Diagnostic and prognostic potential of the intra-tumoral microbiota profile in HPV-independent endocervical adenocarcinoma.

Background: Microbial community dynamics have been involved in numerous diseases, including cancer. The diversity of intertumoral microbiota in human papillomavirus independent endocervical adenocarcinoma (HPVI ECA) is not well-characterized. Objective: Our objective is to delineate the intratumoral microbiota profile in HPVI ECA and investigate its potential influence on oncogenesis. Methods: We analyzed 45 HPVI ECA cases, comprising 36 gastric-type ECA (GEA) and 9 clear cell carcinomas (CCC). We compared the microbial composition within cancerous and adjacent noncancerous tissue samples using 5R-16S ribosomal DNA sequencing. Further, we investigated the correlation between specific microbes and clinical-pathological metrics as well as patient outcomes. Results: Our findings demonstrate notable differences in the microbial spectra between cancerous and adjacent noncancerous tissues. Amongst HPVI ECA subtypes, GEAs exhibit more microbial variations compared to CCCs. Using the Random Forest algorithm, we identified two distinct microbial signatures that could act as predictive biomarkers for HPVI ECA and differentiate between GEA and CCC. Varied microbial abundances was related to clinical characteristics of HPVI ECA patients. In addition, high levels of Micrococcus and low levels of unknown genus75 from the Comamonadaceae family were associated with poorer outcomes in HPVI ECA patients. Similarly, an abundance of Microbacterium correlated with reduced overall survival (OS), and a high presence of Streptococcaceae family microbes was linked to reduced recurrence-free survival (RFS) in GEA patients. Intriguingly, a high abundance of Micrococcus was also associated with a worse OS in GEA patients. Conclusion: The study reveals distinct microbial signatures in HPVI ECA, which have potential as biomarkers for disease prognosis. The correlation between these tumor-associated microbiota features and clinicopathological characteristics underscores the possibility of microbiome-based interventions. Our research provides a foundation for more in-depth studies into the cervical microbiome's role in HPVI ECA.

Epithelial­derived head and neck squamous tumourigenesis (Review).

Head and neck squamous cell carcinomas (HNSCCs), a heterogeneous group of cancers that arise from the mucosal epithelia cells in the head and neck areas, present great challenges in diagnosis, treatment and prognosis due to their complex aetiology and various clinical manifestations. Several factors, including smoking, alcohol consumption, oncogenic genes, growth factors, Epstein­Barr virus and human papillomavirus infections can contribute to HNSCC development. The unpredictable tumour microenvironment adds to the complexity of managing HNSCC. Despite significant advances in therapies, the prediction of outcome after treatment for patients with HNSCC remains poor, and the 5­year overall survival rate is low due to late diagnosis. Early detection greatly increases the chances of successful treatment. The present review aimed to bring together the latest findings related to the molecular mechanisms of HNSCC carcinogenesis and progression. Comprehensive genomic, transcriptomic, metabolomic, microbiome and proteomic analyses allow researchers to identify important biological markers such as genetic alterations, gene expression signatures and protein markers that drive HNSCC tumours. These biomarkers associated with the stages of initiation, progression and metastasis of cancer are useful in the management of patients with cancer in order to improve their life expectancy and quality of life.

Treatment De-escalation in Oropharyngeal Carcinoma and the Role of Robotic Surgery.

Oropharyngeal squamous cell carcinoma (OPSCC) related to human papillomavirus (HPV) infection has better survival outcomes compared to non-HPV-related OPSCC, leading to efforts to de-escalate the intensity of treatment to reduce associated morbidity. This article reviews recent clinical efforts to explore different de-escalation frameworks with a particular emphasis on the emergence of transoral robotic surgery and surgically driven de-escalation approaches. It discusses the current evidence for incorporating surgery into an evolving treatment paradigm for HPV-related OPSCC.

Trends in the treatment of human papillomavirus-associated oropharyngeal carcinoma in Slovakia.

The optimal treatment of oropharyngeal cancer (OPC) associated with human papillomavirus (HPV) is currently a subject of clinical research. This questionnaire study investigated current trends in the treatment of HPV-associated (HPV+) OPC in Slovakia with the incorporation of deintensification of oncological treatment into routine clinical practice outside of clinical trials. The Slovak Cooperative Head and Neck Cancer Group (SCHNCG) developed a questionnaire aimed at identifying trends in the oncological treatment of HPV+ OPC intended for all radiation oncology (RO) facilities in Slovakia. Specialists in the field of RO responded to general questions about the character of their individual institutions as well as to 4 theoretical clinical scenarios (case reports) regarding the treatment of HPV+ OPC, focusing primarily on the applied dose of radiotherapy (RT), the extent of target volumes, and the type of concurrent chemotherapy (CHT). The questionnaire study involved 35 RO specialists from 14 institutions in Slovakia. Regarding primary chemoradiotherapy (CRT) in T1N1M0 HPV+ OPC, 16 respondents (45.7%) would consider de-escalation of the RT dose to <70 Gy. In the case of postoperative RT in pT1pN1M0 HPV+ OPC with negative resection margins (R0) and absent extracapsular extension (ECE), 4 physicians (11.4%) would consider de-escalation of the RT dose to <60 Gy in the tumor bed area, while the majority of the treating specialists (n=19, 54.3%) would omit concurrent CHT. In the case of primary RT in elderly patient with T2N1M0 HPV+ OPC, the same number of physicians (n=16, 45.7%) would consider de-escalation of the RT dose to <70 Gy, and 14 respondents (40.0%) would completely omit CHT. In a high-risk patient with T2N3M0 HPV+ OPC with a complete response after 3 cycles of induction chemotherapy (iCHT), none of the respondents would indicate a reduction in the RT dose to the area of the original tumor and lymphadenopathy to <60 Gy. The doses and extent of irradiated volumes in the treatment of HPV+ OPC in Slovakia vary among different institutions. The tendency to de-escalate RT doses and reduce doses of concurrent systemic therapy in Slovakia is high and there was also an observed trend to reduce the extent of radiation treatment fields.

Exosomal transcript cargo and functional correlation with HNSCC patients' survival.

BACKGROUND: HPV status in a subset of HNSCC is linked with distinct treatment outcomes. Present investigation aims to elucidate the distinct clinicopathological features of HPV-positive and HPV-negative HNSCC and investigate their association with the HNSCC patient survival. MATERIALS AND METHODS: The total RNA of exosomes from HPV-positive (93VU147T) and HPV-negative (OCT-1) HNSCC cells was isolated, and the transcripts were estimated using Illumina HiSeq X. The expression of altered transcripts and their clinical relevance were further analyzed using publicly available cancer transcriptome data from The Cancer Genome Atlas (TCGA). RESULTS: Transcriptomic analyses identified 3785 differentially exported transcripts (DETs) in HPV-positive exosomes compared to HPV-negative exosomes. DETs that regulate the protein machinery, cellular redox potential, and various neurological disorder-related pathways were over-represented in HPV-positive exosomes. TCGA database revealed the clinical relevance of altered transcripts. Among commonly exported abundant transcripts, SGK1 and MAD1L1 showed high expression, which has been correlated with poor survival in HNSCC patients. In the top 20 DETs of HPV-negative exosomes, high expression of FADS3, SGK3, and TESK2 correlated with poor survival of the HNSCC patients in the TCGA database. CONCLUSION: Overall, our study demonstrates that HPV-positive and HPV-negative cells' exosomes carried differential transcripts cargo that may be related to pathways associated with neurological disorders. Additionally, the altered transcripts identified have clinical relevance, correlating with patient survival in HNSCC, thereby highlighting their potential as biomarkers and as therapeutic targets.

Human papillomavirus disease in GATA2 deficiency: a genetic predisposition to HPV-associated female anogenital malignancy.

Objective: Patients with pathogenic variants in the GATA Binding Protein 2 (GATA2), a hematopoietic transcription factor, are at risk for human papillomavirus-related (HPV) anogenital cancer at younger than expected ages. A female cohort with GATA2 haploinsufficiency was systematically assessed by two gynecologists to characterize the extent and severity of anogenital HPV disease, which was also compared with affected males. Methods: A 17-year retrospective review of medical records, including laboratory, histopathology and cytopathology records was performed for patients diagnosed with GATA2 haploinsufficiency followed at the National Institutes of Health. Student's t-test and Mann-Whitney U test or Fisher's exact test were used to compare differences in continuous or categorical variables, respectively. Spearman's rho coefficient was employed for correlations. Results: Of 68 patients with GATA2 haploinsufficiency, HPV disease was the initial manifestation in 27 (40%). HPV occurred at median 18.9 (15.2-26.2) years in females, and 25.6 (23.4-26.9) years in males. Fifty-two (76%), 27 females and 25 males, developed HPV-related squamous intraepithelial lesions (SIL) including two males with oral cancer. Twenty-one patients developed anogenital high-grade SIL (HSIL) or carcinoma (16 females versus 5 males, (59% versus 20%, respectively, p=0.005) at median 27 (18.6-59.3) years for females and 33 (16.5-40.1) years for males. Females were more likely than males to require >2 surgeries to treat recurrent HSIL (p=0.0009). Of 30 patients undergoing hematopoietic stem cell transplant (HSCT) to manage disease arising from GATA2 haploinsufficiency, 12 (nine females, three males) had persistent HSIL/HPV disease. Of these nine females, eight underwent peri-transplant surgical treatment of HSIL. Five of seven who survived post-HSCT received HPV vaccination and had no or minimal evidence of HPV disease 2 years post-HSCT. HPV disease persisted in two receiving immunosuppression. HPV disease/low SIL (LSIL) resolved in all three males. Conclusion: Females with GATA2 haploinsufficiency exhibit a heightened risk of recurrent, multifocal anogenital HSIL requiring frequent surveillance and multiple treatments. GATA2 haploinsufficiency must be considered in a female with extensive, multifocal genital HSIL unresponsive to multiple surgeries. This population may benefit from early intervention like HSCT accompanied by continued, enhanced surveillance and treatment by gynecologic oncologists and gynecologists in those with anogenital HPV disease.

Benefits and challenges of Mohs micrographic surgery for human papilloma virus-associated cutaneous malignancies: a systematic review.

Mohs micrographic surgery is the gold standard for treating many types of skin cancer, particularly skin cancers of high-risk areas such as the face, genitalia, and digits, due to its tissue-sparing technique and low recurrence rates. The use of Mohs micrographic surgery for human papilloma virus-associated cutaneous malignancies has yet to be explored in a systematic review. The authors sought to assess outcomes including recurrence rates of Mohs micrographic surgery for human papilloma virus-associated cutaneous malignancies. PubMed was searched for the use of Mohs micrographic surgery in types of human papilloma virus-associated cutaneous malignancies. After application of exclusion and inclusion criteria, 33 articles were included. 700 cases from 33 studies were included. Overall recurrence rate following Mohs micrographic surgery was 39/478 (8.2%) at a mean follow-up time of 51.5 months. Recurrence rate for nail unit/digit squamous cell carcinoma was 10/103 (9.7%) at mean follow-up of 47.6 months. Recurrence rate for penile squamous cell carcinoma was 15/181 (8.3%) at mean follow-up of 45.9 months. Recurrence rate for Bowen's disease in extragenital areas was 11/189 (5.9%) at mean follow-up of 59.7 months. Patients overall reported satisfactory functional and cosmetic results. Mohs micrographic surgery demonstrates low recurrence rates and excellent functional and cosmetic outcomes in the treatment of human papilloma virus-associated cutaneous malignancies.

Cervical cancer: Part II the landscape of treatment for persistent, recurrent and metastatic diseases (I).

The WHO (World Health Organization) conducted an elimination of cervical cancer program using triple pillar intervention strategy to target 90%-70%-90% of women before the year 2030, including (1) a full vaccination of HPV (human papillomavirus) vaccine to 90% of girls <15 years of age; (2) a high-performance screening procedure to 70% of women during the reproductive age (at the age of 35 and 45 years of age); and (3) an appropriate and adequate treatment to 90% of women with confirmed diagnosis of cervical lesions. Among the aforementioned three pillars, a full HPV vaccination has been introduced in our previous review, of which we have discussed the policy and strategy of HPV vaccination in the world and also reviewed the efficacy of HPV vaccination, with a successful reduction of over 90% of HPV-associated neoplasms. The aims of the current review will target another pillar-an appropriate and adequate treatment to 90% of women with confirmed diagnosis of cervical lesions. Since the early-stage cervical cancer has a favorable outcome and the treatment recommendation has been established, therefore, the current review focuses on women with persistent, recurrent and metastatic cervical cancers (advanced cervical cancers), which are still a biggest challenge based on its extremely worse outcomes before the introduction of immune checkpoint inhibitors (ICIs). Integration of ICIs into conventional chemotherapy (paclitaxel-cisplatin) has become the new standard therapy for those patients with advanced cervical cancers. The recent clinical trials, such as KENOTE 826 and KENOTE A18 showing a dramatical improvement of both progression free survival and overall survival have approved the therapeutic efficacy of this combination as ICI plus paclitaxel-platinum (cisplatin or carboplatin) with/without bevacizumab to women with persistent, recurrent and metastatic cervical cancers.

The role of cGAS-STING signaling in the development and therapy of head and neck squamous cell carcinoma.

The cGAS-STING signaling pathway plays a critical role in innate immunity and defense against viral infections by orchestrating intracellular and adaptive immune responses to DNA. In the context of head and neck squamous cell carcinoma (HNSCC), this pathway has garnered significant attention due to its potential relevance in disease development and progression. HNSCC is strongly associated with risk factors such as smoking, heavy alcohol consumption, and human papillomavirus (HPV) infection. The presence or absence of HPV in HNSCC patients has been shown to have a profound impact on patient survival and prognosis, possibly due to the distinct biological characteristics of HPV-associated tumors. This review aims to provide a comprehensive overview of the current therapeutic approaches and challenges in HNSCC management, as well as the involvement of cGAS-STING signaling and its potential in the therapy of HNSCC. In addition, by advancing the present understanding of the mechanisms underlying this pathway, Activation of cGAS-STING-dependent inflammatory signaling downstream of chromosomal instability can exert both anti-tumoral and pro-tumoral effects in a cell-intrinsic manner, suggesting individualized therapy is of great importance. However, further exploration of the cGAS-STING signaling pathway is imperative for the effective management of HNSCC.

Analysis of molecular marker expression in cutaneous lesions and cervical carcinoma associated with HPV infection.

The study sought to systematically compare the expression of molecular markers in benign cutaneous lesions and squamous cell cervical carcinoma associated with HPV infection to better understand the pathophysiological mechanisms involved in HPV-related lesions and their progression to malignancy. We included 200 patients recruited from a gynecological clinic divided into two groups: 100 patients with positive HPV tests presenting with cutaneous lesions and 100 patients diagnosed with squamous cell cervical carcinoma and testing positive for HPV. The participants were selected to ensure diverse ethnic and demographic representation. The study utilized different statistical analyses, including Chi-square tests to assess associations between categorical variables and logistic regression to evaluate factors influencing lesion progression and compare marker expressions across different lesion types. The results indicated significant differences in the expression of specific molecular markers between cutaneous lesions and cervical carcinomas, highlighting distinct molecular pathways involved in HPV-related lesion development. Notably, markers such as p16, p53, and E-cadherin showed varying expression, suggesting their potential role in distinguishing between benign and malignant lesions. The findings emphasize the significance of molecular marker profiling in improving diagnostic and therapeutic strategies for HPV-related lesions. The differential expression of molecular markers can offer valuable insights into the pathogenesis of HPV-induced lesions and help develop targeted interventions to prevent malignant transformation. Further research is necessary to validate these markers in larger cohorts and diverse populations.

Looking Back, Moving Forward: Challenges and Opportunities for Global Cervical Cancer Prevention and Control.

Despite the introduction of Pap testing for screening to prevent cervical cancer in the mid-20th century, cervical cancer remains a common cause of cancer-related mortality and morbidity globally. This is primarily due to differences in access to screening and care between low-income and high-income resource settings, resulting in cervical cancer being one of the cancers with the greatest health disparity. The discovery of human papillomavirus (HPV) as the near-obligate viral cause of cervical cancer can revolutionize how it can be prevented: HPV vaccination against infection for prophylaxis and HPV testing-based screening for the detection and treatment of cervical pre-cancers for interception. As a result of this progress, the World Health Organization has championed the elimination of cervical cancer as a global health problem. However, unless research, investments, and actions are taken to ensure equitable global access to these highly effective preventive interventions, there is a real threat to exacerbating the current health inequities in cervical cancer. In this review, the progress to date and the challenges and opportunities for fulfilling the potential of HPV-targeted prevention for global cervical cancer control are discussed.

Human papillomavirus infection of the fallopian tube as a potential risk factor for epithelial ovarian cancer.

Human papillomaviruses (HPVs) and herpesviruses are detected in patients with epithelial ovarian cancer (EOC). We sought to analyze the prevalence of HPV's 16 and 18, cytomegalovirus (CMV), and Epstein-Barr virus (EBV) DNA in peripheral blood, ovarian, and fallopian tube (FT) tissue samples collected from 97 EOC patients, including 71 cases of high-grade serous ovarian carcinoma (HGSOC), and from 60 women with other tumors or non-neoplastic gynecological diseases. DNA isolates were analyzed by PCR methods, including droplet digital PCR. The results demonstrate that (1) HPV16 DNA has been detected in one-third of the FT and tumor samples from EOCs; (2) the prevalence and quantity of HPV16 DNA were significantly higher in FT samples from HGSOCs, non-HGSOCs, and ovarian metastases than in those from non-neoplastic diseases; (3) CMV and EBV have been detected in approximately one-seventh of EOC samples. The results suggest that HPV16 might be a potential risk factor for EOC development.

Invitation strategy of vaginal HPV self-sampling to improve participation in cervical cancer screening: a systematic review and meta-analysis of randomized trials.

BACKGROUND: Human papillomavirus (HPV) self-sampling is recognized as a feasible option for enhancing screening for cervical cancer, particularly among hard-to-reach women. The magnitude of the effectiveness of screening participation under different invitation strategies was reported. This review seeks to compare the effectiveness of invitation strategies in increasing screening participation of HPV self-sampling across diverse study settings. METHODS: A systematic literature search was conducted in Embase, MEDLINE, and PubMed in April 2023. Articles were included if (1) their target participants were aged between 25 and 70 years; (2) participants in the intervention arm were randomized to receive HPV self-sampling devices through various invitation strategies; (3) participants in the control arm who either received invitations for cervical cancer screening other than HPV self-sampling or opportunistic screening as usual care; (4) studies that provided sufficient data on screening participation in HPV self-sampling as outcome measured. The study design of the included articles was limited to randomized controlled trials. RESULTS: A total of 15 articles were included in this review. Invitation strategies of disseminating HPV self-sampling devices included opt-out and opt-in. Meta-analysis revealed screening participation in the self-sampling group was significantly greater than control arm (OR 3.43, 95% CI 1.59-7.38), irrespective of the invitation strategy employed. Among invitation strategies, opt-out appeared to be more effective on increasing screening participation, compared to control and opt-in strategy (opt-out vs. control OR 3.91, 95% CI 1.82-8.42; opt-in vs. control OR 1.34, 95% CI 0.28-6.39). CONCLUSIONS: Opt-out strategy is more successful at improving screening participation compared to opt-in and routine invitation to cervical screening. It is therefore a promising way to improve participation in cervical cancer screening. The findings of this review provide important inputs to optimize strategies for inviting women to participate in vaginal HPV self-sampling across the study setting, thus improving participation in cervical cancer screening.

HPV Infection and Prevention in Patients With Immune-Mediated Inflammatory Diseases: A Scoping Review.

BACKGROUND/HISTORICAL PERSPECTIVE: Human papillomavirus (HPV) infections are a significant public health concern as they cause various cancers, including those of the cervix, vulva, vagina, anus, penis, and oropharynx, in both women and men. SUMMARY INTEGRATING THE CURRENT PUBLISHED LITERATURE: Individuals with immune-mediated inflammatory diseases, particularly systemic lupus erythematosus, have an increased risk of developing persistent HPV infection and subsequent precancerous lesions due to their immunosuppression. MAJOR CONCLUSIONS: Vaccination and screening for precancerous lesions are 2 central management strategies that must be implemented in patients with immune-mediated inflammatory diseases. Although HPV vaccination has been proven to be safe and effective in these patients, coverage remains low and should be encouraged. Screening for cervical cancer should be more widely implemented in this population, as recommended in guidelines for other immunosuppressed patients. FUTURE RESEARCH DIRECTIONS: Catch-up vaccination, vaginal self-sampling screening for HPV detection, and therapeutic vaccination are new options that should be considered.

TNM 8 staging system beyond p16: Double HPV/p16 status is superior to p16 alone in predicting outcome in oropharyngeal squamous cell carcinoma.

PURPOSE: The assessment of p16INK4a (p16) in oropharyngeal squamous cell carcinoma (OPSCC) has been incorporated into tumor classification, as p16 has been shown to impact survival probability. However, a recent study demonstrated that human papillomavirus (HPV) status in addition to p16 may have a better discriminatory effect on survival probability. This study aims to determine the impact of combined evaluation of p16 and HPV on prognosis. METHODS: This was a multicenter, multinational analysis including retrospective and prospective cohorts of patients treated for primary OPSCC with curative intent, based on the data of the HNCIG-EPIC study. The primary outcome was to determine how the combined assessment of HPV and p16 status predicts prognosis of patients with OPSCC compared to p16 assessment alone. We employed multivariable analyses models to compute hazard ratios regarding survival. Analyses were stratified by stage, smoking status, and sub-anatomical region. RESULTS: The study included 7654 patients, with approximately half of the tumors being p16-negative (50.3 %, n = 3849). A total of 9.2 % of patients had discordant p16 and HPV status (n = 704). HPV status significantly impacted overall survival and disease-free survival regardless of p16 status and across both UICC 8th stage I-II and III-IVb cancers. p16-positive/HPV-positive OPSCC patients exhibited the best survival probability. CONCLUSION: The detection of HPV had a significant impact on survival probability for OPSCC patients with both p16-positive and p16-negative tumors. HPV testing should be integrated in cancer staging, especially in regions of low attributable fraction, alongside p16 evaluation to ensure a comprehensive assessment of prognosis.

Relationship between p16/ki67 immunoscores and PAX1/ZNF582 methylation status in precancerous and cancerous cervical lesions in high-risk HPV-positive women.

BACKGROUND: The risk of cervical cancer progression in high-risk human papillomavirus (HR-HPV)-positive women is associated with cervical lesion severity and molecular heterogeneity. Classification systems based on p16 and Ki67 expression cumulative scores (0-3 each)-p16/Ki67 collectively known as an immunoscore [IS]-are an accurate and reproducible method for grading cervical intraepithelial neoplasia (CIN) lesions. Meanwhile, DNA methylation is an early event in the development of cervical cancer. Hence, this study evaluated the relationship among CIN, p16/Ki-67 IS, and PAX1/ZNF582 methylation. METHODS: In this study, 414 HPV-positive paraffin-embedded specimens were collected, and PAX1/ZNF582 methylation and the p16/ki67 IS were determined. A total of 43 invalid samples were excluded and 371 were included in the statistical analyses. There were 103 cervicitis, 95 CIN1, 71 CIN2, 89 CIN3, and 13 squamous cell carcinoma (SCC) cases. The association between PAX1/ZNF582 methylation and p16/Ki6 immunohistochemical staining scores was analyzed. RESULTS: The ΔCp of PAX1m (PAX1 methylation) and ZNF582m (ZNF582 methylation) decreased with cervical lesion severity (Cuzick trend test, all P < 0.001). The severity of the cervical lesions and p16, Ki67, and p16/Ki67 IS showed an increasing trend (Multinomial Cochran-Armitage trend test, all P < 0.001). The prevalence of PAX1m/ZNF582m increased with an increase in the IS of p16, Ki67, and p16/Ki67 (Cochran-Armitage trend test, all P < 0.001). In cervical SCC, the IS was 5-6, and the PAX1m/ZNF582m was positive. Meanwhile, heterogeneity was observed in CIN lesions: 10 cases had an IS of 3-4 and were PAX1m/ZNF582m-positive in ≤ CIN1; 1 case had an IS of 0-2 and was PAX1m/ZNF582m-positive in CIN2/3. CONCLUSIONS: Significant heterogeneity was observed in CIN lesions for p16 and Ki67 immunohistochemical staining scores and PAX1/ZNF582 methylation. This may help clinicians personalize the management of CIN based on the predicted short-term risk of cancer progression, minimizing the rate of missed CIN1 diagnoses and incorrect treatment of CIN2/3.

Analysis of vaginal flora diversity and study on the role of Porphyromonas asaccharolytica in promoting IL-1ß in regulating cervical cancer.

Cervical cancer, a prevalent malignancy in the female reproductive tract, exhibits a high incidence. Existing evidence indicates a robust correlation between alterations in vaginal flora composition and the progression of cervical cancer. Nevertheless, there is a lack of clarity concerning the specific microorganisms within the vaginal microbiota that are linked to the onset and development of cervical cancer, as well as the mechanisms through which they exert carcinogenic effects. The 16 S ribosomal (rRNA) and metagenomic sequencing technology were used to analyze vaginal microorganisms, and screening for human papillomavirus (HPV) positive cervical cancer-associated microbial markers using fold change in mean bacterial abundance. Moreover, vaginal microenvironmental factors were detected, and the local vaginal inflammatory state in patients with cervical cancer was subjected to assay via qRT-PCR and ELISA. The hub inflammatory genes were screened by transcriptome sequencing after co-culture of bacteria and normal cervical epithelial cells, and an in vitro model was utilized to assess the impacts of inflammatory factors on cervical cancer. Both cervical cancer patients and HPV-positive patients showed significant changes in the composition of the vaginal flora, characterised by a decrease in the abundance of Lactobacillus and an increase in the abundance of a variety of anaerobic bacteria; The microbial sequencing identified Porphyromonas, Porphyromonas_asaccharolytica, and Porphyromonas_uenonis as microbial markers for HPV-associated cervical cancer. Vaginal inflammatory factors in patients with cervical cancer were overexpressed. After Porphyromonas_asaccharolytica intervention on cervical epithelial H8 cells, interleukin (IL)-1ß, a hub differential gene, markedly promoted tumor-associated biological behaviors at the in vitro cytological level in cervical cancer. This study for the first demonstrated that Porphyromonas, Porphyromonas_asaccharolytica, and Porphyromonas_uenonis could serve as novel microbial markers for cervical cancer. Moreover, Porphyromonas_asaccharolytica was identified as having the ability to induce the overexpression of inflammatory genes in cervical epithelial cells to create a favorable microenvironment for the onset and development of cervical cancer. The effects of dysbacteriosis on cervical cancer were microbiologically elucidated.

Hotspots of Anal Cancer Screening in a High-risk Population: A Clinical Study on Free Provision, Best Method, Self-sampling, and Independent Risk Factors.

BACKGROUND/AIM: As of 2024, anal cancer (AC) has been steadily increasing worldwide but, due to insufficient evidence, anal cancer screening (ACS) has yet to be standardized. Furthermore, most high-risk people in the world have no help paying for it. Therefore, our primary endpoint was to assess the best screening method for these subjects through a provision that was free of charge (all costs were covered by the Italian public health service). Awareness-raising campaign, determination of risk factors, education on anal self-examination, and sampling (ASS) were secondary objectives. PATIENTS AND METHODS: Screening was on a voluntary basis. Engaging in receptive anal intercourse and having a history of cervical dysplasia were the main inclusion criteria. Level 1 ACS tools included digital ano-rectal examination, anoscopy, anal Pap, and anal human papillomavirus (HPV) DNA test (both through self- and proctologist- sampling); high-resolution anoscopy (HRA) with (HRAB) or without biopsy comprised level 2 screening. High-risk people were enrolled until the available funds were exhausted. RESULTS: Fifty high-risk people (40 men who had sex with men -MSM-, 9 women, and 1 heterosexual man) were enrolled. AC was found in one HIV-seropositive MSM, high-grade squamous intraepithelial lesion in 10 (20%) MSM, low-grade squamous intraepithelial lesion LSIL in 13 cases (12 MSM and 1 woman). The combination of HRAB and Pap smear screening achieved the highest values for sensitivity, specificity, and accuracy. ASS HPV DNA test provided excellent results comparable to clinician retrieval. Overweight and college education were identified as independent factors for the risk of and prevention of AC, respectively. CONCLUSION: A free ACS not only appears justified but also recommended to people screened for AC. Excess weight represents a further risk for this population.

Integrating Single-Cell RNA-Seq and Bulk RNA-Seq to Construct a Novel γδT Cell-Related Prognostic Signature for Human Papillomavirus-Infected Cervical Cancer.

BACKGROUND: Gamma delta (γδ) T cells play dual roles in human tumors, with both antitumor and tumor-promoting functions. However, the role of γδT cells in HPV-infected cervical cancer is still undetermined. Therefore, we aimed to identify γδT cell-related prognostic signatures in the cervical tumor microenvironment. METHODS: Single-cell RNA-sequencing (scRNA-seq) data, bulk RNA-seq data, and corresponding clinical information of cervical cancer patients were obtained from the TCGA and GEO databases. The Seurat R package was used for single-cell analysis, and machine learning algorithms were used to screen and construct a γδT cell-related prognostic signature. Real-time quantitative PCR (RT-qPCR) was performed to detect the expression of prognostic signature genes. RESULTS: Single-cell analysis indicated distinct populations of γδT cells between HPV-positive (HPV+) and HPV-negative (HPV-) cervical cancers. A trajectory analysis indicated γδT cells clustered into differential clusters with the pseudotime. High-dimensional Weighted Gene Co-expression Network Analysis (hdWGCNA) identified the key γδT cell-related gene modules. Bulk RNA-seq analysis also demonstrated the heterogeneity of immune cells, and the γδT-score was positively associated with inflammatory response and negatively associated with MYC stemness. Eight γδT cell-related hub genes (GTRGs), including ITGAE, IKZF3, LSP1, NEDD9, CLEC2D, RBPJ, TRBC2, and OXNAD1, were selected and validated as a prognostic signature for cervical cancer. CONCLUSION: We identified γδT cell-related prognostic signatures that can be considered independent factors for survival prediction in cervical cancer.

The Impact of Tamoxifen Usage in Breast Cancer Patients on the Development of Histopathological Lesions in the Cervix Uteri.

Background and Objectives: The purpose of the present study was to compare the results of colposcopic biopsies in patients with breast cancer and those who tested positive for HPV in cervix uteri cytological screenings, with a control group of HPV-positive individuals without breast cancer. Additionally, through this study, we aimed to investigate the impact of tamoxifen treatment, an anti-oestrogen drug used following breast cancer treatment, on histopathological changes. Breast cancer is the most common type of cancer and cause of death in women worldwide. Cervical cancer ranks as the second most prevalent form of cancer among women globally, with prevalence rates ranking just behind those of breast cancer. Human papillomavirus (HPV) positivity is a requirement for the development of cervical cancer, although it is not the sole factor responsible. Materials and Methods: A comparison was made between the histopathological results of 52 patients diagnosed with breast cancer, who tested positive for HPV in routine cervical cytological screenings and underwent colposcopic biopsy, and 230 cases without any abnormalities. A study was conducted to compare healthy individuals between the ages of 30 and 65 who were diagnosed with breast cancer and those who did not have breast cancer. The participants underwent HPV screening as part of the national cervical cytology screening programme. Results: The average age of those diagnosed with breast cancer was 46.73 ± 7.54; in comparison, the average age of participants in the control group was 47.49 ± 7.95. There was no statistically significant difference in age between the two groups (p: 0.530). A total of 51 cases (98.1%) of breast cancer were found to have actively used the anti-oestrogen drug tamoxifen for a duration ranging from at least 6 months to 5 years. One patient (1.9%) in the breast cancer group did not use tamoxifen. During routine cervical cytological screenings, it was observed that both breast cancer cases and healthy cases tested positive for HPV. The most commonly detected types of HPV in both groups were HPV 16 and 18, with rates of 73.1% noted in the breast cancer group and 92.6% noted in the healthy group, results consistent with the rates found in the general population. HPV 16 was found in 58.7% of participants in the control group and 42.3% of participants in the breast cancer group. There was a statistically significant difference between the two groups (p: 0.032). There was no statistically significant difference observed between the two groups in terms of normal, high-grade cervical intraepithelial lesions (HGSILs); low-grade cervical intraepithelial lesions (LGSILs); and chronic cervicitis histopathological lesions based on colposcopic and endocervical biopsy results, smear cytology, and HPV results (p-values of 0.913 and 0.877, respectively). Conclusions: Our study results indicate that tamoxifen treatment, an anti-oestrogen drug administered for chemoprevention purposes in the management of breast cancer, does not lead to an increase in abnormal histological changes in the cervix uteri. In all cases of breast cancer, gynaecological examination and cervical cytological screening should be advised.