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O'Connell F, Mylod E, Donlon NE, Davern M, Butler C, O'Connor N, Menon MS, Donohoe CL, Ravi N, Doherty DG, Dunne MR, Reynolds JV, Roche HM, O'Sullivan J. Adipose tissue from oesophageal adenocarcinoma patients is differentially affected by chemotherapy and chemoradiotherapy regimens altering immune cell phenotype and cancer cell metabolism. Transl Oncol 2025; 53:102302. [PMID: 39965288 DOI: 10.1016/j.tranon.2025.102302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 01/17/2025] [Accepted: 01/30/2025] [Indexed: 02/20/2025] Open
Abstract
Oesophageal adenocarcinoma (OAC) is a poor prognosis cancer with limited responses to standard of care treatments including chemotherapy and chemoradiotherapy. OAC has one of the strongest associations with obesity, its anatomical location surrounded by visceral adipose tissue has been postulated to intensify this association. Adipose tissue is a regulatory organ with many unknown downstream functions, including its direct response to chemotherapy and radiotherapy. To elucidate the role of visceral adipose tissue in this disease state, metabolic and secreted pro-inflammatory cytokines analysis was conducted on human ex-vivo adipose tissue explants following exposure to FLOT-chemotherapy and CROSS-chemoradiotherapy. To assess how these complex treated microenvironments impact cancer cell metabolism, dendritic cell, and macrophage phenotype, mitochondrial bioenergetics and surface markers expression were examined using seahorse technology and flow cytometry respectively. This study observed that chemotherapy and chemoradiotherapy differentially alter adipose tissue metabolism and secretome, with chemoradiotherapy increasing pro-inflammatory associated mediators (p<0.05). The chemoradiotherapy-treated adipose secretome increased cancer cell spare respiratory capacity and dendritic cell adhesion markers (p<0.05). In contrast, the chemotherapy-treated adipose microenvironment enhanced mitochondrial dysfunction in cancer cells, increasing their reliance on glycolysis and enhancing pro-inflammatory marker expression on LPS-primed macrophages (p<0.05). This study for the first time demonstrates how adipose tissue, and its microenvironment can be significantly impacted by chemotherapy and chemoradiotherapy. These alterations in the adipose secretome in response to therapeutic regimens elicited distinct effects on immune cell phenotype and cancer cells metabolism, raising the question, does the wider tumour microenvironment including the adipose milieu mitigate the efficacy of current treatments.
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Affiliation(s)
- Fiona O'Connell
- Department of Surgery, Trinity St. James's Cancer Institute and Trinity Translational Medicine Institute, St. James's Hospital and Trinity College Dublin, D08 W9RT Dublin, Ireland
| | - Eimear Mylod
- Department of Surgery, Trinity St. James's Cancer Institute and Trinity Translational Medicine Institute, St. James's Hospital and Trinity College Dublin, D08 W9RT Dublin, Ireland; Cancer Immunology and Immunotherapy Group, Department of Surgery, Trinity College Dublin, St. James's Hospital, D08 W9RT Dublin, Ireland
| | - Noel E Donlon
- Department of Surgery, Trinity St. James's Cancer Institute and Trinity Translational Medicine Institute, St. James's Hospital and Trinity College Dublin, D08 W9RT Dublin, Ireland; Cancer Immunology and Immunotherapy Group, Department of Surgery, Trinity College Dublin, St. James's Hospital, D08 W9RT Dublin, Ireland
| | - Maria Davern
- Department of Surgery, Trinity St. James's Cancer Institute and Trinity Translational Medicine Institute, St. James's Hospital and Trinity College Dublin, D08 W9RT Dublin, Ireland; Cancer Immunology and Immunotherapy Group, Department of Surgery, Trinity College Dublin, St. James's Hospital, D08 W9RT Dublin, Ireland
| | - Christine Butler
- Department of Surgery, Trinity St. James's Cancer Institute and Trinity Translational Medicine Institute, St. James's Hospital and Trinity College Dublin, D08 W9RT Dublin, Ireland
| | - Niamh O'Connor
- Department of Surgery, Trinity St. James's Cancer Institute and Trinity Translational Medicine Institute, St. James's Hospital and Trinity College Dublin, D08 W9RT Dublin, Ireland
| | - Meghana S Menon
- Department of Surgery, Trinity St. James's Cancer Institute and Trinity Translational Medicine Institute, St. James's Hospital and Trinity College Dublin, D08 W9RT Dublin, Ireland
| | - Claire L Donohoe
- Department of Surgery, Trinity St. James's Cancer Institute and Trinity Translational Medicine Institute, St. James's Hospital and Trinity College Dublin, D08 W9RT Dublin, Ireland
| | - Narayanasamy Ravi
- Department of Surgery, Trinity St. James's Cancer Institute and Trinity Translational Medicine Institute, St. James's Hospital and Trinity College Dublin, D08 W9RT Dublin, Ireland
| | - Derek G Doherty
- Department of Immunology, School of Medicine, Trinity College Dublin, Trinity Translational Medicine Institute, St. James's Hospital, Dublin, Ireland
| | - Margaret R Dunne
- Department of Surgery, Trinity St. James's Cancer Institute and Trinity Translational Medicine Institute, St. James's Hospital and Trinity College Dublin, D08 W9RT Dublin, Ireland
| | - John V Reynolds
- Department of Surgery, Trinity St. James's Cancer Institute and Trinity Translational Medicine Institute, St. James's Hospital and Trinity College Dublin, D08 W9RT Dublin, Ireland
| | - Helen M Roche
- Nutrigenomics Research Group, UCD Conway Institute, School of Public Health, Physiotherapy and Sports Science, University College Dublin, D04 C1P1 Dublin, Ireland; Institute for Global Food Security, School of Biological Sciences, Queens University Belfast, Belfast BT9 5DL, UK
| | - Jacintha O'Sullivan
- Department of Surgery, Trinity St. James's Cancer Institute and Trinity Translational Medicine Institute, St. James's Hospital and Trinity College Dublin, D08 W9RT Dublin, Ireland
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Xia F, Wang Y, Wang H, Shen L, Xiang Z, Zhao Y, Zhang H, Wan J, Zhang H, Wang Y, Wu R, Wang J, Yang W, Zhou M, Zhou S, Chen Y, Zhang Z, Wu X, Xuan Y, Wang R, Sun Y, Tong T, Zhang X, Wang L, Huang D, Sheng W, Yan H, Yang X, Shen Y, Xu Y, Zhao R, Mo M, Cai G, Cai S, Xu Y, Zhang Z. Randomized Phase II Trial of Immunotherapy-Based Total Neoadjuvant Therapy for Proficient Mismatch Repair or Microsatellite Stable Locally Advanced Rectal Cancer (TORCH). J Clin Oncol 2024; 42:3308-3318. [PMID: 38950321 DOI: 10.1200/jco.23.02261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 01/17/2024] [Accepted: 04/17/2024] [Indexed: 07/03/2024] Open
Abstract
PURPOSETo assess whether the integration of PD-1 inhibitor with total neoadjuvant therapy (iTNT) can lead to an improvement in complete responses (CRs) and favors a watch-and-wait (WW) strategy in patients with proficient mismatch repair or microsatellite stable (pMMR/MSS) locally advanced rectal cancer (LARC).PATIENTS AND METHODSWe conducted a prospective, multicenter, randomized, open-label, phase II trial using a pick-the-winner design. Eligible patients with clinical T3-4 and/or N+ rectal adenocarcinoma were randomly assigned to group A for short-course radiotherapy (SCRT) followed by six cycles of consolidation immunochemotherapy with capecitabine and oxaliplatin and toripalimab or to group B for two cycles of induction immunochemotherapy followed by SCRT and the rest four doses. Either total mesorectal excision or WW was applied on the basis of tumor response. The primary end point was CR which included pathological CR (pCR) after surgery and clinical CR (cCR) if WW was applicable, with hypothesis of an increased CR of 40% after iTNT compared with historical data of 25% after conventional TNT.RESULTSOf the 130 patients enrolled, 121 pMMR/MSS patients were evaluable (62 in group A and 59 in group B). At a median follow-up of 19 months, CR was achieved at 56.5% in group A and 54.2% in group B. Both groups fulfilled the predefined statistical hypothesis (P < .001). Both groups reported a pCR rate of 50%. Respectively, 15 patients in each group underwent WW and remained disease free. The most frequent grade 3 to 4 toxicities were thrombocytopenia and neutropenia. Patients in group A had higher rate of cCR (43.5% v 35.6%) at restaging and lower rate of grade 3 to 4 thrombocytopenia (24.2% v 33.9%) during neoadjuvant treatment.CONCLUSIONThe iTNT regimens remarkably improved CR rates in pMMR/MSS LARC compared with historical benchmark with acceptable toxicity. Up-front SCRT followed by immunochemotherapy was selected for future definitive study.
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Affiliation(s)
- Fan Xia
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yaqi Wang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Hui Wang
- Department of Oncology, Tianjin Union Medical Center, Nankai University, Tianjin, China
| | - Lijun Shen
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Zuolin Xiang
- Department of Radiation Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Yutian Zhao
- Department of Radiation Oncology, The Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Huojun Zhang
- Department of Radiation Oncology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Juefeng Wan
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Hui Zhang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yan Wang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Ruiyan Wu
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Jingwen Wang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Wang Yang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Menglong Zhou
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Shujuan Zhou
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yajie Chen
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Zhiyuan Zhang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xian Wu
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yan Xuan
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Renjie Wang
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Yiqun Sun
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Department of Radiology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Tong Tong
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Department of Radiology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Xun Zhang
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Department of Medical Ultrasound, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Lei Wang
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
- Institute of Pathology, Fudan University, Shanghai, China
| | - Dan Huang
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
- Institute of Pathology, Fudan University, Shanghai, China
| | - Weiqi Sheng
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
- Institute of Pathology, Fudan University, Shanghai, China
| | - Hao Yan
- Department of Oncology, Tianjin Union Medical Center, Nankai University, Tianjin, China
| | - Xu Yang
- Department of Radiation Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Yuxin Shen
- Department of Radiation Oncology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Yu Xu
- Department of Radiation Oncology, The Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Ruping Zhao
- Department of Radiation Oncology, Jia Hui International Hospital, Shanghai, China
- Department of Radiotherapy, Shuguang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai, China
| | - Miao Mo
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Department of Cancer Prevention, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Guoxiang Cai
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Sanjun Cai
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Ye Xu
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Zhen Zhang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
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Chen H, Zhang JH, Hao Q, Wu XL, Guo JX, Huang CX, Zhang J, Xing GS, An ZL, Ling Y, Zhao JG, Bao YN. Analysis of tumor microenvironment alterations in partially responsive rectal cancer patients treated with neoadjuvant chemoradiotherapy. Int J Colorectal Dis 2024; 39:99. [PMID: 38926205 PMCID: PMC11208236 DOI: 10.1007/s00384-024-04672-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/15/2024] [Indexed: 06/28/2024]
Abstract
PURPOSE Achieving a pathologic complete response (pCR) after neoadjuvant chemoradiotherapy (NCRT) remains a challenge for most patients with rectal cancer. Exploring the potential of combining NCRT with immunotherapy or targeted therapy for those achieving a partial response (PR) offers a promising avenue to enhance treatment efficacy. This study investigated the impact of NCRT on the tumor microenvironment in locally advanced rectal cancer (LARC) patients who exhibited a PR. METHODS This was a retrospective, observational study. Five patients demonstrating a PR after neoadjuvant treatment for LARC were enrolled in the study. Biopsy samples before treatment and resected specimens after treatment were stained with a panel of 26 antibodies targeting various immune and tumor-related markers, each labeled with distinct metal tags. The labeled samples were then analyzed using the Hyperion imaging system. RESULTS Heterogeneity within the tumor microenvironment was observed both before and after NCRT. Notably, tumor-associated macrophages, CD4 + T cells, CD8 + T cells, CD56 + natural killer cells, tumor-associated neutrophils, cytokeratin, and E-cadherin exhibited slight increase in abundance within the tumor microenvironment following treatment (change ratios = 0.78, 0.2, 0.27, 0.32, 0.17, 0.46, 0.32, respectively). Conversely, the number of CD14 + monocytes, CD19 + B cells, CD45 + CD4 + T cells, collagen I, α-smooth muscle actin, vimentin, and β-catenin proteins displayed significant decreases post-treatment (change ratios = 1.73, 1.92, 1.52, 1.25, 1.52, 1.12, 2.66, respectively). Meanwhile, Foxp3 + regulatory cells demonstrated no significant change (change ratio = 0.001). CONCLUSIONS NCRT has diverse effects on various components of the tumor microenvironment in LARC patients who achieve a PR after treatment. Leveraging combination therapies may optimize treatment outcomes in this patient population.
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Affiliation(s)
- Hong Chen
- Affiliated Hospital of Inner Mongolia Medical University, Hohhot, 010050, China
| | - Ji-Hong Zhang
- Department of Radiotherapy, Affiliated Hospital of Inner Mongolia Medical University, Hohhot, 010050, China
| | - Qin Hao
- Department of Gastrointestinal Surgery, Affiliated Hospital of Inner Mongolia Medical University, Hohhot, 010050, China
| | - Xin-Lin Wu
- Department of Gastrointestinal Surgery, Affiliated Hospital of Inner Mongolia Medical University, Hohhot, 010050, China
| | - Jia-Xing Guo
- Department of Radiotherapy, Affiliated Hospital of Inner Mongolia Medical University, Hohhot, 010050, China
| | - Cong-Xiu Huang
- Department of Radiotherapy, Affiliated Hospital of Inner Mongolia Medical University, Hohhot, 010050, China
| | - Jun Zhang
- Department of Radiotherapy, Affiliated Hospital of Inner Mongolia Medical University, Hohhot, 010050, China
| | - Guo-Sheng Xing
- Department of Gastrointestinal Surgery, Affiliated Hospital of Inner Mongolia Medical University, Hohhot, 010050, China
| | - Zhi-Lin An
- Department of Radiotherapy, Affiliated Hospital of Inner Mongolia Medical University, Hohhot, 010050, China
| | - Yu Ling
- Department of Radiotherapy, Affiliated Hospital of Inner Mongolia Medical University, Hohhot, 010050, China
| | - Jian-Guo Zhao
- Department of Radiotherapy, Affiliated Hospital of Inner Mongolia Medical University, Hohhot, 010050, China
| | - Ying-Na Bao
- Department of Radiotherapy, Affiliated Hospital of Inner Mongolia Medical University, Hohhot, 010050, China.
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Li Z, Ge H, Xie Y, Zhang Y, Zhao X, Sun W, Song M. Luteolin inhibits angiogenesis and enhances radiotherapy sensitivity of laryngeal cancer via downregulating Integrin β1. Tissue Cell 2023; 85:102235. [PMID: 37826960 DOI: 10.1016/j.tice.2023.102235] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 10/05/2023] [Accepted: 10/05/2023] [Indexed: 10/14/2023]
Abstract
AIM To demonstrate the role and mechanism of luteolin in radio-sensitization and angiogenesis of laryngeal cancer. METHODS Firstly, we analyzed the cytotoxicity of Luteolin and radiation sensitive cytotoxicity through CCK8, and selected subsequent radiation doses and Luteolin concentrations. Next, we further analyzed the effects of Luteolin on radiation sensitivity and neovascularization of laryngeal cancer, and conducted CCK8, plate cloning, and angiogenesis experiments, respectively. At the same time, the effects of individual treatment and combination treatment on the expression of Integrin β1 and VEGFA were analyzed through immunofluorescence analysis. We also analyzed the regulation of Integrin β1 protein expression by Luteolin through Western blot. To investigate the mechanism of Integrin β1, we transfected overexpressed and silenced Integrin β1 vectors and analyzed the role of Integrin β1 in Luteolin enhancing radiation sensitivity of laryngeal cancer by repeating the above experiments. We have also constructed an in vivo subcutaneous tumor transplantation model to further validate the cell experimental results. The expression of Integrin, KI67, VEGFA, and CD31 was analyzed through Western blot and immunohistochemistry experiments. RESULTS Radiation inhibited cell proliferation and decreased Integrin β1 expression, and increased the radiosensitivity through inhibiting cell proliferation, and inhibit angiogenesis during radiation. Overexpression of Integrin β1 weakened radiotherapy sensitivity on the basis of cells treated with combined administration. Integrin β1 is considered as the downstream molecule of luteolin, participating in radiosensitivity of luteolin to FaDu cells. Animal experiments also demonstrated that luteolin strengthened tumor suppression and anti-angiogenesis during radiation via Integrin β1. CONCLUSION In summary, our results manifested that radio-sensitivity effect of luteolin depended on downregulating Integrin β1 in laryngocarcinoma.
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Affiliation(s)
- Zhen Li
- Department of Otorhinolaryngology, Yantaishan Hospital, Yantai, Shandong, China
| | - Hongzhou Ge
- Department of Otorhinolaryngology, Qingdao Traditional Chinese Medicine Hospital (Qingdao Hiser Hospital) Qingdao Hiser Hospital Affiliated of Qingdao University, Qingdao, Shandong, China
| | - Yonggang Xie
- Department of Anesthesiology, The Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, China
| | - Yueqin Zhang
- Department of Otorhinolaryngology, Yantaishan Hospital, Yantai, Shandong, China
| | - Xiaoyan Zhao
- Department of Otorhinolaryngology, Yantaishan Hospital, Yantai, Shandong, China
| | - Wen Sun
- Department of Otorhinolaryngology, Yantaishan Hospital, Yantai, Shandong, China
| | - Meiyan Song
- Administrative Department, Yantaishan Hospital, Yantai, Shandong, China.
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Jeon SH, Song C, Eom KY, Kim IA, Kim JS. Modulation of CD8 + T Cell Responses by Radiotherapy-Current Evidence and Rationale for Combination with Immune Checkpoint Inhibitors. Int J Mol Sci 2023; 24:16691. [PMID: 38069014 PMCID: PMC10706388 DOI: 10.3390/ijms242316691] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 11/17/2023] [Accepted: 11/22/2023] [Indexed: 12/18/2023] Open
Abstract
Radiotherapy for cancer has been known to affect the responses of immune cells, especially those of CD8+ T cells that play a pivotal role in anti-tumor immunity. Clinical success of immune checkpoint inhibitors led to an increasing interest in the ability of radiation to modulate CD8+ T cell responses. Recent studies that carefully analyzed CD8+ T cell responses following radiotherapy suggest the beneficial roles of radiotherapy on anti-tumor immunity. In addition, numerous clinical trials to evaluate the efficacy of combining radiotherapy with immune checkpoint inhibitors are currently undergoing. In this review, we summarize the current status of knowledge regarding the changes in CD8+ T cells following radiotherapy from various preclinical and clinical studies. Furthermore, key biological mechanisms that underlie such modulation, including both direct and indirect effects, are described. Lastly, we discuss the current evidence and essential considerations for harnessing radiotherapy as a combination partner for immune checkpoint inhibitors.
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Affiliation(s)
| | | | | | | | - Jae-Sung Kim
- Department of Radiation Oncology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam 13620, Republic of Korea; (S.H.J.); (C.S.); (K.-Y.E.); (I.A.K.)
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Sartorius D, Blume ML, Fleischer JR, Ghadimi M, Conradi LC, De Oliveira T. Implications of Rectal Cancer Radiotherapy on the Immune Microenvironment: Allies and Foes to Therapy Resistance and Patients' Outcome. Cancers (Basel) 2023; 15:5124. [PMID: 37958298 PMCID: PMC10650490 DOI: 10.3390/cancers15215124] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Revised: 10/16/2023] [Accepted: 10/19/2023] [Indexed: 11/15/2023] Open
Abstract
Aside from surgical resection, locally advanced rectal cancer is regularly treated with neoadjuvant chemoradiotherapy. Since the concept of cancer treatment has shifted from only focusing on tumor cells as drivers of disease progression towards a broader understanding including the dynamic tumor microenvironment (TME), the impact of radiotherapy on the TME and specifically the tumor immune microenvironment (TIME) is increasingly recognized. Both promoting as well as suppressing effects on anti-tumor immunity have been reported in response to rectal cancer (chemo-)radiotherapy and various targets for combination therapies are under investigation. A literature review was conducted searching the PubMed database for evidence regarding the pleiotropic effects of (chemo-)radiotherapy on the rectal cancer TIME, including alterations in cytokine levels, immune cell populations and activity as well as changes in immune checkpoint proteins. Radiotherapy can induce immune-stimulating and -suppressive alterations, potentially mediating radioresistance. The response is influenced by treatment modalities, including the dosage administered and the highly individual intrinsic pre-treatment immune status. Directly addressing the main immune cells of the TME, this review aims to highlight therapeutical implications since efficient rectal cancer treatment relies on personalized strategies combining conventional therapies with immune-modulating approaches, such as immune checkpoint inhibitors.
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Affiliation(s)
| | | | | | | | - Lena-Christin Conradi
- Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Robert-Koch-Straβe 40, 37075 Göttingen, Germany; (D.S.); (M.L.B.); (J.R.F.); (M.G.)
| | - Tiago De Oliveira
- Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Robert-Koch-Straβe 40, 37075 Göttingen, Germany; (D.S.); (M.L.B.); (J.R.F.); (M.G.)
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Kozin SV. Vascular damage in tumors: a key player in stereotactic radiation therapy? Trends Cancer 2022; 8:806-819. [PMID: 35835699 DOI: 10.1016/j.trecan.2022.06.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 05/23/2022] [Accepted: 06/01/2022] [Indexed: 11/17/2022]
Abstract
The use of stereotactic radiation therapy (SRT) for cancer treatment has grown in recent years, showing excellent results for some tumors. The greatly increased doses per fraction in SRT compared to conventional radiotherapy suggest a 'new biology' that determines treatment outcome. Proposed mechanisms include significant damage to tumor blood vessels and enhanced antitumor immune responses, which are also vasculature-dependent. These ideas are mostly based on the results of radiation studies in animal models because direct observations in humans are limited. However, even preclinical findings are somewhat incomplete and result in ambiguous conclusions. Current evidence of vasculature-related mechanisms of SRT is reviewed. Understanding them could result in better optimization of SRT alone or in combination with immune or other cancer therapies.
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Affiliation(s)
- Sergey V Kozin
- Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
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Shamseddine A, Zeidan YH, El Husseini Z, Kreidieh M, Al Darazi M, Turfa R, Kattan J, Khalifeh I, Mukherji D, Temraz S, Alqasem K, Amarin R, Al Awabdeh T, Deeba S, Jamali F, Mohamad I, Elkhaldi M, Daoud F, Al Masri M, Dabous A, Hushki A, Jaber O, Charafeddine M, Geara F. Efficacy and safety-in analysis of short-course radiation followed by mFOLFOX-6 plus avelumab for locally advanced rectal adenocarcinoma. Radiat Oncol 2020; 15:233. [PMID: 33028346 PMCID: PMC7542723 DOI: 10.1186/s13014-020-01673-6] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Accepted: 09/24/2020] [Indexed: 01/04/2023] Open
Abstract
Background Neoadjuvant chemotherapy and short-course radiotherapy followed by resection has been gaining recognition in the treatment of rectal cancer. Avelumab is a fully human immunoglobulin that binds Programmed Death-Ligand 1 (PD-L1) and prevents the suppression of the cytotoxic T cell immune response. This phase II trial evaluates the safety and pathologic response rate of short-course radiation followed by 6 cycles of mFOLFOX6 with avelumab in patients with locally advanced rectal cancer (LARC).
Methods This study is prospective single-arm, multicenter phase II trial adopting Simon’s two-stage. Short-course radiation is given over 5 fractions to a total dose of 25 Gy. mFOLFOX6 plus avelumab (10 mg/kg) are given every 2 weeks for 6 cycles. Total mesorectal excision is performed 3–4 weeks after the last cycle of avelumab. Follow up after surgery is done every 3 months to a total of 36 months. Adverse event data collection is recorded at every visit. Results 13 out of 44 patients with LARC were enrolled in the first stage of the study (30% from total sample size). All patients met the inclusion criteria and received the full short-course radiation course followed by 6 cycles of mFOLFOX6 plus avelumab. 12 out of the 13 patients completed TME while one patient had progression of disease and was dropped out of the study. The sample consisted of 9 (69%) males and 4 (31%) females with median age of 62 (33–73) years. The first interim analysis revealed that 3 (25%) patients achieved pathologic complete response (pCR) (tumor regression grade, TRG 0) out of 12. While 3 (25%) patients had near pCR with TRG 1. In total, 6 out of 12 patients (50%) had a major pathologic response. All patients were found to be MMR proficient. The protocol regimen was well tolerated with no serious adverse events of grade 4 reported. Conclusion In patients with LARC, neoadjuvant radiation followed by mFOLFOX6 with avelumab is safe with a promising pathologic response rate. Trial Registration Number and Date of Registration ClinicalTrials.gov NCT03503630, April 20, 2018. https://clinicaltrials.gov/ct2/show/NCT03503630?term=NCT03503630&draw=2&rank=1.
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Affiliation(s)
- Ali Shamseddine
- Division of Hematology/Oncology, Department of Internal Medicine, Naef K. Basile Cancer Institute - NKBCI, American University of Beirut Medical Center, Beirut, Lebanon.
| | - Youssef H Zeidan
- Department of Radiation Oncology, American University of Beirut Medical Center, Beirut, Lebanon
| | - Ziad El Husseini
- Division of Hematology/Oncology, Department of Internal Medicine, Naef K. Basile Cancer Institute - NKBCI, American University of Beirut Medical Center, Beirut, Lebanon
| | - Malek Kreidieh
- Division of Hematology/Oncology, Department of Internal Medicine, Naef K. Basile Cancer Institute - NKBCI, American University of Beirut Medical Center, Beirut, Lebanon
| | - Monita Al Darazi
- Division of Hematology/Oncology, Department of Internal Medicine, Naef K. Basile Cancer Institute - NKBCI, American University of Beirut Medical Center, Beirut, Lebanon
| | - Rim Turfa
- Division of Hematology/Oncology, Department of Internal Medicine, King Hussein Cancer Center, Amman, Jordan
| | - Joseph Kattan
- Department of Hematology/Oncology, Hotel-Dieu de France University Hospital, Beirut, Lebanon
| | - Ibrahim Khalifeh
- Department of Pathology and Laboratory Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Deborah Mukherji
- Division of Hematology/Oncology, Department of Internal Medicine, Naef K. Basile Cancer Institute - NKBCI, American University of Beirut Medical Center, Beirut, Lebanon
| | - Sally Temraz
- Division of Hematology/Oncology, Department of Internal Medicine, Naef K. Basile Cancer Institute - NKBCI, American University of Beirut Medical Center, Beirut, Lebanon
| | - Kholoud Alqasem
- Division of Hematology/Oncology, Department of Internal Medicine, King Hussein Cancer Center, Amman, Jordan
| | - Rula Amarin
- Division of Hematology/Oncology, Department of Internal Medicine, King Hussein Cancer Center, Amman, Jordan
| | - Tala Al Awabdeh
- Division of Hematology/Oncology, Department of Internal Medicine, King Hussein Cancer Center, Amman, Jordan
| | - Samer Deeba
- Division of General Surgery, Department of Surgery, American University of Beirut Medical Center, Beirut, Lebanon
| | - Faek Jamali
- Division of General Surgery, Department of Surgery, American University of Beirut Medical Center, Beirut, Lebanon
| | - Issa Mohamad
- Department of Radiation Oncology, King Hussein Cancer Center, Amman, Jordan
| | - Mousa Elkhaldi
- Department of Radiation Oncology, King Hussein Cancer Center, Amman, Jordan
| | - Faiez Daoud
- Department of Surgical Oncology, King Hussein Cancer Center, Amman, Jordan
| | - Mahmoud Al Masri
- Department of Surgical Oncology, King Hussein Cancer Center, Amman, Jordan
| | - Ali Dabous
- Department of Surgical Oncology, King Hussein Cancer Center, Amman, Jordan
| | - Ahmad Hushki
- Division of Gastroenterology, Department of Internal Medicine, King Hussein Cancer Center, Amman, Jordan
| | - Omar Jaber
- Department of Pathology, King Hussein Cancer Center, Amman, Jordan
| | - Maya Charafeddine
- Division of Hematology/Oncology, Department of Internal Medicine, Naef K. Basile Cancer Institute - NKBCI, American University of Beirut Medical Center, Beirut, Lebanon
| | - Fady Geara
- Department of Radiation Oncology, American University of Beirut Medical Center, Beirut, Lebanon
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9
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Shamseddine A, Zeidan YH, Kreidieh M, Khalifeh I, Turfa R, Kattan J, Mukherji D, Temraz S, Alqasem K, Amarin R, Al Awabdeh T, Deeba S, Jamali F, Mohamad I, Elkhaldi M, Daoud F, Al Masri M, Dabous A, Hushki A, Jaber O, Khoury C, El Husseini Z, Charafeddine M, Al Darazi M, Geara F. Short-course radiation followed by mFOLFOX-6 plus avelumab for locally-advanced rectal adenocarcinoma. BMC Cancer 2020; 20:831. [PMID: 32873251 PMCID: PMC7466814 DOI: 10.1186/s12885-020-07333-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Accepted: 08/24/2020] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Current standard practice for locally advanced rectal cancer (LARC) entails a multidisciplinary approach that includes preoperative chemoradiotherapy, followed by total mesorectal excision, and then adjuvant chemotherapy. The latter has been accompanied by low compliance rates and no survival benefit in phase III randomized trials, so the strategy of administering neoadjuvant, rather than adjuvant, chemotherapy has been adapted by many trials, with improvement in pathologic complete response. Induction chemotherapy with oxaliplatin has been shown to have increased efficacy in rectal cancer, while short-course radiation therapy with consolidation chemotherapy increased short-term overall survival rate and decreased toxicity levels, making it cheaper and more convenient than long-course radiation therapy. This led to recognition of total neoadjuvant therapy as a valid treatment approach in many guidelines despite limited available survival data. With the upregulation (PDL-1) expression in rectal tumors after radiotherapy and the increased use of in malignant melanoma, the novel approach of combining immunotherapy with chemotherapy after radiation may have a role in further increasing pCR and improving overall outcomes in rectal cancer. METHODS The study is an open label single arm multi- center phase II trial. Forty-four recruited LARC patients will receive 5Gy x 5fractions of SCRT, followed by 6 cycles of mFOLFOX-6 plus avelumab, before TME is performed. The hypothesis is that the addition of avelumab to mFOLFOX-6, administered following SCRT, will improve pCR and overall outcomes. The primary outcome measure is the proportion of patients who achieve a pCR, defined as no viable tumor cells on the excised specimen. Secondary objectives are to evaluate 3-year progression-free survival, tumor response to treatment (tumor regression grades 0 & 1), density of tumor-infiltrating lymphocytes, correlation of baseline Immunoscore with pCR rates and changes in PD-L1 expression. DISCUSSION Recent studies show an increase in PD-L1 expression and density of CD8+ TILs after CRT in rectal cancer patients, implying a potential role for combinatory strategies using PD-L1- and programmed-death- 1 inhibiting drugs. We aim through this study to evaluate pCR following SCRT, followed by mFOLFOX-6 with avelumab, and then TME procedure in patients with LARC. TRIAL REGISTRATION Trial Registration Number and Date of Registration: ClinicalTrials.gov NCT03503630, April 20, 2018.
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Affiliation(s)
- Ali Shamseddine
- Department of Internal Medicine, Division of Hematology/Oncology, Naef K. Basile Cancer Institute- NKBCI, American University of Beirut Medical Center, Beirut, Lebanon.
| | - Youssef H Zeidan
- Department of Radiation Oncology, American University of Beirut Medical Center, Beirut, Lebanon
| | - Malek Kreidieh
- Department of Internal Medicine, Division of Hematology/Oncology, Naef K. Basile Cancer Institute- NKBCI, American University of Beirut Medical Center, Beirut, Lebanon
| | - Ibrahim Khalifeh
- Department of pathology and laboratory medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Rim Turfa
- Department of Medical Oncology, King Hussein Cancer Center, Amman, Jordan
| | - Joseph Kattan
- Department of Medical Oncology, Hôtel Dieu de France, Beirut, Lebanon
| | - Deborah Mukherji
- Department of Internal Medicine, Division of Hematology/Oncology, Naef K. Basile Cancer Institute- NKBCI, American University of Beirut Medical Center, Beirut, Lebanon
| | - Sally Temraz
- Department of Internal Medicine, Division of Hematology/Oncology, Naef K. Basile Cancer Institute- NKBCI, American University of Beirut Medical Center, Beirut, Lebanon
| | - Kholoud Alqasem
- Department of Medical Oncology, King Hussein Cancer Center, Amman, Jordan
| | - Rula Amarin
- Department of Medical Oncology, King Hussein Cancer Center, Amman, Jordan
| | - Tala Al Awabdeh
- Department of Medical Oncology, King Hussein Cancer Center, Amman, Jordan
| | - Samer Deeba
- Department of General Surgery, American University of Beirut Medical Center, Beirut, Lebanon
| | - Faek Jamali
- Department of General Surgery, American University of Beirut Medical Center, Beirut, Lebanon
| | - Issa Mohamad
- Department of Medical Oncology, King Hussein Cancer Center, Amman, Jordan
| | - Mousa Elkhaldi
- Department of Medical Oncology, King Hussein Cancer Center, Amman, Jordan
| | - Faiez Daoud
- Department of Surgical Oncology, King Hussein Cancer Center, Amman, Jordan
| | - Mahmoud Al Masri
- Department of Surgical Oncology, King Hussein Cancer Center, Amman, Jordan
| | - Ali Dabous
- Department of Surgical Oncology, King Hussein Cancer Center, Amman, Jordan
| | - Ahmad Hushki
- Gastroenterology Department, King Hussein Cancer Center, Amman, Jordan
| | - Omar Jaber
- Pathology Department, King Hussein Cancer Center, Amman, Jordan
| | - Clement Khoury
- Department of Radiation Oncology, Hotel-Dieu de France Hospital, Beirut, Lebanon
| | - Ziad El Husseini
- Department of Internal Medicine, Division of Hematology/Oncology, Naef K. Basile Cancer Institute- NKBCI, American University of Beirut Medical Center, Beirut, Lebanon
| | - Maya Charafeddine
- Department of Internal Medicine, Division of Hematology/Oncology, Naef K. Basile Cancer Institute- NKBCI, American University of Beirut Medical Center, Beirut, Lebanon
| | - Monita Al Darazi
- Department of Internal Medicine, Division of Hematology/Oncology, Naef K. Basile Cancer Institute- NKBCI, American University of Beirut Medical Center, Beirut, Lebanon
| | - Fady Geara
- Department of Radiation Oncology, American University of Beirut Medical Center, Beirut, Lebanon
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Im JH, Buzzelli JN, Jones K, Franchini F, Gordon-Weeks A, Markelc B, Chen J, Kim J, Cao Y, Muschel RJ. FGF2 alters macrophage polarization, tumour immunity and growth and can be targeted during radiotherapy. Nat Commun 2020; 11:4064. [PMID: 32792542 PMCID: PMC7426415 DOI: 10.1038/s41467-020-17914-x] [Citation(s) in RCA: 88] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Accepted: 07/06/2020] [Indexed: 12/14/2022] Open
Abstract
Regulation of the programming of tumour-associated macrophages (TAMs) controls tumour growth and anti-tumour immunity. We examined the role of FGF2 in that regulation. Tumours in mice genetically deficient in low-molecular weight FGF2 (FGF2LMW) regress dependent on T cells. Yet, TAMS not T cells express FGF receptors. Bone marrow derived-macrophages from Fgf2LMW−/− mice co-injected with cancer cells reduce tumour growth and express more inflammatory cytokines. FGF2 is induced in the tumour microenvironment following fractionated radiation in murine tumours consistent with clinical reports. Combination treatment of in vivo tumours with fractionated radiation and a blocking antibody to FGF2 prolongs tumour growth delay, increases long-term survival and leads to a higher iNOS+/CD206+ TAM ratio compared to irradiation alone. These studies show for the first time that FGF2 affects macrophage programming and is a critical regulator of immunity in the tumour microenvironment. Macrophages contribute to tumour progression and response to therapy. Here, the authors show that absence of FGF2 in the tumour microenvironment reduces tumour growth and enhances the anti-tumour immune response by altering macrophage polarization. As a result, disruption of this macrophage programming by anti-FGF2 blocking antibodies enhances the outcome from radiotherapy.
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Affiliation(s)
- Jae Hong Im
- Oxford Institute for Radiation Oncology, University of Oxford, Oxford, OX3 7DQ, UK
| | - Jon N Buzzelli
- Oxford Institute for Radiation Oncology, University of Oxford, Oxford, OX3 7DQ, UK
| | - Keaton Jones
- Oxford Institute for Radiation Oncology, University of Oxford, Oxford, OX3 7DQ, UK
| | - Fanny Franchini
- The Kennedy Institute of Rheumatology, Roosevelt Dr, Oxford, OX3 7FY, UK
| | - Alex Gordon-Weeks
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, OX3 9DU, UK
| | - Bostjan Markelc
- Oxford Institute for Radiation Oncology, University of Oxford, Oxford, OX3 7DQ, UK
| | - Jianzhou Chen
- Oxford Institute for Radiation Oncology, University of Oxford, Oxford, OX3 7DQ, UK
| | - Jin Kim
- Galaxy Biotech, 1230 Bordeaux Dr, Sunnyvale, CA, 94089, USA
| | - Yunhong Cao
- Oxford Institute for Radiation Oncology, University of Oxford, Oxford, OX3 7DQ, UK
| | - Ruth J Muschel
- Oxford Institute for Radiation Oncology, University of Oxford, Oxford, OX3 7DQ, UK.
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11
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Qin X, Liu J, Xu Y, Li B, Cheng J, Wu X, Zhang J, Liu Z, Ning R, Li Y, Zhang Y, Sun Y, Lu JJ. Mesoporous Bi-Containing Radiosensitizer Loading with DOX to Repolarize Tumor-Associated Macrophages and Elicit Immunogenic Tumor Cell Death to Inhibit Tumor Progression. ACS APPLIED MATERIALS & INTERFACES 2020; 12:31225-31234. [PMID: 32551494 DOI: 10.1021/acsami.0c08074] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/26/2023]
Abstract
Tumor-associated macrophages (TAMs) were a major component of tumor, which comprised up to 50% of tumor mass, and correlated with poor prognosis in more than 80% of cases. TAMs were resistant to radiotherapy and chemotherapy, and radiation could further activate TAMs to promote tumor progression. Herein, we explored a kind of Bi-based mesoporous upconversion nanophosphor (UCNP) loaded with doxorubicin (UCNP-DOX) to elicit immunogenic tumor cell death and repolarize TAMs to an antitumor M1-like type for strengthening the tumor-specific antitumor immune effects of X-ray radiotherapy. The repolarization effect of UCNP-DOX with X-ray was confirmed in THP-1 cell line, in vivo mouse model, and hydrothorax of a non-small-cell lung carcinoma patient. Moreover, the UCNP-DOX and X-ray radiation could elicit immunogenic tumor necrosis, presenting more tumor antigens for tumor-specific immune response. In a cell co-incubation system, activated macrophages could significantly inhibit cancer colony formation, migration, and invasion. After treatment, xenografted tumor in mice was also found to be significantly regressed and presented substantial CD8-positive T cells. This study opens the door to further enhance the abscopal effects and inhibit the metastasis in radiotherapy.
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Affiliation(s)
- Xiaojia Qin
- Department of Nuclear Medicine, Shanghai Proton and Heavy Ion Center, Fudan University Shanghai Cancer Center, Shanghai 201321, China
- Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai 201321, China
- Shanghai Engineering Research Center for Molecular Imaging Probes, Shanghai 200032, China
| | - Jie Liu
- Institute of Bismuth Science & College of Science, University of Shanghai for Science and Technology, Shanghai 200093, China
| | - Yunhua Xu
- Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China
| | - Bing Li
- Department of Research and Development, Shanghai Proton and Heavy Ion Center, Shanghai 201321, China
- Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai 201321, China
| | - Jingyi Cheng
- Department of Nuclear Medicine, Shanghai Proton and Heavy Ion Center, Fudan University Shanghai Cancer Center, Shanghai 201321, China
- Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai 201321, China
- Shanghai Engineering Research Center for Molecular Imaging Probes, Shanghai 200032, China
| | - Xiaodong Wu
- Department of Research and Development, Shanghai Proton and Heavy Ion Center, Shanghai 201321, China
- Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai 201321, China
| | - Jianping Zhang
- Department of Nuclear Medicine, Shanghai Proton and Heavy Ion Center, Fudan University Shanghai Cancer Center, Shanghai 201321, China
- Shanghai Engineering Research Center for Molecular Imaging Probes, Shanghai 200032, China
| | - Zhengwang Liu
- Department of Nuclear Medicine, Shanghai Proton and Heavy Ion Center, Shanghai 201321, China
| | - Renli Ning
- Department of Research and Development, Shanghai Proton and Heavy Ion Center, Shanghai 201321, China
- Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai 201321, China
| | - Yuhao Li
- Institute of Bismuth Science & College of Science, University of Shanghai for Science and Technology, Shanghai 200093, China
| | - Yingjian Zhang
- Department of Nuclear Medicine, Shanghai Proton and Heavy Ion Center, Fudan University Shanghai Cancer Center, Shanghai 201321, China
- Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai 201321, China
- Shanghai Engineering Research Center for Molecular Imaging Probes, Shanghai 200032, China
| | - Yun Sun
- Department of Nuclear Medicine, Shanghai Proton and Heavy Ion Center, Shanghai 201321, China
- Department of Research and Development, Shanghai Proton and Heavy Ion Center, Shanghai 201321, China
- Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai 201321, China
- Shanghai Engineering Research Center for Molecular Imaging Probes, Shanghai 200032, China
| | - Jiade J Lu
- Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Shanghai 201321, China
- Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai 201321, China
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12
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Priming the tumor immune microenvironment with chemo(radio)therapy: A systematic review across tumor types. Biochim Biophys Acta Rev Cancer 2020; 1874:188386. [PMID: 32540465 DOI: 10.1016/j.bbcan.2020.188386] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 06/05/2020] [Accepted: 06/08/2020] [Indexed: 12/23/2022]
Abstract
BACKGROUND Chemotherapy (CT), radiotherapy (RT), and chemoradiotherapy (CRT) are able to alter the composition of the tumor immune microenvironment (TIME). Understanding the effect of these modalities on the TIME could aid in the development of improved treatment strategies. Our aim was to systematically review studies investigating the influence of CT, RT or CRT on different TIME markers. METHODS The EMBASE (Ovid) and PubMed databases were searched until January 2019 for prospective or retrospective studies investigating the dynamics of the local TIME in cancer patients (pts) treated with CT, RT or CRT, with or without targeted agents. Studies could either compare baseline and follow-up specimens - before and after treatment - or a treated versus an untreated cohort. Studies were included if they used immunohistochemistry and/or flow cytometry to assess the TIME. RESULTS In total we included 110 studies (n = 8850 pts), of which n = 89 (n = 6295 pts) compared pre-treatment to post-treatment specimens and n = 25 (n = 2555 pts) a treated versus an untreated cohort (4 studies conducted both comparisons). For several tumor types (among others; breast, cervical, esophageal, ovarian, rectal, lung mesothelioma and pancreatic cancer) remodeling of the TIME was observed, leading to a potentially more immunologically active microenvironment, including one or more of the following: an increase in CD3 or CD8 lymphocytes, a decrease in FOXP3 Tregs and increased PD-L1 expression. Both CT and CRT were able to immunologically alter the TIME. CONCLUSION The TIME of several tumor types is significantly altered after conventional therapy creating opportunities for concurrent or sequential immunotherapy.
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13
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Kane C, Glynne-Jones R. Should we favour the use of 5 × 5 preoperative radiation in rectal cancer. Cancer Treat Rev 2019; 81:101908. [DOI: 10.1016/j.ctrv.2019.101908] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Accepted: 10/03/2019] [Indexed: 12/20/2022]
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14
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Castle KD, Kirsch DG. Establishing the Impact of Vascular Damage on Tumor Response to High-Dose Radiation Therapy. Cancer Res 2019; 79:5685-5692. [PMID: 31427377 PMCID: PMC6948140 DOI: 10.1158/0008-5472.can-19-1323] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Revised: 06/17/2019] [Accepted: 08/07/2019] [Indexed: 12/26/2022]
Abstract
Approximately half of all patients with cancer receive radiotherapy, which is conventionally delivered in relatively small doses (1.8-2 Gy) per daily fraction over one to two months. Stereotactic body radiation therapy (SBRT), in which a high daily radiation dose is delivered in 1 to 5 fractions, has improved local control rates for several cancers. However, despite the widespread adoption of SBRT in the clinic, controversy surrounds the mechanism by which SBRT enhances local control. Some studies suggest that high doses of radiation (≥10 Gy) trigger tumor endothelial cell death, resulting in indirect killing of tumor cells through nutrient depletion. On the other hand, mathematical models predict that the high radiation dose per fraction used in SBRT increases direct tumor cell killing, suggesting that disruption of the tumor vasculature is not a critical mediator of tumor cure. Here, we review the application of genetically engineered mouse models to radiosensitize tumor cells or endothelial cells to dissect the role of these cellular targets in mediating the response of primary tumors to high-dose radiotherapy in vivo These studies demonstrate a role for endothelial cell death in mediating tumor growth delay, but not local control following SBRT.
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Affiliation(s)
- Katherine D Castle
- Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina
| | - David G Kirsch
- Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.
- Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, North Carolina
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15
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Potez M, Fernandez-Palomo C, Bouchet A, Trappetti V, Donzelli M, Krisch M, Laissue J, Volarevic V, Djonov V. Synchrotron Microbeam Radiation Therapy as a New Approach for the Treatment of Radioresistant Melanoma: Potential Underlying Mechanisms. Int J Radiat Oncol Biol Phys 2019; 105:1126-1136. [PMID: 31461675 DOI: 10.1016/j.ijrobp.2019.08.027] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Revised: 07/04/2019] [Accepted: 08/18/2019] [Indexed: 01/30/2023]
Abstract
PURPOSE Synchrotron microbeam radiation therapy (MRT) is a method that spatially distributes the x-ray beam into several microbeams of very high dose (peak dose), regularly separated by low-dose intervals (valley dose). MRT selectively spares normal tissues, relative to conventional (uniform broad beam [BB]) radiation therapy. METHODS AND MATERIALS To evaluate the effect of MRT on radioresistant melanoma, B16-F10 murine melanomas were implanted into mice ears. Tumors were either treated with MRT (407.6 Gy peak; 6.2 Gy valley dose) or uniform BB irradiation (6.2 Gy). RESULTS MRT induced significantly longer tumor regrowth delay than did BB irradiation. A significant 24% reduction in blood vessel perfusion was observed 5 days after MRT, and the cell proliferation index was significantly lower in melanomas treated by MRT compared with BB. MRT provoked a greater induction of senescence in melanoma cells. Bio-Plex analyses revealed enhanced concentration of monocyte-attracting chemokines in the MRT group: MCP-1 at D5, MIP-1α, MIP-1β, IL12p40, and RANTES at D9. This was associated with leukocytic infiltration at D9 after MRT, attributed mainly to CD8 T cells, natural killer cells, and macrophages. CONCLUSIONS In light of its potential to disrupt blood vessels that promote infiltration of the tumor by immune cells and its induction of senescence, MRT could be a new therapeutic approach for radioresistant melanoma.
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Affiliation(s)
- Marine Potez
- Institute of Anatomy, University of Bern, Bern, Switzerland
| | | | - Audrey Bouchet
- Institute of Anatomy, University of Bern, Bern, Switzerland; Synchrotron Radiation for Biomedicine, INSERM UA7, 71 rue des Martyrs, 38000 Grenoble, France
| | | | - Mattia Donzelli
- Biomedical Beamline ID17, European Synchrotron Radiation Facility, Grenoble, France; Joint Department of Physics, The Institute of Cancer Research and the Royal Marsden Hospital, London, United Kingdom
| | - Michael Krisch
- Biomedical Beamline ID17, European Synchrotron Radiation Facility, Grenoble, France
| | - Jean Laissue
- Institute of Anatomy, University of Bern, Bern, Switzerland
| | - Vladislav Volarevic
- Department of Microbiology and Immunology, Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Serbia
| | - Valentin Djonov
- Institute of Anatomy, University of Bern, Bern, Switzerland.
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16
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Trinidad López C, De La Fuente Aguado J, Oca Pernas R, Delgado Sánchez-Gracián C, Santos Armentia E, Vaamonde Liste A, Prada González R, Souto Bayarri M. Evaluation of response to conventional chemotherapy and radiotherapy by perfusion computed tomography in non-small cell lung cancer (NSCLC). Eur Radiol Exp 2019; 3:23. [PMID: 31197486 PMCID: PMC6565789 DOI: 10.1186/s41747-019-0101-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Accepted: 05/02/2019] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND To evaluate changes in perfusion computed tomography (PCT) parameters induced by treatment with conventional chemotherapy (CCT) alone or with CCT and radiation therapy (RT) in patients with non-small cell lung cancer (NSCLC) and to determine whether these changes correlate with response as defined by the response evaluation criteria in solid tumours version 1.1 (RECIST-1.1). METHODS Fifty-three patients with a histological diagnosis of NSCLC prospectively underwent PCT of the whole tumour, before/after CCT or before/after CCT and RT. Blood flow (BF), blood volume (BV), permeability (PMB), and mean transit time (MTT) were compared before and after treatment and with the response as defined by RECIST-1.1. The relationship between changes in the perfusion parameters and in tumour size was also evaluated. RESULTS PCT parameters decreased after treatment, significantly for BV (p = 0.002) and MTT (p = 0.027). The 30 patients with partial response had a significant decrease of 21% for BV (p = 0.006) and 17% for MTT (p = 0.031). A non-significant decrease in all perfusion parameters was found in patients with stable disease (p > 0.137). In patients with progressive disease, MTT decreased by 10% (p = 0.465) and the other parameters did not significantly vary (p > 0.809). No significant correlation was found between changes in size and PCT parameters (p > 0.145). CONCLUSIONS Treatment of NSCLC with platinum derivatives, with or without RT, induces changes in PCT parameters. Partial response is associated with a significant decrease in BV and MTT, attributable to the effect of the treatment on tumour vascularisation.
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Affiliation(s)
- Carmen Trinidad López
- Department of Radiology, POVISA Hospital, 5 Salamanca st, 36208, Vigo, Pontevedra, Spain.
| | | | - Roque Oca Pernas
- Department of Radiology, Osatek, Urduliz Hospital, Vizcaya, Spain
| | | | - Eloisa Santos Armentia
- Department of Radiology, POVISA Hospital, 5 Salamanca st, 36208, Vigo, Pontevedra, Spain
| | - Antonio Vaamonde Liste
- Department of Statistics and Operational Research, Faculty of Economic and Business Sciences, Vigo University Spain, Vigo, Spain
| | - Raquel Prada González
- Department of Radiology, POVISA Hospital, 5 Salamanca st, 36208, Vigo, Pontevedra, Spain
| | - Miguel Souto Bayarri
- Department of Radiology, Complexo Hospitalario Universitario de Santiago de Compostela, Santiago de Compostela, Spain
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Mafu TS, September AV, Shamley D. The potential role of angiogenesis in the development of shoulder pain, shoulder dysfunction, and lymphedema after breast cancer treatment. Cancer Manag Res 2018; 10:81-90. [PMID: 29391829 PMCID: PMC5772395 DOI: 10.2147/cmar.s151714] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Shoulder morbidity is a well-documented sequela of breast cancer treatment, which includes various manifestations such as pain, reduced range of motion, and lymphedema, among others. The multifactorial nature of such morbidities has long been appreciated, and research on reliable risk predictors of development thereof still continues. Previous studies have demonstrated the potential of different types of physical therapy to treat such shoulder problems, and the integration of such interventions into routine care for breast cancer survivors is a requirement in most high-income countries. Although patients at risk for developing shoulder problems would most likely benefit from posttreatment physical therapy, currently, there is no gold standard for identifying this patient group. This is particularly important in low- and middle-income countries where scarce monetary resources need to be directed specifically to those most in need. Modulators of the angiogenesis pathway have been implicated in noncancer shoulder conditions such as rotator cuff disease, adhesive capsulitis, and tendon injuries. The present review summarizes the role of angiogenesis in the development of shoulder morbidity among breast cancer survivors and sets forth the rationale for our belief that angiogenesis signaling may help explain a proportion of the reported clinical variability noted in the development of shoulder pain and dysfunction and upper-limb lymphedema after breast cancer treatment.
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Affiliation(s)
- Trevor S Mafu
- Division of Exercise Science and Sports Medicine, Department of Human Biology, Faculty of Health Sciences, University of Cape Town
| | - Alison V September
- Division of Exercise Science and Sports Medicine, Department of Human Biology, Faculty of Health Sciences, University of Cape Town
| | - Delva Shamley
- Clinical Research Centre, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
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Kuo LJ, Ngu JCY, Huang YJ, Lin YK, Chen CC, Tong YS, Huang SC, Hu CC, Tan SH. Anorectal complications after robotic intersphincteric resection for low rectal cancer. Surg Endosc 2017; 31:4466-4471. [PMID: 28374259 DOI: 10.1007/s00464-017-5499-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2017] [Accepted: 03/08/2017] [Indexed: 12/17/2022]
Abstract
BACKGROUND Robotic intersphincteric resection (ISR) has been introduced for sphincter-preservation in the treatment of low rectal cancer. However, many patients experience anorectal symptoms and defecatory dysfunction after ISR. This study aims to evaluate the anorectal complications that develop after ISR. METHODS The medical records of 108 patients who underwent robotic ISR at Taipei Medical University Hospital, Taipei, Taiwan between December 2011 and June 2016 were retrospectively reviewed. Photographic records of perineal conditions were documented at the following time intervals after surgery: 1 day, 2 weeks, 1, 2, 3 and 6 months. Clinical outcomes and treatment results were analysed. RESULTS Eighty-five patients (78.7%) developed edematous hemorrhoids after surgery. These subsided at a median of 56 days after operation (range 23-89 days). Forty-six patients (42.6%) were found to have anal stenosis requiring anal dilatation. Sixteen patients (14.8%) had neorectal mucosal prolapse, which was noted to occur at an average of 98 days after surgery (range 41-162 days). Multivariate analysis showed that the occurrence of edematous hemorrhoids was associated with operating time (P = 0.043), and male gender was a significant risk factor for anal stenosis (P = 0.007). CONCLUSIONS This is the first study reporting on the clinical outcomes of anorectal status after robotic ISR. Further studies are needed to assess the long-term effects of these anorectal complications.
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Affiliation(s)
- Li-Jen Kuo
- Division of Colorectal Surgery, Department of Surgery, Taipei Medical University Hospital, 252 Wuxing Street, Sinyi District, Taipei, 11031, Taiwan.
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
| | | | - Yan-Jiun Huang
- Division of Colorectal Surgery, Department of Surgery, Taipei Medical University Hospital, 252 Wuxing Street, Sinyi District, Taipei, 11031, Taiwan
- The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, Taiwan
| | - Yen-Kuang Lin
- Biostatistics and Research Consultation Center, Taipei Medical University, Taipei, Taiwan
| | - Chia-Che Chen
- Division of Acute Care Surgery and Traumatology, Department of Surgery, Taipei Medical University Hospital, Taipei, Taiwan
| | - Yiu-Shun Tong
- Division of Acute Care Surgery and Traumatology, Department of Surgery, Taipei Medical University Hospital, Taipei, Taiwan
| | - Szu-Chia Huang
- Department of Physical Medicine and Rehabilitation, Taipei Medical University Hospital, Taipei, Taiwan
| | - Chia-Chen Hu
- Division of Colorectal Surgery, Department of Surgery, Taipei Medical University Hospital, 252 Wuxing Street, Sinyi District, Taipei, 11031, Taiwan
| | - Shu-Hwa Tan
- Department of Nursing, Taipei Medical University Hospital, Taipei, Taiwan
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Hu MH, Huang RK, Zhao RS, Yang KL, Wang H. Does neoadjuvant therapy increase the incidence of anastomotic leakage after anterior resection for mid and low rectal cancer? A systematic review and meta-analysis. Colorectal Dis 2017; 19:16-26. [PMID: 27321374 DOI: 10.1111/codi.13424] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2015] [Accepted: 04/28/2016] [Indexed: 12/13/2022]
Abstract
AIM The aim was to evaluate the association of neoadjuvant therapy with increases in the incidence of anastomotic leakage (AL) after middle and low rectal anterior resection. METHOD The electronic databases of PubMed, Web of Science, Scopus and Ovid were searched between 1980 and 2015. The random effects model was used to model the pooled data to determine the odds ratio with 95% confidence interval. Heterogeneity was evaluated using the Q test and I2 statistics. Subgroup, sensitivity and meta-regression analysis was conducted to explore heterogeneity. RESULTS Neoadjuvant therapy was not shown to increase the incidence of postoperative AL as demonstrated by an OR of 1.16 [95% CI 0.99-1.36; P = 0.07 (random effects model)]. The subgroup analysis of neoadjuvant radiotherapy using the random effects model suggested that it did not increase the rate of postoperative AL (OR = 1.24, 95% CI 0.97-1.58; P = 0.08). The subgroup analysis of neoadjuvant chemoradiotherapy indicated that the rate of postoperative AL again did not increase with an OR = 1.06 [95% CI 0.86-1.30; P = 0.59 (random effects model)]. The interval to surgery after neoadjuvant therapy and preoperative radiotherapy (short or long course) was not associated with an increased incidence of postoperative AL. CONCLUSION Neoadjuvant therapy does not appear to increase the incidence of postoperative AL after anterior resection for mid and low rectal cancer. In addition, neither the interval to surgery after neoadjuvant therapy nor the radiotherapy regimen increases the rate of postoperative AL.
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Affiliation(s)
- M-H Hu
- Department of Colorectal Surgery, Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - R-K Huang
- Department of Colorectal Surgery, Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - R-S Zhao
- Department of Colorectal Surgery, Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - K-L Yang
- Department of Colorectal Surgery, Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - H Wang
- Department of Colorectal Surgery, Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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20
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Wang L, Zhai ZW, Ji DB, Li ZW, Gu J. Prognostic value of CD45RO(+) tumor-infiltrating lymphocytes for locally advanced rectal cancer following 30 Gy/10f neoadjuvant radiotherapy. Int J Colorectal Dis 2015; 30:753-60. [PMID: 25935450 DOI: 10.1007/s00384-015-2226-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/20/2015] [Indexed: 02/04/2023]
Abstract
AIM This study aims to evaluate the prognostic value of CD45RO(+) tumor-infiltrating lymphocytes (TILs) in locally advanced rectal cancer treated with 30 Gy/10 fraction (10 f) neoadjuvant radiotherapy. METHODS This retrospective study involved 185 patients with locally advanced rectal cancer who underwent 30 Gy/10 f nRT (biologic equivalent dose, 30 Gy) followed by total mesorectal excision (TME) between August 2003 and October 2009. The density of CD45RO(+) TILs was assessed by immunohistochemistry using an image-analysis system and tissue microarray and was evaluated for its association with histopathologic features along with disease-free survival (DFS). RESULTS Following neoadjuvant radiotherapy, the median density of CD45RO(+) TILs is 654/mm(2). High density of CD45RO(+) TILs was significantly associated with increased T and N downstaging effect (p = 0.006; p = 0.014), lesser-advanced T stage (p = 0.003) and TNM stage (p = 0.022). Prolonged DFS (89.0 vs. 68.1%) was also observed in CD45RO(+Hi) cases. On multivariate regression model, CD45RO(+) TILs (p = 0.026; odds ratio (OR), 0.436 (95% confidence interval (CI), 0.209-0.907)), tumor differentiation (p = 0.057; OR, 1.878 (95% CI, 0.982-3.593)), ypT stage (p = 0.066; OR, 2.383 (95% CI, 0.943-6.025)), and ypN stage (p = 0.009; OR, 2.612 (95% CI, 1.266-5.388)) were independent factors for DFS. CONCLUSION The density of CD45RO(+) TILs cannot only predict tumor downstaging and ypTNM stage for rectal cancer following 30 Gy/10 f nRT but also promisingly predict long-term outcomes. These findings may be used to stratify patients and make alternative strategy of adjuvant treatment.
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Affiliation(s)
- Lin Wang
- Department of Colorectal Surgery, Peking University Cancer Hospital and Institute, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), 52 Fu Cheng Lu, Haidian district, Beijing, 100142, People's Republic of China
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21
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Correlations Between Intratumoral Microvessel Density and Histopathological Type or Neoadjuvant Radiotherapy for Rectal Carcinoma. CURRENT HEALTH SCIENCES JOURNAL 2015; 41:152-157. [PMID: 30364876 PMCID: PMC6201205 DOI: 10.12865/chsj.41.02.10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/07/2015] [Accepted: 04/01/2015] [Indexed: 11/25/2022]
Abstract
Purpose: This study aims to evaluate intratumoral microvessel density in rectal carcinoma cases with different histopathological type (adenocarcinoma and mucinous carcinoma) and different preoperatory neoadjuvant radiotherapy status (irradiated / non-irradiated) ,thus analyzing any possible statistical correlation between these parameters. Material and methods: Our prospective study consists in standard immunohistochemistry procedures using CD34, CD31 and CD105 antibodies, which were performed on 25 samples of rectal carcinoma, in order to determine intratumoral microvessel density. Results: The 25 case study group was divided either by histopathological type or by prior radiotherapeutical treatment as follows: 9 cases of mucinous carcinoma versus 16 cases of adenocarcinoma and 13 cases of rectal cancer that have not received neoadjuvant radiotherapy versus 12 cases of rectal cancer with preoperatory radiotherapy. Conclusions: The number of intratumoral microvessels is higher in non-irradiated rectal tumors and in adenocarcinomas, this remark being statistical significant (with only one exception – CD34 staining in non-irradiated versus irradiated tumors) for all types of vessels (new-grown and mature). This result is due to the benefic effect of neoadjuvant radiotherapy on decreasing angiogenic activity, thus having an important prognostic value for rectal cancer.
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22
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Head and neck cancer relapse after chemoradiotherapy correlates with CD163+ macrophages in primary tumour and CD11b+ myeloid cells in recurrences. Br J Cancer 2014; 111:1509-18. [PMID: 25093488 PMCID: PMC4200089 DOI: 10.1038/bjc.2014.446] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2014] [Revised: 06/27/2014] [Accepted: 07/13/2014] [Indexed: 12/22/2022] Open
Abstract
Background: We investigated the prognostic role of tumour-associated macrophages (TAMs) in patients with head and neck squamous cell carcinoma (HNSCC) treated with definitive chemoradiotherapy (CRT). Methods: The expression of CD68+, CD163+ and CD11b+ cells was assessed using immunohistochemistry in n=106 pre-treatment tumour biopsy samples and was correlated with clinicopathological characteristics, including T-stage, N-stage, grading, tumour localisation, age and sex as well as local failure-free survival (LFFS), distant metastases-free survival (DMFS), progression-free (PFS), and overall survival (OS). Finally, TAMs expression and vessel density (CD31) were examined in n=12 available early local recurrence samples and compared with their matched primary tumours . The diagnostic images and radiotherapy plans of these 12 patients were also analysed. All local recurrences occurred in the high radiation dose region (⩾70 Gy). Results: With a median follow-up of 40 months, OS at 2 years was 60.5%. High CD163 expression in primary tumours was associated with decreased OS (P=0.010), PFS (P=0.033), LFFS (P=0.036) and DMFS (P=0.038) in multivariate analysis. CD163 demonstrated a strong prognostic value only in human papillomavirus (p16INK4)-negative patients. Early local recurrence specimens demonstrated a significantly increased infiltration of CD11b+ myeloid cells (P=0.0097) but decreased CD31-positive vessel density (P=0.0004) compared with their matched primary samples. Conclusions: Altogether, baseline CD163 expression predicts for an unfavourable clinical outcome in HNSCC after definitive CRT. Early local recurrences showed increased infiltration by CD11b+ cells. These data provide important insight on the role of TAMs in mediating response to CRT in patients with HNSCC.
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Bhargava A, Bunkar N, Khare NK, Mishra D, Mishra PK. Nanoengineered strategies to optimize dendritic cells for gastrointestinal tumor immunotherapy: from biology to translational medicine. Nanomedicine (Lond) 2014; 9:2187-2202. [PMID: 25405796 DOI: 10.2217/nnm.14.115] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Nanomedicine may play an important role in improving the clinical efficacy of dendritic cell-based immunotherapy against GI tract malignancies. Dendritic cell-based vaccines have proven their effectiveness against different established GI tract tumors, yet their success is mainly hindered by the strong tumor-induced suppressive microenvironment. The sustained and targeted release of tumor antigens to dendritic cells using different nanoengineered approaches would be an efficient strategy to overcome established immune tolerance. Encapsulation would result in low diffusivity, restricted movement, effective crosspresentation and enhanced T-cell responses. These nanotherapy-based approaches will certainly help with the designing of clinically translatable dendritic cell-based therapeutic vaccines and facilitate the selective removal of residual disease in gastrointestinal cancer patients following standard treatments.
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Affiliation(s)
- Arpit Bhargava
- Translational Research Laboratory, School of Biological Sciences, Dr H. S. Gour Central University, Sagar, India
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24
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Wasserberg N. Interval to surgery after neoadjuvant treatment for colorectal cancer. World J Gastroenterol 2014; 20:4256-4262. [PMID: 24764663 PMCID: PMC3989961 DOI: 10.3748/wjg.v20.i15.4256] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2013] [Revised: 11/11/2013] [Accepted: 01/14/2014] [Indexed: 02/06/2023] Open
Abstract
The current standard treatment of low-lying locally advanced rectal cancer consists of chemoradiation followed by radical surgery. The interval between chemoradiation and surgery varied for many years until the 1999 Lyon R90-01 trial which compared the effects of a short (2-wk) and long (6-wk) interval. Results showed a better clinical tumor response (71.7% vs 53.1%) and higher rate of positive and pathologic tumor regression (26% vs 10.3%) after the longer interval. Accordingly, a 6-wk interval between chemoradiation and surgery was set to balance the oncological results with the surgical complexity. However, several recent retrospective studies reported that prolonging the interval beyond 8 or even 12 wk may lead to significantly higher rates of tumor downstaging and pathologic complete response. This in turn, according to some reports, may improve overall and disease-free survival, without increasing the surgical difficulty or complications. This work reviews the data on the effect of different intervals, derived mostly from retrospective analyses using a wide variation of treatment protocols. Prospective randomized trials are currently ongoing.
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25
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Russell JS, Brown JM. The irradiated tumor microenvironment: role of tumor-associated macrophages in vascular recovery. Front Physiol 2013; 4:157. [PMID: 23882218 PMCID: PMC3713331 DOI: 10.3389/fphys.2013.00157] [Citation(s) in RCA: 97] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2013] [Accepted: 06/11/2013] [Indexed: 12/12/2022] Open
Abstract
Radiotherapy is an important modality used in the treatment of more than 50% of cancer patients in the US. However, despite sophisticated techniques for radiation delivery as well as the combination of radiation with chemotherapy, tumors can recur. Thus, any method of improving the local control of the primary tumor by radiotherapy would produce a major improvement in the curability of cancer patients. One of the challenges in the field is to understand how the tumor vasculature can regrow after radiation in order to support tumor recurrence, as it is unlikely that any of the endothelial cells within the tumor could survive the doses given in a typical radiotherapy regimen. There is now considerable evidence from both preclinical and clinical studies that the tumor vasculature can be restored following radiotherapy from an influx of circulating cells consisting primarily of bone marrow derived monocytes and macrophages. The radiation-induced influx of bone marrow derived cells (BMDCs) into tumors can be prevented through the blockade of various cytokine pathways and such strategies can inhibit tumor recurrence. However, the post-radiation interactions between surviving tumor cells, recruited immune cells, and the remaining stroma remain poorly defined. While prior studies have described the monocyte/macrophage inflammatory response within normal tissues and in the tumor microenvironment, less is known about this response with respect to a tumor after radiation therapy. The goal of this review is to summarize existing research studies to provide an understanding of how the myelomonocytic lineage may influence vascular recovery within the irradiated tumor microenvironment.
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Affiliation(s)
- Jeffery S Russell
- Department of Medical Oncology, Stanford University School of Medicine Stanford, CA, USA
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26
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Bhargava A, Mishra D, Banerjee S, Mishra PK. Engineered dendritic cells for gastrointestinal tumor immunotherapy: opportunities in translational research. J Drug Target 2013; 21:126-136. [PMID: 23061479 DOI: 10.3109/1061186x.2012.731069] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Gastrointestinal (GI) malignancies are one of the most frequently occurring tumors found worldwide. Surgery remains the primary treatment for most solid tumors and adjuvant chemotherapy and radiotherapy are limited by lack of specificity and toxicity. In view of the poor survival rate, there is a great need to introduce new and effective therapeutic modalities. Recently, dendritic cells (DCs)-based vaccines are being explored as a promising therapeutic strategy but their success is limited by the tumor-induced immune escape mechanisms. This article provides a comprehensive analysis of clinical trials conducted using this approach. It also showcases the necessity of exploring nano-engineered strategies for improving the clinical utility of DC-vaccination for GI tract malignancies to overcome immune tolerance.
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Affiliation(s)
- Arpit Bhargava
- Division of Translational Research, Tata Memorial Centre, ACTREC, Navi, Mumbai, India
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28
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The role of the tumor endothelium in leukocyte recruitment in pancreatic cancer. Surgery 2012; 152:S89-94. [DOI: 10.1016/j.surg.2012.05.027] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2012] [Accepted: 05/11/2012] [Indexed: 12/13/2022]
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Kozin SV, Duda DG, Munn LL, Jain RK. Neovascularization after irradiation: what is the source of newly formed vessels in recurring tumors? J Natl Cancer Inst 2012; 104:899-905. [PMID: 22572994 DOI: 10.1093/jnci/djs239] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Local relapse of tumors after radiation therapy remains a challenge in oncology. To devise rational approaches for preventing this relapse, we have to improve our understanding of how new vessels form in previously irradiated tumors. We propose that tumor regrowth after local irradiation is dependent on blood vessel formation by local endothelial cells without the need for recruitment of endothelial precursor cells from distant nonirradiated tissues or bone marrow. We also suggest that infiltrating myeloid bone marrow-derived cells promote survival of local endothelial cells during the early period after irradiation and angiogenesis during the later stage of tumor regrowth, both via paracrine mechanisms.
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Affiliation(s)
- Sergey V Kozin
- Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, 100 Blossom Street, Cox-734, Boston, MA 02114, USA
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30
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Pereira Lima MN, Biolo A, Foppa M, Rosa PRD, Rohde LEP, Clausell N. A prospective, comparative study on the early effects of local and remote radiation therapy on carotid intima–media thickness and vascular cellular adhesion molecule-1 in patients with head and neck and prostate tumors. Radiother Oncol 2011; 101:449-53. [DOI: 10.1016/j.radonc.2010.03.026] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2009] [Revised: 03/30/2010] [Accepted: 03/30/2010] [Indexed: 10/19/2022]
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Leong QM, Son DN, Baek SJ, Cho JS, Amar A, Kwak JM, Kim SH. Edematous and painful external hemorrhoids following intersphincteric resection for low rectal cancer. JOURNAL OF THE KOREAN SURGICAL SOCIETY 2011; 81 Suppl 1:S39-42. [PMID: 22319736 PMCID: PMC3267063 DOI: 10.4174/jkss.2011.81.suppl1.s39] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/17/2011] [Revised: 03/24/2011] [Accepted: 04/11/2011] [Indexed: 12/05/2022]
Abstract
Intersphincteric resection (ISR) is the ultimate sphincter saving procedure for low rectal cancer. Hemorrhoids are a common benign condition. We present and discuss a case of ISR which developed painful edematous hemorrhoids after ISR. A 62-year-old female with low rectal cancer received neoadjuvant chemoradiotherapy with successful down staging of tumor before undergoing robot assisted ISR with coloanal hand-sewn anastomosis. She had pre-existing external hemorrhoids which were not excised. She developed painful and edematous external hemorrhoids 4 days after surgery. These were treated conservatively before discharge. Many colorectal surgeons performing ISR have experienced similar situations in their patients, but none have reported on this phenomenon. We discuss the possible factors that may contribute to this situation. A possible solution is prophylactic excision of the hemorrhoids during coloanal anastomosis. Painful hemorrhoids may occur after ISR and if managed conservatively, the outcome is skin tags.
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Affiliation(s)
- Quor Meng Leong
- Division of Colorectal Surgery, Department of Surgery, Korea University Anam Hospital, Seoul, Korea
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32
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Takeichi T, Mocevicius P, Deduchovas O, Salnikova O, Castro-Santa E, Büchler MW, Schmidt J, Ryschich E. αL β2 integrin is indispensable for CD8+ T-cell recruitment in experimental pancreatic and hepatocellular cancer. Int J Cancer 2011; 130:2067-76. [PMID: 21647874 DOI: 10.1002/ijc.26223] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2011] [Accepted: 05/23/2011] [Indexed: 12/30/2022]
Abstract
Recruitment of activated leukocytes from peripheral blood into the tumor tissue is a crucial step of the immune response, which is controlled by the interaction between specific adhesion molecules such as endothelial ICAM-1 and leukocyte β(2) -integrins. Although attenuated expression of adhesion molecules on tumor endothelium has been proposed to represent a mechanism, which suppresses the intratumoral leukocyte infiltration, the relevance of adhesion molecules for leukocyte recruitment in tumor tissue is poorly understood. The present study is the first investigation of the role of ICAM-1 and β(2) -integrins in leukocyte recruitment in pancreatic and hepatocellular cancer in vivo, which was studied using knockout mice, intravital time-lapse microscopy and immunohistochemistry. We found that tumor tissue of both pancreatic and hepatocellular cancer was infiltrated with numerous active lymphoid and myeloid leukocytes, although the leukocyte extravasation rate in tumor blood vessels was very low. The knockout of LFA-1 (also known as α(L) β(2) integrin) strongly suppressed recruitment of CD8(+) T cells whereas no significant differences of leukocyte adhesion and infiltration were found in ICAM-1(-/-) and Mac-1(-/-) mice. Analysis of the interstitial leukocyte migration demonstrated that intratumoral leukocytes used haptokinetic type of migration, however, no significant differences of leukocyte migration between any knockout strains were found. We concluded that leukocyte recruitment in pancreatic and hepatocellular cancer is a slow-going process whose dynamics clearly contrasts to a high-speed leukocyte recruitment during acute inflammation. In contrast to acute inflammatory reaction, only LFA-1 controls recruitment of CD8(+) T-cells in both pancreatic and hepatocellular cancer, whereas ICAM-1 and Mac-1 are dispensable.
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Affiliation(s)
- Takayuki Takeichi
- Department of Surgery, University of Heidelberg, Heidelberg, Germany
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Holmqvist A, Gao J, Adell G, Carstensen J, Sun XF. The location of lymphangiogenesis is an independent prognostic factor in rectal cancers with or without preoperative radiotherapy. Ann Oncol 2009; 21:512-517. [PMID: 19889620 DOI: 10.1093/annonc/mdp486] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Lymphangiogenesis and angiogenesis are essential for tumour development and progression. The lymphatic vessel density (LVD) and blood vessel density (BVD) and their relationship to outcome have been studied extensively, however the clinical significance of the location of LVD/BVD in tumour is not known. In the present study, the location and degree of LVD/BVD and their relationship to preoperative radiotherapy (RT), clinicopathological, histopathological and biological factors were studied in rectal cancer patients participating in a Swedish clinical trial of preoperative RT. PATIENTS AND METHODS The location and degree of LVD/BVD were analysed in primary tumours (n = 138/140) and in their subgroups of non-RT (n = 74) and RT (n = 64/66). Further, the degree of LVD/BVD was examined in the corresponding distant normal mucosa (n = 35/31) and adjacent normal mucosa (n = 72/91). All sections were immunohistochemically examined by using D2-40 and CD34 antibodies. RESULTS In the whole series of the patients, a higher LVD at the periphery was related to negative p53 expression (P = 0.03) and favourable survival independent of tumour-node-metastasis stage, differentiation and p53 expression (P = 0.03). LVD was increased in p53-negative tumours after RT (P = 0.01). CONCLUSION LVD at the periphery of the tumour was an independent prognostic factor in rectal cancer patients.
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Affiliation(s)
- A Holmqvist
- Department of Medical Oncology, Institute of Clinical and Experimental Medicine.
| | - J Gao
- Department of Medical Oncology, Institute of Clinical and Experimental Medicine
| | - G Adell
- Department of Medical Oncology, Institute of Clinical and Experimental Medicine
| | - J Carstensen
- Department of Health and Society, Faculty of Arts and Sciences, Linköping University, Linköping, Sweden
| | - X-F Sun
- Department of Medical Oncology, Institute of Clinical and Experimental Medicine
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Svagzdys S, Lesauskaite V, Pavalkis D, Nedzelskiene I, Pranys D, Tamelis A. Microvessel density as new prognostic marker after radiotherapy in rectal cancer. BMC Cancer 2009; 9:95. [PMID: 19323831 PMCID: PMC2666763 DOI: 10.1186/1471-2407-9-95] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2008] [Accepted: 03/26/2009] [Indexed: 02/06/2023] Open
Abstract
Background The extent of angiogenesis is an important prognostic factor for colorectal carcinoma, however, there are few studies concerning changes in angiogenesis with radiotherapy (RTX). Our aim was to investigate changes in tumor angiogenesis influenced by radiotherapy to assess the prognostic value of angiogenesis the microvessel density (MVD) in overall survival after radiotherapy. Methods Tumor specimens were taken from 101 patients resected for rectal cancer. The patients were divided into three groups according to the treatment they received before surgery (not treated, a short course, or long course of RTX). Tumor specimens were paraffin-embedded and immunohistochemistry was performed with primary antibody against CD-34 to count MVD. Results MVD was significantly lower in the group of patients treated with a long course of RTX (p <0.025). The mean MVD for the long RTX group was 134.8; for the short RTX group – 192.5; and for those not treated with RTX – 193.0. There were no significant statistical correlations between MVD and age, sex, grade of tumor differentiation (G) and tumor size (T) in those untreated with RTX. In long RTX group we found a significant prognostic rate for MVD when the density cut off was near 130 with 92.3% sensitivity and 64.7% specificity. When the MVD was lower than a cut off of 130, the survival period significantly increased (p = 0.001), the mortality rate is significantly higher if the MVD is higher than 130 (microvessel/mm2) (1953.047; p = 0.002), if the histological grade is moderate/poor (127.407; p = 0.013), if the tumor is T3/T4 (111.618; p = 0.014), and if the patient is male (17.92; p = 0.034) adjusted by other variable in model. Conclusion Our results show that a long course of radiotherapy significantly decreased angiogenesis in rectal cancer tissue. MVD was found to be a favourable marker for tumor behaviour during RTX and a predictor of overall survival after long course of RTX. Further investigations are now needed to determine the changes in angiogenesis during a shorter course of RTX.
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Affiliation(s)
- Saulius Svagzdys
- Unit of Coloproctology, Department of Surgery, Kaunas Medical University Clinics, Eiveniu 2, Kaunas, Lithuania.
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Kerr SF, Norton S, Glynne-Jones R. Delaying surgery after neoadjuvant chemoradiotherapy for rectal cancer may reduce postoperative morbidity without compromising prognosis. Br J Surg 2008; 95:1534-40. [PMID: 18942057 DOI: 10.1002/bjs.6377] [Citation(s) in RCA: 95] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND This retrospective study investigated whether the interval between neoadjuvant chemoradiotherapy and surgery for rectal cancer influences postoperative morbidity or prognosis. METHODS Data from 189 patients receiving neoadjuvant 5-fluorouracil-based chemoradiotherapy were examined. Associations between interval length and clinicopathological characteristics were analysed. RESULTS The median interval was 73 (range 6-215) days. Operations performed were abdominoperineal resection (60.3 per cent), anterior resection (37.6 per cent) and Hartmann's procedure (2.1 per cent). Forty-six patients (24.3 per cent) received postoperative chemotherapy. Interval was not significantly associated with pathological tumour (P = 0.648) or node (P = 0.964) category after chemoradiotherapy, or pathological complete response (P = 0.499). Logistic regression showed that shorter intervals (by 1 week) independently predicted anastomotic leakage (odds ratio (OR) 0.97 (95 per cent confidence interval (c.i.) 0.94 to 1.00)) and perineal wound complications (OR 0.97 (0.95 to 0.99)). Interval was not related to local recurrence (hazard ratio (HR) 1.01 (95 per cent c.i. 1.00 to 1.02)), metastasis (HR 1.00 (0.99 to 1.01)) or death (HR 1.00 (0.99 to 1.01)). Only circumferential resection margin and nodal involvement were independent predictors of survival. CONCLUSION Delaying surgery beyond 8 weeks after neoadjuvant chemoradiotherapy may reduce postoperative morbidity, without compromising prognosis.
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Affiliation(s)
- S F Kerr
- Centre for Cancer Treatment, Mount Vernon Hospital, Northwood HA62RN, UK
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Ahn GO, Brown JM. Matrix metalloproteinase-9 is required for tumor vasculogenesis but not for angiogenesis: role of bone marrow-derived myelomonocytic cells. Cancer Cell 2008; 13:193-205. [PMID: 18328424 PMCID: PMC2967441 DOI: 10.1016/j.ccr.2007.11.032] [Citation(s) in RCA: 352] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2007] [Revised: 10/16/2007] [Accepted: 11/28/2007] [Indexed: 11/23/2022]
Abstract
Tumor vasculature is derived from sprouting of local vessels (angiogenesis) and bone marrow (BM)-derived circulating cells (vasculogenesis). By using a model system of transplanting tumors into an irradiated normal tissue to prevent angiogenesis, we found that tumors were unable to grow in matrix metalloproteinase-9 (MMP-9) knockout mice, but tumor growth could be restored by transplantation of wild-type BM. Endothelial progenitor cells did not contribute significantly to this process. Rather, CD11b-positive myelomonocytic cells from the transplanted BM were responsible for tumor growth and the development of immature blood vessels in MMP-9 knockout mice receiving wild-type BM. Our results suggest that MMP-9 could be an important target for adjunct therapy to enhance the response of tumors to radiotherapy.
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MESH Headings
- Animals
- Antineoplastic Agents/pharmacology
- Antineoplastic Agents/therapeutic use
- Bone Marrow Cells/drug effects
- Bone Marrow Cells/enzymology
- Bone Marrow Cells/immunology
- Bone Marrow Transplantation
- CD11b Antigen/metabolism
- Diphosphonates/pharmacology
- Diphosphonates/therapeutic use
- Endothelial Cells/enzymology
- Imidazoles/pharmacology
- Imidazoles/therapeutic use
- Matrix Metalloproteinase 9/deficiency
- Matrix Metalloproteinase 9/genetics
- Matrix Metalloproteinase 9/metabolism
- Matrix Metalloproteinase Inhibitors
- Melanoma, Experimental
- Mice
- Mice, Inbred C3H
- Mice, Inbred C57BL
- Mice, Knockout
- Monocytes/drug effects
- Monocytes/enzymology
- Monocytes/immunology
- Monocytes/transplantation
- Myeloid Cells/drug effects
- Myeloid Cells/enzymology
- Myeloid Cells/immunology
- Myeloid Cells/transplantation
- Neoplasms, Experimental/blood supply
- Neoplasms, Experimental/drug therapy
- Neoplasms, Experimental/enzymology
- Neoplasms, Experimental/pathology
- Neoplasms, Experimental/radiotherapy
- Neovascularization, Pathologic/enzymology
- Neovascularization, Pathologic/pathology
- Neovascularization, Pathologic/prevention & control
- Protease Inhibitors/pharmacology
- Protease Inhibitors/therapeutic use
- Signal Transduction
- Stem Cells/enzymology
- Subcutaneous Tissue/blood supply
- Subcutaneous Tissue/radiation effects
- Subcutaneous Tissue/surgery
- Time Factors
- Zoledronic Acid
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Affiliation(s)
- G-One Ahn
- Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, 269 Campus Drive, CCSR-South, Room 1255, Stanford, CA 94305, USA
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Abstract
The vascular endothelial growth factor (VEGF) family of polypeptide growth factors regulates a family of VEGF receptor (VEGFR) tyrosine kinases with pleiotropic downstream effects. Angiogenesis is the best known of these effects, but additional VEGF-dependent actions include increased vascular permeability, paracrine/autocrine growth factor release, enhancement of cell motility, and inhibition of apoptosis. In theory, therapeutic inhibition of angiogenesis should reduce tumor perfusion and thus increase tumor hypoxia and chemoresistance, but in clinical practice the VEGF antibody bevacizumab acts as a broad-spectrum chemosensitizer. Since VEGFR expression occurs in many tumor types, such chemosensitization is more readily explained by direct inhibition of tumor cell survival signals than by indirect stromal/vascular effects. The emerging model of anti-VEGF drug action being mediated primarily by tumoral (as distinct from endothelial) VEGFRs has clinically important implications for optimizing the anti-metastatic efficacy of this expanding drug class.
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Affiliation(s)
- Richard J Epstein
- Department of Medicine, The University of Hong Kong, Pokfulam, Hong Kong.
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Maingon P, Créhange G, Peignaux K, Truc G. Place potentielle des thérapies ciblées en association avec la radiothérapie dans les cancers digestifs. Cancer Radiother 2008; 12:25-30. [DOI: 10.1016/j.canrad.2007.11.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2007] [Revised: 11/20/2007] [Accepted: 11/23/2007] [Indexed: 10/22/2022]
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Prestwich RJ, Errington F, Hatfield P, Merrick AE, Ilett EJ, Selby PJ, Melcher AA. The immune system--is it relevant to cancer development, progression and treatment? Clin Oncol (R Coll Radiol) 2007; 20:101-12. [PMID: 18037277 DOI: 10.1016/j.clon.2007.10.011] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2007] [Revised: 09/21/2007] [Accepted: 10/17/2007] [Indexed: 01/12/2023]
Abstract
The ability of the immune system to effectively respond to human tumours is a matter of long-term controversy. There is an increasing body of recent evidence to support a role for the immune system in eliminating pre-clinical cancers, an old concept termed 'immunosurveillance'. 'Immunoediting' is an updated hypothesis, in which selection pressures applied by the immune response to tumours modulate tumour immunogenicity and growth. Tumour infiltration by immune cells has been shown to have powerful prognostic significance in a host of cancer types. Paradoxically, in some circumstances the immune system can promote tumour development. Cytotoxic therapies, including radiotherapy and chemotherapy, induce potentially immunogenic cell death, releasing tumour-associated antigens in the context of a 'danger' signal to the immune system. An understanding of the interaction between immune cells, tumour cells and treatment modalities will therefore guide the future combination of immunotherapy with conventional therapy to achieve optimal anti-tumour effects.
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Affiliation(s)
- R J Prestwich
- Cancer Research UK, Leeds Institute of Molecular Medicine, St. James's University Hospital, Beckett Street, Leeds LS9 7TF, UK.
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