Multiomics sequencing and immune microenvironment characteristics define three subtypes of small cell neuroendocrine carcinoma of the cervix.

Small cell cervical carcinoma (SCCC) is the most common neuroendocrine tumor in the female genital tract, with an unfavorable prognosis and lacking an evidence-based therapeutic approach. Until now, the distinct subtypes and immune characteristics of SCCC combined with genome and transcriptome have not been described. We performed genomic (n = 18), HPV integration (n = 18), and transcriptomic sequencing (n = 19) of SCCC samples. We assessed differences in immune characteristics between SCCC and conventional cervical cancer, and other small cell neuroendocrine carcinomas, through bioinformatics analysis and immunohistochemical assays. We stratified SCCC patients through non-negative matrix factorization and described the characteristics of these distinct types. We further validated it using multiplex immunofluorescence (n = 77) and investigated its clinical prognostic effect. We confirmed a high frequency of PIK3CA and TP53 alterations and HPV18 integrations in SCCC. SCCC and other small cell carcinoma had similar expression signatures and immune cell infiltration patterns. Comparing patients with SCCC to those with conventional cervical cancer, the former presented immune excluded or 'desert' infiltration. The number of CD8+ cells in the invasion margin of SCCC patients predicted favorable clinical outcomes. We identified three transcriptome subtypes: an inflamed phenotype with high-level expression of genes related to the MHC-II complex (CD74) and IFN-α/ß (SCCC-I), and two neuroendocrine subtypes with high-level expression of ASCL1 or NEUROD1, respectively. Combined with multiple technologies, we found that the neuroendocrine groups had more TP53 mutations and SCCC-I had more PIK3CA mutations. Multiplex immunofluorescence validated these subtypes and SCCC-I was an independent prognostic factor of overall survival. These results provide insights into SCCC tumor heterogeneity and potential therapies. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Stretchable Photonic Crystal-Assisted Glycoprotein Identification for Ovarian Cancer Diagnosis.

Photonic crystals with specific wavelengths can realize surface-enhanced excitation and emission intensities of fluorophores and enhance the fluorescence signals of fluorescent molecules. Herein, stretchable photonic crystals with good mechanochromic properties provide continuously adjustable forbidden wavelengths by stretching to change the lattice spacing, with reflectance peaks blue-shifted up to 110 nm to match indicators of different wavelengths and produce differentiated optical enhancement effects. Glycoproteins are significantly identified as clinical markers. However, the wide participation of glycoproteins in various life processes poses enormous complexity and critical challenges for rapid, facile, high-throughput, and accurate clinical analysis or health assessment. In this work, we proposed a stretchable photonic crystal-assisted glycoprotein identification approach for early ovarian cancer diagnosis. Stretchable photonic crystals can provide rich optical information to efficiently identify glycoproteins in complex matrices. A double-indicator fluorescence sensor was designed to respond to the protein trunk and oligosaccharide segment of glycoproteins separately for improved recognition accuracy. Seven typical glycoproteins could be discriminated from proteins, saccharides, or mixture interferents. Clinical ovarian cancer samples for early, intermediate, and advanced ovarian cancer and healthy subjects were verified with 100% accuracy. This strategy of stretchable photonic crystal-assisted glycoprotein identification provides an effective method for accurate, rapid ovarian cancer diagnosis and timely clinical treatment.

Biomarker-driven targeted therapy in patients with recurrent platinum-resistant epithelial ovarian cancer (BRIGHT): protocol for an open-label, multicenter, umbrella study.

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.

Oncological outcomes of fertility-sparing surgery versus radical surgery in stage - epithelial ovarian cancer: a systematic review and meta-analysis.

BACKGROUND: The oncological outcomes of fertility-sparing surgery (FSS) compared to radical surgery (RS) in patients with stage I epithelial ovarian cancer (EOC) remain a subject of debate. We evaluated the risk ratios (RRs) for outcomes in patients with stage I EOC who underwent FSS versus RS. METHODS: We conducted a systematic search of PubMed, Web of Science, and Embase for articles published up to November 29, 2023. Studies that did not involve surgical procedures or included pregnant patients were excluded. We calculated the RRs for disease-free survival, overall survival, and recurrence rate. The quality of the included studies was assessed using the Cochrane Risk of Bias in Nonrandomized Studies of Interventions (ROBINS-I) tool. The meta-analysis was registered on PROSPERO (CRD42024546460). RESULTS: From the 5,529 potentially relevant articles, we identified 83 articles for initial screening and included 12 articles in the final meta-analysis, encompassing 2,906 patients with epithelial ovarian cancer. There were no significant differences between the two groups in disease-free survival (RR [95% confidence interval {CI}], 0.90 [0.51, 1.58]; P = 0.71), overall survival (RR [95% CI], 0.74 [0.53, 1.03]; P = 0.07), and recurrence rate (RR [95% CI], 1.10 [0.69, 1.76]; P = 0.68). In sensitivity analyses, the significant difference was observed only for overall survival (before exclusion: RR [95% CI], 0.74 [0.53-1.03], P = 0.07; after exclusion: RR [95% CI], 0.70 [0.50-0.99]; P = 0.04). CONCLUSIONS: This is the first and only individual patient data meta-analysis comparing disease-free survival, overall survival, and recurrence rate of patients with early-stage epithelial ovarian cancer undergoing FSS and RS. FSS was associated with similar disease-free survival and risk of recurrence as RS. We hypothesized that the decreased overall survival in the FSS group could not be attributed to distant metastases from epithelial ovarian cancer.

The prognosis of patients with small cell carcinoma of the cervix: a retrospective study of the SEER database and a Chinese multicentre registry.

BACKGROUND: Small cell carcinoma of the cervix is a rare but poor prognosis pathological type of cervical cancer, for which advice in clinical guidelines is unspecific. We therefore aimed to investigate the factors and treatment methods that affect the prognosis of patients with small cell carcinoma of the cervix. METHODS: In this retrospective study, we collected data from the Surveillance, Epidemiology, and End Results (SEER) 18 registries cohort and a Chinese multi-institutional registry. The SEER cohort included females diagnosed with small cell carcinoma of the cervix between Jan 1, 2000, and Dec 31, 2018, whereas the Chinese cohort included women diagnosed between Jun 1, 2006, and April 30, 2022. In both cohorts, eligibility was limited to female patients older than 20 years with a confirmed diagnosis of small cell carcinoma of the cervix. Participants who were lost to follow-up or those for whom small cell carcinoma of the cervix was not the primary malignant tumour were excluded from the multi-institutional registry, and those with an unknown surgery status (in addition to those for whom small cell carcinoma of the cervix was not the primary malignant tumour) were excluded from the SEER data. The primary outcome of this study was overall survival (length of time from the date of first diagnosis until the date of death from any cause, or the last follow-up). Kaplan-Meier analysis, propensity score matching, and Cox-regression analyses were used to assess treatment outcomes and risk factors. FINDINGS: 1288 participants were included in the study; 610 in the SEER cohort and 678 in the Chinese cohort. Both univariable and multivariable Cox regression analysis (SEER hazard ratio [HR] 0·65 [95% CI 0·48-0·88], p=0·0058; China HR 0·53 [0·37-0·76], p=0·0005) showed that surgery was associated with a better prognosis. In subgroup analyses, surgery remained a protective factor for patients with locally advanced disease in both cohorts (SEER HR 0·61 [95% CI 0·39-0·94], p=0·024; China HR 0·59 [0·37-0·95]; p=0·029). Furthermore, the protective effect of surgery was observed among patients with locally advanced disease after propensity score matching in the SEER cohort (HR 0·52 [95% CI 0·32-0·84]; p=0·0077). In the China registry, surgery was associated with better outcomes in patients with stage IB3-IIA2 cancer (HR 0·17 [95% CI 0·05-0·50]; p=0·0015). INTERPRETATION: This study provides evidence that surgery improves outcomes of patients with small cell carcinoma of the cervix. Although guidelines recommend non-surgical methods as first-line treatment, patients with locally advanced disease or stage IB3-IIA2 cancer might benefit from surgery. FUNDING: The National Key R&D Program of China and the National Natural Science Foundation of China.

Suppressive stroma-immune prognostic signature impedes immunotherapy in ovarian cancer and can be reversed by PDGFRB inhibitors.

BACKGROUND: As the most lethal gynecologic cancer, ovarian cancer (OV) holds the potential of being immunotherapy-responsive. However, only modest therapeutic effects have been achieved by immunotherapies such as immune checkpoint blockade. This study aims to propose a generalized stroma-immune prognostic signature (SIPS) to identify OV patients who may benefit from immunotherapy. METHODS: The 2097 OV patients included in the study were significant with high-grade serous ovarian cancer in the III/IV stage. The 470 immune-related signatures were collected and analyzed by the Cox regression and Lasso algorithm to generalize a credible SIPS. Correlations between the SIPS signature and tumor microenvironment were further analyzed. The critical immunosuppressive role of stroma indicated by the SIPS was further validated by targeting the major suppressive stroma component (CAFs, Cancer-associated fibroblasts) in vitro and in vivo. With four machine-learning methods predicting tumor immune subtypes, the stroma-immune signature was upgraded to a 23-gene signature. RESULTS: The SIPS effectively discriminated the high-risk individuals in the training and validating cohorts, where the high SIPS succeeded in predicting worse survival in several immunotherapy cohorts. The SIPS signature was positively correlated with stroma components, especially CAFs and immunosuppressive cells in the tumor microenvironment, indicating the critical suppressive stroma-immune network. The combination of CAFs' marker PDGFRB inhibitors and frontline PARP inhibitors substantially inhibited tumor growth and promoted the survival of OV-bearing mice. The stroma-immune signature was upgraded to a 23-gene signature to improve clinical utility. Several drug types that suppress stroma-immune signatures, such as EGFR inhibitors, could be candidates for potential immunotherapeutic combinations in ovarian cancer. CONCLUSIONS: The stroma-immune signature could efficiently predict the immunotherapeutic sensitivity of OV patients. Immunotherapy and auxiliary drugs targeting stroma could enhance immunotherapeutic efficacy in ovarian cancer.

The MYBL2-CCL2 axis promotes tumor progression and resistance to anti-PD-1 therapy in ovarian cancer by inducing immunosuppressive macrophages.

BACKGROUND: An immunosuppressive tumor microenvironment in ovarian cancer facilitates tumor progression and resistance to immunotherapy. The function of MYB Proto-Oncogene Like 2 (MYBL2) in the tumor microenvironment remains largely unexplored. METHODS: A syngeneic intraovarian mouse model, flow cytometry analysis, and immunohistochemistry were used to explore the biological function of MYBL2 in tumor progression and immune escape. Molecular and biochemical strategies-namely RNA-sequencing, western blotting, quantitative reverse transcription-polymerase chain reaction (qRT-PCR), enzyme-linked immunosorbent assay, multiplex immunofluorescence, chromatic immunoprecipitation assay (CHIP) and luciferase assay-were used to reveal the mechanisms of MYBL2 in the OVC microenvironment. RESULTS: We found tumor derived MYBL2 indicated poor prognosis and selectively correlated with tumor associated macrophages (TAMs) in ovarian cancer. Mechanically, C-C motif chemokine ligand 2 (CCL2) transcriptionally activated by MYBL2 induced TAMs recruitment and M2-like polarization in vitro. Using a syngeneic intraovarian mouse model, we identified MYBL2 promoted tumor malignancyand increased tumor-infiltrating immunosuppressive macrophages. Cyclin-dependent kinase 2 (CDK2) was a known upstream kinase to phosphorylate MYBL2 and promote its transcriptional function. The upstream inhibitor of CDK2, CVT-313, reprogrammed the tumor microenvironment and reduced anti-PD-1 resistance. CONCLUSIONS: The MYBL2/CCL2 axis contributing to TAMs recruitment and M2-like polarization is crucial to immune evasion and anti-PD-1 resistance in ovarian cancer, which is a potential target to enhance the efficacy of immunotherapy.

The first Chinese National Union of Real-world Gynaecological Oncology Research and Patient Management Platform: A retrospective study.

OBJECTIVE: To produce high-quality, real-world evidence for oncologists by collating scattered gynaecologic oncology (GO) medical records in China. DESIGN: Retrospective study. SETTING: The National Union of Real-world Gynaecological Oncology Research and Patient Management Platform (NUWA platform). SAMPLE: Patient-centred data pool. METHODS: The NUWA platform integrated inpatient/outpatient clinical, gene and follow-up data. Data of 11 456 patients with ovarian cancer (OC) were collected and processed using 91 345 electronic medical records. Structured and unstructured data were de-identified and re-collated into a patient-centred data pool using a predefined GO data model by technology-aided abstraction. MAIN OUTCOME MEASURES: Recent treatment pattern shifts towards precision medicine for OC in China. RESULTS: Thirteen first-tier hospitals across China participated in the NUWA platform up to 7 December 2021. In total, 3504 (30.59%) patients were followed up by a stand-alone patient management centre. The percentage of patients undergoing breast cancer gene (BRCA) mutation tests increased by approximately six-fold between 2017 and 2018. A similar trend was observed in the administration rate of poly(ADP-ribose) polymerase inhibitors as first-line treatment and second-line treatment after September 2018, when olaparib was approved for clinical use in China. CONCLUSION: The NUWA platform has great potential to facilitate clinical studies and support drug development, regulatory reviews and healthcare decision-making.

Adipose tissue area as a predictor for the efficacy of apatinib in platinum-resistant ovarian cancer: an exploratory imaging biomarker analysis of the AEROC trial.

BACKGROUND: Vascular endothelial growth factor (VEGF)-targeted therapy is effective in patients with ovarian cancer. Whether adipose tissue (AT) could predict the efficacy of VEGF receptor (VEGFR) inhibitors in ovarian cancer is unknown. We aimed to evaluate the ability of distinct AT depots to predict the efficacy of apatinib, a VEGFR inhibitor, in recurrent ovarian cancers included in the AEROC trial. METHODS: The AEROC was a single-arm phase 2 trial of apatinib and oral etoposide in patients with platinum-resistant or platinum-refractory ovarian cancer. Apatinib was administered continuously, and oral etoposide was administered every 21 days for a maximum of six cycles. This was a post hoc study based on the AEROC trial. Areas of visceral AT (VAT), subcutaneous AT (SAT), and intermuscular AT (IMAT) were measured using computed tomography scan at baseline to assess their association with the objective response rate, progression-free survival, and overall survival. RESULTS: Of the 35 treated patients, 31 patients with at least one post-baseline efficacy assessment by computed tomography scan were included in this study. After adjusting for apatinib exposure, high VAT (odds ratio [OR], 0.16; 95% confidence interval [CI], 0.03-0.90, P = 0.037) and SAT (OR, 0.16; 95% CI, 0.03-0.87, P = 0.034) were significantly associated with a higher objective response rate. Further, decreased risks of disease progression and death were associated with high VAT (hazard ratio [HR], 0.39; 95% CI, 0.17-0.92, P = 0.031, and HR, 0.12; 95% CI, 0.04-0.40, P < 0.001, respectively), SAT (HR, 0.35; 95% CI, 0.15-0.83, P = 0.027, and HR, 0.24; 95% CI, 0.08-0.67, P = 0.007, respectively), and IMAT (HR, 0.20; 95% CI, 0.06-0.74, P = 0.016, and HR, 0.13; 95% CI, 0.03-0.62, P = 0.011, respectively). CONCLUSIONS: High areas of VAT, SAT, and IMAT were significantly associated with better outcomes in patients with platinum-resistant or platinum-refractory ovarian cancer who received VEGFR inhibitors. AT assessments may be valuable as patient-specific imaging biomarkers for predicting response to VEGFR inhibitors. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02867956 .

GANT61 and Valproic Acid Synergistically Inhibited Multiple Myeloma Cell Proliferation via Hedgehog Signaling Pathway.

BACKGROUND Multiple myeloma is featured by the proliferation of malignant plasma cell in bone marrow. We aimed to demonstrate the effects of valproic acid combined with GANT61 on multiple myeloma cell proliferation and clarify its mechanism. MATERIAL AND METHODS Multiple myeloma cells were exposed to valproic acid, GANT61, or the combination of valproic acid and GANT61, respectively. MTT assay was performed to detect the cell viability. Quantitative reverse transcriptase polymerase chain reaction and western blotting were used to detect mRNA and expression levels of proteins in Hedgehog signaling pathway. The Q-value of the combination regime was calculated to evaluate the drug combination effect. RESULTS Both valproic acid and GANT61 alone inhibited multiple myeloma cell proliferation in a dose-dependent manner compared to the control. In the presence of GANT61 or not, valproic acid inhibited multiple myeloma cell proliferation in a time-dependent manner. These 2 drugs had a synergistic effect at valproic acid concentration of ≥4 mM. Expression analysis showed that valproic acid significantly inhibited the expression levels of PTCH1, GLI1, and HES-1. GANT61 enhanced the inhibition of Hedgehog signaling pathway mediated by valproic acid. CONCLUSIONS GANT61 and valproic acid inhibited multiple myeloma cell proliferation synergistically by inhibiting the Hedgehog signaling pathway. The present study may provide a combination regime for the therapy of multiple myeloma.

HFIP-Functionalized Co3 O4 Micro-Nano-Octahedra/rGO as a Double-Layer Sensing Material for Chemical Warfare Agents.

Semiconductor metal oxides (SMO)-based gas-sensing materials suffer from insufficient detection of a specific target gas. Reliable selectivity, high sensitivity, and rapid response-recovery times under various working conditions are the main requirements for optimal gas sensors. Chemical warfare agents (CWA) such as sarin are fatal inhibitors of acetylcholinesterase in the nerve system. So, sensing materials with high sensitivity and selectivity toward CWA are urgently needed. Herein, micro-nano octahedral Co3 O4 functionalized with hexafluoroisopropanol (HFIP) were deposited on a layer of reduced graphene oxide (rGO) as a double-layer sensing materials. The Co3 O4 micro-nano octahedra were synthesized by direct growth from electrospun fiber templates calcined in ambient air. The double-layer rGO/Co3 O4 -HFIP sensing materials presented high selectivity toward DMMP (sarin agent simulant, dimethyl methyl phosphonate) versus rGO/Co3 O4 and Co3 O4 sensors after the exposure to various gases owing to hydrogen bonding between the DMMP molecules and Co3 O4 -HFIP. The rGO/Co3 O4 -HFIP sensors showed high stability with a response signal around 11.8 toward 0.5 ppm DMMP at 125 °C, and more than 75 % of the initial response was maintained under a saturated humid environment (85 % relative humidity). These results prove that these double-layer inorganic-organic composite sensing materials are excellent candidates to serve as optimal gas-sensing materials.

Apatinib combined with oral etoposide in patients with platinum-resistant or platinum-refractory ovarian cancer (AEROC): a phase 2, single-arm, prospective study.

BACKGROUND: Anti-angiogenic therapy combined with chemotherapy could improve the outcomes of patients with platinum-resistant ovarian cancer. Apatinib is an oral tyrosine kinase inhibitor that selectively inhibits VEGF receptor 2. We assessed the efficacy and safety of the combination therapy of apatinib and oral etoposide, considering the potential advantage of home administration without hospital admission, in patients with platinum-resistant or platinum-refractory ovarian cancer. METHODS: In this phase 2, single-arm, prospective study, we recruited patients aged 18-70 years with platinum-resistant or platinum-refractory ovarian cancer at the Sun Yat-sen University Cancer Center (China). The treatment consisted of apatinib at an initial dose of 500 mg once daily on a continuous basis, and oral etoposide at a dose of 50 mg once daily on days 1-14 of a 21-day cycle. Oral etoposide was administered for a maximum of six cycles. Treatment was continued until disease progression, patient withdrawal, or unacceptable toxic effects. The primary endpoint was the proportion of patients achieving an objective response according to Response Evaluation Criteria in Solid Tumors, version 1.1. We used Simon's two-stage design, and analysed efficacy in the intention-to-treat and per-protocol populations. Safety analyses included enrolled patients who had received at least one dose of study medication, but excluded those without any safety data. This study is registered with ClinicalTrials.gov, number NCT02867956. FINDINGS: Between Aug 10, 2016, and Nov 9, 2017, we screened 38 and enrolled 35 patients. At the data cutoff date (Dec 31, 2017), 20 (57%) patients had discontinued the study, and 15 (43%) patients remained on treatment. Objective responses were achieved in 19 (54%; 95% CI 36·6-71·2) of 35 patients in the intention-to-treat population and in 19 (61%; 42·2-78·2) of 31 patients in the per-protocol population. The most common grade 3 or 4 adverse events were neutropenia (17 [50%]), fatigue (11 [32%]), anaemia (ten [29%]), and mucositis (eight [24%]). Serious adverse events were reported in two patients who were admitted to hospital (one patient had anaemia and anorexia; the other patient had increased ascites due to disease progression). No treatment-related deaths were recorded. INTERPRETATION: The combination of apatinib with oral etoposide shows promising efficacy and manageable toxicities in patients with platinum-resistant or platinum-refractory ovarian cancer, and further study in phase 3 trials is warranted. FUNDING: None.

Survival Impact of Ovarian Preservation on Women With Early-Stage Endometrial Cancer: A Systematic Review and Meta-analysis.

OBJECTIVE: The aim of this article was to investigate the survival impact of ovarian preservation in surgically treated patients with early-stage endometrial cancer using a meta-analysis. METHODS: Major online databases, including PubMed, EMBASE, Web of Science, the Cochrane Library, as well as Grey Literature database, were searched to collect studies on the effects of ovarian preservation compared with bilateral salpingo-oophorectomy (BSO) for surgical treatment in endometrial cancer patients. The literature search was performed up to April 2016. The results were analyzed using RevMan 5.0 software and Stata/SE 12.0 software. RESULTS: Totally, 7 retrospective cohort studies including 1419 patients in ovarian preservation group and 15,826 patients in BSO group were enrolled. Meta-analysis showed that there was no significant difference in overall survival between the patients treated with ovarian preservation and BSO (hazards ratio [HR], 1.00; 95% confidence interval [CI], 0.72-1.39; P = 1.00). Similar result was achieved in the young and premenopausal women (HR, 0.99; 95% CI, 0.70-1.39; P = 0.39). Furthermore, the disease-free survival of patients whose ovaries were preserved was slightly compromised but with no statistical significance (HR, 1.49; 95% CI, 0.56-3.93; P = 0.42). CONCLUSIONS: Ovarian preservation may be safe in patients with early-stage endometrial cancer, and it could be cautiously considered in treating young and premenopausal women because it is not associated with an adverse impact on the patients' survival. Given the inherent limitations of the included studies, further well-designed randomized controlled trial are needed to confirm and update this analysis.

The cyano group as a traceless activation group for the intermolecular [3+2] cycloaddition of azomethine ylides: a five-step synthesis of (±)-isoretronecanol.

The cyano group was used as a traceless activation group for the [3+2] cycloaddition of azomethine ylides in a two-step process, thereby providing a highly effective approach to 5-unsubstituted pyrrolidines. The transformation includes the silver acetate catalyzed intermolecular 1,3-dipolar cycloaddition of α-iminonitriles and an unprecedented sodium borohydride induced reductive decyanation reaction. A diverse array of substrates is amenable to this transformation. The methodology was further extended to a five-step total synthesis of the pyrrolizidine natural product isoretronecanol.

Clinicopathological and molecular markers associated with prognosis and treatment effectiveness of endometrial stromal sarcoma: a retrospective study in China.

PURPOSE: To evaluate the clinicopathological and immunophenotypic characteristics of endometrial stromal sarcoma (ESS) in China. METHODS AND MATERIALS: Seventy-two consecutive ESS cases treated between 1995 and 2009 were retrospectively reviewed. RESULTS: Sixty-three patients received surgical treatment. Forty-one patients underwent pelvic lymphadenectomy. In paraffin-embedded specimens, expression of the following molecular markers was detected: CD10 (27/36), vimentin (37/38), HHF35 (3/32), S-100 (0/25), desmin (2/29), CD117 (0/23), CD34 (2/24), alpha-inhibin (0/17), CK (1/34), CD99 (4/9), smooth muscle actin (5/25), EMA (0/7), estrogen receptor (13/16) and progesterone receptor (13/16). CD10 and vimentin were expressed more frequently in these specimens. Tumor classification, CD10 and surgical procedures were significantly associated with disease-free survival (DFS). Surgical procedures were significantly associated with overall survival (OS). Tumor stage (P = 0.024) and surgical procedure (P = 0.042) were found to be significant independent prognostic factors for DFS. No complete or partial response was observed among patients who received radiotherapy or chemotherapy. CONCLUSIONS: Our results indicate that total hysterectomy with bilateral salpingo-oophorectomy followed by pelvic lymphadenectomy is associated with an improved treatment outcome. CD10-negative expression may contribute to the malignant characteristics and recurrence associated with ESS.

Graph learning for particle accelerator operations.

Particle accelerators play a crucial role in scientific research, enabling the study of fundamental physics and materials science, as well as having important medical applications. This study proposes a novel graph learning approach to classify operational beamline configurations as good or bad. By considering the relationships among beamline elements, we transform data from components into a heterogeneous graph. We propose to learn from historical, unlabeled data via our self-supervised training strategy along with fine-tuning on a smaller, labeled dataset. Additionally, we extract a low-dimensional representation from each configuration that can be visualized in two dimensions. Leveraging our ability for classification, we map out regions of the low-dimensional latent space characterized by good and bad configurations, which in turn can provide valuable feedback to operators. This research demonstrates a paradigm shift in how complex, many-dimensional data from beamlines can be analyzed and leveraged for accelerator operations.

Targeting the Cdc2-like kinase 2 for overcoming platinum resistance in ovarian cancer.

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.

Expression of c-Src and phospho-Src in epithelial ovarian carcinoma.

Abnormal c-Src expression and activation has been observed in a number of tumors. To determine the therapeutic potential of Src inhibitors for ovarian cancer patients, this study aimed to explore the expression patterns of c-Src and phospho-Src in epithelial ovarian cancer. A total of 82 patients with epithelial ovarian cancer treated at Sun Yat-sen University Cancer Center from January 1999 to December 2005 were enrolled along with 25 patients with benign ovarian lesions; 20 normal ovarian tissues served as controls. Expression of c-Src and phospho-Src (Tyr416) was examined using immunohistochemistry. Survival analyses were performed using Kaplan-Meier curves. As compared to the control group, a significantly greater proportion of ovarian cancer tissues were positive for c-Src and phospho-Src expression (P < 0.001). c-Src expression was associated with age, while phospho-Src expression was significantly associated with age, FIGO stage, histology grade, and residual tumor size after surgery (all P < 0.05). The mean survival time was associated with phospho-Src expression, but not with c-Src expression. The mean survival times of patients with phospho-Src-positive tumors were significantly greater than those with phospho-Src-negative tumors (87.4 months, 95 % CI = 74.3-100.5 months and 91.5 months, 95 % CI = 84.7-98.2 months, respectively; P = 0.013). The increased c-Src expression and activation in epithelial ovarian cancer suggests that ovarian cancer patients may benefit from tyrosine kinase inhibitors such as Dasatinib. Activation of c-Src through phosphorylation at Tyr416 may play a role in the early stages of ovarian cancer development, and evaluation of its expression may be a useful prognostic marker of epithelial ovarian cancer.

[Umbilicus metastasis in patients with epithelial ovarian cancer : clinical features of 21 patients].

OBJECTIVE: To analyze the clinical features, treatments and prognosis of patients with Sister Mary Joseph's nodule of umbilicus (SMJN) from epithelial ovarian cancer (EOC) patients. METHODS: Among a total of 2642 pathologically diagnosed EOC cases, 21 cases with SMJN were histopathologically diagnosed and had an age range of 40-66 years at Sun Yat-sen University Cancer Center between January 1991 and January 2011. Their clinical data were retrospectively analyzed. RESULTS: The incidence of SMJN in EOC was 0.79 %. The 1, 2 and 5-year survival rates were 61.8%, 26.8% and 9.5% respectively. The diagnosis was confirmed via local excision biopsy, fine-needle aspiration biopsy or gross pathological diagnosis. Univariate analysis showed that patients with progressive disease or relapsing with umbilical metastasis after treatment had worse prognosis than those diagnosed at pre-treatment (22 vs 6 months, P < 0.01) . Patients with suboptimal cytoreductive surgery and/or less than 6 circles of chemotherapy or palliative treatment had worse prognosis than those with optional cytoreductive surgery during 6-8 circles of chemotherapy (21 vs. 4 months). Multivariate analysis showed that the time to diagnose and treatment regimen were independent predictors of survival (relative risk = 41.28, P < 0.01). CONCLUSIONS: SMJN is a rare manifestation of EOC. Improving the diagnostic vigilance, optimal debulking surgery plus regular chemotherapy and other new individualized postoperative treatments may arrest the progression of EOC and prolong patient survival.

Learning Representations by Graphical Mutual Information Estimation and Maximization.

The rich content in various real-world networks such as social networks, biological networks, and communication networks provides unprecedented opportunities for unsupervised machine learning on graphs. This paper investigates the fundamental problem of preserving and extracting abundant information from graph-structured data into embedding space without external supervision. To this end, we generalize conventional mutual information computation from vector space to graph domain and present a novel concept, Graphical Mutual Information (GMI), to measure the correlation between input graph and hidden representation. Except for standard GMI which considers graph structures from a local perspective, our further proposed GMI++ additionally captures global topological properties by analyzing the co-occurrence relationship of nodes. GMI and its extension exhibit several benefits: First, they are invariant to the isomorphic transformation of input graphs-an inevitable constraint in many existing methods; Second, they can be efficiently estimated and maximized by current mutual information estimation methods; Lastly, our theoretical analysis confirms their correctness and rationality. With the aid of GMI, we develop an unsupervised embedding model and adapt it to the specific anomaly detection task. Extensive experiments indicate that our GMI methods achieve promising performance in various downstream tasks, such as node classification, link prediction, and anomaly detection.