BACKGROUND: Concurrent chemo-radiotherapy (CCRT) is the standard treatment for locally advanced cervical cancer (LACC), but there are still many patients who suffer tumor recurrence. However, valuable predictors of treatment outcomes remain limited. This study aimed to assess the value of the serum immune biomarkers to predict the prognosis. METHODS: We reviewed cervical cancer patients treated with CCRT between January 2014 and May 2018 at Peking Union Medical College Hospital. The systemic immune inflammation index (SII), systemic inflammation response index (SIRI), and lactate dehydrogenase (LDH) were calculated using blood samples. The relationship between immune markers and the treatment outcome was analyzed. The area under the receiver operating characteristic (ROC) curve was used to evaluate the predictive efficiency. The Cox proportional hazards model and log-rank were used to predict overall survival (OS) and disease-free survival (DFS). RESULTS: This study included 667 patients. Among them, 195 (29.2%) patients were defined as treatment failure, including 127 (19.0%) patients with pelvic failure, 94 (14.1%) distant failure, and 25 (3.7%) concurrent pelvic and distant failure. It revealed that the tumor stage, size, metastatic lymph nodes (MLNs), and serum immune biomarkers, such as SII, SIRI, and LDH, were significantly related to treatment outcomes. We demonstrated that the optimal cut-off of the SII, SIRI, and LDH were 970.4 × 10 9 /L, 1.3 × 10 9 /L, and 207.52 U/L, respectively. Importantly, this study presented that LDH level had the highest OR (OR = 4.2; 95% CI [2.3-10.8]). Furthermore, the OS and DFS for patients with pre-SII ≥970.5 × 10 9 /L were significantly worse than those with pre-SII <970.5 × 10 9 /L. Similarly, pre-SIRI ≥1.25 × 10 9 /L and pre-LDH ≥207.5 U/L were related to poor survival outcomes. CONCLUSIONS This study demonstrated that the baseline SII, SIRI, and LDH levels can be used to accurately and effectively predict the treatment outcomes after CCRT and long-term prognosis. Our results may offer additional prognostic information in clinical, which helps to detect the potential recurrent metastasis in time.
Humans ; Female ; Uterine Cervical Neoplasms/drug therapy* ; Middle Aged ; Adult ; Aged ; Chemoradiotherapy/methods* ; L-Lactate Dehydrogenase/blood* ; Treatment Outcome ; Disease-Free Survival ; Prognosis ; ROC Curve ; Biomarkers, Tumor/blood* ; Proportional Hazards Models

Humans ; Uterine Cervical Neoplasms/pathology* ; Female ; Patient Care Team ; Consensus ; China ; Neoplasm Staging ; Combined Modality Therapy ; Quality of Life ; Neoplasm Recurrence, Local/therapy* ; East Asian People

BACKGROUND: Hyperthermia (HT), while a cancer treatment approach, isn't always effective alone. Therefore, identifying hyperthermia enhancers is crucial. We demonstrated that Mito-TEMPO ([2-[(1-Hydroxy-2,2,6,6-tetramethylpiperidin-4-yl) amino]-2-oxoethyl]-triphenylphosphanium, MT) acts as a potent thermosensitizer, promoting cell death in human cervical cancer (HeLa) cells. METHODS: Cells were pretreated with 0.4 mM MT for 5 minutes, followed by exposure to hyperthermia (42 °C for 60 minutes). The impacts of MT/HT on cell viability, proliferation, apoptosis, endoplasmic reticulum (ER) stress, apoptosis-related proteins and autophagy, autophagy-related proteins expression were measured. The relationships between autophagy and apoptosis were further investigated using the specific autophagy inhibitor chloroquine (CQ) and the autophagy inducer rapamycin (Rapa). RESULTS: The combined treatment reduced the mitochondrial membrane potential (MMP) and increased ROS production. It also upregulated the pro-apoptotic protein Bax and downregulated anti-apoptotic proteins such as Bcl-2 and MCL-1. As a result, Caspase-3 was activated. Additionally, the combined treatment upregulated the expression of p-PERK/PERK, ATF-4, CHOP proteins. Moreover, the combined treatment also increased the expression of LC3 II and p62, decreased expression of LAMP 1 and Cathepsin D and increased lysosomal pH, indicating coordinated changes in autophagy regulation. Notably, intensification of apoptosis induced by the combined treatment was observed with CQ, whereas attenuation was seen with Rapa. CONCLUSIONS MT effectively enhanced HT-induced apoptosis in HeLa cells. Elevated ER stress and interruption of autophagy flux are the possible underlying molecular mechanisms for this phenomenon. These findings suggested MT can act as a potential thermosensitizer, highlighting its versatility in cancer treatment strategies.
Humans ; Apoptosis/drug effects* ; Autophagy/drug effects* ; HeLa Cells ; Uterine Cervical Neoplasms/therapy* ; Female ; Hyperthermia, Induced ; Spin Labels ; Endoplasmic Reticulum Stress/drug effects* ; Cyclic N-Oxides/pharmacology* ; Cell Survival/drug effects*

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.
Female ; Humans ; Uterine Cervical Neoplasms/drug therapy* ; Prospective Studies ; Quality of Life ; Neoplasm Staging ; Chemoradiotherapy ; Chemotherapy, Adjuvant/adverse effects* ; Adjuvants, Immunologic ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Retrospective Studies

OBJECTIVE: "Multi-targeting" drugs can prove fruitful to combat drug-resistance of multifactorial disease-cervical cancer. This study envisioned to reveal if Thuja homeopathic mother tincture (MT) and its bioactive component could combat human papillomavirus (HPV)-16-infected SiHa cervical cancer cells since it is globally acclaimed for HPV-mediated warts. METHODS: Thuja MT was studied for its antiproliferative and antimigratory properties in SiHa cells followed by microscopic determination of reactive oxygen species (ROS) generation by 2',7'-dichlorodihydrofluorescein diacetate (DCFDA) staining and loss in mitochondrial membrane potential (MtMP) by rhodamine 123 (Rh123) staining. Apoptosis and autophagy inductions were studied by acridine orange/ethidium bromide (AO/EB) staining and immunoblot analyses of marker proteins. The bioactive component of Thuja MT detected by gas chromatography-mass spectrometry was studied for antiproliferative and antimigratory properties along with in silico prediction of its cellular targets by molecular docking and oral drug forming competency. RESULTS: Thuja MT showed significant antiproliferative and antimigratory potential in SiHa cells at a 50% inhibitory concentration (IC₅₀) of 17.3 µL/mL. An increase in DCFDA fluorescence and loss in Rh123 fluorescence prove that Thuja MT acted through the burst of ROS and loss in MtMP respectively. AO/EB-stained cells under the microscope and immunoblot analyses supported Thuja-induced cellular demise via dual pathways-apoptosis and autophagy. Immunoblots showed cleavage of caspase-3 and poly(adenosine diphosphate-ribose) polymerase-1 (PARP-1) along with upregulation of Beclin-1, microtubule-associated protein 1 light chain 3B (LC3B)-II, and p62 proteins. Hence, the apoptotic cascade followed a caspase-3-dependent pathway supported by PARP-1 cleavage, while autophagic death was Beclin-1-dependent and mediated by accumulation of LC3BII and p62 proteins. Thujone, detected as the bioactive principle of Thuja MT, showed greater anti-proliferative and anti-migratory potential at an IC₅₀ of 77 µg/mL, along with excellent oral drug competency with the ability for gastrointestinal absorption and blood-brain-barrier permeation with nil toxicity. Molecular docking depicted thujone with the strongest affinity for mammalian target of rapamycin, phosphoinositide 3-kinase, and protein kinase B followed by B-cell lymphoma 2, murine double minute 2 and adenosine monophosphate-activated protein kinase, which might act as upstream triggers of apoptotic-autophagic crosstalk. CONCLUSION Robust "multi-targeting" anticancer potential of Thuja drug and thujone for HPV-infected cervical cancer ascertained its therapeutic efficacy for HPV infections.
Animals ; Apoptosis ; Autophagy ; Beclin-1/pharmacology* ; Bicyclic Monoterpenes ; Caspase 3 ; Cell Line, Tumor ; Female ; Humans ; Mammals/metabolism* ; Mice ; Molecular Docking Simulation ; Papillomavirus Infections/drug therapy* ; Phosphatidylinositol 3-Kinases ; Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use* ; Reactive Oxygen Species/metabolism* ; Thuja/metabolism* ; Uterine Cervical Neoplasms/pathology*

Objective: To systematically summarize and analyze the clinical research progress of therapeutic vaccines for cervical cancer or precancerous lesions. Methods: English databases (PubMed, Embase, Web of Science, Cochrane library, Proquest, and ClinicalTrails.gov) and Chinese databases (SinoMed, CNKI, WanFang, and VIP Database) were systematically searched to collect literature on therapeutic vaccines for cervical cancer or precancerous lesions from inception to February 18, 2021. After screening, we evaluated the risk of bias of included studies, and combed the basic information of the literature, research designs, information of vaccines, study patients, outcome indicators and so on, qualitatively summarized the clinical research progress. Results: A total of 71 studies were included in this systematic review, including 14 random controlled trials, 15 quasi-random controlled trials, 4 cohort studies, 1 case-control study, 34 case series studies and 3 case reports. The study patients included women aged 15~79 with cervical cancer or precancerous lesions in 18 countries from 1989 to 2021. On the one hand, there were 40 studies on therapeutic vaccines for cervical precancerous lesions (22 867 participants), involving 21 kinds of vaccines in 6 categories. Results showed 3 marketed vaccines (Cervarix, Gardasil, Gardasil 9) as adjuvant immunotherapies were significant effective in preventing the recurrence of precancerous lesions compared with the conization only. In addition, MVA E2 vaccine had been in phase Ⅲ clinical trials as a specific therapeutic vaccine, with relative literature showing it could eliminate most high-grade precancerous lesions. Therapeutic vaccines for precancerous lesions all showed good safety. On the other hand, there were 31 studies on therapeutic vaccines for cervical cancer (781 participants), involving 19 kinds of vaccines in 7categories, with none had been marketed. 25 studies were with no control group, showing the vaccines could effectively eliminate solid tumors, prevent recurrence, and prolong the median survival time. However, the vaccines effectiveness couldn't be statistically calculated due to the lack of a control group. As for the safety of therapeutic vaccines for cervical cancer, 9 studies showed that patients experienced serious adverse events after treatments, where 7 studies reported that serious adverse events occurred in patients couldn't be ruled out as the results of therapeutic vaccines. Conclusions: The literature review shows that the literature evidence for the therapeutic vaccines for cervical precancerous lesions is relatively mature compared with the therapeutic vaccines for cervical cancer. The four kinds of vaccines on the market are all therapeutic vaccines for precancerous lesions, but they are generally used as vaginal infection treatments or adjuvant immunotherapies for cervical precancerous lesions, not used for the specific treatments of cervical precancerous lesions. Other specific therapeutic vaccines are in the early stage of clinical trials, mainly phase Ⅰ/Ⅱ clinical trials with small sample size. The effectiveness and safety data are limited, and further research is still needed.
Cancer Vaccines/therapeutic use* ; Cervical Intraepithelial Neoplasia/prevention & control* ; Female ; Humans ; Papillomavirus Infections/prevention & control* ; Papillomavirus Vaccines/therapeutic use* ; Precancerous Conditions/therapy* ; Uterine Cervical Neoplasms/prevention & control*

BACKGROUND: Recently, T-helper 17 (Th17) cells have been proved to play an important role in promoting cervical cancer. But, till now, few study has been carried out to understand the involvement of these cells in efficacy of anti-tumor treatments. This study aimed to investigate the alterations in the percentage of circulating Th17 cells and related cytokines in locally advanced cervical cancer (LACC) patients before and after concurrent chemoradiotherapy (cCRT) and to analyze the correlations between the alterations in Th17 cells and treatment efficacy. METHODS: A prospective study with 49 LACC (International federation of gynecology and obstetrics [FIGO] stage IIB-IIIB) patients and 23 controls was conducted. Patients received the same cCRT schedule and were followed up for 3 years. Circulating Th17 cells (CD3+CD8- interleukin [IL]-17+ T cells) and related cytokines IL-17, transforming growth factor-β (TGF-β), IL-10, IL-23, IL-6, and IL-22 were detected before and after cCRT. Correlations between alterations of circulating Th17 cells and treatment efficacy were analyzed. Kaplan-Meier analysis was used for overall survival (OS) and progression-free survival (PFS). RESULTS: We found that 40 patients finished the entire cCRT schedule and met the endpoint of this study. The percentage of circulating Th17 cells in the LACC patients was higher than that in the controls, and it significantly decreased after cCRT (P < 0.05). After cCRT, patients were divided into two groups based on the average of the Th17 cells declined. The subgroup of patients with a prominent decrease in circulating Th17 cells after cCRT had a higher treatment efficacy and longer PFS and OS times. Compared with the control patients, LACC patients had higher IL-6, IL-10, IL-22, TGF-β levels and a lower IL-23 level (P < 0.05). After cCRT, IL-6, IL-10, IL-17, IL-23 level significantly increased and TGF-β level significantly decreased compared with the levels before cCRT (P < 0.05). CONCLUSION Circulating Th17 cells in the LACC patients (FIGO stage IIB-IIIB) were higher than those in the controls, but they generally decreased after cCRT. A more pronounced decrease in circulating Th17 cells after cCRT was correlated with better therapeutic effect and longer PFS and OS times.
Chemoradiotherapy ; Disease-Free Survival ; Female ; Humans ; Neoplasm Staging ; Prospective Studies ; Retrospective Studies ; Th17 Cells ; Treatment Outcome ; Uterine Cervical Neoplasms/therapy*

The paclitaxel-loaded and folic acid-modified poly(lactic-co-glycolic acid) nano-micelles(PTX@FA-PLGA-NMs) were prepared by the emulsion solvent evaporation method, and the parameters of paclitaxel-loaded nano-micelles were optimized with the particle size and PDI as evaluation indexes. The morphology of the nano-micelles was observed by transmission electron microscopy(TEM), and the stability, drug loading and encapsulation efficiency were systematically investigated. In vitro experiments were performed to study the cytotoxic effects of nano-micelles, apoptosis, and cellular uptake. Under the optimal parameters, the nano-micelles showed the particle size of(125.3±1.2) nm, the PDI of 0.086±0.026, the zeta potential of(-20.0±3.8) mV, the drug loading of 7.2%±0.75%, and the encapsulation efficiency of 50.7%±1.0%. The nano-micelles were in regular spherical shape as observed by TEM. The blank FA-PLGA-NMs exhibited almost no inhibitory effect on the proliferation and growth of tumor cells, while the drug-loaded nano-micelles and free PTX exhibited significant inhibitory effects. The IC_(50) of PTX@FA-PLGA-NMs and PTX was 0.56 μg·mL~(-1) and 0.66 μg·mL~(-1), respectively. The paclitaxel-loaded nano-micelles were potent in inhibiting cell migration as assessed by the scratch assay. PTX@FA-PLGA-NMs had good pro-apoptotic effect on cervical cancer HeLa cells and significantly promoted the uptake of HeLa cells. The results of in vitro experiments suggested that PTX@FA-PLGA-NMs could target and treat cervical cancer HeLa cells. Therefore, as nanodrug carriers, PTX@FA-PLGA-NMs with anti-cancer activity are a promising nano-system for improving the-rapeutic effects on tumors.
Antineoplastic Agents, Phytogenic/pharmacology* ; Cell Line, Tumor ; Drug Carriers ; Female ; Folic Acid ; Glycolates ; HeLa Cells ; Humans ; Micelles ; Paclitaxel ; Particle Size ; Uterine Cervical Neoplasms/drug therapy*

Cervical cancer (CC) is recognized as the most common neoplasm in the female reproductive system worldwide. The lack of chemotherapeutic agents with outstanding effectiveness and safety severely compromises the anti-cipated prognosis of patients. Aloperine (ALO) is a natural quinolizidine alkaloid with marked anti-cancer effects on multiple malignancies as well as favorable activity in relieving inflammation, allergies and infection. However, its therapeutic efficacy and underlying mechanism in CC are still unclear. In the current study, MTT assay was employed to evaluate the viability of HeLa cells exposed to ALO to preliminarily estimate the effectiveness of ALO in CC. Then, the effects of ALO on the proliferation and apoptosis of HeLa cells were further investigated by plate colony formation and flow cytometry, respectively, while the migration and invasion of ALO-treated HeLa cells were evaluated using Transwell assay. Moreover, nude mice were subcutaneously inoculated with HeLa cells to demonstrate the anti-CC properties of ALO in vivo. The molecular mechanisms underlying these effects of ALO were evaluated by Western blot and immunohistochemical analysis. This study experimentally demonstrated that ALO inhibited the proliferation of HeLa cells via G2 phase cell cycle arrest. Simultaneously, ALO promoted an increase in the percentage of apoptotic HeLa cells by increasing the Bax/Bcl-2 ratio. Additionally, the migration and invasion of HeLa cells were attenuated by ALO treatment, which was considered to result from inhibition of epithelial-to-mesenchymal transition. For molecular mechanisms, the expression and activation of the IL-6-JAK1-STAT3 feedback loop were markedly suppressed by ALO treatment. This study indicated that ALO markedly suppresses the proliferation, migration and invasion and enhances the apoptosis of HeLa cells. In addition, these prominent anti-CC properties of ALO are associated with repression of the IL-6-JAK1-STAT3 feedback loop.
Animals ; Apoptosis ; Cell Line, Tumor ; Cell Movement ; Cell Proliferation ; Feedback ; Female ; HeLa Cells ; Humans ; Interleukin-6/genetics* ; Janus Kinase 1 ; Mice ; Mice, Nude ; Quinolizidines ; STAT3 Transcription Factor/genetics* ; Signal Transduction ; Uterine Cervical Neoplasms/drug therapy*

cervical cancer in patients who have already received more than two kinds of comprehensive treatment.METHODS: Forty-eight patients with recurrent or metastatic cervical cancer after radiotherapy or surgery who received apatinib between June 2016 and June 2017 were involved in this study. These patients experienced progression after first-line or second-line chemotherapy. There were 38 patients with cervical squamous cell carcinoma, 8 with adenocarcinoma, and 2 with adenosquamous carcinoma. Progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (AEs) were reviewed and evaluated.RESULTS: All patients had complete follow-up records, and the median follow-up time was 14.5 months (5.5–20.5 months). Among the 48 patients, 14.58% achieved a partial response and 52.08% achieved stable disease. The overall response rate and disease control rate were 14.58% and 66.67%, respectively. The median time that the 48 patients received oral apatinib was 8.2 months. The median PFS was 4.6 months (95% confidence interval [CI]=3.31–5.26) and OS was 13.9 months (95% CI=8.37–17.96). The main apatinib-related adverse reactions were leukopenia (37.5%), neutropenia (41.67%), hemorrhage (37.5%), hypertension (33.33%), proteinuria (12.5%), fatigue (37.5%), and hand-foot syndrome (27.08%). Most of them were grade 1–2, and no drug-related death occurred.CONCLUSIONS: Apatinib can improve the disease control rate of recurrent and metastatic cervical cancer when chemotherapy has failed, and the treatment is well tolerated. This represents that apatinib may be a new treatment option for metastatic cervical cancer patients.]]>
Adenocarcinoma ; Carcinoma, Adenosquamous ; Carcinoma, Squamous Cell ; Disease-Free Survival ; Drug Therapy ; Drug-Related Side Effects and Adverse Reactions ; Fatigue ; Follow-Up Studies ; Hand-Foot Syndrome ; Hemorrhage ; Humans ; Hypertension ; Leukopenia ; Molecular Targeted Therapy ; Neutropenia ; Proteinuria ; Radiotherapy ; Retrospective Studies ; Uterine Cervical Neoplasms