Neutrophils are the most abundant type of white blood cells circulating throughout the bloodstream and are often considered the frontline defenders in innate immunity. However, neutrophils are increasingly being recognized as having an important role in tumorigenesis and carcinogenesis due to their aberrant activation by molecules released into the tumor microenvironment. One defensive response of neutrophils that is aberrantly triggered during the neoplastic process is called NETosis, where activated neutrophils expel their DNA and intracellular contents in a web-like structure known as a neutrophil extracellular trap (NET). In cancer, NETosis has been linked to increased disease progression, metastasis, and complications such as venous thromboembolism. NET structures released by neutrophils can also serve as a scaffold for clot formation, shining new light on the role of neutrophils and NETosis in coagulation-mediated diseases.Here, we review current available knowledge regarding NET and the related NETosis process in cancer patients, with an emphasis on pre-clinical and clinical data fostering the identification and validation of biomarkers of NET with a predictive/prognostic role in cancer patients treated with immunotherapy agents. NETosis biomarkers, e.g., citH3, may integrate correlates of immunogenicity currently available (e.g., PD-L1 expression, TMB, TILs) and help select the subsets of patients who may most benefit from the use of the therapeutic weapons under discussion.

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The DNA damage response (DDR) network is exploited by cancer cells to withstand chemotherapy. Gastric cancer (GC) carries deregulation of the DDR and harbors genetic defects that fuel its activation. The ATM-Chk2 and ATR-Chk1-Wee1 axes are deputed to initiate DNA repair. Overactivation of these pathways in cancer cells may represent an adaptive response for compensating genetic defects deregulating G 1 -S transition (e.g., TP53) and ATM/ATR-initiated DNA repair (e.g., ARID1A). We hypothesized that DDR-linked biomarkers may predict clinical outcomes in GC patients treated with chemotherapy. Immunohistochemical assessment of DDR kinases (pATM, pChk2, pChk1 and pWee1) and DNA damage markers (c-H2AX and pRPA32) was performed in biological samples from 110 advanced GC patients treated with first-line chemotherapy, either in phase II trials or in routine clinical practice. In 90 patients, this characterization was integrated with targeted ultra-deep sequencing for evaluating the mutational status of TP53 and ARID1A. We recorded a positive association between the investigated biomarkers. The combination of two biomarkers (c-H2AX high /pATM high ) was an adverse factor for both progression-free survival (multivariate Cox: HR 2.23, 95%CI: 1.47-3.40) and overall survival (multivariate Cox: HR: 2.07, 95%CI: 1.20-3.58). The relationship between the c-H2AX high /pATM high model and progression-free survival was consistent across the different TP53 backgrounds and was maintained in the ARID1A wild-type setting. Conversely, this association was no longer observed in an ARID1A-mutated subgroup. The c-H2AX high /pATM high model negatively impacted survival outcomes in GC patients treated with chemotherapy. The mutational status of ARID1A, but apparently not TP53 mutations, affects its predictive significance.Key words: DNA damage repair, g-H2AX, pATM, TP53, ARID1A Abbreviations: ATM: ataxia-telangiectasia mutated; ATR: ataxia telangiectasia and rad3-related protein; Chk1: checkpoint kinase 1; Chk2: checkpoint Kinase 2; DDR: DNA damage and repair; DNA DSBs: DNA double-strand breaks; DNA SSBs: DNA single-strand breaks; OS: overall survival; g-H2AX: phosphorylated H2A histone family member X; PFS: progression-free survival; pRPA32: phosphorylated replication protein A2; Wee1: Wee1-like protein kinase Additional Supporting Information may be found in the online version of this article. Livia Ronchetti, Elisa Melucci, Francesca De Nicola and Frauke Goeman contributed equally to this work. Ruggero De Maria and Marcello Maugeri-Sacc a share senior authorship MM-S and RDM conceived and designed the study. LR, EM, BC, CAA, EG, EP, MGD, SB and MM were involved in molecular pathology analysis. FDN, FG and MF carried out targeted DNA deep sequencing. FS, MP, IT and MB performed bioinformatic and statistical analyses. LP, PV, DS and LDL acquired the data related to clinical features, treatment administered and therapeutic outcomes. IV was involved in study design and provided critical revision of the manuscript for important intellectual con...

The immune escape mechanisms at the base of tumor progression in endometrial cancer mimic immune tolerance mechanisms occurring at the maternal-fetal interface. The biological and immunological processes behind the maternal-fetal interface are finely tuned in time and space during embryo implantation and subsequent pregnancy stages; conversely, those behind cancer progression are often aberrant. The environment composition at the maternal-fetal interface parallels the pro-tumor microenvironment identified in many cancers, pointing to the possibility for the use of the maternal-fetal interface as a model to depict immune therapeutic targets in cancer. The framework of cancer environment signatures involved in immune adaptations, precisely timed in cancer progression, could reveal a specific "immune clock" in endometrial cancer, which might guide clinicians in patient risk class assessment, diagnostic workup, management, surgical and therapeutic approach, and surveillance strategies. Here, we review studies approaching this hypothesis, focusing on what is known so far about oncofetal similarities in immunity with the idea to individualize personalized immunotherapy targets, through the downregulation of the immune escape stage or the reactivation of the pro-inflammatory processes suppressed by the tumor.

BACKGROUND:The increasing incidence of human papillomavirus (HPV)-related head and neck squamous cell carcinoma (HNSCC) highlights the need for simple and effective tools to evaluate head and neck lesions and their HPV status. The main objective of the current study was to investigate the association between abnormal cytology and HPV infection, assessed on cytobrushing samples, and histologically confirmed HNSCC. Second, the authors attempted to investigate whether HPV status on cytobrushing samples reflected that of the tumoral tissue. METHODS: A total of 164 samples from HNSCC, nonmalignant lesions, or healthy mucosae of the oral cavity and oropharynx were collected by cytobrushing in PreservCyt solution and evaluated by liquid-based cytology and Linear Array HPV genotyping test. All the findings from the cytologic samples were compared with those from the corresponding histologic samples. RESULTS: Patients with abnormal cytology had a significantly higher risk of having an HNSCC (odds ratio [OR], 9.18; 95% confidence inteval [95% CI], 3.27-26.49). The association was stronger for oral cancer (OR, 10.86; 95% CI, 2.51-51.06) than oropharyngeal cancer (OR, 8.45; 95% CI,. HPV positivity in the oropharyngeal cytobrushing was associated with a nearly 5-fold higher risk of having abnormal cytology (OR, 4.57; 95% CI, 1.57-13.57) as well as histologically proven oropharyngeal cancer (OR, 5.09; 95% CI, 1.09-31.61). Comparing the HPV status on cytologic and corresponding histologic samples from patients with HNSCC, we found that 90.4% of the cases were concordant (kappa, 0.796). CONCLUSIONS: Abnormal brushing cytology is strongly associated with a diagnosis of HNSCC, whereas HPV positivity on cytobrushing samples is only associated with oropharyngeal cancer. HPV testing on cytobrushing samples represents a valid option for the assessment of HPV infection in patients with oropharyngeal cancer. Cancer 2014;120:3477-84. V C 2014 American Cancer Society.KEYWORDS: cytology, human papillomavirus, head and neck, squamous cell carcinoma. INTRODUCTIONThe incidence of human papillomavirus (HPV)-related head and neck squamous cell carcinoma (HNSCC) has been significantly increasing over the last few years, as demonstrated by a growing number of studies conducted in Europe and North America. 1,2 HPV, particularly the HPV type 16, has been found to be etiologically associated especially with SCC of the oropharynx. 3,4 Notably, HPV-positive cancers differ from the HPV-negative ones with regard to response to treatment and survival, with HPV infection being a favorable prognostic marker. 5-7 Therefore, HPV testing is acquiring a growing significance for patients with HNSCC, particularly those with oropharyngeal SCC, and there is an increasing demand for simple, rapid, and effective methods for sample collection and the evaluation of HPV infection. Importantly, diagnostic tissues may be very scant in patients with small primary tumors, making it difficult to perform further analyses such as HPV testing. In addition, there is a growing ...