Higher Microbial Abundance and Diversity in Bronchus-Associated Lymphoid Tissue (BALT) Lymphomas than in Non-Cancerous Lung Tissues.

Purpose: It is well known that the majority of the extranodal marginal zone lymphomas of mucosa-associated lymphoid tissues (MALT lymphomas) are associated with microbiota, e.g., gastric MALT lymphoma with Helicobacter pylori. In general, they are very sensitive to low-dose radiotherapy and chemotherapeutic agents. The microbiota profile is not clearly elucidated in bronchus-associated lymphoid tissue (BALT) lymphoma, a rare type of MALT lymphoma in the lung. Thus, this study aimed to clarify the intratumor microbiome in BALT lymphoma using the third-generation NGS method. Materials and Methods: DNAs were extracted from 12 formalin-fixed paraffin-embedded (FFPE) tumor tissues obtained from BALT lymphoma patients diagnosed between 1990 and 2016. 16S rRNA gene was amplified by polymerase chain reaction. Amplicons were sequenced using a Nanopore platform. Next-generation sequencing analysis was performed to assess microbial profiles. For comparison, FFPE specimens from nine non-cancerous lung tissues were also analyzed. Results: Specific bacterial families including Burkholderiaceae, Bacillaceae, and Microbacteriaceae were associated with BALT lymphoma by a linear discriminant analysis effect size approach. Although the number of specimens was limited, BALT lymphomas exhibited significantly higher microbial abundance and diversity with distinct microbial composition patterns and correlation networks than non-cancerous lung tissues. Conclusion: This study provides the first insight into intratumor microbiome in BALT lymphoma using the third-generation NGS method. A distinct microbial composition suggests the presence of a unique tumor microenvironment of BALT lymphoma.

Development of a novel tool for high-precision focal irradiation using a clinical brachytherapy system.

PURPOSE: This study aims to emphasize the necessity of a focal irradiation tool for small animals and compare the beam characteristics of a tool developed using a brachytherapy system with a linear accelerator (LINAC)-based tool. METHODS: A 1-mm tungsten collimator was designed for a Ir-192 brachytherapy system. The percent depth dose (PDD) and horizontal profile of the collimator were measured and compared with a 4-mm commercial cone in the LINAC. Monte Carlo simulations validated all the measurements. Mouse brains were irradiated using a focal irradiation tool, and immunohistochemistry was performed on the brain samples to assess the dose accuracy. RESULTS: PDD showed that the maximum dose (dmax) for Ir-192 was at the surface in both measurements and simulations. At a depth of 1 mm, the collimator measured doses of 25.6 % and 21.0 %, respectively. At 6 MV in the LINAC, the dmax was observed at depths of 0.7 and 0.8 cm in measurements and simulations, respectively. The full width at half maximum (FWHM) at a depth of 1 mm was 1.0 and 1.1 mm for Ir-192 in the measurements and simulations, respectively. For small cone sizes at dmax, FWHM was 4.0 and 4.1 mm for the measurements and simulations, respectively. Immunohistochemistry results indicated that focal irradiation with Ir-192 affected small superficial brain areas while sparing the contralateral side and subventricular zone. CONCLUSION: The focal irradiation tool accurately delivered doses to small regions and shallow depths in the mouse brain, making it valuable for precise radiotherapy during small animal experiments.

Palliative Radiotherapy for Symptomatic Primary Tumors in Patients With Locally Advanced Breast Cancer.

Breast cancer remains a significant health concern for women, with a significant number of women facing unresectable, symptomatic, and advanced disease that severely affects their quality of life. Palliative radiotherapy (RT) is a well-established modality for managing such cases and alleviating symptoms. Recent advancements in systemic therapies and the resulting increase in long-term survival rates have not only heightened the need for retreatment in certain patients, but have also emphasized the importance of achieving durable local control. Additionally, inconsistencies in RT referral timing and variations in disease severity and extent contribute to diverse RT objectives and expected outcomes. The optimal dose fractionation for RT remains underexplored. Furthermore, a deeper understanding of breast radiobiology, along with the introduction of ultra- and moderately hypofractionated regimens and the widespread adoption of conformal techniques such as intensity-modulated RT, has diversified the approaches in RT dose and target volume. This review aimed to provides a comprehensive summary of the current evidence on the efficacy, outcomes, and toxicity profiles of palliative RT for symptomatic breast cancer. It highlights the need for more optimized regimens and further research to address the evolving treatment landscape and differing expectations of patients and physicians regarding RT.

Abscopal effect in metastatic breast cancer treated with stereotactic body radiotherapy in the absence of immunotherapy.

Purpose: In this study, we aimed to assess the abscopal effect (AE) after CyberKnife stereotactic body radiotherapy (SBRT) in metastatic breast cancer patients without immunotherapy. Methods: We reviewed breast cancer patients who received SBRT with a fraction size of ≥ 6 Gy for metastatic lesions between July 2008 and December 2021. We selected patients who had at least one measurable extracranial lesion in addition to SBRT target lesions and were not treated with immunotherapy. A total of 40 SBRT cases from 34 patients were included in the analysis. The AE was defined as occurring before the overall progression of the disease, regardless of the use of systemic treatment. Results: The median follow-up duration was 16.4 months. Among 40 SBRT cases, the AE was observed in 10 (25.0%) with a median interval of 2.1 months. Of these lesions, 70.0% did not progress for one year. In multivariate logistic regression analysis, no change in systemic treatment after SBRT was significantly associated with an increase in the AE (odds ratio [OR] = 1.428, 95% confidence interval [CI] = 1.108 - 1.841, p = 0.009). A post-SBRT neutrophil-to-lymphocyte ratio (NLR) of < 2 marginally increased the AE (OR = 1.275, 95% CI = 0.998 - 1.629, p = 0.060). However, a high SBRT dose and large planning target volume did not (p = 0.858 and 0.152, respectively) in univariate analysis. Conclusions: One out of four patients experienced the AE after SBRT in the absence of immunotherapy. The AE could occur more frequently when systemic treatment remains unchanged, and patients have a low NLR after SBRT.

Clinicopathological Outcomes in Patients With Locally Advanced Rectal Cancer Undergoing Preoperative Short-Versus Long-course Chemoradiotherapy With Delayed Surgery.

BACKGROUND/AIM: We aimed to compare the clinicopathological outcomes in patients with locally advanced rectal cancer after short- or long-course concurrent chemoradiotherapy (CCRT) followed by delayed surgery. PATIENTS AND METHODS: The records of 94 patients with cT3-4N0-2M0 rectal cancer who received CCRT between 2010 and 2017 were reviewed. Short-course radiotherapy (RT) was delivered with a median total dose of 25 Gy in five fractions (n=27), and long-course RT was delivered with a median total dose of 50.4 Gy in 28 fractions (n=67). The following concurrent chemotherapy regimens were administered: 5-fluorouracil plus leucovorin in 58 and capecitabine in 24; in 12 cases agents were unknown. The median interval between CCRT and surgery was 8 weeks. Adjuvant chemotherapy was administered after surgery in 80 patients (5-fluorouracil plus leucovorin, n=54; capecitabine, n=9; other, n=14; and unknown, n=3). Propensity-score matching analysis was conducted. RESULTS: The median follow-up duration was 4.3 years. There were no statistically significant differences between the short- and long-course RT groups in sphincter preservation (85.2% vs. 92.5%, p=0.478), pathological complete remission (18.5% vs. 14.9%, p=0.905), downstaging (44.4% vs. 26.9%, p=0.159), and negative circumferential resection margin (92.6% vs. 89.6%, p=0.947) rates. No differences were found in survival outcomes between the short- and long-course groups at 3 years (overall survival: 91.8% vs. 88.1%, p=0.790; disease-free survival, 75.2% vs. 72.5%, p=0.420; locoregional relapse-free survival, 90.5% vs. 98.4%, p=0.180; and distant metastasis-free survival, 79.6% vs. 73.5%, p=0.490). Similar results were observed after PSM. CONCLUSION: Clinically, short-course CCRT may be a feasible alternative to long-course CCRT in patients with locally advanced rectal cancer.

Exploring the past, present, and future of postoperative radiotherapy for N2 stage non-small cell lung cancer.

Despite conventionally applied postoperative radiotherapy (PORT) in pathological N2 (pN2) stage non-small cell lung cancer (NSCLC) considering high locoregional recurrence, its survival benefit has been a continuous topic of debate. Although several randomized clinical trials have been conducted, many of them have been withdrawn or analyzed without statistical significance due to slow accrual, making it difficult to determine the efficacy of PORT. Recently, the results of large-scale randomized clinical trials have been published, which showed some improvement in disease-free survival with PORT, but finally had no impact on overall survival. Based on these results, it was expected that the debate over PORT in pN2 patients with NSCLC would come to an end. However, since pN2 patients have different clinicopathologic features, it has become more important to carefully select the patient population who will benefit from PORT. In addition, given the development of systemic treatments such as molecular-targeted therapy and immunotherapy, it is crucial to evaluate whether there is any benefit to PORT in the midst of these recent changes. Therefore, determining the optimal treatment approach for NSCLC pN2 patients remains a complex issue that requires further research and evaluation.

Evaluating the Necessity of Adaptive RT and the Role of Deformable Image Registration in Lung Cancer with Different Pathologic Classifications.

BACKGROUND: This study aimed to analyze differential radiotherapy (RT) responses according to the pathological type of lung cancer to see the possibility of applying adaptive radiotherapy (ART). METHODS: ART planning with resampled-computed tomography was conducted for a total of 30 patients (20 non-small-cell lung cancer patients and 10 small-cell lung cancer patients) using a deformable image registration technique to reveal gross tumor volume (GTV) changes according to the duration of RT. RESULTS: The small-cell lung cancer group demonstrated an average GTV reduction of 20.95% after the first week of initial treatment (p = 0.001), whereas the adenocarcinoma and squamous cell carcinoma groups showed an average volume reduction of 20.47% (p = 0.015) and 12.68% in the second week. The application of ART according to the timing of GTV reduction has been shown to affect changes in radiation dose irradiated to normal tissues. This suggests that ART applications may have to be different depending on pathological differences in lung cancer. CONCLUSION: Through these results, the present study proposes the possibility of personalized treatment options for individual patients by individualizing ART based on specific radiation responses by pathologic types of lung cancer.

Evaluation of Efficacy and Safety Using Low Dose Radiation Therapy with Alzheimer's Disease: A Protocol for Multicenter Phase II Clinical Trial.

BACKGROUND: Alzheimer's disease (AD), the most common cause of dementia, is a neurodegenerative disease resulting from extracellular and intracellular deposits of amyloid-ß (Aß) and neurofibrillary tangles in the brain. Although many clinical studies evaluating pharmacological approaches have been conducted, most have shown disappointing results; thus, innovative strategies other than drugs have been actively attempted. OBJECTIVE: This study aims to explore low-dose radiation therapy (LDRT) for the treatment of patients with AD based on preclinical evidence, case reports, and a small pilot trial in humans. METHODS: This study is a phase II, multicenter, prospective, single-blinded, randomized controlled trial that will evaluate the efficacy and safety of LDRT to the whole brain using a linear accelerator in patients with mild AD. Sixty participants will be randomly assigned to three groups: experimental I (24 cGy/6 fractions), experimental II (300 cGy/6 fractions), or sham RT group (0 cGy/6 fractions). During LDRT and follow-up visits after LDRT, possible adverse events will be assessed by the physician's interview and neurological examinations. Furthermore, the effectiveness of LDRT will be measured using neurocognitive function tests and imaging tools at 6 and 12 months after LDRT. We will also monitor the alterations in cytokines, Aß42/Aß40 ratio, and tau levels in plasma. Our primary endpoint is the change in cognitive function test scores estimated by the Alzheimer's Disease Assessment Scale-Korea compared to baseline after 6 months of LDRT. CONCLUSIONS: This study is registered at ClinicalTrials.gov [NCT05635968] and is currently recruiting patients. This study will provide evidence that LDRT is a new treatment strategy for AD.

Plasma Circulating Cell-free DNA in Advanced Hepatocellular Carcinoma Patients Treated With Radiation Therapy.

BACKGROUND/AIM: Although radiation therapy (RT) is an effective and safe treatment when administered locally for various stages of hepatocellular carcinoma (HCC), adequate biomarkers that are predictive of therapeutic efficacy have not been identified. We evaluated the clinical utility of circulating cell-free DNA (cfDNA) to predict treatment response of patients with HCC treated with RT. PATIENTS AND METHODS: We prospectively recruited 37 patients diagnosed with HCC between March 2019 and May 2020. All patients were treated with RT as salvage therapy. Whole peripheral blood was collected twice, one before RT (baseline; V1) and another aliquot one week after the end of RT (V2). We determined whether cfDNA genomic copy number variations (CNVs) could predict treatment outcome. An I-score was calculated from the plasma cfDNA that reflected CNVs of cfDNA, which is evidence of genomic instability. RESULTS: The I-score at V1 exhibited a strong correlation with the planning target volume (PTV) (coefficient=0.65) and was a predictive marker for progression-free survival (PFS). In particular, a mean I-score value at V1 of ≥6.3 had a significant positive correlation with PFS (p=0.017). Compared with patients who had a complete response (CR) following RT, non-CR patients had a higher mean I-score value at V2 ≥6.2 (p=0.034). Furthermore, I-score values at V1 and V2 and the delta I-score ratio were significantly associated with a pre-RT alpha-fetoprotein level ≥200 among non-CR patients. CONCLUSION: I-score values calculated from plasma cfDNA represent a potential biomarker for predicting treatment outcomes in patients with advanced HCC receiving RT.

Comparison of initial and sequential salvage brain-directed treatment in patients with 1-4 vs. 5-10 brain metastases from breast cancer (KROG 16-12).

PURPOSE: We aimed to compare the initial and salvage brain-directed treatment and overall survival (OS) between patients with 1-4 brain metastases (BMs) and those with 5-10 from breast cancer (BC). We also organized a decision tree to select the initial whole-brain radiotherapy (WBRT) for these patients. METHODS: Between 2008 and 2014, 471 patients were diagnosed with 1-10 BMs. They were divided into two groups based on the number of BM: 1-4 BMs (n = 337) and 5-10 BMs (n = 134). Median follow-up duration was 14.0 months. RESULTS: Stereotactic radiosurgery (SRS)/fractionated stereotactic radiotherapy (FSRT) was the most common treatment modality (n = 120, 36%) in the 1-4 BMs group. In contrast, 80% (n = 107) of patients with 5-10 BMs were treated with WBRT. The median OS of the entire cohort, 1-4 BMs, and 5-10 BMs was 18.0, 20.9, and 13.9 months, respectively. In the multivariate analysis, the number of BM and WBRT were not associated with OS, whereas triple-negative BC and extracranial metastasis decreased OS. Physicians determined the initial WBRT based on four variables in the following order: number and location of BM, primary tumor control, and performance status. Salvage brain-directed treatment (n = 184), mainly SRS/FSRT (n = 109, 59%), prolonged OS by a median of 14.3 months. CONCLUSION: The initial brain-directed treatment differed notably according to the number of BM, which was chosen based on four clinical factors. In patients with ≤ 10 BMs, the number of BM and WBRT did not affect OS. The major salvage brain-directed treatment modality was SRS/FSRT and increased OS.

Identification of Genes Involved in EGF-induced Apoptosis Using CRISPR/Cas9 Knockout Screening: Implications for Novel Therapeutic Targets in EGFR-Overexpressing Cancers.

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 genome-wide 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,<.i> 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.

Plasma Cell-Free DNA in Uterine Cervical Cancer: Therapeutic Monitoring and Prognostic Values after Radical Radiotherapy.

PURPOSE: In the present study, we aimed to establish a liquid biopsy-based monitoring method using peripheral blood cell-free DNA (cfDNA) for patients with cervical cancer who underwent radical radiotherapy (RT). Materials and Methods: Twenty-five patients with cervical cancer were prospectively recruited and treated with external beam RT and brachytherapy. In all patients, except one, chemotherapy was administered concurrently during RT. Whole peripheral blood samples were obtained at least twice from each patient. We performed next-generation sequencing (NGS) for the target-captured libraries (67 oncogenes and human papillomavirus [HPV] type 16/18) using 64 plasma cfDNA samples from the 25 participants. The ratio of HPV cfDNA and the variant allele frequency (VAF) in cfDNA was calculated, and their dynamic changes were monitored. The median follow-up duration was 25.4 months. RESULTS: In total, we identified 21,866 cfDNA variants. ARID1A and frameshift variants occupied the largest portion of altered genes and HIGH-grade variant types, respectively. In most cases, tumor shrinkage was followed by a decrease in the HPV ratio; however, an increase in HPV ratio indicated distant metastasis, despite the reduced tumor size. The initial HPV ratio reflecting the tumor burden was likely associated with treatment outcomes (p = 0.16). We did not determine a role for serial changes in the VAF in cfDNA. CONCLUSION: Our findings suggest that the HPV cfDNA ratio, calculated after targeted NGS, may be valuable for monitoring and predicting treatment responses. Accordingly, further validation of these findings is warranted.

Feasibility of low-dose radiotherapy for patients with stage I/II extranodal NK-/T-cell lymphoma, nasal type achieving complete response after l-asparaginase-containing chemotherapy.

Purpose: To assess treatment outcomes in patients with stage I/II extranodal NK-/T-cell lymphoma, nasal type (ENKTCL-NT) and the feasibility of low-dose radiotherapy (RT) for achieving complete response (CR, defined as showing no residual hypermetabolic uptake on positron emission tomography [PET] or no residual lesions on computed tomography [CT]) after l-asparaginase-containing chemotherapy (l-ASP). Materials and methods: Between 1992 and 2018, 76 patients with early-stage ENKTCL-NT who achieved CR or partial response (PR) after induction chemotherapy received adjuvant RT. RT doses (using biologically equivalent doses in 2 Gy fractions [EQD2]) and rates of local recurrence-free survival (LRFS), locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS), progression-free survival (PFS), and cancer-specific survival (CSS) were determined. Results: Median follow-up was 5.1 years (range, 0.5-20.8). The median RT dose was 45 Gy (range, 20-54). The 5-year LRFS, LRRFS, DMFS, PFS, and CSS rates were 82.7 %, 78.2 %, 81.1 %, 68.7 %, and 84.4 %, respectively. CR after induction chemotherapy was notably linked to better survival outcomes across each endpoint. Survival outcomes were not affected either by the administration of l-ASP or EQD2 < 40 Gy in patients displaying CR after l-ASP. Adverse events (AEs) ≥ Grade 2 were significantly reduced with EQD2 < 40 Gy, compared with EQD2 ≥ 40 Gy. Conclusion: Achieving CR after chemotherapy was the most predictive factor of survival outcomes in early-stage ENKTCL-NT. Decreasing RT doses in patients with CR after l-ASP appeared to minimize the occurrence of AE without compromising LRR risk; however, longer follow-ups and cautious application are warranted.

Near-maximum rib dose is the most relevant risk factor for ipsilateral spontaneous rib fracture: a dosimetric analysis of breast cancer patients after radiotherapy.

PURPOSE: Spontaneous rib fracture (SRF) is a common late complication in treated breast cancer patients. This study evaluated the incidence and risk factors of ipsilateral SRF after radiotherapy (RT) in breast cancer patients. In addition, we identified dosimetric parameters that were significantly associated with ipsilateral SRF. METHODS: We retrospectively reviewed 2204 patients with breast cancer who underwent RT between 2014 and 2016, and were followed up with bone scans. We evaluated clinical risk factors for ipsilateral SRF. Dose-volume histogram analysis was also performed for patients (n = 538) whose dosimetric data were available. All ipsilateral ribs were manually delineated, and dosimetric parameters of the ribs were converted into the equivalent dose in 2 Gy fractions (EQD2). RESULTS: Most of the patients with SRF (87.3%) were asymptomatic, and the remaining symptomatic patients complained of mild tenderness or chest wall discomfort; these symptoms all resolved within 6 months without any treatment. Ipsilateral SRF occurred in 14.5% of patients 3 years after RT. The median time to develop ipsilateral SRF was 15 months. In dosimetric analysis, near-maximum rib dose (D2cc) best predicted ipsilateral SRF. The cut-off value of D2cc was EQD2 52 Gy, as determined by receiver operating characteristic analysis. In multivariate analysis including dosimetric variables, D2cc EQD2 ≥ 52 Gy was the only significant risk factor for ipsilateral SRF. CONCLUSION: Our data demonstrated that near-maximum rib dose was the best dosimetric parameter to predict ipsilateral SRF in RT-treated breast cancer patients. In addition, our results suggest that patients who received RT with exceeding rib dose cut-off value and had ipsilateral SRF on bone scan be recommended routine follow-up without additional imaging tests.

Prediction of breast cancer-related lymphedema risk after postoperative radiotherapy via multivariable logistic regression analysis.

Purpose: We identified novel clinical and dosimetric prognostic factors affecting breast cancer-related lymphedema after postoperative radiotherapy (RT) and developed a multivariable logistic regression model to predict lymphedema in these patients. Methods and materials: In total, 580 patients with unilateral breast cancer were retrospectively reviewed. All patients underwent breast surgery and postoperative RT with or without systemic treatment in 2015. Among the 580 patients, 532 with available RT plan data were randomly divided into training (n=372) and test (n=160) cohorts at a 7:3 ratio to generate and validate the lymphedema prediction models, respectively. An area under the curve (AUC) value was estimated to compare models. Results: The median follow-up duration was 5.4 years. In total, 104 (17.9%) patients experienced lymphedema with a cumulative incidence as follows: 1 year, 10.5%; 3 years, 16.4%; and 5 years, 17.6%. Multivariate analysis showed that body mass index ≥25 kg/m2 (hazard ratio [HR] 1.845), dissected lymph nodes ≥7 (HR 1.789), and taxane-base chemotherapy (HR 4.200) were significantly associated with increased lymphedema risk. Conversely, receipt of RT at least 1 month after surgery reduced the risk of lymphedema (HR 0.638). A multivariable logistic regression model using the above factors, as well as the minimum dose of axillary level I and supraclavicular lymph node, was created with an AUC of 0.761 and 0.794 in the training and test cohorts, respectively. Conclusions: Our study demonstrated that a shorter interval from surgery to RT and other established clinical factors were associated with increased lymphedema risk. By combining these factors with two dosimetric parameters, we propose a multivariable logistic regression model for breast cancer-related lymphedema prediction after RT.

Protocol for the postoperative radiotherapy in N1 breast cancer patients (PORT-N1) trial, a prospective multicenter, randomized, controlled, non-inferiority trial of patients receiving breast-conserving surgery or mastectomy.

BACKGROUND: Postoperative radiotherapy (PORT) could be useful for pN1 breast cancer patients who have undergone breast-conserving surgery (BCS) or mastectomy. However, the value of regional nodal irradiation (RNI) for BCS patients, and the indications for post-mastectomy radiotherapy (PMRT) for pN1 breast cancer mastectomy patients, have recently been challenged due to the absence of relevant trials in the era of modern systemic therapy. "PORT de-escalation" should be assessed in patients with pN1 breast cancer. METHODS: The PORT-N1 trial is a multicenter, randomized, phase 3 clinical trial for patients with pN1 breast cancer that compares the outcomes of control [whole-breast irradiation (WBI) and RNI/PMRT] and experimental (WBI alone/no PMRT) groups. PORT-N1 aims to demonstrate non-inferiority of the experimental group by comparing 7-year disease-free survival rates with the control group. Female breast cancer patients with pT1-3 N1 status after BCS or mastectomy are eligible. Participants will be randomly assigned to the two groups in a 1:1 ratio. Randomization will be stratified by surgery type (BCS vs. mastectomy) and histologic subtype (triple-negative vs. non-triple-negative). In patients who receive mastectomy, dissection of ≥5 nodes is required when there is one positive node, and axillary lymph node dissection when there are two or three positive nodes. Patients receiving neoadjuvant chemotherapy are not eligible. RNI includes a "high-tangent" or wider irradiation field. This study will aim to recruit 1106 patients. DISCUSSION: The PORT-N1 trial aims to verify that PORT de-escalation after BCS or mastectomy is safe for pN1 breast cancer patients in terms of oncologic outcomes and capable of reducing toxicity rates. This trial will provide information crucial for designing PORT de-escalation strategies for patients with pN1 breast cancer. TRIAL REGISTRATION: This trial was registered at ClinicalTrials.gov (NCT05440149) on June 30, 2022.

Validation of a nomogram for predicting the risk of lymphedema following contemporary treatment for breast cancer: a large multi-institutional study (KROG 20-05).

PURPOSE: We previously constructed a nomogram for predicting the risk of arm lymphedema following contemporary breast cancer treatment. This nomogram should be validated in patients with different background characteristics before use. Therefore, we aimed to externally validate the nomogram in a large multi-institutional cohort. METHODS: Overall, 8835 patients who underwent breast cancer surgery during 2007-2017 were identified. Data of variables in the nomogram and arm lymphedema were collected. The nomogram was validated externally using C-index and integrated area under the curve (iAUC) with 1000 bootstrap samples and by calibration plots. RESULTS: Overall, 1377 patients (15.6%) developed lymphedema. The median time from surgery to lymphedema development was 11.4 months. Lymphedema rates at 2, 3, and 5 years were 11.2%, 13.1%, and 15.6%, respectively. Patients with lymphedema had significantly higher body mass index (median, 24.1 kg/m2 vs. 23.4 kg/m2) and a greater number of removed nodes (median, 17 vs. 6) and more frequently underwent taxane-based chemotherapy (85.7% vs. 41.9%), total mastectomy (73.1% vs. 52.1%), conventionally fractionated radiotherapy (71.9% vs. 54.2%), and regional nodal irradiation (70.7% vs 22.4%) than those who did not develop lymphedema (all P < 0.001). The C-index of the nomogram was 0.7887, and iAUC was 0.7628, indicating good predictive accuracy. Calibration plots confirmed that the predicted lymphedema risks were well correlated with the actual lymphedema rates. CONCLUSION: This nomogram, which was developed using factors related to multimodal breast cancer treatment and was validated in a large multi-institutional cohort, can well predict the risk of breast cancer-related lymphedema.

The Pattern of Care for Brain Metastasis from Breast Cancer over the Past 10 Years in Korea: A Multicenter Retrospective Study (KROG 16-12).

PURPOSE: We aimed to investigate manifestations and patterns of care for patients with brain metastasis (BM) from breast cancer (BC) and compared their overall survival (OS) from 2005 through 2014 in Korea. MATERIALS AND METHODS: We retrospectively reviewed 600 BC patients with BM diagnosed between 2005 and 2014. The median follow-up duration was 12.5 months. We categorized the patients into three groups according to the year when BM was initially diagnosed (group I [2005-2008], 98 patients; group II [2009-2011], 200 patients; and group III [2012-2014], 302 patients). RESULTS: Over time, the median age at BM diagnosis increased by 2.2 years (group I, 49.0 years; group II, 48.3 years; and group III, 51.2 years; p=0.008). The percentage of patients with extracranial metastasis was 73.5%, 83.5%, and 86.4% for group I, II, and III, respectively (p=0.011). The time interval between BC and BM was prolonged in patients with stage III primary BC (median, 2.4 to 3 years; p=0.029). As an initial brain-directed treatment, whole-brain radiotherapy alone decreased from 80.0% in 2005 to 41.1% in 2014. Meanwhile, stereotactic radiosurgery or fractionated stereotactic radiotherapy alone increased from 13.3% to 34.7% during the same period (p=0.005). The median OS for group I, II, and III was 15.6, 17.9, and 15.0 months, respectively, with no statistical significance. CONCLUSION: The manifestations of BM from BC and the pattern of care have changed from 2005 to 2014 in Korea. However, the OS has remained relatively unchanged over the 10 years.

Novel prognostic classification predicts overall survival of patients receiving salvage whole-brain radiotherapy for recurrent brain metastasis from breast cancer: A recursive partitioning analysis (KROG 16-12).

BACKGROUND: To investigate outcomes of salvage whole-brain radiotherapy (WBRT) for recurrent brain metastases (BM) from breast cancer (BC), to identify prognostic factors of overall survival (OS), and to propose a novel prognostic classification for OS in these patients. MATERIALS AND METHODS: We identified 54 patients who had received salvage WBRT as the second brain-focused treatment for recurrent BM from BC (2000-2014). The median follow-up duration was 4.9 months. A recursive partitioning analysis (RPA) was conducted to develop a model to predict OS at the time of salvage WBRT. RESULTS: The median OS was 6.8 months. OS according to BC-specific graded prognostic assessment (breast-GPA), modified breast-GPA, and updated breast-GPA did not represent our cohort. In the multivariate analysis, a long time before salvage WBRT (≥16 months), control of primary BC or extracranial metastases, systemic treatment after salvage WBRT, and administration of a biologically effective dose for an α/ß of 10 Gy (BED10) of salvage WBRT >37.5 Gy showed superior OS. We proposed three RPA classes based on the control of both primary BC and extracranial metastasis and BED10 of salvage WBRT: class I, class II, and class III. In this model, patients with class I experienced the best OS (34.6 months; class II, 5.0 months; class III, 2.4 months; P < 0.001). CONCLUSIONS: In our RPA classification according to the control of both primary BC and extracranial metastasis and the dose of salvage WBRT, significant differences in OS were observed. The subsequent use of a systemic treatment showed better OS.

Population-based study on the association between autoimmune disease and lymphoma: National Health Insurance Service-National Sample Cohort 2002-2015 in Korea.

BACKGROUND: We aimed to evaluate the association between autoimmune disease (AID) and lymphoma incidence in the Korean population. We also aimed to compare the overall survival (OS) in patients with AID-associated lymphoma (AAL) with that in patients with lymphoma without AID. MATERIAL AND METHODS: We used National Sample Cohort 2002-2015 provided by National Health Insurance Service. Among 1,011,638 patients, 994,496 were recruited for the final cohort: 130,987 patients (13.2%) in the AID group and 863,509 (86.8%) in control. Lymphoma was diagnosed in 1162 patients and 322 patients with accompanying AID, irrespective of the time point of diagnosis, were defined as AAL. Of those, patients who experienced lymphoma development at least one year after AID diagnosis were defined as post-AID lymphoma (N = 155). RESULTS: The median follow-up duration was 13.7 years. AAL accounted for 0.03% of total and 27.7% of lymphoma cases. AID patients experienced more Epstein-Barr virus (0.02 vs. 0.01%, P = 0.027) or Helicobacter pylori infection (63.9 vs. 41.4%, P < 0.001) than the control group did. AID was associated with a 1.45-fold increased risk of lymphoma. The median time interval from AID to AAL was 10.9 months. The risk of lymphoma increased in the order of: psoriasis (adjusted odds ratio [AOR] 1.61), systemic lupus erythematosus (AOR 3.99), multiple sclerosis (AOR 4.52), and sarcoidosis (AOR 26.37). Sjogren syndrome was not related to lymphoma in this cohort. The 5-year OS in AAL was not different from that in lymphoma patients without AID (60.9 vs. 61.5%, P = 0.970). CONCLUSIONS: The association patterns in AAL in Korean population were different from those of Western countries. Further studies on lymphomatogenesis from distinct baseline characteristics (e.g. chronic infection status) would elucidate the difference based on race and ethnicity.