Exposure to polycyclic aromatic hydrocarbons promotes the progression of low-grade cervical intraepithelial neoplasia: A population-based cohort study in China.

Low-grade cervical intraepithelial neoplasia (CIN1) is an early stage of cervical cancer development. Previously, we reported that exposure to polycyclic aromatic hydrocarbons (PAHs) increases the risk of cervical precancerous lesions, especially in females with a high-risk human papillomavirus (HR-HPV) infection. However, the effects of PAHs on CIN1 progression remain unclear. A community-based prospective cohort study was conducted to evaluate the role of exposure to PAHs in the progression of CIN1. A total of 564 patients diagnosed with CIN1 were followed-up at 6, 12, and 24 months, post-diagnosis, to determine CIN1 reversion, persistence, and progression. Exposure to PAHs was determined by the urine 1-hydroxipayrene (1-OHP) level. Our results showed that the 1-OHP level was significantly higher in patients with CIN1 persistence/progression than in those with reversion (P < .05). High exposure to PAHs increased the risk of CIN1 persistence/progression, with hazard ratios (HR), 95% confidence intervals (CI) of (1.62, 1.24-2.67), (1.98, 1.42-2.75), and (2.37, 1.61-3.49) at 6, 12, and 24 months, post-diagnosis, respectively. The effect was enhanced with HR-HPV positivity, as determined at 6 (1.82, 1.24-2.67), 12 (3.02, 1.74-5.23), and 24 (2.51, 1.48-4.26) months, post-diagnosis. Moreover, the predictive value of exposure to PAHs for CIN1 persistence/progression was higher in HR-HPV-positive patients than in HR-HPV-negative patients. The results revealed that exposure to PAHs facilitated the malignant progression of CIN1 and hindered its reversal, particularly in patients with HR-HPV infection. Our findings provide novel insights into early prevention and intervention targeting the initiation and progression of cervical neoplasia.

Cancer-associated fibroblasts-derived exosomal ZNF250 promotes the proliferation, migration, invasion, and immune escape of hepatocellular carcinoma cells by transcriptionally activating PD-L1.

Hepatocellular carcinoma (HCC) is a lethal form of liver cancer, and the tumor microenvironment, particularly cancer-associated fibroblasts (CAFs), plays a critical role in its progression. This study aimed to elucidate the mechanism by which CAF-derived exosomes regulate the development of HCC. The study employed quantitative real-time polymerase chain reaction for mRNA expression analysis and western blot analysis for protein expression detection. Chromatin immunoprecipitation assay and dual-luciferase reporter assay were performed to investigate the relationship between zinc finger protein 250 (ZNF250) and programmed cell death 1 ligand 1 (PD-L1). Transmission electron microscopy and western blot analysis were used to characterize the isolated exosomes. The transferability of CAF-derived exosomes and normal fibroblasts (NFs)-derived exosomes into HCC cells was analyzed using a green fluorescent labeling dye PKH67. Cell proliferation was assessed via a 5-Ethynyl-2'-deoxyuridine assay, while Transwell assays were conducted to evaluate cell migration and invasion. Flow cytometry was performed to measure cell apoptosis, while enzyme-linked immunosorbent assays were used to assess the levels of tumor necrosis factor-α and perforin. Finally, a xenograft mouse model was constructed to examine the effects of exosomes derived from ZNF250-deficient CAFs on the tumor properties of HCC cells. The study revealed increased expression of ZNF250 in HCC tissues and cells, with ZNF250 transcriptionally activating PD-L1 in HCC cells. ZNF250 expression was associated with HbsAg, clinical stage and tumor size of HCC patients. CAF-derived exosomal ZNF250 can regulate PD-L1 expression in HCC cells. Furthermore, exosomes derived from ZNF250-deficient CAFs inhibited the proliferation, migration, invasion, and immune escape of HCC cells by downregulating PD-L1 expression. Moreover, CAF-derived exosomal ZNF250 promoted tumor formation in vivo. These findings provide insights into the role of CAF-derived exosomes in the suppression of HCC development, highlighting the significance of ZNF250 and PD-L1 regulation in tumor progression.

A randomized trial of Bacteroides fragilis 839 on preventing chemotherapy-induced myelosuppression and gastrointestinal adverse effects in breast cancer patients.

BACKGROUND AND OBJECTIVES: To evaluate the potential benefits of Bacteroides fragilis 839 (BF839), a next-generation probiotics, in reducing myelosuppression and gastrointestinal toxicity associated with chemotherapy in breast cancer patient. METHODS AND STUDY DESIGN: 40 women with early breast cancer were randomly assigned to the BF839 (n=20) or placebo (n=20) during the administration of adjuvant chemotherapy (4 cycles of epirubicin 100mg/m2 and cyclophosphamide 600mg/m2). Myelosuppression and gastrointestinal adverse effects were monitored in both groups. RESULTS: Throughout the four treatment cycles, the percentage of patients experiencing myelosuppression was 42.5% in the BF839 group, significantly lower than the 66.3% observed in the control group (p=0.003). Two patients in the BF839 group and three patients in the placebo group received recombinant human granulocyte colony-stimulating factor (rhG-CSF) due to leuko-penia/neutropenia. When considering an ITT analysis, which included all patients regardless of rhG-CSF treatment, the BF839 group exhibited less reduction from baseline in white blood cells (-0.31±1.19 vs -1.15±0.77, p=0.012) and neutrophils (0.06±1.00 vs -0.84±0.85, p=0.004) compared to the placebo group. The difference became even more significant when excluding the patients who received rhG-CSF injections. Throughout the four treatment cycles, compared to the placebo group, the BF839 group had significantly lower rates of 3-4 grade nausea (35.0% vs 71.3%, p=0.001), vomiting (20.0% vs 45.0%, p=0.001), and diarrhea (15.0% vs 30.0%, p=0.023). CONCLUSIONS: These findings suggest that BF839 has the potential to effectively mitigate myelosuppression and gastrointestinal toxicity associated with chemotherapy in breast cancer patients.

Prognostic significance of Ki67 in Chinese women diagnosed with ER+/HER2- breast cancers by the 2015 St. Gallen consensus classification.

BACKGROUND: This study evaluated the distribution pattern of the Ki67-labeling index (LI) among patients at a Chinese breast cancer center, and analyzed its prognostic significance in the 2015 St Gallen consensus breast cancer classification, estrogen receptor-positive and human epidermal growth factor receptor 2-negative(ER+/HER2-)subtype. METHODS: We classified 939 women with ER+/HER2- breast cancer into three groups by Ki67-LI levels, and followed their clinicopathologic characteristics and prognoses. RESULTS: In the 939 eligible subjects, 342 had Ki67-LI ≤10% (Ki67Low), 281 had Ki67-LI between 10 and 30% (Ki67Medium), and 316 had Ki67-LI ≥30% (Ki67High). Although the Ki67High group had less favorable clinicopathologic factors, the Ki67Medium group's factors varied considerably. Kaplan-Meier estimates showed that disease-free survival(DFS) for the Ki67Medium group was significantly shorter than the Ki67Low group but longer than the Ki67High group. Ki67-LI had independent prognostic significance in multivariate analysis. Other diagnostic factors, including tumor size >2 cm, positive lymph nodes, and grade III disease, were significantly associated with poorer disease-free survival only in the Ki67Medium group. CONCLUSIONS: For patients with ER+/HER2- breast cancer, we confirmed three distinct risk patterns by Ki67-LI levels according to the 2015 St Gallen consensus. For patients with clearly low or high Ki67-LI, straightforward clinical decisions could be offered, but for patients with intermediate Ki67-LI, other factors might provide valuable information.

Assessment of prognostic scores of brain metastases from lung adenocarcinoma with EGFR mutations.

The aim of this study was to analyze prognostic factors and evaluate the value of four prognostic scores including RPA, DS-GPA BS-BM, GGS for the EGFR mutant BM patients from lung adenocarcinoma treated with EGFR-TKI. Data of NSCLC were retrospectively reviewed from August 2010 to June 2015 using the medical database of Shanxi Provincial Cancer Hospital. Patients with BM from lung adenocarcinoma with mutant EGFR treated by EGFR-TKI or a combination of EGFR-TKI and WBRT were included. Potential prognostic factors were statistically examined. The C-index of each prognostic score was calculated. A total of 1063 BM patients with lung adenocarcinoma that had been identified with EGFR mutations were reviewed. A total of 104 patients that had been diagnosed with BM were confirmed to have mutant EGFR in primary tumors. These patients received treatment with EGFR-TKI or EGFR-TKI with WBRT to BM. The potential predictive factors in multivariable analysis included KPS (70 vs.70-80 vs. 90-100) and number of brain metastatic lesions. In the log-rank test, the indexes of RPA, DS-GPA BS-BM, and GGS were all significant predictors of OS. The C-indexes of each prognostic score were 0.79, 0.76, 0.77, and 0.74 in DS-GPA, RPA, GGS, and BS-BM, respectively. The indexes of RPA, DS-GPA BS-BM, GGS were applicable for asessing survival stratification in brain metastases from lung adenocarcinoma with presented EGFR mutations in our independent population. The DS-GPA appears to be the best predictive value. However, all four of the indexes could not evaluate the exact independent prognostic factors in multivariable analysis. A prognostic index specific for this group of patients was needed for targeted lung cancer therapy.

HER-2 positive breast cancer is associated with an increased risk of positive cavity margins after initial lumpectomy.

BACKGROUND: The effect of breast cancer subtype on margin status after lumpectomy remains unclear. This study aims to determine whether approximated breast cancer subtype is associated with positive margins after lumpectomy, which could be used to determine if there is an increased risk of developing local recurrence (LR) following breast-conserving surgery. METHODS: We studied 1,032 consecutive patients with invasive cancer who received lumpectomies and cavity margin (CM) assessments from January 2003 to November 2012. The following data were collected: patient age, cT stage, pT stage, grade, status of CM, lymph node status, menopausal status, ER, PR, HER-2, and Ki67, as well as the presence of extensive intraductal component (EIC) and lymphovascular invasion (LVI). A χ2 test was used to compare categorical baseline characteristics. Univariate and multivariate logistic regression analyses were performed to evaluate associations between pathologic features of CM status. Kaplan-Meier actuarial cumulative rates of LR (ipsilateral in-breast) were calculated. RESULTS: A total of 7,884 pieces of marginal tissue were collected from 1,032 patients, and 209 patients had positive CMs. Of the patients tested, 52.3% had luminal A subtype, 14.9% were luminal B, 12.8% were luminal-HER-2, 8.1% were HER-2 enriched, and 11.8% were triple negative. Univariate analysis showed that EIC (P < 0.001), LVI (P = 0.026), pN stage (N1 vs. N0: P = 0.018; N3 vs. N0: P < 0.001), and luminal B (P = 0.001) and HER-2 (P < 0.001) subtypes were associated with positive CMs. Multivariable analysis indicated that only EIC (P < 0.001), pN stage (P = 0.003), and HER-2 subtype (P < 0.001) were significantly correlated with positive CMs. On multivariable analysis, HER-2 subtype was an independent prognostic factor in LR (P = 0.031). CONCLUSIONS: The HER-2 subtype was the predictive factor most associated with positive CMs and an independent prognostic factor for LR. This result suggests that the increased risk of LR in HER-2 breast cancer is due to an increased microscopic invasive tumor burden, which is indicated by margin status after lumpectomy.

A nomogram for predicting overall survival of breast cancer with regional lymph node metastasis in young women.

Background: Young breast cancer (YBC) patients demonstrate a heightened propensity for regional lymph node metastasis (RLNM) in contrast to cohorts across varying age demographics. The aim of our study was to identify clinicopathologic prognostic variables in YBC patients with RLNM and construct a practical and reliable nomogram for the prediction of overall survival (OS) using the Surveillance, Epidemiology, and End Results (SEER) database. Methods: Young individuals (≤40 years) with a diagnosis of breast cancer with RLNM were recognized from the SEER database between 2010 and 2015, and further randomly split into two cohorts: the training set (n=4,497) and the validation set (n=1,927). We first performed univariate and multivariate Cox regression analyses to confirm independent survival predictors of OS. A novel prognostic nomogram was developed and evaluated using Harrell's concordance index (C-index), receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA). To make a clear distinction between high- and low-risk patients in terms of patient survival, Kaplan-Meier survival curves were assessed using the log-rank test. Results: Nine risk factors were found as independent prognostic variables in predicting OS, including race, grade, histology, surgery, radiation, molecular subtype, American Joint Committee on Cancer (AJCC) stage 7th edition, T stage, and N stage. The C-index values of our nomogram were 0.786 [95% confidence interval (CI): 0.767-0.805] and 0.791 (95% CI: 0.760-0.822) in our training and validation groups, respectively. The ROC curves demonstrated sufficient discriminating ability, while the predicted and real survival rates were fairly consistent, as shown by the calibration plots. The prediction model had a higher net benefit and acceptable clinical value, as shown by the DCA curves. Conclusions: In YBC patients with RLNM, we successfully established a unique nomogram to forecast the 2-, 3-, and 5-year OS. Clinicians may utilize this nomogram to pinpoint patients at higher risk and provide them with appropriate customized therapies.

Estimating Bidirectional Transitions and Identifying Predictors of Mild Cognitive Impairment.

BACKGROUND AND OBJECTIVES: Various resources exist for treating mild cognitive impairment (MCI) or dementia separately as terminal events or for focusing solely on a 1-way path from MCI to dementia without taking into account heterogeneous transitions. Little is known about the trajectory of reversion from MCI to normal cognition (NC) or near-NC and patterns of postreversion, which refers to cognitive trajectories of patients who have reversed from MCI to NC. Our objectives were to (1) quantitatively predict bidirectional transitions of MCI (reversion and progression), (2) explore patterns of future cognitive trajectories for postreversion, and (3) estimate the effects of demographic characteristics, APOE, cognition, daily activity ability, depression, and neuropsychiatric symptoms on transition probabilities. METHODS: We constructed a retrospective cohort by reviewing patients with an MCI diagnosis at study entry and at least 2 follow-up visits between June 2005 and February 2021. Defining NC or near-NC and MCI as transient states and dementia as an absorbing state, we used continuous-time multistate Markov models to estimate instantaneous transition intensity between states, transition probabilities from one state to another at any given time during follow-up, and hazard ratios of reversion-related variables. RESULTS: Among 24,220 observations from 6,651 participants, there were 2,729 transitions to dementia and 1,785 reversions. As for postreversion, there were 630 and 73 transitions of progression to MCI and dementia, respectively. The transition intensity of progression to MCI for postreversion was 0.317 (2.48-fold greater than that for MCI progression or reversion). For postreversion participants, the probability of progressing to dementia increased by 2% yearly. Participants who progressed to MCI were likely to reverse again (probability of 40% over 15 years). Age, independence level, APOE, cognition, daily activity ability, depression, and neuropsychiatric symptoms were significant predictors of bidirectional transitions. DISCUSSION: The nature of bidirectional transitions cannot be ignored in multidimensional MCI research. We found that postreversion participants remained at an increased risk of progression to MCI or dementia over the longer term and experienced recurrent reversions. Our findings may serve as a valuable reference for future research and enable health care professionals to better develop proactive management plans and targeted interventions.

Clinical outcomes of breast-conserving surgery in patients using a modified method for cavity margin assessment.

BACKGROUND: This study describes a modified intraoperative method for cavity margin (CM) assessment in place of lumpectomy margin assessment in patients undergoing breast-conserving surgery (BCS). METHODS: This is a retrospective review of 422 breast cancer patients undergoing BCS with intraoperative CM assessment. After an initial lumpectomy with intent to obtain ≥1-cm margins, separate specimens 1 × 1 cm, 0.5-cm thick were taken from the cavity margin circumferentially. These were frozen without reference to the side of the new margin as a time-saving measure, and parallel sections of the resected surface were evaluated. RESULTS: After a median follow-up of 55.5 months, a cumulative 5-year locoregional recurrence-free survival rate of 95.3%, metastasis-free survival rate of 97.8%, disease-free survival rate of 88.3%, and overall survival rate of 96.0%, was achieved. The CM positivity rates were of no statistical difference when <7, 7-8, and >8 CMs were assessed. The second operation rate was 3.5% because of the false-negative results of the frozen section analysis on CMs. Univariate and multivariate analysis revealed that a higher pN stage and cT stage as well as a lack of adjuvant chemotherapy or radiation demonstrated significantly worse clinical outcomes. Locoregional recurrences and metastasis are both correlated with worse overall survival. The number of the CMs assessed was not associated with clinical outcomes. CONCLUSIONS: The modified CM assessment presented here is a rapid, accurate, and oncologically safe approach for margin evaluation in BCS patients. Lumpectomy margin assessment might be spared when this method is used.

Prediction of prognosis, immune infiltration and immunotherapy response with N6-methyladenosine-related lncRNA clustering patterns in cervical cancer.

LncRNAs and tumor microenvironment (TME) exert an important effect in antitumor immunity. Nonetheless, the role of m6A-related lncRNA clustering patterns in prognosis, TME and immunotherapy of cervical cancer (CC) remains unknown. Here, based on 7 m6A-related prognostic lncRNAs obtained from TCGA-CC dataset, two m6AlncRNA clustering patterns were determined. m6AlncRNA clusterA was characterized by immune cell infiltrates and immune activation. m6AlncRNA clusterB was characterized by enrichment of immune evasion and tumorigenic activation pathways as well as survival and clinical stage disadvantage. Then, principal component analysis algorithms were used to construct m6AlncRNAscore based on prognostic differentially expressed genes between two m6AlncRNA clusters to quantify m6AlncRNA clustering patterns. m6AlncRNAscore was an independent prognostic protective factor. Higher Th2 and Treg cells and enrichment of immunosuppressive pathways were observed in the low-m6AlncRNAscore group, with poorer survival. High-m6AlncRNAscore was characterized by increased infiltration of activated CD8 T cell, enrichment of immune activation pathways, lower IL-10 and TGF-beta1 levels, and higher immunophenscore values, indicating inflamed TME and better anti-tumor immunotherapy efficacy. Quantitative Real-Time Polymerase Chain Reaction was used for detection of m6A-related prognostic lncRNAs. Collectively, we identified two m6AlncRNA clustering patterns which play a nonnegligible role in the prognosis, TME heterogeneity and immunotherapy of CC patients.

m6A-Related lncRNAs Are Potential Prognostic Biomarkers of Cervical Cancer and Affect Immune Infiltration.

The correlation of m6A-related lncRNAs with the prognosis and immune microenvironment of cervical cancer is not yet clear. In this study, we identified 7 m6A-related prognostic lncRNAs by Pearson correlation and univariate Cox regression analyses based on TCGA-cervical cancer dataset. Then, patients were divided into two clusters by consensus clustering based on the 7 m6A-related prognostic lncRNA expression. Cluster 1 was characterized by survival and stage disadvantage, enrichment of immunosuppressive and carcinogenic activation pathways. Besides, cluster 1 had higher immunosuppressive factor TGFbeta and lower immune cell infiltration compared with cluster 2. According to the expression of 7 m6A-related lncRNA, a 6-m6A-related lncRNA risk score model was established in the training set by LASSO regression analysis. The high-risk group had worse overall survival than the low-risk group. No matter in the training or validation sets, the m6A-related lncRNA risk score was an independent prognostic factor for overall survival. Meanwhile, we validated the independent prognostic value of risk score in the disease-specific survival and progression-free survival by multivariate Cox analysis. The high-risk group was characterized by higher TGFbeta and regulatory T cell and was rich in malignant pathways. Additionally, we also detected and compared the expression levels of four m6A-related prognostic lncRNA in 9 tumor samples and 9 normal tissues using quantitative real-time polymerase chain reaction assay. In conclusion, the novel m6A-related lncRNA risk score is a potential prognostic predictor of cervical cancer patients. These 6 m6A-related lncRNAs might serve as key mediators of the immune microenvironment and represent promising therapeutic targets for improving cervical cancer prognosis.

Development and validation of a model to predict the risk of recurrence in patients with laryngeal squamous cell carcinoma after total laryngectomy.

Background: Recurrence is still the main obstacle to the survival of laryngeal squamous cell carcinoma (LSCC) patients who have undergone a total laryngectomy. Previous models for recurrence prediction in patients with LSCC were based on pathological information, while the role of easily accessible inflammatory markers in the prognosis of LSCC patients has rarely been reported. This study sought to develop and validate a model to predict the risk of recurrence in LSCC patients who underwent total laryngectomy. Methods: A total of 204 LSCC patients who underwent a total laryngectomy were included in this retrospective cohort study. Demographics, pathology, and inflammatory markers of patients were collected. All the patients were randomly divided into a training set and a test set at a ratio of 4:1. Patients were followed up for 3 years after surgery or until death occurred during this period. The random-forest method was used to develop a predictive model. The performance of the model was evaluated by calculating the area under the receiver operating characteristic (ROC) curve (AUC) with the 95% confidence interval (CI), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Results: Of the 204 LSCC patients, 56 (27.45%) patients had a recurrence. The random-forest prediction model was an all-factor model, and the most important predictors of the model were the albumin/globulin ratio (AGR), neutrophil/lymphocyte ratio (NLR), and platelet/lymphocyte ratio (PLR), with proportions of 0.121, 0.100, and 0.092, respectively. The AUCs of the model in predicting the recurrence of LSCC in the training set and the test set were 0.960 (95% CI, 0.931-0.989) and 0.721 (95% CI, 0.716-0.726), respectively. The sensitivity, specificity, accuracy, PPV, and NPV of the model in the test set were 0.750 (95% CI, 0.505-0.995), 0.690 (95% CI, 0.521-0.858), 0.707 (95% CI, 0.568-0.847), 0.500 (95% CI, 0.269-0.921), and 0.870 (95% CI, 0.732-1.000), respectively. Conclusions: A model to predict the risk of recurrence in LSCC patients who have undergone a total laryngectomy was established, and inflammatory markers AGR, NLR, and PLR play an important role in the predictive model.

hnRNP E1 Regulates HPV16 Oncogene Expression and Inhibits Cervical Cancerization.

hnRNP E1 (heterogeneous nuclear ribonucleoprotein E1) is an important RNA-binding protein (RBPs) that plays a vital role in tumor development. Human papillomavirus 16 (HPV16) contains numerous sites that can bind to RNA/DNA and may be modified by multiple RBPs, which contribute to HPV gene expression and HPV-associated cancer development. However, the effects of hnRNP E1 on HPV16 oncogenes in the development of cervical lesions remain unclear. A total of 816 participants with different grades of cervical lesions were enrolled in a community-based cohort established in Shanxi Province, China. The Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases were used to analyze the association between hnRNP E1 mRNA expression and cervical lesions. Cells with up_ and down_regulated hnRNP E1 were established. hnRNP E1 functions were evaluated using cell counting kit-8, flow cytometry analyses, and chromatin immunoprecipitation sequencing. Our results showed that hnRNP E1 expression was linearly dependent on the severity of the cervical lesions. Low expression of HPV16 E2, high expression of E6, and a low ratio of E2 to E6 could increase the risk of cervical lesions. hnRNP E1 expression was correlated with HPV16 oncogene expression. hnRNP E1-relevant genes were involved in the dopaminergic synapses, Wnt signaling pathway, gnRH secretion, and mTOR signaling pathway. hnRNP E1 significantly inhibited cell proliferation, induced apoptosis, arrested the cell cycle at the G0/G1 stage, and decreased HPV16 E6 expression. Our results indicate that hnRNP E1 could downregulate HPV16 E6 oncogene expression and inhibit cervical cancerization, which sheds new light on preventing the carcinogenicity of HPV across a range of diseases by regulating RNA-binding proteins.

Genotype-specific Distribution and Change of High-risk Human Papillomavirus Infection and the Association with Cervical Progression Risk in Women with Normal Pathology and Abnormal Cytology in a Population-based Cohort Study in China.

Objectives: Women with normal pathology screened from abnormal cervical cytology are a special population with higher progression risk than women with normal cytology. However, the associations between genotype distribution and changes of high-risk human papillomavirus (HR-HPV) infection and cervical progression risk in this special population remain unclear. Methods: A total of 1232 women with normal pathology screened from abnormal cervical cytology were enrolled into this cohort with 2-year follow-up. HPV genotyping detection was performed through flow-through hybridization. Hazard ratios (HRs) and Odds ratios (ORs) were calculated using Cox proportional hazard regression and logistic regression models, respectively. Results: Overall HR-HPV prevalence at baseline was 29.0%, with HPV16, 52, 58, 53 and 51 the top five genotypes. The 2-year persistence rate of HR-HPV infection was 31.9%. Compared with HR-HPV negative, the adjusted HRs of overall HR-HPV, HPV16, 31/33, 58, 51, and 53 infections for the progression risk of normal cervix were 5.31, 7.10, 6.95, 5.74, 5.04, and 4.88, respectively. Multiple HR-HPV infection cannot lead to an additional risk of progression relative to single HR-HPV infection. In comparison with HR-HPV persistently negative, same-type HR-HPV persistence was positively associated with progression risk of normal cervix (adjusted OR: 22.26), but different-type HR-HPV persistence was not linked to cervical progression. Conclusion: Genotypes and persistence of HR-HPV infection could stratify the cervical progression risk in women with normal cervical pathology and abnormal cytology and provide evidence for development of next generation of vaccines. HPV51 and 53 deserved attention apart from HPV16, 31, 33, and 58.

A novel therapy for granulomatous lobular mastitis: Local heat therapy.

Granulomatous lobular mastitis (GLM) is a chronic inflammatory breast condition that is characterized by granulomatous inflammation. GLM remains a refractory disease due to its failure to respond to routine anti-inflammatory therapies and its high recurrence rate. Thus, the present study aimed to investigate the application of local heat therapy in GLM as a potential therapeutic strategy. The results revealed that the application of local heat therapy was associated with a shortened remission time for GLM, while the remission and recurrence rates were similar to those of existing therapies. The median first remission time following local heat therapy was significantly decreased compared with that following corticosteroid therapy (5.30 months vs. 11.27 months; P<0.05). The remission rates were not significantly different between the local heat therapy (76.9%), extensive excision (90.4%) and the corticosteroid therapy (85.7%) groups (P>0.05). In addition, the recurrence rates were not statistically different between the groups (local heat therapy, 8.3%; extensive excision, 10%; and corticosteroid therapy, 10%; P>0.05). The local heat therapy showed mild adverse effects and shortened healing times compared to the other therapies; however, further confirmation is required.

A new nomogram for predicting the malignant diagnosis of Breast Imaging Reporting and Data System (BI-RADS) ultrasonography category 4A lesions in women with dense breast tissue in the diagnostic setting.

BACKGROUND: Biopsy has been recommended for Breast Imaging Reporting and Data System (BI-RADS) category 4 lesions. However, the malignancy rate of category 4A lesions is very low (2-10%). Therefore, most biopsies of category 4A lesions are benign, and the results will generally cause additional health care costs and patient anxiety. METHODS: A prediction model was developed based on an analysis of 418 BI-RADS ultrasonography (US) category 4A patients at Sun Yat-sen Memorial Hospital. Univariate and multivariate logistic regression analyses were applied to identify significant variables for inclusion in the final nomogram. The predictive accuracy and discriminative ability were evaluated using the concordance index (C-index) and calibration curves. An independent cohort of 97 patients from the Second Affiliated Hospital of Guangzhou Medical University was used for external validation. RESULTS: The independent risk factors from the multivariate analysis for the training cohort were family history of breast cancer (OR =4.588, P=0.004), US features [margin (OR =2.916, P=0.019), shape (irregular vs. oval, OR =2.474, P=0.044; round vs. oval, OR =1.935, P=0.276), parallel orientation vs. not parallel (OR =2.204, P=0.040)], low suspicious lymph nodes (OR =7.664, P=0.019), and suspicious calcifications on mammography (MG) (OR =6.736, P=0.001). The C-index was good in the training [0.813, 95% confidence interval (95% CI), 0.733 to 0.893] and validation cohorts (0.765, 95% CI, 0.584 to 0.946). The calibration curves showed optimal agreement between the nomogram prediction and actual observations for the probability of malignancy. Also, the cutoff score was set to 100 for discriminating high and low risk. The model performed well in discerning different risk groups. CONCLUSIONS: We developed a well-discriminated and calibrated nomogram to predict the malignancy of BI-RADS US category 4A lesions in dense breast tissue, which may help clinicians identify patients at lower or higher risk.

Impact of intraoperative radiotherapy on the perioperative period of patients after breast-conserving surgery.

BACKGROUND: To investigate the effect of intraoperative radiotherapy (IORT) in the perioperative period of patients after breast-conserving surgery (BCS). METHODS: The clinical data of 100 patients with early breast cancer undergoing breast-conserving surgery (BCS) followed by treatment with IORT using the Intrabeam system (Carl Zeiss Meditec, Oberkochen, Germany) (BCS + IORT group, n=100) between June 2016 and December 2019 were analyzed and compared with the data of 60 matched patients who only underwent breast-conserving therapy over the same period (BCS group, n=60). The surgical settings and postoperative acute complications between the groups were assessed. RESULTS: There was no significant statistical difference between the groups in terms of age, tumor size, grading, lymph node status, hormone receptor status, and human epidermal growth factor receptor 2 (HER-2) status (P>0.05). The BCS + IORT group had a significantly longer surgery duration (P<0.05), but there was no significant statistical difference in terms of intraoperative blood loss, amount of bleeding, drainage tube removal time, postoperative length of hospitalization, incision suture removal time, or incidence of postoperative complications (P>0.05). CONCLUSIONS: IORT using the Intrabeam system safely delivers radiation therapy, is well-tolerated, has acceptable acute toxicity, and does not significant increase the risk of surgery or the incidence of perioperative complications.

Sam68 Promotes the Progression of Human Breast Cancer through inducing Activation of EphA3.

BACKGROUND: Src associated with mitosis of 68 kDa (Sam68), is often highly expressed in human cancers. Overexpression of Sam68 has been shown to be correlated with poor survival prognosis in some cancer patients. However, little is known whether Sam68 plays a role in promoting metastasis in breast cancer. MATERIALS AND METHODS: The expression of Sam68 protein in breast cancer tissue was detected by immunohistochemistry. Trans-well assay, wound-healing, real-time PCR and Western blotting analysis were used to detect the effect of Sam68 on promoting EMT or metastasis of breast cancer. Next-generation RNA sequencing was used to analyze genes that may be regulated by Sam68. RESULTS: Sam68 plays a positive role in promoting breast cancer metastasis. Sam68 was found to be overexpressed in breast cancer along with lymph node metastasis. MMP-9 was also found to be overexpressed in breast cancer tissue and was correlated to the expression of Sam68 (P<0.01). Xenograft in NOD/SCID mice and in vitro experiments confirmed that the invasion and metastatic ability of breast cancer cells were regulated by Sam68. And EPHA3 could be up-regulated by Sam68 in breast cancer. CONCLUSION: High expression of Sam68 participates in breast cancer metastasis by up-regulating the EPHA3 gene.

Development and validation of a prognostic nomogram for patients with triple-negative breast cancer with histology of infiltrating duct carcinoma.

BACKGROUND: The purpose of this study was to develop prognostic nomograms from a cohort of patients with triple-negative breast cancer (TNBC) with histology of infiltrating duct carcinoma (IDC) by correlating their clinical and pathological parameters with the rates of disease-free survival (DFS) and overall survival (OS). METHODS: We retrospectively analyzed TNBC patients with histology of IDC at our institution between 2009 and 2012. Age, family history, menopausal status, surgery type, T stage, N stage, histological grade, vascular invasion, perineural invasion, cytokeratin 5/6 status, Ki-67 expression, and epithelial cadherin (E-cadherin) status were analyzed. Predictors were used in multivariable logistic regression analysis to develop a nomogram to predict DFS and OS rates. The nomograms were then subjected to internal validation, with external validation of the nomogram for predicting OS using separate cohorts of TNBC patients known from the Cancer Genome Atlas (TCGA) database. Using the concordance index (C-index) with calibration curves, the predictive accuracy and discriminative ability were calculated. RESULTS: A total of 242 eligible TNBC patients were included for analysis. The median follow-up time was 70.73 months. Of the patients, 32.6%, 42.6%, and 24.8% had stage I, II, and III disease, respectively. The 3- and 5-year survival rates were 81.0% and 76.5% for DFS, and 86.5% and 81.1%, for OS, respectively. Age, T stage, N stage, and E-cadherin status were found to be risk factors. The nomograms based on those risk factors accurately predicted the 3- and 5-year survival rates. The C-index was 0.798 and 0.821 for DFS and OS, respectively. Besides, the nomogram for OS showed relatively reliable performance in stratifying different risk groups of patients in training and validation cohorts identified from the TCGA database. The C-index reached 0.843. DFS validation was not completed, as there was insufficient data. CONCLUSIONS: Using clinicopathological information, we produced a prognostic nomogram that accurately predicts the 3- and 5-year DFS and OS for patients with TNBC with histology of IDC. More external confirmation is required.

Association between Vaginal Micro-environment Disorder and Cervical Intraepithelial Neoplasia in a Community Based Population in China.

There are other factors that contribute to cervical carcinogenesis except HPV infection. This study aimed to investigate the association between vaginal micro-environment factors, including H2O2, vaginal PH value, vagina cleanness, ß-glucuronidase, coagulase, neuraminidase and leukocyte esterase and cervical intraeipithelial neoplasia (CIN). In total 1019 participants, including 623 normal cervical (NC) women, 303 patients with low-grade cervical intraepithelial neoplasia (CIN1) and 93 patients with high-grade cervical intraepithelial neoplasia (CIN2/3), were enrolled into the study. HPV genotyping was detected by flow-through hybridization and gene chip. Vaginal H2O2, ß-glucuronidase, coagulase, neuraminidase and leukocyte esterase were detected by Aerobic Vaginitis (AV) / Bacterial Vaginal Disease (BV) Five Joint Test Kit. Vaginal PH was measured on the glass slide after microscopy, using color strips with a PH range of 3.8-5.4. Vagina cleanness was determined according to the National Clinical Laboratory Practice Guideline. χ2 test and Logistic regression were operated using SPSS 22.0 software. Our results showed that HPV16 infection rate and the abnormal rates of H2O2, PH, vagina cleanness, ß-glucuronidase or neuraminidase increased gradually along with the severity of CIN (P<0.05). Abnormities of H2O2, cleanness, ß-glucuronidase and neuraminidase were risk factors for CIN regardless of HPV16 infection, furthermore, abnormities of PH value, leukocyte esterase could also increase the risk of CIN in HPV16 positive group. In addition, women with abnormal vaginal micro-environment factors in HPV16 positive group had a significantly higher risk of developing CIN than HPV16 negative group. The results from generalized multifactor dimensionality reduction (GMDR) model showed that there was interaction effect with abnormities of vagina cleanness, H2O2, ß-glucuronidase and neuraminidase on CIN2/3 in HPV16 negative group, while, there was interaction effect with abnormities of vagina cleanness, ß-glucuronidase and neuraminidase on CIN1 and with abnormities of vagina cleanness, PH, H2O2, ß-glucuronidase, neuraminidase and leukocyte esterase on CIN2/3 in HPV16 positive group. Our results suggested that vaginal micro-environment disorder could increase the risk of CIN, especially, the abnormality of H2O2, cleanness, ß-glucuronidase and neuraminidase. There were interaction effects with abnormities of H2O2, vagina cleanness, ß-glucuronidase and neuraminidase on CIN whether HPV16 was infected or not.