Transitional Epidemiology of Human Papillomavirus Infection in Iran: A Cross-Sectional Study and National Review.

Background: The high prevalence of cervical cancer in developing countries, despite its preventive nature, makes the disease a principal matter of concern for scientific studies. Providing global availability of primary and secondary preventive methods based on the high-risk human papillomavirus (HPV), which is the well-known pathogenesis in most malignant cervical lesions, has become the World Health Organization's (WHO's) critical target for 2030. Considering the demographic diversity and manufacturing of the internal vaccine in Iran, there is need for more study on the cost-effectiveness of these strategies. Materials and Methods: This study intends to assess female HPV prevalence at the time in Iran provinces, especially in the capital province, Khorasan Razavi, in the north to establish a scientific rationale for conducting further studies on arguments for and against national HPV prevention strategies in line with the WHO. In this population-based study, the HPV prevalence was evaluated in 900 cervical samples accumulated between 2012 and 2015. The data were later compared with recently published data in the same province, in the north of Iran. Result: Based on the results of our cross-sectional study, the estimated prevalence of HPV infection in the northern female population was 4.1% in 2015 and significantly increased to 35% in 2021. Conclusion: The hypothesis of the impact of behavioral and cultural changes in addition to population aging on general health indicates the need for national health promotion strategies. Additionally, it emphasizes the critical significance of conducting further investigational studies to obtain the actual and updated prevalence of HPV in Iran.

Association of dietary intake and cervical cancer: a prevention strategy.

INTRODUCTION: Cervical cancer is one of lethal cancers in women. As a global concern, identifying important factors of cancer is a useful strategy for prevention. Due to the role of diet/nutrition factors for cancer, the purpose of our study was to determine the impact of 150 nutrition/vitamin factors and 50 non-nutritional factor in cervical cancer and phase. METHODS: Population samples of 2088 healthy subjects and patients with cervical cancer were investigated. 200 factors such as vitamin E, B1, B6, fruits, HPV, and age were gathered. Deep learning, Decision tree, and correlation matrix were used for modeling and identifying important factors. SPSS 26, R4.0.3, and Rapid miner were utilized for implementation. RESULTS: Our findings indicated that zinc, Iron, Niacin, Potassium, Phosphorous, and Cooper have a beneficial impact in reducing the risk of cervical cancer and progression of phase in Iranian women, as well as Salt, snacks and milk Were identified as high-risk food factors (P value < 0.05 and coefficient correlation > 0.6). Also, alcohol, and sex patient with two groups, HPV positive have an impact on cervical cancer incidence. Phosphorus and selenium in the Micronutrients category (R2 = 0.85, AUC = 0.993) and polyunsaturated fatty acid and salt in the Macronutrients category and other categories of nutrients were identified as the most effective factors in cervical cancer using deep learning (R2 = 0.93, AUC = 0.999). CONCLUSIONS: A diet and rich nutrition can be helpful for the prevention of cervix cancer and may reduce the risk of disease. Additional research is necessary for different countries.

The effect of education based on the theory of planned behavior on the intention of vaccination against human papillomavirus in female students: A controlled educational trial.

BACKGROUND: Human papillomavirus (HPV) is the most common sexually transmitted infection and causes more than 90% of cervical cancers. The highest rate of infection occurs between the ages of 18 and 28. This study aimed to determine the effect of education based on the theory of planned behavior (TPB) on the intention of vaccination against HPV in female students. MATERIALS AND METHODS: This controlled educational trial study was performed on 72 female students aged 18-26 years of Mashhad University of Medical Sciences by random assignment to intervention and control groups. For random assignment in the intervention and control groups, random blocking with four blocks was performed using a random number table with a ratio of 1:1. Data collection tools included demographic questionnaire, awareness about HPV vaccination, and TPB theory constructs. The control group was received the university routine training. The intervention group was received the virtual group training in four sessions, 60-90 min at weekly intervals and with educational content including TPB constructs on HPV vaccination with the method of lecture training, group discussion, questions and answers, and presentation of training package. Questionnaires were completed before, instantly, and 1 month after the educational intervention. Data were analyzed using the Chi-square test, Fisher's exact, t-test, Mann-Whitney test, and Friedman test. RESULTS: The mean age of students was 18.9 ± 1.1 years. The intervention and control groups were homogeneous in terms of demographic characteristics (P > 0.05). Before the intervention, the mean score of model constructs did not show a statistically significant difference between the two groups (P > 0.05), but after the intervention, in the intervention group, mean scores of attitude, subjective norms, perceived behavioral control, and behavioral intention in the intervention group was significantly higher than the control group (P < 0.001). In the intervention group, the difference in the mean score of HPV vaccination intention instantly (P < 0.001) and 1 month (P < 0.001) after the intervention significantly increased. CONCLUSION: TPB-based education was effective in increasing attitudes, subjective norms, and perceived behavioral control and the intention to vaccinate against HPV in the female students of Mashhad University of Medical Sciences. Therefore, it is suggested that the present educational intervention be widely used to educate female students.

Targeting the Transforming Growth Factor-beta Signaling Pathway in the Treatment of Gynecologic Cancer.

The transforming growth factor-beta (TGF-ß) signaling pathway has been reported to be dysregulated in the pathogenesis of several malignancies, including gynecologic cancers. This provides proof of concept of its potential value as a therapeutic target and prognostic biomarker in cervical cancer. Here we provide an overview of the biological role and clinical impact of TGF-ß inhibitors either as a single agent or as a combinatorial therapy in gynecological cancers, concentrating on phase I to phase II/III clinical trials. Aberrant TGF-ß signaling may lead to carcinogenesis. Inhibition of TGF-ß represents an interesting area of focus for the treatment of gynecological cancer. Several TGF-ß inhibitors are potential anticancer agents and are undergoing clinical trials in cancer, including galunisertib, dalantercept, and vigil. There is a growing body of data showing the potential therapeutic impact of targeting the TGF-ß pathway in different cancer types, although further studies are still warranted to explore the value of this strategy and finding the most appropriate patients who could most benefit from therapy.

Association of a genetic variant in Interleukin-10 gene with increased risk and inflammation associated with cervical cancer.

BACKGROUND: Cervical-cancer is among the most commonly diagnosed cancers in women, and infection with human papillomavirus (HPV) is associated with an increased risk of cervical cancer and altered serum concentrations of inflammatory cytokines. We have explored the association between a genetic variation in the Interleukin-10 (IL-10) gene (rs1800896) and cervical cancer risk and its relationship with tissue Interferon gamma (IFN-γ), Transforming growth factor beta (TGF-ß), Tumor necrosis factor alpha (TNF-α) concentrations in women with cervical cancer. METHODS: A total of 315 women with, or without cervical cancer, were recruited into the study. DNA was extracted from cervical cells, and genotyping was undertaken using Taq-man real-time PCR. The genotype frequency and allele distribution were analyzed together with their association with pathological data. The association of the rs1800896 gene variation with tissue levels of the inflammatory cytokines was also investigated. RESULTS: Our data showed a significant association between the A allele of the rs1800896 gene variant and the presence of cervical cancer. In particular, patients with AG/AA genotypes had an increased risk of cervical cancer with an odds ratio of 1.929 (95% confidence interval [CI]: 0.879-4.23, P < 0.001) in a recessive model, compared with the GG genotype. Also, the tissue concentrations of IFN-γ, TGF-ß, and TNF-α in cervical tissues were significantly higher in women with cervical cancer (P < 0.001) and were associated with the AA genotype. CONCLUSION: We have found an association between the polymorphism rs1800896 in the IL-10 gene and an increased risk of cervical cancer as well as a higher level of tissue inflammatory cytokines. Further investigations are necessary on the value of emerging biomarkers for the risk stratification for the management of cervical cancer patients.

Clinical significance of circulating tumor cell related markers in patients with epithelial ovarian cancer before and after adjuvant chemotherapy.

Circulating tumor cells (CTCs) have recently been considered as new prognostic and diagnostic markers for various human cancers; however, their significance in epithelial ovarian cancer (EOC) remains to be elucidated. In this study, using quantitative real-time PCR, we evaluated the expression of EPCAM, MUC1, CEA, HE4 and CA125 mRNAs, as putative markers of CTCs, in the blood of 51 EOC patients before and/or after adjuvant chemotherapy. Our results demonstrated that, before chemotherapy, the expression of EPCAM, MUC1, CEA and HE4 mRNAs were correlated to each other. CEA expression was correlated with tumor stage (r = 0.594, p = 0.000) before chemotherapy, whereas its expression after chemotherapy was correlated with serum levels of CA125 antigen (r = 0.658, p = 0.000). HE4 mRNA showed the highest sensitivity both before and after chemotherapy (82.98% and 85.19%, respectively) and the persistence of this marker after chemotherapy was associated with advanced disease stage. The expression of CA125 mRNA had negative correlation with the other markers and with tumor stage and therapy response (evaluated by the measurement of serum CA125 antigen). Collectively, our results indicated a better clinical significance of tumor-specific markers (CEA and HE4 mRNAs) compared to epithelial-specific markers (EPCAM and MUC1 mRNAs).

A comprehensive systematic review of the therapeutic effects and mechanisms of action of quercetin in sepsis.

BACKGROUND: Sepsis is a life-threatening condition caused by a dysregulated host response to infection. Several studies have indicated that flavonoids exhibit a wide variety of biological actions including free radical scavenging and antioxidant activities. Quercetin, one of the most extensively distributed flavonoids in the vegetables and fruits, presents various biological activities including modulation of oxidative stress, anti-infectious, anti-inflammatory, and neuroprotective activities. METHODS: The present systematic review was conducted according to the guidelines of the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statements. We searched Web of Sciences, Google Scholar, PubMed, Scopus, and Embase databases up to February 2021 by using the relevant keywords. RESULTS: Out of 672 records screened, 35 articles met the study criteria. The evidence reviewed here indicates that quercetin supplementation may exert beneficial effects on sepsis by attenuating inflammation and oxidative stress, downregulating the mRNA expression of toll-like receptors (TLRs), modulating the immune response, and alleviating sepsis-related organ dysfunctions. CONCLUSION: Due to the promising therapeutic effects of quercetin on sepsis complications and the lack of clinical trials in this regard, future human randomized clinical trials are warranted.

Association of a variant in the tumor necrosis factor alpha gene with risk of cervical cancer.

Tumor necrosis factor alpha (TNF-α) is a pro-inflammatory cytokine involved in the regulation of the immune system and potentially the progression of cervical neoplastic lesions. In this study, we aimed to explore the possible relationship between polymorphisms of the TNF-α gene and susceptibility to cervical cancer. The relationship between a single nucleotide polymorphism (SNP) in the TNF-α gene (rs1800629) and the risk of cervical cancer was evaluated in a total of 445 subjects with (n = 153), or without (n = 292) cancer. Genotyping was performed using a Taq-Man based real time PCR method. Logistic regression analysis showed that individuals with AG/AA genotypes had an increased risk of cervical cancer compared to those with a GG genotype (OR 3.79, 95% CI 2.4-5.7, < 0.001). Our findings demonstrated that a genetic variant in the TNF-α gene (rs1800629) was associated with increased level and risk of developing cervical cancer, suggesting its potential use as a genetic risk factor for cervical neoplasia.

Distribution of the most common types of HPV in Iranian women with and without cervical cancer.

Cervical cancer is an important cause of death in women worldwide. About 99.7% of all cervical cancers have been related to human papillomavirus, especially types 16 and 18. Types 6 and 11 cause genital warts. We aimed to determine the prevalence of common HPV genotypes among women in the general population and women with cervical cancer. A total of 571 healthy women cytology specimens and 113 tissue samples of cervical cancer were investigated using HPV type-specific primers. HPV DNA was detected in 24% of healthy women: 3.3% were positive for high-risk HPV and 11.6% for low-risk HPV. HPV6 (9.3%) had the highest prevalence followed by HPV11 (2.3%), HPV16 (1.8%), HPV18 (1.2%), and 9.1% of samples were positive for unknown types. Among cervical cancer samples, HPV DNA was found in 78.8% including 43.4% HPV16, 8% HPV18, and 27.4% an unknown HPV type. HPV6 and HPV11 were not detected in any cervical cancer cases and 21.2% were negative for HPV. We found no association between HPV-16/18 and age in cervical cancer. The prevalence of HPV infection is relatively high in Iran without vaccination backgrounds. HPV DNA screening and vaccination programs can prevent cervical cancer and health problems caused by genital warts.

Covid-19: What is the best approach in gynecological oncology patient management during the coronavirus pandemic?

Coronavirus (COVID-19) infection is a new major concern and a global emergency in almost all countries worldwide; due to the higher sensibility of cancer patients, they are more susceptible to severe and fatal infections, being nearly 10 times more likely than in healthy individuals infected with this virus. Although the aggressive nature of a cancer is a matter of concern, our exact role as oncologists in this time of restricted resources is not fully clarified. Regarding some consensus recommendation for postponing surgery, there is still an essential need for a single approved protocol regarding each type of malignancy. Iran, as one of the first involved countries in this crisis in Asia, which also has a high prevalence of gynecological malignancies, will certainly require an individualized decision-making schedule based on the most accepted global consensus opinion. Considering our restricted health system resources, herein we tried to introduce a logical gynecologic cancer management protocol based on the stage and survival expectancy of each tumor, along with reviewing all recent recommendations. The limited statistics published in this short period of time have obliged us to mainly focus on expert opinions, and the individualized clinical judgments should be agreed upon by multidisciplinary tumor board consensus. In conclusion, the COVID-19 pandemic overshadows all aspects of medicine, and decision making in gynecological oncology patients requires precise and appropriate judgment based on the available local resources.

Association of a genetic variant in the angiopoietin-like protein 4 gene with cervical cancer.

BACKGROUND: Cervical cancer is among the most aggressive gynecological tumors and is a consequence of interactions between genetic and epigenetic factors. Several genetic polymorphisms related to cervical cancer have been reported in previous clinical studies. In this study, we aimed to explore the possible relationship between polymorphisms of the ANGPTL4 gene locus and susceptibility to cervical cancer. METHODS: We investigated the relationship between a single nucleotide polymorphism (SNP) in the ANPGTL4 gene (rs116843064) and risk of cervical cancer in a total of 378 individuals with (n = 151), or without (n = 227) cancer. DNA was extracted, and genotyped using a Taq-Man based real time PCR. RESULTS: The ANPGTL4 polymorphism was found to be associated with an increased risk of developing cervical neoplasia using dominant model (OR = 12.48, CI = 4.9-31.82, p < 0.0001) and additive model (OR = 30.54, CI = 7.35-126.89, p < 0.0001). CONCLUSION: Our results indicate that there is a strong association between ANPGTL4 and the susceptibility for cervical cancer suggesting that it is a potential risk factor for cervical neoplasia.

Current insights into the metastasis of epithelial ovarian cancer - hopes and hurdles.

BACKGROUND: Ovarian cancer is the most lethal gynecologic cancer and the fifth leading cause of cancer-related mortality in women worldwide. Despite various attempts to improve the diagnosis and therapy of ovarian cancer patients, the survival rate for these patients is still dismal, mainly because most of them are diagnosed at a late stage. Up to 90% of ovarian cancers arise from neoplastic transformation of ovarian surface epithelial cells, and are usually referred to as epithelial ovarian cancer (EOC). Unlike most human cancers, which are disseminated through blood-borne metastatic routes, EOC has traditionally been thought to be disseminated through direct migration of ovarian tumor cells to the peritoneal cavity and omentum via peritoneal fluid. It has recently been shown, however, that EOC can also be disseminated through blood-borne metastatic routes, challenging previous thoughts about ovarian cancer metastasis. CONCLUSIONS: Here, we review our current understanding of the most updated cellular and molecular mechanisms underlying EOC metastasis and discuss in more detail two main metastatic routes of EOC, i.e., transcoelomic metastasis and hematogenous metastasis. The emerging concept of blood-borne EOC metastasis has led to exploration of the significance of circulating tumor cells (CTCs) as novel and non-invasive prognostic markers in this daunting cancer. We also evaluate the role of tumor stroma, including cancer associated fibroblasts (CAFs), tumor associated macrophages (TAMs), endothelial cells, adipocytes, dendritic cells and extracellular matrix (ECM) components in EOC growth and metastasis. Lastly, we discuss therapeutic approaches for targeting EOC. Unraveling the mechanisms underlying EOC metastasis will open up avenues to the design of new therapeutic options. For instance, understanding the molecular mechanisms involved in the hematogenous metastasis of EOC, the biology of CTCs, and the detailed mechanisms through which EOC cells take advantage of stromal cells may help to find new opportunities for targeting EOC metastasis.

Molar Changes With a Normal Viable Fetus: A Case Report.

Objective: The presence of a normal fetus with normal karyotype accompanied by molar changes in the placenta is a rare condition, which carries a significant risk to the mother and fetus. There is a controversy regarding the proper management of this condition. Here, we present the case of a singleton pregnancy that showed molar changes in the pathological study of the placenta, but ended up with a normal viable neonate. Case Report: A 23-year-old primigravida woman, with a 3-year history of infertility, presented with vaginal bleeding and spotting. Her ß-human chorionic gonadotropin (HCG) at 13th week was 36500 mIU/ml. Serial sonography assessments were suggestive for molar changes and a normal fetus with growth retardation but normal Doppler assessment. The patient underwent elective Cesarean section at 37 weeks gestation and a healthy female neonate with an Apgar score of 9-10, weighing 2270 g was born. Pathological assessment of the placenta confirmed the diagnosis of incomplete hydatidiform mole. After two months, the mother had no complications, her ß-HCG level was untraceable, and the infant was in good condition. Conclusion: Despite being a rare condition, partial moles can be accompanied by delivery of a normal fetus. The management of this condition still remains challenging and should be done under close monitoring with extreme caution.

Small Cell Neuroendocrine Cervical Carcinoma: A Case Report.

Objective: Small cell neuroendocrine cervical carcinoma is a neuroendocrine tumor with the great aggravation that comprises 0.5 to 3 percent of cervical tumors and progresses rapidly with early lymphogenous and hematogenous metastases. Case report: We reported a 40 years old woman with cervical cancer in stage IB2 that had radical hysterectomy with mistaken diagnosis of squamous cervical cancer. The disease has progressed after 50 days of surgery with a 6 cm tumor in vaginal cuff; review of pathology demonstrated small cell neuroendocrine cervical carcinoma. Conclusion: Recognition of this separate histopathological entity with IHC analysis is important. Chemoradiotherapy and multimodality therapeutic approaches could improve the survival rates.

Circulating and Tissue microRNAs as Biomarkers for Ovarian Cancer Prognosis.

Ovarian cancer (OC) is one of the most common cancers globally with a high rate of cancer- associated mortality. OC may be classified into epithelial cell neoplasms, germ cell neoplasms and stromal cell neoplasms. The five-year survival in the early and advanced stages of disease is approximately 90% and 15%, respectively. microRNAs are short, single-stranded, non-coding ribonucleic acid (RNA). miRNAs play critical roles in post transcriptionally regulations of gene expression. miRNAs are found in different tissues and body fluids. In carcinogenesis the expression of miRNAs are altered. Recent studies have revealed that there is a relationship between alteration of miRNAs expression and the prognosis of patients with OC. The aim of this review was to summarize the findings of recent studies that have investigated the expression of circulating and tissue miRNAs as novel biomarkers in the prognosis of OC.

Unusual vaginal bleeding due to a leech bite in a girl from a tropical area: A case report.

This study describes the isolation of a leech following the presentation of unusual vaginal bleeding. Vaginal bleeding in children due to a leech bite is very rare. This is the first report of severe bleeding in a virgin 14-year-old girl from Mashhad, Iran due to the presence of a leech in the vagina.

Primary Clear Cell Carcinoma with no Diethylstilbestrol Exposure; Case Series.

One of the rare neoplasms of cervix uteri and vagina is clear cell carcinoma; mostly in patients with a positive past medical history of intrauterine diethylstilbestrol (DES) exposure which reveals the importance of other unknown risk factors of gynecologic neoplasms. 2 Asian women referred to the gynecology-oncology department. The first one came with a complaint of prolonged vaginal discharge and the second one with irregular bleeding. Neither did report a history of DES-exposure. On vaginal examination, it was found that both cases had mass which biopsied for histologic study. They were diagnosed with primary Clear Cell Carcinoma of Vagina in the first case and Cervix uteri in the other one. Both patients underwent cytoreductive surgery soon after diagnosis.

The interaction of high and low-risk human papillomavirus genotypes increases the risk of developing genital warts: A population-based cohort study.

Cervical cancer is among the most common type of cancers in women and is associated with human papillomavirus (HPV) infection. Genital warts are also reported to be linked with HPV infection types 11 and 6. In turn, clinical characteristics and morphological features of warts may be useful in the prediction of prognosis and in making treatment decisions. Thus, we have investigated the association of high and low-risk HPVs genotype with genital wart risk, as well as pathological and cytological information in cases recruited from a population-based cohort study of 1380 patients. Patients infected with HPV genotype 6 or 11 had an increased risk of having warts, with OR of 2.34 (95% CI: 0.955-5.737, P = 0.06). Also, this association was enhanced in the presence of high plus low-risk HPV for having genital wart (OR: 2.814; 95%: 1.208-6.55, P = 0.017) and cases having high-risk HPV (OR: 2.329; 95% CI: 1.029-5.269, P = 0.042). Moreover, we observed patients with genital warts having CIN2/3, indicating the importance of informing the physician to the patient to prevent more severe lesions. Our data demonstrated that patients with both low/high-risk HPV types had an increased risk of developing genital warts and persistent infection with HPV was a necessary precursor for the increase in cervical lesions.

Therapeutic potential of toll-like receptors in treatment of gynecological cancers.

Toll-like receptors (TLRs) play an important role in the innate and adaptive immune system. They are expressed in various regions of the female reproductive tract, and their regulation may be involved in the pathogenesis of gynecological lesions. There is growing evidence that ligands for several TLRs are potentially anticancer agents, some of which have already been approved by the FDA, and these compounds are now undergoing clinical evaluation. There is a rationale for using these ligands as adjuvants in the treatment or prevention of gynecological cancer. Some TLR agonists that are of potential interest in the treatment of gynecological lesions include imiquimod, motolimod, cervarix, and CpG-oligodeoxynucleotides (ODNs). In this review, we outline the different functions of TLRs in gynecological cancer with particular emphasis on the value of TLR agonists as a potential therapeutic target in the treatment of gynecological cancer. © 2019 IUBMB Life, 71(5):549-564, 2019.