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Purpose: The target delineation of whole ventricle radiotherapy (WVRT) in germinoma varies among radiation oncologists, especially regarding the inclusion of the prepontine cistern (PC). We evaluated the outcome of PC-sparing WVRT in localized germinoma. Materials and Methods: We identified 87 localized intracranial germinoma patients who received radiotherapy (RT) following chemotherapy between 1999 and 2020. By institutional policy, RT for localized germinoma excluded PC from the target volume. WVRT was delivered to 65 patients (74.7%) and involved field radiotherapy (IFRT) to 22 patients (25.3%). The median dose was 45.0 Gy (range, 23.4 to 55.8 Gy) for the primary tumor and 19.8 Gy (rangem 14.4 to 36.0 Gy) for the whole ventricle. We analyzed the dosimetric differences of the organs at risk between the PC-excluding plans and the PC-including ones. Results: The median follow-up duration was 7.8 years (range, 1.0 to 22.5 years). The 10-year recurrence-free survival and overall survival rates were 86.3% and 90.9%, respectively. The recurrences occurred in eight patients (8.7%), including five patients after IFRT and three after WVRT. Five of them showed recurrences at lateral ventricles and only one patient experienced spinal cord relapse. However, no relapse in the PC occurred. Endoscopic third ventriculostomy was not a significant prognostic factor. The dosimetric comparisons showed significantly lower mean doses to the brainstem and the cochleae when the PC was excluded. Conclusion: WVRT for localized germinoma can safely exclude the PC in the target volume, reducing radiation dose to the brain stem. The target protocol needs to reach a consensus regarding the PC in prospective trials.

Background The benefit of regular follow-up after curative resection for gastric cancer is controversial as there is no evidence that it will improve survival. This study assessed whether regular follow-up leads to improved survival in patients after surgery for gastric cancer. Methods A secondary analysis was undertaken of patients who participated in an RCT of laparoscopic versus open distal gastrectomy for advanced gastric cancer between November 2011 and April 2015. Depending on whether patients were compliant with the initial trial follow-up protocol or not, they were analysed as having had either regular or irregular follow-up. Clinicopathological characteristics, recurrence patterns, detection, treatments, and survival were compared between the groups. Results The regular and irregular follow-up groups comprised 712 and 263 patients respectively. Disease recurrence within 36 months was more common in the regular group than in the irregular group (17.0 versus 11.4 per cent; P = 0.041). Recurrence patterns did not differ between the groups. The 3-year recurrence-free survival rate was worse in the regular than in the irregular group (81.2 versus 86.5 per cent; P = 0.031). However, the 5-year overall survival rate was comparable (84.5 versus 87.5 per cent respectively; P = 0.160). Multivariable analysis revealed that type of follow-up was not an independent factor affecting 5-year overall survival. Conclusion Regular follow-up after radical gastrectomy was not associated with improved overall survival.

Purpose: This study aimed to identify the radiation dose–response relationship in patients with newly diagnosed atypical meningioma (AM) treated with adjuvant radiotherapy (ART) using conventional fractionation. Methods: In total, 158 patients who underwent surgery and ART between 1998 and 2018 were reviewed. Among these patients, 135 with complete information on radiotherapy (RT) dose/fractionation and pathological reports were analyzed. We entered RT dose as a continuous variable into the Cox regression model using penalized spline to allow for a nonlinear relationship between RT dose and events. Local control (LC), progression-free survival (PFS), and overall survival (OS) were evaluated. The corresponding biological equivalent dose in 2 Gy fractions (EQD2) was calculated using an α/β ratio of 4 Gy. Results: The median follow-up duration was 56.0 months. The median ART dose delivered was 61.2 Gy in 24–34 daily fractions, corresponding to a median EQD2 of 59.16 Gy. In multivariate analysis, larger size and higher mitotic count significantly reduced LC (P < 0.001 and P = 0.002, respectively), PFS (P < 0.001 and P = 0.006, respectively), and OS (P = 0.006 and P = 0.001, respectively). Meanwhile, a higher RT dose was significantly associated with improved LC, PFS, and OS. Moreover, RT showed a dose-dependent effect on LC, PFS, and OS; local failure, tumor progression, and death were reduced by 12%, 12%, and 16%, respectively, per 1 Gy increase in the dose (EQD2). Conclusion: The dose of ART in AM has a dose–response relationship with LC and survival outcomes.

Post-operative weight loss in patients with gastric cancer lead to a poor quality of life and long-term survival. This study aims to evaluate the effects of gut regulatory hormones on post-operative weight loss in patients with subtotal gastrectomy for gastric cancer.This prospective study was conducted for 12 months post-surgery in 14 controls and 13 gastrectomy patients who underwent subtotal gastrectomy for gastric cancer. Serum plasma ghrelin, glucagon-like peptide-1, gastric inhibitory peptide-1, peptide YY, insulin, and homeostatic model assessment for insulin resistance responses to a standardized test meal were recorded at multiple time points before and after gastrectomy at 4 and 12 months.The mean weight difference between the pre-operative state and the 4-month period was significantly reduced to 6.6 kg (Significant weight reduction was common after subtotal gastrectomy for gastric cancer with a negative correlation pre-operative plasma ghrelin levels. Incretin hormones are modestly but significantly increased after subtotal gastrectomy; however, these changes did not affect the weight changes.

Using trifluoroacetyl sulfuric acid (TFAOSO

Purpose: The purpose of this study was to evaluate the treatment outcomes and toxicity profile of patients with early glottic cancer who underwent hypofractionated radiation therapy (RT) with 3.5 Gy per fraction.Materials and Methods: A retrospective review was performed of the medical records of 35 patients with early stage (T1-2N0M0) glottic cancer who underwent definitive RT. The dose fractionation scheme was 59.5 Gy in 17 fractions. Posterior commissure was excluded from the clinical target volume (CTV) for 26 patients (74.3%) without glottic lesions close to this region. Results: With a median follow-up of 16.23 months (range, 6.82 to 67.15 months), no local, regional, or distant recurrence was reported. Acute hoarseness (65.7%), mucositis (68.6%), radiation dermatitis (60.0%) was frequent. One patient (2.9%) reported grade 3 acute toxicity (mucositis) and there was no grade 4–5 acute toxicity. There was no grade ≥3 late toxicities; however, grade 1 late intermittent hoarseness was frequent (45.7%). The receiver operative characteristic analysis revealed that mean hypopharyngeal dose was predictive for acute grade ≥2 mucositis (area under the curve=0.9314; 95% confidence interval, 0.8524–1). The optimal threshold of mean hypopharyngeal dose for occurrence of acute grade ≥2 mucositis was 26.31 Gy, with a specificity and sensitivity of 83.3% and 88.2%, respectively.Conclusion: Hypofractionated RT with fraction size of 3.5 Gy for early glottic cancer is effective. The hypopharyngeal mean dose could predict the occurrence of grade ≥2 acute mucositis. The posterior commissure can be safely excluded from the CTV.

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.

To evaluate the efficacy and safety of reducing target volume in definitive radiotherapy for HPV-associated tonsil cancer.A single-institution cohort of 90 patients with human papillomavirus (HPV)-associated tonsil cancer who received definitive radiotherapy with a 5-mm expansion from the gross tumor volume to clinical target volume between 2008 and 2019 were included. The overlapping volume of initial planning target volume and the recurrent tumor was calculated and categorized as one of three failure types: in-field: ≥95%; marginal-field: 50%-94%; and out-field:50%.With a median follow-up of 59.4 months, the 3-year and 5-year local control rates were 94.4% and 92.8%, respectively. A total of seven local failures were identified, of which 4 (4.4%) were in-field, 2 (2.2%) were marginal-field, and 1 (1.1%) was out-field. Grade 3 acute and late toxicities developed in 30 (33.3%) and 5 (5.6%) patients, respectively.Reducing target volume could be an alternative option for selected patients with HPV-associated tonsil cancer.

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.

In an effort to combat air pollutants, we developed a new strategy to convert the greenhouse gas methane and toxic sulfur dioxide into value-added liquid methanesulfonic acid in high yield with the use of molecular oxygen under mild conditions.

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.

Gait analysis has been studied for a long time and applied to fields such as security, sport, and medicine. In particular, clinical gait analysis has played a significant role in improving the quality of healthcare. With the growth of machine learning technology in recent years, deep learning-based approaches to gait analysis have become popular. However, a large number of samples are required for training models when using deep learning, where the amount of available gait-related data may be limited for several reasons. This paper discusses certain techniques that can be applied to enable the use of deep learning for gait analysis in case of limited availability of data. Recent studies on the clinical applications of deep learning for gait analysis are also reviewed, and the compatibility between these applications and sensing modalities is determined. This article also provides a broad overview of publicly available gait databases for different sensing modalities.

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.

Purpose The aim of this study was to show that bariatric surgery (BS) is more effective than medical therapy (MT) in Asian obese patients. Methods In this prospective, multicenter, nonrandomized, controlled trial, obese patients with body mass index of ≥35 kg/m2 or 30.0–34.9 kg/m2 with obesity-related comorbidities were assigned to undergo BS, such as laparoscopic sleeve gastrectomy and Roux-en-Y gastric bypass, or MT. Patients who underwent BS were evaluated 4, 12, 24, and 48 weeks after surgery, whereas patients who received MT were monitored at a hospital every 6 weeks for 1 year. At each visit, weight, waist and hip circumference, and blood pressure were measured, and patients underwent physical examination and laboratory testing. Health-related quality of life (HQOL) was investigated using Euro QOL-5 Dimension, Impact of Weight on Quality of Life questionnaire-Lite and Obesity-related Problems scale. Results The study included 264 patients from 13 institutions; of these, 64 underwent BS and 200 received MT. Of the patients who underwent BS, 6.3% experienced early complications. Relative weight changes from baseline to 48 weeks were significantly greater in the BS than in the MT group (26.9% vs. 2.1%, P < 0.001), as were the rates of remission of diabetes (47.8% vs. 16.7%, P = 0.014), hypertension (60.0% vs. 26.1%, P < 0.001), and dyslipidemia (63.2% vs. 22.0%, P < 0.001). HQOL was better in the BS than in the MT group at 48 weeks. Conclusion BS was safe and effective in Korean obese patients, with greater weight reduction, remission of comorbidities, and quality of life improvement than MT.

Exogenous epidermal growth factor (EGF) causes apoptosis in EGF receptor (EGFR)-overexpressing cell lines. The apoptosis-inducing factors could be a therapeutic target. We aimed to determine the mechanism of EGF-induced apoptosis using a genome-wide clustered regularly interspaced short palindromic repeat (CRISPR)-based knockout screen.Two-vector system of the human genome-scale CRISPR knockout library v2 was used to target 19,050 genes using 123,411 single guide RNAs (sgRNAs). Recombinant human EGF (100 nM) or distilled water four times was administered to the experimental and control groups, respectively. The read counts of each sgRNA obtained from next-generation sequencing were analyzed using the edgeR algorithm. We used another EGFR-overexpressing cell line (A549) and short hairpin RNAs (shRNAs) targeting five EGF-resistance genes for validation. DUSP1 expression in A431, A549, and HEK293FT cells was calculated using reverse transcription-quantitative polymerase chain reaction.We found 77 enriched and 189 depleted genes in the experimental group using the CRISPR-based knockout screen and identified the top five EGF-resistance genes: DDX20, LHFP, REPS1, DUSP1, and KRTAP10-12. Transfecting shRNAs targeting these genes into A549 cells significantly increased the surviving fractions after EGF treatment, compared with those observed in the control shRNA-transfected cells. The expression ratio of DUSP1 (inhibits ERK signaling) increased in A431 and A549 cells after EGF treatment. However, DUSP1 expression remained unchanged in HEK293FT cells after EGF treatment.The CRISPR-based knockout screen revealed 266 genes possibly responsible for EGF-induced apoptosis. DUSP1 might be a critical component of EGF-induced apoptosis and a novel target for EGFR-overexpressing cancers.

OBJECTIVE To develop a radiomics risk score based on dynamic contrast-enhanced (DCE) MRI for prognosis prediction in patients with glioblastoma. MATERIALS AND METHODS One hundred and fifty patients (92 male [61.3%]; mean age ± standard deviation, 60.5 ± 13.5 years) with glioblastoma who underwent preoperative MRI were enrolled in the study. Six hundred and forty-two radiomic features were extracted from volume transfer constant (Ktrans), fractional volume of vascular plasma space (Vp), and fractional volume of extravascular extracellular space (Ve) maps of DCE MRI, wherein the regions of interest were based on both T1-weighted contrast-enhancing areas and non-enhancing T2 hyperintense areas. Using feature selection algorithms, salient radiomic features were selected from the 642 features. Next, a radiomics risk score was developed using a weighted combination of the selected features in the discovery set (n = 105); the risk score was validated in the validation set (n = 45) by investigating the difference in prognosis between the "radiomics risk score" groups. Finally, multivariable Cox regression analysis for progression-free survival was performed using the radiomics risk score and clinical variables as covariates. RESULTS 16 radiomic features obtained from non-enhancing T2 hyperintense areas were selected among the 642 features identified. The radiomics risk score was used to stratify high- and low-risk groups in both the discovery and validation sets (both p < 0.001 by the log-rank test). The radiomics risk score and presence of isocitrate dehydrogenase (IDH) mutation showed independent associations with progression-free survival in opposite directions (hazard ratio, 3.56; p = 0.004 and hazard ratio, 0.34; p = 0.022, respectively). CONCLUSION We developed and validated the "radiomics risk score" from the features of DCE MRI based on non-enhancing T2 hyperintense areas for risk stratification of patients with glioblastoma. It was associated with progression-free survival independently of IDH mutation status.

This study aimed to evaluate whether arterial input functions (AIFs) obtained from dynamic susceptibility contrast (DSC)–MRI (AIFDSC) improve the reliability and diagnostic accuracy of dynamic contrast–enhanced (DCE)–derived pharmacokinetic (PK) parameters for differentiating glioblastoma from primary CNS lymphoma (PCNSL) compared with AIFs derived from DCE-MRI (AIFDCE). This retrospective study included 172 patients with glioblastoma (n = 147) and PCNSL (n = 25). All patients had undergone preoperative DSC- and DCE-MRI. The volume transfer constant (Ktrans), volume of the vascular plasma space (vp), and volume of the extravascular extracellular space (ve) were acquired using AIFDSC and AIFDCE. The relative cerebral blood volume (rCBV) was obtained from DSC-MRI. Intraclass correlation coefficients (ICC) and ROC curves were used to assess the reliability and diagnostic accuracy of individual parameters. The mean Ktrans, vp, and ve values revealed better ICCs with AIFDSC than with AIFDCE (Ktrans, 0.911 vs 0.355; vp, 0.766 vs 0.503; ve, 0.758 vs 0.657, respectively). For differentiating all glioblastomas from PCNSL, the mean rCBV (AUC = 0.856) was more accurate than the AIFDSC-driven mean Ktrans, which had the largest AUC (0.711) among the DCE-derived parameters (p = 0.02). However, for glioblastomas with low rCBV (≤ 75th percentile of PCNSL; n = 30), the AIFDSC-driven mean Ktrans and vp were more accurate than rCBV (AUC: Ktrans, 0.807 vs rCBV, 0.515, p = 0.004; vp, 0.715 vs rCBV, p = 0.045). DCE-derived PK parameters using the AIFDSC showed improved reliability and diagnostic accuracy for differentiating glioblastoma with low rCBV from PCNSL. • An accurate differential diagnosis of glioblastoma and PCNSL is crucial because of different therapeutic strategies. • In contrast to the rCBV from DSC-MRI, another perfusion imaging technique, the DCE parameters for the differential diagnosis have been limited because of the low reliability of AIFs from DCE-MRI. • When we analyzed DCE-MRI data using AIFs from DSC-MRI (AIFDSC), AIFDSC-driven DCE parameters showed improved reliability and better diagnostic accuracy than rCBV for differentiating glioblastoma with low rCBV from PCNSL.

R-peakdetection and heartbeat recognition methods are important techniques used to diagnose cardiac diseases. We introduce novel approaches for R-peak detection and heartbeat recognition based on the local binary pattern (1DLBP). The proposed R-peak detection method is based on the modified 1DLBP with an adaptive threshold (1DLBPAT). In addition, the heartbeat recognition method using empirical mode decomposition and the 1DLBP method with SVM-recursive feature elimination (SVM-RFE) are presented. Public databases such as MIT-BIH arrhythmia database (MITDB) and the QT database (QTDB) were used to evaluate the proposed method, and we validated the heartbeat recognition approach from five heartbeat classes: normal or bundle branch block; supraventricular ectopic; ventricular ectopic; fusion of ventricular and normal; and unknown beat. During R-peak detection, significant performance was observed when the proposed 1DLBPAT method was validated using the MITDB (sensitivity [SEN]: 99.83%; positive predictivity [+P]: 99.92%; false-positive rate [FPR]: 0.25%) and QTDB (SEN: 99.99%; +P: 99.98%; FPR: 0.03%). The heartbeat recognition method using intrinsic mode function 3 and 32 feature dimensions of the SVM-RFE showed robust performance (SEN: 92.5%; +P: 73.9%; accuracy: 98.2%). Our study demonstrated the crucial function and reliable performance of ECG processing, which can be used to diagnosis cardiac disease and information accurately.

PurposeThe treatment outcomes and genomic profiles of diffuse midline glioma (DMG) in adult patients are rarely characterized. We performed a retrospective study to evaluate the clinicogenomic profiles of adult patients with brain DMG.Materials and MethodsPatients aged ≥ 18 years diagnosed with brain DMG at Seoul National University Hospital were included. The clinicopathological parameters, treatment outcomes, survival, and genomic profiles using 82-gene targeted next-generation sequencing (NGS) were analyzed. The 6-month progression-free survival (PFS6) after radiotherapy and overall survival (OS) were evaluated.ResultsThirty-three patients with H3-mutant brain DMG were identified. The median OS from diagnosis was 21.8 months (95% confidence interval [CI], 13.2 to not available [NA]) and involvement of the ponto-medullary area tended to have poor OS (median OS, 20.4 months [95% CI, 9.3 to NA] vs. 43.6 months [95% CI, 18.2 to NA]; p=0.07). Twenty-four patients (72.7%) received radiotherapy with or without temozolomide. The PFS6 rate was 83.3% (n=20). Patients without progression at 6 months showed significantly prolonged OS compared with those with progression at 6 months (median OS, 24.9 months [95% CI, 20.4 to NA] vs. 10.8 months [95% CI, 4.0 to NA]; p=0.02, respectively). Targeted NGS was performed in 13 patients with DMG, among whom nine (69.2%) harbored concurrent TP53 mutation. Two patients (DMG14 and DMG23) with PIK3CAR38S+E545K and KRASG12A mutations received matched therapies. Patient DMG14 received sirolimus with a PFS of 8.4 months.ConclusionPFS6 after radiotherapy was associated with prolonged survival in adult patients with DMG. Genome-based matched therapy may be an encouraging approach for progressive adult patients with DMG.

Bacterial cytochrome P450 (CYP) enzymes are responsible for the hydroxylation of diverse endogenous substances with a heme molecule used as a cofactor. This study characterized two CYP154C3 proteins from Streptomyces sp. W2061 (CYP154C3-1) and Streptomyces sp. KCCM40643 (CYP154C3-2). The enzymatic activity assays of both CYPs conducted using heterologous redox partners' putidaredoxin and putidaredoxin reductase showed substrate flexibility with different steroids and exhibited interesting product formation patterns. The enzymatic characterization revealed good activity over a pH range of 7.0 to 7.8 and the optimal temperature range for activity was 30 to 37°C. The major product was the C16-hydroxylated product and the kinetic profiles and patterns of the generated hydroxylated products differed between the two enzymes. Both enzymes showed a higher affinity toward progesterone, with CYP154C3-1 demonstrating slightly higher activity than CYP154C3-2 for most of the substrates. Oxidizing agents (diacetoxyiodo) benzene (PIDA) and hydrogen peroxide (H2O2) were also utilized to actively support the redox reactions, with optimum conversion achieved at concentrations of 3 mM and 65 mM, respectively. The oxidizing agents affected the product distribution, influencing the type and selectivity of the CYP-catalyzed reaction. Additionally, CYP154C3s also catalyzed the C-C bond cleavage of steroids. Therefore, CYP154C3s may be a good candidate for the production of modified steroids for various biological uses.

IntroductionThe dosimetric factors of radiotherapy have an acute impact on the host immune system during chemoradiotherapy (CRT) in locally advanced non-small cell lung cancer (NSCLC). However, even after CRT, a substantial number of patients remain immunosuppressed with delayed lymphopenia. Therefore, we aimed to evaluate clinical and dose-volumetric predictors of delayed lymphopenia after CRT in locally advanced NSCLC.Materials and methodsWe retrospectively reviewed 272 patients with locally advanced NSCLC who received definitive CRT from January 2012 to August 2020. Differential blood count data, including serum albumin values, were obtained at baseline, during and at first follow up after CRT. Acute and delayed lymphopenia events were defined as grade III/IV lymphopenia developed during or 4-12 weeks after CRT completion, which accounted for 84% and 10% of cases, respectively. Dose-volume histogram parameters for planned target volume, whole body, heart, lung, great vessels, spleen, esophagus and thoracic vertebral bodies were evaluated.ResultsMultivariate analysis revealed that patients with delayed lymphopenia were associated with inferior overall survival (HR 2.53, P = 0.001) and progression-free survival (HR 1.98, P = 0.006). However, there was no significant survival difference between groups stratified by acute lymphopenia. On multivariable logistic regression models, lung V5, baseline ALC, during-CRT ALC, and albumin nadir were significant predictors for delayed lymphopenia. Furthermore, the nomogram for delayed lymphopenia based on these variables had good discrimination (area under the curve, 0.905).ConclusionsIn this study, we investigated the prognostic significance of delayed lymphopenia and identified clinico-dosimetric parameters to predict delayed lymphopenia.

Background The activation of the telomere maintenance mechanism (TMM) is one of the critical drivers of cancer cell immortality. In gliomas, TERT expression and TERT promoter mutation are considered to reliably indicate telomerase activation, while ATRX mutation and/or loss indicates an alternative lengthening of telomeres (ALT). However, these relationships have not been extensively validated in tumor tissues. Methods Telomerase repeated amplification protocol (TRAP) and C-circle assays were used to profile and characterize the TMM cross-sectionally (n = 412) and temporally (n = 133) across glioma samples. WES, RNA-seq, and NanoString analyses were performed to identify and validate the genetic characteristics of the TMM groups. Results We show through the direct measurement of telomerase activity and ALT in a large set of glioma samples that the TMM in glioma cannot be defined solely by the combination of telomerase activity and ALT, regardless of TERT expression, TERT promoter mutation, and ATRX loss. Moreover, we observed that a considerable proportion of gliomas lacked both telomerase activity and ALT. This telomerase activation-negative and ALT negative group exhibited evidence of slow growth potential. By analyzing a set of longitudinal samples from a separate cohort of glioma patients, we discovered that the TMM is not fixed and can change with glioma progression. Conclusions This study suggests that the TMM is dynamic and reflects the plasticity and oncogenicity of tumor cells. Direct measurement of telomerase enzyme activity and evidence of ALT should be considered when defining TMM. An accurate understanding of the TMM in glioma is expected to provide important information for establishing cancer management strategies.

Background: External beam radiation therapy (EBRT) is one of the treatment modalities for meningioma, and there are a few clinical reports about its short-term efficacy. However, studies reporting the long-term clinical outcomes with serial volumetric analysis are rare. This study reports the long-term clinical outcome of primary EBRT for meningioma with a comprehensive analysis of the volumetric changes and the annual reduction rate.Methods: A retrospective analysis was performed of patients who received conventional EBRT as a first-line treatment for meningioma between 1998 and 2020. The clinical outcomes and volumetric changes after primary EBRT were analyzed.Results: A total of 43 cases with a mean follow-up of 86.4 months were included. Most of the meningiomas were located in the skull base (40 cases, 93%). During the follow-up period, the tumor volume decreased in 38 (88.4%) patients and increased in 5 (11.6%) patients. The tumor volume generally decreased up to 6 months after EBRT, and transient volume expansion was observed between 6 and 12 months. When the tumor volume decreased 10% or more during the first 6 months after EBRT, a favorable therapeutic response was achieved. The mean overall reduction rate of tumor volume was 37.1%, and the mean annual reduction rate was 11.3%.Conclusions: Primary EBRT could be a feasible treatment option for meningioma from the perspective of volume control with favorable clinical outcomes.

The discrepancy between preoperative and final pathological staging has been a long-standing challenge for the application of clinical trials or appropriate treatment options. This study aimed to demonstrate the accuracy of preoperative staging of locally advanced gastric cancer using data from a large-scale randomized clinical trial.Of the 1050 patients enrolled in the clinical trial, 26 were excluded due to withdrawal of consent (Regarding T staging by computed tomography, accuracy rates were 74.48, 61.62, 58.56, and 85.16% for T1, T2, T3 and T4a, respectively. Multivariate analysis for underestimation of T staging revealed that younger age, ulcerative gross type, circular location, larger tumor size, and undifferentiated histology were independent risk factors. Regarding nodal status estimation, 54.9% of patients with clinical N0 disease were pathologic N0, and 36.4% of patients were revealed to have pathologic N0 among clinical node-positive patients. The percentage of metastasis involvement at the D1, D1+, and D2 lymph node stations significantly increased with the advanced clinical N stage. Among all patients, 29 (2.8%), including 26 with peritoneal seeding, exhibited distant metastases.Estimating the exact pathologic staging remains challenging. A thorough evaluation is mandatory before treatment selection or trial enrollment. Moreover, we need to set a sufficient case number when we design the clinical trial considering the stage migration.

The long-term safety of laparoscopic distal gastrectomy for locally advanced gastric cancer (AGC) remains uncertain given the lack of 5-year follow-up results.To compare the 5-year follow-up results in patients with clinically AGC enrolled in the Korean Laparoendoscopic Gastrointestinal Surgery Study (KLASS)-02 randomized clinical trial who underwent laparoscopic or open distal gastrectomy.The KLASS-02, a multicenter randomized clinical trial, showed that laparoscopic surgery was noninferior to open surgery for patients with locally AGC. The present study assessed the 5-year follow-up results, including 5-year overall survival (OS) and relapse-free survival (RFS) rates and long-term complications, in patients enrolled in KLASS-02. From November 21, 2011, to April 29, 2015, patients aged 20 to 80 years diagnosed preoperatively with locally AGC were enrolled. Final follow-up was on June 15, 2021. Data were analyzed June 24 to September 9, 2021.Patients were treated with R0 resection either by laparoscopic gastrectomy or open gastrectomy as the full analysis set of the KLASS-02 trial.Five-year OS and RFS rates, recurrence patterns, and long-term surgical complications were evaluated.This study enrolled a total of 1050 patients. A total of 974 patients were treated with R0 resection; 492 (50.5%) in the laparoscopic gastrectomy group (mean [SD] age, 59.8 [11.0] years; 351 men [71.3%]) and 482 (49.5%) in the open gastrectomy group (mean [SD] age, 59.4 [11.5] years; 335 men [69.5%]). In patients who underwent laparoscopic and open distal gastrectomy, the 5-year OS (88.9% vs 88.7%) and RFS (79.5% vs 81.1%) rates did not differ significantly. The most common types of recurrence were peritoneal carcinomatosis (73 of 173 [42.1%]), hematogenous metastases (36 of 173 [20.8%]), and locoregional recurrence (23 of 173 [13.2%]), with no between-group differences in types of recurrence at each cancer stage. The correlation between 3-year RFS and 5-year OS at the individual level was highest in patients with stage III gastric cancer (ρ = 0.720). The late complication rate was significantly lower in the laparoscopic than in the open surgery group (32 of 492 [6.5%] vs 53 of 482 [11.0%]). The most common type of complication in both groups was intestinal obstruction (13 of 492 [2.6%] vs 24 of 482 [5.0%]).The 5-year outcomes of the KLASS-02 trial support the 3-year results, which is the noninferiority of laparoscopic surgery compared with open gastrectomy for locally AGC. The laparoscopic approach can be recommended in patients with locally AGC to achieve the benefit of low incidence of late complications.ClinicalTrials.gov Identifier: NCT01456598.

Non-germinomatous germ cell tumors (NGGCTs) are rare pediatric conditions. This multicenter study using Asian multinational patient data investigated treatment outcomes and prognostic factors for NGGCTs.Medical records of 251 patients with NGGCTs treated from 1995 to 2015 were retrospectively analyzed from participating centers in Asian countries (Korea, Taiwan, Singapore, and Japan).The median follow up was 8.5 years (95% CI 7.8-9.9). In the total cohort, 5-year event-free survival (EFS) and overall survival (OS) rates were 78.2% and 85.4%, respectively. In 17.9% of the patients, diagnosis was determined by tumor markers alone (alpha-fetoprotein ≥ 10 ng/mL (Korea) or 25 ng/mL (Taiwan and Singapore), and/or β-human chorionic gonadotropin (β-hCG) ≥ 50 mIU/mL). Patients with immature teratomas and mature teratomas comprised 12.0% and 8.4%, respectively. The 5-year EFS rate was higher in patients with histologically confirmed germinoma with elevated β-hCG (n = 28) than those in patients with malignant NGGCTs (n = 127). Among malignant NGGCTs, patients with choriocarcinoma showed the highest 5-year OS of 87.6%, while yolk sac tumors showed the lowest OS (68.8%). For malignant NGGCT subgroups, an increase in serum β-hCG levels by 100 mIU/mL was identified as a significant prognostic factor associated with the EFS and OS.Our result shows excellent survival outcomes of overall CNS NGGCT. However, treatment outcome varied widely across the histopathologic subgroup of NGGCT. Hence, this study suggests the necessity for accurate diagnosis by surgical biopsy and further optimization of diagnosis and treatment according to the histopathology of NGGCTs. Future clinical trials should be designed for individualized treatments for different NGGCTs subsets.

Glucosyltransferases catalyze the glucosidic bond formation by transferring a glucose molecule from an activated sugar donor to an acceptor substrate. Glucocorticoids (GCs) are adrenal-derived steroid hormones most widely used for anti-inflammatory treatments. In this study, we biotransformed two selected GCs, cortisone and prednisone, into their O-glucoside derivatives using a versatile UDP-glycosyltransferase UGT-1. Complete structural assignment of glucosylated products revealed that the bioconversion by regio-selective glucosylation of cortisone and prednisone produced cortisone 21-glucoside and prednisone 21-glucoside, respectively. We also combined molecular dynamics (MD) simulation to study the binding feature and mechanism of glucosylation. MD simulation studies showed the formation of a stable complex between protein, glucose donor, and substrate, stabilized by hydrogen bonds. Overall, we were able to provide explanations for the experimentally observed selectivity for glucosylation by integrating experimental and computational techniques.

To understand the tumor immune microenvironment precisely, it is important to secure the quantified data of tumor-infiltrating immune cells, since the immune cells are true working unit. We analyzed unit immune cell number per unit volume of core tumor tissue of high-grade gliomas (HGG) to correlate their immune microenvironment characteristics with clinical prognosis and radiomic signatures. The number of tumor-infiltrating immune cells from 64 HGG core tissue were analyzed using flow cytometry and standardized. After sorting out patient groups according to diverse immune characteristics, the groups were tested if they have any clinical prognostic relevance and specific radiomic signature relationships. Sparse partial least square with discriminant analysis using multimodal magnetic resonance images was employed for all radiomic classifications. The median number of CD45 + cells per one gram of HGG core tissue counted 865,770 cells which was equivalent to 8.0% of total cells including tumor cells. There was heterogeneity in the distribution of immune cell subpopulations among patients. Overall survival was significantly better in T cell-deficient group than T cell-enriched group (p = 0.019), and T8 dominant group than T4 dominant group (p = 0.023). The number of tumor-associated macrophages (TAM) and M2-TAM was significantly decreased in isocitrate dehydrogenase mutated HGG. Radiomic signature classification showed good performance in predicting immune phenotypes especially with features extracted from apparent diffusion coefficient maps. Absolute quantification of tumor-infiltrating immune cells confirmed the heterogeneity of immune microenvironment in HGG which harbors prognostic impact. This immune microenvironment could be predicted by radiomic signatures non-invasively.

Purpose Alpha-fetoprotein (AFP) is a prognostic marker for hepatocellular carcinoma (HCC). We investigated the prognostic value of AFP levels in patients who achieved complete response (CR) to transarterial chemoembolization (TACE) for HCC. Materials and methods Between 2005 and 2018, 890 patients with HCC who achieved a CR to TACE were recruited. An AFP responder was defined as a patient who showed elevated levels of AFP (>10 ng/mL) during TACE, but showed normalization or a >50% reduction in AFP levels after achieving a CR. Results Among the recruited patients, 569 (63.9%) with naive HCC and 321 (36.1%) with recurrent HCC after complete resection were treated. Before TACE, 305 (34.3%) patients had multiple tumors, 219 (24.6%) had a maximal tumor size >3 cm, and 22 (2.5%) had portal vein tumor thrombosis. The median AFP level after achieving a CR was 6.36 ng/mL. After a CR, 473 (53.1%) patients experienced recurrence, and 417 (46.9%) died [median progression-free survival (PFS) and overall survival (OS) of 16.3 and 62.8 months, respectively]. High AFP levels at CR (>20 ng/mL) were independently associated with a shorter PFS [hazard ratio (HR)=1.403] and OS (HR=1.284), together with tumor multiplicity at TACE (HR=1.518 and 1.666, respectively). AFP non-responders at CR (76.2%, n=359 of 471) showed a shorter PFS (median 10.5 months vs. 15.5 months, HR=1.375) and OS (median 41.4 months vs. 61.8 months, HR=1.424) than AFP responders (all p=0.001). Conclusion High AFP levels and AFP non-responders were independently associated with poor outcomes after TACE. AFP holds clinical implications for detailed risk stratification upon achieving a CR after TACE.

BACKGROUND The Hippo signaling pathway regulates organ size by regulating cell proliferation and apoptosis with terminal effectors including Yes-associated protein-1 (YAP-1). Dysregulation in Hippo pathway has been proposed as one of the therapeutic targets in hepatocarcinogenesis. The levels of reactive oxygen species (ROS) increase during the progression from early to advanced hepatocellular carcinoma (HCC). AIM To study the activation of YAP-1 by ROS-induced damage in HCC and the involved signaling pathway. METHODS The expression of YAP-1 in HCC cells (Huh-7, HepG2, and SNU-761) was quantified using real-time polymerase chain reaction and immunoblotting. Human HCC cells were treated with H2O2, which is a major component of ROS in living organisms, and with either YAP-1 small interfering RNA (siRNA) or control siRNA. To investigate the role of YAP-1 in HCC cells under oxidative stress, MTS assays were performed. Immunoblotting was performed to evaluate the signaling pathway responsible for the activation of YAP-1. Eighty-eight surgically resected frozen HCC tissue samples and 88 nontumor liver tissue samples were used for gene expression analyses. RESULTS H2O2 treatment increased the mRNA and protein expression of YAP-1 in HCC cells (Huh-7, HepG2, and SNU-761). Suppression of YAP-1 using siRNA transfection resulted in a significant decrease in tumor proliferation during H2O2 treatment both in vitro and in vivo (both P < 0.05). The oncogenic action of YAP-1 occurred via the activation of the c-Myc pathway, leading to the upregulation of components of the unfolded protein response (UPR), including 78-kDa glucose-regulated protein and activating transcription factor-6 (ATF-6). The YAP-1 mRNA levels in human HCC tissues were upregulated by 2.6-fold compared with those in nontumor tissues (P < 0.05) and were positively correlated with the ATF-6 Levels (Pearson’s coefficient = 0.299; P < 0.05). CONCLUSION This study shows a novel connection between YAP-1 and the UPR through the c-Myc pathway during oxidative stress in HCC. The ROS-induced activation of YAP-1 via the c-Myc pathway, which leads to the activation of the UPR pathway, might be a therapeutic target in HCC.

Background An optimal radiological surveillance plan is crucial for high-grade glioma (HGG) patients, which is determined arbitrarily in daily clinical practice. We propose the radiological assessment schedule using a parametric model of standardized progression-free survival (PFS) curves. Methods A total of 277 HGG patients (178 glioblastoma [GBM] and 99 anaplastic astrocytoma [AA]) from a single institute who completed the standard treatment protocol were enrolled in this cohort study and retrospectively analyzed. The patients were stratified into each layered risk group by genetic signatures and residual mass or through recursive partitioning analysis. PFS curves were estimated using the piecewise exponential survival model. The criterion of a 10% progression rate among the remaining patients at each observation period was used to determine the optimal radiological assessment time point. Results The optimal follow-up intervals for MRI evaluations of isocitrate dehydrogenase (IDH) wild-type GBM was every 7.4 weeks until 120 weeks after the end of standard treatment, followed by a 22-week inflection period and every 27.6 weeks thereafter. For the IDH mutated GBM, scans every 13.2 weeks until 151 weeks are recommended. The optimal follow-up intervals were every 22.8 weeks for IDH wild-type AA, and 41.2 weeks for IDH mutated AA until 241 weeks. Tailored radiological assessment schedules were suggested for each layered risk group of the GBM and the AA patients. Conclusions The optimal schedule of radiological assessments for each layered risk group of patients with HGG could be determined from the parametric model of PFS.

Background/Aims The role of serum myokine levels in sarcopenia and the outcome of hepatocellular carcinoma (HCC) patients are not clear. This study investigated the serum levels of myostatin, follistatin, and interleukin-6 (IL-6) in HCC patients and their association with sarcopenia and survival. Methods Using prospectively collected pretreatment samples from 238 HCC patients in a hospital from 2012 to 2015, the serum levels of 3 myokines were determined and compared to 50 samples from age and sex-matched healthy controls. Sarcopenia was evaluated using the psoas muscle index (PMI) measured at the third lumbar level in the computed tomography, and clinical data were collected until 2017. Results The median levels of the 3 myokines for the male and female HCC patients were as follow: myostatin (3,979.3 and 2,976.3 pg/mL), follistatin (2,118.5 and 2,174.6 pg/mL), and IL-6 (2.5 and 2.7 pg/mL), respectively. Those in the HCC patients were all significantly higher than in the healthy controls. In the HCC patient, the median PMI was 4.43 (males) and 2.17 cm2/m2 (females) with a sarcopenic prevalence of 56.4%. The serum levels of myostatin, IL-6 and follistatin in the HCC patients showed a positive, negative, and no correlation with PMI, respectively. The serum follistatin level was an independent factor for poor survival in HCC patients. Conclusions The serum levels of myostatin, follistatin, and IL-6 and their correlation with sarcopenia and survival were presented in HCC patients for the first time. The role of the serum follistatin level as a poor prognostic biomarker warrants further study.

Conflicting results have been reported regarding which of entecavir (ETV) or tenofovir disoproxil fumarate (TDF) is associated with better outcomes. Chronic hepatitis B patients who started ETV or TDF between 2010 and 2015 were analysed. The primary outcomes were hepatocellular carcinoma and death and transplantation. The impact of the treatment on the primary outcomes was analysed using Cox proportional hazards models in the entire and propensity score-matched cohorts. A total of 404 patients (180 and 224 in the ETV and TDF groups, respectively) were analysed. The median duration of follow-up was significantly longer in the ETV group (64.0 vs. 49.1 months; P P = 0.018) and sustained virological suppression (59.7% vs. 45.2%; P = 0.005) were significantly higher in the TDF group. TDF was associated with lower hepatocellular carcinoma [hazard ratio (HR) 0.31, 95% confidence interval (95% CI), 0.12‒0.79; P = 0.014]; however, statistical significance was not reached after adjusting sustained virological suppression using propensity score matching (HR 0.36, 95% CI 0.12‒1.14; P = 0.08). Death and transplantation was comparable. In conclusion, the impact of TDF on the lower hepatocellular carcinoma was blunted after adjusting sustained virological suppression. Further comparison in a larger number of patients who show sustained virological suppression over a longer period of time is needed.