Search

To investigate whether peritoneal disease extent can predict the survival benefit of intraperitoneal/intravenous (IP/IV) chemotherapy in ovarian cancer.A treatment-free survival (TFS) analysis.Five-centre trial.An extended follow-up of the Additional Intraperitoneal Cisplatin and Etoposide in ovarian cancer (AICE) trial (NCT01669226), with data cut-off on 27 August 2020. Patients were categorised into subgroups with high tumour burden (HTB) and low tumour burden (LTB).Overall survival (OS) was divided into time on protocol treatment exposure (T), time free of subsequent treatment or death (TFS) and time after the first subsequent therapy (REL). TFS analyses and quality-adjusted OS were calculated by multiplying the mean time in each health state by its assigned utility: quality-adjusted OS = uThe area under each Kaplan-Meier curve was estimated using the 96-month restricted mean time, with threshold utility analyses used to illustrate quality-adjusted OS comparisons.In the HTB subgroup, the restricted mean TFS was 33.9 months and 18.7 months in the IP/IV and IV groups, respectively (p = 0.005), with a significant quality-adjusted OS gain (13.2-16.0 months). In the LTB subgroup, IP/IV therapy yielded no survival benefit in either TFS (p = 0.268) or quality-adjusted OS (range: 1.4-6.3 months).Both TFS and quality-adjusted OS was longer across all utility weight values with IP/IV than with standard IV therapy in the HTB subgroup, whereas patients in the LTB subgroup did not benefit from the therapy. The tumour burden of ovarian cancer should be assessed before deciding on IP/IV versus IV treatment.

The expression level of GSK3β/β-catenin in SiHa and MS751 cells with PIK3CA-WT and E545K after 4Gy of IR exposure pretreated with AKT inhibitor for 24h.

The incidence of cervical cancer (CC) ranks the fourth in female malignant tumors globally. Chemoresistance is one of the main causes of treatment failure in advanced recurrent CC. Prolyl isomerase 1 (PIN1) is overexpressed in a variety of tumors, and is closely associated with the malignant potential of tumor cells, such as transformation, proliferation, invasion and metastasis. In the present study, we demonstrate that cell death induced by suppression of PIN1 could be inhibited by ferrostatin-1 (Fer-1) and ferroptosis biomarkers including lactate dehydrogenase (LDH) release, lipid peroxidation and malondialdehyde (MDA) are upregulated by downregulating PIN1. We then discover that abrogation of PIN1 greatly decreases the level of glutathione peroxidase 4 (GPX4) and the level of PIN1 is positively correlated with the level of GPX4. Furthermore, the knockdown of PIN1 promotes ferroptosis induced by RSL3. The mechanism involves PIN1 silencing which downregulates GPX4 by decreasing the level of nuclear factor E2-related factor 2 (NRF2). Furthermore, overexpression of NRF2 inhibits RSL3-mediated ferroptosis of CC cells when PIN1 is silenced. In addition, our results indicate that cisplatin (DDP) induces ferroptosis, which is restrained by overexpression of PIN1. The PIN1 inhibitor, KPT-6566, promotes the cytotoxic effect of DDP. The present study reveals that PIN1 affects ferroptosis and sensitivity to DDP in CC cells via the NRF2/GPX4 axis, thereby identifying PIN1 as a potential therapeutic target for CC.

Shuang Ye,1,2,* Shuling Zhou,2,3,* Wei Chen,1,2,4,* Libing Xiang,1,2 Xiaohua Wu,1,2 Huijuan Yang1,2 1Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China; 2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China; 3Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China; 4Department of Obstetrics and Gynecology, Minhang Hospital, Fudan University, The Central Hospital of Minhang District, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Huijuan YangDepartment of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, People’s Republic of ChinaTel +86-21-65260535Fax +86-21-64174774Email huijuanyang@hotmail.comBackground: To evaluate the recurrence patterns and survival outcomes of surgically treated relapsed ovarian clear cell carcinoma (OCCC) patients.Methods: We performed a comprehensive retrospective analysis of all the patients who underwent secondary debulking from 2004/10 to 2019/04.Results: In total, 45 eligible patients were included. 75.6% of the patients had early-stage disease and platinum-sensitive recurrence accounted for 70.5%. The median progression-free survival after primary surgery (PFS 1) was 20 months (range, 2– 137). Of all, 64.4% patients had solitary recurrence and 86.7% patients had no residual disease after secondary surgery. Regarding tumor distribution, the most common site was pelvis (47.5%), followed by lymph node metastases (18.0%) and abdominal wall lesions (8.2%). For the entire population, the median disease-free survival after recurrence (PFS 2) and post-relapse survival (PRS) was 15 months (range, 0– 96), and 24 months (range, 3– 159), respectively. Eight patients (17.8%) had a prolonged PFS2 more than 30 months. Patients with localized relapse had better survival including PFS 2 (P=0.023), PRS (P=0.004), and overall survival (OS) (P=0.029). Patients who achieved complete resection tended to have longer PFS 2 (P=0.017). After multivariate analysis, complete resection at recurrence remained as an independent positive predictor for PFS 2 (P=0.022). The median OS was 50 months and was significantly associated with platinum response (P=0.003) and number of relapsed lesions (P=0.002).Conclusion: A high rate of pelvic recurrence was noted in this population. Patients with focal recurrence had a favorable prognosis. Complete resection at secondary debulking proved to be an independent predictor for disease-free survival.Keywords: ovarian neoplasms, clear cell carcinoma, recurrence, survival

This study aims to explore whether E545K, the most common hotspot mutation of PIK3CA in cervical cancer, confers radioresistance to cervical cancer cells, to demonstrate the underling mechanism, and to develop the effective targets. SiHa and MS751 cells with PIK3CA-WT and PIK3CA-E545K were established by lentiviral transfection. The radiosensitivity was assessed by colony formation, cell cycle, cell apoptosis, DNA damage, and repair assay. The growth and immunohistochemical assay of xenograft tumor–related toxicity were evaluated in vivo. It was indicated that more cells with PIK3CA-E545K arrested in S phase. Irradiation (IR) led to more survival percentage, less apoptosis, fewer pH2A.X foci, and higher expression of Chk1/2 in SiHa and MS751 cells bearing PIK3CA-E545K. Mechanically, AKT/GSK3β/β-catenin pathway was highly activated, and more β-catenin was found accumulated in nucleus in cells with PIK3CA-E545K after IR. Furthermore, targeting β-catenin by shRNA or XAV939 enhanced IR sensitivity in cells with PIK3CA-WT and PIK3CA-E545K, whereas it was more notably in the latter. β-Catenin shRNA and XAV939 increased IR-mediated inhibition of colony formation with highly activated p53/bcl2/bax pathway. XAV939 enhanced IR-caused apoptosis, DNA damage, overcame S-phase arrest, DNA repair and reversed β-catenin nuclear accumulation in MS751 cells with PIK3CA-E545K. In vivo, XAV939 enhanced the radiosensitivity of cervical cancer xenografts with PIK3CA-E545K with invisible viscera toxicity. The findings demonstrate that cervical cancer cells with PIK3CA-E545K are resistant to IR by enhancing the expression and nuclear accumulation of β-catenin. Targeting β-catenin reverses the radioresistance, which suggests possible areas for preclinical research on β-catenin inhibition for strengthening the radiosensitivity of cervical cancer.

Background In China, secondary cytoreductive surgery (SCR) has been widely used in ovarian cancer (OC) over the past two decades. Although Gynecologic Oncology Group-0213 trial did not show its overall survival benefit in first relapsed patients, the questions on patient selection and effect of subsequent targeting therapy are still open. The preliminary data from our pre-SOC1 phase II study showed that selected patients with second relapse who never received SCR at recurrence may still benefit from surgery. Moreover, poly(ADP-ribose) polymerase inhibitors (PARPi) maintenance now has been a standard care for platinum sensitive relapsed OC. To our knowledge, no published or ongoing trial is trying to answer the question if patient can benefit from a potentially complete resection combined with PARPi maintenance in OC patients with secondary recurrence. Methods SOC-3 is a multi-center, open, randomized, controlled, phase II trial of SCR followed by chemotherapy and niraparib maintenance vs chemotherapy and niraparib maintenance in patients with platinum-sensitive second relapsed OC who never received SCR at recurrence. To guarantee surgical quality, if the sites had no experience of participating in any OC-related surgical trials, the number of recurrent lesions evaluated by central-reviewed positron emission tomography–computed tomography image shouldn't be more than 3. Eligible patients are randomly assigned in a 1:1 ratio to receive either SCR followed by 6 cycles of platinum-based chemotherapy and niraparib maintenance or 6 cycles of platinum-based chemotherapy and niraparib maintenance alone. Patients who undergo at least 4 cycles of chemotherapy and must be, in the opinion of the investigator, without disease progression, will be assigned niraparib maintenance. Major inclusion criteria are secondary relapsed OC with a platinum-free interval of no less than 6 months and a possibly complete resection. Major exclusion criteria are borderline tumors and non-epithelial ovarian malignancies, received debulking surgery at recurrence and impossible to complete resection. The sample size is 96 patients. Primary endpoint is 12-month non-progression rate. Trial Registration ClinicalTrials.gov Identifier: NCT03983226

Background To investigate changes in peripheral lymphocyte subsets after splenectomy during cytoreductive surgery for advanced or recurrent ovarian cancers. Methods We enrolled 83 patients with advanced or recurrent ovarian cancer who underwent cytoreductive surgery. Twenty patients who also underwent splenectomy were assigned to the splenectomy cohort and the rest were assigned to the non-splenectomy cohort. Flow cytometry was used to measure peripheral lymphocyte subsets consisting of T cells, regulatory T cells, natural killer cells, B cells, and activation antigens before and after surgery. Results There was no difference in the number and distribution of peripheral lymphocyte subsets between the two cohorts before surgery. After surgery, we observed elevated levels of T cells (CD3+, CD3+CD8+) in the splenectomy cohort compared to those in the non-splenectomy cohort, and the difference was statistically significant. CD8+CD28+ T cells had a significant decreasing tendency (P = 0.011) while CD3+/HLA-DR+ T cells showed the opposite trend (P = 0.001) in the splenectomy cohort. The proportion of Tregs (P = 0.005) and B cells (P −/HLA-DR+ B cells (P = 0.007) increased after surgery, and the absolute number of T cells and NK cells decreased to different extents (P +CD28+ T cells was less than the pre-operative percentage (P = 0.022), which was similar to the splenectomy cohort. There was no significant difference in progression-free survival or overall survival between the groups after a median follow-up time of 41 months. Conclusions The changes in peripheral lymphocyte populations were different between patients with and those without splenectomy during cytoreductive surgery for ovarian cancers. T cells were increased and activated in the splenectomy cohort, whereas, B cells were increased and activated in the non-splenectomy cohort.

Regulatory T cells (Tregs) are crucial for the maintenance of peripheral tolerance, but they also limit beneficial responses through cancer-induced immunoediting. The roles of Treg subsets in cervical squamous cell carcinoma (CSCC) are currently unknown. Here, we aimed to perform an extensive study with an increased resolution of the Treg compartment in the peripheral blood and tumor tissues of CSCC patients. We first identified that an HLADRhi Treg population in the peripheral blood was significantly increased in CSCC patients compared to precancer patients and healthy donors. We found that HLADRhi Tregs express high levels of a panel of inhibition and activation markers and the TCR-responsive transcription factors BATF and IRF4. However, this Treg subset showed reduced calcium influx after TCR crosslinking. In addition, HLADRhi Tregs are highly proliferative and vulnerable to apoptosis. Further studies demonstrated that the HLADRhi Tregs display high levels of suppressive activity. Quantitative multiplexed immunohistochemistry revealed that an increase in the number of tumor-infiltrating HLADRhi Tregs is associated with unfavorable classical risk parameters of advanced disease stage and stromal invasion. Context-based quantification revealed that a high frequency of stromal HLADRhi Tregs in patients is significantly associated with worse progression-free survival. In the current study, we characterized a population of highly activated and immunosuppressive HLADRhi Tregs in CSCC patients. An increased HLADRhi Treg frequency may be a potential biomarker to stratify CSCC patients and evaluate therapeutic efficacies in personalized immuno-oncology studies.

BACKGROUND Verrucous carcinoma (VC) of the vulva is a variation of squamous carcinoma (SCC). Etiology and treatment of VC are still unclear. CASE REPORT A 50-year-old female visited our clinic with a giant vulvar tumor (8 cm of diameter maximum). Biopsy revealed a suspicious well differentiation squamous cancer. PET/CT (positron emission tomography/computed tomography) scan found suspicious lymph node in bilateral iliac vessel region and bilateral inguinal region. She underwent radical vulvectomy and bilateral inguinal lymph node dissection, and bilateral pelvic lymph node dissection. Pathology turns out to be VC and no lymph nodes involvement. Due to the large defection, vulvar reconstruction was performed 5 weeks later using skin grafts and pudendal thigh flap. This patient was disease free after 12 months follow-up. CONCLUSIONS In patients with VC, a satisfactory biopsy is important and systemic inguinal lymphadenectomy might be omitted. For patients with large defection, flap-based reconstruction is recommended.

Objective Small cell neuroendocrine carcinoma of the cervix (SCNEC) is a lethal malignancy and little treatment progress has been made for decades. We sought to map its genetic profiles, and identify whether SCNEC harbor mutations and potential targets for therapeutic interventions. Methods Primary tumor tissue and blood samples were obtained from 51 patients with SCNEC. The next-generation sequencing was carried out to detect mutations of 520 cancer-related genes, including the entire exon regions of 312 genes and the hotspot mutation regions of 208 genes. Quantitative multiplex PCR was performed for the detection of seven high-risk HPV types. Results Of the 51 detected patients, 92.16% were positive for HPV 18. Ninety-eight percent of cases harbored genetic alterations. Two cases were observed with hypermutated phenotype and determined as MSI-H/dMMR. Genetic mutations were clustering in RTK/RAS(42.86%), PI3K-AKT(38.78%), p53 pathway(22.45%) and MYC family(20.41%). Mutations in genes involved in the p53 pathway indicate a poorer prognosis (3-year OS, 33.5% vs 59.9%, p = 0.031). A total of seven patients harboring mutations in homogeneous recombination repair (HRR) genes were reported. In addition, IRS2 and SOX2 were amplified in 14.9% and 6.12% of SCNEC patients, respectively. Conclusions SCNEC is specifically associated with HPV 18 infection. Its genetic alterations are characterized by a combined feature of high-risk HPV driven events and mutations observed in common neuroendocrine carcinoma. We identified several targetable mutated genes, including KRAS, PIK3CA, IRS2, SOX2, and HRR genes, indicating the potential efficacy of target therapies in these patients. MSI-H/dMMR individuals may benefit from checkpoint blockade therapies.

Background: To investigate the change of peripheral lymphocyte subsets after splenectomy during cytoreductive surgery for advanced or recurrent ovarian cancersMethods: We enrolled 83 patients with advanced or recurrent ovarian cancer who underwent cytoreductive surgery between 09/2016 and 01/2019. Twenty patients who also underwent splenectomy were assigned to the splenectomy cohort and the rest to the non-splenectomy cohort. Flow cytometry was used to measure the peripheral lymphocyte subsets consisting of T cells, regulatory T cells, natural killer cells, B cells, and activation antigens before and after surgery.Results: There was not any difference in the number and distribution of peripheral lymphocyte subsets between the two cohorts before surgery. We observed elevated levels of T cells (CD3+, CD3+CD8+) in the splenectomy cohort compared to those in the non-splenectomy cohort after surgery, which achieved statistical significance. The post-operative CD4/CD8 ratio was lower in the splenectomy cohort than in the non-splenectomy cohort (P = 0.048). Regarding the changes of lymphocyte subsets after surgery, CD8+CD28+ T cells had a significant decreasing tendency (P = 0.011) while CD3+/HLA-DR+ T cells were the opposite (P = 0.001) in the splenectomy cohort. In the non-splenectomy cohort, the proportion of Tregs (P = 0.005) and B cells (P −/HLA-DR+ B cells (P = 0.007) increased after surgery, and the absolute number of T cells and NK cells decreased to different extents (P +CD28+ T cells was less than the pre-operative one (P = 0.022), which was similar to the splenectomy cohort.Conclusions: The changes of peripheral lymphocyte populations were different between patients with splenectomy and without splenectomy during cytoreductive surgery for advanced or recurrent ovarian cancers. T cells were increased and activated in splenectomy cohort, whereas, B cells were increased and activated in non-splenectomy.

Background Two randomized phase III trials (EORTC55971 and CHORUS) showed similar progression-free and overall survival in primary or interval debulking surgery in ovarian cancer, however both studies had limitations with lower rate of complete resection and lack of surgical qualifications for participating centers. There is no consensus on whether neoadjuvant chemotherapy followed by interval debulking surgery (NACT-IDS) could be a preferred approach in the management of advanced epithelial ovarian cancer (EOC) in the clinical practice. Methods The Asian SUNNY study is an open-label, multicenter, randomized controlled, phase III trial to compare the effect of primary debulking surgery (PDS) to NACT-IDS in stages IIIC and IV EOC, fallopian tube cancer (FTC) or primary peritoneal carcinoma (PPC). The hypothesis is that PDS enhances the survivorship when compared with NACT-IDS in advanced ovarian cancer. The primary objective is to clarify the role of PDS and NACT-IDS in the treatment of advanced ovarian cancer. Surgical quality assures include at least 50% of no gross residual (NGR) in PDS group in all centers and participating centers should be national cancer centers or designed ovarian cancer section or those with the experience participating surgical trials of ovarian cancer. Any participating center should be monitored evaluating the proportions of NGR by a training set. The aim of the surgery in both arms is maximal cytoreduction. Tumor burden of the disease is evaluated by diagnostic laparoscopy or positron emission tomography/computed tomography scan. Patients assigned to PDS group will undergo upfront maximal cytoreductive surgery within 3 weeks after biopsy, followed by 6 cycles of standard adjuvant chemotherapy. Patients assigned to NACT group will undergo 3 cycles of NACT-IDS, and subsequently 3 cycles of adjuvant chemotherapy. The maximal time interval between IDS and the initiation of adjuvant chemotherapy is 8 weeks. Major inclusion criteria are pathologic confirmed stage IIIC and IV EOC, FTC or PPC; ECOG performance status of 0 to 2; ASA score of 1 to 2. Major exclusion criteria are non-epithelial tumors as well as borderline tumors; low-grade carcinoma; mucinous ovarian cancer. The sample size is 456 subjects. Primary endpoint is overall survival. Trial Registration ClinicalTrials.gov Identifier: NCT02859038

Background In China, secondary cytoreductive surgery (SCR) has been widely used in ovarian cancer (OC) over the past two decades. Although Gynecologic Oncology Group-0213 trial did not show its overall survival benefit in first relapsed patients, the questions on patient selection and effect of subsequent targeting therapy are still open. The preliminary data from our pre-SOC1 phase II study showed that selected patients with second relapse who never received SCR at recurrence may still benefit from surgery. Moreover, poly(ADP-ribose) polymerase inhibitors (PARPi) maintenance now has been a standard care for platinum sensitive relapsed OC. To our knowledge, no published or ongoing trial is trying to answer the question if patient can benefit from a potentially complete resection combined with PARPi maintenance in OC patients with secondary recurrence. Methods SOC-3 is a multi-center, open, randomized, controlled, phase II trial of SCR followed by chemotherapy and niraparib maintenance vs chemotherapy and niraparib maintenance in patients with platinum-sensitive second relapsed OC who never received SCR at recurrence. To guarantee surgical quality, if the sites had no experience of participating in any OC-related surgical trials, the number of recurrent lesions evaluated by central-reviewed positron emission tomography-computed tomography image shouldn't be more than 3. Eligible patients are randomly assigned in a 1:1 ratio to receive either SCR followed by 6 cycles of platinum-based chemotherapy and niraparib maintenance or 6 cycles of platinum-based chemotherapy and niraparib maintenance alone. Patients who undergo at least 4 cycles of chemotherapy and must be, in the opinion of the investigator, without disease progression, will be assigned niraparib maintenance. Major inclusion criteria are secondary relapsed OC with a platinum-free interval of no less than 6 months and a possibly complete resection. Major exclusion criteria are borderline tumors and non-epithelial ovarian malignancies, received debulking surgery at recurrence and impossible to complete resection. The sample size is 96 patients. Primary endpoint is 12-month non-progression rate. Trial registration ClinicalTrials.gov Identifier: NCT03983226.

Background Alterations in peripheral blood lymphocytes in cervical cancer have been reported, although conflicting views exist. The present study investigated the distributions of lymphocyte subsets in tumor tissue and peripheral blood samples from cervical cancer patients and precancerous lesion patients, and evaluated the correlations of lymphocyte subsets with clinicopathological and prognostic variables. Methods A total of 44 patients with stage IB1-IIA2 cervical cancer and 13 precancerous lesion patients were included. Lymphocytes were collected from the tumor tissue and the peripheral blood, and isolated by Lymphoprep density gradient centrifugation. The percentages of lymphocyte subsets were quantified by flow cytometry analysis, and the differences between lymphocyte subsets in the tumor tissue and peripheral blood were compared by SPSS. In addition, the relationships between lymphocyte subsets and clinicopathological and prognostic variables were analyzed. Results Our results revealed that the amount of total T lymphocytes, CD8+ T cells, granulocytes, pDCs, CD16+ monocytes and CD56high NK cells were significantly higher in the tumor tissue than in the peripheral blood in the cervical cancer patients, while those of CD4+ T cells, CD4+/CD8+ cell ratio, rdT cells, BDCA1+ mDCs, total monocytes, CD14+ monocytes, NK cells and CD56low NK cells exhibited the opposite trend (p p Conclusions These results suggested that distinct alterations in infiltrating lymphocyte subsets occurred in the tumor and were associated with clinicopathological and prognostic parameters. Systemic impairment of the immune system may occur in the antitumor response of cervical cancer patients.

Background To study the kinetic profile and clinicopathological implications of squamous cell carcinoma antigen (SCC-Ag) in cervical cancer patients who underwent surgery by a self-developed SCC-Ag single molecule assay (Simoa) prototype immunoassay. Methods Participants were prospectively enrolled between 04/2016 and 06/2017. Consecutive serum samples were collected at five points: day 0 (the day before surgery), postoperative day 4, weeks 2–4, months 2–4 and months 5–7. In total, 92 patients and 352 samples were included. The kinetic change in SCC-Ag levels and their associations with clinicopathological characteristics were studied. Results Simoa SCC-Ag was validated by comparison with the Architect assay. SCC-Ag levels measured by the Simoa assay were highly correlated with the Architect assay’s levels (Pearson’s correlation coefficient = 0.979, Passing-Bablok regression slope 0.894 (0.847 to 0.949), intercept − 0.009 (− 0.047 to 0.027)). The median values for each time-point detected by the Simoa assay were 2.49, 0.66, 0.61, 0.72, and 0.71 ng/mL, respectively. The SCC-Ag levels decreased dramatically after surgery and then stabilized and fluctuated to some extent within 6 months. Patients with certain risk factors had significantly higher SCC-Ag values than their negative counterparts before surgery and at earlier time points after surgery, while no difference existed at the end of observation. Furthermore, although patients with positive lymph nodes had sustained higher SCC-Ag levels compared to those with negative lymph nodes, similar kinetic patterns of SCC-Ag levels were observed after surgery. Patients who received postoperative treatment had significantly higher SCC-Ag values than those with surgery only at diagnosis, while no difference existed after treatment. Conclusions The Simoa SCC-Ag prototype was established for clinical settings. The SCC-Ag levels were higher in patients with risk factors, whereas the kinetic trend of SCC-Ag might be mainly affected by postoperative adjuvant therapy. These data indicate that the SCC-Ag level might be a good predictor for the status of cervical cancer, including disease aggressiveness and treatment response.

Objective ERBB2 mutations have been found in a subset of invasive cervical cancer (ICC). Nevertheless, the prevalence, mutation spectrum, clinicopathological relevance, human papillomavirus (HPV)-genotype association and prognostic significance of ERBB2-mutated ICCs have not been well established. Methods In this study, ICC samples ( N =1015) were assessed for mutations in ERBB2, KRAS, and PIK3CA by cDNA-based Sanger sequencing. Results Somatic ERBB2 mutations were detected in 3.15% patients. The ERBB2 mutation rate was significantly higher in adenocarcinoma (4.52%, 7/155), adenosquamous carcinoma (7.59%, 6/79) and neuroendocrine carcinoma (10.34%, 3/29) than that in squamous carcinoma (2.14%, 16/749) ( P =0.004, Fisher exact test). In addition, 18.75% of the patients carrying ERBB2 mutations concomitantly harbored PIK3CA or KRAS mutations. Patients with ERBB2-mutated ICCs tended to have a worse prognosis than those with wild-type or PIK3CA-mutated ICCs but a better prognosis than those with KRAS-mutated ICCs. Conclusions This study provided a promising rationale for the clinical investigation of tyrosine kinase inhibitors for the treatment of cervical cancer with ERBB2 mutations. Patients with non-squamous cell carcinomas have priority as candidates for ERBB2-targeted therapy. Concurrent PIK3CA/RAS mutations should be considered in the design of clinical trials.

// Yuqin Zhang 1, * , Tingyan Shi 1, * , Sheng Yin 1 , Sining Ma 1 , Di Shi 1 , Jun Guan 2, 3 , Libing Xiang 4 , Yang Liu 4 , Yulan Ren 4 , Deyan Tan 5 and Rongyu Zang 1 1 Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Zhongshan Hospital, Fudan University, Shanghai, China 2 Department of Gynecology, Tumor Bank Ovarian Cancer, European Competence Center for Ovarian Cancer, Campus Virchow Clinic, Charite Medical University of Berlin, Berlin, Germany 3 Nuffield Department of Obstetrics and Gynecology, University of Oxford, Oxford, United Kingdom 4 Department of Gynecologic Oncology, Fudan University Cancer Center, Shanghai, China 5 Department of Anatomy, Shanghai Medical College, Fudan University, Shanghai, China * These authors contributed equally to the work Correspondence to: Rongyu Zang, email: ryzang@yahoo.com Keywords: paravesico-vaginal space, nerve-sparing radical hysterectomy, deep uterine vein, terminal ureter, cervical cancer Received: April 11, 2017 Accepted: June 16, 2017 Published: July 05, 2017 ABSTRACT Bladder dysfunction remains a major postoperative challenge for early stage cervical cancer patients. The present prospective phase 2 trial in patients with stage IB1 and IIA1 cervical cancer follows up on our previous, unpublished work describing a new surgical landmark, the paravesico-vaginal space. We describe a novel nerve-sparing radical hysterectomy (NSRH) approach to treat early stage cervical cancer without compromising local control rate or survival. Between September 2015 and August 2016, 49 patients were enrolled to receive NSRH. The bladder catheter was routinely removed on postoperative day 4. The primary endpoints were rate of postvoid residual urine volume (PVR) ≤ 50 ml and proportion of patients with successful catheter removal (ClinicalTrials.gov Identifier: NCT02562729). Anatomically, from ventral to dorsal, the terminal ureter, deep uterine vein, and cardinal ligament were the three markers of the paravesico-vaginal space. The median operative time was 100 min, and the median blood loss was 200 ml. Thirty-four patients (69.4%) had successful catheter removal on postoperative day 4, and 17 patients (34.7%) had a PVR ≤ 50 ml. Our results suggest that by accessing the paravesico-vaginal space landmark, the bladder branch of the inferior hypogastric plexus can be completely preserved, contributing to greater NSRH efficiency without compromising outcomes for patients with early stage cervical cancer.

Additional file 1.

To determine the incidence and predisposing factors of preoperative venous thromboembolism (VTE), especially pulmonary embolism (PE) in patients with ovarian cancer.This retrospective study included 387 patients with primary ovarian cancer, whose preoperative work up included both ultrasonography of lower extremity vein and spiral computed tomography pulmonary angiogram, from September 2013 to November 2016. SPSS 22 was used for statistical analyses.The incidence of preoperative VTE and PE was 13.4% (52 patients), 9.3%(36 patients), respectively. Both the univariate and multivariate analyses revealed that D-dimer (DDI) level, age, and massive ascites were associated with preoperative VTE. Moreover, DDI level (odds ratio [OR] 3.133, 95% confidence interval [CI] 1.193-8.225, p = .02), massive ascites (OR 9.972, 95% CI 3.687-26.968, p .001), and preoperative deep vein thrombosis (OR 5.977, 95% CI 2.073-17.228, p = .001) were independent predictors for preoperative PE. Additionally, the incidence of preoperative VTE and PE increased with increasing DDI levels (p .001). DDI level 1.5 μg/ml has 100% negative predictive value and 100% sensitivity for diagnosis of preoperative VTE and PE; however, DDI5 μg/ml, the incidence of preoperative VTE and PE were 18.4% and 14.2% respectively. Moreover, DDI value was significantly correlated with preoperative PE volume (r = 0.746, p .001).Preoperative VTE and PE are common events in patients with ovarian cancer. DDI level is a useful parameter for diagnosing and evaluating preoperative VTE and PE.

Introduction/Background To study the kinetic profile and clinicopathological implication of squamous cell carcinoma antigen (SCC-Ag) in cervical cancer patients who underwent radical hysterectomy by a self-developed Single Molecule Assay (Simoa) immunoassay. Methodology We prospectively enrolled cervical cancer patients who were scheduled for surgery between 2016/04 and 2017/06. Consecutive serum samples were collected at five points: Day 0 (the day before surgery), Day 4 (post-operative day 4), Week 2–4, Month 2–4 and Month 5–7. A total of 92 patients and 352 samples were tested using Simoa, which were compared with commercially available Architect assay. The median SCC-Ag values for each time-point and kinetic profiles were analyzed. We further assessed the correlations between SCC-Ag value/profiles and clinicopathological parameters. Results We demonstrated that Simoa was quite comparable to Architect. The median SCC-Ag value for each time-point using Simoa was 2.49ng/mL, 0.66ng/mL, 0.61ng/mL, 0.72ng/mL, 0.71ng/mL, respectively. The kinetic curve showed that the SCC-Ag levels decreased dramatically after surgery, and then stabilized and fluctuated to some extent within 6 months. Patients with some intermediate- or high-risk factors had significantly higher SCC-Ag values than those negative counterparts before surgery and within 3 months after surgery, but reach the same levels after 6 months. Furthermore, although patients with positive lymph node had sustained higher SCC-Ag values compared to those negative counterparts, similar kinetic tendencies were observed in both groups. Different from this finding, in comparison to the patients with surgery only, patients who received post-operative adjuvant treatment had significantly higher SCC-Ag values at the beginning, while no difference existed after completion of treatment. Conclusion The user-friendly Simoa SCC-Ag assay was established for clinical setting. The SCC-Ag levels were higher in intermediate- or high-risk patients, whereas, the kinetic trend of SCC-Ag might be mainly affected by postoperative adjuvant therapy. The prognostic role needs follow-up data, which warranted further investigation. Disclosure Nothing to disclose.

Introduction/Background En bloc pelvic resection including hysterectomy, bilateral salpingo-oophorectomy and rectosigmoid colon resection and anastomosis is often performed to achieve optimal cytoreduction in ovarian cancer patients with extensive pelvic carcinomatosis. We presented specific surgical details of total pelvic peritonectomy avoiding rectosigmoid colon resection in a well-selected patient. Methodology A 41 year-old women with good performance status (ECOG 0) presented with disseminated disease in abdominal and pelvic cavity. The patient underwent primary debulking surgery including total pelvic peritonectomy. The procedure is initiated by accessing the retroperitoneum by incision of the anterior and lateral peritoneum. After retroperitoneum exposure, the round ligament, infundibulo-pelvic ligament, medial umbilical ligament, and umbilical artery are dissected and ligated. The bladder is mobilized caudally and the vesico-vaginal space is exposed after completely dissecting off the prevesical peritoneum. In the next step, the ureter is isolated and mobilized laterally. Then, uterine vessels and parametria are divided and ligated, which is followed by colpotomy to access the recto-vaginal septum. By retracting the total specimen cranially, the Douglas pouch is dissected from the anterior side of rectum. The mesorectum is further divided and dissected in the extraperitoneal space. The specimen is removed en bloc with the uterus, adnexa, pelvic peritoneum, and tumor nodules, leaving a tumor-invisible pelvis (figure 1). The sigmoid is also deperitonized. Results Complete removal of the disseminated tumors in two layers of peritoneum (parietal and visceral) was achieved by the method introduced in our video. Conclusion Total pelvic peritonectomy is effective for complete cytoreduction in selected ovarian cancer patients with extensive peritoneal carcinomatosis sparing rectosigmoid resection. Disclosure Nothing to disclose

Introduction/Background Glucose metabolism has been suggested as a therapeutic target in ovarian clear cell carcinoma (CCC). We attempted to clarify 18F-FDG PET/CT-based metabolic metrics in the recurrent ovarian CCC patients and their prognostic values. Methodology Quantitative metabolic parameters included maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV) and total lesion glycolysis (TLG). Two different methods were employed for defining the threshold SUV to delineate MTV: 1) SUV of 2.5 (designated as MTV); 2) a fixed ratio including 40% (MTV40), 50% (MTV50) and 60% (MTV60) of SUVmax. The Kaplan-Meier model and Cox regression were used in survival analysis. Results Among the 35 patients, platinum-resistant recurrence accounted for 34.3% and the median progression-free survival was 13 months (range, 2–135). Fifteen (42.9%) patients presented with single tumor recurrence, while 51 recurrent lesions were identified, with the most common sites in pelvis (29.4%), followed by lymph node metastases (19.6%) and peritoneal carcinomatosis (15.7%). Except four patients with FDG-inavid tumor, the median SUVmax of the 31 patients with high glucose metabolic activity was 7.10 (range, 3.00–20.60). After a median follow-up of 36.5 months (range, 7–155), 22 patients (64.7%) were dead from disease. The median post-relapse survival (PRS) was 17 months (range, 4–126). High TLG60 level was associated with shorter overall survival (OS) (P=0.044) and PRS (P=0.031) on univariate analysis, while retained significance on multivariate analysis for OS (P=0.024). Conclusion PET/CT-based metabolic volumetric parameters might be predicators for survival in recurrent ovarian CCC patients. More patients should be included in further study. Disclosure The study was supported by grants from National Natural Science Foundation of China (81702558) and Fudan University Shanghai Cancer Center (YJ201603). The funding bodies didn´t participate in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript. Shuang Ye declares that she has no competing interest. Shuai Liu Shuang Ye declares that she has no competing interest. Libing Xiang declares that he has no competing interest. Xiaohua Wu declares that he has no competing interest. Huijuan Yang declares that she has no competing interest.

Purpose: To study the kinetic profile and clinicopathological implications of squamous cell carcinoma antigen (SCC-Ag) in cervical cancer patients who underwent surgery by a self-developed SCC-Ag Single Molecule Assay (Simoa) prototype immunoassay. Methods: Participants were prospectively enrolled between 04/2016 and 06/2017. Consecutive serum samples were collected at five points: Day 0 (the day before surgery), post-operative Day 4, Week 2-4, Month 2-4 and Month 5-7. Totally, 92 patients and 352 samples were included. Results: Simoa SCC-Ag was validated by comparison with the Architect assay. The median value for each time-point was 2.49, 0.66, 0.61, 0.72, 0.71 ng/mL, respectively. The SCC-Ag levels decreased dramatically after surgery, and then stabilized and fluctuated to some extent within six months. Patients with some intermediate or high-risk factors had significantly higher SCC-Ag values than their negative counterparts before surgery and at earlier time points after surgery, while no difference existed at the end of observation. Furthermore, although patients with positive lymph node had sustained higher SCC-Ag levels compared to those negative counterparts, similar tendencies were observed. Patients who received post-operative treatment had significantly higher SCC-Ag values than those with surgery only at diagnosis, while no difference existed after treatment. Conclusions: Simoa SCC-Ag prototype was established for clinical setting. The SCC-Ag levels were higher in intermediate or high-risk patients, whereas the kinetic trend of SCC-Ag might be mainly affected by post-operative adjuvant therapy. These data indicate that SCC-Ag level might be a good predictor for the status of cervical cancer, including disease aggressiveness and treatment response.

Ovarian cancer is characteristic of superficial implantation and peritoneal carcinomatosis. Hudson introduced a novel technique 50 years ago, which removed the entire Douglas pouch as a false capsule of the tumor (Hudson, 1968 [1]). Angeles et al. standardized the procedure in 10 steps in a previous publication (Angeles et al., 2019 [2]). We made small modifications of the Hudson procedure in this video. Ovarian cancer is characteristic of superficial implantation and peritoneal carcinomatosis. Hudson introduced a novel technique 50 years ago, which removed the entire Douglas pouch as a false capsule of the tumor (Hudson, 1968 [1]). Angeles et al. standardized the procedure in 10 steps in a previous publication (Angeles et al., 2019 [2]). We made small modifications of the Hudson procedure in this video.The key points of the procedure were summarized as follows. Firstly, dissecting off the pelvic parietal peritoneum very superficially. Secondly, the round ligament, infundibulo-pelvic ligament, medial umbilical ligament, and umbilical artery are divided and ligated in the extraperitoneal space. Thirdly, the bladder is mobilized caudally and the vesico-vaginal space is exposed after completely dissecting off the vesical peritoneum. Fourthly, the ureter is isolated and mobilized laterally. Then, uterine vessels and parametria are divided and ligated, which is followed by colpotomy to access the recto-vaginal septum. By retracting the total specimen cranially, the Douglas pouch is dissected retrogradely according to Hudson procedure. Lastly, the peritoneum of the mesorectum and mesosigmoid is shaved at the pelvic brim. Therefore, using this method, almost all the pelvic visceral peritoneum was dissected (). In addition, we didn't intentionally expose the anatomical spaces (pre-vesical, para-vesical, para-rectal, and pre-sacral) completely, which was effective and time-saving.Complete removal of the disseminated tumors in both parietal and visceral peritoneum was achieved by the method introduced in our video.Our method, modified from Hudson procedure, is effective for complete cytoreduction in selected ovarian cancer patients with extensive peritoneal carcinomatosis sparing rectosigmoid resection.

Regulatory T cells (Tregs) are crucial for the maintenance of peripheral tolerance, but they also limit beneficial responses through cancer-induced immunoediting. The roles of Treg subsets in cervical squamous cell carcinoma (CSCC) are currently unknown. Here, we aimed to perform an extensive study with an increased resolution of the Treg compartment in the peripheral blood and tumor tissues of CSCC patients. We first identified that an HLADR

This study aims to explore whether E545K, the most common hotspot mutation of

Background The study aims to present the effect of PIK3CA E542K and E545K mutations on glucose metabolism and proliferation and identify their underlying mechanisms in cervical cancer. Methods The maximum standard uptake value (SUVmax) of tumors was detected by18F-FDG PET/CT scan. In vitro, glycolysis analysis, extracellular acidification rate analysis, and ATP production were used to evaluate the impact of PIK3CA E542K and E545K mutations on glucose metabolism. The expression level of key glycolytic enzymes was evaluated by western blotting and immunohistochemical staining in cervical cancer cells and tumor tissues, respectively. Immunofluorescence analysis was used to observe the nuclear translocation of β-catenin. The target gene of β-catenin was analyzed by using luciferase reporter system. The glucose metabolic ability of the xenograft models was assessed by SUVmax from microPET/CT scanning. Results Cervical cancer patients with mutant PIK3CA (E542K and E545K) exhibited a higher SUVmax value than those with wild-type PIK3CA (P = 0.037), which was confirmed in xenograft models. In vitro, enhanced glucose metabolism and proliferation was observed in SiHa and MS751 cells with mutant PIK3CA. The mRNA and protein expression of key glycolytic enzymes was increased. AKT/GSK3β/β-catenin signaling was highly activated in SiHa and MS751 cells with mutant PIK3CA. Knocking down β-catenin expression decreased glucose uptake and lactate production. In addition, the nuclear accumulation of β-catenin was found in SiHa cells and tumors with mutant PIK3CA. Furthermore, β-catenin downregulated the expression of SIRT3 via suppressing the activity of the SIRT3 promotor, and the reduced glucose uptake and lactate production due to the downregulation of β-catenin can be reversed by the transfection of SIRT3 siRNA in SiHa cells with mutant PIK3CA. The negative correlation between β-catenin and SIRT3 was further confirmed in cervical cancer tissues. Conclusions These findings provide evidence that the PI3K E542K and E545K/β-catenin/SIRT3 signaling axis regulates glucose metabolism and proliferation in cervical cancers with PIK3CA mutations, suggesting therapeutic targets in the treatment of cervical cancers. Trial registration FUSCC 050432–4-1212B. Registered 24 December 2012 (retrospectively registered). Electronic supplementary material The online version of this article (10.1186/s13045-018-0674-5) contains supplementary material, which is available to authorized users.

Background Ovarian clear cell carcinoma is a distinct histologic subtype with grave survival. The underlying molecular mechanism is not fully elucidated. However, we don’t have many cell lines, which are useful experimental tools for research. We describe the establishment and characterization of a new ovarian clear cell carcinoma cell line from a Chinese patient. Results FDOV1 has been subcultured for more than 80 generations. Monolayer cultured cells are polygonal in shape, showing a transparent cytoplasm full of vacuoles. The number of chromosomes ranges from 45 to 90. FDOV1 cells produces CA-125, but not CA-199. The cells could be transplanted and produced tumors mimicking the donor tumor morphologically and immunohistochemically. Whole exome sequence showed both FDOV1 and tissue block harbored PIK3CA H1047R mutation and ARID1A frameshift mutations (p.L2106 fs, p.N201 fs). More interestingly, we observed SPOP mutation (p.D82H) and ZNF217 (chromosome 20q13) amplification in FDOV1, which are quite novel. Conclusions Only a few patient-derived ovarian clear cell carcinoma cell lines have been reported in the literature. FDOV1 is the very first one, to the best of our knowledge, from a Mainland Chinese patient. It showed infinite multiplication until now and tumorigenicity in vivo. FDOV1 has co-existing PIK3CA and ARID1A mutations. It also harbored SPOP mutation and ZNF217 amplification, which would probably be a good model for exploring the molecular mechanism of ovarian clear cell carcinoma. Electronic supplementary material The online version of this article (10.1186/s13048-018-0429-5) contains supplementary material, which is available to authorized users.

Table S1. The primer of Sanger sequence for specific genes mutation in FDOV1. (DOCX 15 kb)

Table S1. The primer sequences are used for qRT-PCR detection. (DOCX 15 kb)

OBJECTIVE The predictive and prognostic role of KRAS mutations in cervical cancer remains inconclusive. The aim of this study was to explore the clinicopathological and prognostic relevance of KRAS mutations in invasive cervical cancers (ICC). METHODS Reverse transcription polymerase chain reaction (PCR) and Sanger sequencing were employed to detect KRAS mutations in 876 ICC patients. Quantitative real-time PCR was used to detect human papillomavirus (HPV) 16 and HPV 18. RESULTS Non-synonymous mutations of KRAS were identified in 30 (3.4%) patients. These mutations were more common in non-squamous cell carcinoma than in squamous cell carcinoma (SCC) (8.2% vs. 2.2%, respectively, p