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.

Exploration of glycosyltransferases mutation status in cervical cancer reveals PARP14 as a potential prognostic marker.

This study investigates the potential role of Glycosyltransferases (GTs) in the glycosylation process and their association with malignant tumors. Specifically, the study focuses on PARP14, a member of GTs, and its potential as a target for tumors in the diagnosis and treatment of cervical cancer. To gather data, the study used somatic mutation data, gene expression data and clinical information from TCGA-CESE dataset as well as tissue samples from cervical cancer patients. Further verification was conducted through RT-qPCR and immunohistochemistry staining on cervical cancer tissues to confirm the expression of PARP14. The study utilized Kaplan-Meier for survival analysis of cervical cancer patient and found significant mutational abnormalities in GTs. The high frequency mutated gene was identified as PARP14. RT-qPCR revealed significantly higher mRNA expression of PARP14 compared to precancerous tissue. Using IHC combined with Kaplan-Meier,patients in the PARP14 high expression group had a better prognosis than the low expression group. The study identified PARP14 as a frequently mutated gene in cervical cancer and proposed its potential role in diagnosis and treatment.

Modulation of intracellular kinase signaling to improve TIL stemness and function for adoptive cell therapy.

INTRODUCTION: Adoptive cellular therapy with tumor-infiltrating lymphocytes (TIL) has demonstrated promising clinical benefits in several solid tumors, but the efficacy of this therapy might be compromised by the "prone-to-exhaustion" phenotype of TIL and poor persistence in vivo. This calls for a robust expansion process to produce a large number of cells for clinical usage while at the same time maintaining favorable anti-tumor function and memory phenotype. Previous studies showed that the PI3K-AKT signaling pathway plays a key role in the regulation of T cell activation, differentiation and memory formation. METHOD: We modulated the PI3K-AKT pathway in TIL isolated from cervical and ovarian cancer by application of AKT or PI3K inhibitors or CRISPR knockout of AKT1 and/or AKT2, and characterized their effects on TIL phenotype and effector function. Mechanistic study was further performed with RNA-seq analysis of AKT1/2 KO TIL in comparison to control TIL. RESULT: The inhibition of either PI3K or AKT led to an increase in the population of effector CD8+ T cells with upregulation of activation markers, elevated CD39- CD69- memory T cells, and significantly enhanced cytotoxicity when cocultured with tumor cell lines and patient-derived tumor samples. Moreover, dual knockout of AKT1 and AKT2 largely phenocopies the functional impact of AKT or PI3K inhibition on TIL. This result was further validated by RNA-seq analysis indicating that AKT1/2 ablation primarily regulates T cell differentiation and function-related programs. CONCLUSION: Modulation of PI3K-AKT signaling represents a promising strategy to enhance TIL stemness and cytotoxicity and improve the clinical outcome of current TIL-based therapy to treat solid tumors.

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).

Characterization of the Genomic Landscape in Cervical Cancer by Next Generation Sequencing.

Cervical cancer is the fourth leading cause of cancer-related deaths in women worldwide. Although many sequencing studies have been carried out, the genetic characteristics of cervical cancer remain to be fully elucidated, especially in the Asian population. Herein, we investigated the genetic landscape of Chinese cervical cancer patients using a validated multigene next generation sequencing (NGS) panel. We analyzed 64 samples, consisting of 32 tumors and 32 blood samples from 32 Chinese cervical cancer patients by performing multigene NGS with a panel targeting 571 cancer-related genes. A total of 810 somatic variants, 2730 germline mutations and 701 copy number variations (CNVs) were identified. FAT1, HLA-B, PIK3CA, MTOR, KMT2D and ZFHX3 were the most mutated genes. Further, PIK3CA, BRCA1, BRCA2, ATM and TP53 gene loci had a higher frequency of CNVs. Moreover, the role of PIK3CA in cervical cancer was further highlighted by comparing with the ONCOKB database, especially for E545K and E542K, which were reported to confer radioresistance to cervical cancer. Notably, analysis of potential therapeutic targets suggested that cervical cancer patients could benefit from PARP inhibitors. This multigene NGS analysis revealed several novel genetic alterations in Chinese patients with cervical cancer and highlighted the role of PIK3CA in cervical cancer. Overall, this study showed that genetic variations not only affect the genetic susceptibility of cervical cancer, but also influence the resistance of cervical cancer to radiotherapy, but further studies involving a larger patient population should be undertaken to validate these findings.

KHDRBS3 promotes paclitaxel resistance and induces glycolysis through modulated MIR17HG/CLDN6 signaling in epithelial ovarian cancer.

Paclitaxel (PTX) resistance contributes to mortality in epithelial ovarian cancer (EOC). Aerobic glycolysis is elevated in the tumor environment and may influence resistance to PTX in EOC. KH domain-containing, RNA-binding signal transduction-associated protein 3 (KHDRBS3) is an RNA binding protein that is up-regulated in EOC, but its underlying mechanism in EOC is unclear. Here, we investigate the role of KHDRBS3 in glycolysis and increased resistance to PTX. Expression of KHDRBS3 and Claudin (CLDN6) were measured in EOC tissue and cells by quantitative real-time PCR, western blotting and immunohistochemistry. The biological functions of KHDRBS3, MIR17HG and CLDN6 were examined using MTT, colony formation, apoptosis and seahorse assays in vitro. For in vivo experiments, a xenograft model was used to investigate the effects of KHDRBS3 and MIR17HG in EOC. Here, we investigate the role of KHDRBS3 in glycolysis and increased resistance to PTX. The expression of KHDRBS3 was up-regulated in PTX-resistant cells. KHDRBS3 knockdown restrained the IC50 of PTX, cell proliferation, colony formation and glycolysis in SKOV3-R and A2780-R cells in vitro and enhanced PTX sensitivity in a xenograft mouse model in vivo. KHDRBS3 interacts with lncRNA MIR17HG, which is down-regulated in EOC tissue and cells. The effect of KHDRBS3 overexpression on PTX resistance and glycolysis was rescued by MIR17HG overexpression. Additionally, MIR17HG interacts with the 3'UTR of CLDN6 and negatively regulates CLDN6 expression. MIR17HG overexpression suppressed the IC50 of PTX and glycolysis by targeting CLDN6. Our results reveal a KHDRBS3-MIR17HG-CLDN6 regulatory axis that contributes to enhanced glycolysis in EOC and represents a potential target for therapy.