Functioning gonadotroph adenoma with hyperestrogenemia and ovarian hyperstimulation in a reproductive-aged woman:A case report and review of literature

BACKGROUND Functioning gonadotroph adenomas are extremely rare pituitary tumors that secrete gonadotropins and exhibit distinct clinical manifestations.Here,we report a case of functioning gonadotroph adenoma in a reproductive-aged woman and discuss its diagnosis and management.CASE SUMMARY A 21-year-old female patient with abdominal pain,irregular menstruation,hyperestrogenemia,and an ovarian mass was included.Brain magnetic resonance imaging(MRI)revealed a pituitary macroadenoma,and transsphenoidal surgery relieved her clinical symptoms.Before transsphenoidal surgery,plasma CA125,estradiol levels were elevated,while prolactin,luteinizing hormone,follicle-stimulating hormone,PROG,cortisol,FT4,thyroid-stimulating hormone,para-thyroid hormone,and GH levels were maintained at normal levels.After trans-sphenoidal surgery,the patient was diagnosed with a functioning gonadotroph adenoma.During follow-up,pelvic ultrasound confirmed normal-sized ovaries in the patient,the menstrual cycle returned to regular,and her hormones were maintained within a normal range.There was no evidence of tumor recurrence after two years of follow-up.CONCLUSION Early diagnosis of functioning gonadotroph adenomas should be considered in patients with hyperestrogenism,irregular menstruation,large or recurrent ovarian cysts,and visual field defects.Pituitary MRI should be performed,and transsphenoidal surgery is recommended for the management of this disease.

Tankyrase 2 promotes lung cancer cell malignancy

BACKGROUND Tankyrase 2(TNKS2)is a potential candidate molecular target for the prognosis and treatment of non-small cell lung cancer(NSCLC),but its biological functions are unclear.AIM To investigate the biological functions of TNKS2 in NSCLC.METHODS Using a lentiviral vector,we generated H647 model cells with TNKS2 knockdown by RNA interference and A549 model cells with TNKS2 overexpression by tran-sfection with a TNKS2 overexpressing plasmid.Increased and decreased exp-ression levels of TNKS2 in the two cell lines were verified using real-time reverse transcriptase-polymerase chain reaction and Western blot analyses.Cell apopto-sis,proliferation,and migration were determined using flow cytometry,carbo-xyfluorescein succinimidyl ester staining,and scratch assay,respectively.Im-munofluorescence staining was conducted to examine TNKS2 andβ-catenin ex-pression levels in the two transfected cell lines and the non-transfected cells.RESULTS TNKS2 mRNA and protein expression was significantly higher in the highly malignant NCI-H647 cells,while it remained at a low level in the less malignant A549 cells.Lentivirus-mediated overexpression of TNKS2 in A549 cells resulted in a 3-fold increase in gene expression and a 1.7-fold increase in protein expression(P<0.01).Conversely,shRNA interference targeting TNKS2 Led to an 8-fold decrease in gene expression and a 3-fold decrease in protein expression(P<0.01)in NCI-H647 cells.Furthermore,the cell apoptosis rate was significantly reduced(50%)and cell migration rate was increased(35%)in the TNKS2 overexpression group than in the control group(P<0.05).In contrast,shTNKS2 promoted apoptosis by more than one fold and reduced migration by 60%(P<0.05).Immunofluorescence analysis revealed enhanced nuclear localization ofβ-catenin fluorescence signal associated with high TNKS2 expression levels.Western blot analysis investigating TNKS2/β-catenin-related proteins indicated consistent changes between TNKS2 andβ-catenin expression in lung cancer cells,whereas Axin displayed an opposite trend(P<0.05).CONCLUSION The obtained results revealed that TNKS2 may serve as an adverse prognostic factor and a potential therapeutic target in NSCLC.

Incidence of human papilloma virus in esophageal squamous cell carcinoma in patients from the Lublin region

AIM:To assess the prevalence of human papilloma virus(HPV) in esophageal squamous cell carcinoma(ESCC) in the south-eastern region of Poland.METHODS:The study population consisted of 56 ESCC patients and 35 controls.The controls were patients referred to our department due to other nonesophageal and non-oncological disorders with no gross or microscopic esophageal pathology as confirmed by endoscopy and histopathology.In the ESCC patients,samples were taken from normal mucosa(56 mucosa samples) and from the tumor(56 tumor samples).Tissue samples from the controls were taken from normal mucosa of the middle esophagus(35 control samples).Quantitative determination of DNA was carried out using a spectrophotometric method.Genomic DNA was isolated using the QIAamp DNA Midi Kit.HPV infection was identified following PCR amplification of the HPV gene sequence,using primers MY09 and MY11 complementary to the genome sequence of at least 33 types of HPV.The sequencing results were computationally analyzed using the basic local alignment search tool database.RESULTS:In tumor samples,HPV DNA was identified in 28 of 56 patients(50%).High risk HPV phenotypes(16 or/and 18) were found in 5 of 56 patients(8.9%),low risk in 19 of 56 patients(33.9%) and other types of HPV(37,81,97,CP6108) in 4 of 56 patients(7.1%).In mucosa samples,HPV DNA was isolated in 21 of 56 patients(37.5%).High risk HPV DNA was confirmed in 3 of 56 patients(5.3%),low risk HPV DNA in 12 of 56 patients(21.4%),and other types of HPV in 6 of 56 patients(10.7%).In control samples,HPV DNA was identified in 4 of 35 patients(11.4%) with no high risk HPV.The occurrence of HPV in ESCC patients was significantly higher than in the controls [28 of 56(50%) vs 4 of 35(11.4%),P < 0.001].In esophageal cancer patients,both in tumor and mucosa samples,the predominant HPV phenotypes were low risk HPV,isolated 4 times more frequently than high risk phenotypes [19 of 56(33.9%) vs 5 of 56(8.9%),P < 0.001].A higher prevalence of HPV was identified in female patients(71.4% vs 46.9%).Accordingly,the high risk phenotypes were isolated more frequently in female patients and this difference reached statistical significance [3 of 7(42.9%) vs 2 of 49(4.1%),P < 0.05].Of the pathological characteristics,only an infiltrative pattern of macroscopic tumor type significantly correlated with the presence of HPV DNA in ESCC samples [20 of 27(74.1%) vs 8 of 29(27.6%) for ulcerative or protruding macroscopic type,P < 0.05].The occurrence of total HPV DNA and both HPV high or low risk phenotypes did not significantly differ with regard to particular grades of cellular differentiation,phases in depth of tumor infiltration,grades of nodal involvement and stages of tumor progression.CONCLUSION:Low risk HPV phenotypes could be one of the co-activators or/and co-carcinogens in complex,progressive,multifactorial and multistep esophageal carcinogenesis.

Prevalence of HPV Infection And Cervical Intraepithelial Neoplasia And Attitudes towards HPV Vaccination among Chinese Women Aged 18-25 in Jiangsu Province

Objective：Few data are available on the epidemiology of HPV and cervical cancer among Chinese women younger than 25 years old.This study aimed to estimate the HPV infection rate and the prevalence of cervical intraepithelial neoplasia（CIN） in women aged 18-25,as well as their knowledge of and attitudes towards HPV vaccination.Methods：A population-based cervical cancer screening study was conducted on women aged 18-25 in Jiangsu province in 2008.Participants provided socio-demographic,reproductive and behavioral information and completed a survey about their knowledge of and attitudes towards HPV vaccination.Women then underwent a gynecologic exam to provide two cervical exfoliated cell samples for high risk HPV DNA testing and liquid-based cytology（LBC） as well as visual inspection with acetic acid（VIA）.Women testing positive for any test were referred to colposcopy and biopsy.The gold standard for diagnosis of cervical lesions was directed or random biopsies.Results：Within the sample of 316 women,3.4% of them were diagnosed with CIN grade 2 or worse lesions and 17.1% were found to be positive for HPV DNA.Among these young women,extra-marital sexual behavior of them（OR=2.0,95%CI：1.1-3.8） or their husbands（OR=2.6,95%：1.4-4.7） were associated with an increased risk of HPV positivity.Although overall HPV awareness was low,after a brief educational intervention,98.4% reported they would electively receive HPV vaccination and would also recommend that their daughters be vaccinated.However,most urban and rural women reported their ideal maximum out-of-pocket contribution for HPV vaccination to be less than 500 RMB and 50-100 RMB,respectively.Conclusion：Our study indicates cervical disease burden is relatively high among sampled Chinese women aged 18-25.Appropriate educational interventions for female adolescents and strategies to subsidize vaccine costs are definitely needed to ensure the effectiveness of vaccination campaigns in China.

PhaseⅠdose-escalation and expansion study of PARP inhibitor,fluzoparib(SHR3162),in patients with advanced solid tumors

Objective:Fluzoparib(SHR3162)is a novel,potent poly(ADP-ribose)polymerases(PARP)1,2 inhibitor that showed anti-tumor activity in xenograft models.We conducted a phaseⅠ,first-in-human,dose-escalation and expansion(D-Esc and D-Ex)trial in patients with advanced solid cancer.Methods:This was a 3+3 phaseⅠD-Esc trial with a 3-level D-Ex at 5 hospitals in China.Eligible patients for DEsc had advanced solid tumors refractory to standard therapies,and D-Ex enrolled patients with ovarian cancer(OC).Fluzoparib was administered orally once or twice daily(bid)at 11 dose levels from 10 to 400 mg/d.Endpoints included dose-finding,safety,pharmacokinetics,and antitumor activity.Results:Seventy-nine patients were enrolled from March,2015 to January,2018[OC(47,59.5%);breast cancer(BC)(16,20.3%);colorectal cancer(8,10.1%),other tumors(8,10.1%)];48 patients were treated in the D-Esc arm and 31 in the D-Ex arm.The maximum tolerated dose(MTD)was 150 mg bid,with a half-life of 9.14 h.Grade 3/4 adverse events included anemia(7.6%)and neutropenia(5.1%).The objective response rate(ORR)was 30%(3/10)in patients with platinum-sensitive OC and 7.7%(1/13)in patients with BC.Among patients treated with fluzoparib≥120 mg/d,median progression-free survival(m PFS)was 7.2[95%confidence interval(95%CI),1.8-9.3]months in OC,9.3(95%CI,7.2-9.3)months in platinum-sensitive OC,and 3.5(range,2.0-28.0)months in BC.In patients with germline BC susceptibility gene mutation(g BRCAMut)(11/43 OC;2/16 BC),m PFS was 8.9 months for OC(range,1.0-23.2;95%CI,1.0-16.8)and 14 and 28 months for BC(those two patients both also had somatic BRCAMut).Conclusions:The MTD of fluzoparib was 150 mg bid in advanced solid malignancies.Fluzoparib demonstrated single-agent antitumor activity in BC and OC,particularly in BRCAMut and platinum-sensitive OC.

Accuracy of triage strategies for human papillomavirus DNA-positive women in low-resource settings:A cross-sectional study in China

Objective： CareHPV is a human papillomavirus （HPV） DNA test for low-resource settings （LRS）. This study assesses optimum triage strategies for careHPV-positive women in LRS. Methods： A total of 2,530 Chinese women were concurrently screened for cervical cancer with visual inspection with acetic acid （VIA）, liquid-based cytology and HPV testing by physician- and self-collected careHPV, and physician-collected Hybrid Capture 2 （HC2）. Screen-positive women were referred to colposcopy with biopsy and endocervical curettage as necessary. HPV-positivity was defined as _〉1.0 relative light units/cutoff （RLU/CO） for both careHPV and HC2. Primary physician-HC2, physician-careHPV and self-careHPV and in sequential screening with cytology, VIA, or increased HPV test-positivity performance, stratified by age, were assessed for cervical intraepithelial neoplasia （CIN） grade 2/3 or worse （CIN2/3＋） detection. Results： The sensitivities and specificities of primary HPV testing for CIN2＋ were： 83.8%, 88.1% for physician- careHPV; 72. 1%, 88.2% for self-careHPV; and 97.1%, 86.0% for HC2. Physician-careHPV test-positive women with VIA triage had a sensitivity of 30.9% for CIN2＋ versus 80.9% with cytology triage. Self-careHPV test- positive women with VIA triage was 26.5% versus 66.2 % with cytology triage. The sensitivity of HC2 test-positive women with VIA triage was 38.2 % versus 92.6% with cytology triage. The sensitivity of physician-careHPV testing for CIN2＋ decreased from 83.8% at _〉1.0 RLU/CO to 72.1% at _〉10.00 RLU/CO, while the sensitivity of self- careHPV testing decreased from 72.1% at _〉1.0 RLU/CO to 32.4% at _〉10.00 RLU/CO; similar trends were seen with age-stratification. Conclusions： VIA and cytology triage improved specificity for CIN2/3 than no triage. Sensitivity with VIA triage was unsuitable for a mass-screening program. VIA provider training might improve this strategy. Cytology triage could be feasible where a high-quality cytology program exists. Triage of HPV test-positive women by increased test positivity cutoff adds another LRS triage option.

Comparison of the short-term and long-term outcomes of laparoscopic hysterectomies and of abdominal hysterectomies： a case study of 4,895 patients in the Guangxi Zhuang Autonomous Region, China

Background： To evaluate the short-term and long-term outcomes after laparoscopic hysterectomy （LH） compared with abdominal hysterectomy （AH） in case of benign gynecological disease. Methods： A multi-center cohort retrospective comparative study of population among 4,895 hysterectomies （3,539 LH vs.1,356 AH） between 2007 and 2013 was involved. Operative time （OT）, estimated blood loss （EBL）, intra-operative and post-operative complications, passing flatus; days with indwelling catheter, questionnaires covering pelvic floor functions and sexual functions were assessed. Results： The EBL （174.1±157.4 vs. 263.1±183.2 cc, LH and AH groups, respectively）, passing flatus （38.7±14.1 vs. 48.1±13.2 hours）, days with indwelling catheter （1.5±0.6 vs. 2.2±0.8 days）, use of analgesics （6.5% vs. 73.1%）, intra-operative complication rate （2.4% vs. 4.1%）, post-operative complication rate （2.3 % vs. 5.7%）, post-operative constipation （12.1% vs. 24.6%）, mild and serious stress urinary incontinence （SUI） post-operative （P〈0.001; P=0.014）, and proportion of Female Sexual Functioning Index （FSFI） total score 〈26.55 post-operative （P〈0.001） of the LH group were significantly less than those of AH group. There were no significant differences in OT （106.5±34.5 vs. 106.2±40.3 min） between the two groups. Conclusions： LH is a safe and efficient operation for improving patients＇ long-term quality of life （QoL）, and LH is a cost-effectiveness procedure for treating benign gynecological disease. LH is superior to AH due to reduced EBL, reduced post-operative pain and earlier passing flatus.

Abdominopelvic leiomyoma with large ascites:A case report and review of the literature

BACKGROUND Leiomyoma of the uterus is relatively common,but uterine leiomyoma of the greater omentum is rare.CASE SUMMARY Here,we report the case of a 22-year-old woman who presented with a 3 mo history of progressive abdominal distension and a hypervascular abdominopelvic mass.Due to a high serum concentration of CA125,the preoperative diagnosis was unclear.During surgery,5 L of ascites was removed.An 18.8 cm solid mass,which was pedunculated from the uterine fundus and exhibited complex adhesion to the greater omentum,was removed.The CA125 level was reduced postoperatively,and a pathologic study confirmed that the mass was a leiomyoma that originated in the uterus.CONCLUSION Uterine leiomyoma can share vessels with the greater omentum.This case highlights the difficulty of diagnosing pseudo-Meigs syndrome and the importance of imaging and laboratory examinations.

Expression and Clinical Significance of HMGB1 and RAGE in Cervical Carcinoma

OBJECTIVE To study the expression level and clinical significance of HMGB1 and RAGE in cervical squamous epithelial carcinoma. METHODS Real time quantitative polymerase chain reaction （qRT-PCR） was employed to examine the expression of HMGB1 （high mobility group box protein1）, and RAGE （receptor for advanced glycation endproducts） in 60 cervical squamous epithelial carcinomas （CSEC）, their paraneoplastic tissues （PS） and 30 normal cervix tissues （NCS）. RESULTS The expression of HMGB1 in the CSEC samples and PS was similar （P〉0.05）, but higher compared to NCS （P〈0.05）. Overexpression of HMGB1 in the CESC tissues was significantly correlated with the tumor （P〈0.05）, and the presence of metastasis （P〈0.01）, but not correlated with the tumor diameter or tumor grade.RAGE expression was not significantly different among these tissue types, and showed no significant correlation with the the tumor stage, diameter or grade. But there was a significant positive correlation between RAGE expression and CSEC metastasis. CONCLUSION The results suggest that HMGB1 may be related to the proliferation, progression and metastasis of CSEC. The relationship of HMGBI/RAGE may be of importance for CSEC metastasis. HMGB1 presents a new potential gene target for prevention and treatment of CSEC. Study of HMGBI/RAGE expression will offer an experimental foundation for understanding the pathogenesis of CSES.

Evaluation of triage strategies for high-risk human papillomavirus-positive women in cervical cancer screening:A multicenter randomized controlled trial in different resource settings in China

Objective:We aimed to evaluate the effectiveness of different triage strategies for high-risk human papillomavirus(hrHPV)-positive women in primary healthcare settings in China.Methods:This study was undertaken in 11 rural and 9 urban sites.Women aged 35-64 years old were enrolled.HrHPV-positive women were randomly allocated to liquid-based cytology(LBC),visual inspection with acetic acid and Lugol’s iodine(VIA/VILI)(rural only)triage,or directly referred to colposcopy(direct COLP).At 24 months,hrHPV testing,LBC and VIA/VILI were conducted for combined screening.Results:In rural sites,1,949 hrHPV-positive women were analyzed.A total of 852,218 and 480 women were randomly assigned to direct COLP,LBC and VIA/VILI.At baseline,colposcopy referral rates of LBC or VIA/VILI triage could be reduced by 70%-80%.LBC(n=3 and n=7)or VIA/VILI(n=8 and n=26)could significantly decrease the number of colposcopies needed to detect one cervical intraepithelial neoplasia(CIN)2 or worse and CIN3+compared with direct COLP(n=14 and n=23).For the 24-month cumulative detection rate of CIN2+,VIA/VILI triage was 0.50-fold compared with LBC triage and 0.46-fold with the direct COLP.When stratified by age,baseline LBC triage+performed best(P<0.001),peaking among women aged 35-44 years(Ptrend=0.002).In urban sites,1,728 women were hrHPV genotyping test positive.A total of 408,571 and 568women were randomly assigned to direct COLP for HPV16/18+,direct COLP for other hrHPV subtypes+,and LBC triage for other hrHPV subtypes+.LBC(n=12 and n=31)significantly decreased the number of colposcopies needed to detect one CIN2+and CIN3+compared with direct COLP(n=14 and n=44).HPV16/18+increased the 24-month cumulative detection rate of CIN2+(17.89%,P<0.001).Conclusions:LBC triage for hrHPV-positive women in rural settings and direct COLP for HPV16/18+women and LBC triage for other hrHPV subtype+women in urban settings might be feasible strategies.

DETECTION OF SENTINEL LYMPH NODE IN EARLY CERVICAL CANCER

Objective: To assess the value of sentinel lymph node (SLN) localization by lymphoscintigraphy and gamma probe detection in early cervical cancer. Methods: A total of 27 patients with operable invasive early cervical cancer and clinically proved negative pelvic lymph nodes were included in this study. The 99Tcm-dextran of 74 MBq (2 mCi) was injected around the cervix at 2 and 10. Lymphoscintigraphy and gamma probe detection were used to find the SLN. Results: The SLN was identified in 27 patients. The sensitivity and specificity of the SLN detection to predict the metastasis of the pelvic lymph node were 100% and 100% respectively. Conclusion: Identification of the SLN using radionuclide is feasible and possible in women with early cervical cancer.

CLINICAL ANALYSIS OF EXTRAMAMMARY PAGET’S DISEASE OF VULVA

Objective: To review our experience in diagnosis, pathology, treatment, and prognosis of extramammary Paget's disease of the vulva. Methods: Seven patients with vulvar Paget's disease who were treated at the Cancer Hospital cAMS were retrospectively reviewed for the period from 1960 to 2002. The symptoms, location of disease, pathology, mode of treatment and current status of the patients were evaluated. Results: A total of seven women with Paget抯 disease of the vulva were admitted to the Department of Gynecologic of Oncology. The mean age was 67.3 years (range 54~81 years). Vulvar lesion and pruritus were the common symptoms and it took average 3.4 years to confirm the diagnosis. All patients underwent surgery as initial treatment, vulvectomy was performed for 2 patients and radical vulvectomy plus groin node dissection for 5 patients. Two patients had invasive disease and four were associated with underlying adenocarcinoma. Five patients experienced recurrence, on average, 16.2 months after the surgery. Four of them underwent radiotherapy or chemotherapy and the other received no further treatment. The mean follow-up time was 41.1 months. Three patients, with invasive lesion or underlying adenocarcinoma were dead of the disease. Conclusion: There is a delay in the diagnosis of vulvar Paget's disease. The major treatment is surgery. Recurrence is relatively common. Patients with invasive disease or underlying carcinoma have a poor prognosis.

THE INFECTION OF EBV FOR CERVICAL EPITHELIUM-A NEW CAUSITIVE AGENT IN THE DEVELOPMENT OF CERVICAL CARCINOMAS?

Epstein-Barr virus was considered as a caustive agent for Burrkitt' s lymphoma and non-malignant B lymphocytes proliferation. The recent studies revealed the striking association of the Infection of EBV with the development of human epithelial tumors. 43 specimens of normal exfoliated cervical epithelial cells, 47 biopsies of chronic cervlcitis and 80 tissue samples of cervical carcinomas were tested for the presences of EBV W fragments by using dot blot hybridization method. The results showed that the detectable rates of EBV DNA sequences In the normal exfoliated epithelium, the chronic cervlcitis and cervical carcinomas were 44.16%, 12.77% and 13.75%, respectively. Eleven EBV positive DNA samples from cervical cancers were also examined for the presence of HPV DNA. The result showed 9 out of 11 were HPV DNA positive, the cultanious infectious rate of both viruses was about 81.81%.In this paper, the EBV genomes existed In the part of biopsies of cervical carcinomas were first reported. The results Implied that the development of cervical cancer might be associated with asymptomatic EBV Infection In early stage and might be the result from the synergistic carcinogenesis of EBV with other cervical oncovinises, especially with HPV.

Comparative analysis of ATP-based tumor chemosensitivity assay-directed chemotherapy versus physician-decided chemotherapy in platinum-resistant recurrent ovarian cancer

Objective The aim of the study was to evaluate the role of ATP-based tumor chemosensitivity assay(ATP-TCA) in patients with platinum-resistant recurrent ovarian cancer(PRROC).Methods A total of 43 patients with PRROC who underwent chemotherapy based on the results of ATPTCA in the Cancer Hospital,Chinese Academy of Medical Sciences were included in the present study.As controls,we selected another 43 patients with PRROC who were treated at the physician's discretion within the same time period and had the same clinical characteristics as the patients in the ATP-TCA group.Logrank test and Cox proportional hazards model were adopted for analysis.Results A total of 86 patients were retrospectively analyzed in the present study.Patients were routinely monitored to evaluate the rate of progression-free survival(PFS).The median follow-up time was 13 months.The PFS for the ATP-TCA and control groups was 5 and 3 months,respectively(P = 0.027).Multivariate analysis showed that the type of treatment was an independent prognostic factor for PFS(P = 0.040;HR:0.623;95% CI:0.313–0.973).Subgroup analysis showed that among patients with a treatmentfree interval(TFI) of ≥ 3 months(n = 50),those in the ATP-TCA group had longer PFS than those in the control group(7 vs 4 months,P = 0.010).Meanwhile,the median PFS of patients who underwent ≤ 2 prior chemotherapy regimens(PCR,n = 52) in the ATP-TCA and control groups was 6 months and 4 months,respectively(P = 0.025).Conclusion ATP-TCA-directed chemotherapy might improve the PFS in PRROC.In particular,the survival benefit from ATP-TCA is higher in patients with a TFI of ≥ 3 months or treated with ≤ 2 PCR.

Down-Modulation of Notch1 Expression in Cervical Cancer Is Associated with HPV-Induced Carcinogenesis

OBJECTIVE Notch1 signaling has been implicated intumorigenesis. The purpose of this study was to investigate theputative role of the Notch1 receptor in carcinogenesis and in theprogression of the cervical cancer. Since human papillomavirus(HPV) is a causative agent in cervical carcinoma, the interactionbetween Notch1 and HPV infection was examined.METHODS Forty cervical cancer samples and 30 normalcervical tissue specimens were examined using Western blot andRT-PCR to detect Notch1 protein and mRNA levels. HPV16 DNAwas examined in all samples using PCR.RESULTS The level of Notch1 protein expression wassignificantly lower in cervical cancer tissue than in normal tissue.Levels of Notch1 mRNA were found to be substantially downregulatedin cancer tissue. Notch1 protein expression levelswere significantly higher in carcinomas without HPV DNAthan that in carcinomas with HPV infection (55.5% vs. 3.3%, P <0.05). Down-modulation of Notch1 mRNA levels in carcinomawas demonstrated to be associated with HPVE6 transcription.Moreover, levels of Notch1 expression were shown to besignificantly higher in early stage disease than in advanced stagedisease (P = 0.001).CONCLUSION Down-modulation of Notch1 expressionprobably plays an important role in the late stages of HPVinducedcervical cancer.

Primary Malignant Amelanotic Melanoma in the Female Genital Tract:A Report of Six Cases and a Review of the Literature

OBJECTIVE To analyze the clinical characteristics,pathologic diagnosis,treatment and prognosis of amelanotic melanoma in the female genital tract(AMFGT).METHODS The medical records of 6 patients with AMFGT between 1991 and 2006 in our hospital were reviewed.RESULTS Of these cases,4 were preliminarily misdiagnosed as chorioepithelioma,sarcoma,adenocarcinoma or lymphoma.Two patients were determined to have AMFGT preoperatively after positive immunohistochemical staining for both S-100 protein and HMB-45.Specimens removed from all 6 cases were tested for immunohistochemical staining,as well as H&E histochemical stains.S-100 and vimentin were both positive in all patients,and HMB-45 was positive in 3 out of 5 patients.Four patients recurred(at 6,6,12 and 19 months) a er primary treatments.Three patients died(at 13,18 and 19 months) a er the initial diagnosis.CONCLUSION Because of an absence of pigmentation AMFGT is extremely difficult to diagnose.Combined immunohistochemical staining,such as the S-100 protein,HMB-45 and vimentin etc,is important in the evaluation of AMFGT.Correct diagnosis plays a crucial role in the treatment of this disease.

Clinical Significance of Lymph Node Sampling in Endometrial Carcinoma

OBJECTIVE To study the clinical significance of pelvic and para-aortic lymph node sampling in endometrial carcinoma.METHODS Data were analyzed from 311 patients who received surgical treatment in our hospital during the period from January 1995 to December 2002.Among the patients,197 underwent lymph node sampling or lymph-adenectomy.The patients were divided into 2 groups based on the nature of their lymph node dissection,i.e.a)The sampling group included 114 patients with an extrafascial hysterectomy or modified radical hysterectomy plus pelvic or paraaortic lymph node sampling of the abdominal aorta;b)The dis-section group,included 83 patients with a radical or modified radical hyster-ectomy plus systemic pelvic lymph node clearance or paraaortic lymph node dissection of the abdominal aorta.RESULTS The median of the sampling sites for lymph node removal was 5 in the sampling group,and the median of the lymph nodes removed was 15 per case.Lymph node metastasis was found in 8 cases.In the dissection group,the median of the cases for lymph node removal was 8,and the me-dian of the lymph nodes removed was 27 per case.Lymph node metastasis was found in 6 cases.The 5-year survival rates were 90.2% and 90.9% in the 2 groups,respectively.CONCLUSION Lymph node sampling of endometrial cancer is a good way of precisely finding lymphatic metastases,and is suitable for surgical staging without causing immoderate surgical treatment and without affecting the survival rate.

Aberrant Expression of Notch1 in Cervical Cancer

OBJECTIVE To investigate the putative role of the Notch1 receptor in cervical cancer carcinogenesis and progression. METHODS The expression of the Notch1 protein was analyzed by a Western-blotting approach in 40 cervical cancer and 30 normal cervical tissues. Some tissues were examined using RT-PCR to determine mRNA levels. Celluar localization of the Notch1 protein in the paraffin-embedded cervical tissues was also analyzed by immunohistochemistry. RESULTS The Notch1 protein was detected in all 30 normal cervical tissues. In contrast, only 6 samples of 40 cervical cancer tissues showed Notch1 expression. The level of the Notch1 protein expression was significantly lower in cervical cancer tissues than that in normal tissue samples. In agreement with these observations, levels of Notch1 mRNA were found to be substantially down-regulated in cervical cancer tissues. In the immunohistochemistry staining assay, the Notch1 protein was shown to localize predominantly in the cytoplasm and nucleoli of the normal cervical squamous epithelium of the cervix, but no staining was observed in the cervical cancer cells. Notch1 expression was observed to correlate with the clinical disease stage, but there were no correlations with age, tumor size, grade or lymph node metastasis （P〉0.05）. The levels of Notch1 protein expression were significantly higher in early stages （Ⅰ-Ⅱa, 66.7%） compared to those in the advanced stages （Ⅱb～Ⅳ,12.6%）（P=0.001）. CONCLUSION Notch1 may play a role as a tumor suppressor in cervical tumorigenesis. Determination of Notch1 expression may be helpful for preoperative diagnosis and accuracy of staging. But its clinical use for cervical cancer requires further investigation.

Immune evasion and therapeutic opportunities based on natural killer cells

Natural killer(NK)cells can elicit an immune response against malignantly transformed cells without recognizing antigens,and they also exhibit cytotoxic effects and immune surveillance functions in tumor immunotherapy.Although several studies have shown the promising antitumor effects of NK cells in immunotherapy,their function is often limited in the tumor microenvironment because tumor cells can easily escape NK cell-induced death.Thus,for efficient tumor immunotherapy,the mechanism by which tumor cells escape NK cell-induced cytotoxicity must be fully understood.Various novel molecules and checkpoint receptors that mediate the disruption of NK cells in the tumor microenvironment have been discovered.In this review,we analyze and detail the major activating and inhibitory receptors on the surface of NK cells to delineate the mechanism by which tumor cells suppress NKG2D ligand expression and increase tumor receptor and inhibitory receptor expression[NKG2A,programmed cell death1(PD-1),and T-cell immunoglobulin and immunoreceptor tyrosine inhibitory motif(TIGIT)]on the NK cell surface,and thus inhibit NK cell activity.We also reviewed the current status of treatments based on these surface molecules.By comparing the therapeutic effects related to the treatment status and bypass mechanisms,we attempt to identify optimal single or combined treatments to suggest new treatment strategies for tumor immunotherapy.

Reversal of the immunosuppressive tumor microenvironment via platinum-based neoadjuvant chemotherapy in cervical cancer

Background Immunotherapy favors patients with tumors;however,only 3-26.3%of patients with cervical cancer benefit from single-agent immune checkpoint inhibitors.Combined immunotherapy and chemotherapy has been explored against tumor;however,the combination remains controversial.This study aimed to investigate the tumor immune microenvironment(TIME)and the effects of platinum-based neoadjuvant chemotherapy(NACT)in cervical cancer to identify the clinical value of combining chemotherapy with immunotherapy.Methods Multiplex immunohistochemistry(IHC)with 11 markers(cluster of differentiation[CD]3,CD8,CD4,CD11c,CD68,forkhead box P3[Foxp3],programmed cell death 1[PD-1],programmed cell death 1 ligand 1[PD-L1],indoleamine 2,3-dioxygenase[IDO],cyclin-dependent kinase inhibitor 2A[p16],and cytokeratin[CK])was performed to evaluate TIME from 108 matched pre-and post-NACT cervical cancer samples.The mechanism of antitumor immunity triggered by NACT was explored using RNA sequencing(RNA-seq)from four paired samples and subsequently verified in 41 samples using IHC.Results The infiltration rate of the CD8^(+)T cells in treatment-naive cervical cancer was 0.73%,and those of Foxp3^(+)regulatory T cells(Tregs)and IDO^(+)cells were 0.87%and 17.15%,respectively.Moreover,immunoreactive T cells,dendritic cells,and macrophages were more in the stromal than the intratumor region.NACT increased dendritic,CD3^(+)T,CD8^(+)T,and CD4^(+)T cells and decreased Tregs.The aforementioned alterations occurred predominantly in the stromal region and were primarily in responders.Non-responders primarily showed decreased Tregs and no increase in CD8^(+)T or dendritic cell infiltration.Furthermore,dendritic cells interacted more closely with CD3^(+)T cells after NACT,an effect primarily observed in responders.RNA-seq data revealed activation of the antigen receptor-mediated signaling pathway and upregulation of major histocompatibility complex(MHC)I and MHC II after chemotherapy,validated using IHC.Conclusions NACT can reduce Tregs,and when tumor cells are effectively killed,antigen presentation is enhanced,subsequently activating antitumor immunity finitely.Our study provides the molecular characteristics and theoretical basis for the simultaneous or sequential combination of platinum-based NACT and immunotherapy for cervical cancer.