Intraoperative Integrated Diagnostic System for Malignant Central Nervous System Tumors.

PURPOSE: The 2021 World Health Organization (WHO) classification of central nervous system (CNS) tumors uses an integrated approach involving histopathology and molecular profiling. Because majority of adult malignant brain tumors are gliomas and primary CNS lymphomas (PCNSL), rapid differentiation of these diseases is required for therapeutic decisions. In addition, diffuse gliomas require molecular information on single-nucleotide variants (SNV), such as IDH1/2. Here, we report an intraoperative integrated diagnostic (i-ID) system to classify CNS malignant tumors, which updates legacy frozen-section (FS) diagnosis through incorporation of a qPCR-based genotyping assay. EXPERIMENTAL DESIGN: FS evaluation, including GFAP and CD20 rapid IHC, was performed on adult malignant CNS tumors. PCNSL was diagnosed through positive CD20 and negative GFAP immunostaining. For suspected glioma, genotyping for IDH1/2, TERT SNV, and CDKN2A copy-number alteration was routinely performed, whereas H3F3A and BRAF SNV were assessed for selected cases. i-ID was determined on the basis of the 2021 WHO classification and compared with the permanent integrated diagnosis (p-ID) to assess its reliability. RESULTS: After retrospectively analyzing 153 cases, 101 cases were prospectively examined using the i-ID system. Assessment of IDH1/2, TERT, H3F3AK27M, BRAFV600E, and CDKN2A alterations with i-ID and permanent genomic analysis was concordant in 100%, 100%, 100%, 100%, and 96.4%, respectively. Combination with FS and intraoperative genotyping assay improved diagnostic accuracy in gliomas. Overall, i-ID matched with p-ID in 80/82 (97.6%) patients with glioma and 18/19 (94.7%) with PCNSL. CONCLUSIONS: The i-ID system provides reliable integrated diagnosis of adult malignant CNS tumors.

Genetic alterations that deregulate RB and PDGFRA signaling pathways drive tumor progression in IDH2-mutant astrocytoma.

In IDH-mutant astrocytoma, IDH2 mutation is quite rare and biological mechanisms underlying tumor progression in IDH2-mutant astrocytoma remain elusive. Here, we report a unique case of IDH2 mutant astrocytoma, CNS WHO grade 3 that developed tumor progression. We performed a comprehensive genomic and epigenomic analysis for primary and recurrent tumors and found that both tumors harbored recurrent IDH2R172K and TP53R248W mutation with CDKN2A/B hemizygous deletion. We also found amplifications of CDK4 and MDM2 with PDGFRA gain in the recurrent tumor and upregulated protein expressions of these genes. We further developed, for the first time, a xenograft mouse model of IDH2R172K and TP53R248W mutant astrocytoma from the recurrent tumor, but not from the primary tumor. Consistent with parent recurrent tumor cells, amplifications of CDK4 and MDM2 and PDGFRA gain were found, while CDKN2A/B was identified as homozygous deletion in the xenografts, qualifying for integrated diagnosis of astrocytoma, IDH2-mutant, CNS WHO grade 4. Cell viability assay found that CDK4/6 inhibitor and PDGFR inhibitor potently decreased cell viability in recurrent tumor cells, as compared to primary tumor cells. These findings suggest that gene alterations that activate retinoblastoma (RB) signaling pathways and PDGFR may drive tumor progression and xenograft formation in IDH2-mutant astrocytoma, which is equivalent to progressive IDH1-mutant astrocytoma. Also, our findings suggest that these genomic alterations may represent therapeutic targets in IDH2-mutant astrocytoma.

Intraoperative extracorporeal irradiation for giant sarcoma-infiltrated calvarium: a case report.

Large bone defects that occur after resection of calvarial tumours are commonly remedied using titanium meshes or bone prostheses. However, these methods have several problems. While intraoperative extracorporeal radiotherapy for bone flaps could avoid these problems, there have been only a few reports wherein meningiomas were treated with 120 Gy irradiation. Moreover, no reports are available on calvarial metastasis of sarcoma, and the therapeutic radiation dose remains uncertain. Here, we report a case of giant calvarial metastasis of myxoid liposarcoma treated with intraoperative extracorporeal radiotherapy at a dose of 50 Gy. The treatment resulted in successful tumour control followed by favourable bone reconstruction.

Fractionated Gamma Knife radiosurgery after cyst aspiration for large cystic brain metastases: case series and literature review.

Tumor cyst aspiration followed by Gamma Knife radiosurgery (GKRS) for large cystic brain metastases is a reasonable and effective management strategy. However, even with aspiration, the target lesion tends to exceed the dimensions of an ideal target for stereotactic radiosurgery. In this case, the local tumor control rate and the risk of complication might be a critical challenge. This study is aimed to investigate whether fractionated GKRS (f-GKRS) could solve these problems. Between May 2018 and April 2021, eight consecutive patients with nine lesions were treated with f-GKRS in five or ten sessions after cyst aspiration. The aspiration was repeated as needed throughout the treatment course to maintain the cyst size and shape. The patient characteristics, radiologic tumor response, and clinical course were reviewed using medical records. The mean follow-up duration was 10.2 (2-28) months. The mean pre-GKRS volume and maximum diameter were 16.7 (5-55.8) mL and 39.0 (31-79) mm, respectively. The mean tumor volume reduction achieved by aspiration was 55.4%. The tumor volume decreased for all lesions, and symptoms were alleviated in all patients. The median overall survival was 10.0 months, and the estimated 1-year survival rate was 41.7% (95% CI: 10.9-70.8%). The local tumor control rate was 100%. No irradiation-related adverse events were observed. f-GKRS for aspirated cystic brain metastasis is a safe, effective, and less invasive management option for large cystic brain metastases.

HSP90 Inhibition Overcomes Resistance to Molecular Targeted Therapy in BRAFV600E-mutant High-grade Glioma.

PURPOSE: Molecular targeted therapy using BRAF and/or MEK inhibitors has been applied to BRAFV600E-mutant high-grade gliomas (HGG); however, the therapeutic effect is limited by the emergence of drug resistance. EXPERIMENTAL DESIGN: We established multiple paired BRAFV600E-mutant HGG patient-derived xenograft models based on tissues collected prior to and at relapse after molecular targeted therapy. Using these models, we dissected treatment-resistant mechanisms for molecular targeted therapy and explored therapeutic targets to overcome resistance in BRAFV600E HGG models in vitro and in vivo. RESULTS: We found that, despite causing no major genetic and epigenetic changes, BRAF and/or MEK inhibitor treatment deregulated multiple negative feedback mechanisms, which led to the reactivation of the MAPK pathway through c-Raf and AKT signaling. This altered oncogenic signaling primarily mediated resistance to molecular targeted therapy in BRAFV600E-mutant HGG. To overcome this resistance mechanism, we performed a high-throughput drug screening to identify therapeutic agents that potently induce additive cytotoxicity with BRAF and MEK inhibitors. We discovered that HSP90 inhibition combined with BRAF/MEK inhibition coordinately deactivated the MAPK and AKT/mTOR pathways, and subsequently induced apoptosis via dephosphorylation of GSK3ß (Ser9) and inhibition of Bcl-2 family proteins. This mediated potent cytotoxicity in vitro and in vivo in refractory models with acquired resistance to molecular targeted therapy. CONCLUSIONS: The combination of an HSP90 inhibitor with BRAF or MEK inhibitors can overcome the limitations of the current therapeutic strategies for BRAFV600E-mutant HGG.

Primary midbrain germinoma relapse-free for 5 years: A case report.

Background: The biology and clinical course of intracranial germinomas differ as per their location of occurrence. Germinoma of the primary midbrain is particularly rare, and its clinical features, treatment strategies, and long-term prognosis remain uncertain. Case Description: A 39-year-old man who had been diagnosed with midbrain germinoma by open biopsy through the occipital transtentorial approach had undergone chemoradiotherapy and achieved 5 years with no recurrence. Conclusion: Germinomas should be considered as a differential diagnosis for adolescents and young adult men with mesencephalic tumors, and reliable sampling followed by chemoradiotherapy must be performed.

Superficial siderosis and nonobstructive hydrocephalus due to subependymoma in the ventricle: An illustrative case report.

Background: Intraventricular tumors can generally result in obstructive hydrocephalus as they grow. Rarely, however, some intraventricular tumors develop superficial siderosis (SS) and trigger hydrocephalus, even though the tumor has hardly grown. Here, we present an illustrative case of SS and nonocclusive hydrocephalus caused by subependymoma of the lateral ventricles. Case Description: A 78-year-old man with an intraventricular tumor diagnosed 7 years ago had been suffering from gait disturbance for 2 years. He also developed cognitive impairment. Intraventricular tumors showed little growth on annual magnetic resonance imaging (MRI). MRI T2-star weighted images (T2*WI) captured small intratumoral hemorrhages from the beginning of the follow-up. Three years before, at the same time as the onset of ventricular enlargement, T2*WI revealed low intensity in the whole tumor and cerebral surface. Subsequent follow-up revealed that this hemosiderin deposition had spread to the brain stem and cerebellar surface, and the ventricles had expanded further. Cerebrospinal fluid (CSF) examination revealed xanthochromia. The tumor was completely removed en bloc. Histopathological findings were consistent with those of subependymoma. Although CSF findings improved, SS and hydrocephalus did not improve. Therefore, the patient underwent a lumboperitoneal shunt for CSF diversion after tumor resection. Conclusion: Some intraventricular tumors cause SS and nonobstructive hydrocephalus due to microbleeding, even in the absence of tumor growth. T2*WI and, if necessary, timely CSF examination can allow identification of presymptomatic SS. This follow-up strategy may provide a favorable course by facilitating early intervention in patients with intraventricular lesions, not just subependymomas.

Frontal Base Endodermal Cyst: A Case Report and Review of Literature.

BACKGROUND: Endodermal cyst (EC) is a rare congenital cyst of endodermal origin, but the pathogenesis of this entity remains uncertain. Supratentorial EC is particularly uncommon, but some cases have been reported. Here, we report a case of supratentorial EC that developed at the frontal base which indicates posttraumatic development rather than a congenital origin. CASE DESCRIPTION: A 65-year-old man who had a history of orbital bone fracture without rhinorrhea sustained in a traffic accident presented with gradually enlarging frontal-base cystic lesions. Multiple cystic lesions were removed via left frontal craniotomy. The cysts showed no communication with the frontal sinus. Histological examination identified EC. Postoperative course was uneventful and no recurrences have been identified as of 2 years later. CONCLUSIONS: According to reported cases, unlike ECs in other intracranial locations, frontal base ECs tend to present at advanced ages. The present case also presented with EC enlargement at an advanced age and two lesions located at the bone hiatus in the frontal base that were presumably caused by trauma. It is possible that sinus communication was repaired as the bone fracture was remodeled, and the remnant sinus epithelial tissues developed into ECs over time. This situation makes it reasonable to presume a posttraumatic rather than a congenital origin. In conclusion, as for frontal base ECs, contrary to the traditional theory, the developmental mechanisms may not necessarily be congenital.

PEGylation of Co-Zn Ferrite Nanoparticles for Theranostics.

Multi-element ferrite nanoparticles (NPs) were synthesized as heat agents for use in magnetic hyperthermia treatments, specifically, Co0.8Zn0.2Fe2O4 NPs coating with polyethylene glycol. The crystal structures of these particles were examined by X-ray diffraction. Particle diameters were controlled to be approximately 10 nm by controlling the annealing temperature and time. The modification of polyethylene glycol (PEG) on the particles was confirmed by mass spectrometry and Fourier-transform infrared spectrometry. The heat dissipation characteristics of the particles were investigated by measuring AC magnetic susceptibility and temperature increase in AC magnetic fields. A peak in the imaginary part of AC magnetic susceptibility χ″ appeared, depending on the frequency. The value of χ″ was found to contribute to the effective heat dissipation according to the Neel relaxation system. The temperature increase of the particles was measured in AC magnetic fields of 64-146 Oe, with an observed temperature increase of ~10 K. Finally, to test the applications of these particles in theranostics, in vitro experiments using human breast cancer cells were conducted.

Cerebral amyloid-ß-related angiitis without cerebral microbleeds in a patient with subarachnoid hemorrhage.

Amyloid-ß-related angiitis (ABRA), a subtype of cerebral amyloid angiopathy (CAA), is vasculitis occurring in relation to amyloid-ß (Aß) deposition in the walls of intracranial blood vessels. ABRA is presumed to be caused by some immune response to the deposited Aß. An 81-year-old man on oral anticoagulant therapy complained of headache, nausea, and difficulty with standing after a head injury. Head computed tomography revealed subcortical bleeding in the right temporoparietal lobe, and 3 days after admission, magnetic resonance imaging (MRI) showed subarachnoid hemorrhage (SAH) around the hematoma. Cerebral microbleeds, a characteristic of CAA, were not detected on MRI. On worsening of his symptoms, intracranial brain biopsy and hematoma removal were performed. Intraoperative rapid diagnosis with a frozen section suspected vasculitis, which enabled the prompt initiation of steroid therapy. He was pathologically diagnosed with ABRA (granulomatous angiitis) using a formalin-fixed paraffin-embedded section. Vasculitis was prominent around blood vessels in the pia matter covering the cerebrum. In this case, the inflammatory cells seemed to appear via the subarachnoid space following cerebral hemorrhage and SAH. ABRA seemed to be developed by intracranial hemorrhage in this case.

Optimal implantation of Ommaya reservoirs for cystic metastatic brain tumors preceding Gamma Knife radiosurgery.

INTRODUCTION: Although Ommaya reservoir implantation is effective in reducing the target volume of cystic brain metastases preceding stereotactic radiosurgery, adequate volume reduction cannot be achieved in some cases, and the factors leading to failure in volume reduction have not been clearly identified. In this study, we investigated the factors leading to failure in volume reduction after use of the Ommaya reservoir. MATERIALS AND METHODS: Between December 2007 and February 2015, 38 consecutive patients with 40 cystic metastases underwent Ommaya reservoir implantation at our institution. The patient characteristics, treatment parameters, and all available clinical and neuroimaging follow-ups were analyzed retrospectively. RESULTS: The rate of volume reduction was significantly related to the location of the tube tip inside the cyst. By placing the tip at or near the center, 58.7% reduction was achieved, whereas reduction of 42.6% and 7.7% occurred with deep and shallow tip placement, respectively (p=0.011). Although there was no additional surgery in the center placement group, additional surgeries were performed in 5 out of the 23 deep and shallow cases due to inadequate volume reduction. No other factors were correlated with successful volume reduction. CONCLUSION: For adequate volume reduction using the Ommaya reservoir in the treatment of cystic brain metastases prior to stereotactic radiosurgery, the tip of the reservoir tube should be placed at the center of the cyst.