Oncological outcomes in patients with residual triple-negative breast cancer after preoperative chemotherapy.

PURPOSE: This study aimed to evaluate the clinical outcomes and prognostic implications of regional nodal irradiation (RNI) after neoadjuvant chemotherapy (NAC) in patients with residual triple-negative breast cancer (TNBC). MATERIALS AND METHODS: We analyzed 152 patients with residual TNBC who underwent breast-conserving surgery after NAC between December 2008 and December 2017. Most patients (n = 133; 87.5%) received taxane-based chemotherapy. Adjuvant radiotherapy (RT) was administered at a total dose of 45-65 Gy in 15-30 fractions to the whole breast, with some patients also receiving RT to regional nodes. Survival was calculated using the Kaplan-Meier method, and prognostic factors influencing survival were analyzed using the Cox proportional-hazards model. RESULTS: During a median follow-up of 66 months (range, 9 to 179 months), the 5-year disease-free survival (DFS) rate was 68.0%. The 5-year locoregional recurrence-free survival, distant metastasis-free survival, and overall survival rates were 83.6%, 72.6%, and 78.7%, respectively. In the univariate analysis, the cN stage, ypT stage, ypN stage, axillary operation type, and RT field were associated with DFS. Multivariate analysis revealed that higher ypT stage (hazard ratio [HR] = 2.0; 95% confidence interval [CI] 1.00-3.82; p = 0.049) and ypN stage (HR = 4.7; 95% CI 1.57-14.24; p = 0.006) were associated with inferior DFS. Among clinically node-positive patients, those who received RT to the breast only had a 5-year DFS of 73.7%, whereas those who received RNI achieved a DFS of 59.6% (p = 0.164). There were no differences between the DFS and RNI. CONCLUSION: In patients with residual TNBC, higher ypT and ypN stages were associated with poorer outcomes after NAC. RNI did not appear to improve DFS. More intensive treatments incorporating systemic therapy and RT should be considered for these patients.

Patient-reported outcomes between whole-breast plus regional irradiation and whole-breast irradiation only in pN1 breast cancer after breast conserving surgery and taxane-based chemotherapy: A randomized phase 3 clinical trial (KROG 17-01).

BACKGROUND: The role of regional node irradiation (RNI) with whole-breast irradiation (WBI) in patients with pN1 breast cancer receiving taxane-based adjuvant chemotherapy is not well defined. The KROG 1701 trial, a phase III, multicenter, non-inferiority study, aimed to compare the disease-free survival between WBI+RNI and WBI alone in this patient cohort. Comprehensive patient-reported outcomes (PROs) collected at multiple time points are reported. METHODS: The trial (NCT03269981) enrolled patients with pN1 breast cancer after breast-conserving surgery and taxane-based adjuvant chemotherapy, allocating them to receive either WBI +RNI or WBI only. PROs were assessed using EORTC QLQ-C30 and QLQ-BR23 modules at baseline, during RT, and at subsequent follow-up intervals of 3-6 months, and annually up to 4years. RESULTS: From April 2017 to December 2021, 840 patients were enrolled; 777 received intervention as assigned, and 750 completed baseline PRO questionnaires (387 in WBI+RNI, 363 in WBI only). All PRO domains showed improvements over time (p<0.001). During RT, the WBI+RNI group reported greater fatigue and nausea. Higher arm symptom scores were observed in the WBI+RNI group 3 months post-treatment (p=0.030). No other significant PRO domain differences, including arm/breast symptoms, were observed between the two groups. CONCLUSION: In patients with pN1 breast cancer treated with taxane-based chemotherapy, adding RNI to WBI resulted in minor, temporary declines in specific PRO domains, but these differences were not clinically significant. This indicates that overall patient experience between WBI+RNI and WBI is comparable, supporting the safety and patient tolerability of both treatments.

Scapula position test reliability and comparisons of scapula position and shoulder function among individuals with and without adolescent idiopathic scoliosis.

BACKGROUND: An evaluation of scapula position is important to predict spine curvature and shoulder function in patients with adolescent idiopathic scoliosis (AIS). Therefore, a reliable scapula position is required to assess posture in patients with AIS. OBJECTIVE: This study investigated the reliabilities of scapula position tests and differences in scapula position and shoulder function between individuals with and without AIS. METHODS: The study compared 18 patients with AIS and 18 healthy controls to identify differences in scapula position and shoulder function. The acromion-table distance, lateral displacement of the scapula, acromion depression, winged scapula, upward rotation of the scapula, and anterior tilt of the scapula were measured. Scapula position test reliabilities were assessed using the intraclass correlation coefficient (ICC), standard error of measurement (SEM), and minimum clinically important difference (MCID). Shoulder function was measured using the Shoulder Pain and Disability Index. RESULTS: The reliabilities of scapula position tests (ICC 0.85-0.93, SEM 0.1-1.2, and MCID 0.2-2.5) were good. There were significant differences in scapula position and shoulder function between patients with AIS and healthy controls (p< 0.05). CONCLUSION: Scapula position tests were highly reliable in patients with AIS; they can be used to evaluate scapula position during clinical assessment of posture in patients with AIS.

Tailored radiation dose according to margin width for patients with ductal carcinoma in situ after breast-conserving surgery.

A 2 mm resection margin is considered adequate for ductal carcinoma in situ (DCIS). We assessed the effectiveness of a tailored radiation dose for margins < 2 mm and the appropriate margin width for high-risk DCIS. We retrospectively evaluated 137 patients who received adjuvant radiotherapy after breast-conserving surgery for DCIS between 2013 and 2019. The patients were divided into three- positive, close (< 2 mm), and negative (≥ 2 mm) margin groups. Radiation dose to the tumor bed in equivalent dose in 2 Gy fractions were a median of 66.25 Gy, 61.81 Gy, and 59.75 Gy for positive, close, and negative margin groups, respectively. During a median follow-up of 58 months, the crude rates of local recurrence were 15.0%, 6.7%, and 4.6% in the positive, close, and negative margin groups, respectively. The positive margin group had a significantly lower 5-year local recurrence-free survival (LRFS) rate compared to the close and negative margin groups in propensity-weighted log-rank analysis (84.82%, 93.27%, and 93.20%, respectively; p = 0.008). The difference in 5-year LRFS between patients with the high- and non-high-grade tumors decreased as the margin width increased (80.4% vs. 100.0% for margin ≥ 2 mm, p < 0.001; 92.3% vs. 100.0% for margin ≥ 6 mm, p = 0.123). With the radiation dose tailored for margin widths, positive margins were associated with poorer local control than negative margins, whereas close margins were not. Widely clear margins (≥ 2 mm) were related to favorable local control for high-grade DCIS.

Combined High-Dose Radiotherapy with Sequential Gemcitabine-Cisplatin Based Chemotherapy Increase the Resectability and Survival in Locally Advanced Unresectable Intrahepatic Cholangiocarcinoma: A Multi-institutional Cohort Study.

PURPOSE: The locally advanced unresectable intrahepatic cholangiocarcinoma (ICC) has detrimental oncological outcomes. In this study, we aimed to investigate the efficacy of radiotherapy in patients with locally advanced unresectable ICC. MATERIALS AND METHODS: Between 2001 and 2021, 116 patients were identified through medical record who underwent radiotherapy for locally advanced unresectable ICC. The resectability of ICC is determined by the multidisciplinary team at each institution. Overall survival (OS) were analyzed using the Kaplan-Meier method, and prognostic factors were analyzed using the Cox proportional hazards model. RESULTS: The median equivalent radiotherapy dose in 2 Gy fractions (EQD2) was 52 Gy (range, 30 to 110 Gy). Forty-seven patients (40.5%) received sequential gemcitabine-cisplatin based chemotherapy (GEM-CIS CTx). Multivariate analysis identified two risk factors, EQD2 of ≥ 60 Gy and application of sequential GEM-CIS CTx for OS. Patients were grouped by these two risk factors: group 1, EQD2 ≥ 60 Gy with sequential GEM-CIS CTx (n=25); group 2, EQD2 < 60 Gy with sequential GEM-CIS CTx or fluoropyrimidine-based concurrent chemoradiotherapy (n=70); and group 3, radiotherapy alone (n=21). Curative resection was more frequently undergone in group 1 than in groups 2 or 3 (28% vs. 8.6% vs. 0%, respectively). Consequently, OS was significantly better in group 1 than in groups 2 and 3 (p < 0.05). CONCLUSION: Combined high-dose radiotherapy with sequential GEM-CIS CTx improved oncologic outcomes in patients with locally advanced unresectable ICC. Further prospective studies are required to validate these findings.

Risk Factors for Distant Metastasis in Extrahepatic Bile Duct Cancer after Curative Resection (KROG 1814).

PURPOSE: Risk factors predicting distant metastasis (DM) in extrahepatic bile duct cancer (EHBDC) patients treated with curative resection were investigated. MATERIALS AND METHODS: Medical records of 1,418 EHBDC patients undergoing curative resection between Jan 2000 and Dec 2015 from 14 institutions were reviewed. After resection, 924 patients (67.6%) were surveilled without adjuvant therapy, 297 (21.7%) were treated with concurrent chemoradiotherapy (CCRT) and 148 (10.8%) with CCRT followed by chemotherapy. To exclude the treatment effect from innate confounders, patients not treated with adjuvant therapy were evaluated. RESULTS: After a median follow-up of 36.7 months (range, 2.7 to 213.2 months), the 5-year distant metastasis-free survival (DMFS) rate was 57.7%. On multivariate analysis, perihilar or diffuse tumor (hazard ratio [HR], 1.391; p=0.004), poorly differentiated histology (HR, 2.014; p < 0.001), presence of perineural invasion (HR, 1.768; p < 0.001), positive nodal metastasis (HR, 2.670; p < 0.001) and preoperative carbohydrate antigen (CA) 19-9 ≥ 37 U/mL (HR, 1.353; p < 0.001) were significantly associated with inferior DMFS. The DMFS rates significantly differed according to the number of these risk factors. For validation, patients who underwent adjuvant therapy were evaluated. In patients with ≥ 3 factors, additional chemotherapy after CCRT resulted in a superior DMFS compared with CCRT alone (5-year rate, 47.6% vs. 27.7%; p=0.001), but the benefit of additional chemotherapy was not observed in patients with 0-2 risk factors. CONCLUSION: Tumor location, histologic differentiation, perineural invasion, lymph node metastasis, and preoperative CA 19-9 level predicted DM risk in resected EHBDC. These risk factors might help identifying a subset of patients who could benefit from additional chemotherapy after resection.

Quantitative assessment of breast volume changes after whole-breast irradiation for breast cancer using breast auto-segmentation.

PURPOSE: This study aimed to quantitatively estimate the changes in breast volume associated with radiotherapy in patients undergoing breast-conserving surgery and whole-breast irradiation (WBI). METHODS: Pre-WBI simulation computed tomography (CT) scans and post-WBI follow-up chest CT scans from a total of 1,151 breast cancer patients were analyzed using a deep-learning-driven auto-segmentation approach. The CT-based asymmetry index (CTAI) was calculated by dividing the volume of the irradiated breast by the volume of the contralateral breast. Significant breast shrinkage was defined as a CTAI < 0.85. To quantify changes in CTAI over the follow-up period, the CTAI ratio was determined as the post-WBI CTAI divided by the pre-WBI CTAI. A multivariate logistic regression analysis was conducted to identify potential variables associated with post-WBI significant breast shrinkage. RESULTS: The median CTAI values for pre- and post-WBI CT scans were 0.973 (interquartile range: 0.887-1.069) and 0.866 (interquartile range: 0.773-0.967), respectively. The difference between them was statistically significant (p < 0.001). Following WBI, there was an increase in the rate of significant breast shrinkage from 16.3 to 44.8%. The CTAI ratio showed a negative association with the time interval (p < 0.001, Pearson r = - 0.310). In the multivariate logistic regression analysis, lower pre-WBI CTAI, younger age, and longer interval between CT scans were found to be significantly associated with a higher occurrence of post-WBI significant breast shrinkage. CONCLUSION: Breast volume decreases following WBI, and this decrease is correlated with an increased duration after WBI. These findings highlight the long-term consequences of WBI on breast asymmetry.

Assessment of deep learning-based auto-contouring on interobserver consistency in target volume and organs-at-risk delineation for breast cancer: Implications for RTQA program in a multi-institutional study.

PURPOSE: To quantify interobserver variation (IOV) in target volume and organs-at-risk (OAR) contouring across 31 institutions in breast cancer cases and to explore the clinical utility of deep learning (DL)-based auto-contouring in reducing potential IOV. METHODS AND MATERIALS: In phase 1, two breast cancer cases were randomly selected and distributed to multiple institutions for contouring six clinical target volumes (CTVs) and eight OAR. In Phase 2, auto-contour sets were generated using a previously published DL Breast segmentation model and were made available for all participants. The difference in IOV of submitted contours in phases 1 and 2 was investigated quantitatively using the Dice similarity coefficient (DSC) and Hausdorff distance (HD). The qualitative analysis involved using contour heat maps to visualize the extent and location of these variations and the required modification. RESULTS: Over 800 pairwise comparisons were analysed for each structure in each case. Quantitative phase 2 metrics showed significant improvement in the mean DSC (from 0.69 to 0.77) and HD (from 34.9 to 17.9 mm). Quantitative analysis showed increased interobserver agreement in phase 2, specifically for CTV structures (5-19 %), leading to fewer manual adjustments. Underlying IOV differences causes were reported using a questionnaire and hierarchical clustering analysis based on the volume of CTVs. CONCLUSION: DL-based auto-contours improved the contour agreement for OARs and CTVs significantly, both qualitatively and quantitatively, suggesting its potential role in minimizing radiation therapy protocol deviation.

Senescent tumor cells in colorectal cancer are characterized by elevated enzymatic activity of complexes 1 and 2 in oxidative phosphorylation.

BACKGROUND: Cellular senescence is defined as an irreversible cell cycle arrest caused by various internal and external insults. While the metabolic dysfunction of senescent cells in normal tissue is relatively well-established, there is a lack of information regarding the metabolic features of senescent tumor cells. METHODS: Publicly available single-cell RNA-sequencing data from the GSE166555 and GSE178341 datasets were utilized to investigate the metabolic features of senescent tumor cells. To validate the single-cell RNA-sequencing data, we performed senescence-associated ß-galactosidase (SA-ß-Gal) staining to identify senescent tumor cells in fresh frozen colorectal cancer tissue. We also evaluated nicotinamide adenine dinucleotide dehydrogenase-tetrazolium reductase (NADH-TR) and succinate dehydrogenase (SDH) activity using enzyme histochemical methods and compared the staining with SA-ß-Gal staining. MTT assay was performed to reveal the complex 1 activity of the respiratory chain in in-vitro senescence model. RESULTS: Single-cell RNA-sequencing data revealed an upregulation in the activity of complexes 1 and 2 in oxidative phosphorylation, despite overall mitochondrial dysfunction in senescent tumor cells. Both SA-ß-Gal and enzyme histochemical staining using fresh frozen colorectal cancer tissues indicated a high correlation between SA-ß-Gal positivity and NADH-TR/SDH staining positivity. MTT assay showed that senescent colorectal cancer cells exhibit higher absorbance in 600 nm wavelength. CONCLUSIONS: Senescent tumor cells exhibit distinct metabolic features, characterized by upregulation of complexes 1 and 2 in the oxidative phosphorylation pathway. NADH-TR and SDH staining represent efficient methods for detecting senescent tumor cells in colorectal cancer.