Para-aortic and pelvic lymphadenectomy in locally advanced cervical cancer with pelvic lymph node metastasis.

OBJECTIVE: This study sought to explore the efficiency of para-aortic and pelvic lymphadenectomy in the treatment of locally advanced cervical cancer (LACC) with pelvic lymph node (PLN) metastasis. METHODS: A total of 171 LACC patients with imaging-confirmed pelvic lymph node metastasis were included in this study. These patients were divided into two groups: the surgical staging group, comprising 58 patients who had received para-aortic and pelvic lymphadenectomy (surgical staging) along with concurrent chemoradiation therapy (CCRT), and the imaging staging group, comprising 113 patients who had received only CCRT. The two groups' progression-free survival (PFS), overall survival (OS) and treatment-related complications were compared. RESULTS: The surgical staging group started radiotherapy 10.2 days (range 9-12 days) later than the imaging staging group. The overall incidence of lymphatic cysts was 9.30%. In the surgical staging group, para-aortic lymph node metastasis was identified in 34.48% (20/58) of patients, while pathology-negative PLN was observed in 12.07% (7/58). Over a median follow-up period of 52 months, no significant differences in PFS and OS rates were found between the two groups (p > 0.05). Subgroup analysis of patients with lymph node diameters of ≥ 1.5 cm revealed a five-year PFS rate of 75.0% and an OS rate of 80.0% in the surgical staging group, compared to 41.5% and 50.1% in the imaging staging group, respectively, showing statistically significant differences (p = 0.022, HR:0.34 [0.13, 0.90] and p = 0.038, HR: 0.34 [0.12,0.94], respectively for PFS and OS). Additionally, in patients with two or more metastatic lymph nodes, the five-year PFS and OS rates were 69.2% and 73.1% in the surgical staging group, versus 41.0% and 48.4% in the imaging staging group, with these differences also being statistically significant (p = 0.025, HR: 0.41[0.19,0.93] and p = 0.046, HR: 0.42[0.18,0.98], respectively). CONCLUSION: Performing surgical staging before CCRT is safe and delivers accurate lymph node details crucial for tailoring radiotherapy. This approach merits further investigation, particularly in women with pelvic lymph nodes measuring 1.5 cm or more in diameter or patients with two or more imaging-positive PLNs.

Treatment for locally resectable stage IIIC1r cervical cancer: surgery or chemoradiotherapy?

OBJECTIVE: The aim of this study was to compare the therapeutic value and treatment-related complications of radical hysterectomy with those of concurrent chemoradiotherapy (CCRT) for locally resectable (T1a2-T2a1) stage IIIC1r cervical cancer. METHODS: A total of 213 patients with locally resectable stage IIIC1r cervical cancer who had been treated at Jiangxi Maternal and Child Health Care Hospital between January 2013 and December 2021 were included in the study and classified into two groups: surgery (148 patients) and CCRT (65 patients). The disease-free survival (DFS) rate, overall survival (OS) rate, side effects, and economic costs associated with the two groups were compared. RESULTS: 43.9% (65/148) patients in the surgical group had no pelvic lymph node metastasis, and 21of them did not require supplementary treatment after surgery due to a low risk of postoperative pathology. The median follow-up time was 46 months (range: 7-108 months). The five-year DFS and OS rates of the surgery group were slightly higher than those of the CCRT group (80.7% vs. 75.1% and 81.6% vs. 80.6%, respectively; p > 0.05). The incidences of grade III-IV gastrointestinal reactions in the surgery and CCRT groups were 5.5% and 9.2%, respectively (p = 0.332). Grade III-IV myelosuppression was identified in 27.6% of the surgery group and 26.2% of the CCRT group (p = 0.836). The per capita treatment cost was higher for the surgery group than for the CCRT group (RMB 123, 918.6 0 vs. RMB 101, 880.90, p = 0.001). CONCLUSION: The therapeutic effects and treatment-related complications of hysterectomy and CCRT are equivalent in patients with locally resectable stage IIIC1r cervical cancer, but surgery can provide accurate lymph node information and benefit patients with unnecessary radiation.

Kynureninase knockdown inhibits cisplatin resistance in vivo and in vitro and impacts the prognosis of cervical adenocarcinoma.

BACKGROUND: Chemotherapy resistance is a leading cause of treatment failure in cases of cervical adenocarcinoma (ADC), and no effective treatment approach has yet been found. We previously identified the differentially expressed kynureninase (KYNU) mRNA in cervical adenocarcinoma cells (HeLa) and cervical adenocarcinoma cisplatin resistance cells (HeLa/DDP) using gene chips. However, the role and potential mechanism of KYNU in the cisplatin resistance of cervical adenocarcinoma remain unclear. METHODS: We verified the expression of KYNU in the cells and tissues of ADC patients and analyzed its correlation with patient prognosis. A stable HeLa/DDP cell line with KYNU mRNA knockdown was constructed. We then used a CCK8 assay to detect cell survival, a transwell assay to evaluate cell migration and proliferation and flow cytometry to measure apoptosis. The effect of KYNU silence on cisplatin sensitivity was evaluated in an orthotopic model of metastatic ADC. Immunohistochemistry was performed to determine the changes in relevant drug resistance-associated protein expression, aiming to explore the underlying mechanism of KYNU-mediated drug resistance. RESULTS: KYNU is overexpressed in HeLa/DDP cells and tissues and is associated with the poor prognoses of patients with ADC. After KYNU mRNA knockdown, the invasion, migration, and proliferation of HeLa/DDP cells in the cisplatin environment significantly reduced, while the apoptosis rate of HeLa/DDP cells significantly increased. Meanwhile, KYNU knockdown improved the DDP sensitivity of ADC in vivo. Furthermore, silencing KYNU decreased the expressions of CD34 and the drug-resistance related proteins P-gp, MRP1, and GST-π and increased the level of the proapoptotic regulatory protein Bax. CONCLUSION: KYNU deficiency enhanced DDP sensitivity by suppressing cell proliferation, migration, and invasion and promoting apoptosis in DDP-resistant ADC cells in vitro. Furthermore, KYNU knockdown improved the drug sensitivity of ADC in vivo. The results showed that KYNU is involved in the chemotherapy resistance of cervical adenocarcinoma.

The Therapeutic Value of Adjuvant Chemotherapy after Concurrent Chemoradiotherapy for Locally Advanced Cervical Cancer.

OBJECTIVE: The aim of this study was to evaluate the therapeutic value and treatment-related complications of adjuvant chemotherapy after concurrent chemoradiotherapy (CCRT) for locally advanced cervical cancer (LACC). DESIGN: The medical records of LACC patients who underwent CCRT were reviewed retrospectively. METHODS: A total of 1,138 patients with LACC who had been treated at our hospital between January 2013 and December 2017 were included in the study and classified into two groups: the CCRT group, comprising 726 patients who had received only CCRT, and the CCRT + adjuvant chemotherapy (ACT) group, comprising 412 patients who had received three cycles of adjuvant chemotherapy after CCRT. 39 patients in the CCRT group and 50 patients in the CCRT + ACT group had undergone lymphadenectomy, which revealed pathology-positive lymph nodes in 22 patients and 35 patients, respectively. Progression-free survival (PFS), overall survival (OS), and adverse events were compared. RESULTS: The median follow-up time was 61 months (range: 2-96 months). No significant differences in PFS and OS were found between the two groups (p > 0.05), but more grade 3-4 acute hematologic toxicities were observed in the CCRT + ACT group than in the CCRT group (24.8% vs. 31.8%, p = 0.01). A subgroup analysis of patients with pathology-positive lymph nodes showed that the 5-year PFS and OS rates were 76.5% and 74.9%, respectively, for the CCRT + ACT group and 45.0% and 49.2%, respectively, for the CCRT group; the differences were statistically significant (p = 0.015 and 0.042, respectively). LIMITATIONS: First, the sample size of the subgroup of patients with pathology-positive lymph nodes was too small for a confirmative conclusion. The heterogeneous population and the selection bias resulting from the retrospective design were the other flaws of our study. CONCLUSION: The application of adjuvant chemotherapy after CCRT may be worth investigating further for women with LACC and pathology-positive lymph nodes, but this approach is associated with an increase in acute hematology toxicities.

Consolidation chemotherapy in early-stage cervical cancer patients with lymph node metastasis after radical hysterectomy.

OBJECTIVE: Post-operative concurrent chemoradiotherapy has become the standard treatment for patients with positive lymph nodes after radical surgery. The aim of this study was to explore the efficiency and safety of consolidation chemotherapy in early-stage cervical cancer patients with lymph node metastasis after radical hysterectomy. METHOD: We reviewed the medical records of patients with early-stage cervical cancer with lymph node metastasis after radical hysterectomy from January 2010 to January 2017. All patients underwent adjuvant concurrent chemoradiotherapy (n=49) or three cycles of platinum-based consolidation chemotherapy following concurrent chemoradiotherapy (n=89). The primary end points of the study were disease-free survival and overall survival. RESULTS: The median follow-up time was 51 months (range 10-109). No significant difference was noted in disease-free survival, overall survival, or grade 3/4 gastrointestinal disorder between the consolidation chemotherapy group (78.1% vs 83.1% vs 6.7%) and the concurrent chemoradiotherapy alone group (75.4% vs 75.3% vs 4.1%), (p=0.42, 0.26, 0.80, respectively). However, the grade 3/4 myelosuppression rate in the consolidation group was higher than in the concurrent chemoradiotherapy alone group (40.4% vs 22.4%, p=0.03). For patients with >3 positive lymph nodes or patients with >2 positive lymph nodes+lymphovascular space invasion/≥1/3 stromal invasion, disease-free survival and overall survival were superior in the consolidation chemotherapy group compared with the concurrent chemoradiotherapy alone group (p<0.05). CONCLUSION: In patients with >3 positive lymph nodes or patients with >2 positive lymph nodes, lymphovascular space invasion, and greater than 1/3 stromal invasion, disease-free survival and overall survival were superior with consolidation chemotherapy. However, consolidation chemotherapy was also associated with an increased grade 3/4 myelosuppression rate.

Overexpression of P16 reversed the MDR1-mediated DDP resistance in the cervical adenocarcinoma by activating the ERK1/2 signaling pathway.

BACKGROUND: To investigate the role of P16 (INK4a)-extracellular signal related kinase 1/2 (ERK1/2) signaling pathway in cisplatin (DDP) resistance induced by multidrug resistance protein 1 (MDR1), also known as P-glycoprotein (P-gp), in cervical adenocarcinoma. METHODS: A human DDP-resistant HeLa cell line (HeLa/DDP) was constructed using the combination of incremental and intermittent administration of DDP. Cell Counting Kit-8 (CCK-8) assay was used to measure the IC50 and resistance index (RI) of cells. The morphological changes and population doubling time were observed under an inverted microscope. Plate cloning formation assay was performed to evaluate the cell proliferation and tumorigenic ability. Cell invasion and migration were determined by transwell assays. Besides, the expression of P16, phosphorylated extracellular signal related kinase 1 and 2 (pERK1/2), total ERK1/2 and MDR1 were measured using western blot analysis. The ERK-specific inhibitor U0126 and agonist TPA was used to explore the role of ERK. RESULTS: The DDP-resistant cervical adenocarcinoma HeLa/DDP cell line was successfully established, which showed stronger cell growth, invasion, and migration. In the HeLa/DDP cells, pERK1/2 was downregulated, P-gp was upregulated and P16 was downregulated. Overexpression of P16 led to a significant decrease in the proliferation rate, migration ability, and invasion ability of the HeLa/DDP cells. Furthermore, overexpression of P16 increased and the decreased expression of pERK1/2 and P-gp in the HeLa/DDP cells, respectively. Treatment of HeLa/DDP cells transfected with P16 plasmid with ERK-specific inhibitor U0126 significantly decreased the expression of pERK1/2 and increased the expression of P-gp from 6 h to 48 h. Moreover, after 72 h, the expression of pERK1/2 was up-regulated and the expression of P-gp was inhibited. CONCLUSION: Overexpression of P16 could partially reverse the MDR1-mediated DDP resistance in the cervical adenocarcinoma by the enhancement of phosphorylation of ERK signaling pathway, which provided a theoretical basis for the treatment of DDP resistance in cervical adenocarcinoma.

The Expression of MBD6 Is Associated with Tumor Size in Uterine Leiomyomas.

Background: Uterine leiomyoma (UL) is the most common benign smooth muscle tumor of the uterus in reproductive women. Prior studies indicated that methyl-CpG-binding domain proteins (MBDs) may be involved in the pathogenesis of UL. Materials and Methods: In this study, UL tissues and paired adjacent myometrium were collected from a total of 51 patients. The expression of MBD mRNAs and their cognate proteins were analyzed via quantitative polymerase chain reaction assays and western blotting, respectively. The relationships between the MBD expression levels and the patients' clinicopathologic variables were assessed using Student's t test, nonparametric tests, or Pearson χ2 methods. Results: Our results show that both the mRNA and protein levels of MBD2 were significantly decreased in ULs compared to the adjacent myometrium. In addition, MBD6 protein expression was also decreased significantly in UL samples when compared to the adjacent myometrium. There was, however, no significant difference on the mRNA expression of MBD6 between these two groups. Neither the mRNA nor the protein levels of the other MBD members (MBD1, MBD3, MBD4, MBD5, and MeCP2) showed any significant differences between ULs and the adjacent myometria. The decreased expression of the MBD6 protein was correlated with the tumor size of ULs. Conclusions: These results suggest that the dysregulated expression of MBD2 and MBD6 in ULs may play a role in their development; however, a larger sample size together with cellular functional assays should be carried out to further elucidate the precise role of MBD6 in ULs.

Down-regulated serum microRNA-101 is associated with aggressive progression and poor prognosis of cervical cancer.

OBJECTIVE: MicroRNAs (miRNAs) play a vital role in pathogenesis and progression of many cancers, including cervical cancer. However, importance of serum level of miR-101 in cervical cancer has rarely been studied. In the present study, clinical significance and prognostic value of serum miR-101 for cervical cancer was investigated. METHODS: Association between miR-101 level in cervical cancer tissues and prognosis of patients was analyzed by using data retrieved from The Cancer Genome Atlas (TCGA) database, which was followed with our clinical study in which miR-101 serum level comparison between cervical cancer patients and healthy controls was conducted by real-time quantitative polymerase chain reaction (PCR). RESULTS: TCGA database demonstrated that miR-101 was down-regulated in cervical cancer tissues compared with normal cervical tissues, and univariate Cox regression analysis indicated that decreased miR-101 expression was a highly significant negative risk factor. Similar trend was found in the serum miR-101. Serum level of miR-101 was associated with International Federation of Gynecology and Obstetrics (FIGO) stage (p=0.003), lymph node metastasis (p=0.001), and serum squamous cell carcinoma antigen (SCC-Ag) level >4 (p=0.007). The overall survival time of cervical cancer patients with a higher level of serum miR-101 was significantly longer than that of patients with a lower level of serum miR-101. Moreover, multivariate Cox regression analysis indicated that the down-regulated serum level of miR-101 was an independent predictor for the unfavorable prognosis of cervical cancer. CONCLUSION: Serum level of miR-101 is closely associated with metastasis and prognosis of cervical cancer; and, hence could be a potential biomarker and prognostic predictor for cervical cancer.

[Application of transvaginal external fascia trachelectomy in the treatment of CIN and micro-invasive cervical cancer].

OBJECTIVE: To explore the feasibility and safety of transvaginal external fascia trachelectomy to conservatively treat patients with stage Ia1 squamous carcinoma of the uterine cervix (SCC) and cervical intraepithelial neoplasia (CIN) III, who are not suitable to take cold knife conization (CKC). METHODS: From July 2002 to September 2010, those patients who had a strong desire to preserve the uterus or fertility but also are confronted with following situations received transvaginal external fascia trachelectomy: CIN III with large area lesion (colposcopically observed lesion area was larger than 3/4 of the cervix), or patients with CIN II-III suffered recurrence or had persistent lesion or positive margin after CKC or LEEP, or patients with CIN II-III upgraded into stage Ia1 SCC through LEEP and pathological confirmation (except for those with lymphovascular space invasion), or CIN III patients complicated with upper vaginal intraepithelial neoplasia (VAIN). Their clinical information and data were reviewed and analyzed. RESULTS: Among the 79 cases, who underwent transvaginal external fascia trachelectomy, six were stage Ia1 SCC, 61 were CIN III with a large area lesion (23 cases had glandular involvement), three were CIN III complicated with VAIN, six were CIN III with persistent lesion after LEEP, two were CIN III with positive margins after LEEP, and one case had recurrence after conization. The median age of these patients was 33 years old, ranging from 23 to 40 years old. The mean operation time was 39 min (rang 20-60 min), the average amount of bleeding was 40 ml (rang 1-300 ml) and the mean hospital stay was 10 d ( rang 6-17 d). The CIN III patients complicated with VAIN received this surgery with resection of the adjacent vaginal mucosa more than 2 cm in 3.8% (3/79). The median follow-up time was 49 months (8-85 months) and none of these patients had ureteral injury or large amount of intraoperative or postoperative bleeding or post-operative recurrence. No patient complained any effect on their sexual life. Among the five patients with reproductive desire, one was at her 22 w gestation after one induced abortion and one spontaneous abortion, four patients experienced term birth in which three were cesarean section and one was natural labour. CONCLUSIONS: Transvaginal external fascia trachelectomy is a safe and effective conservative treatment for stage Ia1 SCC, CIN III with large area lesion, CIN III complicated with VAIN and CIN II-III suffering recurrence, persistent lesion or positive margins after CKC and others that are not suitable to take CKC.

[Study on the clinicopathologic features of 88 cases with mucinous cervical adenocarcinoma].

OBJECTIVE: To analyze the clinicopathologic features of mucinous cervical adenocarcinoma (ADC) and supply some reference for its diagnosis, treatment and prognosis. METHODS: Totally 88 cases with primary mucinous ADC diagnosed between January 2003 and December 2007 in Jiangxi Maternal and Child Health Hospital were retrieved. Their clinical and pathological data were reviewed and analyzed. RESULTS: Among 88 patients, 70 cases of them were endocervical ADC, 11 cases were minimal deviation adenocarcinoma (MDA), 2 cases were intestinal subtype and 5 cases were villoglandular ADC. The positive rate of cervical Pap smear cytology was only 28% (10/36). There were 10 cases were performed several times of cervical Pap smear cytology test and biopsies, while still no abnormality was found. Finally, 7 cases of them were diagnosed by cervical excisional biopsy and endocervical curettage, including 5 cases with endocervical ADC and 2 cases with MDA; 2 cases (1 case with stage Ib1 endocervical ADC and 1 case with Ib1 MDA) were diagnosed by cold knife conization, and 1 case with stageIb1 endocervical were diagnosed by uteroscopically directed biopsy. The overall 5-year survival rate was 60.0%. Using univariate analysis results showed that age (P = 0.046), stage (P = 0.007), tumor size (P = 0.007) and therapeutic methods (P = 0.009) were significant prognostic factors. Multivariate analysis showed that therapeutic methods was an independent predictor for survival (P = 0.013). Stage IIb-IIIb MDA patients occupied 7/11 of all MDA patient, while there was only one such patient of 5 cases with villoglandular ADC. The overall HPV infection rate was 65% (57/88), and there was no obvious differences about the HPV infection rates among different types of mucinous ADC. CONCLUSIONS: Cervical smear cytology is of little significance to the diagnosis of mucinous cervical adenocarcinoma. Early stage mucinous ADC is difficult to be detected, especially for MDA. Cervical excisional biopsy, endocervical curettage, cold knife conization, uteroscope are beneficial to its diagnosis. Therapeutic methods is an important prognostic factor for mucinous ADC and comprehensive treatment should be given to those patients with risky postsurgical factors.

[Efficacy of complications of different surgical treatments in cervical intraepithelial neoplasia III].

OBJECTIVE: To compare the rate of surgical complications and surgical failure of different surgical treatments in cervical intraepithelial neoplasia (CIN) III. METHODS: From Jan 2002 to Jun 2007, 1256 patients with CIN III confirmed by histopathologic punch biopsy and excision biopsy of cervical specimens were analyzed retrospectively. Among them, 74 patients accepted loop electrosurgical excision procedure (LEEP), 869 patients adopted cold knife conization (CKC), 49 patients received vaginal enlarged amputation of cervix, as well as 264 patients accepted external fascia hysterectomy, Chi-square test was used to compare the rate of surgical efficacy and complications of different surgical treatments. RESULTS: The surgical failure incidence of LEEP, CKC, vaginal enlarged amputation of cervix and external fascia hysterectomy were 4.1% (3/74), 0.2% (2/869), 0 and 0.4% (1/264) respectively, which was significantly higher in LEEP than that in CKC (P = 0.004) and external fascia hysterectomy (P = 0.034), while there was no statistical difference between CKC and external fascia hysterectomy (P = 0.549). The rate of surgical complications of LEEP, CKC, vaginal enlarged amputation of cervix and external fascia hysterectomy were 8.1% (6/74), 6.2% (54/869), 6.1% (3/49) and 2.3% (6/264) respectively, which were not statistically significant (P = 0.067) among them. CONCLUSION: LEEP, CKC, vaginal enlarged amputation of cervix and external fascia hysterectomy are all secure and effective procedures for patients with CIN III, who can take the individual choice depending on their different conditions.

[Analysis of 4223 hospitalized patients with cervical cancer during 1990-2007].

OBJECTIVE: To analyze the changes in epidemiology and treatment of hospitalized patients with cervical cancer during 1990-2007. METHODS: Overall, 4648 patients with cervical cancer were diagnosed in our hospital from Jan 1990 to Nov 2007, but only 4223 patients with initial treatment in our hospital were studied retrospectively. Pearson Chi-square test was used to compare the age, stage, histopathologic type and treatment methods between different times. RESULTS: (1) The mean age of cervical cancer patients gradually decreased over the past 18 years, from 54.4 years during 1990-1999 to 47.2 years during 2000-2007; the proportion of young patients aged < or = 35 years increased from 4.77% (89/1865) during 1990-1999 to 11.75% (277/2358) during 2000-2007. (2) The proportion of patients with cervical cancer (stage I a-II a) increased from 14. 32% (267/1865) during 1990-1999 to 40.75% (961/2358) during 2000-2007, whereas the proportion of patients with cervical cancer (stage II b-IV) decreased from 85.68% (1598/1865) during 1990-1999 to 59.25% (1397/2358) during 2000-2007. (3) There was no significant change in histopathologic type of cervical cancer, and squamous cell carcinoma of cervix remained the main type of cervical cancer. (4) The treatment pattern of cervical cancer changed significantly: radiotherapy was the main method (75.28%) for cervical cancer during 1990-1999, but during 2000-2007, it was replaced by concurrent chemoradiotherapy (35.79%). CONCLUSIONS: The proportion of young women with cervical cancer was increased during 1990-2007, and at the same period early stage cervical cancer increased, but late stage cervical cancer decreased. It is obvious that chemotherapy has become the important therapy in cervical cancer.

[Clinical analysis of 48 patients with vaginal enlarged amputation of cervix].

OBJECTIVE: To evaluate the feasibility and safety of vaginal enlarged amputation of cervix to treat patients with cervical cancer of stage Ia1 and cervical intraepithelial neoplasia grade III (CIN III) who were unfit for conization surgery. METHODS: From July 2002 to May 2007, patients with cervical cancer at stage Ia1, diagnosed by pathology after loop electrosurgical excision procedure (LEEP), large area CIN III (the area of lesion>or=3/4 on colposcopy), CIN III coexisted with vaginal intraepithelial neoplasia (VAIN) in the superior segment of vagina, CIN II-III recurrence or with residual lesion, positive margin after conization of cervix, who wanted to preserve fertility and (or) corpus uteri were selected to receive vaginal enlarged amputation of cervix. RESULTS: Forty-eight cases including 5 with cervical cancer in stage Ia1, 38 with large area CIN III (9 with gland involvement), 2 with residual lesion and 2 with positive margin after LEEP, 1 recurrence after cold knife conization, received the procedure successfully. The median age was 34 years (range 27-40), median operation time was 60 minutes (range 30-100), median blood loss was 40 ml (range 5-300), and median hospital stay was 10 days (range 7-17). After follow-up 1-39 months, no patient had postoperative complications and recurrence, and all patients resumed normal menstrual cycle and sexual life. CONCLUSION: Vaginal enlarged amputation of cervix appears to be a safe and feasible procedure for patients with cervical cancer at stage Ia1 and CIN III who are unfit for conization surgery.