Response of Elymus nutans Griseb. seedling physiology and endogenous hormones to drought and salt stress.

Elymus nutans Griseb. (E. nutans), a pioneer plant for the restoration of high quality pasture and vegetation, is widely used to establish artificial grasslands and ecologically restore arid and salinized soils. To investigate the effects of drought stress and salt stress on the physiology and endogenous hormones of E. nutans seedlings, this experiment configured the same environmental water potential (0 (CK), - 0.04, - 0.14, - 0.29, - 0.49, - 0.73, and - 1.02 MPa) of PEG-6000 and NaCl stress to investigate the effects of drought stress and salt stress, respectively, on E. nutans seedlings under the same environmental water potential. The results showed that although the physiological indices and endogenous hormones of the E. nutans seedlings responded differently to drought stress and salt stress under the same environmental water potential, the physiological indices of E. nutans shoots and roots were comprehensively evaluated using the genus function method, and the physiological indices of the E. nutans seedlings under the same environmental water potential exhibited better salt tolerance than drought tolerance. The changes in endogenous hormones of the E. nutans seedlings under drought stress were analyzed to find that treatment with gibberellic acid (GA3), gibberellin A7 (GA7), 6-benzyladenine (6-BA), 6-(y,y-dimethylallylaminopurine) (2.IP), trans-zeatin (TZ), kinetin (KT), dihydrozeatin (DHZ), indole acetic acid (IAA), and 2,6-dichloroisonicotininc acid (INA) was more effective than those under drought stress. By analyzing the amplitude of changes in the endogenous hormones in E. nutans seedlings, the amplitude of changes in the contents of GA3, GA7, 6-BA, 2.IP, TZ, KT, DHZ, IAA, isopentenyl adenosine (IPA), indole-3-butyric acid (IBA), naphthalene acetic acid (NAA), and abscisic acid was larger in drought stress compared with salt stress, which could be because the endogenous hormones are important for the drought tolerance of E. nutans itself. The amplitude of the changes in the contents of DHZ, TZR, salicylic acid, and jasmonic acid was larger in salt stress compared with drought stress. Changes in the content of melatonin were larger in salt stress compared with drought stress, which could indicate that endogenous hormones and substances are important for the salt tolerance of E. nutans itself.

HLA-class II restricted TCR targeting human papillomavirus type 18 E7 induces solid tumor remission in mice.

T cell receptor (TCR)-engineered T cell therapy is a promising potential treatment for solid tumors, with preliminary efficacy demonstrated in clinical trials. However, obtaining clinically effective TCR molecules remains a major challenge. We have developed a strategy for cloning tumor-specific TCRs from long-term surviving patients who have responded to immunotherapy. Here, we report the identification of a TCR (10F04), which is human leukocyte antigen (HLA)-DRA/DRB1*09:01 restricted and human papillomavirus type 18 (HPV18) E784-98 specific, from a multiple antigens stimulating cellular therapy (MASCT) benefited metastatic cervical cancer patient. Upon transduction into human T cells, the 10F04 TCR demonstrated robust antitumor activity in both in vitro and in vivo models. Notably, the TCR effectively redirected both CD4+ and CD8+ T cells to specifically recognize tumor cells and induced multiple cytokine secretion along with durable antitumor activity and outstanding safety profiles. As a result, this TCR is currently being investigated in a phase I clinical trial for treating HPV18-positive cancers. This study provides an approach for developing safe and effective TCR-T therapies, while underscoring the potential of HLA class II-restricted TCR-T therapy as a cancer treatment.

STEAP4 inhibits cisplatin-induced chemotherapy resistance through suppressing PI3K/AKT in hepatocellular carcinoma.

Chemotherapy resistance is the leading cause for hepatocellular carcinoma (HCC)-induced death. Exploring resistance generation mechanism is an urgent need for HCC therapy. Here, we found STEAP4 was significantly downregulated in HCC patients with recurrence. Patients with low STEAP4 had poor outcome, suggesting STEAP4 might inhibit chemotherapy resistance. Cell viability assay, colony formation assay, apoptosis assay, soft agar growth assay, and tumor animal model showed STEAP4 inhibited cisplatin resistance. Mechanism analysis showed STEAP4 inhibited PI3K/AKT pathway through directly interacting with AKT. Double knockdown of STEP4 and AKT significantly inhibited cisplatin resistance. We also found STEAP4 expression was negatively correlated with PI3K/AKT pathway activity in clinic specimens. In summary, our findings suggested STEAP4 inhibited cisplatin resistance through suppressing PI3K/AKT pathway activity, providing a target for HCC therapy.

Effects of drought and salt stress on seed germination and seedling growth of Elymus nutans.

Drought and soil salinization are global environmental issues, and Elymus nutans play an important role in vegetation restoration in arid and saline environments due to their excellent stress resistance. In the process of vegetation restoration, the stage from germination to seedling growth of forage is crucial. This experiment studied the effects of PEG-6000 simulated drought stress and NaCl simulated salinization stress on the germination of E. nutans seeds, and explored the growth of forage seedlings from sowing to 28 days under drought and salinization stress conditions. The results showed that under the same environmental water potential, there were significant differences in responses of seed germination, seedling growth, organic carbon, total nitrogen and total phosphorus of above-ground and underground parts of E. nutans to drought stress and salinization stress. Using the membership function method to comprehensively evaluate the seed germination and seedling indicators of E. nutans, it was found that under the same environmental water potential, E. nutans was more severely affected by drought stress during both the seed germination and seedling growth stages. E. nutans showed better salt tolerance than drought resistance.

m6 A-Dependent Modulation via IGF2BP3/MCM5/Notch Axis Promotes Partial EMT and LUAD Metastasis.

The importance of mRNA N6-methyladenosine (m6 A) modification during tumor metastasis is controversial as it plays distinct roles in different biological contexts. Moreover, how cancer cell plasticity is shaped by m6 A modification is interesting but remains uncharacterized. Here, this work shows that m6 A reader insulin like growth factor 2 mRNA binding protein 3 (IGF2BP3) is remarkably upregulated in metastatic lung adenocarcinoma (LUAD) and indicates worse prognosis of patients. Interestingly, IGF2BP3 induces partial epithelial-mesenchymal-transition (EMT) and confers LUAD cells plasticity to metastasize through m6 A-dependent overactivation of Notch signaling. Mechanistically, IGF2BP3 recognized m6 A-modified minichromosome maintenance complex component (MCM5) mRNAs to prolong stability of them, subsequently upregulating MCM5 protein, which competitively inhibits SIRT1-mediated deacetylation of Notch1 intracellular domain (NICD1), stabilizes NICD1 protein and contributes to m6 A-dependent IGF2BP3-mediated cellular plasticity. Notably, a tight correlation of the IGF2BP3/MCM5/Notch axis is evidenced in clinical LUAD specimens. Therefore, this study elucidates a critical role of m6 A modification on LUAD cell plasticity in fostering tumor metastasis via the above axis, providing potential targets for metastatic LUAD.

METTL1-Mediated m7G tRNA Modification Promotes Lenvatinib Resistance in Hepatocellular Carcinoma.

The tyrosine kinase inhibitor lenvatinib is a first-line drug for treating patients with advanced hepatocellular carcinoma (HCC). However, its efficacy is severely hampered by drug resistance. Insights into the molecular mechanisms underlying lenvatinib resistance could provide new strategies to improve and prolong responses. Here, we performed unbiased proteomic screening of parental and lenvatinib-resistant HCC cells and discovered that methyltransferase-like protein-1 (METTL1) and WD repeat domain 4 protein (WDR4), the two key components of the tRNA N7-methylguanosine (m7G) methyltransferase complex, were dramatically upregulated in lenvatinib-resistant cells. METTL1 knockdown overrode resistance by impairing the proliferation capacity of HCC cells and promoting apoptosis under lenvatinib treatment. In addition, overexpression of wild-type METTL1 but not its catalytic dead mutant induced lenvatinib resistance. Animal experiments including hydrodynamic injection, subcutaneous implantation, and orthotopic xenograft mouse models further demonstrated the critical function of METTL1/WDR4-mediated m7G tRNA modification in promoting lenvatinib resistance in vivo. Mechanistically, METTL1 promoted translation of EGFR pathway genes to trigger drug resistance. This work reveals the important role of METTL1-mediated m7G tRNA modification in promoting lenvatinib resistance and provides a promising prediction marker and intervention target for resistance. SIGNIFICANCE: Upregulation of tRNA m7G methyltransferase complex components METTL1 and WDR4 promotes lenvatinib resistance in HCC and confers a sensitivity to METTL1 targeting, providing a promising strategy to override resistance.

Robust and durable response to first-line treatment of pembrolizumab combined with chemotherapy in two patients with metastatic thymic squamous cell carcinoma: Case report.

Thymic carcinoma is a rare and aggressive disease with poor outcome. There is no established treatment regimen for advanced thymic carcinoma. While the efficacy of pembrolizumab was proved to be promising, as a single agent, in patients with refractory/recurrent thymic carcinoma that progressed after chemotherapy, the efficacy and safety of combination of pembrolizumab and chemotherapy as front-line treatment in metastatic thymic carcinoma have not been explored yet. Herein, we report the first two cases of metastatic thymic squamous cell carcinoma receiving the combined approaches of pembrolizumab and chemotherapy as first-line treatment. Of the two patients, one had a complete radiological response of mediastinal masses with sustained remission over 3 years, and the other one with widespread disease had a good partial response over 20 months and achieved no evidence of disease radiologically after undergoing percutaneous radiofrequency ablation for residual liver metastases. Next-generation sequencing (NGS) showed low tumor mutation burden and MSS in both patients. Immunohistochemistry analysis of the tumor showed high PD-L1 expression in patient 1 and low PD-L1 expression in patient 2. Pembrolizumab combined with chemotherapy may be an attractive strategy for the first-line treatment of metastatic thymic carcinoma and thus warrants further evaluation.

Non-invasive diagnosis strategy of hepatocellular carcinoma in low-risk population.

AIMS: With prevalence of hepatocellular carcinoma (HCC) in low-risk population (LRP), establishing a non-invasive diagnostic strategy becomes increasingly urgent to spare unnecessary biopsies in this population. The purposes of this study were to find characterisics of HCC and to establish a proper non-invasive method to diagnose HCC in LRP. METHODS: A total of 681 patients in LRP (defined as the population without cirrhosis, chronic HBV infection or HCC history) were collected from 2 institutions. The images of computed tomography (CT) and magnetic resonance imaging (MRI) were manually analysed. We divided the patients into the training cohort (n = 324) and the internal validating cohort (n = 139) by admission time in the first institution. The cohort in the second institution was viewed as the external validation (n = 218). A multivariate logistic regression model incorporating both imaging and clinical independent risk predictors was developed. C-statistics was used to evaluate the diagnostic performance. RESULTS: Besides the major imaging features of HCC (non-rim enhancement, washout and enhancing capsule), tumor necrosis or severe ischemia (TNSI) on imaging and two clinical characteristics (gender and alpha fetoprotein) were also independently associated with HCC diagnosis (all P < 0.01). A clinical model (including 3 major features, TNSI, gender and AFP) was built to diagnose HCC and achieved good diagnostic performance (area under curve values were 0.954 in the training cohort, 0.931 in the internal validation cohort and 0.902 in the external cohort). CONCLUSIONS: The clinical model in this study developed a satisfied non-invasive diagnostic performance for HCC in LRP.

miR-500a-3p is a Potential Prognostic Biomarker in Hepatocellular Carcinoma.

PURPOSE: miR-500a-3p has been extensively reported to be implicated in the development and progression in several human cancer types. This study aimed to investigate the diagnostic and prognostic significance of miR-500a-3p as a biomarker in hepatocellular carcinoma (HCC). METHODS: miR-500a-3p expression was evaluated by in situ hybridization (ISH) and real-time PCR in 10 adjacent normal tissues (ANT), 21 liver fibrosis tissues, and 110 HCC tissues. Statistical analysis was used to investigate the correlation of miR-500a-3p expression with clinicopathological features in HCC patients. Kaplan-Meier survival analysis was performed to evaluate the prognostic significance of miR-500a-3p in overall survival and recurrence-free survival in HCC patients. RESULTS: In this study, we found that expression levels of miR-500a-3p were enhanced in HCC tissues. High miR-500a-3p levels were positively correlated with multiple clinicopathological features, including advanced clinical stage, distant metastatic status, increased AFP levels and poor tumor differentiation degree. More importantly, high miR-500a-3p levels predicted poor overall survival and early recurrence in HCC patients. Finally, a strong and positive correlation of miR-500a-3p mRNA expression with ISH staining scores was observed in clinical HCC tissues. CONCLUSION: Our findings suggest that miR-500a-3p might be used as a novel biomarker to facilitate early diagnosis and predict prognosis in HCC patients.

SphK1 Promotes Cancer Progression through Activating JAK/STAT Pathway and Up-Regulating S1PR1 Expression in Colon Cancer Cells.

BACKGROUND: SphK1 is a conserved lipid kinase, which can catalyze the formation of tumorpromoting factor sphingosine phosphate-1 (S1P). OBJECTIVE: This study aimed to investigate the effect of SphK1 on the proliferation/migration of colon cancer cells and associated mechanisms. METHODS: Transcription of the SphK1 gene in colon cancer cells was detected. Gene transcription of SphK1 was inhibited by transfecting with the si-SphK1 gene in colon cancer cells. Effects of SphK1 inhibition (si-SphK1) on cell migration/proliferation were detected using the transwell system and MTS. Gene transcription of SIP, S1PR1, S1PR2, S1PR3, and activation of JAK/STAT3 pathway were examined using RT-PCR and western blot assay. S1PR1 over-expressing plasmid was constructed and transfected into cells. Effects of S1PR1 overexpression on migration/proliferation of si-SphK1 transfected colon cancer cells and activation of JAK/STAT3 pathway were determined using RT-PCR and western blotting. RESULTS: Gene transcription of SphK1 in SW480 and HT-29 colon cancer cells was significantly inhibited by transfection of the si-SphK1 gene. Transwell migration and MTS findings showed that si-SphK1 transfection (si- SphK1 group) could reduce migration quantity and cell viability of colon cancer cells compared to the negative control (NC) (p<0.0001). SphK1 inhibition (si-SphK1 group) significantly down-regulated S1PR1 and S1PR3 gene transcription in SW480 and HT-29 cells (p<0.0001) and decreased activation level of JAKSTAT3 signaling pathway compared to NC group (p<0.05). Over-expression of S1PR1 reversed inhibitory effects of si-SphK1 on migration/proliferation of SW480 and activation of JAK/Stat3. CONCLUSION: SphK1 promoted proliferation and migration of colon cancer cells through promoting JAK/STAT activation and up-regulating S1PR1 expression.

Treatment strategies for hepatocellular carcinoma with extrahepatic metastasis.

Extrahepatic metastasis (EHM) of hepatocellular carcinoma (HCC) has increasingly been seen due to improved survival with effective management of intrahepatic lesions. The presence of EHM indicates an advanced stage of HCC, for which systemic therapy serves as the standard treatment modality. Since the approval of Sorafenib as the first systemic agent in 2007, it took almost a decade to show its efficacy in both first and further lines of setting until the landscape of systemic drugs was finally expanded. Moreover, with inspiring results from immunotherapy trials in HCC, it appears that the introduction of immunotherapy may lead to an evolution in the portfolio of HCC treatment. Although the locoregional approach in the management of EHM is not recommended for advanced-stage HCC, efforts have been made to demonstrate its efficacy in symptom relief and potential benefit for overall survival. This review provides a summary of recent updates of the systemic agents in the treatment of advanced HCC, with an emphasis on aggressive locoregional management of EHM by various treatment modalities.

Camrelizumab versus placebo in combination with gemcitabine and cisplatin as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma (CAPTAIN-1st): a multicentre, randomised, double-blind, phase 3 trial.

BACKGROUND: The addition of camrelizumab to gemcitabine and cisplatin showed promising activity as first-line therapy in patients with recurrent or metastatic nasopharyngeal carcinoma in a phase 1 trial. We therefore compared camrelizumab plus gemcitabine and cisplatin with placebo plus gemcitabine and cisplatin in a randomised phase 3 trial. METHODS: In this randomised, double-blind, phase 3 trial done at 28 hospitals in China, patients were eligible if they were aged 18-75 years, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and had previously untreated recurrent or metastatic nasopharyngeal carcinoma. Patients were randomly assigned (1:1; using an interactive web-response system with a block size of four) to receive either camrelizumab (200 mg on day 1) or matching placebo intravenously, plus gemcitabine and cisplatin (gemcitabine 1000 mg/m2 on days 1 and 8; cisplatin 80 mg/m2 on day 1) intravenously every 3 weeks for four to six cycles, followed by maintenance therapy with camrelizumab or placebo, until radiographic progression, unacceptable toxicity, start of new anticancer treatment, investigator decision, or withdrawal of consent. Stratification factors used in randomisation were liver metastases, previous radical concurrent chemoradiotherapy, and ECOG performance status. The allocation sequence was generated by an independent randomisation group. The primary endpoint was progression-free survival per independent review committee. The significance threshold for independent review committee-assessed progression-free survival was p=0·0086 (one-sided) at the interim analysis. Efficacy and safety analyses included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT03707509, and is closed for enrolment but is ongoing. FINDINGS: Between Nov 13, 2018, and Nov 29, 2019, 343 patients were screened and 263 were eligible and were randomly assigned to the camrelizumab group (n=134) or placebo group (n=129). At the prespecified interim analysis (June 15, 2020), independent review committee-assessed progression-free survival was significantly longer in the camrelizumab group (median 9·7 months [95% CI 8·3-11·4]) than in the placebo group (median 6·9 months [5·9-7·3]; hazard ratio 0·54 [95% CI 0·39-0·76]; one-sided p=0·0002). As of Dec 31, 2020, the most common grade 3 or worse adverse events of any cause were decreased white blood cell count (89 [66%] of 134 patients in the camrelizumab group vs 90 [70%] of 129 patients in the placebo group), decreased neutrophil count (86 [64%] vs 85 [66%]), anaemia (53 [40%] vs 57 [44%]), and decreased platelet count (53 [40%] vs 52 [40%]). Serious adverse events were reported in 59 (44%) of 134 patients in the camrelizumab group and 48 (37%) of 129 patients in the placebo group. Treatment-related deaths occurred in five (4%) patients in the camrelizumab group (two unknown cause of death, one multiple organ dysfunction syndrome, one pharyngeal haemorrhage, and one arrhythmia) and one (<1%) patient in the placebo group (unknown cause of death). INTERPRETATION: Our findings suggest that camrelizumab plus gemcitabine and cisplatin could be a new standard of care for patients with recurrent or metastatic nasopharyngeal carcinoma in the first-line setting. Longer follow-up is needed to confirm this conclusion. FUNDING: Jiangsu Hengrui Pharmaceuticals (formerly Jiangsu Hengrui Medicine). TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Feasibility and outcomes of percutaneous radiofrequency ablation for intrahepatic recurrent hepatocellular carcinoma after liver transplantation: a single-center experience.

PURPOSE: To evaluate the feasibility, effectiveness, and treatment outcomes of percutaneous radiofrequency ablation (RFA) in the application of intrahepatic recurrent hepatocellular carcinoma (r-HCC) after liver transplantation (LT). METHODS: From April 2008 to December 2019, a total of 37 patients (34 male and 3 female, mean age: 48.7 ± 10.5 years) with 61 r-HCCs after LT treated by RFA as a first-line option were enrolled. The technical success, recurrence-free survival (RFS), overall survival (OS) and complications were evaluated. RESULTS: After the first session of RFA, three patients were detected with residual foci. All of them received additional session of RFA and two tumors were successfully ablated. Therefore, the technical success was 97.3% (36/37). During the follow-up period, a total of 7 tumors developed local tumor progression (LTP) after 2.2-10.8 months. The LTP rate was 11.7% for r-HCC in the transplanted liver. The median RFS was 4.8 months (95% confidence interval [CI]: 2.2-7.3 months). The 1-, 3-, and 5-year cumulative OS rates were 68.5%, 40.3%, and 40.3%, respectively. Multivariate analyses revealed that tumor size was the only independent predictor for RFS (hazard ratio [HR] = 2.557, 95% CI, 1.015-6.444; p = .046) and limited extrahepatic metastasis was the only independent prognostic factors of OS after RFA for post-LT r-HCC (HR = 4.031, 95%CI, 1.218-13.339; p = .022). Major complications after RFA occurred in two patients (2/37, 5.4%). CONCLUSION: Percutaneous RFA is safe and effective for intrahepatic r-HCC after LT, especially for those without limited extrahepatic metastasis.

Anti-PD-1 Immunotherapy and Radiotherapy for Stage IV Intrahepatic Cholangiocarcinoma: A Case Report.

Due to the unsatisfactory robustness of current predictive biomarkers in many cases, application of immunotherapy in advanced cancers with limited treatment options, such as stage IV intrahepatic cholangiocarcinoma (ICC), was quite common. Hence, strategies to enhance the therapeutic effect of immunotherapy or to extend the scope of potential beneficial patients were urgently needed. Combination of radiotherapy and anti-programmed death receptor-1 (PD-1) immunotherapy was a promising one, since they were found to have a synergistic anti-tumor effect in animal models and a couple of patients. We here present a 68-years-old male with chemotherapy-intolerable stage IV ICC, whose primary tumor had low PD-L1 expression level, scarce CD8+ cells in tumor microenvironment, high microsatellite instability (MSI), and high tumor mutation burden (TMB). These biomarkers showed a conflicting prediction of the treatment response and clinical benefit of anti-PD-1 immunotherapy. Combination therapy of anti-PD-1 immunotherapy and radiotherapy was adopted as first-line treatment for the patient. After six cycles of immunotherapy, shrinkage of the primary liver tumor and metastatic lymph nodes happened, alongside with new lung metastasis, which indicated a mixed response. Radiotherapy was then administered to both the liver and lung lesions, accompanied with continued immunotherapy. The combined therapy eventually led to a complete response for both the primary tumor and all metastases without treatment-related adverse effects. The patient has survived for 26 months after the combined therapy and remains tumor-free currently. This case demonstrates the high inconsistency between immunotherapy response biomarkers and the synergetic anti-tumor effect of immunotherapy and radiotherapy in ICC.

MYB Proto-oncogene-like 1-TWIST1 Axis Promotes Growth and Metastasis of Hepatocellular Carcinoma Cells.

MYB proto-oncogene-like 1 (MYBL1) has been reported to be a strong activator of transcription and plays an important role in the development of cancer. However, the precise biological function and molecular mechanism of MYBL1 in hepatocellular carcinoma (HCC) cells remain unclear. In the present study, we found that the expression of MYBL1 was markedly overexpressed in HCC cell lines and HCC samples, respectively. Moreover, MYBL1 expression positively correlated with tumor progression and inversely correlated with patient survival in 368 human HCC tissue samples. Overexpression of MYBL1 induced, whereas knockdown of MYBL1 reduced, HCC proliferation and metastasis both in vitro and in vivo. Furthermore, we demonstrated that HCC patients with high MYBL1 expression had significantly shorter overall and poorer disease-free survival than those with low MYBL1 expression. MYBL1 transcriptionally upregulated TWIST1 expression by directly targeting the TWIST1 promoter. More importantly, the in vitro analysis was consistent with the significant correlation between MYBL1 and TWIST1 expression observed in a large cohort of human HCC specimens. Taken together, our results demonstrate that MYBL1 plays an important role in HCC growth and metastasis and reveal a plausible mechanism for upregulation of TWIST1 in HCC.

Apatinib potentiates irradiation effect via suppressing PI3K/AKT signaling pathway in hepatocellular carcinoma.

BACKGROUND: Limited effective intervention for advanced hepatocellular carcinoma (HCC) is available. This study aimed to investigate the potential clinical utility of apatinib, a highly selective inhibitor of the vascular endothelial growth factor receptor-2 (VEGFR2) tyrosine kinase, as a radiosensitizer in the treatment of HCC. METHODS: Four human HCC cell lines SMMC-7721, MHCC-97H, HCCLM3 and Hep-3B were treated with apatinib, irradiation or combination treatment. Colony formation assay, flow cytometry and nuclear γ-H2AX foci immunofluorescence staining were performed to evaluate the efficacy of combination treatment. RNA sequencing was conducted to explore the potential mechanism. The impact of combination treatment on tumor growth was assessed by xenograft mice models. RESULTS: Colony formation assay revealed that apatinib enhanced the radiosensitivity of HCC cell lines. Apatinib suppressed repair of radiation-induced DNA double-strand breaks. Flow cytometry analysis showed that apatinib increased radiation-induced apoptosis. Apatinib radiosensitized HCC via suppression of radiation-induced PI3K/AKT pathway. Moreover, an in vivo study indicated apatinib combined with irradiation significantly decreased xenograft tumor growth. CONCLUSIONS: Our results indicate that apatinib has therapeutic potential as a radiosensitizer in HCC, and PI3K/AKT signaling pathway plays a critical role in mediating radiosensitization of apatinib.

Predictive factors of treatment outcomes after percutaneous ablation of hepatocellular carcinoma in the caudate lobe: a retrospective study.

BACKGROUND: Hepatocellular carcinomas (HCC) arising in the caudate lobe is rare and the treatment is difficult. The aim of this study is to summarize the experience of ultrasound-guided percutaneous ablation therapy for HCC located in the caudate lobe and to investigate the predictive factors of the treatment outcomes. METHODS: From August 2006 to June 2017, 73 patients (63 males and 10 females; mean age, 54.9 ± 11.6 years; age range, 25-79 years) with 73 caudate lobe HCCs (mean size, 2.6 ± 1.1 cm; size range, 1.0-5.0 cm) were treated with percutaneous ablation, including 33 patients with radiofrequency ablation (RFA), 23 patients with ethanol ablation (EA), and 17 patients with combination of RFA and EA. The treatment outcome and survival after ablation for caudate lobe HCC were assessed and the predictive factors were calculated by univariate and multivariate analyses. RESULTS: A total of 72 patients achieved complete ablation after the first or second session of ablation. The treatment effectiveness was 98.6% (72/73). During the follow-up, 16 tumors developed local tumor progression (LTP) and a total of 61 patients (61/73, 83.6%) were detected distant recurrence (DR). According to univariate and multivariate analyses, tumor size > 2 cm (hazard ratio[HR] = 3.667; 95% confidence interval[CI], 1.043-12.889; P = 0.043) was a significant prognostic factor of LTP after ablation for HCC in the caudate lobe, while tumor number (HR = 2.245; 95%CI, 1.168-4.317; P = 0.015) was a significant prognostic factor of DR. The mean overall survival time after ablation was 28.7 ± 2.8 months, without independent predictive factors detected. Four patients (4/73, 5.5%) were detected treatment-related major complications, without independent predictive factor detected. CONCLUSION: Ultrasound-guided percutaneous ablation is a feasible treatment for a selected case with HCC in the caudate lobe. Tumor size > 2 cm increases the risk of LTP and intrahepatic tumor number is associated with DR after ablation.

Comparison of the 7th and 8th edition of American Joint Committee on Cancer (AJCC) staging systems for breast cancer patients: a Surveillance, Epidemiology and End Results (SEER) Analysis.

BACKGROUND: The 8th edition of the American Joint Committee on Cancer (AJCC) staging system for breast cancer has incorporated tumor grade, estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 status as staging biologic factors reflecting prognosis. The purpose of this study was to compare the 7th and 8th edition of AJCC staging system for prognostic impact. MATERIALS AND METHODS: Primary breast cancer patients diagnosed from 2010 to 2014 were identified using the Surveillance, Epidemiology and End Results 18 registries research database. Breast cancer-specific survival (BCSS) and overall survival (OS) between stages were estimated using the Kaplan-Meier method and compared using the log-rank test. Multivariable analysis was performed using Cox proportional hazards regression analysis to identify factors independently associated with outcome. Akaike's information criterion (AIC) was calculated to estimate how well the staging system fitted the data and the complexity of the model. RESULTS: A total of 184,221 primary breast cancer patients were identified in the 7th AJCC staging system; 16,145 (8.8%) patients could not be categorized according to 8th AJCC prognostic staging system leaving 168,076 patients included for final analyses. The 8th AJCC performed well with the BCSS and OS concordant with stage. A total of 89,494 (53.2%) of patients were restaged to a different stage group in the 8th AJCC; stage IIIA in the 7th AJCC migrated to stage IB with a worse prognosis than IIA and IIB in the 8th AJCC. Nevertheless, the 8th AJCC had a better AIC than the 7th staging system. CONCLUSION: The prognostic accuracy of the 8th AJCC staging system was generally superior to the 7th AJCC, although subtle differences between the two systems should be noted in comparative studies.

Low-dose Bacillus Calmette-Guerin versus full-dose for intermediate and high-risk of non-muscle invasive bladder cancer: a Markov model.

BACKGROUND: To compare the efficacy of low dose (27 mg) Bacillus Calmette-Guérin (BCG) and a full dose (81 mg) BCG immunotherapy for patients with intermediate and high-risk non-muscle invasive bladder cancer (NMIBC) after a typical transurethral bladder resection. METHODS: We constructed a Markov model for a 20-year simulation of the disease to compare the overall survival of patients with intermediate and high-risk of NMIBC between the full-dose therapy (FD group) and the low-dose therapy (LD group). Base case analysis, one-way and two-way sensitivity analysis and a second-order Monte Carlo analysis were performed based on data from 15 published articles. RESULTS: The expected overall survivals were 9.56 (9.55-9.57) years for FD group and 9.63 (9.61-9.64) years for LD group(P < 0.001). The estimated mortality in the FD group at 5, 10, and 20 years were 34.23%, 57.51% and 83.14%, respectively. The corresponding values in the LD group were 34.11%, 57.17%, 82.16%, respectively. Age-specific mortality and metastatic rate after undergoing radical cystectomy (RC) were the most two sensitive parameters in both groups. The rate of disease recurrence with disease worsening is the determining factor when choosing the optimal dose of BCG treatment. CONCLUSIONS: A low-dose BCG treatment may act slightly better than a full-dose BCG treatment for patients with intermediate and high-risk of NMIBC. This finding will require further high-quality studies to validate.

Prognostic value of inflammation-based scores in patients receiving radical resection for colorectal cancer.

BACKGROUND: The modified Glasgow Prognostic Score (mGPS) and the neutrophil-to-lymphocyte ratio (NLR) are conventional inflammation-based scores for colorectal cancer (CRC). The systemic inflammation score (SIS) has been shown to be more informative than the mGPS in CRC. The albumin-NLR, composed of albumin and the NLR, can also be a candidate for a valuable inflammation score. However, about the utility of the mGPS, SIS, and albumin-NLR for CRC patients who have received radical resections remains unclear. METHODS: This study enrolled 877 CRC patients, who underwent radical surgical resection between January 1, 2007 and December 31, 2014. The prognostic values of the mGPS, SIS, and albumin-NLR were compared by the Kaplan-Meier survival analysis, multivariate Cox regression modelling, and the time-dependent receiver operating characteristic curve analysis (ROC). RESULTS: In the Kaplan-Meier analysis, all three inflammation scores were significantly associated with overall survival (OS) in the group including all the patients (mGPS, p = 0.016; SIS, p < 0.001; albumin-NLR, p = 0.007) and in the left-sided colon tumour subgroup (mGPS, p = 0.029; SIS p = 0.0013; albumin-NLR, p = 0.001). In the right-sided colon tumour subgroup, only the albumin-NLR was associated with OS (p = 0.048). The albumin-NLR was the only independent prognostic factor of the three scores for OS in the multivariate survival analysis. CONCLUSIONS: The albumin-NLR outperformed both the SIS and mGPS in predicting OS in CRC patients undergoing radical resection.