Related Precancerous Lesions Research Articles

Vaginal microbiome disorders as the prognostic factor in the hpv hr related precancerous lesions

Vaginal microbiome disorders as the prognostic factor in the hpv hr related precancerous lesions

Deoxyribonucleic acid methylation driven aberrations in pancreatic cancer-related pathways.

Pancreatic cancer (PanCa) presents a catastrophic disease with poor overall survival at advanced stages, with immediate requirement of new and effective treatment options. Besides genetic mutations, epigenetic dysregulation of signaling pathway-associated enriched genes are considered as novel therapeutic target. Mechanisms beneath the deoxyribonucleic acid methylation and its utility in developing of epi-drugs in PanCa are under trails. Combinations of epigenetic medicines with conventional cytotoxic treatments or targeted therapy are promising options to improving the dismal response and survival rate of PanCa patients. Recent studies have identified potentially valid pathways that support the prediction that future PanCa clinical trials will include vigorous testing of epigenomic therapies. Epigenetics thus promises to generate a significant amount of new knowledge of biological and medical importance. Our review could identify various components of epigenetic mechanisms known to be involved in the initiation and development of pancreatic ductal adenocarcinoma and related precancerous lesions, and novel pharmacological strategies that target these components could potentially lead to breakthroughs. We aim to highlight the possibilities that exist and the potential therapeutic interventions.

Noninvasive early detection of colorectal cancer by hypermethylation of the LINC00473 promoter in plasma cell-free DNA

BackgroundCurrent noninvasive assays have limitations in the early detection of colorectal cancer. We evaluated the clinical utility of promoter methylation of the long noncoding RNA LINC00473 as a noninvasive biomarker to detect colorectal cancer and associated precancerous lesions.MethodsWe evaluated the epigenetic regulation of LINC00473 through promoter hypermethylation in colorectal cancer cell lines using bisulfite genomic sequencing and expression analyses. DNA methylation of LINC00473 was analyzed in primary colorectal tumors using 450K arrays and RNA-seq from The Cancer Genome Atlas (TCGA). Tissue-based findings were validated in several independent cohorts of colorectal cancer and advanced colorectal polyp patients by pyrosequencing. We explored the clinical utility of LINC00473 methylation for the early detection of colorectal cancer in plasma cell-free DNA by quantitative methylation-specific PCR and droplet digital PCR.ResultsLINC00473 showed transcriptionally silencing due to promoter hypermethylation in colorectal cancer cell lines and primary tumors. Methylation of the LINC00473 promoter accurately detected primary colorectal tumors in two independent clinical cohorts, with areas under the receiver operating characteristic curves (AUCs) of 0.94 and 0.89. This biomarker also identified advanced colorectal polyps from two other tissue-based clinical cohorts with high diagnostic accuracy (AUCs of 0.99 and 0.78). Finally, methylation analysis of the LINC00473 promoter in plasma cell-free DNA accurately identified patients with colorectal cancer and advanced colorectal polyps (AUCs of 0.88 and 0.84, respectively), which was confirmed in an independent cohort of patients.ConclusionsHypermethylation of the LINC00473 promoter is a new promising biomarker for noninvasive early detection of colorectal cancer and related precancerous lesions.

Health-Related Quality of Life and Utility Scores of Posttreatment Patients with Gastric Cancer at Different Pathological Stages: A Cross-Sectional Study.

Background Health-related quality of life (HRQoL) is a key variable in the evaluation of health economics. We aimed to evaluate the HRQoL and utility scores of patients with gastric cancer and related precancerous lesions by assessing their quality of life using a single standardized health measurement instrument. Methods A cross-sectional study was conducted in six counties in Shangdong Province from November 2019 to March 2020. Subjects with precancerous lesions and gastric cancer (cardia and noncardia) were included and surveyed. Patients were divided into four groups: low-grade intraepithelial neoplasia (LGIN), high-grade intraepithelial neoplasia (HGIN), early gastric cancer (EGC), and advanced gastric cancer (AGC). All patients, except those with LGIN, received treatment. The five-level EQ-5D was used to assess HRQoL and generate utility scores using the Chinese-specific tariff published in 2017. Results The study included 566 respondents. The average utility was 0.927 for precancerous lesions (LGIN: 0.930; HGIN: 0.926), 0.906 for early gastric cancer (EGC), and 0.756 for advanced gastric cancer (AGC). Visual analogue scale (VAS) means were 76.82 (LGIN: 78.08; HGIN: 74.81), 72.26, and 69.16 for precancerous lesions, EGC, and AGC, respectively. HRQoL was lower in women with AGC than in men (0.612 vs. 0.792, P = 0.035). AGC patients were more likely to report problems across all five dimensions than patients in other stages. The proportion of patients reporting pain/discomfort problems was highest across all gastric cancer stages (LGIN, 35.6%; HGIN, 34.4%; EGC, 35.6%; and AGC, 55.7%), followed by anxiety/depression (LGIN, 17.5%; HGIN, 18%; EGC, 22.8%; and AGC, 47.7%). Conclusions HRQoL declined as cancer progressed, with the most dramatic decline observed in patients with AGC. A more advanced pathological stage was associated with a greater decrease in health utility. The obtained utilities for different pathological stages of gastric cancer were significant parameters for researchers to perform further cost-utility analysis. Pain/discomfort and anxiety/depression were problems that seriously affected the patients in all groups.

Genital human papillomavirus infections.

Human papillomavirus (HPV) infections can have clinical presentations from self-limited benign growth in the skin and mucosal epithelia to malignant growth. HPV infects basal epithelial cells (undifferentiated keratinocytes) of the squamous-columnar junction, especially of the cervix. Although today we understand HPV oncogenesis very well, we have very powerful methods of diagnosis, treatment and prevention of HPV related precancerous lesions, however, more than 270,000 women annually die from cervical cancer worldwide. Integrating HPV vaccination with new, more sensitive, cervical screening assays as part of routine preventive care will improve healthcare for all women. The availability of prophylactic HPV vaccines has provided powerful tools for primary prevention of cervical cancer and other HPV-associated diseases. Secondary prevention through primary high-risk HPV (hr-HPV) testing has the potential to further reduce morbidity and mortality of cervical cancer. However, to achieve the maximum benefit of screening, there is need to continue to identify women who are either unscreened or under-screened. Synergies between HPV vaccination and HPV screening is recommended to improve the effectiveness and cost-effectiveness of prevention HPV-related disease.

Abstract 806: Modeling human UV-induced skin cancer through genetic manipulation of Src-kinases and Srcasm

Abstract UV-induced skin cancer is the most common form of cancer and its incidence continues to increase. Novel in vivo models that mimic human UV-induced skin cancer are needed to further studies and evaluate new therapies. Keratinocyte growth is regulated through oncogenic signals from EGFR and Src-family tyrosine kinases (SFKs); these tyrosine kinases are primary drivers of keratinocyte growth in UV-induced skin cancer. At the proteomic level, activated EGFR and SFKs are negatively regulated by Srcasm which targets activated tyrosine kinases for lysosomal degradation. Studies have shown that SFK activity is increased and Srcasm levels are decreased in human cutaneous squamous cell carcinomas and related precancerous lesions. We hypothesized that genetic downregulation of Srcasm by gene deletion or lentivirally mediated shRNA knockdown would promote oncogenic signaling and keratinocyte growth thereby promoting UV-induced skin cancer. To test this hypothesis Srcasm null mice and Srcasm lentiviral knockdown in human keratinocytes were generated and studied. Western blotting of epidermal lysates from Srcasm null mice demonstrates that loss of Srcasm promotes activation of EGFR and Src kinases and decreases levels of p53, NICD and p21. Activation of the canonical Erk1/2, STAT-3 and PDK-1 oncogenic pathways also was seen in Srcasm null keratinocytes. The epidermis of Srcasm null mice exhibits a higher Ki-67 index of 8.7 +/- 2.0 compared to 1.5 +/- 1.1 in controls (p<0.001). UVB irradiation (500 mJ/cm2 × 15 doses) produced precancerous lesions in Srcasm null mice resembling human actinic keratoses but not in controls; the precancerous lesions show an increased Ki-67 index and activation of Src kinases, STAT-3 and PDK-1. Acute UVB irradiation (1200 mJ/cm2 × 1 dose) of Srcasm null mice induced prominent erythema, epidermal necrosis and a prominent increase in the TUNEL-positive index (14.0 vs 1.3). Srcasm knockdown in human keratinocytes accelerated keratinocyte growth 130%; it also increased levels of EGFR and accelerated the kinetics of EGFR and MAPK activation in response to EGF stimulation. In human keratinocytes, Srcasm knockdown accelerated cell growth post-UV exposure which could promote neoplasia. These data show that loss of Srcasm is associated with increased oncogenic signaling, impaired p53 function and keratinocyte proliferation. Loss of Srcasm promotes keratinocyte proliferation post-UV exposure leading to the early stages of UVB-induced cutaneous neoplasia. Citation Format: Xiaoping Yang, Sheila Shankar, Hiroshi Maeno, Micheal Gober, Christine Marshall, Tzvete Dentchev, John Seykora. Modeling human UV-induced skin cancer through genetic manipulation of Src-kinases and Srcasm. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 806. doi:10.1158/1538-7445.AM2015-806

Detection of precancerous gastric lesions and gastric cancer through exhaled breath

ObjectivesTimely detection of gastric cancer (GC) and the related precancerous lesions could provide a tool for decreasing both cancer mortality and incidence.Design968 breath samples were collected from 484 patients (including...

HPV Vaccination to Prevent HIV Infection: Time for Randomized Controlled Trials

Despite many years of rigorous evaluation of a variety of interventions, HIV incidence rates in parts of Africa remain unacceptably high. A recent review identified 37 randomized controlled trials testing interventions to reduce HIV incidence.1 Except for 3 randomized controlled trials of male circumcision2‐4 and 1 trial of syndromic treatment of sexually transmitted diseases,5 and, recently, 1 trial of a vaginal microbicide,6 no significant reductions in HIV incidence were observed. In some trials of vaginal microbicides, trial participants in the active treatment arm actually had increased HIV incidence rates.7 Trials with candidate vaccines have been equally disappointing.8 A recently completed trial of a prime-boost strategy conducted in Thailand showed statistically significant, but limited, protection against HIV.9 Nevertheless, even vaccine optimists think that a preventive HIV vaccine is many years away. Sexually transmitted infections (STIs) were identified as important cofactors for HIV transmission early in the epidemic.10,11 Many prospective observational studies showed that the presence of ulcerative and nonulcerative STIs increased the likelihood of HIV transmission.10,11 Several interventions were based on this observation including mass treatment with antibiotics,12 improved syndromic management of STIs,5,13 and herpes simplex virus (HSV)-2 suppressive treatment.14 Null findings of these interventions should be interpreted with caution. Failure to show an effect does not necessarily mean that the STI is not causally associated with HIV. As Barnabas and Wasserheit highlight,15 the stage of the HIV epidemic in which an intervention trial is conducted may significantly influence observed efficacy. Another possible reason for the failure of these trials to demonstrate efficacy is that the intervention may not have adequately controlled the STI or its biologic effects.

HPV-16 infection and cervical cancer: Modeling the influence of duration of infection and precancerous lesions

The patterns of transmission, clearance, and progression of HPV infection and the related precancerous lesions are key to accurately model cervical cancer epidemiology and prevention.We have developed an age-structured dynamic model of the transmission of HPV-16 infection. This mathematical model accounts, for the first time, for the effect of infection and precancerous lesions duration on the natural history of HPV-16 infection and precancerous lesions. The model's output has been fitted to contemporaneous sets of data from Turin, Italy, to estimate parameters that have had been indirectly tested by comparing them with other estimates reported in the literature.The average probability of HPV-16 infection transmission per sexual partnership was about 40%. The HPV-16 clearance and progression rates decreased as the length of time with infection increased, clearance ranging between 1.6 per woman-year (in the first 6months of infection) and 0.036 (after more than 6years of infection), and progression between 0.072 and 0.018 per woman-year. The rate of clearance of precancerous lesions (CIN2+) was inversely dependent on age, while the progression of CIN2+ toward invasive cervical cancer increased as the precancerous lesions persisted. The present study also suggests that an exclusive role of women's age in shaping the rate of progression to cancer is unlikely.These results should inform future analyses. Including more accurately the role of the duration of infection and precancerous lesions as determinants of the cervical cancer occurrence in models of cervical cancer control may influence predictors of the effectiveness of intervention strategies.

Prévention du cancer du col utérin : enjeux et perspectives de la vaccination antipapillomavirus

Cervical cancer remains a critical public health problem that is second only to breast cancer in overall disease burden for women throughout the world. In spite of the success of cervical cancer screening, Pap cytology screening is yet to be effectively implemented or has failed to reduce cervical cancer rates to an appreciable extent. Screening appears to benefit only a small fraction of women although a much larger percentage endures the inconvenience of the Pap test in order to avoid cervical cancer. The establishment of Human Papillomavirus (HPV) infection as the necessary cause of cervical precancers and cancers provides a tremendous opportunity for cervical cancer prevention through vaccination. HPV 16 and 18 which cause 70% of cervical cancers worldwide. Thus a prophylactic vaccine to prevent HPV related precancerous lesions and cancers would save lives, reduce the need for costly medical procedures and provide both women and communities throughout the world with substantial benefits. Based on the induction of neutralizing antibodies by non infectious Virus Like Particles (VLP) of L1 capside protein, prophylactic HPV vaccines have consistently induced high titter of neutralizing antibodies with minimal side effects and induce more than 90% protection from persistent HPV 16-18 infection and HPV 16 and 18 associated high-grade Cervical Intraepithelial Neoplasia (CIN) in proof of concept efficacy trials. HPV 16-18 vaccination will prevent HPV16-18 incident infection, and subsequently decrease in 90% the frequency of abnormal Pap attributable to these types and in about 50% overall abnormal Pap. HPV vaccination will reduce the number of women who require colposcopy, biopsy and cervical treatment for precancerous cervical lesions. The level of protection from death due to cervical cancer could exceed 95%. Three large phases prophylactic HPV VLP trials are now in progress and will form the basis for licensing of candidate vaccines in 2006. HPV vaccination targeting young female adolescents, aged 11 to 16 years, with a catch-up of those aged 17-25 years, would be a strategy to be addressed. Cervical cancer screening strategies, that will be cost-effective for the proper surveillance of women protected by HPV vaccination, are under analysis.

Fhit protein expression in human gastric cancer and related precancerous lesions.

The FHIT gene is altered in several types of tumors and abnormal expression of Fhit protein have also been reported in some preneoplastic lesions. We have determined the Fhit expression on histological samples of 26 patients affected by preneoplastic lesions who developed a gastric cancer within 2 years. The expression of the Fhit protein was always present in all preneoplastic lesions, while the Fhit protein immunostaining was distributed unevenly in 10 cases and completely lost in 6. The complete loss of Fhit expression only in areas of neoplastic low differentiation suggests that FHIT gene takes part in late gastric carcinogenesis.

High incidence of oral precancerous lesions in a hyperendemic area of hepatitis C virus infection

We have investigated the incidence of oral precancerous lesions among the inhabitants in a hepatitis C virus (HCV) hyperendemic area. Two oral surgeons examined the oral lesions of 685 (295 men, 390 women; mean age of 56.1 years) adult inhabitants, hyperendemic area of HCV infection. All sera were examined for antibodies to HCV (anti-HCV) and serum HCV RNA. Anti-HCV or HCV RNA were detected in sera from 84 (12.3%) or 61 (8.9%) of all. Oral lichen planus (OLP), leukoedema, or leukoplakia were observed in 10 (1.5%), 82 (12%), or 47 (6.9%) subjects, respectively. The incidences of OLP, leukoedema, and leukoplakia in the subjects with HCV infection were significantly higher than those without HCV. These results indicated that HCV may play an important role in oral cancer and related precancerous lesions. Moreover, our study also emphasized the need for periodic examination of the oral cavity in patients with HCV.

Inhibition by selenium of intrahepatic cholangiocarcinoma induction in Syrian golden hamsters by N'-nitrosobis(2-oxopropyl)amine.

The effects of selenium supplementation on induction of cholangiocarcinomas and related precancerous lesions in female Syrian Golden hamsters by N'-nitrosobis(2-oxopropyl)amine (BOP) were investigated. Four-week-old animals were divided into two groups according to the selenium level contained in the drinking water (0.1 ppm or 4.0 ppm) and fed a purified diet containing less than 0.05 ppm of the trace element. Starting at Week 4 of the experiment, hamsters were administered 10 weekly injections of BOP (10 mg/kg body wt) and then killed 18 weeks after the last carcinogen administration. Animals receiving physiological saline alone served as controls. Cholangiocellular carcinomas tended to be reduced, and putative preneoplastic lesions of cholangiofibrosis were significantly decreased in the high-as opposed to the low-selenium groups in terms of both incidence rate and number per effective animal. The respective high and low selenium values for incidence and number were 24/38% and 0.34/0.66, respectively, for cholangiocarcinomas and 50/89% and 1.21/8.44, respectively, for cholangiofibroses. Proliferation of intrahepatic bile ducts was also significantly inhibited in the high-selenium group along with cyst formation. Biochemical investigation revealed both selenium level and glutathione peroxidase activity to be significantly greater in the high-than in the low-selenium group livers. The results thus suggest that selenium may inhibit BOP-induction of bile duct lesions, possibly via glutathione peroxidase-mediated alteration of carcinogenesis.