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.
PurposeTo investigate the clinical characteristics and prognosis of primary malignant melanoma of the uterine cervix.ResultsThe median age of the patients was 61.2 years (range, 42-78 years). The median overall survival of the patients at stage I, II and III were 39.2 months, 47.8 months and 9.0 months (P=0.574) and the 2-year overall survival for each stage were 80.0%, 50.0% and 0.0% respectively. Twelve (85.7%) patients developed recurrence and eleven patients (78.6%) died. Ten patients received surgery and four patients were treated with chemotherapy and/or radiotherapy. Immunotherapy was administrated to two patients after surgery. The mean survival time of patients with surgery and without surgery were 47.9 vs.7.75 months (P=0.047). Patients received radical hysterectomy had longer survival than patients underwent total hysterectomy (66.8 months vs 19.5 months, P=0.016).MethodsClinical data from 14 patients with primary malignant melanoma of the cervix between January 1981 and December 2014 were reviewed.ConclusionsPatients with primary malignant melanoma of the cervix have a poor prognosis. Radical hysterectomy and pelvic lymphnode dissection may offer better prognosis for stage I and II patients.
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.
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.
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