BackgroundAdvanced cervical cancer (aCC) is associated with a poor prognosis for patients. While immune checkpoint inhibitors (ICIs) have demonstrated potential therapeutic benefits, their effectiveness can be hindered by inherent resistance mechanisms and the onset of immune-related adverse events (irAEs). The strategy of combining ICIs with anti-angiogenic agents has gained traction as a potentially effective treatment approach. Nonetheless, there is a notable absence of robust, systematic evidence to confirm the efficacy and safety of this combination specifically for aCC patients.MethodsWe conducted a thorough search of relevant studies across multiple databases, including PubMed, Embase, Cochrane Library, Web of Science, and Scopus. We extracted key outcome measures, such as overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs) for further analysis.ResultsThe analysis included three randomized controlled trials (RCTs;all evaluating first-line treatment for persistent, recurrent, or metastatic cervical cancer) and eight single-arm trials(predominantly later-line or mixed-line settings), encompassing a total of 1, 491 patients. The meta-analysis revealed that in RCTs, ICIs significantly improved OS, decreasing the risk of death by 16% (hazard ratio [HR] = 0.84, 95% confidence interval [CI]:0.78-0.91, P <0.001), and enhanced PFS, reducing the risk of disease progression by 18% (HR = 0.82, 95% CI:0.77-0.88, P <0.001). The combination group exhibited a higher objective response rate (ORR, risk ratio [RR] = 1.19, 95% CI:1.10-1.30, P <0.001) compared to the control group. Findings from single-arm studies provided supportive exploratory evidence, showing a pooled ORR of 0.57 (95% CI: 0.46-0.68).Safety profiles were generally acceptable in RCTs, but the absolute rate of severe toxicity in single−arm studies was substantial (51% grade ≥3).Sensitivity analyses affirmed the robustness of the OS results (I² = 0%), with a stable ORR despite observed heterogeneity.ConclusionPooled analysis of first-line RCTs indicates that combining ICIs with anti-angiogenic agents and chemotherapy demonstrates promising efficacy and a manageable safety profile in persistent, recurrent, or metastatic cervical cancer. However, vigilant monitoring and prompt management of immune therapy-related adverse events are crucial for patient safety.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO, identifier CRD420251050867.

Cervical cancer (CC) ranks the fourth most common malignancies and its burden is increasingly affecting younger women. However, the correlation between age and CC prognosis is still uncertain. This retrospective study aims to analyze the efficacy and safety of definitive volumetric modulated arc therapy (VMAT) combined with adaptive brachytherapy (BT) with or without concurrent chemotherapy in CC patients of different age groups. Totally 541 CC patients diagnosed from 2014 to 2019 in our institution were enrolled and classified into 3 groups: the youth (18–44 years old), the middle-aged (45–59 years old) and the elderly ( ≥ 60 years old). Clinical outcomes including locoregional control (LC), progression-free survival (PFS), overall survival (OS) and distant metastasis-free survival (DMFS) were analyzed. Toxicities graded by the Common Terminology Criteria for Adverse Events (CTCAE, version 5.0) including hematologic, gastrointestinal and urinary toxicities were analyzed. Comparison among three groups was conducted by χ ^2 test and Fisher’s exact test before and after 1:1:1 ratio propensity score matching (PSM). The median follow-up time was 65 months. Of 541 CC patients, the age-standardized 5-year rates for OS, PFS, LC and DMFS were 83.2

Background and purpose:Adaptive radiotherapy (ART) manages anatomical variations through real-time plan adjustments. Herein, we aimed to evaluate the efficacy of ART in improving target coverage and reducing organ-at-risk (OAR) irradiation doses in cervical cancer. Materials and methods:A prospective single-arm study enrolled 15 patients with cervical cancer. Participants received definitive chemoradiotherapy (45-50 Gy/25Fractions) using cone-beam computed tomography-guided online ART workflow. Endpoints included geometric miss volume (target volume underdosed), planning target volume (PTV) coverage (V100%), OAR sparing (generalized equivalent uniform dose [gEUD] and normal tissue complication probability [NTCP]), and dose homogeneity/conformity parameters (coefficient of variation [CV], Paddick Index [PI]). Mixed-effects models compared ART and simulated image-guided radiotherapy (IGRT) plans, with Wilcoxon signed-rank and Mann-Whitney U tests for statistical analysis. Results:Among 375 adaptive sessions, ART outperformed IGRT, reduced geometric miss volume by 85.1% (0.28 cm3 vs. 1.88 cm3; P < 0.001) and achieved V100% ≥ 99% in 99.2% of fractions (vs. 75.0% with IGRT; P < 0.001). ART improved PTV dose homogeneity (median CV: -0.29% vs. 3.89%; P < 0.001) and conformity (median PI: 0.75 vs. 0.60; P < 0.001). Additionally, ART reduced rectum gEUD by 4.39% (P < 0.001) and NTCP by 52.27% (P < 0.001), with similar benefits for other OARs (P < 0.001). ART maintained robustness against intrafractional anatomical changes, with minimal target coverage loss and stable OAR doses despite bladder/rectum volume fluctuations. Patients exhibited 100% complete response and mild acute side effects (no grade ≥ 3 enteritis; no cystitis). Conclusions:Online ART with 3-mm isotropic margins is feasibile for cervical cancer, achieved high target coverage while reduced OAR doses and NTCP.

This study evaluated the therapeutic effect of a third-generation intracavitary interstitial brachytherapy (IC-ISBT) technique combined with a source applicator template for locally advanced cervical cancer. This retrospective study examined 113 patients with stage IB3-IVB disease admitted to Sun Yat-sen University Cancer Center between January 2023 and January 2024. The high-risk clinical target area was defined based on residual tumor after external irradiation, and a third-generation IC-ISBT source donor template was developed. We compared the dosimetry and efficacy of the donor template (template interpolation group) and traditional manual implantation method (manual interpolation group) for treating cervical cancer. Regarding dosimetry coverage, the template group differed significantly from the freehand group, showing better target suitability (index) and dose coverage (V100%) (both P < 0.01). Simultaneously, the template protected the rectum and sigmoid colon, potentially reducing the high-dose areas (D0.1 cm³). However, the primary cervical remission rates did not differ significantly between groups. The study findings indicate that the design of the third-generation IC-ISBT applicator template was scientific and reasonable, especially for patients with large tumor volumes and late-stage disease. It is easy to operate and highly reproducible, proving beneficial for dose distribution and protecting surrounding key structures.

Purpose This study evaluated the safety and efficacy of polyethylene glycol (PEG) hydrogels in reducing rectal radiation dose and complication during cervical cancer radical concurrent chemoradiation therapy. Methods and Materials This phase 3, randomized, parallel-controlled trial (NCT 05690906) conducted across 9 centers in China (July 2022-January 2025). Participants were randomly assigned 1:1 to receive a 10 mL PEG hydrogel injection (experimental group) or no injection (control group) after 50.4 Gy/28 fractions (f) or 45 Gy/25 f external beam radiation therapy. Three-dimensional image guided brachytherapy plans were developed before each brachytherapy session using computed tomography or magnetic resonance imaging (MRI) imaging, delivered in a prescribed dose of 6 Gy × 5 f or 7 Gy × 4 f. Concurrent chemotherapy was administered during the radiation therapy course. Patients were followed up for 72 weeks. The primary endpoint was the cumulative rectal D2cc dose. Secondary endpoints included rectal D0.1cc and D5cc doses and D2cc of the sigmoid, bladder, and small intestine; changes in the perirectal space and hydrogel volume; quality of life (QOL) scores (QLQ-C30 and QLQ-CX24); and incidence of radiation-induced rectal complication. QOL was assessed before brachytherapy, immediately after completing brachytherapy, and at 4, 12, 24, 36, 48, and 72 weeks after brachytherapy. Radiation-induced rectal complication was assessed at each of the aforementioned follow-up timepoints and additionally evaluated on a weekly basis throughout the entire radiation therapy course. Results Of 94 analyzed patients (45 experimental and 49 control), the experimental group showed significant reductions in rectal D2cc (64.23 ± 6.58 Gy vs 69.79 ± 6.10 Gy; P < .001), D0.1cc (74.67 ± 12.22 Gy vs 84.38 ± 9.91 Gy; P < .001), and D5cc (60.23 ± 4.96 Gy vs 63.18 ± 5.04 Gy; P = .003) doses, with no significant changes in doses to other organs The hydrogel increased the cervix-rectum distance during brachytherapy and remained stable until 24 weeks after treatment, with noticeable absorption occurring between weeks 24 and 36. No significant differences were observed between experimental group and control group in acute radiation-induced rectal injuries (55.6% vs 46.9%), chronic injuries (9.5% vs 16.7%), or QOL scores, except for higher constipation scores and symptom experience scores in the experimental group. One case (2.2%) of rectovaginal fistula occurred in the experimental group, with no other grade ≥3 adverse events observed. Conclusions PEG hydrogel injection effectively reduced rectal radiation dose during cervical cancer radical concurrent chemoradiation therapy without increasing doses to other organs, preserving overall safety and QOL despite transient QOL variations and an isolated rectovaginal fistula.

Endometrial cancer (EC) is the sixth most common cancer in women worldwide, with an increasing incidence rate in China. Radiotherapy (RT) is important for the treatment of EC, especially for high risk or advanced stage tumors. The Brachytherapy Committee of China Anti-Cancer Association (CACA) organized relevant experts to develop this guideline and provide evidence-based RT recommendations tailored to China’s epidemiological and clinical landscape. Highlighting key updates in molecular subtyping and the revised 2023 FIGO staging system, this portion of the CACA Guidelines for EC emphasizes personalized strategies across disease stages and details protocols for postoperative settings (radical resection, incomplete staging), recurrent/metastatic disease, and palliative care. By consolidating contemporary practices and regional data, this framework aims to standardize RT delivery, and improve survival outcomes while minimizing toxicities. We hope that this guideline will provide effective references for radiation oncologists, so as to achieve the best radiation treatment effects for EC patients in China.

In persons living with HIV, antiretroviral therapy (ART) reduces HIV RNA in their plasma and increases CD4 + T lymphocytes, thus restoring their immune function and reducing mortality rates. The heavy and light chains of B cell receptor (BCR) were amplified, sequenced, analyzed, and determined to be anti-CD4 mAb. The cytotoxicity of NK cells mediated by the anti-CD4 mAb was assessed using CCK-8, flow cytometry, ELISA, and western blotting. Detecting the viability/regulation of CD4 cells involved inhibiting the attachment of autoantibodies against CD4 to crucial receptors and detecting the inhibition of key molecules in B cells to produce anti-CD4 mAb in patients with immune non-responders (INR). Furthermore, through Phage Random Peptide Library Screening, we discovered that the AAPMFHSSVQLP-CD4 peptide has an affinity for the anti-CD4 mAb. Administering anti-CD4 mAb enhanced NK cytotoxicity. The simultaneous administration of anti-CD4 mAb alongside GST-CD4 alleviated the harmful impacts of anti-CD4 mAb on the CD3 + population in humanized mice, and HIV virus (p24). Individuals diagnosed with INR displayed abnormal B cell activity, particularly with elevated BAFFR expression and increased levels of anti-CD4 mAb. Nevertheless, suppression of BAFFR hindered B cell function and decreased the production of anti-CD4 mAb. In HIV-infected individuals, the dysregulation of B-cells led to the production of anti-CD4 mAb, which in turn facilitated NK cell cytotoxicity and the CD4 + T effect by upregulating the expression of BAFFR. The dysregulation of B-cells in person living with HIV increased the production of anti-CD4 mAb, which in turn promoted NK cell cytotoxicity and the CD4 + T effect. 1) B-cell dysregulation increased anti-CD4 mAb levels. 2) B cells are abnormally active in patients with INR. 3) Knockdown of BAFFR obviously reduced the secretion of anti-CD4 mAb.

Cervical cancer metastasis is characterized by the systemic spread of tumor cells. However, the underlying mechanism remains incompletely understood. Herein, we demonstrate that RAB33A promoted metastasis by enhancing RhoC accumulation and that higher RAB33A expression predicted poorer prognosis in patients with cervical cancer. Mechanistically, RhoC typically degraded via canonical autophagy due to the binding of two LIR motifs (LC3 interaction region) in RhoC to LC3; however, RAB33A induced non-canonical autophagy, resulting in RhoC stabilization, which facilitated pseudopodia formation and consequently cervical cancer metastasis. The fusion of RAB33A-induced autophagosomes with lysosomes was impaired, as RAB33A inactivated RAB7 by interacting with TBC1D2A, a GTPase-activating protein that targets RAB7. Our findings reveal a pivotal role of the RAB33A-RhoC axis in cervical cancer metastasis, indicating that RhoC inhibitors may be beneficial for treating cervical cancer patients with high levels of RAB33A.

Background:Clear cell adenocarcinoma of the cervix (CCAC) is a rare malignancy without a well-established prognostic model. Our study aimed to develop and validate a nomogram to estimate overall survival in CCAC patients. Methods:We collected data on 630 CCAC patients from the Surveillance, Epidemiology, and End Results (SEER) database (2000-2021). Missing clinicopathological data were imputed using the missForest package. The imputed dataset served as the training cohort, while the dataset with missing values removed acted as the validation cohort. The nomogram's performance was assessed through discriminative ability, calibration, C-index, AUC, and calibration plots. Clinical benefits were compared against the International Federation of Gynecology and Obstetrics (FIGO) staging using decision curve analysis (DCA), net reclassification index (NRI), and integrated discrimination improvement (IDI). Results:The nomogram, based on nine variables, demonstrated strong discriminative power, with C-index values of 0.82 for the training cohort and 0.81 for the validation cohort, and AUCs exceeding 0.80 in both sets. Calibration plots showed a strong agreement between the nomogram's predictions and actual outcomes in both cohorts. The NRI values for the training set were 0.21 for 3-year, 0.20 for 5-year, and 0.30 for 10-year overall survival (OS) predictions, and for the validation set were 0.34 for 3-year, 0.25 for 5-year, and 0.31 for 10-year OS predictions. The IDI results for the training set were 0.17 across 3-, 5-, and 10-year OS predictions, and for the validation set were 0.21 for 3-year, 0.17 for 5-year, and 0.15 for 10-year OS predictions. The nomogram significantly outperformed the FIGO criteria (p < 0.01), and DCA highlighted its superior clinical utility in identifying high-risk patients. Conclusion:The nomogram, which integrates treatment data, was successfully developed and validated to assist clinicians in assessing the prognosis of CCAC patients. It demonstrated superior performance to FIGO criteria in predicting overall survival.

To identify the hub genes that associated with chemo-radiotherapy sensitivity for cervical cancer and to explore the relationship between hub genes and various cellular processes and potential mechanism of cervical cancer. The gene expression data of 21 patients with CESC and the mRNA expression profiles of 296 patients with CESC were obtained from the Gene Expression Omnibus(GEO) and The Cancer Genome Atlas (TCGA) databases, respectively. The potential functions and regulatory mechanisms of differentially expressed genes (DEGs) were identified using GO and KEGG enrichment analyses. Hub genes were identified using random survival forest analysis. The relationship between hub genes and various cellular processes was comprehensively analyzed. The expression of hub genes was assessed using clinical data extracted from the Human Protein Atlas (HPA) database. A total of 139 and 13 DEGs were found to be upregulated and downregulated, respectively, in CESC. The six hub genes, namely, SELP, PIM2, CCL19, SDS, NRP1, and SF3A2, were significantly correlated with immune cell infiltration, chemotherapy sensitivity, disease-related genes, and enriched signaling pathways (all p-value < 0.05). A nomogram and calibration curve were generated using the six hub genes to predict prognosis with high accuracy. A regulatory network comprising TFs (ZBTB3) and mRNAs (NRP1/PIM2/SELP) and several competitive endogenous RNA (ceRNA) networks comprising mRNAs, miRNAs, and lncRNAs were constructed. Data from HPA indicated that the protein expression of the six hub genes differed significantly between patients with CESC and healthy individuals. Upregulation of SELP, PIM2, CCL19, SDS, NRP1, and SF3A2 is associated with radiotherapy sensitivity and is involved in various cellular processes in CESC. These six genes may serve as biomarkers for predicting the radiotherapy response and prognosis in patients with CESC.

Platinum resistance represents a major barrier to the survival of patients with ovarian cancer (OC). Cdc2-like kinase 2 (CLK2) is a major protein kinase associated with oncogenic phenotype and development in some solid tumors. However, the exact role and underlying mechanism of CLK2 in the progression of OC is currently unknown. Using microarray gene expression profiling and immunostaining on OC tissues, we found that CLK2 was upregulated in OC tissues and was associated with a short platinum-free interval in patients. Functional assays showed that CLK2 protected OC cells from platinum-induced apoptosis and allowed tumor xenografts to be more resistant to platinum. Mechanistically, CLK2 phosphorylated breast cancer gene 1 (BRCA1) at serine 1423 (Ser1423) to enhance DNA damage repair, resulting in platinum resistance in OC cells. Meanwhile, in OC cells treated with platinum, p38 stabilized CLK2 protein through phosphorylating at threonine 343 of CLK2. Consequently, the combination of CLK2 and poly ADP-ribose polymerase inhibitors achieved synergistic lethal effect to overcome platinum resistance in patient-derived xenografts, especially those with wild-type BRCA1. These findings provide evidence for a potential strategy to overcome platinum resistance in OC patients by targeting CLK2.

Concrete filled steel tube columns (CFSTCs) are commonly used in large-span bridges and high-rise buildings. As the shrinkage of concrete may lead to significant degradation in the mechanical performance of CFSTCs, expansive concrete or fibre reinforced concrete is usually employed to improve the mechanical performance of CFSTCs. This study presents an experimental study on the combined effects of expansive agents and steel fibres on the axial compressive behaviour of circular CFSTCs. 13 CFSTCs were designed and manufactured using concrete mixes with varying expansive agent rates and steel fibre contents. The time-dependent expansive behaviours of the specimens were monitored during the concrete curing period. Then, the 13 specimens were tested under axial compression load. The failure modes, compression load-axial strain relationship, hoop strain and axial strain relationship, and ductility were investigated. The results demonstrated that the combined addition of expansive agents and steel fibres would substantially improve the compressive strength and ductile behaviour of CFSTCs.

ABSTRACT Background Highly heterogeneity and inconsistency in terms of prognosis are widely identified for early‐stage cervical cancer (esCC). Herein, we aim to investigate for an intuitional risk stratification model for better prognostication and decision‐making in combination with clinical and pathological variables. Methods We enrolled 2071 CC patients with preoperative biopsy‐confirmed and clinically diagnosed with FIGO stage IA‐IIA who received radical hysterectomy from 2013 to 2018. Patients were randomly assigned to the training set (n = 1450) and internal validation set (n = 621), in a ratio of 7:3. We used recursive partitioning analysis (RPA) to develop a risk stratification model and assessed the ability of discrimination and calibration of the RPA‐derived model. The performances of the model were compared with the conventional FIGO 2018 and 9th edition T or N stage classifications. Results RPA divided patients into four risk groups with distinct survival: 5‐year OS for RPA I to IV were 98%, 95%, 85.5%, and 64.2%, respectively, in training cohort; and 99.5%, 93.2%, 85%, and 68.3% in internal validation cohort (log‐rank p < 0.001). Calibration curves confirmed that the RPA‐predicted survivals were in good agreement with the actual survivals. The RPA model outperformed the existing staging systems, with highest AUC for OS (training: 0.778 vs. 0.6–0.717; internal validation: 0.772 vs. 0.595–0.704; all p < 0.05), and C‐index for OS (training: 0.768 vs. 0.598–0.707; internal validation: 0.741 vs. 0.583–0.676; all p < 0.05). Importantly, there were associations between RPA groups and the efficacy of treatment regimens. No obvious discrepancy was observed among different treatment modalities in RPA I (p = 0.922), whereas significant survival improvements were identified in patients who received adjuvant chemoradiotherapy in RPA II–IV (p value were 0.028, 0.036, and 0.024, respectively). Conclusion We presented a validated novel clinicopathological risk stratification signature for robust prognostication of esCC, which may be used for streamlining treatment strategies.

5533 Background: Immunotherapy in combination with chemoradiotherapy has shown good efficacy in locally advanced cervical cancer (LACC). We report on the efficacy of neoadjuvant camrelizumab plus chemotherapy (TP) following concurrent immuno-chemoradiotherapy and maintenance immunotherapy for LACC. Methods: Eligible participants were adults with histologically confirmed squamous cell carcinoma, adenosquamous cell carcinoma, or adenocarcinoma of the cervix (FIGO 2018 stage IIB-IVA disease), ECOG PS score 0-2, and adequate bone marrow and organ function. All pts received 2 cycles neoadjuvant camrelizumab (200 mg d1 q3w) plus TP (albumin-bound Paclitaxel 260mg/m2 d1 q3w; cisplatin 75 mg/m2 d1-3 q3w) treatment, following 5-week external beam radiotherapy (EBRT) protocol (45-50 Gy/25 fractions with concurrent triweekly camrelizumab and cisplatin) to the whole pelvis plus brachytherapy every 3 weeks for 2 cycles, and then maintenance therapy of camrelizumab (200mg q3w, up to one year). The primary endpoint was progression-free survival (PFS) at 2 years. PFS was evaluated when at least 13 events were observed using a stratified log-rank test with an overall one-sided significance level of 0.05. Results: 67 pts provided informed consent and 12 were excluded for not meeting eligibility. 55 pts received the investigational agent and were evaluable for safety and efficacy analyses. The median age was 54 years [IQR 50 to 60]; 51 [92.7%] were squamous cell carcinoma, and 4 [7.3%] were adenocarcinoma; 9 [16.4%] were stage IIB, 2 [3.6%] were IIIA, 5 [9.1%] were IIIB, 30 [54.5%] were IIIC1r, 6 [10.9%] were IIIC2r, and 3 [5.5%] were IVA. As of data cutoff (Jan. 15, 2024), median follow-up was 9.5 (IQR 7.1 to 10.3) months. Of the 55 pts, 1 (1.8%) pt underwent hysterectomy after EBRT because of pelvic empyema, and was excluded from response evaluation. At three months after brachytherapy, the overall remission rate was 100% (53 [98.1%] complete remission and 1 [1.9%] partial remission). We identified 3 (5.5%) pts with treatment failure (2 [3.6] distant metastasis, and 1 [(1.8%] para-aortic lymph node relapse) during follow-up; 1-year PFS was 90.6% (85.4%-95.8%). The most common clinically significant grade 3-4 adverse events (AEs) were decreased neutrophils (18.2%), thrombocytopenia (9.1%) and anemia (27.3%). Serious AEs occurred in 7 (12.7%), most commonly due to infectious complications. There were no treatment-related deaths. Conclusions: The interim data support Camrelizumab plus TP neoadjuvant chemo-immunotherapy following immuno-chemoradiotherapy and Camrelizumab maintenance therapy as an active go-forward regimen in LACC. No new safety signals were observed, and most AEs were mild to moderate. Clinical trial information: ChiCTR2200061097.

Abstract Background This study aimed to assess the impact of coronavirus disease 2019 (COVID-19) on hospital service utilization and revenue in Chinese tertiary hospitals and develop an optimal pandemic control strategy (OPCS) for the peak period of the Omicron wave. Methods Retrospective data from three Chinese tertiary hospitals (provincial, city, and county level) were analyzed for three phases: pre-outbreak (Jan-Apr 2019), outbreak (Jan-Apr 2020), and post-outbreak (Jan-Apr 2021). OPCS was developed under the guidance of the China government pandemic control policy during post-break phase of COVID-19. A decision-tree model was constructed to compare OPCS to strict pandemic control strategy during outbreak phase for the hospital service utilization and hospital revenue in a provincial tertiary hospital during the Omicron wave. Results Outpatient, emergency room (ER) visits, hospitalizations, and intensive care admissions dropped by 33.8–53.4% during the outbreak, with the provincial hospital being the most affected. Hospital revenue also declined, especially for the provincial hospital (40.1%). Post-outbreak, most services recovered, but ER visits remained lower (11.6% decrease for provincial hospital, 46.5% for county hospital). Total income and expenditure decreased, with the provincial hospital experiencing the most significant revenue reduction (45.7%). OPCS showed greater utilization of medical services (31.6 times more outpatient visits; 1.7 times more inpatient days; 3.4% more surgery volume) and higher revenue (¥220.8 million more) compared to the strict pandemic control strategy. Conclusions COVID-19 measures were associated with less hospital service utilization and revenue in Chinese tertiary hospitals. The developed OPCS in Chinese tertiary hospitals, focusing on isolating infected inpatients but not shutting down the hospital facilities exposed to virus, could be effective in optimizing hospital service utilization and hospital revenue during the Omicron wave.

Background Many urothelial bladder carcinoma (UBC) patients don’t respond to immune checkpoint blockade (ICB) therapy, possibly due to tumor-associated neutrophils (TANs) suppressing lymphocyte immune response. Methods We conducted a meta-analysis on the predictive value of neutrophil-lymphocyte ratio (NLR) in ICB response and investigated TANs’ role in UBC. We used RNA-sequencing, HALO spatial analysis, single-cell RNA-sequencing, and flow cytometry to study the impacts of TANs and prostaglandin E2 (PGE2) on IDO1 expression. Animal experiments evaluated celecoxib’s efficacy in targeting PGE2 synthesis. Results Our analysis showed that higher TAN infiltration predicted worse outcomes in UBC patients receiving ICB therapy. Our research revealed that TANs promote IDO1 expression in cancer cells, resulting in immunosuppression. We also found that PGE2 synthesized by COX-2 in neutrophils played a key role in upregulating IDO1 in cancer cells. Animal experiments showed that targeting PGE2 synthesis in neutrophils with celecoxib enhanced the efficacy of ICB treatment. Conclusions TAN-secreted PGE2 upregulates IDO1, dampening T cell function in UBC. Celecoxib targeting of PGE2 synthesis represents a promising approach to enhance ICB efficacy in UBC.

Cervical cancer is the most common gynecologic cancer, etiologically related to persistent infection of human papillomavirus (HPV). Both the host innate immunity system and the invading HPV have developed sophisticated and effective mechanisms to counteract each other. As a central innate immune sensing signaling adaptor, stimulator of interferon genes (STING) plays a pivotal role in antiviral and antitumor immunity, while viral oncoproteins E7, especially from HPV16/18, are responsible for cell proliferation in cervical cancer, and can inhibit the activity of STING as reported. In this report, we find that activation of STING-TBK1 (TANK-binding kinase 1) promotes the ubiquitin-proteasome degradation of E7 oncoproteins to suppress cervical cancer growth. Mechanistically, TBK1 is able to phosphorylate HPV16/18 E7 oncoproteins at Ser71/Ser78, promoting the ubiquitination and degradation of E7 oncoproteins by E3 ligase HUWE1. Functionally, activated STING inhibits cervical cancer cell proliferation via down-regulating E7 oncoproteins in a TBK1-dependent manner and potentially synergizes with radiation to achieve better effects for antitumor. Furthermore, either genetically or pharmacologically activation of STING-TBK1 suppresses cervical cancer growth in mice, which is independent on its innate immune defense. In conclusion, our findings represent a new layer of the host innate immune defense against oncovirus and provide that activating STING/TBK1 could be a promising strategy to treat patients with HPV-positive cervical cancer.

Background: To investigate the prognostic role of pretreatment squamous cell carcinoma antigen (SCCA) in early-stage cervical cancer (CC). Methods: We enrolled 487 cases of pathology-proven early-stage [International Federation of Gynecology and Obstetrics (FIGO) I/II] squamous or adenosquamous CC that were treated from 2012 to 2015. Restricted cubic splines (RCS) with a full Cox regression model were used to evaluate the association between SCCA levels and survival outcomes. Recursive partitioning analysis (RPA) was used to construct a risk stratification model for overall survival (OS). The performance of the RPA-based model was assessed using a receiver operating characteristic (ROC) curve. Results: RCS analysis revealed an association between SCCA and OS and disease-free survival (DFS); SCCA ⩾2.5 ng/mL was robust for risk discrimination in our cohort. SCCA had an interaction effect with FIGO classification: Patients with FIGO I and SCCA ⩾2.5 ng/mL overlapped with those with FIGO II and SCCA < 2.5 ng/mL for OS [hazard ratio, 1.04 (95% confidence interval (CI): 0.49–2.24), p = 0.903] and DFS [1.05 (0.56–1.98), p = 0.876]. RPA modeling incorporating SCCA (<2.5 ng/mL and ⩾2.5 ng/mL) and FIGO classification divided CC into three prognostic groups: RPA I, FIGO stage I, and SCCA < 2.5 ng/mL; RPA II, FIGO stage I, and SCCA ⩾ 2.5 ng/mL, or FIGO stage II and SCCA < 2.5 ng/mL; and RPA III, FIGO stage II, and SCCA ⩾ 2.5 ng/mL; with 5-year OS of 94.0%, 85.1%, and 73.5%, respectively ( p < 0.001). ROC analysis confirmed that the RPA model outperformed the FIGO 2018 stage with significantly improved accuracy for survival prediction [area under the curve: RPA versus FIGO, 0.663 (95% CI: 0.619–0.705] versus 0.621 (0.576–0.664), p = 0.045]. Importantly, the RPA groupings were associated with the efficacy of treatment regimens. Surgery followed by adjuvant treatment had a higher OS ( p < 0.01) and DFS ( p = 0.024) than other treatments for RPA III, whereas outcomes were comparable among treatment regimens for RPA I–II. Conclusion: Herein, the role of SCCA for prognostication was confirmed, and a robust clinicomolecular risk stratification system that outperforms conventional FIGO classification in early-stage squamous and adenosquamous CC was presented. The model correlated with the efficacy of different treatment regimes.

患者,女,43岁,发现颈部多发淋巴结肿大11个月,取淋巴结活检后诊断为"淋巴结核",抗结核治疗期间患者左上眼睑出现肿胀,行"左眼眼眶肿物摘除术(前路开眶)+带蒂皮瓣移植术",术后脓液培养示:马尔尼菲篮状菌,初始予两性霉素B治疗,后因肌酐升高改为口服伊曲康唑200 mg,2次/天,治疗7周后好转出院.院外口服伊曲康唑200 mg,2次/天,6个月后续以200 mg,1次/天,治疗8个月,随访两年未复发.

Abstract FGFR3 alterations are common in patients with bladder cancer. While the FGFR tyrosine kinase inhibitor erdafitinib has been approved as a targeted therapy for patients with FGFR3-altered (aFGFR3) bladder cancer, the response rate remains suboptimal, prompting development of strategies to improve treatment response. Here, we observed an immune-desert tumor microenvironment (TME) phenotype in human aFGFR3 bladder cancer and demonstrated that mutant FGFR3 indirectly induces a “cold” TME in mouse bladder cancer models. Single-cell RNA sequencing revealed the central role of macrophages in inducing the cold TME of aFGFR3 tumors. Macrophages in aFGFR3 tumors exhibited reduced T-cell recruitment and antigen presentation capabilities. Increased serine synthesis in bladder cancer cells that was induced by mutant FGFR3 activated the PI3K/Akt pathway in macrophages, shifting them to an immune-inert phenotype. Targeting PI3K in aFGFR3 tumors with duvelisib achieved promising efficacy by reversing the macrophage phenotype, and combination therapy with duvelisib and erdafitinib demonstrated increased antitumor activity. Overall, these findings reveal the critical role of enhanced serine synthesis efflux from cancer cells with mutant FGFR3 in shifting macrophages to an immune-inert phenotype. Reversing the macrophage phenotype holds promise for enhancing erdafitinib efficacy. Significance: Metabolic reprogramming of bladder cancer cells driven by mutant FGFR3 increases serine synthesis that suppresses macrophage immunostimulatory functions to generate an immunosuppressive TME, which can be overcome by targeting PI3K.