Search

The combination of nitric oxide (NO) and siRNA is highly desirable for cancer therapy. Here, the furoxans-grafted PEI polymer (FDP) with caspase-3 responsive cleavable DEVD linker was synthesized, and used to bind siRNAs via electrostatic interaction and self-assembled into FDP/siRNA nanoplexes by hydrophobic force. After cellular uptake and lysosomal escape, the FDP/siRNA nanoplexes could achieve GSH-triggered NO release, and then increase the activity of caspase-3. The activated caspase-3 could specifically cleave the DEVD peptide sequence and enhance cell apoptosis. With the cleavage of DEVD peptide sequence, the disassembly of FDP/siRNA nanoplexes was further promoted, thereby resulting in increased siRNAs of ~40% were released at 48 h compared with the caspase-3 non-responsive FDnP/siRNA nanoplexes. By this way, cell apoptosis promotion and cell proliferation inhibition was achieved by siRNA-based downregulation of EGFR protein and the upregulated activity of caspase-3, followed by the enhanced cascade release of NO from FDP/siRNA nanoplexes. Furthermore, in vivo results demonstrated the improved anti-cancer efficiency of FDP/siEGFR nanoplexes without any detectable side effects. Therefore, it is believed that the caspase-3 responsive cleavable furoxans-grafted PEI polymers could provide a potential and efficient enhancement for cancer therapeutic efficiency by the co-delivery of nitric oxide and siRNA.

Debate exists on the prognostic significance of spontaneous myocardial infarction (SMI) and periprocedural myocardial infarction (PMI), which could be diagnosed by various definitions.A total of 10,724 patients undergoing percutaneous coronary intervention (PCI) were consecutively enrolled and followed up for a median of 2.4 years. We evaluated outcomes of all-cause death, cardiac death, and major adverse cardiovascular events (MACE). Patients were stratified into three groups, including the No MI group, PMI group, and SMI group. PMI was defined based on different diagnostic criteria, including the third and fourth universal myocardial infarction (MI) definitions, the society for cardiovascular angiography and interventions (SCAI) definition, and the independent biomarker definition. Regardless of these definitions, the PMI groups were all associated with a significantly increased MACE risk at one year or 1000 days (all P0.05), but not all-cause or cardiac death. The SMI group was associated with a markedly elevated risk of death and MACE, but it showed no significant different risk of MACE to PMI using varying definitions.According to various PMI definitions, PMI and SMI were associated with an increased risk of MACE, but not death for PMI. No significantly different risk of MACE was observed between PMI and SMI.

Purpose/Objective(s) Radiation induce pneumonitis (RP), is a common adverse event after thoracic radiotherapy in patients with breast cancer. The biologically predictive marker of RP in breast cancer is not so abundant as that in lung cancer. Systematic inflammation-immune status (SIS) has been thought to play a crucial role in tumorigenesis, prognosis, and inflammation. Therefore, we proposed this study to evaluate the association between systematic inflammation-immune status and the incidence of RP in patients with breast cancer after whole breast irradiation. Materials/Methods We searched cases of patients treated at the two institutions, between January 1 2018 and December 31 2018. Inclusion criteria included: pathologically confirmed breast cancer and received breast conserving surgery as the first treatment; patients received postoperative whole breast irradiation; intensity modulated radiotherapy or volumetric modulated arc therapy is delivered to; available blood counts before the radiation and within 1 months from the accomplishment of radiation, available CT scan within one year from the accomplishment of radiotherapy. Pre-radiation and post-radiation inflammation-immune status score were calculated using the formula Platelet X Neutrophil/Lymphocyte. Radiation induced pneumonitis was evaluated by a senior radiation oncologist and a senior radiologist according to CTC AE 4.0. Training group included half of the patients from one center and validation group included the other half of the patients as well as patients from the other center. Receiver operating characteristic (ROC) curve analysis is utilized to define the cut-off value of SIS in affecting RP development. Results Totally, 562 patients fulfilled the eligibility criteria. The predictive model was built based on data of 232 patients and validated by 330 patients. After ROC analysis, cut off value was 482.98*109 and 895.32*109 at the time of pre-radiation and post-radiation, respectively. According to the cutoff value of pre-radiation SIS, patients were divided into PrLIS group (pre-radiation SIS≤482.98*109) and PrHIS group (pre-radiation SIS > 482.98*109). Similarly, according to the cutoff value of post-radiation SIS, patients were divided into PoLIS group (post-radiation SIS≤895.32*109) and PoHIS group (post-radiation SIS > 895.32*109). The validation showed that there is no significant difference of RIP (56.1% vs.60.1%, P = 0.455) between patients in PrLIS and PrHIS group. Patients in PoHIS group were more likely to get RP than that in PoLIS group (72.7% vs 54.5%, P = 0.001) Conclusion The post radiation SIS is a sensitive predictor of RP in patients with breast cancer after whole breast irradiation. For patients with high SIS after radiation, CT scan after radiation might be taken into consideration.

PURPOSE/OBJECTIVE(S) To compare the prognostic value of neoadjuvant rectal (NAR) score and MRI-based nomogram model for locally advanced rectal cancer (LARC) treated with neoadjuvant therapy. MATERIALS/METHODS Retrospective analysis was performed for 233 patients with LARC (T3-4 and/or N1-2, M0), who were initially treated in our institution from Mar.2015 to Mar.2018. All patients had baseline MRI assessments and received neoadjuvant therapy and TME surgery. The neoadjuvant rectal (NAR) score was calculated according to the baseline MRI factor (cT) and pathological stage (pT, pN). NAR = [5pN-3(cT-pT)+12]2/9.61. The patients were sequentially allocated to two cohorts (training cohort and validation cohort) in a ratio of 4:3 based on the date of image examination. The nomogram model was constructed based on the results of univariate logistic regression analysis and multivariable cox regression analysis of the training cohort for disease-free survival (DFS). The nomogram and NAR score were evaluated by Harrell's concordance index (C-index), calibration plots, receiver operating characteristic curve (ROC) analysis, and decision curve analysis (DCA) in both training and validation cohort. RESULTS With a median follow-up of 43.2 months (13.3-61.3months) in the training cohort and 32.0 months (12.3-39.5 months) in the validation cohort. Multivariate cox regression analysis identified the MRI-detected extramural vascular invasion (mrEMV), pathological T stage (ypT) and perineural invasion (PNI) as independent predictors. According to previous studies, lymph vascular invasion (LVI) (which was founded to be significant after univariate regression analysis) and three other independent predictors are included in the nomogram model. The univariate survival analysis showed that the nomogram model and NAR score were correlated with 3-year DFS (P < 0.05). For comparison, the nomogram performed better over the NAR score (C-index 0.76 (95% CI 0.70-0.84) versus 0.66 (95% CI 0.60-0.71) for the training cohort, and 0.77 (95% CI 0.70-0.85) versus 0.69(0.60-0.78) for the validation cohort).The nomogram model achieved a better 3-year DFS predictive capacity (AUC = 0.84 in the training cohort; AUC = 0.77 in the validation cohort) than NAR score (AUC = 0.70 in the training cohort; AUC = 0.73 in the validation cohort). DCA revealed that the use of the nomogram model was associated with better benefit gains relative to the prediction of 3-year DFS compared to NAR score in training cohort (threshold probability range between 0.06 and 0.54) and validation cohort (threshold probability range between 0.08 and 0.50). CONCLUSION We developed and validated a novel nomogram model based on MRI factor and pathological factors for predicting DFS in LARC treated with neoadjuvant therapy. Compared with NAR score, nomogram model shows the better potential predictive value of prognosis, which could improve the risk stratification and individual treatment for LARC patients.

Purpose/Objective(s) Portal vein or hepatic vein tumor thrombosis is a leading predictor of poor prognosis in patients with hepatocellular carcinoma (HCC). We conduct this phase II clinical trial to investigate the efficacy and safety of concurrent sorafenib and radiotherapy for advanced HCC with portal vein and/or hepatic vein tumor thrombosis. Materials/Methods We designed a single-arm, prospective phase II trial to evaluate median survival time (MST), overall response rate (ORR), time to progression (TTP) and toxicities in patients of HCC with portal vein and/or hepatic vein tumor thrombosis receiving concurrent sorafenib and radiotherapy. Eligibility criteria included the following: clinical or histologic diagnosis of HCC with portal vein or hepatic vein tumor thrombosis; liver-GTV > 700ml; and ECOG performance status score of 0 or 1 etc. Eligibility patients would receive radiotherapy to hepatic primary tumor and vein tumor thrombosis with concurrently sorafenib with a dose of 400mg twice daily. Prescription of radiotherapy would be a conventional fraction dose of 2-2.6Gy to a total dose of 40 to 65Gy to tumor. Sorafenib will be maintained with a dose of 400mg twice daily after radiotherapy until disease progression, or unacceptable adverse events. Results Between April 2018 and January 2020, a total of 86 eligible patients were enrolled. Seventy patients were with portal vein thrombosis, 5 patients were with hepatic vein tumor thrombosis, and 11 patients were with portal vein and hepatic vein tumor thrombosis. For portal vein thrombosis, 87.5% patients involved main trunk or first branches of portal vein. For hepatic vein tumor thrombosis, 43.8% patients involved inferior vena cava, and 2 patients involved right atrium. The median dose of radiotherapy was 54Gy (40-65Gy). ORR was 53.4% and disease control rate (DCR) was 76.6%. With a median follow-up of 24 months for living patients, MST and TTP was 16.8 months and 7.1 months, respectively. The 2-year local control rate for hepatic primary tumor and tumor thrombosis were 83.0% and 90.7%, respectively. Out-field recurrence in liver and distance metastasis were the main failure pattern. The 2-year out-field recurrence rate in liver and distance metastasis rate were 43.6% and 45.7%. Concurrent sorafenib and radiotherapy was well tolerated by patients. All patients were able to complete radiotherapy as planned. And 87.2% patients could complete concurrent sorafenib as a dose of 400mg twice daily. The most common grade 3 toxicities were thrombocytopenia (23.3%), leukopenia (14.0%), dermatitis (4.7%), anemia (3.5%), hand-foot syndrome (2.3%) and elevated alanine aminotransferase (2.3%). Classical or non-classical radiation-induced liver disease was not noted. Conclusion Concurrent sorafenib and radiotherapy is an effective, well tolerated and promising treatment in HCC patients with portal vein and/or hepatic vein tumor thrombosis. This trial was registered at ClinicalTrials.gov (number NCT03535259).

Purpose/Objective(s) Anti-programmed death-1 (PD-1) is an emerging paradigm for treating metastatic malignancies. However, limited response rate and unsatisfactory results of PD-1 inhibitor as monotherapy in advanced liver cancer prompted the exploration of combination strategies. Preclinical studies demonstrated that combination of radiation and PD-1 inhibitors can synergistically augment the anti-tumor efficacy induced by both agents. This study addressed the hypothesis that the application of radiation combined with Toripalimab, an anti-PD-1 agent, may foster immune efficacy in metastatic and recurrent liver cancer. Materials/Methods We did this study in patients with stage IV (defined by the American Joint Committee on Cancer 8th edition staging system) or recurrent liver cancer in 2nd-line or 3rd-line treatment, with an Eastern Cooperative Oncology Group performance score of 0-2, child-Pugh grade of A-B. All enrolled patients received radiation at doses of 40-60Gy. Toripalimab (240mg per day, 21 days per cycle) was delivered during and/or after radiation until progression or severe toxicities. The primary endpoint was progression-free survival and the secondary endpoints were objective response, overall survival and toxicities. Survivals were calculated from the beginning of immunotherapy. Results From April 2017 to September 2020, 17 patients were enrolled and evaluable. Sixteen patients (94.1%) were male and 1(5.9%) was female. The median age was 56 years old (range 36-74 years old). Ten patients (58.8%) had hepatocellular carcinoma. Sixteen patients (94.1%) were with Child-Pugh grade A. Fifty-two lesions, including 15 venous tumor emboli, 13 metastatic bones, 12 lymph nodes, 11 liver malignancies and 2 other sites, received radiation. The median radiation dose is 53Gy (40-60Gy, 2-4Gy per fraction). Sixteen patients received targeted therapy (9 patients with sorafenib, 3 patients with lenvatinib, 3 patients with regorafenib and 1 patient with apatinib) during the treatment of immunotherapy and radiotherapy. The objective response rate and disease control rate were 64.7% (the complete response was 5.9% and partial response was 58.8%) and 88.2%. Grade≥3 adverse events were observed in 5 patients (29.4%), including 3 with thrombocytopenia (2 with grade 4, 1 with grade 3),1 with gastrointestinal event and 1 with infection. All the adverse events were cured after treatment. The median follow-up time was 15.9 months. At the last follow up, 6 patients died. No in-field relapse was recorded. Progression-free survival was 43.3% at 1 year and 21.6% at 2 years, overall survival was 60% at 1 year and 24% at 2 years. The median survival time and progression free survival time were 12.1 months and 11.1 months, respectively. Conclusion For patients with advanced or recurrent liver cancer, toripalimab in combination with concurrent or previous radiotherapy is an effective treatment with tolerable toxicities. A prospective trial with large number of patients is warranted.

Purpose/Objective(s) To create a radiomics model of prognostic prediction for soft-tissue sarcoma (STS) of the extremities and trunk treated with neoadjuvant radiotherapy. Materials/Methods we used a dataset of 62 STS patients treated with neoadjuvant radiotherapy from our institution between January 2015 and December 2019 (n = 20) and the NCI's Cancer Imaging Archive between November 2004 and November 2011(TCIA, n = 42). After tumor segmentation and preprocessing, 851 radiomic features were extracted from pretreatment fat saturated T2-weighted MRI image. The Radiomics-score was to be constructed based on the least absolute shrinkage and selection operator (LASSO) regression results. Kaplan-Meier analysis (log-rank test) and Cox's proportional hazards regression model were used to evaluate the prognostic factor of the 2-years disease-free survival (DFS). The nomogram model was established based on log-rank test and Cox's proportional hazards regression model. The Harrell's concordance index (C-index), receiver operating characteristic curve (ROC) analysis and calibration curves were used to evaluate the nomogram models. Decision curve analysis (DCA) was performed to analyze the clinical usefulness of the model. Results The cohort included 62 patients (30 females (48.4%), mean age: 50.9 ± 19.1 years). The most frequent histotypes were liposarcoma (24.2%) and undifferentiated sarcoma (22.6%). Most of tumors were deep-seated (74.2%) and located in the extremity (88.5%). A total of 851 radiomic features were extracted from T2-FS images. After data dimension reduction with LASSO, 42 most valuable features remained and their coefficients were from lasso-cox regression. The radiomics-score calculation formula consisted of these features. The univariate survival analysis showed that tumor location (P = 0.032), clinical stage (P = 0.022), tumor size (P = 0.005) and radiomics-score were correlated with DFS (P Conclusion The radiomics-score based pretreatment MRI was an independent prognostic factor for DFS of the extremities and trunk STS patients. The combined clinical-radiomics model added accuracy to predict DFS and thus contributed to the individual selection of neoadjuvant therapy.

The morbidity of lower extremity atherosclerotic disease(LEAD) has increased year by year. Chronic stress attenuates the ability of angiogenesis and deteriorates the prognosis of LEAD. Chronic stress increases plasma and tissue DPP-4 activities in mice. DPP-4 plays an important role in angiogenesis

Background Statins are commonly administrated daily, while rosuvastatin can be given every other day due to its longer half-lives. We evaluated the potential efficacy of alternate-day dosing of 10 mg rosuvastatin compared with daily dosing of 10 mg rosuvastatin with regarding to lipid and inflammatory markers in patients with dyslipidemia. Methods Thirty-seven patients were randomly divided into the 2 groups: alternate-day group (rosuvastatin 10 mg every other day, n = 19) and once-daily group (rosuvastatin 10 mg every day, n = 18) for 6 weeks. The primary endpoints of the study were changes of the serum concentrations of low-density lipoprotein cholesterol (LDL-C), C-reactive protein (CRP) and interleukin-6 (IL-6) following 6-week rosuvastatin therapy. Results Baseline characteristics of the 2 groups were well balanced. LDL-C decreased by 37.5% after the once-daily dosing period and by 36.9% after alternate-day dosing period (p > 0.05). Both dosing regimens provided similar improvement in high-density lipoprotein cholesterol and triglyceride. And also, both dosing regimens significantly decreased serum concentrations of CRP, which had an 18.3% reduction in once-daily dosing and a 16.7% reduction in alternate-day dosing of rosuvastatin (p > 0.05). Moreover, the pattern of plasma IL-6 concentrations was also similar between the two groups (p > 0.05). Conclusions Alternate-day dosing of rosuvastatin could be effective comparable with once-daily dosing of rosuvastatin in Chinese patients in improving not only lipid profile but also inflammatory markers, which may provide some cost savings and increase the compliance of patients.

Post-exercise heart rate recovery (HRR) is an index of parasympathetic function associated with clinical outcomes in populations with and without documented coronary heart disease. Decreased parasympathetic activity is thought to be associated with disease progression in chronic heart failure (HF), but an independent association between post-exercise HRR and clinical outcomes among such patients has not been established.We measured HRR (calculated as the difference between heart rate at peak exercise and after 1 minute of recovery) in 202 HF subjects and recorded 17 mortality and 15 urgent transplantation outcome events over 624 days of follow-up. Reduced post-exercise HRR was independently associated with increased event risk after adjusting for other exercise-derived variables (peak oxygen uptake and change in minute ventilation per change in carbon dioxide production slope), for the Heart Failure Survival Score (adjusted HR 1.09 for 1 beat/min reduction, 95% CI 1.05-1.13, P.0001), and the Seattle Heart Failure Model score (adjusted HR 1.08 for one beat/min reduction, 95% CI 1.05-1.12, P.0001). Subjects in the lowest risk tertile based on post-exercise HRR (or=30 beats/min) had low risk of events irrespective of the risk predicted by the survival scores. In a subgroup of 15 subjects, reduced post-exercise HRR was associated with increased serum markers of inflammation (interleukin-6, r = 0.58, P = .024; high-sensitivity C-reactive protein, r = 0.66, P = .007).Post-exercise HRR predicts mortality risk in patients with HF and provides prognostic information independent of previously described survival models. Pathophysiologic links between autonomic function and inflammation may be mediators of this association.