Glypican-1-targeted antibody-drug conjugate inhibits the growth of glypican-1-positive glioblastoma.

Glioblastoma is the deadliest form of brain tumor. The presence of the blood-brain barrier (BBB) significantly hinders chemotherapy, necessitating the development of innovative treatment options for this tumor. This report presents the in vitro and in vivo efficacy of an antibody-drug conjugate (ADC) that targets glypican-1 (GPC1) in glioblastoma. The GPC1-ADC was created by conjugating a humanized anti-GPC1 antibody (clone T2) with monomethyl auristatin E (MMAE) via maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl linkers. Immunohistochemical staining analysis of a glioblastoma tissue microarray revealed that GPC1 expression was elevated in more than half of the cases. GPC1-ADC, when bound to GPC1, was efficiently and rapidly internalized in glioblastoma cell lines. It inhibited the growth of GPC1-positive glioma cell lines by inducing cell cycle arrest in the G2/M phase and triggering apoptosis in vitro. We established a heterotopic xenograft model by subcutaneously implanting KALS-1 and administered GPC1-ADC intravenously. GPC1-ADC significantly inhibited tumor growth and increased the number of mitotic cells. We also established an orthotopic xenograft model by intracranially implanting luciferase-transfected KS-1-Luc#19. After injecting Evans blue and resecting brain tissues, dye leakage was observed in the implantation area, confirming BBB disruption. We administered GPC1-ADC intravenously and measured the luciferase activity using an in vivo imaging system. GPC1-ADC significantly inhibited tumor growth and extended survival. In conclusion, GPC1-ADC demonstrated potent intracranial activity against GPC1-positive glioblastoma in an orthotopic xenograft model. These results indicate that GPC1-ADC could represent a groundbreaking new therapy for treating glioblastoma beyond the BBB.

Utility of arterial spin labeling for objective assessment of intratumoral microvessels in diffuse hemispheric glioma, H3 G34R-mutant: A case report and literature review.

Imaging findings of diffuse hemispheric glioma H3 G34-mutant (DHG, H3 G34m), a new variant of glioma under the World Health Organization classification, have recently been vigorously debated. Here, we report a case of DHG, H3 G34m in which objective assessments of intratumoral microvessels using arterial spin labeling (ASL) were useful for preoperative diagnosis, selection of anti-tumor drugs, and tracking therapeutic responses. The patient was a 34-year-old woman who presented with weakness in the left arm. Preoperative magnetic resonance imaging (MRI) showed no specific findings of hyperintensity on fluid-attenuated inversion recovery imaging and faint enhancement on T1-weighted imaging with contrast media in the tumor. However, ASL showed a convincing finding of high blood flow in the entire tumor, allowing identification of the tumor as malignant glioma. Tumor specimens obtained from biopsy showed that the tumor comprised low-differentiated tumor cells, abundant histiocytes, and highly dense microvessels. Immunohistochemical findings such as positive findings for H3 G34R and p53, and negative findings for IDH-1, ATRX, and OLIG2 led to the diagnosis of DHG, H3 G34m. Based on findings of hyperperfusion on ASL and detection of vascular endothelial growth factor (VEGF), we administered the anti-VEGF antibody bevacizumab. The tumor shrank significantly but remained. However, the residual tumor showed hypoperfusion on ASL, strongly suggesting tumor remission. Objective assessments of blood flow using ASL are useful in clinical practice for patients with DHG, H3 G34 showing non-specific findings on conventional MRI.

Development of cerebral microbleeds and its impact on cognitive function in adult patients receiving medical management alone for ischemic moyamoya disease: supplementary analysis of a 5-year prospective cohort.

OBJECTIVE: De novo cerebral microbleeds (CMBs) on T2*-weighted magnetic resonance imaging (MRI) develop over time in adult moyamoya disease (MMD) and are generally associated with a decline in global cognitive function. The present supplementary analysis of a 5-year prospective cohort aimed to elucidate the incidence of an interval increase in CMBs in adult patients receiving medical management alone for ischemic MMD and its impact on cognitive function. METHODS: Sixty-four patients without misery perfusion in the symptomatic cerebral hemispheres at inclusion who did not experience any further ischemic symptoms or new hemorrhagic events during a 5-year follow-up period underwent T2*-weighted MRI and five kinds of neuropsychologic tests at inclusion and the end of the 5-year follow-up. RESULTS: When T2*-weighted MRI was compared between inclusion and the end of the 5-year follow-up, 10 patients (15%) had an interval increase in CMBs in the symptomatic cerebral hemisphere at inclusion. The scores from two kinds of neuropsychologic tests significantly deteriorated at the end of the 5-year follow-up compared with those at inclusion in patients with an interval increase in CMBs, whereas the scores of four kinds of neuropsychologic tests significantly improved at the end of the 5-year follow-up compared with those at inclusion in patients without interval increases in CMBs, asymptomatic ischemic lesions, or angiographic disease progression. CONCLUSIONS: The incidence of an interval increase in CMBs was 15% per 5 years in adult patients receiving medical management alone for ischemic MMD, and this increase was associated with a decline in cognitive decline.

Five-Year Outcomes of Medical Management Alone for Adult Patients with Ischemic Moyamoya Disease without Cerebral Misery Perfusion.

INTRODUCTION: No clear guidelines for treating adult patients with ischemic moyamoya disease (MMD) without cerebral hemodynamic compromise such as misery perfusion have been established. Our previous prospective cohort study of adult patients with MMD without misery perfusion who were treated with medical management alone, including an antiplatelet drug, showed a recurrent ischemic event rate of 3% per 2 years. The present prospective study aimed to elucidate the 5-year clinical, cerebral perfusion, and cognitive outcomes of medical management alone for Japanese adult patients with ischemic MMD without cerebral misery perfusion by following the same patients for another 3 years. METHODS: In total, 68 patients without recurrent events at a 2-year follow-up were prospectively followed up for another 3 years. Cerebral blood flow (CBF) in the symptomatic cerebral hemisphere was measured using brain perfusion single-photon emission computed tomography at inclusion and at the end of the subsequent 3-year follow-up. Neuropsychological testing was performed at inclusion and at the end of the initial 2- and subsequent 3-year follow-ups. RESULTS: During the subsequent 3-year follow-up, 2 patients (3%) developed further ischemic events. In patients without further ischemic events, CBF was significantly greater at the end of the subsequent 3-year follow-up than at inclusion (p = 0.0037), and all neuropsychological test scores improved or remained unchanged at the end of initial 2- and subsequent 3-year follow-ups compared with that at inclusion. CONCLUSION: In adult patients receiving medical management alone for ischemic MMD without cerebral misery perfusion, the incidence of further ischemic events was 6% per 5 years and did not change between the initial 2 years after the last is-chemic event and the subsequent 3 years. In patients without further ischemic events, CBF and cognitive function had not deteriorated at 5 years after the last ischemic event.

Angiographic disease progression in medically treated adult patients with ischemic moyamoya disease without cerebral misery perfusion: supplementary analysis of a 5-year prospective cohort.

Angiographic disease progression reportedly develops in adult moyamoya disease (MMD). However, more than half of patients analyzed underwent revascularization surgery. The present supplementary analysis of a 5-year prospective cohort with follow-up using magnetic resonance angiography (MRA) and cerebral blood flow (CBF) measurements was to elucidate the incidence and clinical features of angiographic disease progression in adult patients receiving medical management alone for ischemic MMD. Sixty-eight patients without misery perfusion in the symptomatic cerebral hemispheres underwent MRA and CBF measurement using brain perfusion single-photon emission computed tomography at inclusion and at the end of the 5-year follow-up. When neurological symptoms recurred or newly developed during the 5-year follow-up period, additional MRA and CBF measurements were also performed at that time. All four patients with further ischemic events during the 5-year follow-up period exhibited angiographic disease progression on MRA at such events. Of the remaining 64 patients without further events during the 5-year follow-up period, four exhibited angiographic disease progression on MRA at the end of the 5-year follow-up. CBF was significantly lower at the time of further ischemic events or at the end of the 5-year follow-up than at inclusion in eight patients with angiographic disease progression (p = 0.0117). The incidence of angiographic disease progression was 12% for 5 years in medically treated adult patients with ischemic MMD without cerebral misery perfusion. Patients with further ischemic events always exhibited angiographic disease progression. Cerebral perfusion was reduced in patients with angiographic disease progression even when further ischemic events did not occur.

Long-Term Cognitive Changes after Revascularization Surgery in Adult Patients with Ischemic Moyamoya Disease.

INTRODUCTION: Revascularization surgery for adult moyamoya disease (MMD) with ischemic presentation changes cognitive function and prevents further cerebral ischemic events. Most studies however repeated neuropsychological evaluation within 1 year after surgery. Our previous prospective cohort study of adult patients with MMD with misery perfusion who underwent direct revascularization surgery showed cognitive improvement and decline in 31% and 44%, respectively, of the patients 2 months after surgery. The present prospective study aimed to elucidate the 5-year cognitive changes after direct revascularization surgery in adult patients with cerebral misery perfusion due to ischemic MMD by following the same patients. METHODS: In total, 31 patients were prospectively followed up for 5 years after direct revascularization surgery. Five types of neuropsychological tests were performed preoperatively, 2 months after surgery, and at the end of the 5-year follow-up. Cerebral blood flow (CBF) in the symptomatic cerebral hemisphere relative to that in the ipsilateral cerebellar hemisphere (hemispheric relative CBF [RCBF]) was measured using brain perfusion single-photon emission computed tomography preoperatively and at the end of the 5-year follow-up. RESULTS: Based on results of pre- and postoperative neuropsychological tests, 11, 10, and 10 patients showed cognitive improvement, no change in cognitive function, and cognitive decline, respectively, at the end of the 5-year follow-up. These ratios were not significantly different compared with those 2 months after surgery (cognitive improvement, no change in cognitive function, and cognitive decline in 10, 8, and 13 patients, respectively). Although hemispheric RCBF was significantly greater at the end of the 5-year follow-up than before surgery in patients with cognitive improvement (80.7 ± 6.1% vs. 92.9 ± 5.5%; p = 0.0033) and in those showing no change in cognitive function (85.6 ± 3.5 vs. 91.5 ± 5.2%; p = 0.0093), this value was significantly lower at the end of the 5-year follow-up than before surgery in patients with cognitive decline (83.8 ± 3.7 vs. 81.0 ± 5.8%; p = 0.0367). CONCLUSION: One-third of adult patients with cerebral misery perfusion due to ischemic MMD who underwent direct revascularization surgery exhibited cognitive improvement, and one-third exhibited decline at the end of the 5-year follow-up. The former and latter patients had increased and decreased CBF, respectively, in the affected cerebral hemisphere at the end of the 5-year follow-up compared with preoperative brain perfusion.