Incidental detection of ground glass nodules and primary lung cancer in patients with breast cancer: prevalence and long-term follow-up on chest computed tomography.

Background: Patients with breast cancer have a higher risk of developing lung cancer than the general population. The study aimed to evaluate the prevalence of ground glass nodule (GGN) and risk factors for GGN growth in patients with breast cancer and to evaluate the prevalence and pathologic features of lung cancer. Methods: We retrospectively reviewed the clinical data and chest computed tomography (CT) of 1,384 patients diagnosed with breast cancer who underwent chest CT between January 2008 and December 2022. We evaluated the prevalence of GGNs and their size changes on follow-up chest CT with volume doubling time (VDT) and identified independent risk factors associated with the growth of GGN using multivariable logistic regression analyses. Furthermore, the prevalence and pathologic features of lung cancer were also evaluated. Results: We detected persistent GGNs in 69 of 1,384 (5.0%) patients. The initial diameter of GGNs was 6.3±3.6 mm on average, with primarily (85.5%) pure GGNs. Among them, 27 (39.1%) exhibited interval growth with a median VDT of 1,006.0 days (interquartile range, 622.0-1,528.0 days) during the median 959.0 days (interquartile range, 612.0-1,645.0 days) follow-up period. Older age (P=0.026), part-solid nodules (P=0.006), and total number of GGNs (≥2) (P=0.007) were significant factors for GGN growth. Lung cancer was confirmed in 13 of 1,384 patients (0.9%), all with adenocarcinoma, including one case of minimally invasive adenocarcinoma. The cancers demonstrated a high rate of epidermal growth factor receptor (EGFR) mutation (69.2%). Conclusions: Persistent GGNs in breast cancer patients with high-risk factors should be adequately monitored for early detection and treatment of lung cancer.

Role of Radical Surgery Following Preoperative Chemoradiotherapy in Octogenarians With Rectal Cancer: A SEER Analysis.

BACKGROUND/AIM: There has been a growing trend toward a watch-and-wait strategy to avoid surgery. This study evaluated the prognostic outcomes of nonoperative management following chemoradiotherapy (CRT) in the very old patients with rectal cancer. PATIENTS AND METHODS: Using the Surveillance, Epidemiology, and End Results database, we conducted a retrospective analysis of octogenarians (age ≥80 years) with stage II-III rectal cancer who received neoadjuvant CRT with or without radical surgery between 2005 and 2016. Long-term survival outcomes of the two treatment strategies were compared. RESULTS: Propensity-matched cohorts were identified and analyzed for CRT followed by radical surgery vs. CRT alone (n=782). The 7-year rates of overall survival (OS) and disease-specific survival (DSS) of the two groups were 43% vs. 11% and 57% vs. 26%, respectively (p<0.001 for both comparisons). Radical surgery after CRT was the strongest prognostic factor associated with improved OS and DSS [hazard ratio (HR)=2.66 and 95% confidence interval (CI)=2.15-3.28 for OS; HR=2.50 and 95%CI=1.94-3.24 for DSS]. Based on the time-course hazard rate function plots of disease-specific mortality, short-term and late risk increments were observed in patients who underwent nonoperative management. CONCLUSION: This study highlights the importance of an active treatment strategy with radical surgery even in the highest age population with rectal cancer. Omitting surgery may not generally be considered safe when it is considered solely on chronological age. Further research is needed to identify the appropriate indications for nonoperative management.

Effects of Cinnamon (Cinnamomum zeylanicum) Extract on Adipocyte Differentiation in 3T3-L1 Cells and Lipid Accumulation in Mice Fed a High-Fat Diet.

Flavonoids and phenolic acid are two of the rich polyphenols found in cinnamon (Cinnamomum zeylanicum). The effects of cinnamon extract on the inhibition of adipocyte differentiation in 3T3-L1 fibroblast cells and prohibitory lipid accumulation in male mice fed a high-fat diet were examined. Upon treating 3T3-L1 cells with cinnamon for 3 days, the cinnamon inhibited lipid accumulation and increased gene expression levels, such as those of adiponectin and leptin. In in vivo experiments, mice were randomized into four groups after a one-week acclimation period, as follows: normal diet, normal diet + 1% cinnamon extract, high-fat diet, and high-fat diet + 1% cinnamon extract. After 14 weeks of supplementation, we found that cinnamon extract increased the expression of lipolysis-related proteins, such as AMPK, p-ACC, and CPT-1, and reduced the expression of lipid-synthesis-related proteins, such as SREBP-1c and FAS, in liver tissue. Our results show that cinnamon extract may exhibit anti-obesity effects via the inhibition of lipid synthesis and adipogenesis and the induction of lipolysis in both 3T3-L1 fibroblast cells and mice fed a high-fat diet. Accordingly, cinnamon extract may have potential anti-obesity effects.

Dynamic alterations in PD-1/PD-L1 expression level and immune cell profiles based on radiation response status in mouse tumor model.

Introduction: Based on the immunologic effects of anti-cancer treatment and their therapeutic implications, we evaluated radiotherapy (RT)-induced dynamic alterations in programmed death-1 (PD-1)/PD ligand-1 (PD-L1) expression profiles. Methods: Local RT with 2 Gy × 5 or 7.5 Gy × 1 was administered to the CT26 mouse model. Thereafter, tumors were resected and evaluated at the following predefined timepoints according to radiation response status: baseline, early (immediately after RT), middle (beginning of tumor shrinkage), late (stable status with RT effect), and progression (tumor regrowth). PD-1/PD-L1 activity and related immune cell profiles were quantitatively assessed. Results: RT upregulated PD-L1 expression in tumor cells from the middle to late phase; however, the levels subsequently decreased to levels comparable to baseline in the progression phase. RT with 2 Gy × 5 induced a higher frequency of PD-L1+ myeloid-derived suppressor cells, with a lesser degree of tumor regression, compared to 7.5 Gy. The proportion of PD-1+ and interferon (IFN)-γ+CD8α T cells continued to increase. The frequency of splenic PD-1+CD8+ T cells was markedly elevated, and was sustained longer with 2 Gy × 5. Based on the transcriptomic data, RT stimulated the transcription of immune-related genes, leading to sequentially altered patterns. Discussion: The dynamic alterations in PD-1/PD-L1 expression level were observed according to the time phases of tumor regression. This study suggests the influence of tumor cell killing and radiation dosing strategy on the tumor immune microenvironment.

Prognostic stratification based on the levels of tumor-infiltrating myeloid-derived suppressor cells and PD-1/PD-L1 axis in locally advanced rectal cancer.

Background: Although rectal cancer remains somewhat sanctuary to the contemporary immunotherapy, there is increasing knowledge on clinical implications of anti-tumor immunity. This study evaluated the prognostic relevance of two immune-inhibitory functions, myeloid-derived suppressor cells (MDSCs) and programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis. Methods: Study cohort is comprised of 165 patients with locally advanced rectal cancer who underwent neoadjuvant chemoradiotherapy followed by definitive resection. Using postsurgical tissue microarrays, the number of MDSCs, PD-1+/CD8+ tumor-infiltrating lymphocyte (TIL) ratio, and PD-L1 expression scores in stromal immune cells and tumor cells were assessed. Results: Positive correlation was observed between the PD-1+/CD8+ TIL ratio and number of MDSCs (P < 0.001). The greater the immune infiltrates, the higher the PD-L1 immune cell score (P < 0.001). MDSCHigh, PD-1+/CD8+ TILHigh, PD-L1 immune cell scoreLow, and PD-L1 tumor H-scoreHigh were associated with worse disease-free survival (DFS) (P < 0.001, P = 0.042, 0.047, and P < 0.001, respectively). To integrate the adverse effects of MDSCHigh, PD-1+/CD8+ TILHigh, and either PD-L1 immune cell scoreLow (set I) or tumor H-scoreHigh (set II), prognostic risks were stratified according to the number of factors: 0, 1, and 2-3 (P < 0.001 for I and II). On multivariate analyses, patients with multiple risk factors for set I and II had worse prognosis (P < 0.001; 2-3 vs. 0 for models I and II), and the two prognostic models had acceptable predictability. Conclusion: In this study, integration of the prognostic impact of MDSCs and PD-1/PD-L1 stratified the long-term risks of patients with locally advanced rectal cancer. Thus, further exploration could be focused to the identified subset of patients carrying worse prognosis, where potential benefits could be derived by targeting the two components contributing to the immunosuppressive microenvironment.

Chronic hyperglycemia is an adverse prognostic factor for locoregional recurrence-free survival in small cell lung cancer patients treated with radical radiotherapy.

BACKGROUND: Plasma glucose levels might be associated with the severity of tumor hypoxia in patients with cancer. In our previous study, we found that chronic hyperglycemia significantly increased the risk of locoregional recurrence in patients with non-small cell lung cancer treated with radical radiotherapy (RT). Here, we evaluated the association between plasma glucose levels in terms of hemoglobin A1c (HbA1c) and locoregional recurrence-free survival in patients with limited-stage small cell lung cancer treated with radical RT. METHODS: We retrospectively analyzed the clinical data of 59 patients with small cell lung cancer. HbA1c levels were measured 1 week before the start of RT. Survival outcomes were analyzed according to HbA1c levels. Multivariable analysis was conducted to identify whether HbA1c level was a significant prognostic factor for survival. RESULTS: The 1-, 2-, and 3-year locoregional recurrence-free survival rates were 90.9, 86.1, and 78.9%, respectively, in the low HbA1c group, and 45.1, 27.1, and 20.3%, respectively, in the high HbA1c group (p < 0.001). The 1-, 2-, and 3-year distant metastasis-free survival rates were 67.2, 57, and 57%, respectively, in the low HbA1c group, while it was 56.6, 24.9, and 24.9%, respectively, in the high HbA1c group (p = 0.024). HbA1c level remained a significant prognostic factor for locoregional recurrence-free survival in the multivariable analysis (p = 0.010). CONCLUSIONS: Chronic hyperglycemia is a significant prognostic factor for locoregional recurrence-free survival in patients with limited-stage small cell lung cancer treated with radical RT. Routine monitoring of plasma glucose levels and aggressive glycemic control should be conducted to prevent locoregional recurrence.

Survival impact of prophylactic cranial irradiation in small-cell lung cancer in the modern era of magnetic resonance imaging staging.

BACKGROUND: In the modern era of magnetic resonance imaging (MRI) staging, the benefit of prophylactic cranial irradiation (PCI) in patients with small-cell lung cancer (SCLC) has been controversial. This study evaluated the prognostic impact of PCI in patients with limited- or extensive-stage SCLC who had no brain metastases at diagnosis according to MRI. METHODS: Data from newly diagnosed patients in 2014 from the Korean Association for Lung Cancer Registry database were used. Patients with limited- or extensive-stage SCLC who had no brain metastases according to MRI were identified. Univariate and multivariate survival analyses were conducted to assess the prognostic association of PCI. RESULTS: Of 107 and 122 patients with limited- and extensive-stage SCLC, 24% and 14% received PCI, respectively. In the limited-stage SCLC group, the 2-year overall survival (OS) rates of patients who received PCI and those who did not were 50% and 29% (P = 0.018), respectively. However, there was no significant difference in OS for patients with extensive-stage SCLC (P = 0.336). After adjusting for other covariates, PCI was found to be associated with improved OS in the limited-stage SCLC group (P = 0.005). Based on the time-course hazard rate function plots in the limited-stage SCLC group, the OS benefit of PCI was maximized within the first year of follow-up. CONCLUSIONS: In the modern era of MRI staging, PCI might be beneficial for patients with limited-stage SCLC but not for those with extensive-stage SCLC. Further studies with a large sample size are needed to verify the prognostic association of PCI.

Radiomic models based on magnetic resonance imaging predict the spatial distribution of CD8+ tumor-infiltrating lymphocytes in breast cancer.

Infiltration of CD8+ T cells and their spatial contexture, represented by immunophenotype, predict the prognosis and therapeutic response in breast cancer. However, a non-surgical method using radiomics to evaluate breast cancer immunophenotype has not been explored. Here, we assessed the CD8+ T cell-based immunophenotype in patients with breast cancer undergoing upfront surgery (n = 182). We extracted radiomic features from the four phases of dynamic contrast-enhanced magnetic resonance imaging, and randomly divided the patients into training (n = 137) and validation (n = 45) cohorts. For predicting the immunophenotypes, radiomic models (RMs) that combined the four phases demonstrated superior performance to those derived from a single phase. For discriminating the inflamed tumor from the non-inflamed tumor, the feature-based combination model from the whole tumor (RM-wholeFC) showed high performance in both training (area under the receiver operating characteristic curve [AUC] = 0.973) and validation cohorts (AUC = 0.985). Similarly, the feature-based combination model from the peripheral tumor (RM-periFC) discriminated between immune-desert and excluded tumors with high performance in both training (AUC = 0.993) and validation cohorts (AUC = 0.984). Both RM-wholeFC and RM-periFC demonstrated good to excellent performance for every molecular subtype. Furthermore, in patients who underwent neoadjuvant chemotherapy (n = 64), pre-treatment images showed that tumors exhibiting complete response to neoadjuvant chemotherapy had significantly higher scores from RM-wholeFC and lower scores from RM-periFC. Our RMs predicted the immunophenotype of breast cancer based on the spatial distribution of CD8+ T cells with high accuracy. This approach can be used to stratify patients non-invasively based on the status of the tumor-immune microenvironment.

Safety analysis of ex vivo-expanded canine natural killer cells in a xenogeneic mouse model of graft-versus-host disease.

Canine natural killer (NK) cells are large, granular lymphocytes that are neither B lymphocytes nor T lymphocytes. However, it has been reported that canine NK cells share some of the phenotypic characteristics of T lymphocytes, such as CD3 and CD5. Studies are needed to assess the safety of canine NK cells for immunotherapy, especially because the safety of using allogeneic NK cells as an immunotherapy for dogs has yet to be shown. In this study, the safety of cultured canine NK cells was assessed using a xenogeneic mouse model of graft-versus-host disease (GVHD). Mice were injected with either canine peripheral blood mononuclear cells (PBMCs) or cultured NK cells for 2 or 3 weeks. Data were then collected on changes in mice body weights, disease severity scores, and survival rates. Histopathological and immunohistochemical evaluations were also performed. All mice injected with canine PBMCs died within 45 days after injection. Severe clinical signs were caused by GVHD. The histopathological and immunohistochemical evaluations showed that mice injected with canine PBMCs had multiple lesions, including necrosis in their lungs, livers, kidneys, and stomachs, and the injected cells were present around the lesions. By contrast, no mice injected with cultured NK cells without removing the CD3+ TCR- cells exhibited any clinical abnormalities. Moreover, they all survived the 90-day experimental period without exhibiting any histopathological changes. Accordingly, the results of this study suggest that canine NK cells do not cause significant side effects such as GVHD and allogeneic NK cells can safely be used for cancer immunotherapy in dogs.

Population-based comparative survival analysis of surgery with or without adjuvant radiotherapy and non-operative primary radiotherapy in patients with early-stage oral tongue squamous cell carcinoma.

PURPOSE: Although recent clinical guidelines do allow primary radiotherapy for selected patients with early-stage oral tongue cancer, there has been little knowledge on the treatment outcomes of non-operative radiotherapy using modern treatment techniques. This study evaluated recent prognostic differences between primary radiotherapy and surgical resection in T1‒2N0 oral tongue squamous cell carcinoma. METHODS: Patients diagnosed with T1‒2N0 oral tongue squamous cell carcinoma were identified from the Surveillance, Epidemiology, and End Results database. After propensity score matching, the disease-specific survival of primary radiotherapy and surgery was compared. RESULTS: From a total of 8,458 patients initially identified, we defined matched cohorts: cohort A, comparing surgery alone vs. primary radiotherapy (n = 230 vs. 230), and cohort B, comparing surgery plus adjuvant radiotherapy vs. primary radiotherapy (n = 230 vs. 230). The 7-year disease-specific survival rates were 77% vs. 35% (cohort A) and 65% vs. 35% (cohort B) (P < 0.001 for all comparisons). Primary radiotherapy was independently associated with worse disease-specific survival in both cohorts A (hazard ratio 4.06; 95% confidence interval 2.53‒6.52) and B (hazard ratio 2.81; 95% confidence interval 1.96‒4.04). Time-course hazard rate function plots showed a distinct short-term risk increment in disease-specific mortality in the primary radiotherapy group. CONCLUSION: In the contemporary treatment era, the use of radiotherapy as a definitive treatment resulted in an inferior prognosis in patients with T1‒2N0 oral tongue squamous cell carcinoma. The present population-based data suggest that primary radiotherapy cannot be used as an alternative to surgical management and it needs to be avoided as much as possible in early-stage tumors.

Hemoglobin A1c level is a prognostic factor for locoregional recurrence in stage III non-small cell lung cancer patients treated with radiotherapy.

BACKGROUND: The level of hemoglobin A1c (HbA1c) might be associated with the severity of tumor hypoxia in patients with cancer. Here, we evaluated the association between the level of HbA1c and survival outcome in stage III non-small cell lung cancer patients treated with radical radiotherapy. METHODS: We retrospectively analysed the clinical data of 104 patients with lung cancer treated with radiotherapy. The HbA1c levels of all patients were checked 1 week before the start of radiotherapy. Survival outcomes were analysed according to the HbA1c level. RESULTS: The 1-, 2-, and 3-year locoregional recurrence-free survival rates were 88.3%, 68.8%, and 63.0%, respectively, in the patient group with HbA1c levels ≤6% and 75.5%, 54.4%, and 41.8%, respectively, in the patient group with HbA1c levels >6% (p = 0.015). The HbA1c level remained a significant prognostic factor for locoregional recurrence-free survival on multivariable analysis (hazard ratio = 2.014, 95% confidence interval = 1.088-3.726, p = 0.026). CONCLUSIONS: Pretreatment HbA1c level is a significant prognostic factor for locoregional recurrence-free survival in patients with stage III non-small cell lung cancer treated with radical radiotherapy. Routine monitoring of pretreatment HbA1c levels and aggressive glycemic control may be considered to prevent the development of locoregional recurrence in these patients.

A radiomic signature model to predict the chemoradiation-induced alteration in tumor-infiltrating CD8+ cells in locally advanced rectal cancer.

BACKGROUND AND PURPOSE: Regarding the altered tumor immune status following cytotoxic treatment, this study aims to develop a radiomic signature to predict CD8+ tumor-infiltrating lymphocyte (TIL) density changes in chemoradiotherapy (CRT) of rectal cancer. MATERIALS AND METHODS: We used the magnetic resonance imaging (MRI) and immunohistochemistry data before and after neoadjuvant CRT. The discovery datasets consisted of pre-CRT dataset A1 (n = 113), post-CRT datasets A2 (n = 32; predominance of tumor) and A3 (n = 20; pure fibrosis). The developed model was validated in dataset B (n = 28). Thirty-eight radiomic features from T2-weighted MRI scans were incorporated into the least absolute shrinkage and selection operator method. RESULTS: In pre-CRT dataset A1, the area under the receiver operating characteristic curve (AUC) values of radiomic score for predicting CD8+ TILs were 0.760 and 0.729 for training and validation subsets, respectively. A significant correlation was observed between the signature and CD8+ TIL density in the post-CRT dataset A2 (Pearson's R = -0.372, P = 0.036), whereas no association was found in dataset A3 (Pearson's R = -0.069, P = 0.77). The association was also observed in the validation dataset B (Pearson's R = -0.374, P = 0.049). In dataset A2, the radiomic score difference predicted changes in CD8+ TIL density (AUC = 0.824). CONCLUSION: We established the MRI-derived radiomic signature for predicting CRT-induced alterations in CD8+ TILs. This study suggests the clinical utility of radiomics-immunophenotype modeling to evaluate tumor immune status following neoadjuvant chemoradiation in rectal cancer.

Image-based deep learning model for predicting pathological response in rectal cancer using post-chemoradiotherapy magnetic resonance imaging.

INTRODUCTION: To develop an image-based deep learning model for predicting pathological response in rectal cancer using post-chemoradiotherapy magnetic resonance (MR) imaging. MATERIALS AND METHODS: A total of 466 patients with locally advanced rectal cancer who received preoperative chemoradiotherapy followed by surgical resection were collected from single center, among whom 113 (24.3%) were allocated to the holdout testing set. Complete response (pCR) was defined as Dworak tumor regression grade (TRG) 4, while good response (GR) was defined as TRG 3 or 4. Based on post-chemoradiotherapy T2-weighted axial MR images, two deep learning models were developed to predict pCR and GR, respectively. The prediction performance of the deep learning models was evaluated in the testing set and was compared to that of a senior radiologist and a radiation oncologist. RESULTS: The deep learning model showed an area under the receiver operating characteristic curve, sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 0.76, 0.30, 0.96, 0.67, 0.87, and 85.0% for predicting pCR and 0.72, 0.54, 0.81, 0.60, 0.77, and 71.7% for predicting GR, respectively. The deep learning model had a superior predictive performance than the observers. Fair agreement between the ground truth and the model was shown for pCR prediction (kappa = 0.34) and GR prediction (kappa = 0.36). CONCLUSIONS: The post-chemoradiotherapy T2-weighted axial MR image-based deep learning model showed acceptable performance in predicting pCR or GR in patients with rectal cancer, compared with human observers.

Optimal use of radiotherapy in the definitive treatment of non-bulky IB-IIA cervical cancer: A population-based long-term survival analysis.

PURPOSE: Although current clinical guidelines recommend surgery or radiotherapy for non-bulky IB-IIA cervical cancer, clinical data supporting the curative role of radiotherapy in the early-stage disease are insufficient. We evaluated the prognostic implications of definitive radiotherapy and determined its optimal use in clinical practice. METHODS: Patients with non-bulky (<4 cm) IB-IIA cervical cancer who underwent hysterectomy or primary radiotherapy between 1988 and 2015 were identified from the Surveillance, Epidemiology, and End Results database. Based on the use of brachytherapy and/or chemotherapy, the primary radiotherapy group was classified into three cohorts: hysterectomy vs. radiotherapy overall, with/without brachytherapy and/or chemotherapy (cohort A); radiotherapy and brachytherapy with/without chemotherapy (patients with external beam radiation alone were excluded, cohort B); radiotherapy with brachytherapy and chemotherapy (patients who did not receive chemotherapy were additionally excluded, cohort C). Disease-specific survival (DSS) after hysterectomy was compared to that after primary radiotherapy in each cohort. RESULTS: Among the 9,391 initially identified patients, 1,762, 1,244, and 750 patients were classified into cohorts A, B, and C, respectively, after propensity score matching. In cohort A, DSS after primary radiotherapy was inferior to that after hysterectomy (P = 0.001). In cohort B, a trend toward differential survival in favor of hysterectomy was observed with marginal significance (P = 0.061). However, in cohort C, DSS after primary radiotherapy was not significantly different to that after hysterectomy (P = 0.127). According to hazard rate function plots, patients receiving external beam radiation alone had an increased short-term risk of disease-specific mortality, whereas patients without evidence of chemotherapy had a distinct late risk surge at approximately 15 years of follow-up. CONCLUSION: Optimizing radiotherapy methods with brachytherapy and the use of chemotherapy should be considered for the long-term curative efficacy of primary radiotherapy for non-bulky IB-IIA cervical cancer. Further studies are warranted to corroborate our results.

Safety and immunological effects of recombinant canine IL-15 in dogs.

Interleukin-15 (IL-15) is a pleiotropic cytokine that plays pivotal roles in innate and adaptive immunity. It is also a promising cytokine for treating cancer. Despite growing interest in its use as an immunotherapeutic, its safety and immunological effects in dogs have not been reported. In this study, healthy dogs were given recombinant canine IL-15 (rcIL-15) intravenously at a daily dose of 20 µg/kg for 8 days and monitored for 32 days to determine the safety and immunological effects of rcIL-15. The repeated administration of rcIL-15 was well tolerated, did not cause any serious side effects, and promoted the selective proliferation and activation of canine anti-cancer effector cells, including CD3+CD8+ cytotoxic T lymphocytes, CD3+CD5dimCD21-, and non-B/non-T NK cell populations, without stimulating Treg lymphocytes. The rcIL-15 injections also stimulated the expression of molecules and transcription factors associated with the activation and effector functions of NK cells, including CD16, NKG2D, NKp30, NKp44, NKp46, perforin, granzyme B, Ly49, T-bet, and Eomes. These results suggest that rcIL-15 might be a valuable therapeutic adjuvant to improve immunity against cancer in dogs.

Heart-related mortality after postoperative breast irradiation in patients with ductal carcinoma in situ in the contemporary radiotherapy era.

Although radiation-induced cardiotoxicity has been addressed, its prognostic relevance to modern radiotherapy (RT) techniques is unclear. This study assessed the impact of adjuvant RT on heart-related deaths in patients with ductal carcinoma in situ. Patients who underwent adjuvant RT after breast-conserving surgery between 1988 and 2008 were identified from the Surveillance, Epidemiology, and End Results database. Kaplan‒Meier and competing risks analyses were conducted after propensity score-matching according to tumor laterality. A total of 41,526 propensity-matched patients were identified (n = 20,763 for either left- or right-sided tumor). In the analysis of the cumulative incidence of heart-related mortality events, there was a greater risk increment in the left-sided group over the first to second decades after RT in patients aged ≤ 50 years (P = 0.048). Competing risks analysis of the young patients showed that left-sided RT was associated with higher heart-related mortality rates (Grey's test, P = 0.049). The statistical significance remained after adjusting for other covariates (subdistribution hazard ratio 2.35; 95% confidence interval 1.09‒5.10). Regarding the intrinsic effect of modern RT techniques, further strategies to reduce heart-related risks are needed for young patients. Close surveillance within an earlier follow-up period should be considered for these patients in clinics.

Risk Stratification Using Neoadjuvant Rectal Score in the Era of Neoadjuvant Chemoradiotherapy: Validation With Long-term Outcome Data.

BACKGROUND: Despite the widespread use of neoadjuvant chemoradiotherapy, there is no prognostic surrogate marker established in locally advanced rectal cancer. OBJECTIVE: This study evaluated the role of neoadjuvant rectal score as a prognostic factor to stratify individual-level risks of survival and tumor recurrence. DESIGN: This is a retrospective study. SETTINGS: This study was conducted at the Seoul National University Hospital. PATIENTS: A total of 397 patients who underwent chemoradiotherapy plus total mesorectal excision were analyzed. INTERVENTIONS: There was no intervention. MAIN OUTCOME MEASURES: Harrell C statistic and receiver operating characteristic analysis, as well as Cox regression analysis, were used to assess the prognostic strength. RESULTS: The low (<8), intermediate (8-16), and high (>16) neoadjuvant rectal score groups included 91 (23%), 208 (52%), and 98 patients (25%). A high neoadjuvant rectal score was independently associated with inferior overall survival and disease-free survival (p = 0.011 and 0.008). Regarding the prognostic models adjusted for neoadjuvant rectal score (I) and ypT/N stage (II), the c-index was higher in model I (0.799 and 0.787, p = 0.009 for overall survival; 0.752 and 0.743, p = 0.093 for disease-free survival). The predictive ability of the neoadjuvant rectal score was superior to tumor regression grade, ypT, and ypN in the receiver operating characteristic analyses (p < 0.05 for all). Adjuvant chemotherapy was associated with better overall and disease-free survival (p = 0.003 and 0.052) in the high neoadjuvant rectal score group. LIMITATIONS: Potential selection bias attributed to the retrospective study design was a limitation. CONCLUSIONS: We verified the applicability of the neoadjuvant rectal score to stratify the relapse risk at the individual level for patients with stage II/III rectal cancer undergoing neoadjuvant chemoradiotherapy. Additional studies are needed to validate the usability of neoadjuvant rectal score levels as a determinant of adjuvant strategy. See Video Abstract at http://links.lww.com/DCR/B354. ESTRATIFICACIÓN DE RIESGO UTILIZANDO LA PUNTUACIÓN RECTAL NEOADYUVANTE EN LA ERA DE LA QUIMIORRADIOTERAPIA NEOADYUVANTE: VALIDACIÓN CON DATOS DE RESULTADOS A LARGO PLAZO: A pesar del uso generalizado de la quimiorradioterapia neoadyuvante, no existe un marcador subrogado pronóstico establecido en el cáncer de recto localmente avanzado.Este estudio evaluó el papel de la puntuación rectal neoadyuvante como factor pronóstico para estratificar los riesgos a nivel individual de supervivencia y recurrencia tumoral.Este es un estudio retrospectivo.Este estudio se realizó en el Hospital de la Universidad Nacional de Seúl.Se analizaron un total de 397 pacientes que se sometieron a quimiorradioterapia más escisión mesorrectal total.No hubo intervención.El análisis estadístico C de Harrell y las características operativas del receptor, así como el análisis de regresión de Cox, se utilizaron para evaluar la fuerza pronóstica.Los grupos de puntaje rectal neoadyuvante bajo (<8), intermedio (8-16) y alto (> 16) incluyeron 91 (23%), 208 (52%) y 98 (25%) pacientes, respectivamente. Una puntuación rectal neoadyuvante alta se asoció independientemente con una supervivencia general y una supervivencia libre de enfermedad inferiores (p = 0.011 y 0.008, respectivamente). Con respecto a los modelos pronósticos ajustados por la puntuación rectal neoadyuvante (I) y el estadio ypT/N (II), el índice c fue mayor en el modelo I (0.799 y 0.787, p = 0.009 para la supervivencia general; 0.752 y 0.743, p = 0.093 para supervivencia libre de enfermedad). La capacidad predictiva de la puntuación rectal neoadyuvante fue superior al grado de regresión tumoral, ypT y ypN en los análisis de características operativas del receptor (p <0.05 para todos). La quimioterapia adyuvante se asoció con una mejor supervivencia global y libre de enfermedad (p = 0.003 y 0.052, respectivamente) en el grupo de puntaje rectal neoadyuvante alto.El sesgo de selección potencial debido al diseño retrospectivo del estudio fue la limitación.Verificamos la aplicabilidad de la puntuación rectal neoadyuvante para estratificar el riesgo de recurrencia a nivel individual para pacientes con cáncer rectal en estadio II/III sometidos a quimiorradioterapia neoadyuvante. Se necesitan más estudios para validar la usabilidad de los niveles de puntuación rectal neoadyuvante como determinante de la estrategia adyuvante. Consulte Video Resumen en http://links.lww.com/DCR/B354.

Low-Dose Ionizing Radiation Modulates Microglia Phenotypes in the Models of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common type of dementia. AD involves major pathologies such as amyloid-ß (Aß) plaques and neurofibrillary tangles in the brain. During the progression of AD, microglia can be polarized from anti-inflammatory M2 to pro-inflammatory M1 phenotype. The activation of triggering receptor expressed on myeloid cells 2 (TREM2) may result in microglia phenotype switching from M1 to M2, which finally attenuated Aß deposition and memory loss in AD. Low-dose ionizing radiation (LDIR) is known to ameliorate Aß pathology and cognitive deficits in AD; however, the therapeutic mechanisms of LDIR against AD-related pathology have been little studied. First, we reconfirm that LDIR (two Gy per fraction for five times)-treated six-month 5XFAD mice exhibited (1) the reduction of Aß deposition, as reflected by thioflavins S staining, and (2) the improvement of cognitive deficits, as revealed by Morris water maze test, compared to sham-exposed 5XFAD mice. To elucidate the mechanisms of LDIR-induced inhibition of Aß accumulation and memory loss in AD, we examined whether LDIR regulates the microglial phenotype through the examination of levels of M1 and M2 cytokines in 5XFAD mice. In addition, we investigated the direct effects of LDIR on lipopolysaccharide (LPS)-induced production and secretion of M1/M2 cytokines in the BV-2 microglial cells. In the LPS- and LDIR-treated BV-2 cells, the M2 phenotypic marker CD206 was significantly increased, compared with LPS- and sham-treated BV-2 cells. Finally, the effect of LDIR on M2 polarization was confirmed by detection of increased expression of TREM2 in LPS-induced BV2 cells. These results suggest that LDIR directly induced phenotype switching from M1 to M2 in the brain with AD. Taken together, our results indicated that LDIR modulates LPS- and Aß-induced neuroinflammation by promoting M2 polarization via TREM2 expression, and has beneficial effects in the AD-related pathology such as Aß deposition and memory loss.

Effectiveness, safety, and economic evaluation of adjuvant moxibustion therapy for aromatase inhibitor-induced arthralgia of postmenopausal breast cancer stage I to III patients: Study protocol for a prospective, randomized, assessor-blind, usual-care controlled, parallel-group, pilot clinical trial.

INTRODUCTION: This study is a prospective, assessor-blinded, parallel-group, randomized controlled pilot trial to explore the effectiveness of 12-week adjuvant moxibustion therapy for arthralgia in menopausal females at stage I to III breast cancer on aromatase inhibitor (AI) administration, compared with those receiving usual care. METHODS/DESIGN: Forty-six menopausal female patients with breast cancer who completed cancer therapy will be randomly allocated to either adjuvant moxibustion or usual care groups with a 1:1 allocation ratio. The intervention group will undergo 24 sessions of adjuvant moxibustion therapy with usual care for 12 weeks, whereas the control group will receive only usual care during the same period. The usual care consists of acetaminophen administration on demand and self-directed exercise education to manage AI-related joint pain. The primary outcome is the mean change of the worst pain level according to the Brief Pain Inventory-Short Form between the initial visit and the endpoint. The mean changes in depression, fatigue, and quality of life will also be compared between groups. Safety and pharmacoeconomic evaluations will also be included. DISCUSSION: Continuous variables will be compared by an independent t test or Wilcoxon rank-sum test between the adjuvant moxibustion and usual care groups. Adverse events will be analyzed using the chi-square or Fisher exact test. The statistical analysis will be performed by a 2-tailed test at a significance level of .05.

Diabetes mellitus is a predictive factor for radiation pneumonitis after thoracic radiotherapy in patients with lung cancer.

PURPOSE: We evaluated the effects of diabetes mellitus (DM) and DM-related serologic factors (HbA1c and fasting glucose) on the development of radiation pneumonitis in patients with lung cancer. METHODS: We retrospectively analyzed the clinical data of 123 patients with lung cancer treated with radiotherapy. Radiation pneumonitis was scored according to the toxicity criteria of the Radiation Therapy Oncology Group. We used binary logistic regression analysis to find significant predictive factors for the development of grade ≥3 radiation pneumonitis. RESULTS: On univariable analysis, V20, mean lung dose, DM, HbA1c, and fasting glucose level were significantly associated with the development of grade ≥3 radiation pneumonitis. On multivariable analysis, V20, mean lung dose, DM, HbA1c, and fasting glucose level remained significant predictive factors for grade ≥3 radiation pneumonitis. The incidence of grade ≥3 radiation pneumonitis was 44.4% in patients with DM and 20.7% in patients without DM. The incidence of grade ≥3 radiation pneumonitis was 12.7% for HbA1c level ≤6.15% and 41.5% for HbA1c level >6.15%. The incidence of grade ≥3 radiation pneumonitis was 17.2% for fasting glucose level ≤121 mg/dL and 35.5% for fasting glucose level >121 mg/dL. CONCLUSION: DM, HbA1c, and fasting glucose level are significant predictive factors for the development of grade ≥3 radiation pneumonitis in patients with lung cancer. Patients with DM, patients who have HbA1c >6.15%, and patients who have fasting glucose >121 mg/dL should be treated with greater caution.