Influence of age as a continuous variable on the prognosis of patients with pT1-2N1 breast cancer.

PURPOSE: To assess the influence of age as a continuous variable on the prognosis of pT1-2N1 breast cancer and examine its decision-making value for postmastectomy radiotherapy (PMRT). METHODS: We retrospectively evaluated 5438 patients with pT1-2N1 breast cancer after mastectomy in 11 hospitals. A multivariable Cox proportional hazards regression model with penalized splines was used to examine the relationship between age and oncologic outcomes. RESULTS: The median follow-up was 67.0 months. After adjustments for confounding characteristics, nonsignificant downward trend in locoregional recurrence (LRR) risk was observed with increasing age (P-non-linear association = 0.640; P-linear association = 0.078). A significant non-linear association was found between age and disease-free survival (DFS) and overall survival (OS) (P-non-linear association <0.05; P-linear association >0.05, respectively). The DFS and OS exhibited U-shaped relationships, with the hazard ratios (HRs), reaching a nadir at 50 years old. A decreased risk of LRR with PMRT vs. no PMRT (HR = 0.304, 95% CI: 0.204-0.454) was maintained in all ages. The HR of PMRT vs. no PMRT for DFS and OS gradually increased with age. In patients ≤50 years old, PMRT was independently associated with favorable LRR, DFS, and OS, all P < 0.05). In patients >50 years old, PMRT was independently associated with reduced LRR (P = 0.004), but had no effect on DFS or OS. CONCLUSIONS: Age was an independent prognostic factor for pT1-2N1 breast cancer; PMRT provided survival benefits for patients ≤50 years old, but not for patients >50 years old.

Effect of postmastectomy radiotherapy on pT1-2N1 breast cancer patients with different molecular subtypes.

OBJECTIVE: To clarify the effect of postmastectomy radiotherapy (PMRT) on pT1-2N1 breast cancer patients with different molecular subtypes. METHODS: We retrospectively analyzed the data of 5442 patients with pT1-2N1 breast cancer treated using modified radical mastectomy in 11 hospitals in China. Univariate, multivariate, and propensity score matching (PSM) analyses were used to evaluate the effect of PMRT on locoregional recurrence (LRR). RESULTS: With a median follow-up duration of 63.8 months, the 5-year LRR rates were 4.0% and 7.7% among patients treated with and without PMRT, respectively (p < 0.001). PMRT was independently associated with reduced LRR after adjustments for confounders (p < 0.001). After grouping the patients according to the molecular subtype of cancer and conducting PSM, we found that the 5-year LRR rates among patients treated with and without PMRT (in that order) were as follows: luminal HER2-negative cancer, 1.9% and 6.5% (p < 0.001); luminal HER2-positive cancer, 3.8% and 13.7% (p = 0.041); HER2-overexpressing cancer, 10.2% and 15.5% (p = 0.236); and triple-negative cancer, 4.6% and 15.9% (p = 0.002). Among patients with HER2-overexpressing and triple-negative cancers, the LRR hazard rate displayed a dominant early peak, and was extremely low after 5 years. However, patients with luminal cancer continued to have a long-lasting high annual LRR hazard rate during follow-up. CONCLUSION: PMRT significantly reduced the LRR risk in patients with pT1-2N1 luminal and triple-negative breast cancers, but had no effect on the LRR risk in patients with HER2-overexpressing cancer. Patients with different molecular subtypes displayed different annual LRR patterns, and the late recurrence of the luminal subtype suggests the necessity of long-term follow-up to evaluate the efficacy of PMRT.

Association of Epstein-Barr virus infection with peripheral immune parameters and clinical outcome in advanced nasopharyngeal carcinoma.

The purpose of this study was to investigate the association of Epstein-Barr virus (EBV) with peripheral blood immune cell counts and clinical outcomes in advanced nasopharyngeal carcinoma (NPC) patients. In a retrospective design, 146 patients with NPC at stage IV were enrolled in this study. The association of EBV status with peripheral blood immune cell counts, distant metastases, and long-term survival in patients with advanced NPC were determined. Eighty-seven (59.6%) of all patients were positive for EBV. Compared with patients with normal NK cell count, patients with lower NK cell count showed a significantly lower EBV viral load (median: 614.0 vs. 2190.0 copies/mL, P = 0.024). EBV-positive patients showed a significantly higher incidence of liver metastasis than EBV-negative patients (32.6% vs. 23.7%, P = 0.021). Multi-variant regression analysis showed that EBV infection was independently associated with liver metastasis (OR: 2.33, P = 0.043). EBV positive patients showed a significantly worse PFS (P = 0.001) and OS (P = 0.001) than EBV negative patients. Multivariate Cox regression analysis revealed that EBV infection was independently associated with a worse PFS (HR: 1.94, P = 0.003), and OS (HR: 2.12, P = 0.014) in advanced NPC. In conclusion, EBV infection is associated with a high risk of liver metastasis and is also an independent negative predictor for PFS and OS in patients with advanced NPC. EBV infection is associated with lower CD8% and higher NK%, while lower NK cell count is associated with lower EBV viral load.

Nomogram predicting survival as a selection criterion for postmastectomy radiotherapy in patients with T1 to T2 breast cancer with 1 to 3 positive lymph nodes.

BACKGROUND: The role of postmastectomy radiotherapy (PMRT) in women with pT1-T2N1 breast cancer is controversial. The authors developed a nomogram that was predictive for overall survival (OS) and identified patients who derived no benefit from PMRT. METHODS: The authors retrospectively evaluated 4869 patients with pT1-T2N1 breast cancer who were treated with mastectomy between 2000 and 2014 in 11 Chinese hospitals. Rates of locoregional recurrence and distant metastasis were calculated using competing risk analysis, and disease-free survival and OS rates were calculated using the Kaplan-Meier method. Based on the risk factors identified from Cox regression analysis in 3298 unirradiated patients, a nomogram predicting OS was developed. The benefit of PMRT was evaluated in different risk groups stratified by the nomogram model. RESULTS: After a median follow-up of 65.9 months, the 5-year OS, disease-free survival, locoregional recurrence, and distant metastasis rates were 93.3%, 84.3%, 5.2%, and 8.3%, respectively. A total of 1571 patients (32.3%) underwent PMRT. On multivariable analyses, PMRT was found to increase OS significantly (hazard ratio, 0.61; P = .002). An OS prediction nomogram evaluated the effect of age; tumor location; tumor size; positive lymph node ratio; estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 status; and treatment with trastuzumab. Based on nomogram scores, the entire patient cohort was classified into 3 risk groups. PMRT significantly improved the OS of patients in the intermediate-risk (P < .001) and high-risk groups (P = .004), but not in the low-risk group (P = .728). CONCLUSIONS: The authors developed a nomogram that is predictive of OS among women with pT1-T2N1 breast cancer after mastectomy. This nomogram may help to select a subgroup of patients with a good prognosis who will not benefit from PMRT.

Clinical Impact of the Bolus in Intensity-Modulated Radiotherapy and Volumetric-Modulated Arc Therapy for Stage I-II Nasal Natural Killer/T-Cell Lymphoma.

INTRODUCTION: To estimate the clinical impact of bolus in intensity-modulated radiotherapy (IMRT) and volumetric-modulated arc therapy (VMAT) for stage I-II nasal natural killer/T-cell lymphoma (NNKTCL), including target quality, organs at risk (OARs) sparing, and tumor control probability (TCP). METHODS: Two different treatment plans were designed in IMRT and VMAT for 10 stage I-II NNKTCL patients. The clinical plans added bolus perfectly contacting the nose skin, similar to common clinical planning design practices. The edited bolus plans resulted from dose recalculation with the edited bolus, which simulated the actual shape of a commercial flat bolus during treatment. All the plans were with no beam passing through the couch avoiding beam attenuation caused by the couch. Differences between both types of plans in target quality, OARs sparing, and TCP were evaluated. RESULTS: Compared with clinical plans, the D98%, D2%, Dmean, and TCP of edited bolus plans with IMRT slightly decreased (p = 0.002, 0.015, 0.000, and 0.000), the homogeneity index increased 8.33% (p = 0.024), and the doses to a small number of OARs slightly changed. Similar results were obtained for VMAT. CONCLUSION: The bolus deformation in practical clinical treatment resulted clinically in tiny changes with respect to the target coverage, OARs sparing, and TCP in both IMRT and VMAT for stage I-II NNKTCL. This implied that the clinical impact of the boluscan be negligible when utilizing it to increase the dose to irregularly shaped tumors in the nasal area.

Estimation of radiotherapy modalities for patients with stage I-II nasal natural killer T-Cell lymphoma.

PURPOSE: The objective of this study is to estimate radiotherapy (RT) modalities for patients with stage I-II nasal natural killer T-Cell lymphoma (NNKTCL), including plan quality, radiation delivery efficiency, cost of RT and excess absolute risk (EAR). MATERIALS AND METHODS: Twenty-four representative patients with stage I-II NNKTCL treated with fix-field intensity-modulated radiotherapy (FF-IMRT) were re-planned for volumetric modulated arc therapy (VMAT), TomoDirect (TD) and TomoHelical (TH) on the TomoHDA system, respectively. Plan characteristics, cost of RT and EAR were compared. RESULTS: Compared with IMRT, TD and TH showed significant improvement in terms of D98%, D2%, cold spot volume and homogeneity index (HI) of planning target volume (PTV), while achieving worse Dmean and conformity index (CI). The mean dose of oropharynx, thyroid and left salivary, and the maximum dose of right salivary by TD (249.20%, p=0.000; 52.94%, p=0.000; 160.23%, p=0.022; 122.67%, p=0.027), VMAT (15.76%, p=0.000; 23.53%, p=0.000; 34.09%, p=0.000; 31.33%, p=0.000) and TH (250.32%, p=0.000; 58.82%, p=0.000; 120.45%, p=0.020; 117.33%, p=0.032) increased significantly compared to IMRT. VMAT reduced treatment time (p=0.000; 0.000; 0.000) and monitor units (MUs) (p=0.000; 0.000; 0.000) obviously compared with IMRT, TD and TH. The cost of RT for TD and TH increased 150% compared with IMRT and VMAT. IMRT obtained the lowest EAR to oropharynx, thyroid, left and right salivary gland in the four treatment modalities. CONCLUSION: The results show that both TD and TH can achieve higher conformal target quality while getting worse organs at risk (OARs) sparing and EAR to some organs than IMRT for patients with stage I-II NNKTCL. IMRT delivers the lowest dose to most OARs, VMAT requires the lower cost of RT and shortest delivery time, and TH obtained the optimal target coverage. The results could provide direction for selecting proper RT modalities for different cases.

Downregulation of peroxiredoxin I by a novel fully human phage display recombinant antibody induces apoptosis and enhances radiation sensitization in A549 lung carcinoma cells.

BACKGROUND: Antibodies have been proved to be effective in cancer treatment. Peroxiredoxin I (Prx I) is a potential target for cancer radiotherapy. The aim of this article is to investigate the effect of a novel phage display single-chain variable fragment (scFv) antibody targeting Prx I on human lung carcinoma cell line A549 radiosensitivity and the underlying mechanisms. MATERIALS AND METHODS: A549 cell radiosensitivity was measured by colony-forming assay; cell cycle, cell apoptosis, and intracellular reactive oxygen species (ROS) level were determined by flow cytometer; RAD51 and γ-H2AX expression was evaluated by Western blot; and caspase 3 expression was determined by immunocytochemistry. A nude mouse bearing A549 tumor was established, and radiation sensitivity was measured to verify the in vitro data. RESULTS: Prx I scFv incubation significantly increased A549 cell radiosensitivity, and this might be through enhanced intracellular ROS level and caspase 3 expression. In addition, protein expression of radiosensitivity-related proteins, RAD51 and γ-H2AX, was also modulated. The nude mouse xenograft model bearing A549 tumor treated with Prx I scFv also exibited enhanced radiosensitivity compared with the PBS group. CONCLUSIONS: These results suggested that Prx I scFv could become a new therapy candidate for lung cancer radiotherapy.

[Effect of peroxiredoxin I gene silencing on the radiosensitivity of breast carcinoma MCF-7 cell xenograft in nude mice].

OBJECTIVE: To investigate the effect of peroxiredoxin I (Prx I) gene silencing on the radiosensitivity of breast carcinoma MCF-7 cell xenograft in nude mice and explore the mechanism. METHODS: MCF-7 cells were transfected with the recombinant plasmids pGPU6-PrxI and pGPU6-HK separately. The pGPU6-PrxI-transfected cells stably expressing Prx I shRNA and pGPU6-HK-transfected cells were inoculated subcutaneously into BALB/c nude mice. After exposure to ionizing radiation (IR) with 6 MV X-ray, the xenografts were harvested for measuring the tumor volume and mass, and the tumor inhibition rates were calculated. Immunohistochemistry was employed for detecting the expressions of Prx I and caspase-3 proteins. The ultrastructural changes of the tumor tissues following the exposure were observed using electron microscopy. Western blotting was used to analyze the expressions of γ-H2AX and Rad51 proteins. RESULTS: Following IR exposure, the pGPU6-Prx I-transfected cell xenograft showed a significantly delayed growth and smaller tumor volume as compared with pGPU6-HK xnegraft, with a tumor inhibition rate reaching 79.76%, significantly higher than that in non-exposed pGPU6-Prx I group (34.92%) and pGPU6-HK+IR group (56.94%) (P<0.05). The pGPU6-Prx I-transfected xenografts showed significantly increased tumor cell apoptosis and necrosis, down-regulated the expressions of Prx I and Rad51 proteins, and up-regulated the expressions of caspase-3 and γ-H2AX proteins; these changes were even more obvious after IR exposure, which caused a decrease of Rad51 protein by 84.8% and an increase in γ-H2AX protein by 5.6 folds compared with those in pGPU6-HK group (P<0.05). CONCLUSION: Prx I gene silencing can significantly enhance the radiosensitivity of breast carcinoma xenograft in nude mice possibly by increasing DNA damage and lowering the capacity of the cells for DNA repair. Prx I may serve as an ideal molecular target for radiosensitization of breast carcinoma.