Surgery versus no surgery in platinum-sensitive relapsed ovarian cancer: final overall survival analysis of the SOC-1 randomized phase 3 trial.

Surgery for platinum-sensitive, relapsed ovarian cancer (PSROC) is widely practiced but had contradictory survival outcomes in previous studies. In this multicenter, open-label, phase 3 trial, women with PSROC, and having had one previous therapy and no platinum-based chemotherapy (platinum-free interval) of 6 months or more, were randomly assigned to either the surgery group (182 patients) or the no-surgery group (control) (175 patients). Patients with resectable diseases were eligible according to the international model (iMODEL), combined with a positron emission tomography-computed tomography imaging. Overall survival (OS) and progression-free survival were coprimary endpoints in hierarchical testing, and a significantly longer progression-free survival with surgery was previously reported. Final analysis of OS was planned at data maturity of 59%. Between 19 July 2012 and 3 June 2019, 357 patients were enrolled. Median follow-up was 82.5 months. Median OS was 58.1 months with surgery and 52.1 months for control (hazard ratio (HR) 0.80, 95% confidence interval (CI) 0.61-1.05, P = 0.11). The predefined threshold for statistical significance was not met, but prespecified sensitivity analysis was performed. Overall, 61 of 175 (35%) patients in control had crossed over to surgery following subsequent relapse, and adjusted HR for death in the surgery group compared with control was 0.76, 95% CI 0.58-0.99. In subgroup analysis of relapse sites by imaging, median survival was not estimable in the surgery group and was 69.5 months in control in patients with <20 sites (HR 0.69, 95% CI 0.46-1.03). Patients with a complete resection had the most favorable outcome, with a median OS of 73.0 months. Twenty-four of 182 (13.2%) patients remained relapse free and alive >60 months in the surgery group as compared with five of 175 (2.9%) patients in the control group. In patients with PSROC, surgery did not increase OS in the intention-to-treat population but resulted in a prolongation of survival following adjustment of crossover.ClinicalTrials.gov registration: NCT01611766 .

PD-1 and TIGIT coexpressing CD8 + CD103 + tissue-resident memory cells in endometrial cancer as potential targets for immunotherapy.

BACKGROUND: Immunotherapy has shown promise in treating various cancers; however, its efficacy in endometrial cancer (EC) remains suboptimal owing to the complex dynamics of the tumour immune microenvironment. This study focuses on exploring the potential of targeting the programmed cell death protein 1 gene (PD-1) and the T cell Immunoreceptor with Ig and ITIM domains gene (TIGIT) coexpressing tissue-resident memory cells in EC. METHODS: A comprehensive approach, utilizing RNA sequencing, single-cell RNA sequencing, mass cytometry, and flow cytometry, was employed to analyse the expression patterns of PD-1 and TIGIT in the EC tumor environment and to characterize the phenotypic properties of tumor-infiltrating lymphocytes (TILs), particularly tissue-resident memory (TRM) cells. Additionally, in vitro cell experiments were conducted to assess the functional impact of PD-1 and TIGIT blockade on T-cell activity. RESULTS: Our analysis identified a significant co-expression of PD-1 and TIGIT in TRM cells within the EC tumor microenvironment. These TRM cells displayed an exhausted phenotype with impaired cytotoxicity, enhanced proliferative capacity, and diminished cytotoxic activity. In vitro T-cell assays showed that a dual blockade of PD-1 and TIGIT more effectively restored T-cell functionality compared to single blockade, suggesting enhanced therapeutic potential. CONCLUSIONS: TRM cells co-expressing PD-1 and TIGIT represent potential targets for EC immunotherapy. Dual immune checkpoint blockade targeting PD-1 and TIGIT may offer an effective therapeutic strategy for EC, providing valuable insights for the development of immunotherapeutic approaches.

Sediment-seawater exchange altered adverse effects of ocean acidification towards marine microalgae.

Ocean acidification (OA) exhibits high threat to marine microalgae. However, the role of marine sediment in the OA-induced adverse effect towards microalgae is largely unknown. In this work, the effects of OA (pH 7.50) on the growth of individual and co-cultured microalgae (Emiliania huxleyi, Isochrysis galbana, Chlorella vulgaris, Phaeodactylum tricornutum, and Platymonas helgolandica tsingtaoensis) were systematically investigated in the sediment-seawater systems. OA inhibited E. huxleyi growth by 25.21 %, promoted P. helgolandica (tsingtaoensis) growth by 15.49 %, while did not cause any effect on the other three microalgal species in the absence of sediment. In the presence of the sediment, OA-induced growth inhibition of E. huxleyi was significantly mitigated, because the released chemicals (N, P and Fe) from seawater-sediment interface increased the photosynthesis and reduced oxidative stress. For P. tricornutum, C. vulgaris and P. helgolandica (tsingtaoensis), the growth was significantly increased in the presence of sediment in comparison with those under OA alone or normal seawater (pH 8.10). For I. galbana, the growth was inhibited when the sediment was introduced. Additionally, in the co-culturing system, C. vulgaris and P. tricornutum were the dominant species, while OA increased the proportions of dominant species and decreased the community stability as indicated by Shannon and Pielou's indexes. After the introduction of sediment, the community stability was recovered, but remained lower than that under normal condition. This work demonstrated the role of sediment in the biological responses to OA, and could be helpful for better understanding the impact of OA on marine ecosystems.

Retrospective analysis of clinical features and fertility outcomes with fertility-sparing treatment of placental site trophoblastic tumor.

OBJECTIVE: To analyze the methods, feasibility, efficiency, and fertility outcomes of fertility-sparing treatment for patients with placental site trophoblastic tumor (PSTT). METHODS: Clinical data of patients diagnosed with PSTT between April 1998 and April 2020 from Peking Union Medical College Hospital (PUMCH) were retrospectively collected. The clinical features, treatment, and outcomes of patients received fertility-sparing treatment were analyzed and compared with patients suffered hysterectomy. RESULTS: In total, 126 patients were included in the study and 29 of them received fertility-sparing treatment. Besides significantly younger age and lower proportion of antecedent term delivery were seen in fertility-sparing group than hysterectomy group, no significant differences were observed in stage, serum ß-hCG level, or interval from antecedent pregnancy between the two groups. Conservative surgery was selected individualized and none of them suffered salvage hysterectomy. Patients with clinical or pathological high-risk factors received adjuvant chemotherapy, yet the fertility-sparing treatment did not significantly lengthen chemotherapy duration. All patients in fertility-sparing group achieved complete remission without relapse after 36 to 176 months of follow-up and had sixteen healthy term delivery more than one year after the treatment. CONCLUSIONS: Fertility-sparing treatment for PSTT can be considered for young patients with localized uterine lesions who strongly desire to preserve their fertility potential. With individualized conservative surgery and selected adjuvant chemotherapy, fertility-sparing treatment will not influence the risk of relapse or overall survival and patients will achieve favorable pregnancy and live birth outcomes.

Immunologic Signatures across Molecular Subtypes and Potential Biomarkers for Sub-Stratification in Endometrial Cancer.

Current molecular classification approaches for endometrial cancer (EC) often employ multiple testing platforms. Some subtypes still lack univocal prognostic significance, highlighting the need for risk sub-stratification. The tumor immune microenvironment (TIME) is associated with tumor progression and prognosis. We sought to investigate the feasibility of classifying EC via DNA sequencing and interrogate immunologic signatures and prognostic markers across and within subtypes, respectively. Formalin-fixed paraffin-embedding (FFPE) samples from 50 EC patients underwent targeted DNA and RNA sequencing, and multiplex immunofluorescence assay for TIME. DNA sequencing classified 10%, 20%, 52%, and 18% of patients into the subtype of POLE-mutant, microsatellite instability-high (MSI-H), TP53-wt, and TP53-mutant. POLE-mutant tumors expressed the highest T-effector and IFN-γ signature and the lowest innate anti-PD-1 resistance signature among subtypes. TP53-wt revealed a converse enrichment trend for these immunologic signatures. Survival analyses using the Cancer Genome Atlas Uterine Corpus Endometrial Carcinoma (TCGA-UCEC) dataset identified associations of CCR5 (hazard ratio (HR) = 0.71, p = 0.035), TNFRSF14 (HR = 0.58, p = 0.028), and IL-10 (HR = 2.5, p = 0.012) with overall survival within MSI-H, TP53-mutant, and TP53-wt subtype, respectively. A TIME comparison between the sub-stratified subgroups of our cohort revealed upregulated tumor infiltration of immune cells in the low-risk subgroups. Our study demonstrates that targeted DNA sequencing is an effective one-stop strategy to classify EC. Immunomodulatory genes may serve as prognostic markers within subtypes.

Efficacies of FAEV and EMA/CO regimens as primary treatment for gestational trophoblastic neoplasia.

BACKGROUND: Guidelines recommend etoposide, methotrexate, actinomycin D (EMA)/cyclophosphamide, vincristine (CO) as first-line treatment for high-risk gestational trophoblastic neoplasia (GTN). However, the floxuridine, actinomycin D, etoposide and vincristine (FAEV) regimen is commonly used to treat these patients in China. We conducted a randomised controlled trial to compare the efficacies and toxicities of FAEV and EMA/CO. METHODS: Ninety-four patients with GTN were enrolled between May 2015 and April 2019 and randomly assigned to the FAEV or EMA/CO regimen. The rates of complete remission and relapse and the toxicities were compared in August 2021. RESULTS: Five patients were excluded from the analysis. There were 46 patients in the FAEV group and 43 patients in the EMA/CO group. The complete remission rates following primary treatment were 89.1% and 79.1% (P = 0.193), respectively. The relapse rates were 8.7% and 9.3% (P = 0.604). The apparent incidences of grade 4 myelosuppression were 60.9% and 32.6% (P = 0.008), respectively; however, they became both 32.6% (P = 0.996) after granulocyte colony-stimulating factor support. Other adverse reactions were similar in the two groups. No patient died of disease. CONCLUSION: FAEV has comparable efficacy and toxicity to EMA/CO as the primary treatment for high-risk GTN, and may thus be another first-line choice of chemotherapy. CLINICAL TRIAL REGISTRATION: chictr.org.cn: ChiCTR1800017423.

High-resolution temporal transcriptome sequencing unravels ERF and WRKY as the master players in the regulatory networks underlying sesame responses to waterlogging and recovery.

Major crops are generally sensitive to waterlogging, but our limited understanding of the waterlogging gene regulatory network hinders the efforts to develop waterlogging-tolerant cultivars. We generated high-resolution temporal transcriptome data from root of two contrasting sesame genotypes over a 48 h period waterlogging and drainage treatments. Three distinct chronological transcriptional phases were identified, including the early-waterlogging, late-waterlogging and drainage responses. We identified 47 genes representing the core waterlogging-responsive genes. Waterlogging/drainage-induced transcriptional changes were mainly driven by ERF and WRKY transcription factors (TF). The major difference between the two genotypes resides in the early transcriptional phase. A chronological transcriptional network model predicting putative causal regulations between TFs and downstream waterlogging-responsive genes was constructed and some interactions were validated through yeast one-hybrid assay. Overall, this study unveils the architecture and dynamic regulation of the waterlogging/drainage response in a non-model crop and helps formulate new hypotheses on stress sensing, signaling and sophisticated adaptive responses.

Transcriptomic profiling of sesame during waterlogging and recovery.

Sesame is naturally adapted to arid environments but highly susceptible to waterlogging stress. A few hours of waterlogging (lasting over 36 h) are detrimental to the crop growth, yield and survival. To better understand the molecular mechanisms underlying sesame responses to waterlogging and recovery, it is essential to design a high-resolution time-series experiment. In this study, we reported the RNA-seq profiling of two contrasting genotypes under waterlogging and recovery. The plants were grown in pots and subjected to waterlogging treatment at the flowering stage for 36 h and subsequently, 12 h drainage. Root samples were collected in triplicate at 22 time points under waterlogging/drainage treatments and at 10 time points in the control condition. This represents a total of 195 biological samples and the RNA-seq yielded over eight billion reads. Basic data analyses demonstrated a clear separation of transcriptomes from control, waterlogging and drainage treatments. Overall, the generated high-quality and comprehensive RNA-seq resources will undoubtedly advance our understanding of waterlogging/drainage responses in a non-model sensitive crop.