Abstract
The elucidation of the mechanism of action and resistance is imperative to overcome resistance to Bev and develop a more effective therapy. This study aims to investigate the status and ...change of alternative angiogenic factors regarding Bev usage using human specimens. The present study used 54 glioblastoma tissues obtained at 3 different settings: tumors of initial resection (naive Bev group), tumors resected following Bev therapy (effective Bev group), and recurrent tumors after Bev therapy (refractory/autopsied Bev group). Importantly, naive Bev-refractory Bev of 22 specimens in 11 cases (including 4 autopsy specimens and 7 salvage surgery specimens) were obtained as paired specimens from the same patient. The expression of alternative angiogenic factors including basic fibroblast growth factor (bFGF), placental growth factor (PlGF), Angiopoietin1 (Ang-1), Angiopoietin2(Ang-2) and EphrinA2 were investigated via immunohistochemistry. PlGF expression was higher in the effective group than in the Naive group (p=0.048), and Ang-2 (0.047) and EphA2 (p=0.028) were higher in the relapse group than in the Naive group. Interestingly, in paired specimens, PlGF expression was higher in the refractory group than in the Naive group (p=0.036). This suggests that angiogenic factors other than VEGF are involved in recurrence. We provide the first clinicopathological evidence of the status of alternative angiogenic pathway after the Bev usage. These in situ observations will help to optimize therapy.
Abstract
We are conducting a clinical study of immunotherapy using tumor-fused dendritic cells (TFDC) as a modality of multidisciplinary treatment for patients with glioblastoma (GBM). In this study, ...we analyzed the additional effect of TFDC-immunotherapy for standard therapy. Newly diagnose GBM patients who treated at four of Jikei University Hospitals were analyzed in this study. Adjuvant therapy after tumor removal surgery was maintained according to the Supp's regimen. Bevacizumab (10 mg/kg, every 2 weeks) was added when a recurred tumor was confirmed. TFDC vaccine was generated from cultured tumor cells derived from autologous surgical specimen and dendritic cells from peripheral blood, and were subcutaneously administered in the cervical region for 3-14 times. All patients who had not participated in any other immunotherapy-related clinical studies were compared as a control group in a Propensity score matching analysis. The number of analyzed patients was 55 in the immunotherapy group and 35 in the control group. The 2-year survival rate and 5-year survival rate were 20.9% and 0% in the control group, respectively, while the immunotherapy group was 45.7% and 22.7%, respectively. A statistically significant difference in overall survival was observed between them (p=0.0045). There was no difference in the observed adverse events in the two groups. Specific adverse events for TFDC-immunotherapy was not observed. In the biomarker analysis, low HLA-A expression and lack of CCDC88A, KRT4, TACC2, and TONSL mutations in tumor cells were suggested as biomarkers of better prognosis. We are currently analyzing IDH profile in those patients for further analysis. TFDC-immunotherapy should be adopted as one of the modality of multidisciplinary treatments for GBM because it is expected to have some additional effects for standard therapeutic reagents without adversely affecting them. Since there are a certain number of poor responders for this immunotherapy, predictive biomarkers of therapeutic efficacy are awaited.
Abstract
BACKGROUND
Preoperative bevacizumab (Bev) is a standard treatment strategy for colorectal cancers, but not malignant gliomas. This multi-institutional phase I/II study was conducted to ...confirm the safety and explore the clinical utility of preoperative Bev for newly diagnosed glioblastoma (GB).
METHODS
Patients were enrolled based on magnetic resonance imaging (MRI) findings typically suggestive of GB. Preoperative Bev and temozolomide (TMZ) were administered at doses of 10 mg/kg on day 0 and 150 mg/m2 on days 1-5, respectively. Surgical resection was performed between days 21 and 30, inclusive. The initial safety evaluation was performed for the initial 7 cases and efficacy was evaluated in a total of 15 cases by progression-free survival (PFS), changes in tumor volume, Karnofsky Performance Scale (KPS) and Mini-Mental State Examination (MMSE) scores after preoperative therapy.
RESULTS
The study protocol was judged as acceptable. Tumor resection was performed on a mean of day 23.7. Pathological diagnosis was GB, isocitrate dehydrogenase (IDH)-wildtype in 14 cases and GB, IDH-mutant in 1 case, according to the WHO 2016 criteria. Severe adverse events possibly related to preoperative Bev and TMZ were observed in 2 of the 15 patients, as wound infection and postoperative hematoma and thrombocytopenia. KPS and MMSE scores were significantly improved with preoperative therapy. Tumor volume was decreased in all but one case on T1-weighted imaging with contrast-enhancement (T1CE) and in all cases on fluid-attenuated inversion recovery, with mean volume decrease rates of 36.2% and 54.0%, respectively. Tumor volume decrease rate on T1CE and PFS tended to correlate. Median PFS and overall survival were 9.5 months and 16.5 months, respectively.
CONCLUSIONS
Preoperative Bev and TMZ is confirmed to be safe. The strategy might be useful for GB in some patients, not only reducing tumor burden, but also improving patient KPS preoperatively.
Cancer stemness and immunosuppressive tumor microenvironment (TME) in accordance with tumor oxygenation are variable during bevacizumab (Bev) therapy for glioblastoma (GBM). Positron emission ...tomography (PET) using
F-fluoromisonidazole (FMISO) reflects hypoxic TME. The aim of this study was to compare FMISO-PET and immunohistochemical findings of tumor oxygenation in the TME of GBM during Bev treatment.
Seven patients with newly diagnosed IDH-wildtype GBM underwent FMISO-PET during follow-up. Three patients received preoperative neoadjuvant Bev (neo-Bev) and subsequently underwent surgical resection. Reoperation was performed at the recurrence. FMISO-PET was performed before and after neo-Bev. Four patients who underwent tumor resection without neo-Bev were included as the control group. Expressions of hypoxic markers (carbonic anhydrase; CA9), stem cell markers (nestin, FOXM1), and immunoregulatory molecules (CD163, FOXP3, PD-L1) in tumor tissues were analyzed by immunohistochemistry (IHC).
All 3 patients treated with neo-Bev showed decrease in FMISO accumulation in accordance with expressions of CA9 and FOXM1 compared with the control group. Two of these 3 patients at the recurrence showed increase in FMISO accumulation. IHC showed increased CA9-and FOXM1-positive cells in recurrent tumors. Expression of PD-L1 tended to be lower after neo-Bev compared with the control group.
FMISO-PET effectively visualized TME oxygenation after neo-Bev. Increased FMISO accumulation at the time of recurrence, even under Bev treatment, suggests that FMISO-PET might be useful for monitoring the duration of Bev efficacy by reflecting tumor oxygenation.
Abstract
BACKGROUND: Rapid recurrence of a pilocytic astrocytoma with anaplastic transformation is extremely rare. The case of an elderly patient with a cerebellar pilocytic astrocytoma with ...anaplastic transformation during short-term follow-up is reported. CASE DESCRIPTION: An 83-year-old woman presented initially with dizziness and a gait deviation to the right. Magnetic resonance imaging (MRI) demonstrated a homogeneously enhanced mass in the right cerebellar hemisphere, and the tumor was subtotally removed by right suboccipital craniotomy. Histological examination showed that the tumor cells contained eosinophilic cytoplasm and spindle-shaped processes with Rosenthal fibers and eosinophilic granular bodies, diagnosed as a typical pilocytic astrocytoma (PA). The MIB-1 index was less than 1%. The patient did not receive postoperative adjuvant radiation and chemotherapy. Two months after surgery, MRI showed growth of the residual tumor adjacent to the fourth ventricle, causing obstructive hydrocephalus. She underwent surgery again, and the tumor was totally removed. Histological findings showed mitotic cells and increased cellularity compared with the primary tumor, which was compatible with anaplastic transformation of PA with a MIB-1 index of 50%. Postoperatively, she was observed with best supportive care without postoperative adjuvant therapy. Nine months after the second operation, she died due to tonsillar herniation and obstructive hydrocephalus caused by a recurrent tumor. An autopsy was performed. CONCLUSION: It is extremely rare, as in the present case, that a cerebellar PA in an elderly patient recurs rapidly with anaplastic transformation, despite deferred postoperative adjuvant therapy including radiation and chemotherapy A novel molecular-targeted therapy is needed for anaplastic PA showing aggressive biological behavior.
Abstract
Introduction: Malignant glioma is the most common and aggressive primary brain tumor and requires multimodality treatment. Regarding surgical treatment, it is desirable to achieve maximum ...resection while considering function preservation. There is consensus that the survival prognosis is prolonged in gross or subtotal resection. However, there are cases in which biopsy or partial resection is performed due to the spread of lesions at the time of onset, underlying diseases, and social background. The purpose of this study was to retrospectively analyze the cases of malignant glioma at our university and to find out the factors related to the prognosis of cases in which removal was insufficient.
Target: 55 cases of malignant glioma treated at our university since 2013 who underwent biopsy or partial resection.
Method: Overall/progression-free survival period is the end point, and parameters are age, bevacizumab use, pathological diagnosis, photodynamic diagnosis use at operation, immunotherapy, ventricular invasion, contralateral invasion, sex, preoperative Performance Status (PS), postoperative PS, left or right, navigation use, steroid use, anticonvulsant drug type, radiation, IDH mutation, 1p19q co-deletion, MGMT methylation, TERT mutation, p53 mutation, biopsy or partial resection. After narrowing down the evaluation items by univariate analysis(Logrank test), multivariate analysis(Cox proportional hazard model)was performed.
Result: The univariate analysis was significant in 5 items including bevacizumab use, radiation therapy, levetiracetam use, postoperative PS70 or higher, and partial resection instead of biopsy. Multivariate analysis detected two statistically significant differences, bevacizumab use and post-operative PS70 and above. There was no difference in the timing of bevacizumab use.
Consideration: In poorly resection cases, the weight of postoperative treatment is high, so continuity of treatment and selection of postoperative treatment are important, and maintenance of ADL and use of bevacizumab are significant among them.
Interleukin-18 (IL-18) exhibits antitumor activity in various laboratory models. In the current study, brain tumors in naive mice regressed after an intratumoral injection of a single dose of ...recombinant IL-18 (rIL-18). Intraperitoneal rIL-18 substantially delayed the growth of subcutaneously inoculated gliomas but not gliomas located in the brain. Efficacy was reduced when studies were performed in mice depleted of natural killer cells. Although intracerebral administration of rIL-18 increased the serum interferon-gamma concentration, the antitumor effect of IL-18 was not mediated by interferon-gamma. These data suggest the therapeutic potential for control of tumor growth by intratumoral administration of rIL-18 in patients with glioma.
Abstract
Background: Previously we reported that bevacizumab (Bev) produces tumor oxygenation with immunosupportive tumor microenvironment (TME) and inhibition of stemness. To confirm whether those ...effects might contribute prolongation of clinical outcome, in the present study paired samples from same patients with newly diagnosed GBM who received Bev during its effectiveness and refractoriness were investigated by immunohistochemistry. Methods: Eighteen samples from 9 patients with newly diagnosed GBM who received preoperative neoadjuvant Bev (neoBev) followed by surgical operation and chemoradiotherapy in addition to salvage surgery after recurrence were investigated. Expressions of FOXM1, HIF-1, and CD163 were evaluated by immunohistochemistry. Overall survial (OS) were analyzed with the present cohort divided into two groups between good and poor responder (GR and PR, respectively) of Bev defined as tumor regression rate judged by T1 gadolinium enhancement (T1Gd) and fluid attenuated inversion recovery (FLAIR) images. Results: In the group of good responder of T1Gd (T1Gd-GR; defined as >38% of regression rate after neoBev), OS was prolonged compared with T1Gd-PR along with inhibition of FOXM1 expression and HIF-1a. In contrast, in the group of good responder of FLAIR (FLAIR-GR; defined as >54% of regression rate after neoBev), there were no significant differences of OS and FOXM1 expression between GR and PR. HIF-1a expression tended to be elevated in T1Gd-PR of initial tumors, T1Gd-GR of recurrent tumors, and FLAIR-PR of both initial and recurrent tumors.Conclusion: T1Gd-GR after neoBev might attribute to inhibition of FOXM1 and oxygenation. Bev might provide tumor oxygenation, leading to inhibition of stemness and M2 TAM infiltration during its effectiveness. These results suggested that Bev combined with immunotherapy for newly diagnosed GBM might provide clinical benefits including inhibition of stemness and induction of immunosupportive TME, when tumor volume assessed by T1 Gd. was significantly decreased following neoBev.
Abstract
Background
Preoperative neoadjuvant bevacizumab (neoBev) reduces enhancement and perifocal edema by inhibition of angiogenesis and vascular permeability for glioblastoma (GBM). The aim of ...this study was to investigate safety and efficacy of neoBev for newly diagnosed GBM through an exploratory prospective multi-center study.
METHODS & PATIENTS
15 patients with newly diagnosed GBM were enrolled in the present study. Eligibility was a patient with a brain tumor representing with ring-shaped enhancement and perifocal edema on magnetic resonance imaging (MRI). Based on neuroimage of typical GBM, neoBev and temozolomide (TMZ) were administered prior to craniotomy. Two weeks after neoBev, the tumor volume on T1-weighted gadolinium enhancement (T1Gd) and fluid attenuated inversion recovery (FLAIR) were assessed. Three to four weeks after neoBev and TMZ administration, patients underwent surgical resection. The primary endpoint was feasibility and safety, and the secondary endpoint was efficacy. Adverse events including systemic toxicity and wound healing delay during radiation (RT), TMZ, and Bev combined therapy were carefully monitored throughout clinical course including extent of resection.
RESULTS
Average of tumor regression rate two weeks after neoBev on T1Gd and FLAIR were 37.0% and 54.0%, respectively. Cerebral blood flow and cerebral blood volume were reduced after neoBev. Patients underwent surgical resection safely without excess blood loss due to less vascular and less degree of brain swelling. Two patients underwent awake surgery without any complications. Postoperative MRI showed that the all tumors were totally removed except one with multiple invasive tumors. Histological diagnosis of all patients was GBM, IDH-1 wild-type. Postoperative course was uneventful without neurological deficit and adverse effects except one postoperative hematoma in the resection cavity and one wound infection due to wound dehiscence.
CONCLUSION
Preoperative neoBev for newly diagnosed GBM might contribute to safe surgery. Clinical outcome of this therapeutics is now currently under investigation.
Abstract
Since a diffuse midline glioma (DMG) has no effective therapy, it is an urgent need to develop new therapeutic strategy. We performed immunotherapy using fusions of autologous dendritic ...cells (DC) with tumor cells in DMG cases in which tumor tissue was collected by surgery aimed at biopsy, and evaluate the effectiveness and examine the pros and cons of surgical intervention against DMG. Among the patients with basal ganglia or brain stem tumors received surgery at our hospital, 5 adult cases of DMG with H3K27M gene mutation were registered. All patients received radiation therapy and temozolomide chemotherapy. 4 cases received bevacizumab chemotherapy when the patients had recurrence or progression of the disease. The tumor-fused DCs (TFDC) were made by DCs induced from autologous peripheral blood mononuclear cells and tumor cells established from surgical specimens. They were injected subcutaneously into the neck 3 ~ 6 times in a 14 ~ 28 day cycle as the immunotherapy. The adverse events, PFS, and OS were evaluated. A transient complication of facial numbness was observed in one case on right after surgery. Although two patients had CR in those therapies, both of them died of disease (OS at 18 and 32 months, respectively). Since the remaining three cases were registered very recently, adverse event or treatment efficacy judgment have not been determined at the time of submission of the abstract. Serious surgical complications have not been observed in the presented cases. Surgery may be acceptable for DMG as long as the surgery is performed by sufficiently experienced surgeon in an appropriate environment. The TFDC immunotherapy, which can be performed only by collecting a small amount of tumor tissue, expects to be a novel treatment for MDG. In this presentation, the pros and cons of surgical intervention aimed at TFDC immunotherapy for DMG will be examined.
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