and localized at perivascular, perinecrotic, and border niches in GBM tissues. siRNA-mediated RPS6 knock-down significantly suppressed the characteristics of GSCs, including their tumorsphere potential and GSC marker expression; STAT3 was downregulated in GBM cells. RPS6 overexpression enhanced the tumorsphere potential of GSCs and these effects were attenuated by STAT3 inhibitor (AG490). Moreover, RPS6 expression was significantly correlated with SOX2 expression in different glioma grades. Immunohistochemistry data herein indicated that RPS6 was predominant in GSC niches, concurrent with the data from IVY GAP databases. Furthermore, RPS6 and other ribosomal proteins were upregulated in GSC-predominant areas in this database. The present results indicate that, in GSC niches, ribosomal proteins play crucial roles in the development and maintenance of GSCs and are clinically associated with chemoradioresistance and GBM recurrence.

Multiplex ligation-dependent probe amplification analysis is useful for detecting a copy number gain of the FGFR1 tyrosine kinase domain in dysembryoplastic neuroepithelial tumors.

PURPOSE: Dysembryoplastic neuroepithelial tumors (DNTs) are slow-growing glioneuronal tumors, and their genetic backgrounds are getting unveiled. Recently, fibroblast growth factor receptor 1 internal tandem duplication (FGFR1-ITD) of the tyrosine kinase domain (TKD) has been demonstrated by whole-genome sequencing. METHODS AND RESULTS: Here, we analyzed 22 DNTs using multiplex ligation-dependent probe amplification (MLPA) with formalin-fixed paraffin-embedded specimens and found a copy number gain in TKD of FGFR1 (13 cases, 59%), which suggested the presence of FGFR1-ITD. Another 5 DNTs harbored FGFR1 hot spot mutations including a double mutant case, and FGFR1 alterations were detected in 18 DNTs (82%). The BRAF V600E mutation, another important mutation in DNTs, was not observed. CONCLUSIONS: With recent findings of less frequent or absent FGFR1-ITD in pilocytic astrocytomas or rosette-forming glioneuronal tumors, the analysis of FGFR1 aberrations, especially FGFR1-ITD, was suggested to be helpful to discriminate DNTs from their histological mimics.

Regulation of growth hormone biosynthesis by Cdk5 regulatory subunit associated protein 1-like 1 (CDKAL1) in pituitary adenomas.

CDK5 regulatory subunit associated protein 1-like 1 (CDKAL1) is a tRNA-modifying enzyme that catalyzes 2-methylthiolation (ms2) and has been implicated in the development of type 2 diabetes (T2D). CDKAL1-mediated ms2 is important for efficient protein translation and regulates insulin biosynthesis in pancreatic cells. Interestingly, an association between T2D and release of growth hormone (GH) has been reported in humans. However, it is unknown whether CDKAL1 is important for hormone production in the pituitary gland. The present study investigated the role of CDKAL1 in GH-producing pituitary adenomas (GHPAs). CDKAL1 activity was suppressed in GHPAs, as evidenced by a decrease in ms2, compared with non-functioning pituitary adenomas (NFPAs), which do not produce specific hormones. Downregulation of Cdkal1 using small interfering and short hairpin RNAs increased the biosynthesis and secretion of GH in rat GH3 cells. Depletion of Cdkal1 increased the cytosolic calcium level via downregulation of DnaJ heat shock protein family (Hsp40) member C10 (Dnajc10), which is an endoplasmic reticulum protein related to calcium homeostasis. This stimulated transcription of GH via upregulation of Pit-1. Moreover, CDKAL1 activity was highly sensitive to proteostatic stress and was upregulated by suppression of this stress. Taken together, these results suggest that dysregulation of CDKAL1 is involved in the pathogenesis of GHPAs, and that modulation of the proteostatic stress response might control CDKAL1 activity and facilitate treatment of GHPAs.

BCL2 expression is associated with a poor prognosis independent of cellular origin in primary central nervous system diffuse large B-cell lymphoma.

PURPOSE: Primary central nervous system diffuse large B-cell lymphoma (CNS-DLBCL) is a distinct clinicopathological entity with a poor prognosis. Concurrent MYC and BCL2 overexpression predicts inferior prognosis in systemic DLBCL, although their prognostic significance remains unclear in primary CNS-DLBCL. METHODS: Pretreatment diagnostic biopsy samples were retrospectively evaluated for 79 patients with primary CNS-DLBCL who were treated between January 2001 and December 2017. Histological and immunohistochemical testing were performed to evaluate the patients' statuses for various markers, which were also evaluated for associations with survival outcomes. RESULTS: According to the Hans criteria, 26 patients (32.9%) had the germinal center B-cell subtype and 53 patients (67.1%) had the activated B-cell subtype. Forty-one cases (51.9%) were positive for MYC (expression of ≥ 40%), 33 cases (41.8%) were positive for BCL2 (expression of ≥ 70%), 22 patients (27.8%) were positive for both MYC and BCL2, and 27 patients (34.2%) were negative for both MYC and BCL2. There were no significant differences in survival between the germinal center and activated B-cell subtypes. Furthermore, MYC positivity was not associated with overall survival (p = 0.369) or progression-free survival (PFS) (p = 0.253). However, BCL2 positivity was significantly associated with poor overall survival (p = 0.039) and PFS (p = 0.036). Co-expression of MYC and BCL2 was not associated with survival. CONCLUSION: Our data suggest that evaluating BCL2 expression may help predict the prognosis in cases of primary CNS-DLBCL.

Mesenchymal Stem Cells Isolated From Human Gliomas Increase Proliferation and Maintain Stemness of Glioma Stem Cells Through the IL-6/gp130/STAT3 Pathway.

Although mesenchymal stem cells (MSCs) have been implicated as stromal components of several cancers, their ultimate contribution to tumorigenesis and their potential to drive cancer stem cells, particularly in the unique microenvironment of human brain tumors, remain largely undefined. Consequently, using established criteria, we isolated glioma-associated-human MSCs (GA-hMSCs) from fresh human glioma surgical specimens for the first time. We show that these GA-hMSCs are nontumorigenic stromal cells that are phenotypically similar to prototypical bone marrow-MSCs. Low-passage genomic sequencing analyses comparing GA-hMSCs with matched tumor-initiating glioma stem cells (GSCs) suggest that most GA-hMSCs (60%) are normal cells recruited to the tumor (group 1 GA-hMSCs), although, rarely (10%), GA-hMSCs may differentiate directly from GSCs (group 2 GA-hMSCs) or display genetic patterns intermediate between these groups (group 3 GA-hMSCs). Importantly, GA-hMSCs increase proliferation and self-renewal of GSCs in vitro and enhance GSC tumorigenicity and mesenchymal features in vivo, confirming their functional significance within the GSC niche. These effects are mediated by GA-hMSC-secreted interleukin-6, which activates STAT3 in GSCs. Our results establish GA-hMSCs as a potentially new stromal component of gliomas that drives the aggressiveness of GSCs, and point to GA-hMSCs as a novel therapeutic target within gliomas.

Subthalamic nucleus stimulation improves Parkinson's disease-associated camptocormia in parallel to its preoperative levodopa responsiveness.

OBJECTIVE: The aim of this work was to identify factors predictive of postoperative improvement of camptocormia in patients with Parkinson's disease (PD) treated by subthalamic nucleus (STN) stimulation. BACKGROUND: Camptocormia, one of the most disabling features of PD, often responds poorly to medical therapies. The reported effects of deep brain stimulation on PD-associated camptocormia vary, and preoperative characteristics affecting the surgical outcome remain unclear. METHODS: We evaluated 17 patients with camptocormia whose preoperative off-medication thoracolumbar angle exceeded 45°. We used photographs to measure their thoracolumbar angle preoperatively, 3 months after surgery, and at the last follow-up (mean 36.5 months postoperatively) in status on-medication and off-medication. The patient age, duration of PD and camptocormia, daily medications, Unified Parkinson's Disease Rating Scale (UPDRS) subscores and the Schwab-England activity of daily living scale (S-E) were also recorded. Univariate analysis was performed to identify factors predictive of the postoperative improvement of camptocormia. RESULTS: STN stimulation significantly improved the UPDRS subscores and S-E, and resulted in a reduction of daily medications 3 months post-treatment. The preoperative thoracolumbar angle (mean±SD) in status off-medication (84.0±29.5°) was significantly ameliorated 3 months postoperatively (49.8±29.3°) and at the last follow-up (54.8±28.3°). There was no correlation between the postoperative camptocormia improvement rate and preoperative parameters other than the duration and severity of camptocormia and the levodopa responsiveness of the thoracolumbar angle. Symptom duration negatively affected levodopa responsiveness. CONCLUSIONS: STN stimulation improves PD-associated camptocormia in parallel with preoperative levodopa responsiveness. Long symptom duration interferes with levodopa responsiveness.

Antitumor effect of fibrin glue containing temozolomide against malignant glioma.

Temozolomide (TMZ), used to treat glioblastoma and malignant glioma, induces autophagy, apoptosis and senescence in cancer cells. We investigated fibrin glue (FG) as a drug delivery system for the local administration of high-concentration TMZ aimed at preventing glioma recurrence. Our high-power liquid chromatography studies indicated that FG containing TMZ (TMZ-FG) manifested a sustained drug release potential. We prepared a subcutaneous tumor model by injecting groups of mice with three malignant glioma cell lines and examined the antitumor effect of TMZ-FG. We estimated the tumor volume and performed immunostaining and immunoblotting using antibodies to Ki-67, cleaved caspase 3, LC3 and p16. When FG sheets containing TMZ (TMZ-FGS) were inserted beneath the tumors, their growth was significantly suppressed. In mice treated with peroral TMZ plus TMZ-FGS the tumors tended to be smaller than in mice whose tumors were treated with TMZ-FGS or peroral TMZ alone. The TMZ-FGS induced autophagy, apoptosis and senescence in subcutaneous glioma tumor cells. To assess the safety of TMZ-FG for normal brain, we placed it directly on the brain of living mice and stained tissue sections obtained in the acute and chronic phase immunohistochemically. In both phases, TMZ-FG failed to severely damage normal brain tissue. TMZ-FG may represent a safe new drug delivery system with sustained drug release potential to treat malignant glioma.

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.

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.

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.

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.

p53 activation of mesenchymal stromal cells partially abrogates microenvironment-mediated resistance to FLT3 inhibition in AML through HIF-1α-mediated down-regulation of CXCL12.

Fms-like tyrosine kinase-3 (FLT3) inhibitors have been used to overcome the dismal prognosis of acute myeloid leukemia (AML) with FLT3 mutations. Clinical results with FLT3 inhibitor monotherapy have shown that bone marrow responses are commonly less pronounced than peripheral blood responses. We investigated the role of p53 in bone marrow stromal cells in stromal cell-mediated resistance to FLT3 inhibition in FLT3 mutant AML. While the FLT3 inhibitor FI-700 induced apoptosis in FLT3 mutant AML cells, apoptosis induction was diminished under stromal coculture conditions. Protection appeared to be mediated, in part, by CXCL12 (SDF-1)/CXCR4 signaling. The protective effect of stromal cells was significantly reduced by pre-exposure to the HDM2 inhibitor Nutlin-3a. p53 activation by Nutlin-3a was not cytotoxic to stromal cells, but reduced CXCL12 mRNA levels and secretion of CXCL12 partially through p53-mediated HIF-1α down-regulation. Results show that p53 activation in stroma cells blunts stroma cell-mediated resistance to FLT3 inhibition, in part through down-regulation of CXCL12. This is the first report of Nutlin effect on the bone marrow environment. We suggest that combinations of HDM2 antagonists and FLT3 inhibitors may be effective in clinical trials targeting mutant FLT3 leukemias.