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Background & aims Nonalcoholic fatty liver disease (NAFLD) has become a tremendous burden for public health, however, there is no drug for NAFLD therapy at present. Impaired endo-lysosome-mediated protein degradation is observed in a variety of metabolic disorders, such as atherosclerosis, type 2 diabetes mellitus and NAFLD. Small integral membrane protein of lysosome/late endosome (SIMPLE) is a regulator of endosome-to-lysosome trafficking and cell signaling. But the role that SIMPLE plays in NAFLD progression remains unknown. Here we investigated SIMPLE function in NAFLD development and sophisticated mechanism therein. Approach & results This study found in vitro knockdown of SIMPLE significantly aggravated lipid accumulation, inflammation in hepatocytes treated with metabolic stimulation. Consistently, in vivo experiments showed that liver-specific Simple-knockout (Simple-HKO) mice exhibited more severe high-fat diet (HFD)-, high-fat-high-cholesterol diet (HFHC)-, and methionine-choline-deficient diet (MCD)- induced steatosis, glucose intolerance, inflammation, and fibrosis than those fed with normal-chow diet. Meanwhile, RNA-sequencing demonstrated the up-regulated signaling pathways and signature genes involved in lipid metabolism, inflammation and fibrosis in Simple-HKO mice compared to control mice under metabolic stress. Mechanically, we found SIMPLE directly interact with epidermal growth factor receptor (EGFR). SIMPLE deficiency results in dysregulated degradation of EGFR, subsequently hyperactivated EGFR phosphorylation, exaggerating NAFLD development. Moreover, we further demonstrated that using EGFR inhibitor or silencing EGFR expression could ameliorate lipid accumulation induced by the knockdown of SIMPLE. Conclusions SIMPLE ameliorated NASH by prompting EGFR degradation and can also be a potential therapeutic candidate for NASH.

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.

Growing evidences have revealed that a histone deacetylase inhibitor (HDACi), suberoylanilide hydroxamic acid (SAHA) has anti-fibrotic effect in different diseases. In this study, we first evaluated whether SAHA could suppress cardiac fibrosis. Mice with MI-induced cardiac fibrosis were treated with SAHA by intraperitoneal injection and their cardiac function was improved after SAHA treatment. Results of western blotting and qRT-PCR in heart tissues suggested that TGFβ1/P38 pathway was activated in MI mice, and this effect was reversed by SAHA. Cell proliferation assay suggested that SAHA could suppress TGF-β1-induced cardiac fibroblasts proliferation. Furthermore, results of western blotting and qRT-PCR in cardiac fibroblasts depicted that SAHA may exert its anti-fibrotic effect through inhibiting TGF-β1-induced P38 phosphorylation by promoting DUSP4 expression. Our findings may substantiate SAHA as a promising treatment for MI-induced cardiac fibrosis.

Background and aims NAFLD prevalence has increased rapidly and become a major global health problem. Tumor necrosis factor α-induced protein 8-like 2 (TIPE2) plays a protective role in a cluster of liver diseases, such as autoimmune hepatitis, hepatitis B, and hepatocellular carcinoma. However, the function of TIPE2 in NAFLD remains unknown. Here, we investigated the role of TIPE2 in the development of NAFLD. Approach and results Our study found that in vitro overexpression or knockout of TIPE2 significantly ameliorated or aggravated lipid accumulation and inflammation in hepatocytes exposed to metabolic stimulation, respectively. Consistently, in vivo hepatic steatosis, insulin resistance, inflammation, and fibrosis were alleviated in hepatic Tipe2-transgenic mice but exaggerated in hepatic Tipe2-knockout mice treated by metabolic challenges. RNA sequencing revealed that TIPE2 was significantly associated with the mitogen-activated protein kinase pathway. Mechanistic experiments demonstrated that TIPE2 bound with transforming growth factor beta-activated kinase 1 (TAK1), prevented tumor necrosis factor receptor-associated factor 6-mediated TAK1 ubiquitination and subsequently inhibited the TAK1 phosphorylation and activation of TAK1-c-Jun N-terminal kinase (JNK)/p38 signaling. Further investigation showed that blocking the activity of TAK1 reversed the worsening of hepatic metabolic disorders and inflammation in hepatic-specific Tipe2-knockout hepatocytes and mice treated with metabolic stimulation. Conclusions TIPE2 suppresses NAFLD advancement by blocking TAK1-JNK/p38 pathway and is a promising target molecule for NAFLD therapy.

The present study aimed to explore the clinical characteristics and management of retroperitoneal hematoma (RPH) after invasive intervention during a 12-year period in China. A retrospective review of patients with RPH after various invasive interventions was conducted at the China National Center for Cardiovascular Diseases. A total of 42 patients with a mean age of 63.1±2.5 years were continuously recruited in the study between January 2007 and September 2018. The incidence, manifestations and management of RPH were analyzed. A total of 20 patients had punctures in the femoral arterial access under the inguinal ligament and 5 patients had punctures above the inguinal ligament. The majority of RPH occurred within 24 h after intervention, while some occurred after postoperative 24 h. Pain was the most common symptom in patients with RPH. All patients who underwent intervention presented a reduction in hemoglobin (HB) concentration. The overall incidence of nosocomial infection was 38.1% and mortality was 7.1%. The findings demonstrated that RPH is a rare complication after invasive intervention of cardiovascular diseases with non-specific clinical manifestations. The reduction of HB concentration was a vital manifestation for RPH. Most RPH cases could be treated by conservative treatment and blood transfusion. A puncture in the femoral arterial access under the inguinal ligament may result in RPH.

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 rapidly increasing prevalence of metabolic disorders associated with nonalcoholic fatty liver disease (NAFLD) warrants further study of the underlying mechanisms to identify key regulators as targets for the development of therapeutic interventions. Caspase recruitment domain protein 6 (Card6), as a member of the CARD family that regulates cell death and immunity, may potentially control this process. Indeed, Card6 down-regulation was found to be closely associated with the fatty livers observed in NAFLD patients, obese mice, and a palmitate-treated hepatocyte model. Gain-of-function and loss-of-function Card6 mouse models demonstrated that Card6 protected mice from insulin resistance, hepatic steatosis, and inflammatory responses upon high-fat diet administration. Mechanistically, Card6 interacted with and inhibited apoptosis signal-regulating kinase 1 (Ask1) and its subsequent downstream c-Jun N-terminal kinase/p38 signaling. Furthermore, Ask1 was sufficient to mediate Card6 function, and the interaction between Ask1 and Card6 was absolutely required for Card6 function in vivo. Adenovirus-mediated Card6 overexpression in the liver effectively ameliorated insulin resistance and hepatic steatosis in ob/ob mice. Therefore, we identified Card6 as an important negative regulator in NAFLD. Conclusion: Targeting Ask1 by Card6 may be a good strategy to develop a therapeutic method against NAFLD.

Background: This phase I/II clinical trial investigated S-1 administered with intensity-modulated radiotherapy (IMRT) as adjuvant therapy for node-positive gastric cancer. Patients had undergone radical resection and D1/D2 lymph node dissection. Methods: In phase I, patients received adjuvant chemoradiotherapy of IMRT (45 Gy in 25 fractions) with concurrent S-1 administered on a dose-escalation schedule to determine the recommended dose (RD). In phase II, the safety and efficacy of the RD of S-1 combined with IMRT were assessed. Results: We consecutively enrolled 73 patients (56 men; median age, 53 years; range, 29–73 years) and the phase I portion of the study included 27 patients. The RD of S-1 administered concomitantly with IMRT was 80 mg m−2 day−1 orally, twice daily. The phase II analysis included 52 patients (46 new patients plus 6 from phase I). 8 patients (15.4%) developed grade 3 or 4 toxicities. There were 21 recurrence events and 15 deaths (1 bowel obstruction, 14 gastric cancer). Three-year disease-free survival and overall survival were 62.2% (95% confidence interval (CI), 48.5–75.9) and 70.0% (95% CI, 56.3–83.7), respectively. The median time to recurrence was 17.5 months (range, 3.8–42.0). The median time from recurrence to death was 7.0 months (range, 1.5–28.7). Conclusions: S-1 combined with IMRT adjuvant chemoradiotherapy is safe and efficacious for advanced gastric cancer.