Journal Articles

Conventional therapies

Immunological effects of conventional cancer therapies such as chemotherapy, radiotherapy or targeted therapy

Stereotactic radiosurgery and immunotherapy in melanoma brain metastases: Patterns of care and treatment outcomes

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PURPOSE: Preclinical studies have suggested that radiation therapy (RT) enhances antitumor immune response and can act synergistically when administered with immunotherapy. However, this effect in melanoma brain metastasis is not well studied. We aim to explore the clinical effect of combining RT and immunotherapy in patients with melanoma brain metastasis (MBM). MATERIALS AND METHODS: Patients with MBM between 2011 and 2013 were obtained from the National Cancer Database. Patients who did not have identifiable sites of metastasis and who did not receive RT for the treatment of their MBM were excluded. Patients were separated into cohorts that received immunotherapy versus patients who did not. Univariable and multivariable analyses were performed using Cox model to determine predictors of OS. Kaplan-Meier method was used to compare OS. Univariable and multivariable analyses using logistic regression model were used to determine the factors predictive for the use of immunotherapy. Propensity score analysis was used to account for differences in baseline patient characteristics between the RT and RT+immunotherapy groups. Significance was defined as a P value

Author Info: (1) Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, United States. (2) Department of Radiation Oncology, Washington University School of Medicine, Saint

Author Info: (1) Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, United States. (2) Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, United States. (3) Division of Oncology, Department of Medicine, Washington University School of Medicine, Saint Louis, United States. (4) Division of Oncology, Department of Medicine, Washington University School of Medicine, Saint Louis, United States. (5) Division of Oncology, Department of Medicine, Washington University School of Medicine, Saint Louis, United States. (6) Department of Neurosurgery, Washington University School of Medicine, Saint Louis, United States. (7) Department of Neurosurgery, Washington University School of Medicine, Saint Louis, United States. (8) Department of Neurosurgery, Washington University School of Medicine, Saint Louis, United States. (9) Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, United States. (10) Department of Neurosurgery, Washington University School of Medicine, Saint Louis, United States. (11) Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, United States. (12) Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, United States. Electronic address: cabraham@wustl.edu.

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It is finally time for adjuvant therapy in melanoma

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Although melanoma is amenable to early detection, there has been no decline in the mortality rate of this disease and the prognosis of patients with high-risk primary melanoma or with macroscopic nodal involvement remains poor. The best option for patients with higher-risk melanoma is to receive effective adjuvant therapy in order to reduce their chances of recurrence. Multiple systemic therapeutic agents have been tested as adjuvant therapy for melanoma with durable benefits seen only with interferon- to date. More recently ipilimumab at the high dose of 10mg/kg has shown a significant improvement in terms of Relapse free survival and Overall survival for stage III melanoma patients but at a significant cost in terms of immune-related toxicities. More recently, novel treatment options have emerged. The results from the latest trials with immunotherapy (PD-1 inhibitors) and molecular targeted therapy (BRAF inhibitor+MEK inhibitor) have revolutionized the management of adjuvant treatment for melanoma. As the results from these trials will mature in the next years, a change in the landscape of adjuvant treatment for melanoma is expected, resulting in new challenges in treatment decisions such as optimizing patients' selection through predictive and prognostic biomarkers, and management of treatment related adverse events, in particular immune related toxicities.

Author Info: (1) Oncologia Medica, Dipartimento di Internistica Clinica e Sperimentale "F. Magrassi", Universita degli Studi della Campania "Luigi Vanvitelli", Via S. Pansini 5, Napoli 80131, Italy

Author Info: (1) Oncologia Medica, Dipartimento di Internistica Clinica e Sperimentale "F. Magrassi", Universita degli Studi della Campania "Luigi Vanvitelli", Via S. Pansini 5, Napoli 80131, Italy. (2) Dermatologia e Venerologia, Dipartimento di salute mentale e fisica e medicina riabilitativa, Universita degli Studi della Campania "Luigi Vanvitelli", Via S. Pansini 5, Napoli 80131, Italy. (3) Dermatologia e Venerologia, Dipartimento di salute mentale e fisica e medicina riabilitativa, Universita degli Studi della Campania "Luigi Vanvitelli", Via S. Pansini 5, Napoli 80131, Italy. (4) Oncologia Medica, Dipartimento di Internistica Clinica e Sperimentale "F. Magrassi", Universita degli Studi della Campania "Luigi Vanvitelli", Via S. Pansini 5, Napoli 80131, Italy. (5) Oncologia Medica, Dipartimento di Internistica Clinica e Sperimentale "F. Magrassi", Universita degli Studi della Campania "Luigi Vanvitelli", Via S. Pansini 5, Napoli 80131, Italy. (6) Oncologia Medica, Dipartimento di Internistica Clinica e Sperimentale "F. Magrassi", Universita degli Studi della Campania "Luigi Vanvitelli", Via S. Pansini 5, Napoli 80131, Italy. (7) Oncologia Medica, Dipartimento di Internistica Clinica e Sperimentale "F. Magrassi", Universita degli Studi della Campania "Luigi Vanvitelli", Via S. Pansini 5, Napoli 80131, Italy. Electronic address: teresa.troiani@unicampania.it.

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Intraperitoneal oxaliplatin administration inhibits the tumor immunosuppressive microenvironment in an abdominal implantation model of colon cancer

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Recent studies have demonstrated that some chemotherapeutic drugs can enhance antitumor immunity by eliminating and inactivating immunosuppressive cells. Oxaliplatin (OXP) induces immunogenic cell death by increasing the immunogenicity of cancer cells. However, the effects of OXP on the tumor immunosuppressive microenvironment remain unclear. The aim of the present study was to evaluate the antitumor activity of OXP by intraperitoneal (i.p.) administration in an abdominal implantation model of colon cancer and tested the tumor immune microenvironment to observe whether OXP affects the local immune inhibitory cell populations. Abdominal metastasis models were established by inoculation of CT26 cells. The antitumor efficacy of OXP and the tumor immune microenvironment were evaluated. The tumors and spleens of mice were harvested for flow cytometric analysis. Cluster of differentiation (CD)8+CD69+ T cells, regulatory T cells (Tregs), CD11b+F4/80high macrophages and myeloidderived suppressor cells (MDSCs) were evaluated by flow cytometric analysis. In vivo i.p. administration of OXP inhibited tumor growth in the abdominal metastasis model. Furthermore, OXP was observed to increase tumorinfiltrating activated CD8+ T cells in tumors, decrease CD11b+F4/80high macrophages in tumors and decrease MDSCs in the spleen. These results suggested that i.p. administration of OXP alone may inhibit tumor cell growth and induce the antitumor immunostimulatory microenvironment by eliminating immunosuppressive cells.

Author Info: (1) Department of Abdominal Cancer, Cancer Center, The State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041

Author Info: (1) Department of Abdominal Cancer, Cancer Center, The State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, P.R. China. (2) Department of Abdominal Cancer, Cancer Center, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, P.R. China. (3) Department of Abdominal Cancer, Cancer Center, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, P.R. China. (4) Department of Hematology, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, P.R. China.

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Inhibition of SRC family kinases facilitates anti-CTLA4 immunotherapy in head and neck squamous cell carcinoma

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The immune system plays a critical role in the establishment, development, and progression of head and neck squamous cell carcinoma (HNSCC). As treatment with single-immune checkpoint agent results in a lower response rate in patients, it is important to investigate new strategies to maintain favorable anti-tumor immune response. Herein, the combination immunotherapeutic value of CTLA4 blockade and SFKs inhibition was assessed in transgenic HNSCC mouse model. Our present work showed that tumor growth was not entirely controlled when HNSCC model mice were administered anti-CTLA4 chemotherapeutic treatment. Moreover, it was observed that Src family kinases (SFKs) were hyper-activated and lack of anti-tumor immune responses following anti-CTLA4 chemotherapeutic treatment. We hypothesized that activation of SFKs is a mechanism of anti-CTLA4 immunotherapy resistance. We, therefore, carried out combined drug therapy using anti-CTLA4 mAbs and an SFKs' inhibitor, dasatinib. As expected, dasatinib and anti-CTLA4 synergistically inhibited tumor growth in Tgfbr1/Pten 2cKO mice. Furthermore, dasatinib and anti-CTLA4 combined to reduce the number of myeloid-derived suppressor cells and Tregs, increasing the CD8(+) T cell-to-Tregs ratio. We also found that combining dasatinib with anti-CTLA4 therapy significantly attenuated the expression of p-STAT3(Y705) and Ki67 in tumoral environment. These results suggest that combination therapy with SFKs inhibitors may be a useful therapeutic approach to increase the efficacy of anti-CTLA4 immunotherapy in HNSCC.

Author Info: (1) The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine, Ministry of Education, School and Hospital

Author Info: (1) The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine, Ministry of Education, School and Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan, 430079, China. (2) The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine, Ministry of Education, School and Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan, 430079, China. (3) The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine, Ministry of Education, School and Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan, 430079, China. (4) The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine, Ministry of Education, School and Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan, 430079, China. (5) The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine, Ministry of Education, School and Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan, 430079, China. Department of Oral Maxillofacial-Head Neck Oncology, School and Hospital of Stomatology, Wuhan University, Wuhan, China. (6) The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine, Ministry of Education, School and Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan, 430079, China. (7) The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine, Ministry of Education, School and Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan, 430079, China. (8) The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine, Ministry of Education, School and Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan, 430079, China. (9) The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine, Ministry of Education, School and Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan, 430079, China. (10) The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine, Ministry of Education, School and Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan, 430079, China. zhangwf59@whu.edu.cn. Department of Oral Maxillofacial-Head Neck Oncology, School and Hospital of Stomatology, Wuhan University, Wuhan, China. zhangwf59@whu.edu.cn. (11) The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine, Ministry of Education, School and Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan, 430079, China. sunzj@whu.edu.cn. Department of Oral Maxillofacial-Head Neck Oncology, School and Hospital of Stomatology, Wuhan University, Wuhan, China. sunzj@whu.edu.cn.

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The Integration of Radiotherapy With Immunotherapy for the Treatment of Non-Small Cell Lung Cancer

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Five-year survival rates for non-small cell lung cancer (NSCLC) range from 14% to 49% for stage I to stage IIIA disease, and are <5% for stage IIIB/IV disease. Improvements have been made in the outcomes of patients with NSCLC due to advancements in radiotherapy (RT) techniques, the use of concurrent chemotherapy with radiation, and the emergence of immunotherapy as first- and second-line treatment in the metastatic setting. RT remains the mainstay treatment in patients with inoperable early-stage NSCLC, and is given concurrently or sequentially with chemotherapy in patients with locally advanced unresectable disease. There is emerging evidence that RT not only provides local tumor control, but may also influence systemic control. Multiple preclinical studies have demonstrated that RT induces immunomodulatory effects in the local tumor microenvironment, supporting a synergistic combination approach with immunotherapy to improve systemic control. Immunotherapy options that could be combined with RT include programmed cell death-1/programmed cell death ligand-1 blockers, as well as investigational agents such as OX-40 agonists, toll-like receptor agonists, indoleamine 2,3-dioxygenase-1 inhibitors, and cytokines. Here, we describe the rationale for the integration of RT and immunotherapy in patients with NSCLC, present safety and efficacy data that support this combination strategy, review planned and ongoing studies, and highlight unanswered questions and future research needs.

Author Info: (1) Radiation Oncology, Weill Cornell Medicine. (2) Radiation Oncology, University of Colorado Denver. (3) Department of Radiation Oncology, Weill Cornell Medicine formenti@med.cornell.edu.

Author Info: (1) Radiation Oncology, Weill Cornell Medicine. (2) Radiation Oncology, University of Colorado Denver. (3) Department of Radiation Oncology, Weill Cornell Medicine formenti@med.cornell.edu.

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ATR kinase inhibitor AZD6738 potentiates CD8+ T cell-dependent antitumor activity following radiation

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DNA damaging chemotherapy and radiation therapy are integrated into the treatment paradigm of the majority of cancer patients. Recently, immunotherapy that targets the immunosuppressive interaction between Programmed Death 1 (PD-1) and its ligand PD-L1 has been approved for malignancies including non-small lung cancer (NSCLC), melanoma, and head and neck squamous cell carcinoma (HNSCC). ATR is a DNA damage signaling kinase activated at damaged replication forks and ATR kinase inhibitors potentiate the cytotoxicity of DNA damaging chemotherapies. We show here that the ATR kinase inhibitor AZD6738 combines with conformal radiation therapy to attenuate radiation-induced CD8+ T cell exhaustion and potentiate CD8+ T cell activity in mouse models of Kras-mutant cancer. Mechanistically, AZD6738 blocks radiation-induced PD-L1 upregulation on tumor cells and dramatically decreases the number of tumor-infiltrating T regulatory (Treg) cells. Remarkably, AZD6738 combines with conformal radiation therapy to generate immunologic memory in complete responder mice. Our work raises the exciting possibility that a single pharmacologic agent may enhance the cytotoxic effects of radiation while concurrently potentiating radiation-induced antitumor immune responses.

Author Info: (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) (14) (15) (16)

Author Info: (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) (14) (15) (16)

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Complete Local and Abscopal Responses from a Combination of Radiation and Nivolumab in Refractory Hodgkin's Lymphoma

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Until recently, patients with relapsed Hodgkin's lymphoma after brentuximab vedotin (Bv) treatments had poor treatment outcomes. Checkpoint inhibitors such as nivolumab and pembrolizumab that bind to and inhibit programmed cell death protein-1 (PD-1), have demonstrated an overall response rate of 70% in Hodgkin's lymphoma patients; however, complete response is still low at 20% with median progression-free survival of 14 months. There are ongoing clinical studies to seek out synergistic combinations, with the goal of improving the complete response rates for the cure of Hodgkin's lymphoma. Although radiotherapy has a limited survival benefit in such refractory patients, several preclinical models and anecdotal clinical evidence have suggested that combining local tumor irradiation with checkpoint inhibitors can produce systemic regression of distant tumors, an abscopal effect. Most of these reported studies on the response with local conformal radiotherapy and checkpoint inhibitors in combination with the anti-cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) antibody-ipilimumab are in melanoma. Here we report that the checkpoint inhibitors that block CTLA4 and B7-homolog 1 (B7-H1) or PD-1 in preclinical radiotherapy models have shown an increased the rate of tumor regression. Our case series demonstrates that combining local irradiation with anti-PD-1 checkpoint blockade treatment is feasible and synergistic in refractory Hodgkin's lymphoma. Correlative studies also suggest that the expression of programmed death-ligand 1 (PD-L1), DNA damage response and mutational tumor burden can be used as potential biomarkers for treatment response.

Author Info: (1) Department of a Internal Medicine, Houston Methodist Research Institute, Houston, Texas 77030. (2) Department of a Internal Medicine, Houston Methodist Research Institute, Houston, Texas

Author Info: (1) Department of a Internal Medicine, Houston Methodist Research Institute, Houston, Texas 77030. (2) Department of a Internal Medicine, Houston Methodist Research Institute, Houston, Texas 77030. (3) b Department of Pathology and Genomic Medicine, Houston Methodist Research Institute, Houston, Texas 77030. (4) c Department of Radiology, Houston Methodist Research Institute, Houston, Texas (5) d Department of Radiation Oncology, Houston Methodist Research Institute, Houston, Texas 77030. (6) f Department of Medical Oncology, University of Toledo Medical Center, Toledo, Ohio, 43614. (7) d Department of Radiation Oncology, Houston Methodist Research Institute, Houston, Texas 77030. (8) Department of a Internal Medicine, Houston Methodist Research Institute, Houston, Texas 77030. f Department of Medical Oncology, University of Toledo Medical Center, Toledo, Ohio, 43614. (9) d Department of Radiation Oncology, Houston Methodist Research Institute, Houston, Texas 77030. (10) d Department of Radiation Oncology, Houston Methodist Research Institute, Houston, Texas 77030. (11) d Department of Radiation Oncology, Houston Methodist Research Institute, Houston, Texas 77030. (12) Department of a Internal Medicine, Houston Methodist Research Institute, Houston, Texas 77030. e Houston Methodist Cancer Center, Houston Methodist Research Institute, Houston, Texas 77030. g University of Texas MD Anderson Cancer Center, Houston, Texas 77030.

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A Syngeneic Pancreatic Cancer Mouse Model to Study the Effects of Irreversible Electroporation

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Pancreatic cancer (PC), a disease which kills approximately 40,000 patients each year in the US, has successfully evaded several therapeutic approaches including the promising immunotherapeutic strategies. Irreversible electroporation (IRE) is a non-thermal ablation technique that induces tumor cell death without destruction of adjacent collagenous structures, thus enabling the procedure to be performed in tumors very close to blood vessels. Unlike thermal ablation techniques, IRE results in gradual apoptotic cell death, along with immediate ablation induced necrosis, and is currently in clinical use for selected patients with locally advanced PC. An ablative, non-target specific procedure like IRE can induce a myriad of responses in the tumor microenvironment. A few studies have addressed the effects of IRE on tumor growth in other tumor types, but none have focused on PC. We have developed a syngeneic mouse model of PC in which subcutaneous (SQ) and orthotopic tumors can be successfully treated with IRE in a highly controlled setting, facilitating various longitudinal studies post procedure. This animal model serves as a robust system to study the effects of IRE and ways to improve the clinical efficacy of IRE.

Author Info: (1) Moores Cancer Center, University California San Diego. (2) Moores Cancer Center, University California San Diego. (3) Duke University School of Medicine. (4) Moores Cancer

Author Info: (1) Moores Cancer Center, University California San Diego. (2) Moores Cancer Center, University California San Diego. (3) Duke University School of Medicine. (4) Moores Cancer Center, University California San Diego; rewhite@ucsd.edu.

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Fever-Inspired Immunotherapy Based on Photothermal CpG Nanotherapeutics: The Critical Role of Mild Heat in Regulating Tumor Microenvironment

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Although there have been more than 100 clinical trials, CpG-based immunotherapy has been seriously hindered by complications in the immunosuppressive microenvironment of established tumors. Inspired by the decisive role of fever upon systemic immunity, a photothermal CpG nanotherapeutics (PCN) method with the capability to induce an immunofavorable tumor microenvironment by casting a fever-relevant heat (43 degrees C) in the tumor region is developed. High-throughput gene profile analysis identifies nine differentially expressed genes that are closely immune-related upon mild heat, accompanied by IL-6 upregulation, a pyrogenic cytokine usually found during fever. When treated with intratumor PCN injection enabling mild heating in the tumor region, the 4T1 tumor-bearing mice exhibit significantly improved antitumor immune effects compared with the control group. Superb efficacy is evident from pronounced apoptotic cell death, activated innate immune cells, enhanced tumor perfusion, and intensified innate and adaptive immune responses. This work highlights the crucial role of mild heat in modulating the microenvironment in optimum for improved immunotherapy, by converting the tumor into an in situ vaccine.

Author Info: (1) Shanghai East Hospital The Institute for Biomedical Engineering and Nano Science Tongji University School of Medicine Shanghai 200092 P. R. China. (2) Shanghai East

Author Info: (1) Shanghai East Hospital The Institute for Biomedical Engineering and Nano Science Tongji University School of Medicine Shanghai 200092 P. R. China. (2) Shanghai East Hospital The Institute for Biomedical Engineering and Nano Science Tongji University School of Medicine Shanghai 200092 P. R. China. (3) Shanghai East Hospital The Institute for Biomedical Engineering and Nano Science Tongji University School of Medicine Shanghai 200092 P. R. China. (4) Shanghai East Hospital The Institute for Biomedical Engineering and Nano Science Tongji University School of Medicine Shanghai 200092 P. R. China. (5) School of Materials Science and Engineering Tongji University 4800 Caoan Road Shanghai 201804 P. R. China. (6) School of Life Science and Technology Tongji University 1239 Siping Road Shanghai 200092 P. R. China. (7) School of Materials Science and Engineering Tongji University 4800 Caoan Road Shanghai 201804 P. R. China. (8) Shanghai East Hospital The Institute for Biomedical Engineering and Nano Science Tongji University School of Medicine Shanghai 200092 P. R. China. The Materials Science and Engineering Program Department of Mechanical and Materials Engineering College of Engineering and Applied Science University of Cincinnati Cincinnati OH 45221 USA. (9) Shanghai East Hospital The Institute for Biomedical Engineering and Nano Science Tongji University School of Medicine Shanghai 200092 P. R. China.

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Whole Blood Gene Expression Profiling in patients undergoing colon cancer surgery identifies differential expression of genes involved in immune surveillance, inflammation and carcinogenesis

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INTRODUCTION: Cancer surgery may represent a potential risk of enhanced growth and metastatic ability of residual cancer cells due to post-operative immune dysfunction. This study identifies changes in transcription of genes involved in immune surveillance, immune suppression and carcinogenesis in the post-operative period of laparoscopic colon-cancer surgery within an ERAS regime. METHODS: Patients undergoing elective, curatively intended laparoscopic surgery for colon cancer stage I-III UICC were included in the study. Patients followed standard of care in an ERAS setting. Whole blood gene expression profiling (WBGP) was performed on the day prior to surgery and 1, 2, 3 and 10-14 days after surgery. Samples were collected in Paxgene tubes and Labeled cDNA was fragmented and hybridized to Affymetrix GeneChip 2.0. Results were corrected for multiple hypothesis testing using the false discovery rate. Pathway analysis was performed through the Molecular Signature Database. Paired fold changes of gene expression were calculated for post-operative compared to pre-operative samples. A mixed effect model was used to test differential gene expression by repeated-measures ANOVA. RESULTS: WBGP of 33,804 genes at five timepoints in six patients showed 302 significantly differentially expressed genes between samples from the day prior to surgery and the day after surgery. Pathway gene enrichment analysis showed a downregulation of immunologically relevant pathways. There was a significant downregulation of genes involved in T-cell receptor signaling, antigen presentation and NK-cell activity after surgery. Furthermore, there was an upregulation of cytokines related to metastatic ability, growth and angiogenesis. CONCLUSION: Whole blood gene expression profiling revealed dysregulation of genes involved in immune surveillance, inflammation and carcinogenesis, after laparoscopic colon cancer surgery.

Author Info: (1) Zealand University Hospital, Department of Surgery, Sygehusvej 10, 4000 Roskilde, Denmark. Electronic address: sakw@regionsjaelland.dk. (2) Zealand University Hospital, Department of Hematology, Sygehusvej 10, 400

Author Info: (1) Zealand University Hospital, Department of Surgery, Sygehusvej 10, 4000 Roskilde, Denmark. Electronic address: sakw@regionsjaelland.dk. (2) Zealand University Hospital, Department of Hematology, Sygehusvej 10, 4000 Roskilde, Denmark. (3) Zealand University Hospital, Department of Hematology, Sygehusvej 10, 4000 Roskilde, Denmark. (4) Zealand University Hospital, Department of Hematology, Sygehusvej 10, 4000 Roskilde, Denmark. (5) Odense University Hospital, Department of Clinical Genetics, Denmark. (6) Odense University Hospital, Department of Clinical Genetics, Denmark. (7) Odense University Hospital, Department of Clinical Genetics, Denmark. (8) Zealand University Hospital, Department of Surgery, Sygehusvej 10, 4000 Roskilde, Denmark; Institute for Clinical Medicine, Copenhagen University and Danish Colorectal Cancer Group, Copenhagen, Denmark.

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