The prognostic improvement of add-on bevacizumab for progressive disease during concomitant temozolomide and radiation therapy in patients with glioblastoma and anaplastic astrocytoma

BACKGROUND: Although newly diagnosed high-grade glioma patients in Japan can receive bevacizumab (BEV) as first-line chemotherapy. randomized clinical trials have not shown a survival benefit for BEV for these patients. In this study, we investigated whether selective add-on BEV for patients with newly diagnosed glioblastoma (GBM) and anaplastic astrocytoma (AA) improves prognosis, in cases where tumors were continuously growing during radiotherapy concomitant with temozolomide (TMZ). METHODS: We conducted a retrospective survey of the overall survival (OS) of patients with GBM;AAs who were treated in our institution between 2006 and 2016. Patients whose tumors were continuously growing regardless of radiotherapy were categorized as the "progressive" group; remaining patients were categorized as the "non-progressive" group. Since 2013, patients in the "progressive" group received add-on BEV therapy with the Stupp regimen during or just after radiotherapy. RESULTS: Of 151 GBM/AA patients, 34 (22.5%) were categorized in the "progressive" group. Median OSs of the "progressive" and "nonprogressive" groups were 13.2 months and 25.3 months, respectively (P<0.001). Twelve patients in the "progressive" group received add-on BEV therapy, and their median OS was 20.2 months; whereas for the remaining 22 patients in the "progressive" group who were treated before the BEV era, their median OS was 10.5 months. In the "progressive" group, add-on BEV significantly extended OS (P 0.018) and was the lone clinical factor of better prognosis. CONCLUSIONS: We found that, for patients with GBM/AAs whose tumors were continuously growing during radiotherapy, add-on BEV treatment resulted in survival benefits

Tetracyclines enhance antitumor T-cell immunity via the Zap70 signaling pathway

Background Cancer immunotherapy including immune checkpoint inhibitors is only effective for a limited population of patients with cancer. Therefore, the development of novel cancer immunotherapy is anticipated. In preliminary studies, we demonstrated that tetracyclines enhanced T-cell responses. Therefore, we herein investigated the efficacy of tetracyclines on antitumor T-cell responses by human peripheral T cells, murine models, and the lung tumor tissues of patients with non-small cell lung cancer (NSCLC), with a focus on signaling pathways in T cells.Methods The cytotoxicity of peripheral and lung tumor-infiltrated human T cells against tumor cells was assessed by using bispecific T-cell engager (BiTE) technology (BiTE-assay system). The effects of tetracyclines on T cells in the peripheral blood of healthy donors and the tumor tissues of patients with NSCLC were examined using the BiTE-assay system in comparison with anti-programmed cell death-1 (PD-1) antibody, nivolumab. T-cell signaling molecules were analyzed by flow cytometry, ELISA, and qRT-PCR. To investigate the in vivo antitumor effects of tetracyclines, tetracyclines were administered orally to BALB/c mice engrafted with murine tumor cell lines, either in the presence or absence of anti-mouse CD8 inhibitors.Results The results obtained revealed that tetracyclines enhanced antitumor T-cell cytotoxicity with the upregulation of granzyme B and increased secretion of interferon-γ in human peripheral T cells and the lung tumor tissues of patients with NSCLC. The analysis of T-cell signaling showed that CD69 in both CD4+ and CD8+ T cells was upregulated by minocycline. Downstream of T-cell receptor signaling, Zap70 phosphorylation and Nur77 were also upregulated by minocycline in the early phase after T-cell activation. These changes were not observed in T cells treated with anti-PD-1 antibodies under the same conditions. The administration of tetracyclines exhibited antitumor efficacy with the upregulation of CD69 and increases in tumor antigen-specific T cells in murine tumor models. These changes were canceled by the administration of anti-mouse CD8 inhibitors.Conclusions In conclusion, tetracyclines enhanced antitumor T-cell immunity via Zap70 signaling. These results will contribute to the development of novel cancer immunotherapy

Determination of brain tumor recurrence using C-11-methionine positron emission tomography after radiotherapy

We conducted a prospective multicenter trial to compare the usefulness of C-11-methionine (MET) and F-18-fluorodeoxyglucose (FDG) positron emission tomography (PET) for identifying tumor recurrence. Patients with clinically suspected tumor recurrence after radiotherapy underwent both C-11-MET and F-18-FDG PET. When a lesion showed a visually detected uptake of either tracer, it was surgically resected for histopathological analysis. Patients with a lesion negative to both tracers were revaluated by magnetic resonance imaging (MRI) at 3 months after the PET studies. The primary outcome measure was the sensitivity of each tracer in cases with histopathologically confirmed recurrence, as determined by the McNemar test. Sixty-one cases were enrolled, and 56 cases could be evaluated. The 38 cases where the lesions showed uptake of either C-11-MET or F-18-FDG underwent surgery; 32 of these cases were confirmed to be subject to recurrence. Eighteen cases where the lesions showed uptake of neither tracer received follow-up MRI; the lesion size increased in one of these cases. Among the cases with histologically confirmed recurrence, the sensitivities of C-11-MET PET and F-18-FDG PET were 0.97 (32/33, 95% confidence interval [CI]: 0.85-0.99) and 0.48 (16/33, 95% CI: 0.33-0.65), respectively, and the difference was statistically significant (P < .0001). The diagnostic accuracy of C-11-MET PET was significantly better than that of F-18-FDG PET (87.5% vs. 69.6%, P = .033). No examination-related adverse events were observed. The results of the study demonstrated that C-11-MET PET was superior to F-18-FDG PET for discriminating between tumor recurrence and radiation-induced necrosis

Determination of Brain Tumor Recurrence using 11

We conducted a prospective multicenter trial to compare the usefulness of C-11-methionine (MET) and F-18-fluorodeoxyglucose (FDG) positron emission tomography (PET) for identifying tumor recurrence. Patients with clinically suspected tumor recurrence after radiotherapy underwent both C-11-MET and F-18-FDG PET. When a lesion showed a visually detected uptake of either tracer, it was surgically resected for histopathological analysis. Patients with a lesion negative to both tracers were revaluated by magnetic resonance imaging (MRI) at 3 months after the PET studies. The primary outcome measure was the sensitivity of each tracer in cases with histopathologically confirmed recurrence, as determined by the McNemar test. Sixty-one cases were enrolled, and 56 cases could be evaluated. The 38 cases where the lesions showed uptake of either C-11-MET or F-18-FDG underwent surgery; 32 of these cases were confirmed to be subject to recurrence. Eighteen cases where the lesions showed uptake of neither tracer received follow-up MRI; the lesion size increased in one of these cases. Among the cases with histologically confirmed recurrence, the sensitivities of C-11-MET PET and F-18-FDG PET were 0.97 (32/33, 95% confidence interval [CI]: 0.85-0.99) and 0.48 (16/33, 95% CI: 0.33-0.65), respectively, and the difference was statistically significant (P < .0001). The diagnostic accuracy of C-11-MET PET was significantly better than that of F-18-FDG PET (87.5% vs. 69.6%, P = .033). No examination-related adverse events were observed. The results of the study demonstrated that C-11-MET PET was superior to F-18-FDG PET for discriminating between tumor recurrence and radiation-induced necrosis