Azusa Hayano

Radiation-Induced Meningiomas: An Exhaustive Review of the Literature

OBJECTIVE Radiation-induced meningioma (RIM) is an uncommon late risk of cranial irradiation. We conducted an exhaustive review of individual patient data to characterize RIM. METHODS Using a systematic search of the PubMed database, we performed a comprehensive literature review to characterize and investigate RIM. Student t tests were used to evaluate differences between variables. A Kaplan-Meier analysis was used to assess survival. Statistical significance was assessed using a log-rank test. RESULTS Our analysis included 251 cases of RIM. The average age at onset for the primary lesion was 13.0 ± 13.5 years, and the average radiation dose delivered to this lesion was 38.8 ± 16.8 Gy. Secondary meningiomas could be divided into grades I (140), II (55), and III (10) tumors. Thirty patients (11.9%) had multiple lesions, and 46 (18.3%) had recurrent meningiomas. The latency period between radiotherapy for primary lesions and the onset of meningiomas was 22.9 ± 11.4 years. The latency period was shorter for patients with grade III meningioma and for those in the high-dose and intermediate-dose radiation groups who received systemic chemotherapy. Aggressive meningiomas and multiple meningiomas were more common in the high-dose and intermediate-dose groups than in the low-dose group. The 5-year and 10-year survival rates for all patients with meningioma were 77.7% and 66.1%, respectively. CONCLUSIONS For patients treated with cranial radiotherapy, the risk of secondary meningioma warrants a longer follow-up period beyond the standard time frame typically designated for determining the risk of primary tumor relapse.

Radiation-Induced Sarcomas of the Central Nervous System: A Systematic Review

OBJECTIVE Radiation-induced sarcomas (RISs) of the central nervous system are an uncommon late risk of irradiation. We conducted a systematic review of individual patient data to characterize RISs. METHODS We conducted a systemic search of the PubMed databases and compiled a comprehensive literature review. Student t tests were used to evaluate differences between variables. Kaplan-Meier analysis was used to estimate survival. Statistical significance was assessed using a log-rank test. RESULTS We analyzed 180 cases of RISs, including 59 osteosarcomas, 50 fibrosarcomas, and 16 malignant fibrous histiocytomas. The average age of onset for primary lesions was 28.8 ± 17.9 years, and the average dose of radiation delivered to the primary lesion was 51.4 ± 18.6 Gy. The latency period between radiotherapy and the onset of sarcomas was 12.4 ± 8.6 years. The median overall survival time for all sarcoma patients was 11 months, with a 5-year survival rate of 14.3%. The median survival in patients who received chemotherapy was 18 months, with a 2-year survival rate of 39.4%, whereas patients who did not receive chemotherapy had a median survival of 5 months and a 2-year survival rate of 13.7% (P < 0.0001). CONCLUSIONS The risk of secondary sarcomas in patients treated with cranial radiotherapy warrants longer follow-up periods beyond the standard time frame typically designated for determining the risk of primary tumor relapse. Moreover, chemotherapy should be considered a potential treatment option for RISs.

Radiation-Induced Schwannomas and Neurofibromas: A Systematic Review

OBJECTIVE Radiation-induced benign peripheral nerve sheath tumors are uncommon late complications of irradiation. We conducted the largest systematic review of individual patient data. METHODS We performed a systematic search of PubMed databases and compiled a comprehensive literature review. Kaplan-Meier analysis was used to investigate survival, and statistical significance was assessed with a log-rank test. RESULTS We analyzed 40 cases of radiation-induced benign peripheral nerve sheath tumors. The histologic distributions were 28 schwannomas, 11 neurofibromas, and 1 ganglioneuroma. The average age of radiation exposure for development of primary lesions was 14.9 ± 15.5 years, and the latency period between radiotherapy to the onset of secondary tumors was 24.5 ± 12.7 years. The average irradiation dose delivered was 26.3 ± 20.3 Gy. The median overall survival for all cases was not reached (95% confidence interval, 22-not reached) months, with 10-year survival rates of 65.2%. Surgical negative margin was a positive prognostic factor for radiation-induced benign peripheral nerve sheath tumors. CONCLUSIONS The risk of incidence of secondary benign peripheral nerve sheath tumors in patients treated with radiotherapy should be considered in long-term follow-up periods. At present, complete surgical resection is the main stay for the treatment of radiation-induced benign peripheral nerve sheath tumors.

Secondary Intracranial Tumors Following Radiotherapy for Pituitary Adenomas: A Systematic Review

Pituitary adenomas are often treated with radiotherapy for the management of tumor progression or recurrence. Despite the improvement in cure rates, patients treated by radiotherapy are at risk of development of secondary malignancies. We conducted a comprehensive literature review of the secondary intracranial tumors that occurred following radiotherapy to pituitary adenomas to obtain clinicopathological characteristics. The analysis included 48 neuroepithelial tumors, 37 meningiomas, and 52 sarcomas which were published between 1959–2017, although data is missing regarding overall survival and type of irradiation in a significant proportion of the reports. The average onset age for the pituitary adenoma was 37.2 ± 14.4 years and the average latency period before the diagnosis of the secondary tumor was 15.2 ± 8.7 years. Radiotherapy was administered in pituitary adenomas at an average dose of 52.0 ± 19.5 Gy. The distribution of pituitary adenomas according to their function was prolactinoma in 10 (7.2%) cases, acromegaly in 37 (27.0%) cases, Cushing disease in 4 (2.9%) cases, PRL+GH in 1 (0.7%) case, non-functioning adenoma in 57 (41.6%) cases. Irradiation technique delivered was lateral opposing field in 23 (16.7%) cases, 3 or 4 field technique in 27 (19.6%) cases, rotation technique in 10 (7.2%) cases, radio surgery in 6 (4.3%) cases. Most of the glioma or sarcoma had been generated after lateral opposing field or 3/4 field technique. Fibrosarcomas were predominant before 1979 (p < 0.0001). The median overall survival time for all neuroepithelial tumors was 11 months (95% confidence intervals (CI), 3–14). Patients with gliomas treated with radiotherapy exhibited a non-significant positive trend with longer overall survival. The median overall survival time for sarcoma cases was 6 months (95% CI, 1.5–9). The median survival time in patients with radiation and/or chemotherapy for sarcomas exhibited a non-significant positive trend with longer overall survival. In patients treated with radiotherapy for pituitary adenomas, the risk of secondary tumor incidence warrants a longer follow up period. Moreover, radiation and/or chemotherapy should be considered in cases of secondary glioma or sarcoma following radiotherapy to the pituitary adenomas.

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.

Correlation between lower balance of Th2 helper T-cells and expression of PD-L1/PD-1 axis genes enables prognostic prediction in patients with glioblastoma

Common cancer treatments include radiation therapy, chemotherapy including molecular targeted drugs and anticancer drugs, and surgical treatment. Recent studies have focused on investigating the mechanisms by which immune cells attack cancer cells and produce immune tolerance-suppressing cytokines, as well as on their potential application in cancer immunotherapy. We conducted expression profiling of CD274 (PD-L1), GATA3, IFNG, IL12R, IL12RB2, IL4, PDCD1 (PD-1), PDCD1LG2 (PD-L2), and TBX21 (T-bet) using data of 158 glioblastoma multiforme (GBM) patients with clinical information available at The Cancer Genome Atlas. Principal component analysis of the expression profiling data was used to derive an equation for evaluating the status of Th1 and Th2 cells. GBM specimens were divided based on the median of the Th scores. The results revealed that Th1HighTh2Low and Th1LowTh2Low statuses indicated better prognosis than Th1HighTh2High, and were evaluated based on the downregulation of PD-L1, PD-L2, and PD-1. Furthermore, Th2Low divided based on the threshold, as well as CD274Low and PDCD1Low, were associated with good prognosis. In the Th2Low subgroup, 14 genes were identified as potential prognostic markers. Of these, SLC11A1Low, TNFRSF1BLow, and LTBRLow also indicated good prognosis. These results suggest that low Th2 balance and low activity of the PD-L1/PD-1 axis predict good prognosis in GBM. The set of genes identified in the present study could reliably predict survival in GBM patients and serve as useful molecular markers. Furthermore, this set of genes could prove to be novel targets for cancer immunotherapy.

The expression of PD-1 ligands and IDO1 by macrophage/microglia in primary central nervous system lymphoma

Recent progress in anti-tumor immunotherapy has focused on the significance of the tumor microenvironment in tumor progression and resistance to chemo/radio-therapy. Myeloid cells such as macrophages are predominant stromal components in hematological malignancies. In the present study, we investigated the regulation of programmed death-1 (PD-1) ligand expression in primary central nervous system lymphoma (PCNSL) using PCNSL cell lines and human monocyte-derived macrophages. TK PCNSL cell line-derived soluble factors induced overexpression of PD-1 ligands, indoleamine 2,3-dioxygenase (IDO1), and several other cytokines in macrophages. The expression of PD-1 ligands was dependent on the activation of signal transducer and activator of transcription 3. PD-L1 and IDO1 were overexpressed by macrophage/microglia in PCNSL tissues, and gene expression profiling indicated that IDO1 expression was positively correlated with the expression of macrophage and lymphocyte markers. Macrophage-derived factors did not influence the proliferation or chemo-sensitivity of cell lines. These data suggest that the expression of immunosuppressive molecules, including PD-1 ligands and IDO1, by macrophage/microglia may be involved in immune evasion of lymphoma cells.

Experiences and Expectations for Glioma Immunotherapeutic Approaches

Malignant gliomas are the most prevalent type of primary central nervous system (CNS) tumor in adults. Despite progress in brain tumor therapy, the prognosis for malignant glioma patients remains dismal. Standard treatment with temozolomide and radiotherapy for patients with newly diagnosed glioblastoma has increased the median overall survival (OS) by 15–20 months (1), but tumor recurrence is inevitable. Salvage treatments upon recurrence are palliative at best and rarely provide significant survival benefit. Among the new treatments currently being investigated for malignant glioma, immunotherapy is theoretically attractive, because it offers the potential for high tumor-specific cytotoxicity (2). Although recent clinical trials of immunotherapy protocols for malignant gliomas focused on initiating and amplifying a host response with some clinical success, most of them failed to induce objective tumor shrinkage in patients (2). Antitumor activities of tumor cytotoxic T cells (CTL) and antibodies induced by these therapies are insufficient to overcome tumor growth because tumors have immune evasion mechanisms instigated by myeloid derived suppressor cells (MDSCs) and regulatory T cells (Treg) (3). In this paper, we will review past experiences and discuss the promising future of immunotherapeutic approach for glioma treatment.