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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.

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.