Search

We aimed to retrospectively determine the resection rate of fluid-attenuated inversion recovery (FLAIR) lesions to evaluate the clinical effects of supramaximal resection (SMR) on the survival of patients with glioblastoma (GBM). Thirty-three adults with newly diagnosed GBM who underwent gross total tumor resection were enrolled. The tumors were classified into cortical and deep-seated groups according to their contact with the cortical gray matter. Pre- and postoperative FLAIR and gadolinium-enhanced T1-weighted imaging tumor volumes were measured using a three-dimensional imaging volume analyzer, and the resection rate was calculated. To evaluate the association between SMR rate and outcome, we subdivided patients whose tumors were totally resected into the SMR and non-SMR groups by moving the threshold value of SMR in 10% increments from 0% and compared their overall survival (OS) change. An improvement in OS was observed when the threshold value of SMR was 30% or more. In the cortical group (n = 23), SMR (n = 8) tended to prolong OS compared with gross total resection (GTR) (n = 15), with the median OS of 69.6 and 22.1 months, respectively (p = 0.0945). Contrastingly, in the deep-seated group (n = 10), SMR (n = 4) significantly shortened OS compared with GTR (n = 6), with median OS of 10.2 and 27.9 months, respectively (p = 0.0221). SMR could help prolong OS in patients with cortical GBM when 30% or more volume reduction is achieved in FLAIR lesions, although the impact of SMR for deep-seated GBM must be validated in larger cohorts.

Abstract Glioblastoma, a malignant tumor, has no curative treatment. Recently, mitochondria have been considered a potential target for treating glioblastoma. Previously, we reported that agents initiating mitochondrial dysfunction were effective under glucose-starved conditions. Therefore, this study aimed to develop a mitochondria-targeted treatment to achieve normal glucose conditions. This study used U87MG (U87), U373, and patient-derived stem-like cells as well as chloramphenicol (CAP) and 2-deoxy-d-glucose (2-DG). We investigated whether CAP and 2-DG inhibited the growth of cells under normal and high glucose concentrations. In U87 cells, 2-DG and long-term CAP administration were more effective under normal glucose than high-glucose conditions. In addition, combined CAP and 2-DG treatment was significantly effective under normal glucose concentration in both normal oxygen and hypoxic conditions; this was validated in U373 and patient-derived stem-like cells. 2-DG and CAP acted by influencing iron dynamics; however, deferoxamine inhibited the efficacy of these agents. Thus, ferroptosis could be the underlying mechanism through which 2-DG and CAP act. In conclusion, combined treatment of CAP and 2-DG drastically inhibits cell growth of glioblastoma cell lines even under normal glucose conditions; therefore, this treatment could be effective for glioblastoma patients.

Abstract This study aimed to determine whether quantitative relaxometry using synthetic magnetic resonance imaging (SyMRI) could differentiate between two diffuse glioma groups with isocitrate dehydrogenase (IDH)-mutant tumors, achieving an increased sensitivity compared to the qualitative T2-fluid-attenuated inversion recovery (FLAIR) mismatch sign. Between May 2019 and May 2020, thirteen patients with IDH-mutant diffuse gliomas, including seven with astrocytomas and six with oligodendrogliomas, were evaluated. Five neuroradiologists independently evaluated the presence of the qualitative T2-FLAIR mismatch sign. Interrater agreement on the presence of the T2-FLAIR mismatch sign was calculated using the Fleiss kappa coefficient. SyMRI parameters (T1 and T2 relaxation times and proton density) were measured in the gliomas and compared by the Mann–Whitney U test. Receiver operating characteristic curve analysis was used to evaluate the diagnostic performance. The sensitivity, specificity, and kappa coefficient were 57.1%, 100%, and 0.60, respectively, for the qualitative T2-FLAIR mismatch sign. The two types of diffuse gliomas could be differentiated using a cutoff value of 178 ms for the T2 relaxation time parameter with 100% sensitivity, specificity, accuracy, and positive and negative predictive values, with an area under the curve (AUC) of 1.00. Quantitative relaxometry using SyMRI could differentiate astrocytomas from oligodendrogliomas, achieving an increased sensitivity and objectivity compared to the qualitative T2-FLAIR mismatch sign.

Abstract Objective Accumulating evidence from recent molecular diagnostic studies has indicated the prognostic significance of various genetic markers for patients with glioblastoma (GBM). To evaluate the impact of such genetic markers on prognosis, we retrospectively analyzed the outcomes of patients with IDH‐wildtype GBM in our institution. In addition, to assess the impact of bevacizumab (BEV) treatment, we compared overall survival (OS) between the pre‐ and post‐BEV eras. Methods We analyzed the data of 100 adult patients (over 18 years old) with IDH‐wildtype GBM from our database between February 2006 and October 2018. Genetic markers, such as MGMT methylation status, EGFR amplification, CDKN2A homozygous deletion, and clinical factors were analyzed by evaluating the patients’ OS. Results CDKN2A homozygous deletion showed no significant impact on OS in patients with methylated MGMT status (p = 0.5268), whereas among patients with unmethylated MGMT status, there was a significant difference in OS between patients with and without CDKN2A homozygous deletion (median OS: 14.7 and 16.9 months, respectively, p = 0.0129). This difference was more evident in the pre‐BEV era (median OS: 10.1 and 15.6 months, respectively, p = 0.0351) but has become nonsignificant in the post‐BEV era (median OS: 16.0 and 16.9 months, respectively, p = 0.1010) due to OS improvement in patients with CDKN2A homozygous deletion. However, these findings could not be validated in The Cancer Genome Atlas cohort. Conclusions MGMT and CDKN2A status subdivided our cohort into three race‐specific groups with different prognoses. Our findings indicate that BEV approval in Japan led to OS improvement exclusively for patients with concurrent unmethylated MGMT status and CDKN2A homozygous deletion.

Background: Advances in neurosurgical techniques and neuroimaging resolution questions the modern-day reliability of the Simpson grade for predicting meningioma recurrence. Therefore, we evaluated the reliability of predictors for recurrence and outcomes in detail in patients with non-skull base meningiomas (NSBMs). Methods: We retrospectively analyzed data from consecutive 175 NSBMs underwent surgical resection. We performed Kaplan–Meier analyses of recurrence-free survival (RFS) according to Simpson and World Health Organization (WHO) grades. Predictors of RFS and clinical deterioration were estimated by univariate and multivariate analyses. Correlation between the Simpson grade and change in Karnofsky Performance Scale scores was assessed by Fisher's exact test. Results: Log-rank tests revealed significant correlations of both the Simpson and WHO grades with RFS for the overall cohort, convexity, and falx/tentorium meningioma. Unlike patients undergoing Simpson grade I and II resections, RFS in patients with WHO grade I and II/III tumors differed significantly from the early postoperative stage. Multivariate analysis identified tumor size, Simpson grade, and MIB-1 labeling index as significant predictors of RFS. Clinical deterioration was more frequent among patients undergoing less aggressive resection. Tumor location was the only significant predictor of clinical deterioration. Conclusions: Our findings indicate that tumor size, Simpson and WHO grades, and MIB-1 labeling index are significant predictors of NSBM recurrence. Moreover, the risk of recurrence markedly decreases within the follow-up duration of 80 months. Aggressive resection appears to minimize the risk of recurrence without evidence of clinical deterioration. Follow-up schedules should be based on the WHO grade and extent of resection. Keywords: Meningioma, Non-skull base, Outcome, Recurrence, Simpson grade, WHO grade

The preoperative imaging-based differentiation of primary central nervous system lymphomas (PCNSLs) and glioblastomas (GBs) is of high importance since the therapeutic strategies differ substantially between these tumors. In this study, we investigate whether the gamma distribution (GD) model is useful in this differentiation of PNCSLs and GBs. Twenty-seven patients with PCNSLs and 57 patients with GBs were imaged with diffusion-weighted imaging using 13 b-values ranging from 0 to 1000 sec/mm2. The shape parameter (κ) and scale parameter (θ) were obtained with the GD model. Fractions of three different areas under the probability density function curve (f1, f2, f3) were defined as follows: f1, diffusion coefficient (D) 1.0×10-3 and 3.0 × 10-3 mm2/sec. The GD model-derived parameters were compared between PCNSLs and GBs. Receiver operating characteristic (ROC) curve analyses were performed to assess diagnostic performance. The correlations with intravoxel incoherent motion (IVIM)-derived parameters were evaluated. The PCNSL group's κ (2.26 ± 1.00) was significantly smaller than the GB group's (3.62 ± 2.01, p = 0.0004). The PCNSL group's f1 (0.542 ± 0.107) was significantly larger than the GB group's (0.348 ± 0.132, p

Abstract Background Although surgical resection is the only curative treatment for gallbladder cancer (GBC), concomitant peritoneal dissemination is considered far beyond the scope of resection. We report a long-term survivor with a residual GBC with multiple peritoneal disseminations who underwent an extended resection after effective chemotherapy. Case presentation A 59-year-old male underwent an open cholecystectomy for Mirizzi syndrome at a local hospital. Because of severe inflammation, the gallbladder was perforated during surgery, ending in a piecemeal resection. A pathological examination revealed GBC with positive margins, and the patient was referred to our hospital 1 month after surgery for further treatment. A multidetector-row computed tomography (MDCT) showed three hypoattenuated tumours: a tumour (3.9 cm) at the left medial segment corresponding to the gallbladder bed, a tumour (1.8 cm) around the hepatic flexure of the transverse colon, and a tumour (1.0 cm) at the stump of the cystic duct. Percutaneous needle biopsy was performed, which provided histologic evidence of adenocarcinoma. Thus, the patient had a rapidly progressive local relapse with limited peritoneal dissemination, labelled ycT3N0M1, stage IVB disease according to the UICC system. After the administration of 3 cycles of gemcitabine plus cisplatin combination chemotherapy, the size of all tumours and the CA19-9 level decreased significantly. Since the patient’s general condition and liver function reserve were satisfactory, we decided the initial unresectable scenario to perform surgical therapy. After portal vein embolization, right hepatectomy, resection of the extrahepatic bile duct, partial duodenectomy, and partial colectomy were performed. Operative time was 555 min, and intraoperative blood loss was 1654 mL. Pathologic diagnosis of residual gallbladder carcinoma with peritoneal dissemination was confirmed, and the surgical margins were tumour-free. The patient was discharged on postoperative day 29, with a Clavien-Dindo IIIa complication (abdominal wall abscess). Postoperative adjuvant chemotherapy with tegafur/gimeracil/oteracil was administered during 1 year after surgery. The patient is doing well 6 years after the second surgery without evidence of disease. Conclusions Although specific clinical factors were associated with a favourable outcome in this patient, the present report suggests that multidisciplinary therapy may be a promising option in selected patients with distant metastatic GBC.

Three-dimensional (3D) high-definition endoscopy is an innovative technical advancement that helps surgeons gain precise depth perception and spatial recognition during endoscopic surgery. Here, we describe a new dual optical channel 3D neuroendoscopic technique and its clinical application. We performed endoscopic endonasal surgery on 88 patients using 3D and two-dimensional (2D) endoscopes in conjunction. We evaluated the usefulness of stereoscopic images acquired by dual optical channel 3D endoscopy during endoscopic surgery and compared the image resolution between dual optical channel 3D endoscopy and 2D endoscopy. Additionally, we compared the stereoscopic images acquired by dual optical channel and Visionsense 3D endoscopy in three cases. Combination surgery using 3D and 2D endoscopy was found to be safe. Stereoscopic images were useful in several surgical steps, especially in recognition of complex bony structures, bone drilling, and suprasellar manipulation. The magnitude of binocular disparity was greater in dual optical channel 3D endoscopy than in Visionsense 3D endoscopy. Stereoscopic images acquired by dual optical channel 3D neuroendoscopy were of adequate quality and were useful for endoscopic endonasal surgery. In consideration of its lower image resolution compared to that of 2D high-definition endoscopy, dual optical channel 3D neuroendoscopy can be applied as an assistive technique in endoscopic endonasal surgery. The magnitude of binocular disparity is one of the key factors to be considered for evaluation of the clinical significance of 3D endoscopy.

Glioblastoma, the most common primary brain tumor in adults, has one of the most dismal prognoses in cancer. In 2009, bevacizumab was approved for recurrent glioblastoma in the USA. To evaluate the clinical impact of bevacizumab as a first-line drug for glioblastoma, two randomized clinical trials, AVAglio and RTOG 0825, were performed. Bevacizumab was found to improve progression-free survival (PFS) and was reported to be beneficial for maintaining patient performance status as an initial treatment. These outcomes led to bevacizumab approval in Japan in 2013 as an insurance-covered first-line drug for glioblastoma concurrently with its second-line application. However, prolongation of overall survival was not evinced in these clinical trials; hence, the clinical benefit of bevacizumab for newly diagnosed glioblastomas remains controversial. A recent meta-analysis of randomized controlled trials of bevacizumab combined with temozolomide in recurrent glioblastoma also showed an effect only on PFS, and the benefit of bevacizumab even for recurrent glioblastoma is controversial. Here, we discuss the clinical impact of bevacizumab for glioblastoma treatment by reviewing previous clinical trials and real-world evidence by focusing on Japanese experiences. Moreover, the efficacy and safety of bevacizumab are summarized, and we provide suggestions for updating the approaches and management of bevacizumab.

High resolution melting (HRM) is a simple and rapid method for screening mutations. It offers various advantages for clinical diagnostic applications. Conventional HRM analysis often yields equivocal results, especially for surgically obtained tissues. We attempted to improve HRM analyses for more effective applications to clinical diagnostics. HRM analyses were performed for IDH1R132 and IDH2R172 mutations in 192 clinical glioma samples in duplicate and these results were compared with sequencing results. BRAFV600E mutations were analyzed in 52 additional brain tumor samples. The melting profiles were used for differential calculus analyses. Negative second derivative plots revealed additional peaks derived from heteroduplexes in PCR products that contained mutations; this enabled unequivocal visual discrimination of the mutations. We further developed a numerical expression, the HRM-mutation index (MI), to quantify the heteroduplex-derived peak of the mutational curves. Using this expression, all IDH1 mutation statuses matched those ascertained by sequencing, with the exception of three samples. These discordant results were all derived from the misinterpretation of sequencing data. The effectiveness of our approach was further validated by analyses of IDH2R172 and BRAFV600E mutations. The present analytical method enabled an unequivocal and objective HRM analysis and is suitable for reliable mutation scanning in surgically obtained glioma tissues. This approach could facilitate molecular diagnostics in clinical environments.

Background: Glioependymal cysts (GECs) are rare, benign congenital intracranial cysts that account for 1% of all intracranial cysts. Surgical interventions are required for patients with symptomatic GECs. However, the optimal treatment remains controversial, especially in infants. Here, we report a male infant case of GECs that successfully underwent minimally invasive combined neuroendoscopic cyst wall fenestration and cyst-peritoneal (CP) shunt. Case Description: The boy was delivered transvaginally at 38 weeks and 6 days of gestation with no neurological deficits. Magnetic resonance imaging (MRI) at birth revealed multiple cysts with smooth and rounded borders and a non-enhancing wall in the right parieto-occipital region. The size of the cyst had increased rapidly compared to that of the prenatal MRI, which was performed at 37 weeks and 2 days. On the day of birth, Ommaya cerebrospinal fluid (CSF) reservoir was placed into the largest outer cyst. The patient underwent intermittent CSF drainage; however, he experienced occasional vomiting. At 2 months, he underwent combined neuroendoscopic cyst wall fenestration and CP shunt through a small hole. The patient's postoperative course was uneventful and there was no recurrence of the cyst. The pathological diagnosis was GEC. Conclusion: Combined neuroendoscopic cyst wall fenestration and CP shunt are a minimally invasive and effective treatment for infants with GECs. [ABSTRACT FROM AUTHOR]

Background: Temporal lobe epilepsy (TLE) associated with temporal lobe encephalocele is rare, and the precise epileptogenic mechanisms and surgical strategies for such cases are still unknown. Although the previous studies have reported good seizure outcomes following chronic subdural electrode recording through invasive craniotomy, only few studies have reported successful epilepsy surgery through endoscopic endonasal lesionectomy. Case Description: An 18-year-old man developed generalized convulsions at the age of 15 years. Despite treatment with optimal doses of antiepileptic drugs, episodes of speech and reading difficulties were observed 2-3 times per week. Long-term video electroencephalogram (EEG) revealed ictal activities starting from the left anterior temporal region. Magnetic resonance imaging revealed a temporal lobe encephalocele in the left lateral fossa of the sphenoidal sinus (sphenoidal encephalocele). Through the endoscopic endonasal approach, the tip of the encephalocele was exposed. A depth electrode was inserted into the encephalocele, which showed frequent spikes superimposed with high-frequency oscillations (HFOs) suggesting intrinsic epileptogenicity. The encephalocele was resected 8 mm from the tip. Twelve months postoperatively, the patient had no recurrence of seizures on tapering of the medication. Conclusion: TLE associated with sphenoidal encephalocele could be controlled with endoscopic endonasal lesionectomy, after confirming the high epileptogenicity with analysis of HFOs of intraoperative EEG recorded using an intralesional depth electrode. [ABSTRACT FROM AUTHOR]

Background: Brain metastasis from undifferentiated pleomorphic sarcoma (UPS) is a rare occurrence, and its clinical course is little known. In this report, we investigate a case of a rapidly growing brain metastasis from gastric UPS. Case Description: An 82-year-old man with a known gastric tumor, pathologically compatible with UPS, underwent partial gastrectomy at an outside facility. 3 months later, a 4-cm brain tumor was detected, which was completely resected. The patient was diagnosed with metastatic tumor from previously treated gastric UPS. Within 2 months of the initial resection, a large recurrent mass was detected in the same location, which was again removed. Although the patient underwent radiotherapy and chemotherapy for other metastatic tumors, he died 5 months after the second craniotomy. Conclusions: Brain metastasis from gastric UPS is rare and difficult to treat. Although aggressive treatment, such as surgical intervention, may improve patient survival in some cases, the timing of treatment is challenging because cerebral metastasis rapidly grows and and patients frequently suffer from synchronous systematic metastasis. Therefore, early detection and close follow-up of rapidly progressing brain metastasis are important to improve treatment outcomes. [ABSTRACT FROM AUTHOR]

Purpose: The AVAglio trial established the beneficial effect of add-on bevacizumab (BEV) for the treatment of newly diagnosed glioblastomas (nd-GBMs) that led to the approval of BEV for the treatment of these patients in Japan. However, the rationality of using BEV as a first-line treatment for nd-GBMs remains controversial. The purpose of this study was to analyze the outcomes of a case series of nd-GBM patients. Patients and methods: The outcomes of 69 nd-GBM patients treated after 2006 were retrospectively analyzed. Clinical and genetic analyses were performed, and estimates of progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan- Meier method. Since add-on BEV therapy was only used for partially resected GBMs (pr-GBMs) after its approval in 2013, the patients were subdivided into 3 treatment groups: Type I, partial removal with temozolomide (TMZ)/BEV and concurrent radiotherapy (CCRT); Type II, partial removal with TMZ and CCRT; and Type III, gross total removal with TMZ and CCRT. Results: The PFS rate of Type I patients was significantly higher than that of Type II patients (P=0.014), but comparable to that of Type III patients. Differences in OS rates between Type I and Type II patients were less apparent (P=0.075), although the median OS of Type I patients was ~8 months higher than that of Type II patients (17.4 vs 9.8 months, respectively). The clinical deterioration rate during initial treatment was significantly (P=0.024) lower in Type I than in Type II patients (7.7% vs 47.4%, respectively). Differences in OS rates between Type I and Type II patients with a poor performance status (PS) were significant (P=0.017). Conclusion: Our findings suggest that add-on BEV can prevent early clinical deterioration of pr-GBM patients and contribute to a prolonged survival, especially for those with a poor PS. [ABSTRACT FROM AUTHOR]

Recently updated phase III trials revealed the favorable effect of add-on procarbazine-lomustine-vincristine chemotherapy (CT) to radiotherapy (RT) in treating anaplastic oligodendrogliomas with 1p19q codeletion (codel). However, the underlying rationality of deferring RT and upfront CT administration for these tumors is yet to be elucidated. Here, we retrospectively analyzed the long-term outcome of our case series with oligodendroglial tumors treated with deferred RT and upfront procarbazine+nimustine+vincristine (PAV) in the introduction administration. We enrolled 36 patients with newly diagnosed oligodendroglial tumors (17, grade II and 19, grade III) treated during 1999-2012 and followed up for a median period of 69.0 months. Their clinical and genetic prognostic factors were analyzed, and progression-free survival, overall survival (OS), and deterioration-free survival (DFS) were evaluated. Regardless of the WHO grade, the 25 patients with 1p19q codel tumors never received RT initially, and of these 25, 23 received PAV treatment upfront. The 75% OS of patients with 1p19q codel tumor was 135.3 months (did not reach the median OS), indicating a favorable outcome. Multivariate analysis revealed that IDH mutation and 1p19q, not WHO grade, are independent prognostic factors; furthermore, IDH and 1p19q status stratified the cohort into 3 groups with significantly different OS. The DFS explained the prolonged survival without declining performance in patients with both grade II and III 1p19q codel tumors. Deferred RT and upfront PAV treatment for 1p19q codel oligodendrogliomas were associated with favorable outcomes without compromising performance status, regardless of WHO grade. [ABSTRACT FROM AUTHOR]

Abstract  Medulloblastoma (MB) is the most common malignant neuroepithelial tumor of childhood. The DNA topoisomerase II (Topo II) inhibitor etoposide has been widely used for the treatment of MBs; however, it remains unknown whether MB cells are more sensitive to etoposide than other malignant neuroepithelial tumor cells. In this study, we tested the chemosensitivities of malignant neuroepithelial tumors (26 glioblastomas, 9 anaplastic astrocytomas, and 5 MBs) to etoposide and vincristine using the succinate dehydrogenase inhibition test and found that MB cells are more sensitive to etoposide and more resistant to vincristine than other tumor cells. We performed quantitative reverse-transcription polymerase chain reaction to evaluate the expression of genes related to etoposide sensitivity, and found co-overexpression of DNA topoisomerase II (Topo II) α and β mRNA in MBs. In addition, the levels of Topo IIα and β mRNA in these tumors correlated with etoposide sensitivity. Immunohistochemical studies using surgical samples of these tumors demonstrated that the percentages of Topo IIα immunopositive cells (Topo IIα labeling index) correlated with those of Ki-67 immunopositive cells (MIB-1 labeling index); however, neither the Topo IIα nor the MIB-1 labeling index correlated with the levels of Topo IIα mRNA or etoposide sensitivity. Based on these observations, Topo IIα and β mRNA expression, but not the Topo IIα labeling index, might be a useful marker for sensitivity to etoposide in human malignant neuroepithelial tumors. [ABSTRACT FROM AUTHOR]

Despite recent advances in molecular classification, surgery, radiotherapy, and targeted therapies, the clinical outcome of patients with malignant brain tumors remains extremely poor. In this study, we have identified the tetraspan protein epithelial membrane protein-2 (EMP2) as a potential target for glioblastoma (GBM) killing. EMP2 had low or undetectable expression in normal brain but was highly expressed in GBM as 95% of patients showed some expression of the protein. In GBM cells, EMP2 enhanced tumor growth in vivo in part by up-regulating αvβ3 integrin surface expression, activating focal adhesion kinase and Src kinases, and promoting cell migration and invasion. Consistent with these findings, EMP2 expression significantly correlated with activated Src kinase in patient samples and promoted tumor cell invasion using intracranial mouse models. As a proof of principle to determine whether EMP2 could serve as a target for therapy, cells were treated using specific anti-EMP2 antibody reagents. These reagents were effective in killing GBM cells in vitro and in reducing tumor load in subcutaneous mouse models. These results support the role of EMP2 in the pathogenesis of GBM and suggest that anti-EMP2 treatment may be a novel therapeutic treatment. [ABSTRACT FROM AUTHOR]