Influence of Combined Therapy on Generation of Neutrophil Extracellular Traps in Patients with Cervical Cancer

BACKGROUND: According to several authors, neutrophil extracellular traps (NETs) play an important role in the mechanisms of cancer development and metastatic processes, which allows them to be considered as a potential new target for the treatment of cancer. AIM: To investigate the presence of extracellular neutrophil traps in the blood of patients with cervical cancer on the background of the combined treatment. MATERIALS AND METHODS: The study was conducted in 28 patients with cervical cancer. Group 1 received only radiation therapy; Groups 2-radiation therapy with ftorafur; Group 3-radiation therapy with cisplatin. To determine the number of spontaneous extracellular neutrophilic traps in the blood of the examined individuals, we used a technique of I.I. Dolgushin and Yu.S. Andreeva. RESULTS: Peripheral blood neutrophils in 53.57% (33.87; 72.49) of cervical cancer patients showed the ability to generate NETs before treatment. The ability to form NETs was observed in neutrophils isolated from 66.67% (9.43; 99.16) patients of the Group 1. After radiation therapy with ftorafur, the ability of blood neutrophils to form NETs was observed in 50% (1.26; 98.74) of cervical cancer patients. After radiotherapy with cisplatin, 37.50% (15.20; 64.57) of patients were found to have NETs formation CONCLUSION: The ability to form NETs varied greatly after radiotherapy. The addition of chemotherapy drugs to radiation therapy did not increase the percentage of NETs in the blood of patients with cervical cancer but stimulated the appearance of basophil extracellular traps.

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Gut microbiome diversity is an independent predictor of survival in cervical cancer patients receiving chemoradiation

Communications Biology ◽

10.1038/s42003-021-01741-x ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Travis T. Sims ◽

Molly B. El Alam ◽

Tatiana V. Karpinets ◽

Stephanie Dorta-Estremera ◽

Venkatesh L. Hegde ◽

...

Keyword(s):

Cervical Cancer ◽

Radiation Therapy ◽

Gut Microbiota ◽

Cancer Patients ◽

Gut Microbiome ◽

Compositional Variation ◽

Short Term ◽

Microbiome Diversity ◽

Term Survivor

AbstractDiversity of the gut microbiome is associated with higher response rates for cancer patients receiving immunotherapy but has not been investigated in patients receiving radiation therapy. Additionally, current studies investigating the gut microbiome and outcomes in cancer patients may not have adjusted for established risk factors. Here, we sought to determine if diversity and composition of the gut microbiome was independently associated with survival in cervical cancer patients receiving chemoradiation. Our study demonstrates that the diversity of gut microbiota is associated with a favorable response to chemoradiation. Additionally, compositional variation among patients correlated with short term and long-term survival. Short term survivor fecal samples were significantly enriched in Porphyromonas, Porphyromonadaceae, and Dialister, whereas long term survivor samples were significantly enriched in Escherichia Shigella, Enterobacteriaceae, and Enterobacteriales. Moreover, analysis of immune cells from cervical tumor brush samples by flow cytometry revealed that patients with a high microbiome diversity had increased tumor infiltration of CD4+ lymphocytes as well as activated subsets of CD4 cells expressing ki67+ and CD69+ over the course of radiation therapy. Modulation of the gut microbiota before chemoradiation might provide an alternative way to enhance treatment efficacy and improve treatment outcomes in cervical cancer patients.

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755 CXCR1 and CXCR2 chemokine receptor agonists produced by tumors induce neutrophil extracellular traps that interfere with immune cytotoxicity

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0755 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A803-A803 ◽

Cited By ~ 1

Author(s):

Alvaro Teijeira ◽

Saray Garasa ◽

Itziar Migueliz ◽

Assunta Cirella ◽

Ignacio Melero

Keyword(s):

Cancer Patients ◽

Tumor Cells ◽

Mouse Models ◽

Chemokine Receptor ◽

Suppressor Cells ◽

Neutrophil Extracellular Traps ◽

Myeloid Derived Suppressor Cells ◽

Extracellular Traps ◽

Tumor Associated Neutrophils

BackgroundNeutrophils are expanded and abundant in an important fraction (up to 35% of patients) in cancer-bearing hosts. When neutrophils are expanded, they usually promote exert immunomodulatory functions promoting tumor progression and the generation of metastases. Neutrophils can undergo a specialized form of cell death called NETosis that is characterized by the extrusion of their DNA to contain infections. In cancer NETs have been described to promote metastases in mouse models. IL-8, a CXCR1/2 ligand clinically targeted by blocking antibodies, has been described to induce NETosis and is upregulated in many cancer patients. Our hypothesis is that chemokines secreted by cancer cells can mediate NETosis in tumor associated neutrophils and that NETs can be one of the immunomodulatory mechanisms provided by tumor associated neutrophils.MethodsNETosis induction of peripheral neutrophils and granulocytic myeloid derived suppressor cells by different chemotactic stimuli, tumor cell supernatants and cocultures upon CXCR1/2 blockade. NET immunodetection in mouse models and xenograft tumors upon CXCR1/2 blockade. In vitro tumor cytotoxicity assays in the presence/absence of NETs, and videomicroscopy studies in vitro and by intravital imaging to test NETs inhibition of immune cytotoxicity by immune-cell/target-cell inhibition. Tumor growth studies and metastases models in the presence of NETosis inhibitors and in combination with checkpoint blockade in mouse cancer models.ResultsUnder the influence of CXCR1 and CXCR2 chemokine receptor agonists and other chemotactic factors produced by tumors, neutrophils, and granulocytic myeloid-derived suppressor cells (MDSCs) from cancer patients extrude their neutrophil extracellular traps (NETs). In our hands, CXCR1 and CXCR2 agonists proved to be the major mediators of cancer-promoted NETosis. NETs wrap and coat tumor cells and shield them from cytotoxicity, as mediated by CD8+ T cells and natural killer (NK) cells, by obstructing contact between immune cells and the surrounding target cells. Tumor cells protected from cytotoxicity by NETs underlie successful cancer metastases in mice and the immunotherapeutic synergy of protein arginine deiminase 4 (PAD4) inhibitors, which curtail NETosis with immune checkpoint inhibitors. Intravital microscopy provides evidence of neutrophil NETs interfering cytolytic cytotoxic T lymphocytes (CTLs) and NK cell contacts with tumor cells.ConclusionsCXCR1 and 2 are the main receptors mediating NETosis of tumor associated neutrophils in our in-vitro and in vivo systems expressing high levels of CXCR1 and 2 ligands. NETs limit cancer cell cytotoxicity by impeding contacts with cancer cells.

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Post-radiation damage to the pelvic girdle in cervical cancer patients: Is intensity modulated radiation therapy safer than conventional radiation?

Gynecologic Oncology ◽

10.1016/j.ygyno.2012.07.028 ◽

2012 ◽

Vol 127 (1) ◽

pp. S10

Author(s):

Y. Ioffe ◽

T. Hillen ◽

G. Zhou ◽

J. Schwarz ◽

D. Mutch ◽

...

Keyword(s):

Cervical Cancer ◽

Radiation Therapy ◽

Radiation Damage ◽

Cancer Patients ◽

Intensity Modulated Radiation Therapy ◽

Pelvic Girdle ◽

Intensity Modulated ◽

Conventional Radiation ◽

Post Radiation

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Effectiveness of intensity-modulated radiation therapy with simultaneous integrated boost in cervical cancer patients with PET positive lymph nodes

Journal of Radiation Oncology ◽

10.1007/s13566-017-0294-7 ◽

2017 ◽

Vol 6 (2) ◽

pp. 167-173

Author(s):

John W Shumway ◽

Alfredo E Echeverria ◽

Umang Patel ◽

Joshua Asper ◽

Mark Bonnen ◽

...

Keyword(s):

Cervical Cancer ◽

Radiation Therapy ◽

Lymph Nodes ◽

Cancer Patients ◽

Intensity Modulated Radiation Therapy ◽

Simultaneous Integrated Boost ◽

Intensity Modulated ◽

Integrated Boost ◽

Positive Lymph Nodes

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Predictive factors of posttreatment fracture by definitive radiotherapy for uterine cervical cancer

Japanese Journal of Radiology ◽

10.1007/s11604-020-01039-8 ◽

2020 ◽

Author(s):

Kazuki Ishikawa ◽

Tsuneo Yamashiro ◽

Takuro Ariga ◽

Takafumi Toita ◽

Wataru Kudaka ◽

...

Keyword(s):

Quality Of Life ◽

Risk Factors ◽

Cervical Cancer ◽

Multivariate Analysis ◽

Radiation Therapy ◽

Cancer Patients ◽

Clinical Characteristics ◽

Univariate Analysis ◽

Uterine Cervical Cancer

Abstract Purpose Fractures are known to shorten life expectancy and worsen the quality of life. The risk of fractures after radiation therapy in cervical cancer patients is known to be multifactorial. In this study, we examined risk factors for fractures in cervical cancer patients, especially by evaluating bone densities and DVH parameters for fractured bones. Materials and Methods For 42 patients, clinical characteristics, pretreatment CT bone densities, and radiation dose were compared between patients with and without fractures. Results Posttreatment fractures occurred in 25 bones among ten patients. Pretreatment CT bone densities were significantly lower in patients with fractures (P < 0.05–0.01 across sites, except for the ilium and the ischium). Although DVH parameters were also significantly associated with fractures in univariate analysis, only CT densities were significantly associated with fractures in multivariate analysis. Conclusion Pretreatment CT densities of spinal and pelvic bones, which may reflect osteoporosis, have a significant impact on the risk for posttreatment fractures.

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Self-Reported Sexual, Bowel and Bladder Function in Cervical Cancer Patients Following Different Treatment Modalities: Longitudinal Prospective Cohort Study

International Journal of Gynecological Cancer ◽

10.1097/igc.0b013e3182a80a65 ◽

2013 ◽

Vol 23 (9) ◽

pp. 1717-1725 ◽

Cited By ~ 48

Author(s):

Quirine D. Pieterse ◽

Gemma G. Kenter ◽

Cornelis P. Maas ◽

Cor D. de Kroon ◽

Carien L. Creutzberg ◽

...

Keyword(s):

Cervical Cancer ◽

Radiation Therapy ◽

Cohort Study ◽

Cancer Patients ◽

Early Stage ◽

Unexpected Finding ◽

Prognostic Features ◽

Sexual Symptoms ◽

Significant Difference ◽

Early Stage Cervical Cancer

ObjectiveConventional radical hysterectomy with pelvic lymphadenectomy (RHL) for early-stage cervical cancer is associated with significant bladder, anorectal, and sexual dysfunction. Nerve-sparing modification of RHL (NS-RHL) has been developed with the aim to reduce surgical treatment-related morbidity. Postoperative radiation therapy (RT) is offered to patients with unfavorable prognostic features to improve local control. The aim of the study was to assess self-reported morbidity of various types of treatment in cervical cancer patients.MethodsSelf-reported symptoms were prospectively assessed before and 1 and 2 years after treatment by the Dutch Gynaecologic Leiden Questionnaire.ResultsIncluded were 229 women (123 NS-RHL and 106 conventional RHL). Ninety-four (41%) received RT. Up to 2 years (response rate, 81%), women reported significantly more bowel, bladder, and sexual symptoms compared with the pretreatment situation. No significant difference was found between the conventional RHL and NS-RHL with the exception of the unexpected finding that a smaller percentage in the NS-RHL group (34% vs 68%) complained about numbness of the labia and/ or thigh. Radiation therapy had a negative impact on diarrhea, urine incontinence, lymphedema, and sexual symptoms (especially a narrow/short vagina).ConclusionsIn the current longitudinal cohort study, treatment for early-stage cervical cancer was associated with worse subjective bladder, anorectal, and sexual functioning, irrespective of the surgical procedure used. Postoperative RT resulted in a significant deterioration of these functions. The results have to be interpreted with caution in view of the study design and method used.

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