Cervical metastasis of breast cancer: A case report and literature review.

RATIONALE: Cervical metastasis of breast cancer is rare and its clinical manifestations are similar to those of primary cervical cancer. It is thus easy to misdiagnose, with diagnosis mainly depending on pathology and immunohistochemistry. There have been few studies on its treatment and there is thus no standard treatment plan. PATIENT CONCERNS: This is a 64-year-old female patient presented with a 2-month history of abnormal postmenopausal vaginal discharge, who had previous history of breast cancer. DIAGNOSES: Based on the gynecological examination, imaging results, pathology, and immunohistochemical results, a diagnosis of metastatic carcinoma of the cervix and breast cancer was confirmed. INTERVENTIONS: She received computed tomography-guided 3-dimensional high-dose-rate brachytherapy in combination with chemotherapy. OUTCOMES: She achieved complete response locally. This case provides a new local treatment option for patients with inoperable localized cervical metastases. LESSONS: We hope that this report and the accompanying review help to enrich the literature pertaining to the treatment of rare cervical metastases, providing a foundation for the improved survival of affected patients.

Improvement of accumulated dose distribution in combined cervical cancer radiotherapy with deep learning-based dose prediction.

Purpose: Difficulties remain in dose optimization and evaluation of cervical cancer radiotherapy that combines external beam radiotherapy (EBRT) and brachytherapy (BT). This study estimates and improves the accumulated dose distribution of EBRT and BT with deep learning-based dose prediction. Materials and methods: A total of 30 patients treated with combined cervical cancer radiotherapy were enrolled in this study. The dose distributions of EBRT and BT plans were accumulated using commercial deformable image registration. A ResNet-101-based deep learning model was trained to predict pixel-wise dose distributions. To test the role of the predicted accumulated dose in clinic, each EBRT plan was designed using conventional method and then redesigned referencing the predicted accumulated dose distribution. Bladder and rectum dosimetric parameters and normal tissue complication probability (NTCP) values were calculated and compared between the conventional and redesigned accumulated doses. Results: The redesigned accumulated doses showed a decrease in mean values of V50, V60, and D2cc for the bladder (-3.02%, -1.71%, and -1.19 Gy, respectively) and rectum (-4.82%, -1.97%, and -4.13 Gy, respectively). The mean NTCP values for the bladder and rectum were also decreased by 0.02‰ and 0.98%, respectively. All values had statistically significant differences (p < 0.01), except for the bladder D2cc (p = 0.112). Conclusion: This study realized accumulated dose prediction for combined cervical cancer radiotherapy without knowing the BT dose. The predicted dose served as a reference for EBRT treatment planning, leading to a superior accumulated dose distribution and lower NTCP values.

Application of Recombinant Human Superoxide Dismutase in Radical Concurrent Chemoradiotherapy for Cervical Cancer to Prevent and Treat Radiation-induced Acute Rectal Injury: A Multicenter, Randomized, Open-label, Prospective Trial.

PURPOSE: The purpose of this study was to evaluate the efficacy of recombinant human superoxide dismutase (rhSOD) enemas in radiation-induced acute rectal injury (RARI) in patients with locally advanced cervical cancer. METHODS AND MATERIALS: In this phase 3, randomized, open-label trial (NCT04819685) conducted across 14 medical centers in China from June 2021 to August 2023, all patients received concurrent chemoradiation therapy (CCRT). The experimental group was treated with a rhSOD enema during chemoradiation therapy, and the control group had no enema. The Common Terminology Criteria for Adverse Events (version 5.0) was used to evaluate radiation therapy-induced side effects. Endoscopic appearance was assessed using the Vienna Rectoscopy Score. The primary endpoint in the acute phase was the occurrence rate and duration of grade ≥1 (≥G1) diarrhea during CCRT. Secondary endpoints included the occurrence rate and duration of ≥G2 and ≥G3 diarrhea, ≥G1 and ≥G2 diarrhea lasting at least 3 days, and damage to the rectal mucosa due to radiation therapy measured by endoscopy. RESULTS: Two hundred and eighty-three patients were randomly divided into the experimental (n = 141) or control group (n = 142). The mean number of ≥G1 and ≥G2 diarrhea days were significantly lower in the experimental group than in the control group (3.5 and 0.8 days vs 14.8 and 4.5 days, respectively; P < .001). The incidence of ≥G2 diarrhea decreased from 53.6% to 24.1% when rhSOD enemas were used. Use of antidiarrheals was lower in the experimental group (36.2% vs 55.7%, P < .001). Three patients felt intolerable or abdominal pain after rhSOD enema. RARI grades in the experimental group tended to be lower than those in the control group (P = .061). Logistic regression analysis revealed that rhSOD enema was associated with a lower occurrence rate of ≥G1/2 diarrhea for at least 3 days (P < .001). CONCLUSIONS: The results of this study suggest that rhSOD enema is safe and significantly reduces the incidence, severity, and duration of RARI, protecting the rectal mucosa.

Applying Multi-Metric Deformable Image Registration for Dose Accumulation in Combined Cervical Cancer Radiotherapy.

(1) Purpose: Challenges remain in dose accumulation for cervical cancer radiotherapy combined with external beam radiotherapy (EBRT) and brachytherapy (BT) as there are many large and complex organ deformations between different treatments. This study aims to improve deformable image registration (DIR) accuracy with the introduction of multi-metric objectives for dose accumulation of EBRT and BT. (2) Materials and methods: Twenty cervical cancer patients treated with EBRT (45-50 Gy/25 fractions) and high-dose-rate BT (≥20 Gy in 4 fractions) were included for DIR. The multi-metric DIR algorithm included an intensity-based metric, three contour-based metrics, and a penalty term. Nonrigid B-spine transformation was used to transform the planning CT images from EBRT to the first BT, with a six-level resolution registration strategy. To evaluate its performance, the multi-metric DIR was compared with a hybrid DIR provided by commercial software. The DIR accuracy was measured by the Dice similarity coefficient (DSC) and Hausdorff distance (HD) between deformed and reference organ contours. The accumulated maximum dose of 2 cc (D2cc) of the bladder and rectum was calculated and compared to simply addition of D2cc from EBRT and BT (ΔD2cc). (3) Results: The mean DSC of all organ contours for the multi-metric DIR were significantly higher than those for the hybrid DIR (p ≤ 0.011). In total, 70% of patients had DSC > 0.8 using the multi-metric DIR, while 15% of patients had DSC > 0.8 using the commercial hybrid DIR. The mean ΔD2cc of the bladder and rectum for the multi-metric DIR were 3.25 ± 2.29 and 3.54 ± 2.02 GyEQD2, respectively, whereas those for the hybrid DIR were 2.68 ± 2.56 and 2.32 ± 3.25 GyEQD2, respectively. The multi-metric DIR resulted in a much lower proportion of unrealistic D2cc than the hybrid DIR (2.5% vs. 17.5%). (4) Conclusions: Compared with the commercial hybrid DIR, the introduced multi-metric DIR significantly improved the registration accuracy and resulted in a more reasonable accumulated dose distribution.

Concurrent definitive chemoradiation incorporating intensity-modulated radiotherapy followed by adjuvant chemotherapy in high risk locally advanced cervical squamous cancer: a phase II study.

BACKGROUND: Although the prognosis of locally advanced cervical cancer has improved dramatically, survival for those with stage IIIB-IVA disease or lymph nodes metastasis remains poor. It is believed that the incorporation of intensity-modulated radiotherapy into the treatment of cervical cancer might yield an improved loco-regional control, whereas more cycles of more potent chemotherapy after the completion of concurrent chemotherapy was associated with a diminished distant metastasis. We therefore initiated a non-randomized prospective phaseII study to evaluate the feasibility of incorporating both these two treatment modality into the treatment of high risk locally advanced cervical cancer. OBJECTIVES: To determine whether the incorporation of intensity-modulated radiotherapy and the addition of adjuvant paclitaxel plus cisplatin regimen into the treatment policy for patients with high risk locally advanced cervical cancer might improve their oncologic outcomes. STUDY DESIGN: Patients were enrolled if they had biopsy proven stage IIIA-IVA squamous cervical cancer or stage IIB disease with metastatic regional nodes. Intensity-modulated radiotherapy was delivered with dynamic multi-leaf collimators using 6MV photon beams. Prescription for PTV ranged from 45.0 ~ 50.0 Gy at 1.8 Gy ~ 2.0 Gy/fraction in 25 fractions. Enlarged nodes were contoured separately and PTV-nodes were boosted simultaneously to a total dose of 50.0-65 Gy at 2.0- 2.6 Gy/fraction in 25 fractions. A total dose of 28 ~ 35 Gy high-dose- rate brachytherapy was prescribed to point A in 4 ~ 5 weekly fractions using an iridium- 192 source. Concurrent weekly intravenous cisplatin at 30 mg/m2 was initiated on the first day of radiotherapy for over 1-h during external-beam radiotherapy. Adjuvant chemotherapy was scheduled within 4 weeks after the completion of concurrent chemo-radiotherapy and repeated 3 weeks later. Paclitaxel 150 mg/m2 was given as a 3-h infusion on day1, followed by cisplatin 35 mg/m2 with 1-h infusion on day1-2 (70 mg/m2 in total). RESULTS: Fifty patients achieved complete response 4 weeks after the completion of the treatment protocol, whereas 2 patients had persistent disease. After a median follow-up period of 66 months, loco-regional (including 2 persistent disease), distant, and synchronous treatment failure occurred in 4,5, and 1, respectively. The 5-year disease-free survival, loco-regional recurrence-free survival, distant-metastasis recurrence-free survival was 80.5%, 90.3%, and 88.0%, respectively. Four of the patients died of the disease, and the 5-year overall survival was 92.1%. Most of the toxicities reported during concurrent chemo-radiotherapy were mild and transient. The occurrence of hematological toxicities elevated mildly during adjuvant chemotherapy, as 32% (16/50) and 4% (2/50) patients experienced grade 3-4 leukopenia and thrombocytopenia, respectively. Grade 3-4 late toxicities were reported in 3 patients. CONCLUSIONS: The incorporation of intensity-modulated radiotherapy and adjuvant paclitaxel plus cisplatin chemotherapy were highly effective and well-tolerated in the treatment of high-risk locally advanced cervical cancer. The former yields an improved loco-regional control, whereas distant metastases could be effectively eradicated with mild toxicities when adjuvant regimen was prescribed.

A feasibility study of a modified treatment strategy combined external beam radiation therapy and brachytherapy for cervical cancer.

PURPOSE: To evaluate the feasibility of a modified treatment strategy combined external beam radiation therapy (EBRT) and brachytherapy (BT) for cervical cancer through a dosimetry analysis. MATERIAL AND METHODS: This study retrospectively selected 12 cervical cancer patients treated with the conventional treatment strategy, which consisted of 45─50 Gy/25 fractions of EBRT using volumetric-modulated arc therapy (VMAT) and image-guided BT with a fraction dose of 5─7 Gy. The modified treatment strategy decreased the central EBRT dose while increasing the number of BT fractions. New target volumes were additionally contoured, and new VMAT EBRT plans were generated for the modified treatment strategy. The dosimetric parameters for evaluation included the doses to the most irradiated 2 cc (D2cc) of the organs at risk (OARs) and doses to at least 90% (D90) of the gross tumor volume (GTV) and high-risk clinical target volume (HR-CTV). The total doses to OARs and targets obtained by adding the equivalent doses in 2 Gy fraction (EQD2) from the EBRT and BT plans were used for quantitative comparison between the modified and conventional treatment strategies. RESULTS: Comparison to the conventional treatment strategy, the modified treatment strategy resulted in a higher bladder D2cc, a slightly lower rectal D2cc and a similar HR-CTV D90, all with no significant differences (p > 0.05). The GTV D90 of the modified treatment strategy was significantly higher than that of the conventional treatment strategy (p < 0.01). CONCLUSION: The modified treatment strategy can significantly increase the BT dose while remaining the total doses to the bladder and rectum basically unchanged, demonstrating its feasibility and promising prospect in clinical use.

Therapeutic strategy analysis of patients with advanced stage high-grade neuroendocrine cervical cancer: A real-world multicenter study.

OBJECTIVE: To explore the management of high-grade neuroendocrine cervical cancer (HGNECC) since there has been no standard treatment for it. METHODS: Data on the management of HGNECC were retrospectively analyzed. Patients with FIGO stage IIB to IVB HGNECC from six hospitals were enrolled. The Kaplan-Meier method was used for survival analysis. Prognostic factors were determined using a Cox proportional-hazards regression model. RESULTS: A total of 43 patients were included in the study. The multivariate analysis showed that chemotherapy was the preferred treatment as it improved progression-free survival (PFS; P = 0.008) and overall survival (OS; P = 0.005). Distance metastasis was a significant negative prognostic factor for OS (P = 0.002), while radical surgery was a significant positive prognostic factor for PFS (P = 0.05). Compared with those who had received cisplatin and etoposide (≥5 cycles), patients who had received paclitaxel plus platinum-based chemotherapy showed better PFS and OS. Five patients (two at stage IIB and three at stage IV) showed relatively long-term survival. Of these patients, four had undergone radical surgery including tumor-debulking, while three also received adjuvant chemotherapy. CONCLUSION: Paclitaxel plus cisplatin or paclitaxel plus carboplatin may be more effective than etoposide plus cisplatin. Radical surgery followed by chemotherapy may be a favorable alternative intervention for selected patients with advanced stage cancer.

The Fgl2 interaction with Tyrobp promotes the proliferation of cutaneous squamous cell carcinoma by regulating ERK-dependent autophagy.

Human fibroleukin 2 (Fgl2), a member of the fibrinogen superfamily, can cleave prothrombin to generate thrombin or is secreted in a soluble form as a new type of effector of Tregs with immunomodulatory functions. However, there is little research on the role of Fgl2 in cutaneous squamous cell carcinoma (CSCC) growth. We examined the expression of Fgl2 in samples from CSCC patients and CSCC cell lines. Then, the effect of Fgl2 on CSCC was evaluated in vitro and in animals. Regulation of autophagy by Fgl2 was explored in CSCC. Coimmunoprecipitation (Co-IP) and immunofluorescence colocalization experiments were conducted to identify the regulatory effect of Fgl2 on the downstream protein Tyrobp. Then, gain- or loss-of-function analyses and evaluation of Tyrobp expression were performed to validate its role in autophagy and proliferation promoted by Fgl2. Here, our study demonstrated that Fgl2 promoted the proliferation of CSCC cells in vitro and in vivo. Knocking down Fgl2 reduced CSCC cell proliferation and inhibited autophagy in CSCC. Mechanistically, Fgl2 interacted with Tyrobp and promoted ERK-dependent autophagy, resulting in the proliferation of CSCC cells. Our study suggested that Fgl2 could be a promising prognostic biomarker and useful therapeutic target for CSCC.

Intensity-modulated radiotherapy combined with intracavitary brachytherapy for locally advanced cervical cancer with uterus didelphys.

The purpose of this study was to investigate the clinical application of intensity-modulated radiotherapy combined with intracavitary radiotherapy for locally advanced cervical cancer complicated with uterus didelphys. We retrospectively reviewed the medical records of six patients with locally advanced cervical cancer associated with uterine malformations treated at the National Cancer Center/Cancer Hospital (Beijing, China) between 2015 and 2018. Six cases, including cervical squamous cell carcinoma (n = 3), cervical adenocarcinoma (n = 2), and clear cell adenocarcinoma (n = 1) were identified by pathological diagnosis. Uterine malformation included uterus didelphys (n = 6), with vaginal subseptum (n = 2). Six cases were treated with pelvic intensity-modulated radiotherapy. Four patients received three- dimensional intracavitary brachytherapy based on computed tomography, and two patients received conventional two-dimensional intracavitary brachytherapy. The acute and delayed responses of gastrointestinal and genitourinary toxicities were ≤grade 2 in 5 patients. Five patients achieved clinical complete remission and four patients had no recurrence during the follow-up period. One patient with cervical adenocarcinoma expired due to progression of the disease. The clinical results suggest that advanced cervical cancer associated with uterus didelphys required individual radiotherapy. The use of intensity-modulated radiotherapy combined with three-dimensional intracavitary brachytherapy is recommended in concurrent chemoradiotherapy.

Comparison of two inverse planning algorithms for cervical cancer brachytherapy.

PURPOSE: To compare two inverse planning algorithms, the hybrid inverse planning optimization (HIPO) algorithm and the inverse planning simulated annealing (IPSA) algorithm, for cervical cancer brachytherapy and provide suggestions for their usage. MATERIAL AND METHODS: This study consisted of 24 cervical cancer patients treated with CT image-based high-dose-rate brachytherapy using various combinations of tandem/ovoid applicator and interstitial needles. For fixed catheter configurations, plans were retrospectively optimized with two methods: IPSA and HIPO. The dosimetric parameters with respect to target coverage, localization of high dose volume (LHDV), conformal index (COIN), and sparing of organs at risk (OARs) were evaluated. A plan assessment method which combines a graphical analysis and a scoring index was used to compare the quality of two plans for each case. The characteristics of dwell time distributions of the two plans were also analyzed in detail. RESULTS: Both IPSA and HIPO can produce clinically acceptable treatment plans. The rectum D2cc was slightly lower for HIPO as compared to IPSA (P = 0.002). All other dosimetric parameters for targets and OARs were not significantly different between the two algorithms. The generated radar plots and scores intuitively presented the plan properties and enabled to reflect the clinical priorities for the treatment plans. Significant different characteristics were observed between the dwell time distributions generated by IPSA and HIPO. CONCLUSIONS: Both algorithms could generate high-quality treatment plans, but their performances were slightly different in terms of each specific patient. The clinical decision on the optimal plan for each patient can be made quickly and consistently with the help of the plan assessment method. Besides, the characteristics of dwell time distribution were suggested to be taken into account during plan selection. Compared to IPSA, the dwell time distributions generated by HIPO may be closer to clinical preference.

Prognostic Nomograms Predicting Survival in Patients With Locally Advanced Cervical Squamous Cell Carcinoma: The First Nomogram Compared With Revised FIGO 2018 Staging System.

OBJECTIVES: To develop nomograms to assess prognostic factors for 5-year overall survival (OS) and 5-year progression-free survival (PFS) in locally advanced cervical squamous cell carcinoma (LACSC). METHODS: Overall, 618 patients with LACSC were included in this retrospective analysis. Nomograms for 5-year OS and PFS were developed based on Cox proportional hazards regression models. Concordance index (C-index) and calibration curves were used to define the predictive and discriminatory capacity of the nomogram. A comparison between the nomogram and the International Federation of Gynecology and Obstetrics (FIGO) staging system was conducted using time-dependent receiver operating characteristic (tROC) and area under the curve (tAUC). RESULTS: Multivariate analysis identified several prognostic factors for OS including squamous cell carcinoma antigen (SCC-Ag), body mass index (BMI), tumor size, pelvic wall involvement, and para-aortic lymph node metastasis (PALNM). Prognostic factors for PFS included BMI, hemoglobin (HGB), tumor size, pelvic wall involvement, pelvic lymph node metastasis (PLNM) and PALNM. Following bootstrap correction, the C-index of OS and PFS was 0.713 and 0.686, respectively. These nomograms showed superior performance compared with the FIGO 2009 and 2018 staging schema. CONCLUSIONS: Nomograms were developed to identify prognostic factors for 5-year OS and PFS in patients with LACSC. These nomograms showed good prognostication and are more comprehensive in predicting survival outcomes than existing staging criteria.

IMRT and HDR-ICBT for Locally Advanced Clear Cell Adenocarcinoma of the Cervix in Uterus Didelphys Associated With Unilateral Renal Agenesis.

Clear cell adenocarcinoma of the cervix (CCAC) with genitourinary malformations is rare. Here, we report a case of CCAC in uterus didelphys (UD) associated with unilateral renal agenesis (URA) that was treated with intensity-modulated radiotherapy (IMRT) and high-dose rate intracavitary brachytherapy (HDR-ICBT). We also retrospectively reviewed the medical records of CCAC cases with genitourinary malformations treated at the National Cancer Center/Cancer Hospital (Beijing, China) between December 2006 and June 2017. Eight cases of this rare condition were identified by pathologic diagnosis. Seven patients received surgical treatment including radical hysterectomy (n = 4), modified radical hysterectomy (n = 1), and total hysterectomy (n = 2). Five patients received adjuvant radiotherapy and chemotherapy after surgery. One patient with CCAC in UD associated with URA was treated with radical IMRT and adjuvant chemotherapy. The eight patients were followed up for an average of 7.9 years; in seven cases, there was no evidence of disease recurrence, while one patient relapsed and died after 1.5 years of treatment. On the basis of these findings, locally advanced CCAC in UD associated with URA can be effectively treated with radical IMRT.

Long-Term Survival and Late Toxicity Associated With Pelvic Intensity Modulated Radiation Therapy (IMRT) for Cervical Cancer Involving CT-Based Positive Lymph Nodes.

The purpose of this study was to evaluate the outcomes and toxicity experienced by cervical cancer patients with positive lymph nodes (LNs) who were treated with intensity-modulated radiation therapy (IMRT) and intracavitary brachytherapy (ICBT) plus concurrent chemotherapy. We retrospectively evaluated 108 cervical cancer patients with computed tomography (CT)-based positive LNs treated with IMRT and ICBT plus concurrent chemotherapy between 2009 and 2011. IMRT plans were designed to deliver 50 Gy to 95% of the planning target volume (PTV; cervical tumor, pelvis, and parametrium), with daily doses of 1.6-1.8 and 60-70 Gy to 95% of the planning gross tumor volume (PGTV)-LN (pelvic or para-aortic LNs), with daily doses of 2.0-2.2 Gy. Overall survival (OS) and progression-free survival (PFS) Kaplan-Meier curves were plotted. Acute and late toxicities were evaluated according to the Radiation Therapy Oncology Group and European Organization for Research and Treatment of Cancer toxicity criteria. Of the 108 cases, 45 were stage IIB and 63 were stage IIIB. The median follow-up was 65 months (range 2-83). Overall, the 5 year cumulative incidences of pelvic failure alone, distant failure alone, and synchronous pelvic and distant failure were 8.3, 12.9, and 8.3%, respectively. The 5 year OS rate was 67.6%, and the 5 year PFS rate was 53.7%. The 5 year cumulative incidence was 9.2% for late gastrointestinal and genitourinary toxicities of Grade ≥3 and 51.8% for acute leukopenia of Grade ≥3. The clinical results suggest that IMRT and ICBT with concurrent chemotherapy is an effective treatment, with acceptable toxicity, for advanced cervical cancer involving positive LNs.

Nomograms based on HPV load for predicting survival in cervical squamous cell carcinoma: An observational study with a long-term follow-up.

OBJECTIVE: To investigate the prognostic value of pretreatment human papillomavirus (HPV) viral load for cervical cancer, and to develop nomograms based on HPV load and other clinicopathological factors for long-term survival. METHODS: We conducted a prospective study on cervical squamous cell carcinoma (SCC) patients diagnosed between January 2003 and December 2008. Cervical samples were tested for HPV viral load by the Hybrid Capture II (HCII) assay before treatment and 6 months after treatment. Clinical characteristics and follow-up information were also collected. A multivariable Cox proportional hazards model was used to adjust covariates in both the radical hysterectomy (RH) treatment group and concurrent chemoradiotherapy (CCRT) treatment group to identify relevant covariates, and then nomograms were constructed and used for internal validation. RESULTS: A total of 520 SCC patients enrolled in this study with a median follow-up of 127 months, 360 patients received RH, whereas 160 patients received CCRT. The median HPV viral load in RH and CCRT groups was 356.10 and 294.29, respectively. Tumor size was positively correlated with high pretreatment HPV load in both groups. In CCRT group, the advanced International Federation of Gynecology and Obstetrics (FIGO) stage and enlarged retroperitoneal lymph node status determined by computed tomography (LNSCT) were correlated with low HPV load group. Initial HPV viral load, FIGO stage and lymph node metastasis were prognostic factors for RH group, whereas HPV viral load, squamous cell carcinoma antigen (SCC-Ag) level and LNSCT were identified as prognostic factors for CCRT group. Nomograms incorporating these predictors for 10-year progression-free survival (PFS) were constructed [concordance index (C-index): 0.756, 0.749]. CONCLUSIONS: A low pretreatment HPV viral load is an independent prognostic factor for poor prognosis of cervical SCC and is related to other clinicopathological factors. The survival nomogram based on HPV viral load could predict the long-term prognosis.

MicroRNA-492 overexpression involves in cell proliferation, migration, and radiotherapy response of cervical squamous cell carcinomas.

MicroRNAs (miRNAs) are small non-coding RNA that target protein-coding mRNAs at the post-transcriptional level. The aim of this study was to define the role of miR-492 in cervical squamous cell carcinomas. After microRNA profiling and comparison, we firstly detected miR-492 expression in 104 tumor tissues biopsies derived from advanced staged (FIGO IIB-IIIB) cervical squamous cell carcinoma patients before receiving concomitant chemoradiotherapy and found miR-492 expression was significantly higher in the specimens that were sensitive to concomitant chemoradiotherapy, as compared with insensitive cancer specimens (P < 0.05). Moreover, higher expression of miR-492 was associated with pelvic lymph node metastasis (LNM) (P < 0.05). Further studies illustrated ectopic miR-492 overexpression in SiHa cells promoted cell proliferation, migration, and enhanced the sensitivity of cervical cancer cells to irradiation by promoting apoptosis. In addition, we identified TIMP2 as a direct miR-492 target, which has been shown to be critical in modulating cancer cell migration and invasion. We also confirmed that miR-492 expression levels in positive pelvic LNM were much higher than negative LNM and miR-492 played a vital role in pelvic lymph node metastasis via regulating miR-492/TIMP2/MMP10 axis. In particular, miR-492 was correlated with prognosis in the subgroup of patients with negative pelvic LNM (P < 0.05) and had a promising value in predicting treatment response in the subgroup of patients with positive pelvic LNM (an AUC of 85%, 75.00% specificity, and 95.24% sensitivity). Taken together, the results suggested that miR-492 may serve as a potential biomarker for cervical cancer treatment and prognosis.

Distribution and attribution of high-risk human papillomavirus genotypes in cervical precancerous lesions in China.

While human papillomavirus vaccine was recently approved by China Food and Drug Administration, mapping of high-risk human papillomavirus distribution and attribution in cervical precancerous lesions in China becomes critical in development of a high-risk human papillomavirus-based cervical cancer screening and prevention strategy. In total, 1016 patients with cervical precancerous lesions diagnosed in the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences were analyzed retrospectively, including 111 patients with low-grade squamous intraepithelial lesions and 905 patients with high-grade squamous intraepithelial lesions. HPV16, 58, 52, 33, and 31 were the most common high-risk human papillomavirus genotypes in order of decreasing frequency among high-risk human papillomavirus-positive high-grade squamous intraepithelial lesions; this differed from the high-risk human papillomavirus distribution in low-grade squamous intraepithelial lesions (HPV16, 52, 39, 56, and 58). The distribution of high-risk human papillomavirus genotypes in single-type infections for high-grade squamous intraepithelial lesions (HPV16, 58, 33, and 52) was similar to that in multiple-type infections (HPV16, 58, 52, and 33). By contrast, a more diverse distribution spectrum of high-risk human papillomavirus genotypes for low-grade squamous intraepithelial lesions was observed between single-type (HPV16, 52, 39, and 56) and multiple-type infection (HPV52, 68, 58, 59, 39 and 56). A previously published method was adopted to calculate the fractional proportion of individual high-risk human papillomavirus genotypes in multiple infections. For this proportional attribution, HPV16 (48.9%), 58 (10.0%), 33 (5.5%), and 52 (5.5%) were the most frequent among all high-grade squamous intraepithelial lesions, whereas HPV16 (13.2%), 52 (11.6%), 39 (9.5%), and 56 (7.6%) were the most frequent among all low-grade squamous intraepithelial lesions. Differences in high-risk human papillomavirus distribution and proportional attribution in different cervical pathology statuses (high-grade squamous intraepithelial lesions and low-grade squamous intraepithelial lesions) demonstrated the critical role of persistent infection of certain high-risk human papillomavirus such as HPV16, 58, 33, and 52 in carcinogenesis of cervical cancer. Distinctively high prevalence of HPV58, 33 and 52 in Chinese cervical intraepithelial neoplasia population, especially in high-grade squamous intraepithelial lesions, should be taken into consideration in cervical cancer screening strategy and vaccine development.

Pooled analysis on the necessity of random 4-quadrant cervical biopsies and endocervical curettage in women with positive screening but negative colposcopy.

Controversy remains over whether random cervical biopsies and endocervical curettage (ECC) should be used in women with positive screening but negative colposcopy. Our paper aims to determine the indications for random biopsies and ECC among these screened positive women.Three thousand two hundred thirteen women with any positive screening test result but negative colposcopy, who received random 4-quadrant biopsies, were pooled from 17 population-based cervical cancer screening studies done in China from 1999 to 2008. The detection rates of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) and CIN grade 3 or worse (CIN3+) stratified by cytology and high-risk human papillomavirus (HR-HPV) status were assessed, as well as the false negative rates for CIN2+ and CIN3+ by random biopsies without ECC.Compared with women with negative cytology and positive HR-HPV, those with atypical squamous cells of undetermined significance/low-grade squamous intraepithelial lesion (ASC-US/LSIL) and negative HR-HPV had the equivalent lower risks of CIN2+ and CIN3+, but ascending risks were observed in the groups of ASC-US/LSIL and positive HR-HPV, and atypical glandular cells/atypical squamous cells cannot exclude high-grade squamous intraepithelial lesion/high-grade squamous intraepithelial lesion or worse (AGC/ASC-H/HSIL+). If random biopsies were only taken without ECC, 9.3% of CIN2+ and 18.5% of CIN3+ would have been missed.For women with any positive screening but negative colposcopy, in areas with good cytological infrastructure, it was necessary to perform random biopsies plus ECC on those with cytological ASC-US/LSIL and positive HR-HPV, AGC, ASC-H, or HSIL+. In contrast, those with other results should be followed up.

Serum MicroRNAs Related with Chemoradiotherapy Resistance in Advanced-Stage Cervical Squamous Cell Carcinoma.

OBJECTIVE: To investigate the serum microRNAs as biomarkers in predicting chemoradiotherapy resistance in advanced-stage cervical squamous cell carcinoma (ACSCC) patients. METHODS: Serum samples were collected from International Federation of Gynecology and Obstetrics (FIGO) stage IIB to IIIB cervical squamous cell carcinoma patients treated with platinum based Concomitant Chemoradiotherapy (CCRT) in our hospital during September 2013 to November 2015. Twenty well-matched samples (10 resistant and 10 sensitive) were chosen to screen the miRNA expression profile using serum samples pooled with microarrays. miRNAs expressed significantly different between two groups were further verified in 131 patients (29 resistant and 102 sensitive) serum samples with TaqMan Real-time PCR. The AUC was used to evaluate the accuracy of the biomarkers for prediction. RESULTS: MiR-136-5, miR-152-3p and miR-206 were expressed significantly different between sensitive and resistant groups. Results of 131 patients verification showed that the levels of miR-206 in sensitive samples and resistant samples were 2.715±0.2115 and 14.64±1.184, respectively, which was significantly different (P<.0001), while miR-136-5p and miR-152-3p could not be tested without pre-amplification reactions. Univariate analysis revealed that miR-206 expression was significantly associated with patients' DFS. Multivariate analysis demonstrated that miR-206 expression, tumor differentiation and pelvic lymph nodes metastasis were the independent prognostic factors associated with DFS in this cohort (P=.008, 0.000, 0.000, respectively). The probability of the prognostic accuracy of miR-206 expression in predicting chemoradiotherapy sensitivity of ACSCC patients was 91.3% (79.3% sensitivity and 92.2% specificity). CONCLUSION: Serum miR-206 is a powerful tool in predicting chemoradiotherapy sensitivity in ACSCC patients.