Recent advances in liquid biopsy of central nervous system lymphomas: case presentations and review of the literature.

Surgical biopsy is the gold standard for diagnosing central nervous system (CNS) lymphomas. However, reliable liquid biopsy methods for diagnosing CNS lymphomas have quickly developed and have been implicated in clinical decision-making. In the current report, we introduce two patients for whom liquid biopsy was essential for diagnosing CNS lymphomas and discuss the rapidly growing applications of this technology.

Importance of changes in abnormal muscle responses during microvascular decompression for hemifacial spasm.

Objective: To determine if compression sites of the facial nerve correlate with immediate postoperative outcomes in patients with hemifacial spasm (HFS), and if changes in the waveform of abnormal muscle response (AMR) during microvascular decompression (MVD) for HFS can predict the postoperative course. Methods: In this retrospective review, we evaluated 50 patients with HFS who underwent AMR monitoring during MVD. The ratios of amplitude and duration of AMR waveforms were computed by comparing baseline with final examinations. Vascular compression sites were categorized into four portions of the facial nerve. Postoperatively, we classified patients into two groups based on symptom relief as those whose symptoms disappeared immediately (DI group), and those whose symptoms disappeared gradually (DG group). Results: The compression sites significantly correlated with postoperative outcomes at discharge (p < 0.001) but not with outcomes after 6 months of MVD. Lower duration ratios of AMRs from the mentalis muscle were significantly associated with an increased chance of classification into the DI group based on the results of multivariate logistic regression analysis (p = 0.017). Conclusions: Relationship between compression sites and immediate outcomes could provide useful information to surgeons for predicting if symptoms will resolve over long term. Moreover, changes in AMRs recorded from the mentalis muscle could predict the postoperative course of HFS. Significance: These findings can help surgeons evaluate the changes in AMR amplitude and duration during MVD for HFS.

Non-sinus type of transverse sinus dural arteriovenous fistulas on the arachnoid granulation of the dural sinus wall.

Background: The etiology of a non-sinus-type dural arteriovenous fistulas (DAVFs) with shunt points located on the sinus wall, previously described as on-the-wall-type DAVFs, is unknown. Case Description: Two cases of non-sinus-type transverse sinus DAVF with a shunt point limited to the dural sinus wall, causing cortical venous reflux, were successfully treated with endovascular transarterial Onyx embolization. The Onyx cast showed multiple feeders from the occipital and middle meningeal arteries aggregated in the arachnoid granulation (AG), which dilated the draining vein. Conclusion: Non-sinus-type DAVFs with shunt points located on the AG may be one of the presentations of an on-the-wall-type DAVF.

[Interactive Virtual Simulation with Haptics for Neurosurgery].

We established a unique pre-surgical simulation method by applying interactive virtual simulation(IVS)using multi-fusion three-dimensional imaging data, presenting high-quality visualization of microsurgical anatomies. Our IVS provided a realistic environment for imitating surgical manipulations, such as dissecting bones, retracting brain tissues, and removing tumors, with tactile and kinesthetic sensations delivered through a specific haptic device. The great advantage of our IVS was in deciding the most appropriate craniotomy and bone resection to create the optimal surgical window and obtain the best working space with a thorough understanding of the lesion-bone relationship. Particularly for skull-base tumors, tailoring the procedures to individual patients for craniotomy and bone resection was sufficiently achieved using our IVS. In cases of large skull base meningiomas, our IVS was also helpful preoperatively regarding tumors, as several compartments were achievable in every potentially usable surgical direction. Additionally, the non-risky realistic microsurgical environments of the IVS provided improvement in the microsurgical senses and skills of young trainees through the repetition of surgical tasks. Finally, our presurgical IVS simulation method provided a realistic environment for practicing microsurgical procedures virtually and enabled us to ascertain the complex microsurgical anatomy, determine optimal surgical strategies, and efficiently educate neurosurgical trainees.

[Intraoperative Monitoring During Microvascular Decompression].

During microvascular decompression(MVD)for hemifacial spasm(HFS), trigeminal neuralgia(TN), and glossopharyngeal neuralgia(GPN), brainstem auditory-evoked potential monitoring is widely used to preserve hearing function. In MVD for HFS, abnormal muscle response monitoring is useful for identifying the offending vessels compressing the facial nerve and confirming the completion of decompression intraoperatively. The amplitude of facial motor-evoked potential by transcranial electrical stimulation in the orbicularis oculi muscle is reported to decrease after completing MVD. The Z-L response(ZLR)probably confirms the true offending vessels by stimulating the culprit vessels; then, the ZLR could disappear after decompressing the offending vessels away from the compression sites. Spontaneous electromyographic activities obtained from the mentalis muscles by injection of saline into the facial nerve reportedly decreased after MVD compared with those before MVD. In MVD for the GPN, glossopharyngeal motor-evoked potential by transcranial electrical stimulation is used to preserve swallowing function and not to assess the completion of MVD. Because MVD for both the TN and GPN can result in normalization of the hyperactivity of the sensory nerve, it may be difficult to develop any monitoring to confirm the completion of MVD during surgery.

Missense mutation of NRAS is associated with malignant progression in neurocutaneous melanosis.

Neurocutaneous melanosis (NCM) is a rare congenital neurocutaneous syndrome characterized by congenital melanocytic nevus of skin and abnormal proliferation of leptomeningeal melanocytes. Early acquisition of post-zygotic somatic mutations has been postulated to underlie the pathogenesis of NCM. The pathogenesis of NCM remains to be fully elucidated, and treatment options have not been established. Here, we report for the first time, multiregional genomic analyses in a 3-year-old autopsied girl with leptomeningeal melanomatosis associated with NCM, in which a ventriculo-peritoneal (VP) shunt was inserted for the treatment of hydrocephalus. The patient expired six months after the onset due to respiratory failure caused by abdominal dissemination via VP shunt. We performed multiregional exome sequencing to identify genomic differences among brain and abdominal tumors, nevus, and normal tissues. A total of 87 somatic mutations were found in 71 genes, with a significantly large number of gene mutations found in the tumor site. The genetic alterations detected in the nevus were only few and not shared with other sites. Three mutations, namely GNAQ R183Q, S1PR3 G89S and NRAS G12V, considered pathogenic, were found, although S1PR3 mutations have not been previously reported in melanocytic tumors. GNAQ and S1PR3 mutations were shared in both tumor and normal sites. Moreover, the mutant allele frequencies of the two mutations were markedly higher in tumor sites than in normal sites, with copy-neutral loss-of-heterozygosity (CN-LOH) occurring in tumor. NRAS mutation was found only in the abdominal tumor and was thought to be responsible for malignant progression in the present case. Multiregional comprehensive genetic analysis may lead to discovering novel driver mutations associated with tumorigenesis and targeted therapy.

Multi-omics analyses of choroid plexus carcinoma cell lines reveal potential targetable pathways and alterations.

PURPOSE: Choroid plexus carcinomas (CPCs) are extremely rare brain tumors and carry a dismal prognosis. Treatment options are limited and there is an urgent need to develop models to further research. In the present study, we established two CPC cell lines and performed multi-omics analyses. These cell lines serve as valuable models to propose new treatments in these rare but deadly brain tumors. METHODS: Multi-omic profiling including, (i) methylation array (EPIC 850 K), (ii) whole genome sequencing (WGS), (iii) CANCERPLEX cancer genome panel testing, (iv) RNA sequencing (RNA-seq), and (v) proteomics analyses were performed in CCHE-45 and NGT131 cell lines. RESULTS: Both cell lines were classified as methylation class B. Both harbored pathogenic TP53 point mutations; CCHE-45 additionally displayed TP53 loss. Furthermore, alterations of the NOTCH and WNT pathways were also detected in both cell lines. Two protein-coding gene fusions, BZW2-URGCP, and CTTNBP2-ERBB4, mutations of two oncodrivers, GBP-4 and KRTAP-12-2, and several copy number alterations were observed in CCHE-45, but not NGT131. Transcriptome and proteome analysis identified shared and unique signatures, suggesting that variability in choroid plexus carcinoma tumors may exist. The discovered difference's importance and implications highlight the possible diversity of choroid plexus carcinoma and call for additional research to fully understand disease pathogenesis. CONCLUSION: Multi-omics analyses revealed that the two choroid plexus carcinoma cell lines shared TP53 mutations and other common pathway alterations and activation of NOTCH and WNT pathways. Noticeable differences were also observed. These cell lines can serve as valuable models to propose new treatments in these rare but deadly brain tumors.

Reliable detection of genetic alterations in cyst fluid DNA for the diagnosis of brain tumors.

PURPOSE: Liquid biopsy of cyst fluid in brain tumors has not been extensively studied to date. The present study was performed to see whether diagnostic genetic alterations found in brain tumor tissue DNA could also be detected in cell-free DNA (cfDNA) of cyst fluid in cystic brain tumors. METHODS: Cyst fluid was obtained from 22 patients undergoing surgery for a cystic brain tumor with confirmed genetic alterations in tumor DNA. Pathological diagnoses based on WHO 2021 classification and diagnostic alterations in the tumor DNA, such as IDH1 R132H and TERT promoter mutation for oligodendrogliomas, were detected by Sanger sequencing. The same alterations were analyzed by both droplet digital PCR (ddPCR) and Sanger sequencing in cyst fluid cfDNA. Additionally, multiplex ligation-dependent probe amplification (MLPA) assays were performed to assess 1p/19q status, presence of CDKN2A loss, PTEN loss and EGFR amplification, to assess whether differentiating between astrocytomas and oligodendrogliomas and grading is possible from cyst fluid cfDNA. RESULTS: Twenty-five genetic alterations were found in 22 tumor samples. All (100%) alterations were detected in cyst fluid cfDNA by ddPCR. Twenty of the 25 (80%) alterations were also detected by Sanger sequencing of cyst fluid cfDNA. Variant allele frequency (VAF) in cyst fluid cfDNA was comparable to that of tumor DNA (R = 0.62, Pearson's correlation). MLPA was feasible in 11 out of 17 (65%) diffuse gliomas, with close correlation of results between tumor DNA and cyst fluid cfDNA. CONCLUSION: Cell-free DNA obtained from cyst fluid in cystic brain tumors is a reliable alternative to tumor DNA when diagnosing brain tumors.

Preoperative interactive virtual simulation applying three-dimensional multifusion images using a haptic device for lumbosacral lipoma.

PURPOSE: Untethering surgery for lumbosacral lipoma is a preventive procedure, and avoidance of complications and good long-term outcomes are required. We introduced presurgical interactive virtual simulation (IVS) applying three-dimensional multifusion images using a haptic device aimed at improving operative outcomes. METHODS: Fourteen patients with newly diagnosed lumbosacral lipoma were recruited and underwent preoperative IVS. The median age at surgery was 8 months. A three-dimensional image analysis system was used to extract and fuse structures necessary for surgery, such as the lipoma, spinal cord and skin, from CT and MRI, and create three-dimensional multifusion images. The created images were individually converted to standard triangulated language format and loaded onto a workstation (Geomagic freeform™) that could be freely transformed, and the laminectomy range and lipoma extraction procedure were examined. Presurgical IVS was performed, and the actual surgery was performed. RESULTS: The disease types were dorsal, caudal, lipomyelomeningocele, transitional, and filum in 5, 5, 2, 1, and 1 patients, respectively. The surgical procedure and extent of the laminectomy were as planned for all patients. Resection of the lipomas tended to be less than expected preoperatively because of positive reactions on intraoperative monitoring. No postoperative complications were observed. The median postoperative follow-up period was 29 months, and there were no reoperations during the observation period. CONCLUSIONS: Although there are various types of lumbosacral lipoma, surgery can be safely performed by performing presurgical IVS. The short-term course is good; however, long-term follow-up is necessary for the appearance of neurological symptoms associated with growth and re-tethering.

Unilateral chorea linked to cavernous haemangioma involving the putamen improved by surgery.

Unilateral chorea movements caused by cavernous haemangioma in the putamen are extremely rare. We report a case with chorea movements linked to cavernous haemangioma, localised to an area including the putamen in which pharmacotherapy was found to be ineffective. Symptoms were, however, improved by resection of the cavernous haemangioma. In cases where chorea movements linked to cavernous haemangioma, involving the putamen, prove intractable with watchful waiting or pharmacotherapy, improvement can be expected with surgical removal of the cavernous haemangioma. It is also possible to reduce the risk of complications through the use of intraoperative navigation and monitoring.

Clinical, imaging, and molecular features of radiation-induced glioblastomas developing more than 20 years after radiation therapy for intracranial germinomatous germ cell tumor: illustrative cases.

BACKGROUND: Germinomatous germ cell tumor is highly sensitive to chemoradiotherapy; patients are expected to survive for decades. Many radiation-induced malignant gliomas (RIMGs) occur >10 years after radiotherapy. Standard therapy for RIMGs has not been established because of the lesion's rarity, the patient's shorter survival period, and the risk of radiation necrosis by repeat radiation. OBSERVATIONS: Two patients, a 32-year-old man and a 50-year-old man, developed glioblastomas more than 20 years after radiation monotherapy for germinoma with or without mature teratoma. The first patient showed a tumor in the left frontotemporal region with disseminated lesions and died 2 months after partial resection of the tumor without responding to the chemotherapy with temozolomide and bevacizumab. Methylation classifier analysis classified the pathology as closest to diffuse pediatric-type high-grade glioma, Rtk1 subtype. The second patient showed a tumor mass in the brainstem and left cerebellar peduncle, which worsened progressively during chemotherapy with temozolomide and bevacizumab. The tumor transiently responded to stereotactic radiotherapy with the CyberKnife. However, the patient died of RIMG recurrence-related aspiration pneumonia 11 months after the biopsy. Methylation classifier analysis classified the pathology as closest to infratentorial pilocytic astrocytoma. LESSONS: Chemoradiotherapy may improve the survival of patients with RIMGs. Furthermore, molecular features may influence the clinical, locoregional, and pathological features of RIMG.

Usefulness of Y-shaped PulseRider-assisted coil embolization for basilar artery tip aneurysm with a misaligned axis: A case report.

Background: Endovascular treatment of wide-necked bifurcation aneurysms remains challenging. Although the advent of PulseRider and Web has expanded treatment options, aneurysms with a large deviation from the parent artery axis remains difficult to treat. We present the case of a wide-necked bifurcation aneurysm that was misaligned with the angle between the long axis of the parent artery and the aneurysm and was successfully treated with Y-shaped PulseRider-assisted coil embolization. Case Description: A 64-year-old woman presented with an unruptured basilar tip aneurysm. Cerebral angiography showed a wide-necked aneurysm measuring 8.1 mm × 6.1 mm, neck 5.7 mm. The aneurysm was strongly tilted to the right and posterior relative to the basilar artery, and the bilateral posterior cerebral artery (PCA) and superior cerebellar artery (SCA) diverged from the aneurysm body. PulseRider-assisted coil embolization was performed. A Y-shaped PulseRider was selected to be placed in a hybrid fashion with the right arch in the aneurysm and the left arch in the branch. Adequate coil embolization with preservation of the bilateral PCA and SCA was possible, and cerebral angiography immediately after the treatment showed slight dome filling. Cerebral angiography 6 months after the procedure showed that the embolic status had improved to complete occlusion. Conclusion: For wide-neck bifurcation aneurysms with a misaligned axis, a Y-shaped PulseRider used in a hybrid fashion, in which the leaflet on the side with the tilted axis is placed in the aneurysm, allows the PulseRider to be deployed more closely to the aneurysm, thereby enabling good coil embolization.

Investigation of Mechanical Thrombectomy in Elderly Patients over 85 Years Old: A Multicenter Study.

In Japan, which has a super-aging society, there are increasing opportunities to perform mechanical thrombectomy for the elderly; however, there is no recorded evidence of thrombectomy for the elderly. This study examined the usefulness of thrombectomy in the elderly. We retrospectively analyzed patient data using a multicenter acute ischemic stroke registry (NGT-FAST). We examined outcomes in patients 75 years and older who underwent thrombectomies between January 1, 2021, and December 31, 2021. The patients were divided into two groups: the 75-84-year-old group and the 85+-year-old group. There was no difference in the pretreatment National Institutes of Health Stroke Scale score or Alberta Stroke Program Early Computed Tomography Score between the two groups, but the 85+-year-old group had a significantly lower rate of pre-stroke modified Rankin Scale (mRS) score of 0-2. There were no differences in time from onset to treatment or effective recanalization rate, but complications tended to be more common in the 85+-year-old group. The number of patients with a good outcome at discharge (an mRS score of 0-3) was significantly lower in the 85+-year-old group than in the 75-84-year-old group. In addition, 90.9% of patients in the 85+-year-old group with a pre-stroke mRS score of 3 deteriorated after treatment. The pre-stroke mRS score is very important in determining the indication for thrombectomy in the elderly because their preoperative condition is more likely to influence the outcome than that of younger patients.

Usefulness of silent magnetic resonance angiography for intracranial aneurysms treated with a flow re-direction endoluminal device.

PURPOSE: Flow re-direction endoluminal device (FRED) is a novel dual-layer flow-diverting stent to treat cerebral aneurysms with high obliteration rates, however, it induces inevitable metal-related artifacts. We compared silent magnetic resonance angiography (MRA), a new MRA method using ultra-short time of echo and arterial spin-labeling, with conventional time-of-flight (TOF)-MRA for imaging aneurysms treated using FRED. METHODS: Between May 2020 and September 2022, 16 patients with unruptured internal carotid aneurysms treated using FRED simultaneously underwent silent MRA and TOF-MRA after treatment, with 36 follow-up sessions in total. Two observers independently graded the quality of intra-aneurysmal flow and stented parent arteries under both types of MRA from 1 (not visible) to 4 (nearly equal to digital subtraction angiography [DSA]), with reference to DSA images as a standard criterion. RESULTS: The mean scores for intra-aneurysmal flow and stented parent arteries were significantly better for silent MRA (3.93 ± 0.21 and 3.82 ± 0.32, respectively) than for TOF-MRA (2.08 ± 0.99 and 1.92 ± 0.79, respectively) (P < 0.01). Intermodality agreements for intra-aneurysmal flow and stented parent arteries were 0.87 and 0.90, respectively. CONCLUSION: Silent MRA is superior to TOF-MRA for assessing patients treated with FRED, with potential as an alternative imaging modality to DSA.

Superior Visualization of Neovascularization with Silent Magnetic Resonance Angiography Compared to Time-of-Flight Magnetic Resonance Angiography After Bypass Surgery in Moyamoya Disease.

OBJECTIVE: The evaluation of postsurgical neoangiogenesis in patients with moyamoya disease (MMD) is crucial for appropriate patient management. This study aimed to assess the visualization of neovascularization after bypass surgery using noncontrast-enhanced silent magnetic resonance angiography (MRA) with ultrashort echo time and arterial spin labeling. METHODS: After bypass surgery, 13 patients with MMD were followed up for >6 months between September 2019 and November 2022. They underwent silent MRA in the same session as time-of-flight magnetic resonance angiography (TOF-MRA) and digital subtraction angiography (DSA). Two observers independently rated the visualization of neovascularization in both types of MRA from 1 (not visible) to 4 (nearly equal to DSA), with reference to DSA images as the standard. RESULTS: The mean scores were significantly higher for silent MRA compared with TOF-MRA (3.81 ± 0.48 and 1.92 ± 0.70, respectively) (P < 0.01). The intermodality agreements were 0.83 and 0.71 for silent MRA and TOF-MRA, respectively. TOF-MRA depicted the donor artery and recipient cortical artery after direct bypass surgery, although fine neovascularization developed after indirect bypass surgery was poorly visualized. Silent MRA could reveal the developed bypass flow signal and perfused middle cerebral artery territory, which was almost equal to the DSA images. CONCLUSIONS: Silent MRA achieves better visualization of postsurgical revascularization in patients with MMD than TOF-MRA. Moreover, it may have the potential to provide visualization of the developed bypass flow equivalent to DSA.

Preoperative three-dimensional multifusion imaging aiding successful microvascular decompression of a cerebellopontine angle lipoma: associated hemifacial spasm. Illustrative case.

BACKGROUND: Cerebellopontine angle (CPA) lipoma-associated hemifacial spasm (HFS) is rare. As the removal of CPA lipomas has a high risk of worsening the neurological symptoms, surgical exploration is warranted only in selected patients. Preoperative identification of the lipoma affected site of the facial nerve, and offending artery are crucial for patient selection and successful microvascular decompression (MVD). OBSERVATIONS: Presurgical simulation using three-dimensional (3D) multifusion imaging showed a tiny CPA lipoma wedged between the facial and auditory nerves, as well as an affected facial nerve by the anterior inferior cerebellar artery (AICA) at the cisternal segment. Although a recurrent perforating artery from the AICA anchored the AICA to the lipoma, successful MVD was achieved without lipoma removal. LESSONS: The presurgical simulation using 3D multifusion imaging could identify the CPA lipoma, affected site of the facial nerve, and offending artery. It was helpful for patient selection and successful MVD.

A Case of Paradoxical Cerebral Embolism Due to Pulmonary Arteriovenous Fistula Mimicking Vertebral Artery Dissection With Wallenberg Syndrome.

Pulmonary arteriovenous fistula (PAVF) leads to paradoxical cerebral embolism, which can be fatal if left untreated. We report a rare case of brainstem infarction with acute severe headache and Wallenberg syndrome caused by a PAVF mimicking vertebral artery (VA) dissection. A 40-year-old man presented with a sudden occipital headache accompanied by right hemisensory disturbance. Magnetic resonance imaging revealed left lateral medullary infarction and poor depiction of the left VA. However, it was clearly recanalized on day six, and there were no findings of VA dissection. Whole-body contrast-enhanced computed tomography (CT) revealed a PAVF in the right lung and a thrombus in the feeding artery. The patient was diagnosed with hereditary hemorrhagic telangiectasia due to recurrent epistaxis and peripheral vasodilation of the tongue. An anticoagulant was administered for preventing further ischemic stroke, and a follow-up CT confirmed the disappearance of the thrombus in three months. Thoracoscopic partial lung resection was performed five months after the onset, and no recurrence of ischemic stroke was observed.

Elevated ratio of C-type lectin-like receptor 2 level and platelet count (C2PAC) aids in the diagnosis of post-operative venous thromboembolism in IDH-wildtype gliomas.

INTRODUCTION: Podoplanin (PDPN) is known to induce platelet aggregation via interacting with the C-type lectin-like receptor-2 on platelets and is involved in postoperative venous thromboembolism (VTE) formation. In this study, we investigate the correlation between soluble C-type lectin-like receptor (sCLEC-2) levels and PDPN expression in patients with high grade gliomas and the relationship between sCLEC-2 levels and the occurrence of VTE. MATERIALS AND METHODS: Forty-four patients harboring high grade gliomas, treated surgically at the Department of Neurosurgery, Niigata University from April 2018 to August 2020, were included. Patients with high grade gliomas were divided into isocitrate dehydrogenase (IDH)- wildtype and mutant groups, and the presence or absence of VTE and the intensity of PDPN by immunohistochemistry were confirmed. Platelet counts, as well as plasma sCLEC-2 and PDPN were measured in these patients. Furthermore, the levels of sCLEC-2 concentration were divided by the platelet count (C2PAC index) for comparison. RESULTS: IDH-wildtype glioma patients highly expressed PDPN (P < 0.001) compared to IDH-mutant glioma patients. In total, 9 (20.5 %) patients were diagnosed with VTE during the follow-up period, of which 8 patients harbored IDH-wildtype gliomas, and one patient an IDH-mutant glioma. Mean sCLEC-2 levels and C2PAC index in patients with IDH-wildtype gliomas were significantly higher than that of low or no PDPN expression group, which included patients with IDH-mutant gliomas (P = 0.0004, P = 0.0002). In patients with IDH-wildtype gliomas, the C2PAC index in patients with VTE was significantly higher than in patients without VTE (P = 0.0492). The optimal cutoff point of C2PAC for predicting VTE in IDH-wildtype glioma patients was 3.7 with a sensitivity of 87.5 % and specificity of 51.9 %. CONCLUSION: Platelet activation is strongly involved in the development of VTE in patients with IDH-wildtype high grade gliomas, and C2PAC index is a potential marker to detect VTE formation after surgery.

Epigenetic upregulation of Schlafen11 renders WNT- and SHH-activated medulloblastomas sensitive to cisplatin.

BACKGROUND: Intensive chemotherapeutic regimens with craniospinal irradiation have greatly improved survival in medulloblastoma patients. However, survival markedly differs among molecular subgroups and their biomarkers are unknown. Through unbiased screening, we found Schlafen family member 11 (SLFN11), which is known to improve response to DNA damaging agents in various cancers, to be one of the top prognostic markers in medulloblastomas. Hence, we explored the expression and functions of SLFN11 in medulloblastoma. METHODS: SLFN11 expression for each subgroup was assessed by immunohistochemistry in 98 medulloblastoma patient samples and by analyzing transcriptomic databases. We genetically or epigenetically modulated SLFN11 expression in medulloblastoma cell lines and determined cytotoxic response to the DNA damaging agents cisplatin and topoisomerase I inhibitor SN-38 in vitro and in vivo. RESULTS: High SLFN11 expressing cases exhibited significantly longer survival than low expressing cases. SLFN11 was highly expressed in the WNT-activated subgroup and in a proportion of the SHH-activated subgroup. While WNT activation was not a direct cause of the high expression of SLFN11, a specific hypomethylation locus on the SLFN11 promoter was significantly correlated with high SLFN11 expression. Overexpression or deletion of SLFN11 made medulloblastoma cells sensitive and resistant to cisplatin and SN-38, respectively. Pharmacological upregulation of SLFN11 by the brain-penetrant histone deacetylase-inhibitor RG2833 markedly increased sensitivity to cisplatin and SN-38 in SLFN11-negative medulloblastoma cells. Intracranial xenograft studies also showed marked sensitivity to cisplatin by SLFN11-overexpression in medulloblastoma cells. CONCLUSIONS: High SLFN11 expression is one factor which renders favorable outcomes in WNT-activated and a subset of SHH-activated medulloblastoma possibly through enhancing response to cisplatin.