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.

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).

Preclinical therapeutic efficacy of a novel blood-brain barrier-penetrant dual PI3K/mTOR inhibitor with preferential response in PI3K/PTEN mutant glioma.

Glioblastoma (GBM) is an ideal candidate disease for signal transduction targeted therapy because the majority of these tumors harbor genetic alterations that result in aberrant activation of growth factor signaling pathways. Loss of heterozygosity of chromosome 10, mutations in the tumor suppressor gene PTEN, and PI3K mutations are molecular hallmarks of GBM and indicate poor prognostic outcomes in many cancers. Consequently, inhibiting the PI3K pathway may provide therapeutic benefit in these cancers. PI3K inhibitors generally block proliferation rather than induce apoptosis. To restore the sensitivity of GBM to apoptosis induction, targeted agents have been combined with conventional therapy. However, the molecular heterogeneity and infiltrative nature of GBM make it resistant to traditional single agent therapy. Our objectives were to test a dual PI3K/mTOR inhibitor that may cross the blood-brain barrier (BBB) and provide the rationale for using this inhibitor in combination regimens to chemotherapy-induced synergism in GBM. Here we report the preclinical potential of a novel, orally bioavailable PI3K/mTOR dual inhibitor, DS7423 (hereafter DS), in in-vitro and in-vivo studies. DS was tested in mice, and DS plasma and brain concentrations were determined. DS crossed the BBB and led to potent suppression of PI3K pathway biomarkers in the brain. The physiologically relevant concentration of DS was tested in 9 glioma cell lines and 22 glioma-initiating cell (GIC) lines. DS inhibited the growth of glioma tumor cell lines and GICs at mean 50% inhibitory concentration values of less than 250 nmol/L. We found that PI3K mutations and PTEN alterations were associated with cellular response to DS treatment; with preferential inhibition of cell growth in PI3KCA-mutant and PTEN altered cell lines. DS showed efficacy and survival benefit in the U87 and GSC11 orthotopic models of GBM. Furthermore, administration of DS enhanced the antitumor efficacy of temozolomide against GBM in U87 glioma models, which shows that PI3K/mTOR inhibitors may enhance alkylating agent-mediated cytotoxicity, providing a novel regimen for the treatment of GBM. Our present findings establish that DS can specifically be used in patients who have PI3K pathway activation and/or loss of PTEN function. Further studies are warranted to determine the potential of DS for glioma treatment.

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.

A high Notch pathway activation predicts response to γ secretase inhibitors in proneural subtype of glioma tumor-initiating cells.

Genomic, transcriptional, and proteomic analyses of brain tumors reveal subtypes that differ in pathway activity, progression, and response to therapy. However, a number of small molecule inhibitors under development vary in strength of subset and pathway-specificity, with molecularly targeted experimental agents tending toward stronger specificity. The Notch signaling pathway is an evolutionarily conserved pathway that plays an important role in multiple cellular and developmental processes. We investigated the effects of Notch pathway inhibition in glioma tumor-initiating cell (GIC, hereafter GIC) populations using γ secretase inhibitors. Drug cytotoxicity testing of 16 GICs showed differential growth responses to the inhibitors, stratifying GICs into responders and nonresponders. Responder GICs had an enriched proneural gene signature in comparison to nonresponders. Also gene set enrichment analysis revealed 17 genes set representing active Notch signaling components NOTCH1, NOTCH3, HES1, MAML1, DLL-3, JAG2, and so on, enriched in responder group. Analysis of The Cancer Genome Atlas expression dataset identified a group (43.9%) of tumors with proneural signature showing high Notch pathway activation suggesting γ secretase inhibitors might be of potential value to treat that particular group of proneural glioblastoma (GBM). Inhibition of Notch pathway by γ secretase inhibitor treatment attenuated proliferation and self-renewal of responder GICs and induces both neuronal and astrocytic differentiation. In vivo evaluation demonstrated prolongation of median survival in an intracranial mouse model. Our results suggest that proneural GBM characterized by high Notch pathway activation may exhibit greater sensitivity to γ secretase inhibitor treatment, holding a promise to improve the efficiency of current glioma therapy.

Treatment of moyamoya syndrome associated with systemic lupus erythematosus and hypothyroidism in an adult by encephaloduroarteriosynangiosis: a case report.

A 54-year-old woman presented to our hospital with progressive motor weakness of the right arm. She had a medical history of systemic lupus erythematosus (SLE) and hypothyroidism. Magnetic resonance imaging indicated a watershed infarction of the left hemisphere. Cervical echogram indicated severe stenosis of the internal carotid artery (ICA) without wall thickening. Cerebral angiography indicated left ICA occlusion, development of unilateral moyamoya vessels, and leptomeningeal anastomosis. Encephaloduroarteriosynangiosis (EDAS) was performed after cerebral (99) (m)Technetium-ethyl-cysteinate-dimer single-photon emission computed tomography indicated a decreased cerebral blood flow, diminished cerebrovascular perfusion reserve. Motor weakness finally disappeared 6 months after surgery. Moyamoya syndrome is a rare complication of both SLE and hypothyroidism, and the surgical indication remains controversial. By evaluating the decreased cerebral perfusion reserve capacity and the existence of leptomeningeal anastomosis, EDAS could be an efficient method for the treatment of moyamoya syndrome associated with SLE and hypothyroidism.

Erwinia uzenensis sp. nov., a novel pathogen that affects European pear trees (Pyrus communis L.).

Bacteria were isolated from black lesions on shoots of European pear trees (Pyrus communis L.) in an orchard in Japan. Previous characterization of this novel pathogen by phenotypic and genotypic methods suggested that it should belong to the genus Erwinia but might not correspond to either Erwinia amylovora or Erwinia pyrifoliae. Here, phylogenetic analyses of the 16S rRNA gene, gyrB, and rpoD gene sequences indicated that it could not be assigned to any recognized species of the genus Erwinia. DNA-DNA hybridization confirmed that the bacterial strains represented a novel species. The DNA G+C contents, the fatty acid profile and phenotypic characteristics resembled those previously reported for members of the genus Erwinia. On the basis of these and previous results, the pathogen represents a novel species of the genus Erwinia, for which the name Erwinia uzenensis sp. nov. (type strain: YPPS 951(T) = LMG 25843(T) = NCPPB 4475(T)) is proposed.

Posttraumatic cranial cystic fibrous dysplasia.

A 14-year-old was girl admitted to our hospital with a subcutaneous mass of the occipital head. The mass had grown for 6 years, after she had sustained a head injury at the age of 6, and was located directly under a previous wound. Skull X-ray Photograph (xp), computed tomography (CT), and magnetic resonance imaging (MRI) showed a bony defect and cystic changes in the skull corresponding to a subcutaneous mass. Bone scintigraphy revealed partial accumulation. The patient underwent total removal of the skull mass, and the diagnosis from the pathological findings of the cyst wall was fibrous dysplasia (FD). The radiographic findings for cystic cranial FD can be various. Progressive skull disease has been reported to be associated with head trauma, but the relationship between cranial FD and head trauma has not been previously reported. Previous studies have suggested that c-fos gene expression is a key mechanism in injury-induced FD.

Linezolid treatment for intracranial abscesses caused by methicillin-resistant Staphylococcus aureus--two case reports.

Two patients were treated for intracranial infections involving methicillin-resistant Staphylococcus aureus (MRSA). A 30-year-old woman was admitted to our hospital for intracerebral hemorrhage related to arteriovenous malformation. After decompressive craniectomy, the patient developed an epidural abscess. MRSA was isolated from the pus culture. The infection did not improve after intravenous vancomycin (VCM) administration for 15 days. However, after administration of linezolid (LZD) for 14 days, the infection had improved, and the white blood cell count and C-reactive protein values had normalized. A 53-year-old woman had previously undergone 3 operations for craniopharyngioma before the age of 35 years. She was admitted to our hospital with fever and disturbance of consciousness. Magnetic resonance imaging with contrast medium revealed a brain abscess caused by MRSA. After 14 days of intravenous administration of VCM, the infection had not improved and intravenous administration of LZD was initiated. After administration of LZD for 14 days intravenously and 14 days orally, the infection had improved, and the white blood cell count and C-reactive protein values had normalized. VCM is highly effective against MRSA infection, but penetration into the central nervous system (CNS) is poor. LZD has good CNS penetration, so should be considered for secondline antibiotic therapy for VCM-resistant intracranial MRSA infection.

Dynamics of global gene expression changes during brain metastasis formation.

As methods of cancer diagnosis and treatment improve, interest in metastatic brain tumors continues to increase. In the present study, we attempted to characterize genetically the dynamic changes occurring during brain metastasis formation by DNA microarray, and attempted to compare these findings with histological observations. Lewis lung carcinoma cells were injected into C57BL/6Ncrj mice carotid arteries. The mice were sacrificed at days 1-9 after injection. We performed histological observation and genome-wide expression profiling using a DNA microarray. In histological observation, tumor cells were observed in capillary vessels at day 1 after injection. At day 3, the tumor cells had begun to proliferate. At day 6, the metastatic foci showed "perivascular proliferations". Next, we performed a pairwise comparison of gene expression microarray data from day 1 to day 9 after injection. The first major change occurred between Phase Two and Phase Three. When hierarchical clustering was performed between different samples using the 867 genes, they could be classified into identical clusters for days 1 and 2, identical clusters for day 3 to day 5, and identical clusters for day 6 to day 9. For time course analysis, we extracted 623 genes by the pairwise comparison. By using the quality threshold (QT) nonhierarchical clustering method, we identified 37 expression patterns. These patterns can be separated into eight clusters by using the k-means method. The microarray results reported here strongly suggest that a large number of genes exhibit a spike pattern, which is tantamount to phase-specific expression.

Comparison of metastatic brain tumour models using three different methods: the morphological role of the pia mater.

As methods of cancer diagnosis and treatment progress, interest in metastatic brain tumours continues to increase. There are many studies using various methods of animal model and we considered that each model reflects different pathological processes because of the unique composition of the brain. We prepared metastatic brain tumour models using three different methods. In this study, we attempted to elucidate the roles of the pia mater in brain metastasis. The metastatic foci showed an angiocentric pattern, forming collars of neoplastic cells, and were designated 'perivascular proliferations'. Furthermore, we observed neoplastic cells that infiltrated the brain parenchyma, the border of which had become indistinct. These were labelled 'invasive proliferations'. The internal carotid artery injection model reflects haematogenous metastasis. In this model, both perivascular and invasive proliferations were observed. The intrathecal injection model reflects leptomeningeal carcinomatosis. In this model, metastasis to the meninges was observed. In the stereotactic injection model, the tumour proliferation at the injection site and the infiltration into the brain parenchyma were observed. The pia-glial membrane serves as a scaffold when neoplastic cells spread to the perivascular space forming angiocentric pattern. The pia-glial membrane is found between the brain parenchyma and blood vessels. Blood vessels penetrate the brain through tunnels known as perivascular spaces that are covered by pia mater. Three different methods which we prepared reflect three different pathological processes. Our findings suggest that the pia mater is a critical factor in brain metastasis.

A case of concomitant occurrence of struma ovarii and malignant transformation of cystic teratoma.

A 77-year-old woman received a total abdominal hysterectomy and bilateral salpingo-oophorectomy because of a tumor in the left ovary. The surgical specimen measured 8.5x4.5x4.0 cm, and the solid lesion measured 4.0x3.5x3.5 cm. The solid lesion was diagnosed as struma ovarii. The cyst wall partially comprised squamous epithelium-like and ciliated columnar epithelium-like cells. The tumorous lesion of the cyst wall revealed a poorly differentiated adenocarcinoma. Immunohistochemically, the tumor cells were positive for cytokeratin7, and were negative for cytokeratin20 and thyroid transcription factor-1. The authors diagnosed that struma ovarii and other parats coexisted as a poorly differentiated adenocarcinoma that had arisen from a mature ovarian cystic teratoma. As for the identification of the origin of adenocarcinomas arising from mature ovarian cystic teratomas, more cases need to be identified and investigated.

[Abdominal aortic aneurysm with chronic contained rupture in a ninety-year-old woman: a case report].

A 90-year-old woman was admitted to a local clinic with fever, anorexia, and right lower abdominal pain on March 25, 2004. She was referred to our hospital for detailed examination of an abdominal aortic aneurysm on May 18. Computed tomography revealed an abdominal aortic aneurysm measuring 78mm in maximal diameter and a retroperitoneal hematoma, suggesting chronic contained rupture of the abdominal aortic aneurysm. Emergency Y-shaped graft replacement was performed. The intraoperative findings included a perforation on the posterior wall of the abdominal aortic aneurysm and an organized thrombus on the retroperitoneum. The postoperative course was uneventful, and the patient was discharged 21 days after surgery.

Granuloma and cryptococcosis.

This review describes the general histopathological features of cryptococcosis in immunocompetent individuals, as well as in patients with acquired immunodeficiency syndrome (AIDS). Details of the histological examination of cryptococcal lesions are described, with the consideration of morphological modifications induced by treatment with highly active antiretroviral therapy (HAART). The essential histological features of cryptococcosis in individuals with impaired T-cell functioning are yeast-cell proliferation with a histiocytic response, but only minor lymphocytic and neutrophilic components. Several histological patterns of pulmonary cryptococcal lesions are introduced in this article, some of which could be graded with respect to the degree and type of inflammatory reaction. One pattern was a mild lesion consisting of scattered small foci of intraalveolar cryptococcal proliferation with a histiocytic response. Another pattern involved massive cryptococcal infection, which may have been simply more extensive than that in the mild lesion. Capillary involvement of alveolar septa should be understood as an important common finding in patients with AIDS who had not been treated with HAART. In those patients, the absence of T cells and a decreasing function of antigen-presenting activity in histiocytes were confirmed by immunohistological examination. These findings suggest that the lungs of AIDS patients without HAART offer little resistance to bloodstream dissemination by cryptococci. The unique histological feature demonstrated in patients treated with HAART is characterized by the presence of CD4+ cells, greater response of histiocytes and multinucleated giant-cell formation, and lack of massive capillary involvement.