Survival in patients with glioblastoma at a first progression does not correlate with isocitrate dehydrogenase (IDH)1 gene mutation status.

BACKGROUNDS: Mutations in the isocitrate dehydrogenase (IDH)1 gene are favourable prognostic factors in newly diagnosed diffuse gliomas, whereas it remains controversial in the recurrent glioblastoma setting. METHODS: A total of 171 patients with newly diagnosed glioblastoma, either 'primary' glioblastoma or 'secondary' glioblastoma, treated at Kyorin University Hospital or Japanese Red Cross Medical Center from 2000 to 2015 were included. Patients with confirmed IDH1 status and O6-methylguanine-DNA methyltransferase promoter methylation status were retrospectively analysed for overall survival from the initial diagnosis (n = 147) and after the first progression (n = 122). RESULTS: IDH1 mutation but not IDH2 was noted in 19 of 147 patients with glioblastoma (12.9%). In patients with 'primary' glioblastoma (n = 136), median overall survival after the first progression was 13.5 and 10.5 months for mutant IDH1 and wild-type IDH1 glioblastoma, respectively (P = 0.747). Multivariate analysis revealed O6-methylguanine-DNA methyltransferase promoter methylation, and Karnofsky Performance status 60 or higher, were independent prognostic factors for better overall survival after the first progression. When 'primary' glioblastoma and 'secondary' glioblastoma were combined, median overall survival from the first progression was not significantly different between the mutant IDH1 group (10.1 months) and wild-type IDH1 group (10.5 months) (P = 0.559), whereas median overall survival from the initial diagnosis was significantly different (47.5 months vs.18.3 months, respectively; P = 0.035). CONCLUSIONS: These results suggest that IDH1 mutation may not be a prognostic factor for survival at the first progression of patients with 'primary' glioblastoma and pretreated 'secondary' glioblastoma, and further warrant investigation in prospective studies.

Long-term results of hypofractionated stereotactic radiotherapy with CyberKnife for growth hormone-secreting pituitary adenoma: evaluation by the Cortina consensus.

The aim of the present study was to evaluate the safety and feasibility of hypofractionated stereotactic radiotherapy (SRT) with CyberKnife for growth hormone-secreting pituitary adenoma (GH-PA). Fifty-two patients with GH-PA were treated with hypofractionated SRT between September 2001 and October 2012. Eight patients had clinically silent GH-PA and 44 were symptomatic. Only 1 patient was inoperable. The other patients had recurrent or postoperative residual tumors on MRI. All patients had received pharmacotherapy prior to SRT with a somatostatin analog, dopamine agonist, and/or GH receptor antagonist. The marginal doses were 17.4-26.8 Gy for the 3-fraction schedule and 20.0-32.0 Gy for the 5-fraction schedule. Endocrinological remission was assessed by the Cortina consensus criteria 2010 (random GH <1 ng/ml or nadir GH after an oral glucose tolerance test <0.4 ng/ml and normalization of age- and sex-adjusted insulin-like growth factor-1). The median follow-up period was 60 months (range 27-137). The 5-year overall survival, local control, and disease-free survival rates were 100, 100, and 96 %, respectively. Nine patients (5 clinically silent and 4 symptomatic patients) satisfied the Cortina criteria without receiving further pharmacotherapy, whereas the remaining 43 patients did not. No post-SRT grade 2 or higher visual disorder occurred. Symptomatic post-SRT hypopituitarism was observed in 1 patient. CyberKnife hypofractionated SRT is safe and effective when judged by imaging findings for GH-PA. However, it may be difficult to satisfy the Cortina consensus criteria in most symptomatic patients with SRT alone. Further investigations of optimal treatments are warranted.

Damage to the left ventral, arcuate fasciculus and superior longitudinal fasciculus-related pathways induces deficits in object naming, phonological language function and writing, respectively.

The anatomic localization of brain functions can be characterized via diffusion tensor imaging in patients with brain tumors and neurological symptoms. The goal of the present study was to evaluate the function of the ventral, arcuate fasciculus (AF) and the superior longitudinal fasciculus (SLF)-related language pathways using these techniques by analyzing 9 patients treated in our hospital between 2007 and 2011. In cases 1-3, the left ventral pathways, namely, the inferior longitudinal fasciculus, uncinate fasciculus or inferior fronto-occipital fasciculus, were mainly damaged, and the common dysfunction experienced by these patients was a deficit in object naming. In cases 4-6, the left SLF was mainly damaged, and the common deficit was dysgraphia. In cases 7-9, the left AF was mainly damaged, and almost all language functions related to phonology were abnormal. These results suggest that the left ventral, AF and SLF-related pathways are closely related to visual, auditory and hand-related language function, respectively.

[Multidisciplinary approach to management of patients with brain metastases].

The incidence of brain metastases has increased over time as a consequence of an increase in the overall survival of patients with various types of cancer and the improved detection by magnetic resonance imaging (MRI). In this study, the guidelines and evidence for the radiotherapeutic, surgical, and chemotherapeutic management of patients newly diagnosed with brain metastases have been reviewed. For patients with good prognosis (expected survival, ≥ 3 months) and single brain metastases (> 3-4 cm) in whom safe complete resection is possible, whole brain radiotherapy (WBRT) and surgery (level 1) should be considered. Another alternative is surgery and radiation boost to the resection cavity (level 3). For single brain metastases (< 3-4 cm) that are not resectable, WBRT and radiosurgery, or radiosurgery alone should be considered (level 1). For selected patients with a limited number of multiple brain metastases (all < 3-4 cm) and good prognosis (expected survival, ≥ 3 months), radiosurgery alone, WBRT and radiosurgery, or WBRT alone should be considered (level 1). However, data from recent clinical trials have shown that adjuvant WBRT after radiosurgery or surgery for a limited number of brain metastases reduces intracranial relapses and neurologic deaths but fails to improve the duration of functional independence and overall survival. Many clinical studies have reported the effectiveness of molecular targeted therapies for brain metastases. Gefitinib or erlotinib should be considered for the treatment of asymptomatic patients harboring activating epidermal growth factor receptor (EGFR) mutations. Lapatinib should also be considered for the treatment of patients with brain metastases from human epidermal growth factor receptor (HER)-2-overexpressing metastatic breast cancer. In Japan, the intravenous administration of bevacizumab is currently being used for the treatment of symptomatic radiation necrosis of the brain.

Double pituitary neuroendocrine tumors in a patient with normal growth hormone level acromegaly: A case report and review of the literature.

Background: Acromegaly is a rare disease caused by growth hormone (GH) hypersecretion caused by a pituitary neuroendocrine tumor (PitNET). However, some acromegaly patients show normal GH levels, and they can be a pitfall in clinical diagnosis. Moreover, rarely, synchronous true double or multiple PitNETs are encountered. Moreover, these PitNETs increase the risk of a left lesion during surgical exploration. Case Description: The patient, who was a 73-year-old female, was referred to our hospital with a chief complaint of headache. Assessment of basal anterior pituitary function revealed a slightly high level of insulin-like growth factor-1 (IGF-1) (standard deviation, 2.4), and her physical findings exhibited mild acromegalic features. The endocrine evaluation confirmed acromegaly and magnetic resonance imaging (MRI) showed a macro PitNET with suprasellar extension. Endoscopic endonasal surgery (EES) was performed to remove the macro PitNET. Although postoperative MRI showed complete removal of the macro PitNET, endocrinological testing indicated no improvement in GH or IGF-1 excess. Pathological examination of the surgical specimen revealed a gonadotropic PitNET. Therefore, we repeated the MRI scan and found a micro PitNET in the thin left normal pituitary gland. A second EES was successfully performed to remove the micro PitNET completely, and both endocrinological and pathological examinations confirmed that the disease was cured. Conclusion: Diagnosing acromegaly with low GH levels requires close monitoring. Double PitNETs are relatively rare and can cause incomplete remission of functional PitNETs.

A multicenter, randomized, placebo-controlled phase IIb trial of an autologous formalin-fixed tumor vaccine for newly diagnosed glioblastomas.

OBJECTIVE: An autologous formalin-fixed tumor vaccine (AFTV) derived from resected glioblastoma (GBM) tissue can be used against unidentified tumor antigens. Thus, the authors conducted a multicenter double-blind phase IIb trial to investigate the efficacy of an AFTV. METHODS: Eligible patients were adults with supratentorial GBMs, 16-75 years of age, with Karnofsky Performance Scale (KPS) scores ≥ 60%, and no long-term steroid administration. An AFTV comprising fixed paraffin-embedded tumor tissue with immune adjuvants or an identical placebo without fixed tumor tissue was injected intradermally over three courses before and after chemoradiotherapy. The primary and secondary end points were overall survival (OS), progression-free survival (PFS), and 3-year survival rate. RESULTS: Sixty-three patients were enrolled. The average patient age was 61 years. The median KPS score was 80%, and the median resection rate was 95%. The full analysis set of 57 patients indicated no significant difference in OS (p = 0.64) for the AFTV group (median OS 25.6 months, 3-year OS rate 38%) compared with the placebo group (31.5 months and 41%, respectively) and no difference in PFS (median PFS 13.3 months in both groups, p = 0.98). For patients with imaging-based total tumor removal, the 3-year PFS rate was 81% in the AFTV group versus 46% in the placebo group (p = 0.067), whereas the 3-year OS rate was 80% versus 54% (p = 0.16), respectively. Similar results were obtained in the p53-negative subgroups. Severe adverse effects were not observed. CONCLUSIONS: The AFTV may have potential effects in certain patient subgroups. A phase III study for patients with total tumor removal remains warranted to confirm these findings. Clinical trial registration no.: UMIN000010602 (UMIN Clinical Trials Registry).

Significance of IDH mutations varies with tumor histology, grade, and genetics in Japanese glioma patients.

Mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 are found frequently in malignant gliomas and are likely involved in early gliomagenesis. To understand the prevalence of these mutations and their relationship to other genetic alterations and impact on prognosis for Japanese glioma patients, we analyzed 250 glioma cases. Mutations of IDH1 and IDH2 were found in 73 (29%) and 2 (1%) cases, respectively. All detected mutations were heterozygous, and most mutations were an Arg132His (G395A) substitution. IDH mutations were frequent in oligodendroglial tumors (37/52, 71%) and diffuse astrocytomas (17/29, 59%), and were less frequent in anaplastic astrocytomas (8/29, 28%) and glioblastomas (13/125, 10%). The pilocytic astrocytomas and gangliogliomas did not have either mutation. Notably, 28 of 30 oligodendroglial tumors harboring the 1p/19q co-deletion also had an IDH mutation, and these alterations were significantly correlated (P < 0.001). The association between TP53 and IDH mutation was significant in diffuse astrocytomas (P = 0.0018). MGMT promoter methylation was significantly associated with IDH mutation in grade 2 (P < 0.001) and grade 3 (P = 0.02) gliomas. IDH mutation and 1p/19q co-deletion were independent favorable prognostic factors for patients with grade 3 gliomas. For patients with grade 3 gliomas and without 1p/19q co-deletion, IDH mutation was strongly associated with increased progression-free survival (P < 0.0001) and overall survival (P < 0.0001), but no such marked correlation was observed with grade 2 gliomas or glioblastomas. Therefore, IDH mutation would be most useful when assessing prognosis of patients with grade 3 glioma with intact 1p/19q; anaplastic astrocytomas account for most of these grade 3 gliomas.

Advantages and disadvantages of awake surgery for brain tumours in the primary motor cortex: institutional experience and review of literature.

Patients undergoing awake surgery for resection of brain tumours in the primary motor cortex (M1) are at high risk of developing new motor deficits. Thus, use of this procedure requires consideration of several important points, including the optimal modality to localise M1 on the affected side and the overall advantages and disadvantages of the procedure. In our experience with awake surgery for 21 brain tumours located in the M1 from January 2004 through October 2008, we found that functional magnetic resonance imaging was the most reliable modality in terms of localising the M1 and that the anatomic relationship between motor tracts and brain tumours is a critical determinant of postoperative motor function. Other considerations, including potential complications of this procedure and relative efficacy and safety versus surgery under general anaesthesia for patients with brain tumours in the M1, are discussed.

Emergent Carotid Artery Stenting Following Intravenous Alteplase Infusion After Rapid Negative Diagnosis for COVID-19 by Loop-Mediated Isothermal Amplification Assay.

BACKGROUND: During the coronavirus disease 2019 (COVID-19) pandemic, a rapid screening method for COVID-19 detection is needed to decide the appropriate strategy to treat stroke patients. In acute ischemic stroke treatment, the efficacy and safety of emergent carotid artery stenting (eCAS) for hyperacute ischemic stroke (hAIS) due to internal carotid artery stenosis (ICS) have not been sufficiently established. CASE DESCRIPTION: A 71-year-old man with hAIS caused by severe ICS was treated via intravenous alteplase infusion. The patient underwent screening for COVID-19 by the loop-mediated isothermal amplification (LAMP) assay shortly after arrival at our institution. The LAMP result was obtained within 90 minutes, during intravenous alteplase infusion, and turned out to be negative. The symptom of hemiplegia worsened during alteplase infusion, and he, therefore, underwent eCAS after administration of aspirin (200 mg). Recanalization was achieved successfully by eCAS, and dual antiplatelet therapy and argatroban were administrated following eCAS. Hemorrhagic complications or restenosis/occlusion of the carotid artery were not observed. He was discharged without neurologic deficits 15 days following eCAS. Because of the rapid negative diagnosis for COVID-19 using the LAMP method, eCAS could be performed following standard procedures, along with infectious defense, without delay. CONCLUSIONS: This case report suggests that eCAS for hAIS due to ICS following intravenous alteplase can be an effective treatment, along with appropriate antiplatelet medication and management in select patients. During the COVID-19 pandemic, the LAMP assay for COVID-19 detection might be a suitable diagnostic strategy preceding stroke treatment because of the rapid turnaround time.

Combined movement of multi-joint muscles activates a smaller area compared to the sum of areas activated by respective single-joint muscles after restoration of paresis.

Awake surgery provides accurate localization of brain function based on rapid reversible neurological changes during surgical manipulation. In this study, hand clenching rapidly deteriorated due to surgical manipulation during awake surgery and instantly recovered not by hand clenching alone but by combined movement of hand clenching and elbow flexion. Postoperative fMRI (functional MRI) showed a smaller area activated by combined movement of hand clenching and elbow flexion than the sum of areas activated by hand clenching alone and elbow flexion alone. Conversely, the activated area by combined movement of hand clenching and elbow flexion was almost the same as the sum of areas by hand clenching alone and elbow flexion alone in fMRI of normal volunteers. These findings indicate reorganization of the motor area by combined movement including the motor function of previous transient weakness, and might suggest the effectiveness of combined movement to improve motor paresis in rehabilitation.

Damage of left temporal lobe resulting in conversion of speech to Sutra, a Buddhist prayer stored in the right hemisphere.

The present study describes a case of a right-handed 74-year-old woman with a brain tumor who showed conversion of speech to Sutra, a Buddhist prayer, which was stored in the right hemisphere according to the Wada test. After surgery, relative improvement in the speech disorder was observed, and frequency of speech production of simple normal words with normal phonology increased. These observations indicate that damage to left temporal lobe resulted in conversion of speech to Sutra, and that Sutra was stored in this patient's right hemisphere.

Deficits in the left inferior longitudinal fasciculus results in impairments in object naming.

The functional characteristics of the left inferior longitudinal fasciculus (ILF) remain unclear. The present study describes a case of a right-handed 74-year-old woman with a brain tumor who showed marked deterioration in object naming ability after invasion of the tumor into the medial region of the left posterior (middle and inferior) temporal lobe just beside the atrium of the lateral ventricle. Diffusion tensor imaging showed possible interruption of the left ILF after invasion of tumor at this site. By contrast, the left superior longitudinal fasciculus (SLF) remained intact after invasion of tumor, and the inferior fronto-occipital fasciculus (IFOF) was already disrupted prior to tumor invasion. These observations indicate that intact ILF function may be required for object naming ability.

Damage to the upper portion of area 19 and the deep white matter in the left inferior parietal lobe, including the superior longitudinal fasciculus, results in alexia with agraphia.

Analysis of lesions and symptoms in patients with brain tumors combined with information from diffusion tensor imaging provides direct evidence of the anatomical localization of brain function. Using these methods, we evaluated 8 patients who underwent surgery for metastatic brain tumors located in the left occipital lobes between 2007 and 2009. Preoperatively, 4 patients (cases 1-4) had alexia with agraphia while the other 4 patients (cases 5-8) did not. Tractography for the superior longitudinal fasciculus (SLF) was performed before surgery in case 1. The common brain tumors in cases 1-4 were located in the upper portion of area 19, and peritumor edema in that area resulted in compromise of the deep white matter of the inferior parietal lobe (IPL). The SLF was compressed and disrupted in the white matter of the IPL near the upper portion of area 19 in case 1. In cases 5-8, the brain tumors were not located in the upper portion of area 19. These results suggest that damage to the upper portion of area 19 and to the white matter in the left IPL, including the SLF, resulted in alexia with agraphia.

Relationships between brain tumor and optic tract or calcarine fissure are involved in visual field deficits after surgery for brain tumor.

PURPOSE: Diffusion tensor tractography provides useful information regarding the surgical strategy for brain tumors. The goal of the present study was to analyze relationships between visual field deficits and the locations of brain tumors compared with optic tracts as visualized by tractography, and compared with the calcarine fissure. METHODS: Subjects comprised 11 patients with brain tumor in the occipital lobe or atrium of the lateral ventricle who underwent surgery between October 2006 and February 2009. Tumors were categorized as Type A, with almost all the optic tract in the occipital lobe or atrium of the lateral ventricle running close to and stretched by the brain tumor; and Type B, with the optic tract running at least partially distant to the brain tumor and remaining unstretched. RESULTS: Those type A optic tracts that were laterally compressed by brain tumors (Cases 1-3) displayed hemianopsia after surgery. When the brain tumor was located rostro-medial to the calcarine fissure and optic tracts were compressed caudally by the tumor, lower quadrant hemianopsia remained after surgery (Cases 4, 5). In other cases, the visual field remained or improved to normal after surgery. CONCLUSION: The relationship between optic tracts or the calcarine fissure, and brain tumors in the occipital lobe or atrium of the lateral ventricle is related to visual field deficits after surgery. In particular, those Type A optic tracts that are compressed laterally show hemianopsia of the visual field after surgery.

Awake surgery with continuous motor testing for resection of brain tumors in the primary motor area.

Resection of brain tumors in the primary motor area (M1) is difficult to achieve without adversely affecting motor function. Between November 2003 and November 2006, 16 patients with 18 brain tumors involving the M1 (11 metastatic, 6 gliomas, 1 cavernous angioma) underwent craniotomy and awake surgery with continuous motor testing at our hospital. Patients were classified as either type A (9 patients), indicating that motor tracts ran in close proximity to the brain tumors, or type B (7 patients), indicating that motor tracts ran distant to the tumor. The relationship between the extent of resection and post-operative motor function was subsequently evaluated. In 17 out of 18 cases, final post-operative motor function was either preserved or improved relative to pre-operative levels, although transient deterioration of motor function and partial removal of the tumor were observed in 7 and 8 cases, respectively. The remaining patients experienced slight deterioration in motor function of the upper extremities. All type A patients experienced suboptimal outcomes, involving transient or permanent deterioration of motor function after surgery or only partial removal of the tumor. By contrast, most type B patients experienced good outcomes (no deterioration of motor function and gross total removal of the tumor). In conclusion, awake surgery with continuous motor testing allowed for resection of brain tumors in the M1 and preservation of motor function, although the patients in whom motor tracts ran in close proximity to the tumors experienced suboptimal outcomes.

Mirror therapy activates outside of cerebellum and ipsilateral M1.

Mirror therapy is effective in the rehabilitation of patients with hemiparesis, but its mechanism is not clear. In this study, a patient with brain tumor (patient 1) who underwent mirror therapy after surgery and showed drastic recovery of hand paresis, a patient with visual memory disturbance (patient 2), and five normal volunteers performed tasks related to mirror therapy in fMRI study. In patient 1 and all normal volunteers, right and left hand clenching with looking at a mirror (eye open) activated outside of cerebellum, while right and left hands clenching with eye closed activated inside of cerebellum. In patient 2, mirror therapy did not activate outside of cerebellum. In patient 1, and 3 out of 5 normal volunteers, the area of right (affected) M1 activated by right and left hands clenching with eye open was more than that by right and left hands clenching with eye closed, and that right M1 was activated by right hand clenching with eye open. In conclusion, mirror therapy facilitate the paresis of patients by activating ipsilateral M1 and outside of cerebellum, which is possibly related to visual memory function.

[Temozolomide: Temodal].

The oral alkylating agent, temozolomide (Temodal: TMZ), is the only anticancer drug that has been shown in a phase III study to improve survival in glioblastoma (GBM) when administered with concomitant radiotherapy. Pharmacokinetic studies have documented relatively high concentrations of TMZ in brain tumors and cerebrospinal fluid (20-40% of the area under the plasma concentration curve), and other studies have demonstrated that TMZ is effective for treatment of various brain tumors, including recurrent and newly diagnosed glioma, primary CNS lymphoma, metastatic melanoma, and neuroblastoma. Molecular markers that predict a favorable response to TMZ plus concomitant radiotherapy include methylguanine methyltransferase (MGMT) promoter methylation patients with GBM and chromosome 1p/19q deletion in patients with anaplastic oligodendroglioma or low-grade glioma. Myelosuppression, nausea and constipation are relatively frequent in patients undergoing treatment with TMZ, and prophylaxis against Pneumocystis carinii pneumonia should be instituted. This article will summarize and discuss these issues as well as review ongoing and anticipated studies of TMZ in combination with other anti-cancer therapies.