[Risk Factors for Adverse Events after Implantation of BCNU Wafers in High-grade Gliomas].

BACKGROUND: In Japan, patients with malignant glioma have been treated with BCNU wafers (Gliadel®) since January 2013. Several adverse events(AEs)associated with implantation of BCNU wafers, including cerebral edema or cyst formation, are recognized. Here, we report a retrospective review of the experience with implantation of BCNU wafers in our institutions and our findings regarding the risk factors for the AEs. METHODS: We reviewed the records of patients with malignant glioma who were implanted with BCNU wafers between April 2013 and September 2014. Their AEs were examined clinically and radiologically and evaluated according to Common Terminology Criteria for Adverse Events (CTCAE) grading. For investigating the association between risk factors and incidence of AEs, histological diagnosis, extent of resection, and period of BCNU wafers implantation surgery were selected as possible risk factors. RESULTS: Twenty-one patients were included in this investigation. There were no associations among incidence of AEs and histological diagnosis or extent of tumor resection. However, regarding the period of BCNU wafers implantation, additional resection for newly diagnosed tumors and resection for recurrent tumors tended to increase the rate and severity of AEs, especially cerebral edema, compared to primary resection. CONCLUSION: In cases of BCNU wafers implantation, the incidence and degree of AEs might increase if additional resection for newly diagnosed tumors or resection for recurrent tumors is performed. Our investigation revealed that AEs associated with implantation of BCNU wafers tend to occur in the repeated glioma surgery.

Type 1 collagen as a potential niche component for CD133-positive glioblastoma cells.

Cancer stem cells are thought to be closely related to tumor progression and recurrence, making them attractive therapeutic targets. Stem cells of various tissues exist within niches maintaining their stemness. Glioblastoma stem cells (GSCs) are located at tumor capillaries and the perivascular niche, which are considered to have an important role in maintaining GSCs. There were some extracellular matrices (ECM) on the perivascular connective tissue, including type 1 collagen. We here evaluated whether type 1 collagen has a potential niche for GSCs. Imunohistochemical staining of type 1 collagen and CD133, one of the GSCs markers, on glioblastoma (GBM) tissues showed CD133-positive cells were located in immediate proximity to type 1 collagen around tumor vessels. We cultured human GBM cell lines, U87MG and GBM cells obtained from fresh surgical tissues, T472 and T555, with serum-containing medium (SCM) or serum-free medium with some growth factors (SFM) and in non-coated (Non-coat) or type 1 collagen-coated plates (Col). The RNA expression levels of CD133 and Nestin as stem cell markers in each condition were examined. The Col condition not only with SFM but SCM made GBM cells more enhanced in RNA expression of CD133, compared to Non-coat/SCM. Semi-quantitative measurement of CD133-positive cells by immunocytochemistry showed a statistically significant increase of CD133-positive cells in Col/SFM. In addition, T472 cell line cultured in the Col/SFM had capabilities of sphere formation and tumorigenesis. Type 1 collagen was found in the perivascular area and showed a possibility to maintain GSCs. These findings suggest that type 1 collagen could be one important niche component for CD133-positive GSCs and maintain GSCs in adherent culture.

Immunohistochemical evaluation of O6 -methylguanine DNA methyltransferase (MGMT) expression in 117 cases of glioblastoma.

Temozolomide (TMZ) is an oral alkylating agent which is widely used in the treatment of glioblastoma (GBM) and is composed of astrocytic and/or oligodendroglial tumors, and the evaluation of O(6) -methylguanine DNA methyltransferase (MGMT) expression is important to predict the response to TMZ therapy. In this study, we conducted immunohistochemical analysis of 117 cases of Japanese GBM including 19 cases of GBM with oligodendroglioma component (GBMO), using a scoring system for quantitative evaluation of staining intensity and proportion of MGMT, and performed survival analysis of these patients. Immunohistochemically, 55 cases (47%) were positive for MGMT with various intensities and proportions (total score (TS) ≥ 2), while 62 cases (53%) were negative (TS = 0). The distribution of MGMT expression pattern was not affected by any clinicopathological parameters such as the histological subtype (GBM vs. GBMO), age and gender. The survival analysis of these patients revealed that the minimal expression of MGMT (TS ≥ 2) was a significant unfavorable prognostic factor (P < 0.001) as well as resectability (P = 0.004). Moreover, multivariate analysis showed that minimal MGMT expression in GBM was the most potent independent predictor for progression free survival (P < 0.001) and also overall patient survival (P < 0.001). This is the first report employing the scoring system for both staining intensity and proportion to evaluate immunohistochemical MGMT expression in GBM. In addition, our results emphases the clinicopathological values of the immunohistochemical approach for MGMT expression in glioma patients as a routine laboratory examination.

[Analyses of IDH1 mutation and MGMT promoter methylation status for 5 cases of long-term survivors with glioblastoma].

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor with an extremely poor prognosis in spite of multimodal treatment approaches. The median survival time of patients with GBM is 15 months, and only 3-5% of patients survive longer than 36 months. Those patients who survive over 36 months after the initial diagnosis are defined as long-term survivors. In this study, we retrospectively performed clinical and molecular analyses of five long-term survivors of GBM (>36 months) and twenty four GBM patients with poor survival time as control group (<36 months) to identify any prognostic factors that potentially contribute to survival. The O6-methylguanine-DNA methyltransferase (MGMT) gene methylation status was evaluated by performing methylation specific polymerase chain reaction assays. The mutation of isocitrate dehydrogenase 1 and 2 were evaluated by the direct sequencing method. All five cases were primary GBMs and the coexistence of the oligodendroglioma component was checked for each case as GBM with oligodendroglioma component. All five cases showed MGMT promoter methylation (5/5). IDH1 mutation was detected in two of the long-term survivors with oligodendroglioma component (2/5) while no IDH1 mutation was detected in the control group. All patients were treated by gross total removal followed by radiotherapy and various chemotherapies including temozolomide. MGMT promoter methylation and IDH1 mutation might be favorable factors for long-term survival in GBM patients.

[A cranial reconstruction using an autologous split calvarial bone combined with a free graft of temporal loose areolar tissue].

We report a new simple method of cranial reconstruction using an autologous split calvarial bone, combined with free graft of temporal loose areolar tissue. A 58-year-old woman suffered from a cranium defect on her left side. The originating bone infection happened after initial brain tumor surgery. Part of the left side of her scalp just above the damaged cranial area had become very thin due to previous cranioplasty, which involved a titanium mesh plate and postoperative infections. We performed a cranial reconstruction with an autologous split calvarial bone, combined with loose areolar tissue free graft, for the damaged area with skin from the inner side. In our case, we expect that the addition of the free graft of loose areolar tissue to the autologous calvarial bone graft will effectively contribute to the skin's healing and provide good cosmetic results in our short follow-up period. A free graft of loose areolar tissue for the damaged skin area may be a new optional method for cranial reconstruction in a patient with skin trouble.

[Case of surgical treatment for giant hemangioblastoma in the dorsal medulla oblongata].

Hemangioblastoma in the medulla oblongata is a relatively rare tumor. We present the case of a giant hemangioblastoma occurring in the dorsal medulla oblongata. A 33-year-old man with no neurological symptoms was diagnosed with a hemangioblastoma in the dorsal medulla oblongata, and opted for observation in the outpatient department. After 22 months of observation time, MRI scans showed rapid local tumor progression and obstructive hydrocephalus. At this point, he presented with mild dysphagia as a preoperative neurological deficit. Total surgical removal of the tumor was performed after temporary ventricle drainage and preoperative embolization of the feeding artery. Postoperatively, he became fully conscious but developed bulbar palsy followed by tracheostomy. During the 12 months of postoperative follow-up, severe dysphagia was still present.

[A novel adherent culture method of glioblastoma cells expressing CD133 using collagen-1-coated plates].

BACKGROUND AND AIMS: Glioblastoma is one of the most malignant brain tumors, causing death within two years despite maximal tumor resection and concurrent radio-chemotherapy. Tumor stem cells are thought to be closely related to tumor progression and recurrence and are attractive therapeutic targets. It is common to culture cell lines in serum-free medium with growth factors to stimulate spheres of enriched tumor stem cells. To avoid spontaneous differentiation and cell death in the sphere environment, Pollard et al. formulated an adherent culture method using laminin-coated plates. We here evaluated collagen-1-coated plates, which are superior to laminin-coated plates in handling and cost, as an alternative adherent culture method of CD133 expressing glioblastoma cells. MATERIALS AND METHODS: We cultured the human glioblastoma cell line, U87MG, under serum contained medium (SCM) or serum free medium with EGF, FGF2, LIF, B27 and N2 supplements (SFM) in non-coated, laminin or collagen-1-coated plates. The growth morphology in various cultures was evaluated, and the number of living cells in each plate on day 5 after cell seeding was calculated. The RNA expression level of CD133 as a stem cell marker in each plate was examined. Semi-quantitative measurement of CD133 positive cells by immunocytochemistry was performed. RESULTS: In collagen-1-coated plates with SFM, cell lines were cultured in an adherent monolayer. Cell proliferation was statistically encouraged in collagen-1-coated plates. Both laminin-coated plates and collagen-1-coated plates with SFM enhanced the RNA expression of CD133 compared to non-coated plates with SCM. Immunocytochemistry showed a statistically significant increase of CD133 positive cells in collagen-1-coated plates with SFM. CONCLUSION: Collagen-1-coated plates with SFM was used for cell morphology and cell proliferation of CD133 expression in the U87MG malignant glioma cell line.

[Cranial reconstruction using autologous split calvarial bone combined with calcium phosphate bone cement: a case report].

We report a case of cranial reconstruction using autologous split calvarial bone combined with calcium phosphate bone cement (CPC). A 19-years-old man suffered from cranium defect and rhinorrhea originating from frontal skull base fracture in a traffic accident. After CSF hydration treatment had finished, continuously we performed cranial reconstruction with autologous split calvarial bone so that the patient could return to work at an early stage. The use of autologous split calvarial bone with CPC was able to increase stability of the construct and provide excellent cosmetic result in our short follow up period. The combination use of these two materials may be useful for cranial reconstruction in patients with cranium defect.

[A case of hemifacial spasm in a juglar foramen tumor patient treated by microvascular decompression].

Hemifacial spasm is a movement disorder characterized by involuntary paroxysmal chronic contractions of the facial musculature. The usual cause is simple vascular compression of the facial nerve, at its root exit zone of the brain stem. Previously only a case of hemifacial spasm associated with a juglar foramen tumor has been reported in the literature. In this article, we report a case in which hemifacial spasm accompanied an ipsilateral juglar foramen tumor in a 62-year-old woman. The sole use of arterial decompression of the facial nerve at the root exit zone resulted in complete resolution of the patient's symptoms.

[A case of ectopic pituitary adenoma occurring in the sphenoid sinus].

Ectopic pituitary adenomas are relatively rare tumors. We present a case of ectopic pituitary adenoma occurring in the sphenoid sinus. A 63-year-old woman was referred to our hospital complaining of headache. She had no endocrinological abnormalities. Magnetic resonance imaging showed a tumor in the sphenoid sinus, adjacent to the sellar floor and appearing as a low-signal on T1-weighted image and a high signal on T2-weighted image. No connection between the normal pituitary gland and tumor was observed. Using an endonasal-transsphenoidal approach assisted with neuro-endoscopy, we performed total removal of the tumor. No connection between the normal pituitary gland and the tumor was found. Histopathological analysis showed a pituitary adenoma. As demonstrated by our case report, differential diagnosis of a tumor occurring in the sphenoid sinus must include consideration of the existence of an ectopic pituitary adenoma.

[A rare case of diffuse astrocytoma complicated with giant pigmented hairy nevi, suspected neurocutaneous melanosis].

A 1-year-old female infant presented with congenital giant, hairy and pigmented nevi. MRI scan as screening test revealed a cerebellar tumor. A diagnosis of provisional neurocutaneous melanosis was made on the basis of the patient's MRI and physical findings. At her 6 years of age, MRI revealed the tumor grown up to 3 cm diameter in 5 years. The cerebellar tumor was removed partially using the occipital transtentorial approach for tissue diagnosis. The color of the cerebellar tumor was whitish and contained neither benign nor malignant melanocyte. Pathological examination revealed diffuse astrocytoma. Finally residual cerebellar tumor was totally removed at a second surgical resection. To our knowledge, this is the first patient to be reported with astrocytoma complicated giant skin nevus except neurocutaneous syndrome cases.

[The repair of traumatic cerebrospinal fluid leak using temporal loose areolar connective tissue insertion into the frontal sinus and pericranial flap covering: a case report].

We report a case of cerebrospinal fluid (CSF) leak repair using loose areolar connective tissue insertion into the frontal sinus and pericranial flap covering. A 61-years-old man suffered from skull fracture including frontal sinus fracture in violence inflicted by others. Fifty days later, he presented rhinorrhea and pneumocephalus caused by a bone defect site of the frontal sinus and anterior skull base. We performed CSF leak repair with insertion of pedunculated loose areolar connective tissue into his frontal sinus, covering the leak point using pericranial flap. In general, frontal sinus obliteration has been accomplished with autologous grafts such as fat, muscle, or bone. These avascular grafts carry an increased risk of resorption and infection. The use of loose areolar tissue insertion into the frontal sinus was able to increase stability of the construct and caused no cosmetic troubles in our short follow up period. The combined use of these two autologous materials may be useful for repair of CSF leak from an anterior skull base fracture.

[A case of metastatic choroid plexus tumor from cholangiocellular carcinoma].

Metastatic intraventricular tumor located in the choroid plexus is very rare. Only a few cases have been reported in the past. According to past reports, these tumors originated from lung, colon, and so on, but not from the bile duct. This is the first case report of choroid plexus metastasis from cholangiocellular carcinoma. A 57-year-old woman who had a history of cholagiocellular carcinoma, demonstrated intraventricular tumor. Although sufficient examination was performed, the tumor was difficult to diagnose as being a metastatic tumor or a choroid plexus carcinoma. Because of this, we performed endoscopic biopsy of the intraventricular tumor. However intraoperative findings were not helpful in distinguishing metastatic tumor and choroid plexus carcinoma. Postoperatively, histological examination was performed. However it was still difficult to differentiate this rare tumor from choroid plexus carcinoma by only hematoxylin and eosin stain. For further examination, Ber EP-4 stain was performed. Ber EP-4 showed strongly positive which indicates metastatic tumor. This method led us to make an appropriate diagnosis of this extremely rare tumor. We considered that in order to diagnose this rare tumor, appropriate histopathological examination, including immunohistopathological examination should be performed.

[Cranioplasty using autologous calvarial bone graft in combination with titanium mesh plates for patients with a history of bone infections after initial cranioplasty].

We present a modified method for reconstruction of calvarial bone defects for patients with a history of infectious complications. Three patients who had experienced implanted bone infections underwent reconstruction of calvarial bone defect. For reconstruction of the calvarial bone defects, autologous split calvarial bone grafts were used to cover the calvarial bone defect. The full or half layered fronto-parietal bone used as implants were fixed with titanium mini-plates for primary bone defect site, while the new bone defect site caused by getting autologous bone graft were covered with titanium mesh plates assisted by residual half layered calvarias. The average follow-up span of patients was 64 months. Evaluated clinical and radiologic results are stable, showing no measurable side effects. Split calvarial bone graft in combination with titanium mesh plates is recommended in patients with a history of infection or high risk of infection.

[A case of symptomatic pituitary metastases from renal cell carcinoma].

Symptomatic metastases to the pituitary from renal cell carcinoma are rare. We present a case of pituitary metastases from renal cell carcinoma showing panhypopituitarism. A 50-year-old man who had renal cell carcinoma with distant metastases in skin, bone and lymph nodes was referred to our department. Clinically he showed severe cognitive function disorder. Endocrinological evaluation revealed central adrenal and gonadal insufficiencies. Brain magnetic resonance imaging demonstrated a hemorrhagic mass in left frontal lobe and a sellar mass with supra sellar cistern extension. After hormonal replacement and surgical removal of the frontal tumor, he immediately recovered from his cognitive function disorder. Subsequently, whole brain radiotherapy for metastatic pituitary tumor was performed. At present, he is being treated with molecular targeting drugs for other distant metastases and he presents no neurological deficit. Palliative therapy for CNS metastases from renal cell carcinoma may result in better quality of life for patients with advanced stage of renal cell carcinoma.

Loss of H3K27 trimethylation is frequent in IDH1-R132H but not in non-canonical IDH1/2 mutated and 1p/19q codeleted oligodendroglioma: a Japanese cohort study.

Oligodendrogliomas are defined by mutation in isocitrate dehydrogenase (NADP(+)) (IDH)1/2 genes and chromosome 1p/19q codeletion. World Health Organisation diagnosis endorses testing for 1p/19q codeletion to distinguish IDH mutant (Mut) oligodendrogliomas from astrocytomas because these gliomas require different treatments and they have different outcomes. Several methods have been used to identify 1p/19q status; however, these techniques are not routinely available and require substantial infrastructure investment. Two recent studies reported reduced immunostaining for trimethylation at lysine 27 on histone H3 (H3K27me3) in IDH Mut 1p/19q codeleted oligodendroglioma. However, the specificity of H3K27me3 immunostaining in this setting is controversial. Therefore, we developed an easy-to-implement immunohistochemical surrogate for IDH Mut glioma subclassification and evaluated a validated adult glioma cohort. We screened 145 adult glioma cases, consisting of 45 IDH Mut and 1p/19q codeleted oligodendrogliomas, 30 IDH Mut astrocytomas, 16 IDH wild-type (Wt) astrocytomas, and 54 IDH Wt glioblastomas (GBMs). We compared immunostaining with DNA sequencing and fluorescent in situ hybridization analysis and assessed differences in H3K27me3 staining between oligodendroglial and astrocytic lineages and between IDH1-R132H and non-canonical (non-R132H) IDH1/2 Mut oligodendroglioma. A loss of H3K27me3 was observed in 36/40 (90%) of IDH1-R132H Mut oligodendroglioma. In contrast, loss of H3K27me3 was never seen in IDH1-R132L or IDH2-mutated 1p/19q codeleted oligodendrogliomas. IDH Mut astrocytoma, IDH Wt astrocytoma and GBM showed preserved nuclear staining in 87%, 94%, and 91% of cases, respectively. A high recursive partitioning model predicted probability score (0.9835) indicated that the loss of H3K27me3 is frequent to IDH1-R132H Mut oligodendroglioma. Our results demonstrate H3K27me3 immunohistochemical evaluation to be a cost-effective and reliable method for defining 1p/19q codeletion along with IDH1-R132H and ATRX immunostaining, even in the absence of 1p/19q testing.

Update on current standard treatments in central nervous system germ cell tumors.

PURPOSE OF REVIEW: Various approaches have been used for the management of patients with germ cell tumors (GCTs) in the central nervous system (CNS); however, the optimal treatment of both germinoma and nongerminomatous GCTs remains unknown. This review discusses current management strategies and late effects of therapy for CNS GCTs. RECENT FINDINGS: To reduce the late complications of radiation therapy for patients with germinoma, many investigators have introduced dose reduction of radiation therapy in association with platinum-based chemotherapy. In addition, the radiation field has been restricted to the whole ventricular area for localized germinoma. This type of combination therapy has shown promising results and preserves cognitive function and quality of life. Despite various approaches including high-dose chemotherapy against highly malignant or relapsed GCTs, the prognoses of these patients remain dismal except for a few successful reports. SUMMARY: The 10-year survival rate of CNS germinoma is approximately 90%. Most patients with CNS GCTs are children and young adults. Therefore, with the improving life prognosis of young patients, secondary neoplasms, secondary cerebral vasculopathy, neurocognitive deficits, and many other adverse effects induced by the initial treatments are problems to be solved in the next decade.

Progressive Multifocal Leukoencephalopathy during Tocilizumab Treatment for Rheumatoid Arthritis.

A 61-year-old woman was diagnosed with rheumatoid arthritis 12 years ago and received multiple treatment regimens before achieving symptomatic stability with methotrexate plus tocilizumab, a humanized monoclonal antibody against the IL-6 receptor, about 2 years prior to the current presentation. Sixteen months after tocilizumab initiation, she exhibited dysarthria and disorientation; five months later, she was hospitalized with movement difficulties. Her neurological symptoms deteriorated thereafter, accompanied by enlarged cerebral white matter lesions on magnetic resonance imaging. A biopsy of the right frontal lesion confirmed progressive multifocal leukoencephalopathy (PML). While several therapeutic monoclonal antibodies have been linked to PML, this is the first case associated with tocilizumab.

Chemotherapy with cisplatin and vincristine for optic pathway/hypothalamic astrocytoma in young children.

OBJECTIVE: Optic pathway/hypothalamic astrocytomas (OPHA) in young children often show accelerated growth and require rather intensive induction chemotherapy. METHODS: Fifteen children (median age: 3 years) with a large OPHA were treated. All of them presented with progressive disease, and the tumor size was larger than 34 mm. Pilocytic astrocytoma was confirmed histologically in 10 patients. Eleven patients had visual disturbance, six had diencephalic syndrome and four had hydrocephalus. RESULTS: The children received six to eight cycles of cisplatin (20 mg/m(2): days 1-5) and vincristine (1.4 mg/m(2): days 1, 8, 15), every 4 weeks. Objective response was obtained in 11 patients (73%); one complete response, eight partial responses and two minor responses. Although the remaining four cases were evaluated as stable disease, all tumors decreased in volume. All children tolerated the chemotherapy well under careful audiological monitoring. CONCLUSION: Although the present series was small, this chemotherapy is a useful regimen for induction therapy in children with an aggressive deep-seated pilocytic astrocytoma.

Role of surgery for optic pathway/hypothalamic astrocytomas in children.

Optic pathway/hypothalamic pilocytic astrocytomas in children are usually treated with chemotherapy following a surgical biopsy. In this report, we retrospectively considered the role of surgical intervention. In a series of 25 patients without neurofibromatosis type 1, the median age at initial treatment was 3.1 years (range, 0-15 years). Twenty cases were verified by histology, and five cases were diagnosed by MRI findings. Twenty-three patients received chemotherapy. All patients were alive at median follow-up of 66 months. Aims of surgery at the initiation of treatment were biopsy in 12 cases (1 stereotactic and 11 craniotomies) and debulking in 7 cases. The 11 open biopsies revealed pilocytic astrocytoma; however, noticeable complications occurred in five children after the biopsies. Review of preoperative MRIs showed that all had typical findings indicating pilocytic astrocytoma. The open biopsy offered no noteworthy benefit for the patients despite surgical risk and delay of chemotherapy. The extent of the seven resection surgeries was 70% or less removal, and postoperative adjuvant therapy was needed for six of the seven patients. The remaining six children who did not undergo surgery obtained remission with chemotherapy alone. After relapse in nine patients, 15 bulk-reduction surgeries were performed. Surgical resection was not curative in any patient. In five patients, mostly older children, cystic expansion of tumor was partially resected, resulting in additional remission. In conclusion, considering the risk of open surgery and the effectiveness of chemotherapy, the role of surgical intervention is restricted to bulk-reduction surgery only when it is inevitable, especially at relapse after chemotherapy.