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Supplementary Figures S1-S2.

Histone deacetylase inhibitors (HDI) are emerging as potentially useful components of the anticancer armamentarium and as useful tools to dissect mechanistic pathways. HDIs that globally inhibit histone deacetylases (HDAC) have radiosensitizing effects, but the relative contribution of specific HDAC classes remains unclear. Newly characterized HDIs are now available that preferentially inhibit specific HDAC classes, including SK7041 (inhibits class I HDACs) and splitomicin (inhibits class III HDACs). We investigated in human cancer cells the relative radiosensitizations that result from blocking specific HDAC classes. We found that trichostatin A (TSA; inhibitor of both class I and II HDACs) was the most effective radiosensitizer, followed by the class I inhibitor SK7041, whereas splitomicin (inhibitor of class III) had least effect. Interestingly, radiosensitization by TSA in cell lines expressing p53 was more pronounced than in isogenic lines lacking p53. Radiosensitization of cells expressing p53 by TSA was reduced by pifithrin-α, a small-molecule inhibitor of p53. In contrast, the radiosensitization by TSA of cells expressing low levels of p53 was enhanced by transfection of wild-type p53–expressing vector or pretreatment with leptomycin B, an inhibitor of nuclear export that increased intracellular levels of p53. These effects on radiosensitization were respectively muted or not seen in cells treated with SK7041 or splitomicin. To our knowledge, this may be among the first systematic investigations of the comparative anticancer effects of inhibiting specific classes of HDACs, with results suggesting differences in the degrees of radiosensitization, which in some cell lines may be influenced by p53 expression.

Supplementary Figures 1-2 from Histone Deacetylase Inhibitor–Mediated Radiosensitization of Human Cancer Cells: Class Differences and the Potential Influence of p53

Purpose: Reports on results of radiation therapy (RT) for Kasabach-Merritt syndrome (KMS) are limited. We performed a retrospective study to evaluate the response rates and late complications and to determine the adequate RT dose for patients with KMS patients.Materials and Methods: We studied 11 patients who received RT between October 1988 and September 2008 for KMS refractory to pharmacologic therapy. All patients had external hemangiomas and received the diagnosis of KMS within 12 months of birth. All 11 patients received steroids as the first-line therapy; eight patients additionally received interferon-α therapy, and one patient underwent surgery. Nine patients underwent single-course RT with a total dose of 4.5–8 Gy (1.5–2 Gy/fraction). Two patients received multiple courses of RT, with a cumulative total dose of 12 Gy (2 Gy/fraction) and 18Gy (1.5 Gy/fraction), respectively.Results: The median follow-up period was 156 months (interquartile range [IQR], 75 to 226 months). The median total dose of RT was 6 Gy, and all patients maintained complete remission until the last follow-up. An additional course of RT was performed for refractory cases or cases of local relapse after initial RT. Rapid platelet count increase after RT was seen in most patients, which returned to normalcy in a median of 20 days (IQR, 5 to 178 days). However, seven patients experienced radiation-related long-term complications.Conclusion: Low-dose RT is effective and yields rapid response in patients with KMS. However, given growth-related late complications, RT should be carefully considered.

The role of adjuvant radiotherapy (RT) for benign or atypical meningioma is controversial.To identify prognostic factors and a subgroup that could be potentially indicated for adjuvant RT.A total of 336 patients with benign and 157 patients with atypical meningioma underwent surgical resection between January 2015 and December 2019. We retrospectively analyzed 407 patients who did not receive adjuvant RT to stratify risk groups for recurrence. A recursive partitioning analysis (RPA) with the prognostic factors for their failure-free survival (FFS) divided the patients into risk groups.The 3-year FFS with surgical resection only was 76.5%. Identified prognostic factors for FFS were skull base location, tumor size, brain invasion, a Ki-67 proliferation index of ≥5%, and subtotal resection. The RPA-classified patients were divided into 4 risk groups: very low, low, intermediate, and high, and their 3-year FFS were 98.9%, 78.5%, 59.8%, and 34.2%, respectively. Intermediate-risk and high-risk groups comprise the patients with meningioma of sizes ≥2 cm after subtotal resection or meningioma of sizes3 cm, located in the skull base or with brain invasion, respectively. After combining with patients treated with adjuvant RT, no FFS benefit was found in the very low-risk and low-risk groups after adjuvant RT, whereas significantly improved FFS was found in the intermediate-risk and high-risk groups (P.05).The RPA classification revealed a subgroup of patients who could be potentially indicated for adjuvant RT even after gross total resection or for whom adjuvant RT could be deferred.

Purpose This study aimed to evaluate the role of postoperative radiotherapy (PORT) in intracranial solitary fibrous tumor/hemangiopericytoma (SFT/HPC).Materials and Methods A total of 133 patients with histologically confirmed HPC were included from eight institutions. Gross total resection (GTR) and subtotal resection (STR) were performed in 86 and 47 patients, respectively. PORT was performed in 85 patients (64%). The prognostic effects of sex, age, performance, World Health Organization (WHO) grade, location, size, Ki-67, surgical extent, and PORT on local control (LC), distant metastasis-free survival (DMFS), progression-free survival (PFS), and overall survival (OS) were estimated by univariate and multivariate analyses.Results The 10-year PFS, and OS rates were 45%, and 71%, respectively. The multivariate analysis suggested that PORT significantly improved LC (p < 0.001) and PFS (p < 0.001). The PFS benefit of PORT was maintained in the subgroup of GTR (p=0.001), WHO grade II (p=0.001), or STR (p < 0.001). In the favorable subgroup of GTR and WHO grade II, PORT was also significantly related to better PFS (p=0.028). WHO grade III was significantly associated with poor DMFS (p=0.029). In the PORT subgroup, the 0-0.5 cm margin of the target volume showed an inferior LC to a large margin with 1.0-2.0 cm (p=0.021). Time-dependent Cox proportion analysis showed that distant failures were significantly associated with poor OS (p=0.003).Conclusion This multicenter study supports the role of PORT in disease control of intracranial SFT/HPC, irrespective of the surgical extent and grade. For LC, PORT should enclose the tumor bed with sufficient margin.

Background This multinational study was conducted to report clinical presentations and treatment strategies in patients with intracranial germinomas across selected Asian centers, including failure patterns, risk factors, and outcomes. Methods A retrospective data collection and analysis of these patients, treated between 1995 and 2015 from eight healthcare institutions across four countries was undertaken. Results From the results, 418 patients were analyzed, with a median follow-up of 8.9 years; 79.9% of the patients were M0, and 87.6% had β-human chorionic gonadotropin values Conclusions Survival outcomes of patients with germinoma were excellent. Thus, the focus of treatment for intracranial germinoma should be on survivorship. Further studies are warranted to find the optimal intensity and volume of radiation, including the role of chemotherapy in the survival of patients with intracranial germinomas, considering age, primary tumor location, and extent of disease.

Purpose We aimed to refine the radiotherapy (RT) volume and dose for intracranial germinoma considering recurrences and long-term toxicities.Materials and Methods Total 189 patients with intracranial germinoma were treated with RT alone (n=50) and RT with upfront chemotherapy (CRT) (n=139). All cases were confirmed histologically. RT fields comprised the extended-field and involved-field only for primary site. The extended-field, including craniospinal, whole brain (WB), and whole ventricle (WV) for cranial field, is followed by involved-field boost. The median follow-up duration was 115 months.Results The relapses developed in 13 patients (6.9%). For the extended-field, cranial RT dose down to 18 Gy exhibited no cranial recurrence in 34 patients. In CRT, 74 patients (56.5%) showed complete response to chemotherapy and no involved-field recurrence with low-dose RT of 30 Gy. WV RT with chemotherapy for the basal ganglia or thalamus germinoma showed no recurrence. Secondary malignancy developed in 10 patients (5.3%) with a latency of 20 years (range, 4 to 26 years) and caused mortalities in six. WB or craniospinal field rather than WV or involved-field significantly increased the rate of hormone deficiencies, and secondary malignancy. RT dose for extended-field correlated significantly with the rate of hormone deficiencies, secondary malignancy, and neurocognitive dysfunction.Conclusion De-intensifying extended-field rather than involved-field or total scheme of RT will be critical to decrease the late toxicities. Upfront chemotherapy could be beneficial for the patients with complete response to minimize the RT dose down to 30 Gy. Prospective trials focused on de-intensification of the extended-field RT are warranted.

To assess treatment outcomes in patients with stage I/II extranodal NK-/Between 1992 and 2018, 76 patients with early-stage ENKTCL-NT who achieved CR or partial response (PR) after induction chemotherapy received adjuvant RT. RT doses (using biologically equivalent doses in 2 Gy fractions [EQD2]) and rates of local recurrence-free survival (LRFS), locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS), progression-free survival (PFS), and cancer-specific survival (CSS) were determined.Median follow-up was 5.1 years (range, 0.5-20.8). The median RT dose was 45 Gy (range, 20-54). The 5-year LRFS, LRRFS, DMFS, PFS, and CSS rates were 82.7 %, 78.2 %, 81.1 %, 68.7 %, and 84.4 %, respectively. CR after induction chemotherapy was notably linked to better survival outcomes across each endpoint. Survival outcomes were not affected either by the administration of l-ASP or EQD2 40 Gy in patients displaying CR after l-ASP. Adverse events (AEs) ≥ Grade 2 were significantly reduced with EQD2 40 Gy, compared with EQD2 ≥ 40 Gy.Achieving CR after chemotherapy was the most predictive factor of survival outcomes in early-stage ENKTCL-NT. Decreasing RT doses in patients with CR after l-ASP appeared to minimize the occurrence of AE without compromising LRR risk; however, longer follow-ups and cautious application are warranted.

PurposeWe aimed to compare the outcomes of adjuvant radiotherapy (ART) and surveillance in patients with grade 2 meningiomas (MNG2) who underwent surgical resection.Materials and MethodsData from four hospitals, in which patients aged ≥18 years underwent Simpson grade 1−4 surgical resection for newly diagnosed MNG2 between 1998 and 2018, were examined in this multicenter retrospective cohort study. Patients receiving ART with conventional fractionation were compared with those undergoing surveillance. Progression-free survival (PFS), progression/recurrence (P/R) were evaluated.ResultsThis study included 518 patients, 158 of whom received ART. The median follow-up duration was 64.9 months. In the total cohort, ART was independently associated with significantly improved PFS (HR, 0.35; 95% CI, 0.23–0.55; PConclusionsART significantly improved PFS and P/R in patients with MNG2, irrespective of the surgical extent, and can be recommended after gross total resection. A prognostic model may guide decision-making for the use of ART.

PurposeThis study was designed to investigate the incidence of interim disease progression (IPD) and volumetric changes of the surgical cavity (SC) during the surgery-to-radiotherapy interval (SRI), and eventually assess the value of magnetic resonance imaging (MRI) at the time of radiotherapy (RT) planning in newly diagnosed anaplastic gliomas.Materials and MethodsAmong 195 anaplastic glioma patients who underwent RT, 121 were evaluable with two separate MRIs during SRI. The presence of IPD was determined using the updated Response Assessment in Neuro-Oncology size criteria. In 84 patients who underwent surgical resection, each SC was contoured by a radiation oncologist and the volumetric changes of the SCs were calculated between the two separate MRIs. Daily rate of change in the SC volume was calculated assuming an exponential and linear change.ResultsFive of 121 patients (4.13%) demonstrated IPD during SRI, and the incidence was significantly higher in patients undergoing biopsy (vs. surgical resection, 12.9% vs. 1.1%, p=0.015) and in patients with remnant contrast-enhancing tumor after surgery (15.8 vs. 2.0%, p=0.027). The mean daily rate of absolute change in SC was 1.06% (95% confidence interval [CI], 0.89 to 1.23) and 0.89% (95% CI, 0.77 to 1.02) according to the exponential and linear model, respectively. The expected mean volumetric change at 2 weeks were 16.64% (95% CI, 13.77 to 19.52) and 12.51% (95% CI, 10.77 to 14.26), respectively.ConclusionIPD during the SRI is rare in surgically resected anaplastic gliomas. However, pre-RT MRI is essential for accurate RT-target delineation and disease evaluation for patients initiating RT beyond postoperative 2 weeks and undergoing biopsy, respectively.

Purpose This retrospective study compares higher-dose whole-brain radiotherapy (hdWBRT) with reduced-dose WBRT (rdWBRT) in terms of clinical efficacy and toxicity profile in patients treated for primary central nervous system lymphoma (PCNSL). Materials and methods Radiotherapy followed by high-dose methotrexate (HD-MTX)-based chemotherapy was administered to immunocompetent patients with histologically confirmed PCNSL between 2000 and 2016. Response to chemotherapy was taken into account when prescribing the radiation dose to the whole brain and primary tumor bed. The whole brain dose was ≤23.4 Gy for rdWBRT (n = 20) and >23.4 Gy for hdWBRT (n = 68). Patients manifesting cognitive disturbance, memory impairment and dysarthria were considered to have neurotoxicity. A median follow-up was 3.62 years. Results The 3-year overall survival (OS) and progression-free survival (PFS) were 70.0% and 48.9% with rdWBRT, and 63.2% and 43.2% with hdWBRT. The 3-year OS and PFS among patients with partial response (n = 45) after chemotherapy were 77.8% and 53.3% with rdWBRT, and 58.3% and 45.8% with hdWBRT (p > 0.05). Among patients with complete response achieved during follow-up, the 3-year freedom from neurotoxicity (FFNT) rate was 94.1% with rdWBRT and 62.4% with hdWBRT. Among patients aged ≥60 years, the 3-year FFNT rate was 87.5% with rdWBRT and 39.1% with hdWBRT (p = 0.49). Neurotoxicity was not observed after rdWBRT in patients aged below 60 years. Conclusion rdWBRT with tumor bed boost combined with upfront HD-MTX is less neurotoxic and results in effective survival as higher-dose radiotherapy even in partial response after chemotherapy.

Purpose This multicenter retrospective study aimed to investigate prognostic factors for survival, encompassing clinical and radiologic features and treatments, in newly diagnosed diffuse intrinsic pontine glioma (DIPG) patients treated with radiotherapy. Methods Patients

BACKGROUND To compare the outcomes between adjuvant radiotherapy (ART) and surveillance in patients with grade 2 intracranial meningiomas (MNG2s) after surgical resection.Materials and METHODS This multicenter study included 518 patients with newly diagnosed MNG2 who underwent resection between 1998–2018. Patients receiving ART with conventional fractionation (n = 158) were compared with those undergoing surveillance (n = 360). Progression-free survival (PFS) and progression/recurrence (P/R) rates were evaluated. Propensity score matching was performed to adjust for covariables (n = 43 in each group). RESULTS The median follow-up was 64.9 months. The median ART dose was 60 Gy in 30 fractions. Patients receiving ART had larger tumors (median, 5.0 vs. 4.5 cm, P < 0.001) and less frequent gross total resection (69.6% vs. 85.3%, P < 0.001). In multivariable analysis, ART was associated with significantly improved PFS (HR, 0.34; 95% CI, 0.22–0.53; P< 0.001) and P/R (HR, 0.29; 95% CI, 0.18–0.46; P< 0.001). In the propensity score matched cohort, the 5-year PFS rates were 80.8% vs 57.7% (P = 0.020) in the ART and surveillance group, respectively. Even in patients receiving gross total resection, the 5-year PFS (85.0% vs. 64.7%; HR, 0.50; 95% CI, 0.27–0.91; P = 0.023) and P/R rates (15.2% vs. 32.0%; HR, 0.50; 95% CI, 0.25–0.96; P = 0.038) were significantly improved by ART. Using recursive partitioning analysis in patients undergoing surveillance, we classified patients to low-, intermediate-, or high-risk of P/R based on surgical extent, tumor size, and Ki-67 index. The 5-year P/R rates in the low-, intermediate-, and high-risk groups were 18.6%, 37.9%, and 65.3%, respectively. CONCLUSION ART significantly improved PFS and P/R in MNG2s irrespective of surgical extent and should be recommended after both gross total and partial resection. A recursive partitioning analysis model for P/R may guide clinicians for decision making in resected MNG2s.

Purpose To assess the efficacy of upfront chemotherapy followed by response-adapted reduced-dose/reduced-volume radiotherapy (RT) for intracranial germinoma. Materials and methods Ninety-one patients from five institutions were registered in the KSPNO G051/G081 Protocol. Germinomas were classified as solitary or multiple/disseminated diseases, and upfront chemotherapy was administered. For all patients with multiple or disseminated disease, and patients with partial response after chemotherapy, 19.5–24 Gy of craniospinal irradiation plus 10.8–19.8 Gy of tumor bed boost were planned. For patients with complete response (CR), reduced-dose RT (30.6 Gy) was planned, along with a reduced field for solitary lesions. Results The median patient age was 14 (range, 3–30) years. Sixty-five patients (71.4%) had a solitary lesion. The median follow-up duration was 67.9 (range, 6.6–119.3) months. Recurrence was not observed in 32 patients in the protocol compliant group. Four patients (4.4%) in the protocol non-compliant group experienced relapse after CR and one patient died of the disease. The 5-year and 7-year overall survival rates were 98.8% and 98.8%, while the corresponding event-free survival rates were 96.6% and 93.8%, respectively. All three patients with basal ganglia germinomas who were treated with local RT experienced recurrence outside the RT field. Among the 23 patients with pineal or suprasellar lesions who received whole-ventricle RT, there was no recurrence. Conclusions Currently used upfront chemotherapy followed by reduced-dose, reduced-volume RT appears acceptable, when whole-ventricle RT for pineal or suprasellar tumors and, at minimum, whole-brain RT for basal ganglia/thalamus lesions are applied.

The aim of this study was to establish a test method with improved reliability and reproducibility for the accelerated weathering test of automotive interior materials. For this purpose, this study measured the spectral power distribution (SPD) of the glass used in actual vehicles in the oceanic climate region of South Korea (Seosan) and in the desert climate region of North America (California Proving Ground). In addition, the SPD was measured according to the position of automotive interior parts, and cumulative light intensity was calculated using the curve fitting method. Results showed that the measured light intensity varied according to the position of interior parts because of numerous variables such as the type of glass, angle of sunlight, and frames of vehicles. We investigated the cumulative light intensity of the solar glass used in this study and the glass of other manufacturers, and the obtained data were incorporated into a data base (DB). Understanding the optical characteristics of filters is important accelerated weathering tests (Xenon). Therefore, we compared the SPD and cumulative light intensity of each filter combination and actual automotive glass to confirm the suitability of the filters for weathering tests.

BACKGROUND/AIM Regional lymph node recurrence (RLNR) is the most common pattern of recurrence within 2 years from the diagnosis of patients with non-metastatic malignant cutaneous melanoma. However, isolated RLNR without distant metastasis has been rarely studied. PATIENTS AND METHODS Forty patients with isolated RLNR as a first recurrence were analyzed retrospectively. The clinical outcomes and prognostic impact of clinicopathologic parameters were analyzed. Immunostaining for FOXP3, VEGF, pAKT, and pS6 was also performed. RESULTS The median disease-free interval from first diagnosis to isolated RLNR and post-recurrence recurrence-free survival (pRFS) were 12 months and 7.2 months, respectively. Distant failure was the most common pattern of failure after isolated RLNR (67.5%). The number of initially harvested lymph nodes (LN) >7 and LN ratio >22.2% at the time of recurrence were prognosticators for pRFS in multivariate analysis. None of the tested biomarkers were significantly related to prognosis. The 5-year post-recurrence overall survival rate was 84.9%. CONCLUSION Most patients with isolated RLNR will experience a second failure within months, especially distantly. The number of initially harvested LNs and LN ratio at the time of recurrence could predict pRFS.

Lymphopenia in patients with glioblastoma (GBM) is related to treatment as well as disease progression. This retrospective study investigated the prevalence, influencing factors, recoverability, and clinical significance of lymphopenia in GBM patients treated with concomitant chemoradiotherapy (CCRT). A total of 219 patients with newly diagnosed GBM who had received at least 3 cycles of adjuvant temozolomide (TMZ) followed by CCRT with TMZ were enrolled. Serial data on complete blood cell counts, including differential cell counts, were collected just before a new phase and before every treatment cycle of the regimen. Relationships between white blood cell (WBC) variable changes and treatment modalities as well as survival were analyzed. Lymphopenia was classified using the definition of the Common Terminology Criteria for Adverse Events version 5.0. A total of 92 patients (42.0%) showed decreased levels of lymphocytes (

Despite recent innovation in treatment techniques and subsequently improved outcomes, the majority of glioblastoma (GBL) have relapses, especially in locoregional areas. Local re-irradiation (re-RT) has been established as a feasible option for recurrent GBL of all ages with safety, tolerability, and effectiveness both in survival and quality of life regardless of fractionation schedule. To keep adverse effects under acceptable range, cumulative dose limit in equivalent dose at 2 Gy fractions by the linear-quadratic model at α/β = 2 for normal brain tissue (EQD2) with narrow margin should be observed and single/hypofractionated re-RT should be undertaken very carefully to recurrent tumor with large volume or adjacent to the brainstem. Promising outcome of re-operation (re-Op) plus re-RT (re-Op/RT) need to be validated and result from re-RT with temozolomide/bevacizumab (TMZ/BV) or new strategy is expected. Development of new-concept prognostic scoring or risk group is required to select patients properly and make use of predictive biomarkers such as O(6)-methylguanine-DNA methyltransferase (MGMT) promotor methylation that influence outcomes of re-RT, re-Op/RT, or re-RT with TMZ/BV.

Purpose To identify prognostic factors influencing progression-free survival (PFS) of aggressive fibromatosis (AF) after postoperative radiotherapy (PORT) and assess correlations between immunohistochemistry (IHC) features of β-catenin/smooth muscle actin (SMA) and PFS. Materials and Methods Records of 37 patients with AF treated by PORT from 1984 to 2015 were retrospectively reviewed. Fifteen patients underwent wide excision for AF and 22 patients received debulking operation. The median total dose of PORT was 59.4 Gy. IHC staining results of β-catenin and SMA were available for 11 and 12 patients, respectively. Results The median follow-up duration was 105.9 months. Five-year PFS rate was 70.9%. Tumor size or margin status was not related to PFS in univariate analysis (p = 0.197 and p = 0.716, respectively). Multivariate analysis showed that increased interval from surgery to PORT (>5.7 weeks) was a marginal risk factor for PFS (p = 0.054). Administration of PORT at the initial diagnosis resulted in significantly improved PFS compared to deferring PORT after recurrence (p = 0.045). Patient with both risk factors of deferring PORT after recurrence and interval from surgery to PORT >5.7 weeks had significantly lower 5-year PFS than patients without risk factor (34.1% vs. 100.0%; p = 0.012). Nuclear β-catenin intensity tended to inversely correlate with 5-year PFS, although it did not reach statistical significance (62.5% at low vs. 100.0% at high; p = 0.260). SMA intensity was not related to PFS (p = 0.700). Conclusion PORT should be performed immediately after surgery irrespective of margin status or tumor size especially in recurrent case. Nuclear β-catenin staining intensity of IHC might correlate with local recurrence.

Background: Psammaplin A (PsA) is a radiosensitizer whereas its clinical application is hampered by poor bioavailability. This study aimed to synthesize novel radiosensitizers using PsA as the lead compound. Materials and Methods: Eight homodimeric disulfides were synthesized from corresponding acid and cystamine dihydrochloride in N-hydroxysuccinimide and dicyclohexylcarbodiimide coupling conditions. One monomeric thiol analog was obtained by reduction of homodimeric disulfide with dithiothreitol. Clonogenic assay was used to measure cell survival after irradiation and drug treatment in human lung cancer (A549) and glioblastoma (U373MG) cells. Results and Discussion: Using the PsA backbone, nine compounds were synthesized. Eight compounds showed variable cytotoxicity with 50% inhibitory concentrations ranging 16.14 μM to 150.10 μM (A549), and 13.25 μM to 50.15 μM (U373MG). Four and six compounds radiosensitized A549 and U373MG cells, respectively. Two compounds that radiosensitized both cell lines were tested for its inhibitory effects on DNMT1. One of them was shown to significantly inhibit DNMT1 activity. Conclusion: Novel compounds with radiosensitizing activity were synthesized. These compounds have a great potential to serve as a basis for the development of future radiosensitizers. Further investigation is warranted for their clinical application.

BACKGROUND/AIM Improvement of the efficacy of radiotherapy for lung cancer and glioblastoma is urgently needed. MATERIALS AND METHODS We synthesized several novel DNA methyltransferase inhibitors and evaluated their potentials as possible radiosensitizers. Eleven non-nucleoside compounds were synthesized and evaluated along with one known compound using human lung cancer (A549) and glioblastoma (U373MG) cells. Cytotoxicity and radiosensitizing effects were evaluated using clonogenic assay. Sensitizer enhancement ratios at a survival fraction of 0.5 were calculated, and statistical analysis was performed using the ratio paired t-test. The inhibitory effects of three selected compounds on the activity of DNA methyltransferase 1 (DNMT1) and the pharmacokinetic profiles were analyzed. RESULTS All twelve compounds demonstrated various levels of cytotoxicity. Of the twelve compounds, eleven and eight compounds radiosensitized A549 and U373MG cells, respectively, with at least marginal significance (p

The time-sequential change in immune-related gene expression of the glioblastoma cell line after irradiation was evaluated to speculate the effect of combined immunotherapy with radiotherapy. The U373 MG glioblastoma cell line was irradiated with 6 Gy single dose. Next-generation sequencing (NGS) transcriptome data was generated before irradiation (control), and at 6, 24, and 48 hours post-irradiation. Immune-related pathways were analyzed at each time period. The same analyses were also performed for A549 lung cancer and U87 MG glioblastoma cell lines. Western blotting confirmed the programmed death-ligand 1 (PD-L1) expression levels over time. In the U373 MG cell line, neutrophil-mediated immunity, type I interferon signaling, antigen cross-presentation to T cell, and interferon-γ signals began to increase significantly at 24 hours and were upregulated until 48 hours after irradiation. The results were similar to those of the A549 and U87 MG cell lines. Without T cell infiltration, PD-L1 did not increase even with upregulated interferon-γ signaling in cancer cells. In conclusions, In the glioblastoma cell line, immune-related signals were significantly upregulated at 24 hours after irradiation. Therefore, the time interval between daily radiotherapy might not be enough to expect full immune responses by combined immune checkpoint inhibitors and newly infiltrating immune cells after irradiation.

Background Central nervous system germ cell tumors (CNS GCTs) are a heterogeneous group of brain tumors, which are more common in Asian countries. There have been different therapeutic strategies in treating germinoma and non-germinomatous germ cell tumors (NGGCT), depending on prognosis. Moreover, long-term follow up should be emphasized due to higher late complication rates. Here, we investigated long-term outcomes and complication profiles of 127 CNS GCT patients who received uniform upfront chemotherapy. Methods We retrospectively evaluated outcomes of CNS GCT patients treated in Seoul National University Children’s Hospital from August 2004 to April 2019. Patients were classified as low risk (LR) or high risk (HR) based on pathologic diagnosis and tumor markers. Most patients received upfront systemic chemotherapy with carboplatin, cyclophosphamide, etoposide, and/or bleomycin, followed by either proton or photon radiation therapy according to patients’ choice. Results The median age at diagnosis was 11.9 (range, 3.8–25.1) years, and 54.3% of patients were LR. Photon and proton radiation therapy were administered to 73.2 and 25.2% of patients, respectively. In both LR and HR groups, there were no significant differences in survival between photon and proton radiation therapy. The 10-year relapse incidences were 9.3 and 5.6% in the LR and HR groups, respectively. All recurrences, except one, were local relapse. Six secondary malignancies occurred; the 10-year incidences of secondary malignancy were 2.2 and 7.6% in the LR and HR groups, respectively. The 10-year overall survival rates were 98.3 ± 1.7 and 91.8 ± 3.9% in the LR and HR groups, respectively. In a subgroup analysis of HR group, pathologically diagnosed NGGCT patients (n = 20) showed worse 10-year EFS (65.9 ± 11.9%, p p = 0.024) rates compared to other HR patients who were not pathologically diagnosed or were confirmed as germinoma with elevated tumor markers. All mortalities were related to disease progression or secondary malignancy. Conclusion The strategy of treating CNS GCTs with upfront chemotherapy according to risk groups resulted in good clinical outcomes and acceptable relapse incidence. However, further modification in the definition of the HR group is needed to reduce long-term complications.

Some patients with glioblastoma show a worsening presentation in imaging after concurrent chemoradiation, even when they receive gross total resection. Previously, we showed the feasibility of a machine learning model to predict pseudoprogression (PsPD) versus progressive disease (PD) in glioblastoma patients. The previous model was based on the dataset from two institutions (termed as the Seoul National University Hospital (SNUH) dataset, N = 78). To test this model in a larger dataset, we collected cases from multiple institutions that raised the problem of PsPD vs. PD diagnosis in clinics (Korean Radiation Oncology Group (KROG) dataset, N = 104). The dataset was composed of brain MR images and clinical information. We tested the previous model in the KROG dataset, however, that model showed limited performance. After hyperparameter optimization, we developed a deep learning model based on the whole dataset (N = 182). The 10-fold cross validation revealed that the micro-average area under the precision-recall curve (AUPRC) was 0.86. The calibration model was constructed to estimate the interpretable probability directly from the model output. After calibration, the final model offers clinical probability in a web-user interface.

The name of author Do Hoon Lim was incorrect in the initial online publication. The original article has been corrected.

To evaluate the impact of adjuvant postoperative radiotherapy (PORT) in adult WHO grade II-III intracranial ependymoma (IEPN).A total of 172 pathologically confirmed adult grade II-III IEPN patients from 12 institutions were eligible. Of them, 106 (61.6%) and 66 (38.4%) patients were grade II and III, respectively. For grade II and III IEPNs, 51 (48.1%) and 59 (89.4%) patients received PORT, respectively. The median dose to the primary tumor bed was 54.0 Gy and 59.4 Gy for grade II and III patients, respectively. The prognostic impact of sex, age, performance, WHO grade, location, size, surgical extent, and PORT on local control (LC), progression-free survival (PFS), and overall survival (OS) were evaluated by univariate and multivariate analysis.The median follow-up period for survivors was 88.1 months. The 5-/10-year LC, PFS, and OS rates were 64.8%/54.0%, 56.4%/44.8%, and 76.6%/71.0%, respectively. On multivariate analysis, adjuvant PORT significantly improved LC (P = 0.002), PFS (P = 0.002), and OS (P = 0.043). Older age (P 0.001), WHO grade III (P 0.001), larger tumor size (P = 0.004), and lesser surgical extent (P 0.001) were also negative factors for OS. Adjuvant PORT also improved LC (P = 0.010), PFS (P = 0.007), and OS (P = 0.069) on multivariate analysis for grade II IEPNs.This multicenter retrospective study supports the role of adjuvant PORT in terms of disease control and survival in adult grade II-III IEPNs. Prospective randomized trials focused on individualized treatment based on molecular subtypes is warranted.

The optimal radiotherapy regimen in elderly patients with glioblastoma treated by chemoradiation needs to be addressed. We provide the results of a comparison between conventionally fractionated standard radiotherapy (CRT) and short-course radiotherapy (SRT) in those patients treated by temozolomide-based chemoradiation.Patients aged 65 years or older from the GBM-molRPA cohort were included. Patients who were planned for a ≥ 6-week or ≤ 4-week radiotherapy were regarded as being treated by CRT or SRT, respectively. The median RT dose in the CRT and SRT group was 60 Gy in 30 fractions and 45 Gy in 15 fractions, respectively.A total of 260 and 134 patients aged older than 65 and 70 years were identified, respectively. CRT- and SRT-based chemoradiation was applied for 192 (73.8%) and 68 (26.2%) patients, respectively. Compared to SRT, CRT significantly improved MS from 13.2 to 17.6 months and 13.3 to 16.4 months in patients older than 65 years (P 0.001) and 70 years (P = 0.002), respectively. Statistical significance remained after adjusting for age, performance status, surgical extent, and MGMT promoter methylation in both age groups. The benefit was clear in all subgroup analyses for patients with Karnofsky performance score 70-100, Karnofsky performance score ≤ 60, gross total resection, biopsy, methylated MGMT promoter, and unmethylated MGMT promoter (all P 0.05).CRT significantly improved survival compared to SRT in elderly glioblastoma patients treated with chemoradiation in selected patients amenable for chemoradiation. This study is hypothesis-generating and a prospective randomized trial is urgently warranted.

Patient's CT images taken with metallic shields for radiotherapy suffer from artifacts. Furthermore, the treatment planning system (TPS) has a limitation on accurate dose calculations for high density materials. In this study, a Monte Carlo (MC)-based method was developed to accurately evaluate the dosimetric effect of the metallic shield. Two patients with a commercial tungsten shield of lens and two patients with a custom-made lead shield of lip were chosen to produce their non-metallic dummy shields using 3D scanner and printer. With these dummy shields, we generated artifact-free CT images. The maximum CT number allowed in TPS was assigned to metallic shields. MC simulations with real material information were carried out. In addition, clinically relevant dose-volumetric parameters were calculated for the comparison between MC and TPS. Relative dosimetry was performed using radiochromic films. The dose reductions below metallic structures were shown on MC dose distributions, but not evident on TPS dose distributions. The differences in dose-volumetric parameters of PTV between TPS and MC for eye shield cases were not clearly shown. However, the mean dose of lens from TPS and MC was different. The MC results were in superior agreement with measured data in relative dosimetry. The lens dose could be overestimated by TPS. The differences in dose-volumetric parameters of PTV between TPS and MC were generally larger in lip cases than in eye cases. The developed method is useful in predicting the realistic dose distributions around the organs blocked by the metallic shields.

Introduction A majority of high-grade gliomas relapse despite combined surgery, radiotherapy and chemotherapy. There is no consensus on standard treatment for recurrent high-grade gliomas, or defined efficacy of adjuvant re-RT after re-Op. This retrospective study evaluated the benefit and safety of re-RT after re-Op (re-Op/RT). Materials and methods A total of 84 patients with recurrent high-grade gliomas who underwent reoperation from 2009 to 2015 were analyzed. All patients received neurosurgical intervention and adjuvant radiotherapy previously before recurrence. At recurrence and after reoperation, treatment options were discussed in multidisciplinary clinic or brain tumor joint conference. For re-RT, cumulative EQD2 (equivalent dose in 2 Gy fractions at α/β = 2) was below 106.9 Gy. Result Median progression free survival (PFS) was 6.5 months; 3.5 months with re-Op, 9.0 months with re-Op/RT (p = 0.025). Age 50, WHO grade IV, and unmethylated promoter of MGMT) were significantly associated with poor OS in multivariate analysis. Benefit of re-RT in both OS and PFS was established in patients carrying 2 or more risk factors. During re-RT, 4 patients (8%) had grade 2 or higher toxicity, and 3 patients (6%) did not complete re-RT. No radionecrosis was observed. Conclusion Re-RT after re-Op was tolerable with a cumulative median EQD2 of 99.3 Gy and resulted in clear benefit in PFS and marginal gain in OS. Survival gain with re-Op/RT was more prominent in patients with two or more risk factors (age ≥50, WHO pathologic grade IV, unmethylated MGMT promoter), and needs to be validated.

Purpose To identify the clinical usefulness of serum M protein and to establish a rationale for regular follow-up with serum protein electrophoresis in solitary plasmacytoma. Materials and methods Sixty-nine patients with solitary plasmacytoma and solitary plasmacytoma with minimal marrow involvement according to the International Myeloma Working Group criteria were retrospectively reviewed. Results At a median follow-up of 6.2 years, 5-year local control (LC), 5-year multiple myeloma-free survival (MMFS), 5-year failure-free survival (FFS), and 5-year overall survival (OS) were 82.6%, 44.1%, 41.8%, and 85.1%, respectively. Among the patients whose initial serum M protein was present or not evaluated, 37.3% of patients showed disappearance of serum M protein after various treatment. MMFS of these patients were comparable to non-secretory plasmacytoma with undetectable levels of M protein, and significantly better than patients with persistent M protein. Increase of serum M protein ≥0.1 g/dL was most predictive of treatment failure with area under the curve of 0.731. Conclusion Patients who eventually showed persistence of serum M protein after treatment showed worse MMFS and FFS compared to those whose serum M protein disappeared or who had initially non-secretory disease. The increase of serum M protein level ≥0.1 g/dL from current nadir was predictive of treatment failure. Therefore, regular follow-up with serum M protein is highly recommended especially unless the patient had initially non-secretory disease.

We performed this study to identify the treatment patterns of patients with low-grade gliomas (LGG) in Korea. A total of 555 patients diagnosed as WHO grade II gliomas between 2000 and 2010 at 14 Korean institutions were included. The patients were divided into four adjuvant treatment groups: adjuvant fractionated radiotherapy (RT, N = 204), adjuvant chemotherapy (N = 20), adjuvant fractionated RT and chemotherapy (N = 65), and non-adjuvant treatment (N = 266) groups. We examined differences among the groups and validated patient/tumor characteristics associated with the adjuvant treatments. Astrocytoma was diagnosed in 210 patients (38%), oligoastrocytoma in 85 patients (15%), and oligodendroglioma in 260 patients (47%). Gross total resection was performed in 200 patients (36%), subtotal resection in 153 (28%), partial resection in 71 patients (13%), and biopsy in 131 patients (24%). RT was most commonly applied as an adjuvant treatment. The use of chemotherapy with or without RT decreased after 2008 (from 38 to 4%). The major chemotherapeutic regimen was procarbazine, lomustine, and vincristine (PCV); however, the proportion of temozolomide increased since 2005 (up to 69%). Patient/tumor characteristics related with RT were male gender, non-seizure, multiple lobes involvement, and non-gross total resection. Chemotherapy was associated with non-gross total resection and non-astrocytoma. A preference for RT and increased use of temozolomide was evident in the treatment pattern of LGG. The extent of resection was associated with a decision to perform RT and chemotherapy. To establish a robust guideline for LGG, further studies including molecular information are needed.

Dynamic contrast-enhanced (DCE) MR imaging pharmacokinetic parameters derived by using arterial input functions (AIFs) at dynamic susceptibility-contrast imaging showed better diagnostic performance and reliability for differentiating high-grade from low-grade astrocytoma than those derived by using AIFs at DCE MR imaging alone.

We retrospectively evaluated an efficacy of adjuvant radiotherapy (RT) in the intracranial hemangiopericytoma (HPC) and analyzed prognostic factors influencing treatment outcomes. Among 49 patients diagnosed as localized intracranial HPC between 1995 and 2016, 31 patients received adjuvant RT after surgery; 26 with fractionated RT and 5 with stereotactic radiosurgery using Gamma Knife. After gross total resection (GTR) (n = 32) and subtotal resection (STR) (n = 17), histopathological grade was confirmed to be grade II (n = 9) or grade III (n = 40). The median follow-up period was 50 months (range 3–216 months). The local recurrence was defined as intracranial relapse within 15 mm and regional recurrence as beyond 15 mm from the margin of surgical bed. The 10-year overall survival (OS) and progression-free survival (PFS) were 69.9 and 34.4%, respectively. The 10-year local, regional, and distant failure-free rates were 56.6, 88.2, and 73.3%, respectively. Local tumor control was better with GTR followed by RT than GTR alone (p = 0.056), while there was no difference in OS. Local tumor control and OS after STR plus RT were equivalent to those after GTR alone. There were no differences in distant metastasis-free survival (DMFS) among GTR plus RT, GTR alone, and STR plus RT. Tumor volume > 40 cm3 was associated with poor PFS (p = 0.024). The local tumor recurrence was reduced by adjuvant RT after surgery. But OS or DMFS was not improved with adjuvant RT. PFS was better in the tumor with small volume at diagnosis.

Intracranial ependymomas are rare tumors in adults. Although recent advancements from demographic, clinical, and biological studies provide new perspectives on this rare tumor, they are not yet widely applied in clinical practice. Currently, most ependymoma patients are treated in the same way: via surgical resection with adjuvant radiation therapy. However, it is reasonable to apply more aggressive treatment for high-risk patients. From this point of view, we performed a study to investigate risk grouping for disease progression of intracranial ependymomas in adults. A total of 53 patients were included in this study. Data were extracted for patient and tumor characteristics, extent of resection, progression-free survival (PFS), and overall survival. Prognostic variables from univariate and multivariate survival analyses were included in a recursive partitioning analysis for the hierarchical risk grouping of the estimated PFS. Three risk groups were defined based on the clinical prognostic factors. Survival analysis showed significant differences in mean PFS between the different groups: 160.5±22.1months in the complete resection group, 100.4±36.8months in the incomplete-resection and intraventricular-location group, and 23.5±6.9months in the incomplete-resection and extraventricular-location group (p0.001). The risk of disease progression in adult intracranial ependymoma patients could be stratified by degree of resection and tumor location. In clinical practice, this result could provide useful information, such as when "second-look" surgery should be performed or whether small tumors invading the fourth ventricle floor should be resected at the expense of neurological deficit.

We aimed to evaluate the association between autoimmune disease (AID) and lymphoma incidence in the Korean population. We also aimed to compare the overall survival (OS) in patients with AID-associated lymphoma (AAL) with that in patients with lymphoma without AID.We used National Sample Cohort 2002-2015 provided by National Health Insurance Service. Among 1,011,638 patients, 994,496 were recruited for the final cohort: 130,987 patients (13.2%) in the AID group and 863,509 (86.8%) in control. Lymphoma was diagnosed in 1162 patients and 322 patients with accompanying AID, irrespective of the time point of diagnosis, were defined as AAL. Of those, patients who experienced lymphoma development at least one year after AID diagnosis were defined as post-AID lymphoma (N = 155).The median follow-up duration was 13.7 years. AAL accounted for 0.03% of total and 27.7% of lymphoma cases. AID patients experienced more Epstein-Barr virus (0.02 vs. 0.01%, P = 0.027) or Helicobacter pylori infection (63.9 vs. 41.4%, P 0.001) than the control group did. AID was associated with a 1.45-fold increased risk of lymphoma. The median time interval from AID to AAL was 10.9 months. The risk of lymphoma increased in the order of: psoriasis (adjusted odds ratio [AOR] 1.61), systemic lupus erythematosus (AOR 3.99), multiple sclerosis (AOR 4.52), and sarcoidosis (AOR 26.37). Sjogren syndrome was not related to lymphoma in this cohort. The 5-year OS in AAL was not different from that in lymphoma patients without AID (60.9 vs. 61.5%, P = 0.970).The association patterns in AAL in Korean population were different from those of Western countries. Further studies on lymphomatogenesis from distinct baseline characteristics (e.g. chronic infection status) would elucidate the difference based on race and ethnicity.

We analyzed patterns of care and outcomes for patients with primary central nervous system lymphoma (PCNSL) in this multi-institutional retrospective study. Between January 2000 and December 2011, 220 patients with PCNSL received radiotherapy (RT). Among these patients, 26 patients received RT alone; 179 patients were treated with chemotherapy and radiotherapy; the rest of the patients (N = 15) initially underwent chemotherapy alone, then received RT as a salvage treatment. Most of the patients (N = 188) received methotrexate-based chemotherapy. The median follow up duration was 38 months (range 3-179 months). The median RT dose and whole brain RT (WBRT) dose were 45.0 Gy (range 20.0-59.4) and 30.6 Gy (range 18.0-45.0), respectively. Seventy-seven (35%) patients received WBRT alone, and 143 patients (65%) underwent WBRT plus boost RT. Total RT dose and WBRT dose decreased during the study period. The median survival was 64 months and actuarial 5-year overall survival was 51.4%. In multivariate analysis, age (P

Radiation necrosis (RN) in brain tumor patients is often symptomatic, persistent without immediate resolution, and confused with tumor recurrence. Cerebral vascular pericytes are essential for endothelial function, vascular integrity, and angiogenesis. In this study, we showed that the loss of pericytes is involved in the pathogenesis of RN. From a brain tumor tissue repository, we identified three patients since 2011 with pathologically confirmed RN after the standard treatment for glioblastoma (GBM). The RN and their preradiation GBM tissues were serially processed for Western blotting using cell-type-specific antibodies against endothelial (CD31, active RhoA), pericyte [platelet-derived growth factor receptor-beta (PDGFR-β)], alpha-smooth muscle actin (α-SMA), astrocyte (GFAP), myelin sheath protein (MBP), and microglial markers (Iba1). Normal brain tissues from a brain bank were used as normal controls. The expressions of PDGFR-β and α-SMA were remarkably reduced in the RN, compared to those of GBM. However, the levels of CD31 or RhoA were not different between the two groups, which suggest that there was no change in the number of endothelial cells or their cytoskeletal assembly. The RN tissues showed a decreased ratio of pericyte/endothelial markers and an increased level of Iba1 compared to the GBM and even to the normal brain. The levels of GFAP and MBP were not changed in the RN. In the histopathology, the RN tissues showed a loss of markers (PDGFR-β), whereas the GBM tissues had abundant expression of the markers. The loss of pericytes and vascular smooth muscle cells, and the unsupported endothelial cells might be the cause of the leaky blood-brain barrier and tissue necrosis.

To analyze the treatment outcomes and the effects of adjuvant radiotherapy (RT) in patients with synovial sarcoma (SS). The medical records of 103 patients treated with definitive surgery for SS, with/without RT, from August 1982 to July 2013 were reviewed retrospectively. The median age of the patients was 33 years (range, 5 to 72 y). The most frequent tumor location was the extremities (79 patients, 77%). Seventy-five patients (73%) received adjuvant RT and 26 (25%) did not. The median dose of adjuvant RT was 61.2 Gy (range, 45 to 66.6 Gy). The median follow-up period was 5.4 years (range, 0.2 to 31.0 y). The 5- and 10-year overall survival rates were 77 % and 65%, respectively. The progression-free survival (PFS) rates at 5 and 10 years were 52% and 43%, respectively. The most common site of initial failure was the lung (24 patients), followed by local recurrence (14 patients). The 5-year local-recurrence-free survival (LRFS) and distant-metastasis-free survival (DMFS) rates were 80% and 63%, respectively. On multivariate analysis, a mitosis count of

Although craniospinal irradiation (CSI) of 2340 cGy plus tumor booster with chemotherapy have been established as a standard treatment of childhood average-risk (AvR) medulloblastoma (MBL) in Western counties, there are a few recent reports in outcomes of AvR MBL using this strategy in Korean and other Asian children. We investigated the outcome of the Korean children with AvR MBL who were treated with CSI

Purpose Homeobox (HOX) genes are essential developmental regulators that should normally be in the silenced state in an adult brain. The aberrant expression of HOX genes has been associated with the prognosis of many cancer types, including glioblastoma (GBM). This study examined the identity and role of HOX genes affecting GBM prognosis and treatment resistance. Materials and methods The full series of HOX genes of five pairs of initial and recurrent human GBM samples were screened by microarray analysis to determine the most plausible candidate responsible for GBM prognosis. Another 20 newly diagnosed GBM samples were used for prognostic validation. In vitro experiments were performed to confirm the role of HOX in treatment resistance. Mediators involved in HOX gene regulation were searched using differentially expressed gene analysis, gene set enrichment tests, and network analysis. Results The underexpression of HOXA11 was identified as a consistent signature for a poor prognosis among the HOX genes. The overall survival of the GBM patients indicated a significantly favorable prognosis in patients with high HOXA11 expression (31±15.3 months) compared to the prognoses in thosewith low HOXA11 expression (18±7.3 months, p=0.03). When HOXA11 was suppressed in the GBM cell lines, the anticancer effect of radiotherapy and/or temozolomide declined. In addition, five candidate mediators (TGFBR2, CRIM1, TXNIP, DPYSL2, and CRMP1) that may confer an oncologic effect after HOXA11 suppression were identified. Conclusion The treatment resistance induced by the underexpression of HOXA11 can contribute to a poor prognosis in GBM. Further investigation will be needed to confirm the value of HOXA11 as a potential target for overcoming the treatment resistance by developing chemo- or radiosensitizers.

Purpose Bevacizumab±irinotecan is effective for treatment of recurrent malignant gliomas. However, the optimal duration of treatment has not been established. Materials and methods Ninety-four consecutive patients with recurrent malignant glioma who were treated with bevacizumab at our institutions were identified. Patients who continued bevacizumab until tumor progression were enrolled in a late discontinuation (LD) group, while those who stopped bevacizumab before tumor progression were enrolled in an early discontinuation (ED) group. Landmark analyses were performed at weeks 9, 18, and 26 for comparison of patient survival between the two groups. Results Among 89 assessable patients, 62 (69.7%) and 27 (30.3%) patients were categorized as the LD and ED groups, respectively. According to landmark analysis, survival times from weeks 9, 18, and 26 were not significantly different between the two groups in the overall population. However, the LD group showed a trend toward increased survival compared to the ED group among responders. In the ED group, the median time from discontinuation to disease progression was 11.4 weeks, and none of the patients showed a definite rebound phenomenon. Similar median survival times after disease progression were observed between groups (14.4 weeks vs. 15.7 weeks, p=0.251). Of 83 patients, 38 (45.8%) received further therapy at progression, and those who received further therapy showed longer survival in both the LD and ED groups. Conclusion In recurrent malignant glioma, duration of bevacizumab was not associated with survival time in the overall population. However, ED of bevacizumab in responding patients might be associated with decreased survival.