PolyQ-expanded ataxin-2 aggregation impairs cellular processing-body homeostasis via sequestering the RNA helicase DDX6.

Ataxin-2 (Atx2) is a polyglutamine (polyQ) tract-containing RNA-binding protein, while its polyQ expansion may cause protein aggregation that is implicated in the pathogenesis of neurodegenerative diseases such as spinocerebellar ataxia type 2 (SCA2). However, the molecular mechanism underlying how Atx2 aggregation contributes to the proteinopathies remains elusive. Here, we investigated the influence of Atx2 aggregation on the assembly and functionality of cellular processing bodies (P-bodies) by using biochemical and fluorescence imaging approaches. We have revealed that polyQ-expanded (PQE) Atx2 sequesters the DEAD-box RNA helicase (DDX6), an essential component of P-bodies, into aggregates or puncta via some RNA sequences. The N-terminal like-Sm (LSm) domain of Atx2 (residues 82-184) and the C-terminal helicase domain of DDX6 are responsible for the interaction and specific sequestration. Moreover, sequestration of DDX6 may aggravate pre-mRNA mis-splicing, and interfere with the assembly of cellular P-bodies, releasing the endoribonuclease MARF1 that promotes mRNA decay and translational repression. Rescuing the DDX6 protein level can recover the assembly and functionality of P-bodies, preventing targeted mRNA from degradation. This study provides a line of evidence for sequestration of the P-body components and impairment of the P-body homeostasis in dysregulating RNA metabolism, which is implicated in the disease pathologies and a potential therapeutic target.

Confinement-Induced Indium Oxide Nanolayers Formed on Oxide Support for Enhanced CO2 Hydrogenation Reaction.

An enclosed nanospace often shows a significant confinement effect on chemistry within its inner cavity, while whether an open space can have this effect remains elusive. Here, we show that the open surface of TiO2 creates a confined environment for In2O3 which drives spontaneous transformation of free In2O3 nanoparticles in physical contact with TiO2 nanoparticles into In oxide (InOx) nanolayers covering onto the TiO2 surface during CO2 hydrogenation to CO. The formed InOx nanolayers are easy to create surface oxygen vacancies but are against over-reduction to metallic In in the H2-rich atmospheres, which thus show significantly enhanced activity and stability in comparison with the pure In2O3 catalyst. The formation of interfacial In-O-Ti bonding is identified to drive the In2O3 dispersion and stabilize the metastable InOx layers. The InOx overlayers with distinct chemistry from their free counterpart can be confined on various oxide surfaces, demonstrating the important confinement effect at oxide/oxide interfaces.

RNA-assisted sequestration of RNA-binding proteins by cytoplasmic inclusions of the C-terminal 35-kDa fragment of TDP-43.

TDP-43 (also known as TARDBP) is a nuclear splicing factor functioning in pre-mRNA processing. Its C-terminal 35-kDa fragment (TDP-35) forms inclusions or aggregates in cytoplasm, and sequesters full-length TDP-43 into the inclusions through binding with RNA. We extended the research to investigate whether TDP-35 inclusions sequester other RNA-binding proteins (RBPs) and how RNA-binding specificity has a role in this sequestration process. We have characterized T-cell restricted intracellular antigen-1 (TIA1) and other RBPs that can be sequestered into the TDP-35 inclusions through specific RNA binding, and found that this sequestration leads to the dysfunction of TIA1 in maturation of target pre-mRNA. Moreover, we directly visualized the dynamic sequestration of TDP-43 by the cytoplasmic TDP-35 inclusions by live-cell imaging. Our results demonstrate that TDP-35 sequesters some specific RBPs and this sequestration is assisted by binding with RNA in a sequence-specific manner. This study provides further evidence in supporting the hijacking hypothesis for RNA-assisted sequestration and will be beneficial to further understanding of the TDP-43 proteinopathies.

Conversion chemoradiotherapy combined with nab-paclitaxel plus cisplatin in patients with locally advanced borderline-resectable or unresectable esophageal squamous cell carcinoma: a phase i/ii prospective cohort study.

BACKGROUND: To evaluate the efficacy and safety of nab-paclitaxel plus cisplatin as the regimen of conversional chemoradiotherapy (cCRT) in locally advanced borderline resectable or unresectable esophageal squamous cell carcinoma (ESCC). METHODS: Patients with locally advanced ESCC (cT3­4, Nany, M0­1, M1 was limited to lymph node metastasis in the supraclavicular area) were enrolled. All the patients received the cCRT of nab-paclitaxel plus cisplatin. After the cCRT, those resectable patients received esophagectomy; those unresectable patients continued to receive the definitive chemoradiotherapy (dCRT). The locoregional control (LRC), overall survival (OS), event-free survival (EFS), distant metastasis free survival (DMFS), pathological complete response (pCR), R0 resection rate, adverse events (AEs) and postoperative complications were calculated. RESULTS: 45 patients with ESCC treated from October 2019 to May 2021 were finally included. The median follow-up time was 30.3 months. The LRC, OS, EFS, DMFS at 1 and 2 years were 81.5%, 86.6%, 64.3%, 73.2 and 72.4%, 68.8%, 44.8%, 52.7% respectively. 21 patients (46.7%) received conversional chemoradiotherapy plus surgery (cCRT+S). The pCR rate and R0 resection rate were 47.6 and 84.0%. The LRC rate at 1 and 2 years were 95.0%, 87.1% in cCRT+S patitents and 69.3%, 58.7% in dCRT patients respectively (HR, 5.14; 95%CI, 1.10-23.94; P = 0.021). The toxicities during chemoradiotherapy were tolerated, and the most common grade 3-4 toxicitiy was radiation esophagitis (15.6%). The most common postoperative complication was pleural effusion (38.1%) and no grade ≥ IIIb complications were observed. CONCLUSION: nab-paclitaxel plus cisplatin are safe as the regimen of conversional chemoradiotherapy of ESCC.

Higher immune cell radiation dose is correlated with poor tumor control and survival in patients with non-small cell lung cancer receiving postoperative radiotherapy.

INTRODUCTION: The estimated dose of radiation to immune cells (EDRIC) has been shown to correlate with the overall survival (OS) of patients who receive definitive thoracic radiotherapy. However, the planning target volume (PTV) may be a confounding factor. We assessed the prognostic value of EDRIC for non-small cell lung cancer (NSCLC) in patients who underwent postoperative radiotherapy (PORT) with homogeneous PTV. METHODS: Patients with NSCLC who underwent PORT between 2004 and 2019 were included. EDRIC was computed as a function of the number of radiation fractions and mean doses to the lungs, heart, and remaining body. The correlations between EDRIC and OS, disease-free survival (DFS), locoregional-free survival (LRFS), and distant metastasis-free survival (DMFS) were analyzed using univariate and multivariate Cox models. Kaplan-Meier analysis was performed to assess the survival difference between low- and high-EDRIC groups. RESULTS: In total, 345 patients were analyzed. The mean EDRIC was 6.26 Gy. Multivariate analysis showed that higher EDRIC was associated with worse outcomes in terms of OS (hazard ratio [HR] 1.207, P = .007), DFS (HR 1.129, P = .015), LRFS (HR 1.211, P = .002), and DMFS (HR 1.131, P = .057). In the low- and high-EDRIC groups, the 3-year OS was 81.2% and 74.0%, DFS 39.8% and 35.0%, LRFS 70.4% and 60.5%, and DMFS 73.9% and 63.1%, respectively. CONCLUSIONS: EDRIC is an independent prognostic factor for survival in patients with NSCLC undergoing PORT. Higher doses of radiation to the immune system are associated with tumor progression and poor survival. Organs at risk for the immune system should be considered during radiotherapy planning.

Hippocampal avoidance whole-brain radiotherapy with simultaneous integrated boost in lung cancer brain metastases and utility of the Hopkins verbal learning test for testing cognitive impairment in Chinese patients: a prospective phase II study.

BACKGROUND: This study aimed to evaluate the efficiency of hippocampal avoidance whole-brain radiotherapy with a simultaneous integrated boost (HA-WBRT-SIB) treating brain metastases (BM) and utility of the Hopkins Verbal Learning Test-Revised (HVLT-R) (Chinese version) in Chinese lung cancer patients. METHODS: Lung cancer patients with BM undergone HA-WBRT-SIB at our center were enrolled. Brain magnetic resonance imaging, The HVLT total learning score, and side effects were evaluated before radiotherapy and 1, 3, 6, and 12 months after radiotherapy. This study analyzed the overall survival rate, progression-free survival rate, and changes in HVLT-R immediate recall scores. RESULTS: Forty patients were enrolled between Jan 2016 and Jan 2020. The median follow-up time was 14.2 months. The median survival, progression-free survival, and intracranial progression-free survival of all patients were 14.8 months, 6.7 months and 14.8 months, respectively. Multivariate analysis indicated that male sex and newly diagnosed stage IV disease were associated with poor overall survival and progression-free survival, respectively. HVLT-R scores at baseline and 1, 3, and 6 months after radiotherapy were 21.94 ± 2.99, 20.88 ± 3.12, 20.03 ± 3.14, and 19.78 ± 2.98, respectively. The HVLT-R scores at 6 months after radiotherapy decreased by approximately 9.8% compared with those at baseline. No grade 3 toxicities occurred in the entire cohort. CONCLUSIONS: HA-WBRT-SIB is of efficiency and cognitive-conserving in treating Chinese lung cancer BM. TRIAL REGISTRATION: This study was retrospectively registered on ClinicalTrials.gov in 24th Feb, 2024. The ClinicalTrials.gov ID is NCT06289023.

Enhanced Methanol Synthesis over Self-Limited ZnOx Overlayers on Cu Nanoparticles Formed via Gas-Phase Migration Route.

Supported metal catalysts are widely used for chemical conversion, in which construction of high density metal-oxide or oxide-metal interface is an important means to improve their reaction performance. Here, Cu@ZnOx encapsulation structure has been in situ constructed through gas-phase migration of Zn species from ZnO particles onto surface of Cu nanoparticles under CO2 hydrogenation atmosphere at 450 °C. The gas-phase deposition of Zn species onto the Cu surface and growth of ZnOx overlayer is self-limited under the high temperature and redox gas (CO2 /H2 ) conditions. Accordingly, high density ZnOx -Cu interface sites can be effectively tailored to have an enhanced activity in CO2 hydrogenation to methanol. This work reveals a new route for the construction of active oxide-metal interface and classic strong metal-support interaction state through gas-phase migration of support species induced by high temperature redox reaction atmosphere.

In-Situ Dynamic Carburization of Mo Oxide with Unprecedented High CO Formation Rate in Reverse Water-Gas Shift Reaction.

In-situ construction of active structure under reaction conditions is highly desired but still remains challenging in many important catalytic processes. Herein, we observe structural evolution of molybdenum oxide (MoOx) into highly active molybdenum carbide (MoCx) during reverse water-gas shift (RWGS) reaction. Surface oxygen atoms in various Mo-based catalysts are removed in H2-containing atmospheres and then carbon atoms can accumulate on surface to form MoCx phase with the RWGS reaction going on, both of which are enhanced by the presence of intercalated H species or Pt-dopants in MoOx. The structural evolution from MoOx to MoCx is accompanied by enhanced CO2 conversion, which is positively correlated with the surface C/Mo ratio but negatively with the surface O/Mo ratio. As a result, an unprecedented CO formation rate of 7544.6 mmol·gcatal-1·h-1 at 600 °C has been achieved over in-situ carbonized H-intercalated MoO3 catalyst, which is even higher than those from noble metal catalysts. During 100 h stability test only a minimal deactivation rate of 2.3% is observed.

Effectiveness and safety of combined nimotuzumab and S-1 chemotherapy with concurrent radiotherapy for locally advanced esophageal cancer in malnourished and elderly patients: A prospective phase II study.

Objective: Definitive chemoradiotherapy (dCRT) is the standard treatment for unresectable locally advanced esophageal cancer. However, this treatment is associated with substantial toxicity, and most malnourished or elderly patients are unable to complete this therapy. Therefore, there is a need for a more suitable radiotherapy combination regimen for this population. This study was aimed to evaluate the efficacy and safety of a combination regimen comprising chemotherapy with nimotuzumab and S-1 and concurrent radiotherapy for patients with fragile locally advanced esophageal cancer with a high Nutritional Risk Screening 2002 (NRS-2002) score. Methods: Eligible patients with unresectable esophageal carcinoma who had an NRS-2002 score of 2 or higher were enrolled. They were treated with S-1 and nimotuzumab with concurrent radiotherapy, followed by surgery or definitive radiotherapy. The primary endpoint was the locoregional control (LRC) rate. Results: A total of 55 patients who met the study criteria were enrolled. After completion of treatment, surgery was performed in 15 patients and radiotherapy was continued in 40 patients. The median follow-up period was 33.3 [95% confidence interval (95% CI), 31.4-35.1)] months. The LRC rate was 77.2% (95% CI, 66.6%-89.4%) at 1 year in the entire population. The overall survival (OS) rate and event-free survival (EFS) rate were 57.5% and 51.5% at 3 years, respectively. Surgery was associated with better LRC [hazard ratio (HR)=0.16; 95% CI, 0.04-0.70; P=0.015], OS (HR=0.19; 95% CI, 0.04-0.80; P=0.024), and EFS (HR=0.25; 95% CI, 0.08-0.75; P=0.013). Most adverse events were of grade 1 or 2, and no severe adverse events occurred. Conclusions: For malnourished or elderly patients with locally advanced esophageal cancer, radiotherapy combined with nimotuzumab and S-1 is effective and has a good safety profile.

Disentangling Local Interfacial Confinement and Remote Spillover Effects in Oxide-Oxide Interactions.

Supported oxides are widely used in many important catalytic reactions, in which the interaction between the oxide catalyst and oxide support is critical but still remains elusive. Here, we construct a chemically bonded oxide-oxide interface by chemical deposition of Co3O4 onto ZnO powder (Co3O4/ZnO), in which complete reduction of Co3O4 to Co0 has been strongly impeded. It was revealed that the local interfacial confinement effect between Co oxide and the ZnO support helps to maintain a metastable CoOx state in CO2 hydrogenation reaction, producing 93% CO. In contrast, a physically contacted oxide-oxide interface was formed by mechanically mixing Co3O4 and ZnO powders (Co3O4-ZnO), in which reduction of Co3O4 to Co0 was significantly promoted, demonstrating a quick increase of CO2 conversion to 45% and a high selectivity toward CH4 (92%) in the CO2 hydrogenation reaction. This interface effect is ascribed to unusual remote spillover of dissociated hydrogen species from ZnO nanoparticles to the neighboring Co oxide nanoparticles. This work clearly illustrates the equally important but opposite local and remote effects at the oxide-oxide interfaces. The distinct oxide-oxide interactions contribute to many diverse interface phenomena in oxide-oxide catalytic systems.

Radiotherapy Improves Survival of Patients With Lymphovascular Invasion in pT1b Esophageal Squamous Cell Cancer After Endoscopic Submucosal Dissection.

INTRODUCTION: Adjuvant radiotherapy is recommended for pT1b esophageal squamous cell cancer (ESCC) after endoscopic submucosal dissection (ESD). However, it is unclear whether additional radiotherapy can improve patient survival. This study aimed to evaluate the efficacy of adjuvant radiotherapy after ESD for pT1b ESCC. METHODS: This was a multicenter, cross-sectional study involving 11 hospitals in China. Between January 2010 and December 2019, patients with T1bN0M0 ESCC treated with or without adjuvant radiotherapy after ESD were included. Survival between groups was compared. RESULTS: Overall, 774 patients were screened, and 161 patients were included. Forty-seven patients (29.2%) received adjuvant radiotherapy after ESD (RT group) and 114 (70.8%) underwent ESD alone (non-RT group). There were no significant differences in overall survival (OS) and disease-free survival (DFS) between the RT and non-RT groups. Lymphovascular invasion (LVI) was the only prognostic factor. In the LVI+ group, adjuvant radiotherapy significantly improved survival (5-year OS: 91.7% vs 59.5%, P = 0.050; 5-year DFS: 92.9% vs 42.6%, P = 0.010). In the LVI- group, adjuvant radiotherapy did not improve survival (5-year OS: 83.5% vs 93.9%, P = 0.148; 5-year DFS: 84.2% vs 84.7%, P = 0.907). The standardized mortality ratios were 1.52 (95% confidence interval 0.04-8.45) in the LVI+ group with radiotherapy and 0.55 (95% confidence interval 0.15-1.42) in the LVI- group without radiotherapy. DISCUSSION: Adjuvant radiotherapy could improve survival in pT1b ESCC with LVI+ other than LVI- after ESD. Selective adjuvant radiotherapy based on LVI status achieved survival rates similar to those of the general population.

Coaggregation of polyglutamine (polyQ) proteins is mediated by polyQ-tract interactions and impairs cellular proteostasis.

Nine polyglutamine (polyQ) proteins have already been identified that are considered to be associated with the pathologies of neurodegenerative disorders called polyQ diseases, but whether these polyQ proteins mutually interact and synergize in proteinopathies remains to be elucidated. In this study, 4 polyQ-containing proteins, androgen receptor (AR), ataxin-7 (Atx7), huntingtin (Htt) and ataxin-3 (Atx3), are used as model molecules to investigate their heterologous coaggregation and consequent impact on cellular proteostasis. Our data indicate that the N-terminal fragment of polyQ-expanded (PQE) Atx7 or Htt can coaggregate with and sequester AR and Atx3 into insoluble aggregates or inclusions through their respective polyQ tracts. In vitro coprecipitation and NMR titration experiments suggest that this specific coaggregation depends on polyQ lengths and is probably mediated by polyQ-tract interactions. Luciferase reporter assay shows that these coaggregation and sequestration effects can deplete the cellular availability of AR and consequently impair its transactivation function. This study provides valid evidence supporting the viewpoint that coaggregation of polyQ proteins is mediated by polyQ-tract interactions and benefits our understanding of the molecular mechanism underlying the accumulation of different polyQ proteins in inclusions and their copathological causes of polyQ diseases.

Nfatc1+ colonic stem cells contribute to regeneration upon colitis.

BACKGROUND AND AIM: Colonic stem cells play important roles in both normal epithelial turnover and injury repair. Lgr5+ colonic stem cells are highly susceptible to DSS-induced damage. However, it is still unclear how colonic stem cells regenerate injured epithelium during colitis. Here, we explored the functions of a new population of NFATc1+ colonic stem cells in experimental colitis. METHODS: Nfatc1+ colonic stem cells were labeled using Nfatc1CreERT2 ;R26mTmG reporter mice. Immunostaining assays were used to detect Goblet cells, enteroendocrine cells, and intestinal stem/progenitor cells. We performed lineage tracing assay to investigate whether Nfatc1+ cells are real colonic stem cells using Nfatc1CreERT2 ;R26mTmG mice. The contribution of Nfatc1+ stem cells on epithelial regeneration was detected in experimental colitis induced by DSS. RESULTS: Nfatc1-reporter marked cells are enriched for +3 to +5 position in colonic crypts, and they are overlapped with Sox9+ cells and Hopx+ cells that have been identified as stem cells in small intestine. However, Nfatc1-reporter marked cells are not overlapped with Lgr5+ colonic stem cells, as well as differentiated goblet cells and enteroendocrine cells. Furthermore, Nfatc1-reporter marked cells are able to give rise to all lineages of the colonic epithelium, and they preferentially contribute to the regeneration of colonic epithelium in DSS-induced experimental colitis. CONCLUSION: Nfatc1+ cells were identified as a novel population of colonic stem cells that are primarily located at +3 to +5 position and contribute to epithelial regeneration during colitis.

MiR-320b/RAD21 axis affects hepatocellular carcinoma radiosensitivity to ionizing radiation treatment through DNA damage repair signaling.

Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world and is associated with high mortality. Ionizing radiation (IR)-based therapy causes DNA damage, exerting a curative effect; however, DNA damage repair signaling pathways lead to HCC resistance to IR-based therapy. RAD21 is a component of the cohesion complex, crucial for chromosome segregation and DNA damage repair, while it is still unclear whether RAD21 is implicated in DNA damage and influences IR sensitivity in HCC. The current research explores the effect and upstream regulatory mechanism of RAD21 on IR sensitivity in HCC. In the present study, RAD21 mRNA and protein expression were increased within HCC tissue samples, particularly within IR-insensitive HCC tissues. The overexpression of RAD21 partially attenuated the roles of IR in HCC by promoting the viability and suppressing the apoptosis of HCC cells. RAD21 overexpression reduced the culture medium 8-hydroxy-2-deoxyguanosine concentration and decreased the protein levels of γH2AX and ATM, suggesting that RAD21 overexpression attenuated IR treatment-induced DNA damage to HCC cells. miR-320b targeted RAD21 3'-UTR to inhibit RAD21 expression. In HCC tissues, particularly in IR-insensitive HCC tissues, miR-320b expression was significantly downregulated. miR-320b inhibition also attenuated IR treatment-induced DNA damage to HCC cells; more importantly, RAD21 silencing significantly attenuated the effects of miR-320b inhibition on IR treatment-induced DNA damage, suggesting that miR-320b plays a role through targeting RAD21. In conclusion, an miR-320b/RAD21 axis modulating HCC sensitivity to IR treatment through acting on IR-induced DNA damage was demonstrated. The miR-320b/RAD21 axis could be a novel therapeutic target for further study of HCC sensitivity to IR treatment.

Effectiveness of the AJCC 8th edition staging system for selecting patients with T1-2N1 breast cancer for post-mastectomy radiotherapy: a joint analysis of 1986 patients from two institutions.

BACKGROUND: The role of post-mastectomy radiotherapy (PMRT) in the treatment of patients with T1-2N1 breast cancer is controversial. This study's purpose was to evaluate the risk of recurrence of T1-2N1 breast cancer and the efficacy of PMRT in low-, medium- and high-risk groups of patients. METHODS: Post-mastectomy patients with T1-2N1 breast cancer were restaged according to the American Joint Committee on Cancer Staging Manual, 8th edition (AJCC 8th ed.) staging system. Recurrence scores were generated using prognostic factors identified for loco-regional recurrence and distant metastasis in patients without PMRT, and three risk groups were identified. Rates of loco-regional recurrence and distant metastasis were calculated with a competing risk model and compared using Gray's test. Disease-free survival and overall survival were calculated using the Kaplan-Meier method and compared using the log-rank test. The Cox proportional hazards regression model was used for the multivariate analysis. RESULTS: Data from 1986 patients (1521without PMRT; 465 with PMRT) were analyzed. Patients without PMRT were stratified into low-, intermediate- and high-risk groups by age, tumor location, AJCC 8th ed. stage, number of positive nodes and lympho-vascular invasion. The 5-year loco-regional recurrence rate and distant metastasis rates for the three risk groups were significant at 2.5, 5.4 and 16.2% (p <  0.001) respectively, and 4.9, 8.4 and 18.6% (p <  0.001) respectively. In the high-risk group, loco-regional recurrence (p <  0.001), and distant metastasis (p = 0.044) were significantly reduced, and disease free survival (p = 0.004), and overall survival (p = 0.029) were significantly improved after PMRT. In the low- and intermediate-risk groups, PMRT had no significant effect on loco-regional recurrence (p = 0.268), distant metastasis (p = 0.252), disease free survival (p = 0.608) or overall survival (p = 0.986). CONCLUSION: Our results showed no benefits of PMRT in the low-risk group, and thus, omitting PMRT radiotherapy in this population could be considered.

A multicenter prospective phase III clinical randomized study of simultaneous integrated boost intensity-modulated radiotherapy with or without concurrent chemotherapy in patients with esophageal cancer: 3JECROG P-02 study protocol.

BACKGROUND: Since the development of three-dimensional conformal radiotherapy and intensity-modulated radiotherapy (IMRT), no prospective study has investigated whether concurrent chemoradiotherapy (SIB-IMRT with 60 Gy) remains superior to radiotherapy (SIB-IMRT) alone for unresectable esophageal cancer (EC). Furthermore, the optimal therapeutic regimen for patients who cannot tolerate concurrent chemoradiotherapy is unclear. We recently completed a phase I/II radiation dose-escalation trial using simultaneous integrated boost (SIB), elective nodal irradiation, and concurrent chemotherapy for unresectable EC. We now intend to conduct a prospective, phase III, randomized study of SIB-IMRT with or without concurrent chemotherapy. We aim to find a safe, practical, and effective therapeutic regimen to replace the conventional segmentation (1.8-2.0 Gy) treatment mode (radiotherapy ± chemotherapy) for unresectable EC. METHODS: This two-arm, open, randomized, multicenter, phase III trial will recruit esophageal squamous cell carcinoma patients (stage IIA-IVB [UICC 2002]; IVB only with metastasis to the supraclavicular or celiac lymph nodes). In all, 164 patients will be randomized using a 1:1 allocation ratio, and stratified by study site and disease stage, especially the extent of lymph node metastasis. Patients in the SIB arm will receive definitive SIB radiotherapy (95% planning target volume/planning gross tumor volume, 50.4 Gy/59.92 Gy/28 f, equivalent dose in 2-Gy fractions = 60.62 Gy). Patients in the SIB + concurrent chemotherapy arm will receive definitive SIB radiotherapy with weekly paclitaxel and a platinum-based drug (5-6 weeks). Four cycles of consolidated chemoradiotherapy will also be recommended. The primary objective is to compare the 1-year, 2-year, and 3-year overall survival of the SIB + chemotherapy group and SIB groups. Secondary objectives include progression-free survival, local recurrence-free rate, completion rate, and adverse events. Detailed radiotherapy protocol and quality-assurance procedures have been incorporated into this trial. DISCUSSION: In unresectable, locally advanced EC, a safe and effective total radiotherapy dose and reasonable segmentation doses are required for the clinical application of SIB-IMRT + two-drug chemotherapy. Whether this protocol will replace the standard treatment regimen will be prospectively investigated. The effects of SIB-IMRT in patients with poor physical condition who cannot tolerate definitive chemoradiotherapy will also be investigated. TRIAL REGISTRATION: clinicaltrials.gov ( NCT03308552 , November 1, 2017).

Risk stratification for prediction of locoregional recurrence in patients with pathologic T1-2N0 breast cancer after mastectomy.

BACKGROUND: Previous studies have revealed that nearly 15-20% of selected high-risk T1-2N0 breast cancers developed LRR after mastectomy. This study is aim to indentify the risk factors of locoregional recurrence (LRR) in patients with pathologic T1-2N0 breast cancer after mastectomy in a real-world and distinguish individuals who warrant postmastectomy radiotherapy (PMRT). METHODS: Female patients treated from 1999 to 2014 in National Cancer Center of China were retrospectively reviewed. A competing risk model was developed to estimate the cumulative incidence of LRR with death treated as a competing event. RESULTS: A total of 4841 patients were eligible. All underwent mastectomy plus axillary nodes dissection or sentinel node biopsy without PMRT. With a median follow-up of 56.4 months (range, 1-222 months), the 5-year LRR rate was 3.9%.Besides treatment era, age ≤ 40 years old (p < 0.001, hazard ratio [HR] = 2.262), tumor located in inner quadrant (p < 0.001, HR = 2.236), T2 stage (p = 0.020, HR = 1.419), and negative expressions of estrogen receptor (ER) and progesterone receptor (PR) (p = 0.032, HR = 1.485), were patients-related independent risk factors for LRR. The 5-year LRR rates were 1.7, 3.5, and 15.0% for patients with zero, 1-2, and 3-4 risk factors (p < 0.001). CONCLUSIONS: Risk Stratification based on age, T stage, ER/PR status and tumor location can stratify patients with pT1-2 N0 breast cancer into subgroups with different risk of LRR. PMRT might be suggested for patients with 3-4 risk factors.

Radiotherapy plays an important role in improving the survival outcome in patients with T1-2N1M0 breast cancer - a joint analysis of 4262 real world cases from two institutions.

BACKGROUND: To compare the survival outcomes between breast-conserving surgery (BCS) and modified radical mastectomy (MRM), and to investigate the role of radiotherapy (RT) in patients with pT1-2N1M0 breast cancer. METHODS: A total of 4262 women with T1-2N1M0 breast cancer treated at two institutions were retrospectively reviewed. A total of 3858 patients underwent MRM, and 832 (21.6%) of them received postoperative RT (MRM + RT). A total of 404 patients received BCS plus postoperative RT (BCS + RT). All patients received axillary lymph node dissection, while 3.8% of them had upfront sentinel node biopsy. The association of survival outcomes with different surgical modalities (BCS vs. MRM) and the role of RT were evaluated using multivariable proportional hazards regression and confirmed by the propensity score-matching (PSM) method. RESULTS: At a median follow-up of 71 months (range of 6-230 months), the 5-year overall survival (OS) rates of the BCS and MRM groups were 96.5 and 92.7%, respectively (P = .001), and the corresponding 5-year disease-free-survival (DFS) and locoregional recurrence (LRR) rates were 92.9 and 84.0%, and 2.0 and 7.0% (P = .001), respectively (P < .001). Multivariate analysis revealed that RT was an independent prognostic factor for improved OS (P = .001) and DFS (P = .009), and decreased LRR (P < .001). However, surgery procedure was not independently associated with either OS (P = .495), DFS (P = .204), or LRR (P = .996), which was confirmed by PSM analysis. CONCLUSION: Postoperative radiotherapy rather than the surgery procedures was associated with superior survival outcomes in patients with T1-2N1M0 breast cancer.

Postoperative radiotherapy is effective in improving survival of patients with stage pIII-N2 non-small-cell lung Cancer after pneumonectomy.

BACKGROUND: There were few reports of postoperative radiotherapy (PORT) in stage pIII-N2 Non-small-cell Lung Cancer (NSCLC) patients receiving pneumonectomy followed by adjuvant chemotherapy. This study aims to evaluate safety and efficacy of PORT among these patients. METHODS: Between Jan. 2004 and Dec. 2015, stage pIII-N2 NSCLC patients receiving pneumonectomy and adjuvant chemotherapy with or without PORT in our institution were retrospectively reviewed. RESULTS: Totally 119 patients were included, 32 patients receiving adjuvant chemotherapy and PORT (PORT group) and 87 receiving adjuvant chemotherapy alone (Control group). There were more patients with non-R0 resection in PORT group than Control group (25% vs. 8%, p = 0.031). In PORT group, ≥Grade 2 radiation-induced pneumonitis was 2/32. No severe radiation-related heart injury was observed. There was no PORT-related death. Of all patients, median follow-up time was 25 months. Median overall survival time (mOS) and median disease-free survival time (mDFS) were 46 months and 15 months, respectively. The PORT group had significantly better OS (not reached vs. 34 months, p = 0.003), DFS (19 months vs. 13 months, p = 0.024), local recurrence free survival (LRFS, p = 0.012), and distant metastasis free survival (DMFS, p = 0.047) than the Control group. As for failure pattern, PORT significantly reduced local regional failure rate (39.1% vs. 15.6%, p = 0.016). In subgroup analysis, patients with R0 resection (n = 104), OS and LRFS in PORT group were significantly longer, and PORT tended to increase DFS and DMFS. CONCLUSION: For patients with stage pIII-N2 NSCLC after pneumonectomy and adjuvant chemotherapy, PORT can improve OS, DFS, LRFS and DMFS with tolerable toxicity.