Adjuvant chemotherapy versus adjuvant concurrent chemoradiotherapy after radical surgery for early-stage cervical cancer: a randomized, non-inferiority, multicenter trial / 医学前沿

We conducted a prospective study to assess the non-inferiority of adjuvant chemotherapy alone versus adjuvant concurrent chemoradiotherapy (CCRT) as an alternative strategy for patients with early-stage (FIGO 2009 stage IB-IIA) cervical cancer having risk factors after surgery. The condition was assessed in terms of prognosis, adverse effects, and quality of life. This randomized trial involved nine centers across China. Eligible patients were randomized to receive adjuvant chemotherapy or CCRT after surgery. The primary end-point was progression-free survival (PFS). From December 2012 to December 2014, 337 patients were subjected to randomization. Final analysis included 329 patients, including 165 in the adjuvant chemotherapy group and 164 in the adjuvant CCRT group. The median follow-up was 72.1 months. The three-year PFS rates were both 91.9%, and the five-year OS was 90.6% versus 90.0% in adjuvant chemotherapy and CCRT groups, respectively. No significant differences were observed in the PFS or OS between groups. The adjusted HR for PFS was 0.854 (95% confidence interval 0.415-1.757; P = 0.667) favoring adjuvant chemotherapy, excluding the predefined non-inferiority boundary of 1.9. The chemotherapy group showed a tendency toward good quality of life. In comparison with post-operative adjuvant CCRT, adjuvant chemotherapy treatment showed non-inferior efficacy in patients with early-stage cervical cancer having pathological risk factors. Adjuvant chemotherapy alone is a favorable alternative post-operative treatment.

Chemotherapy initiation with single-course methotrexate alone or combined with dactinomycin versus multi-course methotrexate for low-risk gestational trophoblastic neoplasia: a multi-centric randomized clinical trial / 医学前沿

We aimed to evaluate the effectiveness and safety of single-course initial regimens in patients with low-risk gestational trophoblastic neoplasia (GTN). In this trial (NCT01823315), 276 patients were analyzed. Patients were allocated to three initiated regimens: single-course methotrexate (MTX), single-course MTX + dactinomycin (ACTD), and multi-course MTX (control arm). The primary endpoint was the complete remission (CR) rate by initial drug(s). The primary CR rate was 64.4% with multi-course MTX in the control arm. For the single-course MTX arm, the CR rate was 35.8% by one course; it increased to 59.3% after subsequent multi-course MTX, with non-inferiority to the control (difference -5.1%,95% confidence interval (CI) -19.4% to 9.2%, P = 0.014). After further treatment with multi-course ACTD, the CR rate (93.3%) was similar to that of the control (95.2%, P = 0.577). For the single-course MTX + ACTD arm, the CR rate was 46.7% by one course, which increased to 89.1% after subsequent multi-course, with non-inferiority (difference 24.7%, 95% CI 12.8%-36.6%, P < 0.001) to the control. It was similar to the CR rate by MTX and further ACTD in the control arm (89.1% vs. 95.2%, P =0.135). Four patients experienced recurrence, with no death, during the 2-year follow-up. We demonstrated that chemotherapy initiation with single-course MTX may be an alternative regimen for patients with low-risk GTN.

Evaluation and simplification of risk factors in FIGO 2000 scoring system for gestational trophoblastic neoplasia: a 19-year retrospective analysis / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

OBJECTIVES@#The International Federation of Gynecology and Obstetrics (FIGO) 2000 scoring system classifies gestational trophoblastic neoplasia (GTN) patients into low- and high-risk groups, so that single- or multi-agent chemotherapy can be administered accordingly. However, a number of FIGO-defined low-risk patients still exhibit resistance to single-agent regimens, and the risk factors currently adopted in the FIGO scoring system possess inequable values for predicting single-agent chemoresistance. The purpose of this study is therefore to evaluate the efficacy of risk factors in predicting single-agent chemoresistance and explore the feasibility of simplifying the FIGO 2000 scoring system for GTN.@*METHODS@#The clinical data of 578 GTN patients who received chemotherapy between January 2000 and December 2018 were retrospectively reviewed. Univariate and multivariate logistic regression analyses were carried out to identify risk factors associated with single-agent chemoresistance in low-risk GTN patients. Then, simplified models were built and compared with the original FIGO 2000 scoring system.@*RESULTS@#Among the eight FIGO risk factors, the univariate and multivariate analyses identified that pretreatment serum human chorionic gonadotropin (hCG) level and interval from antecedent pregnancy were consistently independent predictors for both first-line and subsequent single-agent chemoresistance. The simplified model with two independent factors showed a better performance in predicting single-agent chemoresistance than the model with the other four non-independent factors. However, the addition of other co-factors did improve the efficiency. Overall, simplified models can achieve favorable performance, but the original FIGO 2000 prognostic system still features the highest discrimination.@*CONCLUSIONS@#Pretreatment serum hCG level and interval from antecedent pregnancy were independent predictors for both first-line and subsequent single-agent chemoresistance, and they had greater weight than other non-independent factors in predicting single-agent chemoresistance. The simplified model composed of certain selected factors is a promising alternative to the original FIGO 2000 prognostic system, and it shows comparable performance.

Single-cell transcriptomics reveals tissue architecture in ovarian carcinosarcoma / 부인종양

Objective@#Ovarian carcinosarcoma (OCS) is one of rarest and most challenging histologic subtype of ovarian cancer. It features remarkable cellular heterogeneity. Using single-cell RNA sequencing (scRNA-seq), we characterize the cellular composition of OCS and identify their molecular characteristics. @*Methods@#We applied scRNA-seq to resected primary OCS for the in-depth analysis of tumor cells and the tumor microenvironment. Immunohistochemistry staining was used for validation. @*Results@#Malignant epithelial and fibroblast cells displayed a high-degree of intratumoral heterogeneity. We revealed that certain epithelial cell subclusters had high levels of drug resistance scores and many active metabolic pathways. Furthermore, γδ T cells exhibited enriched interferon (IFN)-γ and IFN-α response characteristics. Analyzing ligand-receptor interaction pairs between cell types, we identified broadly interacting cells and observed an interaction between the ANXA1+ epithelial population and FPR1+/FPR3+ myeloid cells. @*Conclusion@#Our findings provide a single-cell transcriptomic signature of human OCS and present a well-established resource for elucidating OCS diversity.

The 16-year experience in treating low-risk gestational trophoblastic neoplasia patients with failed primary methotrexate chemotherapy / 부인종양

Objective@#To assess the outcomes and toxic effects of 5-day actinomycin D (Act-D) salvage therapy and to explore the predictors of Act-D resistance in patients with low-risk gestational trophoblastic neoplasia (GTN)who failed 5-day methotrexate (MTX) chemotherapy. @*Methods@#This retrospective study analyzed patients with low-risk GTN administered Act-D salvage therapy after failing MTX chemotherapy at Women's Hospital, School of Medicine Zhejiang University between January 2000 and December 2015. The clinical parameters of these patients were collected and analyzed. @*Results@#The final analysis included 89 cases. Of these, 73 cases (82.02%) responded to salvage Act-D. The remaining 16 resistant cases were switched to etoposide, MTX, Act-D/ cyclophosphamide, and vincristine chemotherapy and achieved complete remission. Serum human chorionic gonadotrophin levels before Act-D salvage therapy (hCG Act-D )in the Act-Dresistant cases were significantly higher than those in the Act-D responders (median 605 vs.103 IU/L, p=0.009). However, the range of hCGAct-D values in Act-D responders was wider than that in Act-D-resistant cases (5.76–16,664 IU/L vs. 11.43–6,732 IU/L). Thus, assigning a general cut-off value was difficult considering the individual setting. Except for 2 cases requiring other salvage regimens due to Act-D toxicity, 97.80% of cases (89/91) tolerated the toxicity. During at least 1-year follow-up, the survival rate was 100.00% and no case developed recurrence. @*Conclusion@#Based on the good therapeutic effect and tolerable toxicity, we recommend Act-D salvage therapy for all patients with low-risk GTN who fail primary MTX chemotherapy.The higher serum hCG levels before Act-D salvage therapy may be associated with resistance to this treatment.

SURF4 maintains stem-like properties via BIRC3 in ovarian cancer cells / 부인종양

Objective@#As cancer stem cells (CSCs) are considered as the origin of tumor development, recurrence, and drug resistance, we aimed to explore the mechanism related to modulating stemness in CSCs, thus facilitating to search for new therapeutic strategy for ovarian cancer. @*Methods@#In this study, ovarian cancer stem cells (OCSCs) induced from cell line 3AO and A2780 were enriched in serum-free medium (SFM). The effect of SURF4 on CSC-like properties was evaluated by sphere-forming assays, re-differentiation assays, quantitative real-time polymerase chain reaction, flow cytometry, Western blotting, cell viability assays and in vivo xenograft experiments. The downstream molecule participating in SURF4 maintaining stemness was screened by RNA-sequencing and identified by the experiments of gene function. @*Results@#SURF4 was upregulated expressed in OCSCs. Knockdown of SURF4 reduced the expression of the related stem markers (SOX2 and c-MYC), inhibited self-renewal ability, and improved the sensitivity to chemotherapeutic drugs (paclitaxel and cisplatin) in OCSCs.SURF4 knockdown also inhibited tumorigenesis in nonobese diabetic/severe combined immunodeficiency mice. BIRC3 expression was controlled by SURF4, and BIRC3 showed the similar effect as SURF4 did, and BIRC3 overexpression partially recovered stem-like properties abolished by SURF4 knockdown. @*Conclusion@#Our findings suggest that SURF4 possesses the ability to maintain stemness of OCSCs via BIRC3, and may serve as a potential target in stem cell-targeted therapy for ovarian cancer.

The 16-year experience in treating low-risk gestational trophoblastic neoplasia patients with failed primary methotrexate chemotherapy / 부인종양

Objective@#To assess the outcomes and toxic effects of 5-day actinomycin D (Act-D) salvage therapy and to explore the predictors of Act-D resistance in patients with low-risk gestational trophoblastic neoplasia (GTN)who failed 5-day methotrexate (MTX) chemotherapy. @*Methods@#This retrospective study analyzed patients with low-risk GTN administered Act-D salvage therapy after failing MTX chemotherapy at Women's Hospital, School of Medicine Zhejiang University between January 2000 and December 2015. The clinical parameters of these patients were collected and analyzed. @*Results@#The final analysis included 89 cases. Of these, 73 cases (82.02%) responded to salvage Act-D. The remaining 16 resistant cases were switched to etoposide, MTX, Act-D/ cyclophosphamide, and vincristine chemotherapy and achieved complete remission. Serum human chorionic gonadotrophin levels before Act-D salvage therapy (hCG Act-D )in the Act-Dresistant cases were significantly higher than those in the Act-D responders (median 605 vs.103 IU/L, p=0.009). However, the range of hCGAct-D values in Act-D responders was wider than that in Act-D-resistant cases (5.76–16,664 IU/L vs. 11.43–6,732 IU/L). Thus, assigning a general cut-off value was difficult considering the individual setting. Except for 2 cases requiring other salvage regimens due to Act-D toxicity, 97.80% of cases (89/91) tolerated the toxicity. During at least 1-year follow-up, the survival rate was 100.00% and no case developed recurrence. @*Conclusion@#Based on the good therapeutic effect and tolerable toxicity, we recommend Act-D salvage therapy for all patients with low-risk GTN who fail primary MTX chemotherapy.The higher serum hCG levels before Act-D salvage therapy may be associated with resistance to this treatment.

SURF4 maintains stem-like properties via BIRC3 in ovarian cancer cells / 부인종양

Objective@#As cancer stem cells (CSCs) are considered as the origin of tumor development, recurrence, and drug resistance, we aimed to explore the mechanism related to modulating stemness in CSCs, thus facilitating to search for new therapeutic strategy for ovarian cancer. @*Methods@#In this study, ovarian cancer stem cells (OCSCs) induced from cell line 3AO and A2780 were enriched in serum-free medium (SFM). The effect of SURF4 on CSC-like properties was evaluated by sphere-forming assays, re-differentiation assays, quantitative real-time polymerase chain reaction, flow cytometry, Western blotting, cell viability assays and in vivo xenograft experiments. The downstream molecule participating in SURF4 maintaining stemness was screened by RNA-sequencing and identified by the experiments of gene function. @*Results@#SURF4 was upregulated expressed in OCSCs. Knockdown of SURF4 reduced the expression of the related stem markers (SOX2 and c-MYC), inhibited self-renewal ability, and improved the sensitivity to chemotherapeutic drugs (paclitaxel and cisplatin) in OCSCs.SURF4 knockdown also inhibited tumorigenesis in nonobese diabetic/severe combined immunodeficiency mice. BIRC3 expression was controlled by SURF4, and BIRC3 showed the similar effect as SURF4 did, and BIRC3 overexpression partially recovered stem-like properties abolished by SURF4 knockdown. @*Conclusion@#Our findings suggest that SURF4 possesses the ability to maintain stemness of OCSCs via BIRC3, and may serve as a potential target in stem cell-targeted therapy for ovarian cancer.

Expression and significance of LMP2 and PPM1A in gestational trophoblastic disease / 中华妇产科杂志

Objective To investigate the expression of low molecular mass polypeptide-2 (LMP2)and protein phosphatase 1A (PPM1A) in gestational trophoblastic disease and elucidate their predictive value in malignant transformation of hydatidiform mole. Methods The expressions of LMP2 and PPM1A protein in 196 complete hydatidiform moles (in which 28 cases with malignant transformation) , 7 invasive moles, 5 choriocarcinomas and 20 normal chorionic villus were detected with the method of En Vision immunohistochemistry. Their clinicopathologic data were retrospectively analyzed. Results LMP2 and PPM1A protein expressed in cytotrophocytes, syncytiotrophoblast and extravillous trophoblast. The level of LMP2 expression in deteriorative hydatidiform mole was significantly higher than that in non-deteriorative hydatidiform mole or normal chorionic villus (6. 79 ±2. 38, 5.26 ±2.63 and 3. 10 ±1.65, all P 0. 05). Conclusions High expression of LMP2 and low expression of PPM1A might play an important role in the motility and invasiveness of trophohlast cells and malignant transformation of hydatidiform mole. Testing the expression of LMP2 and PPM1A in hydatidiform mole tissues of initial uterine evacuation might be have some reference significance in judging outcomes of hydatidiform mole.

Identification of miR-23a as a novel microRNA normalizer for relative quantification in human uterine cervical tissues

Quantitative real-time RT-PCR (RT-qPCR) is being widely used in microRNA expression research. However, few reports detailed a robust identification and validation strategy for suitable reference genes for normalisation in microRNA RT-qPCR studies. The aim of this study was to identify the most stable reference gene(s) for quantification of microRNA expression analysis in uterine cervical tissues. A microarray was performed on 6 pairs of uterine cervical tissues to identify the candidate reference genes. The stability of candidate reference genes was assessed by RT-qPCR in 23 pairs of uterine cervical tissues. The identified most stable reference genes were further validated in other cohort of 108 clinical uterine cervical samples: (HR-HPV- normal, n = 21; HR-HPV+ normal, n = 19; cervical intraepithelial neoplasia [CIN], n = 47; cancer, n = 21), and the effects of normalizers on the relative quantity of target miR-424 were assessed. In the array experiment, miR-26a, miR-23a, miR-200c, let-7a, and miR-1979 were identified as candidate reference genes for subsequent validation. MiR-23a was identified as the most reliable reference gene followed by miR-191. The use of miR-23a and miR-191 to normalize expression data enabled detection of a significant deregulation of miR-424 between normal, CIN and cancer tissue. Our results suggested that miR-23a and miR-191 are the optimal reference microRNAs that can be used for normalization in profiling studies of cervical tissues; miR-23a is a novel microRNA normalizer.

Function study of acid-sensing ion channels in non-neuronal tissues / 中国药理学通报

Acid-sensing ion channels(ASICs) are a novel class of ligand-gated cation channels activated by extracellular acidification and belong to the epithelial sodium channels(DEG/ENaC) superfamily.Their biological functions have recently been found not only in the central nervous system but also relevant to the physiology and pathology of non-neuronal tissues such as taste buds, cardiovascular system and bones.This review concerns the latest research on the expression and functions of ASICs in non-neuronal tissues so as to promote the understanding of their physiological and pathological functions.

Advances in treatment of echinococcosis / 中国血吸虫病防治杂志

Echinococcosis is a zoonotic parasitic disease caused by infection of Echinococcus granulosus and Echinococcus multilocularis in the human body,which may endanger the health and life of patients.Surgical treatment is presently the main method for the treatment of echinococcosis,with drug therapy as a subsidiary measure.The paper summarizes the advances in the treatment of echinococcosis.

Value of serum CA125 detection for predicting recurrence and prognosis in ovarian epithelial cancer / 中华妇产科杂志

Objective To analyze the association of serum CA125 level at the different phases with recurrence and survival, for providing simple and efficient methods about predicting recurrence and prognosis in epithelial ovarian cancer.Methods The clinical-pathological data from 151 patients were collected, who were histologically confirmed as primary ovarian cancer between Jan 2002 and Dec 2005.All the patients were followed up.The relationship between serum CA125 level at different phases and clinical-pathological data were analyzed, including prognostic associated factors, 2-year or 5-year recurrent rate, 5-year survival rate, progression-free survival times, and overall survival times.Results Serum CA125 level at pre-surgery and the end of 3-course chemotherapy were associated with most of the clinical-pathological parameters,included stage, pathological grade, amount of ascites, residual tumor size, type of recurrence, 2-year and 5-year recurrent rate, and 5-year survival rate ( all P ＜ 0.05 ).Progression-free survival and overall survival times were shorter in the patients with higher CA125 level at pre-surgery or abnormal CA125 level at the end of 3-course chemotherapy (P ＜0.01 ).There was no relationship between the ratio of CA125 level at pre- and post-surgery and recurrence or prognosis ( all P ＞ 0.05).Conclusion Serum CA125 level at pre-surgery and the end of 3-course chemotherapy can be used for predicting the recurrence and prognosis of epithelial ovarian cancer.

Study on high risk factors associated with positive margin of cervix conization in patient with cervical intraepithelial neoplasia / 中华妇产科杂志

Objective To assess the high risk factors associated with the positive margin of conization in patients with cervical intraepithelial neoplasia (CIN). Methods From January 2000 to February 2008, 1699 consecutive patients with CIN undergoing conization was reviewed retrospectively in order to analyze the relationship between the positive margin of conization with clinical prognostic factors,such as patients age, disease grade, size of lesion, the procedure of excision and menopause. X<'2> tests was used to compare the different frequencies of factors in groups of positive and negative margin conization, then seven factors with positive margin were processed into unconditional logistic regression analysis. Results The rate of the positive margin in 1699 patients was 14.01% (238/1699). The mean age of patients with positive margins was (39±9 ) years old, while patients with negative margins was ( 39±8 ) years old, which didn't reach statistical difference(P>0.05). The rate of the positive margin was 8.63% in cold knife cone (CKC) and 18.66% in loop electrosurgical excision procedure (LEEP), which showed significant difference( P<0.01 ). Among 1699 patients, 90 patients were with CIN Ⅰ ,339 patients were with CIN Ⅱ ,1113 patients were with CIN Ⅲ [ including 972 with severe dysplasia and 141 with cancer in situ(CIS) ],87 patients were with cervical cancer stage Ⅰ al, 70 patients were with stage Ⅰ a2 or advanced stages. The rate of positive margin was 1.11% ( 1/90), 3.83% ( 13/339), 10.70% (104/972), 26.24% (37/141),35. 63% (31/87) and 74.29% (52/70),respectively. There was statistic difference among them, except CIN Ⅰ and CIN Ⅱ . When combined CIN Ⅰ with CIN Ⅱ , then compared with CIN Ⅲ, cervical cancer withⅠ al and Ⅰ a2, it also showed statistical difference (P<0.05 ) . The rate of positive margin in postmenopausal women was 21.54% (28/130), which was significantly higher than 13.38% (210/1569)in premenopausal women (P=0.010 ). The logistic regression analysis showed that the procedure of excision, grade of disease, size of lesion, surface of cervix, and menopause were high risk factors associated with the positive margin, the risk ratio were 5.147, 3.048, 1.271, 1.905 and 1.860, respectively.Conclusions High grade, the extent of CIN disease, LEEP and postmenopausal age are high-risk factors associated with positive margin in patients treated by conization. It should be warranted in those patients when designing conization treatment.

Case report and literature review of epithelioid trophoblastic tumor / 中华妇产科杂志

Objective To evaluate the clinical characteristics of epithelioid trophoblastic tumor (ETT).Methods Six cases of ETT treated in Women's Hospital,School of Medicine,Zhejiang University from 2005 to 2007 were retrospectively analyzed,together with a literature review.Results Six cases of ETT were diagnosed pathologically after surgery.The age of patients ranged from 27 to 46 years.The most common presentation was abnormal vaginal bleeding(5/6).The preceding gestational events were hydatidiform mole in 1 case,abortion in 2 cases,and term delivery in 3 cases.The interval between the preceding gestation and the diagnosis of ETT ranged from 15-48 months.The serum human chorionic gonadotropin(hCG)level was 46-121 147 IU/L.Four cases presented with metastasis,including lung metastasis in all of the 4 cases,liver metastasis in 1 case,and pancreas metastasis in another 1 case.The main therapies were surgery combined with chemotherapy.All of the 6 cases received total abdominal hysterectomy.and 1 case also had lung lobectomy.One ease had a recurrence but refused any treatment again,and was lost to follow up;the therapy of 1 case unfinished;another 4 cases were without evidence of disease 9 to 19 months after surgery.Condusions The confirmation of ETF diagnosis is difficult before surgery.Surgical management is mostly recommended in ETT. The role of chemotherapy in ETT is not clear yet.

Analysis of the relationship between clinicopathological features and pelvic lymph node metastasis in patients with early stage squamous cell carcinoma of the uterine cervix / 中华妇产科杂志

Objective To evaluate clinical and pathologic factors associated with pelvic lymph node metastasis in patients with early-stage squamous cell carcinoma of the uterine cervir.Methods From February 2004 to January 2007,135 patients with stage Ⅰ b-Ⅱ a cervical squamous cell carcinoma in Women's Hospital,School of Medicine,Zhejiang University,were retrospectively studied.The relationship between pelvic lymph node metastasis and age,clinical stage,tumor size,grade of differentiation,depth of muscular invasion,lymphatic vascular space invasion,pretreatment level of serum squamous cell carcinoma antigen,pretreatment plasma level of fibrinogen,pretreatment leveh of hemoglobin and platelet were evaluated by univariate and multivariate analyses.Results Totally 3996 lymph nodes were dissected in 135 patients,with an average of 29.6 lymph nodes in each patient.12.6%of the patients(17/135)had metastasized pelvic lymph nodes.Univariate analysis indicated that tumor size(P=0.003),depth of muscular invasion(P=0.004),vasular space invasion(P<0.01),pretreatment levels of platelet(P=0.006)and fibrinogen(P<0.01)were significantly related to pelvic lymph node metastasis.Multivariate logistic regression analysis showed that lymphatic vascular space invasion(OR:3.674,95%CI:1.825-7.393,P<0.01)and pretreatment plasma level of fibrinogen(OR:4.568,95%CI:1.779-11.725,P=0.002)were significantly related to pelvic lymph node metastasis in patients with early-stage squamous cell carcinoma of the uterine cervix.Conclusion In early-stage cervical squamous cell carcinoma,lymphatic vascular space invasion and higher pretreatment plasma levels of fibrinogen are risk factors of pelvic lymph node metastasis.