Delayed Pseudoprogression in Glioblastoma Patients Treated With Tumor-Treating Fields.

Tumor-treating fields (TTFields) is an established treatment modality for glioblastoma. False progression to chemoradiation is a known problem in patients with glioblastoma multiforme (GBM), with most cases occurring within three months of radiation therapy. In this report, we present two cases of delayed pseudoprogression caused by TTFields. Two patients with GBM who received TTFields showed signs of radiographic progression six months after the completion of radiation therapy. Patient 1 was a 37-year-old female with a glioblastoma in the right temporal lobe. Patient 2 was a 70-year-old male with glioblastoma in the left temporal lobe. Both patients received radiation therapy, followed by temozolomide (TMZ) maintenance therapy and TTFields. Patient 1 underwent a second resection; however, the pathology revealed only a treatment effect, and the final diagnosis was a pseudoprogression. In Case 2, the disease resolved with steroid therapy alone. In both patients, the lesions appeared later than during the typical pseudoprogression period. A recent study reported that TTFields increase the permeability of the plasma cell membrane, which may result in further leakage of gadolinium into the extracellular lumen. Further studies are needed to better characterize delayed pseudoprogression and improve treatment outcomes.

Comparative Study of Postmortem MRI and Pathological Findings in Malignant Brain Tumors.

This study compared magnetic resonance imaging (MRI) findings of postmortem brain specimens with neuropathological findings to evaluate the value of postmortem MRI. Postmortem MRI was performed on five formalin-fixed whole brains with malignant tumors. Postmortem T2-weighted images detected all neuropathological abnormalities as high-signal regions but also showed histological tumor invasion in areas without edema. Tumor lesions with high necrosis and edema showed high signal intensity on T2-weighted images; in three cases, lesion enlargement was detected on the final prenatal imaging and postmortem MRI. Disease progression immediately before death may have contributed to this difference. In conclusion, the correlation between MRI and neuropathological findings facilitates understanding of the mechanisms responsible for MRI abnormalities. Increased free water due to edema, necrosis, and brain tissue injury can explain the increased signal intensity observed on T2-weighted images. Postmortem MRI may contribute to effective pathology by identifying subtle abnormalities prior to brain dissection.

Evaluation of Treatment Strategies for Male Prolactin-Secreting Pituitary Neuroendocrine Tumors.

Prolactin-secreting pituitary neuroendocrine tumors (PitNETs) are more common in women. Male patients may also have few symptoms and have macroadenomas extending outside the sella turcica. This study aimed to report the results of cabergoline treatment in male patients with prolactin-secreting PitNET. The study included nine male patients aged 26-65 years (median, 46 years) diagnosed with prolactin-secreting PitNETs. The age at onset, prolactin values, tumor size, symptoms, and treatment were assessed. The mean prolactin value at the initial presentation was 2734.6 ng/mL, and the mean maximum tumor diameter was 40.4 mm. Visual field disturbance was the most common symptom (44.4%), followed by headaches (33.3%), asymptomatic symptoms (11.1%), and galactorrhea (11.1%). Eight patients responded to cabergoline treatment with normalization of prolactin levels and tumor shrinkage. One patient did not respond to the cabergoline treatment and required surgical intervention. There were no cases of cerebrospinal fluid leakage. Cabergoline was found to be an effective treatment for male prolactin-secreting PitNETs.

Nuclear transport surveillance of p53 by nuclear pores in glioblastoma.

Nuclear pore complexes (NPCs) are the central apparatus of nucleocytoplasmic transport. Disease-specific alterations of NPCs contribute to the pathogenesis of many cancers; however, the roles of NPCs in glioblastoma (GBM) are unknown. In this study, we report genomic amplification of NUP107, a component of NPCs, in GBM and show that NUP107 is overexpressed simultaneously with MDM2, a critical E3 ligase that mediates p53 degradation. Depletion of NUP107 inhibits the growth of GBM cell lines through p53 protein stabilization. Mechanistically, NPCs establish a p53 degradation platform via an export pathway coupled with 26S proteasome tethering. NUP107 is the keystone for NPC assembly; the loss of NUP107 affects the integrity of the NPC structure, and thus the proportion of 26S proteasome in the vicinity of nuclear pores significantly decreases. Together, our findings establish roles of NPCs in transport surveillance and provide insights into p53 inactivation in GBM.

Therapeutic potential of pentamidine for glioma-initiating cells and glioma cells through multimodal antitumor effects.

Glioma-initiating cells, which comprise a heterogeneous population of glioblastomas, contribute to resistance against aggressive chemoradiotherapy. Using drug reposition, we investigated a therapeutic drug for glioma-initiating cells. Drug screening was undertaken to select candidate agents that inhibit proliferation of two different glioma-initiating cells lines. The alteration of proliferation and stemness of the two glioma-initiating cell lines, and proliferation, migration, cell cycle, and survival of these two differentiated glioma-initiating cell lines and three different glioblastoma cell lines treated with the candidate agent were evaluated. We also used a xenograft glioma mouse model to evaluate anticancer effects of treated glioma cell lines. Among the 1301 agents, pentamidine-an antibiotic for Pneumocystis jirovecii-emerged as a successful antiglioma agent. Pentamidine treatment suppressed proliferation and stemness in glioma-initiating cell lines. Proliferation and migration were inhibited in all differentiated glioma-initiating cells and glioblastoma cell lines, with cell cycle arrest and caspase-dependent apoptosis induction. The in vivo study reproduced the same findings as the in vitro studies. Pentamidine showed a stronger antiproliferative effect on glioma-initiating cells than on differentiated cells. Western blot analysis revealed pentamidine inhibited phosphorylation of signal transducer and activator of transcription 3 in all cell lines, whereas Akt expression was suppressed in glioma-initiating cells but not in differentiated lines. In the present study, we identified pentamidine as a potential therapeutic drug for glioma. Pentamidine could be promising for the treatment of glioblastomas by targeting both glioma-initiating cells and differentiated cells through its multifaceted antiglioma effects.

Prognostic value of MR spectroscopy in patients with acute excitotoxic encephalopathy.

PURPOSE: Acute excitotoxic encephalopathy is the most common encephalopathy syndrome in Japan, and consists of acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) and mild encephalopathy associated with excitotoxicity (MEEX). Neurological sequelae remain in approximately 70% of patients with AESD, however, it is difficult to predict the prognosis early in the course. We evaluated the brain metabolites observed on MRS as to whether they can predict the neurological outcome. METHODS: 16 previously healthy Japanese patients with excitotoxic encephalopathy (8 with AESD and 8 with MEEX) were included in this study. MR spectroscopy (MRS) was acquired from the fronto-parietal white matter (TR/TE = 5000/30 msec) with a 3.0 T scanner. Quantification of metabolites was performed using an LCModel. Neurological outcome was assessed with the Pediatric Cerebral Performance Category score, score 1 being classified as G1 (normal), scores 2 and 3 as G2 (mild to moderate), and scores 4-6 as G3 (severe). RESULTS: MRS data which predict a poor neurological outcome (G2 and 3) include the following: decreased N-acetyl aspartate (NAA) (sensitivity 88%, specificity 100%), decreased creatine (47%, 100%), increased lactate (47%, 100%), and decreased glutamate (sensitivity 35%, specificity 100%). Limited to the acute stage within seven days of onset, those for a poor prognosis are as follows, decreased NAA (88%, 100%), decreased creatine (38%, 100%), and increased lactate (38%, 100%). CONCLUSION: MRS is useful for prognosis prediction of acute excitotoxic encephalopathy. Decreased NAA will be the most effective metabolite for neurological prognosis prediction.

Genetic and Lineage Classification of Glioma-Initiating Cells Identifies a Clinically Relevant Glioblastoma Model.

The Cancer Genome Atlas (TCGA) project described a robust gene expression-based molecular classification of glioblastoma (GBM), but the functional and biological significance of the subclasses has not been determined. The present comprehensive analysis of 25 glioma-initiating cell (GIC) lines classifies GIC lines into four subtypes (classical, mesenchymal, proneural, and neural) that are closely related to the TCGA GBM subclasses and display distinct lineage characteristics and differentiation behavior that recapitulate neural development. More importantly, the GIC subtypes exhibit distinct biological phenotypes in relation to self-renewal capacity, proliferation, invasiveness, and angiogenic potential in vitro and in vivo. In addition, the GIC subtypes exhibit divergent patterns of signaling pathway activation and deactivation of the Wnt, Notch, and TGF-ß pathways. These results will improve drug discovery targeting certain genetic mutation in glioblastoma and improve the development of precision medicine.

The Oncogene Addiction Switch from NOTCH to PI3K Requires Simultaneous Targeting of NOTCH and PI3K Pathway Inhibition in Glioblastoma.

The NOTCH pathway regulates neural stem cells and glioma initiating cells (GICs). However, blocking NOTCH activity with γ-secretase inhibitors (GSIs) fails to alter the growth of GICs, as GSIs seem to be active in only a fraction of GICs lines with constitutive NOTCH activity. Here we report loss of PTEN function as a critical event leading to resistance to NOTCH inhibition, which causes the transfer of oncogene addiction from the NOTCH pathway to the PI3K pathway. Drug cytotoxicity testing of eight GICs showed a differential growth response to GSI, and the GICs were thus stratified into two groups: sensitive and resistant. In the sensitive group, GICs with loss of PTEN function appeared less sensitive to GSI treatment. Here we show that NOTCH regulates PTEN expression and the activity of the PI3K pathway in GICs, as treatment with GSI attenuated the NOTCH pathway and increased PTEN expression. NOTCH regulates PTEN expression via Hes-1, as knockdown of Notch or Hes1 increased expression of PTEN. This novel observation suggests that both pathways must be simultaneously inhibited in order to improve therapeutic efficacy in human glioblastomas (GBMs).

Excitotoxicity in encephalopathy associated with STEC O-157 infection.

Cytokines play an important role in the pathogenesis of the severe complications of Shiga toxin-producing Escherichia coli (STEC) infection, such as hemolytic uremic syndrome (HUS) and acute encephalopathy. A 3-year-old boy with acute encephalopathy associated with STEC O-157 HUS showed increased levels of IL-6 and IL-10, which normalized after methylprednisolone pulse therapy, and additionally exhibited a transient increase of glutamine on MR spectroscopy. This finding suggests that excitotoxicity, in addition to hypercytokinemia, may play an important role in the pathogenesis of HUS encephalopathy.

A new infectious encephalopathy syndrome, clinically mild encephalopathy associated with excitotoxicity (MEEX).

Acute infectious encephalopathy is often observed in children in East Asia including Japan. More than 40% of the patients remain unclassified into specific syndromes. To investigate the underlying pathomechanisms in those with unclassified encephalopathy, we evaluated brain metabolism by MR spectroscopy. Among seven patients with acute encephalopathy admitted to our hospital from June 2016 to May 2017, three were classified into acute encephalopathy with biphasic seizures and late reduced diffusion (AESD). The other four showed consciousness disturbance lasting more than three days with no parenchymal lesion visible on MRI, which led to a diagnosis of unclassified encephalopathy. MR spectroscopy in these four patients, however, revealed an increase of glutamine with a normal N-acetyl aspartate level on days 5 to 8, which had normalized by follow-up studies on days 11 to 16. The four patients clinically recovered completely. Among 27 patients with encephalopathy, including the present seven patients, admitted to our hospital from January 2015 to March 2017, seven (26%) were classified into this type, which we propose is a new encephalopathy syndrome, clinically mild encephalopathy associated with excitotoxicity (MEEX). MEEX is the second most common subtype, following AESD (30%). This study suggests that excitotoxicity may be a common underlying pathomechanism of acute infectious encephalopathy, and prompt astrocytic neuroprotection from excitotoxicity may prevent progression of MEEX into AESD.

Clinically mild infantile encephalopathy associated with excitotoxicity.

Acute infectious encephalopathy is very frequently observed in children in East Asia including Japan. Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is the most common subtype in Japan; however, more than 40% of the patients remain unclassified into specific syndromes. To investigate the underlying pathomechanism in those with unclassified acute encephalopathy, we evaluated brain metabolism by MR spectroscopy. Among 20 patients with acute encephalopathy admitted to our hospital during January 2015 to May 2016, 12 could not be classified into specific syndromes. MR spectroscopy was performed in 8 of these 12 patients with unclassified encephalopathy. MR spectroscopy showed an increase of glutamine with a normal N-acetyl aspartate level on days 3 to 8 in three of the 8 patients, which had normalized by follow-up studies. The three patients clinically recovered completely. This study suggests that excitotoxicity may be the underlying pathomechanism in some patients with unclassified mild encephalopathy.

Elevated taurine and glutamate in cerebral juvenile xanthogranuloma on MR spectroscopy.

MRI in a 2-year-old female presenting afebrile seizures and left blepharoptosis revealed multiple well-marginated round-shaped lesions, isointensity to gray matter on T1- and T2-weighted images with homogenously reduced diffusion and diffuse contrast enhancement. MRS revealed elevation of taurine, choline and glutamate, and reduction of N-acetylaspartate. A brain biopsy confirmed a diagnosis of juvenile xanthogranuloma (JXG). JXG should be considered when MR spectroscopy shows elevated taurine and glutamate, which has only previously been reported in medulloblastomas.

Effect of Notch expression in glioma stem cells on therapeutic response to chemo-radiotherapy in recurrent glioblastoma.

Glioma stem cells (GSCs) have the capacity to repopulate tumors and mediate resistance to radiotherapy and chemotherapy. The Notch signaling pathway is important in proliferation, stem cell maintenance, cell differentiation, and tumorigenesis in GSCs. In this study, we compared CD133, Notch, and VEGF expressions in histological sections of primary and recurrent glioblastomas after radiotherapy and chemotherapy. In vitro study, the γ-secretase inhibitor inhibited NICD, Hes1 and pVEGFR2 expressions in GSCs. GSCs cultured under endothelial conditions undergo endothelial differentiation. Tumor samples were collected from 27 patients at the time of tumor recurrence. We used immunohistochemical techniques to compare expression of CD133, Notch-1 and VEGF. Expressions of CD133-, Notch-1-, and VEGF-positive glioma cells were higher in recurrent glioblastoma after radiotherapy and chemotherapy. To determine the clinical importance of Notch-1 expression in glioblastoma, we analyzed 15 patients who had received bevacizumab therapy followed by a second surgery at recurrence. OS was significantly longer in cases with Notch-1 negativity (8.8 months) than in those with I Notch-1 positivity (6.8 months). We noted that GSCs have the potential for endothelial differentiation with Notch activity. We believe that Notch-1 is a potential target and/or biomarker for antiangiogenic treatments.