Effects of vaginal dilation therapy on vaginal condition and sexual function of endometrial cancer patients treated with radiotherapy after surgery.

OBJECTIVE: This study aimed to evaluate the effect of vaginal dilation therapy on vaginal length, vaginal stenosis, vaginal elasticity, and sexual function of endometrial cancer patients treated with radiotherapy after surgery. METHODS: A total of 117 women were enrolled in this study. They received 6 months of vaginal dilation therapy. We evaluated their vaginal length, vaginal diameter, vaginal elasticity, and sexual function before radiotherapy, after radiotherapy, and after 6 months of vaginal dilation therapy. Their vaginal condition was assessed by customized vaginal dilating molds. Their sexual function was assessed by female sexual function index. The SPSS 25 software was used to analyze all the data. RESULTS: According to multivariate analysis, vaginal diameter (ß = 0.300, 95% CI [0.217-1.446], p = 0.010) and sexual intercourse frequency before diagnosis (ß = 0.424, 95% CI [0.164-0.733], p = 0.006) were significantly correlated with female sexual function after radiotherapy. Vaginal dilation therapy helped increase vaginal length, improve vaginal stenosis and sexual function (p < 0.05), though most of the figures at the end of the intervention did not fully return to those before radiotherapy. Noticeably, vaginal dilation therapy was ineffective in improving vaginal elasticity and the incidence rate of female sexual dysfunction (p > 0.05). Moreover, patients with medium or good vaginal elasticity benefited more from vaginal dilation therapy than patients with poor vaginal elasticity (p < 0.05). CONCLUSION: Vaginal dilation therapy should be carried out timely and preventatively in endometrial cancer patients treated with radiotherapy after surgery to improve their vaginal condition and sexual function.

Effects of vaginal dilation therapy on vaginal length, vaginal stenosis, vaginal elasticity and sexual function of cervical cancer survivors.

BACKGROUND: Cervical cancer survivors can experience vaginal length shortening, vaginal stenosis, vaginal elasticity deterioration, sexual frequency reduction and sexual dysfunction. This prospective, uncontrolled, monocentric clinical interventional study aimed to evaluate the effect of vaginal dilation therapy on vaginal condition and sexual function of cervical cancer survivors who had not received timely vaginal dilation. METHODS: A total of 139 patients completed the study. They received 6 months of vaginal dilation therapy. We evaluated their vaginal elasticity, vaginal diameter, vaginal length and sexual function before and after vaginal dilation therapy. Their vaginal conditions were evaluated by customised vaginal moulds, and the sexual function was assessed by female sexual function index. The SPSS 25 software was used to analyse all the data. RESULTS: Age, vaginal diameter and sexual intercourse frequency before diagnosis were significantly associated with female sexual dysfunction of the patients after cancer treatment. Vaginal dilation therapy improved vaginal stenosis, vaginal length and sexual function in all the patients; however, the vaginal elasticity and incidence of sexual dysfunction did not improve significantly. Sexual intercourse frequency before diagnosis, vaginal elasticity, time interval from last treatment and treatment modalities were significantly associated with the change in female sexual function index score before and after vaginal dilation therapy. Patients with a time interval from the last treatment less than 24 months or those who had moderate or good vaginal elasticity, benefitted more from vaginal dilatation therapy. CONCLUSIONS: Cervical cancer survivors who had not received timely vaginal dilation still benefitted from vaginal dilation therapy, irrespective of the treatment methods they received. Moreover, vaginal dilation therapy should be performed as early as possible after cervical cancer treatment.

Cervical cancer survivors can experience vaginal condition deterioration and sexual dysfunction after treatment. Vaginal dilation can help improve vaginal stenosis, vaginal length and sexual function of these patients. However, some medical institutions in China do not provide timely vaginal dilation for this population. This study aimed to explore whether vaginal dilation was still effective for cervical cancer survivors who had not received timely vaginal dilation. The results showed that these patients still benefitted from vaginal dilation, irrespective of the treatment methods they received. Patients with a time interval from the last treatment less than 24 months or those who had moderate or good vaginal elasticity, benefitted more from vaginal dilation. The findings of the study is an indication to developing countries that more attention should be given to sexual issue of cervical cancer survivors in clinical practice, and vaginal dilation therapy should be performed promptly after treatment.

Bile duct ligation causes opposite impacts on the expression and function of BCRP and P-gp in rat brain partly via affecting membrane expression of ezrin/radixin/moesin proteins.

Breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp) are co-located at blood-brain barrier (BBB) cells, preventing their substrates from entering brain. Accumulating evidence demonstrates that liver failure impairs P-gp and BCRP expression and function in the brain. In the current study, we investigated how liver failure influenced the expression and function of brain BCRP and P-gp in rats subjected to bile duct ligation (BDL). The function of BCRP, P-gp and BBB integrity was assessed using distribution of prazosin, rhodamine 123 and fluorescein, respectively. We showed that BDL significantly decreased BCRP function, but increased P-gp function without affecting BBB integrity. Furthermore, we found that BDL significantly downregulated the expression of membrane BCRP and upregulated the expression of membrane P-gp protein in the cortex and hippocampus. In human cerebral microvascular endothelial cells, NH4Cl plus unconjugated bilirubin significantly decreased BCRP function and expression of membrane BCRP protein, but upregulated P-gp function and expression of membrane P-gp protein. The decreased expression of membrane BCRP protein was linked to the decreased expression of membrane radixin protein, while the increased expression of membrane P-gp protein was related to the increased location of membrane ezrin protein. Silencing ezrin impaired membrane location of P-gp, whereas silencing radixin impaired membrane location of BCRP protein. BDL rats showed the increased expression of membrane ezrin protein and decreased expression of membrane radixin protein in the brain. We conclude that BDL causes opposite effects on the expression and function of brain BCRP and P-gp, attributing to the altered expression of membrane radixin and ezrin protein, respectively, due to hyperbilirubinemia and hyperammonemia.

Physiologically based pharmacokinetic-pharmacodynamic modeling for prediction of vonoprazan pharmacokinetics and its inhibition on gastric acid secretion following intravenous/oral administration to rats, dogs and humans.

Vonoprazan is characterized as having a long-lasting antisecretory effect on gastric acid. In this study we developed a physiologically based pharmacokinetic (PBPK)-pharmacodynamic (PD) model linking to stomach to simultaneously predict vonoprazan pharmacokinetics and its antisecretory effects following administration to rats, dogs, and humans based on in vitro parameters. The vonoprazan disposition in the stomach was illustrated using a limited-membrane model. In vitro metabolic and transport parameters were derived from hepatic microsomes and Caco-2 cells, respectively. We found the most predicted plasma concentrations and pharmacokinetic parameters of vonoprazan in rats, dogs and humans were within twofold errors of the observed data. Free vonoprazan concentrations (fu × C2) in the stomach were simulated and linked to the antisecretory effects of the drug (I) (increases in pH or acid output) using the fomula dI/dt = k × fu × C2 × (Imax - I) - kd × I. The vonoprazan dissociation rate constant kd (0.00246 min-1) and inhibition index KI (35 nM) for H+/K+-ATPase were obtained from literatures. The vonoprazan-H+/K+-ATPase binding rate constant k was 0.07028 min-1· µM-1 using ratio of kd to KI. The predicted antisecretory effects were consistent with the observations following intravenous administration to rats (0.7 and 1.0 mg/kg), oral administration to dogs (0.3 and 1.0 mg/kg) and oral single dose or multidose to humans (20, 30, and 40 mg). Simulations showed that vonoprazan concentrations in stomach were 1000-fold higher than those in the plasma at 24 h following administration to human. Vonoprazan pharmacokinetics and its antisecretory effects may be predicted from in vitro data using the PBPK-PD model of the stomach. These findings may highlight 24-h antisecretory effects of vonoprazan in humans following single-dose or the sustained inhibition throughout each 24-h dosing interval during multidose administration.

Bile duct ligation enhances AZT CNS toxicity partly by impairing the expression and function of BCRP in rat brain.

Breast cancer resistance protein (BCRP) is one of ATP-binding cassette (ABC) transporters in brain microvessel endothelial cells that transport their substrates from brain to blood, thus limiting substrates to crossing into brain through blood-brain barrier. Our previous works show that bile duct ligation (BDL) impairs expression and function of brain BCRP in rats. Since zidovudine (AZT) is BCRP substrate, we investigated whether impaired expression and function of BCRP increased brain distribution and toxicity of AZT in BDL-D7 rats. After administration of AZT (10 mg/kg, i.v.), BDL markedly increased brain AZT concentrations, compared with sham-operated (SO) rats. The ratio of AZT brain-to-plasma area under concentration curve (AUC) in BDL rats was increased to 1.6-folds of SO rats. After treatment with AZT (100 mg/kg every day, i.v.) for 7 days, BDL significantly impaired cognitive functions compared with SO rats, evidenced by the significantly decreased percentage of alternation in Y-maze test and prolonged escaped latency in two-way passive avoidance trial. Furthermore, AZT treatment caused significant decrease in copies of mitochondrial DNA and mitochondrial membrane potential in hippocampus of BDL rats. Moreover, AZT treatment caused a significant decrease of cortex microtubule-associated protein 2 and hippocampus synaptophysin levels in BDL rats. AZT-induced CNS adverse alterations in BDL rats were not observed in SO rats treated with AZT. In conclusion, BDL decreases the function and expression of brain BCRP in rats, leading to increased brain distribution of AZT, which in turn enhances AZT CNS toxicity, leading to mitochondrial dysfunction, neuronal damage, and ultimately cognitive dysfunction.

Degradation of high-concentration p-nitrophenol by Fenton oxidation.

This work aimed to degrade high-concentration p-nitrophenol (PNP) by Fenton oxidation. We studied various reaction parameters during Fenton oxidation, such as the iron dosage (as Fe2+), the initial concentration and temperature of PNP, and the dosage of hydrogen peroxide (H2O2), especially the influence of temperature on the PNP degradation rate and degree. Under the addition of the same molar ratio of H2O2/Fe2+ and H2O2 dosage according to the theoretical stoichiometry, the PNP degradation rate and the removal rate of total organic carbon (TOC) increased significantly with the increase in the initial PNP concentration. Moreover, the oxidative degradation effect was significantly affected by temperature. The increased reaction temperature not only significantly reduced the Fe2+ dosage, but also greatly promoted the removal rate of chemical oxygen demand (COD) and TOC, and improved the utilization efficiency of H2O2. For example, when the initial concentration of PNP was 4,000 mg·L-1, and the dosage of Fe2+ was 109 mg·L-1 (H2O2/Fe2+ = 200), the removal rates of COD and TOC at 85 °C reached 95% and 71% respectively. Both were higher than the 93% COD removal rate and 44% TOC removal rate when the dosage of Fe2+ was 1,092 mg·L-1 (H2O2/Fe2+ = 20) at room temperature.

The negative conversion of high-risk human papillomavirus and its performance in surveillance of cervical cancer after treatment: a retrospective study.

PURPOSE: To determine the negative conversion regularity of high-risk human papillomavirus (HR-HPV) and to evaluate the prognostic implications of HR-HPV testing in patients with cervical cancer after treatment. METHODS: A retrospective post-treatment analysis of 173 patients with cervical cancer was performed from January 2011 to December 2012. Patients who had HR-HPV infection before treatment were included. Clinical and pathological characteristics, as well as follow-up information, were reviewed. RESULTS: The negative conversion rate of HR-HPV reached 68.9 % within half a year and increased most rapidly within the first 2 years after treatment. Univariate and multivariate analyses suggested that the negative conversion rate of HR-HPV was significantly correlated with clinical stage, treatment regimens, and HR-HPV type (P < 0.05). In our analysis of 173 patients, we found that HR-HPV status was predictive of 3-year survival rate and disease recurrence (P < 0.05). Pelvic recurrence, but not distant metastasis, was influenced by HR-HPV status (P < 0.05). Through 2 × 2 table analysis, we found that HR-HPV was more sensitive (71.43 %) and specific (94.20 %) than cervical cytology (sensitivity 62.86 % and specificity 78.26 %). CONCLUSIONS: The negative conversion rate of HR-HPV increased most rapidly within the first 2 years of cervical cancer surveillance. Persistent HPV infection was associated with a poor prognosis and had an impact on recurrence sites. Further large and multi-center prospective studies should be performed, but these results of this study suggested that HR-HPV monitoring is necessary to be used as a means of cervical cancer surveillance.

Clinical value of cold knife conization as conservative management in patients with microinvasive cervical squamous cell cancer (stage IA1).

OBJECTIVE: The aim of the study is to evaluate the clinical value of cold knife conization (CKC) as a conservative management in patients with microinvasive cervical squamous cell cancer (SCC). METHODS: This retrospective study enrolled 108 women with diagnosis of microinvasive cervical SCC (stage IA1) by pathology between 2009 to 2012 at Beijing Obstetrics and Gynecology Hospital, Capital Medical University. Eighty-three patients underwent further hysterectomy. RESULTS: Of the 83 patients (76.9%) who underwent further hysterectomy, 48 patients (57.8%) underwent extrafascial hysterectomy, 30 patients (36.1%) underwent extensive hysterectomy, and 5 patients (6.1%) underwent radical hysterectomy. A total of 19 patients underwent pelvic lymph node dissection without any lymph node metastasis, and a total of 5 patients (4.6%) had lymph vascular space invasion without any positive pelvic lymph node dissection. Of the 83 patients who underwent further hysterectomy and were followed up for 1 year, 18 patients with positive resection margins indicating cervical residual lesions (CIN1-3) have greater likelihood than 65 patients with clear resection margins, but there were no significant differences (P = 0.917); of the 25 patients who underwent CKC as final therapy and were followed up for 1 year, 2 patients with positive resection margins had the second CKC surgery, 1 was diagnosed with CIN1, and the other was diagnosed with cervicitis by pathology; 23 patients had clear resection margins, 2 patients underwent the second CKC 3 months after the first CKC because of the abnormal Thinprep Cytologic Test (TCT) result, and they were both diagnosed with microinvasive cervical SCC (stage IA1) by pathology with clear resection margins. No one enrolled in this study presented metastasis and progression within 1 year of follow-up. CONCLUSIONS: These findings provide the clinical evidences for the possibility of fertility-sparing treatments, especially CKC as conservative treatment for microinvasive cervical SCC. Appropriate further treatments (the second CKC) and follow-up are recommended for patients who strongly desire fertility sparing.

Therapeutic effect of laser vaporization for vaginal intraepithelial neoplasia following hysterectomy due to premalignant and malignant lesions.

AIM: The aim of this study was to evaluate the therapeutic effect of laser vaporization for vaginal intraepithelial neoplasia (VAIN) after hysterectomy in Chinese women and to identify factors affecting persistence/recurrence. MATERIAL AND METHODS: Twenty-eight VAIN patients after hysterectomy due to cervical intraepithelial neoplasia (group 1) and 11 VAIN patients due to cervical cancer (group 2) were reviewed retrospectively. All patients were treated with at least one episode of laser vaporization between 2010 and 2011, and then followed up every 3 months for at least 1 year. Cox regression analysis was used to identify independent factors predicting persistence/recurrence. RESULTS: All VAIN patients achieved remission after two episodes of laser treatment, with 85.7% complete regression in group 1 and 54.5% in group 2. The first episode of the treatment had a significantly higher success rate in group 1 than in group 2 (46.2% vs 0.0%). All patients had no recurrence during a mean follow-up time of 22.8-27.8 months (range 12-39 months). However, infection persisted in 21 (61.8%) of 34 human-papillomavirus-positive patients after laser vaporization. Severity of VAIN was the only significant independent predictor of persistence/recurrence after one episode of the treatment (adjusted odds ratio, 4.08; 95% confidence interval, 1.28-12.96; P = 0.017). Laser treatments were well tolerated with no major side-effects. CONCLUSION: Laser vaporization may be a useful option for the treatment of VAIN after hysterectomy. However, a follow-up is required to assess the long-term efficacy of laser treatment.

Clinical management of cervical intraepithelial neoplasia in pregnant and postpartum women.

OBJECTIVE: To evaluate the clinical management of cervical intraepithelial neoplasia (CIN) and cervical microinvasive squamous cell carcinoma in pregnant and postpartum women. METHODS: This prospective study enrolled 27,230 pregnant women undergoing routine gestational examinations between August 1, 2007 and July 31, 2010 in the Beijing Obstetrics and Gynecology Hospital, Capital Medical University. Colposcopy and cervical biopsy were performed for patients with abnormal Thin Prep® Papanicolaou test (TCT) results. Periodic colposcopy was performed every 8-12 weeks and cervical biopsy was performed if progression was suspected. Cervical cold knife conization was recommended to patients diagnosed with CINIII or microinvasive cervical carcinoma 6-12 weeks after delivery. RESULTS: A total of 2,260 patients had abnormal TCT results (8.12 %). Colposcopy and cervical biopsy were performed for 369 patients. Fifteen patients had microinvasive squamous cell carcinoma, 116 patients had cervicitis, and the number of CIN patients with histological grades I, II, and III were 124, 49, and 65, respectively. Tumor progression during pregnancy was found in 253 patients (CINI or above). Prognosis varied depending on the highest grade of pathological diagnosis results during pregnancy or initial pathological diagnosis results performed 6-12 weeks after delivery by cervical biopsy under colposcopy. Treatment and follow-up were carried out according to diagnoses, state of progression, and reversion (if any). CONCLUSION: These findings underline a need for cervical lesion screening for all women during pregnancy, and colposcopy should be performed for pregnant women who have abnormal TCT results. Appropriate treatment and follow-up were recommended according to different diagnosis of CIN.

[Diagnostic approaches of cervical glandular intraepithelial neoplasia].

OBJECTIVE: To investigate diagnostic approaches of cervical glandular intraepithelial neoplasia (CGIN) for improving the diagnostic levels of CGIN. METHODS: Clinical data of 106 cases with CGIN admitted in hospital from Jan.2008 to Dec. 2010 were analyzed retrospectively.All data from preoperative thin-prep cytologic test (TCT), cervical biopsies and postoperative pathological examination of the excised cervical tissues were reviewed. RESULTS: Among 106 patients, 62 cases (58.5%, 62/106) were low grade CGIN (L-CGIN), 44 cases (41.5%, 44/106) were high grade CGIN (H-CGIN); 25 cases (23.6%, 25/106) were pure CGIN and 81 cases (76.4%, 81/106) were CGIN mixed with cervical intraepithelial neoplasia (CIN). Fifteen cases (14.2%, 15/106) were found atypical glandular cell (AGC) by TCT. In the 15 cases, there were 4 cases (6.5%, 4/62) L-CGIN, and 11 cases (25.0%, 11/44) H-CGIN, there was significant difference between the two groups (P < 0.05); among 15 cases with AGC, 11 cases of them (44.0%, 11/25) were pure CGIN, 4 cases (4.9%, 4/81) mixed with CIN, in which there were significant difference (P < 0.01).Seven cases (25.0%, 7/28) were detected glandular lesions in 28 cases by endocervical curettage (ECC). Totally 23 cases (22.8%, 23/101) were detected CGIN by colposcopy-directed biopsy, 11 cases (19.0%, 11/58) were with L-CGIN, 12 cases (27.9%, 12/43) H-CGIN, there was no significant difference between them (P > 0.05).Among the 23 cases, 13 cases (52.0%, 13/25) were pure CGIN, 10 cases (12.3%, 10/81) CGIN mixed with CIN, which showed significant difference (P < 0.01). All 106 patients were treated, 101 cases treated with cervical conization and 5 cases performed hysterectomy; 23 cases were diagnosed CGIN preoperation, the ratio of preoperative diagnosis was 21.7% (23/106), 83 cases (80.3%, 83/106) diagnosed postoperatively. CONCLUSIONS: Routine diagnostic methods of CGIN were not satisfaction, most CGIN were diagnosed after cervical resection.Cervical conization may play a very important role in diagnosis of CGIN.The positivity of TCT in H-CGIN was higher than L-CGIN. There was no different in diagnosing different CGIN grades by colposcopy-directed biopsy. The ratio of preoperative diagnosis of pure CGIN was higher than those with CGIN mixed with CIN.

BTN2A1-BRAF fusion may be a novel mechanism of resistance to osimertinib in lung adenocarcinoma: a case report.

Background: Non-small cell lung cancer (NSCLC) is one of the most common malignancies in the world. Osimertinib is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) indicated for NSCLC that effectively targets sensitive epidermal growth factor receptor mutation and exon20 T790M. Despite initially impressive outcomes, acquired resistance (AR) develops rapidly, typically within 9-13 months, and the mechanisms of resistance are not fully understood. Over the past years, EGFR-TKI and programmed cell death-ligand 1 (PD-L1) inhibitors have been widely used to treat for patients with advanced lung adenocarcinoma. Case Description: Herein we report a middle-aged female who suffered from lung adenocarcinoma based on the pathological diagnosis. Epidermal growth factor receptor exon 19 deletion was detected by next-generation sequencing (NGS). After the patient underwent a series of treatments, including osimertinib, BTN2A1-BRAF fusion was identified. After assessing PD-L1 expression by immunohistochemistry (IHC), the patient was switched to duvalizumab, a PD-L1 inhibitor, but no significant improvements were observed. NGS and IHC assays were conducted to analyze the biopsy and blood samples obtained during treatment. Conclusions: This case substantiates that the acquisition of BTN2A1-BRAF fusion potentially serves as a mechanism of AR to osimertinib in NSCLC. Patients with sensitive epidermal growth factor receptor mutation derive minimal benefit from PD-L1 inhibitors irrespective of the degree of PD-L1 expression in the tumor tissue in IHC. Our case provides a new train of thought for treating this patient population.

[Cervical microinvasive squamous carcinoma during pregnancy: observation and outcome of pregnancy with planned delayed treatment].

OBJECTIVE: To evaluate the maternal and fetal outcomes of planned delay in treatment for cervical microinvasive squamous cancer during pregnancy. METHODS: A prospective study of pregnant women was done from August 1, 2007 to May 31, 2010. Pregnant women who had not been carried out cervical cytological screening within one year were got thin-prep cytology test (TCT) screening at their initial prenatal visit. Patients with abnormal cytological results were performed colposcopic examination and directed biopsy. Women with cervical microinvasive cancer were followed up every 8 to 12 weeks. If lesion progression were suspected, compared with previous image, repeated biopsy directed by colposcopy should be performed. Once worsening invasive cancer was confirmed, the pregnancy should be terminated timely. All patients should be reevaluated 6 to 12 weeks postpartum with repeated colposcopic examination and biopsy. All mothers were performed cold knife conization (CKC) at 6 to 12 weeks postpartum. RESULTS: We totally diagnosed 17 cases cervical microinvasive squamous carcinoma during pregnancy. The positive rate is 6.2/10 000 (17/27 230). After informed consent, 15 pregnant women decided to delay treatment until fetal maturation. The mean gestational age of initial diagnosis was (19.3 ± 5.9) weeks. The women were followed up 2 to 4 times during pregnancy. Only 1 patient was verified lesion progression by directed biopsy at 34 weeks and delivered by cesarean section. The progression rate during pregnancy was 1/15. The mean delivered time was (37.1 ± 1.8) weeks (ranged from 34 to 40 weeks). The mean diagnosis-to-delivery interval was (18.4 ± 5.2) weeks. All patients were delivered by cesarean section and all newborns had good outcomes. Finally we confirmed 1 case with cervical cancer stage Ia2, 11 cases with stage Ia1, 3 cases with cervical intraepithelial neoplasia (CIN) III by pathological diagnosis after CKC during 6 to 12 weeks postpartum. All cases were disease free after follow-up ranged from 22 to 48 months. CONCLUSIONS: It is necessary to perform TCT screening for pregnant women who have not been carried out cervical cytology screening within 1 year. If cervical microinvasive squamous cancer were suspected during pregnancy, in order to achieve fetal maturity it is acceptable for the women who desired pregnancy to delay treatment under closely monitoring until postpartum.

[Clinical study on cervical intraepithelial neoplasia with high-risk HPV infection among pregnant women].

OBJECTIVE: To investigate the relationship between cervical intraepithelial neoplasia (CIN) and high-risk (HR) HPV infection among late pregnant women. METHODS: From Aug. 2007 to Feb. 2010, 168 women at 13 to 32 gestational weeks undergoing prenatal examination in Beijing Obstetrics and Gynecology Hospital went through three stage cervical disease screening, including 21 women with cervicitis and 147 women with CIN (42 women with CIN III, 37 women with CIN II and 68 women with CIN I). Hybrid capture assay version II (HC-II) test was used to measure HR-HPV DNA load, and the logarithmic transtormation (log(10)) was performed. All 168 women were followed up to postpartum 3 - 6 months. HR-HPV infections rates of cervicitis and different CIN, the rate of HR-HPV infection turned naturally negative at postpartum of 3 to 6 months, and HR-HPV load at pregnancy and 3 - 6 months postpartum were observed. RESULTS: (1) HR-HPV infection rate: CIN III, II, I and cervicitis pregnant women's HR-HPV positive infection rates were 98% (41/42), 86% (32/37), 76% (52/68) and 62% (13/21) respectively, which reached statistical difference (P = 0.002). (2) HR-HPV naturally negative: the rate of pregnant women with different levels of CIN who turned HR-HPV naturally negative within 3 - 6 months of postpartum were CIN III 5% (2/41), CINII 47% (15/32), CINI52% (27/52) and cervicitis 10/13, which also reached statistical difference among those four groups (P = 0.000). (3) HR-HPV load: pregnant women with different grade of CIN and cervicitis HR-HPV DNA load were CIN III 2.02 ng/L(1.53, 2.67 ng/L), CINII 1.94 ng/L (0.75, 2.75 ng/L), CINI2.04 ng/L (0.08, 2.95 ng/L) and cervicitis 1.98 ng/L (-0.07, 2.47 ng/L). There was no significantly different HPV load in women with cervicitis and different CIN (P = 0.719). At 3 - 6 months postpartum, HR-HPV load was CIN III 1.55 ng/L (0.90, 2.10 ng/L), which was significantly higher than the amount of CINII 0.09 ng/L (-0.69, 1.74 ng/L), CINI0.48 ng/L (-0.56, 2.2 ng/L) and cervicitis -0.46 ng/L (-0.78, 1.40 ng/L, P = 0.036). CONCLUSIONS: With the increasing of CIN grade, the rate of HR-HPV infection in pregnant women was increased, however, the rate of HR-HPV turning negative naturally at 3 - 6 months postpartum decreased. With different CIN grade during pregnancy, HR-HPV DNA load did not change significantly, but HR-HPV DNA load increased at 3 - 6 months of postpartum. HR-HPV DNA loads with the same grade of CIN and cervicitis during pregnancy higher than that of postpartum among pregnant women.

PMEPA1 Serves as a Prognostic Biomarker and Correlates with Immune Infiltrates in Cervical Cancer.

Emerging studies have demonstrated that Prostate transmembrane protein androgen induced 1 (PMEPA1) plays crucial roles in the carcinogenesis of many developing human tumors. However, the clinical significance of PMEPA1 expression in cervical cancer (CC) and its contribution to cancer immunity have not been investigated. In this study, we identified PMEPA1 as a survival-related gene in CC based on TCGA datasets. Univariate and multivariate analysis showed that PMEPA1 expression was an independent predictor for overall survival in CC patients. We could observe a strong negative correlation between PMEPA1 expression and PMEPA1 methylation. Two CpG sites of PMEPA1 were associated with overall survival, and one CpG site of PMEPA1 was associated with progression-free survival. The low level of PMEPA1 methylation was associated with advanced clinical stage of CC patients. KEGG assays revealed the genes associated with PMEPA1 expression were mainly enriched in several tumor-related pathways. Increased PMEPA1 expressions were observed to be positively related to high immune infiltration levels in several immune cells. Finally, the pan-cancer assays revealed that PMEPA1 expression was associated with the overall survival of UVM, PAAD, LUSC, BLCA, CESC, and LUAD. Taken together, PMEPA1 is a prognosis-related biomarker for multiple cancer types, especially CC. PMEPA1 is involved in tumor immunity, suggesting PMEPA1 may be a potential immunotherapeutic target in CC.

[Analysis of relative factors of bone marrow suppression after chemotherapy with carboplatin and paclitaxel on the patients with ovarian cancer].

OBJECTIVE: To analyze the relative factors of bone marrow suppression after chemotherapy with different-dose carboplatin and paclitaxel (TC) on the patients with ovarian cancer. METHODS: Sixty-two patients with ovarian cancer admitted in Beijing Obstetrics and Gynecology Hospital from January 2002 to December 2007, using TC regimen, a total of 196 cycles of chemotherapy, were divided into two groups by the doses of carboplatin [area under concentration-time curve (AUC) 4 - 6 for low-dose, AUC > 6 - 7 for hight-dose, the carboplatin dose calculated with AUC] or by the doses of paclitaxel (135- < 150 mg/m(2) low-dose, 150 - 175 mg/m(2) hight-dose). After each TC cycle, the routine blood was test to determine the graduation of the marrow suppression, and then the correlation factors were analyzed with logistic regression. RESULTS: (1) The occurrence rate of bone marrow suppression: there were 159 cycles (81.1%) grade 0-II bone marrow suppression, while 37 cycles (18.9%) of grade III-IV. (2) Factors related to bone marrow suppression: the results shown that there were not related to bone marrow suppression, which incluced cellular differentiation, tumor type, height, weight and paclitaxel dose (P > 0.05). While, the different cycle, age, the later stages of tumor, serum creatinine concentration, endogenous creatinine clearance rate, AUC values were the relative factors of bone marrow suppression (P = 0.000, 0.000, 0.018, 0.033, 0.001, 0.000). Seven variables were conducted into the logistic regression and the results shown that the different cycles, the age, AUC grades were independent risk factors (P = 0.030, 0.043, 0.009). (3) When low-dose of paclitaxel was given, the occurrence of bone marrow suppression was related to the carboplatin dose AUC. The higher AUC values for carboplatin were chosen, the higher of severe bone marrow suppression would happen. (4/14 vs 0, P = 0.015). When the dose of high grade of paclitaxel was given, the occurrence of bone marrow suppression in cases with hight-dose carboplatin was statistically significant than that in cases treated with low-dose carboplatin [45.7% (16/35) vs 13.7% (17/124), P = 0.000]. CONCLUSIONS: The independent risk factors of myelosuppression after chemotherapy with TC regime on the patients with ovarian cancer including the cycles, age and AUC values. The carboplatin dose calculating with AUC is related to the occurrence of bone marrow suppression, the higher AUC values for carboplatin would chosen, the higher of severe bone marrow suppression would be happen.

[Clinical study on cervix biopsy guided by colposcopy in diagnosis of cervical diseases in pregnant women].

OBJECTIVE: To investigate the value and safety of biopsy guided by colposcopy in diagnosis of cervical diseases in pregnant women. METHODS: From Aug. 2007 to Feb. 2009, 17 828 pregnant women who receive antenatal examination underwent cervical cytological screening thinprep cytology test (TCT) in Beijing Obstetrics and Gynecology Hospital. If abnormal cytological results were found, those pregnant women were administered by colposcopic examination and biopsy after they signed informed consent. RESULTS: (1) TCT: the abnormal TCT results of 1502 pregnant women (8.425%, 1502/17 828) were found in 17 828 cases. (2) Colposcopic examination: two hundred and four pregnant women underwent colposcopic examination. The rate of satisfied colposcopic imaging was 92.6% (189/204), colposcopic examination identified 125 cases with cervical inflammation or cervical intraepithelial neoplasia (CIN)I, 25 cases with CINII and 54 cases with CINIII or microinvasive squamous carcinoma (MIVC) of squamous cervical carcinoma (SCC). (3) The results of biopsy guided by colposcopy: among 204 cases, it was found 33 cases with cervical inflammation or wart, 95 cases with CINI, 28 CINII, 36 cases with CINIII and 12 cases with MIVC. (4) The rate of concordance: compared with biopsy pathologic examination, colposcopy examination found 113 cases with cervical inflammation and CINI, the rate of concordance was 90.4% (113/125). And 54 cases with CINIII or SCC diagnosed by colposcopy examination, however biopsy pathologic examination confirm 23 cases with CINIII and 10 cases with SCC at stage Ia, the concordance rate was 61% (33/54). (5) Complication: eight (3.9%, 8/204) pregnant women underwent cervical wound suturing due to continuous bleeding after colposcopy exam or biopsy. No other complications were recorded. CONCLUSIONS: It is necessary that TCT should be performed in pregnant women without cytological screening within one year. Colposcopic examination and biopsy were indicated if pregnant woman with abnormal cytological result were found. Pregnant women with cervicitis or CINI diagnosed by colposcopy should be followed up. If pregnant woman was suspected with CINII or advanced disease, biopsy guided by colposcopy should be performed.

Prevalence and genotypes of human papilloma virus infection in CIN3 in Beijing, China.

BACKGROUND: To investigate the incidence of single and multiple human papillomavirus (HR-HPV) infection in CIN3 patients before operation. METHODS: The complete clinical data of patients with CIN3 by biopsy were collected. HPV23 typing in the first 3 months of the treatment was detected. The infection rate of HPV was analyzed. RESULTS: One thousand and fifty-one HPV subtypes were detected in 679 patients with HPV (+) CIN3 with primary conization, of which the top ten were HPV16, 33, 31, 58, 6, 52, 18, 43, 51, 11, 68, respectively. Among them, single subtype HPV infection accounted for 64.36%, while multiple HPV infection accounted for 35.64%. For multiplex HPV infection, there were 2, 3, 4 species, and 148 (21.80%), 69 (10.16%), 16 (2.36%), 9 (1.33%) cases of multiple HPV infection of 5 and above HPV subtypes respectively. The incidence of multiple HPV infection in CIN3 patients in 2015 was higher than that in 2012 (39.01% vs. 30.08%, P=0.019), and the proportion of multiple infections in HPV was higher than that in the 2014 group. CONCLUSIONS: The top 10 HPV subtypes of the CIN3 patients were included in HPV nine valence vaccines except HPV43 and 51.

Physiologically-Based Pharmacokinetic-Pharmacodynamics Model Characterizing CYP2C19 Polymorphisms to Predict Clopidogrel Pharmacokinetics and Its Anti-Platelet Aggregation Effect Following Oral Administration to Coronary Artery Disease Patients With or Without Diabetes.

Background and Objective: Clopidogrel (CLOP) is commonly used in coronary artery disease (CAD) patients with or without diabetes (DM), but these patients often suffer CLOP resistance, especially those with diabetes. This study was aimed to develop a physiologically-based pharmacokinetic-pharmacodynamic (PBPK-PD) model to describe the pharmacokinetics and pharmacodynamics of clopidogrel active metabolite (CLOP-AM) in CAD patients with or without DM. Methods: The PBPK-PD model was first established and validated in healthy subjects and then in CAD patients with or without DM. The influences of CYP2C19, CYP2C9, CYP3A4, carboxylesterase 1 (CES1), gastrointestinal transit rates (K t,i) and platelets response to CLOP-AM (k irre) on predicted pharmacokinetics and pharmacodynamics were investigated, followed with their individual and integrated effects on CLOP-AM pharmacokinetics due to changes in DM status. Results: Most predictions fell within 0.5-2.0 folds of observations, indicating successful predictions. Sensitivity analysis showed that contributions of interested factors to pharmacodynamics were CES1> k irre> K t,i> CYP2C19 > CYP3A4> CYP2C9. Mimicked analysis showed that the decreased exposure of CLOP-AM by DM was mainly attributed to increased CES1 activity, followed by decreased CYP2C19 activity. Conclusion: The pharmacokinetics and pharmacodynamics of CLOP-AM were successfully predicted using the developed PBPK-PD model. Clopidogrel resistance by DM was the integrated effects of altered K t,i, CYP2C19, CYP3A4, CES1 and k irre.

[Prognostic factors of stage III endometrial carcinoma].

OBJECTIVE: To investigate the prognostic factors of surgery-pathological stage III endometrial cancer. METHOD: The clinical data of 102 patients with stage III endometrial cancer, aged 54.9 (27-79), 71 with endometrioid adenocarcinoma, 31 with non-endometrioid adenocarcinoma, 9 undergoing simple surgical treatment, and 42 receiving radiation, 16 receiving chemotherapy, and 35 receiving chemoradiation after surgery, were analyzed retrospectively. Follow-up was conducted for 56 (3-192) months. RESULTS: Cox risk model analysis showed that the risk factors for the prognosis of stage III endometrial cancer were pathological types, method of treatment, vascular thrombosis, and age (all P < 0.05). The average survival time of stage III a endometrial cancer patients purely positive in peritoneal cytology was 74.4 months, significantly longer than that of the patients with serosa and/or annex involvement (53.8 months, P < 0.05). CONCLUSION: The independent prognostic factors of stage III endometrial cancer are pathological type, method of treatment, vascular thrombosis, and age. The patients with, the prognosis of stage III a endometrial cancer simply positive in peritoneal cytology is better than that with serous and/or annex involvement.