Search

Purpose 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 genomewide clustered regularly interspaced short palindromic repeats (CRISPR)-based knockout screen. Materials and Methods 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. Results 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. Conclusion 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. [ABSTRACT FROM AUTHOR]

Purpose We aimed to evaluate the effectiveness of prophylactic cranial irradiation (PCI) for "early brain metastasis", which occurs before extracranial recurrence (ECR), and "late brain metastasis", which occurs after ECR, in limited-stage small cell lung cancer (LS-SCLC). Materials and Methods We retrospectively analyzed 271 LS-SCLC patients who underwent definitive chemoradiation. All patients were initially staged with brain magnetic resonance imaging and positron emission tomography. Intracranial recurrence (ICR), ECR, progression-free rate (PFR), and overall survival (OS) were analyzed as clinical endpoints. The competing risk of the first recurrence with ICR (ICRfirst) was evaluated. Significantly associated variables in multivariate analysis of ECR were considered as ECR risk factors. Patients were stratified according to the number of ECR risk factors. Results The application of PCI was associated with higher PFR (p=0.008) and OS (p=0.045). However, PCI was not associated with any of the clinical endpoints in multivariate analysis. The competing risk of ICRfirst was significantly decreased with the application of PCI (hazard ratio, 0.476; 95% confidence interval, 0.243 to 0.931; p=0.030). Stage III disease, sequential, and stable disease after thoracic radiation were selected as ECR risk factors. For patients without these risk factors, the application of PCI was significantly associated with increased OS (p=0.048) and a decreased risk of ICRfirst (p=0.026). Conclusion PCI may play a role in preventing early brain metastasis rather than late brain metastasis after ECR, suggesting that only patients with a low risk of ECR may currently benefit from PCI. [ABSTRACT FROM AUTHOR]

Purpose We investigated the clinical effects and predictive factors of severe post-chemoradiotherapy pulmonary complications (PCPC) in locally advanced non-small cell lung cancer (LA-NSCLC). Materials and Methods Medical records of 317 patients who underwent definitive concurrent chemoradiation (CCRT) for LA-NSCLC were reviewed retrospectively. PCPC was defined as an event of admission or emergency department visit for acute or subacute pulmonary inflammatory complications, including pneumonitis and pneumonia, within 6 months after CCRT initiation. Patient characteristics, baseline lung function tests, radiation dosimetric parameters, and laboratory tests were analyzed to investigate their association with PCPC. Prognostic endpoints were disease progression rate (DPR) and overall survival (OS). Results PCPC was reported in 53 patients (16.7%). The OS of patients with PCPC was significantly worse (35.0% in 2 years) than that of patients without PCPC (67.0% in 2 years, p < 0.001). However, 2-year DPRs were 77.0% and 70.7% in patients with and without PCPC, respectively, which were not significantly different (p=0.087). In multivariate logistic regression, PCPC was independently associated with grade = 1 hypoalbuminemia during CCRT (odds ratio [OR], 5.670; 95% confidence interval [CI], 2.487 to 13.40; p < 0.001), lower diffusing capacity of carbon monoxide (DLCO) (per mL/min/mmHg; OR, 0.855; 95% CI, 0.743 to 0.974; p=0.022), and higher lung V5 (per 10%; OR, 1.872; 95% CI, 1.336 to 2.699; p < 0.001). Conclusion PCPC might be a clinical endpoint to evaluate complications and predict the survival of patients subjected to CCRT for LA-NSCLC. Hypoalbuminaemia, DLCO, and lung V5 might predict PCPC in LA-NSCLC. [ABSTRACT FROM AUTHOR]

Purpose This multicenter retrospective study aimed to investigate clinical, radiologic, and treatment-related factors affecting survival in patients with newly diagnosed diffuse intrinsic pontine glioma (DIPG) treated with radiotherapy. Materials and Methods Patients aged < 30 years who underwent radiotherapy as an initial treatment for DIPG between 2000 and 2018 were included; patients who did not undergo magnetic resonance imaging at diagnosis and those with pathologically diagnosed grade I glioma were excluded. We examined medical records of 162 patients collected from 10 participating centers in Korea. The patients’ clinical, radiological, molecular, and histopathologic characteristics, and treatment responses were evaluated to identify the prognosticators for DIPG and estimate survival outcomes. Results The median follow-up period was 10.8 months (interquartile range, 7.5 to 18.1). The 1- and 2-year overall survival (OS) rates were 53.5% and 19.0%, respectively, with a median OS of 13.1 months. Long-term survival rate (≥ 2 years) was 16.7%, and median OS was 43.6 months. Age (< 10 years), poor performance status, treatment before 2010, and post-radiotherapy necrosis were independently associated with poor OS in multivariate analysis. In patients with increased post-radiotherapy necrosis, the median OS estimates were 13.3 months and 11.4 months with and without bevacizumab, respectively (p=0.138). Conclusion Therapeutic strategy for DIPG has remained unchanged over time, and the associated prognosis remains poor. Our findings suggest that appropriate efforts are needed to reduce the occurrence of post-radiotherapy necrosis. Further well-designed clinical trials are recommended to improve the poor prognosis observed in DIPG patients. [ABSTRACT FROM AUTHOR]

Purpose This study aimed to compare the outcomes of primary radiotherapy (RT) versus surgery in early-stage human papilloma virus-positive oropharyngeal squamous cell carcinoma (hpv+OPC), and investigate the preoperative clinical factors that can predict the requirement for postoperative adjuvant treatment. Materials and Methods This multicenter study included 166 patients with American Joint Committee on Cancer 8th edition-Stages I-II hpv+OPC. Sixty (36.1%) and 106 (63.9%) patients underwent primary (concurrent chemo)radiotherapy [(CC)RT] and surgery, respectively. Seventy-eight patients (73.6%) in the surgery group received postoperative (CC)RT. Results With a median follow-up of 45.6 months for survivors, the 2-year overall survival (OS), progression-free survival (PFS), and locoregional control (LC) for RT/surgery were 97.8%/96.4%, 91.1%/92.0%, and 92.9%/93.3%, respectively. In multivariate analyses, patients with synchronous radiologic extranodal extension and conglomeration (ENEcong) of metastatic lymph nodes (LNs) showed significantly poorer OS (p=0.047), PFS (p=0.001), and LC (p=0.003). In patients undergoing primary surgery, two or more clinically positive LN metastases (odds ratio [OR], 5.15; p=0.004) and LN metastases with ENEcong (OR, 3.75; p=0.009) were predictors of postoperative chemoradiotherapy. No patient in the primary RT group demonstrated late severe toxicity whereas three (2.8%), one (0.9%), and one (0.9%) patient in the surgery group showed grade 3 dysphagia, grade 3 xerostomia, and fatal oral cavity bleeding. Conclusion We found no differences in OS, PFS, and LC between upfront RT and surgery in stage I-II hpv+OPC which warrants comparison through a prospective trial in the treatment de-escalation era. However, most early-stage hpv+OPC patients undergoing surgery received adjuvant (CC)RT. Pretreatment LN findings were prognostic and predictive for adjuvant treatment. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose We aimed to refine the radiotherapy (RT) volume and dose for intracranial germinoma considering recurrences and longterm 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. [ABSTRACT FROM AUTHOR]

Purpose The 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 Methods Patients 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. Results Thirty-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. Conclusion PFS6 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. [ABSTRACT FROM AUTHOR]

Purpose The purpose of this study was to demonstrate the prognostic significance of changes in body composition in patients with newly diagnosed hepatocellular carcinoma (HCC). Materials and Methods Patients (n=178) newly diagnosed with HCC participated in the study between 2007 and 2012. Areas of skeletal muscle and abdominal fat were directly measured using a threedimensional workstation. Cox proportional-hazards modes were used to estimate the effect of baseline variables on overall survival. The inverse probability of treatment weighting (IPTW) method was used to minimize confounding bias. Results Cutoff values for sarcopenia, obtained from receiver-operating characteristic curves, were defined as skeletal muscle index at the third lumbar vertebra of ≤ 45.8 cm/m² for males and ≤ 43.0 cm/m² for females. Sarcopenia patients were older, more likely to be female, and had lower body mass index. Univariable analysis showed that the presence of sarcopenia and visceral to subcutaneous fat area ratio (VSR) were significantly associated with prognosis. The multivariable analyses revealed that VSR was predictive of overall survival. However, in the multivariable Cox model adjusted by IPTW, sarcopenia, not VSR, were associated with overall survival. Conclusion The presence of sarcopenia at HCC diagnosis is independently associated with survival. [ABSTRACT FROM AUTHOR]

Purpose This study was conducted to validate the prognostic influence of treatment response among patients with positive circumferential resection margin for locally advanced rectal cancer. Materials and Methods Clinical data of 197 patients with positive circumferential resection margin defined as P 2 mm after preoperative chemoradiotherapy followed by total mesorectal excision between 2004 and 2009 were collected for this multicenter validation study. All patients underwent median 50.4 Gy radiation with concurrent fluoropyrimidine based chemotherapy. Treatment response was dichotomized to good response, including treatment response of grade 2 or 3, and poor response, including grade 0 or 1. Results After 52 months median follow-up, 5-year overall survival (OS) for good responders and poor responders was 79.1% and 48.4%, respectively (p < 0.001). In multivariate analysis, circumferential resection margin involvement and treatment response were a prognosticator for OS and locoregional recurrence-free survival. In subgroup analysis, good responders with close margin showed significantly better survival outcomes for survival. Good responders with involved margin and poor responders with close margin shared similar results, whereas poor responders with involved margin had worst survival (5-year OS, 81.2%, 57.0%, 50.0%, and 32.4%, respectively; p < 0.001). Conclusion Among patients with positive circumferential resection margin after preoperative chemoradiotherapy, survival of the good responders was significantly better than poor responders. Subgroup analysis revealed that definition of positive circumferential resection margin may be individualized as involvement for good responders, whereas ≤2 mm for poor responders. [ABSTRACT FROM AUTHOR]

Purpose The current study was conducted in order to evaluate the clinical outcome of radical radiotherapy (RT) with or without chemotherapy for elderly patients with stage III non-small cell lung cancer (NSCLC). Materials and Methods Between 1990 and 2010,125 patients, aged 70 years or more, received radical RTwith or without chemotherapy for treatment of stage III NSCLC. We reviewed the patients' prognostic factors, including comorbidities. Comorbidity status was evaluated using a simplified comorbidity score (SCS). Of the patients reviewed, 82 received radical RT alone, whereas the other 43 patients underwent chemoradiotherapy (CRT). A platinum-based chemotherapy regimen was most commonly used (42/43). Results The two-year overall-survival (OS) and progression-free survival (PFS) rates were 32.2% and 21.8%, respectively. SCS was the independent prognostic factor for OS. In the frail elderly subgroup with a SCS of ≥10, CRT demonstrated a significant difference in PFS, but not in OS. In contrast, OS and PFS following CRT were significantly superior to RT in the fit elderly subgroup with a SCS of <10. The incidence of severe pulmonary toxicities in the frail elderly subgroup was significantly higher than that in the fit elderly subgroup. Conclusion Multiple comorbidities evaluated according to the SCS are related to poor OS in elderly patients with stage III NSCLC. CRT improved clinical outcome when compared to RT in the fit elderly subgroup, however, the gain from this treatment was negated in the frail elderly subgroup with multiple comorbidities. Therefore, evaluation of comorbidity is necessary in orderto determine whether chemotherapy should be combined with RT in elderly patients with stage III NSCLC. [ABSTRACT FROM AUTHOR]