Evaluation of Pretreatment Albumin-Bilirubin Grade as a Better Prognostic Factor Compared to Child-Pugh Classification in Patients with Hepatocellular Carcinoma Receiving Transarterial Chemoembolization Combined with Radiotherapy.

This study assessed the use of pretreatment albumin--bilirubin (ALBI) grade as a prognostic factor in patients with hepatocellular carcinoma (HCC) receiving combined transarterial chemoembolization (TACE) and radiotherapy (RT). Patients who underwent RT following TACE between January 2011 and December 2020 were analyzed retrospectively. The survival outcomes of patients in regard to the ALBI grade and Child-Pugh (C-P) classification were evaluated. A total of 73 patients with a median follow-up of 16.3 months were included. Thirty-three (45.2%) and forty patients (54.8%) were categorized into ALBI grades 1 and 2-3, respectively, while sixty-four (87.7%) and nine (12.3%) were C-P classes A and B, respectively (p = 0.003). The median progression-free survival (PFS) and overall survival (OS) for ALBI grade 1 vs. 2-3 were 8.6 months vs. 5.0 months (p = 0.016) and 27.0 months vs. 15.9 months (p = 0.006), respectively. The median PFS and OS for C-P class A vs. B were 6.3 months vs. 6.1 months (p = 0.265) and 24.8 months vs. 19.0 months (p = 0.630), respectively. A multivariate analysis showed that ALBI grades 2-3 were significantly associated with worse PFS (p = 0.035) and OS (p = 0.021). In conclusion, the ALBI grade could be a good prognosticator in HCC patients who were treated with combined TACE-RT.

Dual Oxidase 2 (DUOX2) as a Proteomic Biomarker for Predicting Treatment Response to Chemoradiation Therapy for Locally Advanced Rectal Cancer: Using High-Throughput Proteomic Analysis and Machine Learning Algorithm.

High-throughput mass-spectrometry-based quantitative proteomic analysis was performed using formalin-fixed, paraffin-embedded (FFPE) biopsy samples obtained before treatment from 13 patients with locally advanced rectal cancer (LARC), who were treated with concurrent chemoradiation therapy (CCRT) followed by surgery. Patients were divided into complete responder (CR) and non-complete responder (nCR) groups. Immunohistochemical (IHC) staining of 79 independent FFPE tissue samples was performed to validate the predictive ability of proteomic biomarker candidates. A total of 3637 proteins were identified, and the expression of 498 proteins was confirmed at significantly different levels (differentially expressed proteins-DEPs) between two groups. In Gene Ontology enrichment analyses, DEPs enriched in biological processes in the CR group included proteins linked to cytoskeletal organization, immune response processes, and vesicle-associated protein transport processes, whereas DEPs in the nCR group were associated with biosynthesis, transcription, and translation processes. Dual oxidase 2 (DUOX2) was selected as the most predictive biomarker in machine learning algorithm analysis. Further IHC validation ultimately confirmed DUOX2 as a potential biomarker for predicting the response of nCR to CCRT. In conclusion, this study suggests that the treatment response to RT may be affected by the pre-treatment tumor microenvironment. DUOX2 is a potential biomarker for the early prediction of nCR after CCRT.

Prostate-Specific Antigen Bounce after 125I Brachytherapy Using Stranded Seeds with Intraoperative Optimization for Prostate Cancer.

Prostate-specific antigen (PSA) bounce is common in patients undergoing 125I brachytherapy (BT), and our study investigated its clinical features. A total of 100 patients who underwent BT were analyzed. PSA bounce and large bounce were defined as an increase of ≥0.2 and ≥2.0 ng/mL above the initial PSA nadir, respectively, with a subsequent decline without treatment. Biochemical failure was defined using the Phoenix definition (nadir +2 ng/mL), except for a large bounce. With a median follow-up of 49 months, 45% and 7% of the patients experienced bounce and large bounce, respectively. The median time to bounce was 24 months, and the median PSA value at the bounce spike was 1.62 ng/mL, a median raise of 0.44 ng/mL compared to the pre-bounce nadir. The median time to bounce recovery was 4 months. The post-bounce nadir was obtained at a median of 36 months after low-dose-rate BT. On univariate analysis, age, the PSA nadir value at 2 years, and prostate volume were significant factors for PSA bounce. The PSA nadir value at 2 years remained significant in multivariate analysis. We should carefully monitor young patients with high prostate volume having a >0.5 PSA nadir value at 2 years for PSA bounce.

Automated Computer-Aided Detection of Lung Nodules in Metastatic Colorectal Cancer Patients for the Identification of Pulmonary Oligometastatic Disease.

PURPOSE: This study aimed to explore the possibility and clinical utility of existing artificial intelligence (AI)-based computer-aided detection (CAD) of lung nodules to identify pulmonary oligometastases. PATIENTS AND METHODS: The chest computed tomography (CT) scans of patients with lung metastasis from colorectal cancer between March 2006 and November 2018 were analyzed. The patients were selected from a database of 1395 patients and studied in 2 cohorts. The first cohort included 50 patients, and the CT scans of these patients were independently evaluated for lung-nodule (≥3 mm) detection by a CAD-assisted radiation oncologist (CAD-RO) as well as by an expert radiologist. Interobserver variability by 2 additional radiation oncologists and 2 thoracic surgeons were also measured. In the second cohort of 305 patients, survival outcomes were evaluated based on the number of CAD-RO-detected nodules. RESULTS: In the first cohort, the sensitivity and specificity of the CAD-RO for identifying oligometastatic disease (OMD) from varying criteria by ≤2 nodules, ≤3 nodules, ≤4 nodules, and ≤5 nodules were 71.9% and 88.9%, 82.9% and 93.3%, 97.1% and 73.3%, and 97.5% and 90.0%, respectively. The sensitivity of the CAD-RO in the nodule detection compared with the radiologist was 81.6%. The average (standard deviation) sensitivity in interobserver variability analysis was 80.0% (3.7%). In the second cohort, the 5-year survival rates of patients with 1, 2, 3, 4, or ≥5 metastatic nodules were 75.2%, 52.9%, 45.7%, 29.1%, and 22.7%, respectively. CONCLUSIONS: Proper identification of the pulmonary OMD and the correlation between the number of CAD-RO-detected nodules and survival suggest the potential practicality of AI in OMD recognition. Developing a deep learning-based model specific to the metastatic setting, which enables a quick estimation of disease burden and identification of OMD, is underway.

Adjuvant Radiotherapy Versus Surveillance for Grade 2 Intracranial Meningiomas: A Multi-Institutional Propensity Score-Matched Study.

Purpose: We aimed to compare the outcomes of adjuvant radiotherapy (ART) and surveillance in patients with grade 2 meningiomas (MNG2) who underwent surgical resection. Materials and Methods: Data from four hospitals, in which patients aged ≥18 years underwent Simpson grade 1-4 surgical resection for newly diagnosed MNG2 between 1998 and 2018, were examined in this multicenter retrospective cohort study. Patients receiving ART with conventional fractionation were compared with those undergoing surveillance. Progression-free survival (PFS), progression/recurrence (P/R) were evaluated. Results: This study included 518 patients, 158 of whom received ART. The median follow-up duration was 64.9 months. In the total cohort, ART was independently associated with significantly improved PFS (HR, 0.35; 95% CI, 0.23-0.55; P<0.001) and P/R (HR, 0.30; 95% CI, 0.18-0.48; P<0.001). In the propensity score-matched cohort (n=143 in each group), the 5-year PFS rates were 80.8% and 57.7% (P=0.004), and the 5-year P/R rates were 16.5% and 40.0% (P=0.002) in the ART and surveillance groups, respectively. After gross total resection, the 5-year PFS (85.0% vs. 64.7%; P=0.020) and P/R rates (15.2% vs. 32.0%; P=0.035) were significantly better in the ART group than in the surveillance group. A model for P/R was developed using recursive partitioning analysis with surgical extent, tumor size, and Ki-67 index. ART reduced the risk of P/R in the low- (P=0.069), intermediate- (P=0.044), and high-risk groups (P<0.001). Local control was also significantly enhanced by ART among all the risk groups (all P<0.05). Conclusions: ART significantly improved PFS and P/R in patients with MNG2, irrespective of the surgical extent, and can be recommended after gross total resection. A prognostic model may guide decision-making for the use of ART.

Risk factor analysis of dental implants in patients with irradiated head and neck cancer.

BACKGROUND: We investigated dental implant outcomes in patients who had previously received radiotherapy (RT) for head and neck malignancies. METHODS: We reviewed 90 dental implants in 27 patients who received RT for head and neck cancer and received dental implants afterwards. The cumulative implant survival rate (CISR) was calculated. In addition, the implant quality was assessed using "Health Scale for Dental Implants." RESULTS: The CISR at 3 years was 79.6%. The mean radiation dose at the implant site (Dmean ) was identified as an independent prognostic factor for implant survival. No implant failed if Dmean was less than 38 Gy. Regarding implant quality, dental implants in grafted bone and Dmean were independent risk factors. CONCLUSIONS: Dmean was identified as an independent prognostic factor for implant survival and quality. Dental implants can be safely considered when Dmean is lower than 38 Gy.

Dosimetric outcomes of preoperative treatment planning with intraoperative optimization using stranded seeds in prostate brachytherapy.

This study aimed to evaluate the quality of low-dose-rate (LDR) prostate brachytherapy (BT) based on treatment-related dosimetric outcomes. Data of 100 patients treated using LDR BT with stranded seeds from November 2012 to November 2017 were collected. The prescription dose for the prostate was 145 Gy. The dose constraints for the preoperative plan were: V100% ≥ 95%, V150% ≤ 60%, V200% ≤ 20% for the prostate; V100% for rectum, ≤ 1 cc; and V200 Gy for urethra, 0.0 cc. Intraoperative real-time dose calculation and postoperative dose distribution analysis on days 0 and 30 were performed. Median dosimetric outcomes on days 0 and 30 respective were: V100% 92.28% and 92.23%, V200% 18.63% and 25.02%, and D90% 150.88 Gy and 151.46 Gy for the prostate; V100% for the rectum, 0.11 cc and 0.22 cc; and V200 Gy for the urethra, 0.00 cc and 0.00 cc, respectively. Twenty patients underwent additional seed implantation to compensate for insufficient dose coverage of the prostate. No loss or substantial migration of seeds or severe toxicity was reported. With stranded seed implantation and intraoperative optimization, appropriate dose delivery to the prostate without excessive dose to the organs at risk could be achieved.

Increased Radiosensitivity of Solid Tumors Harboring ATM and BRCA1/2 Mutations.

PURPOSE: Preclinical data indicate that response to radiotherapy (RT) depends on DNA damage repair. In this study, we investigated the role of mutations in genes related to DNA damage repair in treatment outcome after RT. MATERIALS AND METHODS: Patients with solid tumor who participated in next generation sequencing panel screening using biopsied tumor tissue between October 2013 and February 2019 were reviewed and 97 patients that received RT were included in this study. Best response to RT and the cumulative local recurrence rate (LRR) were compared according to absence or presence of missense, nonsense, and frameshift mutations in ATM and/or BRCA1/2. RESULTS: Of the 97 patients, five patients harbored mutation only in ATM, 22 in only BRCA1/2, and six in both ATM and BRCA1/2 (ATMmtBRCAmt). Propensity score matching was performed to select the control group without mutations (ATMwtBRCAwt, n=33). In total, 90 RT-treated target lesions were evaluated in 66 patients. Highest objective response rate of 80% was observed in ATMmtBRCAmt lesions (p=0.007), which was mostly durable. Furthermore, the cumulative 1-year LRR was the lowest in ATMmtBRCAmt lesions and the highest in ATMwtBRCAwt lesions (0% vs. 47.9%, p=0.008). RT-associated toxicities were observed in 10 treatments with no significant difference among the subgroups (p=0.680). CONCLUSION: Tumors with ATM and BRCA1/2 mutations exhibited superior tumor response and local control after RT compared to tumors without these mutations. The results are hypothesis generating and suggest the need for integrating the tumor mutation profile of DNA repair genes during treatment planning.

Medical student education through flipped learning and virtual rotations in radiation oncology during the COVID-19 pandemic: a cross sectional research.

BACKGROUND: The COVID-19 pandemic has stripped many medical students worldwide of their right to quality education. In response, we developed hybrid courses involving aspects of both online and in-person teaching for radiation oncology medical student clerkship. METHODS: We entitled students to customize their own rotation schedule using Google Forms and developed a flipped learning online class, which consisted of at least one video clip on basic knowledge of radiation oncology per day (yonsei-radonc.com). Students were instructed to watch online videos before the next day's discussion session. Required components of the medical education program (e.g., target drawing, site visits to treatment facilities) were also prepared and conducted in accordance with the appropriate level of social distancing measures. Finally, we conducted questionnaire surveys after the completion of the week-long course and clerkship. RESULTS: From March to June 2020, 110 fourth-year medical students undertook a clinical module in our 1-week radiation oncology program course. Each day, students completed the flipped learning prior to meeting with the educator and then participated in the online discussion session and conference. All activities were well performed as scheduled. Students' motivation was high, as was their overall satisfaction with the course. The students were satisfied with the online contents, flipped learning strategy, and instructors. CONCLUSIONS: We successfully integrated open and virtual educational platforms to improve access to and satisfaction with student clerkship. In the future "new normal," minimized face-to-face learning interactions, such as flipped learning, should be actively utilized for medical and other students' education.

Clinical Implications of Geometric and Dosimetric Uncertainties of Inter- and Intra-Fractional Movement during Volumetric Modulated Arc Therapy for Breast Cancer Patients.

With the introduction of modern sophisticated radiotherapy (RT) techniques, the significance of accuracy has increased considerably. This study evaluated the necessity of pre-treatment and intra-fractional cone-beam computed tomography (CBCT) by analyzing inter- and intra-fractional CBCT images of breast cancer patients receiving RT. From 57 patients, 1206 pre-treatment CBCT and 1067 intra-fractional CBCT images were collected. Geometric movements of patients were measured quantitively in both inter- and intra-fractional CBCT, and changes in dosimetric parameters were evaluated in selected patients with extreme intra-fractional movement. For right-sided breast cancer patients, left-sided breast cancer patients treated using deep-inspiration breath hold (DIBH), and left-sided breast cancer patients treated using continuous positive airway pressure (CPAP), median inter-fractional deviations were 0.53 (range 0.06-2.98) cm, 0.66 (range 0.08-4.41) cm, and 0.69 (range 0.04-3.80) cm, and median intra-fractional deviations were 0.14 (range 0.00-0.62) cm, 0.23 (range 0.02-0.96) cm, and 0.24 (0.00-1.15) cm, respectively. Modified plans reflecting large changes in intra-fractional position in 10 selected cases revealed insufficient target coverage in seven cases and more than 20-fold increase in the volume of heart receiving at least 25 Gy in two cases. Intra-fractional verification, as well as pre-treatment verification, might be considered in patients using DIBH or CPAP.

Analysis of patterns of failure and appraisal of postoperative radiation field for grade II-III meningioma.

PURPOSE: To analyze patterns of failure according to treatment modalities and evaluate the adequacy of an institution's current volume of postoperative radiotherapy (PORT) for World Health Organization (WHO) grade II or III meningiomas. PATIENTS AND METHODS: Data of 98 patients treated by either surgery and PORT (PORT group, n = 53) or surgery alone (surgery group, n = 45) between March 2000 and December 2013 were reviewed. Clinical target volume of PORT was delineated as a 1.5-2-cm expansion from the tumor bed. Local failure (LF) was defined as recurrence within a 2-cm margin from the tumor bed. Failures other than LF were defined as out-field failure (OFF). Median total dose of PORT was 59.4 (range 45.0-69.0) Gy. RESULTS: The PORT group had larger proportions of grade III meningiomas (18/53, 34.0%) than the surgery group (8/46, 15.6%) (p = 0.037). After a median 73.4-month follow-up, 29 patients experienced LF and 5 developed OFF. The actuarial 5-year local control (LC) rates were 86.7% and 59.3% in the PORT and surgery groups, respectively (p = 0.002). PORT was a significant factor of LC in the univariate (p = 0.003, hazard ratio [HR] 3.449, 95% confidence interval [CI] 1.516-7.846) and multivariate analyses (p < 0.001, HR 5.486, 95% CI 2.178-13.820). CONCLUSIONS: Despite the larger proportion of grade III meningiomas in the PORT group, PORT reduced LF in patients with WHO grade II or III meningiomas compared with the surgery group. The current PORT field seems reasonable because LF was the dominant pattern of failure in patients treated by surgery alone.

Combining deep-inspiration breath hold and intensity-modulated radiotherapy for gastric mucosa-associated lymphoid tissue lymphoma: Dosimetric evaluation using comprehensive plan quality indices.

BACKGROUND: Although there have been many attempts to increase the therapeutic ratio of radiotherapy for gastric mucosa-associated lymphoid tissue lymphoma (MALToma), only a few planning studies have reported the efficacy of the modern radiotherapy technique till date. Therefore, we performed the dosimetric comparison among 3-dimensional conformal radiotherapy (3D-CRT) and intensity-modulated radiotherapy (IMRT) plans, using deep-inspiration breath hold (DIBH) or free-breathing (FB) techniques, to determine the most optimal plan for gastric MALToma. METHODS: We evaluated 9 patients with gastric MALToma for whom 3D-CRT, step-and-shoot IMRT (SIMRT), volumetric-modulated arc therapy (VMAT), and tomotherapy plans with identical prescribed doses were generated using DIBH or FB computed tomography (CT). Planning target volume (PTV) coverage and non-target doses were calculated for each plan and compared with plan quality metric (PQM) scores. RESULTS: All 72 plans of 9 patients satisfied our dosimetric goals, and the IMRT plans and 3D-CRT plans had similarly good conformity index values with no differences related to respiratory movement. IMRT plans yielded significantly better doses to the organs-at-risk, and DIBH plans yielded significantly lower liver, heart, and lung Dmean and spinal cord Dmax with smaller irradiated volumes compared to FB plans. For the mean PQM scores, VMAT-DIBH and SIMRT-DIBH yielded the best scores, whereas 3D plans provided reduced beam monitor unit values. CONCLUSION: Our findings demonstrate that modern RT technologies (DIBH with VMAT or SIMRT) could potentially provide excellent target coverage for gastric MALToma while reducing doses to organs-at-risk. However, the relevance of the most optimal plan considering clinical outcomes should be confirmed further in a larger patient cohort.

Clinical safety and efficacy of salvage reirradiation for upper abdominal malignancies.

PURPOSE: Reirradiation has the potential to provide effective local control of upper abdominal malignancies. This study aimed to evaluate the safety and efficacy of reirradiation for upper abdominal malignancies. METHODS: A total of 42 patients with a history of prior radiotherapy (RT) received reirradiation for abdominal malignancies between 2005 and 2017. Each patient's medical records, contours, and dose distribution for both RT courses were reviewed. The median dose of the prior RT was 50.0 Gy (range, 30.0-60.0 Gy) and the median dose of reirradiation was 45.0 Gy (range, 15.0-75.0 Gy). RESULTS: With a median follow-up of 10.9 months, the median infield-failure-free survival (IFFS) rate was 9.2 months. Gross tumor volume (GTV) significantly related to IFFS in both the univariate (p = 0.009) and multivariate analyses (p = 0.024), and patients with a GTV of <60.0 mL had an improved IFFS (p = 0.001). Four patients experienced ≥grade 3 late toxicities. In the retrospective dose reconstruction analysis in these patients, the cumulative dose to the most exposed 2 cc (D2cc) of the duodenum was >60.0 Gy (range, 60.1-73.7 Gy). In the univariate analysis, the D2cc of the duodenum and a preexisting duodenal ulcer identified using endoscopy prior to reirradiation significantly correlated with late severe toxicity (p = 0.021 and 0.017, respectively). CONCLUSIONS: Reirradiation for upper abdominal malignancies could be safely performed for patients without preexisting gastrointestinal morbidity unless the duodenum received excessive radiation doses. Reirradiation could also provide substantial IFFS, especially for patients with a GTV of <60.0 mL.

Predictive factors of symptomatic radiation pneumonitis in primary and metastatic lung tumors treated with stereotactic ablative body radiotherapy.

PURPOSE: Although stereotactic ablative body radiotherapy (SABR) is widely used therapeutic technique, predictive factors of radiation pneumonitis (RP) after SABR remain undefined. We aimed to investigate the predictive factors affecting RP in patients with primary or metastatic lung tumors who received SABR. MATERIALS AND METHODS: From 2012 to 2015, we reviewed 59 patients with 72 primary or metastatic lung tumors treated with SABR, and performed analyses of clinical and dosimetric variables related to symptomatic RP. SABR was delivered as 45-60 Gy in 3-4 fractions, which were over 100 Gy in BED when the α/ß value was assumed to be 10. Tumor volume and other various dose volume factors were analyzed using median value as a cutoff value. RP was graded per the Common Terminology Criteria for Adverse Events v4.03. RESULTS: At the median follow-up period of 11 months, symptomatic RP was observed in 13 lesions (12 patients, 18.1%), including grade 2 RP in 11 lesions and grade 3 in 2 lesions. Patients with planning target volume (PTV) of ≤14.35 mL had significantly lower rates of symptomatic RP when compared to others (8.6% vs. 27%; p = 0.048). Rates of symptomatic RP in patients with internal gross tumor volume (iGTV) >4.21 mL were higher than with ≤4.21 mL (29.7% vs. 6.1%; p = 0.017). CONCLUSIONS: The incidence of symptomatic RP following treatment with SABR was acceptable with grade 2 RP being observed in most patients. iGTV over 4.21 mL and PTV of over 14.35 mL were significant predictive factors related to symptomatic RP.

In vivo dosimetry and acute toxicity in breast cancer patients undergoing intraoperative radiotherapy as boost.

PURPOSE: To report the results of a correlation analysis of skin dose assessed by in vivo dosimetry and the incidence of acute toxicity. This is a phase 2 trial evaluating the feasibility of intraoperative radiotherapy (IORT) as a boost for breast cancer patients. MATERIALS AND METHODS: Eligible patients were treated with IORT of 20 Gy followed by whole breast irradiation (WBI) of 46 Gy. A total of 55 patients with a minimum follow-up of 1 month after WBI were evaluated. Optically stimulated luminescence dosimeter (OSLD) detected radiation dose delivered to the skin during IORT. Acute toxicity was recorded according to the Common Terminology Criteria for Adverse Events v4.0. Clinical parameters were correlated with seroma formation and maximum skin dose. RESULTS: Median follow-up after IORT was 25.9 weeks (range, 12.7 to 50.3 weeks). Prior to WBI, only one patient developed acute toxicity. Following WBI, 30 patients experienced grade 1 skin toxicity and three patients had grade 2 skin toxicity. Skin dose during IORT exceeded 5 Gy in two patients: with grade 2 complications around the surgical scar in one patient who received 8.42 Gy. Breast volume on preoperative images (p = 0.001), ratio of applicator diameter and breast volume (p = 0.002), and distance between skin and tumor (p = 0.003) showed significant correlations with maximum skin dose. CONCLUSIONS: IORT as a boost was well-tolerated among Korean women without severe acute complication. In vivo dosimetry with OSLD can help ensure safe delivery of IORT as a boost.