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.

Sarcoma of the uterine cervix: experience of a single center.

OBJECTIVES: To investigate the clinicopathological characteristics and prognosis of patients with primary sarcoma of the uterine cervix. METHODS: We identified all patients with primary cervical sarcomas treated at our institution from 2002 to 2020 and analyzed the clinicopathological characteristics and prognosis. RESULTS: 34 patients were identified, 7 (20.6%) patients had leiomyosarcoma, 6 (17.6%) had carcinosarcoma, 5 (14.7%) had Ewing sarcoma, 4 (11.8%) had rhabdomyosarcoma, 4 (11.8%) had undifferentiated sarcoma, 2 (5.9%) had adenosarcoma, 2 (5.9%) had endometrial stromal sarcoma, 1 (2.9%) had dermatofibrosarcoma protuberans, 1 (2.9%) had alveolar soft tissue sarcoma and 2 (5.9%) had sarcoma not otherwise specified. The median age of the whole patients was 43.5 years (range, 13-63). The median age of patients with Ewing sarcoma or rhabdomyosarcoma was 22 years (range, 13-39) and 17 years (range, 13-36 years), respectively. The distribution by stage was: stage I in 21 (61.8%) patients, stage II in 4 (11.8%), stage III in 6 (17.6%) and stage IV in 3 (8.8%). Overall, 30 patients (88.2%) received surgical treatment. The median follow-up was 33.3 months (range 3.6-187.3 months). 11 patients died within 2 years after diagnosis, most of them were patients with carcinosarcoma or undifferentiated sarcoma (45.5%, 5/11). In the entire cohort, 2- and 5-year OS were 67.2% and 56.9%, respectively. 5-year OS was 25.0% for undifferentiated sarcoma, 50.0% for rhabdomyosarcoma, 50.0% for carcinosarcoma, 53.3% for Ewing sarcoma, 57.1% for leiomyosarcoma. CONCLUSION: Cervical sarcomas are rare neoplasms with multiple histological subtypes and follow an aggressive course. Prognosis may be associated with tumor histology and stage.

Subsequent management and outcomes after first-line PARP inhibitors progression in ovarian cancer patients.

OBJECTIVES: This retrospective study aims to evaluating the subsequent management and outcomes after first-line PARPi progression in Chinese ovarian cancer population. METHODS: Clinical and pathologic variables, treatment modalities, and outcomes were assessed. We investigated the subsequent management and outcomes after first-line PARPi progression. The objective response rate (ORR) and disease control rate (DCR) parameters were evaluated to determine the response to subsequent chemotherapy. For the survival analyses, progression-free survival 1 (PFS1), PFS2, overall survival (OS) and PFS2 - PFS1 were analysed. RESULTS: A total of 124 patients received PARPi maintenance treatment after first-line chemotherapy during the study period in our center. 44 of them (35.5%) experienced a recurrence. The median duration of PARPi in these patients was 11.1 months (range: 1.2-75.1 months). A total of 40 patients (40/44, 90.9%) received subsequent chemotherapy with 35 (35/44, 79.5%) and 5 (5/44, 11.4%) patients received platinum-based and non-platinum-based chemotherapy in our center. 2 patients (4.5%) received target therapy and other 2 patients (4.5%) received best supportive care. 27.3% (12/44) patients received secondary cytoreduction surgery (SCS). After subsequent chemotherapy, 14 patients received PARPi retreatment as maintenance therapy. In patients who received platinum-based regimens (n = 35), 23 of 35 patients (65.7%) had complete/partial response (CR/PR), 8 of 35 (22.9%) had stable disease (SD), and 4 of 35 (12.1%) had progressive disease (PD). The ORR and DCR of patients who received subsequent chemotherapy was 65.7% and 88.6%, respectively. 15 patients (57.7%, 15/26) were reported to be platinum resistant with a platinum-free interval (PFI) of < 6 months in patients whose platinum sensitivity of the second line platinum-based regimens was evaluable. Patients who received SCS after PARPi resistant associated with a borderline better PFS2 (median PFS2: 41.9 vs. 29.2 months, P = 0.051) and a non-significantly increased PFS2-PFS1 (median PFS2-PFS1: 12.2 vs. 9.8 months, P = 0.551). Patients with a PFI ≥ 12 months had a significantly better PFS2 (median PFS2: 37.0 vs. 25.3 months, P < 0.001) and a tendency towards a better PFS2-PFS1 than those with a PFI < 12 months (median PFS2-PFS1: 11.2 vs. 8.5 months, P = 0.334). A better PFS2 was observed in patients who received second PARPi maintenance therapy (median PFS2 of 35.4 vs. 28.8 months); however, the difference was not statistically significant (P = 0.200). A better PFS2-PFS1 was observed in patients who received second PARPi maintenance therapy (median PFS2-PFS1: 13.6 vs. 8.9 months, P = 0.002) than those without. CONCLUSIONS: In summary, some degree of resistance to standard subsequent platinum and non-platinum chemotherapy is noted in the entire cohort. A trend towards higher benefit from subsequent chemotherapy after first-line PARP inhibitors progression was observed in the PFI ≥ 12 months subgroup than those with PFI < 12 months. PARPi retreatment as maintenance therapy and SCS can be offered to some patients with PARPi resistance.

Primary fallopian tube cancer followed by primary breast cancer in RAD51C mutation carrier treated with niraparib as first line maintenance therapy: a case report.

Given the rarity of RAD51C mutations, the risk and treatment of metachronous breast cancer after the diagnosis of ovarian cancer in RAD51C mutation carriers is not clear, especially for those who have received PARPi treatment. We report the case of a 65-year-old woman diagnosed with stage IIIC high-grade serous primary fallopian tube cancer. The patient had no family history of breast or ovarian cancer. The patient received three cycles of neoadjuvant chemotherapy with paclitaxel and carboplatin and achieved a complete response. After interval debulking surgery, the patient received three cycles of adjuvant chemotherapy. Collection and extraction of saliva DNA for next-generation sequencing identified a RAD51C mutation c.838-2 A > G. The patient received niraparib as front-line maintenance treatment. After 36 months of niraparib treatment, the patient had grade II invasive ductal carcinoma of the left breast that was positive for estrogen receptor (90%) and Ki-67 (30%) and negative for progesterone receptor and human epidermal growth factor receptor 2. Computed tomography revealed the absence of distant metastases. Modified radical mastectomy and axillary lymph node dissection were then performed. The final pathological report of the breast showed a 1.8 cm Bloom-Richardson grade II invasive ductal carcinoma in the left breast with axillary lymph node metastasis (1/21). Finally, the breast cancer was stage IIA, pT1cN1M0. The metachronous breast cancer in this case may be the first report of second primary cancer in fallopian tube cancer patient harboring a RAD51C mutation during niraparib treatment. Further studies are required to determine optimal treatment.

PARPis response and outcome of ovarian cancer patients with BRCA1/2 germline mutation and a history of breast cancer.

OBJECTIVE: The aim of this study was to determine the poly (ADP-ribose) polymerase inhibitors (PARPis) response and outcome of ovarian cancer (OC) patients with BRCA1/2 germline mutation and a history of breast cancer (BC). METHODS: Thirty-nine OC patients with BRCA1/2 germline mutation and a history of BC were included. The clinicopathological characteristics, PARPis response and prognosis were analyzed. RESULTS: The median interval from BC to OC diagnosis was 115.3 months (range=6.4-310.1). A total of 38 patients (38/39, 97.4%) received platinum-based chemotherapy after surgical removal. The majority of these patients were reported to be platinum sensitive (92.1%, 35/38). 21 patients (53.8%) received PARPis treatment with 16 patients (76.2%) for maintenance treatment and 5 patients (5/21, 23.8%) for salvage treatment. The median duration for PARPis maintenance and salvage treatment was 14.9 months (range=2.0-56.9) and 8.2 months (range=5.2-20.7), respectively. In the entire cohort, 5-year progression-free survival (PFS) and overall survival (OS) rate was 33.1% and 78.9%, respectively. Patients with BRCA1 mutation had a non-significantly worse 5-year PFS (28.6% vs. 45.8%, p=0.346) and 5-year OS (76.9% vs. 83.3%, p=0.426) than those with BRCA2 mutation. In patients with stage III-IV (n=31), first line PARPis maintenance treatment associated with a non-significantly better PFS (median PFS: NR vs. 22.4 months; 5-year PFS: 64.3% vs. 21.9%, p=0.096). CONCLUSION: The current study shows that these patients may have a good response to platinum-based chemotherapy and a favorable survival. And these patients can benefit from PARPis treatment and will likely be suitable candidates for PARPis.

Establishing Molecular Subgroups of CD8+ T Cell-Associated Genes in the Ovarian Cancer Tumour Microenvironment and Predicting the Immunotherapy Response.

BACKGROUND: The mechanism by which infiltrating CD8+ T lymphocytes in the tumour microenvironment influence the survival of patients with ovarian cancer (OC) remains unclear. METHODS: To identify biomarkers to optimise OC treatment, 13 immune-cell-line-associated datasets, RNA sequencing data, and clinical data from the GEO, TCGA, and the ICGC were collected. Gene expression in OC was assessed using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC) staining. RESULTS: We identified 520 genes and three immunological clusters (IC1, IC2, and IC3) associated with CD8+ T cells. Higher IFN scores, immune T cell lytic activity, and immune cell infiltration and upregulated expression of immune-checkpoint-related genes indicated that IC3 is more responsive to immunotherapy, whereas IC1 and IC2 have a poorer prognosis. A 10-gene signature, including SEMA4F, CX3CR1, STX7, PASK, AKIRIN2, HEMGN, GBP5, NSG1, and CXorf65, was constructed, and a multivariate Cox regression analysis revealed a significant association between the 10-gene signature-based risk model and overall survival (p < 0.001). A nomogram was constructed with age and the 10-gene signature. Consistent with the bioinformatics analysis, IHC and qRT-PCR confirmed the accuracy of the signatures in OC tissue samples. The predictive ability of the risk model was demonstrated using the Imvigor210 immunotherapy dataset. CONCLUSIONS: The development of a novel gene signature associated with CD8+ T cells could facilitate more accurate prognostics and prediction of the immunotherapeutic response of patients with OC.

Clinical analysis of 312 patients with stage IB1-IIA2 cervical squamous cell carcinoma and research on the influencing factors of postoperative recurrence.

OBJECTIVE: To investigate the influencing factors of the recurrence of IB1-IIA2 cervical squamous cell carcinoma after surgical treatment, and to explore the relationship between high-risk human papillomavirus (HR-HPV) infection and postoperative cervical squamous cell carcinoma recurrence. METHODS: Patients (n = 312) diagnosed with stage IB1-IIA2 cervical cancer and treated by radical hysterectomy and lymphadenectomy at this hospital were accrued between January 2014 and December 2016. The clinical data of these patients were analysed, and the association among clinicopathological factors, the association among clinicopathological factors, HPV infection and recurrences was investigated through Cox regression. RESULTS: The median follow-up time was 59.2 months (with a range of 14-77.9 months). The pre-operative HPV infection rate was 85.3% (266/312), and 74 patients had a high level of HPV-DNA (> 5 × 106 copy number / 104 cells). Twenty-nine patients had a postoperative persistent high level of HPV-DNA (9.3%). On multivariate analysis, deep 1/3 stromal invasion (hazard ratio [HR] 114.79, 95% confidence interval [CI] 2.821-4670.111, p = 0.012*) and postoperative persistence of high HPV-DNA levels within 12 months (HR 269.044, 95% CI 14.437-5013.754, p < 0.001*) and 24 months (HR 31.299, 95% CI 1.191-822.215, p = 0.039*) were associated with a higher local recurrence rate. CONCLUSION: Continuous high HPV-DNA levels within 24 months of an operation and deep 1/3 interstitial infiltration were independent risk factors for local recurrences of cervical cancer.

Clinical characteristics and survival analysis of Chinese ovarian cancer patients with RAD51D germline mutations.

OBJECTIVES: We aimed to describe the behavior among Chinese ovarian cancer patients with RAD51D germline mutations at our institution. METHODS: Next-generation sequencing (NGS) was conducted for the entire coding regions and exon/intron boundaries of the RAD51D genes in 781 Chinese ovarian cancer patients treated at our institution from January 1, 2015 to August 1, 2021. Clinicopathological characteristics, treatment modalities, and outcomes were assessed for ovarian cancer patients with RAD51D germline mutations. RESULTS: RAD51D germline pathogenic mutations were detected in 1.7% (13/781) of patients in this cohort. RAD51D c. 270_271dup (p. Lys91fs) mutation was the most common mutation which was found in 7 patients (7/13, 53.1%). Patients median age at diagnosis was 58 years (range: 45-69 years). 46.2% (6/13) of them were diagnosed after 60 years. Only 1 patient (1/13, 7.7%) had a family history of ovarian or breast cancer. And 1 patient (1/13, 7.7%) had a personal history of breast cancer. The FIGO 2014 distribution by stage was: stage II in 1 patient (7.7%), stage III in 9 patients (69.2%) and stage IV in 3 patient (23.1%). 92.3% (12/13) patients had high-grade serous carcinoma. 2 patients (2/13, 15.4%) had a primary peritoneal cancer. The majority of patients in the entire cohort were reported to be platinum sensitive (92.3%, 12/13) with a platinum-free interval (PFI) of > 6 months. For patients who received PARPis for 2nd line maintenance treatment (n = 5), 2 patients discontinued PARPis treatment after 33.5 and 8.1 months of duration. Other 3 patients are still on therapy with a duration of 2.4, 13.8 and 30.1 months at the date of data cutoff. 1 patient received PARPi as salvage treatment with a duration of only 1.2 months. Nine patients (9/13, 69.2%) relapsed during follow up and all of them relapsed within 2 years after diagnosis, among which 88.9% (8/9) were classified as platinum-sensitive recurrence (PSR), and only 1 patient was classified as platinum-resistant recurrence (PRR). Median PFS for the entire cohort was 17.3 months. Median PFS for the PSR subgroup was 15.9 months. 2 patients died during follow-up. The OS of these 2 patients was 17.2 and 39.6 months. The 5-year OS rate was 67.5%. CONCLUSIONS: RAD51D germline mutations are more frequent in Chinese ovarian cancer patients than other population. Few patients have a family history of ovarian or breast cancer, and personal history of breast cancer. Most patients are diagnosed after 50 years. The sensitivity to PARP inhibitors of patients with RAD51D germline mutations need a further analysis.

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.

Prognosis and Prognostic Factors of Serous Borderline Tumor-Micropapillary Variant: Retrospective Study of 200 Patients with Long-Term Follow-Up.

Objective: To determine the oncofertility outcomes and prognostic factors in a large series of serous borderline ovarian tumor-micropapillary variant (SBOT-M) with a long-term follow-up. Methods: Consecutive patients with SBOT-Ms treated from two affiliated hospitals of the Chinese Academy of Medical Sciences were retrospectively reviewed. Prognostic factors on invasive recurrence, disease-free survival (DFS), and overall survival were analyzed, and outcomes of patients treated with conservative and radical surgery were compared. Results: From 2000 to 2020, 200 patients were identified and followed. After a median follow-up of 68 months, 81 patients relapsed. In the multivariate analyses, younger age at diagnosis and conservative surgery that preserved fertility potential were independently associated with worse DFS (p = 0.018 and <0.001, respectively). Twenty-three patients experienced invasive recurrence, and seven died of progressive disease. Multivariate analysis showed that nulliparous and advanced FIGO stage were independently adversely associated with lethal recurrence (p = 0.022 and 0.029, respectively). Only advanced FIGO stage at diagnosis was associated with worse overall survival at univariate analysis (p = 0.02). Among 61 patients attempting conception, 37 achieved 44 pregnancies and resulted in 32 live births. Conclusions: In this series, patients with SBOT-M have an acceptable oncofertility outcomes. The use of conservative surgery was independently associated with worse DFS, but without an impact on neither invasive relapse nor on overall survival. Patients with advanced FIGO stages had a significantly higher risk of lethal recurrence and worse overall survival, suggesting that adequate staging surgery and intensive postoperative surveillance should be warranted.

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.

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.

Efficient isolation, culture, purification, and stem cell expression profiles of primary tumor cells derived from uterine cervical squamous cell carcinoma.

PROBLEM: Since not too many human uterus cervical squamous cell carcinoma (CSCC) cell lines in existence, efficient isolation, culture, and purification protocols for primary CSCC cells were optimized as a tool for the study of uterus CSCC. METHOD OF STUDY: The protocols for partial multiple enzymatic digestion and explant cell culture were combined and then the resulting mixed cell component cultures were purified by magnetic-activated cell sorting. Colony-forming assay was utilized for detection of cell carcinogenesis potential, and immunofluorescence was used to detect protein expression of CSCC. Finally, flow cytometry (FCM) was performed to analyze cancer stem cells (CSCs) phenotypic markers as well as programmed cell death ligand 1(PD-L 1). RESULTS: Freshly isolated cells containing tumor cells and cancer-associated fibroblasts (CAFs) efficiently proliferate to 85% confluence on a 6 cm petri dish in 5-7 days. Anti-epithelial cell adhesion molecule antibody (EpCAM) microbeads were used to successfully separate a homogeneous subpopulation of epithelial tumor cells. Both EpCAM+ and EpCAM- cell subpopulations were able to be passaged more than 30 times. Proportions of tumor cell populations expressed CSCs markers such as CD133, CD24, aldehyde dehydrogenase 1 (ALDH1), and CD44. The vimentin+ & EpCAM- population, defined with CAFs, could express CD146 mesenchymal stem cells marker. Meanwhile, PD-L 1 was identified in most subpopulation of CD44+ cells at low passage numbers. CONCLUSION: Efficient isolation, culture, and purification protocols for primary CSCC cells were successfully built. Additionally, the profiling of CSCs cell markers might provide promising therapeutic targets and clinic strategies.

Long-term impact of lymphadenectomies in patients with low-grade, early-stage uterine endometrial stroma sarcoma.

AIM: The aim of our study was to investigate the lymph node metastasis (LNM) rate and effect of lymph node dissection (LND) in patients with stage I, low-grade endometrial stromal sarcoma (LGESS). METHODS: Patients with stage I LGESS (n = 119) that underwent surgery from July 1969 to July 2017, following up over 48 years at the China National Cancer Center were retrospectively analyzed in this study. RESULTS: Surgical records and consulting data for patients with LGESS were analyzed to find that 47 patients received systematic pelvic LND. The number of patients with menopause in the LND(+) group were significantly lower than those in LND(-) group (2.1% vs 22.2%, P = 0.005), meanwhile, patients received bilateral salpingo-oophorectomy procedure in LND(+) group were significantly higher than LND(-) (97.9% vs 58.3%, P < 0.001). Neither progression-free survival nor overall survival was significantly improved in the LND(+) group even after propensity score matching although the progression-free survival has a stronger trend in LND(+) population. CONCLUSION: A systematic LND was not significantly associated with prognosis for patients with early-stage LGESS. There is no sufficient indication for a systematic LND for patients with early-stage LGESS. A systematic LND might be necessary if enlarged lymph nodes were detected by image graphology or observation during surgery.

Role of Smac, survivin, XIAP, and Omi/HtrA2 proteins in determining the chemotherapeutic response of patients with cervical cancer treated with neoadjuvant chemotherapy.

Neoadjuvant chemotherapy (NACT) followed by radical surgical hysterectomy and pelvic lymph node dissection is considered an effective method to treat patients with bulky stage IB-IIA cervical cancer, but not all patients benefit from NACT. Apoptotic proteins play important roles in the progression of chemotherapy, and second mitochondria-derived activator of caspase (Smac) may have a cooperative relationship with Omi/HtrA2, leading to carcinogenesis and chemotherapy resistance. Chemosensitivity is an important prognostic factor for cervical cancer patients. The aim of this study was to evaluate the significance of Smac, survivin, X-linked inhibitor-of-apoptosis protein (XIAP), and Omi/HtrA2 expression in predicting the response to neoadjuvant chemotherapy and the prognostic significance of te expression of these proteins in cervical cancer patients. Our findings showed that low expression levels of survivin and high expression levels of Omi/HtrA2 in chemotherapy-responsive cervical carcinoma patients significantly increased chemosensitivity.

Stage 1 embryonal rhabdomyosarcoma of the female genital tract: a retrospective clinical study of nine cases.

BACKGROUND: The aim of the study is to investigate the clinical features, treatments, and prognosis of stage 1 embryonal rhabdomyosarcoma of the female genital tract. METHODS: A retrospective analysis was performed on nine cases of stage 1 embryonal rhabdomyosarcoma of the female genital tract. Clinical characteristics, treatments, recurrence, and prognosis were analyzed. RESULTS: Of the nine patients with embryonal rhabdomyosarcoma, three originated from the vagina and six from the cervix. For the eight patients who initially received surgery, the median survival time was 88 months. As for the six patients that received adjuvant chemotherapy, five of them who received six or more cycles of treatment achieved tumor-free survival and the survival time ranged from 9 to 228 months. The remaining patient, who declined further treatment after two cycles of chemotherapy, relapsed 11 months following the surgery and died 3 months later. Out of the nine patients, only one was initially treated with chemotherapy, and achieved complete remission, but relapsed 21 months later. After a combination of surgery and chemotherapy, this patient remained tumor-free for total of 117 months. CONCLUSIONS: Patients with early stage embryonal rhabdomyosarcoma of the female genital tract have good prognosis, and the combination of surgery and chemotherapy can lead to better outcomes.

[Protein levels and its clinical significance of septin-9 and clusterin in peripheral blood of epithelial ovarian cancer patients].

OBJECTIVE: To evaluate septin-9 and clusterin protein levels in the peripheral blood samples from epithelial ovarian cancer patients, and explore its clinical significance. METHODS: Clinical data of 200 patients in Cancer Hospital, Chinese Academy of Medical Sciences from Jan. 29, 2008 to Feb. 1, 2010 were collected. The peripheral blood samples were obtained from 137 epithelial ovarian cancer patients, 12 borderline ovarian tumor patients, 10 benign ovarian tumor patients, 41 benign pelvic lesion patients and 58 healthy women. The septin-9 and clusterin protein levels in the plasma were measured by double antibody sandwich ELISA or ELISA. The clinical significance of clusterin and septin-9 in plasma was analyzed. The diagnostic efficacy of septin-9 and clusterin protein in the detection of ovarian cancer was evaluated by the area under the curve (AUC) of the receiver operating characteristic (ROC) curve. RESULTS: Double antibody sandwich ELISA showed: the mean levels of plasma septin-9 in epithelial ovarian cancer patients or benign pelvic lesion patients were significantly higher than that in healthy women detedted by double antibody sandwich ELISA (P < 0.01). The mean levels of plasma septin-9 in epithelial ovarian carcinoma patients with tumor family history or distance metastasis were significantly higher than those patients without (P < 0.05). While the expression level of septin-9 protein in peripheral blood of ovarian cancer patients was not related to the patient age, pathologic stage, pathologic differentiation, smoking history, treatment history (including surgery, radiotherapy and chemotherapy) and lymph node metastasis (all P > 0.05). ELISA showed: the mean level of plasma clusterin in epithelial ovarian cancer patients was significantly higher than that in healthy women deteded by ELISA (P = 0.021). The expression level of clusterin protein in peripheral blood of ovarian cancer patients was not related to the above clinical pathological parameters (all P > 0.05). To distinguish between ovarian cancer patients and healthy women by septin-9 protein expression level in plasma, when AUC was 0.712 and cut off was 0.28, the sensitivity of detection ovarian cancer by septin-9 protein expression was 82.5%, and the specificity was 50.0%. To distinguish between ovarian cancer patients and healthy women by clusterin protein expression level in plasma, when AUC was 0.636 and cut off was 87.96 pg/L, the sensitivity of detection ovarian cancer by clusterin protein expression was 71.5%, and the specificity was 41.4%. CONCLUSIONS: The expression of septin-9 and clusterin protein in peripheral blood of ovarian cancer patients is increased, especially the expression level of septin-9 protein with related to the distant metastasis. The study results shown that the detection of septin-9 and clusterin in plasma has a certain diagnosis value in ovarian cancer, which may be a potential markers for ovarian cancer.

[Clinical analysis of 32 cases with neuroendocrine carcinoma of the uterine cervix in early-stage disease].

OBJECTIVE: To investigate the survival and recurrence data after treatment in neuroendocrine carcinoma of the uterine cervix (NECUC) with stage Ib-IIa, and to analyse its prognostic factors. METHODS: Thirty-two cases of primary NECUC in early-stage disease treated from Jan. 2005 to Dec. 2013 at Cancer Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences were reviewed, and their data of clinicopathologic characteristics were collected and analysed. The median age was 37 years (range, 23-57 years). The distribution by International Federation of Gynecology and Obstetrics (FIGO) clinical stage: 19 cases stage Ib1, 10 cases stage Ib2, 1 case stage IIa1, 2 cases stage IIa2. Pathologic types: 22 cases of small cell carcinoma, 1 case of atypical carcinoid, 9 cases of mixed carcinoma. The diameter of cervical tumor: 12 cases ≥4 cm, 20 cases <4 cm. All patients underwent radical hysterectomy and pelvic ± para-aortic lymphadenectomy, and 15 cases of them were preserved unilateral or bilateral ovaries. Pathologic examination showed that 25 cases with cervical deep stromal invasion thickness ≥1/2, 21 cases with lymph-vascular space invasion (LVSI), and 18 cases with pelvic and (or) para-aortic lymph nodes involvement. Ten cases were performed neoadjuvant chemotherapy (range,1-3 cycles), all patients received postoperative chemotherapy (range,3-6 cycles), and 15 patients were treated with radiotherapy after surgery. The follow-up data were updated on Jul. 2014. The median follow-up time was 18 months (range, 7-71 months). A retrospective analysis was conducted to analyse the survival and recurrence data,and to explore the prognostic factors of NECUC. RESULTS: Thirteen patients died during the follow-up period. The cumulative progression-free survival (PFS) of 2 and 5 years were respectively 54.2% and 38.1%, and the estimated median PFS was 29 months. The cumulative overall survival (OS) of 2 and 5 years were respectively 56.1% and 44.9%, and the estimated median OS was 31 months. Fourteen cases had recurrence, and the median recurrence time was 9 months (range, 3-30 months). Recurrent or metastatic sites: 2 cases in pelvis, 4 cases in liver, 3 cases in lung, 3 cases in adrenal glands, 3 cases in bones, 2 cases in brain, 1 case in pancreas, 1 case in lymph nodes of para-aorta and neck, and 3 cases had metastasis in two or more organs. Thirteen cases with recurrence died of disease, and another one is alive with disease. The univariate analysis showed that lesion size of the cervix and FIGO stage were significant prognostic factors (P<0.01), while age, tumor components, deep invasion in cervical stromal, LVSI, pelvic and (or) para-aortic lymph nodes involvement, neoadjuvant chemotherapy, adjuvant radiotherapy and preserving ovaries were not significantly associated with prognosis (all P>0.05). CONCLUSION: The prognosis of NECUC in early-stage is poor and the lesion size of the cervix and FIGO stage are prognostic factors.

[The role of HPV genotyping testing in follow-up of high grade squamous intraepithelial lesion after treatment].

OBJECTIVE: To assess the clinical value of HPV genotyping in follow-up after treatment for cervical high grade squamous intraepithelial lesion (HSIL). METHODS: Two hundred and thirty eight patients with HSIL receiving conization in Cancer Hospital, Chinese Academy of Medical Sciences from Dec, 2006 to Jan, 2009 were accrued in our study. All the patients were prospectively observed after conization every 6 months for 3 times or till histologically confirmed recurrence. The items in every visit included pelvic examination, cervical cytology and HPV genotyping. Twenty-one HPV genotypes were detected by PCR-hybridization method. The last follow-up was July 31, 2010, and the median follow-up time was 28.3 months (range 6.5-43.0 months). Kaplan-Meire method as used for analyzed the median recurrent time, and the relationships between HPV status and recurrent disease were calculated by and log-rank test and Cox-regression model. RESULTS: Among the 238 patients, 110 cases (46.2%, 110/238) had positive result of HPV DNA testing at any visit. The most common HPV types detected in follow-up were HPV16 (45.6%), HPV58 (26.5%), and HPV52 (16.9%). There was no correlation between recurrent disease and any individual high risk HPV infections (P>0.05). Seventeen recurrent cases (7.1%) were identified in 238 patients within a median recurrent time of 14.9 months (range 6.0-32.1 months). In univariate analyses, HPV positive at any visit, persistent infection, multiple infection, type specific persistent infection and positive HPV at 18 months after conization were indicators for residual/recurrent disease (P<0.05). In multivariate analysis, only multiple HPV infection (HR=8.6, 95% CI: 1.8-41.7, P=0.008) and type specific persistent HPV infection (HR=5.1, 95% CI: 1.0-24.8, P=0.042) had an elevated risk of recurrent disease. CONCLUSIONS: HSIL with multiple HPV infection and type specific persistent HPV infection in follow-up are at high risk of recurrent disease. Patients with HPV turning into negative within 18 months after treatment have a low risk of recurrence.

Nidogen-1: a candidate biomarker for ovarian serous cancer.

OBJECTIVE: Effective biomarkers for early detection of ovarian cancer are needed. Our study previously showed that basement membrane protein, nidogen-1 plasma level was significantly increased in ovarian cancer patients. This study aimed to examine the plasma levels of nidogen-1 in a large patient population to evaluate its effectiveness in ovarian serous carcinoma and expression in tumor tissues. METHODS: The concentration of nidogen-1 in circulating plasma specimens of 265 ovarian serous cancer patients and 98 healthy individuals were assayed by enzyme linked immunosorbent assay. The medical records of 265 ovarian serous cancer cases were reviewed retrospectively. The expression status of nidogen-1 in tumor tissues of 44 ovarian serous carcinoma patients was examined by immunohistochemical analysis. For statistical analysis, we used the Mann-Whitney U test, Fisher's exact test and receiver operating characteristic. RESULTS: Protein levels of nidogen-1 were considerably raised in the plasma from ovarian serous cancer patients compared with those in healthy controls (P < 0.001), especially elevated in patients with advanced stage and those received neoadjuvant chemotherapy followed by interval debulking surgery. However, it was irrelevant to the grade, chemotherapy sensitivity or residual tumor of the ovarian serous carcinoma cases investigated (P > 0.05). Receiver operating characteristic curve analysis for nidogen-1 showed that it could discriminate patients with ovarian serous carcinomas from healthy controls [areas under the curve (AUC): 0. 65, 95%CI, 0.59-0.71], but CA125 was superior (AUC: 0. 98, 95%CI, 0.96-0.99). The immunohistochemical staining result showed that nidogen-1 protein was localized both in the cancer cell cytoplasm and intercellular substance, mainly expressed in extracellular matrix of ovarian serous carcinoma tissues (the positive rate was 77.3%). CONCLUSIONS: Our study suggests that plasma nidogen-1 may be used as a diagnostic biomarker for ovarian serous carcinoma and can reflect the tumor burden.