Clinicopathologic analysis of pineal parenchymal tumors of intermediate differentiation: a multi-institutional cohort study by the Kyushu Neuro-Oncology Study Group.

PURPOSE: Pineal parenchymal tumors of intermediate differentiation (PPTIDs), which were recognized in the 2007 World Health Organization (WHO) classification, are rare, accounting for less than 1% of all central nervous system tumors. This rarity and novelty complicate the diagnosis and treatments of PPTID. We therefore aimed to evaluate the clinicopathological significance of this tumor. METHODS: At 11 institutions participating in the Kyushu Neuro-Oncology Study Group, data for patients diagnosed with PPTID were collected. Central pathology review and KBTBD4 mutation analysis were applied to attain the diagnostically accurate cohort. RESULTS: PPTID was officially diagnosed in 28 patients: 11 (39%) with WHO grade 2 and 17 (61%) with WHO grade 3 tumors. Median age was 49 years, and the male:female ratio was 1:2.1. Surgery was attempted in all 28 patients, and gross total resection (GTR) was achieved in 46% (13/28). Adjuvant radiotherapy and chemotherapy were administered to, respectively, 82% (23/28) and 46% (13/28). The 5-year progression-free survival (PFS) and overall survival rates were 64.9% and 70.4% respectively. Female sex (p = 0.018) and GTR (p < 0.01) were found to be independent prognostic factors for PFS and female sex (p = 0.019) was that for OS. Initial and second recurrences were most often leptomeningeal (67% and 100% respectively). 80% (20/25) of patients harbored a KBTBD4 mutation. CONCLUSIONS: Female sex and GTR were independent prognostic factors in our patients with PPTID. Leptomeningeal recurrence was observed to be particularly characteristic of this tumor. The rate of KBTBD4 mutation observed in our cohort was acceptable and this could prove the accuracy of our PPTID cohort.

Primary diffuse leptomeningeal atypical teratoid rhabdoid tumor (AT/RT) demonstrating atypical imaging findings in an adolescent patient.

Atypical teratoid rhabdoid tumor (AT/RT) is a highly malignant central nervous system embryonal tumor, which typically affects the posterior fossa of young children. Primary diffuse leptomeningeal AT/RT, affecting the leptomeninges without any intraparenchymal mass in the brain and spinal cord, is an extremely rare form of AT/RT. Only 5 such cases have been reported previously, none of which underwent Fluorine-18-Fluorodeoxyglucose Positron Emission Tomography (FDG-PET). We herein report a case of primary leptomeningeal AT/RT in an adolescent patient who underwent computed tomography, magnetic resonance imaging and FDG-PET. The computed tomography and magnetic resonance imaging indicated diffusely thickened leptomeninges without any intraparenchymal masses in the head and spine. Furthermore, there were multiple nodules on the thickened leptomeninges. On FDG-PET, the thickened leptomeninges and nodules demonstrated a lower standardized uptake value than that of the normal cerebral cortex. Biopsy and histopathological studies confirmed the diagnosis of AT/RT. Despite its rare occurrence, it is important to recognize primary diffuse leptomeningeal AT/RT for correct diagnosis and management of patients.

Study protocol for a single-centre, prospective, non-blinded, randomised, 12-month, parallel-group superiority study to compare the efficacy of pharmacist intervention versus usual care for elderly patients hospitalised in orthopaedic wards.

INTRODUCTION: Given that polypharmacy and potentially inappropriate prescribing are common in elderly orthopaedic patients, pharmacist interventions to improve medication practices among this population are important. However, past studies have reported mixed results regarding the effectiveness of pharmacist-led interventions in inpatient elderly care. Furthermore, few randomised controlled trials have evaluated patient-relevant outcomes as a primary endpoint. Therefore, we will evaluate whether a pharmacist-led intervention could reduce readmission of hospitalised elderly orthopaedic patients with polypharmacy or potentially inappropriate prescribing. METHODS AND ANALYSIS: This is an ongoing single-centre, prospective, non-blinded, randomised controlled trial designed to evaluate the superiority of a pharmacist-led intervention for hospitalised elderly patients compared with usual care. The trial will include newly admitted orthopaedic patients 70 years of age and older with polypharmacy or at least one potentially inappropriate prescription, as identified by the screening tool of older people's prescriptions (STOPP) criteria. Usual care includes medication reconciliation, patient education and monitoring, as well as providing information about discharge medications. Pharmacist interventions, in addition to usual care, include advising the patient's physician to stop unnecessary or inappropriate medications and start necessary medications. The primary outcome is the 1-year readmission rate. Secondary outcomes are the proportion of patients who undergo emergency department visits and the occurrences of all-cause death, a new fracture, myocardial infarction and ischaemic stroke. The study started in November 2017, and up to approximately 220 patients will be enrolled. ETHICS AND DISSEMINATION: The protocol was approved by the Medical Ethics Committee of the National Hospital Organization Tochigi Medical Center (No. 29-22). The trial was registered at the University Hospital Medical Information Network (UMIN) clinical registry. The results of this trial will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: UMIN000029404.

The usefulness of indocyanine green during surgery for hypervascular posterior fossa tumors.

BACKGROUND: Cerebral hemangioblastomas are benign tumors with abundant blood flow that occur mainly in the posterior fossa. Tumor removal en bloc is important in surgical treatment because of the risk of bleeding; however, it is actually rather difficult in practice. Therefore, we propose a surgical strategy for visualizing hypervascular tumors of the posterior fossa utilizing indocyanine green (ICG). CASE DESCRIPTION: Case 1 involved a 48-year-old male with a history of von Hippel-Lindau (VHL) disease. Magnetic resonance imaging (MRI) revealed a solid tumor measuring 3.0 cm in diameter in the right cerebellopontine angle. We performed surgery because the tumor was pressing against the brainstem. Surgery was performed via the posterior subtemporal transtentorial approach in order to visualize the feeding artery and draining vein intraoperatively. The vessels were confirmed by ICG and the tumor was removed en bloc. Case 2 involved a 30-year-old woman. Signs of increased intracranial pressure were noted, and an MRI revealed a solid tumor 3.5 cm in diameter in the left cerebellar hemisphere. Surgery was performed via the midline suboccipital approach. Similarly, we confirmed the vessels using ICG and the tumor was removed en bloc. CONCLUSIONS: For hypervascular tumors of the posterior fossa, preoperative image assessment is important. Furthermore, the use of ICG during surgery is advantageous for surgical strategies where the feeding arteries and draining veins exist superficially in the operative field and are therefore easier to remove en bloc.

Characteristics of elderly patients with polypharmacy who refuse to participate in an in-hospital deprescribing intervention: a retrospective cross-sectional study.

BACKGROUND: Few studies have evaluated the characteristics of elderly patients with polypharmacy refusing deprescribing. The aim of this study was to evaluate the prevalence of potentially inappropriate medication (PIM) use in elderly patients accepting and refusing a deprescribing intervention and to investigate factors associated with deprescribing refusal. METHODS: We conducted a retrospective cross-sectional study by analyzing the electronic medical records from a single hospital. All consecutive patients aged 65 years or older who reported the use of five or more medications upon admission to the orthopedic ward from January 2015 to December 2016 and who were approached by a pharmacist for polypharmacy screening were included. Patients who had provided consent for the deprescribing intervention by the internal medicine physicians were defined as the acceptance group, and patients who did not were defined as the refusal group. The primary outcome was the use of any PIMs at admission, based on the 2015 American Geriatric Society Beers Criteria. Using multivariable logistic regression, predictive factors of refusing deprescribing were also evaluated. RESULTS: During the study period, 136 patients were eligible. Of those, 82 patients (60.3%) accepted the deprescribing intervention, and 54 patients (39.7%) declined the intervention. The mean age of all the patients was 81.1 years, and the mean number of medications at admission was 9.3. The overall proportion of patients taking any PIMs at admission was 77.2%. The proportion of patients taking any PIMs at admission was not different between the acceptance and refusal groups (78.0% and 75.9%, respectively; p = 0.84). None of the measured characteristics, including age, gender, residential status, comorbidity, alcohol use, smoking status, number of medications, or number of PIMs, were found to be associated with deprescribing refusal. CONCLUSION: The prevalence of any PIM use did not differ among elderly orthopedic patients with polypharmacy according to refusal or acceptance of the deprescribing intervention. Furthermore, none of the analyzed characteristics were found to be associated with deprescribing refusal. Given the high prevalence of PIM use, a strategy is needed for combating polypharmacy among elderly patients reluctant to undergo deprescribing.

Clinical value of fluorine-18α-methyltyrosine PET in patients with gliomas: comparison with fluorine-18 fluorodeoxyglucose PET.

BACKGROUND: We investigated the relationship between metabolic activity and histological features of gliomas using fluorine-18α-methyltyrosine (18F-FAMT) positron emission tomography (PET) compared with fluorine-18 fluorodeoxyglucose (18F-FDG) PET in 38 consecutive glioma patients. The tumor to normal brain ratios (T/N ratios) were calculated, and the relationships between T/N ratio and World Health Organization tumor grade or MIB-1 labeling index were evaluated. The diagnostic values of T/N ratios were assessed using receiver operating characteristic (ROC) curve analyses to differentiate between high-grade gliomas (HGGs) and low-grade gliomas (LGGs). RESULTS: Median T/N ratio of 18F-FAMT PET was 2.85, 4.65, and 4.09 for grade II, III, and IV gliomas, respectively, with significant differences between HGGs and LGGs (p = 0.006). Both T/N ratio (p = 0.016) and maximum standardized uptake value (p = 0.033) of 18F-FDG PET showed significant differences between HGGs and LGGs. ROC analysis yielded an optimal cut-off of 3.37 for the T/N ratio of 18F-FAMT PET to differentiate between HGGs and LGGs (sensitivity 81%, specificity 67%, accuracy 76%, area under the ROC curve 0.776). Positive predictive value was 84%, and negative predictive value was 62%. T/N ratio of 18F-FAMT PET was not correlated with MIB-1 labeling index in all gliomas, whereas T/N ratio of 18F-FDG PET was positively correlated (r s = 0.400, p = 0.013). Significant positive correlation was observed between T/N ratios of 18F-FDG and 18F-FAMT (r s = 0.454, p = 0.004), but median T/N ratio of 18F-FAMT PET was significantly higher than that of 18F-FDG PET in all grades of glioma. CONCLUSIONS: The T/N ratio of 18F-FAMT uptake has high positive predictive value for detection of HGGs. 18F-FAMT PET had higher T/N ratio, with better tumor-normal brain contrast, compared to 18F-FDG PET in both LGGs and HGGs. Therefore, 18F-FAMT is a useful radiotracer for the preoperative visualization of gliomas.

Resection extent of the supplementary motor area and post-operative neurological deficits in glioma surgery.

Objective The supplementary motor area (SMA) is important for the prediction of post-operative symptoms after surgical resection of gliomas. We investigated the relationships between clinical factors and the resection range of SMA gliomas, and the post-operative neurological symptoms. Methods We retrospectively studied 18 consecutive surgeries for gliomas involving the SMA proper performed in 13 patients. Seven cases were recurrence of the tumour. Clinical factors and details of specific resection of the SMA proper (resection of posterior part, medial wall) and cingulate motor area (CMA) were examined. Results Eight cases suffered new post-operative neurological deficits. Six of these eight cases had transient deficits. Permanent deficits persisted in two cases with partial weakness or paresis, after rapid improvement of post-operative global weakness or hemiplegia, respectively. The risk of post-operative neurological deficits was not associated with the resection of the posterior part of the SMA proper or the CMA, but was associated with resection of the medial wall of the SMA proper. Surgery for recurrent tumour was associated with post-operative neurological deficits. The medial wall was frequently resected in recurrent cases. Discussion The frequency of post-operative neurological symptoms, including SMA syndrome, may be higher after resection of the medial wall of the SMA proper compared with the resection of only the lateral surface of the SMA proper.

Microrecording and image-guided stereotactic biopsy of deep-seated brain tumors.

OBJECT: Image-guided stereotactic brain tumor biopsy cannot easily obtain samples of small deep-seated tumor or selectively sample the most viable region of malignant tumor. Image-guided stereotactic biopsy in combination with depth microrecording was evaluated to solve such problems. METHODS: Operative records, MRI findings, and pathological specimens were evaluated in 12 patients with small deep-seated brain tumor, in which image-guided stereotactic biopsy was performed with the aid of depth microrecording. The tumors were located in the caudate nucleus (1 patient), thalamus (7 patients), midbrain (2 patients), and cortex (2 patients). Surgery was performed with a frameless stereotactic system in 3 patients and with a frame-based stereotactic system in 9 patients. Microrecording was performed to study the electrical activities along the trajectory in the deep brain structures and the tumor. The correlations were studied between the electrophysiological, MRI, and pathological findings. Thirty-two patients with surface or large brain tumor were also studied, in whom image-guided stereotactic biopsy without microrecording was performed. RESULTS: The diagnostic yield in the group with microrecording was 100% (low-grade glioma 4, high-grade glioma 4, diffuse large B-cell lymphoma 3, and germinoma 1), which was comparable to 93.8% in the group without microrecording. The postoperative complication rate was as low as that of the conventional image-guided method without using microelectrode recording, and the mortality rate was 0%, although the target lesions were small and deep-seated in all cases. Depth microrecording revealed disappearance of neural activity in the tumor regardless of the tumor type. Neural activity began to decrease from 6.3 ± 4.5 mm (mean ± SD) above the point of complete disappearance along the trajectory. Burst discharges were observed in 6 of the 12 cases, from 3 ± 1.4 mm above the point of decrease of neural activity. Injury discharges were often found at 0.5-1 mm along the trajectory between the area of decreased and disappeared neural activity. Close correlations between electrophysiological, MRI, and histological findings could be found in some cases. CONCLUSIONS: Image-guided stereotactic biopsy performed using depth microrecording was safe, it provided accurate positional information in real time, and it could distinguish the tumor from brain structures during surgery. Moreover, this technique has potential for studying the epileptogenicity of the brain tumor.

Superficial siderosis of the central nervous system caused by hemorrhagic intraventricular craniopharyngioma: case report and literature review.

Superficial siderosis is a rare condition caused by hemosiderin deposits in the central nervous system (CNS) due to prolonged or recurrent low-grade bleeding into the cerebrospinal fluid (CSF). CNS tumor could be one of the sources of bleeding, both pre- and postoperatively. We report an extremely rare case of superficial siderosis associated with purely third ventricle craniopharyngioma, and review previously reported cases of superficial siderosis associated with CNS tumor. A 69-year-old man presented with headache, unsteady gait, blurred vision, and progressive hearing loss. Brain magnetic resonance (MR) imaging with gadolinium revealed a well enhanced, intraventricular mass in the anterior part of the third ventricle. T2*-weighted gradient echo (GE) MR imaging revealed a hypointense rim around the brain particularly marked within the depth of the sulci. Superficial siderosis was diagnosed based on these findings. The tumor was diffusely hypointense on T2*-weighted GE imaging, indicating intratumoral hemorrhage. The lateral ventricles were dilated, suggesting hydrocephalus. [(18)F]fluorodeoxyglucose positron emission tomography revealed increased uptake in the tumor. The whole brain surface appeared dark ocher at surgery. Histological examination showed the hemorrhagic tumor was papillary craniopharyngioma. His hearing loss progressed after removal of the tumor. T2*-weighted GE MR imaging demonstrated not only superficial siderosis but also diffuse intratumoral hemorrhage in the tumor. Superficial siderosis and its related symptoms, including hearing loss, should be considered in patients with hemorrhagic tumor related to the CSF space. Purely third ventricle craniopharyngioma rarely has hemorrhagic character, which could cause superficial siderosis and progressive hearing loss.

Radiotherapy plus concomitant adjuvant temozolomide for glioblastoma: Japanese mono-institutional results.

This study was conducted to investigate the feasibility and survival benefits of combined treatment with radiotherapy and temozolomide (TMZ), which has been covered by the national health insurance in Japanese patients with glioblastoma since September 2006. Between September 2006 and December 2011, 47 patients with newly diagnosed and histologically confirmed glioblastoma received radiotherapy for 60 Gy in 30 fractions. Among them, 45 patients (TMZ group) received concomitant TMZ (75 mg/m(2)/day, every day) and adjuvant TMZ (200 mg/m(2)/day, 5 days during each 28-days). All 36 of the glioblastoma patients receiving radiotherapy between January 1988 and August 2006 were analyzed as historical controls (control group). All patients were followed for at least 1 year or until they died. The median survival was 15.8 months in the TMZ group and 12.0 months in the control group after a median follow-up of 14.0 months. The hazard ratio for death in the TMZ group relative to the control group was 0.52 (P<0.01); the 2-year survival rate was 27.7% in the TMZ group and 14.6% in the control group. Hematologic toxicity of grade 3 and higher was observed in 20.4% in the TMZ group. Multivariate analysis showed that extent of surgery had the strongest impact on survival (P<0.01), while the use of TMZ had the second largest impact on survival (P = 0.035). The results indicate that combined treatment with radiotherapy and TMZ has a significant survival benefit for Japanese patients with newly diagnosed glioblastoma with slightly higher toxicities than previously reported.

Nestin expression in brain tumors: its utility for pathological diagnosis and correlation with the prognosis of high-grade gliomas.

One of the type VI intermediate filament proteins, nestin, is expressed in neuroepithelial stem cells during neural embryogenesis. Nestin is also expressed in a variety of neoplasms. Its expression in brain tumors has not been thoroughly studied. The objectives of this study were to survey nestin expression in different types of brain tumor, and to evaluate nestin as a marker for diagnosis and prognosis. We used tissue microarrays of 257 brain tumors for an immunohistochemical overview of nestin expression: nestin was frequently expressed in gliomas and schwannomas. Most of the gliomas that expressed high levels of nestin were high-grade gliomas (anaplastic astrocytomas, anaplastic oligodendrogliomas, anaplastic oligoastrocytomas, and glioblastomas). We then focused on high-grade gliomas and performed immunohistochemistry again, using whole-mount slides. As a result, we found (1) significantly different nestin expression between glioblastomas and other high-grade gliomas, and (2) worse overall survival for high-grade gliomas with high nestin expression. Our results suggest that: (1) nestin is a useful marker for diagnosis of high-grade gliomas, (2) nestin is helpful in diagnosis of schwannomas, and (3) nestin expression is related to poor prognosis in high-grade gliomas.

Ca2+-permeable AMPA receptors regulate growth of human glioblastoma via Akt activation.

Evidence has been accumulated that glioblastoma cells release and exploit glutamate for proliferation and migration by autocrine or paracrine loops through Ca2+-permeable AMPA-type glutamate receptors. Here, we show that Ca2+ signaling mediated by AMPA receptor regulates the growth and motility of glioblastoma cells via activation of Akt. Ca2+ supplied through Ca2+-permeable AMPA receptor phosphorylated Akt at Ser-473, thereby facilitating proliferation and mobility. A dominant-negative form of Akt inhibited cell proliferation and migration accelerated by overexpression of Ca2+-permeable AMPA receptor. In contrast, introduction of a constitutively active form of Akt rescued tumor cells from apoptosis induced by the conversion of Ca2+-permeable AMPA receptor to Ca2+-impermeable receptors by the delivery of GluR2 cDNA. Therefore, Akt functions as downstream effectors for Ca2+-signaling mediated by AMPA receptor in glioblastoma cells. The activation of the glutamate-AMPA receptor-Akt pathway may contribute to the high degree of anaplasia and invasive growth of human glioblastoma. This novel pathway might give an alternative therapeutic target.

Nestin expression in vascular malformations: a novel marker for proliferative endothelium.

Cavernous angiomas (CAs) and arteriovenous malformations (AVMs) sometimes show growth or de novo appearance. Proliferative capacity of the endothelium is evident in such malformations. Intermediate filament nestin is a newly identified marker for proliferative endothelium, which was originally detected in the neuroepithelial stem cells of the embryonal central nervous system. Immunohistochemical analysis of nestin was evaluated as a marker for proliferative capacity of endothelial cells by comparison with proliferating cell nuclear antigen (PCNA). Sixteen of 27 CAs and 13 of 20 AVMs were positive for nestin. Likewise, 12 of 27 CAs and 10 of 20 AVMs were positive for PCNA. Nestin staining was stronger in the typical malformative vessels of CAs than in AVMs, in both the endothelial cells and the interstitial cells. Newly formed endothelial cells expressed nestin strongly in the reactive tissues including organizing or encapsulated hematomas. These results suggest that neovascularization occurs in the process of repeated bleeding and remodeling of hematomas.

Angiogenic endothelium-specific nestin expression is enhanced by the first intron of the nestin gene.

Nestin is a member of intermediate filaments abundantly expressed in neural stem cells and glioblastomas. The nestin gene has four exons and three introns, and neural cell-specific expression is regulated by the second intron. We previously reported that nestin was invariably detected in the tumor endothelium in gliomas even though tumor cells were negative for nestin. In the present study, we further confirmed nestin immunostaining in tumor endothelium of a variety of common cancers, including lung, stomach, colon, and cervical carcinomas. We examined an endothelium-specific regulator using human umbilical vein endothelial cells (HUVECs) and human glioblastoma-derived U251 cells. In a luciferase reporter assay, the first intron plus 5' upstream promoter (5'UP) gave the highest activity, followed by 5'UP, and the second intron plus 5'UP. However, the assay values were much lower by HUVEC extracts than by U251 cell extracts. Although green fluorescent protein expression was positive over all U251 cells under either the first intron, second intron, or ubiquitously active CAG promoter, the fluorescence in HUVECs was limited to a few cells even under the first intron. This difference came from the growth feature of HUVECs which exhibit growth arrest by contact inhibition. We found that the nestin expression was specific to proliferative endothelium, by using proliferation markers in hemangioblastomas and in situ hybridization. Using an endothelial tube formation assay, tyrosine kinase domain-deleted VEGF receptor KDR effectively abolished the tube formation under the first intron. We suggest that the nestin expression in tumor endothelium is enhanced by the first intron.

Nestin as a marker for proliferative endothelium in gliomas.

Nestin is one of the intermediate filaments abundantly produced in the developing central nervous system and somites in the embryonic stage. Nestin is also reportedly detected in gliomas/glioblastomas. We retested nestin expression in brain tumors having a range of malignancy grades using immunostaining. The intensity of nestin immunostaining roughly paralleled the malignancy grade of the gliomas. However, many tumors were negative for nestin immunostaining, while nestin immunostaining was invariably detected in tumor endothelium regardless of glioma malignancy grades or brain tumor types. We suspected that angiogenic epithelial cells may express nestin, and we found that nestin was highly positive in bovine aortic endothelial cells in static culture. However, nestin expression decreased when the endothelial cells underwent laminar shear stress flow, under which endothelial cells exhibit differentiated features and a decreased rate of growth. Because nestin is highly expressed in growing endothelial cells, we examined its expression in hemangioblastomas because hemangioblasts are thought to be a precursor for angiogenic epithelial cells. As expected, nestin immunostained strongly in all four samples of hemangioblastomas. We suggest that nestin is not only a marker for neuroepithelial stem cells and glioma cells but also for tumor endothelial cells during rapid growth.