He Huang

A phase II trial of cytoreductive surgery combined with niraparib maintenance in platinum-sensitive, secondary recurrent ovarian cancer: SGOG SOC-3 study

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. 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. ClinicalTrials.gov Identifier: NCT03983226.

The impact of lymph node dissection on survival in patients with clinical early-stage ovarian cancer

To estimate the impact of lymph node dissection on survival in patients with apparent early-stage epithelial ovarian cancer (EOC). We conducted a retrospective review of patients with clinical stage I-II EOC. All patients underwent primary surgery at Sun Yat-sen University Cancer Center between January 2003 and December 2015. Demographic features and clinicopathological information as well as perioperative adverse events were investigated, and survival analyses were performed. A total of 400 ovarian cancer patients were enrolled, and patients were divided into 2 groups: 81 patients did not undergo lymph node resection (group A), and 319 patients underwent lymph node dissection (group B). In group B, the median number of removed nodes per patient was 25 (21 pelvic and 4 para-aortic nodes). In groups A and B, respectively, the 5-year progression-free survival (PFS) rates were 83.3% and 82.1% (p=0.305), and the 5-year overall survival (OS) rates were 93.1% and 90.9% (p=0.645). The recurrence rate in the retroperitoneal lymph nodes was not associated with lymph node dissection (p=0.121). The median operating time was markedly longer in group B than in group A (220 minutes vs. 155 minutes, p<0.001), and group B had a significantly higher incidence of lymph cysts at discharge (32.9% vs. 0.0%, p<0.001). In patients with early-stage ovarian cancer, lymph node dissection was not associated with a gain in OS or PFS and was associated with an increased incidence of perioperative adverse events.

Perineural Invasion Should Be Regarded as an Intermediate-Risk Factor for Recurrence in Surgically Treated Cervical Cancer: A Propensity Score Matching Study

Background. Perineural invasion (PNI) is considered as a poor prognostic factor in cervical cancer, but there has been no postoperative adjuvant therapy for it, because whether it belongs to high- or intermediate-risk factors has not been determined, this study intends to provide evidences to solve this problem. Methods. We conducted a retrospective analysis of cervical cancer patients who underwent radical surgery and be reported PNI from January 2012 to June 2017 at the Sun Yat-sen University Cancer Center. After 1 : 1 propensity score matching (PSM), a group of patients without PNI was matched according to the clinical pathological features. Postoperative pathological parameters and prognosis were evaluated between the PNI and the matched groups. Results. 1836 patients were screened, of which 162 (8.8%) diagnosed as stages IB1 to IIB reported PNI. Comparing to the matched group, more PNI (+) patients had deep outer cervix stromal invasion, cervical tunica adventitia invasion, positive lymph nodes, and positive margins. Among patients without high-risk factors, PNI (+) patients had worse 3-year overall survival (90.8% vs. 98.1%, P = 0.02 ), PNI (+) patients with single intermediate-risk factor and PNI (-) patients who meet with SEDLIS criteria had similar progress free survival ( P = 0.63 ) and overall survival ( P = 0.63 ), even similar survival curves. Conclusion. PNI is related to a worse overall survival among cervical cancer patients without high-risk factors and play the role as an intermediate-risk factor.

Phase I study of adjuvant immunotherapy with autologous tumor-infiltrating lymphocytes in locally advanced cervical cancer

BACKGROUNDAdoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TILs) has achieved remarkable clinical efficacy in metastatic cancers such as melanoma and cervical cancer (CC). Here, we explored the safety, feasibility, and preliminary tumor response and performed translational investigations of adjuvant immunotherapy using infusion of autogenous TILs (auto-TILs) following concurrent chemoradiotherapy (CCRT) in patients with CC who had locally advanced disease.METHODSTwenty-seven patients with CC with stage III-IV disease were recruited in this single-center, phase I study. TILs were isolated from lesions in the uterine cervix and generated under good manufacturing practice (GMP) conditions and then infused after CCRT plus i.m. IL-2 injections.RESULTSTILs from 20 of the 27 patients were successfully expanded, with a feasibility of 74.1%. Twelve patients received TILs following CCRT. Adverse events (AEs) were primarily attributable to CCRT. Only 1 (8.3%) patient experienced severe toxicity with a grade 3 hypersensitivity reaction after TIL infusion. No autoimmune AEs, such as pneumonitis, hepatitis, or myocarditis, occurred, and there were no treatment-related mortalities. Nine of 12 patients (75.0%) attained a complete response, with a disease control duration of 9-22 months. Translational investigation showed that the transcriptomic characteristics of the infused TIL products and some immune biomarkers in the tumor microenvironment and serum of patients with CC at baseline were correlated with the clinical response.CONCLUSIONTIL-based ACT following CCRT was safe in an academic center setting, with potentially effective responses in patients with locally advanced CC. "Hot" inflammatory immune environments were beneficial to the clinical efficacy of TIL-based ACT as adjuvant therapy.TRIAL REGISTRATIONClinicalTrials.gov NCT04443296.FUNDINGNational Key R&D Program; Sci-Tech Key Program of the Guangzhou City Science Foundation; the Guangdong Province Sci-Tech International Key Program; the National Natural Science Foundation of China.

FOXM1 Promotes Drug Resistance in Cervical Cancer Cells by Regulating ABCC5 Gene Transcription

Objective. The aim of the present study was to investigate the effect of forkhead box M1 (FOXM1) to paclitaxel resistance in cervical cancer cells, to determine the underlying mechanism, and to identify novel targets for the treatment of paclitaxel‐resistant cervical cancer. Methods. Paclitaxel‐resistant Caski cells (Caski/Taxol cells) were established by intermittently exposing the Caski cells to gradually increasing concentrations of paclitaxel. The association between FOXM1, ATP‐binding cassette subfamily C member 5 (ABCC5), and cervical cancer cell drug resistance was assessed by overexpressing or knocking down the expression of FOXM1 in Caski or Caski/Taxol cells. The protein and mRNA expression levels, the ratio of cellular apoptosis, and cell migration as well as intracellular drug concentrations were measured in cells following the different treatments. Results. After the successful establishment of resistant Caski/Taxol cells, cell cycle distribution analysis showed that a significantly larger percentage of Caski/Taxol cells was in the G0/G1 stage compared with the Caski cells (P &lt; 0.01), whereas a significantly larger percentage of Caski cells was in the S and G2/M stage compared with the Caski/Taxol cells following treatment with paclitaxel (P &lt; 0.01). Both the protein and mRNA expression levels of FOXM1 and ABCC5 transporters were significantly higher in the paclitaxel‐resistant Caski/Taxol cells compared with Caski cells (P &lt; 0.05). Knockdown of FOXM1 significantly lowered the protein expression levels of FOXM1 and ABCC5. Intracellular paclitaxel concentrations were significantly higher amongst the Caski/Taxol cells following the knockdown of FOXM1 by shRNA or Siomycin A (P &lt; 0.05). Conclusion. FOXM1 promotes drug resistance in cervical cancer cells by regulating ABCC5 gene transcription. The knockdown of FOXM1 with shRNA or Siomycin A promotes paclitaxel‐induced cell death by regulating ABCC5 gene transcription.

Comprehensive Multiomics Characterization of Perineural Invasion in Cervical Cancer Reveals Diagnostic Markers, Molecular Drivers, and Therapeutic Strategies

Abstract Perineural invasion (PNI) is an important pathologic feature of cervical cancer that is associated with poor prognosis and provides key information for clinical decisions. A better understanding of the molecular mechanisms underlying PNI could lead to improved patient treatment strategies. Here, we generated whole-exome, whole-genome, and RNA sequencing data from tumors and matched normal clinical samples of 45 patients with cervical cancer and performed a comparative analysis between 23 PNI and 22 non-PNI tumors. A robust machine learning approach identified a three-gene expression signature of MT1G, NPAS1, and SPRY1 that could predict the tumor PNI status with high accuracy, which was validated using an independent cohort (18 PNI and 19 non-PNI). Loss-of-function FBXW7 mutations were identified as driver events for PNI that lead to increased MYC activity and an immunosuppressive tumor microenvironment. Finally, a deep learning model for predicting drug efficacy over patients’ transcriptomic data revealed OTX015, a BET inhibitor, as a promising treatment that targets mutated FBXW7 PNI tumors. This study provides a rich resource for elucidating the molecular mechanisms of PNI tumors, laying a critical foundation for developing effective diagnostic and therapeutic strategies for PNI tumors in cervical cancer. Significance: Generation of a rich resource for characterizing the molecular basis of perineural invasion in tumors lays a critical foundation for developing effective diagnostic and therapeutic strategies in cervical cancer. This article is part of a special series: Driving Cancer Discoveries with Computational Research, Data Science, and Machine Learning/AI .

Surgery and Niraparib in Secondary Recurrent Ovarian Cancer (SOC-3 Trial)

This is a Phase II, open-label, multicenter, randomized umbrella study to evaluate the efficacy of cytoreductive surgery and Niraparib maintenance in participants with platinum-sensitive secondary recurrent ovarian cancer. Cohort 1 will focus on participants without prior use of PARP inhibitor, and without prior secondary cytoreduction (SCR) when first recurrence. Cohort 2 will focus on participants with prior use of PARP inhibitor, but without prior SCR when first recurrence. Cohort 3 will focus on participants with SCR when first recurrence, but without prior use of PARP inhibitor.

Study of Tumor Infiltrating Lymphocytes Following CCRT in the Treatment of Patients With Cervical Carcinoma

A Phase I trial to evaluate the feasibility, toxicity and effectiveness of cisplatin concurrent chemoradiotherapy plus TIL in treating patients with FIGO stage IIIA to IVA cervical carcinoma.