PD-1/CD80+ small extracellular vesicles from immunocytes induce cold tumours featured with enhanced adaptive immunosuppression.

Only a minority of cancer patients benefit from immune checkpoint blockade therapy. Sophisticated cross-talk among different immune checkpoint pathways as well as interaction pattern of immune checkpoint molecules carried on circulating small extracellular vesicles (sEV) might contribute to the low response rate. Here we demonstrate that PD-1 and CD80 carried on immunocyte-derived sEVs (I-sEV) induce an adaptive redistribution of PD-L1 in tumour cells. The resulting decreased cell membrane PD-L1 expression and increased sEV PD-L1 secretion into the circulation contribute to systemic immunosuppression. PD-1/CD80+ I-sEVs also induce downregulation of adhesion- and antigen presentation-related molecules on tumour cells and impaired immune cell infiltration, thereby converting tumours to an immunologically cold phenotype. Moreover, synchronous analysis of multiple checkpoint molecules, including PD-1, CD80 and PD-L1, on circulating sEVs distinguishes clinical responders from those patients who poorly respond to anti-PD-1 treatment. Altogether, our study shows that sEVs carry multiple inhibitory immune checkpoints proteins, which form a potentially targetable adaptive loop to suppress antitumour immunity.

Therapy-induced senescent tumor cell-derived extracellular vesicles promote colorectal cancer progression through SERPINE1-mediated NF-κB p65 nuclear translocation.

BACKGROUND: Cellular senescence frequently occurs during anti-cancer treatment, and persistent senescent tumor cells (STCs) unfavorably promote tumor progression through paracrine secretion of the senescence-associated secretory phenotype (SASP). Extracellular vesicles (EVs) have recently emerged as a novel component of the SASP and primarily mediate the tumor-promoting effect of the SASP. Of note, the potential effect of EVs released from STCs on tumor progression remains largely unknown. METHODS: We collected tumor tissues from two cohorts of colorectal cancer (CRC) patients to examine the expression of p16, p21, and SERPINE1 before and after anti-cancer treatment. Cohort 1 included 22 patients with locally advanced rectal cancer (LARC) who received neoadjuvant therapy before surgical resection. Cohort 2 included 30 patients with metastatic CRC (mCRC) who received first-line irinotecan-contained treatment. CCK-8, transwell, wound-healing assay, and tumor xenograft experiments were carried out to determine the impacts of EVs released from STCs on CRC progression in vitro and in vivo. Quantitative proteomic analysis was applied to identify protein cargo inside EVs secreted from STCs. Immunoprecipitation and mass spectrometer identification were utilized to explore the binding partners of SERPINE1. The interaction of SERPINE1 with p65 was verified by co-immunoprecipitation, and their co-localization was confirmed by immunofluorescence. RESULTS: Chemotherapeutic agents and irradiation could potently induce senescence in CRC cells in vitro and in human CRC tissues. The more significant elevation of p16 and p21 expression in patients after anti-cancer treatment displayed shorter disease-free survival (DFS) for LARC or progression-free survival (PFS) for mCRC. We observed that compared to non-STCs, STCs released an increased number of EVs enriched in SERPINE1, which further promoted the progression of recipient cancer cells. Targeting SERPINE1 with a specific inhibitor, tiplaxtinin, markedly attenuated the tumor-promoting effect of STCs-derived EVs. Additionally, the patients with greater increment of SERPINE1 expression after anti-cancer treatment had shorter DFS for LARC or PFS for mCRC. Mechanistically, SERPINE1 bound to p65, promoting its nuclear translocation and subsequently activating the NF-κB signaling pathway. CONCLUSIONS: We provide the in vivo evidence of the clinical prognostic implications of therapy-induced senescence. Our results revealed that STCs were responsible for CRC progression by producing large amounts of EVs enriched in SERPINE1. These findings further confirm the crucial role of therapy-induced senescence in tumor progression and offer a potential therapeutic strategy for CRC treatment.

Integrated neutrophil-to-lymphocyte ratio and handgrip strength better predict survival in patients with cancer cachexia.

OBJECTIVES: Systemic inflammation and skeletal muscle strength play crucial roles in the development and progression of cancer cachexia. In this study we aimed to evaluate the combined prognostic value of neutrophil-to-lymphocyte ratio (NLR) and handgrip strength (HGS) for survival in patients with cancer cachexia. METHODS: This multicenter cohort study involved 1826 patients with cancer cachexia. The NLR-HGS (NH) index was defined as the ratio of neutrophil-to-lymphocyte ratio to handgrip strength. Harrell's C index and receiver operating characteristic (ROC) curve analysis were used to assess the prognosis of NH. Kaplan-Meier analysis and Cox regression models were used to evaluate the association of NH with all-cause mortality. RESULTS: Based on the optimal stratification, 380 women (NH > 0.14) and 249 men (NH > 0.19) were classified as having high NH. NH has shown greater predictive value compared to other indicators in predicting the survival of patients with cancer cachexia according to the 1-, 3-, and 5-y ROC analysis and Harrell's C index calculation. Multivariate survival analysis showed that higher NH was independently associated with an increased risk of death (hazard ratio = 1.654, 95% confidence interval = 1.389-1.969). CONCLUSION: This study demonstrates that the NH index, in combination with NLR and HGS, is an effective predictor of the prognosis of patients with cancer cachexia. It can offer effective prognosis stratification and guidance for their treatment.

Sarcopenia prevalence in patients with cancer and association with adverse prognosis: A nationwide survey on common cancers.

OBJECTIVE: Although previous studies have implicated the negative outcomes of sarcopenia, evidence is limited to one or a few types of cancer. The aim of this study was to evaluate the distribution and influencing factors of sarcopenia, and explore the relationship between sarcopenia and cancer prognosis in a large oncological population. METHODS: This observational cohort study included patients diagnosed with malignant cancer between May 2011 and January 2019. Hematologic and anthropometric parameters were collected prospectively. Low skeletal muscle mass and radiodensity were diagnosed using clinical indicators, according to the two prediction models. The importance of potential risk factors for sarcopenia was estimated by subtracting the predicted degrees of freedom from the partial χ2 statistic. Hazard rates of death were calculated using the hazard function and Cox regression analyses. RESULTS: We included 13 761 patients with cancer; the prevalence of sarcopenia was 33%. The median age was 58 y and 7135 patients (52%) were men. Patients with sarcopenia had a worse nutritional status and quality of life than those without sarcopenia. Age was the most important risk factor for sarcopenia compared with body mass index or TNM stage. Additionally, patients with sarcopenia had a significantly higher and earlier peak risk for mortality. After adjusting for baseline characteristics, sarcopenia was independently associated with mortality in the research population (hazard ratio, 1.429; P < 0.001) and most cancer types. CONCLUSION: Age is the most important risk factor for sarcopenia even in patients with cancer. Sarcopenia is strongly associated with a poor quality of life and reduced overall survival.

HRS Regulates Small Extracellular Vesicle PD-L1 Secretion and Is Associated with Anti-PD-1 Treatment Efficacy.

PD-L1 localized to immunosuppressive small extracellular vesicles (sEV PD-L1) contributes to tumor progression and is associated with resistance to immune-checkpoint blockade (ICB) therapy. Here, by establishing a screening strategy with a combination of tissue microarray (TMA), IHC staining, and measurement of circulating sEV PD-L1, we found that the endosomal sorting complex required for transport (ESCRT) member protein hepatocyte growth factor-regulated tyrosine kinase substrate (HRS) was the key regulator of circulating sEV PD-L1 in head and neck squamous cell carcinoma (HNSCC) patients. Increased HRS expression was found in tumor tissues and positively correlated with elevated circulating sEV PD-L1 in patients with HNSCC. The expression of HRS was also negatively correlated to the infiltration of CD8+ T cells. Knockdown of HRS markedly reduced PD-L1 expression in HNSCC cell-derived sEVs, and these sEVs from HRS knockdown cells showed decreased immunosuppressive effects on CD8+ T cells. Knockout of HRS inhibited tumor growth in immunocompetent mice together with PD-1 blockade. Moreover, a higher HRS expression was associated with a lower response rate to anti-PD-1 therapy in patients with HNSCC. In summary, our study reveals HRS, the core component of ESCRT-0, regulates sEV PD-L1 secretion, and is associated with the response to ICB therapy in patients with HNSCC, suggesting HRS is a promising target to improve cancer immunotherapy.

A Randomized, Open-Label, Multicenter, Phase 3 Study of High-Dose Vitamin C Plus FOLFOX ± Bevacizumab versus FOLFOX ± Bevacizumab in Unresectable Untreated Metastatic Colorectal Cancer (VITALITY Study).

PURPOSE: To compare the efficacy and safety of high-dose vitamin C plus FOLFOX ± bevacizumab versus FOLFOX ± bevacizumab as first-line treatment in patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Between 2017 and 2019, histologically confirmed patients with mCRC (n = 442) with normal glucose-6-phosphate dehydrogenase status and no prior treatment for metastatic disease were randomized (1:1) into a control (FOLFOX ± bevacizumab) and an experimental [high-dose vitamin C (1.5 g/kg/d, intravenously for 3 hours from D1 to D3) plus FOLFOX ± bevacizumab] group. Randomization was based on the primary tumor location and bevacizumab prescription. RESULTS: The progression-free survival (PFS) of the experimental group was not superior to the control group [median PFS, 8.6 vs. 8.3 months; HR, 0.86; 95% confidence interval (CI), 0.70-1.05; P = 0.1]. The objective response rate (ORR) and overall survival (OS) of the experimental and control groups were similar (ORR, 44.3% vs. 42.1%; P = 0.9; median OS, 20.7 vs. 19.7 months; P = 0.7). Grade 3 or higher treatment-related adverse events occurred in 33.5% and 30.3% of patients in the experimental and control groups, respectively. In prespecified subgroup analyses, patients with RAS mutation had significantly longer PFS (median PFS, 9.2 vs. 7.8 months; HR, 0.67; 95% CI, 0.50-0.91; P = 0.01) with vitamin C added to chemotherapy than with chemotherapy only. CONCLUSIONS: High-dose vitamin C plus chemotherapy failed to show superior PFS compared with chemotherapy in patients with mCRC as first-line treatment but may be beneficial in patients with mCRC harboring RAS mutation.

Reference values of low body mass index, mid-upper arm circumference, and calf circumference in cancer patients: A nationwide multicenter observational study.

OBJECTIVE: Anthropometric measurements including body mass index (BMI), mid-upper arm circumference (MUAC), and calf circumference (CC) are simple and convenient indicators of nutritional status and muscle mass. However, most of their reference values come from studies based on healthy Western populations. The optimal reference values of these anthropometric factors in Asian patients with cancer are unclear. The aim of this study was to develop reference values of severely and moderately low BMI, MUAC, and CC by analyzing a large sample of patients with cancer from a nationwide population. METHODS: We conducted a retrospective analysis of 16 104 patients who were diagnosed with malignant diseases from June 2012 to January 2019. The median age of the patients was 58 y, and 52.5% were men. Optimal stratification was used to calculate reference values using X-tile software. Kaplan-Meier and multivariate Cox analysis were performed to analyze survival data. A receiver operating characteristic analysis was conducted to test the performance of new reference values in diagnosing malnutrition. RESULTS: The optimal reference values were calculated for BMI (moderately low: 19.7 [women] and 19 [men]; severely low: 16.7 [women] and 16.7 [men]), MUAC (moderately low: 24.5 [women] and 23.2 [men] severely low: 20.6 [women] and 19.4 [mnen]), and CC (moderately low: 29.1 [women] and 29.3 [men]; severely low: 26.7 [women] and 26.9 [men]). New reference values had more significant affects on mortality risk and better performance in predicting malnutrition than existing ones. CONCLUSIONS: The present study defined reference values of moderately and severely low BMI, MUAC, and CC, which showed strong associations with quality of life, malnutrition, and mortality risk. New reference values from the present study are classification references specifically for the Asian population, which is a new step to promote the application of Global Leadership Initiative on Malnutrition criteria and its severity grading system in Asia.

Characterization of the immune cell infiltration landscape in lung adenocarcinoma.

Immune checkpoint inhibitors (ICIs) have played an important role in the treatment of lung adenocarcinoma (LUAD). However, their effectiveness is limited, and many patients exhibit a weak response. In this study, we propose a new and more effective immunophenotyping method for evaluating the prognosis and tumor microenvironment (TME) cellular infiltration characteristics in LUAD patients and their response to immunotherapy. Based on the transcriptomic and prognostic data of 584 patients with LUAD collected from TCGA cohort and GEO dataset, we combined tumor immune infiltration, the TME, and immune-related genes to score each sample using principal component analysis (PCA) and divided the patients into two subgroups with high and low tumor immune infiltration (TII) scores. The high-TII score group was characterized by increased immune activation and apoptosis signaling pathways. Moreover, clinical subgroup analysis demonstrated that the TII immune score was also applicable to different clinical groups and the high-TII score group still exhibited good prognosis and better response to ICIs. This study mapped the TII landscape in LUAD patients and confirmed that the TII score is helpful for predicting patient response to immunotherapy and may guide more effective immunotherapeutic strategies.

The combination of body composition conditions and systemic inflammatory markers has prognostic value for patients with gastric cancer treated with adjuvant chemoradiotherapy.

OBJECTIVE: The aim of this study was to explore the prognostic value of the association between systemic inflammation response markers (red blood cell distribution width, neutrophil platelet score, prognostic nutritional index, neutrophil-to-lymphocyte ratio, neutrophil-to-platelet ratio, lymphocyte-to-monocyte ratio, and systemic immune-inflammation index) and poorer body composition conditions (sarcopenia, myosteatosis, and sarcopenic obesity) among patients with gastric cancer who underwent adjuvant chemoradiotherapy after radical gastrectomy. METHODS: A computed tomography scan was performed within 2 wk of prechemoradiotherapy to identify sarcopenia, myosteatosis and sarcopenic obesity. Tumor and systemic inflammatory response information was recorded. Logistic analysis was used to explore the potential risk factors associated with body composition. Univariate and multivariate Cox analyses were performed for survival analysis. A nomogram was constructed to serve as a prognostic prediction tool for the 3- and 5-y overall survival rates. RESULTS: The study included 223 patients (74 women and 149 men) with gastric cancer treated with adjuvant chemoradiotherapy after radical gastrectomy. The incidences of sarcopenia, myosteatosis, and sarcopenic obesity were 30%, 39%, and 16%, respectively. Logistic analysis demonstrated that a low prognostic nutritional index is a risk factor for sarcopenia, myosteatosis, and sarcopenic obesity. Based on survival analysis, stage (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.23-0.84; P = 0.01), the neutrophil platelet score (HR, 0.50; 95% CI, 0.31-0.82; P = 0.01), the prognostic nutritional index (HR, 0.40; 95% CI, 0.24-0.68; P = 0.00) and sarcopenic obesity (HR, 0.54; 95% CI, 0.31-0.93; P = 0.03) remained independent prognostic factors for overall survival. Accuracy was improved when systemic inflammation markers were incorporated into the nomogram compared with when they were excluded, and the predicted C indexes of the nomogram with and without systemic inflammatory markers were 0.71 (95% CI, 0.67-0.73) and 0.63 (95% CI, 0.57-0.68), respectively. CONCLUSION: The systemic inflammatory response associated with progressive nutritional conditions and body composition conditions with systemic inflammation markers incorporated presented better prognostic value.

The Application of Fat-Free Mass Index for Survival Prediction in Cancer Patients With Normal and High Body Mass Index.

Background: Fat-free mass (FFM) depletion can be masked by a stable body weight or weight gain in the presence of a normal or high body mass index (BMI). This study investigated the prognostic value of low fat-free mass index (FFMI) in cancer patients with normal or high BMI. Methods: This multicenter retrospective cohort study included 1,602 cancer patients with normal/high BMI. The association of FFMI with patients' overall survival (OS) was analyzed by the Kaplan-Meier method and a Cox model. Results: In this analysis, there were 974 (60.8%) females and 628 (39.2%) males. Low FFMI was associated with worse OS when compared with those patients with normal FFMI. After multivariate adjustment, low FFMI was demonstrated to be an independent unfavorable prognostic factor (HR: 1.69; 95% CI: 1.28, 2.23; P < 0.001) in cancer patients with normal/high BMI. For specific tumor type, low FFMI was found to be associated with worse prognosis in patients with lung cancer, breast cancer and upper gastrointestinal cancer. In subgroup analysis, the association of low FFMI with worse survival was significantly modified by weight loss (P for interaction = 0.012), and those patients with concurrent low FFMI and weight loss showed the worst prognosis (HR: 3.53; 95% CI: 2.04, 6.11; P < 0.001). Conclusion: Low FFMI was associated with worse prognosis in cancer patients with normal/high BMI. This study highlights the usefulness of FFMI for prognostic estimation in these patients.

Chemoprophylaxis, diagnosis, treatments, and discharge management of COVID-19: An evidence-based clinical practice guideline (updated version).

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of a rapidly spreading illness, coronavirus disease 2019 (COVID-19), affecting more than seventeen million people around the world. Diagnosis and treatment guidelines for clinicians caring for patients are needed. In the early stage, we have issued "A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version)"; now there are many direct evidences emerged and may change some of previous recommendations and it is ripe for develop an evidence-based guideline. We formed a working group of clinical experts and methodologists. The steering group members proposed 29 questions that are relevant to the management of COVID-19 covering the following areas: chemoprophylaxis, diagnosis, treatments, and discharge management. We searched the literature for direct evidence on the management of COVID-19, and assessed its certainty generated recommendations using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. Recommendations were either strong or weak, or in the form of ungraded consensus-based statement. Finally, we issued 34 statements. Among them, 6 were strong recommendations for, 14 were weak recommendations for, 3 were weak recommendations against and 11 were ungraded consensus-based statement. They covered topics of chemoprophylaxis (including agents and Traditional Chinese Medicine (TCM) agents), diagnosis (including clinical manifestations, reverse transcription-polymerase chain reaction (RT-PCR), respiratory tract specimens, IgM and IgG antibody tests, chest computed tomography, chest x-ray, and CT features of asymptomatic infections), treatments (including lopinavir-ritonavir, umifenovir, favipiravir, interferon, remdesivir, combination of antiviral drugs, hydroxychloroquine/chloroquine, interleukin-6 inhibitors, interleukin-1 inhibitors, glucocorticoid, qingfei paidu decoction, lianhua qingwen granules/capsules, convalescent plasma, lung transplantation, invasive or noninvasive ventilation, and extracorporeal membrane oxygenation (ECMO)), and discharge management (including discharge criteria and management plan in patients whose RT-PCR retesting shows SARS-CoV-2 positive after discharge). We also created two figures of these recommendations for the implementation purpose. We hope these recommendations can help support healthcare workers caring for COVID-19 patients.

Chemoprophylaxis, diagnosis, treatments, and discharge management of COVID-19: an evidence-based clinical practice guideline (updated version)

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of a rapidly spreading illness, coronavirus disease 2019 (COVID-19), affecting more than seventeen million people around the world. Diagnosis and treatment guidelines for clinicians caring for patients are needed. In the early stage, we have issued "A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version)"; now there are many direct evidences emerged and may change some of previous recommendations and it is ripe for develop an evidence-based guideline. We formed a working group of clinical experts and methodologists. The steering group members proposed 29 questions that are relevant to the management of COVID-19 covering the following areas: chemoprophylaxis, diagnosis, treatments, and discharge management. We searched the literature for direct evidence on the management of COVID-19, and assessed its certainty generated recommendations using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. Recommendations were either strong or weak, or in the form of ungraded consensus-based statement. Finally, we issued 34 statements. Among them, 6 were strong recommendations for, 14 were weak recommendations for, 3 were weak recommendations against and 11 were ungraded consensus-based statement. They covered topics of chemoprophylaxis (including agents and Traditional Chinese Medicine (TCM) agents), diagnosis (including clinical manifestations, reverse transcription-polymerase chain reaction (RT-PCR), respiratory tract specimens, IgM and IgG antibody tests, chest computed tomography, chest x-ray, and CT features of asymptomatic infections), treatments (including lopinavir-ritonavir, umifenovir, favipiravir, interferon, remdesivir, combination of antiviral drugs, hydroxychloroquine/chloroquine, interleukin-6 inhibitors, interleukin-1 inhibitors, glucocorticoid, qingfei paidu decoction, lianhua qingwen granules/capsules, convalescent plasma, lung transplantation, invasive or noninvasive ventilation, and extracorporeal membrane oxygenation (ECMO)), and discharge management (including discharge criteria and management plan in patients whose RT-PCR retesting shows SARS-CoV-2 positive after discharge). We also created two figures of these recommendations for the implementation purpose. We hope these recommendations can help support healthcare workers caring for COVID19 patients

Predictive value of pancreatic dose-volume metrics on sarcopenia rate in gastric cancer patients treated with adjuvant chemoradiotherapy.

OBJECTIVE: To evaluate the relationship of sarcopenia with the pancreatic dose-volume histogram (DVH) in gastric cancer patients treated with adjuvant chemoradiotherapy (CRT) after radical gastrectomy. METHODS: A retrospective study was performed on the data in Zhongnan Hospital of Wuhan University from January 2008 to December 2016. Skeletal muscle index (SMI) was analyzed by cross-sectional areas of body composition at the level of third lumbar (L3) vertebrae, which was measured using single-slice computer tomograph (CT) prior to CRT, at 6 months and 12 months after CRT respectively. Logistic regression analysis was conducted to explore the potential clinical risk factors of sarcopenia in this patients cohort. Regarding the dosimetrics of pancreas, the sarcopenia rate was compared between the two groups divided according to the cut-off value determined by the receiver operating characteristic (ROC) curves. RESULTS: One hundred and fifty-three gastric cancer patients were eligible in this study. The median postoperative follow-up was 36 (7-115) months. The mean dose of pancreas was 4399.7 ± 396.0 cGy. The incidence of sarcopenia prior to CRT, at 6 months and 12 months later were 29.4% (45/153), 27.3% (35/128) and 37.0% (37/100). Both sarcopenia at 6 months (HR = 2.038, 95%CI = 1.084-3.833, P = 0.027) and sarcopenia at 12 months (HR = 2.216, 95%CI = 1.007-4.873, P = 0.048) were the independent prognostic factor of gastric cancer patients. V46 remained to be the only independent risk factor of sarcopenia at 6 months (OR = 3.889, 95%CI = 1.099-13.764, P = 0.035) and 12 months (OR = 6.067, 95%CI = 1.687-21.821, P = 0.006) in multivariate logistic regression analysis. Among the dosimetric parameters used for ROC analysis, the V46 showed the highest area under the curve (AUC = 0.707). Here is the relationship between sarcopenia rate and the cut-off value for V46. Higher sarcopenia rate at 6 months was noted in 42.6% patients with V46 ≥ 57% compared with 9% of patients with V46 < 57% (P < 0.001). The sarcopneia rate at 12 months was 52% with V46 ≥ 57% and 25% with V46 < 57% (P = 0.010). CONCLUSION: Gastric cancer with sarcopenia after adjuvant CRT had poorer survival. Higher dose and larger irradiated volume of pancreas correlated with higher risk of sarcopenia. Appropriated administration of pancreas dose-volume may be conducive to reduce the risk of sarcopenia and improve survival in gastric cancer patients treated with adjuvant CRT.

Mitochondrial DNA content reduction induces aerobic glycolysis and reversible resistance to drug-induced apoptosis in SW480 colorectal cancer cells.

Mutations and reductions in mitochondrial DNA (mtDNA), which are frequent in human tumors, may contribute to enhancing their malignant phenotypes. However, the effects of mtDNA abnormalities in colorectal cancer remain largely unknown. In this study, mtDNA-reduced cell model was established by partial depletion of mtDNA in SW480 cells and the effects of mtDNA reduction in colorectal cancer cells were investigated. We found that mtDNA-reduced cells had enhanced glucose uptake and generated markedly higher level of lactate. These changes were accompanied by only a slight reduction in ATP production compared with the parent cells. Furthermore, the activity of the glycolytic enzymes, hexokinase (HK) and phosphofructokinase (PFK), was increased in mtDNA-reduced cells. These results suggested a switch to aerobic glycolysis in mtDNA-reduced cells, which helped the cells to gain a survival advantage. Notably, when mtDNA content was restored, metabolism returned to normal. In addition, the mtDNA-reduced cells were highly resistant to 5-fluorouracil- and oxaliplatin-induced apoptosis and this drug resistance was reversible following recovery of the mtDNA content. We also found that the Akt/mTOR pathway was activated in the mtDNA-reduced cells. This pathway might play a significant role in drug resistance in the mtDNA-reduced cells as drug susceptibility was restored when this pathway was inhibited. Taken together, our results supported the notion that mtDNA reduction induced aerobic glycolysis and a reversible apoptosis-resistant phenotype in SW480 cells, and that the Akt/mTOR pathway might be involved in the drugs-induced apoptosis resistance.

Aberrant high expression level of MORC2 is a common character in multiple cancers.

Microrchidia 2 (MORC2) plays important roles in DNA damage repair and lipogenesis, but the clinical and functional role of MORC2 in cancer remains largely unexplored. In this study, we showed that MORC2 was widely expressed in human tissues while significantly up-regulated in most cancer types using immunohistochemical staining and analysis of messenger RNA expression profile of more than 2000 human tissue samples from 15 different organs (lung, prostate, liver, breast, brain, stomach, colon/rectum, pancreas, ovary, endometrium, skin, nasopharynx, kidney, esophagus, and bladder). We also found that the MORC2 expression level in high-grade cancer tissues was much more elevated and associated with unfavorable pathological characteristics, poor overall survival, and disease-free survival in several kinds of cancers such as non-small cell lung cancer and breast cancer. Gene set enrichment analysis was used to predict the genes modulated by MORC2, and the results showed that dysregulation of MORC2 in tumor may take part in the cell cycle regulation and genomic instability. We observed that MORC2 knockdown would arrest the cell cycle progress, and the genome of tumors with high MORC2 expression contained more point mutations and gene copy number variation, which validates our gene set enrichment analysis results. The results also showed that MORC2 knockdown would significantly inhibit the proliferation, colony forming, migration, and invasion in multiple cancer cell lines. Taken together, these results highlight the importance of MORC2 in tumorigenesis and cancer progression, and it may act as a potential diagnostic marker and therapeutic target for these diseases.

Log odds of positive lymph nodes is superior to the number- and ratio-based lymph node classification systems for colorectal cancer patients undergoing curative (R0) resection.

The metastatic lymph node status (N classification) is an important prognostic factor for patients with colorectal cancer (CRC). The aim of the present study was to evaluate and compare the prognostic assessment of three different lymph node staging methods, namely standard lymph node (pN) staging, metastatic lymph node ratio (LNR) and log odds of positive lymph nodes (LODDS) in CRC patients who undergo curative resection (R0). Data were retrospectively collected from 192 patients who had undergone R0 resection. Kaplan-Meier survival curves, Cox proportional hazards model and accuracy of the three methods (pN, LNR and LODDS) were compared to evaluate the prognostic effect. Univariate analysis demonstrated that pN, LNR and LODDS were all significantly correlated with survival (P=0.001, P<0.001 and P<0.001, respectively). The final result of the 3-step multivariate analysis demonstrated that LODDS was superior to the other two N categories. Patients in the same pN or LNR classifications may be classified into different LODDS stages with different prognoses. Thus, LODDS may be a meaningful prognostic indicator and superior to the pN and LNR classifications in CRC patients who undergo curative (R0) resection.

Optimal postoperative nutrition support for patients with gastrointestinal malignancy: A systematic review and meta-analysis.

OBJECTIVE: To improve clinical outcomes, parenteral nutrition, standard enteral nutrition and immuno-enhanced nutrition are widely used in the gastrointestinal tumor patients undergoing surgery, but the optimal management of postoperative nutrition support remains uncertain. METHODS: We systematically searched the PUBMED, EMBASE and CNKI to identify latent studies which the effects of standard EN compared with PN or IEN on gastrointestinal tumor patients until the end of November, 2015. The quality of included trials was assessed according to the handbook for Cochrane reviewer. Statistical analysis was carried out by RevMan5.1 software. RESULTS: 30 randomized controlled trials containing 3854 patients were contained in our meta-analysis, the results indicated that postoperative SEN could absolutely reduce the incidence of postoperative infectious (P < 0.00001) and non-infectious complications (P = 0.0003), together with its positive effect on the length of hospital stay (P < 0.00001). Additionally, enteral nutrition enhanced with immune stimulation was confirmed to be better, with a significant difference between groups in terms of total infectious (P < 0.00001) and non-infectious complications (P = 0.04), and IEN could also significantly shorten the length of hospital stay (P < 0.00001). CONCLUSION: Early use of Enteral nutrition in digestive tumor patients after surgery could significantly reduce the postoperative complications and shorten the length of hospital stay, IEN should be the optimal management, while the use of parenteral nutrition should be restrict to few patients with severe intolerance to enteral nutrition.

Efficacy of cetuximab-based chemotherapy in metastatic colorectal cancer according to RAS and BRAF mutation subgroups: A meta-analysis.

The epidermal growth factor receptor (EGFR)-targeting monoclonal antibody, cetuximab, has been added to standard chemotherapy regimens for treating metastatic colorectal cancer (mCRC). However, the efficacy of adding cetuximab to chemotherapy regimens for patients of differing genetic backgrounds remains controversial. The present study aimed to investigate the efficacy of adding cetuximab to chemotherapeutic regimens in subgroups of patients defined according to the RAS and BRAF mutation status in the first-line treatment of patients with mCRC. A systematic literature search was performed in databases (including PubMed, Embase, the Cochrane library, the American Society of Clinical Oncology and the European Society For Medical Oncology) up to August 2015. Randomized controlled trials analyzing overall survival (OS) and progression-free survival (PFS) in mCRC treated with cetuximab, and grouped by RAS and BRAF mutation status, were identified. The major outcome measures were hazard ratios (HRs). Pooled HRs were calculated using fixed- or random-effects models, according to the magnitude of the heterogeneity. A total of nine studies met the inclusion criteria. Use of cetuximab was significantly associated with longer OS in KRAS exon 2 wild-type tumors [HR=0.87, 95% confidence interval (CI)=0.79-0.96, Z=2.91, P=0.004] and wild-type KRAS/RAS (in exons 2, 3 and 4 of KRAS and exons 2, 3 and 4 of an associated gene, NRAS; HR=0.72, 95% CI=0.60-0.85, Z=3.74, P=0.0002). No significant differences in OS and PFS were identified between KRAS exon 2 mutations and tumors with the other RAS mutations (in exons 3 and 4 of KRAS and exons 2, 3 and 4 of an associated gene, NRAS). The meta-analysis demonstrated that cetuximab-based chemotherapeutic regimens led to a marked improvement in OS in patients with mCRC who lacked any RAS mutations (either KRAS exon 2 or any other RAS mutation). By contrast, the subgroup analyses revealed no evident PFS or OS benefit in using cetuximab for patients with any RAS mutation. Taken together, the evidence indicates that cetuximab should only be used for mCRC patients with the wild-type RAS gene. Some benefits were observed in patients with wild-type KRAS/BRAF who received cetuximab-based chemotherapy, even though there were insufficient data to perform meta-analysis with the BRAF mutation status.

MicroRNA-320 regulates the radiosensitivity of cervical cancer cells C33AR by targeting ß-catenin.

Cervical cancer is the second most common malignancy in women worldwide and always has recurrence owing to radioresistance. MicroRNA (miRNA or miR) has been identified to relate to the sensitivity of cancer radiotherapy. Here, we investigated the potential of miRNA-320 as a biomarker for radiosensitivity by targeting ß-catenin in cervical cancer. A radioresistant cervical cancer cell line, C33AR, was established, and the radioresistance of C33AR cells was confirmed by a colony-formation assay. The expression of miRNA-320 was detected by reverse transcription-quantitative polymerase chain reaction, and compared between C33A and C33AR. ß-catenin, the target of miRNA-320, was determined at the protein level by western blotting after transfecting the inhibitor of miRNA-320. The expression of miRNA-320 was markedly decreased in C33AR cells, which appeared to be more radioresistant, compared with its parental cell line C33A. Target prediction suggested that miRNA-320 negatively regulated the expression of ß-catenin. Knockdown of ß-catenin increased C33AR radiosensitivity, which revealed that the inhibition of ß-catenin could rescue the miRNA-320-mediated cell radioresistance. On the other hand, overexpressing miRNA-320 increased C33AR radiosensitivity. In conclusion, miRNA-320 regulated the radiosensitivity of C33AR cells by targeting ß-catenin. This finding provides evidence that miRNA-320 may be a potential biomarker of radiosensitivity in cervical cancer.

Extrapleural locating method in computed tomography-guided needle biopsies of 1,106 lung lesions.

Transthoracic needle biopsy is considered to be safe and effective for the diagnosis of focal lung lesions. The aim of the present study was to evaluate factors affecting the accuracy and safety of automated cutting needle lung biopsy (ACNB) using a new extrapleural locating (EPL) method. Computed tomography (CT)-guided needle biopsies were performed on 1,065 patients between March 2005 and May 2012 using the EPL method. The locating needle remained in the chest following extrapleural positioning, while the radiologist confirmed the puncture angle and distance between the locating needle and lesion. The biopsy instrument was advanced into the lung, and the core needle was subsequently fired into the lesion based on the direction indicated by the locating needle. Univariate and multivariate regression analyses were used to evaluate the diagnostic accuracy and safety of the procedure. The sensitivity, specificity, positive predictive value and negative predictive value of the extrapleural method were 91.9, 100, 100 and 82.9%, respectively, and the overall diagnostic accuracy was 94.2%. Significant risk factors affecting accuracy were younger age, atelectasis, hemoptysis and lesion depth (P<0.03). Multivariate logistic regression analysis revealed that the risk of malignant lesions receiving a false-negative diagnosis decreased for each additional year of subject age [odds ratio (OR), 0.97; P=0.027] and increased with each millimeter increase in lesion depth (OR, 1.03; P=0.008). Among the 1,106 lesions biopsied, 207 were associated with pneumothorax, 251 with hemorrhage and 58 with hemoptysis. Multivariate analysis revealed that lesion size and emphysema affected pneumothorax incidence, while age, lesion location and depth and emphysema significantly affected hemorrhage incidence (P<0.05). In conclusion, low-dose, CT-guided ACNB with the EPL method provides a safe and accurate diagnosis.