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).

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.

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.

A prospective, multicentre, single-arm clinical trial of bevacizumab for patients with surgically untreatable, symptomatic brain radiation necrosis†.

BACKGROUND: Brain radiation necrosis (BRN) can be a complication of radiotherapy for primary and secondary brain tumors, as well as head and neck tumors. Since vascular endothelial growth factor (VEGF) is also a vascular permeability factor in the brain, bevacizumab, a humanized antibody that inhibits VEGF, would be expected to reduce perilesional edema that often accompanies BRN. METHODS: Patients with surgically untreatable, symptomatic BRN refractory to conventional medical treatments (eg, corticosteroid, anticoagulants, or hyperbaric oxygen therapy) were enrolled. We judged that a major cause of perilesional edema with a lesion-to-normal brain ratio ≤1.8 on 11C-methionine or ≤2.5 on 18F-boronophenylalanine PET was BRN, not tumor recurrence, and 6 cycles of biweekly bevacizumab (5 mg/kg) were administered. The primary endpoint was a ≥30% reduction from the patients' registration for perilesional edema continuing for ≥1 month. RESULTS: Of the 41 patients enrolled, 38 were fully eligible for the response assessment. The primary endpoint was achieved in 30 of the 38 (78.9%) patients at 3.0 months (median) after enrollment. Sixteen patients (42.1%) experienced improvement of their Karnofsy Performance Score. Corticosteroid use could be reduced in 29 patients (76.3%). Adverse events at grade ≥3 occurred in 10 patients (24.4%). CONCLUSIONS: Bevacizumab treatment offers certain clinical benefits for patients with surgically untreatable, symptomatic BRN. The determination of BRN using amino-acid PET, not biopsy, is adequate and less invasive for determining eligibility to receive bevacizumab.

Histopathological investigation of glioblastomas resected under bevacizumab treatment.

To date, no clinical observations have been reported for histopathological changes in human gliomas under antiangiogenic treatment.We collected six glioblastomas resected under bevacizumab treatment. Histopathological investigation was performed by hematoxilyn-eosin staining and immunohistochemistry for CD34, VEGF, VEGFR1/2, HIF-1α, CA9, and nestin as compared to eleven control glioblastomas to assess the differences in histological features, microvessel density, expression of VEGF and its receptors, tumor oxygenation, and status of glioma stem-like cells.In the six tumors resected under bevacizumab, microvascular proliferation was absent, and microvessel density had significantly decreased compared with that of the controls. The expressions of VEGF and its receptors were downregulated in two cases of partial response. HIF-1α or CA9 expression was decreased in five of the six tumors, whereas the decreased expression of these markers was noted in only one of the 11 control glioblastomas. The expression of nestin significantly decreased in the six tumors compared with that of the controls, with the remaining nestin-positive cells being relatively concentrated around vessels.We provide the first clinicopathological evidence that antiangiogenic therapy induces the apparent normalization of vascular structure, decrease of microvessel density, and improvement of tumor oxygenation in glioblastomas. These in situ observations will help to optimize therapy.

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.

Toxicity and outcome of radiotherapy with concomitant and adjuvant temozolomide in elderly patients with glioblastoma: a retrospective study.

Radiation therapy with concomitant and adjuvant temozolomide (TMZ) is the standard therapy for nonelderly patients with glioblastoma. However, TMZ-based chemoradiotherapy for elderly patients with glioblastoma is controversial. The aim of this study was to investigate the benefits and adverse effects of this combined therapy in elderly patients with glioblastoma. Of the 76 newly diagnosed glioblastoma patients who were treated with standard radiotherapy (60 Gy/30 fractions) and TMZ, treatment toxicity and therapeutic outcome were evaluated in 27 elderly patients (age 65 years or older) and compared with those of 49 nonelderly counterparts (age younger than 65 years). The incidence of common toxicity criteria Grade 4 adverse events during the concomitant course was higher in the elderly group than that in the nonelderly group (26% versus 8%; p = 0.046). Cognitive dysfunction was observed only in the elderly group (p = 0.042). The median overall survival (OS) and median progression-free survival in the elderly group were 15.2 months (95% confidence interval [CI]; 12.9-18.5) and 8.4 months (95% CI; 5.1-11.7), respectively. OS was significantly shorter in the elderly group than in the nonelderly group (p = 0.021). The recursive partitioning analysis score was a prognostic factor for OS. TMZ-based chemoradiotherapy was associated with an increased risk of Grade 4 adverse events in the elderly patients during concomitant use. Thus, elderly patients who undergo a concomitant course of TMZ must be closely monitored for adverse events. Treatment of glioblastoma in elderly patients must be optimized to reduce toxicity to acceptable levels and to maintain efficacy.

[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.

The right dorsal anterior cingulate cortex may play a role in anxiety disorder and visual function.

Recent investigation suggests that the dorsal anterior cingulate cortex (ACC) is involved in the interplay between cognition and emotion. The present study described three patients who underwent removal of brain tumors just above the right dorsal ACC. These patients had residual tumor following surgery and showed anxiety disorder (AD) both before and after surgery. Visual memory or attention was abnormal before surgery in these patients, but these deficits improved following surgery, possibly due to a decrease in compression of the right dorsal ACC. These results suggest that damage to the right dorsal ACC is involved in AD and well as in deficits in visual memory or attention. Therefore, the right dorsal ACC might play a role in vision-related cognition and emotion, such as anxiety.

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.

The left superior longitudinal fasciculus within the primary sensory area of inferior parietal lobe plays a role in dysgraphia of kana omission within sentences.

Functional neurological changes after surgery combined with diffusion tensor imaging (DTI) tractography can directly provide evidence of anatomical localization of brain function. Using these techniques, a patient with dysgraphia before surgery was analyzed at our hospital in 2011. The patient showed omission of kana within sentences before surgery, which improved after surgery. The brain tumor was relatively small and was located within the primary sensory area (S1) of the inferior parietal lobe (IPL). DTI tractography before surgery revealed compression of the branch of the superior longitudinal fasciculus (SLF) by the brain tumor. These results suggest that the left SLF within the S1 of IPL plays a role in the development of dysgraphia of kana omission within sentences.

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.

Right temporal lobe plays a role in verbal memory.

OBJECTIVES: Comparison of preoperative and postoperative neurological functions in patients undergoing resection of brain tumors, in combination with data from diffusion tensor imaging (DTI) studies, can provide direct evidence of anatomical localization of brain function. The goal of the present study was to use these techniques to characterize memory function of the right temporal lobe in five patients with right temporal lobe brain tumors. METHODS: Memory function was tested using the Wechsler Memory Scale-Revised (WMS-R) before and after surgery in five patients with right temporal lobe brain tumors. Preoperative DTI was performed in four of five cases. RESULTS: In all cases, general and verbal memory, including verbal paired association, significantly improved after surgery (P<0.05). The right inferior longitudinal fasciculus (ILF) was compressed by the tumor in all cases. CONCLUSION: These results suggest that the right temporal lobe plays a role in verbal memory and that this function may be associated with the right ILF.

Damage to the right dorsal anterior cingulate cortex induces panic disorder.

Brain imaging studies suggest that panic disorder (PD) is mediated by several brain regions, including the anterior cingulate cortex (ACC). In the present report we describe a patient who experienced a panic attack during awake surgery (case 1) and another patient who developed PD after surgery and radiotherapy (case 2). In case 1, the patient experienced repeated panic attacks when the tumor at the upper border of right dorsal ACC was removed during awake surgery. In case 2, the patient developed PD at six months after surgery and Cyberknife radiotherapy. MRI examination revealed that the dorsal ACC size was reduced at six months after surgery and that the dorsal ACC was absent at two years after surgery, possibly due to radiotherapy-induced damage by radiotherapy. Profile of mood states (POMS) testing characterized the presence of tension-anxiety as the common abnormal symptom in cases 1 and 2. In conclusion, these results suggest that damage to the right dorsal ACC can induce PD and that this structure likely plays a pathophysiologic role in PD.

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.

Left or right temporal lesion might induce aggression or escape during awake surgery, respectively: role of the amygdala.

OBJECTIVE: Some patients with temporal lobe brain tumours show aggressive or escape behaviour during awake surgery. As the amygdala plays a critical role in coping with stress, we evaluated whether the left or right amygdala was involved in aggressive or escape behaviour in six patients undergoing awake surgery for temporal lobe brain tumours. METHODS: Brain tumours were located in the left temporal lobe in cases 1-3 and in the right temporal lobe in cases 4-6. In cases 1, 2, 4 and 5, the tumours invaded the amygdala. RESULTS: In case 1, the patient showed aggressive behaviour before partial removal of the left amygdala during awake surgery; just after partial removal of left amygdala, the patient was calm and cooperative. In case 2, the patient showed aggressive behaviour when the tumour near the left amygdala was removed. In case 3, the patient showed aggressive behaviour when awakening during awake surgery. In case 4, the patient showed escape behaviour when removal of the tumour near the right amygdala was initiated. In cases 5 and 6, patients showed escape behaviour upon awakening and upon initiation of tumour removal from the temporal lobe. CONCLUSION: In conclusion, these results suggest that left or right temporal lesions might induce aggressive or escape behaviour during awake surgery, respectively, and that the amygdala on the respective side may play a role in these behaviours.

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.