The clearance of oral high-risk human papillomavirus infection is impaired by long-term persistence of cervical human papillomavirus infection

AbstractPersistence of high-risk (HR-) human papillomavirus (HPV) infection of the uterine cervix increases the risk of cervical cancer. Oral HPV infections are among potential covariates of long-term genotype-specific persistent cervical HR-HPV infections. It is not known whether this persistence reflects inability of the host to reject HPV infections in general. A case–control setting was designed to estimate the covariates of long-term persistent cervical HR-HPV infections using multivariate generalized estimating equation (GEE) models. HPV was detected with PCR using GP05+/GP06+-primers and genotyped for 24 HPVs with a Multimetrix-kit. The cases (n = 43) included women who had genotype-specific persistent cervical HR-HPV infection for at least 24 months (24M+) and controls were women who tested repeatedly HPV-negative in their cervical samples (n = 52). These women represent a sub-cohort of the Finnish Family HPV Study. The cases differed significantly from the HPV-negative controls in several aspects: they were younger, had a longer mean time to incident oral HPV infection (40.7 versus 23.6 months), longer duration of oral HPV persistence (38.4 versus 14.1 months), and longer time to clearance of their oral HPV infection (50.0 versus 28.2 months). In multivariate GEE analysis, the second pregnancy during the follow up was the only independent predictor with significant protective effect against 24M+ persistent cervical HR-HPV infections, OR of 0.15 (95% CI 0.07–0.34). To conclude, long-term persistent cervical HR-HPV infections are associated with a prolonged clearance of oral HR-HPV infections while new pregnancy protects against persistent cervical HR-HPV infections

Epstein-Barr virus (EBV)-encoded small RNAs (EBERs) associated with poor prognosis of head and neck carcinomas

BACKGROUND: Epstein-Barr virus (EBV) is the main cause of nasopharyngeal carcinoma (NPC), also found in other head and neck carcinomas (HNSCCs) where its role remains controversial.RESULTS: EBV was found in 80% and 21% of the samples with PCR and ISH (in cancer cells), respectively. Eight of ISH-positive samples were not NPCs. EBER-RNA detection in carcinoma cells was associated with worse prognosis, whether or not NPCs were included. HPV/EBV and HSV/HPV coinfections associated with a shorter survival. LMP-1 expression, positive in 51% of samples did not correlate with the disease outcome.MATERIALS AND METHODS: We analyzed EBV in 73 HNSCC samples with a known HPV and HSV-1 status, using in situ hybridization (ISH) and immunohistochemistry (IHC) for EBV-early transcripts (EBER) and LMP-1 protein, respectively. EBV-DNA was detected with a Luminex-based method. The results were correlated with HPV-status and disease outcome.CONCLUSIONS: EBV is transcriptionally active in NPC cells but also in a subgroup of other HNSCCs.</p

Behavior of FDG-avid supradiaphragmatic lymph nodes in PET/CT throughout primary therapy in advanced serous epithelial ovarian cancer: a prospective study

BackgroundEpithelial ovarian cancer (EOC) typically spreads intra-abdominally, but preoperative evaluation with FDG PET/CT often reveals metabolically active supradiaphragmatic lymph nodes (sdLNs). Their clinical significance and behavior during treatment has not been established.MethodsEOC patients with PET positive sdLNs at diagnosis were prospectively followed with PET/CT after primary chemotherapy and at the first recurrence. In each patient, 2 most active LNs in 5 different supradiaphramatic regions were evaluated and the size and changes in FDG uptake (SUVmax) were recorded. The patients overall response to primary treatment was defined with RECIST criteria. The behavior of sdLNs during chemotherapy were compared in treatment responders and non-responders. Recurrence patterns were monitored.ResultsForty-one patients with 127 PET/CT scans were systematically evaluated. In pretreatment scan, 76% (31/41) of patients had FDG-avid sdLNs in multiple anatomical sites. Only a minority (22/136) of the sdLNs were enlarged in size, but their histopathologic confirmation by biopsy was not possible. Only 6/41 patients had FDG-avid sdLNs in a single surgically approachable site. The sdLNs became inactive during primary chemotherapy more often in the RECIST responders compared to the non-responders (HR 1.46 (95%CI: 1.09-1.96), p=0.002). The size and SUVmax values did not predict treatment outcome. In 50% of the responders the same sdLNs reactivated when recurrence occurred. Persistent post-treatment metabolic activity did not predict earlier disease relapse (p=0.59).ConclusionThe behavior of metabolically active sdLNs during chemotherapy supports their metastatic nature. Due to their distribution to multiple regions, the benefit of removal of reachable sdLNS seems unlikely.Trial registration>NCT, NCT01276574. Registered 1 September 2010

Tumor cell-specific AIM2 regulates growth and invasion of cutaneous squamous cell carcinoma

Cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer. Inflammation is a typical feature in cSCC progression. Analysis of the expression of inflammasome components in cSCC cell lines and normal human epidermal keratinocytes revealed upregulation of the expression of AIM2 mRNA and protein in cSCC cells. Elevated levels of AIM2 mRNA were noted in cSCCs in vivo compared with normal skin. Strong and moderate tumor cell specific expression of AIM2 was detected with immunohistochemistry (IHC) in sporadic human cSCCs in vivo, whereas expression of AIM2 was moderate in cSCC in situ (cSCCIS) and low or absent in actinic keratosis (AK) and normal skin. IHC of cSCCs, cSCCIS and AKs from organ transplant recipients also revealed strong and moderate tumor cell specific expression of AIM2 in cSCCs. Knockdown of AIM2 resulted in reduction in viability of cSCC cells and onset of apoptosis. RNA-seq and pathway analysis after knockdown of AIM2 in cSCC cells revealed downregulation of the biofunction category Cell cycle and upregulation of the biofunction category Cell Death and Survival. Knockdown of AIM2 also resulted in reduction in invasion of cSCC cells and downregulation in production of invasion proteinases MMP1 and MMP13. Knockdown of AIM2 resulted in suppression of growth and vascularization of cSCC xenografts in vivo. These results provide evidence for the role of AIM2 in the progression of cSCC and identify AIM2 inflammasome function as a potential therapeutic target in these invasive and metastatic tumors.</p

Co-evolution of matrisome and adaptive adhesion dynamics drives ovarian cancer chemoresistance

Due to its dynamic nature, the evolution of cancer cell-extracellular matrix (ECM) crosstalk, critically affecting metastasis and treatment resistance, remains elusive. Our results show that platinum-chemotherapy itself enhances resistance by progressively changing the cancer cell-intrinsic adhesion signaling and cell-surrounding ECM. Examining ovarian high-grade serous carcinoma (HGSC) transcriptome and histology, we describe the fibrotic ECM heterogeneity at primary tumors and distinct metastatic sites, prior and after chemotherapy. Using cell models from systematic ECM screen to collagen-based 2D and 3D cultures, we demonstrate that both specific ECM substrates and stiffness increase resistance to platinum-mediated, apoptosis-inducing DNA damage via FAK and β1 integrin-pMLC-YAP signaling. Among such substrates around metastatic HGSCs, COL6 was upregulated by chemotherapy and enhanced the resistance of relapse, but not treatment-naïve, HGSC organoids. These results identify matrix adhesion as an adaptive response, driving HGSC aggressiveness via co-evolving ECM composition and sensing, suggesting stromal and tumor strategies for ECM pathway targeting. </p