The efficacy of slow-rate ventriculolumbar perfusion chemotherapy for leptomeningeal carcinomatosis: a phase II study.

PURPOSE: This study aimed to evaluate the symptomatic response and side effects of ventriculolumbar perfusion (VLP) methotrexate chemotherapy with a low perfusion rate in patients with leptomeningeal metastasis. METHODS: Patients in a single-arm, two-stage phase II trial based on Simon's minimax design received VLP with a reduced (15 cc/h) perfusion rate with the purpose of decreasing constitutional side effects such as nausea/vomiting, insomnia, and confusion. The primary outcome was control of increased intracranial pressure (ICP). The secondary outcome was an occurrence of side effects. The results were compared with those of a previous trial of VLP with a 20-cc/h perfusion rate. RESULTS: Total 90 patients were enrolled. Out of 65 patients with increased ICP, 32 achieved normalized ICP after VLP chemotherapy (bias-adjusted response rate = 51%). The incidence of moderate-to-severe nausea/vomiting was reduced to 46% from 64% in the previous study, and that of sleep disturbance was increased to 13% from 9%, but both failed to reach statistical significance. The incidence of moderate-to-severe confusion was significantly reduced to 12% from 23% in the previous study (p = 0.04). Median overall survival was better among patients with controlled ICP than among those who remained with increased ICP (193 days vs. 94 days, p = 0.013). CONCLUSION: Compared with a higher perfusion rate, the low perfusion rate failed to provide non-inferior ICP control or improved side effects, except for confusion. The relationship between VLP perfusion rate and ICP control needs to be evaluated in future trials adjusting for bias from uncompleted protocol due to poor general condition.

Extracellular Vesicles from Cerebrospinal Fluid of Leptomeningeal Metastasis Patients Deliver MiR-21 and Induce Methotrexate Resistance in Lung Cancer Cells.

Leptomeningeal metastasis (LM) is a common and fatal complication of advanced non-small cell lung cancer (NSCLC) caused by the spread of malignant cells to the leptomeninges and cerebrospinal fluid (CSF). While intra-CSF methotrexate (MTX) chemotherapy can improve prognosis, eventual MTX resistance deters continued chemotherapy. Recent studies have shown that increased miRNA-21 (miR-21) expression in the CSF of patients with LM after intraventricular MTX-chemotherapy is associated with poor overall survival; however, the molecular mechanisms underlying this resistance are poorly understood. Here, we confirm, in 36 patients with NSCLC-LM, that elevated miR-21 expression prior to treatment correlates with poor prognosis. MiR-21 overexpression or sponging results in a corresponding increase or decrease in MTX resistance, demonstrating that cellular miR-21 expression correlates with drug resistance. MiR-21-monitoring sensor and fluorescent extracellular vesicle (EV) staining revealed that EV-mediated delivery of miR-21 could modulate MTX resistance. Moreover, EVs isolated from the CSF of LM patients containing miR-21 could enhance the cell proliferation and MTX resistance of recipient cells. These results indicate that miR-21 can be transferred from cell-to-cell via EVs and potentially modulate MTX sensitivity, suggesting that miR-21 in CSF EVs may be a prognostic and therapeutic target for overcoming MTX resistance in patients with NSCLC-LM.

Modulation of Nogo receptor 1 expression orchestrates myelin-associated infiltration of glioblastoma.

As the clinical failure of glioblastoma treatment is attributed by multiple components, including myelin-associated infiltration, assessment of the molecular mechanisms underlying such process and identification of the infiltrating cells have been the primary objectives in glioblastoma research. Here, we adopted radiogenomic analysis to screen for functionally relevant genes that orchestrate the process of glioma cell infiltration through myelin and promote glioblastoma aggressiveness. The receptor of the Nogo ligand (NgR1) was selected as the top candidate through Differentially Expressed Genes (DEG) and Gene Ontology (GO) enrichment analysis. Gain and loss of function studies on NgR1 elucidated its underlying molecular importance in suppressing myelin-associated infiltration in vitro and in vivo. The migratory ability of glioblastoma cells on myelin is reversibly modulated by NgR1 during differentiation and dedifferentiation process through deubiquitinating activity of USP1, which inhibits the degradation of ID1 to downregulate NgR1 expression. Furthermore, pimozide, a well-known antipsychotic drug, upregulates NgR1 by post-translational targeting of USP1, which sensitizes glioma stem cells to myelin inhibition and suppresses myelin-associated infiltration in vivo. In primary human glioblastoma, downregulation of NgR1 expression is associated with highly infiltrative characteristics and poor survival. Together, our findings reveal that loss of NgR1 drives myelin-associated infiltration of glioblastoma and suggest that novel therapeutic strategies aimed at reactivating expression of NgR1 will improve the clinical outcome of glioblastoma patients.

Correction: Pigment Epithelium-Derived Factor (PEDF) Expression Induced by EGFRvIII Promotes Self-renewal and Tumor Progression of Glioma Stem Cells.

[This corrects the article DOI: 10.1371/journal.pbio.1002152.].

Association of MRI findings with clinical characteristics and prognosis in patients with leptomeningeal carcinomatosis from non-small cell lung cancer.

PURPOSE: Magnetic resonance imagining (MRI) is helpful for diagnosis of leptomeningeal carcinomatosis (LMC) and localizing LMC symptoms. Goal of this study is how MRI findings of LMC are associated with clinical characteristics or prognosis in patients with non-small cell lung cancer (NSCLC). METHODS: We retrospectively collected data on 283 patients with LMC from NSCLC, adenocarcinoma based on cerebrospinal fluid cytology. All patients had brain MRI with gadolinium enhancement at LMC diagnosis, and spinal MRI was performed at the physician's discretion. We evaluated the prognostic factors for overall survival (OS) of all patients and subgroup of patients with central nervous system cause of death. RESULTS: Two-hundred sixteen patients (76%) had definite or suggestive LMC findings and 67 had negative findings on brain MRI. Of the 37 patients who presented with cauda equina syndrome, 35 (95%) exhibited typical spinal MRI findings. Median OS of all patients was 3.65 months (95% confidence interval, 3.06-4.18). There was no significant difference in median OS between MRI-negative and MRI-positive groups (4.31 vs. 3.48 months, p = 0.711), whereas negative MRI finding showed longer median OS significantly in a subgroup of 77 patients with a central nervous system cause of death (p = 0.035). Considering clinical characteristics, progressive systemic disease, and altered mentality were significant prognostic factors associated with poor OS, whereas presenting symptom of headache with nausea/vomiting, intra-CSF chemotherapy, WBRT after LMC diagnosis, and concurrent RTKi treatment were significant for favorable OS in multivariable analysis. CONCLUSIONS: Positive MRI findings suggests heavier disease burden than negative MRI findings in patients with LMC who died of a central nervous system cause. Spinal MRI findings in patients with LMC correlate with cauda equina symptoms.

Local recurrence of brain metastasis reduced by intra-operative hyperthermia treatment.

PURPOSE: Brain metastasis is a common complication in cancer patients. Local recurrence after total resection of metastatic brain tumor has been frequently reported. In this study, we developed a new hyperthermia device and applied it to metastatic brain tumor patients intra-operatively to study if hyperthermia treatment could reduce local tumor recurrence. MATERIALS AND METHODS: A total of 63 metastatic brain patients were enrolled in the study with an informed consent obtained from every patient. After total resection of the tumor, the hyperthermia device was applied intra-operatively to the resection cavity. The surrounding brain tissue at 5 mm in depth from the tumor resection margin was raised to 42.5 °C for a total of 60 minutes (Clinical Research Information Service Registration Number: KCT0001308). RESULTS: A total of 10 local recurrences were observed in 63 patients who received hyperthermia treatment showing a local recurrence rate of 15.8%. It was significantly lower than the local recurrence rate of those who received conventional treatment (34%) when analyzed with one tailed z-test (p value: .001). Kaplan-Meier analysis also showed a significantly lower recurrence rate in the hyperthermia treatment group (p value: .0003). Complications included two cases of seizures and two cases of wound infection. CONCLUSIONS: Results of this study suggest that intra-operative hyperthermia treatment after total resection of metastatic brain tumor could reduce local recurrence of tumor. We believe that intra-operative hyperthermia treatment could be used as an adjuvant therapy to surgery and post-operative radiotherapy, or as a salvage treatment in patients who cannot receive further radiotherapy.

Clinical outcome of cerebrospinal fluid shunts in patients with leptomeningeal carcinomatosis.

BACKGROUND: Leptomeningeal carcinomatosis (LMC) is frequently associated with hydrocephalus, which quickly devastates the performance of the patient. Cerebrospinal fluid (CSF) shunt is a widely accepted treatment of choice, but the clinical outcomes in patients with LMC are not well studied. This study aimed to examine the efficacy of a CSF shunt in patients with LMC. METHODS: Seventy patients with LMC confirmed by cytology or magnetic resonance imaging (MRI) underwent ventriculoperitoneal (VP) or lumboperitoneal (LP) shunt surgery. We retrospectively analyzed the clinical characteristics of patients, symptom improvement after the shunt, rate of complications associated with the surgery, and overall survival. RESULTS: Fifty-five patients had systemic cancer as a preceding disease, including lung cancer (45), breast cancer (6), and others (4). Primary brain tumors were mainly glioma (7) and medulloblastoma (5). Fifty-one patients had VP shunt, and 19 had LP shunt. After surgery, preoperative symptoms "improved" in 35 patients (50%) and were "normalized" in 24 of those patients (34%). Shunt malfunction occurred in eight patients, and infection occurred in eight patients. Seventeen patients underwent revision due to infection, shunt malfunction, or over-drainage. There were no complications associated with peritoneal seeding during a median follow-up of 3.3 months after surgery. The median overall survival was 8.7 months (95% confidence interval, 6.0-11.4) from LMC diagnosis and 4.1 months from shunt surgery. CONCLUSION: VP or LP shunt is effective for patients with hydrocephalus from LMC in terms of symptom improvement and prolonging of overall survival with an acceptable rate of procedure-related complications. TRIAL REGISTRATION: This study was approved by the Institutional Review Board (IRB) of the National Cancer Center (retrospectively registered, NCC2018-0051 ).

Pigment Epithelium-Derived Factor (PEDF) Expression Induced by EGFRvIII Promotes Self-renewal and Tumor Progression of Glioma Stem Cells.

Epidermal growth factor receptor variant III (EGFRvIII) has been associated with glioma stemness, but the direct molecular mechanism linking the two is largely unknown. Here, we show that EGFRvIII induces the expression and secretion of pigment epithelium-derived factor (PEDF) via activation of signal transducer and activator of transcription 3 (STAT3), thereby promoting self-renewal and tumor progression of glioma stem cells (GSCs). Mechanistically, PEDF sustained GSC self-renewal by Notch1 cleavage, and the generated intracellular domain of Notch1 (NICD) induced the expression of Sox2 through interaction with its promoter region. Furthermore, a subpopulation with high levels of PEDF was capable of infiltration along corpus callosum. Inhibition of PEDF diminished GSC self-renewal and increased survival of orthotopic tumor-bearing mice. Together, these data indicate the novel role of PEDF as a key regulator of GSC and suggest clinical implications.

Discordances in ER, PR, and HER2 between primary breast cancer and brain metastasis.

When distant metastases are discovered, it is important to determine receptor profiles of these lesions through histologic examination. However, brain metastasis sites are difficult to reach to be routinely biopsied. The purpose of this study was to determine expression profiles of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) in breast cancer brain metastasis (BCBM) and the existence of discordance between primary breast cancer and brain metastasis. A total of 37 patients who underwent craniotomies for metastatic brain tumors arising from breast cancer at National Cancer Center (NCC) of Korea between 2002 and 2014 were retrospectively reviewed. Clinicopathologic data were collected from electronic medical records. Receptor profiles of primary breast cancer and brain metastasis in each patient were identified. Data of ER, PR, and HER2 expression in brain metastasis were available in electronic medical records for 21 (56.8%) of 37 cases. Results of ER, PR, and HER2 expression were positive in 47.6, 42.9, and 38.1% of patients with brain metastasis, respectively. Receptor conversion occurred in 11 (52.4%) of 21 patients (for ER, 9.5%; for PR, 38.1%; for HER2, 23.8%). Overall survival was longer in patients with concordant receptor expression patterns between primary breast cancer and brain lesion compared to that in patients with discordant patterns. However, such difference was not statistically significant (discordant vs. concordant median survival: 19.2 versus 31.1 months, p = 0.181). Receptor conversion in BCBMs was observed in over 50% of Korean patients used in this study. HER2 conversion was observed in 23.8% of patients in this study. Therefore, if resistance to anti-HER2 treatment is suspected in patients with BCBM, biopsy is needed to determine receptor profiles of brain lesion.

Multi-institutional study of treatment patterns in Korean patients with WHO grade II gliomas: KNOG 15-02 and KROG 16-04 intergroup study.

INTRODUCTION: We performed this study to identify the treatment patterns of patients with low-grade gliomas (LGG) in Korea. METHODS: A total of 555 patients diagnosed as WHO grade II gliomas between 2000 and 2010 at 14 Korean institutions were included. The patients were divided into four adjuvant treatment groups: adjuvant fractionated radiotherapy (RT, N = 204), adjuvant chemotherapy (N = 20), adjuvant fractionated RT and chemotherapy (N = 65), and non-adjuvant treatment (N = 266) groups. We examined differences among the groups and validated patient/tumor characteristics associated with the adjuvant treatments. RESULTS: Astrocytoma was diagnosed in 210 patients (38%), oligoastrocytoma in 85 patients (15%), and oligodendroglioma in 260 patients (47%). Gross total resection was performed in 200 patients (36%), subtotal resection in 153 (28%), partial resection in 71 patients (13%), and biopsy in 131 patients (24%). RT was most commonly applied as an adjuvant treatment. The use of chemotherapy with or without RT decreased after 2008 (from 38 to 4%). The major chemotherapeutic regimen was procarbazine, lomustine, and vincristine (PCV); however, the proportion of temozolomide increased since 2005 (up to 69%). Patient/tumor characteristics related with RT were male gender, non-seizure, multiple lobes involvement, and non-gross total resection. Chemotherapy was associated with non-gross total resection and non-astrocytoma. CONCLUSIONS: A preference for RT and increased use of temozolomide was evident in the treatment pattern of LGG. The extent of resection was associated with a decision to perform RT and chemotherapy. To establish a robust guideline for LGG, further studies including molecular information are needed.

Impact of adjuvant treatments on survival in Korean patients with WHO grade II gliomas: KNOG 15-02 and KROG 16-04 intergroup study.

INTRODUCTION: Optimal treatment strategies for low-grade glioma (LGG) remain controversial. We analyzed treatment outcomes and evaluated prognostic factors of adult LGG patients in Korea. METHODS: We reviewed the medical records of 555 patients diagnosed with WHO grade II LGG (astrocytoma 37.8%, oligoastrocytoma 15.3%, and oligodendroglioma 46.8%) at 14 institutions between 2000 and 2010. Primary and secondary endpoints were progression-free survival (PFS) and overall survival (OS). Propensity-score matching (PSM) analyses were performed to correct imbalances in patient/tumor characteristics among adjuvant treatment groups. RESULTS: The median follow-up time was 83.4 months, and the 5-year PFS and OS rates were 52.2% and 83.0%, respectively. Male, older age, poorer performance status, multiple lobe involvement, and astrocytoma histology were associated with poorer survival. Among the treatment factors, gross total resection (GTR) was associated with better PFS and OS, and adjuvant chemotherapy with improved PFS. Interestingly, adjuvant radiotherapy (RT) did not improve PFS; rather, it was related with poorer OS. Regarding patient/tumor characteristics, the RT group had poorer characteristics than the non-RT group. After PSM, we detected a tendency for improved PFS in the matched RT group, and no significant difference in OS compared with the matched non-RT group. CONCLUSIONS: The achievement of GTR is important to improve survival in LGG patients. Adjuvant chemotherapy may enhance PFS, but adjuvant RT did not improve survival outcomes. After PSM, we observed potential impacts of adjuvant RT on PFS. Our results may reflect real-world practice and consequently may help to optimize treatment strategies for LGG.

Treatment Results and Prognostic Factors of Brain Metastases From Ovarian Cancer: A Single Institutional Experience of 56 Patients.

OBJECTIVES: The most appropriate treatments for brain metastases from ovarian cancer have not been established mainly because of its rarity. The objective of this study was to describe clinical results of treatment and prognostic factors of patients with brain metastases from ovarian cancer treated at a single institution. MATERIALS AND METHODS: We retrieved information from the electronic medical records of 56 consecutive patients (2.8%) with brain metastases, from a total of 2008 patients with ovarian cancer. Endpoints were the pattern of treatment failure, progression-free survival, and overall survival (OS). RESULTS: Radiation was the most common initial treatment for brain metastases (59%), followed by surgery (23%). The median progression-free survival was 9.8 months. Radiological progression was confirmed in 20 patients: 7 had leptomeningeal carcinomatosis (37%), 8 had local recurrence, and 5 had distant recurrence. Median OS was 11.25 months, and the 1-year OS rate was 48.2%. Patients received surgery for single metastasis as initial treatment showed median OS of 24.1 months, which was significantly prolonged compared with the other patients (P = 0.0002). Of the 48 patients who died, 29 (60%) died of systemic disease and 7 (15%) died of central nervous system progression. Karnofsky Performance Status greater than or equal to 70, control of systemic cancer, serous histology, and surgery for brain metastases were associated with improved OS in multivariable analysis (P < 0.05). CONCLUSIONS: Surgical resection for single or symptomatic brain metastases from ovarian cancer prolonged OS significantly. Multimodality treatment, including control of systemic cancer, appeared to be an important factor in prolonging OS.

The ubiquitin ligase human TRIM71 regulates let-7 microRNA biogenesis via modulation of Lin28B protein.

let-7 microRNA (miRNA) is implicated in various biological processes, and its downregulation essentially linked to human malignancy. Regulation of gene expression of the let-7 family is critically linked to RNA-binding proteins. For instance, Lin28B and its paralog, Lin28A, inhibit the pre-let-7 precursor from being processed to mature miRNA by recruiting terminal uridyltransferase, TUT4, which adds oligomeric U at the 3' end, suggesting that deregulation of Lin28B, together with Lin28A, may alter various biological processes through modulation of let-7 expression. Here, we showed that the Lin28B protein level is regulated via ubiquitin-mediated proteasomal degradation, and identified the ubiquitin ligase as human TRIM-NHL domain-containing TRIM71. In cells, TRIM71 negatively regulates Lin28B protein stability by catalyzing polyubiquitination. Compared with its paralog, Lin28A, a C-terminal unique ~50 amino acid stretch of Lin28B is essential for TRIM71 interactions and subsequent polyubiquitination. Moreover, the N-terminal RING finger motif of TRIM71 is critical for protein-protein interactions and polyubiquitination of Lin28B, and consequent let-7 expression. Consistent with the let-7 stimulatory role of TRIM71 via Lin28B polyubiquitination, specific knockdown of TRIM71 led to downregulation of let-7 expression. Expression of one of the known let-7 targets, HMGA2, was derepressed after knockdown of TRIM71. We additionally showed that enhanced expression of let-7 is part of a feedback loop that targets TRIM71 3'UTR, which contains two conserved let-7 target sites. Our findings collectively reveal critical aspects of regulatory complexity of let-7 biogenesis at the posttranscriptional level.

Clinical characteristics and follow-up of intracranial metastases from thyroid cancer.

BACKGROUND: Intracranial metastasis from thyroid cancer is extremely rare. However, less is known about the risk factors for intracranial metastasis and its treatment from few retrospective studies. The aim of this study was to contribute to the understanding of this disease by analyzing patients with intracranial metastases from thyroid cancer. METHODS: Between 2001 and 2014, the database of the National Cancer Center of Korea was searched for thyroid cancer patients. The clinical characteristics and site of distant metastasis according to the histological type were evaluated in the thyroid cancer cohort. Among the patients with intracranial metastases, the characteristics, histological type of primary cancer and metastatic brain tumor, additional synchronous or previous distant metastasis, treatment modalities, locations and characteristics on radiologic findings, time interval between the first diagnosis of the primary thyroid cancer and brain metastasis, thyroglobulin level at the first detection of intracranial metastasis and survival were reviewed. RESULTS: A total of 10 (0.032 %) out of 3,090 thyroid cancer patients in the National Cancer Center database were identified as having intracranial metastases. The histological types of the primary thyroid cancers were papillary for six patients, follicular for three, and poorly differentiated carcinoma for one. Six of these ten patients underwent surgical resection for intracranial lesions. Whole-brain radiotherapy or tyrosine kinase inhibitors were applied to the patients as postoperative adjuvant treatment, and stereotactic radiosurgery was considered for recurrent or surgically inoperable lesions. The overall median survival time was 33 months (range, 0.5-78 months) after diagnosis of intracranial metastasis. CONCLUSIONS: Surgical resection and adjuvant treatments in the contemporary era seem to result in improved survival after intracranial metastases compared with what has been reported in past studies. Considering the grave course of intracranial metastasis, the early detection and aggressive treatment of patients with a good performance status are crucial.

Ventriculolumbar perfusion chemotherapy with methotrexate for treating leptomeningeal carcinomatosis: a Phase II Study.

BACKGROUND: The efficacy of ventriculolumbar perfusion (VLP) chemotherapy with methotrexate (MTX) was evaluated for treatment of leptomeningeal carcinomatosis (LMC). METHODS: The primary outcome was the response rate of increased intracranial pressure (ICP), which was available for comparison from historical data on conventional intraventricular chemotherapy. Secondary endpoints were response rates of other LMC symptoms and overall survival of patients. Artificial cerebrospinal fluid (CSF) premixed with MTX was continuously perfused intraventricularly through a preinstalled intraventricular reservoir and drained via lumbar catheter for 72 hours. The VLP was repeated twice at 3-day intervals for each cycle. RESULTS: Forty-five of 65 patients had increased ICP, and 32 patients (71%) showed response after VLP chemotherapy, including 31 patients with normalization of ICP. Altered mentation improved in 7 of 21 patients (33%). Cauda equina symptoms responded in 5 of 27 patients (19%), including 4 patients who became ambulatory from a bedridden state. Median overall survival was 187 days, and the 1-year survival rate was 27%. All side effects, including nausea, vomiting, confusion, and sleep disturbance, were tolerable and transient except for two cases of CSF infection. CONCLUSION: VLP chemotherapy with MTX provided better control of increased ICP, improved symptom response, and prolonged survival at a cost of acceptable toxicity in patients with LMC.

Excessively Delayed Radiation Changes After Proton Beam Therapy for Brain Tumors: Report of Two Cases.

Delayed cerebral necrosis is a well-known complication of radiation therapy (RT). Because of its irreversible nature, it should be avoided if possible, but avoidance occurs at the expense of potentially compromised tumor control, despite the use of the modern advanced technique of conformal RT that minimizes radiation to normal brain tissue. Risk factors for radiation-induced cerebral necrosis include a higher dose per fraction, larger treatment volume, higher cumulative dose, and shorter time interval (for re-irradiation). The same principle can be applied to proton beam therapy (PBT) to avoid delayed cerebral necrosis. However, conversion of PBT radiation energy into conventional RT is still short of clinical support, compared to conventional RT. Herein, we describe two patients with excessively delayed cerebral necrosis after PBT, in whom follow-up MRI showed no RT-induced changes prior to 3 years after treatment. One patient developed radiation necrosis at 4 years after PBT to the resection cavity of an astroblastoma, and the other developed brainstem necrosis that became symptomatic 6 months after its first appearance on the 3-year follow-up brain MRI. We also discuss possible differences between radiation changes after PBT versus conventional RT.

Spontaneous Regression of Glioma-Mimicking Brainstem Lesion in a Child: A Case Report.

Differential diagnosis of focal brainstem lesions detected on MRI is challenging, especially in young children. Formerly, brainstem gliomas were classified mainly based on MRI features and location. However, since 2016, the World Health Organization's brainstem lesion classification requires tissue biopsy to reveal molecular characteristics. Although modern techniques of stereotactic or navigation-guided biopsy ensure accurate biopsy of the lesion with safety, biopsy of brainstem lesions is still generally not performed. Here, we report a focal brainstem lesion mimicking brainstem glioma in a 9-year-old girl. Initial MRI, MR spectroscopy, and 11C-methionine positron emission tomography (PET) features suggested low-grade glioma or diffuse intrinsic pontine glioma. However, repeated MR spectroscopy, perfusion MRI, and 18fluorodeoxyglucose PET findings suggested that it was more likely a non-tumorous lesion. As the patient presented not with a neurological manifestation but with precocious puberty, the attending oncologist chose to observe with regular follow-up MRI. The pontine lesion with high signal intensity on T2-weighted MRI regressed from the 6-month follow-up and became invisible on the 1.5-year follow-up MRI. We reviewed brainstem glioma-mimicking lesions in the literature and discussed the key points of differential diagnosis.

Disseminating Necrotizing Leukoencephalopathy Associated With Intra-CSF Methotrexate Chemotherapy: A Retrospective Observational Study.

BACKGROUND AND OBJECTIVES: Leptomeningeal metastases (LMs) are neoplasms that proliferate to membranes lining the brain and spinal cord. Intra-CSF methotrexate (MTX) chemotherapy is a prevalent treatment option. However, resultant long-term neurotoxicity can lead to irreversible disseminated necrotizing leukoencephalopathy (DNL). This study aims to determine the incidence, characteristics, risk factors, and outcomes of DNL following intra-CSF MTX chemotherapy for LM. METHODS: We retrospectively reviewed patients with LM who received intra-CSF MTX between 2001 and 2021 at the National Cancer Center of Korea. Patients with a follow-up duration of <3 months and those without follow-up MRI after MTX administration were excluded. The primary outcome was the development of DNL, evaluated based on the clinical and radiologic definitions of DNL. Logistic and Cox proportional regression models were used to assess the risk of DNL in patients with LM receiving intra-CSF MTX chemotherapy. RESULTS: Of the 577 patients included in the DNL investigation, 13 (2.3%) were identified to have irreversible DNL. The MRI features of DNL typically include necrotic changes in the bilateral anterior temporal region, extensive white matter, and/or brainstem lesions. All patients with DNL experienced fatal clinical course despite MTX cessation. Logistic regression analysis revealed that a cumulative dose of MTX significantly affected DNL occurrence. Multivariable analysis showed that the factor of ≥10 MTX rounds was significant for DNL development after adjusting for route of MTX administration and prior brain radiotherapy (odds ratio 7.32, 95% CI 1.42-37.77 at MTX rounds ≥10 vs < 10). In the Cox proportional hazards model considering time to occurrence of DNL, ≥10 rounds of MTX were identified as an independent predictor of DNL (hazard ratio 12.57, 95% CI 1.62-97.28, p = 0.015), even after adjusting for the synergistic effect of brain radiotherapy. DISCUSSION: DNL is a rare but fatal complication of intra-CSF MTX chemotherapy, and its progression cannot be prevented despite early recognition. The cumulative dose of intra-CSF MTX was an independent risk factor for DNL occurrence. Thus, intra-CSF MTX treatment for patients with LM should be administered with caution considering the possibility of the cumulative irreversible neurotoxicity.

Integrated proteogenomic characterization of glioblastoma evolution.

The evolutionary trajectory of glioblastoma (GBM) is a multifaceted biological process that extends beyond genetic alterations alone. Here, we perform an integrative proteogenomic analysis of 123 longitudinal glioblastoma pairs and identify a highly proliferative cellular state at diagnosis and replacement by activation of neuronal transition and synaptogenic pathways in recurrent tumors. Proteomic and phosphoproteomic analyses reveal that the molecular transition to neuronal state at recurrence is marked by post-translational activation of the wingless-related integration site (WNT)/ planar cell polarity (PCP) signaling pathway and BRAF protein kinase. Consistently, multi-omic analysis of patient-derived xenograft (PDX) models mirror similar patterns of evolutionary trajectory. Inhibition of B-raf proto-oncogene (BRAF) kinase impairs both neuronal transition and migration capability of recurrent tumor cells, phenotypic hallmarks of post-therapy progression. Combinatorial treatment of temozolomide (TMZ) with BRAF inhibitor, vemurafenib, significantly extends the survival of PDX models. This study provides comprehensive insights into the biological mechanisms of glioblastoma evolution and treatment resistance, highlighting promising therapeutic strategies for clinical intervention.

Molecular Biology of Brain Metastases.

Brain metastases (BMs) often occur in patients with lung cancer, breast cancer, and melanoma and are the leading cause of morbidity and mortality. The incidence of BM has increased with advanced neuroimaging and prolonged overall survival of cancer patients. With the advancement of local treatment modalities, including stereotactic radiosurgery and navigation-guided microsurgery, BM can be controlled long-term, even in cases with multiple lesions. However, radiation/chemotherapeutic agents are also toxic to the brain, usually irreversibly and cumulatively, and it remains difficult to completely cure BM. Thus, we must understand the molecular events that begin and sustain BM to develop effective targeted therapies and tools to prevent local and distant treatment failure. BM most often spreads hematogenously, and the blood-brain barrier (BBB) presents the first hurdle for disseminated tumor cells (DTCs) entering the brain parenchyma. Nevertheless, how the DTCs cross the BBB and settle on relatively infertile central nervous system tissue remains unknown. Even after successfully taking up residence in the brain, the unique tumor microenvironment is marked by restricted aerobic glycolysis metabolism and limited lymphocyte infiltration. Brain organotropism, certain phenotype of primary cancers that favors brain metastasis, may result from somatic mutation or epigenetic modulation. Recent studies revealed that exosome secretion from primary cancer or over-expression of proteolytic enzymes can "pre-condition" brain vasculoendothelial cells. The concept of the "metastatic niche," where resident DTCs remain dormant and protected from systemic chemotherapy and antigen exposure before proliferation, is supported by clinical observation of BM in patients clearing systemic cancer and experimental evidence of the interaction between cancer cells and tumor-infiltrating lymphocytes. This review examines extant research on the metastatic cascade of BM through the molecular events that create and sustain BM to reveal clues that can assist the development of effective targeted therapies that treat established BMs and prevent BM recurrence.