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BACKGROUND: Patients with choriocarcinoma (CC) accompanying chemoresistance conventionally present a poor prognosis. Whether ras protein activator like-1 (RASAL1) functions as a tumor promoter or suppressor depends on tumor types. However, the role of RASAL1 in process of chemoresistance of CC and underlying molecular mechanism remain elusive. METHODS: The expression pattern of RASAL1 in CC cells and tissues was measured using Western blotting, immunohistochemistry and qRT-PCR. Cell viability and proliferative ability were assessed by MTT assay, Tunnel assay and flow cytometric analysis. Additionally, the stemness was evaluated by the colony formation and tumor sphere formation. Methotrexate (MTX) was applied to exam the chemosensitivity of CC cells. RESULTS: The expression of RASAL1 was reduced both at the protein and mRNA levels in CC tissues and cells compared to hydatidiform mole (HM) and invasive mole (IM). Loss of RASAL1 was attributed to its promoter hypermethylation and could be restored by 5-Aza. Knock-down of RASAL1 promoted the viability, proliferative potential, stemness and EMT phenotype of JEG-3 cells. However, induced overexpression of RASAL1 by 5-Aza significantly prohibited cell proliferation and stemness potential of the JAR cell. Additionally, the xenograft model indicated that knockdown of RASAL1 led to a remarkable increase of tumor volume and weight in comparison with its counterpart. Moreover, the stimulatory activity brought by decrease of RASAL1 could be deprived by ß-catenin inhibitor XAV 939, yet the suppressive activity resulted from its promoter demethylation could be rescued by ß-catenin activator BML-284, indicating that function of RASAL1 depends on ß-catenin. Besides, the co-immunoprecipitation assay confirmed the physical binding between RASAL1 and ß-catenin. Further investigations showed hypermethylated RASAL1 was regulated by TET2 but not DNMTs. CONCLUSION: Taken together, the present data elucidated that reduced RASAL1 through its promoter hypermethylation regulated by TET2 promoted the tumorigenicity and chemoresistance of CC via modulating ß-catenin both in vitro and in vivo.
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Coriocarcinoma , Metilação de DNA , Proteínas de Ligação a DNA , Dioxigenases , Resistencia a Medicamentos Antineoplásicos , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas , Humanos , Resistencia a Medicamentos Antineoplásicos/genética , Coriocarcinoma/metabolismo , Coriocarcinoma/patologia , Coriocarcinoma/genética , Animais , Feminino , Camundongos , Dioxigenases/metabolismo , Dioxigenases/genética , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas/genética , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologia , Neoplasias Uterinas/metabolismo , Carcinogênese/genética , GravidezRESUMO
BACKGROUND: Platinum-resistant or refractory ovarian cancer is a highly lethal gynecologic disease with limited treatment options. Chiauranib is a novel small-molecule selective inhibitor, which could effectively target multiple pathways including Aurora B and CSF-1R to inhibit cell cycle process and improve anti-tumor immune function, as long as VEGF pathway for tumor extinction. METHODS: A phase II study was sequentially conducted after a phase Ib monotherapy study to evaluate the efficacy of chiauranib combined with chemotherapy. Chinese patients with recurrent ovarian cancer were enrolled. Eligible patients received chiauranib combined with a maximum of six cycles of chemotherapy: etoposide (CE group) or weekly-paclitaxel (CP group). Patients, who exhibited a complete or partial response, or stable disease following combo treatment, progressed to maintenance phase to receive chiauranib monotherapy. Primary endpoint was progression-free survival (PFS) according to RECIST v1.1. RESULTS: From November 2017 to March 2019, 25 patients were enrolled in a phase 1b study and a median PFS of 3.7 months (95% CI 1.8-NE) was achieved by chiauranib monotherapy. From July 2019 to December 2020, a total of 47 patients were enrolled in the phase II study. One CP patient did not receive the study drugs, and three patients withdrew before the first tumor assessment. Thus, 43 patients (CE group: 22 patients; CP group: 21 patients) were included in the evaluation. The median PFS was 5·4 months (95% CI 2·8-5·6) and 5·6 months (95% CI 3·4-7·0), respectively. CONCLUSIONS: This was the first study to evaluate chiauranib, a novel multi-targeted kinase inhibitor in patients with ovarian cancer. The administration of chiauranib along with etoposide or weekly-paclitaxel significantly enhanced the efficacy with manageable adverse events. This warrants further clinical studies on this novel treatment. A phase III study is promising and ongoing. TRIAL REGISTRATION: ClinicaTrials.gov identifier: NCT03901118 (phase II) and NCT03166891 (phase Ib).
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Protocolos de Quimioterapia Combinada Antineoplásica , Resistencia a Medicamentos Antineoplásicos , Neoplasias Ovarianas , Humanos , Feminino , Pessoa de Meia-Idade , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Idoso , Adulto , Resultado do Tratamento , Paclitaxel/uso terapêutico , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversosRESUMO
OBJECTIVE: First-line bevacizumab plus carboplatin and paclitaxel (CP) is approved for stage III/IV ovarian cancer treatment following initial surgical resection, based on global phase III GOG-0218 and ICON7 trials. This study evaluated the efficacy and safety of bevacizumab + CP as first-line ovarian cancer therapy in Chinese patients. METHODS: Patients with newly diagnosed, International Federation of Gynecology and Obstetrics (FIGO) stage III/IV epithelial ovarian, fallopian tube, or primary peritoneal cancer post-primary surgery were randomized 1:1 to receive 6 cycles of CP with bevacizumab/placebo, followed by bevacizumab/placebo maintenance until unacceptable toxicity or disease progression. Primary endpoint was investigator-assessed progression-free survival (PFS). Stratification factors were FIGO stage and debulking status (stage III optimally debulked vs stage III suboptimally debulked vs stage IV) and Eastern Cooperative Oncology Group performance status (0 vs 1 or 2). RESULTS: Of randomized patients, 51 received bevacizumab + CP and 49 received placebo + CP. Median PFS was 22.6 months with bevacizumab + CP (95% confidence interval [CI]=18.6, not estimable) and 12.3 months (95% CI=9.5, 15.0) with placebo + CP (stratified hazard ratio=0.30; 95% CI=0.17, 0.53). Treatment-related grade 3/4 adverse events occurred in 46 of 49 (94%) patients receiving bevacizumab + CP, and 34 of 50 (68%) receiving placebo + CP. CONCLUSION: Bevacizumab + CP showed clinically meaningful improvement in PFS vs placebo + CP, consistent with GOG-0218 results. Safety data were aligned with the known bevacizumab safety profile. These results support first-line bevacizumab + CP therapy in Chinese patients with ovarian cancer. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03635489.
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Background: Niraparib significantly prolonged progression-free survival versus placebo in patients with platinum-sensitive, recurrent ovarian cancer (PSROC), regardless of germline BRCA mutation (gBRCAm) status, in NORA. This analysis reports final data on overall survival (OS). Methods: This randomised, double-blind, placebo-controlled, phase 3 trial enrolled patients across 30 centres in China between 26 September 2017 and 2 February 2019 (clinicaltrials.gov, NCT03705156). Eligible patients had histologically confirmed, recurrent, (predominantly) high-grade serous epithelial ovarian cancer, fallopian tube carcinoma, or primary peritoneal carcinoma (no histological restrictions for those with gBRCAm) and had received ≥2 prior lines of platinum-based chemotherapy. Patients were randomised (2:1) to receive niraparib or placebo, with stratification by gBRCAm status, time to recurrence following penultimate platinum-based chemotherapy, and response to last platinum-based chemotherapy. Following a protocol amendment, the starting dose was individualised: 200 mg/day for patients with bodyweight <77 kg and/or platelet count <150 × 103/µL at baseline and 300 mg/day otherwise. OS was a secondary endpoint. Findings: Totally, 265 patients were randomised to receive niraparib (n = 177) or placebo (n = 88), and 249 (94.0%) received an individualised starting dose. As of 14 August 2023, median follow-up for OS was 57.9 months (IQR, 54.8-61.6). Median OS (95% CI) with niraparib versus placebo was 51.5 (41.4-58.9) versus 47.6 (33.3-not evaluable [NE]) months, with hazard ratio [HR] of 0.86 (95% CI, 0.60-1.23), in the overall population; 56.0 (36.1-NE) versus 47.6 (31.6-NE) months, with HR of 0.86 (95% CI, 0.46-1.58), in patients with gBRCAm; and 46.5 (41.0-NE) versus 46.9 (31.8-NE) months, with HR of 0.87 (95% CI, 0.56-1.35), in those without. No new safety signals were identified, and myelodysplastic syndromes/acute myeloid leukaemia occurred in three (1.7%) niraparib-treated patients. Interpretation: Niraparib maintenance therapy with an individualised starting dose demonstrated a favourable OS trend versus placebo in PSROC patients, regardless of gBRCAm status. Funding: Zai Lab (Shanghai) Co., Ltd; National Major Scientific and Technological Special Project for "Significant New Drugs Development" in 2018, China [grant number 2018ZX09736019].
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BACKGROUND: The prospective phase III multi-centre L-MOCA trial (NCT03534453) has demonstrated the encouraging efficacy and manageable safety profile of olaparib maintenance therapy in the Asian (mainly Chinese) patients with platinum-sensitive relapsed ovarian cancer (PSROC). In this study, we report the preplanned exploratory biomarker analysis of the L-MOCA trial, which investigated the effects of homologous recombination deficiency (HRD) and programmed cell death ligand 1 (PD-L1) expression on olaparib efficacy. METHODS: HRD status was determined using the ACTHRD assay, an enrichment-based targeted next-generation sequencing assay. PD-L1 expression was assessed by SP263 immunohistochemistry assay. PD-L1 expression positivity was defined by the PD-L1 expression on ≥ 1% of immune cells. Kaplan-Meier method was utilised to analyse progression-free survival (PFS). RESULTS: This exploratory biomarker analysis included 225 patients and tested HRD status [N = 190; positive, N = 125 (65.8%)], PD-L1 expression [N = 196; positive, N = 56 (28.6%)], and BRCA1/2 mutation status (N = 219). The HRD-positive patients displayed greater median PFS than the HRD-negative patients [17.9 months (95% CI: 14.5-22.1) versus 9.2 months (95% CI: 7.5-13.8)]. PD-L1 was predominantly expressed on immune cells. Positive PD-L1 expression on immune cells was associated with shortened median PFS in the patients with germline BRCA1/2 mutations [14.5 months (95% CI: 7.4-18.2) versus 22.2 months (95% CI: 18.3-NA)]. Conversely, positive PD-L1 expression on immune cells was associated with prolonged median PFS in the patients with wild-type BRCA1/2 [20.9 months (95% CI: 13.9-NA) versus 8.3 months (95% CI: 6.7-13.8)]. CONCLUSIONS: HRD remained an effective biomarker for enhanced olaparib efficacy in the Asian patients with PSROC. Positive PD-L1 expression was associated with decreased olaparib efficacy in the patients with germline BRCA1/2 mutations but associated with improved olaparib efficacy in the patients with wild-type BRCA1/2. TRIAL REGISTRATION: NCT03534453. Registered at May 23, 2018.
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Antígeno B7-H1 , Biomarcadores Tumorais , Quimioterapia de Manutenção , Neoplasias Ovarianas , Ftalazinas , Piperazinas , Humanos , Feminino , Ftalazinas/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Piperazinas/uso terapêutico , Biomarcadores Tumorais/genética , Pessoa de Meia-Idade , Quimioterapia de Manutenção/métodos , Idoso , Adulto , Estudos Prospectivos , Recidiva Local de Neoplasia/tratamento farmacológico , Proteína BRCA2/genética , Antineoplásicos/uso terapêutico , Proteína BRCA1/genética , Recombinação HomólogaRESUMO
PURPOSE: To evaluate the efficacy and safety of oral ibrexafungerp (HS-10366) versus placebo in Chinese patients with vulvovaginal candidiasis (VVC). METHODS: A double-blind, placebo-controlled, randomized, multicenter phase III study was conducted in symptomatic VVC patients. Patients received (2:1) twice-daily oral ibrexafungerp 300 mg or matching placebo for 1 day. The primary endpoint was clinical cure (vulvovaginal signs and symptoms [VSS] score = 0) at test-of-cure (TOC) on day 11 ± 3. The secondary endpoints included mycological eradication, overall response, and clinical improvement (VSS score ≤ 1) at TOC, and vulvovaginal symptom resolution at follow-up on day 25 ± 4. RESULTS: In total, 360 patients were included in the modified intention-to-treat set (defined as positive Candida cultured and receiving at least one study drug; 239 for ibrexafungerp, 121 for placebo). Compared with placebo, patients receiving ibrexafungerp had a significantly higher proportion of clinical cure (51.0% vs. 25.6%), mycological eradication (55.6% vs. 18.2%), overall response (33.9%, vs. 8.3%) at TOC and complete symptom resolution (74.5% vs. 39.7%, all P < 0.001) at follow-up. Subgroup analysis of clinical cure indicated that patients with C. albicans could benefit from ibrexafungerp over placebo. A similar benefit trend was also observed in those with non-albicans Candida by post-hoc analysis. Further analyses revealed similar efficacy of ibrexafungerp between patients with fluconazole non-susceptible C. albicans and fluconazole susceptible C. albicans regarding clinical cure and mycological eradication. Ibrexafungerp was generally well tolerated. Adverse events were primarily gastrointestinal and were mainly mild in severity. CONCLUSIONS: As a first-in-class antifungal agent, ibrexafungerp demonstrated promising efficacy and favorable safety for VVC treatment in Chinese patients. CHINADRUGTRIALS.ORG. CN REGISTRY NUMBER: CTR20220918.
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OBJECTIVE: QL1604 is a highly selective, humanized monoclonal antibody against programmed death protein 1. We assessed the efficacy and safety of QL1604 plus chemotherapy as first-line treatment in patients with advanced cervical cancer. METHODS: This was a multicenter, open-label, single-arm, phase II study. Patients with advanced cervical cancer and not previously treated with systemic chemotherapy were enrolled to receive QL1604 plus paclitaxel and cisplatin/carboplatin on day 1 of each 21-day cycle for up to 6 cycles, followed by QL1604 maintenance treatment. RESULTS: Forty-six patients were enrolled and the median follow-up duration was 16.5 months. An 84.8% of patients had recurrent disease and 13.0% had stage IVB disease. The objective response rate (ORR) per Response Evaluation Criteria in Advanced Solid Tumors (RECIST) v1.1 was 58.7% (27/46). The immune ORR per immune RECIST was 60.9% (28/46). The median duration of response was 9.6 months (95% confidence interval [CI]=5.5-not estimable). The median progression-free survival was 8.1 months (95% CI=5.7-14.0). Forty-five (97.8%) patients experienced treatment-related adverse events (TRAEs). The most common grade≥3 TRAEs (>30%) were neutrophil count decrease (50.0%), anemia (32.6%), and white blood cell count decrease (30.4%). CONCLUSION: QL1604 plus paclitaxel-cisplatin/carboplatin showed promising antitumor activity and manageable safety profile as first-line treatment in patients with advanced cervical cancer. Programmed cell death protein 1 inhibitor plus chemotherapy may be a potential treatment option for the patient population who have contraindications or can't tolerate bevacizumab, which needs to be further verified in phase III confirmatory study. Trial RegistrationClinicalTrials.gov Identifier: NCT04864782.
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BACKGROUND: Platinum-resistant, recurrent ovarian cancer has an abysmal prognosis with limited treatment options. Poly-(ADP-ribose)-polymerase (PARP), angiogenesis, and immune checkpoint inhibitors might improve the outcomes of platinum-resistant, recurrent ovarian cancer, but accurate patient selections for those therapies remain a significant clinical challenge. PRIMARY OBJECTIVE: To evaluate the efficacy and safety of biomarker-driven combinatorial therapies of pamiparib, tislelizumab, bevacizumab, and nab-paclitaxel in platinum-resistant, recurrent ovarian cancer. STUDY HYPOTHESIS: A precision medicine combination of PARP inhibitors, anti-angiogenic therapy, immunotherapy, and chemotherapy will improve disease outcomes of platinum-resistant, recurrent ovarian cancer by accounting for genomic and immunologic features. TRIAL DESIGN: The BRIGHT Trial is a prospective, open-label, multicenter, phase II, umbrella study planning to enroll 160 patients with serous, endometrioid, or clear cell platinum-resistant, recurrent ovarian cancer from 11 clinical centers in China. Patients are assigned to one of three experimental arms based on biomarkers. Patients with BRCA1/2 mutations will receive pamiparib plus bevacizumab (arm 1, n=40) regardless of CD8+ tumor-infiltrating lymphocytes count. Patients with wild-type BRCA1/2 (BRCAwt) and ≥3 CD8+ tumor-infiltrating lymphocytes count will receive the combination of tislelizumab, bevacizumab, and nab-paclitaxel (arm 2, n=50), while BRCAwt patients with <3 CD8+ tumor-infiltrating lymphocytes count will receive bevacizumab plus dose-dense nab-paclitaxel (arm 3, n=50). After completing patient enrollment in arm 2, another 20 BRCAwt patients with ≥3 CD8+ tumor-infiltrating lymphocytes count will be included as an arm 2 expansion. Treatment will continue until disease progression or intolerable toxicity, and all adverse events will be recorded. MAJOR INCLUSION/EXCLUSION CRITERIA: Eligible patients include those aged ≥18 with serous, endometrioid, or clear cell ovarian cancer, platinum-resistant recurrence, and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. PRIMARY ENDPOINT: Objective response rate (ORR) assessed by the investigators by the RECIST 1.1 criteria. SAMPLE SIZE: 160 patients. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Recruitment is estimated to be completed by 2024 and results may be published by 2027. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05044871.
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Background: Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been reported to play a diagnostic and predictive role in gestational trophoblastic disease. However, the conclusions are still ambiguous. This meta-analysis aimed to evaluate the combined predictive value of NLR and PLR in the malignant progression of gestational trophoblastic disease. Method: Electronic databases including PubMed, Embase, the Cochrane Library, Web of Science, Chinese National Knowledge Infrastructure, Wanfang and China Biomedical Literature Database were searched for the relevant literature published up to 1 October 2022. Study selection and data extraction were performed independently by two reviewers. All analyses were performed using Revman, MetaDisc and STATA software. Results: A total of 858 patients from five studies were included in this meta-analysis. The pooled sensitivity and specificity of NLR were 0.8 (95% CI: 0.71-0.88) and 0.73 (95% CI: 0.69-0.76), respectively, and the area under curve of the summary receiver operating curve was 0.81. The pooled sensitivity and specificity of PLR were 0.87 (95% CI: 0.75-0.95) and 0.49 (95% CI: 0.44-0.54), respectively, and the area under curve of the summary receiver operating curve was 0.88. I2 statistic and Deek's funnel plot showed no heterogeneity and publication bias. Conclusion: NLR can accurately predict the progression from hydatidiform mole to gestational trophoblastic neoplasia and is a promising biomarker in further follow-up.
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Biomarcadores Tumorais , Doença Trofoblástica Gestacional , Feminino , Humanos , Gravidez , Biomarcadores Tumorais/sangue , Plaquetas/patologia , Doença Trofoblástica Gestacional/sangue , Doença Trofoblástica Gestacional/diagnóstico , Contagem de Linfócitos , Linfócitos , Neutrófilos , Contagem de Plaquetas , Valor Preditivo dos Testes , Prognóstico , Curva ROC , Sensibilidade e Especificidade , Contagem de LeucócitosRESUMO
INTRODUCTION: Gestational trophoblastic neoplasia (GTN) is a highly invasive tumor, mainly spreading to the lungs. However, lung metastasis in GTN is usually not considered as an adverse prognostic factor. Therefore, the aim of this study was to summarize the results of previous studies and evaluate the effects of lung metastasis on the treatment and prognosis of GTN. MATERIAL AND METHODS: The study was prospectively registered in PROSPERO (CRD42023372371). Electronic databases including PubMed, Embase, the Cochrane Library, Chinese National Knowledge Infrastructure, Wanfang, and China Biomedical Literature Database were used for a systematical search of relevant studies published up to November 21, 2022. The observational studies reporting the clinical outcomes of GTN patients with and without lung metastasis were selected. The incidences of resistance, relapse, and mortality of GTN patients were extracted and successively grouped based on the presence of lung metastasis. The pooled relative risks (RRs) and 95% confidence interval (95% CI) of the eligible studies were calculated. The qualities of included studies were assessed with the Newcastle-Ottawa Scale and the certainty of evidence was graded based on the GRADE. The meta-analysis was performed using Stata 12.0 and GradePro software. RESULTS: Five publications with 3629 GTN patients were included. The meta-analysis revealed that the GTN with lung metastasis was strongly correlated with first-line chemoresistance (pooled RR = 1.40, 95% CI: 1.22 to 1.61, p < 0.001), recurrence (pooled RR = 3.03, 95% CI: 1.21 to 7.62, p = 0.018), and disease-specific death (pooled RR = 22.11, 95% CI: 3.37 to 145.08, p = 0.001). Ethnicity was also an important factor and Caucasian GTN patients with lung metastasis showed a higher risk of recurrence as revealed by the subgroup analysis (pooled RR = 5.10, 95% CI: 2.38 to 10.94, p < 0.001). CONCLUSIONS: GTN patients with lung metastasis exhibited a higher risk of chemoresistance, relapse, and disease-specific death. Patients with lung metastasis among the Caucasian population had a higher risk of recurrence than Asian populations. Therefore, the presence of lung metastases might be considered as a high-risk factor for prognosis of GTN and deserves more attention in the choice of first-line chemotherapy regimens and follow-up.
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Doença Trofoblástica Gestacional , Neoplasias Pulmonares , Humanos , Feminino , Doença Trofoblástica Gestacional/tratamento farmacológico , Doença Trofoblástica Gestacional/mortalidade , Doença Trofoblástica Gestacional/patologia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/patologia , Gravidez , Prognóstico , Recidiva Local de NeoplasiaRESUMO
Choriocarcinoma can be cured by chemotherapy, but this causes resistance and severe side effects that bring about physical and psychological consequences for patients. Therefore, there is still an urgent need to find other alternative minimally invasive therapies to halt the progression of choriocarcinoma. Novel carbon-coated selenium nanoparticles (C-Se) were successfully synthesized for choriocarcinoma photothermal therapy. C-Se combined with near-infrared laser irradiation can inhibit the proliferation of human choriocarcinoma (JEG-3) cells and induce cell apoptosis. C-Se killed cells and produced ROS under near-infrared laser irradiation. Finally, the therapeutic mechanism of C-Se + laser was explored showing that C-Se + laser influenced numerous biological processes. Taken together, C-Se exhibited significant potential for choriocarcinoma photothermal therapy.
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Vulvovaginal candidiasis (VVC) is a common condition among women. Fluconazole remains the dominant treatment option for VVC. Oteseconazole is a highly selective inhibitor of fungal CYP51. This randomized, double-blinded, phase 3 trial was conducted to evaluate the efficacy and safety of oteseconazole compared with fluconazole in treating severe VVC. Female subjects presenting with vulvovaginal signs and symptoms score of ≥7 and positive Candida infection determined by potassium hydroxide test or Gram staining were randomly assigned to receive oteseconazole (600 mg on D1 and 450 mg on D2) or fluconazole (150 mg on D1 and D4) in a 1:1 ratio. The primary endpoint was the proportion of subjects achieving therapeutic cure [defined as achieving both clinical cure (absence of signs and symptoms of VVC) and mycological cure (negative culture of Candida species)] at D28. A total of 322 subjects were randomized and 321 subjects were treated. At D28, a statistically significantly higher proportion of subjects achieved therapeutic cure in the oteseconazole group than in the fluconazole group (66.88% vs 45.91%; P = 0.0002). Oteseconazole treatment resulted in an increased proportion of subjects achieving mycological cure (82.50% vs 59.12%; P < 0.0001) and clinical cure (71.25% vs 55.97%; P = 0.0046) compared with fluconazole. The incidence of treatment-emergent adverse events was similar between the two groups. No subjects discontinued study treatment or withdrew study due to adverse events. Oteseconazole showed statistically significant and clinically meaningful superiority over fluconazole for the treatment of severe VVC and was generally tolerated.
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Candidíase Vulvovaginal , Fluconazol , Feminino , Humanos , Fluconazol/farmacologia , Candidíase Vulvovaginal/tratamento farmacológico , Candidíase Vulvovaginal/microbiologia , Antifúngicos/efeitos adversos , Candida , Administração Oral , Candida albicansRESUMO
The aim of this study was to analyze the clinical features and demographic characteristics of gestational trophoblastic neoplasia (GTN) patients, specifically choriocarcinoma (CC), placental site trophoblastic tumour (PSTT), and epithelioid trophoblastic tumor (ETT). We utilized data from a local hospital and the SEER database, as well as survival outcomes of CC in SEER database. Additionally, we used multiple risk factors to create a prognostic nomogram model for CC patients. The study included GTN patients from the SEER database between 1975 and 2016 as well as those from the First Affiliated Hospital of Xi 'an Jiaotong University between January 2005 and May 2022. Related factors of patients were compared using the chi-square (χ2) or Fisher's exact test. For assessing overall survival we employed the Kaplan-Meier method and log-rank test. To construct the nomogram, we used Cox regression. Statistically significant differences were found between CC and PSTT/ETT patients in terms of surgery in local hospital, as well as age and year of diagnosis in the SEER database. Moreover, significant differences were observed between low and high (HR) /ultra-high risk (UHR) groups regarding FIGO stage, surgery and chief complaint at the local hospital, and FIGO stage, surgery and unemployment in the SEER database. The Cox regression analysis confirmed that age, race, surgery, marital status, FIGO stage, and unemployment were correlated with CC prognosis. Furthermore, the analysis showed that patients aged 40 years or older and those with FIGO â ¢/â £ were independent prognostic factors of CC. The study indicates that atypical symptoms or signs may be the main reasons for HR /UHR patients to seek medical treatment. Therefore, providing multidisciplinary care is recommended for CC patients experiencing psychological distress due to unfavorable marital status or unemployment.
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Coriocarcinoma , Doença Trofoblástica Gestacional , Tumor Trofoblástico de Localização Placentária , Neoplasias Uterinas , Humanos , Feminino , Gravidez , Placenta/patologia , Doença Trofoblástica Gestacional/epidemiologia , Coriocarcinoma/patologia , Tumor Trofoblástico de Localização Placentária/diagnóstico , Neoplasias Uterinas/diagnóstico , DemografiaRESUMO
BACKGROUND: Immune checkpoint inhibitors targeting PD-1 or CTLA-4 individually have shown substantial clinical benefits in the treatment of malignancies. We aimed to assess the safety and antitumour activity of cadonilimab monotherapy, a bispecific PD-1/CTLA-4 antibody, in patients with advanced solid tumours. METHODS: This multicentre, open-label, phase 1b/2 trial was conducted across 30 hospitals in China. Patients aged 18 years or older with histologically or cytologically confirmed, unresectable advanced solid tumours, unsuccessful completion of at least one previous systemic therapy, and an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible for inclusion. Patients who had previously received anti-PD-1, anti-PD-L1, or anti-CTLA-4 treatment were not eligible for inclusion. In the dose escalation phase of phase 1b, patients received intravenous cadonilimab at 6 mg/kg and 10 mg/kg every 2 weeks. In the dose expansion phase of phase 1b, cadonilimab at 6 mg/kg and a fixed dose of 450âmg were given intravenously every 2 weeks. In phase 2, cadonilimab at 6 mg/kg was administered intravenously every 2 weeks in three cohorts: patients with cervical cancer, oesophageal squamous cell carcinoma, and hepatocellular carcinoma. The primary endpoints were the safety of cadonilimab in phase 1b and objective response rate in phase 2, based on the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. The safety analysis was done in all patients who received at least one dose of cadonilimab. Antitumour activity was assessed in the full analysis set for the cervical cancer cohort, and in all patients with measurable disease at baseline and who received at least one dose of cadonilimab in the oesophageal squamous cell carcinoma and hepatocellular carcinoma cohorts. The study is registered on ClinicalTrial.gov, NCT03852251, and closed to new participants; follow-up has been completed. FINDINGS: Between Jan 18, 2019, and Jan 8, 2021, 240 patients (83 [43 male and 40 female] in phase 1b and 157 in phase 2) were enrolled. Phase 2 enrolled 111 female patients with cervical cancer, 22 patients with oesophageal squamous cell carcinoma (15 male and seven female), and 24 patients with hepatocellular carcinoma (17 male and seven female). During dose escalation, no dose-limiting toxicities occurred. Grade 3-4 treatment-related adverse events occurred in 67 (28%) of 240 patients; the most frequent grade 3 or worse treatment-related adverse events were anaemia (seven [3%]), increased lipase (four [2%]), decreased bodyweight (three [1%]), decreased appetite (four [2%]), decreased neutrophil count (three [1%]), and infusion-related reaction (two [1%]). 17 (7%) patients discontinued treatment due to treatment-related adverse events. 54 (23%) of 240 patients reported serious treatment-related adverse events, including five patients who died (one due to myocardial infarction; cause unknown for four). In phase 2, in the cervical cancer cohort, with a median follow-up of 14·6 months (IQR 13·1-17·5), the objective response rate was 32·3% (32 of 99; 95% CI 23·3-42·5). In the oesophageal squamous cell carcinoma cohort, with a median follow-up of 17·9 months (IQR 4·0-15·1), the objective response rate was 18·2% (four of 22; 95% CI 5·2-40·3). In the hepatocellular carcinoma cohort, with a median follow-up of 19·6 months (IQR 8·7-19·8), the objective response rate was 16·7% (four of 24; 95% CI 4·7-37·4). INTERPRETATION: Cadonilimab showed an encouraging tumour response rate, with a manageable safety profile, suggesting the potential of cadonilimab for the treatment of advanced solid tumours. FUNDING: Akeso Biopharma. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.
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Antineoplásicos Imunológicos , Carcinoma Hepatocelular , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Neoplasias Hepáticas , Neoplasias do Colo do Útero , Humanos , Masculino , Feminino , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Neoplasias do Colo do Útero/tratamento farmacológico , Antígeno CTLA-4 , Receptor de Morte Celular Programada 1 , Empatia , Anticorpos Monoclonais Humanizados , Antineoplásicos Imunológicos/efeitos adversos , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/induzido quimicamente , Neoplasias Hepáticas/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
Ovarian cancer (OC), is a tumor that poses a serious threat to women's health due to its high mortality rate and bleak prognosis. Pyroptosis, a type of programmed cell death, is important for determining the prognosis of a patient's prognosis for cancer and may represent a novel target for treatment. However, research into how prognosis is impacted by pyroptosis-related genes (PRGs) is poorly understood. In this study, a prognostic model was created using bioinformatic analysis of PRGs in OC. In OC, we discovered 18 pyroptosis regulators that were either up- or down-regulated. By analyzing prognoses, we developed a 9-genes based prognostic model. Each OC patient received a risk score that could be used to categorize them into two subgroups: those with high risk and/or low chance of survival and those with low risk and/or high chance of survival. Functional enrichment and immunoinfiltration analysis indicated that low expression of immune pathways in high-risk group may account for the decrease of survival possibility. In Multivariable cox regression studies, age, clinical stage and the prognostic model were discovered to be independent factors impacting the prognosis for OC. To forecast OC patient survival, a predictive nomogram was developed. Furthermore, we found a correlation between predictive PRGs and clinical stage, indicating that AIM2, CASP3, ZBP1 and CASP8 may play a role in the growth of tumor in OC. After detailed and complete bioinformatics analysis, the lncRNA RP11-186B7.4/hsa-miR-449a/CASP8/AIM2/ZBP1 regulatory axis was identified in OC. Our study may provide a novel approach for prognostic biomarkers and therapeutic targets of OC.
Assuntos
Neoplasias Ovarianas , RNA Longo não Codificante , Feminino , Humanos , Prognóstico , RNA Longo não Codificante/genética , Piroptose/genética , Neoplasias Ovarianas/genética , ApoptoseRESUMO
The aim of this study was to explore risk factors of recurrent bacterial vaginosis (RBV) among women of reproductive age. This cross-sectional study was carried out in real-world conditions. Women with RBV were selected, and simultaneously uncomplicated bacterial vaginosis (UBV) and those who underwent routine gynecological examination and had normal vaginal microflora were also recruited as the control. Totally, 316 participants were enrolled. Univariate analysis showed that unemployment, desserts, and wiping were related to UBV, while there was no definite relationship between education, high body mass index, smoking, sedentary lifestyle, and RBV or UBV. History of human papillomavirus infection, contraceptive methods, age at first sexual intercourse, and not cleaning vulva during sexual activity were connected with UBV, while the history of other vaginitis and number of sexual partners in the previous year were related to both RBV and UBV. Multivariate logistic regression analysis revealed that lower educational level increased the risk of suffering RBV. Interestingly, no smoking was a protective factor. Moreover, the absence of other vaginitis and an exclusive sexual partner could also weaken the risk of incurring RBV. These various adverse factors alter endocrine function and vaginal immunity, further leading to the recurrence of BV. It is necessary to take corresponding measures to avoid risk factors and to help lessening the prevalence of RBV among women of reproductive age.
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Background: Vaginal microecology has a definite influence on human papillomavirus (HPV) infection and clearance, but the specific correlation is still controversial. This research aimed to investigate the differences in the vaginal microenvironment of different types of HPV infection and also provide data supporting clinical diagnosis and treatment. Methods: According to strict inclusion and exclusion criteria, the case data of 2,358 female patients who underwent vaginal microecology and HPV-DNA tests at the same time in the Department of Obstetrics and Gynecology of the First Affiliated Hospital of Xi'an Jiaotong University from May 2021 to March 2022 were retrospectively analyzed. The population was divided into two groups: an HPV-positive group and an HPV-negative group. HPV-positive patients were further classified into HPV16/18-positive group and HPV other subtypes positive group. The vaginal microecology of HPV-infected patients was analyzed using the chi-square test, Fisher's exact test, and logistic regression. Results: Among the 2,358 female patients, the HPV infection rate was 20.27% (478/2,358), of which the HPV16/18 infection rate was 25.73% (123/478), and the HPV other subtypes infection rate was 74.27% (355/478). The difference in HPV infection rates between the age groups was statistically significant (P < 0.01). The prevalence of mixed vaginitis was 14.37% (339/2,358), with bacterial vaginosis (BV) paired with aerobic vaginitis (AV) accounting for the majority (66.37%). The difference in HPV infection rates among mixed vaginitis was not statistically significant (P > 0.05). The prevalence of single vaginitis was 24.22% (571/2,358), with the most frequent being vulvovaginal Candidiasis (VVC; 47.29%, 270/571), and there was a significant difference in HPV infection rates among single vaginitis (P < 0.001). Patients with BV had a higher risk of being positive for HPV16/18 (OR: 1.815, 95% CI: 1.050-3.139) and other subtypes (OR: 1.830, 95% CI: 1.254-2.669). Patients with Trichomoniasis were at higher odds of other HPV subtype infections (OR: 1.857, 95% CI: 1.004-3.437). On the contrary, patients with VVC had lower odds of becoming infected with other HPV subtypes (OR: 0.562, 95% CI: 0.380-0.831). Conclusion: There were disparities in HPV infection among different age groups; therefore, we should pay attention to the prevention and treatment of susceptible individuals. BV and Trichomoniasis are linked to HPV infection; hence, restoring the balance of vaginal microecology could assist in the prevention of HPV infection. As a protective factor for other HPV subtype infections, VVC may provide new insights into the development of immunotherapeutic therapies.
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This study was conducted to illustrate the origin of these PE-related ncRNAs in maternal circulation and their underlying transport methods into target cells. We selected 10 women with severe pre-eclampsia (PE group) and 10 healthy participants who served as controls (NC group). Exosomes were isolated from their sera and their origin was determined by a specific marker, placental alkaline phosphatase (PLAP). We compared the ncrna associated with PE in exosomes and whole serum to observe the exchange of serum exosomes with trophoblast cells. The results showed that PLAP was enriched in the isolated exosomes. Seven PE-associated ncRNAs, including lnc-SNHG5, miR-26a-5p, miR-221-3p, miR-30a-3p, miR-18a, miR-152 and miR-155, were analyzed in placenta-derived exosomes and whole serum from both groups. miR-26a-5p, miR-152 and miR-155 were upregulated in the PE group compared with the NC group. 152 and miR-155 were upregulated. 152 and miR-155 were upregulated, while miR-18a and miR-221-3p were downregulated (P<0.05). ncRNAs were altered in serum and placenta-derived serum exosomes in a consistent trend. Fluorescence microscopy results showed that the nuclei were counterstained in HTR-8 cells exposed to PKH26-labeled exosomes. PE-associated ncRNAs can enter the maternal circulation through secretion and encapsulation into placenta-derived exosomes and participate in the development and progression of PE by targeting trophoblast cells. differential expression of ncRNAs in exosomes has the potential to be used as predictors for targeted therapy, providing new ideas and perspectives for improving maternal and infant outcomes.
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Objective: We report the efficacy and safety of serplulimab, a novel humanized anti-programmed death-1 antibody, plus nanoparticle albumin-bound (nab)-paclitaxel in previously treated patients with programmed death ligand-1 (PD-L1)-positive advanced cervical cancer. Methods: Patients diagnosed with PD-L1-positive (combined positive score ≥1) cervical cancer were enrolled in this single-arm, open-label, phase II study. They were given serplulimab 4.5 mg/kg for up to 2 years (35 dosing cycles) plus nab-paclitaxel 260 mg/m2 for up to six cycles once every 3 weeks. Primary endpoints were safety and objective response rate (ORR) assessed by independent radiological review committee (IRRC) per RECIST version 1.1. Secondary endpoints included ORR assessed by the investigator, duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Results: Between December 2019 and June 2020, 52 patients were screened and 21 were enrolled. IRRC-assessed ORR was 57.1% (95% confidence interval [CI] 34.0-78.2%); 3 (14.3%) patients achieved complete response and 9 (42.9%) partial response. The median DOR was not reached (NR) (95% CI 4.1-NR). IRRC-assessed median PFS was 5.7 months (95% CI 3.0-NR), and median OS was 15.5 months (95% CI 10.5-NR). Investigator-assessed ORR was 47.6% (95% CI 25.7-70.2%). Seventeen (81.0%) patients experienced grade ≥3 treatment-emergent adverse events. Grade ≥3 adverse drug reactions were reported in 7 (33.3%) patients. Immune-related adverse events occurred in 12 (57.1%) patients. Conclusions: In previously treated patients with PD-L1-positive advanced cervical cancer, serplulimab plus nab-paclitaxel provided durable clinical activity and a manageable safety profile. Clinical trial registration: ClinicalTrials.gov, identifier NCT04150575.
Assuntos
Anticorpos Monoclonais Humanizados , Antígeno B7-H1 , Neoplasias do Colo do Útero , Feminino , Humanos , Albuminas , Anticorpos Monoclonais Humanizados/uso terapêutico , Paclitaxel/uso terapêutico , Neoplasias do Colo do Útero/tratamento farmacológicoRESUMO
[This corrects the article DOI: 10.3389/fbioe.2022.990249.].