BACKGROUND:Radiation (IR)-induced DNA damage triggers cell cycle arrest and has a suppressive effect on the tumor microenvironment (TME). Wee1, a cell cycle regulator, can eliminate G2/M arrest by phosphorylating cyclin-dependent kinase 1 (CDK1). Meanwhile, programed death-1/programed death ligand-1 (PD-1/PDL-1) blockade is closely related to TME. This study aims to investigate the effects and mechanisms of Wee1 inhibitor AZD1775 and anti-PD-1 antibody (anti-PD-1 Ab) on radiosensitization of hepatoma.METHODS:The anti-tumor activity of AZD1775 and IR was determined by 3-(4,5-dimethylthiazol-2-y1)-2,5-diphenyltetrazolium bromide (MTT) assay on human and mouse hepatoma cells HepG2, Hepa1-6, and H22. The anti-hepatoma mechanism of AZD1775 and IR revealed by flow cytometry and Western blot in vitro . A hepatoma subcutaneous xenograft mice model was constructed on Balb/c mice, which were divided into control group, IR group, AZD1775 group, IR + AZD1775 group, IR + anti-PD-1 Ab group, and the IR + AZD1775 + anti-PD-1 Ab group. Cytotoxic CD8 + T cells in TME were analyzed by flow cytometry.RESULTS:Combining IR with AZD1775 synergistically reduced the viability of hepatoma cells in vitro . AZD1775 exhibited antitumor effects by decreasing CDK1 phosphorylation to reverse the IR-induced G2/M arrest and increasing IR-induced DNA damage. AZD1775 treatment also reduced the proportion of PD-1 + /CD8 + T cells in the spleen of hepatoma subcutaneous xenograft mice. Further studies revealed that AZD1775 and anti-PD-1 Ab could enhance the radiosensitivity of hepatoma by enhancing the levels of interferon γ (IFNγ) + or Ki67 + CD8 T cells and decreasing the levels of CD8 + Tregs cells in the tumor and spleen of the hepatoma mice model, indicating that the improvement of TME was manifested by increasing the cytotoxic factor IFNγ expression, enhancing CD8 + T cells proliferation, and weakening CD8 + T cells depletion.CONCLUSIONS:This work suggests that AZD1775 and anti-PD-1 Ab synergistically sensitize hepatoma to radiotherapy by enhancing IR-induced DNA damage and improving cytotoxic CD8 + T cells in TME.

Objectives To test if intravesical instillation of both an anti‐programmed cell death protein 1 (PD‐1) inhibitor and an oncolytic reovirus would demonstrate a greater effect than either treatment alone, as non‐muscle‐invasive bladder cancer that is refractory to intravesical bacillus Calmette–Guérin can be treated by systemic anti‐PD‐1 immunotherapy and we previously demonstrated improved overall survival (OS) with six once‐weekly instillations of intravesical anti‐PD‐1 in a murine model. Materials and Methods Using an orthotopic syngeneic C3H murine model of MBT2 urothelial bladder cancer, groups of 10 mice were compared between no treatment, intravesical anti‐PD‐1, intravesical oncolytic reovirus, or intravesical reovirus + anti‐PD‐1. A single intravesical treatment session was given. The primary outcome was OS, and the secondary outcomes included long‐term immunity and tumour–immune profile. Results With a median follow‐up of 9 months, all mice that received no treatment died with a median survival of 41 days, while the comparison median OS was not reached for reovirus (hazard ratio [HR] 14.4, 95% confidence interval [CI] 3.9–32.6; P < 0.001), anti‐PD‐1 (HR 28.4, 95% CI 7.0–115.9; P < 0.001), and reovirus + anti‐PD‐1 (HR 28.4, 95% CI 7.0–115.9; P < 0.001). Monotherapy with anti‐PD‐1 or reovirus demonstrated no significant differences in survival ( P = 0.067). Mass cytometry showed that reovirus + anti‐PD‐1 treatment enriched monocytes and decreased myeloid‐derived suppressor cells, generating an immuno‐responsive tumour microenvironment. Depletion of CD8 + T cells eliminated the survival advantage provided by the intravesical treatment. Conclusions Treatment of murine orthotopic bladder tumours with a single instillation of intravesical reovirus, anti‐PD‐1 antibody, or the combination confers superior survival compared to controls. Tumour–immune microenvironment differences indicated myeloid‐derived suppressor cells and CD8 + T cells mediate the treatment response.

Free Article from Predicting Outcomes in Cervical Cancer: A Kinetic Model of Tumor Regression during Radiation Therapy

XLSX file - 44KB, Supplementary Table S3. Main specimen and methodological characteristics of the 92 included high-quality cohort studies of this systematic review.

Background:Delayed post-hypoxic leukoencephalopathy (DPHL) is a demyelinating syndrome that occurs days to weeks after the brain has recovered from a coma. It is caused by the period of hypoxia and is characterized by mental disorders, extrapyramidal system symptoms, and motor changes. Common causes include cardiogenic shock, severe anemia, massive blood loss, and poisoning. Poisoning, mostly resulting from intoxication with carbon monoxide and several narcotic drugs, has been reported to be a cause of DPHL. There are only a few reports of DPHL due to nitrite poisoning in literature. We report DPHL in a patient following nitrite poisoning and a review of the literature in this context.Case Presentation:A 64-year-old man presented with dizziness and nausea without vomiting. He later went into a coma after consuming a spare rib soup. After blood gas analysis, we suspected nitrite poisoning combined with metabolic acidosis, hypoxemia, and electrolyte imbalance. He gradually showed neurologic recovery to premorbid baseline after intravenous administration of methylene blue (40 mg) and symptomatic treatment. Two months later, the patient's cerebral magnetic resonance imaging (MRI) showed signs that are compatible with injury, with the patient in late stages of mental decline.Conclusion:Nitrite poisoning can cause DPHL. There is a period of intermittent recovery between the time of poisoning and the development of DPHL, but the specific pathogenesis and treatment are still unclear.

PURPOSE:This study aimed to analyze clinicopathological, survival, prognostic factors, as well as the timing of brain metastases (BM) in colorectal cancer (CRC) using data from a Chinese center.PATIENTS AND METHODS:Data of 65 consecutive CRC patients with BM were collected from a single institution in China. The time from primary tumor surgery to the occurrence of BM was calculated. Kaplan-Meier analysis was used to evaluate cumulative survival of patients. Factors associated with prognosis of overall survival (OS) were explored using Cox's proportional hazard regression models.RESULTS:The median time interval from CRC surgery to the diagnosis of BM was 24 months. After diagnosis of BM, median OS values for patients were 11 months. Extracranial metastases occurred in 45 cases (69.2%) when BM was diagnosed, and 58.5% of these patients with lung metastases Time of BMs (P=0.018), presence of extracranial metastases (P=0.033), treatment (P=0.003), CA199 (P=0.034), CA125 (P<0.001), CA242 (P=0.018), and CA211 (P=0.012) were associated with OS of patients through univariate analysis. Multivariate analysis using a Cox regression model showed that only treatment was an independent predictor for OS (conservative treatment; HR=1.861, 95% CI=1.077-3.441; P=0.048).CONCLUSION:Surgical treatment of metastatic lesions may be an alternative choice for CRC patients with BM. Identifying the timing of brain metastases can help to detect this disease early, leading to a better survival outcome.

Background Esophageal squamous cell carcinoma (ESCC) is an aggressive type of cancer, associated with poor prognosis. The development of an accurate and non-invasive method to evaluate the pathologic response of patients with ESCC to chemoradiotherapy remains a critical issue. Therefore, the aim of this study was to assess the importance of vascular permeability and texture parameters in predicting the response to neoadjuvant chemoradiotherapy (NACRT) in patients with ESCC. Methods This prospective analysis included patients with T1–T2 stage of ESCC, without either lymphatic or metastasis, and distant metastasis. All patients underwent surgery having received two rounds of NACRT. All patients underwent dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) twice, i.e., before the first NACRT and after the second NACRT. Patients were assessed for treatment response at 30 days after the second NACRT. Patients were divided into the complete response (CR) and partial response (PR) groups based on their responses to NACRT. Vascular permeability and texture parameters were extracted from the DCE-MRI scans. After assessing the diagnostic performance of individual parameters, a combined model with vascular permeability and texture parameters was generated to predict the response to NACRT. Results In this study, the CR and PR groups included 16 patients each. The volume transfer constant (Ktrans), extracellular extravascular volume fraction (ve), and entropy values, as well as changes to each of these parameters, extracted from the second DCE-MRI scans, showed significant differences between the CR and PR groups. The area under the curve (AUC) of Ktrans, ve, and entropy values showed good diagnostic ability (0.813, 0.789, and 0.707, respectively). A logistic regression model combining Ktrans, ve, and entropy had significant diagnostic ability (AUC=0.977). Conclusions The use of a combined model with vascular permeability and texture parameters can improve post-NACRT prognostication in patients with ESCC.

Background Radioimmunotherapy has a promising antitumor effect in hepatocellular carcinoma (HCC), depending on the regulatory effect of radiotherapy on tumor immune microenvironment. Ionizing radiation (IR)-induced DNA damage repair (DDR) pathway activation leads to the inhibition of immune microenvironment, thus impairing the antitumor effect of radioimmunotherapy. However, it is unclear whether inhibition of the DDR pathway can enhance the effect of radioimmunotherapy. In this study, we aim to explore the role of DDR inhibitor AZD6738 on the combination of radiotherapy and immune checkpoint inhibitors (ICIs) in HCC.Methods C57BL/6 mouse subcutaneous tumor model was used to evaluate the ability of different treatment regimens in tumor growth control and tumor recurrence inhibition. Effects of each treatment regimen on the alterations of immunophenotypes including the quantification, activation, proliferating ability, exhaustion marker expression, and memory status were assessed by flow cytometry.Results AZD6738 further increased radiotherapy-stimulated CD8+ T cell infiltration and activation and reverted the immunosuppressive effect of radiation on the number of Tregs in mice xenografts. Moreover, compared with radioimmunotherapy (radiotherapy plus anti-PD-L1 (Programmed death ligand 1)), the addition of AZD6738 boosted the infiltration, increased cell proliferation, enhanced interferon (IFN)-γ production ability of TIL (tumor-infiltrating lymphocyte) CD8+ T cells, and caused a decreasing trend in the number of TIL Tregs and exhausted T cells in mice xenografts. Thus, the tumor immune microenvironment was significantly improved. Meanwhile, triple therapy (AZD6738 plus radiotherapy plus anti-PD-L1) also induced a better immunophenotype than radioimmunotherapy in mice spleens. As a consequence, triple therapy displayed greater benefit in antitumor efficacy and mice survival than radioimmunotherapy. Mechanism study revealed that the synergistic antitumor effect of AZD6738 with radioimmunotherapy relied on the activation of cyclic GMP–AMP synthase /stimulator of interferon genes (cGAS/STING) signaling pathway. Furthermore, triple therapy led to stronger immunologic memory and lasting antitumor immunity than radioimmunotherapy, thus preventing tumor recurrence in mouse models.Conclusions Our findings indicate that AZD6738 might be a potential synergistic treatment for radioimmunotherapy to control the proliferation of HCC cells, prolong survival, and prevent tumor recurrence in patients with HCC by improving the immune microenvironment.

Clinical and Translational MedicineVolume 10, Issue 3 e121 LETTER TO EDITOROpen Access Benefits of multi-disciplinary treatment strategy on survival of patients with colorectal cancer liver metastasis Yang Lv, Yang Lv orcid.org/0000-0002-6013-0558 Department of General Surgery, ZhongShan Hospital, Fudan University, Shanghai, Shanghai, China Y.L., Q.Y.F., Y.W., and L.R. contributed equally to this work.Search for more papers by this authorQing-Yang Feng, Qing-Yang Feng Department of General Surgery, ZhongShan Hospital, Fudan University, Shanghai, Shanghai, China Y.L., Q.Y.F., Y.W., and L.R. contributed equally to this work.Search for more papers by this authorYe Wei, Ye Wei Department of General Surgery, ZhongShan Hospital, Fudan University, Shanghai, Shanghai, China Y.L., Q.Y.F., Y.W., and L.R. contributed equally to this work.Search for more papers by this authorLi Ren, Li Ren Department of General Surgery, ZhongShan Hospital, Fudan University, Shanghai, Shanghai, China Y.L., Q.Y.F., Y.W., and L.R. contributed equally to this work.Search for more papers by this authorQingHai Ye, QingHai Ye Department of Liver Surgery, ZhongShan Hospital, Fudan University, Shanghai, Shanghai, ChinaSearch for more papers by this authorXiaoYing Wang, XiaoYing Wang Department of Liver Surgery, ZhongShan Hospital, Fudan University, Shanghai, Shanghai, ChinaSearch for more papers by this authorYueHong Cui, YueHong Cui Department of Oncology, ZhongShan Hospital, Fudan University, Shanghai, Shanghai, ChinaSearch for more papers by this authorTianShu Liu, TianShu Liu orcid.org/0000-0002-8604-6311 Department of Oncology, ZhongShan Hospital, Fudan University, Shanghai, Shanghai, ChinaSearch for more papers by this authorBo Zhou, Bo Zhou Department of Intervention treatment, ZhongShan Hospital, Fudan University, Shanghai, Shanghai, ChinaSearch for more papers by this authorMingLiang Wang, MingLiang Wang Department of Radiology, ZhongShan Hospital, Fudan University, Shanghai, Shanghai, ChinaSearch for more papers by this authorShengXiang Rao, ShengXiang Rao Department of Radiology, ZhongShan Hospital, Fudan University, Shanghai, Shanghai, ChinaSearch for more papers by this authorJian Wang, Jian Wang Department of Radiotherapy, ZhongShan Hospital, Fudan University, Shanghai, Shanghai, ChinaSearch for more papers by this authorJianYong Ding, JianYong Ding Department of Thoracic Surgery, ZhongShan Hospital, Fudan University, Shanghai, Shanghai, ChinaSearch for more papers by this authorGuo-dong He, Corresponding Author Guo-dong He angelhgd@163.com Department of General Surgery, ZhongShan Hospital, Fudan University, Shanghai, Shanghai, China Correspondence Jian-Min Xu, Department of General Surgery, Zhongshan Hospital, Fudan University, and Guo-Dong He, Department of General Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China. Email: xujmin@aliyun.com; angelhgd@163.comSearch for more papers by this authorJian-Min Xu, Corresponding Author Jian-Min Xu xujmin@aliyun.com Department of General Surgery, ZhongShan Hospital, Fudan University, Shanghai, Shanghai, China Correspondence Jian-Min Xu, Department of General Surgery, Zhongshan Hospital, Fudan University, and Guo-Dong He, Department of General Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China. Email: xujmin@aliyun.com; angelhgd@163.comSearch for more papers by this author Yang Lv, Yang Lv orcid.org/0000-0002-6013-0558 Department of General Surgery, ZhongShan Hospital, Fudan University, Shanghai, Shanghai, China Y.L., Q.Y.F., Y.W., and L.R. contributed equally to this work.Search for more papers by this authorQing-Yang Feng, Qing-Yang Feng Department of General Surgery, ZhongShan Hospital, Fudan University, Shanghai, Shanghai, China Y.L., Q.Y.F., Y.W., and L.R. contributed equally to this work.Search for more papers by this authorYe Wei, Ye Wei Department of General Surgery, ZhongShan Hospital, Fudan University, Shanghai, Shanghai, China Y.L., Q.Y.F., Y.W., and L.R. contributed equally to this work.Search for more papers by this authorLi Ren, Li Ren Department of General Surgery, ZhongShan Hospital, Fudan University, Shanghai, Shanghai, China Y.L., Q.Y.F., Y.W., and L.R. contributed equally to this work.Search for more papers by this authorQingHai Ye, QingHai Ye Department of Liver Surgery, ZhongShan Hospital, Fudan University, Shanghai, Shanghai, ChinaSearch for more papers by this authorXiaoYing Wang, XiaoYing Wang Department of Liver Surgery, ZhongShan Hospital, Fudan University, Shanghai, Shanghai, ChinaSearch for more papers by this authorYueHong Cui, YueHong Cui Department of Oncology, ZhongShan Hospital, Fudan University, Shanghai, Shanghai, ChinaSearch for more papers by this authorTianShu Liu, TianShu Liu orcid.org/0000-0002-8604-6311 Department of Oncology, ZhongShan Hospital, Fudan University, Shanghai, Shanghai, ChinaSearch for more papers by this authorBo Zhou, Bo Zhou Department of Intervention treatment, ZhongShan Hospital, Fudan University, Shanghai, Shanghai, ChinaSearch for more papers by this authorMingLiang Wang, MingLiang Wang Department of Radiology, ZhongShan Hospital, Fudan University, Shanghai, Shanghai, ChinaSearch for more papers by this authorShengXiang Rao, ShengXiang Rao Department of Radiology, ZhongShan Hospital, Fudan University, Shanghai, Shanghai, ChinaSearch for more papers by this authorJian Wang, Jian Wang Department of Radiotherapy, ZhongShan Hospital, Fudan University, Shanghai, Shanghai, ChinaSearch for more papers by this authorJianYong Ding, JianYong Ding Department of Thoracic Surgery, ZhongShan Hospital, Fudan University, Shanghai, Shanghai, ChinaSearch for more papers by this authorGuo-dong He, Corresponding Author Guo-dong He angelhgd@163.com Department of General Surgery, ZhongShan Hospital, Fudan University, Shanghai, Shanghai, China Correspondence Jian-Min Xu, Department of General Surgery, Zhongshan Hospital, Fudan University, and Guo-Dong He, Department of General Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China. Email: xujmin@aliyun.com; angelhgd@163.comSearch for more papers by this authorJian-Min Xu, Corresponding Author Jian-Min Xu xujmin@aliyun.com Department of General Surgery, ZhongShan Hospital, Fudan University, Shanghai, Shanghai, China Correspondence Jian-Min Xu, Department of General Surgery, Zhongshan Hospital, Fudan University, and Guo-Dong He, Department of General Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China. Email: xujmin@aliyun.com; angelhgd@163.comSearch for more papers by this author First published: 05 July 2020 https://doi.org/10.1002/ctm2.121 AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Dear editor: More than 25% of colorectal cancer (CRC) have liver metastasis (CRLM),1 for which the multi-disciplinary treatment (MDT) has emerged as an alternative of therapeutic strategies in China.2 In the present study, we reported a long-term MDT treatment experiences and assessed the advantages of the MDT strategy, and furthermore, we also aimed to define the criteria of the suitable CRLM patients who can be benefited more from MDT strategy. This study retrospectively enrolled two independent cohorts of consecutive CRLM patients (MDT cohort and No-MDT cohort). Management of MDT and statistical methods are described in Supporting Information Section 1. From February 9, 2009 to December 28, 2017, a total of 3740 consecutive MDT discussions were studied, and MDT times are shown in Figure S1. The management workflow of two independent cohort is shown in Figure 1A. A total of 1027 CRLM patients received MDT and 401 CRLM patients were treated without MDT. Of 1027 MDT patients, 51% were males and 54% were older than 60 years. The majority of MDT cohort patients with CRLM had more liver metastatic lesions (P < .01) and shorter tumor size (P < .01). More advanced CRLM received MDT (Table S1). FIGURE 1Open in figure viewerPowerPoint A, Flow diagram of two independent CRLM patients enrolled from Zhongshan Hospital (MDT cohort and No-MDT cohort); B, Kaplan-Meier OS curves for CRLM patients of MDT and No-MDT cohorts; C, Kaplan-Meier OS curves for low CRS patients of MDT and No-MDT cohorts; D, Kaplan-Meier OS curves for high CRS patients MDT and No-MDT cohorts; E, Kaplan-Meier OS curves for low CRS patients with extra-hepatic metastasis of MDT and No-MDT cohorts; F, Kaplan-Meier OS curves for low CRS patients without extra-hepatic metastasis of MDT and No-MDT cohorts, P-values were determined by the log-rank test. Abbreviations: CRLM, colorectal cancer liver metastasis; OS, overall survival; MDT, multi-disciplinary treatment; CRLM, colorectal cancer liver metastasis; CRS, clinical risk score Figure S2 demonstrates the compliance rate of surgical and no-surgical plan in MDT and No-MDT cohorts. Univariate and multivariate logistics analysis for compliance to treatment suggestion are performed in Table S2, and MDT was regarded as an independent factor for adherence (P < .01). Reasons for changes to treatment plan are shown in Table S3. In addition, thoracic CT scan, CA125/CA724 and pelvic MRI scan, liver MRI scan, RAS/RAF mutation status, and PET/CT of CRLM patients in MDT cohort showed significant difference from No-MDT controls (Table S4; P < .01). Of 1027 patients in MDT cohort, 264 patients had extra-hepatic metastasis (25.7%), including 212 lung (21%), 43 bone (4%), and 54 transcelomic metastases (5%). Resectability change in 202 patients (20%) and additional targeted therapies were added in selective 307 patients (30%) (Table S5). The larger proportion of MDT cohort patients received chemotherapy plus targeted therapy at the first line or second line treatments (P < .01). FOLFOXIRI regimen and VIC regimen were performed in MDT cohort patients more than in those without MDT (P < .01) (Table S6). Initially unresectable CRC patients received conversion resection demonstrated better median survival duration in both MDT (42.0 vs 37.0 months) and No-MDT cohorts (36.6 vs 28.4 months) and had liver metastasectomy rate in MDT significantly higher than No-MDT (P < .01), as shown in Table S7. The overall survival (OS) rate in recruited patients is shown in Table S8, independent upon clinical T stage (P < .05), N stage (P < .05), metastatic tumor number (P < .05), and tumor size (P < .05), and resection of primary site (P < .05). There was no significant difference of OS rates between patients with and without MDT (Median OS: 47.0 months vs 41.0 months, P = .06) (Figure 1B). To further identify effective discriminator on survival benefits, risk stratified analysis was performed in Table 1. We found that the OS rate of No-MDT patients with high clinical risk score (CRS) was significantly worse than those with MDT(Figure 1C, P < .01), rather than No-MDT patients with low CRS (P > .08) as shown in Figure 1D. TABLE 1. stratified analysis for overall survival between different CRLM cohorts MDT cohort (N = 1027) No-MDT cohort (N = 401) Characteristics Median IQR Median IQR HR (95%CI) P-value Age ≥60 45.0 28.0-54.0 44.0 26.0-53.0 0.945 (0.768-1.221) .87 <60 42.0 25.0-57.0 43.0 23.0-57.0 1.021 (0.452-1.203) .68 Gender Male 39.0 22.0-61.0 40.0 23.0-52.0 1.198 (0.956-1.324) .96 Female 43.0 24.0-58.0 42.0 25.0-61.0 1.043 (0.867-1.192) .88 Primary site Left colon 41.0 26.0-57.0 42.0 21.0-57.0 1.324 (0.803-1.672) .54 Right colon 40.0 20.0-51.0 38.0 21.0-50.0 1.254 (0.876-1.422) .32 Rectum 44.0 25.0-58.0 43.0 22.0-57.0 0.975 (0.824-1.306) .21 cT stage T1/T2 49.0 39.0-62.0 48.0 37.0-60.0 0.754 (0.670-2.432) .60 T3/T4 36.0 25.0-58.0 38.0 22.0-57.0 1.035 (0.934-1.216) .24 CRS score low 53.0 45.0-61.0 54.0 19.0-42.0 1.019 (0.776-1.334) .78 high 45.0 43.0-64.0 31.0 23.0-51.0 1.294 (1.157-1.615) <.001 Extra-hepatic metastasis Yes 40.0 21.0-56.0 41.0 19.0-56.0 1.295 (0.876-2.323) .32 No 44.0 25.0-58.0 45.0 22.0-57.0 0.785 (0.643-1.224) .14 CRLM patients were furthermore divided into low and high CRS subgroups according to CRS system.3 Clinical T stage, metastatic tumor size, and extra-hepatic metastasis were regarded as independent risk factors for OS in low CRS patients, while clinical T stage, number of metastasis, metastatic tumor size, and MDT were regarded as independent risk factors for OS in high CRS patients, as shown in Table S9. Among low CRS patients, significant survival benefit of MDT for OS was observed in patients with extra-hepatic metastasis (Figure 1E, P < .05), while not in patients without extra-hepatic metastasis (Figure 1F, P > .05). This is the first study to complementarily evaluate long-term experiences of MDT on CRLM cases. The number of Zhongshan CRLM MDT increased gradually from 235 to 564 per year. MDT as an independent method could improve adherence, although there are many risk factors for non-adherence, such as patient factors (eg, age, sex, and emotional functions), family environment, and therapeutic settings.4 Although MDT patients received more necessary diagnostic tests and more standardized systematic treatment regimen, no significant difference on prognosis was noticed between patients with or without MDT. However, the stratified analysis on factors for OS among demonstrated that MDT was more effective and improved survival outcome from 31 to 45 months in high CRS subgroup (P < .01) and in patients with low CRS and extra-hepatic metastasis (P < .05). These findings were not consistent with previous studies,5, 6 which could be explained as follows: (1) Lordan's report5 evaluated CRLM cases after hepatic resection, which was limited to represent all CRLM; (2) Jen-Kou Lin6 reported cases from 2001 to 2010 and there were significant differences for diagnosis and treatment for CRLM such as targeted therapy, which was widely used on CRLM patients after 2009. Besides, our results was also reasonable for, (1) in the new era of MDT that is composed of many doctors, after reviews and experiences of many cases, one specialist doctor could be able to provide appropriate suggestions for selective CRLM cases; (2) after analysis, low CRS CRC liver-limited metastasis patients had better prognosis and were not hard to be properly dealt with. Considering the high incidence of CRLM and time-consuming nature of MDT, we suggested that MDT should not be recommended to selective low CRS liver-limited patients due to the low efficacy on decision making and long-term prognosis, when patients could be managed according to a standard guidelines.7-9 In summary, we found that MDT could be helpful to improve the accuracy of diagnosis, efficacy of adherence and standardized treatment, and rate of conversion resection. Benefits of MDT on overall survival were more obvious in high CRS patients and low CRS patients with extra-hepatic metastasis. ACKNOWLEDGMENTS We thank all the doctors and nurses during the treatment process. This work was supported by National Natural Science Foundation of China (Grant No. 81602040 and 81402341), Clinical Science and Technology Innovation Project of Shanghai (SHDC12016104), and Shanghai Science and Technology Committee Project (17411951300). The funding bodies had no role in the design of the study and collection, analysis, and interpretation of data and in the writing of the manuscript. CONFLICT OF INTEREST The authors declare no conflicts of interest for the publication of this manuscript. ETHICS APPROVAL AND CONSENT TO PARTICIPATE Written informed consent was obtained by all the patients. The study protocol followed the ethical guidelines of the Declaration of Helsinki and was approved by the Ethical Committee of Zhongshan Hospital of Fudan University. AVAILABILITY OF DATA AND MATERIAL The datasets used and/or analyzed during the current study are available from the corresponding authors on reasonable request. Supporting Information Filename Description ctm2121-sup-0001-SuppMat.docx9.4 MB Supporting Information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. REFERENCES 1Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015. CA Cancer J Clin. 2016; 66(2): 115- 132. 2Morris E, Haward RA, Gilthorpe MS, Craigs C, Forman D. The impact of the Calman-Hine report on the processes and outcomes of care for Yorkshire's colorectal cancer patients. Br J Cancer. 2006; 95(8): 979- 985. 3Fong Y, Fortner J, Sun RL, Brennan MF, Blumgart LH. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg. 1999; 230(3): 309- 318. discussion 318–321. 4Mitchell AE, Scarcella DL, Rigutto GL, et al. Cancer in adolescents and young adults: treatment and outcome in Victoria. Med J Aust. 2004; 180(2): 59- 62. 5Lordan JT, Karanjia ND, Quiney N, Fawcett WJ, Worthington TR. A 10-year study of outcome following hepatic resection for colorectal liver metastases - The effect of evaluation in a multidisciplinary team setting. Eur J Surg Oncol. 2009; 35(3): 302- 306. 6Lan YT, Jiang JK, Chang SC, et al. Improved outcomes of colorectal cancer patients with liver metastases in the era of the multidisciplinary teams. Int J Colorectal Dis. 2016; 31(2): 403- 411. 7Xu J, Fan J, Qin X, et al. Chinese guidelines for the diagnosis and comprehensive treatment of colorectal liver metastases (version 2018). J Cancer Res Clin Oncol. 2019; 145(3): 725- 736. 8 Diagnosis, Treatment Guidelines For Colorectal Cancer Working Group C. Chinese Society of Clinical Oncology (CSCO) diagnosis and treatment guidelines for colorectal cancer 2018 (English version). Chin J Cancer Res. 2019; 31(1): 117- 134. 9Chakedis J, Squires MH, Beal EW, et al. Update on current problems in colorectal liver metastasis. Curr Probl Surg. 2017; 54(11): 554- 602. Volume10, Issue3July 2020e121 FiguresReferencesRelatedInformation

目的 探究肝癌脊柱转移患者术后肺部感染对其免疫系统和内分泌系统的影响.方法 选取 2018年 1月-2019年 1月于唐山市第二医院接受手术治疗的 114例肝癌脊柱转移患者为研究对象,根据患者术后是否发生肺部感染分为两组,其中发生肺部感染的47例患者为研究组,未发生肺部感染的 67例患者为对照组.比较两组患者手术前后指标水平.结果 手术治疗前,两组患者各指标比较无显著差异.手术治疗后研究组患者细胞免疫指标CD3+T淋巴细胞(50.49±5.38)%、CD4+/CD8+比值(1.53±0.33)、NK 细胞[(11.24±4.38)]×109/L均低于对照组(P＜0.05);手术治疗后研究组患者体液免疫指标 IgM、IgG、IgA 水平分别为(1.09± 0.34)g/L、(10.08±2.43)g/L、(1.87±0.52)g/L均低于对照组(P＜0.05);手术治疗后研究组患者内分泌系统指标血管紧张素(Angiotensin,Ang-II)、去甲肾上腺素(Norepinephrine,NE)、醛固酮(Aldosterone,ALD)水平分别为(73.20± 5.77)ng/L、(75.68±6.39)μg/L、(44.23±3.41)ng/L均高于对照组患者(P＜0.05);手术治疗后研究组患者总蛋白(50.18±4.68)g/L 和白蛋白(25.20±3.97)g/L 水平均低于对照组,基质金属蛋白酶-1水平(7.88±0.38)ng/L高于对照组(P＜0.05).结论 肝癌脊柱转移患者手术后发生肺部感染会引起患者免疫系统和内分泌系统失调,导致免疫指标水平下降,内分泌指标发生紊乱,不利于患者营养水平的提高.

Rationale and Objectives: To investigate whether transcatheter intraarterial perfusion (TRIP) magnetic resonance imaging (MRI) can differentiate reversible electroporation (RE) zones from irreversible electroporation (IRE) zones immediately after IRE procedure in the rabbit liver. Materials and Methods: All studies were approved by the institutional animal care and use committee and performed in accordance with institutional guidelines. A total of 13 healthy New Zealand White rabbits were used. After selective catheterization of the hepatic artery under X-ray fluoroscopy, we acquired TRIP-MRI at 20 minutes post-IRE using 3 mL of 5% intraarterial gadopentetate dimeglumine. Semi-quantitative (peak enhancement, PE; time to peak, TTP; wash-in slope, WIS; areas under the time-intensity curve, AUT, over 30, 60, 90, 120, 150, and 180 seconds after the initiation of enhancement) and quantitative (K-trans, v(e), and v(p)) TRIP-MRI parameters were calculated. The relationships between TRIP-MRI parameters and histological measurements and the differential ability of TRIP-MRI parameters was assessed. Results: PE, AUT(60), AUT(90), AUT(120), AUT(150), AUT(180), K-trans, and ve were significantly higher in RE zones than in IRE zones (all P < 0.05), and AUC for these parameters ranged from 0.91(95% CI, 0.80, 1.00) to 0.99 (95% CI, 0.98, 1.00). There was no significant difference in AUC between any two parameters (Z, 0-1.47; P, 0.14-1.00). Hepatocyte apoptosis strongly correlated with PE, AUT(60), AUT(90), AUT(120), AUT(150), AUT(180), K-trans, and v(p) (the absolute value r, 0.6-0.7, all P < 0.0001). Conclusion: AUT(150) or AUT(180) could be a potential imaging biomarker to differentiate RE from IRE zones, and TRIP-MRI permits to differentiate RE from IRE zones immediately after IRE procedure in the rabbit liver.

Radiation therapy is often combined with androgen deprivation therapy in the treatment of aggressive localized prostate cancer. However, castration-resistant disease may not respond to testosterone deprivation approaches. Enzalutamide is a second-generation anti-androgen with high affinity and activity that is used for the treatment of metastatic disease. Although radiosensitization mechanisms are known to be mediated through androgen receptor activity, this project aims to uncover the detailed DNA damage repair factors influenced by enzalutamide using multiple models of androgen-sensitive (LNCaP) and castration-resistant human prostate cancer (22Rv1 and DU145). Enzalutamide is able to radiosensitize both androgen-dependent and androgen-independent human prostate cancer models in cell culture and xenografts in mice, as well as a treatment-resistant patient-derived xenograft. The enzalutamide-mediated mechanism of radiosensitization includes delay of DNA repair through temporal prolongation of the repair factor complexes and halting the cell cycle, which results in decreased colony survival. Altogether, these findings support the use of enzalutamide concurrently with radiotherapy to enhance the treatment efficacy for prostate cancer.

Purpose: Nimotuzumab is a humanized monoclonal antibody that targets the epidermal growth factor receptor (EGFR) to inhibit tumor growth. Nimotuzumab has demonstrated desirable therapeutic activity in various types of tumors. However, the benefit of nimotuzumab for the treatment of cervical cancer is not entirely clear. The present study aimed to investigate the effects of nimotuzumab in the presence of CCRT in the first-line treatment of locally advanced cervical cancer (LACC). Methods: The therapeutic efficacy and side effects of nimotuzumab combined with concurrent radiochemotherapy (CCRT) were retrospectively assessed in inoperable patients with LACC (stage IIb-IIIb) who were treated using CCRT with or without nimotuzumab. Results: The complete response rate of study group was significantly better than control group (78.3% vs 50%, P=0.035). The difference in median progression-free survival (PFS) in the two groups was statistically significan (not reach vs 27 months, P=0.037). Multivariate comparisons of prognostic factors in the two groups indicated that both the Federation Internationale de Gynecologie et d'Obstetrique (FIGO) stage and combined nimotuzumab treatment affected PFS (P<0.05). Although generally tolerable, grade 3-4 toxicities including leukopenia (P=0.025) and hemoglobin (P=0.026) reduction were more frequent in the control group than those in the study group. Conclusion: These data suggest that combining nimotuzumab with CCRT for the treatment of LACC resulted in extended PFS and higher complete remission rates, without an increased incidence of adverse events.

Despite significant advances over the past decades of research, pancreatic cancer (PC) continues to have the worst 5-year survival of any malignancy. Dendritic cells (DCs) are the most potent professional antigen-presenting cells and are involved in the induction and regulation of antitumor immune responses. DC-based immunotherapy has been used in clinical trials for PC. Although safety, efficacy, and immune activation were reported in patients with PC, DC vaccines have not yet fulfilled their promise. Additional strategies for combinatorial approaches aimed to augment and sustain the antitumor specific immune response elicited by DC vaccines are currently being investigated. Here, we will discuss DC vaccination immunotherapies that are currently under preclinical and clinical investigation and potential combination approaches for treating and improving the survival of PC patients.

DNA double strand breaks (DSBs) are a severe threat to genome integrity and a potential cause of tumorigenesis, which is a multi-stage process and involves many factors including the mutation of oncogenes and tumor suppressors, some of which are transcribed microRNAs (miRNAs). Among more than 2000 known miRNAs, miR-21 is a unique onco-miRNA that is highly expressed in almost all types of human tumors and is associated with tumorigenesis through its multiple targets. However, it remains unclear whether there is any functional link between DSBs and miR-21 expression and, if so, does the link contribute to DSB-induced genomic instability/tumorigenesis. To address this question, we used DNA-PKcs-/- (deficient in non-homologous end-joining (NHEJ)) and Rad54-/- (deficient in homologous recombination repair (HRR)) mouse embryonic fibroblasts (MEFs) since NHEJ and HRR are the major pathways for DSB repair in mammalian cells. Our results indicate that levels of miR-21 are elevated in these DSB repair (DSBR) deficient cells, and ionizing radiation (IR) further increases these levels in both wild-type (WT) and DSBR-deficient cells. Interestingly, IR stimulated growth in soft agar and this effect was greatly reduced by blocking miR-21 expression in both WT and DSBR-deficient cells. Taken together, our results suggest that either IR or DSBR-deficient can lead to an upregulation of miR-21 levels and that miR-21 is associated with IR-induced cell growth in soft agar. These results may help our understanding of DSB-induced tumorigenesis and provide information that could facilitate the development of new strategies to prevent DSB-induced carcinogenesis.

Objective To investigate the effect of recombinant human endostatin combined with chemotherapy on serum LMTK-3 and IGFBP-7 in patients with advanced non-small cell lung cancer. Methods Totally 86 cases of patients diagnosed with advanced non-small cell lung cancer in our hospital from January 2012 to January 2015 were involved in this study. Patients were randomly divided into observation group and control group (n = 43). Patients from control group received gemcitabine + cisplatin chemotherapy. Patients from observation group received endostar in addition to standard treatment. The therapeutic efficacy, side effects and concentration of VEGF, IGF-1, LMTK-3 and IGFBP were recorded. Results The therapeutic efficacy in observation group was significantly higher than that of the control group (χ2 = 5.403,7.493,P ＜ 0.05). No statistically significant difference in the incidence of adverse events between the two groups was observed. The levels of VEGF, IGF-1 and LMTK-3 in both groups were significantly increased while GFBP decreased post treatments when compared with that prior to treatments (P ＜ 0.05). Concentrations of VEGF, IGF-1 and LMTK-3 in observation group were downregulated while IGFBP-7 upregulated significantly when compared with control group (P ＜ 0.05). Conclusion Recombinant human endostatin combined with chemotherapy is a promising option for treatment of NSCLC patients with good efficacy and less adverse reactions.

Skeletal tumour burden is a biomarker of prognosis and survival in cancer patients. This study proposes a novel method based on the linear quadratic model to predict the reduction in metastatic tumour burden as a function of the absorbed doses delivered from molecular radiotherapy treatments. The range of absorbed doses necessary to eradicate all the bone lesions and to reduce the metastatic burden was investigated in a cohort of 22 patients with bone metastases from castration-resistant prostate cancer. A metastatic burden reduction curve was generated for each patient, which predicts the reduction in metastatic burden as a function of the patient mean absorbed dose, defined as the mean of all the lesion absorbed doses in any given patient. In the patient cohort studied, the median of the patient mean absorbed dose predicted to reduce the metastatic burden by 50% was 89 Gy (interquartile range: A M Denis-Bacelar et al Printed in the UK 2859 PHMBA7 © 2017 Institute of Physics and Engineering in Medicine 62 Phys. Med. Biol.

Purpose: Although MRI is generally considered a very safe imaging modality, potential risks do exist for RF heating during the patient imaging studies and there have been reported skin burn incidents and cases of patient discomforts due to RF heating. RF heating‐related safety issues have become more relevant as increasing numbers of high‐field (3.0 Tesla or higher) MRI systems are being installed and used in clinical settings. In this study, we reviewed the SAR values on the spine MRI exams over the past few years at our institution and we studied the over‐all trend of SAR values and their correlations with patient size (weight). Methods: With IRB approval, we selected total of 36,051 MRI scans of the spine, dating from September 2005 to June 2012, from the EMR archive at our institution. For each scan sequence, DICOM header information such as SAR value, body weight, scan date, scanner ID, software version are extracted using a MATLAB program developed in‐house. The header information was exported to Microsoft Excel for further analysis. Results: Most of the scans performed on 1.5T scanners have SAR values less than 2.5W/kg while all the 3T scans have reported SAR values less than 3W/kg. However, there are some scans with SAR values above 4W/kg. Additionally, we noticed a gradual upward trend in the SAR values as well as some inconsistencies in the correlations of the reported SAR values to patient weight. Conclusion: The survey results suggest the need for clinical user involvement in the validation and monitoring of the SAR values. Without proper validation, the reported SAR values may not be accurate and even contain errors, making it difficult to accurately assess the SAR values at the hotspots in patient scans.

To retrospectively investigate treatment outcomes of stereotactic ablative body radiation therapy (SABR) for octogenarians with non-small cell lung cancer (NSCLC).Between 2005 and 2012, 109 patients aged ≥80 years with T1-2N0M0 NSCLC were treated with SABR: 47 patients had histology-unproven lung cancer; 62 patients had pathologically proven NSCLC. The prescribed doses were either 50 Gy/5 fractions for peripheral tumors or 40 Gy/5 fractions for centrally located tumors. The treatment outcomes, toxicities, and the correlating factors for overall survival (OS) were evaluated.The median follow-up duration after SABR was 24.2 (range, 3.0-64.6) months. Only limited toxicities were observed, except for 1 grade 5 radiation pneumonitis. The 3-year local, regional, and distant metastasis-free survival rates were 82.3%, 90.1%, and 76.8%, respectively. The OS and lung cancer-specific survival rates were 53.7% and 70.8%, respectively. Multivariate analysis revealed that medically inoperable, low body mass index, high T stage, and high C-reactive protein were the predictors for short OS. The OS for the operable octogenarians was significantly better than that for inoperable (P<.01).Stereotactic ablative body radiation therapy for octogenarians was feasible, with excellent OS. Multivariate analysis revealed that operability was one of the predictors for OS. For medically operable octogenarians with early-stage NSCLC, SABR should be prospectively compared with resection.

目的 探讨不同年龄段绝经前女性正常宫颈组织在不同生理周期的表观弥散系数值(apparent diffusion coefficient,ADC)变化.方法 将82名健康女性按年龄段分成3组(A组27例,20～29岁;B组28例,30～39岁;C组27例,40～49岁),采用3.0T MRI分别于增殖中期及分泌中期行2次盆腔MR检查,研究不同结构区、年龄段及生理周期的宫颈ADC值的变化.结果 子宫3层结构的ADC值两两比较差异均有统计学意义(肌层最高,黏膜层居中,结合带最低),宫颈黏膜层及结合带的ADC值在分泌中期均低于增殖中期,而肌层的ADC值在不同周期间差异不明显,宫颈每层结构在同一周期的各年龄组之间无明显差异,宫颈粘膜层在增殖中期的ADC值更为稳定.结论 不同结构区及生理周期会对正常宫颈组织的ADC值产生影响,当利用ADC值探测早期宫颈癌、监测疗效及鉴别肿瘤早期复发时应考虑这些因素,绝经前女性应在增殖期行盆腔MR扫描.