Suvemcitug plus chemotherapy for platinum-resistant epithelial ovarian, fallopian tube and primary peritoneal cancer: A phase 1b dose-escalation trial.

OBJECTIVE: The use of bevacizumab has been hampered by safety concerns despite demonstrable progression-free survival (PFS) benefit in subjects with platinum-resistant ovarian cancer, highlighting the need for novel effective and safe antiangiogenic agents. This study aimed to characterize the tolerability, safety, and antitumor activities of escalating doses of anti-VEGF antibody suvemcitug plus chemotherapy in platinum-resistant ovarian cancer patients. METHODS: This open-label, dose-escalation trial enrolled adult patients (≥18 years) with platinum-resistant histologically or cytologically-confirmed epithelial ovarian, fallopian tube and primary peritoneal cancer. Eligible patients received paclitaxel or topotecan plus escalating doses of suvemcitug 0.5, 1, 1.5, or 2 mg/kg once every two weeks. The primary endpoints were safety and tolerability, and antitumor activities of suvemcitug. RESULTS: Twenty-nine subjects received paclitaxel (n = 11) or topotecan (n = 18). No dose-limiting toxicities occurred. The most common adverse events of special interest were proteinuria (41.4%), hypertension (20.7%) and epistaxis (10.3%). No gastrointestinal perforations occurred. Nine subjects (31.0%, 95% CI 15.3-50.8) demonstrated investigators-confirmed objective response, including complete response in 1 and partial response in 8. The median PFS was 5.4 months (95% CI 2.2-7.4). CONCLUSIONS: Suvemcitug demonstrated an acceptable safety profile and promising antitumor activities in platinum-resistant ovarian cancer patients, supporting its further clinical development.

Outcomes of secondary cytoreductive surgery in patients with platinum-sensitive recurrent ovarian cancer progressed after prior poly (adenosine diphosphate-ribose) polymerase inhibitors: A retrospective cohort study.

OBJECTIVE: To evaluate the impact of previous poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor therapy on the effectiveness of secondary cytoreductive surgery (SCS) in patients with platinum-sensitive recurrent ovarian cancer (PSROC). METHODS: We identified patients with PSROC who underwent SCS at the Cancer Hospital, Chinese Academy of Medical Science, between January 2010 and December 2022. Postoperative complications within 30 days were categorized using the Accordion Severity Grading System. The Kaplan‒Meier method was used to estimate both overall survival (OS) and progression-free survival (PFS), and multivariate analysis was used to identify independent prognostic factors. RESULTS: Of the 265 patients included, 39 received prior PARP inhibitor therapy (Group A), and 226 did not (Group B). The rates of complete resection after SCS did not significantly differ between the two groups (79.5 % for Group A vs. 81.0 % for Group B; p = 0.766). As of December 2023, Group A exhibited a significantly shorter median PFS (14.2 months) than Group B (22.5 months; p = 0.002). Furthermore, the 3-year OS rate was lower in Group A (72.5 %) than in Group B (82.7 %; p = 0.015). The incidence of severe postoperative complications was comparable between Groups A and B (7.7 % vs. 1.8 %; p = 0.061). Multivariate analysis revealed that prior PARP inhibitor therapy significantly reduced the median PFS (hazard ratio (HR) = 4.434; p = 0.021) and OS (HR = 2.076; p = 0.010). CONCLUSIONS: SCS for PSROC demonstrated reduced efficacy in patients previously treated with PARP inhibitors compared to those without prior PARP inhibitor treatment.

TTN Mutation in Endometrial Endometrioid Carcinoma Is Associated with Poor Clinical Outcomes and High Tumor Mutation Burden.

Endometrioid endometrial carcinoma (EEC) stands as a prevalent gynecologic malignancy in developed regions. However, predicting relapse cases remains challenging, necessitating the identification of a novel biomarker for EEC relapse. The assessment of tumor mutational burden (TMB) is pivotal for immunotherapy in EEC patients. However, both whole-exome sequencing (WES) and targeted sequencing encountered application-related difficulties. In light of this, standardized and simplified techniques for TMB measurement are imperative. In this study, we employed WES on 25 EEC patients (12 relapsed cases and 13 non-relapsed cases) who accepted hysterectomy surgery (CHCAMS cohort). We additionally obtained a total of 391 tumor samples with clinicopathological features from TCGA website to broaden the study cohort. In the CHCAMS cohort, the TTN mutant group showed shorter progression-free survival (p < 0.001) and overall survival (p < 0.001) than TTN wild-type group. Additionally, we discovered that the number of TTN mutations per sample was significantly linked with TMB-WES in CHCAMS cohort and TCGA cohort (p < 0.05). And the number of TTN mutations per sample in POLE mutant group was greater than in the POLE wild-type group (p < 0.0001). In conclusion, TTN mutation may serve as a biomarker for EEC prognosis. TTN mutation is also associated with WES-TMB, and could be a simplified TMB measurement technique.

Prevalence and Prognostic Relevance of Homologous Recombination Repair Gene Mutations in Uterine Serous Carcinoma.

Uterine serous carcinoma (USC) is a rare but aggressive subtype of endometrial cancer lacking efficacious treatments. USC bears molecular and pathological resemblance to high-grade serous ovarian cancer, for which mutations in homologous recombination repair (HRR) genes have been associated with better treatment outcomes with platinum-based chemotherapy and poly-ADP ribose polymerase 1/2 inhibitors (PARPi). We aimed to investigate the prevalence of tumor HRR (tHRR) gene mutations and its potential prognostic value in USC patients. Sixty consecutive USC patients with available tumor tissue samples and complete follow-up records were included. Tumor mutations in relevant HRR genes were identified using next-generation sequencing and correlated with the progress-free survival (PFS) and disease-specific survival (DSS) of the patients. Among the 60 patients' USC, 22 (36.7%) carried tumor HRR gene mutations (tHRRmt), with ATM, BRCA1, and BRCA2 being the most frequently mutated genes. Survival analysis showed similar PFS (HR, 0.500; 95% CI, 0.203-1.232; p = 0.132), but significantly longer DSS in the tHRRmt patients than in the HRR gene wild-type (tHRRwt) patients (HR, 0.176; 95% CI, 0.050-0.626; p = 0.007). In FIGO stage III and IV patients, the tHRRmt group also displayed longer DSS than the tHRRwt group (p = 0.008). Notably, USC patients with abnormal p53 in our cohort, both PFS and DSS were significantly longer in the tHRRmt group over the tHRRwt group (p = 0.040 and p = 0.008, respectively). The HRR gene mutations are highly prevalent in USC and may be related to better clinical outcomes as a prognostic marker. Further study is needed to confirm whether tHRRmt patients may benefit from treatments targeting homologous recombination such as platinum and PARPi.

Epidemiology of adenosarcoma and the inverse probability of treatment weighting (IPTW) adjusted survival analysis of lymph node dissection in uterine adenosarcoma.

The objective for the study was to analysis the epidemiology of adenosarcoma, and independent prognostic factors and impact of lymph node dissection (LND) of uterine adenosarcoma. Cases of patients with primary adenosarcoma were obtained from the Surveillance, Epidemiology, and End Results (SEER) database from 2000 to 2016. Overall survival was analyzed by the Kaplan-Meier method and log-rank test. The differences in baseline covariates between the 2 groups were adjusted by inverse probability of treatment weighting method. The prognostic factors were identified by univariate and multivariate Cox regression analysis and hazard ratio and 95% confidence interval (CI) of covariates were also estimated. 1129 patients with pathological primary adenosarcoma between 2000 and 2016 were identified from the surveillance, epidemiology, and end results database. The only 4 patients were male. 1027 patients with primary uterine adenosarcoma, and 53.1% underwent LND and only 3.5% patients were with positive lymph node. Age, marital status, largest tumor size, tumor grade, T stage and chemotherapy were significantly correlated with survival. Race, tumor number, LND, and radiotherapy did not affect overall survival in patients. Inverse probability of treatment weighting-adjusted K-M curve showed that LND did not improve survival and lymph node metastasis (LNM) did not affect survival. The majority of primary adenosarcoma patients are female with high incidence of uterus and rare incidence of distant metastasis. Age, marital status, tumor size, T stage, grade, and chemotherapy are independent prognostic factors of uterine adenosarcoma. LNM was not a significant prognostic risk factor, and LND did not benefit survival.

Immune Subtypes and Immune Landscape Analysis of Endometrial Carcinoma.

Some patients with endometrial cancer (EC) suffer from limited survival benefits after immunotherapy, suggesting that there may be a specific pattern associated with immunotherapy. Immune-related genes were extracted from The Cancer Genome Atlas databases. We analyzed the differences among immune subtypes (ISs) in the distribution of the tumor mutational burden, chemotherapy-induced immune response markers, immune checkpoint-related genes, immunotherapy, and chemotherapy. We applied dimensionality reduction and defined the immune landscape of EC. Then, we used the Weighted Gene Co-Expression Network Analysis package to identify the coexpression modules of these immune genes. Finally, hub genes were selected and detected by quantitative PCR and immunohistochemistry. We obtained three ISs. There were differences in the distribution of the tumor mutational burden, chemotherapy-induced immune response markers, and immune checkpoint-related genes among the ISs. Regarding immunotherapy and chemotherapy, the IS2 subtypes were more sensitive to programmed cell death protein 1 inhibitors. In addition, different positions in the immune landscape map exhibited different prognostic characteristics, providing further evidence of the ISs. The IS2 subtypes were significantly positively correlated with yellow module gene list, indicating a good prognosis with high score. SIRPG and SLAMF1 were identified as the final characteristic genes. The quantitative PCR and immunohistochemistry results showed that the expression levels of SIRPG and SLAMF1 were low in human EC tissue. In this study, we identified three reproducible ISs of EC. The immune landscape analysis further revealed the intraclass heterogeneity of the ISs. SIRPG and SLAMF1 were identified to be associated with progression, suggesting that they may be novel immune-related biomarkers of EC.

Blood-based DNA methylation profiling for the detection of ovarian cancer.

OBJECTIVES: Ovarian cancer is a fatal gynecological cancer due to the lack of effective screening strategies at early stage. This study explored the utility of DNA methylation profiling of blood samples for the detection of ovarian cancer. METHODS: Targeted bisulfite sequencing was performed on tissue (n = 152) and blood samples (n = 373) obtained from healthy women, women with benign ovarian tumors, or malignant epithelial ovarian tumors. Based on the tissue-derived differentially-methylated regions, a supervised machine learning algorithm was implemented and cross-validated using the blood-derived DNA methylation profiles of the training cohort (n = 178) to predict and classify each blood sample as malignant or non-malignant. The model was further evaluated using an independent test cohort (n = 184). RESULTS: Comparison of the DNA methylation profiles of normal/benign and malignant tumor samples identified 1272 differentially-methylated regions, with 49.4% hypermethylated regions and 50.6% hypomethylated regions. Five-fold cross-validation of the model using the training dataset yielded an area under the curve of 0.94. Using the test dataset, the model accurately predicted non-malignancy in 96.2% of healthy women (n = 53) and 93.5% of women with benign tumors (n = 46). For patients with malignant tumors, the model accurately predicted malignancy in 44.4% of stage I-II (n = 9), 86.4% of stage III (n = 59), 100.0% of stage IV tumors (n = 6), and 81.8% of tumors with unknown stage (n = 11). Overall, the model yielded a predictive accuracy of 89.5%. CONCLUSIONS: Our study demonstrates the potential clinical application of blood-based DNA methylation profiling for the detection of ovarian cancer.

Plasma cfDNA methylation markers for the detection and prognosis of ovarian cancer.

BACKGROUND: Plasma cell-free DNA (cfDNA) methylation has shown the potential in the detection and prognostic testing in multiple cancers. Herein, we thoroughly investigate the performance of cfDNA methylation in the detection and prognosis of ovarian cancer (OC). METHODS: The OC-specific differentially methylated regions (DMRs) were identified by sequencing ovarian tissue samples from OC (n = 61), benign ovarian disease (BOD, n = 49) and healthy controls (HC, n = 37). Based on 1,272 DMRs, a cfDNA OC detection model (OC-D model) was trained and validated in plasma samples from patients of OC (n = 104), BOD (n = 56) and HC (n = 56) and a prognostic testing model (OC-P model) was developed in plasma samples in patients with high-grade serous OC (HG-SOC) in the training cohort and then tested the rationality of this model with International Cancer Genome Consortium (ICGC) tissue methylation data. Mechanisms were investigated in the TCGA-OC cohort. FINDINGS: In the validation cohort, the cfDNA OC-D model consisting of 18 DMRs achieved a sensitivity of 94.7% (95% CI: 85.4%‒98.9%) at a specificity of 88.7% (95% CI: 78.7%‒94.9%), which outperformed CA 125 (AUC: 0.967 vs 0.905, P = 0.03). Then the cfDNA OC-P model consisting of 15 DMRs was constructed and associated with a better prognosis of HG-SOC in multivariable Cox regression analysis (HR: 0.29, 95% CI, 0.11‒0.78, P = 0.01) in the training cohort, which was also observed in the ICGC cohort using tissue methylation (HR: 0.56, 95% CI, 0.32‒0.98, P = 0.04). Investigation into mechanisms revealed that the low-risk group had higher homologous recombination deficiency and immune cell infiltration (P < 0.05). INTERPRETATION: Our study demonstrated the potential utility of cfDNA methylation in the detection and prognostic testing in OC. Future studies with a larger population are warranted. FUNDING: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sector.

Differences in Treatment Modalities and Prognosis of Elderly Patients with Ovarian Cancer: A Two-Center Propensity Score-Matched Study.

Background: The prognosis of older patients with ovarian cancer is poor. We evaluated the effect of chronological age and different treatment characteristics on the prognosis of older patients with ovarian cancer; Methods: The study retrospectively analyzed patients aged over 60 years who underwent cytoreduction followed by platinum-based adjuvant chemotherapy between January 2011 and December 2019 in two national centers in China. Propensity score matching (PSM, 1:1) was performed to stratify the comorbidity- and treatment-related factors. The Kaplan−Meier method was employed to estimate progression-free survival (PFS) in the original cohort and the cohort after PSM; Results: A total of 324 patients were evaluated. The Age ≥ 70 group often received more neoadjuvant chemotherapy (62.3% vs. 31.2%, p < 0.001), more discontinuation of adjuvant chemotherapy (31.2% vs. 10.8%, p < 0.001), and had more severe chemotherapy-related toxicity (45.6% vs. 34.2%, p = 0.040) than the Age < 70 group. After matching, the PFS of the Age < 70 group was not significantly different from the Age ≥ 70 group (median PFS = 12.4 and 11.9 months, respectively, p = 0.850). Furthermore, the advanced FIGO stage, non-R0 cytoreduction, and discontinuation of adjuvant chemotherapy were all found to be poor prognostic factors. Serum albumin level <40 g/L (HR = 2.441, p = 0.018) and age ≥ 70 years (HR = 2.639, p = 0.008) led to more severe chemotherapy-related toxicity. Additionally, poor renal function (HR = 5.128, p = 0.002) was in association with discontinuation of adjuvant chemotherapy; Conclusions: The chronological age of older patients cannot be seen as a poor prognostic factor. Older patients may benefit most from R0 cytoreduction followed by the completion of chemotherapy. Postoperative poor renal function and serum albumin level <40 g/L may help predict the discontinuation of adjuvant chemotherapy.

Comprehensive Analysis and Experimental Validation of a Novel Estrogen/Progesterone-Related Prognostic Signature for Endometrial Cancer.

Estrogen and progesterone are the major determinants of the occurrence and development of endometrial cancer (EC), which is one of the most common gynecological cancers worldwide. Our purpose was to develop a novel estrogen/progesterone-related gene signature to better predict the prognosis of EC and help discover effective therapeutic strategies. We downloaded the clinical and RNA-seq data of 397 EC patients from The Cancer Genome Atlas (TCGA) database. The "limma" R package was used to screen for estrogen/progesterone-related differentially expressed genes (DEGs) between EC and normal tissues. Univariate and multivariate Cox proportional hazards regression analyses were applied to identify these DEGs that were associated with prognosis; then, a novel estrogen/progesterone-related prognostic signature comprising CDC25B, GNG3, ITIH3, PRXL2A and SDHB was established. The Kaplan-Meier (KM) survival analysis showed that the low-risk group identified by this signature had significantly longer overall survival (OS) than the high-risk group; the receiver operating characteristic (ROC) and risk distribution curves suggested this signature was an accurate predictor independent of risk factors. A nomogram incorporating the signature risk score and stage was constructed, and the calibration plot suggested it could accurately predict the survival rate. Compared with normal tissues, tumor tissues had increased mRNA levels of GNG3 and PRXL2A and a reduced mRNA level of ITIH3. The knockdown of PRXL2A and GNG3 significantly inhibited the proliferation and colony formation of Ishikawa and AN3CA cells, while the inhibition of PRXL2A expression suppressed xenograft growth. In this study, five estrogen/progesterone-related genes were identified and incorporated into a novel signature, which provided a new classification tool for improved risk assessment and potential molecular targets for EC therapies.

Whole-Exome Sequencing Could Distinguish Primary Pulmonary Squamous Cell Carcinoma From Lung Metastases in Individuals With Cervical Squamous Cell Carcinoma.

Aims: Metastatic cervical carcinoma is hard to cure using traditional treatment and new therapeutic approaches are needed. However, the process of clonal evolution and the molecular alterations that contribute to tumor progression from primary to metastatic carcinoma remain unclear. It is currently difficult to distinguish between the primary pulmonary squamous cell carcinoma (PPSCC) and metastatic cervical squamous cell carcinoma (CSCC). Methods: Paired primary CSCC and lung/lymph nodes metastatic lesions from eight patients were analyzed by whole-exome sequencing (WES). WES data of matched specimens and normal samples were aligned to the human reference genome and analyzed to identify somatic mutations in primary and metastatic lesions. Results: A total of 1,254 somatic variants were identified. All the primary lesions and metastatic lesions shared mutations, the percentage of shared mutations between primary lesions and corresponding metastatic lesions varied significantly, ranging from 6% to 70%. In other words, all the metastatic lesions are clonally related to primary lesions, confirming WES could prove they are metastatic from the cervix but not PPSCC. We tried to apply a gene panel to help distinguish PPSCC and metastatic CSCC but failed because the mutations were widely distributed in CSCC. Interestingly, lymph nodes metastasis (LNM) harbored fewer cancer driver mutations than primary CSCC specimens with a significant difference. Besides this, there was no significant difference in somatic mutations and copy number variation (CNV) between primary and metastatic CSCC. Conclusion: Our data demonstrate that WES is an additional helpful tool in distinguishing PPSCC and metastatic CSCC, especially for certain difficult cases.

Upregulation of NOD1 and NOD2 contribute to cancer progression through the positive regulation of tumorigenicity and metastasis in human squamous cervical cancer.

BACKGROUND: Metastatic cervical squamous cell carcinoma (CSCC) has poor prognosis and is recalcitrant to the current treatment strategies, which warrants the necessity to identify novel prognostic markers and therapeutic targets. Given that CSCC is a virus-induced malignancy, we hypothesized that the pattern recognition receptors (PRRs) involved in the innate immune response likely play a critical role in tumor development. METHODS: A bioinformatics analysis, qPCR, IHC, immunofluorescence, and WB were performed to determine the expression of NOD1/NOD2. The biological characteristics of overexpression NOD1 or NOD2 CSCC cells were compared to parental cells: proliferation, migration/invasion and cytokines secretion were examined in vitro through CCK8/colony formation/cell cycle profiling/cell counting, wound healing/transwell, and ELISA assays, respectively. The proliferative and metastatic capacity of overexpression NOD1 or NOD2 CSCC cells were also evaluated in vivo. FCM, mRNA and protein arrays, ELISA, and WB were used to identify the mechanisms involved, while novel pharmacological treatment were evaluated in vitro and in vivo. Quantitative variables between two groups were compared by Student's t test (normal distribution) or Mann-Whitney U test (non-normal distribution), and one-way or two-way ANOVA was used for comparing multiple groups. Pearson χ2 test or Fisher's exact test was used to compare qualitative variables. Survival curves were plotted by the Kaplan-Meier method and compared by the log-rank test. P values of < 0.05 were considered statistically significant. RESULTS: NOD1 was highly expressed in CSCC with lymph-vascular space invasion (LVSI, P < 0.01) and lymph node metastasis (LM, P < 0.01) and related to worse overall survival (OS, P = 0.016). In vitro and in vivo functional assays revealed that the upregulation of NOD1 or NOD2 in CSCC cells promoted proliferation, invasion, and migration. Mechanistically, NOD1 and NOD2 exerted their oncogenic effects by activating NF-κb and ERK signaling pathways and enhancing IL-8 secretion. Inhibition of the IL-8 receptor partially abrogated the effects of NOD1/2 on CSCC cells. CONCLUSIONS: NOD1/2-NF-κb/ERK and IL-8 axis may be involved in the progression of CSCC; the NOD1 significantly enhanced the progression of proliferation and metastasis, which leads to a poor prognosis. Anti-IL-8 was identified as a potential therapeutic target for patients with NOD1high tumor.

Genome-wide mutation analysis in precancerous lesions of endometrial carcinoma.

Clinicopathological evidence supports endometrial atypical hyperplasia (AH) or endometrial intraepithelial neoplasia as the precursor of uterine endometrioid carcinoma (EC), the most common gynecologic malignancy. However, the pathogenic progression from AH to EC remains unclear. Here, we employed whole-exome sequencing to identify somatic mutations and copy number changes in micro-dissected lesions from 30 pairs of newly diagnosed AH and EC. We found that all but one pair of AHs shared the same DNA mismatch repair status as their corresponding ECs. The percentage of common mutations between AH lesions and corresponding ECs varied significantly, ranging from 0.1% to 82%. Microsatellite stable AHs had fewer cancer driver mutations than ECs (5 versus 7, p = 0.017), but among microsatellite unstable AHs and ECs there was no difference in mutational numbers (36 versus 38, p = 0.65). As compared to AH specimens, 19 (79%) of 24 microsatellite stable EC tumors gained new cancer driver mutations, most of which involved PTEN, ARID1A, PIK3CA, CTNNB1, or CHD4. Our results suggest that some AH lesions are the immediate precursor of ECs, and progression depends on acquisition of additional cancer driver mutations. However, a complex clonal relationship between AH and EC can also be appreciated, as in some cases both lesions diverge very early or arise independently, thus co-developing with distinct genetic trajectories. Our genome-wide profile of mutations in AH and EC shines new light on the molecular landscape of tumor progression. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Telomere Maintenance Associated Mutations in the Genetic Landscape of Gynecological Mucosal Melanoma.

PURPOSE: Gynecological melanomas (GMs) are rare tumors with a poor prognosis. Here, we performed exome sequencing to generate the mutational landscape of GMs. METHODS: Next-generation sequencing was carried out on mucosal melanoma samples (n = 35) obtained from gynecological sites. The alternative telomere lengthening (ALT) phenotype was verified by fluorescence in situ hybridization and the C-circle assay. Immunohistochemistry was performed to detect ATRX protein. Copy number variations in TERT were detected by droplet digital polymerase chain reaction. RESULTS: In the 58 formalin-fixed paraffin-embedded samples, we identified 33 (56.9%) ALT-positive cases, with 23 showing loss of ATRX protein. TERT promoter mutation was not detected in GMs (n = 40), but copy number variations in the TERT region were observed in 20% (7/35) of the samples. TERT amplification was mutually exclusive with ALT (P < 0.05). Kaplan-Meier revealed that ALT relative to TERT amplification was associated with longer overall survival in GM patients without metastasis. CONCLUSION: These findings indicate that telomere maintenance mechanisms play a critical role in the tumorigenesis of GMs and may aid in the prediction of clinical prognosis and the development of targeted therapy for the treatment of GM.

Detection of sentinel lymph node in laparoscopic surgery for uterine cervical cancer using carbon nanoparticles.

BACKGROUND AND OBJECTIVES: Carbon nanoparticles (CNPs) has been widely confirmed the efficiency in sentinel lymph node (SLN) mapping for various solid tumors. This study aims to explore the feasibility and effectiveness of CNPs during laparoscopic surgery for cervical cancer. METHODS: We analyzed 45 women with stage IB1-IIA1 cervical cancer who underwent SLN mapping using CNPs during laparoscopic surgery. The effectiveness of CNPs was evaluated by the detection rate and accuracy parameters. Factors associated with SLN laterality and SLNs localizations were analyzed. RESULTS: The overall and bilateral detection rate was 93.3% (42/45) and 60.0% (27/45), respectively. Elevated body mass index was associated with decreased bilateral detection rate (P = .015). A total of 225 SLNs were harvested, with a mean number of 5.0 ± 3.6. A total of 81.3% of SLNs were in expected localizations including external iliac (39.1%), internal iliac (25.8%), and obturator (16.4%) regions, while 18.7% in unusual localizations including common iliac (10.7%), parametrial (7.6%), and presarcal (0.4%) regions. None positive lymph node was found in non-SLNs with a false-negative rate of 0%. CONCLUSION: Laparoscopic SLN mapping with CNPs appears to be simple and efficient for patients with early-stage cervical cancer.

An Oral Small Molecule VEGFR2 Inhibitor, Apatinib, in Patients with Recurrent or Refractory Cervical Cancer: A Real World Study.

To evaluate the efficacy and safety of apatinib, an oral antiangiogenic drug, in patients with recurrent or refractory cervical cancer as salvage treatment, we retrospectively analyzed the medical records of recurrent or refractory cervical cancer patients admitted to the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Hunan Cancer Hospital, from October 1, 2016, to December 31, 2017. Patients who progressed within 6 months after the last treatment were given apatinib orally at a dose of 250 mg daily until disease progression or unacceptable toxicity. Twenty-nine patients were enrolled in our retrospective study. Up to February 1, 2019, the median follow-up time was 18 months. The median progression-free survival was 128 days (95% confidence interval (CI): 20-540 days), and the median overall survival was 9 months (95% CI: 4-23 months). The longest period of apatinib administration was 540 days. No complete response was observed, 5 (17.2%) patients achieved partial response, and 11 (37.9%) achieved stable disease. The objective response rate and disease control rate were 17.2% and 55.1%, respectively. The most common adverse events were hypertension (G1, 65.5%, 19/29), mucositis (G1, 55.2%, 16/29), hand-foot syndrome (G1-2, 44.8%, 13/29), and proteinuria (G1-2, 20.7%, 6/29). Grade 3 proteinuria occurred in only one patient (3.4%, 1/29). Apatinib single-agent use might be an effective and tolerable choice as salvage therapy for patients with recurrent or refractory cervical cancer.

Separate lateral parametrial lymph node dissection improves detection rate of parametrial lymph node metastasis in early-stage cervical cancer: 10-year clinical evaluation in a single center in China.

OBJECTIVE: To investigate the clinical significance of separate lateral parametrial lymph node dissection (LPLND) in improving parametrial lymph node (PLN) and its metastasis detection rate during radical hysterectomy for early-stage cervical cancer. METHODS: From July 2007 to August 2017, 2,695 patients with cervical cancer in stage IB1-IIA2 underwent radical hysterectomy were included. Of these patients, 368 underwent separate dissection of PLNs using the LPLND method, and 2,327 patients underwent conventional radical hysterectomy (CRH). We compared the surgical parameters, PLN detection rate and PLN metastasis rate between the two groups. RESULTS: Compared with CRH group, the rate of laparoscopic surgery was higher (60.3% vs. 15.9%, P<0.001), and the blood transfusion rate was lower (19.0%vs. 29.0%, P<0.001) in the LPLND group. PLNs were detected in 356 cases (96.7%) in the LPLND group, and 270 cases (11.6%) in the CRH group (P<0.001), respectively. The number of PLNs detected in the LPLND group was higher than that in the CRH group (median 3vs. 1, P<0.001). The PLN metastases were detected in 25 cases (6.8%) in the LPLND group, and 18 cases (0.8%) in the CRH group (P<0.001), respectively. In multivariable analysis, LPLND is an independent factor not only for PLN detection [odds ratio (OR)=228.999, 95% confidence interval (95% CI): 124.661-420.664; P<0.001], but also for PLN metastasis identification (OR=10.867, 95% CI: 5.381-21.946; P<0.001). CONCLUSIONS: LPLND is feasible and safe. The surgical method significantly improves the detection rate of PLN and avoids omission of PLN metastasis during radical hysterectomy for early-stage cervical cancer.

Clinical Outcomes in Early Cervical Cancer Patients Treated with Nerve Plane-sparing Laparoscopic Radical Hysterectomy.

STUDY OBJECTIVE: To explore the feasibility of nerve plane-sparing laparoscopic radical hysterectomy (NPS-LRH) as a simplified C1-type surgery for cervical cancer patients and to compare this technique with laparoscopic radical hysterectomy (LRH). DESIGN: A retrospective comparative study. SETTING: An academic tertiary hospital affiliated with the Chinese National Cancer Center. PATIENTS: Six hundred fifteen patients with Fédération Internationale de Gynécologie et d'Obstétrique stage Ib and IIa cervical cancer who underwent laparoscopic radical hysterectomy between January 2010 and December 2017 were enrolled. Among them, 263 patients underwent the NPS-LRH surgery, and 352 patients underwent the LRH surgery. Intraoperative data and postoperative outcomes were compared between the 2 groups. INTERVENTIONS: NPS-LRH is a simplified type C1 procedure that preserves the ureteral mesentery and its nerve plane, whereas LRH is a type C2 procedure in the Querleu-Morrow surgical classification system. MEASUREMENTS AND MAIN RESULTS: There were no statistically significant differences in age, body mass index, Fédération Internationale de Gynécologie et d'Obstétrique stage, tumor differentiation, pathological type, depth of invasion, lymphovascular space invasion, parametrial tissue invasion, lymphatic metastasis, neoadjuvant chemotherapy, or postoperative adjuvant radiotherapy and chemotherapy between the 2 groups. Compared with the LRH group, the NPS-LRH group had a shorter length of operation (238.7 ± 53.9 minutes vs 259.8 ± 56.6 minutes, p < .01), less intraoperative bleeding (p < .01), more resected lymph nodes (p = .028), shorter duration of urinary catheterization (p < .01), lower incidences of postoperative hydronephrosis (p = .044), less long-term frequent urination (p < .01), less acute urinary incontinence (p < .01), poor bladder sensation (p = .028), and constipation (p = .029). There were no statistically significant differences in the disease-free survival and overall survival between the 2 groups (p = .769 and .973, respectively). CONCLUSION: NPS-LRH is a simplified, safe, and feasible type C1 operation that had a shorter length of operation, less intraoperative bleeding, more resected lymph nodes, and better postoperative bladder function compared with the LRH group. Further studies are required to assess its benefits on rectal function and long-term prognosis.

Interaction of HCCR-1 and Bax in breast cancer.

PURPOSE: To evaluate the effect on breast cancer cell proliferation and apoptosis after silencing the HCCR-1 and to study its mechanism. METHODS: HCCR-1 siRNA was transfected into the breast cancer cell line MCF -7, and mRNA and protein level of HCCR-1 and Bax were evaluated by real-time quatitative PCR (qRT-PCR) and Western blotting, respectively. The cell proliferation and apoptosis were studied by MTT assay and flow cytometry. RESULTS: The apoptosis rate in the experimental, control and blank groups were 32.57±2.35%, 3.53±0.60% and 3.15±0.46% respectively. The apoptosis rate of MCF-7 cells was significantly increased in the experimental group, compared with the other two groups (p<0.05). The A490 value in the experimental, control and blank groups were: 24h: 0.78±0.06, 1.18±0.05, 1.24±0.05; 48h: 1.09±0.05, 1.48±0.02, 1.54±0.04; 72h: 1.29±0.01, 1.81±0.02, 1.84±0.04. The proliferation of MCF-7 cells was significantly decreased in the experimental group, compared with the other two groups (p<0.05). The mRNA levels of HCCR-1 and Bax in the experimental, control and blank groups were: HCCR-1 0.46±0.03, 1.01±0.11, 1.00; and Bax 4.40±0.99, 1.03±0.10, 1.00. The protein levels were: HCCR-1 0.62±0.07, 0.89±0.09, 0.94±0.17; and Bax 0.95±0.22, 0.67±0.19, 0.69±0.11. The expressions of mRNA and protein of HCCR-1 were significantly reduced, however the expressions of mRNA and protein of Bax were significantly increased in the experimental group compared with the other two groups (p<0.05). CONCLUSIONS: HCCR-1 siRNA transfection causes significant increase in the apoptosis and decreases in the proliferation of MCF-7 cells．These effects are related to the upregulation of the Bax expression in the MCF-7 cells.

LncRNA-MIR17HG mediated upregulation of miR-17 and miR-18a promotes colon cancer progression via activating Wnt/ß-catenin signaling.

BACKGROUND: Long non-coding RNA MIR17HG (miR-17-92 cluster host gene lncRNA) is synthesized from miR-17-92 cluster host gene due to pre-miRNA processing, and is referred as miRNA-host gene lncRNA (lnc-miRHG). Until now, the biologic function of most lnc-miRHGs in tumor progression is not well understood. This study aimed to investigate the expression and clinical significance of MIR17HG in colon cancer. METHODS: Quantitative real-time PCR analysis was used to evaluate MIR17HG expression in colon cancer tissues and paired adjacent normal mucosa. The levels of miR-17-92 cluster and important components of Wnt/ß-catenin signaling pathway were also explored. Cell biology assays were used to investigate biologic consequences of MIR17HG in regulating cell proliferation, colony formation and invasion, as well as the roles in regulating epithelial-mesenchymal transition (EMT). Moreover, a colon tumor xenograft model was established to explore the in vivo effect of MIR17HG on cell proliferation. RESULTS: Expression of MIR17HG was found to be elevated in colon cancer (P<0.001). Upregulation of MIR17HG was significantly correlated with lymph node metastasis (P=0.005) and TNM stage (P<0.001), and also an independent prognostic indicator of overall survival and disease-free survival in colon cancer patients. Suppression of MIR17HG inhibited colon cancer cell viability, invasion, and EMT process, and significantly reduced the ability of the cells to form tumors in vivo. Moreover, miR-17 and miR-18a, two key components of miR-17-92 cluster, were suppressed after knockdown of MIR17HG. Furthermore, the Wnt/ß-catenin signaling, activated by miR-17 and miR-18a, was required for the oncogenic role of MIR17HG in colon cancer. CONCLUSIONS: MIR17HG mediated upregulation of miR-17 and miR-18a promotes the progression of colon cancer via activating Wnt/ß-catenin signaling.