Jumpei Homma

Immunologic Evaluation of Personalized Peptide Vaccination for Patients with Advanced Malignant Glioma

Purpose: The primary goal of this phase I study was to assess the safety and immunologic responses of personalized peptide vaccination for patients with advanced malignant glioma. Experimental Design: Twenty-five patients with advanced malignant glioma (8 grade 3 and 17 grade 4 gliomas) were evaluated in a phase I clinical study of a personalized peptide vaccination. For personalized peptide vaccination, prevaccination peripheral blood mononuclear cells and plasma were provided to examine cellular and humoral responses to 25 or 23 peptides in HLA-A24+ or HLA-A2+ patients, respectively; then, only the reactive peptides (maximum of four) were used for in vivo administration. Results: The protocols were well tolerated with local redness and swelling at the injection site in most cases. Twenty-one patients received more than six vaccinations and were evaluated for both immunologic and clinical responses. Increases in cellular or humoral responses specific to at least one of the vaccinated peptides were observed in the postvaccination (sixth) samples from 14 or 11 of 21 patients, respectively. More importantly, significant levels of peptide-specific IgG were detected in the postvaccination tumor cavity or spinal fluid of all of the tested patients who showed favorable clinical responses. Clinical responses were 5 partial responses, 8 cases of stable disease, and 8 cases of progressive disease. The median overall survival for patients with recurrent glioblastoma multiforme in this study (n = 17) was 622 days. Conclusions: Personalized peptide vaccinations were recommended for the further clinical study to malignant glioma patients.

Gene expression signature-based prognostic risk score in patients with primary central nervous system lymphoma.

Purpose: Better understanding of the underlying biology of primary central nervous system lymphomas (PCNSL) is critical for the development of early detection strategies, molecular markers, and new therapeutics. This study aimed to define genes associated with survival of patients with PCNSL. Experimental Design: Expression profiling was conducted on 32 PCNSLs. A gene classifier was developed using the random survival forests model. On the basis of this, prognosis prediction score (PPS) using immunohistochemical analysis is also developed and validated in another data set with 43 PCNSLs. Results: We identified 23 genes in which expressions were strongly and consistently related to patient survival. A PPS was developed for overall survival (OS) using a univariate Cox model. Survival analyses using the selected 23-gene classifiers revealed a prognostic value for high-dose methotrexate (HD-MTX) and HD-MTX–containing polychemotherapy regimen–treated patients. Patients predicted to have good outcomes by the PPS showed significantly longer survival than those with poor predicted outcomes (P < 0.0001). PPS using immunohistochemical analysis is also significant in test (P = 0.0004) and validation data set (P = 0.0281). The gene-based predictor was an independent prognostic factor in a multivariate model that included clinical risk stratification (P < 0.0001). Among the genes, BRCA1 protein expressions were most strongly associated with patient survival. Conclusion: We have identified gene expression signatures that can accurately predict survival in patients with PCNSL. These predictive genes should be useful as molecular biomarkers and they could provide novel targets for therapeutic interventions. Clin Cancer Res; 18(20); 5672–81. ©2012 AACR.

Salvage therapy and late neurotoxicity in patients with recurrent primary CNS lymphoma treated with a modified ProMACE-MOPP hybrid regimen

We report the efficacy of salvage therapy with a modified ProMACE-MOPP combined with radiation in patients with primary central nervous system lymphoma (PCNSL). Thirty-two immunocompetent patients were treated with a regimen of pirarubicin, cyclophosphamide, etoposide, vincristin, and methotrexate (MTX: 500 mg/m2) administered in 21-day cycles. Patients received 20 Gy of whole-brain radiotherapy after three cycles of chemotherapy. A single cycle of chemotherapy was repeated every four months for two years. Nine patients with CNS relapse were retreated with additional cycles of the ProMACE-MOPP hybrid regimen with a 90% objective response rate. Median complete response (CR) duration was 13.2 months and median survival time (MST) for the nine patients treated after initial relapse was 30 months. One of 17 patients (5.8%) who had less than 20 Gy of whole brain irradiation developed dementia. In contrast, six of seven (85.7%) patients who had more than 30 Gy of whole brain radiotherapy became demented. Maintaining a moderate dose of MTX, while adding chemotherapeutic agents and 20 Gy of whole brain radiation therapy, improved disease control and overall survival and lowered the incidence of delayed neurologic toxicity in patients with PCNSL. Additional treatment with a ProMACE-MOPP hybrid regimen is still effective for relapsed disease.

Gene expression signature-based prognostic risk score in patients with glioblastoma

The present study aimed to identify genes associated with patient survival to improve our understanding of the underlying biology of gliomas. We investigated whether the expression of genes selected using random survival forests models could be used to define glioma subgroups more objectively than standard pathology. The RNA from 32 non‐treated grade 4 gliomas were analyzed using the GeneChip Human Genome U133 Plus 2.0 Expression array (which contains approximately 47 000 genes). Twenty‐five genes whose expressions were strongly and consistently related to patient survival were identified. The prognosis prediction score of these genes was most significant among several variables and survival analyses. The prognosis prediction score of three genes and age classifiers also revealed a strong prognostic value among grade 4 gliomas. These results were validated in an independent samples set (n = 488). Our method was effective for objectively classifying grade 4 gliomas and was a more accurate prognosis predictor than histological grading.

Identification and validation of a gene expression signature that predicts outcome in malignant glioma patients

Better understanding of the underlying biology of malignant gliomas is critical for the development of early detection strategies and new therapeutics. This study aimed to define genes associated with survival. We investigated whether genes selected using random survival forests model could be used to define subgroups of gliomas objectively. RNAs from 50 non-treated gliomas were analyzed using the GeneChip Human Genome U133 Plus 2.0 Expression array. We identified 82 genes whose expression was strongly and consistently related to patient survival. For practical purposes, a 15-gene set was also selected. Both the complete 82 gene signature and the 15 gene set subgroup indicated their significant predictivity in the 3 out of 4 independent external dataset. Our method was effective for objectively classifying gliomas, and provided a more accurate predictor of prognosis. We assessed the relationship between gene expressions and survival time by using the random survival forests model and this performance was a better classifier compared to significance analysis of microarrays.

Late relapse of primary central nervous system lymphoma

Ryuya Yamanaka, Ken Morii, Yoshikatsu Shinbo, Masakazu Sano, Jumpei Homma, Naoto Tsuchiya, Naoki Yajima, Yoshihiro Tsukamoto, Ryouske Ogura, Manabu Natsumeda, Hiroshi Aoki, Katsuhiko Akiyama, Takafumi Saitoh, Tetsuro Tamura, Hiroaki Hondoh, Atsushi Kawaguchi, Hitoshi Takahashi and Yukihiko Fujii Department of Neurosurgery, Brain Research Institute, Niigata University, Niigata, Japan; Laboratory of Molecular Target Therapy for Cancer, Graduate School for Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan; Department of Neurosurgery, Kitanihon Neurosurgical Hospital, Gosen, Japan; Department of Neurosurgery, Shibata Prefectural Hospital, Shibata, Japan; Department of Neurosurgery, Toyama Prefectural Central Hospital, Toyama, Japan; Department of Neurosurgery, Nagano Red Cross Hospital, Nagano, Japan; Department of Neurosurgery, Uonuma-Kikan Hospital, Minamiuonuma, Japan; Department of Neurosurgery, Niigata Prefectural Central Hospital, Joetsu, Japan; Center for Comprehensive Community Medicine, Faculty of Medicine, Saga University, Saga, Japan; Department of Pathology, Brain Research Institute, Niigata University, Niigata, Japan

Long-term survivors of primary central nervous system lymphoma

Objective: In this study, we provide long‐term outcome data of patients with primary central nervous system lymphoma Methods: The long‐term outcomes of PCNSL patients diagnosed between 1982 and 2006 were reviewed. Neurological late neurotoxicity symptoms, neuroradiological brain atrophy and leukoencephalopathy were evaluated. Surviving patients completed the Quality of Life Questionnaire‐30 and Brain Cancer Module‐20. The differences in overall survival were assessed using the Kaplan‐Meier method and log‐rank test. The differences between groups in terms of each investigated parameter were analyzed using the Wilcoxon signed‐rank test Results: Among 112 PCNSL patients, there were 33 (29.4%) long‐term (> 5 years) survivors. The median survival of all long‐term survivors was 105.7 months; of these, 8 (7.1%) were alive at the latest follow‐up, with a mean survival time of 170.2 months (range, 121.8‐286.4). Clinical assessment revealed severe neurotoxicity in 14 patients (42.4%), moderate neurotoxicity in 5 (15.1%), and normal status in 14 (42.4%). Correlations were seen between the neuroradiological imaging score changes and neurocognitive condition (P=0.0001), neurocognitive condition and the whole brain irradiation dose (P=0.0004), and atrophy and the whole brain irradiation dose (P=0.0035). Conclusions: A more severe clinical condition was found to be associated with increasing age and whole brain irradiation dose in long‐term survivors with PCNSL.

Target amplicon exome-sequencing identifies promising diagnosis and prognostic markers involved in RTK-RAS and PI3K-AKT signaling as central oncopathways in primary central nervous system lymphoma

Exome-sequencing for somatic mutation detection and copy number variation analysis are effective and valid methods for evaluating human cancers in current molecular medicine. We conducted target amplicon exome-sequencing analyses using PCR target enrichment and next-generation sequencing on Ion Proton semiconductor sequencers. Twenty-seven primary central nervous system lymphoma (PCNSL) specimens and their corresponding noncancerous tissues were used for multiplex PCR amplification to obtain targeted coverages of the entire coding regions of 409 cancer-related genes. The average of the total numbers of somatic mutations including single-nucleotide variations and insertion/deletion mutations in each specimen was 13.3. Of these, the average of the ratios of nonsynonymous substitutions in each specimen was 74.8%. The most frequent mutations in 27 specimens were in PIM1, MYD88, CD79B, DST, IRF4, ERBB3, MYH11, DCC, and KMT2D. Furthermore, somatic mutations of MYH11 were related to poor prognoses in PCNSL patients. Copy number variations were also duplicated and/or deleted from deep-sequencing in segmental genomic islands. In addition to these prognostic marker candidates, analysis of RTK-RAS-MAPK signaling and the PTEN-PI3K-AKT proapoptotic pathway showed that somatic activations and aberrations, respectively, may be involved in a promising central oncopathway harboring mTOR, c-Myc, FOXO1, and p53. This study provides a foundation for molecular targeted therapies based on genome diagnostics and prognosis in PCNSL.