A multicenter noninferior randomized controlled study comparing the efficacy of laparoscopic versus abdominal radical hysterectomy for cervical cancer (stage IB3 and IIA2): study protocol of the LAUNCH 3 trial.

BACKGROUND: Cervical cancer is and will remain to be an important health problem in China, especially with an increasing proportion of younger patients who has more specific needs. In China, surgery to remove tumor burden followed by postoperative treatment with radiotherapy and chemotherapy based on clinicopathologic factors may be the best choice for stages IB3 and IIA2 patients. Radical hysterectomy in cervical cancer has been a classic landmark surgery in gynecology. The current trial is designed to evaluate whether there is a difference between laparoscopic RH and abdominal RH in cervical cancer (stages IB3 and IIA2) patient survival under stringent operation standards and consistent surgical oncologic principles. This paper reports the rationale, design, and implementation of the trial. METHODS/DESIGN: This is an investigator-initiated, prospective, randomized, open, blinded endpoint (PROBE) controlled trial. A total of 1104 patients with stage IB3 and IIA2 cervical cancer will be enrolled over a period of 3 years. Patients are randomized (1:1) to either the laparoscopic RH or the abdominal RH group. Patients will then be followed up for at least 5 years. The primary end point will be 5-year overall survival, and secondary endpoints include 5-year progression-free survival, recurrence, and quality of life measurements. DISCUSSION: The study results will provide more convincing evidence-based information for stages IB3 and IIA2 cervical cancer patients and their gynecologic cancer surgeons in their choice of surgical method. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04939831 , retrospectively registered on 25 June 2021.

A multicenter non-inferior randomized controlled study comparing the efficacy of laparoscopic versus abdominal radical hysterectomy for cervical cancer (stages IB1, IB2, and IIA1): study protocol of the LAUNCH 2 trial.

BACKGROUND: A retrospective study and a randomized controlled trial published in late 2018 have shown that laparoscopic radical hysterectomy (RH) was associated with worse survival than abdominal RH among patients with early-stage cervical cancer. Radical hysterectomy in cervical cancer has been a classic landmark surgery in gynecology; therefore, this conclusion is pivotal. The current trial is designed to reconfirm whether there is a difference between laparoscopic RH and abdominal RH in cervical cancer (stages IB1, IB2, and IIA1) patient survival under stringent operation standards and consistent surgical oncologic principles. METHODS/DESIGN: This is an investigator-initiated, Prospective, Randomized, Open, Blinded End-point (PROBE)-controlled non-inferiority trial. A total of 780 patients with stage IB1, IB2, and IIA1 cervical cancer will be enrolled over a period of 3 years. Patients are randomized (1:1) to either the laparoscopic RH or the abdominal RH group. Patients will then be followed up for at least 5 years. The primary endpoint will be 5-year progression-free survival, and secondary endpoints include 5-year overall survival, recurrence, and quality of life measurements. DISCUSSION: The debate on laparoscopic versus abdominal RH is still ongoing, and high-quality evidences are needed to guide clinical practice. The study results will provide more convincing evidence-based information for early-stage cervical cancer patients and their gynecologic cancer surgeons in their choice of surgical method. TRIAL REGISTRATION: ClinicalTrials.gov NCT04929769 . Registered on 18 June 2021.

A multicenter noninferior randomized controlled study comparing the efficacy of laparoscopic versus abdominal radical hysterectomy for cervical cancer (stage IA1 with LVSI, IA2): study protocol of the LAUNCH 1 trial.

BACKGROUND: A retrospective study and a randomized controlled trial published in a high quality journal in late 2018 have shown that laparoscopic radical hysterectomy (RH) was associated with worse survival than abdominal RH among patients with early stage cervical cancer. Radical hysterectomy in cervical cancer has been a classic landmark surgery in gynecology, therefore this conclusion is pivotal. The current trial is designed to reconfirm whether there is a difference between laparoscopic RH and abdominal RH in cervical cancer (stage IA1 with LVSI, IA2) patient survival under stringent operation standards and consistent tumor-free technique. This paper reports the rationale, design, and implementation of the trial. METHODS: This is an investigator-initiated, prospective, randomized, open, blinded endpoint (PROBE) controlled trial. A total of 690 patients with stage IA1 (with intravascular), and IA2 cervical cancer will be enrolled over a period of three years. Patients are randomized (1:1) to either the laparoscopic RH or the abdominal RH group. Patients will then be followed-up for at least five years. The primary endpoint will be 5-year progression-free survival. Secondary endpoints will include 5-year overall survival rates, recurrence rates, operation time, intraoperative blood loss, surgery-related complications, and quality of life. DISCUSSION: The results of the trial will provide valuable evidence for guiding clinical decision of choosing appropriate treatment strategies for stage IA1 (LVSI) and stage IA2 cervical cancer patients. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT04934982 , Registered on 22 June 2021).

Obstetrical outcomes after vaginal repair of caesarean scar diverticula in reproductive-aged women.

BACKGROUND: Although vaginal repair has been conducted to manage caesarean scar diverticula, most studies evaluated only the gynaecological outcomes post-surgery, and their obstetrical outcomes were unknown. This study aimed to evaluate the obstetrical outcomes in vaginal repair-treated caesarean scar diverticula patients. METHODS: A series of 51 symptomatic women with caesarean scar defects or a thickness of the remaining muscular layer of less than 3 mm according to transvaginal ultrasound were included. We retrospectively evaluated the gynaecological and obstetrical outcomes after vaginal repair and histologically analysed the defect. RESULTS: Transvaginal ultrasound revealed that the thickness of the remaining muscular layer significantly increased from 2.24 ± 0.81 mm to 6.10 ± 1.43 mm 3 months after vaginal repair. The duration of menstruation significantly decreased from 14.29 ± 3.13 days to 8.31 ± 2.14 days post-vaginal repair. Notably, 26 of the 51 (50.98%) women who were followed for more than 15.04 months post-surgery achieved pregnancy. A total of 6 of the 26 pregnancies (23.08%) resulted in miscarriages, including 5 early miscarriages and 1 late miscarriage. Among the 20 women who achieved pregnancy without miscarriage, 18 had term deliveries, 2 had preterm birth, and none reported uterine rupture. Histological analysis was performed in all 51 cases. Muscle fibre density was significantly lower in the scar than in the myometrium adjacent to the scar and collagen expression was markedly increased in the scar tissue. CONCLUSION: Satisfactory gynaecological and subsequent obstetrical outcomes can be achieved in vaginal repair-treated caesarean scar diverticula patients.

PAK5 Induces EMT and Promotes Cell Migration and Invasion by Activating the PI3K/AKT Pathway in Ovarian Cancer.

Ovarian cancer is the most lethal gynecologic cancer and currently ranks fifth in causing cancer-related deaths among women. P21cdc42/rac1-activated kinase 5 (PAK5) is a newly identified protein that has been indicated to have oncogenic potential. The present study investigated the expression level of PAK5 in clinical ovarian cancer and the functional roles of PAK5 in ovarian cancer progression. It was initially found that PAK5 was highly expressed in ovarian cancer tissues, particularly in patients with distant metastasis. Higher expression of PAK5 predicted poor survival fates in patients with ovarian cancer (p = 0.008). Knockdown of PAK5 in SKOV3 cells caused epithelial cell phenotypes, whereas overexpression of PAK5 led to remarkable mesenchymal cell phenotypes in A2780 cells. When PAK5 was depleted from SKOV3 cells, cells exhibited impaired wound recovery abilities. Cell migration and invasion abilities were also significantly inhibited. On the contrary, when PAK5 was overexpressed in A2780 cells, the wound recovery ability was enhanced by 68%. Cell migration and invasion abilities were consistently increased to approximately 2-fold. After knockdown of PAK5, the phosphorylation levels of PI3K p85 at Tyr458 and its downstream AKT at Ser473 were both decreased. The total protein of PI3K and AKT as well as the phosphorylation level of AKT at Thr308 remained unaffected. These data suggested that PI3K induced epithelial-to-mesenchymal transition and promoted cell migration and invasion by activating the PI3K/AKT pathway in ovarian cancer. The oncogenic potential of PAK5 in ovarian cancer might suggest that any therapeutic strategies targeting PAK5 had the promising value for ovarian cancer treatment.

Ovarian Cancer-Intrinsic Fatty Acid Synthase Prevents Anti-tumor Immunity by Disrupting Tumor-Infiltrating Dendritic Cells.

Fatty acid synthase (FASN), the key metabolic enzyme of de novo lipogenesis, provides proliferative and metastatic capacity directly to cancer cells have been described. However, the impact of aberrant activation of this lipogenic enzyme on host anti-tumor immune milieu remains unknown. In this study, we depicted that elevated FASN expression presented in ovarian cancer with more advanced clinical phenotype and correlated with the immunosuppressive status, which characterized by the lower number and dysfunction of infiltrating T cells. Notably, in a mouse model, we showed that tumor cell-intrinsic FASN drove ovarian cancer (OvCa) progression by blunting anti-tumor immunity. Dendritic cells (DCs) are required to initiate and sustain T cell-dependent anti-tumor immunity. Here, our data showed that constitutive activation of FASN in ovarian cancer cell lead to abnormal lipid accumulation and subsequent inhibition of tumor-infiltrating DCs (TIDCs) capacity to support anti-tumor T cells. Mechanistically, FASN activation in ovarian cancer cell-induced the resulting increase of lipids present at high concentrations in the tumor microenvironment. Dendritic cells educated by FASNhigh OvCa ascites are defective in their ability to present antigens and prime T cells. Accordingly, inhibiting FASN by FASN inhibitor can partly restore the immunostimulatory activity of TIDCs and extended tumor control by evoking protective anti-tumor immune responses. Therefore, our data provide a mechanism by which ovarian cancer-intrinsic FASN oncogenic pathway induce the impaired anti-tumor immune response through lipid accumulation in TIDCs and subsequently T-cells exclusion and dysfunction. These results could further indicate that targeting the FASN oncogenic pathway concomitantly enhance anti-tumor immunity, thus offering a unique approach to ovarian cancer immunotherapy.

Up-regulated FASN expression promotes transcoelomic metastasis of ovarian cancer cell through epithelial-mesenchymal transition.

Fatty acid synthase (FASN), responsible for the de novo synthesis of fatty acids, has been shown to act as an oncogene in various human cancers. However, the mechanisms by which FASN favors the progression of ovarian carcinoma remain unknown. In this study, we evaluated FASN expression in ovarian cancer and investigated how FASN regulates the aggressiveness of ovarian cancer cells. Our results show that increased FASN is associated with the peritoneal metastasis of ovarian cancers. Over-expression of FASN results in a significant increase of tumor burden in peritoneal dissemination, accompanied by augment in cellular colony formation and metastatic ability. Correspondingly, FASN knockdown using RNA interference in ovarian cancer cells inhibits the migration in vitro and experimental peritoneal dissemination in vivo. Mechanistic studies reveal that FASN promotes Epithelial-mesenchymal Transition (EMT) via a transcriptional regulation of E-cadherin and N-cadherin, which is also confirmed by luciferase promoter activity analysis. Taken together, our work demonstrates that FASN promotes the peritoneal dissemination of ovarian cancer cells, at least in part through the induction of EMT. These findings suggest that FASN plays a critical role in the peritoneal metastasis of ovarian cancer. Targeting de novo lipogenesis may have a therapeutic potential for advanced ovarian cancer.

Performance of high-risk human papillomavirus testing in the triage of abnormal cervical cytology among Chinese younger women in Shanghai, China.

OBJECTIVE: This study aimed to evaluate the role of high risk HPV DNA testing in identifying Chinese younger women with abnormal cytology at risk of harboring cervical intraepithelial neoplasia at grade 2 (CIN2) or worse so as to popularize an effective triage strategy for younger women. METHODS: A total of 246 younger women aged 25 - 36 years old with abnormal cytology were recruited in our study. All were assessed by liquid-based cytology, high-risk HPV DNA test, and colposcopy with directed biopsy and endocervical curettage as necessary. Residual specimens from liquid-based cytology were subjected to real-time PCR testing to identify the presence of 10 high-risk HPV types that are prevalent in China. RESULTS: Among the 246 abnormal cytology samples, 97 (39.4%) were found to be positive for high risk HPV. A clear association was observed between cytological findings and the proportion of patients with positive high risk HPV DNA: namely 29.8% HPV positivity in the ASCUS group; 43.5% in LSIL group; and 90.0% in HSIL group (p<0.01). Overall, high risk HPV test achieved a high specificity (79.8%) and PPV (86.5%) for an endpoint of CIN2+, and higher sensitivity (91.3%) and NPV (98.7%) for an endpoint of CIN3+. For younger women with ASCUS+ cytology, high risk HPV test achieved a higher NPV for CIN2+ and CIN3+ (96.0%, 99.0%). For LISL+ cytology, high risk HPV testing had a high sensitivity with LSIL (90.0%) and HSIL (100%), but there was also a corresponding decrease in specificity. CONCLUSIONS: The results indicate that high risk HPV DNA testing is highly sensitive and moderately specific for CIN grade 2 or worse in women younger than 36 years. LBC primary testing followed by high risk HPV DNA triage improved sensitivity and the false-positive rate for cervical cancer screening and are suitable for developed regions in China.