Impact of 5-Fu/oxaliplatin on mouse dendritic cells and synergetic effect with a colon cancer vaccine.

OBJECTIVE: The aim of the present study was to investigate the effects of 5-fluorouracil (5-Fu) and oxaliplatin on the function and activation pathways of mouse dendritic cells (DCs), and to clarify whether 5-Fu/oxaliplatin combined with the CD1d-MC38/α-galactosylceramide (α-GC) tumor vaccine exhibits synergistic effects on the treatment of colon cancer in mice. METHODS: The combination of the Toll like receptor (TLR) ligands and/or 5-Fu/oxaliplatin was added into myeloid-derived DCs in vitro culture. DC phenotypic changes were detected by flow cytometry, and the secretion of DC cytokines was detected by cytometric bead array (CBA). A MC38 mouse colon cancer model was constructed and the DCs were isolated from the spleen, tumor tissue and lymph nodes following intraperitoneal injection of 5-Fu/oxaliplatin. The cell phenotypes were detected by flow cytometry. The tumor infiltrating leukocytes, splenocytes and lymph node cells were co-cultured with the dead MC38 tumor cells, and the secretion levels of interferon-γ (IFN-γ) were detected. 5-Fu/oxaliplatin combined with our previously developed CD1d-MC38/α-GC tumor vaccine was used to inhibit the growth of MC38 colon cancer in mice, and the tumor growth rate and survival time were recorded. RESULTS: 5-Fu/oxaliplatin exerted no significant effect on the expression of the stimulating phenotypes of DCs in vitro, while it could reduce the expression of programmed death ligand 1/2 (PD-L1/L2) and promote interleukin-12 (IL-12) secretion by DCs. Furthermore 5-Fu/oxaliplatin was beneficial to the differentiation of T-helper 1 (Th1) cells. 5-Fu/oxaliplatin further enhanced the stimulating phenotypic expression of DCs in tumor bearing mice, decreased PD-L1/L2 expression, and specifically activated the lymphocytes. The CD1d-MC38/α-GC tumor vaccine combined with 5-Fu/oxaliplatin could exert a synergistic role that resulted in a significant delay of the tumor growth rate, and an increase in the survival time of tumor bearing mice. CONCLUSIONS: 5-Fu/oxaliplatin decreased the expression of the DC inhibitory phenotypes PD-L1/L2, promoted DC phenotypic maturation in tumor bearing mice, activated the lymphocytes of tumor bearing mice, and exerted synergistic effects with the CD1d-MC38/α-GC colon cancer tumor vaccine.

Co-operation of α-galactosylceramide-loaded tumour cells and TLR9 agonists induce potent anti-tumour responses in a murine colon cancer model.

Dendritic cells (DCs) and invariant natural killer T (iNKT) cells play important roles in linking innate immunity and adaptive immunity. Mature DCs activated by Toll-like receptor (TLR) agonists directly activate iNKT cells and the iNKT ligand α-galactosylceramide (α-Galcer) can induce DC maturation, resulting in enhanced protective immune responses. In the present study, we aimed to boost anti-tumour immunity in a murine colon cancer model by synergizing DCs and iNKT cells using α-Galcer-loaded tumour cells (tumour-Gal) and the TLR9 agonist cytosine-phosphorothioate-guanine (CpG1826). The vaccine strategy was sufficient to inhibit growth of established tumours and prolonged survival of tumour-bearing mice. Importantly, the immunization induced an adaptive memory immune response as the survivors from primary tumour inoculations were resistant to a tumour re-challenge. Furthermore, injection of tumour-Gal with CpG1826 resulted in iNKT cell activation and DC maturation as defined by interferon (IFN)-γ secretion by iNKT, natural killer (NK) cells and interleukin (IL)-12 by DCs. Immunohistochemistry analysis revealed that cluster of differentiation (CD)4(+) T-cells and CD8(+) T-cells played important roles in anti-tumour immunity. Additionally, the vaccine redirected Th2 (T-helper cell type 2) responses toward Th1 (T-helper cell type 1) responses with increases in IL-2, IFN-γ expression and decreases in IL-4 and IL-5 expression after immunization with tumour-Gal with CpG1826. Taken together, our results demonstrated a novel vaccination by synergizing tumour-Gal and CpG1826 against murine colon cancer, which can be further developed as tumour-specific immunotherapy against human cancer.

Clinical assessment of cerebral hemodynamics in Moyamoya disease via multiple inversion time arterial spin labeling and dynamic susceptibility contrast-magnetic resonance imaging: A comparative study.

BACKGROUND AND PURPOSE: For Moyamoya disease (MMD) patients, accurate hemodynamic assessment is critical for treatment selection and efficacy assessment. This study aims to investigate the clinical value of mTI-ASL in assessing the cerebral hemodynamics of MMD patients before and after revascularization, relative to DSC-MRI. MATERIALS AND METHODS: Forty-one MMD patients underwent mTI-ASL and DSC-MRI during blood perfusion. Quantitative parameters for the bilateral supply vessels of middle and anterior cerebral arteries, including DSC-TTP, DSC-CBF, ASL-BAT, and ASL-CBF were measured. The correlations between DSC-ΔTTP (TTPhemisphere - TTPbrainstem) and ASL-ΔBAT (BAThemisphere - BATbrainstem) and between DSC-CBF and ASL-CBF were determined. The consistency between the two techniques in assessing the cerebral ischemic state before and after revascularization was analyzed. RESULTS: DSC-ΔTTP and ASL-ΔBAT (r=0.36, P<0.001) and DSC-CBF and ASL-CBF (r=0.32, P<0.001) exhibited significant correlation on 824 regions of interest (ROIs) and similar numbers of ischemic areas on 902 ROIs (κ=0.82, P<0.001). The ischemic scores were 3.17±3.02 and 2.98±2.81 by DSC-MRI and ASL-MRI, respectively (ICC=0.92). For 15 surgically treated patients, the scores for blood perfusion improvement on the operated side were 3.13±1.68 and 3.27±1.33 with DSC-TTP and ASL-BAT, respectively (ICC=0.94). CONCLUSION: Compared to DSC-MRI, mTI-ASL can assess the cerebral hemodynamics in MMD and evaluate ischemic state before revascularization and ischemia reduction after revascularization effectively. And mTI-ASL is more advantageous because it does not require contrast agents.

Self-expandable metallic stent as a bridge to elective surgery versus emergency surgery for acute malignant colorectal obstruction.

BACKGROUD: The efficacy and safety of self-expandable metallic stents (SEMSs) as a bridge for patients with acute malignant colorectal obstructions (AMCOs) are still controversial. We conducted this study to evaluate the outcomes of patients with AMCOs treated by different strategies. METHODS: From January 2010 to March 2014, a total of 171 patients with AMCOs from Zhongshan Hospital were retrospectively enrolled in this study. One hundred twenty patients successfully received stent placement followed by one-stage laparoscopic or open resection in the stent group, and 51 patients received emergency operations in the emergency group. RESULTS: The operation duration and postoperative hospital stay were significantly shorter in the stent group (114.51 ± 28.65 vs. 160.39 ± 58.94 min, P < 0.001; 8.00 ± 3.97 vs. 12.59 ± 9.07 days, P = 0.001). The stent group also had significantly reduced intraoperative blood loss and the incidence of postoperative complications compared with the emergency group (61.00 ± 43.70 vs. 121.18 ± 85.90 ml, P < 0.001; 16.7 vs. 37.3%, P = 0.003). Kaplan-Meier survival curves showed that the median survival time in the stent group was significantly longer than that in the emergency group (53 vs. 41 months, P = 0.034). In subgroup analysis of stent group, the stent laparoscopy group had significantly decreased postoperative complications (P = 0.025), and similar long-term survival (P = 0.81). CONCLUSIONS: Stent placement as a bridge to surgery is a safe and feasible procedure and provides significant advantages in terms of short-term outcomes and favorable prognoses for patients with AMCOs. Laparoscopic surgery could be considered as an optimal treatment after stent placement.

Synergistical toll-like receptors activated dendritic cells induce antitumor effects against carcinoembryonic antigen-expressing colon cancer.

PURPOSE: Dendritic cell (DC)-based cancer vaccine represents a promising immunotherapy against cancer. There has been recent evidence which have suggested that toll-like receptor (TLR) ligands may be critical for DC preparation; this was usually omitted in the past. Our study is designed to investigate if the vaccination of synergistical toll-like receptors activated DCs can induce more potent cytotoxic T Lymphocytes (CTL) responses and antitumor activity in carcinoembryonic antigen (CEA) transgenic mouse tumor models. METHODS: We involved combination of TLR3 and TLR7/8 ligands in culture protocol of DCs. The DCs' surface molecules expression, IL-12 secretion and proliferation capacity of lymphocytes were tested. We also investigate the CTL activity against MC38-CEA colon tumor cells and the prophylactic and therapeutic effects of DC vaccination in subcutaneous mouse colon tumor models. RESULTS: Compared with conventionally generated DCs, we showed synergistic TLR-activated DCs exhibited higher surface molecule expression, significantly higher secretion of IL-12 and more potent proliferating capacity of lymphocytes. Synergistic TLR-activated DCs were also able to induce lymphocytes possessing the specific cytotoxicity against MC38-CEA cells in vitro. Vaccination with CEA epitope pulsed TLR-activated DCs elicited antigen-specific preventive effect on MC38-CEA tumors, but failed to cure the tumor-bearing mice, that may be due to the suboptimal epitope selected and host immunosuppression. CONCLUSIONS: Our results have proved that combined activation of TLRs can lead to better maturation status of DCs and also induce more effective antitumor immune responses against colon cancer, suggesting this may be a potential strategy to develop more powerful DC cancer vaccines.

Tumor cell stemness in gastrointestinal cancer: regulation and targeted therapy.

The cancer stem cells are a rare group of self-renewable cancer cells capable of the initiation, progression, metastasis and recurrence of tumors, and also a key contributor to the therapeutic resistance. Thus, understanding the molecular mechanism of tumor stemness regulation, especially in the gastrointestinal (GI) cancers, is of great importance for targeting CSC and designing novel therapeutic strategies. This review aims to elucidate current advancements in the understanding of CSC regulation, including CSC biomarkers, signaling pathways, and non-coding RNAs. We will also provide a comprehensive view on how the tumor microenvironment (TME) display an overall tumor-promoting effect, including the recruitment and impact of cancer-associated fibroblasts (CAFs), the establishment of an immunosuppressive milieu, and the induction of angiogenesis and hypoxia. Lastly, this review consolidates mainstream novel therapeutic interventions targeting CSC stemness regulation.

Functions and mechanisms of cytosolic phospholipase A2 in central nervous system trauma.

Central nervous system (CNS) trauma, including traumatic brain injury and spinal cord injury, has a high rate of disability and mortality, and effective treatment is currently lacking. Previous studies have revealed that neural inflammation plays a vital role in CNS trauma. As the initial enzyme in neuroinflammation, cytosolic phospholipase A2 (cPLA2) can hydrolyze membranous phosphatides at the sn-2 position in a preferential way to release lysophospholipids and ω3-polyunsaturated fatty acid dominated by arachidonic acid, thereby inducing secondary injuries. Although there is substantial fresh knowledge pertaining to cPLA2, in-depth comprehension of how cPLA2 participates in CNS trauma and the potential methods to ameliorate the clinical results after CNS trauma are still insufficient. The present review summarizes the latest understanding of how cPLA2 participates in CNS trauma, highlighting novel findings pertaining to how cPLA2 activation initiates the potential mechanisms specifically, neuroinflammation, lysosome membrane functions, and autophagy activity, that damage the CNS after trauma. Moreover, we focused on testing a variety of drugs capable of inhibiting cPLA2 or the upstream pathway, and we explored how those agents might be utilized as treatments to improve the results following CNS trauma. This review aimed to effectively understand the mechanism of cPLA2 activation and its role in the pathophysiological processes of CNS trauma and provide clarification and a new referential framework for future research.

Short-Term and Long-Term Outcomes in Mid and Low Rectal Cancer With Robotic Surgery.

OBJECTIVE: To investigate the risk factors for postoperative complications and anastomotic leakage after robotic surgery for mid and low rectal cancer and their influence on long-term outcomes. METHODS: A total of 641 patients who underwent radical mid and low rectal cancer robotic surgery at Zhongshan Hospital Fudan University from January 2014 to December 2018 were enrolled in this study. The clinicopathological factors of the patients were collected. The risk factors for short-term outcomes of complications and anastomotic leakage were analyzed, and their influences on recurrence and overall survival were studied. RESULTS: Of the 641 patients, 516 (80.5%) underwent AR or LAR procedures, while 125 (19.5%) underwent the NOSES procedure. Only fifteen (2.3%) patients had stoma diversion. One hundred and seventeen patients (17.6%) experienced surgical complications. Anastomotic leakage occurred in 44 patients (6.9%). Eleven patients (1.7%) underwent reoperation within 90 days after surgery. Preoperative radiotherapy did not significantly increase anastomotic leakage in our study (7.4% vs. 6.8%, P = 0.869). The mean postoperative hospital stay was much longer with complication (10.4 vs. 7.1 days, P<0.05) and leakage (12.9 vs. 7.4 days, P < 0.05). Multivariate analysis showed that male sex (OR = 1.855, 95% CI: 1.175-2.923, P < 0.05), tumor distance 5 cm from the anus (OR = 1.563, 95% CI: 1.016-2.404, P < 0.05), and operation time length (OR = 1.563, 95% CI: 1.009-2.421, P < 0.05) were independent risk factors for complications in mid and low rectal cancer patients. The same results for anastomotic leakage: male sex (OR = 2.247, 95% CI: 1.126-4.902, P < 0.05), tumor distance 5 cm from the anus (OR = 2.242, 95% CI: 1.197-4.202, P < 0.05), and operation time length (OR = 2.114, 95% CI: 1.127-3.968, P < 0.05). The 3-year DFS and OS were 82.4% and 92.6% with complication, 88.4% and 94.0% without complication, 88.6% and 93.1% with leakage, and 87.0% and 93.8% without leakage, respectively. The complication and anastomotic leakage showed no significant influences on long-term outcomes. CONCLUSION: Being male, having a lower tumor location, and having a prolonged operation time were independent risk factors for complications and anastomotic leakage in mid and low rectal cancer. Complications and anastomotic leakage might have no long-term impact on oncological outcomes for mid and low rectal cancer with robotic surgery.

Reprogramming immunosuppressive myeloid cells by activated T cells promotes the response to anti-PD-1 therapy in colorectal cancer.

Overcoming local immunosuppression is critical for immunotherapy to produce robust anti-tumor responses. Myeloid-derived suppressor cells (MDSCs) are key regulators of immunosuppressive networks and promote tumor progression. However, it remains unclear whether and how tumor-infiltrating MDSCs are shaped in response to anti-PD-1 treatment and what their impact on therapeutic efficacy is in colorectal cancer (CRC). In this study, the levels of infiltrating MDSCs were significantly higher in the non-responding organoids and were selectively reduced in the responding group, with MDSCs showing increased apoptosis and attenuated functional activity after anti-PD-1 treatment. A negative correlation between T-cell activation and MDSC function was also observed in fresh human CRC tissues. Mechanistic studies revealed that autocrine IFN-α/ß upregulated TRAIL expression on activated T cells to elicit MDSC apoptosis via the TRAIL-DR5 interaction and acted synergistically with TNF-α to inhibit MDSC function of suppressing the T-cell response through the JNK-NMDAR-ARG-1 pathway. Moreover, blockade of IFN-α/ß and TNF-α abolished the therapeutic efficacy of anti-PD-1 treatment by preserving the frequency and suppressive activity of infiltrating MDSCs in a CRC mouse model. This result suggested that reprogramming MDSCs by IFN-α/ß and TNF-α from activated T cells was necessary for successful anti-PD-1 treatment and might serve as a novel strategy to improve the response and efficacy of anticancer therapy.

Retinoic Acid Synthesis Deficiency Fosters the Generation of Polymorphonuclear Myeloid-Derived Suppressor Cells in Colorectal Cancer.

Metabolism is reprogrammed in cancer to fulfill the demands of malignant cells for cancer initiation and progression. Apart from its effects within cancer cells, little is known about whether and how reprogramed metabolism regulates the surrounding tumor microenvironment (TME). Myeloid-derived suppressor cells (MDSC) are key regulators of the TME and greatly affect tumor progression and therapeutic responses. In this study, our results revealed that retinol metabolism-related genes and enzymes were significantly downregulated in human colorectal cancer compared with adjacent colonic tissues, and tumors exhibited a defect in retinoic acid (RA) synthesis. Reduced ADH1-mediated retinol metabolism was associated with attenuated RA signaling and accumulated MDSCs in colorectal cancer tumors. Using an in vitro model, generating MDSCs from CD34+ myeloid precursors, we found that exogenous RA could abrogate the generation of polymorphonuclear MDSCs (PMN-MDSC) with negligible impact on myeloid differentiation. Mechanistically, RA could restrain the glycolytic capacity of myeloid cells, which in turn activated the AMP-activated protein kinase (AMPK) pathway, further impairing the suppressive capacity of myeloid cells. Supplementation with RA could significantly delay tumor growth, with reduced arginase-1-expressing myeloid cells and increased CD8+ and granzyme B+ T cells in both colitis-associated and implanted MC38 mouse colorectal cancer models. Our results indicated that the defect in ADH1-mediated RA synthesis could provide a possible mechanism that fosters the generation of PMN-MDSCs in colorectal cancer and that restoring RA signaling in the TME could serve as a promising therapeutic strategy to abrogate the generation of PMN-MDSCs.

Tough synthetic spider-silk fibers obtained by titanium dioxide incorporation and formaldehyde cross-linking in a simple wet-spinning process.

Due to its unique mechanical properties, spider silk shows great promise as a strong super-thin fiber in many fields. Although progress has been made in the field of synthesizing spider-silk fiber from recombinant spidroin (spider silk protein) in the last few decades, methods to obtain synthetic spider-silk fibers as tough as natural silk from small-sized recombinant protein with a simple spinning process have eluded scientists. In this paper, a recombinant spidroin (MW: 93.4 kDa) was used to spin tough synthetic spider-silk fibers with a simple wet-spinning process. Titanium oxide incorporation and formaldehyde cross-linking were used to improve the mechanical properties of synthetic spider-silk fibers. Fibers treated with incorporation or/and cross-linking varied in microstructure, strength and extensibility while all exhibited enhanced strength and toughness. In particular, one fiber possessed a toughness of 249 ± 22 MJ/m3. This paper presents a new method to successfully spin tough spider-silk fibers in a simple way.

Tensile properties of synthetic pyriform spider silk fibers depend on the number of repetitive units as well as the presence of N- and C-terminal domains.

Spiders can spin seven different types of silk, some of which are well characterized, but studies on natural and synthetic pyriform silks are few. In this study, recombinant spidroins composed of one to three pyriform repeat units from Araneus ventricosus, in some cases flanked with non-repetitive N- and C-terminal domains (NT and CT), were produced and spun into continuous silk fibers using a wet-spinning process in organic solvents. All the fibers showed high and similar tensile strain (60-80%), but the Young's modulus, stress and toughness of fibers increased with increasing number of repeat units and in the presence of NT and CT as well. Systematic studies of the secondary structure contents of the different spinning dopes and spun fibers revealed no major differences between the different types of recombinant spidroins. This suggests that optimal tensile properties of artificial spider silks require the presence of several repetitive units as well as terminal domains and that secondary structure content of silk dope and fibers have limited correlation with mechanical behaviors.

Glutamine Deprivation Promotes the Generation and Mobilization of MDSCs by Enhancing Expression of G-CSF and GM-CSF.

Solid tumors are often challenged by hypoxic and nutrient-deprived tumor microenvironments (TME) as tumors progress, due to limited perfusion and rapid nutrient consumption. While cancer cells can demonstrate the ability to survive in nutrient-deprived conditions through multiple intrinsic alterations, it is poorly understood how nutrient-deprived cancer cells co-opt the TME to promote cancer cell survival and tumor progression. In the present study, we found that glutamine deprivation markedly potentiated the expression of G-CSF and GM-CSF in mouse mammary cancer cells. The IRE1α-JNK pathway, which is activated by glutamine starvation, was found to be important for the upregulation of these cytokines. G-CSF and GM-CSF are well-known facilitators of myelopoiesis and mobilization of hematopoietic progenitor cells (HPC). Consistently, as tumors progressed, we found that several myeloid HPC compartments were gradually decreased in the bone marrow but were significantly increased in the spleen. Mechanistically, the HPC-maintaining capacity of the bone marrow was significantly impaired in tumor-bearing mice, with lower expression of HPC maintaining genes (i.e., CXCL12, SCF, ANGPT1, and VCAM1), and reduced levels of mesenchymal stem cells and CXCL12-producing cells. Furthermore, the mobilized HPCs that displayed the capacity for myelopoiesis were also found to accumulate in tumor tissue. Tumor-infiltrating HPCs were highly proliferative and served as important sources of immunosuppressive myeloid-derived suppressor cells (MDSCs) in the TME. Our work has identified an important role for glutamine starvation in regulating the expression of G-CSF and GM-CSF, and in facilitating the generation of immunosuppressive MDSCs in breast cancer.

Macrophages induce CD47 upregulation via IL-6 and correlate with poor survival in hepatocellular carcinoma patients.

CD47 is known to be involved in phagocyte-mediated tumor clearance; however, its expression, clinical significance, and regulatory mechanism in hepatocellular carcinoma (HCC) remain poorly understood. In the present study, we found that upregulation of CD47 expression on tumor cells was correlated with poor overall survival and recurrence-free survival in patients with HCC. Abundance of macrophages (Mϕs) infiltration was found in CD47+ tumor tissues. Mechanistic studies revealed that IL-6 derived from tumor-infiltrating Mϕs could upregulate CD47 expression on hepatoma cells through activation of the STAT3 pathway. Neutralization of CD47 or disruption of the IL-6-STAT3 axis reduced the ability of tumor cells to escape phagocytosis. Moreover, CD47 blockade could enhance Mϕ-mediated phagocytosis in the presence of chemotherapeutic drugs, and HCC patients with lower CD47 expression were more likely to benefit from adjuvant transcatheter arterial chemoembolization (TACE) treatment. These findings revealed that Mϕ-derived IL-6 was responsible for CD47 expression on hepatoma cells, which might be served as a potential prognostic marker and a predictor for patients who might benefit from adjuvant TACE treatment.

Differences in clinical characteristics and mutational pattern between synchronous and metachronous colorectal liver metastases.

PURPOSE: To investigate differences in clinical characteristics and mutational patterns between synchronous and metachronous colorectal liver metastases (CLMs). PATIENTS AND METHODS: From June 2008 to December 2014, patients with RAS wild-type CLMs treated at Zhongshan Hospital, Fudan University were included. DNA extracted from formalin-fixed paraffin-embedded tissue of primary tumors was sequenced with next-generation sequencing for single-nucleotide polymorphism of 96 genes according to custom panel. Mutations were compared between synchronous and metachronous liver metastases and correlated with clinical characteristics. RESULTS: A total of 161 patients were included: 93 patients with synchronous CLM and 68 patients with metachronous CLM. Patients with metachronous CLM were obviously elder. For pathology of primary tumors, synchronous CLMs were larger in size, poorly differentiated, and more frequently local advanced and lymph node positive. For evaluation of liver metastases, synchronous CLM had more and larger metastatic lesions. The median number of mutations in synchronous CLMs was significantly higher than in metachronous group (22 vs. 18, p<0.001). EGFR rs2227983 is the most prevalent mutation in both groups and only a part of prevalent mutations is shared in both groups. Prevalent mutations were correlated with many clinical characteristics. EGFR rs2227983, RBMXL3 rs12399211, and PTCH1 rs357564 were prognostic for latency of metachronous CLM. CONCLUSION: Clinically, synchronous CLMs, compared with metachronous CLMs, were younger and showed heavier tumor burden for both primaries and liver metastases. Genetically, we identified different mutational patterns between synchronous and metachronous CLMs and several correlations between mutations and clinical characteristics. Further researches were needed to confirm these potential key mutations of CLMs.

Patients with RAS wild-type right-sided unresectable liver-confined mCRC also benefit from cetuximab plus chemotherapy in first-line treatment.

Growing evidence indicates that primary tumor location of metastatic colorectal cancer (mCRC) can affect response to specific therapy. This study aimed to assess the impact of primary tumor location on efficacy of cetuximab in Chinese patients with mCRC. We included patients with RAS wild-type liver-limited mCRC treated with first-line cetuximab plus chemotherapy or chemotherapy alone between June 2008 and December 2016. All patients were categorized as having left-sided tumors or right-sided tumors. Progression free survival (PFS), overall survival (OS), objective response rate (ORR) and conversion rate of surgery for liver metastases was analyzed according to tumor location and treatment. Right-sided tumors were characterized with larger primary tumor, poorer differentiation, more lymph node metastases and larger and more liver metastases. For patients with left-sided tumors (N=233), addition of cetuximab to chemotherapy significantly improved ORR (68.9% vs. 30.6%, OR=5.01, P < 0.001), conversion rate of liver surgery (33.5% vs. 10.8%, OR=4.18, P < 0.001), PFS (12.1 months vs. 6.1 months, HR=0.42, P < 0.001), and OS (not evaluable vs. 23.1 months, HR=0.31, P < 0.001). Among patients with right-sided tumors (N=85), cetuximab plus chemotherapy, compared with chemotherapy alone, also significantly improved ORR (56.8% vs. 29.3%, OR=3.18, P=0.010), PFS (9.3 months vs. 5.1 months, OR=0.57, P=0.012) and OS (25.3 months vs. 16.8 months, HR=0.56, P=0.032) but conversion rate of liver surgery (20.5% vs. 9.8%, HR=2.38, P=0.171). Our results demonstrated differential effect of cetuximab on efficacy outcomes based on tumor sidedness. Also, we found that patients with right-sided tumors also benefit from cetuximab plus chemotherapy but not as great as left-sided tumors and in general, did worse. In conclusion, findings of previous studies about differential effect of anti-EGFR therapy based on tumor sidedness are applicable to an Asian population.

Progress on development and application of the diet-related inflammatory index in cancer epidemiological studies / 中华流行病学杂志

Cancer is a major public health problem worldwide, causing an more serious burden of disease. Inflammation is considered a predisposing factor for cancer with close relationship with its incidence. In recent years, the public and epidemiologists has paid more attention to the association between nutrition and cancer and other chronic diseases in the perspective of inflammation. This paper summarizes the development and application of the diet-related inflammatory index in cancer epidemiological studies based on the literature retrieval of common diet-related inflammatory index. Firstly, we highlight the common diet-related inflammatory indices and their construction methods, such as the Dietary Inflammatory Index, a literature-derived diet-related inflammatory index, and the Empirical Dietary Inflammatory Index, an empirically derived diet-related inflammatory index, and so on. Secondly, the epidemiological research progress on the commonly used diet-related inflammatory indices is briefly introduced. Finally, the advantages and disadvantages of the two types of this inflammatory indices are also briefly described for the purpose of providing reference for nutrition epidemiological studies of cancer and other chronic diseases in China.

Additional Biomarkers beyond RAS That Impact the Efficacy of Cetuximab plus Chemotherapy in mCRC: A Retrospective Biomarker Analysis.

PURPOSE: We aimed to identify new predictive biomarkers for cetuximab in first-line treatment for patients with RAS wild-type metastatic colorectal cancer (mCRC). METHODS: The study included patients with KRAS wild-type unresectable liver-limited mCRC treated with chemotherapy with or without cetuximab. Next-generation sequencing was done for single nucleotide polymorphism according to custom panel. Potential predictive biomarkers were identified and integrated into a predictive model within a training cohort. The model was validated in a validation cohort. RESULTS: Thirty-one of 247(12.6%) patients harbored RAS mutations. In training cohort (N=93), six potential predictive genes, namely, ATP6V1B1, CUL9, ERBB2, LY6G6D, PTCH1, and RBMXL3, were identified. According to predictive model, patients were divided into responsive group (n=66) or refractory group (n=27). In responsive group, efficacy outcomes were significantly improved by addition of cetuximab to chemotherapy. In refractory group, no benefit was observed. Interaction test was significant across all endpoints. In validation cohort (N=123), similar results were also observed. CONCLUSIONS: In the first-line treatment of mCRC, the predictive model integrating six new predictive mutations divided patients well, indicating a promising approach to further refine patient selection for cetuximab on the basis of RAS mutations.

Statistical methods for relative risk estimation and applications in case-cohort study / 中华流行病学杂志

Objective: To systematically introduce the design of case-cohort study and the statistical methods of relative risk estimation and their application in the design. Methods: First, we introduced the basic principles of case-cohort study design. Secondly, Prentice's method, Self-Prentice method and Barlow method were described in the weighted Cox proportional hazard regression models in detail, finally, the data from the Shanghai Women's Health Study were used as an example to analyze the association between obesity and liver cancer incidence in the full cohort and case-cohort sample, and the results of parameters from each method were compared. Results: Significant association was observed between obesity and risk for liver cancer incidence in women in both the full cohort and the case-cohort sample. In the Cox proportional hazard regression model, the partial regression coefficients of the full cohort and the case-cohort sample fluctuated with the adjustment of confounding factors, but the hazard ratio estimates of them were close. There was a difference in the standard error of the partial regression coefficient between the full cohort and the case-cohort sample. The standard error of the partial regression coefficient of the case-cohort sample was larger than that of the full cohort, resulting in a wider 95% confidence interval of the relative risk. In the weighted Cox proportional hazard regression model, the standard error of the partial regression coefficient of Prentice's method was closer to the parameter estimates from full cohort than Self-Prentice method and Barlow method, and the 95% confidence interval of hazard ratio was closer to that of the full cohort. Conclusions: Case-cohort design could yield parameter results closer to the full cohort by collecting and analyzing data from sub-cohort members and patients with the disease, and reduce sample size and improve research efficiency. The results suggested that Prentice's method would be preferred in case-cohort design.

Ribosomal protein S15A promotes malignant transformation and predicts poor outcome in colorectal cancer through misregulation of p53 signaling pathway.

Ribosomal protein S15A (RPS15A), which has been identified as a highly conserved 40S ribosomal protein, is essential for cell survival and proliferation. The present study evaluated the functional role of RPS15A in colorectal cancer (CRC), and our investigation found that RPS15A was highly expressed in a cohort of human CRC. High RPS15A expression was associated with older age (P=0.035), not receiving preoperative neoadjuvant treatment (P=0.048), higher primary pN stage (P=0.007) and slightly more synchronous distant metastases (P=0.058). The Cox univariate and multivariate hazard regression analysis revealed that higher expression of RPS15A led to a reduction of overall survival rate in CRC, indicating that enhanced RPS15A expression functions as an independent risk factor for the prognosis of CRC patients (P<0.001). Cell based analysis showed that RPS15A was widely expressed in human CRC cell lines. Knockdown of RPS15A significantly suppressed cell proliferation and colony formation in HCT116 and DLD-1 cells, and induced cell cycle arrest at G0/G1 phase. Genechip analysis suggested that knockdown of RPS15A might affect the p53 signaling pathway. Further study indicated that RPS15A knockdown upregulated p53 and p21 expression whereas downregulated CDK1 expression. In summary, the present study identified RPS15A as a novel univariate prognostic factor predicting a poor outcome in CRC patients. The RPS15A overexpression induced by malignant transformation of CRC might function through the p53 signaling pathway.